Patent ID: 6730783
Filing Date: 2004-05-04
Classification: A61P,C07C,C07D

Abstract:
A process for preparing an aminoguanidine or an alkoxyguanidine compound having the Formula I: or a solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof, wherein:R1 is one of aryl substituted by R13R14NSO2â€”, or heteroaryl, any of which may be optionally substituted; R13 and R14 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle, heterocycloalkyl, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, mono- and di-alkylaminoalkyl, provided that at least one of R13 and R14 is heterocycle or heterocycloalkyl, or R13 and R14 can be taken together with the nitrogen atom to which they are attached to form a three to seven membered ring, optionally containing one or more heteroatoms in addition to said nitrogen, such as oxygen, sulfur, or nitrogen (NR15), said ring being unsaturated or saturated, and said ring having one or two optional substituents, wherein said optional substituents and R15 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle, heterocycloalkyl, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, mono- and di-alkylaminoalkyl, carboxy, alkoxycarbonyl, carboxamido, formyl, alkanoyl, aroyl, aralkanoyl, alkylsulfonyl, alkoxysulfonyl, sulfonamide, phosphonyl, phosphoramido, or phosphinyl; Z is one of â€”NR10SO2â€”, â€”SO2NR10â€”, â€”NR10C(RyRz)â€”, â€”C(RyRz)NR10â€”, â€”OSO2â€”, â€”SO2Oâ€”, â€”OC(RyRz)â€”, â€”C(RyRz)Oâ€”, â€”NR10COâ€” or â€”CONR10â€”; Ry and Rz are each independently one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxy; R2, R3 and R4 are each independently one of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, â€”CO2Rx, â€”CH2ORx or â€”ORx, or when present on adjacent carbon atoms, R2 and R3 may also be taken together to form one of â€”CH&boxH;CHâ€”CH&boxH;CHâ€” or â€”(CH2)qâ€”, where q is from 2 to 6, and R4 is defined as above; Rx, in each instance, is independently one of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations; Y is one of â€”Oâ€”, â€”NR10â€”, â€”Sâ€”, â€”CHR10â€” or a covalent bond; X is oxygen or NR9; R9 is one of hydrogen, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl can be optionally substituted with amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano or trifluoromethyl; R6 is one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C2-10)alkyl, dialkylamino(C2-10)alkyl or carboxyalkyl; or R6 and R12 are taken together to form â€”(CH2)wâ€”, where w is 1-5; R7 is one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, hydroxy, alkoxy, aralkoxy, aryloxy, heteroaryloxy, or mono- or di-alkylamino, provided that n is other than zero when R7 is hydroxy, alkoxy, aralkoxy, aryloxy, heteroaryloxy, or mono- or di-alkylamino; R8, R11 and R12 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxyalkyl; or R7 and R8 are taken together to form â€”(CH2)y, where y is zero (a bond), 1 or 2, while R11 and R12 are defined as above; or R7 and R12 are taken together to form â€”(CH2)qâ€”, where q is zero (a bond), or 1 to 8, while R8 and R11 are defined as above; or R8 and R11 are taken together to form â€”(CH2)râ€”, where r is 2-8, while R7 and R12 are defined as above; R10, in each instance, is independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C2-10)alkyl, dialkylamino(C2-10)alkyl or carboxyalkyl; Ra, Rb and Rc are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or â€”CO2Rw; Rw is alkyl, cycloalkyl, phenyl, benzyl, â€ƒwhere Rd and Re are independently hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rf is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rg is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, and Rh is aralkyl or C1-6 alkyl; n is from zero to 8; and m is from zero to 4, comprising (a) reacting an aminoguanidine of the formula wherein R6, Ra, Rb and Rc are as defined above, with a carbonyl-containing compound of the formula wherein R1-R4, Z, Y, n, m, R7, R8, R11 and R12 are as defined above to form an amidinohydrazone, and thereafter selectively reducing the hydrazone carbon to nitrogen double bond of the amidinohydrazone; or(b) reacting an alkoxyamine compound of the formula wherein R1-R4, Z, Y, n, m, R7, R8, R11 and R12 are as defined above, with a guanidinylating reagent.