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US4772686A Expired / Lapsed US ⏱️ 0.0 years remaining

Enzyme inhibition

Assignee: Thrombosis Research Institute
•
Filing: 1987-01-09
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Granted: 1988-09-20
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Expires: 2007-01-09
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Abstract

Abstract PCT No. PCT/GB84/00063 Sec. 371 Date Oct. 31, 1984 Sec. 102(e) Date Oct. 31, 1984 PCT Filed Feb. 28, 1984 PCT Pub. No. WO84/03507 PCT Pub. Date Sep. 13, 1984.Peptides wherein an amide bond is replaced by nonhydrolyzable isosteric linkage are disclosed as thrombogenic inhibitors.

Inventors

  • 👤 Michael Szelke
  • 👤 David M. Jones

Bibliographic Details

Application Number —
Jurisdiction US
Data Source google_patents
Last Synchronized 2026-11-05 14:17
CPC Classifications
C; C07; C07K; C07K5/00; C07K5/02; C07K5/0207; C07K14/00; C07K14/435; C07K14/745; C07K14/75; A; A61; A61K; A61K38/00; Y; Y10; Y10S; Y10S930/00; Y10S930/01; Y10S930/27

Claims Analysis

Total Claims: 6
Claim 1
Independent Claim 312 words
Polypeptide analogues of the formula: ##STR27## where X=H or an N-protective group: F, Cl, Br, I, --CF 3 , --OH, --OR or --R (R=C 1 -C 6 alkyl) or R--O--CO-- where R═t-butyl, benzyl, 2,2,2-trichloroethyl or R 6 --SO 2 -- where R 6 =Ph, α-naphthyl β-naphthyl or one or more amino acyl residues as such or in N-protected form bearing a group X above; Y=absent, or glycine, or D- or L-phenylalanine or a lipophilic amino acid residue selected from the group consisting of Phg, Cha, α-Nal, β-Nal and p-iodophenylalanyl; Z=L- or D-proline or a ring homologue selected from the group consisting of azetidine-2-carboxylic acid and piperidine-2-carboxylic acid, or L- or D-valine, or N-methyl-alanine, or glycine; or Y and Z are as: ##STR28## where the peptide bond --CO--NH-- between Y and Z has been reduced (and protected) to give --CH 2 --N(X)--, X being a protective group as defined above; A= ##STR29## where: (i) ##STR30## (ii) R 2 =H, lower alkyl (C 1 -C 4 ) or 1-hydroxy-ethyl, (iii) R 3 =a protective group as defined above; (iv) configuration at the asymmetric centres* is either R or S Arg or both Pro and Arg may be absent, Pro or Pro substituted with hydroxy-proline and Arg or Arg substituted with Z, Tos or --NO 2 B=D- or L-valine or D- or L-proline or --NH--(CH 2 ) n --CO--, where n=0-5, or absent W=(i) --OR 4 , where R 4 is hydrogen or an O-protecting group; or (ii) --NHR 5 or --N(R 5 ) 2 where each R 5 is hydrogen or an N-protecting group; or (iii) a group with one or more further amino acyl residues or B-W represents an aminoalcohol derivative of B as such or in protected form, and where further in said compounds of Formula I the two terminals are optionally linked by a peptide bond to form a cyclic structure.
Claim 2
Dependent Claim 312 words
Polypeptide analogues of the formula: ##STR27## where X=H or an N-protective group: F, Cl, Br, I, --CF 3 , --OH, --OR or --R (R=C 1 -C 6 alkyl) or R--O--CO-- where R═t-butyl, benzyl, 2,2,2-trichloroethyl or R 6 --SO 2 -- where R 6 =Ph, α-naphthyl β-naphthyl or one or more amino acyl residues as such or in N-protected form bearing a group X above; Y=absent, or glycine, or D- or L-phenylalanine or a lipophilic amino acid residue selected from the group consisting of Phg, Cha, α-Nal, β-Nal and p-iodophenylalanyl; Z=L- or D-proline or a ring homologue selected from the group consisting of azetidine-2-carboxylic acid and piperidine-2-carboxylic acid, or L- or D-valine, or N-methyl-alanine, or glycine; or Y and Z are as: ##STR28## where the peptide bond --CO--NH-- between Y and Z has been reduced (and protected) to give --CH 2 --N(X)--, X being a protective group as defined above; A= ##STR29## where: (i) ##STR30## (ii) R 2 =H, lower alkyl (C 1 -C 4 ) or 1-hydroxy-ethyl, (iii) R 3 =a protective group as defined above; (iv) configuration at the asymmetric centres* is either R or S Arg or both Pro and Arg may be absent, Pro or Pro substituted with hydroxy-proline and Arg or Arg substituted with Z, Tos or --NO 2 B=D- or L-valine or D- or L-proline or --NH--(CH 2 ) n --CO--, where n=0-5, or absent W=(i) --OR 4 , where R 4 is hydrogen or an O-protecting group; or (ii) --NHR 5 or --N(R 5 ) 2 where each R 5 is hydrogen or an N-protecting group; or (iii) a group with one or more further amino acyl residues or B-W represents an aminoalcohol derivative of B as such or in protected form, and where further in said compounds of Formula I the two terminals are optionally linked by a peptide bond to form a cyclic structure.
Claim 3
Dependent Claim 185 words
Polypeptide analogues according to claim 1, wherein: X=H or a protecting group: F, Cl, Br, I, --CF 3 , --OH, --OR or --R (R=C 1 -C 6 alkyl) or R--O--CO-- where R=t-butyl, benzyl, 2,2,2-trichloroethyl or R 6 --SO 2 -- where R 6 =Ph, α-naphthy; β-naphthyl of an amino acyl residue as such or in protected form bearing a group X above, Y=D- or L-phenylalanine, or glycine, Z=L- or D-proline, or L- or D-valine In A: ##STR31## with n=2, 3 or 4 R 2 =H, methyl, isospropyl, sec-butyl, iso-butyl or 1-hydroxy-ethyl R 3 =H, lower aliphatic acyl C 1 -C 5 or lower alkyl C 1 -C 5 , or t-butyl, benzyl, or 2,2,2-trichloroethyl configuration at the asymmetric centres* is either R or S B=D- or L-valine, or D- or L-proline, or absent W=--OH, or --OR 4 where R 4 =lower alkyl C 1 -C 5 , or --NH 2 , or --NHR 5 or NR 2 5 where R 5 =lower alkyl (C 1 -C 5 ) or alternatively R 2 5 =lower cycloalkyl --(CH 2 ) n -- with n=3, 4 or 5.
Claim 4
Dependent Claim 13 words
Polypeptide analogues according to claim 1 wherein A is the `keto` isostere (II).
Claim 5
Dependent Claim 24 words
Polypeptide analogues according to claim 1, modified by isosteric replacement of one or more remaining peptide bonds by `keto` `hydroxy` or `reduced` isosteric links.
Claim 6
Dependent Claim 26 words
Polypeptide analogues according to claim 1, in protected form at one or more remaining amino, imino, amide (including peptide), guanidino, hydroxyl, carboxyl or other functional groups.

References Cited (Backward Citations)

US4638047A Cited
US4629724A Cited

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