US 5,750,549 A · Cycloalkyl tachykinin receptor antagonists

Abstract

The present invention is directed to certain novel compounds represented by structural formula I: ##STR1## or a pharmaceutically acceptable salt thereof, wherein R.sup.3, R.sup.6, R.sup.7, R.sup.8, R.sup.11, R.sup.12, R.sup.13, A, Q, W, X, Y, Z and n are defined herein. The invention is also concerned with pharmaceutical formulations comprising these novel compounds as active ingredients and the use of the novel compounds and their formulations in the treatment of certain disorders. The compounds of this invention are tachykinin receptor antagonists and are useful in the treatment of inflammatory diseases, pain or migraine, asthma and emesis.

A compound of the formula:

##STR153## or a pharmaceutically acceptable salt thereof, wherein:
the circle A:
##STR154## is selected from the group consisting of:
(A) phenyl,
(B) benzofuranyl,
(C) benzothiophenyl,
(D) benzothiazoyl,
(E) indolyl,
(F) imidazolyl,
(G) oxadiazolyl,
(H) pyridyl,
(I) pyrimidyl,
(J) quinolinyl,
(K) thiazolyl,
(L) thienyl,
(M) thiophenyl, and
(N) dihydrobenzofuranyl;
Q is selected from the group consisting of:
(1) hydrogen, and
(2) C.sub.1-6 alkyl;
W is selected from the group consisting of:
(1) --O--,
(2) --NH--,
(3) --N(C.sub.1-6 alkyl)--,
(4) --NH--CO--, and
(3) --N(C.sub.1-6 alkyl)--CO--,
wherein if W is --NHCO-- or --N(C.sub.1-6 alkyl)--CO--, then optionally Q and the carbon atom to which it is attached are absent;
X is selected from the group consisting of:
(1) hydrogen, and
(2) C.sub.1-6 alkyl;
Y is selected from the group consisting of:
(1) a single bond,
(2) C.sub.1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C.sub.1-6 alkoxy,
(d) phenyl-C.sub.1-3 alkoxy,
(e) phenyl,
(f) --CN,
(g) halo, wherein halo is fluoro, chloro, bromo or iodo,
(h) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are independently selected from:
(I) hydrogen,
(II) C.sub.1-6 alkyl,
(III) phenyl,
(IV) (C.sub.1-6 alkyl)-phenyl,
(V) (C.sub.1-6 alkyl)-hydroxy, and
(VI) (C.sub.1-6 alkyl)-(C.sub.1-4 alkoxy),
(i) --NR.sup.9 --COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,
(j) --NR.sup.9 --CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,
(k) --CO--NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above,
(l) --COR.sup.9, wherein R.sup.9 is as defined above, and
(m) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above;
Z is selected from the group consisting of:
(1) --NR.sup.15 --, wherein R.sup.15 is selected from the group consisting of:
(a) hydrogen;
(b) C.sub.1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(i) hydroxy,
(ii) oxo,
(iii) C.sub.1-6 alkoxy,
(iv) phenyl-C.sub.1-3 alkoxy,
(v) phenyl,
(vi) --CN,
(vii) halo,
(viii) --NR.sup.9 R.sup.10,
(ix) --NR.sup.9 --COR.sup.10,
(x) --NR.sup.9 --CO.sub.2 R.sup.10,
(xi) --CO--NR.sup.9 R.sup.10,
(xii) --COR.sup.9,
(xiii) --CO.sub.2 R.sup.9 ;
(c) phenyl, unsubstituted or substituted with one or more of the substituents selected from:
(i) hydroxy,
(ii) C.sub.1-6 alkoxy,
(iii) C.sub.1-6 alkyl,
(iv) C.sub.2-5 alkenyl,
(v) halo,
(vi) --CN,
(vii) --NO.sub.2,
(viii) --CF.sub.3,
(ix) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, wherein m is 0, 1 or 2,
(x) --NR.sup.9 --COR.sup.10,
(xi) --NR.sup.9 --CO.sub.2 R.sup.10,
(xii) --CO--NR.sup.9 R.sup.10,
(xiii) --CO.sub.2 --NR.sup.9 R.sup.10,
(xiv) --COR.sup.9,
(xv) --CO.sub.2 R.sup.9,
(2) --CO--NR.sup.15 --,
(3) --NR.sup.15 --CO--,
(4) --SO.sub.2 --NR.sup.15 --,
(5) --NR.sup.15 --SO.sub.2 --,
(6) --SO.sub.2 --,
(7) --CO--O--R.sup.15,
(8) --O--CO--R.sup.15,
(9) --CO--R.sup.15,
(10) --CH.sub.2 --OR.sup.15 ;
or if R.sup.3 is other than hydrogen, then Z is optionally absent;
or if X is other than hydrogen, then R.sup.15 and X may be joined together to form a 3- to 7-membered heterocyclic ring containing a group selected from:
--NR.sup.3 --, --CO--NR.sup.3 --, --NR.sup.3 --CO--, --SO.sub.2 --NR.sup.3 --, --NR.sup.3 --SO.sub.2 --, --SO.sub.2 --, --CO--O--, --O--CO--, --O--, and --CO--, and wherein the heterocyclic ring is optionally substituted with one or more of the substitutents selected from:
(i) hydroxy,
(ii) oxo,
(iii) C.sub.1-6 alkoxy,
(iv) phenyl-C.sub.1-3 alkoxy,
(v) phenyl,
(vi) --CN,
(vii) halo,
(viii) --NR.sup.9 R.sup.10,
(ix) --NR.sup.9 --COR.sup.10,
(x) --NR.sup.9 --CO.sub.2 R.sup.10,
(xi) --CO--NR.sup.9 R.sup.10,
(xii) --COR.sup.9,
(xiii) --CO.sub.2 R.sup.9 ;
R.sup.3 is selected from the group consisting of:
(1) hydrogen,
(2) --R.sup.5, and
(3) C.sub.1-6 alkyl substituted with --R.sup.5, and if Z is --CO--O--R.sup.15, --O--CO-R.sup.15, --CO--R.sup.15, or --CH.sub.2 --OR.sup.15, then R.sup.3 is absent;
R.sup.5 is selected from the group consisting of:
(1) hydroxy,
(2) C.sub.1-6 alkoxy,
(3) phenyl-C.sub.1-3 alkoxy,
(4) phenyl,
(5) --CN,
(6) halo,
(7) --NR.sup.9 R.sup.10,
(8) --NR.sup.9 --COR.sup.10,
(9) --NR.sup.9 --CO.sub.2 R.sup.10,
(10) --CO--NR.sup.9 R.sup.10,
(11) --COR.sup.9,
(12) --CO.sub.2 R.sup.9 ;
(13) heterocycle, wherein the heterocycle is selected from the group consisting of:
(A) benzimidazolyl,
(B) benzofuranyl,
(C) benzothiophenyl,
(D) benzoxazolyl,
(E) furanyl,
(F) imidazolyl,
(G) indolyl,
(H) isooxazolyl,
(I) isothiazolyl,
(J) oxadiazolyl,
(K) oxazolyl,
(L) pyrazinyl,
(M) pyrazolyl,
(N) pyridyl,
(O) pyrimidyl,
(P) pyrrolyl,
(Q) quinolyl,
(R) tetrazolyl,
(S) thiadiazolyl,
(T) thiazolyl,
(U) thienyl,
(V) triazolyl,
(W) azetidinyl,
(X) 1,4-dioxanyl,
(Y) hexahydroazepinyl,
(Z) piperazinyl,
(AA) piperidinyl,
(AB) pyrrolidinyl,
(AC) morpholinyl,
(AD) thiomorpholinyl,
(AE) dihydrobenzimidazolyl,
(AF) dihydrobenzofuranyl,
(AG) dihydrobenzothiophenyl,
(AH) dihydrobenzoxazolyl,
(AI) dihydrofuranyl
(AJ) dihydroimidazolyl,
(AK) dihydroindolyl,
(AL) dihydroisooxazolyl,
(AM) dihydroisothiazolyl,
(AN) dihydrooxadiazolyl,
(AO) dihydrooxazolyl,
(AP) dihydropyrazinyl,
(AQ) dihydropyrazolyl,
(AR) dihydropyridinyl,
(AS) dihydropyrimidinyl,
(AT) dihydropyrrolyl,
(AU) dihydroquinolinyl,
(AV) dihydrotetrazolyl,
(AW) dihydrothiadiazolyl,
(AX) dihydrothiazolyl,
(AY) dihydrothienyl,
(AZ) dihydrotriazolyl,
(BA) dihydroazetidinyl,
(BB) dihydro-1,4-dioxanyl,
(BC) tetrahydrofuranyl, and
(BD) tetrahydrothienyl,
and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C.sub.1-6 alkyl, unsubstituted or substituted with halo, --CF.sub.3, --OCH.sub.3, or phenyl,
(ii) C.sub.1-6 alkoxy,
(iii) oxo,
(iv) hydroxy,
(v) thioxo,
(vi) --SR.sup.9,
(vii) halo,
(viii) cyano,
(ix) phenyl,
(x) trifluoromethyl,
(xi) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10,
(xii) --NR.sup.9 COR.sup.10,
(xiii) --CONR.sup.9 R.sup.10,
(xiv) --CO.sub.2 R.sup.9, and
(xv) --(CH.sub.2).sub.m --OR.sup.9,
(14) --CO-heterocycle, wherein heterocycle is as defined above;
R.sup.6, R.sup.7 and R.sup.8 are independently selected from the group consisting of:
(1) hydrogen,
(2) C.sub.1-6 alkoxy,
(3) halo,
(4) C.sub.1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C.sub.1-6 alkoxy,
(d) phenyl-C.sub.1-3 alkoxy,
(e) phenyl,
(f) --CN,
(g) halo,
(h) --NR.sup.9 R.sup.10,
(i) --NR.sup.9 --COR.sup.10,
(j) --NR.sup.9 --CO.sub.2 R.sup.10,
(k) --CO--NR.sup.9 R.sup.10,
(l) --COR.sup.9,
(m) --CO.sub.2 R.sup.9,
(n) heterocycle, wherein heterocycle is as defined above,
(5) hydroxy,
(6) --CN,
(7) --CF.sub.3,
(8) --NO.sub.2,
(9) --SR.sup.14, wherein R.sup.14 is hydrogen or C.sub.1-6 alkyl,
(10) --SOR.sup.14,
(11) --SO.sub.2 R.sup.14,
(12) --NR.sup.9 --COR.sup.10,
(13) --CO--NR.sup.9 --COR.sup.10,
(14) --NR.sup.9 R.sup.10,
(15) --NR.sup.9 --CO.sub.2 R.sup.10,
(16) --COR.sup.9,
(17) --CO.sub.2 R.sup.9,
(18) heterocycle, wherein heterocycle is as defined above,
(19) --(C.sub.1-6 alkyl)-heterocycle, wherein heterocycle is as defined above,
(20) --N(heterocycle)--SO.sub.2 R.sup.14, wherein heterocycle is as defined above;
R.sup.11, R.sup.12 and R.sup.13 are independently selected from:
(1) hydrogen,
(2) C.sub.1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C.sub.1-6 alkoxy,
(d) phenyl-C.sub.1-3 alkoxy,
(e) phenyl,
(f) --CN,
(g) halo,
(h) --NR.sup.9 R.sup.10,
(i) --NR.sup.9 --COR.sup.10,
(j) --NR.sup.9 --CO.sub.2 R.sup.10,
(k) --CO--NR.sup.9 R.sup.10,
(l) --COR.sup.9,
(m) --CO.sub.2 R.sup.9 ;
(3) halo,
(4) --CN,
(5) --CF.sub.3,
(6) --NO.sub.2,
(7) hydroxy,
(8) C.sub.1-6 alkoxy,
(9) --COR.sup.9,
(10) --CO.sub.2 R.sup.9 ;
and
n is an integer selected from 1, 2 or 3;
with the proviso that if A is phenyl and W is --O--, --NH-- or --N(C.sub.1-6 alkyl)--, then at least one of the following four conditions must be met:
(1) Q is other than hydrogen
(2) Y is a single bond,
(3) X is other than hydrogen, or
(4) at least one of R.sup.6, R.sup.7 and R.sup.8 is heterocycle --(C.sub.1-6 alkyl)-heterocycle or --N(heterocycle)--SO.sub.2 R.sup.14 wherein heterocycle and R.sup.14 are as defined above.

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Cycloalkyl tachykinin receptor antagonists

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Cycloalkyl tachykinin receptor antagonists

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Abstract

Claims30