Substituted peptide derivatives

Claim 1

A process for producing a compound of the following formula la, Ib or Ic(as set out hereinbelow wherein R 1 is an alkyl group containing from 1 to 5 carbon atoms; R 2 and R 5 are each selected independently from a group consisting of: (I) an alkyl group containing from 1 to 10 carbons; (II) an alkyl group containing from 1 to 6 carbons substituted by at least one member selected from a group consisting of: (a) hydroxy; (b) amino; (c) alkylamino containing from 1 to 6 carbons; (d) dialkylamino wherein each alkyl group contains from 1 to 6 carbons; (e) alkanoyl containing from 1 to 6 carbons; (f) arylcarbonyl wherein the aryl contains 6,10 or 12 carbons; (g) aralkanoyl containing 8 to 13 carbons; (h) amido which may be attached to the alkyl group via either a nitrogen or carbon of said amido; (i) alkylcarbonylamino wherein the alkyl group contains from 1 to 6 carbons; (j) alkylaminocarbonyl wherein the alkyl group contains from 1 to 6 carbons; (k) arylcarbonylamino wherein the aryl group contains 6,10 or 12 carbons; (I) aralkylcarbonylamino wherein the aralkyl group contains from 7 to 13 carbons; (m) arylaminocarbonyl wherein the aryl group contains 6,10 or 12 carbons; (n) aralkylaminocarbonyl wherein the aralkyl group contains from 7 to 13 carbons; (o) carboxy; (p) aryloxycarbonyl wherein the aryl group contains 6,10 or 12 carbons; (q) aralkoxycarbonyl wherein the aralkoxy group contains from 7 to 13 carbons; (r) alkanoyloxy containing from 1 to 6 carbons; (s) aroyloxy wherein the aryl portion contains 6,10 or 12 carbons; (t) aralkanoyloxy containing from 8 to 14 carbons; (u) alkylsulfonamido wherein the alkyl group contains from 1 to 6 carbons; (v) aralkylsulfonamido wherein the aralkyl group contains from 7 to 13 carbons; (w) arylsulfonamido wherein the aryl group contains 6, 10 or 12 carbons; (x) acylsulfonamido containing 1 to 15 carbons, including acylsulfonamido wherein the acyl group contains 1 to 7 carbons when it is the terminal portion of the acylsulfonamide and provided that when the acylsulfonamido contains an aryl the aryl may be further substituted by a member selected from fluoro, chloro, bromo, iodo and nitro; (y) alkoxycarbonyl wherein the alkoxy group contains from 1 to 6 carbons; (z) aralkoxycarbonylamino containing from 8 to 13 carbons; (aa) aryloxycarbonylamino wherein the aryloxy group contains 6,10 or 12 carbons; (bb) alkoxycarbonylamino wherein the alkyloxy group contains from 1 to 6 carbons; (cc) aryl containing 6,10 or 12 carbons; (dd) aryl containing 6, 10 or 12 carbons and substituted by 1 to 3 members selected from a group consisting of chloro, bromo, iodo, fluoro, trifluoromethyl, hydroxy, alkyl (1 to 6 carbons), alkoxy (1 to 6 carbons), alkoxycarbonyl (1 to 6 carbons), carboxy, 5-tetrazolo, and acylsufonamido (1 to 15 carbons) and provided that when the acylsulfonamido contains an aryl the aryl may be further substituted by a member selected from fluoro, chloro, bromo, iodo and nitro; (ee) cycloalkyl containing from 3 to 15 carbons; (ff) alkylureido wherein the alkyl group contains from 1 to 6 carbons; (gg) aralkylureido containing from 8 to 13 carbons; and (hh) arylureido wherein the aryl group contains 6,10 or 12 carbons; and (III) phenyl; R 4 and R 6 are each independently hydrogen or methyl; and A is an acidic radical selected from a group consisting of a carbamoylsulfonamido radical of formula R 7 .NH.CO.NH.S(0 2 )-, a sulfonylureido radical of formula R S .S(0 2 ).NH.CO.NR S- , a heterocyclic acylsulfonamido radical of formula Q.B-, and a trifluoromethylsulfonamido radical of formula CF 3 .S(0 2 ).NH-wherein R 7 is selected from a group consisting of: (I) an alkyl group containing from 1 to 10 carbons; (II) a cycloalkyl group containing from 3 to 10 carbons; (III) an arylmethyl group containing 7 to 11 carbons; wherein the aryl group is optionally substituted by 1 to 3 members of the group consisting of fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, an alkyl group of 1 to 4 carbons, methoxy, ethoxy, and methylthio; (IV) an aryl group containing 6 or 10 carbons and optionally substituted by 1 to 3 members of the group consisting of fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, an alkyl group of 1 to 4 carbons, methoxy, ethoxy, and methylthio; (V) an aromatic heterocyclic group as defined below for Q; R 8 is hydrogen or methyl; R 9 is selected from a group consisting of: (I) an alkyl group containing from 1 to 10 carbons; (II) a cycloalkyl group containing from 3 to 10 carbons; (III) an aryl group containing 6 or 10 carbons and optionally substituted by 1 to 3 members of the group consisting of fluoro, chloro, bromo, iodo, trifluormethyl, methyl, nitro, hydroxy, carboxy, amino, dimethylamino, phenyl, and an alkylcarbonylamino group wherein the alkyl group contains 1 to 4 carbons; (IV) an aromatic heterocyclic group as defined below for Q; (V) a 2-phenylethyl group; and (VI) a 2,2,2-trifluoroethyl group; Q is an aromatic heterocyclic group of from 1 to 15 carbons and from 1 to 4 heteroatoms each of which is selected independently from a group consisting of sulfur, nitrogen and oxygen, and which form 1 to 3 five or six-membered rings at least one of which is aromatic, and optionally, wherein up to 3 carbons of the aromatic ring(s) may be substituted at any carbon atom with a member of a group consisting of fluoro, chloro, bromo, iodo and trifluoromethyl, and provided further that any nitrogen may be substituted by an alkyl group containing from 1 to 6 carbons; and B is an acylsulfonamide linkage selected from a group consisting of those represented by formulae (i) -S(0 2 )NHCO- and (ii) -CONHS(0 2 )-; or, where appropriate, a pharmaceutically acceptable acid- or base-addition salt thereof, which method is selected from (A) for a compound of formula la, Ib or Ic, oxidizing a corresponding hydroxy compound of formula Vlla, VIIb or VIIc; (B) for a compound of formula Ia, Ib or Ic wherein A is a radical of formula R 7. NH.CO.NH.S(0 2 )-, treating a corresponding compound of formula Xa, Xb or Xc wherein M is an aminosulfonyl radical of formula H 2 NS(0 2 )-with an isocyanate of formula R 7. NCO; (C) for a compound of formula Ia, Ib or Ic wherein A is a radical of formula R 9 .S(O 2 ).NH.CO.NR 8 -, treating a corresponding compound of formula Xa, Xb or Xc wherein M is an amino radical of formula HNR 8 -with a sulfonylisocyanate of formula R 9 .S(0 2 ).NCO; (D) for a compound of formula la, Ib or Ic wherein A is a radical of formula R 9 .S(0 2 ).NH.CO.NR 8- and wherein R 8 is H, treating a corresponding compound of formula Xa, Xb or Xc wherein M is an isocyanate radical of formula ONC-with a sulfonamide of formula R 9 .S(O 2 ).NH 2 ; (E) for a compound of formula la, Ib or Ic wherein A is a radical of formula Q.B- in which -B- is -S(0 2 )NHCO-, coupling a corresponding acid of formula Xa, Xb or Xc wherein M is COOH with a sulfonamide of formula Q.S(0 2 ).NH 2 ; (F) for a compound of formula la, Ib or Ic wherein A is a radical of formula Q.B- in which -B- is -CO.NH.S(O) 2 )-, coupling a corresponding sulfonamide of formula Xa, Xb or Xc wherein M is H 2 N.S(0 2 )-with a heterocyclic acid of formula Q.COOH; and (G) for a compound of formula la, Ib or Ic wherein A is a radical of formula CF 3 .S(0 2 ).NH-, treating a corresponding amine of formula Xa, Xb or Xc wherein M is H2N-with trifluoromethanesulfonic anhydride; and wherein the chemical formulae Vlla, Vllb, Vllc, Xa, Xb and Xc are set out hereinbelow and wherein R 1 , R2, R 4- R 8 , and A have the meanings defined in above; and whereafter, when a pharmaceutically acceptable salt is required, reacting an acid form of the compound of formula la, Ib or Ic with a base affording a physiologically acceptable cation or reacting a suitably basic compound of formula la, Ib or Ic with an acid affording a physiologically acceptable anion.