Renin inhibitory peptides having phe 13 deletion

Claim 1

A method of preparing a peptide of the formula: wherein: A is hydrogen; where n is 0 to 5 and R 3 has the same meaning as set out further below, and may additionally be hydrogen; B is absent; glycyl; sarcosyl; or D is absent; or where Z is (CH 2 ) n and n is 1 or 2; or-S-; R' is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; phenyl; phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; indolyl; 4-imidazolyl; amine C 2 - 4 alkyl; guanidyl C 2 - 3 alkyl; or methylthiomethyl; R 2 is hydrogen C 1-4 alkyl; phenyl; phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; or indolyl; R 3 is C 3 - 6 alkyl; C 3 - 7 cycloalkyl; phenyl; or C 3 - 7 cycloalkyl or phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; R 4 is hydrogen; or where R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3 - 7 cycloalkyl; and E is where Y is -NH- or -0-; n is 0 to 5; and R 6 is hydrogen; hydroxy; C 1-4 alkyl; C 3 - 7 cycloalkyl; aryl; aryl substituted with up to five members independently selected from the group consisting of C 1 - 6 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino, mono- or di- C 1-4 alkylamino, and halo; amino; mono-, di-, or tri-C 1 - 4 alkylamino; guanidyl; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 salkyl, hydroxy, trifluoromethyl, C 1-4 alkoxy, halo, aryl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; where Y is as defined above; n is 0 or 1; k is 0 or 1; l is 1 to 4; m is 1 to 4; and R 6 and may be the same or different and have the same meaning as R 6 above and Ra may additionally be where R 7 is hydrogen or C 1-3 alkyl; or where Y is as defined above; n is 0 or 1; and Z is where n is 0 or 1; and R 7 is as defined above; or where n is 0 or 1; wherein all of the asymmetric carbon atoms have an S configuration, except for those in the B, D, and E substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof, said peptide being comprised of from five to seven amino acids identified as I through VII, amino acid (AA) I being at the C-terminus of said peptide, to which substituent E is attached, and amino acid (AA) VII being at the N-terminus of said peptide, to which substituents A-B-B-D are attached, comprising the steps of: (A) treating the desired ester or amide of the C-terminus amino acid (AA I) with the next adjacent amino acid (AA II) of said peptide, the amino group of said amino acid being protected by a protecting group, in the presence of a condensing agent, whereby a dipeptide of the two amino acids (AA I and II) is formed; (B) deprotecting the dipeptide formed in Step (A) by removing the protecting group from the amino group of AA II; (C) treating the dipeptide of AA I and AA II with AA III, the amino group of which is protected by a protecting group, in the presence of a condensing agent, whereby a tripeptide of AA I, AA II and AA III is formed; (D) deprotecting the tripeptide formed in Step (C) by removing the protecting group from the amino group of AA III; (E) forming a quadripeptide up to a heptapeptide of AA I, through AA IV, AA V, AA VI or AA VII, by repeating the procedure of Step (C) using protected AA IV through protected AA VII; (F) deprotecting the quadripeptide through heptapeptide formed in Step (E) to give the peptide of formula I wherein A is hydrogen; and optionally (G) treating the quadripeptide through heptapeptide formed in Step (F) with where R 3 and n are as defined above and W is an acid halide, anhydride, or other carboxyl activating group, to give the peptide of formula I wherein A is other than hydrogen and optionally (H) treating the quadripeptide through heptapeptide formed in Steps (F) or (G) where an ester ofAA I is employed with hydrazine to give the corresponding hydrazide, followed by teatment of said hydrazide with acidic nitrite to give the corresponding acyl azide, followed by treatment of said acyl azide with the appropriate amine compound to give the desired E substituent in the peptide of Formula I; said method also comprising, where necessary, protection of sidechain substituents of the component amino acids AA I through AA VII, with deprotection being carried out as a final step; said method also comprising any combination of the steps set out above, whereby the amino acids I through VII and substituents A, B, D, and E are assembled in any desired order to prepare the peptide of formula I; and said method also comprising employment of the steps set out above in a solid phase sequential synthesis, whereby in the initial step the carboxyl group of the selected amino acid is bound to a synthetic resin substrate while the amino group of said amino acid is protected, followed by removal of the protecting group, the succeeding steps being as set out above, the peptide as it is assembled being attached to said synthetic resin substrate; followed by a step of removing the peptide of formula I from said synthetic resin substrate: (a) by strong acid cleavage to give E=OH; (b) by transesterification with a C ' - 4 alkanol to give E=O-C 1-4 alkyl (followed by hydrolysis to give E=OH); or (c) by ammonolysis with NH 2 R' where R' is hydrogen or C 1-4 alkyl; and after removal of the peptide of Formula I from said synthetic resin substrate by transesterification to form the ester thereof as recited above, optionally the step of treating said ester thereof in accordance with the procedures described in Step (H) above to give the desired E substituent in the peptide of Formula I; removal of sidechain protecting groups being accomplished either before or after removal of the peptide of Formula I from said synthetic resin substrate.

Claim 2

A method of preparing a peptide of the formula: wherein: A is hydrogen; where n is 0 to 5 and R 3 has the same meaning as set out further below, and may additionally be hydrogen; B is absent; glycyl; sarcosyl; or D is absent; or where Z is (CH 2 ) n and n is 1 or 2; or-S-; R' is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; phenyl; phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; indolyl; 4-imidazolyl; amine C 2 - 4 alkyl; guanidyl C 2 - 3 alkyl; or methylthiomethyl; R 2 is hydrogen C 1-4 alkyl; phenyl; phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; or indolyl; R 3 is C 3 - 6 alkyl; C 3 - 7 cycloalkyl; phenyl; or C 3 - 7 cycloalkyl or phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; R 4 is hydrogen; or where R 5 is hydrogen; C 1-4 alkyl; hydroxy; or C 3 - 7 cycloalkyl; and E is where Y is -NH- or -0-; n is 0 to 5; and R 6 is hydrogen; hydroxy; C 1-4 alkyl; C 3 - 7 cycloalkyl; aryl; aryl substituted with up to five members independently selected from the group consisting of C 1 - 6 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino, mono- or di- C 1-4 alkylamino, and halo; amino; mono-, di-, or tri-C 1 - 4 alkylamino; guanidyl; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 salkyl, hydroxy, trifluoromethyl, C 1-4 alkoxy, halo, aryl, aryl C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; where Y is as defined above; n is 0 or 1; k is 0 or 1; l is 1 to 4; m is 1 to 4; and R 6 and may be the same or different and have the same meaning as R 6 above and Ra may additionally be where R 7 is hydrogen or C 1-3 alkyl; or where Y is as defined above; n is 0 or 1; and Z is where n is 0 or 1; and R 7 is as defined above; or where n is 0 or 1; wherein all of the asymmetric carbon atoms have an S configuration, except for those in the B, D, and E substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof, said peptide being comprised of from five to seven amino acids identified as I through VII, amino acid (AA) I being at the C-terminus of said peptide, to which substituent E is attached, and amino acid (AA) VII being at the N-terminus of said peptide, to which substituents A-B-B-D are attached, comprising the steps of: (A) treating the desired ester or amide of the C-terminus amino acid (AA I) with the next adjacent amino acid (AA II) of said peptide, the amino group of said amino acid being protected by a protecting group, in the presence of a condensing agent, whereby a dipeptide of the two amino acids (AA I and II) is formed; (B) deprotecting the dipeptide formed in Step (A) by removing the protecting group from the amino group of AA II; (C) treating the dipeptide of AA I and AA II with AA III, the amino group of which is protected by a protecting group, in the presence of a condensing agent, whereby a tripeptide of AA I, AA II and AA III is formed; (D) deprotecting the tripeptide formed in Step (C) by removing the protecting group from the amino group of AA III; (E) forming a quadripeptide up to a heptapeptide of AA I, through AA IV, AA V, AA VI or AA VII, by repeating the procedure of Step (C) using protected AA IV through protected AA VII; (F) deprotecting the quadripeptide through heptapeptide formed in Step (E) to give the peptide of formula I wherein A is hydrogen; and optionally (G) treating the quadripeptide through heptapeptide formed in Step (F) with where R 3 and n are as defined above and W is an acid halide, anhydride, or other carboxyl activating group, to give the peptide of formula I wherein A is other than hydrogen and optionally (H) treating the quadripeptide through heptapeptide formed in Steps (F) or (G) where an ester ofAA I is employed with hydrazine to give the corresponding hydrazide, followed by teatment of said hydrazide with acidic nitrite to give the corresponding acyl azide, followed by treatment of said acyl azide with the appropriate amine compound to give the desired E substituent in the peptide of Formula I; said method also comprising, where necessary, protection of sidechain substituents of the component amino acids AA I through AA VII, with deprotection being carried out as a final step; said method also comprising any combination of the steps set out above, whereby the amino acids I through VII and substituents A, B, D, and E are assembled in any desired order to prepare the peptide of formula I; and said method also comprising employment of the steps set out above in a solid phase sequential synthesis, whereby in the initial step the carboxyl group of the selected amino acid is bound to a synthetic resin substrate while the amino group of said amino acid is protected, followed by removal of the protecting group, the succeeding steps being as set out above, the peptide as it is assembled being attached to said synthetic resin substrate; followed by a step of removing the peptide of formula I from said synthetic resin substrate: (a) by strong acid cleavage to give E=OH; (b) by transesterification with a C ' - 4 alkanol to give E=O-C 1-4 alkyl (followed by hydrolysis to give E=OH); or (c) by ammonolysis with NH 2 R' where R' is hydrogen or C 1-4 alkyl; and after removal of the peptide of Formula I from said synthetic resin substrate by transesterification to form the ester thereof as recited above, optionally the step of treating said ester thereof in accordance with the procedures described in Step (H) above to give the desired E substituent in the peptide of Formula I; removal of sidechain protecting groups being accomplished either before or after removal of the peptide of Formula I from said synthetic resin substrate.