WO2005116013A1 - Cristal de composé pharmaceutique - Google Patents

Cristal de composé pharmaceutique Download PDF

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Publication number
WO2005116013A1
WO2005116013A1 PCT/JP2005/009751 JP2005009751W WO2005116013A1 WO 2005116013 A1 WO2005116013 A1 WO 2005116013A1 JP 2005009751 W JP2005009751 W JP 2005009751W WO 2005116013 A1 WO2005116013 A1 WO 2005116013A1
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WO
WIPO (PCT)
Prior art keywords
crystal
crystals
compound
phenyl
acid
Prior art date
Application number
PCT/JP2005/009751
Other languages
English (en)
Japanese (ja)
Inventor
Ikutaro Sugimoto
Norio Iwano
Original Assignee
Takeda Pharmaceutical Company Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Pharmaceutical Company Limited filed Critical Takeda Pharmaceutical Company Limited
Publication of WO2005116013A1 publication Critical patent/WO2005116013A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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

Definitions

  • the present invention relates to a pharmaceutical compound, specifically, (S) -8- [4- (2 butoxyethoxy) phenyl] 1 isobutyl N— (4 — ⁇ [(1 propyl 1 H imidazole 5 yl) ) Methyl] sulfiel ⁇ phenyl) -1-1,2,3,4-tetrahydro-1-benzazosin-5-carboxamide (hereinafter sometimes referred to as compound I).
  • compound I a pharmaceutical compound, specifically, (S) -8- [4- (2 butoxyethoxy) phenyl] 1 isobutyl N— (4 — ⁇ [(1 propyl 1 H imidazole 5 yl) ) Methyl] sulfiel ⁇ phenyl) -1-1,2,3,4-tetrahydro-1-benzazosin-5-carboxamide
  • Compound I and the monomethanesulfonate of compound I are both pharmaceutical compounds having CCR5 antagonistic activity. These are known compounds disclosed in WO 03Z014105 pamphlet (Patent Document 1). However, while crystals of monomethanesulfonate of Compound I have been obtained (Patent Document 1), crystals of Compound I have not been obtained so far.
  • Patent Document 1 International Publication No. 03Z014105 pamphlet
  • an object of the present invention is to provide a crystal of Compound I and the like.
  • the crystal according to the above (1) having a peak;
  • a crystal of Compound I can be obtained.
  • the crystals have high purity, high quality, and high stability, and can be used as a medicine as such. Also, when used as a raw material for monomethanesulfonate, a purification effect by crystallization can be expected.
  • FIG. 1 is an X-ray powder diffraction pattern of crystal A.
  • FIG. 2 is a powder X-ray diffraction pattern of crystal A ′.
  • FIG. 3 is an X-ray powder diffraction pattern of crystal B.
  • FIG. 4 is an HPLC chart of crystal A.
  • crystal is used in its ordinary meaning, and refers to a solid having a spatially ordered atomic arrangement. Even if the same compound is used, a plurality of crystals having different spatially regular atomic arrangement and different physical properties may be produced (polymorphism). Any of these polymorphs may be used, and a mixture of two or more polymorphs may be used. Further, the crystals of the present invention may be solvates or hydrates.
  • Compound I can be produced, for example, by the method described in WO 03Z014105 pamphlet or a method analogous thereto.
  • Crystals of compound I can be obtained by a method such as mixing a solution of compound I with a poor solvent, cooling the solution, or concentrating the solution.
  • a method of mixing a poor solvent with a solution of compound I in a suitable solvent is preferred.
  • the solvent in the “solution of compound I” are not particularly limited as long as it is a good solvent for compound I, but esters (eg, ethyl acetate), nitriles (eg, acetonitrile), alcohols (eg, , Methanol, ethanol), ketones (eg, acetone), aromatic hydrocarbons (eg, toluene), ethers (eg, tetrahydrofuran, isopropyl ether,
  • the powerful solvent may be a water-containing solvent.
  • ethanol tetrahydrofuran and acetone are preferred, and ethyl acetate is particularly preferred.
  • aceto nitrile or acetone is preferred.
  • Examples of the “poor solvent” are not particularly limited as long as they are poor solvents for compound I, and include saturated hydrocarbons (eg, n-hexane) and the like. Among them, n-xane is preferable.
  • the “solution of the compound I” is described, for example, in WO 03Z014105 pamphlet.
  • the crystallization may be promoted by adding a seed crystal, physical stimulation (eg, ultrasonic stimulation), cooling, etc., if necessary.
  • a preferable cooling temperature is about 0 ° C to about 5 ° C.
  • the precipitated crystals can be isolated by a known method such as filtration, centrifugation, or decanter method.
  • the isolated crystals can be dried by a known method such as air drying.
  • the crystals isolated before drying may be washed with a suitable solvent.
  • crystal A in this specification One form of the crystal of the present invention (may be referred to as crystal A in this specification) obtained by the above method or the like has the following physicochemical properties.
  • a force having characteristic peaks at 20 about 6.0 °, about 15.0 °, about 16.2 °, and about 17.4 ° in the powder X-ray diffraction spectrum, or FIG. It has a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction spectrum shown in FIG.
  • the melting point measured by a differential operation calorimeter is about 123 ° C to about 128 ° C.
  • crystal B Another form of the crystal of the present invention obtained by the above method or the like (hereinafter sometimes referred to as crystal B) has the following physical properties.
  • the melting point measured by a differential operation calorimeter is about 128 ° C to about 130 ° C.
  • the crystals of the present invention preferably have an area ratio of the peak of the substance of about 4 minutes to the peak of the compound I in HPLC analysis under the following conditions of less than 0.1%.
  • the crystals of the present invention have excellent CCR antagonism, particularly CCR5 and Z or CCR2 antagonism, especially strong CCR5 antagonism, so that the prevention and treatment of HIV infections in humans, such as AIDS, It can be used for prevention and treatment of various other diseases.
  • the crystal of the present invention may be used as a pharmaceutical as it is, or a pharmaceutical composition comprising the crystal of the present invention and a pharmaceutically acceptable carrier (e.g., tablet, Solid preparations such as capsules, granules and powders; or liquid preparations such as syrups and injections).
  • the crystal of the present invention or the pharmaceutical composition of the present invention may be used in combination with another drug depending on the type of the target disease.
  • Such drugs may be formulated separately with the crystals of the present invention or with the crystals of the present invention.
  • the drugs When the drugs are formulated separately, they can be mixed and administered separately at the time of use.However, the separately formulated products can be mixed at the same time or separately at different times. It may be administered to a subject.
  • Kit products for administration of separately formulated products at the time of use e.g., an ampoule containing a powdered individual drug and a diluent for mixing and dissolving two or more drugs at the time of use
  • Kit products for administering the same subject separately or separately at the same time or separately at different times for example, containing individual drugs.
  • Kit products for administering the same subject separately or separately at the same time or separately at different times for example, containing individual drugs.
  • Put tablets in the same or separate bags and, if necessary, provide a column for the time of drug administration, such as a tablet kit for administering two or more tablets simultaneously or separately at different times are also included in the pharmaceutical composition of the present invention.
  • the dose of the crystal of the present invention or the pharmaceutical composition of the present invention can be appropriately selected from the administration subject, age and weight of the administration subject, symptoms, administration time, administration method, dosage form, and the like. it can.
  • the dosage for a particular patient may vary depending on age, weight, general health, sex, diet, time of administration, mode of administration, rate of excretion, and the extent of the condition the patient is treating at the time. Is determined in consideration of other factors.
  • the dosage varies depending on the patient's condition, body weight, and administration method.
  • a salt of compound I can be produced from the crystals of the present invention using a conventional method.
  • Preferred pharmacologically acceptable salts are pharmacologically acceptable salts, such as salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and basic or acidic amino acids. And the like.
  • the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt, ammonium salt and the like.
  • No. Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine.
  • salts with min and the like Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p — Salts with toluenesulfonic acid and the like.
  • salts with a basic amino acid include, for example, salts with arginine, lysine, or-tin
  • salts with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Salt.
  • a desired salt can be produced by adding the above-mentioned base or acid to a solution of the crystals of the present invention dissolved in the above-mentioned solvent.
  • the concentrated residue was extracted with 450 mL of ethyl acetate, and the extracted ethyl acetate layer was washed successively with 225 mL of water, 450 mL of saturated aqueous sodium bicarbonate, 450 mL of water, and 225 mL of water, and allowed to stand overnight.
  • the ethyl acetate extract was fractionated, the solvent was distilled off from the extract under reduced pressure with a 1 L 4-necked kolben, the residual oil was suspended in 225 mL of ethyl acetate, and concentrated again. This operation was repeated once.
  • n-heptane 1: 1 450 mL and n-heptane 45 mL cooled to 5 ° C. or lower sequentially.
  • the washed crystals (77.04 g) were taken out and dried at 40 ° C. for 10 hours or more to obtain Compound I crystals (Crystal A) in a yield of 63.97 g and an HPLC area of 99.02%.
  • the melting point of the crystals measured by a differential operation calorimeter was 126.4 ° C.
  • Figure 1 shows the powder X-ray diffraction pattern of this crystal.
  • Crystals were collected by suction filtration and washed with ethyl acetate-n-heptane (1: 1) 110 mL. The crystals were dried under vacuum at 40 ° C., and a crystal of Compound I (crystal ⁇ ′) was obtained in a yield of 50.4 g and an HPLC area of 99.7%. The melting point of the crystals measured by a differential operation calorimeter was 127.9 ° C. Fig. 2 shows the powder X-ray diffraction pattern of this crystal.
  • the HPLC analysis chart of the crystals is shown in FIG. The HPLC analysis was performed under the same conditions as in Example 1.
  • the organic layer was washed sequentially with 45 L of water, 90 L of a 10% aqueous solution of sodium bicarbonate, 90 L of water and 45 L of water, and ethyl acetate was distilled off under reduced pressure. 45 L of acetonitrile was added, and the solvent was replaced. Again, 45 L of acetonitrile was added and the solvent was replaced to obtain a crystal of Compound I.
  • the following (1), (2), (3) and (4) are mixed and granulated.
  • (5) and (6) are added to the granules and pressed into tablets (mantol, microcrystalline cellulose, hydroxypropyl cellulose, magnesium stearate, titanium oxide, macrogol 6000, iron sesquioxide All of them are compliant with the 14th revision of the Japanese Pharmacopoeia).
  • An aqueous solution in which the following (7) and (9) are dissolved or dispersed, and an aqueous suspension in which the (8) and (10) are dispersed are mixed, and the obtained press-molded product is coated.
  • Croscarmellose sodium (trade name AXIDISOL) 15mg
  • a 1 L 4-necked corben is charged with 70.Og (0.1 mol) of compound I and 420 mL of acetonitrile, and dissolved by heating at 40 ° C to 50 ° C on a water bath, and then 3.5 g of activated carbon (5wZw% ) Was added and the mixture was stirred at the same temperature for 5 minutes. Next, the dissolved and decolorized solution was subjected to suction filtration with filter paper (No. 5C), and the filter was washed with 21 OmL of ethyl acetate.
  • the crystallization liquid was stirred at room temperature (about 25 ° C) for 6 hours, cooled with ice water, and aged at 5 ° C or less for 6 hours.
  • the precipitated crystals were collected by filtration under a nitrogen purge, and the crystals were washed with 210 mL of room temperature ethyl acetate.
  • the obtained wet crystals were dried at 40 ° C until a constant weight was obtained, yielding 76.2 g, yield 95.7%, chemical purity 99.01%, optical purity 99.96% ee, and moisture 0.36%. Obtained.
  • crystals of the present invention and the pharmaceutical composition of the present invention are useful as pharmaceuticals, particularly as agents for preventing and treating AIDS.

Abstract

Il est exposé un cristal de (S)-8-[4-(2-butoxyéthoxy)phényl]-1-isobutyl-N-(4-{[(1-propyl-1H-imidazol-5-yl)méthyl]sulfinyl}phényl)-1,2,3,4-tétrahydro-1-benzazocine-5-carboxamide.
PCT/JP2005/009751 2004-05-28 2005-05-27 Cristal de composé pharmaceutique WO2005116013A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2004-158842 2004-05-28
JP2004158842A JP2007269628A (ja) 2004-05-28 2004-05-28 医薬化合物の結晶

Publications (1)

Publication Number Publication Date
WO2005116013A1 true WO2005116013A1 (fr) 2005-12-08

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JP (1) JP2007269628A (fr)
WO (1) WO2005116013A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006059716A1 (fr) * 2004-12-03 2006-06-08 Takeda Pharmaceutical Company Limited Preparation solide
WO2008093853A1 (fr) * 2007-01-29 2008-08-07 Eisai R & D Management Co., Ltd. Solide de composé de macrolide, son procédé de fabrication et composition pharmaceutique le comprenant
US7893068B2 (en) 2002-05-29 2011-02-22 Mercian Corporation Physiologically active substances
WO2021133811A1 (fr) 2019-12-26 2021-07-01 Teva Pharmaceuticals International Gmbh Formes solides de cenicriviroc et leur procédé de préparation

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2017008280A (es) * 2014-12-23 2017-12-07 Tobira Therapeutics Inc Proceso para elaborar cenicriviroc y analogos relacionados.
WO2017223155A1 (fr) * 2016-06-21 2017-12-28 Tobira Therapeutics, Inc. Céniriviroc purifié et intermédiaires purifiés pour la production de cénicriviroc
BR112019003987A2 (pt) * 2016-08-31 2019-05-28 Tobira Therapeutics Inc formas sólidas de mesilato de cenicriviroc e processos de produção das formas sólidas de mesilato de cenicriviroc

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003076411A1 (fr) * 2002-03-12 2003-09-18 Takeda Pharmaceutical Company Limited Procede de production d'un derive sulfoxyde actif sur le plan optique
JP2003335776A (ja) * 2001-08-08 2003-11-28 Takeda Chem Ind Ltd 二環性化合物、その製造法および用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003335776A (ja) * 2001-08-08 2003-11-28 Takeda Chem Ind Ltd 二環性化合物、その製造法および用途
WO2003076411A1 (fr) * 2002-03-12 2003-09-18 Takeda Pharmaceutical Company Limited Procede de production d'un derive sulfoxyde actif sur le plan optique

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7893068B2 (en) 2002-05-29 2011-02-22 Mercian Corporation Physiologically active substances
WO2006059716A1 (fr) * 2004-12-03 2006-06-08 Takeda Pharmaceutical Company Limited Preparation solide
WO2008093853A1 (fr) * 2007-01-29 2008-08-07 Eisai R & D Management Co., Ltd. Solide de composé de macrolide, son procédé de fabrication et composition pharmaceutique le comprenant
US7790887B2 (en) 2007-01-29 2010-09-07 Eisai R&D Management Co., Ltd. Macrolide compound in solid form, process for preparation thereof, and pharmaceutical composition containing the same
WO2021133811A1 (fr) 2019-12-26 2021-07-01 Teva Pharmaceuticals International Gmbh Formes solides de cenicriviroc et leur procédé de préparation

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