公开(公告)号：JP2001097952A

公开(公告)日：2001-04-10

申请号：JP2000298078

申请日：2000-09-29

Applicant: HOFFMANN LA ROCHE

Inventor： ALANINE ALEXANDER ,  BURNER SERGE ,  BUETTELMANN BERND ,  NEIDHART MARIE-PAULE HEITZ ,  JAESCHKE GEORG ,  PINARD EMMANUEL ,  WYLER RENE

IPC: C07D215/22 ,  A61K31/47 ,  A61K31/4709 ,  A61K31/4725 ,  A61P9/10 ,  A61P21/00 ,  A61P25/00 ,  A61P25/14 ,  A61P25/16 ,  A61P25/28 ,  C07D215/233 ,  C07D215/42 ,  C07D215/46 ,  C07D401/04 ,  C07D401/12 ,  C07D405/04 ,  C07D405/12 ,  C07D409/04 ,  C07D413/12

Abstract: PROBLEM TO BE SOLVED: To provide a new quinolin-4-yl derivative. SOLUTION: A compound of formula (I) [R1 is H, a lower alkyl, a lower alkoxy, hydroxy, amino, nitro or the like; R2 is phenyl (if necessary, substituted by a lower alkyl, a lower alkoxy, a halogen, trifluoromethyl, amino, a lower alkyl-amino or a di-lower alkyl-amino), 2, 3-dihydro-benzofuran-5-yl, chroman-6- yl, naphthalen-2-yl, indan-5-yl or the like; R3 and R4 are each mutually independently H or a lower alkyl; R5 is H, a lower alkyl, CH2OH or the like; X is NR8 or O; or X and R5 together form >N-(CH2)2; X and R3 together form >N(CH2)3; R8 is H or a lower alkyl].

公开(公告)号：JP2001114777A

公开(公告)日：2001-04-24

申请号：JP2000304354

申请日：2000-10-04

Applicant: HOFFMANN LA ROCHE

Inventor： ALANINE ALEXANDER ,  BURNER SERGE ,  BUETTELMANN BERND ,  NEIDHART MARIE-PAULE HEITZ ,  JAESCHKE GEORG ,  PINARD EMMANUEL ,  WYLER RENE

IPC: C07D215/42 ,  A61K31/4709 ,  A61K31/4725 ,  A61P21/00 ,  A61P25/00 ,  A61P25/04 ,  A61P25/14 ,  A61P25/16 ,  A61P25/28 ,  A61P29/00 ,  A61P43/00 ,  C07D401/04 ,  C07D401/14

Abstract: PROBLEM TO BE SOLVED: To obtain a new N-methyl-D-aspartic acid (NMDA) receptor subtype specific blocker. SOLUTION: This compound is represented by the formula (I) [wherein R1 is hydrogen, a lower alkyl, a lower alkoxy, hydroxyl, amino, nitro, cyano, a lower alkylamino, a di-lower alkylamino or a halogen; R2 is hydrogen, a lower alkyl, amino, pyrrolidin-3-ol, pyrrolidin-2-ylmethanol or NHCH2CHROH; R3 is hydrogen or a halogen; R is hydrogen, a lower alkyl or CH2OH; and n is 1 or 2] and its pharmaceutically acceptable acid addition salt.

公开(公告)号：JP2000063384A

公开(公告)日：2000-02-29

申请号：JP2985099

申请日：1999-02-08

Applicant: HOFFMANN LA ROCHE

Inventor： ALANINE ALEXANDER ,  BUETTELMANN BERND ,  HEITZ NEIDHART MARIE-PAULE ,  PINARD EMMANUEL ,  WYLER RENE

IPC: C07D211/22 ,  A61K31/00 ,  A61K31/40 ,  A61K31/4025 ,  A61K31/42 ,  A61K31/424 ,  A61K31/435 ,  A61K31/437 ,  A61K31/443 ,  A61K31/445 ,  A61K31/4525 ,  A61K31/505 ,  A61K31/535 ,  A61K31/5375 ,  A61K31/5383 ,  A61P9/10 ,  A61P25/00 ,  A61P25/14 ,  A61P25/16 ,  A61P25/18 ,  A61P25/22 ,  A61P25/24 ,  A61P25/28 ,  A61P43/00 ,  C07D20060101 ,  C07D207/06 ,  C07D207/08 ,  C07D207/09 ,  C07D211/32 ,  C07D263/52 ,  C07D265/34 ,  C07D265/36 ,  C07D405/06 ,  C07D498/04

Abstract: PROBLEM TO BE SOLVED: To obtain a new compound useful for treatment of acute neurodegeneration caused by cerebral stroke or the like, chronic neurodegeneration such as Alzheimer's disease, Parkinson's disease and Huntington's disease, schizophrenia, anxiety, depression or the like. SOLUTION: This new compound is the one of formula I or II [R1 and R2 are each H, a lower alkoxy or the like; R3 and R4 are each H, benzyloxy or the like; R5 is H or a lower alkyl; X and Y are each CH(OH) or (CH2)m; (m), (n) and (p) are each 1 or 2], e.g. 4-[(RS)-hydroxy-[(2SR,5RS)-5-phenethyl- pyrrolidin-2-yl]-methyl]-phenol. The compound of formula II is obtained by cyclizing a compound of formula III by the reaction with a compound for providing an oxazole ring.

公开(公告)号：JP2000109429A

公开(公告)日：2000-04-18

申请号：JP22965899

申请日：1999-08-16

Applicant: HOFFMANN LA ROCHE

Inventor： ALANINE ALEXANDER ,  BUETTELMANN BERND ,  HEITZ NEIDHART MARIE-PAULE ,  PINARD EMMANUEL ,  WYLER RENE

IPC: C07D319/06 ,  A61K31/135 ,  A61K31/137 ,  A61K31/138 ,  A61K31/18 ,  A61K31/357 ,  A61K31/4468 ,  A61K31/451 ,  A61K31/535 ,  A61P25/00 ,  A61P25/14 ,  A61P25/16 ,  A61P25/28 ,  A61P43/00 ,  C07C215/46 ,  C07D211/58

Abstract: PROBLEM TO BE SOLVED: To use a specific compound for producing a medicine useful for treating and preventing diseases caused by excessive activation of MMDA receptor subtype. SOLUTION: A compound of formula I [Ar1 and Ar2 are each a (substituted) phenyl, naphthyl or tetrahydronaphthyl; X is C, CH or C(OH)N; Y is CH2, CH or O; Z is CH2, CH(CH3) or the like; R1 is H, a lower alkyl or acetyl; A is C=O, (CHR2)n (R2 is H, a lower alkyl or the like; (n) is 0-4); B is (CH2)n, O, CH(CH) or the like] or its pharmaceutically acceptable acid addition salt, preferably trans-4-[4-(3-phenyl-propylamino)cyclohexyl]-phenol, etc., is used. The compound is obtained by heating a compound of formula II and a compound of formula III in a solvent such as toluene, etc., by a Dean and Stark apparatus.

公开(公告)号：JPH1067742A

公开(公告)日：1998-03-10

申请号：JP19217397

申请日：1997-07-17

Applicant: HOFFMANN LA ROCHE

Inventor： ALANINE ALEXANDER ,  BUTELMAN BERRNT ,  HEIRGHT NIDART MARI-PAUL ,  PINARR EMMANUEL ,  WILLER LENER

IPC: C07D211/14 ,  A61K31/445 ,  A61K31/452 ,  A61K31/4523 ,  A61P25/00 ,  A61P25/16 ,  A61P25/28 ,  A61P43/00 ,  C07D20060101 ,  C07D211/18 ,  C07D211/20 ,  C07D211/48 ,  C07D401/06 ,  C07D401/08 ,  C07D401/12 ,  C07D521/00

Abstract: PROBLEM TO BE SOLVED: To obtain a novel compound which is useful in an N-methyl-D-aspartic acid receptor subtype-specific blocker in diseases, for example, an acute neurodegeneration caused by cerebral apoplexy, Alzheimer's disease, Parkinson's disease, Huntington's disease and the like. SOLUTION: This compound is represented by formula I (X is -O-, -NH-, -CH2 -; R -R are H, a halogen, OH, a lower alkylsulfonylamino; R -R are each H, a lower alkyl, a halogen; n is 0, 1), typically 1[2-(4-hydroxy-phenoxy) ethyl]-4-(4-methyl-benzyl)-piprtidine-4-ol. The compound of formula I is prepared by reaction of a compound of formula II with a compound of formula III.

公开(公告)号：JP2001064263A

公开(公告)日：2001-03-13

申请号：JP2000220748

申请日：2000-07-21

Applicant: HOFFMANN LA ROCHE

Inventor： ALANINE ALEXANDER ,  BUETTELMANN BERND ,  HEITZ NEIDHART MARIE-PAULE ,  JAESCHKE GEORG ,  PINARD EMMANUEL ,  WYLER RENE

IPC: A61K31/4164 ,  A61K31/4178 ,  A61K31/4196 ,  A61K31/4427 ,  A61K31/443 ,  A61K31/4439 ,  A61K31/454 ,  A61K31/496 ,  A61K31/5377 ,  A61P21/04 ,  A61P25/00 ,  A61P25/16 ,  A61P25/18 ,  A61P25/22 ,  A61P25/24 ,  A61P25/28 ,  A61P43/00 ,  C07B61/00 ,  C07D233/54 ,  C07D233/64 ,  C07D249/08 ,  C07D249/14 ,  C07D401/06 ,  C07D401/10 ,  C07D403/10 ,  C07D405/04 ,  C07D405/10

Abstract: PROBLEM TO BE SOLVED: To obtain a novel compound useful for treating diseases caused by excessive activation of N-methyl-D-aspartate acceptor subtype, including neurodegeneration of acute morphology caused by cerebral hemorrhage, or the like, and other diseases, e.g. schizophrenia. SOLUTION: This compound is represented by formula I R1 to R4 are each H, CF3, a lower alkyl, a halogen, phenyl, or the like, wherein R2 and R3 may be combined with each other to form (CH2)3, or the like; X is N, CH, or the like; Y is N, or the like, wherein at least one of X and Y contains N; and R5 is represented by formula II [R6 and R7 are each H, a lower alkyl, or the like, wherein R6 and R7 may be combined with N to form (CH2)2-O-(CH2)2, or the like], e.g. 3-[5-(4-difluoromethoxy-phenyl)-1H-[1,2,4]triazol-3- yl]benzyl}dimethylamine(mixture of tautomers). The compound represented by formula I may be produced by, e.g. reacting a compound represented by formula III with a compound represented by formula IV to form a compound represented by formula V.

公开(公告)号：JPH10168060A

公开(公告)日：1998-06-23

申请号：JP32989197

申请日：1997-12-01

Applicant: HOFFMANN LA ROCHE

Inventor： ALANINE ALEXANDER ,  BUETTELMANN BERND ,  HEITZ NEIDHART MARIE-PAULE ,  PINARD EMMANUEL ,  WYLER RENE

IPC: C07D211/44 ,  A61K31/38 ,  A61K31/4427 ,  A61K31/443 ,  A61K31/445 ,  A61K31/451 ,  A61K31/453 ,  A61K31/454 ,  A61K31/47 ,  A61P25/00 ,  A61P25/14 ,  A61P25/16 ,  A61P25/28 ,  A61P43/00 ,  C07D211/14 ,  C07D211/48 ,  C07D215/12 ,  C07D215/18 ,  C07D307/78 ,  C07D335/06 ,  C07D401/06 ,  C07D405/06 ,  C07D417/06

Abstract: PROBLEM TO BE SOLVED: To obtain a 4-hydroxypiperidine derivative useful as a specific blocker of N-methyl-D-aspartic acid(NMDA) receptor sub-type and effective for an acute nerval degeneration induced by cerebral hemorrhage or cerebral trauma, etc., or a chronic nerval degeneration such as Alzheimer's disease. SOLUTION: This 4-hydroxypiperidine derivative is a compound of formula I X is O, NH, CH2 , etc.; R to R are each independently H, hydroxy, a lower alkyl-sulfonylamino, etc.; R to R are each independently H, hydroxy, a lower alkyl, etc.; (a) and (b) are each independently double bond or signal bond and when (a) is double bond, (b) is not double bond; (n) is an integer of 0 to 2; (m) is an integer of 1 to 3; (p) is 0 or 1} or its pharamaceutically permissible addition salt, e.g. (RS)-1-(5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl)-4-(4- methylbenzyl)piperidin-4-ol is exemplified. The compound of the formula I is obtained by, e.g. reacting a compound of formula II (L is OH, a halogen, etc.) with a compound of formula III.

公开(公告)号：US6432985B2

公开(公告)日：2002-08-13

申请号：US81188801

申请日：2001-03-19

Applicant: HOFFMANN LA ROCHE

Inventor： ALANINE ALEXANDER ,  BUETTELMANN BERND ,  NEIDHART MARIE-PAULE HEITZ ,  JAESCHKE GEORG ,  PINARD EMMANUEL ,  WYLER RENE

IPC: C07D211/50 ,  A61K31/445 ,  A61P21/04 ,  A61P25/06 ,  A61P25/14 ,  A61P25/16 ,  A61P25/18 ,  A61P25/22 ,  A61P25/24 ,  A61P25/28 ,  A61P29/00 ,  C07D211/48 ,  C07D211/40 ,  C07D211/44

CPC classification number: C07D211/48

Abstract: The invention relates to a compound of the formulaits R,R-, S,S-enantiomers and racemic mixtures thereof and to their pharmaceutically acceptable acid addition salts.The compound of formula I and its R,R- and S,S-enantiomers may be used as medicaments for the treatment of diseases, wherein the therapeutic indications include acute forms of neurodegeneration caused by stroke or brain trauma; chronic forms of neurodegeneration such as Alzheimer's disease, Parkinson's disease, Huntington's disease or ALS (amyotrophic lateral sclerosis); neurodegeneration associated with bacterial or viral infections, and, diseases such as schizophrenia, anxiety, depression and chronic/acute pain.

Abstract translation: 本发明涉及式R，R-，S，S-对映异构体及其外消旋混合物及其药学上可接受的酸加成盐的化合物。式I化合物及其R，R-和S，S-对映异构体可以 用作治疗疾病的药物，其中治疗适应症包括由中风或脑外伤引起的急性形式的神经变性; 慢性形式的神经变性如阿尔茨海默病，帕金森病，亨廷顿病或ALS（肌萎缩性侧索硬化）; 与细菌或病毒感染相关的神经变性，以及精神分裂症，焦虑症，抑郁症和慢性/急性疼痛等疾病。

公开(公告)号：WO0129011A3

公开(公告)日：2001-11-08

申请号：PCT/EP0009553

申请日：2000-09-29

Applicant: HOFFMANN LA ROCHE

Inventor： ADAM GEO ,  ALANINE ALEXANDER ,  GOETSCHI ERWIN ,  MUTEL VINCENT ,  WOLTERING THOMAS JOHANNES

IPC: A61K31/55 ,  A61K31/551 ,  A61K31/5513 ,  A61P1/08 ,  A61P3/08 ,  A61P9/00 ,  A61P9/10 ,  A61P13/00 ,  A61P21/02 ,  A61P25/00 ,  A61P25/04 ,  A61P25/06 ,  A61P25/14 ,  A61P25/16 ,  A61P25/18 ,  A61P25/22 ,  A61P25/24 ,  A61P25/28 ,  A61P25/34 ,  A61P25/36 ,  A61P27/02 ,  A61P43/00 ,  C07D243/12 ,  C07D401/04 ,  C07D401/06 ,  C07D401/14 ,  C07D403/10 ,  C07D403/14 ,  C07D405/04 ,  C07D405/06 ,  C07D409/04 ,  C07D413/04 ,  C07D413/10 ,  C07D413/14 ,  C07D417/04 ,  C07D417/10 ,  C07D417/14 ,  C07D491/056 ,  C07D491/113 ,  C07F7/10

CPC classification number: C07D243/12

Abstract: The present invention relates to compounds of general formula (I) wherein X is a single bond or an ethynediyl group, wherein, in case X is a single bond, R is halogen or phenyl which is optionally substituted with halogen, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, or cyano; In case X is an ethynediyl group, R is phenyl, optionally substituted with halogen, lower alkyl, halo-lower alkyl, lower cycloalkyl, lower alkoxy or halo-lower alkoxy; R is a 5 or 6 membered aryl or heteroaryl which are optionally substituted. The compounds according to the present invention can be used for treating or preventing acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits.

Abstract translation: 本发明涉及通式（I）的化合物，其中X为单键或亚乙二基，其中，在X为单键的情况下，R 1为卤素或任选被卤素取代的苯基，低级烷基 ，卤代低级烷基，低级烷氧基，卤代低级烷氧基或氰基; 在X为乙炔二基的情况下，R 1为苯基，任选被卤素，低级烷基，卤代低级烷基，低级环烷基，低级烷氧基或卤代低级烷氧基取代; R 3是任选被取代的5或6元芳基或杂芳基。 根据本发明的化合物可用于治疗或预防急性和/或慢性神经障碍，例如精神病，精神分裂症，阿尔茨海默病，认知障碍和记忆缺陷。

公开(公告)号：WO0129012A3

公开(公告)日：2001-11-08

申请号：PCT/EP0009554

申请日：2000-09-29

Applicant: HOFFMANN LA ROCHE

Inventor： ADAM GEO ,  ALANINE ALEXANDER ,  GOETSCHI ERWIN ,  MUTEL VINCENT ,  WOLTERING THOMAS JOHANNES

IPC: A61K31/55 ,  A61K31/551 ,  A61K31/5513 ,  A61P1/08 ,  A61P3/08 ,  A61P9/08 ,  A61P13/02 ,  A61P21/02 ,  A61P21/04 ,  A61P25/00 ,  A61P25/06 ,  A61P25/14 ,  A61P25/16 ,  A61P25/18 ,  A61P25/22 ,  A61P25/24 ,  A61P25/28 ,  A61P25/34 ,  A61P25/36 ,  A61P27/02 ,  A61P29/02 ,  A61P43/00 ,  C07D243/12 ,  C07D401/04 ,  C07D401/06 ,  C07D401/14 ,  C07D403/10 ,  C07D405/04 ,  C07D405/06 ,  C07D409/04 ,  C07D409/08 ,  C07D409/14 ,  C07D413/10 ,  C07D417/02 ,  C07D417/04 ,  C07D417/06 ,  C07D417/10 ,  C07D417/14 ,  C07F7/10

CPC classification number: C07D401/04 ,  C07D243/12 ,  C07D403/10 ,  C07D405/06 ,  C07D413/10 ,  C07D417/06 ,  C07D417/10

Abstract: The present invention relates to compounds of general formula (I) wherein R is phenyl; pyridine; thiophenyl or thiazolyl, which are optionally substituted. The compounds according to the present invention can be used for treating or preventing acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits.

Abstract translation: 本发明涉及通式（I）的化合物，其中R 3是苯基; 吡啶; 噻吩基或噻唑基，其任选被取代。 根据本发明的化合物可用于治疗或预防急性和/或慢性神经障碍，例如精神病，精神分裂症，阿尔茨海默病，认知障碍和记忆缺陷。