1-substituted-4-(thiazolyl-2-)-piperazines, -piperidines and -tetrahydropyridines useful as anxiolytic, psychogeriatric, antidepressant and antischizophrenic agents

• US 4,737,500 A
• Filed: 06/20/1986
• Issued: 04/12/1988
• Est. Priority Date: 06/22/1985
• Status: Expired due to Fees

• Current Assignee: Sandoz Pharmaceuticals Corp. (Novartis Ag)
• Original Assignee: Sandoz Pharmaceuticals Corp. (Novartis Ag)
• Inventors: Sorg, Dieter
• Primary Examiner(s): Daus, Donald G.
• Assistant Examiner(s): Shen, Cecilia
• Application Number:
  US06/876,617
• Time in Patent Office: 662 Days
• Field of Search: 544/3, 544/8, 544/96, 544/97, 544/284, 544/286, 544/295, 544/315, 544/316, 544/319, 544/363, 544/364, 544/367, 544/368, 544/369, 544/370, 544/371, 544/357, 514/227, 514/222, 514/252, 514/253, 514/278
• US Class Current: 514/222.8
• CPC Class Codes: C07D 277/42 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Thiazoles or pharmaceutically acceptable acid addition salts thereof are useful as anxiolytic, psychogeriatric, antidepressant and antischizophrenic agents.

Claims

1. A compound of formula I:

##STR89## wherein R₁ and R₂, independently, are hydrogen, (C_1-6)alkyl, (C_3-6)cycloalkyl, (C_3-6)cycloalkyl(C_1-3)alkyl, phenyl, phenyl(C_1-3)alkyl, or

R₁ and R₂ signify together trimethylene, tetramethylene or pentamethylene, optionally substituted at the same of different carbon atoms by 1 or 2 methyl groups, or

R₁ and R₂ signify together --(CH₃)₂ C--O--C(CH₃)₂ --,

R₁ may additionally signify trifluoromethyl;

W is alkylene of 2 to 6 carbon atoms, or alkenylene or alkynylene of 4 to 6 carbon atoms, whereby the unsaturation is not adjacent to the nitrogen atoms; and

R₃ is a group of formulae (a)-(n) ##STR90## m is 0 or 1, R₄ and R₄ '"'"' independently are hydrogen or (C_1-4)alkyl,

R₅ and R₅ '"'"' independently are hydrogen, (C_1-4)alkyl, phenyl or phenyl(C_1-4)alkyl,

t is 4 or 5,

R₆ is hydrogen or (C_1-3)alkyl, and

R₇ is hydrogen, (C_1-3)alkyl, phenyl(C_1-3)alkyl or phenoxy(C_1-3)alkyl,

or R₃ is a group of formula (o) ##STR91## in which R₈ is hydrogen or (C_1-3)alkyl,

R₉ is --COR₁₀, --CON(R₁₁)R₁₂, --SO₂ R₁₀ or --SO₂ N(R₁₁)R₁₂, wherein R₁₀ is (C_1-6)alkyl, (C_3-6)cycloalkyl, phenyl or phenyl(C_1-3)alkyl, wherein each phenyl is optionally mono- or independently di- or trisubstituted by (C_1-3)alkyl, hydroxy, methoxy, methylenedioxy, amino, chloro, fluoro or trifluoromethyl, and

R₁₁ and R₁₂ are each, independently, hydrogen or (C_1-3)alkyl or

R₁₁ and R₁₂ together signify tetramethylene or pentamethylene,

provided that when W is dimethylene and R₉ is --COR₁₀, wherein R₁₀ is 4-aminophenyl, at least one of R₁, R₂ and R₈ is other than hydrogen,

or a pharmaceutically acceptable acid addition salt thereof.

2. A compound according to claim 1 wherein

R₁ and R₂, independently, are hydrogen, (C_1-6)alkyl, (C_3-6)cycloalkyl, (C_3-6)cycloalkyl(C_1-3)alkyl, phenyl, phenyl(C_1-3)alkyl, or

R₁ and R₂ signify together trimethylene, tetramethylene or pentamethylene, optionally substituted at the same or different carbon atoms by 1 or 2 methyl groups,

R₁ may additionally signify trifluoromethyl;

W is alkylene of 2 to 6 carbon atoms; and

R₃ is a group of formulae (a)-(n)

in which ##STR92## m is 0 or 1, R₄ and R₄ '"'"', independently, are hydrogen or (C_1-4)alkyl,

R₅ and R₅ '"'"', independently, are hydrogen, (C_1-4)alkyl, phenyl or phenyl(C_1-4)alkyl,

t is 4 or 5,

R₆ is hydrogen or (C_1-3)alkyl, and

R₇ is hydrogen, (C_1-3)alkyl, phenyl(C_1-3)alkyl or phenoxy(C_1-3)alkyl,

or a pharmaceutically acceptable acid addition salt thereof.

3. A compound according to claim 1 wherein

R₁ and R₂, independently, are hydrogen, (C_1-6)alkyl, (C_3-6)cycloalkyl, (C_3-6)cycloalkyl(C_1-3)alkyl, phenyl, phenyl(C_1-3)alkyl, or

R₁ and R₂ signify together trimethylene, tetramethylene or pentamethylene, optionally substituted at the same or different carbon atoms by 1 or 2 methyl groups,

R₁ may additionally signify trifluoromethyl'"'"',

W is alkylene of 2 to 6 carbon atoms;

and

R₃ is a group of formula (o)

in which

R₈ is hydrogen or (C_1-3)alkyl,

R₉ is --COR₁₀, --CON(R₁₁)R₁₂, --SO₂ R₁₀ or --SO₂ N(R₁₁)R₁₂, wherein R₁₀ is (C_1-6)alkyl, (C_3-6)cycloalkyl, phenyl or phenyl(C_1-3)alkyl, wherein each phenyl is optionally mono- or independently di- or trisubstituted by (C_1-3)alkyl, hydroxy, methoxy, methylenedioxy, amino, chloro, fluoro or trifluoromethyl; and

R₁₁ and R₁₂ are each, independently, hydrogen or (C_1-3)alkyl or

R₁₁ and R₁₂ together signify tetramethylene or pentamethylene,

provided that when W is dimethylene and R₉ is --COR₁₀, wherein R₁₀ is 4-aminophenyl, at least one of R₁, R₂ and R₈ is other than hydrogen,

or a pharmaceutically acceptable acid addition salt thereof.

4. A compound according to claim 1 wherein

R₁ and R₂ independently are hydrogen, (C_1-6)alkyl, (C_3-6)cycloalkyl, (C_3-6)cycloalkyl(C_1-3)alkyl, phenyl, phenyl(C_1-3)alkyl, or

R₁ and R₂ signify together pentamethylene, or

R₁ and R₂ signify together --(CH₂)₂ C--O--C(CH₃)₂ --,

R₁ is additionally trifluoromethyl;

W is alkylene of 2 to 6 carbon atoms, or alkenylene or alkynylene of 4 to 6 carbon atoms, whereby the unsaturation is not adjacent to the nitrogen atoms, and

R₃ is a group of formula (a) in which A is CH₂, B is CO, m is 1, R₄ '"'"' and R₅ '"'"' are each hydrogen, and R₄ and R₅ are each methyl, or a group of formula (a) in which A is CH₂, B is CH₂, m is 0 and R₄ and R₅ are each hydrogen, or

R₃ is a group of formula (b), in which t is 4;

or

R₃ is a group of formula (f), in which B is CO;

or

R₃ is a group of formula (g), in which A is NH;

or

R₃ is a group of formula (i), in which E is N;

or

R₃ is a group of formula (j), in which A'"'"' is CH₂ and B is CO;

or

R₃ is a group of formula (o), in which R₈ is hydrogen or (C_1-3)alkyl, R₉ is --COR₁₀ or --SO₂ R₁₀, wherein R₁₀ is (C_1-6)alkyl or phenyl, wherein phenyl is optionally mono- or independently di- or trisubstituted by hydroxy, methoxy, amino, chloro or fluoro, provided that when W is dimethylene and R₉ is --COR₁₀, wherein R₁₀ is 4-aminophenyl, at least one of R₁, R₂ and R₈ is other than hydrogen,

or a pharmaceutically acceptable acid addition salt thereof.

5. A compound of claim 1 which is 4,4-dimethyl-1-(4-(4-(4-(1,1-dimethylethyl)-2-thiazolyl)-1-piperazinyl)butyl)-2,6-piperidin-dione or a pharmaceutically acceptable acid addition salt thereof.

6. A compound of claim 1 which is 5-chloro-2-methoxy-N-(2-(4-(4-(1,1-dimethylethyl)-2-thiazolyl)-1-piperazinyl)ethyl)benzamide or a pharmaceutically acceptable acid addition salt thereof.

7. A pharmaceutical composition useful in treating anxiety, geriatric disorders, depressions or schizophrenia comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable acid addition salt thereof.

8. A compound of claim 1 wherein R₁ is trifluoromethyl, R₂ is hydrogen, W is --CH₂ --₄ and R₃ is a group of formula (a) in which A is CH₂, B is CH₂, m is 0 and R₄ and R₅ are each hydrogen, or a pharmaceutically acceptable acid addition salt thereof.

9. A method of effecting anxiolytic or psychogeriatric treatment in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable acid addition salt thereof.

10. A method of effecting antischizophrenic treatment in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable acid addition salt thereof.

11. A method of effecting antidepressant treatment in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable acid addition salt thereof.