US 2016/0096811 A1 · BENZOISOTHIAZOLE COMPOUNDS AND USE IN PREPARATION OF ANTIPSYCHOTIC DRUGS

Abstract

Disclosed are benzoisothiazole compounds and a use in the preparation of anti-schizophrenia drugs. The benzoisothiazole compounds of the present invention not only have strong affinity for dopamine D3 receptor, 5-HT1A receptor and 5-HT2A receptor, but also can observably improve the symptoms of schizophrenia relevant to apomorphine model and MK-801 model mice, with oral absorption being good, safety being high and side-effect being less, and having developmental value as new anti-neurotic disease drugs. The present invention is the compounds having a structure of general formula (I), or geometric isomers, free alkalies, salts, hydrates or solvates thereof.

Claims19

Dependent claims

A benzoisothiazole compound, characterized in that it is a compound having the structure of general formula (I) or the geometric isomers, free alkalies, salts, hydrates or solvates thereof:

wherein:
W is:
R1 and R2 independently represent heteroaryl or substituted heteroaryl;
n is 0, 1, 2 or 3;
m is 0, 1 or 2;
R3 represents C3-C4 alkyl, substituted C1-C4 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, heteroaryl, substituted heteroaryl, heteroarylmethyl, or substituted heteroarylmethyl;
R4 is hydrogen atom or C1-C4 alkyl;
R5 is phenyl, substituted phenyl, heteroaryl or substituted heteroaryl.

5 more elements

The benzoisothiazole compound, characterized in that it is the compound having the structure of general formula (I) or the geometric isomers, free alkalies, salts, hydrates or solvates thereof:

wherein:
W is:
R1 and R2 independently represent heteroaryl or substituted heteroaryl;
n is 0, 1, 2 or 3;
m is 0, 1 or 2;
R3 represents C1-C4 alkyl, substituted C1-C4 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, heteroaryl, substituted heteroaryl, heteroarylmethyl, or substituted heteroarylmethyl;
R4 is hydrogen atom or C1-C4 alkyl;
R5 is phenyl, substituted phenyl, heteroaryl or substituted heteroaryl;
the heteroaryl represented by R1 and R2 is selected from furyl, pyrrolyl, thienyl, benzofuryl, indolyl or benzothienyl;
the substituent of the substituted heteroaryl represented by R1 and R2 is selected from halogen, cyano, C1-C2 alkyl carbonyl, nitro, methoxyl or C1-C4 alkyl;
the C1-C4 alkyl represented by R3 can be substituted by 1-3 fluorine atom(s);
the substituent of the substituted cycloalkyl represented by R3 is selected from C1-C2 alkyl;
the substituent of the substituted phenyl, substituted benzyl, substituted heteroaryl or substituted heteroarylmethyl represented by R3 is selected from halogen, C1-C2 alkoxy, nitro or C1-C2 alkyl;
the heteroaryl represented by R3, is selected from furyl, thienyl, pyridyl or benzofuryl;
the heteroarylmethyl represented by R3 is selected from furylmethyl, thenyl, picolyl, benzofurylmethyl or benzothienyl;
the substituent of the substituted heteroaryl represented by R3 is selected from halogen, C1-C2 alkoxy, nitro or C1-C2 alkyl-substituted furyl, thienyl, pyridyl or benzofuryl;
the substituent of the substituted heteroarylmethyl represented by R3 is selected from halogen, C1-C2 alkoxy, nitro or C1-C2 alkyl-substituted furylmethyl, thenyl, picolyl, benzofurylmethyl or benzothienyl;
the heteroaryl represented by R5 is selected from furyl, pyrrolyl, thienyl, pyridyl, benzofuryl, benzothienyl or indolyl;
and
the substituent of the substituted phenyl or substituted heteroaryl represented by R5 is selected from halogen, C1-C2 alkoxy, nitro or C1-C2 alkyl.

17 more elements

A benzoisothiazole compound, characterized in that the compound is:

I-1 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)furyl-2-carboxamide,
I-2 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)thienyl-2-carboxamide,
I-3 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1H-pyrrolyl-2-carboxamide,
I-4 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1H-indolyl-2-carboxamide,
I-5 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzofuryl-2-carboxamide,
I-6 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzo[b]thienyl-2-carboxamide,
I-7 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-cyano-furyl-2-carboxamide,
I-8 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-tert-butylfuryl-2-carboxamide,
I-9 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl) 5-methyl-1H-pyrrolyl-2-carboxamide,
I-10 trans 5-acetyl-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)furyl-2-carboxamide,
I-11 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-methylthienyl-2-carboxamide,
I-12 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-bromothienyl-2-carboxamide,
I-13 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-methylbenzo[b]thienyl-2-carboxamide,
I-14 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-chlorobenzo[b]thienyl-2-carboxamide,
I-15 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-nitro-1H-indolyl-2-carboxamide,
I-16 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-methoxylbenzofuryl-2-carboxamide,
I-17 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-2-(thien-2-yl)acetamide,
I-18 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-2-(benzofuran-3-yl)acetamide,
I-19 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)furyl-2-carboxamide,
I-20 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)thienyl-2-carboxamide,
I-21 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1H-pyrrolyl-2-carboxamide,
I-22 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1H-indolyl-2-carboxamide,
I-23 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzofuryl-2-carboxamide,
I-24 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzo[b]thienyl-2-carboxamide,
II-1 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)ethyl)cyclohexyl)thienyl-2-sulfamide,
II-2 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1H-pyrrolyl-3-sulfamide,
II-3 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)furyl-2-sulfamide,
II-4 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzo[b]thienyl-2-sulfamide,
II-5 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzofuryl-2-sulfamide,
II-6 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1H-indolyl-3-sulfamide,
II-7 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-cyanofuryl-2-sulfamide,
II-8 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-chlorofuryl-2-sulfamide,
II-9 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-methylfuryl-2-sulfamide,
II-10 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-tert-butylthienyl-2-sulfamide,
II-11 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-chlorobenzo[b]thienyl-2-sulfamide,
II-12 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-cyanobenzo[b]thienyl-2-sulfamide,
II-13 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-methylbenzo[b]thienyl-2-sulfamide,
II-14 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-nitrobenzo[b]thienyl-2-sulfamide,
II-15 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-methoxylbenzofuryl-2-sulfamide,
II-16 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)thienyl-2-sulfamide,
II-17 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1H-pyrrolyl-3-sulfamide,
II-18 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)furyl-2-sulfamide,
II-19 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzo[b]thienyl-2-sulfamide,
II-20 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzofuryl-2-sulfamide,
II-21 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1H-indolyl-3-sulfamide,
II-22 cis-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-methylfuryl-2-sulfamide,
III-1 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)methylcarbamate,
III-2 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)ethylcarbamate,
III-3 trans-N-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)isobutylcarbamate,
III-4 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)cyclopropylcarbamate,
III-5 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)cyclohexylcarbamate,
III-6 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)phenylcarbamate,
III-7 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-methoxylphenylcarbamate,
III-8 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl-2-methylphenylcarbamate,
III-9 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-4-chlorophenyl carbamate,
III-10 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-4-nitrophenylcarbamate,
III-11 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzylcarbamate,
III-12 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzofuryl-2-methylcarbamate,
III-13 trans-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)thienyl-2-methylcarbamate,
III-14 cis-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)methylcarbamate,
III-5 cis-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)ethylcarbamate,
III-16 cis-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)benzylcarbamate,
IV-1 trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-phenylurea,
IV-2 trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-phenylethylurea,
IV-3 trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-(pyridin-3-yl)urea,
IV-4 trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-(furan-2-yl)urea,
IV-5 trans-1-(benzo[b]thien-2-yl)-3-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)urea,
IV-6 trans-3-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-methyl-1-phenylurea,
IV-7 trans-3-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-butyl-1-phenylurea,
IV-8 trans-3-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-methyl-1-(thien-2-yl)urea,
IV-9 trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-(3-methoxyphenyl)urea,
IV-10 trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-(3-nitrophenyl)urea,
IV-11 trans-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-benzoylurea,
IV-12 cis-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-phenylurea,
IV-13 cis-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-benzoylurea, or
IV-14 cis-1-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-(furan-2-yl)urea.

73 more elements

Dependencies are inferred from the claim text.

Benzoisothiazole compounds and use in preparation of antipsychotic drugs

Life of this patent

Benzoisothiazole compounds and use in preparation of antipsychotic drugs

Life of this patent

Abstract

Claims19