RU95122587A

RU95122587A - 1-PHYLALALCANONS NEW 5-HT * 004 RECEPTOR LIGANDS

Info

Publication number: RU95122587A
Application number: RU95122587/04A
Authority: RU
Inventors: Д.Кларк Робин; ЭГЛЕН Ричард; ДЖАХАНГИР Элам; Б.Миллер Аарон; О.Гарднер Джон
Original assignee: Синтекс (Ю.ЭС.ЭЙ.) Инк.
Priority date: 1993-05-26
Filing date: 1994-05-25
Publication date: 1997-11-27

Claims

1. The compound of formula I

Where
R ¹ is halogen;
R ² denotes hydrogen or C ₁ - C ₄ -alkyloxy and
R ³ stands for C ₁ - C ₄ -alkyloxy or phenyl C ₁ - C ₄ -alkyloxy (where phenyl is optionally substituted with one to three substituents independently selected from halogen, hydroxyl, C ₁ - C ₄ -alkyl, C ₁ - C ₄ - alkyloxy, nitro, amino, aminocarbonyl, C ₁ - C ₄ -alkylamino, diC ₁ - C ₄ -alkylamino, C ₁ - C ₄ -alkanoylamino and 3,4-methylenedioxy),
or R ² and R ³ together represent methylenedioxy or ethylenedioxy;
R ⁴ denotes a group of formula (a) or (b)

or

where n is 3, 4 or 5;
p is 0 or 1;
q is 1 or 2;
R ⁵ and R ⁶ each represent C ₁ - C ₄ -alkyl or together form - (CH ₂ ) ₄ - (CH ₂ ) ₆ -, - (CH ₂ ) ₂ O (CH ₂ ) ₂ - or -CHR ⁸ CH ₂ CR ⁹ R ¹ ⁰ CHR ¹ ¹ CH ₂ -, where R ⁸ and R ¹ ¹ each denotes hydrogen or together denotes - (CH ₂ ) _t where t is 1, 2 or 3, R ⁹ denotes hydrogen, hydroxyl, C ₁ - C ₈ -alkyl, C ₃ - C ₈ -alkenyl or C ₁ - C ₄ -alkyloxy and R ¹ ⁰ denotes hydrogen, C ₁ - C ₈ -alkyl or C ₃ - C ₈ -alkenyl, or phenyl, thienyl, pyrrolyl or furyl (optionally substituted with one to two substituents independently selected from C ₁ - C ₄ -alkyl, C ₁ - C ₄ -alkyloxy, trifluoromethyl and halogen), or - (CH ₂ ) _x R ¹ ² , where x is o 0, 1, 2 or 3 and R ¹ ² is hydroxyl, C ₁ - C ₄ -alkyloxy, C (O) NR ¹ ³ R ¹ ⁴ , -NR ¹ ³ C (OR ¹ ⁴ , -NR ¹ ³ C ( O) OR ¹ ⁴ , -SO ₂ NR ¹ ³ R ¹ ⁴ , -NR ¹ ³ SO ₂ R ¹ ⁴ , NR ¹ ³ SO ₂ NR ¹ ⁴ R ¹ ⁵ or -NR ¹ ³ C (O) NR ¹ ⁴ R ¹ ⁵ ,
where R ¹ ³ , R ¹ ⁴ and R ¹ ⁵ independently represent hydrogen, C ₁ - C ₄ -alkyl, trifluoromethyl or aryl;
R ⁷ is hydrogen, C ₁ -C ₈ -alkyl or C ₃ -C ₈ -alkenyl, or phenyl C ₁ -C ₄ -alkyl (where phenyl is optionally substituted with one to three substituents independently selected from C ₁ -C ₄ -alkyloxy , methylenedioxy, ethylenedioxy or halogen), or - (CH ₂ ) _z R ¹ ² where z is 2 or 3 and R ¹ ² is as defined above,
and its pharmaceutically acceptable salts, individual isomers and mixtures of isomers.

2. The compound according to claim 1, having the following formula I (a)

where n is 3, 4 or 5;
p is 0 or 1;
R ¹ is halogen;
R ³ denotes C ₁ - C ₄ -alkyloxy;
R ⁵ and R ⁶ each denotes C ₁ - C ₄ -alkyl or together form - (CH ₂ ) ₄ -, - (CH ₂ ) ₆ -, - (CH ₂ ) ₂ O (CH ₂ ) ₂ - or -CHR ⁸ CH ₂ CR ⁹ R ¹ ⁰ CHR ¹ ¹ CH ₂ -,
where R ⁸ and R ¹ ¹ each denotes hydrogen or together denote - (CH ₂ ) _t , where t is 1, 2 or 3;
R ⁹ denotes hydrogen, hydroxyl, C ₁ - C ₈ -alkyl, C ₃ - C ₈ -alkenyl or C ₁ - C ₄ -alkyloxy;
R ¹ ⁰ denotes hydrogen, C ₁ -C ₈ -alkyl, or C ₃ -C ₈ -alkenyl, or phenyl, thienyl, pyrrolyl or furyl (optionally substituted with one to two substituents independently selected from C ₁ -C ₄ -alkyl, C ₁ - C ₄ -alkyloxy, trifluoromethyl and halogen), or - (CH ₂ ) _x R ¹ ² , where x is 0, 1, 2 or 3 and R ¹ ² is hydroxyl, C ₁ - C ₄ -alkyloxy, - C (O) NR ¹ ³ R ¹ ⁴ , -NR ¹ ³ C (O) R ¹ ⁴ , -NR ¹ ³ C (O) OR ¹ ⁴ , -SO ₂ NR ¹ ³ R ¹ ⁴ , -NR ¹ ³ SO ₂ R ¹ ⁴ , -NR ¹ ³ SO ₂ NR ¹ ⁴ R ¹ ⁵ or NR ¹ ³ C (O) NR ¹ ⁴ R ¹ ⁵ , where R ¹ ³ , R ¹ ⁴ and R ¹ ⁵ independently represent hydrogen, C ₁ - C ₄ -alkyl or trifluoromethyl,
and its pharmaceutically acceptable salts, individual isomers and mixtures of isomers.

3. The compound according to claim 2, where p is 0, and R ⁵ and R ⁶ together form -CHR ⁸ CH ₉ CR ⁶ R ¹⁰ CHR ¹ ¹ CH ₂ -.

4. The compound according to claim 3, where n is equal to 4.

5. The compound according to claim 4, where R ¹ denotes chlorine, R ³ denotes methoxy and each of R ⁸ , R ⁹ and R ¹ ¹ denotes hydrogen.

6. The compound according to claim 5, where R ¹ ⁰ denotes hydrogen, namely, 1- (4-amino-5-chloro-2-methoxyphenyl) -5- (piperidinyl-1-yl) pentan-1-one and pharmaceutically acceptable salts.

7. The compound according to claim 6, which is 1- (4-amino-5-chloro-2-methoxyphenyl) -5- (piperidinyl-1-yl) pentan-1-one hydrochloride.

8. The compound according to claim 5, where R ¹ ⁰ denotes methyl, namely 1- (4-amino-5-chloro-2-methoxyphenyl) -5- (4-methylpiperidinyl-1-yl) pentan-1-one and its pharmaceutically acceptable salts.

9. The compound according to claim 8, which is 1- (4-amino-5-chloro-2-methoxyphenyl) -5- (4-methylpiperidinyl-1-yl) -pentan-1-one hydrochloride.

10. The compound according to claim 1, having the formula I (b):

where p is 0 or 1;
q is 1 or 2;
R ¹ is halogen;
R ² is hydrogen or C ₁ - C ₄ -alkyloxy;
R ³ denotes C ₁ - C ₄ -alkyloxy or
R ³ denotes C ₁ - C ₄ -alkyloxy or
R ² and R ³ together represent methylenedioxy or ethylenedioxy;
R ⁷ is hydrogen, C ₁ -C ₈ -alkyl, C ₃ -C ₈ -alkenyl, or phenyl C ₁ -C ₄ -alkyl (where phenyl is optionally substituted with one to three substituents independently selected from C ₁ -C ₄ -alkyloxy , methylenedioxy, ethylenedioxy or halogen), or - (CH ₂ ) _z R ¹ ² , where z is 2 or 3 and R ¹ ² is hydroxyl, C ₁ - C ₄ -alkyloxy, -C (O) NR ¹ ³ R ¹ ⁴ , -NR ¹ ³ C (O) R ¹ ⁴ , -NR ¹ ³ C (O) OR ¹ ⁴ , -SO ₂ NR ¹ ³ R ¹ ⁴ ,
-NR ¹ ³ SO ₂ R ¹ ⁴ , -NR ¹ ³ SO ₂ NR ¹ ⁴ R ¹ ⁵ or -NR ¹ ³ C (O) NR ¹ ⁴ R ¹ ⁵ where R ¹ ³ , R ¹ ⁴ and R ¹ ⁵ independently represent hydrogen, C ₁ -C ₄ -alkyl, trifluoromethyl or aryl;
and its pharmaceutically acceptable salts, individual isomers and mixtures of isomers.

11. The compound of claim 10, where q is equal to 2.

12. The compound according to claim 11, where R ¹ denotes chlorine, R ² denotes hydrogen and R ³ denotes methoxy.

13. A compound according to claim 12, wherein p is O and R ⁷ is p-butyl, namely 1- (4-amino-5-chloro-2-methoxyphenyl) -3- [1- (p-butyl) piperidine 4-yl] propan-1-one and its pharmaceutically acceptable salts.

14. The compound according to claim 13, which is 1- (4-amino-5-chloro-2-methoxyphenyl) -3- [1- (p-butyl) piperidin-4-yl] propan-1-one hydrochloride.

15. A compound according to claim 12, wherein p is O and R ⁷ is 2 - [(methylsulfonyl) amino] ethyl, namely 1- (4-amino-5-chloro-2-methoxyphenyl) -3- {2- [ methylsulfonyl) amino] ethyl} piperidin-4-yl] propan-1-one and its pharmaceutically acceptable salts.

16. A compound according to claim 15, which is 1- (4-amino-5-chloro-2-methoxyphenyl) -3- {2- [methylsulfonyl) amino] ethyl} piperidin 4-yl] propan-1-one hydrochloride.

17. The compound according to claim 12, wherein p is O and R ⁷ is 3- (3,4-dimethoxyphenyl) prop-1-yl, namely, 1- (4-amino-5-chloro-2-methoxyphenyl) - 3- {1- [3- (3,4-dimethoxyphenyl) prop-1-yl] piperidin-4-yl} propan-1-one and its pharmaceutically acceptable salts.

18. The compound according to claim 17, which is 1- (4-amino-5-chloro-2 methoxyphenyl) -3- {1- [3- (3,4 dimethoxyphenyl) prop-1-yl] piperidine 4-yl hydrochloride ] propan-1-she.

19. The compound according to claim 11, wherein R ¹ is chlorine and R ² and R ³ together represent ethylenedioxy.

20. The compound according to claim 19, wherein p is O and R ⁷ is 3- (4-methoxyphenyl) prop-1-yl, namely 1- (4-amino-5-chloro-2,3-ethylenedioxyphenyl) 3- {1- [3- (4-methoxyphenyl) prop-1-yl] piperidin-4-yl} propan-1-one and its pharmaceutically acceptable salts.

21. The compound according to claim 20, which is 3- (4-methoxyphenyl) prop-1-yl, namely the hydrochloride of 1- (4-amino-5-chloro-2,3-ethylenedioxyphenyl) -3- {1- [ 3- (4-methoxyphenyl) prop-1-yl] piperidin-4-yl} propan-1-one.

22. The compound according to claim 1, having the following formula I (c):

where R ¹ denotes halogen;
R ³ denotes C ₁ - C ₄ -alkylphenyloxy (where phenyl is optionally substituted with one to three substituents independently selected from halogen, hydroxyl, C ₁ - C ₄ -alkyl, C ₁ - C ₄ -alkyloxy, nitro, amino, aminocarbonyl, C ₁ - C ₄ -alkylamino, diC ₁ - C ₄ -alkylamino, C ₁ - C ₄ -alkanoylamino and 3,4-methylenedioxy);
R ⁴ denotes a group of formula (a) or (b):

or

where n is 3, 4 or 5;
p is 0 or 1;
q is 1 or 2;
R ⁵ and R ⁶ each represents C ₁ - C ₄ -alkyl or together form - (CH ₂ ) ₄ -, - (CH ₂ ) ₆ -, - (CH ₂ ) ₂ O (CH ₂ ) ₂ - or -CHR ⁸ CH ₂ CR ⁹ R ¹ ⁰ CHR ¹ ¹ CH ₂ -, where R ⁸ and R ¹ ¹ each denotes hydrogen or together denote - (CH ₂ ) _t -, where t is 1, 2 or 3; R ⁹ is hydrogen, hydroxyl, C ₁ - C ₈ -alkyl, C ₃ - C ₈ -alkenyl or C ₁ - C ₄ -alkyloxy, and R ¹ ⁰ denotes hydrogen, C ₁ - C ₈ -alkyl, or C ₃ - C _8- alkenyl, or phenyl, thienyl, pyrrolyl or furyl (optionally substituted with one to two substituents independently selected from C ₁ - C ₄ -alkyl, C ₁ - C ₄ -alkyloxy, trifluoromethyl and halogen), or - (CH ₂ ) _x R ¹ ² where x is 0, 1, 2 or 3 and R ¹ ² denotes hydroxyl, C ₁ - C ₄ -alkyloxy, -C (O) NR ¹ ³ R ¹ ⁴ , -NR ¹ ³ C (O) R ¹ ⁴ , -NR ¹ ³ C (O) OR ¹ ⁴ , -SO ₂ NR ¹ ³ R ¹ ⁴ ,
-NR ¹ ³ SO ₂ R ¹ ⁴ , -NR ¹ ³ SO ₂ NR ¹ ⁴ R ¹ ⁵ or -NR ¹ ³ C (O) NR ¹ ⁴ R ¹ ⁵ where R ¹ ³ , R ¹ ⁴ and R ¹ ⁵ independently represent hydrogen, C ₁ - C ₄ -alkyl or trifluoromethyl; R ⁷ is hydrogen, C ₁ -C ₈ -alkyl, or C ₃ -C ₈ -alkenyl, or phenyl C ₁ -C ₄ -alkyl (where phenyl is optionally substituted with one to three substituents independently selected from C ₁ -C ₄ - alkyloxy, methylenedioxy, ethylenedioxy or halogen), or - (CH ₂ ) _z R ¹ ² , where z is 2 or 3 and R ¹ ² is as defined above,
and its pharmaceutically acceptable salts, individual isomers and mixtures of isomers.

23. The compound according to claim 22, wherein R ³ is an optionally substituted phenyl C ₁ -C ₄ -alkyloxy, and R ⁴ is a group of formula (a).

24. The compound according to claim 23, wherein R ⁵ and R ⁶ together form -CHR ⁸ CH ₂ CR ⁹ R ¹ ⁰ CHR ¹ ¹ CH ₂ -.

25. The compound according to claim 24, where n is equal to 4.

26. The compound according to claim 22, wherein R ³ is an optionally substituted phenyl C ₁ -C ₄ -alkyloxy, and R ⁴ is a group of the formula (b).

27. The compound according to claim 26, where q is equal to 2.

28. Pharmaceutical composition comprising a therapeutically effective amount of a compound according to claims 1 - 27.

29. A method of treating a condition that can be alleviated with a drug that interacts with the 5-HT ₄ -receptors of an animal, if necessary, such treatment, the method comprising administering to such an animal a therapeutically effective amount of the compound according to claims 1-27.

30. The method of claim 29, wherein the condition is selected from a disorder of the central nervous system, disorders of the gastrointestinal tract, disorders of the cardiovascular system and disorders of the urinary tract.

31. The method of obtaining the compounds of formula I

where R ¹ denotes halogen;
R ² denotes hydrogen or C ₁ - C ₄ -alkyloxy
R ³ stands for C ₁ - C ₄ -alkyloxy or phenyl C ₁ - C ₄ -alkyloxy (where phenyl is optionally substituted with one to three substituents independently selected from halogen, hydroxyl, C ₁ - C ₄ -alkyl, C ₁ - C ₄ - alkyloxy, nitro, amino, aminocarbonyl, C ₁ - C ₄ -alkylamino, diC ₁ - C ₄ -alkylamino, C ₁ - C ₄ -alkanoylamino and 3,4-methylenedioxy), or
R ² and R ³ together represent methylenedioxy or ethylenedioxy;
R ⁴ denotes a group of formula (a) and (b)

or

where n is 3, 4 or 5;
p is 0 or 1;
q is 1 or 2;
R ⁵ and R ⁶ each represent C ₁ - C ₄ -alkyl or together form - (CH ₂ ) ₄ -, - (CH ₂ ) ₆ -, - (CH ₂ ) ₂ O (CH ₂ ) ₂ - or CHR ⁸ CH ₂ CR ⁹ R ¹ ⁰ CHR ¹ ¹ CH ₂ -, where R ⁸ and R ¹ ¹ each denotes hydrogen or together denote - (CH ₂ ) _t , where t is 1, 2 or 3; R ⁹ denotes hydrogen, hydroxyl, C ₁ - C ₈ -alkyl, C ₃ - C ₈ -alkenyl or C ₁ - C ₄ -alkyloxy and R ¹ ⁰ denotes hydrogen, C ₁ - C ₈ -alkyl or C ₃ - C ₈ α-alkenyl, or phenyl, thienyl, pyrrolyl or furyl (optionally substituted with one to two substituents independently selected from C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, trifluoromethyl and halogen), or - (CH ₂ ) _x R ¹ ² , where x is 0, 1, 2 or 3 and R ¹ ² denotes hydroxyl, C ₁ - C ₄ -alkyloxy, -C (O) NR ¹ ³ R ¹ ⁴ , -NR ¹ ³ C (O) R ¹ ⁴ , -NR ¹ ³ C (O) OR ¹ ⁴ , -SO ₂ NR ¹ ³ R ¹ ⁴ , -NR ¹ ³ SO ₂ R ¹ ⁴ , -NR ¹ ³ SO ₂ NR ¹ ⁴ R ¹ ⁵ or -NR ^{January ³} C (O) NR ⁴ R ¹ ¹ ⁵ where R ^{January ^3,} R ¹ ⁴ and R ¹ ⁵ are independently hydrogen, C ₁ - C ₄ - lkil, trifluoromethyl or aryl; R ⁷ is hydrogen, C ₁ - C ₈ alkyl, or C ₃ - C ₈ alkenyl, or phenyl C ₁ - C ₄ alkyl (wherein phenyl is optionally substituted with one to three substituents independently selected from C ₁ - C ₄ - alkyloxy, methylenedioxy, ethylenedioxy or halogen), or - (CH ₂ ) _z R ¹ ² , where z is 2 or 3 and R ¹ ² is as defined above,
and its pharmaceutically acceptable salts, individual isomers and mixtures of isomers, including
(A) interaction in the presence of a strong base of the compound of formula II

or a protected derivative thereof, where R ⁴ is as defined above in this paragraph with a compound of formula III

where each of R ¹ , R ² and R ³ has the meanings indicated above in this paragraph,
acidification; decarboxylation and, if necessary, removal of any protective groups; or
(B) to obtain the compounds of formula 1, where R ² denotes hydrogen and R ⁴ denotes a group of formula (a), the interaction in the presence of Lewis acid compounds of formula V

where R denotes a protective group and R ¹ denotes halogen,
with a compound of formula VI

where R ¹ ⁸ denotes halogen or hydroxyl; R ¹ ⁹ is halogen and n is 3, 4 or 5;
alkylation with a compound of the formula L - R ³ , where L denotes a leaving group and R ³ is as defined above,
interaction with the compound of the formula HNR ⁵ R ⁶ or its N-oxide, where R ⁵ and R ⁶ have the above values,
and unprotect; or
(B) to obtain the compounds of formula 1, where R ⁴ denotes a group of formula (b), where p is 0 and q is 2, the interaction of the compounds of formula VIII

where R ¹ , R ² and R ³ have the meanings indicated above in this paragraph, with the compound of the formula IX

where R ⁷ has the meanings indicated above in this clause;
dehydration and subsequent hydrogenation; or
(G) to obtain the compounds of formula 1, where R ⁴ denotes a group of formula (a), the processing of the compounds of formula XI

where n is as defined above in this clause,
magnesium to obtain the corresponding Grignard reagent, the interaction of the Grignard reagent with the compound of formula XII

where each P denotes a protective group and R ¹ , R ² and R ³ have the meanings indicated above in this paragraph,
removing the protection and subsequent interaction with the compound of the formula HNR ⁵ R ⁶ ; or
(D) to obtain the compounds of formula 1, where R ⁴ denotes a group of formula (a), the interaction in the presence of a strong base of the compounds of formula II (a)

where R ⁵ and R ⁶ have the meanings indicated above in this paragraph,
with a compound of formula XIII

where each R denotes a protective group and the values of R ¹ , R ² and R ³ have the meanings indicated above in this paragraph; or
(E) optionally alkylation of a compound of formula 1, where R ⁴ denotes a group of formula (b) and R ⁷ denotes hydrogen, a compound of formula L - R ² ⁰ , where L denotes a leaving group and R ² ⁰ denotes C ₁ - C ₈ -alkyl, C ₃ - C ₈ -alkenyl or phenyl C ₁ - C ₄ -alkyl (where phenyl is optionally substituted with one to three substituents independently selected from C ₁ - C ₄ -alkyloxy, methylenedioxy, ethylenedioxy or halogen), or L - (CH ₂ ) _z R ¹ ² have the meanings indicated above in this paragraph) for the preparation of the compound of formula 1, where R ⁴ denotes a group of formula (b), where R ^{7 is} not hydrogen om; or
(G) optionally alkylation of a compound of formula 1, where R ⁴ denotes a group of formula (b) and R ⁷ denotes hydrogen, a compound of formula X is R ² ¹ , where X denotes azacycloprop-1-yl and R ² ¹ denotes -C (O) R ¹ ⁴ , SO ₂ R ¹ ⁴ , -SO ₂ NR ¹ ⁴ R ¹ ⁵ or -CONR ¹ ⁴ R ¹ ⁵ (where R ¹ ⁴ and R ¹ ⁵ have the meanings specified above in this paragraph) to obtain the compounds of formula 1 where R ⁴ denotes a group of formula (b), where R ⁷ denotes-CH ₂ CH ₂ NHC (O) R ¹ ⁴ , -CH ₂ CH ₂ NH SO ₂ R ¹ ⁴ , -CH ₂ CH ₂ NHSO ₂ NR ¹ ⁴ R ¹ ⁵ or -CH ₂ CH ₂ NHCON R ¹ ⁴ R ¹ ⁵ ; or
(H) optionally demethylation of a compound of formula I, where R ³ is methoxy, and subsequent alkylation with a compound of the formula L - R ² ² , where R ² ² is C ₂ -C ₄ -alkyl or phenyl C ₁ -C ₄ -alkyl (where phenyl optionally substituted with one to three substituents independently selected from halogen, hydroxyl, C ₁ - C ₄ -alkyl, C ₁ - C ₄ -alkyloxy, nitro, amino, aminocarbonyl, C ₁ - C ₄ -alkylamino, di C ₁ - C ₄ alkylamino, C ₁ - C ₄ alkanoylamino and 3,4-methylenedioxy) to give a compound of formula 1 wherein R ³ represents C ₂ - C ₄ -alkyloxy or phenyl C ₁ - C ₄ -alkyloxy (rk phenyl optionally substituted similarly to the above in this paragraph); or
(I) optionally oxidizing a compound of formula I, where p is 0, to form a compound of formula I, where p is 1; or
(K) optionally reducing the compound of formula 1, where p is 1, to obtain the compound of formula I, where p is 0; or
(L) optionally, reacting the corresponding non-salt form of the compound of formula I with a pharmaceutically acceptable inorganic or organic acid or base to form a pharmaceutically acceptable salt; or
(M) Optionally, reacting the appropriate acid addition salt or base addition salt of the compound of Formula I with a suitable base or acid, respectively, to produce the free acid or free base.