Renin inhibitors and treatments using them

Claim 2

Compounds of the general formula ##STR134## where X=H or an N-protecting group or groups D=absent or is Phe, αNal, βNal, Tyr, His, Trp or cyclohexyl alanyl as such or reduced at carbonyl E=absent or is His Ala, Phe, Tyr, Trp, 2-aminobutyrl or α, δ-diaminovaleryl as such or Nα-alkylated or reduced at carbonyl ##STR135## all compounds being in free form or protected at one or more remaining peptide, carbonyl, amino or other reactive groups including peptide nitrogen or in salt form at amino imidazole or carboxyl groups in particular as physiologically acceptable acid addition salts at basic centres.

Claim 3

Compounds according to claim 1 wherein for any value of n in the definition of M, when M=(i), (iii) or (iv) then two, three or four and when M=(v) then three or four of said residues are present.

Claim 4

Compounds according to claim 1, wherein said group X is ______________________________________ (a) R.sup.3 --(CH.sub.2).sub.n, where n = 0-4, or (b) R.sup.3 --CO-- or (c) R.sup.3 --O--CO-- or (d) R.sup.3 --(CH.sub.2).sub.n --CO-- or (e) R.sup.3 --(CH.sub.2).sub.n --O--CO or where n = 0-5 (f) R.sup.3 --O--(CH.sub.2).sub.n --CO-- or (g) R.sup.3 SO.sub.2 -- or (h) (R.sup.3).sub.2 --N--CO-- ______________________________________ In (a)-(h), R.sup.3 =- (i) H (except in (c)) or (ii) alkyl or (iii) cycloalkyl C.sub.3-7 or (iv) bicycloalkyl or tricycloalkyl or (v) aryl or aryl alkyl.

Claim 5

Compounds according to claim 1, wherein R 1 and R 2 are selected from (i) alkyl or (ii) ArCH 2 or (iii) cyclohexyl-methyl) or (iv) H.

Claim 6

Compounds according to claim 1 wherein said group W= ______________________________________ OH (a) OR.sup.3 (b) R.sup.3 as above NH.sub.2, NHR.sup.3, N(R.sup.3).sub.2 (c) ##STR136## (d) ______________________________________ where N is part of a heterocyclic ring optionally substituted with R 3 or CH 2 - groups at one or more positions.

Claim 7

Compounds according to claim 1 in the form of compounds in which, when one or more of the peptide bonds of the chain is represented by a `reduced` isostere, the N atom of such isostere and the preceding or succeeding N atom in the chain are linked by a moiety as defined for G 1 and giving a five or six membered ring, and together further with compounds in which the above residues are present with further, N- or C-terminal, aminoacyl or aminoacyl analogue residue(s) interposed between X and D, J being His residue, and compounds in which one or more remianing peptide links have been replaced by analogues M.

Claim 8

Compounds according to claim 1, wherein Y-Pro is inserted between X and D, Y being D- or L- His residue and Pro being as such or substituted by OH or replaced by pGlu.

Claim 9

Compounds according to claim 1, wherein W is serine or L- or D- lysine, arginine residue as such or in amide form, substituted amide form or ester form or an amino alcohol residue derived therefrom as such or protected in ester or ether form.

Claim 10

The compounds of claim 1, wherein, in M, n=1.

Claim 11

The compounds of claim 1, or 9 wherein M=-CH(OH)-(CH 2 ) n -.

Claim 12

The compounds of claim 1, or 9, wherein M=-CH(NH 2 )-(CH 2 ) n -.

Claim 13

The compounds of claim 1, or 9, wherein M=-CH(NH 2 )-(CH 2 ) n -CO-NH-.

Claim 14

The compounds of claim 1, wherein A= ##STR137## as defined herein.

Claim 15

The compounds of any of claims 1 or 9, wherein in A, R 5 and R 6 are hydrogen.

Claim 16

Compounds of the general formula: ##STR138## where Phe and His are optional but are not both absent when A has the `reduced` link below ##STR139## such compound being in the above form or modified by isosteric replacement of one or more remaining peptide bonds and further being in free form or in protected form at one or more remaining amino or amide, nitrogen, carboxyl, hydroxy or other reactive groups, or in salt form at amino imidazole or carboxyl groups.

Claim 17

Compounds of the general formula: ##STR138## where Phe and His are optional but are not both absent when A has the `reduced` link below ##STR139## such compound being in the above form or modified by isosteric replacement of one or more remaining peptide bonds and further being in free form or in protected form at one or more remaining amino or amide, nitrogen, carboxyl, hydroxy or other reactive groups, or in salt form at amino imidazole or carboxyl groups.

Claim 18

Compounds according to claim 15, wherein Phe and His are in substituted form, Phe by OH F Cl Br or Me, at the 4-position, or His by Me; or Phe is replaced by Tyr, or His by spinacin.

Claim 19

Compounds according to claim 15, wherein group X is an acyl group 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 and in particular may be Gly or D- or L-Pro, Val or Ile.

Claim 20

Compounds according to claim 15, wherein said hydroxy isostere A is in ether -OR 12 or ester ##STR140## form where R 12 is as given under W below.

Claim 21

Compounds according to claim 15, wherein in A, R 9 and R 10 , the same or different=isopropyl, isobutyl, benzyl or other amino-acid side chain.

Claim 22

Compounds according to claim 15 wherein R 11 is lower alkyl (C 1 -C 5 ), or t-butyloxycarbonyl or benzyloxycarbonyl as such or ring substituted, or aryl sulphonyl e.g. -SO 2 Ph or -SO 2 -C 6 H 4 CH 3 (p), or formyl.

Claim 23

Compounds according to claim 15, wherein when W is -OH it is in protected ester form as -OR 12 where R 12 =lower alkyl primarily C 1 -C 5 and t Bu, or cycloalkyl primarily C 3 -C 7 , or other ester forming group.

Claim 24

Compounds according to claim 15, wherein W is -NH 2 , it is in protected amide form as -NHR 13 or -N(R 13 ) 2 (where R 13 =an N-protecting group, and (R 13 ) 2 =two such or e.g. cycloalkyl, primarily C 3 -C 7 ) or as -NH-(CH 2 ) n -Q 1 or -NR 13 - (CH 2 ) n -Q 1 (where n=2 to 6 and Q 1 =NH 2 or ##STR141## and wherein G is hydrogen.

Claim 25

Compounds according to claim 15, wherein said serine or basic amino acyl residue W is an L- or D-serine or L- or D-lysine or arginine.

Claim 26

The compounds of claim 15, wherein A contains the `hydroxy` isostere bond.

Claim 27

Compounds as in claim 15 but having in place of A the group ##STR142## where M is as in claim 1 and R 1 and R 2 are as in claim 15.

Claim 28

The compounds of claim 24 wherein, in M, n=1.

Claim 29

The compounds of claim 24 or 25, wherein M=-CH(OH)-(CH 2 ) n -.

Claim 30

The compounds of claim 24 or 25 wherein M=-CH(NH 2 )-(CH 2 ) n -CO-NH-.

Claim 31

Compounds as in claim 15 but having in place of A the group ##STR143## as defined in claim 1.

Claim 32

The compound ##STR144##

Claim 33

The compound ##STR144##

Claim 34

The compound ##STR145##

Claim 35

The compound ##STR145##

Claim 36

The compound Boc-Phe His Ast.sup.(R) ILe His-OH Boc-Phe His Ast.sup.(S) Ile His-OH.

Claim 37

The compound Boc-Phe His Ast.sup.(R) ILe His-OH Boc-Phe His Ast.sup.(S) Ile His-OH.

Claim 38

The compound ##STR146##

Claim 39

The compound ##STR146##

Claim 40

The compound ##STR147##

Claim 41

The compound ##STR147##

Claim 42

The compound ##STR148##

Claim 43

The compound ##STR148##