US 5,891,917 A · Certain acrylonitrile-sulfonamide derivatives

Abstract

The present invention relates to molecules capable of modulating tyrosine signal transduction to prevent and treat cell proliferative disorders or cell differentiation disorders associated with particular tyrosine kinases by inhibiting one or more abnormal tyrosine kinase activities.

Claims16

Dependent claims

A compound of the formula ##STR5## or a pharmaceutically acceptable salt thereof, wherein:

X is NH;
m is 0 or 1;
n is 0, 1, 2, 3, or 4;
Q is a phenyl ring optionally substituted with one or more substituents selected from the group consisting of halo, trihalo, alkyl, alkoxy, hydroxy, H, nitro, cyano, amide, sulfonyl, sulfonamide, carboxy, carboxamide, and amino;
and
R.sub.1-4 are independently selected from the group consisting of halo, trihalo, alkyl, alkoxy, hydroxy, H, nitro, cyano, amide, sulfonyl, sulfonamide, carboxy, carboxamide, and amino;
with the proviso that when m and n are both 0, said phenyl ring is substituted.

4 more elements

A compound selected from the group consisting of:

(E)-3-(3,5-Dimethyl4-hydroxyphenyl)-2-(phenylsulfonyl)acrylonitrile,
(E)-3-(3,5-Di -t-butyl-4-hydroxyphenyl)-2-(phenylsulfonyl)acrylonitrile,
(E)-2-(Benzylaminosulfonyl)-3-(3,5-di-t-butyl4-hydroxyphenyl)acrylonitrile,
(E)-2-(Benzylaminosulfonyl)-3-(3,5-diisopropyl-4-hydroxyphenyl)acrylonitril e,
(E)-2-(Benzylaminosulfonyl)-3-(3,5-dimethyl-4-hydroxyphenyl)acrylonitrile,
(E)-3-(3,5-Di-t-butyl-4-hydroxyphenyl)-2-(3-phenyl-n-propyl)aminosulfonyl! acrylonitrile,
(E)-3-(3,5-Diisopropyl-4-hydroxyphenyl)-2-(3-phenyl) -n-propyl)aminosulfonyl!acrylonitrile),
(E)-3-(3,5-Dimethyl-4-hydroxyphenyl)-2-(3-phenyl-n-propyl)aminosulfonyl!ac rylonitrile,
(E)-3-(3-t-Butyl-4-hydroxyphenyl)-2-(4-fluorophenylsulfonyl)acrylonitrile,
(E)-3-(3-Bromo4,5-dihydroxyphenyl)-2-(phenylsulfonyl)acrylonitrile,
(E)-3-(3,4-Dihydroxyphenyl)-2-(phenylsulfonyl)acrylonitrile,
(E)-2-(Benzylaminosulfonyl)-3-(3,4-dihydroxyphenyl)acrylonitrile,
(E)-2-(Benzylaminosulfonyl)-3-(4-hydroxy-3-ethoxyphenyl)acrylonitrile,
(E)-2-(Benzylaminosulfonyl)-3-(3-bromo-4,5-dihydroxyphenyl)acrylonitrile,
(E)-3-(3-Bromo-4,5-dihydroxyphenyl)-2-(4-phenyl-n-butyl)aminosulfonyl!acry lonitrile,
(E)-3-(3-Ethoxy-4-hydroxyphenyl)-2-(3-phenyl-n-propyl)aminosulfonyl!acrylo nitrile,
(E)-3-(3,4-Dihydroxyphenyl)-2-(3-phenyl-n-propyl)aminosulfonyl!acrylonitri le,
(E)-3-(4-Hydroxy-3-ethoxyphenyl)-2-(phenylsulfonyl)acrylonitrile,
(E) -3-(3,5-Di-t-butyl4-hydroxyphenyl)-2-3-(trifluoromethyl)benzylsulfonyl!ac rylonitrile,
(E)-3-(3,5-Diisopropyl-4-hydroxyphenyl)-2-3-(trifluoromethyl)benzylsulfony l!acrylonitrile,
(E)-3-(3-Ethoxy-4-hydroxyphenyl)-2-(3-trifluoromethyl)benzylsulfonyl!acryl onitrile,
(E)-3-(3-Bromo-4,5-dihydroxyphenyl)-2-3-(trifluoromethyl)benzylsulfonyl!ac rylonitrile,
(E)-3-(3,5-Dimethyl-4-hydroxyphenyl)-2-3-(trifluoromethyl)benzylsulfonyl!a crylonitrile,
(E)-3-(3,4-Dihydroxyphenyl)-2-3-(trifluoromethyl)benzylsulfonyl!acrylonitr ile,
(E)-2-(4-Fluorophenylsulfonyl)-3-(4-hydroxy-3,5-di-t-butylphenyl)acrylonitr ile,
(E)-3-(3,5-Diisopropyl-4-hydroxyphenyl)-2-(4-fluorophenylsulfonyl)acrylonit rile,
(E)-3-(3,4-Dihydroxyphenyl)-2-(4-fluorophenylsulfonyl)acrylonitrile,
(E)-3-(3-Bromo-4,5-dihydroxyphenyl)-2-(4-fluorophenylsulfonyl)acrylonitrile
(E)-3-(3-Ethoxy-4-hydroxyphenyl)-2-(4-fluorophenylsulfonyl)acrylonitrile,
(E)-3-(3,5-Dimethyl-4-hydroxyphenyl)-2-(4-fluorophenylsulfonyl)acrylonitril e,
(E)-3-(3,5-Di-t-butyl4-hydroxyphenyl)-2-4-(trifluoromethyl)phenylsulfonyl! acrylonitrile,
(E)-3-(3,5-Diisopropyl-4hydroxyphenyl)-2-4-(trifluoromethyl)phenylsulfonyl !acrylonitrile,
(E)-3-(3,5-Dimethyl4-hydroxyphenyl)-2-4(trifluoromethyl)phenylsulfonyl!acr ylonitrile,
(E)-3-(3,4-Dihydroxyphenyl)-2-4-(trifluoromethyl)phenylsulfonyl!acrylonitr ile,
(E)-3-(3-Bromo-4,5-dihydroxyphenyl)-2-4-(trifluoromethyl)phenylsulfonyl!ac rylonitrile,
(E)-3-(3-Ethoxy-4-hydroxyphenyl)-2-4-(trifluoromethyl)phenylsulfonyl!acryl onitrile,
(E)-3-(3,5-Di-t-butyl-4-hydroxyphenyl)-2-3-(trifluoromethyl)phenylsulfonyl !acrylonitrile,
(E)-3-(3,5-Dimethyl-4-hydroxyphenyl)-2-3-(trifluoromethyl)phenylsulfonyl!a crylonitrile,
(E) -3-(3,5-Diisopropyl-4-hydroxyphenyl)-2-3-(trifluoromethyl)phenylsulfonyl! acrylonitrile,
(E)-3-(3,4Dihydroxyphenyl)-2-3-(trifluoromethyl)phenylsulfonyl!acrylonitri le,
(E)-3-(3-Bromo-4,5-dihydroxyphenyl)-2-3-(trifluoromethyl)phenylsulfonyl!ac rylonitrile,
(E)-3-(3-Ethoxy4-hydroxyphenyl)-2-3-(trifluoromethyl)phenylsulfonyl!acrylo nitrile,
(E)-3-(2-Chloro-4-hydroxyphenyl)-2-3-(trifluoromethyl)phenylsulfonyl!acryl onitrile,
(E)-3-(2-Chloro-4-hydroxyphenyl)-2-4-(trifluoromethyl)phenylsulfonyl!acryl onitrile,
(E)-2-(Benzylaminosulfonyl)-3-(2-chloro-4-hydroxyphenyl)acrylonitrile,
(E)-3-(2-Chloro-4-hydroxyphenyl)-2-(4-phenyl-n-butyl)aminosulfonyl!acrylon itrile,
(E)-3-(3,5-Di-t-butyl-4-hydroxyphenyl)-2-(2,4-difluorophenylsulfonyl)acrylo nitrile,
(E)-3-(3,5-Diisopropyl4-hydroxyphenyl)-2-(2,4-difluorophenylsulfonyl)acrylo nitrile,
(E)-3-(3,5-Dimethyl-4-hydroxyphenyl)-2-(2,4-difluorophenylsulfonyl)acryloni trile,
(E)-3-(3,5-Di-t-butyl4-hydroxyphenyl)-2-(4-fluorophenylsulfonyl)acrylonitri le,
(E)-2-(Benzylaminosulfonyl)-3-(3-t-butyl-4-hydroxyphenyl)acrylonitrile,
(E)-3-(3-t-Butyl-4-hydroxyphenyl)-2-(3-phenyl-n-propyl)aminosulfonyl!acryl onitrile,
(E)-3-(3-t-Butyl-4-hydroxyphenyl)-2-(phenylsulfonyl)acrylonitrile,
(E)-3-(3-t-Butyl -4-hydroxyphenyl)-2-(2,4-difluorophenylsulfonyl)acrylonitrile,
(E)-3-(3-t-Butyl-4-hydroxyphenyl)-2-(4-trifluoromethylphenyl sulfonyl)acrylonitrile,
(E)-3-(3-t-Butyl -4-hydroxyphenyl)-2-(3-trifluoromethylphenyl sulfonyl)acrylonitrile,
(E)-2-(Benzylaminosulfonyl)-3-(3-bromo-5-t-butyl-4-hydroxyphenyl)acrylonitr ile,
(E)-3-(3-Bromo-5-t-butyl-4-hydroxyphenyl)-2-(4-fluorophenylsulfonyl)-acrylo nitrile,
(E)-3-(3-Bromo-5-t-butyl-4-hydroxyphenyl)-2-(3-trifluoromethylphenylsulfony l)-acrylonitrile,
(E)-3-(3-Bromo-5-t-butyl-4-hydroxyphenyl) -2-(4-trifluoromethylphenylsulfonyl)-acrylonitrile,
(E)-3-(3-Bromo-5-t-butyl-4-hydroxyphenyl)-2-(2,4-difluorophenylsulfonyl)-ac rylonitrile, and
(E)-3-(3-Bromo-5-t-butyl-4-hydroxyphenyl)-2-(3-phenyl-n-propyl)aminosulfon yl!acrylonitrile;
or a pharmaceutically acceptable salt of said compound.

60 more elements

Dependencies are inferred from the claim text.

Facts

Application

08/957,260Filed 24 Oct 1997 · continuation

Priority

7 Jun 1995

Granted

6 Apr 1999

Term ends

Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 333/34
Hetero atoms other than halogen: sulfur atoms
C07C 311/27
Having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms: of an unsaturated carbon skeleton containing rings
C07C 317/46
Having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton: the carbon skeleton being further substituted by…
C07D 213/71
Sulfur atoms: to which a second hetero atom is attached

Abstract

Claims16

Dependent claims

A compound of the formula ##STR5## or a pharmaceutically acceptable salt thereof, wherein:

X is NH;
m is 0 or 1;
n is 0, 1, 2, 3, or 4;
Q is a phenyl ring optionally substituted with one or more substituents selected from the group consisting of halo, trihalo, alkyl, alkoxy, hydroxy, H, nitro, cyano, amide, sulfonyl, sulfonamide, carboxy, carboxamide, and amino;
and
R.sub.1-4 are independently selected from the group consisting of halo, trihalo, alkyl, alkoxy, hydroxy, H, nitro, cyano, amide, sulfonyl, sulfonamide, carboxy, carboxamide, and amino;
with the proviso that when m and n are both 0, said phenyl ring is substituted.

4 more elements

A compound selected from the group consisting of:

(E)-3-(3,5-Dimethyl4-hydroxyphenyl)-2-(phenylsulfonyl)acrylonitrile,
(E)-3-(3,5-Di -t-butyl-4-hydroxyphenyl)-2-(phenylsulfonyl)acrylonitrile,
(E)-2-(Benzylaminosulfonyl)-3-(3,5-di-t-butyl4-hydroxyphenyl)acrylonitrile,
(E)-2-(Benzylaminosulfonyl)-3-(3,5-diisopropyl-4-hydroxyphenyl)acrylonitril e,
(E)-2-(Benzylaminosulfonyl)-3-(3,5-dimethyl-4-hydroxyphenyl)acrylonitrile,
(E)-3-(3,5-Di-t-butyl-4-hydroxyphenyl)-2-(3-phenyl-n-propyl)aminosulfonyl! acrylonitrile,
(E)-3-(3,5-Diisopropyl-4-hydroxyphenyl)-2-(3-phenyl) -n-propyl)aminosulfonyl!acrylonitrile),
(E)-3-(3,5-Dimethyl-4-hydroxyphenyl)-2-(3-phenyl-n-propyl)aminosulfonyl!ac rylonitrile,
(E)-3-(3-t-Butyl-4-hydroxyphenyl)-2-(4-fluorophenylsulfonyl)acrylonitrile,
(E)-3-(3-Bromo4,5-dihydroxyphenyl)-2-(phenylsulfonyl)acrylonitrile,
(E)-3-(3,4-Dihydroxyphenyl)-2-(phenylsulfonyl)acrylonitrile,
(E)-2-(Benzylaminosulfonyl)-3-(3,4-dihydroxyphenyl)acrylonitrile,
(E)-2-(Benzylaminosulfonyl)-3-(4-hydroxy-3-ethoxyphenyl)acrylonitrile,
(E)-2-(Benzylaminosulfonyl)-3-(3-bromo-4,5-dihydroxyphenyl)acrylonitrile,
(E)-3-(3-Bromo-4,5-dihydroxyphenyl)-2-(4-phenyl-n-butyl)aminosulfonyl!acry lonitrile,
(E)-3-(3-Ethoxy-4-hydroxyphenyl)-2-(3-phenyl-n-propyl)aminosulfonyl!acrylo nitrile,
(E)-3-(3,4-Dihydroxyphenyl)-2-(3-phenyl-n-propyl)aminosulfonyl!acrylonitri le,
(E)-3-(4-Hydroxy-3-ethoxyphenyl)-2-(phenylsulfonyl)acrylonitrile,
(E) -3-(3,5-Di-t-butyl4-hydroxyphenyl)-2-3-(trifluoromethyl)benzylsulfonyl!ac rylonitrile,
(E)-3-(3,5-Diisopropyl-4-hydroxyphenyl)-2-3-(trifluoromethyl)benzylsulfony l!acrylonitrile,
(E)-3-(3-Ethoxy-4-hydroxyphenyl)-2-(3-trifluoromethyl)benzylsulfonyl!acryl onitrile,
(E)-3-(3-Bromo-4,5-dihydroxyphenyl)-2-3-(trifluoromethyl)benzylsulfonyl!ac rylonitrile,
(E)-3-(3,5-Dimethyl-4-hydroxyphenyl)-2-3-(trifluoromethyl)benzylsulfonyl!a crylonitrile,
(E)-3-(3,4-Dihydroxyphenyl)-2-3-(trifluoromethyl)benzylsulfonyl!acrylonitr ile,
(E)-2-(4-Fluorophenylsulfonyl)-3-(4-hydroxy-3,5-di-t-butylphenyl)acrylonitr ile,
(E)-3-(3,5-Diisopropyl-4-hydroxyphenyl)-2-(4-fluorophenylsulfonyl)acrylonit rile,
(E)-3-(3,4-Dihydroxyphenyl)-2-(4-fluorophenylsulfonyl)acrylonitrile,
(E)-3-(3-Bromo-4,5-dihydroxyphenyl)-2-(4-fluorophenylsulfonyl)acrylonitrile
(E)-3-(3-Ethoxy-4-hydroxyphenyl)-2-(4-fluorophenylsulfonyl)acrylonitrile,
(E)-3-(3,5-Dimethyl-4-hydroxyphenyl)-2-(4-fluorophenylsulfonyl)acrylonitril e,
(E)-3-(3,5-Di-t-butyl4-hydroxyphenyl)-2-4-(trifluoromethyl)phenylsulfonyl! acrylonitrile,
(E)-3-(3,5-Diisopropyl-4hydroxyphenyl)-2-4-(trifluoromethyl)phenylsulfonyl !acrylonitrile,
(E)-3-(3,5-Dimethyl4-hydroxyphenyl)-2-4(trifluoromethyl)phenylsulfonyl!acr ylonitrile,
(E)-3-(3,4-Dihydroxyphenyl)-2-4-(trifluoromethyl)phenylsulfonyl!acrylonitr ile,
(E)-3-(3-Bromo-4,5-dihydroxyphenyl)-2-4-(trifluoromethyl)phenylsulfonyl!ac rylonitrile,
(E)-3-(3-Ethoxy-4-hydroxyphenyl)-2-4-(trifluoromethyl)phenylsulfonyl!acryl onitrile,
(E)-3-(3,5-Di-t-butyl-4-hydroxyphenyl)-2-3-(trifluoromethyl)phenylsulfonyl !acrylonitrile,
(E)-3-(3,5-Dimethyl-4-hydroxyphenyl)-2-3-(trifluoromethyl)phenylsulfonyl!a crylonitrile,
(E) -3-(3,5-Diisopropyl-4-hydroxyphenyl)-2-3-(trifluoromethyl)phenylsulfonyl! acrylonitrile,
(E)-3-(3,4Dihydroxyphenyl)-2-3-(trifluoromethyl)phenylsulfonyl!acrylonitri le,
(E)-3-(3-Bromo-4,5-dihydroxyphenyl)-2-3-(trifluoromethyl)phenylsulfonyl!ac rylonitrile,
(E)-3-(3-Ethoxy4-hydroxyphenyl)-2-3-(trifluoromethyl)phenylsulfonyl!acrylo nitrile,
(E)-3-(2-Chloro-4-hydroxyphenyl)-2-3-(trifluoromethyl)phenylsulfonyl!acryl onitrile,
(E)-3-(2-Chloro-4-hydroxyphenyl)-2-4-(trifluoromethyl)phenylsulfonyl!acryl onitrile,
(E)-2-(Benzylaminosulfonyl)-3-(2-chloro-4-hydroxyphenyl)acrylonitrile,
(E)-3-(2-Chloro-4-hydroxyphenyl)-2-(4-phenyl-n-butyl)aminosulfonyl!acrylon itrile,
(E)-3-(3,5-Di-t-butyl-4-hydroxyphenyl)-2-(2,4-difluorophenylsulfonyl)acrylo nitrile,
(E)-3-(3,5-Diisopropyl4-hydroxyphenyl)-2-(2,4-difluorophenylsulfonyl)acrylo nitrile,
(E)-3-(3,5-Dimethyl-4-hydroxyphenyl)-2-(2,4-difluorophenylsulfonyl)acryloni trile,
(E)-3-(3,5-Di-t-butyl4-hydroxyphenyl)-2-(4-fluorophenylsulfonyl)acrylonitri le,
(E)-2-(Benzylaminosulfonyl)-3-(3-t-butyl-4-hydroxyphenyl)acrylonitrile,
(E)-3-(3-t-Butyl-4-hydroxyphenyl)-2-(3-phenyl-n-propyl)aminosulfonyl!acryl onitrile,
(E)-3-(3-t-Butyl-4-hydroxyphenyl)-2-(phenylsulfonyl)acrylonitrile,
(E)-3-(3-t-Butyl -4-hydroxyphenyl)-2-(2,4-difluorophenylsulfonyl)acrylonitrile,
(E)-3-(3-t-Butyl-4-hydroxyphenyl)-2-(4-trifluoromethylphenyl sulfonyl)acrylonitrile,
(E)-3-(3-t-Butyl -4-hydroxyphenyl)-2-(3-trifluoromethylphenyl sulfonyl)acrylonitrile,
(E)-2-(Benzylaminosulfonyl)-3-(3-bromo-5-t-butyl-4-hydroxyphenyl)acrylonitr ile,
(E)-3-(3-Bromo-5-t-butyl-4-hydroxyphenyl)-2-(4-fluorophenylsulfonyl)-acrylo nitrile,
(E)-3-(3-Bromo-5-t-butyl-4-hydroxyphenyl)-2-(3-trifluoromethylphenylsulfony l)-acrylonitrile,
(E)-3-(3-Bromo-5-t-butyl-4-hydroxyphenyl) -2-(4-trifluoromethylphenylsulfonyl)-acrylonitrile,
(E)-3-(3-Bromo-5-t-butyl-4-hydroxyphenyl)-2-(2,4-difluorophenylsulfonyl)-ac rylonitrile, and
(E)-3-(3-Bromo-5-t-butyl-4-hydroxyphenyl)-2-(3-phenyl-n-propyl)aminosulfon yl!acrylonitrile;
or a pharmaceutically acceptable salt of said compound.

60 more elements

Dependencies are inferred from the claim text.

Facts

Application

08/957,260Filed 24 Oct 1997 · continuation

Priority

7 Jun 1995

Granted

6 Apr 1999

Term ends

Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 333/34
Hetero atoms other than halogen: sulfur atoms
C07C 311/27
Having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms: of an unsaturated carbon skeleton containing rings
C07C 317/46
Having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton: the carbon skeleton being further substituted by…
C07D 213/71
Sulfur atoms: to which a second hetero atom is attached

Certain acrylonitrile-sulfonamide derivatives

Life of this patent

Abstract

Claims16

Certain acrylonitrile-sulfonamide derivatives

Life of this patent

Abstract

Claims16