US 2004/0002504 A1 · N-(3-(4-substituted-1-piperidinyl)-1-phenylpropyl) substituted sulfonamides as NK-3 receptor antagonists

Abstract

The present invention provides a method of treatment of a subject suffering from a disease, such as schizophrenia, for which the administration of an NK-3 antagonist is indicated which comprises administering to that subject a therapeutically effective amount of a compound of formula I: 1 wherein, generally, Q is 2 R1 is benzyl, phenyl, thiophene or imidazolyl optionally substituted with C1-4alkyl or halogen, such as methyl, fluorine or bromine; R2 is hydrogen or C1-4alkyl such as methyl; R3 is phenyl; R4 is hydrogen; R5 is hydrogen or C1-6alkylcarbonyl such as methylcarbonyl; X is —SO2— or —C(O)N(R2)SO2— where R2 is preferably hydrogen; Y is a bond, CH2 or Z1 where Z1 is —N(Rf)— in which Rf is C1-6alkylcarbonyl such as ethylcarbonyl; and R6 is phenyl, pyrazolyl, pyridyl, pyrimidinyl or benzimidazolonyl optionally substituted with one or two groups chosen from C1-6alkyl and benzyl, such as methyl, ethyl and benzyl; or a pharmaceutically acceptable salt thereof.

A method of treatment of a subject suffering from a disease for which the administration of an NK-3 antagonist is indicated which comprises administering to that subject a therapeutically effective amount of a compound of Formula (I):

52
wherein
Q is
53
wherein denotes the point of attachment;
R1 is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C5-8 cycloalkenyl, —O—C3-8 cycloalkyl, —NRaRb, phenyl, naphthyl, or heterocycle;
wherein any one of which except —NRaRb is optionally substituted with one or more substituents independently selected from:
(a) halo,
(b) cyano,
(c) —OH,
(d) C1-6 alkyl,
(e) —O—C1-6 alkyl,
(f) C1-6 haloalkyl,
(g) —O—C1-6 haloalkyl,
(h) C3-6 cycloalkyl,
(i) —O—C3-6 cycloalkyl,
(j) C2-6 alkenyl,
(k) —NO2,
(l) phenyl, which is optionally substituted with one or more sustituents independently selected from C1-4 alkyl, —O—C1-4 alkyl, halo, and —CO2Rc,
(m) —CO2Rc,
(n) —NRcRd,
(o) —NRc—CORd,
(p) —NRc—CO2Rd,
(q) —CO—NRcRd,
(r) —OCO—NRcRd,
(s) —NRcCO—NRcRd,
(t) —S(O)p—Rc,
(u) —S(O)2—NRcRd,
(v) —NRcS(O)2—Rd,
(w) —NRcS(O)2—NRcRd,
(x) oxo,
(y) heterocyclyl, which is optionally substituted with one or more substituents independently selected from C1-4 alkyl, —O—C1-4 alkyl, halo, —CO2Rc, and oxo,
(z) —C5-7 cycloalkenyl, and
(aa) —C(═O)Rc;
X is —SO2— or —C(═O)N(Re)SO2—;
R2 is hydrogen or C1-8 alkyl which is optionally substituted with one or more substituents independently selected from halo, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, C3-6 cycloalkyl, and —O—C3-6 cycloalkyl;
or alternatively R1 and R2 together with the N to which R2 is attached and the X, as defined above, to which R1 is attached, form a 4- to 8-membered monocyclic ring containing from 1 to 3 nitrogen atoms, zero to 2 oxygen atoms, and zero to 2 sulfur atoms;
wherein the ring is optionally substituted on one or more ring carbons with one or more substituents independently selected from:
(a) halo,
(b) cyano,
(c) —OH,
(d) C1-6 alkyl,
(e) —O—C1-6 alkyl,
(f) C1-6 haloalkyl, and
(g) —S(O)p—Rc;
R3 is hydrogen, —CO—NRcRd, or C1-4 alkyl;
wherein the alkyl is optionally substituted with one or more substituents independently selected from halo, —OH, —O—C1-4 alkyl, or —O—C1-4 haloalkyl;
R4 is phenyl, naphthyl, or heterocycle, any one of which is optionally substituted with one or more substituents independently selected from
(a) halo,
(b) —CN,
(c) —OH,
(d) C1-6 alkyl,
(e) —O—C1-6 alkyl,
(f) C1-6 haloalkyl,
(g) —NO2,
(h) phenyl,
(i) —CO2Rc,
(j) —NRcRd,
(k) —NRc—CORd,
(l) —NRc—CO2Rd,
(m) —CO—NRcRd,
(n) —OCO—NRcRd,
(o) —NRcCO—NRcRd,
(p) —S(O)p—Rc, wherein p is an integer selected from 0, 1 and 2,
(q) —S(O)2—NRcRd,
(r) —NRcS(O)2—Rd,
(s) —NRcS(O)2—NRcRd,
(t) C3-6 cycloalkyl,
(u) —O—C3-6 cycloalkyl,
(v) —O—C1-6 haloalkyl,
(w) C2-6 alkenyl and
(x) oxo;
R5 is:
(1) hydrogen,
(2) C1-6 alkyl, which is optionally substituted with 1-4 substituents independently selected from —OH, cyano, and halo,
(3) cyano,
(4) —OH,
(5) halo, or
(6) C1-6alkylcarboxy;
Y is:
(1) a direct single bond;
(2) —C1-10 alkyl- or —(C0-6 alkyl)C3-6cycloalkyl(C0-6 alkyl)-, either of which is optionally substituted with 1-7 substituents independently selected from:
(a) halo,
(b) —OH,
(c) —O—C1-3 alkyl,
(d) trifluoromethyl,
(e) —(C1-3 alkyl)hydroxy, and
(f) ethylenedioxy;
(3) —(C0-6 alkyl)-Z1-(C0-6 alkyl)-, wherein each alkyl is optionally substituted with 1-7 substituents independently selected from:
(a) halo,
(b) —OH,
(c) —O—C1-3 alkyl, and
(d) trifluoromethyl;
and where Z1 is selected from —SO2—, —N(Rf)—, —N(Rf)C(═CHRu)N(Rf)—, —N(Rf)C(═NRu)N(Rf)—, —S—, —O—, —SO—, —SO2N(Rf)—, —N(Rf)SO2—, and —PO2—;
(4) —(C0-6 alkyl)-Z2-(C0-6 alkyl)-, wherein each alkyl is optionally substituted with 1-7 substituents independently selected from:
(a) halo,
(b) —OH,
(c) —O—C1-3 alkyl, and
(d) trifluoromethyl;
and where Z2 is selected from —C(═O)—, —C(═O)O—, —OC(═O)—, —C(—O)NRg—, —NRgC(═O)—, —OC(═O)NRg—, —NRgC(═O)O—, and —NRhC(═O)NRg—;
R6 is phenyl, naphthyl, indanyl, tetrahydronaphthyl, biphenyl, or heterocycle;
wherein any one of which is optionally substituted with 1-7 substituents independently selected from:
(a) halo,
(b) cyano,
(c) —OH,
(d) C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R7,
(e) —O—C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R7,
(f) —O—phenyl, which is unsubstituted or substituted with 1-5 of R8,
(g) —O-heterocycle, which is unsubstituted or substituted with 1-5 of R8,
(h) —NO2,
(i) phenyl,
(j) —CO2Rs,
(k) tetrazolyl,
(l) —NRsRt,
(m) —NRs—CORt,
(n) —NRs—CO2Rt,
(o) —CO—NRsRt,
(p) —OCO—NRsRt,
(q) —NRsCO—NRsRt,
(r) —S(O)p—Rs,
(s) —S(O)2—NRsRt,
(t) —NRsS(O)2—Rt,
(u) —NRsS(O)2—NRsRt,
(v) C2-6 alkenyl,
(w) furanyl, which is unsubstituted or substituted with benzyl which is unsubstituted or substituted with 1-7 of R8,
(x) —C3-6 cycloalkyl, and
(y) —O—C3-6 cycloalkyl;
each R7 is independently halo, cyano, —OH, —O—C1-6 alkyl, —C3-6 cycloalkyl, —CO2H, —CO2—(C1-6 alkyl), —CF3, —SO2Rs, —NRsRt, phenyl, naphthyl, biphenyl, or heterocycle;
wherein phenyl, naphthyl, biphenyl, or heterocycle is optionally substituted with 1-7 of R8;
each R8 is independently halo, cyano, —OH, C1-6 alkyl, C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —CO2H, —CO2(C1-6 alkyl), —NRsRt, —(C1-6 alkyl)-NRsRt, —SO2Rs, —N(Rs)SO2Rt, —N(Rs)CORt, —(C1-6 alkyl)-OH, —O—C3-6 cycloalkyl, benzyloxy, phenoxy, or —NO2;
each of Ra and Rb is independently C1-6 alkyl which is optionally substituted with one or more substituents independently selected from C3-6 cycloalkyl, halo, CF3, —O—C1-6 alkyl, and —O—C3-6 cycloalkyl;
each Rc is independently hydrogen or C1-4 alkyl;
each Rd is independently hydrogen or C1-4 alkyl;
Re is hydrogen or C1-4 alkyl;
Rf is hydrogen, C1-6 alkyl, C2-6 alkenyl, benzyl, phenyl, C(O)C1-6 alkyl, —SO2-C1-6 alkyl, —SO2-phenyl, —SO2-heterocycle, or C1-6 alkyl-C3-6 cycloalkyl;
wherein any of which except hydrogen is optionally substituted with 1-3 substituents independently selected from halo, C1-3 alkyl, —O—C1-3 alkyl and trifluoromethyl;
Rg is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, benzyl, phenyl, or C1-6 alkyl-C3-6 cycloalkyl;
wherein any of which except hydrogen is optionally substituted with 1-3 substituents independently selected from halo, C1-3 alkyl, —O—C1-3 alkyl and trifluoromethyl;
Rh is hydrogen or C1-6 alkyl;
each Rs is independently hydrogen, C1-6 alkyl, C5-6 cycloalkyl, benzyl or phenyl;
wherein any of which except hydrogen is optionally substituted with 1-3 substituents independently selected from halo, C1-3 alkyl, —O—C1-3 alkyl and trifluoromethyl;
each Rt is independently hydrogen, C1-6 alkyl, C5-6 cycloalkyl, benzyl or phenyl;
wherein any of which except hydrogen is optionally substituted with 1-3 substituents independently selected from halo, C1-3 alkyl, —O—C1-3 alkyl and trifluoromethyl;
Ru is hydrogen, C1-4 alkyl, —NO2 or —CN;
and
each p is independently an integer equal to 0, 1, or 2;
and with the proviso that when Q is
54
and Y is a direct single bond, then R6 is phenyl, naphthyl, indanyl, tetrahydronaphthyl, biphenyl, or a heterocycle selected from pyrazolyl and tetrahydropyridopyrazolyl;
wherein any one of which is optionally substituted as defined above;
or a pharmaceutically acceptable salt thereof.

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N-(3-(4-substituted-1-piperidinyl)-1-phenylpropyl) substituted sulfonamides as NK-3 receptor antagonists

Life of this patent

N-(3-(4-substituted-1-piperidinyl)-1-phenylpropyl) substituted sulfonamides as NK-3 receptor antagonists

Life of this patent

Abstract

Claims8