WO2014168103A1 - ピロール誘導体の結晶及びその製造方法 - Google Patents
ピロール誘導体の結晶及びその製造方法 Download PDFInfo
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- WO2014168103A1 WO2014168103A1 PCT/JP2014/060055 JP2014060055W WO2014168103A1 WO 2014168103 A1 WO2014168103 A1 WO 2014168103A1 JP 2014060055 W JP2014060055 W JP 2014060055W WO 2014168103 A1 WO2014168103 A1 WO 2014168103A1
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- phenyl
- trifluoromethyl
- methyl
- pyrrole
- hydroxyethyl
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- URLCPRZFFUXXIO-UHFFFAOYSA-N Cc1c(-c2ccccc2C(F)(F)F)[n](CCOC(C(Cl)=O)=O)cc1C(Cl)=O Chemical compound Cc1c(-c2ccccc2C(F)(F)F)[n](CCOC(C(Cl)=O)=O)cc1C(Cl)=O URLCPRZFFUXXIO-UHFFFAOYSA-N 0.000 description 2
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- C—CHEMISTRY; METALLURGY
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- A—HUMAN NECESSITIES
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- 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
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- 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
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- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- 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
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- 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
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
- C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention relates to an atropisomer crystal of a pyrrole derivative having an excellent mineralocorticoid receptor antagonistic action, a method for producing the same, and a production intermediate.
- MR Mineralcorticoid receptor
- aldosterone receptor is known to play an important role in the control of electrolyte balance and blood pressure in the body.
- MR antagonists such as spironolactone and eplerenone having a steroid structure are known to be useful for the treatment of hypertension and heart failure.
- Patent Document 1 A pyrrole derivative having an excellent mineralocorticoid receptor antagonistic action is disclosed in Patent Document 1 and Patent Document 2, and includes hypertension, angina pectoris, acute coronary syndrome, congestive heart failure, nephropathy, arteriosclerosis, It is known to be useful for the treatment of cerebral infarction, fibrosis, primary aldosteronism or heart disease (especially hypertension or diabetic nephropathy).
- Substances used in pharmaceuticals are required to have a particularly strict and high purity so that unexpected side effects (for example, toxicity) due to the impurities do not occur. Further, in the industrial production method (mass production method), it is required to remove impurities by a simpler operation.
- the present inventors have developed a method for producing a pyrrole derivative having an excellent MR antagonistic action in a higher quality, higher yield, industrially advantageous operation method, and less environmental impact.
- a method for producing a pyrrole derivative having an excellent MR antagonistic action in a higher quality, higher yield, industrially advantageous operation method, and less environmental impact.
- the present invention has been completed.
- the present inventors In order to improve the medical usefulness of an atropisomer of a pyrrole derivative having an excellent mineralocorticoid receptor antagonistic activity, the present inventors have developed an atropisomer of a pyrrole derivative in order to improve solubility, purity, stability and the like. The present inventors have intensively studied the body crystal, its production intermediate and its efficient production method. Hereinafter, the present invention will be described in detail.
- the present invention (1) An optically active amine having a cinchonane skeleton is used, and the following general formula (I)
- R 1 represents a methyl group or a trifluoromethyl group
- R 2 represents a hydrogen atom or a C1-C3 alkoxy group
- n represents an integer selected from 1 to 3.
- R 1 represents a methyl group or a trifluoromethyl group
- R 2 represents a hydrogen atom or a C1-C3 alkoxy group
- n represents an integer selected from 1 to 3.
- An optically active amine salt of the compound represented by the formula (the optically active amine is one selected from cinchonine, quinine, cinchonidine and quinidine): (8-1) (S) -1- (2-hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H-pyrrole-3-carboxylic acid quinine salt, (9)
- a pharmaceutical composition comprising the crystals described in (9) or (10) as an active ingredient, (12) Hypertension, angina pectoris, acute coronary syndrome, congestive heart failure, nephropathy, arteriosclerosis, cerebral infarction, fibrosis, containing the crystal described in (9) or (10) as an active ingredient, Preventive or therapeutic agent for primary aldosteronism or heart disease, (13)
- a prophylactic or therapeutic agent for hypertension comprising the crystal described in (9) or (10) as an active ingredient, (13-1)
- a crystal means a solid whose internal structure is composed of regularly repeated constituent atoms (or groups thereof) three-dimensionally, and is distinguished from an amorphous solid having no such regular internal structure.
- the crystal of the present invention absorbs moisture by being left in the atmosphere, and forms a hydrate by adhering water or heating to 25 to 150 ° C. under normal atmospheric conditions. There is a case. Furthermore, the crystal
- the crystal of the present invention may be represented based on powder X-ray diffraction data.
- powder X-ray diffraction is usually measured and analyzed by a technique used in this field. It can be carried out by the method described in the examples.
- the lattice constant of hydrates and dehydrates changes depending on the attachment and detachment of crystal water, which may change the diffraction angle (2 ⁇ ) in powder X-ray diffraction.
- the intensity of the peak may change due to a difference in crystal growth surface or the like (crystal habit).
- One preferred form of the crystal of the present invention is a crystal of a pyrrole derivative compound (A).
- the “characteristic peak” means a peak having a relative intensity of 50 or more when the maximum peak intensity is 100 in the powder X-ray diffraction diagram.
- the “main peak” means a peak having a relative intensity of 15 or more when the maximum peak intensity is 100 in the powder X-ray diffraction diagram.
- examples of the “C1-C3 alkoxy group” include methoxy, ethoxy, propoxy, and isopropoxy groups.
- R 2 is preferably a methoxy group.
- R 1 is preferably a hydrogen atom or a C1-C4 alkoxy group, more preferably a hydrogen atom or a methoxy group, and particularly preferably a hydrogen atom.
- R 2 is preferably a hydrogen atom or a C1-C4 alkoxy group, more preferably a hydrogen atom or a methoxy group, and particularly preferably a hydrogen atom.
- N is preferably 2.
- R 1 represents a methyl group or a trifluoromethyl group
- R 2 represents a hydrogen atom or a C1-C3 alkoxy group
- n represents an integer selected from 1 to 3.
- the pyrrole derivative compound (A ′) can be produced using a known compound as a starting material and using the following production method and intermediate of the present invention.
- R 1 , R 2 and n have the same meaning as described above.
- Process B Production of pyrrole derivative compound (A ')
- This step is a step for producing compound (VII) by reacting compound (VIII) with ethyl cyanoacetate in the presence of a base.
- the starting material is preferably 2-bromo-1- [2- (trifluoromethyl) phenyl] propan-1-one.
- an organic solvent that does not inhibit the reaction and dissolves the starting material to some extent is used.
- amides such as N, N-dimethylacetamide and N, N-dimethylacetamide, and more preferable is N, N-dimethylacetamide.
- the base is preferably a metal hydride such as sodium hydride, or an alkali metal carbonate such as potassium carbonate, and more preferably potassium carbonate.
- the reaction temperature is 0 ° C to 100 ° C, preferably 40 ° C to 60 ° C.
- Step A-2 This step is a step for producing compound (VI) by cyclizing compound (VII) to a pyrrole ring.
- an organic solvent that does not inhibit the reaction and dissolves the starting material to some extent is used.
- ethers such as tetrahydrofuran
- aromatic hydrocarbons such as toluene
- esters such as ethyl acetate, more preferred is ethyl acetate or tetrahydrofuran, and particularly preferred is ethyl acetate. is there.
- hydrochloric acid gas is preferably blown in the presence of thionyl chloride, and concentrated sulfuric acid may be added.
- the reaction temperature is 0 ° C. to 40 ° C., preferably room temperature.
- Step A-3 This step is a step of producing compound (V) by removing the chlorine group of compound (VI).
- a mixed solvent of an organic solvent and water that does not inhibit the reaction and dissolves the starting material to some extent is used.
- a mixed solvent of ethanol, tetrahydrofuran and water is preferable.
- sodium formate and 5% palladium-carbon catalyst are suitable.
- the reaction temperature is 0 ° C to 100 ° C, preferably 40 ° C to 60 ° C.
- the reaction time is 0.5 to 12 hours, preferably 0.5 to 2 hours.
- Step A-4 This step is a step for producing compound (IV) by introducing a hydroxy C1-3 alkyl group onto nitrogen of the pyrrole group of compound (V) in the presence of a base in a solvent.
- amides such as N, N-dimethylacetamide.
- the base is preferably a metal alkoxide such as t-butoxy potassium or t-butoxy sodium, or an organic base such as 4-dimethylaminopyridine, and more preferably 4-dimethylaminopyridine.
- Preferred as a reagent for introducing a hydroxyalkyl group are 2-iodoethanol, 2-bromoethanol and ethylene carbonate, and ethylene carbonate is more preferred.
- the reaction temperature is from room temperature to 150 ° C, preferably from 100 ° C to 120 ° C.
- reaction time is 1 hour to 20 hours, preferably 5 hours to 15 hours.
- This step is a step for obtaining compound (I) by alkaline hydrolysis of the ester of compound (IV).
- the solvent is preferably a mixed solvent of alcohol such as ethanol and water.
- the reagent is not particularly limited as long as it is a basic reagent that hydrolyzes a carboxylic acid ester, but sodium hydroxide is preferable.
- the reaction temperature is room temperature to 100 ° C, preferably 50 ° C to 80 ° C.
- This step is a step of producing the compound (s)-(I) by optically resolving the atropisomer by stirring the intermediate compound (I) of the present invention and the optically active amine in a solvent. This can be achieved by stirring (I) and an optically active amine having a cinchonane skeleton in a solvent. The diastereomeric excess can be measured by a usual method.
- the solvent is preferably an acetate ester, an amide or a mixed solvent of water selected from them and water, and more preferably a mixed solvent of N, N-dimethylacetamide, ethyl acetate and water. If necessary, the compound (I) and the optically active amine may be dissolved separately, and the optically active amine solution may be dropped into the solution of the compound (I).
- the optically active amine having a cinchonane skeleton is preferably one selected from cinchonine, quinine, cinchonidine and quinidine shown in the following compound group,
- quinine represented by the following formula.
- the amount of the optically active amine having a cinchonane skeleton is preferably 0.5 to 1 equivalent relative to compound (I), and more preferably 0.5 to 1 equivalent relative to compound (I).
- the reaction mixture may be heated or cooled as necessary.
- a method in which the reaction solution is heated and stirred and then cooled to produce crystals is preferred.
- the heating temperature is preferably from room temperature to 100 ° C, more preferably from 60 to 70 ° C.
- the cooling temperature is preferably 20-30 ° C.
- the amine salt of the compound (s)-(I) obtained by this step can also be made into a free form using an acid.
- the acid used at this time is not particularly limited as long as it is usually an acid (inorganic acid such as hydrochloric acid) used for removing an amine salt.
- This step is a step of obtaining compound (II) by reacting compound (s)-(I) with oxalyl chloride in the presence of a base. Step B-3 can also be continued without isolating and purifying compound (II).
- the solvent is preferably an acetate ester, an ether, or a mixed solvent thereof, and more preferably a mixed solvent of 1,2-dimethoxyethane, ethyl acetate, and tetrahydrofuran.
- an organic base such as pyridine is preferable.
- the reaction temperature is 0 ° C to 20 ° C, preferably 0 ° C to 10 ° C.
- reaction time is 1 hour to 20 hours, preferably 1 hour to 10 hours.
- This step is a step of obtaining compound (III) by reacting compound (II) with 4- (methylsulfonyl) aniline in the presence of a base.
- the solvent is preferably a nitrile, and more preferably a mixed solvent of acetonitrile and water.
- an organic base such as pyridine is preferable.
- the reaction temperature is 0 ° C to 20 ° C, preferably 0 ° C to 15 ° C.
- the reaction time is 1 to 2 hours, preferably 1 hour.
- Compound (III) can be carried out by continuing Step B-4 without isolation and purification, but Compound (III) is preferably a step comprising an isolation method.
- This step is a step of obtaining the pyrrole derivative compound (A ′) by making the hydroxyl group of the compound (III) free in the presence of a base.
- This method is usually performed in a solvent.
- the solvent include acetate esters, nitriles, ethers, or a mixed solvent of water selected from them, and a mixed solvent of t-butyl methyl ether, acetonitrile, and water.
- the base is preferably a metal hydroxide such as potassium hydroxide.
- the reaction temperature is 0 ° C to 100 ° C, preferably 10 ° C to 30 ° C.
- the reaction time is 0.5 to 20 hours, preferably 0.5 to 2 hours.
- the target compound is collected from the reaction mixture according to a conventional method.
- the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, washed with water, and the target compound is then contained.
- the organic layer is separated, dried over anhydrous magnesium sulfate and the like, and then the solvent is distilled off.
- the obtained target product can be obtained by a conventional method such as recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, such as adsorption column chromatography, distribution column chromatography, etc. Separation and purification by eluting with an appropriate eluent by combining a method using a synthetic adsorbent, a method using ion exchange chromatography, or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel. can do.
- Another aspect of the present invention relates to a medicine containing the crystal of the present invention as an active ingredient and a pharmaceutical composition containing the crystal of the present invention.
- the medicament containing the crystal of the present invention as an active ingredient is preferably provided in the form of a pharmaceutical composition comprising the crystal of the present invention and one or more pharmaceutically acceptable carriers.
- the dosage form of the medicament of the present invention is not particularly limited and can be administered orally or parenterally, but is preferably administered orally.
- the pharmaceutical composition of the present invention contains at least a part of the crystal of the present invention as the compound (A).
- a crystal form other than the crystal of the present invention may exist as the compound (A).
- the proportion of the crystal of the present invention contained in the pharmaceutical composition is in the range of 0.01% to 99.9% by weight, for example, 0.01% by weight or more and 0.05% by weight with respect to the whole compound (A) in the pharmaceutical composition.
- the pharmaceutical composition of the present invention comprises the crystal of the present invention and a pharmaceutically acceptable carrier, and is used as various injections such as intravenous injection, intramuscular injection, subcutaneous injection, or oral administration or transdermal administration. Administration can be by a variety of methods.
- a pharmaceutically acceptable carrier is a pharmaceutically acceptable material (eg, excipient, diluent) involved in transporting the crystals of the invention from one organ or organ to another. , Additives, solvents, etc.).
- an appropriate preparation for example, an oral preparation or an injection
- oral preparations include tablets, powders, granules, capsules, pills, troches, solutions, syrups, elixirs, emulsions, and oily or aqueous suspensions.
- stabilizers, preservatives or solubilizers can be used in the preparation.
- a solution that may contain these adjuvants and the like may be stored in a container and then prepared as a solid preparation by lyophilization or the like.
- the single dose may be stored in one container, and the multiple doses may be stored in one container.
- solid preparations include tablets, powders, granules, capsules, pills, and lozenges. These solid preparations may contain pharmaceutically acceptable additives together with the crystals of the present invention.
- the additive include fillers, extenders, binders, disintegrants, dissolution accelerators, wetting agents, and lubricants, which are selected and mixed as necessary. And can be formulated.
- liquid preparations include solutions, syrups, elixirs, emulsions, and suspensions. These liquid formulations may contain pharmaceutically acceptable additives along with the crystals of the present invention.
- the additive include a suspending agent or an emulsifier, and these can be selected and mixed as necessary to prepare a formulation.
- the content of the binder is usually 1 to 10 parts by weight (preferably 2 to 5 parts by weight) in the total drug composition, and the content of the disintegrant is usually 1 To 40 parts by weight (preferably 5 to 30 parts by weight), and the lubricant content is usually 0.1 to 10 parts by weight (preferably 0.5 to 3 parts by weight).
- the content is 0.1 to 10 parts by weight (preferably 0.5 to 5 parts by weight).
- the pharmaceutical composition of the present invention can be administered to warm-blooded animals (particularly humans), and the dose of the active ingredient compound (A) or a pharmacologically acceptable salt thereof depends on the patient's symptoms, age, body weight.
- the dose of the active ingredient compound (A) or a pharmacologically acceptable salt thereof depends on the patient's symptoms, age, body weight.
- 0.1 mg / body to 20 mg / body (preferably 0.5 mg / body to 10 mg / body) per dose is given to a human per day per day.
- a method for producing a pyrrole derivative compound (A ′) having a mineralocorticoid receptor antagonistic action and a production intermediate compound thereof Further, (S) -1- (2-hydroxyethyl) -4-methyl-N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H-pyrrole-3 -Carboxamide crystals, methods for their preparation and intermediate compounds for their production are provided.
- the crystal of the present invention is excellent in stability and useful as a medicine such as an antihypertensive agent.
- FIG. 6 is a powder X-ray diffraction pattern of the crystals obtained in Example 8.
- the vertical axis indicates the diffraction intensity in units of count / second (cps), and the horizontal axis indicates the value of the diffraction angle 2 ⁇ .
- FIG. 9 is a DSC curve diagram of the crystal (A crystal) obtained in Example 8. In the figure, the vertical axis indicates heat flow (mW), and the horizontal axis indicates temperature (° C.).
- Example 7 (S) -1- (2-hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H-pyrrole-3-carboxylic acid quinine salt (7-1) (S) -1- (2-hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H-pyrrole-3-carboxylic acid quinine salt Obtained by the production method of Example 6.
- N, N-dimethylacetamide (25 mL), ethyl acetate (350 mL) and water (15 mL) were added to 31.05 g (96 mmol) of quinine and heated to 65-70 ° C., and then Solution 1 was added dropwise. The mixture was stirred at 65-70 ° C. for about 1 hour, then slowly cooled to 0-5 ° C. (cooling rate guideline: about 0.3 ° C./min), and stirred at that temperature for about 0.5 hour.
- Example 8 (S) -1- (2-hydroxyethyl) -4-methyl-N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H-pyrrole -3-Carboxamide (Compound (A)) (8-1) (S) -1- (2-hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H-pyrrole-3-carboxylic acid According to the production method of Example 7.
- Example (8-1) the solution obtained in Example (8-1) was added while maintaining 10 to 15 ° C., and the mixture was heated to 15 to 20 ° C. and stirred for about 1 hour. After stirring, acetonitrile (120 mL) and pyridine 2.46 g (31 mmol) were added, and the reaction mixture was concentrated under reduced pressure (120 mL), acetonitrile (200 mL) was added, and the mixture was further concentrated under reduced pressure (120 mL).
- reaction solution 1 After completion of concentration under reduced pressure, acetonitrile (200 mL) was added and cooled to 10 to 15 ° C. (reaction solution 1).
- the mixture was stirred at 25 to 35 ° C. for about 2 hours. After stirring, the mixture was separated, and the obtained organic layer was concentrated under reduced pressure (120 mL), ethanol (240 mL) was added, and the mixture was further concentrated under reduced pressure (120 mL). After concentration under reduced pressure, ethanol (36 mL) and water (12 mL) were added and heated to 35 to 45 ° C., and water (280 mL) was added dropwise while maintaining 35 to 45 ° C. to crystallize crystals. After cooling the crystallized solution to room temperature, the crystals were filtered.
- Enantiomeric amount (%) (peak area of enantiomer ⁇ peak area of the title compound) x 100 (8-5) (S) -1- (2-hydroxyethyl) -4-methyl-N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H-pyrrole -3-Carboxamide X-ray diffraction measurement Using the RINT2200V type X-ray diffractometer manufactured by Rigaku Corporation, the sample compound crystals obtained in (8-3) were filled into a glass sample holder and subjected to the following conditions. It was measured. FIG.
- EtOAc represents ethyl acetate
- CH 3 CN represents acetonitrile
- DME dimethoxyethane
- Example 12 (S) -1- (2-hydroxyethyl) -4-methyl-N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H-pyrrole -3- Preparation of carboxamide (compound (A)) 2 (12-1) (S) -1- (2-hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H-pyrrole-3-carboxylic acid According to the production method of Example 7.
- Example (12-1) the solution obtained in Example (12-1) was added while maintaining 0 to 5 ° C., and the mixture was stirred at 0 to 10 ° C. for 6 hours. After stirring, acetonitrile (30 mL) and pyridine 0.62 g (8 mmol) were added, the reaction mixture was concentrated under reduced pressure (30 mL), acetonitrile (50 mL) was added, and the mixture was further concentrated under reduced pressure (30 mL).
- reaction solution 1 acetonitrile (10 mL) and 0.10 ⁇ g (1 mmol) of oxalyl chloride were added and cooled to 0 to 5 ° C. (reaction solution 1).
- the mixture was stirred at 15 to 25 ° C. for about 2 hours. After stirring, the layers were separated, and the obtained organic layer was concentrated under reduced pressure (30 mL), ethanol (60 mL) was added, and the mixture was further concentrated under reduced pressure (30 mL). After concentration under reduced pressure, ethanol (14 mL) and water (20 mL) were added, and seed crystals were added to crystallize the crystals. Water (50 mL) was added dropwise over about 1 hour, and the mixture was stirred for about 1 hour, and the crystals were filtered. Thereafter, the crystals were washed with a 30 v / v% aqueous ethanol solution (10 mL) and dried under reduced pressure at 40 ° C.
Abstract
Description
以下、本発明を詳細に説明する。
(1) シンコナン骨格を有する光学活性アミンを用いることを特徴とする、下記一般式(I)
(2) 光学活性アミンが、下記式であらわされる化合物群から選択される1つである、上記(1)に記載の方法、
(5) 一般式(I)であらわされる化合物が、下記化合物(Ia)
(6) 下記式(Ia)
(6-1) 上記中間体化合物 (IIa) を得るための、塩化オキサリルとの反応時、及び上記中間体化合物(IIa)と4-(メチルスルホニル)アニリンとの反応時の反応温度が20℃以下である、上記(6)に記載の製法、
(6-2) 上記中間体化合物(IIIa)を単離する工程を含む、上記(6)に記載の製法、
(6-3) (RS)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸の一方のアトロプ異性体が、(S)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸である、上記(6)に記載の製法、
(7) 下記式(A)
(8) 下記一般式(I)
(8-1) (S)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸 キニーネ塩、
(9) 銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折図において、回折角度2θ=6.80、 17.06、 19.24、 22.80および25.48に特徴的ピークを示す、上記式(A)で表される(S)-1-(2-ヒドロキシエチル)-4-メチル-N-[4-(メチルスルホニル)フェニル]-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボキサミドの結晶、
(10) 銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折図において、回折角度2θ=6.80、 12.32、 13.60、 14.46、 16.30、 17.06、 18.42、 19.24、 19.86、 20.36、 20.82、 21.84、 22.50、 22.80、 23.20、 23.50、 24.60、 24.88、 25.48、 26.96、 27.52、 29.26、 31.80、 32.08、 35.82、 40.32、および41.36に主要ピークを示す、上記式(A)で表される(S)-1-(2-ヒドロキシエチル)-4-メチル-N-[4-(メチルスルホニル)フェニル]-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボキサミドの結晶、
(10-1) 銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折図において、図1に示すX線回折図を有する、(S)-1-(2-ヒドロキシエチル)-4-メチル-N-[4-(メチルスルホニル)フェニル]-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボキサミドの結晶、
(11) 上記(9)又は(10)に記載された結晶を有効成分として含有する医薬組成物、
(12) 上記(9)又は(10)に記載された結晶を有効成分として含有する高血圧症、狭心症、急性冠症候群、うっ血性心不全、腎症、動脈硬化症、脳梗塞、繊維症、原発性アルドステロン症又は心疾患の予防薬若しくは治療薬、
(13) 上記(9)又は(10)に記載された結晶を有効成分として含有する高血圧症の予防薬又は治療薬、
(13-1) 上記(9)又は(10)に記載された結晶を有効成分として含有する高血圧症の治療薬、
(14) 上記(9)又は(10)に記載された結晶を有効成分として含有する糖尿病性腎症の予防薬又は治療薬、
(14-1) 上記(9)又は(10)に記載された結晶を有効成分として含有する糖尿病性腎症の治療薬、
(15) 医薬を製造するための、上記(9)又は(10)のいずれか1項に記載の結晶の使用、
(16) 高血圧症、狭心症、急性冠症候群、うっ血性心不全、腎症、動脈硬化症、脳梗塞、繊維症、原発性アルドステロン症又は心疾患の予防若しくは治療のための医薬を製造するための、上記(9)又は(10)に記載の結晶の使用、
(17) 高血圧症の治療のための医薬を製造するための、上記(9)又は(10)に記載の結晶の使用、
(18) 糖尿病性腎症の治療のための医薬を製造するための、上記(9)又は(10)に記載の結晶の使用である。
(工程A-1)
本工程は、化合物(VIII)に、塩基存在下、シアノ酢酸エチルを反応させることにより、化合物(VII)を製造する工程である。
(工程A-2)
本工程は、化合物(VII)をピロール環に環化することにより、化合物(VI)を製造する工程である。
(工程A-3)
本工程は、化合物(VI)の塩素基を除去することにより、化合物(V)を製造する工程である。
本工程は、溶媒中、塩基存在下、化合物(V)のピロール基の窒素上に、ヒドロキシC1-3アルキル基を導入することにより、化合物(IV)を製造する工程である。
(工程A-5)
本工程は、化合物(IV)のエステルをアルカリ加水分解し、化合物(I)を取得する工程である。
(工程B-1)
本工程は、本発明の中間体化合物(I)と光学活性アミンを溶媒中撹拌することで、アトロプ異性体を光学分割し、化合物(s)-(I)を製造する工程であり、 上記化合物(I)とシンコナン骨格を有する光学活性アミンを溶媒中撹拌することで、達成することができる。ジアステレオマー過剰率は通常の方法により測定できる。
(工程B-2)
本工程は、化合物(s)-(I)と塩化オキサリルを、塩基存在下で反応させることにより、化合物(II)を取得する工程である。化合物(II)を単離精製することなく、工程B-3を続けておこなうこともできる。
(工程B-3)
本工程は、化合物(II)と4-(メチルスルホニル)アニリンを、塩基存在下で反応させることにより、化合物(III)を取得する工程である。
(工程B-4)
本工程は、化合物(III)の水酸基を塩基存在下フリーにすることにより、ピロール誘導体化合物(A’)を取得する工程である。
1H NMR(400MHz、DMSO-d6)δ:1.87(3H,s)、3.38~3.68(4H,m)、7.43~7.89(5H,m).
(7-1) (S)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸 キニーネ塩
実施例6の製造方法により得られた(RS)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸 50.00 g(160 mmol)に、N,N-ジメチルアセトアミド(25 mL)、酢酸エチル(85 mL)を室温にて加え溶解した(溶解液1)。
1H NMR(400MHz、DMSO-d6)δ: 1.30~2.20(10H,m)、2.41~2.49(2H,m)、2.85~3.49(6H,m)、3.65~3.66(1H,m)、3.88(3H,s)、4.82(1H,broad singlet)、4.92~5.00(2H,m)、5.23~5.25(1H,m)、5.60(1H,br)、5.80~6.00(1H,m)、7.36~7.92(9H,m)、8.67(1H,d,J = 4.6 Hz)
(7-2) (S)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸 キニーネ塩のジアステレオマー過剰率(%de)のHPLC測定
標記化合物 約10 mgを採取し、50v/v%アセトニトリル水溶液で希釈して10 mLとしたものを試料溶液とした。
移動相A:0.02mol/L リン酢緩衝溶液(pH 3)
移動相B:アセトニトリル
移動相の送液:移動相A及び移動相Bの混合比を以下の表1に示す。
流速 :約0.8 mL/min
カラム温度:30℃付近の一定温度
測定時間 :約20 min
注入量 :5 μL
ジアステレオマー過剰率(%de)は、標記化合物 (保持時間約12 min)、R体 (保持時間約13 min)のピーク面積比を用いて下記の式で算出した。
%de ={[(標記化合物(S体)ピーク面積比)-(R体 ピーク面積比)]÷[(標記化合物(S体)ピーク面積比)+ (R体ピーク面積比)]}×100
(8-1) (S)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸
実施例7の製造方法により得られた(S)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸(8α,9R)-6’-メトキシシンコナン-9-オール 40.00 g(63 mmol)に酢酸エチル(400 mL)、2規定 塩酸水(100 mL)を加えて室温で撹拌し、分液した。得られた有機層を減圧濃縮し(120 mL)、酢酸エチル(200 mL)を加え、さらに減圧濃縮し標記化合物を含む溶液を得た(120 mL)。
(8-2) N-{[4-(メチルスルホニル)フェニル]アミノ}オキサミド酸2-((S)-3-メチル-4-{[4-(メチルスルホニル)フェニル]カルバモイル}-2-[2-(トリフルオロメチル)フェニル]-1H-ピロール-1-イル)エチル
酢酸エチル(240 mL)、テトラヒドロフラン(80 mL)及び塩化オキサリル 20.72 g(163 mmol)を混合し、10~15℃に冷却した。続いて10~15℃を保ちながら実施例(8-1)で得られた溶液を加え、15~20℃に加熱して約1時間撹拌した。撹拌後、アセトニトリル(120 mL)およびピリジン 2.46 g(31 mmol)を加え、反応液を減圧濃縮し(120 mL)、アセトニトリル(200 mL)を加え、さらに減圧濃縮した(120 mL)。
1H NMR(500MHz、DMSO-d6) δ: 1.94 (s, 3H), 3.19 (s, 3H), 3.20 (s, 3H), 3.81 (t, 1H), 4.12 (t, 1H), 4.45 (t, 2H, J = 5.81 Hz), 7.62 (t, 1H, J = 4.39 Hz), 7.74 (t, 2H, J = 3.68 Hz), 7.86 (dd, 3H), 7.92 (dd, 3H, J = 6.94, 2.13 Hz), 7.97 (dd, 2H, J = 6.80, 1.98 Hz), 8.02 (dd, 2H), 10.03 (s, 1H), 11.19 (s, 1H)
(8-3) (S)-1-(2-ヒドロキシエチル)-4-メチル-N-[4-(メチルスルホニル)フェニル]-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボキサミド(化合物(A))
(8-2)で得られた湿品の結晶に、t-ブチルメチルエーテル(200 mL)、アセトニトリル(40 mL)、48w/w水酸化カリウム水溶液(16 g)と水(200 mL)を加え、25~35℃で約2時間撹拌した。撹拌後、分液し、得られた有機層を減圧濃縮し(120 mL)、エタノール(240 mL)を加え、さらに減圧濃縮した(120 mL)。減圧濃縮終了後、エタノール(36 mL)、水(12 mL)を加えて35~45℃に加熱し、35~45℃を保ちながら水(280 mL)を滴下し、結晶を晶出させた。晶出液を室温まで冷却後、結晶を濾過した。その後、結晶を30v/v%エタノール水溶液(80 mL)で洗浄し、40℃で減圧乾燥したところ、標記化合物を結晶で得た(26.26 g、収率89.7%)。また、得られた結晶のエナンチオマー量は0.3%であった。
1H NMR(400MHz、CDCl3)δ:1.74(1H,broad singlet)、2.08(3H,s)、3.04(3H,s)、3.63~3.80(4H,m)、7.36(1H,d,J = 7.2 Hz)、7.48(1H,s)、7.58~7.67(2H,m)、7.77~7.90(6H,m).
(8-4) (S)-1-(2-ヒドロキシエチル)-4-メチル-N-[4-(メチルスルホニル)フェニル]-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボキサミドのエナンチオマー量(%)のHPLC測定法
標記化合物 約10 mgを採取し、50v/v%アセトニトリル水溶液で希釈して10 mLとしたものを試料溶液とした。
移動相A:アセトニトリル/水 = 9/16
移動相B:アセトニトリル
移動相の送液:移動相A及び移動相Bの混合比を以下の表2に示す。
流速 :約0.8 mL/min
カラム温度 :30℃付近の一定温度
測定時間 :約30 min
注入量 :5 μL
標記化合物 (保持時間約9.2 min)の標準溶液、エナンチオマー (保持時間約8.2 min)のピーク面積を用いて下記の式で計算した。
エナンチオマー量(%) =(エナンチオマーのピーク面積 ÷標記化合物のピーク面積)×100
(8-5) (S)-1-(2-ヒドロキシエチル)-4-メチル-N-[4-(メチルスルホニル)フェニル]-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボキサミドのX線回折測定
(8-3)で得られた表記化合物の結晶を、リガク社製 RINT2200V型 X線回折装置を用い、試料をガラス製サンプルホルダに充填し、下記条件にて測定した。得られた結晶の粉末X線回折(CuKα、λ=1.54オングストローム)の回折パターンを図1に、図1において最大ピーク強度を100とした場合の相対強度5以上のピークを表3に示す。
X線:Cu Kα1/40kV/40mA
ゴニオメータ:Ultima+水平ゴニオメータI型
2θ走査範囲:2~45°
(8-6) (S)-1-(2-ヒドロキシエチル)-4-メチル-N-[4-(メチルスルホニル)フェニル]-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボキサミドの示差走査熱量測定法
マック・サイエンス社製 DSC3100型 示差走査熱量測定装置を用い、被検化合物 約5mgを、測定用アルミ製パンに量り取り、パンをオープンの状態で、室温から250℃まで、毎分5℃の昇温速度で昇温して測定した。示差走査熱量測定により得られたDSC曲線図を図2に示した。
(9-1)各種アミン又は各種溶媒による影響
(RS)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸100 mg(319.2 mmol)、種々のアミン(0.5 当量)に室温で種々の溶媒を加えた。室温で約1時間攪拌又は、加熱して約1時間撹拌後、ゆっくりと20~30℃まで冷却し、その温度で約0.5時間撹拌した。その後、結晶を濾過して、得られた湿品結晶を減圧乾燥し、結晶を得た。また、得られた塩のジアステレオマー過剰率を測定した。
(9-2)標記化合物 ジアステレオマー過剰率のHPLC測定方法
標記化合物 約10 mgを採取し、移動相で希釈して20 mLとしたものを試料溶液とした。
移動相 :0.1v/v%酢酸水溶液(蒸留水1000mLに酢酸 1mLを混合して調製):アセトニトリル = 75:25
検出 :UV 220 nm
流速 :約1.0 mL/min
カラム温度:40℃付近の一定温度
測定時間 :約25 min
注入量 :5 μL
標記化合物 (保持時間約14.5 min)、R体 (保持時間約15.5 min)のピーク面積比を用いて下記の式で計算した。
%de ={[(標記化合物(S体)ピーク面積比)-(R体 ピーク面積比)]÷[(標記化合物(S体)ピーク面積比)+(R体ピーク面積比)]}×100
上記アミンにて結晶(ジアステレオマー塩)が得られた系にて、種々検討したところ、キニーネ、 キニジンが所望の絶対配置(S体)を有するジアステレオマー塩、シンコニジンは逆の絶対配置(R体)を有するジアステレオマー塩を与えた。主な結果を表4に示す。
(10-1) (R)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸のラセミ化による(S)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸 キニーネ塩の製造
(実施例7)に記載の(RS)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸の光学分割方法により得られた濾洗液(583.63 g、(R)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸及び(S)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸の含量 22.23 g)を減圧濃縮(75.73 g)した。得られた濃縮液を140~150℃に加熱し、約5時間撹拌後、冷却し、減圧濃縮した(反応液1、40 mL)。
(10-2-1)(R)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸のラセミ化
(実施例7)に記載の(RS)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸の光学分割方法により得られた濾洗液を減圧濃縮した。残渣15.46 g(泡沫状、R体84.6%ee、Net 14.38 g)にN,N-ジメチルホルムアミド(77 mL)を加え、140~145℃に加熱し約6時間撹拌した。その後、室温まで冷却し、水(77 mL)、トルエン(464 mL)を加え抽出し、得られた有機層を水(77 mL)で3回洗浄した。洗浄した有機層を減圧濃縮し(155 mL)、0~5℃へ冷却してその温度で約1時間撹拌した。結晶を濾過して、0~5℃に冷却したトルエン(31 mL)を用いて結晶を洗浄し、得られた湿品結晶を40℃ にて減圧乾燥したところ、(RS)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸を得た(10.70 g、含量95.2%(Net 10.19 g)、0.5%ee、収率70.9%)。含量は(10-2-2)に記載の方法を用いて測定した。
(10-2-2)含量のHPLC測定方法
(R)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸 約25 mgを採取し、移動相で希釈して50 mLとしたものを標準溶液または試料溶液とした。
移動相:A液 アセトニトリル:5 mMりん酸水素二ナトリウム水 = 20:80
B液 アセトニトリル:水 = 80:20
グラジェント組成を表6に示す。
流速 :約1.0 mL/min
カラム温度:40℃付近の一定温度
測定時間 :約30 min
注入量 :5 μL
標記化合物 (保持時間約6.5 min)のピーク面積を用いて下記の式で計算した(絶対検量線法)。
Ws:標準品の重量(mg)、Wt:未知試料の重量(mg)、Qs:標準溶液のピーク面積、Qt:試料溶液のピーク面積、F:標準品の含量(%)
シンコニジン 46.98 g(159.6 mmol)に酢酸エチル(1400 mL)を加えて加熱し、還流撹拌を行っているところに(約78℃)、(RS)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸 50.00 g(159.6 mmol)を加えた。約1時間撹拌後、ゆっくりと20~30℃まで冷却し、その温度で約1時間撹拌した。析出した結晶を濾過して、酢酸エチル(250 mL)を用いて結晶を洗浄し、得られた湿品結晶を40℃にて減圧乾燥したところ、標記化合物の粗生成物 52.73 g を得た(収率 54.4%)。また、得られた塩のジアステレオマー過剰率は71.9%deであった。
1H NMR(400MHz、CDCl3)δ:1.27~1.67(m, 2H)、1.75~2.04(m, 4H)、2.13~2.33(m, 1H)、2.52~2.94(m, 2H)、3.14~3.23(m, 2H)、3.46~4.12(m, 2H)、4.76~5.10(m, 2H)、5.58~5.90(m, 2H)、6.10~6.95(m, 2H)、7.00~8.25(m, 7H)、8.55~9.01(m, 1H).
MS (ESI): 313、294
(12-1) (S)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸
実施例7の製造方法により得られた(S)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸(8α,9R)-6’-メトキシシンコナン-9-オール 10.00 g(16 mmol)にt-ブチルメチルエーテル(90 mL)、水(10 mL)36w/w% 塩酸水(5 mL)を加えて室温で撹拌し、分液した。得られた有機層を減圧濃縮し(30 mL)、酢酸エチル(50 mL)を加え、さらに減圧濃縮し標記化合物を含む溶液を得た(30 mL)。
(12-2) N-{[4-(メチルスルホニル)フェニル]アミノ}オキサミド酸2-((S)-3-メチル-4-{[4-(メチルスルホニル)フェニル]カルバモイル}-2-[2-(トリフルオロメチル)フェニル]-1H-ピロール-1-イル)エチル
酢酸エチル(50 mL)、テトラヒドロフラン(20 mL)及び塩化オキサリル5.18 g(41 mmol)を混合し、0~5℃に冷却した。続いて0~5℃を保ちながら実施例(12-1)で得られた溶液を加え、0~10℃で6時間撹拌した。撹拌後、アセトニトリル(30 mL)およびピリジン0.62 g(8 mmol)を加え、反応液を減圧濃縮し(30 mL)、アセトニトリル(50 mL)を加え、さらに減圧濃縮した(30 mL)。
1H NMR(500MHz、DMSO-d6) δ: 1.94 (s, 3H), 3.19 (s, 3H), 3.20 (s, 3H), 3.81 (t, 1H), 4.12 (t, 1H), 4.45 (t, 2H, J = 5.81 Hz), 7.62 (t, 1H, J = 4.39 Hz), 7.74 (t, 2H, J = 3.68 Hz), 7.86 (dd, 3H), 7.92 (dd, 3H, J = 6.94, 2.13 Hz), 7.97 (dd, 2H, J = 6.80, 1.98 Hz), 8.02 (dd, 2H), 10.03 (s, 1H), 11.19 (s, 1H)
(12-3) (S)-1-(2-ヒドロキシエチル)-4-メチル-N-[4-(メチルスルホニル)フェニル]-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボキサミド(化合物(A))
(12-2)で得られた湿品の結晶に、t-ブチルメチルエーテル(50 mL)、アセトニトリル(10 mL)、48w/w水酸化カリウム水溶液(4 g)と水(50 mL)を加え、15~25℃で約2時間撹拌した。撹拌後、分液し、得られた有機層を減圧濃縮し(30 mL)、エタノール(60 mL)を加え、さらに減圧濃縮した(30 mL)。減圧濃縮終了後、エタノール(14 mL)、水(20 mL)を加えた後、種晶を加え、結晶を晶出させた。約1時間かけて水(50 mL)を滴下後、約1時間攪拌し、結晶を濾過した。その後、結晶を30v/v%エタノール水溶液(10 mL)で洗浄し、40℃で減圧乾燥したところ、標記化合物を結晶で得た(6.36 g、収率87.0%)。また、得られた結晶のエナンチオマー量は0.05%であった。エナンチオマー量は、(実施例8-4)の方法で測定した。
1H NMR(400MHz、CDCl3)δ:1.74(1H,broad singlet)、2.08(3H,s)、3.04(3H,s)、3.63~3.80(4H,m)、7.36(1H,d,J = 7.2 Hz)、7.48(1H,s)、7.58~7.67(2H,m)、7.77~7.90(6H,m).
実施例8で得られた結晶5g、乳糖115g、トウモロコシデンプン58gおよびステアリン酸マグネシウム2gをV型混合機を用いて混合した後、カプセルに180mgずつ充填するとカプセル剤が得られる。
(製剤例2)<錠剤>
実施例8で得られた結晶5g、乳糖90g、トウモロコシデンプン34g、結晶セルロース20gおよびステアリン酸マグネシウム1gをV型混合機を用いて混合した後、1錠当り150mgの質量で錠剤機で打錠すると錠剤が得られる。
(製剤例3)<懸濁剤>
メチルセルロースを精製水に分散、溶解させた分散媒を調製し、実施例8で得られた結晶を乳鉢に量りとり、前述した分散媒を少量ずつ加えながらよく練り合わせ、精製水を加えて懸濁液100gを調製する。
Claims (15)
- 有機溶媒又は有機溶媒と水の混合溶媒中でおこなわれる、請求項1乃至3のいずれか1項に記載の方法。
- 下記式(Ia)
であらわされる(RS)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸の一方のアトロプ異性体を、シンコナン骨格を有する光学活性アミンを用いて分割して取得し、酸性下で光学活性アミンを除去後、塩化オキサリルと反応させることにより、下記中間体化合物 (IIa)
とし、さらに中間体化合物 (IIa)と4-(メチルスルホニル)アニリンと反応させ、中間体化合物(IIIa)
とした後、塩基処理をすることを特徴とする、下記式(A)
であらわされる(S)-1-(2-ヒドロキシエチル)-4-メチル-N-[4-(メチルスルホニル)フェニル]-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボキサミドの製法。
- (S)-1-(2-ヒドロキシエチル)-4-メチル-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボン酸 キニーネ塩。
- 銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折図において、回折角度2θ=6.80、 12.32、 13.60、 14.46、 16.30、 17.06、 18.42、 19.24、 19.86、 20.36、 20.82、 21.84、 22.50、 22.80、 23.20、 23.50、 24.60、 24.88、 25.48、 26.96、 27.52、 29.26、 31.80、 32.08、 35.82、 40.32、および41.36に主要ピークを示す、下記式(A)
で表される(S)-1-(2-ヒドロキシエチル)-4-メチル-N-[4-(メチルスルホニル)フェニル]-5-[2-(トリフルオロメチル)フェニル]-1H-ピロール-3-カルボキサミドの結晶。
- 請求項9又は10に記載された結晶を有効成分として含有する医薬組成物。
- 請求項9又は10に記載された結晶を有効成分として含有する高血圧症、狭心症、急性冠症候群、うっ血性心不全、腎症、動脈硬化症、脳梗塞、繊維症、原発性アルドステロン症又は心疾患の予防薬若しくは治療薬。
- 請求項9又は10に記載された結晶を有効成分として含有する高血圧症の治療薬。
- 請求項9又は10に記載された結晶を有効成分として含有する糖尿病性腎症の治療薬。
- 医薬を製造するための、請求項9又は10のいずれか1項に記載の結晶の使用。
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EP17157692.9A EP3190102B1 (en) | 2013-04-10 | 2014-04-07 | CRYSTAL OF (S)-1-(2-HYDROXYETHYL)-4-METHYL-N- [4-(METHYLSULFONYL)PHENYL]-5-[2-(TRIFLUOROMETHYL)& xA;PHENYL]- 1H-PYRROLE-3-CARBOXAMIDE |
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WO2021167095A1 (ja) * | 2020-02-21 | 2021-08-26 | 大日本住友製薬株式会社 | 光学分割されたトロロックス中間体およびその製造方法 |
WO2022228215A1 (zh) | 2021-04-26 | 2022-11-03 | 广东东阳光药业有限公司 | 吡咯酰胺化合物的制备方法 |
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AU2022248168A1 (en) * | 2021-03-30 | 2023-10-05 | Sunshine Lake Pharma Co., Ltd. | Crystalline form of pyrrole amide compound, preparation method therefor and use thereof |
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