A clutch for a manual or automatic transmission according to the present invention includes an axial fan or turbine disposed on a shaft extending between the clutch and the transmission. Air is supplied to the turbine through one or more radial passageways between the clutch and transmission housings and is provided through an annular passageway around the shaft. Air from the annular passageway is then dispersed generally radially between the clutch plates or disks and other clutch components to absorb and carry away heat generated during clutch operation.

The statements in this section merely provide background information related to the present disclosure and may or may not constitute prior art.
Clutches for motor vehicle powertrains provide a frictional, variable torque transmitting coupling between the vehicle prime mover and the transmission. Because of this function, significant heat may be developed in the clutch plates, especially if the vehicle is driven hard or the clutch is operated partially engaged for any period of time. Such worst case operating scenarios, which much be addressed, typically result in a clutch designs that comprehend larger clutch plates, more numerous clutch plates, a larger flywheel, more robust clutch materials (facings) and other design approaches. Such larger clutch components are not solely driven by higher torque requirements but also by operating temperature and heat dissipation considerations. That is, larger clutch plates and faces, while carrying less torque and therefore generating less heat per square unit of measure than smaller clutches, also have the capability of dissipating more heat, more rapidly than smaller clutches, not only because of their larger size but also the larger size of their housings which, in turn, increases the rate at which heat can be transferred to the ambient.
Increasing the size of a clutch, while thus clearly advantageous from heat generation and dissipation viewpoints, is not an engineering solution without serious consequences. First of all, it clearly adversely affects the weight of the clutch and housing and thus the overall weight of the vehicle. In an age when every ounce of removed vehicle weight is considered a small victory, adding several ounces or pounds to a clutch assembly requires the most sound justification. Second of all, increased clutch and housing size affects not only the size of the overall powertrain but also its packaging. Whereas a smaller clutch and housing will permit enhanced packaging flexibility, a larger clutch may create additional constraints. Last of all, increasing the weight of the rotating powertrain components will have a small but tangible effect on the fuel consumption of the associated vehicle as well as its performance.
From the foregoing, it is apparent that approaches to clutch heat dissipation other than simply increasing the size of the clutch may provide better solutions with fewer compromises. The present invention addresses this problem.

Transmission clutch with improved cooling


A fixing device capable of easily detecting a wrap jam of a recording sheet without increasing costs. A fixing roller fixes a toner image on a recording medium under heating control. A central thermistor and an end thermistor detect first and second temperatures of the fixing roller in respective sheet-passing and non-sheet-passing areas. A first temperature difference-detecting circuit compares a temperature difference between the first and second detected temperatures and a first threshold and outputs a first comparison result. A second temperature difference-detecting circuit compares the temperature difference and a second threshold larger than the first threshold and outputs a second comparison result. A switching circuit selects one of the first or second comparison results according to a switching signal from a CPU, and the CPU controls heating of the fixing roller based on the selected comparison result.

1. Field of the Invention
The present invention relates to a fixing device that is used for fixing an unfixed toner image transferred onto a recording medium to form an image thereon, and an image forming apparatus that uses the fixing device.
2. Description of the Related Art
In general, an image forming apparatus using an electrophotographic process is equipped with a fixing device that heats and fixes an unfixed toner image transferred onto a recording medium (hereinafter also referred to as the "recording sheet"), and there are various types of heat sources used for the fixing device. In recent years, there is a demand for reduction of a warm-up time at the start of an image forming apparatus, and in view of this, there is a tendency to use a heater or the like which performs heating by so-called electromagnetic induction as a heat source.
A fixing device is generally provided with a fixing roller and a pressing roller, and a recording sheet is conveyed into a nip between the fixing roller and the pressing roller, where an unfixed toner image on the recording sheet is heated and fixed onto the recording sheet.
The above-mentioned fixing roller can be heated, and on-off control of the heater is performed based on a temperature detection signal obtained from a temperature sensor, such as a thermistor disposed on a surface of the fixing roller. Then, by the on-off control of the heater, the surface temperature of the fixing roller is controlled such that it becomes a predetermined temperature.
By the way, a recording sheet inevitably curls depending on the amount of toner attached thereto and the water content thereof. Then, due to the amount of curl, which is a degree of curling of a recording sheet, a recording sheet is sometimes wrapped around the fixing roller when fixing an image.
If a printing operation is performed in a state of the fixing roller in which a recording sheet is wrapped therearound, image defectivenesses, such as image roughness and faulty image fixing, may be caused on the image on the recording sheet when the printing operation has been executed, since the surface of the fixing roller is covered with the recording sheet.
Further, in a heater using electromagnetic induction heating, if a Curie material is used for the fixing roller, the surface temperature of the fixing roller is detected on the recording sheet wrapped around the fixing roller. That is, the surface temperature of the fixing roller is detected via the recording sheet, and as a result, the actual surface temperature of the fixing roller becomes higher than the temperature detected by the temperature sensor. Further, the surface temperature of the fixing roller sometimes becomes higher than the Curie temperature.
At this time, the impedance of an electromagnetic induction heating coil is rapidly reduced, and hence overcurrent flows into the electromagnetic induction coil, which sometimes causes failures, such as blowout of an AC fuse of the power source.
As mentioned above, when a failure occurs in the power source, it takes much time to recover the power source, which increases downtime in which the image forming apparatus is not available. To prevent such an inconvenience, it is necessary to immediately detect that a recording sheet is wrapped around the fixing roller. In short, it is required to reduce time to detect a wrap jam of a recording sheet.
To this end, there has been proposed a fixing device that detects a wrap jam of a recording sheet by disposing recording sheet-detecting sensors for detecting a recording sheet, on an inlet side and an exit side of the fixing device, respectively (see e.g. Japanese Laid-Open Patent Publication No. 2004-354983).
In Japanese Laid-Open Patent Publication No. 2004-354983, it is determined whether or not a recording sheet is wrapped around the fixing roller based on results of detection by the recording sheet-detecting sensors, and depending on a result of the determination, the driving and heating of the fixing roller are stopped.
Further, there has been also proposed a fixing device of a belt type in which a noncontact temperature sensor is disposed in an area where a sheet passes and a contact temperature sensor is disposed in an area where no sheet passes (see e.g. Japanese Laid-Open Patent Publication No. 2006-251488).
In Japanese Laid-Open Patent Publication No. 2006-251488, when the temperature detected by the contact temperature sensor becomes equal to a predetermined temperature, whether or not a recording sheet exists between the noncontact temperature sensor and a fixing belt is judged depending on whether or not the temperature detected by the noncontact temperature sensor has reached a predetermined temperature.
By the way, in the image forming apparatus described in Japanese Laid-Open Patent Publication No. 2004-354983, when a paper jam is caused, the user takes the fixing device out of the body of the image forming apparatus to perform jam removal. In this jam removal, the user manually rotates a fixing roller, which sometimes causes a recording sheet to be wrapped around the fixing roller.
If the power of the image forming apparatus is restored in this state, the recording sheet cannot be detected by the recording sheet-detecting sensor disposed on the inlet side of the fixing device, so that the fixing roller is heated.
To prevent such a situation, it is necessary to restrict manual rotation of the fixing roller by a user in jam removal by adding e.g. a mechanism for restricting the direction of rotating the fixing roller to thereby prevent a recording sheet from being wrapped around the fixing roller. However, there is a problem that addition of such a mechanism inevitably causes costs to be increased.
On the other hand, in the image forming apparatus described in Japanese Laid-Open Patent Publication No. 2006-251488, when the temperature detected in the area outside the sheet-passing area has reached a predetermined temperature, it is judged whether or not the temperature detected in the sheet-passing area is correct. Thus, the judgment on whether or not the temperature detected in the sheet-passing area is correct is performed according to the temperature detected in the area outside the sheet-passing area, which depends largely on the environment temperature, and hence it is difficult to uniquely determine a set value (i.e. predetermined value) for the temperature detected in the sheet passing area depending on the environment where the image forming apparatus is installed, or the last printing operation.
Further, if the contact temperature sensor disposed in the area outside the sheet-passing area is not normally brought into abutment with the fixing belt, it is becomes impossible to detect an increase in the temperature of an end portion of the fixing belt during the printing operation, and hence even when the difference between the actual temperature in the area outside the sheet-passing area and the temperature in the central area of the fixing belt is large, it is sometimes judged that the state of the fixing device is normal.
Therefore, in the image forming apparatus described in Japanese Laid-Open Patent Publication No. 2006-251488, there can be an increase in the difference between temperatures in the central area and the end portion of the fixing belt, causing an inconvenience, such as generation of wrinkles on a recording sheet.

Fixing device capable of detecting wrap jam of recording sheet and image forming apparatus


A magnetoresistive effective film responds commensurate with an external magnetic field. Magnetic domain-controlling films apply a perpendicular biasing magnetic field to the magnetoresistive effective film. The forefronts of first electrode films constituting a pair of electrode films are overlaid on the magnetoresistive effective film, and the forefront surfaces of the first electrode films are risen at an inner angle of θ1. Second electrode films are overlaid on the first electrode films, and the forefront surfaces of the second electrode films are risen at an inner angle of θ2 smaller than the inner angle θ1.

1. Field of the Invention
This invention relates to a thin film magnetic head, a magnetic head device, a magnetic recording/reproducing device and a method for fabricating a thin film magnetic head.
2. Related Art Statement
In a magnetic recording field, a thin film magnetic head having a spin-valve film (hereinafter, called as a "SV film") as a reading element is mainly employed for developing the recording density and the miniaturization.
The SV film is composed of a pinned layer, a non-magnetic layer and a free layer which are stacked in turn. The magnetization of the pinned layer is fixed in a given direction, and the magnetization of the free layer is rotated commensurate with an external magnetic field. The resistance of the SV film is minimized as the direction of the magnetization of the pinned layer is parallel to that of the free layer, and the resistance of the SV film is maximized as the direction of the magnetization of the pinned layer is anti-parallel to that of the free layer. Therefore, a given external magnetic field is detected by measuring the change in resistance as the free layer is rotated.
In addition, a magnetic domain-controlling film is prepared to apply a perpendicular biasing magnetic field to the free layer. In this case, the free layer is made single domain to prevent Barkhausen noise due to the movement of magnetic wall. The magnetic domain-controlling film may be made of a given antiferromagnetic film. In this case, the perpendicular biasing magnetic field is applied through the bonding with exchange interaction between the antiferro-magnetic film and the magnetic film constituting the free layer. Moreover, the magnetic domain-controlling film may be made of a hard magnetic film. In this case, the perpendicular biasing magnetic field is applied from the hard magnetic film. The former biasing means is called as exchange biasing method, and the latter biasing means is called as hard magnetic biasing method.
In the area of the SV film adjacent to the magnetic domain-controlling film, only the perpendicular biasing magnetic field is generated larger, and a longitudinal biasing magnetic field is not almost generated to form a non-sensitive region, which does not function as a sensor and increase the electric resistance of the magnetic resistive sensor circuit. As the electric resistance of the magnetic resistive sensor circuit is increased, the performance of the magnetic resistive sensor circuit is restricted and electro-migration due to large current density may occur.
In order to decrease the electric resistance of the non-sensitive region, a so-called lead overlaying structure where electrode films are provided at both sides of the SV film beyond the non-sensitive region.
In order to realize the lead overlaying structure, such technique is disclosed in Japanese Patent Application Laid-open No. Tokukai Hei 11-53716 (JP A 11-53716) as that a first electrode film not constituting a lead overlaying structure is formed on a magnetic domain-controlling film, and a second electrode film constituting the lead overlaying structure is formed on the first electrode film by means of reactive ion etching (RIE).
With the above technique, however, since the second electrode film is formed by means of RIE, the rising angle of the second electrode film becomes large to be 60-80 degrees.
In a thin film magnetic head having such a lead overlaying structure, a gap film made of an inorganic film is formed on electrode films and a magnetoresistive effective film by means of sputtering, and a shielding film is formed on the gap film. When the rising angle of a second electrode film is set within 60-80 degrees as mentioned above, however, the gap film can not be formed sufficiently thick at the rising surface of the second electrode film, so that electric insulation can not be created between the second electrode film and the shielding film to be formed on the gap film.
In order to realize the lead overlaying structure, such a technique is also disclosed in Japanese Patent Application Laid-open No. 2000-276719 as to form an electrode film constituting a lead overlaying structure by means of lift-off.
With the lift-off technique, however, the lead overlaying structure is formed in wedge so that the electrode film is risen from on the magnetoresistive effective film by a constant angle, and thus, the forefront of the electrode film is formed in thin blade. Therefore, a large current density is generated at the blade-shaped forefront of the electrode film, and thus, electro-migration due to the larger current density may occur.

Thin film magnetic head, magnetic head device, magnetic recording/reproducing device and method for fabricating a thin film magnetic head


This invention is a system and method related to restoring data in a data storage environment and includes program logic.

Computer systems may include different resources used by one or more host processors. Resources and host processors in a computer system may be interconnected by one or more communication connections. These resources may include, for example, data storage systems, such as the Symmetrix™ or CLARiiON™ family of data storage systems manufactured by EMC Corporation. These data storage systems may be coupled to one or more host processors and provide storage services to each host processor. An example data storage system may include one or more data storage devices, such as those of the Symmetrix™ family, that are connected together and may be used to provide common data storage for one or more host processors in a computer system.
A host processor may perform a variety of data processing tasks and operations using the data storage system. For example, a host processor may perform basic system I/O operations in connection with data requests such as data read and write operations. Host processor systems may store and retrieve data using a storage device containing a plurality of host interface units, disk drives, and disk interface units. Such storage devices are provided, for example, by EMC Corporation of Hopkinton, Mass. and disclosed in U.S. Pat. No. 5,206,939 to Yanai et al., U.S. Pat. No. 5,778,394 to Galtzur et al., U.S. Pat. No. 5,845,147 to Vishlitzky et al., and U.S. Pat. No. 5,857,208 to Ofek. The host systems access the storage device through a plurality of channels provided therewith. Host systems provide data and access control information through the channels to the storage device and storage device provides data to the host systems also through the channels. The host systems do not address the disk drives of the storage device directly, but rather, access what appears to the host systems as a plurality of logical disk units. The logical disk units may or may not correspond to the actual disk drives. Allowing multiple host systems to access the single storage device unit allows the host systems to share data stored therein.
It is known that is desirable to copy or replicate data, including for a backup operation. Once data is replicated, copied, or otherwise backed up it may be used for a recovery or restoration process, wherein the copy of the data is restored back onto the source. This may be done for a variety of reasons including failures. So for example, data may be restored from the last good copy. However, the inventors of the present invention discussed below have critically recognized that it would be advantageous to protect such a last good copy itself from being corrupted during a recovery or restoration process.

This patent is subject to a terminal disclaimer.

System and method for managing data associated with copying and recovery procedures in a data storage environment


A system for providing secure browsing via a transparent network proxy is disclosed. The system may receive, from a client, a request to access a resource. The request may include an identifier that may be utilized to locate the resource. Once the request is received, the system may determine if the resource is not trusted, such as if the identifier is determined to be unknown or suspicious. If the resource is determined to not be trusted by the system, the system may forward the request to a virtual machine manager that may select a browser virtual machine from a pool of browser virtual machines. After the browser virtual machine is selected, the browser virtual machine may stream a rendering of the resource to the client based on the request. The rendering of the resource may be provided in lieu of the actual resource.

Currently, users utilize network and other service providers to gain access to the Internet, access software services, request and receive various types of content, access software applications, and perform a variety of other tasks and functions. In order to do so, such users often utilize browsers or other software applications on computing devices, such as, but not limited to, personal computers, laptops, smartphones, tablets, phablets, and other devices to access such services, content, and applications. However, as users have become increasingly comfortable with using such technologies, malware such as, but not limited to, computer viruses, worms, trojan horses, keyloggers, spyware, adware, and other malicious programs has also similarly increased. Such malware is often utilized by malware developers, fraudsters, and hackers to disrupt communications and to compromise personal, financial or other information associated with users and companies. Additionally, malware often disrupts communications and compromises information without the users or companies even knowing that such intrusions have taken place. As an example, a user may unknowingly visit a malicious website, and the user's device may be infected with malware without any warning or without the user's explicit consent. The malware may then be utilized by fraudsters to access the user's personal information, such as, but not limited to, social security information, financial information, driver's license information, or other personal information. Fraudsters may utilize such information to steal user identities, sign users up for fraudulent or even legitimate services without the user's consent, or perform a host of other fraudulent activities.
Many of the current malware attacks rely on tricking users into navigating to unknown uniform resource locators (URLs) that host zero-day exploits and drive-by-download attacks. Notably, such zero-day exploits and attacks are typically undetected by conventional anti-virus and anti-malware technologies, and are often capable of compromising many users' devices, personal accounts, and information in rapid fashion. In order to mitigate this problem, one solution is to use a proxy to block unknown, suspicious, and potentially compromised URLs. However, such proxies often do not have information about every URL that exists on the Internet or elsewhere, and, as a result, such a solution dramatically reduces a user's ability to browse many unknown URLs that are actually benign in nature. As another possible solution, a warning web page may be displayed on a user's internet browser whenever a user attempts to navigate to an unknown URL. Such warning web pages typically require some interaction with or acceptance from the user before the users proceed to the intended destination. While this solution often provides some awareness of potential malware to the user, the security decision is still placed on the user. By placing the security decision for proceeding on the user, this provides the user with the opportunity to accept the risk of proceeding and to navigate to a potentially malicious website that is associated with the URL.

Secure browsing via a transparent network proxy


A combination screwdriver includes a handle having a receiving chamber, a fixed plate secured in the receiving chamber of the handle, a push button movably mounted in the receiving chamber of the handle, a compression spring mounted in the receiving chamber of the handle and biased between the fixed plate and the push button, a tool holder movably mounted in the receiving chamber of the handle and holding a plurality of tips, and a restoring spring mounted in the receiving chamber of the handle and biased between the fixed plate and the tool holder. Thus, the tool holder is sprung outward and partially protruded from the handle by pressing the push button to expose the tips for selection of the user so that the user can take and operate the tips easily and quickly.

1. Field of the Invention
The present invention relates to a hand tool and, more particularly, to a combination screwdriver.
2. Description of the Related Art
A conventional combination screwdriver comprises a handle having a first end provided with a receiving chamber and a second end provided with a socket, a plurality of tips mounted in the receiving chamber of the handle, and a cover removably mounted on the handle to cover the receiving chamber of the handle and to limit the tips in the receiving chamber of the handle. When in use, the cover is removed from the handle to expose the tips. Then, one of the tips is taken out of the receiving chamber of the handle and is inserted into the socket for operation of a user. Thus, the tips are stored in the receiving chamber of the handle to largely reduce the whole volume of the combination screwdriver. However, the receiving chamber of the handle has a small diameter so that when many tips are contained in the receiving chamber of the handle, the required tip cannot be taken out of the receiving chamber of the handle easily and quickly, thereby causing inconvenience to the user.


Various embodiments of tracheal tube assemblies disclosed herein may include a tubular body having an open distal end for ventilating a patient and a cuff disposed around the tubular body above the open distal end. The cuff may be adapted to be inflated to seal the cuff against a wall of a trachea of the patient. The cuff may include a first portion that spaces the tubular body a first distance from the tracheal wall when inflated and a second portion that spaces the tubular body a second distance from the tracheal wall when inflated. The second distance may be greater than the first distance.

The present disclosure relates generally to medical devices and, more particularly, to airway devices, such as tracheal tubes.
This section is intended to introduce the reader to various aspects of art that may be related to various aspects of the present disclosure, which are described and/or claimed below. This discussion is believed to be helpful in providing the reader with background information to facilitate a better understanding of the various aspects of the present disclosure. Accordingly, it should be understood that these statements are to be read in this light, and not as admissions of prior art.
In the course of treating a patient, a tube or other medical device may be used to control the flow of air, food, fluids, or other substances into the patient. For example, medical devices, such as tracheal tubes, may be used to control the flow of air and medicaments into or out of a patient's airway. In many instances, it is desirable to provide a seal between the outside of the tube or device and the interior of the passage in which the tube or device is inserted. In this way, substances can only flow through the passage via the tube or other medical device, allowing a medical practitioner to maintain control over the type and amount of substances flowing into and out of the patient. For example, tracheal tubes may be used to control the flow of air or other gases through a patient's trachea. Such tracheal tubes may include endotracheal (ET) tubes, tracheostomy tubes, transtracheal tubes, and so forth.
To seal these types of tracheal tubes, an inflatable cuff may be provided. When inflated, the cuff generally expands into the surrounding anatomy, for example, into the trachea to seal the tracheal passage around the tube. Because the cuffs are generally made from a relatively thin and flexible material, the cuffs may inflate in such a way that the placement of the tubular body of the tracheal tube within the patient's airway is subject to substantial variations. For example, the cuffs may inflate to an irregular shape such that one side of the cuff has a greater incidence of wrinkles than another side of the cuff, and, accordingly, the tracheal tube may be positioned off center with respect to a central axis of the patient's trachea. In certain instances, such as when auxiliary devices (e.g., imaging devices) are coupled to the tracheal tube, it may be desirable to control the positioning of the tubular body of the tracheal tube within the patient's trachea. Accordingly, there remains a need in the art for improved tracheal tubes and cuffs that enable proper patient ventilation without the drawbacks associated with current designs.

Tracheal tube positioning devices and methods


A compound of general formula (I)

The present invention relates to new cyclopropanes of general formula
the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, their use and processes for preparing them.
In the above general formula (I)    R denotes a saturated or mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza, or S,S-dioxido-thiadiaza heterocyclic group,    whilst the abovementioned heterocyclic groups are linked via a carbon or nitrogen atom, and    may contain one or two carbonyl groups adjacent to a nitrogen atom,    may be substituted by an alkyl group at one of the nitrogen atoms,    may be substituted at one or two carbon atoms by a straight-chain or branched alkyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl, or 1-methylimidazolyl group, whilst the substituents may be identical or different,    and wherein an olefinic double bond of one of the abovementioned unsaturated heterocyclic groups may be fused with a benzene, pyridine, diazine, 1,3-oxazole, thiophene, furan, thiazole, pyrrole, N-methylpyrrole, quinoline, imidazole, or N-methylimidazole ring,    while the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl, or 1-methylimidazolyl groups contained in R and the benzo-, thieno-, pyrido-, and diazino-fused heterocyclic groups in the carbon skeleton may additionally be mono-, di-, or trisubstituted by fluorine, chlorine, or bromine atoms, by alkyl, dialkylaminoalkoxy, nitro, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, phenyl, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, [N-alkyl-N-(dialkylaminoalkyl)amino]carbonyl, [(hydroxycarbonylalkyl)amino]carbonyl, [(alkoxy-carbonylalkyl)amino]carbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino, aminocarbonylaminoalkyl, alkylaminocarbonylamino, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl, trifluoromethylsulfonyl, or cycloalkyl groups with 3 to 8 carbon atoms,    by 4- to 8-membered alkyleneimino groups wherein a methylene group in the 3-, 4-, or 5-position may be replaced by an oxygen atom or a methylimino group,    by alkoxy groups which may be substituted in the co-position by a 5- to 7-membered heteroalicyclic group, where the heteroalicyclic group is linked via a carbon or nitrogen atom and contains one or two heteroatoms not directly connected to each other selected from among oxygen and nitrogen,    while multiple substitution by cyclic groups or those groups which contain a carbocyclic or heterocyclic group is excluded and wherein the substituents may be identical or different,    and R1 denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, 1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzo[b]fur-3-yl, benzo[b]thien-3-yl, pyridinyl, quinolinyl, or isoquinolinyl group,    whilst the abovementioned aromatic and heteroaromatic groups may additionally be mono-, di-, or trisubstituted in the carbon skeleton by fluorine, chlorine, or bromine atoms, by branched or unbranched alkyl groups, by cycloalkyl groups with 3 to 8 carbon atoms, by phenylalkyl, alkenyl, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, dialkylaminoalkoxy, nitro, hydroxy, amino, acetylamino, propionylamino, methylsulfonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl, or trifluoromethylsulfonyl groups and the substituents may be identical or different,    while the hydroxy, amino, indolyl, and imidazolyl groups contained in the abovementioned groups may be substituted by protecting groups familiar from peptide chemistry, preferably with the acetyl, benzyloxycarbonyl, or tert-butyloxycarbonyl group, and    all the abovementioned alkyl and alkoxy groups and the alkyl or alkylene moieties present within the other groups specified may contain 1 to 5 carbon atoms, unless otherwise stated.
By the protecting groups mentioned in the preceding definitions are meant the protecting groups familiar from peptide chemistry, especially    a phenylalkoxycarbonyl group with 1 to 3 carbon atoms in the alkoxy moiety optionally substituted in the phenyl nucleus by a halogen atom, by a nitro or phenyl group, by one or two methoxy groups,    for example, the benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 4-biphenylyl-α,α-dimethylbenzyloxycarbonyl, or 3,5-dimethoxy-α,α-dimethylbenzyloxycarbonyl group,    an alkoxycarbonyl group having a total of 1 to 5 carbon atoms in the alkyl moiety,    for example, the methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxycarbonyl, or tert-butyloxycarbonyl group,    the allyloxycarbonyl, 2,2,2-trichloro-(1,1-dimethylethoxy)carbonyl, or 9-fluorenylmethoxycarbonyl group, or    the formyl, acetyl, or trifluoroacetyl group.
The present invention also includes the individual diastereomeric pairs of antipodes of general formula (I), the associated enantiomers and mixtures of the diastereomers and enantiomers which come under general formula (I).
Particularly preferred are the racemates and enantiomers which come under general formula (I) and are trans-configured in relation to the cyclopropane ring.
The compounds of general formula (I) have valuable pharmacological properties, based on their selective CGRP-antagonistic properties. The invention further relates to pharmaceutical compositions containing these compounds, their use, and the preparation thereof.
Preferred compounds of the above general formula (I) are those wherein    R denotes a mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, or thiaza heterocyclic group,    whilst the abovementioned heterocyclic groups are linked via a carbon or nitrogen atom, and    may contain one or two carbonyl groups adjacent to a nitrogen atom,    may be substituted at a carbon atom by a phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, or 1-methylpyrazolyl group,    and wherein an olefinic double bond of one of the abovementioned unsaturated heterocyclic groups may be fused to a benzene, pyridine, diazine, or quinoline ring,    while the phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, or 1-methylpyrazolyl groups contained in R and the benzo-, pyrido-, and diazino-fused heterocyclic groups in the carbon skeleton may additionally be mono-, di-, or trisubstituted by fluorine, chlorine, or bromine atoms, by alkyl, dialkylaminoalkoxy, nitro, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, [N-alkyl-N-(dialkylaminoalkyl)amino]carbonyl, [(hydroxycarbonylalkyl)amino]carbonyl, [(alkoxycarbonylalkyl)amino]carbonyl, aminocarbonylamino, aminocarbonylaminoalkyl, alkylaminocarbonylamino, alkanoyl, or trifluoromethoxy groups,    by 5- to 7-membered alkyleneimino groups wherein a methylene group in the 3-, 4-, or 5-position may be replaced by an oxygen atom or a methylimino group,    by alkoxy groups which may be substituted in the ω-position by a 5- to 7-membered heteroalicyclic group, where the heteroalicyclic group is linked via a carbon or nitrogen atom and contains one or two heteroatoms not directly connected to each other selected from among oxygen and nitrogen,    while multiple substitution by cyclic groups or those groups which contain a carbocyclic or heterocyclic group is ruled out and wherein the substituents may be identical or different,    and R1 denotes a phenyl, 1-naphthyl, or 2-naphthyl group,    while the abovementioned aromatic groups may be mono-, di-, or trisubstituted by fluorine, chlorine, or bromine atoms, by branched or unbranched alkyl groups, alkoxy, trifluoromethyl, nitro, hydroxy, amino, or acetylamino groups and the substituents may be identical or different,    and wherein all the abovementioned alkyl and alkoxy groups and the alkyl or alkylene moieties present within the other groups mentioned may contain 1 to 4 carbon atoms, unless otherwise stated,    the tautomers, diastereomers, enantiomers, and salts thereof.
Particularly preferred compounds of the above general formula (I) are those wherein    R denotes a monounsaturated 5- to 7-membered diaza or triaza heterocyclic group,    while the abovementioned heterocyclic groups are linked via a nitrogen atom,    may contain a carbonyl group adjacent to a nitrogen atom, and    may be substituted at a carbon atom by a phenyl group, or    an olefinic double bond of one of the abovementioned unsaturated heterocyclic groups may be fused with a benzene, pyridine, or quinoline ring,    and the phenyl groups contained in R as well as the benzo- and pyrido-fused heterocyclic groups in the carbon skeleton may additionally be mono-, di-, or trisubstituted by fluorine, chlorine, or bromine atoms, by alkyl, dialkylaminoalkoxy, nitro, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, carboxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, [N-alkyl-N-(dialkylaminoalkyl)-amino]carbonyl, [(hydroxycarbonylalkyl)amino]carbonyl, [(alkoxycarbonylalkyl)amino]carbonyl, alkanoyl, or trifluoromethoxy groups,    by 5- to 7-membered alkyleneimino groups wherein a methylene group in the 3- or 4-position may be replaced by an oxygen atom or a methylimino group, for example, 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperazinyl, 4-methyl-1,4-diazacyclohept-1-yl, or 4-morpholinyl groups,    by alkoxy groups which may be substituted in the co-position by a 5- or 6-membered heteroalicyclic group, wherein the heteroalicyclic group is linked via a carbon atom and contains an oxygen atom in each of the 2- and 2′-positions or is linked via a carbon or nitrogen atom and contains one or two nitrogen atoms not directly linked to one another or an oxygen and a nitrogen atom which are separated from each other by at least one methylene group, for example, methoxy, ethoxy, propoxy, 2,5-dioxacyclopentylmethoxy, 2,6-dioxacyclohexylmethoxy, 2-(1-pyrrolidinyl)ethoxy, 2-(1-piperidinyl)ethoxy, 2-(4-methyl-1-piperazinyl)ethoxy, or 2-(4-morpholinyl)ethoxy groups,    while multiple substitution by cyclic groups or those groups which contain a carbocyclic or heterocyclic group is excluded and wherein the substituents may be identical or different,    and R1 denotes a phenyl group which may be mono-, di-, or trisubstituted by fluorine, chlorine, or bromine atoms, by alkoxy, trifluoromethyl, nitro, hydroxy, or amino groups, while the substituents may be identical or different,    and wherein all the abovementioned alkyl and alkoxy groups and the alkyl or alkylene moieties present within the other groups mentioned may contain 1 to 3 carbon atoms, unless otherwise stated,    the tautomers, diastereomers, enantiomers, and salts thereof.
Most particularly preferred compounds of the above general formula (I) are those wherein    R denotes a 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 2,4-dihydro-5-phenyl-3 (3H)-oxo-1,2,4-triazol-2-yl, 3,4-dihydro-2(1H)-oxopyrido[4,3-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl, or 1,3-dihydro-2 (2H)-oxoimidazo[4,5-c]quinolin-3-yl group,    wherein the abovementioned mono- and bicyclic heterocyclic groups may be mono- or disubstituted in the carbon skeleton by fluorine, chlorine, or bromine atoms or may be monosubstituted by a 4-methyl-1-piperazinyl, 2,5-dioxacyclopentylmethoxy, methoxy, 2-(4-morpholinyl)ethoxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, methoxycarbonylmethoxy, hydroxycarbonylmethoxy, nitro, trifluoromethyl, methoxycarbonyl, carboxy, hydroxy, aminocarbonyl, diethylaminocarbonyl, [N-(2-dimethylaminoethyl)-N-methylamino]carbonyl, [(methoxycarbonylmethyl)amino]carbonyl, or [(hydroxycarbonylmethyl)amino]carbonyl group,    and R1 denotes a phenyl group,    which may be mono-, di-, or trisubstituted by fluorine, chlorine, or bromine atoms or by hydroxy or amino groups, wherein the substituents may be identical or different, for example, the 4-chlorophenyl, 4-amino-3,5-dibromophenyl, or 3,5-dibromo-4-hydroxyphenyl group,    the tautomers, diastereomers, enantiomers, and salts thereof.
The following are mentioned as examples of particularly preferred compounds:    (1) cis-3-{1-[2-(4-chlorobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone;    (2) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-(3-methoxyphenyl)-2 (2H)-imidazolone;    (3) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone;    (4) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-6-bromo-3,4-dihydro-2(1H)-quinazolinone;    (5) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-phenyl-2 (2H)-imidazolone;    (6) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]4-piperidinyl}-1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-imidazolone;    (7) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-(3-hydroxyphenyl)-2(2H)-imidazolone;    (8) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-hydroxy-2(1H)-quinazolinone;    (9) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-[(1,3-dioxolan-2-yl)methoxy]-2(1H)-quinazolinone;    (10) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-4-(3,4-dichlorophenyl)-1,3-dihydro-2(2H)-imidazolone;    (11) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-pyrido[4,3-d]pyrimidinone;    (12) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-(2-methoxyphenyl)-2(2H)-imidazolone;    (13) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-4-(3-chlorophenyl)-1,3-dihydro-2(2H)-imidazolone;    (14) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-(3-nitrophenyl)-2(2H)-imidazolone;    (15) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-pyrido[3,4-d]pyrimidinone;    (16) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-[2-(dimethylamino)ethoxy]-2(1H)-quinazolinone;    (17) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-(4-methyl-1-piperazinyl)-2(1H)-quinazolinone;    (18) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-[2-(trifluoromethyl)phenyl]-2(2H)-imidazolone;    (19) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-[3-(dimethylamino)propoxy]-2(1H)-quinazolinone;    (20) trans-3-{1-[2-(3,5-dibromo-4-hydroxybenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone;    (21) trans-1-{1-[2-(3,5-dibromo-4-hydroxybenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-4-phenyl-2(2H)-imidazolone;    (22) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-(methoxycarbonylmethoxy)-2(1H)-quinazolinone;    (23) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-(hydroxycarbonylmethoxy)-2(1H)-quinazolinone;    (24) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-[2-(4-morpholinyl)ethoxy]-2(1H)-quinazolinone;    (25) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-7-methoxy-2(1H)-quinazolinone;    (26) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-7-(methoxycarbonylmethoxy)-2(1H)-quinazolinone;    (27) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-7-carboxy-3,4-dihydro-2(1H)-quinazolinone;    (28) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-7-methoxycarbonyl-3,4-dihydro-2(1H)-quinazolinone;    (29) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-1,3-dihydro-2(2H)-imidazo[4,5-c]quinolinone;    (30) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-7-{[(methoxycarbonylmethyl)amino]carbonyl}-2(1H)-quinazolinone;    (31) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-7-{[N-(2-dimethylaminoethyl)-N-methylamino]carbonyl}-2(1H)-quinazolinone;    (32) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-7-diethylaminocarbonyl-3,4-dihydro-2(1H)-quinazolinone;    (33) trans-7-aminocarbonyl-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone;    (34) trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-7-{[(hydroxycarbonylmethyl)amino]carbonyl}-2(1H)-quinazolinone; and    (35) trans-1-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-2,4-dihydro-5-phenyl-3 (3H)-1,2,4-triazolone,    particularly compounds (2), (3), (5), (7), (8), (9), (13), (19), (22), (23), and (35) mentioned above,    and the salts thereof.
The compounds of general formula (I) are prepared by methods known in principle. The following methods have proved particularly suitable for preparing the compounds of general formula (I) according to the invention:
a) Coupling a Carboxylic Acid of General Formula
wherein    R1 is as hereinbefore defined,    with a compound of general formula
wherein    R is as hereinbefore defined.
The coupling is preferably carried out using methods known from peptide chemistry (cf., e.g., Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example, using carbodiimides such as, e.g., dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC), or ethyl-(3-dimethylaminopropyl)carbodiimide, or O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), tetrafluoroborate (TBTU), or 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt), any possible racemization can additionally be suppressed, if desired, or the reaction speed can be increased. The couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between −30° C. and +30° C., preferably −20° C. and +25° C. If necessary, N-ethyldiisopropylamine (DIEA) (Hünig base) is preferably used as an additional auxiliary base.
The so-called anhydride process is used as a further coupling method for synthesizing compounds of general formula (I) (cf. also: M. Bodanszky, "Peptide Chemistry", Springer-Verlag 1988, pp. 58-59; M. Bodanszky, "Principles of Peptide Synthesis", Springer-Verlag 1984, pp. 21-27). The Vaughan variant of the mixed anhydride process is preferred (J. R. Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), in which the mixed anhydride of the carboxylic acid of general formula (III) which is to be coupled and monoisobutyl carbonate, is obtained using isobutyl chlorocarbonate in the presence of bases such as 4-methylmorpholine or 4-ethylmorpholine. The preparation of this mixed anhydride and the coupling with amines are carried out in a one-pot process, using the abovementioned solvents and at temperatures between −20° C. and +25° C., preferably 0° C. and +25° C.
b) Coupling a Compound of General Formula
wherein    R1 is as hereinbefore defined, and Nu denotes a leaving group, e.g., a halogen atom such as the chlorine, bromine, or iodine atom, an alkylsulfonyloxy group with 1 to 10 carbon atoms in the alkyl moiety, a phenylsulfonyloxy or naphthylsulfonyloxy group optionally mono-, di-, or trisubstituted by chlorine or bromine atoms, by methyl or nitro groups, whilst the substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl optionally substituted by 1 or 2 methyl groups in the carbon skeleton, a 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, a vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyranyl, or pyridinyl, a dimethylaminyloxy, 2(1H)-oxopyridin-1-yloxy, 2,5-dioxopyrrolidin-1-yloxy, phthalimidyloxy, 1H-benzotriazol-1-yloxy, or azide group,with a compound of general formula
wherein    R is as hereinbefore defined.
The reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e., the components are reacted in the presence of at least one equivalent of an auxiliary base at temperatures between −50° C. and +120° C., preferably −10° C. and +30° C., and optionally in the presence of solvents. The auxiliary bases used are preferably alkali metal and alkaline earth metal hydroxides, e.g., sodium hydroxide, potassium hydroxide, or barium hydroxide, alkali metal carbonates, e.g., sodium carbonate, potassium carbonate, or cesium carbonate, alkali metal acetates, e.g., sodium or potassium acetate, as well as tertiary amines, e.g., pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyldiisopropylamine, N-ethyldicyclohexylamine, 1,4-diazabicyclo[2,2,2]octane, or 1,8-diazabicyclo[5,4,0]undec-7-ene, the solvents used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as the auxiliary bases, water may also be added to the reaction mixture as cosolvent.
c) Cyclopropanization of a Compound of General Formula
wherein    R and R1 are as hereinbefore defined.
The cyclopropanization may be carried out catalytically with diazomethane, using starting compounds of formula (V) in which the olefinic double bond is preferably (E)-configured. The reaction is carried out at temperatures between 0° C. and +50° C., preferably at ambient temperature. The preferred catalysts are palladium (II) compounds, for example, PdCl2(PhCN)2 or palladium (II) acetate, Pd3(OAc)6. Suitable solvents include inert ethers, for example, diethyl ether, hydrocarbons and most preferably chlorohydrocarbons such as dichloromethane or 1,2-dichloroethane, or mixtures of these solvents (cf. also: H. Abdallah, R. Green, and R. Carrie, Tetrahedron Letters 23, 503-506 (1982)). The cyclopropanization of (E)-configured compounds of general formula (V) can also be made asymmetric by using the semicorrin copper catalysts described by A. Pfaltz, Acc. Chem. Res. 26, 339-345 (1993), thereby obtaining a high enantiomeric excess. The diazomethane required may also be produced in situ, by adding N-methyl-N-nitrosourea batchwise to a mixture of an alkene of general formula (V), the palladium catalyst, the organic solvent, and 40% to 50% aqueous potassium hydroxide solution; with this method, at most 2 moles of N-methyl-N-nitrosourea are generally needed per mol of the alkene of general formula (V).
Moreover, the cyclopropanization of alkenes of general formula (V) wherein the olefinic double bond may be in any orientation, but preferably the (E)-configuration, may be carried out analogously to the so-called Simmons-Smith reaction with diiodomethane and the zinc/copper pair (cf. also: Simmons, Cairns, Vladuchik, and Hoiness, Org. React. 20, 1-131 (1973); Furukawa and Kawabata, Adv. Organomet. Chem. 12, 83-134 (1974)) or the zinc/silver pair (cf. also: J. M. Denis, C. Girard, and J. M. Conia, Synthesis 1972, 549). The zinc/copper pair can be produced by numerous alternative methods (cf., for example, Shank and Shechter, J. Org. Chem. 24, 1525 (1959); LeGoff, J. Org. Chem. 29, 2048 (1964)), of which the heating of zinc powder with copper (I) chloride in diethyl ether and under nitrogen (Rawson and Harrison, J. Org. Chem. 35, 2057 (1970)) is particularly suitable. The reaction also works with non-activated zinc in an ultrasound bath (cf. also: Repi{hacek over (c)} and Vogt, Tetrahedron Letters 23, 2729 (1982); Repi{hacek over (c)}, Lee, and Giger, Org. Prep. Proced. Int. 16, 25 (1984). The species attacking the alkene of general formula (V) is an organozinc compound which occurs as an intermediate, bis-(iodomethyl)-zinc (cf. also: Georg Wittig and Frank Wingler, Chem. Ber. 97, 2146 (1964)) or the adduct (ICH2)2Zn.ZnI2 (Blanchard and Simmons, J. Am. Chem. Soc. 86, 1337 (1964)), the solutions of which are sufficiently stable for physicochemical investigations. The cyclopropanization takes place stereospecifically syn. The reactivity of the reagent can be increased by the addition of a Lewis acid, for example, nickel(II) bromide (cf also: H. Kanai et al., Bull. Chem. Soc. Jap. 56, 1025-1029 (1983), Synthesis 1984, 987), while the diiodomethane required can also be produced in situ from dibromomethane and sodium iodide. In another variant of cyclopropanization, the substrate of general formula (V) is reacted with diiodomethane or another dihalomethane and diethylzinc (cf. also: Furukawa, Kawabata and Nishimura, Tetrahedron 24, 53 (1968), Tetrahedron Letters 1968, 3495; Nishimura, Kawabata, and Furukawa, Tetrahedron 25, 2647 (1969); Miyano and Hashimoto, Bull. Chem. Soc. Jpn. 46, 892 (1973); Friedrich and Biresaw, J. Org. Chem. 47, 1615 (1982)). Finally, the reagent required may also be produced from dihalomethanes and copper (Kawabata, Kamemura, and Naka, J. Am. Chem. Soc. 101, 2139 (1979); Kawabata, Tanimoto, and Fujiwara, Tetrahedron 35, 1919 (1979)). The cyclopropanization is carried out at temperatures between 0° C. and +70° C., preferably at ambient temperature, and using ethereal solvents, for example, diethyl ether or tetrahydrofuran.
The cyclopropanization of an alkene of general formula (V) in which the olefinic double bond may have any desired orientation, but is preferably in the (E)-configuration, may also be carried out with the dimethyloxosulfonium methylide of formula
or a dialkylamino-oxosulfonium methylide of general formula
wherein    R2 denotes the methyl or ethyl group.
The reaction is carried out in dipolar aprotic solvents, preferably in dimethylsulfoxide, and at temperatures between +10° C. and +80° C., preferably +20° C. and +60° C. The oxosulfonium ylides VI and VII may be put in as such but are also produced in situ from the trimethyloxosulfonium iodide of formula
by the action of methanesulfinylmethyl sodium (cf. also: E. J. Corey and M. Chaykowsky, J. Am. Chem. Soc. 87, 1353 (1965), Org. Syn. 49, 78 (1969); H. Schmidbauer and W. Tronich, Tetrahedron Letters 1968, 5335) or from a dialkylamino-oxosulfonium iodide of general formula
wherein    R2 is as hereinbefore defined, by the action of sodium hydride (cf. also: C. R. Johnson, E. R. Janiga, and M. Haake, J. Am. Chem. Soc. 90, 3890 (1968); C. R. Johnson and C. W. Schroeck, J. Am. Chem. Soc. 90, 6852 (1968); C. R. Johnson and G. F. Katekar, J. Am. Chem. Soc. 92, 5753 (1970); C. R. Johnson, M. Haake, and C. W. Schroeck, J. Am. Chem. Soc. 92, 6594 (1970); C. R. Johnson and P. E. Rogers, J. Org. Chem. 38, 1793 (1973) in dimethylsulfoxide. Ylides of general formula (VII) can also be obtained in optically active form and are thus suitable for the asymmetric synthesis of compounds of general formula (I).d) In order to prepare a compound of general formula (I) wherein at least one of the groups R and R1 contains one or more carboxy groups:    alkaline saponification of a carboxylic acid ester of general formula (Ia)
    wherein Ra and R1a have the meanings given above for R and R1, respectively, with the proviso that at least one of these groups contains one or more alkoxycarbonyl groups,    and if desired subsequent treatment with dilute organic or inorganic acids in order to liberate the basic carboxylic acids from the salts initially formed.
For the alkaline saponification of the esters of general formula (Ia), lithium hydroxide, sodium hydroxide, and potassium hydroxide are preferred; however, other alkali metal hydroxides such as cesium hydroxide, or alkaline earth metal hydroxides, for example, barium hydroxide, or tetraalkylammonium hydroxides are also suitable. The procedure is carried out in aqueous solution and advantageously with the addition of water-miscible co-solvents, preferably alcohols such as methanol, ethanol or 2-ethoxyethanol, or ethers such as tetrahydrofuran or 1,4-dioxane. Suitable temperatures for alkaline saponification are between −10° C. and the boiling temperature of the water/solvent mixture used, but ambient temperature is preferred. Dilute aqueous organic or inorganic acids, e.g., acetic acid, oxalic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, and phosphoric acid are suitable for liberating the basic carboxylic acids from the salts thereof initially formed.
e) In order to prepare a compound of general formula (I) wherein the group R in the carbon skeleton is similarly mono-, di-, or trisubstituted by an aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, [N-alkyl-N-(dialkylaminoalkyl)amino]carbonyl, hydroxycarbonylalkylaminocarbonyl, alkoxycarbonylalkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, or (4-methyl-1-piperazinyl)carbonyl group:
Coupling a compound of general formula
wherein    R1 is as hereinbefore defined, and the group Rb has the meanings given for R hereinbefore, with the proviso that it is mono-, di-, or trisubstituted in the carbon skeleton by the carboxy group,    with ammonia, alkylamines, N-alkyl-N-(dialkylaminoalkyl)amines, hydroxycarbonylalkylamines, alkoxycarbonylalkylamines, or dialkylamines, for example, 1-methylpiperazine, morpholine, pyrrolidine, piperidine, or hexahydroazepine.
The coupling is preferably carried out using methods known from peptide chemistry (cf., e.g., Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example, using carbodiimides such as, e.g., dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC), or ethyl-(3-dimethylaminopropyl)carbodiimide, or O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), tetrafluoroborate (TBTU), or 1H-benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt), any possible racemization can additionally be suppressed, if desired, or the reaction speed can be increased. The couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NWP) or mixtures thereof and at temperatures between −30° C. and +30° C., preferably −20° C. and +25° C. If necessary, N-ethyldiisopropylamine (DIEA) (Hünig base) is preferably used as an additional auxiliary base.
The so-called anhydride process is used as a further coupling method for synthesizing compounds of general formula (I) (see also: M. Bodanszky, "Peptide Chemistry", Springer-Verlag 1988, pp. 58-59; M. Bodanszky, "Principles of Peptide Synthesis", Springer-Verlag 1984, pp. 21-27). The Vaughan variant of the mixed anhydride process is preferred (J. R. Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), in which the mixed anhydride of the carboxylic acid of general formula (III) which is to be coupled and monoisobutyl carbonate, is obtained using isobutyl chlorocarbonate in the presence of bases such as 4-methylmorpholine or 4-ethylmorpholine. The preparation of this mixed anhydride and the coupling with amines are carried out in a one-pot process, using the abovementioned solvents and at temperatures between −20° C. and +25° C., preferably 0° C. and +25° C.
The new cyclopropanes of general formula (I) according to the invention contain at least one chiral centre. Occasionally, the compounds may occur in the form of two diastereomeric pairs of antipodes. The invention includes the individual isomers and the mixtures thereof.
The diastereomers may be separated on the basis of their different physico-chemical properties, e.g., by fractional crystallization from suitable solvents, by high pressure liquid or column chromatography, using chiral or preferably non-chiral stationary phases.
Racemates covered by general formula (D may be separated, for example, by HPLC on suitable chiral stationary phases (e.g., Chiral AGP, Chiralpak AD). Racemates which contain a basic or acidic function can also be separated via the diastereomeric, optically active salts which are produced on reacting with an optically active acid, for example, (+)- or (−)-tartaric acid, (+)- or (−)-diacetyl tartaric acid, (+)- or (−)-monomethyl tartrate, or (+)-camphorsulfonic acid, or an optically active base, for example, with (R)-(+)-1-phenylethylamine, (S)-(−)-1-phenylethylamine, or (S)-brucine.
According to a conventional method of separating isomers, the racemate of a compound of general formula (I) is reacted with one of the abovementioned optically active acids or bases in equimolar amounts in a solvent and the resulting crystalline, diastereomeric, optically active salts thereof are separated using their different solubilities. This reaction may be carried out in any type of solvent provided that it is sufficiently different in terms of the solubility of the salts. Preferably, methanol, ethanol, or mixtures thereof, for example, in a ratio by volume of 50:50, are used. Then each of the optically active salts is dissolved in water, neutralized with a base such as sodium carbonate, potassium carbonate, sodium hydroxide solution, or potassium hydroxide solution and in this way the corresponding free compound is obtained in the (+) or (−) form.
The (R) or (S) enantiomer alone or a mixture of two optically active diastereomeric compounds covered by general formula (I) may also be obtained by performing the syntheses described above with a suitable reaction component in the (R) or (S) configuration.
The starting compounds of general formula (Ia) and (Ib) may be prepared by methods a) to c) described in this application. The starting materials of general formula (II) required for the synthesis of the compounds of general formula (I), if not already known from the literature, may easily be prepared, for example, from the corresponding carboxylic acid esters, such as the methyl or ethyl esters, by saponification with aqueous lithium, sodium, or potassium hydroxide solution followed by acidification with hydrochloric acid analogously to methods known in the art. The carboxylates required for this may be obtained from the corresponding 4-aryl- or hetaryl-4-oxo-2-butenoates, for example, by reacting with dimethyloxosulfonium methylide analogously to the process described in c) above. Finally, 4-aryl- or hetaryl-4-oxo-2-butenoates are either known from the literature or may easily be obtained from 4-aryl- or hetaryl-4-oxo-2-butenoic acids known from the literature (cf. also published German applications 2 047 806 and 2 103 749).
Secondary amines of general formula (II) are either known or may be synthesized, for example, analogously to processes described in WO 98/11128.
Starting compounds of general formula (IV) may be obtained from the starting compounds of general formula (II) by current methods.
The starting compounds of general formula (V) may easily be prepared, for example, by acylating compounds of formula (III) with unsaturated carboxylic acid derivatives.
The compounds of general formula (I) obtained may, if they contain suitable basic functions, be converted, particularly for pharmaceutical use, into their physiologically acceptable salts with inorganic or organic acids. Suitable acids include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid, or maleic acid.
Moreover, the new compounds of formula (I), if they contain an acid function, for example, a carboxy group, may if desired be converted into the addition salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable addition salts thereof. Suitable bases for this include, for example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine, and triethanolamine.
The new compounds of general formula (I) and the physiologically acceptable salts thereof have CGRP-antagonistic properties and exhibit good affinities in CGRP receptor binding studies. The compounds display CGRP-antagonistic properties in the pharmacological test systems described hereinafter.
The following experiments were carried out to demonstrate the affinity of compounds of general formula (I) for human CGRP-receptors and their antagonistic properties:
A. Binding Studies with SK-N-MC Cells (Expressing the Human CGRP Receptor)
SK-N-MC cells are cultivated in "Dulbecco's modified Eagle medium". The medium is removed from confluent cultures. The cells are washed twice with PBS buffer (Gibco 041-04190 M), detached by the addition of PBS buffer, mixed with 0.02% EDTA, then detached again and isolated by centrifuging. After resuspension in 20 mL of "Balanced Salts Solution" [BSS (in mM): NaCl 120, KCl 5.4, NaHCO3 16.2, MgSO4 0.8, NaHPO4 1.0, CaCl2 1.8, D-glucose 5.5, HEPES 30, pH 7.40], the cells are centrifuged twice at 100×g and resuspended in BSS. After the number of cells has been determined, the cells are homogenized using an Ultra-Turrax and centrifuged for 10 minutes at 3000×g. The supernatant is discarded and the pellet is recentrifuged in Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl2, 1 mM EDTA, pH 7.40), enriched with 1% bovine serum albumin and 0.1% bacitracin) and resuspended (1 mL/1000000 cells). The homogenized product is frozen at −80° C. The membrane preparations are stable for more than 6 weeks under these conditions.
After thawing, the homogenized product is diluted 1:10 with assay buffer (50 mM Tris, 150 mM NaCl, 5 mM MgCl2, 1 mM EDTA, pH 7.40) and homogenized for 30 seconds with an Ultra-Turrax. 230 μL of the homogenized product are incubated for 180 minutes at ambient temperature with 50 pM 125I-iodotyrosyl-Calcitonin-Gene-Related Peptide (Amersham) and increasing concentrations of the test substances in a total volume of 250 μL. The incubation is ended by rapid filtration through GF/B-glass fibre filters treated with polyethyleneimine (0.1%) using a cell harvester. The protein-bound radioactivity is measured using a gamma counter. Non-specific binding is defined as the bound radioactivity in the presence of 1 μM human CGRP-alpha during incubation.
The concentration binding curves are analyzed using computer-aided non-linear curve matching.
The compounds of general formula (I) show IC50 values≦10000 nM in the test described.
B. CGRP Antagonism in SK-N-MC Cells
SK-N-MC cells (1 million cells) are washed twice with 250 μl incubation buffer (Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) and pre-incubated at 37° C. for 15 minutes. After the addition of CGRP (10 μL) as agonist in increasing concentrations (10−11 to 10−6 M), or additionally the substance in 3 to 4 different concentrations, the mixture is incubated for another 15 minutes.
Intracellular cAMP is then extracted by the addition of 20 μL of 1M HCl and centrifugation (2000×g, 4° C., for 15 minutes). The supernatants are frozen in liquid nitrogen and stored at −20° C.
The cAMP contents of the samples are determined by radioimmunoassay (Amersham) and the pA2 values of antagonistically acting substances are determined graphically.
The compounds of general formula (I) exhibit CGRP-antagonistic properties in the in vitro test model described, in a dosage range of between 10−11 to 10−5 M.
In view of their pharmacological properties the compounds of general formula (I) and the salts thereof with physiologically acceptable acids or bases are thus suitable for the acute and prophylactic treatment of headaches, particularly migraine or cluster headaches. Moreover, the compounds of general formula (I) also have a positive effect on the following diseases: non-insulin-dependent diabetes mellitus ("NIDDM"), cardiovascular diseases, morphine tolerance, skin diseases, particularly thermal and radiation-induced skin damage including sunburn, inflammatory diseases, e.g., inflammatory diseases of the joints (arthritis), inflammatory lung diseases, allergic rhinitis, asthma, diseases accompanied by excessive vasodilatation and consequent reduced circulation of blood through the tissues, e.g., shock and sepsis. The symptoms of menopausal hot flushes in oestrogen-deficient women caused by vasodilatation and increased blood flow are favorably affected by the CGRP-antagonists of the present application in a preventive and acute-therapeutic capacity, this therapeutic approach being distinguished from hormone replacement by the absence of side effects. Furthermore, the compounds of general formula (I) have an alleviating effect on pain in general.
The dosage required to achieve a corresponding effect is conveniently 0.001 to 30 mg/kg of body weight, preferably 0.01 to 5 mg/kg of body weight, when administered intravenously or subcutaneously and 0.01 to 50 mg/kg of body weight, preferably 0.1 to 30 mg/kg of body weight when administered orally, nasally, or by inhalation, 1 to 3× a day in each case.
For this, the compounds of general formula (I) prepared according to the invention, optionally combined with other active substances such as, e.g., antiemetics, prokinetics, neuroleptics, antidepressants, neurokinine antagonists, anticonvulsants, histamine-H1 receptor antagonists, antimuscarinics, β-blockers, α-agonists, and α-antagonists, ergot alkaloids, mild analgesics, non-steroidal antiinflammatories, corticosteroids, calcium antagonists, 5-HT1D agonists or other anti-migraine agents, together with one or more inert conventional carriers and/or diluents, e.g., with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetylstearyl alcohol, carboxymethylcellulose, or fatty substances such as hard fat or suitable mixtures thereof, may be formulated into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, metered dose aerosols, or suppositories.
The active substances which may be used for the abovementioned combinations thus include, for example, meloxicam, ergotamine, dihydroergotamine, metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, dexamethasone, flunarizine, dextropropoxyphene, meperidine, propranolol, nadolol, atenolol, clonidine, indoramine, carbamazepine, phenytoin, valproate, amitriptyline, lidocaine, diltiazem, or sumatriptan and other 5-HT1D-agonists such as, for example, naratriptan, zolmitriptan, avitriptan, rizatriptan and eletriptan. The dosage of these active substances is expediently 1/5 of the lowest recommended dose to 1/1 of the normally recommended dose, i.e., for example, 20 to 100 mg of sumatriptan.
The invention further relates to the use of the compounds of general formula (I) as valuable adjuvants for the production and purification (by affinity chromatography) of antibodies as well as, after suitable radioactive labeling, for example, by direct labeling with 125I or 131I or by tritiation of suitable precursors, for example, by replacing halogen atoms with tritium, in RIA and ELISA assays and as a diagnostic or analytical adjuvant in neurotransmitter research.
The Examples which follow are intended to illustrate the invention:
Preliminary Remarks: Satisfactory elementary analyses, IR, UV, 1H-NMR, and generally also mass spectra have been obtained for all of the compounds. Unless otherwise stated, Rf values were obtained using ready-made silica gel TLC plates 60 F254 (E. Merck, Darmstadt, Item No. 1.05714) without chamber saturation. If no detailed information is given as to the configuration, it is not clear whether it is a pure enantiomer or whether partial or even complete racemization has occurred. The following eluants or mixtures of eluants were used for the chromatography:    El A=ethyl acetate/methanol 100/5 (v/v)    El B=ethyl acetate/methanol 80/20 (v/v)    El C=ethyl acetate/methanol/conc. ammonia 80/20/1 (v/v/v)    El D=dichloromethane/cyclohexane/methanol/conc. ammonia 70/15/15/2 (v/v/v/v)    El E=ethyl acetate/glacial acetic acid 99/1 (v/v)    El F=ethyl acetate/methanol/glacial acetic acid 90/10/1 (v/v/v)    El G=dichloromethane/methanol/conc. ammonia 90/10/1 (v/v/v)    El H=petroleum ether/ethyl acetate 1/1 (v/v)    El I=dichloromethane/methanol/glacial acetic acid 90/10/1.5 (v/v/v)    El K=dichloromethane/isopropanol 9/1 (v/v)    El L=ethyl acetate/methanol 9/1 (v/v)    El M=dichloromethane/methanol/conc. ammonia 75/25/0.5 (v/v/v)    El N=dichloromethane/ethyl acetate 1/1 (v/v)    El O=dichloromethane/methanol 95/5 (v/v)    El P=dichloromethane/ethyl acetate/cyclohexane/methanol/conc. ammonia (60/16/5/5/0.6 v/v/v/v/v)
The following abbreviations are used in the description of the experiments:    Mp.: melting point    (D): (decomposition)    DIEA: N,N-diisopropylethylamine    Boc: (1,1′-dimethylethoxy)carbonyl    TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate    HOBt: 1-hydroxybenzotriazole hydrate    CDT: 1,1′-carbonyldi-(1,2,4-triazole)    THF: tetrahydrofuran    DMF: dimethylformamide    EE: ethyl acetate    PE: petroleum ether    LM: solvents    I. No.: Item number
The meanings of the symbols consisting of letters and numbers used in the Examples are shown in the following summary:
A. Preparation of Intermediate Compounds

Cyclopropane CGRP antagonists, medicaments containing these compounds, and method for the production thereof

Abstract: A compound of general formula (I)

Abstract: wherein R and R1 are as defined herein, or a tautomer, diastereomer, enantiomer, or salt thereof, particularly the physiologically acceptable salts thereof, which have valuable pharmacological properties, particularly CGRP-antagonistic properties, pharmaceutical compositions containing the compound, their use, and processes for preparing them.

Boehringer Ingelheim Pharma GmbH & Co. KG


The present invention provides a microwave integrated circuit device in which a sufficiently large gain can be obtained even in a high-frequency region by effectively reducing a ground inductance of a transistor. The device includes both a semiconductor substrate on which a bipolar transistor is formed and a microstrip line formed on the semiconductor substrate. The microstrip line is constituted of a grounded conductive layer, which is electrically connected to both ends of a base electrode, and input and output signal lines connected to emitter and collector electrodes of the transistor, respectively.

The present invention relates to a microwave integrated device and, more specifically, to a microwave integrated circuit device of a monolithic structure in which a transistor amplifier and a transmission line are formed on a single semiconductor substrate.
In a microwave integrated circuit (MIC) used in a microwave band and a millimeter wave band, especially in a monolithic microwave integrated circuit (MMIC) wherein a bipolar transistor is used for an active device and both a transistor amplifier and a transmission line are formed on a single semiconductor substrate, the transmission line is generally constituted of a microstrip line and a coplanar line.
FIG. 1 is a plan view of the arrangement of a prior art MMIC using a microstrip line.
As illustrated in FIG. 1, a multi-emitter transistor having a collector region 103, a base region 104 and an emitter region 105 is formed, as a bipolar transistor 102, on a semiconductor substrate (e.g., GaAs substrate) 101.
The transistor 102 serves as a base-grounded amplifier, and its emitter electrode is connected to an input signal line 108, and its collector electrode is connected to an output signal line 109.
Base electrodes of the transistor 102 are connected in common by a drawing line 110, and both ends of the line 110 are connected to a grounded conductive layer (not shown) formed on the undersurface of the semiconductor substrate 101 through via holes 111 and 112, respectively.
Since, in the arrangement of the prior art MMIC, a line extending from the base electrode and the grounded conductive layer is long, a parasitic inductor (hereinafter referred to as a ground inductor) L is formed on the line between the base electrode and grounded conductive layer (GND).
The value of ground inductor L is generally small and thus causes no specific problem in a frequency region of several gigahertz (GHz). In a high-frequency region of 10 odd gigahertz (GHz), however, the gain of the transistor 102 will be decreased.
If, in particular, the transistor 102 is constituted as a multi-emitter one, as shown in FIG. 1, with a view to increasing in output, the transistor 102 is expanded up and down in FIG. 1, or in a direction perpendicular to a transmission direction of a signal which flows from the emitter electrode to the collector electrode and thus the drawing line 110 is lengthened. By the multi-emitter, a low impedance of the transistor will be brought in addition to an increase in the value of ground inductor L, and thus susceptible to the ground inductor; therefore, the gain of the transistor is greatly lowered.
If a coplanar line is used as a transmission line in place of the microstrip line, the base electrode is connected to a ground conductor provided outside a transistor region on the semiconductor substrate without using any via holes. In this case, too, the problem of the decrease in gain occurs and if, in particular, the transistor is formed as a multi-emitter one, the problem becomes more serious.
In the foregoing prior art MMIC using a microstrip line or a coplanar line as a transmission line, the gain of the transistor is lowered by the ground inductor of the transistor in a high-frequency region of 10 odd megahertz (MHz). If, in particular, the transistor is constituted as a multi-emitter one to increase in output, its gain is greatly decreased, and thus the multi-emitter transistor cannot be taken advantage of.


Systems and methods for maintaining an order of transactions in the coherence point. The coherence point stores attributes associated with received transactions in an input request queue (IRQ). When a new transaction is received by the coherence point, the IRQ is searched for other entries with the same request address or the same victim address as the new transaction. If one or more matches are found, the new transaction entry points to the entry storing the most recently received transaction with the same address. The new transaction is stalled until the transaction it points to has been completed in the coherence point.

1. Field of the Invention
The present invention relates generally to the field of computer systems, and in particular to methods and mechanisms for maintaining order among memory transactions.
2. Description of the Related Art
A system on chip (SoC) often includes multiple input/output (I/O) devices and a processor sharing one or more memory devices via a memory controller. Many different agents may generate memory transactions and convey these memory transactions to the memory controller. Often, a coherence point is used to maintain the ordering and coherence of these memory transactions within the SoC.
Transactions received by a coherence point may include a request address and in some cases, a victim address. If multiple transactions received by the coherence point target the same address, then these transactions should be completed in the order in which they were received by the coherence point. However, the coherence point may store the transactions in a queue which is not a first-in-first-out (FIFO) queue, and so the order of entries in the queue is not an indication of order.


Transmission patterns for pilot symbols transmitted from a mobile station or base station are provided. The patterns may be selected according to a location of the mobile station with respect to one or more antennas are provided. In some aspects, the pattern may be selected based upon the distance between the mobile station and the one or more antennas. In other aspect, the pattern may be based upon whether the mobile station is in handoff.

I. Field
The present document relates generally to wireless communication and amongst other things to handoff in a wireless communication system.
II. Background
An orthogonal frequency division multiple access (OFDMA) system utilizes orthogonal frequency division multiplexing (OFDM). OFDM is a multi-carrier modulation technique that partitions the overall system bandwidth into multiple (N) orthogonal frequency subcarriers. These subcarriers may also be called tones, bins, and frequency channels. Each subcarrier is associated with a respective sub carrier that may be modulated with data. Up to N modulation symbols may be sent on the N total subcarriers in each OFDM symbol period. These modulation symbols are converted to the time-domain with an N-point inverse fast Fourier transform (IFFT) to generate a transformed symbol that contains N time-domain chips or samples.
In a frequency hopping communication system, data is transmitted on different frequency subcarriers in different time intervals, which may be referred to as "hop periods". These frequency subcarriers may be provided by orthogonal frequency division multiplexing, other multi-carrier modulation techniques, or some other constructs. With frequency hopping, the data transmission hops from subcarrier to subcarrier in a pseudo-random manner. This hopping provides frequency diversity and allows the data transmission to better withstand deleterious path effects such as narrow-band interference, jamming, fading, and so on.
An OFDMA system can support multiple mobile stations simultaneously. For a frequency hopping OFDMA system, a data transmission for a given mobile station may be sent on a "traffic" channel that is associated with a specific frequency hopping (FH) sequence. This FH sequence indicates the specific subcarrier to use for the data transmission in each hop period. Multiple data transmissions for multiple mobile stations may be sent simultaneously on multiple traffic channels that are associated with different FH sequences. These FH sequences may be defined to be orthogonal to one another so that only one traffic channel, and thus only one data transmission, uses each subcarrier in each hop period. By using orthogonal FH sequences, the multiple data transmissions generally do not interfere with one another while enjoying the benefits of frequency diversity.
An accurate estimate of a wireless channel between a transmitter and a receiver is normally needed in order to recover data sent via the wireless channel. Channel estimation is typically performed by sending a pilot from the transmitter and measuring the pilot at the receiver. The pilot signal is made up of pilot symbols that are known a priori by both the transmitter and receiver. The receiver can thus estimate the channel response based on the received symbols and the known symbols.
A code division multiple access (CDMA) system has a universal frequency reuse that makes it possible for mobile users to receive and send the same signal simultaneously from and to multiple base stations or sectors of a base station. Soft and softer handoff in CDMA systems are techniques whereby mobiles near cell, and sector in the case of softer handoff, boundaries communicate the same transmitted signals to more than one base station or sector of a base station. Soft and softer handoff provides enhanced communication quality and a smoother transition compared to the conventional hard handoff. Soft and softer handoff is intrinsic to a CDMA system, as transmitted signals of different users occupy the same time and frequency allocation. Different users can be separated based on the respective spreading signatures.
Supporting soft and softer handoff in orthogonal multiple-access systems such as TDMA, FDMA and OFDMA is far more difficult and often requires special planning Consider a reverse link transmission in FH-OFDMA. Each user is assigned a non-overlapping time and frequency resource. As such there is little or no intra-cell. However, it is often not possible to reliably detect the signal in a nearby sector or cell, as the interference is considerably large compared to the signal. Low signal-to-noise ratio causes the channel estimation to be inaccurate, further degrading the overall detection performance. Often, the post-detection signal-to-noise ratio (SNR) is too low for the signal observed in a nearby cell/sector to be useful. Techniques such as active set based restricted frequency (ASBR) hopping and common hopping sequence can be used to help improve the detection reliability of the signal observed in a nearby sector/cell. These techniques, however, result in smaller usable system resources (e.g., bandwidth) and often require significant planning.
Therefore, there is a need to find efficient approaches to provide soft and softer handoff in OFDMA systems while minimizing the amount of overhead required to perform the soft and softer handoff.

Softer and soft handoff in an orthogonal frequency division wireless communication system


A method for manufacturing a lead frame includes degreasing and activating the surface of a metal sheet, providing the plating solution containing nickel(II) sulfamate tetrahydrate, (Ni(H.sub.2 NSO.sub.3).sub.2.4H.sub.2 O), manganese(II) sulfamate tetrahydrate (Mn(H.sub.2 NSO.sub.3).sub.2.4H.sub.2), nickel (II) chloride hexahydrate (NiCl.sub.2.6H.sub.2 O) and boric acid, plating the metal sheet in the plating solution to form a Ni--Mn alloy layer, and forming a Pd or Pd alloy layer on the Ni--Mn alloy layer.

1. Field of the Invention
The present invention relates to a lead frame having an improved plating layer and a method for manufacturing the same.
2. Description of the Related Art
As shown in FIG. 1, Silver(Ag) plating is selectively performed on a coined part 11 and a pad part 12, where a chip is mounted on a conventional lead frame 10. To enhance soldering properties after resin molding in a semiconductor package process, solder plating is performed on an outer lead 13 of the lead frame 10 using tin-lead (Sn--Pb). The wet process required for solder plating the resin-molded structure causes deterioration in the reliability of the lead frame.
To solve the above problem, a method for pre-coating a lead frame 20 has been developed with a plating layer having good solder wettability before the semiconductor packaging process. As shown in FIG. 2, the lead frame material, a copper (Cu) sheet 21, is coated with a nickel (Ni) layer 22. A palladium (Pd)--Ni alloy layer 23 is coated on the Ni layer 22. A Pd layer 24 is coated on the Pd--Ni alloy layer 23.
The Ni layer 22 is formed using a plating solution based on nickel(II) sulfamate tetrahydrate (Ni(H.sub.2 NSO.sub.3).sub.2.4H.sub.2 O). The nickel (II) sulfamate tetrahydrate is a Ni salt of amid sulfonic acid available in the form of a crystal or oversaturated nickel(II) sulfamate tetra hydrate solution, which has a high solubility and increases the metal concentration of the plating bath. As the plating thickness increases, the internal stress and ductility of the metal sheet tend to decrease.
To solve the above problem, first and second additives of an organic compound are added to the Ni plating solution. The first additive is an auxiliary additive for controlling adsorption of a main polish, and enhancing crack-resistance of the plating layer. The first additive includes saccharine, naphthalene-1,3,6-trisulfonic acid trisodium salt hydrate (C.sub.10 H.sub.5 Na.sub.3 O.sub.9 S.sub.3) and naphthalene-1.5-disulfonic acid disodium salt (C.sub.10 H.sub.6 Na.sub.2 O.sub.6 S.sub.2), and each includes an .dbd.C--SO.sub.2 group.
A second additive is added because the first additive has no leveling effect for planarizing the plating surface. The second additive is a leveler, having strong adsorption, and is co-deposited with Ni to allow polishing and leveling of the plating. The second additive which is most widely used has C.dbd.O, C.dbd.C, C.tbd.C, C.dbd.N, C.tbd.N and N.dbd.N groups.
Also, an additional additive is a surface active agent for lowering the surface tension of the solution. This additional additive draws hydrogen (H.sub.2) bubbles away from the plating material to reduce the number of pits caused by the H.sub.2 bubbles.
However, the Ni layer 22 contains sulfur which is a main component of the first additive, and thus the chemical solubility is sharply increased. During annealing at 200.degree. C. or higher, the sulfur causes rearrangement of atoms, which causes brittleness of the plating layer. This causes brittleness of the Ni layer 22 as an indirect thermal effect of a process of assembling a semiconductor, and thereby causes cracking of the plating during a subsequent trimming and forming process.

Lead frame having a Ni-Mn alloy layer and a Pd layer


A surge arrester having electrical connections to a source of power and to electrical ground is retrofitted with a spark gap assembly to improve performance of the surge arrester. This is accomplished by a providing a spark gap module including at least one spark gap assembly sealed within a housing, disconnecting an electrical connection of the surge arrester, and connecting the spark gap module between the electrical connection and the surge arrester.

The invention relates to surge arresters.
Electrical transmission and distribution equipment is subject to operating voltages within a fairly narrow range under normal conditions. However, system disturbances, such as lightning strikes, poor regulation, unbalanced loads, and switching surges, may produce momentary or extended voltage levels, especially on one or more phases of a multi-phase system, that greatly exceed the levels experienced by the equipment during normal operating conditions. These system variations often are referred to as overvoltage conditions and may lead to the damage of surge arresters installed to protect against transient overvoltages.
If not protected from transient current surges, critical and expensive equipment, such as transformers, switching devices, computer equipment, and electrical machinery, may be damaged or destroyed. Accordingly, system designers routinely use surge arresters to protect system components from dangerous overvoltage conditions.
A surge arrester is a protective device that is commonly connected in parallel with a comparatively expensive piece of electrical equipment so as to shunt or divert overvoltage-induced current surges safely around the equipment, thereby protecting the equipment and its internal circuitry from damage. The surge arrester normally operates in a high impedance mode that provides a relatively high impedance current path to ground. When exposed to a transient overvoltage condition, the surge arrester operates in a low impedance mode that provides a relatively low impedance current path to electrical ground (or earth). The impedance of the current path is substantially lower than the impedance of the equipment being protected by the surge arrester when the surge arrester is operating in the low impedance mode, and is otherwise substantially higher than the impedance of the protected equipment when in the high impedance mode.
Upon discharge of the transient overvoltage condition, the surge arrester returns to operation in the high impedance mode. This prevents normal current at the system frequency from following the surge current to ground (or earth) through the surge arrester.
Gapless surge arresters typically include an outer enclosure or housing made of an electrically insulating material, a pair of electrical terminals for connecting the arrester between a line-potential conductor and electrical ground (or earth), and an array of other electrical components that form a series electrical path between the terminals. These components typically include a series assembly of voltage-dependent, nonlinear resistive elements, referred to as varistors. A varistor is characterized by having a relatively high resistance when exposed to a normal operating voltage, and a much lower resistance when exposed to a higher voltage, such as is associated with a transient overvoltage condition. A metal-oxide varistor (xe2x80x9cMOVxe2x80x9d) is one type of varistor. In addition to varistors, a surge arrester may include one or more spark gap assemblies housed within or outside the insulating enclosure and electrically connected in series with the varistors.
In one general aspect, the invention features retrofitting a surge arrester having electrical connections to a source of power and to electrical ground with a series connected spark gap assembly to improve performance of the surge arrester. A spark gap module including at least one spark gap assembly sealed within a housing is provided. An electrical connection of the surge arrester is disconnected, and the spark gap module is connected between the electrical connection and the surge arrester.
Embodiments may include one or more of the following features. For example, the spark gap module may be connected between the surge arrester and the source of power, or between the surge arrester and electrical ground.
The surge arrester may be a gapless surge arrester. For example, the surge arrester may be a gapless distribution arrester having a 3-36 kV rating, and rated for normal duty (5 kA) or heavy duty (10 kA) operation, although not limited to these ratings.
The spark gap module may consist of one or more gap assemblies positioned between a pair of terminals, with the one or more gap assemblies and the terminals sealed within the housing. Each terminal may include a threaded bolt hole. The housing may be a porcelain or polymer housing that may or may not have defined weathersheds.
The spark gap assembly may include a resistive or capacitive graded gap structure. The gap structure may include electrodes separated by silicon carbide grading resistors, ceramic capacitors, or other impedance elements.
In another general aspect, the invention features a retrofit module for adding a spark gap assembly to a surge arrester to improve performance of the surge arrester. The module includes a housing, at least one spark gap assembly sealed within the housing, and structure for electrically connecting the spark gap assembly to a surge arrester, the structure being accessible from outside the housing.
Other features and advantages will be apparent from the following description, including the drawings and the claims.

Spark gap retrofit module for surge arrester