EP0341915A2
Expired / Lapsed
EP
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Anti-aggregatory peptides
Assignee: SmithKline Beecham Corp
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Filing: 1989-05-05
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Granted: —
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Expires: 2009-05-05
Abstract
Abstract Compounds of the formula (I) or (II) or pharmaceutically acceptable salts thereof are described : X-(A) m -B-Gly-Asp-(C) n -Y (I) wherein: A is Arg, HArg, (Me₂)Arg, (Et₂)Arg, Ala, Gly, His, Abu or an α-R′ substituted derivative thereof, or Pro; B is Arg, HArg, (Me₂)Arg, (Et₂)Arg or an α-R′ substituted derivative thereof; C is a D or L amino acid chosen from Tyr, (Alk)Tyr, Phe, (4′W)Phe, HPhe, Phg, Trp, His, Ser, (Alk)Ser, Thr, (Alk)Thr, Cys, (Alk)Cys, Pen, (Alk)Pen, Ala, Val, Nva, Met, Leu, Ile, Nle or Nal; A′ is a D- or L- amino acid chosen from Arg, HArg, (Me₂)Arg, (Et₂)Arg, Ala, Gly, His, Abu, Lys or an α-R′ substituted derivative thereof, or Pro; B′ is a D- or L- amino acid chosen from Arg, HArg, (Me₂)Arg, (Et₂)Arg, Lys or an α-R′ substituted derivative thereof; C′ is a D or L amino acid chosen from Tyr, (Alk)Tyr, Phe, (4′W)Phe, HPhe, Phg, Trp, His, Ser, (Alk)Ser, Thr, (Alk)Thr, (Alk)Cys, (Alk)Pen, Ala, Val, Nva, Met, Leu, Ile, Nle or Nal, or an α-R′ substituted derivative thereof; W is halogen or Alk; Y is NR₁R₂ or OR₃; R₁ and R₂ are each independently H, Alk or (CH₂) p Ph; R₃ is Alk, (CH₂) p Ph or, when B or B′ is HArg, (Me₂)Arg, (Et₂)Arg, or an α-R′ substituted derivative of Arg, HArg, (Me₂)Arg or (Et₂)Arg, H; X is R₄R₅N or H; R₄ is H or Alk; R₅ is H, Alk, HCO, AlkCO, PhCH₂ or Ph(CH₂) q CO; R′ is Alk or PhCH₂; Z₁ is a D- or L-isomer of Cys, Pen or APmp; Z₂ is a D- or L- isomer of Cys, Pen or APmp; q, m and n are independently 0 or 1; and p is 0, 1, 2 or 3. Pharmaceutical compositions containing them, their use as medicaments and processes for their preparation are also described.
Inventors
- 👤 Fadia El-Fehail Ali
- 👤 James Martin Samanen
- 👤 Ronald John Shebuski
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-26 18:37
CPC Classifications
C; C07; C07K; C07K7/00; C07K7/04; C07K7/06; C07K14/00; C07K14/435; C07K14/745; C07K14/75; A; A61; A61P; A61P7/00; A61P7/02; C07K14/78; A61K; A61K38/00
Claims Analysis
Total Claims: 26
Claim 1
Independent Claim
246 words
A process for preparing a compound of the formula (I): X-(A) m -B-Gly-Asp-(C) n -Y (I) wherein: A is Arg, HArg, (Me₂)Arg, (Et₂)Arg, Ala, Gly, His, Abu or an α-R′ substituted derivative thereof, or Pro; B is Arg, HArg, (Me₂)Arg, (Et₂)Arg or an α-R′ substituted derivative thereof; C is a D or L amino acid chosen from Tyr, (Alk)Tyr, Phe, (4′W)Phe, HPhe, Phg, Trp, His, Ser, (Alk)Ser, Thr, (Alk)Thr, Cys, (Alk)Cys, Pen, (Alk)Pen, Ala, Val, Nva, Met, Leu, Ile, Nle or Nal; W is halogen or Alk; Y is NR₁R₂ or OR₃; R₁ and R₂ are each independently H, Alk or (CH₂) p Ph; R₃ is Alk, (CH₂) p Ph or, when B is HArg, (Me₂)Arg, (Et₂)Arg, or an α-R′ substituted derivative of Arg, HArg, (Me₂)Arg or (Et₂)Arg, H; X is R₄R₅N; R₄ is H or Alk; R₅ is H, Alk, HCO, AlkCO, PhCH₂ or Ph(CH₂) q CO; R′ is Alk or PhCH₂; q, m and n are 0 or 1; and p is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof; which process comprises, a) coupling protected amino acids to form a suitably protected compound of the formula: X-(A) m -B-Gly-Asp-(C) n -[Y˝] wherein, X, A, B, C, m and n are as hereinbefore defined and [Y˝] is a chloromethyl, benzhydrylamine or methylbenzhydrylamine resin, or Y as defined above for formula (I); b) deprotecting and, if necessary, cleaving the peptide from the resin; and c) optionally forming a pharmaceutically acceptable salt thereof.
Claim 2
Dependent Claim
246 words
A process for preparing a compound of the formula (I): X-(A) m -B-Gly-Asp-(C) n -Y (I) wherein: A is Arg, HArg, (Me₂)Arg, (Et₂)Arg, Ala, Gly, His, Abu or an α-R′ substituted derivative thereof, or Pro; B is Arg, HArg, (Me₂)Arg, (Et₂)Arg or an α-R′ substituted derivative thereof; C is a D or L amino acid chosen from Tyr, (Alk)Tyr, Phe, (4′W)Phe, HPhe, Phg, Trp, His, Ser, (Alk)Ser, Thr, (Alk)Thr, Cys, (Alk)Cys, Pen, (Alk)Pen, Ala, Val, Nva, Met, Leu, Ile, Nle or Nal; W is halogen or Alk; Y is NR₁R₂ or OR₃; R₁ and R₂ are each independently H, Alk or (CH₂) p Ph; R₃ is Alk, (CH₂) p Ph or, when B is HArg, (Me₂)Arg, (Et₂)Arg, or an α-R′ substituted derivative of Arg, HArg, (Me₂)Arg or (Et₂)Arg, H; X is R₄R₅N; R₄ is H or Alk; R₅ is H, Alk, HCO, AlkCO, PhCH₂ or Ph(CH₂) q CO; R′ is Alk or PhCH₂; q, m and n are 0 or 1; and p is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof; which process comprises, a) coupling protected amino acids to form a suitably protected compound of the formula: X-(A) m -B-Gly-Asp-(C) n -[Y˝] wherein, X, A, B, C, m and n are as hereinbefore defined and [Y˝] is a chloromethyl, benzhydrylamine or methylbenzhydrylamine resin, or Y as defined above for formula (I); b) deprotecting and, if necessary, cleaving the peptide from the resin; and c) optionally forming a pharmaceutically acceptable salt thereof.
Claim 3
Dependent Claim
367 words
A process for preparing a compound of the formula (II): wherein, A′ is a D- or L- amino acid chosen from Arg, HArg, (Me₂)Arg, (Et₂)Arg, Ala, Gly, His, Abu, Lys or an α-R′ substituted derivative thereof, or Pro; B′ is a D- or L- amino acid chosen from Arg, HArg, (Me₂)Arg, (Et₂)Arg, Lys or an α-R′ substituted derivative thereof; C′ is a D or L amino acid chosen from Tyr, (Alk)Tyr, Phe, (4′W)Phe, HPhe, Phg, Trp, His, Ser, (Alk)Ser, Thr, (Alk)Thr, (Alk)Cys, (Alk)Pen, Ala, Val, Nva, Met, Leu, Ile, Nle or Nal, or an α-R′ substituted derivative thereof; W is halogen or Alk; Y is NR₁R₂ or OR₃; R₁ and R₂ are each independently H, Alk or (CH₂) p Ph; R₃ is Alk, (CH₂) p Ph or, when B′ is HArg, (Me₂)Arg, (Et₂)Arg, or an α-R′ substituted derivative of Arg, HArg, (Me₂)Arg or (Et₂)Arg, H; X is R₄R₅N or H; R₄ is H or Alk; R₅ is H, Alk, HCO, AlkCO, PhCH₂ or Ph(CH₂) q CO; R′ is Alk or PhCH₂; Z₁ is a D- or L-isomer of Cys, Pen or APmp; Z₂ is a D- or L- isomer of Cys, Pen or APmp; q, m and n are independently 0 or 1; and p is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof, which comprises: a) i. cyclizing with a base an optionally protected compound of the formula: wherein, X, Z₁, A′, B′, C′, Z₂, m and n are as defined above for formula (II); T¹ and T² are H or a displaceable group; and [Y˝] is a chloromethyl, benzhydrylamine or methylbenzhydrylamine resin, or Y as defined above for formula (II); ii. removing any protecting groups and, if necessary, cleaving the peptide from the resin; and iii. optionally forming a pharmaceutically acceptable salt thereof; or b) i. oxidatively cyclizing an optionally protected compound of the formula: wherein, X, Z₁, A′, B′, C′, Z₂, Y, m and n are as defined above for formula (II); [Y˝] is a chloromethyl, benzhydrylamine or methylbenzhydrylamine resin, or Y as defined above for formula (II); ii. removing any protecting groups and, if necessary, cleaving the peptide from the resin; and iii. optionally forming a pharmaceutically acceptable salt thereof.
Claim 4
Dependent Claim
367 words
A process for preparing a compound of the formula (II): wherein, A′ is a D- or L- amino acid chosen from Arg, HArg, (Me₂)Arg, (Et₂)Arg, Ala, Gly, His, Abu, Lys or an α-R′ substituted derivative thereof, or Pro; B′ is a D- or L- amino acid chosen from Arg, HArg, (Me₂)Arg, (Et₂)Arg, Lys or an α-R′ substituted derivative thereof; C′ is a D or L amino acid chosen from Tyr, (Alk)Tyr, Phe, (4′W)Phe, HPhe, Phg, Trp, His, Ser, (Alk)Ser, Thr, (Alk)Thr, (Alk)Cys, (Alk)Pen, Ala, Val, Nva, Met, Leu, Ile, Nle or Nal, or an α-R′ substituted derivative thereof; W is halogen or Alk; Y is NR₁R₂ or OR₃; R₁ and R₂ are each independently H, Alk or (CH₂) p Ph; R₃ is Alk, (CH₂) p Ph or, when B′ is HArg, (Me₂)Arg, (Et₂)Arg, or an α-R′ substituted derivative of Arg, HArg, (Me₂)Arg or (Et₂)Arg, H; X is R₄R₅N or H; R₄ is H or Alk; R₅ is H, Alk, HCO, AlkCO, PhCH₂ or Ph(CH₂) q CO; R′ is Alk or PhCH₂; Z₁ is a D- or L-isomer of Cys, Pen or APmp; Z₂ is a D- or L- isomer of Cys, Pen or APmp; q, m and n are independently 0 or 1; and p is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof, which comprises: a) i. cyclizing with a base an optionally protected compound of the formula: wherein, X, Z₁, A′, B′, C′, Z₂, m and n are as defined above for formula (II); T¹ and T² are H or a displaceable group; and [Y˝] is a chloromethyl, benzhydrylamine or methylbenzhydrylamine resin, or Y as defined above for formula (II); ii. removing any protecting groups and, if necessary, cleaving the peptide from the resin; and iii. optionally forming a pharmaceutically acceptable salt thereof; or b) i. oxidatively cyclizing an optionally protected compound of the formula: wherein, X, Z₁, A′, B′, C′, Z₂, Y, m and n are as defined above for formula (II); [Y˝] is a chloromethyl, benzhydrylamine or methylbenzhydrylamine resin, or Y as defined above for formula (II); ii. removing any protecting groups and, if necessary, cleaving the peptide from the resin; and iii. optionally forming a pharmaceutically acceptable salt thereof.
Claim 5
Dependent Claim
22 words
A process according to claim 1 or 2 in which C or C′ is Ser, (Me)Ser, Thr, Tyr, Phe, Nal or Val.
Claim 6
Dependent Claim
18 words
A process according to any one of claims 1-3 in which A or A′ is Gly or Arg.
Claim 7
Dependent Claim
34 words
A process according to any one of claims 1-4 in which B′ or B is HArg or an α-R′ substituted derivative of Arg or HArg and in which either m or n is O.
Claim 8
Dependent Claim
13 words
A process according to claim 2 in which m and n are 0.
Claim 9
Dependent Claim
16 words
A process according to any one of claims 1-6 in which B or B′ is MeArg.
Claim 10
Dependent Claim
62 words
A process according to claim 1 for preparing a compound which is: N α -Ac-MeArg-Gly-Asp-Ser-NH₂; N α -Ac-Arg-Gly-Asp-Ser-NH₂; N α -Ac-Arg-Gly-Asp-Tyr-NH₂; N α -Ac-Arg-Gly-Asp-NH₂; N α -Ac-Arg-Gly-Asp-D-Ser-NH₂; N α -Ac-Arg-Gly-Asp-Val-NH₂; N α -Ac-Arg-Gly-Asp-Nal-NH₂; N α -Ac-Arg-Arg-Gly-Asp-Phe-NH₂; N α -Ac-Arg-Gly-Asp-NH-CH₂-CH₂-C₆H₅; N α -Ac-MeArg-Gly-Asp-Phe-NH₂; N α -Ac-HArg-Gly-Asp-Ser-NH₂; N α -Ac-Arg-Gly-Asp-Ser-NHEt; N α -MeArg-Gly-Asp-Ser-NH₂; N α -Formyl-MeArg-Gly-Asp-Ser-NH₂; or Gly-MeArg-Gly-Asp-Ser-NH₂; or a pharmaceutically acceptable salt thereof.
Claim 11
Dependent Claim
89 words
A process according to claim 2 for preparing a compound which is: N α -Ac-Cyclo(S,S) Cys-MeArg-Gly-Asp-Ser-Cys-NH₂; N α -Ac-Cyclo(S,S) Cys-Arg-Gly-Asp-(D,L) APmp-NH₂; N α -Ac-Cyclo(S,S) Cys-Arg-Gly-Asp-Ser-Cys-NH₂; Cyclo(S,S)Mpr-Arg-Gly-Asp-Ser-Cys-NH₂; N α -Ac-Cyclo(S,S)Cys-MeArg-Gly-Asp-Ser-Pen-NH₂; N α -Ac-Cyclo(S,S)Cys-MeArg-Gly-Asp-(Me)Ser-Cys-NH₂; Cyclo(S,S)Mpr-MeArg-Gly-Asp-Ser-Cys-NH₂; N α -Ac-Cyclo(S,S)Cys-MeArg-Gly-Asp-Cys-NH₂; Cyclo(S,S)Mpr-MeArg-Gly-Asp-Pen-NH₂; N α -Ac-Cyclo(S,S)Cys-Arg-Gly-Asp-Pen-NH₂; N α -Ac-Cyclo(S,S)Cys-Arg-Gly-Asp-D-Pen-NH₂; N α -Ac-Cyclo(S,S)Cys-Lys-Gly-Asp-Pen-NH₂; N α -Ac-Cyclo(S,S)Cys-HArg-Gly-Asp-Pen-NH₂; N α -Ac-Cyclo(S,S)Cys-MeArg-Gly-Asp-Pen-NH₂; N α -Ac-Cyclo(S,S)Cys-Arg-Gly-Asp-Pen-NHEt; N α -Ac-Cyclo(S,S)Cys-D-Arg-Gly-Asp-Pen-NH₂; N α -Ac-Cyclo(S,S)Cys-MeArg-Gly-Asp-Tyr-Cys-NH₂; N α -Ac-Cyclo(S,S)Pen-MeArg-Gly-Asp-Pen-NH₂; N α -Ac-Cyclo(S,S)Pen-Arg-Gly-Asp-Cys-NH₂; N α -Ac-Cyclo(S,S)Cys-D-Arg-Gly-Asp-Ser-Cys-NH₂; N α -Ac-Cyclo(S,S)Cys-Sar-Arg-Gly-Asp-Pen-NH₂; N α -Ac-Cyclo(S,S)Cys-Arg-Gly-Asp-Cys-NH₂; N α -Ac-Cyclo(S,S)Cys-Arg(Et₂)-Gly-Asp-Pen-NH₂; or N α -Ac-Cyclo(S,S)Cys-D-MeArg-Gly-Asp-Pen-NH₂; or a pharmaceutically acceptable salt thereof.
Claim 12
Dependent Claim
11 words
A process according to claim 2 for preparing N α -Ac-Cyclo(S,S)Cys-MeArg-Gly-Asp-Pen-NH₂.
Claim 13
Dependent Claim
41 words
A process for preparing a pharmaceutical composition which comprises bringing into association a compound of formula I, as defined in claim 1, or formula II, as defined in claim 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Claim 14
Dependent Claim
23 words
A process for preparing a pharmaceutical composition which comprises bringing into association a fibrinolytic agent, an anti-fibrotic agent and a pharmaceutically acceptable carrier.
Claim 15
Dependent Claim
23 words
A process for preparing a pharmaceutical composition which comprises bringing into association a fibrinolytic agent, an anti-fibrotic agent and a pharmaceutically acceptable carrier.
Claim 16
Dependent Claim
34 words
A process for preparing a pharmaceutical composition according to claim 12 in which the fibrinolytic agent is streptokinase (SK), urokinase (UK), pro-urokinase (pUK) or tissue plasminogen activator (tPA) or a mutant or derivative thereof.
Claim 17
Dependent Claim
30 words
A process for preparing a pharmaceutical composition according to claim 12 or 13 in which the anti-fibrotic agent is a peptide or polypeptide which contains the amino acid sequence -ArgGlyAsp-.
Claim 18
Dependent Claim
35 words
A process for preparing a pharmaceutical composition according to claim 14 in which the anti-fibrotic agent is a peptide or polypeptide fragment, or derivative thereof, of von Willebrands factor, human plasma fibrinogen or human fibronectin.
Claim 19
Dependent Claim
37 words
A process for preparing a pharmaceutical composition according to claim 12 or 13 in which the anti-fibrotic agent is a compound of formula (I), as defined in claim 1, or formula (II) as defined in claim 2.
Claim 20
Dependent Claim
56 words
A process for preparing a compound of the formula: wherein, X, Z₁, A′, B′, C′, Z₂, m and n are as defined in claim 2; and T¹ and T² are H or displaceable group; and [Y˝] is a chloromethyl, benzhydrylamine or methylbenzhydrylamine, or Y as defined in claim 2, which comprises, coupling suitably protected amino acids.
Claim 21
Dependent Claim
27 words
The use of a fibrinolytic agent and an anti-fibrotic agent in the manufacture of a medicament for inhibiting reocclusion of an artery or vein following fibrinolytic therapy.
Claim 22
Dependent Claim
27 words
The use of a fibrinolytic agent and an anti-fibrotic agent in the manufacture of a medicament for inhibiting reocclusion of an artery or vein following fibrinolytic therapy.
Claim 23
Dependent Claim
29 words
The use according to claim 18 in which the fibrinolytic agent is streptokinase (SK), urokinase (UK), pro-urokinase (pUK) or tissue plasminogen activator (tPA) or a mutant or derivative thereof.
Claim 24
Dependent Claim
25 words
The use according to claim 18 or 19 in which the anti-fibrotic agent is a peptide or polypeptide which contains the amino acid sequence -ArgGlyAsp-.
Claim 25
Dependent Claim
30 words
The use according to claim 20 in which the anti-fibrotic agent is a peptide or polypeptide fragment, or derivative thereof, of von Willebrands factor, human plasma fibrinogen or human fibronectin.
Claim 26
Dependent Claim
30 words
The use according to claim 19 in which the anti-fibrotic agent is a compound of formula (I), as defined in claim 1, or formula (II), as defined in claim 2.
References Cited (Backward Citations)
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