WO2012105708A1 - Nouveau cristal de composé de tétrahydronaphtalène - Google Patents

Nouveau cristal de composé de tétrahydronaphtalène Download PDF

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Publication number
WO2012105708A1
WO2012105708A1 PCT/JP2012/052575 JP2012052575W WO2012105708A1 WO 2012105708 A1 WO2012105708 A1 WO 2012105708A1 JP 2012052575 W JP2012052575 W JP 2012052575W WO 2012105708 A1 WO2012105708 A1 WO 2012105708A1
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WIPO (PCT)
Prior art keywords
crystal
disease
receptor
caused
prophylactic
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2012/052575
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English (en)
Inventor
Takao TESHIMA
Yukako TAOKA
Atsushi MORODA
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Tanabe Pharma Corp
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Mitsubishi Tanabe Pharma Corp
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Publication of WO2012105708A1 publication Critical patent/WO2012105708A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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

Definitions

  • the present invention relates to a novel, isolated crystal form of (IS) - (-) -N- [ (l-ethyl-lH-pyrazol-4-yl) methyl] - 5-hydroxy-N- ( 6-isopropylpyridin-3-yl) -1, 2,3,4- tetrahydronaphthalene-l-carboxamide represented by the followin formula (I)
  • the S isomer ( IS) - (-) -N- [ (l-ethyl-lH-pyrazol-4-yl) methyl] -5- hydroxy-N- ( 6-isopropylpyridin-3-yl) -1,2,3,4- tetrahydronaphthalene-l-carboxamide has a superior C5a receptor antagonistic action, and is useful as a prophylactic and/or therapeutic drug for the diseases caused by binding of C5a to a C5a receptor, for example, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and the like; sepsis; adult respiratory distress syndrome; chronic obstructive pulmonary disease; allergic diseases such as asthma and the like; atherosclerosis; cardiac infarction;
  • autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and the like
  • sepsis adult respiratory distress syndrome
  • Patent document 2 describes two free crystal forms of (IS) - (-) -N- [ (1-ethyl-lH- pyrazol-4-yl)methyl] -5-hydroxy-N- ( 6-isopropylpyridin-3-yl) - 1,2,3, -tetrahydronaphthalene-l-carboxamide .
  • patent document 1 WO2002/22556
  • One object of the present invention is to provide a crystal that is uniform, pure, and more stable.
  • Another object is to provide a production method capable of providing the crystal in an industrial scale safely and efficiently.
  • absorbability and the like may vary among crystals for
  • novel crystal can be selectively produced as uniform crystal by crystallization using water or an organic solvent having a carbon number of two or more at a solvent temperature within the range of from not less than the melting point of the solvent to less than 60°C.
  • the crystal has peaks at diffraction angles 2 ⁇ of at least about 10.5°+0.2° and 14.0°+0.2° in a powder X-ray diffraction spectrum.
  • the crystal may have endothermic peaks at 143-149°C
  • the crystal may have a physicochemical property of. the following A and/or B where A is having a powder X-ray diffraction pattern of peaks shown in Fig. 1, and B is having a differential scanning calorimetry curve shown in Fig 2.
  • a method of producing the aforementioned crystal where a solvent temperature is set to fall within the range of from not less than a melting point of water or an organic solvent having a carbon number of two or more to less than 60°C, a crystal of (IS) - (-) -N- [ (l-ethyl-lH-pyrazol-4-yl) methyl] -5- hydroxy-N- ( 6-isopropylpyridin-3-yl) -1,2,3,4- tetrahydronaphthalene-l-carboxamide dissolved in the water or the organic solvent is formed, and the crystal is recovered.
  • a solvent temperature is set to fall within the range of from not less than a melting point of water or an organic solvent having a carbon number of two or more to less than 60°C
  • a medicament including the aforementioned crystal, wherein the crystal has a purity of at least 95%.
  • a pharmaceutical composition including the aforementioned crystal and a
  • a method of treating a disease caused by binding of C5a to a C5a receptor where an effective amount of the aforementioned crystal is administered to a subject in need thereof.
  • a method of treating a disease caused by binding of C5a to a C5a receptor where the disease caused by binding of C5a to a C5a receptor is one of an autoimmune disease, sepsis, adult respiratory distress syndrome, chronic obstructive pulmonary disease, an allergic disease, atherosclerosis, cardiac infarction, cerebral infarction, .psoriasis, Alzheimer's disease, and serious organ injury due to leukocyte activation caused by ischemia
  • a method of treating an infectious disease where an effective amount of a C5a receptor antagonist comprising the aforementioned crystal is administered to a subject in need thereof.
  • a method of treating an infectious disease where the infectious disease is caused by bacteria or virus that invades via a C5a receptor.
  • a method of treating rheumatoid arthritis where an effective amount of the aforementioned crystal is administered to a subject in need thereof.
  • a prophylactic and/or therapeutic drug for a disease caused by binding of C5a to a C5a receptor comprising the aforementioned crystal.
  • a prophylactic and/or therapeutic drug for a disease caused by binding of C5a to a C5a receptor where the disease caused by binding of C5a to a C5a receptor is one of an autoimmune disease, sepsis, adult respiratory distress syndrome, chronic obstructive pulmonary disease, an allergic disease, atherosclerosis, cardiac infarction, cerebral infarction, psoriasis, Alzheimer's disease, and serious organ injury due to leukocyte activation caused by ischemia reperfusion, trauma, burn or surgical invasion .
  • an antiinflammatory agent comprising the aforementioned crystal.
  • a prophylactic and/or therapeutic drug for an infectious disease comprising the aforementioned crystal.
  • a prophylactic and/or therapeutic drug for an infectious disease where the infectious disease is caused by bacteria or virus that invades via a C5a receptor.
  • a prophylactic and/or therapeutic drug for rheumatoid arthritis comprising the aforementioned crystal.
  • a C5a receptor antagonist comprising the aforementioned crystal.
  • the crystal of the present invention is stable under conditions of less than 60°C, and has properties preferable as a bulk drug of pharmaceutical products.
  • the production method of the present invention can provide the crystal of the present invention in an industrial scale safely and constantly.
  • Fig. 1 shows a powder X-ray diffraction pattern of the crystal of the present invention.
  • Fig. 2 shows the results of differential scanning calorimetry (DSC) of the crystal of the present invention.
  • Fig. 3 shows powder X-ray diffraction patterns before and after preservation of the crystal (Form I crystal) described in Example 3 of patent document 2 under conditions of
  • Fig. 4 shows powder X-ray. diffraction patterns before and 1 day, 3 days and 8 days after preservation of the crystal (Form II crystal) described in Example 22 of patent document 2 under conditions of 40°C/75%RH for 8 days, and powder X-ray diffraction pattern of the crystal (Form I crystal) described in Example 3 of patent document 2, wherein the vertical axis shows intensity (CPS) .
  • Fig. 5 shows powder X-ray diffraction patterns before and after preservation of the crystal of the present invention under conditions of 40°C/75%RH for 6 months, wherein the
  • the crystal of the present invention can be produced by 1) synthesizing the compound according to a method, for
  • the method of the crystallization is not limited, and methods such as cooling of the reaction mixture, standing after
  • the compound N- [ (l-ethyl-lH-pyrazol-4-yl)methyl] -5-hydroxy-N- (6- isopropylpyridin-3-yl) -1,2,3, 4-tetrahydronaphthalene-l- carboxamide does not need to be completely dissolved in a solvent, and the crystal can also be produced, for example, by adding a solvent to a free Form I crystal described in Example 3 of patent document 2 to give a suspension, and continuously stirring the suspension at a solvent temperature of not less than the melting point of the solvent and less than 60°C.
  • the range of the solvent temperature for obtaining the crystal is not particularly limited as long as it is from not less than the melting point of the solvent to less than 60°C, in case of water, preferably it is from not less than 5°C to less than 60°C and more preferably it is from not less than 10°C to less than 60°C, in case of an organic solvent,
  • preferably it is from not less than -20°C to less than 60°C and more preferably it is from not less than 10°C to less than 60°C in general.
  • the solvent usable for the production of the crystal is not particularly limited as long as it is water or an organic solvent having a carbon number of two or more, use of a solvent acceptable for the production of a pharmaceutical product is desirable.
  • the organic solvent having a carbon number of two or more means that the molecule constituting the solvent has a carbon number of two or more. Examples thereof include ethanol, acetic acid, acetonitrile, acetone,
  • preferred examples thereof include ethanol, acetone, 1-propanol, 2-propanol, 2-butanol, 2- methyl-2-propanol, ethyl acetate, 3-methyl-l-butanol, toluene, anisole, heptane and tetrahydrofuran.
  • a mixed solvent thereof for example, a mixed solvent of water and ethanol, a mixed solvent of ethanol and heptane and the like can also be used.
  • the thus-obtained crystal of the present invention shows peaks at diffraction angles 2 ⁇ of about 4.6° ⁇ 0.2°, 10.9° ⁇ 0.2°, 13.2° ⁇ 0.2° and 16.6°+0.2°, and further, at diffraction angles 2 ⁇ of about 10.5°+0.2° and 14.0° ⁇ 0.2°, in powder X-ray diffraction spectrum. These peaks are not observed in the crystals described in Example 3 (Form I crystal) and Example 22 (Form II crystal) of patent document 2.
  • the crystal of the present invention shows endothermic peaks at 145-152°C (extrapolated onset temperature) and 171-177°C (extrapolated onset temperature) in differential scanning calorimetry measurement. While the measurement conditions of the powder X- ray diffraction and differential scanning calorimetry are not particularly limited, the measurements are preferably
  • peaks at diffraction angles 2 ⁇ in powder X-ray diffraction spectrum may vary, irrespective of the crystal forms, depending on the temperature and relative humidity during sample analysis and changes in the amount of water and the like contained in the sample, and therefore, ⁇ 0.2° variation of peak values at 2 ⁇ does not prevent identification of the crystal of the present invention. Therefore, the present invention includes not only crystals with peak values of complete match but also those showing peak values with a difference of ⁇ 0.2°.
  • the "prophylactic drug” means a drug to be administered to a healthy subject before onset of a disease, which is, for example, a drug administered for the purpose of preventing the onset of the disease.
  • the "therapeutic drug” means a drug to be administered to a subject (patient) diagnosed by a physician to have developed a disease, which is, for example, a drug administered for the purpose of alleviation of disease or symptom, or recovery of health.
  • a disease which is, for example, a drug administered for the purpose of alleviation of disease or symptom, or recovery of health.
  • the drug is to be administered to a patient, even if the administration purpose is prevention of aggravation of a disease or symptom, or prevention of a fit, the drug is a therapeutic drug.
  • the "substances that bind to a C5a receptor” means C5a, a decomposition product of C5a (e.g., C5a desArg wherein the carboxy terminal arginine of C5a has been deleted) , and known or unknown substances, which are other than C5a, having affinity for C5a receptor.
  • the "C5a receptor antagonist” is a substance _ that inhibits binding of a C5a receptor with a "substance that binds with a C5a receptor”.
  • the "C5a receptor antagonistic action” means an action that inhibits a reaction that causes some physiological changes (e.g., increase of intracellular Ca 2+ , and the like) by binding of a "substance that binds with a C5a receptor" via the C5a receptor with a cell that expresses the C5a receptor.
  • the crystal of the present invention could be used in a purified and/or isolated ' form.
  • the term “pure” or “purified” means at least 50% pure based on the total mass of the target crystal found within an isolated crystal mixture.
  • pure or “purified” further embraces the following ranges: at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% and at least 98%, at least 99%, at least 99.5%.
  • the compound in the crystal form of the present invention shows a C5a receptor antagonistic action, and is useful as a drug for the prophylaxis or treatment of diseases caused by binding of C5a with a C5a receptor, for example, autoimmune diseases such as rheumatoid arthritis, systemic lupus
  • erythematosus and the like erythematosus and the like; sepsis; adult respiratory distress syndrome; chronic obstructive pulmonary disease; allergic diseases such as asthma and the like; atherosclerosis;
  • Alzheimer's disease serious organ injury due to leukocyte activation caused by ischemia reperfusion, trauma, burn,
  • autoimmune diseases include rheumatoid arthritis.
  • the compound in the crystal form of the present invention is useful as an anti-inflammatory agent, and further, a drug for the prophylaxis and/or treatment of infectious diseases caused by bacteria or virus that invades via a C5a receptor.
  • the compound in the crystal form of the present invention When used as the aforementioned prophylactic and/or therapeutic drug, it is generally administered systemically or topically and orally or parenterally in an effective amount.
  • the dose to patients varies depending on the age, body weight, sex, general health conditions, treatment effect, diet,
  • administration time administration method, clearance rate, combination of drugs, the condition of the disease under
  • parenteral administration preferably intravenous administration
  • the dose is more desirably increased or decreased as appropriate according to the condition of patients.
  • the compound in the crystal form of the present invention can be used orally or parenterally, for example, by inhalation, rectal administration, topical administration and the like as a pharmaceutical composition or preparation (e.g., powder, granule, tablet, pill, capsule, syrup, elixir, suspension, solution and the like) , wherein at least one compound in the crystal form of the present invention can be used alone or used upon admixing with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, corrigent, corrective, emulsifier, diluent and/or dissolution aids and the like) .
  • a pharmaceutically acceptable carrier excipient, binder, disintegrant, corrigent, corrective, emulsifier, diluent and/or dissolution aids and the like
  • a pharmaceutical composition can be prepared according to a general method.
  • parenteral is meant subcutaneous injection, intravenous
  • a composition for injection such as sterile suspension for injection and oil suspension can be prepared using a suitable dispersing agent, wetting agent, or suspending agent according to a method known in the art .
  • a solid composition for oral administration is exemplified by tablet, pill, capsule, powder, granule and the like.
  • one or more active compounds can be admixed with at least one additive.
  • composition can contain further additives such as lubricant, preservative, antioxidant, disintegrant, stabilizer, dissolution aids, binder, thickener, sweetener, flavor, perfume and the like.
  • the tablet and pill may be coated with a film of a gastric soluble or enteric material, or may be coated with two or more layers.
  • the liquid composition for oral administration comprises pharmaceutically acceptable solution, emulsion, syrup, elixir and the like, and may contain a generally used inactive diluent.
  • This composition may contain, besides the inactive diluent, auxiliaries such as wetting agent, suspending agent, and the like, sweetening agent, flavor, perfume and preservative.
  • Other compositions for oral administration are, for example, spray agent containing one or more active substances and formulated by a method known per se.
  • administration may comprise sterile aqueous or non-aqueous solution, suspension and emulsion.
  • the above-mentioned composition may further contain auxiliaries such as preservative, wetting agent, emulsifier, dispersing agent, stabilizer and dissolution aids. These can be sterilized by, for example, filtration through a bacteria-retaining filter, addition of microbicide or irradiation.
  • composition for injection can be also used by the composition for injection.
  • the lyophilized product in sterile water or sterile solvent for injection before use.
  • composition for parenteral administration include external solution, ointment, liniment, suppository and the like, containing one or more active substances and formulated by a conventional method.
  • the suppository for rectal administration can be produced by admixing the drug and a suitable non-irritant vehicle, such as a substance which is solid at ambient temperature but shows liquid properties at the temperature of intestinal tract and which melts in the rectum to release the drug.
  • a suitable non-irritant vehicle such as a substance which is solid at ambient temperature but shows liquid properties at the temperature of intestinal tract and which melts in the rectum to release the drug.
  • Example 1 Production method of the crystal of the present invention (1)
  • the powder X-ray diffraction pattern is shown in Fig. 1, and peaks with relative intensity of not less than 15 when the peak intensity at a diffraction angle 2 ⁇ of 16.6° is 100, and the relative intensities thereof are shown in Table 1.
  • the characteristic peaks of the crystals obtained in Example 1 at diffraction angles 2 ⁇ were 4.6°, 10.5°, 10.9°, 13.2°, 14.0° and 16.6° (respectively ⁇ 0.2°).
  • Example 1 is a novel crystal of (IS) - (-) -N- [ (1-ethyl-lH- pyrazol-4-yl)methyl] -5-hydroxy-N- ( 6-isopropylpyridin-3-yl) - 1,2,3, 4-tetrahydronaphthalene-l-carboxamide .
  • Example 1 the crystal (1.59 mg) obtained in Example 1 was placed on a differential scanning calorimeter DSC-1
  • Example 1 did not change even after lapse of 6 months. However, Form II crystal transformed into Form I crystal 8 days later ( see Figs . 3 - 5 ) .
  • the wet crystal was subjected to powder X-ray measurement under similar conditions as in Example 1.
  • Form I crystal was partially transformed into the crystal obtained by the method described in Example 1.
  • the compound in the crystal form of the present invention can be used as an active ingredient of a medicament.
  • a medicament is formulated into a preparation and distributed in the market, and water is mostly used during the formulation step.
  • Form I crystal when used as an active ingredient, partial crystal transformation may take place during the formulation step, which may lead to inconsistent expression of efficacy and side effects, thus possibly causing an unexpected situation.
  • the crystal of the present invention when used as an active ingredient, such a problem can be suppressed, and a more uniform preparation can be obtained.
  • Example 2 The crystals obtained according to the method described in the above-mentioned Example 1 and Form I crystal were added to a solvent, and the mixture was stirred in a suspension s.tate. Thereafter, a part of the suspension was collected, and the crystal in the suspension was subjected to powder X-ray measurement under similar conditions as in Example 1.
  • the weight of the crystal added to the solvent, the solvent used, the temperature of the solvent and the stirring time are as shown in Table 2. The results are shown in Table 4.
  • Table 2 The results are shown in Table 4.
  • Example 1 After the temperature of the remaining suspension was confirmed to have reached 60°C, the crystals (5 to 10 mg) obtained according to the method described in the above-mentioned Example 1 were further added and the mixture was stirred for 10 min while maintaining the temperature of the suspension at 60°C. 40 to 60 ⁇ of the suspension was collected, and the crystal in the suspension was subjected to powder X-ray measurement under similar conditions as in Example 1. Furthermore, the crystals (ca 20 mg) obtained according to the method described in the above-mentioned Example 1 were further added to the remaining suspension and the mixture was stirred for l ' hr while
  • the solvent temperature is preferably low.
  • the solvent temperature needs to be not less than 60°C.
  • a lower temperature solvent can be used.
  • the crystal of the present invention can be produced more safely and efficiently as compared to Form I crystal.
  • the crystal of the present invention is more stable around room temperature as compared to Form I. crystal and does not transform into other crystals during the formulation step and the like, it is easy to handle and has advantageous properties as a bulk pharmaceutical product.
  • the crystal of the present invention is stable under conditions of less than 60°C and does not transform into other crystals, it is useful as a bulk drug of pharmaceutical products as compared to other previously-identified crystals.
  • the production method of the present invention can selectively produce the crystal of the present invention safely, efficiently and selectively.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un cristal isolé de (1S)-(-)-N-[(1-éthyl-1H-pyrazol-4-yl)méthyle]-5-hydroxy-N-(6-isopropylpyridin-3-yl-1,2,3,4-tétrahydronaphtalène-1-carboxamide qui présente des pics à des angles de diffraction 2θ d'au moins environ 4,6°±0,2°, 10,9°±0,2°, 13,2°±0,2° et 16,6°±0,2°, dans un spectre de diffraction des rayons X sur poudre. Comme le cristal est stable dans des conditions de température inférieure à 60°C et ne se transforme pas en d'autres cristaux, il est utile en tant que médicament en vrac de produits pharmaceutiques par comparaison avec d'autres cristaux précédemment identifiés.
PCT/JP2012/052575 2011-01-31 2012-01-31 Nouveau cristal de composé de tétrahydronaphtalène Ceased WO2012105708A1 (fr)

Applications Claiming Priority (2)

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US201161437949P 2011-01-31 2011-01-31
US61/437,949 2011-01-31

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WO2012105708A1 true WO2012105708A1 (fr) 2012-08-09

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002022556A1 (fr) 2000-09-14 2002-03-21 Mitsubishi Pharma Corporation Derives amides et utilisations associees
WO2006082975A1 (fr) 2005-02-07 2006-08-10 Mitsubishi Pharma Corporation Derive de tetrahydronaphtalene optiquement actif

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002022556A1 (fr) 2000-09-14 2002-03-21 Mitsubishi Pharma Corporation Derives amides et utilisations associees
WO2006082975A1 (fr) 2005-02-07 2006-08-10 Mitsubishi Pharma Corporation Derive de tetrahydronaphtalene optiquement actif
EP1852431A1 (fr) * 2005-02-07 2007-11-07 Mitsubishi Pharma Corporation Derive de tetrahydronaphtalene optiquement actif

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