Enzyme inhibitors

Claim 1

A polypeptide analogue of the formula: where:- ' Pro, Phe and His may be in substituted form; X = H; or an acyl or other N-protecting group e.g. acetyl, pivaloyl, t-butyloxycarbonyl (Boc), benzoyl or lower alkyl (primarily C 1 -C 5 ); or an L- or D-amino- acyl residue, which may itself be N-protected similarly; Y = D- or L-His or other D- or L- basic or aromatic amino-acyl residue, or is absent; "reduced" isostere bond or "keto" isostere bond or "hydroxy" isostere bond or "hydrocarbon" isostere bond where the configuration at asymmetric centres * is either R or S, where in VIII the hydroxy group may be present as such or protected in ether -OR 4 or ester form where R 4 is as given under W below and where R 1 and R 2 , the same or different = i Pro (isopropyl), i Bu (isobutyl), Bzl (benzyl) or other lipophilic or aromatic amino-acid side chain R 3 = -H; lower alkyl (C 1 -C 5 ); or -SO 2 Ph, -SO 2 C 6 H 4 CH 3 (p), Boc, formyl or other N-protecting group; B= D- or L- Val or Ile or other D- or L- lipophilic amino-acyl residue; Z = D- or L- Tyr, Phe, His or other L- or D-aromatic amino-acyl residue; and W = -OH as such or in protected ester form as -OR 4 where R4 = lower alkyl primarily C 1 -C 5 and particularly t Bu, or cycloalkyl primarily C 3 -C 7 , or Bzl, or other ester forming group; or -NH 2 as such or in protected amide form as -NHR 5 or -N(R 5 ) 2 (where R 5 = an N-protecting or other substituent group e.g. lower alkyl as for R 4 and (R 5 ) 2 = two such or e.g, cyclo- alkyl, primarily C 3 -C 7 ) or as -NH-(CH 2 ) n -Q or -NR -(CH 2 ) n -Q (where n = 2 to 6 and Q = NH 2 or and wherein any of the hydrogens attached to nitrogen may be substituted by R 5 or (R 5 ) 2 ); an L- or D-serine or lysine, arginine or other basic amino-acyl residue as such or in amide form, substituted amide form or ester form e.g. containing a group or groups as given for R 4 and R 5 above as the case may be; or an amino alcohol residue derived therefrom as such or protected in ester or ether form e.g. containing a group as given for R 4 above or L- or D-Z + W = an alcohol derived from/Tyr, Phe, His or other L-or D- aromatic amino-acyl residue as such or protected in ester or ether form as above; such polypeptide being in the above form or modified by isosteric replacement of one or more remaining peptide bonds by reduced,-CH 2 -NH-, keto, hydroxy, -CH(OH)-CH 2 -,or hydrocarbon, -CH 2 -CH 2 - isosteric links and further being in free form or in protected form at one or more remaining peptide, carboxyl, amino, hydroxy or other reactive groups.

Claim 46

A method of making a keto isostere of a dipeptide wherein a hydroxy isostere is made by the method of any of claims 24 to 26 and the -CH(OH)- group is oxidised to give the desired isostere as such or in protected form.