Benzoxazinone and benzopyrimidinone piperidinyl tocolytic oxytocin receptor antagonists

A compound of the formula ##STR298## wherein Y is CH.sub.2, C.dbd.O, C.dbd.S, C.dbd.N--H or C.dbd.N--CHH.sub.3 ;

• X is selected from the group consisting of CH.sub.2 --O--, --C(R.sup.8).sub.2 --O--, --C(R.sup.8).sub.2 --CH.sub.2 --, --CH(R.sup.11)--O--, --CH(R.sup.11)--CH.sub.2, --C(O)--CH.sub.2 --, --CH.sub.2 --NH--, --CH.sub.2 --NR.sup.8 --, --O--CH.sub.2 --, --C(R.sup.8).dbd.N--,--N.dbd.C(R.sup.8)--,--NH--CH.sub.2 --,--NR.sup.8 --CH.sub.2 --, --CH.sub.2 '--CH.sub.2, --CH.dbd.CH--, --C(OH).dbd.CH--, and --S(O).sub.m --CH.sub.2 --;
• "A" represents a fused aromatic or heteroaromatic ring such that the bicyclic ring system containing the A ring is selected from the group consisting of ##STR299## B is a heterocyclic or heterobicyclic ring selected from the group consisting of ##STR300## W is --CO--, --COO--, --CONRS--, --C(.dbd.NR.sup.8)--, --C(O)--CH(R.sup.10)--, --C(.dbd.NCH.sub.2 Ph)-- or --SO.sub.2 --;
• R.sup.1 is selected from the group consisting of camphor-10-yl, C.sub.1-5 alkoxyl, styryl, hydroxystyryl, furyl, thienyl, pyrrolyl, naphthyl, indolyl, tetrahydronaphthyl, unsubstituted, mono- or di-substituted pyridyl where said substituent on said pyridyl are each independently selected from C.sub.1-5 alkyl, C.sub.1-5 alkoxy, halogen, hydroxyl or R.sup.7, pyrazinyl, quinolinyl, substituted thienyl where said substituent is selected from the group consisting of C.sub.1-5 alkoxycarbonyl, C.sub.1-5 alkylcarbonyl, carboxyl and pyridyl, C.sub.1-5 alkyl-substituted pyrrolyl, unsubstituted or substituted cyclohexyl where said substituent is R.sup.4, and unsubstituted or substituted phenyl where said substituents are one or more of R.sup.5, R.sup.6 or R.sup.7 ;
• R.sup.2 is selected from the group consisting of hydrogen, hydroxyl, C.sub.1-5 alkoxyl, C.sub.1-5 alkyl, amino, C.sub.1-5 alkylcarbonylamino, nitro, methanesulfonylamino, trifluoromethyl and halogen;
• R.sup.3 is selected from the group consisting of hydrogen, amino, C.sub.1-5 alkyl, C.sub.1-5 alkoxycarbonyl, hydroxy-C.sub.1-10 alkyl, methylthio-C.sub.1-10 alkyl, methylsulfonyl-C.sub.1-10 alkyl, methylsulfonyl, cyano, carbamoyl and carboxy;
• R.sup.4 is independently one or two members of the group consisting of hydrogen, oxo, hydroxyl, C.sub.1-5 alkoxyl, C.sub.1-5 alkoxy-carbonylamino-C.sub.1-5 alkyl and amino-C.sub.1-5 alkyl;
• R.sup.5 and R.sup.6 are each independently selected from the group consisting of hydrogen, halogen, phenyl, hydroxyphenyl, phenoxy, hydroxyphenoxy, phenyl-C.sub.1-5 alkyl, C.sub.1-10 alkyl, trifluoromethyl, C.sub.3-6 cycloalkyl, cyano, carboxy-C.sub.1-5 alkyl, C.sub.1-10 alkoxy-C.sub.1-5 alkyl, C.sub.1-10 alkoxycarbonyl-C.sub.1-5 alkyl, C.sub.1-10 alkoxycarbonyl-C.sub.2-6 alkenyl, mono- or di-C.sub.1-10 alkylamino-C.sub.1-5 alkyl, cyano-C.sub.1-5 alkyl, halo-C.sub.1-5 alkyl, --S(O).sub.m --CH.sub.3, --NO.sub.2, hydroxyl, hydroxy-C.sub.1-5 alkyl, C.sub.1-10 alkoxyl, substituted C.sub.1-5 alkoxy in which the alkyl group of said alkyloxy substitutent is substituted with a C.sub.2-6 alkenyl group, substituted C.sub.1-5 alkoxy in which the alkyl group of said alkyloxy substitutent is substituted with a C.sub.2-6 alkynyl group, C.sub.3-6 cycloalkyloxy, C.sub.3-6 cycloalkyl-C.sub.1-5 alkoxy, trifluoromethoxy, carboxy, C.sub.1-10 alkoxycarbonyl, C.sub.1-10 alkylcarbonyl, --N(R.sup.13).sub.2 and --NH--COR.sup.14 ;
• R.sup.7 is selected from the group consisting of hydrogen, C.sub.1-5 alkoxy, carboxyl, amino-C.sub.2-5 alkoxy, --CO--R.sup.16, ##STR301## R.sup.8 is independently selected from hydrogen or C.sub.1-5 alkyl;
• R.sup.9 is selected from the group consisting of Het, amino, --N(R.sup.8)--(CH.sub.2).sub.q --CO--R.sup.14, C.sub.1-5 alkoxyl, mono- or di-C.sub.1-10 alkylamino-C.sub.1-5 alkyl, mono- or di-C.sub.1-10 alkylamino-C.sub.2-6 alkylamino, unsubstituted C.sub.1-5 alkyl and substituted C.sub.1-5 alkyl where said substitutent is selected from the group consisting of carboxyl, hydroxyl, amino, methylsulfonyl, --N(R.sup.8).sub.2, --NHR.sup.8, C.sub.1-5 alkoxycarbonyl, C.sub.1-10 alkoxycarbonylamino and Het;
• R.sup.10 is selected from the group consisting of hydrogen, hydroxyl, C.sub.1-5 alkoxycarbonyl, C.sub.1-5 alkoxycarbonylamino, hydroxy-C.sub.1-5 alkyl, amino, --N(R.sup.8).sub.2, --NHR.sup.8, cyano, C.sub.1-5 alkyl and C.sub.1-5 alkoxy;
• R.sup.11 is selected from the group consisting of C.sub.1-5 alkyl, trifluoromethyl and unsubstituted, mono-, di- or tri- substituted phenyl wherein said substituents on said phenyl are independently selected from the group consisting of C.sub.1-5 alkyl, C.sub.1-10 alkoxyl, halogen and trifluoromethyl;
• R.sup.12 is selected from the group consisting of hydrogen, C.sub.1-10 alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-5 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-10 alkoxycarbonyl, C.sub.1-5 alkylcarbonyl, tetrazolyl, cyano, 4-tetrahydropyranyl, 4-tetrahydrothiopyranyl, 4-piperidinyl, N-(C.sub.1-10 alkoxy-carbonyl)-4-piperidinyl, N-(C.sub.1-5 alkyl)-4-piperidinyl, 2-pyrimidinyl optionally substituted with one to two members of the group consisting of halogen, carbamoyl, carboxyl, cyano, 5-tetrazolyl, aminothiocarbonyl, --C(NHR.sup.18).dbd.NR.sup.17, amino-C.sub.1-5 -alkyl, and mono- or di- C.sub.1-10 -alkylamino-C.sub.1-5 -alkyl, ##STR302## --SO.sub.2 --R.sup.15, --CO--R.sup.16, unsubstituted or substituted pyridyl wherein said substituent on said pyridyl is selected from hydrogen, halogen, C.sub.1-10 alkoxycarbonyl, carboxy, nitro or amino, and mono- or di-substituted C.sub.1-10 alkyl wherein said substituents on said C.sub.1-10 alkyl are independently selected from the group consisting of hydroxyl, C.sub.1-10 alkoxycarbonyl, carboxyl, hydroxyl, C.sub.1-5 alkoxyl, cyano, methylsulfonyl, aminocarbonyl, imidazolyl, tetrazolyl, morpholinyl, piperazinyl, benzodioxanyl, quinolinyl, isoquinolinyl, furyl, furopyridyl, thienyl, 5-halo-2-thienyl, 3,5-dimethyl-4-isoxazolyl, pyrazinyl, C.sub.1-5 akyl-substituted pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, C.sub.1-10 alkyl-substituted thiazolyl, oxadiazolyl, phenyl-substituted oxadiazolyl, chlorophenyl-substituted thiazolyl, benzimidazolyl, thienopyridyl, mono or di- chlorothienopyridyl, furopyridyl, uracil, tinsubstituted, mono-, or di-substituted pyridyl wherein said substituents on said pyridyl are independently selected from hydrogen, halogen, C.sub.1-10 alkoxy, C.sub.1-10 alkyl, amino-C.sub.1-5 alkyl, mono or di-C.sub.1-5 alkylamino-C.sub.1-5 alkyl, C.sub.1-10 alkyl-carbonyl, C.sub.1-10 alkoxycarbonyl, carboxy, nitro, hydroxy, hydroxy C.sub.1-5 alkyl, C.sub.1-5 alkoxy-C.sub.1-5 alkyl or amino, mono-, or di-substituted pyridyl-N-oxide wherein said substituents on said pyridyl-N-oxide are independently selected from hydrogen, halogen, C.sub.1-10 alkoxy, C.sub.1-10 alkyl, amino-C.sub.1-5 alkyl, mono or di-C.sub.1-5 alkyl-amino-C.sub.1-5 alkyl, C.sub.1-10 alkylcarbonyl, C.sub.1-10 alkoxy-carbonyl, carboxy, nitro, hydroxy, hydroxy C.sub.1-5 alkyl, C.sub.1-5 alkoxy-C.sub.1-5 alkyl or amino, and unsubstituted, mono- or di-substituted phenyl wherein said substituents on said phenyl are independently selected from hydrogen, halogen, hydroxyl, C.sub.1-10 alkoxyl, C.sub.1-10 alkoxycarbonyl, cyano or carboxyl;
• R.sup.13 is independently selected from the group consisting of hydrogen, C.sub.1-5 alkyl and C.sub.1-5 alkylsulfonyl;
• R.sup.14 is selected from the group consisting of C.sub.1-5 alkyl, C.sub.1-5 alkoxyl, amino-C.sub.1-5 alkyl, phenyl and benzimidazolyl;
• R.sup.15 is selected from the group consisting of amino, C.sub.1-10 alkoxy-carbonylamino, amino-C.sub.2-10 alkylamino, mono- or di- C.sub.1-10 alkylamino-C.sub.2-10 alkylamino, 3-azetidinyl, 1-benzyl-3-azetidinyl, 1-(C.sub.1-10 alkyl)-3-azetidinyl, unsubstituted or 1-substituted piperidinyl in which said substituent on said piperidinyl is selected from the group consisting of benzyl, C.sub.1-5 alkoxycarbonyl, C.sub.1-5 alkyl, hydroxy-C.sub.2-5 alkyl, C.sub.1-5 alkoxy-C.sub.2-5 alkyl, pyridylmethyl, or C.sub.1-5 alkylpyridylmethyl, unsubstituted or 1-substituted 3-pyrrolidinyl in which said substituent on said pyrrolidinyl is selected from the group consisting of benzyl, C.sub.1-5 alkoxycarbonyl, C.sub.1-5 alkyl, hydroxy-C.sub.2-5 alkyl, C.sub.1-5 alkoxy-C.sub.2-5 alkyl, pyridylmethyl, or C.sub.1-5 alkylpyridylmethyl, unsubstituted or 4-substituted 1-piperazinyl in which said substituent on said piperazinyl is selected from the group consisting of benzyl, C.sub.1-5 alkoxycarbonyl, C.sub.1-5 alkyl, hydroxy-C.sub.2-5 alkyl, C.sub.1-5 alkoxy-C.sub.2-5 alkyl, pyridylmethyl, or C.sub.1-5 alkyl-pyridylmethyl, 1-(C.sub.3-6 cycloalkyl)-4-piperazinyl, mono- or di-C.sub.1-10 alkylamino-C.sub.2-10 alkylamino, vinyl, pyridyl, unsubstituted or substituted phenyl wherein said substitutent on said phenyl is selected from C.sub.1-5 alkyl, nitro, amino, C.sub.1-10 alkoxycarbonyl or carboxy, and unsubstituted or substituted C.sub.1-10 alkyl wherein said substituent on said alkyl is selected from halogen, R.sup.20, carboxy, cyano, C.sub.1-10 alkoxycarbonyl, azido, acetamidinyl, guanido, morpholino, pyrrolidinyl, piperidinyl, 2,2,6,6-tetramethyl-1-piperidinyl, hydroxy-pyrrolidinyl, tetrazolyl, piperazinyl, C.sub.1-5 alkoxy-C.sub.1-5 alkyl-substituted 1-pyrrolidinyl, 3-(C.sub.1-5 alkoxy)-1-pyrrolidinyl, 4-(C.sub.1-5 alkoxy-C.sub.2-5 alkyl)-1-piperazinyl, 1-(C.sub.1-10 alkyl)-4-piperazinyl, N-tetrahydroisoquinolinyl, aza-cycloheptyl, mono- or di-substituted 1-piperidinyl wherein said substitutents on said piperidinyl are independently selected from C.sub.1-5 alkyl, hydroxyl, C.sub.1-5 alkoxy, cyano, phenyl, 1-piperidinyl, trihalomethyl, spiro-cyclopropyl, or spiro-cyclopentyl, mono- or di-substituted 1-pyrrolidinyl wherein said substitutents on said pyrrolidinyl are independently selected from C.sub.1-5 alkyl, trihalomethyl, spiro-cyclopropyl, or spiro-cyclopentyl, C.sub.3-8 cycloalkyl wherein said cycloalkyl is optionally substituted with carboxy, nitro, amino, mono- or di-C.sub.1-5 alkylamino, R.sup.20, 1-pyrrolidinyl, 4-morpholinyl, 1-piperidinyl, 4-(C.sub.1-5 alkyl)-1-piperidinyl, or 4,4-di-(C.sub.1-5 alkyl)-1-piperidinyl, and unsubstituted, mono- or di-substituted amino wherein said substituents on said amino are independently selected from benzyl, C.sub.1-10 alkyl, hydroxy-C.sub.2-10 alkyl, C.sub.1-10 alkoxy-C.sub.2-10 alkyl, C.sub.3-8 cycloalkyl, carboxy-C.sub.1-10 alkyl, C.sub.1-10 alkoxycarbonyl-C.sub.1-10 alkyl, C.sub.3 -6 cycloalkyl-substituted-C.sub.1-10 alkyl or allyl;
• R.sup.16 is selected from the group consisting of hydrogen, Het, 1-(C.sub.1-10 alkoxycarbonyl)-4-piperidinyl, imidazolyl, unsubstituted or 1-substituted piperidinyl in which said substituent on said piperidinyl is selected from the group consisting of benzyl, C.sub.1-5 alkoxycarbonyl, C.sub.1-5 alkyl, hydroxy-C.sub.2-5 alkyl, C.sub.1-5 alkoxy-C.sub.2-5 alkyl, pyridylmethyl, or C.sub.1-5 alkylpyridylmethyl, unsubstituted or 1-substituted 3-pyrrolidinyl in which said substituent on said pyrrolidinyl is selected from the group consisting of benzyl, C.sub.1-5 alkoxycarbonyl, C.sub.1-5 alkyl, hydroxy-C.sub.2-5 alkyl, C.sub.1-5 alkoxy-C.sub.2-5 alkyl, pyridylmethyl, or C.sub.1-5 alkylpyridylmethyl, unsubstituted or 4-substituted 1-piperazinyl in which said substituent on said piperazinyl is selected from the group consisting of benzyl, C.sub.1-5 alkoxycarbonyl, C.sub.1-5 alkyl, hydroxy-C.sub.2-5 alkyl, C.sub.1-5 alkoxy-C.sub.2-5 alkyl, pyridylmethyl, or C.sub.1-5 alkyl-pyridylmethyl, pyridyl, 1-(C.sub.3-6 cycloalkyl)-4-piperazinyl, trihalomethyl, C.sub.1-10 alkoxycarbonyl, carboxyl, phenylamino, vinyl, C.sub.1-10 alkoxycarbonylamino, methylsulfonylamino, trihalomethyl-sulfonylamino, amino, guanido, propargylamino, mono- or di-C.sub.1-10 alkylamino-C.sub.2-10 alkylamino, C.sub.1-10 alkylamino, cyanoamino, C.sub.1-10 alkoxycarbonyl-C.sub.1-10 alkylamino, C.sub.1-10 alkoxy-carbonyl-C.sub.1-10 alkylamino-C.sub.1-10 alkyl, carboxy-C.sub.1-10 alkylamino-C.sub.1-10 alkyl, unsubstituted, mono- or di- substituted phenyl wherein said substituents on said phenyl are independently selected from halogen, amino-C.sub.1-10 alkyl, mono- or di-C.sub.1-10 alkylamino-C.sub.2-10 alkyl-amino, C.sub.1-10 alkoxycarbonyl, carboxyl, C.sub.1-10 alkoxyl, 1-(C.sub.1-10 alkoxycarbonyl)-4-piperidinyloxy or 4-piperidinyloxy, and mono- or di-substituted C.sub.1-10 alkyl wherein said substituents on said alkyl are independently selected from halogen, R.sup.20, azido, guanido, acetamidinyl, C.sub.1-10 alkoxycarbonyl, carboxy, carboxymethoxy, carboxy-C.sub.1-10 alkylcyclopentyl, C.sub.1-10 alkoxycarbonyl-amino, amino, cyano, methylsulfonyl, imidazolyl, morpholinyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, 2,2,6,6-tetramethyl-1-piperidinyl, 3-hydroxy-1-pyrrolidinyl, C.sub.1-5 alkoxy-C.sub.1-5 alkyl-substituted 1-pyrrolidinyl, 1-(C.sub.1-10 alkyl)-4-piperazinyl, piperidinyl, N-tetrahydroisoquinolinyl, aza-cycloheptyl, mono- or di- substituted 1-piperidinyl wherein said substitutents on said piperidinyl are independently selected from C.sub.1-5 alkyl, hydroxyl, C.sub.1-5 alkoxyl, cyano, or spiro-cyclopentyl, C.sub.3-8 cycloalkyl wherein said cycloalkyl is optionally substituted with nitro, amino, tri- or di-C.sub.1-5 alkyl-amino, R.sup.20, 1-pyrrolidinyl, or 1-piperidinyl, unsubstituted, mono- or di-substituted amino wherein said substituents on said amino are independently selected from benzyl, C.sub.1-10 alkyl, hydroxy-C.sub.2-10 alkyl, C.sub.1-10 alkoxy-C.sub.2-10 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-5 alkoxycarbonyl-C.sub.1-10 alkyl, carboxy-C.sub.1-10 alkyl or C.sub.3-8 cycloalkyl-substituted C.sub.1-10 alkyl, C.sub.1-10 alkoxycarbonyl, carboxy, carboxymethoxy, carboxy-C.sub.1-10 alkylcyclopentyl, C.sub.1-10 alkoxycarbonylamino, cyano, methylsulfonyl, imidazolyl, morpholinyl, azetidinyl, or 1-(C.sub.1-10 alkyl)-4-piperazinyl;
• R.sup.17 is selected from the group consisting of hydrogen, hydroxyl, cyano, C.sub.1-10 alkylsulfonyl, trihalomethylsulfonyl, C.sub.1-10 alkylcarbonyl and trihalomethylcarbonyl;
• R.sup.18 is selected from the group consisting of hydrogen, C.sub.1-10 alkyl, mono- or di-C.sub.1-10 alkylamino-C.sub.2-10 alkyl and C.sub.3-6 cycloalkyl;
• R.sup.19 is selected from the group consisting of C.sub.1-10 alkoxy, hydroxyl, mono- or di-C.sub.1-10 alkylamino-C.sub.2-10 alkylamino and di-C.sub.1-10 alkylamino --C.sub.1-10 alkyl;
• R.sup.20 is ##STR303## R.sup.21 is selected from the group consisting of hydrogen, C.sub.1-10 alkyl, and C.sub.3-8 cycloalkyl;
• R.sup.22 is independently one to two members from the group consisting of hydrogen, C.sub.1-5 alkyl, halogen, C.sub.1-5 alkoxylcarbonyl, C.sub.1-5 alkoxy, and carboxy;
• R.sup.23 is selected from the group consisting of hydrogen, cyano, amino, C.sub.1-5 alkylcarbonylamino, halogen, halomethyl, --CHO, nitro, carboxy, C.sub.1-5 alkoxycarbonyl, and unsubstituted or substituted C.sub.1-5 alkyl wherein said substituent on said alkyl is selected from amino, mono- or di-C.sub.1-5 alkylamino, cyano, C.sub.1-5 alkoxycarbonyl, carboxy, piperazinyl, 4-[C.sub.1-5 alkoxycarbonyl]-1-piperazinyl, 4-(C.sub.1-5 alkylcarbonyl)-1-piperazinyl, piperidinyl or substituted piperidinyl wherein said substituent on said piperidine is selected from hydroxyl, C.sub.1-5 alkoxycarbonyl or carboxyl;
• and
• Het is selected from the group consisting of imidazolyl, piperidinyl, C.sub.1-5 alkyl-substituted piperidinyl, piperazinyl, C.sub.1-5 alkyl-substituted piperizinyl, C.sub.1-5 alkoxycarbonyl-substituted piperazinyl, morpholinyl, tetrazolyl, C.sub.1-5 alkylcarbonyl-substituted piperidinyl, C.sub.1-5 alkoxy-carbonyl-substituted piperidinyl, pyrrolidinyl, C.sub.1-5 alkyl-substituted pyrrolidinyl, and pyridyl;
• Z is --CO-- or --SO.sub.2 --;
• m is an integer of from 0 to 2;
• n is an integer of from 0 to 3;
• p is an integer of from 1 to 4;
• q is an integer from 1 to 2;
• and
• r is an integer of from 2 to 4;
• provided that when the A containing bicyclic ring system is ##STR304## and Y is --C.dbd.O, and X is --(CH.sub.2).sub.2 --, --CH.dbd.CH--, --C(R.sup.8).sub.2 --CH.sub.2 --, --CH(R.sup.11)--CH.sub.2 or --C(OH).dbd.CH--, then R.sup.1 is substituted phenyl wherein R.sup.7 is ##STR305## and the pharmaceutically acceptable salts thereof.