US 2013/0172339 A1 · SULFONAMIDE COMPOUNDS

Abstract

A compound of formula (I), wherein A is S, O or a double bond, and L is a substituted thiazolyl, phenyl or pyridyl. The compound is useful for the treatment of inflammation and cancer.

Claims21

Dependent claims

1-19. (canceled)

A compound of formula (I)

wherein:
(i) A is O or S;
and
R1 is selected from H;
halogen;
and C1-C6 alkyl optionally substituted with at least one halogen;
or
R1 and R2 form, together with the carbon atoms to which they are attached, a benzene ring optionally substituted with at least one R6;
or a 5- or 6-membered heteroaromatic or heterocyclic ring, optionally substituted with at least one R6;
R2 and R3 are independently selected from H;
halogen;
C1-C6 alkyl optionally substituted with at least one halogen;
phenyl optionally substituted with at least one R6;
5- or 6-membered heteroaryl optionally substituted with at least one R6;
and 5- or 6-membered arylsulfonyl or heteroarylsulfonyl, optionally substituted with at least one R6;
provided that
at least one of R2 and R3 is selected from said phenyl, heteroaryl, arylsulfonyl and heteroarylsulfonyl, and
when L is (a), neither R2 nor R3 is unsubstituted phenyl;
or
R2 and R3 form, together with the carbon atoms to which they are attached, a benzene ring optionally substituted with at least one R6;
or a 5- or 6-membered heteroaromatic or heterocyclic ring, optionally substituted with at least one R6;
or
(ii) A is CR′═CR′;
each R′ is independently selected from H;
halogen;
and C1-C6 alkyl optionally substituted with at least one halogen;
R1 is selected from H;
halogen;
and C1-C6 alkyl optionally substituted with at least one halogen;
R2 is selected from H, halogen, C1-C6 alkyl optionally substituted with at least one halogen;
and phenyl optionally substituted with at least one R6;
R3 is selected from H, halogen, and C1-C6 alkyl optionally substituted with at least one halogen;
provided that:
when R2 is selected from H, halogen and C1-C6 alkyl optionally substituted with at least one halogen, the ring containing A is substituted in ortho position relative to the sulphonamide bond with at least one substituent selected from halogen and C1-C6 alkyl optionally substituted with at least one halogen;
when L is (a), R2 is not unsubstituted phenyl;
and
when L is (c), R2 is unsubstituted phenyl only when R4 is not hydroxy;
L is
wherein
R4 is COOR12;
and
R5 is selected from H and C1-C6 alkyl;
or
R4 is selected from H and C1-C6 alkyl;
and
R5 is COOR12;
or
wherein
R4 is selected from H and C1-C6 alkyl;
R5 is selected from H and C1-C6 alkyl;
and
R″ is selected from C0-C1 alkyl-COOR12;
or
R5 is selected from COOR12;
and
R″ is selected from H and C1-C6 alkyl;
and
R7 is selected from H, C1-C6 alkyl, and nitro;
or
wherein
R4 is selected from H, hydroxy and C1-C6 alkyl;
R5 is selected from H, C1-C6 alkyl;
and
R″ is selected from C0-C1 alkyl-COOR12;
or
R5 is selected from COOR12 and tetrazol-5-yl, said tetrazol-5-yl optionally being substituted by R9;
and
R″ is selected from H, C1-C6 alkyl, and nitro;
R7 is selected from H, C1-C6 alkyl, and nitro;
and
R8 is selected from H, hydroxy, and C1-C6 alkyl;
or
wherein
R4 is selected from H and C1-C6 alkyl;
and
R5 is COOR12;
R7 is selected from H, C1-C6 alkyl, and nitro;
and
R8 is selected from H, hydroxy, and C1-C6 alkyl;
provided that in any of (a), (b), (c) and (d), R4, R5 and R″ are selected from C0-C1 alkyl-COOR12 only when at least one of R2 or R3 is optionally substituted phenyl or optionally substituted heteroaryl;
or when R2 and R3 together with the carbon atoms to which they are attached form a benzene ring optionally substituted by at least one R6;
R6 is selected from C1-C6 alkyl, cyano, halogen, hydroxy, C1-C6 alkoxy, C1-C6 alkylthio, tetrahydropyrrolyl, R10R11N, carbamoyl, and C1-C6 alkylcarbonylamino, or is an ethyleneoxy biradical forming, together with the atoms to which it is attached, a five-membered oxygen containing cycle;
wherein any alkyl is optionally substituted with at least one halogen;
R9 is selected from C0-C1 alkyl-COOR12;
R10 and R11 are independently selected from H and C1-C6 alkyl or form, together with the nitrogen to which they are attached, a 5- or 6-membered cyclic amino optionally containing one other cyclic heteroatom;
R12 is selected from H, C1-C6 alkyl;
heteroaryl-C0-C2 alkyl;
(C1-C3 alkoxy)pC1-C3 alkyl;
aryl-C0-C2 alkyl;
heterocyclyl-C0-C2 alkyl;
and C1-C6 dialkylamino-C1-C6 alkyl, wherein any cyclic moiety is optionally substituted with C1-C6 alkyl;
p is 1 or 2;
or a pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof;
provided that the compound is not:
ethyl 2-(benzofuran-2-sulfonamido)thiazole-4-carboxylate;
ethyl 2-(5-methylbenzo[b]thiophene-2-sulfonamido)thiazole-4-carboxylate;
ethyl 2-(benzo[b]thiophene-2-sulfonamido)thiazole-4-carboxylate;
2-(3-(benzo[b]thiophene-2-sulfonamido)phenyl)acetic acid;
methyl 2-(3-(benzo[b]thiophene-2-sulfonamido)phenyl)acetate;
ethyl 3-(5-(6-oxo-1,6-dihydropyridazin-3-yl)furan-2-sulfonamido)benzoate;
ethyl 3-(5-(5-(trifluoromethyl)isoxazol-3-yl)furan-2-sulfonamido)benzoate;
ethyl 3-(5-(4,5-dimethyl-1H-pyrazol-3-yl)thiophene-2-sulfonamido)benzoate;
ethyl 3-(5-(5-methyl-1H-pyrazol-3-yl)thiophene-2-sulfonamido)benzoate;
ethyl 3-(5-(5-(trifluoromethyl)isoxazol-3-yl)thiophene-2-sulfonamido)benzoate;
ethyl 3-(5-(3-(trifluoromethyl)isoxazol-5-yl)thiophene-2-sulfonamido)benzoate;
ethyl 3-(5-(3-methylisoxazol-5-yl)thiophene-2-sulfonamido)benzoate;
ethyl 3-(4-(4-(tert-butyl)thiazol-2-yl)thiophene-2-sulfonamido)benzoate;
methyl 3-(4-(4-(tert-butyl)thiazol-2-yl)thiophene-2-sulfonamido)benzoate;
N-(3-(2H-tetrazol-5-yl)phenyl)-2,3,5,6-tetramethylbenzenesulfonamide;
N-(3-(2H-tetrazol-5-yl)phenyl)-2,4,5-trichlorobenzenesulfonamide;
N-(3-(2H-tetrazol-5-yl)phenyl)-5-(tert-butyl)-2-methylbenzenesulfonamide;
N-(3-(1H-tetrazol-5-yl)phenyl)-2,4,5-trichlorobenzenesulfonamide;
or
N-(3-(1H-tetrazol-5-yl)phenyl)-5-(tert-butyl)-2-methylbenzenesulfonamide.

111 more elements

A pharmaceutical composition comprising a compound of formula (I)

wherein:
(i) A is O or S;
and
R1 is selected from H;
halogen;
and C1-C6 alkyl optionally substituted with at least one halogen;
or
R1 and R2 form, together with the carbon atoms to which they are attached, a benzene ring optionally substituted with at least one R6;
or a 5- or 6-membered heteroaromatic or heterocyclic ring, optionally substituted with at least one R6;
R2 and R3 are independently selected from H;
halogen;
C1-C6 alkyl optionally substituted with at least one halogen;
phenyl optionally substituted with at least one R6;
5- or 6-membered heteroaryl optionally substituted with at least one R6;
and 5- or 6-membered arylsulfonyl or heteroarylsulfonyl, optionally substituted with at least one R6;
provided that
at least one of R2 and R3 is selected from said phenyl, heteroaryl, arylsulfonyl and heteroarylsulfonyl, and
when L is (a), neither R2 nor R3 is unsubstituted phenyl;
or
R2 and R3 form, together with the carbon atoms to which they are attached, a benzene ring optionally substituted with at least one R6;
or a 5- or 6-membered heteroaromatic or heterocyclic ring, optionally substituted with at least one R6;
or
(ii) A is CR′═CR′;
each R′ is independently selected from H;
halogen;
and C1-C6 alkyl optionally substituted with at least one halogen;
R1 is selected from H;
halogen;
and C1-C6 alkyl optionally substituted with at least one halogen;
R2 is selected from H, halogen, C1-C6 alkyl optionally substituted with at least one halogen;
and phenyl optionally substituted with at least one R6;
R3 is selected from H, halogen, and C1-C6 alkyl optionally substituted with at least one halogen;
provided that:
when R2 is selected from H, halogen and C1-C6 alkyl optionally substituted with at least one halogen, the ring containing A is substituted in ortho position relative to the sulphonamide bond with at least one substituent selected from halogen and C1-C6 alkyl optionally substituted with at least one halogen;
when L is (a), R2 is not unsubstituted phenyl;
and
when L is (c), R2 is unsubstituted phenyl only when R4 is not hydroxy;
L is
wherein
R4 is COOR12;
and
R5 is selected from H and C1-C6 alkyl;
or
R4 is selected from H and C1-C6 alkyl;
and
R5 is COOR12;
or
wherein
R4 is selected from H and C1-C6 alkyl;
R5 is selected from H and C1-C6 alkyl;
and
R″ is selected from C0-C1 alkyl-COOR12;
or
R5 is selected from COOR12;
and
R″ is selected from H and C1-C6 alkyl;
and
R7 is selected from H, C1-C6 alkyl, and nitro;
or
wherein
R4 is selected from H, hydroxy and C1-C6 alkyl;
R5 is selected from H, C1-C6 alkyl;
and
R″ is selected from C0-C1 alkyl-COOR12;
or
R5 is selected from COOR12 and tetrazol-5-yl, said tetrazol-5-yl optionally being substituted by R9;
and
R″ is selected from H, C1-C6 alkyl, and nitro;
R7 is selected from H, C1-C6 alkyl, and nitro;
and
R8 is selected from H, hydroxy, and C1-C6 alkyl;
or
wherein
R4 is selected from H and C1-C6 alkyl;
and
R5 is COOR12;
R7 is selected from H, C1-C6 alkyl, and nitro;
and
R8 is selected from H, hydroxy, and C1-C6 alkyl;
provided that in any of (a), (b), (c) and (d), R4, R5 and R″ are selected from C0-C1 alkyl-COOR12 only when at least one of R2 or R3 is optionally substituted phenyl or optionally substituted heteroaryl;
or when R2 and R3 together with the carbon atoms to which they are attached form a benzene ring optionally substituted by at least one R6;
R6 is selected from C1-C6 alkyl, cyano, halogen, hydroxy, C1-C6 alkoxy, C1-C6 alkylthio, tetrahydropyrrolyl, R10R11N, carbamoyl, and C1-C6 alkylcarbonylamino, or is an ethyleneoxy biradical forming, together with the atoms to which it is attached, a five-membered oxygen containing cycle;
wherein any alkyl is optionally substituted with at least one halogen;
R9 is selected from C0-C1 alkyl-COOR12;
R10 and R11 are independently selected from H and C1-C6 alkyl or form, together with the nitrogen to which they are attached, a 5- or 6-membered cyclic amino optionally containing one other cyclic heteroatom;
R12 is selected from H, C1-C6 alkyl;
heteroaryl-C0-C2 alkyl;
(C1-C3 alkoxy)pC1-C3 alkyl;
aryl-C0-C2 alkyl;
heterocyclyl-C0-C2 alkyl;
and C1-C6 dialkylamino-C1-C6 alkyl, wherein any cyclic moiety is optionally substituted with C1-C6 alkyl;
p is 1 or 2;
or a pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof;
provided that the compound is not
ethyl 3-(5-(4,5-dimethyl-1H-pyrazol-3-yl)thiophene-2-sulfonamido)benzoate;
or
ethyl 3-(5-(5-methyl-1H-pyrazol-3-yl)thiophene-2-sulfonamido)benzoate.

94 more elements

A method of treatment of a disorder selected from cancer, inflammation and an inflammatory disorder, which method comprises administration of a therapeutically effective amount of a compound of formula (I)

wherein:
(i) A is O or S;
and
R1 is selected from H;
halogen;
and C1-C6 alkyl optionally substituted with at least one halogen;
or
R1 and R2 form, together with the carbon atoms to which they are attached, a benzene ring optionally substituted with at least one R6;
or a 5- or 6-membered heteroaromatic or heterocyclic ring, optionally substituted with at least one R6;
R2 and R3 are independently selected from H;
halogen;
C1-C6 alkyl optionally substituted with at least one halogen;
phenyl optionally substituted with at least one R6;
5- or 6-membered heteroaryl optionally substituted with at least one R6;
and 5- or 6-membered arylsulfonyl or heteroarylsulfonyl, optionally substituted with at least one R6;
provided that
at least one of R2 and R3 is selected from said phenyl, heteroaryl, arylsulfonyl and heteroarylsulfonyl, and
when L is (a), neither R2 nor R3 is unsubstituted phenyl;
or
R2 and R3 form, together with the carbon atoms to which they are attached, a benzene ring optionally substituted with at least one R6;
or a 5- or 6-membered heteroaromatic or heterocyclic ring, optionally substituted with at least one R6;
or
(ii) A is CR′═CR′;
each R′ is independently selected from H;
halogen;
and C1-C6 alkyl optionally substituted with at least one halogen;
R1 is selected from H;
halogen;
and C1-C6 alkyl optionally substituted with at least one halogen;
R2 is selected from H, halogen, C1-C6 alkyl optionally substituted with at least one halogen;
phenyl optionally substituted with at least one R6;
R3 is selected from H, halogen, and C1-C6 alkyl optionally substituted with at least one halogen;
provided that:
when R2 is selected from H, halogen and C1-C6 alkyl optionally substituted with at least one halogen, the ring containing A is substituted in ortho position relative to the sulphonamide bond with at least one substituent selected from halogen and C1-C6 alkyl optionally substituted with at least one halogen;
when L is (a), R2 is not unsubstituted phenyl;
and
when L is (c), R2 is unsubstituted phenyl only when R4 is not hydroxy;
L is
wherein
R4 is COOR12;
and
R5 is selected from H and C1-C6 alkyl;
or
R4 is selected from H and C1-C6 alkyl;
and
R5 is COOR12;
or
wherein
R4 is selected from H and C1-C6 alkyl;
R5 is selected from H and C1-C6 alkyl;
and
R″ is selected from C0-C1 alkyl-COOR12;
or
R5 is selected from COOR12;
and
R″ is selected from H and C1-C6 alkyl;
and
R7 is selected from H, C1-C6 alkyl, and nitro;
or
wherein
R4 is selected from H, hydroxy and C1-C6 alkyl;
R5 is selected from H, C1-C6 alkyl;
and
R″ is selected from C0-C1 alkyl-COOR12;
or
R5 is selected from COOR12 and tetrazol-5-yl, said tetrazol-5-yl optionally being substituted by R9;
and
R″ is selected from H, C1-C6 alkyl, and nitro;
R7 is selected from H, C1-C6 alkyl, and nitro;
and
R8 is selected from H, hydroxy, and C1-C6 alkyl;
or
wherein
R4 is selected from H and C1-C6 alkyl;
and
R5 is COOR12;
R7 is selected from H, C1-C6 alkyl, and nitro;
and
R8 is selected from H, hydroxy, and C1-C6 alkyl;
provided that in any of (a), (b), (c) and (d), R4, R5 and R″ are selected from C0-C1 alkyl-COOR12 only when at least one of R2 or R3 is optionally substituted phenyl or optionally substituted heteroaryl;
or when R2 and R3 together with the carbon atoms to which they are attached form a benzene ring optionally substituted by at least one R6;
R6 is selected from C1-C6 alkyl, cyano, halogen, hydroxy, C1-C6 alkoxy, C1-C6 alkylthio, tetrahydropyrrolyl, R10R11N, carbamoyl, and C1-C6 alkylcarbonylamino, or is an ethyleneoxy biradical forming, together with the atoms to which it is attached, a five-membered oxygen containing cycle;
wherein any alkyl is optionally substituted with at least one halogen;
R9 is selected from C0-C1 alkyl-COOR12;
R10 and R11 are independently selected from H and C1-C6 alkyl or form, together with the nitrogen to which they are attached, a 5- or 6-membered cyclic amino optionally containing one other cyclic heteroatom;
R12 is selected from H, C1-C6 alkyl;
heteroaryl-C0-C2 alkyl;
(C1-C3 alkoxy)pC1-C3 alkyl;
aryl-C0-C2 alkyl;
heterocyclyl-C0-C2 alkyl;
and C1-C6 dialkylamino-C1-C6 alkyl, wherein any cyclic moiety is optionally substituted with C1-C6 alkyl;
p is 1 or 2;
or a pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof,
to a mammal in need of such treatment.

91 more elements

Dependencies are inferred from the claim text.

Facts

Application

13/823,810Filed 19 Sep 2011

Priority

EP 10177376.017 Sep 2010

Published

4 Jul 2013

Term ends

Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 333/62
Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most…
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents
A61P 35/00
Antineoplastic agents
C07C 311/21
Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings: having the nitrogen atom of at least…

Abstract

A compound of formula (I), wherein A is S, O or a double bond, and L is a substituted thiazolyl, phenyl or pyridyl. The compound is useful for the treatment of inflammation and cancer.

Sulfonamide compounds

Life of this patent

Abstract

Claims21

Sulfonamide compounds

Life of this patent

Abstract

Claims21