Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/02—Nasal agents, e.g. decongestants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • 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
• • 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
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/14—Decongestants or antiallergics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • 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
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to a salt of (2S) — [4 (carboxymethyl) thiazole-2-ylthio] N — ⁇ [4 (3,4-dichlorodibenzyl) morpholine-2-yl] methyl ⁇ acetamide and its pharmaceutical use.
• Example 2 of Patent Document 1 a free form of the compound is described, but there is no specific description of the salt form of the compound.
• Patent Document 1 International Publication WO2006 / 028284 Pamphlet
• the present invention relates to (2S)-[4 (carboxymethyl) thiazole-2-ilthio] N ⁇ [4
• the gist of the present invention is as follows.
• A It has the powder X-ray diffraction pattern shown in FIG.
• any one of (2), (11), and (12) shows a peak near 16.0 ° ( ⁇ 0.2 °) as the diffraction angle represented by 2 ⁇ 1
• the crystal according to item In the powder X-ray diffraction spectrum, any one of (2), (11), and (12) shows a peak near 16.0 ° ( ⁇ 0.2 °) as the diffraction angle represented by 2 ⁇ 1
• the crystal according to item In the powder X-ray diffraction spectrum, any one of (2), (11), and (12) shows a peak near 16.0 ° ( ⁇ 0.2 °) as the diffraction angle represented by 2 ⁇ 1
• a pharmaceutical comprising the compound according to any one of (1) to (; 19).
• FIG. 1 is a graph showing a powder X-ray diffraction pattern of compound 1-3.
• FIG. 2 is a diagram showing a DSC curve of compound 13
• FIG. 3 is a diagram showing a powder X-ray diffraction pattern of Compound 2.
• FIG. 4 is a diagram showing a DSC curve of Compound 2.
• FIG. 5 shows a powder X-ray diffraction pattern of Compound 3.
• FIG. 6 is a view showing a powder X-ray diffraction pattern of compound 4.
• FIG. 7 shows the results of moisture adsorption measurement of hydrobromide Form I crystals.
• FIG. 8 shows the results of moisture adsorption measurement of hydrobromide type II crystals.
• FIG. 9 is a diagram showing the result of moisture adsorption measurement of a free body.
• This crystal preferably has the powder X-ray diffraction pattern shown in FIG. 1 and / or the differential scanning calorimetry (DSC) curve shown in FIG.
• the characteristic peak in the powder X-ray diffraction pattern is 29.9 °, 22.3 °, 24.1 ° and / or 25.6 ° ( ⁇ 0. 2 °).
• the melting point (extrapolated onset temperature) by DSC is about 163 ° C to about 171 ° C, preferably about 169 ° C.
• Another preferred crystal can include those having the powder X-ray diffraction pattern shown in FIG. 3 and / or the DSC curve shown in FIG.
• a characteristic peak in the powder X-ray diffraction pattern is around 16.0 °, 21.7 ° and / or 24 ⁇ 9 ° (each ⁇ 0 ⁇ 2 °) as the diffraction angle represented by 2 ⁇ .
• the melting point (extrapolated onset temperature) by DSC is about 135 ° C to about 143 ° C, preferably about 141 ° C.
• the compound of the present invention can also be obtained as an amorphous form.
• This potassium salt can be obtained as crystals, and the characteristic peak in the powder X-ray diffraction pattern is 11.5 °, 23.1 °, 26.9 °, 29 as diffraction angles represented by 2 ⁇ . Examples include around 8 °, 30.7 °, 31.8 °, 34.0 °, and / or 35.5 ° ( ⁇ 0.2 °, respectively).
• the characteristic peak in the powder X-ray diffraction pattern of the compound crystallized from tetrahydrofuran solvent in potassium salt is 23.1 °, 29.8 ° and 30 ⁇ 7 ° (2 ⁇ ). Each may be around ⁇ 0 ⁇ 2 °).
• the compound of the present invention in the solution state is (2S) [4 (carboxymethyl) thiazonole
• the compound of the present invention is useful as a CCR3 antagonist, and further, diseases in which cells having CCR3 play an important role in the onset, progression and maintenance of pathological conditions such as asthma, sinusitis, allergic properties.
• rhinitis atopic dermatitis
• allergic conjunctivitis allergic conjunctivitis
• allergic myelitis allergic myelitis
• ulcerative colitis Crohn's disease
• chronic rheumatoid arthritis and the like.
• the compound of the present invention When used as the aforementioned preventive and / or therapeutic agent, it is usually a pharmaceutical composition or formulation obtained by mixing the compound of the present invention with a pharmaceutically acceptable carrier (for example, tablets, liquids, etc.) ) Orally or parenterally.
• a pharmaceutically acceptable carrier for example, tablets, liquids, etc.
• the pharmaceutical composition can be formulated according to a usual method.
• Dosage is age, weight, general health, sex, meal, administration time, administration method, excretion It will be determined by considering these and other factors depending on the speed, combination of drugs, and the extent of the patient being treated at the time.
• the compound of the present invention has low toxicity and can be used safely, and its daily dose varies depending on the patient's condition and body weight, the type of compound, the route of administration, etc. ⁇ ; 1000 mg / kg bw / day, administered once to several times a day, or parenterally about 0.01 ⁇ ; 100 mg / kg bw / day divided into one to several times a day Are preferably administered.
• the "prophylactic agent” is a drug administered to a healthy person who has not developed a disease, for example, a drug administered for the purpose of preventing the onset of a disease. That is.
• a “therapeutic agent” is a drug that is administered to a person (patient) who has been diagnosed with a disease by a doctor. For example, it is administered for the purpose of reducing the disease or symptom or restoring health. Is a drug to be used.
• the purpose of administration is prevention of worsening of diseases and symptoms, or prevention of seizures, it is a therapeutic agent if administered to a patient.
• the chemical shift value of ifi-NMR is expressed in terms of relative delta ( ⁇ straightness in parts per million (ppm) using tetramethylsilane (TMS) as an internal standard.
• TMS tetramethylsilane
• the coupling constant is self-evident. Multiplicity in hertz (Hz), s (singlet), d (doublet), t (triplet), q (quartet), sept (septet), m (multiplet), dd (double doublet), It was written as brs (broad singlet).
• the XRD pattern was measured under the following conditions.
• the characteristic peaks of the crystals are the diffraction angles represented by 2 ⁇ as 20.9 °, 22.3 °, 24.1
• Elemental analysis of the obtained compound revealed that C: 39.99, H: 3.70, N: 7.39, S: l 1.19, Cl: 12.41, ⁇ : 13 ⁇ 60 (theoretical value; C: 39.94, ⁇ : 3 ⁇ 88, ⁇ : 7.35, S: 11.22, Cl: 12.41, Br: l 3.99).
• Compound 12 can also be synthesized by the following method.
• the extract was washed with saturated brine, then dried over sodium sulfate, and the solvent was evaporated under reduced pressure.
• the obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was distilled off from the eluate under reduced pressure to obtain 360 mg of Compound A as a pale yellow oil.
• the powder X-ray diffraction pattern measured under the same conditions as the XRD analysis conditions described in Example 1 is shown in FIG.
• the characteristic peaks of the crystals were around 16.0 °, 21.7 °, and 24 ⁇ 9 ° ( ⁇ 0 ⁇ 2 ° respectively) as diffraction angles expressed by 2 ⁇ .
• DSC Differential scanning calorimetry
• the powder X-ray diffraction pattern measured under the same conditions as the XRD analysis conditions described in Example 1 is shown in FIG.
• the characteristic peak showed a broad pattern (no, low) peculiar to an amorphous material that could never be shown as a diffraction angle expressed by 2 ⁇ .
• WO2006 / 028284 Pamphlet Compound obtained according to the method described in Example 2 Add 1--7mol / L potassium hydroxide aqueous solution 10L to 1-5 about 5mg and dissolve in tetrahydrofuran, mix well, then warm to 40 ° C. Thereafter, the solvent was naturally evaporated at room temperature to obtain a white solid.
• the measurement was performed under the same conditions as the XRD analysis conditions described in Example 1 except that the scanning speed was 2 ° / min.
• the powder X-ray diffraction pattern obtained is shown in FIG.
• the characteristic peaks of the crystals were around 2 ⁇ 1 °, 29.8 ° and 30 ⁇ 7 ° ( ⁇ 0.2 °, respectively) as diffraction angles expressed by 2 ⁇ .
• Moisture adsorption measurement serving as a hygroscopic index was performed using a DVS-1 type moisture adsorption device (manufactured by SMS) under the following conditions. Using about 7 mg of sample, the relative humidity was increased every 10% in the range from 0% to 90% relative humidity, and finally increased to 95% relative humidity. The change in weight was recorded for each set relative humidity, and converted into change (%) based on the weight at 0% relative humidity.
• Example 1 2 (hereinafter referred to as the free form), Compound 1 3 obtained by the method described in Example 1 ( Hereinafter, the compound 2 (hereinafter referred to as hydrobromide type II crystal) obtained by the method described in Example 2 was used.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Pulmonology (AREA)
• Immunology (AREA)
• Physical Education & Sports Medicine (AREA)
• Rheumatology (AREA)
• Ophthalmology & Optometry (AREA)
• Pain & Pain Management (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Otolaryngology (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Dermatology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

Priority Applications (5)

Applications Claiming Priority (2)

Publications (1)

Family

ID=38923247

Family Applications (1)

Country Status (6)

Cited By (2)

Families Citing this family (2)

Citations (4)

Family Cites Families (1)

• 2007
  • 2007-07-11 US US12/309,196 patent/US8030303B2/en not_active Expired - Fee Related
  • 2007-07-11 EP EP07790605.5A patent/EP2042499B1/en not_active Not-in-force
  • 2007-07-11 WO PCT/JP2007/063801 patent/WO2008007691A1/ja not_active Ceased
  • 2007-07-11 ES ES07790605.5T patent/ES2687756T3/es active Active
  • 2007-07-11 JP JP2008524814A patent/JP5501615B2/ja not_active Expired - Fee Related
  • 2007-07-11 TW TW096125165A patent/TWI399375B/zh not_active IP Right Cessation
• 2013
  • 2013-10-30 JP JP2013225889A patent/JP2014015489A/ja active Pending

Patent Citations (4)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events