EP0584066A1 - Antithrombotische peptid- und pseudopeptidderivate - Google Patents
Antithrombotische peptid- und pseudopeptidderivateInfo
- Publication number
- EP0584066A1 EP0584066A1 EP91910671A EP91910671A EP0584066A1 EP 0584066 A1 EP0584066 A1 EP 0584066A1 EP 91910671 A EP91910671 A EP 91910671A EP 91910671 A EP91910671 A EP 91910671A EP 0584066 A1 EP0584066 A1 EP 0584066A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- aspartyl
- valine
- trifluoroacetate
- guanidinocinnamoyl
- compound
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
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
- C07K5/08—Tripeptides
- C07K5/0819—Tripeptides with the first amino acid being acidic
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
-
- 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
- C07K5/0202—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-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
-
- 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
- C07K5/0205—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)3-C(=0)-, e.g. statine or derivatives thereof
-
- 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
- C07K5/0207—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)4-C(=0), e.g. 'isosters', replacing two amino acids
-
- 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
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
-
- 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 peptide and
- pseudopeptide derivatives 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.
- Haemostasis the biochemistry of blood coagulation, is an extremely complex and as yet not completely understood phenomena whereby normal whole blood and body tissue spontaneously arrest bleeding from injured blood vessels. Effective haemostasis requires the combined activity of vascular, platelet and plasma factors as well as a controlling mechanism to prevent excessive clotting. Defects, deficiencies, or excesses of any of these
- 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 glycoprotein complex IIb/IIIa.
- Adhesive glycoproteins 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 fibrinogen.
- the novel molecules described in this invention may block the fibrinogen receptor, thus inhibiting platelet aggregation and subsequent thrombus formation.
- 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.
- the present invention is directed to novel peptide and pseudopeptide derivatives which inhibit platelet aggregation and subsequent thrombus formation.
- the present invention comprises novel peptide and pseudopeptide derivatives of the general formula:
- Z is -OR 1 , , a D- or L-amino acid or its corresponding carfaoximide, a synthetic amino acid of the formula »
- n 1, 2 or 3;
- n 0 to 6;
- R 1 and R 2 are independently H, alkyl, aryl, aralkyl or allyl;
- R 3 is H, -CO 2 H. -CO 2 R 1 , -CONH 2 , or
- R 4 and R 5 are independently H, alkyl, cycloalkyl, cycloalkylmethyl,
- p 0 to 8.
- R 6 and R 7 form a ring with the nitrogen to which they are attached and are -(CH 2 ) 4 -, (CH 2 ) 5 -, -(CH 2 ) 6 -, -CH 2 CH 2 OCH 2 CH 2 -,
- X 2 is H, Cl, Br, F, -ORL -NO 2 ,
- novel compounds are provided which inhibit platelet aggregation by inhibiting fibrinogen binding and other adhesive glycoproteins involved in platelet aggregation and blood clotting to activated platelets.
- Compounds of the present invention as tested by methods predictive of anti-thrombotic activity, are believed to be 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.
- the present compounds may also be useful for the treatment of certain cancerous diseases since they may interfere with adhesive interactions between cancer cells and the extracellular matrix (Joum. of Biol. Chem., Vol. 262, No. 36 1987, pp. 17703-17711 ; Science, Vol. 233, 1986, pp. 467-470; and Cell, Vol. 57, 59-69, Apr. 1989).
- the following terms unless otherwise indicated, shall be understood to have the following meanings:
- Alkyl means a saturated aliphatic hydrocarbon group which may be straight or branched and having about 1 to about 20 carbon atoms in the chain. Branched means that a lower alkyl group such as methyl, ethyl or propyl. is attached to a linear alkyl chain. Preferred alkyl groups are the "lower alkyl” groups which are those alkyl groups having from 1 to about 6 carbons. Alkyl may be substituted by other moieties such as halogen or alkoxy.
- Halogen means Cl, Br, I or F.
- Alkoxy means an alkyl-O- group. Lower alkoxy groups are preferred. Exemplary groups include methoxy, ethoxy, n-propoxy, i-propoxy and n-butoxy.
- Aryl means a mononuclear and polynuclear aromatic hydrocarbon radical which can be substituted or unsubstituted in one or more positions. Examples of aryl groups include phenyl, naphthyl, anthranyl, phenanthranyl, azulyl and the like which can be substituted with one or more of the
- Aryl is preferrably substituted or unsubstituted phenyl or naphthyl.
- Aryl substituents include hydrogen, alkyl, alkoxy, amino, halo, aryl, aryloxy, carboalkoxy, nitro, dialkylamino, trifluoromethyl, thioalkyl and carbamoyl.
- Alkyl means an alkyl group substituted by an aryl radical, wherein "aryl” means a phenyl or phenyl substituted with one or more substituents which may be alkyl, alkoxy, amino, nitro, carboxy, carboalkoxy, cyano, alkylamino, halo, hydroxy, hydroxyalkyl, mercapto, alkylthio, acyl or carbamoyl.
- substituents may be alkyl, alkoxy, amino, nitro, carboxy, carboalkoxy, cyano, alkylamino, halo, hydroxy, hydroxyalkyl, mercapto, alkylthio, acyl or carbamoyl.
- Exemplary groups include benzyl and phenethyl.
- Carboalkoxy means an . Preferred carboalkoxy groups are those in which the alkyl group is lower alkyl.
- Alkylamino means an alkyl-NH- group. Preferred groups are lower alkylamino groups.
- Alkylthio means an alkyl-S- group. Preferred groups are lower alkylthio.
- acyl means an Preferred acyl groups are those in which the alkyl group is lower alkyl.
- D- and L-amino acids include: Asp, Arg, Ala, Asn, Cys, Gly, Glu, Gln, His, Ile, Leu, Lys, Met, Orn, Phe, Pro, Ser, Thr, Trp, Tyr and Val.
- Stereoisomers and diastereomers of the compounds covered by the general formula also constitute a part of the present invention and intended to be covered by the appended claims.
- the invention also comprises pharmaceutical compositions useful for the prevention and treatment of thrombosis comprising an aforesaid compound in a pharmaceutically acceptable carrier.
- Another aspect of this invention comprises a method for the prevention and treatment of thrombosis associated with the aforesaid diseases.
- the compounds of the present invention may be readily prepared by standard solid phase or solution phase peptide synthesis techniques using starting materials and/or intermediates available from chemical supply companies such as Aldrich and Sigma or may be synthesized by standard organic chemical techinques.
- the solid phase method is represented schematically as follows:
- the solid support may be, but is not limited to, p-alkoxybenzyl alcohol resin
- the amino acid derivatives are added one at a time to the insoluble resin to give the desired dipeptide resin derivative, then the amino or guanidino acid derivative is coupled to the N-terminal of the chain.
- Any reactive functional groups of these derivatives are blocked by protecting groups to prevent cross reactions during the coupling procedures.
- protecting groups include, but are not limited to, tertiary butoxycarbonyl (BOC), carbobenzoxy (CBZ), benzyl, t-butyl, 9-fluorenylmethoxycarbonyl (FMOC) and methoxy-2,3,6-trimethylbenzene- sulfonyl (MTR).
- the N-terminal amino protecting group is removed by standard procedures and the deprotected amino group coupled to a derivative having a free carboxylic acid function. The procedure is repeated until the desired product derivative is formed. The final product is obtained by deprotection and cleavage of the product from the resin by standard techniques.
- the compounds of the present invention may be prepared in solution, i.e., without using a solid support.
- the protected derivatives are coupled, then deprotected using standard procedures.
- the guanidine was then prepared essentially by the method of Miller, et. al., Synthesis. 777(1986), which is incorporated herein by reference.
- To the amine solution was added 0.849g of potassium carbonate, then 0.76g aminoimino-methanesulfonic acid was added, portionwise, over 10 minutes. The mixture was stirred at room temperature for four hours. Upon reduction of the volume by half, in vacuo. a precipitate formed which was collected and recrystallized from water. The solid was suspended in 20% aqueous tetrahydrofuran. 1 N hydrogen chloride in ether was added to give a homogeneous solution which was evaporated in vacuo. The residue was crystallized from methanol/ether to give 3-(2-guanidinoethyl)benzoic acid hydrochloride.
- Example 1 D The product from Example 1 D was shaken with 0.822g N-FMOC-L-aspartic acid- ⁇ -t-butyl ester, 0.38 g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 0.270g 1-hydroxybenzotriazole (HOBT) and 0.28 ml of triethylamine in 10 ml of dimethylformamide for two hours. The mixture was filtered and the resin derivative washed with methylene chloride. The resin derivative was then deprotected as in Example 1 D to give L-aspartyl- ⁇ -t-butyl ester-L-valine-p-alkoxybenzyl alcohol resin ester.
- EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
- HOBT 1-hydroxybenzotriazole
- Example 2B When the amine from Example 2A was treated in a manner similar to that in Example 1 B, 4-(2-aminoethyl)benzoic acid sulfate was obtained.
- Example 2C When the benzoic acid derivative from Example 2B was treated in a manner similar to that in Example 2C, 4-(2-guanidinoethyl)benzoic acid hydrochloride was obtained.
- 3-guanidinobenzoic acid was prepared from 3-aminobenzoic acid by the method of Miller, et. al., cited in Example 1 C.
- the guanidine was treated with ethereal hydrogen chloride to give 3-guanidinobenzoic acid
- 3-guanidinomethylbenzoic acid hydrochloride was prepared from 3-aminomethylbenzoic acid in a manner similar to that of Example 3A.
- Example 1 B is stirred with one equivalent of di-t-butyl-dicarbonate in the presence of two equivalents of sodium carbonate in tetrahydrofuran/water (1 :1).
- the reaction mixture is evaporated to remove the tetrahydrofuran and the aqueous is acidified with dilute hydrochloric acid.
- the product is extracted into ethyl acetate and the solution is dried, then evaporated to give N-tert- butoxycarbonyl-3-(2-aminoethyl)benzoic acid.
- N-BOC-3-(2-aminoethyl)benzoic acid is substituted for 3-(2-guanidino- ethyI)benzoic acid hydrochloride in Example 1F, and treated similarly, then N-[3-(2-amlnoethyl)benzoyl]-L-aspartyl-L-valine is obtained as the trifluoroacetate salt.
- Example 7A N-tert-butoxycarbonyl-4-amino-phenylacetic acid is obtained.
- B If N-BOC-4-aminophenylacetic acid is substituted for 3-(2-guanidino-ethyl)benzoic acid hydrochloride in Example 1 F, and treated similarly, then N-(4-aminophenylacetoyl)-L-aspartyl-L-valine is obtained as the
- EXAMPLE 11 4-Guanidinobenzoyl-N-ethylglycyl-L-aspartyl-L-valine trifluoroacetate A. To 14.8 g of a 50% aqueous solution of glyoxylic acid was added 50 ml of water. The resulting solution was cooled to 0°C and treated with 10 ml of a 70% solution of ethylamine in water added by dropwise addition over 15 minutes. The reaction mixture was transferred to a Parr bottle, then 10% palladium on carbon was added and the reaction vessel was shaken under hydrogen at 44 psi for 24 hours. The reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo to give a tan oil. The oil was treated with 1 N aqueous HCl and concentrated in vacuo to give a solid which was recrystalized from acetic acid.
- L-aspartyl- ⁇ -t-butyl ester-L-valine-p-alkoxybenzyl alcohol resin ester was prepared as described in Example 1 E and treated with 0.33g of FMOC-N-ethyl glycine, from the preceding procedure, 0.191 g EDC, 0.135g HOBT and 0.14 ml of triethylamine in 10 ml of DMF for two hours. The mixture was filtered and washed with methylene chloride. The FMOC protecting group was removed by the procedure described in Example 1 D to give N-ethyl glycyl-L-aspartic acid- ⁇ -t-butylester-L-valine-p-alkoxybenzyl alcohol resin ester.
- Example 6A was dissolved in 5 ml of DMF and treated with 0.10g of triethylamine. The solution was cooled to 0°C and 0.25g of bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) was added. The reaction mixture was stirred at 0°C for 5 minutes than the peptide resin from Example 11 B was added. Shaking was continued for 2 hours at room temperature. Applylng the procedure for removal of the peptide from the resin described in Example 1FF resulted in 4-guanidinobenzoyl-N-ethyl glycyl-L-aspartyl-L-valine as the trifluoroacetate salt.
- BOP-Cl bis(2-oxo-3-oxazolidinyl)phosphinic chloride
- This compound was prepared in a similar manner to the compound prepared in Example 11 , by replacing 4-guanidinobenzoic acid hydrochloride in Example 11C with 4-guanidinocinnamic acid hydrochloride (prepared as described in Example 10A).
- Mtr protecting group 4-methoxy-2,3,5-trimethylbenzenesulfonylchloride
- triphenylphosphoranylidine acetate was added in a single portion. The resulting solution was heated at reflux for 24 hours. Chloroform was removed in vacuo and the residue was taken up in ether and filtered. The filtrate was concentrated in vacuo and subjected to flash chromatography to provide 4-(N9- Mtr-guanidino)-homocinnamic acid methyl ester.
- the methyl ester (1.07g, 2.4 mmol) was dissolved in 16 ml of methanol and 4 ml of 1 N aqueous sodium hydroxide. The solution was allowed to stir 3 hours at 60°C. Methanol was removed in vacuo and the residue was diluted with water, brought to pH ⁇ 2 with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic extracts were dried, filtered and concentrated to provide 4-(N9-Mtr-guanidino)-homocinnamic acid.
- Example 10B 4-(N9-Mtr-guanidino)-homocinnamic acid, when substituted for 4- guanidinocinnamic acid in Example 10B, was coupled to L-aspartyl- ⁇ -t-butyl ester-L-valine-p-alkoxybenzyl alcohol resin (which was prepared as described in Example 1E).
- the peptide was cleaved from the resin and deprotected when the 95% trifluoroacetic acid/5% water/5% ethanediol method of Example 10B was employed and the reaction time was extended to 24 hours.
- the isolation and purification of the peptide proceeded as described in Example 10B to give 4-guanidinohomocinnamoyl-L-aspartyl-L-valine trifluoroacetate was a white powder.
- 4-Hmidazol-1-yl)-cinnamoyl-L-aspartyl-L-valine trifluoroacetate A. 4-(lmidazol-1-yl)-cinnamic acid hydrochloride salt was prepared according to the procedure of Lizuka, et al. described in U.S. Patent No.
- EXAMPLE 15 4-Guanidinocinnamoyl-L-asDartyl-L-leucine amide trifluoroacetate A. 0.50g of N-t-butoxycarbonyl(BOC)-L-leucine-p-methyl benzhydrylamine (MBHA) resin (containing 0.71 mmol of amino acid per gram of resin) was shaken with 50% trifluoroacetic acid in methylene chloride for 1 hour to remove the BOC group.
- BOC N-t-butoxycarbonyl(BOC)-L-leucine-p-methyl benzhydrylamine
- Example 14A The resin from Example 14A was shaken with 0.45g of N-BOC- ⁇ -cyclohexyl ester-L-aspartic acid, 0.19g of HOBT, 0.27g of EDC and 198 ⁇ l of triethylamine in 10 ml of DMF for 2 hours. The mixture was filtered and the resin was washed with DMF (4 x 10 ml) followed by treatment with 10 ml of 50% trifluoroacetic acid in CH 2 CI 2 for 1 hour. The resin was filtered and then washed with the same sequence of solvents listed in Example 14A to give L-aspartic acid- ⁇ -cyclohexyl ester-L-leucine-MBHA resin.
- Example 14B The resin from Example 14B was shaken with 0.34g of 4-guanidino- cinnamic acid, HCI, 0.19g of HOBT, 0.27g of EDC and 198 ⁇ l of triethylamine in 10 ml of DMF overnight. The resin was filtered and then washed with DMF and CH 2 CI 2 . The peptide was cleaved from the resin and deprotected at the same time by treatment with hydrofluoric acid and lyophilized to give 200 mg of crude product. This was taken up into 150 ml of water, filtered and the filtrate was washed with ethyl acetate.
- the aqueous portion was then frozen and lyophilized to give a white powder which was purified by reverse phase HPLC using a C-18 reverse phase column and a methanol/water gradient.
- the purified fractions were lyophilized to give 4-guanidinocinnamoyl-L-aspartyl-L-ieucine amide trifluoroacetate as a white powder.
- Platelets are washed free of plasma constituents by the albumin density-gradient technique. In each experimental mixture platelets in modified
- Tyrode's buffer are stimulated with human ⁇ -thrombin at 22-25°C for 10 minutes (3.125 x 10 11 platelets per liter and thrombin at 0.1 NIH units/ml).
- Hirudin is then added at a 25-fold excess for 5 minutes before addition of the radiolabeled ligand and any competing ligand. After these additions, the final platelet count in the mixture is 1 x 10 11 /liter. After incubation for an additional 30 minutes at 22-25°C, bound and free ligand are separated by centrifuging 50 ⁇ l of the mixture through 300 ⁇ l of 20% sucrose at 12,000xg for 4 minutes. The platelet pellet is then separated from the rest of the mixture to determine platelet-bound radioactivity. Nonspecific binding is measured in mixtures containing an excess of unlabeled ligand. When binding curves are analyzed by Scatchard analysis, nonspecific binding is derived as a fitted parameter from the binding isotherm by means of a computerized program.
- each inhibitory compound is tested at 0.176 ⁇ gmol/1iter (60 ⁇ g/ml).
- the IC 50 is derived by plotting residual fibrinogen binding against the logarithm of the sample compound's
- Human Platelets were isolated from freshly drawn whole blood and were suspended in 0.14 mol/L NaCI, 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 compound may be incorporated into pharmaceutical formulations having excipients suitable for these
- 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.
- compounds of this invention is administered in dosages of approximately 1 to 200 mg per dosage unit or higher.
- 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 as 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 administration, on the rate of excretion, on the combination of medicaments and on the severity of the disease.
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Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US1991/002471 WO1992018117A1 (en) | 1991-04-11 | 1991-04-11 | Anti-thrombotic peptide and pseudopeptide derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0584066A1 true EP0584066A1 (de) | 1994-03-02 |
EP0584066A4 EP0584066A4 (de) | 1994-10-12 |
Family
ID=22225448
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19910910671 Withdrawn EP0584066A4 (de) | 1991-04-11 | 1991-04-11 | Antithrombotische peptid- und pseudopeptidderivate. |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0584066A4 (de) |
JP (1) | JPH08503920A (de) |
AU (1) | AU661659B2 (de) |
WO (1) | WO1992018117A1 (de) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994014775A1 (en) * | 1992-12-29 | 1994-07-07 | Smithkline Beecham Corporation | Platelet aggregation inhibiting compounds |
ZW4294A1 (en) * | 1993-03-29 | 1994-12-21 | Zeneca Ltd | Heterocyclic derivatives |
CA2155307A1 (en) * | 1993-03-29 | 1994-10-13 | Michael Garth Wayne | Heterocyclic compounds as platelet aggregation inhibitors |
US5753659A (en) * | 1993-03-29 | 1998-05-19 | Zeneca Limited | Heterocyclic compouds |
US5750754A (en) * | 1993-03-29 | 1998-05-12 | Zeneca Limited | Heterocyclic compounds |
US5652242A (en) * | 1993-03-29 | 1997-07-29 | Zeneca Limited | Heterocyclic derivatives |
GB9313268D0 (en) * | 1993-06-28 | 1993-08-11 | Zeneca Ltd | Chemical compounds |
US5463011A (en) * | 1993-06-28 | 1995-10-31 | Zeneca Limited | Acid derivatives |
GB9313285D0 (en) * | 1993-06-28 | 1993-08-11 | Zeneca Ltd | Acid derivatives |
AU703854B2 (en) * | 1993-10-15 | 1999-04-01 | Aventis 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 |
Citations (8)
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EP0352249A1 (de) * | 1988-07-20 | 1990-01-24 | Monsanto Company | Inhibitoren für die Blutplättchen-Aggregation |
US4952562A (en) * | 1989-09-29 | 1990-08-28 | Rorer Pharmaceutical Corporation | Anti-thrombotic peptides and pseudopeptides |
EP0445796A2 (de) * | 1990-03-09 | 1991-09-11 | F. Hoffmann-La Roche Ag | Essigsäurederivate |
EP0452257A2 (de) * | 1990-04-05 | 1991-10-16 | Ciba-Geigy Ag | Plättchenaggregationshemmstoffe |
US5086069A (en) * | 1990-02-05 | 1992-02-04 | Rorer Pharmaceutical Corporation | Anti-thrombotic peptide and pseudopeptide derivatives |
WO1992013552A1 (en) * | 1991-02-05 | 1992-08-20 | Smithkline Beecham Corporation | Anti-aggregatory peptides containing an aromatic ester or amide |
WO1992015607A2 (en) * | 1991-03-06 | 1992-09-17 | G.D. Searle & Co. | Phenyl amidines derivatives useful as platelet aggregation inhibitors |
EP0319506B1 (de) * | 1987-12-03 | 1994-03-09 | Monsanto Company | Peptidderivate des Blutplättchen-Aggregations-Inhibitors |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4105789A (en) * | 1976-05-10 | 1978-08-08 | E. R. Squibb & Sons, Inc. | Carboxyalkylacylamino acids |
JPS5753446A (en) * | 1980-09-16 | 1982-03-30 | Torii Yakuhin Kk | Peptide derivative |
US4634715A (en) * | 1981-02-17 | 1987-01-06 | Merck & Co., Inc. | Aza analogs of carboxyalkyl dipeptide derivatives as antihypertensives |
JPS606647A (ja) * | 1983-06-17 | 1985-01-14 | Microbial Chem Res Found | アルフアメニン及びその関連化合物と合成法 |
ATE64378T1 (de) * | 1986-04-04 | 1991-06-15 | Microbial Chem Res Found | Spergualinaehnliche verbindungen und ihr herstellungsverfahren. |
-
1991
- 1991-04-11 JP JP3510398A patent/JPH08503920A/ja active Pending
- 1991-04-11 EP EP19910910671 patent/EP0584066A4/de not_active Withdrawn
- 1991-04-11 AU AU80896/91A patent/AU661659B2/en not_active Ceased
- 1991-04-11 WO PCT/US1991/002471 patent/WO1992018117A1/en not_active Application Discontinuation
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0319506B1 (de) * | 1987-12-03 | 1994-03-09 | Monsanto Company | Peptidderivate des Blutplättchen-Aggregations-Inhibitors |
EP0352249A1 (de) * | 1988-07-20 | 1990-01-24 | Monsanto Company | Inhibitoren für die Blutplättchen-Aggregation |
US4952562A (en) * | 1989-09-29 | 1990-08-28 | Rorer Pharmaceutical Corporation | Anti-thrombotic peptides and pseudopeptides |
US5086069A (en) * | 1990-02-05 | 1992-02-04 | Rorer Pharmaceutical Corporation | Anti-thrombotic peptide and pseudopeptide derivatives |
EP0445796A2 (de) * | 1990-03-09 | 1991-09-11 | F. Hoffmann-La Roche Ag | Essigsäurederivate |
EP0452257A2 (de) * | 1990-04-05 | 1991-10-16 | Ciba-Geigy Ag | Plättchenaggregationshemmstoffe |
WO1992013552A1 (en) * | 1991-02-05 | 1992-08-20 | Smithkline Beecham Corporation | Anti-aggregatory peptides containing an aromatic ester or amide |
WO1992015607A2 (en) * | 1991-03-06 | 1992-09-17 | G.D. Searle & Co. | Phenyl amidines derivatives useful as platelet aggregation inhibitors |
Non-Patent Citations (1)
Title |
---|
See also references of WO9218117A1 * |
Also Published As
Publication number | Publication date |
---|---|
JPH08503920A (ja) | 1996-04-30 |
WO1992018117A1 (en) | 1992-10-29 |
EP0584066A4 (de) | 1994-10-12 |
AU8089691A (en) | 1992-11-17 |
AU661659B2 (en) | 1995-08-03 |
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