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WO2006006691A2 - Solid dispersion of a p38 map kinase inhibitor - Google Patents

Solid dispersion of a p38 map kinase inhibitor Download PDF

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Publication number
WO2006006691A2
WO2006006691A2 PCT/JP2005/013099 JP2005013099W WO2006006691A2 WO 2006006691 A2 WO2006006691 A2 WO 2006006691A2 JP 2005013099 W JP2005013099 W JP 2005013099W WO 2006006691 A2 WO2006006691 A2 WO 2006006691A2
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WO
WIPO (PCT)
Prior art keywords
solid dispersion
pyridyl
thiazol
substituent
methylphenyl
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/JP2005/013099
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French (fr)
Other versions
WO2006006691A3 (en
Inventor
Yoshihiro Omachi
Takashi Kurasawa
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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Publication of WO2006006691A2 publication Critical patent/WO2006006691A2/en
Publication of WO2006006691A3 publication Critical patent/WO2006006691A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • 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 solid dispersion of a p38 MAP kinase inhibitor and a manufacturing method thereof.
  • solid dispersions produced by preparing a homogeneous solution or molten product of a poorly soluble compound in a hydrophilic polymer matrix, and coagulating the mixture by cooling or removing the solvent improve solubility and absorption, and enhance bioavailability of pharmaceutical agents.
  • griseofulvin is dispersed in polyethylene glycol, which is a hydrophilic polymer, to give a solid dispersion, and its solubility and the like are improved (J. Pharm. Sci. , 60(9) , 1281-1302 (1971)) .
  • a solid dispersion of sulfathiazole in polyvinylpyrrolidone J. Pharm.
  • JP-B-2527107 a manufacturing method of a solid dispersion using a twin screw extruder has been described. This method is a superior method in that an organic solvent is not used.
  • the prior arts all comprise forming a solid dispersion for the purpose of improving solubility of poorly soluble or insoluble drugs, and do not intend to improve solubility of drugs and provide release-controlling function of drugs simultaneously in a single manufacturing process.
  • WO 00/64894, WO 01/10865, WO 01/74811 and WO 02/51442 describe compounds having a superior p38 MAP kinase activity. Disclosure of the Invention
  • the present invention intends to improve solubility of poorly soluble or insoluble drugs and provide drug release- controlling function simultaneously in a single manufacturing process, and aims at providing a solid dispersion having a uniform composition and superior in sustained-release of drugs, and a manufacturing method thereof.
  • the present inventors have found that, in a mixing step of a solid dispersion containing (i) a drug such as a p38 MAP kinase inhibitor and the like, (ii) carrier(s) , (iii) plasticizer (s) and (iv) drug release- controlling component (s) , kneading while heat-melting without using a solvent results in the manufacturing of a solid dispersion showing improved solubility of a drug which is afforded by amorphosizing the drug and permitting control of the drug release rate.
  • the present inventors have further studied and surprisingly found that the solid dispersion of the present invention shows fine sustained-release of drugs, which resulted in the completion of the present invention.
  • the present invention relates to
  • R 1 is a hydrogen atom, a hydrocarbon group optionally having substituent (s) , a heterocyclic group optionally having substituent (s) , an amino group optionally having substituent (s) or an acyl group
  • R 2 is an aromatic group optionally having substituent (s)
  • R 3 is a hydrogen atom, a pyridyl group optionally having substituent (s) or an aromatic hydrocarbon group optionally having substituent (s)
  • X is an oxygen atom or an optionally oxidized sulfur atom;
  • Y is a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR 4 (wherein R 4 is a hydrogen atom, a hydrocarbon group optionally having substituent (s) or an acyl group) ; and Z is a bond or a divalent chain hydrocarbon group optionally having substituent (s) (hereinafter, abbreviated as compound (I) sometimes) , or a salt thereof ;
  • the solid dispersion according to (1) which prevents a steep rise in the blood concentration after administration and affords a sustained blood concentration ; (7) the solid dispersion according to (1) , which affords a blood concentration such that the maximum blood concentration after administration is not more than about 60% of that of immediate-release preparations and an area under the blood concentration-time curve is not less than about 60% of that of immediate-release preparations ;
  • solid dispersion according to (1) which further comprises plasticizer (s) and/or drug release- controlling component (s) ;
  • the solid dispersion according to (9) wherein the plasticizer is selected from polyethylene oxide, polyethylene glycol and triethyl citrate;
  • a manufacturing method of a solid dispersion which comprising mixing (i) a drug, (ii) carrier(s) , (iii) plasticizer (s) and (iv) drug release-controlling component (s) , without using a solvent;
  • a pharmaceutical composition (particularly sustained-release preparation) comprising the solid dispersion according to (1) ; and the like.
  • Fig. 1 is a graph showing changes of plasma concentration of compound A contained in the solid dispersion of the present invention, wherein the transverse axis shows time (hour) after administration of the solid dispersion of the present invention and the vertical axis shows concentration ( ⁇ g/mL) of compound A in plasma.
  • Fig. 2 is a graph showing changes of plasma concentration of compound A contained in the solid dispersion of the present invention, wherein the transverse axis shows time (hour) after administration of the solid dispersion of the present invention and the vertical axis shows concentration ( ⁇ g/mL) of compound A in plasma.
  • solid dispersion for example, a dispersion of one or more kinds of active ingredients in a solid state dispersed in an inactive carrier or a matrix thereof, which can be prepared by molten methods, solvent methods, molten- solvent methods and the like (see J. Pharm. Sci., Vol. 60, 1281-1302, 1971) .
  • the drug contained in the solid dispersion of the present invention is desirably mostly amorphous (specifically, the proportion of crystals in the drug is not more than 20 wt%, preferably not more than 5 wt%) .
  • the solid dispersion of the present invention can be obtained by melting the constituent components to give a homogeneous kneaded mixture, extruding the mixture and molding the extruded product.
  • the product can be cut into any size according to the object of use.
  • the solid dispersion of the present invention can be obtained as particles having any particle size by pulverizing in a suitable pulverizer, and may be utilized as they are in the form of as a powder or granules. It is also possible to use the pulverized ultrafine particles for tablets, granules, fine granules, capsules and the like.
  • p38 MAP kinase inhibitors thiazole compounds described in WO00/64894, WO01/10865, WO01/74811, WO02/51442 and the like, and the like, which are used as therapeutic agents for arthrosis and the like
  • JNK inhibitors compounds described in WO02/62792 and the like
  • the solid drug to be used in the present invention is preferably a p38 MAP kinase inhibitor or a JNK inhibitor, such as a thiazole compound, an oxazole compound and the like.
  • the drug is preferably an optionally N-oxidized compound represented by the formula (I) :
  • R 1 is a hydrogen atom, a hydrocarbon group optionally having substituent (s) , a heterocyclic group optionally having substituent (s) , an amino group optionally having substituent (s) or an acyl group;
  • R 2 is an aromatic group optionally having substituent (s) ;
  • R 3 is a hydrogen atom, a pyridyl group optionally having substituent (s) or an aromatic hydrocarbon group optionally having substituent (s) ;
  • X is an oxygen atom or an optionally oxidized sulfur atom;
  • Y is a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR 4 (wherein R 4 is a hydrogen atom, a hydrocarbon group optionally having substituent (s) or an acyl group) ; and Z is a bond or a divalent chain hydrocarbon group optionally having substituent (s) , or a salt thereof.
  • R 1 is a hydrogen atom, a hydrocarbon group optionally having substituent (s) , a heterocyclic group optionally having substituent (s) , an amino group optionally having substituent (s) or an acyl group.
  • hydrocarbon group of the “hydrocarbon group optionally having substituent (s) " for R 5
  • a chain or cyclic hydrocarbon group e.g. , alkyl, alkenyl, alkynyl, cycloalkyl, aryl , aralkyl etc.
  • a chain or cyclic hydrocarbon group having 1 to 16 carbon atoms and the like are preferable.
  • alkyl for example, Ci- 6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, hexyl etc.) and the like are preferable, and C1-3 alkyl (e.g., methyl, ethyl, propyl, isopropyl) is particularly preferable.
  • Ci- 6 alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, hexyl etc.
  • C1-3 alkyl e.g., methyl, ethyl, propyl, isopropyl
  • alkenyl for example, C 2 -6 alkenyl (e.g., vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3- butenyl, 2-methyl-2-propenyl, l-methyl-2-propenyl, 2- methyl-1-propenyl etc.) and the like are preferable.
  • alkenyl for example, C 2 -6 alkenyl (e.g., vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3- butenyl, 2-methyl-2-propenyl, l-methyl-2-propenyl, 2- methyl-1-propenyl etc.) and the like are preferable.
  • alkynyl for example, C 2 -6 alkynyl (e.g., ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- hexynyl etc.) and the like are preferable.
  • cycloalkyl for example, C 3 _6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.) and the like are preferable.
  • aryl for example, C ⁇ -n aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4- biphenylyl, 2-anthryl etc.) and the like are preferable.
  • C 7 - I6 aralkyl e.g., benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2- naphthylmethyl, 2,2 ⁇ diphenylethyl, 3-phenylpropyl, 4- phenylbutyl, 5-phenylpentyl etc.
  • aralkyl e.g., benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2- naphthylmethyl, 2,2 ⁇ diphenylethyl, 3-phenylpropyl, 4- phenylbutyl, 5-phenylpentyl etc.
  • substituted for R 5 , for example, oxo, halogen atom (e.g., fluorine, chlorine, bromine, iodine) ,
  • C ⁇ - 3 alkylenedioxy e.g. , methylenedioxy, ethylenedioxy etc.
  • Ci- 6 alkyl optionally halogenated C 2 -6 alkenyl, carboxy-C 2 -6 alkenyl (e.g., 2-carboxyethenyl, 2-carboxy-
  • Ci_ 8 alkoxy e.g., phenyl, 1-naphthyl, 2-naphthyl, 2- biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl etc.
  • Ci_ 8 alkoxy e.g., phenyl, 1-naphthyl, 2-naphthyl, 2- biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl etc.
  • Ci_ 8 alkoxy e.g., phenyl, 1-naphthyl, 2-naphthyl, 2- biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl etc.
  • Ci_ 8 alkoxy e.g., phenyl, 1-naphthyl, 2-naphthyl, 2- biphenylyl, 3-biphenylyl, 4-biphenyly
  • Ci- 6 alkylthio optionally halogenated Ci- 6 alkylthio
  • arylthio e.g., phenylthio, 1-naphthylthio, 2- naphthylthio etc.
  • C7-16 aralkylthio e.g., benzylthio, phenethylthio etc.
  • amino, mono-Ci-B alkylamino e.g., methylamino, ethylamino etc.
  • mono-Ce-H arylamino e.g., phenylamino, 1-naphthylamino, 2-naphthylamino etc.
  • di-Ci- 6 alkylamino e.g., dimethylamino, diethylamino, ethylmethylamino etc.
  • di-C 6 _ 14 arylamino e.g., diphenylamino etc.
  • Ci_ 6 alkyl-carbonyl e.g., acetyl, propionyl etc.
  • C3_ 6 cycloalkyl-carbonyl e.g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl etc.
  • Ci_ 6 alkoxy-carbonyl e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl etc.
  • C 6 -i4 aryl-carbonyl e.g., benzoyl, 1-naphthoyl, 2- naphthoyl etc.
  • C7-16 aralkyl-carbonyl e.g., phenylacetyl, 3- phenylpropionyl etc.
  • C7_i6 aralkyloxy-carbonyl e.g., benzyloxycarbonyl, phenethyloxycarbonyl etc.
  • 5- or 6-membered heterocyclylcarbonyl e.g., nicotinoyl, isonicotinoyl, thenoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl etc.
  • carbamoyl, thiocarbamoyl, mono-Ci-6 alkyl-carbamoyl e.g., methylcarbamoyl, ethylcarbamoyl etc.
  • di-Ci- 6 alkyl-carbamoyl e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.
  • C 6 - H aryl-carbamoyl e.g., phenylcarbamoyl, 1- naphthylcarbamoyl, 2-naphthylcarbamoyl etc
  • 5- or 6-membered heterocyclylcarbamoyl e.g., 2- pyridylcarbamoyl, 3-pyridylcarbamoyl, 4- pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl etc.
  • 2- pyridylcarbamoyl 3-pyridylcarbamoyl
  • 4- pyridylcarbamoyl 2-thienylcarbamoyl
  • 2-thienylcarbamoyl 3-thienylcarbamoyl etc.
  • Ci-6 alkylsulfonyl e.g. , methylsulfonyl, ethylsulfonyl etc. .
  • C 6 -i4 arylsulfonyl e.g., phenylsulfonyl, 1- naphthylsulfonyl, 2-naphthylsulfonyl etc.
  • Ci_ 6 alkylsulfinyl e.g., methylsulfinyl, ethylsulfinyl etc. .
  • C 6 - I4 arylsulfinyl e.g., phenylsulfinyl, 1- naphthylsulfinyl, 2-naphthylsulfinyl etc.
  • arylsulfinyl e.g., phenylsulfinyl, 1- naphthylsulfinyl, 2-naphthylsulfinyl etc.
  • formylamino e.g., phenylsulfinyl, 1- naphthylsulfinyl, 2-naphthylsulfinyl etc.
  • Ci-6 alkyl-carbonylamino e.g. , acetylamino etc.
  • Ci-6 alkoxy-carbonylamino e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino etc.
  • Ci-6 alkylsulfonylamino e.g., methylsulfonylamino, ethylsulfonylamino etc.
  • arylsulfonylamino e.g., phenylsulfonylamino, 2- naphthylsulfonylamino, 1-naphthylsulfonylamino etc.
  • Ci-6 alkyl-carbonyloxy e.g., acetoxy, propionyloxy etc.
  • C ⁇ -14 aryl-carbonyloxy e.g., benzoyloxy, naphthylcarbonyloxy etc.
  • Ci-6 alkoxy-carbonyloxy e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy etc.
  • mono-Ci-6 alkyl-carbamoyloxy e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.
  • di-Ci- 6 alkyl-carbamoyloxy e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy etc.
  • C ⁇ -14 aryl-carbamoyloxy e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy etc.
  • nicotinoyloxy 5- to 7-rnembered saturated cyclic amino optionally having substituent (s)
  • a 5- to 10-membered aromatic heterocyclic group e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8- quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2- benzothiazolyl, 2-benzo [b] thienyl, 3-benzo [b] thienyl, 2- benzo [b] furanyl, 3-benz
  • the "hydrocarbon group” optionally has, for example, 1 to 5, preferably 1 to 3, substituents mentioned above at substitutable positions. When the number of the substituents is 2 or more, the respective substituents may be the same or different.
  • Ci-e alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, hexyl etc.
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • C 2 -6 alkenyl for example, C 2 -6 alkenyl (e.g., vinyl, propenyl, isopropenyl, 2-buten-l-yl, 4-penten-l-yl, 5- hexen-1-yl etc.) optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine) , and the like can be mentioned.
  • C 2 -6 alkenyl e.g., vinyl, propenyl, isopropenyl, 2-buten-l-yl, 4-penten-l-yl, 5- hexen-1-yl etc.
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • C 2 - ⁇ alkynyl for example, C 2 -6 alkynyl (e.g., 2-butyn-l-yl, 4-pentyn-l-yl, 5-hexyn-l-yl etc.) optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine) , and the like can be mentioned.
  • C 2 -6 alkynyl e.g., 2-butyn-l-yl, 4-pentyn-l-yl, 5-hexyn-l-yl etc.
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • C3- 6 cycloalkyl for example, C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.) optionally having 1 to 5, preferably 1 to 3 , halogen atoms (e.g., fluorine, chlorine, bromine, iodine) , and the like can be mentioned.
  • C3-6 cycloalkyl e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4- dichlorocyclohexyl, 2,2 ,3,3-tetrafluorocyclopentyl, 4- chlorocyclohexyl and the like can be mentioned.
  • Ci_ 8 alkoxy for example, d- ⁇ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine) , and the like can be mentioned.
  • d- ⁇ alkoxy e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2- trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4- trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like can be mentioned.
  • Ci_ 6 alkylthio e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio etc.
  • halogen atoms e.g. , fluorine, chlorine, bromine, iodine
  • methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4- trifluorobutylthio, pentylthio, hexylthio and the like can be mentioned.
  • W 5- to 7-membered saturated cyclic amino of the above-mentioned W 5- to 7-membered saturated cyclic amino optionally having substituent (s) "
  • substituent (s) for example, 5- to 7-membered saturated cyclic amino containing one nitrogen atom and optionally containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and the like can be mentioned.
  • substituent (s) for example, 5- to 7-membered saturated cyclic amino containing one nitrogen atom and optionally containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and the like
  • pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl and the like can be mentioned.
  • substituent (s) for example, Ci- 6 alkyl (e.g. , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) , C ⁇ -i4 aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4- biphenylyl, 2-anthryl etc.) , C ⁇ -6 alkyl-carbonyl (e.g.
  • a 5- to 10-membered aromatic heterocyclic group e.g., 2-thienyl, 3-thienyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3- isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2- indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo [b]thienyl, 3-benzo [b] thienyl, 2-benzo [b] furanyl, 3-benzo [b] furanyl etc.) , oxo and the like can be mentioned.
  • the "5- to 7- membered saturated cyclic amino” optionally has 1 to 3 substituents mentioned above at substitutable positions. When the number of the substituents is 2 or more, the respective substituents may be the same or different.
  • substituent(s) " for R 5 for example, a monovalent group obtained by removing one of hydrogen atoms from 5- to 14-membered (monocyclic, bicyclic or tricyclic) heterocycle containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, preferably, (i) 5- to 14-membered (preferably 5- to 10-membered, particularly preferably 5- or 6-membered) aromatic heterocycle, (ii) 5- to 10- membered (preferably 5- or 6-membered) non-aromatic heterocycle, (iii) 7- to 10-membered crosslinked heterocycle, and the like
  • aromatic heterocycle such as thiophene, benzo [b]thiophene, benzo [b] furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphto[2,3- b]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, IH-indazole, purine, 4H-quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, ⁇ - carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole,
  • aromatic heterocycle such as thiophene, benzo [b]thiophene, benzo [b] furan,
  • pyrrolidine imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dioxazole, oxadiazoline, thiadiazoline, triazoline, thiadiazole, dithiazole and the like can be mentioned.
  • heterocyclic group a 5- to 14-membered (preferably 5- to 10-membered) (monocyclic or bicyclic) heterocyclic group containing, besides carbon atom, 1 or
  • aromatic heterocyclic group such as 2-thienyl, 3-thienyl, 2- furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8- quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl , 2-oxazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 3- indolyl, 2-benzothiazolyl, 2-benzo [b]thienyl, 3-
  • hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and the like are more preferable.
  • 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3- furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3- pyridazinyl, 3-isothiazolyl, 2-oxazolyl, 3-isoxazolyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2- imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl, 3- pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino and the like can be mentioned
  • heterocyclic group optionally has, for example, 1 to 5, preferably 1 to 3 , substituents mentioned above at substitutable positions.
  • substituents mentioned above at substitutable positions.
  • the respective substituents may be the same or different.
  • Ci-6 alkyl group for R 6 , for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, hexyl and the like can be mentioned.
  • hydrocarbon group optionally having substituent (s) " and “heterocyclic group optionally having substituent(s) " for R 7 for example, those similar to the "hydrocarbon group optionally having substituent (s) " and “heterocyclic group optionally having substituent (s) ", respectively, for the above- mentioned R 5 , and the like can be mentioned.
  • hydrocarbon group optionally having substituent (s) " and “heterocyclic group optionally having substituent (s) “ for R 1 for example, those similar to the “hydrocarbon group optionally having substituent (s) " and “heterocyclic group optionally having substituent (s) ", respectively, for the above- mentioned R 5 , and the like can be mentioned.
  • amino group optionally having substituent (s) " for R 1 for example,
  • substituted of the "amino group optionally having 1 or 2 substituents” in the above-mentioned (1) , for example, a hydrocarbon group optionally having substituent (s) , a heterocyclic group optionally having substituent (s) , an acyl group, an alkylidene group optionally having substituent (s) and the like can be mentioned.
  • hydrocarbon group optionally having substituent (s) " and “heterocyclic group optionally having substituent (s) “ for example, those similar to the “hydrocarbon group optionally having substituent (s) " and “heterocyclic group optionally having substituent (s) ", respectively, for the above-mentioned R 5 , and the like can be mentioned.
  • acyl group fox example, those similar to the “acyl group” for the above-mentioned R 1 , and the like can be mentioned.
  • alkylidene group of the “alkylidene group optionally having substituent (s) ", for example, a Ci- 6 alkylidene group (e.g. , methylidene, ethylidene, propylidene etc. ) and the like can be mentioned.
  • substituent for example, those similar to the "substituent” of the “hydrocarbon group optionally having substituent (s) " for the above-mentioned R 5 , and the like can be mentioned.
  • the “alkylidene group” optionally has 1 to 5, preferably 1 to 3, substituents mentioned above at substitutable positions. When the number of the substituents is 2 or more, the respective substituents may be the same or different.
  • the respective substituents may be the same or different.
  • cyclic amino group of the “cyclic amino group optionally having substituent (s) " in the above- mentioned (2) for example, a 5- to 7-membered non- aromatic cyclic amino group containing one nitrogen atom and optionally containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and the like can be mentioned.
  • pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl, imidazolidin-1-yl, 2 ,3-dihydro-lH- imidazol-1-yl, tetrahydro-1 (2H) -pyrimidinyl, 3,6- dihydro-1 (2H) -pyrimidinyl, 3,4-dihydro-l (2H) -pyrimidinyl and the like can be mentioned.
  • substituents of the "cyclic amino optionally having substituent(s) " for example, those similar to the "substituent” of the "5- to 7-membered saturated cyclic amino optionally having substituent (s) group", exemplified as the "substituent” of the "hydrocarbon group optionally having substituent (s) " for the above-mentioned R 5 , and the like can be mentioned.
  • the "cyclic amino” optionally has 1 to 3 substituents mentioned above at substitutable positions. When the number of the substituents is 2 or more, the respective substituents may be the same or different.
  • the 5- to 7-membered non- aromatic cyclic amino group having one oxo, 2- oxoimidazolidin- ⁇ -yl, 2-oxo-2,3-dihydro-lH-imidazol-l- yl, 2-oxotetrahydro-l (2H) -pyrimidinyl, 2-oxo-3,6- dihydro-1 (2H) -pyrimidinyl, 2-oxo-3 ,4-dihydro-l (2H) - pyrimidinyl, 2-oxopyrrolidin-l-yl, 2-oxopiperidino, 2- oxopiperazin-1-yl, 3-oxopiperazin-l-yl, 2-oxo- 2 ,3 ,4 , 5,6 ,7-hexahydroazepin-l-yl and the like can be mentioned.
  • R 1 an amino group optionally having substituent (s) , an aryl group optionally having substituent (s) , an alkyl group optionally having substituent (s) and the like are preferable.
  • aryl group optionally having substituent (s) for example, a C 6 -i4 aryl group (preferably phenyl etc.) optionally having 1 to 5 substituents selected from Ci_ 6 alkylthio, C 6 -i4 arylthio, Ci-6 alkylsulfinyl, Ce-i 4 arylsulfinyl, Ci- 6 alkylsulfonyl, C ⁇ - 14 arylsulfonyl , carboxy, halogen atom and the like, and the like are preferable.
  • alkyl group optionally having substituent (s) for example, a Ci- 6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl etc.) optionally having 1 to 3 substituents selected from halogen atom, Ci-6 alkoxy, hydroxy, carboxy, Ci_6 alkoxy-carbonyl and the like, and the like are preferable, and a Ci_3 alkyl group (e.g. , methyl, ethyl etc. ) and the like are particularly preferable .
  • a Ci- 6 alkyl group e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl etc.
  • 1 to 3 substituents selected from halogen atom, Ci-6 alkoxy, hydroxy, carboxy, Ci_
  • a Ci-6 alkyl group e.g. , a Ci_ 4 alkyl group such as methyl, ethyl, propyl, butyl
  • a Ci-6 alkyl group e.g. , a Ci_ 4 alkyl group such as methyl, ethyl, propyl, butyl
  • a C ⁇ - 14 aryl group e.g. , a phenyl group
  • substituent (s) selected from Ci- 6 alkylthio (e.g. , methylthio) , C ⁇ - 6 alkylsulfonyl (e.g. , methylsulfonyl) and halogen atom (e.g. , chlorine atom, fluorine atom) ,
  • Ci- 6 alkyl group e.g. , a C 1 - 3 alkyl group such as methyl
  • a 5- to 14-membered heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom e.g. , a 5- or 6-membered heterocyclic group containing, besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as a pyridyl group
  • an amino group optionally having 1 or 2 acyl represented by the formula: -(C O)-R 5" [wherein R 5' is
  • a 5- to 14-membered heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom e.g. , a 5- or 6-membered heterocyclic group containing, besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as a pyridyl
  • R 5' and R 5" are preferably each independently a phenyl group or a pyridyl group.
  • R 2 is an aromatic group optionally having substituent(s) .
  • aromatic group of the “aromatic group optionally having substituent (s) " for R 2 , for example, an aromatic hydrocarbon group, an aromatic heterocyclic group and the like can be mentioned.
  • aromatic hydrocarbon group for example, a monocyclic or fused polycyclic (bicyclic or tricyclic) aromatic hydrocarbon group having 6 to 14 carbon atoms, and the like can be mentioned.
  • a C 6 -i 4 aryl group e.g., phenyl, 1-naphthyl, 2-naphthyl, 2- biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl etc.
  • a C ⁇ -io aryl group e.g., phenyl, 1-naphthyl, 2-naphthyl etc, preferably phenyl etc.
  • aromatic heterocyclic group for example, a monovalent group obtained by removing one of hydrogen atoms from 5- to 14-membered (preferably 5- to 10- membered) aromatic heterocycle containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and the like can be mentioned.
  • aromatic heterocycle such as thiophene, benzo [b]thiophene, benzo[b] furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphto[2,3- b]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, lH-indazole, purine, 4H-quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, ⁇ - carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole
  • aromatic heterocycle such as thiophene, benzo [b]thiophene, benzo[b] furan,
  • aromatic heterocyclic group for example, a 5- to 14-membered (preferably 5- to 10-membered) (monocyclic or bicyclic) aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and the like are preferable.
  • aromatic group optionally has 1 to 5, preferably 1 to 3, substituents mentioned above at substitutable positions. When the number of the substituents is 2 or more, the respective substituents may be the same or different. As R 2 ,
  • a 5- to 14-rnembered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, which heterocyclic group optionally has substituent (s) , and the like are preferable.
  • a C 6 - H aryl group e.g. , a phenyl group, a naphthyl group
  • substituent (s) selected from halogen atom e.g. , chlorine atom, fluorine atom
  • Ci- 6 alkoxy e.g.
  • a 5- to 14-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom e.g. , a 5- or 6-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as a pyridyl group, a thienyl group
  • a 5- or 6-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom such as a pyridyl group, a thienyl group
  • a C 6 - I4 aryl group e.g. , a phenyl group
  • a 5- to 14-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom e.g. , a 5- or 6-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as a pyridyl group
  • a phenyl group, a pyridyl group and the like are particularly preferable .
  • R 3 is a hydrogen atom, a pyridyl group optionally having substituent (s) or an aromatic hydrocarbon group optionally having substituent (s) .
  • substituents of the "pyridyl group optionally having substituent(s) " for R 3 for example, those similar to the "substituent” of the "hydrocarbon group optionally having substituent(s)" for the above- mentioned R 5 , and the like can be mentioned.
  • the "pyridyl group” optionally has, for example, 1 to 5, preferably 1 to 3 , substituents mentioned above at substitutable positions. When the number of the substituents is 2 or more, the respective substituents may be the same or different.
  • the nitrogen atom, which is an atom constituting "pyridyl group” is optionally N-oxidized.
  • a C 6 -i4 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3- biphenylyl, 4-biphenylyl, 2-anthryl and the like, and the like are preferable, and a C 6 -io aryl group (e.g., phenyl, 1-naphthyl, 2-naphthyl etc., preferably phenyl etc.) and the like are more preferable.
  • a C ⁇ - 14 aryl group optionally having substituent (s) and the like are preferable.
  • a Ce-14 aryl group optionally having 1 or 2 substituents selected from Ci_ 6 alkyl (e.g., methyl, ethyl etc.) and Ci-6 alkoxy (e.g., methoxy, ethoxy etc.) , and the like are more preferable, and a phenyl group optionally having 1 or 2 substitutes selected from Ci- 6 alkyl (e.g. , methyl, ethyl etc.) and Ci_ 6 alkoxy (e.g., methoxy, ethoxy etc.) , (e.g.
  • X is an oxygen atom or an optionally oxidized sulfur atom.
  • an optionally oxidized sulfur atom is preferable, and S is more preferable.
  • Y is a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR 4 (wherein R 4 is a hydrogen atom, a hydrocarbon group optionally having substituent (s) or an acyl group) .
  • hydrocarbon group optionally having substituent (s) for R 4
  • those similar to the “hydrocarbon group optionally having substituent (s) " for the above-mentioned R 5 , and the like can be mentioned.
  • a Ci_ 6 alkyl group such as methyl, ethyl and the like are preferable
  • a C 1 - 3 alkyl group such as methyl and the like are particularly preferable.
  • acyl group for R 4 , for example, those similar to the "acyl group” for the above-mentioned R 1 , and the like can be mentioned.
  • an oxygen atom, an optionally oxidized sulfur atom, a group represented by the formula: NR 4 (wherein R 4 is as defined above) and the like are preferable.
  • an oxygen atom, an optionally oxidized sulfur atom, a group represented by the formula: NR 4' (wherein R 4' is a hydrogen atom or a Ci_6 alkyl group) and the like are more preferable, an oxygen atom, S, SO 2 , NH, N(CH 3 ) and the like are still more preferable, and 0, NH, S and the like are particularly preferable.
  • Z is a bond or a divalent chain hydrocarbon group optionally having substituent (s) .
  • a Ci-is alkylene group e.g., methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene etc., preferably a Ci- 6 alkylene etc.
  • a C 2 -16 alkenylene group e.g., vinylene, propylene, 1-butenylene, 2-butenylene, 1-pentenylene, 2- pentenylene, 3-pentenylene etc.
  • a C2-16 alkynylene group ethynylene, propynylene, 1-butynylene, 2-butynylene, 1- pentynylene, 2-pentynylene, 3-pentynylene etc.
  • Ci-15 alkylene group and the like are preferable, and a Ci-6 alkylene group and the like are particularly preferable.
  • substituents of the "divalent chain hydrocarbon group optionally having substituent (s) " for Z for example, those similar to the “substituent” of the "hydrocarbon group optionally having substituent(s) " for the above-mentioned R 5 , and the like can be mentioned.
  • a bond, a lower alkylene group and the like are preferable, and a bond, a Ci- 6 alkylene group (e.g., a Ci-3 alkylene group such as methylene, ethylene, trimethylene) optionally having substituent (s) selected from oxo, Ci- 6 alkyl (e.g., C1-3 alkyl such as methyl) and the like, and the like are more preferable.
  • a bond, a Ci- 6 alkylene group e.g. , a C1-3 alkylene group such as methylene, ethylene, trimethylene, particularly a methylene group
  • -CH 2 -, -(CH 2 J 2 -, -(CH 2 I 3 -, - CO-, -CH 2 CO-, -(CH 2 J 2 CO-, -CH(CH 3 )- and the like can be mentioned, and -CH 2 -, -CO- and the like are particularly preferable.
  • the nitrogen atom in compound (I) is optionally N- oxidized.
  • n is 0 or 1 and other symbols are as defined above, or a salt thereof and the like are preferable.
  • R 1 is an amino group optionally having substituent(s) , an aryl group optionally having substituent (s) or an alkyl group optionally having substituent (s) ;
  • R 2 is
  • a C 6 -i 4 aryl group optionally having substituent (s) or (2) a 5- to 14-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, which optionally has substituent (s) ;
  • R 3 is a C 6 -i 4 aryl group optionally having substituent (s) ;
  • X is a sulfur atom;
  • Y is an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR 4 (wherein R 4 is as defined above) ; and Z is a bond or a lower alkylene group optionally having substituent (s) .
  • R 1 is (1) a Ci- 6 alkyl group (e.g. , a Ci_ 4 alkyl group such as methyl, ethyl, propyl, butyl) ,
  • a C 6 - H i aryl group e.g. , a phenyl group
  • substituent selected from Ci_ 6 alkylthio (e.g. , methylthio) , C ⁇ - 6 alkylsulfonyl (e.g. , methylsulfonyl) and halogen atom (e.g. , chlorine atom, fluorine atom) , or
  • R 5' is (a) a Ci_ 6 alkyl group (e.g. , a Ci_ 3 alkyl group such as methyl) ,
  • a 5- to 14-membered heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom e.g. , a 5- or 6-membered heterocyclic group containing, besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as a pyridyl group
  • R 2 is
  • a Ce- 14 aryl group e.g. , a phenyl group, a naphthyl group
  • substituent selected from halogen atom (e.g. , chlorine atom, fluorine atom) and C ⁇ _ 6 alkoxy (e.g. , methoxy)
  • halogen atom e.g. , chlorine atom, fluorine atom
  • C ⁇ _ 6 alkoxy e.g. , methoxy
  • a 5- to 14-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom e.g. , a 5- or 6-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as a pyridyl group, a thienyl group
  • R 3 is a C 6 -i 4 aryl group (particularly a phenyl group) optionally having 1 or 2 substitutes selected from Ci- 6 alkyl (e.g.
  • Ci- 6 alkoxy e.g. , methoxy, ethoxy etc.
  • X is a sulfur atom
  • Y is an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR 4' (wherein R 4' is a hydrogen atom or a Ci-6 alkyl group)
  • Z is a bond, a Ci- 6 alkylene group (e.g. , a C 1 - 3 alkylene group such as methylene, ethylene, trimethylene) optionally having substituent (s) selected from oxo and Ci- 6 alkyl (e.g. , C 1 -3 alkyl such as methyl) .
  • a 5- to 14-membered heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom e.g. , a 5- or 6-membered heterocyclic group containing, besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as a pyridyl
  • R 2 is
  • a C 6 - I4 aryl group e.g. , a phenyl group
  • a C 6 - I4 aryl group e.g. , a phenyl group
  • R 3 is a phenyl group optionally having 1 or 2 substitutes selected from Ci_ 6 alkyl (e.g. , methyl, ethyl etc.) and Ci- 6 alkoxy (e.g.
  • N- [4- [2-ethyl-4- (3-methylphenyl) -1 , 3—thiazol-5-yl] -2- pyridyl] -4-phenylbutyramide (Reference Example 16-5) , N- [4- [4- (3-methylphenyl) -2-propyl-l , 3-thiazol-5-yl] -2- pyridyl] benzamide (Reference Example 16-7) , N _ [4_ [4_ (3-methylphenyl) -2-propyl-l , 3-thiazol-5-yl] -2- pyridyl] -3-phenylpropionamide (Reference Example 16-8) , N- [4-[2-butyl-4- (3-methylphenyl) -l,3-thiazol-5-yl]-2- pyridyl] benzamide (Reference Example 16-9) , N- [4- [2-butyl-4- (3-methylphenyl
  • the drug is more preferably N- [4- [2-ethy1-4- (3-methylphenyl) -l,3-thiazol-5-yl]-2- pyridyl]benzamide (Reference Example 16-1) , N-benzyl-N- [4- [2-ethy1-4- (3-methylphenyl) -1 ,3-thiazol-5-yl] -2- pyridyl]amine (Reference Example 19-2) , or N-[4-[4-(3- methylphenyl) -2- (4-methylsulfonylphenyl) -l,3-thiazol-5- yl] -2-pyridyl] -N- (2-phenylethy
  • the thiazole compound and the like exemplarily shown above can be produced by, for example, methods disclosed in WO00/64894 and the like.
  • salt of compound (I) for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.
  • metal salt alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like can be mentioned.
  • salts with organic bases salts with trimethylamine, triethylarnine, pyridine, picoline, 2,6- lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'- dibenzylethylenediamine and the like can be mentioned.
  • salts with inorganic acids salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like can be mentioned.
  • salts with organic acids salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned.
  • salts with basic amino acids salts with arginine, lysine, ornithine and the like can be mentioned.
  • salts with acidic amino acids salts with aspartic acid, glutamic acid and the like can be mentioned.
  • salts with inorganic bases such as alkali metal salts (e.g., sodium salt, potassium salt and the like) , alkaline earth metal salts (e.g. , calcium salt, magnesium salt, barium salt and the like) and the like, ammonium salt and the like can be mentioned.
  • alkali metal salts e.g., sodium salt, potassium salt and the like
  • alkaline earth metal salts e.g. , calcium salt, magnesium salt, barium salt and the like
  • ammonium salt and the like can be mentioned.
  • salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like
  • salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like
  • inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like
  • organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like
  • a polymeric carrier is preferable.
  • hydrophilic polymer and the like can be preferably used.
  • hydrophilic polymer for example, water- soluble polymer, enteric polymer, gastrosoluble polymer and the like can be used.
  • water-soluble polymer for example, cellulose derivative such as hydroxyalkylcellulose (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose) , alkylcellulose (e.g., methylcellulose) and the like, polyalkenylpyrrolidone such as polyvinylpyrrolidone and the like, polyalkylene glycol such as polyethylene glycol and the like, polyvinyl alcohol and the like can be used.
  • cellulose derivative such as hydroxyalkylcellulose (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose)
  • alkylcellulose e.g., methylcellulose
  • polyalkenylpyrrolidone such as polyvinylpyrrolidone and the like
  • polyalkylene glycol such as polyethylene glycol and the like
  • polyvinyl alcohol and the like can be used.
  • enteric polymer for example, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethyl ethylcellulose, cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer S, dried methacrylic acid copolymer LD and the like can be used.
  • gastrosoluble polymer for example, aminoalkyl methacrylate copolymer E, polyvinylacetal diethylaminoacetate and the like can be used.
  • carboxymethylcellulose Eudragit
  • carboxyvinyl polymer polyvinyl alcohol, gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, chitosan and the like
  • hydrophilic polymers may be used as a mixture of one or more kinds thereof.
  • polymers such as hydroxypropylmethylcellulose phthalate (HP-55, HP-50, manufactured by Shin-Etsu Chemical Co., Ltd.) , hydroxypropylmethylcellulose acetate succinate (AS-LF, manufactured by Shin-Etsu Chemical Co., Ltd.) , cellulose acetate phthalate, carboxymethyl ethylcellulose (CMEC, manufactured by Freund Corporation) , methyl methacrylate-methacrylic acid copolymer (Eudragit LlOO (methacrylic acid copolymer L) or Eudragit SlOO (methacrylic acid copolymer S) , manufactured by Rohm) , methacrylic acid-ethyl acrylate copolymer (Eudragit L100-55 (dried methacrylic acid copolymer LD) or Eudragit L30D-55 (methacrylic acid copolymer LD) , manufactured by Rohm) , methacrylic acid-methyl acrylate-methyl meth
  • the plasticizer is used in the present invention to lower the glass transition temperature of the carrier during formation of a solid dispersion.
  • the plasticizer for example, polyoxyethylene, polyethylene glycol, triethyl citrate, macrogols, triacetine, fatty acid triglyceride and the like can be mentioned.
  • the plasticizer is not limited to these examples and any compound can be used as long as it has an action to lower the glass transition temperature of the carrier. More specifically, as the plasticizer, various compounds such as triethyl citrate, polyethylene glycol (PEG6000 and the like) , polyethylene oxide (Polyox and the like) and the like can be used. Of these, polyethylene oxide (Polyox and the like) is preferable since it can also act as a drug release-controlling component.
  • the drug release-controlling component is used in the present invention to facilitate invasion of water into a solid dispersion for control of the drug release.
  • the drug release-controlling component of the present invention only needs to have hydrophilicity to draw water into the solid dispersion, and is preferably a hydrophilic compound.
  • the drug release rate can be controlled by determining the kind and amount of the drug release-controlling component according to the size, shape and the like of the solid dispersion.
  • hydrophilic compound hydrophilic polymers and hydrophilic low-molecular weight compounds can be preferably used.
  • a hydrophilic polymer is used to suppress or accelerate the drug release rate
  • the hydrophilic low-molecular weight compound is used to accelerate the drug release rate. It is also possible to use a hydrophilic low-molecular weight compound to further adjust the drug release rate suppressed or accelerated using a hydrophilic polymer.
  • hydrophilic polymer for example, the aforementioned water-soluble polymer, enteric polymer, gastrosoluble polymer and the like can be used.
  • the hydrophilic polymer used in the present invention has a high release-controlling function such as gel-forming function and the like, the level of sustained-release can be enhanced.
  • a gel-forming polymer any polymer can be used as long as it rapidly forms a highly viscous gel upon contact with water, and prolongs residence in the gastrointestinal tract.
  • a polymer having a viscosity of 5% aqueous solution at 25 0 C of not less than about 3000 mPa• s is preferable.
  • the molecular weight thereof is generally preferably about 400000 to 10000000.
  • Such gel-forming polymer is preferably a powder, granule or fine granule when a preparation is formed.
  • PEO polyethylene oxide
  • Polyox WSR303 molecular weight 7000000
  • Polyox WSR Coagulant molecular weight 5000000
  • Polyox WSR 301 molecular weight 4000000
  • Polyox WSR N-60K molecular weight 2000000
  • Polyox WSR 205 molecular weight 600000
  • HPMC hydroxypropylmettiylcellulose
  • carboxymethylcellulose sodium CMC-Na, Sanlose F-IOOOMC
  • HPCMC-Na carboxymethylcellulose sodium
  • HPC hydroxypropylcellulose
  • PEO polyethylene oxide
  • Polyox WSR303 molecular weight 7000000
  • Polyox WSR Coagulant molecular weight 5000000
  • Polyox WSR 301 molecular weight 4000000
  • hydrophilic low-molecular weight compound for example, saccharides such as lactose, sucrose and the like, sugar alcohols such as sorbitol, mannitol and the like, inorganic salts, organic salts and the like are used, with preference given to lactose, sucrose, mannitol and the like.
  • the drug release-controlling component can contain disintegrant, in addition to the above- mentioned components.
  • disintegrant for example, fumed silica (AEROSIL, manufactured by NIPPON AEROSIL CO., LTD.) , carboxymethylcellulose calcium (ECG-505, manufactured by Gotoku Yakuhin) , croscarmellose sodium (e.g., Ac-Di-SoI, manufactured by Asahi Kasei Chemicals Co.
  • crospovidone e.g., Kollidon CL, manufactured by BASF
  • low-substituted hydroxypropylcellulose manufactured by Shin-Etsu Chemical Co., Ltd.
  • carboxymethyl starch manufactured by Matsutani Kagaku K.K.
  • sodium carboxymethyl starch (Explotab, manufactured by Kimura Sangyo)
  • partially pregelatinized starch (PCS, manufactured by Asahi Kasei Chemicals Co., Ltd.) and the like can be used.
  • a solid dispersion means a solid composition, wherein the above-mentioned (i) drug, (ii) carrier(s) , (iii) plasticizer (s) , (iv) drug release-controlling component (s) , and, where necessary, other substance are homogeneously mixed.
  • other substances those other than the above-mentioned constituent components and is not particularly limited.
  • surfactant, glidant, lubricant, antioxidant, coloring agent, sweetening agent and the like can be used.
  • a solid dispersion may contain one kind of other substance or two or more kinds thereof. While the content of the (i) drug in the solid dispersion of the present invention varies depending on the form etc. of the preparation, it is determined to be generally about 0.1 to about 99.9 wt%, preferably about 0.1 to about 50 wt%, more preferably about 0.5 to about 30 wt%, relative to the whole solid dispersion.
  • the content of the (ii) carrier in the solid dispersion of the present invention varies depending on the dosage form, administration method and the like, it is generally about 0.1 to about 99.9% (w/w) , relative to the whole solid dispersion.
  • the content of the (iii) plasticizer in the solid dispersion of the present invention varies depending on the dosage form, administration method and the like, it is generally about 0 to about 99.9% (w/w) , preferably about 0.1 to about 99.9% (w/w) , relative to the whole solid dispersion.
  • the content of the (iv) drug release- controlling component in the solid dispersion of the present invention varies depending on the dosage form, administration method and the like, it is generally about 0 to about 99.9% (w/w) , preferably about 0.1 to about 99.9% (w/w) , relative to the whole solid dispersion.
  • the drug release- controlling component is a hydrophilic polymer
  • it is generally about 0 to about 90% (w/w) , relative to the whole solid dispersion
  • the drug release- controlling component is a hydrophilic low-molecular weight compound
  • it is generally about 0 to about 90% (w/w) , relative to the whole solid dispersion.
  • the weight ratio of the drug release-controlling component and the drug in the solid dispersion of the present invention only needs to be within the range of generally 0.01:1 to 100:1, preferably 0.02:1 to 50:1, more preferably 0.1:2 to 20:1, still more preferably 0.3:1 to 10:1, particularly preferably 1:1 to 10:1.
  • the ratio of other substances in the solid dispersion of the present invention can be determined optionally according to the object of use. While the content of other substances in the solid dispersion varies depending on the form etc. of the preparation, it is generally about 0 to about 99.9 wt%, preferably about 0.1 to about 50 wt%, more preferably about 0.5 to about 30 wtl, relative to the whole solid dispersion.
  • a "sustained-release preparation” means, for example, a preparation that shows a "drug dissolution rate from a preparation at 30 min after the start of the test" of less than 85% when The Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method) is performed using a suitable test solution (900 mL) ' at a paddle rotation of 100 rpm.
  • a test solution for example, a test solution that shows a drug concentration of not more than 1/3 of the saturated solubility of the drug, when the drug in a preparation is dissolved by 100% in a test solution, is used.
  • the test solution one conventionally employed in the technical field of formulation of preparations, such as water, buffer and the like, is used.
  • a preparation that shows a "drug dissolution rate from a preparation at 30 min after the start of the test" of not less than 85%, when The Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle method) is performed under the same conditions as above, is referred to as a immediate-release preparation.
  • Immediate-release preparations show a steep rise in the blood concentration after administration to living organisms , reaches the maximum blood concentration in a short time, and then shows rapid decrease.
  • the solid dispersion of the present invention shows sustained-release, the blood concentration after administration to living organisms gradually increases and remains at a sustained level.
  • the maximum blood concentration after administration of the solid dispersion of the present invention is suppressed to a low level as compared to immediate-release preparations and is not more than about 60% of that of immediate- release preparations, when compared at the same dose.
  • the solid dispersion of the present invention shows a sustained blood concentration, the area under the blood concentration-time curve is not less than about 60% of that of immediate-release preparations, when compared at the same dose.
  • the solid dispersion of the present invention permits sustained-release, the blood concentration after administration to living organisms increases gradually, reaches the maximum blood concentration and then decreases gradually. Therefore, the time period in which the blood concentration exceeds half the maximum blood concentration after administration of the solid dispersion of the present invention becomes twice or more longer than that of immediate-release preparations, when compared at the same dose.
  • heat-melting and “mixing” can be performed using conventional methods and apparatuses .
  • the “heat-melting” and “mixing” can be performed using, for example, conventional stirrer, kneader and the like having a heat source.
  • one having a structure permitting pressurization of the inside is more preferable.
  • extruder having a screw in a cylinder e.g., single screw extruder, twin screw extruder etc.
  • twin screw extruder is preferable.
  • a solvent is not used and the above- mentioned (i) drug, (ii) carrier(s) , (iii) plasticizer (s) and (iv) drug release-controlling component (s) , and, where necessary, other substance are cast into an apparatus maintaining a suitable heat- melting temperature from a hopper of the apparatus, and homogeneously kneaded by rotating the screw to allow melting of the solid substances.
  • a preliminary mixing may be applied as necessary before casting into the apparatus.
  • a solid dispersion (pharmaceutical composition) having the following characteristics can be obtained.
  • a solid dispersion (pharmaceutical composition) having an improved solubility.
  • a drug e.g. , p38 MAP kinase inhibitor
  • the solid dispersion obtained by the manufacturing method of the present invention can be used as it is as a pharmaceutical composition for oral administration after pulverization etc. as necessary. While the shape of the solid dispersion of the present invention may be any and can be extruded into any shape and size, for example, pellet, granule and the like can be mentioned.
  • the solid dispersion of the present invention can be mixed with additives conventionally used in the field of pharmaceutical preparation to give a pharmaceutical composition of fine granules, ultrafine granules, granules, tablets, capsules, and the like by conventional methods.
  • additives pharmacologically acceptable carriers such as various organic, inorganic carrier substances and the like, which are conventionally used as materials for preparations, are mixed as excipient, lubricant, binder, disintegrant, surfactant and the like.
  • additives for preparations such as adsorbent, preservative, antioxidant, coloring agent, sweetening agent and the like can be used.
  • lactose lactose
  • sucrose D-mannitol
  • starch crystalline cellulose
  • perforated starch mannitol
  • calcium silicate trade name: Florite RE
  • magnesium aluminate metasilicate trade name: Neusilin
  • light silicic anhydride trade name: sylysia
  • sucrose starch sphere trade name: Nonpareil
  • crystalline cellulose • carboxymethylcellulose trade name: Avicel RC
  • hydroxypropylstarch and the like can be mentioned.
  • lubricant magnesium stearate, calcium stearate, talc, colloidal silica, crystalline cellulose, cornstarch, magnesium oxide and the like can be mentioned.
  • binder crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like can be mentioned.
  • starch carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethylstarch, methylcellulose (trade name: Metolose SM) , carrnellose calcium, low-substituted hydroxypropylcellulose, sodium starch glycolate, partially pregelatinized starch and the like can be mentioned.
  • methylcellulose trade name: Metolose SM
  • carrnellose calcium low-substituted hydroxypropylcellulose
  • sodium starch glycolate sodium starch glycolate
  • partially pregelatinized starch and the like can be mentioned.
  • surfactant polyoxyethylene polyoxypropylene glycol (trade name: pluronic) , glycerol esters of fatty acids, sucrose esters of fatty acids, polyoxyethylene hydrogenated castor oil, polysorbate 80, cetanol and the like can be mentioned.
  • perforated starch calcium silicate (trade name: Florite RE) , magnesium aluminate metasilicate (trade name: Neusilin) , light silicic anhydride (trade name: sylysia) and the like can be mentioned.
  • p- oxybenzoates chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like can be mentioned.
  • antioxidant sulfite, ascorbic acid and the like can be mentioned.
  • coloring agent tar color, caramel, colcothar, titanium oxide, riboflavins and the like can be mentioned.
  • sucrose As preferable examples of the sweetening agent, sucrose, lactose, saccharine and the like can be mentioned.
  • additives can be used alone or in a mixture of two or more kinds thereof.
  • the content of the solid dispersion in the pharmaceutical composition of the present invention thus obtained varies depending on the dosage form, administration method, carrier and the like, it is generally 0.1 to 100% (w/w) relative to the whole preparation.
  • the content of the additive in the pharmaceutical composition of the present invention varies depending on the dosage form, administration method, carrier and the like, it is generally 0 to 99.9% (w/w) relative to the whole preparation.
  • the solid dispersion obtained by the manufacturing method of the present invention and a pharmaceutical composition containing the same can be administered to mammals (e.g., rat, mouse, guinea pig, monkey, bovine, dog, pig, human etc.) depending on the kind of the drug.
  • mammals e.g., rat, mouse, guinea pig, monkey, bovine, dog, pig, human etc.
  • the drug when it is compound (I) or a salt thereof, it shows an excellent adenosine A 3 receptor antagonistic activity in mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.) and is also excellent in (oral) absorption, (metabolism) stability and the like and, therefore, can be used as an agent for the prophylaxis or treatment of adenosine A3 receptor- related diseases, for example, asthma, allergic disease, inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, central nervous disease (e.g., cerebrovascular disease such as cerebral hemorrhage, cerebral infarction and the like, head trauma, spinal trauma, brain edema, multiple sclerosis and the like) , neurodegenerative disease (e.g., Alzheimer's disease, Parkinson's syndrome, amyotrophic lateral sclerosis (ALS) ) , diabetes and the
  • the drug when the drug is compound (I) or a salt thereof, it also shows an excellent p38 MAP kinase inhibitory activity and a TNF- ⁇ inhibitory activity (TNF- ⁇ production inhibitory activity, TNF- ⁇ action inhibitory activity) and is also useful as a safe drug based on these activities .
  • a pharmaceutical composition containing compound (I) or a salt thereof as a drug can be used as an agent for the prophylaxis or treatment of p38 MAP kinase related diseases and TNF- ⁇ related diseases, such as arthritis (e.g.
  • toxemia e.g., sepsis, septic shock, endotoxin shock, Gram-negative sepsis, toxic shock syndrome
  • inflammatory bowel disease e.g., Crohn's disease, ulcerative colitis
  • inflammatory pulmonary disease e.g., chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis
  • cachexia e.g., cachexia derived from infection, carcinocachexia, cachexia derived from acquired immunodeficiency syndrome (AIDS)
  • arteriosclerosis Creutzfeldt-Jakob disease
  • virus infection e.g., virus infection such as cytomegalovirus, influenzavirus, herpesvirus and the like
  • atopic dermatitis systemic lupus erythemato
  • compound (I) is used as an agent for the prophylaxis or treatment of rheumatism and the like.
  • the drug when it is compound (I) or a salt thereof, it can be used as an agent for the prophylaxis or treatment of various pain as mentioned below in mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.) .
  • Cancer pain acute pain caused by inflammation, pain associated with chronic inflammation, postoperative pain (pain of incision, deep pain, visceral pain, postoperative chronic pain disease and the like) , muscle pain (muscle pain associated with chronic pain disease, stiff neck and the like) , arthritic pain, toothache, pain of temporomandibular joint, headache (migraine, tension headache, headache caused by fever, headache associated with hypertension) , visceral pain (cardiac pain, anginal pain, abdominal pain, kidney pain, ureteral pain, cystalgia, obstetric and gynecologic pain (intermenstrual pain, dysmenorrhea, labor pain)) , neuralgia (hernia of intervertebral disk, radicular pain, post herpetic neuralgia pain, trigeminal neuralgia pain) , reflex sympathetic atrophy, complex topalgia syndrome and the like.
  • the drug when it is compound (I) or a salt thereof, it can be used as a suppressing agent of osteoclast activation or an inhibiting agent of osteoclasts formation for mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc. ) .
  • mammals e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.
  • Osteoclast is a multinucleated cell produced by differentiation and fusion of hematopoietic cells and has a bone substrate degradation function. In the bone metabolism, it plays a role of absorbing bone in contrast to osteoblast that newly creates bone. The maintenance of bone mass and morphology depends on the balance of the formation and absorption that the both cells perform, and when osteoclast is activated to promote bone absorption, the balance is broken and reduced bone mass, and morphological destruction and deformation occur. Since osteoclast is involved in the control of the blood calcium concentration via absorption of bone, which is a calcium reservoir organ, extreme activation of osteoclast increases the blood calcium concentration.
  • the drug when it is compound (I) or a salt thereof, it suppresses activation of osteoclast, and inhibits formation of osteoclasts.
  • it can be used as an agent for the prophylaxis or treatment of, for example, (i) postmenopausal or senile primary osteoporosis, (ii) inflammation (rheumatism and the like) , hematologic malignancy (malignant lymphoma, leukemia and the like) , endocrine disturbance (hyperthyroidism, diabetes and the like) or secondary osteoporosis caused by administration of pharmaceutical agents such as adrenal cortex hormone and the like, (iii) destruction or deformation of bone or joint tissue due to bone metastasis of tumor or rheumatism, (iv) Paget's disease or (v) hypercalcemia and the like.
  • the compound is useful because it has a prophylactic or therapeutic effect on the diseases relating to osteoclasts such as destruction or deformation of bone or joint tissue and the like.
  • the dose of the compound of the present invention or a concomitant drug can be reduced as compared to single administration of the compound of the present invention or a concomitant drug
  • the drug to be used in combination with the compound of the present invention can be selected depending on the condition of patients (mild, severe and the like) ,
  • the period of treatment can be set longer by selecting a concomitant drug having different action and mechanism from those of the compound of the present invention ,
  • a sustained treatment effect can be designed by selecting a concomitant drug having different action and mechanism from those of the compound of the present invention,
  • a pharmaceutical agent containing the compound of the present invention and a concomitant drug in combination is sometimes referred to as a "concomitant agent of the present invention".
  • the administration time of the compound of the present invention and the concomitant drug is not restricted, and a solid dispersion containing the compound of the present invention or a pharmaceutical composition thereof, and a concomitant drug or a pharmaceutical composition thereof, can be administered to an administration subject simultaneously, or may be administered at staggered times.
  • the concomitant agent of the present invention can be used after synovectomy, after a treatment using prosorba column, after a treatment using mononuclear cell and the like.
  • the dosage of the concomitant drug may be determined according to the dose clinically used, and can be appropriately selected depending on an administration subject, administration route, disease, combination and the like.
  • the administration mode of the concomitant agent of the present invention is not particularly restricted, as long as the compound of the present invention and the concomitant drug are combined in administration.
  • Examples of such administration mode include the following methods: (1) The compound of the present invention and the concomitant drug are simultaneously formulated to give a single solid dispersion to be administered. (2) A solid dispersion containing the compound of the present invention or a pharmaceutical composition thereof and a pharmaceutical composition containing a concomitant drug are separately formulated to give two kinds of preparations which are administered simultaneously by the same administration route.
  • a solid dispersion containing the compound of the present invention or a pharmaceutical composition thereof and a pharmaceutical composition containing a concomitant drug are separately formulated to give two kinds of preparations which are administered by the same administration route at staggered times.
  • a solid dispersion containing the compound of the present invention or a pharmaceutical composition thereof and a pharmaceutical composition containing a concomitant drug are separately formulated to give two kinds of preparations which are administered simultaneously by the different administration routes.
  • a solid dispersion containing the compound of the present invention or a pharmaceutical composition thereof and a pharmaceutical composition containing a concomitant drug are separately formulated to give two kinds of preparations which are administered by the different administration routes at staggered times (for example, the compound of the present invention and the concomitant drug are administered in this order, or in the reverse order) , and the like.
  • a concomitant agent of the present invention has low toxicity, and for example, a solid dispersion containing the compound of the present invention and the above-mentioned concomitant drug or a pharmaceutical composition thereof is produced according to the above- mentioned method, or the above-mentioned concomitant drug is mixed with a pharmacologically acceptable carrier according to a method known per se to give a pharmaceutical composition, such as tablets (including a sugar-coated tablet, film-coated tablet) , powders, granules, capsules (including soft capsules) , suppositories, sustained-release preparations and the like, which is safely administered orally or parenterally (e.g., topical administration, rectal administration and the like) together with a solid dispersion containing the compound of the present invention or a pharmaceutical composition thereof.
  • a pharmaceutical composition such as tablets (including a sugar-coated tablet, film-coated tablet) , powders, granules, capsules (including soft capsules) ,
  • pharmacologically acceptable carriers usable for the production of a pharmaceutical composition containing the above-mentioned concomitant drug
  • various organic or inorganic carrier substances conventionally used as preparation materials can be mentioned.
  • suitable amounts of additives such as excipient, lubricant, binder and disintegrant for solid preparations, and where necessary, conventional preservative, antioxidant, coloring agent, sweetening agent, adsorbent, wetting agent and the like can be used appropriately.
  • the mixing ratio of the compound of the present invention to the concomitant drug in the concomitant agent of the present invention can be appropriately selected depending on an administration subject, administration route, diseases and the like.
  • the content of the compound of the present invention in the concomitant agent of the present invention differs depending on the form of a preparation, and usually from about 0.01 to about 99.9 wtl, preferably from about 0.1 to about 50 wt%, further preferably from about 0.5 to about 20 wt%, based on the preparation.
  • the content of the concomitant drug in the concomitant agent of the present invention differs depending on the form of a preparation, and usually from about 0.01 to about 99.9 wt%, preferably from about 0.1 to about 50 wt%, further preferably from about 0.5 to about 20 wt%, based on the preparation.
  • the content of additives such as a carrier and the like in the concomitant agent of the present invention differs depending on the form of a preparation, and usually from about 1 to about 99.98 wtl , preferably from about 10 to about 90 wtl, based on the preparation.
  • the content of the compound of the present invention and the concomitant drug differs depending on the form of a preparation, and usually from about 0.01 to about 99.9 wtl, preferably from about 0.1 to about 50 wtl, more preferably from about 0.5 to about 20 wtl, based on the preparation.
  • the content of additives such as a carrier and the like differs depending on the form of a preparation, and usually from about 1 to about 99.99 wtl, preferably from about 10 to about 90 wtl, based on the preparation.
  • the dosage of a concomitant agent of the present invention differs depending on the kind of the drug, age, body weight, condition, dosage form, administration method, administration period and the like, and for example, for one arthritis patient (adult, body weight: about 60 kg) , the concomitant agent is administered, at a dose of about 0.01 to about 1000 mg/kg/day, preferably about 0.01 to about 100 mg/kg/day, more preferably about 0.1 to about 100 mg/kg/day, particularly about 0.1 to about 50 mg/kg/day, especially about 1.5 to about 30 mg/kg/day, in terms of the compound of the present invention or the concomitant drug, respectively, once or divided several times in a day.
  • amounts smaller than the above-mentioned dosage may sometimes be sufficient, further, amounts over that range sometimes have to be administered.
  • the amount of the concomitant drug can be set at any value unless side effects are problematical.
  • the daily dosage in terms of the concomitant drug differs depending on the severity, age, sex, body weight, sensitivity difference of the subject, administration period, interval, and nature, pharmacology, kind of the pharmaceutical preparation, kind of effective ingredient, and the like, and not particularly restricted, and the amount of a drug is, in the case of oral administration for example, usually from about
  • the compound of the present invention may be administered after administration of the concomitant drug or the concomitant drug may be administered after administration of the compound of the present invention, though they may be administered simultaneously.
  • the interval varies depending on the effective ingredient, dosage form and administration method, and, for example, when the concomitant drug is administered first, a method in which the compound of the present invention is administered within time range of from 1 minute to 3 days, preferably from 10 minutes to 1 day, more preferably from 15 minutes to 1 hour, after administration of the concomitant drug is exemplified.
  • a method in which the concomitant drug is administered within time range of from 1 minute to 1 day, preferably from 10 minutes to 6 hours, more preferably from 15 minutes to 1 hour after administration of the compound of the present invention is exemplified.
  • the concomitant drug, which has been formed into an oral administration preparation is administered orally at a daily dose of about 0.001 to 200 mg/kg, and about 15 minutes after, the compound of the present invention which has been formed into an oral administration preparation is administered orally at a daily dose of about 0.005 to 100 mg/kg.
  • Hydroxypropylmethylcellulose phthalate (6 g, trade name: HPMCP, brand: HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.)
  • hydroxypropylmethylcellulose 2910 (3 g, trade name: TC-5, brand: TC-5S, manufactured by Shin-Etsu Chemical Co., Ltd.)
  • polyethylene oxide 7 g, trade name: Polyox, brand: WSR 303, manufactured by Dow Chemical
  • the mixture (20 g) was extruded using a twin screw extruder eguipped with a die (bore 3 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 90 0 C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion.
  • the thus-obtained extruded product was cut into a length of about 10 mm with a retractable knife to give a pellet sample.
  • Example 2
  • Hydroxypropylmethylcellulose phthalate (6 g, trade name: HPMCP, brand: HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.)
  • hydroxypropylmethylcellulose 2910 (3 g, trade name: TC-5, brand: TC-5S, manufactured by Shin-Etsu Chemical Co., Ltd.)
  • polyethylene oxide 7 g, trade name: Polyox, brand: WSR 303, manufactured by Dow Chemical
  • the mixture (20 g) was extruded using a twin screw extruder equipped with a die (bore 6 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 90°C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion.
  • the thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample.
  • Hydroxypropylmethylcellulose phthalate (18 g, trade name: HPMCP, brand: HP-55, manufactured by Shin-Etsu Chemical Co. , Ltd.)
  • hydroxypropylmethylcellulose 2910 (9 g, trade name: TC-5, brand: TC-5S, manufactured by Shin-Etsu Chemical Co. , Ltd.)
  • polyethylene oxide 21 g, trade name: Polyox, brand: WSR Coagulant, manufactured by Dow Chemical
  • Example 5 From the mixture (60 g) prepared in Example 3, 2O g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of 100°C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample.
  • a twin screw extruder equipped with a die (bore 3 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of 100°C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give
  • Hydroxypropylmethylcellulose phthalate (18 g, trade name: HPMCP, brand: HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.)
  • hydroxypropylmethylcellulose 2910 (9 g, trade name: TC-5, brand: TC-5S, manufactured by
  • Example 7 From the mixture (60 g) prepared in Example 6, 2O g thereof was extruded using a twin screw extruder equipped with a die (bore 1 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 100 0 C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 1 mm with a rapid pelletizer (manufactured by Imoto Machinery Co., Ltd.) to give a granule sample.
  • Example 8 From the mixture (60 g) prepared in Example 6, 2O g thereof was extruded using a twin screw extruder equipped with a die (bore 1 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 100 0 C and a screw rotation speed of 80 rpm to give an extruded product of
  • Hydroxypropylmethylcellulose acetate succinate (13.5 g, trade name: Shin-Etsu AQOAT, brand: AS-LF, manufactured by Shin-Etsu Chemical Co., Ltd.)
  • hydroxypropylmethylcellulose 2910 (6.75 g, trade name: TC-5, brand: TC-5S, manufactured by Shin-Etsu Chemical Co., Ltd.)
  • polyethylene oxide 15.75 g, trade name: Polyox, brand: WSR Coagulant, manufactured by Dow Chemical
  • Example 10 From the mixture (45 g) prepared in Example 9, 15 g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 100 0 C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample.
  • Example 11 Example 11
  • Hydroxypropylmethylcellulose phthalate (6 g, trade name: HPMCP, brand: HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.)
  • hydroxypropylmethylcellulose 2910 (7 g, trade name: TC-5, brand: TC-5S, manufactured by Shin-Etsu Chemical Co., Ltd.)
  • polyethylene oxide (3 g, trade name: Polyox, brand: WSR 303, manufactured by Dow Chemical
  • the mixture (20 g) was extruded using a twin screw extruder equipped with a die (bore 3 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 90°C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion.
  • the thus-obtained extruded product was cut into a length of about 10 mm with a retractable knife to give a pellet sample.
  • Hydroxypropylmethylcellulose phthalate (6 g, trade name: HPMCP, brand: HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.)
  • hydroxypropylmethylcellulose 2910 (9 g, trade name: TC-5, brand: TC-5S, manufactured by Shin-Etsu Chemical Co., Ltd.)
  • polyethylene oxide (1 g, trade name: Polyox, brand: WSR 303, manufactured by Dow Chemical
  • the mixture (20 g) was extruded using a twin screw extruder equipped with a die (bore 3 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 90 0 C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion.
  • the thus-obtained extruded product was cut into a length of about 10 mm with a retractable knife to give a pellet sample.
  • Hydroxypropylmethylcellulose acetate succinate (6 g, trade name: Shin-Etsu AQOAT, brand: AS-LF, manufactured by Shin-Etsu Chemical Co., Ltd.) , lactose (9 g) and macrogol 6000 (3 g, manufactured by NOF Corporation) were weighed and manually mixed with compound A (12 g) in a mortar for about 3 min.
  • Example 16 From the mixture (30 g) prepared in Example 14, 1O g thereof was extruded using a twin screw extruder equipped with a die (bore 1 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of 100°C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 1 mm with a rapid pelletizer (manufactured by Imoto Machinery Co. , Ltd.) to give a granule sample.
  • a twin screw extruder equipped with a die (bore 1 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of 100°C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about
  • Example 17 From the mixture (30 g) prepared in Example 14, 1O g thereof was extruded using a twin screw extruder equipped with a die (bore 1 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of HO 0 C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 1 mm with a rapid pelletizer (manufactured by Imoto Machinery Co. , Ltd.) to give a granule sample.
  • a twin screw extruder equipped with a die (bore 1 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of HO 0 C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion.
  • the thus-obtained extruded product was cut
  • Hydroxypropylmethylcellulose acetate succinate (9 g, trade name: Shin-Etsu AQOAT, brand: AS-LF, manufactured by Shin-Etsu Chemical Co. , Ltd.) , AEROSIL (6 g, manufactured by NIPPON AEROSIL CO. , LTD.) and macrogol 6000 (3 g, manufactured by NOF Corporation) were weighed and manually mixed with compound A (12 g) in a mortar for about 3 min. From the mixture (30 g) , 1O g thereof was extruded using a twin screw extruder equipped with a die (bore 1 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co.
  • Example 18 At a barrel temperature of 90 0 C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion.
  • the thus- obtained extruded product was cut into a length of about 1 mm with a rapid pelletizer (manufactured by Imoto Machinery Co. , Ltd.) to give a granule sample.
  • a rapid pelletizer manufactured by Imoto Machinery Co. , Ltd.
  • Hydroxypropylmethylcellulose acetate succinate (18 g, trade name: Shin-Etsu AQOAT, brand: AS-LF, manufactured by Shin-Etsu Chemical Co. , Ltd.)
  • hydroxypropylmethylcellulose 2910 (9 g, trade name: TC-5 , brand: TC-5S, manufactured by Shin-Etsu Chemical Co. , Ltd.)
  • polyethylene oxide 21 g, trade name: Polyox, brand: WSR Coagulant, manufactured by Dow Chemical
  • Example 22 From the mixture (60 g) prepared in Example 20, 20 g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 70°C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample.
  • a twin screw extruder equipped with a die (bore 3 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 70°C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion.
  • the thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give
  • Example 23 From the mixture (60 g) prepared in Example 20, 20 g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 8O 0 C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample.
  • a twin screw extruder equipped with a die (bore 3 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 8O 0 C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion.
  • the thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable
  • Hydroxypropylmethylcellulose acetate succinate (18 g, trade name: Shin-Etsu AQOAT, brand: AS-LF, manufactured by Shin-Etsu Chemical Co. , Ltd. )
  • hydroxypropylmethylcellulose 2910 21 g, trade name: TC- 5, brand: TC-5S, manufactured by Shin-Etsu Chemical Co., Ltd.
  • polyethylene oxide 9 g, trade name: Polyox, brand: WSR Coagulant, manufactured by Dow Chemical
  • Example 25 From the mixture (60 g) prepared in Example 23, 2O g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of 100 0 C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample.
  • a twin screw extruder equipped with a die (bore 3 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of 100 0 C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion.
  • the thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retract
  • Hydroxypropylmethylcellulose acetate succinate (18 g, trade name: Shin-Etsu AQOAT, brand: AS-HF, manufactured by Shin-Etsu Chemical Co., Ltd.)
  • hydroxypropylmethylcellulose 2910 (9 g, trade name: TC-5, brand: TC-5S, manufactured by Shin-Etsu Chemical Co., Ltd.)
  • polyethylene oxide 21 g, trade name: Polyox, brand: WSR Coagulant, manufactured by Dow Chemical
  • Example 28 From the mixture (60 g) prepared in Example 26, 2O g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mm ⁇ ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of 100°C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample.
  • Example 28 Example 28
  • Compound A (22,500 g) , lactose (33,730 g) and cornstarch (6,750 g) were placed in a fluidized bed granulating dryer (manufactured by POWREX) , preliminarily mixed, and granulated by spraying an aqueous solution (40,510 g) containing hydroxypropylcellulose (HPC-L, 2,025 g) dissolved therein.
  • the obtained granules (62,690 g) was passed through a power mill (manufactured by Showa Kagaku Kikai Kosakusho Co., Ltd.) to give a sized powder.
  • the oral absorption was evaluated in dogs for the pellet solid dispersion obtained in Example 1 and the film-coated tablet obtained in Comparative Example 1.
  • a fluid diet (pulverized solid feed 50 g + water 80 g) was fed before administration of the preparation, and the preparation was orally administered with 60 mL of water 30 min after the food intake. The dose was 100 mg/body based on the amount of compound A.
  • blood about 1 mL was drawn from the median antebrachial vein.
  • the plasma was centrifuged and plasma concentration was measured by HPLC.
  • the area under the blood concentration-time curve (AUC) and mean residence time (MRT) were calculated by the trapezoid method.
  • the maximum plasma concentration (C max ) and the time to reach the maximum plasma concentration (T max ) were determined from the measured values.
  • the plasma concentration of compound A after oral administration of each preparation to the dogs is shown in Fig. 1, and the pharmacokinetic parameters calculated from the result are shown in Table 8.
  • Example 2 As is clear from the results of Fig. 1 and Table 8, the solid dispersion of Example 1 showed an AUC that was not much different from that of the film-coated tablet of Comparative Example 1, but a C max that decreased to about 40%, and a T 103x that was prolonged to about 5 hrs and an MRT to about 3 hrs, thus exhibiting clear sustained-release.
  • Experimental Example 2
  • Example 3 The oral absorption was evaluated in dogs for the pellet solid dispersions obtained in Example 3, Example 4, Example 5, Example 9, Example 22 and Example 26 and the film-coated tablet obtained in Comparative Example 1.
  • a fluid diet (pulverized solid feed 50 g + water 80 g) was fed before administration of the preparation, and the preparation was orally administered with 60 mL of water 30 min after the food intake. The dose was 100 mg/body based on the amount of compound A.
  • blood (about 1 mL) was drawn from the median antebrachial vein. The plasma was centrifuged and plasma concentration was measured by HPLC.
  • the area under the blood concentration (AUC) and average residence time (MRT) were calculated by the trapozoid method.
  • the maximum plasma concentration (C raax ) and the time to reach the maximum plasma concentration (T max ) were determined from the measured values.
  • Example 3 As is clear from the results of Fig. 2 and Table 9, the solid dispersions of Example 3, Example 4, Example 5, Example 9, Example 22 and Example 26 showed an AUC that was not much different from that of the film-coated tablet of Comparative Example 1, but a C max that decreased to about 40% to about 50%, and a T max that was prolonged to about 5 hrs to 7 hrs and an MRT to about 3 hrs to 4 hrs, thus exhibiting clear sustained-release.
  • improvement of solubility of poorly soluble or insoluble drugs and a drug release- controlling function can be provided simultaneously in a single manufacturing process and a solid dispersion having a uniform composition and superior sustained- release can be provided.

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Abstract

The present invention provides a solid dispersion containing (i) a p38 MAP kinase inhibitor, (ii) carrier(s), (iii) plasticizer(s) and (iV) drug release-controlling component(s). According to the present invention, the solubility of poorly soluble or insoluble drugs can be improved and a drug release-controlling function can be provided simultaneously in a single manufacturing process, and a solid dispersion having a uniform composition and permitting sustained- release of drugs can be provided.

Description

DESCRIPTION
NOVEL SOLID DISPERSION AND MANUFACTURING METHOD THEREOF
Technical Field
The present invention relates to a solid dispersion of a p38 MAP kinase inhibitor and a manufacturing method thereof.
Background Art:
It is known that solid dispersions produced by preparing a homogeneous solution or molten product of a poorly soluble compound in a hydrophilic polymer matrix, and coagulating the mixture by cooling or removing the solvent, improve solubility and absorption, and enhance bioavailability of pharmaceutical agents. For example, it is known that griseofulvin is dispersed in polyethylene glycol, which is a hydrophilic polymer, to give a solid dispersion, and its solubility and the like are improved (J. Pharm. Sci. , 60(9) , 1281-1302 (1971)) . Moreover, a solid dispersion of sulfathiazole in polyvinylpyrrolidone (J. Pharm. Sci., 58(5) , 538-549 (1969)) , a solid dispersion of fisoxazole, sufamethizol in polyvinylpyrrolidone (Chem. Pharm. Bull., 27(5) , 1223-1230 (1979)) and the like are also known.
In JP-B-2527107, moreover, a manufacturing method of a solid dispersion using a twin screw extruder has been described. This method is a superior method in that an organic solvent is not used. However, the prior arts all comprise forming a solid dispersion for the purpose of improving solubility of poorly soluble or insoluble drugs, and do not intend to improve solubility of drugs and provide release-controlling function of drugs simultaneously in a single manufacturing process.
In addition, WO 00/64894, WO 01/10865, WO 01/74811 and WO 02/51442 describe compounds having a superior p38 MAP kinase activity. Disclosure of the Invention
In view of the above-mentioned problems , the present invention intends to improve solubility of poorly soluble or insoluble drugs and provide drug release- controlling function simultaneously in a single manufacturing process, and aims at providing a solid dispersion having a uniform composition and superior in sustained-release of drugs, and a manufacturing method thereof. The present inventors have found that, in a mixing step of a solid dispersion containing (i) a drug such as a p38 MAP kinase inhibitor and the like, (ii) carrier(s) , (iii) plasticizer (s) and (iv) drug release- controlling component (s) , kneading while heat-melting without using a solvent results in the manufacturing of a solid dispersion showing improved solubility of a drug which is afforded by amorphosizing the drug and permitting control of the drug release rate. The present inventors have further studied and surprisingly found that the solid dispersion of the present invention shows fine sustained-release of drugs, which resulted in the completion of the present invention.
Accordingly, the present invention relates to
(1) a solid dispersion comprising a p38 MAP kinase inhibitor;
(2) the solid dispersion according to (1) , wherein the p38 MAP kinase inhibitor is an optionally N-oxidized compound represented by the formula (I) :
Figure imgf000003_0001
wherein R1 is a hydrogen atom, a hydrocarbon group optionally having substituent (s) , a heterocyclic group optionally having substituent (s) , an amino group optionally having substituent (s) or an acyl group; R2 is an aromatic group optionally having substituent (s) ; R3 is a hydrogen atom, a pyridyl group optionally having substituent (s) or an aromatic hydrocarbon group optionally having substituent (s) ; X is an oxygen atom or an optionally oxidized sulfur atom;
Y is a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR4 (wherein R4 is a hydrogen atom, a hydrocarbon group optionally having substituent (s) or an acyl group) ; and Z is a bond or a divalent chain hydrocarbon group optionally having substituent (s) (hereinafter, abbreviated as compound (I) sometimes) , or a salt thereof ;
(3) the solid dispersion according to (1) , wherein the p38 MAP kinase inhibitor is N- [4- [2-ethyl-4- (3- methylphenyl) -l,3-thiazol-5-yl] -2-pyridyl] benzamide , N- benzyl-N- [4- [2-ethyl-4- (3-methylphenyl) -1 , 3-thiazol-5- yl] -2-pyridyl] amine or N- [4- [4- (3-methylphenyl) -2- (4- methylsulfonylphenyl) -1 , 3-thiazol-5-yl] -2-pyridyl] -N- (2- phenylethyl) amine ;
(4) the solid dispersion according to (1) , wherein the p38 MAP kinase inhibitor is mostly amorphous;
(5) the solid dispersion according to (1) , which provides sustained-release (sustained-release solid dispersion) ;
(6) the solid dispersion according to (1) , which prevents a steep rise in the blood concentration after administration and affords a sustained blood concentration ; (7) the solid dispersion according to (1) , which affords a blood concentration such that the maximum blood concentration after administration is not more than about 60% of that of immediate-release preparations and an area under the blood concentration-time curve is not less than about 60% of that of immediate-release preparations ;
(8) the solid dispersion according to (1) , which affords a blood concentration such that a time period in which a blood concentration exceeds half the maximum blood concentration after administration is twice or more longer than that of immediate-release preparations;
(9) the solid dispersion according to (1) , which further comprises plasticizer (s) and/or drug release- controlling component (s) ;
(10) the solid dispersion according to (1) , wherein the carrier is a polymeric carrier (s) ;
(11) the solid dispersion according to (1) , wherein the carrier has a softening temperature of about 600C to about 35O0C;
(12) the solid dispersion according to (1) , wherein the carrier is a hydrophilic polymer;
(13) the solid dispersion according to (9) , wherein the plasticizer is selected from polyethylene oxide, polyethylene glycol and triethyl citrate;
(14) the solid dispersion according to (9) , wherein the drug release-controlling component is a hydrophilic compound;
(15) a manufacturing method of a solid dispersion, which comprising mixing (i) a drug, (ii) carrier(s) , (iii) plasticizer (s) and (iv) drug release-controlling component (s) , without using a solvent;
(16) the manufacturing method according to (15) , wherein the mixing is performed by kneading with heat-melting; (17) the manufacturing method according to (15) , wherein the mixing is performed by kneading in a twin screw extruder ;
(18) the manufacturing method according to (15) , wherein the drug is a p38 MAP kinase inhibitor;
(19) a solid dispersion (particularly sustained-release solid dispersion) obtained by the manufacturing method according to (15) ;
(20) a pharmaceutical composition (particularly sustained-release preparation) comprising the solid dispersion according to (1) ; and the like.
According to the present invention, the solubility of poorly soluble or insoluble drugs can be improved and a drug release-controlling function can be provided simultaneously in a single manufacturing process, and a solid dispersion having a uniform composition and permitting sustained-release of drugs can be provided. Brief Description of the Drawings Fig. 1 is a graph showing changes of plasma concentration of compound A contained in the solid dispersion of the present invention, wherein the transverse axis shows time (hour) after administration of the solid dispersion of the present invention and the vertical axis shows concentration (μg/mL) of compound A in plasma.
Fig. 2 is a graph showing changes of plasma concentration of compound A contained in the solid dispersion of the present invention, wherein the transverse axis shows time (hour) after administration of the solid dispersion of the present invention and the vertical axis shows concentration (μg/mL) of compound A in plasma.
Best Mode for Embodying the Invention In the present invention, by the "solid dispersion" is meant, for example, a dispersion of one or more kinds of active ingredients in a solid state dispersed in an inactive carrier or a matrix thereof, which can be prepared by molten methods, solvent methods, molten- solvent methods and the like (see J. Pharm. Sci., Vol. 60, 1281-1302, 1971) .
Particularly, the drug contained in the solid dispersion of the present invention is desirably mostly amorphous (specifically, the proportion of crystals in the drug is not more than 20 wt%, preferably not more than 5 wt%) .
The solid dispersion of the present invention can be obtained by melting the constituent components to give a homogeneous kneaded mixture, extruding the mixture and molding the extruded product. The product can be cut into any size according to the object of use.
The solid dispersion of the present invention can be obtained as particles having any particle size by pulverizing in a suitable pulverizer, and may be utilized as they are in the form of as a powder or granules. It is also possible to use the pulverized ultrafine particles for tablets, granules, fine granules, capsules and the like. As the drug to be used in the present invention, p38 MAP kinase inhibitors (thiazole compounds described in WO00/64894, WO01/10865, WO01/74811, WO02/51442 and the like, and the like) , which are used as therapeutic agents for arthrosis and the like, JNK inhibitors (compounds described in WO02/62792 and the like) and the like, can be mentioned.
Of these drugs, the solid drug to be used in the present invention is preferably a p38 MAP kinase inhibitor or a JNK inhibitor, such as a thiazole compound, an oxazole compound and the like. Moreover, the drug is preferably an optionally N-oxidized compound represented by the formula (I) :
Figure imgf000008_0001
wherein
R1 is a hydrogen atom, a hydrocarbon group optionally having substituent (s) , a heterocyclic group optionally having substituent (s) , an amino group optionally having substituent (s) or an acyl group; R2 is an aromatic group optionally having substituent (s) ; R3 is a hydrogen atom, a pyridyl group optionally having substituent (s) or an aromatic hydrocarbon group optionally having substituent (s) ; X is an oxygen atom or an optionally oxidized sulfur atom;
Y is a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR4 (wherein R4 is a hydrogen atom, a hydrocarbon group optionally having substituent (s) or an acyl group) ; and Z is a bond or a divalent chain hydrocarbon group optionally having substituent (s) , or a salt thereof. In the above-mentioned formula, R1 is a hydrogen atom, a hydrocarbon group optionally having substituent (s) , a heterocyclic group optionally having substituent (s) , an amino group optionally having substituent (s) or an acyl group.
As the "acyl group" for R1, for example, an acyl group represented by the formula: -(C=O)-R5, -(C=O)-OR5, -(C=O)-NR5R6, -(C=S)-NHR5 or -SO2-R7 [wherein R5 is a hydrogen atom, a hydrocarbon group optionally having substituent (s) or a heterocyclic group optionally having substituent (s) , R6 is a hydrogen atom or a Cι-6 alkyl group, and R7 is a hydrocarbon group optionally having substituent (s) or a heterocyclic group optionally having substituent (s) ] and the like can be mentioned.
In the above-mentioned formula, as the "hydrocarbon group" of the "hydrocarbon group optionally having substituent (s) " for R5, for example, a chain or cyclic hydrocarbon group (e.g. , alkyl, alkenyl, alkynyl, cycloalkyl, aryl , aralkyl etc.) and the like can be mentioned. Of these, a chain or cyclic hydrocarbon group having 1 to 16 carbon atoms and the like are preferable.
As the "alkyl", for example, Ci-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, hexyl etc.) and the like are preferable, and C1-3 alkyl (e.g., methyl, ethyl, propyl, isopropyl) is particularly preferable.
As the "alkenyl", for example, C2-6 alkenyl (e.g., vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3- butenyl, 2-methyl-2-propenyl, l-methyl-2-propenyl, 2- methyl-1-propenyl etc.) and the like are preferable.
As the "alkynyl", for example, C2-6 alkynyl (e.g., ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- hexynyl etc.) and the like are preferable. As the "cycloalkyl", for example, C3_6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.) and the like are preferable.
As the "aryl", for example, Cε-n aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4- biphenylyl, 2-anthryl etc.) and the like are preferable.
As the "aralkyl", for example, C7-I6 aralkyl (e.g., benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2- naphthylmethyl, 2,2~diphenylethyl, 3-phenylpropyl, 4- phenylbutyl, 5-phenylpentyl etc.) and the like are preferable.
As the "subs'tituent" of the "hydrocarbon group optionally having substituent (s) " for R5, for example, oxo, halogen atom (e.g., fluorine, chlorine, bromine, iodine) ,
Cχ-3 alkylenedioxy (e.g. , methylenedioxy, ethylenedioxy etc. ) , nitro, cyano, optionally halogenated Ci-6 alkyl, optionally halogenated C2-6 alkenyl, carboxy-C2-6 alkenyl (e.g., 2-carboxyethenyl, 2-carboxy-
2-methylethenyl etc.) , optionally halogenated C2-B alkynyl, optionally halogenated C3.$ cycloalkyl,
C6-H aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2- biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl etc.) , optionally halogenated Ci_8 alkoxy, Ci-6 alkoxy-carbonyl-Ci-6 alkoxy (e.g., ethoxycarbonylmethyloxy etc. ) , hydroxy,
C6-i4 aryloxy (e.g., phenyloxy, 1-naphthyloxy, 2- naphthyloxy etc. ) , C7-16 aralkyloxy (e.g., benzyloxy, phenethyloxy etc.) , mercapto, optionally halogenated Ci-6 alkylthio,
Cε-14 arylthio (e.g., phenylthio, 1-naphthylthio, 2- naphthylthio etc.) , C7-16 aralkylthio (e.g., benzylthio, phenethylthio etc.) , amino, mono-Ci-B alkylamino (e.g., methylamino, ethylamino etc. ) , mono-Ce-H arylamino (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino etc.) , di-Ci-6 alkylamino (e.g., dimethylamino, diethylamino, ethylmethylamino etc.) , di-C6_14 arylamino (e.g., diphenylamino etc.), formyl, carboxy,
Ci_6 alkyl-carbonyl (e.g., acetyl, propionyl etc.) ,
C3_6 cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl etc.) , Ci_6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl etc. ) ,
C6-i4 aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2- naphthoyl etc.) , C7-16 aralkyl-carbonyl (e.g., phenylacetyl, 3- phenylpropionyl etc.) ,
Cβ-14 aryloxy-carbonyl (e.g., phenoxycarbonyl etc.) ,
C7_i6 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl etc.) , 5- or 6-membered heterocyclylcarbonyl (e.g., nicotinoyl, isonicotinoyl, thenoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl etc.) , carbamoyl, thiocarbamoyl, mono-Ci-6 alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc. ) , di-Ci-6 alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.) , C6-H aryl-carbamoyl (e.g., phenylcarbamoyl, 1- naphthylcarbamoyl, 2-naphthylcarbamoyl etc) ,
5- or 6-membered heterocyclylcarbamoyl (e.g., 2- pyridylcarbamoyl, 3-pyridylcarbamoyl, 4- pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl etc. ) ,
Ci-6 alkylsulfonyl (e.g. , methylsulfonyl, ethylsulfonyl etc. ) ,
C6-i4 arylsulfonyl (e.g., phenylsulfonyl, 1- naphthylsulfonyl, 2-naphthylsulfonyl etc.) ,
Ci_6 alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl etc. ) ,
C6-I4 arylsulfinyl (e.g., phenylsulfinyl, 1- naphthylsulfinyl, 2-naphthylsulfinyl etc.) , formylamino,
Ci-6 alkyl-carbonylamino (e.g. , acetylamino etc.) ,
C6-i4 aryl-carbonylamino (e.g., benzoylamino, naphthoylamino etc.) ,
Ci-6 alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino etc.) ,
Ci-6 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino etc.) ,
Cε-14 arylsulfonylamino (e.g., phenylsulfonylamino, 2- naphthylsulfonylamino, 1-naphthylsulfonylamino etc.) ,
Ci-6 alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc. ) ,
Cβ-14 aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy etc.) , Ci-6 alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy etc. ) , mono-Ci-6 alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.) , di-Ci-6 alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy etc.) ,
Cε-14 aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy etc.) , nicotinoyloxy, 5- to 7-rnembered saturated cyclic amino optionally having substituent (s) , a 5- to 10-membered aromatic heterocyclic group (e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8- quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2- benzothiazolyl, 2-benzo [b] thienyl, 3-benzo [b] thienyl, 2- benzo [b] furanyl, 3-benzo [b] furanyl etc.) , sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl, and the like can be mentioned. The "hydrocarbon group" optionally has, for example, 1 to 5, preferably 1 to 3, substituents mentioned above at substitutable positions. When the number of the substituents is 2 or more, the respective substituents may be the same or different. As the above-mentioned "optionally halogenated Ci-6 alkyl", for example, Ci-e alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, hexyl etc.) optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine) , and the like can be mentioned. As specific examples, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3 ,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4- trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl and the like can be mentioned.
As the above-mentioned "optionally halogenated C2-6 alkenyl", for example, C2-6 alkenyl (e.g., vinyl, propenyl, isopropenyl, 2-buten-l-yl, 4-penten-l-yl, 5- hexen-1-yl etc.) optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine) , and the like can be mentioned. As the above-mentioned "optionally halogenated C2-β alkynyl", for example, C2-6 alkynyl (e.g., 2-butyn-l-yl, 4-pentyn-l-yl, 5-hexyn-l-yl etc.) optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine) , and the like can be mentioned.
As the above-mentioned "optionally halogenated C3-6 cycloalkyl", for example, C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.) optionally having 1 to 5, preferably 1 to 3 , halogen atoms (e.g., fluorine, chlorine, bromine, iodine) , and the like can be mentioned. As specific examples, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4- dichlorocyclohexyl, 2,2 ,3,3-tetrafluorocyclopentyl, 4- chlorocyclohexyl and the like can be mentioned. As the above-mentioned "optionally halogenated Ci_8 alkoxy", for example, d-β alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine) , and the like can be mentioned. As specific examples, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2- trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4- trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like can be mentioned.
As the above-mentioned "optionally halogenated Ci-6 alkylthio", for example, Ci_6 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio etc.) optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g. , fluorine, chlorine, bromine, iodine) and the like can be mentioned. As specific examples, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4- trifluorobutylthio, pentylthio, hexylthio and the like can be mentioned.
As the W5- to 7-membered saturated cyclic amino" of the above-mentioned W5- to 7-membered saturated cyclic amino optionally having substituent (s) " , for example, 5- to 7-membered saturated cyclic amino containing one nitrogen atom and optionally containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and the like can be mentioned. As specific examples, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl and the like can be mentioned.
As the "substituent" of the W5- to 7-membered saturated cyclic amino optionally having substituent (s) ", for example, Ci-6 alkyl (e.g. , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) , Cε-i4 aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4- biphenylyl, 2-anthryl etc.) , Cχ-6 alkyl-carbonyl (e.g. , acetyl, propionyl etc.) , a 5- to 10-membered aromatic heterocyclic group (e.g., 2-thienyl, 3-thienyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3- isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2- indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo [b]thienyl, 3-benzo [b] thienyl, 2-benzo [b] furanyl, 3-benzo [b] furanyl etc.) , oxo and the like can be mentioned. The "5- to 7- membered saturated cyclic amino" optionally has 1 to 3 substituents mentioned above at substitutable positions. When the number of the substituents is 2 or more, the respective substituents may be the same or different. As the "heterocyclic group" of the "heterocyclic group optionally having substituent(s) " for R5, for example, a monovalent group obtained by removing one of hydrogen atoms from 5- to 14-membered (monocyclic, bicyclic or tricyclic) heterocycle containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, preferably, (i) 5- to 14-membered (preferably 5- to 10-membered, particularly preferably 5- or 6-membered) aromatic heterocycle, (ii) 5- to 10- membered (preferably 5- or 6-membered) non-aromatic heterocycle, (iii) 7- to 10-membered crosslinked heterocycle, and the like, can be mentioned.
As the above-mentioned "5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle", for example, aromatic heterocycle such as thiophene, benzo [b]thiophene, benzo [b] furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphto[2,3- b]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, IH-indazole, purine, 4H-quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β- carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isoxazole, furazan, phenoxazine and the like; heterocycle formed by condensing such heterocycle
(preferably monocycle) with one or more (preferably 1 or 2) aromatic rings (e.g. , benzene ring etc.) , and the like can be mentioned.
As the above-mentioned "5- to 10-membered non- aromatic heterocycle", for example, pyrrolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dioxazole, oxadiazoline, thiadiazoline, triazoline, thiadiazole, dithiazole and the like can be mentioned.
As the above-mentioned "7- to 10-membered crosslinked heterocycle", for example, quinuclidine, 7- azabicyclo [2.2.1]heptane and the like can be mentioned.
As the "heterocyclic group", a 5- to 14-membered (preferably 5- to 10-membered) (monocyclic or bicyclic) heterocyclic group containing, besides carbon atom, 1 or
2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and the like are preferable. Specifically, for example, aromatic heterocyclic group such as 2-thienyl, 3-thienyl, 2- furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8- quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl , 2-oxazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 3- indolyl, 2-benzothiazolyl, 2-benzo [b]thienyl, 3- benzo [b]thienyl, 2-benzo [b] furanyl, 3-benzo [b] furanyl and the like; non-aromatic heterocycle group such as 1- pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2- imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl, 3- pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino and the like, and the like can be mentioned.
Of these, for example, a 5- or 6-membered heterocyclic group containing, besides carbon atom, 1 to
3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and the like are more preferable. Specifically, for example, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3- furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3- pyridazinyl, 3-isothiazolyl, 2-oxazolyl, 3-isoxazolyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2- imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl, 3- pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino and the like can be mentioned.
As the "substituenf of the "heterocyclic group optionally having substituent (s) ", for example, those similar to the "substituent" of the "hydrocarbon group optionally having substituent (s) " for the above- mentioned R5, and the like can be mentioned.
The "heterocyclic group" optionally has, for example, 1 to 5, preferably 1 to 3 , substituents mentioned above at substitutable positions. When the number of the substituents is 2 or more, the respective substituents may be the same or different.
As the "Ci-6 alkyl group" for R6, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, hexyl and the like can be mentioned. As the "hydrocarbon group optionally having substituent (s) " and "heterocyclic group optionally having substituent(s) " for R7, for example, those similar to the "hydrocarbon group optionally having substituent (s) " and "heterocyclic group optionally having substituent (s) ", respectively, for the above- mentioned R5, and the like can be mentioned.
As the "hydrocarbon group optionally having substituent (s) " and "heterocyclic group optionally having substituent (s) " for R1, for example, those similar to the "hydrocarbon group optionally having substituent (s) " and "heterocyclic group optionally having substituent (s) ", respectively, for the above- mentioned R5, and the like can be mentioned. As the "amino group optionally having substituent (s) " for R1, for example,
(1) an amino group optionally having 1 or 2 substituents ,
(2) a cyclic amino group optionally having substituent (s) , and the like can be mentioned.
As the "substituent" of the "amino group optionally having 1 or 2 substituents" in the above-mentioned (1) , for example, a hydrocarbon group optionally having substituent (s) , a heterocyclic group optionally having substituent (s) , an acyl group, an alkylidene group optionally having substituent (s) and the like can be mentioned. As the "hydrocarbon group optionally having substituent (s) " and "heterocyclic group optionally having substituent (s) ", for example, those similar to the "hydrocarbon group optionally having substituent (s) " and "heterocyclic group optionally having substituent (s) ", respectively, for the above-mentioned R5, and the like can be mentioned. As the "acyl group", fox example, those similar to the "acyl group" for the above-mentioned R1, and the like can be mentioned.
As the "alkylidene group" of the "alkylidene group optionally having substituent (s) ", for example, a Ci-6 alkylidene group (e.g. , methylidene, ethylidene, propylidene etc. ) and the like can be mentioned. As the "substituent" of the "alkylidene group optionally having substituent (s) ", for example, those similar to the "substituent" of the "hydrocarbon group optionally having substituent (s) " for the above-mentioned R5, and the like can be mentioned. The "alkylidene group" optionally has 1 to 5, preferably 1 to 3, substituents mentioned above at substitutable positions. When the number of the substituents is 2 or more, the respective substituents may be the same or different.
When the number of the "substituents" of the above- mentioned "amino group optionally having 1 or 2 substituents" is 2, the respective substituents may be the same or different. As the "cyclic amino group" of the "cyclic amino group optionally having substituent (s) " in the above- mentioned (2) , for example, a 5- to 7-membered non- aromatic cyclic amino group containing one nitrogen atom and optionally containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and the like can be mentioned. As specific examples, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl, imidazolidin-1-yl, 2 ,3-dihydro-lH- imidazol-1-yl, tetrahydro-1 (2H) -pyrimidinyl, 3,6- dihydro-1 (2H) -pyrimidinyl, 3,4-dihydro-l (2H) -pyrimidinyl and the like can be mentioned. As the "substituent" of the "cyclic amino optionally having substituent(s) ", for example, those similar to the "substituent" of the "5- to 7-membered saturated cyclic amino optionally having substituent (s) group", exemplified as the "substituent" of the "hydrocarbon group optionally having substituent (s) " for the above-mentioned R5, and the like can be mentioned. The "cyclic amino" optionally has 1 to 3 substituents mentioned above at substitutable positions. When the number of the substituents is 2 or more, the respective substituents may be the same or different.
As specific examples of the 5- to 7-membered non- aromatic cyclic amino group having one oxo, 2- oxoimidazolidin-ϊ-yl, 2-oxo-2,3-dihydro-lH-imidazol-l- yl, 2-oxotetrahydro-l (2H) -pyrimidinyl, 2-oxo-3,6- dihydro-1 (2H) -pyrimidinyl, 2-oxo-3 ,4-dihydro-l (2H) - pyrimidinyl, 2-oxopyrrolidin-l-yl, 2-oxopiperidino, 2- oxopiperazin-1-yl, 3-oxopiperazin-l-yl, 2-oxo- 2 ,3 ,4 , 5,6 ,7-hexahydroazepin-l-yl and the like can be mentioned.
As R1, an amino group optionally having substituent (s) , an aryl group optionally having substituent (s) , an alkyl group optionally having substituent (s) and the like are preferable.
As the "amino group optionally having substituent (s) ", for example, an amino group optionally having 1 or 2 acyl represented by the formula: -(C=O)-R5, -(C=O)-OR5, -(C=O)-NR5R6, -(C=S)-NHR5 or -SO2-R7 [wherein each symbol is as defined above] , and the like are preferable, and an amino group optionally having 1 or 2 acyl represented by the formula: -(C=O)-R5 or -(C=O)- NR5R5 [wherein each symbol is as defined above] , and the like are particularly preferable.
As the "aryl group optionally having substituent (s) ", for example, a C6-i4 aryl group (preferably phenyl etc.) optionally having 1 to 5 substituents selected from Ci_6 alkylthio, C6-i4 arylthio, Ci-6 alkylsulfinyl, Ce-i4 arylsulfinyl, Ci-6 alkylsulfonyl, Cε-14 arylsulfonyl , carboxy, halogen atom and the like, and the like are preferable.
As the "alkyl group optionally having substituent (s) ", for example, a Ci-6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl etc.) optionally having 1 to 3 substituents selected from halogen atom, Ci-6 alkoxy, hydroxy, carboxy, Ci_6 alkoxy-carbonyl and the like, and the like are preferable, and a Ci_3 alkyl group (e.g. , methyl, ethyl etc. ) and the like are particularly preferable .
Of these, as R1, (1) a Ci-6 alkyl group (e.g. , a Ci_4 alkyl group such as methyl, ethyl, propyl, butyl) ,
(2) a Cε-14 aryl group (e.g. , a phenyl group) optionally having substituent (s) selected from Ci-6 alkylthio (e.g. , methylthio) , Cχ-6 alkylsulfonyl (e.g. , methylsulfonyl) and halogen atom (e.g. , chlorine atom, fluorine atom) ,
(3) an amino group optionally having 1 or 2 acyl represented by the formula: -(C=O)-R5' [wherein R5' is
(a) a Ci-6 alkyl group (e.g. , a C1-3 alkyl group such as methyl) ,
(b) a C6-i4 aryl group (e.g. , a phenyl group) , or
(c) a 5- to 14-membered heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (e.g. , a 5- or 6-membered heterocyclic group containing, besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as a pyridyl group) ] , and the like are more preferable. Particularly, an amino group optionally having 1 or 2 acyl represented by the formula: -(C=O)-R5" [wherein R5' is
(b) a C6-i4 aryl group (e.g. , a phenyl group) , or
(c) a 5- to 14-membered heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (e.g. , a 5- or 6-membered heterocyclic group containing, besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as a pyridyl) ] , and the like are preferable.
R5' and R5" are preferably each independently a phenyl group or a pyridyl group. In the above-mentioned formula, R2 is an aromatic group optionally having substituent(s) .
As the "aromatic group" of the "aromatic group optionally having substituent (s) " for R2, for example, an aromatic hydrocarbon group, an aromatic heterocyclic group and the like can be mentioned.
As the "aromatic hydrocarbon group", for example, a monocyclic or fused polycyclic (bicyclic or tricyclic) aromatic hydrocarbon group having 6 to 14 carbon atoms, and the like can be mentioned. As specific examples, a C6-i4 aryl group (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2- biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl etc.) and the like can be mentioned. Preferably, a Cε-io aryl group (e.g., phenyl, 1-naphthyl, 2-naphthyl etc, preferably phenyl etc.) and the like can be mentioned. As the "aromatic heterocyclic group", for example, a monovalent group obtained by removing one of hydrogen atoms from 5- to 14-membered (preferably 5- to 10- membered) aromatic heterocycle containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and the like can be mentioned.
As the above-mentioned "5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle", for example, aromatic heterocycle such as thiophene, benzo [b]thiophene, benzo[b] furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphto[2,3- b]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, lH-indazole, purine, 4H-quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β- carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isoxazole, furazan, phenoxazine and the like; heterocycle formed by condensing such heterocycle (preferably monocycle) with one or more (preferably 1 or 2) aromatic rings (e.g., benzene ring etc.) , and the like can be mentioned. As the "aromatic heterocyclic group", for example, a 5- to 14-membered (preferably 5- to 10-membered) (monocyclic or bicyclic) aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and the like are preferable. Specifically, for example, aromatic heterocyclic group such as 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3- isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2- pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3- pyridazinyl, 3-isothiazolyl, 2-oxazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2- benzo [b]thienyl, 3-benzo tb]thienyl, 2-benzo [b] furanyl, 3-benzo[b] furanyl and the like can be mentioned. As the "substituent" of the "aromatic group optionally having substituent (s) ", for example, those similar to the "substituent" of the "hydrocarbon group optionally having substituent(s) " for the above- mentioned R5, and the like can be mentioned. The
"aromatic group" optionally has 1 to 5, preferably 1 to 3, substituents mentioned above at substitutable positions. When the number of the substituents is 2 or more, the respective substituents may be the same or different. As R2,
(1) a C6-I4 aryl group optionally having substituent (s) ,
(2) a 5- to 14-rnembered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, which heterocyclic group optionally has substituent (s) , and the like are preferable. Of these, (1) a C6-H aryl group (e.g. , a phenyl group, a naphthyl group) optionally having substituent (s) selected from halogen atom (e.g. , chlorine atom, fluorine atom) and Ci- 6 alkoxy (e.g. , methoxy) , (2) a 5- to 14-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (e.g. , a 5- or 6-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as a pyridyl group, a thienyl group) , and the like are more preferable, and
(1) a C6-I4 aryl group (e.g. , a phenyl group) ,
(2) a 5- to 14-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (e.g. , a 5- or 6-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as a pyridyl group) , and the like are still more preferable, and a phenyl group, a pyridyl group and the like are particularly preferable . In the above-mentioned formula, R3 is a hydrogen atom, a pyridyl group optionally having substituent (s) or an aromatic hydrocarbon group optionally having substituent (s) . As the "substituent" of the "pyridyl group optionally having substituent(s) " for R3, for example, those similar to the "substituent" of the "hydrocarbon group optionally having substituent(s)" for the above- mentioned R5, and the like can be mentioned. The "pyridyl group" optionally has, for example, 1 to 5, preferably 1 to 3 , substituents mentioned above at substitutable positions. When the number of the substituents is 2 or more, the respective substituents may be the same or different. In addition, the nitrogen atom, which is an atom constituting "pyridyl group", is optionally N-oxidized.
As the "aromatic hydrocarbon group" of the "aromatic hydrocarbon group optionally having substituent (s) " for R3, for example, those similar to the "aromatic hydrocarbon group" of the "aromatic group optionally having substituent (s) " for the above-mentioned R2, and the like can be mentioned. Of these, a C6-i4 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3- biphenylyl, 4-biphenylyl, 2-anthryl and the like, and the like are preferable, and a C6-io aryl group (e.g., phenyl, 1-naphthyl, 2-naphthyl etc., preferably phenyl etc.) and the like are more preferable.
As the "substituent" of the "aromatic hydrocarbon group optionally having substituent (s)" for R3, for example, those similar to the "substituent" of the
"hydrocarbon group optionally having substituent (s) " for the above-mentioned R5, and the like can be mentioned.
As R3, a Cβ-14 aryl group optionally having substituent (s) and the like are preferable. Of these, a Ce-14 aryl group optionally having 1 or 2 substituents selected from Ci_6 alkyl (e.g., methyl, ethyl etc.) and Ci-6 alkoxy (e.g., methoxy, ethoxy etc.) , and the like are more preferable, and a phenyl group optionally having 1 or 2 substitutes selected from Ci-6 alkyl (e.g. , methyl, ethyl etc.) and Ci_6 alkoxy (e.g., methoxy, ethoxy etc.) , (e.g. , 3-methoxyphenyl , 2-methylphenyl, 2 ,4-dimethylphenyl etc.) , and the like are particularly, preferable. In the above-mentioned formula, X is an oxygen atom or an optionally oxidized sulfur atom.
As the "optionally oxidized sulfur atom" for X, S, SO, SO2 can be mentioned.
As X, an optionally oxidized sulfur atom is preferable, and S is more preferable.
In the above-mentioned formula, Y is a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR4 (wherein R4 is a hydrogen atom, a hydrocarbon group optionally having substituent (s) or an acyl group) .
As the "optionally oxidized sulfur atom" for Y, S, SO, SO2 can be mentioned.
As the "hydrocarbon group optionally having substituent (s)" for R4, for example, those similar to the "hydrocarbon group optionally having substituent (s) " for the above-mentioned R5, and the like can be mentioned. Of these, a Ci_6 alkyl group such as methyl, ethyl and the like are preferable, and a C1-3 alkyl group such as methyl and the like are particularly preferable. As the "acyl group" for R4, for example, those similar to the "acyl group" for the above-mentioned R1, and the like can be mentioned.
As Y, an oxygen atom, an optionally oxidized sulfur atom, a group represented by the formula: NR4 (wherein R4 is as defined above) and the like are preferable. Of these, an oxygen atom, an optionally oxidized sulfur atom, a group represented by the formula: NR4' (wherein R4' is a hydrogen atom or a Ci_6 alkyl group) and the like are more preferable, an oxygen atom, S, SO2, NH, N(CH3) and the like are still more preferable, and 0, NH, S and the like are particularly preferable.
In the above-mentioned formula, Z is a bond or a divalent chain hydrocarbon group optionally having substituent (s) .
As the "divalent chain hydrocarbon group" of the "divalent chain hydrocarbon group optionally having substituent (s) " for Z, for example, a Ci-is alkylene group (e.g., methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene etc., preferably a Ci-6 alkylene etc.) , a C2-16 alkenylene group (e.g., vinylene, propylene, 1-butenylene, 2-butenylene, 1-pentenylene, 2- pentenylene, 3-pentenylene etc.) , a C2-16 alkynylene group (ethynylene, propynylene, 1-butynylene, 2-butynylene, 1- pentynylene, 2-pentynylene, 3-pentynylene etc.) and the like can be mentioned. Of these, a Ci-15 alkylene group and the like are preferable, and a Ci-6 alkylene group and the like are particularly preferable. As the "substituent" of the "divalent chain hydrocarbon group optionally having substituent (s) " for Z, for example, those similar to the "substituent" of the "hydrocarbon group optionally having substituent(s) " for the above-mentioned R5, and the like can be mentioned.
As Z, a bond, a lower alkylene group and the like are preferable, and a bond, a Ci-6 alkylene group (e.g., a Ci-3 alkylene group such as methylene, ethylene, trimethylene) optionally having substituent (s) selected from oxo, Ci-6 alkyl (e.g., C1-3 alkyl such as methyl) and the like, and the like are more preferable. Of these, a bond, a Ci-6 alkylene group (e.g. , a C1-3 alkylene group such as methylene, ethylene, trimethylene, particularly a methylene group) optionally having oxo, and the like are particularly preferable.
More specifically, as Z, -CH2-, -(CH2J2-, -(CH2I3-, - CO-, -CH2CO-, -(CH2J2CO-, -CH(CH3)- and the like can be mentioned, and -CH2-, -CO- and the like are particularly preferable.
The nitrogen atom in compound (I) is optionally N- oxidized. For example, the nitrogen atom as an atom constituting 4-pyridyl group, with which the 5-position of the ring represented by the following formula is substituted:
Figure imgf000029_0001
wherein the symbols in the formula are as defined above, is optionally N-oxidized. As compound (I) , for example, a compound represented by the formula:
Figure imgf000029_0002
wherein n is 0 or 1 and other symbols are as defined above, or a salt thereof and the like are preferable.
As compound (I) , for example, the following Compounds (A)-(F) and the like are preferable. Compound (A)
A compound wherein
R1 is an amino group optionally having substituent(s) , an aryl group optionally having substituent (s) or an alkyl group optionally having substituent (s) ; R2 is
(1) a C6-i4 aryl group optionally having substituent (s) , or (2) a 5- to 14-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, which optionally has substituent (s) ; R3 is a C6-i4 aryl group optionally having substituent (s) ; X is a sulfur atom;
Y is an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR4 (wherein R4 is as defined above) ; and Z is a bond or a lower alkylene group optionally having substituent (s) . Compound (B)
A compound wherein R1 is (1) a Ci-6 alkyl group (e.g. , a Ci_4 alkyl group such as methyl, ethyl, propyl, butyl) ,
(2) a C6-Hi aryl group (e.g. , a phenyl group) optionally having substituent (s) selected from Ci_6 alkylthio (e.g. , methylthio) , Cχ-6 alkylsulfonyl (e.g. , methylsulfonyl) and halogen atom (e.g. , chlorine atom, fluorine atom) , or
(3) an amino group optionally having 1 or 2 acyl represented by the formula: -(C=O)-R5' [wherein R5' is (a) a Ci_6 alkyl group (e.g. , a Ci_3 alkyl group such as methyl) ,
(b) a C6-i4 aryl group (e.g. , a phenyl group) , or
(c) a 5- to 14-membered heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (e.g. , a 5- or 6-membered heterocyclic group containing, besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as a pyridyl group) ] ; R2 is
(1) a Ce-14 aryl group (e.g. , a phenyl group, a naphthyl group) optionally having substituent (s) selected from halogen atom (e.g. , chlorine atom, fluorine atom) and Cχ_ 6 alkoxy (e.g. , methoxy) , or
(2) a 5- to 14-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (e.g. , a 5- or 6-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as a pyridyl group, a thienyl group) ; R3 is a C6-i4 aryl group (particularly a phenyl group) optionally having 1 or 2 substitutes selected from Ci-6 alkyl (e.g. , methyl, ethyl etc.) and Ci-6 alkoxy (e.g. , methoxy, ethoxy etc.) ; X is a sulfur atom; Y is an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR4' (wherein R4' is a hydrogen atom or a Ci-6 alkyl group) ; and Z is a bond, a Ci-6 alkylene group (e.g. , a C1-3 alkylene group such as methylene, ethylene, trimethylene) optionally having substituent (s) selected from oxo and Ci-6 alkyl (e.g. , C1-3 alkyl such as methyl) . Compound (C)
A compound wherein
R1 is an amino group optionally having 1 or 2 acyl represented by the formula: -(C=O)-R5" [ where i n R5 " i s
(b) a C6-I4 aryl group (e.g. , a phenyl group) , or
(c) a 5- to 14-membered heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (e.g. , a 5- or 6-membered heterocyclic group containing, besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as a pyridyl) ] ; R2 is
(1) a C6-I4 aryl group (e.g. , a phenyl group) , or
(2) a 5- to 14-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (e.g. , a 5- or 6-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as a pyridyl group) ; R3 is a phenyl group optionally having 1 or 2 substitutes selected from Ci_6 alkyl (e.g. , methyl, ethyl etc.) and Ci-6 alkoxy (e.g. , methoxy, ethoxy etc.) ; X is a sulfur atom; Y is 0, NH or S; Z is a bond or a Cx-6 alkylene group optionally having oxo (especially, a C1-3 alkylene group such as methylene, ethylene optionally having oxo) . Compound (D)
The compounds (I) of Reference Examples 1-28. Compound (E)
[4- (3 , 5-dimethylphenyl) -5- (2-phenylmethyloxy-4-pyridyl) - 1 , 3-thiazol-2-yl] amine (Reference Example 1) , N- [4- [2-benzoylamino-4- (4-methoxyphenyl) -l,3-thiazol-5- yl] -2-pyridyl] benzamide (Reference Example 2) , N- [4- (4-methoxyphenyl) -5- [2- [ (3-pyridylcarbonylamino) ] - 4-pyridyl] -1 , 3-thiazol-2-yl] nicotinamide (Reference Example 3) ,
N- [4- [2-amino-4- (4-methoxyphenyl) -1 , 3-thiazol-5-yl] -2- pyridyl] benzamide (Reference Example 4) ,
N- [4- [2-amino-4- (3 , 5-dimethylphenyl) -1 , 3-thiazol-5-yl] - 2-pyridyl]benzamide (Reference Example 5) , N- [4- [2-amino-4- (3 , 5-dimethylphenyl) -1 , 3-thiazol-5-yl] - 2-pyridyl]benzylamine (Reference Example 6) , N- [4- [2-amino-4- (3 , 5-dimethylphenyl) -1 , 3-thiazol-5-yl] - 2-pγridyl]benzamide hydrochloride (Reference Example 7) , N- [4- [2-amino-4- (3 , 5-dimethylphenyl) -1 , 3-thiazol-5-yl] - 2-pyridyl]benzylamine dihydrochloride (Reference Example 8) . Compound (F)
N- [5- (2-benzoylamino-4-pyridyl) -4- (3 , 5-dimethylphenyl) - 1 , 3-thiazol-2-yl] acetamide (Reference Example 9) , N- [5- (2-benzylamino-4-pyridyl) -4- (3 , 5-dimethylphenyl) - 1 , 3-thiazol-2-yl] acetamide (Reference Example 10) , N- [4- [4- (4-methoxyphenyl) -2-methy1-1 , 3-thiazol-5-yl] -2- pyridyl]benzamide (Reference Example 13) ,
N- [4- [2- (4-fluorophenyl) -4- (3-methylphenyl) -1,3-thiazol- 5-yl] -2-pyridyl]phenylacetamide (Reference Example 14) , N- [4- [2-ethyl-4- (3-methylphenyl) -l,3-thiazol-5-yl]-2- pyridyl]phenylacetamide (Reference Example 15-2) ,
N- [4- [4- (3-methylphenyl) -2-propyl-l , 3-thiazol-5-yl] -2- pyridyl]phenylacetamide (Reference Example 15-3) , N- [4- [2-butyl-4- (3-methylphenyl) -l,3-thiazol-5-yl]-2- pyridyl]phenylacetamide (Reference Example 15-4) , N- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1 ,3- thiazol-5-yl] -2-pyridyl] phenylacetamide (Reference Example 15-6) ,
N- [4- [2-ethyl-4- (3-methylphenyl) -1 , 3-thiazol-5-yl] -2- pyridyl]benzamide (Reference Example 16-1) , N- [4- [2-ethyl-4- (3-methylphenyl) -1 , 3—thiazol-5-yl] -2- pyridyl] -3-phenylpropionamide (Reference Example 16-2) , N- [4- [2-ethy1-4- (3-methylphenyl) -1 , 3-thiazol-5-yl] -2- pyridyl] -3- (4-methoxyphenyl) propionamide (Reference Example 16-3) ,
N- [4- [2-ethyl-4- (3-methylphenyl) -1 , 3—thiazol-5-yl] -2- pyridyl] -4-phenylbutyramide (Reference Example 16-5) , N- [4- [4- (3-methylphenyl) -2-propyl-l , 3-thiazol-5-yl] -2- pyridyl] benzamide (Reference Example 16-7) , N_ [4_ [4_ (3-methylphenyl) -2-propyl-l , 3-thiazol-5-yl] -2- pyridyl] -3-phenylpropionamide (Reference Example 16-8) , N- [4-[2-butyl-4- (3-methylphenyl) -l,3-thiazol-5-yl]-2- pyridyl] benzamide (Reference Example 16-9) , N- [4- [2-butyl-4- (3-methylphenyl) -1, 3-thiazol-5-yl] -2- pyridyl] -3-phenylpropionamide (Reference Example 16-10) , N- [4- [2- (4-fluorophenyl) -4- (3-methylphenyl) -1, 3-thiazol- 5-yl] -2-pyridyl] benzamide (Reference Example 16-11) , N- [4- [2- (4-fluorophenyl) -4- (3-methylphenyl) -1, 3-thiazol- 5-yl] -2-pyridyl] -3-phenylpropionamide (Reference Example 16-12) ,
N- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3- thiazol-5-yl] -2-pyridyl] benzamide (Reference Example 16- 15) , N- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1 , 3- thiazol-5-yl] -2-pyridyl] -3-phenylpropionamide (Reference Example 16-16) ,
N-benzyl-N- [4- [2-ethyl-4- (3-methylphenyl) -l,3-thiazol-5- yl] -2-pyridyl ] amine (Reference Example 19-2) , N- [4- [2-ethyl-4- (3-methylphenyl) -1 , 3—thiazol-5-yl] -2- pyridyl] -N- (2-phenylethyl) amine (Reference Example 19-
3) ,
N- [4- [2-ethyl-4- (3-methylphenyl) -1 , 3-thiazol-5-yl] -2- pyridyl] -N- (3-phenylpropyl) amine (Reference Example 19-
4) , N-benzyl-N- [4- [4- (3-methylphenyl) -2-propyl-l , 3-thiazol- 5-yl] -2-pyridyl] amine (Reference Example 19-5) , N- [4- [4- (3-methylphenyl) -2-propyl-l , 3-thiazol-5-yl] -2- pyridyl] -N- (2-phenylethyl) amine (Reference Example 19- 6) ,
N- [4- [4- (3-methylphenyl) -2-propyl-l , 3-thiazol-5-yl] -2- pyridyl] -N- (3-phenylpropyl) amine (Reference Example 19- 7) ,
N-benzyl-N- [4- [2-butyl-4- (3-methylphenyl) -1 , 3-thiazol-5- yl] -2-pyridyl] amine (Reference Example 19-8) ,
N- [4- [2-butyl-4- (3-methylphenyl) -1 , 3—thiazol-5-yl] -2- pyridyl] -N- (2-phenylethyl) amine (Reference Example 19-
9) ,
N- [4- [2-butyl-4- (3-methylphenyl) -1 , 3-thiazol-5-yl] -2- pyridyl] -N- (3-phenylpropyl) amine (Reference Example 19-
10) ,
N-benzyl-N- [4- [4- (3-methylphenyl) -2- (4- methylthiophenyl) -1 , 3-thiazol-5-yl] -2-pyridyl] amine
(Reference Example 19-17) , N_ [4_ [4_ (3-methylphenyl) -2- (4-methylthiophenyl) -1 , 3- thiazol-5-yl] -2-pyridyl ] -N- (2-phenylethyl) amine
(Reference Example 19-18) ,
N- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1 , 3- thiazol-5-yl] -2-pyridyl] -N- (3-phenylpropyl) amine (Reference Example 19-19) ,
N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1 , 3- thiazol-5-yl] -2-pyridyl] benzamide (Reference Example
20) ,
N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3- thiazol-5-yl] -2-pyridyl] phenylacetamide (Reference
Example 21-1) ,
N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3- thiazol-5-yl] -2-pyridyl] -3-phenylpropionamide (Reference
Example 21-2) , N-benzyl-N- [4- [4- (3-methylphenyl) -2- (4- methylsulfonylphenyl) -1,3-thiazol-5-yl]-2-pyridyl]amine
(Reference Example 21-5) ,
N- [4- [4- (3-methylphenyl) -2- (4-methylsuIfonylphenyl) -1,3- thiazol-5-yl] -2-pyridyl] -N- (3-phenylpropyl) amine
(Reference Example 21-6) ,
N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1 ,3- thiazol-5-yl] -2-pyridyl]-N- (2-phenylethyl) amine
(Reference Example 25-1) , N_ (4-fluorobenzyl) -N- [4- [4- (3-methylphenyl) -2- (4- methylsuIfonylphenyl) -1 ,3-thiazol-5-yl] -2-pyridyl] amine
(Reference Example 25-2) ,
(S) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4- pyridyl) -l,3-thiazol-2-yl]nicotinamide, (R) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4- pyridyl) -l,3-thiazol-2-yl]nicotinamide,
(S) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4- pyridyl)-l,3-thiazol-2-yl]-2-methylnicotinamide,
(R) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4- pyridyl) -l,3-thiazol-2-yl] -2-methylnicotinamide,
(S) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4- pyridyl) -l,3-thiazol-2-yl]-2-chIoronicotinamide,
(R) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4- pyridyl) -l,3-thiazol-2-yl] -2-chlor©nicotinamide, (S) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4- pyridyl) -l,3-thiazol-2-yl]-2-methoxynicotinamide,
(R) -N- [4- (3-methylphenyl) -5- (2- (1-phenylethylamino) -4- pyridyl) -l,3-thiazol-2-yl] -2-methoxynicotinamide, N- [5- (2-benzylamino-4-pyridyl) -4- (3-methylphenyl) -1,3- thiazol-2-yl] nicotinamide,
N- [5- (2-benzylamino-4-pyridyl) -4- (3-methylphenyl) -1,3- thiazol-2-yl] -2-methoxynicotinamide,
N- [5- (2-benzylamino-4-pyridyl) -4- (3-methylphenyl) -1,3- thiazol-2-yl] -2-chlor©nicotinamide, N- [5- (2-benzylamino-4-pyridyl) -4- (3-methylphenyl) -1,3- thiazol-2-yl] -2-methylnicotinamide,
N- [5- (2-benzoylamino-4-pyridyl) -4- (3-methylphenyl) -1,3- thiazol-2-yl] nicotinamide, N- [5- (2-benzoylamino-4-pyridyl) -4- (3-methylphenyl) -1,3- thiazol-2-yl] -2-methylnicotinamide,
N- [5- (2-benzoylamino-4-pyridyl) -4- (3-methylphenyl) -1,3- thiazol-2-yl] -2-chloronicotinamide,
N- [5- (2-benzoylamino-4-pyridyl) -4- (3-methylphenyl) -1,3- thiazol-2-yl] -2-methoxynicotinamide,
(S) -N- (1-phenylethyl) -4- [2-ethyl-4- (3-methylphenyl) -1,3- thiazol-5-yl] -2-pyridylamine,
(R) -N- (1-phenylethyl) -4- [2-ethyl-4- (3-methylphenyl) -1,3- thiazol-5-yl] -2-pyridylamine, (S) -N- (1-phenylethyl) -4- [4- (3-methylphenyl) -2-propyl- l,3-thiazol-5-yl] -2-pyridylamine,
(R) -N- (1-phenylethyl) -4- [4- (3-methylphenyl) -2-propyl- l,3-thiazol-5-yl] -2-pyridylamine,
(S) -N- (1-phenylethyl) -4- [2-butyl-4- (3-methylphenyl) -1,3- thiazol-5-yl] -2-pyridylamine,
(R) -N- (1-phenylethyl) -4- [2-butyl-4- (3-methylphenyl) -1 ,3- thiazol-5-yl] -2-pyridylamine,
(S) -N- (1-phenylethyl) -4- [4- (3-methylphenyl) -2- (4- methylthiophenyl) -1,3-thiazol-5-yl] -2-pyridylamine, (R) -N- (1-phenylethyl) -4- [4- (3-methylphenyl) -2- (4- methylthiophenyl) -1 ,3-thiazol-5-yl] -2-pyridylamine,
(S) -N- (1-phenylethyl) -4- [4- (3-methylphenyl) -2- (4- methy1suIfonylphenyl) -1,3-thiazol-5-yl] -2-pyridylamine,
(R) -N- (1-phenylethyl) -4- [4- (3-methylphenyl) -2- (4- methylsuIfonylphenyl) -1 ,3-thiazol-5-yl] -2-pyridylamine,
(S) -N- (1-phenylethyl) -4- [2- (4-fluorophenyl) -4- (3- methylphenyl) -1 ,3-thiazol-5-yl]-2-pyridylamine,
(R) -N- (1-phenylethyl) -4- [2- (4-fluorophenyl) -4- (3- methylphenyl) -1,3-thiazol-5-yl]-2-pyridylamine. To be more specific, the drug is more preferably N- [4- [2-ethy1-4- (3-methylphenyl) -l,3-thiazol-5-yl]-2- pyridyl]benzamide (Reference Example 16-1) , N-benzyl-N- [4- [2-ethy1-4- (3-methylphenyl) -1 ,3-thiazol-5-yl] -2- pyridyl]amine (Reference Example 19-2) , or N-[4-[4-(3- methylphenyl) -2- (4-methylsulfonylphenyl) -l,3-thiazol-5- yl] -2-pyridyl] -N- (2-phenylethyl) amine (Reference Example 25-1) .
The thiazole compound and the like exemplarily shown above can be produced by, for example, methods disclosed in WO00/64894 and the like.
As a salt of compound (I) , for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned. As preferable examples of the metal salt, alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like can be mentioned. As preferable examples of the salts with organic bases, salts with trimethylamine, triethylarnine, pyridine, picoline, 2,6- lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'- dibenzylethylenediamine and the like can be mentioned. As preferable examples of the salts with inorganic acids, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like can be mentioned. As preferable examples of the salts with organic acids, salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned. As preferable examples of the salts with basic amino acids, salts with arginine, lysine, ornithine and the like can be mentioned. As preferable examples of the salts with acidic amino acids, salts with aspartic acid, glutamic acid and the like can be mentioned.
Of those, pharmaceutically acceptable salts are preferable. For example, when a compound has an acidic functional group therein, salts with inorganic bases such as alkali metal salts (e.g., sodium salt, potassium salt and the like) , alkaline earth metal salts (e.g. , calcium salt, magnesium salt, barium salt and the like) and the like, ammonium salt and the like can be mentioned. When a compound has a basic functional group therein, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like can be mentioned.
As the carrier in the present invention, those having a softening temperature of preferably about 600C to about 3500C, more preferably about 800C to about 2700C, particularly preferably about 1000C to about 2200C, can be used.
As the carrier to be used in the present invention, a polymeric carrier is preferable. As the polymeric carrier, hydrophilic polymer and the like can be preferably used.
As the hydrophilic polymer, for example, water- soluble polymer, enteric polymer, gastrosoluble polymer and the like can be used.
As the water-soluble polymer, for example, cellulose derivative such as hydroxyalkylcellulose (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose) , alkylcellulose (e.g., methylcellulose) and the like, polyalkenylpyrrolidone such as polyvinylpyrrolidone and the like, polyalkylene glycol such as polyethylene glycol and the like, polyvinyl alcohol and the like can be used.
As the enteric polymer, for example, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethyl ethylcellulose, cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer S, dried methacrylic acid copolymer LD and the like can be used. As the gastrosoluble polymer, for example, aminoalkyl methacrylate copolymer E, polyvinylacetal diethylaminoacetate and the like can be used.
Additionally, carboxymethylcellulose, Eudragit, carboxyvinyl polymer, polyvinyl alcohol, gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, chitosan and the like can be used. These hydrophilic polymers may be used as a mixture of one or more kinds thereof.
More specifically, polymers such as hydroxypropylmethylcellulose phthalate (HP-55, HP-50, manufactured by Shin-Etsu Chemical Co., Ltd.) , hydroxypropylmethylcellulose acetate succinate (AS-LF, manufactured by Shin-Etsu Chemical Co., Ltd.) , cellulose acetate phthalate, carboxymethyl ethylcellulose (CMEC, manufactured by Freund Corporation) , methyl methacrylate-methacrylic acid copolymer (Eudragit LlOO (methacrylic acid copolymer L) or Eudragit SlOO (methacrylic acid copolymer S) , manufactured by Rohm) , methacrylic acid-ethyl acrylate copolymer (Eudragit L100-55 (dried methacrylic acid copolymer LD) or Eudragit L30D-55 (methacrylic acid copolymer LD) , manufactured by Rohm) , methacrylic acid-methyl acrylate-methyl methacrylate copolymer (Eudragit FS30D, manufactured by Rohm) , polyvinyl acetate phthalate, shellac and the like are preferably used, and hydroxypropylmethylcellulose phthalate (HP-55, HP-50, manufactured by Shin-Etsu Chemical Co., Ltd.) and hydroxypropylmethylcellulose acetate succinate (AS-LF, manufactured by Shin-Etsu Chemical Co., Ltd.) can be preferably used.
The plasticizer is used in the present invention to lower the glass transition temperature of the carrier during formation of a solid dispersion. As the plasticizer, for example, polyoxyethylene, polyethylene glycol, triethyl citrate, macrogols, triacetine, fatty acid triglyceride and the like can be mentioned. The plasticizer is not limited to these examples and any compound can be used as long as it has an action to lower the glass transition temperature of the carrier. More specifically, as the plasticizer, various compounds such as triethyl citrate, polyethylene glycol (PEG6000 and the like) , polyethylene oxide (Polyox and the like) and the like can be used. Of these, polyethylene oxide (Polyox and the like) is preferable since it can also act as a drug release-controlling component.
The drug release-controlling component is used in the present invention to facilitate invasion of water into a solid dispersion for control of the drug release. The drug release-controlling component of the present invention only needs to have hydrophilicity to draw water into the solid dispersion, and is preferably a hydrophilic compound. The drug release rate can be controlled by determining the kind and amount of the drug release-controlling component according to the size, shape and the like of the solid dispersion. As the above-mentioned hydrophilic compound, hydrophilic polymers and hydrophilic low-molecular weight compounds can be preferably used.
For example, a hydrophilic polymer is used to suppress or accelerate the drug release rate, and the hydrophilic low-molecular weight compound is used to accelerate the drug release rate. It is also possible to use a hydrophilic low-molecular weight compound to further adjust the drug release rate suppressed or accelerated using a hydrophilic polymer.
As the hydrophilic polymer, for example, the aforementioned water-soluble polymer, enteric polymer, gastrosoluble polymer and the like can be used.
When the hydrophilic polymer used in the present invention has a high release-controlling function such as gel-forming function and the like, the level of sustained-release can be enhanced. As such a gel-forming polymer, any polymer can be used as long as it rapidly forms a highly viscous gel upon contact with water, and prolongs residence in the gastrointestinal tract. As such gel-forming polymer, a polymer having a viscosity of 5% aqueous solution at 250C of not less than about 3000 mPa• s is preferable.
Moreover, the molecular weight thereof is generally preferably about 400000 to 10000000. Such gel-forming polymer is preferably a powder, granule or fine granule when a preparation is formed. As such gel-forming polymer, polyethylene oxide (PEO, e.g., Polyox WSR303 (molecular weight 7000000) , Polyox WSR Coagulant (molecular weight 5000000) , Polyox WSR 301 (molecular weight 4000000) , Polyox WSR N-60K (molecular weight 2000000) , Polyox WSR 205 (molecular weight 600000) ; manufactured by Dow Chemical) , hydroxypropylmettiylcellulose (HPMC, Metlose 90SH10000, Metlose 90SH50000, Metlose 90SH30000, manufactured by Shin-Etsu Chemical Co., Ltd.) , carboxymethylcellulose sodium (CMC-Na, Sanlose F-IOOOMC) , hydroxypropylcellulose (HPC, e.g., HPC-H, manufactured by Nippon Soda Co. , Ltd.) , hydroxyethylcellulose (HEC) , carboxyvinyl polymer (HIVISWAKO®103, 104, 105, manufactured by Wako Pure Chemical Industries; carbopol 943, manufactured by Goodrich) , chitosan, sodium alginate, pectin, and the like can be specifically mentioned, with preference given to polyethylene oxide (PEO, e.g., Polyox WSR303 (molecular weight 7000000) , Polyox WSR Coagulant (molecular weight 5000000) , Polyox WSR 301 (molecular weight 4000000)) and the like.
These may be used alone or as a mixture of at least 2 kinds of powders at a suitable mixing ratio. Particularly, PEO, HPMC, HPC, CMC-Na, carboxyvinyl polymer and the like are preferably used as a gel- forming polymer.
As the hydrophilic low-molecular weight compound, for example, saccharides such as lactose, sucrose and the like, sugar alcohols such as sorbitol, mannitol and the like, inorganic salts, organic salts and the like are used, with preference given to lactose, sucrose, mannitol and the like.
Moreover, the drug release-controlling component can contain disintegrant, in addition to the above- mentioned components. As such disintegrant, for example, fumed silica (AEROSIL, manufactured by NIPPON AEROSIL CO., LTD.) , carboxymethylcellulose calcium (ECG-505, manufactured by Gotoku Yakuhin) , croscarmellose sodium (e.g., Ac-Di-SoI, manufactured by Asahi Kasei Chemicals Co. , Ltd.) , crospovidone (e.g., Kollidon CL, manufactured by BASF) , low-substituted hydroxypropylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.) , carboxymethyl starch (manufactured by Matsutani Kagaku K.K.) , sodium carboxymethyl starch (Explotab, manufactured by Kimura Sangyo) , partially pregelatinized starch (PCS, manufactured by Asahi Kasei Chemicals Co., Ltd.) and the like can be used.
In the present specification, a solid dispersion means a solid composition, wherein the above-mentioned (i) drug, (ii) carrier(s) , (iii) plasticizer (s) , (iv) drug release-controlling component (s) , and, where necessary, other substance are homogeneously mixed. As other substances, those other than the above-mentioned constituent components and is not particularly limited. As other substances, for example, surfactant, glidant, lubricant, antioxidant, coloring agent, sweetening agent and the like can be used.
A solid dispersion may contain one kind of other substance or two or more kinds thereof. While the content of the (i) drug in the solid dispersion of the present invention varies depending on the form etc. of the preparation, it is determined to be generally about 0.1 to about 99.9 wt%, preferably about 0.1 to about 50 wt%, more preferably about 0.5 to about 30 wt%, relative to the whole solid dispersion.
While the content of the (ii) carrier in the solid dispersion of the present invention varies depending on the dosage form, administration method and the like, it is generally about 0.1 to about 99.9% (w/w) , relative to the whole solid dispersion.
While the content of the (iii) plasticizer in the solid dispersion of the present invention varies depending on the dosage form, administration method and the like, it is generally about 0 to about 99.9% (w/w) , preferably about 0.1 to about 99.9% (w/w) , relative to the whole solid dispersion.
While the content of the (iv) drug release- controlling component in the solid dispersion of the present invention varies depending on the dosage form, administration method and the like, it is generally about 0 to about 99.9% (w/w) , preferably about 0.1 to about 99.9% (w/w) , relative to the whole solid dispersion. Particularly, when the drug release- controlling component is a hydrophilic polymer, it is generally about 0 to about 90% (w/w) , relative to the whole solid dispersion, and when the drug release- controlling component is a hydrophilic low-molecular weight compound, it is generally about 0 to about 90% (w/w) , relative to the whole solid dispersion.
The weight ratio of the drug release-controlling component and the drug in the solid dispersion of the present invention only needs to be within the range of generally 0.01:1 to 100:1, preferably 0.02:1 to 50:1, more preferably 0.1:2 to 20:1, still more preferably 0.3:1 to 10:1, particularly preferably 1:1 to 10:1.
The ratio of other substances in the solid dispersion of the present invention can be determined optionally according to the object of use. While the content of other substances in the solid dispersion varies depending on the form etc. of the preparation, it is generally about 0 to about 99.9 wt%, preferably about 0.1 to about 50 wt%, more preferably about 0.5 to about 30 wtl, relative to the whole solid dispersion. In the present specification, a "sustained-release preparation" means, for example, a preparation that shows a "drug dissolution rate from a preparation at 30 min after the start of the test" of less than 85% when The Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method) is performed using a suitable test solution (900 mL)' at a paddle rotation of 100 rpm. As used herein, as the test solution, for example, a test solution that shows a drug concentration of not more than 1/3 of the saturated solubility of the drug, when the drug in a preparation is dissolved by 100% in a test solution, is used. As the test solution, one conventionally employed in the technical field of formulation of preparations, such as water, buffer and the like, is used.
In the present specification, moreover, a preparation that shows a "drug dissolution rate from a preparation at 30 min after the start of the test" of not less than 85%, when The Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle method) is performed under the same conditions as above, is referred to as a immediate-release preparation.
Immediate-release preparations show a steep rise in the blood concentration after administration to living organisms , reaches the maximum blood concentration in a short time, and then shows rapid decrease. In contrast, since the solid dispersion of the present invention shows sustained-release, the blood concentration after administration to living organisms gradually increases and remains at a sustained level. The maximum blood concentration after administration of the solid dispersion of the present invention is suppressed to a low level as compared to immediate-release preparations and is not more than about 60% of that of immediate- release preparations, when compared at the same dose. In addition, since the solid dispersion of the present invention shows a sustained blood concentration, the area under the blood concentration-time curve is not less than about 60% of that of immediate-release preparations, when compared at the same dose.
Since the solid dispersion of the present invention permits sustained-release, the blood concentration after administration to living organisms increases gradually, reaches the maximum blood concentration and then decreases gradually. Therefore, the time period in which the blood concentration exceeds half the maximum blood concentration after administration of the solid dispersion of the present invention becomes twice or more longer than that of immediate-release preparations, when compared at the same dose.
In the present specification, "heat-melting" and "mixing" can be performed using conventional methods and apparatuses . The "heat-melting" and "mixing" can be performed using, for example, conventional stirrer, kneader and the like having a heat source. In addition, one having a structure permitting pressurization of the inside is more preferable. As a different method, extruder having a screw in a cylinder (e.g., single screw extruder, twin screw extruder etc.) can be used. Of these, twin screw extruder is preferable.
In this case, a solvent is not used and the above- mentioned (i) drug, (ii) carrier(s) , (iii) plasticizer (s) and (iv) drug release-controlling component (s) , and, where necessary, other substance are cast into an apparatus maintaining a suitable heat- melting temperature from a hopper of the apparatus, and homogeneously kneaded by rotating the screw to allow melting of the solid substances. Alternatively, a preliminary mixing may be applied as necessary before casting into the apparatus. While the conditions of pressure, temperature, powder feeding rate, die diameter, shape of screw, screw rotation speed and the like in the manufacturing method of the present invention vary depending on the drug, carrier, plasticizer and drug release-controlling component to be used, model of apparatus and the like, it is significant to combine them to achieve a temperature not more than the decomposition temperatures of the drug, carrier, plasticizer and drug release-controlling component, and to change them according to the object product characteristics.
According to the manufacturing method of the present invention, a solid dispersion (pharmaceutical composition) having the following characteristics can be obtained. (1) A solid dispersion (pharmaceutical composition) having a controlled drug release rate.
(2) A solid dispersion (pharmaceutical composition) superior in sustained-release.
(3) A solid dispersion (pharmaceutical composition) having an improved solubility.
(4) A solid dispersion (pharmaceutical composition) containing a drug (e.g. , p38 MAP kinase inhibitor) in a mostly amorphous state.
The solid dispersion obtained by the manufacturing method of the present invention can be used as it is as a pharmaceutical composition for oral administration after pulverization etc. as necessary. While the shape of the solid dispersion of the present invention may be any and can be extruded into any shape and size, for example, pellet, granule and the like can be mentioned.
Moreover, the solid dispersion of the present invention can be mixed with additives conventionally used in the field of pharmaceutical preparation to give a pharmaceutical composition of fine granules, ultrafine granules, granules, tablets, capsules, and the like by conventional methods.
As the additives, pharmacologically acceptable carriers such as various organic, inorganic carrier substances and the like, which are conventionally used as materials for preparations, are mixed as excipient, lubricant, binder, disintegrant, surfactant and the like. Where necessary, additives for preparations such as adsorbent, preservative, antioxidant, coloring agent, sweetening agent and the like can be used.
As preferable examples of the excipient, lactose, sucrose, D-mannitol, starch, crystalline cellulose, perforated starch, mannitol, calcium silicate (trade name: Florite RE) , magnesium aluminate metasilicate (trade name: Neusilin) , light silicic anhydride (trade name: sylysia) , sucrose starch sphere (trade name: Nonpareil) , crystalline cellulose•carboxymethylcellulose (trade name: Avicel RC) , hydroxypropylstarch and the like can be mentioned. As preferable examples of the lubricant, magnesium stearate, calcium stearate, talc, colloidal silica, crystalline cellulose, cornstarch, magnesium oxide and the like can be mentioned.
As preferable examples of the binder, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like can be mentioned.
As preferable examples of the disintegrant, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethylstarch, methylcellulose (trade name: Metolose SM) , carrnellose calcium, low-substituted hydroxypropylcellulose, sodium starch glycolate, partially pregelatinized starch and the like can be mentioned. As preferable examples of the surfactant, polyoxyethylene polyoxypropylene glycol (trade name: pluronic) , glycerol esters of fatty acids, sucrose esters of fatty acids, polyoxyethylene hydrogenated castor oil, polysorbate 80, cetanol and the like can be mentioned.
As preferable examples of the adsorbents, perforated starch, calcium silicate (trade name: Florite RE) , magnesium aluminate metasilicate (trade name: Neusilin) , light silicic anhydride (trade name: sylysia) and the like can be mentioned.
As preferable examples of the preservative, p- oxybenzoates , chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like can be mentioned.
As preferable examples of the antioxidant, sulfite, ascorbic acid and the like can be mentioned.
As preferable examples of the coloring agent, tar color, caramel, colcothar, titanium oxide, riboflavins and the like can be mentioned.
As preferable examples of the sweetening agent, sucrose, lactose, saccharine and the like can be mentioned.
These additives can be used alone or in a mixture of two or more kinds thereof.
While the content of the solid dispersion in the pharmaceutical composition of the present invention thus obtained varies depending on the dosage form, administration method, carrier and the like, it is generally 0.1 to 100% (w/w) relative to the whole preparation.
While the content of the additive in the pharmaceutical composition of the present invention varies depending on the dosage form, administration method, carrier and the like, it is generally 0 to 99.9% (w/w) relative to the whole preparation.
The solid dispersion obtained by the manufacturing method of the present invention and a pharmaceutical composition containing the same can be administered to mammals (e.g., rat, mouse, guinea pig, monkey, bovine, dog, pig, human etc.) depending on the kind of the drug. When the drug is compound (I) or a salt thereof, it shows an excellent adenosine A3 receptor antagonistic activity in mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.) and is also excellent in (oral) absorption, (metabolism) stability and the like and, therefore, can be used as an agent for the prophylaxis or treatment of adenosine A3 receptor- related diseases, for example, asthma, allergic disease, inflammation, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, psoriasis, rheumatism, central nervous disease (e.g., cerebrovascular disease such as cerebral hemorrhage, cerebral infarction and the like, head trauma, spinal trauma, brain edema, multiple sclerosis and the like) , neurodegenerative disease (e.g., Alzheimer's disease, Parkinson's syndrome, amyotrophic lateral sclerosis (ALS) ) , diabetes and the like. Preferably, compound (I) is an agent for the prophylaxis or treatment of central nervous disease, asthma, allergic disease and the like.
When the drug is compound (I) or a salt thereof, it also shows an excellent p38 MAP kinase inhibitory activity and a TNF-α inhibitory activity (TNF-α production inhibitory activity, TNF-α action inhibitory activity) and is also useful as a safe drug based on these activities .
For example, a pharmaceutical composition containing compound (I) or a salt thereof as a drug can be used as an agent for the prophylaxis or treatment of p38 MAP kinase related diseases and TNF-α related diseases, such as arthritis (e.g. , rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, synovitis) , toxemia (e.g., sepsis, septic shock, endotoxin shock, Gram-negative sepsis, toxic shock syndrome) , inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) , inflammatory pulmonary disease (e.g., chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis) , or cachexia (e.g., cachexia derived from infection, carcinocachexia, cachexia derived from acquired immunodeficiency syndrome (AIDS)) , arteriosclerosis, Creutzfeldt-Jakob disease, virus infection (e.g., virus infection such as cytomegalovirus, influenzavirus, herpesvirus and the like) , atopic dermatitis, systemic lupus erythematosus, AIDS encephalopathy, meningitis, angina, cardiac infarction, congestive heart failure, hepatitis, transplantation, dialysis hypotension, disseminated intravascular coagulation and the like to a mammal
(e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.) . Preferably, compound (I) is used as an agent for the prophylaxis or treatment of rheumatism and the like. Moreover, when the drug is compound (I) or a salt thereof, it can be used as an agent for the prophylaxis or treatment of various pain as mentioned below in mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.) . Cancer pain, acute pain caused by inflammation, pain associated with chronic inflammation, postoperative pain (pain of incision, deep pain, visceral pain, postoperative chronic pain disease and the like) , muscle pain (muscle pain associated with chronic pain disease, stiff neck and the like) , arthritic pain, toothache, pain of temporomandibular joint, headache (migraine, tension headache, headache caused by fever, headache associated with hypertension) , visceral pain (cardiac pain, anginal pain, abdominal pain, kidney pain, ureteral pain, cystalgia, obstetric and gynecologic pain (intermenstrual pain, dysmenorrhea, labor pain)) , neuralgia (hernia of intervertebral disk, radicular pain, post herpetic neuralgia pain, trigeminal neuralgia pain) , reflex sympathetic atrophy, complex topalgia syndrome and the like.
In addition, when the drug is compound (I) or a salt thereof, it can be used as a suppressing agent of osteoclast activation or an inhibiting agent of osteoclasts formation for mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc. ) .
Osteoclast is a multinucleated cell produced by differentiation and fusion of hematopoietic cells and has a bone substrate degradation function. In the bone metabolism, it plays a role of absorbing bone in contrast to osteoblast that newly creates bone. The maintenance of bone mass and morphology depends on the balance of the formation and absorption that the both cells perform, and when osteoclast is activated to promote bone absorption, the balance is broken and reduced bone mass, and morphological destruction and deformation occur. Since osteoclast is involved in the control of the blood calcium concentration via absorption of bone, which is a calcium reservoir organ, extreme activation of osteoclast increases the blood calcium concentration.
When the drug is compound (I) or a salt thereof, it suppresses activation of osteoclast, and inhibits formation of osteoclasts. Thus, it can be used as an agent for the prophylaxis or treatment of, for example, (i) postmenopausal or senile primary osteoporosis, (ii) inflammation (rheumatism and the like) , hematologic malignancy (malignant lymphoma, leukemia and the like) , endocrine disturbance (hyperthyroidism, diabetes and the like) or secondary osteoporosis caused by administration of pharmaceutical agents such as adrenal cortex hormone and the like, (iii) destruction or deformation of bone or joint tissue due to bone metastasis of tumor or rheumatism, (iv) Paget's disease or (v) hypercalcemia and the like.
When the drug is compound (I) or a salt thereof and the compound has a prophylactic or therapeutic effect on a pain as well as an osteoclasts activation suppressing and/or formation inhibitory effect, the compound is useful because it has a prophylactic or therapeutic effect on the diseases relating to osteoclasts such as destruction or deformation of bone or joint tissue and the like.
When using the solid dispersion of the present invention, a superior effect can be obtained by combining the above-mentioned drug (hereinafter to be abbreviated as the compound of the present invention) and other drug (hereinafter to be abbreviated as concomitant drug) :
(1) the dose of the compound of the present invention or a concomitant drug can be reduced as compared to single administration of the compound of the present invention or a concomitant drug,
(2) the drug to be used in combination with the compound of the present invention can be selected depending on the condition of patients (mild, severe and the like) ,
(3) the period of treatment can be set longer by selecting a concomitant drug having different action and mechanism from those of the compound of the present invention ,
(4) a sustained treatment effect can be designed by selecting a concomitant drug having different action and mechanism from those of the compound of the present invention,
(5) a synergistic effect can be afforded by a combined use of the compound of the present invention and a concomitant drug, and the like, can be achieved.
In the present specification, a pharmaceutical agent containing the compound of the present invention and a concomitant drug in combination is sometimes referred to as a "concomitant agent of the present invention". For the use of the concomitant agent of the present invention, the administration time of the compound of the present invention and the concomitant drug is not restricted, and a solid dispersion containing the compound of the present invention or a pharmaceutical composition thereof, and a concomitant drug or a pharmaceutical composition thereof, can be administered to an administration subject simultaneously, or may be administered at staggered times. In addition, the concomitant agent of the present invention can be used after synovectomy, after a treatment using prosorba column, after a treatment using mononuclear cell and the like. The dosage of the concomitant drug may be determined according to the dose clinically used, and can be appropriately selected depending on an administration subject, administration route, disease, combination and the like.
The administration mode of the concomitant agent of the present invention is not particularly restricted, as long as the compound of the present invention and the concomitant drug are combined in administration. Examples of such administration mode include the following methods: (1) The compound of the present invention and the concomitant drug are simultaneously formulated to give a single solid dispersion to be administered. (2) A solid dispersion containing the compound of the present invention or a pharmaceutical composition thereof and a pharmaceutical composition containing a concomitant drug are separately formulated to give two kinds of preparations which are administered simultaneously by the same administration route. (3) A solid dispersion containing the compound of the present invention or a pharmaceutical composition thereof and a pharmaceutical composition containing a concomitant drug are separately formulated to give two kinds of preparations which are administered by the same administration route at staggered times. (4) A solid dispersion containing the compound of the present invention or a pharmaceutical composition thereof and a pharmaceutical composition containing a concomitant drug are separately formulated to give two kinds of preparations which are administered simultaneously by the different administration routes. (5) A solid dispersion containing the compound of the present invention or a pharmaceutical composition thereof and a pharmaceutical composition containing a concomitant drug are separately formulated to give two kinds of preparations which are administered by the different administration routes at staggered times (for example, the compound of the present invention and the concomitant drug are administered in this order, or in the reverse order) , and the like.
A concomitant agent of the present invention has low toxicity, and for example, a solid dispersion containing the compound of the present invention and the above-mentioned concomitant drug or a pharmaceutical composition thereof is produced according to the above- mentioned method, or the above-mentioned concomitant drug is mixed with a pharmacologically acceptable carrier according to a method known per se to give a pharmaceutical composition, such as tablets (including a sugar-coated tablet, film-coated tablet) , powders, granules, capsules (including soft capsules) , suppositories, sustained-release preparations and the like, which is safely administered orally or parenterally (e.g., topical administration, rectal administration and the like) together with a solid dispersion containing the compound of the present invention or a pharmaceutical composition thereof.
As pharmacologically acceptable carriers usable for the production of a pharmaceutical composition containing the above-mentioned concomitant drug, various organic or inorganic carrier substances conventionally used as preparation materials can be mentioned. For example, suitable amounts of additives such as excipient, lubricant, binder and disintegrant for solid preparations, and where necessary, conventional preservative, antioxidant, coloring agent, sweetening agent, adsorbent, wetting agent and the like can be used appropriately.
The mixing ratio of the compound of the present invention to the concomitant drug in the concomitant agent of the present invention can be appropriately selected depending on an administration subject, administration route, diseases and the like.
For example, the content of the compound of the present invention in the concomitant agent of the present invention differs depending on the form of a preparation, and usually from about 0.01 to about 99.9 wtl, preferably from about 0.1 to about 50 wt%, further preferably from about 0.5 to about 20 wt%, based on the preparation. The content of the concomitant drug in the concomitant agent of the present invention differs depending on the form of a preparation, and usually from about 0.01 to about 99.9 wt%, preferably from about 0.1 to about 50 wt%, further preferably from about 0.5 to about 20 wt%, based on the preparation.
The content of additives such as a carrier and the like in the concomitant agent of the present invention differs depending on the form of a preparation, and usually from about 1 to about 99.98 wtl , preferably from about 10 to about 90 wtl, based on the preparation.
When the compound of the present invention and a concomitant drug are separately formulated into preparations, the content of the compound of the present invention and the concomitant drug differs depending on the form of a preparation, and usually from about 0.01 to about 99.9 wtl, preferably from about 0.1 to about 50 wtl, more preferably from about 0.5 to about 20 wtl, based on the preparation. The content of additives such as a carrier and the like differs depending on the form of a preparation, and usually from about 1 to about 99.99 wtl, preferably from about 10 to about 90 wtl, based on the preparation.
The dosage of a concomitant agent of the present invention differs depending on the kind of the drug, age, body weight, condition, dosage form, administration method, administration period and the like, and for example, for one arthritis patient (adult, body weight: about 60 kg) , the concomitant agent is administered, at a dose of about 0.01 to about 1000 mg/kg/day, preferably about 0.01 to about 100 mg/kg/day, more preferably about 0.1 to about 100 mg/kg/day, particularly about 0.1 to about 50 mg/kg/day, especially about 1.5 to about 30 mg/kg/day, in terms of the compound of the present invention or the concomitant drug, respectively, once or divided several times in a day. Of course, since the dosage as described above varies depending on various conditions, amounts smaller than the above-mentioned dosage may sometimes be sufficient, further, amounts over that range sometimes have to be administered.
The amount of the concomitant drug can be set at any value unless side effects are problematical. The daily dosage in terms of the concomitant drug differs depending on the severity, age, sex, body weight, sensitivity difference of the subject, administration period, interval, and nature, pharmacology, kind of the pharmaceutical preparation, kind of effective ingredient, and the like, and not particularly restricted, and the amount of a drug is, in the case of oral administration for example, usually from about
0.001 to 2000 mg, preferably from about 0.01 to 500 mg, further preferably from about 0.1 to 100 mg, per 1 kg of a mammal and this is usually administered once to 4- times divided in a day. For administration of pharmaceutical agent of the present invention, the compound of the present invention may be administered after administration of the concomitant drug or the concomitant drug may be administered after administration of the compound of the present invention, though they may be administered simultaneously. When administered at a time interval, the interval varies depending on the effective ingredient, dosage form and administration method, and, for example, when the concomitant drug is administered first, a method in which the compound of the present invention is administered within time range of from 1 minute to 3 days, preferably from 10 minutes to 1 day, more preferably from 15 minutes to 1 hour, after administration of the concomitant drug is exemplified. When the compound of the present invention is administered first, a method in which the concomitant drug is administered within time range of from 1 minute to 1 day, preferably from 10 minutes to 6 hours, more preferably from 15 minutes to 1 hour after administration of the compound of the present invention is exemplified.
In a preferable administration method, for example, the concomitant drug, which has been formed into an oral administration preparation, is administered orally at a daily dose of about 0.001 to 200 mg/kg, and about 15 minutes after, the compound of the present invention which has been formed into an oral administration preparation is administered orally at a daily dose of about 0.005 to 100 mg/kg.
Examples
While the present invention is explained in detail by way of the following Reference Examples, Examples, Comparative Example and Experimental Examples, these are mere examples and do not limit the present invention. The present invention can be modified without departing from the scope of the present invention.
The "%" in the following Examples indicates percent by weight unless otherwise specified. According to the methods described in WO00/64894, the following compounds of Reference Example 1 to Reference Example 28 were synthesized. Reference Example 1
[4- (3, 5-dimethylphenyl) -5- (2-phenylmethyloxy-4-pyridγl) - l,3-thiazol-2-yl] amine
Reference Example 2 N- [4- [2-benzoylamino-4- (4-methoxyphenyl) -l,3-thiazol-5- yl]-2-pyridyl]benzamide
Reference Example 3
N- [4- (4-methoxyphenyl) -5- [2- [ (3-pyridylcarbonylamino) ]-
4-pyridyl]-l,3-thiazol-2-yl]nicotinamide Reference Example 4
N- [4- [2-amino-4- (4-methoxyphenyl) -l,3-thiazol-5-yl]-2- pyridyl]benzamide
Reference Example 5
N- [4- [2-amino-4- (3 , 5-dimethylphenyl) -1 ,3-thiazol-5-yl] - 2-pyridyl]benzamide
Reference Example 6
N- [4- [2-amino-4- (3,5-dimethylphenyl) -1,3-thiazol-5-yl] -
2-pyridyl]benzylamine
Reference Example 7 N- [4- [2-amino-4- (3, 5-dimethylphenyl) -1, 3-thiazol-5-yl]-
2-pyridyl]benzamide hydrochloride
Reference Example 8
N- [4- [2-amino-4- (3 , 5-dimethylphenyl) -l,3-thiazol-5-yl]-
2-pyridyl]benzylamine dihydrochloride Reference Example 9
N- [5- (2-benzoylamino-4-pyridyl) -4- (3,5-dimethylphenyl) - l,3-thiazol-2-yl]acetamide
Reference Example 10
N- [5- (2-benzylamino-4-pyridyl) -4- (3,5-dimethylphenyl) - 1 ,3-thiazol-2-yl] acetamide
Reference Example 11
N-[4-[4- (4-methoxyphenyl) -2-methylamino-l,3-thiazol-5- yl] -2-pyridyl]benzamide Reference Example 12
N- [4- [2-amino-4- (3-methylphenyl) -l,3-thiazol-5-yl]-2- pyridyl]benzamide
Reference Example 13 N- [4- [4- (4-methoxyphenyl) -2-methy1-1,3-thiazol-5-yl]-2- pyridyl]benzamide
Reference Example 14
N- [4-[2- (4-fluorophenyl) -4- (3-methylphenyl) -1, 3-thiazol-
5-yl]-2-pyridyl]phenylacetamide Reference Example 15-1
N- [4- [4- (4-methoxyphenyl) -2-methyl-l,3-thiazol-5-yl]-2- pyridyl]phenylacetamide
Reference Example 15-2
N-[4-[2-ethyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2- pyridyl]phenylacetamide
Reference Example 15-3
N- [4- [4- (3-methylphenyl) -2-propyl-l ,3-thiazol-5-yl] -2- pyridyl]phenylacetamide
Reference Example 15-4 N- [4- [2-butyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2- pyridyl]phenylacetamide
Reference Example 15-5
N- [4-[2- (2-chlorophenyl) -4- (3-methylphenyl) -1 , 3-thiazol-
5-yl]-2-pyridyl]phenylacetamide Reference Example 15-6
N- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3- thiazol-5-yl]-2-pyridyl]phenylacetamide
Reference Example 16-1
N-[4- [2-ethy1-4- (3-methylphenyl) -1 ,3-thiazol-5-yl] -2- pyridyl]benzamide
Reference Example 16-2
N-[4- [2-ethy1-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2- pyridyl]-3-phenylpropionamide Reference Example 16-3
N- [4- [2-ethyl-4- (3-methylρhenyl) -1,3-thiazol-5-yl]-2- pyridyl] -3- (4-methoxyphenyl)propionamide
Reference Example 16-4 N- [4- [2-ethyl-4- (3-methylphenyl) -1,3-thiazol-5-yl]-2- pyridyl] -3- (4-fluorophenyl)propionamide
Reference Example 16-5
N- [4- [2-ethyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2- pyridyl] -4-phenylbutyramide Reference Example 16-6
N- [4- [2-ethyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2- pyridyl]-5-phenylvaleramide
Reference Example 16-7
N- [4- [4- (3-methylphenyl) -2-propyl-l ,3-thiazol-5-yl] -2- pyridyl]benzamide
Reference Example 16-8
N- [4- [4- (3-methylphenyl) -2-propyl-l,3-thiazol-5-yl] -2- pyridyl]-3-phenylpropionamide
Reference Example 16-9 N- [4- [2-butyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2- pyridyl]benzamide
Reference Example 16-10
N- [4- [2-butyl-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2- pyridyl]-3-phenylpropionamide Reference Example 16-11
N- [4- [2- (4-fluorophenyl) -4- (3-methylphenyl) -1, 3-thiazol-
5-yl]-2-pyridyl]benzamide
Reference Example 16-12
N- [4- [2- (4-fluorophenyl) -4- (3-methylphenyl) -1,3-thiazol- 5-yl] -2-pyridyl] -3-phenylpropionamide
Reference Example 16-13
N- [4- [2- (2-chlorophenyl) -4- (3-methylphenyl) -1 , 3-thiazol-
5-yl]-2-pyridyl]benzamide Reference Example 16-14
N- [4- [2- (2-chlorophenyl) -4- (3-methylphenyl) -1 , 3-thiazol
5-yl] -2-pyridyl] -3-phenylpropionamide
Reference Example 16-15 N- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3- thiazol-5-yl] -2-pyridyl]benzamide
Reference Example 16-16
N- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3- thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide Reference Example 16-17
N- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3- thiazol-5-yl] -2-pyridyl]-2-thiophenecarboxamide
Reference Example 16-18
N- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1 ,3- thiazol-5-yl]-2-pyridyl] -2-naphthamide
Reference Example 17
N- [4- [2-ethyl-4- (3-methylphenyl) -1 ,3-thiazol-5-yl] -2- pyridyl] -N-methylphenylacetamide
Reference Example 18 N- [4- [2-ethyl-4- (3-methylphenyl) -1 ,3-thiazol-5-yl] -2- pyridyl]-N-methyl-3-phenylpropionamide
Reference Example 19-1
N-benzyl-N- [4- [4- (4-methoxyphenyl) -2-methyl-1,3-thiazol- 5-yl] -2-pyridyl] amine Reference Example 19-2
N-benzyl-N- [4- [2-ethyl-4- (3-methylphenyl) -1,3-thiazol-5- yl]-2-pyridyl] amine
Reference Example 19-3
N- [4- [2-ethyl-4- (3-methylphenyl) -1 ,3-thiazol-5-yl] -2- pyridyl]-N- (2-phenylethyl) amine
Reference Example 19-4
N-[4- [2-ethyl-4- (3-methylphenyl) -1,3-thiazol-5-yl]-2- pyridyl]-N- (3-phenylpropyl) amine Reference Example 19-5
N-benzyl-N- [4- [4- (3-methylphenyl) -2-propyl-l,3-thiazol-
5-yl]-2-pyridyl]amine
Reference Example 19-6 N- [4- [4- (3-methylphenyl) -2-propyl-l ,3—thiazol-5-yl] -2- pyridyl]-N- (2-phenylethyl) amine
Reference Example 19-7
N- [4-[4- (3-methylphenyl) -2-propyl-l,3-thiazol-5-yl]-2- pyridyl]-N- (3-phenylpropyl) amine Reference Example 19-8
N-benzyl-N- [4- [2-butyl-4- (3-methylphenyl) -1 ,3-thiazol-5- yl]-2-pyridyl]amine
Reference Example 19-9
N- [4- [2-butyl-4- (3-methylphenyl) -1 ,3-thiazol-5-yl]-2- pyridyl] -N- (2-phenylethyl) amine
Reference Example 19-10
N- [4- [2-butyl-4- (3-rnethylphenyl) -1 ,3-thiazol-5-yl]-2- pyridyl] -N- (3-phenylpropyl) amine
Reference Example 19-11 N-benzyl-N- [4- [2- (4-fluorophenyl) -4- (3-methylphenyl) -
1,3-thiazol-5-yl]-2-pyridyl]amine
Reference Example 19-12
N- [4- [2- (4-fluorophenyl) -4- (3-methylphenyl) -1 , 3-thiazol-
5-yl]-2-pyridyl] -N- (2-phenylethyl) amine Reference Example 19-13
N- [4-[2- (4-fluorophenyl) -4- (3-methylphenyl) -1,3-thiazol-
5-yl] -2-pyridyl] -N- (3-phenylpropyl) amine
Reference Example 19-14
N-benzyl-N- [4- [2- (2-chlorophenyl) -4- (3-methylphenyl) - 1,3-thiazol-5-yl] -2-pyridyl] amine
Reference Example 19-15
N- [4- [2- (2-chlorophenyl) -4- (3-methylphenyl) -1, 3-thiazol- 5-yl] -2-pyridyl] -N- (2-phenylethyl) amine Reference Example 19-16
N-[4- [2- (2-chlorophenyl) -4- (3-methylphenyl) -1,3-thiazol-
5-yl] -2-pyridyl] -N- (3-phenylpropyl) amine
Reference Example 19-17 N-benzyl-N- [4- [4- (3-methylphenyl) -2- (4- methylthiophenyl) -1,3-thiazol-5-yl]-2-pyridyl] amine
Reference Example 19-18
N- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3- thiazol-5-yl] -2-pyridyl] -N- (2-phenylethyl) amine Reference Example 19-19
N- [4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3- thiazol-5-yl]-2-pyridyl]-N- (3-phenylpropyl) amine
Reference Example 19-20
N-[4- [4- (3-methylphenyl) -2- (4-methylthiophenyl) -1,3- thiazol-5-yl] -2-pyridyl] -N- (2-naphthylmethyl) amine
Reference Example 20
N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3- thiazol-5-yl] -2-pyridyl]benzamide
Reference Example 21-1 N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3- thiazol-5-yl] -2-pyridyl]phenylacetamide
Reference Example 21-2
N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3- thiazol-5-yl] -2-pyridyl]-3-phenylpropionamide Reference Example 21-3
N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3- thiazol-5-yl] -2-pyridyl] -2-thiophenecarboxamide
Reference Example 21-4
N- [4-[4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3- thiazol-5-yl] -2-pyridyl]-2-naphthamide
Reference Example 21-5
N-benzyl-N- [4- [4- (3-methylphenyl) -2- (4- methylsuIfonylphenyl) -1,3-thiazol-5-yl] -2-pyridyl]amine Reference Example 21-6
N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1 ,3- thiazol-5-yl]-2-pyridyl] -N- (3-phenylpropyl) amine
Reference Example 21-7 N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3- thiazol-5-yl] -2-pyridyl] -N- (2-naphthylmethyl) amine
Reference Example 22
N- [4- [2-amino-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2- pyridyl]-N-benzylamine Reference Example 23-1
N- [4- [2-amino-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2- pyridyl] -N- (4-methoxybenzyl) amine
Reference Example 23-2
N- [4- [2-amino-4- (3-methylphenyl) -1 ,3-thiazol-5-yl] -2- pyridyl] -N- (3-methoxybenzyl) amine
Reference Example 23-3
N- [4- [2-amino-4- (3-methylphenyl) -1 ,3-thiazol-5-yl] -2- pyridyl] -N- (2-methoxybenzyl) amine
Reference Example 23-4 N- [4- [2-amino-4- (3-methylphenyl) -1 ,3-thiazol-5-yl] -2- pyridyl] -N- (4-chlorobenzyl) amine
Reference Example 23-5
N- [4- [2-amino-4- (3-methylphenyl) -1,3-thiazol-5-yl] -2- pyridyl] -N- (3-chlorobenzyl) amine Reference Example 23-6
(R) -N- [4- [2-amino-4- (3-methylphenyl) -1,3-thiazol-5-yl] -
2-pyridyl] -N- (1-phenylethyl) amine
Reference Example 23-7
(S) -N- [4- [2-amino-4- (3-methylphenyl) -1 ,3-thiazol-5-yl] - 2-pyridyl] -N- (1-phenylethyl) amine
Reference Example 23-8
N- [4- [2-amino-4- (3-methylphenyl) -l,3-thiazol-5-yl]-2- pyridyl]-N-benzyl-N-methylamine Reference Example 24
N- [4- [2-amino-4- (3-methoxyphenyl) -1,3-thiazol-5-yl] -2- pyridyl] -N-benzylamine
Reference Example 25-1 N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3- thiazol-5-yl] -2-pyridyl] -N- (2-phenylethyl) amine
Reference Example 25-2
N- (4-fluorobenzyl) -N- [4- [4- (3-methylphenyl) -2- (4- methylsuIfonylphenyl) -l,3-thiazol-5-yl] -2-pyridyl]amine Reference Example 25-3
N-benzyl-N-methyl-N- [4- [4- (3-methylphenyl) -2- (4- methylsuIfonylphenyl) -1 ,3-thiazol-5-yl] -2-pyridyl] amine
Reference Example 25-4
N-methyl-N- [4- [4- (3-methylphenyl) -2- (4- methylsuIfonylphenyl) -l,3-thiazol-5-yl] -2-pyridyl] -N- (2- phenylethyl) amine
Reference Example 25-5
N- [4- [4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -1,3- thiazol-5-yl] -2-pyridyl] -N- (2-thienylmethyl) amine Reference Example 26
4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -5- (2- phenylthio-4-pyridyl) -1 ,3-thiazole
Reference Example 27
5- (2-benzylthio-4-pyridyl) -4- (3-methylphenyl) -2- (4- methylsulfonylphenyl) -1 ,3-thiazole
Reference Example 28
4- (3-methylphenyl) -2- (4-methylsulfonylphenyl) -5- (2- phenylsulfony1-4-pyridyl) -1,3-thiazole
The structural formulas of the compounds obtained in Reference Examples 1 to 6 are shown below. Reference Example 1
Figure imgf000069_0001
Reference Example 2
Figure imgf000069_0002
Reference Example 3
Figure imgf000069_0003
Reference Example 4
Figure imgf000069_0004
Reference Example 5
Figure imgf000070_0001
Reference Example 6
Figure imgf000070_0002
The compounds produced in the above-mentioned Reference Examples 9 to 28 are shown in Table 1 to Table 6.
Table 1
Figure imgf000071_0001
-CO- -NH- -NHCOMe 238-241
10 -CH2- -NH- -NHCOMe 217-219
Figure imgf000071_0003
11 -CO- -NH- -NHMe MeO- 237-241
12 -CO- -NH- -NH2 216-217
Figure imgf000071_0004
13 -CO- -NH- -Me MeC 134-135
Figure imgf000071_0002
14 187-190
Figure imgf000071_0005
15-1 £ } -CH2CO- -NH- -Me Mel 118-120
15-2 -CH2CO- -NH- -CH2Me 107-108
Figure imgf000071_0007
15-3 ■C j -CH2CO- -NH- -(CHj)2Me 109-111
15-4 -CH2CO- -NH- -(CH2)SMe 92-93
Figure imgf000071_0008
Figure imgf000071_0006
15-5 4 } -CH2CO- -NH- 141-142
15-6 4 y) -CH2CO- -NH- 205-206
Figure imgf000071_0009
16-1 -CO- -NH- -CH2Me 113-114
16-2 -(CH2J2Ca -NH- -CH2Me 126-127
Figure imgf000071_0011
Figure imgf000071_0010
Table 2
Figure imgf000072_0001
Ref . Ex . compound R2 R1 m . p . j 'Q1
16-3 137-138
16-4 116-117
Figure imgf000072_0002
16-5 -(CH2)3C0- -NH- -CH2Me 92-93
16-6 ■ -(CH2J4CO- .NH- -CH2Me 86-87
16-7 • -CO- -NH- -(CH2J2Me amorphous powder
16-8 -(CH2J2CO- -NH- -(CH2J2Me 103-104
16-9 -CO- -NH- -(CH2J3Me amorphous powder
16-10 -(CH2J2CO- -NH- -(CH2J3Me
Figure imgf000072_0003
77-78
Figure imgf000072_0004
Figure imgf000072_0005
16-12 -(CH2J2CO- -NH-
Figure imgf000072_0007
169-171
Figure imgf000072_0006
Figure imgf000072_0008
16-14 -(CH2J2CO- -NH- 156-158
Figure imgf000072_0010
16-15 -CO- -NH- SMe 1 B0-182
16-16 -(CH2J2CO- -NH- SMe 174-175
Figure imgf000072_0009
Figure imgf000072_0011
Table 3
Figure imgf000073_0001
ME
16-17 — Q -CO- -NH- -^TSMe ^Λ_ 145-147
Figure imgf000073_0002
17 4 /> -CH2CO- -NMe- -CH2Me 75-76
18 -(CHa)2CO- -NMe- -CH2Me oil
Figure imgf000073_0003
19-1 -CH2 - -NH- -Me MeC 132-133
19-2 -CH2 - -NH- -CH2Me 106-107
19-3 -(CH2J2 - -NH- -CH2Me 97-98
19-4 -(CH2J3 - -NH- -CH2Me 52-53
19-5 -CH2- -NH- -(CH2J2Me oil
19-6 -(CH2J2- -NH- -(CH2J2Me oil
19-7 -(CH2J3- -NH- -(CH2J2Me oil
19-8 -CH2- -NH- -(CH2J3Me oil
19-9 -(CH2J2- -NH- -(CH2J3Me oil
Figure imgf000073_0004
Figure imgf000073_0005
Table 4
Figure imgf000074_0001
19-10 —% } -(CH2J3- -NH- -(CH2)SMe oil
Figure imgf000074_0002
Figure imgf000074_0003
19-12 97-98
Figure imgf000074_0004
19-13 — 4 y -(CH2J3- -NH- 110-112
Figure imgf000074_0005
Figure imgf000074_0006
19-16 -(CHa)3- -NH- 101-102
Figure imgf000074_0007
19-17 -CH2 -
Figure imgf000074_0008
-NH- -SMe 134-136
Figure imgf000074_0009
19-18 137-139
Figure imgf000074_0010
19-19 O -(CH2J3- -NH- 106-107
Figure imgf000074_0011
19-20 144-145
Figure imgf000074_0012
20 -CO- -NH- <>SO2Me 212-214
Figure imgf000074_0014
Figure imgf000074_0013
Table 5
Figure imgf000075_0002
compound
Figure imgf000075_0001
m.p. / «c
21-1 -CH2CO- .NH- — /3~s°2Mβ 244-245
21-2 -(CH2J2Ca -NH- -SO2Me
Figure imgf000075_0004
236-237
Figure imgf000075_0003
21-3 -ό -CO- -NH- 199-201
Figure imgf000075_0005
21-4 -CO- -NH- —V ff- SO2Me 231-233
21-5 -CH2- -NH- -SO2Me 148-150
Figure imgf000075_0007
Figure imgf000075_0006
21*6 167-1S8
Figure imgf000075_0008
Figure imgf000075_0009
22 -CH2- -NH- -NH9 178-179
Figure imgf000075_0011
Figure imgf000075_0010
23-1 183-184
23-2 152-154
23-3 158-159
23-4 182-183
Figure imgf000075_0012
23-5 -CH2- -NH- -NH2 180-181
Figure imgf000075_0014
23-6 —L ) -CHMe-(R) -NH- -NH, 94-98
Figure imgf000075_0013
Table 6
R3 m . p . / -c
Figure imgf000076_0001
23-7 —i } -CHMe- (S) -NH- -NH2 93-96
23-B > V -CH2 - -NMe- -NH2 138-140
Figure imgf000076_0002
24 217-218
Figure imgf000076_0003
25-1 4 # -(CHg)2 - -NH- —f_V SO2Me 174-176
Figure imgf000076_0004
25-2 155-158
Figure imgf000076_0005
25-3 -CH5 -NMe- -SO2Me 165-166
25-4 -(CH2J2 - -NMe-
Figure imgf000076_0007
-SO2Me 116-117
Figure imgf000076_0006
25-5 107-109
Figure imgf000076_0008
Figure imgf000076_0009
27 182-185
Figure imgf000076_0010
Figure imgf000076_0011
Example 1
Hydroxypropylmethylcellulose phthalate (6 g, trade name: HPMCP, brand: HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.) , hydroxypropylmethylcellulose 2910 (3 g, trade name: TC-5, brand: TC-5S, manufactured by Shin-Etsu Chemical Co., Ltd.) and polyethylene oxide (7 g, trade name: Polyox, brand: WSR 303, manufactured by Dow Chemical) were weighed and manually mixed with N- [4- [2-ethyl-4- (3-methylphenyl) -1 ,3-thiazol-5-yl] -2- pyridyl]benzamide (4 g) obtained in Reference Example 16-1 (hereinafter to be referred to as compound A) in a mortar for about 3 min. The mixture (20 g) was extruded using a twin screw extruder eguipped with a die (bore 3 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 900C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm with a retractable knife to give a pellet sample. Example 2
Hydroxypropylmethylcellulose phthalate (6 g, trade name: HPMCP, brand: HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.) , hydroxypropylmethylcellulose 2910 (3 g, trade name: TC-5, brand: TC-5S, manufactured by Shin-Etsu Chemical Co., Ltd.) and polyethylene oxide (7 g, trade name: Polyox, brand: WSR 303, manufactured by Dow Chemical) were weighed and manually mixed with compound A (4 g) in a mortar for about 3 min. The mixture (20 g) was extruded using a twin screw extruder equipped with a die (bore 6 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 90°C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample. Example 3
Hydroxypropylmethylcellulose phthalate (18 g, trade name: HPMCP, brand: HP-55, manufactured by Shin-Etsu Chemical Co. , Ltd.) , hydroxypropylmethylcellulose 2910 (9 g, trade name: TC-5, brand: TC-5S, manufactured by Shin-Etsu Chemical Co. , Ltd.) and polyethylene oxide (21 g, trade name: Polyox, brand: WSR Coagulant, manufactured by Dow Chemical) were weighed and manually mixed with compound A (12 g) in a mortar for about 3 min. From the mixture (60 g) , 2O g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of 900C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample. Example 4
From the mixture (60 g) prepared in Example 3, 2O g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of 100°C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample. Example 5
From the mixture (60 g) prepared in Example 3, 2O g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of 1100C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample. Example 6
Hydroxypropylmethylcellulose phthalate (18 g, trade name: HPMCP, brand: HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.) , hydroxypropylmethylcellulose 2910 (9 g, trade name: TC-5, brand: TC-5S, manufactured by
Shin-Etsu Chemical Co., Ltd.) and polyethylene oxide (21 g, trade name: Polyox, brand: WSR 303, manufactured by Dow Chemical) were weighed and manually mixed with compound A (12 g) in a mortar for about 3 min. From the mixture (60 g) , 20 g thereof was extruded using a twin screw extruder equipped with a die (bore 1 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 90°C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 1 mm with a rapid pelletizer (manufactured by Imoto Machinery Co., Ltd.) to give a granule sample. Example 7 From the mixture (60 g) prepared in Example 6, 2O g thereof was extruded using a twin screw extruder equipped with a die (bore 1 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 1000C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 1 mm with a rapid pelletizer (manufactured by Imoto Machinery Co., Ltd.) to give a granule sample. Example 8
From the mixture (60 g) prepared in Example 6, 2O g thereof was extruded using a twin screw extruder equipped with a die (bore 1 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 110°C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 1 mm with a rapid pelletizer (manufactured by Imoto Machinery Co., Ltd.) to give a granule sample. Example 9
Hydroxypropylmethylcellulose acetate succinate (13.5 g, trade name: Shin-Etsu AQOAT, brand: AS-LF, manufactured by Shin-Etsu Chemical Co., Ltd.) , hydroxypropylmethylcellulose 2910 (6.75 g, trade name: TC-5, brand: TC-5S, manufactured by Shin-Etsu Chemical Co., Ltd.) and polyethylene oxide (15.75 g, trade name: Polyox, brand: WSR Coagulant, manufactured by Dow Chemical) were weighed and manually mixed with compound A (9 g) in a mortar for about 3 min. From the mixture (45 g) , 15 g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 900C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample. Example 10 From the mixture (45 g) prepared in Example 9, 15 g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 1000C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample. Example 11
From the mixture (45 g) prepared in Example 9, 15 g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 1100C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample. Example 12
Hydroxypropylmethylcellulose phthalate (6 g, trade name: HPMCP, brand: HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.) , hydroxypropylmethylcellulose 2910 (7 g, trade name: TC-5, brand: TC-5S, manufactured by Shin-Etsu Chemical Co., Ltd.) and polyethylene oxide (3 g, trade name: Polyox, brand: WSR 303, manufactured by Dow Chemical) were weighed and manually mixed with compound A (4 g) in a mortar for about 3 min. The mixture (20 g) was extruded using a twin screw extruder equipped with a die (bore 3 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 90°C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm with a retractable knife to give a pellet sample. Example 13
Hydroxypropylmethylcellulose phthalate (6 g, trade name: HPMCP, brand: HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.) , hydroxypropylmethylcellulose 2910 (9 g, trade name: TC-5, brand: TC-5S, manufactured by Shin-Etsu Chemical Co., Ltd.) and polyethylene oxide (1 g, trade name: Polyox, brand: WSR 303, manufactured by Dow Chemical) were weighed and manually mixed with compound A (4 g) in a mortar for about 3 min. The mixture (20 g) was extruded using a twin screw extruder equipped with a die (bore 3 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 900C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm with a retractable knife to give a pellet sample. Example 14
Hydroxypropylmethylcellulose acetate succinate (6 g, trade name: Shin-Etsu AQOAT, brand: AS-LF, manufactured by Shin-Etsu Chemical Co., Ltd.) , lactose (9 g) and macrogol 6000 (3 g, manufactured by NOF Corporation) were weighed and manually mixed with compound A (12 g) in a mortar for about 3 min. From the mixture (30 g) , 10 g thereof was extruded using a twin screw extruder equipped with a die (bore 1 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 900C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 1 mm with a rapid pelletizer (manufactured by Imoto Machinery Co., Ltd.) to give a granule sample. Example 15
From the mixture (30 g) prepared in Example 14, 1O g thereof was extruded using a twin screw extruder equipped with a die (bore 1 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of 100°C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 1 mm with a rapid pelletizer (manufactured by Imoto Machinery Co. , Ltd.) to give a granule sample. Example 16
From the mixture (30 g) prepared in Example 14, 1O g thereof was extruded using a twin screw extruder equipped with a die (bore 1 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of HO0C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 1 mm with a rapid pelletizer (manufactured by Imoto Machinery Co. , Ltd.) to give a granule sample. Example 17
Hydroxypropylmethylcellulose acetate succinate (9 g, trade name: Shin-Etsu AQOAT, brand: AS-LF, manufactured by Shin-Etsu Chemical Co. , Ltd.) , AEROSIL (6 g, manufactured by NIPPON AEROSIL CO. , LTD.) and macrogol 6000 (3 g, manufactured by NOF Corporation) were weighed and manually mixed with compound A (12 g) in a mortar for about 3 min. From the mixture (30 g) , 1O g thereof was extruded using a twin screw extruder equipped with a die (bore 1 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of 900C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus- obtained extruded product was cut into a length of about 1 mm with a rapid pelletizer (manufactured by Imoto Machinery Co. , Ltd.) to give a granule sample. Example 18
From the mixture (30 g) prepared in Example 17, 1O g thereof was extruded using a twin screw extruder equipped with a die (bore 1 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of 1000C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 1 mm with a rapid pelletizer (manufactured by Imoto Machinery Co. , Ltd.) to give a granule sample. Example 19
From the mixture (30 g) prepared in Example 17, 1O g thereof was extruded using a twin screw extruder equipped with a die (bore 1 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of 1100C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 1 mm with a rapid pelletizer (manufactured by Imoto Machinery Co. , Ltd.) to give a granule sample. Example 20
Hydroxypropylmethylcellulose acetate succinate (18 g, trade name: Shin-Etsu AQOAT, brand: AS-LF, manufactured by Shin-Etsu Chemical Co. , Ltd.) , hydroxypropylmethylcellulose 2910 (9 g, trade name: TC-5 , brand: TC-5S, manufactured by Shin-Etsu Chemical Co. , Ltd.) and polyethylene oxide (21 g, trade name: Polyox, brand: WSR Coagulant, manufactured by Dow Chemical) were weighed and manually mixed with compound A (12 g) in a mortar for about 3 min. From the mixture (60 g) , 2O g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of 600C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample. Example 21
From the mixture (60 g) prepared in Example 20, 20 g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 70°C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample. Example 22
From the mixture (60 g) prepared in Example 20, 20 g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 8O0C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample. Example 23
Hydroxypropylmethylcellulose acetate succinate (18 g, trade name: Shin-Etsu AQOAT, brand: AS-LF, manufactured by Shin-Etsu Chemical Co. , Ltd. ) , hydroxypropylmethylcellulose 2910 (21 g, trade name: TC- 5, brand: TC-5S, manufactured by Shin-Etsu Chemical Co., Ltd.) and polyethylene oxide (9 g, trade name: Polyox, brand: WSR Coagulant, manufactured by Dow Chemical) were weighed and manually mixed with compound A (12 g) in a mortar for about 3 min. From the mixture (60 g) , 2O g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 900C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample. Example 24
From the mixture (60 g) prepared in Example 23, 2O g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of 1000C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample. Example 25
From the mixture (60 g) prepared in Example 23, 2O g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of 1100C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample. Example 26
Hydroxypropylmethylcellulose acetate succinate (18 g, trade name: Shin-Etsu AQOAT, brand: AS-HF, manufactured by Shin-Etsu Chemical Co., Ltd.) , hydroxypropylmethylcellulose 2910 (9 g, trade name: TC-5, brand: TC-5S, manufactured by Shin-Etsu Chemical Co., Ltd.) and polyethylene oxide (21 g, trade name: Polyox, brand: WSR Coagulant, manufactured by Dow Chemical) were weighed and manually mixed with compound A (12 g) in a mortar for about 3 min. From the mixture (60 g) , 2O g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of 900C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample. Example 27
From the mixture (60 g) prepared in Example 26, 2O g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co. , Ltd.) at a barrel temperature of 100°C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample. Example 28
From the mixture (60 g) prepared in Example 26, 20 g thereof was extruded using a twin screw extruder equipped with a die (bore 3 mmφ) (conical screw HB-I, manufactured by Imoto Machinery Co., Ltd.) at a barrel temperature of 1100C and a screw rotation speed of 80 rpm to give an extruded product of a solid dispersion. The thus-obtained extruded product was cut into a length of about 10 mm to 15 mm with a retractable knife to give a pellet sample.
Comparative Example 1
[Production of film coating solution]
Hydroxypropylmethylcellulose (TC-5, 3,038 g) and macrogol 6000 (PEG6000, 705.6 g) were dissolved in purified water (34.50 L) . To the obtained solution was added purified water (7.840 L) containing titanium oxide (940.8 g) and yellow diiron trioxide (18.82 g) dispersed therein to give a film coating solution. [Production of plain tablets]
Compound A (22,500 g) , lactose (33,730 g) and cornstarch (6,750 g) were placed in a fluidized bed granulating dryer (manufactured by POWREX) , preliminarily mixed, and granulated by spraying an aqueous solution (40,510 g) containing hydroxypropylcellulose (HPC-L, 2,025 g) dissolved therein. The obtained granules (62,690 g) was passed through a power mill (manufactured by Showa Kagaku Kikai Kosakusho Co., Ltd.) to give a sized powder. The obtained powder (61,540 g) , carmellose calcium (ECG-505, 1,917 g) and magnesium stearate (447.3 g) were mixed in a tumbler mixer (manufactured by Showa Kagaku Kikai Kosakusho Co., Ltd.) and the resulting powder mixture (62,550 g) was tableted with a tableting machine (manufactured by KIKUSUI SEISAKUSHO LTD.) to give plain tablets. [Production of film-coated tablets]
The aforementioned film coating solution was sprayed on the obtained plain tablets (196,000 tablets) in a film coating machine (manufactured by POWREX) to give film-coated tablets (196,000 tablets) containing 100 mg of compound A per tablet and having the following formulation. Table 7 Formulation Example (composition per tablet, unit: mg) compound A 100.0 lactose 149.9 cornstarch 30.0 hydroxypropylcellulose (HPC-L) 9.0 carmellose calcium (ECG-505) 9.0 magnesium stearate 2.1 hydroxypropylmethylcellulose 2910 (TC-5) 7.752 macrogol 6000 (PEG6000) 1.8 titanium oxide 2.4 yellow diiron trioxide 0.048 total 312.0
Experimental Example 1
The oral absorption was evaluated in dogs for the pellet solid dispersion obtained in Example 1 and the film-coated tablet obtained in Comparative Example 1. Male beagles (n=5, body weight about 12 kg) were fasted overnight before the test, with free intake of water. A fluid diet (pulverized solid feed 50 g + water 80 g) was fed before administration of the preparation, and the preparation was orally administered with 60 mL of water 30 min after the food intake. The dose was 100 mg/body based on the amount of compound A. After 1, 2, 4, 6, 8 and 12 hrs from the administration, blood (about 1 mL) was drawn from the median antebrachial vein. The plasma was centrifuged and plasma concentration was measured by HPLC. From the obtained plasma concentration, the area under the blood concentration-time curve (AUC) and mean residence time (MRT) were calculated by the trapezoid method. The maximum plasma concentration (Cmax) and the time to reach the maximum plasma concentration (Tmax) were determined from the measured values. The plasma concentration of compound A after oral administration of each preparation to the dogs is shown in Fig. 1, and the pharmacokinetic parameters calculated from the result are shown in Table 8.
Table 8
Pharmacokinetic parameters after administration of preparation (mean ±standard error)
preparation Cmax Tmax AUC MRT (μg/mL) (hrs) (μg-h/mL) (hrs)
Example 1 0.429±0.064 5.6±0.7 2.83±0.42 6.1±0.3
Comparative
Example 1 1.102±0.103 1. O±O .0 3.36±0.41 3.1±0.1
As is clear from the results of Fig. 1 and Table 8, the solid dispersion of Example 1 showed an AUC that was not much different from that of the film-coated tablet of Comparative Example 1, but a Cmax that decreased to about 40%, and a T103x that was prolonged to about 5 hrs and an MRT to about 3 hrs, thus exhibiting clear sustained-release. Experimental Example 2
The oral absorption was evaluated in dogs for the pellet solid dispersions obtained in Example 3, Example 4, Example 5, Example 9, Example 22 and Example 26 and the film-coated tablet obtained in Comparative Example 1. Male beagles (n=5, body weight about 12 kg) were fasted overnight before the test, with free intake of water. A fluid diet (pulverized solid feed 50 g + water 80 g) was fed before administration of the preparation, and the preparation was orally administered with 60 mL of water 30 min after the food intake. The dose was 100 mg/body based on the amount of compound A. After 1, 2, 4, 6, 8 and 12 hrs from the administration, blood (about 1 mL) was drawn from the median antebrachial vein. The plasma was centrifuged and plasma concentration was measured by HPLC. From the obtained plasma concentration, the area under the blood concentration (AUC) and average residence time (MRT) were calculated by the trapozoid method. The maximum plasma concentration (Craax) and the time to reach the maximum plasma concentration (Tmax) were determined from the measured values.
The plasma concentration of compound A after oral administration of each preparation to the dogs is shown in Fig. 2, and the pharmacokinetic parameters calculated from the result are shown in Table 9.
Table 9 Pharmacokinetic parameters after administration of preparation (mean ±standard error)
preparation T AUC MRT
(μg/mL) (hrs) (μg-h/mL) (hrs)
Example 3 0.469±0.097 6.8±0.5 2.67±0.56 6.6±0.3
Example 4 0.399±0.055 6.8±0.5 2.29±0.39 6.8±0.2
Example 5 0.502±0. Ill 8.4±1.0 2.42±0.53 7.6±0.4
Example 9 0.564±0.024 6.4±0.4 3.22±0.23 6.8±0.3
Example 22 0.492±0.068 5.6±1.2 2.93±0.45 6.4±0.6
Example 26 0.407±0.041 5.8±1.3 2.38±0.40 5.7±0.6
Comparative
Example 1 1.102±0.103 1. O±O.0 3.36±0.41 3. l±O.1
As is clear from the results of Fig. 2 and Table 9, the solid dispersions of Example 3, Example 4, Example 5, Example 9, Example 22 and Example 26 showed an AUC that was not much different from that of the film-coated tablet of Comparative Example 1, but a Cmax that decreased to about 40% to about 50%, and a Tmax that was prolonged to about 5 hrs to 7 hrs and an MRT to about 3 hrs to 4 hrs, thus exhibiting clear sustained-release.
Industrial Applicability
As is clear from the foregoing, according to the present invention, improvement of solubility of poorly soluble or insoluble drugs and a drug release- controlling function can be provided simultaneously in a single manufacturing process and a solid dispersion having a uniform composition and superior sustained- release can be provided.
This application is based on patent application No. 2004-203799 filed in Japan, the contents of which are hereby incorporated by reference.

Claims

1. A solid dispersion comprising a p38 MAP kinase inhibitor.
2. The solid dispersion according to claim 1, wherein the p38 MAP kinase inhibitor is an optionally N-oxidized compound represented by the formula (I) :
Figure imgf000093_0001
wherein
R1 is a hydrogen atom, a hydrocarbon group optionally having substituent (s) , a heterocyclic group optionally having substituent (s) , an amino group optionally having substituent (s) or an acyl group; R2 is an aromatic group optionally having substituent (s) ; R3 is a hydrogen atom, a pyridyl group optionally having substituent(s) or an aromatic hydrocarbon group optionally having substituent (s) ; X is an oxygen atom or an optionally oxidized sulfur atom;
Y is a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR4 (wherein R4 is a hydrogen atom, a hydrocarbon group optionally having substituent (s) or an acyl group) ; and Z is a bond or a divalent chain hydrocarbon group optionally having substituent (s) , or a salt thereof.
3. The solid dispersion according to claim 1, wherein the p38 MAP kinase inhibitor is N- [4- [2-ethyl-4- (3- methylphenyl) -1, 3-thiazol-5-yl] -2-pyridyl]benzamide, N- benzyl-N- [4- [2-ethyl-4- (3-methylphenyl) -1 ,3-thiazol-5- yl]-2-pyridyl]amine or N- [4- [4- (3-methylphenyl) -2- (4- methylsulfonylphenyl) -l,3-thiazol-5-yl] -2-pyridyl] -N- (2- phenylethyl) amine.
4. The solid dispersion according to claim 1, wherein the p38 MAP kinase inhibitor is mostly amorphous.
5. The solid dispersion according to claim 1, which provides sustained-release.
6. The solid dispersion according to claim 1, which prevents a steep rise in the blood concentration after administration and affords a sustained blood concentration.
7. The solid dispersion according to claim 1, which affords a blood concentration such that the maximum blood concentration after administration is not more than about 60% of that of immediate-release preparations and an area under the blood concentration-time curve is not less than about 60% of that of immediate-release preparations.
8. The solid dispersion according to claim 1, which affords a blood concentration such that a time period in which a blood concentration exceeds half the maximum blood concentration after administration is twice or more longer than that of immediate-release preparations.
9. The solid dispersion according to claim 1, which further comprises plasticizer (s) and/or drug release- controlling component (s) .
10. The solid dispersion according to claim 1, wherein the carrier is polymeric carrier (s) .
11. The solid dispersion according to claim 1, wherein the carrier has a softening temperature of about 600C to about 3500C.
12. The solid dispersion according to claim 1, wherein the carrier is a hydrophilic polymer.
13. The solid dispersion according to claim 9, wherein the plasticizer is selected from polyethylene oxide, polyethylene glycol and triethyl citrate.
14. The solid dispersion according to claim 9, wherein the drug release-controlling component is a hydrophilic compound.
15. A manufacturing method of a solid dispersion, which comprising mixing (i) a drug, (ii) carrier (s) , (iii) plasticizer (s) and (iv) drug release-controlling component (s) , without using a solvent.
16. The manufacturing method according to claim 15, wherein the mixing is performed by kneading with heat- melting.
17. The manufacturing method according to claim 15, wherein the mixing is performed by kneading in a twin screw extruder.
18. The manufacturing method according to claim 15, wherein the drug is a p38 MAP kinase inhibitor.
19. A solid dispersion obtained by the manufacturing method according to claim 15.
20. A pharmaceutical composition comprising the solid dispersion according to claim 1.
PCT/JP2005/013099 2004-07-09 2005-07-08 Solid dispersion of a p38 map kinase inhibitor Ceased WO2006006691A2 (en)

Applications Claiming Priority (2)

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JP2004203799A JP2007223903A (en) 2004-07-09 2004-07-09 Novel solid dispersion and its manufacturing method

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008142031A1 (en) 2007-05-18 2008-11-27 Institut Curie P38alpha as a therapeutic target in bladder carcinoma
EP2540317A4 (en) * 2010-02-22 2014-04-16 Daiichi Sankyo Co Ltd SOLID RELEASE PREPARATION FOR ORAL USE
EP2282636B1 (en) 2008-05-06 2016-03-23 Novartis AG Benzene sulfonamide thiazole and oxazole compounds
US9629808B2 (en) 2010-02-22 2017-04-25 Daiichi Sankyo Company, Limited Sustained-release solid preparation for oral use
US10231929B2 (en) 2014-03-18 2019-03-19 Takeda Pharmaceutical Company Limited Solid dispersion
US20220110934A1 (en) * 2019-06-26 2022-04-14 Ricoh Company, Ltd. Pharmaceutical composition

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL146105A (en) * 1999-04-23 2005-09-25 Tadeda Pharmaceutical Company 5-pyridyl-1, 3-azole compounds, process for producing the same and use therefor
KR100381834B1 (en) * 2000-05-20 2003-04-26 이상득 Solid dispersion system of pranlukast with improved dissolution, and the method thereof
EP1490025B1 (en) * 2002-03-20 2008-02-13 Elan Pharma International Limited Nanoparticulate compositions of map kinase inhibitors

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008142031A1 (en) 2007-05-18 2008-11-27 Institut Curie P38alpha as a therapeutic target in bladder carcinoma
EP2282636B1 (en) 2008-05-06 2016-03-23 Novartis AG Benzene sulfonamide thiazole and oxazole compounds
EP2540317A4 (en) * 2010-02-22 2014-04-16 Daiichi Sankyo Co Ltd SOLID RELEASE PREPARATION FOR ORAL USE
US9629808B2 (en) 2010-02-22 2017-04-25 Daiichi Sankyo Company, Limited Sustained-release solid preparation for oral use
US10231929B2 (en) 2014-03-18 2019-03-19 Takeda Pharmaceutical Company Limited Solid dispersion
US20220110934A1 (en) * 2019-06-26 2022-04-14 Ricoh Company, Ltd. Pharmaceutical composition

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