RU2002110104A

RU2002110104A - Derivatives of benzodiazepine

Info

Publication number: RU2002110104A
Application number: RU2002110104/04A
Authority: RU
Inventors: Гео Адам; Александер АЛАНИН; Эрвин ГЁТШИ; Венсан МЮТЕЛЬ; Томас Иоганнес ВОЛЬТЕРИНГ
Original assignee: Ф.Хоффманн-Ля Рош Аг
Priority date: 1999-10-15
Filing date: 2000-09-29
Publication date: 2003-12-27

Claims

1. Compounds of the general formula

where X denotes a single bond or ethindylyl group, in which, when X denotes a single bond,

R ¹ means halogen or phenyl, which is optionally substituted with halogen, lower alkyl, halogen lower alkyl, lower alkoxy, halide lower alkoxy or cyano;

in the case where X is an ethyndiyl group,

R ¹ is phenyl optionally substituted with halogen, lower alkyl, halogen lower alkyl, lower cycloalkyl lower alkoxy, or lower alkoxy halogen;

R ² means halogen, hydroxy, (ness.) Alkyl, halogen (ness.) Alkyl, (ness.) Alkoxy, hydroxymethyl, hydroxyethoxy, (ness.) Alkoxy (ethoxy) _n (n = 1-4), (ness. ) alkoxymethyl, cyanomethoxy, morpholin-4-yl, thiomorpholin-4-yl, 1-oxothiomorpholin-4-yl, 1,1-dioxothiomorpholin-4-yl, 4-oxopiperidin-1-yl, 4-alkoxypiperidin-1-yl , 4-hydroxypiperidin-1-yl, 4-hydroxyethoxypiperidin-1-yl, 4- (ness.) Alkylpiperazin-1-yl, alkoxycarbonyl, 2-dialkylaminoethylsulfanyl, N, N-bis (ness.) Alkylamino (ness.) Alkyl , carbamoylmethyl, alkylsulfonyl, (ness.) alkoxycarbonyl (ness.) alkyl, alkylcarboxy (ness.) a keel, carboxy (ness.) alkyl, alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro [4.5] dec-8-yl, carboxy (ness.) alkoxy, cyano (ness.) alkyl, 2,3-dihydroxy (ness.) alkoxy, carbamoylmethoxy, 2-oxo [1,3] dioxolan-4-yl (ness.) alkoxy, 2-hydroxy (ness.) alkyl (ness.) alkylamino, hydroxycarbamoyl (ness.) alkoxy, 2, 2-dimethyltetrahydro [1,3] dioxolo [4,5-s] pyrrol-5-yl, (ness.) Alkoxycarbamoyl (ness.) Alkoxy, (3R) -hydroxypyrrolidin-1-yl, 3,4-dihydroxypyrrolidin-1 -yl, 2-oxooxazolidin-3-yl; (ness.) alkylcarbamoylmethoxy or aminocarbamoyl (ness.) alkoxy;

R ³ is a 5- or 6-membered aryl or heteroaryl, which is optionally substituted with halogen, cyano, nitro, azido, hydroxy, carboxy, morpholine-4-carbonyl, carbamoyl, thiocarbamoyl, N-hydroxycarbamoyl; trimethylsilylethinyl; or (ness.) alkyl, (ness.) alkoxy, halogen (ness.) alkyl, 4- (ness.) alkylpiperazine-1-carbonyl, (ness.) alkylcarbamoyl, which are optionally substituted by amino, (ness.) alkylamino, acylamino , oxo, hydroxy, (ness.) alkoxy, (ness.) alkylthio or carboxy, which is optionally esterified or amidated; or an optionally substituted five-membered aromatic heterocycle, which may be optionally substituted by amino, (ness.) alkylamino, acylamino, oxo, hydroxy, (ness.) alkoxy, (ness.) alkylthio, or carboxy, which is optionally esterified or amidated, or (ness. .) alkyl, which is optionally substituted with halogen, amino, (ness.) alkylamino, acylamino, hydroxy, (ness.) alkoxy, (ness.) alkylthio, acyloxy, (ness.) alkenoyl, (ness.) alkylsulfinyl, (ness. ) alkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, hydroxyimino, alkox imino, carboxy, which is optionally esterified or amidated, (ness.) alkenyl, oxo, cyano, carbamoyloxy, sulfamoyl, which is optionally substituted by (ness.) alkyl, or an amidino group, which is optionally substituted by (ness.) alkyl, -C (NRR ′) ) = NR ″ (where R, R ′ and R ″ are hydrogen or lower alkyl); and their pharmaceutically acceptable salts.

2. The compounds according to claim 1, wherein R ³ is phenyl substituted in the meta position with cyano, halogen or imidazolyl, which is optionally substituted with lower alkyl or methylsulfanyl; 1,2,3-triazolyl, 1,2,4-triazolyl, or isoxazolyl, which is optionally substituted with lower alkyl.

3. The compounds according to claim 2, which are 3- (8-Chloro-4-oxo-7-phenylethinyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl) benzonitrile; 3- [8- (4-Methylpiperazin-1-yl) -4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl] benzonitrile; 3- (8-Chloro-4-oxo-7-phenyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl) benzonitrile; [4- (3-Cyanophenyl) -2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo [b] [1,4] diazepin-7-ylsulfanyl] acetic acid methyl ester; 2- [4- (3-cyanophenyl) -2-oxo-8-phenylethinyl-2,3-dihydro-1H-benzo [b] [1,4] diazepin-2-yl] diazepin-7-yl] acetamide; 3- (8-Methoxy-4-oxo-7-phenylethinyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl] benzonitrile; 3- (8-Cyanomethyl-4-oxo -7-phenylethynyl-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl) benzonitrile; 4- (3-Iodophenyl) -7- (2-methoxyethoxy) -8-phenylethinyl- 1,3-dihydrobenzo [b] [1,4] diazepin-2-one; 4- (3-imidazol-1-ylphenyl) -7- (2-methoxyethoxy) -8-phenylethynyl-1,3-dihydrobenzo [b ] [1,4] diazepin-2-one; [RS] -3- [4-Oxo-8- (2-oxo [1,3] dioxolan-4-ylmethoxy) -7-phenylethynyl-4,5-dihydro -3H-benzo [b] [1,4] diazepin-2-yl] benzonitrile; 7-hydroxymethyl-4- (3-imidazol-1-ylphenyl) -8-phenylethynyl-1,3-dihydrobenzo [b] [1 , 4] diazepin-2-one; [4- (3-imidazol-1-ylphenyl) -2-oxo-8-fe itethynyl-2,3-dihydro-1H-benzo [b] [1,4] diazepin-7-yloxy] acetonitrile; 8- (4-Fluorophenylethynyl) -7-hydroxymethyl-4- (3-imidazol-1-ylphenyl) -1,3-dihydrobenzo [b] [1,4] diazepin-2-one; 7- (2-hydroxyethoxy) -4- (3-imidazol-1-ylphenyl) -8-phenylethynyl-1,3-dihydrobenzo [ b] [1,4] diazepin-2-one; 8- (4-Fluorophenyl) -7- [4- (2-hydroxyethoxy) piperidin-1-yl] -4- (3-imidazol-1-ylphenyl) - 1,3-dihydrobenzo [b] [1,4] diazepin-2-one; 8- (4-Fluorophenyl) -7-hydroxy-4- (3-imidazol-1-ylphenyl) -1,3-dihydrobenzo [b] [1,4] diazepin-2-one; 8- (2-Fluorophenyl) -7-methoxy-4- [3- (2-methylimidazol-1-yl) phenyl] -1,3-dihydrobenzo [b] [1,4] diazepin-2-one; 8- (2-Fluorophenyl) -7-hydroxy-4- (3- [1,2,3] triazol-1-ylphenyl) -1,3-dihydrobenzo [b] [1,4] diazepin-2-one; 8- (2-Fluorophenyl) -7-hydroxy-4- [3- (2-methylimidazol-1-yl) phenyl] -1,3-dihydrobenzo [b] [1,4] diazepin-2-one; 8- (2-Fluorophenyl) -7-hydroxy-4- [3- (2-methylsulfanylimidazol-1-yl) phenyl] -1,3-dihydrobenzo [b] [1,4] diazepin-2-one; 8- (2,5-Difluorophenyl) -7-methoxy-4- (3- [1,2,3] triazol-1-ylphenyl) -1,3-dihydrobenzo [b] [1,4] diazepin-2- he; 8- (2-Fluorophenyl) -7-hydroxy-4- [3- (3-methylisoxazol-5-yl) phenyl] -1,3-dihydrobenzo [b] [1,4] diazepin-2-one; 3- [7- (2,5-Difluorophenyl) -8-hydroxy-4-oxo-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl] benzonitrile; 8- (4-Fluorophenylethynyl) -7-hydroxy-4- (3-imidazol-1-ylphenyl) -1,3-dihydrobenzo [b] [1,4] diazepin-2-one; and 8- (4-Fluorophenylethynyl) -7-hydroxy-4- (3- [1,2,3] triazol-1-ylphenyl) -1,3-dihydrobenzo [b] [1,4] diazepin-2-one .

4. The compounds of claim 1, wherein R ³ is thiophenyl optionally substituted with cyano or halogen; pyridinyl optionally substituted at position 2 with cyano or halogen, or thiazolyl optionally substituted at position 2 with imidazolyl or 4-methylimidazolyl.

5. The compounds according to claim 4, which are 5- [7- (2-Fluorophenyl) -8-methoxy-4-oxo-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2- yl] thiophene-2-carbonitrile; 2- [7- (2-Fluorophenyl) -8-hydroxy-4-oxo-4,5-dihydro-1H-benzo [b] [1,4] diazepin-2-yl] thiophen-3-carbonitrile; 4- [7- (2-Fluorophenyl) -8-methoxy-4-oxo-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl] pyridin-2-carbonitrile; 4- [7- (4-Fluorophenyl) -8-hydroxy-4-oxo-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl] pyridin-2-carbonitrile; 4- [7- (2-Fluorophenyl) -8-hydroxy-4-oxo-4,5-dihydro-3H-benzo [b] [1,4] diazepin-2-yl] pyridin-2-carbonitrile; and 8- (2-Fluorophenyl) -4- [2- (4-methylimidazol-1-yl) thiazol-4-yl] -1,3-dihydrobenzo [b] [1,4] diazepin-2-one.

6. A medicament containing one or more compounds according to any one of claims 1 to 5 and pharmaceutically acceptable excipients.

7. The drug according to claim 6 for the treatment or prevention of acute and / or chronic neurological disorders, including psychosis, schizophrenia, Alzheimer's disease, cognitive impairment and memory impairment.

8. A method for producing compounds of formula I, as defined in claim 1, a method that includes reacting a compound of formula II

with a compound of formula IV or IVa

where R is ethyl or butyl, with the formation of the compounds of formula III

which is subsequently subjected to the release of the amino group and cyclization in order to obtain the compounds of formula I according to claim 1.

9. The compound according to any one of claims 1 to 5, obtained by the method according to claim 9, or by any equivalent method.

10. The use of a compound according to any one of claims 1 to 5 for the treatment of acute and / or chronic neurological disorders, including psychosis, schizophrenia, Alzheimer's disease, cognitive impairment and memory impairment.

11. The use of one or more compounds according to claims 1-5 and / or one or more of their acid additive salts in the manufacture of medicines for the treatment or prevention of diseases.

12. The use according to claim 13 for the treatment of acute and / or chronic neurological disorders, including psychosis, schizophrenia, Alzheimer's disease, cognitive impairment and memory impairment.

13. The invention as described above.