US 5,536,752 AGranted

Phenyl heterocycles as COX-2 inhibitors

AssigneeMerck Frosst Canada, Inc.

InventorsYves Ducharme, Jacques Y. Gauthier, Petpiboon Prasit, Yves Leblanc, Zhaoyin Wang, Serge Leger, Michel Therien

Life of this patent

Estimating the term…

Abstract

The invention encompasses the novel compound of Formula I useful in the treatment of cyclooxygenase-2 mediated diseases. ##STR1## The invention also encompasses certain pharmaceutical compositions for treatment of cyclooxygenase-2 mediated diseases comprising compounds of Formula I.

Claims18

Dependent claims

A compound of formula I ##STR219## or a pharmaceutically acceptable salt thereof wherein:

X--Y--Z-- is selected from the group consisting of:
(a) --CH.sub.2 CH.sub.2 CH.sub.2 --,
(b) --C(O)CH.sub.2 CH.sub.2 --, and
(c) --CH.sub.2 CH.sub.2 C(O)--,
wherein side b is a double bond, and sides a an c are single bonds;
R.sup.1 is selected from the group consisting of
(a) S(O).sub.2 CH.sub.3,
(b) S(O).sub.2 NH.sub.2,
(c) S(O).sub.2 NHC(O)CF.sub.3,
(d) S(O)(NH)CH.sub.3,
(e) S(O)(NH)NH.sub.2,
(f) S(O)(NH)NHC(O)CF.sub.3,
(g) P(O)(CH.sub.3)OH, and
(h) P(O)(CH.sub.3)NH.sub.2,
R.sup.2 is selected from the group consisting of
(a) C.sub.3, C.sub.4, C.sub.5, C.sub.6, and C.sub.7, cycloalkyl,
(b) mono-, di- or tri-substituted phenyl wherein the substituent is selected from the group consisting of
(1) hydrogen,
(2) halo,
(3) C.sub.1-6 alkoxy,
(4) C.sub.1-6 alkylthio,
(5) CN,
(6) CF.sub.3,
(7) C.sub.1-6 alkyl,
(8) N.sub.3,
(9) --CO.sub.2 H,
(10) --CO.sub.2 --C.sub.1-4 alkyl,
(11) --C(R.sup.5)(R.sup.6)--OH,
(12) --C(R.sup.5)(R.sup.6)--O--C.sub.1-4 alkyl, and
(13) --C.sub.1-6 alkyl-CO.sub.2 --R.sup.5 ;
(c) mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1, 2, or 3 additional N atoms;
or
the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1, 2 or 3 additional N atoms;
said substituents are selected from the group consisting of
(1) hydrogen,
(2) halo, including fluoro, chloro, bromo and iodo,
(3) C.sub.1-6 alkyl,
(4) C.sub.1-6 alkoxy,
(5) C.sub.1-6 alkylthio,
(6) CN,
(7) CF.sub.3,
(8) N.sub.3,
(9) --C(R.sup.5)(R.sup.6)--OH, and
(10) --C(R.sup.5)(R.sup.6)--O--C.sub.1-4 alkyl;
R.sup.5 and R.sup.6 are each independently selected from the group consisting of
(a) hydrogen, and
(b) C.sub.1-6 alkyl,
or R.sup.5 and R.sup.6 or R.sup.7 and R.sup.8 together with the carbon to which they are attached form a monocyclic saturated carbon ring of 3, 4, 5, 6 or 7 atoms.

45 more elements

A compound according to claim 8 wherein R.sup.2 is a mono- or di-substituted heteroaryl wherein heteroaryl is selected from the group consisting of

(1) 2-furanyl,
(2) 3-furanyl,
(3) 2-thienyl,
(4) 3-thienyl,
(5) 3-isoxazolyl,
(6) 4-isoxazolyl,
(7) 5-isoxazolyl,
(8) 3-isothiazolyl,
(9) 4-isothiazolyl,
(10) 5-isothiazolyl,
(11) 2-oxazolyl,
(12) 4-oxazolyl,
(13) 5-oxazolyl,
(14) 2-thiazolyl,
(15) 4-thiazolyl,
(16) 5-thiazolyl,
(17) 1,2,3-thiadiazol-4-yl,
(18) 1,2,3-thiadiazol-5-yl,
(19) 1,2,4-thiadiazol-3-yl,
(20) 1,2,4-thiadiazol-5-yl,
(21) 1,3,4-thiadiazol-2-yl,
(22) 1,2,5-thiadiazol-3-yl,
(23) 1,2,3-oxadiazol-4-yl,
(24) 1,2,3-oxadiazol-5-yl,
(25) 1,2,4-oxadiazol-3-yl,
(26) 1,2,4-oxadiazol-5-yl,
(27) 1,3,4-oxadiazol-2-yl,
(28) 1,2,5-oxadiazol-3-yl,
(29) pyrazol-4-yl,
(30) pyrazol-5-yl,
(31) 1,2,3-triadiazol-4-yl,
(32) 1,2,3-triadiazol-5-yl,
(33) 1,2,4-triadiazol-3-yl,
(34) 1,2,4-triadiazol-5-yl,
(35) 1,2-diazinyl,
(36) 1,3-diazinyl,
(37) 1,4-diazinyl,
(38) 1,2,3,4-tetrazin-5-yl,
(39) 1,2,4,5-tetrazin-4-yl,
(40) 1,3,4,5-tetrazin-2-yl, and
(41) 1,2,3,5-tetrazin-4-yl.

38 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/436,672Filed 8 May 1995 · division
Priority: 24 Jun 1993
Granted: 16 Jul 1996
Term ends: Not estimatedThe source records don’t support an estimate.

Classification31 codes

C07D 275/02
Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings: not condensed with other rings
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…

Family

Serial82,196Parent of this continuation-in-part · filed 24 Jun 1993
Serial179,467Parent of this division · filed 10 Jan 1994
US 5,474,995 AParent of this division
US 5,536,752 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of formula I ##STR219## or a pharmaceutically acceptable salt thereof wherein:

X--Y--Z-- is selected from the group consisting of:
(a) --CH.sub.2 CH.sub.2 CH.sub.2 --,
(b) --C(O)CH.sub.2 CH.sub.2 --, and
(c) --CH.sub.2 CH.sub.2 C(O)--,
wherein side b is a double bond, and sides a an c are single bonds;
R.sup.1 is selected from the group consisting of
(a) S(O).sub.2 CH.sub.3,
(b) S(O).sub.2 NH.sub.2,
(c) S(O).sub.2 NHC(O)CF.sub.3,
(d) S(O)(NH)CH.sub.3,
(e) S(O)(NH)NH.sub.2,
(f) S(O)(NH)NHC(O)CF.sub.3,
(g) P(O)(CH.sub.3)OH, and
(h) P(O)(CH.sub.3)NH.sub.2,
R.sup.2 is selected from the group consisting of
(a) C.sub.3, C.sub.4, C.sub.5, C.sub.6, and C.sub.7, cycloalkyl,
(b) mono-, di- or tri-substituted phenyl wherein the substituent is selected from the group consisting of
(1) hydrogen,
(2) halo,
(3) C.sub.1-6 alkoxy,
(4) C.sub.1-6 alkylthio,
(5) CN,
(6) CF.sub.3,
(7) C.sub.1-6 alkyl,
(8) N.sub.3,
(9) --CO.sub.2 H,
(10) --CO.sub.2 --C.sub.1-4 alkyl,
(11) --C(R.sup.5)(R.sup.6)--OH,
(12) --C(R.sup.5)(R.sup.6)--O--C.sub.1-4 alkyl, and
(13) --C.sub.1-6 alkyl-CO.sub.2 --R.sup.5 ;
(c) mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1, 2, or 3 additional N atoms;
or
the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1, 2 or 3 additional N atoms;
said substituents are selected from the group consisting of
(1) hydrogen,
(2) halo, including fluoro, chloro, bromo and iodo,
(3) C.sub.1-6 alkyl,
(4) C.sub.1-6 alkoxy,
(5) C.sub.1-6 alkylthio,
(6) CN,
(7) CF.sub.3,
(8) N.sub.3,
(9) --C(R.sup.5)(R.sup.6)--OH, and
(10) --C(R.sup.5)(R.sup.6)--O--C.sub.1-4 alkyl;
R.sup.5 and R.sup.6 are each independently selected from the group consisting of
(a) hydrogen, and
(b) C.sub.1-6 alkyl,
or R.sup.5 and R.sup.6 or R.sup.7 and R.sup.8 together with the carbon to which they are attached form a monocyclic saturated carbon ring of 3, 4, 5, 6 or 7 atoms.

45 more elements

Facts

Application

08/436,672Filed 8 May 1995 · division

Priority

24 Jun 1993

Granted

16 Jul 1996

Term ends

Not estimatedThe source records don’t support an estimate.

Classification31 codes

C07D 275/02
Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings: not condensed with other rings
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…