Peptide derivatives

Claim 1

A process for producing a compound of formula Ia, Ib or Ic wherein R 1 is an alkyl group containing from 1 to 5 carbon atoms, and more preferably from 2 to 5 carbons; R 2 and R 5 are each selected independently from the group consisting of: (I) an alkyl group containing from 1 to 10 carbons; (II) an alkyl group containing from 1 to 6 carbon atoms substituted by at least one member selected from the 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; (1) 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 (i.e. acylaminosulfonyl and sulfonylaminocarbonyl) 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 wherein the aralkoxy group contains from 8 to 13 carbons (e.g., benzyloxycarbonyl amino); (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 (e.g., phenyl, biphenyl, naphthyl); (dd) aryl containing 6, 10 or 12 carbons and substituted by 1 to 3 members selected from the 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 (i.e. acylaminosulfonyl and sulfonylaminocarbonyl) (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 (e.g., cyclohexyl, adamantyl, norbornyl). (ff) alkylureido wherein the alkyl group contains from 1 to 6 carbons; (gg) aralkylureido wherein the aralkyl group contains from 8 to 13 carbons; (hh) arylureido wherein the aryl group contains 6, 10 or 12 carbons; and (III) an aryl group of 6 carbons, e.g. phenyl. R 3 is selected from the group consisting of: (I) an alkyl group containing from 1 to 12 carbons; (II) an alkyl group containing from 1 to 12 carbons and from 1 to 4 hetero atoms each of which is selected independently from the group consisting of nitrogen and oxygen; (III) an alkyl group containing from 1 to 12 carbons and, optionally, 1 to 4 hetero atoms each of which is selected independently from the group consisting of nitrogen and oxygen, and substituted on at least one of carbon or nitrogen by 1 to 3 members selected independently from the group consisting of: For carbon: (a) hydroxy, provided that it may not be on a carbon directly bonded to A; (b) amino, provided that it may not be on a carbon directly bonded to A; (c) alkylamino containing from 1 to 6 carbons, provided that it may not be on a carbon directly bonded to A; (d) dialkylamino wherein each alkyl group contains from 1 to 6 carbons, provided that it may not be on a carbon directly bonded to A; (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; (k)-(l) arylcarbonylamino wherein the aryl group contains 6, 10 or 12 carbons and is substituted by a member selected from carboxy, alkoxycarbonyl, where alkoxy is 1 to 3 carbons, 5-tetrazolo, and acylsulfonamido (i.e. acylaminosulfonyl and sulfonylaminocarbonyl) containing 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; (1) aralkylcarbonylamino wherein the aralkyl group contains from 7 to 13 carbons; (l)-(l) aralkylcarbonylamino wherein the aralkyl group contains 7 to 13 carbons and is substituted by a member selected from carboxy, alkoxycarbonyl, where the alkoxy has 1 to 3 carbons, 5-tetrazolo, and acylsulfonamido (i.e. acylaminosulfonyl and sulfonylaminocarbonyl) containing 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; (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 13 carbons; (u) alkylsulfonamido wherein the alkyl group contains from 1 to 6 carbons; (u)-(l) cycloalkylsulfonamido wherein the cycloalkyl portion contains 3 to 15 carbons (e.g., cyclohexyl, adamantyl, norbornyl); (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 (i.e. acylaminosulfonyl and sulfonylaminocarbonyl) (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 wherein the aralkoxy group contains from 8 to 13 carbons (e.g., benzyloxycarbonylamino); (z)-(l) aralkylaminocarbonyloxy wherein the aralkyl group contains 8 to 13 carbons; (z)-(2) aryloxy wherein the aryl contains 6, 10 or 12 carbons; (z)-(3) aryloxy wherein the aryl contains 6, 10 or 12 carbons and is substituted by a member selected from aminocarbonyl, aminocarbonylalkyl where the alkyl has 1 to 3 carbons, alkoxycarbonyl having 1 to 3 carbons, and carboxy; (aa) aryloxycarbonylamino wherein the aryloxy group contains 6, 10 or 12 carbons; (aa)-(l) arylaminocarbonyloxy wherein the aryl group contains 6, 10 or 12 carbons; (bb) alkoxycarbonylamino wherein the alkyloxy group contains from 1 to 6 carbons; (bb)-(l) alkoxycarbonylamino wherein the alkoxy group contains 1 to 6 carbons and is optionally bonded on carbon to a carbon of an aromatic heterocyclic group as described in (gg) under R 3 ; (bb)-(2) alkoxycarbonylamino wherein the alkoxy group contains 1 to 6 carbons substituted by an aliphatic heterocyclic group as described in (ff) under R 3 ; (bb)-(3) aryloxyalkylcarbonylamino wherein the aryl contains 6 or 10 carbons and the alkyl has 1 to 6 carbons; (bb)-(4) alkylaminocarbonyloxy wherein the alkyl group contains 1 to 6 carbons; (cc) aryl containing 6, 10 or 12 carbons (e.g., phenyl, naphthyl, biphenyl); (cc)-(l) aryloxy containing 6, 10 or 12 carbons; (dd) aryl containing 6, 10 or 12 carbons and substituted by 1 to 3 members independently selected from the group consisting of chloro, bromo, iodo, fluoro, hydroxy, trifluoromethyl, alkyl (1 to 6 carbons), alkoxy (1 to 6 carbons), alkoxycarbonyl (2 to 6 carbons), carboxy, aminocarbonylalkyl (2 to 6 carbons), aminocarbonyl, 5-tetrazolo, and acylsulfonamido (i.e. acylaminosulfonyl and sulfonylaminocarbonyl) (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; (dd)-(l) aryloxy containing 6, 10 or 12 carbons and substituted on carbon by 1 to 3 members independently selected from the group consisting of chloro, bromo, iodo, fluoro, hydroxy, trifluoromethyl, alkyl (1 to 6 carbons), alkoxy (1 to 6 carbons), alkoxycarbonyl (2 to 6 carbons), carboxy, aminocarbonylalkyl (2 to 6 carbons), aminocarbonyl, 5-tetrazolo, acylsulfonamido (i.e. acylaminosulfonyl and sulfonylaminocarbonyl) (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 (e.g., cyclohexyl, adamantyl, norbornyl); (ee)-(l) cycloalkyloxy containing from 3 to 15 carbons; (ff) an aliphatic heterocyclic group of at least 4 atoms containing from 1 to 5 carbons and from 1 to 4 hetero atoms each of which is selected independently from the group consisting of nitrogen and oxygen (e.g., morpholine, piperazine), wherein the aliphatic heterocyclic group may optionally contain 1 or 2 double bond(s), which aliphatic heterocyclic group may be substituted at any nitrogen with an alkyl group containing from 1 to 6 carbons, an alkanoyl group containing from 1 to 6 carbons, an aryloxycarbonyl group wherein the aryl group contains 6, 10 or 12 carbon atoms, an aralkyloxycarbonyl group wherein the aralkyl group contains from 7 to 13 carbons or an alkoxycarbonyl group wherein the alkyl group contains from 1 to 6 carbons; (ff)-(l) an aliphatic heterocyclic oxy group wherein the oxy link the is bonded directly to a carbon atom of the aliphatic heterocyclic group of at least 5 atoms containing from 1 to 5 carbons and from 1 to 4 hetero atoms each of which is selected independently from the group consisting of nitrogen and oxygen, (e.g., morpholine, piperazine), wherein the aliphatic heterocyclic group may optionally contain 1 or 2 double bond(s), which aliphatic heterocyclic group may be substituted at any nitrogen with an alkyl group containing from 1 to 6 carbons, an alkanoyl group containing from 1 to 6 carbons, an aryloxycarbonyl group wherein the aryl group contains 6, 10 or 12 carbons, an aralkyloxycarbonyl group wherein the aralkyl group contains from 7 to 13 carbons or an alkoxycarbonyl group wherein the alkyl group contains from 1 to 6 carbons; (gg) an aromatic heterocyclic group containing (1) from 1 to 15 carbons and from 1 to 4 heteroatoms each of which is selected independently from the group consisting of sulfur, nitrogen and oxygen and (2) from 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 with a member of the group consisting of fluoro, chloro, bromo, iodo, trifluoromethyl, alkyl containing from 1 to 6 carbons, alkoxy containing from 1 to 6 carbons, alkanoyl containing from 2 to 6 carbons, carboxy, aminocarbonylalkyl (2 to 6 carbons) and aminocarbonyl, and provided further that any nitrogen atom may be substituted by an alkyl group containing from 1 to 6 carbon atoms; (gg)-(l) an aromatic heterocyclic oxy group wherein the oxy link is bonded directly to a carbon of an aromatic heterocyclic group containing (1) from 1 to 15 carbons and from 1 to 4 heteroatoms each of which is selected independently from the group consisting of sulfur, nitrogen and oxygen and (2) from 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 with a member of the group consisting of fluoro, chloro, bromo, iodo, trifluoromethyl, alkyl containing from 1 to 6 carbons, alkoxy containing from 1 to 6 carbons, alkanoyl containing from 2 to 6 carbons, carboxy, aminocarbonylalkyl (2 to 6 carbons) and aminocarbonyl, and provided further that any nitrogen atom may be substituted by an alkyl group containing from 1 to 6 carbons; (hh) alkylureido wherein the alkyl group contains from 1 to 6 carbon atoms; (hh)-(l) cycloalkylureido wherein the alkyl group contains 3 to 15 carbons; (ii) aralkylureido wherein the aralkyl group contains from 7 to 13 carbons; (jj) arylureido wherein the aryl group contains 6, 10 or 12 carbons; (jj)-(l) arylureido wherein the aryl group contains 6, 10 or 12 carbons and is substituted by 1 to 3 members selected independently from the group consisting of chloro, bromo, iodo, fluoro, hydroxy, trifluoromethyl, alkyl (1 to 6 carbons), alkoxy (1 to 6 carbons), alkoxycarbonyl (2 to 6 carbons), carboxy, aminocarbonylalkyl (2 to 6 carbons), aminocarbonyl, 5-tetrazolo, and acylsulfonamido (i.e. acylaminosulfonyl and sulfonylaminocarbonyl) (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; For nitrogen: (a) alkyl of 1 to 3 carbons; (b) alkanoyl containing from 2 to 6 carbon atoms; (c) arylcarbonyl wherein the aryl contains 6, 10 or 12 carbons; (d) aralkanoyl containing 8 to 14 carbons; (e) formyl; (f) an aliphatic heterocyclic group wherein the amino link is bonded directly to a carbon of an aliphatic heterocyclic group defined in (ff) for the carbon substituents; (g) an aromatic heterocyclic group wherein the amino link is bonded directly to a carbon of the aromatic heterocyclic group defined in (gg) for the carbon substituents. (IV) an aryl group containing 6, 10 or 12 carbons; (V) an aryl group containing 6, 10 or 12 carbons suitably substituted by 1 to 3 members selected independently from the group consisting of fluoro, chloro, bromo, iodo, trifluoromethyl, hydroxy, alkyl containing from 1 to 6 carbons, alkoxy containing from 1 to 6 carbons, alkoxycarbonyl containing from 2 to 6 carbons, carboxy, alkylcarbonylamino wherein the alkyl group contains 1 to 6 carbons, 5-tetrazolo, and acylsulfonamido (i.e. acylaminosulfonyl and sulfonylaminocarbonyl) containing from 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; (VI) a cycloalkyl group containing from 3 to 15 carbons (e.g., cyclohexyl, adamantyl, norbornyl); (VI)-(l) a cycloalkyl group containing from 3 to 15 carbons (e.g., cyclohexyl, adamantyl, norbornyl), substituted by a member selected from the group consisting of carboxy and alkoxycarbonyl wherein the alkoxy group contains 1 to 4 carbons; (VII) an aliphatic heterocyclic group of at least 5 atoms containing from 1 to 5 carbons and from 1 to 4 hetero atoms each of which is selected independently from the group consisting of nitrogen and oxygen, (e.g., morpholine, piperazine) which may be substituted at any nitrogen with a member selected from the group consisting of an alkyl group containing from 1 to 6 carbon atoms, an alkanoyl group containing from 1 to 6 carbons, an aryloxycarbonyl group wherein the aryl group contains 6, 10 or 12 carbons, an aralkoxycarbonyl group wherein the aralkyl group contains from 7 to 13 carbons and an alkoxycarbonyl group containing from 2 to 7 carbons, provided that when A is OCO or NHCO then A must be bonded to a carbon atom of the aliphatic heterocyclic group; (VIII) an aromatic heterocyclic group containing (a) from 1 to 15 carbons and from 1 to 4 heteroatoms each of which is selected independently from the group consisting of sulfur, nitrogen and oxygen, and (b) from 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 the group consisting of fluoro, chloro, bromo, iodo, trifluoromethyl, alkyl containing from 1 to 6 carbons, alkoxy containing from 1 to 6 carbons, alkanoyl containing from 2 to 6 carbons, carboxy, and provided further that any nitrogen may be substituted by an alkyl group containing from 1 to 6 carbons, provided that when A is OCO or NHCO then A must be bonded to a carbon of the aromatic heterocycle; (IX) an alkenyl group of 2 to 10 carbons, having at least one double bond; and (X) an alkenyl group of 2 to 10 carbons, having at least one double bond and substituted by a member selected from the group consisting of (a) aryl of 6 or 10 carbons; (b) aryl of 6 or 10 carbons substituted by 1 to 3 members selected independently from the group consisting of chloro, bromo, iodo, fluoro, hydroxy, trifluoromethyl, alkyl (1 to 6 carbons), alkoxy (1 to 6 carbons), alkoxycarbonyl (2 to 6 carbons), carboxy, 5-tetrazolo, and acylsulfonamido (i.e. acylaminosulfonyl and sulfonylaminocarbonyl) (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; and (c) ureidocarbonyl. R 4 and R 6 are independently selected from hydrogen or methyl; n is 0, 1 or 2; and A is selected from the group consisting of and where appropriate, the acid- and base-addition salts thereof and provided that: (1) alkyls may be straight or branched chain; (2) no carbon of an alkyl may be directly bonded to two heteroatoms; (3) no heteroatom may be directly bonded to a sulfur, nitrogen or oxygen; and (4) alkenyls of IX and X for R 3 may not be 1,1-disubstituted, and a carbon of a double bond may not be directly bonded to an oxygen or nitrogen wherein said process comprises oxidizing a compound of formula VIIa, VIIb, or VIIc, respectively.