Synthesis of peptide analogues

Claim 1

A method for isosterically replacing the nitrogen atom of the linking amide group of a dipeptide of the formula: ##STR10## by a trivalent group ##STR11## to thereby obtain a dipeptide analogue of the formula (I): ##STR12## wherein R is hydrogen, or a monofunctional organic group, or a bond to the group --CH(R 5 )-- forming a cyclic group ##STR13## NR 1 R 2 is an amino group, or an imino group or derivative thereof, bonded to the group --CH(R 4 )-- forming a cyclic group ##STR14## COR 3 is a carboxyl group or a derivative thereof, R 4 and R 5 are the same or different side chain residues of an α-amino aicd, or R 4 is a divalent group bonded to the group R 1 R 2 N--, or R 5 is a divalent organic group bonded to the group ##STR15## which comprises: reacting a ketone of the formula (II): ##STR16## wherein A is an amine-protecting group, with zinc, to obtain a compound of formula (III): ##STR17## reacting the compound of formula (III) with a compound of the formula ##STR18## wherein Z is a group capable of acting as a leaving group in a nucleophilic substitution reaction, and B is a carboxy-protecting group to obtain a compound of the formula ANR 2 --CHR 4 --COCHRCHR 5 --COB; removing the amine- and carboxy-protecting groups if necessary, thereby obtaining a compound of the formula (I).

Claim 2

A method for isosterically replacing the nitrogen atom of the linking amide group of a dipeptide of the formula: ##STR10## by a trivalent group ##STR11## to thereby obtain a dipeptide analogue of the formula (I): ##STR12## wherein R is hydrogen, or a monofunctional organic group, or a bond to the group --CH(R 5 )-- forming a cyclic group ##STR13## NR 1 R 2 is an amino group, or an imino group or derivative thereof, bonded to the group --CH(R 4 )-- forming a cyclic group ##STR14## COR 3 is a carboxyl group or a derivative thereof, R 4 and R 5 are the same or different side chain residues of an α-amino aicd, or R 4 is a divalent group bonded to the group R 1 R 2 N--, or R 5 is a divalent organic group bonded to the group ##STR15## which comprises: reacting a ketone of the formula (II): ##STR16## wherein A is an amine-protecting group, with zinc, to obtain a compound of formula (III): ##STR17## reacting the compound of formula (III) with a compound of the formula ##STR18## wherein Z is a group capable of acting as a leaving group in a nucleophilic substitution reaction, and B is a carboxy-protecting group to obtain a compound of the formula ANR 2 --CHR 4 --COCHRCHR 5 --COB; removing the amine- and carboxy-protecting groups if necessary, thereby obtaining a compound of the formula (I).

Claim 3

A method for isosterically replacing the nitrogen atom of the linking amide group of a dipeptide of the formula: ##STR19## by a trivalent group ##STR20## to thereby obtain a dipeptide analogue of the formula (I): ##STR21## wherein R is hydrogen, or a monofunctional organic group, or a bond to the group --CH(R 5 )-- forming a cyclic group ##STR22## NR 1 R 2 is an amino group, or an imino group or derivative thereof, bonded to the group --CH(R 4 )-- forming a cyclic group ##STR23## COR 3 is a carboxy group or a derivative thereof, R 4 and R 5 are the same or different side chain residues of an α-amino acid, or R 4 is a divalent group bonded to the group R 1 R 2 N--, or R 5 is a divalent organic group bonded to the group ##STR24## which comprises: reacting a compound of formula (II): ##STR25## with triphenylphosphine and a mild base to obtain an ylide of formula (III): ##STR26## reacting the ylide of formula III with a compound of the formula ##STR27## wherein Z is a group capable of acting as a leaving group in a nucleophilic substitution reaction, and B is a carboxy-protecting group, and then cleaving the C--P bond, to thereby obtain a compound of formula (IV): ##STR28## removing the amine- and carboxy-protecting group if necessary; and thereby obtaining a compound of formula (I).

Claim 4

A method for isosterically replacing the nitrogen atom of the linking amide group of a dipeptide of the formula: ##STR19## by a trivalent group ##STR20## to thereby obtain a dipeptide analogue of the formula (I): ##STR21## wherein R is hydrogen, or a monofunctional organic group, or a bond to the group --CH(R 5 )-- forming a cyclic group ##STR22## NR 1 R 2 is an amino group, or an imino group or derivative thereof, bonded to the group --CH(R 4 )-- forming a cyclic group ##STR23## COR 3 is a carboxy group or a derivative thereof, R 4 and R 5 are the same or different side chain residues of an α-amino acid, or R 4 is a divalent group bonded to the group R 1 R 2 N--, or R 5 is a divalent organic group bonded to the group ##STR24## which comprises: reacting a compound of formula (II): ##STR25## with triphenylphosphine and a mild base to obtain an ylide of formula (III): ##STR26## reacting the ylide of formula III with a compound of the formula ##STR27## wherein Z is a group capable of acting as a leaving group in a nucleophilic substitution reaction, and B is a carboxy-protecting group, and then cleaving the C--P bond, to thereby obtain a compound of formula (IV): ##STR28## removing the amine- and carboxy-protecting group if necessary; and thereby obtaining a compound of formula (I).

Claim 5

A method for isosterically replacing the nitrogen atom of the linking amide group of a dipeptide of the formula: ##STR29## by a methylene group --CH 2 --, and for replacing the carbonyl group of said linking amide group by a methylene group --CH 2 --, to thereby obtain a dipeptide analogue of the formula (I): ##STR30## wherein NR 1 R 2 is an amino group, or an imino group or derivative thereof, bonded to the group --CH(R 4 )-- forming a cyclic group ##STR31## COR 3 is a carboxy group or derivative thereof, R 4 is the side chain residue of an α-amino acid, or R 4 is a divalent group bonded to the group R 1 R 2 N--, which comprises: reacting an amino acid derivative selected from the group consisting of amino acid halide, amino acid imidazolylamide and amino acid anhydride, of the formula (II): ##STR32## wherein A is an amine-protecting group, and Q is selected from the group consisting of halogen atom ##STR33## group and oxocarbonyl-containing group, with diazomethane to obtain an α-diazomethyl compound of formula (III): ##STR34## reacting said compound of formula (III) with a catalyst and an alcohol of formula R 6 OH wherein R 6 is a C 1 -C 6 alkyl group, to yield an ester of formula (IV): ##STR35## transforming the ester of formula (IV) to an α-diazomethyl ketone of formula (V): ##STR36## reacting said α-diazomethyl ketone of formula (V) with a catalyst and an alcohol to yield an ester of formula (VI): ##STR37## transforming said ester of formula (VI) to an α-diazomethyl ketone of formula (VII): ##STR38## reacting said α-diazomethyl ketone of formula (VII) with a catalyst and an alcohol R 6 OH to yield an ester of formula (VIII): ##STR39## removing the amino protecting group and transforming the carboxy ester to a group COR 3 if necessary: thereby obtaining a dipeptide analogue of formula (I).

Claim 6

A method for isosterically replacing the nitrogen atom of the linking amide group of a dipeptide of the formula: ##STR29## by a methylene group --CH 2 --, and for replacing the carbonyl group of said linking amide group by a methylene group --CH 2 --, to thereby obtain a dipeptide analogue of the formula (I): ##STR30## wherein NR 1 R 2 is an amino group, or an imino group or derivative thereof, bonded to the group --CH(R 4 )-- forming a cyclic group ##STR31## COR 3 is a carboxy group or derivative thereof, R 4 is the side chain residue of an α-amino acid, or R 4 is a divalent group bonded to the group R 1 R 2 N--, which comprises: reacting an amino acid derivative selected from the group consisting of amino acid halide, amino acid imidazolylamide and amino acid anhydride, of the formula (II): ##STR32## wherein A is an amine-protecting group, and Q is selected from the group consisting of halogen atom ##STR33## group and oxocarbonyl-containing group, with diazomethane to obtain an α-diazomethyl compound of formula (III): ##STR34## reacting said compound of formula (III) with a catalyst and an alcohol of formula R 6 OH wherein R 6 is a C 1 -C 6 alkyl group, to yield an ester of formula (IV): ##STR35## transforming the ester of formula (IV) to an α-diazomethyl ketone of formula (V): ##STR36## reacting said α-diazomethyl ketone of formula (V) with a catalyst and an alcohol to yield an ester of formula (VI): ##STR37## transforming said ester of formula (VI) to an α-diazomethyl ketone of formula (VII): ##STR38## reacting said α-diazomethyl ketone of formula (VII) with a catalyst and an alcohol R 6 OH to yield an ester of formula (VIII): ##STR39## removing the amino protecting group and transforming the carboxy ester to a group COR 3 if necessary: thereby obtaining a dipeptide analogue of formula (I).

Claim 7

A method for isosterically replacing the nitrogen atom of the linking amide group of a dipeptide of the formula: ##STR40## by a trivalent group ##STR41## and for replacing the carbonyl group of said linking amide group by a methylene group --CH 2 --, to thereby obtain a dipeptide analogue of the formula (I): ##STR42## which comprises: preparing a dipeptide analogue of formula (II): ##STR43## according to the process of any of claims 1 or 2, wherein the symbols A, R 1 , R 2 , R 3 , R 4 , R 5 , and B have the meaning given in said claims; reducing said compound of formula (II) to a compound of formula (III): ##STR44## removing the amino- and carboxy-protecting groups if necessary, thereby obtaining a compound of formula (I).

Claim 11

The method of any of claims 1, 2 or 3 wherein R 4 and R 5 are the same or different side chain residues of an α-amino acid selected from the group consisting of α-alanine, β-alanine, arginine, asparagine, aspartic acid, 3,5-dibromotyrosine, cystine, cysteine, dopa, N-formyl glycine, glycine, glutamic acid, glutamine, histidine, hydroxylysine, hydroxyproline, 3,5-diiodotyrosine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, pyroglutamic acid, hydroxyproline, serine, spinacin, threonine, thyroxine, tryptophan, tyrosine and valine.

Claim 12

The method of any of claims 1, 2 or 3 wherein said amine-protecting group A is selected from the group consisting of benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, amyloxycarbonyl, biphenylisopropoxycarbonyl, o-nitrophenylsulfonyl, phthaloyl, and p-butoxycarbonyl.

Claim 13

The method of any of claims 1 or 2 wherein said carboxy protecting group B is selected from the group consisting of C 1 -C 4 alkyl esters, amides, N-substituted amides, benzyl esters and t-butylester.

Claim 14

The method of any of claims 1 or 2 wherein said leaving group Z is selected from the group consisting of p-toluene sulphonate and bromide.

Claim 15

The method of any of claims 1, 2 or 3 which comprises removing the amino-protecting group A by acid hydrolysis.