WO2009088063A1 - 医薬組成物、医薬組成物製造のための2-イミノピロリジン誘導体の使用および心疾患の治療用または改善用キット - Google Patents
医薬組成物、医薬組成物製造のための2-イミノピロリジン誘導体の使用および心疾患の治療用または改善用キット Download PDFInfo
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- WO2009088063A1 WO2009088063A1 PCT/JP2009/050184 JP2009050184W WO2009088063A1 WO 2009088063 A1 WO2009088063 A1 WO 2009088063A1 JP 2009050184 W JP2009050184 W JP 2009050184W WO 2009088063 A1 WO2009088063 A1 WO 2009088063A1
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Definitions
- the present invention relates to a pharmaceutical composition, the use of a 2-iminopyrrolidine derivative for producing a pharmaceutical composition, a kit for treating or improving heart disease, and the like.
- Heart diseases include acute coronary syndrome, atherothrombosis, restenosis, hypertension, stable angina, arrhythmia, heart failure, ST-elevation myocardial infarction, and the like.
- thrombin which is one of blood coagulation factors
- the receptor for GP (Glycoprotein) IIb / IIIa which is a platelet membrane glycoprotein, can also be a target for treating heart disease.
- the thrombin receptor is known to be present in cells such as platelets, vascular smooth muscle cells, endothelial cells, and fibroblasts. The thrombin receptor can also be a target for treating heart disease.
- the present inventors have obtained effective effects on heart disease and the like by using at least one predetermined 2-iminopyrrolidine derivative in combination with at least one other compound (B).
- the present invention has been completed by finding that it can be treated or ameliorated. That is, the present invention is as follows.
- composition is a pharmaceutical composition for treating or ameliorating heart disease.
- Group B Cyclooxygenase inhibitor, thromboxane A2 biosynthesis inhibitor, thromboxane receptor antagonist, adenosine diphosphate receptor antagonist, GPIIb / IIIa antagonist, PGE1 or PGI2 derivative, platelet aggregation inhibitor, serotonin receptor antagonist, thrombin inhibitor, Heparin, small molecule heparin, Xa inhibitor, VIIa inhibitor, K + channel inhibitor, vitamin K antagonist, angiotensin antagonist, angiotensin converting enzyme inhibitor, endothelin antagonist, phosphodiesterase inhibitor, calcium antagonist, beta blocker, Nitrate drugs, thrombolytic agents, HMGCoA reductase inhibitors, fibrate drugs, nicotinic acid drugs, bile acid adsorbents, cholesterol absorption inhibitors, PPAR ⁇ agonists, PPA ⁇ agonist, PPAR [beta] agonists, endopeptidase inhibitors and diuretics neutral.
- examples of at least one compound selected from the group consisting of formulas (I) to (VII) or a pharmaceutically acceptable salt thereof include hydrobromide salts of compounds represented by formula (I). It is done.
- the heart disease is selected from the group consisting of acute coronary syndrome, atherothrombosis, restenosis, hypertension, stable angina, arrhythmia, heart failure, ST elevation myocardial infarction and cerebral infarction, for example.
- examples of the compound (B) include aspirin, which is a cyclooxygenase inhibitor, and clopidogrel, which is an adenosine diphosphate receptor antagonist.
- the present invention provides a pharmaceutical composition that can effectively treat or ameliorate a disease.
- heart disease can be effectively treated or ameliorated.
- a pharmaceutical composition containing at least one 2-iminopyrrolidine derivative and at least one other compound (B).
- a pharmaceutical composition for use in combination with at least one other compound (B) containing at least one 2-iminopyrrolidine derivative is provided.
- the pharmaceutical composition is preferably a pharmaceutical composition for treating or improving heart disease.
- the 2-iminopyrrolidine derivative contained in the pharmaceutical composition of the present invention is at least one compound (for example, one) selected from the group consisting of formulas (I) to (VII) or a compound thereof A pharmaceutically acceptable salt.
- the 2-iminopyrrolidine derivative used in the present invention is preferably a compound of formula (I) or a pharmaceutically acceptable salt thereof, more preferably a hydrobromide of a compound of formula (I). .
- the pharmaceutically acceptable salt is not particularly limited as long as it has a therapeutic action or an improvement action on diseases such as heart disease and is pharmaceutically acceptable.
- a hydrohalide eg, hydrofluoride, hydrochloride, hydrobromide, and hydroiodide
- an inorganic acid salt eg, sulfate, nitrate, perchlorate
- organic carboxylates eg acetate, oxalate, maleate, tartrate, fumarate and citrate
- organic sulfonates eg methanesulfone
- Acid salts trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate and camphorsulfonate
- amino acid salts eg aspartate and glutamate
- quaternary amine salts alkali metal salts
- the 2-iminopyrrolidine derivative has optical isomers such as geometric isomers and diastereomers
- these isomers may be used in the present invention as long as they have therapeutic action or amelioration action for diseases such as heart disease. It can be included in the compound or a pharmaceutically acceptable salt thereof.
- the 2-iminopyrrolidine derivative may be an anhydride, or may form a solvate such as a hydrate.
- the solvate may be either a hydrate or a non-hydrate, but a hydrate is preferred.
- water, alcohol (for example, methanol, ethanol, n-propanol), dimethylformamide and the like can be used.
- solvates are also included in the compound of the present invention or a pharmacologically acceptable salt thereof as long as it has a therapeutic or ameliorating effect on diseases such as heart disease.
- the 2-iminopyrrolidine derivative (preferably the hydrobromide salt of the compound of the formula (I)) contained in the pharmaceutical composition of the present invention is a protease activated receptor (PAR1) which is one of thrombin receptors. ) Antagonists.
- PAR1 protease activated receptor
- the PAR1 antagonist has at least one activity selected from the group consisting of antithrombotic activity, antiplatelet aggregation activity, antiatherosclerotic activity, and antirestenosis activity
- a 2-iminopyrrolidine derivative preferably represented by the formula ( Hydrobromides of the compounds of I) are associated with acute coronary syndromes (eg ST non-elevation myocardial infarction and anxious angina), atherothrombosis (eg peripheral arterial occlusion), restenosis, hypertension, stable angina , Exertion angina, resting angina, arrhythmia, heart failure, ST-elevation myocardial infarction, thrombotic stroke, thromboembolic stroke, venous thromboembolism, deep vein thrombosis, pulmonary embolism, atherosclerosis, Peripheral vascular disease, inflammatory disease, cerebral ischemia, cerebral infarction, other obstructive vascular disease, disseminated intravascular blood coagulation syndrome
- the 2-iminopyrrolidine derivative used in the present invention that is, at least one (eg, one) compound selected from the group consisting of formulas (I) to (VII) or
- the pharmaceutically acceptable salt can be produced, for example, by the method described in International Publication No. 02/085855 pamphlet, International Publication No. 04/078721 pamphlet or the like. More specifically, these compounds or pharmaceutically acceptable salts thereof are described in, for example, the specification of WO 02/085855 pamphlet, page 40, line 24 to page 139, line 15 and page 170, line 6 to 177, page 12.
- Example 7 177 pages 13 lines to 183 pages 1 line (Example 8), 190 pages 21 lines to 193 pages 2 lines (Example 11), 200 pages 11 lines to 203 pages 1 line (Example 14) ), 203 pages 2 lines to 205 pages 17 lines (Example 15), 316 pages 7 lines to 317 pages 3 lines (Example 112), and 325 pages 3 lines to 13 lines (Example 125).
- It can manufacture by the method or a method according to it.
- these compounds or pharmaceutically acceptable salts thereof can be produced by the method described in the entire specification of WO 04/078721 or a method analogous thereto.
- Example 1 which will be described later, a method for producing a 2-iminopyrrolidine derivative is described by taking as an example the case of producing a hydrobromide salt and a hydrogen chloride salt of a compound of formula (I).
- the compounds of the formulas (II) to (VII) or pharmaceutically acceptable salts thereof can be produced, for example, by a method analogous to the method of Example 1.
- composition of the present invention contains at least one (eg, one) 2-iminopyrrolidine derivative as described above.
- the predetermined 2-iminopyrrolidine derivative is at least one compound selected from the group consisting of formulas (I) to (VII) or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition of the present invention is used for treating or improving heart diseases.
- Treatment or “amelioration” generally means obtaining a desired pharmacological and / or physiological effect. The effect is prophylactic in terms of completely or partially preventing the disease and / or symptoms and therapeutic in terms of partial or complete cure of the adverse effects caused by the disease and / or disease.
- treatment or “amelioration” means any treatment or amelioration of a disease in a patient mammal, particularly a human, and includes the meaning of the above general treatment.
- Treatment or improvement includes, for example, at least one of the following items (a) to (c): (A) prevent a disease or symptom from occurring in a patient who may have a predisposition to the disease or symptom but has not yet been diagnosed; (B) inhibit disease symptoms, ie prevent or delay its progression; (C) Alleviating disease symptoms, ie, causing the disease or symptoms to reverse, disappear, or reverse the progression of symptoms.
- the 2-iminopyrrolidine derivative is at least one compound selected from the group consisting of formulas (I) to (VII) or a pharmaceutically acceptable salt thereof, preferably a compound of formula (I) or Its pharmaceutically acceptable salt, more preferably the hydrobromide salt of the compound of formula (I).
- a pharmaceutically acceptable salt thereof preferably a compound of formula (I) or Its pharmaceutically acceptable salt, more preferably the hydrobromide salt of the compound of formula (I).
- at least one compound selected from the group consisting of formulas (I) to (VII) or a pharmaceutically acceptable salt thereof may be used as it is, or a known pharmaceutically acceptable carrier. It is also possible to formulate by blending and the like.
- Such pharmaceutically acceptable carriers include excipients, binders, disintegrants, lubricants, colorants, flavoring agents, stabilizers, emulsifiers, absorption enhancers, surfactants, A pH adjuster, a preservative, an antioxidant and the like can be mentioned.
- the administration form of the pharmaceutical composition of the present invention is not particularly limited, and can be administered orally or parenterally based on the above dosage form.
- parenteral administration include intravenous injection, intravenous drip, subcutaneous injection, intradermal injection, and intraperitoneal injection.
- the dosage forms for formulation include tablets, powders, fine granules, granules, capsules, syrups, etc. used for oral dosage forms, and suppositories, injections, ointments used for parenteral dosage forms. Agents, bapping agents and the like.
- excipients When preparing an oral preparation for use in an oral dosage form, excipients, and further binders, disintegrants, lubricants, coloring agents, flavoring agents, etc. were added to the active ingredients as necessary. Thereafter, tablets, coated tablets, granules, fine granules, powders, capsules and the like can be obtained by conventional methods.
- excipient examples include lactose, corn starch, sucrose, glucose, sorbit, crystalline cellulose, silicon dioxide, and the like
- binder examples include polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and the like.
- magnesium stearate, talc, silica and the like are permitted to be added to pharmaceuticals as a coloring agent, and as a flavoring agent, cocoa powder, mint brain, aromatic acid, etc.
- Mint oil, Borneolum, cinnamon powder, etc. are used.
- these tablets and granules may be appropriately coated with sugar coating, gelatin coating, etc. as required.
- the injection is a non-aqueous diluent (for example, glycols such as propylene glycol and polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol), suspension agents, solubilizers, and stable agents. It can be prepared by adding an agent, an isotonic agent, a preservative, a pH adjusting agent, a buffering agent and the like. Sterilization of the injection may be performed by filtration sterilization using a filter, blending of a bactericide, and the like. Moreover, an injection can be manufactured as a form of preparation at the time of use.
- a non-aqueous diluent for example, glycols such as propylene glycol and polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol
- suspension agents such as olive oil
- solubilizers such as ethanol
- stable agents for example, glycols such as propylene glycol and polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol
- the injection can be an intravenous infusion or a intravenous, subcutaneous or intramuscular injection by a conventional method.
- suspending agent examples include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate and the like.
- solubilizer examples include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol, and castor oil fatty acid ethyl ester.
- examples of the stabilizer include sodium sulfite and sodium metasulfite
- examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.
- Effective doses of the compounds of formulas (I) to (VII) or pharmaceutically acceptable salts thereof for oral administration are the degree of symptoms, patient age, sex, body weight, sensitivity difference, administration method, administration time, although it varies depending on the administration interval, administration period, properties of the preparation, preparation, type, type of active ingredient, etc., those skilled in the art can appropriately set it. For example, 0.001 to 10,000 mg, preferably 0.1 to 1,000 mg, more preferably 1 to 1,000 mg per day can be orally administered to an adult (body weight 60 kg).
- parenteral administration for example, the effective dosage of a compound of formula (I)-(VII) or a pharmaceutically acceptable salt thereof in an injection is the degree of symptoms, patient age, sex, body weight, sensitivity difference, administration Although it varies depending on the method, administration time, administration interval, administration period, properties of the preparation, formulation, type, type of active ingredient, etc., those skilled in the art can appropriately set it, and can use physiological saline or commercially available distilled water for injection. In a pharmaceutically acceptable carrier such as those dissolved or suspended to an appropriate concentration, it can be appropriately administered to a patient in need of treatment. For example, in the case of an injection, 0.001 to 10,000 mg, preferably 0.01 to 1,000 mg, more preferably 0.1 to 1,000 mg per day can be administered to an adult (body weight 60 kg).
- At least one other compound (B) is used as at least one (for example, 1) in combination with the 2-iminopyrrolidine derivative.
- the combined use means a combination of at least one other compound (B) and the 2-iminopyrrolidine derivative, wherein the compound (B) and the 2-iminopyrrolidine derivative are administered simultaneously or successively, and It includes both forms as a mixture (compound). That is, it does not mean that the administration timing of the compound (B) and the 2-iminopyrrolidine derivative is completely the same, but the compound (B) and the 2-iminopyrrolidine derivative are administered in one administration schedule. As long as such embodiments are included, such dosage forms mean “combination”.
- the other compound (B) may be further contained in a pharmaceutical composition containing the 2-iminopyrrolidine derivative, or different from the pharmaceutical composition containing the 2-iminopyrrolidine derivative. It may be contained in a pharmaceutical composition.
- the other compound (B) is preferably a drug having at least one action selected from the group consisting of antithrombosis, antiplatelet aggregation, antiatherosclerosis, antirestenosis and anticoagulation.
- the other compound (B) is preferably at least one therapeutic agent selected from the following group B.
- Group B Cyclooxygenase inhibitor, thromboxane A2 biosynthesis inhibitor, thromboxane receptor antagonist, adenosine diphosphate (ADP) receptor antagonist, GPIIb / IIIa antagonist, PGE1 or PGI2 derivative, platelet aggregation inhibitor, serotonin receptor antagonist, thrombin Inhibitor, heparin, low molecular weight heparin, Xa inhibitor, VIIa inhibitor, K + channel inhibitor, vitamin K antagonist, angiotensin antagonist, angiotensin converting enzyme (ACE) inhibitor, endothelin antagonist, phosphodiesterase inhibitor, calcium antagonist , ⁇ -blocker, nitrite, thrombolytic agent, HMGCoA reductase inhibitor, fibrate, nicotinic acid, bile acid adsorbent, cholesterol absorption inhibitor, PPAR Agonists, PPARa agonists, PPAR [beta] agonists, endopeptidase inhibitors and
- the compound (B) include the following. (1) Cyclooxygenase inhibitors: aspirin, meloxicam, rofecoxib, celecoxib, etc. (2) Thromboxane A2 biosynthesis inhibitors: ozagrel, etc. (3) Thromboxane receptor antagonists: seratrodast, picotamide, ramatroban, etc. 4) Adenosine diphosphate receptor antagonists: Clopidogrel, Prasugrel, AZD-6140, Cangrelor and Ticlopidine, etc.
- GPIIb / IIIa antagonists Abixiximab, Epitifibatide and Eptifibatide (6) PGE1 or PGI2 derivatives: Limaprost and Beraprost, etc. (7) Platelet aggregation inhibitors: Cilostazol, Dipyridamole, etc. (8) Serotonin receptor antagonist: Hydrochloric acid Sarpogrelate, etc. (9) Thrombin inhibitors: Argatroban, Bivalirudin, Dabigatran, etc. (10) Heparin, low molecular weight heparins: Unfractionated heparin, Enoxaparin, etc.
- Xa Inhibitors Honda Parinux, Rivaroxaban, Apixaban, etc.
- VIIa inhibitors rNAPc2, PCI-27483, etc.
- K + channel inhibitors bepridil, sotalol, etc.
- Vitamin K antagonists Warfarin, etc.
- Angiotensin antagonists Valsartan, Telmisartan, Candesartran, Irbesartran, Isosartan, Eprosartan, etc.
- Angiotensin converting enzyme inhibitors Captopril, Enalapril, Enaliprirat (Enaliprilat) Spirapril, quinapril, perindopril, ramipril, fosinopril (Fosinopril), trandolapril, lisinopril, moexipril, and benazapril
- Endothelin antagonists Tezosentan, etc.
- Calcium antagonists amlodipine (20) ⁇ -blockers: atenolol and propranolol (21) Nitrite: nitroglycerin and isosorbide nitrate (22) Thrombolytic agents: urokinase, strepto Kinase and tissue plasminogen activator, etc. (23) HMGCoA reductase inhibitors: Atorvastatin, fluvastatin, pravastatin, etc. (24) Fibrates: gemfibrozi (Gemfibrozil), fenofibrate, and bezafibrate (25) Nicotinic acid drugs: niacin, etc.
- Bile acid adsorbents cholestyramine, Cholestipol, etc.
- Cholesterol absorption inhibitor Ezetimibe (Ezetimibe) etc.
- PPAR ⁇ agonist Pioglitazone etc.
- PPAR ⁇ agonist LY518674, WY14643 etc.
- PPAR ⁇ / ⁇ agonist GW501516, L165041, etc.
- Neutral endopeptidase inhibitor Candoxatril and Ecadotril, etc.
- Diuretics Chlorothiazide, hydrochlorothiazide, ethacrynic acid, furosemide, amiloride, etc.
- the other compound (B) used in combination with the 2-iminopyrrolidine derivative is preferably a cyclooxygenase inhibitor, a thromboxane A2 biosynthesis inhibitor, a thromboxane receptor antagonist, an adenosine diphosphate (ADP) receptor antagonist A GPIIb / IIIa antagonist, a PGE1 or PGI2 derivative, a phosphodiesterase inhibitor or a platelet aggregation inhibitor. More preferably, the other compound (B) is aspirin or clopidogrel.
- the other compound (B) can be administered orally or parenterally, and can be formulated by a method similar to the method for formulating the pharmaceutical composition.
- the effective dose of the other compound (B) is not particularly limited as long as it is a dose showing a medicinal effect, but is preferably a dose at which each compound (B) is prescribed as a single agent or less.
- the dose of the other compound (B) is, for example, 0.015-4000 mg, preferably 50-400 mg per day for an adult (body weight 60 kg), and with respect to the 2-iminopyrrolidine derivative, For example, it is about 0.0001 to 100 times (weight ratio), preferably about 0.1 to 10 times (weight ratio).
- the dose of the 2-iminopyrrolidine derivative may be, for example, 1 to 1000 mg per day for an adult (body weight 60 kg), Preferably, it is 10 to 600 mg, more preferably 50 to 400 mg, and the dose of aspirin is 10 to 1000 mg, preferably 50 to 600 mg, more preferably 80 to 350 mg per day for an adult (body weight 60 kg), Further, the dose of aspirin is, for example, about 0.1 to 10 times (weight ratio), preferably about 0.2 to 2 times (weight ratio) with respect to the dose of 2-iminopyrrolidine derivative.
- the dose of the 2-iminopyrrolidine derivative is, for example, 1 to 1000 mg, preferably 10 to 1000 mg per day for an adult (body weight 60 kg). 600 mg, more preferably 50 to 400 mg, and the dose of clopidogrel is 10 to 1000 mg, preferably 50 to 600 mg, more preferably 75 to 300 mg per day for an adult (body weight 60 kg).
- the dose is, for example, about 0.1 to 10 times (weight ratio), preferably about 0.2 to 2 times (weight ratio) with respect to the dose of the 2-iminopyrrolidine derivative.
- At least one predetermined 2-iminopyrrolidine derivative and at least one other compound (B) are used in combination, for example, acute coronary syndrome (eg, non-ST elevation myocardial infarction and anxiety angina), Atherothrombosis (eg peripheral artery occlusion), restenosis, hypertension, stable angina, exertion angina, resting angina, arrhythmia, heart failure, ST-elevation myocardial infarction, thrombotic stroke, thromboembolic stroke, Venous thromboembolism, deep vein thrombosis, pulmonary embolism, atherosclerosis, peripheral vascular disease, inflammatory disease, cerebral ischemia, cerebral infarction, other occlusive vascular diseases, disseminated intravascular coagulation syndrome And at least one disease selected from the group consisting of rheumatism, asthma, glomerulonephritis, osteoporosis, neurological disease and the like.
- acute coronary syndrome eg, non-ST elevation myocardi
- the present invention can treat or ameliorate heart disease.
- the heart disease that can be treated or improved is selected from the group consisting of acute coronary syndrome, atherothrombosis, restenosis, hypertension, stable angina, arrhythmia, heart failure, ST-elevation myocardial infarction and cerebral infarction, for example.
- At least one disease is selected from the group consisting of acute coronary syndrome, atherothrombosis, restenosis, hypertension, stable angina, arrhythmia, heart failure, ST-elevation myocardial infarction and cerebral infarction, for example.
- At least one disease is selected from the group consisting of acute coronary syndrome, atherothrombosis, restenosis, hypertension, stable angina, arrhythmia, heart failure, ST-elevation myocardial infarction and cerebral infarction, for example.
- At least one disease is selected from the group consisting of acute coronary syndrome, atherothrombosis, restenosis, hypertension, stable angina
- the present invention is characterized in that an effective amount of at least one (eg, one) predetermined 2-iminopyrrolidine derivative and at least one other compound (B) is administered to a patient.
- a method for treating or ameliorating a disease such as heart disease is provided.
- the predetermined 2-iminopyrrolidine derivative is a compound of the above formulas (I) to (VII), preferably a compound of the formula (I), and more preferably a compound of the formula (I) The hydrobromide salt of the compound.
- the compounds of the formulas (I) to (VII) include pharmaceutically acceptable salts of the compounds of the formulas (I) to (VII).
- the description of the combined use of the 2-iminopyrrolidine derivative and the other compound (B) can be referred to.
- the route of administration and the method of administration of the compounds of formulas (I) to (VII) and compound (B) are not particularly limited, but reference can be made to the description of the above pharmaceutical composition.
- the predetermined 2-iminopyrrolidine derivative is a compound of formulas (I) to (VII), preferably a compound of formula (I), and more preferably a compound of formula (I) Of hydrobromide.
- the kit of the present invention for the other compound (B), the description of the combined use of the 2-iminopyrrolidine derivative and the other compound (B) can be referred to.
- the kit may include accessories, instructions for use, and the like as necessary.
- the present invention includes at least for producing a pharmaceutical composition for treating or ameliorating a disease such as heart disease for use in combination with at least one (eg, one) other compound (B).
- a predetermined 2-iminopyrrolidine derivative is included.
- the predetermined 2-iminopyrrolidine derivative is a compound of formulas (I) to (VII), preferably a compound of formula (I), and more preferably a compound of formula (I ) Hydrobromide of the compound.
- the present invention includes at least one compound selected from the group consisting of formulas (I) to (VII) for treating or ameliorating diseases such as heart disease in combination with at least one other compound (B). Or a pharmaceutically acceptable salt thereof.
- THF (18.7 Kg) was charged into the reaction vessel under a nitrogen stream, followed by n-heptane (13.7 kg), and 2,2,6,6-tetramethylpiperidine (TMP) (7.50 kg, 53 0.1 mol) was added and stirred. The system was closed, cooled to ⁇ 15 ° C. with slightly positive nitrogen pressure, and stirred overnight. A 15% n-butyllithium-hexane solution (22.4 kg, 50.2 mol) with an internal temperature of ⁇ 42.3 ° C. was added dropwise at an internal temperature of ⁇ 10 ° C. or lower. The inside of the dropping pipe was rinsed with n-heptane (0.68 kg).
- the wet body was put into a reaction can, water (40 L) and n-heptane (80 L) were added, and the mixture was stirred at 25 ° C. for 18.7 hours.
- the reaction solution was extracted, and the can wall was rinsed with a mixed solution of n-heptane (5 L) and water (10 L).
- the reaction solution and the rinse solution were combined and then centrifuged.
- the obtained crystals were washed with n-heptane (5 L), water (5 L), and n-heptane (5 L) to obtain 10.30 kg of the title compound as a wet substance.
- the wet body was put into a conical dryer and then dried under reduced pressure at 50 ° C. for 20 hours and at 55 ° C. for 4 hours to obtain 5.98 kg (yield: 75.3%) of the title compound as fine greenish white powdery crystals.
- the outer bath was brought to 50 ° C. and concentrated under reduced pressure to a liquid volume of about 14 L.
- the outer bath was brought to 10 ° C., n-heptane (59 L) was added, and the mixture was stirred for 2.8 hours.
- the precipitated crystals were filtered and washed with n-heptane (5.9 L) to obtain 5.66 kg of the wet title compound.
- This wet body was dried under reduced pressure at 50 ° C. for 18.3 hours with a conical dryer to obtain 5.17 kg (yield: 87%) of the title compound as slightly yellowish white powdery crystals.
- Toluene (45 L) and 0.5 N hydrochloric acid (9 L) were added to the reaction solution to separate the layers.
- the obtained organic layer was washed with water (18 L), 10% aqueous sodium hydrogen carbonate solution (18 L), 10% brine (18 L) and water (18 L), and the organic layer was concentrated under reduced pressure.
- Toluene (45 L) was added to the concentrated liquid, and then concentrated again under reduced pressure. After cooling the concentrated liquid, toluene (40 L) was added for dilution, and the diluted liquid was evenly extracted from the reaction can into two containers.
- the reaction can wall was rinsed with toluene (5 L).
- the rinse solution was divided into two equal parts and mixed with the previous diluted solution to obtain a toluene solution of 2-cyano-4,5-diethoxy-3-fluorobenzyl methanesulfonate.
- the solutions were A and B, respectively, and after weighing the solution (A solution: 32.16 Kg, B solution: 32.24 kg), a part of the solution was sampled and quantified by HPLC.
- the reaction solution was stirred as it was overnight, and then ammonia gas was leaked.
- Water (35 L) was added to the reaction solution, and then 2N hydrochloric acid (35 L) was added, followed by liquid separation.
- 1N Hydrochloric acid (23.4 L) was added to the obtained organic layer for liquid separation.
- the obtained aqueous layer was mixed with the previous aqueous layer and clarified and filtered. After rinsing with water (10 L), it was transferred to a reaction can. Rinse with water (15 L) and cool the reaction. 5N aqueous sodium hydroxide solution (7.18 L) was added dropwise, and the reaction mixture was heated at 30 ° C. in the outer bath and stirred for about 4 hours.
- reaction solution was cooled, 5N aqueous sodium hydroxide solution (12.82 L) was added dropwise at a reaction solution temperature of 17.4 ° C., and the reaction solution was stirred overnight.
- the precipitated crystals were filtered, and the crystals were washed with water (30 L) and tert-butyl methyl ether (6 L) to obtain 2.29 kg of a wet body.
- the wet body was dried under reduced pressure at 40 ° C. with a conical dryer to obtain the title compound (1.85 kg) as slightly yellowish white powdery crystals. Properties: Slight yellowish white powder, yield: 1.85 kg, yield: 84%, HPLC purity: 97.5%, moisture content: 0.22%
- the wet crystals (693.5 g) were dissolved in 50% tetrahydrofuran / water tank (5 L) at 50 ° C., then clarified and washed with 50% tetrahydrofuran / water tank (0.5 L). Under ice-cooling and stirring, water (2.5 L) was added to the filtrate, seed crystals (1.52 L) were added, and then water (7.5 L) was added dropwise. After stirring at 8 ° C. for 15 hours, the crystals were collected by filtration, washed with water tank (2 L), and then dried with ventilation (26 ° C.) for 26 hours to obtain 622.1 mg of the title compound as white crystals (yield: 81.5). %, HPLC purity: 99.6%).
- Step B-6 Alternative method (1): Final step) 5,6-Diethoxy-4-fluoro-1H-3-isoindoleamine (20 g), 2-bromo-1- [3- (tert-butyl) -4-methoxy-5-morpholinophenyl] -1-ethanone (34.2 g) was dissolved in dimethylformamide (300 ml) and stirred at room temperature for 48 hours. After distilling off the solvent under reduced pressure, the residue was crystallized by adding ethyl acetate (500 ml). The obtained crystals were filtered and washed with ethyl acetate to obtain the target compound (40 g) as white crystals.
- Step B-6 Alternative method (2): Final step) 1- (3-tert-butyl 4-methoxy-5-morpholino-phenyl) -2- (5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-isoindol-2-yl)- Ethanone hydrochloride
- the activity of the compounds of formulas (I) to (VII) can be determined by the following procedure.
- the obtained platelet membrane was DMSO (dimethyl sulfoxide) to a concentration of 1% in 50 mM Tris-HCl buffer (buffer 1) of pH 7.5 containing 10 mM MgCl 2 and 1 mM EGTA (ethylene glycol tetraacetic acid). Suspend in a solution to which is added and store at -80 ° C.
- DMSO dimethyl sulfoxide
- Thrombin receptor antagonist activity uses a modification of Ahn et al. Thrombin receptor radioligand binding assay (Ahn et al., Mol. Pharmacol., 51, p. 350-356 (1997)). And evaluate. Bovine albumin and DMSO are added to Buffer 1 (50 mM Tris-HCl, pH 7.5, 10 mM MgCl 2 , 1 mM EGTA) so as to be 0.1% and 20%, respectively, to prepare a test compound preparation solution. Test compound solutions (20 ⁇ l) diluted to various concentrations with this preparation are added to a 96-well multiscreen plate.
- Buffer 1 50 mM Tris-HCl, pH 7.5, 10 mM MgCl 2 , 1 mM EGTA
- the specific binding is a value obtained by adding 10 ⁇ M high affinity TRAP.
- the drug is administered intravenously over a period of time, for example 90 minutes, using an infusion pump.
- Blood is collected before oral administration of the test substance and after the administration of both test substances.
- 1.8 mL is collected from the brachial vein or saphenous vein using a syringe containing 200 ⁇ L of a 3.8% citric acid solution as an anticoagulant.
- PRP aggregation The collected blood is transferred to an Eppendorf tube, centrifuged at 6400 rpm for 5 seconds at room temperature, and the supernatant is separated as PRP. The separated blood is further centrifuged at 10,000 rpm for 5 minutes to separate platelet poor plasma (PPP). The platelet concentration of PRP is diluted with PPP to prepare 3 ⁇ 10 5 / ⁇ L. PRP aggregation is performed according to the turbidity method of Born et al.
- PRP thrombin receptor activating peptide
- Example 3-1 The at least one compound selected from the group consisting of the formulas (I) to (VII) or a pharmaceutically acceptable salt thereof, and at least one other compound (B) selected from the group B are used alone or in combination. And orally administered to male Hartley guinea pigs.
- a 0.5% methylcellulose solution or an aqueous solution containing dimethyl sulfoxide and Tween 20 is used. (It may be repeated.)
- sodium pentobarbitate is intraperitoneally administered and anesthetized.
- the jugular vein is exposed under anesthesia and a polyethylene tube is cannulated for administration of rose bengal.
- the femoral artery is exposed and a probe for blood flow measurement is attached. Irradiate green light (wavelength 540 nm, 500,000 lux) to the upstream part of the probe, 5 minutes after irradiation, Rose Bengal solution (5 mg / kg) dissolved in physiological saline so as to be 5 mg / mL over about 1 minute Dosing. Measure the time until blood flow stops completely.
- Example 3-2 The hydrobromide salt of the compound of the above formula (I) (hereinafter referred to as the compound of Example 1) and aspirin were dissolved in DMSO so as to be 200 and 1000 mg / ml, respectively.
- DMSO solutions Tween20, and distilled water, Vehicle without compound, Example 1 compound alone 6 mg / ml, Aspirin alone 50 mg / ml so that the concentrations of DMSO and Tween20 are 5% and 2% aqueous solutions, respectively.
- Four types of administration solutions were prepared: a mixed solution of 6 mg / ml of Example 1 compound and 20 mg / ml of aspirin.
- a pharmaceutical composition comprising at least one 2-iminopyrrolidine derivative and at least one other compound (B).
- the pharmaceutical composition is useful for treating or ameliorating heart disease, for example.
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Abstract
Description
すなわち、本発明は以下のとおりである。
本発明のある態様によれば、組成物は心疾患の治療用又は改善用の医薬組成物である。
シクロオキシゲナーゼ阻害剤、トロンボキサンA2生合成阻害剤、トロンボキサン受容体アンタゴニスト、アデノシン二リン酸受容体アンタゴニスト、GPIIb/IIIaアンタゴニスト、PGE1またはPGI2誘導体、血小板凝集阻害剤、セロトニン受容体アンタゴニスト、トロンビン阻害剤、ヘパリン、低分子ヘパリン、Xa阻害剤、VIIa阻害剤、K+チャネル阻害剤、ビタミンK拮抗剤、アンジオテンシンアンタゴニスト、アンジオテンシン変換酵素阻害剤、エンドセリンアンタゴニスト、ホスホジエステラーゼ阻害剤、カルシウム拮抗剤、β遮断薬、亜硝酸薬、血栓溶解剤、HMGCoA還元酵素阻害剤、フィブラート系薬剤、ニコチン酸系薬剤、胆汁酸吸着薬、コレステロール吸収阻害剤、PPARγアゴニスト、PPARαアゴニスト、PPARβアゴニスト、中性のエンドペプチダーゼ阻害剤および利尿薬。
また、本発明の1つの態様において、心疾患としては、たとえば急性冠症候群、アテローム血栓症、再狭窄、高血圧、安定狭心症、不整脈、心不全、ST上昇心筋梗塞および脳梗塞からなる群より選ばれる少なくとも1つの疾患が挙げられる。
本発明において、上記化合物(B)としては、シクロオキシゲナーゼ阻害剤であるアスピリン、またはアデノシン二リン酸受容体アンタゴニストであるクロピドグレルを例示することができる。
なお、本明細書において引用した文献、および公開公報、特許公報その他の特許文献は、参照として本明細書に組み込むものとする。また、本明細書は、本願の優先権主張の基礎となる日本特許出願2008-4318号及び米国仮出願 61/020,426号の明細書又は図面に記載された内容を包含する。
本発明の医薬組成物に含まれる2-イミノピロリジン誘導体は、式(I)~(VII)からなる群より選ばれる少なくとも1つ(例えば1つ)の化合物またはその薬学的に許容される塩である。
本発明で使用される2-イミノピロリジン誘導体、すなわち、式(I)~(VII)からなる群より選ばれる少なくとも1つ(例えば1つ)の化合物またはその薬学的に許容される塩は、例えば、国際公開02/085855号パンフレット、国際公開04/078721号パンフレットなどに記載された方法で製造することができる。より具体的には、これらの化合物またはその薬学的に許容される塩は、例えば、国際公開02/085855号パンフレットの明細書40頁24行~139頁15行、170頁6行~177頁12行(実施例7)、177頁13行~183頁1行(実施例8)、190頁21行~193頁2行(実施例11)、200頁11行~203頁1行(実施例14)、203頁2行~205頁17行(実施例15)、316頁7行~317頁3行(実施例112)、および325頁3行~13行(実施例125)などに記載された方法又はそれに準じる方法で製造することができる。あるいは、これらの化合物またはその薬学的に許容される塩は、国際公開04/078721号パンフレットの明細書全体に記載された方法又はそれに準じる方法で製造することができる。
尚、後述の実施例1では、式(I)の化合物の臭化水素酸塩および塩化水素塩を製造する場合を例に挙げて、2-イミノピロリジン誘導体の製造方法を説明している。式(II)~(VII)の化合物またはその薬学的に許容される塩は、例えば、実施例1の方法に準ずる方法で製造することができる。
本発明の医薬組成物は、前述のように少なくとも1つ(例えば1つ)の2-イミノピロリジン誘導体を含有する。本発明において、所定の2-イミノピロリジン誘導体は、式(I)~(VII)からなる群より選ばれる少なくとも1つの化合物またはその薬学的に許容される塩である。
(a)疾病又は症状の素因を持ちうるが、まだ持っていると診断されていない患者において、疾病又は症状が起こることを予防すること;
(b)疾病症状を阻害する、即ち、その進行を阻止又は遅延すること;
(c)疾病症状を緩和すること、即ち、疾病又は症状の後退、消失、又は症状の進行の逆転を引き起こすこと。
本発明の医薬組成物では、式(I)~(VII)からなる群より選ばれる少なくとも1つの化合物またはその薬学的に許容される塩をそのまま用いることも、公知の薬学的に許容される担体などを配合して製剤化することも可能である。このような薬学的に許容される担体としては、例えば、賦形剤、結合剤、崩壊剤、滑沢剤、着色剤、矯味矯臭剤、安定化剤、乳化剤、吸収促進剤、界面活性剤、pH調整剤、防腐剤、および抗酸化剤などを挙げることができる。
本発明では、心疾患等の疾患を治療または改善するために、少なくとも1つの他の化合物(B)を、少なくとも1つ(例えば1つ)の前記2-イミノピロリジン誘導体と併用する。併用とは、少なくとも1つの他の化合物(B)と、前記2-イミノピロリジン誘導体との組合せを意味し、上記化合物(B)及び2-イミノピロリジン誘導体を、同時にまたは続けて投与する形態、および混合物(配合剤)としての形態の両方を含む。すなわち、化合物(B)と2-イミノピロリジン誘導体との投与時期が完全同一であることのみを意味するものではなく、1つの投与スケジュールの中に化合物(B)と2-イミノピロリジン誘導体とを投与する態様が含まれている限り、そのような投与形態は「併用」を意味する。
他の化合物(B)は、好ましくは、抗血栓、抗血小板凝集、抗アテローム性動脈硬化、抗再狭窄および抗血液凝固等からなる群から選ばれる少なくとも1つの作用を有する薬剤である。
他の化合物(B)は、好ましくは、以下のB群から選ばれる少なくとも1つの治療薬である。
シクロオキシゲナーゼ阻害剤、トロンボキサンA2生合成阻害剤、トロンボキサン受容体アンタゴニスト、アデノシン二リン酸(ADP)受容体アンタゴニスト、GPIIb/IIIaアンタゴニスト、PGE1またはPGI2誘導体、血小板凝集阻害剤、セロトニン受容体アンタゴニスト、トロンビン阻害剤、ヘパリン、低分子ヘパリン、Xa阻害剤、VIIa阻害剤、K+チャネル阻害剤、ビタミンK拮抗剤、アンジオテンシンアンタゴニスト、アンジオテンシン変換酵素(ACE)阻害剤、エンドセリンアンタゴニスト、ホスホジエステラーゼ阻害剤、カルシウム拮抗剤、β遮断薬、亜硝酸薬、血栓溶解剤、HMGCoA還元酵素阻害剤、フィブラート系薬剤、ニコチン酸系薬剤、胆汁酸吸着薬、コレステロール吸収阻害剤、PPARγアゴニスト、PPARαアゴニスト、PPARβアゴニスト、中性のエンドペプチダーゼ阻害剤ならびに利尿薬。
(1) シクロオキシゲナーゼ阻害剤:アスピリン、メロキシカム、ロフェコキシブ(rofecoxib)およびセレコキシブ(celecoxib)など
(2) トロンボキサンA2生合成阻害剤:オザグレル等
(3)トロンボキサン受容体アンタゴニスト:セラトロダスト、ピコタミドおよびラマトロバン等
(4) アデノシン二リン酸受容体アンタゴニスト:クロピドグレル(Clopidogrel)、プラスグレル(Prasugrel)、AZD-6140、Cangrelorおよびチクロピジン(Ticlopidine)など
(5) GPIIb/IIIaアンタゴニスト:アブシキシマブ(Abciximab)、エピチフィバチド(Eptifibatide)およびチロフィバン(Tirofiban)など
(6) PGE1またはPGI2誘導体:リマプロスト(Limaprost)およびベラプロスト(Beraprost)など
(7) 血小板凝集阻害剤:シロスタゾール(Cilostazol)およびジピリダモール(Dipyridamole)など
(8) セロトニン受容体アンタゴニスト:塩酸サルポグレラート(Sarpogrelate) など
(9) トロンビン阻害剤:アルガトロバン(Argatroban)、ビバリルジン(Bivalirudin)およびダビガトラン(Dabigatran) など
(10) ヘパリン、低分子ヘパリン:未分画ヘパリンおよびエノキサパリン(Enoxaparin)など
(11) Xa阻害剤:ホンダパリナックス(Fondaparinux)、リバロキサバン(Rivaroxaban)およびアピキサバン(Apixaban) など
(12) VIIa阻害剤:rNAPc2、PCI-27483など
(13) K+チャネル阻害剤:ベプリジル、ソタロールなど
(14) ビタミンK拮抗剤:ワーファリン(Warfarin) など
(15) アンジオテンシンアンタゴニスト:バルサルタン、テルミサルタン、カンデサルタン(Candesartran)、イルベサルタン(Irbesartran)、イソサルタンおよびエプロサルタンなど
(16) アンジオテンシン変換酵素阻害剤:カプトプリル、エナラプリル、エナリプリラット(Enaliprilat)、スピラプリル、キナプリル、ペリンドプリル,ラミプリル、ホシノプリル(Fosinopril)、トランドラプリル、リシノプリル、モエキシプリルおよびベナザプリルなど
(17) エンドセリンアンタゴニスト:テゾセンタン等
(18) ホスホジエステラーゼ阻害剤:ミルリノン(Milrinone)およびエノキシモン(Enoximone) など
(19) カルシウム拮抗剤:アムロジピン(Amrodipine) など
(20) β遮断薬:アテノロール(Atenolol)およびプロプラノロール(Propranolol)等
(21) 亜硝酸薬:ニトログリセリンおよび硝酸イソソルビド等
(22) 血栓溶解剤:ウロキナーゼ、ストレプトキナーゼおよび組織プラスミノゲン活性化因子等
(23) HMGCoA還元酵素阻害剤:アトルバスタチン(Atorvastatin)、フルバスタチン(Fluvastatin)およびプラバスタチン(Pravastatin) など
(24) フィブラート系薬剤:ゲムフィブロジル(Gemfibrozil)、フェノフィブラート(Fenofibrate)およびベザフィブラートなど
(25) ニコチン酸系薬剤:ナイアシンなど
(26) 胆汁酸吸着薬:コレスチラミン(Cholestyramine)およびコレスチポール(Cholestipol) など
(27) コレステロール吸収阻害薬:エゼチミブ(Ezetimibe) など
(28) PPARγアゴニスト:ピオグリタゾンなど
(29) PPARαアゴニスト:LY518674、WY14643など
(30) PPARβ/δアゴニスト:GW501516、L165041など
(31) 中性のエンドペプチダーゼ阻害剤:カンドキサトリル(Candoxatril)およびエカドトリル(Ecadotril) など
(32) 利尿薬:クロロチアジド、ヒドロクロロチアジド、エタクリン酸(Ethacrynic acid)、フロセミドおよびアミロライドなど
他の化合物(B)の有効な投与量は、薬効を示す用量であれば特に限定されないが、好ましくは、各化合物(B)が単剤にて処方される用量もしくはそれ以下である。具体的には、他の化合物(B)の投与量は、成人(体重60kg)に1日あたり、例えば、0.015~4000mg、好ましくは50~400mgであり、前記2-イミノピロリジン誘導体に対して、例えば、約0.0001~100倍(重量比)、好ましくは約0.1~10倍(重量比)である。
より具体的には、前記2-イミノピロリジン誘導体とアスピリンとを組み合わせる場合、特に限定されないが、2-イミノピロリジン誘導体の投与量を、成人(体重60 kg)1日あたり、例えば、1~1000mg、好ましくは10~600mg、さらに好ましくは50~400mgとし、アスピリンの投与量を、成人(体重60 kg)1日あたり、例えば、10~1000mg、好ましくは50~600mg、さらに好ましくは80~350mgとし、さらに、アスピリンの投与量を、2-イミノピロリジン誘導体の投与量に対して、例えば、約0.1~10倍(重量比)、好ましくは約0.2~2倍(重量比)となるようにする。
また、前記2-イミノピロリジン誘導体とクロピドグレルとを組み合わせる場合、特に限定されないが、2-イミノピロリジン誘導体の投与量を、成人(体重60 kg)1日あたり、例えば、1~1000mg、好ましくは10~600mg、さらに好ましくは50~400mgとし、クロピドグレルの投与量を、成人(体重60 kg)1日あたり、例えば、10~1000mg、好ましくは50~600mg、さらに好ましくは75~300mgとし、さらに、クロピドグレルの投与量を、2-イミノピロリジン誘導体の投与量に対して、例えば、約0.1~10倍(重量比)、好ましくは約0.2~2倍(重量比)となるようにする。
本発明において、前記本発明の2-イミノピロリジン誘導体と他の化合物(B)とを併用した場合、前記本発明の2-イミノピロリジン誘導体以外の化合物と他の化合物(B)とを併用した場合と比較してこれらの疾患をより効果的に治療又は改善することができる。
本発明は、少なくとも1つ(例えば1つ)の所定の2-イミノピロリジン誘導体および少なくとも1つの他の化合物(B)の有効量を患者に投与することを特徴とする、心疾患等の疾患の治療または改善方法を提供する。本発明の方法において、所定の2-イミノピロリジン誘導体は、前記式(I)~(VII)の化合物等であり、好ましくは式(I)の化合物等であり、さらに好ましくは式(I)の化合物の臭化水素酸塩である。ここで、式(I)~(VII)の化合物等には、式(I)~(VII)の化合物の薬学的に許容される塩も包含される。また、他の化合物(B)については、前記2-イミノピロリジン誘導体と他の化合物(B)の併用の記載を参照することができる。本発明の方法において、式(I)~(VII)の化合物及び化合物(B)の投与径路および投与方法は特に限定されないが、上記医薬組成物の記載を参照することができる。
本発明には、少なくとも1つの所定の2-イミノピロリジン誘導体を含有する医薬組成物と、少なくとも1つの他の化合物(B)を含有する医薬組成物を含む、心疾患等の疾患の治療用または改善用キットが含まれる。本発明のキットにおいて、所定の2-イミノピロリジン誘導体は、式(I)~(VII)の化合物等であり、好ましくは式(I)の化合物等であり、さらに好ましくは式(I)の化合物の臭化水素酸塩である。本発明のキットにおいて、他の化合物(B)については、前記2-イミノピロリジン誘導体と他の化合物(B)の併用の記載を参照することができる。
キットには、必要に応じて、アクセサリーおよび使用説明書等が含まれていても良い。
本発明には、少なくとも1つ(例えば1つ)の他の化合物(B)と併用するための心疾患等の疾患の治療用または改善用医薬組成物を製造するための、少なくとも1つの所定の2-イミノピロリジン誘導体の使用が含まれる。本発明の使用において、所定の2-イミノピロリジン誘導体は、式(I)~(VII)の化合物等であり、好ましくは式(I)で表される化合物等であり、さらに好ましくは式(I)の化合物の臭化水素酸塩である。本発明の使用において、他の化合物(B)については、前記2-イミノピロリジン誘導体と他の化合物(B)の併用の記載を参照することができる。
さらに、本発明には、少なくとも1つの他の化合物(B)と併用し心疾患等の疾患を治療または改善するための、式(I)~(VII)からなる群より選ばれる少なくとも1つの化合物またはその薬学的に許容される塩が包含される。
1-(3-第3ブチル4-メトキシ-5-モルフォリノ-フェニル)-2-(5,6-ジエトキシ-7-フルオロ-1-イミノ-1,3-ジヒドロ-イソインドール-2-イル)-エタノン;臭化水素酸塩
1-ブロモ-3,4-ジエトキシ-2-フルオロベンゼン
1H-NMR(CDCl3)δ:1.35(3H,t,J=6.8Hz),1.42(3H,t,J=6.8Hz),4.03(2H,q,J=6.8Hz),4.11(2H,q,J=6.8Hz),6.57(1H,dd,J=2.0,9.3Hz),7.15(1H,dd,J=7.3,8.8Hz).
MS m/z:262(M+)
3,4-ジエトキシ-2-フルオロベンゾニトリル
MS m/z:209(M+)
3,4-ジエトキシ-2-フルオロ-6-ホルミルベンゾニトリル
MS m/z:238[(M+H)+]
3,4-ジエトキシ-2-フルオロ-6-ヒドロキシメチルベンゾニトリル
MS m/z:240(M+H)+
メタンスルホン酸2-シアノ-4,5-ジエトキシ-3-フルオロベンジル
性状:褐色トルエン溶液、定量値:5.79kg(A溶液2.92kg,B溶液2.87kg)、収率:96.9%、HPLC純度:A溶液98.8%,B溶液98.6%
1H-NMR(400MHz,CDCl3)δ:1.38(3H,t,J=6.8Hz),1.50(3H,t,J=6.8Hz),3.13(3H,s),4.17(4H,q,J=6.8Hz),5.28(2H,s),6.89(1H,d,J=1.0Hz).
MS m/z:317(M+)
5,6-ジエトキシ-7-フルオロ-3H-イソインドール-1-イルアミン
反応缶に上記工程で得られたメタンスルホン酸2-シアノ-4,5-ジエトキシ-3-フルオロベンジルのトルエンA溶液[32.16kg(メタンスルホン酸2-シアノ-4,5-ジエトキシ-3-フルオロベンジルとして2.92kg),9.20mol]とトルエン(170L)を投入し、室温下撹拌した。反応液を20℃以下になるまで冷却し、撹拌を停止後アンモニアで系内を置換した。撹拌後、再度アンモニアを0.86MPaまで加圧した。反応液はこのまま終夜撹拌後、アンモニアガスをリークした。反応液に水(35L)を加えた後、2N塩酸を(35L)加え、分液した。得られた有機層に1N塩酸(23.4L)を加え、分液した。得られた水層を先の水層と混合し、清澄ろ過した。水(10L)でリンスし後、反応缶へ移送した。水(15L)で洗い込み、反応液を冷却した。5N水酸化ナトリウム水溶液(7.18L)を滴下し、反応液を外浴30℃で加熱し約4時間撹拌した。反応液を冷却し、反応液温17.4℃で5N水酸化ナトリウム水溶液(12.82L)を滴下後、反応液を終夜撹拌した。析出した結晶をろ過後、結晶を水(30L)、tert-ブチル メチル エーテル(6L)で洗浄し、湿体を2.29kg得た。この湿体をコニカルドライヤーで、40℃下、減圧乾燥を行い、標記化合物(1.85kg)を微黄白色粉末状結晶として得た。
性状:微黄白色粉末状結、収量:1.85kg、収率:84%、HPLC純度:97.5%、水分含量:0.22%
MS m/z:239(M+H)+
1-(3-tert-ブチル-4-ヒドロキシフェニル)エタノン
1H-NMR (400MHz, CDCl3) δ: 1.43 (9H, s), 2.57 (3H, s), 6.17 (1H, s), 6.76 (1H, d, J=8.0 Hz), 7.73 (1H, dd, J=2.4, 8.0 Hz), 7.96 (1H, d, J=2.4 Hz).
MS m/z: 193 [(M+H)+]
1-(5-ブロモ-3-tert-ブチル-4-ヒドロキシフェニル)エタノン
1H-NMR (400MHz, CDCl3) δ: 1.42 (9H, s), 2.55 (3H, s), 6.26 (1H, s), 7.88 (1H, d, J=2.0 Hz), 7.99 (1H, d, J=2.0 Hz).
MS m/z: 271 [(M+H)+]
2-ブロモ-6-tert-ブチル-4-(1,1-ジメトキシエチル)アニソール
MS m/z: 330 (M+)
4-[3-tert-ブチル-5-(1,1-ジメトキシエチル)-2-メトキシフェニル]モルホリン
MS m/z: 337 (M+)
2-ブロモ-1-(3-tert-ブチル-4-メトキシ-5-モルホリノフェニル)エタノン
1H-NMR (400MHz, CDCl3) δ: 1.37 (9H, s), 3.07 (4H, t, J=4.4 Hz), 3.24 (6H, s), 3.57 (2H, s), 3.88 (4H, t, J=4.4 Hz), 3.94 (3H, s), 6.98 (1H, d, J=2.4 Hz), 7.08 (1H, d, J=2.4 Hz).
1H-NMR (400MHz, CDCl3) δ: 1.40 (9H, s), 3.09 (4H, t, J=4.4 Hz), 3.90 (4H, t, J=4.4 Hz), 3.99 (3H, s), 4.41 (2H, s), 7.52 (1H, d, J=2.0 Hz), 7.69 (1H, d, J=2.0 Hz).
MS m/z: 369 (M+)
1-(3-tert-ブチル-4-メトキシ-5-モルホリノフェニル)-2-(5,6-ジエトキシ-7-フルオロ-1-イミノ-1,3-ジヒドロ-2H-イソインドール-2-イル)エタノン ハイドロブロミド
5,6-ジエトキシ-4-フルオロ-1H-3-イソインドールアミン(20g),2-ブロモ-1-[3-(第3ブチル)-4-メトキシ-5-モルフォリノフェニル]-1-エタノン(34.2g)をジメチルフォルムアミド(300ml)に溶解し室温で48時間攪拌した。溶媒を減圧留去後、残沙に酢酸エチル(500ml)を加え結晶化した。得られた結晶を濾過後、酢酸エチルで洗浄して目的化合物(40g)を白色結晶として得た。
1.29(3H,t,J=6.8Hz)1.36(9H,s)1.39(3H,t,J=6.8Hz))2.95~3.12(4H,m)3.75~3.84(4H,m)3.94(3H,s)4.12(2H,q)4.20(2H,q,J=6.8Hz)4.78(2H,s)5.46(2H,s)7.33(1H,s)7.49(1H,s)7.59(1H,s)
MS:m/e(ESI)528.2(MH+)
1-(3-第3ブチル4-メトキシ-5-モルフォリノ-フェニル)-2-(5,6-ジエトキシ-7-フルオロ-1-イミノ-1,3-ジヒドロ-イソインドール-2-イル)-エタノン;塩酸塩
1.29(3H,t,J=6.8Hz)1.36(9H,s)1.39(3H,t,J=6.8Hz))2.95~3.04(4H,m)3.77~3.85(4H,m)3.94(3H,s)4.11(2H,q)4.20(2H,q,J=6.8Hz)4.77(2H,s)5.46(2H,s)7.32(1H,s)7.49(1H,s)7.59(1H,s)
(a)血小板膜の調製
1週間以内に薬物を服用していない健常人より採血を行い、凝固阻止剤として3.8%クエン酸(血液9に対して1の割合)を添加する。室温下、100gで10分間遠心することで多血小板血漿(PRP:platelet rich plasma)を得る。PRPを遠心して得た血小板をpH7.5の5mMTris-HCl、5mM EDTAに懸濁し、Dounce homogenizerでホモジナイズし、40,000gで60分間遠心し血小板膜を得た。得られた血小板膜は、10mM MgCl2と1mM EGTA(エチレングリコール四酢酸)を含むpH7.5の50mM Tris-HCl緩衝液(緩衝液1)に1%の濃度になるようにDMSO(ジメチルスルホキシド)を添加した溶液で懸濁し、-80℃で保存する。
トロンビンレセプターアンタゴニスト活性は、Ahnらのトロンビンレセプター放射リガンド結合アッセイ法(Ahnら、Mol.Pharmacol.,51巻,p.350-356(1997))の改変を使用して評価する。緩衝液1(pH7.5の50mM Tris-HCl、10mM MgCl2、1mM EGTA)にウシアルブミンおよびDMSOをそれぞれ0.1%および20%となるように添加して被験化合物の調製液とする。この調製液で種々の濃度に希釈した被験化合物溶液(20μl)を96穴のマルチスクリーンプレートに添加する。その後、緩衝液1にて25nMに希釈した[3H]Ala-(4-fluoro)Phe-Arg-(cyclohexyl)Ala-(homo)Arg-Tyr-NH2(high affinityTRAP)80μlを添加する。さらに、あらかじめ調製しておいた血小板膜溶液(0.4mg/ml)100μlを添加して混和した後、37℃で1時間インキュベーションする。反応液を吸引ろ過後に200μlの緩衝液1にて3回洗浄する。その後、液体シンチレーター30μlを添加してトップカウンター(パッカード)によりプレートの放射活性を測定する。被験物質存在時の放射活性から非特異的結合分を差し引いた値を、特異的結合(化合物非存在時の結合から非特異的結合分を差し引いた値)で除することにより結合率を求め、IC50値を算出する。なお、特異的な結合は10μMのhigh affinity TRAP)を添加した値とする。
(a)薬物投与および血液採取
覚醒下においてカニクイザルに前記式(I)~(VII)からなる群より選ばれる少なくとも1つの化合物またはその薬学的に許容される塩、および前記B群より選ばれる少なくとも1つの他の化合物(B)を、単独あるいは混合して経口投与する。前記B群より選ばれる少なくとも1つの他の化合物(B)を静脈内持続投与する場合、ケタミンで導入麻酔後、麻酔ガス(組成:笑気2L/min、酸素1L/min、イソフルラン0.5%)で吸入麻酔を行う。留置針を用いて試験物質の注入のためのカテーテルを上腕静脈に挿入する。インフュージョンポンプを用いて、一定時間、例えば90分間にわたって薬物を静脈内に投与する。採血は被験物質の経口投与前、及び両被験物資の投与終了後に行う。採血は、上腕静脈または伏在静脈から、抗凝固剤として3.8%クエン酸溶液200μLを入れたシリンジを用いて1.8mL採取する。
採血した血液をエッペンドルフチューブに移し、室温にて6400rpmで5秒間遠心を行い、上清をPRPとして分離する。分離したあとの血液はさらに10,000rpmで5分間遠心を行い乏血小板血漿(PPP:platelet poor plasma)を分離する。PPPを用いてPRPの血小板濃度を希釈して3×105/μLとなるように調製する。PRP凝集はBornらの濁度法に従って行う。PRP(225μl)を測定チャンネルに入れ、37℃に温めた後、トロンビン受容体活性化ペプチド(TRAP)を25μL添加し、6分間濁度変化に基づく凝集カーブを記録する。この凝集カーブ下の面積値を凝集強度として評価する。
1週間以内に薬物を服用していない健常人より採血を行い、凝固阻止剤として3.8%クエン酸(血液9に対して1の割合)を添加する。室温下、100gで10分間遠心することでPRPを得る。PRPを除去した血液をさらに1000gで10分間遠心することでPPPを得る。血小板数は他項目自動血球計数装置(K4500、シスメックス)で測定し、約30万/μlとなるようにPRPをPPPで希釈する。前記式(I)~(VII)からなる群より選ばれる化合物を種々の濃度に希釈した溶液とPRPを37℃にて60分間プレインキュベーションする。プレインキュベーション処理したPRP(175μl)に前記B群の化合物(B)の種々の濃度の溶液(25μl)を添加し、フィブリン重合阻止剤としてGPRP-NH2(最終濃度1mM)25μlを添加する。血小板凝集能はアグリゴメータ(エムシーメディカル)を用いて測定を行い、37℃で3分間保温した後、25μlのトロンビン溶液(1U/ml)を添加し、6分間の凝集反応を調べ、凝集曲線の曲線下面積を比較することで抑制作用を評価する。トロンビン以外の凝集惹起剤を使用する場合は、GPRP-NH2の添加は行わず、PRPの容量を200μlに変更して行う。
前記式(I)~(VII)からなる群より選ばれる少なくとも1つの化合物またはその薬学的に許容される塩、および前記B群より選ばれる少なくとも1つの他の化合物(B)を、単独あるいは混合して雄性ハートレー系モルモットに経口にて投与する。媒体には0.5%メチルセルロース溶液またはジメチルスルホキシド、Tween20を含む水溶液を用いる。(反復投与してもよい。)
上記式(I)の化合物の臭化水素酸塩(以下、実施例1化合物)及びアスピリンをそれぞれ200及び1000mg/mlとなるようにDMSOで溶解した。これらのDMSO溶液とTween20ならびに蒸留水を用いて、DMSO及びTween20の濃度がそれぞれ5%及び2%の水溶液となるように化合物非存在のVehicle、実施例1化合物単独6mg/ml、アスピリン単独50mg/ml並びに実施例1化合物6mg/mlとアスピリン20mg/mlの混合溶液の4種類の投与溶液を調製した。雄性ハートレー系モルモットに5ml/kgの割合で経口投与を行い、約80分を経過した時点でペントバルビタール酸ナトリウムを腹腔内投与して麻酔を行った。麻酔下にて頸静脈を露出し、ローズベンガル投与用にポリエチレンチューブをカニュレーションした。大腿動脈を露出し血流測定用のプローブを装着した。化合物投与約115分後にプローブの上流部位に緑色光(波長540nm、500,000ルクス)を照射し、照射5分後、5mg/mLとなるように生理食塩液に溶解したローズベンガル溶液(5mg/kg)を約1分間かけて投与を行った。ローズベンガル溶液投与開始から完全に血流が停止するまでの血流時間を測定することで抗血栓作用を評価した。
図1に示したようにVehicleを投与したコントロール群では血流時間が6.72分であったのに対し、実施例1化合物30mg/kg及びアスピリン100mg/kgの血流時間を、それぞれ10.77分及び11.30分と血流時間をそれぞれ延長した。さらに両者を併用した群では血流時間を24.19分に延長した。
この結果は、一般式(I)~(VII)からなる群より選ばれる少なくとも1つの化合物とアスピリンなどの所定の化合物(B)とを併用投与することで、優れた抗血栓作用が得られることを示している。よって、この結果から、両化合物を患者に併用投与することで、心疾患などの疾患を治療または改善できることがわかる。
Claims (8)
- 下記式(I)~(VII)からなる群より選ばれる少なくとも1つの化合物またはその薬学的に許容される塩、および下記B群より選ばれる少なくとも1つの他の化合物(B)を含有する、医薬組成物。
(B群)
シクロオキシゲナーゼ阻害剤、トロンボキサンA2生合成阻害剤、トロンボキサン受容体アンタゴニスト、アデノシン二リン酸受容体アンタゴニスト、GPIIb/IIIaアンタゴニスト、PGE1またはPGI2誘導体、血小板凝集阻害剤、セロトニン受容体アンタゴニスト、トロンビン阻害剤、ヘパリン、低分子ヘパリン、Xa阻害剤、VIIa阻害剤、K+チャネル阻害剤、ビタミンK拮抗剤、アンジオテンシンアンタゴニスト、アンジオテンシン変換酵素阻害剤、エンドセリンアンタゴニスト、ホスホジエステラーゼ阻害剤、カルシウム拮抗剤、β遮断薬、亜硝酸薬、血栓溶解剤、HMGCoA還元酵素阻害剤、フィブラート系薬剤、ニコチン酸系薬剤、胆汁酸吸着薬、コレステロール吸収阻害剤、PPARγアゴニスト、PPARαアゴニスト、PPARβアゴニスト、中性のエンドペプチダーゼ阻害剤および利尿薬。 - 式(I)~(VII)からなる群より選ばれる少なくとも1つの化合物またはその薬学的に許容される塩が、式(I)の化合物の臭化水素酸塩である、請求項1に記載の組成物。
- 組成物が心疾患の治療用又は改善用の医薬組成物である、請求項1または2に記載の組成物。
- 心疾患が、急性冠症候群、アテローム血栓症、再狭窄、高血圧、安定狭心症、不整脈、心不全、ST上昇心筋梗塞および脳梗塞からなる群より選ばれる少なくとも1つの疾患である、請求項3に記載の組成物。
- 他の化合物(B)がアスピリンまたはクロピドグレルである、請求項1~4のいずれか1項に記載の組成物。
- 下記B群より選ばれる少なくとも1つの他の化合物(B)と併用する心疾患の治療用または改善用医薬組成物の製造のための、式(I)~(VII)からなる群より選ばれる少なくとも1つの化合物またはその薬学的に許容される塩の使用。
(B群)
シクロオキシゲナーゼ阻害剤、トロンボキサンA2生合成阻害剤、トロンボキサン受容体アンタゴニスト、アデノシン二リン酸受容体アンタゴニスト、GPIIb/IIIaアンタゴニスト、PGE1またはPGI2誘導体、血小板凝集阻害剤、セロトニン受容体アンタゴニスト、トロンビン阻害剤、ヘパリン、低分子ヘパリン、Xa阻害剤、VIIa阻害剤、K+チャネル阻害剤、ビタミンK拮抗剤、アンジオテンシンアンタゴニスト、アンジオテンシン変換酵素阻害剤、エンドセリンアンタゴニスト、ホスホジエステラーゼ阻害剤、カルシウム拮抗剤、β遮断薬、亜硝酸薬、血栓溶解剤、HMGCoA還元酵素阻害剤、フィブラート系薬剤、ニコチン酸系薬剤、胆汁酸吸着薬、コレステロール吸収阻害剤、PPARγアゴニスト、PPARαアゴニスト、PPARβアゴニスト、中性のエンドペプチダーゼ阻害剤および利尿薬。 - 下記式(I)~(VII)からなる群より選ばれる少なくとも1つの化合物もしくはその薬学的に許容される塩を含有する医薬組成物と、下記B群より選ばれる少なくとも1つの他の化合物(B)を含有する医薬組成物を含む、心疾患の治療用または改善用キット。
(B群)
シクロオキシゲナーゼ阻害剤、トロンボキサンA2生合成阻害剤、トロンボキサン受容体アンタゴニスト、アデノシン二リン酸(ADP)受容体アンタゴニスト、GPIIb/IIIaアンタゴニスト、PGE1またはPGI2誘導体、血小板凝集阻害剤、セロトニン受容体アンタゴニスト、トロンビン阻害剤、ヘパリン、低分子ヘパリン、Xa阻害剤、VIIa阻害剤、K+チャネル阻害剤、ビタミンK拮抗剤、アンジオテンシンアンタゴニスト、アンジオテンシン変換酵素(ACE)阻害剤、エンドセリンアンタゴニスト、ホスホジエステラーゼ阻害剤、カルシウム拮抗剤、β遮断薬、亜硝酸薬、血栓溶解剤、HMGCoA還元酵素阻害剤、フィブラート系薬剤、ニコチン酸系薬剤、胆汁酸吸着薬、コレステロール吸収阻害剤、PPARγアゴニスト、PPARαアゴニスト、PPARβアゴニスト、中性のエンドペプチダーゼ阻害剤および利尿薬。 - 下記式(I)~(VII)からなる群より選ばれる少なくとも1つの化合物またはその薬学的に許容される塩および下記B群より選ばれる少なくとも1つの他の化合物(B)の有効量を患者に投与することを特徴する、心疾患の治療又は改善方法。
(B群)
シクロオキシゲナーゼ阻害剤、トロンボキサンA2生合成阻害剤、トロンボキサン受容体アンタゴニスト、アデノシン二リン酸受容体アンタゴニスト、GPIIb/IIIaアンタゴニスト、PGE1またはPGI2誘導体、血小板凝集阻害剤、セロトニン受容体アンタゴニスト、トロンビン阻害剤、ヘパリン、低分子ヘパリン、Xa阻害剤、VIIa阻害剤、K+チャネル阻害剤、ビタミンK拮抗剤、アンジオテンシンアンタゴニスト、アンジオテンシン変換酵素阻害剤、エンドセリンアンタゴニスト、ホスホジエステラーゼ阻害剤、カルシウム拮抗剤、β遮断薬、亜硝酸薬、血栓溶解剤、HMGCoA還元酵素阻害剤、フィブラート系薬剤、ニコチン酸系薬剤、胆汁酸吸着薬、コレステロール吸収阻害剤、PPARγアゴニスト、PPARαアゴニスト、PPARβアゴニスト、中性のエンドペプチダーゼ阻害剤および利尿薬。
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CA2711612A CA2711612A1 (en) | 2008-01-11 | 2009-01-09 | Pharmaceutical composition, use of 2-iminopyrrolidine derivative for production of pharmaceutical composition, and kit for treatment or amelioration of heart diseases |
US12/812,058 US8658620B2 (en) | 2008-01-11 | 2009-01-09 | Pharmaceutical composition, use of 2-iminopyrrolidine derivative for production of pharmaceutical composition, and kit for treatment or amelioration of heart diseases |
JP2009548960A JP5571389B2 (ja) | 2008-01-11 | 2009-01-09 | 医薬組成物、医薬組成物製造のための2−イミノピロリジン誘導体の使用および心疾患の治療用または改善用キット |
CN2009801018349A CN101917990B (zh) | 2008-01-11 | 2009-01-09 | 药物组合物、2-亚氨基吡咯烷衍生物用于制造药物组合物的用途和心脏病治疗用或改善用试剂盒 |
BRPI0906395A BRPI0906395A2 (pt) | 2008-01-11 | 2009-01-09 | composição farmacêutica, uso de pelo menos um composto ou um sal farmacologicamente aceitável do mesmo, kit, e, método para tratar ou melhorar as doenças cardíacas |
AU2009203368A AU2009203368A1 (en) | 2008-01-11 | 2009-01-09 | Pharmaceutical composition, use of 2-iminopyrrolidine derivative for production of pharmaceutical composition, and kit for treatment or amelioration of heart diseases |
EP09701323.9A EP2241315B1 (en) | 2008-01-11 | 2009-01-09 | Pharmaceutical composition, use of 2-iminopyrrolidine derivative for production of pharmaceutical composition, and kit for treatment or amelioration of heart diseases |
MX2010007527A MX2010007527A (es) | 2008-01-11 | 2009-01-09 | Composicion farmaceutica, uso del derivado 2-iminopirrolidina para la produccion de la composicion farmaceutica y kit para el tratamiento o mejora de enfermedaes cardiacas. |
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PCT/JP2009/050184 WO2009088063A1 (ja) | 2008-01-11 | 2009-01-09 | 医薬組成物、医薬組成物製造のための2-イミノピロリジン誘導体の使用および心疾患の治療用または改善用キット |
Country Status (11)
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US (1) | US8658620B2 (ja) |
EP (1) | EP2241315B1 (ja) |
JP (1) | JP5571389B2 (ja) |
KR (1) | KR20100119862A (ja) |
CN (1) | CN101917990B (ja) |
AU (1) | AU2009203368A1 (ja) |
BR (1) | BRPI0906395A2 (ja) |
CA (1) | CA2711612A1 (ja) |
IL (1) | IL206464A0 (ja) |
MX (1) | MX2010007527A (ja) |
WO (1) | WO2009088063A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2012014889A1 (ja) * | 2010-07-29 | 2013-09-12 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | フタロニトリル誘導体の製造方法 |
US8673890B2 (en) | 2009-10-29 | 2014-03-18 | Janssen Pharmaceutica Nv | 2,3-dihydro-1H-isoindol-1-imine derivatives useful as thrombin PAR-1 receptor antagonist |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US20100056519A1 (en) * | 2008-07-15 | 2010-03-04 | Serebruany Victor L | Composition and method for reducing platelet activation and for the treatment of thrombotic events |
CN113929736B (zh) * | 2020-06-29 | 2024-01-26 | 首都医科大学 | Gly-Pro-Arg-Pro-氧乙氨羰基华法林,其合成,活性和应用 |
Citations (3)
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WO2002085855A1 (fr) | 2001-04-19 | 2002-10-31 | Eisai Co., Ltd. | Derives de 2-iminopyrrolidine |
WO2004078721A1 (ja) | 2003-02-19 | 2004-09-16 | Eisai Co., Ltd. | 環状ベンズアミジン誘導体の製造方法 |
WO2007075964A2 (en) * | 2005-12-22 | 2007-07-05 | Schering Corporation | Thrombin receptor antagonists as prophylaxis to complications from cardiopulmonary surgery |
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US6245782B1 (en) | 1999-05-17 | 2001-06-12 | Heartdrug Research L.L.C. | Methods of inhibiting platelet activation with selective serotonin reuptake inhibitors |
CA2558191C (en) * | 2004-03-04 | 2011-01-04 | Eisai R&D Management Co., Ltd. | Composition containing benzamidine derivative and method for stabilizing benzamidine derivative |
EP1813282A4 (en) * | 2004-11-09 | 2011-03-02 | Eisai R&D Man Co Ltd | MEANS FOR THE TREATMENT OF ANGIOSPASM IN SUBARACHO-OAL BLOODING WITH THROMBIN RECEPTOR ANTAGONIST AS AN ACTIVE AGENT |
PE20080183A1 (es) * | 2006-04-06 | 2008-03-10 | Schering Corp | Terapias de combinacion de tra |
US20100056519A1 (en) | 2008-07-15 | 2010-03-04 | Serebruany Victor L | Composition and method for reducing platelet activation and for the treatment of thrombotic events |
-
2009
- 2009-01-09 WO PCT/JP2009/050184 patent/WO2009088063A1/ja active Application Filing
- 2009-01-09 EP EP09701323.9A patent/EP2241315B1/en active Active
- 2009-01-09 MX MX2010007527A patent/MX2010007527A/es unknown
- 2009-01-09 CN CN2009801018349A patent/CN101917990B/zh not_active Expired - Fee Related
- 2009-01-09 AU AU2009203368A patent/AU2009203368A1/en not_active Abandoned
- 2009-01-09 US US12/812,058 patent/US8658620B2/en not_active Expired - Fee Related
- 2009-01-09 KR KR1020107017487A patent/KR20100119862A/ko not_active Application Discontinuation
- 2009-01-09 BR BRPI0906395A patent/BRPI0906395A2/pt not_active IP Right Cessation
- 2009-01-09 CA CA2711612A patent/CA2711612A1/en not_active Abandoned
- 2009-01-09 JP JP2009548960A patent/JP5571389B2/ja not_active Expired - Fee Related
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2010
- 2010-06-17 IL IL206464A patent/IL206464A0/en unknown
Patent Citations (3)
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WO2002085855A1 (fr) | 2001-04-19 | 2002-10-31 | Eisai Co., Ltd. | Derives de 2-iminopyrrolidine |
WO2004078721A1 (ja) | 2003-02-19 | 2004-09-16 | Eisai Co., Ltd. | 環状ベンズアミジン誘導体の製造方法 |
WO2007075964A2 (en) * | 2005-12-22 | 2007-07-05 | Schering Corporation | Thrombin receptor antagonists as prophylaxis to complications from cardiopulmonary surgery |
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BROUWER, M.A. ET AL.: "Adjunctive treatment in patients treated with thrombolytic therapy", HEART, vol. 90, no. 5, 2004, pages 581 - 588, XP008138524 * |
CHACKALAMANNIL, S.: "Thrombin receptor (protease activated receptor-1) antagonists as potent antithrombotic agents with strong antiplatelet effects", J MED CHEM, vol. 49, no. 18, 2006, pages 5389 - 5403, XP002582198 * |
JOSEPH, J.E. ET AL.: "New antiplatelet drugs", BLOOD REV, vol. 11, no. 4, 1997, pages 178 - 190, XP009130017 * |
See also references of EP2241315A4 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8673890B2 (en) | 2009-10-29 | 2014-03-18 | Janssen Pharmaceutica Nv | 2,3-dihydro-1H-isoindol-1-imine derivatives useful as thrombin PAR-1 receptor antagonist |
JPWO2012014889A1 (ja) * | 2010-07-29 | 2013-09-12 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | フタロニトリル誘導体の製造方法 |
Also Published As
Publication number | Publication date |
---|---|
AU2009203368A1 (en) | 2009-07-16 |
BRPI0906395A2 (pt) | 2016-11-01 |
MX2010007527A (es) | 2010-10-05 |
EP2241315B1 (en) | 2013-12-11 |
JP5571389B2 (ja) | 2014-08-13 |
US20100286087A1 (en) | 2010-11-11 |
IL206464A0 (en) | 2010-12-30 |
CN101917990A (zh) | 2010-12-15 |
CA2711612A1 (en) | 2009-07-16 |
EP2241315A4 (en) | 2012-03-28 |
EP2241315A1 (en) | 2010-10-20 |
JPWO2009088063A1 (ja) | 2011-05-26 |
CN101917990B (zh) | 2012-11-28 |
KR20100119862A (ko) | 2010-11-11 |
US8658620B2 (en) | 2014-02-25 |
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