US 5,710,170 AGranted

Tri-aryl ethane derivatives as PDE IV inhibitors

AssigneeMerck Frosst Canada, Inc.

InventorsDaniel Guay, Yves Girard, Yves Ducharme, Marc Blouin, Pierre Hamel, Mario Girard

Life of this patent

Estimating the term…

Abstract

The invention encompasses the novel compound of Formula I useful in the treatment of diseases, including asthma, by raising the level of cyclic adenosine-3',5'-monophosphate (cAMP) through the inhibition of phosphodiesterase IV (PDE IV). ##STR1## The invention also encompasses certain pharmaceutical compositions and methods for treatment of diseases by inhibition of PDE IV, resulting in an elevation of cAMP, comprising the use of compounds of Formula I.

Claims9

Dependent claims

A compound of formula I ##STR11## or a pharmaceutically acceptable salt thereof wherein:

R is selected from
(a) hydrogen,
(b) C.sub.1-6 alkyl,
(c) halo and
(d) CF.sub.3 ;
R.sup.1 is selected from
--(CH.sub.2).sub.m --CO--N(R.sup.4)--S(O).sub.2 --R.sup.5, wherein m is 0, 1 or 2,
--(CH.sub.2).sub.m --CO--N(R.sup.4)--S(O).sub.2 --NR.sup.6 R.sup.7,
--(CH.sub.2).sub.m --S(O).sub.2 --N (R.sup.4)--CO--R.sup.4,
--(CH.sub.2).sub.m --S(O).sub.2 --N(R.sup.4)--CO--NR.sup.6 R.sup.7,
--C(OH)(C.sub.1-6 haloalkyl).sub.2,
R.sup.2 and R.sup.3 are independently selected from
(a) C.sub.1-7 alkyl,
(b) substituted C.sub.1-7 alkyl, wherein the substituent is F, Cl, Br or I,
(c) 2-phenethyl or 2-indanyl, optionally mono or di-substituted, wherein the substituents on the benzene ring are independently selected from the group consisting of
(1) halo,
(2) C.sub.1-6 alkoxy,
(3) C.sub.1-6 alkylthio,
(4) CN,
(5) CF.sub.3,
(6) C.sub.1-6 alkyl,
(7) N.sub.3,
(8) --CO.sub.2 H,
(d) C.sub.3-6 cycloalkyl,
R.sup.4 is selected from
(a) hydrogen,
(b) C.sub.1-6 alkyl,
(c) phenyl, benzyl or 2-phenethyl, optionally mono or di-substituted, wherein the substituents on the benzene ring are independently selected from the group consisting of
(1) halo,
(2) C.sub.1-6 alkoxy,
(3) C.sub.1-6 alkylthio,
(4) CN,
(5) CF.sub.3,
(6) C.sub.1-6 alkyl,
(7) N.sub.3,
(8) --CO.sub.2 H,
R.sup.5, R.sup.8 and R.sup.11 are each independently selected from
(a) --CF.sub.3,
(b) C.sub.1-6 alkyl,
(c) phenyl, benzyl or 2-phenethyl, optionally mono or di-substituted, wherein the substituents on the benzene ring are independently selected from the group consisting of
(1) halo,
(2) C.sub.1-6 alkoxy,
(3) C.sub.1-6 alkylthio,
(4) CN,
(5) CF.sub.3,
(6) C.sub.1-6 alkyl,
(7) N.sub.3,
(8) --CO.sub.2 H,
R.sup.6, R.sup.7, R.sup.9 and R.sup.10 are each independently selected from
(a) hydrogen, and
(b) C.sub.1-6 alkyl, or
R.sup.6 and R.sup.7 may be joined to form a saturated 5, 6 or 7 membered heterocycle, said heterocycle containing a heteroatom which is nitrogen and optionally containing an additional hetero atom which is an O or an S atom or NR.sup.4 , and optionally containing a carbonyl group;
HET is selected from
pyridyl and imidazolyl, optionally mono-, or disubstituted, wherein the substituents are independently selected from halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, benzyl, 2-phenethyl, NHCOR.sup.8, NR.sup.9 R.sup.10, NHS(O).sub.2 R.sup.11, OH, CN, or CF.sub.3, and the N-oxides thereof;
and
X is selected from N, N.fwdarw.O or CH.

53 more elements

Dependencies are inferred from the claim text.

patentgrep

Loading patent…

Abstract

A compound of formula I ##STR11## or a pharmaceutically acceptable salt thereof wherein:

R is selected from
(a) hydrogen,
(b) C.sub.1-6 alkyl,
(c) halo and
(d) CF.sub.3 ;
R.sup.1 is selected from
--(CH.sub.2).sub.m --CO--N(R.sup.4)--S(O).sub.2 --R.sup.5, wherein m is 0, 1 or 2,
--(CH.sub.2).sub.m --CO--N(R.sup.4)--S(O).sub.2 --NR.sup.6 R.sup.7,
--(CH.sub.2).sub.m --S(O).sub.2 --N (R.sup.4)--CO--R.sup.4,
--(CH.sub.2).sub.m --S(O).sub.2 --N(R.sup.4)--CO--NR.sup.6 R.sup.7,
--C(OH)(C.sub.1-6 haloalkyl).sub.2,
R.sup.2 and R.sup.3 are independently selected from
(a) C.sub.1-7 alkyl,
(b) substituted C.sub.1-7 alkyl, wherein the substituent is F, Cl, Br or I,
(c) 2-phenethyl or 2-indanyl, optionally mono or di-substituted, wherein the substituents on the benzene ring are independently selected from the group consisting of
(1) halo,
(2) C.sub.1-6 alkoxy,
(3) C.sub.1-6 alkylthio,
(4) CN,
(5) CF.sub.3,
(6) C.sub.1-6 alkyl,
(7) N.sub.3,
(8) --CO.sub.2 H,
(d) C.sub.3-6 cycloalkyl,
R.sup.4 is selected from
(a) hydrogen,
(b) C.sub.1-6 alkyl,
(c) phenyl, benzyl or 2-phenethyl, optionally mono or di-substituted, wherein the substituents on the benzene ring are independently selected from the group consisting of
(1) halo,
(2) C.sub.1-6 alkoxy,
(3) C.sub.1-6 alkylthio,
(4) CN,
(5) CF.sub.3,
(6) C.sub.1-6 alkyl,
(7) N.sub.3,
(8) --CO.sub.2 H,
R.sup.5, R.sup.8 and R.sup.11 are each independently selected from
(a) --CF.sub.3,
(b) C.sub.1-6 alkyl,
(c) phenyl, benzyl or 2-phenethyl, optionally mono or di-substituted, wherein the substituents on the benzene ring are independently selected from the group consisting of
(1) halo,
(2) C.sub.1-6 alkoxy,
(3) C.sub.1-6 alkylthio,
(4) CN,
(5) CF.sub.3,
(6) C.sub.1-6 alkyl,
(7) N.sub.3,
(8) --CO.sub.2 H,
R.sup.6, R.sup.7, R.sup.9 and R.sup.10 are each independently selected from
(a) hydrogen, and
(b) C.sub.1-6 alkyl, or
R.sup.6 and R.sup.7 may be joined to form a saturated 5, 6 or 7 membered heterocycle, said heterocycle containing a heteroatom which is nitrogen and optionally containing an additional hetero atom which is an O or an S atom or NR.sup.4 , and optionally containing a carbonyl group;
HET is selected from
pyridyl and imidazolyl, optionally mono-, or disubstituted, wherein the substituents are independently selected from halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, benzyl, 2-phenethyl, NHCOR.sup.8, NR.sup.9 R.sup.10, NHS(O).sub.2 R.sup.11, OH, CN, or CF.sub.3, and the N-oxides thereof;
and
X is selected from N, N.fwdarw.O or CH.

53 more elements