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CHIRAL ORGANOMETALLIC COMPOUNDS FOR USE IN ASYMMETRIC SYNTHESIS |
Chiral organometallic compounds are provided which comprise certain non-symmetrically substituted cyclopentadiene complexed to a transition metal. The cyclopentadiene has a second coordinating group which also complexes the transition metal and is attached to the cyclopentadiene by means of a chiral connecting chain. Preferred transition metals include rhodium, ruthenium, iridium, cobalt, iron, manganese, chromium, tungsten, molybdenum, nickel, palladium, or platinum. These chiral organometallic compounds find use in asymmetric synthesis to produce chiral compounds. |
1. A compound of formula (1): wherein: L is optionally one or more groups which are removable during a chemical reaction; M is a transition metal selected from Groups 6, 7, 8, 9 and 10; Y is an optionally substituted linking group; A is an optionally substituted heteroatom capable of bonding or coordinating to metal (M); and EITHER: (a) R5 and R6 are hydrogen: R1 is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or tri-hydrocarbylsilyl, or R1 & Y are linked in such a way as to form an asymmetrically substituted ring, or R1 & A are linked in such a way as to form an optionally substituted heterocyclic ring; R2 is optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or tri-hydrocarbylsilyl; R3 and R4 are independently optionally substituted hydrocarbyl, optionally substituted heterocyclyl, tri-hydrocarbylsilyl or hydrogen; or one or more of R2 & R3 and R3 & R4 are linked in such a way as to form an optionally substituted ring optionally comprising one or more heteroatoms; provided that R2, R3 and R4 are selected such that the cyclopentadiene ring to which they are attached is asymmetrically substituted; OR: (b) R3 is hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or tri-hydrocarbylsilyl; and either (i) R5 & R2 are linked in such a way as to form an optionally substituted non-aromatic ring system optionally comprising one or more heteroatoms; and R4, R4 and R6 are independently hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or tri-hydrocarbylsilyl; or R1 & R6 are linked in such a way as to form an optionally substituted non-aromatic ring system optionally comprising one or more heteroatoms and R4 is hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or tri-hydrocarbylsilyl; or R4 & R6 are linked in such a way as to form an optionally substituted ring optionally comprising one or more heteroatoms and R1 is hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or tri-hydrocarbylsilyl; or (ii) R5, R1 & R2 are linked in such a way as to form an optionally substituted non-aromatic asymmetric ring system optionally comprising one or more heteroatoms; and R4 and R6 are idependently hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl, or tri-hydrocarbylsilyl; or R4 & R6 are linked in such a way as to form an optionally substituted ring optionally comprising one or more heteroatoms. 2. A compound of formula (1); wherein: L is, independently, one or more groups which are removable during a chemical reaction; M is rhodium, ruthenium, iridium, cobalt, iron, manganese, chromium, tungsten, molybdenum, nickel, palladium, or platinum; Y is a linking chain comprising an optionally substituted C1-5 alkyl or alkylaryl, or optionally substituted silyl bridge, or optionally substituted heteroatom containing bridge; A is an atom (which may carry substituents) which may bond to the metal; EITHER: (a) R5 and R6 are hydrogen; R1 and R2 are trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkyl, aryl, arylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl or heteroaryloxyalkyl; or R2 is as above and R1 joins to Y to form an asymmetrically substituted C3-8 cycloalkyl, C3-8 cycloalkenyl or C3-8 heterocyclyl ring optionally substituted with hydroxy, trialkylsilyl, alkyl, alkoxy, aryl, arylalkyl, aryloxyallyl, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalky, cycloalkylalkyl, heteroaryl, heteroarylalkyl or heteroaryloxyalkyl; or R2 is as above and R1 joins to A to form an optionally substituted heterocyclic ring; R3 and R4 are the same or different and are selected from the substituents already recited for R1 and R2 and may also be, independently, hydrogen; or, one or more of R2 and R3, R3 and R4 join to form an optionally substituted ring optionally comprising one or more heteroatoms OR: (b) R3 is hydrogen, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkyl, aryl, arylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl or heteroaryloxyalkyl; and either (i) R5 and R2 join to form an optionally substituted non-aromatic ring system optionally comprising one or more heteroatoms; and R1, R4 and R5 are independently hydrogen, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkyl, aryl, arylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl or heteroaryloxyalkyl; or R1 & R6 join to form an optionally substituted non-aromatic ring system optionally comprising one or more heteroatoms and R4 is hydrogen, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkyl, aryl, arylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl or heteroaryloxyalkyl; or R4 & R6 join to form an optionally substituted ring system optionally comprising one or more heteroatoms and R1 is hydrogen, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkyl, aryl, arylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl or heteroaryloxyalkyl; or (ii) R5, R1 and R2 are linked in such a way as to form an optionally substituted non-aromatic asymmetric ring system comprising one or more heteroatoms; and R4 and R6 is hydrogen, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkyl, aryl, arylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl or heteroaryloxyalkyl; or R4 & R6 join to form an optionally substituted ring system optionally comprising one or more heteroatoms. 3. A compound of Formula (2) or (3): wherein: L are independently one or more groups which are removable during a chemical reaction; M is rhodium, ruthenium, iridium, cobalt, iron, manganese, chromium, tungsten, molybdenum, nickel, palladium, or platinum; Y is a linking chain comprising an optionally substituted C1-5alkyl or alkylaryl, or optionally substituted silyl bridge, or optionally substituted hetereoatom containing bridge; A is an atom (which may carry substituents) which may bond to the metal; R1 is trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkyl, aryl, arylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl or heteroaryloxyalkyl; or R1 joins to Y to form an asymmetrically substituted C3-8cycloalkyl, C3-8cycloalkenyl or C3-8heterocyclyl ring optionally substituted with hydroxy, trialkylsilyl, alkyl, alkoxy, aryl, arylalkyl, aryloxyallyl, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalky, cycloalkylalkyl, heteroaryl, heteroarylalkyl or heteroaryloxyalkyl; or R1 joins to A to form an optionally substituted heterocyclic ring; R4 is hydrogen, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkyl, aryl, arylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl or heteroaryloxyalkyl; R6 is hydrogen; and T1, T2, T3, T4 are the same or different and are hydrogen, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkyl, aryl, arylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl or heteroaryloxyalkyl. 4. A compound according to claim 3 wherein: Y is (CH2)n, where n is 1, 2, or 3; M-L is Rh(CO) or Ru(PPh3)Cl; T1-4 are independently hydrogen or alkyl; R1 is alkyl, aryl, cycloalkyl; and R4 is hydrogen, alkyl, aryl, cycloalkyl or trialkylsilyl. 5. A compound according to claim 3 wherein: Y is CR10R11 M-L is Rh(CO) or Ru(PPh3)Cl; T1-4 are hydrogen; R1 is alkyl, aryl, cycloalkyl; R4 is hydrogen; and one of R10 and R11 is hydrogen the other being napthyl or phenyl. 6. A compound of formula (4) or (5): wherein: L is independently one or more groups which are removable during a chemical reaction; M is rhodium, ruthenium, iridium, cobalt, iron, manganese, chromium, tungsten, molybdenum, nickel, palladium, or platinum; Y is a linking chain comprising an optionally substituted C1-5alkyl or alkylaryl, or optionally substituted silyl bridge, or optionally substituted hetereoatom containing bridge; A is an atom (which may carry substituents) which may bond to the metal; B is a bridge comprising an optionally substituted C1-3alkyl bridge or an optionally substituted 1-3 atom bridge wherein at least one atom is a heteroatom and any remaining atoms are carbon atoms, preferably wherein any heteroatoms are selected from the group comprising N, O, P, S and Si; Y is an optionally substituted C1-3alkyl bridge; and R3, R4, R6, R8, R9, Q1, Q2, Q3, Q4, Q5, Q6, Q7 are the same or different and are hydrogen, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkyl, aryl, arylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl or heteroaryloxyalkyl; or R4 & R6 are linked in such a way as to form an optionally substituted ring optionally comprising one or more heteroatoms; or Q4 & R6 are linked in such a way as to form an optionally substituted non-aromatic ring system comprising one or more heteratoms; and additionally Q2 and Q3 may also be alkoxy, aryloxy or silyloxy; or Q2 and Q3 combine to form a carbonyl, mine, or alkylidene group. 7. A compound according to claim 6 wherein the compound is a compound of formula (8) and (9): wherein: M-L is Rh(CO) or Ru(PPh3)Cl; Y is (CH2)n where n=1, 2 or 3; Q3 & Q5 are each H; A is PPh2; Q1 is hydrogen or alkyl; Q2 is hydrogen, alkyl, aryl or cycloalkyl; and EITHER Q4 is hydrogen, alkyl or aryl; and R4 and R6 are each hydrogen or R4 & R6 are —(CH2)4—; OR R4 is hydrogen; and Q4 & R6 are —(CH2)3—. 8. A compound according to claim 6 wherein the compound is a compound of formula (10) and (11): wherein: M-L=Rh(CO) or Ru(PPh3)Cl; Q3 & Q5 are each H; A is PPh2; Q1 is hydrogen or alkyl: Q2 is hydrogen, alkyl, aryl or cycloalkyl; and EITHER Q4 is hydrogen, alkyl or aryl; and R4 and R6 are each hydrogen or R4 & R6 are —(CH2)4—: OR R4 is hydrogen; and Q4 & R6 are —(CH2)3—. 9. A compound according to claim 6 wherein the compound is a compound of formula (12) and (13): wherein: M-L is Rh(CO) or Ru(PPh3)Cl; Y is (CH2)n where n=1, 2 or 3; Q1, Q3 & Q5 are each H; A is PPh2; Q2 is CHMe2 or C(Me)=CH2; and EITHER Q4 is hydrogen, alkyl or aryl; and R4 and R6 are each hydrogen or R4 & R6 are —(CH2)4—; OR R4 is hydrogen; and Q4 & R6 are —(CH2)3—. 10. A compound according to claim 6 wherein the compound is a compound of formula (14) and (15): wherein: M-L is Rh(CO) or Ru(PPh3)Cl; Q1, Q3 & Q5 are each H; A is PPh2; Q2 is CHMe2 or C(Me)=CH2; and EITHER Q4 is hydrogen, alkyl or aryl; and R4 and R6 are each hydrogen or R4 & R6 are —(CH2)4—; OR R4 is hydrogen; and Q4 & R6 are —(CH2)3—. 11. A compound according to any one of claims 1, 2, 3 or 6 wherein M is rhodium, iridium or ruthenium. 12. (canceled) 13. In a catalytic asymmetric synthesis for producing a chiral product, the improvement wherein the catalyst is a compound according to any one of claims 1, 2, 3 or 6. 14. A compound according to claim 2 wherein A is PR8R9, NR8, NR8R9O, OR8, S or SR8 wherein R8 and R9 may be independently hydrogen, alkyl, aryl, arylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, acyl, arylsulphonate or alkylsulphonate. 15. A compound according to claim 3 wherein A is PR8R9, NR8, NR8R9 or SR8 wherein R8 and R9 may be independently hydrogen, alkyl, aryl, arylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, acyl, arylsulphonate or alkylsulphonate. 16. A compound according to claim 6 wherein A is PR8R9, NR8, NR8R9 or SR8 wherein R8 and R9 may be independently hydrogen, alkyl, aryl, arylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, acyl, arylsulphonate or alkylsulphonate. |
Secure method and system for handling and distributing digital media |
A great deal of intellectual property is currenttly handled digitally, in the from of audible, visual, or audio-visual files or data streams. With today's powerful electronic equipment and communication networks such as the internet, this digital content can be reproduced flawlessly and distributed without control. While attemps have been made to protect such digital content, none of the existing protection techniques have been successful. The invention provides a system and method of protecting digital content by integrating the digital content with an executable software package such as a digital media player, executing some sort of protection mechanism (such as password, watermark or encryption protection), and then encoding the software into a tamper-resistant form. In this way, the digital content can be used by initiating the executable software it was encoded with, but the content itself cannot be accessed, nor can the protection mechanism be cracked. |
1. A method of protecting digital content comprising the steps of: integrating a digital media player with a set of data content; effecting a protection mechanism; and encoding said protected, integrated digital media player and data content, to tamper-resistant form; thereby securing said data content in an executable file, and playable. 2. The method of claim 1, wherein said step of encoding comprises the step of performing data-flow encoding. 3. The method of claim 1, wherein said step of encoding comprises the step of performing control-flow encoding. 4. The method of claim 1, wherein said step of encoding comprises the step of performing mass-data encoding. 5. The method of claim 1, wherein said step of encoding comprises the step of performing white-box cryptographic encoding. 6. The method of claim 1, where said step of integrating comprises the step of: integrating a digital media player with a set of data content, into a media batch file, said media batch file being executable to perform the steps of effecting and encoding; whereby said media batch file can be easily prepared, stored and transported, while the resource-intensive processing is only performed when a user attempts to execute it. 7. The method of claim 1, further comprising the step of compiling said digital media player from high level code to executable code. 8. The method of claim 2 wherein said step of encoding said protected, integrated digital media player and data content comprises the step of transforming the data-flow in said protected, integrated digital media player and data content, to dissociate its observable operation from the intent of the original software code. 9. The method of claim 2 wherein said step of encoding comprises the step of combining the data values in said integrated digital media player, said data content, and said protection mechanism such that they cannot be disassembled. 10. The method of claim 3 wherein said step of encoding comprises the step of control-flow encoding a step of comparing an input password value to a stored password value, in said protected digital media player. 11. The method of claim 3 wherein said step of encoding comprises the steps of: dispersing subsequences of instructions within said protected, integrated digital media player and data content into a plurality of locations; merging multiple dispersed subsequences into single blocks of code; and selecting said subsequences of instructions from merged blocks of code for either functionally effective or decoy execution, as needed, to separate the observable operation of resulting code from the intent of the original software during execution. 12. The method of claim 3 wherein said step of encoding comprises the step of adding fake-robust control transfers to said protected, integrated digital media player and data content, to increase the tamper-resistance of said protected, integrated digital media player and data content. 13. The method of claim 4 wherein said step of encoding comprises the steps of storing data values within said data content at virtual addresses by mapping each said virtual address onto a randomly selected actual address; and storing each said data value in a memory location indexed by each said actual address. 14. The method of claim 5, wherein inputs are protected according to the scheme Input′=D2′ (D1′ (Input)) for importing an ordinary value Input into the TRS world as Input′ where D1 and D2 are arbitrary complicated functions, D1′ and D2′ are their conversion to TRS using some combination of one or more of the data-flow, control-flow, and mass-data encodings, with D2=D1−1. 15. The method of claim 5 wherein said step of encoding comprises the step of representing one or more algorithmic steps or components as tables, thereby permitting encodings to be completely arbitrary nonlinear bijections. 16. The method of claim 5 wherein said step of encoding comprises the step of: identifying functions and transforms substantive to the targeted software program; generating new functions and transforms which alter the processing activity visible to the attacker; and replacing those identified functions and transforms with the new functions and transforms in the software program. 17. The method of claim 1, in which the level of obscurity is sufficient to make attacks prohibitively expensive for attackers. 18. An electronic device comprising: means for integrating a digital media player with a set of data content; means for effecting a protection mechanism; and means for encoding said protected, integrated digital media player and data content, to tamper-resistant form. 19. A computer readable memory medium for storing software code executable to perform the steps of: integrating a digital media player with a set of data content; effecting a protection mechanism; and encoding said protected, integrated digital media player and data content, to tamper resistant form; thereby securing said data content in an executable file, and playable. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Much valuable intellectual property takes audible, visual, or audio-visual forms, and can be transported electronically as digital files or digital streams. Such highvalue information, representable as a digital file or a digital stream, is referred to herein as content. Such content includes books (transmissible forms for print media), popular songs, both in audible form and in audio-visual (‘rock video’) forms, movies, sports broadcasts, and news in a variety of forms including text, audio, or audio-visual. Such digital content is well structured for presentation to end users, however, it is poorly structured for enforcement of ownership rights. Digital devices and communication networks are now almost pervasive in industrialized nations. Because these systems are digital, the storage, transfer and reproduction of data can be performed flawlessly; each successive copy of a digital file may be made precisely the same as the original. This ability to copy and transfer digital data with virtually no loss in quality is having a great impact on many digital rights holders, including music, movie and software producers. Many techniques for protecting the intellectual property rights of these digital content and software producers have been proposed but have had little success. Currently, the protection of this intellectual property is provided by means which separate the protection from the content. For example, if the content is protected by encryption, it cannot be used without decryption, and the device or program which performs the decryption is separate from the file or stream containing the encrypted content. This model does have an advantage in that a media player can be distributed once and then can handle various forms of content. However, content files are now becoming sufficiently large that the resource savings from using a single, universal player, is becoming less and less significant. A two-minute movie trailer, for example, may require 4 MB (megabytes, or millions of bytes) of data, while a simple MPEG (motion picture experts group) player may only require 80 KB (kilobytes); 2% of the size of the data file. As well, universal media players have a number of weaknesses as noted below. First, the media player, since it covers much content, is re-used a great deal. If the protections in the media player are ever compromised, all content played via that media player is exposed. That is, when the media player is separate from the content, it is vulnerable to class cracks: cracking the media player effectively cracks the protection for all content that it can play. Some audio players, for example, will allow the user to play AVI files (a common format for digital audio files), but because a certain flag has been set in the AVI file, will not allow it to be copied or stored. If the audio player can be modified so that it can no longer detect this flag, then the audio playerwill allow all AVI files to be copied or stored without restriction. Also, in practice, the separation of the protection measures from the protected content has meant that the protection is not provided by the content owner. For example, the National Basketball Association (NBA) does not own the media via which NBA games are broadcast or web-cast, and does not provide the hardware or software used to protect this content. Even content owners such as Warner Brothers do not typically own the means whereby the presentation of their content is protected when displayed on a personal computer (PC) or transmitted via a set-top box on a television set. Hence, the separation requires that the content owner trust intermediaries in order to be paid for providing it. Digital marking may be used to provide legally enforceable copyright protection. The two most common digital marking techniques are: 1. watermarking; the embedding of a hidden copyright message in a data file; and 2. fingerprinting; the embedding of a hidden identification number such as a serial number in a data file. (see, for example, Protecting Ownership Rights ThroughDigital Watermarking, H. Berghel and L. O'Gorman, 1996, IEEE Computer 29: 7, pp. 101-103, and Protecting Digital Media Content, Nasir Memon and Ping Wah Wong, 1998, Communications of the ACM 41: 7, pp. 34-43). Additional marking techniques are known in the art. However, the nature of digital media makes it so difficult to provide effective digital marking that some consider it impossible to provide an indelible digital mark (i.e. one which must be preserved if the content is substantially preserved). Memon et al provide commentary on this, as do Fabien A. P. Petitcolas, Ross J. Anderson, and Markus G. Kuhn in Attacks on Copyright Marking Systems” 1998, 2nd Workshop on Information Hiding, LNCS vol. 1525 (isbn 3-540-65386-4), pp. 218-238. In this case, the separation of the protection (legal enforcement) from the would-be protection (the watermark) is not the problem: rather, the easy erasure of the mark is. Digital marking, were it truly feasible, would provide an alternative protection model, based on legal enforcement (as with the current copyright for printed matter). However, it is currently trapped between two incompatible needs (see Memon et al, Bender et al, or W. Bender, D. Gruhl, N. Morimoto, and A. Lu. 1996. Techniques for data hiding. IBM Systems Journal 35: 3-4, pp. 313-336, for example). A digital mark is a steganographic embedding of a copyright message or an identification code in a digital information stream (such as a video or audio stream). Its concealment from the attacker is required so that it cannot be removed trivially. Hence, it must affect those aspects of the data stream which are unimportant to the content as perceived by the human viewer or listener. One such technique is to store a digital mark in the least significant bits of data points which are not critical to the user's enjoyment of the data file. However, an attacker, knowing that the digital mark is embedded in such ‘perceptually irrelevant ’ information, can simply scramble all such perceptually unimportant aspects of the data stream or data file, thereby either erasing the mark or rendering it sufficiently ambiguous that it becomes useless. That is, the very nature of digital media-the digitization of a perceptually imprecise analog signal=militates against the feasibility of indelible digital marking in such media files or streams. While this problem may well be solved in the long run, in the current state of the art, it remains an unsolved problem (even if it were solved, it would still be safer to deploy it in concert with the instant invention, in order to increase the protection of the digital content). There is therefore a need for a method and system of handling and distributing digital media in a manner which is secure against attack. This method and system should preferably reduce the content owner's cost of content presentation to consumers, and to change the nature of the protected entity so that effective digital watermarking is feasible. |
<SOH> SUMMARY OF THE INVENTION <EOH>It is therefore an object of the invention to provide a novel method and system of access control which obviates or mitigates at least one of the disadvantages of the prior art. The instant invention addresses the above needs by combining the informational and protective aspects of digital content, whether in files or in transmitted streams, into a single entity which contains both an instance of digital content and the protection needed for such content. In other words, the invention provides means whereby the protective machinery for the content (much of which is executable) and the digital content itself (which is usually not executable per se) can be combined, reducing the risk of piracy and reducing the cost of players which provide the content to consumers. It also changes the nature of what is protected so that indelible digital watermarking becomes feasible in the present, instead of at some unknown future date. Finally, it permits protection to be provided individually for different instances of active content, preventing the exposure of a great deal of content via a class crack on the player. We call such a combination, containing: 1. enforced behaviour, 2. content protection, 3. a form suitable for digital watermarking, and 4. protected digital content, active content, and its use in connection with appropriate media, secure digital media. According to the preferred embodiment of the invention, active content is in the form of tamper-resistant software (TRS) which either contains or accesses a large volume of information (the digital content). Active content has three highly desirable characteristics: 1. protection can be ab initio, that is, the content can be released to any intermediary distributor in an already-protected form; 2. since the protection is not separable from the content, there is no fear of class cracks. Each new piece of content requires a separate crack of the separate instance of active content in which it is embedded; and 3. the fact that active content is essentially a program containing or emitting a large digital information stream, rather than the digital information stream itself, permits effectively indelible digital marking. That is, it permits the application of a digital mark which is prohibitively effortful for an attacker to remove. One aspect of the invention is broadly defined as a method of protecting digital content comprising the steps of: integrating a digital media player with a set of data content; effecting a protection mechanism; and encoding the protected, integrated digital media player and data content, to tamper-resistant form; thereby securing the data content in an executable file, and payable. Another aspect of the invention is defined as an electronic device comprising: means for integrating a digital media player with a set of data content; means for effecting a protection mechanism; and means for encoding the protected, integrated digital media player and data content, to tamper-resistant form. |
Information processing system for manufacturing building material, building material manufacturing method and facility, and building information circulating system |
An information processing system for producing a building material comprises a design drawing generating means for generating the design drawing information of an objective building, a list generating means for generating the list information of the members used for the objective building, and a member production control means for controlling the production of the members used for the objective building, based on the list information obtained by the list generating means. |
1-25. (Canceled). 26. An information processing system for producing a building material, comprising: a design drawing generating arrangement configured to generate design drawing information of an objective building; a list generating arrangement configured to generate list information of members used for the objective building, the list being generated based on the design drawing information generated by the design drawing generating arrangement; and a member production control arrangement configured to control a production of the members used for the objective building, the production being controlled based on the list information generated by the list generating arrangement. 27. The information processing system according to claim 26, wherein the design drawing generating arrangement includes a computer aided design (“CAD”) system for generating the design drawing information, and wherein the member production control arrangement includes a computer aided manufacturing (“CAM”) system for controlling the production of the members. 28. The information processing system according to claim 26, wherein the design drawing information includes particular drawing information of at least one of a wall panel drawing, a floor panel drawing and a roof truss drawing. 29. The information processing system according to claim 26, wherein the list generating arrangement generates, as the list information, particular information including specification and quantity of the members used for the objective building. 30. The information processing system according to claim 29, wherein the specification of the members includes the information for positioning the members when the members are assembled. 31. The information processing system according to claim 26, wherein the list generating arrangement generates the list information for each predetermined one of the members. 32. An information processing system for producing a building material, comprising: a communication arrangement configured to conduct communication with an external arrangement; and a member production control arrangement adapted to control a production of members used for an objective building, the production of the members being controlled based on information received by the communication arrangement, wherein the communication arrangement receives list information of the members used for the objective building from the external arrangement, the list information being generated based on design drawing information of the objective building. 33. A method for producing a building material, comprising the steps of: generating design drawing information of an objective building using a processing arrangement; generating list information of members used for the objective building, the list information being generated based on the design drawing information; and controlling a production of the members used for the objective building based on the list information. 34. The method according to claim 33, further comprising step of transmitting the list information via an arbitrary network from a first arrangement for executing the design drawing generating step and the list generating step, to a second arrangement for executing the member production control step. 35. A method for producing a building material, comprising the steps of: generating design drawing information which includes at least any one of a wall panel drawing, a floor panel drawing and a roof truss drawing of an objective building by a computer aided design (“CAD”) system; generating list information by utilizing specification and quantity of the members used for the objective building, the list information being generated based on the design drawing information; and producing members used for the objective building based on the list information by a computer aided manufacturing (“CAM”) system. 36. The method according to claim 35, wherein the specification of the members includes positioning information for assembling the members. 37. The method according to claim 35, wherein the list generating step includes the substep of generating the list information for each panel used for the objective building. 38. A computer-readable storage medium which stores a program thereon, the program being capable to configure a processing arrangement to execute the steps comprising of: generating design drawing information of an objective building using a processing arrangement; generating list information of members used for the objective building, the list information being generated based on the design drawing information; and controlling a production of the members used for the objective building based on the list information. 39. A computer-readable storage medium which stores a program thereon, the program being capable to configure a processing arrangement to execute the steps comprising of: generating design drawing information which includes at least any one of a wall panel drawing, a floor panel drawing and a roof truss drawing of an objective building by a computer aided design (“CAD”) system; generating list information by utilizing specification and quantity of the members used for the objective building, the list information being generated based on the design drawing information; and producing members used for the objective building based on the list information by a computer aided manufacturing (“CAM”) system. 40. A program being capable to configure a processing arrangement to execute the steps comprising of: generating design drawing information of an objective building using a processing arrangement; generating list information of members used for the objective building, the list information being generated based on the design drawing information; and controlling a production of the members used for the objective building based on the list information. 41. A program being capable to configure a processing arrangement to execute the steps comprising of: generating design drawing information which includes at least any one of a wall panel drawing, a floor panel drawing and a roof truss drawing of an objective building by a computer aided design (“CAD”) system; generating list information by utilizing specification and quantity of the members used for the objective building, the list information being generated based on the design drawing information; and producing members used for the objective building based on the list information by a computer aided manufacturing (“CAM”) system. 42. An equipment for producing light gauge shape sheet steel for a steel house by supplying flat sheet steel on a main production line which includes an uncoiler, a leveler arranged downstream of the uncoiler, an end portion cutter arranged downstream of the leveler, a waiting table arranged downstream of the end portion cutter, a stationary fastening hole forming machine arranged downstream of the waiting table, and a roll forming machine arranged downstream of the stationary fastening hole forming machine, the equipment comprising: a non-stationary fastening hole forming machine configured to form fastening holes without stopping a supply of the sheet steel, the non-stationary fastening hole forming machine being arranged downstream of the leveler, and independent of the stationary fastening hole forming machine. 43. The equipment according to claim 42, wherein the fastening holes that do not require a high machining accuracy are formed by the non-stationary fastening hole forming machine arranged during an operation of the leveler, and wherein the fastening holes that require the high machining accuracy are formed by the stationary fastening hole forming machine. 44. A computer-controlled production control system, comprising: an equipment for producing a light gauge shape sheet steel for a steel house, the equipment including a general member constituting a basic structure, an application member having a shape different at end portions thereof from the general member, and a further member subjected to a machining procedure, wherein the equipment comprises a main production line including an uncoiler, a leveler arranged downstream of the uncoiler, an end portion cutter arranged downstream of the leveler, a waiting table arranged downstream of the end portion cutter, a stationary fastening hole forming machine arranged downstream of the waiting table and a roll forming machine arranged downstream of the stationary fastening hole forming machine, and a further production line arranged in parallel to the main production line, wherein the general member, the application member and the further member are distinguished from one another before the usage of the leveler based on member control information of the production control system, and wherein the general member and the application member are produced on the production line, and the further member is transferred to the further production line that different from the main production line after being machined in procedures shared by the general member and the application member on the main production line, the special member being returned to the main production line after being machined to a shape that is unique to the further member on the special production line. 45. The production control system according to claim 44, wherein, in order to generate a fastening hole information of the member control information, a computer aided design (“CAD”) system building is designed so that the fastening hole information that includes the position, shape and the machining accuracy of the fastening holes are generated automatically in accordance with individual attributes of the members, and wherein the generated fastening hole information is obtained as the member control information. 46. The production control system according to claim 45, wherein one of the member having a two-dimensional cross section after a roll forming process and requiring a two-dimensional control for development information associated with the fastening hole position is produced, and wherein the development information is controlled as a one-dimensional information along a length of the one of the members for each shape of the one of the members. 47. A building information distribution aiding system including a server arrangement configured to provide a building information distribution site for distributing building information of a building having common standards of materials and construction processes, and a client arrangement connectable with the server arrangement via a network, the system comprising: a first arrangement which is capable to program at least one of the server arrangement, the client arrangement and a further arrangement to allow said server to indicate actual cases of buildings; a second arrangement which is capable to program at least one of the server arrangement, the client arrangement and a further arrangement to allow the client arrangement to select at least one of the actual cases shown in a case collection page; and a third arrangement which is capable to program at least one of the server arrangement, the client arrangement and a further arrangement to allow the building information corresponding to the selected actual case to be forwarded to the client arrangement. 48. The building information distribution aiding system according to claim 47, wherein the server arrangement includes a fourth arrangement which is adapted to receive a member order and a specification from the client arrangement. 49. The building information distribution aiding system according to claim 47, comprising: a fifth arrangement which is capable to program at least one of the server arrangement, the client arrangement and a further arrangement to allow the client arrangement to transmit to the server arrangement one of the building information corrected from the downloaded building information and the building information newly generated by the client arrangement as new building information; a sixth arrangement which is capable to program at least one of the server arrangement, the client arrangement and a further arrangement to allow the server arrangement to receive the new building information from the client arrangement; and a seventh arrangement which is capable to program at least one of the server arrangement, the client arrangement and a further arrangement to allow a manager of the server arrangement to transmit to the client arrangement an expression of a will to purchase the new building information when the manager of the server arrangement decided to purchase the received new building information. |
<SOH> BACKGROUND INFORMATION <EOH>The use of a steel house constituting a low building including a house built of building materials such as a light gauge shape sheet steel and panels has been recently extending as the result of improvement in the living comfort, structure and production cost. One problem of a steel house is the building cost. In order to reduce the building cost, the workability is improved by structural improvement of the building materials such as shape steel and panels or by improvement of the production system of the building materials. The present invention relates to a reduction of production costs of the building materials by improving the productivity as due to improved production equipment and an improved production control system for the light gauge shape sheet steel for a steel house. In connecting the light gauge shape sheet steel, the time consumed for the connecting work at the factory or the construction site can be shortened while at the same time siginificantly improving the connection a strength of the shape steel by forming connecting holes in the frame member in advance. According to the present invention, a shape steel formed of sheet steel having a thickness of not less than 0.4 mm but less than 2.3 mmcan be used (called a light gauge shape sheet steel). Each of the fastening tools such as a tapping screw and a one-side rivet generally used for connecting the light gauge shape sheet steel are low in connection strength as compared with the bolt used for an iron frame building. In order to secure a sufficient connection strength, many fastening tools are usually utilize which in turn need a multiplicity of fastening holes to be formed in the light gauge shape sheet steel for the fastening tools. In producing the light gauge shape sheet steel formed with fastening holes, the fastening holes are generally formed with the sheet steel kept stationary before the roll forming step, but the fastening holes are not formed in the sheet steel moving after the step of straightening the curl caused by the leveler. An increased number of fastening holes formed with the sheet steel kept stationary extremely reduces the production efficiency. Also, in the case where the fastening holes are formed with the sheet steel kept stationary, a comparatively large waiting table for holding the sheet steel in standby state is required as a buffer, and therefore a large space is required to install the production line. Further, the problem of a reduced overall production is posed depending on the productivity of the machine for forming the fastening holes. On the other hand, a CAD system (Computer Aided Design system) can be used as a design aiding system in various fields. Also, a CAM system (Computer Aided Manufacturing system) may be used to control the production equipment for machining and assembly based on the data obtained from the CAD system. In the field of the low house using light gauge shape sheet steel, buildings and building materials, such as shape steel and panels, have been designed using the CAD system. However, the building materials are not produced using the CAD/CAM systems. In order to produce building materials in accordance with the building design data generated by CAD, therefore, various processes need to be executed manually to move the building design data from CAD to the building materials production machine. This, in turn, reduces the production efficiency of the building materials for a steel house. Japanese Patent Publication No. 11-232320 describes a design aiding CAD system for iron frame structures using a steel plate not thinner than 2.3 mm and the data generated by the CAD system for machining in the factory. The application field of this system disclosed in the publication is limited to the iron frame structure and the system is not applicable to the production of building materials from sheet steel having a thickness not less than 0.4 mm but less than 2.3 mm used for a low building. Also, the configuration described in this publication is not a system for aiding the design and production by relating the CAD system to the CAM system. Accordingly, exemplary embodiments of the present invention are provided to solve the problem of the prior art described above. One of the objects of the present invention is to provide an information processing system, a building material production method and production equipment capable of efficiently producing a building material of a steel house. The light gauge shape sheet steel can be classified into three types including a general member used for general purposes of a steel house, an application member having the same cross section and the same fastening hole specification as the general member but a different shape of the end portion connected to other shape steel, and a special member having a unique shape and difficult to produce on a production line adapted for the general member and the application member. In the prior art, therefore, the special member is unavoidably produced on a production line, for machining the special member, different from the production line for the general member and the application member. The provision of the two production lines including the one for the general member and the application member and the one for the special member not only increases the installation area of the production lines but also requires an independent control system for controlling each production line, thereby complicating the production control system. In the conventional production control system for the light gauge shape sheet steel for a steel house, the productivity of the light gauge shape sheet steel for a steel house is generally reduced by the facts that (i) the work of opening the fastening holes for connecting the members is one factor reducing the productivity, (ii) the shape steel has different types including the general member, the application member and the special member, and especially the existence of “the special member” is a factor reducing the working efficiency of the conventional production equipment and the conventional production control system, (iii) the necessity of opening a multiplicity of fastening holes requires long time and a great amount of labor to fetch the information on the fastening holes such as the position, the shape and the machining accuracy of the fastening holes in the design stage, as the member control information for the production control system, and (iv) the information on the positions of the fastening holes to be formed are complicated. Thus, another object of the present invention is to solve the problems (i), (ii), (iii) and (iv) described above. Further, houses and other buildings are generally built individually by reflecting the propensity of each customer. Therefore, the design drawing, the working drawing, the material order and the like construction information prepared at the time of constructing a building are rarely reused. In recent years, the extension of ownership of prefabricated houses has increased the chance of reusing the building information in the same company. For the reasons explained below, however, the building information are not generally reused between different companies. (a) The standards of the members making up a building are not shared by companies. (b) The building information is rarely reused as it is, and correction to some degree is required. The manner in which the building information is stored varies from one company to another. Especially, the building information which may be stored in the form of paper media cannot be easily corrected. (c) Conventionally, the building information are not very helpful to both the party providing them and the party using them, and therefore are not extensively used by other companies. On the other hand, the building materials and the construction methods of a steel house can be easily shared and the building information on them can be distributed among a plurality of companies. Nevertheless, companies generally do not construct a building by reusing the building information of another building constructed by another company. Another object of the present invention is to solve these problems of the prior art and to provide a building information distribution aiding system for distributing the building information through a network. The entire disclosures of the references cited herein are incorporated herein by reference. |
<SOH> SUMMARY OF THE INVENTION <EOH>According to the present invention, an information processing system is provided for producing a building material. The system includes a design drawing generating arrangement for generating the design drawing information on an objective building, a list generating arrangement for generating the list information of members used for the objective building, based on the design drawing information obtained by the design drawing generating arrangement, and a member production control arrangement for controlling the production of the members used for the objective building, based on the list information obtained by the list generating arrangement. For example, in order to efficiently produce the members such as light gauge shape sheet steel for a building or especially a steel house, the light gauge shape sheet steel for a steel house is produced by the CAD system and the CAN system, e.g., systems for assisting in controlling the preparation for production such as the process design, the work design and the NC (numerically controlled) programming and the production process such as machining and assembly, in such a manner that the design drawings, including a wall panel drawing, a floor panel drawing and a roof truss drawing, of a low building are first generated on a computer. The specification and quantity of the light gauge shape sheet steel can be determined from these design drawings. Based on these drawings, a steel member order list may be prepared, and based on this steel member order list information, the light gauge shape sheet steel can be produced under a control of a computer. According to an exemplary embodiment of the present invention, the specification and the quantity of the light gauge shape sheet steel are automatically determined from the design drawing information of a steel house, and based on them, a steel member order list is automatically output. Therefore, the material (steel member) totaling work required for producing the light gauge shape sheet steel which has conventionally been conducted manually may be eliminated, either fully or to the large extent. As a result, not only the transfer error is substantially eliminated, the whole work can be siginificantly simplified, and at the same time, the complicated desk work for ordering steel members may be reduced. addition, in view of the fact that the light gauge shape sheet steel is produced using the information of the specification and the quantity input to the computer, the light gauge shape sheet steel can be supplied accurately, rapidly and at low cost. Further, in case of a need of a design change for some reason or other, the specification, the quantity and the contents of the order for the light gauge shape sheet steel are automatically corrected very efficiently by correcting the original design drawing information. The light gauge shape sheet steel includes members formed of shape steel using the sheet steel having a thickness not less than 0.4 mm but less than 2.3 mm and fittings and hardware. Also, the specification of the light gauge shape sheet steel includes the product standard, length and the quantity of the members and the member positioning information for assembling the members. The specification of the light gauge shape sheet steel includes the member positioning information for assembling the members. Thus, the risk of machining a member for positioning not conforming with the design drawing is eliminated, and it is possible to machine the light gauge shape sheet steel efficiently. The “member positioning information” (position machining information) generally includes information for determining the relative positions of the members being assembled such as the positions of the bolt holes for assembling the members, and the notching and embossing, and the like. Further, by calculating the specification and the quantity of the light gauge shape sheet steel for each panel used for a low building, the light gauge shape sheet steel preferred for assembling a panel can be easily specified, thereby making efficient assembly work possible. The “panel” (predetermined unit member) generally includes a wall panel and a floor panel configured of a plurality of the light gauge shape sheet steel combined with one another. Further, according to another embodiment of the present invention, a production equipment is provided for producing the light gauge shape sheet steel for a steel house by supplying flat steel on a main production line. The production line includes an uncoiler, a leveler arranged downstream of the uncoiler, an end portion cutter arranged downstream of the leveler, a waiting table arranged downstream of the end portion cutter, a stationary fastening hole forming machine arranged downstream of the waiting table and a roll forming machine arranged downstream of the stationary fastening hole forming machine. In particular, the equipment includes a non-stationary fastening hole forming machine for forming the fastening holes without stopping the flow of the sheet steel is arranged downstream of the leveler independently of the stationary fastening hole forming machine. Further, according to another embodiment of the present invention, a computer-controlled production control system is provided for producing light gauge shape sheet steel for a steel house configured of a general member of the basic structure, an application member having only the shape of the end portion thereof different from that of the general member and a special member requiring a special machining process, by a production equipment for producing the light gauge shape sheet steel for a steel house, comprising a main production line including an uncoiler, a leveler arranged downstream of the uncoiler, an end portion cutter arranged downstream of the leveler, a waiting table arranged downstream of the end portion cutter, a stationary fastening hole forming machine arranged downstream of the waiting table and a roll forming machine arranged downstream of the stationary fastening hole forming machine, and a special production line arranged in parallel to the main production line. Using the control system, based on the member control information of the production control system, the general member, the application member and the special member can be discriminated in the step preceding to the leveler. The general member and the application member can be produced on the main production line, while the special member, after being machined through the machining steps shared by the general member and the application member on the main production line, is moved onto the special production line different from the main production line, and after being machined to a unique shape, returned to the main production line. In the stationary fastening hole forming machine, the production efficiency is reduced due to the fact that the fastening holes are formed by stopping the sheet steel temporarily during the line assembly work to form the fastening holes in the work with high accuracy. In the non-stationary fastening hole forming machine, the fastening holes can be formed in the moving sheet steel. Thus, the production efficiency can be improved, although the accuracy with which the fastening holes are formed is reduced as compared with the stationary fastening hole forming machine. As described herein, the fastening holes formed in the light gauge shape sheet steel of a steel house can be classified into holes of a high accuracy and generally not depending on the position and purpose of the individual holes. According to the present invention, based on this point, the fastening holes which do not need to have high accuracy are produced by the non-stationary fastening hole forming machine on the main production line, and those holes that should be of high accuracy by the stationary fastening hole forming machine thereby to improve the productivity. By employing this production control system, the production efficiency of the whole production line of the light gauge shape sheet steel of a steel house including the general member, the application member and the special member can be improved. In contrast with prior art, according to the present invention invention, in designing a steel house with the CAD system, the information including the positions, shape and the machining accuracy of the fastening holes can be automatically generated in accordance with the attributes of the individual members, and the fastening hole information thus generated are fetched into the member control information. In this manner, a multiplicity of fastening hole information are efficiently obtained automatically at the same time as the building design, so that the member control information of the production control system can be generated. Also, according to the present invention, the shape of the shape steel is developed into a flat form, and the fastening hole position information is controlled one-dimensionally along the length of the members of each portion of the developed shape steel, so that the process of forming the fastening holes is easily controlled, thereby making it possible to secure the versatility of the data. Further, according to the present invention, a building information distribution aiding system is provided. The system includes a server arrangement for providing a building information distribution site for distributing the building information of buildings having a common standard of the material and the construction method, and a client arrangement connectable with the server arrangement through a network. The system further comprise a first arrangement which allows the server arrangement to list actual cases of buildings, a second arrangement allowing the client arrangement to select at least one of the actual cases listed in the case collection page, and a third arrangement allowing the building information corresponding to the selected actual case to be downloaded into the client arrangement. |
Novel amine derivative having human beta-tryptase inhibitory activity and drugs containing the same |
It is intended to provide a novel low-molecular weight amine derivative, that is absorbed well, has low toxicity, and has an excellent human β-tryptase inhibitory activity with extremely high selectivity, a pharmaceutically acceptable salt thereof, and a medicine containing the same as an active ingredient. The medicine of the present invention is efficacious as a prophylactic/therapeutic agent for diseases in the crisis and evolution of which are considered to be attributed to β-tryptase, for example, respiratory diseases, allergic diseases, inflammatory bowel diseases, hyperprolliferative skin diseases, vascular edema and rheumatoid arthritis. |
1. An amine derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof: wherein R1, R2, and R3 each independently is hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a lower acyl group; R1 and R2 may be bonded to each other to form one of a 5-membered ring and a 6-membered ring each containing nitrogen atom to which R1 and R2 are bonded; and 1 to 5 hydrogen atoms in each of the lower alkyl group, the lower alkenyl group, the lower alkynyl group, and the lower acyl group may be substituted by a hydroxyl group, an amino group, a carboxyl group, a lower alkoxyl group, or a lower alkoxycarbonyl group; R4 is hydrogen atom or a lower alkyl group; A is an aromatic ring which is a 5-membered aromatic ring or 6-membered aromatic ring, wherein the aromatic ring may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen atom, sulfur atom, and oxygen atom, and A may be substituted; B is a saturated or unsaturated hydrocarbon group which is a 5-to-7-membered monocyclic hydrocarbon group or 6-to-12-membered condensed bicyclic hydrocarbon group, wherein the hydrocarbon group may contain 1 to 3 hetero atoms selected from the group consisting of nitrogen atom, sulfur atom, and oxygen atom, and each of these groups may be substituted with any of substituents excluding an amino group, an amidino group, and a guanidino group, with the proviso that B is a benzene ring the substituent is any one of substituents excluding a carboxyl group, an alkoxycarbonyl group, and a carbamoyl group; and X is a carbonyl group (—CO—), a sulfonyl group (—SO2—), a methylene group (—CH2—), a vinylenecarbonyl group (—CO—CH═CH—), a vinylenesulfonyl group (—SO2—CH═CH—), an oxymethylenecarbonyl group (—CO—CH2O—), or an oxymethylenesulfonyl group (—SO2—CH2O—). 2. The amine derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein each of R1 and R2 is hydrogen atom. 3. The amine derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein the aromatic ring A is a benzene ring. 4. The amine derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein X is a carbonyl group (—CO—), a sulfonyl group (—SO2—), or a methylene group (—CH2—). 5. The amine derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein B is a saturated or unsaturated 6-to-12-membered condensed dicyclic hydrocarbon group which may contain 1 to 3 hetero atoms selected from the group consisting of nitrogen atom, sulfur atom, and oxygen atom. 6. A medicine characterized by containing the amine derivative or the pharmaceutically acceptable salt thereof according to claim 1. 7. The medicine according to claim 6 characterized in that the medicine is a β-tryptase inhibitor. 8. A prophylactic/therapeutic agent for an allergic disease comprising the medicine according to claim 6. 9. A medicine characterized by containing the amine derivative or the pharmaceutically acceptable salt thereof according to claim 2. 10. A medicine characterized by containing the amine derivative or the pharmaceutically acceptable salt thereof according to claim 3. 11. A medicine characterized by containing the amine derivative or the pharmaceutically acceptable salt thereof according to claim 4. 12. A medicine characterized by containing the amine derivative or the pharmaceutically acceptable salt thereof according to claim 5. 13. A prophylactic/therapeutic agent for an allergic disease comprising the medicine according to claim 7. 14. A prophylactic/therapeutic method for a desease, a crisis or evolution thereof being attributed to β-tryptase comprising a step of; administering a medicine characterized by containing the amine derivative or the pharmaceutically acceptable salt thereof according to claim 1. |
<SOH> BACKGROUND ART <EOH>Tryptase (EC 3. 4. 21. 59) is a proteinase similarly to trypsin, thrombin, Factor Xa (FXa), and kalliklein. Heretofore, tryptase c DNAs' such as: α I and II; β I, II, and III; γ I and II; δ I; and e have been known. Of those, α-tryptase and β-tryptase specifically localize in granules of mast cells or of basophils. Although α-tryptase and β-tryptase have an amino acid sequence homology of 93%, there is a point of difference between α-tryptase and β-tryptase in that α-tryptase is constantly secreted from a mast cell, whereas β-tryptase is specifically secreted outside the cell by degranulation of the mast cell (Schwartz et al: Journal of Clinical Investigation (J. Clin. Invest.), vol. 96, pp. 2702 to 2710 (1995)). β-tryptase has characteristics largely different from those of other serine proteinases. For example, the sensitivity to various serine protease inhibitors of β-tryptase is remarkably different from those of other serine proteinases (Schwartz et al: Journal of Immunology (J. Immunol.), vol. 126, pp. 1290 to 1294 (1981)). Furthermore, for example, the enzyme activity reveals by the formation of a tetramer (Schwartz et al: Journal of Biological Chemistry (J. Biol. Chem.), vol. 261, pp. 7372 to 7379 (1986); Pereira et al: Nature, vol. 392, pp. 306 to 311 (1998)). The relationship of tryptase with many pathological states has also been suggested. For example, in a patient suffering from a systematic anaphylactic shock such as an allergy to bee venoms, the β-tryptase content in the blood increases continuously (Schwartz et al: New England Journal of Medicine (N. Engl. J. Med.), vol. 316, pp. 1622 to 1626 (1987)). Furthermore, for example, the inhalation of allergen in patients suffering from atopic asthma increases the content of β-tryptase in their blonchoalveolar fluid (Bousquet et al: Journal of Allergy and Clinical Immunology (J. Allergy Clin. Immunol.), vol. 88, pp. 649 to 660 (1991)). That is, there have been many reports showing that β-tryptase level increase at the site of allergen exposure in such allergic diseases. Proteinase activated receptor-2 (PAR-2), complement C3, Vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), and the like have been reported as natural substrates of tryptase. In addition, it has been suggested that protein processing action of those substrates leads to airway contraction, increase of vascular permiability, activation of airway epithelial cells or fibroblasts, or the like. Furthermore, β-tryptase is specifically secreted outside a cell by the degranulation of mast cells, and, in the granule of the mast cells, β-tryptase localizes with trypstatin that is a natural inhibitor of β-tryptase and that is a basic protein (Katsunuma et al: Biochemistry, vol. 62, pp. 18 to 31 (1990)). Therefore, it appears that β-tryptase specifically induces airway contraction and airway inflammation owing to the degranulation of mast cells, and does not act on a living body unless the mast cells are degranulated. From the above, it is conjectured that a substance inhibiting human β-tryptase is useful in a treatment for the disease due to the mast cell activation, in particular, an allergic disease such as bronchial asthma. As examples of a currently known inhibitor for human β-tryptase, trypstatin (Kido et al: Archives of Biochemistry and Biophysics (Arch. Biochem. Biophys), vol. 239, pp. 436 to 443 (1985)) and leech derived tryptase inhibitor (LDTI) (Sommerhoff et al: Biological Chemistry Hoppe-Seyler (Biol. Chem. Hoppe-Seyler), vol. 375, pp. 685 to 694 (1994)) can be given as natural inhibitors, and several of peptide derivatives, nonpeptidic compounds having amidino groups (aminoiminomethyl groups) and guanidino groups (aminoiminomethylamino groups), and the like have been reported as synthetic compounds. For instance, U.S. Pat. No. 5,525,623 and EP 504,064 B each disclose a peptide analog having a guanidino group, WO 99/24407 discloses a compound having an amidino group, and WO 99/55661 discloses a compound having an aminomethyl group. However, each of those compounds involves a problem to be solved in that: the selectivity of β-tryptase inhibition is not high; or the presence of an amidino group or a guanidino group is likely to cause such a compound to be poorly absorbed or to exhibit toxicity. |
Automated processing method for fish and installation for preparing and processing fish, particularly for slaughtering and gutting the same |
An automated processing method for fish and an installation for preparing and processing fish has a conveying element for linking a central feed device to a processing machine for processing fish. A number of machines are combined in an installation and are supplied with fish via the central feed belt. Fish are transferred from the central feed device by the conveying element so that the fish automatically reach the respective entry position of the processing machine. |
1. Installation for the preparation and processing of fish, in particular for the slaughter and gutting thereof, essentially including a) a transport device (16) for fish, b) a central storage tank (14) for holding or for collecting the fish delivered, and c) at least two processing machines (11) for processing fish, d) a central delivery device for continuously delivering the fish to each processing machine, characterised in that e) in the region of each processing machine for processing the fish the delivery device comprises means for transfer of the fish from the delivery device to each processing machine, wherein f) the means for transfer are designed in such a way that the fish move automatically to the respective input position of the processing machine. 2. Installation according to claim 1, characterised in that several processing machines for slaughtering and gutting fish are arranged parallel to each other, wherein the processing machines are connected to each other by the central delivery device, namely by a delivery belt. 3. Installation according to claim 1, characterised in that the installation has a central computer unit for control and/or regulation, by means of which all components can be controlled and/or regulated according to demand and/or priority and/or position. 4. Installation according to claim 3, characterised in that the computer unit or control/regulation system is freely programmable. 5. Installation according to claims 1, characterised in that the delivery belt has controllable and regulatable deflectors by means of which the fish can be deflected from the delivery belt in the direction of the processing machine being controlled at the time. 6. Installation according to claims 1, characterised in that the delivery belt has belt markings. 7. Installation according to claims 1, characterised in that the region of the delivery belt, behind the position of laying the fish on the delivery belt in the direction of transport of the fish and before the first processing machine are arranged means for detecting fish. 8. Installation according to claim 7, characterised in that the or each means is designed as a sensor for recording and/or for detecting the position and/or for gathering geometrical data of the fish. 9. Installation according to claims 1, characterised in that between the sensor and the first processing machine in the direction of transport of the fish is arranged a return device or the like with which fish are detected by the sensor as being incorrectly positioned and/or surplus can be returned to the storage tank. 10. Installation according to claims 1, characterised in that in the region of the storage tank is arranged a monitoring means for quantitative regulation inside the storage tank. 11. Installation according to claims 1, characterised in that each processing machine for slaughtering and gutting is connected to a central discharge belt. 12. Installation according to claim 1, characterised in that the means for transfer is designed as an active conveying element. 13. Installation according to claim 12, characterised in that the active conveying element is essentially composed of a storage buffer. 14. Installation according to claim 13, characterised in that the conveying element additionally has a single-stroke unit, wherein the single-stroke unit is arranged behind the storage buffer in the direction of transport of the fish. 15. Installation according to claim 13, characterised in that the storage buffer and/or the single-stroke unit is designed as a continuously moving belt. 16. Installation according to claim 14, characterised in that the single-stroke unit is designed as a cassette. 17. Installation according to claim 13, characterised in that the storage buffer is designed for holding and for transport of the fish tail or head first in their longitudinal direction. 18. Installation according to claim 13, characterised in that the storage buffer comprises several holding compartments for holding a single fish each, wherein the holding compartments are separated from each other by pivotable flaps, slides or the like. 19. Installation according to claim 18, characterised in that associated with each holding compartment is a monitoring means. 20. Installation according to claim 14, characterised in that the single-stroke unit is designed for transport of the fish in their transverse direction. 21. Installation according to claim 14, characterised in that the single-stroke unit is designed as a drum conveyor or active conveyor belt, wherein drum conveyor or conveyor belt are designed in such a way that the fish lie with their tail end in a predefined position. 22. Installation according to claim 1, characterised in that the means for transfer is designed as a passive conveying element. 23. Installation according to claim 1, characterised in that the means for transfer is composed of a combination of active and passive conveying elements. 24. Installation according to claim 1, characterised in that the means for transfer is designed as a conveying element. 25. Conveying element for linking a central delivery device to a processing machine for processing fish, essentially including a chute, characterised in that the chute is inclined in two planes in such a way that each fish automatically moves from the delivery device over the chute directly into the input position of the processing machine. 26. Conveying element according to claim 25, characterised in that the chute comprises at least one receptacle for the storage of a fish. 27. Conveying element according to claim 25, characterised in that several receptacles are provided for storage. 28. Conveying element according to claim 26, characterised in that the individual receptacles are separated from each other by pivotable flaps, slides or the like. 29. Conveying element according to claim 28, characterised in that the flaps, slides or the like are individually controllable. 30. Conveying element according to claim 26, characterised in that associated with each receptacle is a monitoring means. 31. Conveying element according to claim 26, characterised in that each receptacle comprises positioning aids for the fish. 32. Conveying element according to claim 25, characterised in that the conveying element is connected to a computer unit for the control and/or regulation of all components. 33. Conveying element according to claim 25, characterised in that associated with the chute is a means for delivery of liquids. 34. Conveying element according to claim 26, characterised in that the last receptacle before the processing machine is designed or arranged in such a way that the fish is arranged with its longitudinal axis essentially parallel to the discharge edge of the processing machine. 35. Method for the automated processing of fish, essentially including the following steps: delivery and collection of the fish in a central storage tank, separation of the fish, manual alignment of the fish into a predefined position, automated processing of the fish, characterised in that before automated processing the fish are laid on a central delivery device and aligned and then delivered to the processing machines for processing, wherein the fish are passed through from the delivery device by a means for transfer to the respective processing machine according to demand and priority. 36. Method according to claim 35, characterised in that the delivery device supplies several apparatuses for slaughtering and gutting. 37. Method according to claim 35, characterised in that with monitoring means and a master computer unit for the control and/or regulation of all components with reference to demand messages and/or priority commands of the delivery device and/or the processing machines for slaughtering and gutting and/or storage buffers, it is determined where the next fish is deposited each time. 38. Method according to claim 37, characterised in that the individual components, namely in particular the deflectors, pivotable flaps and the like as well as the belt speed of the delivery belt are controlled and regulated separately and in coordination with each other. 39. Method according to claims 35, characterised in that the fish is transported into the region of the selected processing machine and there deflected by the deflector from the delivery device onto the means for transfer to the processing machine. 40. Method according to claims 35, characterised in that the fish is conveyed actively or passively into a receptacle or compartment in the means for transfer, wherein a monitoring means detects the presence or absence of a fish in the receptacle or compartment and sends corresponding commands/signals to the computer unit for transmission of the demand. 41. Method according to claims 35, characterised in that after a calming period the fish is guided into a subsequent receptacle in the direction of the processing machine, provided that the monitoring means of the subsequent receptacle has indicated a demand. 42. Method according to claims 35, characterised in that the fish inside the storage buffer is conveyed or slides downwards as far as possible in the direction of the processing machine, wherein the flaps, which are basically open, close only when the preceding compartment in the direction of transport is occupied. 43. Method according to claims 35, characterised in that the fish is guided stepwise to a point immediately in front of the single-stroke unit or single-stroke flap (46) of the processing machine. 44. Method according to claims 35, characterised in that, after opening of the single-stroke flap, the fish drops into the processing machine with its longitudinal axis parallel to the discharge edge of the processing machine. |
Line driver for transmitting data |
A line driver (3) for transmitting data with high bit rates, in particular for wire-bound data transmission in the full-duplex process, comprises a differential pair with differential pair transistors (14, 15) for generating transmission impulses as a function of the data to be transmitted, whereby the transmission impulses are preferably output via cascode transistors (16, 17), each with the differential pair transistors (14, 15) forming a cascode circuit, onto the data transmission line (8, 9) connected to the line driver (3). For reproducing the behaviour of the differential pair a replica differential pair with replica differential pair transistors (18, 19) is provided, generating replica impulses corresponding to the transmission impulses, which replica impulses can be fed via replica cascode transistors (20, 21) to a hybrid integrated circuit (6) for effecting echo compensation in relation to impulses received via the data transmission line (8, 9) |
1-16. (canceled) 17. A line driver including at least one driver stage, the at least one driver stage comprising: a first pair of transistors differentially driven as a function of data to be transmitted, the first pair of transistors configured to generate an impulse for a transmission line, and a second pair of transistors associated with the first pair of transistors and configured to generate a replica impulse that corresponds to the impulse generated by the first pair of transistors, wherein the second pair of transistors are switched in a synchronous manner with respect to the first pair of transistors. 18. The line driver according to claim 17, wherein the first pair of transistors and the second pair of transistors are configured to receive the same drive signals. 19. The line driver according to claim 18, wherein the at least one driver stage further comprises: a control circuit configured to generate the drive signals in the form of first and second differential control signals, a first differential control signal provided to a transistor of the first pair of transistors and a transistor of the second pair of transistors, and a second differential control signal provided to the other transistor of the first pair of transistors and the other transistor of the second pair of transistors. 20. The line driver according to claim 17, wherein the at least one driver stage further comprises: a third pair of transistors, each of the third pair of transistors being coupled between a data transmission output of the line driver and a corresponding transistor of the first pair of transistors, and a fourth pair of transistors, each of the fourth pair of transistors coupled in series with a corresponding transistor of the second pair of transistors. 21. The line driver according to claim 20, wherein the transistors of the third pair of transistors and the transistors of the fourth pair of transistors are biased with a common bias voltage. 22. The line driver according to claim 20, wherein the transistors of the third pair of transistors are biased with a first bias voltage and the transistors of the fourth pair of transistors are biased with a second bias voltage. 23. The line driver according to claim 20, wherein each of a bias voltage for the third pair of transistors and a bias voltage for the fourth pair of transistors is bled off from a control circuit. 24. The line driver according to claim 17 wherein each of the first pair of transistors and each of second pair of transistors includes a port connected to a common power source. 25. The line driver according to claim 24, wherein the at least one driver stage further includes: a bias transistor configured to couple to a power source, the bias transistor having a control port coupled to control ports of the third pair of transistors and control ports of the fourth pair of transistors, a linear device having a linear voltage/current characteristic coupled in series between the bias transistor and the common power source. 26. The line driver according to claim 17, wherein: each of the transistors of the first pair of transistors includes a port connected to a common first power source, and each of the transistors of the second pair of transistors includes a port connected to a common second power source. 27. The line driver according to claim 17, wherein the at least one drive stage further comprises a first capacitor coupled in parallel to a first of the first pair of transistors, and a second capacitor coupled in parallel to a second of the first pair of transistors. 28. The line driver according to claim 17, further comprising a hybrid integrated circuit operably coupled to the second pair of transistors to receive replica impulses therefrom, the hybrid integrated circuit operable to subtract the replica impulses from impulses received via a data transmission line coupled to the first pair of transistors. 29. The line driver according to claim 28, wherein the hybrid integrated circuit is integrated onto a common substrate with the at least one driver stage. 30. A line driver comprising at least one control circuit and at least one driver stage, the at least one driver stage comprising: a first pair of transistors differentially driven as a function of the data to be transmitted, the first pair of transistors configured to generate an impulse for a transmission line, and a second pair of transistors associated with the first pair of transistors configured to generate a replica impulse that corresponds to the impulse generated by the first pair of transistors, and wherein the at least one control circuit is operable to switch the second pair of transistors and the second pair of transistors in a contemporaneous manner. 31. The line driver according to claim 30, wherein the at least one driver stage further comprises: a third pair of transistors, each of the third pair of transistors being coupled between a data transmission output of the line driver and a corresponding transistor of the first pair of transistors, and a fourth pair of transistors, each of the fourth pair of transistors coupled in series with a corresponding transistor of the second pair of transistors. 32. The line driver according to claim 31, wherein one or more bias voltages for the third pair of transistors and the fourth pair of transistors is bled off of the control circuit. 33. The line driver according to claim 32, wherein: the control circuit comprises two logic elements switched complementarily as a function of the data to be transmitted, the two logic elements connected to corresponding nodes on which differential control signals for the first pair of transistors and the second pair of transistors are picked up, and the at least one driver stage further comprises an intermediate circuit coupled to receive the voltages on the corresponding nodes of the control circuit, the intermediate circuit operable to generate an average of these voltages as the bias voltage for at least the third pair of transistors. 34. The line driver according to claim 33, wherein the intermediate circuit comprises two transistors of a first type and a third transistor of a second type, each of the two transistors having a control port connected to a corresponding one of the corresponding nodes, each of the two transistors having a second port connected in common with the third transistor, the third transistor providing the bias voltage to the third pair of transistors. 35. A line driver including at least one driver stage, the at least one driver stage comprising: a first pair of transistors differentially driven as a function of the data to be transmitted, the first pair of transistors configured to generate an impulse for a transmission line, and a second pair of transistors associated with the first pair of transistors configured to generate a replica impulse that corresponds to the impulse generated by the first pair of transistors, a hybrid integrated circuit operably coupled to the second pair of transistors to receive replica impulses therefrom, the hybrid integrated circuit operable to subtract the replica impulses from impulses received via a data transmission line coupled to the first pair of transistors, wherein the first pair of transistors and the second pair of transistors are configured to receive the same drive signals. 36. The line driver according to claim 35, wherein the at least one driver stage further comprises: a third pair of transistors, each of the third pair of transistors being coupled between a data transmission output of the line driver and a corresponding transistor of the first pair of transistors, and a fourth pair of transistors, each of the fourth pair of transistors coupled in series with a corresponding transistor of the second pair of transistors. |
Sequential vibration preventer and vibration control structure for ball hitting implement |
A sequential vibration preventer for a ball hitting implement in which impact vibration that is generated when a ball is hit is transmitted to the human body from the impact generation source via the ball hitting implement. The sequential vibration preventer is detachably mounted on a portion of the implement where the vibration amplitude is large, such as the frame shaft or grip, so that the impact vibration is attenuated, and injury to the body is prevented. A ring body consisting of a soft material that has extendability or viscoelasticity is provided, and a plurality of vibrators are sequentially embedded in the circumferential direction in a single ring configuration or in a multiple ring configuration in the interior of the ring body. Alternatively, a belt body consisting of a soft material that has extendability or viscoelasticity or of a flexible material that is non-extendable, is provided, and a plurality of vibrators are embedded in the interior of the belt body so that these vibrators are sequentially disposed in one direction in a single row or in a multiple rows. A two-sided adhesive tape is disposed on either the outer surface or inner surface of the belt body. |
1. A sequential vibration preventer for a ball hitting implement, characterized in that the preventer comprises: a ring body (1) which consists of a soft material that has extendability or viscoelasticity and is mounted on a portion of the ball hitting implement where vibration amplitude is large when a ball is hit, and a plurality of vibrators (2); and said vibrators (2) are integrated in an interior or on a body surface of said ring body (1) by being contained, embedded, sunken, half-sunken or caused to protrude so that the vibrators (2) are sequentially or continuously lined up either regularly or irregularly. 2. The sequential vibration preventer for a ball hitting implement according to claim 1, wherein a single ring configuration is formed by sequentially disposing a plurality of vibrators (2) in an annular configuration in a radial direction or circumferential direction, or multiple ring configuration is formed by disposing said single rings side by side. 3. The sequential vibration preventer for a ball hitting implement according to claim 1 or 2, wherein an inner circumferential surface of the ring body (1) that contacts the ball hitting implement when the ring body is mounted is formed in an arch shape in cross-section. 4. The sequential vibration preventer for a ball hitting implement according to any one of claims 1 through 3, wherein a two-sided adhesive tape is disposed on the inner circumferential surface or side circumferential surface of the ring body (1) that contacts the ball hitting implement when the ring body is mounted. 5. The sequential vibration preventer for a ball hitting implement according to any one of claims 1 through 4, wherein a cut slit is formed in a portion of the ring body (1) so that said cut slit can be opened, and joining surfaces of said cut slit are bonded following mounting of the ring body (1). 6. A sequential vibration preventer for a ball hitting implement which is characterized in that: a belt body (1′) consisting of a soft material that has extendability or viscoelasticity or a flexible material that is non-extendable is provided; a plurality of vibrators (2) are integrated by being embedded, contained, sunken, half-sunken or caused to protrude in an interior or on a body surface of said belt body (1′) so that the vibrators (2) are sequentially or continuously lined up in a direction of length of the belt body either regularly or irregularly; cut grooves (4), which are formed by making cut-outs in a cross-sectional direction through a sectional thickness of the belt body (1′), are formed in a surface on at least one side of said belt body (1′) and are lined up at equal intervals in a direction of length of the belt body (1′); and a two-sided adhesive tape (3) is disposed on either an outer surface or an inner surface of the belt body (1′). 7. The sequential vibration preventer for a ball hitting implement according to claim 6, wherein a plurality of vibrators (2) are disposed in a single row or multiple rows in a direction of length of the belt body (1′). 8. The sequential vibration preventer for a ball hitting implement according to any one of claims 1 through 7, which is characterized in that the shape of the vibrators (2) is one selected from the group consisting of spheres, circular plates, cubes, rectangular solids, plate bodies, linear bodies and belt-form bodies. 9. A vibration control structure for a ball hitting implement that uses the sequential vibration preventer according to any one of claims 1 through 8, wherein said vibration control structure being characterized in that: a recessed portion or recessed groove is formed in portions of the implement where vibration amplitude is large when a ball is hit; said vibration preventer is press-fitted or engaged in the recessed portion or recessed grooves directly or with a two-sided adhesive tape interposed; vibrators are disposed with a soft material interposed and caused to contact the ball hitting implement; and said vibrators are surrounded by said soft material. 10. A vibration control structure for a grip portion of a ball hitting implement, the vibration control structure being characterized in that: the sequential vibration preventer according to any one of claims 1 through 8 is mounted on a grip portion of a shaft of the ball hitting implement; a covering with a rubber grip or leather grip is made on an outer circumference of the sequential vibration preventer, said covering being made so that a recessed portion or recessed groove is formed in an outer circumference of said shaft or in an inside surface of the rubber grip or leather grip, so that said sequential vibration preventer is accommodated in said recessed portion or recessed groove; vibrators are disposed with a soft material interposed and caused to contact said shaft; and the vibrators are surrounded by said soft material. 11. A vibration control structure for a racquet face portion in a tennis racquet or other ball hitting implement, characterized in that: the sequential vibration preventer comprising the ring body according to any one of claims 1 through 5 is disposed on an inside surface of a frame of the racquet face portion with an inner circumferential surface of said ring body aligned with an outer circumferential edge of a protruding portion of each grommet on which such a ring body is installed, so that the gut can be strung through both holes, said disposition being a fixing disposition that is accomplished by bonding the sequential vibration preventer via a two-sided adhesive tape or by forming a recessed portion or a recessed groove in an outer circumferential edge of the protruding portion of said grommet and press-fitting said ring body in said recessed portion or recessed groove directly or with a two-sided adhesive tape interposed; the vibrators are disposed with a soft material interposed and caused to contact said frame; and the vibrators are surrounded by said soft material. |
<SOH> BACKGROUND ART <EOH>In a tennis racquet, the vibration of the impact when the ball is hit is transmitted to the frame from the gut plane (strings) and is further transmitted to the body of the player, i.e., wrist, elbow, etc., from the grip portion via the handle portion. If the body is frequently subjected to such impact vibration over a long period of time, cases of injuries such as peritendinitis and tennis elbow are commonly seen. From the incidence rate as well, this is viewed as a problem of sports injuries that cannot be ignored. In the past, there have been vibration preventers that are mounted on the gut plane, bottom surface of the grip end or interior of the frame shaft in order to alleviate impact vibration of this type; however, no impact preventer that is detachably mounted on the outer circumferential portion of the frame shaft has been seen. Typical vibrations that are the greatest in the frame shaft vibrations transmitted to the body when the ball is hit, and that have an effect on bodily injuries, include a two-node bending mode at approximately 120 Hz that is the fundamental mode characteristic of the frame shaft, as well as relatively higher-frequency vibrations such as a three-node bending mode at approximately 330 Hz, a two-node twisting mode at approximately 360 Hz, and a primary membrane vibrational mode of the strings at approximately 560 Hz. Besides these vibrations, there are numerous other vibrations up to high frequencies of approximately 2000 Hz, and it is known that respective characteristic non-vibrating parts or “nodes” are formed on the frame shaft in the main vibrational modes. Here, the conditions of the “nodes” of the main vibrational modes are black and white boundary line portions as shown in FIG. 9 (cited from Yoshihiko Kawazoe: Rakketo no Kagaku [Racquet Science] II-: Gekkan Tenisu Jaanaru (Monthly Tennis Journal), 123, pp. 76-81 (1994.1)). The areas that are distant from these nodes are areas in which the vibration amplitude of the frame shaft is large, and are referred to as “bellies” of vibration. Especially in regard to the fundamental vibrational mode of the racquet, it has been found that the modes that make a large contribution to an unpleasant ball hitting sensation and injuries to the body are the two-node and three-node bending modes. Furthermore, it would appear that the mounting of vibration preventers in the areas forming the common “bellies” of both modes is an effective means of absorbing or attenuating vibration. Furthermore, as is shown in FIG. 10 , the respective implement portions that correspond to the racquet face portions (B 1 , B 2 , B 3 , B 4 ), the front end portion (A) of the grip and the rear end (C) of the grip (in the vicinity of the grip end) constitute “bellies” where the vibration amplitude of the three-node bending mode that is generated in the case of relatively high-velocity center hitting is large. Accordingly, an improvement in the ball hitting sensation during center hitting would be expected when vibration preventers are mounted on these portions. Furthermore, these implement portions are also common to the two-node bending mode that is generated mainly in low-velocity hitting and off-center hitting. Accordingly, in light of the fact that the impact vibration caused by hitting of the ball is transmitted to the human body from the impact generating source via the frame shaft portion and handle portion, the present invention provides a sequential vibration preventer in which impact vibration is attenuated by mounting vibration preventers on the frame shaft that propagates such impact vibration, so that deleterious effects of such impact vibration on the body are prevented, and a grip vibration control structure using this sequential vibration preventer. The term “sequential vibration preventer” refers to a vibration preventer that has sequential or continuously lined up vibrators, and it is not a term indicating a special vibration mode for “sequential vibration.” |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 illustrates an embodiment in which a ring body is formed, in which (a) is a front view and (b) is a central sectional view, respectively. FIG. 2 illustrates an example of use of the same in a tennis racquet, in which (a) is a partial side view explanatory diagram and (b) is a sectional explanatory diagram. FIG. 3 is a partial side view explanatory diagram illustrating an example of use of the same in a baseball bat, in which (a) shows vibrators with a multiple ring configuration and (b) shows vibrators with a single ring configuration. FIG. 4 is a partial side view explanatory diagram illustrating an example of use of the same in a golf club, in which (a) shows the mounting on the front end portion of the grip, and (b) shows the mounting on the rear end of the grip. FIG. 5 is a partial side view explanatory diagram illustrating an example of use of an embodiment in which a belt body is formed on the shaft of a tennis racquet. FIG. 6 is a partially cut-away sectional explanatory diagram illustrating an example of use of the same on the grip of a tennis racquet. FIG. 7 illustrate an example of use of another embodiment equipped with plate-form vibrators that form a slit-equipped ring body, in which (a) shows a partial side view explanatory diagram and a sectional explanatory diagram (b). FIG. 8 shows longitudinal sectional explanatory diagrams (a, b, c) of an embodiment in which a belt body equipped with cut grooves is constructed, and a cross-sectional explanatory diagram (d) of FIG. 8 ( c ), in which (a) is an embedded installation, (b) is an protruding installation or semi-recessed installation, (c) shows linear or belt-form vibrators, and (d) shows a configuration in which a plurality of rows are installed. FIG. 9 is an explanatory diagram that shows the respective vibrational modes (a, b, c, d) generated in a racquet. FIG. 10 is an explanatory diagram which shows the positions (A, B 1 through B 4 , C) of “bellies” where the vibration amplitude that is common to the two-node and three-node bending modes generated by the hitting of a ball is large. FIG. 11 is an explanatory diagram illustrating an example of use on the inside surface of the frame in the racquet face portions, with mounting on the implement portions B 1 through B 4 shown in FIG. 10 . detailed-description description="Detailed Description" end="lead"? The symbols used in the Figures are listed and explained below. 1 : Ring body 1 ′: Belt body 2 : Vibrators 3 : Two-sided adhesive tape 4 : Cut grooves 5 : Cut slit V: Grip (construction part) W: Frame shaft (or club shaft) X: Racquet Y: Baseball bat Z: Golf club |
Method for determining inhibition activity of a compound on one of the enzymes of the folate synthesis pathway |
The invention is directed to a method for determining the inhibition activity of a compound to be tested on at least the DHPS activity of the folate synthesis pathway, which is coupled with the detection of the release of formed inorganic phosphate. An enzymatic assay, implementing this method of determination on an enzymatic composition, is also within the scope of the invention. This assay is suitable for high throughput screening of compounds affecting folate pathway. |
1. A method for determining the inhibition activity of a compound to be tested on one of the enzymes of the folate synthesis pathway, comprising the steps of: (i) incubating said compound with an enzymatic composition comprising a DHPS activity, and (ii) detecting the release of phosphate. 2. The method of claim 1, wherein the enzymatic composition further comprises a pyrophosphatase, and step (ii) detects the release of inorganic phosphate. 3. The method of claim 1, wherein the enzymatic composition further comprises an HPPK activity or HPPK and DHNA activities. 4. The method of claim 3, wherein the DHPS activity is Fol1. 5. The method of claim 3, wherein at least one of the DHPS, HPPK or DHNA activities are encoded by (i) SEQ ID No: 1 or a homolog or functional fragment thereof or (ii) a nucleotide encoding the protein of SEQ ID No: 2 or a functional polypeptidic fragment thereof. 6. The method of claim 3, wherein the enzymatic composition is derived from fungi, bacteria or protozoa. 7. The method of claim 3, which comprises incubating the compound to be tested with 7,8-dihydroneopterin, ATP, pABA, Fol1, pyrophosphatase and detecting the release of inorganic phosphate. 8. The method of claim 3, wherein the enzymatic composition comprises a DHNA activity, and the DHNA activity is measured, the method comprising the incubation of the compound to be tested with 7,8-dihydroneopterin, ATP, pABA, Fol1, pyrophosphatase and the detection of the release of inorganic phosphate. 9. The method of claim 3, wherein the HPPK activity is measured in a single assay by: (i) adding 7,8-dihydroneopterin and pABA , but with omission of ATP, to the enzymatic composition containing Fol1and pyrophosphate; (ii) adding the compound to be tested and ATP when the product of the DHNA reaction, which is 6-hydroxymethyl-7,8-dihydropterin, is accumulated in the enzymatic composition after a defined period of time; and (iii)monitoring the release of inorganic phosphate after the addition of the compound and ATP. 10. The method of claim 3, wherein the enzymatic composition comprises DHPS, HPPK and DHNA activities and the DHPS activity is measured in a single assay by: (i) adding 7,8-dihydroneopterin and ATP but with omission of pABA, to the enzymatic composition containing Fol1and pyrophosphate; (ii) adding the compound to be tested and pABA when the substrate of DHPS reaction, which is 6-hydroxymethyl-7,8-dihydropterin pyrophosphate, is accumulated in the enzymatic composition after a defined period of time; and (iii) monitoring the release of inorganic phosphate after the addition of the compound and pABA. 11. The method of claim 1, wherein the enzymatic composition comprises a DHPS substrate is synthesized in vitro. 12. The method of claim 3, wherein the detection of phosphate is performed by colorimetry. 13. The method of claim 3, wherein the detection of phosphate is performed by fluorometry. 14. The method of claim 3, wherein the detection of phosphate is performed by radioactive labeling. 15. (canceled) 16. An Enzymatic assay kit for in vitro testing of compounds for their inhibitory effect on the folate synthesis pathway, the kit comprising: (i) the substrate 7,8-dihydroneopterin, and (ii) the Fol1 enzyme, and (iii) the enzyme pyrophosphatase, and (iv) pABA and ATP for simultaneous or sequential use. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Reduced folate cofactors are essential for the synthesis of purines, thymidilate, glycine methionine, panthotenic acid and N-formyl methionyl-tRNA. Folates are vitamins for humans while most microbial cells must synthesize folates de novo since they lack the carrier mediated active transport system of mammalian cells that allows the use of preformed dietary folates. In P.carinii (Volpe et al 1995), S.cerevisiae (Sen-Gupta et al, 1997), and C.albicans , one gene encodes for three of the enzymes of the folate de novo pathway. The fol 1 gene from C.albicans codes for a putative protein of 88.6 kDa (788 amino acids), see PCT Application WO00/15838 (CaNL 256), see SEQ ID 1. The Fol 1 protein sequences show significant homology with proteins to be involved in the biosynthesis of dihydropteroate (Lopez & Lacks, 1993, Slock et al, 1990) in both eukaryotic and prokaryotic microorganisms. The fol 1 gene from P.carinii, S.cerevisiae and C.albicans encodes a multifunctional enzyme that catalyses the last three consecutive steps of the 7,8-dihydropteroate biosynthesis pathway (see FIG. 1 ). The first activity is the 7,8-dihydroneopterin aldolase or DHNA which catalyses the conversion of 7,8-dihydroneopterin to 6-hydroxymethyl-7,8-dihydropterin. The second activity is the 7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase or HPPK; it converts the product of DHNA reaction to 6-hydroxymethyl-7,8-dihydropterin pyrophosphate. The third activity is the dihydropteroate synthase or DHPS, it catalyses the condensation of para-aminobenzoic acid (pABA) with the 6-hydroxymethyl-7,8-dihydropterin pyrophosphate to form 7,8-dihydropteroate. With no mammalian counterparts, these enzymes are attractive chemotherapeutics targets, since it is possible to target highly selective drugs against them for treating microbial diseases. A number of compounds have been developed as antimicrobial agents which target two of the seven enzymes in the folate pathway. Trimethoprim inhibits dihydrofolate reductase, thereby preventing the formation of tetrahydrofolate (Huovinen et al, 1995). The sulphonamides exert their antimicrobial effect on a different biosynthetic enzyme, dihydropteroate synthase (Slock et al, 1990). Amino acid sequence comparisons and functional studies reveal marked diversity in DHNA, HPPK and DHPS structure and organization in the different species (Slock et al, 1990 ; Lopez & Lacks, 1993). Depending on the source, these three activities are expressed as a mono-, bi- or tri-functional enzyme on the same polypeptide. Taking into account the difficulty of producing multifunctional enzymes, in the case of multifunctional enzymes, the approaches in the literature were to isolate and express the monofunctional domain sequences with an aim to study the enzymatic system (Volpe et al, 1995). Previous studies with monofunctional protein require the coupling of DHNA activity with extrinsic purified HPPK and DHPS activities, or the coupling of HPPK with extrinsic purified DHPS (Lopez & Lacks, 1993). Moreover, it also involves synthesis of the HPPK or the DHPS substrates. Assays described in the literature (Lopez & Lacks, 1993, Volpe et al, 1995) are not amenable to high throughput screening (H.T.S). They generally used radiolabelled substrate: para-amino benzoic acid ([ 3 H]PABA or [ 14 C]pABA), that involves a separation step of the substrate from the products before counting the radioactivity. Formed radioactive dihydropteroate is separated from substrates by paper chromatography and measured in a scintillation counter (Volpe et al, 1995). The radioactive dihydropteroate can be separated from unreacted [ 3 H] pABA by the ether extraction method before measuring the radioactivity in the scintillation counter. These steps, solvent extraction or paper chromatography, are not adaptable to H.T.S. |
<SOH> SUMMARY OF THE INVENTION <EOH>The invention is directed to a method for determining the inhibition activity of a compound to be tested on one of the enzymes of the folate synthesis pathway, comprising the steps of incubation of said compound with an enzymatic composition having at least the DHPS activity, and of detection of the release of phosphate. In a preferred embodiment, the DHPS activity is coupled with pyrophosphatase. According to one embodiment of the invention, the enzymatic composition has a DHPS activity, or DHPS and HPPK activities, or DHPS and HPPK and DHNA activities. This method of determination involves also the use of an (the) enzyme(s) which is (are) encoded by SEQ ID No. 1 or a homolog thereof and functional fragments thereof as well as by the corresponding encoded protein of SEQ ID No. 1 or a functional polypeptidic fragment thereof. According to another embodiment, the method of determination is performed on an enzymatic composition which is derived from fungi, bacteria or protozoa. The method of determination comprises an incubation step of the compound to be tested with 7,8-dihydroneopterin, ATP, pABA, Fol1, pyrophosphatase and a detection step of the release of phosphate. This can be applied by the measurement of DHPS activity but also of the DHNA and/or HPPK activities. This method of determination allows the in vitro synthesis of the HPPK substrate, DHPS substrate and product. The preferred embodiment in the present invention is the detection of phosphate by colorimetry method. However, detection of phosphate can also be performed by fluorometry or by radioactive means. The invention is also directed to a method of screening of compounds with potential inhibitory effect on enzymatic composition by implementing the method of determination presented above. Finally, the invention concerns an enzymatic assay for in vitro testing compounds for their inhibitory effect on an enzymatic composition as disclosed earlier, comprising the substrate 7,8-dihydroneopterin, and the Fol1 enzyme, and the enzyme pyrophosphatase, and PABA and ATP for simultaneous or sequential use. |
Process for xylanase production |
The invention provides a process of obtaining a xylanase, said process comprising: providing a protein-containing extract of a transplastomic plant tissue comprising plastids transformed with a polynucleotide encoding said xylanase, said extract having been subjected to heat treatment that has denatured at least some of the protein content of said tissue but under which the xylanase has remained stable; and recovering said xylanase from said extract. |
1. A process of obtaining a xylanase, said process comprising: providing a protein-containing extract of a transplastomic plant tissue comprising plastids transformed with a polynucleotide encoding said xylanase, said extract having been subjected to heat treatment that has denatured at least some of the protein content of said tissue but under which the xylanase has remained stable; and recovering said xylanase from said extract. 2. A process of obtaining a xylanase, said process comprising: providing a transplastomic plant tissue comprising plastids transformed with a polynucleotide encoding said xylanase; preparing a protein-containing extract therefrom; subjecting said extract to heat treatment that denatures at least some of the protein content of said extract but under which the xylanase remains stable; and recovering said xylanase. 3. A process of obtaining a xylanase, said process comprising: transforming a plant cell with a polynucleotide encoding said xylanase, thereby to obtain a transplastomic cell comprising plastids transformed with a polynucleotide encoding said xylanase; regenerating a transplastomic plant from said transplastomic cell; providing a transplastomic plant tissue from said plant; preparing a protein-containing extract therefrom; subjecting said extract to heat treatment that denatures at least some of the protein content of said extract but under which the xylanase remains stable; and recovering said xylanase. 4. A process according to claim 1 wherein said plastids are chloroplasts and/or wherein said plant tissue is homotransplastomic. 5. A process according to claim 1 wherein recovery of said xylanase comprises ammonium sulfate fractionation, and optionally one or more further purification steps. 6. A process according to claim 1 wherein said heat-treatment is at a temperature of 60° C. or above. 7. A process according to claim 1 wherein the transplastomic plant tissue has undergone senescence and/or has been sun-dried or artificially dried, optionally at a temperature of 42° C. or above. 8. A process according to claim 1 wherein said xylanase is a bacterial or fungal xylanase. 9. A process according to claim 8 wherein said xylanase is encoded by the xynA gene of Bacillus sp NG-27. 10. A process according to claim 1 wherein said plant tissue is tobacco plant tissue. 11. A process according to claim 10 wherein said plant tissue is tobacco leaf tissue. 12. A process according to claim 1 wherein the polynucleotide encoding the xylanase is operably linked to a prokaryotic or chloroplast promoter. 13. A process according to claim 1 wherein the polynucleotide encoding the xylanase is operably linked to a rice rrn or psbA promoter and/or to a psbA or rbcl 3′untranslated region. 14. A process according to claim 1 wherein: the xylanase accounts for 5% or more of the total tissue protein; and/or where ammonium sulfate fractionation is used, the ammonium sulfate fraction 90% or more of the protein in the ammonium sulfate fraction is xylanase; from tissue as defined in claim 7, recovery of 50% or greater or 80% or greater, of the xylanase activity present is obtained. 15. A transplastome transformed with a polynucleotide encoding a xylanase, optionally a xylanase as defined in claim 8. 16. A transplastomic or homotransplastomic plastid comprising a transplastome as defined in claim 15. 17. A plastid according to claim 16 which is a chloroplast. 18. A transplastomic or homotransplastomic cell comprising a plastid as defined in claim 16, or a transplastomic or homotransplastomic plant, plant seed, or plant tissue comprising said cell. 19. A plant, plant seed, or plant tissue according to claim 18 wherein the xylanase is one which remains stable under conditions that denature at least some of the protein content of said plant, seed or tissue but under which the xylanase. 20. A plant, plant seed, or plant tissue comprising the cell of claim 18. 21. A process of obtaining a xylanase comprising expressing said xylanase in a cell, plant, seed or tissue as defined in claim 18 and recovering said xylanase therefrom. 22. A process according to claim 1 further comprising employing the xylanase obtained in the manufacture of paper, for improvement of product quality in baked or brewed products or feed; in the conversion of xylan to polysaccharides, optionally for further conversion to ethanol; in the preparation of complex polysaccharide diets for monogastric animals; or in the processing of plant fibres by selective removal of xylan components. 23. A xylanase obtained by the process of claim 1. 24. A method comprising using the xylanase obtained by the process of claim 1 in the manufacture of paper; for improvement of product quality in baked or brewed products or feed; in the conversion of xylan to polysaccharides, optionally for further conversion to ethanol; in the preparation of complex polysaccharide diets for monogastric animals; or in the processing of plant fibres by selective removal of xylan components. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Plastids Plastids are organelles found in plant cells. Various plastids exist and are derived from undifferentiated proplastids. Differentiated plastids include amyloplasts, chromoplasts, chloroplasts, etioplasts and leucoplasts. Chloroplasts are the most common plastids, and are the site of photosynthesis. Each photosynthetic cell contains multiple chloroplasts, typically from 50 to 100. Chloroplasts have their own genome, the plastome, which exists in addition to the main cellular (nuclear) genome, and transcription and translation systems. The latter resemble prokaryotic transcription and translation systems. Each chloroplast contains multiple genome copies, typically from 50 to 100. A plastid genome, referred to as a plastome, comprises a double stranded circular DNA molecule. Nuclear Transformation Typically, transgene expression in plants is achieved by the integration of a transgene construct into nuclear DNA. In the majority of transformation experiments using Agrobacterium and/or gene guns, the number of copies of the transgene integrated into the transformed plant nuclear genome is typically low, and expression levels achieved are also low. Expression may also be affected by other factors, such as the site of integration. This means that the levels of expression achieved by independently derived nuclear transformed plants harbouring the same transgene can also be highly variable. Plant zygotes contain nuclear DNA derived from both the female (ova) and male (pollen) gametes, both of which contribute to the characteristics of the mature plant. Therefore, nuclear-encoded transgenes can be spread in the ecosystem by the dispersal of pollen, which contains the male gametes, from plants containing a nuclear transgene and subsequent fertilisation of wild type plants. The dispersal of pollen derived from a nuclear transformed plant, therefore, provides a potential vehicle for the unwanted “lateral” transmission of transgenes into other species. There is considerable concern about tis, especially over the possible transmission of herbicide/insecticide/disease resistance traits from transgenic crops to weedy relatives growing around the crop fields, leading to the possibility of resistant weeds (so-called “super-weeds”) which are hard to eliminate because of their resistant traits. Chloroplast Transformation Many of the disadvantages of nuclear transformation can be avoided by targeting transgene integration to the plastome. A transformed plastome is referred to as a transplastome. Due to the existence of multiple plastome copies within each chloroplast, the copy number of an integrated transgene is high. This leads to a level of expression of a transplastomic gene that is typically higher than for an equivalent transgene integrated into nuclear DNA. Such plants are referred to as transplastomic plants. Plastids are maternally inherited. That is, zygotes derive plastids from the cytoplasm inherited from the female gamete, whereas pollen does not contribute plastids to the zygote. Pollen derived from transplastomic plants does not, therefore, contain the transgene and so transgene transmission to other species is not possible. This is particularly beneficial in view of public fears related to the spread of transgenes and their potential impact on the ecosystem. Foreign DNA has previously been introduced into chloroplasts using a biolistic method (Boynton et al, 1988; Svab et al, 1990; Svab and Maliga, 1993; U.S. Pat. No. 5,451,513; U.S. Pat. No. 5,545,817; U.S. Pat. No. 5,545,818; U.S. Pat. No. 5,576,198; U.S. Pat. No. 5,866,421) and a PEG-based procedure (Golds et al, 1993). Typically, the transgene in a chloroplast transformation vector is flanked by DNA regions homologous to regions of the plastome. These flanking regions enable the site-specific integration of the transgene construct into plastome by the process of homologous recombination, a process which naturally occurs in plastids. Therefore, the site of transgene integration is more assured in chloroplast-based techniques relying on homologous recombination than in nuclear-based processes. Therefore, more uniform transgene expression results between independently derived transplastomic plants than between independently derived nuclear transformed ones. Improved techniques for high, uniform, reliable transplastomic expression are provided in PCT/EP00/12446, published as WO01/42441. Hemicellulose and Xylanase Hemicellulose is the second most abundant renewal polysaccharide in nature after cellulose. β-1,4-xylan is a major component of hemicellulose and has a backbone of β-1,4-linked D-xylopyranoside residues substituted with acetyl, arabinosyl and uronyl side chains. Complete digestion of xylan requires the action of several hydrolytic enzymes, the most important among which is endo-1,4-xylanse (EC 3.2.1.8). Xylanases have been detected in a number of microorganisms and thermostable xylanases are of special interest for their potential use in: (1) paper industry for the production of pulp with improved qualities, (2) baking, brewing and feed industry for the improvement of product quality, (3) conversation of xylan to monosaccharides that can be further converted into ethanol, (4) the preparation of complex polysaccharide diet for monogastric animals and, (5) processing of plant fibers (e.g. flax and hemp) by selectively removing xylan components (Herbers et al, 1995; Liu et al, 1997). Despite these important applications, currently xylanases are not being used routinely by the industry mainly because of the high costs involved in their production (Liu et al, 1997). WO95/12668 reports the cloning and expression in bacteria of the xylanase XynA from the fungus Thermonospora fusca . Cellulolytic enzymes have been expressed in filamentous fungi (WO97/27306). Production of cellulolytic enzymes in plants had been a major challenge as these enzymes can potentially degrade the cell wall components of the very cell that is expressing these enzymes, affecting the normal growth and development of the transgenic plants. Xylanase genes have been expressed in plants by targeting the recombinant enzyme to accumulate in the intercellular space (Herbers et al, 1995), in the oil body membrane in seeds (Liu et al, 1997) and by secreting the enzyme through roots into a hydroponic culture medium (Borisijuk et al, 1999). In all these cases, the xylanase gene was introduced into the nuclear genome of the target plant. The expression levels were low. Nuclear transformation of B. napus with xylanase XynC from the fungus Neocallimastix patricarum is also reported in U.S. Pat. No. 6,137,032. |
<SOH> SUMMARY OF THE INVENTION <EOH>Plastids have been transformed with cellulase genes (WO98/11235, U.S. Pat. No. 6,013,860). Plastid transformation with xylanase genes has not been previously been reported. We have transformed the xynA gene coding for an alkali and thermostable xylanase from a mesophilic obligate alkalophilic Bacillus sp. NG-27 into chloroplast genome of tobacco plants. We report here the successful high level expression and purification of this industrially important enzyme and thus provide its significant benefits related to technical industry, agriculture and the environment. For the first time, we have shown that chloroplasts can overexpress and contain a cellulolytic alkali and thermostable xylanase in large amounts without any harmful effects on plant growth for generations. The expression levels of xylanase were found to be very high, reaching up to 6% of the total soluble protein. The recombinant protein was purified to more than 95% homogeneity by simply heating the crude leaf extract to 60° C. followed by ammonium sulfate precipitation, and without any involvement of conventional chromatography techniques. This is advantageous because plant bioreactor systems have a much higher ratio of biomass to recombinant proteins than yeast or E. coli -based expression systems (˜10,000:1 for plants, ˜100:1 for microbial systems). Thus, simple, effective, large-scale purification techniques are particularly import in plant-based systems. 95% purity may be sufficient for direct use in the pulp industry and the enzyme was purified further for use in the animal feed and bakery industries via conventional chromatography techniques. Surprisingly, the enzyme was active even in leaves that had undergone senescence and that had been dried at 42° C. or sun-dried, with a recovery of 85% activity. This finding is of utmost importance to the farmer in judging the time to harvest the leaf material and store them until a desired price is realised. It also offers enormous flexibility for transportation, storage and in the initial stages of extraction. The chloroplast-expressed xylanase retained its substrate specificity, pH and temperature optima. Most importantly, the transgenic plants were indistinguishable from the control untransformed plants in their morphology, growth and development and in seed setting. These results open up an excellent and simple system for the cost-effective production of xylanases in large quantities for various industrial applications. This has not been possible through any other transformation system in plants. Accordingly, the present invention provides: a process of obtaining a xylanase, said process comprising: providing a protein-containing extract of a transplastomic plant tissue comprising plastids transformed with a polynucleotide encoding said xylanase, said extract having been subjected to heat treatment that has denatured at least some of the protein content of said tissue but under which the xylanase has remained stable; and recovering said xylanase from said extract. The invention also provides: a transplastome transformed with a polynucleotide encoding a xylanase. The invention also provides: a transplastomic or homotransplastomic plastid comprising such a transplastome. The invention also provides: a transplastomic or homotransplastomic cell comprising such a plastid, or a transplastomic or homotransplastomic plant, plant seed, or plant tissue comprising said cell. The invention also provides: a process of obtaining a xylanase comprising expressing said xylanase in such a cell, plant, seed or tissue. The invention also provides: a xylanase obtained by a process of the invention. The invention also provides: use of a xylanase obtained a process of the invention in the manufacture of paper; for improvement of product quality in baked or brewed products or feed; in the conversion of xylan to polysaccharides, optionally for further conversion to ethanol; in the preparation of complex polysaccharide diets for monogastric animals; or in the processing of plant fibres by selective removal of xylan components. |
Device for cooling housing, areas. components, media and the like |
A device for air conditioning housings areas, components, media and the like, especially for cooling components (3) situated in electric or electronic installations, appliances or the like, by an air or liquid flow. A chamber (1) is provided, which includes at least one adjustable membrane (5) and a group of openings (7) which is arranged at a distance (9) directly in front of a partition wall (2) containing openings (8). An air or liquid flow which is oriented through the openings (8) of the partition wall (2) is caused by the adjustment of the membrane (5) and the difference between the flow behaviour of the suction process and that of the discharge process. |
1. Means for climate-control of housings, spaces, components, media and the like, especially for cooling of components (3) located in electrical and electronic systems and devices, by means of a fluid flow, especially an air or liquid flow, characterized in that there is a chamber (1) which has at least one movable membrane (5) and at least one opening (7) in the wall of the chamber (1), that the partition (2, 10a) is provided with at least one opening (8), which is directly opposite the opening (8) in the wall of the chamber (1), by the displacement of the membrane (5) a fluid flow being caused through the opening (8) of the partition (2, 10a) by fluid being intaken through a gap (9) between the opening (7) in the wall of the chamber (1) and the opening (8) in the partition (2, 10a) and through the opening (7) in the wall of the chamber (1) into the latter and being forced out of the chamber (1) through the openings (7, 8) of the chamber (1) and the partition (2, 10a). 2. Means as claimed in claim 1, wherein the fluid is intaken through a gap (9) between the wall of the chamber (1) with the opening (7) and the partition (2, 10a) and through the opening (7) of the chamber (1) into the latter and is forced out of the chamber (1) through the openings (7, 8) of the chamber (1) and the partition (2, 10a). 3. Means as claimed in claim 1, wherein there is a group of openings (7) in the wall of the chamber (1) to which is assigned a preferably corresponding number of openings (8) in the partition (2, 10a). 4. Means as claimed in claim 1, wherein a distance (9) is formed between the opposing openings (7) of the chamber (1) and the openings (8) of the partition. 5. Means as claimed in claim 1, wherein the diameter of the openings (8) or the mouth of the openings (8) in the partition (2, 10a) is greater than the diameter of the openings (7) or the mouth of the openings (7) of the chamber. 6. Means as claimed in claim 1, wherein the fluid is intaken through the gap (9) which has been formed between the facing edges of the openings (7, 8) in the wall of the chamber (1) and the partition (2, 10a). 7. Means as claimed in claim 1, wherein the openings (7) of the chamber (1) are made tubular or in the shape of a truncated cone or trumpet-shaped. 8. Means as claimed in claim 7, wherein the openings in the wall of the chamber are formed by tubes which are cylindrical, in the shape of a truncated cone, or trumpet-shaped. 9. Means as claimed in claim 6, wherein the partition (11) is formed by at least one, preferably several passages which are tubular or are in the shape of a truncated cone. 10. Means as claimed in claim 1, wherein the partition is made as a side wall (10a) of a housing (10) which encompasses the components (3) to be cooled. 11. Means as claimed in claim 1, wherein the chamber (1) is divided into two spaces by an intermediate wall (1a), wherein the membrane (5) is located in the intermediate wall and wherein each space has at least one opening (7) to which one opening (8) in the partition (2, 10a) is assigned. 12. Means as claimed in claim 1, wherein in the chamber (1) there are two membranes (5, 5a) which are assigned to one another and are opposite one another and which can be moved synchronously toward one another or apart from one another. 13. Means as claimed in claim 1, wherein the membrane (5) is formed by one wall part of the chamber (1) which can move relative to the adjacent parts of the wall of the chamber (1) and wherein between the adjacent edges (7) of the wall part (5) and the wall of the chamber (1) a gap (9) is formed which forms an opening which is tubular in cross section and which is directly opposite the opening (8) in the partition (2). |
Reduction in the virulence of mycrobacterium tuberculosis and protection against tuberculosis by means of phop gene inactivation |
The construction of a mutant in the phoP gene by means of homologous recombination from a clinically isolated Mycobacterium tuberculosis reduces the virulence thereof in mouse bone marrow macrophage. Moreover, the phoP mutant reduces the virulence thereof in the experimental mouse model. Said phoP mutant can persist without being eliminated both in the macrophage and in the mouse. Mice inoculated with the phoP mutant are protected against M. tuberculosis infection. The use of mutants of mycobacteria in which the phoP gene or the genes regulated by phoP have been inactivated are candidates for vaccines against human and animal tuberculosis as well as possible recombinant vaccines against other pathogens. |
1. A Mycobacterium strain characterized by attenuating its virulence upon inactivation of the phoP gene. 2. A strain of Mycobacterium tuberculosis according to claim 1 characterized by the reduction of virulence in mammal macrophage. 3. A strain of Mycobacterium tuberculosis according to claim 1 characterized by the reduction of virulence in the mouse experimental model. 4. A strain of Mycobacterium tuberculosis characterized by the phoP mutant, which is also able of persisting without being eliminated both in the macrophage and in the mouse. 5. A strain of Mycobacterium tuberculosis characterized by the finding that upon inactivating the phoP gene the regulation of different genes involved in M. tuberculosis virulence is altered. 6. A strain of Mycobacterium tuberculosis characterized by the finding that the phoP gene protects the mouse against M. tuberculosis infection. 7. A strain of Mycobacterium characterized by the inactivation of the phoP gene, for which its use as vaccine against human tuberculosis is proposed. 8. A strain of Mycobacterium characterized by the inactivation of the phoP gene, for which its use as vaccine against tuberculosis in animals is proposed. 9. A strain of Mycobacterium characterized by the inactivation of the phoP gene, for which its use as possible recombinant vaccine against other pathogens is proposed. 10. A strain of Mycobacterium characterized by the inactivation of the genes regulated by phoP, for which its use as vaccine against human tuberculosis is proposed. 11. A strain of Mycobacterium characterized by the inactivation of the genes regulated by phoP, for which its use as vaccine against tuberculosis in animals is proposed. 12. A strain of Mycobacterium characterized by the inactivation of the genes regulated by phoP, for which its use as possible recombinant vaccine against other pathogens is proposed. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Recent developments of genetic tools for manipulating the tuberculosis bacillus make possible the construction of mutants in specific genes. In other intracellular pathogen microorganisms such as Salmonella it has been described that the phoP gene is involved in the virulence. Inactivation of this gene has permitted the construction of attenuated mutants, which have been studied as vaccines against Salmonellosis in humans. Our preliminary results (University of Zaragoza) in strains of the M. tuberculosis complex isolated from humans have indicated that possibly the most virulent strains have an alteration of the gene annotated in the M. tuberculosis genome as phoP. The gene was inactivated in clinical isolation for the purpose of studying the involvement of phoP in M. tuberculosis virulence and its multiplication ability and persistence in macrophage and mouse. |
3,4-Dihydroisoquinolin-1-one derivatives as inducers of apoptosis |
The present invention related to certain 3,4-dihydroisoquinolin-1-ones that are activators of caspases and inducers of apoptosis, pharmaceutical composition comprising these compounds, and method of treating cancer utilizing these compounds. |
1. A compound of Formula I: wherein: R1 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, or -alkylene-CONR8R9 where R8 is hydrogen, alkyl or alkoxyalkyl, and R9 is alkyl, optionally substituted aryl, optionally substituted aralkyl, alkoxyalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, heterocycloalkylalkyl, or saturated or unsaturated heterocycloaminoalkyl, or R8 and R9 together with the nitrogen atom to which they are attached form heterocycloamino; R2 is hydrogen or alkyl; R3 is alkyl, alkoxy, hydroxy, haloalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, substituted carboxyalkyl, guanidino, heterocycloamino, aminoalkyl, substituted aminoalkyl, heterocycloaminoalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, aralkenyl, aryloxyalkyl, heteroaryloxyalkyl, -[(alkylene)-O]m-(alkylene)-NH2 (where m is 1, 2, or 3), heterocycloalkylalkyl, —C(O)R12 where R12 is optionally substituted heteroaryl, or -(alkylene)-NR10R10 where R10 and R11 are independently selected from hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or R10 and R11 together with the nitrogen atom to which they are attached form saturated or unsaturated heterocycloamino; R3′ is hydrogen or alkyl, or R3′ together with R3 and the nitrogen to which they are attached form heteroaryl or heterocycloamino; R4 and R5 are independently of each other hydrogen, alkyl, halo, trifluoromethylthio, haloalkoxy, or haloalkyl; and R6 and R7 are independently of each other hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, or acylamino; or a pharmaceutically acceptable salt thereof; provided that: a) when R1 is methyl, R2, R3′, R4, R5, R6 and R7 are hydrogen, then R3 is not —CH2CO2CH3; b) when R1 is phenyl and R2, R4, R5, R6, and R7 are hydrogen, then R3 and R3′ together with the nitrogen to which they are attached do not form pyrrolidinyl, piperidinyl, or morpholin-4-yl; c) when R1 is -alkylene-CONR8R9 and R2 and R8 are hydrogen, then R3′ is hydrogen and R3 is aryloxyalkyl or substituted heterocycloalkyl (provided that substituted heterocycloamino is not substituted with alkoxyalkyl, alkyl, or hydroxyalkyl); or R3 and R3′ together with the nitrogen to which they are attached form substituted heterocycloamino (provided that the heterocycloamino is not substituted with hydroxy, hydroxyalkyl, or alkyl); or R9 is optionally substituted phenylalkyl. 2. The compound of claim 1 wherein R1 is hydrogen or alkyl. 3. The compound of claim 1 wherein R1 is -alkylene-CONR8R9, where R8 and R9 together with the nitrogen atom to which they are attached form heterocycloamino. 4. The compound of claim 3 wherein R1 is 2-(piperidin-1-ylcarbonyl)ethyl, 2-(4-hydroxypiperidin-1-ylcarbonyl)ethyl, 2-(morpholin-4-ylcarbonyl)ethyl, 2-(4-acetylpiperazin-1-ylcarbonyl)ethyl, 2-(4-methylpiperidin-1-ylcarbonyl)ethyl, 2-(thiomorpholin-4-ylcarbonyl)ethyl, or 2-(4-formylpiperazin-1-ylcarbonyl)ethyl. 5. The compound of claim 2 wherein R4 and R5 are trifluoromethyl and are located at the 3- and 5-position of the phenyl ring; and R6 and R7 are hydrogen. 6. The compound of claim 3 wherein R4 and R5 are trifluoromethyl and are located at the 3- and 5-position of the phenyl ring; and R6 and R7 are hydrogen. 7. The compound of claim 5 wherein R2 is hydrogen; R3 is alkyl, alkoxy, hydroxy, haloalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, substituted carboxyalkyl, guanidino, heterocycloamino, aminoalkyl, substituted aminoalkyl, heterocycloaminoalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, aralkenyl, aryloxyalkyl, heteroaryloxyalkyl, -[(alkylene)-O]m-(alkylene)-NH2 (where m is 1, 2, or 3), heterocycloalkylalkyl, —C(O)R12 where R12 is optionally substituted heteroaryl, or -(alkylene)-NR10R11 where R10 and R11 are independently selected from hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or R10 and R11 together with the nitrogen atom to which they are attached form saturated or unsaturated heterocycloamino; and R3′ is hydrogen or alkyl; or R3′ together with R3 and the nitrogen to which they are attached form heteroaryl or heterocycloamino. 8. The compound of claim 5 wherein R2 is methyl; R3 is alkyl, alkoxy, hydroxy, haloalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, substituted carboxyalkyl, guanidino, heterocycloamino, aminoalkyl, substituted aminoalkyl, heterocycloaminoalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arallyl, optionally substituted heteroaralkyl, aralkenyl, aryloxyalkyl, heteroaryloxyalkyl, -[(alkylene)-O]m-(alkylene)-NH2 (where m is 1, 2, or 3), heterocycloalkylalkyl, —C(O)R12 where R12 is optionally substituted heteroaryl, or -(alkylene)-NR10R11 where R10 and R11 are independently selected from hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or R10 and R11 together with the nitrogen atom to which they are attached form saturated or unsaturated heterocycloamino; and R3′ is hydrogen or alkyl; or R3′ together with R3 and the nitrogen to which they are attached form heteroaryl or heterocycloamino. 9. The compound of claim 6 wherein R2 is hydrogen; R3 is alkyl, alkoxy, hydroxy, haloalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, substituted carboxyalkyl, guanidino, heterocycloamino, aminoalkyl, substituted aminoalkyl, heterocycloaminoalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, aralkenyl, aryloxyalkyl, heteroaryloxyalkyl, -[(alkylene)-O]m-(alkylene)-NH2 (where m is 1, 2, or 3), heterocycloalkylalkyl, —C(O)R12 where R12 is optionally substituted heteroaryl, or -(alkylene)-NR10R11 where R10 and R11 are independently selected from hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or R10 and R11 together with the nitrogen atom to which they are attached form saturated or unsaturated heterocycloamino; and R3′ is hydrogen or alkyl; or R3′ together with R3 and the nitrogen to which they are attached form heteroaryl or heterocycloamino. 10. The compound of claim 7 wherein R3 is 2-hydroxypyrid-6-yl, 2-chloropyrid-3-yl, 2-thio-[1,3,4]-thiadiazol-2-yl, 5,8-diphenyl-[1,2,4]triazocin-3-yl, 6-ethoxy-benzothiazol-2-yl, 6-fluoro-benzothiazol-2-yl, 3,5-dimethylisoxazol-4-yl, 5-methylisoxazol-3-ylmethyl, pyrimidin-2-yl, 3-methylpyrid-2-yl, 4-methylpyrid-2-yl, 5-methylpyrid-2-yl, 6-methylpyrid-2-yl, 4,6-dimethylpyrid-2-yl, 3-methylpyrid-4-yl, 2-methylpyrid-4-yl, 1,3-dimethylpyrazol-5-yl, 5-methylpyrazol-3-yl, 4-methylpyrimidin-2-yl, 4,6-dimethylpyrimidin-2-yl, 2,4-dimethylpyrimidin-6-yl, pyrazin-2-yl, pyrid-4-yl, pyrid-2-yl, pyrid-3-yl, pyrazol-3-yl, furan-2-ylmethyl, furan-2-ylcarbonyl, 5,6-dimethyl-[1,2,4]-triazin-3-yl, pyrimidin-4-yl, [1,3,4]-thiadiazol-2-yl, thiazol-2-yl, isoxazol-3-yl, cyclopentyl, 1H-pyrimidin-2,4-dione-5-yl, 2-methoxyethyl, cyclobutyl, cyclopropylmethyl, 3-hydroxyprop-2-yl, cyclohexylmethyl, pyrid-2-ylmethyl, pyrid-3-ylmethyl, pyrid-4-ylmethyl, pyrid-4-ylethyl, imidazol-4-ylethyl, thiophen-2-ylmethyl, cyclopentylmethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-hydroxyethyl, 2-ethoxyethyl, 5-methylfuran-2-ylmethyl, cyclopropyl, cyclohexyl, 3-methoxypropyl, 1-hydroxy-4-methylpent-2-yl, 1-(furan-2-yl)ethyl, 5-(dimethylaminomethyl)furan-2-ylmethyl, 5-bromofuran-2-ylmethyl, 5-chlorofuran-2-methyl, 1,3-dihydroxyprop-2-yl, 1,3-dihydroxy-2-methylprop-2-yl, 3-hydroxy-2-methylprop-2-yl, 3-methoxyprop-2-yl, 1-tert-butyl-2-hydroxyethyl, 1-hydroxy-3-methylpent-2-yl, 1,3-dihydroxy-2-hydroxymethylprop-2-yl, 1,3-dihydroxybut-2-yl, 1,2-dimethylpyrrol-5-ylmethyl, 1-methylpyrrol-2-ylmethyl, imidazol-1-ylpropyl, furan-3-ylmethyl, 2,5-dimethylfuran-3-ylmethyl, 3-(methoxycarbonyl)furan-2-ylmethyl, 6-hydroxyhexyl, N-benzylpiperidin-4-yl, N-benzylpyrrolidin-3-yl, 2-phenyloxyethyl, benzyl, morpholin-4-yl, 2-(morpholin-4-yl)ethyl, 4,5-dihydrothiazol-2-yl, piperidin-4-yl, piperidin-4-ylmethyl, 2-methylpropyl, tert-butyl, methyl, tetrahydrofuran-2-ylmethyl, hydroxy, methoxy, ethyl, propyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, 2-methylthioethyl, —(CH2)2O(CH2)2O(CH2)2NH2, 1-carboxy-3-methylbut-1-yl, 2-carboxyethyl, 3-aminocarbonyl-1-carboxypropyl, 1-carboxy-2-methylbutyl, carboxymethyl, 1-carboxy-2-methylpropyl, 2-phenyl-1-carboxyethyl, 2,3-dimethoxyphenylmethyl, 3,5-dimethoxyphenylmethyl, 3,4-difluorophenylmethyl, 2,4-difluorophenylmethyl, 4-fluorophenylmethyl, 3-difluoromethoxyphenylmethyl, 2,6-dimethoxyphenylmethyl, 2-(methylsulfinyl)ethyl, 2-(methylsulfonyl)ethyl, 2-hydroxyphenyl, 4-chloro-2-hydroxyphenyl, 2-amino-4-oxo-3H-pyrimidin-6-yl, 2-cyanophenyl, 5-amino-1-carboxypentyl, 5-amino-1-aminocarbonylpentyl, 2-(4-methoxyphenyl)ethyl, or guanidino; and R3′ is hydrogen or methyl. 11. The compound of claim 8 wherein R3 is 2-hydroxypyrid-6-yl, 2-chloropyrid-3-yl, 2-thio-[1,3,4]-thiadiazol-2-yl, 5,8-diphenyl-[1,2,4]triazocin-3-yl, 6-ethoxy-benzothiazol-2-yl, 6-fluoro-benzothiazol-2-yl, 3,5-dimethylisoxazol-4-yl, 5-methylisoxazol-3-ylmethyl, pyrimidin-2-yl, 3-methylpyrid-2-yl, 4-methylpyrid-2-yl, 5-methylpyrid-2-yl, 6-methylpyrid-2-yl, 4,6-dimethylpyrid-2-yl, 3-methylpyrid-4-yl, 2-methylpyrid-4-yl, 1,3-dimethylpyrazol-5-yl, 5-methylpyrazol-3-yl, 4-methylpyrimidin-2-yl, 4,6-dimethylpyrimidin-2-yl, 2,4-dimethylpyrimidin-6-yl, pyrazin-2-yl, pyrid-4-yl, pyrid-2-yl, pyrid-3-yl, pyrazol-3-yl, furan-2-ylmethyl, furan-2-ylcarbonyl, 5,6-dimethyl-[1,2,4]-triazin-3-yl, pyrimidin-4-yl, [1,3,4]-thiadiazol-2-yl, thiazol-2-yl, isoxazol-3-yl, cyclopentyl, 1H-pyrimidin-2,4-dione-5-yl, 2-methoxyethyl, cyclobutyl, cyclopropylmethyl, 3-hydroxyprop-2-yl, cyclohexylmethyl, pyrid-2-ylmethyl, pyrid-3-ylmethyl, pyrid-4-ylmethyl, pyrid-4-ylethyl, imidazol-4-ylethyl, thiophen-2-ylmethyl, cyclopentylmethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-hydroxyethyl, 2-ethoxyethyl, 5-methylfuran-2-ylmethyl, cyclopropyl, cyclohexyl, 3-methoxypropyl, 1-hydroxy-4-methylpent-2-yl, 1-(furan-2-yl)ethyl, 5-(dimethylaminomethyl)furan-2-ylmethyl, 5-bromofuran-2-ylmethyl, 5-chlorofuran-2-methyl, 1,3-dihydroxyprop-2-yl, 1,3-dihydroxy-2-methylprop-2-yl, 3-hydroxy-2-methylprop-2-yl, 3-methoxyprop-2-yl, 1-tert-butyl-2-hydroxyethyl, 1-hydroxy-3-methylpent-2-yl, 1,3-dihydroxy-2-hydroxymethylprop-2-yl, 1,3-dihydroxybut-2-yl, 1,2-dimethylpyrrol-5-ylmethyl, 1-methylpyrrol-2-ylmethyl, imidazol-1-ylpropyl, furan-3-ylmethyl, 2,5-dimethylfuran-3-ylmethyl, 3-(methoxycarbonyl)furan-2-ylmethyl, 6-hydroxyhexyl, N-benzylpiperidin-4-yl, N-benzylpyrrolidin-3-yl, 2-phenyloxyethyl, benzyl, morpholin-4-yl, 2-(morpholin-4-yl)ethyl, 4,5-dihydrothiazol-2-yl, piperidin-4-yl, piperidin-4-ylmethyl, 2-methylpropyl, tert-butyl, methyl, tetrahydrofuran-2-ylmethyl, hydroxy, methoxy, ethyl, propyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, 2-methylthioethyl, —(CH2)2O(CH2)2O(CH2)2NH2, 1-carboxy-3-methylbut-1-yl, 2-carboxyethyl, 3-aminocarbonyl-1-carboxypropyl, 1-carboxy-2-methylbutyl, carboxymethyl, 1-carboxy-2-methylpropyl, 2-phenyl-1-carboxyethyl, 2,3-dimethoxyphenylmethyl, 3,5-dimethoxyphenylmethyl, 3,4-difluorophenylmethyl, 2,4-difluorophenylmethyl, 4-fluorophenylmethyl, 3-difluoromethoxyphenylmethyl, 2,6-dimethoxyphenylmethyl, 2-(methylsulfinyl)ethyl, 2-(methylsulfonyl)ethyl, 2-hydroxyphenyl, 4-chloro-2-hydroxyphenyl, 2-amino-4-oxo-3H-pyrimidin-6-yl, 2-cyanophenyl, 5-amino-1-carboxypentyl, 5-amino-1-aminocarbonylpentyl, 2-(4-methoxyphenyl)ethyl, or guanidino; and R3′ is hydrogen or methyl. 12. The compound of claim 9 wherein R3 is 2-hydroxypyrid-6-yl, 2-chloropyrid-3-yl, 2-thio-[1,3,4]-thiadiazol-2-yl, 5,8-diphenyl-[1,2,4]triazocin-3-yl, 6-ethoxy-benzothiazol-2-yl, 6-fluoro-benzothiazol-2-yl, 3,5-dimethylisoxazol-4-yl, 5-methylisoxazol-3-ylmethyl, pyrimidin-2-yl, 3-methylpyrid-2-yl, 4-methylpyrid-2-yl, 5-methylpyrid-2-yl, 6-methylpyrid-2-yl, 4,6-dimethylpyrid-2-yl, 3-methylpyrid-4-yl, 2-methylpyrid-4-yl, 1,3-dimethylpyrazol-5-yl, 5-methylpyrazol-3-yl, 4-methylpyrimidin-2-yl, 4,6-dimethylpyrimidin-2-yl, 2,4-dimethylpyrimidin-6-yl, pyrazin-2-yl, pyrid-4-yl, pyrid-2-yl, pyrid-3-yl, pyrazol-3-yl, furan-2-ylmethyl, furan-2-ylcarbonyl, 5,6-dimethyl-[1,2,4]-triazin-3-yl, pyrimidin-4-yl, [1,3,4]-thiadiazol-2-yl, thiazol-2-yl, isoxazol-3-yl, cyclopentyl, 1H-pyrimidin-2,4-dione-5-yl, 2-methoxyethyl, cyclobutyl, cyclopropylmethyl, 3-hydroxyprop-2-yl, cyclohexylmethyl, pyrid-2-ylmethyl, pyrid-3-ylmethyl, pyrid-4-ylmethyl, pyrid-4-ylethyl, imidazol-4-ylethyl, thiophen-2-ylmethyl, cyclopentylmethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-hydroxyethyl, 2-ethoxyethyl, 5-methylfuran-2-ylmethyl, cyclopropyl, cyclohexyl, 3-methoxypropyl, 1-hydroxy-4-methylpent-2-yl, 1-(furan-2-yl)ethyl, 5-(dimethylaminomethyl)furan-2-ylmethyl, 5-bromofuran-2-ylmethyl, 5-chlorofuran-2-methyl, 1,3-dihydroxyprop-2-yl, 1,3-dihydroxy-2-methylprop-2-yl, 3-hydroxy-2-methylprop-2-yl, 3-methoxyprop-2-yl, 1-tert-butyl-2-hydroxyethyl, 1-hydroxy-3-methylpent-2-yl, 1,3-dihydroxy-2-hydroxymethylprop-2-yl, 1,3-dihydroxybut-2-yl, 1,2-dimethylpyrrol-5-ylmethyl, 1-methylpyrrol-2-ylmethyl, imidazol-1-ylpropyl, furan-3-ylmethyl, 2,5-dimethylfuran-3-ylmethyl, 3-(methoxycarbonyl)furan-2-ylmethyl, 6-hydroxyhexyl, N-benzylpiperidin-4-yl, N-benzylpyrrolidin-3-yl, 2-phenyloxyethyl, benzyl, morpholin-4-yl, 2-(morpholin-4-yl)ethyl, 4,5-dihydrothiazol-2-yl, piperidin-4-yl, piperidin-4-ylmethyl, 2-methylpropyl, tert-butyl, methyl, tetrahydrofuran-2-ylmethyl, hydroxy, methoxy, ethyl, propyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, 2-methylthioethyl, —(CH2)2O(CH2)2O(CH2)2NH2, 1-carboxy-3-methylbut-1-yl, 2-carboxyethyl, 3-aminocarbonyl-1-carboxypropyl, 1-carboxy-2-methylbutyl, carboxymethyl, 1-carboxy-2-methylpropyl, 2-phenyl-1-carboxyethyl, 2,3-dimethoxyphenylmethyl, 3,5-dimethoxyphenylmethyl, 3,4-difluorophenylmethyl, 2,4-difluorophenylmethyl, 4-fluorophenylmethyl, 3-difluoromethoxyphenylmethyl, 2,6-dimethoxyphenylmethyl, 2-(methylsulfinyl)ethyl, 2-(methylsulfonyl)ethyl, 2-hydroxyphenyl, 4-chloro-2-hydroxyphenyl, 2-amino-4-oxo-3H-pyrimidin-6-yl, 2-cyanophenyl, 5-amino-1-carboxypentyl, 5-amino-1-aminocarbonylpentyl, 2-(4-methoxyphenyl)ethyl, or guanidino; and R3′ is hydrogen or methyl. 13. The compound of claim 1 wherein R3 is 2-hydroxypyrid-6-yl, 2-chloropyrid-3-yl, 2-thio-[1,3,4]-thiadiazol-2-yl, 5,8-diphenyl-[1,2,4]triazocin-3-yl, 6-ethoxy-benzothiazol-2-yl, 6-fluoro-benzothiazol-2-yl, 3,5-dimethylisoxazol-4-yl, 5-methylisoxazol-3-ylmethyl, pyrimidin-2-yl, 3-methylpyrid-2-yl, 4-methylpyrid-2-yl, 5-methylpyrid-2-yl, 6-methylpyrid-2-yl, 4,6-dimethylpyrid-2-yl, 3-methylpyrid-4-yl, 2-methylpyrid-4-yl, 1,3-dimethylpyrazol-5-yl, 5-methylpyrazol-3-yl, 4-methylpyrimidin-2-yl, 4,6-dimethylpyrimidin-2-yl, 2,4-dimethylpyrimidin-6-yl, pyrazin-2-yl, pyrid-4-yl, pyrid-2-yl, pyrid-3-yl, pyrazol-3-yl, furan-2-ylmethyl, furan-2-ylcarbonyl, 5,6-dimethyl-[1,2,4]-triazin-3-yl, pyrimidin-4-yl, [1,3,4]-thiadiazol-2-yl, thiazol-2-yl, isoxazol-3-yl, cyclopentyl, 1H-pyrimidin-2,4-dione-5-yl, 2-methoxyethyl, cyclobutyl, cyclopropylmethyl, 3-hydroxyprop-2-yl, cyclohexylmethyl, pyrid-2-ylmethyl, pyrid-3-ylmethyl, pyrid-4-ylmethyl, pyrid-4-ylethyl, imidazol-4-ylethyl, thiophen-2-ylmethyl, cyclopentylmethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-hydroxyethyl, 2-ethoxyethyl, 5-methylfuran-2-ylmethyl, cyclopropyl, cyclohexyl, 3-methoxypropyl, 1-hydroxy-4-methylpent-2-yl, 1-(furan-2-yl)ethyl, 5-(dimethylaminomethyl)furan-2-ylmethyl, 5-bromofuran-2-ylmethyl, 5-chlorofuran-2-methyl, 1,3-dihydroxyprop-2-yl, 1,3-dihydroxy-2-methylprop-2-yl, 3-hydroxy-2-methylprop-2-yl, 3-methoxyprop-2-yl, 1-tert-butyl-2-hydroxyethyl, 1-hydroxy-3-methylpent-2-yl, 1,3-dihydroxy-2-hydroxymethylprop-2-yl, 1,3-dihydroxybut-2-yl, 1,2-dimethylpyrrol-5-ylmethyl, 1-methylpyrrol-2-ylmethyl, imidazol-1-ylpropyl, furan-3-ylmethyl, 2,5-dimethylfuran-3-ylmethyl, 3-(methoxycarbonyl)furan-2-ylmethyl, 6-hydroxyhexyl, N-benzylpiperidin-4-yl, N-benzylpyrrolidin-3-yl, 2-phenyloxyethyl, benzyl, morpholin-4-yl, 2-(morpholin-4-yl)ethyl, 4,5-dihydrothiazol-2-yl, piperidin-4-yl, piperidin-4-ylmethyl, 2-methylpropyl, tert-butyl, methyl, tetrahydrofuran-2-ylmethyl, hydroxy, methoxy, ethyl, propyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, 2-methylthioethyl, —(CH2)2O(CH2)2O(CH2)2NH2, 1-carboxy-3-methylbut-1-yl, 2-carboxyethyl, 3-aminocarbonyl-1-carboxypropyl, 1-carboxy-2-methylbutyl, carboxymethyl, 1-carboxy-2-methylpropyl, 2-phenyl-1-carboxyethyl, 2,3-dimethoxyphenylmethyl, 3,5-dimethoxyphenylmethyl, 3,4-difluorophenylmethyl, 2,4-difluorophenylmethyl, 4-fluorophenylmethyl, 3-difluoromethoxyphenylmethyl, 2,6-dimethoxyphenylmethyl, 2-(methylsulfinyl)ethyl, 2-(methylsulfonyl)ethyl, 2-hydroxyphenyl, 4-chloro-2-hydroxyphenyl, 2-amino-4-oxo-3H-pyrimidin-6-yl, 2-cyanophenyl, 5-amino-1-carboxypentyl, 5-amino-1-aminocarbonylpentyl, 2-(4-methoxyphenyl)ethyl, or guanidino; and R3′ is hydrogen or methyl. 14. The compound of claims 5 wherein R3′ is hydrogen. 15. The compound of claims 6 wherein R3′ is hydrogen. 16. A compound of Formula I wherein: R4 and R5 are trifluoromethyl and are located at the 3- and 5-position of the phenyl ring; R6 and R7 are hydrogen; R1 is hydrogen, alkyl, or -alkylene-CONR8R9 where R8 and R9 together with the nitrogen atom to which they are attached form heterocycloamino; R2 is hydrogen or alkyl; and R3′ is hydrogen. 17. The compound of claim 16 wherein R3 is optionally substituted heteroaryl, optionally substituted heteroaralkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, —C(O)R12 where R12 is optionally substituted heteroaryl or heterocycloalkyl. 18. The compound of claim 17 wherein R3 is furan-2-ylcarbonyl, furan-2-ylmethyl, cyclohexylmethyl, pyrid-2-ylmethyl, pyrid-3-ylmethyl, pyrid-4-ylmethyl, pyrid-4-ylethyl, imidazol-4-ylethyl, thiophen-2-ylmethyl, cyclopentylmethyl, 2-hydroxypropyl, 3-hydroxyprop-2-yl, hydroxypropyl, 2,3-dihydroxypropyl, hydroxyethyl, ethoxyethyl, 5-methylfuran-2-ylmethyl, cyclopropyl, cyclohexyl, 3-methoxypropyl, 1-hydroxy-4-methylpent-2-yl, 1-(furan-2-yl)ethyl, 5-(dimethylaminomethyl)furan-2-ylmethyl, 5-bromofuran-2-ylmethyl, 5-chlorofuran-2-methyl, 1,3-dihydroxyprop-2-yl, 1,3-dihydroxy-2-methylprop-2-yl, 3-hydroxy-2-methylprop-2-yl, 3-methoxyprop-2-yl, 1-tert-butyl-2-hydroxyethyl, 1-hydroxy-3-methylpent-2-yl, 1,3-dihydroxy-2-hydroxymethylprop-2-yl, 1,3-dihydroxybut-2-yl, 1,2-dimethylpyrrol-5-ylmethyl, 1-methylpyrrol-2-ylmethyl, imidazol-1-ylpropyl, furan-3-ylmethyl, 2,5-dimethylfuran-3-ylmethyl, 3-methoxycarbonylfuran-2-ylmethyl, 6-hydroxyhexyl, cyclopentyl, 1H-pyrimidin-2,4-dione-5-yl, 2-methoxyethyl, cyclobutyl, cyclopropylmethyl, furan-2-ylmethyl, or 3-hydroxyprop-2-yl. 19. A compound selected from the group consisting of: 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-2,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-methoxyethyl)-aminocarbonyl]-2-[2-(piperidin-1-ylcarbonyl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-methoxyethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopentyl)-aminocarbonyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(1H-pyrimidin-2,4-dione-5-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-{([1,3,4]-thiadiazol-2-yl)-aminocarbonyl}-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-methoxyethyl)-aminocarbonyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(3-hydroxyprop-2-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(1-hydroxy-3,3-dimethyl-2-butyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-2-[2-(4-hydroxypiperidin-1-yl-carbonyl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopropylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(thiophen-2-ylmethyl)-aminocarbonyl]-2,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-ethoxyethyl)-aminocarbonyl)-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trfluoromethylphenyl)-4-[(2-fluoroethyl)-aminocarbonyl]-2-methyl-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-methoxyethyl)-aminocarbonyl]-2,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-methylthioethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(3-hydroxypropyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclobutyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(n-propyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(1-furan-2-ylethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(5-methylfuran-2-yl-methyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopropylmethyl)-aminocarbonyl]-2,3-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-hydroxyethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopropyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(tetrahydrofuran-2-ylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(5-methylfuran-2-yl-methyl)-aminocarbonyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(thiazol-2-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(pyridin-2-ylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-2-yl-methyl)-aminocarbonyl]-2-(2-piperidin-1-ylcarbonylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopentyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopropylmethyl)-aminocarbonyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-2-(cyclopropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(thiazol-2-yl)-aminocarbonyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopentyl)-aminocarbonyl]-2-[2-(4-hydroxypiperidin-1-yl-carbonyl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(benzyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(benzyl)-aminocarbonyl]-2-(2-dimethylaminocarbonylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopentyl)-aminocarbonyl]-2-(2-dimethylaminocarbonylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-3-ylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(pyridin-3-ylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopentyl)-aminocarbonyl]-2-cyclopropyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-methoxyethyl)-aminocarbonyl]-2-cyclopropyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-chloro-pyridin-3-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(4,5-dihydrothiazol-2-yl)-aminocarbonyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopropylmethyl)-aminocarbonyl]-2-[2-(4-hydroxypiperidin-1-ylcarbonyl)-ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(4,5-dihydrothiazol-2-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-methoxyethyl)-aminocarbonyl]-2-(2-dimethylaminocarbonylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(benzyl)-aminocarbonyl]-2-[2-(morpholin-4-ylcarbonyl)-ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(benzyl)-aminocarbonyl]-2-[2-(4-hydroxypiperidin-1-yl-carbonyl)-ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopentyl)-aminocarbonyl]-2-[2-(4-acetylpiperazin-1-yl-carbonyl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopentyl)-aminocarbonyl]-2-(2-morpholin-4-ylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(benzyl)-aminocarbonyl]-2-{(CH2)2C(O){N(CH3)—[(CH2)2OCH3]}}-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-2-(2-propyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopropylmethyl)-aminocarbonyl]-2-(2-dimethylaminocarbonylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-2-(2-dimethylaminocarbonylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(benzyl)-aminocarbonyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopentyl)-aminocarbonyl]-2-(2-piperidin-1-ylcarbonylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopentyl)-aminocarbonyl]-2-(2-propyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(pyridin-4-ylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopentyl)-aminocarbonyl]-2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopentylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(benzyl)-aminocarbonyl]-2-{(CH2)2C(O){N(CH3)—[(CH2)3CH3]}}-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-methoxyethyl)-aminocarbonyl]-2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-2-(morpholin-4-ylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(benzyl)-aminocarbonyl]-2-{(CH2)2CO{N(CH3)(benzyl)}}-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(benzyl)-aminocarbonyl]-2-{(CH2)2CO{N(CH3)[2-(3,4-dimethyoxyphenyl)ethyl]}}-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-imidazol-4-ylethyl)-aminocarbonyl]-2-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopropylmethyl)-aminocarbonyl]-2-[2-(4-acetylpiperazin-1-yl-carbonyl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-methoxyethyl)-aminocarbonyl]-2-(furan-2-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-methoxyethyl)-aminocarbonyl]-2-[2-(4-acetylpiperazin-1-yl-carbonyl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-3-ylmethyl)-aminocarbonyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(morpholin-4-yl)-aminocarbonyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-methoxyethyl)-aminocarbonyl]-2-(2-morpholin-4-ylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-hydroxypyridin-6-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-pyridin-4-ylethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(benzyl)-aminocarbonyl]-2-[2-(4-formylpiperazin-1-yl-carbonyl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-morpholin-4-ylethyl)-aminocarbonyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-methoxyethyl)-aminocarbonyl]-2-(2-propyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopentyl)-aminocarbonyl]-2-(furan-2-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(piperidin-4-ylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(5-dimethylaminofuran-2-ylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(5-bromofuran-2-y-methyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(hydroxy)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(isoxazol-3-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(1-carboxy-2-methyl-1-butyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(isoxazol-3-yl)-aminocarbonyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2,4-dimethylpyrid-6-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(pyrazol-3-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(4-methylpyrimidin-2-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(4,6-dimethylpyrimidin-2-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2,4-dimethylpyrimidin-6-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(pyrazin-2-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(pyridin-4-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(pyridin-2-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(pyridin-3-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(5,6-dimethyl-[1,2,4]triazin-3-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(5,6-dimethyl-[1,2,4]triazin-3-yl)-aminocarbonyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(pyrimidin-4-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-2-ylcarbonyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-methylpyrid-4-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-methylpyrid-6-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(3-methylpyrid-4-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(3-methylpyrid-6-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(4-methylpyrid-2-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(pyrimidin-2-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-{[2-(4-methoxyphenyl)ethyl]-aminocarbonyl}-2-(ethoxycarbonylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(N-benzylpiperidin-4-yl)-aminocarbonyl]-2-(aminocarbonylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(N-benzylpyrrolidin-3-yl)-aminocarbonyl]-2-(aminocarbonylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-phenoxyethyl)-aminocarbonyl]-2-(aminocarbonylethyl)-1oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(benzyl)-aminocarbonyl]-2-{[2-(3-methoxyphenyl)ethyl]aminocarbonylethyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(benzyl)-aminocarbonyl]-2-(tetrahydrofuran-2-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(benzyl)-aminocarbonyl]-2-[(4-methylpiperidin-1-yl)carbonylethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(benzyl)-aminocarbonyl]-2-(thiomorpholin-4-ylcarbonylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-methoxyethyl)-aminocarbonyl]-2-[2-(3-methoxyphenyl)ethylaminocarbonylethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-2-(4-acetylpiperazin-1-ylcarbonylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclohexylmethyl)-aminocarbonyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-methoxyethyl)-aminocarbonyl]-2-(4-methoxyphenylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopropylmethyl)-aminocarbonyl]-2-(4-methoxyphenylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2,3-dihydroxypropyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(methoxy)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopentyl)-aminocarbonyl]-2-(methoxycarbonylpentyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-aminoethyloxyethyloxyethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-carboxy-3-methylbutyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-{[2-hydroxy-1,1-(dihydroxymethyl)ethyl]-aminocarbonyl}-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(3-aminocarbonyl-1-carboxypropyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(1-carboxy-2-phenylethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(N-methylpyrrol-2-ylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(1,2-dimethylpyrrol-5-ylmethyl)-aminocarbonyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2,3-dimethoxyphenylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2,4-difluorophenylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-{[3-(difluoromethoxy)phenylmethyl]-aminocarbonyl}-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(imidazol-1-ylpropyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-{[2-(methylsulfinyl)ethyl]-aminocarbonyl}-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(methylsulfonylethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-amino-4-oxo-3H-pyrimidin-6-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(4-chloro-2-hydroxyphenyl)-aminocarbonyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-cyanophenyl)-aminocarbonyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(3-methoxycarbonylfuran-2-ylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-{(5-mercapto-[1,3,4]-thiadiazol-2-yl)-aminocarbonyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(5-amino-1-carboxypentyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(5-amino-1-aminocarbonylpentyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(5,8-diphenyl-[1,2,4]triazocin-3-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(6-ethoxybenzothiazol-2-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(guanidino)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(3,5-dimethylisoxazol-4-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(piperidin-4-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(1,3-pyrazol-5-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3-trifluoromethylthiophenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3-trifluoromethylthiophenyl)-4-[(2-methoxyethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3-trifluoromethylthiophenyl)-4-[(cyclopentyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-dimethylphenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-dimethylphenyl)-4-[(cyclopentyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-dimethylphenyl)-4-[(cyclopropylmethyl)-aminocarbonyl]-2-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-dichlorophenyl)-4-[(2-methoxyethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3-trifluoromethylphenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3-trifluoromethylphenyl)-4-[(cyclopentyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3-trifluoromethylphenyl)-4-[(2-methoxyethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3-trifluoromethoxyphenyl)-4-[(2-methoxyethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3-trifluoromethoxyphenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3-trifluoromethoxyphenyl)-4-[(thiazol-2-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(2,4-bis-trifluoromethylphenyl)-4-[(thiazol-2-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(2,4-bis-trifluoromethylphenyl)-4-[(thiophen-2-ylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-dibromophenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-phenyl-4-[(2,4-dimethylpyrid-6-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-phenyl-4-[(pyrazol-3-yl)-aminocarbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-phenyl-4-[(2-methoxyethyl)-aminocarbonyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-7-methoxy-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(pyridin-2-ylmethyl)-aminocarbonyl]-2,7-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-2,7-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(thiazol-2-ylmethyl)-aminocarbonyl]-2,7-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-6,7-dimethoxy-2-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-methoxyethyl)-aminocarbonyl]-2,7-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(2-methoxyethyl)-aminocarbonyl]-7-methoxy-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopropylmethyl)-aminocarbonyl]-2,6-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-6,7-dimethoxy-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(thiazol-2-yl)-aminocarbonyl]-6,7-dimethoxy-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopropylmethyl)-aminocarbonyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(pyrid-4-ylmethyl)-aminocarbonyl]-7-methoxy-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(piperidin-4-ylmethyl)-aminocarbonyl]-7-methoxy-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(furan-2-ylmethyl)-aminocarbonyl]-2,6-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(4,5-dihydro-thiazol-2-yl)-aminocarbonyl]-2,6-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopropylmethyl)-aminocarbonyl]-6-chloro-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(cyclopentyl)-aminocarbonyl]-7-chloro-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(5-methylfuran-2-ylmethyl)-aminocarbonyl]-7-chloro-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(3,5-dimethylmorpholin-4-yl)-carbonyl]-2-(aminocarbonylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(4-acetylpiperazin-1-yl)-carbonyl]-2-(aminocarbonylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(4-acetylpiperazin-1-yl)-carbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(4-acetylpiperazin-1-yl)-carbonyl]-2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-[(piperazin-1-yl)-carbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trfluoromethylphenyl)-4-[(morpholin-4-yl)-carbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-6,7-dimethoxy-4-[(piperazin-1-yl)-carbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-6,7-dimethoxy-4-[(morpholin-4-yl)-carbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-{[N-methyl-N-(2-pyrid-4-ylethyl)]-aminocarbonyl}-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; 3-(3,5-bis-trifluoromethylphenyl)-4-{[N-methyl-N-(furan-2-ylmethyl)]-aminocarbonyl}-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; or 3-(3,5-bis-trifluoromethylphenyl)-4-[(3-aminopyrazol-1-yl)-carbonyl]-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline; or a pharmaceutically acceptable salt thereof. 20. A method of treating a disorder responsive to the induction of apoptosis in an animal suffering said disorder, comprising administering to said animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient. 21. The method of claim 20 wherein the disease is a cancer, autoimmune disease, rheumatoid arthritis, inflammatory bowel disease, or psoriasis. 22. The method of claim 21 wherein the disease is a cancer and is selected from the group consisting of Hodgkin's disease, non-Hodgkin's lymphoma, acute and chronic lymphocytic leukemias, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, chronic lymphocytic leukemia, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, head and neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer and prostatic carcinoma, and the animal is a human. 23. A method of treating cancer in an animal which method comprises administering to said animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient in combination with radiation therapy and optionally in combination with one or more chemotherapeutic compound(s) independently selected from an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic agent, another antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, or an angiogenesis inhibitor. 24. The method of claim 23 wherein the chemotherapeutic compound(s) is independently selected from Taxol®, Taxotere®, epothilone A, epothilone B, desoxyepothilone A, desoxyepothilone B or their derivatives); epidophyllotoxin; procarbazine; mitoxantrone; the mitomycins, discodermolide, podophyllotoxins. doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, porfiromycin, Herceptin®, Rituxan®, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, colchicines, etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel, estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-1 1, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins. 25. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The present invention relates to certain 3,4-dihydroisoquinolin-1-one derivatives that are activators of caspases and inducers of apoptosis, pharmaceutical composition comprising these compounds, and method of treating cancer utilizing these compounds. Methods of preparing these compounds are also disclosed. 2. State of the Art Organisms eliminate unwanted cells by a process variously known as regulated cell death, programmed cell death or apoptosis. Such cell death occurs as a normal aspect of animal development as well as in tissue homeostasis and aging (Glucksmann, A., Biol. Rev. Cambridge Philos. Soc. 1951, 26, 59-86; Glucksmann, A., Archives de Biologie 1965, 76, 419437; Ellis, et al., Dev. 1991, 112, 591-603; Vaux, et al. Cell 1994, 76, 777-779). Apoptosis regulates cell number, facilitates morphogenesis, removes harmful or otherwise abnormal cells and eliminates cells that have already performed their function. Additionally, apoptosis occurs in response to various physiological stresses, such as hypoxia or ischemia (The General Hospital Corporation. Programmed Cell Death Genes and Proteins. PCT published application WO96/20721, Jan. 4, 1996). There are a number of morphological changes shared by cells experiencing regulated cell death, including plasma and nuclear membrane blebbing, cell shrinkage (condensation of nucleoplasm and cytoplasm), organelle relocalization and compaction, chromatin condensation and production of apoptotic bodies (membrane enclosed particles containing intracellular material) (Orrenius, S., J. Internal Medicine 1995, 237, 529-536. Apoptosis is achieved through an endogenous mechanism of cellular suicide (Wyllie, A. H. In Cell Death in Biology and Pathology; Bowen and Lockshin, Eds.; Chapman and Hall, 1991; pp. 9-34). A cell activates its internally encoded suicide program as a result of either internal or external signals. The suicide program is executed through the activation of a carefully regulated genetic program (Wyllie, et al., Int Rev. Cyt. 1980, 68, 251; Ellis, et al., Ann Rev. Cell Bio. 1991, 7, 663). Apoptotic cells and bodies are usually recognized and cleared by neighboring cells or macrophages before lysis. Because of this clearance mechanism, inflammation is not induced despite the clearance of great numbers of cells (Orrenius, S., J. Internal Medicine 1995, 237, 529-536). A group of proteases is a key element in apoptosis (see, e.g., Thorneberry, Chemistry and Biology 1998, 5, R97-R103; Thornberry, British Med. Bull. 1996, 53, 478-490). Genetic studies in the nematode Caenorhabditis elegans revealed that apoptotic cell death involves at least fourteen genes, two of which are the pro-apoptotic (death-promoting) ced (for cell death abnormal) genes, ced-3 and ced-4. CED-3 is homologous to interleukin 1 beta-converting enzyme, a cysteine protease, which is now called caspase-1. Further extensive research revealed that the mammalian apoptosis system appears to involve a cascade of caspases, or a system that behaves like a cascade of caspases. At present, the caspase family of cysteine proteases comprises fourteen different members, and more may be discovered in the future. All known caspases are synthesized as zymogens that require cleavage at an aspartyl residue prior to forming the active enzyme. Thus, caspases are capable of activating other caspases in the manner of an amplifying cascade. Apoptosis and caspases are thought to be crucial in the development of cancer ( Apoptosis and Cancer Chemotherapy; Hickman and Dive, Eds.; Humana Press: 1999). There is mounting evidence that cancer cells, while containing caspases, lack parts of the molecular machinery that activate the caspase cascade. This makes the cancer cells lose their capacity to undergo cellular suicide and the cells become immortal, i.e., they become cancerous. Control points are known to exist in the apoptosis process that represent points for intervention leading to activation. These control points include the CED-9-BCL-like and CED-3-ICE-like gene family products, which are intrinsic proteins regulating the fate of a cell to survive or die, respectively, and executing part of the cell death process itself (see, Schmitt, et al., Biochem. Cell. Biol. 1997, 75, 301-314). BCL-like proteins include BCL-XL and BAX-alpha, which appear to function upstream of caspase activation. BCL-XL appears to prevent activation of the apoptotic protease cascade, whereas BAX-alpha accelerates activation of the apoptotic protease cascade. Chemotherapeutic (anti-cancer) drugs can trigger cancer cells to undergo suicide by activation of the dormant caspase cascade. This may be a crucial aspect of the mode of action of most, if not all, known anticancer drugs (Los, et al., Blood 1997, 90, 3118-3129; Friesen, et al., Nat. Med. 1996, 2, 574). The mechanism of action of current antineoplastic drugs frequently involves an attack at specific phases of the cell cycle. The cell cycle refers to the stages through which cells normally progress during their lifetimes. Normally, cells exist in a resting phase termed G 0 During multiplication, cells progress to a stage in which DNA synthesis occurs, termed S. Later, cell division, or mitosis, occurs in a phase called M. Antineoplastic drugs such as cytosine arabinoside, hydroxyurea, 6-mercaptopurine, and methotrexate are S phase specific, whereas antineoplastic drugs such as vincristine, vinblastine, and paclitaxel are M phase specific. Many slow growing tumors, for example colon cancers, exist primarily in the G 0 phase, whereas rapidly proliferating normal tissues, for example bone marrow, exist primarily in the S or M phase. Thus, the possibility exists for the activation of the caspase cascade, although the exact mechanisms for doing so presently are not clear. Furthermore, insufficient activity of the caspase cascade and consequent apoptotic events are implicated in various types of cancer. The development of caspase cascade activators and inducers of apoptosis is a highly desirable goal in the development of therapeutically effective antineoplastic agents. Moreover, since autoimmune disease and certain degenerative diseases also involve the proliferation of abnormal cells, therapeutic treatment for these diseases could be effected by enhancement of the apoptotic process through the administration of appropriate caspase cascade activators and inducers of apoptosis. |
<SOH> SUMMARY OF THE INVENTION <EOH>In one aspect, this invention is directed to a compound of Formula I: wherein: R 1 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, or -alkylene-CONR 8 R 9 where R 8 is hydrogen, alkyl or alkoxyalkyl, and R 9 is alkyl, optionally substituted aryl, optionally substituted aralkyl, alkoxyalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, heterocycloalkylalkyl, or saturated or unsaturated heterocycloaminoalkyl, or R 8 and R 9 together with the nitrogen atom to which they are attached form heterocycloamino; R 2 is hydrogen or alkyl; R 3 is alkyl, alkoxy, hydroxy, haloalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, substituted carboxyalkyl, guanidino, heterocycloamino, aminoalkyl, substituted aminoalkyl, heterocycloaminoalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, aralkenyl, aryloxyalkyl, heteroaryloxyalkyl, -[(alkylene)-O] m -(alkylene)-NH 2 (where m is 1, 2, or 3), heterocycloalkylalkyl, —C(O)R 12 where R12 is optionally substituted heteroaryl, or -(alkylene)-NR 10 R 11 where R 10 and R 11 are independently selected from hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or R 10 and R 11 together with the nitrogen atom to which they are attached form saturated or unsaturated heterocycloamino; R 3′ is hydrogen or alkyl, or R 3 ′ together with R 3 and the nitrogen to which they are attached form heteroaryl or heterocycloamino; R 4 and R 5 are independently of each other hydrogen, alkyl, halo, trifluoromethylthio, haloalkoxy, or haloalkyl; and R 6 and R 7 are independently of each other hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, or acylamino; or a pharmaceutically acceptable salt thereof; provided that: a) when R 1 is methyl, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are hydrogen, then R3 is not —CH 2 CO 2 CH 3 ; b) when R 1 is phenyl and R 2 , R 4 , R 5 , R 6 , and R 7 are hydrogen, then R 3 and R 3′ together with the nitrogen to which they are attached do not form pyrrolidinyl, piperidinyl, or morpholin-4-yl; c) when R 1 is -alkylene-CONR 8 R 9 and R 2 and R 5 are hydrogen, then R 3′ is hydrogen and R 3 is aryloxyalkyl or substituted heterocycloalkyl (provided that substituted heterocycloamino is not substituted with alkoxyalkyl, alkyl, or hydroxyalkyl); or R 3 and R 3′ together with the nitrogen to which they are attached form substituted heterocycloamino (provided that the heterocycloamino is not substituted with hydroxy, hydroxyalkyl, or alkyl); or R 9 is optionally substituted phenylalkyl. Preferably a compound of Formula I, as represented by Ia: wherein: R 1 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, alkoxy, alkoxyalkyl, hydroxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, or -alkylene-CONR 8 R 9 where R 8 is alkyl or alkoxyalkyl, and R 9 is alkyl, optionally substituted aryl, optionally substituted aralkyl, alkoxyalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, heterocycloalkylalkyl, or saturated or unsaturated heterocycloaminoalkyl, or R 8 and R 9 together with the nitrogen atom to which they are attached form heterocycloamino; R 2 is hydrogen or alkyl; R 3 is hydrogen, alkyl, alkoxy, hydroxy, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, alkylsulfonylalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, aralkenyl, aryloxyalkyl, heteroaryloxyalkyl, or heterocycloalkylalkyl, or -alkylene)-NR 10 R 11 where R 10 and R 11 are independently selected from hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or R 10 and R 11 together with the nitrogen atom to which they are attached form saturated or unsaturated heterocycloamino; R 4 is hydrogen, alkyl, halo, trifluoromethylthio, or haloalkyl; R 5 is alkyl, halo, trifluoromethylthio, or haloalkyl; R 6 and R 7 are independently of each other hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, or acylamino; or a pharmaceutically acceptable salt thereof; provided that: a) when R 1 is methyl, R 2 , R 3′ , R 4 , R 5 , R 6 and R 7 are hydrogen, then R 3 is not —CH 2 CO 2 CH 3 ; and b) when R 1 is phenyl and R 2 , R 4 , R 5 , R 6 , and R 7 are hydrogen, then R 3 and R 3′ together with the nitrogen to which they are attached do not form pyrrolidinyl, piperidinyl, or morpholin-4-yl. In a second aspect, this invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or Ia and a pharmaceutically acceptable excipient. In a third aspect, this invention is directed to a method of treating a disorder responsive to the induction of apoptosis in an animal suffering said disorder, comprising administering to said animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Preferably, the disorder is a cancer, autoimmune disease, rheumatoid arthritis, inflammatory bowel disease, or psoriasis. Preferably, the cancer is selected from the group consisting of Hodgkin's disease, non-Hodgkin's lymphoma, acute and chronic lymphocytic leukemias, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, chronic lymphocytic leukemia, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, head and neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer and prostatic carcinoma, and the animal is a human. In a fourth aspect, this invention is directed to a method of treating cancer in an animal which method comprises administering to said animal a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula J or Ia and a pharmaceutically acceptable excipient in combination with radiation therapy and optionally in combination with one or more chemotherapeutic compound(s) independently selected from an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic agent, another antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, or an angiogenesis inhibitor. Preferably, the chemotherapeutic compound(s) is independently selected from Taxol®, Taxotere®, epothilone A, epothilone B, desoxyepothilone A, desoxyepothilone B or their derivatives; epidophyllotoxin; procarbazine; mitoxantrone; the mitomycins, discodermolide, podophyllotoxins, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexate, mitomycin C, porfiromycin, Herceptin®, Rituxan®, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, colchicines, etoposide, etoposide phosphate, teniposide, melphalan, vinblastine, vincristine, vinorelbein, leurosidine, vindesine, leurosine, paclitaxel, estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons, interleukins, capecitabine, and gefitinib. In a fifth aspect, this invention is directed to a process of preparing a compound of Formula I comprising: (a) reacting a compound of formula I where R 1 and R 4 -R 7 are as defined in the Summary of the Invention with an amine of the formula R 3 R 3′ NH where R 3 and R 3′ are as defined in the Summary of the Invention; (b) optionally converting the compound obtained in step (a) above, to an acid addition salt; (c) optionally converting a salt form of the compound obtained in step (a) above, to a free base; (d) optionally separating individual isomers; and (e) optionally modifying any of the R 1 and R 4 -R 7 groups. detailed-description description="Detailed Description" end="lead"? |
Cyclopentanone derivative |
A novel cyclopentanone derivative having a cyclopentanone or cyclopentanol ring having substituents at the 2- and 5-positions is provided. The cyclopentanone derivative preferably has 13 to 17 carbon atoms. A perfume composition comprising the cyclopentanone derivative emits a flora fragrance emphasizing a natural and fresh feeling. It is useful for perfuming a variety of toiletries and households. A process for preparing the above-mentioned cyclopentanone derivative is also provided by which the cyclopentanone derivative can be obtained in a practically acceptable yield. |
1. A cyclopentanone derivative represented by the following general formula (1): wherein R1 represents an alkyl group having 4 to 7 carbon atoms, an alkylidene group having 4 to 7 carbon atoms a cyclohexyl group or a cyclohexylidene group, R2 represents an alkyl group having 4 to 7 carbon atoms, an alkylidene group having 4 to 7 carbon atoms, a cyclopentyl group, a cyclopentylidene group, a cyclohexyl group or a cyclohexylidene group, R3 and R4 independently represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and −Y represents —OH or ═O. 2. A cyclopentanone derivative represented by the following general formula (2): wherein R5 represents an alkyl group having 4 or 5 carbon atoms or an alkylidene group having 4 or 5 carbon atoms, R6 represents an alkyl group having 4 or 5 carbon atoms, an alkylidene group having 4 or 5 carbon atoms, a cyclopentyl group or a cyclopentylidene group, and R3, R4 and —Y are the same as defined above. 3. A cyclopentanone derivative represented by the following general formula (3): wherein R7 represents an alkyl group having 5 carbon atoms, or an alkylidene group having 5 carbon atoms, R8 represents an alkyl group having 5 carbon atoms, an alkylidene group having 5 carbon atoms, a cyclopentyl group, or a cyclopentylidene group, and R3, R4 and —Y are the same as defined above. 4. The cyclopentanone derivative according to any one of claims 1 to 3, which has 13 to 17 carbon atoms in total. 5. The cyclopentanone derivative according to any one of claims 1 to 4, wherein both of R3 and R4 are hydrogen atoms. 6. A perfume composition comprising at least one cyclopentanone derivative selected from those which are described in claims 1 to 5. 7. A perfume composition comprising 0.1 to 90% by weight of a cyclopentanone derivative selected from those which are described in claims 1 to 5. 8. A process for preparing a cyclopentanone derivative represented by the following general formula (6): wherein R1, R3 and R4 are the same as defined above, and R11 represents an alkylidene group having 4 to 7 carbon atoms, a cyclopentylidene group or a cyclohexylidene group, characterized in that a cyclopentanone derivative represented by the following general formula (4): wherein R1, R3 and R4 are the same as defined above, is reacted under alkaline conditions with a ketone or aldehyde represented by the following general formula (5): wherein R9 and R10 represents a hydrogen atom, or an alkyl group having 1 to 6 carbon atoms; the alkyl groups for R9 and R10 may be bonded together to form a ring; and the total number of carbon atoms in the sum of the alkyl groups for R9 and R10 is in the range of 3 to 6. 9. A process for preparing a cyclopentanone derivative represented by the following general formula (7): wherein R3 and R4 are the same as defined above, R12 represents an alkyl group having 4 to 7 carbon atoms or a cyclohexyl group, and R13 represents an alkyl group having 4 to 7 carbon atoms, a cyclopentyl group or a cyclohexyl group, characterized in that a cyclopentanone derivative represented by the above-mentioned general formula (6) is reduced with hydrogen. 10. A process for preparing a cyclopentanone derivative represented by the following general formula (8): wherein R3, R4, R12 and R13 are the same as defined above, characterized in that a cyclopentanone derivative represented by the above-mentioned general formula (7) is reduced with hydrogen. 11. A process for preparing a cyclopentanone derivative represented by the above-mentioned general formula (a), characterized in that a cyclopentanone derivative represented by the following general formula (9): wherein R3 and R4 are the same as defined above, R14 represents an alkyl group having 4 to 7 carbon atoms, an alkylidene group having 4 to 7 carbon atoms, a cyclohexyl group or a cyclohexylidene group, R15 represents an alkyl group having 4 to 7 carbon atoms, an alkylidene group having 4 to 7 carbon atoms, a cyclopentyl group, a cyclopentylidene group, a cyclohexyl group or a cyclohexylidene group, and at least one of R14 and R15 is the alkylidene group, a cyclohexylidene group or a cyclopentylidene group, is reduced with hydrogen. |
<SOH> BACKGROUND ART <EOH>It is known that cyclopentanone derivatives include those which are useful as a perfume. As specific examples of the cyclopentanone derivatives used as a perfume, there can be mentioned methyl 2-(cis-2-pentenyl)-3-oxocyclopent-3-yl-acetate (trivial name: methyl jasmonate) and methyl 2-n-pentenyl-3-oxocyclopent-3-yl-acetate (trivial name: methyl dihydrojasmonate), which are known as a perfume emitting a jasmin-like floral scent; and 2-cyclopentyl cyclopentylorotonate which is known as a perfume emitting a fruity and juicy scent. A cyclopentanone derivative represented by the following general formula (A): wherein R L represents an alkyl group having 4 to 6 carbon atoms, and a fragrance-emitting or flavor-giving preparation comprising the cyclopentanone derivative have been proposed in Japanese Unexamined Patent Publication No. S52-139046. It is described in this publication that this cyclopentanone derivative emits a fruity and fresh apricot-like fragrance, User's or consumer's fancy for fragrance-emitting preparations and products varies depending upon the particular age and sex distinction. The kinds of such products and the purposes of use thereof are being rapidly expanded, and therefore, various fragrance-emitting or modifying ingredients giving products emitting fragrant scents, which are delicately different in primary tone, depth, amplitude and volume, are desired. A perfume ingredient is a kind of physiologically active substance. It is known that modification of its chemical structure delicately influences and occasionally greatly changes the fragrance of the ingredient, perceived by a human being. Therefore it is important for developing a novel perfume compound to synthesize analogues and derivatives of a known perfume compound and assess the fragrance thereof. |
Method of removing acid component in deteriorated acetate film |
There is provided a method of removing acids from the surface and interior of an acetate film produced by deterioration during storage. Such methods are characterized by extracting and removing the acids from the surface and interior of the acetate film, and the extraction treatment includes solvent extraction or evacuation (heating). This method suppresses the deterioration process in the storage of the acetate film. |
1. A method of removing acids from a deteriorated acetate film, the method comprising removing the acids by extraction from the surface and interior of the deteriorated acetate film. 2. The method of removing acids from a deteriorated acetate film according to claim 1, wherein the acids are removed by solvent extraction treatment. 3. The method of removing acids from a deteriorated acetate film according to claim 2, wherein the solvent is supercritical carbon dioxide. 4. The method of removing acids from a deteriorated acetate film according to claim 2 or 3, further comprising evaporating and removing any remaining acids by reducing pressure and/or heating after the solvent extraction treatment. 5. The method of removing acids from a deteriorated acetate film according to claim 2 or 3, wherein the deteriorated acetate film is wound on a reel. 6. The method of removing acids from a deteriorated acetate film according to claim 5, wherein the reel is made of metal. 7. The method of removing acids from a deteriorated acetate film according to claim 2 or 3, wherein the acids are removed so that the acidity is less than 0.5. 8. The method of removing acids from a deteriorated acetate film according to claim 1, wherein the acids are evaporated and removed by reducing pressure and/or heating. 9. The method of removing acids from a deteriorated acetate film according to claim 8, wherein the acids are removed so that the acidity is less than 0.5. 10. The method of removing acids from a deteriorated acetate film according to claim 8 or 9, wherein the deteriorated acetate film is wound on a reel. 11. The method of removing acids from a deteriorated acetate film according to claim 10, wherein the reel is made of metal. 12. A method of suppressing the deterioration of a developed acetate film due to acid, the method comprising removing acids from the surface and interior of the developed acetate film. |
<SOH> BACKGROUND ART <EOH>Cellulose acetate films (which may be referred to as “acetate film” or “cellulose acetate film”) are widely used as a film base for information storage due to their stability and long-term storage capacity (e.g., N. S. Allen et al, J. Photogr. Sci. 36, 194-198, 1988). However, recently, there has been a problem in that, depending on the way the film is stored, the deterioration progresses more seriously than expected. As one of the reasons for this deterioration process, the presence of free (released) acids (especially acetic acid) resulting from decomposition of the film base has been mentioned. In particular, it was found that when these free acids exceeded a specific value (threshold value), the deterioration was accelerated rapidly. This phenomenon is referred to as “vinegar syndrome”, and is thought to be a kind of autocatalyzed hydrolysis reaction by acid. Although methods have been proposed to solve this deterioration problem by washing the film with water or an alkaline solution and drying, or neutralizing with ammonia gas, deterioration was not sufficiently suppressed, and the qualities of the film were spoiled, which was problematic. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 shows TG curves for a deteriorated film prior to treatment, and after 2 hours treatment at 100° C. detailed-description description="Detailed Description" end="lead"? |
Braking system for trailers of utility vehicles |
The brakes of the front axle of the trailer of a utility vehicle are impinged upon with a brake pressure by way of a single, common ABS valve. Said ABS valve is electrically actuated by an EBS module associated with the rear wheel brakes depending on a differential slip between the front axle and the rear axle. |
1. Braking system for a utility vehicle trailer having a steerable front axle, the system comprising: front axle brake cylinders, rear axle brake cylinders, and rotational wheel speed sensors; an ABS valve assigned jointly to both front axle brake cylinders for controlling brake pressure into the front axle brake cylinders; an EBS module assigned to the rear axle brake cylinders for controlling brake pressure into the rear axle brake cylinders; an electric control output of the EBS module coupled with an electric control input of the ABS valve; wherein the rotational wheel speed sensors are connected to the EBS module for determining a differential slip (Δs) between the steerable front axle and a rear axle of the trailer; and wherein the EBS module controls the ABS valve as a function of the determined differential slip (Δs). 2. Braking system according to claim 1, wherein for controlling the ABS valve, the EBS module determines a desired front axle brake pressure (pVA) as a function of a control pressure defined by a driver, the control pressure being defined by the driver by way of a pneumatic control line, or a momentarily controlled-in rear axle brake pressure (pVA) and a momentary differential slip (ΔVA). 3. Braking system according to claim 1, wherein the ABS valve or the desired front axle brake pressure (pVA) are controlled such that the same slip occurs at the front axle and at the rear axle or that the differential slip (Δs) is held in a defined permissible value range. 4. Braking system according to claim 1, wherein the differential slip (Δs) is determined from a mean front axle speed (vVA) and a front axle reference speed (vVA,Ref), according to the formula: Δ s = v VA - v VA , Ref v VA , Ref = v VA v VA , Ref - 1 5. Braking system according to claim 4, wherein the front axle reference speed (vVA,Ref) is determined from a mean rear axle speed (vHA), a speed difference of the rear wheels (ΔvHA) and a wheel base-track ratio (Φ) of the trailer vehicle according to the formula: vVA,Ref={square root}{square root over (vHA2+ΔvHA·φ)2)} 6. Braking system according to claim 5, wherein the wheel base-track ratio (Φ) of the trailer is determined from the mean front axle speed (vVA), the mean rear axle speed (vHA), and the speed difference of the rear wheels (ΔvHA) according to the formula: ϕ = v VA 2 - v HA 2 Δ v HA 7. Braking system according to claim 6, wherein an initial value of Ø=2.5 is defined for the wheel base-track ratio (Φ) of the trailer. 8. Braking system according to claim 1, wherein the ABS valve has a control input coupled with a pneumatic control line, and further wherein, in the case of a disturbance of the EBS module, the ABS valve controls a brake pressure defined by the driver by way of the pneumatic control line into the front axle brake cylinders. 9. Braking system according to claim 1, wherein in the case of a disturbance of one or more of the rotational wheel speed sensors, the ABS valve is controlled such that the front axle brake pressure (pVA) is identical with the rear axle brake pressure (pVA) controlled in by the EBS module. 10. Braking system according to claim 2, wherein the ABS valve or the desired front axle brake pressure (pVA) are controlled such that the same slip occurs at the front axle and at the rear axle or that the differential slip (Δs) is held in a defined permissible value range. 11. Braking system according to claim 2, wherein the differential slip (Δs) is determined from a mean front axle speed (vVA) and a front axle reference speed (vVA,Ref), according to the formula: Δ s = v VA - v VA , Ref v VA , Ref = v VA v VA , Ref - 1 12. Braking system according to claim 3, wherein the differential slip (Δs) is determined from a mean front axle speed (vVA) and a front axle reference speed (vVA,Ref), according to the formula: Δ s = v VA - v VA , Ref v VA , Ref = v VA v VA , Ref - 1 13. Braking system according to claim 11, wherein the front axle reference speed (vVA,Ref) is determined from a mean rear axle speed (vHA), a speed difference of the rear wheels (ΔvHA) and a wheel base-track ratio (Φ) of the trailer vehicle according to the formula: vVA,Ref={square root}{square root over (vHA2+ΔvHA·φ)2)} 14. Braking system according to claim 12, wherein the front axle reference speed (vVA,Ref) is determined from a mean rear axle speed (vHA), a speed difference of the rear wheels (ΔvHA) and a wheel base-track ratio (Φ) of the trailer vehicle according to the formula: vVA,Ref={square root}{square root over (vHA2+ΔvHA·φ)2)} 15. Braking system according to claim 13, wherein the wheel base-track ratio (Φ) of the trailer is determined from the mean front axle speed (vVA), the mean rear axle speed (vHA), and the speed difference of the rear wheels (ΔvHA) according to the formula: ϕ = v VA 2 - v HA 2 Δ v HA 16. Braking system according to claim 14, wherein the wheel base-track ratio (Φ) of the trailer is determined from the mean front axle speed (vVA), the mean rear axle speed (vHA), and the speed difference of the rear wheels (ΔvHA) according to the formula: ϕ = v VA 2 - v HA 2 Δ v HA 17. Braking system according to claim 15, wherein an initial value of Ø=2.5 is defined for the wheel base-track ratio (Φ) of the trailer. 18. Braking system according to claim 16, wherein an initial value of Ø=2.5 is defined for the wheel base-track ratio (Φ) of the trailer. 19. Braking system according to claim 2, wherein the ABS valve has a control input coupled with a pneumatic control line, and further wherein, in the case of a disturbance of the EBS module, the ABS valve controls a brake pressure defined by the driver by way of the pneumatic control line into the front axle brake cylinders. 20. Braking system according to claim 2, wherein in the case of a disturbance of one or more of the rotational wheel speed sensors, the ABS valve is controlled such that the front axle brake pressure (pVA) is identical with the rear axle brake pressure (pVA) controlled in by the EBS module. 21. A braking control system for a utility vehicle trailer having a steerable front axle, a rear axle, front axle brake cylinders, rear axle brake cylinders, and rotational wheel speed sensors, the braking control system comprising: an ABS valve adapted to control brake pressures into the front axle brake cylinders; an EBS module having an electric control output, the EBS module adapted to control brake pressures into the rear axle brake cylinders, the electrical control output being coupled with an electric control input of the ABS valve; wherein the EBS module receives wheel speed sensor signals in order to determine a differential slip between the steerable front axle and the rear axle, the EBS module controlling the ABS valve as a function of the determined differential slip. 22. A braking system for a utility vehicle trailer having a steerable front axle, the braking system comprising: a single joint ABS valve assigned to both front axle brake cylinders; and an EBS module coupled to control the ABS valve, the EBS module being assigned to both rear axle brake cylinders and controlling the ABS valve as a function of a differential slip value between the front and rear axles. 23. The braking control system according to claim 22, wherein the EBS module controls the ABS valve electrically. 24. The braking control system according to claim 23, wherein the ABS valve controls the front axle brake pressures based on rotational wheel speed signals and the differential slip value thrived from the wheel speed signals. 25. The braking control system according to claim 23, wherein the ABS valve controls the front axle brake pressures such that a slip occurring during a braking of the front wheels and the rear wheels is identical or a difference between a slip signal of the front axle and the rear axle is within a defined range. 26. A braking method for a utility vehicle trailer having a steerable front axle, the braking method comprising the acts of: controlling brake pressures into front axle brake cylinders via a single joint ABS valve; controlling brake pressures into rear axle brake cylinders via an EBS module, said EBS module being electrically coupled with the ABS valve; determining a differential slip value between the steerable front axle and a rear axle via the EBS module; and controlling the ABS valve via the EBS module as a function of the determined differential slip value. 27. Braking method according to claim 26, wherein for controlling the ABS valve, the EBS module determines a desired front axle brake pressure (pVA) as a function of a control pressure defined by a driver, the control pressure being defined by the driver by way of a pneumatic control line, or a momentarily controlled-in rear axle brake pressure (pVA) and a momentary differential slip (ΔVA). 28. Braking method according to claim 26, wherein the ABS valve or the desired front axle brake pressure (pVA) are controlled such that the same slip occurs at the front axle and at the rear axle or that the differential slip (Δs) is held in a defined permissible value range. 29. Braking method according to claim 26, wherein the differential slip (Δs) is determined from a mean front axle speed (vVA) and a front axle reference speed (vVA,Ref), according to the formula: Δ s = v VA - v VA , Ref v VA , Ref = v VA v VA , Ref - 1 30. Braking method according to claim 26, wherein the front axle reference speed (vVA,Ref) is determined from a mean rear axle speed (vHA), a speed difference of the rear wheels (ΔvHA) and a wheel base-track ratio (Φ) of the trailer vehicle according to the formula: vVA,Ref={square root}{square root over (vHA2+ΔvHA·φ)2)} 31. Braking method according to claim 26, wherein the wheel base-track ratio (Φ) of the trailer is determined from the mean front axle speed (vVA), the mean rear axle speed (vHA), and the speed difference of the rear wheels (ΔvHA) according to the formula: ϕ = v VA 2 - v HA 2 Δ v HA 32. Braking method according to claim 26, wherein an initial value of Ø=2.5 is defined for the wheel base-track ratio (Φ) of the trailer. |
<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>The present invention relates to a braking system for trailers of utility vehicles which have a steerable front axle, including front axle brake cylinders, rear axle brake cylinders, rotational wheel speed sensors and an ABS valve. From German Patent Document DE 38 29 951 C2, a utility vehicle braking system for the load-dependent brake pressure control is known in which a solenoid valve, corresponding to a conventional ABS valve, as well as a rotational wheel speed sensor are assigned to each of the brake cylinders of the four vehicle wheels. The solenoid valves and the rotational wheel speed sensors are connected with a central control unit, which controls the solenoid valves during braking as a function of the axle load distribution. In the case of this system, there is no determination at all of the absolute wheel slips for the axle-load-dependent brake pressure control. On the contrary, for the analysis of the rotational wheel speed signals, the exceeding of a rather rough interaxle “rotational wheel speed difference threshold” is, in each case, used as a criterion for the brake pressure limitation. From German Patent Document DE 44 43 522 A1, a method is known for determining the incline of a road by which, for a powered driving condition and a free-rolling driving condition, in each case, a rotational wheel speed difference of a powered axle and of a non-powered axle is determined and, from these differences, an incline constant is determined. From German Patent Document DE 198 09 546 C1, a method for automatically determining the wheel base of steerable vehicles during cornering is known, in which case the wheel base is determined from a defined wheel track and measured wheel circumference speeds. From the applicant's internal state of the art, an electronic braking system for utility vehicle trailers is known, in which an active pressure control module is, in each case, assigned to the brakes of the front axle and the brakes of the rear axle. These pressure control modules each have three solenoid valves, specifically for ventilating and bleeding, and for a “back-up circuit”, as well as a pressure sensor. The controlling of the pressure control module of the front axle takes place by way of the pressure control module of the rear axle, which leads to high wiring expenditures. Specifically, three control lines and one grounding conductor for the solenoid valves, as well as a sensor line and a grounding conductor for the pressure sensor, are required for this purpose. It is an object of the present invention to provide a braking system for utility vehicle trailers which is cost-effective and requires lower constructional expenditures. This object is achieved by providing a braking system for utility vehicle trailers which have a steerable front axle, including front axle brake cylinders, rear axle brake cylinders, rotational wheel speed sensors and an ABS valve. The ABS valve is assigned jointly to both brake cylinders and is provided for controlling brake pressure into the front axle brake cylinders. An EBS module is assigned to the rear axle brake cylinders for controlling brake pressure into the rear axle brake cylinders. An electric control output of the EPS module is connected with an electric control input of the ABS valve. The rotational wheel speed sensors are connected to the EBS module for determining a differential slip between the front axle and the rear axle. The EBS module controls the ABS valve as a function of the determined differential slip. Advantageous embodiments and further developments of the invention are contained in the subclaims. It is the main principle of the invention to control the brakes of the front axle of the utility vehicle trailer by a single joint ABS valve, which is assigned to the two front axle brakes and which is controlled by an electronic braking system, that is, by an EBS module, primarily assigned to the rear axle brakes, specifically as a function of a so-called “differential slip” between the front axle and the rear axle. More simply stated, the brake pressure control of the rear axle brakes takes place by means of a pressure control module which electrically controls the ABS valve assigned to the two front axle brakes. The ABS relay valve consists only of two solenoid valves for the holding or bleeding of brake pressure. A pressure sensor for the front axle brakes is not required here. A back-up valve is also not provided. Thus, for connecting the pressure control module with the ABS valve, only three connection lines are required. Since, according to the invention, no pressure sensor is provided at the front axle, it is true that the pressure control at the front axle brakes cannot be implemented quite as precisely as by means of a pressure sensor. However, the “absence” of a pressure sensor at the front axle can largely be compensated by a so-called “differential slip control algorithm” because the wheel speeds are measured and wheel slips at the wheels of both axles are determined therefrom, which permits the obtaining of “information” concerning the momentary braking power distribution. The brake pressure control at the front axle therefore takes place as a function of the rotational wheel speed signals supplied by rotational wheel speed sensors and a “differential slip signal” between the front axle and the rear axle derived therefrom. The object of the control consists of controlling the front axle brake pressure such that the slip occurring during a braking at the front wheels and the rear wheels is identical, or that the difference between a “slip signal” of the front axle and of the rear axle is kept in a defined value range. In this manner, an approximately uniform deceleration of both axles or a uniform deceleration ratio is ensured. For this purpose, the front axle brake pressure is modulated correspondingly; that is, the brake pressure defined by way of the pneumatic control line is reduced, as required. The reason is that the brake pressure defined by way of the pneumatic control line corresponds to the brake pressure which can be maximally controlled by way of the ABS valve into the front axle brake cylinders. |
<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>The present invention relates to a braking system for trailers of utility vehicles which have a steerable front axle, including front axle brake cylinders, rear axle brake cylinders, rotational wheel speed sensors and an ABS valve. From German Patent Document DE 38 29 951 C2, a utility vehicle braking system for the load-dependent brake pressure control is known in which a solenoid valve, corresponding to a conventional ABS valve, as well as a rotational wheel speed sensor are assigned to each of the brake cylinders of the four vehicle wheels. The solenoid valves and the rotational wheel speed sensors are connected with a central control unit, which controls the solenoid valves during braking as a function of the axle load distribution. In the case of this system, there is no determination at all of the absolute wheel slips for the axle-load-dependent brake pressure control. On the contrary, for the analysis of the rotational wheel speed signals, the exceeding of a rather rough interaxle “rotational wheel speed difference threshold” is, in each case, used as a criterion for the brake pressure limitation. From German Patent Document DE 44 43 522 A1, a method is known for determining the incline of a road by which, for a powered driving condition and a free-rolling driving condition, in each case, a rotational wheel speed difference of a powered axle and of a non-powered axle is determined and, from these differences, an incline constant is determined. From German Patent Document DE 198 09 546 C1, a method for automatically determining the wheel base of steerable vehicles during cornering is known, in which case the wheel base is determined from a defined wheel track and measured wheel circumference speeds. From the applicant's internal state of the art, an electronic braking system for utility vehicle trailers is known, in which an active pressure control module is, in each case, assigned to the brakes of the front axle and the brakes of the rear axle. These pressure control modules each have three solenoid valves, specifically for ventilating and bleeding, and for a “back-up circuit”, as well as a pressure sensor. The controlling of the pressure control module of the front axle takes place by way of the pressure control module of the rear axle, which leads to high wiring expenditures. Specifically, three control lines and one grounding conductor for the solenoid valves, as well as a sensor line and a grounding conductor for the pressure sensor, are required for this purpose. It is an object of the present invention to provide a braking system for utility vehicle trailers which is cost-effective and requires lower constructional expenditures. This object is achieved by providing a braking system for utility vehicle trailers which have a steerable front axle, including front axle brake cylinders, rear axle brake cylinders, rotational wheel speed sensors and an ABS valve. The ABS valve is assigned jointly to both brake cylinders and is provided for controlling brake pressure into the front axle brake cylinders. An EBS module is assigned to the rear axle brake cylinders for controlling brake pressure into the rear axle brake cylinders. An electric control output of the EPS module is connected with an electric control input of the ABS valve. The rotational wheel speed sensors are connected to the EBS module for determining a differential slip between the front axle and the rear axle. The EBS module controls the ABS valve as a function of the determined differential slip. Advantageous embodiments and further developments of the invention are contained in the subclaims. It is the main principle of the invention to control the brakes of the front axle of the utility vehicle trailer by a single joint ABS valve, which is assigned to the two front axle brakes and which is controlled by an electronic braking system, that is, by an EBS module, primarily assigned to the rear axle brakes, specifically as a function of a so-called “differential slip” between the front axle and the rear axle. More simply stated, the brake pressure control of the rear axle brakes takes place by means of a pressure control module which electrically controls the ABS valve assigned to the two front axle brakes. The ABS relay valve consists only of two solenoid valves for the holding or bleeding of brake pressure. A pressure sensor for the front axle brakes is not required here. A back-up valve is also not provided. Thus, for connecting the pressure control module with the ABS valve, only three connection lines are required. Since, according to the invention, no pressure sensor is provided at the front axle, it is true that the pressure control at the front axle brakes cannot be implemented quite as precisely as by means of a pressure sensor. However, the “absence” of a pressure sensor at the front axle can largely be compensated by a so-called “differential slip control algorithm” because the wheel speeds are measured and wheel slips at the wheels of both axles are determined therefrom, which permits the obtaining of “information” concerning the momentary braking power distribution. The brake pressure control at the front axle therefore takes place as a function of the rotational wheel speed signals supplied by rotational wheel speed sensors and a “differential slip signal” between the front axle and the rear axle derived therefrom. The object of the control consists of controlling the front axle brake pressure such that the slip occurring during a braking at the front wheels and the rear wheels is identical, or that the difference between a “slip signal” of the front axle and of the rear axle is kept in a defined value range. In this manner, an approximately uniform deceleration of both axles or a uniform deceleration ratio is ensured. For this purpose, the front axle brake pressure is modulated correspondingly; that is, the brake pressure defined by way of the pneumatic control line is reduced, as required. The reason is that the brake pressure defined by way of the pneumatic control line corresponds to the brake pressure which can be maximally controlled by way of the ABS valve into the front axle brake cylinders. |
Method of controlling asphaltene precipitation in a fluid |
A method of reducing the aggregation and deposition of asphaltene from a fluid containing asphaltene, such as crude oil, which method comprises the addition to the fluid of a compound of formula (I): wherein A is an optionally substituted ring system containing 6 to 14 carbon atoms; n is at least 1 and may equal the number of positions available for substitution in A; each X is independently a linker group; and each R is independently a hydrocarbyl group containing 10 to 25 carbon atoms. |
1. A method of reducing the aggregation and deposition of asphaltene from a fluid containing asphaltene, such as crude oil, which method comprises the addition to the fluid of a compound of formula (I): wherein A is an optionally substituted ring system containing 6 to 14 carbon atoms; n is at least 1 and may equal the number of positions available for substitution in A; each X is independently a linker group; and each R is independently a hydrocarbyl group containing 10 to 25 carbon atoms. 2. A method of preventing asphaltene precipitation in a fluid containing asphaltene which method comprises the addition of a compound formula (I) to the fluid. 3. A method according to claim 1 wherein the fluid is crude oil. 4. A method of reducing particulate and or soot emission during combustion which method comprises the addition of a compound of formula (I) to a combustible fluid, such as a diesel fuel. 5. A method according to claim 1 wherein A is selected from benzene, naphthalene and anthracene. 6. A method according to claim 5 wherein A is naphthalene. 7. A method according to claim 1 wherein R is C12-18 alkyl chain. 8. A method according to claim 7 wherein R is n-hexadecyl. 9. A method according to claim 1 wherein and X is a C1-4 alkyl ether group, a C1-4 alky thio group, a C1-4 alkyl amino group, an ether, and amine or a thio ether link. 10. A method according to claim 1 wherein A is naphthalene, X is selected from an ether, an amine or a thio ether link, n is 1 and R is a C14-18 alkyl chain. 11. A method according to claim 1 wherein A is naphthalene, X is selected from a C1-4 alkyl ether group, a C1-4 alkyl thio group or a C1-4 alkyl amino group, n is 1 and R is a C12-16 alkyl chain. 12. A method according to claim 1 wherein A is naphthalene, X is selected from a carbonyl group or an ester group, n is 1 and R is a C14-18 alkyl chain. 13. A method according to claim 1 wherein A is naphthalene, X is an ether link, n is 1 and R is n-hexadecyl. 14. A method according to claim 1 wherein A is naphthalene, n is 2, both X's are ether and both R's are different C14-18 alkyl chains. 15. A method according to claim 1 wherein A is naphthalene, n is 2, both X's are ether, and both R's are n-hexadecyl. 16. A method according to claim 1 wherein the compound of formula (I) is a mixture of compounds of formula (I). 17. A compound of formula (I) for use in reducing the aggregation and deposition of asphaltene from a fluid containing asphaltene. 18. A compound of formula (I) wherein A is naphthalene, X is an ether link, n is 1 and R is n-hexadecyl for use in reducing the aggregation and deposition of asphaltene from a fluid containing asphaltene. 19. A solution comprising a compound of formula (I) and a carrier fluid. 20. A solution comprising a mixture of compounds of formula (I) and a carrier fluid. 21. A process for the preparation of a compound of formula (I) which comprises reacting a compound of formula (II): wherein A is an optionally substituted ring system containing 6 to 14 carbon atoms and X′ is a linker group precursor moiety with a compound of formula (III): L—R (III) wherein R is a hydrocarbyl group containing 10 to 25 carbon atoms and L is a leaving group such as a halogen atom or an alkyl or aryl sulphonate. 22. A process for the preparation of compound formula (I) wherein A is naphthalene, X is an ether link, n is 1 and R is n-hexadecyl which comprises reacting naphthol with n-hexadecylchloride in the presence of a base. 23. A method, compound or solution substantially as hereinbefore described with reference to the accompanying Examples. |
Chondroitin synthase |
A vector of the present invention has DNA encoding a protein or a product having the same effect as the protein, the protein containing an amino acid sequence from amino acid numbers 47 to 802 in SEQ. ID. NO:2. Expression of the DNA gives human chondroitin synthase. By using human chondroitin synthase, it is possible to produce a saccharide chain having a repeating disaccharide unit of chondroitin. The DNA or part thereof may be used as a probe for hybridization for the human chondroitin synthase. |
1-15. (canceled) 16. A vector carrying one of DNA (a), (b) or (c), the DNA (b) or (c) encoding a protein having catalytic activities (a) and (i), excluding a DNA encoding a protein at amino-acid position #1 to 802 in SEQ. ID. NO: 2): (a) DNA encoding a protein having an amino acid sequence from amino acid numbers 47 to 802 in SEQ. ID. NO: 2; (b) DNA that, in a stringent condition, hybridizes with the DNA (a), the DNA complementary with DNA (a),.or DNA having part of a nucleotide sequence of the DNA (a) or the DNA complementary with the DNA (a); (c) DNA encoding a protein having an amino acid sequence from amino acid numbers 47 to 802 in SEQ. ID. NO:2, wherein one or several amino acids in the amino acid sequence are substituted, deleted, inserted, or transpositioned; (α) catalytic activity that transferase GalNAc from UDP-GalNAc to chondroitin; (where UDP is uridine 5′diphosphate, and GalNAc is N-acetylgalactosamine residue), and (β) catalytic activity that transferase GlcUA from UDP-GlcUA to chondroitin, (where UDP is uridine 5′diphosphate and GlcUA is N-glucuronic acid residue). 17. The vector as set forth in claim 16, wherein: the DNA (a) encodes finding from nucleotide numbers 633 to 2900 in SEQ. ID. NO: 1. 18. The vector as set forth in claim 16, wherein the proteins are soluble. 19. The vector as set forth in claim 17, wherein the proteins are soluble. 20. The vector as set forth in claim 16, being an expression vector. 21. The vector as set forth in claim 17, being an expression vector. 22. The vector as set forth in claim 18, being an expression vector. 23. The vector as set forth in claim 19, being an expression vector. 24. A transformant whose host is transformed by a vector having any one of DNA (a) to (c), the DNA (b) or (c) encoding a protein having catalytic activities (a) and (f): (a) DNA encoding a protein having an amino acid sequence from amino acid numbers 47 to 802 in SEQ. ID. NO: 2; (b) DNA that, in a stringent condition, hybridizes with the DNA (a), the DNA complementary with DNA (a), or DNA having part of a nucleotide sequence of the DNA (a) or the DNA complementary with the DNA (a); (c) DNA encoding a protein having an amino acid sequence from amino acid numbers 47 to 802 in SEQ. ID. NO:2, wherein one or several amino acids in the amino acid sequence are substituted, deleted, inserted, or transpositioned; (α) catalytic activity that transferase GalNAc from UDP-GalNAc to chondroitin; (where UDP is uridine 5′diphosphate, and GalNAc is N-acetylgalactosamine residue), (β) catalytic activity that transferase from UDP-GlcUA to chondroitin, (where UDP is uridine 5′diphosphate and GlcUA is N-glucuronic acid residue). 25. The transformant as set forth in claim 24, wherein: the DNA (a) encodes finding from nucleotide numbers 633 to 2900 in SEQ. ID. NO: 1. 26. The transformant as set forth in claim 24, wherein: the proteins are soluble. 27. The transformant as set forth in claim 25, wherein: the proteins are soluble. 28. A method for producing chondroitin synthase, the method comprising the steps of: growing a transformant set forth in claim 24; and obtaining the chondroitin synthase from the transformant thus grown. 29. A method for producing chondroitin synthase, the method comprising the steps of: growing a transformant set forth in claim 25; and obtaining the chondroitin synthase from the transformant thus grown. 30. A method for producing chondroitin synthase, the method comprising the steps of: growing a transformant set forth claim 26; and obtaining the chondroitin synthase from the transformant thus grown. 31. A method for producing chondroitin synthase, the method comprising the steps of: growing a transformant set forth claim 27; and obtaining the chondroitin synthase from the transformant thus grown. 32. A reagent for use in chondroitin synthesis, the reagent having an enzyme protein that has an amino acid sequence including an amino acid sequence (A) or (B) and has catalytic activities (α) and (β) (A) amino acid sequence from amino acid numbers 47 to 802 in SEQ. ID. NO: 2; (B) amino acid sequence from amino acid numbers 47 to 802 in SEQ. ID. NO:2, wherein one or several amino acids in the amino acid sequence are substituted, deleted, inserted, or transpositioned. (α) catalytic activity that transferase GalNAc from UDP-GalNAc to chondroitin, (where UDP is uridine 5′diphosphate, and GalNAc is N-acetylgalactosamine residue); (β) catalytic activity that transferase GlcUA from UDP-GlcUA to chondroitin, (where UDP is uridine 5′diphosphate and GlcUA is glucuronic acid residue). 33. The reagent as set forth in claim 32, wherein the enzyme protein is soluble. 34. A method for producing a saccharide chain expressed by Formula (3), the method comprising at least the step of causing a reagent to contact with GalNAc donor and a saccharide chain expressed by Formula (1), the reagent set forth in claim 32: GlcUA-GalNAc-R1 (1), GalNAc-GlcUA-GalNAc-R1 (3), (where GlcUA and GalNAc are as defined above, “-” indicates a glycoside linkage, R1 is an arbitrary group). 35. A method for producing a saccharide chain expressed by Formula (3), the method comprising at least the step of causing a reagent to contact with GalNAc donor and a saccharide chain expressed by Formula (1), the reagent set forth in claim 33: GlcUA-GalNAc-R1 (1), GalNAc-GlcUA-GalNAc-R1 (3), (where GlcUA and GalNAc are as defined above, “-” indicates a glycoside linkage, R1 is an arbitrary group) 36. A method for producing a saccharide chain expressed by Formula (4), the method comprising at least the step of causing a reagent to contact with GlcUA donor and a saccharide chain expressed by Formula (2), the reagent set forth in claim 32: GalNAc-GlcUA-R2 (2), GlcUA-GalNAc-GlcUA-R2 (4), (where GlcUA, GalNAc, and “-” are as defined above, R2 is an arbitrary group). 37. A method for producing a saccharide chain expressed by Formula (4), the method comprising at least the step of causing a reagent to contact with GlcUA donor and a saccharide chain expressed by Formula (2), the reagent set forth in claim 33: GalNAc-GlcUA-R2 (2), GlcUA-GalNAc-GlcUA-R2 (4), (where GlcUA, GalNAc, and “-” are as defined above, R2 is an arbitrary group). 38. A method for producing a saccharide chain selected from saccharide chains expressed by Formulas (5) and (7) respectively, the method comprising at least the step of causing a reagent to contact with GalNAc donor, GlcUA donor and a saccharide chain expressed by Formula (1), the reagent set forth in claim 32: GlcUA-GalNAc-R1 (1), (GlcUA-GalNAc)n-GlcUA-GalNAc-R1 (5), GalNAc-(GlcUA-GalNAc)n-GlcUA-GalNAc-R1 (7), (where n is an integer not less than 1, GlcUA, GalNAc, and “-” are as defined above, R1 is an arbitrary group). 39. A method for producing a saccharide chain selected from saccharide chains expressed by Formulas (5) and (7) respectively, the method comprising at least the step of causing a reagent to contact with GalNAc donor, GlcUA donor and a saccharide chain expressed by Formula (1), the reagent set forth in claim 33: GlcUA-GalNAc-R1 (1), (GlcUA-GalNAc)n-GlcUA-GalNAc-R1 (5), GalNAc-(GlcUA-GalNAc)n-GlcUA-GalNAc-R1 (7), (where n is an integer not less than 1, GlcUA, GalNAc, and “-” are as defined above, R1 is an arbitrary group). 40. A method for producing a saccharide chain selected from saccharide chains expressed by Formulas (6) and (8) respectively, the method comprising at least the step of causing a reagent to contact with GalNAc donor, GlcUA donor and a saccharide chain expressed by Formula (2), the reagent set forth in claim 32: GalNAc-GlcUA-R2 (2), (GalNAc-GlcUA)n-GalNAc-GlcUA-R2 (6), GlcUA-(GalNAc-GlcUA)n-GalNAc-GlcUA-R2 (8), (where n is an integer not less than 1, GlcUA, GalNAc, and “-” are as defined above, R2 is an arbitrary group). 41. A method for producing a saccharide chain selected from saccharide chains expressed by Formulas (6) and (8) respectively, the method comprising at least the step of causing a reagent to contact with GalNAc donor, GlcUA donor and a saccharide chain expressed by Formula (2), the reagent set forth in claim 33: GalNAc-GlcUA-R2 (2), (GalNAc-GlcUA)n-GalNAc-GlcUA-R2 (6), GlcUA-(GalNAc-GlcUA)n-GalNAc-GlcUA-R2 (8), (where n is an integer not less than 1, GlcUA, GalNAc, and “-” are as defined above, R2 is an arbitrary group). 42. A probe for hybridization, the probe containing a nucleotide sequence from nucleotide numbers 495 to 2900 in SEQ. ID. NO: 1, or a sequence complementary with part of the nucleotide sequence. |
<SOH> BACKGROUND ART <EOH>Chondroitin sulfate, which is a kind of glycosaminoglycan (GAG), exists as a proteoglycan on cell surfaces and in an extra cellular matrix. Chondroitin sulfate draws attention because Chondroitin sulfate plays an important role in neural network formation in the developing mammalian brain (Arch. Biochem. Biophys. 374, 24-34 (2000); Trends Glycosci, Glycotechnol. 12, 321-349 (2000)). Chondroitin sulfate has a straight-chained polymer structure having a repeating disaccharide unit having a glucuronic acid residue (GlcUA) and an N-acetylgalactosamine residue (GalNAc). A serine residue in a core protein is covalent-bonded with chondroitin sulfate via 4-saccharide structure (GlcUAβ1-3Galβ1-3Galβ1-4Xylβ1) peculiar thereto (Glycoproteins, ed. Gottschalk, A. (Elsevier Science, New York), pp. 491-517 (1972); The Biochemistry of Glycoproteins and Proteoglycans, ed. Lennarz, W. J. (Plenum, New York), pp. 267-371 (1980)). GAG is biosynthesized by sequentially transferring saccharides from UDP-sugar to a non-reducing end of a saccharide chain. It was found that (a) purification of bovine serum gave a glycosyltransferase that involves in biosynthesis of a repeating disaccharide unit of heparin/heparan sulfate, and (b) cDNA cloning revealed that a single protein of the glycosyltransferase catalyses both transferase reactions of N-acetylglucosamine residue (GlcNAc) and GlcUA. On the other hand, a glycosyltransferase that involved in biosynthesis of the repeating disaccharide unit of chondroitin sulfate has not been cloned yet except the chondroitin synthase derived from a bacterium (J. Biol. Chem. 275, 24124-24129 (2000)). GlcUA transferase II (GlcAT-II) and GalNAc transferase II (GalNAcT-II) have been purified from avian cartilage (J. Biol. Chem. 272, 14399-14403 (1997)) and from bovineserum (Eur. J. Biochem. 264, 461-467 (1999)). However, cDNA cloning of those enzymes has not been performed yet because it is difficult to purify those enzymes to form homogeneity. An object of the present invention is to provide (a) a vector having DNA encoding human chondroitin synthase, (b) a method of producing human chondroitin synthase, (c) a method of producing a saccharide chain having a repeating disaccharide unit of chondroitin, and (d) a probe for hybridization of human chondroitin synthase. |
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