Enzyme inhibitors

Claim 2

Polypeptide analogues of the general formula: or the partial sequences where X = hydrogen, an amino-nitrogen protecting group or an amino acyl residue; Y = a D- or L- basic or aromatic amino-acyl residue; where with n = 0, 1, 2, 3 n = 1, 2, 3, 4 n = 0, 1, 2, 3 n = 1, 2, 3, 4 n = 1, 2, 3 n = 3, 4 and where the configuration at asymmetric centres * is either R or S and R and R 2 , the same or different, are amino acid side chains; R 3 = hydrogen or an amino-nitrogen protecting group; R 6 = hydrogen or a hydroxyl protecting group; B = a lipophilic amino acyl residue; Z = an aromatic amino acyl residue; and W = a hydroxyl group, an amide nitrogen group, or a basic amino acyl residue or amino alcohol residue derived therefrom; or Z + W- = the amino alcohol residue corresponding to the amino acyl residue Z.

Claim 3

A polypeptide analogue according to claim 1, wherein one or more of said Pro Phe and His are substituted in the ring, Pro by OH, Phe by OH, F, Cl, Br or Me, His by Me, or are replaced by, respectively, 4-hydroxyproline (HPro) or pGlu; Tyr, Phe(4-Cl) or Phe(4-F); His (Me) or spinacin.

Claim 4

A polypeptide analogue according to claim 1 or 2 wherein said protecting group X is an acyl or lower alkyl group and particularly said acyl group is acetyl, pivaloyl, t-butoxycarbonyl (Boc) benzyloxycarbonyl or benzoyl and said lower alkyl group is a C 1 -C 5 alkyl group.

Claim 5

A polypeptide analogue according to claim 1 or 2, wherein said amino acyl group X is D- or L- Pro, Val or Ile, or Gly, and/or is in protected form carrying a group as set out in claim 3.

Claim 6

A polypeptide analogue according to any preceding claim, wherein said amino acyl residue Y is D- or L-His.

Claim 7

A polypeptide analogue according to any preceding claim, wherein said amino acid side chains R 1 and R 2 are lipophilic or aromatic, e.g. isopropyl, isobutyl and benzyl, and particularly those of Leu Ile Val Phe cyclohexyl-Ala adamantyl-Ala, or Phe Tyr Trp or His.

Claim 8

A polypeptide analogue according to any preceding claim, wherein said protecting group R 3 is lower alkyl, lower acyl, -S0 2 Ph, -SO 2 C 5 H 4 CH 3 (p), t-butoxy carbonyl (Boc), benzyloxycarbonyl or ring substituted benxyloxycarbonyl, and particularly wherein said alkyl or acyl group is a C 1 -C 5 group.

Claim 9

A polypeptide analogue according to any preceding claim, wherein said hydroxyl protecting group R 6 is lower alkyl or lower acyl, particularly C 1 -C 5 alkyl or acyl ,or benzyl or tetrahydropyranyl.

Claim 10

A polypeptide analogue according to any preceding claim, wherein said residue B is a D- or L-Val Leu or Ile residue.

Claim 11

A polypeptide analogue according to any preceding claim, wherein said residue Z is a D- or L-Tyr Phe or His residue.

Claim 12

A polypeptide analogue according to any preceding claim, wherein said hydroxyl group W is protected in ester form, e.g. by a lower alkyl or cycloalkyl group, or Bzl, and particularly wherein said lower alkyl group is a C 1 -C 5 alkyl group and said cycloalkyl group a C 3 -C 7 cycloalkyl group.

Claim 13

A polypeptide analogue according to any preceding claim, wherein said amide nitrogen group W is in protected form, especially i) a group -NHR or -N(R 5 ) 2 where R 5 is lower alkyl and (R 5 ) 2 is two lower alkyl groups the same or different or a cycloalkyl group, particularly where the Q r each said alkyl group is a C 1 -C 5 alkyl group and said cycloalkyl group is a C 3 -C 7 cycloalkyl group or ii) a group -NH-(CH 2 ) n - Q or NR 5 -(CH 2 ) n -Q where n =.2 to 6 and Q = an amino or guanidyl group where R S is lower alkyl, particularly where one or more of the hydrogens attached to nitrogen in said protecting group is replaced by R 5 or (R 5 ) 2 , defined as above.

Claim 14

A polypeptide analogue according to any preceding claim, wherein said amino acid residue W is a D- or L- Ser, Lys or Arg residue as such or as i) an amide or protected amide particularly when protected by a group as set out in claim 12, or ii) an ester particularly when the esterifying group is as set out in claim 11.

Claim 15

A polypeptide analogue according to any preceding claim, wherein said amino alcohol residue W is the amino alcohol residue derived from D- or L- Ser, Lys or Arg or said amino alcohol residue Z + W is derived from D- or L- Tyr Phe or His, in either case as such or protected in ester or ether form, e.g. by a protective group R 6 as set out in claim 8.

Claim 16

A polypeptide analogue according to any preceding claim, wherein G is selected from:

Claim 17

A polypeptide analogue according to any preceding claim, wherein said polypeptide analogue is in further modified form by isosteric replacement of one or more remaining peptide bonds by "reduced" isostere bond or "keto" isostere bond or "hydroxy" isostere bond or "hydrocarbon" isostere bond where the significance of *, R 1 , R 2 and R 3 is as before, particularly where one or both of the Pro-Phe and Phe-His bonds in formula V is the site of the isosteric replacement.

Claim 18

A polypeptide analogue according to any preceding claim, wherein said polypeptide analogue is in protected form at one or more remaining amino or amide (including peptide) nitrogen, carboxyl, hydroxy or other reactive groups, or in salt form at aminp, imidazole or carboxyl groups, or is as an acid addition salt at one or more basic centres.

Claim 19

Polypeptide analogue of the general I formula: or the partial sequences: where: Pro, Phe, and His may be in substituted form, e.g. carrying OH, F, Cl, Br or Me; X = H; or an acyl or other N-protecting group e.g. acetyl, pivaloyl, benzyloxycarbonyl, t-butyloxycarbonyl (Boc), benzoyl or lower alkyl (primarily C 1 -C 5 ); or an D- or L- amino acyl residue (especially Pro), 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; where with n = 0, 1, 2, 3 n = 1, 2, 3, 4 n = 0, 1, 2, 3 n = 1, 2, 3, 4 n = 1, 2, 3 n = 3, 4 and where the configuration at asymmetric centres * is either R or S, R 1 and R 2 , the same or different, being = 1 Pr (isopropyl), i Bu (isobutyl), Bzl (benzyl) or other amino-acid side chain preferably lipophilic or aromatic; R 3 = H; lower alkyl (C 1 -C 5 ); or t-butyloxycarbonyl, benzyloxycarbonyl, ring substituted benzyloxycarbonyl, -SO 2 PH, -SO 2 C 5 H 4 CH 3 (p), formyl or other N-protecting group including lower acyl (C 1 -C 5 ) generally; R 6 = H, or lower alkyl, lower acyl, benzyl, tetrahydropyranyl, or other hydroxyl protecting group; B = D- or L- Valleur 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 =i)- O H as such or in protected ester form e.g. as - OR 4 where R 4 = 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 ii)-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 groups or e.g. c y clo- alkyl, primarily C3-C7) , or as -NH-(CH 2 ) n -Q or -NR 5 -(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 ); or iii D- or L- an D- or L- 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 iv) 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 or 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, for example by reduced -CH 2 -NH-, keto, hydroxy, -CH(OH)-CH 2 , or hydrocarbon -CH 2 -CH 2 - isosteric links in the form: "reduced" isostere bond or "keto" isostere bond or "hydroxy" isostere bond or "hydrocarbon" isostere bond where the significance of *, R 1 , R and R 3 is as before; and said polypeptide further being in free form or in protected form at one or more remaining amino or amide (including peptide) nitrogen, carboxyl, hydroxy or other reactive groups, or in salt form at amino, imidazole or carboxyl groups, in particular as their physiologically acceptable acid addition salts at basic centres.

Claim 20

Polypeptide analogue of the general I formula: or the partial sequences: where: Pro, Phe, and His may be in substituted form, e.g. carrying OH, F, Cl, Br or Me; X = H; or an acyl or other N-protecting group e.g. acetyl, pivaloyl, benzyloxycarbonyl, t-butyloxycarbonyl (Boc), benzoyl or lower alkyl (primarily C 1 -C 5 ); or an D- or L- amino acyl residue (especially Pro), 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; where with n = 0, 1, 2, 3 n = 1, 2, 3, 4 n = 0, 1, 2, 3 n = 1, 2, 3, 4 n = 1, 2, 3 n = 3, 4 and where the configuration at asymmetric centres * is either R or S, R 1 and R 2 , the same or different, being = 1 Pr (isopropyl), i Bu (isobutyl), Bzl (benzyl) or other amino-acid side chain preferably lipophilic or aromatic; R 3 = H; lower alkyl (C 1 -C 5 ); or t-butyloxycarbonyl, benzyloxycarbonyl, ring substituted benzyloxycarbonyl, -SO 2 PH, -SO 2 C 5 H 4 CH 3 (p), formyl or other N-protecting group including lower acyl (C 1 -C 5 ) generally; R 6 = H, or lower alkyl, lower acyl, benzyl, tetrahydropyranyl, or other hydroxyl protecting group; B = D- or L- Valleur 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 =i)- O H as such or in protected ester form e.g. as - OR 4 where R 4 = 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 ii)-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 groups or e.g. c y clo- alkyl, primarily C3-C7) , or as -NH-(CH 2 ) n -Q or -NR 5 -(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 ); or iii D- or L- an D- or L- 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 iv) 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 or 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, for example by reduced -CH 2 -NH-, keto, hydroxy, -CH(OH)-CH 2 , or hydrocarbon -CH 2 -CH 2 - isosteric links in the form: "reduced" isostere bond or "keto" isostere bond or "hydroxy" isostere bond or "hydrocarbon" isostere bond where the significance of *, R 1 , R and R 3 is as before; and said polypeptide further being in free form or in protected form at one or more remaining amino or amide (including peptide) nitrogen, carboxyl, hydroxy or other reactive groups, or in salt form at amino, imidazole or carboxyl groups, in particular as their physiologically acceptable acid addition salts at basic centres.

Claim 21

The polypeptide analogues: H-His-Pro-Phe-His-Sta-Val-Ile-His-OH H-Pro-His-Pro-Phe-His-Sta-Val-Ile-His-Lys-OH or corresponding analogues wherein the -CH(OH)CH 2 CO- link of the statine residue is replaced by one of the links set out in claim 15. -

Claim 22

When for use in a diagnostic test for high renin states wherein a polypeptide analogue is administered, a positive result being indicated by a fall in blood pressure related to said administration, or for use in treatment of heart failure or hypertension wherein an effective amount of a polypeptide analogue is administered, a polypeptide analogue according to any preceding claim.

Claim 23

A pharmaceutical composition comprising a polypeptide analogue according to any preceding claim 1 to 19, in a pharmaceutically acceptable medium.