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WO1996033717A1 - Composition therapeutique destinee a traiter l'arthrite - Google Patents

Composition therapeutique destinee a traiter l'arthrite Download PDF

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Publication number
WO1996033717A1
WO1996033717A1 PCT/JP1996/001102 JP9601102W WO9633717A1 WO 1996033717 A1 WO1996033717 A1 WO 1996033717A1 JP 9601102 W JP9601102 W JP 9601102W WO 9633717 A1 WO9633717 A1 WO 9633717A1
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WO
WIPO (PCT)
Prior art keywords
pyrazol
phenyl
benzenesulfonamide
pharmaceutical composition
quinoline
Prior art date
Application number
PCT/JP1996/001102
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English (en)
Inventor
Haruhiko Makino
Takashi Sohda
Original Assignee
Takeda Chemical Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to EP96912213A priority Critical patent/EP0830133A1/fr
Priority to AU55136/96A priority patent/AU715358B2/en
Publication of WO1996033717A1 publication Critical patent/WO1996033717A1/fr
Priority to NO974956A priority patent/NO974956D0/no

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Classifications

    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines

Definitions

  • the present invention relates to a pharmaceutical composition that serves well as a therapeutic agent for arthritis, especially as an anti-rheumatic agent.
  • Rheumatoid arthritis also called chronic rheumatism
  • rheumatoid arthritis is a chronic multiple arthritis characterized by inflammatory changes in the synovial membrane of the articular capsule inner layer.
  • Arthritic diseases such as rheumatoid arthritis are progressive, and cause joint disorders such as deformation and acampsia, often resulting in severe physical disorder due to a lack of effective treatment and subsequent deterioration.
  • these forms of arthritis have been chemotherapeutically treated with various agents, including steroids such as cortisone and other adrenocortical hormones, non-steroidal anti-inflammatory agents such as aspirin, piroxicam and indomethacin, gold agents such as aurothiomalate, antirheumatic agents such as chloroquine preparations and D-penicillamine, anti-gout agents such as colchicine, and immunosuppressors such as cyclophosphamide, azathioprine, methotrexate and levamisole.
  • steroids such as cortisone and other adrenocortical hormones
  • non-steroidal anti-inflammatory agents such as aspirin, piroxicam and indomethacin
  • gold agents such as aurothiomalate
  • antirheumatic agents such as chloroquine preparations and D-penicillamine
  • anti-gout agents such as colchicine
  • immunosuppressors such as cyclopho
  • the present inventors found that excellent anti- inflammatory analgesic effect against chronic arthritis can be obtained from initial treatment, and sustained safely for an extended period of time, by administering a pharmaceutical comprising a combination of a quinoline or quinazoline compound for the prophylaxis or therapy of arthritis and a rapidly acting anti-inflammatory analgesic agent possessing acute inflammation-suppressing and analgesic activities, providing clinical effect in 30 minutes, in 2 to 3 days or at latest within 1 week, such as ⁇ a cyclooxygenase inhibitor, (2) a central analgesic, (3) a steroid, or ® an anti-inflammatory enzyme agent.
  • the inventors conducted further investigation based on this finding, and developed the present invention.
  • the present invention relates to:
  • a pharmaceutical composition comprising a combination of a quinoline or quinazoline compound for the prophylaxis or therapy of arthritis and a rapidly acting anti-inflammatory analgesic agent.
  • Y represents a nitrogen atom or C-G (G represents a carboxyl group which may be esterified or amidated, an acyl, or a hydroxyalkyl group); R represents an optionally substituted hydrocarbon residue, or an optionally substituted heterocyclic group; X represents an oxygen atom or an optionally oxidized sulfur atom; n represents 0 or 1; k represents 0 or 1; G and R may bind together to form a ring; rings A and B may each have a substituent; or a pharmaceutically acceptable salt thereof.
  • a therapeutic agent for arthritis comprising a combination of a qunoline or quinazoline compound for the prophylaxis or therapy of arthritis and a rapidly acting anti-inflammatory analgesic agent.
  • a method of treating an arthritis and/or an inflammation in mammals which comprises administering to the mammals a therapeutically effective amount of a quinoline or quinazoline compound for the prophylaxis or therapy of arthritis and a rapidly acting anti-inflammatory analgesic agent.
  • Quinoline or quinazoline compound for the prophylaxis or therapy of arthritis useful for the present invention generically refer to the class of prophylactic/therapeutic agents for arthritis comprising compounds having a quinoline or quinazoline skeleton as an active ingredient.
  • These compounds and their production methods are described in detail, for instance, in Japanese Patent Unexamined Publication (Kokai tokkyo koho) Nos. 306052/1994(EP-A- 0567107), 118266/1995(EP-A-0608870), 69890/1995(EP-A- 0634169), 53419/1996(EP-A-0686630) and W095/24394.
  • Those compounds are practically represented by the above formula (I), all possess prophylactic/therapeutic activity against arthritis and are advantageously used for the present invention
  • the optionally substituted hydrocarbon residue for R is exemplified by aliphatic hydrocarbon residues, alicyclic hydrocarbon residues, alicyclic-aliphatic hydrocarbon residues, aromatic carbon ring-aliphatic hydrocarbon residues and aromatic hydrocarbon residues.
  • Such aliphatic hydrocarbon residues include saturated aliphatic hydrocarbon residues having 1 to 8 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert- pentyl, hexyl, isohexyl, heptyl, octyl); and unsaturated aliphatic hydrocarbon residues having 2 to 8 carbon atoms (e.g., vinyl (ethenyl), 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-l-propenyl, 1-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1- hexenyl, 3-hexenyl, 2,4
  • Such alicyclic hydrocarbon residues include saturated alicyclic hydrocarbon residues having 3 to 7 carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl) ; and unsaturated alicyclic hydrocarbon residues having 5 to 7 carbon atoms (e.g., 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2- cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2- cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadienyl) .
  • saturated alicyclic hydrocarbon residues having 3 to 7 carbon atoms e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl
  • Such alicyclic-aliphatic hydrocarbon residues include those comprising a combination of C 4 - 9 one of the above- mentioned alicyclic hydrocarbon residues and one of the above-mentioned aliphatic hydrocarbon residues (e.g., cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3- cyclopentenylmethyl, cyclohexylmethyl, 2- cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl) .
  • aromatic carbon ring-aliphatic hydrocarbon residues include phenylalkyls having 7 to 9 carbon atoms (e.g., benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2- phenylpropyl, 1-phenylpropyl); and naphthylalkyls having 11 to 13 carbon atoms (e.g., ⁇ -naphthylmethyl, ⁇ -naphthylethyl, ?-naphthylmethyl and /?-naphthylethyl) .
  • aromatic hydrocarbon residues include phenyl and naphthyl (e.g., ⁇ -naphthyl, /?-naphthyl) .
  • the optionally substituted hydrocarbon residue for R is preferably a group represented by the formula: -CH -X 1 -Z 1 wherein X 1 represents an oxygen atom, an optionally oxidized sulfur atom, or -(CH 2 ) m ⁇ (m represents an integer from 0 to 5); Z 1 represents an optionally substituted hydrocarbon residue, an optionally substituted heterocyclic group, or an optionally substituted amino group.
  • the optionally oxidized sulfur atom for X 1 is exemplified by the thio group, sulfinyl group and sulfonyl group, with preference given to the thio group.
  • X 1 is preferably -(CH 2 ) m ⁇ (m represents 0, 1 or 2, preferably 0 or 1).
  • the optionally substituted hydrocarbon residue for Z 1 is exemplified by the same residues as those exemplifying the optionally substituted hydrocarbon residue for R mentioned above.
  • the heterocyclic group of the optionally substituted heterocyclic group for Z 1 is exemplified by (i) 5- to 7- membered heterocyclic groups containing 1 sulfur, nitrogen or oxygen atom; (ii) 5- or 6-membered heterocyclic groups containing 2 to 4 nitrogen atoms, and (iii) 5- or 6- membered heterocyclic groups containing 1 or 2 nitrogen atoms and 1 sulfur atom or 1 oxygen atom; these heterocyclic groups may be condensed with a 6-membered ring containing 2 or fewer nitrogen atoms, a benzene ring, or a 5-membered ring containing 1 sulfur atom.
  • heterocyclic groups examples include 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4- pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-pyrrolyl, 2- imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4- pyrazolyl, isothiazolyl, isoxazolyl, 2-thiazolyl, 4- thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, l,2,4-triazol-3-yl, l,3,4-triazol-2-yl, l,2,3-triazol-4-yl, tetrazol-5-yl, benzimidazol-2-yl, indol-3-yl,
  • the optionally substituted heterocyclic group for Zi is preferably an aromatic 5-membered heterocyclic groups containing 2 or 3 hetero atoms (e.g., oxygen atom, nitrogen atom, sulfur atom) , with greater preference given to 2- imidazolyl, l,2,4-triazol-3-yl.
  • hetero atoms e.g., oxygen atom, nitrogen atom, sulfur atom
  • the optionally substituted heterocyclic group for R is exemplified by the same groups as those exemplifying the optionally substituted heterocyclic group for Zi mentioned above.
  • the hydrocarbon residue and the heterocyclic group each represented by R or Z 1 mentioned above may have 1 to 3 substituents at any optionally substitutional positions on the ring thereof.
  • substituents include aliphatic chain hydrocarbon groups, alicyclic hydrocarbon groups, aryl groups, aromatic heterocyclic groups, non-aromatic heterocyclic groups, halogen atoms, nitro groups, optionally substituted amino groups, optionally substituted acyl groups, optionally substituted hydroxyl groups, optionally substituted thiol groups, and optionally esterified carboxyl groups.
  • Aliphatic chain hydrocarbon groups mentioned as substituents for the hydrocarbon residue and heterocyclic group each represented by R or Z 1 include linear or branched-chain aliphatic hydrocarbon groups such as alkyl groups (preferably C ⁇ - ⁇ o alkyl), alkenyl groups (preferably C2-10 alkenyl), and alkinyl groups (preferably C 2 - 10 alkinyl) .
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert- pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl and decyl.
  • alkenyl groups include vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-l-butenyl, 3- methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4- pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3- hexenyl, 4-hexenyl and 5-hexenyl.
  • alkinyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3- butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
  • Alicyclic hydrocarbon groups mentioned as substituents for the hydrocarbon residue and heterocyclic group, each represented by R or Z 1 , include saturated or unsaturated
  • C 3 -. 8 alicyclic hydrocarbon groups such as C 3 -. 8 cycloalkyl groups, C 3 - 8 cycloalkenyl groups and C - 8 cycloalkadienyl groups.
  • C 3 - 8 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo
  • C 3 _ ⁇ cycloalkenyl groups include those having 5 to 7 carbon atoms, such as 2- cyclopenten-1-yl, 3-cyclopenten-l-yl, 2-cyclohexen-l-yl and
  • C-j- ⁇ cycloalkadienyl groups include those having 5 to 7 carbon atoms, such as 2,4- cyclopentadien-1-yl, 2,4-cyclohexadien-l-yl and 2,5- cyclohexadien-1-yl.
  • Aryl groups mentioned as substituents for the hydrocarbon residue and heterocyclic group, each represented by R or Z 1 are monocyclic or condensed polycyclic aromatic hydrocarbon groups, preferably phenyl. naphthyl, anthryl, phenanthryl, acenaphthylenyl and others, with greater preference given to phenyl, 1-naphthyl, 2- naphthyl and others.
  • aromatic heterocyclic groups mentioned as substituents for the hydrocarbon residue and heterocyclic group, each represented by R or Z 1 include aromatic monocyclic heterocyclic groups (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl); and aromatic condensed heterocyclic groups (e.g., benzofurany
  • non-aromatic heterocyclic groups mentioned as substituents for the hydrocarbon residue and heterocyclic group include oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperizinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and piperazinyl.
  • halogens mentioned as substituents for the hydrocarbon residue and heterocyclic group, each represented by R or Z 1 include fluorine, chlorine, bromine and iodine, with preference given to fluorine and chlorine.
  • Examples of the optionally substituted amino groups mentioned as substituents for the hydrocarbon residue and heterocyclic group, each represented by R or Z 1 include the amino group and substituted amino groups having 1 or 2 substituents selected from C ⁇ - ⁇ o alkyl groups, C 2 - 10 alkenyl groups, C 2 - 10 alkinyl groups, aromatic groups and so on (e.g., methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino) .
  • Examples of the optionally substituted acyl groups mentioned as substituents for the hydrocarbon residue and heterocyclic group, each represented by R or Z 1 include formyl and groups resulting from binding of an C ⁇ - 10 alkyl group, an C2- 1 0 alkenyl group, C 2 -10 alkinyl group or an aromatic group, and a carbonyl group (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2- cyclohexenecarbonyl, benzoyl, nicotinoyl).
  • Examples of the optionally substituted hydroxyl groups mentioned as substituents for the hydrocarbon residue and heterocyclic group, each represented by R or Z 1 include hydroxyl group and substituted hydroxyl groups having an appropriate substituent, particularly a substituent for use as a hydroxyl group protecting group, such as alkoxy, alkenyloxy, aralkyloxy and acyloxy, as well as aryloxy.
  • Said alkoxy is preferably C ⁇ - 10 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy) .
  • alkoxy e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy
  • alkenyloxy is exemplified by C 2 - 1 0 alkenyloxy (e.g., allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2- cyclopentenylmethoxy and 2-cyclohexenylmethoxy) .
  • Said alkinyloxy is exemplified by C 2 - 1 0 alkinyloxy.
  • Said aralkyloxy is exemplified by phenyl-C ⁇ - 4 alkyloxys (e.g., benzyloxy, phenethyloxy) .
  • Said acyloxy is preferably an C 2 - 4 alkanoyloxy (e.g., acetyloxy, propionyloxy, n-butyryloxy, isobutyryloxy) .
  • Said aryloxy is exemplified by phenoxy and 4- chlorophenoxy.
  • Examples of the optionally substituted thiol groups mentioned as substituents for the hydrocarbon residue and heterocyclic group, each represented by R or Z 1 , include thiol group and substituted thiol groups having an appropriate substituent, particularly a substituent for use as a thiol group protecting group, such as alkylthio, alkenylthio, alkinylthio, aralkylthio and acylthio.
  • Said alkylthio is preferably C ⁇ - 10 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio) .
  • alkylthio e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopenty
  • Said alkenylthio is preferably C 2 - 10 alkenylthio.
  • Said alkinylthio is preferably C 2 - 10 alkinylthio.
  • Said aralkylthio is exemplified by phenyl-C ⁇ - 4 alkylthios (e.g., benzylthio, phenethylthio) .
  • Said acylthio is preferably a C 2 - 4 alkanoylthio (e.g., acetylthio, propionylthio, n-butyrylthio, isobutyrylthio) .
  • Examples of the optionally esterified carboxyl groups mentioned as substituents for the hydrocarbon residue and heterocyclic group, each represented by R or Z 1 include carboxyl group, groups resulting from binding of a carboxyl group and an C 1 - 6 alkyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl.
  • tert-butoxycarbonyl pentyloxycarbonyl and hexyloxycarbonyl
  • groups resulting from binding of a carboxyl group and an C 3 -. 6 alkenyl group e.g., allyloxycarbonyl, crotyloxycarbonyl, 2-pentenyloxycarbonyl and 3-hexenyloxycarbonyl
  • groups resulting from binding of a carbonyl group and an aralkyl group e.g., benzyloxycarbonyl and phenethyloxycarbonyl
  • the substituent on the hydrocarbon residue and heterocyclic group may optionally have further one or more, preferably 1 to 3, substituents at any substitutional positions.
  • substituents include C ⁇ _ ⁇ o lower alkyl groups, C 2 - 10 lower alkenyl groups, C 2 - 10 lower alkinyl groups, C 3 - 7 cycloalkyl groups, aryl groups, aromatic heterocyclic groups, non-aromatic heterocyclic groups, aralkyl groups (e.g., aryl-C ⁇ - 6 alkyl), amino groups, N-mono-substituted amino groups, N,N-di-substituted amino groups, amidino groups, acyl groups, carbamoyl groups, N-mono-substituted carbamoyl groups (e.g., methylcarbamoyl, ethylcarbamoyl, phenylcarbamoyl)
  • R is -CH 2 -X 1 - Z 1
  • the optionally substituted amino group for Z* is represented by -N(R 1 )(R 2 ) (R 1 and R 2 , whether identical or not, represent a hydrogen atom, an optionally substituted hydrocarbon residue, or an optionally substituted heterocyclic group; or R 1 and R 2 may bind together to form a ring) .
  • the optionally substituted hydrocarbon residue or optionally substituted heterocyclic group for R 1 or R 2 is exemplified by the same optionally substituted hydrocarbon residues or optionally substituted heterocyclic group as those mentioned to exemplify the group for R above.
  • the hydrocarbon residue and heterocyclic group may have 1 to 3 substituents at any substitutional positions on the chain or the ring thereof.
  • substituents are exemplified by the same substituents as those for the hydrocarbon residue and heterocyclic group for R.
  • substituents on the hydrocarbon residue and heterocyclic group for R 1 or R 2 may have 1 or more, preferably 1 to 3, substituents at any substitutional positions. Examples of such substituents include C ⁇ - 10 lower alkyl groups, C 2 - 10 lower alkenyl groups, C 2 - 10 lower alkinyl groups, C 3 ..
  • R 1 and R 2 may bind together to form a ring; such -NfR 1 ) ⁇ 2 ) rings include 1-pyrrolidinyl, 1-imidazolidinyl, 1-pyrazolidinyl, 1-piperidinyl, 1-piperazinyl, 4- morpholinyl, 4-thiomorpholinyl, homopiperazin-1-yl, 1,2,4- triazol-1-yl, 1,3,4-triazol-l-yl, pyrazol-1-yl, imidazol-1- yl, 1,2,3-triazol-l-yl, l,2,3-triazol-2-yl, tetrazol-1-yl, benzimidazol-1-yl, indol-1-yl and lH-indazol-1-yl.
  • the optionally oxidized sulfur atom, represented by X, is exemplified by thio group, sulfinyl group and sulfonyl group, with preference given to the thio group.
  • rings A and B may each have a substituent.
  • substituents include halogen atoms, nitro groups, optionally substituted C ⁇ _ ⁇ o alkyl, C 2 - 10 alkenyl, C 2 - 10 alkinyl groups, optionally substituted hydroxyl groups, optionally substituted thiol groups, optionally substituted amino groups, optionally substituted acyl groups (e.g., C ⁇ _ ⁇ o alkanoyl, C2-10 alkenoyl, C 2 - 1 0 alkinoyl groups etc.), optionally esterified carboxyl groups, and optionally substituted aromatic ring groups.
  • halogens mentioned as substituents for rings A and B include fluorine, chlorine, bromine and iodine, with preference given to fluorine and chlorine.
  • optionally substituted C ⁇ - 10 alkyl groups mentioned as substituents for rings A and B may be linear C ⁇ - 10 alkyl, branched C 3 - 10 alkyl or C 3 - 1 0 cyclic alkyl, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • substituents for rings A and B examples include the hydroxyl group and substituted hydroxyl groups having an appropriate substituent, particularly a substituent for use as a hydroxyl group-protecting group, such as alkoxy, alkenyloxy, aralkyloxy and acyloxy, as well as aryloxy.
  • Said alkoxy is preferably a C ⁇ - ⁇ o alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy) .
  • a C ⁇ - ⁇ o alkoxy e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy
  • Said alkenyloxy is exemplified by C 2 - 10 alkenyloxys (e.g., allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2- cyclopentenyl ethoxy and 2-cyclohexenylmethoxy) .
  • Said alkinyloxy is preferably a C 2 - 10 alkinyloxy.
  • Said aralkyloxy is exemplified by phenyl-C ⁇ _ 4 alkoxy (e.g., benzyloxy, phenethyloxy) .
  • Said acyloxy is preferably a C 2 - 4 alkanoyloxy (e.g., acetyloxy, propionyloxy, n-butyryloxy, isobutyryloxy) .
  • Said aryloxy is exemplified by phenoxy, 4- chlorophenoxy and so on.
  • Examples of the optionally substituted thiol groups mentioned as substituents for rings A and B include thiol group and substituted thiol groups having an appropriate substituent, particularly a substituent for use as a thiol group-protecting group, such as alkylthio, alkenylthio, alkinylthio, aralkylthio, acylthio and arylthio.
  • Said alkylthio is preferably a C ⁇ - 10 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio) .
  • alkylthio e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopen
  • Said alkenylthio is preferably a C 2 - 10 alkenylthio.
  • Said alkinylthio is preferably a C 2 - 10 alkinylthio.
  • Said aralkylthio is exemplified by phenyl-C_,_ 4 alkylthios (e.g., benzylthio, phenethylthio) .
  • Said acylthio is preferably a C 2 - 4 alkanoylthio (e.g., acetylthio, propionylthio, n-butyrylthio, isobutyrylthio) .
  • Said arylthio is exemplified by phenylthio, 4- chlorophenyl, and so on.
  • Examples of the optionally substituted amino groups mentioned as substituents for rings A and B include amino group and substituted amino groups having 1 or 2 substituted selected from C ⁇ - 10 alkyl groups, C 2 - 10 alkenyl groups, C 2 - 10 alkinyl groups and aromatic groups and so on (e.g., methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino) .
  • 1 or 2 substituted selected from C ⁇ - 10 alkyl groups, C 2 - 10 alkenyl groups, C 2 - 10 alkinyl groups and aromatic groups and so on e.g., methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamin
  • Examples of the optionally substituted acyl groups mentioned as substituents for rings A and B, include formyl and the groups resulting from binding of a C ⁇ _ ⁇ o alkyl group, C 2 - 10 alkenyl group, C 2 - 10 alkinyl group or aromatic group and a carbonyl group (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl).
  • a carbonyl group e.g., acetyl, propionyl, butyryl, isobutyryl, va
  • Examples of the optionally esterified carboxyl groups mentioned as substituents for rings A and B include carboxyl group, groups resulting from binding of a carboxyl group and a Ci- ⁇ alkyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl) , groups resulting from binding of a carboxyl group and a C 3 - 6 alkenyl group (e.g., allyloxycarbonyl, crotyloxycarbonyl, 2-pentenyloxycarbonyl and 3-hexenyloxycarbonyl) , and groups resulting from binding of a carbonyl group and an aralkyloxy group, (e.g., benzyloxycarbonyl, phenethyl
  • Examples of the optionally substituted aromatic ring groups mentioned as substituents for rings A and B include C ⁇ - 1 aromatic hydrocarbon residues (e.g., phenyl, naphthyl, anthryl etc.), and heterocyclic aromatic residues (e.g., pyridyl, furyl, thienyl, imidazolyl and thiazolyl).
  • C ⁇ - 1 aromatic hydrocarbon residues e.g., phenyl, naphthyl, anthryl etc.
  • heterocyclic aromatic residues e.g., pyridyl, furyl, thienyl, imidazolyl and thiazolyl.
  • substituents for rings A and B may each be present at any substitutional position of the ring thereof; 1 to 4 identical or different substituents may be present.
  • substituents on ring A or B are mutually adjoining, they may bind together to form a ring represented by -(CH 2 ) t ⁇ or -0-(CH 2 ) ⁇ 0- (t is an integer from 3 to 5; 1 is an integer from 1 to 3); such rings include 5- to 7-membered rings formed in cooperation with carbon atoms of the benzene ring.
  • ring A is substituted for by at least 1 alkoxy group, preferably C ⁇ _ 3 alkoxy group, more preferably by at least 1 methoxy group. Still more preferably, ring A is substituted for by 2 identical or different alkoxy groups, preferably C 1 - 3 alkoxy group, more preferably by methoxy groups. Most preferably, ring A is substituted for by 2 methoxy groups respectively at the 6- and 7-positions of the quinoline ring or quinazoline ring.
  • ring B is substituted for by at least 1 alkoxy group, preferably C 1 -. 3 alkoxy group, more preferably at least 1 methoxy or isopropoxy group.
  • ring B is substituted for by 2 identical or different alkoxy groups, preferably C 1 -. 3 alkoxy group. Most preferably, ring B is substituted for by a methoxy or isopropoxy group at the 3-position and by a methoxy group at the 4-position.
  • the optionally esterified carboxyl group for G is exemplified by carboxyl group, alkoxycarbonyl groups and aralkyloxycarbonyl group.
  • the alkyl group in said alkoxycarbonyl groups is exemplified by Ci- ⁇ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl).
  • the aralkyl group in said aralkyloxycarbonyl groups is an alkyl group having an aryl group as a substituent (aryl- alkyl group) .
  • Said aryl group is exemplified by phenyl and naphthyl, each of which may have the same substituents as those for ring A above.
  • Said alkyl group is preferably a lower C ⁇ - 6 alkyl group.
  • Preferable aralkyl groups include benzyl, phenethyl, 3-phenylpropyl, (l-naphthyl)methyl and (2-naphthyl)methyl, with preference given to benzyl, phenetyl and others.
  • G is an amidated carboxyl group, it is represented by -CONfR 1 ) ⁇ 2 ) (R 1 and R 2 have the same definitions as those given above).
  • the acyl group for G in the above formula (I) is represented, for example, by the formula: -CO-R3 in which R3 is an alkyl group or an aryl group.
  • R3 is an alkyl group or an aryl group.
  • the alkyl group for R3 include C 1 - 5 alkyl groups (e.g., methyl, ethyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, etc.).
  • Preferred examples of the alkyl group for R3 include methyl, butyl, isobutyl, pentyl, etc..
  • Examples of the aryl gorup for R 3 includes a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms.
  • Preferred examples of the aryl group for R3 include phenyl, naphthyl, anthryl, phenanthryl, etc.. In particular, phenyl, 1-naphthyl, 2-naphthyl, etc., are more preferred.
  • G is hydroxyalkyl
  • the alkyl group of the hydroxyalkyl group for G includes the above alkyl groups represented by Ri or R2.
  • the hydroxyalkyl group is represented by the formula: -CH 2 OH or -CH(OH)-R3 in which R3 is an defined above.
  • R3 in this formula is preferably methyl, ethyl, etc..
  • the protected hydroxy moiety may be the above substituted hydroxyl group as the substituent of the hydrocarbon group or heterocyclic group represented by R* or R2.
  • the protected hydroxyalkyl group is represented by the formula: -C ⁇ OCOR-i or -CH(OCOR-»)-R3 in which R3 is as defined above and R4 is an alkyl group, aralkyl group or aryl group each of which may optionally be substituted.
  • the alkyl group for R4 includes, for example, C ⁇ - 6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc..
  • the aralkyl group for R4 means, for example, a C ⁇ - 14 aryl-C ⁇ _ 4 alkyl group.
  • Specific examples of the alkyl group in the aralkyl group include the above alkyl groups represented by R4.
  • specific examples of the aryl group in the aralkyl group include phenyl, naphthyl, etc.
  • aralkyl group examples include benzyl, phenethyl, 3-phenylpropyl, (1- naphthy1)methyl, (2-naphthyl)methyl, etc.
  • the aryl group for R4 includes, for example, aryl group having 6 to 14 carbon atoms such as phenyl, naphthyl, etc..
  • R 3 represents a hydrogen atom, an optionally substituted hydrocarbon residue or an optionally substituted heterocyclic group; the other symbols have the same definitions as those given above.
  • Y is preferably C-G, with greater preference given to a C ⁇ - 6 alkoxycarbonyl group for G, and greatest preference given to an ethoxycarbonyl group for G.
  • n in the above formula (I) is preferably 0.
  • k in the above formula (I) is preferably 0.
  • Y is C-G (G is ethoxycarbonyl)
  • R is -CH 2 -Z 1
  • Z 1 is 1,2,4-triazol-l-yl
  • the substituents for ring A are methoxy groups each present at the 6- and 7-position of the quinoline ring
  • each substituent for ring B is methoxy or isopropoxy group present at the 3-position and methoxy groups present at the 4-position thereof
  • n is 0, and k is 0.
  • the above compound (I) can be produced according to the production methods described in detail, for instance, in Japanese Patent Unexamined Publication (Kokai tokkyo koho) Nos. 306052/1994(EP-A-0567107), 118266/1995(EP-A- 0608870), 69890/1995(EP-A-0634169), 53419/1996(EP-A- 0686630) and W095/24394.
  • the salt of compound (I) for the present invention is preferably a pharmaceutically acceptable salt, exemplified by salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids and salts with basic or acidic amino acids.
  • Preferable salts with inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt.
  • Preferable salts with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N,N'-dibenzylethylenediamine.
  • Preferable salts with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.
  • Preferable salts with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
  • Preferable salts with basic amino acid include salts with arginine, lysine and ornithine.
  • Preferable salts with acidic amino acid include salts with aspartic acid and glutamic acid. Amont these salts, sodium or patassium salts are most preferable.
  • the compound (I) or a salt thereof of the present invention may be a hydrate.
  • the pharmaceutical agent combined with a little slowly acting quinoline or quinazoline compound for the prophylaxis or therapeuticy of arthritis is what is called a rapidly acting anti- inflammatory analgesic agent which clinically suppresses inflammation and accompanying pain in 30 minutes or in 2 to 3 days, at latest within 1 week, after administration.
  • rapidly acting anti-inflammatory analgesics can be classified in various manners according to chemical structure, action etc., but those advantageous for use in the present invention include ® cyclooxygenase inhibitors, (D central analgesics, D steroids, and (D anti- inflammatory enzyme agents.
  • Cyclooxygenase inhibitors are compounds that suppress cyclooxygenase 1 and/or cyclooxygenase 2; preferable examples include the following compounds and salts thereof.
  • Salicylic acid derivatives possessing anti- inflammatory analgesic activity such as aspirin; pyrazolone derivatives possessing anti-inflammatory analgesic activity, such as antipyrine; phenylbutazone, oxybutazone, sulfinpyrazone, acemetacin, alclofenac, alminoprofen, anfenac, ampiroxicam, butybufen, calprofen, dichlofenac, diflunisal, droxicam, etodolac, fenbufen, fenoprofen, flufenamic acid, flurbiprofen, ibuprofen, indomethacin, indomethacin farnesil ester, ketoprofen, ketorolac, loxoprofen, mefenamic acid, meclofenamate, meloxicam, nabumetone, naproxen, oxaprozin, pirazolac, piroxi
  • W095/15315 W095/ 15316, W095/15317 and W095/15318 and salts thereof. More specifically, preferable compounds include the compounds described in claim 16 for W095/15315 above [e.g., l-[(4- alkylsulfonyl)phenyl]-3-substitutional-5-substitutional-lH- pyrazole derivatives], i.e.,
  • R5 is aryl which is substituted with substituent(s) selected from the group consisting of C ⁇ - 6 alkylthio, cyclo C ⁇ _6 alkyl, hydroxy, hydroxy C ⁇ - 6 alkyl, cyano, Ci- ⁇ alkylenedioxy, acyl, acyloxy, aryloxy and Ci- ⁇ alkoxy optionally substituted with acyl or C ⁇ - 6 alkoxy;
  • R6 is halogen, halo C ⁇ - 6 alkyl, cyano or acyl, and
  • R7 is aryl substituted with nitro, hydroxy, C ⁇ -_. alkoxy, Ci 6 alkylthio, C ⁇ -e alkylsulfinyl or Ci- ⁇ alkylsulfonyl; provided that when R? is aryl substituted with nitro, hydroxy or lower alkoxy, then R5 is aryl substituted with C ⁇ - 6 alkylthio, C ⁇ - 6 alkylsulfinyl or C ⁇ _6 alkylsulfonyl.
  • 5 is phenyl which is substituted with substituent(s) selected from the group consisting of hydroxy, hydroxy C ⁇ _g alkyl, cyano, C_.- 6 alkylenedioxy, acyl, acyloxy, aryloxy and C ⁇ _ 6 alkoxy optionally substituted with acyl or C ⁇ - 6 alkoxy, and preferably phenyl substituted with cyano, C ⁇ - 6 alkanoyl or C ⁇ _ 6 alkoxy, and more preferably phenyl substituted with cyano or methoxy.
  • substituent(s) selected from the group consisting of hydroxy, hydroxy C ⁇ _g alkyl, cyano, C_.- 6 alkylenedioxy, acyl, acyloxy, aryloxy and C ⁇ _ 6 alkoxy optionally substituted with acyl or C ⁇ - 6 alkoxy, and preferably phenyl substituted with cyano, C ⁇ - 6 alkanoyl or C ⁇ _ 6 alkoxy,
  • R 7 is phenyl substituted with C ⁇ - 6 alkylthio, C ⁇ - 6 alkylsulfinyl or C ⁇ - 6 alkylsulfonyl, preferably phenyl substituted with methylthio, methylsulfinyl or methylsulfonyl.
  • R6 is halogen or halo Ci- ⁇ alkyl, preferably bromine, difluoromethyl or trifluoromethyl.
  • Preferable examples of compounds represented by the formula (IV) is 3-(difluoromethyl)-l-(4-methoxyphenyl)-5- [4-(methylsulfonyl)phenyl]pyrazole, or 3-(difluoromethyl)- 1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]pyrazole.
  • Central analgesics generically refer to narcotic or non-narcotic analgesics; preferable examples include the following compounds and salts thereof.
  • Steroids refer to all corticosteroids possessing anti- inflammatory activity; preferable examples include the following compounds and salts thereof.
  • Betamethasone, dexamethasone, fludrocortisone, hydrocortisone, methylprednisolone, prednisolone, triamcinolone and paramethasone are examples of dexamethasone, fludrocortisone, hydrocortisone, methylprednisolone, prednisolone, triamcinolone and paramethasone.
  • Anti-inflammatory enzyme agents generically refer to proteins possessing acute inflammation-suppressing activity and/or analgesic activity; preferable examples include the following.
  • Bromelins Bromelins, lysozyme, promelase, pronase, serrapeptase, streptokinase, chymotrypsin and amylase.
  • anti-inflammatory analgesics may be in the form of pharmaceutically acceptable salts, as with compound (I).
  • the pharmaceutical composition of the present invention comprising a combination of a quinoline or quinazoline compound for the prophylaxis or therapy of arthritis and a rapidly acting anti-inflammatory analgesic, can be administered orally or non-orally in the form of granules, powders, tablets, capsules, syrups, suppositories, injectable preparations, emulsions, elixirs, suspensions, solutions etc., as prepared separately or simultaneously by mixing with physiologically acceptable carriers, excipients, binders, diluents etc.
  • the resulting separate preparations can be administered in the form of a mixture with diluents etc. prepared freshly at the time of use; however, separate preparations may be administered to the same subject separately, simultaneously or at intervals.
  • the pharmaceutical composition of the present invention can be prepared as various dosage forms in accordance with ordinary methods.
  • non-oral encompasses subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection and drip infusion.
  • Preparations for injection e.g., aqueous or oily suspensions for aseptic injection, can be prepared by methods known to those skilled in the art, using an appropriate dispersing agent or a wetting agent and a suspending agent.
  • the preparation for aseptic injection may be a solution or suspension permitting aseptic injection in a diluent or solution that is non-toxic and administrable non-orally, such as an aqueous solution.
  • Useful vehicles or solvents include water. Ringer's solution and isotonic saline.
  • Aseptic nonvolatile oils can also be used as solvents or suspending media.
  • any nonvolatile oils or fatty acids can be used, including natural, synthetic or semi-synthetic fatty oils and fatty acids, and natural, synthetic or semi- synthetic mono-, di- or tri-glycerides.
  • Suppositories for rectal administration can be produced by mixing the drug and an appropriate non- irritative excipient that is solid at normal temperature but liquid at gut temperature and melts to release the drug in the rectum, such as cocoa butter or polyethylene glycol.
  • Solid dosage forms for oral administration include powders, granules, tablets, pills and capsules, as mentioned above.
  • the active ingredient compound can be mixed with at least 1 additive selected from the group consisting of sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectins, gum tragacanth, gum arabic, gelatins, collagens, casein, albumin, and synthetic or semi-synthesis polymers and glycerides.
  • these dosage forms can contain additional additives, including inert diluents, lubricants such as magnesium stearate, preservatives such as parabens and sorbic acid, antioxidants such as ascorbic acid, a- tocopherol and cysteine, disintegrating agents, binders, thickening agents, buffers, sweetening agents, flavoring agents and perfumes. Tablets and pills can also be produced with enteric coating.
  • Liquid preparations for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions and solutions, and may contain inert diluents in common use in the relevant art, such as water.
  • a daily dose of each pharmaceutical agent can be chosen appropriately, according to patient age, body weight, symptoms, administration time, dosage form, administration method, combination of each pharmaceutical agent etc., it can be chosen over the range of 5-1000 mg preferably 10-200 mg, per adult person, the likely clinical dose range for oral administration, and over the range of 0.1-100 mg, preferably 1-100 mg per adult person for non- oral adminstration in the case of quinoline or quinazoline compound for prophylaxis or therapy of arthritis; and can be increased or decreased as appropriate on the basis of the likely clinical dose range for oral administration in the case of rapidly acting anti-inflammatory analgesics such as ⁇ cyclooxygenase inhibitors, ⁇ central analgesics, ⁇ steroids, and (D anti-inflammatory enzyme agents.
  • analgesics such as ⁇ cyclooxygenase inhibitors, ⁇ central analgesics, ⁇ steroids, and (D anti-inflammatory enzyme agents.
  • the dose can be chosen as appropriate according to the situation on the basis of the likely clinical dose range when individual drugs are used singly.
  • the dose for oral administration can be chosen over the range of 1- 5000 mg, preferably 25-4500 mg per adult person, for example, 1000-4500 mg for aspirin, 50-150 mg for indomethachin, 25-75 mg for diclofenac, 60-180 mg for loxoprofen, and the dose for non-oral administration can be chosen over the range of 0.2-200 mg, preferably 1-100 mg per adult person.
  • the dose for oral administration can be chosen over the range of 1-1000 mg, preferably 5-300 mg per adult person, for example, 10-60 mg for morphine, and the dose for non-oral administration can be chosen over the range of 0.1-300 mg, preferably 0.5-100 mg per adult person for example, 5-60 mg, for morphine.
  • the dose for oral administration can be chosen over the range of 0.1-400 mg, preferably 0.5-100 mg per adult person, for example, 5-100 mg, for prednisolone, and 0.5-10 mg for dexamethasone
  • the dose for non-oral administration can be chosen over the range of 0.1-100 mg, preferably 0.5-25 mg per adult person for example, 5-25 mg for prednisolone, 0.5-2.5 mg for dexamethasone.
  • the dose for oral administration can be chosen over the range of 5-40 mg, per adult person.
  • Appropriate administration frequency is 1 to 3 times daily.
  • a pharmaceutical composition of the present invention comprising a combination of the agents mentioned above has low toxity.
  • the combined pharmaceutical provided by the present invention exhibits excellent rapidly acting and sustained anti-inflammatory analgesic action against arthritis, especially rheumatoid arthritis, with very low prevalence of side effects even in chronic administration, provided that drug combination, administration method, dose etc. are appropriately chosen according to symptoms.

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Abstract

La présente invention se rapporte à un produit pharmaceutique, à action rapide et à effet analgésique anti-inflammatoire prolongé, utilisé dans le traitement de l'arthrite chronique, et dont les effets secondaires sont de faible prévalence. Le produit pharmaceutique de l'invention est une combinaison d'un agent thérapeutique, d'un agent prophylactique de la famille de la quinazoline et de la quinoline, utilisé dans le traitement de l'arthrite, et d'analgésiques à action anti-inflammatoire rapide comprenant (1) un inhibiteur de la cyclooxygénase, (2) un analgésique central, (3) un stéroïde ou (4) un agent enzymatique anti-inflammatoire. Ce produit pharmaceutique a un excellent effet dans le traitement de l'arthrite dès la première période d'administration, favorisant une action analgésique anti-inflammatoire stable, et dont les effets secondaires sont de faible prévalence, même dans le cas d'une administration prolongée, à condition que le choix de la combinaison du médicament, du procédé d'administration et du dosage soit fait correctement en fonction des symptômes.
PCT/JP1996/001102 1995-04-28 1996-04-24 Composition therapeutique destinee a traiter l'arthrite WO1996033717A1 (fr)

Priority Applications (3)

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EP96912213A EP0830133A1 (fr) 1995-04-28 1996-04-24 Composition therapeutique destinee a traiter l'arthrite
AU55136/96A AU715358B2 (en) 1995-04-28 1996-04-24 Therapeutic composition for arthritis
NO974956A NO974956D0 (no) 1995-04-28 1997-10-27 Terapeutisk sammensetning for artritis

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JP10631695 1995-04-28
JP7/106316 1995-04-28
JP27085695 1995-10-19
JP7/270856 1995-10-19

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
WO1998034115A1 (fr) * 1997-02-04 1998-08-06 Trega Biosciences, Inc. Derives de la quinoline substituee en 4- et bibliotheques combinatoires les contenant
US6262269B1 (en) 1997-02-04 2001-07-17 Trega Biosciences, Inc. 4-Substituted-quinoline derivatives and 4-substituted-quinoline combinatorial libraries
WO2002012192A1 (fr) * 2000-08-09 2002-02-14 F. Hoffmann-La Roche Ag Derives quinoline utiles en tant qu'agents anti-inflammatoires
WO2002051442A1 (fr) * 2000-12-26 2002-07-04 Takeda Chemical Industries, Ltd. Co-prescriptions

Citations (6)

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EP0339485A1 (fr) * 1988-04-26 1989-11-02 The Du Pont Merck Pharmaceutical Company Dérivés de l'acide quinoléine-carboxylique-4 utiles comme agents immuno-suppresseurs
EP0468789A2 (fr) * 1990-07-26 1992-01-29 Merck Frosst Canada Inc. (Quinoléin-2-ylméthoxy)hétérotétrahydrocarbazoles comme inhibiteurs de la biosynthèse de leucotriènes
EP0500360A1 (fr) * 1991-02-21 1992-08-26 Merck Frosst Canada Inc. Des céto-acides contenant une quinoléine comme antagonistes des leukotriènes
EP0567107A1 (fr) * 1992-04-24 1993-10-27 Takeda Chemical Industries, Ltd. Dérivés de quinoléine et de quinazoline pour le traitement d'arthritis
EP0608870A1 (fr) * 1993-01-28 1994-08-03 Takeda Chemical Industries, Ltd. Dérivés de quinoline ou quinazoline, leur préparation et application
EP0686630A1 (fr) * 1994-06-07 1995-12-13 Takeda Chemical Industries, Ltd. Dérivés de quinoléine et compositions pharmaceutiques les contenant

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EP0339435B1 (fr) * 1988-04-26 1993-08-18 Asahi Glass Company Ltd. Composition d'un prépolymère, son procédé de préparation et son utilisation

Patent Citations (6)

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Publication number Priority date Publication date Assignee Title
EP0339485A1 (fr) * 1988-04-26 1989-11-02 The Du Pont Merck Pharmaceutical Company Dérivés de l'acide quinoléine-carboxylique-4 utiles comme agents immuno-suppresseurs
EP0468789A2 (fr) * 1990-07-26 1992-01-29 Merck Frosst Canada Inc. (Quinoléin-2-ylméthoxy)hétérotétrahydrocarbazoles comme inhibiteurs de la biosynthèse de leucotriènes
EP0500360A1 (fr) * 1991-02-21 1992-08-26 Merck Frosst Canada Inc. Des céto-acides contenant une quinoléine comme antagonistes des leukotriènes
EP0567107A1 (fr) * 1992-04-24 1993-10-27 Takeda Chemical Industries, Ltd. Dérivés de quinoléine et de quinazoline pour le traitement d'arthritis
EP0608870A1 (fr) * 1993-01-28 1994-08-03 Takeda Chemical Industries, Ltd. Dérivés de quinoline ou quinazoline, leur préparation et application
EP0686630A1 (fr) * 1994-06-07 1995-12-13 Takeda Chemical Industries, Ltd. Dérivés de quinoléine et compositions pharmaceutiques les contenant

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998034115A1 (fr) * 1997-02-04 1998-08-06 Trega Biosciences, Inc. Derives de la quinoline substituee en 4- et bibliotheques combinatoires les contenant
US6262269B1 (en) 1997-02-04 2001-07-17 Trega Biosciences, Inc. 4-Substituted-quinoline derivatives and 4-substituted-quinoline combinatorial libraries
WO2002012192A1 (fr) * 2000-08-09 2002-02-14 F. Hoffmann-La Roche Ag Derives quinoline utiles en tant qu'agents anti-inflammatoires
US7049325B2 (en) 2000-08-09 2006-05-23 Syntex (U.S.A.) Llc Quinoline derivatives as anti-inflammatory agents
US7186840B2 (en) 2000-08-09 2007-03-06 Roche Palo Alto Llc Quinoline derivatives as anti-inflammatory agents
WO2002051442A1 (fr) * 2000-12-26 2002-07-04 Takeda Chemical Industries, Ltd. Co-prescriptions

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KR19990008148A (ko) 1999-01-25
CA2216138A1 (fr) 1996-10-31
NO974956D0 (no) 1997-10-27
AU715358B2 (en) 2000-01-20
HUP9801628A2 (hu) 1999-01-28
EP0830133A1 (fr) 1998-03-25
AU5513696A (en) 1996-11-18

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