WO1997009984A1 - Agent immunosuppresseur - Google Patents

Agent immunosuppresseur Download PDF

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Publication number
WO1997009984A1
WO1997009984A1 PCT/JP1996/001693 JP9601693W WO9709984A1 WO 1997009984 A1 WO1997009984 A1 WO 1997009984A1 JP 9601693 W JP9601693 W JP 9601693W WO 9709984 A1 WO9709984 A1 WO 9709984A1
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WO
WIPO (PCT)
Prior art keywords
quinoline
ethyl
immunosuppressant
group
dimethoxyphenyl
Prior art date
Application number
PCT/JP1996/001693
Other languages
English (en)
Inventor
Haruhiko Makino
Takashi Sohda
Yoshikazu Ohta
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 HU9900169A priority Critical patent/HUP9900169A2/hu
Priority to AU61373/96A priority patent/AU6137396A/en
Priority to NZ310561A priority patent/NZ310561A/xx
Priority to BR9610314A priority patent/BR9610314A/pt
Priority to EP96918849A priority patent/EP0850061A1/fr
Publication of WO1997009984A1 publication Critical patent/WO1997009984A1/fr
Priority to NO980788A priority patent/NO980788L/no

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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • 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
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

Definitions

  • the present invention relates to a pharmaceutical composition, more specifically to an immunosuppressant useful in the prevention or treatment of diseases assumed to be associated with immunity, including autoimmune diseases, or in the prevention of graft rejection following organ transplantation.
  • autoimmune diseases In diseases assumed to be associated with immune reac ⁇ tion, including autoimmune diseases, accentuation of immune reaction or accentuation of body defence reaction based on immune reaction may be involved in their pathology, whose site is affected varies among diseases. Traditionally, these diseases have been treated using steroids or certain immunosuppressants (e.g., azathioprine, cyclophosphamide, methotrexate, mizoribine, cyclosporine A, Tacrolimus (FK506; THE MERCK INDEX 12th Edition, pl546. No. 9200 (1996)).
  • immunosuppressants e.g., azathioprine, cyclophosphamide, methotrexate, mizoribine, cyclosporine A, Tacrolimus (FK506; THE MERCK INDEX 12th Edition, pl546. No. 9200 (1996)).
  • the diseases associated with immune reaction including autoimmune diseases are chronic and their cases are complicated. Therefore, the most suitable agent for the each condition of a patient should be chosen. But, it is usually difficult to chose a proper agent in a chlinical use because of several problems such as side effects due to the increase of dose and the long-term administration, since the treatment of the diseases associated with immune reaction takes long time. And all these agents, which have been used for the treatment of those diseases and for the prevention of graft rejection following organ transplantation, have severe side effects as mentioned above. Therefore there is strong demand for the development of a drug of very low prevalence of side effects.
  • the present inventors inves ⁇ tigated in search of a new agent possessing immunosup- pressing activity, and discovered a safe quinoline- or quinazoline-series compound with low toxicity.
  • the present inventors found that a quinoline or quinazoline compound or a pharmaceutically acceptable salt thereof possesses immune cytokine production-suppressing activity, and that it is effective in the prevention or treatment of diseases assumed to be associated with immunity, or in the prevention of graft rejection following organ transplantation.
  • the present inventors also found unexpectedly that a combination comprising the quinoline or qunazoline compound and the traditionally used immunosappressant has a remarkable immunosuppressing activity.
  • the inventors made further investigation based on these finding, and developed the present invention. Accordingly, the present invention relates to: (1) an immunosuppressant containing as an active ingredient a compound represented by the formula (I):
  • Y is a nitrogen atom or C-G (G is an optionally esterified or amidated carboxyl group, an acyl group, an optionally protected hydroxyalkyl group, or a halogen atom) ;
  • R is an optionally substituted hydrocarbon residue or an optionally substituted heterocyclic group;
  • X is an oxygen atom or an optionally oxidized sulfur atom;
  • n is 0 or 1;
  • k is 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,
  • the immunosuppressant of the above item (1) wherein k is 0,
  • the immunosuppressant of the above item (1) wherein the compound represented by the formula (I) is methyl 4-(3,4-dimethoxyphenyl)-2-ethyl-6,7-dimethoxy- quinoline-3-carboxylate; ethyl 6-chloro-2-methyl-4-(3,4- dimethoxyphenyl)quinoline-3-carboxylate;
  • autoimmune diseases is systemic lupus erythematosus, chronic hepatitis, interstitial liver diseases, asthma, psoriasis, ulcerative colitis, Crohn disease, regional ileitis or multiple sclerosis
  • (21) a method of preventing graft rejection following organ transplation in mammals which comprises administering to the mannals a therapeutically effective amount of a compound represented by the formula (I) of the above item (1) or a pharmaceutically acceptable salt thereof,
  • Y is a nitrogen atom or C-G (G is an optionally esterified or amidated carboxyl group, an acyl group, an optionally protected hydroxyalkyl group, or a halogen atom) ;
  • R is an optionally substituted hydrocarbon residue or an optionally substituted heterocyclic group;
  • X is an oxygen atom or an optionally oxidized sulfur atom;
  • n is 0 or 1;
  • k is 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; and an immunosuppressant except for a quinoline or quinazoline compound mentioned above,
  • autoimmune diseases is systemic lupus erythematosus, chronic hepatitis, interstitial liver diseases, asthma, psoriasis, ulcerative colitis, Crohn disease, regional ileitis or multiple sclerosis,
  • generi ⁇ cally refers to the class of immunosuppressants possessing a quinoline or quinazoline skeleton. Their active ingredi ⁇ ents, along with production methods, are described in de- tail in Japanese Patent Unexamined Publication Nos.
  • the optionally substituted hydrocarbon residue represented by 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 Ci- ⁇ saturated aliphatic hydrocarbon residues (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl) and C 2 - 8 unsaturated aliphatic hydrocarbon residues (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-hexadienyl,
  • Such alicyclic hydrocarbon residues include C 3 - 7 saturated alicyclic hydrocarbon residues (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) and C 5 - 7 unsaturated alicyclic hydrocarbon residues (e.g., 1-cyclopentenyl, 2-cyclopentenyl, 3- cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3- cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3- cycloheptenyl and 2,4-cycloheptadienyl) .
  • saturated alicyclic hydrocarbon residues e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl
  • C 5 - 7 unsaturated alicyclic hydrocarbon residues
  • Such alicyclic-aliphatic hydrocarbon residues include those C 4 - 9 ones comprising a combination of one of the above-mentioned alicyclic hydrocarbon residues and one of the above-mentioned aliphatic hydrocarbon residues, (e.g., cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentyl ethyl, 2-cyclopentenylmethyl, 3- cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenyl- methyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexyl- propyl, cycloheptylmethyl, cycloheptylethyl) .
  • Such aromatic carbon ring-aliphatic hydrocarbon re ⁇ sidues include C 7 - 9 phenylalkyls (e.g., benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1- phenylpropyl) and Cn- 13 naphthylalkyls (e.g., a- naphthylethyl, /?-naphthylmethyl, ?-naphthylethyl) .
  • Such aromatic hydrocarbon residues include phenyl, naphthyl (e.g., ⁇ -naphthyl, 9-naphthyl) .
  • the optionally substituted heterocyclic group represented by R is exemplified by (i) 5- to 7-membered heterocyclic groups containing 1 sulfur atom, 1 nitrogen atom or 1 oxygen atom; (ii) 5- or 6- membered heterocyclic groups containing 2 to 4 nitrogen atoms; (iii) 5- or 6-membered heterocyclic groups containing 1 or 2 nitrogen atoms and 1 sulfur atom or 1 oxygen atom; (iv) 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-pyrid- yl, 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-imid- azolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, isothiaz ⁇ olyl, isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2- oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-triazol-3-yl, 1,2,3-triazol-4-yl, tetrazol-5-yl, benzimidazol-2-yl, indol-3-yl, lH-indazol-3-yl
  • the hydrocarbon residue for R is preferably a group represented by the formula: -CH 2 -X 1 -Z 1 wherein X 1 is an oxygen atom, an optionally oxidized sulfur atom, or -(CH 2 ) m ⁇ (m is an integer from 0 to 5); Z 1 is an optionally substituted a hydrocarbon residue, an optionally substituted heterocyclic group, or an optionally substituted amino group.
  • the optionally oxidized sulfur atom for X 1 is exemplified by thio group, sulfinyl group and sulfonyl group, with preference given to thio group.
  • X 1 is preferably -(CH 2 ) m ⁇ (m is an integer from 0 to 2, preferably 0).
  • the optionally substituted hydrocarbon residue for Z 1 is exemplified by the same hydrocarbon residues as those exemplifying the optionally substituted hydrocarbon residue for R mentioned above.
  • the optionally substituted heterocyclic group for Z 1 is exemplified by the same heterocyclic groups as those exemplifying the optionally substituted heterocyclic group for R mentioned above.
  • aromatic 5-membered heterocyclic groups containing 2 or 3 hetero atoms e.g., oxygen atom, nitrogen atom, sulfur atom
  • 2-imidazolyl or l,2,4-triazol-3-yl are preferred, with greater preference given to 2-imidazolyl or l,2,4-triazol-3-yl.
  • the hydrocarbon residue and heterocyclic group each represented by R or Z 1 mentioned above may have 1 to 3 substituents at any substitutable positions on the chain or 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, optionally esterified carboxyl groups and so on.
  • Aliphatic chain hydrocarbon groups mentioned as sub- stituents for the hydrocarbon residue and heterocyclic group each represented by R or Z 1 include linear or branched aliphatic hydrocarbon groups such as alkyl groups (preferably Ci-io alkyl), alkenyl groups (preferably C 2 - 1 0 alkenyl), and alkinyl groups (preferably C 2 - 10 alkinyl).
  • Preferable 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-di- methylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl and decyl.
  • Preferable alkenyl groups include vinyl, allyl, iso- propenyl, 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.
  • Preferable 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 4 - 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, bicyclot3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl and bicyclo[4.3.1]decyl.
  • C 3 - 8 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 3-cyclohexen-l-yl.
  • C 4 - 8 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 hydro ⁇ carbon 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., benzofuranyl, is
  • non-aromatic heterocyclic groups mentioned as substituents for the hydrocarbon resi ⁇ due and heterocyclic group each represented by R or Z 1 include oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperizinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and piper ⁇ azinyl.
  • 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 (i) amino group and (ii) substituted amino groups having 1 or 2 substituents selected from Ci-io alkyl groups, C 2 - 10 alkenyl groups, C2-10 alkinyl groups, C ⁇ _ ⁇ o acyl groups, C6- 1 2 aromatic groups, heterocyclic groups and so on (e.g., methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino) .
  • substituents for the hydrocarbon residue and heterocyclic group each represented by R or Z 1 include (i) amino group and (ii) substituted
  • 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 (i) formyl and (ii) groups resulting from binding of an C ⁇ - 10 alkyl group, C 2 - 1 0 alkenyl group or aromatic group and a carbonyl group (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentane- carbonyl, 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 (i) hydroxyl group and (ii) substituted hydroxyl groups having an appropriate substituent, particularly a substituent for use as a hydroxyl group protecting group, such as alkoxy, alkenyloxy, alkinyloxy, aralkyloxy, acyloxy and aryloxy.
  • Said alkoxy is preferably 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 alkenyloxy
  • Said alkinyloxy is preferably C 2 - 10 alkinyloxy (e.g., ethynyloxy, 2-propinyloxy) .
  • Said aralkyloxy is exemplified by phenyl-C ⁇ - 4 alkyloxy (e.g., benzyloxy, phenethyloxy) .
  • Said acyloxy is preferably 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 the (i) thiol group and (ii) 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 C ⁇ _ ⁇ o 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, neopent
  • alkenylthio is exemplified by C 2 - 10 alkenylthio (e.g., allylthio, crotylthio, 2-pentenylthio, 3- hexenylthio, 2-cyclopentenylmethylthio and 2- cyclohexenylmethylthio) .
  • Said alkinylthio is preferably C 2 - 10 alkinylthio (e.g., ethynylthio, 2-propinylthio) .
  • Said aralkylthio is exemplified by phenyl-C ⁇ - 4 alkyl- thios (e.g., benzylthio, phenethylthio) .
  • Said acylthio is preferably an alkanoylthio having 2 to 4 carbon atoms (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio) .
  • Said arylthio is exemplified by phenylthio and 4- chlorophenylthio.
  • 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 (i) carboxyl group, (ii) groups resulting from binding of a carboxyl group and a Ci- ⁇ alkyl group (i.e., alkoxycarbonyl, e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl) , (iii) groups resulting from binding of a carboxyl group and a C 3 -6 alkenyl group (i.e., alkenyloxycarbonyl e.g., allyloxycarbonyl, crotyloxycarbonyl, 2-pentenyloxycarbonyl, 3-hexenyl
  • the substituent on the hydrocarbon residue and heterocyclic group each represented by R or Z 1 may optionally have further 1 or more, preferably 1 to 3, substituents at any substitutable positions.
  • substituents include C ⁇ _ ⁇ o lower alkyl groups, C2-10 lower alkenyl groups, C 2 - 10 lower alkinyl groups, C 3 - 8 cycloalkyl groups, C 3 - 8 cycloalkenyl groups, C 4 - 8 cycloalkadienyl groups, aryl groups, aromatic heterocyclic groups, non-aromatic heterocyclic groups, aralkyl groups (e.g., aryl-C ⁇ _ 6 -alkyl groups etc.), 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., methyl
  • substituents are exemplified by the same substituents as those for the hydrocarbon residue and heterocyclic group each represented by R or Z 1 .
  • R is -CH 2 -X 1 - Z 1
  • the optionally substituted amino group for Z 1 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, or an optionally substituted heterocyclic group; or Rl and R 2 may bind together to form a ring).
  • the optionally substituted hydrocarbon residue or the optionally substituted heterocyclic group represented by R 1 or R 2 is exemplified by the same optionally substituted hydrocarbon residues or optionally substituted heterocyclic groups as those mentioned to exemplify the group for R above.
  • R 1 and R 2 may bind together to form a ring.
  • -N(R 1 )(R 2 ) rings include 1-pyrrolidinyl, 1- imidazolidinyl, 1-pyrazolidinyl, 1-piperidyl, piperazinyl, 4-morpholinyl, 4-thiomorpholinyl, homopiperazin-1-yl, 1,2,4-triazol-l-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 1H- indazol-1-yl.
  • the hydrocarbon residue and heterocyclic group each represented by R 1 or R 2 may have 1 to 3 substituents at any substitutable positions on the chain or the ring thereof. Such substituents are exemplified by the same substituents as those for the optionally substituted hydrocarbon residue and optionally substituted heterocyclic group each represented by R. These substituents on the hydrocarbon residue and heterocyclic group each represented by R 1 or R 2 may have 1 or more, preferably 1 to 3, substituents at any substitutable positions.
  • substituents include Ci-io lower alkyl groups, C 2 - 1 0 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, amino groups, N-mono- substituted amino groups, N,N-di-substituted amino groups, amidino groups, acyl groups, carbamoyl groups, N-mono- substituted carbamoyl groups, N,N-di-substituted carbamoyl groups, sulfamoyl groups, N-mono-substituted sulfamoyl groups, N,N-di-substituted sulfamoyl groups, carboxyl groups, lower alkoxycarbonyl groups, hydroxyl groups, lower alkoxy groups, lower alkenyloxy groups, cycloalkyloxy groups, carb
  • rings A and B may each have substituents.
  • substituents include halogen atoms, nitro group, optionally substituted Ci-io alkyl groups, optionally substituted C 2 - 10 alkenyl groups, optionally substituted C 2 - 1 0 alkinyl groups, optionally substituted hydroxyl groups, optionally substituted thiol groups, optionally substituted amino groups, optionally substituted acyl groups (e.g., C ⁇ -10 alkanoyl, C 2 - 10 alkenoyl, C 2 -10 alkinoyl), optionally esterified carboxyl groups, and optionally substituted aromatic ring groups.
  • substituents include halogen atoms, nitro group, optionally substituted Ci-io alkyl groups, optionally substituted C 2 - 10 alkenyl groups, optionally substituted C 2 - 1 0 alkinyl groups, optionally substituted hydroxyl groups, optionally substituted thiol groups, optionally substituted amino groups, optionally substitute
  • halogens mentioned as substituents for rings A and B include fluorine, chlorine, bromine and io- dine, with preference given to fluorine and chlorine.
  • substituents for rings A and B may be C ⁇ - 10 linear alkyl, C 3 - 10 branched alkyl or C 3 - 10 cyclic alkyl, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neo ⁇ pentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • C ⁇ -10 alkyl gorups C 2 - 10 alkenyl groups or C2- 10 alkinyl groups, respectively may have 1 to 3 substituents exemplified by the same substituents as those for the optionally substituted hydrocarbon residue and the optionally substituted heterocyclic gorup each represented by R or Zl.
  • Examples of the optionally substituted hydroxyl groups mentioned as substituents for rings A and B include (i) hydroxyl group and (ii) substituted hydroxyl groups having an appropriate substituent, particularly a substituent for use as a hydroxyl group protecting group, such as alkoxy, alkenyloxy, alkinyloxy, aralkyloxy and acyloxy, as well as aryloxy.
  • Said alkoxy is preferably an Ci-io 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 - 1 0 alkenyloxys
  • alkinyloxy is exemplified by C 2 - 10 alkinyloxys (e.g., propinyloxy) .
  • Said aralkyloxy is exemplified by phenyl-C ⁇ - 4 alkoxys (e.g., benzyloxy, phenethyloxy) .
  • Said acyloxy is preferably a C 2 - 4 alkanoyloxy (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy) .
  • Said aryloxy is exemplified by phenoxy and 4- chlorophenoxy.
  • Examples of the optionally substituted thiol groups mentioned as substituents for rings A and B include (i) thiol group and (ii) 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, arylthio and so on.
  • 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
  • alkenylthio is exemplified by C 2 - 1 0 alkenylthio (e.g., allylthio, crotylthio, 2-pentenylthio, 3- hexenylthio, 2-cyclopentenylmethylthio and 2- cyclohexenylmethylthio) .
  • Said alkinylthio is preferably C 2 - 10 alkinylthio (e.g., ethynylthio, 2-propinylthio) .
  • Said aralkylthio is exemplified by phenyl-C ⁇ - 4 alkyl- thios (e.g., benzylthio, phenethylthio) .
  • Said acylthio is preferably an alkanoylthio having 2 to 4 carbon atoms (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio) .
  • Said arylthio is exemplified by phenylthio and 4- chlorophenylthio.
  • substituents for rings A and B include (i) amino group and (ii) substituted amino groups having 1 or 2 substituents selected from C1- 1 0 of alkyl groups, C 2 -10 alkenyl groups, C 2 -10 alkinyl groups, C ⁇ - 10 acyl groups, C ⁇ -
  • aromatic groups e.g., methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino
  • methylamino dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino
  • acyl groups mentioned as substituents for rings A and B include (i) formyl and (ii) groups resulting from binding of a C ⁇ - 1 0 alkyl group, a C2- 1 0 alkenyl group, a C 2 - 1 0 alkinyl or a C ⁇ -
  • 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, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbon
  • Examples of the optionally substituted aromatic ring groups mentioned as substituents for rings A and B include C ⁇ -14 aromatic hydrocarbon residues (e.g., phenyl, naphthyl, anthryl) and heterocyclic aromatic residues (e.g., pyridyl, furyl, thienyl, imidazolyl, thiazolyl).
  • C ⁇ -14 aromatic hydrocarbon residues e.g., phenyl, naphthyl, anthryl
  • heterocyclic aromatic residues e.g., pyridyl, furyl, thienyl, imidazolyl, thiazolyl.
  • substituents for rings A and B may each be pre ⁇ sent at any substitutable 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 gorup), more preferably at least 1 methoxy group.
  • ring A is substituted for by 2 identical or different alkoxy groups (preferably C 1 - 3 alkoxy gorup), more preferably by methoxy groups.
  • ring I 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 gorup), more preferably at least 1 methoxy or isopropoxy group. Still more preferably, ring B is substituted for by 2 identical or different alkoxy groups (preferably C 1 - 3 alkoxy gorup). Most preferably, ring B is substituted for by a methoxy or isopropoxy group at the 3-position and by a methoxy gorup at the 4-position of the quinoline ring or quinazoline ring.
  • the optionally oxidized sulfur atom represented by X is exemplified by the thio group, sulfinyl group and sulfonyl group, with preference given to the thio group.
  • the optionally esterified carboxyl group for G include the (i) carboxyl group, (ii) groups resulting from binding of a carboxyl group and a C ⁇ - 6 alkyl group (i.e., alkoxycarbonyl e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec- butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl), (iii) groups resulting from binding of a carboxyl group and a C 3 - G alkenyl group (i.e., alken
  • the aralkyl group in said aralkyloxycarbonyl groups is an alkyl group having an aryl group as a substituent (arylalkyl 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 1 - 6 alkyl group.
  • Preferable aralkyl groups include benzyl, phenethyl, 3- phenylpropyl, (1-naphthyl)methyl and (2-naphthyl)methyl, with preference given to benzyl, phenetyl and others.
  • the amidated carboxyl group for G is represented by - CON(R x )(R 2 ) (R 1 and R 2 have the same definitions as those given above) .
  • the acyl group for G is represented by -CO-R 4 (R 4 is a C1-5 alkyl group or an aryl group) .
  • the C 1 - 5 alkyl group for R 4 is exemplified by methyl, ethyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl and 1-ethylpropyl, preferably methyl, butyl, isobutyl and pentyl.
  • the aryl group for R 4 is a monocyclic or condensed polycyclic aromatic hydrocarbon group, preferably examples including C ⁇ -i4 monocyclic or condensed polycyclic aromatic hydrocarbon group such as phenyl, naphthyl, anthryl and phenanthryl. In particular, phenyl, 1-naphtyl and 2-naphtyl are more preferred.
  • G is a hydroxyalkyl group
  • the alkyl group thereof is exemplified by the Ci- ⁇ saturated aliphatic hydrocarbon residues, mentioned to exemplify the hydrocarbon residue represented by R above.
  • Said hydroxyalkyl group is preferably represented by -CH 2 OH or - CH(OH)-R 4 (R 4 has the same definition as that given above), wherein R 4 is preferably methyl, ethyl, or the like.
  • G is a protected hydroxyalkyl group
  • said protected hydroxyalkyl group is represented by - CH 2 OCOR 5 or -CH(OCOR 5 )-R 4 (R 4 has the same definition as that given above; R 5 represents an alkyl group, aralkyl group or aryl group each of which may have a substituent).
  • the alkyl group represented by R 5 is exemplified by C ⁇ _e alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • the aralkyl group represented by R 5 is a C 1 - 4 alkyl group having an C ⁇ - 14 aryl group as a substituent (arylalkyl group), or the like.
  • Said aryl group is exemplified by phenyl and naphthyl.
  • Said aralkyl group is exemplified by benzyl, phenethyl, 3-phenylpropyl, (l-naphthyl)methyl and (2- naphthyl)methyl.
  • the aryl group for R 5 is exemplified by phenyl and naphthyl.
  • G is a halogen atom
  • said halogen atom is an atom of chlorine, bromine, iodine or fluorine, with preference given to chlorine or bromine.
  • 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 Ci- ⁇ alkyloxycarbonyl 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- or 7-position of the quinoline ring
  • each sub ⁇ stituent for ring B is methoxy or isopropoxy group present at the 3- position and methoxy group present at the 4- position thereof
  • n is 0, and k is 0.
  • Preferable examples of compounds represented by the formula (I) is methyl 4-(3,4-dimethoxyphenyl)-2-ethyl-6,7-dimethoxy- quinoline-3-carboxylate; ethyl 6-chloro-2-methyl-4-(3,4- dimethoxyphenyl)quinoline-3-carboxylate;
  • 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 bases include alkali metal salts such as sodium salt and potassium salt; alka- line earth metal salts such as calcium salt and magnesium salt; aluminum salt and ammonium salt.
  • Preferable salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanol ⁇ amine, diethanolamine, triethanolamine, dicyclohexylamine and N,N'-dibenzylethylenediamine.
  • Preferable salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.
  • Preferable salts with organic acids 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, benzene ⁇ sulfonic acid and p-toluenesulfonic acid.
  • Preferable salts with basic amino acids include salts with arginine, lysine and ornithine.
  • Preferable salts with acidic amino acids include salts with aspartic acid and glutamic acid. Among these salts, sodium or potassium salts are most preferable.
  • Compound (I) or a pharmaceutically acceptable salt thereof for the present invention may be a hydrate.
  • Compound (I) for the present invention can, for example, be produced by or according to the methods described in Japanese Patent Unexamined Publication Nos. 306052/1994 (EP-A-0567107) , 118266/1995 (EP-A-0608870) and 069890/1995 (EP-A-0634169) , 53419/1996 (EP-A-0686630) and W095/24394.
  • These dosage forms can be manufactured by the per se known technique conventionally used in pharmaceutical procedures.
  • Compound (I) for the present invention can be admin- istered orally or non-orally to mammals, including humans, as formulated with a pharmaceutically acceptable carrier, in the form of solid preparations such as tablets, cap ⁇ sules, granules, powders or suppositories, or liquid prepa ⁇ rations such as syrups and injectable preparations.
  • Pharmaceutically acceptable carriers are various or ⁇ ganic or inorganic carrier substances in common use as pharmaceutical materials, including excipients, lubricants, binders and disintegrating agents for solid preparations, and solvents, dissolution aids, suspending agents, isoton- izing agents, buffers and soothing agents for liquid preparations.
  • Other pharmaceutical additives such as preservatives, antioxidants, coloring agents and sweetening agents may be used as necessary.
  • Preferable excipients include lactose, sucrose, D- mannitol, erythritol, starch, crystalline cellulose and light silicic anhydride.
  • Preferable lubricants include magnesium stearate, calcium stearate, talc and colloidal silica.
  • Preferable binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and polyvinylpyrrolidone.
  • Preferable disintegrating agents include starch, car ⁇ boxymethyl cellulose, carboxymethyl cellulose calcium, crosscarmellose sodium and carboxymethyl starch sodium.
  • Preferable solvents include water for injection, alco ⁇ hol, propylene glycol, macrogol, sesame oil and corn oil.
  • Preferable dissolution aids include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate.
  • Preferable suspending agents include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl- aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and monostearic glycerol; and hydro- philic polymers such as polyvinyl alcohol, polyvinylpyr ⁇ rolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hy ⁇ droxypropyl cellulose.
  • Preferable isotonizing agents include sodium chloride, glycerol and D-mannitol.
  • Preferable buffers include buffer solutions of phos ⁇ phates, acetates, carbonates and citrates.
  • Preferable soothing agents include benzyl alcohol.
  • Preferable preservatives include p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
  • Preferable antioxidants include sulfites and ascorbic acid.
  • Compound (I) for the present invention is of low tox- icity; no deaths occurred during a 1-week observation period following oral administration of compound (A) , for instance, to female F344/Jcl rats at 6 weeks of age at a dose of 2,000 mg/kg.
  • compound (I) for the present invention is useful as an immunosuppressant for mammals (e.g., humans, horses, bovines, pigs, dogs, cats).
  • the dose of compound (I) for the present in ⁇ vention can be chosen over a wide range, depending on tar ⁇ get disease, route of administration, and patient condition to be treated, it can normally be chosen over the range from 1 mg to 2,000 mg a day, preferably 10 mg to 400 mg, for oral administration, and from 1 mg to 1,000 mg, preferably from 1 mg to 100 mg, for non-oral administration, per adult. These doses can be administered in about 1 to 3 portions a day.
  • examples of the drug which is used in combination with the quinoline or quinazoline compound represented by the formula (I) or a pharmaceutically acceptable salt thereof include immunosuppressants ecept for a quinoline or quinazoline compound mentioned above, for example, (i) T cell inhibitors, (ii) cytotoxic chemicals, (iii) anti-tumor antibiotics, (iv) anti-lymphocyte immunoglobulins, and so on.
  • T cell inhibitors are drugs having the property to suppress the immune response of T cells by inhibiting the production of both Thi and Th2 cytokines which are derived from the T cells (e.g., Tacrolimus (FK506), cyclosporin A, cyclosporin G), or drugs having the property to inhibit the activity of cytokines produced by T cells (e.g., rapamycin). Consequently, these drugs suppress the immune reaction.
  • Cytotoxic chemicals are drugs, which are also used as anticancer drugs, having the property to act nonspecifically on actively proliferating cells, i.e. hematopoietic stem cells, germ cells, malignant cells or lymphocytes (T lymphocytes and B lymphocytes), which inhibit both responses of cellular immunity and humoral immunity as a result of the suppression of both T lymphocytes and B lymphocytes. Accordingly, these drugs always have both activities of myelosuppression and hypofertility as well as immunosuppressing activity.
  • Examples of the cytotoxic chemicals include ⁇ alkylating agents, (2) nucleic acid metabolic antagonists, folic acid metabolic antagonists and so on.
  • the alkylating agents are drugs having the property to suppress the immune response by damaging T cells or B cells, mainly through the inhibition of DNA symthesis or DNA replication.
  • Examples of the alkylating agents include cyclophosphamide, ifosfamide, chlorambucil and the like.
  • the nucleic acid metabolic antagonists, which inhibit the metabolism of nucleic acid are drugs having the property to suppress the antibody production by damaging mainly T cells.
  • nucleic acid metabolic antagonists examples include 6- mercaptopurine, azathiopurine, 6-thioguanine, 5- fluorouracil, cytosine arabinoside, mizoribine and the like, ⁇
  • the folic acid metabolic antagonists, which inhibit the metabolism of folic acid are drugs having the property to suppress the antibody production by damaging mainly T cells.
  • examples of the folic acid metabolic antagonists include methotrexate and the like.
  • Anti-tumor antibiotics are drugs having the property to inhibit DNA or RNA synthesis by intercalating therein, as a result of damaging T cells or B cells.
  • Examples of the anti-tumor antibiotics include adriamycin, daunomycin and the like.
  • Anti-lymphocyte immunoglobulins are drugs having the property to suppress the immune response by damaging mainly T cells.
  • the anti-lymphocyte immunoglobulins include anti-CD3 antibody, anti-CD4 antibody, anti-CD5 antibody, anti-I -2 receptor antibody and the like.
  • a quinoline or quinazoline compound represented by the formula (I) of the present invention are the drugs having the property to suppress the immune response of T cells by specific inhibition of the production of Thi cytokines such as interferon- / (IFN-y) and interleukin-2 (IL-2) among the cytokines which are derived from the T cells.
  • the inhibition mechanism of the quinoline or quinazoline compound represented by the formula (I) is different from those of the immunosuppressants mentioned above.
  • the pharmaceutical composition which comprises a quinoline or quinazoline compound represented by the formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound A or compound B) in combination with Tacrolimus (FK506), methotrexate or cyclosporin A, particularly Tacrolimus (FK506).
  • the pharmaceutical composition of the present invention comprising the quinoline or quinazoline compound represented by the formula (I) or pharmaceutically acceptable salt thereof in combination with an immunosuppressant except for a quinoline or quinazoline compound mentioned above, which is provided in accordance with the present invention, can be respectively put to use by mixing the respective active components either all together or independently with a physiologically acceptable carrier, excipient, binder, diluent, etc. and administering the mixture or mixtures either orally or non orally as a pharmaceutical composition.
  • the respective formulations can be extemporaneously admixed using a diluent or the like and aministered or can be administered independently of each other, either concurrently or at staggered times to the same subject.
  • the dosage form for said pharmaceutical composition includes such oral dosage forms as granules, powders, tablets, capsules, syrups, emulsions, suspensions, etc. and such non-oral dosage forms as injections (e.g. subcutaneous, intravenous, intramuscular and intraperitoneal injections), drip infusions, external application forms (e.g. nasal spray preparations, transdermal preparations, ointments, etc.), and suppositories (e.g. rectal and vaginal suppositories).
  • injections e.g. subcutaneous, intravenous, intramuscular and intraperitoneal injections
  • external application forms e.g. nasal spray preparations, transdermal preparations, ointments, etc.
  • suppositories e.g. rectal and vaginal suppositories.
  • an excipient e.g. lactose, sucrose, starch, mannitol, etc.
  • a dis-integrator e.g. calcium carbonate, carboxymethylcellulose calcium, etc.
  • a binder e.g. a-starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, trehalose etc.
  • a lubricant e.g. talc, magnesium stearate, polyethylene glycol 6000, etc.
  • the compressed product is coated, by the per se known technique, for masking the taste or for enteric dissolution or sustained release.
  • the coating material that can be used includes, for instance, ethyl ⁇ cellulose, hydroxymethylcellulose, polyoxyethyleneglycol, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, and Eudragit (Rohm & Haas, Germany, methacrylic- acrylic copolymer).
  • Injections can be manufactured typically by the following procedure.
  • the active component or components are dissolved, suspended or emulsified in an aqueous vehicle (e.g. distilled water, physiological saline, Ringer's solution, etc.) or an oily vehicle (e.g. vegitable oil such as olive oil, sesame oil, cottonseed oil, corn oil, etc. or propylene glycol) together with a dispersant (e.g. Tween 80 (Atlas Powder, U.S.A.), HCO 60 (Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.), a preservative (e.g.
  • an isotonizing agent e.g. sodium chloride, glycerol, sorbitol, glucose, inverted sugar, etc.
  • a solubilizer e.g. sodium salicylate, sodium acetate, etc.
  • a stabilizer e.g. human serum albumin
  • a soothing agent e.g. benzalkonium chloride, procaine hydrochloride, etc.
  • a dosage form for external application can be manufactured by processing the active component or components into a solid, semi-solid or liquid composition.
  • a solid composition for instance, the active component or components, either as they are or in admixture with an excipient (e.g. lactose, mannitol, starch, microcrystalline cellulose, sucrose, etc.), a thickener (e.g. natural gums, cellulose derivatives. acrylic polymers, etc.), etc., are processed into powders.
  • the liquid composition can be manufactured in substantially the same manner as the injections mentioned above.
  • the semi-solid composition is preferably provided in a hydrous or oily gel form or an ointment form. These compositions may optionally contain a pH control agent (e.g.
  • Suppositories can be manufactured by processing the active component or components into an oily or aqueous composition, whether solid, semi-solid or liquid.
  • the oleaginous base that can be used includes, for instance, higher fatty acid glycerides [e.g. cacao butter, Witepsols (Dynamite-Nobel), etc.], medium-chain fatty acids [e.g. Migriols (Dynamite-Nobel), etc.], vegetable oils (e.g. sesame oil, soybean oil, cotton-seed oil, etc.), etc.
  • Ther water-soluble base includes, for instance, polyethylene glycols, propylene glycol, etc.
  • the hydrophilic base includes, for instance, natural gums, cellylose derivatives, vinyl polymers, and acrylic polymers, etc.
  • the pharmaceutical composition of the present invention is low in toxicity and can be safely used in mammals (e.g. humans, mice, rats, rabbits, dogs, cats, bovines, horses, swines, monkeys).
  • the dosage of the pharmaceutical composition of the present invention may be appropriately determined with reference to the dosages recommended for the respective active components and can be selected appropriately according to the recipient, the recipient's age and body weight, current clinical status, administration time, dosage form, method of administration, and combination of the active components, among other factors.
  • the preferred frequency of administration is 1 to 3 times a day.
  • the proportions of the active components in the pharmaceutical composition of the present invention can be appropriately selected according to the recipient, the recipient's age and body weight, current clinical status, administration time, dosage form, method of administration, and combination of active components, among other factors.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof e.g.
  • Tacrolimus (FK506) which is an example of T cell inhibiting agents, are to be administered in combination to a human subject
  • Tacrolimus (FK506) is used in a proportion of usually about 0.001 to 10 weight parts and preferably about 0.01 to 1 weight parts relative to 1 weight part of the compound or a salt thereof.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof e.g.
  • cyclosporin A is used in a proportion of usually about 0.01 to 100 weight parts and preferably about 0.1 to 10 weight parts relative to 1 weight part of the compound or a salt thereof.
  • methotrexate is used in a proportion of usually about 0.0001 to 1 weight parts and preferably about 0.001 to 0.1 weight parts, relative to 1 weight part of the compound or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically composition of the present invention shows a marked synergistic effect compared with administration of either active component alone. For example, compared with cases in which each of these active components was administered to patients with the diseases associated with immunity, administration of these active components in combination resulted in marked improvements in both efficacy and toxicity.
  • the pharmaceutical composition of the present invention improves the disorder of immune response more effectively than it is the case with administration of each component drug alone and, therefore, can be used advantageously for the prophylaxis and treatment of diseases assumed to be associated with immunity including autoimmunity, and the prevention of graft rejection following transplantation.
  • the pharmaceutical composition of the present invention develops sufficient efficacy with reduced doses as compared with the administration of any one of the active components alone, the side effects of the respective components (e.g. nephrotoxicity, myelosuppression, pneumonitis, etc.) can be reduced.
  • the immunosuppressant of the present invention spe ⁇ cifically suppresses the production of immune cytokines [e.g., interleukin-2 (IL-2), interferon-y (IFN-y)], and is useful in treating or preventing diseases assumed to be associated with immunity, including autoimmune diseases, in mammals, including humans.
  • immune cytokines e.g., interleukin-2 (IL-2), interferon-y (IFN-y)
  • IL-2 interleukin-2
  • IFN-y interferon-y
  • target diseases include systemic lupus erythematosus, ulcerative colitis, Crohn disease, multiple sclerosis, psoriasis, chronic hepatitis, gallbladder cancer, breast cancer, uterine cervical cancer, chronic lymphatic leukemia, chronic myelocytic leukemia, large intestine cancer, colic cancer, rectal cancer, Helicobacter pylori infection, Hodgkin's disease, insulin- dependent diabetes mellitus, malignant melanoma, multiple myeloma, non-Hodgkin lymphoma, non-small cell lung cancer, ovarian cancer, digestive ulcer, prostatic cancer, septic shock, tuberculosis, infertility, arteriosclerosis, Behcet's disease, asthma, atopic dermatitis, nephritis, systemic fungal infection, acute bacterial meningitis, acute myocardial infarction, acute pancreatitis, acute viral encephalitis, adult respiratory distress syndrome,
  • Fig. 1 shows the effect of concomitant administration of compound A and Tacrolimus (FK506) on body weight change in adjuvant arthritic rats.
  • Fig. 2 shows the effect of concomitant administration of compound A and methotrexate on body weight change in adjuvant arthritic rats.
  • the immunosuppressing activity of the pharmaceutical composition of the present invention is hereinafter de ⁇ scribed with reference to experimental examples.
  • Interleukin-2 (I -2) and interferon-y (IFN-y), both cytokines produced by T-cells, show diverse actions, in ⁇ cluding T-cell growth and macrophage activation, respec ⁇ tively, and play key roles in immune reaction. Suppression of production of these cytokines serves as a good index of immunosuppressing activity.
  • Splenocytes were isolated from the spleen of a Lewis rat (male, 8 weeks of age), and suspended in RPMI-1640 (containing penicillin, streptomycin and 2-mercaptoethanol) supplemented with 5% fetal bovine serum) , followed by cul ⁇ tivation of 1 x IO 7 splenocytes in the presence of 2 ⁇ g/ml concanavalin A for 24 hours. After completion of the cul ⁇ tivation, the supernatant was collected.
  • RPMI-1640 containing penicillin, streptomycin and 2-mercaptoethanol
  • 5% fetal bovine serum fetal bovine serum
  • the IL-2 content in the supernatant was determined with 3 H-thymidine incor ⁇ poration as an index, by 50 fold diluting the culture su ⁇ pernatant, and carrying out a reaction for growing CTLL-2 cells, an IL-2 dependent cell line.
  • the IFN-y content was determined by a commonly known method using an ELISA kit (GIBCO PBL, USA) .
  • Lymphocytes were isolated from a lymph node of a
  • Lymph node cells were subjected to alternative cultivation in the presence of splenocytes from an X-ray- irradiated mouse of the same line and 50 / g/ml OVA, and in the presence of 20 ng/ml IL-2, to yield an OVA-reactive T cell line, from which an OVA-reactive T cell clone was es ⁇ tablished by the limiting dilution analysis method.
  • An allo-reactive T-cell line was prepared by subjecting Balb/c mouse splenocytes to alternative cultivation in the pres ⁇ ence of splenocytes from an X-ray-irradiated A/J mouse, and in the presence of 20 ng/ml IL-2.
  • subject cells were cultured with each drug in the presence of splenocytes from an X- ray-irradiated mouse of the same line and 50 g/ml OVA for 48 hours for the OVA-reactive T cells, and in the presence of splenocytes from an X ray-irradiated A/J mouse for 24 hours for the allo-reactive T-cells, after which the IFN-y and IL-2 contents in the supernatant were determined by ELISA (according to the same method mentioned in Experimental Example 1).
  • Reaction was carried out using the same starting quin ⁇ oline and triazole compounds as those used in Reference Example 5 in a 1:1.3 molar ratio and the same procedure, but different reaction solvents and additives were used.
  • the tablets obtained were all found to have excellent tablet properties, including hardness, disintegrability and solubility.
  • the immunosuppressant containing compound (I) or a pharmaceutically acceptable salt thereof for the present invention is safe and of low toxicity, and can be used to prevent or treat diseases assumed to be associated with immunity, including autoimmune diseases, and to prevent graft rejection following organ transplantation.
  • the pharmaceutical composition comprising a quinoline or quinazoline compound (I) or a pharmaceutically acceptable salt thereof and an immunosuppressant except for the quinoline or quinazoline compound mentioned above, has a remarkable effect beyond the sum effect of both agents in comparison with either agent administered above.
  • the pharmaceutical composition can be used to prevent or treat diseases assumed to be associated with immunity, including autoimmune diseases, and to pre ⁇ vent graft rejection following organ transplantation, 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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  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

La présente invention concerne un nouvel agent immunosuppresseur contenant en tant qu'ingrédient actif un composé correspondant à la formule (I) où Y représente un atome d'azote ou C-G (G étant un groupe carboxyle éventuellement estérifié ou amidé, un groupe acyle, un groupe hydroxyalkyle éventuellement protégé ou un atome d'halogène); R représente un résidu d'hydrocarbure éventuellement substitué ou un groupe hétérocyclique éventuellement substitué; X représente un atome d'oxygène ou un atome de soufre éventuellement oxydé; n vaut 0 ou 1; k vaut 0 ou 1; G et R peuvent se lier afin de former un noyau; et, enfin, les noyaux A et B peuvent avoir chacun un substituant. Cette invention concerne également un sel de ce composé acceptable sur le plan pharmaceutique, et une composition pharmaceutique contenant le composé représenté par la formule (I) susmentionnée ou un de ses sels acceptables sur le plan pharmaceutique, ainsi qu'un agent immunosuppresseur à l'exception du composé représenté par ladite formule (I), qui est utile en tant qu'agent immunosuppresseur.
PCT/JP1996/001693 1995-09-13 1996-06-19 Agent immunosuppresseur WO1997009984A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
HU9900169A HUP9900169A2 (hu) 1995-09-13 1996-06-19 Immunoszuppresszáns hatású kinolin- vagy kinozalinszármazékok és ezeket tartalmazó gyógyászati készítmények
AU61373/96A AU6137396A (en) 1995-09-13 1996-06-19 Immunosuppressant
NZ310561A NZ310561A (en) 1995-09-13 1996-06-19 Immunosuppressant of the aromatic variety based upon the quinoline family
BR9610314A BR9610314A (pt) 1995-09-13 1996-06-19 Imunossupressor processos para prevenir ou tratar doenças autoimunes em mamíferos e prevenir rejeição de enxerto uso de um composto composição farmacêutica e uso da mesma
EP96918849A EP0850061A1 (fr) 1995-09-13 1996-06-19 Agent immunosuppresseur
NO980788A NO980788L (no) 1995-09-13 1998-02-25 Immunosuppressant

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP7/235704 1995-09-13
JP23570495 1995-09-13

Publications (1)

Publication Number Publication Date
WO1997009984A1 true WO1997009984A1 (fr) 1997-03-20

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PCT/JP1996/001693 WO1997009984A1 (fr) 1995-09-13 1996-06-19 Agent immunosuppresseur

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EP (1) EP0850061A1 (fr)
KR (1) KR19990044618A (fr)
CN (1) CN1195988A (fr)
AU (1) AU6137396A (fr)
BR (1) BR9610314A (fr)
CA (1) CA2226915A1 (fr)
HU (1) HUP9900169A2 (fr)
NO (1) NO980788L (fr)
NZ (1) NZ310561A (fr)
WO (1) WO1997009984A1 (fr)

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Publication number Priority date Publication date Assignee Title
EP0941987A1 (fr) * 1998-03-13 1999-09-15 Lonza A.G. Procédé pour la préparation de 2-amino-4,5,3',4'-benzophénone
WO1999064400A1 (fr) * 1998-06-12 1999-12-16 Vertex Pharmaceuticals Incorporated INHIBITEURS DE p38
EP1277740A1 (fr) * 1998-06-12 2003-01-22 Vertex Pharmaceuticals Incorporated Inhibiteurs de p38
CN102050780A (zh) * 2010-11-18 2011-05-11 中国科学院昆明植物研究所 喹啉衍生物,其药物组合物及其用途
US8399514B2 (en) 2007-02-08 2013-03-19 Biogen Idec Ma Inc. Treatment for multiple sclerosis
US8524773B2 (en) 1998-11-19 2013-09-03 Biogen Idec International Gmbh Utilization of dialkylfumarates
US8980832B2 (en) 2003-09-09 2015-03-17 Biogen Idec International Gmbh Use of fumaric acid derivatives for treating cardiac insufficiency, and asthma
WO2017151947A1 (fr) * 2016-03-02 2017-09-08 George Robert Pettit Composés 4-azapodophylotoxines

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EP0343684A1 (fr) * 1988-05-27 1989-11-29 Synergen, Inc. Inhibiteurs d'interleukine-1
EP0398817A1 (fr) * 1989-05-19 1990-11-22 Hadassah Medical Organization Inhibiteur d'interleukine-1
EP0567107A1 (fr) * 1992-04-24 1993-10-27 Takeda Chemical Industries, Ltd. Dérivés de quinoléine et de quinazoline pour le traitement d'arthritis
JPH06340658A (ja) * 1993-04-08 1994-12-13 Kyowa Hakko Kogyo Co Ltd ベンゾイミダゾール誘導体
EP0658624A2 (fr) * 1993-12-08 1995-06-21 Intermune Life Sciences, Inc. Gènes recombinants exprimant pp14
EP0664128A1 (fr) * 1992-10-07 1995-07-26 Sumitomo Pharmaceuticals Company, Limited Composition pharmaceutique utilisee pour inhiber la production des facteurs de necrose tumorale
WO1995020655A1 (fr) * 1994-01-28 1995-08-03 The Scripps Research Institute Nouveau recepteur de surface cellulaire, compositions d'anticorps et procedes utilisant un tel recepteur

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EP0343684A1 (fr) * 1988-05-27 1989-11-29 Synergen, Inc. Inhibiteurs d'interleukine-1
EP0541920A1 (fr) * 1988-05-27 1993-05-19 Synergen, Inc. Inhibiteurs de l'interleukine-1
EP0398817A1 (fr) * 1989-05-19 1990-11-22 Hadassah Medical Organization Inhibiteur d'interleukine-1
EP0567107A1 (fr) * 1992-04-24 1993-10-27 Takeda Chemical Industries, Ltd. Dérivés de quinoléine et de quinazoline pour le traitement d'arthritis
EP0664128A1 (fr) * 1992-10-07 1995-07-26 Sumitomo Pharmaceuticals Company, Limited Composition pharmaceutique utilisee pour inhiber la production des facteurs de necrose tumorale
JPH06340658A (ja) * 1993-04-08 1994-12-13 Kyowa Hakko Kogyo Co Ltd ベンゾイミダゾール誘導体
EP0658624A2 (fr) * 1993-12-08 1995-06-21 Intermune Life Sciences, Inc. Gènes recombinants exprimant pp14
WO1995020655A1 (fr) * 1994-01-28 1995-08-03 The Scripps Research Institute Nouveau recepteur de surface cellulaire, compositions d'anticorps et procedes utilisant un tel recepteur

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6011178A (en) * 1998-03-13 2000-01-04 Lonza, Ltd. Process for the preparation of 2-amino-4,5,3',4'-tetramethoxybenzophenone
EP0941987A1 (fr) * 1998-03-13 1999-09-15 Lonza A.G. Procédé pour la préparation de 2-amino-4,5,3',4'-benzophénone
US7151101B2 (en) 1998-06-12 2006-12-19 Vertex Pharmaceuticals Incorporated Inhibitors of p38
EP1277740A1 (fr) * 1998-06-12 2003-01-22 Vertex Pharmaceuticals Incorporated Inhibiteurs de p38
US6528508B2 (en) 1998-06-12 2003-03-04 Vertex Pharmaceuticals Incorporated Inhibitors of p38
US6800626B2 (en) 1998-06-12 2004-10-05 Vertex Pharmaceuticals Incorporated Inhibitors of p38
WO1999064400A1 (fr) * 1998-06-12 1999-12-16 Vertex Pharmaceuticals Incorporated INHIBITEURS DE p38
US8524773B2 (en) 1998-11-19 2013-09-03 Biogen Idec International Gmbh Utilization of dialkylfumarates
US8759393B2 (en) 1998-11-19 2014-06-24 Biogen Idec International Gmbh Utilization of dialkylfumarates
US8980832B2 (en) 2003-09-09 2015-03-17 Biogen Idec International Gmbh Use of fumaric acid derivatives for treating cardiac insufficiency, and asthma
US8399514B2 (en) 2007-02-08 2013-03-19 Biogen Idec Ma Inc. Treatment for multiple sclerosis
CN102050780A (zh) * 2010-11-18 2011-05-11 中国科学院昆明植物研究所 喹啉衍生物,其药物组合物及其用途
WO2017151947A1 (fr) * 2016-03-02 2017-09-08 George Robert Pettit Composés 4-azapodophylotoxines
US11098052B2 (en) 2016-03-02 2021-08-24 Arizona Board Of Regents On Behalf Of Arizona State University 4-azapodophylotoxins compounds

Also Published As

Publication number Publication date
NO980788L (no) 1998-03-31
NZ310561A (en) 1999-07-29
KR19990044618A (ko) 1999-06-25
BR9610314A (pt) 1999-07-06
CA2226915A1 (fr) 1997-03-20
HUP9900169A2 (hu) 2000-03-28
EP0850061A1 (fr) 1998-07-01
AU6137396A (en) 1997-04-01
NO980788D0 (no) 1998-02-25
CN1195988A (zh) 1998-10-14

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