RU2001133458A

RU2001133458A - 4-phenylpyrimidine derivatives

Info

Publication number: RU2001133458A
Application number: RU2001133458/04A
Authority: RU
Inventors: Мишель БОЭ; Гуидо Галлей; Тирри Годель; Торстен Хоффманн; Вальтер Хункелер; Патрик Шнидер; Хайнц Штадлер
Original assignee: Ф.Хоффманн-Ля Рош Аг
Priority date: 1999-05-31
Filing date: 2000-05-24
Publication date: 2003-06-27

Claims

1. Compounds of the general formula

where R ¹ means hydrogen or halogen;

R ² means hydrogen, halogen, (ness.) Alkyl or (ness.) Alkoxy;

R ¹ and R ² together with two carbon atoms can mean a group

-CH = CH-CH = CH-,

R ³ means halogen, trifluoromethyl, (ness.) Alkyl or (ness.) Alkoxy;

R ⁴ / R ^{4 '} independently from each other each means hydrogen or (ness.) Alkyl;

R ⁵ means (ness.) Alkyl, (ness.) Alkoxy, amino, phenyl, hydroxy (ness.) Alkyl, cyano (ness.) Alkyl, carbamoyl (ness.) Alkyl, pyridyl, pyrimidyl, - (CH ₂ ) _n -piperazinyl optionally substituted with one or two lower alkyl groups or hydroxy lower alkyl, - (CH ₂ ) _n- morpholinyl, - (CH ₂ ) _n- piperidinyl, - (CH ₂ ) _{n + 1} -imidazolyl, (ness.) alkylsulfanyl, (ness.) alkylsulfonyl, benzylamino, -NH- (CH ₂ ) _{n + 1} N (R ⁴ ") ₂ , - (CH ₂ ) _{n + 1} N (R ⁴ "), -O- (CH ₂ ) _{n + 1-} morpholinyl, -O- (CH ₂ ) _{n + 1-} piperidinyl or -O- (CH ₂ ) _{n + 1} N (R ^{4 ”} ) ₂ , where R ^4” means hydrogen or (lower .) alkyl;

n = 0-2,

X is —C (O) N (R ⁴ ″) - or –N (R ^{4 ″} ) ₂ C (O) -;

and their pharmaceutically acceptable acid addition salts.

2. The compound of claim 1, wherein X is —C (O) N (R ^{4 ″} ) -, R ^{4 ″} is methyl, and R ⁵ is piperazinyl optionally substituted with one or two methyl groups.

3. The compound according to claim 2, which means:

4- (2-bromophenyl) -2- (4-methylpiperazin-1-yl) pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethylbenzyl) methylamide,

(3,5-bis-trifluoromethylbenzyl) methylamide (3R, 5S) -4- (2-bromophenyl) -2- (3,5-dimethylpiperazin-1-yl) pyrimidine-5-carboxylic acid,

4- (2-bromophenyl) -2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethylbenzyl) methylamide,

4- (2-chlorophenyl) -2- (4-methylpiperazin-1-yl) pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethylbenzyl) methylamide,

(3,5-bis-trifluoromethylbenzyl) methylamide (3R, 5S) -4- (2-chlorophenyl) -2- (3,5-dimethylpiperazin-1-yl) pyrimidine-5-carboxylic acid,

4- (2-chlorophenyl) -2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethylbenzyl) methylamide,

(3,5-bis-trifluoromethylbenzyl) methylamide 2- (4-methylpiperazin-1-yl) -4-o-tolylpyrimidine-5-carboxylic acid,

(3,5-bis-trifluoromethylbenzyl) methylamide (3R, 5S) -2- (3,5-dimethylpiperazin-1-yl) -4-o-tolylpyrimidine-5-carboxylic acid,

(3,5-bis-trifluoromethylbenzyl) 2-piperazin-1-yl-4-o-tolylpyrimidine-5-carboxylic acid methylamide,

4- (2-Methoxyphenyl) -2- (4-methylpiperazin-1-yl) pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethylbenzyl) methylamide,

(3,5-bis-trifluoromethylbenzyl) methylamide (3R, 5S) -2- (3,5-dimethylpiperazin-1-yl) -4- (2-methoxyphenyl) pyrimidine-5-carboxylic acid,

4- (2-methoxyphenyl) -2-25 piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethylbenzyl) methylamide,

4- (4-fluorophenyl) -2- (4-methylpiperazin-1-yl) pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethylbenzyl) methylamide,

(3,5-bis-trifluoromethylbenzyl) methylamide 4- (2-4) torphenyl) -2- (4-methylpiperazin-1-yl) pyrimidine-5-carboxylic acid,

(3,5-bis-trifluoromethylbenzyl) methylamide (3R, 5S) -2- (3,5-dimethylpiperazin-1-yl) -4- (2-fluorophenyl) pyrimidine-5-carboxylic acid,

4- (4-fluorophenyl) -2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethylbenzyl) methylamide,

4- (4-fluoro-2-methylphenyl) -2- (4-methylpiperazin-1-yl) pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethylbenzyl) methylamide,

(3,5-bis-trifluoromethylbenzyl) methylamide (3R, 5S) -2- (3,5-dimethylpiperazin-1-yl) -4- (4-fluoro-2-methylphenyl) pyrimidine-5-carboxylic acid,

4- (4-fluoro-2-methyl-phenyl) -2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethylbenzyl) methylamide,

(3,5-bis-trifluoromethylbenzyl) methylamide 2- (4-methylpiperazin-1-yl) -4-naphthalene-1-ylpyrimidine-5-carboxylic acid,

(3,5-bis-trifluoromethylbenzyl) methylamide (3R, 5S) -2- (3,5-dimethylpyrazine-1-yl) -4-naphthalene-1-ylpyrimidine-5-carboxylic acid and

(3,5-bis-trifluoromethylbenzyl) 4-naphthalen-1-yl-2-piperazin-1-yl-pyrimidine-5-carboxylic acid methylamide.

4. The compound according to claim 1, in which X is —C (O) N (R ^{4 ”} ) -, R ^4” is methyl, and R ⁵ is morpholinyl or –O (CH ₂ ) ₂ -morpholinyl.

5. The compound according to claim 4, which means:

4- (2-bromophenyl) -2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethylbenzyl) methylamide,

4- (2-chlorophenyl) -2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethylbenzyl) methylamide,

(3,5-bis-trifluoromethylbenzyl) methylamide 4- (2-chlorophenyl) -2- (2-morpholin-4-ylethoxy) pyrimidine-5-carboxylic acid,

(3,5-bis-trifluoromethylbenzyl) 2-morpholin-4-yl-4-o-tolylpyrimidine-5-carboxylic acid methylamide,

4- (2-methoxyphenyl) -2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethylbenzyl) methylamide,

4- (4-fluoro-2-methyl-phenyl) -2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethylbenzyl) methylamide and

(3,5-bis-trifluoromethylbenzyl) methylamide 2-morpholin-4-yl-4-naphthalene-1-yl-pyrimidine-5-carboxylic acid.

6. The compound according to claim 1, in which X is —C (O) N (R ^{4 ”} ) -, R ^4” is methyl, and R ⁵ is —NH (CH ₂ ) ₂ N (CH ₃ ) ₂ , - O (CH ₂ ) ₂ N (CH ₃ ) ₂ or -O (CH ₂ ) ₃ N (CH ₃ ) ₂ .

7. The compound according to claim 6, which means:

4- (2-chlorophenyl) -2- (2-dimethylaminoethylamino) pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethylbenzyl) methylamide,

4- (2-Chlorophenyl) -2- (2-dimethylaminoethoxy) pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethylbenzyl) methylamide,

4- (2-Chlorophenyl) -2- (3-dimethyl-laminopropoxy) -pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethylbenzyl) methylamide,

(3,5-bis-trifluoromethylbenzyl) methyl- 2- (2-dimethylaminoethoxy) -4-o-tolylpyrimidine-5-carboxylic acid or

(3,5-bis-trifluoromethylbenzyl) methyl- 2- (3-dimethylaminopropoxy) -4-o-tolylpyrimidine-5-carboxylic acid.

8. The compound according to claim 1, in which X is —N (R ^{4 ”} ) C (O) -, R ^4” is methyl, and R ⁵ is morpholinyl or piperazinyl, optionally substituted with lower alkyl.

9. The compound of claim 8, which means:

2- (3,5-bis-trifluoromethylphenyl) -N-methyl-N- [2- (4-methylpiperazin-1-yl) -4-o-tolylpyrimidin-5-yl] isobutyramide and

2- (3,5-bis-trifluoromethylphenyl) -N-methyl-N- (2-morpholin-4-yl-4-o-tolylpyrimidin-5-yl) isobutyramide.

10. A medicament containing one or more compounds according to any one of claims 1 to 9 and pharmaceutically acceptable excipients.

11. The drug of claim 10 for the treatment of diseases mediated by NK-1 receptor antagonists.

12. The method of obtaining the compounds of formula I according to claim 1, which includes

a) the interaction of the compounds of formula

with a compound of the formula

with the formation of the compounds of formula

where R ¹ -R ⁵ and n have the meanings indicated in claim 1, or

b) the interaction of the compounds of formula

with a compound of the formula

with the formation of the compounds of formula

where R ¹ -R ⁵ and n have the meanings indicated in claim 1, or

c) modifying one or more of the substituents R ¹ -R ⁵ having the meanings indicated above, and, if necessary, converting the resulting compound into a pharmaceutically acceptable acid addition salt thereof.

13. The compound according to any one of claims 1 to 9, obtained by the method according to item 12 or an equivalent method.

14. The use of the compounds of formula I according to any one of claims 1 to 9 for the treatment of diseases.

15. The use of a compound of formula I according to any one of claims 1 to 9 for the preparation of a medicament containing one or more compounds of formula I for the treatment of diseases mediated by the NK-1 receptor.

16. The invention, as described in the description and any claim.