WO2005116013A1 - Crystal of pharmaceutical compound - Google Patents

Crystal of pharmaceutical compound Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
crystal
crystals
compound
phenyl
acid
Prior art date
Application number
PCT/JP2005/009751
Other languages
French (fr)
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/en

Links

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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Virology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Disclosed is a crystal of (S)-8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-(4-{[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide.

Description

医薬化合物の結晶  Pharmaceutical compound crystals
技術分野  Technical field
[0001] 本発明は、医薬化合物、具体的には（S) -8- [4- (2 ブトキシエトキシ)フエ- ル] 1 イソブチル N— (4— { [ ( 1 プロピル 1 H イミダゾール 5 ィル）メ チル]スルフィエル }フエ-ル）一 1, 2, 3, 4—テトラヒドロ一 1—ベンズァゾシン一 5— カルボキサミド (本明細書中、化合物 Iと称する場合がある。）の結晶等に関する。 背景技術  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). Background art
[0002] 化合物 Iおよび化合物 Iのモノメタンスルホン酸塩は、いずれも CCR5アンタゴ-スト 活性を有する医薬化合物である。これらは、国際公開第 03Z014105号パンフレット (特許文献 1)に開示されている公知の化合物である。しかし、化合物 Iのモノメタンス ルホン酸塩の結晶は得られているのに対し (特許文献 1)、化合物 Iの結晶はこれまで 得られていなかった。  [0002] 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.
特許文献 1：国際公開第 03Z014105号パンフレット  Patent Document 1: International Publication No. 03Z014105 pamphlet
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0003] 化合物 Iの安定な結晶が得られれば、それ自体を医薬の有効成分として利用する 場合の取り扱いが容易になる。また、モノメタンスルホン酸塩の原料として用いる場合 にも、結晶化による精製効果が期待できる。さら〖こ、モノメタンスルホン酸塩の製造ェ 程の省力化が期待できる。したがって、本発明は、化合物 Iの結晶等を提供すること を目的とする。 [0003] If stable crystals of Compound I can be obtained, the handling of the compound itself as an active ingredient of a drug becomes easy. Also, when used as a raw material for monomethanesulfonate, a purification effect by crystallization can be expected. In addition, labor saving in the production process of monomethanesulfonate can be expected. Therefore, an object of the present invention is to provide a crystal of Compound I and the like.
課題を解決するための手段  Means for solving the problem
[0004] 本発明者らは、鋭意検討の結果、化合物 Iの酢酸ェチル溶液に n ヘプタンを添加 することにより初めて化合物 Iの結晶を得ることに成功し、さらなる研究により、本発明 を完成させるに至った。 As a result of intensive studies, the present inventors succeeded in obtaining a crystal of Compound I for the first time by adding n-heptane to a solution of Compound I in ethyl acetate, and by further study, completed the present invention. Reached.
すなわち、本発明は、  That is, the present invention
(1) (S)— 8— [4一（2 ブトキシエトキシ）フ -ル] 1 イソブチルー N— [4一 [ [ (1 プロピル 1H—イミダゾールー 5 ィル）メチル]スルフィエル]フエ-ル] 1, 2, 3, 4—テトラヒドロー 1—ベンズァゾシン一 5—カルボキサミドの結晶； (1) (S) —8— [4- (2-butoxyethoxy) fur] 1 isobutyl-N— [4- [ [(1 propyl 1H-imidazole-5-yl) methyl] sulfiel] phenyl] 1,2,3,4-tetrahydro-1-benzazosin-5-carboxamide crystal;
(2)粉末 X線回折スぺク卜ノレ【こお!ヽて、 2 Θ =約 6. 0° 、約 15. 0° 、約 16. 2° 、 および約 17. 4° に特徴的なピークを有する上記（1)に記載の結晶；  (2) X-ray powder diffraction pattern [2! = 2 ° = about 6.0 °, about 15.0 °, about 16.2 °, and about 17.4 ° The crystal according to the above (1) having a peak;
(3)粉末 X線回折スぺク卜ノレ【こお!ヽて、 2 Θ =約 6. 0° 、約 15. 0° 、約 15. 7° 、 および約 17. 4° に特徴的なピークを有する上記（1)に記載の結晶；  (3) Powder X-ray diffraction spectrum (2) = 2 ° = about 6.0 °, about 15.0 °, about 15.7 °, and about 17.4 ° The crystal according to the above (1) having a peak;
(4)融点が約 123°C〜約 128°Cである上記（1)記載の結晶；  (4) The crystal according to the above (1), having a melting point of about 123 ° C to about 128 ° C;
(5)融点が約 128°C〜約 130°Cである上記（1)記載の結晶；  (5) The crystal according to the above (1), which has a melting point of about 128 ° C to about 130 ° C;
(6) (S) 8— [4一（2 ブトキシエトキシ）フ ニル]一 1一イソブチルー N— [4— [ [ (1 プロピル 1H—イミダゾールー 5 ィル）メチル]スルフィエル]フエ-ル] 1, 2, 3, 4—テトラヒドロ一 1—ベンズァゾシン一 5—カルボキサミドのァセトニトリルまた はアセトン溶液に、貧溶媒を添加することを特徴とする上記（3)または（5)記載の結 晶の製造方法；  (6) (S) 8— [4- (2-butoxyethoxy) phenyl] 1-11-isobutyl-N— [4 -— [[(1-Propyl 1H-imidazole-5-yl) methyl] sulfiel] phenyl] 1, A method for producing crystals according to the above (3) or (5), wherein a poor solvent is added to a solution of 2,3,4-tetrahydro-11-benzazosin-15-carboxamide in acetonitrile or acetone;
(7)上記（1)記載の結晶を溶解させた溶液に酸を添加することを特徴とする（S)— 8— [4一（2 ブトキシエトキシ）フエ-ル] 1 イソブチル N— [4 [ [ ( 1 プロピ ルー 1H—イミダゾールー 5 ィル）メチル]スルフィエル]フエ-ル ] 1, 2, 3, 4ーテ トラヒドロ 1 ベンズァゾシン 5 カルボキサミドの酸との塩の製造方法；  (7) An acid is added to the solution in which the crystals described in (1) are dissolved, and (S) -8- [4- (2-butoxyethoxy) phenyl] 1isobutyl N— [4 [ [(1 propyl 1H-imidazole-5-yl) methyl] sulfiel] phenyl] 1,2,3,4-tetrahydro 1-benzazosin 5 A method for producing a salt of carboxamide with an acid;
(8)上記（1)記載の結晶を溶解させた溶液にメタンスルホン酸を添加することを特 徴とする（S) 8— [4— (2—ブトキシエトキシ）フエ-ル] 1—イソブチル—N— [4 — [ [ ( 1 プロピル 1H イミダゾール 5 ィル）メチル]スルフィエル]フエ-ル] —1, 2, 3, 4—テトラヒドロ一 1—ベンズァゾシン一 5—カルボキサミド メタンスルホン 酸塩の製造方法；  (8) Methanesulfonic acid is added to the solution in which the crystal described in (1) above is dissolved. (S) 8- [4- (2-butoxyethoxy) phenyl] 1-isobutyl N— [4 — [((1 propyl 1H imidazole 5yl) methyl] sulfiel] phenyl] -1,2,3,4-tetrahydro-1-benzazosin-1 5-carboxamide methanesulfonate;
(9)上記（1)記載の結晶を含有する医薬組成物；  (9) a pharmaceutical composition comprising the crystal according to (1);
などを提供するものである。 And so on.
発明の効果 The invention's effect
本発明によれば、化合物 Iの結晶を得ることができる。当該結晶は、高純度、高品質 、高安定性であり、それ自体を医薬として利用することができる。また、モノメタンスル ホン酸塩の原料として用いる場合にも、結晶化による精製効果が期待できる。 図面の簡単な説明 According to the present invention, 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. Brief Description of Drawings
[0006] [図 1]結晶 Aの粉末 X線回折パターンである。  FIG. 1 is an X-ray powder diffraction pattern of crystal A.
[図 2]結晶 A'の粉末 X線回折パターンである。  FIG. 2 is a powder X-ray diffraction pattern of crystal A ′.
[図 3]結晶 Bの粉末 X線回折パターンである。  FIG. 3 is an X-ray powder diffraction pattern of crystal B.
[図 4]結晶 A，の HPLCチャートである。  FIG. 4 is an HPLC chart of crystal A.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0007] 本明細書中、「結晶」なる語は、通常の意味で用いられ、空間的に規則的な原子配 列を有する固体を意味する。同じィ匕合物であっても、空間的に規則的な原子配列お よび物理ィ匕学的性質が異なる複数の結晶が生成することがある (結晶多形)が、本発 明の結晶は、これら結晶多形のいずれであってもよぐ 2以上の結晶多形の混合物で あってもよい。また、本発明の結晶は、溶媒和物または水和物であってもよい。 [0007] In the present specification, the term "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.
化合物 Iは、例えば国際公開第 03Z014105号パンフレットに記載の方法またはこ れに準じた方法により製造することができる。  Compound I can be produced, for example, by the method described in WO 03Z014105 pamphlet or a method analogous thereto.
化合物 Iの結晶は、化合物 Iの溶液に貧溶媒を混合すること、当該溶液を冷却する こと、または当該溶液を濃縮すること等の方法により得ることができる。  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.
なかでも、適当な溶媒中の化合物 Iの溶液に貧溶媒を混合する方法が好ましい。 当該「化合物 Iの溶液」における溶媒の例としては、化合物 Iの良溶媒であれば特に 限定されないが、エステル類 (例、酢酸ェチル）、二トリル類 (例、ァセトニトリル）、アル コール類 (例、メタノール、エタノール)、ケトン類 (例、アセトン)、芳香族炭化水素類（ 例、トルエン）、エーテル類（例、テトラヒドロフラン、イソプロピルエーテル、および 1, Of these, a method of mixing a poor solvent with a solution of compound I in a suitable solvent is preferred. Examples of 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,
2—ジメトキシェタン）、ならびにこれらの混合物等が挙げられる。また、力かる溶媒は 、含水溶媒であってもよい。なかでも、好ましくはエタノール、テトラヒドロフランおよび アセトン、特に好ましくは酢酸ェチルである。特に、下記の結晶 Bを得るには、ァセト 二トリルまたはアセトンが好まし 、。 2-dimethoxyethane), and mixtures thereof. The powerful solvent may be a water-containing solvent. Of these, ethanol, tetrahydrofuran and acetone are preferred, and ethyl acetate is particularly preferred. Particularly, in order to obtain the following crystal B, aceto nitrile or acetone is preferred.
当該「貧溶媒」の例としては、化合物 Iの貧溶媒であれば特に限定されないが、飽和 炭化水素類 (例、 n キサン)等が挙げられる。なかでも、好ましくは n キサンで ある。  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.
当該「ィ匕合物 Iの溶液」は、例えば、国際公開第 03Z014105号パンフレットに記載 の製造方法またはこれに準じた方法等に従って得られる反応液または当該反応液ま たはその濃縮液として、または化合物 Iの油状物もしくは結晶等を上記のような溶媒 に溶解した溶液として得ることができる。 The “solution of the compound I” is described, for example, in WO 03Z014105 pamphlet. A reaction solution obtained according to the method for producing or a method analogous thereto, or a reaction solution or a concentrated solution thereof, or a solution in which an oily substance or crystals of Compound I is dissolved in a solvent as described above. it can.
結晶化は必要に応じて、種結晶の添加、物理的刺激 (例、超音波刺激）、冷却等に より結晶化を促進してもよい。このとき、好ましい冷却温度は約 0°C〜約 5°Cである。  The crystallization may be promoted by adding a seed crystal, physical stimulation (eg, ultrasonic stimulation), cooling, etc., if necessary. At this time, a preferable cooling temperature is about 0 ° C to about 5 ° C.
[0008] 析出した結晶は、ろ過、遠心分離、またはデカンタ法等の公知の方法によって単離 することができる。単離した結晶は、風乾等の公知の方法によって乾燥させることが できる。ここで、乾燥前に単離した結晶を適当な溶媒で洗浄してもよい。 [0008] 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. Here, the crystals isolated before drying may be washed with a suitable solvent.
[0009] 上記の方法等で得られた本発明の結晶の一形態 (本明細書中、結晶 Aと称する場 合がある）は、下記の物理化学的性質を有する。 [0009] 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.
(1)粉末 X線回折スペクトルにおいて 2 0 =約 6. 0° 、約 15. 0° 、約 16. 2° 、お よび約 17. 4° に特徴的なピークを有する力、または図 1もしくは図 2に示される粉末 X線回析スペクトルと実質的に同じ粉末 X線回析スペクトルを有する。  (1) 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.
(2)示差操作熱量計で測定した融点が、約 123°C〜約 128°Cである。  (2) The melting point measured by a differential operation calorimeter is about 123 ° C to about 128 ° C.
[0010] 上記の方法等で得られた本発明の結晶の別の一形態 (本明細書中、結晶 Bと称す る場合がある）は、下記の物理ィ匕学的性質を有する。  [0010] 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.
(1)粉末 X線回折スペクトルにおいて 2 0 =約 6. 0° 、約 15. 0° 、約 15. 7° 、お よび約 17. 4° に特徴的なピークを有するカゝ、または図 3に示される粉末 X線回析ス ベクトルと実質的に同じ粉末 X線回析スペクトルを有する。  (1) A powder having characteristic peaks at 20 = about 6.0 °, about 15.0 °, about 15.7 °, and about 17.4 ° in the powder X-ray diffraction spectrum, or FIG. Has the same powder X-ray diffraction spectrum as the powder X-ray diffraction spectrum shown in FIG.
(2)示差操作熱量計で測定した融点が、約 128°C〜約 130°Cである。  (2) The melting point measured by a differential operation calorimeter is about 128 ° C to about 130 ° C.
[0011] また、本発明の結晶は、好適には、下記の条件の HPLC分析において、化合物 Iの ピークに対する溶出時間約 4分の物質のピークのエリア比が 0. 1%未満である。  [0011] 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%.
[HPLC分析の条件]  [Conditions for HPLC analysis]
カラム： ODS C18、長さ 150mm X内径 4. 6mm  Column: ODS C18, length 150mm X inner diameter 4.6mm
カラム温度： 40°C  Column temperature: 40 ° C
移動層： 0. 01M酢酸アンモ-ゥム Zァセトニトリル = 25Z75 (v/v)  Moving layer: 0.01M ammonium acetate Zacetonitrile = 25Z75 (v / v)
流速： 1. OmLZ分  Flow rate: 1. OmLZ min
検出： 295nm [0012] 本発明の結晶は、優れた CCR拮抗作用、特に CCR5および Zまたは CCR2拮抗 作用、とりわけ、強い CCR5拮抗作用を有するので、人における HIVの感染症、例え ば AIDSの予防ならびに治療や、その他の種々の疾患の予防ならびに治療のため に使用できる。この場合、本発明の結晶をそのまま医薬として用いてもよぐまたは慣 用の方法を用いて、本発明の結晶と薬学的に許容される担体等を配合した医薬組 成物 (例:錠剤、カプセル剤、顆粒剤、散剤などの固形製剤;またはシロップ剤、注射 剤などの液状製剤)を製造して用いてもよ!ヽ。 Detection: 295nm [0012] 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. In this case, 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).
本発明の結晶または本発明の医薬組成物は、対象疾患の種類に応じて、他の薬 剤と組み合わせて用いてもよい。かかる薬物は、本発明の結晶と別々に製剤化しても よぐ本発明の結晶と一緒に製剤化してもよい。また、薬物を別々に製剤化する場合 、別々に製剤化したものを使用時に混合して投与することができるが、別々に製剤化 した個々の製剤を、同時に、あるいは時間差をおいて別々に同一対象に投与しても よい。別々に製剤化したものを使用時に混合して投与するためのキット製品（例えば 、粉末状の個々の薬物を含有するアンプルと 2種以上の薬物を使用時に混合して溶 解するための希釈剤などを含有する注射用キットなど）、別々に製剤化した個々の製 剤を、同時に、あるいは時間差をおいて別々に、同一対象に投与するためのキット製 品（例えば、個々の薬物を含有する錠剤を同一または別々の袋に入れ、必要に応じ 、薬物を投与する時間の記載欄を設けた、 2種以上の錠剤を同時にあるいは時間差 をおいて別々に投与するための錠剤用キットなど)なども本発明の医薬組成物に含ま れる。  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. 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). (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.
[0013] 本発明の結晶、または本発明の医薬組成物の投与量は、投与対象、投与対象の 年令および体重、症状、投与時間、投与方法、剤型などのより、適宜選択することが できる。  [0013] 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.
ある特定の患者の投与量は、年令、体重、一般的健康状態、性別、食事、投与時 間、投与方法、***速度、患者のその時に治療を行なっている病状の程度に応じ、 それらある 、はその他の要因を考慮して決められる。  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.
上記医薬組成物を AIDS予防治療剤および AIDSの病態進行抑制剤として用いる 場合の投与量は、患者の状態や体重、投与の方法により異なる力 経口投与の場合 、成人（体重 50kg) 1人当り化合物 Iとして、約 5から 1000mg、好ましくは約 10から 6 OOmgであり、さらに好ましくは約 10〜300mgであり、とりわけ好ましくは約 15〜150 mgであり、 1日当たり 1回または 2から 3回にわけて投与される。 When the above pharmaceutical composition is used as an AIDS prophylactic or therapeutic agent and an AIDS disease progression inhibitor, the dosage varies depending on the patient's condition, body weight, and administration method. About 5 to 1000 mg, preferably about 10 to 600 mg, more preferably about 10 to 300 mg, particularly preferably about 15 to 150 mg, as compound I per adult (body weight 50 kg). Administered once or twice or three times daily.
[0014] また、慣用の方法を用いて本発明の結晶から化合物 Iの塩を製造することができる。 [0014] A salt of compound I can be produced from the crystals of the present invention using a conventional method.
力かる塩としては、薬理学的に許容される塩が好ましぐ例えば無機塩基との塩、有 機塩基との塩、無機酸との塩、有機酸との塩、塩基性または酸性アミノ酸との塩など が挙げられる。無機塩基との塩の好適な例としては、例えばナトリウム塩、カリウム塩 などのアルカリ金属塩；カルシウム塩、マグネシウム塩などのアルカリ土類金属塩；な らびにアルミニウム塩、アンモ-ゥム塩などが挙げられる。有機塩基との塩の好適な 例としては、例えばトリメチルァミン、トリェチルァミン、ピリジン、ピコリン、エタノールァ ミン、ジエタノールァミン、トリエタノールァミン、ジシクロへキシルァミン、 N, N'—ジ ベンジルエチレンジァミンなどとの塩が挙げられる。無機酸との塩の好適な例として は、例えば塩酸、臭化水素酸、硝酸、硫酸、リン酸などとの塩が挙げられる。有機酸と の塩の好適な例としては、例えばギ酸、酢酸、トリフルォロ酢酸、フマル酸、シユウ酸、 酒石酸、マレイン酸、クェン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスル ホン酸、 p—トルエンスルホン酸などとの塩が挙げられる。塩基性アミノ酸との塩の好 適な例としては、例えばアルギニン、リジン、オル-チンなどとの塩が挙げられ、酸性 アミノ酸との塩の好適な例としては、例えばァスパラギン酸、グルタミン酸などとの塩が 挙げられる。  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. Preferable examples of 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. Preferable examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, or-tin, and preferable examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Salt.
例えば、本発明の結晶を上記した溶媒に溶解させた溶液に上記した塩基や酸を添 加することにより所望の塩が製造できる。  For example, 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.
[0015] 以下に、参考例、実施例、製剤例および試験例を挙げて本発明をさらに詳細に説 明するが、本発明はこれらにより限定されるものではない。また、以下の参考例およ び実施例において、％は特記しない限り重量パーセントを示す。融点は示差走査熱 量計 (DSC220C、セイコー電子工業 (株)）を用いて測定した。粉末 X線結晶回折の データは、線源として Cu— K 線を用い、 RINT2500V (理学電気 (株））を用いて 測定した。 [0015] Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples, Formulation Examples, and Test Examples, but the present invention is not limited thereto. Further, in the following Reference Examples and Examples,% indicates percent by weight unless otherwise specified. The melting point was measured using a differential scanning calorimeter (DSC220C, Seiko Denshi Kogyo KK). The powder X-ray crystal diffraction data were measured using RINT 2500V (Rigaku Denki Co., Ltd.) using a Cu-K line as a radiation source.
参考例 1 [0016] 化合物 Iの製造 Reference example 1 [0016] Production of Compound I
300mLの 4頸コルベンに、 8— [4— (2—ブトキシエトキシ）フエ-ル]— 1—イソブ チル一 1, 2, 3, 4—テトラヒドロ一 1—ベンゾァゾシン一 5—カルボン酸 45. Og (99. 65mmol, 1. Oaq)と THF135mLを仕込み、 8— [4— (2 ブトキシエトキシ）フエ- ル]— 1—イソブチル 1, 2, 3, 4—テトラヒドロ一 1—ベンゾァゾシン一 5—カルボン 酸を溶解させた後、 DMF230mgを加えて力ゝら、氷水冷却して内温を 10〜15°Cにし た。これに、同温度を保持しながら塩化チォ -ル 12. 45g (0. 105mol, 1. 05aq)を 約 30分間かけて滴下した。ついで、 10〜15°Cで 40分撹拌してから室温下で 2時間 撹拌して反応を終了させ、反応液 Aを得た。  In a 300 mL 4-necked corbene, add 8- [4- (2-butoxyethoxy) phenyl] -1-isobutyl-1,2,3,4-tetrahydro-1-benzoazosin-5-carboxylic acid 45.Og ( 99. 65 mmol, 1. Oaq) and 135 mL of THF are charged, and 8- [4- (2-butoxyethoxy) phenyl] -1-isobutyl 1,2,3,4-tetrahydro-1-benzobenzosin-15-carboxylic acid is added. After dissolving, 230 mg of DMF was added, and the mixture was cooled with ice water to bring the internal temperature to 10 to 15 ° C. To this, 12.45 g (0.105 mol, 1.05 aq) of thiol chloride was added dropwise over about 30 minutes while maintaining the same temperature. Then, the mixture was stirred at 10 to 15 ° C. for 40 minutes, and then stirred at room temperature for 2 hours to complete the reaction.
別途、 2Lの 4頸コルベンに 4— { [ (1 プロピル— 1H—イミダゾールー 5—ィル)メ チル]スルフィエル }フエ-ルァミン 28. 87g (0. l lOmol, 1. laq)と THF270mLを 仕込み、懸濁液にピリジン 27. 59g (3. 488mol, 3. 5aq)を加えてから、氷水冷却し て内温を 5°C以下にした。得られた反応液に先の反応液 Aを THF45mLを用いて滴 下ロートに移し、 5°C以下を保持しながら、 1. 5時間を要して滴下した。さら〖こ、同温 度下で 2時間撹拌した。  Separately, 4-L [((1propyl-1H-imidazole-5-yl) methyl] sulfiel} phenamine is added to a 2L 4-necked colben with 28.87g (0. l lOmol, 1. laq) and 270mL of THF. After adding 27.59 g (3.488 mol, 3.5aq) of pyridine to the suspension, the mixture was cooled with ice water to lower the internal temperature to 5 ° C or lower. To the obtained reaction solution, the reaction solution A was transferred to a dropping funnel using 45 mL of THF, and added dropwise over 1.5 hours while maintaining the temperature at 5 ° C or lower. The mixture was further stirred at the same temperature for 2 hours.
つ！ヽで、巿水 270mLと 20%クェン酸水溶液 180mLの混合液を約 30分で滴下し た後、室温放冷下に約 10分撹拌してから、外温 40°C以下で減圧下に溶媒 THFを One! In ヽ, add a mixture of 270 mL of water and 180 mL of 20% aqueous citric acid solution dropwise in about 30 minutes, stir the mixture at room temperature for about 10 minutes, and then remove the solvent under reduced pressure at an external temperature of 40 ° C or less. THF
*y した。 * y
酢酸ェチル 450mLで濃縮残留液を抽出し、抽出酢酸ェチル層を巿水 225mL、 飽和重曹水 450mL、巿水 450mL、および巿水 225mLで順次洗浄し、一夜放置し た。  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.
酢酸ェチル抽出液を分取し、抽出液は 1Lの 4頸コルベンで減圧下に溶媒を留去し 、残留油状物は酢酸ェチル 225mL中に懸濁させた後、再度濃縮した。この操作をも う一度繰り返した。  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.
油状の化合物 I 81. 9g、化学純度 97. 25%を得た。  81.9 g of oily compound I, 97.25% of chemical purity were obtained.
実施例 1  Example 1
[0017] 化合物 Iの結晶の製造 Production of Compound I Crystal
参考例 1で得た油状の化合物 I 81. 9gに、酢酸ェチル 360mLを加えて溶解後、 内温を約 40°Cに保持しながら、 n—ヘプタン 360mLを滴下した。化合物 Iの種結晶 を約 lOmgを添加後、 1時間攪拌した。ついで、室温放置冷却してから室温 (約 25°C )で 2時間の後、更に氷水冷却して 5°C以下で 1時間熟成した。晶出結晶を減圧ろ取 し、 5°C以下に冷却した酢酸ェチル： n—ヘプタン = 1 : 1 450mL、および n—へプタ ン 45mLで順次ろ取結晶を洗浄した。洗浄した結晶（77. 04g)を取り出し、 40°Cで 1 0時間以上乾燥し、収量 63. 97g、 HPLC面積 99. 02%で、化合物 Iの結晶（結晶 A )を得た。この結晶を示差操作熱量計で測定した融点は、 126. 4°Cであった。この結 晶の粉末 X線回折パターンを図 1に示す。 To 81.9 g of the oily compound I obtained in Reference Example 1, 360 mL of ethyl acetate was added and dissolved, While maintaining the internal temperature at about 40 ° C, 360 mL of n-heptane was added dropwise. After adding about 10 mg of the compound I seed crystal, the mixture was stirred for 1 hour. Then, the mixture was left standing and cooled at room temperature, and after 2 hours at room temperature (about 25 ° C), further cooled with ice water and aged at 5 ° C or less for 1 hour. The crystallized crystals were collected by filtration under reduced pressure, and washed with ethyl acetate: 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.
[HPLC分析条件] [HPLC analysis conditions]
カラム： YMC ProC18, 150 X 4. 6mm I. D Column: YMC ProC18, 150 X 4.6mm I. D
移動層： 0. 01M CH COONH /MeCN = 25 : 75 Moving bed: 0.01M CH COONH / MeCN = 25:75
3 4  3 4
検出： 295nm Detection: 295nm
流速： 1. OmL/ mm Flow rate: 1. OmL / mm
温度： 40°C Temperature: 40 ° C
実施例 2 Example 2
化合物 Iの結晶の製造  Preparation of Compound I crystals
3Lの 4頸コルベンに化合物 Iの結晶 56. 2gを仕込み、酢酸ェチル 169mLに溶解 させた後、再濃縮した。再度酢酸ェチル 280mLを仕込み室温で溶解した。活性炭（ 白鷺 A) 2. 77g (5wZw%)を仕込み、室温で約 10分攪拌した。ろ紙 No. 5Cを用い て活性炭をろ去し、酢酸ェチル 52mLで洗浄した。ろ液、洗浄液を 1Lの 4頸コルベン に受け、 35〜40°Cにカロ温した。同温下、 n—ヘプタン 332mLを約 13分かけて滴下 した。同温下、約 1時間攪拌し、結晶を析出させた。室温まで放冷し、室温で 4時間 攪拌した。  56.2 g of the compound I crystal was charged into a 3 L 4-necked colben, dissolved in 169 mL of ethyl acetate, and then re-concentrated. Again, 280 mL of ethyl acetate was charged and dissolved at room temperature. 2.77 g (5 wZw%) of activated carbon (Shirasagi A) was charged and stirred at room temperature for about 10 minutes. Activated carbon was removed by filtration using filter paper No. 5C, and washed with 52 mL of ethyl acetate. The filtrate and washing solution were received in a 1L 4-necked corvette and heated to 35-40 ° C. At the same temperature, 332 mL of n-heptane was added dropwise over about 13 minutes. The mixture was stirred at the same temperature for about 1 hour to precipitate crystals. The mixture was allowed to cool to room temperature and stirred at room temperature for 4 hours.
結晶を吸引濾取し、酢酸ェチル—n—ヘプタン（1： 1) l lOmLで洗浄した。 40°Cで 真空乾燥し、収量 50. 4g、 HPLC面積 99. 7%で、で化合物 Iの結晶（結晶 Α' )を得 た。この結晶を示差操作熱量計で測定した融点は、 127. 9°Cであった。この結晶の 粉末 X線回折パターンを図 2に示す。  The 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 Α ′) 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.
この結晶の HPLC分析のチャートを図 4に示す。 なお、 HPLC分析は実施例 1と同条件で行なった。 The HPLC analysis chart of the crystals is shown in FIG. The HPLC analysis was performed under the same conditions as in Example 1.
実施例 3  Example 3
[0019] 化合物 Iの結晶の製造 Production of Compound I Crystal
50mLのナス型コルベンに化合物 Iの結晶 5. Og、ァセトニトリル 10. 5mLを仕込み 、水浴上で約 80°Cに加温して溶解した。室温まで放冷した後、化合物 Iの種結晶（結 晶 A)を添加し、冷蔵庫内で 3日間放置した。晶出結晶を濾取し、 5°Cに冷却したァセ トニトリル 10mLで洗浄した。得られた湿結晶を 40°Cで恒量となるまで減圧下乾燥し 、収量 4. 5g、収率 90. 0%で化合物 1 (結晶 B)を得た。この結晶を示差操作熱量計 で測定した融点は、 129. 7°Cであった。この結晶の粉末 X線回折パターンを図 3に 示す。  5. Og of Compound I crystal and 10.5 mL of acetonitrile were charged into a 50 mL eggplant-shaped corben, and dissolved by heating to about 80 ° C. on a water bath. After allowing to cool to room temperature, a seed crystal of Compound I (crystal A) was added, and the mixture was allowed to stand in a refrigerator for 3 days. The precipitated crystals were collected by filtration and washed with 10 mL of acetonitrile cooled to 5 ° C. The obtained wet crystals were dried under reduced pressure at 40 ° C. until a constant weight was obtained, to obtain 4.5 g of the compound 1 (crystal B) at a yield of 90.0%. The melting point of the crystals measured with a differential calorimeter was 129.7 ° C. Figure 3 shows the powder X-ray diffraction pattern of this crystal.
実施例 4  Example 4
[0020] 化合物 Iの結晶の製造 Production of Compound I Crystal
100Lの反応釜に 8— [4— (2—ブトキシエトキシ）フエ-ル ] 1 イソブチルー 1, 2, 3, 4—テトラヒドロ一 1—ベンゾァゾシン一 5—カルボン酸 9kg、テトラヒドロフラン 2 7Lを仕込み、溶解し、 DMF4. 6gを添加し、 10〜15°Cに冷却した。 10〜15°Cで塩 化チォニル 2. 49kgを滴下し、 10〜15°Cで 1. 5時間攪拌した。（溶液 A)  9-kg of 8- [4- (2-butoxyethoxy) phenyl] 1-isobutyl-1,2,3,4-tetrahydro-1-benzobenzosin-5-carboxylic acid and 27 L of tetrahydrofuran are charged and dissolved in a 100 L reaction vessel. Then, 4.6 g of DMF was added and cooled to 10 to 15 ° C. 2.49 kg of thionyl chloride was added dropwise at 10 to 15 ° C, and the mixture was stirred at 10 to 15 ° C for 1.5 hours. (Solution A)
300Lの反応釜に 4 { [ (1 プロピル— 1H—イミダゾールー 5—ィル)メチル]スル フィエル）フエ-ルァミン 5. 77kg, THF54L、ピリジン 5. 52kgを仕込み、 0〜5。Cに 冷却し、溶液 Aを 0〜5°Cで滴下した。 0〜5°Cで 3時間攪拌後、 15°C以下で 8%タエ ン酸水溶液 90Lを滴下した。 THFを減圧下留去した後、酢酸ェチル 90Lをカ卩え、抽 出した。有機層を水 45L、 10%重曹水溶液 90L、水 90L、水 45Lで順次洗浄し、酢 酸ェチルを減圧下留去した。ァセトニトリル 45Lを加え溶媒置換を実施した。再度ァ セトニトリル 45Lを加え溶媒置換を実施し、化合物 Iの結晶を得た。  In a 300 L reactor, 4 {[(1 propyl-1H-imidazole-5-yl) methyl] sulfiel) feluamine 5.77 kg, 54 L of THF and 5.52 kg of pyridine were charged, and 0-5. C. and solution A was added dropwise at 0-5 ° C. After stirring at 0 to 5 ° C. for 3 hours, 90 L of an 8% aqueous solution of formic acid was added dropwise at 15 ° C. or lower. After THF was distilled off under reduced pressure, 90 L of ethyl acetate was collected and extracted. 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.
実施例 5  Example 5
[0021] 製剤例 [0021] Formulation Examples
下記の（1)、（2)、（3)および (4)を混和、顆粒ィ匕する。この顆粒に（5)および (6)を 加えて錠剤に加圧成型する（マン-トール、結晶セルロース、ヒドロキシプルピルセル ロース、ステアリン酸マグネシウム、酸化チタン、マクロゴール 6000、三二酸化鉄は いずれも第十四改正日本薬局方適合品である)。下記の（7)、（9)を溶解もしくは分 散した水溶液および、（8)、（10)を分散した水懸濁液を混和し、先に得られた加圧 成型物にコーティングする。 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.
(1)化合物 Iの結晶 lOOmg  (1) Crystal of Compound I lOOmg
(2)マンニトーノレ 143. Omg  (2) Mannithonore 143.Omg
(3)結晶セルロース 30mg  (3) crystalline cellulose 30mg
(4)ヒドロキシプルピルセルロース 9. Omg  (4) Hydroxypropyl cellulose 9.Omg
(5)クロスカルメロースナトリウム（商品名ァクジゾル） 15mg  (5) Croscarmellose sodium (trade name AXIDISOL) 15mg
(6)ステアリン酸マグネシウム 3mg  (6) Magnesium stearate 3mg
(7)ヒドロキシプロピルメチルセルロース 2910 (商品名 TC— 5) 8. 8mg  (7) Hydroxypropyl methylcellulose 2910 (brand name TC-5) 8.8 mg
(8)酸化チタン 1. Omg  (8) Titanium oxide 1.Omg
(9)マクロゴール 6000 2. Omg  (9) Macrogol 6000 2.Omg
(10)三二酸化鉄 0. 2mg  (10) Iron sesquioxide 0.2 mg
1錠 312mg  1 tablet 312mg
実施例 6 Example 6
化合物 Iのメタンスルホン酸塩の製造  Preparation of methanesulfonate of compound I
1Lの 4頸コルベンに化合物 Iの結晶 70. Og (0. lOOmol)、ァセトニトリル 420mLを 仕込み、水浴上 40°C〜50°Cに加温して溶解してから、活性炭 3. 5g (5wZw%)を 添加し同温度で 5分間撹拌した。次に、溶解脱色液をろ紙 (No. 5C)で吸引ろ過し、 ろ過器を酢酸ェチル 21 OmLで洗浄した。ろ液および洗浄液は 2Lの 4頸コルベンに 受け、新たに酢酸ェチル 210mL (ァセトニトリル：酢酸ェチル = 1： 1の容量比）をカロ えて、内温 28°Cよりメタンスルホン酸 9. 65g (0. lOOmol)を約 5分間を要して滴下し た。以後、加温して内温を約 40°Cに保ちながら化合物 Iのメタンスルホン酸塩の種結 晶を添加し、同温度下に 1時間撹拌して結晶を析出させた後、 2時間を要して室温（ 約 25°C)とした。晶出液は室温 (約 25°C)で 6時間攪拌後、氷水冷却して 5°C以下で 6時間熟成した。晶出結晶は窒素パージ下に濾取し、結晶は室温の酢酸ェチル 210 mLで洗浄した。得られた湿結晶は 40°Cで恒量となるまで乾燥し、収量 76. 2g,収 率 95. 7%、化学純度 99. 01%、光学純度 99. 96%ee、水分 0. 36%を得た。 産業上の利用可能性 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 filtrate and washings were placed in a 2L 4-necked corvene and freshly charged with 210 mL of ethyl acetate (acetonitrile: ethyl acetate = 1: 1 volume ratio), and 9.65 g of methanesulfonic acid (0. lOOmol) was added dropwise over about 5 minutes. Thereafter, while heating and maintaining the internal temperature at about 40 ° C, seed crystals of methanesulfonate of Compound I are added, and the mixture is stirred at the same temperature for 1 hour to precipitate crystals, and then for 2 hours. In short, it was set to room temperature (about 25 ° C). 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. Industrial applicability
本発明の結晶および本発明の医薬組成物は医薬、特に AIDSの予防ならびに治 療剤として有用である。  The 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.

Claims

請求の範囲 The scope of the claims
(S) -8- [4- (2 ブトキシエトキシ）フエ-ル] 1 イソブチルー N— [4— [ [ (1 —プロピル— 1H—イミダゾールー 5—ィル）メチル]スルフィエル]フエ-ル] 1, 2, 3, 4—テトラヒドロー 1—ベンズァゾシン一 5—カルボキサミドの結晶。  (S) -8- [4- (2 butoxyethoxy) phenyl] 1 isobutyl-N— [4 — [[(1-propyl-1H-imidazole-5-yl) methyl] sulfiel] phenyl] 1, Crystals of 2,3,4-tetrahydro-1-benzazosin-5-carboxamide.
粉末 X線回折スペクトルにおいて、 2 Θ =約 6. 0° 、約 15. 0° 、約 16. 2° 、およ び約 17. 4° に特徴的なピークを有する請求項 1に記載の結晶。  The crystal according to claim 1, having characteristic peaks at 2Θ = about 6.0 °, about 15.0 °, about 16.2 °, and about 17.4 ° in a powder X-ray diffraction spectrum. .
粉末 X線回折スぺク卜ノレ【こお ヽて、 2 Θ =約 6. 0° 、約 15. 0° 、約 15. 7° 、およ び約 17. 4° に特徴的なピークを有する請求項 1に記載の結晶。  Powder X-ray diffraction spectrum [2 お = characteristic peaks at about 6.0 °, about 15.0 °, about 15.7 °, and about 17.4 ° The crystal according to claim 1, which has:
融点が約 123°C〜約 128°Cである請求項 1記載の結晶。  The crystal of claim 1, wherein the melting point is between about 123 ° C and about 128 ° C.
融点が約 128°C〜約 130°Cである請求項 1記載の結晶。  The crystal of claim 1, wherein the melting point is between about 128 ° C and about 130 ° C.
(S)— 8— [4一（2 ブトキシエトキシ）フエ-ル] 1 イソブチルー N— [4— [ [ (1 —プロピル— 1H—イミダゾールー 5—ィル）メチル]スルフィエル]フエ-ル] 1, 2, 3, 4—テトラヒドロ一 1—ベンズァゾシン一 5—カルボキサミドのァセトニトリルまたはァ セトン溶液に、貧溶媒を添加することを特徴とする請求項 3または 5記載の結晶の製 造方法。  (S) —8— [4- (2-butoxyethoxy) phenyl] 1 isobutyl-N— [4 — [[(1—propyl—1H—imidazole-5-yl) methyl] sulfiel] phenyl] 1, 6. The method for producing crystals according to claim 3, wherein a poor solvent is added to a solution of 2,3,4-tetrahydro-11-benzazosin-15-carboxamide in acetonitrile or acetone.
請求項 1記載の結晶を溶解させた溶液に酸を添加することを特徴とする（S) 8— [ 4— (2 ブトキシエトキシ）フエ-ル]― 1—イソブチル N— [4— [ [ ( 1 プロピル - 1H—イミダゾールー 5 ィル）メチル]スルフィエル]フエ-ル ] 1, 2, 3, 4ーテトラヒ ドロ 1 ベンズァゾシン 5 カルボキサミドの酸との塩の製造方法。  An acid is added to the solution in which the crystals according to claim 1 are dissolved. (S) 8— [4- (2 butoxyethoxy) phenyl] -1-isobutyl N— [4 — [[( 1-Propyl-1H-imidazole-5-yl) methyl] sulfiel] phenyl] 1,2,3,4-tetrahydro-1 benzazosin 5 A method for producing a salt of carboxamide with an acid.
請求項 1記載の結晶を溶解させた溶液にメタンスルホン酸を添加することを特徴と する（S) 8— [4一（2 ブトキシエトキシ）フエ-ル] 1 イソブチルー N [4一 [ [ (1 プロピル—1H—イミダゾールー 5 ィル）メチル]スルフィエル]フエ-ル ]—1, 2 , 3, 4—テトラヒドロ一 1—ベンズァゾシン一 5—カルボキサミド メタンスルホン酸塩の 製造方法。  (S) 8— [4- (2-butoxyethoxy) phenyl] 1 isobutyl-N [4-1 — [((1) Propyl-1H-imidazole-5-yl) methyl] sulfiel] phenyl] -1,2,3,4-tetrahydro-1-benzazosin-5-carboxamide methanesulfonate.
請求項 1記載の結晶を含有する医薬組成物。  A pharmaceutical composition comprising the crystal according to claim 1.
PCT/JP2005/009751 2004-05-28 2005-05-27 Crystal of pharmaceutical compound WO2005116013A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2004-158842 2004-05-28
JP2004158842A JP2007269628A (en) 2004-05-28 2004-05-28 Crystal of pharmaceutical compound

Publications (1)

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

Family

ID=35450824

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2005/009751 WO2005116013A1 (en) 2004-05-28 2005-05-27 Crystal of pharmaceutical compound

Country Status (2)

Country Link
JP (1) JP2007269628A (en)
WO (1) WO2005116013A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006059716A1 (en) * 2004-12-03 2006-06-08 Takeda Pharmaceutical Company Limited Solid preparation
WO2008093853A1 (en) * 2007-01-29 2008-08-07 Eisai R & D Management Co., Ltd. Solid of macrolide compound, method for production thereof, and pharmaceutical composition comprising the same
US7893068B2 (en) 2002-05-29 2011-02-22 Mercian Corporation Physiologically active substances
WO2021133811A1 (en) 2019-12-26 2021-07-01 Teva Pharmaceuticals International Gmbh Solid state forms of cenicriviroc and process for preparation thereof

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2017008280A (en) * 2014-12-23 2017-12-07 Tobira Therapeutics Inc Process of making cenicriviroc and related analogs.
KR20190039087A (en) * 2016-06-21 2019-04-10 토비라 쎄라퓨틱스, 인크. Purified intermediates for the preparation of purified < RTI ID = 0.0 > Senicry < / RTI &
CN110167550A (en) * 2016-08-31 2019-08-23 妥必徕疗治公司 The solid form and preparation method thereof of Xi Keliweiluo mesylate

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003076411A1 (en) * 2002-03-12 2003-09-18 Takeda Pharmaceutical Company Limited Process for producing optically active sulfoxide derivative
JP2003335776A (en) * 2001-08-08 2003-11-28 Takeda Chem Ind Ltd Bicyclic compound, method for producing the same and application thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003335776A (en) * 2001-08-08 2003-11-28 Takeda Chem Ind Ltd Bicyclic compound, method for producing the same and application thereof
WO2003076411A1 (en) * 2002-03-12 2003-09-18 Takeda Pharmaceutical Company Limited Process for producing optically active sulfoxide derivative

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 (en) * 2004-12-03 2006-06-08 Takeda Pharmaceutical Company Limited Solid preparation
WO2008093853A1 (en) * 2007-01-29 2008-08-07 Eisai R & D Management Co., Ltd. Solid of macrolide compound, method for production thereof, and pharmaceutical composition comprising the same
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 (en) 2019-12-26 2021-07-01 Teva Pharmaceuticals International Gmbh Solid state forms of cenicriviroc and process for preparation thereof

Also Published As

Publication number Publication date
JP2007269628A (en) 2007-10-18

Similar Documents

Publication Publication Date Title
TWI582077B (en) Alkyl-amide-substituted pyridyl compounds useful as modulators of il-12, il-23 and/or ifnα responses
JP4705956B2 (en) Potassium salt of HIV integrase inhibitor
TWI516263B (en) Substituted 5-fluoro-1h-pyrazolopyridines and their use
TWI352702B (en) Pyrrolopyridine derivatives, pharmaceutical compos
CN108473500A (en) Imidazopyridazine compounds as the conditioning agent that IL-12, IL-23 and/or IFN α respond
WO2011007819A1 (en) Pharmaceutical product containing lactam or benzene sulfonamide compound
CA2890981A1 (en) Amide-substituted heterocyclic compounds useful as modulators of il-12, il-23 and/or ifn.alpha. responses
JP5701246B2 (en) Organic compounds
CA2890929A1 (en) Alkyl-amide-substituted pyridyl compounds useful as modulators of il-12, il-23 and/or ifn.alpha. responses
WO2005116013A1 (en) Crystal of pharmaceutical compound
CN101243085A (en) Process for preparing triazole substituted azaindoleoxoacetic piperazine derivatives and novel salt forms produced therein
MX2007011110A (en) Crystal forms of an imidazole derivative.
EP2343296A1 (en) A process for the purification of paliperidone
WO2018184185A1 (en) Ozanimod addition salt crystal, preparation method, pharmaceutical composition, and uses
KR20210102887A (en) Crystalline spirocyclic compound inhibitors of tryptophan hydroxylase 1 (TPH1) for treating diseases or disorders associated with peripheral serotonin
JP2012517990A (en) Crystalline polymorphic form 631
WO2015176591A1 (en) Betrixaban salts and preparation method and use thereof
WO2018109786A1 (en) Novel polymoprphs and salts of polycyclic carbamoyl pyridone derivatives
TW201100431A (en) N-[(6-azabicyclo[3.2.1]oct-5-yl)arylmethyl]heterobenzamide derivatives, preparation and therapeutic use thereof
WO2009030106A1 (en) 7-(4-oximino-3-amino-1-piperidyl)quinolinecarboxylic acid derivatives and their preparation methods
WO2005103048A1 (en) Quinolone carboxylic acid derivatives, thereof preparation and usage
US7829711B2 (en) Crystalline materials of 1-(4-benzoyl-piperazin-1-yl)-2-[4-methoxy-7-(3-methyl-[1,2,4]triazol-1-yl)-1H-pyrrolo[2,3-C]pyridine-3-yl]-ethane-1,2-dione
JP2019509306A (en) Crystalline form of drug hydrochloride used for treatment or prevention of JAK-related diseases and method for producing the same
JP5888612B2 (en) Crystals of condensed pyridine compound salts
EP4114527A1 (en) Inhibitors of human immunodeficiency virus replication

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP