US 5,817,700 AGranted

Bisaryl cyclobutenes derivatives as cyclooxygenase inhibitors

AssigneeMerck Frosst Canada, Inc.

InventorsDaniel Dube, Rejean Fortin, Richard Frenette, Richard Friesen, Daniel Guay, Sylvie Prescott

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.

Claims21

Dependent claims

A compound of formula I:

##STR18## or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently selected from the group consisting of
(a) H,
(b) halogen,
(c) hydroxy,
(d) C.sub.1-6 alkyl,
(e) C.sub.2-6 alkenyl,
(f) C.sub.2-6 alkynyl,
(g) C.sub.1-6 alkoxy,
(h) hydroxy C.sub.1-6 alkyl,
(i) C.sub.1-6 alkylthio,
(j) CN,
(k) COR.sup.5,
(l) OCOR.sup.6,
(m) OCONHR.sup.7, or
(n) a mono-, di- or tri-substituted phenyl, wherein the substituents are each independently R.sup.11 or R.sup.1 and R.sup.2 or R.sup.3 and R.sup.4 are joined together with the carbon atom to which they are attached to form C.dbd.O,
or R.sup.1 and R.sup.2 or R.sup.3 and R.sup.4 are joined together with the carbon atom to which they are attached to form C.dbd.S,
or R.sup.1 and R.sup.2 or R.sup.3 and R.sup.4 are joined together with the carbon atom to which they are attached to form C.dbd.CR.sup.8 R.sup.9,
or R.sup.1 and R.sup.2 or R.sup.3 and R.sup.4 are joined together with the carbon atom to which they are attached to form C.dbd.NR.sup.10,
or R.sup.1 and R.sup.2 or R.sup.3 and R.sup.4 are joined together with the carbon atom to which they are attached to form a saturated monocyclic ring of 3,4,5,6 or 7 carbon atoms,
Ar.sup.1 is mono-substituted phenyl or naphthyl wherein the substituent is R.sup.12 ;
Ar.sup.2 is mono-, di- or tri-substituted phenyl, wherein the substituents are each independently R.sup.11.
R.sup.5 is
(a) H,
(b) C.sub.1-6 alkyl, or
(c) C.sub.1-6 alkoxy;
R.sup.6 is
(a) C.sub.1-6 alkyl,
(b) C.sub.1-6 alkoxy, or
(c) mono-, di- or tri-substituted phenyl or pyridyl, wherein the substituents are each independently R.sup.11 ;
R.sup.7 is
(a) H,
(b) C.sub.1-6 alkyl, or
(c) mono-, di- or tri-substituted phenyl or pyridyl, wherein the substituents are each independently R.sup.11 ;
R.sup.8 and R.sup.9 are each independently
(a) H,
(b) hydroxyC.sub.1-6 alkyl,
(c) C.sub.1-6 alkyl,
(d) CN, or
(e) COR.sup.5 ;
R.sup.10 is
(a) hydroxy,
(b) C.sub.1-6 alkoxy,
(c) C.sub.1-6 alkyl, or
(d) substituted C.sub.1-6 alkyl or C.sub.1-6 alkoxy, wherein the substituent is a mono-, di- or tri-substituted phenyl or pyridyl and the substituents on the phenyl or pyridyl are R.sup.11 ;
R.sup.11 is
(a) H,
(b) halogen,
(c) C.sub.1-6 alkyl,
(d) hydroxy,
(e) hydroxy C.sub.1-6 alkyl,
(f) C.sub.1-6 alkoxy,
(g) CF.sub.3,
(h) CN,
(i) COR.sup.5, or
(j) S(O).sub.n R.sup.13 wherein n is 0, 1 or 2;
R.sup.12 is S(O).sub.n R.sup.13 or S(O).sub.2 NHR.sup.14 ;
R.sup.13 is C.sub.1-6 alkyl;
R.sup.14 is H or C.sub.1-6 alkyl.

55 more elements

A compound selected from the group consisting of:

(1) 4,4-Dichloro-3-(4-methylthiophenyl)-2-phenyl-2-cyclobuten-1-one;
(2) 4,4-Dichloro-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-one;
(3) 4-Chloro-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-one;
(4) 3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-one
(5) 4,4-Dichloro-3-(4-methylsulfonylphenyl)-2-(4-fluorophenyl)-2-cyclobuten-1- one;
(8) 4-Methyl-3-(4-methylsulfonylphenyl)-2,4-diphenyl-2-cyclobuten-1-one;
(9) 3-(4-Methylsulfonylphenyl)-2-phenylspiro4.6!-2-nonen-1-one;
(10) 3-(4-Methylsulfonylphenyl)-2-phenylspiro4.5!-2-octen-1-one;
(11) 3-(4-Methylsulfonylphenyl)-4-phenyl-3-cyclobuten-1,2-dione-2-(ethylene acetal);
(12) 3-(4-Methylsulfonylphenyl)-4-phenyl-3-cyclobuten-1,2-dione;
(13) 4-Methoxy-4-methyl-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-one;
(14) 4-Methoxy-4-butyl-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-one;
(15) (Z)-Methyl 4-(4-methylsulfonylphenyl)-3-phenyl-3-cyclobuten-2-one-1-ylidene!acetate;
(16) 4,4-Dimethyl-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-one;
(17) 4,4-Dimethyl-3-(4-methylsulfonylphenyl)-2-(3-fluorophenyl)-2-cyclobuten-1- one;
(18) 4,4-Dimethyl-3-(4-methylsulfonylphenyl)-2-(4-fluorophenyl)-2-cyclobuten-1- one;
(19) 4,4-Dimethyl-3-(4-methylsulfonylphenyl)-2-(3,5-difluorophenyl)-2-cyclobute n-1-one;
(20) 4,4-Dimethyl-3-(4-methylsulfonylphenyl)-2-(3,4-difluorophenyl)-2-cyclobute n-1-one;
(21) 4,4-Dimethyl-3-(4-methylthiophenyl)-2-phenyl-2-cyclobuten-1-one;
(22) 4,4-Dimethyl-3-(4-methylsulfinylphenyl)-2-phenyl-2-cyclobuten-1-one;
(23) 4,4-Dimethyl-3-(4-aminosulfonylphenyl)-2-phenyl-2-cyclobuten-1-one;
(25) 2-(4-methylsulfonylphenyl)-3-phenylspiro4.6!-2-nonen-1-one;
(26) 2-(4-methylsulfonylphenyl)-3-phenylspiro4.5!-2-octen-1-one;
(27) 2-(4-Methylsulfonylphenyl)-3-phenylspiro4.4!-2-hepten-1-one;
(28) 4,4-dimethyl-2-(4-methylsulfonylphenyl)-3-(3-fluorophenyl)-2-cyclobuten-1- one;
(29)4,4-dimethyl-2-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)-2-cyclobuten -1-one;
(30)4,4-dimethyl-2-(4-methylsulfonylphenyl)-3-phenyl-2-cyclobuten-1-one;
(31)4,4-dimethyl-2-(4-methylthiophenyl)-3-phenyl-2-cyclobuten-1-one;
(32) 4,4-Dimethyl-2-(4-methylsulfinylphenyl)-3-phenyl-2-cyclobuten-1-one;
(33) (trans)-2,2-Dimethyl-3,4-bis(4-methylthiophenyl)-1-cyclobutanone;
(34) 4-Methyl-2-(4-methylsulfonylphenyl)-3-phenyl-2-cyclobuten-1-one;
(35) 4-Isopropyl-2-(4-methylsulfonylphenyl)-3-phenyl-2-cyclobuten-1-one;
(36) 4,4-Dichloro-3-methylene-1-(4-methylsulfonylphenyl)-2-phenyl-1-cyclobutene ;
(37) Ethyl 4,4-dichloro-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-ylidene!a cetate;
(38) 4,4-Dichloro-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-ylidene!e thanol;
(39) 3-Methylene-1-(4-methylsulfonylphenyl)-2-phenyl-1-cyclobutene;
(40) (E)-Ethyl 3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-ylidene!acetate;
(41) (Z)-Ethyl 3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-ylidene!acetate;
(42) (Z) and (E)-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-ylidene!-2-propano l;
(43) (Z) and (E)-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-ylidene!-2-propano l;
(44) 4,4-Dimethyl-3-methylene-1-(4-methylsulfonylphenyl)-2-phenyl-1-cyclobutene ;
(45) 4,4-Dimethyl-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-one oxime;
(46) 4,4-Dimethyl-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-one t-butyloxime;
(47) 4,4-Dimethyl-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-one methyloxime;
(48) 4,4-Dimethyl-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-one benzyloxime;
(49) 1-N-Benzylimine-4,4-dimethyl-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobu tene;
(50) 4,4-Dimethyl-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-one 3-picolyloxime;
(51) 4,4-Dimethyl-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-one 2-picolyloxime;
(52) 4,4-Dimethyl-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-one (3-carbomethoxy)benzyl oxime;
(53) 4,4-Dimethyl-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1- one (3-carboxy)benzyl oxime;
(54) 3-(4-Methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-one oxime;
(55) 3-(4-Methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-one t-butyloxime;
(56) 4,4-Dimethyl-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-one methyloxime;
(57) 3-(4-Methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-one benzyloxime;
(58) 4,4-Dimethyl-2-(4-methylsulfonylphenyl)-3-phenyl-2-cyclobuten-1-one t-butyloximes;
(59) 4,4-Dimethyl-2-(4-methylsulfonylphenyl)-3-phenyl-2-cyclobuten-1-one benzyloxime;
(60) 1-(4-Methylsulfonylphenyl)-2-phenyl-1-cyclobutene;
(61) 1,4,4-Trimethyl-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-ol;
(62) 4,4-Dimethyl-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-ol;
(63) 4,4-Dimethyl-1-methoxy-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobutene;
(64) 4,4-Dimethyl-1-acetoxy-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobutene;
(65) 4,4-Dimethyl-1-pivaloxy-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobutene;
(66) 4,4-Dimethyl-1-fluoro-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobutene;
(67) 4,4-Dimethyl-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-ol N-phenylcarbamate;
(68) 4,4-Dimethyl-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-1-one (ethylenedithioacetal);
(69) 4,4-Dimethyl-2-(4-methylsulfonylphenyl)-3-phenyl-2-cyclobuten-1-ol;
(70) 4,4-Dimethyl-1-methoxy-2-(4-methylsulfonylphenyl)-3-phenyl-2-cyclobutene;
and
(71) 4,4-Dimethyl-1-acetoxy-2-(4-methylsulfonylphenyl)-3-phenyl-2-cyclobutene.

66 more elements

A compound of formula I:

##STR23## or a pharmaceutically acceptable salt thereof, wherein:
R.sup.1, R.sup.2,R.sup.3 and R.sup.4 are each independently selected from the group consisting of:
(a) H,
(b) halogen,
(c) hydroxy,
(d) C.sub.1-6 alkyl,
(e) C.sub.2-6 alkenyl,
(f) C.sub.2-6 alkynyl,
(g) C.sub.1-6 alkoxy,
(h) hydroxy C.sub.1-6 alkyl,
(i) C.sub.1-6 alkylthio,
(j) CN,
(k) COR.sup.5,
(l) OCOR.sup.6,
(m) OCONHR.sup.7 and
(n) a mono-, di- or tri-substituted phenyl, wherein the substituents are each independently R.sup.11 ;
or R.sup.1 and R.sup.2 or R.sup.3 and R.sup.4 are joined together with the carbon atom to which they are attached to form C.dbd.O,
or R.sup.1 and R.sup.2 or R.sup.3 and R.sup.4 are joined together with the carbon atom to which they are attached to form C.dbd.S,
or R.sup.1 and R.sup.2 or R.sup.3 and R.sup.4 are joined together with the carbon atom to which they are attached to form C.dbd.CR.sup.8 R.sup.9,
or R.sup.1 and R.sup.2 or R.sup.3 and R.sup.4 are joined together with the carbon atom to which they are attached to form C.dbd.NR.sup.10,
or R.sup.1 and R.sup.2 or R.sup.3 and R.sup.4 are joined together with the carbon atom to which they are attached to form a saturated monocyclic ring of 3,4,5,6 or 7 carbon atoms;
Ar.sup.1 is mono-substituted phenyl or naphthyl wherein the substituent is R.sup.12 ;
Ar.sup.2 is mono-, di- or tri-substituted phenyl, wherein the substituents are each independently R.sup.11 ;
R.sup.5 is selected from the group consisting of:
(a) H,
(b) C.sub.1-6 alkyl and
(c) C.sub.1-6 alkoxy;
R.sup.6 is selected from the group consisting of:
(a) C.sub.1-6 alkyl,
(b) C.sub.1-6 alkoxy and
(c) mono-, di- or tri-substituted phenyl, wherein the substituents are each independently R.sup.11 ;
R.sup.7 is selected from the group consisting of:
(a) H,
(b) C.sub.1-6 alkyl and
(c) mono-, di- or tri-substituted phenyl, wherein the substituents are each independently R.sup.11 ;
R.sup.8 and R.sup.9 are each independently selected from the group consisting of:
(a) H,
(b) hydroxy C.sub.1-6 alkyl,
(c) C.sub.1-6 alkyl,
(d) CN and
(e) COR.sup.5 ;
R.sup.10 is selected from the group consisting of:
(a) hydroxy,
(b) C.sub.1-6 alkoxy,
(c) C.sub.1-6 alkyl and
(d) substituted C.sub.1-6 alkyl or C.sub.1-6 alkoxy, wherein the substituent is a mono-, di- or tri-substituted phenyl and the substituent or substituents on the phenyl are R.sup.11 ;
R.sup.11 is selected from the group consisting of:
(a) H,
(b) halogen,
(c) C.sub.16 alkyl,
(d) hydroxy,
(e) hydroxy C.sub.1-6 alkyl,
(f) C.sub.1-6 alkoxy,
(g) CF.sub.3,
(h) CN,
(i) COR.sup.5 and
(j) S(O).sub.n R.sup.13 wherein n is 0, 1 or 2;
R.sup.12 is S(O).sub.n R.sup.13 or S(O).sub.2 NHR.sup.14 ;
R.sup.13 is C.sub.1-6 alkyl, and
R.sup.14 is H or C.sub.1-6 alkyl.

57 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/814,388Filed 11 Mar 1997
Granted: 6 Oct 1998
Term ends: Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07C 311/16
Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings: having the nitrogen atom of at least…
C07C 317/14
Sulfones; Sulfoxides: having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings
C07C 317/22
Having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton: with sulfone or sulfoxide groups bound to…
C07C 317/24
Sulfones; Sulfoxides: having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton

Family

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Abstract

A compound of formula I:

##STR18## or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently selected from the group consisting of
(a) H,
(b) halogen,
(c) hydroxy,
(d) C.sub.1-6 alkyl,
(e) C.sub.2-6 alkenyl,
(f) C.sub.2-6 alkynyl,
(g) C.sub.1-6 alkoxy,
(h) hydroxy C.sub.1-6 alkyl,
(i) C.sub.1-6 alkylthio,
(j) CN,
(k) COR.sup.5,
(l) OCOR.sup.6,
(m) OCONHR.sup.7, or
(n) a mono-, di- or tri-substituted phenyl, wherein the substituents are each independently R.sup.11 or R.sup.1 and R.sup.2 or R.sup.3 and R.sup.4 are joined together with the carbon atom to which they are attached to form C.dbd.O,
or R.sup.1 and R.sup.2 or R.sup.3 and R.sup.4 are joined together with the carbon atom to which they are attached to form C.dbd.S,
or R.sup.1 and R.sup.2 or R.sup.3 and R.sup.4 are joined together with the carbon atom to which they are attached to form C.dbd.CR.sup.8 R.sup.9,
or R.sup.1 and R.sup.2 or R.sup.3 and R.sup.4 are joined together with the carbon atom to which they are attached to form C.dbd.NR.sup.10,
or R.sup.1 and R.sup.2 or R.sup.3 and R.sup.4 are joined together with the carbon atom to which they are attached to form a saturated monocyclic ring of 3,4,5,6 or 7 carbon atoms,
Ar.sup.1 is mono-substituted phenyl or naphthyl wherein the substituent is R.sup.12 ;
Ar.sup.2 is mono-, di- or tri-substituted phenyl, wherein the substituents are each independently R.sup.11.
R.sup.5 is
(a) H,
(b) C.sub.1-6 alkyl, or
(c) C.sub.1-6 alkoxy;
R.sup.6 is
(a) C.sub.1-6 alkyl,
(b) C.sub.1-6 alkoxy, or
(c) mono-, di- or tri-substituted phenyl or pyridyl, wherein the substituents are each independently R.sup.11 ;
R.sup.7 is
(a) H,
(b) C.sub.1-6 alkyl, or
(c) mono-, di- or tri-substituted phenyl or pyridyl, wherein the substituents are each independently R.sup.11 ;
R.sup.8 and R.sup.9 are each independently
(a) H,
(b) hydroxyC.sub.1-6 alkyl,
(c) C.sub.1-6 alkyl,
(d) CN, or
(e) COR.sup.5 ;
R.sup.10 is
(a) hydroxy,
(b) C.sub.1-6 alkoxy,
(c) C.sub.1-6 alkyl, or
(d) substituted C.sub.1-6 alkyl or C.sub.1-6 alkoxy, wherein the substituent is a mono-, di- or tri-substituted phenyl or pyridyl and the substituents on the phenyl or pyridyl are R.sup.11 ;
R.sup.11 is
(a) H,
(b) halogen,
(c) C.sub.1-6 alkyl,
(d) hydroxy,
(e) hydroxy C.sub.1-6 alkyl,
(f) C.sub.1-6 alkoxy,
(g) CF.sub.3,
(h) CN,
(i) COR.sup.5, or
(j) S(O).sub.n R.sup.13 wherein n is 0, 1 or 2;
R.sup.12 is S(O).sub.n R.sup.13 or S(O).sub.2 NHR.sup.14 ;
R.sup.13 is C.sub.1-6 alkyl;
R.sup.14 is H or C.sub.1-6 alkyl.

55 more elements

Facts

Application

08/814,388Filed 11 Mar 1997

Granted

6 Oct 1998

Term ends

Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07C 311/16
Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings: having the nitrogen atom of at least…
C07C 317/14
Sulfones; Sulfoxides: having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings
C07C 317/22
Having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton: with sulfone or sulfoxide groups bound to…
C07C 317/24
Sulfones; Sulfoxides: having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton