WO2010058751A1 - Sel de qualité pharmacologique d'un [1,3,4]oxadiazole ou de l'un de ses hydrates - Google Patents

Sel de qualité pharmacologique d'un [1,3,4]oxadiazole ou de l'un de ses hydrates Download PDF

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Publication number
WO2010058751A1
WO2010058751A1 PCT/JP2009/069431 JP2009069431W WO2010058751A1 WO 2010058751 A1 WO2010058751 A1 WO 2010058751A1 JP 2009069431 W JP2009069431 W JP 2009069431W WO 2010058751 A1 WO2010058751 A1 WO 2010058751A1
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Prior art keywords
acceptable salt
pharmacologically acceptable
acid
compound
hydrate
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PCT/JP2009/069431
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English (en)
Japanese (ja)
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誠 小野
祥子 吉田
大史 長澤
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第一三共株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention exhibits an inhibitory action on activated blood coagulation factor X (FXa), has high water solubility and excellent long-term storage stability, and is useful as a prophylactic / therapeutic agent for thrombotic and / or embolic diseases.
  • the present invention relates to a pharmacologically acceptable salt of compound (1) which is a [1,3,4] oxadiazole derivative, a hydrate thereof, or a crystal thereof, and an industrial production method thereof.
  • the following compound (1) is a compound that exhibits a strong FXa inhibitory action and is useful as a prophylactic / therapeutic agent for thrombotic and / or embolic diseases, as disclosed in Patent Document 1.
  • An object of the present invention is to provide a compound (1) useful as a pharmaceutical compound for the prevention and treatment of thrombotic and / or embolic diseases, which has high water solubility, high quality, and long-term storage stability required as a pharmaceutical product. It is an object to provide a drug substance form having a high molecular weight and an industrial production method for the drug substance form.
  • the present inventors examined not only the pharmacological action but also the final drug substance form of a compound useful as a pharmaceutical in terms of solubility in water and long-term storage stability.
  • basic compounds are known to form acid addition salts with acids for preparing pharmacologically acceptable salts, but for preparing pharmacologically acceptable salts with compound (1).
  • an acid decomposition product (A) accompanied by decomposition of [1,3,4] oxadiazole was obtained, and [1,3,4] oxadiazole was obtained. It became clear that there was a big problem in manufacture of the acid addition salt of the compound (1) having a ring.
  • Step D a step of filtering crystals precipitated by the stirring operation of (Step C) above;
  • the present invention provides the following pharmaceutical (16): a pharmaceutical comprising the compound according to any one of (1) to (9); (17): an activated blood coagulation factor X (FXa) inhibitor comprising the compound according to any one of (1) to (9); (18): a blood coagulation inhibitor containing the compound according to any one of (1) to (9); (19): A prophylactic and / or therapeutic agent for thrombus or embolus containing the compound according to any one of (1) to (9); (20): After cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, deep vein thrombosis, deep vein thrombosis, artificial valve / joint replacement containing the compound according to any one of (1) to (9) Thrombus formation, Thrombus formation and reocclusion after revascularization, Non-valvular atrial fibrillation (NVAF) preventive and / or
  • NVAF Non-valvular atrial fibrillation
  • the pharmacologically acceptable salt of the compound (1) of the present invention or a hydrate thereof, or a crystal thereof, in particular, the 1-maleate crystal (1-a) of the compound (1) has good water solubility. Because there is no change in weight due to moisture absorption and desorption, there are few concerns about formulation as a pharmaceutical, excellent long-term storage stability, and excellent FXa inhibitory action. is there. Therefore, the 1-maleate crystal (1-a) of compound (1) is useful as a pharmaceutical compound for the prevention / treatment of thrombotic and / or embolic diseases.
  • FIG. 3 is a diagram showing a powder X-ray diffraction pattern of 1 ⁇ maleate salt (1-a) of compound (1).
  • FIG. 5 is a graph showing the moisture absorption / desorption property of 1 ⁇ maleate (1-a) of compound (1).
  • FIG. 4 is a table showing the solubility of 1 ⁇ maleate salt (1-a) of compound (1) in water, JP 1 liquid and JP 2 liquid at 37 ° C. : Is a table showing the long-term storage stability prediction by Arrhenius plot based on the actual measurement value of the 1-maleate salt (1-a) of compound (1) when stored for 2 months.
  • Examples of pharmacologically acceptable salts in the present invention include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate and nitrate, acetate, propionate, glycolate, and succinic acid.
  • Organic acid addition salts such as salts, lactate, oxalate, maleate, tartrate, malonate, succinate, fumarate, mesylate, tosylate, ascorbate .
  • Examples of the acid addition salt of compound (1) include hydrochloride, hydrobromide, sulfate, mesylate, benzenesulfonate, tosylate, phosphate, acetate, glycolate, lactate, Malonate, tartrate, malate, maleate, citrate, succinate or hydrates thereof are preferred; hydrochloride and maleate are more preferred; preferable.
  • the pharmacologically acceptable salt of the above compound (1) or a hydrate thereof is preferably a crystal; hydrochloride, hydrobromide, maleate, malate, fumarate and glycolate or Their hydrate crystals are more preferred; hydrochloride crystals and maleate crystals are more preferred; 1 ⁇ maleate crystals are particularly preferred.
  • the diffraction angle (2 ⁇ ) by powder X-ray diffraction is 7.4, 12.6, 14.7, 18.3, 20.9, 22.7. , 24.2, 24.7, and 25.6 degrees ( ⁇ 0.2 degrees) are preferred.
  • the diffraction angle (2 ⁇ ) by powder X-ray diffraction is 6.1, 8.3, 12.3, 13.2, 16.0, 17.8, 19 Those having characteristic peaks at 0.0, 20.9, and 23.6 degrees ( ⁇ 0.2 degrees) are preferred.
  • the crystal of the malate salt of the compound (1) has a diffraction angle (2 ⁇ ) by powder X-ray diffraction of 5.2, 8.0, 8.4, 15.5, and 15.9 degrees ( ⁇ 0. Those having a characteristic peak at 2 degrees are preferred.
  • the diffraction angle (2 ⁇ ) by powder X-ray diffraction is 5.5, 8.4, 13.2, 18.5, 19.2, 22.3, 29. Those having characteristic peaks at 0.0 and 29.5 degrees ( ⁇ 0.2 degrees) are preferred.
  • the maleate salt of compound (1) the following formula (1-a)
  • the crystals of compound (1-a) are 8.4, 13.9, 15.4, 16.7, 17.2, 17.7, 18.8 as the diffraction angle (2 ⁇ ) by powder X-ray diffraction.
  • the crystal of the compound (1-a) is 8.4, 13.9, 15.4, 16.7, 17.2, 17.7, 18 as the diffraction angle (2 ⁇ ) by powder X-ray diffraction. .8, 19.4, 22.3, 22.1, 23.0 and 27.9 degrees ( ⁇ 0.2 degrees) with characteristic peaks, and a) temperatures between 220 ° C. and 225 ° C. Thermal analysis (DTA) profile with endothermic peaks in b) Weight loss at temperatures between 210 ° C. and 230 ° C.
  • DTA thermal analysis
  • melting point Is preferably characterized by:
  • a method of producing a pharmacologically acceptable salt of the above compound (1) or a hydrate crystal thereof in order to suppress the formation of a degradation product [acid degradation product (A)] in the production process, It is preferred to add in portions the acid to prepare the acceptable salt.
  • a method for producing a crystal of compound (1) in a high yield while suppressing the formation of decomposition products in the production process it corresponds to about half the amount of compound (1) and 1 mol of compound (1).
  • the acid for preparing 0.498 to 0.502 mol of a pharmacologically acceptable salt is preferably added in two divided portions.
  • a more specific method for producing a pharmacologically acceptable salt of compound (1) or a hydrate thereof, or a crystal thereof includes the following (Step A) to (Step D). .
  • Step A N 1- (5-chloropyridin-2-yl) -N 2 -[(1S, 2R, 4S) -2- ⁇ [(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino ⁇ -4-([1,3,4] oxadiazol-2-yl) cyclohexyl] ethanediamide (1) and compound (1 ) Adding an acid for preparing 0.498 to 0.502 mol of a pharmacologically acceptable salt with respect to 1 mol of), heating in a solvent and stirring; (Step B): A step of filtering the mixed solution obtained in (Step A) and filtering off insoluble matters while hot; (Step C): In order to prepare the pharmacologically acceptable salt of 0.498 to 0.502 mol with respect to 1 mol of compound (1) by heating the filtrate of (Step B).
  • Step D a step of filtering crystals precipitated by the stirring operation of (Step C) above.
  • the solvent in (Step A) water-containing methanol, water-containing ethanol, water-containing propanol, water-containing isopropanol, water-containing acetone or the like is preferable; More preferably hydrous ethanol or hydrous isopropanol; Ethanol containing 10 to 25% by volume of water is particularly preferred.
  • the amount of the solvent in (Step A) is preferably 5 to 15 times (volume / weight) relative to the weight of the compound (1); more preferably 8 to 12 times (volume / weight).
  • the time for heating and stirring so that the internal temperature of the mixed solution in (Step A) is 60 to 70 ° C. is preferably 30 minutes to 1 hour.
  • the filter paper used in the step of hot filtration in (Step B) may be a commercially available one that is usually used, and filtration may be performed under normal pressure filtration or reduced pressure.
  • the insoluble material is preferably washed with the same solvent as in (Step A) heated to 60 to 70 ° C .; the amount of the solvent used for washing is compound (1) and a pharmacologically acceptable salt. It is preferably 1 to 3 times (volume / weight) relative to the weight of the acid to be used; more preferably 2 times (volume / weight).
  • the acid for preparing the pharmacologically acceptable salt is re-added, so that the acid for preparing the pharmacologically acceptable salt is added dropwise in a solution using a suitable solvent.
  • a suitable solvent and its use amount, and a temperature for preparing an acid solution for preparing a pharmacologically acceptable salt include pharmacology. If the acid to prepare the top acceptable salt is an organic acid, it is preferable to select a solvent and dissolution method that prevents side reactions such as esterification with its own self-acid catalyst.
  • Solvents for preparing acid solutions for preparing pharmacologically acceptable salts include water-containing C1-C3 alcohols; C1-C3 alcohols containing 3-7% by volume of water are preferred; More preferably, ethanol containing 7% by volume or isopropanol containing 3-7% by volume of water; More preferred is an ethanol solution containing 3-7% by volume of water: An ethanol solution containing 5% by volume of water is particularly preferred.
  • the amount of the solvent used to prepare the acid solution for preparing the pharmacologically acceptable salt used in (Step C) is preferably 5 to 15 times (volume / weight) with respect to compound (1); 10 times (capacity / weight) is more preferable.
  • the temperature at which the acid solution for preparing a pharmacologically acceptable salt in (Step C) is added dropwise is preferably 40 to 50 ° C. which is the temperature of the filtrate, and the addition time is about 10 minutes. preferable.
  • Stirring after completion of the dropping in (Step C) gradually lowers the temperature of the solution to complete crystallization.
  • the temperature and time for stirring after completion of the dropping in (Step C) are 40 to 50 ° C. for 1.5 to 3 hours, 20 to 30 ° C. for 1.5 to 3 hours, and 0 to 10 ° C. for 10 to 10 hours. It is preferable to stir for 15 hours.
  • (Step D) is a step of filtering crystals precipitated by the stirring operation of (Step C).
  • the operation of filtering the precipitated crystals in (Step D) is preferably performed at 0 to 10 ° C.
  • the filtered crystals of (Step D) may be washed or washed, and the washing solvent for the washing operation is preferably ethanol containing 10 to 20% by volume of water that has been cooled to 0 to 10 ° C. in advance; Ethanol containing 15% by volume of water that has been cooled to 0 to 10 ° C. in advance is more preferable.
  • the amount of the washing solvent used is preferably 2 to 5 times (volume / weight) relative to compound (1); more preferably 3 times (volume / weight).
  • the drying operation is preferably carried out at 40-60 ° C.
  • N 1- (5-chloropyridin-2-yl) -N 2 -[(1S, 2R, 4S) -2- ⁇ [(5-methyl-4,5,6,7) of compound (1) -Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino ⁇ -4-([1,3,4] oxadiazol-2-yl) cyclohexyl] ethanediamide (1) (3.00 g 5.50 mmol), C1 to C3 alcohol containing 10 to 25% by volume of water is added 8 to 12 times (volume / weight).
  • the wet body is dried under reduced pressure at 40 ° C. to give the corresponding hydrochloride, hydrobromide, maleate, malate, fumarate or glycolate.
  • the thus obtained salt of compound (1), hydrate thereof, or crystal thereof, particularly 1 ⁇ maleate salt (1-a) has good water solubility, high purity and storage stability. It is useful as an excellent medicine.
  • compound (1-a) exhibits a highly activated blood coagulation factor X (FXa) inhibitory action, it is useful as a blood coagulation inhibitor, a prophylactic and / or therapeutic agent for thrombus or embolism.
  • the compound (1-a) is used for various diseases causing thrombus or embolism, such as cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep vein thrombosis, generalized Intravascular coagulation syndrome, thrombus formation after prosthetic valve / joint replacement, thrombus formation and reocclusion after revascularization, multiple organ failure (MODS), thrombus formation during extracorporeal circulation or blood coagulation during blood collection, non-valvular atria It is useful as a prophylactic and / or therapeutic agent for thromboembolism based on fibrillation (NVAF).
  • NVAF non-valvular atria
  • the medicament of the present invention can be administered by various methods including oral administration. Moreover, when it is set as an injection, it can be administered by any method such as intravenous injection, intramuscular injection, and subcutaneous injection. About the preparation method of this formulation, a suitable formulation can be selected according to the administration method, and the preparation method of the various formulation normally used can be used. Examples of oral preparations include tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, and the like. As injections, stabilizers, preservatives, and solubilizing agents may be used in the preparation.
  • the medicament containing the compound (1) of the present invention is preferably administered once per day per adult as the compound (1) and repeated at appropriate intervals.
  • the dose is in the range of 0.01 mg to 1000 mg, preferably in the range of 0.1 mg to 200 mg, more preferably 1 mg to 100 mg.
  • Example 1 The moisture absorption / desorption properties of the compound (1) and various salts of the compound (1) were evaluated. The amount of moisture adsorbed / desorbed was evaluated by measuring the change in weight over time in a relative humidity (RH) range of 10 to 90% in about 20 mg of crystals in a microbalance (automatic water vapor adsorption apparatus).
  • RH relative humidity
  • the 1-maleate salt (1-a) of compound (1) had a weight change of plus or minus 0.5% at 40 to 60% RH.
  • the 1-maleate salt (1-a) of the compound (1) shows that the free form of the crystal of the compound (1) shows a change in weight at a relative humidity of 40-60%, and between the anhydride and hydrate. It became clear to solve the problem of mutual conversion.
  • Test Example 2 According to the test method of the Japanese Pharmacopoeia, the solubility in water (37 ° C.), JP 1 liquid and 2 liquid was evaluated. As a result, as shown in the table in FIG. 6, the solubility of compound (1-a) in water was good.
  • Test Example 4 The thermal analysis (TG / DTA) of various salts of compound (1) such as compound (1-a) and the free form of compound (1) was carried out.
  • Test Example 5 After 2 months of refrigerated storage (5 ° C.) of various salts of compound (1) such as compound (1-a) and room temperature storage (25 ° C.), the acid degradation product (A) and The increase in total impurities was measured. Further, the increase in acid degradation products (A) and total impurities from the time point of 2 months was calculated by Arrhenius plot, and the long-term storage stability of each salt crystal was predicted. As a result, as shown in the table in FIG.
  • the increase rate of the acid degradation product (A) after 2 months storage of the hydrochloride salt of the compound (1) was refrigerated (5 ° C.). Increased by 0.10% and stored at room temperature (25 ° C) by 0.54%. Moreover, in the increase prediction of the acid degradation product (A) at the time of 36 months by Arrhenius plot based on the actual measurement value at the time of storage for 2 months, 0.58% at refrigerated storage (5 ° C), at room temperature (25 ° C) The increase was 3.25%. On the other hand, as shown in the table of [FIG. 7], the actually measured values of the acid decomposition product (A) after the storage of 1-maleate salt (1-a) of compound (1) for 2 months are 5 ° C.
  • the insoluble material was filtered while hot, and washed with ethanol (6 mL) containing 25% water that had been heated to 70 ° C. in advance.
  • the internal temperature of the filtrate was kept at 45 ° C., and a solution of maleic acid (321.64 mg, 2.77 mmol) in 5% water containing ethanol (30 mL) was added dropwise over 10 minutes. After 5 minutes, crystallization started.
  • the mixture was stirred at the same temperature for 2 hours and then allowed to cool. After stirring for 2 hours at an internal temperature of 21 to 28 ° C., the mixture was stirred for 12 hours in a low temperature room (room temperature 3-5 ° C.). Further, the mixture was cooled with ice water and stirred at an internal temperature of 2 ° C.
  • the pharmacologically acceptable salt of the compound (1) of the present invention or a hydrate thereof, or a crystal thereof, in particular, the 1-maleate crystal (1-a) of the compound (1) has good water solubility. Since there is no weight change due to moisture absorption and desorption, there is no concern in the formulation process as a pharmaceutical, and it has excellent long-term storage stability, so that it can be used as a pharmaceutical compound for thrombotic and / or embolic diseases. It is useful as a preventive / therapeutic agent.

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Abstract

Sel de qualité pharmacologique d'un composé (1), qui présente un effet inhibiteur de FXa et peut être employé en tant que composé pharmaceutique dans le traitement prophylactique ou thérapeutique des maladies thrombotiques et/ou emboliques, l'un de ses hydrates, un cristal du sel ou de son hydrate et des méthodes de production commerciale desdits sel et hydrate. La présente invention concerne spécifiquement un sel de qualité pharmacologique du N1-(5-chloropyridin-2-yl)-N2-[(1S,2R,4S)-2-{[(5-méthyl-4,5,6,7-tétrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-([1,3,4]oxadiazol-2-yl)cyclohexyl]éthanediamide, l'un de ses hydrates ou un cristal du sel ou de son hydrate.
PCT/JP2009/069431 2008-11-18 2009-11-16 Sel de qualité pharmacologique d'un [1,3,4]oxadiazole ou de l'un de ses hydrates WO2010058751A1 (fr)

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JP2008-293985 2008-11-18
JP2008293985 2008-11-18

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004058715A1 (fr) * 2002-12-25 2004-07-15 Daiichi Pharmaceutical Co., Ltd. Derives de diamine
WO2008156159A1 (fr) * 2007-06-21 2008-12-24 Daiichi Sankyo Company, Limited Procédé de production de dérivé de diamine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004058715A1 (fr) * 2002-12-25 2004-07-15 Daiichi Pharmaceutical Co., Ltd. Derives de diamine
WO2008156159A1 (fr) * 2007-06-21 2008-12-24 Daiichi Sankyo Company, Limited Procédé de production de dérivé de diamine

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