WO2011024874A1 - Sels d'addition avec une base - Google Patents

Sels d'addition avec une base Download PDF

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Publication number
WO2011024874A1
WO2011024874A1 PCT/JP2010/064416 JP2010064416W WO2011024874A1 WO 2011024874 A1 WO2011024874 A1 WO 2011024874A1 JP 2010064416 W JP2010064416 W JP 2010064416W WO 2011024874 A1 WO2011024874 A1 WO 2011024874A1
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degrees
base addition
addition salt
salt according
powder
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PCT/JP2010/064416
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Japanese (ja)
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エム ディアス ペレス ビクトル
ヒル ジェニファー
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日本新薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
    • C07D241/20—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P11/06—Antiasthmatics
    • 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
    • A61P11/08—Bronchodilators
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • 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

Definitions

  • the present invention relates to 2- ⁇ 4- [N- (5,6-diphenylpyrazin-2-yl) -N-isopropylamino] butyloxy ⁇ -N- (methylsulfonyl) acetamide (hereinafter referred to as “Compound A”). Of the novel base addition salt.
  • Compound A has an excellent PGI2 receptor agonistic action, and is known to exhibit various medicinal effects such as platelet aggregation inhibitory action, vasodilatory action, bronchial muscle dilator action, lipid deposition inhibitory action, leukocyte activation inhibitory action, etc. (For example, refer to Patent Document 1). Specifically, Compound A can be used for transient cerebral ischemic attack (TIA), diabetic neuropathy, diabetic gangrene, peripheral circulatory disturbances (eg, chronic arterial occlusion, intermittent claudication, peripheral arterial embolism, vibrations).
  • TIA transient cerebral ischemic attack
  • TIA transient cerebral ischemic attack
  • diabetic neuropathy e.g, diabetic neuropathy
  • diabetic gangrene e.g, peripheral circulatory disturbances (eg, chronic arterial occlusion, intermittent claudication, peripheral arterial embolism, vibrations).
  • Compound A is also known to be useful as an angiogenesis promoter such as gene therapy or autologous bone marrow cell transplantation, and an angiogenesis promoter in peripheral vascular reconstruction or angiogenesis (for example, patents). Reference 1). As described above, although compound A is known to be useful as a therapeutic agent for various diseases, the presence or absence of the salt of compound A is not described.
  • the main object of the present invention is to provide a novel salt of Compound A.
  • Another object of the present invention is to provide a pharmaceutical composition containing the salt as an active ingredient.
  • the present inventors consider the pKa of Compound A and its medicinal use potential, 5 acids (hydrogen chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid) and 14 bases.
  • Examples of the present invention include the following (1) to (22).
  • the diffraction angle 2 ⁇ of the diffraction peak in the present invention should be understood that the obtained value is within the range of the value ⁇ 0.2 degrees, preferably within the range of the value ⁇ 0.1 degrees.
  • the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • the horizontal axis represents the diffraction angle (2 ⁇ [°]). Represents a powder X-ray diffraction spectrum. The horizontal axis represents the diffraction angle (2 ⁇ [°]). Represents a powder X-ray diffraction spectrum. The horizontal axis represents the diffraction angle (2 ⁇ [°]). Represents a powder X-ray diffraction spectrum. The horizontal axis represents the diffraction angle (2 ⁇ [°]). Represents a powder X-ray diffraction spectrum. The horizontal axis represents the diffraction angle (2 ⁇ [°]). Represents a powder X-ray diffraction spectrum. The horizontal axis represents the diffraction angle (2 ⁇ [°]). Represents a powder X-ray diffraction spectrum. The horizontal axis represents the diffraction angle (2 ⁇ [°]). Represents a powder X-ray diffraction spectrum. The horizontal axis represents the diffraction angle (2 ⁇ [°
  • the salt of the present invention is a base addition salt of compound A and a base selected from the group consisting of the following (a) to (d).
  • the salt of the present invention may be an anhydride, hydrate, or solvate. Further, the salt of the present invention may be a crystal.
  • Examples of the t-butylamine salt of Compound A include type I crystals of t-butylamine salt.
  • Type I crystals of t-butylamine salt can be produced, for example, by the method described in Example 1 described later.
  • Examples of the potassium salt of Compound A include potassium salt I-IV crystals.
  • the potassium salt type I crystal can be produced, for example, by the method described in Example 2 described later.
  • Type II crystals of potassium salt can be produced, for example, by the method described in Example 3 described later.
  • the type III crystal of the potassium salt can be produced, for example, by the method described in Example 4 described later.
  • the IV salt crystal of potassium salt can be produced, for example, by the method described in Example 5 described later.
  • Examples of the sodium salt of Compound A include sodium salt type I to V crystals.
  • the sodium salt type I crystal can be produced, for example, by the method described in Example 6 described later.
  • Sodium salt type II crystals can be produced, for example, by the method described in Example 7 described later.
  • Sodium salt type III crystals can be produced, for example, by the method described in Example 8 described later.
  • Sodium salt type IV crystals can be produced, for example, by the method described in Example 9 described later.
  • Sodium salt V-type crystals can be produced, for example, by the method described in Example 10 described later.
  • Examples of the dimethylaminoethanol salt of Compound A include type I and II crystals of dimethylaminoethanol salt.
  • Type I crystals of dimethylaminoethanol salt can be produced, for example, by the method described in Example 11 described later.
  • Type II crystals of dimethylaminoethanol salt can be produced, for example, by the method described in Example 12 described later.
  • a drug or bulk drug with improved hygroscopicity reduces the storage and quality control problems at humidity in its storage state. Moreover, when manufacturing solid preparations, such as a tablet and a capsule, the problem on the preparation based on the weight change of an active ingredient is reduced.
  • solid preparations such as a tablet and a capsule
  • stable storage and easy quality control can be expected, so that certain effects can be expected. It is of high quality and has a form that is industrially easy to handle.
  • Process 1 6-iodo-2,3-diphenylpyrazine can be produced by reacting 6-chloro-2,3-diphenylpyrazine with sodium iodide. This reaction is performed in an organic solvent (for example, ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, or a mixed solvent thereof) in the presence of an acid. Examples of the acid used include acetic acid, sulfuric acid, and mixed acids thereof.
  • the amount of sodium iodide used is, for example, suitably in the range of 1 to 10 moles per mole of 6-chloro-2,3-diphenylpyrazine, preferably 2 to 3 moles. Is within the range.
  • the reaction temperature varies depending on the raw materials used and the type of acid, but is usually within the range of 60 ° C to 90 ° C.
  • the reaction time varies depending on the raw materials to be used, the type of acid, and the reaction temperature, but is usually within the range of 9 to 15 hours.
  • 5,6-Diphenyl-2- [4-hydroxybutyl (isopropyl) amino] pyrazine can be produced by reacting 6-iodo-2,3-diphenylpyrazine with 4-hydroxybutyl (isopropyl) amine. This reaction is performed in the presence of a base in an organic solvent (for example, sulfolane, N-methylpyrrolidone, N, N-dimethylimidazolidinone, dimethyl sulfoxide, or a mixed solvent thereof).
  • a base for example, sulfolane, N-methylpyrrolidone, N, N-dimethylimidazolidinone, dimethyl sulfoxide, or a mixed solvent thereof.
  • the base to be used include sodium hydrogen carbonate, potassium hydrogen carbonate, potassium carbonate, sodium carbonate or a mixed base thereof.
  • the amount of 4-hydroxybutyl (isopropyl) amine used is, for example, suitably within the range of 1.5 mol to 5.0 mol with respect to 1 mol of 6-iodo-2,3-diphenylpyrazine, preferably It is in the range of 2 mol to 3 mol.
  • the reaction temperature varies depending on the raw materials used and the type of base, but is usually within the range of 170 ° C to 200 ° C.
  • the reaction time varies depending on the raw materials and bases used and the reaction temperature, but it is usually within the range of 5 to 9 hours.
  • Compound A can be prepared by reacting 5,6-diphenyl-2- [4-hydroxybutyl (isopropyl) amino] pyrazine with N- (2-chloroacetyl) -methanesulfonamide. This reaction is carried out in an organic solvent (N-methylpyrrolidone, 2-methyl-2-propanol or a mixed solvent thereof) in the presence of a base.
  • organic solvent N-methylpyrrolidone, 2-methyl-2-propanol or a mixed solvent thereof
  • Examples of the base used include potassium t-butoxide, sodium t-butoxide, and mixed bases thereof.
  • the amount of N- (2-chloroacetyl) -methanesulfonamide used is, for example, from 2 mol to 4 mol per mol of 5,6-diphenyl-2- [4-hydroxybutyl (isopropyl) amino] pyrazine.
  • the range is appropriate, preferably in the range of 2 to 3 moles.
  • the reaction temperature varies depending on the raw materials used and the type of base, but is usually within the range of ⁇ 20 ° C. to 20 ° C.
  • the reaction time varies depending on the raw materials and bases used and the reaction temperature, but it is usually within the range of 0.5 to 2 hours.
  • Each compound used as a raw material in the said manufacturing method of compound A is a well-known compound, or can be manufactured according to a well-known method.
  • the salt of the present invention can be obtained, for example, by the following method.
  • the salt of the present invention comprises compound A in an appropriate solvent (for example, an ether solvent (for example, dimethoxyethane, tetrahydrofuran), an ester solvent (for example, isopropyl acetate), an aromatic hydrocarbon (for example, toluene), acetonitrile).
  • an appropriate solvent for example, an ether solvent (for example, dimethoxyethane, tetrahydrofuran), an ester solvent (for example, isopropyl acetate), an aromatic hydrocarbon (for example, toluene), acetonitrile).
  • an appropriate solvent for example, an ether solvent (for example, dimethoxyethane, tetrahydrofuran), an ester solvent (for example, isopropyl acetate), an aromatic hydrocarbon (for example, toluene), acetonitrile).
  • the mixed solution is concentrated, if necessary,
  • ether solvent eg, t-butyl methyl ether
  • ester solvent eg, ethyl acetate
  • aromatic hydrocarbon eg, toluene
  • the amount of the solvent used for dissolving Compound A is, for example, suitably in the range of 10 ml to 300 ml with respect to 1 g of Compound A.
  • the amount of the base used for producing the salt of the present invention is suitably in the range of 0.5 mol to 1.2 mol with respect to 1 mol of compound A, for example.
  • crystallization can be obtained by the method as described in the below-mentioned Example, for example.
  • the salt of the present invention or the pharmaceutical composition of the present invention is used for transient cerebral ischemic attack (TIA), diabetic neuropathy, diabetic gangrene, peripheral circulation disorder (for example, Chronic arterial occlusion, intermittent claudication, peripheral arterial embolism, vibration disease, Raynaud's disease), collagen disease (eg systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitis syndrome), percutaneous coronary angioplasty Re-occlusion / restenosis after surgery (PTCA), arteriosclerosis, thrombosis (eg acute cerebral thrombosis, pulmonary embolism), hypertension, pulmonary hypertension, ischemic disease (eg cerebral infarction, myocardial infarction) , Angina pectoris (eg, stable angina pectoris, unstable angina pectoris), glomerulonephritis, diabetic nephro
  • TIA transient cerebral ischemic attack
  • diabetic neuropathy diabetic
  • renal diseases eg, tubulointerstitial nephritis
  • respiratory diseases eg, interstitial pneumonia (pulmonary fibrosis), chronic obstruction
  • Pulmonary diseases etc.
  • gastrointestinal diseases eg, cirrhosis, viral hepatitis, chronic pancreatitis, Skills gastric cancer
  • cardiovascular diseases eg, myocardial fibrosis
  • bone / joint diseases eg, myelofibrosis, rheumatoid arthritis
  • Skin diseases eg, post-surgical scars, burn scars, keloids, hypertrophic scars
  • obstetric diseases eg, uterine fibroids
  • urological diseases eg, prostatic hypertrophy
  • other diseases eg, Alzheimer's disease, Sclerosis peritonitis, type I diabetes, postoperative organ adhesion
  • erectile dysfunction eg.
  • the salt of the present invention or the pharmaceutical composition of the present invention is also useful as an accelerator for angiogenesis therapy such as gene therapy or autologous bone marrow cell transplantation, and an angiogenesis promoter in peripheral vascular reconstruction or angiogenesis therapy.
  • angiogenesis therapy such as gene therapy or autologous bone marrow cell transplantation
  • angiogenesis promoter in peripheral vascular reconstruction or angiogenesis therapy.
  • the salt of the present invention is used as it is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, within a range of 0.001 to 99.5% by weight. Preferably, it is contained within the range of 0.01% to 90% by weight.
  • the carrier include auxiliaries such as solid, semi-solid or liquid diluents, fillers, and other commonly used excipients. One or more of these can be used.
  • the pharmaceutical composition of the present invention is a solid or liquid dosage unit, and is an orally administered preparation such as powder, capsule, tablet, dragee, granule, powder, suspension, liquid, syrup, elixir, troche, etc. Any form of parenteral preparations such as injections and suppositories can be used. Further, it may be a sustained-release preparation.
  • the powder can be produced by using the salt of the present invention as it is or by making it fine.
  • the powder can be produced by subjecting the salt of the present invention as it is or to an appropriate fineness and then mixing it with a pharmaceutical carrier, for example, an edible carbohydrate such as starch or mannitol.
  • a flavoring agent, a preservative, a dispersing agent, a coloring agent, a fragrance and the like can be optionally added.
  • Capsules can be produced by first filling powdery powders, powders or tablets granulated as described above into gelatin capsules, for example.
  • Lubricants and fluidizing agents such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol are mixed with powdered powders and powders and then filled. Can be manufactured.
  • the fine powder of the salt of the present invention may be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and a surfactant and wrapped in a gelatin sheet to form a soft capsule. Tablets are prepared by adding the excipients of the salt of the present invention as they are or by making them fine to make a powder mixture, granulating or slugging, adding a disintegrating agent or lubricant, and then tableting.
  • the powder mixture may contain a binder (for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol), a dissolution delaying agent (for example, paraffin), Absorbents (for example, quaternary salts), adsorbents (for example, bentonite, kaolin) and the like can be added.
  • a binder for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol
  • a dissolution delaying agent for example, paraffin
  • Absorbents for example, quaternary salts
  • adsorbents for example, bentonite, kaolin
  • a lubricant for example, stearic acid, stearate, talc, mineral oil or the like can be added to the granules thus produced for tableting.
  • a tablet can also be produced by directly compressing the salt of the present invention after mixing it with a fluid inert carrier without going through the granulation step as described above. Film tablets and sugar coatings can be applied to the tablets thus produced.
  • a transparent or translucent protective coating made of shellac coating, a coating of sugar or polymer material, a polishing agent made of wax, or the like can be used.
  • oral dosage forms such as solutions, syrups, troches, elixirs, can also be in dosage unit form so that a given quantity contains a certain amount of a salt of the invention.
  • a syrup can be produced by dissolving the salt of the present invention in an appropriate flavor aqueous solution.
  • An elixir can be produced by using a non-toxic alcoholic carrier.
  • the suspension can be produced by dispersing the salt of the present invention in a non-toxic carrier.
  • solubilizers and emulsifiers for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters
  • preservatives for example, peppermint oil, saccharin
  • flavoring agents for example, peppermint oil, saccharin
  • dosage unit formulations for oral administration can be microencapsulated.
  • the pharmaceutical composition can also be provided with a coating or embedded in a polymer / wax to prolong the action time or provide sustained release.
  • a parenteral preparation can take the form of a liquid dosage unit, for example, a solution or suspension, which is subcutaneously, intramuscularly or intravenously injected.
  • the parenteral preparation is prepared by suspending or dissolving a certain amount of the salt of the present invention in a non-toxic liquid carrier suitable for injection purposes, for example, an aqueous or oily medium, and then sterilizing the suspension or solution.
  • a non-toxic liquid carrier suitable for injection purposes, for example, an aqueous or oily medium, and then sterilizing the suspension or solution.
  • stabilizers, preservatives, emulsifiers, and the like can be added.
  • Suppositories are solids in which the salt of the present invention is soluble or insoluble in low-melting water, for example, polyethylene glycol, cacao butter, semi-synthetic fats and oils [for example, Witepsol (registered trademark)], higher esters (for example, palmitic acid). Myristyl ester) or a mixture thereof.
  • the dose varies depending on the patient's condition such as body weight and age, administration route, nature and degree of illness, etc., but generally, 0.001 mg per day as the amount of the salt of the present invention for adults.
  • the range of ⁇ 100 mg is suitable, and the range of 0.01 mg to 10 mg is preferable. In some cases, this may be sufficient, and vice versa.
  • it can be administered once to several times a day or at intervals of 1 day to several days.
  • the endothermic peak was measured using a differential scanning calorimeter: DSC-50 (manufactured by Shimadzu Corporation) under the following conditions. Temperature increase rate: 10 ° C / min Atmosphere: Nitrogen Measurement temperature range: 30-300 ° C Cell: Aluminum Sealed cell Although the endothermic peak varies slightly depending on the measurement sample, the obtained value should be understood as being within the range of the value ⁇ 2 degrees, preferably within the range of the value ⁇ 1 degree. .
  • 1 H-NMR spectrum was obtained by Bruker DRX400. The 1 H-NMR spectrum data of Compound A used in the following Examples is as follows.
  • the present inventors have selected a base (potassium hydroxide, sodium hydroxide, L-arginine, calcium hydroxide, magnesium hydroxide, choline, L-lysine, a compound selected in consideration of the pKa of Compound A and its medicinal use potential.
  • a base potassium hydroxide, sodium hydroxide, L-arginine, calcium hydroxide, magnesium hydroxide, choline, L-lysine, a compound selected in consideration of the pKa of Compound A and its medicinal use potential.
  • t-Butylamine, ethylenediamine, ammonia, dimethylaminoethanol, N-methylglucamine, tromethamine, hydroxyethylmorpholine and various forms of solvent, temperature, precipitation conditions, etc. .
  • the base addition salts of Compound A shown in Examples 1 to 12 below were found.
  • Example 1 A t-butylamine salt type I crystalline compound A (40 mg) was dissolved in 0.5 mL of dimethoxyethane (hereinafter referred to as “DME”), t-butylamine (1.1 equivalents) was added, and 25 Stir for 18 hours at ° C. Thereafter, t-butyl methyl ether (1 mL) was added to the reaction solution and kept at ⁇ 20 ° C. for 3 hours. The resulting precipitated crystals were collected by filtration and dried under reduced pressure to obtain type I crystals (39.9 mg) of t-butylamine salt.
  • FIG. 1 shows the powder X-ray diffraction spectrum of the I-type crystal of t-butylamine salt obtained using the B apparatus.
  • Example 2 Potassium salt type I crystalline compound A (40 mg) was dissolved in 12 mL of tetrahydrofuran (hereinafter referred to as “THF”), 0.1 M aqueous potassium hydroxide solution (1.1 equivalents) was added, and 40 ° C. And stirred for 15 minutes. Thereafter, the solvent was distilled off under reduced pressure. To the residue was added ethyl acetate (200 ⁇ L). The mixture was heated to 50 ° C. with shaking and allowed to cool to 25 ° C. over 8 hours. This process was repeated two more times and then held at ⁇ 20 ° C. for 3 hours. The resulting precipitated crystals were collected by filtration and dried under reduced pressure to obtain potassium salt type I crystals.
  • THF tetrahydrofuran
  • Example 3 Type II crystalline compound A (40 mg) of potassium salt was dissolved in 12 mL of THF, 0.1 M aqueous potassium hydroxide solution (1.1 equivalent) was added, and the mixture was heated with stirring at 40 ° C. for 15 min. Thereafter, the solvent was distilled off under reduced pressure. To the residue was added ethyl acetate (200 ⁇ L). The mixture was heated to 50 ° C. with shaking and allowed to cool to 25 ° C. over 8 hours. This operation was repeated two more times and then held at ⁇ 20 ° C. for 3 hours. The resulting precipitated crystals were collected by filtration, dried under reduced pressure, and then left in a constant temperature and humidity chamber at 40 ° C. and a relative humidity of 75% for 7 days to obtain type II crystals of potassium salt.
  • FIG. 3 shows a powder X-ray diffraction spectrum of a type II crystal of potassium salt obtained using the B apparatus.
  • Example 4 Acetonitrile (1 mL) was added to type III crystalline compound A (100 mg) of potassium salt and stirred while heating to dissolve compound A, and then cooled to 20 ° C. To the solution was added 3.5M potassium hydroxide / ethanol solution (1.1 equivalent) and stirred at 20 ° C. for 200 minutes. The mixture was heated to 70 ° C. with stirring, stirred for 1 hour, and then cooled to 10 ° C. over 10 hours. The mixture was further heated to 60 ° C. with heating, t-butyl methyl ether (0.3 mL) was added, and the mixture was cooled to 20 ° C. over 10 hours.
  • FIG. 4 shows a powder X-ray diffraction spectrum of a potassium salt type III crystal obtained using an R apparatus. Further, in the differential scanning calorimetry, an endothermic peak was observed around 74 ° C. Elemental analysis value (as C 26 H 31 N 4 O 4 SK + 0.78H 2 O) Calculated value (%) C: 56.91 H: 5.98 N: 10.21 Actual value (%) C: 56.61 H: 5.55 N: 10.36
  • Example 5 Ethyl acetate (1 mL) was added to type IV crystalline compound A (50 mg) of potassium salt and stirred while heating to dissolve compound A, and then cooled to 20 ° C. To the solution was added 3.5M potassium hydroxide / ethanol solution (2.2 equivalents), and the mixture was stirred at 20 ° C. for 23 hours. The resulting precipitated crystals were collected by filtration and dried under reduced pressure to obtain potassium salt IV type crystals (41 mg).
  • FIG. 5 shows a powder X-ray diffraction spectrum of the IV type crystal of the potassium salt obtained using the R apparatus. Further, in the differential scanning calorimetry, an endothermic peak was observed at about 91 ° C.
  • Example 6 Sodium salt type I crystalline compound A (40 mg) was dissolved in 12 mL of acetonitrile, 0.1 M aqueous sodium hydroxide solution (1.1 equivalents) was added, and the mixture was stirred with heating at 40 ° C. for 15 min. Thereafter, the solvent was distilled off under reduced pressure. To the residue was added t-butyl methyl ether (400 ⁇ L). The mixture was heated to 50 ° C. while shaking and allowed to cool to 25 ° C. over 8 hours, and then the mixture was heated to 50 ° C. and allowed to cool to 25 ° C. over 8 hours. Further, the mixture was heated to 50 ° C. and allowed to cool for 2 hours.
  • FIG. 6 shows a powder X-ray diffraction spectrum of a sodium salt type I crystal obtained using the B apparatus. In the differential scanning calorimetry, an endothermic peak was observed at around 96 ° C.
  • Example 7 Sodium salt type II crystalline compound A (40 mg) was dissolved in 12 mL of THF, 0.1 M aqueous sodium hydroxide solution (1.1 equivalents) was added, and the mixture was heated with stirring at 40 ° C. for 15 min. Thereafter, the solvent was distilled off under reduced pressure. Toluene (200 ⁇ L) was added to the residue. The mixture was heated to 50 ° C. with shaking and allowed to cool to 25 ° C. over 8 hours. This operation was repeated two more times and then held at ⁇ 20 ° C. for 3 hours. The resulting precipitated crystals were collected by filtration and dried under reduced pressure to obtain sodium salt type II crystals.
  • Example 8 Sodium salt type III crystalline compound A (40 mg) was dissolved in 12 mL of THF, 0.1 M aqueous sodium hydroxide solution (1.1 equivalents) was added, and the mixture was heated with stirring at 40 ° C. for 15 min. Thereafter, the solvent was distilled off under reduced pressure. Toluene (200 ⁇ L) was added to the residue. The mixture was heated to 50 ° C. with shaking and allowed to cool to 25 ° C. over 8 hours. This operation was repeated two more times and then held at ⁇ 20 ° C. for 3 hours. The resulting precipitated crystals were collected by filtration, dried under reduced pressure, and then left in a constant temperature and humidity chamber at 40 ° C. and a relative humidity of 75% for 3 days to obtain sodium salt type III crystals.
  • FIG. 8 shows a powder X-ray diffraction spectrum of a sodium salt type III crystal obtained using the B apparatus.
  • Example 9 Sodium salt type IV crystalline compound A (40 mg) was dissolved in 12 mL of THF, 0.1 M aqueous sodium hydroxide solution (1.1 equivalents) was added, and the mixture was heated with stirring at 40 ° C. for 15 min. Thereafter, the solvent was distilled off under reduced pressure. Toluene (200 ⁇ L) was added to the residue. The mixture was heated to 50 ° C. with shaking and allowed to cool to 25 ° C. over 8 hours. This operation was repeated two more times and then held at ⁇ 20 ° C. for 3 hours. The resulting precipitated crystals were collected by filtration, dried under reduced pressure, and then left in a constant temperature and humidity chamber at 40 ° C. and a relative humidity of 75% for 7 days to obtain sodium salt type IV crystals.
  • FIG. 9 shows a powder X-ray diffraction spectrum of a sodium salt type IV crystal obtained using the B apparatus.
  • Example 10 Toluene (1 mL) was added to V-form crystal compound A (50 mg) of sodium salt and stirred while heating to dissolve compound A, and then cooled to 20 ° C. A 3.5 M sodium hydroxide / ethanol solution (1.1 equivalent) was added to the solution, and a small amount of sodium salt type IV crystals was added, followed by stirring at 20 ° C. for 17 hours. Thereafter, the solvent was distilled off under reduced pressure. Toluene (0.5 mL) was added to the residue, followed by stirring at 20 ° C. for 17 hours and 30 minutes. The resulting precipitated crystals were collected by filtration and dried under reduced pressure to obtain sodium salt V-type crystals (35 mg). FIG.
  • Example 11 Form I crystalline compound A (40 mg) of dimethylaminoethanol salt was dissolved in 0.5 mL of DME, dimethylaminoethanol (1.1 equivalents) was added, and the mixture was stirred at 25 ° C. for 18 hours. Thereafter, t-butyl methyl ether (1 mL) was added to the reaction solution and kept at ⁇ 20 ° C. for 3 hours. The resulting precipitated crystals were collected by filtration and dried under reduced pressure to obtain type I crystals (30.09 mg) of dimethylaminoethanol salt.
  • FIG. 11 shows an X-ray powder diffraction spectrum of a type I crystal of dimethylaminoethanol salt obtained using the B apparatus.
  • Example 12 A dimethylaminoethanol salt type II crystalline compound A (40 mg) was dissolved in 0.5 mL of DME, dimethylaminoethanol (1.1 equivalents) was added, and the mixture was stirred at 25 ° C. for 18 hours. Thereafter, t-butyl methyl ether (1 mL) was added to the reaction solution and kept at ⁇ 20 ° C. for 3 hours. The resulting precipitated crystals were collected by filtration, dried under reduced pressure, and then allowed to stand in a constant temperature and humidity chamber at 40 ° C. and a relative humidity of 75% for 7 days to obtain type II crystals of dimethylaminoethanol salt.
  • Test Example 1 Study on Formation of Acid Addition Salt of Compound A
  • the present inventors also selected an acid (hydrogen chloride, sulfuric acid, p-toluenesulfonic acid, methane) in consideration of the pKa of Compound A and its pharmaceutical use. Whether to form a salt with compound A using sulfonic acid or benzenesulfonic acid was examined by the following method. Compound A (15 mg) was dissolved in THF (150 ⁇ L) or acetonitrile (150 ⁇ L), 1.1 equivalents of acid was added to Compound A, and the mixture was stirred at room temperature for 1 hour. Thereafter, the mixture was cooled to ⁇ 20 ° C. over 18 hours, and the solvent was slowly distilled off over 48 hours.
  • an acid hydrogen chloride, sulfuric acid, p-toluenesulfonic acid, methane
  • Test Example 2 Study on stability of the salt of the present invention under high humidity conditions To examine the stability of t-butylamine salt, dimethylaminoethanol salt, potassium salt, and sodium salt under high humidity conditions, It was left for 3 to 7 days in a constant temperature and humidity chamber with a humidity of 75%. After standing, the crystal obtained was subjected to structural analysis using a powder X-ray diffractometer (B apparatus) to confirm the crystal form of the crystal. The results are shown in Table 1.

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Abstract

L'invention porte sur de nouveaux sels d'addition avec une base de 2-{4-[N-(5,6-diphénylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(méthylsulfonyl)acétamide (désignés de ce qui suit comme « composé A »). Comme exemple des sels d'addition avec une base mentionnés ci-dessus, un sel d'addition avec une base composé de composé (A) et une base choisie dans le groupe constitué par (a) à (d) peut être cité : (a) t-butylamine ; (b) potassium ; (c) sodium ; et (d) diméthylaminoéthanol.
PCT/JP2010/064416 2009-08-26 2010-08-25 Sels d'addition avec une base WO2011024874A1 (fr)

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CN106008364A (zh) * 2016-05-26 2016-10-12 河北科技大学 一种selexipag的制备方法
CN106316967A (zh) * 2016-08-19 2017-01-11 上海艾康睿医药科技有限公司 西里帕格中间体及西里帕格的制备方法
WO2017042731A1 (fr) 2015-09-10 2017-03-16 Lupin Limited Forme amorphe du sélexipag et dispersion solide associée
WO2017168401A1 (fr) 2016-04-01 2017-10-05 Honour (R&D) Procédé de préparation de dérivés de diphénylpyrazine
WO2018015974A1 (fr) * 2016-07-20 2018-01-25 Mylan Laboratories Limited Formes polymorphes de sélexipag et dispersion solide amorphe de sélexipag
WO2018162527A1 (fr) 2017-03-08 2018-09-13 Actelion Pharmaceuticals Ltd Composition pharmaceutique comprenant du sélexipag
WO2019154363A1 (fr) 2018-02-07 2019-08-15 南京明德新药研发有限公司 Agoniste du récepteur de la prostacycline
WO2020249602A1 (fr) 2019-06-11 2020-12-17 Actelion Pharmaceuticals Ltd Procédés de traitement de l'hypertension artérielle pulmonaire
WO2021033702A1 (fr) * 2019-08-19 2021-02-25 Nippon Shinyaku Co., Ltd. Sel
WO2021078835A1 (fr) 2019-10-23 2021-04-29 Actelion Pharmaceuticals Ltd Composition pharmaceutique comprenant du sélexipag
WO2021105331A1 (fr) 2019-11-29 2021-06-03 Actelion Pharmaceuticals Ltd Méthodes de traitement de l'hypertension artérielle pulmonaire
WO2021152060A1 (fr) 2020-01-31 2021-08-05 Actelion Pharmaceuticals Ltd Composition de sélexipag à libération contrôlée
WO2021156227A1 (fr) 2020-02-03 2021-08-12 Actelion Pharmaceuticals Ltd Méthodes de traitement et d'évaluation de l'hypertension artérielle pulmonaire au moyen de sélexipag
WO2022106621A1 (fr) 2020-11-20 2022-05-27 Actelion Pharmaceuticals Ltd Sélexipag destiné à être utilisé par l'intermédiaire d'une administration intracôlon
WO2022162158A1 (fr) 2021-01-29 2022-08-04 Actelion Pharmaceuticals Ltd Composition pharmaceutique comprenant un dérivé de diphénylpyrazine
WO2022162163A1 (fr) 2021-01-29 2022-08-04 Actelion Pharmaceuticals Ltd Procédé de fabrication d'un dérivé de diphénylpyrazine
WO2022238375A1 (fr) 2021-05-11 2022-11-17 Actelion Pharmaceuticals Ltd Méthodes de traitement de l'hypertension pulmonaire
WO2023131608A1 (fr) 2022-01-04 2023-07-13 Actelion Pharmaceuticals Ltd Compositions à libération contrôlée
WO2023214059A1 (fr) 2022-05-06 2023-11-09 Actelion Pharmaceuticals Ltd Composés de diphénylpyrazine utilisés en tant que promédicaments
WO2024017964A1 (fr) 2022-07-20 2024-01-25 Actelion Pharmaceuticals Ltd Composition pharmaceutique injectable comprenant un dérivé de diphénylpyrazine

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WO2017042731A1 (fr) 2015-09-10 2017-03-16 Lupin Limited Forme amorphe du sélexipag et dispersion solide associée
EP3436439B1 (fr) 2016-04-01 2022-02-16 Honour (R&D) Procédé de préparation de dérivés de diphénylpyrazine
WO2017168401A1 (fr) 2016-04-01 2017-10-05 Honour (R&D) Procédé de préparation de dérivés de diphénylpyrazine
EP3436439A4 (fr) * 2016-04-01 2020-04-15 Honour (R&D) Procédé de préparation de dérivés de diphénylpyrazine
CN106008364A (zh) * 2016-05-26 2016-10-12 河北科技大学 一种selexipag的制备方法
WO2018015974A1 (fr) * 2016-07-20 2018-01-25 Mylan Laboratories Limited Formes polymorphes de sélexipag et dispersion solide amorphe de sélexipag
CN106316967B (zh) * 2016-08-19 2019-02-05 上海艾康睿医药科技有限公司 西里帕格中间体及西里帕格的制备方法
CN106316967A (zh) * 2016-08-19 2017-01-11 上海艾康睿医药科技有限公司 西里帕格中间体及西里帕格的制备方法
WO2018162527A1 (fr) 2017-03-08 2018-09-13 Actelion Pharmaceuticals Ltd Composition pharmaceutique comprenant du sélexipag
WO2019154363A1 (fr) 2018-02-07 2019-08-15 南京明德新药研发有限公司 Agoniste du récepteur de la prostacycline
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WO2020249602A1 (fr) 2019-06-11 2020-12-17 Actelion Pharmaceuticals Ltd Procédés de traitement de l'hypertension artérielle pulmonaire
WO2021033702A1 (fr) * 2019-08-19 2021-02-25 Nippon Shinyaku Co., Ltd. Sel
WO2021078835A1 (fr) 2019-10-23 2021-04-29 Actelion Pharmaceuticals Ltd Composition pharmaceutique comprenant du sélexipag
WO2021105331A1 (fr) 2019-11-29 2021-06-03 Actelion Pharmaceuticals Ltd Méthodes de traitement de l'hypertension artérielle pulmonaire
WO2021152060A1 (fr) 2020-01-31 2021-08-05 Actelion Pharmaceuticals Ltd Composition de sélexipag à libération contrôlée
WO2021156227A1 (fr) 2020-02-03 2021-08-12 Actelion Pharmaceuticals Ltd Méthodes de traitement et d'évaluation de l'hypertension artérielle pulmonaire au moyen de sélexipag
WO2022106621A1 (fr) 2020-11-20 2022-05-27 Actelion Pharmaceuticals Ltd Sélexipag destiné à être utilisé par l'intermédiaire d'une administration intracôlon
WO2022162158A1 (fr) 2021-01-29 2022-08-04 Actelion Pharmaceuticals Ltd Composition pharmaceutique comprenant un dérivé de diphénylpyrazine
WO2022162163A1 (fr) 2021-01-29 2022-08-04 Actelion Pharmaceuticals Ltd Procédé de fabrication d'un dérivé de diphénylpyrazine
WO2022238375A1 (fr) 2021-05-11 2022-11-17 Actelion Pharmaceuticals Ltd Méthodes de traitement de l'hypertension pulmonaire
WO2023131608A1 (fr) 2022-01-04 2023-07-13 Actelion Pharmaceuticals Ltd Compositions à libération contrôlée
WO2023214059A1 (fr) 2022-05-06 2023-11-09 Actelion Pharmaceuticals Ltd Composés de diphénylpyrazine utilisés en tant que promédicaments
WO2024017964A1 (fr) 2022-07-20 2024-01-25 Actelion Pharmaceuticals Ltd Composition pharmaceutique injectable comprenant un dérivé de diphénylpyrazine

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