CA2269858A1 - Substituted oximes, hydrazones and olefins as neurokinin antagonists - Google Patents

Abstract

Compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof, wherein: a is 0, 1, 2 or 3; b, d and e are independently 0, 1 or 2; R is H, C1-6 alkyl, -OH or C2-C6 hydroxyalkyl; A is an optionally substituted oxime, hydrazone or olefin; X is a bond, -C(O)-, -O-, -NR6-, -S(O)e-, -N(R6)C(O)-, -C(O)N(R6)-, -OC(O)NR6-, -OC(=S)NR6-, N(R6)C(=S)O-, -C(=NOR1)-, -S(O)2N(R6)-, -N(R6)S(O)2-, -N(R6)C(O)O- or -OC(O)-; T is H, phthalimidyl, aryl, heterocycloalkyl, heteroaryl, cycloalkyl or bridged cycloalkyl; Q is -SR6, -N(R6)(R7), -OR6, phenyl, naphthyl or heteroaryl; R6a, R7a, R8a, R9a, R6 and R7 are H, C1-6 alkyl, C2-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, phenyl or benzyl; or R6 and R7, together with the nitrogen to which they are attached, form a ring; R9a is R6 or -OR6; and Z is spiro-substituted piperidinyl or substituted piperazinyl wherein aryl, heterocycloalkyl, heteroaryl, cycloalkyl and bridged cycloalkyl groups are optionally substituted; methods of treating asthma, cough, bronchospasm, inflammatory diseases, and gastrointestinal disorders with said compounds, and pharmaceutical compositions comprising said compounds are disclosed.

Description

SUBSTITUTED OXIMES. ~iYDRAZONES AND OLEFINS AS
NEUROKININ ANTAGONISTS
BACKGROUND OF THE INVENTION
The present invention relates to a genus of substituted oximes, hydrazones and olefins useful as ahtagonists of tachykinin receptors, in particular as antagonists of the neuropeptides neurokinin-1 receptor (NK~ ) and/or neurokinin-2 receptor (NK2) and/or neurokinin-3 receptor (NK3).
Neurokinin receptors are found in the nervous system and the circulatory system and peripheral tissues of mammals, and therefore are involved in a variety of biological processes. Neurokinin receptor antagonists are consequently expected to be useful in the treatment or prevention of various mammalian disease states, for example asthma, cough, bronchospasm, inflammatory diseases such as arthritis) central nervous system conditions such as migraine and epilepsy) nociception, and various gastrointestinal disorders such as Crohn's disease.
In particular, NK1 receptors have been reported to be involved in microvascular leakage and mucus secretion, and NK2 receptors have been associated with smooth muscle contraction, making NK1 and NK2 receptor antagonists especially useful in the treatment and prevention of asthma.
Some NK1 and NK2 receptor antagonists have previously been disclosed: arylalkylamines were disclosed in U.S. Patent 5,350,852, issued September 27, 1994, spiro-substituted azacycles were disclosed in WO 94l29309, published December 22, 1994, and in WO 94l17045, published August 4, 1994; substituted aryl piperazines were disclosed in WO 96/10568, published April 11, 1996.

SUMMARY OF THE INVENTION
Compounds of the present invention are represented by the formula I
Rsa Rsa a i ~ X~C~ T
Q R7a Rea or a pharmaceutically acceptable salt thereof, wherein:
a is 0, 1, 2 or 3;
b and d are independently 0, 1 or 2;
R is H, C1-s alkyl, -ORs or C2-C6 hydroxyalkyl;
A is =N-ORS ~ =N-N(R2)(R3), =C(R> >)(R12) or -NR25;
X is a bond, -C(O)-, -O-, -NRs-) -S(O)e-, -N(Rs)C(O)-, -C(O}N(Rs)--OC(O)NRs-, -OC(=S}NRs-, -N(Rs)C(=S)O-, -C(=NOR1}-, -S(O)2N(Rs)-, -N(Rs}S(O)2-, -N(Rs)C(O)O- or -OC(O)-, provided that when d is 0, X is a bond, -C(O)-) -NRs-, -C(O)N(Rs~)-, -N(Rs)C(O)-, -OC(O)NRs-, -C(=NORM)-, -N(Rs)C(=S)O-, -OC(=S)NRs-, -N(Rs)S(O)2- or -N(Rs)C(O)O-; provided that when A is =C(R~ ~)(R~2) and d is 0, X is not -NRs- or -N(Rs)C(O)-; and provided that when A is =NR25, d is 0 and X is -NRs- or -N(Rs)C(O)-;
T is H) R4-aryl) R4-heterocycloalkyl, R4-heteroaryl, phthalimidyl) R4-cycloalkyl or R~o-bridged cycloalkyl;
Q is R5-phenyl, R~-naphthyl) -SRs, -N{Rs)(R~), -ORs or R5-hetero-aryl, provided that when Q is -SRs) -N(Rs)(R~) or -ORs) R is not -OR6;
R~ is H, C1_s alkyl, -(C(Rs)(R~))n-G~ -G2~ -(C{Rs){R~))p-M_ {C{R13)(R14))n-{C(R8)(R9))u-G, -C(O)N(Rs)'{C{R~3){R14))n-(C(R8){R9))u-G
or -(C(Rs)(R~))p-M-(R4-heteroaryl);
R2 and R3 are independently selected from the group consisting of H, C~_s alkyl) -CN) -(C(Rs)(R~))"-G, -G2, -C(O)-(C(R8)(Rg))~-G and -S(O)eRj3; or R2 and R3, together with the nitrogen to which they are attached, form a ring of 5 to 6 members) wherein 0, 1 or 2 ring members are selected from the group consisting of -O-) -S- and -N(R~9)-;
R4 and R5 are independently 1-3 substituents independently selected from the group consisting of H, halogeno) -ORs, -OC(O)Rs, -OC(O)N(Rs){R~)~ -N{Rs)(R~), C~-s alkyl, -CF3) -C2F5, -CORs) -C02Rs, -CON(Rs)(R~)) -S(O)eR~3, -CN) -OCF3, -NR6CO2Ris, -NR6COR~, -NR8CON{Rs)(R~), R~5-phenyl) R~5-benzyl) N02, -N(Rs)S(O)2R13 or -S(O)2N(Rs)(R~); or adjacent R4 substituents or adjacent R5 substituents can form a -O-CH2-O- group; and R4 can also be R~s-heteroaryl;

R6, R~, R8, Rsa, R7a, R8a) R~3 and R~4 are independently selected from the group consisting of H, C1_6 alkyl, C2-Cs hydroxyalkyl, C1-C6 alkoxy-C~-C6 alkyl, R~5-phenyl) and R15-benzyl; or R6 and R~, together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0) 1 or 2 ring members are selected from the group consisting of -O-) -S- and -N(R~9)-;
R9 and Rga are independently selected from the group consisting of R6 and -OR6 R~o and R~oa are independently selected from the group consisting of H and C1-6 alkyl;
R> > and R12 are independently selected from the group consisting of H, Ci-C6 alkyl, -C02R6, -OR6, -C(O)N(R6)(R~)) C~-C6 hydroxyalkyl, -(CH2)r-OC{O)R6, -(CH2)r-OC(O)CH=CH2, -(CH2)r-O(CH2)s-C02R6, -(CH2)r0-(CH2)s-C(~)N(R6)(R~) and -(CH2)rN(R6)(R~);
R15 is 1 to 3 substituents independently selected from the group consisting of H) C~-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogeno) -CF3, -C2F5, -COR~o, -C02R~o, -C{O)N(R~o)2) _S(O)eRlOa~ _CN, -N(R~o)COR~o, -N(R~o)CON(R~o)2 and -N02;
R16 is C~_s alkyl, R~5-phenyl or R~5-benzyl;
R~9 is H, C1-C6 alkyl) -C(O)N(R~o)2, -CO2Rlo, -(C(R8){R9))t-C02R~o or -(C(R8)(R9))u-C(O)N(Rjo)2~
f, n, p, r and s are independently 1-6;
a is 0-6;
G is selected from the group consisting of H, R4-aryl, R4-hetero-cycloalkyl, R4-heteroaryl, R4-cycloalkyl, -OR6, -N(R6)(R~), -COR6~ -C02R6, -CON(R~)(R9)) -S(O)eR~3~ -NR6C02Rt6, -NR6COR~~ -NR8CON(R6)(R~), -N(R6)S(O)2R~3, -S{O)2N(R6)(R~), -OC(O)R6) -OC(O)N(R6)(R~), -C(=NOR8)N(R6)(R~)) -C(=NR25)N(R6){R~), -N{R8)C(=NR25)N(R6)(R7), -CN, -C(O)N(R6)OR~, and -C(O)N(R9)-(R4-heteroaryl), provided that when n is 1 and a is 0, or when R9 is -OR6, G is not -OH or -N(R6)(R~);
M is selected from the group consisting of a double bond) -O-, -N(R6)-, -C(O)-, -C(R6)(OR~)-, -C(R8)(N{R6)(R~))-, -C(=NOR6)N{R~)-) -C(N(R6)(R~))=NO-) -C{=NR25)N(R6)-, -C(O)N(R9)-, -N(R9)C(O)-, -C(=S)N{R9)-) -N{R9)C(=S)- and -N(R6)C(O)N(R~)-, provided that when n is 1, G is not OH or -NH(R6); and when p is 2-6, M can also be -N(R6)C(=NR25)N(R~)- or -OC(O)N(R6)-;
G2 is R4-aryl, R4-heterocycloalkyl) R4-heteroaryl) R4-cycloalkyl, -CORE, -C02R~6) -S(O)2N(R6)(R~) or -CON(R6)(R~);

a is 0, 1 or 2, provided that when a is 1 or 2, R13 and R~fla are not H;
R2~ is H, C1-C6 alkyl, -CN, R~5-phenyl or R~5-benzyl;
Z is .R2' R~
Ar~N~ R39 R44 / w or ( )h ~ R40%N' R45 ~J ~ ~h g N,~ R4s ~ Nw wherein the nitrogen expressly shown above is optionally quaternized with C1-4 alkyl or phenyl-C1-4 alkyl or is optionally present as the N-oxide CN-O, g and h are each independently 0) 1, 2, 3, 4, or 5, with the proviso that g + h is equal to 1, 2, 3, 4, or 5;
R26 is selected from the group consisting of (1 ) a covalent bond (2) Ci_3 alkylene, unsubstituted or substituted with a substituent selected from the group consisting of =O, -OH) -OR35) halogeno, -CF3, phenyl or mono, di or trisubstituted phenyl) wherein the substituents on the phenyl are independently selected from -OH) -CN) halogeno and -CF3, (3) S(O)k (4) (C~_3 alkylene)-S(O)k (5) S(O)k-(C1_2 alkylene) (6) S(O)kNH

(7) S(O)i_NR35 (8) S(O)j-NR35_(Cj-2 alkylene) (9) CONH

(10) CONR35-(C~_2 alkylene) (11 ) C02 and (12) C02-(C1-2 alkylene) wherein j is 1 or 2 and k is 0, 1 or 2;

R2~ is -NR3~- , -O-) -S-, -S(O)-, or -S02-, with the proviso that when R26 is a covalent nd and R28 is C1_3 alkyl) R2~ must be bo NR3~;

R37 is selected from a group consisting of:

(1 ) H, (2) G~ $ linear or branched alkyl, unsubstituted) monosubstituted or multiply substituted with -OR35, =O, -NHCOR35, -NR35R3s, _CN, -halogeno,-CF3, -phenyl or substituted phenyl, wherein the substitutents on phenyl are selected from the group consisting of -OH, -CN, halogeno and -CF3;
(3) S(O)R38) wherein R38 is C1_s linear or branched alkyl, unsubstituted, mono di or trisubstituted with a substituent selected from the group consisting of =O, -CN, -OR3s, -NR35R3s, _NR3sOR3s,_halogeno,-CF3, -phenyl or mono, di or trisubstituted phenyl, wherein the substituents on the phenyl are independently selected from the group consisting of -OH, =O) -CN) -NR35R3s, _NR35COR3s, -halogeno, -CF3 and Ci_3 alkyl;
7 0 (4) S02R38) (5) COR38, (6) C02R38;

(7) CON R3sR38;

R28 is selected from the group consisting of (1 ) a covalent bond (2) C~ -3 alkylene, unsubstituted or substituted with a substituent selected from the group consisting of =O, -OR35, halogeno) -CF3, phenyl or mono, di or trisubstituted phenyl, wherein the substitutents on the phenyl are ndependently selected from the group consisting i of -OR35) halogeno nd -CF3;
a (3) S(O)k (4) (Cy _3 alkylene)-S(O)k (5) S(O)k-(C1 -2 alkylene) (6) NHS(O)j (7) NH(C1_2 alkylene)-S(O)j (8) S(O)jNR35 (9) S(O)I-NR35_(Ci_2 alkylene) (10) NHCO-(C1 _2 alkylene) (11 ) NR35C0 (12) NR35-(C1_2 alkylene)-CO

(13) O(CO) and (14) (Ct -2 alkyl)O(CO);

R29-R3o considered together are 2 adjoining atoms of the ring R~

R

said ring being a phenyl, naphthyl or heteroaryl group) and wherein the phenyl, naphthyl or heteroaryl group is unsubstituted, mono, di or tri substituted, wherein heteroaryl is selected from the group consisting of WO 98l20010 PCT/I1S97/19164 benzimidazolyl, benzofuranyl, benzoxazolyl, furanyl, imidazolyl, indolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl) pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, quinolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl and triazolyl; and wherein the substitutents are independently selected from the group consisting of:
(a) C1 _s alkyl, branched or unbranched, unsubstituted or mono or disubstituted by hydroxy (b) =O
(c) OR35 (d) halogeno (e) CF3 (f) N 02 (g) CN
(h) NR35R36 (i) NR35COR3s U) NR35C02R3s (k) NR35S{O)jR3s (I) CONR35R3s {m) COR35 (n) C02R35 {o) S(O)jR35 (p) heteroaryl) or mono or di substituted heteroaryl, wherein heteroaryl is as defined above and the substitutents are selected from the group consisting of: C1_s alkyl, branched or unbranched, unsubstituted or mono or disubstituted by OH; =O; OR35; CF3; -N02; CN;
NR35R3s; NR35COR3s; NR35C02R3s; NR35S(O)jR3s; CONR35R3s;
COR35; C02R35; S(O)jR35; and phenyl;
R35 and R3s are independently selected from:
(a) H
(b) C~-s alkyl, or mono or disubstituted C~-s alkyl, wherein the substitutents independently selected from the group consisting of phenyl, unsubstituted or substituted with -OH, C1-3 alkyl, -CN, halogeno, -CF3 or C1-a alkoxy; -OH; =O; -CN; halogeno; or -CF3;
(c) phenyl) pyridinyl or thiophene, or mono, di or trisubstituted phenyl, pyridinyl or thiophene, wherein the substitutents are independently selected from the group consisting of -OH, Ci-4 alkyl, -CN) halogeno and -CF3;
(d) C1-3 alkyloxy, SUBSTITUTE SHEET (RULE 26) _7_ or R35 and R36 are joined together to form a 5-, 6-, or 7-membered monocyclic saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and in which the ring is unsubstituted or mono or disubstituted, wherein the substituents are independently selected from the group consisting of -OH, =O, -CN, halogeno and -CF3;
Ar is selected from the group consisting of phenyl, naphthyl, heteroaryl as defined above, isoquinolyl, benzofuryl) isobenzyofuryl) benzothienyl, isoindolyl, purinyl, triazinyl, benzthiazolyl, imidazopyrazinyl, triazolopyrazinyl) naphthyridinyl, furopyridinyl, thiopyranopyrimidyl and the 5-oxide and 5-dioxide thereof) pyridazinyl, quinazplinyl) pteridinyl, triazolopyrimidyl, triazolopyrazinyl, thiapurinyl, oxapurinyl and deazapurinyl, said groups being optionally mono- or di-substituted by sustituents selected from the group consisting of:
(a) C1 _3 alkyl or C1_3 alkyl substituted by =O) OH, OR4~ , halogen) -CF3, phenyl or mono-, d- or tri-substituted phenyl, wherein the substituents on phenyl are selected from the group consisting of OH, CN, halogen and CF3;
(b) -(CH2)~S(O)k-(Ci-s alkyl), wherein n is 0, 1 or 2 (c) -(CH2)~S(O)j-NHR4~
(d) -(CH2)~S(O)j-NR41-(C1-s alkyl) (e) -(CH2)~CONHR4~
(f) -(CH2)~CONR41-(C~_6 alkyl) (g) -(CH2)nC02H
(h) -(CH2)~C02-(C~-6 alkyl) (i) -(CH2)nN R41 R42 U) -(CH2)nNH-C(O)-(C~-6 alkyl) (k) -(CH2)~NH-C(O)NH2 (I) -(CH2)~NH-C(O)NH-(C1_6alkyl) (m) -(CH2)~NH-C(O)N-(di-C~_s alkyl) (n) -(CH2)nNH-S(O)k-(C1-6 alkyl) (o) -(CH2)~N-(C1_3 alkyl)-C(O)-N-(di-C1-g alkyl) (p) -(CH2)n-heteroaryl, -C(O)-heteroaryl and -(CH2)~-O-heteroaryl wherein heteroaryl is as defined above and wherein heteroaryl can be optionally substituted by 1 to 3 substituents selected from the group consisting of: C1 _6 alkyl, branched or unbranched, unsubstituted or mono or disubstituted by hydroxy; =O; OR35; halogeno; CF3; N02; CN;
SUBSTITUTE SHEET (RULE 26) _g_ NR35R36; NR35COR36; NR35CO2R36; NR35S(O)jR36; CONR35R3s;
COR35; C02R35; and S(O)jR35;
R39 and R4o are independently selected from the group consisting of H, OH, CN, halogen, CF3 and C1_3 alkoxy;
R4~ is (a) H) (b) C1-6 alkyl) or mono or disubstituted C1-6 alkyl) wherein the substitutents independently selected from the group consisting of phenyl;
-OH; =O; -CN; halogeno; and -CF3;
(c) phenyl) mono, di or trisubstituted phenyl, wherein the substitutents are independently selected from the group consisting of -OH, C~-3 alkyl, -CN, halogeno and -CF3;
R42 is (a) H, (b) C1-6 alkyl, or mono or disubstituted C~-6 alkyl) wherein the substitutents independently selected from the group consisting of phenyl, unsubstituted or substituted with -OH) C~-3 alkyl, -CN, halogeno, -CF3 or C1-3 alkoxy; -OH; =O; -CN; halogeno; and -CF3;
(c) phenyl, naphthyl, or mono, di or trisubstituted phenyl or naphthyl, wherein the substitutents are independently selected from the group consisting of -OH) C~-3 alkyl, -CN) halogeno and -CF3; and (d) C~-3 alkyloxy; or R4~ and R42 are joined together to form a 5-, 6-, or 7-membered monocyclic saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and in which the ring is unsubstituted or mono or disubstituted, wherein the substituents are independently selected from the group consisting of -OH, =O, -CN, haiogeno and -CF3;
J is carbon and R43) R44, R45 and R46 are independently selected from the group consisting of H, -OH, =O, -NR4~Rd8 or -NR4~C(O)-NR4~~R48, wherein the nitrogen of -NR47R48 is optionally quaternized with Cy-4 alkyl or phenyl-C1_4 alkyl or is optionally present as the Noxide; or R43 and R44, or R44 and R45, together form a carbon-carbon bond; or R43 and R44 or R44 and R45, or R45 and R46, together with the carbons to which they are attached form an aryl or heteroaryl ring, wherein heteroaryl is as defined above) and wherein the aryl or heteroaryl group is unsubstituted) mono, di or tri substituted, wherein the substitutents are independently selected from the group consisting of:
(a) C~ _6 alkyl, branched or unbranched, unsubstituted or mono or disubstituted by hydroxy (b) =O
{c) OR4~
(d) halogeno (e) CF3 (f) N02 (g) CN
(h) NR~~R48 {i) NR4~COR48 NR~~C02R48 (k) N R4~S (O) j R48 (I) CONR4~R48 (m) COR4~
(n) C02R47 (0) S{~~kR47 (p) heteroaryl, or mono or di substituted heteroaryl, wherein heteroaryl is as defined above and the substitutents are selected from the group consisting of: C~_6 alkyl, branched or unbranched, unsubstituted or mono or disubstituted by OH; =O; OR4~; CF3; -N02; CN;
NR4~R~; NR4~COR48; NR4~C02Ra8; NR4~S(O)jR48; CONR4~R48;
COR4~; C02R4~; S(O)jR4~; and phenyl;
or R43, R44 and R45 are as defined above and J-R46 is oxygen or S(O);, wherein i is 0, 1, or 2; and R4~, R4~' and R48 are independently selected from the group consisting of:
(a) H, (b) C1-6 alkyl, or mono or disubstituted C~-6 alkyl, wherein the substitutents independently selected from the group consisting of phenyl, -OH, =O, -CN, halogeno and -CF3;
(c) phenyl, naphthyl, or mono, di or trisubstituted phenyl or naphthyl, wherein the substitutents are independently selected from the group consisting of -OH) C1-3 alkyl, -CN, halogeno and -CF3; and (d) C1-3 alkyloxy; or R4~ and R48 are joined together to form a 5-, 6-, or 7-membered monocyclic saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and in which the ring is unsubstituted or mono or disubstituted, wherein the substituents are independently selected from the group consisting of -OH, =O, -CN, hafogeno and -CF3.
SUBSTITUTE SHEET (RULE 26) Preferred are compounds of formula 1 wherein X is -O-, -C(O)-, a bond) -NRs-, -S(O)e-, -N(Rs}C(O)-, -OC(O)NRs or -C(=NORM )-.
More preferred are compounds of formula I wherein X is -O-) -NRs-, -N(Rs)C(O)- or -OC(O)NRs~ Additional preferred definitions are: b is 1 or 2 when X is -O- or -N(Rs)-; b is 0 when X is -N(Rs)C(O)-; and d is 1 or 2. T
is preferably R4-aryl, R4-heteroaryl, R~-cycloalkyl or R14-bridged cycloalkyl) with R4-aryl, especially R4-phenyl, being more preferred. Also preferred are compounds wherein Rsa, Rya, R8a and R9a are independently hydrogen, hydroxyalkyl or alkoxyalkyl, with hydrogen being more preferred. Especially preferred are compounds wherein R8a and R9a are each hydrogen, d and b are each 1) X is -O-) -NRs-) -N(Rs)C(O)- or -OC(O)NRs, T is R4-aryl and R4 is two substituents selected from C~-Cs alkyl, halogeno, -CF3 and C~-Cs alkoxy. Preferred definitions for T being R4-heteroaryl include R4-quinolinyl and oxadiazolyl.
Also preferred are compounds of formula I wherein R is hydrogen. Q is preferably R5-phenyl, R5-naphthyl or R5-heteroaryl; an especially preferred definitions for D are R5-phenyl, wherein R5 is preferably two halogeno substituents, and R5-heteroary, especially Rs-benzothienyl wherein R5 is preferably H..
Preferred are compounds of formula I wherein A is =N-ORS
or =N-N(R2)(R3). More preferred are compounds wherein A is =N-ORS.
R1 is preferably H) alkyl, -(CH2)~-G, -(CH2)p-M-(CH2)~-G or -C(O)N(Rs)(R~), wherein M is -O- or -C(O)N(R9)- and G is -C02Rs, -ORs) -C(O)N(Rs}(R9)) -C(=NOR8}N(Rs)(R7}) -C(O}N(R9)(R4-heteroaryl) or R4-heteroaryl. R2 and R3 are independently preferably H) C1-C6 alkyl, -(C(Rs)(R~))n-G or G2.
Preferred definitions of Z having the spirocyclic structure .R27 R2s '~ R2s R~
'R~ ~ ~ )h ( g N~
are exemplified by the following structures, optionally substituted at the positions indicated by numbers 1-8 with -OH) =O) -CN) -NR35R3s, _NHCOR35R3s, halogeno, -CF3, phenyl, mono, di or trisubstituted phenyl, wherein the phenyl substituents are independently selected from the group of substituents defined immediately above and C~ _3 alkyl:

_11_ (~, ~O O
'' N'H Me \ ~ 3 2 Q
NJ 2~ N

~ ~ Me ' N' _ Me ' N' ' OMe ~ N' \ ~ \ ~ \
I i ' Me Me ~", ~Me i r N i N N
\ ~ 2 \ ~ ~.,0 \
4 3 O S, O S,.O
J
~i ~ - ~,o \~ s N' Me ~ \ / N, Me ~ ~ N, Me N~
.! i i ~Me O ~Me O ~ ~ 3N 2 i N
N. s \ 4 O
Me $ 4~ s' J
N I ,, NJ
I ,"~,' .,..~., N,Me / ~Me ~\ ~Me 'N ~ N
\ I S.O \ I S,. \
O O
NJ NJ
I
O
~~ ~ Me 0~~,~
S \N -I
=O

N~

...- 1 ,- 1 O O
O $ ' '~ ~ a ~ ~ 3 2 S ~ ~ 3 2 ~ ~ S ~ ~ S=O
4 4, 3, 4 4, 3, N ~ 2, N 1 2, N J NJ
.,.,... ,",~,. . I

O O
/ NH -- IV S~ Me ..- N H
\ \ / \ /
N-' ~/ N ~/ N
O ! /Me N' 1 Me ~ N OMe N
\ / \ / \ /
N
~,N ~/N
/Me J ~Me N Me ~ N
\ / \ / , ,O \ / S
O S'O ~ O
N-J N--~ N-l \~ \~ \~
, \ N~ Me \ / N- Me \ / N.
Me ~/N ~/N ~/N

Me Me S~O ' ~
\ / , 'N
N' Me O \ J
N~ NJ
\/
~ Me ~ Me ~ ~ Me S
N ~ I N
\ S~ \
O O
''~,/ N ,~'L, N ~'L,/N
O
O,S~ iMe O O..O
N ~ I NH
y O
\ \ S O O
/ N _/ N-I /
~/
-/ O ~/ S ~ SO _- O
\ \ \ / -o \ /
/N NJ N~ NJ
'~c, 'z.~/ ~/

--N ~-.N O-S. 'N
\ I NH \ I N Me \ / N H
N~ Nr NJ
O
Me ~N N~OMe -N ~Me \ ~ \ I N
N N N, -N ~Me _N ~Me ~N ~Me \ / N \ / s,,o \ / s O \\ \\

N N
r'N -N O ~N O..O
, N~ Me \ I N- Me \ I N.
Me N, I r NJ
......~ ....~.,~

,Me Me ~N .O
S
/ N_ Me O
N /Me ~Me ~ ~Me O ~ N ~N S~N
\ S~ \ I S~~
O O \
NJ NJ NJ
O
O
N ~~S\ ~Me ~N
N ~NH ~ NH
\ I \ ~ S;O
O ,_ O
N~ Ni NJ
_N O ~N S ~N S O N O
\ / \ / \ % _/ ~s=o NJ NJ N

O~ ,O
N / NH N~ N'S~ Me O O
~ ~ Me N ~ N' _ Me N~ N' _ OMe N' \ ~ \
N iMe Me N_ ~Me \ ~ S
O ~'O
~O
N~ N
N'' N- O N- S~~O
N_ Me \ ~ N, \ ~ N.
Me Me N~ ~ NJ

WO 98I20010 ~ PCT/US97/19164 ~Me O /Me N~ S.O I N ~ I N
, \ ~ N. Me O \
I N
~ Me Me ~ Me N ~ N/ N ~ SAN/
,O \ I S~ \ I
O O
N~
I
. ,,"", O
~ ,O Me ..
N ~ S~N~ N ~ I NH
\ ~ \ g~ O
O O
N~
N '"'~'' I
N- N
\ ~ O \ I S S O N_ ~=O
NJ
I NJ
'"M ....... I

O
NH --. N'S, Me ' N~H
N~ I N~ I N~ I
NJ NJ NJ
I
O O Me N' _ Me ' N' _ OMe ' N/
N~ I N~ I N~ I
N N N
~Me /Me /Me N
N~ I SAO N~ I ,S~
O
O
N
I
O
O ..- a I ,o N~ N_Me Nv I N_ N~ I N, Me Me N, NJ NJ

~Me O /Me .O ~ ~N
N\ I S ~ O N\ I
N' Me N~ i I
,Me /Me ~ ~Me N ~ S~N
:O N\ ~ S N\ I
\\
p o, .o p o.
Me S~N' ~ fVH
N\ ~ N~ I S\O f \O O
N~
I
'_ o - _ ,0 0 N~ I N~ I S N~ I S N~ I ~S-O
N NJ J
I N NJ
I

O O
",.. '~ O'S~ Me ,-~N I NH ~ I N ~ I N H
N N
NJ NJ NJ
O OiI Me ' N' _ Me ' N~ OMe I N
vN I vN I ~N I
N' N' N
~Me ~ ~ Me ~ ~ Me N
I N ~ I N,~O ~
N O N SAO N S~\O
NJ NJ NJ
O
I -r O -- S, O
N N~ Me ~N I N, ~N I N_ Me Me I _ NJ NJ
."",. t I

Me O ~Me O ~ wN
N ~ S
N_ Me O N
I
~Me ~Me Q Me N , S~Ni O ~ ~ So 7 ~ O N
N~ NJ
., ,",~,. I
O
Me O' ~O
S'N~ ~ I NH
w ~ w S=O
N O O
NJ
i I
/ ~ , / s ' s o ' o=o N N N / \N /
i N nrJ
."",.. ,"",. I I

WO 98/20(110 PCT/L1S97/19164 O O
/ NH / N'S, Me / N~H
S / S / S /
N N N
I I i p ~Me / N' _ Me / N OMe / N
S / S / S
Me Me ~Me / ~ / ~ / N
O /
S / N S / S S S\
O ~~p \ O
NJ NJ NJ
I i i / O O. O
/ / S
v S / N. Me S / N- Me S / N' Me ~Me O ~Me SAO S / N / N
I
S / N' Me O S
NJ N
N r"I
g ~Me /Me ~ /Me / ( N O / I N / I SAN
S S ~O S ~\ S
O
N~
O O
O
O~ ~~
~, ii Me / S~ N~ / I
I S .O
S S~ O O
NJ
.! .!
o ~ s ~ s ~ ~ o=o / s / S / S /
i/

O O
.S. H
S \ NH S \ N Me \ N
N~ NJ N
O ~ Me S \ N' _ Me S \ N OMe S \ N
NJ NJ NJ
Me Me Me S \ Ni \ N/O S N
. ii O S~ S.
O O
Ni Ni N
S \ S \ O S \ O~ O
N.. Me N. N' Me Me NJ
,~~~ I

~Me ~Me S ~ S ~ N
' S
N' Me O
NJ NJ
~Me ,Me ~ ~Me N ~N
w O
S i S\ S i O O
N N, Me 0~ .~
' ~ S~N~ ~ ~ NH
S ~ S ,- S; O
O O
NJ N, O
S \ O S ~ S S ~ g~ S ~ g=O
NJ ~ N N

O~ ,O
N~ N ~ ,S, N
y I NH ~y N Me ~y N H
N N N
NJ NJ NJ

~ ~ Me N ~ N' _ Me N~ N' _ OMe N~ N~
y N N N
NJ NJ NJ
I I
Nl /Me N~ /Me N~ ~Me N
N C~ ~ N ,,O ~ S, N p N S~ N p N~ N~ N
( N / N- O N- S~~O
~~N N. y ~ C~ ~ , Me N N. Me N N~ Me NJ NJ NJ
I

~Me g O ~Me N ~ ~N
I S O 5 ~ I
CN N, O
Me Me Me ~ Me i , N ~ I N O N~ I N N' I SAN
N Sv O r O V
.nnr ' .iw~
O O O
O, // Me N~ ~ N~ N ~ I NHO N~ I NH
N S~ 'N O
N ~ O
N
_ _ I O CN I S N SO N~ ~O
N C~N I C~ I
N
NJ NJ
N N

Preferred definitions of Z having the substituted aryl piperazinyl structure are those wherein R39 is H and Ar is selected from the group consisting of phenyl, pyrazinyl) pyrazolyl, pyridyl) pyrimidyl and thienyl, wherein the Ar group is mono- or d-substituted with C~_3 alkyl) =O, -OR41, halogen, -CF3, -CONR4~-(C~ _2 alkyl), -C02H, -C02-(C~ _2 alkyl), -CH2NR4~-(C~_2 alkyl), -CH2NH-C(O)-(C1_3 alkyl), -CH2NH-C(O)NH2, -GH2NH-C(O)NH-{C~_3 alkyl), -CH2NH-C(O)N-(di-C~_3 alkyl), -CH2NH-S(O)j-(C~_3 alkyl) or -CH2-heteroaryl, wherein heteroaryl is is imidazolyl) oxazoiyl) pyridyl, tetrazolyl or triazolyl) and wherein the heteroaryl is optionally substituted with branched or unbranched) optionally hydroxy-substituted C~_6 alkyl. More preferred are compounds wherein Ar is mono- or d-substituted phenyl wherein the substituents are C~ _g alkyl) =O, -OR4~ ) -CONR4~-(C~_2 alkyl), -CH2NR41-{C~_2 alkyl}) -CH2NH-C(O)-(C~_3 alkyl), -CH2NH-C(O)NH2, -CH2NH-C(O)NH-(C1_3 alkyl), -CH2NH-C(O)N-(di-C~_3 alkyl)) -CH2NH-S(O)j-(C~_3 alkyl) or -CH2-heteroaryl, wherein heteroaryl is as defined immediately above. Typical groups Ar groups wherein Z is a substituted aryl piperazinyl are shown in the following formulae:
COCH3 ~N~ H
Me- N~ H
O N
/ \
/ ~ N
H~N H'N N
i N,CH3 p=S~p C _N NN_N \
N~ N
N ~O
/) \ \
CH3 f~L= N
p~S Nv NH

-N N N N
N~ \ ~ \ / \ ~ \
- N~ - _ NON v N \ /~N p N N
N v H3C ~ \ N ~ \
N N
HsC H2N
N~ N ~--N ~- N
N N
HsC~NuN .S S ~O

Preferred definitions of Z having the spirocyclic stnrcture R~
w R~ ,~~ > )n R46 ~ 9 Nw are exemplified by the following structures, I \ 0 0 / ~3p CH3S02NH \
I \
/ ( / O~N
O ~.N
O
CH3S02 \ O
( / O~N_. CH3S02NH Q30 / N
OH O
CH3SOz \ CH3S02NH
\ /
I / O~N' I / N' S~S Nw O ~ V
OH OH
\ Q30 \ CH30 \
I
I / O~N I / O~N' /
N~
O
CH3S02 ~ O
I / O l~N' CH3S02NH ~ ~
O N
O OH O
\ ~ ~-NHCH3 I ~ I I HN
/ / / \
N~ N~ J I /
N

This invention also relates to the use of a compound of formula I in the treatment of asthma, cough) bronchospasm, inflammatory diseases such as arthritis, central nenrous system conditions such as migraine and epilepsy, nociception, and various gastrointestinal disorders such as Crohn's disease.
In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I in a pharmaceutically acceptable carrier. The invention also relates to the use of said pharmaceutical composition in the treatment of asthma, cough, bronchospasm, inflammatory diseases such as arthritis) migraine, nociception, and various gastrointestinal disorders such as Crohn's disease.
DETAILED DESCRIPTION
As used herein, the term "alkyl" means straight or branched alkyl chains. "Lower alkyl" refers to alkyl chains of 1-6 carbon atoms and, similarly, lower alkoxy refers to alkoxy chains of 1-6 carbon atoms.
"Cycloalkyl" means cyclic alkyl groups having 3 to 6 carbon atoms. "Bridged cycloalkyl" refers to C~-Coo saturated rings comprised of a cycloalkyl ring or a fused bicycloalkyl ring and an alkylene chain joined at each end to non-adjacent carbon atoms of the ring or rings. Examples of such bridged bicycloalkyl rings are adamantyl, myrtanyl, noradamantyl, norbornyl, bicyclo[2.2.1 ]heptyl, 6, 6-dimethylbicyclo(3.1.1 ]heptyl, bicyclo[3.2.1 Joctyl, and bicyclo[2.2.2]octyl.
"Aryl" means phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl or fluorenyl.
"Halogeno" refers to fluoro, chloro, bromo or iodo atoms.
"Heterocycloalkyl" refers to 4- to 6-membered saturated rings comprising 1 to 3 heteroatoms independently selected from the group consisting of -O-, -S- and -N(R~ 9)-) with the remaining ring members being carbon. Examples of heterocycloalkyl rings are tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl. R4-heterocycloalkyl refers to such groups wherein substitutable ring carbon atoms have an R4 substituent.
"Heteroaryl" refers to 5- to 10-membered single or benzofused aromatic rings comprising 1 to 4 heteroatoms independently selected from the group consisting of -O-, -S- and -N=, provided that the rings do not include adjacent oxygen and/or sulfur atoms. Examples of single-ring heteroaryl groups are pyridyl, isoxazolyl, oxazolyl, oxadiazolyl, furanyl) pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl) pyrazinyl) pyrimidyl, pyridazinyl and triazolyl.
Examples of benzofused heteroaryl groups are indolyl, quinolyl, thianaphthenyl (i.e., benzothienyl) benzimidazolyl, benzoxazolyl, and benzofurazanyl. N-oxides of nitrogen-containing heteroaryl groups are also included. All positional isomers are contemplated) e.g., 1-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl. R4-heteroaryl refers to such groups wherein substitutable ring carbon atoms have an R4 substituent.
Where R2 and R3 or R6 and R~ substituents on a nitrogen atom form a ring and additional heteroatoms are present, the rings do not include adjacent oxygen and/or sulfur atoms or three adjacent hetero-atoms. Typical rings so formed are morpholinyl, piperazinyt and piperidinyl.
In the above definitions, wherein variables R6, R~, R8, R9, R~ e) R13, R~ 4 and R~ 5, for example, are said to be independently selected from a group of substituents, we mean that R6, R~, R8, R9, R~, R~3) R~4 and R~ 5 are independently selected, but also that where an Rs) R~, R8, R9, R~, R~3, R~4 or R~5 variable occurs more than once in a molecule, those occurrences are independently selected (e.g., if R is -ORs- wherein R6 is hydrogen, X can be -N(R6)- wherein R6 is ethyl). Similarly, R4 and R5 can be independently selected from a group of substituents, and where more than one R4 and R5 are present, the substitutents are independently selected; those skilled in the art will recognize that the size and nature of the substituent(s) will affect the number of substituents which can be present.
Compounds of formula I can have at least one asymmetrical carbon atom and all isomers, including diastereomers, enantiomers and rotational isomers, as well as E and Z isomers of the oxime) hydrazone and olefin groups, are contemplated as being part of this invention. The invention includes d and I isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of formula I.
Those skilled in the art wilt appreciate that for some compounds of formula I, one isomer will show greater pharmacological activity than other isomers.
Compounds of the invention have at Ic~ast one amino group which can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic) citric, oxalic, malonic, salicylic, malic) fumaric, succinic, ascorbic, malefic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium bicarbonate. The free base form differs from its respective salt form somewhat in certain physical properties, such as solubility in polar solvents, but the salt is otherwise equivalent to its respective free base forms for purposes of the invention.
Certain compounds of the invention are acidic (e.g., those compounds which possess a carboxyl group). These compounds form pharmaceutically acceptable salts with inorganic and organic bases.
Examples of such salts are the sodium) potassium, calcium, aluminum, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methyiglucamine and the like.
Compounds of formula I can be prepared using methods well known to those skilled in the art. Following are typical procedures for preparing various compounds; the skilled artisan will recognize that other procedures may be applicable, and that the procedures may be suitably modified to prepare other compounds within the scope of formula 1.
Procedure A:
Compounds of formula I wherein R is H, a and d are each 1, X is -O- or -S- and the remaining variables are as defined above (Q is exemplified as R5-phenyl, but the procedure is not limited to this definition) can be prepared according to the following reaction scheme:
cooR'9 Step 1 ,o cooR'9 t ~ ~ P9 ' -f-R ~O/P9 B-~--e~-g ~ Rs Step 2 ~ Step 3 Br cOOH
Acid ~ HBr -~ ~
~ Rs Rs WO 98/20010 PCT/US97/191b4 Step 4 CI CHN2 (COCI)2 Br ~ Step 5 B~ O
5_ .~.

Step 6 z O
7 -~- Z-H
_9 R5 O Rsa R9a Ste 7 -I- HX- ( i )b-T ~ Z x (R8a T
R8a I vR5 1 1 Rsa 11 + AH2 Step = Z x-(~ )b-T
R8a Iw R
5 In step 1, the ester (preferably methyl) of the substituted aryl acetic acid of formula 1, wherein Rig is a lower alkyl group, preferably methyl, is reacted with a compound of formula 2, wherein R~' is a leaving group such as Br) I or triflate) and Pg is a suitable protecting group such as tetrahydropyranyl, and a base to prepare a compound of formula ~. The 10 base can be chosen from any strong base including LDA or lithium bis(trimethylsilyl)amide. The reaction is carried out in an inert organic solvent such as THF at temperatures of -15 to about 65~C.
In step 2, a compound of formula 3_ is reacted with an acid in a solvent such as CH30H, at temperatures ranging from -10 to 65~C. The acid need not to be used in stochiometric amount. Alternatively, a compound of formula 4 can be prepared directly from step 1 without isolating the compound of formula ~: the reaction mixture obtained after the work up of the reaction described in step 1 can be dissolved in the solvent and reacted with the acid.
In step 3, a compound of formula 4_ is reacted with an acid such hydrobromic acid (HBr) dissolved in a suitable solvent such as acetic acid.
The reaction is performed at temperatures ranging from 5 to 45~C.

In step 4, the carboxylic acid of formula 5 is reacted with a halogenating agent such as SOCI2 or (COCI)2 in an appropriate solvent such CH2CI2 to form the acid halide of formula 6_.
In step 5, the compound of formula 6 is reacted with an alkylating agent such as diazomethane to obtain the compound of formula 7. This reaction may be performed at temperatures lower than ambient using an appropriate solvent such as Et20.
In step 6, a compound of formula 7 is reacted with a compound of formula _8 to obtain a compound of formula 9_. The reaction is carried out in a suitable solvent, e.g. EtOAc, at temperatures below 85~C. Bases such as Et3N may be beneficial to the reaction.
In step 7, a compound of formula 9_ is reacted with a compound of formula 10 , wherein X is -O- or -S-) T is H, R4-aryl, R4-cycfoalkyl, R4-alkyl, R4-bicyclo or tricycloalkyl, and RBa, R9a, b and R4 are as defined above in an appropriate solvent, e.g. CH2CI2, with a Lewis acid, e.g. BF3) at temperatures lower than 50~C.
in step 8 a compound of formula 11 is reacted with a compound of formula 12, wherein A is as defined above, in a solvent such as pyridine, to obtain the desired product.
Procedure B:
Compounds of formula I, wherein the variables are as defined above, can be prepared as shown in the following reaction scheme:
St_ ep 1:
Rsa Rsa rC02hl p Rsa Rsa R21 ~ ~C)d_x_ ~C~b- T base, Q 14A ~ ~C~d-X- ~C~b- T
1 ~ Q ~7a R8a R7a R8a pr Mt 13 (A: R21 = alkoxy Q 14B 1 ~
B: R21 = CI
C: R21 = -N(CH3)OCH3) In step 1, a compound of formula 14A. wherein Q is as defined above, is reacted with a base such as lithium disopropylamide (LDA) or KH in an inert organic solvent such at THF or DME to generate a dianion.
An acid chloride, ester or amide of formula 13A, ~, or 13C is added to give a ketone of formula 1~. Preferable reaction temperatures ranges from -78~C to 30~C.
Alternatively, compounds of formula 1~ can be generated by the reaction of a compound of formula 13, preferably 13C, with a metallated species of formula QCH2Mt where Mt is a metal, such as MgHal) wherein "Hal" is halogen, or lithium. The metallated species QCH2Mt can be generated by conventional procedures, such as treatment compounds of formula QCH2Hal with Mg or by treating QCH3 with an organolithium base.
Step 2: R ~ Rsa Rsa base I I
1T ~(j)d X (C)b'T 16 R-R or oxidizing agent Q Rya Rsa -In step 2, for compounds of formula I wherein R is not hydrogen, the ketone 15 is reacted with a suitable base, such as LDA or KH in an inert organic solvent such as THF. For compounds wherein R is alkyl or 10 hydroxyalkyl, a compound R-R~', wherein R~' (as defined above) is added. For compounds wherein R is OH, an appropriate oxidizing agent such as dimethyldioxirane or Davis reagent is added. Preferable reaction temperatures range from -78~ to 50~C.
Step 3:
base ~ R' R O Rsa Rsa R1 s a (C)d-X- (C)b- T
R18' Ri~' R1g' C R7a Rsa 18 15 In step 3, ketone 1~. is reacted with a base such as LDA in a solvent such as THF, then an olefin of formula 17 is added, wherein R~ 8 and R18' are independently H or lower alkyl and R~~' is as defined above, to give the adduct ~ 8. Preferable reaction temperatures range from -78 to 60~C.
Step 4: RlB R A. Rsa Rsa HA' R1s' (~)a-X-( ~ )b-T
Q R7a Rea In step 4, ketone 18 is reacted with HA', wherein A' is NH-ORS, NH-N(R2){R3) or NHR26, in an organic solvent such as pyridine at a temperature from 25~C to 150~C to give a compound of formula 19.
to 5:
R A~ Rsa Rsa 19 ~ _ _ OHC~~ (C)d x (C)b-T
R7a Rsa 20 In step 5, a compound of formula 19 is oxidized by ozonolysis to give an aldehyde of formula 20. Suitable organic solvents include EtOAc, ethanol or the like. Preferable reaction temperatures are from -78 to 0~C.

Step fi: R A' Rsa Rsa 20 Z-'~' Z a I I
~~/~~ ~ i )d-X- ~ i )b'T
Q R7a Rsa In step 6, an aldehyde of formula 20 is reacted with a compound of formula Z-H, wherein Z is a suitably substituted amine (as its acid salt e.g.
HCI or maleate or as its free base) and a hydride source such as NaBH3CN or sodium triacetoxyborohydride in a protic solvent (e.g.
CH30H, CH3CH20H, or CF3CH20H) with 3A sieves. Any suitable temperature can be used with preferable temperatures being between O~C and 25C.
Alternatively) a compound of formula I can be prepared from 18 by the following reaction scheme:
R O R6a Rsa ~ I I
18 ~3 ~ OHC~~ ~ ~ )d X ~ ~ )b' T
Q Rya R8a 21 Compound 18 is oxized to a compound of formula 21 under conditions similar to those described for step 5 above. The aldehyde of formula 21 is reacted with a compound of formula Z-H in a manner similar to that described in Step 6) and the resultant ketone is then reacted with a compound of the formula HA' as described above in Step 4 to obtain the compound of formula I.
Procedure C:
Step 1: R ~ Rsa Rsa 16 ---~ O .a ~C)d-X- ~C)b-T
Q R7a Rsa In step 1, compounds of formula 11 fi treated with an appropriate base, such as NaH, are reacted with alkylating agents of the formula R33C{O)CH2R~ or R33C(O)CH=CH2 wherein R33 is alkoxy or -N{CH3)OCH3 and R1~ is a leaving group such as CI or Br.
Ste~~ 2: OR1 R33 R N~ Rsa Rsa 23 ~ a ~C)d-X-~C)b-T
O Q R7a Rea 24 In step 2, compounds of formula 23 can be converted to the corresponding oxime of fomlula 24 in a manner similar to that described in Procedure B, Step 4.

WO 98I20010 ~ PCT/US97/19164 to 3: R N ~ Rsa R9a 24 ---~ ~ ~ I
OHCx~ (~)d'x-(C)b-T
Q R7a Rsa 25 In step..3,.compounds of formula 24 (or 2~, i.e., wherein A' is O) are converted to the corresponding aldehyde 25 (or lactol from the keto-ester 23) by treatment with a suitable reducing agent such a DIBAL) in an suitable inert organic solvent such as THF, at a temperature from about -100 to -20~C.

St-e_p 4: R N~ORsa R9a 25 ~- Z~('~(C)d-X-(C)b-T
R7a Rsa In step 4, compound 25 is reacted with an amine ZH in a manner similar to that of Procedure B, Step 6, to obtain the compound of formula I.
Starting materials Z-H are known in the art or are prepared by methods known in the art, for example procedures for preparing spiro-substituted azacycles were described by Ong, et al) J. Med. Chem.) 26 (1983), p. 981-986 and in WO 94/29309, published December 22, 1994;
substituted aryl piperazines were described in WO 96/10568, published Aprif 11, 1996.
In the above procedures, T and Q generally are exemplified as R5-phenyl and R4-phenyl, respectively, but those skilled in the art will recognize that in many cases, similar procedures can be used to prepare compounds wherein T and Q are other than substituted-phenyl.
Reactive groups not involved in the above processes can be protected during the reactions with conventional protecting groups which can be removed by standard procedures after the reaction. The following Table 1 shows some typical protecting groups:
Table 1 Group to be Grou_pto be Protected and Protected Protecting Group -COOH -COOalkyl, -COObenzyl, -COOphenyl ~ NH ~ NCOalkyl, ~NCObenzyl, ~~" NCOphenyl, ~ NCH20CH2CH2Si(CH3)3 ~ NC{O)OC(CH3)s, ~N-benzyl, ~NSi(CH3)3, N~i-C(CH)3 ~ CH3 Group to be Group to be Protected and Protected Protecting Group -N
O I Hs - OH -OCH3, -0CH20CH3,-OSi(CH3)3, -O'i-C(CH)3 or -OCH2phenyl CHs Compounds of formula 1 have been found to be antagonists of NK1 and/or NK2 and/or NK3 receptors, and are therefore useful in treating conditions caused or aggravated by the activity of said receptors.
The present invention also relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier. Compounds of this invention can be administered in conventional oral dosage forms such as capsules, tablets, powders, cachets, suspensions or solutions, or in injectable dosage forms such as solutions, suspensions, or powders for reconstitution The pharmaceutical compositions can be prepared with conventional excipients and additives, using well known pharmaceutical formulation techniques.
Pharmaceutically acceptable excipients and additives include non-toxic and chemically compatibile fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like.
The daily dose of a compound of formula I for treating asthma, cough, bronchspasm, inflammatory diseases, migraine) nociception and gastrointestinal disorders is about 0.1 mg to about 20 mg/kg of body weight per day, preferably about 0.5 to about 15 mg/kg. For an average body weight of 70 kg, the dosage range is therefore from about 1 to about 1500 mg of drug per day) preferably about 50 to about 200 mg, more preferably about 50 to about 500 mg/kg per day) given in a single dose or 2-4 divided doses. The exact dose, however, is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient.
Following are examples of preparing starting materials and compounds of formula I. As used herein) Me is methyl, Ac is acetyl, Et is ethyl and Ph is phenyl.

Preparation 1 1.2-Dihydro-1'-methyl-1- methylsulfon~~)-spiro[3H-indole-3.4'-piperidine]
Dissolve 1,2-dihydro-1'-methyl-spiro[3H-indole-3,4'-piperidine]
(3.0g, 14.8 mmoles) in dry CH2C12 (25 ml) and cool under N2 in an ice bath. Add, dropwise) methane sulfonyl chloride (1.5 ml, 19.3 mmoles), followed by ethyl diisopropyl amine (5.0 ml, 28.7 mmoles). Warm to room temperature and stir overnight. Dilute the solution to 100 mf with CH2C12.
Wash the solution with saturated aqueous NaHC03 (4x25 ml), then with water. Dry solution with anhydrous Na2S04) then remove the solvent using reduced pressure. Purify the resulting reaction mixture by flash chromatography (Si02) using 5% MeOH(NH3)/EtOAc as eluent. Yield:
3.37 g (81 %) of the title compound. HRMS (FAR): calculated for C141"121 N2025 (M+H)+: 281.1324; found: 281.1324.
Preparation 2 1.2-Dihydro-1-(methyrlsulfonyl)i-spiro[3H-indole-3.4'-loiperidine]
Add 1-chloroethyl chlorocarbonate (1.0 ml, 9.3 mmoles) dropwise to a precooled (ice bath) solution of the product of Preparation 1 (2.0 g, 7.13 mmoles) in 1,2-dichloroethane (20 ml) . After the addition, reflux the solution, under N2, for 2 h. Coo! the solution to room temperature and remove about half the volume of the solvent using reduced pressure. Add CH30H (15.0 ml) and reflux the solution again for another 40 min.
Remove the solvent in vacuo. Treat the resulting foam with a mixture of CH30H:EtOAc:CH2C12 and filter the resulting precipitate. Suspend this precipitate in CH2C12 (80 ml), wash 3 times with 2.5 M aqueous NaOH, then with water, and dry over anhydrous Na2S04. Yield: 0.54 g of the title compound. Purify the filtrate by flash chromatography (Si02) using 2 1/2% CH30H(NH3)/EtOAc as eluent to yield another 0.58 g of product.
Total yield: 1.12 g (58%). HRMS (FAB): Calculated for C13H19N2O2S
(M+H)+:267.1167; found: 267.1174.
Preparation 3 1'-[5-[[3.5-Dichlorophenyl]methoxyr]-3-(3.4-dichlorophen~~)-4-oxopen~ll 1.2-dihydro-spiroj3H-indole-3.4'-piperidine]
Add a solution of HBr (gas) in acetic acid (3.0 ml) to phenylmethyl 1'-[3-(3.4-dichlorophenyl)-5-[(3,5-dichlorophenyl)methoxy]-4-oxopentyl]
1,2-dihydro-spiro[3H-indole-3,4'-piperidine]-1-carboxylate [0.250 g, 0.34 mmoles) dissolved in glacial acetic acid (2.0 ml). Stir the solution at room temperature for 4 h, then add Et20 (30 ml). Decant the liquid and wash the resultant solid with Et20. Suspend the solid in water (10 ml) and add 1.0 M aqueous KOH (5.0 ml). Extract the mixture with Et20 (3x30 ml), combine the extracts, wash with water and dry (Na2S04). Remove the solvent and purify the reaction mixture by preparative thin layer chromato-graphy (Si02), eluting the plates twice with ETOAc:hexanes:CH30H(NH3) (15:85:3). Extract the desired product with 5% CH30H(NH3)/EtOAc.
Yield: 57 mg. Mass Spectrum (FAB): 591 (35C1 +3~CI isotope), 593 (M+H) (35C1 + 3C1 isotope)) 595 (35C1 + 3~CI isotope).
Example 1 CH3S02 .N Nr0 O 3 CF3 N ~ /
~ 1 CF3 CI
CI
1'-[5-[[3,5-Bis(trifluoromethyl)phenyl]methoxy]-3-(3,4-dichlorophenyl)-4-(methoxyimino)pentyl]-1,2-dihydro-1-(methylsulfonyl)-spiro[3H-indole 3,4'-piperidine]
Use the method described in Procedure A to prepare the title compound.
HRMS (FAB) (M+H)+: calc'd for C34H35N304SCI2F6: 765.1630; found:
765.1610.
Example 2 N,.OCH3 O ~N ~ O CI
N
i ~. ~ ~ /
~ 1 CI CI
CI
Phenylmethyl 1'-[3-(3,4-dichlorophenyl)-5-[[3,5-dichlorophenyl]methoxy]-4-(methoxyimino)pentyl]-1,2-dihydro-spiro[3H-indole-3,4'-piperidine]-1-carboxylate Use the method described in Procedure A to prepare the title compound.
HRMS (FAB) (M+H)+: calc'd for CggH40N3~4C14: 754.1773; found:
754.1757.
Example 3 O N,,O H Cl O~N ~ O
N
/ ~ I CI CI
CI
Phenylmethyl 1'-[3-(3,4-dichlorophenyl)-5-[[3,5-dichlorophenyl]methoxy]
4-(hydroxyimino)pentyl]-1,2-dihydro-spiro[3H-indole-3,4'-piperidine]
1-carboxylate Use the method described in Procedure A to prepare the title compound.
HRMS (FAB) (M+H)+: calc'd for C38H38N3O4C14: 740.1616; found:
740.1625.
Example 4 N,,OCH3 O
CH3S02 ~N ~ N ' CH3 N
w CHs I

CI
CI
St-e~ 1:
N,,OCH3 O N,.OCHa O
I N w CH3 O ~ ' N ~ CH3 V, I _ CH3 i ~ CH3 CH3 ~ I CI CH3 CI CI
CI
1~ 101 Cool a solution of ~ (10.21 g, 0.5 mmol) in EtOAc (3.6 ml) to -78~C and subject the solution to a subsurface flow of 02, then 03 (0.4, 1 min.), then 02 for 0.5 h. Add {CH3)2S (1 ml) to quench the reaction) remove the cold bath and allow the mixture to warm to room temperature.
Wash the crude mixture with 10% Na2S203, then brine, dry over MgS04, filter and concentrate to obtain a light yellow oil {MH+ 435.0) to be used without further purification in the next step.
to 2:
To a solution of the product of step 1 in CF3CH20H {2.6 ml), add the product of Preparation 2 (1.123 g, 0.46 mmol). When dissolution is complete, add 3A molecular sieves (0.34 g); after 30 min., add NaCNBH3 (10.17 g, 2.7 mmol). After 2 h, quench the reaction by adding deionized water (10 ml) and stir for 10 min. Partition the reaction mixture between Et20:CH2Cl2 (5:1 ) and water. Extract the aqueous layer twice with Et20:CH2Cl2 (5:1 ), wash the combined organic layers with brine, dry over MgS04, filter and concentrate. Purify the crude product by flash chromatography and prep-TLC (twice) to obtain the title compound as a whit foam. Yield: 25.2%. MS: MH+ 685.3.

WO 98l20010 PCTlUS97/19164 Example 5 N,,OCHs O

N ~ N ~ CI
y CH3 ~ I CI
CI
CI
Treat a compound of the formula N ,,OCH3 O
CI
CH3 I ~
I CI
CI
CI
using a procedure simitar to that described in Example 4 to obtain the title compound. MS (FAB) 727.2 (100%).
The following formulations exemplify some of the dosage forms of this invention. In each, the term "active compound" refers to a compound of formula I.
EXAMPLE A
Tablets No. Ingredient mg/tablet ma/tablet 1 Active Compound 100 500 2 Lactose USP 122 113 3 Corn Starch, Food Grade, as a 10% 30 40 paste in Purified Water 4 Com Starch, Food Grade 45 40 5 Magnesium Stearate 3_ 7 Total 300 700 Method of Manufacture Mix Item Nos. 1 and 2 in suitable mixer for 10-15 minutes.
Granulate the mixture with Item No. 3. Mill the damp granules through a coarse screen (e.g., 1/4") 0.63 cm) if necessary. Dry the damp granules.
Screen the dried granules if necessary and mix with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture to appropriate size and weight on a suitable tablet machine.

EXAMPLE B
a sul s No. Ingredient mgi/tablet mg/tablet 1 Active Compound 100 500 2 Lactose USP 106 123 3 Com Starch, Food Grade 40 70 4 Magnesium Stearate NF 4 7 Total 250 700 Method of Manufacture Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating machine.
EXAMPLE C
Sterile Powder for Injection Ingredient m_g/vial m_ alvial Active sterile powder 100 500 For reconstitution add sterile water for injection or bacteriostatic water for injection.
The in vitro and in vivo activity of the compounds of formula I
can be determined by the following procedures.
In vitro~rocedure to identifyv NKi activity Test compounds are evaluated for their ability to inhibit the activity of the NK1 agonist Substance P on the isolated guinea pig vas deferens. Freshly cut vas deferens are removed from male Hartley guinea pigs (230-350g) and suspended in 25 ml tissue baths containing Kreb's Henseleit solution warmed to 37~C and constantly aerated with 95% 02 and 5% C02. Tissues are adjusted to 0.5 g and allowed to equilibrate for a period of 30 minutes. The vas deferens are exposed to an electrical field stimulation (Grass S48 Stimulator) every fi0 seconds at an intensity that will cause the tissue to contract 80% of its maximum capacity. All responses are recorded isometrically by means of a Grass force displacement transducer (FT03) and Harvard electronic recorder.
Substance P potentiates the electrical field stimulated-induced contractions of the guinea pig vas deferens. In unpaired studies) all tissues (control or drug treated) are exposed to cumulative concentations of Substance P (1X10- c M - 7X10- M). Single log-concentations of the test compounds are given to separate tissues and allowed to equilibrate for 30 minutes before a Substance P concentation-response curve is generated. At least 5 separate tissues are used for each control and individual drug-concentation for every drug assay.
Inhibition of the Substance P is demonstrated by a rightward shift of its concentration-response curve. These shifts are used to determine the pA2 value) which is defined as the negative log of the molar concentration of the inhibitor which would require that twice as much agonist be used to elicit a chosen response. This value is used to determine relative antagonist potency.
Isolated Hamster Trachea NK~ Assa General methodology and characterization of hamster trachea responses to neurokinin agonists as providing an NK2 monoreceptor assay is found in C.A. Maggi, et al., Eur. J. Pharmacol. 166 (1989) 435 and J.L. Ellis, et al., J. Pharm. Exp. Ther. 267 (1993) 95.
Continuous isometric tension monitoring is achieved with Grass FT-03 force displacement transducers connected to Buxco Electronics preamplifiers built into a Graphtec Linearcorder Model WR
3310.
Male Charles River LAK:LVG (SYR) hamsters, 100-200 g fed weight, are stunned by a sharp blow to the head, loss of corneal reflex is assured, the hamsters are sacrificed by thoractomy and cutting the heart.
Cervical trachea segments are removed to room temperature Krebs buffer, pH 7.4) aerated with 95% 02 - 5% C02 gas and cleaned of adhering tissue. The segments are cut into two 3-4 mm long ring segments.
Tracheal rings are suspended from transducers and anchored in 15.0 ml water jacketed organ baths by means of stainless steel hooks and 6-0 silk.
Baths are filled with Krebs buffer, pH 7.4, maintained at 37~C and continuously aerated with 95% 02 - 5% C02 gas. Tracheal rings are placed under 1.0 g initial tension and allowed a 90 min equilibration period with four 1 p.M NKA challenge) wash and recovery cycles at 20 min intervals. 30 min vehicle pretreatment is followed by cumulative additions of rising doses of NKA (3 nM - 1 p.M final concentration, 5 min intervals between additions). The final NKA response is followed by a 15 min wash and recovery period. 30 min pretreatment with a test compound or its vehicle is followed by cumulative additions of rising doses of NKA (3 nM -10 wM final concentration if necessary, 5 min intervals between additions).

The final NKA response is followed by a 1 mM carbachol challenge to obtain a maximal tension response in each tissue.
Tissue responses to NKA are recorded as positive pen displacements over baseline and converted to grams tension by comparison to standard weights. Responses are normalized as a % of the maximal tissue tension. ED5o's are calculated for NKA from the control and treated NKA dose responses and compared. Test compounds resulting in an agonist dose ratio >_ 2 at a screening concentration of 1 p,M
(i.e. pA2 > = 6.0) are considered actives. Further dose response data is obtained for actives so that an apparent pA2 estimate can be calculated.
pA2 is calculated either by estimation of K; as described by Furchgott (where pAz = - Log K;, R.F. Furchgott, Pharm. Rev. 7 [1995] 783) or by Shild Plot Analysis (O. Arunlakshana & H.O. Shild, Br. J. Pharmacol.
14[1959] 48) if the data is sufficient.
Effect of NKi Antagonists on Substance P-Induced Airwav Microvascular Leakage in Guinea Pias Studies are performed on male Hartley guinea pigs ranging in weight from 400-650 g. The animals are given food and water ad libitum. The animals are anesthetized by intraperitoneal injection of dialurethane (containing 0.1 g/ml diallylbarbituric acid) 0.4 g/ml ethylurea and 0.4 g/ml urethane). The trachea is cannulated just below the larynx and the animals are ventilated {VT = 4 ml, f = 45 breaths/min) with a Harvard rodent respirator. The jugular vein is cannulated for the injection of drugs.
The Evans blue dye technique (Danko, G. et al.) Pharmacol.
Commun., 1, 203-209, 1992) is used to measure airway microvascular leakage (AML). Evans blue (30 mg/kg) is injected intravenously, followed 1 min later by i.v. injection of substance P (10 p.g/kg). Five min later) the thorax is opended and a blunt-ended 13-guage needle passed into the aorta. An incision is made in the right atrium and blood is expelled by flushing 100 ml of saline through the aortic catheter. The lungs and trachea are removed en-bloc and the trachea and bronchi are then blotted dry with filter paper and weighed. Evans blue is extracted by incubation of the tissue at 37~C for 18 hr in 2 ml of formamide in stoppered tubes. The absorbance of the formamide extracts of dye is measured at fi20 nm. The amount of dye is calculated by interpolation from a standard curve of Evans blue in the range 0.5-10 p.g/ml in formamide. The dye concentration is expressed as ng dye per mg tissue wet weight. Test compounds were suspended in cyclodextran vehicle and given i.v. 5 min before substance P.
Measurement of NK2 Activityr In Vivo Male Hartley guinea pigs (400-500 gm) with ad lib. access to food and water are anesthetized with an intraperitoneal injection of 0.9 ml/kg dialurethane (containing 0.1 g/m diallylbarbituric acid, 0.4 g/ml ethylurea and 0.4 g/ml urethane}. After induction of a surgical plane of anesthesia, tracheal, esophageal and jugular venous cannulae are implanted to facilitate mechanical respiration, measurement of esophageal pressure and administration of drugs, respectively.
The guinea pigs are placed inside a whole body plethysmograph and the catheters connected to outlet ports in the plethysmograph wall. Airflow is measured using a differential pressure transducer (Validyne, Northridge CA, model MP45-1, range ~ 2 cmH20) which measures the pressure across a wire mesh screen that covers a 1 inch hole in the wall of the plethysmograph. The airflow signal is electrically integrated to a signal proportional to volume. Transpulmonary pressure is measured as the pressure difference between the trachea and the esophagus using a differential pressure transducer (Validyne, Northridge, CA, model MP45-1, range ~ 20 cm H20). The volume, airflow and transpulmonary pressure signals are monitored by means of a pulmonary analysis computer (Buxco Electronics, Sharon, CT) model 6) and used for the derivation of pulmonary resistance (R~) and dynamic lung compliance (Cpyn).
Bronchoconstriction Due to NKA
Increasing iv doses of NKA are administered at half log (0.01-3 p,g/kg) intervals allowing recovery to baseline pulmonary mechanics between each dose. Peak bronchoconstriction occurs within seconds after each dose of agonist. The dose response is stopped 30 when Cpyn is reduced 80-90% from baseline. One dose-response to NKA
is performed in each animal. Test compounds are suspended in cyclodextran vehicle and given i.v. 5 min before the initiation of the NKA
dose response.
For each animal, dose response curves to NKA are constructed by plotting the percent increase in R~ or decrease in Cpyn against log dose of agonist. The doses of NKA that increased R~ by 100%
(R100) or decreased Cpyn by 40% (Cpyn40) from baseline values are obtained by log-linear interpolation of the dose response curves.

Neurokinin Receptor Binding Assav(s) Chinese Hamster ovary (CHO) cells transfected with the coding regions for the human neurokinin 1 (NK1 ) of the human neurokinin 2 (NK2) receptors are grown in Dulbecco's minimal essential medium supplemented with 10% fetal calf serum, 0.1 mM non-essential amino acids, 2 mM glutamine, i OOunits/ml of penicillin and streptomycin, and 0.8 mg of G418/ml at 37~C in a humidified atmosphere containing 5% C02.
Cells are detached from T-175 flasks with a sterile solution containing 5mM EDTA in phosphate buffered saline. Cells are harvested by centrifugation and washed in RPMI media at 40~C for 5 minutes. The pellet is resuspended inTris-HCI (pH7.4) containing 1 uM phsphoramidon and 4 ug/ml of chymostatin at a cell density of 30 x 106 cells/ml. The suspension is then homogenized in a Brinkman Polytron {setting 5) for 30-45 seconds. The homogenate is centrifuged at 800 x g for 5 min at 4~C to collect unbroken cells and nuclei. The supernatant is centrifuged in a Sorvall RCSC at 19,000 rpm (44,00 x g) for 30 min at 4~C. The pellet is resuspended, an aliquot is removed for a protein determination (BCA) and washed again. The resulting pellet is stored at -80~C.
To assay receptor binding, 50 p.l of [3H]-Substance P (9-Sar) 11-Met (02l) (specific activity 41 Ci/mmol) {Dupont-NEN) (0.8 nM for the NK-1 assay) or [3HJ-Neurokinin A (specific activity 114 Ci/ mmole) (Zenca) (1.0 nM for the NK-2 assay) is added to tubes containing buffer (50 mM
Tris-HCI (pH 7.4) with 1 mM MnCl2 and 0.2% Bovine Serum Albumin) and either DMSO or test compound. Binding is initiated by the addition of 100p.1 of membrane (10-20 pg) containing the human NK-1 or NK-2 receptor in a final volume of 200 p.l. After 40 minutes at room temperature, the reaction is stopped by rapid filtration onto Whatman GF/C filters which have been presoaked in 0.3% polyethylenimine. Filters are washed 2 times with 3 ml of 50 mM Tris-HCI {pH7.4). Filters are added to 6 mls of Ready-Safe liquid scintillation cocktail and quantified by liquid scintillation spectrometry in a LKB 1219 RackBeta counter. Non-specific binding is determined by the addition of either 1 p,M of CP-99994 (NK-1 ) or 1 p,M SR-48968 (NK-2) (both synthesized by the chemistry department of Schering-Plough Research Institute). ICSO values are determined from competition binding curves and Ki values are determined according to Cheng and Prusoff using the experimentally determined value of 0.8 nM for the NK-1 receptor and 2.4 nM for the NK-2 receptor.

NK3 activity is determined by following a procedure similar to that described in the literature, e.g., Molecular Pharmacol., 48 (1995), p.
711-716.
Inhibition is the difference between the percent of maximum specific binding (MSB) and 100%. The percent of MSB is defined by the following equation, wherein "dpm" is disintegrations per minute:
% MSB - (dpm of unknown) - (dpm of nonspecific binding) (dpm of total binding) - (dpm of nonspecific binding) It will be recognized that compounds of formula I exhibit NK1, NK2 and/or NK3 antagonist activity to varying degrees, e.g., certain compounds have strong NKi antagonist activity, but weaker NK2 and NK3 antagonist activity, while others are strong NK2 antagonists, but weaker NK1 and NK3 antagonists. While compounds with approximate equipotency are preferred, it is also within the scope of this invention to use compounds of with unequal NK1/NK2/NK3 antagonist activity when clinically appropriate.
Using the test procedures described above, compounds of the present invention are found to exhibit a range of activity: percent inhibition at a dosage of 1 p.M ranges from about 0 to about 100%
inhibition of NK1 and/or about 0 to about 100% inhibition of NK2.
Preferred are compounds having a Ki <_100nM for the NKi receptor. Also preferred are compounds having a Ki 5100nM for the NK2 receptor.
Another group of preferred compounds are those having a Ki <100nM for each of the NKland NK2 receptors.

Claims (9)

We claim:

1. A compound represented by the structural formula or a pharmaceutically acceptable salt thereof, wherein:
a is 0, 1, 2 or 3;
b and d are independently 0, 1 or 2;
R is H, (C1-6)alkyl, -OR6 or C2-C6 hydroxyalkyl;
A is =N-OR1, =N-N(R2)(R3), =C(R11)(R12) or =NR25;
X is a bond, -C(O)-, -O-, -NR6-, -S(O)e-, -N(R6)C(O)-, -C(O)N(R6)--OC(O)NR6-, -OC(=S)NR6-, -N(R6)C(=S)O-, -C(=NOR1)-, -S(O)2N(R6)-, -N(R6)S(O)2-, -N(R6)C(O)O- or -OC(O)-, provided that when d is 0, X is a bond, -C(O)-, -NR6-, -C(O)N(R6)-, -N(R6)C(O)-, -OC(O)NR6-, -C(=NOR1)-, -N(R6)C(=S)O-, -OC(=S)NR6-, -N(R6)S(O)2- or -N(R6)C(O)O-; provided that when A is =C(R11)(R12) and d is 0, X is not -NR6- or -N(R6)C(O)-; and provided that when A is =NR25, d is 0 and X is -NR6- or -N(R6)C(O)-;
T is H, R4-aryl, R4-heterocycloalkyl, R4-heteroaryl, phthalimidyl, R4-cycloalkyl or R10-bridged cycloalkyl;
Q is R5-phenyl, R5-naphthyl, -SR6, -N(R6)(R7), -OR6 or R5-hetero-aryl, provided that when Q is -SR6, -N(R6)(R7) or -OR6, R is not -OR6;
R1 is H, C1-6 alkyl, -(C(R6)(R7))n-G, -G2, -(C(R6)(R7))p-M-(C(R13)(R14))n-(C(R8)(R9))u-G, -C(O)N(R6)-(C(R13)(R14))n-(C(R8)(R9))u-G
or -(C(R6)(R7))p-M-(R4-heteroaryl);
R2 and R3 are independently selected from the group consisting of H, C1-6 alkyl, -CN, -(C(R6)(R7))n-G, -G2, -C(O)-(C(R8)(R9))n-G and -S(O)eR13; or R2 and R3, together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of -O-, -S- and -N(R19)-;
R4 and R5 are independently 1-3 substituents independently selected from the group consisting of H, halogeno, -OR6, -OC(O)R6, -OC(O)N(R6)(R7), -N(R6)(R7), C1-6 alkyl, -CF3, -C2F5, -COR6, -CO2R6, -CON(R6)(R7), -S(O)eR13, -CN, -OCF3, -NR6CO2R16, -NR6COR7, -NR8CON(R6)(R7), R15-phenyl, R15-benzyl, NO2, -N(R6)S(O)2R13 or -S(O)2N(R6)(R7); or adjacent R4 substituents or adjacent R5 substituents can form a -O-CH2-O- group; and R4 can also be R15-heteroaryl;

R6, R7, R8, R6a, R7a, R8a, R13 and R14 are independently selected from the group consisting of H, C1-6 alkyl, C2-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, R15-phenyl, and R15-benzyl; or R6 and R7, together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of -O-) -S- and -N(R19)-;
R9 and R9a are independently selected from the group consisting of R6 and -OR6 R10 and R10a are independently selected from the group consisting of H and C1-6 alkyl;
R11 and R12 are independently selected from the group consisting of H, C1-C6 alkyl, -CO2R6, -OR6, -C(O)N(R6)(R7), C1-C6 hydroxyalkyl, -(CH2)rOC(O)R6, -(CH2)r-OC(O)CH=CH2, -(CH2)r-O(CH2)s-CO2R6, -(CH2)r-O-(CH2)s-C(O)N(R6)(R7) and -(CH2)rN(R6)(R7);
R15 is 1 to 3 substituents independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogeno, -CF3, -C2F5, -COR10, -CO2R10, -C(O)N(R10)2, -S(O)eR10a, -CN, -N(R10)COR10, -N(R10)CON(R10)2 and -NO2;
R16 is C1-6 alkyl, R15-phenyl or R15-benzyl;
R19 is H, C1-C6 alkyl, -C(O)N(R10)2, -C02R10, -(C(R8)(R9))f-CO2R10 or -(C(R8)(R9))u-C(O)N(R10)2;
f, n, p, r and s are independently 1-6;
u is 0-6;
G is selected from the group consisting of H, R4-aryl, R4-hetero-cycloalkyl, R4-heteroaryl) R4-cycloalkyl, -OR6, -N(R6)(R7), -COR6, -CO2R6, -CON(R7)(R9), -S(O)eR13, -NR6CO2R16, -NR6COR7. -NR8CON(R6)(R7), -N(R6)S(O)2R13, -S(O)2N(R6)(R7), -OC(O)R6, -OC(O)N(R6)(R7), -C(=NOR8)N(R6)(R7), -C(=NR25)N(R6)(R7), -N(R8)C(=NR25)N(R6)(R7), -CN, -C(O)N(R6)OR7, and -C(O)N(R9)-(R4-heteroaryl)) provided that when n is 1 and a is 0, or when R9 is -OR6, G is not -OH or -N(R6)(R7);
M is selected from the group consisting of a double bond, -O-, -N(R6)-, -C(O)-, -C(R6)(OR7)-, -C(R8)(N(R6)(R7))-, -C(=NOR6)N(R7)-, -C(N(R6)(R7))=NO-, -C(=NR25)N(R6)-, -C(O)N(R9)-, -N(R9)C(O)-, -C(=S)N(R9)-, -N(R9)C(S)- and -N(R6)C(O)N(R7)-, provided that when n is 1, G is not OH or-NH(R6); and when p is 2-6, M can also be -N(R6)C(=NR25)N(R7)- or -OC(O)N(R6)-;
G2 is R4-aryl, R4-heterocycloalkyl, R4-heteroaryl, R4-cycloalkyl, -CORE, -CO2R16, -S(O)2N(R6)(R7) or -CON(R6)(R7);

a is 0, 1 or 2, provided that when a is 1 or 2, R13 and R10a are not H;
R25 is H, C1-C6 alkyl, -CN, R15-phenyl or R15-benzyl;
Z is , or wherein the nitrogen expressly shown above is optionally quatemized with C1-4 alkyl or phenyl-C1-4 alkyl or is optionally present as the N-oxide g and h are each independently 0, 1, 2, 3, 4, or 5, with the proviso that g + h is equal to 1, 2, 3, 4, or 5;
R26 is selected from the group consisting of (1) a covalent bond (2) C1-3 alkylene, unsubstituted or substituted with a substituent selected from the group consisting of =O, -OH, -OR35, halogeno, -CF3, phenyl or mono, di or trisubstituted phenyl, wherein the substituents on the phenyl are independently selected from -OH, -CN, halogeno and -CF3, (3) S(O)k (4) (C1-3 alkylene)-S(O)k (5) S(O)k-(C1-2 alkylene) (6) S(O)kNH

(7) S(O)j-NR35 (8) S(O)j-NR35-(C1-2 alkylene) (9) CONH

(10) CONR35-(C1-2 alkylene) (11) CO2 and (12) CO2-(C1-2 alkylene) wherein j is 1 or 2 and k is 0, 1 or 2;

R26 is -NR37- , -O-, -S-, -S(O)-, or -SO2-, with the proviso that when R26 is a covalentnd and R28 is C1-3 alkyl, R27 must be NR37;

R37 is selected from a group consisting of:
(1) H, (2) C1-8 linear or branched alkyl, unsubstituted, monosubstituted or multiply substituted with -OR35, =O, -NHCOR35, -NR35R36, -CN, -halogeno,-CF3, -phenyl or substituted phenyl, wherein the substitutents on phenyl are selected from the group consisting of -OH, -CN, halogeno and -CF3;

(3) S(O)R38, wherein R38 is C1-6 linear or branched alkyl, unsubstituted, mono di or trisubstituted with a substituent selected from the group consisting of =O) -CN, -OR35, -NR35R36, -NR36OR36,-halogeno,-CF3, -phenyl or mono, di or trisubstituted phenyl, wherein the substituents on the phenyl are independently selected from the group consisting of -OH, =O, -CN, -NR35R36, -NR35COR36, -halogeno, -CF3 and C1-3 alkyl;
(4) SO2R38, (5) COR38, (6) CO2R38;
(7) CONR36R38;
R28 is selected from the group consisting of (1) a covalent bond (2) C1-3 alkylene, unsubstituted or substituted with a substituent selected from the group consisting of =O, -OR35, halogeno, -CF3, phenyl or mono, di or trisubstituted phenyl, wherein the substitutents on the phenyl are independently selected from the group consisting of -OR35, halogeno and -CF3;
(3) S(O)k (4) (C1-3 alkylene)-S(O)k (5) S(O)k-(C1-2 alkylene) (6) NHS(O)j (7) NH(C1-2 alkylene)-S(O)j (8) S(O)jNR35 (9) S(O)j-NR35-(C1-2 alkylene) (10) NHCO-(C1-2 alkylene) (11) NR35CO
(12) NR35-(C1-2 alkylene)-CO
(13) O(CO) and (14) (C1-2 alkyl)O(CO);
R29-R30 considered together are 2 adjoining atoms of the ring said ring being a phenyl, naphthyl or heteroaryl group, and wherein the phenyl, naphthyl or heteroaryl group is unsubstituted, mono, di or tri substituted, wherein heteroaryl is selected from the group consisting of benzimidazolyl, benzofuranyl, benzoxazolyl, furanyl, imidazolyl, indolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl) pyridyl, pyrimidyl, pyrrolyl, quinolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl and triazolyl; and wherein the substitutents are independently selected from the group consisting of:
(a) C1-6 alkyl, branched or unbranched, unsubstituted or mono or disubstituted by hydroxy (b) =O
(c) OR35 (d) halogeno (e) CF3 (f) NO2 (g) CN
(h) NR35R36 (i) NR35COR36 (j) NR35CO2R36 (k) NR35S(O)jR36 (l) CONR35R36 (m) COR35 (n) CO2R35 (o) S(O)jR35 (p) heteroaryl, or mono or di substituted heteroaryl, wherein heteroaryl is as defined above and the substitutents are selected from the group consisting of: C1-6 alkyl, branched or unbranched, unsubstituted or mono or disubstituted by OH; =O; OR35; CF3; -NO2; CN;
NR35R36; NR35COR36; NR35CO2R36; NR35S(O)jR36; CONR35R36;
COR35; CO2R35; S(O)jR35; and phenyl;
R35 and R36 are independently selected from:
(a) H, (b) C1-6 alkyl, or mono or disubstituted C1-6 alkyl, wherein the substitutents independently selected from the group consisting of phenyl, unsubstituted or substituted with -OH, C1-3 alkyl) -CN, halogeno, -CF3 or C1-4 alkoxy; -OH; =O; -CN; halogeno; or -CF3;
(c) phenyl, pyridinyl or thiophene, or mono, di or trisubstituted phenyl, pyridinyl or thiophene, wherein the substitutents are independently selected from the group consisting of -OH, C1-4 alkyl, -CN, halogeno and -CF3;
(d) C1-3 alkyloxy, or R35 and R36 are joined together to form a 5-, 6-, or 7-membered monocyclic saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and in which the ring is unsubstituted or mono or disubstituted, wherein the substituents are independently selected from the group consisting of -OH, =O, -CN, halogeno and -CF3;
Ar is selected from the group consisting of phenyl, naphthyl, heteroaryl as defined above, isoquinolyl, benzofuryl, isobenzyofuryl, benzothienyl, isoindolyl, purinyl, triazinyl, benzthiazolyl, imidazopyrazinyl, triazolopyrazinyl, naphthyridinyl, furopyridinyl, thiopyranopyrimidyl and the 5-oxide and 5-dioxide thereof, pyridazinyl, quinazpfinyl, pteridinyl, triazolopyrimidyl, triazolopyrazinyl, thiapurinyl, oxapurinyl and deazapurinyl, said groups being optionally mono- or di-substituted by sustituents selected from the group consisting of:
(a) C1-3 alkyl or C1-3 alkyl substituted by =O, OH, OR41, halogen, -CF3, phenyl or mono-, d- or tri-substituted phenyl, wherein the substituents on phenyl are selected from the group consisting of OH, CN, halogen and CF3;
(b) -(CH2)nS(O)k-(C1-6 alkyl)) wherein n is 0, 1 or 2 (c) -(CH2)nS(O)j-NHR41 (d) -(CH2)nS(O)j-NR41-(C1-6 alkyl) (e) -(CH2)nCONHR41 (f) -(CH2)nCONR41-(C1-6 alkyl) (g) -(CH2)nCO2H
(h) -(CH2)nCO2-(C1-6 alkyl) (i) -(CH2)nNR41 R42 (j) -(CH2)nNH-C(O)-(C1-6 alkyl) (k) -(CH2)nNH-C(O)NH2 (I) -(CH2)nNH-C(O)NH-(C1-salkyl) (m) -(CH2)nNH-C(O)N-(di-C1-6 alkyl) (n) -(CH2)nNH-S(O)k-(C1-6 alkyl) (o) -(CH2)nN-(C1-3 alkyl)-C(O)-N-(di-C1-6 alkyl) (p) -(CH2)n-heteroaryl, -C(O)-heteroaryl and -(CH2)n-O-heteroaryl wherein heteroaryl is as defined above and wherein heteroaryl can be optionally substituted by 1 to 3 substituents selected from the group consisting of: C1-6 alkyl, branched or unbranched, unsubstituted or mono or disubstituted by hydroxy; =O; OR35; halogeno; CF3; NO2; CN;

NR35R36; NR35COR36; NR35CO2R36; NR35S(O)jR36; CONR35R36;
COR35; CO2R35; and S(O)jR35;
R41 is (a) H, (b) C1-6 alkyl, or mono or disubstituted C1-6 alkyl, wherein the substitutents independently selected from the group consisting of phenyl;
-OH; =O; -CN; halogeno; and -CF3;
(c) phenyl, mono, di or trisubstituted phenyl, wherein the substitutents are independently selected from the group consisting of -OH, C1-3 alkyl, -CN, halogeno and -CF3;
R42 is (a) H, (b) C1-6 alkyl, or mono or disubstituted C1-6 alkyl, wherein the substitutents independently selected from the group consisting of phenyl, unsubstituted or substituted with -OH, C1-3 alkyl, -CN, halogeno, -CF3 or C1-3 alkoxy; -OH; =O; -CN; halogeno; and -CF3;
(c) phenyl, naphthyl, or mono, di or trisubstituted phenyl or naphthyl, wherein the substitutents are independently selected from the group consisting of -OH, C1-3 alkyl, -CN, halogeno and -CF3;
(d) C1-3 alkyloxy, or R41 and R42 are joined together to form a 5-, 6-, or 7-membered monocyclic saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and in which the ring is unsubstituted or mono or disubstituted, wherein the substituents are independently selected from the group consisting of -OH, =O, -CN, halogeno and -CF3;
R39 and R40 are independently selected from the group consisting of H, OH, CN, halogen, CF3 and C1-3 alkoxy;
J is carbon and R43, R44, R45 and R46 are independently selected from the group consisting of H, -OH, =O, -NR47R48 or -NR47C(O)-NR47'R48, wherein the nitrogen of -NR47R48 is optionally quaternized with C1-4 alkyl or phenyl-C1-4 alkyl or is optionally present as the Noxide; or R43 and R44, or R44 and R45, together form a carbon-carbon bond; or R43 and R44 or R44 and R45, or R45 and R46, together with the carbons to which they are attached form an aryl or heteroaryl ring, wherein heteroaryl is as defined above, and wherein the aryl or heteroaryl group is unsubstituted, mono, di or tri substituted, wherein the substitutents are independently selected from the group consisting of:

(a) C1-6 alkyl, branched or unbranched, unsubstituted or mono or disubstituted by hydroxy (b) =O

(c) OR47 (d) halogeno (e) CF3 (f) NO2 (g) CN

(h) NR47R48 (i) NR47COR48 (j) NR47CO2R48 (k) NR47S(O)j R48 (l) CONR47R48 (m) COR47 (n) CO2R47 (o) S(O)k R47 (p) heteroaryl, or mono or di substituted heteroaryl, wherein heteroaryl is as defined above and the substitutents are selected from the group consisting of: C1-6 alkyl, branched or unbranched, unsubstituted or mono or disubstituted by OH; =O; OR47; CF3; -NO2; CN;
NR47R48; NR47COR48; NR47CO2R48; NR47S(O)j R48; CONR47R48;
COR47; CO2R47; S(O)j R47; and phenyl;
or R43, R44 and R45 are as defined above and J-R46 is oxygen or S(O)j, wherein i is 0, 1, or 2; and R47, R47' and R48 are independently selected from the group consisting of:
(a) H, (b) C1-6 alkyl, or mono or disubstituted C1-6 alkyl, wherein the substitutents independently selected from the group consisting of phenyl, -OH, =O) -CN, halogeno and -CF3;
(c) phenyl, naphthyl, or mono, di or trisubstituted phenyl or naphthyl, wherein the substitutents are independently selected from the group consisting of -OH, C1-3 alkyl, -CN, halogeno and -CF3; and (d) C1-3 alkyloxy; or R47 and R48 are joined together to form a 5-, 6-, or 7-membered monocyclic saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and in which the ring is unsubstituted or mono or disubstituted, wherein the substituents are independently selected from the group consisting of -OH, =O, -CN, halogeno and -CF3.

2. A compound of claim 1 wherein X is -O-, -C(O)-, a bond, -NR6-, -S(O)e-, -N(R6)C(O)-, -C(O)NR6, -OC(O)NR6- or -C(=NOR1)-; T is R4-aryl, R4-heteroaryl, R4-cycloalkyl or R10-bridged cycloalkyl; Q is R5-phenyl, R5-naphthyl or R5-heteroaryl; and R6a, R7a, R8a and R9a are independently selected from the group consisting of H, hydroxyalkyl and alkoxyalkyl.

3. A compound of claim 2 wherein X is -O-, -NR6-, -N(R6)C(O)- or -C(O)NR6-; b and d are each 1; R6a, R7a, R8a and R9a are each H; R is H;
T is R4-aryl; and Q is R5-phenyl or benzothienyl.

4. A compound of claim 1 wherein Q is R5-phenyl or benzothienyl, T is R4-aryl, R is H, a is 1, A is =NOR1, is -CH2-O-CH2, -CH2-N(R6)C(O)-, -CH2NR6CH2- or CH2C(O)NR6-, and Z is ,, , or , wherein Ar is selected from the group consisting of and .

5. A compound of claim 4 wherein R1 is H, alkyl, -(CH2)n-G, -(CH2)p-M-(CH2)n-G or -C(O)N(R6)(R7), wherein M is -O- or -C(O)N(R9)-and G is -CO2R6, -OR6, -C(O)N(R6)(R9), -C(=NOR8)N(R6)(R7), -C(O)N(R9)(R4-heteroaryl) or R4-heteroaryl.

6. A compound of claim 1 represented by the formula wherein G and R4 are as defined in claim 1.

7. A compound of claim 6 represented by the structural formula

8. A pharmaceutical composition comprising an effective amount of a compound of any of claimsl to 7 and a pharmaceutically acceptable carrier.

9. The use of a compound of any of claims 1 to 7 for the preparation of a medicament for treating asthma, cough, bronchospasm, central nervous system diseases, inflammatory diseases and gastrointestinal disorders.