Dihydropyrimidine derivatives

A compound of the formula

• or its isomer ##STR26## or pharmaceutically acceptable salts thereof wherein R.sub.1 is alkyl of 1 to 10 carbon atoms, alkenyl or alkynyl of 3 to 10 carbon atoms or the same groups substituted with F or --CO.sub.2 R.sub.22 ;
• cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms, cycloalkylalkenyl or cycloalkylalkynyl of 5 to 10 carbon atoms;
• --(CH.sub.2).sub.s Z(CH.sub.2).sub.m R' (wherein R' is H, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.2-4 alkenyl or C.sub.2-4 alkynyl) optionally substituted with F or --CO.sub.2 R.sub.22 ;
• benzyl or benzyl substituted on the phenyl ring with 1 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, haloalkyl or nitro;
• --SR.sub.4, --OR.sub.4 (where R.sub.4 .noteq.H) or --NR.sub.4 R.sub.5 ;
• R.sub.2 is hydrogen, halogen, R.sub.4 ', --CN, haloalkyl, --OR.sub.4, --SR.sub.4 --COOR.sub.4, COR.sub.4, (R.sub.4 'O)alkyl, (R.sub.4 'S)alkyl, (substituted amino)alkyl;
• R.sub.3 is R.sub.4, --COOR, --CONH.sub.2, --CO-substituted amino, --COR, --CN, --NO.sub.2, ##STR27## --SO.sub.2 R (wherein R is R.sub.4, aminoalkyl or (substituted amino)alkyl), (R.sub.4 'O)alkyl, (R.sub.4 'S)alkyl, (substituted amino)alkyl, (R.sub.4 'OOC)alkyl, (R.sub.4 'CO)alkyl, (amino-CO)alkyl, (substituted amino-CO)alkyl, (ROCO)alkyl (wherein R is R.sub.4 excluding hydrogen);
• or R.sub.2 and R.sub.3 taken together are ##STR28## to form a 5- to 7-membered ring with the carbons to which they are attached;
• or R.sub.2 and R.sub.3 taken together with the carbon atoms to which they are attached form an aryl;
• R.sub.4 ' is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, (heterocyclo)alkyl, haloalkyl;
• R.sub.4 and R.sub.5 are independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, (heterocyclo)alkyl, haloalkyl;
• R.sub.6 is 4-CO.sub.2 H, 4-CO.sub.2 R.sub.9, ##STR29## R.sub.7 is hydrogen, halogen, --NO.sub.2, --CN, alkyl of 1 to 4 carbons, acyloxy of 1 to 4 carbons, alkoxy of 1 to 4 carbons, --CO.sub.2 H, CO.sub.2 R.sub.9, --NHSO.sub.2 CH.sub.3, --NHSO.sub.2 CF.sub.3, --CONHOR.sub.10, --SO.sub.2 NH.sub.2, aryl, furyl or ##STR30## R.sub.8 is hydrogen, halogen, alkyl of 1 to 4 carbons or alkoxy of 1 to 4 carbons;
• R.sub.9 is hydrogen or ##STR31## R.sub.10 is hydrogen, methyl or benzyl;
• R.sub.11 is alkyl of 1 to 6 carbons, NR.sub.12 R.sub.13 ;
• R.sub.12 and R.sub.13 are independently hydrogen, benzyl, alkyl of 1 to 6 carbons or taken together are 3 to 6 methylene groups forming a 4- to 7-membered ring with the nitrogen atom to which they are attached;
• R.sub.14 is hydrogen, alkyl of 1 to 5 carbons or phenyl;
• R.sub.15 is --CO.sub.2 H, --CO.sub.2 R.sub.9, --CH.sub.2 CO.sub.2 H, --CH.sub.2 CO.sub.2 R.sub.9, ##STR32## R.sub.16 is hydrogen, alkyl of 1 to 4 carbons, --CH.sub.2 CH=CH.sub.2 or --CH.sub.2 C.sub.6 H.sub.4 R.sub.17 ;
• R.sub.17 is hydrogen, --NO.sub.2, --NH.sub.2, --OH or --OCH.sub.3 ;
• R.sub.18 is --CN, --NO.sub.2 or --CO.sub.2 R.sub.19 ;
• R.sub.19 is hydrogen, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons, phenyl or benzyl;
• R.sub.20 and R.sub.20 ' are independently hydrogen, alkyl of 1 to 5 carbons or phenyl;
• X is a carbon-carbon single bond, --CO--, --CH.sub.2 --, --O--, --S--, --N--, ##STR33## --OCH.sub.2 --, --CH.sub.2 O--, --SCH.sub.2 --, --CH.sub.2 --S--, --NHC(R.sub.20)(R.sub.20 '), --NR.sub.13 SO.sub.2 --, --SO.sub.2 NR.sub.13 --, --C(R.sub.20)(R.sub.20 ')NH, --CH.dbd.CH--, --CF.dbd.CF--, --CH.dbd.CF--, --CF.dbd.CH--, --CH.sub.2 CH.sub.2 --, --CF.sub.2 CF.sub.2 --, ##STR34## R.sub.21 is hydrogen, alkyl of 1 to 6 carbons, benzyl or alkyl;
• R.sub.22 is hydrogen, alkyl or perfluoroalkyl of 1 to 8 carbons, cycloalkyl of 3 to 6 carbons, phenyl or benzyl;
• R.sub.23 is --N(R.sub.20)(R.sub.20 '), --NHCONH.sub.2, --NHCSNH.sub.2, ##STR35## R.sub.24 and R.sub.25 are independently alkyl of 1 to 4 carbons or taken together are --(CH.sub.2).sub.q ;
• Z is O, NR.sub.19 or S;
• m is 1 to5;
• n is 0 to 2;
• p is 0 to 2;
• q is 2 to 3;
• and
• s is 0 to 5;
• wherein the term "alkyl", as used by itself or as part of a larger group, refers to groups having 1 to 10 carbon atoms;
• the term "aryl" refers to phenyl, 1-naphthyl, 2-naphthyl, monosubstituted phenyl, 1-naphthyl, or 2-naphthyl wherein said substituent is alkyl of 1 to 4 carbons, alkylthio of 1 to 4 carbons, alkoxy of 1 to 4 carbons, halo, nitro, cyano, hydroxy, amino, --NH-alkyl wherein alkyl is of 1 to 4 carbons, --N(alkyl).sub.2, wherein alkyl is of 1 to 4 carbons, CF.sub.3, ##STR36## OCH.sub.2 -cycloalkyl, or --S--CH.sub.2 -cycloalkyl, and disubstituted phenyl, 1-naphthyl, or 2-naphthyl wherein said substituents are selected from methyl, methoxy, methylthio, halo, CF.sub.3, nitro, amino, and OCHF.sub.2 ;
• the term "heterocyclo" refers to 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and imidazolyl wherein the pyridyls may be substituted with alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons or alkylthio of 1 to 4 carbons;
• and
• the terms "substituted amino" refers to a group of the formula --NZ.sub.1 Z.sub.2 wherein Z.sub.1 is hydrogen, alkyl, or aryl--(CH.sub.2)-- and Z.sub.2 is alkyl or aryl--(CH.sub.2).sub.m -- (where m is 0 to 2) or Z.sub.1 and Z.sub.2 taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl- 1-piperazinyl, 4-arylalkyl- 1-piperazinyl, 4-diarylalkyl-1-piperazinyl, or 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl substituted with alkyl, alkoxy, alkylthio, halo, trifiuoromethyl or hydroxy.