US 5,629,429 AGranted

Process for preparing 4-arylamino-benzopyran and related compounds

AssigneeBristol-Myers Squibb Company

InventorsDavid R. Kronenthal, Richard H. Mueller, Jollie D. Godfrey, Jr.

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Abstract

A method of preparing compounds of the formula ##STR1## and pharmaceutically acceptable salts thereof which comprises converting a compound of the formula ##STR2## where the R.sup.2 substituent contains a hydrogen atom which is more acidic than the starred (*) hydrogen atom in formula II, to the corresponding dianion of formula ##STR3## where M is a counterion preferably lithium or magnesium, using two equivalents of a base in an inert solvent such as tetrahydrofuran; then reacting compounds of formula IIA with an epoxide of formula ##STR4## to produce the compounds of formula I.

Claims15

Dependent claims

A process for preparing compounds of formula ##STR24## or pharmaceutically acceptable salts thereof wherein a, b and d are all carbon atoms or one of a, b and d is a nitrogen atom or --N(O)-- and the others are carbon atoms;

Y is a single bond, --CH.sub.2 --, --C(O)--, --O--, --S-- or --N(R.sup.8)--;
R.sup.1 is aryl or heterocyclo;
R.sup.2 is --COOR.sup.8, --CO-amino, --CO-substituted amino, amino, substituted amino, --NR.sup.8 CO-amino, --NR.sup.8 CO-substituted amino, --NR.sup.8 COR.sup.9, --NR.sup.8 SO.sub.2 R.sup.9, --NR.sup.8 (C.dbd.NCN)-amino, --NR.sup.8 (C.dbd.NCN)-substituted amino, ##STR25## --SR.sup.8, --SOR.sup.8, --SO.sub.2 R.sup.8, --OR.sup.8l , cyano, heterocyclo, pyridine-N-oxide, ##STR26## (where Z is O or H.sub.2) or ##STR27## R.sup.2 is hydroxy;
R.sup.4 and R.sup.5 are each independently hydrogen, alkyl or arylalkyl, or R.sup.4 and R.sup.5 taken together with the carbon atom to which they are attached form a 5- to 7-membered carbocyclic ring;
R.sup.6 is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, (cycloalkyl)alkyl, --CN, --NO.sub.2, --COR.sup.8, --COOR.sup.8, --CONHR.sup.8, --CONR.sup.8 R.sup.9, --CF.sub.3, --S-alkyl, --SOalkyl, --SO.sub.2 alkyl, ##STR28## halogen, amino substituted amino, --O-alkyl, --OCF.sub.3, --OCH.sub.2 CF.sub.3, --OCOalkyl, --OCONR.sup.8 alkyl, --NR.sup.8 COalkyl, --NR.sup.8 COOalkyl or --NR.sup.8 CONR.sup.9, tetrazolyl, imidazole, oxazole, triazole or --S(O).sub.2 NR.sup.10 R.sup.11 ;
R.sup.7 is hydrogen, alkyl, hydroxy, --O-alkyl, amino, substituted amino, --NHCOR.sup.8, --CN or --NO.sub.2 ;
or when R.sup.6 is --S(O).sub.2 NR.sup.10 R.sup.11, then R.sup.7 in addition to the above is halogen, heterocyclo, haloalkyl or aryl;
R.sup.8 and R.sup.9 are independently hydrogen, alkyl, haloalkyl, aryl, arylalkyl, cycloalkyl or (cycloalkyl)alkyl;
R.sup.10 and R.sup.11 are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, hydroxyalkyl substituted with a carboxylic ester or carboxylic acid, alkoxyalkyl, thioalkyl (cycloalkyl)alkyl, morpholinylalkyl, heterocyclo or (heterocyclo)alkyl;
or R.sup.10 and R.sup.11 taken together with the nitrogen atom to which they are attached form a 5- to 7-membered mono or bicyclic ring, or 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 4-thiamorpholine dioxide, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl;
or 1-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl or 1-azepinyl substituted with one or more alkyl, alkoxy, alkylthio, halo, trifluoromethyl, hydroxy, aryl, arylalkyl, --COOR.sup.8 or --CO-substituted amino;
or R.sup.10 and R.sup.7 taken together with the atoms to which they are attached form an unsubstituted 5- to 7-membered ring or a 5- to 7-membered ring substituted with aryl;
X is alkyl;
or X--R.sup.2 together are hydrogen, aryl or heterocyclo when R.sup.1 is heterocyclo;
and
n is an integer of 1 to 3;
which comprises the steps of treating a compound of the formula ##STR29## (where the R.sup.2 substituent contains a hydrogen atom which is more acidic than the starred (*) hydrogen atom in formula II);
with two equivalents of a base in an inert solvent, to form the corresponding dianion of formula ##STR30## where M is a counterion, then reacting the compounds of formula IIA with an epoxide of formula ##STR31## to produce the compounds of formula I.

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A process for preparing compounds of formula ##STR32## or pharmaceutically acceptable salts thereof wherein a, b and d are all carbon atoms or one of a, b and d is a nitrogen atom or --N(O)-- and the others are carbon atoms;

Y is a single bond, --CH.sub.2 --, --C(O)--, --O--, --S--O or --N(R.sup.8)--;
R.sup.1 is aryl or heterocyclo;
R.sup.2 is --COOR.sup.8, --CO-amino, --CO-substituted amino, amino, substituted amino, --NR.sup.8 CO-amino, --NR.sup.8 CO-substituted amino, --NR.sup.8 COR.sup.9, --NR.sup.8 SO.sub.2 R.sup.9, --NR.sup.8 (C.dbd.NCN)-amino, --NR.sup.8 (C.dbd.NCN)-substituted amino, ##STR33## --SR.sup.8, --SOR.sup.8, --SO.sub.2 R.sup.8, --OR.sup.8, cyano, heterocyclo, pyridine-N-oxide, ##STR34## (where Z is O or H.sub.2) or ##STR35## R.sup.3 is hydroxy;
R.sup.4 and R.sup.5 are each independently hydrogen, alkyl or arylalkyl, or R.sup.4 and R.sup.5 taken together with the carbon atom to which they are attached from a 5- to 7-membered carbocyclic ring;
R.sup.6 is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, (cycloalkyl)alkyl, --CN, --NO.sub.2, --COR.sup.8, --COOR.sup.8, --CONHR.sup.8, --CONR.sup.8 R.sup.9, --CF.sub.3, --S-alkyl, --SOalkyl, --SO.sub.2 alkyl, ##STR36## halogen, amino, substituted amino, --O-alkyl, --OCF.sub.3, --OCH.sub.2 CF.sub.3, --OCOalkyl, --OCONR.sup.8 alkyl, --NR.sup.8 COalkyl, --NR.sup.8 COOalkyl or --NR.sup.8 CONR.sup.9, tetrazolyl, imidazole, oxazole, triazole or --S(O).sub.2 NR.sup.10 R.sup.11 ;
R.sup.7 is hydrogen, alkyl, hydroxy, --O-alkyl, amino, substituted amino, --NHCOR.sup.8, --CN or --NO.sub.2 ;
or when R.sup.6 is --S(O).sub.2 NR.sup.10 R.sup.11, then R.sup.7 is also halogen, heterocyclo, haloalkyl or aryl;
R.sup.8 and R.sup.9 are independently hydrogen, alkyl, haloalkyl, aryl, arylalkyl, cycloalkyl or (cycloalkyl)alkyl;
R.sup.10 and R.sup.11 are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, hydroxyalkyl substituted with a carboxylic ester or carboxylic acid, alkoxyalkyl, thioalkyl, (cycloalkyl)alkyl, morpholinylalkyl, heterocyclo or (heterocyclo)alkyl;
or R.sup.10 and R.sup.11 taken together with the nitrogen atom to which they are attached form a 5- to 7-membered mono or bicyclic ring, or 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 4-thiamorpholine dioxide, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl;
or 1-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl or 1-azepinyl substituted with one or more alkyl, alkoxy, alylthio, halo, trifluoromethyl, hydroxy, aryl, arylalkyl, --COOR.sup.8 or --CO-substituted amino;
or R.sup.10 and R.sup.7 taken together with the atoms to which they are attached form an unsubstituted 5- to 7-membered ring or a 5- to 7-membered ring substituted with aryl;
X is alkyl;
or X--R.sup.2 together are hydrogen, aryl or heterocyclo when R.sup.1 is heterocyclo;
and
n is an integer of 1 to 3;
which comprises the steps of treating a compound of the formula ##STR37## (where the R.sup.2 substituent does not contain a hydrogen atom which is more acidic than the starred (*) hydrogen atom in formula II);
with one equivalent of a base in an inert solvent, to form the corresponding monoanion, then reacting the monoanion with an epoxide of formula ##STR38## to produce the compounds of formula I.

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Dependencies are inferred from the claim text.

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Abstract

Y is a single bond, --CH.sub.2 --, --C(O)--, --O--, --S-- or --N(R.sup.8)--;
R.sup.1 is aryl or heterocyclo;
R.sup.2 is --COOR.sup.8, --CO-amino, --CO-substituted amino, amino, substituted amino, --NR.sup.8 CO-amino, --NR.sup.8 CO-substituted amino, --NR.sup.8 COR.sup.9, --NR.sup.8 SO.sub.2 R.sup.9, --NR.sup.8 (C.dbd.NCN)-amino, --NR.sup.8 (C.dbd.NCN)-substituted amino, ##STR25## --SR.sup.8, --SOR.sup.8, --SO.sub.2 R.sup.8, --OR.sup.8l , cyano, heterocyclo, pyridine-N-oxide, ##STR26## (where Z is O or H.sub.2) or ##STR27## R.sup.2 is hydroxy;
R.sup.4 and R.sup.5 are each independently hydrogen, alkyl or arylalkyl, or R.sup.4 and R.sup.5 taken together with the carbon atom to which they are attached form a 5- to 7-membered carbocyclic ring;
R.sup.6 is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, (cycloalkyl)alkyl, --CN, --NO.sub.2, --COR.sup.8, --COOR.sup.8, --CONHR.sup.8, --CONR.sup.8 R.sup.9, --CF.sub.3, --S-alkyl, --SOalkyl, --SO.sub.2 alkyl, ##STR28## halogen, amino substituted amino, --O-alkyl, --OCF.sub.3, --OCH.sub.2 CF.sub.3, --OCOalkyl, --OCONR.sup.8 alkyl, --NR.sup.8 COalkyl, --NR.sup.8 COOalkyl or --NR.sup.8 CONR.sup.9, tetrazolyl, imidazole, oxazole, triazole or --S(O).sub.2 NR.sup.10 R.sup.11 ;
R.sup.7 is hydrogen, alkyl, hydroxy, --O-alkyl, amino, substituted amino, --NHCOR.sup.8, --CN or --NO.sub.2 ;
or when R.sup.6 is --S(O).sub.2 NR.sup.10 R.sup.11, then R.sup.7 in addition to the above is halogen, heterocyclo, haloalkyl or aryl;
R.sup.8 and R.sup.9 are independently hydrogen, alkyl, haloalkyl, aryl, arylalkyl, cycloalkyl or (cycloalkyl)alkyl;
R.sup.10 and R.sup.11 are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, hydroxyalkyl substituted with a carboxylic ester or carboxylic acid, alkoxyalkyl, thioalkyl (cycloalkyl)alkyl, morpholinylalkyl, heterocyclo or (heterocyclo)alkyl;
or R.sup.10 and R.sup.11 taken together with the nitrogen atom to which they are attached form a 5- to 7-membered mono or bicyclic ring, or 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 4-thiamorpholine dioxide, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl;
or 1-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl or 1-azepinyl substituted with one or more alkyl, alkoxy, alkylthio, halo, trifluoromethyl, hydroxy, aryl, arylalkyl, --COOR.sup.8 or --CO-substituted amino;
or R.sup.10 and R.sup.7 taken together with the atoms to which they are attached form an unsubstituted 5- to 7-membered ring or a 5- to 7-membered ring substituted with aryl;
X is alkyl;
or X--R.sup.2 together are hydrogen, aryl or heterocyclo when R.sup.1 is heterocyclo;
and
n is an integer of 1 to 3;
which comprises the steps of treating a compound of the formula ##STR29## (where the R.sup.2 substituent contains a hydrogen atom which is more acidic than the starred (*) hydrogen atom in formula II);
with two equivalents of a base in an inert solvent, to form the corresponding dianion of formula ##STR30## where M is a counterion, then reacting the compounds of formula IIA with an epoxide of formula ##STR31## to produce the compounds of formula I.

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