WO1991004746A1 - Peptides et pseudopeptides antithrombotiques - Google Patents

Peptides et pseudopeptides antithrombotiques Download PDF

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Publication number
WO1991004746A1
WO1991004746A1 PCT/US1990/005448 US9005448W WO9104746A1 WO 1991004746 A1 WO1991004746 A1 WO 1991004746A1 US 9005448 W US9005448 W US 9005448W WO 9104746 A1 WO9104746 A1 WO 9104746A1
Authority
WO
WIPO (PCT)
Prior art keywords
aspartyl
valine
trifluoroacetate
compound
alkyl
Prior art date
Application number
PCT/US1990/005448
Other languages
English (en)
Inventor
Scott I. Klein
Bruce F. Molino
Mark Czekaj
Charles J. Gardner
Jeffrey C. Pelletier
Original Assignee
Rhone-Poulenc Rorer International (Holdings) Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US07/415,006 external-priority patent/US4952562A/en
Application filed by Rhone-Poulenc Rorer International (Holdings) Inc. filed Critical Rhone-Poulenc Rorer International (Holdings) Inc.
Publication of WO1991004746A1 publication Critical patent/WO1991004746A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1019—Tetrapeptides with the first amino acid being basic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C07K5/06113—Asp- or Asn-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0815—Tripeptides with the first amino acid being basic
    • C07K5/0817—Tripeptides with the first amino acid being basic the first amino acid being Arg
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to novel compounds having anti-thrombotic activity. More particularly, the
  • invention relates to novel peptides and pseudopeptides that inhibit platelet aggregation and thrombus formation in mammalian blood thereby being useful in the prevention and treatment of thrombosis associated with certain disease states, such as, myocardial infarction, stroke, peripheral arterial disease and disseminated intravascular coagulation.
  • Platelet adhesion, spreading and aggregation on extracellular matrices are central events in thrombus formation. These events are mediated by a family of platelet adhesive glycoproteins, i.e., fibrinogen, fibronectin, and von Willebrand factor.
  • Fibrinogen is a co-factor for platelet aggregation
  • fibronectin supports platelet attachments and spreading reactions
  • von Willebrand factor is important in platelet attachment to and spreading on subendothelial matrices.
  • the binding sites for fibrinogen, fibronectin and von Willebrand factor have been located on the platelet membrane
  • Adhesive glycoprotein like fibrinogen, do not bind with normal resting platelets. However, when a platelet is activated with an agonist such as thrombin or adenosine diphosphate, the platelet changes its shape, perhaps making the GPIIb/IIIa binding site accessible to
  • invention may block the fibrinogen receptor, thus
  • compositions possessing such an inhibiting effect may be provided for the prophylaxis and treatment of thrombogenic diseases, such as myocardial infarction, stroke, peripheral arterial disease and disseminated intravascular coagulation.
  • fibrinogen namely, the Gly-Pro-Arg sequence
  • dodecapeptide His-His-Leu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-
  • small synthetic peptides containing the RGD or dodecapeptide have been shown to bind to the platelet GPIIb/IIIa receptor and competitively inhibit binding of fibrinogen, fibronectin and von Willebrand factor as well as inhibit aggregation of activated
  • the present invention is directed to novel peptides and pseudopeptides which inhibit platelet aggregation and subsequent thrombus formation.
  • prophylaxis and/or treatment of thrombotic disease states having the general formulae: 2
  • A, B and D are independently -NR 2 ,
  • G is OR 2 ,
  • R 1 and R 2 are independently:
  • Z is OR 1 , NH 2 or NR 1 R 2 ; m is 0-9 ; and n is 0-5 ; provided that, in formula I, when X is NH 2 , then: m is 3,
  • Y is -NH 2
  • Y is NH 2 , m is 3, F is G is OH; and that one radical in A and B is not -NH.
  • Alkyl means, either alone or within the various substitutents, defined hereinbefore, a hydrocarbon having one to about 20 carbon atoms.
  • “Lower alkyl” means alkyl having one to about six carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl and hexyl.
  • Preferred lower alkyl includes methyl, ethyl and propyl.
  • Aryl means a mononuclear and polynuclear aromatic hydrocarbon radical which can be substituted or
  • aryl groups include phenyl, naphthyl, anthranyl, phenanthranyl, azulyl and the like which can be substituted with one or more of the substituents.
  • Aryl is preferably substituted or unsubstituted phenyl or naphthyl.
  • Aryl substituents include hydrogen, alkyl, alkoxy, amino, halo, aryl, eryloxy, carboalkoxy, nitro, dialkylamino,
  • Aralkyl means an alkyl group substituted by an aryl radical.
  • the preferred aralkyl groups are lower alkyl groups substituted by phenyl or substituted phenyl.
  • the most preferred aralkyl group is benzyl.
  • Compounds of the present invention are believed to be useful in the prevention and treatment of thrombosis associated with certain diseased states, such as myocardial infarction, stroke, peripheral arterial disease and disseminated intravascular coagulation.
  • the present compounds may also be useful for the treatment of certain diseases associated with abnormal cell growth since they may interfere with adhesive
  • the compounds of the present invention may be readily prepared by standard solid phase or solution phase peptide synthesis using starting materials and/or readily
  • the solid support may be, but is not limited to, p-alkoxy benzyl resin; and- P is an N-protected amino acid.
  • the amino acid derivatives are added one at a time to the insoluble resin until the total sequence has been built up on the resin.
  • the functional groups of the amino acid derivatives are protected by blocking groups to prevent cross reaction during the coupling procedure.
  • blocking groups include ⁇ -tertiary butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ), benzyl, t-butyl, 9-fluor- enylmethyloxycarbonyl (FMOC), 2-(trimethylsilyl)ethyl, and 4-methoxy-2,3,6-trimethylbenzenesulfonyl.
  • BOC ⁇ -tertiary butyloxycarbonyl
  • CBZ benzyloxycarbonyl
  • FMOC 9-fluor- enylmethyloxycarbonyl
  • 2-(trimethylsilyl)ethyl 2-(trimethylsilyl)ethyl
  • 4-methoxy-2,3,6-trimethylbenzenesulfonyl Upon completion of the coupling reaction a functional group is deprotected by standard methods to give an active ⁇ -amino function which, in turn, is reacted with a protected amino acid derivative having a free ⁇ -carboxyl
  • the compounds of the present invention may be prepared in solution, i.e., without using a solid support.
  • the protected amino acid derivatives or analogs are coupled by using standard procedures, then deprotected to yield the desired final compound.
  • the resulting resin derivative is then treated as above with 1.36g N- ⁇ -FMOC-N- ⁇ -(4- methoxy-2,3,6-trimethylbenzenesulfonyl)-L-arginine in the presence of triethyl-amine, EDC, and HOBT.
  • the FMOC group is removed as above.
  • the peptide is removed from the resin by treating with 20 ml of 95% trifluoroacetic acid for two hours.
  • the arginine residue is deprotected by overnight treatment with concentrated trifluoroacetic acid.
  • N-FMOC glycine and 0.55g of the amide obtained in 2B are treated under the conditions of 2A to give N- ⁇ -(FMOC) -glycyl-L-aspartic acid isobutyl amide- ⁇ - butyl ester.
  • 0.35g of the product obtained in 2E is treated with concentrated trifluoroacetic acid in the presence of two drops of ethanedithiol overnight.
  • the solution is diluted with 0.5% acetic acid and washed with 4x100 ml of ethyl acetate.
  • the aqueous solution was lyophilized to 0.19g of a white solid, L-arginylglycyl-L-aspartyl- ⁇ - isobutylamide as the ditrifluoroacetate salt; m.p. 90- 95°C.
  • the benzyloxycarbonyl protecting group on the product compound of 3C is removed by dissolving 0.45g of the protected compound in 20 ml of cyclohexene and adding O.lOg 10% palladium on carbon and heating at reflux, under nitrogen, for 2 hours.
  • the resulting solution is
  • L-Arginylglycyl-L-Aspartyl Glycine Starting with N-FMOC-glycine-p-alkoxy benzyl resin ester, sequentially coupling L-aspartic acid, glycine and arginine, deprotecting and removing the peptide as in the above examples, L-arginylglycyl-L-aspartyl glycine was obtained as the ditrifluoroacetate salt; m.p. 85-90°C.
  • N-(L-Arginyl-2-Aminoethyl)-L-Aspartyl-L-Valine A 1.18g EDC and 0.86 ml of triethylamine are combined in 20 ml of methylene chloride and stirred for 10 minutes. 2.0g N- ⁇ -CBZ-L-aspartic acid ⁇ -t-butyl ester, 0.83g HOBT, 1.30g L-valine-t-butyl ester and 0.86 ml triethylamine were added and the solution stirred
  • reaction mixture is then stirred with 0.5 N acetic acid and washed with ethyl acetate.
  • the aqueous layer is lyophilized to give L-arginylglycyl-L-aspartic acid ⁇ -benzyl ester ditrifluoroacetate; m.p. 85-7°C.
  • Example 1A The product from Example 1A was shaken with 0.92g of N-FMOC-L-aspartic acid ⁇ -t-butyl ester, 0.30g of 1-hydroxybenzotriazole (HOBT), 0.43 g of 1-(3-dimethyl- aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 0.32 ml of triethylamine in 10 ml of dimethylformamide for 2 hours. The mixture was filtered and the resin washed with methylene chloride. The resin derivative was then deprotected as in Example 1A to give L-aspartyl- ⁇ -t-butyl ester-L-valine p-alkoxybenzyl resin ester.
  • HOBT 1-hydroxybenzotriazole
  • EDC 1-(3-dimethyl- aminopropyl)-3-ethylcarbodiimide hydrochloride
  • 8-guanidinooctanoic acid hydrochloride was prepared from 8-aminooctanoic acid in a manner similar to the process used in Example 3A.
  • N-(6-guanidinohexanoyl)-L-aspartyl-L-valine can be prepared.
  • N-tert-butoxycarbonyl-8- aminooctanoic acid can be prepared.
  • N-BOC-8-aminooctanoic acid is substituted for N-BOC-6-aminohexanoic acid in Example 1D, N-(8-amino- octanoyl)-L-aspartyl-L-valine can be prepared as the trifluoroacetate salt.
  • L-aspartyl- ⁇ -t-butylester-L-valine p- alkoxybenzyl resin ester (prepared from 0.6g of N-FMOC- valine p-alkoxybenzyl resin ester as in Examples 1A and B) is treated with 0.33g of 8-guanidino-2-octenoic acid hydrochloride in the presence of 0.184g of HOBT, 0.26g of EDC and 0.19 ml of triethylamine in 10 ml of
  • Platelets are washed free of plasma constituents by the albumin density-gradient technique.
  • thrombin-stimulated platelets each compound is tested at 6 or more concentrations with 125 I-labeled fibrinogen held at 0.176 ⁇ mol/liter (60 ⁇ g/ml).
  • the IC 50 is derived by plotting residual fibrinogen binding against the logarithm of the sample compound's concentration.
  • Human Platelets were isolated from freshly drawn whole blood and were suspended in 0.14 mol/L NaCl, 2.7 mmol/L K11, 12 mmol/L NaHCO 3 , 0.42 mmol/L Na 2 HPO 4 , 0.55 mmol/L glucose, and 5 mmol/L Hepes, pH 7.35 at 2 x 10 8 platelets/ml. The suspension was incubated at 37°C. An aliquot of 0.4 ml of platelet suspension was activated by human thrombin at a final concentration of 2 ⁇ g/ml of thrombin for one minute. After one minute the reaction was stopped by a thrombin inhibitor.
  • the compounds of the present invention may be orally or parenterally administered to mammals.
  • the compounds may be incorporated into pharmaceutical formulations having excipients suitable for these administrations and which do not adversely react with the compounds, for example, water, vegetable oils, certain alcohols and carbohydrates, gelatin and magnesium stearate.
  • the pharmaceutical formulations containing an active compound of the present invention may be made into: tablets, capsules, elixirs, drops or suppositories for enteral administration; and solutions, suspensions or emulsions for parenteral administration.
  • the daily dosage is approximately 0.02-5 mg/kg of body weight. It is to be understood, however, that the particular dose for each patient usually depends on very diverse factors, such as the age, body weight, general condition of health, sex, diet and the like of the patient, on the time and route of

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

On décrit de nouveaux peptides et pseudopeptides, ainsi que des compositions pharmaceutiques à base de ceux-ci, qui inhibent l'agrégation plaquettaire et la formation des thrombus dans le sang des mammifères.
PCT/US1990/005448 1989-09-29 1990-09-25 Peptides et pseudopeptides antithrombotiques WO1991004746A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US415,006 1989-09-29
US07/415,006 US4952562A (en) 1989-09-29 1989-09-29 Anti-thrombotic peptides and pseudopeptides
US53438590A 1990-06-07 1990-06-07
US534,385 1990-06-07

Publications (1)

Publication Number Publication Date
WO1991004746A1 true WO1991004746A1 (fr) 1991-04-18

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Application Number Title Priority Date Filing Date
PCT/US1990/005448 WO1991004746A1 (fr) 1989-09-29 1990-09-25 Peptides et pseudopeptides antithrombotiques

Country Status (5)

Country Link
EP (1) EP0494248A4 (fr)
JP (1) JPH05500954A (fr)
AU (1) AU646411B2 (fr)
CA (1) CA2066047A1 (fr)
WO (1) WO1991004746A1 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0454651A2 (fr) * 1990-04-23 1991-10-30 Monsanto Company Inhibiteurs de l'aggrégation plaquettaire
EP0512829A1 (fr) * 1991-05-07 1992-11-11 Merck & Co. Inc. Antagonistes des récepteurs fibrinogéniques
WO1993009795A1 (fr) * 1991-11-22 1993-05-27 Yeda Research And Development Co. Ltd. Succedanes non peptidiques de la sequence arg-gly-asp, et compositions pharmaceutiques les contenant
EP0565896A2 (fr) * 1992-04-13 1993-10-20 Hoechst Aktiengesellschaft Dérivés d'acide aspartique et leur préparation et utilisation
FR2693107A1 (fr) * 1992-07-01 1994-01-07 Chauvin Laboratoire Moyens pour la prévention de la cataracte secondaire.
EP0577775A1 (fr) * 1991-03-28 1994-01-12 Rhone-Poulenc Rorer International (Holdings) Inc. Peptides et pseudopeptides antithrombotiques
US5602155A (en) * 1995-01-17 1997-02-11 G. D. Searle & Co. Platelet aggregation inhibitors
US5639765A (en) * 1995-01-17 1997-06-17 G. D. Searle & Co. Guanidinoalkyl glycine β-amino acids useful for inhibiting bone loss
US5672585A (en) * 1990-04-06 1997-09-30 La Jolla Cancer Research Foundation Method and composition for treating thrombosis
US5681820A (en) * 1995-05-16 1997-10-28 G. D. Searle & Co. Guanidinoalkyl glycine β-amino acids useful for inhibiting tumor metastasis
US5780590A (en) * 1993-10-15 1998-07-14 Rhone-Poulenc Rorer Pharmaceuticals Inc. Antithrombotic azacycloalkylalkanoyl peptides and pseudopeptides
NL1005808C2 (nl) * 1997-04-14 1998-10-19 Dsm Nv Hexahydro-aspartaamamiden en werkwijze voor de bereiding ervan.
US5866685A (en) * 1993-10-15 1999-02-02 Rhone-Poulenc Rorer Pharmaceuticals Inc. Antithrombotic azacycloalkylalkanoyl peptides and pseudopeptides
US6103705A (en) * 1996-11-27 2000-08-15 Aventis Pharmaceuticals Products Inc. Pharmaceutical composition comprising a compound having anti-Xa activity and a platelet aggregation antagonist compound
WO2008090073A1 (fr) 2007-01-16 2008-07-31 Pierre Fabre Dermo-Cosmetique Nouveaux derives amino-acides gras insatures et leur utilisation dermo cosmetologique
FR2913685A1 (fr) * 2007-03-15 2008-09-19 Fabre Pierre Dermo Cosmetique Nouveaux derives amino-acides gras insatures et leur utilisation dermo-cosmetologique
CN108610394A (zh) * 2018-05-07 2018-10-02 深圳市维琪医药研发有限公司 一种拟肽类化合物的制备纯化方法以及应用

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005022976A (ja) * 2001-07-18 2005-01-27 Ajinomoto Co Inc カルボン酸誘導体

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4857508A (en) * 1987-12-03 1989-08-15 Monsanto Company Novel platelet-aggregation inhibitor peptide derivatives

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU201964B (en) * 1989-01-13 1991-01-28 Richter Gedeon Vegyeszet Process for producing peptides inhibiting maturation of t-lymphocytes and activity of macrophages, as well as pharmaceutical compositions comprising same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4857508A (en) * 1987-12-03 1989-08-15 Monsanto Company Novel platelet-aggregation inhibitor peptide derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BLOOD, Volume 73, issued 15 May 1989, I. COHEN et al., "The Effect of Peptides and Monoclonal Antibodies That Bind to Platelet Glycoprotein IIb-IIIa Complex on the Development of Clot Tension", pages 1880-1887, see especially pages 1880 and 1881. *
See also references of EP0494248A4 *

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5672585A (en) * 1990-04-06 1997-09-30 La Jolla Cancer Research Foundation Method and composition for treating thrombosis
EP0454651A3 (en) * 1990-04-23 1992-09-16 Monsanto Company Novel platelet-aggregation inhibitors
EP0454651A2 (fr) * 1990-04-23 1991-10-30 Monsanto Company Inhibiteurs de l'aggrégation plaquettaire
EP0577775A1 (fr) * 1991-03-28 1994-01-12 Rhone-Poulenc Rorer International (Holdings) Inc. Peptides et pseudopeptides antithrombotiques
EP0577775A4 (fr) * 1991-03-28 1995-01-11 Rhone Poulenc Rorer Int Peptides et pseudopeptides antithrombotiques.
EP0512829A1 (fr) * 1991-05-07 1992-11-11 Merck & Co. Inc. Antagonistes des récepteurs fibrinogéniques
WO1993009795A1 (fr) * 1991-11-22 1993-05-27 Yeda Research And Development Co. Ltd. Succedanes non peptidiques de la sequence arg-gly-asp, et compositions pharmaceutiques les contenant
US5352667A (en) * 1991-11-22 1994-10-04 Ofer Lider Non-peptidic surrogates of the Arg-Gly-Asp sequence and pharmaceutical compositions comprising them
EP0565896A3 (fr) * 1992-04-13 1994-01-12 Cassella Farbwerke Mainkur Ag
US5399570A (en) * 1992-04-13 1995-03-21 Cassella Aktiengesellschaft Aspartic acid derivatives, and their use for inhibiting platelete aggregation
EP0565896A2 (fr) * 1992-04-13 1993-10-20 Hoechst Aktiengesellschaft Dérivés d'acide aspartique et leur préparation et utilisation
WO1994001456A1 (fr) * 1992-07-01 1994-01-20 Laboratoire Chauvin Derives oligopeptidiques du collagene et leur utilisation pour la prevention de la cataracte secondaire
FR2693107A1 (fr) * 1992-07-01 1994-01-07 Chauvin Laboratoire Moyens pour la prévention de la cataracte secondaire.
US5866685A (en) * 1993-10-15 1999-02-02 Rhone-Poulenc Rorer Pharmaceuticals Inc. Antithrombotic azacycloalkylalkanoyl peptides and pseudopeptides
US5780590A (en) * 1993-10-15 1998-07-14 Rhone-Poulenc Rorer Pharmaceuticals Inc. Antithrombotic azacycloalkylalkanoyl peptides and pseudopeptides
US5602155A (en) * 1995-01-17 1997-02-11 G. D. Searle & Co. Platelet aggregation inhibitors
US5639765A (en) * 1995-01-17 1997-06-17 G. D. Searle & Co. Guanidinoalkyl glycine β-amino acids useful for inhibiting bone loss
US5681820A (en) * 1995-05-16 1997-10-28 G. D. Searle & Co. Guanidinoalkyl glycine β-amino acids useful for inhibiting tumor metastasis
US6103705A (en) * 1996-11-27 2000-08-15 Aventis Pharmaceuticals Products Inc. Pharmaceutical composition comprising a compound having anti-Xa activity and a platelet aggregation antagonist compound
NL1005808C2 (nl) * 1997-04-14 1998-10-19 Dsm Nv Hexahydro-aspartaamamiden en werkwijze voor de bereiding ervan.
WO1998046629A1 (fr) * 1997-04-14 1998-10-22 Dsm N.V. Appareil permettant de mettre graduellement fin a une dependance
WO2008090073A1 (fr) 2007-01-16 2008-07-31 Pierre Fabre Dermo-Cosmetique Nouveaux derives amino-acides gras insatures et leur utilisation dermo cosmetologique
FR2913685A1 (fr) * 2007-03-15 2008-09-19 Fabre Pierre Dermo Cosmetique Nouveaux derives amino-acides gras insatures et leur utilisation dermo-cosmetologique
CN108610394A (zh) * 2018-05-07 2018-10-02 深圳市维琪医药研发有限公司 一种拟肽类化合物的制备纯化方法以及应用
CN108610394B (zh) * 2018-05-07 2021-08-31 深圳市维琪医药研发有限公司 一种拟肽类化合物的制备纯化方法以及应用

Also Published As

Publication number Publication date
AU646411B2 (en) 1994-02-24
AU6539190A (en) 1991-04-28
EP0494248A4 (en) 1992-08-26
JPH05500954A (ja) 1993-02-25
CA2066047A1 (fr) 1991-03-30
EP0494248A1 (fr) 1992-07-15

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