WO1998046589B1 - Indazole amide compounds as serotoninergic agents - Google Patents

Abstract

A compound having general formula (I) wherein R1, R2, R3, R'3, R4, R5 and R6 have the meanings stated in the description, acid addition salts thereof with pharmaceutically acceptable organic and inorganic acids and pharmaceutically acceptable quaternary salts thereof.

Claims

AMENDED CLAIMS[received by the International Bureau on 30 November 1998 (30.11.98); original claims 1-23 replaced by amended claims 1-17 (6 pages)]

1. A compound having the general formula

(I) wherein:

R is hydrogen;

R₂ is isopropyl;

R₃ and R'₃ are hydrogen;

R₄ and R₅ are hydrogen; Re is selected from the group comprising, C₃.7 cycloalkyl, heterocyciic ring having from 5 to 6 members where 1 to 4 members are heteroatoms, the same or different from each other, selected from the group comprising N, O and S, dimethylamino Cι_-3 alkyl, methoxy Cι_-3 alkyl, N-phenyi amide, aminosuiphonylmethyl, dihydroxy C₂.₃ alkyl, aryl substituted by hydroxy; acid addition salts thereof with pharmaceutically acceptable organic and inorganic acids and pharmaceutically acceptable quaternary salts thereof.

2. A compound according to claim 1 , characterized in that heterocyciic rings are thienyl, furanyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furazanyl, pyrrolinyl, imidazoiinyl, pyrazolidinyl, pyrazolinyl, pipehdinyl, piperazinyl, morpholinyl, triazinyl, thiazolyl, tetrazolyl and thiadiazolyl.

3. A compound according to claim 1 , characterized in that Re is selected from the group comprising cyclopropyl, cyclohexyl, pyridinyl, tetrazolyl, mo holinyl, methoxymethyl, methoxypropyl, hydroxyphenyl, dimethylaminomethyl, and aminosulphonylmethyl.

4. A compound according to claim 1 , characterized in that R^ R₃, R'₃, R₄ and R₅ are hydrogen, R₂ is isopropyl and Re is cyclohexyl.

5. A compound according to claim 1 , characterized in that R_1f R₃, R'₃₎ R_A and R₅ are hydrogen, R₂ is isopropyl and Re is pyridinyl.

6. A compound according to claim 1 , characterized in that R^ R3, R'₃, ^ and R₅ are hydrogen, R₂ is isopropyl and Re is dimethylaminomethyl.

7. A compound according to claim 1 , characterized in that R_1? R₃, R'3, R₄ and R₅ are hydrogen, R₂ is isopropyl and Re is morpholinyl.

8. A compound according to claim 1 , characterized in that R₁₍ R₃, R'₃, R₄ and R₅ are hydrogen, R₂ is isopropyl and Re is aminosulphonylmethyl.

9. A process for preparing a compound of the formula (I), acid addition salts thereof with pharmaceutically acceptable organic and inorganic acids and pharmaceutically acceptable quaternary salts thereof, comprising: a) acylating a 4-aminomethyl piperidine of the formula:

(II) wherein

R3, R'3, R4 and R₅ have the above mentioned meanings, and

P is a suitable protecting group; by means of a 1-alkyl-indazole-3-carboxylic acid halide of the formula:

(III) wherein

Ri and R₂ have the above mentioned meanings, and

X is halogen, to give a compound of the formula:

(IV) wherein

Ri, 2, R3, R'3, R4, R5 and P have the above mentioned meanings, b) de-protecting a compound of the formula (IV) to give a compound of the formula:

(V) wherein R_1f R₂, R₃, R'3, R and R₅ have the above mentioned meanings, c) alkylating a compound of the formula (V) with a compound of the formula (VI) to give a compound of the formula (I) according to the following reaction scheme:

(V) (VI) wherein Ri, R₂, R₃, R'3, R , R₅ and R₅ have the above mentioned meanings, and

Y is halogen, d) optionally forming an acid addition salt of an indazole amide compound of the formula (I) with a pharmaceutically acceptable organic or inorganic acid, or a pharmaceutically acceptable quaternary salt of an indazole amide compound of the formula (I).

10. A process according to claim 9, characterized in that P is selected from the group comprising benzyloxycarbonyl, benzyl, terbutoxycarbonyl, trimethylsilylethoxycarbonyl.

11. A process according to claims 9 or 10, characterized in that step a) is carried out by reacting a compound of the formula (II) with a compound of the formula (III) in which X is chlorine, in the presence of a diluent and at a temperature of from 0 to 140°C for a period of time of from 0.5 to 20 hours.

12. A process according to claim 10, characterized in that when P is benzyl or benzyloxycarbonyl, step b) is carried out by catalytic hydrogenation.

13. A process according to any of the preceding claims from 9 to 11 , characterized in that when, in a compound of the formula (VI), Y is chlorine or bromine, step c) is performed in the presence of an acceptor of acids and in the presence of a diluent.

14. A process according to claim 9, characterized in that methyliodide forms a pharmaceutically acceptable quaternary salt of a compound of formula (I), step d).

15. An intermediate compound having the general formula:

(IV) wherein Ri is hydrogen; R₂ is isopropyl; R₃ and R'₃ are hydrogen; R₄ and R₅ are hydrogen; and

P is selected from the group comprising benzyloxycarbonyl, terbutoxycarbonyl and trimethylsilylethoxycarbonyl.

16. A compound according to claim 14, characterized in that R_1t R₃, R'3, R₄ and R₅ are hydrogen and R₂ is isopropyl.

17. A pharmaceutical composition, characterized in that the said composition comprises an effective dose of at least one compound of the formula:

(I) wherein Ri is hydrogen; R₂ is isopropyl; R3 and R'₃ are hydrogen;

R4 and R₅ are hydrogen;

Re is selected from the group comprising C₁-₃ alkyl, C3.7 cycloalkyi, heterocyciic ring having from 5 to 6 members where 1 to 3 members are heteroatoms, the same or different from each other, selected from the group comprising N, O and S, dimethylamino d.

₃ alkyl, methoxy Cι_-3 alkyl, N-phenyl amide, aminosulphonylmethyl, dihydroxy C_2-3 alkyl, aryl, aryl substituted by hydroxy; acid addition salts thereof with pharmaceutically acceptable organic and inorganic acids and pharmaceutically acceptable quaternary salts thereof.