US 5,710,140 AGranted

Phenyl heterocycles as COX-2 inhibitors

AssigneeMerck Frosst Canada, Inc.

InventorsYves Ducharme, Jacques Yves 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.

Claims17

Dependent claims

A compound of formula I ##STR216## or a pharmaceutically acceptable salt thereof wherein:

X--Y--Z-- is selected from the group consisting of:
(a) --CH.sub.2 --NR.sup.3 --CH.sub.2 --,
(b) --CR.sup.5 (R.sup.5')--NR.sup.3 --C(O)--,
(c) --N.dbd.CR.sup.4 --NH--,
(d) --C(O)--NR.sup.3 --CR.sup.5 (R.sup.5')--,
(e) --NR.sup.3 --CH.dbd.CH-- provided R.sup.1 is other than --S(O).sub.2 Me, and
(f) --CH.dbd.CH--NR.sup.3 -- provided R.sup.1 is other than --S(O).sub.2 Me,
wherein side b is a double bond, and sides a and c are single bonds;
and
X--Y--Z-- is .dbd.CH--NR.sup.3 --CH.dbd.,
wherein sides a and c are double bonds and side b is a single bond;
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.1-6 alkyl,
(b) C.sub.3, C.sub.4, C.sub.5, C.sub.6, and C.sub.7, cycloalkyl,
(c) 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 ;
and
(d) 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) halo, including fluoro, chloro, bromo and iodo,
(2) C.sub.1-6 alkyl,
(3) C.sub.1-6 alkoxy,
(4) C.sub.1-6 alkylthio,
(5) CN,
(6) CF.sub.3,
(7) N.sub.3,
(8) --C(R.sup.5)(R.sup.6)--OH, and
(9) --C(R.sup.5)(R.sup.6)--O--C.sub.1-4 alkyl;
R.sup.3 is selected from the group consisting of
(a) hydrogen,
(b) CF.sub.3,
(c) CN,
(d) C.sub.1-6 alkyl,
(e) hydroxy C.sub.1-6 alkyl, and
(f) --C(O)--C.sub.1-6 alkyl,
(g) optionally substituted
(1) --C.sub.1-5 alkyl-Q,
(2) --C.sub.1-3 alkyl-O--C.sub.1-3 alkyl-Q,
(3) --C.sub.1-3 alkyl-S--C.sub.1-3 alkyl-Q,
(4) --C.sub.1-5 alkyl-O--Q, or
(5)--C.sub.1-5 alkyl-S--Q,
wherein the substituent resides on the alkyl and the substituent is C.sub.1-3 alkyl;
and
(h) --Q;
R.sup.4 is selected from the group consisting of
(a) hydrogen,
(b) CF.sub.3,
(c) CN,
(d) C.sub.1-6 alkyl,
(e) --Q,
(f) --O--Q;
(g) --S--Q, and
(h) optionally substituted
(1) --C.sub.1-5 alkyl-Q,
(2)--O--C.sub.1-5 alkyl-Q,
(3)--S--C.sub.1-5 alkyl-Q,
(4) --C.sub.1-3 alkyl-O-C.sub.13 alkyl-Q,
(5) --C.sub.1-3 alkyl-S--C.sub.1-3 alkyl-Q,
(6) --C.sub.1-5 alkyl-O--Q, or
(7) --C.sub.1-5 alkyl-S--Q,
wherein the substituent resides on the alkyl and the substituent is C .sub.1-3 alkyl, and
R.sup.5 and R.sup.6, R.sup.7 and R.sup.8 are each independently selected from the group consisting of
(a) hydrogen,
(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;
Q is CO.sub.2 H, CO.sub.2 -C.sub.1-4 alkyl, tetrazolyl-5-yl, C(R.sup.7)(R.sup.8)(OH), or C(R.sup.7)(R.sup.8)(O--C.sub.1-4 alkyl).

86 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/699,142Filed 16 Aug 1996 · continuation
Priority: 24 Jun 1993
Granted: 20 Jan 1998
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
Serial436,758Parent of this continuation · filed 8 May 1995
US 5,474,995 AParent of this division
US 5,710,140 AThis patent

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

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

A compound of formula I ##STR216## or a pharmaceutically acceptable salt thereof wherein:

X--Y--Z-- is selected from the group consisting of:
(a) --CH.sub.2 --NR.sup.3 --CH.sub.2 --,
(b) --CR.sup.5 (R.sup.5')--NR.sup.3 --C(O)--,
(c) --N.dbd.CR.sup.4 --NH--,
(d) --C(O)--NR.sup.3 --CR.sup.5 (R.sup.5')--,
(e) --NR.sup.3 --CH.dbd.CH-- provided R.sup.1 is other than --S(O).sub.2 Me, and
(f) --CH.dbd.CH--NR.sup.3 -- provided R.sup.1 is other than --S(O).sub.2 Me,
wherein side b is a double bond, and sides a and c are single bonds;
and
X--Y--Z-- is .dbd.CH--NR.sup.3 --CH.dbd.,
wherein sides a and c are double bonds and side b is a single bond;
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.1-6 alkyl,
(b) C.sub.3, C.sub.4, C.sub.5, C.sub.6, and C.sub.7, cycloalkyl,
(c) 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 ;
and
(d) 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) halo, including fluoro, chloro, bromo and iodo,
(2) C.sub.1-6 alkyl,
(3) C.sub.1-6 alkoxy,
(4) C.sub.1-6 alkylthio,
(5) CN,
(6) CF.sub.3,
(7) N.sub.3,
(8) --C(R.sup.5)(R.sup.6)--OH, and
(9) --C(R.sup.5)(R.sup.6)--O--C.sub.1-4 alkyl;
R.sup.3 is selected from the group consisting of
(a) hydrogen,
(b) CF.sub.3,
(c) CN,
(d) C.sub.1-6 alkyl,
(e) hydroxy C.sub.1-6 alkyl, and
(f) --C(O)--C.sub.1-6 alkyl,
(g) optionally substituted
(1) --C.sub.1-5 alkyl-Q,
(2) --C.sub.1-3 alkyl-O--C.sub.1-3 alkyl-Q,
(3) --C.sub.1-3 alkyl-S--C.sub.1-3 alkyl-Q,
(4) --C.sub.1-5 alkyl-O--Q, or
(5)--C.sub.1-5 alkyl-S--Q,
wherein the substituent resides on the alkyl and the substituent is C.sub.1-3 alkyl;
and
(h) --Q;
R.sup.4 is selected from the group consisting of
(a) hydrogen,
(b) CF.sub.3,
(c) CN,
(d) C.sub.1-6 alkyl,
(e) --Q,
(f) --O--Q;
(g) --S--Q, and
(h) optionally substituted
(1) --C.sub.1-5 alkyl-Q,
(2)--O--C.sub.1-5 alkyl-Q,
(3)--S--C.sub.1-5 alkyl-Q,
(4) --C.sub.1-3 alkyl-O-C.sub.13 alkyl-Q,
(5) --C.sub.1-3 alkyl-S--C.sub.1-3 alkyl-Q,
(6) --C.sub.1-5 alkyl-O--Q, or
(7) --C.sub.1-5 alkyl-S--Q,
wherein the substituent resides on the alkyl and the substituent is C .sub.1-3 alkyl, and
R.sup.5 and R.sup.6, R.sup.7 and R.sup.8 are each independently selected from the group consisting of
(a) hydrogen,
(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;
Q is CO.sub.2 H, CO.sub.2 -C.sub.1-4 alkyl, tetrazolyl-5-yl, C(R.sup.7)(R.sup.8)(OH), or C(R.sup.7)(R.sup.8)(O--C.sub.1-4 alkyl).

86 more elements

Facts

Application

08/699,142Filed 16 Aug 1996 · continuation

Priority

24 Jun 1993

Granted

20 Jan 1998

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

Serial436,758Parent of this continuation · filed 8 May 1995

US 5,474,995 AParent of this division

US 5,710,140 AThis patent

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