US 6,794,400 B2Granted

4-substituted-1-(arylmethylidene)thiosemicarbazide, 4-substituted-1-(arylcarbonyl)thiosemicarbazide and analogs as activators of caspases and inducers of apoptosis and the use thereof

AssigneeCytovia, Inc.

InventorsSui Xiong Cai, Bao Ngoc Nguyen, John Drewe, P. Sanjeeva Reddy, Shailaja Kasibhatla, Azra Pervin

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Abstract

The present invention is directed to optionally substituted 4-substituted-1-(arylmethylidene)thiosemicarbazide, 4-substituted-1-(arylcarbonyl)thiosemicarbazide and analogs thereof, represented by the Formulae I and II: wherein A1, A2, Q and R1-R3 are defined herein. The present invention also relates to the discovery that compounds having Formulae I and II are activators of caspases and inducers of apoptosis. Therefore, the activators of caspases and inducers of apoptosis of this invention may be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.

Claims11

Dependent claims

A pharmaceutical composition, comprising a compound selected from the group consisting of:

4-(Bicyclo[2.2.1]hept-5-en-2-yl)-1-benzylidene-thiosemicarbazide;
4-(Bicyclo[2.2.1]hept-5-en-2-yl)-1-(pyridin-4-ylmethylidene)thiosemicarbazide;
4-(Bicyclo[2.2.1]hept-5-en-2-yl)-1-(pyrrol-2-ylmethylidene)thiosemicarbazide;
4-(Bicyclo[2.2.1]hept-5-en-2-yl)-1-(4-hydroxybenzylidene)thiosemicarbazide;
4-(Bicyclo[2.2.1]hept-5-en-2-yl)-1-(pyridin-3-ylmethylidene)thiosemicarbazide;
4-(Bicyclo[2.2.1]hept-5-en-2-yl)-1-(6-methyl-pyridin-2-ylmethylidene)thiosemicarbazide;
4-(Bicyclo[2.2.1]hept-5-en-2-yl)-1-(pyridine-2-carbonyl)thiosemicarbazide;
4-(Bicyclo[2.2.1]hept-5-en-2-yl)-1-(thiazol-2-ylethylidene)thiosemicarbazide;
4-(Bicyclo[2.2.1]hept-5-en-2-yl)-1-(4,5-dimethylfuran-2-ylmethylidene)thiosemicarbazide;
4-(Bicyclo[2.2.1]hept-5-en-2-yl)-1-(2-methoxy-4-dimethylaminobenzylidene)thiosemicarbazide;
4-(Bicyclo[2.2.1]hept-5-en-2-yl)-1-(1-methylpyrrol-2-ylmethylidene)thiosemicarbazide;
4-(Bicyclo[2.2.1]hept-5-en-2-yl)-1-(4-pyrrolidinobenzylidene)thiosemicarbazide;
4-(Bicyclo[2.2.1]hept-5-en-2-yl)-1-(6-bromopyridin-2-ylmethylidene)thiosemicarbazide;
4-(Bicyclo[2.2.1]hept-5-en-2-yl)-1-(1,2,3-thiadiazol-4-ylmethylidene)thiosemicarbazide;
4-(Bicyclo[2.2.1]hept-5-en-2-yl)-1-(4-morpholino-3-nitrobenzylidene)thiosemicarbazide;
4-(Bicyclo[2.2.1]hept-5-en-2-yl)-1-(4-bromo-1H-pyrazol-5-ylmethylidne)thiosemicarbazide;
4-(Bicyclo[2.2.1]hept-5-en-2-yl)-1-(4-chloro-1-methylpyrazol-3-ylmethylidene)thiosemicarbazide;
and
4-(Bicyclo[2.2.1]hept-5-en-2-yl)-1-(2-methylthiazole-5-carbonyl)thiosemicarbazide;
and a pharmaceutically acceptable carrier.

17 more elements

A pharmaceutical composition, comprising a compound selected from the group consisting of:

4-(2,4-Dimethylphenyl)-1-benzylidene-thiosemicarbazide;
4-(2,4-Dimethylphenyl)-1-(6-methyl-pyridin-2-ylmethylidene)thiosemicarbazide;
4-(2,4-Dimethylphenyl)-1-(2-nitrobenzylidene)thiosemicarbazide;
4-(2,4-Dimethylphenyl)-1-(3chlorobenzylidene)thiosemicarbazide;
4-(2,4-Dimethylphenyl)-1-(2-chlorobenzylidene)thiosemicarbazide;
4-(2,4-Dimethylphenyl)-1-(3-hydroxybenzylidene)thiosemicarbazide;
4-(2,4-Dimethylphenyl)-1-(2-hydroxybenzylidene)thiosemicarbazide;
4-(2,4-Dimethylphenyl)-1-(4-dimethylaminobenzylidene)thiosemicarbazide;
4-(2,4-Dimethylphenyl)-1-(furan-2-ylmethylidene)thiosemicarbazide;
4-(2,4-Dimethylphenyl)-1-(thiophen-2-ylmethylidene)thiosemicarbazide;
4-(2,4-Dimethylphenyl)-1-(4,5-dimethylfuran-2-ylmethylidene)thiosemicarbazide;
4-(2,4-Dimethylphenyl)-1-(N-methylpyrrol-2-ylmethylidene)thiosemicarbazide;
4-(2,4-Dimethylphenyl)-1-(5-nitrothiophen-2-ylmethylidene)thiosemicarbazide;
4-(2,4-Dimethylphenyl)-1-(imidazol-2-ylmethylidene)thiosemicarbazide;
4-(2,4-Dimethylphenyl)-1-(6-bromo-pyridin-2-ylmethylidene)thiosemicarbazide;
4-(2,4-Dimethylphenyl)-1-(4-bromo-1H-pyrazol-5-ylmethylidene)thiosemicarbazide;
4-(2,4-Dimethylphenyl)-1-(4-chloro-1-methylpyrazol-3-ylmethylidene)thiosemicarbazide;
4-(2,4-Dimethylphenyl)-1-(1,2,3-thiazol-4-ylmethylidene)thiosemicarbazide;
4-(2,4-Dimethylphenyl)-1-(thiazol-2-ylethylidene)thiosemicarbazide;
4-(2,4-Dimethylphenyl)-1-(2-furan-2-ylmethylidene)semicarbazide;
4-(2,4-Dimethylphenyl)-1-(3-chlorobenzylidene)semicarbazide;
4-(2,4-Dimethylphenyl)-1-(benzylidene)semicarbazide;
4-(2,4-Dimethylphenyl)-1-(4-pyrrolidinobenzylidene)semicarbazide;
4-(2,4-Dimethylphenyl)-1-(pyridin-2-ylmethylidene)semicarbazide;
4-(2,4-Dimethylphenyl)-1-(2-methoxy-4-dimethylaminobenzylidene)semicarbazide;
4-(2,4-Dimethylphenyl)-1-(4-chloro-1-methylpyrazol-3-ylmethylidene)semicarbazide;
4-(2,4-Dimethylphenyl)-1-(3-hydroxybenzylidene)semicarbazide;
4-(2,4-Dimethylphenyl)-1-(1-methylpyrrol-2-ylmethylidene)semicarbazide;
4-(2,4-Dimethylphenyl)-1-(4,5-dimethylfuran-2-ylmethylidene)semicarbazide;
4-(2,4-Dimethylphenyl)-1-(thiophene-2-ylmethylidene)semicarbazide;
4-(2,4-Dimethylphenyl)-1-(6-methylpyridin-2-ylmethylidene)semicarbazide;
4-(2,4-Dimethylphenyl)-1-(2-hydroxy-4-methylbenzylidene)semicarbazide;
4-(2,4-Dimethylphenyl)-1-(2-hydroxy-5-chlorobenzylidene)semicarbazide;
4-(2,4-Dimethylphenyl)-1-(4-bromo-1H-pyrazol-5-ylmethylidne)semicarbazide;
4-(2,4-Dimethylphenyl)-1-(2-methylthiazole-5-carbonyl)semicarbazide;
and
4-(2,4-Dimethylphenyl)-1-(4-chlorobenzoyl)semicarbazide,
and a pharmaceutically acceptable carrier.

35 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/158,827Filed 3 Jun 2002 · us provisional application
Priority: 1 Jun 2001
Published: US 2003/0045581 A16 Mar 2003
Granted: 21 Sep 2004
Term ends: Not estimatedThe source records don’t support an estimate.

Classification34 codes

C07D 207/335
With substituted hydrocarbon radicals, directly attached to ring carbon atoms: radicals substituted by nitrogen atoms not forming part of a nitro…
A61K 31/175
Having the group >N—C—N< or >N—C—N<, e.g. urea, thiourea, carmustine: having the group [IMAGE cpc-sch-A61K-0950.gif] , >N—C—N=N— or[IMAGE…
A61K 31/435
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having six-membered rings with one nitrogen as the only ring hetero atom
A61K 31/44
Having six-membered rings with one nitrogen as the only ring hetero atom: non condensed pyridines; Hydrogenated derivatives thereof