Compounds containing tetrahydrobenzindole which bind to serotonin receptor and are useful in treatment or prevention of disease induced by abnormality of central peripheral serotonin controlling functions.

This invention relates to a tetrahydrobenzindole derivative or an intermediate thereof. Since this tetrahydrobenzindole derivative has the ability to bind to serotonin receptors in the living body, it also relates to the treatment and prevention of various diseases which are induced by the abnormality of serotonin controlling functions.
In the present society, the environment which surrounds us is sharply changing, and adaptation for it is becoming more and more difficult. Thus, a part which is too much for adaptation for the social environment is accumulated in our bodies as stress and sometimes causes abnormality of not only body functions but also mental functions. Under such circumstances, importance of drug therapy has been increasing more and more, so that development of effective drugs has been put forward.
Since the indication about the action of serotonin (5-HT) in the central nervous system, classification and distribution of serotonin receptors have been revealed gradually. By the detailed analysis of serotonin receptors using molecular biological means in recent years, 5-HT1 and its subtypes, 5-HT2 and its subtypes, 5-HT3, 5-HT4, 5-HT6, 5-HT7 and the like have been specified and a total of 14 different serotonin receptors have been proposed [R. D. Ward et al., Neuroscience, 64, 1105-1111 (1995)].
Studies on the physiological functions of serotonin receptors have also been making progress, and not only their relation to appetite, body temperature regulation, blood pressure regulation and the like body functions but also their relation to depression, anxiety, schizophrenia, sleep disorders and the like mental functions have been revealed [P. L. Bonate et al., Clinical Neuropharmacology, 14, 1-16 (1991)]. Actually, 5-HT1A receptor agonists, 5-HT2 receptor inhibitors and 5-HT re-uptake inhibitors are now used in the clinical field. It has been reported also that, since a drug group classified as atypical among already known schizophrenia treating drugs has the affinity particularly for serotonin receptor 5-HT6, the serotonin receptor 5-HT6 is closely related to the efficacy of these drugs [R. D. Ward et al., Neuroscience, 64, 1105-1111 (1995)].
It has been reported that several atypical schizophrenia treating drugs including clozapine have strong affinity for the 5HT6 receptor, and several typical schizophrenia treating drugs show high affinity for both of the 5HT6 and 5HT7 receptors [B. L. Roth et al., J. Pharmacol. Exp. Ther., 268 (3), 1403-1410, 1994]. Also, it has been reported that a 5HT1A partial agonist, buspirone, has high therapeutic effect for patients having both symptoms of depression and anxiety [Tollefson G. D. et al., Psychopharmacol. Bull., 27, 163-170, 1991]. In addition, the importance of serotonin receptors in various physiological functions was been reported in a large number, for example, it has been reported that certain N-butylpiperidines inhibit serotonin receptor 5-HT4 selectively and are useful for the treatment of irritable bowel syndrome [L. M. Gaster et al., J. Med. Chem., 38, 4760-4763, 1995], and it has been assumed that 5-HT7 exerts an important function in the human circadian rhythm regulation [T. W. Lovenberg et al., Neuron, 11, 449-458, 1993].
In addition, it is considered that they are exerting various physiological functions by distributing not only in human and animal brains but also broadly in smooth muscle tissues such as the spleen, stomach, ileum, small intestines, coronary vessel and the like [A. J. Sleight, DN and P, 214-223, 1997]. In consequence, creation of a substance which acts upon 5-HT7 receptor is considerably profitable for the studies of physiological functions in these organs and the treatment and prevention of diseases induced by functional abnormality in these organs.
The present inventors have already found a substance which has strong ability to bind to the 5-HT7 receptor in the living body. That is, according to the inventions by the present inventors (WO 98/00400, Japanese Patent Application No. 9-358380, Japanese Patent Application No. 9-358381, Japanese Patent Application No. 10-85913, Japanese Patent Application No. 10-136872, Japanese Patent Application No. 10-229709 and Japanese Patent Application No. 10-319336), there are provided novel tetrahydrobenzindole derivatives which strongly bind to 5-HT7 receptor in the living body and pharmaceutical compositions which comprise these compounds.
As described above, novel tetrahydrobenzindole derivatives which strongly bind to 5-HT7 receptor in the living body have been provided, but creation of a compound which selectively binds to the 5-HT7 receptor will be useful for the treatment and prevention of various diseases which are considered to be induced by the abnormality of central and peripheral serotonin controlling functions, such as mental diseases (manic-depressive psychosis, anxiety, schizophrenia, epilepsy, sleep disorders, biological rhythm disorders, migraine and the like), cardiovascular diseases (hypertension and the like) and gastrointestinal disorders, and will also provide medicaments having high safety that can prevent generation of unexpected side effects. It will also provide compounds which have high utility value in studies on the elucidation of physiological functions of 5-HT7 receptor whose functions are not clear yet.
Thus, the object of the invention is to provide a compound which has strong affinity for the 5-HT7 receptor in the living body and binds selectively to the 5-HT7 receptor.
In order to solve these problems, the present inventors have examined on various compounds. As a result, it was found that certain tetrahydrobenzindole derivatives have strong affinity for 5-HT7 receptor in the living body and selectively bind to 5-HT7 receptor, thereby resulting in the accomplishment of the invention. That is, according to the invention, novel tetrahydrobenzindole derivatives and pharmaceutical compositions which comprise these compounds are provided, and intermediates useful in producing these compounds are also provided. Accordingly, the invention comprises the following constructions.
1. A compound represented by formula (1):
wherein R1 represents a hydrogen atom, a lower alkyl group or an aralkyl group; R2 represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, an alkoxy group, an acyl group, an acyloxy group, an alkoxycarbonyl group, a nitro group, an amino group, a substituted amino group, a carbamoyl group or an alkylcarbamoyl group, and n is an integer of from 2 to 6; and xcex1 represents the following formula (a), (b), (c), (d) or (e):
wherein
in formulae (a) and (b), R3 represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group or an alkoxy group, X represents NR10, NCONR11R12, S, SO, SO2 or O, R10 represents a hydrogen atom, a lower alkyl group, an alkenyl group, an oxoalkyl group, an aralkyl group, a cyanoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, a substituted aminoalkyl group, an alkoxycarbonylalkyl group, a carbamoylalkyl group, an alkylcarbamoylalkyl group, an acyl group or an alkoxycarbonyl, R11 and R12 independently represent a hydrogen atom or a lower alkyl group, and Y represents a methylene group or a carbonyl group,
in formula (c), R4 represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a cyano group, a trihalomethyl group, an alkoxy group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an alkoxycarbonyl, a sulfamoyl group, an amino group, a substituted amino group, a carbamoyl group, an alkylcarbamoyl group, an acyl group or a carboxy group, R5 represents a hydrogen atom, a lower alkyl group, a hydroxy group, an alkoxy group, an acyl group, a phenyl group or a substituted phenyl group, k is 0 or an integer of from 1 to 3, m is 0 or an integer of from 1 to 3, and each of A and B represents a group which forms a benzene ring, a thiophene ring, a furan ring, an imidazole ring or a pyrazole ring via a double bond, with the proviso that k+m is an integer of from 1 to 3, and
in formulae (d) and (e), R4 is as defined in the foregoing, G represents CH2, S, O or Cxe2x95x90O, D represents CH or N, p is an integer of from 1 to 3, each of E and J represents a group which forms a benzene ring or a pyridine ring via a double bond, and R6 and R7 independently represent a hydrogen atom, a lower alkyl group, a hydroxy group, an alkoxy group, an acyl group, a phenyl group or a substituted phenyl group or a pharmaceutically acceptable salt thereof.
2. A compound according to the aforementioned item 1, which is represented by formula (1a):
wherein R2, R3, X and n are as defined in the foregoing, or a pharmaceutically acceptable salt thereof.
3. A compound according to the aforementioned item 2, which is represented by formula (1a-1):
wherein X and n are as defined in the foregoing, or a pharmaceutically acceptable salt thereof.
4. A compound according to the aforementioned item 1, which is represented by formula (1b):
wherein R2, R3, X, Y and n are as defined in the foregoing, or a pharmaceutically acceptable salt thereof.
5. A compound according to the aforementioned item 4, which is represented by formula (1b-1):
wherein X, Y and n are as defined in the foregoing, or a pharmaceutically acceptable salt thereof.
6. A compound according to the aforementioned item 1, which is represented by formula (1c):
wherein R1, R4, R5, A, B, k, m and n are as defined in the foregoing, or a pharmaceutically acceptable salt thereof.
7. The compound or a pharmceutically acceptable salt thereof according to the aforementioned item 6, wherein k+m is 2.
8. The compound or a pharmaceutically acceptable salt thereof according to the aforementioned item 6 or 7, wherein n is 4.
9. A compound according to claim 1, which is represented by formula (1d):
wherein R4, G, D, E, J, p and n are as defined in the foregoing, or a pharmaceutically acceptable salt thereof.
10. A compound according to the aforementioned item 1, which is represented by formula (1e):
wherein R4, R6, R7, D and n are as defined in the foregoing, or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition which comprises any one of the compounds of the aforementioned items 1 to 10 or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition for treatment or prevention of mental diseases, which comprises any one of the compounds of the aforementioned items 1 to 10 or a pharmaceutically acceptable salt thereof.
13. A compound represented by formula (aQ):
wherein Z represents NR13, NCONR11R12, SO or SO2, R13 represents a carbamoylalkyl group, an alkylcarbamoylalkyl group, an alkenyl group or an oxoalkyl group, R11 and R12 independently represent a hydrogen atom or a lower alkyl group, Q represents a hydrogen atom or a protecting group and R3 is as defined in the foregoing, or a salt thereof.
14. A compound represented by formula (bQ):
wherein R3, Y, Z and Q are as defined in the foregoing, or a salt thereof.
In the descriptions of this specification concerning the chemical substances and production methods thereof, the term halogen atom means each atom of fluorine, chlorine, bromine and iodine, the term lower alkyl means methyl, ethyl or the like straight chain alkyl having from 1 to 4 carbon atoms and isopropyl, isobutyl, t-butyl or the like branched-chain alkyl or a halogen-substituted compound thereof, and the term base to be used as a catalyst means sodium hydroxide, potassium carbonate, triethylamine or the like. In addition, the term substituent group means a group other than hydrogen atom.
In the formula (1), each symbol has the following meaning;
R1 represents hydrogen atom, lower alkyl or aralkyl,
R2 represents hydrogen atom, halogen atom, lower alkyl, hydroxy, alkoxy (preferably having from 1 to 4 carbon atoms, such as methoxy or ethoxy), acyl (preferably having from 1 to 4 carbon atoms), acyloxy (preferably having from 1 to 4 carbon atoms), alkoxycarbonyl (the alkyl moiety preferably having from 1 to 4 carbon atoms), nitro, amino, substituted amino (preferably, amino substituted by lower alkyl, such as dimethylamino or diethylamino), carbamoyl or alkylcarbamoyl (the alkyl moiety preferably having from 1 to 4 carbon atoms), and n is an integer of from 2 to 6.
In the formulae (a) and (b)
R3 represents hydrogen atom, halogen atom, lower alkyl, hydroxy or alkoxy (preferably having from 1 to 4 carbon atoms, such as methoxy or ethoxy), X represents NR10, NCONR11R12, S, SO, SO2 or O, R10 represents hydrogen atom, lower alkyl, alkenyl (preferably having from 1 to 4 carbon atoms), oxoalkyl (preferably having from 1 to 4 carbon atoms), aralkyl, cyanoalkyl (the alkyl moiety preferably having from 1 to 4 carbon atoms), hydroxyalkyl (preferably having from 1 to 4 carbon atoms), alkoxyalkyl (each alkyl moiety preferably having from 1 to 4 carbon atoms), aminoalkyl (preferably having from 1 to 4 carbon atoms), substituted aminoalkyl (preferably an alkylaminoalkyl in which each alkyl moiety has from 1 to 4 carbon atoms, such as dimethylaminoethyl), alkoxycarbonylalkyl (each alkyl moiety preferably having from 1 to 4 carbon atoms), carbamoylalkyl (the alkyl moiety preferably having from 1 to 4 carbon atoms, such as carbamoylmethyl or carbamoylethyl), alkylcarbamoylalkyl (each alkyl moiety preferably having from 1 to 4 carbon atoms), acyl (preferably having from 1 to 4 carbon atoms) or alkoxycarbonyl (the alkyl moiety preferably having from 1 to 4 carbon atoms, such as methoxycarbonyl or ethoxycarbonyl), R11 and R12 independently represent hydrogen atom or lower alkyl, and Y represents methylene or carbonyl.
In the compounds represented by the formula (aQ) or (bQ), which are novel intermediates among compounds in which the free valency N of the group represented by the formula (a) or (b) is substituted with Q (represents hydrogen atom or a protecting group), R3 represents hydrogen atom, halogen atom, lower alkyl, hydroxy or alkoxy (preferably having from 1 to 4 carbon atoms, such as methoxy or ethoxy), Z represents NR13, NCONR11R12, SO or SO2, R13 represents carbamoylalkyl (the alkyl moiety preferably having from 1 to 4 carbon atoms, such as carbamoylmethyl or carbamoylethyl), alkylcarbamoylalkyl (each alkyl moiety preferably having from 1 to 4 carbon atoms), alkenyl (preferably having from 1 to 4 carbon atoms, such as allyl) or oxoalkyl (preferably having from 1 to 4 carbon atoms, such as 2-oxo-propyl), and R11 and R12 independently represent hydrogen atom or lower alkyl.
In the formula (c),
R4 represents hydrogen atom, halogen atom, lower alkyl, hydroxy, cyano, trihalomethyl (wherein the halogen atom is as defined in the foregoing and the three halogen atoms may be the same or different from one another, preferably trifluoromethyl or the like), alkoxy (preferably having from 1 to 4 carbon atoms, such as methoxy or ethoxy), alkylthio (preferably having from 1 to 4 carbon atoms, such as methylthio or ethylthio), alkylsulfinyl (preferably having from 1 to 4 carbon atoms), alkylsulfonyl (preferably having from 1 to 4 carbon atoms), alkoxycarbonyl (the alkyl moiety preferably having from 1 to 4 carbon atoms), sulfamoyl, amino, substituted amino (preferably amino substituted by lower alkyl, such as dimethylamino or diethylamino), carbamoyl, alkylcarbamoyl (preferably the alkyl moiety is lower alkyl, such as dimethylcarbamoyl), acyl (preferably having from 1 to 4 carbon atoms, such as acetyl) or carboxy,
R5 represents hydrogen atom, lower alkyl, hydroxy, alkoxy (preferably having from 1 to 4 carbon atoms, such as methoxy or ethoxy) acyl (preferably having from 1 to 4 carbon atoms, such as acetyl), phenyl or substituted phenyl, and
k is 0 or an integer of from 1 to 3, m is 0 or an integer of from 1 to 3, with the proviso that k+m is an integer of from 1 to 3. Namely, the nitrogen atom binding to the methylene chain forms a five- to seven-membered ring, preferably a six-membered ring, and the nitrogen-containing hetero ring is condensed, via its double bond, with benzene ring, thiophene ring, furan ring, imidazole ring or pyrazole ring formed by A and B, so that the formula (c) as a whole represents indolinyl, tetrahydroquinolyl, tetrahydro isoquinolyl, 2,3,4,5-tetrahydro-3H-benzo[b]azepinyl, 2,3,4,5-tetrahydro-1H-benzo[c]azepinyl, 2,3,4,5-tetrahydro-1H-benzo[d]azepinyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridyl, 4,5,6,7-tetrahydropyrazolo[4,3-c]pyridyl and the like. Preferably, n is 4.
In the formulae (d) and (e),
R4 is as defined in the aforementioned formula (c) and similar group is desirable, G represents CH2, S, O or Cxe2x95x90O, D represents CH or N, p is an integer of from 1 to 3, each of E and J represents a group which forms benzene ring or pyridine ring via a double bond, and R6 and R7 independently represent hydrogen atom, lower alkyl, hydroxy, alkoxy (preferably having from 1 to 4 carbon atoms, such as methoxy or ethoxy), acyl (preferably acetyl or the like), phenyl or substituted phenyl (preferably phenyl substituted by halogen, such as chlorophenyl or bromophenyl).
In this connection, in the formula (1), R2, R3, R4 or R5 is a symbol which can represent all hydrogen atoms on the ring, and when R2, R3, R4 or R5 is a substituent group, it can be substituted on any hydrogen atom on the ring independently, so that there will be no substitution or one or more positions will be substituted by the same or different groups.
The compounds provided by the invention are produced by the chemical synthesis methods described in the following.
The compound represented by the formula (1) (to be referred to as xe2x80x9ccompound (1) of the inventionxe2x80x9d hereinafter) can be obtained by allowing a compound represented by a formula (5) [in the formula, xcex1 is as defined in the foregoing] or a salt thereof prepared in advance to react with a compound represented by a formula (4) [in the formula, W is a halogen atom, an alkylsulfonic ester residue such as methanesulfonyloxy or ethanesulfonyloxy or an arylsulfonic acid ester residue such as benzenesulfonyloxy or p-toluenesulfonyloxy, and R1, R2 and n are as defined in the foregoing] (to be referred to as xe2x80x9ccompound (4)xe2x80x9d hereinafter, the compounds represented by other formulae are also expressed in the same manner) prepared in advance (reaction formula 1).
The above reaction is carried out in the presence or absence of a base without solvent or after dilution with an inert solvent at a temperature within the range of from ordinary temperature to heating temperature. Examples of the inert solvent to be used include dioxane, tetrahydrofuran, acetone, methyl ethyl ketone, acetonitrile, dimethylformamide and the like, and examples of the base to be used include salts of alkali metals, such as sodium carbonate, potassium carbonate and the like carbonates and sodium bicarbonate, potassium bicarbonate and the like bicarbonates, and trialkylamines, pyridine bases and the like.
The aforementioned compounds (1a), (1a-1), (1b), (1b-1), (1c), (1d) and (1e) can be produced by appropriately selecting respective substituent groups of the above compounds (4) and (5).
When R1 is hydrogen atom in the compound (4) of the aforementioned reaction formula 1, a compound (4-2) is obtained by carrying out substitution reaction of respective aromatic ring of an organic synthesis material 2a,3,4,5-tetrahydrobenz[cd]indol-2-(1H)one [compound (2-1)] to obtain a compound (2-2) which is then allowed to react with a compound (3) [in the formula (3), W and n are as defined in the foregoing], or the compound (4-2) can be obtained by carrying out substitution reaction of respective aromatic ring of a compound (4-1) derived from the compounds (2-1) and (3) (reaction formula 2). In addition, the substituent group introduced on the aromatic ring may be converted into other substituent group by a chemical reaction before or after its reaction with the compound (5).
Also, when R1 is a lower alkyl or an aralkyl, the following reaction step can be used.
Benz[cd]indol-2 (1H) one [compound (2-0)] is used as the starting material and allowed to react with a compound (6) [in the formula (6), W is as defined in the foregoing, and R is a lower alkyl group or an aralkyl group] in the presence of a base to obtain a compound (2-0-1),
and then the compound (2-0-1) is allowed to undergo the reaction in an atmosphere of hydrogen using Raney nickel as a catalyst to obtain a compound (2-3).
When the compound (2-3) is used instead of the compound (2-1) in the above reaction formula 2, a compound (4-3) in which R1 in the compound (4) is R or a compound (4-4) in which R2 is a substituent group can be obtained (reaction formula 3)
Also, it is possible to carry out synthesis of the compound (1) of the invention using the following compound (4-5) instead of the compound (4) in the aforementioned reaction formula 1.
The compound (4-5) is synthesized using an alkene represented by CH2xe2x95x90CHxe2x80x94(CH2)nxe2x88x921xe2x80x94W [wherein n and W are as defined in the foregoing] or xe2x80x94(CH2)nxe2x88x921xe2x80x94W [wherein q is protected hydroxyl group, and n and W are as defined in the foregoing] instead of the compound (3) in the aforementioned reaction formula 2 or 3.
The compound (2-1-4) is allowed to react with CH2xe2x95x90CHxe2x80x94(CH2)nxe2x88x921xe2x80x94W or qxe2x80x94(CH2)nxe2x80x94W in the presence of a base and then converted into an aldehyde compound by allowing the alkene to react with osmium tetroxide and sodium periodate, or converted into an aldehyde compound represented by the compound (4-5) by, for example, carrying out deprotection and oxidation of q, and the desired compound (1) can be obtained by carrying out reductive aminoalkylation reaction of the aldehyde compound with a secondary amine represented by the compound (5) using sodium triacetoxyborohydride.
It is desirable to introduce the substituent group R2 into aromatic ring by a generally known aromatic electrophilic substitution reaction. Examples of the aromatic electrophilic substitution reaction include halogenation, Friedel-Crafts"" reaction-based alkylation and acylation and nitration.
In a preferred example of the halogenation, the reaction is carried out at a temperature of from 0xc2x0 C. to reflux temperature in carbon disulfide, carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane, acetic acid, water or the like solvent in the presence or absence of an appropriate catalyst. Examples of the halogenation agent to be used include fluorine, chlorine, bromine and iodine, as well as 1-fluoropyridinium trifurate, 1-fluoro-2,6-dichloropyridinium tetrafluoroborate and the like unsubstituted or substituted N-fluoropyridinium salts, N-fluoro-N-propyl-p-toluenesulfonamide and the like N-fluoro-N-alkyl-sulfonamides, N-fluorobenzenesulfonimide and the like N-fluorosulfonimides, sodium hypochlorite, N-bromosuccinimide and the like.
The Friedel-Crafts"" reaction is carried out at a temperature of from 0xc2x0 C. to reflux temperature in carbon disulfide, chloroform, dichloromethane, 1,2-dichloroethane, nitrobenzene or the like solvent in the presence of a catalyst. Examples of the alkylation agent to be used include halogenated hydrocarbons, as well as methanol, ethanol and the like alcohols and propene and the like olefin compounds. Examples of the acylation agent to be used include acetyl chloride, propyl chloride and the like acyl halides, as well as acetic anhydride and the like acid anhydrides and acetic acid, propionic acid and the like carboxylic acids. Alternatively, an acid chloride derivative is obtained using oxalic acid chloride, triphosgene or the like and then hydrolyzed using water, alcohol, amines and the like to convert it into respective carboxylic acid derivative, ester derivative and amide derivative. Examples of the catalyst to be used desirably include aluminum chloride, iron chloride, boron trifluoride, tin chloride, zinc chloride and the like Lewis acids, as well as hydrogen fluoride, sulfuric acid, polyphosphoric acid and the like proton acids.
In an example of the nitration, the reaction is carried out using concentrated nitric acid and concentrated sulfuric acid or using nitric acid in water, acetic acid or acetic anhydride solution. In addition, ethyl nitrate and the like nitric acid esters, acetyl nitrate and the like mixed acids and nitronium tetrafluoroborate and the like nitronium salts can also be used.
As occasion demands, the substituent group R2 introduced into the aromatic ring may be converted into other substituent group by a chemical reaction. The reaction may be carried out either before the reaction with the compound (5) or after completion of the reaction with the compound (5) in the reaction formula 1, with the proviso that it does not exert influence upon other functional groups, structures and the like. For example, acetyl group or the like acyl group can be converted into corresponding acyloxy group by allowing it to react with m-chloroperbenzoic acid, pertrifluoroacetic acid or the like peroxide in the presence of trifluoroacetic acid or the like acid catalyst as occasion demands, thereby effecting insertion of oxygen atom between the aromatic ring and carbonyl group. Thereafter, the acyloxy group can be converted into alkoxy group by removing the acyl group through hydrolysis or the like method and then allowing it to react with methyl iodide or the like alkylation agent in the presence of potassium carbonate, sodium bicarbonate or the like base. Also, methoxycarbonyl group or the like ester group can be converted into a carbamoyl derivative, an amide derivative or the like, when it is allowed to react, directly or after its hydrolysis into carboxylic acid, with ammonia, a primary amine, a secondary amine or the like via an active ester or the like reactive derivative.
In the aforementioned reaction formula 2, the compound (3) belongs to a so-called reaction intermediate and is generally available as a synthetic reagent or synthesized from diols represented by a formula HOxe2x80x94(CH2)n13 OH [wherein n is as defined in the foregoing]. That is, a diol is obtained as a dihalide by allowing it to react with thionyl chloride or thionyl bromide or as a disulfonate by allowing it to react with methanesulfonyl chloride or the like alkylsulfonic acid halide or benzenesulfonyl chloride or the like arylsulfonic acid halide. As another example of the halogenation reaction, halogenation using carbon tetrachloride or carbon tetrabromide in the presence of triphenylphosphine can also be used.
Next, the compound (5) (xcex1-H) shown in the aforementioned reaction formula 1 is described.
The compound (5) is any one of the groups (a) to (e) in which hydrogen atom is substituted on the N having free valency.
In the following, a compound in which hydrogen atom is substituted on the free valency N of the group (a) is called compound (aH). In the same manner, compounds in which hydrogen atom is substituted on the free valency N of the groups (b) to (e) are called compounds (bH) to (eH).
Compound (aH) is described.
When X represents either NR10 or NCONR11R12, the compound can be derived using commercially available 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles or from a commercially available tryptamine derivative and formaldehyde by, for example, the Pictet-Spengler reaction (e.g., Organic Reactions, 6, 151, 1951). Also, 9-position-modified products of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, derived from them by various chemical reactions, may be used. Their examples include 9-alkyl derivatives, 9-acyl derivatives, 9-carbamoyl derivatives, 9-alkoxycarbonyl derivatives and the like.
The aforementioned 9-position-modified products of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole can be obtained by protecting the 2-position secondary amino group of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles with a generally used protecting group, carrying out alkylation, acylation or the like chemical reaction and then effecting deprotection. It is desirable that the protecting group to be used is stable under alkylation, acylation and the like chemical reaction conditions and can be deprotected easily, and its examples include t-butoxycarbonyl group, benzyloxycarbonyl group or the like carbamate, as well as benzyl group and the like.
As an example of the synthesis of the aforementioned 9-position-modified product of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, it is desirable to carry out the reaction of a 2-position amino group-protected 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole derivative within the range of from low to heating temperature in the presence of sodium hydride, n-butyl lithium, lithium diisopropylamide or the like strong base, after its dilution with tetrahydrofuran, diethyl ether, toluene, 1,2-dimethoxyethane, dimethylformamide, dimethyl sulfoxide or the like inert solvent. Examples of the alkylation agent to be used include methyl iodide, ethyl bromide, allyl bromide or the like straight chain alkyl halide or straight chain alkenyl halide and isopropyl bromide, isobutyl bromide or the like branched-chain alkyl halide, as well as chloromethyl methyl ether, bromoacetonitrile, benzyl bromide, bromoacetamide, methyl bromoacetate, 2-chloro-N,N-dimethylethylamine and the like, and examples of the acylation agent to be used include acetyl chloride, propionyl chloride, isobutyryl chloride or the like acyl halide, as well as dimethylcarbamoyl chloride, diethylcarbamoyl chloride, methyl chloroformate, ethyl chloroformate and the like.
In addition, the 9-carbamoyl derivative and 9-alkoxycarbonyl derivative of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole can also be synthesized by subjecting the compound to chloroformylation with triphosgene and then allowing it to react with ammonia, methylamine and the like amines or methanol, ethanol and the like alcohols, in tetrahydrofuran, diethyl ether, toluene, 1,2-dimethoxyethane, dimethylformamide, dimethyl sulfoxide or the like inert solvent in the presence of sodium hydride, n-butyl lithium, lithium diisopropylamide or the like strong base.
Also, when X is any one of S, SO, SO2 and O, the compound (aH) can be synthesized by a generally known method. For example, 3,4-dihydro-1H-benzo[4,5]thieno[2,3-c]pyridine can be synthesized via cyclization, amidation, amide reduction and Pictet-Spengler cyclization of 4-(phenylthio)acetoacetic acid ethyl ester which is obtained from substituted or unsubstituted thiophenol and 4-chloroacetoacetic acid ethyl ester (J. Heterocyclic Chem., 16, 1321, 1979). In addition, it can be converted into a sulfoxide derivative or a sulfone derivative by oxidizing the 9-position sulfur atom. For example, 3,4-dihydro-9-oxo-9-xcex4-1H-benzo[4,5]thieno[2,3-c]pyridine or 3,4-dihydro-9,9-dioxo-9-xcex6-1H-benzo[4,5]thieno[2,3-c]pyridine can be obtained by protecting the 2-position amino group of 3,4-dihydro-1H-benzo[4,5]thieno[2,3-c]pyridine with t-butoxycarbonyl group, benzyloxycarbonyl group or the like protecting group, and then deprotecting the sulfur atom by its selective oxidation with m-chloroperbenzoic acid or hydrogen peroxide. On the other hand, 3,4-dihydro-1H-benzo[4,5]furo[2,3-c]pyridine can be synthesized, for example, via nitrile reduction, formamidation, cyclization and imine reduction of 3-cyanomethylbenzo[b]furan which is obtained from 3-(2H)-benzo[b]furanone and diethylcyanomethyl phosphate (JP-A-63-22581; the term xe2x80x9cJP-Axe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese patent applicationxe2x80x9d).
The compound (aQ) (Q is hydrogen atom or a protecting group) as a novel intermediate for the production of the compound (1) of the invention is a case in which the aforementioned X is Z and can be synthesized in the same manner as described above.
Next, the compound (bH) is described.
When X is O and Y is methylene, this can be synthesized by a generally known method. That is, as shown in the reaction formula 4, the primary amino group of a benzoxazine derivative (7) (Gupta, S. P. et al., Synthesis, 9, 660, 1974) is protected with benzyloxycarbonyl group or the like appropriate protecting group (Q) to obtain a compound (8), and then a compound (bH-1) can be synthesized via a chloroacetylated derivative (9), its cyclization to a pyrazinobenzoxazine derivative (10), a compound (11) by amide reduction and removal of the protecting group (Q) (E. W. Baxter et al., Bioorg. Med. Chem. Lett., 7, 763, 1997).
Also, when X is any one of S, SO and SO and Y is methylene, 1,2,3,4,4a,5-hexahydropyrazino[2,1-c]-1,4-benzthiazine can be synthesized in accordance with the method shown in the reaction formula 4 from a generally known compound 3,4-dihydro-3-aminomethyl-2H-1,4-benzthiazine (P. Melloni et al., J. Heterocyclic Chem., 20, 139, 1983), and a sulfoxide derivative and a sulfone derivative of the compound (bH) can be obtained by deprotecting the 6-position sulfur atom of the compound (11) through its selective oxidation with m-chloroperbenzoic acid or hydrogen peroxide.
Also, when X is either NR10 or NCONR11R12 and Y is carbonyl or methylene, the compound (bH) can be synthesized from a generally known compound 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one derivative or 2,3,4 ,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline derivative (JP-A-52-114000) by carrying out alkylation, acylation or the like chemical modification. For example, an alkyl group can be introduced to the amido nitrogen by allowing a compound in which the 3-position of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one is protected with benzyloxycarbonyl group or the like appropriate protecting group to react with methyl iodide, ethyl bromide or the like alkylation agent in the presence of sodium hydride or the like base. Also, the compound (bH) as a 6-position-modified product can be obtained by allowing a compound in which the 3-position of 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline is protected with benzyloxycarbonyl group or the like appropriate protecting group to react with acetyl chloride, propionyl chloride, isobutyryl chloride or the like acyl halide and trifluoroacetic acid anhydride, dimethylcarbamoyl chloride, diethylcarbamoyl chloride, methyl chloroformate, ethyl chloroformate or the like acylation agent, in the presence of triethylamine or the like base.
The compound (bQ) (Q is hydrogen atom or a protecting group) as a novel intermediate for the production of the compound (1) of the invention is a case in which the aforementioned X is Z and can be synthesized in the same manner as described above.
Next, the method for synthesizing the compound (cH) which is an intermediate for the production of the compound (1) of the invention is described in detail.
When benzene ring is formed by a carbon-carbon double bond of the nitrogen-containing hetero ring and the groups A and B which bind to its constituting carbon atoms, and also when k+m is 3, it can be derived from a generally known compound 2,3,4,5-tetrahydro-benzo[c]azepin-1-one or 1,3,4,5-tetrahydro-benzo[b]azepin-2-one [Tetrahedron, 49, 1807, 1993].
Also, when thiophene ring is formed by a carbon-carbon double bond of the nitrogen-containing hetero ring and the groups A and B which bind to its constituting carbon atoms, various derivatives of the compound (cH) can be synthesized from a generally known compound 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid [JP-A-5-60836], 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylic acid, 5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepine-2-carboxylic acid or 5,6,7, 8-tetrahydro-4H-thieno[2,3-c]azepine-2-carboxylic acid [WO 94/21599].
Also, when furan ring is formed by a carbon-carbon double bond of the nitrogen-containing hetero ring and the groups A and B which bind to its constituting carbon atoms, various derivatives of the compound (cH) can be synthesized from a generally known compound such as 4,5,6,7-tetrahydrofuro[3,2-c]pyridine, 4,5,6,7-tetrahydrofuro[2,3-c]pyridine, 5,6,7,8-tetrahydro-4H-furo[2,3-c]azepine or 5,6,7,8-tetrahydro-4H-furo[2,3-d]azepine [JP-A-9-118681].
Also, when pyrazole ring is formed by a carbon-carbon double bond of the nitrogen-containing hetero ring and the groups A and B which bind to its constituting carbon atoms, and also when k is 0, it can be synthesized by a generally known method. That is, as shown in the following reaction formula 5, the compound (cH-1) (a compound in which Q1 of the compound (cQ-1) is H) can be synthesized by firstly obtaining a compound (13) by allowing a protected keto-cyclic amine (12) [wherein Q1 is benzyl or the like protecting group, and m is an integer of from 1 to 3] to react with excess amount of an N,N-dialkylformamidodimethylacetal derivative generally at from 50xc2x0 C. to 150xc2x0 C. for a period of from 30 minutes to 10 hours, subsequently obtaining the compound (cQ-1) by condensing the compound (13) with from 1 to 5 equivalents of hydrazine or a lower alkylhydrazine generally at from 20xc2x0 C. to 100xc2x0 C. for from 10 minutes to 30 hours using methanol or the like lower alcohol as the solvent, and then removing the protecting group [JP-A-6-73056].
In the above synthesis method of the compound (cH), the substituent groups R4 and R5 of the compound (cH) can be optionally selected from those which are present on the ring of a compound to be used as the material, with the proviso that they do not hinder the above reactions, and these substituent groups can be substituted after synthesis of the compound (cH). Their typical examples include, as R4, halogen atom, lower alkyl, hydroxy, cyano, trihalomethyl (wherein the halogen atom is as defined in the foregoing and the three halogen atoms may be the same or different from one another, preferably trifluoromethyl or the like), alkoxy (preferably having from 1 to 4 carbon atoms, such as methoxy or ethoxy), alkylthio (preferably having from 1 to 4 carbon atoms, such as methylthio or ethylthio), alkylsulfinyl (preferably having from 1 to 4 carbon atoms), alkylsulfonyl (preferably having from 1 to 4 carbon atoms), alkoxycarbonyl (the alkyl moiety preferably having from 1 to 4 carbon atoms), sulfamoyl, amino, substituted amino (preferably amino substituted by lower alkyl, such as dimethylamino or diethylamino), carbamoyl, alkylcarbamoyl (preferably the alkyl moiety is lower alkyl, such as dimethylcarbamoyl), acyl (preferably having from 1 to 4 carbon atoms, such as acetyl) and carboxy, and as R5, hydrogen atom, lower alkyl, hydroxy, alkoxy (preferably having from 1 to 4 carbon atoms, such as methoxy or ethoxy), acyl (preferably having from 1 to 4 carbon atoms, such as acetyl), phenyl and substituted phenyl.
The secondary amines represented by the compound (cH) are shown below more illustratively;
indoline,
2-methylindoline,
2,3-dimethylindoline,
1,2,3,4-tetrahydroquinoline,
6-fluoro-1,2,3,4-tetrahydro-2-methylquinoline,
1,2,3,4-tetrahydroisoquinoline,
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline,
6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,
6,7-dihydroxy-1,2,3,4-tetrahydro-1-methylisoquinoline,
1-[5-chloro-2-(methylamino)-phenyl]-1,2,3,4-tetrahydroisoquinoline,
2,3,4,5-tetrahydro-1H-benzo[b]azepine,
2,3,4,5-tetrahydro-1H-benzo[c]azepine,
5-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine,
4,5,6,7-tetrahydrothieno[3,2-c]pyridine,
4,5,6,7-tetrahydrothieno[2,3-c]pyridine,
2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine,
3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine,
2,3-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine,
4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid,
4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid methyl ester,
2-carbamoyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine,
2-dimethylcarbamoyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine,
4,5,6,7-tetrahydrofuro[3,2-c]pyridine,
4,5,6,7-tetrahydrofuro[2,3-c]pyridine,
4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine,
4,5,6,7-tetrahydro-2-methyl-2H-pyrazolo[4,3-c]pyridine,
4,5,6,7-tetrahydro-3-methyl-1H-pyrazolo[4,3-c]pyridine,
4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine and the like.
Next, methods for the synthesis of the compounds (dH) and (eH) as intermediates for the production of the compound (1) of the invention are described in detail.
Regarding the compound (dH), ketone of a corresponding compound (14) [wherein R4, G, E, J and p are as defined in the foregoing] is converted into alcohol form of a compound (15) by reducing it with sodium borohydride (reaction formula 6).
Next, the compound (15) is converted into a compound (16) by its chlorination using thionyl chloride (reaction formula 7).
The compound (16) is condensed with a compound (17) N-t-butoxycarbonylpiperazine in the presence of a base to obtain a compound (18) (reaction formula 8).
By further subjecting the compound (18) to de-t-butoxycarbonylation under an acidic condition, a compound (dH-1) is synthesized (reaction formula 9).
As another example of the synthesis of the compound (dH), firstly, 4-bromopyridine as a compound (19) is allowed to react with the corresponding ketone compound (14) in ether using n-butyl lithium to obtain a compound (20) (reaction formula 10).
By reducing the compound (20) in an atmosphere of hydrogen using platinum oxide as a catalyst, a compound (dH-2) is synthesized (reaction formula 11).
Regarding the compound (eH), a compound (21) [wherein y is a halogen atom, and R4, R6 and R7 are as defined in the foregoing] is condensed with the compound (17) N-t-butoxycarbonylpiperazine in the presence of a base to obtain a compound (22).
By further subjecting the compound (22) to de-t-butoxycarbonylation under an acidic condition, a compound (eH-1) is synthesized (reaction formula 13).
As another example of the synthesis of the compound (eH), firstly, 4-bromopyridine as the compound (19) is allowed to react with a corresponding ketone represented by a compound (23) [wherein R4 is as defined in the foregoing, and R8 is lower alkyl, phenyl or substituted phenyl group] in ether using n-butyl lithium to obtain a compound (24) (reaction formula 14).
By reducing the compound (24) in an atmosphere of hydrogen using platinum oxide as a catalyst, a compound (eH-2) is synthesized (reaction formula 15).
By further reducing the compound (eH-2) in an atmosphere of hydrogen using palladium-carbon as a catalyst, a compound (eH-3) is synthesized (reaction formula 16).
As shown in the aforementioned reaction formula 6, the compound (14) can be converted into the compound (15) using sodium borohydride. This reaction is generally carried out after dilution with an alcohol or water and progresses within the range of from ordinary temperature to heating. Examples of the alcohol to be used include methanol, ethanol and the like.
As shown in the aforementioned reaction formula 7, the compound (16) is obtained by chlorinating the compound (15) using thionyl chloride. This reaction is carried out without solvent or by diluting with a chlorinated solvent or an aromatic solvent. Examples of the solvent to be used include dichloromethane or chloroform as the chlorinated solvent and benzene, toluene or the like as the aromatic solvent.
As shown in the aforementioned reaction formulae 8 and 12, the compound (16) or (21) is converted into the desired compound (18) or (22) by carrying out its reaction with the compound (17), N-t-butoxycarbonylpiperazine. This reaction is carried out without solvent or after dilution with an inert solvent and progresses in the presence or absence of a base, in the presence or absence of a catalytically effective amount of potassium iodide or sodium iodide and within the range of from ordinary temperature to heating temperature. Examples of the inert solvent to be used include dioxane, tetrahydrofuran, acetonitrile, dimethylformamide, methyl ethyl ketone and the like, and examples of the base to be used include salts of alkali metals, such as sodium carbonate, potassium carbonate and the like carbonates and sodium bicarbonate, potassium bicarbonate and the like bicarbonates, and trialkylamines, pyridine bases and the like, or the secondary amine itself to be used as the material substance may also serve as the base when used in an excess amount.
As shown in the aforementioned reaction formulae 9 and 13, the compound (18) or (22) can be converted into the compound (dH-1) or (eH-1) by removing the t-butoxycarbonyl group under an acidic condition. Examples of the acid to be used include hydrochloric acid, trifluoroacetic acid and the like. As shown in the aforementioned reaction formulae 10 and 14, the compound (19) can be converted into the compound (20) or (24) by allowing it to react with the compound (14) or (23) using n-butyl lithium. The reaction is carried out after dilution with an ether solvent and progresses within the range of from xe2x88x9278xc2x0 C. to room temperature. Examples of the ether solvent to be used include diethyl ether, tetrahydrofuran, dimethoxyethane and the like.
As shown in the aforementioned reaction formulae 11 and 15, the compound (20) or (24) can be converted into the compound (dH-2) or (eH-2) by its catalytic hydrogen reduction in the presence of platinum oxide. As shown in the aforementioned reaction formula 16, the compound (eH-3) is obtained from the compound (eH-2) by its catalytic hydrogen reduction in the presence of Pd-C.
These reactions are carried out after dilution with a polar solvent or a non-polar solvent and progress under ordinary pressure or under compression. Examples of the solvent to be used include water, an alcohol or acetic acid as the polar solvent and ether, benzene, hexane or the like as the non-polar solvent.
In the aforementioned synthesis method of the compound (dH) or (eH), the substituent groups R4, R6 and R7 can be optionally selected from those which are present on the benzene and pyridine ring of the compound (14), (21) or (23) to be used as the material, with the proviso that they do not hinder the above reactions.
The compound (14) as the synthesis material ketones of the compound (dH) is shown below more illustratively;
1-indanone,
6-methyl-1-indanone,
4-methyl-1-indanone,
5-fluoro-1-indanone,
5-chloro-1-indanone,
5-bromo-1-indanone,
4-hydroxy-1-indanone,
4-methoxy-1-indanone,
5-methoxy-1-indanone,
6-methoxy-1-indanone,
xcex1-tetralone,
5-hydroxy-1-tetralone,
5-methoxy-1-tetralone,
6-methoxy-1-tetralone,
7-methoxy-1-tetralone,
1-benzosuberone,
8-fluoro-1-benzosuberone,
4-chromanone,
thiochromanone-4-one,
6-fluoro-4-chromanone,
6-methyl-4-chromanone,
6-chloro-4-chromanone.
The compound (21) as the synthesis material halides of the compound (eH) is shown below more illustratively;
benzyl chloride,
benzyl bromide,
(1-bromoethyl)benzene,
2-fluorobenzyl chloride,
2-chlorobenzyl chloride,
2-chlorobenzyl bromide,
2-bromobenzyl bromide,
2-methylbenzyl bromide,
2-methylbenzyl chloride,
3-fluorobenzyl chloride,
4-fluorobenzyl bromide,
4-fluorobenzyl chloride,
3-fluorobenzyl bromide,
3-chlorobenzyl chloride,
4-chlorobenzyl chloride,
3-chlorobenzyl bromide,
3-bromobenzyl chloride,
3-bromobenzyl bromide,
4-bromobenzyl bromide,
3-methylbenzyl chloride,
3-methylbenzyl bromide,
4-methylbenzyl chloride,
4-methylbenzyl bromide,
4-t-butylbenzyl bromide,
2-trifluoromethylbenzyl chloride,
2-trifluoromethylbenzyl bromide,
4-trifluoromethylbenzyl chloride,
4-trifluoromethylbenzyl bromide,
4-vinylbenzyl chloride,
chloro-diphenylmethane,
bromo-diphenylmethane,
triphenylmethyl chloride,
triphenylmethyl bromide,
chloro(4-chlorophenyl)-phenylmethane,
chlorobis(4-fluorophenyl)-methane.
The compound (23) as the synthesis material ketones of the compound (eH) is shown below more illustratively;
acetophenone,
propiophenone,
butyrophenone,
isobutyrophenone,
valerophenone,
2,2-dimethylpropiophenone,
4xe2x80x2-methylpropiophenone,
3xe2x80x2-methylacetophenone,
4xe2x80x2-methylacetophenone,
4xe2x80x2-ethylacetophenone,
4xe2x80x2-butylacetophenone,
2xe2x80x2-methoxyacetophenone,
3xe2x80x2-methoxyacetophenone,
3xe2x80x2-(trifluoromethoxy)-acetophenone,
4xe2x80x2-(trifluoromethoxy)-acetophenone,
4xe2x80x2-ethyoxyacetophenone,
2xe2x80x2-nitroacetophenone,
4xe2x80x2-nitroacetophenone,
benzophenone,
2-methylbenzophenone,
3-methylbenzophenone,
4-methylbenzophenone,
4-benzobiphenyl,
2,4-diphenylbenzophenone,
2,5-diphenylbenzophenone,
3,4-diphenylbenzophenone,
3-(trifluoromethyl)-benzophenone,
4-(trifluoromethyl)-benzophenone,
3,3xe2x80x2-bis (trifluoromethyl)-benzophenone,
3,4xe2x80x2-bis (trifluoromethyl)-benzophenone,
4-methoxybenzophenone,
3,3xe2x80x2-dinitrobenzophenone.
In the synthesis of the compound (1) of the invention, purification of a compound of interest from the reaction mixture is carried out by employing usually used techniques in the field of chemical synthesis, namely by effecting separation extraction of the reaction product between water and an organic solvent which does not optionally mixed with water, such as benzene, toluene, ethyl acetate, butyl acetate, methyl isobutyl ketone, chloroform, dichloromethane or the like, and then carrying out concentration, crystallization and the like. Also, as occasion demands, fractional purification may be carried out for example by a column chromatography using alumina, silica gel, adsorption resin or the like.
Being an amine, the compound (I) of the invention exists as a base. In consequence, it forms salts with a number of inorganic and organic acids, and such a property is applied to the production of pure substance and its provisional forms as pharmaceutical preparations. That is, in its production process, acidification of the compound renders possible its solubilization and extraction purification in water or the like polar solvent so that it can be isolated as a salt having desirable physicochemical properties, and, in applying it to pharmaceutical preparations, it can form a pharmacologically acceptable salt. Examples of the salt to be formed include acid addition salts with hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like inorganic acids or with aliphatic monocarboxylic acids, dicarboxylic acids, hydroxyalkanoic acids, hydroxyalkanoic diacids, amino acids and the like, as well as salts derived from aromatic acids, aliphatic and aromatic sulfonic acids and the like nontoxic organic acids. Examples of such acid addition salts include hydrochloride, hydrobromide, nitrate, sulfate, hydrogensulfate, phosphate, monohydrogenphosphate, dihydrogenphosphate, acetate, propionate, tartarate, oxalate, malonate, succinate, fumarate, maleate, mandelate, benzoate, phthalate, methanesulfonate, benzenesulfonate, toluenesulfonate, citrate, lactate, malate, glycolate and the like.
These acid addition salts described above are significant also as pharmacologically acceptable pharmaceutical compositions, and it seems that they have advantages as pharmaceutical compositions in terms of the preparation of medicaments and of the dispersing and absorbing abilities when administered to the human body.
A pharmaceutical composition which contains the compound of the invention as an active ingredient can be administered to human and animals other than human, through the route of either oral administration or parenteral administration (e.g., intravenous injection, intramuscular injection, subcutaneous injection, rectal administration or percutaneous absorption). Thus, the pharmaceutical composition containing the compound of the invention as an active ingredient can be made into appropriate dosage forms depending on each route of administration.
Illustrative examples of dosage forms include tablets, capsules, powders, granules, syrups and the like as oral preparations and intravenous, intramuscular and the like injections, rectal administration preparations, oleaginous suppositories, aqueous suppositories and the like as parenteral preparations.
Each of these various preparations can be produced in the usual way making use of generally used fillers, disintegrators, binders, lubricating agents, coloring agents and the like.
Lactose, glucose, corn starch, sorbitol, crystalline cellulose and the like can be exemplified as the fillers, starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, dextrin and the like can be cited as the disintegrators, dimethyl cellulose, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, acacia, gelatin, hydroxypropyl cellulose, polyvinyl pyrrolidone and the like can be exemplified as the binders and talc, magnesium stearate, polyethylene glycol, hardened plant oil and the like can be exemplified as the lubricating agents. In addition, the aforementioned injections can be produced by further adding a buffer, a pH adjusting agent, a stabilizing agent and the like as occasion demands.
Though the amount of the compound of the invention in the pharmaceutical composition varies depending on its dosage forms, it may be used in an amount of generally from 0.1 to 50% by weight, preferably from 0.1 to 20% by weight, based on the total camposition. Its dose is optionally decided in each case, taking age, body weight, sex, difference in diseases, degree of symptoms and the like of each patient into consideration, but the dose is within the range of generally from 0.1 to 100 mg, preferably from 0.1 to 30 mg, per day per adult, and the daily dose is administered once a day or by dividing it into several doses per day.


An apparatus is provided which comprises at least one processor, at least one memory including computer program code, and the at least one processor, with the at least one memory and the computer program code, being arranged to cause the apparatus to at least perform generating a code block including information bits and parity bits, the parity bits being generated by performing a cyclic redundancy check on the information bits, determining the number of parity bits used in generating the code block based on an applied linear error correcting code base graph and/or based on the number of the information bits, and encoding the code block by using the applied linear error correcting code base graph.

The following meanings for the abbreviations used in this specification apply:
3GPP 3rd Generation Partnership Project
5G 5th Generation
BG Base graph
CB Code block
CBG Code block group
CBS Code block size
CRC Cyclic Redundancy Check
GF(2) Galois field of two elements
gNB 5G base station
FFS For further study
LDPC Low Density Parity Check
LTE Long Term Evolution
MCS Modulation and Coding Scheme
NR New Radio
PC Polar Coding
PCM Parity Check Matrix
TB Transport block
TBS Transport block size
UE user equipment
URLLC ultra-reliable and low latency communications
Embodiments of the present invention, although not limited to this, relate to channel coding optimizations in networks such 5G. In the following, some consideration concerning CRC attachment for smaller TBs are given by referring to reference [1]: R1-1711533 "CRC attachment for Smaller TBs" Nokia, Alcatel-Lucent Shanghai Bell.
In Ran1 NR Ad-Hoc #2 meeting, two LDPC base graphs were agreed to support data channel in 5G. The way those are used agreed as the following.
Agreement:                Base graph #1 is used for the initial transmission and subsequent re-transmissions of the same TB when                    CBS>X or code rate of the initial transmission>Y                        Base graph #2 is used for the initial transmission and subsequent re-transmissions of the same TB when                    CBS<=X and code rate of the initial transmission<=Y                        Working assumption: X=2560 and Y=0.67                    FFS after PCM decisions if X can be extended to 3840 and/or Y can be extended to 0.75                            To be checked how the receiver knows in each case the code rate of the initial transmission, and how exactly it is defined.    FFS whether some UE capabilities may be possible that do not require the implementation of both base graphs.
For CRC attachment, LDPC codes have inherent error detection capability and could be used to reduce the CRC overhead. In Ran1 #88bis meeting, an agreement was made on attaching 24 CRC bits for the TB when the TB is larger than a threshold. However, the threshold was not agreed. In particular, agreement in Ran1 #88bis is:
Agreement:
                Number of bits for TB-level CRC is: LTB,CRC=24 bits, at least for TBs larger than a threshold (e.g. around 512 bits)        FFS the value of LTB,CRC for TBs smaller than the threshold, and the value of the threshold (0 is not precluded)        If a TB is segmented into 2 or more CBs after code block (CB) segmentation,                    CB-level CRC is applied, i.e., CRC bits are attached to each code block individually (as in LTE)            Number bits for CB-level CRC is: 0<LCB,CRC<=24 bits                            Exact value(s) LCB,CRC are to be agreed after base graph(s) are agreed, taking into account inherent LDPC PC capability                                                FFS whether for a code block group (CBG) containing 2 or more CBs but not all CBs of the TB, any additional CRC bits are attached to the CBG                    To be decided after decision on the value(s) of LCB,CRC
On MCS table, LTE uses 5 bits to indicate MCS in the control payload. All these would use Turbo code and there is no relation with the MCS table and the use of the coding scheme. For NR, how to utilize this MCS field needs more discussion as the base graph that is used can be different.
In order to optimize the performance is necessary to consider the use of two base graphs when defining other details of NR.

This patent is subject to a terminal disclaimer.


The present invention is used for monitoring a land vehicle speed relative to a speed limit. An electronic transmit and receiver apparatus, a position location apparatus and a date and time apparatus may be positioned in the land vehicle and may be in communication with a speed and speed limit computation device. The speed and speed limit computation device may have an output to an alert display device and an output device to identify over speed limit conditions.

This invention relates to systems that may be used to monitor a vehicle speed and to alert or warn a vehicle driver when they may be moving faster than a speed limit. The new speed monitoring system may detect an over speed limit condition, alert a vehicle driver of the speed, track the time for driver speed adjustment, and display and record the event.
Apparatus for detecting land vehicle speeds on roadways may be known. Most of these systems may be radar based systems. Examples may include hand held or police car mounted radar transmitter/detectors that measure a particular vehicle speed and provide a display to a user, such as a police officer. This type of apparatus does not alert drivers to over speed limit conditions and may be principally used to catch speeders for the purpose of issuing traffic tickets.
Variations of this use of radar detection may include portable roadside apparatus that may have a radar transmitter/receiver and a large display that may be seen by drivers of land vehicles. This type of apparatus may serve to inform drivers of their vehicle speed and over speed limit conditions. The apparatus may also be used by a police officer positioned in a vehicle to view the apparatus and stop speeding vehicles to issue traffic tickets.


A girt assembly for releasably connecting an evacuation slide to an aircraft includes superimposed flexible panels that are continuous at a pair of spaced connection points for connection with the aircraft. One or more catenary loops are formed in each panel for distributing forces on the flexible panels along a length of the loops. The connection points may be releasably connected to a girt bar with spaced bracket assemblies or directly connected to floor brackets associated with the aircraft.

In the event of an emergency situation aboard a large commercial passenger airplane where evacuation of the passengers and crew becomes necessary, emergency escape slides are typically used. These escape slides are typically stored inside the passenger doors of the airplane. Prior to normal operations for embarking and disembarking passengers at the airport terminal gate, the emergency escape slides are disarmed. This allows the cabin doors to be opened and closed in a normal manner without activating the emergency escape slides.
However, once the airplane leaves the airport terminal gate, the emergency escape slides are armed. Arming the emergency escape slides causes a metal girt bar attached to the girt at the upper end of each slide to be connected to the floor of the airplane cabin. In the event of a situation requiring emergency evacuation of the passengers and crew from the airplane, each emergency escape slide is deployed by moving the door handle connected to the inside of the cabin door to the open position to thereby open the door, causing the uninflated escape slide to fall from its storage pack inside the cabin and inflate outside the airplane. Since the upper end of the inflating escape slide is attached to the girt bar, the escape slide remains connected to the airplane.
During inflation, the escape slide has a tendency to pop open thereby resulting in a significant force being applied to both the girt and the girt bar. Once the slide is inflated, the weight of passengers, crew, equipment, and so on can also create significant loads on both the girt and girt bar.
As shown in FIG. 1, a typical prior art solution includes an escape slide 10 releasable connected to the fuselage 12 (shown in phantom line) of an aircraft by a girt 14 that extends from the doorway (not shown) of the aircraft, wraps around a first sill tube 16, and is cemented, sewn or otherwise connected at one end to the floor 18 of the escape slide. An opposite end (not shown) of the girt 14 is wrapped around a girt bar (not shown) along the entire length thereof. The girt bar is in turn connected to the floor of the aircraft when the escape slide 10 is armed or deployed. Such an arrangement creates an interface between the inflatable slide and the respective aircraft. The loads from slide deployment, passenger egress, wind, and/or water are transmitted through the fabric of the girt into the girt bar and consequently into the floor fittings of the aircraft.
One drawback of such a prior art solution is that when an inflatable slide is loaded, a uniform load is applied across the length of the girt bar which is suspended at its opposite ends. This arrangement results in a substantial bending moment at the center of the bar. Consequently, the girt bar tends to flex and, if inadequately designed, could lead to catastrophic failure. Accordingly, the strength of the material as well as the cross-sectional area and shape of the prior art girt bar must be taken into account during the design process and is typically based on the maximum load generated during sliding tests plus a predefined safety factor. As a consequence, heavy girt bars capable of withstanding such loads are typically required in the prior art evacuation arrangements.
In addition, prior art girts may experience point sources of loading, causing tearing of the fabric and consequent failure. Also, in the event of a water landing, some prior art solutions require release of the entire girt bar itself from the aircraft in order to release the inflated evacuation slide, while other prior art solutions employ a complicated two-piece girt with a series of loops and webbing arranged in a daisy chain that extends across the entire girt bar for release therefrom. Such a solution is complicated to construct, difficult to maintain and awkward to deploy, especially in emergency situations where time is of the essence.

Catenary girt arrangement for emergency evacuation slides


A system is disclosed for providing trusted third-party management of user device domains in a digital rights management environment. The system includes a plurality of content providers that distribute digital content items via user accounts having associated user device domains. The user device domains are managed by an independent domain manager. The domain manager includes a device registrar which is operative, for a given user device domain, to receive a request to add a device to the user device domain. If the request is grantable, a domain controller of the domain manager is operative to cause a domain private key to be transmitted to the device being added to the user device domain. The domain private key is usable at the device to decrypt a content key which was previously released to the user device domain for decrypting protected digital content.

Digital content has become ubiquitous. Music, video, textual works, graphical works, games, and countless other types of content are saved in various digital formats. While digital formats offer many benefits, the ease with which exact duplicates can be made poses some challenges. In particular, because digital duplicates can be made without losing any quality and/or fidelity, it can be difficult to prevent the unauthorized copying and distribution of digital content. Digital rights management and other methods may be employed to control content, but in some cases this may lead to a frustrating user experience and/or prevent legitimate access to content for which the user has properly obtained rights.

Domain manager for extending digital-media longevity


An envelope protein of the etiologic agent of acquired immune deficiency syndrome (AIDS) and a method for its preparation are disclosed. Proviral DNA is transferred into a host cell after engineering into an expression vector which produces the envelope protein. A method of testing human blood for the presence of antibodies to the AIDS virus using the AIDS envelope protein is disclosed.

From 1981 to date, there have been eight thousand (8,000) people diagnosed as having acquired immune deficiency syndrome (AIDS). N.Y. Times, A-11 Jan. 11, 1985. AIDS has been characterized by the onset of severe opportunistic infections secondary to an effect on the body's immune system. Gottlieb, M. S. et al., Pneumocystis Carinic Pneumonia and Mucosal Candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immuno-deficiency, N. Eng. J. Med. 305, 1426-1431 (1981). The disease has been found in male homosexuals, patients receiving blood products, intravenous drug addicts, and individuals originating from Haiti and Central Africa. Piot, P. et al. Acquired immunodeficiency syndrome in a heterosexual population in Zaire. Lancet 11, 65-69 (1984). The causative agent was suspected to be of viral origin as the epidemiological pattern of AIDS was consistent with a transmissable disease. At least three (3) retroviruses have been isolated from cultured T-cells of several patients with AIDS, or from white blood cells of persons at risk for the disease. A novel human retrovirus called lymphadenopathy-associated virus (LAV) was discovered and its properties were consistent with its etiological role in AIDS. That virus was isolated from a patient with lymphadenopathy and hence the name. Montagnier, L. et al. A New Human T-lymphotropic retrovirus: characterization and possible role in lymphadenopathy and acquired immune deficiency syndromes. In Human T-Cell Leukemia/Lymphoma Virus, R. C. Gallo, M. Essex and L. Gross, eds. (Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory) pp. 363-370. Other human retroviruses, specifically two subgroups of the human T-cell leukemia/lymphoma/lymphotropic virus, types I and III have been isolated. (HTLV I: Poicsz, B. J. et al. PNAS (USA) 77, 7415 (1980)); (HTLV-III: Popovic, M. et al. Detection, isolation and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science 224, 797-500 (1984)). Still another virus, the AIDS-associated retrovirus (ARV), was proposed as the causative agent. Levy, J. A. et al. Isolation of lymphocytopathic retroviruses from San Francisco patients with AIDS. Science 225, 840-842 (1984)). Both the HTLV-III and ARV retroviruses display biological and sero-eidemiological properties similar to LAV. Levy et al., supra, Popovic et al. supra. As seen from the above, at least three (3) retroviruses have been postulated as the etiologic agent or AIDS: LAV: ARV; and, HTLV subtypes I and III.
LAV, HTLV III and ARV-II genomes have been molecularly cloned. Shaw, G. M. et al., Serological analysis of a subgroup of human T-lymphotropic retroviruses (HTLV III) associated with AIDS. Science 224, 503-505 (1984). Alizon, M. et al. Molecular Cloning of lymphadenopathy--associated virus. Nature, in press. The complete nucleotide sequence of the proviral genome of LAV, ARV and HTLV III has been determined. Ratner, L. et al. Complete nucleotide sequence of the AIDS virus, HTLV III. Nature 313, 277-284 (1985); Sanchez-Pescadov, R. et al. Nucleotide sequence and expression of an AIDS-associated retrovirus (ARV-2). Science 227, 484-492 (1985); and, Wain-Hobson, S. et al. Nucleotide sequence of the AIDS virus, LAV. Cell 40, 9-17 (1985).
One reason for the difficulty in determining the etiologic agent of AIDS was due to the reactivity of various retroviral antigens with serum samples from AIDS patients. For example, serum samples from AIDS patients have been shown to react with antigens of HTLV I and HTLV III. (HTLV-I: Essex, M., et al., "Antibodies to Cell Membrane Antigens Associated with Human T-Cell Leukemia Virus in Patients with AIDS", Science 220, 859(1983)); (HTLV-III: Sarngadharan, M. G. et al., "Antibodies Reactive With Human T-Lymphotropic Retroviruses (HTLV-III) in the Serum of Patients With AIDS", Science 224, 506-508 (1984)). Envelope gene products of HTLV demonstrated antigenicities cross-reactive with antibodies in sera from adult T-cell leukemia patients. Kiyokana, T. et al. Envelope proteins of human T-cell leukemia virus: Expression in Escherichia coli and its application to studies of env gene functions" PNAS (USA) 81, 6202-6206 (1984). Adult T-cell leukemias (ATL) differ from acquired immune deficiency syndrome (AIDS) in that HTLV-I causes T-cell malignancies, that is uncontrolled growth of T-cell. In AIDS rather than cell growth there is cell death. In fact this cytopathic characteristic of HTLV III was critical to determining ultimately the specific retroviral origin of the disease. Thus the etiologic agent of AIDS was isolated by use of immortalized human neoplastic T cell lines (HT) infected with the cytopathic retrovirus characteristic of AIDS, isolated from AIDS afflicted patients. Seroepidemiological assays using this virus showed a complete correlation between AIDS and the presence of antibodies to HTLV III antigens. Gallo et al. supra 1984; Sarngadharan et al. supra 1984; Schupbach et al. Serological Analysis of a subgroup of human T-lymphotropic retroviruses (HTLV III) associated with AIDS, Science 224, 503-505 (1984). In addition, nearly 85% of patients with lymphadenopathy syndrome and a significant proportion of asymptomatic homosexual men in AIDS endemic areas were also found to carry circulating antibodies to HTLV III. Taken together, all these data indicate HTLV III to be the etiologic agent for AIDS.
Until the successful culturing of AIDS virus using H-9 cell line the env AIDS protein of the AIDS virus had not been isolated, characterized or synthesized. This in major part is due to the fact that the virus is cytopathic and thus isolation of the virus was not possible. Popovic, M. et al., Detection, Isolation, and Continuous Production of Cytopathic Retroviruses (HTLV III) From Patients With AIDS and Pre AIDS, Science 224, 497-500 (1984). Once the human T-cell line resistant to the cytopathic effects of the virus was discovered, a molecular clone of proviral DNA could be achieved.
The need for a sensitive and rapid method for the diagnosis of AIDS in human blood and its prevention by vaccination is very great. Virtually all the assays/tests presently available are fraught with errors. In fact the Center for Disease Control (CDC) has indicated that presently available tests be used solely for screening units of blood for antibody to HTLV III. The CDC went further by stating that the presently available ELISA tests not be used for general screening of high risk populations or as a diagnostic test for AIDS. Federal Register 50(48), 9909, Mar. 12, 1985. The errors have been traced to the failure to use a specific antigenic protein of the etiologic agent for AIDS. The previously used proteins were derived from a viral lysate. Since the lysate is made from human cells infected with the virus, i.e. the cells used to grow the virus, the lysate will contain human proteins as well as viral proteins. Thus preparation of a pure antigen of viral protein is very difficult. The antigen used produced both false positive and false negative results. Budiansky, S., AIDS Screening, False Test Results Raise Doubts, Nature 312, 583(1984). The errors caused by the use of such lysate proteins/peptides can be avoided by using a composition for binding AIDS antibodies which is substantially free of the non-AIDS specific proteins. Compositions that are substantially pure AIDS envelope protein can be used as antigens. The AIDS envelope protein of the instant invention has been established to have conserved epitopes which permit its use to screen for, diagnose and/or prevent by vaccination the AIDS virus. The instant invention demonstrates that the envelope protein with its conserved epitopes includes all the variants which have been claimed as the sole etiologic agent.
The envelope AIDS protein of the present invention may be produced by conventionally known methods. The processes by which the novel protein may be produced can be divided into three groups: (1) chemical synthesis; (2) preparation of a gene prepared by chemical synthesis is inserted into a host and a protein is produced by the host; and (3) a gene obtained biotechnically is inserted into a host and a protein is produced by the host.
In one embodiment of this invention, recombinant DNA techniques are utilized by which env AIDS DNA from a natural source is introduced into a cell to produce the env AIDS protein. One method of obtaining DNA which encodes env AIDS is to read the genetic code in reverse and synthesize an oligodioxynucleotide which should encode the env AIDS amino acid sequence. As the env protein has not been isolated or characterized this approach cannot be pursued.
Alternatively gene expression can be obtained using recombinant DNA technology if DNA isolated from natural sources is used instead of synthetic DNA.

Acquired immune deficiency syndrome (AIDS) viral envelope protein and method of testing for AIDS


A transportable wireless loudspeaker 110 and system 100 for managing multi-user wireless media playback over a media playback system 100. Allows for multiple users on user devices 150 to share their media wirelessly by seamlessly switching between users (501, 601, 701) connected to the media playback system 100. The ability to have multiple users sharing their media provides for more sources of media to be played.

1. Field of the Invention
The present invention relates to media playback over a wireless channel, and more specifically to transportable, wireless media playback systems adapted for use with user-provided portable media (e.g., MP3) players, smartphones and other personal electronics devices when used to store or access a user's media or music files.
2. Discussion of the Prior Art
Music listeners have been accumulating collections of music in digital form for playback over portable media (e.g., MP3) players, smartphones, tablets, personal computers and other personal electronics devices and many have chosen to listen to their music over audio playback systems configured to "dock" with those personal electronics devices. For example, the applicant's I-Sonic® music playback system (U.S. Pat. No. 7,817,812) is a popular choice for music listeners who want high-fidelity playback in a transportable, compact product.
Other users prefer to avoid having to physically connect or "dock" their personal electronics devices, and so wireless (e.g., Bluetooth™) powered speakers often combine integrated Bluetooth technology with battery power, as shown and described in U.S. Patent Application Publication US2012/0300962 (Devoto). Devoto's Bluetooth Speaker permits a listener to send music wirelessly to the stereo speaker via an iPhone™ smartphone or an MP3 player and remotely send commands between the connected personal electronics device and the speaker.
In either case users are limited in their ability to enjoy their combined music collections in group settings because switching between these collections requires switching between streaming source devices (phone, MPS player or other) and the only processes for doing so are slow, clumsy and/or disruptive to the event.
Wireless audio via Bluetooth™, for instance, is awkward to set up, however, since the user's personal electronics device and the Bluetooth™ speaker must be first "paired" and then "connected" in order to allow playback to begin, and once a user begins listening, there is not an easy way to allow another music listener to participate without "pairing" and then connecting the second user's personal electronics device. Even if the second user's personal electronics device is successfully "paired" with the Bluetooth™ speaker, the standardized Bluetooth™ system's protocols do not permit the first and second users to cooperate in creating a shared or blended audio playback experience, because the most recent user to "pair" and connect with the Bluetooth™ speaker abruptly cuts off the prior user and replaces them permanently, or until that prior user turns the tables and again connects to "play" another song with the Bluetooth™ speaker, having abruptly cut off the second user.
Wireless data transmissions using protocols such as the Bluetooth™ protocols are typically controlled by organizations which publish and enforce compliance with specifications. Such wireless transmission system specifications typically describe a wireless system designed to serve a wide range of users exchanging all kinds of information between wireless devices such as personal digital assistants (PDAs), mobile phones, laptops, computers, printers and digital cameras via a short-range radio frequency ("RF") communications channel, and transceiver compatibility among various manufacturers products is required, so the specifications tend to be rigidly followed, which means that users have limited options for sharing media over a wirelessly connected media playback component such as a wireless loudspeaker.
There is a need, therefore, for a convenient, user-friendly, flexible and unobtrusive system and method for music listeners and other users of portable media (e.g., MP3) players, smartphones and other personal electronics devices to use network together and cooperatively share a wirelessly connected media playback component such as a wireless loudspeaker and manage multi-user wireless media playback over the loudspeaker.

Transportable wireless loudspeaker and system and method for managing multi-user wireless media playback over a media playback system


A pair of numerically controlled feed devices are successively operated, with the second feed device taking over from the first feed device when two or more punching steps have been performed. A trailing row of punching tools performs the first punching step with respect to a fresh plate at the same time when a leading row of tools performs the last punching step with respect to the preceding plate. There are provided sensors to determine plate length and/or angularity of the late edges in order to enable a numerical control to compute correction data for correcting the feeding of the plate whereby punching through the trailing and leading edges of the lates is avoided.

The present invention relates to a plate positioning and feeding system for a punch comprising a positioning station disposed upstream of the punch and including positioning means for positioning a plate with respect to a pair of orthogonal axes, and at least one feed device actuated by drive means controlled by a numerical control. The feed device including gripping means gripping the plate and advancing it to the punch in a cycled manner corresponding to cycling of the punch.
Such systems are used to feed plates, for example of steel or aluminum sheet material, to a punch which punches out a predetermined number of blanks from each plate. By means of the feed, devices each plate is moved step by step through the punch and is subjected to punching steps while it is stationary.
Various feeding systems have become known and are shown for example in U.S. Pat. No. 4 382 395, German Patent 34 37 642, European Patent Specification 92 113 561.2 and German Patent 38 41 683.
The punching of the plates should be performed such that as little material as possible will remain in the punched plates in order to save material. On the other hand it is to be avoided that the punching tools punch through the edges of the plates. Accordingly, it is imperative that the plates be advanced as precisely as possible. The prior art feed systems do not allow for precise positioning and/or require sophisticated and costly control systems for precise positioning of the plates.
It has become known to cut the plates from continuous stock material by means of plate scissors. Such cutting results in variations of the plate length and the angularity of the cut edges of the plates within the manufacturing tolerances.
It is an object of the present invention to provide a plate positioning and feeding system for a punch, which ensures precise feeding and advancing of the plates. A further object of the present invention is to provide a plate positioning and feeding system for a punch, which punches the plates so that residual meshes of minimum material result and punching through the trailing and leading edges of the plates is avoided.

Plate positioning and feeding system for a punch


Apparatuses, systems, and methods for faster memory access regions. A memory array may have a first bank which has a greater access speed than a second bank. For example the first bank may have a reduced read latency compared to the second bank. The first bank may have structural differences, such as reduced word line and/or reduced global input output (GIO) line length. In some embodiments, the first and second bank may have separate bank pad data buses, and data terminals. In some embodiments, they may share the bank pads data bus, and data terminals. In some embodiments, when an access command is received for the first (faster) bank while an access command to the second (slower) bank is still processing, the access to the faster bank may interrupt the access to the slower bank.

This disclosure relates generally to semiconductor devices, and more specifically to semiconductor memory devices. In particular, the disclosure relates to volatile memory, such as dynamic random access memory (DRAM). Information may be stored on individual memory cells of the memory as a physical signal (e.g., a charge on a capacitive element). A memory device may have various performance characteristics for writing information to a memory cell and/or reading information from a memory cell. For example, a time required to read/write a reliability of information stored in a memory cell, power consumption to read/write etc. There may be various trade-offs involved in improving the performance of a memory. For example, reducing read/write times may involve increasing a cost of the memory. Since it may be impractical to increase the performance of an entire memory array, there may be a need to increase the performance of certain regions of the memory array relative to other regions of the memory array.
Memory devices may include a memory array which includes a number of memory cells, each of which may store information. For example, each memory cell may store a single bit of information. The memory cells may be located at the intersections of word lines (rows) and digit lines (bit lines/columns). Each word line may be associated with a row address, and each digit line may be associated with a column address. Accordingly, memory cells may be specified by their row and column addresses.                A memory device may have certain performance characteristics for access operations on the memory cells of the device. For example, characteristics may include a time it takes to write information to a given memory cell, the time it takes to read information from a given memory cell, reliability of information read from a memory cell, power consumed while writing or reading information, etc. A device including a memory array may have specified characteristics, which may be based, in part, on the lowest performance characteristics of a memory cell in the array. For example, if it takes longer to write/read data to some memory cells than others, then the overall performance of the memory may be based on the memory cell with the slowest read/write times such that the overall performance specification is based on a maximum time it takes for an access operation to any memory cell of the array. While increased performance characteristics are generally desirable, it may be impractical (e.g., too costly) to improve the performance of all of the memory cells of a memory device in order to improve the overall performance of the entire device.

Apparatuses including memory regions having different access speeds and methods for using the same


An information communication system, having host and remote terminal devices, and method for generating a voice in which one voice tone data is selected from a plurality of types of voice tone data and stored according to received voice generating information. The voice is reproduced by generating a voice waveform according to a meter pattern and selected voice tone data. The discrete voice data may be presented for either one or both of velocity and pitch of a voice correlated to a time lag between discrete voice data. The discrete data is dispensed so that each voice data is not dependent on a time lag between phonemes and at the same time is present at a level relative to a reference value. Voice tone data indicating a sound parameter for each voice element such as a phoneme for each voice tone type is stored in a voice tone data storing section in a terminal device. File information is transferred from a host device to a terminal device according to a request from the terminal device, and the terminal device reads out voice tone data specified by the voice-generating information in the file information thereto from a voice tone storing section. A voice is synthesized according to the voice tone data and the voice generating information.

In the Internet having remarkably developed in recent years, for the purpose to deliver a voice from a server to a client, there has been employed the technology to compress a voice into a form of waveform data (.wav or .au) and transfer the waveform.
In the Internet, there is a tendency that users do not want to download a home page including a large quantity of data to be transferred. Thus, it is a key to popularization of voice communications to enable the transfer of waveform data having a large data size as a small quantity of data to be transferred.
To solve the problems relating to a transfer rate in voice communications as described above, there is, for instance, the technology disclosed in Japanese Patent Publication No. HEI 5-52520. This publication discloses the technology in which a voice is divided into voice source information and voice route information corresponding to the voice source information. The voice source information and voice route information corresponding to each other are then synthesized into a voice when desired.
However, as the Internet is a communication network utilized by many unspecified persons, generally a client accesses arbitrary voice source information, namely voice-generating information from a server, and fetches the voice-generating information. In this process, the client cannot confirm whether the prepared voice route information, namely voice tone information, is identical to the accessed voice-generating information or not.
For this reason, if a speaker providing voice tone information is identical to a speaker providing the voice-generating information, and at the same time conditions for making the voice tone information are the same as those for making the voice-generating information, there is no problem in reproducibility of a voice by means of voice synthesis. However, if the speakers or conditions are different, as an amplitude is specified as an absolute amplitude level and voice pitch is specified as an absolute pitch frequency, an amplitude pattern inherent to the voice tone information is not reflected, and there is the possibility that the voice may be inappropriately reproduced when synthesized.

Voice-generating method and apparatus using discrete voice data for velocity and/or pitch


An acceleration sensor includes a housing member, a spring member attached to the housing member and provided with freedom in at least one direction of acceleration to be detected, a magnetic field generation member with weight fixed to the spring member, and at least one magnetic field detection sensor attached to the housing member to face the magnetic field generation member with weight. Each magnetic field detection sensor is provided with at least one pair of multi-layered MR elements each including a magnetization fixed layer and a magnetization free layer. A magnetized direction of the magnetization fixed layers is fixed to a direction parallel to the direction of acceleration to be detected. The magnetic field generation member with weight includes at least one permanent magnet that provides a closed magnetic loop. At least one pair of multi-layered MR elements is arranged in the closed magnetic loop to receive magnetic field substantially perpendicular to a lamination plane of the multi-layered MR elements when no acceleration is applied.

1. Field of the Invention
The present invention relates to an acceleration sensor with a magnetoresistive effect (MR) element and to a magnetic disk drive apparatus with the acceleration sensor.
2. Description of the Related Art
In a magnetic disk drive apparatus or a hard disk drive (HDD) apparatus assembled in a mobile equipment such as for example a walkabout personal computer, a mobile phone, a digital audio player and other mobile gear, an HDD apparatus used as a mobile storage itself or a removable HDD apparatus, in order to prevent a collision of a magnetic head with a hard disk surface due to drop impact, it is necessary to detect the instant at which the HDD apparatus falls before occurrence of the drop impact and to retract the magnetic head from the hard disk surface. Such instant of the falling can be detected from a slight change in the acceleration of gravity.
Japanese patent publication No. 02-248867A discloses a piezo-electric type acceleration sensor for detecting a small change in the acceleration of gravity from a change in stress of springs. This sensor has springs in dual tuning fork vibrators, a weight supported by the springs, and piezo-electric elements attached on the springs to detect the change in stress applied to the springs from the weight.
U.S. Pat. No. 5,747,991 discloses an electrostatic capacitance type acceleration sensor for detecting a small change in the acceleration of gravity from a displacement of a weight. This sensor has a movable electrode and a static electrode facing each other to detect a change in electrostatic capacitance from a change in distance between the movable and static electrodes due to the acceleration.
Such known piezo-electric type acceleration sensor or electrostatic capacitance type acceleration sensor needs to have electrodes for extracting detection signals there from on the spring or the weight attached to the spring and also lead lines electrically connected to the electrodes. Thus, the structure of the sensor becomes complicated due to the lead lines connected to the electrodes. Also, when the spring and weight are miniaturized, wiring process of such lead lines becomes extremely difficult. Further, the lead lines formed on the miniaturized spring or weight may induce breakage of the lead lines when an excessive value of impact is applied, and prevent movement of the spring to interface with the improvement in sensitivity of the sensor. This tendency becomes more pronounced as the acceleration sensor becomes smaller.
U.S. Pat. No. 6,131,457 discloses an acceleration sensor that may solve the above-mentioned problems in the conventional piezo-electric type acceleration sensor and electrostatic capacitance type acceleration sensor. This acceleration sensor has a magnetic body including a mass point on an axis along a Z-axis, mounted to a vibrator having three-dimensional freedom, and four or more MR detector elements positioned on an X-axis and a Y-axis with their centers located along a perimeter of a concentric circle around the origin point of the orthogonal coordinate axes. The sensor is thus capable of detecting each of acceleration in the direction of X-axis through a relative difference in output voltage between the two detector elements on the X-axis due to a vibration of the magnetic field, acceleration in the direction of Y-axis through a relative difference in output voltage between the two detector elements on the Y-axis due to a vibration of the magnetic field, and acceleration in the direction of Z-axis through a sum total of the output voltages of all the detector elements.
According to the acceleration sensor disclosed in U.S. Pat. No. 6,131,457, as it is not necessary to form electrodes on the spring or the weight, the structure of the sensor becomes simple. However, in such acceleration sensor, with the miniaturization of the magnet, intensity of the magnetic field generated there from weakens, and also with the increase in distance between the magnet and the MR detector element, sensitivity in acceleration detection lowers due to divergence of the magnetic field from the magnet. Furthermore, due to the miniaturization of the magnet and the large leakage of the diverged magnetic field, this acceleration sensor is susceptible to external magnetic filed applied there to, for example, the magnet itself may move in response to the external magnetic filed. Also, using of an anisotropic MR (AMR) element causes lower sensitivity of the magnetic field, so that it is difficult to provide a highly sensitive acceleration sensor.

Acceleration sensor and magnetic disk drive apparatus


A socket apparatus, within which conductive terminals can be secured and electrically connected as desired, comprising of a housing member, lid, and means for securing conductive terminals within the housing member. The socket apparatus includes an aperture that is specifically designed to accommodate conductive terminals varying in size and in variety. Furthermore, the socket apparatus' lid supports the means for securing the conductive terminals.

1. Field of the Invention
The present invention relates to a universal electrical socket and, more particularly, to a medical socket apparatus that is capable of securing conductive terminals of various sizes.
2. Description of Related Art
Universal electrical sockets are often comprised of numerous parts, thus making assembly of the sockets difficult, time-consuming, and expensive. Another limitation is that they are designed only to accommodate conductive terminals of a particular size.
Representative prior art in the field of electrical connectors includes U.S. Pat. No. 1,061,809, disclosing a binding post with an opening into which a conductive wire is inserted and secured.
U.S. Pat. No. 1,559,683 teaches that an electrical connector can secure a conductive terminal within its housing by utilizing a spring.
U.S. Pat. No. 1,943,590 discloses an electrical connector that has a triangular shaped opening for receiving conductive terminals.
U.S. Pat. Nos. 2,010,453, 2,115,012, and 2,164,200, and French Patent No. 25,906 disclose electrical connectors that use a spring to secure conductive terminals. Other electrical connectors that contain a spring are also disclosed in German Patent No. 1,074,693 and in English Patent No. 727,380.
Finally, U.S. Pat. No. 2,424,444 discloses an electrical binding post that can secure wires that vary in diameter.
The prior art is still seeking to provide a simplified universal electrical connector.