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Dihydropyrimidine derivatives

  • US 5,470,975 A
  • Filed: 01/11/1994
  • Issued: 11/28/1995
  • Est. Priority Date: 10/16/1990
  • Status: Expired due to Term
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1. A compound of the formulaor its isomer ##STR26## or pharmaceutically acceptable salts thereof wherein R1 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 --CO2 R22 ;

  • cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms, cycloalkylalkenyl or cycloalkylalkynyl of 5 to 10 carbon atoms;

    --(CH2)s Z(CH2)m R'"'"' (wherein R'"'"' is H, C1-6 alkyl, C3-6 cycloalkyl, C2-4 alkenyl or C2-4 alkynyl) optionally substituted with F or --CO2 R22 ;

    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;

    --SR4, --OR4 (where R4 ≠

    H) or --NR4 R5 ;

    R2 is hydrogen, halogen, R4 '"'"', --CN, haloalkyl, --OR4, --SR4 --COOR4, COR4, (R4 '"'"'O)alkyl, (R4 '"'"'S)alkyl, (substituted amino)alkyl;

    R3 is R4, --COOR, --CONH2, --CO-substituted amino, --COR, --CN, --NO2, ##STR27## --SO2 R (wherein R is R4, aminoalkyl or (substituted amino)alkyl), (R4 '"'"'O)alkyl, (R4 '"'"'S)alkyl, (substituted amino)alkyl, (R4 '"'"'OOC)alkyl, (R4 '"'"'CO)alkyl, (amino-CO)alkyl, (substituted amino-CO)alkyl, (ROCO)alkyl (wherein R is R4 excluding hydrogen);

    or R2 and R3 taken together are ##STR28## to form a 5- to 7-membered ring with the carbons to which they are attached;

    or R2 and R3 taken together with the carbon atoms to which they are attached form an aryl;

    R4 '"'"' is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, (heterocyclo)alkyl, haloalkyl;

    R4 and R5 are independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, (heterocyclo)alkyl, haloalkyl;

    R6 is 4-CO2 H, 4-CO2 R9, ##STR29## R7 is hydrogen, halogen, --NO2, --CN, alkyl of 1 to 4 carbons, acyloxy of 1 to 4 carbons, alkoxy of 1 to 4 carbons, --CO2 H, CO2 R9, --NHSO2 CH3, --NHSO2 CF3, --CONHOR10, --SO2 NH2, aryl, furyl or ##STR30## R8 is hydrogen, halogen, alkyl of 1 to 4 carbons or alkoxy of 1 to 4 carbons;

    R9 is hydrogen or ##STR31## R10 is hydrogen, methyl or benzyl;

    R11 is alkyl of 1 to 6 carbons, NR12 R13 ;

    R12 and R13 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;

    R14 is hydrogen, alkyl of 1 to 5 carbons or phenyl;

    R15 is --CO2 H, --CO2 R9, --CH2 CO2 H, --CH2 CO2 R9, ##STR32## R16 is hydrogen, alkyl of 1 to 4 carbons, --CH2 CH=CH2 or --CH2 C6 H4 R17 ;

    R17 is hydrogen, --NO2, --NH2, --OH or --OCH3 ;

    R18 is --CN, --NO2 or --CO2 R19 ;

    R19 is hydrogen, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons, phenyl or benzyl;

    R20 and R20 '"'"' are independently hydrogen, alkyl of 1 to 5 carbons or phenyl;

    X is a carbon-carbon single bond, --CO--, --CH2 --, --O--, --S--, --N--, ##STR33## --OCH2 --, --CH2 O--, --SCH2 --, --CH2 --S--, --NHC(R20)(R20 '"'"'), --NR13 SO2 --, --SO2 NR13 --, --C(R20)(R20 '"'"')NH, --CH═

    CH--, --CF═

    CF--, --CH═

    CF--, --CF═

    CH--, --CH2 CH2 --, --CF2 CF2 --, ##STR34## R21 is hydrogen, alkyl of 1 to 6 carbons, benzyl or alkyl;

    R22 is hydrogen, alkyl or perfluoroalkyl of 1 to 8 carbons, cycloalkyl of 3 to 6 carbons, phenyl or benzyl;

    R23 is --N(R20)(R20 '"'"'), --NHCONH2, --NHCSNH2, ##STR35## R24 and R25 are independently alkyl of 1 to 4 carbons or taken together are --(CH2)q ;

    Z is O, NR19 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)2, wherein alkyl is of 1 to 4 carbons, CF3, ##STR36## OCH2 -cycloalkyl, or --S--CH2 -cycloalkyl, and disubstituted phenyl, 1-naphthyl, or 2-naphthyl wherein said substituents are selected from methyl, methoxy, methylthio, halo, CF3, nitro, amino, and OCHF2 ;

    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 --NZ1 Z2 wherein Z1 is hydrogen, alkyl, or aryl--(CH2)-- and Z2 is alkyl or aryl--(CH2)m -- (where m is 0 to

         2) or Z1 and Z2 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.

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