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 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
• 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-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) .
• 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.
• 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.
• 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).
• 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.
• 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) .
• 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.
• 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..
• 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.,
• 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.
• 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.
• 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.
• 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.

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• 1996
  • 1996-04-24 WO PCT/JP1996/001102 patent/WO1996033717A1/en not_active Application Discontinuation
  • 1996-04-24 EP EP96912213A patent/EP0830133A1/de not_active Withdrawn
  • 1996-04-24 CA CA002216138A patent/CA2216138A1/en not_active Abandoned
  • 1996-04-24 KR KR1019970707673A patent/KR19990008148A/ko not_active Application Discontinuation
  • 1996-04-24 AU AU55136/96A patent/AU715358B2/en not_active Ceased
  • 1996-04-24 HU HU9801628A patent/HUP9801628A2/hu unknown
• 1997
  • 1997-10-27 NO NO974956A patent/NO974956D0/no unknown

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