KR19990044618A - Immunosuppressant - Google Patents

Abstract

The present invention provides new immunosuppressive agents.

An immunosuppressive agent containing as an active ingredient a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[Formula I]

Wherein Y is a nitrogen atom or CG (G is an optionally esterified or amidated carboxyl group, acyl group, optionally protected hydroxyalkyl group, or halogen atom); R is an optionally substituted hydrocarbon moiety Or an optionally substituted heterocyclic group; X is an oxygen atom or optionally oxidized sulfur atom; n is 0 or 1; k is 0 or 1; G and R may join together to form a ring Ring A and B may each have a substituent). Pharmaceutical compositions containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and an immunosuppressant except for the compound of formula (I) are useful as immunosuppressants.

Description

Immunosuppressant

In diseases considered to be related to an immune response, including autoimmune diseases, the enhancement of the immune response based on the immune response or the enhancement of the human defense response is thought to be associated with the lesion, and its site varies according to the disease.

Traditionally, these diseases have been described as steroids or certain immunosuppressive agents (e.g., azathioprine, cyclophosphamide, methotrexate, myzoribin, cyclosporin A, tacrolimus (FK506; Merck Index 12th edition, 1546 pages, 9200, 1996). These treatments have serious side effects, especially the immunosuppressive agents mentioned above, as well as leukopenia and thrombocytopenia due to myelosuppression, as well as side effects unique to each treatment [The New England Journal of Medicine, Vol. 330 (19), page 1368 (1994)] The same phenomenon occurred in the prevention of transplant rejection after organ transplantation.To overcome this situation, immunosuppressive agents such as cyclosporin A and tacrolimus (KF506) Although they have been developed, all have problems to be solved, including severe kidney toxicity.

Diseases associated with immune responses, including autoimmune diseases, are chronic and have complex symptoms. Therefore, the most appropriate therapeutic agent should be selected for each patient condition. However, the treatment of a disease associated with an immune response takes a long time, so it is generally difficult to select an appropriate therapeutic agent for clinical use due to serious problems such as increased dosage and side effects from long-term administration. In addition, all agents that have been used to treat the disease and to prevent transplant rejection after organ transplantation have serious side effects as mentioned above. Therefore, the development of drugs with very few side effects is strongly desired.

In this situation, the present inventors studied a new drug having immunosuppressive activity, and found a safe quinoline- or quinazoline-based compound with low toxicity.

The present invention relates to pharmaceutical compositions, more particularly immunosuppressive agents useful for the prevention or treatment of diseases believed to be associated with immunity including autoimmune diseases or for the prevention of transplant rejection following organ transplantation.

We believe that quinoline or quinazoline compounds or pharmaceutically acceptable salts thereof have immune cytokine production-inhibiting activity, which prevents or treats a disease for which the compound is considered immune-related, or transplant rejection after organ transplantation. It has been found to be effective in the prevention of. The inventors have also found that unexpectedly combining quinoline or quinazoline compounds with traditionally used immunosuppressants exhibits significant immunosuppressive activity. The present inventors continued to research based on this finding and completed the present invention.

Therefore, the present invention

(1) An immunosuppressive agent containing as an active ingredient a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

Wherein Y is a nitrogen atom or CG (G is an optionally esterified or amidated carboxyl group, acyl group, optionally protected hydroxyalkyl group, or halogen atom); R is an optionally substituted hydrocarbon residue or Optionally substituted heterocyclic group; X is an oxygen atom or optionally oxidized sulfur atom; n is 0 or 1; k is 0 or 1; G and R may join together to form a ring Ring A and B may each have a substituent),

(2) n is 0 and the optionally substituted hydrocarbon residue represented by R is

-CH ₂ -X ¹ -Z ¹ (X ¹ is an oxygen atom, optionally oxidized sulfur atom, or-(CH ₂ ) _m- (m is an integer from 0 to 5); Z ¹ is a hydrogen atom, optionally Immunosuppressant of (1), which is a group represented by a substituted hydrocarbon residue, an optionally substituted heterocyclic group, or an optionally substituted amino group),

(3) the immunosuppressive agent of (2), wherein m is 0 and X ¹ is-(CH ₂ ) _m- ;

(4) the immunosuppressant of (1) above, wherein the optionally substituted heterocyclic group represented by Z ¹ is an aromatic 5 membered heterocyclic group containing 2 or 3 heteroatoms,

(5) the immunosuppressive agent of (1), wherein Y is C-G,

(6) the immunosuppressive agent of (5), wherein G is a C _1-6 alkyloxycarbonyl group,

(7) the immunosuppressant of (1), wherein G is an ethoxycarbonyl group,

(8) the immunosuppressive agent of (1), wherein ring A is substituted with at least one alkoxy group,

(9) the immunosuppressant of (1), wherein ring A is substituted with two methoxy groups,

(10) the immunosuppressive agent of (1), wherein ring A is substituted with two methoxy groups at the 6 and 7 positions of the quinoline or quinazoline ring, respectively,

(11) the immunosuppressive agent of (1), wherein ring B is substituted with one or more alkoxy groups,

(12) the immunosuppressive agent of (1), wherein ring B is substituted with two same or different alkoxy groups,

(13) the immunosuppressive agent of (1), wherein k is 0,

(14) the compound represented by formula (I)

Methyl 4- (3,4-dimethoxyphenyl) -2-ethyl-6,7-dimethoxyquinoline-3-carboxylate,

Ethyl 6-chloro-2-methyl-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylate,

6,7-dimethoxy-9-phenylfuro [3,4-b] quinolin-1 (3H) -one,

Ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(1-methylimidazol-2-yl) thiomethyl] quinoline-3-carboxylate,

4- (3,4-dimethoxyphenyl) -2- (2-hydroxyethylthiomethyl) -6,7-dimethoxyquinazoline,

4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(4-methyl-1,2,4-triazol-3-yl) thiomethyl] quinazolin,

Ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(1-methylimidazol-2-yl) ethyl] quinoline-3-carboxylate,

Methyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-3-methoxycarbonylquinoline-2-acetate,

Ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate,

Ethyl 4- (3-isopropoxy-4-methoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate,

Ethyl 4- (3-hydroxy-4-methoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate,

Ethyl 4- (4-hydroxy-3-methoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate,

Ethyl 7-hydroxy-6-methoxy-4- (3,4-dimethoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate,

Ethyl-4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate 1-oxide or

The immunosuppressive agent of (1) selected from ethyl 2- (N, N-diethylaminomethyl) -4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate,

(15) the immunosuppressive agent of (1), which has an immune cytokine production-inhibiting activity,

(16) the immunosuppressive agent of (1) for the prevention or treatment of autoimmune diseases,

(17) the immunosuppressive agent of (1) above for the prevention or treatment of systemic lupus erythematosus, chronic hepatitis, interstitial liver disease, asthma, psoriasis, ulcerative colitis, Crohn's disease, local ileitis or multiple sclerosis,

(18) the immunosuppressive agent of (1) above for preventing transplant rejection after organ transplantation,

(19) A method for preventing or treating an autoimmune disease in a mammal comprising administering to the mammal a therapeutically effective amount of the compound represented by the formula (I) of (1) or a pharmaceutically acceptable salt thereof,

(20) the method where the autoimmune disease is systemic lupus erythematosus, chronic hepatitis, interstitial liver disease, asthma, psoriasis, ulcerative colitis, Crohn's disease, local ileitis or multiple sclerosis,

(21) A method for preventing transplant rejection after transplantation of a mammal comprising administering to the mammal a therapeutically effective amount of the compound represented by the formula (I) of (1) or a pharmaceutically acceptable salt thereof;

(22) the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use as an immunosuppressive agent,

(23) A pharmaceutical composition containing a quinoline or quinazoline compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, and an immunosuppressive agent except for the quinazoline compound:

[Formula I]

Wherein Y is a nitrogen atom or CG (G is an optionally esterified or amidated carboxyl group, acyl group, optionally protected hydroxyalkyl group, or halogen atom); R is an optionally substituted hydrocarbon residue or Optionally substituted heterocyclic group; X is an oxygen atom or optionally oxidized sulfur atom; n is 0 or 1; k is 0 or 1; G and R may join together to form a ring Ring A and B may each have a substituent),

(24) n is 0 and the optionally substituted hydrocarbon residue represented by R is

-CH ₂ -X ¹ -Z ¹ (X ¹ is an oxygen atom, optionally oxidized sulfur atom, or-(CH ₂ ) _m- (m is an integer from 0 to 5); Z ¹ is a hydrogen atom, optionally The pharmaceutical composition of (23) above as a group represented by a substituted hydrocarbon residue, an optionally substituted heterocyclic group, or an optionally substituted amino group),

(25) the pharmaceutical composition of the above (24) wherein m is 0 and X ¹ is-(CH ₂ ) _m- ,

(26) The pharmaceutical composition of (23) above, wherein the optionally substituted heterocyclic group represented by Z ¹ is an aromatic 5 membered heterocyclic group containing 2 or 3 heteroatoms,

(27) the pharmaceutical composition of (23) above wherein Y is C-G,

(28) the pharmaceutical composition of (23) wherein G is a C _1-6 alkyloxycarbonyl group,

(29) The pharmaceutical composition of the above (23), wherein G is an ethoxycarbonyl group,

(30) The pharmaceutical composition of (23), wherein ring A is substituted with at least one alkoxy group,

(31) the pharmaceutical composition of (23) above, wherein ring A is substituted with two methoxy groups,

(32) the pharmaceutical composition of (23), wherein ring A is substituted with two methoxy groups at the 6 and 7 positions of the quinoline or quinazoline ring, respectively;

(33) The pharmaceutical composition of (23), wherein ring B is substituted with one or more alkoxy groups,

(34) The pharmaceutical composition of (23), wherein ring B is substituted with two same or different alkoxy groups,

(35) the pharmaceutical composition of (23) above wherein k is 0,

(36) the compound represented by formula (I)

Methyl 4- (3,4-dimethoxyphenyl) -2-ethyl-6,7-dimethoxyquinoline-3-carboxylate,

Ethyl 6-chloro-2-methyl-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylate,

6,7-dimethoxy-9-phenylfuro [3,4-b] quinolin-1 (3H) -one,

Ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(1-methylimidazol-2-yl) thiomethyl] quinoline-3-carboxylate,

4- (3,4-dimethoxyphenyl) -2- (2-hydroxyethylthiomethyl) -6,7-dimethoxyquinazoline,

4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(4-methyl-1,2,4-triazol-3-yl) thiomethyl] quinazolin,

Ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(1-methylimidazol-2-yl) ethyl] quinoline-3-carboxylate,

Methyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-3-methoxycarbonylquinoline-2-acetate,

Ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate,

Ethyl 4- (3-isopropoxy-4-methoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate,

Ethyl 4- (3-hydroxy-4-methoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate,

Ethyl 4- (4-hydroxy-3-methoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate,

Ethyl 7-hydroxy-6-methoxy-4- (3,4-dimethoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate,

Ethyl-4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate 1-oxide or

The pharmaceutical composition of (23) above selected from ethyl 2- (N, N-diethylaminomethyl) -4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate,

(37) The pharmaceutical composition of (23), which has an immune cytokine production-inhibiting activity,

(38) the pharmaceutical composition of (23) above for the prevention or treatment of autoimmune diseases,

(39) The pharmaceutical composition of (23) above for the prevention or treatment of systemic lupus erythematosus, chronic hepatitis, interstitial liver disease, asthma, psoriasis, ulcerative colitis, Crohn's disease, local ileitis or multiple sclerosis,

(40) the pharmaceutical composition of (23) for the prevention of transplant rejection after organ transplantation,

(41) The pharmaceutical composition of (23), wherein the immunosuppressive agent is tacrolimus (FK506), cyclosporm, or methotrexate,

(42) A method for preventing or treating an autoimmune disease in a mammal, comprising administering to the mammal a therapeutically effective amount of the pharmaceutical composition of (23) above,

(43) the autoimmune disease is systemic lupus erythematosus, chronic hepatitis, interstitial liver disease, asthma, psoriasis, ulcerative colitis, Crohn's disease, local ileitis or multiple sclerosis,

(44) A method for preventing transplant rejection after transplantation of a mammal comprising administering to the mammal a therapeutically effective amount of the pharmaceutical composition of (23) above,

(45) The use of the pharmaceutical composition of the above (23) for the manufacture of a medicament for use as an immunosuppressant.

Immunosuppressants of the present invention generally relate to a class of immunosuppressive agents having a quinoline or quinazoline backbone. Manufacturing methods and their active ingredients are described, for example, in Japanese Patent Application Laid-Open No. 306052/1994 (EP-A-0567107), 118266/1995 (EP-A-0608870), and 069890/1995 (EP-A- 0634169), WO95 / 24394 and 53419/1996 (EP-A-0686630). The compounds described in these documents all have immunosuppressive activity and are advantageously used in the present invention.

In Formula I, optionally substituted hydrocarbon residues represented by R include aliphatic hydrocarbon residues, cycloaliphatic hydrocarbon residues, cycloaliphatic-aliphatic hydrocarbon residues, aromatic ring-aliphatic hydrocarbon residues and aromatic hydrocarbon residues.

The aliphatic hydrocarbon residues are C _1-8 saturated aliphatic hydrocarbon residues (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, Hexyl, isohexyl, heptyl, octyl) and C _2-8 unsaturated aliphatic hydrocarbon residues (eg, vinyl (ethenyl), 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-part Tenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl , 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadinyl, 5-hexynyl, 1-heptinyl, 1- Octinyl).

The cycloaliphatic hydrocarbon residues include C _3-7 saturated cycloaliphatic hydrocarbon residues (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) and C _5-7 unsaturated alicyclic hydrocarbon residues (eg 1-cyclophene). Tenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl and 2,4-cycloheptadienyl) is mentioned.

The cycloaliphatic-aliphatic hydrocarbon residue is a C _4-9 cycloaliphatic-aliphatic hydrocarbon residue (eg cyclopropyl) containing a combination of one of the aforementioned alicyclic hydrocarbon residues with one of the aforementioned aliphatic hydrocarbon residues. Methyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, Cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl).

The aromatic carbon ring-aliphatic hydrocarbon residues are C _7-9 phenylalkyl (eg benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl) and C _11-13 naphthyl Alkyl (for example, (alpha)-naphthyl ethyl, (beta) -naphthylmethyl, (beta) -naphthylethyl) is mentioned.

Examples of the aromatic hydrocarbon residue include phenyl and naphthyl (eg, α-naphthyl, β-naphthyl).

In Formula I, optionally substituted heterocyclic group represented by R includes (i) a 5-7 membered heterocyclic group containing 1 sulfur atom, 1 nitrogen atom or 1 oxygen atom, (ii) 2 5 or 6 membered heterocyclic groups containing 4 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. And (iv) these heterocyclic groups may be condensed with six-membered rings containing up to two nitrogen atoms, benzene rings, or five-membered rings containing one sulfur atom.

Examples of such heterocyclic groups include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-pyri Dazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyra Zolyl, isothiazolyl, 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, 1H-indazol-3-yl, 1H-pyrrolo [2,3-b] pyrazin-2-yl, 1H-pyrrolo [2,3-b] pyridin-6-yl, 1H-imidazo [4,5-b] pyridin-2-yl, 1H-imi Dazo [4,5-c] pyridin-2-yl and 1H-imidazo [4,5-b] pyrazin-2-yl.

In formula I, the optionally substituted heterocyclic group of R is preferably 2-imidazolyl or 1,2,4-triazol-3-yl.

In formula I, the hydrocarbon moiety of R is preferably CH ₂ -X ¹ -Z ¹ (X ¹ is an oxygen atom, optionally oxidized sulfur atom, or-(CH ₂ ) _m- (m is an integer from 0 to 5 Z ¹ is an optionally substituted hydrocarbon residue, an optionally substituted heterocyclic group, or an optionally substituted amino group).

The optionally substituted sulfur atom of X ¹ may be thio group, sulfinyl group and sulfonyl group, of which thi group is preferable.

X ¹ is preferably — (CH ₂ ) _m − (m is an integer from 0 to 2, preferably 0).

Optionally substituted hydrocarbon residues of Z ¹ include the same hydrocarbon residues as those exemplified above-mentioned optionally substituted hydrocarbon residues of R.

In formula I, optionally substituted heterocyclic groups of Z ¹ include the same heterocyclic groups as those exemplified above-mentioned optionally substituted heterocyclic groups of R. Of the heterocyclic groups, aromatic five-membered heterocyclic groups containing two or three hetero atoms (eg, oxygen atom, nitrogen atom, sulfur atom) are preferable, and more preferably 2-imidazolyl or 1,2, 4-triazol-3-yl.

In Formula I, the hydrocarbon residue and heterocyclic group represented by R or Z ¹ , respectively, may have 1-3 substituents at substitutable positions on the chain or ring thereof. Such 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, and optionally And a hydroxyl group substituted with an optionally substituted thiol group, an optionally esterified carboxyl group and the like.

As the hydrocarbon residue and heterocyclic group represented by R or Z ¹ , respectively, an alkyl group (preferably C _1-10 alkyl), an alkenyl group (particularly C _2-10 alkenyl), and an alkynyl group (preferably C) Linear or branched aliphatic hydrocarbon groups such as _2-10 alkynyl).

Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1 -Dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl and decyl.

Preferred alkenyl groups are vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-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.

Preferred alkynyl groups are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl Yl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.

The alicyclic hydrocarbon group referred to as a substituent of the hydrocarbon moiety and heterocyclic group represented by R or Z ¹ , respectively, is saturated or such as C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group and C _4-8 cycloalkadienyl group or An unsaturated alicyclic hydrocarbon group is included.

Preferred C _3-8 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1 Octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl and bicyclo [4.3.1] decyl.

Preferred C _3-8 cyclo alkenyl groups are C _5-7 cyclo such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl and 3-cyclohexen-1-yl Alkenyl groups.

Preferred C _4-8 cycloalkadienyl groups are C _5-7 such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl and 2,5-cyclohexadien-1-yl And cycloalkadienyl groups.

The aryl groups mentioned as substituents of the hydrocarbon moiety and heterocyclic group represented by R or Z ¹ , respectively, are monocyclic or condensed polycyclic aromatic hydrocarbon groups, preferably phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl . Especially preferred are phenyl, 1-naphthyl, 2-naphthyl and the like.

Preferred aromatic heterocyclic groups mentioned as substituents of the hydrocarbon residue and heterocyclic group represented by R or Z ¹ , respectively, are 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, pyra Aromatic monocyclic heterocyclic groups such as genyl, triazinyl and the like, and benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindoleyl, 1H-indazolyl, benzimidazolyl, benzoxa Zolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthala Genil, Naphthylzinyl, furinyl, putridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxa Thiynyl, thianthrenyl, phenanthridinyl, phenantholinyl, indolinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2 -a] pyridyl, imidazo [1, 5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4- Aromatic condensed heterocyclic groups such as triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl and the like.

Preferred non-aromatic heterocyclic groups mentioned as substituents of the hydrocarbon moiety and heterocyclic group represented by R or Z ¹ , respectively, are oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thio Oranyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, and piperazinyl.

Halogen atoms mentioned as substituents on hydrocarbon residues and heterocyclic groups represented by R or Z ¹ , respectively, include fluorine, chlorine, bromine and iodine. Especially preferred are fluorine and chlorine.

R, or an amino group mentioned as the substituent of each of the indicated hydrocarbon residue and heterocyclic group as Z ¹ is (i) an amino group, and (ii) an alkenyl group of the alkyl group, C _2-10 of C _1-10, C _2-10 alkynyl Substituted amino group having 1 or 2 substituents selected from the group of Nyl, C _1-10 acyl, C _6-10 aromatic, heterocyclic (e.g. methylamino, dimethylamino, ethylamino, diethylamino, dibutyl Amino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino).

An optionally substituted acyl group, referred to as a substituent of a hydrocarbon moiety and a heterocyclic group represented by R or Z ¹ , respectively, is (i) formyl, and (ii) alkyl of C _1-10 , alkenyl group of C _2-10 or Bonding groups of aromatic groups with carbonyl groups (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, Cyclohexanecarbonyl, cycloheptanoyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl and the like).

An optionally substituted hydroxyl group, referred to as a substituent of a heterocyclic group and a hydrocarbon moiety represented by R or Z ¹ , respectively, is a substituted hydroxide having (i) a hydroxyl group and (ii) a suitable substituent, in particular a hydroxyl group protecting group. Hydroxyl groups such as alkoxy, alkenyloxy, aralkyloxy, acyloxy and aryloxy.

The alkoxy mentioned above is a C _1-10 alkoxy group (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy , Neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.) are preferable.

The alkenyloxy is a C _2-10 alkenyloxy group (eg, allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, and 2-cyclohexenylmethoxy) It includes.

The alkynyloxy is preferably C _2-10 alkynyloxy (eg ethynyloxy, 2-propionyloxy).

Examples of such aralkyloxy are phenyl-C _1-4 alkyloxy (eg benzyloxy, phenethyloxy).

The acyloxy is preferably C _2-4 alkanoyloxy (eg, acetyloxy, propionyloxy, n-butyryloxy, isobutyryloxy).

Examples of aryloxy are phenoxy and 4-chlorophenoxy.

An optionally substituted thiol group, referred to as a substituent of a hydrocarbon moiety and a heterocyclic group, each represented by R or Z ¹ , is (i) a thiol group, and (ii) a substituted thiol group having a suitable substituent, in particular a thiol protecting group, such as Alkylthio, aralkylthio, acylthio and the like.

The alkylthio is a C _1-10 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio, isopentylthio , Neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio) are preferable.

The alkenylthio is C _2-10 alkenylthio (eg, allylthio, crotylthio, 2-pentenylthio, 3-hexenylthio, 2-cyclopentenylmethylthio and 2-cyclohexenylmethylthio) Can be mentioned.

The alkynylthio is preferably C _2-10 alkynylthio (eg, ethynylthio, 2-propionylthio).

Examples of such aralkylthios include phenyl-C _1-4 alkylthios (eg benzylthio, phenethylthio).

The acylthio is preferably C _2-4 alkanoylthio (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio).

Examples of the arylthios include phenylthio and 4-chlorophenylthio.

The optionally esterified carboxyl groups mentioned as substituents of the hydrocarbon moiety and heterocyclic group represented by R or Z ¹ , respectively, are (i) a carboxyl group, (ii) a bonding group of a carboxyl group and a C _1-6 alkyl group (ie, alkoxycarbonyl group, such as , Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl , Hexyloxycarbonyl), (iii) a bonding group of a carboxyl group with a C _3-6 alkenyl group (ie, an alkenyloxycarbonyl group such as allyloxycarbonyl, crotyloxycarbonyl, 2-pentenyloxycarbonyl , 3-hexenyloxycarbonyl), and (iv) a bonding group of a carboxyl group with an aralkyl group (ie, an aralkyloxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl).

In the above formula (I), the substituent on the hydrocarbon residue and the heterocyclic group represented by R or Z ¹ , respectively, may optionally contain one or more, preferably 1 to 3 substituents in addition to the substitutable positions.

Examples of such substituents include C _1-10 lower alkyl groups, C _2-10 lower alkenyl groups, C _2-10 lower alkynyl groups, C _3-8 cycloalkyl groups, C _3-8 cycloalkenyl groups, C _4-8 cycloalkadi Enyl group, aryl group, aromatic heterocyclic group, non-aromatic heterocyclic group, aralkyl group (e.g., aryl-C _1-6 -alkyl group, etc.), amino group, N-mono-substituted amino group, N, N-di- Substituted amino group, amidino group, acyl group, carbamoyl group, N-mono-substituted carbamoyl group (e.g. methyl carbamoyl, ethyl carbamoyl, phenylcarbamoyl), N, N-disubstituted carbamoyl group (E.g., N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, piperidinocarbamoyl, morpholinocarbamoyl), sulfamoyl group, N-mono-substituted sulfamoyl group ( For example, methylsulfamoyl, ethylsulfamoyl, phenylsulfamoyl, p-toluenesulfamoyl, N, N-di-substituted sulfamoyl groups (e.g., N, N-dimethylsulfamoyl, N-methyl-N-phenylsulfa) Mole, pipe Lidinosulfamoyl, morpholinosulfamoyl), carboxyl groups, C _1-10 lower alkoxycarbonyl groups (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl), hydroxyl group, C _1-10 lower alkoxy group, C _2-10 lower alkenyloxy group, C _3-7 cycloalkyloxy group, aralkyloxy group, Aryloxy group, mercapto group, C _1-10 lower alkylthio group, aralkylthio group, arylthio group, sulfo group, cyano group, azide group, halogen atom, nitro group, nitroso group. As examples of these substituents, mention may be made of those mentioned as substituents of the hydrocarbon moiety and heterocyclic group represented by R or Z ¹ , respectively.

In Formula I, when R is -CH ₂ -X ¹ -Z ¹ , the optionally substituted amino group of Z ¹ is -N (R ¹ ) (R ² ) (the same or different R ¹ and R ² are halogen atoms , Optionally substituted hydrocarbon, or optionally substituted heterocyclic group, or R ¹ and R ² may combine with each other to form a ring.

The optionally substituted hydrocarbon residue or optionally substituted heterocyclic group represented by R ¹ or R ² includes the same optionally substituted hydrocarbon residue or optionally substituted heterocyclic group as mentioned to exemplify the above R group. have.

R ¹ and R ² may be bonded to each other to form a ring. Examples of —N (R ¹ ) (R ² ) rings include 1-pyrrolidinyl, 1-imidazolidinyl, 1-pyrazolidinyl, 1-piperidyl, pepyrazinyl, 4-morpholinyl, 4-thiomorpholinyl, homopiperazin-1-yl, 1,2,4-triazol-1-yl, 1,3,4-triazol-1-yl, pyrazol-1-yl, imidazole -1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, tetrazol-1-yl, benzamidazol-1-yl, indole-1- 1, and 1H-indazol-1-yl can be mentioned.

The hydrocarbon residue and heterocyclic group, each represented by R ¹ or R ² , may have 1 to 3 substituents at substitutable positions on the chain or ring thereof.

Such substituents include optionally substituted hydrocarbon residues or optionally substituted heterocyclic groups, each of which is the same as those represented by the R groups. The substituent on the hydrocarbon moiety and heterocyclic group represented by R ¹ or R ² may each have one or more, preferably 1 to 3 substituents at substitutable positions.

Examples of such substituents include C _1-10 lower alkyl groups, C _2-10 lower alkenyl groups, C _2-10 lower alkynyl groups, C _3-7 cycloalkyl groups, aryl groups, aromatic heterocyclic groups, non-aromatic heterocyclic groups Group, aralkyl group, amino group, N-mono-substituted amino group, N, N-di-substituted amino group, amidino group, acyl group, carbamoyl group, N-mono-substituted carbamoyl group, N, N-di-substituted Carbamoyl group, sulfamoyl group, N-mono-substituted sulfamoyl group, N, N-di-substituted sulfamoyl group, carboxyl group, lower alkoxycarbonyl group, hydroxyl group, lower alkoxy group, lower alkenyloxy group, cycloalkyl jade And a period, aralkyloxy group, aryloxy group, mercapto group, lower alkylthio group, aralkylthio group, arylthio group, sulfo group, cyano group, azide group, nitro group and nitroso group. As examples of these substituents, mention may be made of those mentioned as substituents of an optionally substituted hydrocarbon residue and an optionally substituted heterocyclic group, each represented by R.

In Formula I, Rings A and B may each have a substituent. Such substituents include halogen atoms, nitro groups, optionally substituted C _1-10 alkyl groups, optionally substituted C _2-10 alkenyl groups, optionally substituted C _2-10 alkynyl groups, optionally substituted hydroxyl groups Optionally substituted thiol groups, optionally substituted amino groups, optionally substituted acyl groups (eg, C _1-10 alkanoyl, C _2-10 alkenoyl, C _2-10 alkinoyl), optionally esterification Carboxyl groups, and optionally substituted aromatic ring groups.

Examples of halogens mentioned as substituents for rings A and B include fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.

Examples of optionally substituted C _1-10 alkyl groups mentioned as substituents for rings A and B are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neo C _1-10 straight chain alkyl, C _3-10 branched alkyl or C _3-10 cyclic including pentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl Alkyl is mentioned. Examples of the C _1-10 alkyl group, C _2-10 alkenyl group or C _2-10 alkynyl group, which may each have 1 to 3 substituents, are optionally substituted hydrocarbon residues each represented by R or Z ¹ and optionally Mention may be made of those mentioned as substituents of the substituted heterocyclic group.

Examples of optionally substituted hydroxyl groups mentioned as substituents for rings A and B include (i) hydroxyl groups, and (ii) substituted hydroxyl groups with suitable substituents, especially hydroxyl group protecting groups such as alkoxy, Alkenyloxy, alkynyloxy, aralkyloxy and acyloxy, and aryloxy.

The alkoxy is a C _1-10 alkoxy group (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neophene Thiol octa, hexyloxy, heptyloxy, nonyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy) are preferred.

The alkenyloxy is C _2-10 alkenyloxyallyloxy (eg, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, and 2-cyclohexenylmethoxy) Include.

Examples of the alkynyloxy include C _2-10 alkynyloxy (eg, propionyloxy).

Examples of such aralkyloxy are phenyl-C _1-4 alkyloxy (eg benzyloxy, phenethyloxy).

The acyloxy is preferably C _2-4 alkanoyloxy (eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy).

Examples of such aryloxy are phenoxy and 4-chlorophenoxy.

Examples of optionally substituted thiol groups mentioned as substituents for rings A and B include (i) thiol groups, and (ii) substituted thiol groups with suitable substituents, in particular thiol protecting groups such as alkylthio, alkenylthio, Alkynylthio, aralkylthio, acylthio, arylthio, and the like.

The alkylthio is C _1-10 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio, isopentylthio, Neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio) are preferred.

The alkenylthio is C _2-10 alkenylthio (eg, allylthio, crotylthio, 2-pentenylthio, 3-hexenylthio, 2-cyclopentenylmethylthio and 2-cyclohexenylmethylthio) Can be mentioned. Examples of the alkynylthio include C _2-10 alkynylthio (eg, ethynylthio, 2-propionylthio). Examples of such aralkylthios include phenyl-C _1-4 alkylthios (eg benzylthio, phenethylthio).

The acylthio is preferably C _2-4 alkanoylthio (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio).

Examples of the arylthios include phenylthio and 4-chlorophenylthio.

Examples of the optionally substituted amino groups mentioned as substituents for rings A and B, (i) an amino group, and (ii) C _1-10 alkyl group, a C _2-10 alkenyl, C _2-10 alkynyl group, C Substituted amino group having 1 or 2 substituents selected from _1-10 acyl group, C _6-12 aromatic group, heterocyclic group and the like (e.g. methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, di Allylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino).

Examples of optionally substituted acyl groups mentioned as substituents for rings A and B include (i) formyl, and (ii) C _1-10 alkyl, C _2-10 alkenyl groups, C _2-10 alkynyl groups or C _Bonding groups of _6-12 aromatic and carbonyl groups (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentane Carbonyl, cyclohexanecarbonyl, cycloheptancarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl and the like).

Examples of optionally esterified carboxyl groups mentioned as substituents for rings A and B include (i) a carboxyl group, (ii) a bonding group of a carboxyl group and a C _1-6 alkyl group (ie, alkoxycarbonyl groups such as methoxycarbonyl, e. Oxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl) (iii) a linking group of a carboxyl group with a C _3-6 alkenyl group (ie, an alkenyloxycarbonyl group such as allyloxycarbonyl, crotyloxycarbonyl, 2-pentenyloxycarbonyl, 3-hexenyloxycarbon Carbonyl), and (iv) a bonding group of a carboxyl group with an aralkyl group (ie, an aralkyloxycarbonyl group, benzyloxycarbonyl, phenethyloxycarbonyl).

Examples of optionally substituted aromatic ring groups mentioned as substituents of rings A and B include C _6-14 aromatic hydrocarbon residues (eg phenyl, naphthyl, anthryl) and heterocyclic aromatic residues (eg pyridyl, furyl) , Thienyl, imidazolyl, thiazolyl).

Each substituent of rings A and B may be present at a substitutable position in its ring, and 1 to 4 identical or different substituents may be present.

When the substituents on ring A or B are adjacent to each other, they are bonded to each other to form-(CH ₂ ) _t -or -O- (CH ₂ ) ₁ -O- (t is an integer of 3 to 5, and l is 1 to 3 Ring), such rings include 5- to 7-membered rings formed with the carbon atoms of the benzene ring.

Preferably, ring A is substituted with one or more alkoxy groups (preferably C _1-3 alkoxy groups), more preferably one or more methoxy groups. Still more preferably ring A is substituted with two identical or different alkoxy groups (preferably C _1-3 alkoxy groups), more preferably methoxy groups. Most preferably ring A is substituted with two methoxy groups each at the 6 and 7 positions of the quinoline ring or quinazoline ring.

Preferably, ring B is substituted with one or more alkoxy groups (preferably C _1-3 alkoxy groups), more preferably one or more methoxy groups or isopropoxy groups. Even more preferably ring B is substituted with two identical or different alkoxy groups (preferably C _1-3 alkoxy groups). Most preferably ring B is substituted with a methoxy or isopropoxy at the 3 position of the quinoline ring or quinazoline ring and a methoxy group at the 4 position.

Optionally oxidized sulfur atoms represented by X are exemplified by thio groups, sulfinyl groups and sulfonyl groups, with thio groups being preferred.

In Formula I, when Y is CG, the optionally esterified carboxyl group of G is (i) a carboxyl group, (ii) a bonding group of a carboxyl group and a C _1-6 alkyl group (ie, an alkoxycarbonyl group such as methoxycarbonyl, Ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl ), (iii) a bonding group of a carboxyl group with a C _3-6 alkenyl group (ie, an alkenyloxycarbonyl group such as allyloxycarbonyl, crotyloxycarbonyl, 2-pentenyloxycarbonyl, 3-hexenyloxy Carbonyl), and (iv) a bonding group of a carboxyl group with an aralkyl group (ie, an aralkyloxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl). The aralkyl group of the aralkyloxycarbonyl group is an alkyl group (arylalkyl group) having an aryl group as a substituent. The aryl group may be phenyl and naphthyl, each may have the same substituent as the ring A. The alkyl group is preferably a lower C _1-6 alkyl group. The aralkyl group includes benzyl, phenethyl, 3-phenylpropyl, (1-naphthyl) methyl and (2-naphthyl) methyl, and benzyl, phenethyl and the like are preferable.

In Formula I, when Y is CG, the amidated carboxyl group of G is represented by -CON (R ¹ ) (R ² ) (R ¹ and R ² are the same as defined above).

In Formula I, when Y is CG, the acyl group of G is represented by -CO-R ⁴ (R ⁴ is a C _1-5 alkyl group or an aryl group). Examples of the C _1-5 alkyl group of R ⁴ include methyl, ethyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl and 1-ethylpropyl Methyl, butyl, isobutyl and pentyl are preferred. Aryl groups of R ⁴ include single ring or condensed polycyclic aromatic hydrocarbon groups, preferably C _6-14 single ring or condensed polycyclic aromatic hydrocarbon groups such as phenyl, naphthyl, anthryl and phenanthryl.

When G is a hydroxyalkyl group, examples of the alkyl group thereof include C _1-8 saturated aliphatic hydrocarbon residues mentioned to exemplify the hydrocarbon residue represented by R above. The hydroxyalkyl group is preferably -CH ₂ OH or -CH (OH) -R ⁴ (R ⁴ is the same as defined above), and R ⁴ is preferably methyl, ethyl or the like.

When G is a protective hydroxyalkyl group, the protective hydroxyalkyl group is CH ₂ OCOR ⁵ or -CH (OCOR ⁵ ) -R ⁴ (R ⁴ is the same as defined above, and R ⁵ may each have a substituent. Alkyl group, aralkyl group, or aryl group).

Examples of the alkyl group represented by R ⁵ include C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl. The aralkyl group represented by R ⁵ is a C _1-4 alkyl group (arylalkyl group) having a C _6-14 aryl group as a substituent. Examples of the aryl group include phenyl and naphthyl. Examples of the aralkyl group include benzyl, phenethyl, 3-phenylpropyl, (1-naphthyl) methyl and (2-naphthyl) methyl. Examples of the aryl group of R ⁵ are phenyl and naphthyl.

When G is a halogen atom, the halogen atom is an atom of chlorine, bromine, iodine or fluorine, with chlorine or bromine being preferred.

In the general formula (I), when Y is C-G, R and G may be bonded together to form a 5-membered ring. Such a structure is represented by the following formula (II) or (III).

Wherein R ³ represents a hydrogen atom, an optionally substituted hydrocarbon residue, or an optionally substituted heterocyclic group, and the other symbols are the same as defined above.

In the above formula II and III, optionally, when a substituted hydrocarbon residue and optionally substituted heteroaryl of R ^3, click group is a heteroaryl substituted by the R and the same optionally substituted hydrocarbon residues and optionally-mentioned to illustrate the Z ¹ Cyclic groups.

In the formula (I), Y is preferably CG, more preferably G is a C _1-6 alkoxycarbonyl group, even more preferably G is an ethoxycarbonyl group.

N in formula I is preferably 0.

In formula I k is preferably zero.

Among the compounds represented by formula I, preferred is Y being CG (G is ethoxycarbonyl), R is -CH ₂ -Z ¹ , Z ¹ is 1,2,4-triazol-1-yl, Ring A substituents are each a methoxy group at the 6 or 7 position of the quinoline ring, each substituent of Ring B is a methoxy or isopropoxy group at its 3 position, a methoxy group at the 4 position, n is 0, k is 0.

Preferred examples of the compound represented by the formula (I) include methyl 4- (3,4-dimethoxyphenyl) -2-ethyl-6,7-dimethoxyquinoline-3-carboxylate,

Ethyl 6-chloro-2-methyl-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylate,

6,7-dimethoxy-9-phenylfuro [3,4-b] quinolin-1 (3H) -one,

Ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(1-methylimidazol-2-yl) thiomethyl] quinoline-3-carboxylate,

4- (3,4-dimethoxyphenyl) -2- (2-hydroxyethylthiomethyl) -6,7-dimethoxyquinazoline,

4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(4-methyl-1,2,4-triazol-3-yl) thiomethyl] quinazolin,

Ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(1-methylimidazol-2-yl) ethyl] quinoline-3-carboxylate,

Methyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-3-methoxycarbonylquinoline-2-acetate,

Ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate,

Ethyl 4- (3-isopropoxy-4-methoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate,

Ethyl 4- (3-hydroxy-4-methoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate,

Ethyl 4- (4-hydroxy-3-methoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate,

Ethyl 7-hydroxy-6-methoxy-4- (3,4-dimethoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate,

Ethyl-4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate 1-oxide or

Ethyl 2- (N, N-diethylaminomethyl) -4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate.

Salts of compounds I of the invention are preferably pharmaceutically acceptable salts, for example salts with organic bases, salts with inorganic bases, salts with inorganic acids, salts with organic acids and with basic and acidic amino acids. Salts.

Preferred salts with inorganic bases include alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts and ammonium salts.

Preferred salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N, N'-dibenzylethylenediamine.

Preferred salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.

Preferred 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, benzenesulfonic acid and p-toluenesulfonic acid.

Preferred salts with basic amino acids include salts with arginine, lysine and ornithine. Preferred salts with acidic amino acids include salts with aspartic acid and glutamic acid. Of these salts, sodium or potassium salts are most preferred.

Compound I of the present invention or a pharmaceutically acceptable salt thereof may be a hydrate. Compound I of the present invention is disclosed in Japanese Patent Application Laid-Open No. 306052/1994 (EP-A-0567107), 118266/1995 (EP-A-0608870), 069890/1995 (EP-A-0634169), 53419/1996 (EP-A-0686630) and WO95 / 24394.

Their dosage forms can be prepared by known techniques commonly used in pharmaceutical methods.

Compound I of the present invention is formulated with pharmaceutically acceptable carriers in the form of solid preparations such as tablets, capsules, granules, powders, suppositories, or liquid preparations such as syrups and injectable preparations orally or in mammals, including humans. It can be administered parenterally.

Pharmaceutically acceptable carriers include various organic or conventionally used pharmaceutical materials, including excipients, lubricants, binders and disintegrants in solid formulations, and solvents, dissolution aids, suspending agents, tonicity agents, buffers and emollients in liquid formulations. There is an inorganic carrier substance. Other pharmaceutical additives such as preservatives, antioxidants, colorants and sweeteners may also be used as needed.

Preferred excipients include lactose, sucrose, D-mannitol, erythritol, starch, crystalline cellulose and light silicic anhydride.

Preferred lubricants include magnesium stearate, calcium stearate, talc and colloidal silica.

Preferred binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and polyvinylpyrrolidone.

Preferred disintegrants include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium and carboxymethyl starch sodium.

Preferred solvents include water for injection, alcohol, propylene glycol, macrogol, sesame oil and corn oil.

Preferred solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate.

Preferred suspending agents are surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl amino propionic acid, lecithin, benzalkonium chloride, benzetonium chloride and monostearic glycerol, and polyvinyl alcohol, polyvinylpyrrolidone Hydrophilic polymers such as sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxy ethyl cellulose and hydroxypropyl cellulose.

Preferred isotonic agents include sodium chloride, glycerol and D-mannitol.

Preferred buffers include phosphate, acetate, carbonate or citrate buffers. Preferred emollients include benzyl alcohol.

Preferred preservatives include p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dihydro acetic acid and sorbic acid.

Preferred antioxidants include sulfite and ascorbic acid.

Compound I of the present invention was low in toxicity and did not cause any mortality, for example, when observed for one week after oral administration of Compound A at a dose of 2,000 mg / kg to 6-week-old female F344 / Jcl mice. As such, Compound I of the present invention is useful as an immunosuppressive agent in mammals (eg, humans, horses, cattle, pigs, dogs, cats).

The dosage of Compound I of the present invention can be selected in a wide range depending on the subject disease, the route of administration and the condition of the patient being treated, but during normal oral administration 1 to 2,000 mg, preferably 10 to 400 mg per adult per day , Parenteral administration may be selected from 1 to 1,000 mg, preferably 1 to 100 mg. Such dosages may be administered in divided doses of about 1 to 3 times a day.

In the present invention, examples of drugs combined with a quinoline or quinazoline compound represented by the formula (I) or a pharmaceutically acceptable salt thereof include, but are not limited to, immunosuppressive agents, such as (i) T cell inhibitors, except for the quinoline or quinazoline compounds mentioned above, (ii) cell disrupting compounds, (iii) antitumor antibiotics, (iv) anti-lymphocyte immunoglobulins, and the like.

(i) T cell inhibitors are drugs that have the property of inhibiting T cell immune responses by inhibiting the production of Th1 and Th2 cytokines derived from T cells (eg, tacrolimus (FK506), cyclosporin A, cyclosporin G) Or drugs that have the property of inhibiting the activity of cytokines produced by T cells (eg, rapamycin). Thus, these drugs suppress the immune response.

(ii) Cytotoxic compounds are also used as anticancer drugs and are drugs that have a nonspecific action on active proliferating cells, ie hematopoietic stem cells, germ cells, malignant cells or lymphocytes (T lymphocytes and B lymphocytes). Inhibition of B lymphocytes inhibits cellular and humoral immune responses. Therefore, these drugs always have both myelosuppression and low fertility as well as immunosuppressive activity.

As an example of a cytotoxic compound, (1) alkylating agent, (2) nucleic acid metabolism antagonist, (3) folic acid metabolic antagonist, etc. are mentioned. ① Alkylating agents are drugs that inhibit the immune response mainly by damaging T cells or B cells through the inhibition of DNA synthesis or DNA replication. Examples of the alkylating agent include cyclophosphamide, ifosfamide, chlorambucil and the like. ② Nucleic acid metabolism antagonists that inhibit the metabolism of nucleic acids are drugs that mainly inhibit the production of antibodies by damaging T cells. Examples of the nucleic acid metabolic antagonist include 6-mercaptopurine, azathiopurine, 6-thioguanine, 5-fluorouracil, cytosine arabinoside, mizoribin, and the like. ③ Folate metabolism antagonists that inhibit the metabolism of folic acid are drugs that have the property of inhibiting antibody production mainly by damaging T cells. Examples of folic acid metabolic antagonists include methotrexate.

(iii) Anti-tumor antibiotics are drugs that have the property of inhibiting DNA or RNA synthesis as a result of damage to T cells or B cells. Examples of anti-tumor antibiotics include adriamycin, daunomycin and the like.

(iv) Anti-lymphocyte immunoglobulins are drugs that inhibit the immune response mainly by damaging T cells. Examples of anti-lymphocyte immunoglobulins include anti-CD3 antibodies, anti-CD4 antibodies, anti-CD5 antibodies, anti-IL-2 receptor antibodies and the like.

On the other hand, the quinoline or quinazoline compounds represented by the formula (I) of the present invention are specific for the production of Th1 cytokines such as interferon-γ (IFN-γ) and interleukin-2 (IL-2) in cytokines derived from T cells. It is a drug having the property of inhibiting the immune response of T cells by inhibition. Thus, the inhibition mechanism of the quinoline or quinazoline compounds represented by formula (I) is different from the immunosuppressive agents mentioned above.

Especially preferred in the present invention are pharmaceutical compositions containing a quinoline or quinazoline compound represented by formula (I) in combination with tacrolimus (FK506), methotrexate or cyclosporin A, in particular tacrolimus (FK506), or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition of the present invention containing a quinoline or quinazoline compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in combination with an immunosuppressive agent, except for the above-mentioned quinoline or quinazoline compounds provided according to the invention, each active ingredient All may be mixed together or independently of a physiologically acceptable carrier, excipient, binder, diluent, and the like, and the mixture may be used by oral or parenteral administration, respectively, as a pharmaceutical composition. When the active ingredients are combined independently, each combination may be administered in admixture immediately using diluents or the like, or may be administered separately to the same patient at the same time or staggered with each other.

The dosage form of the pharmaceutical composition may be in oral dosage forms such as granules, powders, tablets, capsules, syrups, emulsifiers, suspensions and the like, and injections (e.g., subcutaneous, intravenous, intramuscular and intraperitoneal), infusion, external application forms (e. Parenteral dosage forms such as nasal sprays, transdermal preparations, ointments, and the like, and suppositories (eg, rectal and vaginal suppositories).

These dosage forms can be prepared by known techniques conventionally used according to pharmaceutical methods.

To prepare oral dosage forms, for example, excipients (eg, lactose, sucrose, starch, mannitol, etc.), disintegrants (eg, calcium carbonate, carboxymethylcellulose, etc.), binders (eg, α-starch, gum arabic, Carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, trehalose, and the like), and a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) are added to the active ingredient and the resulting composition is compressed. If necessary, the compact is coated by known techniques for masking the taste, dissolving in the intestine or for sustained release. Coating materials that can be used are, for example, ethylcellulose, hydroxymethylcellulose, polyoxyethylene glycol, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, and eudragit (Rom & Hasa, Germany, methacryl-acrylic copolymer) Can be mentioned.

Injections can typically be prepared by the following method.

The active ingredient may be a dispersant (e.g., Toone 80 (Atlas powder, USA), HCO 60 (Nico Chemical), polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.), preservatives (e.g. methyl p-hydroxybenzoate, propyl p Aqueous carriers (e.g. distilled water, saline, Ringer's solution, etc.) with hydroxybenzoate, benzyl alcohol, chlorobutanol, phenol, etc., isotonic agents (e.g. sodium chloride, glycerol, sorbitol, glucose, invert sugar) and other additives ) Or an oily carrier (eg, vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, or propylene glycol), or suspended or emulsified. If desired, solubilizers (eg sodium salicylate, sodium acetate, etc.), stabilizers (eg human serum albumin), emollients (eg benzalkonium chloride, procaine hydrochloride, etc.) and other additives may also be added. .

Dosage forms for external preparations can be prepared by processing the active ingredient into a solid, semi-solid, or liquid composition. For example, to prepare a solid composition, the active ingredient may be mixed as such or mixed with excipients (eg, lactose, mannitol, starch, microcrystalline cellulose, sucrose, etc.), thickening agents (eg, natural rubber, cellulose derivatives, acrylic polymers, etc.). Process into powder

Liquid compositions can be prepared in substantially the same manner as the aforementioned injections. The semisolid composition is preferably provided in hydrated or oily gel form or ointment form. These compositions may optionally contain pH adjusting agents (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), and preservatives (eg, p-hydroxybenzoic acid esters, chlorobutanol, benzalkonium chloride, etc.), among other additives. There is also.

Suppositories can be prepared by processing the active ingredients into oily or aqueous compositions which are solid, semisolid or liquid. Oily bases that can be used are, for example, higher fatty acid glycerides (eg, cacao butter, witepsol (dynamite-nobel, etc.), mid-chain fatty acids (eg, migriol (dynamite-nobel, etc.), vegetable oils [eg, , Sesame oil, soybean oil, cottonseed oil, etc.]. Examples of the water-soluble base include polyethylene glycol and propylene glycol. As a hydrophilic base, natural rubber, a cellulose derivative, a vinyl polymer, an acrylic polymer, etc. are mentioned, for example.

The pharmaceutical composition of the present invention can be safely used in mammals (eg, humans, mice, mice, rabbits, cats, cattle, horses, pigs, monkeys) because of low toxicity.

The dosage of the pharmaceutical composition of the present invention may be appropriately determined according to the dosage recommended for each active ingredient, and among other factors, the patient, the patient's age, weight, current clinical condition, time of administration, dosage form, method of administration And the combination of the active ingredients. Preferred frequency of administration is 1-3 times a day.

The proportion of active ingredient in the pharmaceutical composition of the present invention may be appropriately selected depending on the patient, age and weight of the patient, current clinical condition, time of administration, dosage form, administration method, and combination of active ingredients, among other factors. For example, a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof (e.g. Compound A or B) and tacrolimus (FK506), one of T cell inhibitors, are combined and administered to a human, and tacrolimus (FK506) is It is usually used in a ratio of about 0.001 to 10 parts by weight, preferably about 0.01 to 1 part by weight based on 1 part by weight of the compound or salt thereof. For example, a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof (e.g. Compound A or B) and cyclosporin A, one of the T cell inhibitors, is combined and administered to a human, and cyclosporin A is administered to the compound or It is usually used in a ratio of about 0.01 to 100 parts by weight, preferably about 0.1 to 10 parts by weight, based on 1 part by weight of the salt thereof. For example, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and methotrexate, a metabolic antagonist to folic acid, is administered to a human, wherein methotrexate is typically from about 0.0001 to 1 to 1 part by weight of the compound or salt thereof Parts by weight, preferably about 0.001 to 0.1 parts by weight.

The pharmaceutical compositions of the present invention show a significant synergistic effect compared to the single administration of each active ingredient. For example, as compared to the case where each of these active ingredients is administered to a patient with an immune related disease, the combination of these active ingredients significantly improves both efficacy and toxicity. Therefore, the pharmaceutical composition of the present invention improves the disease of the immune response more effectively than when the drug of each component is administered alone, and therefore, prevents and treats diseases related to immunity including autoimmunity and rejection after transplantation. It can be used advantageously for the prevention of.

Moreover, the pharmaceutical compositions of the present invention exhibit excellent efficacy at reduced dosages compared to the administration of any of the active ingredients alone, and side effects of each ingredient (eg, nephrotoxicity, myelosuppression, pneumonia, etc.) can be suppressed. Can be.

The immunosuppressant of the present invention specifically inhibits the production of immune cytokines [eg, interleukin- (IL-2), interferon- [gamma] (IFN- [gamma]). It is useful for the treatment or prevention of diseases regarded as relevant. Such diseases include systemic lupus erythematosus, ulcerative colitis, Crohn's disease, multiple sclerosis, psoriasis, chronic hepatitis, gallbladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colon cancer, rectal cancer, Helicobacter pylori infection, Hodgkin's disease, insulin dependent diabetes mellitus, malignant melanoma, multiple myeloma, non-Hodgkin's lymphoma, large cell lung cancer, ovarian cancer, peptic ulcer, prostate cancer, septic shock, tuberculosis, infertility, arteriosclerosis, Bethet syndrome , Acute dermatitis, nephritis, systemic fungal infection, acute bacterial meningitis, acute myocardial infarction, acute pancreatitis, acute viral encephalitis, adult respiratory distress, bacterial pneumonia, chronic pancreatitis, herpes simplex viral infection, chickenpox Herpes viral infections, AIDS, human papilloma virus infections, influenza, invasive staphylococcal infections, peripheral vascular disease, sepsis, interstitial liver disease, bureau Korean ileitis and multiple sclerosis, systemic lupus erythematosus, chronic hepatitis, interstitial liver disease, asthma, psoriasis, ulcerative colitis, Crohn's disease, local ileitis and multiple sclerosis. Immunosuppressants of the invention are also useful for the prevention of transplant rejection reactions after organ transplantation.

Brief description of the drawings

Figure 1 shows the effect of simultaneous administration of compound A and tacrolimus (FK506) on body weight change in mice with adjuvants arthritis.

2 shows the effect of simultaneous administration of Compound A and methotrexate on weight change in rats with adjuvant arthritis.

Best Mode for Carrying Out the Invention

The immunosuppressive activity of the pharmaceutical compositions of the present invention is described below with reference to the following experimental examples.

Experimental Example 1

Effects on Interleukin-2 (IL-2) and Interferon-γ Production by Rat Splenocytes

The cytokines produced by T cells, interleukin-2 and interferon-γ, each exhibit various activities, including T cell growth and macrophage activation, and play a major role in immune responses. Inhibition of production of these cytokine families is a good indicator of immunosuppressive activity.

i) experimental materials and methods

Splenocytes were isolated from the spleen of Lewis rats (male, 8 weeks old), suspended in RPMI-1640 (containing penicillin, streptomycin and 2-mercaptoethanol) supplemented with 5% fetal bovine serum, and 2 μg / ml cocana Incubate 1 × 10 ⁷ splenocytes for 24 hours in the presence of valine A. After the incubation is complete, the supernatant is collected. The IL-2 content in the supernatant is measured by ³ H-thymidine insertion as an index by diluting the culture supernatant 50-fold and the growth of CTLL-2 cells, ie the growth response of IL-2 dependent cell lines, is performed. IFN- [gamma] content is measured by commonly known methods using an ELISA kit (GIBCO PBL, USA).

ii) results

Compounds A and B both inhibit IL-2 and IFN-γ production dependently.

density Interleukin-2 Interleukin-γ μM cpm % Inh. ng / ml % Inh. badge 39,093 ± 4,755 54.8 ± 2.9 Compound A One 32,202 ± 752 18% 36.6 ± 2.7 ** 33% 10 22,273 ± 1,088 ** 43% 27.9 ± 0.7 ** 49% 100 446 ± 78 ** 99% 1.1 ± 0.6 ** 98% Compound B One 34,355 ± 1,744 12% 53.2 ± 4.0 3% 10 18,955 ± 661 ** 52% 36.6 ± 1.7 ** 33% 100 248 ± 14 ** 100% 1.0 ± 0.8 ** 98% Data represent 3 means ± standard deviation. *: P <0.05 vs. no drug control **: p <0.01 vs. drug not administered control

Experimental Example 2

Action on interleukin-2 and interferon-γ production by antigen-stimulated mouse T-lymphocytes

i) experimental materials and methods

Lymphocytes were isolated from lymph nodes of Balb / c mice 10 days after sensitization with egg albumin (OVA, 100 μg) and suspended in RPMI-1640 (containing penicillin and streptomycin) supplemented with 10% fetal bovine serum. Lymph node cells were alternately incubated with splenocytes in the presence of 50 μg / ml OVA and in the presence of 20 ng / ml IL-2 from X ray irradiated mice with the same line to obtain OVA-reactive T cell lines, Reactive T cell clones were obtained by limiting dilution assay. Allo-reactive T cell lines were prepared from X-ray irradiated A / J mice by alternately culturing Balb / c mouse splenocytes in the presence of splenocytes and in the presence of 20 ng / ml IL-2.

To assess drug effects, in the presence of 50 μg / ml OVA for 48 hours for non-cell and OVA-reactive T cells from X-ray irradiated mice with the same line and for 24 hours for allo-reactive T cells X-rayed A / J mice were incubated with each drug in the presence of splenocytes. Thereafter, IFN-γ and IL-2 contents in the supernatant were measured by ELISA (according to the same method as mentioned in Experimental Example 1).

ii) results

Compound A significantly inhibited IFN-γ by OVA-reactive T cell lines, OVA-reactive T cell clones and allo-reactive T cell lines at concentrations above 1 μM and also allo-reactive T at concentrations above 1 μM. Significantly inhibited IL-2 production by cell lines (Table 2).

Cytokines Compound A (μM) 0.1 One 10 OVA-Reactive T Cell Line A IFN-γ 27 43 * 72 ** OVA-Reactive T Cell Line B IFN-γ 17 36 * 98 ** OVA-reactive T cell line clone 5A7 IFN-γ ND 35 * 71 ** OVA-reactive T cell line clone 5E3 IFN-γ ND 38 * 69 ** Allo-Reactive T Cell Line A IFN-γ ND 28 * 38 * IL-2 ND 25 * 63 * Allo-Reactive T Cell Line B IFN-γ 11 22 * 30 ** IL-2 ND 26 * 45 ** Data indicate percent inhibition. *: P <0.05 vs. control without drug **: p <0.01 vs. control without drug ND: not performed

Experimental Example 3

Action on Rat Adjuvant Arthritis

Six male Lewis rats (7 weeks old) per group are injected intradermal with 0.05 ml of Freund's complete adjuvant (0.5% liquid paraffin suspension of dead Mycobacterium fungal cells) in the right hind paw (day 0).

Compound A (3.13 mg / kg / day or 12.5 mg / kg / day), tacrolimus (FK506) (0.63 mg / kg / day) in suspension in 0.5% methyl cellulose 5-6 times weekly, immediately before sensitization, up to 30 days And methotrexate (0.05 mg / kg / day) alone or simultaneously. Immediately before the onset of sensitization (day 0) and on days 14 and 18, the volume of the left hind paw was measured in comparison with non-sensitized rats to obtain a swelling inhibition rate. Body weights were measured immediately prior to dosing and weight gain was observed compared to non-sensitized rats (see FIGS. 1 and 2).

The results are expressed as mean ± standard deviation for each group (N = 6) and compared by Student's t-test at significance level <5%.

As shown in Table 3, simultaneous administration of Compound A and tacrolimus (FK506), or Compound A and methotrexate shows a more potent action in terms of edema inhibition compared to administration of each drug alone.

In particular, co-administration of compound A with tacrolimus (FK506) on day 18, and compound A with methotrexate on day 18, in terms of action in terms of suppression of edema, resulted in a significant effect over the sum of the effects of both drugs. As can be seen from Figures 1 and 2, simultaneous administration of Compound A with tacrolimus (FK506), or Compound A with methotrexate showed a very potent effect in terms of weight change (increase) compared to single administration of each drug.

Dosage Form (mg / kg) Swelling inhibition rate (%) 14 days 18 days I) Compound A 3.13FK 506 0.63 Concurrent Administration (Compound A + FK506) 34 * 55 ** 98 ** 31 * 42 ** 100 ** II) Compound A 12.5 methotrexate 0.05 concurrent administration (Compound A + methotrexate) 4083 ** 100 ** 373788 ** *: p <0.05 vs. no drug control **: p <0.01 vs. no drug control

The present invention is explained in more detail by the following working examples and reference examples, but the present invention is not limited thereto.

Reference Example 1

Preparation of N- (3,4-dimethoxyphenyl) acetamide

3,4-dimethoxyaniline (100 g) is suspended in H ₂ O (800 ml) and NaOH (34.0 g / 200 ml) and acetic anhydride (86.6 g) are added to 1/5 portions at 65 ° C. alternately. The mixture is stirred at 55-60 ° C. for about 20 minutes. After cooling the reaction mixture to about 5 ° C. and stirring for 1 hour, the obtained crystals were collected by filtration and dried under reduced pressure to give 119 g (93.2% recovery) of N- (3,4-dimethoxyphenyl) acetamide as brown crystals. To obtain.

Samples for IR and ¹ H-NMR measurements are obtained by recrystallization from ethyl acetate.

IR (cm ^-1 , KBr): 3276, 1653, 1606, 1575, 1520, 1462

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.15 (3H, s), 3.84 (6H, s), 6.78 (1H, d, J = 8.6 Hz), 6.88 (1H, dd, J = 8.6, 2.4 Hz), 7.30 (1H, d, J = 2.4 Hz), 7.55 (1H, brs)

Reference Example 2

Preparation of 2-acetylamino-3 ', 4,4', 5-tetramethoxybenzophenone

N- (3,4-dimethoxyphenyl) acetamide (114 g), 3,4-dimethoxybenzoic acid (117 g) and polyphosphoric acid (1,203 g) are stirred at 95 to 110 ° C. for 3 hours. After addition of cold water (3 liters), the reaction mixture is extracted with ethyl acetate (3 liters) and the extract is washed with an aqueous solution of 2 N NaOH (3 liters) followed by water (3 liters).

After the reaction mixture was concentrated under reduced pressure, n-hexane (1.2 liter) was added to the residue, followed by stirring at about 5 ° C. for 30 minutes. The obtained crystals were collected by filtration and then dried under reduced pressure to yield 129 g (61.3% of recovery) of 2-acetylamino-3 ', 4,4', 5-tetramethoxybenzophenone as yellow crystals.

Samples for IR and ¹ H-NMR measurements are obtained by recrystallization from ethyl acetate.

IR (cm ^-1 , KBr): 2947, 1695, 1678, 1616, 1595

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.22 (3H, s), 3.76 (3H, s), 3.94 (3H, s), 3.98 (3H, s) 4.00 (3H, s), 6.93 (1H , d, J = 7.7 Hz, 7.09 (1H, s), 7.28 (1H, dd, J = 7.7, 1.9 Hz), 7.32 (1H, s), 8.38 (1H, s), 11.0 (1H, brs)

Reference Example 3

Preparation of 2-amino-3 ', 4,4', 5-tetramethoxybenzophenone hydrochloride

2-acetylamino-3 ', 4,4', 5-tetramethoxybenzophenone (129 g) in isobutanol (1.49 liters) is added to concentrated hydrochloric acid (446 ml) and then refluxed thermally for 2 hours. After cooling the reaction mixture, the mixture was stirred at about 5 ° C. for 2 hours, and the obtained crystals were collected by filtration and dried under reduced pressure to yield 117 g (92.3% of 2-amino-3 ′, 4,4 ′) as yellowish white crystals. , 5-tetramethoxybenzophenone hydrochloride is obtained.

Samples for IR and ¹ H-NMR measurements are obtained by recrystallization from EtOH.

IR (cm ^-1 , KBr): 3618, 2839, 2567, 1657, 1628, 1583

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 3.58 (3H, s), 3.80 (6H, s), 3.85 (3H, s), 3.61 (1H, brs) 6.93 (1H, s), 7.06 (1H, d, J = 8.6Hz), 7.20-7.22 (2H, m)

Reference Example 4

36.0 g of 2-amino-3 ', 4,4', 5-tetramethoxybenzophenone hydrochloride and 21.4 g of ethyl ester of 4-chloroacetoacetic acid are refluxed for 7 hours with stirring in 350 ml of ethanol. After the reaction was completed, 10.6 g of triethylamine was added dropwise to 20 ° C, followed by stirring at 5 ° C for 1 hour. The obtained crystals were filtered, washed twice with 50 ml of ethanol and dried under reduced pressure to give 41.0 g (92% recovery) of 2-chloromethyl-4- (3,4-dimethoxyphenyl) -6,7-dimeth Ethyl ester of oxyquinoline-3-carboxylic acid is obtained.

Reference Example 5

4-amino-1- [4- (3,4-dimethoxyphenyl) -3-ethoxycarbonyl-6,7-dimethoxyquinolin-2-ylmethyl] -4H-1,2,4-triazolium Preparation of Bromide

Ethyl ester of 2-chloromethyl-4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylic acid (22.5 g, content ratio 99.1%, 50.0 mmol), sodium bromide (5.81 g, 56.5 mmol) and 4-amino-1,2,4-triazole (5.47 g, 65.1 mmol) are suspended in DMF (50 ml) and stirred at 65 ° C. for 3 hours.

Ethyl acetate (100 ml) was added to the reaction mixture, and the obtained crystals were collected by filtration and dried to give 4-amino-1- [4- (as white crystals (31.1 g, content ratio 83.6%, recovery 90.6%). 3,4-dimethoxyphenyl) -3-ethoxycarbonyl-6,7-dimethoxyquinolin-2-ylmethyl] -4H-1,2,4-triazolium bromide is obtained.

Samples for structural confirmation are purified by silica gel column chromatography (mobile phase CH ₂ Cl ₂ : MeOH = 5: 1) and recrystallization (4.8% hydrated EtOH).

IR (cm ^-1 , KBr): 3196, 1706, 1518, 1472

¹ H-NMR (DMSO-d ₆ , 90 MHz) δ: 0.92 (3H, t, J = 6.9 Hz, CO ₂ CH ₂ CH ₃ ), 3.72 (3H, s, OMe), 3.77 (3H, s, OMe ), 3.86 (3H, s, OMe), 3.96 (3H, s, OMe), 3.72-4.09 (2H, m, CO ₂ CH ₂ ), 5.94 (2H, s, CH ₂ N), 6.93-7.31 (7H , m), 9.28 (1H, s, CH = N), 10.41 (1H, s, CH = N)

Analytical calcd. For C ₂₅ H ₂₈ N ₅ O ₅ Br (0.73 H ₂ O): C, 51.10, H, 5.05, N, 11.92, Br, 13.60

Found: C, 51.10, H, 4.91, N, 11.88, Br, 13.55

Melting Point: 183.8-184.4 ℃

Reference Examples 6 to 12

The reaction is carried out in the same manner using the same starting quinoline and triazole compounds as used in Reference Example 5 in a 1: 1: 3 molar ratio, except that different reaction solvents and additives are used.

The results are shown in Table 4 (percent area ratio to HPLC peaks identified by the reaction mixture).

Reference example number Reaction solvent [molarity (M)] additive Reaction conditions Percent area ratio to HPLC peak (%) collection(%) Temperature (℃) Elapsed time (h) Desired product Starting material 6 CH ₃ CN [0.5] - 100 15 87.5 6.6 93.7 7 CH ₃ CN [0.6] NaBr 70 3.0 61.2 34.8 93.9 8 EtOH [0.2] - 100 15 48.7 46.4 90.9 9 i-PrOH [0.2] - 80-100 7-12 38.6 58.1 92.1 10 DMF [1.0] - 80-100 8-12 88.6 0.2 88.8 11 DMF [1.0] NaI 70 1.5 88.1 - 88.1 12 DMF [1.0] NaBr 70 3.0 94.1 0.01 94.1

Reference Example 13

Preparation of ethyl ester of 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid

4-amino-1- [4- (3,4-dimethoxyphenyl) -3-ethoxycarbonyl-6,7-dimethoxyquinolin-2-ylmethyl] -4H-1,2,4-triazolium Bromide (10.31 g, content ratio 83.6%, 15.0 mmol) is suspended in H ₂ O (37.5 ml), and under ice-cooling conditions, concentrated hydrochloric acid (3.8 ml, 45 mmol) and NaNO ₂ 5.6 M aqueous solution (4.00 ml, 22.5 mmol) ) Is added and then stirred at room temperature for 2 hours.

After neutralizing by adding 5 N aqueous NaOH solution (8.7 ml) to the reaction mixture, the obtained crystals were collected by filtration and washed with water to obtain 6.66 g (92.8% recovery) of 4- (3,4-dimethoxy as white crystals. Ethyl ester of phenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid is obtained.

IR (cm ^-1 , KBr): 1720, 1504, 1468, 1430

¹ H-NMR (CDCl ₃ , 90 MHz) δ: 0.89 (3H, t, J = 7.1 Hz, CO ₂ CH ₂ CH ₃ ), 3.79 (3H, s, OMe), 3.86 (3H, s, OMe), 3.96 (3H, s, OMe), 4.04 (3H, s, OMe), 3.86-4.13 (2H, q, J = 7.1 Hz, CO ₂ CH ₂ ), 5.72 (2H, s, CH ₂ N), 6.86- 6.95 (4H, m), 7.41 (1H, s), 7.93 (1H, s), 8.23 (1H, s)

Melting Point: 175.4-176.0 ℃

Reference Example 14

Preparation of ethyl ester of 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid

4-amino-1- [4- (3,4-dimethoxyphenyl) -3-ethoxycarbonyl-6,7-dimethoxyquinolin-2-ylmethyl] -4H-1,2,4-triazolium Bromide (503 g, content ratio 80.9%, 0.709 mmol) is suspended in H ₂ O (5.44 liters), and under ice-cooling conditions, concentrated hydrochloric acid (159 g, 1.56 mol) and NaNO ₂ 0.63 M aqueous solution (1.46 liters, 0.920 mol) ) Is added and then stirred at room temperature for 3 hours.

After neutralizing by adding 5 N aqueous NaOH solution (295 ml) to the reaction mixture, the obtained crystals were collected by filtration and washed with water to obtain 329 g (97.0% recovery) of 4- (3,4-dimethoxyphenyl) as white crystals. Ethyl ester of) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid is obtained.

Example 1

Composition (per tablet) 12.5 mg tablets 25 mg tablets 50 mg tablets 100 mg tablets (1) Compound A 12.5 mg 25.0 mg 50.0 mg 100.0 mg (2) lactose 133.13 120.63 95.63 45.63 (3) corn starch 26.7 26.7 26.7 26.7 (4) hydroxypropyl cellulose 5.7 5.7 5.7 5.7 (5) croscarmellose sodium 9.5 9.5 9.5 9.5 (6) Macrogol 6000 1.9 1.9 1.9 1.9 (7) magnesium stearate 0.57 0.57 0.57 0.57 all 190.0 mg 190.0 mg 190.0 mg 190.0 mg

In a granulator (Powrex Co. Model FD-5S, FV-25: Japan), 75 g of the component (1), 798.8 g of the component (2) and 160.2 g of the component (3) were used as the binding solution. Granulate with g aqueous solution. After drying and reducing the size, 961.4 g of granules are mixed with 51.3 g of component (5), 10.26 g of component (6) and 3.08 g of component (7) to obtain a powder mixture. The powder mixture is compressed into tablets using a known tableting machine to obtain a tablet formulation having a diameter of 8.0 mm and a weight of 190 mg, containing 12.5 mg of component (1).

The tablets obtained all had excellent tableting properties including hardness, disintegration and solubility.

The immunosuppressive compound represented by Formula I of the present invention or a pharmaceutically acceptable salt thereof can be used to prevent or treat diseases considered safe, low toxic, and related to immunity, including autoimmune diseases, and organ transplantation. It can then be used to prevent transplant rejection.

In addition, the pharmaceutical composition containing the quinoline or quinazoline compound represented by the formula (I) of the present invention, and an immunosuppressive agent except for such quinoline or quinazoline compound, is more than the total effect of all drugs compared to when each drug is administered alone. It has a remarkable effect.

Therefore, the present pharmaceutical composition, if the drug combination, the method of administration, the dosage, and the like are appropriately selected according to the symptoms, the side effects are small even during long-term administration, and to prevent or treat diseases considered to be immune-related, including autoimmunity. It can also be used to prevent transplant rejection after organ transplantation.

Claims (45)

An immunosuppressive agent containing as an active ingredient a compound represented by formula (I) or a pharmaceutically acceptable salt thereof: [Formula I] Wherein Y is a nitrogen atom or CG (G is an optionally esterified or amidated carboxyl group, acyl group, optionally protected hydroxyalkyl group, or halogen atom); R is an optionally substituted hydrocarbon residue or Optionally substituted heterocyclic group; X is an oxygen atom or optionally oxidized sulfur atom; n is 0 or 1; k is 0 or 1; G and R may join together to form a ring Ring A and B may each have a substituent). 2. The compound of claim 1, wherein n is 0 and the optionally substituted hydrocarbon residue represented by R is -CH ₂ -X ¹ -Z ¹ (X ¹ is an oxygen atom, optionally oxidized sulfur atom, or-(CH ₂ ) _m -(m is an integer from 0 to 5); Z ¹ is a hydrogen atom, an optionally substituted hydrocarbon residue, an optionally substituted heterocyclic group, or an optionally substituted amino group). The immunosuppressive agent of claim 2 wherein m is 0, provided that X ¹ is-(CH ₂ ) _m- . 2. An immunosuppressive agent according to claim 1, wherein the optionally substituted heterocyclic group represented by Z ¹ is an aromatic 5 membered heterocyclic group containing 2 or 3 heteroatoms. The immunosuppressive agent of claim 1, wherein Y is C-G. The immunosuppressive agent according to claim 5, wherein G is a C _1-6 alkyloxycarbonyl group. The immunosuppressant according to claim 1, wherein G is an ethoxycarbonyl group. 2. An immunosuppressive agent according to claim 1, wherein ring A is substituted with at least one alkoxy group. 2. An immunosuppressive agent according to claim 1, wherein ring A is substituted with two methoxy groups. 2. The immunosuppressive agent of claim 1, wherein ring A is substituted with two methoxy groups each at the 6 and 7 positions of the quinoline ring or quinazoline ring. 2. An immunosuppressive agent according to claim 1, wherein ring B is substituted with at least one alkoxy group. 2. An immunosuppressive agent according to claim 1, wherein ring B is substituted with two same or different alkoxy groups. 2. The immunosuppressive agent of claim 1, wherein k is zero. The compound of claim 1 wherein Methyl 4- (3,4-dimethoxyphenyl) -2-ethyl-6,7-dimethoxyquinoline-3-carboxylate, Ethyl 6-chloro-2-methyl-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylate, 6,7-dimethoxy-9-phenylfuro [3,4-b] quinolin-1 (3H) -one, Ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(1-methylimidazol-2-yl) thiomethyl] quinoline-3-carboxylate, 4- (3,4-dimethoxyphenyl) -2- (2-hydroxyethylthiomethyl) -6,7-dimethoxyquinazoline, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(4-methyl-1,2,4-triazol-3-yl) thiomethyl] quinazolin, Ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(1-methylimidazol-2-yl) ethyl] quinoline-3-carboxylate, Methyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-3-methoxycarbonylquinoline-2-acetate, Ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate, Ethyl 4- (3-isopropoxy-4-methoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate, Ethyl 4- (3-hydroxy-4-methoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate, Ethyl 4- (4-hydroxy-3-methoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate, Ethyl 7-hydroxy-6-methoxy-4- (3,4-dimethoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate, Ethyl-4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate 1-oxide or An immunosuppressive agent selected from ethyl 2- (N, N-diethylaminomethyl) -4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate. The immunosuppressive agent according to claim 1, which has an immune cytokine production-inhibiting activity. 2. An immunosuppressive agent according to claim 1 for the prevention or treatment of autoimmune diseases. 2. An immunosuppressive agent according to claim 1 for the prevention or treatment of systemic lupus erythematosus, chronic hepatitis, interstitial liver disease, asthma, psoriasis, ulcerative colitis, Crohn's disease, local ileitis or multiple sclerosis. 2. The immunosuppressive agent of claim 1 for the prevention of transplant rejection after organ transplantation. A method of preventing or treating an autoimmune disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. 20. The method of claim 19, wherein the autoimmune disease is systemic lupus erythematosus, chronic hepatitis, interstitial liver disease, asthma, psoriasis, ulcerative colitis, Crohn's disease, local ileitis or multiple sclerosis. A method for preventing a transplant rejection response following a transplantation of a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use as an immunosuppressive agent. A pharmaceutical composition comprising a quinoline or quinazoline compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and an immunosuppressive agent except for the quinazoline compound: [Formula I] Wherein Y is a nitrogen atom or CG (G is an optionally esterified or amidated carboxyl group, acyl group, optionally protected hydroxyalkyl group, or halogen atom); R is an optionally substituted hydrocarbon residue or Optionally substituted heterocyclic group; X is an oxygen atom or optionally oxidized sulfur atom; n is 0 or 1; k is 0 or 1; G and R may join together to form a ring Ring A and B may each have a substituent). The compound of claim 23, wherein n is 0 and the optionally substituted hydrocarbon residue represented by R is —CH ₂ —X ¹ —Z ¹ (X ¹ is an oxygen atom, an optionally oxidized sulfur atom, or — (CH ₂ ) _m and (m is an integer from 0 to 5); Z ¹ is a hydrogen atom, an optionally substituted hydrocarbon residue, an optionally substituted heterocyclic group, or an optionally substituted amino group). The pharmaceutical composition of claim 24, wherein m is 0, provided that X ¹ is-(CH ₂ ) _m- . The pharmaceutical composition of claim 23, wherein the optionally substituted heterocyclic group represented by Z ¹ is an aromatic 5 membered heterocyclic group containing 2 or 3 heteroatoms. The pharmaceutical composition of claim 23, wherein Y is C-G. The pharmaceutical composition according to claim 23, wherein G is a C _1-6 alkyloxycarbonyl group. The pharmaceutical composition according to claim 23, wherein G is an ethoxycarbonyl group. The pharmaceutical composition of claim 23, wherein ring A is substituted with at least one alkoxy group. The pharmaceutical composition of claim 23, wherein ring A is substituted with two methoxy groups. 24. The pharmaceutical composition of claim 23, wherein ring A is substituted with two methoxy groups each at the 6 and 7 positions of the quinoline ring or quinazoline ring. The pharmaceutical composition of claim 23, wherein ring B is substituted with at least one alkoxy group. The pharmaceutical composition of claim 23, wherein ring B is substituted with two same or different alkoxy groups. The pharmaceutical composition of claim 23, wherein k is zero. The compound of claim 23 wherein the compound represented by formula I is Methyl 4- (3,4-dimethoxyphenyl) -2-ethyl-6,7-dimethoxyquinoline-3-carboxylate, Ethyl 6-chloro-2-methyl-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylate, 6,7-dimethoxy-9-phenylfuro [3,4-b] quinolin-1 (3H) -one, Ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(1-methylimidazol-2-yl) thiomethyl] quinoline-3-carboxylate, 4- (3,4-dimethoxyphenyl) -2- (2-hydroxyethylthiomethyl) -6,7-dimethoxyquinazoline, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(4-methyl-1,2,4-triazol-3-yl) thiomethyl] quinazolin, Ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(1-methylimidazol-2-yl) ethyl] quinoline-3-carboxylate, Methyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-3-methoxycarbonylquinoline-2-acetate, Ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate, Ethyl 4- (3-isopropoxy-4-methoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate, Ethyl 4- (3-hydroxy-4-methoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate, Ethyl 4- (4-hydroxy-3-methoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate, Ethyl 7-hydroxy-6-methoxy-4- (3,4-dimethoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate, Ethyl-4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate 1-oxide or Pharmaceutical composition selected from ethyl 2- (N, N-diethylaminomethyl) -4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition has immune cytokine production-inhibiting activity. The pharmaceutical composition of claim 23 for the prevention or treatment of autoimmune diseases. The pharmaceutical composition of claim 23 for the prevention or treatment of systemic lupus erythematosus, chronic hepatitis, interstitial liver disease, asthma, psoriasis, ulcerative colitis, Crohn's disease, localized ileitis or multiple sclerosis. The pharmaceutical composition of claim 23 for the prevention of transplant rejection after organ transplantation. The pharmaceutical composition of claim 23, wherein the immunosuppressive agent is tacrolimus, cyclosporin or methotrexate. A method of preventing or treating autoimmune disease in a mammal comprising administering to the mammal a therapeutically effective amount of the pharmaceutical composition of claim 23. 43. The method of claim 42, wherein the autoimmune disease is systemic lupus erythematosus, chronic hepatitis, interstitial liver disease, asthma, psoriasis, ulcerative colitis, Crohn's disease, local ileitis or multiple sclerosis. A method for preventing a transplant rejection response following organ transplantation in a mammal comprising administering to the mammal a therapeutically effective amount of the pharmaceutical composition of claim 23. Use of the pharmaceutical composition of claim 23 for the manufacture of a medicament for use as an immunosuppressive agent.