RU98123001A

RU98123001A - ARYLPYRIMIDINE DERIVATIVES

Info

Publication number: RU98123001A
Application number: RU98123001/04A
Authority: RU
Inventors: Берджер Джейкоб; Аллен Флиппин Ли; Гринхаус Роберт; Хайме-Фигуероа Саул; Лю Ваньджоу; Керн Миллер Обри; Джордж Путман Дейвид; Курт Вейнхардт Клаус; Джао Чухай
Original assignee: Ф.Хоффманн-Ля Рош Аг
Priority date: 1996-05-23
Filing date: 1997-05-14
Publication date: 2000-10-20

Claims

1. The compound of formula I

where the compound is an antagonist of the 5-HT _2B receptor and where further R ¹ denotes hydrogen, C ₁ -C ₁₂ alkyl, hydroxyC ₁ -C ₁₂ alkyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkyl-C ₁ -C ₆ alkyl, C ₂ -C ₁₂ alkenyl, C ₁ -C ₆ thioalkoxy, halogen, fluoro C ₁ -C ₁₂ alkyl, phenyl C ₁ -C ₆ alkyl, optionally substituted with C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, nitro, C ₁ -C ₆ fluoroalkyl and halogen; —NR ⁶ R ⁷ , —CO ₂ R ⁸ or —O (CH ₂ ) _n R ⁹ , where n is 1, 2 or 3, R ⁶ and R ⁷ independently of one another denote hydrogen or C ₁ -C ₆ alkyl, R ⁸ is hydrogen or C ₁ -C ₆ alkyl and R ⁹ is hydrogen, C ₁ -C ₆ alkyl, hydroxy, hydroxy C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₆ alkoxy, R ² is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen or C ₁ -C ₆ fluoroalkyl, R ³ denotes phenyl, thiophene, naphthalene, anthracene, phenanthrene, quinoline, isoquinoline, 1,2,3,4- tetrahydroquinoline, indole, 2,3-dihydroindole, 1H-benzo [b] azepine, 2,3,4,5-tetrahydro-1H-benzo [b] azepine, 2H-benzo [1,4] oxazine, 3,4- dihydro-2H-benzo [1,4 ] oxazine, 1H, 3H-benzo [de] isochrome, 6,7,8,9-tetrahydro-5-oxa-9-benzocycloheptane, 2,3-dihydro-1,4-benzodioxane, optionally substituted With ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, nitro, C ₁ -C ₆ fluoroalkyl and halogen; R ⁴ is hydrogen, C ₁ -C ₆ alkyl, phenyl C ₁ -C ₆ alkyl, optionally substituted with C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, nitro, C ₁ -C ₆ fluoroalkyl and halogen; hydroxyC ₁ -C ₆ alkyl, C (O) C ₁ -C ₆ alkyl or - (CH ₂ ) _m NR ⁶ R ⁷ , where m is an integer from 1 to 6 and R ⁶ and R ⁷ are hydrogen or C ₁ - C ₆ alkyl, and R ⁵ denotes hydrogen or C ₁ -C ₆ alkyl, provided that (I) when R ³ denotes naphthyl, indol-1-yl or 2,3-dihydroindol-1-yl and R ² , R ⁴ and R ^{5 are} all hydrogen, R ^{1 is} not methyl, (II) when R ³ is phenyl or naphthyl, R ^{1 is} not -NR ⁶ R ⁷ , (III) when R ³ is phenyl, R ^{2 is} not C ₁ -C ₆ alkoxy and R ¹ and R ² do not mean halogen, (IV) when R ³ means phenyl and R ¹ denotes H, R ² does not denote methyl, and (V) when R ³ denotes 1,2,3,4-tetrahydroquinolinyl, R ⁴ and R ⁵ are hydrogen,
or its pharmaceutically acceptable salt or N-oxide.

2. The compound according to claim 1, in which R ⁴ and R ⁵ denote hydrogen or C ₁ -C ₆ alkyl.

3. The compound according to claim 2, in which R ¹ stands for C ₁ -C ₆ alkyl, fluoro C ₁ -C ₁₂ alkyl or hydroxyC ₁ -C ₁₂ alkyl and R ³ denotes 1-naphthyl, optionally substituted with C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, nitro, C ₁ -C ₆ fluoroalkyl and halogen, or its pharmaceutically acceptable salt or N-oxide.

4. The compound according to claim 3, in which R ¹ denotes methyl, R ² , R ⁴ and R ⁵ denote hydrogen and R ³ denotes 2-methylnapht-1-yl, namely, 2-amino-4- (2-methylnaph -1-yl) -6-methylpyrimidine, or its pharmaceutically acceptable salt or N-oxide.

5. The compound according to claim 3, in which R ¹ denotes isopropyl, R ² , R ⁴ and R ⁵ denote hydrogen and R ³ denotes 4-fluoro-naphth-1-yl, namely, 2-amino-4- (4-fluoro-naft -1-yl) -6-isopropylpyrimidine, or its pharmaceutically acceptable salt or N-oxide.

6. The compound according to claim 5, in which the N-oxide is in position 1, namely, 2-amino-4- (4-fluoro-naphth-1-yl) -6-isopropylpyrimidine-1-N-oxide.

7. The compound according to claim 3, wherein R ¹ is 1-fluoro-1-methylethyl, R ² , R ⁴ and R ⁵ are hydrogen and R ³ is 4-fluoro-naphth-1-yl, namely 2-amino 4- (4-fluoro-naphth-1-yl) -6- (1-fluoro-1-methylethyl) pyrimidine, or its pharmaceutically acceptable salt or N-oxide.

8. The compound according to claim 3, wherein R ¹ is 1-hydroxy-1-methylethyl, R ² , R ⁴ and R ⁵ is hydrogen and R ³ is 4-fluoro-naphth-1-yl, namely 2-amino 4- (4-fluoro-naphth-1-yl) -6- (1-hydroxy-1-methylethyl) pyrimidine, or its pharmaceutically acceptable salt or N-oxide.

9. The compound according to claim 3, wherein R ¹ is 1-fluoro-1-methylethyl, R ² , R ⁴ and R ⁵ are hydrogen and R ³ is 4,6-difluoro-naphth-1-yl, namely 2- amino-4- (4,6-difluoro-naphth-1-yl) -6- (1-fluoro-1-methylethyl) pyrimidine, or a pharmaceutically acceptable salt thereof, or N-oxide.

10. The compound according to claim 3, in which R ¹ denotes isopropyl, R ² and R ⁴ denote hydrogen, R ⁵ denotes methyl and R ³ denotes 4-fluoro-naphth-1-yl, namely, 2-methylamino-4- (4 -fluorneft-1-yl) -6-isopropylpyrimidine, or its pharmaceutically acceptable salt or N-oxide.

11. The compound according to claim 3, in which R ¹ denotes 2-methylpropyl, R ² , R ⁴ and R ⁵ denote hydrogen and R ³ denotes 4-fluoro-naphth-1-yl, namely, 2-amino-4- (4 -fluorneft-1-yl) -6- (2-methylpropyl) pyrimidine, or its pharmaceutically acceptable salt or N-oxide.

12. The compound according to claim 3, in which R ¹ denotes tert-butyl, R ² , R ⁴ and R ⁵ denote hydrogen and R ³ denotes 4-fluoro-naphth-1-yl, namely, 2-amino-6- (tert -butyl) -4- (4-fluornaft-1-yl) pyrimidine, or its pharmaceutically acceptable salt or N-oxide.

13. The compound according to claim 2, wherein R ¹ is C ₁ -C ₆ alkyl and R ³ is an optionally substituted indole, or a pharmaceutically acceptable salt thereof, or an N-oxide.

14. The compound according to claim 13, in which R ¹ denotes methyl, R ² , R ⁴ and R ⁵ denote hydrogen and R ³ denotes indol-4-yl, namely, 2-amino-4- (1H-indole-4 -yl) -6-methylpyrimidine, or its pharmaceutically acceptable salt or N-oxide.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims. 1-14 mixed with one or more pharmaceutically acceptable non-toxic carriers.

16. The method of obtaining the compounds of formula I

where R ¹ denotes hydrogen, C ₁ -C ₁₂ alkyl, hydroxy C ₁ -C ₁₂ alkyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkyl-C ₁ -C ₆ alkyl, C ₂ -C ₁₂ alkenyl, C ₁ -C ₆ thioalkoxy, halogen, fluorine ₁ -C ₁₂ alkyl, phenylC ₁ -C ₆ alkyl, optionally substituted with C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, nitro, C ₁ -C ₆ fluoroalkyl and halogen; —NR ⁶ R ⁷ , —CO ₂ R ⁸ , —O (CH ₂ ) _n R ⁹ , where n is 1, 2 or 3; R ⁶ and R ⁷ independently of one another denote hydrogen or C ₁ -C ₆ alkyl, R ⁸ denotes hydrogen or C ₁ -C ₆ alkyl and R ⁹ denotes hydrogen, C ₁ -C ₆ alkyl, hydroxy, hydroxyC ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₆ alkoxy, R ² denotes hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen or C ₁ -C ₆ fluoroalkyl, R ³ denotes phenyl, thiophene , naphthalene, anthracene, phenanthrene, quinoline, isoquinoline, 1,2,3,4-tetrahydroquinoline, indole, 2,3-dihydroindole, 1H-benzo [b] azepine, 2,3,4,5-tetrahydro-1H-benzo [b] azepine, 2H-benzo [1,4] oxazine, 3,4-dihydro-2H-benzo [1,4] oxazine, 1H, 3H-benzo [de] isochromen, 6,7,8,9-tetrahyd ro-5-oxa-9-benzocycloheptane, 2,3-dihydro-1,4-benzodioxane, optionally substituted with C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, nitro, C ₁ -C ₆ fluoroalkyl and halogen, R ⁴ is hydrogen, C ₁ -C ₆ alkyl, phenyl C ₁ -C ₆ alkyl, optionally substituted with C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, nitro, C ₁ -C ₆ fluoroalkyl and halogen; hydroxyC ₁ -C ₆ alkyl, C (O) C ₁ -C ₆ alkyl or - (CH ₂ ) _m NR ⁶ R ⁷ , where m is the integer 1-6 and R ⁶ and R ⁷ are hydrogen or C ₁ -C ₆ alkyl, and R ⁵ denotes hydrogen or C ₁ -C ₆ alkyl; with the proviso that (i) when R ³ is naphthyl, indol-1-yl or 2,3-dihydroindol-1-yl and R ² , R ⁴ and R ^{5 are} all hydrogen, R ^{1 is} not methyl, (II) when R ³ denotes phenyl or naphthyl, R ¹ does not denote -NR ⁶ R ⁷ , (III) when R ³ denotes phenyl, R ² does not denote C ₁ -C ₆ alkoxy, and R ¹ and R ² do not denote halogen, (IV) when R ³ denotes phenyl and R ¹ denotes H, R ² does not denote methyl, and (V) when R ³ denotes 1,2,3,4-tetrahydroquinolinyl, R ⁴ and R ⁵ denote hydrogen,
or its pharmaceutically acceptable salt or N-oxide, including the interaction of the compounds of formula (4)

with a boronic acid derivative of formula (5), i.e. with R ³ B (OR ¹¹ ) ₂ , to obtain a compound of the formula I, in which R ¹ , R ² and R ³ have the meanings indicated for formula I, R ⁴ and R ⁵ are hydrogen or C ₁ -C ₆ alkyl, a R ¹¹ is H or methyl.

17. The method of obtaining the compounds of formula I, including the interaction of the compounds of formula (6)

with a secondary amine of the formula NHR ⁴ R ⁵ to obtain a compound of formula I in which R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meanings indicated for formula I.

18. The method according to p. 16 or 17, further comprising reacting a compound of formula I with an oxidizing agent to obtain the N-oxide of the compound of formula I.

19. The method according to claim 16 or 17, further comprising reacting a compound of formula I with a strong acid to form a pharmaceutically acceptable salt of the compound of formula I.

20. The method according to claim 18, further comprising reacting a N-oxide of the compound of formula I, in which R ¹ is alkyl, with a carboxylic anhydride to obtain a compound of formula I, in which R ¹ is hydroxyalkyl or alkenyl, optionally followed by reacting the compound of the formula I with a strong acid to obtain a pharmaceutically acceptable salt of the compound of formula I.

21. The compound according to any one of paragraphs. 1-14, intended for use as a therapeutic agent.

22. The use of compounds according to any one of paragraphs. 1-14 in the preparation of a medicinal product for the treatment of a painful condition selected from the group including a generalized state of fear, a disorder associated with a state of panic, obsessive-compulsive disorder, alcoholism, depression, migraine, hypertension, sleep disturbance, anorexia nervosa and priapism.

23. A method of treating a mammal having a painful condition, facilitated by treatment with a 5-HT _2B receptor antagonist, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to any one of claims. 1-14.