Novel dopa/dopamine prodrugs

Abstract

Abstract Novel, transient prodrug forms of dopa and dopamine have (i) the structural formula (I): ##STR1## wherein each R is independently selected from the group consisting of hydrogen, R 3 -CO- and ##STR2## wherein X is O, S or NR 6 ; R 1 is hydrogen or --COOR 8 ; R 2 is hydrogen or OR; R 3 is selected from the group consisting of straight or branched chain alkyl having from 1 to 20 carbon atoms; aryl having from 6 to 10 carbon atoms; cycloalkyl having from 3 to 8 carbon atoms; alkenyl having from 2 to 20 carbon atoms; cycloalkenyl having from 4 to 8 carbon atoms; alkynyl having from 2 to 20 carbon atoms; aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl, alkynylaryl, loweracyloxyalkyl, and carboxyalkyl, wherein alkyl, aryl, alkenyl and alkynyl are as defined above; saturated or unsaturated monoheterocyclic or polyheterocyclic, or fused heterocyclic, containing from 1 to 3 of any one or more of the hetero atom N, S or O in each heterocyclic ring thereof and each such ring being from 3- to 8-membered; and mono- or poly-substituted derivatives of the above, each of said substituents being selected from the group consisting of lower alkyl, lower alkoxy, lower acyl, lower acyloxy, halo, haloloweralkyl, cyano, lower alkoxycarbonyl, loweralkylthio, amino, nitro, loweralkylamino, diloweralkylamino, carboxyl, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl and ##STR3## wherein R 5 is hydrogen or alkyl having from 1 to 10 carbons; R 4 is hydrogen, R 3 , lower acyl, cyano, haloloweralkyl, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl, --CH 2 ONO 2 and --CH 2 OCOR 3 ; R 6 is hydrogen or lower alkyl; R 7 is hydrogen, lower alkyl, COCF 3 , COOC(CH 3 ) 3 , COOCH 2 C 6 H 5 , or other N-protective group conventional to amino acid acid chemistry; R 8 is hydrogen, benzyl, or other conventional, cleavable carboxyl protective group; with the proviso that at least one R must be R 3 COXCH(R 4 )--; (ii) the structural formula (I) wherein at least one R 3 CO- moiety comprising at least one R group is the residue of any naturally occurring protein amino acid, the residue of any N-substituted naturally occurring amino acid, which N-substituent is lower alkyl or any amino acid protective group cleavable via hydrogenolysis or hydrolysis, or the residue of an N,N-lower dialkyl or C 4 -C 7 cycloalkylamino acid; and (ii) the non-toxic, pharmaceutically acceptable salts thereof.

Inventors

• 👤 Nicholas S. Bodor
• 👤 Kenneth B. Sloan
• 👤 Stefano A. Pogany

Bibliographic Details