New hypotensive peptides, their preparation and their use

Claim 2

Compounds of formula (I): [wherein: R 1 CO- represents an aliphatic acyl group, an aromatic acyl group, an aromatic aliphatic acyl group, a heterocyclic acyl group or a heterocyclic aliphatic acyl group, said acyl groups being unsubstituted or having one or more amino, protected amino, hydroxy, substituted dithio, alkyl, alkoxy, alkoxycarbonyl, halogen or nitro substituents; But represents an isobutyl or a sec-butyl group; X represents a formyl group, or a group of formula - CH ( R 2 )- Y (in which R 2 represents a hydrogen atom, an alkyl group or a substituted alkyl group having at least one hydroxy, mercapto, amino, carbamoyl, formyl, aryl or heterocyclic substituent and Y represents a hydroxy group, a mercapto group or a formyl group), or a group of formula -P(O)(R 3 )-OH (in which R 3 represents a hydroxy group or a substituted alkyl or alkoxy group having at least one hydroxy, mercapto, amino, carbamoyl, formyl, aryl or heterocyclic substituent); and the carbon atoms marked with (S) are of the S-configuration; provided that R 1 does not represent the benzyloxycarbonyl-L-phenylalanyl group or the benzyloxycarbonyl-L-prolyl-L-phenylalanyl group when X represents the formyl group]; and pharmaceutically acceptable salts and esters thereof.

Claim 3

Compounds as claimed in Claim 1, having the formula (Ia): (in which R 1 , X and S are as defined in Claim 1).

Claim 4

Compounds as claimed in Claim 1, having the formula (Ib): (in which R 1 , X and S are as defined in Claim 1).

Claim 5

Compounds as claimed in any one of Claims 1 to 3, wherein the acyl group represented by R 1 CO- is an acetyl, propionyl, pivaloyl, benzoyl, 2-methoxycarbonylbenzoyl, 1-naphthoyl, 2-naphthoyl, phenylacetyl, benzyloxycarbonyl, phenylalanyl, N-(benzyloxycarbonyl)phenylalanyl, alpha-(benzyloxycarbonylamino)phenylacetyl, N-(4-phenylbutyryl)phenylalanyl, 2-hydroxy-3-phenylpropionyl, N-(benzyloxycarbonyl)-tyrosyl, N-(2-nitrophenylthio)phenylalanyl, N-(3-nitro-2-pyridylthio)phenylalanyl, 2-benzyloxycarbonylamino-3-(1-naphthoyl)propionyl, 2-benzyloxycarbonylamino-3-(2-naphthoyl)propionyl, nicotinyl, 2-pyridinecarbonyl, N-benzyloxycarbonyl-3-(3-quinolyl)-L-alanyl or N-benzyloxycarbonyl-3-(8-quinolyl)-L-alanyl group, or one of the groups having the formulae: in which Boc represents the t-butoxycarbonyl group and Z represents the benzyloxycarbonyl group.

Claim 6

Compounds as claimed in any one of Claims 1 to 4, wherein the group represented by X is a formyl, hydroxymethyl, formylmethyl, 2-formyl-1-hydroxyethyl. 1,2-dihydroxyethyl, 1,3-dihydroxypropyl. 2-hydroxy-l-mercaptoethyl, phosphono, hydroxo(2-hydroxyethyl)oxophosphorio or (formylmethyl)hydroxooxophosphorio group or one of the groups of formulae:

Claim 7

N-(4-Phenylbutyryl)-L-phenylalanyl-L-histidyl-L-leucinal, and pharmaceutically acceptable salts and esters thereof.

Claim 8

N-(4-Phenylbutyryl)-L-phenylalanyl-L-histidyl-L-leucinal, and pharmaceutically acceptable salts and esters thereof.

Claim 9

N-[3-(3-Nitro-2-pyridyldithio)propionyl]-L-phenylalanyl-L-histidyl-L-leucinal, and pharmaceutically acceptable salts and esters thereof.

Claim 10

N-[3-(3-Nitro-2-pyridyldithio)propionyl]-L-phenylalanyl-L-histidyl-L-leucinal, and pharmaceutically acceptable salts and esters thereof.

Claim 11

N-Benzyloxycarbonyl-3-(l-naphthyl)-L-alanyl-L-histidyl-L-leucinal, and pharmaceutically acceptable salts and esters thereof.

Claim 12

N-Benzyloxycarbonyl-3-(l-naphthyl)-L-alanyl-L-histidyl-L-leucinal, and pharmaceutically acceptable salts and esters thereof.

Claim 13

N-Benzyloxycarbonyl-L-phenylalanyl-L-histidyl-L-leucinol, and pharmaceutically acceptable salts and esters thereof.

Claim 14

N-Benzyloxycarbonyl-L-phenylalanyl-L-histidyl-L-leucinol, and pharmaceutically acceptable salts and esters thereof.

Claim 15

N-[3-(3-Nitro-2-pyridyldithio)propionyl]-L-phenylalanyl-L-histidyl-L-leucinol, and pharmaceutically acceptable salts and esters thereof.

Claim 16

N-[3-(3-Nitro-2-pyridyldithio)propionyl]-L-phenylalanyl-L-histidyl-L-leucinol, and pharmaceutically acceptable salts and esters thereof.

Claim 17

N-Benzyloxycarbonyl-3-(l-naphthyl)-L-alanyl-L-histidyl-L-leucinol, and pharmaceutically acceptable salts and esters thereof.

Claim 18

N-Benzyloxycarbonyl-3-(l-naphthyl)-L-alanyl-L-histidyl-L-leucinol, and pharmaceutically acceptable salts and esters thereof.

Claim 19

A compound as claimed in any one of Claims 1 to 11 for use as a renin inhibitor.

Claim 20

A process for preparing a compound as claimed in any one of Claims 1 to 12, which process comprises the steps: (a) reacting an acid of formula (IV): (wherein: R 1 CO - is as defined in Claim 1; His represents an L-histidyl group; and p is 0 or 1) or a reactive derivative of said acid with an amino compound of formula (V): (wherein: His is as defined above; But is as defined in Claim 1: g is 0 when p is 1 or 1 when p is 0; and X' represents any of the groups defined in Claim 1 for X, or any such group defined for X in which the formyl group represented by X or included within the group represented by X is replaced by a hydroxymethyl group, or any such group defined for X in which the formyl group represented by X or included within the group represented by X is protected); (b) if necessary, where X' represents a hydroxymethyl group or a group including a hydroxymethyl group, oxidizing said hydroxymethyl group to a formyl group; (c) if necessary, where X' represents a protected formyl group or a group including a protected formyl group, removing the protecting group; (d) if necessary, where R1CO- includes a protected amino group, removing the protecting group; and (e) if necessary, salifying or esterifying the resulting compound of formula (I).

Claim 21

A process as claimed in Claim 13, wherein But represents an isobutyl group.

Claim 22

A process as claimed in Claim 13, wherein But represents a sec-butyl group.

Claim 23

A process as claimed in any one of Claims 13 to 15, wherein, in step (a), an acid of formula (II): (wherein R 1 CO- and His are as defined in Claim 13), or a reactive derivative thereof, is reacted with an amino compound of formula (III): (wherein But and X' are as defined in Claim 13).

Claim 24

A process as claimed in any one of Claims 13 to 15, wherein, in step (a), an acid of formula (VI): (wherein R 1 CO- is as defined in Claim 13), or a reactive derivative thereof, is reacted with an amino compound of formula (VII): (wherein His, But and X' are as defined in Claim 13).