EP0799240A1 - Peptides de cetoarginine heterocycliques utilises comme inhibiteurs de thrombine - Google Patents
Peptides de cetoarginine heterocycliques utilises comme inhibiteurs de thrombineInfo
- Publication number
- EP0799240A1 EP0799240A1 EP95940926A EP95940926A EP0799240A1 EP 0799240 A1 EP0799240 A1 EP 0799240A1 EP 95940926 A EP95940926 A EP 95940926A EP 95940926 A EP95940926 A EP 95940926A EP 0799240 A1 EP0799240 A1 EP 0799240A1
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- Prior art keywords
- alkyl
- aryl
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- compound according
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- Prior art date
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Classifications
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- 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
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- 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
-
- 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 compounds useful for the treatment of thrombotic disorders, and more particularly to novel heterocyclic inhibitors of the enzyme thrombin.
- BACKGROUND Inordinate thrombus formation on blood vessel walls precipitates acute cardiovascular disease states that are the leading cause of death in economically developed societies.
- Plasma proteins such as fibrinogen, proteases and cellular receptors participating in hemostasis have emerged as important factors that play a role in acute and chronic coronary disease as well as cerebral artery disease by contributing to the formation of thrombus or blood clots that effectively diminish normal blood flow and supply.
- Vascular aberrations stemming from primary pathologic states such as hypertension, rupture of atherosclerotic plaques or denuded endothelium, activate biochemical cascades that serve to respond and repair the injury site.
- Thrombin is a key regulatory enzyme in the coagulation cascade.
- thrombin In addition to its direct effect on hemostasis, thrombin exerts direct effects on diverse cell types that support and amplify pathogenesis of arterial thrombus disease.
- the enzyme is the strongest activator of platelets causing them to aggregate and release substances (e.g. ADP TXA ⁇ NE) that further propagate the thrombotic cycle. Platelets in a fibrin mesh comprise the principal framework of a white thrombus.
- Thrombin also exerts direct effects on endothelial cells causing release of vasoconstrictor substances and translocation of adhesion molecules that become sites for attachment of immune cells.
- the enzyme causes mitogenesis of smooth muscle cells and proliferation of fibroblasts. From this analysis, it is apparent that inhibition of thrombin activity constitutes a viable therapeutic approach towards the attenuation of proliferative events associated with thrombosis.
- ATIII antithrombin III
- Heparin exerts clinical efficacy in venous thrombosis by enhancing ATIII/thrombin binding through catalysis.
- heparin also catalyzes inhibition of other proteases in the coagulation cascade and its efficacy in platelet-dependent thrombosis is largely reduced or abrogated due to inaccessibility of thrombus- bound enzyme.
- Adverse side effects such as thrombocytopenia, osteoporosis and triglyceridemia have been observed following prolonged treatment with Heparin.
- Hirudin derived from the glandular secretions of the leech Hirudo medicinalis is one of the high molecular weight natural anticoagulant protein inhibitors of thrombin activity (Markwardt F. Cardiovascular Drug Reviews, 1_Q., 211, 1992) . It is a biopharmaceutical that has demonstrated efficacy in experimental and clinical thrombosis.
- a potential drawback to the use of hirudin as a therapeutic agent is its weak antigenicity and lack of an effective method of neutralization, especially in view of its extremely tight binding characteristics toward thrombin.
- the exceedingly high affinity for thrombin is unique and is attributed to a simultaneous interaction with the catalytic site as well as a distal "anion binding exosite" on the enzyme.
- Thrombin activity can also be abrogated by hirudin-like molecules such as hirulog (Maraganore, J.M. et al., Biochemistry, 22., 7095, 1990) or hirutonin peptides (DiMaio, J. et al., J. Med. Chem., 23., 3331, 1992) .
- hirudin-like molecules such as hirulog (Maraganore, J.M. et al., Biochemistry, 22., 7095, 1990) or hirutonin peptides (DiMaio, J. et al., J. Med. Chem., 23., 3331, 1992) .
- Thrombin activity can also be inhibited by low molecular weight compounds that compete with fibrinogen for thrombin's catalytic site, thereby inhibiting proteolysis of that protein or other protein substrates such as the thrombin receptor.
- a common strategy for designing enzyme inhibitory compounds relies on mimicking the specificity inherent in the primary and secondary structure of the enzyme's natural substrate.
- Blomback et al. first designed a thrombin inhibitor that was modeled upon the partial sequence of the fibrinogen A ⁇ chain comprising its proteolytically susceptible region (Blomback, et al., J. Clin. Lab. Invest., 21. 59, 1969) . This region of fibrinogen minimally includes the residues commencing with phenylalanine:
- the aldehyde group is presumed to contribute strongly to inhibitory activity in view of its chemical reactivity toward thrombin's catalytic Ser ]95 residue, generating a hemiacetal intermediate.
- thrombin inhibitors bearing the (D) Phe- Pro-Arg general motif are those incorporating COOH- terminal boroarginine variants such as boronic acids or boronates (Kettner, C. et al. , J. Biol . Chem., 268, 4734, 1993) .
- Maraganore et al. disclose a series of thrombin inhibitors that incorporate the D-Phe-Pro- moiety and hypothesize that this preferred structure fits well within the groove adjacent to the active site of thrombin. Variations on these inhibitors are essentially linear or cyclic peptides built upon the D-Phe-Pro moiety.
- Still others have focused their attention on peptides, peptide derivatives, peptidic alcohols, or cyclic peptides as anti-thrombotic agents (WO 93/22344, EP 0276014; EP 0341607; EP 0291982) .
- Others have examined amindine sulfonic acid moieties to achieve this same end (U.S. 4,781,866), while yet others have examined para or meta substituted phenlyalanine derivatives (WO 92/08709; WO 92/6549) .
- An object of the present invention is to provide compounds that display inhibitory activity towards thrombin.
- An aspect of the present invention relates to peptide derivatives represented by formula (I) , and pharmaceutically acceptable salts thereof
- X is one or more aromatic or non-aromatic heterocycle unsubstituted or substituted with one or more amino, oxygen, alkyl, aralkyl, or aryl;
- AS is an active site inhibitor of thrombin having an argininyl residue or an analogue thereof connected to X.
- vascular diseases in a mammal including humans, comprising administering to said mammal an amount of a compound of formula (I) effective to treat vascular diseases.
- Compounds of the present invention include those compounds where X is one or more heterocycle which may be unsubstituted or substituted with amino, oxygen, alkyl, aralkyl, or aryl.
- X includes aromatic or non-aromatic heterocyclic rings.
- X also includes one or more heterocycle which is optionally fused to another carbocycle or heterocycle.
- X is selected from the group consisting of:
- X 5 , X 10 , X u , and X 12 are each independently selected from the group consisting of N, or C-X 7 where X, is hydrogen, C,_ 4 alkyl, or C s _ ⁇ aryl.
- X 6 , and X 13 are each independently selected from the group consisting of C, O, N, S, N-X 7 , or CH-X 7 where X 7 is as defined above.
- R 5 is hydrogen, C._ 16 alkyl optionally carboxyl substituted, carboxyl, -C 0.1£ - alkyl-CO ⁇ C ⁇ ., ; alkyl, C 6 _, 0 aralkyl, C__ 7 cycloalkyl, aryl or an aromatic heterocycle.
- X is selected from the group consisting of:
- R 5 is as defined above.
- X is selected from the group consisting of:
- R j is as defined above.
- X is selected from the group consisting of:
- R is as defined above.
- R 5 is as defined above.
- X is a 1,2 thiazole optionally substituted with R B and ⁇ or is attached to J at the 2, 3, 4 or 5 position of the ring.
- R 5 is hydrogen, or C 1 . l alkyl. Further preferably, R 5 is hydrogen or CH 3 Most preferably, R, is hydrogen.
- Preferred compounds of formula (I) include those wherein the
- G s is arginyl radical or an analogue thereof; with the proviso that AS is an inhibitor of the active site of thrombin.
- G 2 is selected from the following amino acid derivatives prepared according to the procedures described in Bioorg. Med. Chem., 1995, 3:1145.
- Suitable AS portions include amino acids 45-47 of hirudin and analogues thereof, and inhibitors of thrombin based on the D-Phe-Pro-Arg sequence and its analogues such as D- Cha-Pro-Arg, D-Phe-Pip-Arg, and D-Cha-Pip-Arg.
- Other inhibitors of the active site of thrombin which include an argininyl or an analogue thereof at the C-terminus may also be incorporated into formula (I) as AS.
- compounds of the present invention include those compounds where AS is -Phe-Pro-Arg- or an analogue thereof.
- compounds of the present invention include those compounds where AS is (D-Phe) -Pro-Arg- or an analogue thereof.
- R. is selected from the group consisting of one or more aryl or cycloalkyl which is unsubstituted or substituted with hydroxy, C,_ 6 alkyl, C 4 _ 8 aralkyl, C 3 _ 8 aryl, or C 3. ⁇ cycloalkyl .
- R 2 is selected from the group consisting of hydrogen, hydroxy, C j . 6 alkyl, C 4 _ 8 aralkyl, and unsubstituted or substituted amino group.
- R 3 is selected from the group consisting of hydrogen, hydroxy, SH, C,_ 6 alkyl, C 3 _ 8 aryl and C 4 _ 8 aralkyl.
- n is an integer from 0 to 2.
- Q is a bond or -NH-;
- Z is C,_ 4 alkoxy; cyano; -NH 2 ; -CH 2 -NH 2 ; -C(NH) -NH 2 ; -NH-
- X is as defined above.
- Preferred embodiments of the present invention include compounds of formula (III) wherein R. is selected from the group consisting of one or more 5 or 6 membered aromatic or non-aromatic ring which may be unsubstituted or substituted with hydroxy, C ⁇ 4 alkyl, or C 3 . 8 cycloalkyl. More preferably R 1 is a 6 membered aromatic or non-aromatic ring unsubstituted or substituted with C 4 alkyl. Most preferably R x is phenyl unsubstituted or substituted with C j.4 alkyl.
- R x is phenyl
- R is hydrogen, hydroxy, C j _ 6 alkyl, or amino unsubstituted or substituted with hydroxy, or C._ 6 alkyl. More preferably R a is hydroxy or NH 2 . Most preferably R a is NH 2 .
- R 3 is hydrogen, hydroxy, SH, or C ⁇ alkyl. More preferably R. is hydrogen, or C._schreib alkyl. Most preferably R 3 is hydrogen.
- n is 1 or 2. Most preferably n is 1.
- Q is a bond
- Z is linked via a methylene chain or 2-5 carbon atoms and is selected from the group consisting of -NH 2 ; -C(NH)-NH 2 ; -NH-C(NH) -NH 2 ; a C 6 cycloalkyl or aryl substituted with -NH-, -CH 2 -NH 2 , -C(NH) -NH 2 , -NH-C(NH) -NH 2 or -CH,-NH-C(NH)-NH 2 ; and a 5 or 6 member, saturated or unsaturated heterocycle optionally substituted with -NH 2 , - CH,-NH 2 , -C(NH)-NH 2 , -NH-C(NH) -NH 2 or -CH 2 -NH-C(NH)-NH,.
- Z is -NH-C(NH)-NH 2 , -NH-, and -C(NH)-NH 2 linked via a methylene chain of 3-5 carbon atoms. Most preferably, Z is -NH-C(NH) -NH 2 linked via a trimethylene chain.
- Preferred compounds of the invention include:
- More preferred compounds of formula (I) include: (D-Phe) -Pro-alpha-benzothiazolo keto arginine; and (D-Phe) -Pro-alpha-thiazolo keto arginine.
- alkyl represents a saturated or unsaturated, substituted (for example, by a halogen, hydroxyl, amino, oxygen, sulfur, or C 6 _ 2C aryl) or unsubstituted, straight chain, branched chain hydrocarbon moiety having 1 to 10 carbon atoms and preferably from 1 to 6 carbon atoms. This chain may be interrupted by one or more heteroatom such as N, O, or S.
- amino protecting groups are well known in the field of peptide synthesis. Such protecting groups may be found in T. Greene, Protective Groups In Organic Synthesis, (John Wiley _ Sons, 1981) .
- the appropriate protecting group for a particular synthetic scheme will depend on many factors, including the presence of other reactive functional groups and the reaction conditions desired for removal as well known by persons skilled in the art of peptide chemistry.
- aryl represents a carbocyclic moiety which may be substituted by one or more heteroatom (for example N, 0, or S) and containing one benzenoid-type ring preferably containing from 6 to 15 carbon atoms (for example phenyl and naphthyl) .
- This carbocyclic moiety may be interrupted by one or more heteroatom such as N, 0, or S.
- aralkyl represents an alkyl group being uninterrupted or interrupted , unsubstituted or substituted by an aryl substituent (for example benzyl; preferably containing from 6 to 30 carbon atoms.
- amino acid used herein includes naturally-occurring amino acids as well as non natural analogs commonly used by those skilled in the art of chemical synthesis and peptide chemistry.
- a list of non natural amino acids may be found in "The Peptides", vol. 5, 1983, Academic Press, Chapter 6 by D.C. Roberts and F. Vellaccio. It is to be noted that unless indicated otherwise, the amino acids used in the context of the present invention are those in the L-configuration.
- cycloalkyl represents cyclic hydrocarbon groups containing 3 to 12 carbon, preferably 3 to 8 carbon, which includes for example cyclopropyl, cyclobutyl, cyclohexyl, and cyclodecyl, any of which may be substituted with substituents such as halogen, amino, alkyl, and/or hydroxy.
- heterocycle and “heterocyclic rings” represents one or more aromatic or non-aromatic ring which includes one or more heteroatom such as nitrogen, oxygen, and sulfur and which may be substituted with substituents such as halogen, amino, alkyl, and/or hydroxy.
- the ring is 5, 6, or 7 membered.
- a compound of the invention may be administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation.
- the invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) and pharmaceutically acceptable acid addition salt thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients.
- the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- vascular diseases in a mammal including human, comprising the administration of an effective amount of a compound of formula (I) .
- the compounds of the present invention are useful in combinations, formulations and methods for the treatment and prophylaxis of vascular diseases.
- diseases include myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion, restenosis following arterial injury or invasive cardiological procedures, acute or chronic atherosclerosis, edema and inflammation, cancer and metastasis.
- the term "combination" as used herein, includes a single dosage form containing at least one compound of this invention and at least one thrombolytic agent, a multiple dosage form, wherein the thrombin inhibitor and the thrombolytic agent are administered separately, but concurrently, or a multiple dosage form wherein the two components are administered separately, but sequentially.
- the thrombin inhibitor may be given to the patient during the time period ranging from about 5 hours prior to about 5 hours after administration of the thrombolytic agent.
- the thrombin inhibitor is administered to the patient during the period ranging from 2 hours prior to 2 hours following administration of the thrombolytic agent.
- Thrombolytic agents which may be employed in the combinations of the present invention are those known in the art. Such agents include, but are not limited to, tissue plasminogen activator purified from natural sources, recombinant tissue plasminogen activator, streptokinase, urokinase, purokinase, anisolated streptokinase plasminogen activator complex (ASPAC) , animal salivary gland plasminogen activators and known, biologically active derivatives of any of the above.
- tissue plasminogen activator purified from natural sources
- streptokinase streptokinase
- urokinase urokinase
- purokinase purokinase
- anisolated streptokinase plasminogen activator complex ASPAC
- animal salivary gland plasminogen activators animal salivary gland plasminogen activators and known, biologically active derivatives of any of the above.
- a preferred pharmaceutically effective daily dose of the compounds of this invention is between about l ⁇ g/kg body weight of the patient to be treated ("body weight") and about 5 mg/kg body weight.
- the therapeutic and prophylactic compositions of the present invention comprise a dosage of between about 10 ⁇ g/kg body weight and about 500 ⁇ g/kg body weight of the compounds of this invention. It should also be understood that a daily pharmaceutically effective dose of either the compounds of this invention or the thrombolytic agent present in combinations of the invention, may be less than or greater than the specific ranges cited above.
- compounds may be used in compositions and methods for coating the surfaces of invasive devices, resulting in a lower risk of clot formation or platelet activation in patients receiving such devices.
- Surfaces that may be coated with the compositions of this invention include, for example, prostheses, artificial valves, vascular grafts, stents and catheters. Methods and compositions for coating these devices are known to those of skill in the art. These include chemical cross-linking or physical adsorption of the compounds of this invention-containing compositions to the surfaces of the devices.
- compounds may be used for ex vivo thrombus imaging in a patient.
- the compounds of this invention are labeled with a radioisotope.
- the choice of radioisotope is based upon a number of well- known factors, for example, toxicity, biological 'half-life and detectability.
- Preferred radioisotopes include, but are not limited to 126 I, 123 I and n ⁇ I. Techniques for labeling the compounds of this invention are well known in the art. Most preferably, the radioisotope is l23 I and the labeling is achieved using 123 I-Bolton-Hunter Reagent.
- the labeled thrombin inhibitor is administered to a patient and allowed to bind to the thrombin contained in a clot.
- the clot is then observed by utilizing well-known detecting means, such as a camera capable of detecting radioactivity coupled to a computer imaging system. This technique also yields images of platelet-bound thrombin and meizothrombin.
- This invention also relates to compositions containing the compounds of this invention and methods for using such compositions in the treatment of tumor metastases .
- the efficacy of the compounds of this invention for the treatment of tumor metastases is manifested by the inhibition inhibitors to inhibit thrombin-induced endothelial cell activation.
- This inhibition includes the repression of platelet activation factor (PAF) synthesis by endothelial cells.
- PAF platelet activation factor
- These compositions and methods have important applications in the treatment of diseases characterized by thrombin-induced inflammation and edema, which is thought to be mediated be PAF.
- diseases include, but are not limited to, adult respiratory distress syndrome, septic shock, septicemia and reperfusion damage.
- Early stages of septic shock include discrete, acute inflammatory and coagulopathic responses.
- extracorporeal blood includes blood removed in line from a patient, subjected to extracorporeal treatment, and then returned to the patient in such processes as dialysis procedures, blood filtration, or blood bypass during surgery.
- the term also includes blood products which are stored extracorporeally for eventual administration to a patient and blood collected from a patient to be used for various assays. Such products include whole blood, plasma, or any blood fraction in which inhibition of coagulation is desired.
- an effective amount of a compounds of this invention of this invention for preventing coagulation in extracorporeal blood is from about 1 ⁇ g/60 ml of extracorporeal blood to about 5 mg/60 ml of extracorporeal blood.
- the compounds of this invention may also be used to inhibit clot-bound thrombin, which is believed to contribute to clot accretion. This is particularly important because commonly used anti-thrombin agents, such as heparin and low molecular weight heparin, are ineffective against clot-bound thrombin.
- the compounds of this invention may be employed in compositions and methods for treating neurodegenerative diseases. Thrombin is known to cause neurite retraction, a process suggestive of the rounding in shape changes of brain cells and implicated in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.
- the heterocyle 1 in solution was metalated with an appropriate metalating base such as n-BuLi to generate the corresponding metalated heterocylic compound.
- the cyclic activated arginine group 2 was added to this mixture.
- Compound 2 was prepared according to procedures known in the literature and described in, for example, R.T. Shu an, et al . , "Highly Selective Tripeptide Thrombin Inhibitors", J.Med.Chem, 1993, 36, 314.
- the compound yielded was heterocyclic ketoarginine 3.
- Step 2 The heterocyclic ketoarginine 3 is deprotected and coupled to the dipeptide 4 in the presence of a suitable coupling agent, solvent, and base.
- the dipeptide 4 can be purchased or prepared by methods common in the art and the peptide literature.
- Suitable coupling agents include BOP and isopropylchloroformate.
- Suitable solvents include DCM and DMF.
- Suitable bases include iPr2NEt and n-methyl morpholine.
- Suitable deprotecting agents include BBr 3 , HBr in acetic acid, and TMSI. Methods to remove the protecting groups are well known to people skilled in the art.
- Scheme I is used where Z is N.
- Scheme II is used when Z is carbon, linear carbon chain, or forms a ring with Q.
- the compounds of this invention and their intermediates may be purified during their synthesis and/or after their preparation by standard techniques well known to the skilled artisan.
- One preferred purification technique is HPLC.
- other chromatographic methods such as column chromatography may be used for purification of the compounds .
- Crystallization may also be used to purify the products as may washing with appropriate organic solvents.
- amino protecting groups are not necessary for the reaction to occur.
- the process may be carried out without protecting groups . However, they are used to increase the yield of the desired compounds.
- the process described above may use suitable protecting groups for compounds 2, 3, and 4. Suitable deprotection conditions and protocols are described in the synthesis literature and are well known to chemists skilled in the art.
- Desired R,, R-, and R 3 groups may be substituted onto the dipeptide 4 before it is coupled to heterocyclic ketoarginine 3 using techniques well known in the art of peptide chemistry. Also, preferred analogues of each of the peptides or the dipeptide may be purchased with the desired R j , R.,, or R, groups substituents already present.
- This assay was performed with a Perkin Elmer fluorometer model #LS 50B using a fluorogenix thrombin substrate (Tos- Gly-Pro-Arg-AMC.HCl) purchased from Calbiochem. Human thrombin was also obtained from Calbiochem. Measurements were determined at excitation and emission wavelengths of 383 and 455nm respectively.
- the assay was carried out in running buffer consisting of 50mM Tris, lOOmM NaCl, 0.1% and Peg pH 7.8 at 24°C. Buffer, substrate and inhibitor were mixed and the reaction was initiated by adding the enzyme solution. Initial velocities were recorded at several inhibitor and substrate concentrations. Kinetic parameters were determined by fitting the data to a general equation describing enzyme inhibition (Segel, Enzyme Kinetics , Wiley Interscience Publications, 1993).
- Binding is the establishment of the equilibria between enzyme, inhibitor, and enzyme-inhibitor complexes. In slow binding inhibition, this equilibrium is established slowly. Equilibrium dissociation constant for compound 5 is shown in Table 1. The result is compared with known reported tripeptidyl based thrombin inhibitors.
- Fibrinogen, and buffer solution were transferred to disposable tubes and placed in a water bath for about 15 to 30 minutes before the assay to allow equilibration to 37°C.
- the cuvette-strips were incubated for 3 minutes at 37°C. ball was dispensed to each cuvette.
- To the prewarmed cuvettes was added 75 ⁇ l buffer, 50 ⁇ l inhibitor solution, and 50 ⁇ l fibrinogen solution. The timer was started corresponding to the incubation column for an incubation of 60 seconds.
- the cuvettes were transferred to the test column area.
- the multipette was primed once with the start reagent (thrombin solution) .
- the multipette was activated and 25 ⁇ l of thrombin solution was dispensed. When the clotting times were determined, they were displayed and printed.
- IC 50 is defined as the dose required to double the coagulation time compared to control.
- the result showing IC 50 value is shown in Table 1.
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Abstract
Cette invention se rapporte à de nouveaux inhibiteurs utiles de l'enzyme thrombine de la formule (I) et plus particulièrement à un composé utilisé dans leur préparation, et à des compositions pharmaceutiques. L'invention se rapporte également à l'utilisation de ces composés et compositions in vitro comme anticoagulants et in vivo comme agents s'appliquant au traitement et à la prophylaxie de troubles thrombotiques, tels que la thrombose veineuse, l'embolie pulmonaire et la thrombose artérielle donnant lieu à des accidents ischémiques aigus, tels que l'infarctus du myocarde ou l'infarctus cérébral. De plus, ces composés et compositions sont thérapeutiquement utiles dans la prévention et le traitement de la coagulopathie associée aux interventions de pontage coronarien ainsi qu'à des incidents relatifs à la resténose après une angioplastie transluminale.
Applications Claiming Priority (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9426038 | 1994-12-22 | ||
GBGB9426038.7A GB9426038D0 (en) | 1994-12-22 | 1994-12-22 | Low molecular weight bicyclic thrombin inhibitors |
GBGB9503136.5A GB9503136D0 (en) | 1994-12-22 | 1995-02-17 | Low molecular weight bicyclic thrombin inhibitors |
GB9503136 | 1995-02-17 | ||
GBGB9504403.8A GB9504403D0 (en) | 1995-03-06 | 1995-03-06 | Heterocyclic keto arginine peptides as thrombin inhibitors |
GB9504403 | 1995-03-06 | ||
GB9504404 | 1995-03-06 | ||
GBGB9504404.6A GB9504404D0 (en) | 1995-03-06 | 1995-03-06 | Heterocyclic keto arginine peptides as thrombin inhibitors |
PCT/CA1995/000711 WO1996019491A1 (fr) | 1994-12-22 | 1995-12-21 | Peptides de cetoarginine heterocycliques utilises comme inhibiteurs de thrombine |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0799240A1 true EP0799240A1 (fr) | 1997-10-08 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP95940926A Withdrawn EP0799240A1 (fr) | 1994-12-22 | 1995-12-21 | Peptides de cetoarginine heterocycliques utilises comme inhibiteurs de thrombine |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0799240A1 (fr) |
JP (1) | JPH10513151A (fr) |
AU (2) | AU4250896A (fr) |
CA (1) | CA2208773A1 (fr) |
IL (1) | IL116502A0 (fr) |
WO (1) | WO1996019491A1 (fr) |
Families Citing this family (28)
Publication number | Priority date | Publication date | Assignee | Title |
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US6069130A (en) * | 1995-06-07 | 2000-05-30 | Cor Therapeutics, Inc. | Ketoheterocyclic inhibitors of factor Xa |
IL121474A0 (en) * | 1996-08-23 | 1998-02-08 | Akzo Nobel Nv | Thrombin inhibitors |
AU4172397A (en) * | 1996-09-06 | 1998-03-26 | Biochem Pharma Inc. | Lactam inhibitors of thrombin |
US6063794A (en) * | 1996-10-11 | 2000-05-16 | Cor Therapeutics Inc. | Selective factor Xa inhibitors |
US6262047B1 (en) | 1996-10-11 | 2001-07-17 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
WO1998016524A1 (fr) * | 1996-10-11 | 1998-04-23 | Cor Therapeutics, Inc. | DERIVES HETEROCYCLIQUES UTILISES COMME INHIBITEURS DE FACTEUR Xa |
US6369080B2 (en) | 1996-10-11 | 2002-04-09 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
US6194435B1 (en) | 1996-10-11 | 2001-02-27 | Cor Therapeutics, Inc. | Lactams as selective factor Xa inhibitors |
JP2001502674A (ja) * | 1996-10-11 | 2001-02-27 | シーオーアール・セラピューティックス・インコーポレーテッド | 選択的Xa因子阻害物質 |
WO1998016547A1 (fr) * | 1996-10-11 | 1998-04-23 | Cor Therapeutics, Inc. | INHIBITEURS SELECTIFS DU FACTEUR Xa |
WO1998028326A1 (fr) * | 1996-12-23 | 1998-07-02 | Biochem Pharma Inc. | Inhibiteurs bicycliques de thrombine |
NZ500353A (en) | 1997-04-14 | 2002-02-01 | Cor Therapeutics Inc | Cyclic diaza compounds that are selective inhibitors of factor Xa |
EP0977773A1 (fr) | 1997-04-14 | 2000-02-09 | Cor Therapeutics, Inc. | INHIBITEURS SELECTIFS DU FACTEUR Xa |
US6133256A (en) * | 1997-04-14 | 2000-10-17 | Cor Therapeutics Inc | Selective factor Xa inhibitors |
US6333321B1 (en) | 1997-08-11 | 2001-12-25 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
JP2001515842A (ja) * | 1997-08-11 | 2001-09-25 | シーオーアール セラピューティクス インコーポレイテッド | 選択的Xa因子阻害剤 |
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EA200100815A1 (ru) | 1999-01-27 | 2002-08-29 | Орто-Макнейл Фармасьютикал, Инк. | Пептидильные гетероциклические кетоны, применимые в качестве ингибиторов триптазы |
US8431550B2 (en) | 2000-10-27 | 2013-04-30 | Johnson & Johnson Consumer Companies, Inc. | Topical anti-cancer compositions and methods of use thereof |
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WO2009102761A1 (fr) | 2008-02-12 | 2009-08-20 | Bristol-Myers Squibb Company | 1,2,3-triazoles en tant qu'inhibiteurs de 11-bêta-hydroxysteroïde déshydrogénase type i |
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Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US4191753A (en) * | 1978-11-06 | 1980-03-04 | University Of Miami | Anti-hypertensive peptide analogs |
FR2663336B1 (fr) * | 1990-06-18 | 1992-09-04 | Adir | Nouveaux derives peptidiques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
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- 1995-12-21 EP EP95940926A patent/EP0799240A1/fr not_active Withdrawn
- 1995-12-21 CA CA002208773A patent/CA2208773A1/fr not_active Abandoned
- 1995-12-21 JP JP8519385A patent/JPH10513151A/ja active Pending
- 1995-12-21 WO PCT/CA1995/000711 patent/WO1996019491A1/fr not_active Application Discontinuation
- 1995-12-21 AU AU42508/96A patent/AU4250896A/en not_active Abandoned
- 1995-12-22 AU AU40627/95A patent/AU699679B2/en not_active Ceased
- 1995-12-22 IL IL11650295A patent/IL116502A0/xx unknown
Non-Patent Citations (1)
Title |
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See references of WO9619491A1 * |
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AU699679B2 (en) | 1998-12-10 |
IL116502A0 (en) | 1996-03-31 |
AU4250896A (en) | 1996-07-10 |
JPH10513151A (ja) | 1998-12-15 |
WO1996019491A1 (fr) | 1996-06-27 |
AU4062795A (en) | 1996-06-27 |
MX9704594A (es) | 1998-07-31 |
CA2208773A1 (fr) | 1996-06-27 |
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