JPH09169646A - Therapeutic agent for arthritis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject therapeutic agent excellent in immediate effect and long acting antiinflammatory/analgesic effect on rheumatoid arthritis by combining a quinoline or quinazoline-based preventive/therapeutic agent for arthritis with an antiphlogistic-sedative-medicine having an immediate action. SOLUTION: This therapeutic agent for arthritis is obtained by combining (A) a quinoline or quinazoline-based preventive/therapeutic agent for arthritis with (B) an antiphlogistic-sedative-medicine having an immediate action. A compound of the formula [Y is an N atom or a C-G (G is a carboxyl group which may be esterified, etc.; R is a (substituted) hydrocarbon residue or (substituted) heterocyclic ring; X is an O atom or an S atom; (n) and (k) are each 0 or 1], concretely, 6,7-dimethoxy-9-phenylfuro[3,4-b]quinolin-1(3H)-one is preferably used as the component A. A cyclooxygenase inhibitor, a central analgesic, a steroid agent or an antiphlogistic enzyme agent is preferably used as the component B.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a medicament suitable as a therapeutic agent for arthritis, particularly as an antirheumatic agent.

[0002]

2. Description of the Related Art Arthritis is an inflammatory disease of the joint, and the main diseases include rheumatoid arthritis and related diseases in which inflammation is recognized in the joint. Rheumatoid arthritis, which is also called rheumatoid arthritis, is a chronic polyarthritis whose main lesion is inflammatory changes in the synovium of the joint endothelium. Arthritis such as rheumatoid arthritis is progressive and causes joint disorders such as joint deformity and ankylosis, and if advanced without effective treatment, it often leads to severe physical disability. Conventionally, in the treatment of these arthritis, steroid agents such as cortisone and other adrenocortical hormones as drug therapy; nonsteroidal anti-inflammatory agents such as aspirin, piroxicam and indomethacin; gold thiomalate and other gold agents, chloroquine preparations and D- Antirheumatic agents such as penicillamine; antigout agents such as colchicine; immunosuppressive agents such as cyclophosphamide, azathioprine, methotrexate, and levamisole have been used, but these agents are serious and make long-term use difficult. There are problems that there are side effects, that the anti-inflammatory effect is insufficient, and that it is not effective against arthritis that has already developed.

[0003]

Recently, a novel prophylactic / therapeutic agent for arthritis having a quinoline or quinazoline skeleton has been found, and it is in the spotlight due to its low toxicity and excellent prophylactic / therapeutic effect on arthritis. However, since a quinoline or quinazoline arthritis preventive / therapeutic agent prevents / treats the root cause in chronic arthritis through its actions on the immune system and bone / cartilage, it takes weeks to several months for the effect to appear. Therefore, it has been earnestly desired to develop an arthritis therapeutic agent which overcomes these drawbacks and has a symptomatic effect on acute inflammatory symptoms and pain.

[0004]

Means for Solving the Problems The present inventors have a prophylactic / therapeutic agent for quinoline or quinazoline arthritis, and have an acute inflammation-suppressing action and an analgesic action.
By administering a fast-acting anti-inflammatory analgesic that produces a clinical effect within 1 day at the latest, for example, a cyclooxygenase inhibitor, a central analgesic, a steroid drug or an anti-inflammatory enzyme drug in combination, The inventors have found that an excellent anti-inflammatory and analgesic effect is exhibited even from the beginning of treatment for chronic arthritis, and that the effect is safely maintained for a long time, and the present invention has been completed. That is,
The present invention relates to (1) a pharmaceutical comprising a combination of a quinoline or quinazoline arthritis preventive / therapeutic agent and a fast-acting anti-inflammatory analgesic, (2) the pharmaceutical according to (1) above, wherein the fast-acting anti-inflammatory analgesic is a cyclooxygenase inhibitor. (3) The drug according to (1) above, wherein the fast-acting anti-inflammatory analgesic is a central analgesic.
(4) The drug according to (1) above, wherein the fast-acting anti-inflammatory analgesic is a steroid drug, (5) the drug according to (1) above, wherein the fast-acting anti-inflammatory analgesic is an anti-inflammatory enzyme drug.

(6) A quinoline or quinazoline arthritis preventive / therapeutic agent is represented by the general formula (I)

Embedded image [In the formula, Y represents a nitrogen atom or C-G (G represents a carboxyl group which may be esterified or amidated, an acyl group or a hydroxyalkyl group), and R represents a hydrocarbon which may be substituted. A residue or an optionally substituted heterocyclic group, X is an oxygen atom or an optionally oxidized sulfur atom, n is 0 or 1, and k is 0 or 1. G and R may combine with each other to form a ring. Ring A and ring B may each have a substituent. ] The compound represented by the above (1) which is a compound represented by the following or a pharmaceutically acceptable salt thereof, (7) n is 0, and an optionally substituted hydrocarbon represented by R The residue is —CH ₂ —X ¹ —Z ¹ [wherein, X ¹ is an oxygen atom, an optionally oxidized sulfur atom or — (CH ₂ ) _m — (m represents an integer of 0 to 5) To
Z ¹ represents an optionally substituted hydrocarbon residue, an optionally substituted heterocyclic group or an optionally substituted amino group. The pharmaceutical according to (6)] is a group represented by, (8) X ¹ is _{- (CH 2) m - (} m is 0 or 1) The medicament according to the a (7),

(9) The drug according to (7) above, wherein the optionally substituted heterocyclic group represented by Z ¹ is an aromatic 5-membered heterocyclic group containing 2 to 3 heteroatoms, (10)
The drug according to (6) above, wherein Y is CG, (11) G
Wherein the is a C _1-6 alkoxycarbonyl group, the drug according to the above (10), (12) the drug according to the above (10), wherein G is an ethoxycarbonyl group, (13) the ring A has at least one alkoxy group. The drug according to (6) above, wherein (14) A ring is substituted with two methoxy groups, and the drug (15) A above is quinoline ring or quinazoline. The drug according to (14) above, which is substituted with two methoxy groups at the 6- and 7-positions of the ring, (16) The above-mentioned (6), wherein ring B is described with at least one alkoxy group. (17) The drug according to (6) above, wherein the ring B is substituted with two alkoxy groups which are the same or different. (18) The medicine according to (6) above, wherein k is 0,

(19) The compound represented by the general formula (I) is 6,7-dimethoxy-9-phenylfuro [3,4-
b] quinolin-1 (3H) -one, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(1-methylimidazol-2-yl) thiomethyl] quinoline-
3-carboxylic acid ethyl ester, 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] quinazoline, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(1-methylimidazol-2-yl) ethyl ] Quinoline-3-carboxylic acid ethyl ester, 4- (3,4-dimethoxyphenyl)
-6,7-Dimethoxy-3-methoxycarbonylquinoline-2-acetic acid methyl ester, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2,4-
Triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, 4- (3-isopropoxy-4-)
Methoxyphenyl) -6,7-dimethoxy-2- (1,
2,4-triazol-1-ylmethyl) quinoline-3
-Carboxylic acid ethyl ester, 4- (3-hydroxy-
4-methoxyphenyl) -6,7-dimethoxy-2-
(1,2,4-Triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, 4- (4-hydroxy-3-methoxyphenyl) -6,7-dimethoxy-2
-(1,2,4-Triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, 7-hydroxy-
6-methoxy-4- (3,4-dimethoxyphenyl)-
2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, 4- (3,4-
Dimethoxyphenyl) -6,7-dimethoxy-2- (1,
2,4-triazol-1-ylmethyl) quinoline-3
-Carboxylic acid ethyl ester 1-oxide, or 2
-(N, N-diethylaminomethyl) -4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3
And (20) a quinoline- or quinazoline-type arthritis preventive / therapeutic agent and a fast-acting anti-inflammatory analgesic agent in combination, which is a carboxylic acid ethyl ester.

The quinoline or quinazoline arthritis prophylactic / therapeutic agent used in the present invention is a general term for an arthritis prophylactic / therapeutic agent containing a group of compounds having a quinoline or quinazoline skeleton as a main component. JP-A-06-306052 (EP-A-056710
7), JP-A-07-118266 (EP-A-060887)
0), JP-A-07-069890 (EP-A-063416)
9), JP-A-08-053419 (EP-A-068663)
0) and International Patent Application Publication No. WO95 / 24394 and the like, which are described in detail together with the manufacturing method thereof are used.
Specific examples thereof include compounds represented by the above formula (I), which have prophylactic / therapeutic effects on arthritis, and therefore can be advantageously used in the present invention. In the above formula (I), the hydrocarbon residue in the optionally substituted hydrocarbon residue represented by R is an aliphatic hydrocarbon residue, an alicyclic hydrocarbon residue, or an alicyclic- Examples thereof include an aliphatic hydrocarbon residue, an aromatic carbocyclic ring-aliphatic hydrocarbon residue, and an aromatic hydrocarbon residue.

As such an aliphatic hydrocarbon residue, a saturated aliphatic hydrocarbon residue having 1 to 8 carbon atoms (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl or octyl, etc.), and unsaturated aliphatic hydrocarbon residues having 2 to 8 carbon atoms (for example, vinyl).
(Ethenyl), 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 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-hexadiynyl, 5-hexynyl, 1-heptynyl or 1
-Octynyl, etc.) and the like.

As the alicyclic hydrocarbon residue, a saturated alicyclic hydrocarbon residue having 3 to 7 carbon atoms (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), and 5 to 5 carbon atoms. 7 unsaturated alicyclic hydrocarbon residues (eg 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1
-Cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl or 2,4-cycloheptadienyl etc.) and the like. Such alicyclic group-
The aliphatic hydrocarbon residue has 4 to 9 carbon atoms among the above-mentioned alicyclic hydrocarbon residue and aliphatic hydrocarbon residue bonded (for example, cyclopropylmethyl, cyclopropylethyl, cyclobutyl). Methyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl or cycloheptylethyl and the like). . Examples of such aromatic carbocycle-aliphatic hydrocarbon residue include:
Phenylalkyl having 7 to 9 carbon atoms (for example, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl or 1-phenylpropyl, etc.), naphthylalkyl having 11 to 13 carbon atoms (for example, α-naphthylmethyl) , Α-naphthylethyl, β-naphthylmethyl, β-naphthylethyl, etc.) and the like. Examples of the aromatic hydrocarbon residue include phenyl and naphthyl (α-naphthyl, β-naphthyl).

The optionally substituted hydrocarbon residue represented by R is preferably --CH ₂ --X ¹ --Z ¹ [wherein X ¹ is an oxygen atom or an optionally oxidized sulfur atom]. or - a (m is an integer of _{0~5), - (CH 2)} m
Z ¹ represents an optionally substituted hydrocarbon residue, an optionally substituted heterocyclic group or an optionally substituted amino group]. Examples of the optionally oxidized sulfur atom represented by X ¹ include a thio group, a sulfinyl group and a sulfonyl group, and a thio group is particularly preferable. X ¹ is preferably — (CH ₂ ) _m — (m is preferably 0, 1 or 2, particularly 0 or 1).
Examples of the optionally substituted hydrocarbon residue represented by Z ¹ include the same as those listed as the optionally substituted hydrocarbon residue represented by R above. Z ¹
Examples of the heterocyclic group in the optionally substituted heterocyclic group represented by: (i) 5 to 7 membered heterocyclic group containing one sulfur, nitrogen or oxygen atom, (ii) 2 to 4 A 5- or 6-membered heterocyclic group containing a nitrogen atom, (iii) a 5- or 6-membered heterocyclic group containing 1 to 2 nitrogen atoms and 1 sulfur or oxygen atom, and these heterocyclic groups are It may be condensed with a 6-membered ring containing 2 or less nitrogen atoms, a benzene ring or a 5-membered ring containing one sulfur atom.

Specific examples of such a heterocyclic group include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl and 2-pyridyl.
Pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,
6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-pyrrolyl, 2
-Imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, isothiazolyl, isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2 , 4-triazole-3
-Yl, 1,2,3-triazol-4-yl, tetrazol-5-yl, benzimidazol-2-yl, indol-3-yl, 1H-indazol-3-yl, 1
H-pyrrolo [2,3-b] pyrazin-2-yl, 1H-pyrrolo [2,3-b] pyridin-6-yl, 1H-imidazo [4,
5-b] pyridin-2-yl, 1H-imidazo [4,5-c]
Pyridin-2-yl, 1H-imidazo [4,5-b] pyrazin-2-yl and the like can be mentioned. The optionally substituted heterocyclic group represented by Z ¹ is preferably an aromatic 5-membered heterocyclic group containing 2 to 3 hetero atoms (eg, oxygen atom, nitrogen atom or sulfur atom). , Among others,
2-Imidazolyl, 1,2,4-triazol-3-yl is more preferred. In the above formula (I), the optionally substituted heterocyclic group represented by R is the same as those exemplified as the optionally substituted heterocyclic group represented by Z ^1. Is mentioned.

The hydrocarbon residue and the heterocyclic group represented by R in the above formula (I) or Z ¹ have 1 to 3 substituents at any substitutable position on the chain or ring. You may have one. As such a substituent, an aliphatic chain hydrocarbon group, an alicyclic hydrocarbon group, an aryl group, an aromatic heterocyclic group,
Non-aromatic heterocyclic group, halogen atom, nitro group, optionally substituted amino group, optionally substituted acyl group, optionally substituted hydroxyl group, optionally substituted thiol group, esterification Examples thereof include a carboxyl group which may be incorporated. The aliphatic hydrocarbon group represented by R or Z ¹ and the substituent of the heterocyclic group is a straight-chain or branched aliphatic hydrocarbon group, for example, an alkyl group. (Preferably having 1 to 1 carbon atoms
0 alkyl group), alkenyl group (preferably having 2 carbon atoms)
And alkynyl groups (preferably alkynyl groups having 2 to 10 carbon atoms) and the like. Preferable examples of the alkyl group include, for example, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec-
Butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-
Examples thereof include dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl, decyl and the like. Preferable examples of the alkenyl group include vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, and the like.
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, 5-hexenyl and the like can be mentioned. Preferred examples of the alkynyl group include, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-
Examples include pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like.

The alicyclic hydrocarbon group represented as the substituent of the hydrocarbon residue and the heterocyclic group represented by R or Z ¹ is a saturated or unsaturated C _3-8 alicyclic hydrocarbon group ( For example, a C _3-8 cycloalkyl group, a C _3-8 cycloalkenyl group, a C _4-8 cycloalkadienyl group) and the like can be mentioned. Preferable examples of the C _3-8 cycloalkyl group include:
For example, 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, bicyclo [4.3.1] decyl and the like can be mentioned. As a preferable example of the C _3-8 cycloalkenyl group, a cycloalkenyl group having 5 to 7 carbon atoms, for example, 2
-Cyclopenten-1-yl, 3-cyclopenten-1
-Yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like. Preferred examples of the C _4-8 cycloalkadienyl group include a cycloalkadienyl group having 5 to 7 carbon atoms, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadiene-1-yl. Yl, 2,5-cyclohexadien-1-yl and the like.

The aryl group shown as the substituent of the hydrocarbon residue and the heterocyclic group represented by R or Z ¹ means a monocyclic or condensed polycyclic aromatic hydrocarbon group, which is a preferred example. For example, phenyl, naphthyl, anthryl,
Phenanthryl, acenaphthylenyl, etc. are mentioned, and phenyl, 1-naphthyl, 2-naphthyl, etc. are more preferable. Preferable examples of the aromatic heterocyclic group represented by the hydrocarbon residue represented by R or Z ¹ and the substituent of the heterocyclic group include aromatic monocyclic heterocyclic groups (eg, furyl, thienyl, pyrrolyl, Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,
4-oxadiazolyl, 1,3,4-oxadiazolyl,
Frazanil, 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, etc.), aromatic condensed heterocyclic group (for example, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H -Indazolyl, benzimidazolyl, benzoxazolyl, 1,2
-Benzisoxazolyl, benzothiazolyl, 1,2
-Benzoisothiazolyl, 1H-benzotriazolyl,
Quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl,
Purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenathridinyl, phenatrolinyl, indolizinyl, 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-triazolo [4,3
-A] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl) and the like.

Preferred examples of the hydrocarbon residue represented by R or Z ¹ and the non-aromatic heterocyclic group shown as the substituent of the heterocyclic group include, for example, oxiranyl, azetidinyl,
Oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like. Examples of the halogen shown as a substituent of the hydrocarbon residue and the heterocyclic group represented by R or Z ¹ include fluorine, chlorine, bromine and iodine;
Particularly, fluorine and chlorine are preferred. The optionally substituted amino group shown as the substituent of the hydrocarbon residue and the heterocyclic group represented by R or Z ¹ includes, in addition to the amino group, a substituted amino group (for example, having 1 to 10 carbon atoms). An amino group having one or two alkyl, alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms or an aromatic group, specifically, methylamino,
Dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino,
Phenylamino, N-methyl-N-phenylamino and the like).

As the optionally substituted acyl group shown as the substituent of the hydrocarbon residue and the heterocyclic group represented by R or Z ¹ , in addition to formyl, alkyl having 1 to 10 carbons and carbon number 2 to 10 alkenyl, 2 to 1 carbon atoms
A bond of an alkynyl or aromatic group of 0 and a carbonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl) , Crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, etc.). As the optionally substituted hydroxyl group shown as the substituent of the hydrocarbon residue and the heterocyclic group represented by R or Z ¹ , a hydroxyl group and an appropriate substituent for this hydroxyl group, particularly a hydroxyl group-protecting group are used. And aryloxy in addition to those having, for example, alkoxy, alkenyloxy, aralkyloxy, acyloxy and the like. As the alkoxy, alkoxy having 1 to 10 carbon atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like) are preferable. Examples of the alkenyloxy include those having 2 to 10 carbon atoms (eg, allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy, etc.). . Examples of the alkynyloxy include those having 2 to 10 carbon atoms. Examples of the aralkyloxy include phenyl-C _1-4 alkyloxy (eg, benzyloxy, phenethyloxy, etc.)
Is mentioned. The acyloxy has 2 to 4 carbon atoms.
Alkanoyloxy (eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.) are preferred. Examples of the aryloxy include phenoxy, 4-chlorophenoxy and the like.

The thiol group which may be substituted, which is shown as the substituent of the hydrocarbon residue and the heterocyclic group represented by R or Z ¹ , is a thiol group and an appropriate substituent for the thiol group, particularly thiol group. Examples thereof include those used as a protecting group for a group, such as alkylthio, alkenylthio, alkynylthio, aralkylthio, and acylthio. The alkylthio has 1 to 1 carbon atoms.
0 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio,
Cyclopentylthio, cyclohexylthio, etc.) are preferred. Examples of the alkenylthio include alkenylthio having 2 to 10 carbon atoms. Examples of the alkynylthio include alkynylthio having 2 to 10 carbon atoms. Examples of the aralkylthio include phenyl -C _1-4 alkylthio (e.g., benzylthio, etc. phenethylthio) and the like. Examples of the acylthio include alkanoylthio having 2 to 4 carbon atoms (eg, acetylthio, propionylthio,
Butyrylthio, isobutyrylthio, etc.) are preferred. R
Alternatively, the optionally esterified carboxyl group represented as the substituent of the hydrocarbon residue and the heterocyclic group represented by Z ¹ includes, in addition to the carboxyl group, a carboxyl group and an alkyl group having 1 to 6 carbon atoms. Bonded (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), carboxyl group and carbon number Bonded with 3 to 6 alkenyl groups (eg, allyloxycarbonyl, crotyloxycarbonyl, 2-pentenyloxycarbonyl, 3-
Hexenyloxycarbonyl, etc.), those having a carbonyl group and an aralkyl group bonded (eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.) and the like.

In the above formula (I), the hydrocarbon residue represented by R or Z ¹ and the substituents on the heterocyclic group each have one suitable substituent at any substitutable position. As mentioned above, it may have 1 to 3, preferably. Examples of such a substituent include a C _1-10 lower alkyl group, a C _2-10 lower alkenyl group, a C _2-10 lower alkynyl group, a C _3-7 cycloalkyl group, an aryl group, an aromatic heterocyclic group and a non-aromatic group. Group heterocyclic groups, aralkyl groups (eg, aryl C _1-6 alkyl groups, etc.), amino groups, N-monosubstituted amino groups, N, N-
Disubstituted amino group, amidino group, acyl group, carbamoyl group, N-monosubstituted carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, phenylcarbamoyl, etc.), N, N-disubstituted carbamoyl group (eg, N, N-dimethyl Carbamoyl, N, N-diethylcarbamoyl, piperidinocarbamoyl, morpholinocarbamoyl, etc.), sulfamoyl group, N-monosubstituted sulfamoyl group (eg, methylsulfamoyl, ethylsulfamoyl, phenylsulfamoyl, p-toluenesulfol) Famoyl, etc.), N, N-disubstituted sulfamoyl group (eg, N,
N-dimethylsulfamoyl, N-methyl-N-phenylsulfamoyl, piperidinosulfamoyl, morpholinosulfamoyl, etc.), carboxyl group, C _1-10 lower alkoxycarbonyl group (eg, methoxycarbonyl,
Ethoxycarbonyl, isopropoxycarbonyl, sec
-Butoxycarbonyl, isobutoxycarbonyl, tert
-Butoxycarbonyl)), hydroxyl group, C _1-10
Lower alkoxy group, C _2-10 lower alkenyloxy group, C
_Examples thereof include a _3-10 cycloalkyloxy group, a C _1-10 lower alkylthio group, an aralkylthio group, an arylthio group, a sulfo group, a cyano group, an azido group, a halogen atom, a nitro group and a nitroso group. Examples of such a substituent include R
Alternatively, the same groups as those shown as the substituents on the hydrocarbon residue and the heterocyclic group represented by Z ¹ are preferable.

In the above formula (I), R represents --CH ₂ --X ¹ --Z ¹
In the formula, the optionally substituted amino group represented by Z ¹ is —N (R ¹ ) (R ² ) (R ¹ and R ² are the same or different and each represents a hydrogen atom or a substituted A good hydrocarbon residue or an optionally substituted heterocyclic group, or R ¹ and R ²
May be bonded to each other to form a ring). The optionally substituted hydrocarbon residue represented by R ¹ and R ² or the optionally substituted heterocyclic group is, for example, an optionally substituted hydrocarbon residue as exemplified above for R or The same thing as the heterocyclic group which may be substituted is mentioned. The hydrocarbon residue and the heterocyclic group represented by R ¹ and R ² may have 1 to 3 substituents at any substitutable position on the chain or ring. Examples of such a substituent include the same as those exemplified as the substituent on the hydrocarbon residue and the heterocyclic group represented by R. The hydrocarbon residue represented by R ¹ and R ² and the substituent on the heterocyclic group each may have one or more, and preferably 1 to 3 appropriate substituents. Examples of the group include C _1-10 lower alkyl group, C _2-10
Lower alkenyl group, C _2-10 lower alkynyl group, C _3-7 cycloalkyl group, aryl group, aromatic heterocyclic group, non-aromatic heterocyclic group, aralkyl group, amino group, N-monosubstituted amino group, N , N-disubstituted amino group, amidino group, acyl group, carbamoyl group, N-monosubstituted carbamoyl group,
N, N-disubstituted carbamoyl group, sulfamoyl group, N
-Mono-substituted sulfamoyl group, N, N-disubstituted sulfamoyl group, carboxyl group, C _1-10 lower alkoxycarbonyl group, 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, Examples thereof include an azido group, a nitro group, a nitroso group, and halogen. Examples of such a substituent include those shown as a substituent on the ring of the hydrocarbon residue and the heterocyclic group represented by R. R ¹ and R ² may combine with each other to form a ring, and examples of such —N (R ¹ ) (R ² ) include 1-pyrrolidinyl, 1-imidazolidinyl, 1-pyrazolidinyl, 1 and -Piperidinyl, 1-piperazinyl,
4-morpholinyl, 4-thiomorpholinyl, homopiperazin-1-yl, 1,2,4-triazol-1-yl,
1,3,4-triazol-1-yl, pyrazole-1-
Yl, imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, tetrazol-1-yl, benzimidazol-1-yl, indol-1-yl 1H-indazole-1-
Ill and the like.

Examples of the optionally oxidized sulfur atom represented by X in the above formula (I) include a thio group, a sulfinyl group and a sulfonyl group, of which the thio group is preferred.

In the above formula (I), ring A and ring B may have a substituent, and examples of such a substituent include a halogen atom, a nitro group, and an optionally substituted C.
_1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group, _optionally substituted hydroxyl group, optionally substituted thiol group, optionally substituted amino group, acyl group (eg , C _1-10 alkanoyl group, C _2-10 alkenoyl group, C _2-10 alkinoyl group), an optionally esterified carboxyl group or an optionally substituted aromatic ring group. Examples of the halogen shown as a substituent on ring A and ring B include fluorine, chlorine, bromine and iodine, with fluorine and chlorine being particularly preferred. As the alkyl group which may be substituted and is shown as the substituent of ring A and ring B, a straight-chain alkyl having 1 to 10 carbon atoms, a branched alkyl having 3 to 10 carbon atoms, and a carbon atom having 3 to 10 carbon atoms
It may be any of 10 cyclic alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. These alkyl groups may have 1 to 3 substituents similar to the substituents described above for the hydrocarbon residue and heterocyclic group represented by R or Z ¹ at any substitutable position. Good.

As the optionally substituted hydroxyl group shown as the substituents of the ring A and the ring B, for example, an alkoxy group having a hydroxyl group and an appropriate substituent for the hydroxyl group, particularly one used as a protective group for the hydroxyl group, In addition to alkenyloxy, alkynyloxy, aralkyloxy, acyloxy and the like, aryloxy can be mentioned. As the alkoxy, alkoxy having 1 to 10 carbon atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,
(Pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.) are preferred. The alkenyloxy includes alkenyloxy having 2 to 10 carbon atoms (eg,
Allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy and the like). The alkynyloxy has 2 to 1 carbon atoms.
0 alkynyloxy. Examples of the aralkyloxy include phenyl-C _1-4 alkoxy (eg, benzyloxy, phenethyloxy, etc.).
Examples of the acyloxy include alkanoyloxy having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, n-
Butyryloxy, iso-butyryloxy and the like) are preferred. Examples of the aryloxy include phenoxy, 4-chlorophenoxy and the like.

As the optionally substituted thiol group shown as the substituents of the ring A and the ring B, there are a thiol group and an appropriate substituent for the thiol group, particularly a group used as a protective group for the thiol group. Examples include alkylthio, alkenylthio, alkynylthio, aralkylthio, acylthio, arylthio and the like. The alkylthio is an alkylthio having 1 to 10 carbon atoms.
(For example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio. Etc.) are preferred. The alkenylthio is preferably an alkenylthio having 2 to 10 carbon atoms. As the alkynylthio, alkynylthio having 2 to 10 carbon atoms is preferable. Examples of the aralkylthio include phenyl -C _1-4 alkylthio (e.g., benzylthio, etc. phenethylthio) and the like. As the acylthio, alkanoylthio having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.) is preferable. Examples of the arylthio include phenylthio, 4-chlorophenylthio and the like.

The optionally substituted amino group shown as the substituent for ring A and ring B is C _1-10 alkyl,
An amino group having 1 or 2 substituents of C _2-10 alkenyl, C _2-10 alkynyl, C _6-12 aromatic group, heterocyclic group or acyl group having 1 to 10 carbon atoms (eg, methylamino, Dimethylamino, ethylamino, diethylamino,
Dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino and the like). Examples of the optionally substituted acyl group represented by the substituents of ring A and ring B include formyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _6-12 aromatic group. Is bound to a carbonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexene). Carbonyl, benzoyl, nicotinoyl and the like).

As the optionally esterified carboxyl group shown as the substituent of ring A and ring B, in addition to the carboxyl group, a carboxyl group and a C _1-6 alkyl group bonded (eg, methoxycarbonyl, Ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), a bond between a carboxyl group and an alkenyl group having 3 to 6 carbon atoms (For example, allyloxycarbonyl, crotyloxycarbonyl, 2-pentenyloxycarbonyl, 3-hexenyloxycarbonyl, etc.), those in which a carbonyl group and an aralkyloxy group are bonded (for example, benzyloxy Carbonyl, phenethyl oxycarbonyl and the like). Examples of the _optionally substituted aromatic ring group shown as the substituents of ring A and ring B include pyridyl and furyl in addition to C _6-14 aromatic hydrocarbon residue (eg, phenyl, naphthyl, anthryl, etc.). And heteroaromatic residues such as thienyl, imidazolyl and thiazolyl.

The substituents on the ring A and the ring B may be substituted at any substitutable position on each ring, and may be the same or different and each may be substituted by 1 to 4. When substituents on ring A or ring B are adjacent to each other, linked substituents adjacent, - (CH _{2) t}
— Or —O— (CH ₂ ) ₁ —O— (where t represents an integer of 3 to 5, l represents an integer of 1 to 3), and such a ring may be , A 5- to 7-membered ring formed together with carbon atoms of a benzene ring. Ring A is at least 1
Preferably substituted with 1 alkoxy group, preferably a C _1-3 alkoxy group, especially at least one methoxy group. More preferably, ring A is substituted with two identical or different alkoxy groups, preferably C _1-3 alkoxy groups, especially methoxy groups. Specifically, for example, the case where the ring A is substituted with two methoxy groups at the 6-position and the 7-position of the quinoline ring or the quinazoline ring is particularly preferable. Ring B is preferably substituted with at least one alkoxy group, preferably a C _1-3 alkoxy group, especially at least one methoxy group or isopropoxy group. More preferably, ring B is substituted with two alkoxy groups, which may be the same or different, and especially C _1-3 alkoxy groups. Specifically, for example, the B ring is 3
Particularly preferred is a case where it is substituted with a methoxy group or an isopropoxy group at the position and is substituted with a methoxy group at the 4-position.

In the above formula (I), when Y is CG,
Examples of the optionally esterified carboxyl group represented by G include a carboxyl group, an alkyloxycarbonyl group and an aralkyloxycarbonyl group. The alkyl group in the alkyloxycarbonyl group is an alkyl group having 1 to 6 carbon atoms (for example, methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.). The aralkyl group in the aralkyloxycarbonyl group is an alkyl group having an aryl group as a substituent.
(Arylalkyl group) is meant. Examples of the aryl group include phenyl and naphthyl, which may have the same substituents as the aryl group in the ring A has. As the alkyl group, a lower alkyl group having 1 to 6 carbon atoms is preferable. Suitable examples of the aralkyl group include, for example, benzyl, phenethyl,
3-phenylpropyl, (1-naphthyl) methyl, (2-
Naphthyl) methyl, etc., among which benzyl,
Phenethyl and the like are preferable. When G is an amidated carboxyl group, such amidated carboxyl group is represented by ^{-CON (R 1) (R 2} ) ( In the formula, R ¹ and R ² are as defined above) . In the above formula (I), when G is an acyl group, such acyl group, -CO-R ³ (R ³
Represents an alkyl group having 1 to 5 carbon atoms or an aryl group. ). Examples of the alkyl group having 1 to 5 carbon atoms represented by R ³ include methyl, ethyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl and the like can be mentioned. this house,
Methyl, butyl, isobutyl, pentyl and the like are preferable. The aryl group represented by R ³ means a monocyclic or condensed polycyclic aromatic hydrocarbon group, and a preferable example thereof is a monocyclic or condensed monocyclic aromatic hydrocarbon group having 6 to 14 carbon atoms such as phenyl, naphthyl, anthryl and phenanthryl. Examples thereof include cyclic or condensed polycyclic aromatic hydrocarbon groups, with phenyl, 1-naphthyl, 2-naphthyl and the like being particularly preferable.

When G is a hydroxyalkyl group, examples of the alkyl group of the hydroxyalkyl group include the alkyl groups represented by the above R ¹ or R ² . The hydroxyalkyl group is preferably —CH ₂ OH or —CH (OH) —R ³ (R ³ has the same meaning as above).
It is represented by R ^{3 in} this formula is preferably methyl, ethyl or the like. When G is a protected hydroxyalkyl group, the protected hydroxy in this group is the substituted hydroxyl group exemplified as the substituent of the hydrocarbon residue or heterocyclic group represented by R ¹ or R ² above. May be. Such protected hydroxy alkyl group, preferably, -CH ₂ OCOR ⁴ or -CH (OCOR ⁴⁾ -R ³
(R ³ has the same meaning as above, and R ⁴ represents an optionally substituted alkyl group, aralkyl group or aryl group.). The alkyl group represented by R ⁴ is an alkyl group having 1 to 6 carbon atoms, for example, methyl,
Examples thereof include ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like. The aralkyl group represented by R ⁴ means, for example, an alkyl group having 1 to 4 carbon atoms (arylalkyl group) having a C _6-14 aryl group as a substituent. Examples of the alkyl group include the alkyl group represented by R ⁴ above. Examples of the aryl group include phenyl and naphthyl, and examples of the aralkyl group include benzyl, phenethyl, 3-phenylpropyl,
(1-naphthyl) methyl, (2-naphthyl) methyl and the like can be mentioned. Examples of the aryl group represented by R ⁴ include aryl groups having 6 to 14 carbon atoms such as phenyl and naphthyl. In the above formula (I), when Y is CG, R and G may combine with each other to form a 5-membered ring. Such a structure is represented by the following formulas (II) and (III).

[0030]

Embedded image [In the formula, R ³ represents hydrogen, an optionally substituted hydrocarbon residue or an optionally substituted heterocyclic group, and other symbols have the same meanings as described above. In formulas (II) and (III), the optionally substituted hydrocarbon residue represented by R ³ and the optionally substituted heterocyclic group are the same as those exemplified above for R and Z ^1. The same thing is mentioned. In the above formula (I), Y is preferably C-G, in which G is more preferably a C _1-6 alkoxycarbonyl group, and particularly preferably G is an ethoxycarbonyl group. N in the above formula (I) is preferably 0. K in the above formula (I) is preferably 0.

Among the compounds represented by the above formula (I),
Particularly preferred are, Y is C-G (G is ethoxycarbonyl), R is -CH ₂ -Z ^1, Z ¹ is 1,2,4-triazol-1-yl, the substituent of ring A of the quinoline ring A methoxy group at the 6- and 7-positions and a substituent on the B ring is 3 of the B ring.
A compound having a methoxy group or an isopropoxy group at the 4-position, a methoxy group at the 4-position, n of 0, and k of 0. Preferred specific examples of the compound represented by the above formula (I) include 6,7-dimethoxy-9-phenylfuro [3,
4-b] quinolin-1 (3H) -one, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(1-
Methylimidazol-2-yl) thiomethyl] quinoline-3-carboxylic acid ethyl ester, 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] quinazoline, 4- (3,4-dimethoxyphenyl)
-6,7-Dimethoxy-2-[(1-methylimidazol-2-yl) ethyl] quinoline-3-carboxylic acid ethyl ester, 4- (3,4-dimethoxyphenyl) -6,7
-Dimethoxy-3-methoxycarbonylquinoline-2-
Acetic acid methyl ester,

4- (3,4-dimethoxyphenyl) -6,
7-dimethoxy-2- (1,2,4-triazole-1-
Ilmethyl) quinoline-3-carboxylic acid ethyl ester, 4- (3-isopropoxy-4-methoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3- Carboxylic acid ethyl ester, 4- (3-hydroxy-4-methoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, 4- (4-Hydroxy-3-methoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, 7-hydroxy-6-methoxy-4 −
(3,4-Dimethoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy- 2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester 1-oxide, and 2- (N, N-diethylaminomethyl) -4- (3,4-dimethoxyphenyl)- 6,7-dimethoxyquinoline-3-carboxylic acid ethyl ester and the like can be mentioned.

Compound (I) which can be used in the present invention
As a salt of, a pharmaceutically acceptable salt is preferable, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like. No. Preferable examples of salts with inorganic bases include alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.), aluminum salt, ammonium salt, etc. Can be mentioned. Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine,
Picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N '
-Salts with dibenzylethylenediamine and the like.

Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid,
Tartaric acid, maleic acid, citric acid, succinic acid, malic acid,
Salts with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned. Suitable examples of salts with basic amino acids include, for example, arginine, lysine,
Examples thereof include salts with ornithine, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Among these salts, sodium salts and potassium salts are most preferred. Further, the compound (I) or a salt thereof in the present invention may be a hydrate. The compound (I) in the present invention is, for example, JP-A 06-306052 (EP-A-0567107), JP-A 07-118266 (EP-A-0608870) and JP-A 0-158870.
7-069890 (EP-A-0634169), JP-A-08-08
It can be easily produced according to the production method described in JP-A-053419 (EP-A-0686630), International Patent Application Publication WO95 / 24394 or the like, or a method analogous thereto. In the present invention, the quinoline or quinazoline arthritis prophylactic / therapeutic agent which is slightly delayed is used in combination (that is,
The drug (used in combination) can be used for 2 to 30 minutes after administration.
It is a so-called fast-acting anti-inflammatory analgesic that exerts an effect of clinically suppressing inflammation and accompanying pain within 3 days or at most 1 week. This fast-acting anti-inflammatory analgesic can be classified in various ways depending on its chemical structure, action, etc., but examples of those that can be advantageously used in the present invention include cyclooxygenase inhibitors, central analgesics, steroids and anti-inflammatory enzymes. Agents.

The cyclooxygenase inhibitor is cyclooxygenase-1 or / and cyclooxygenase-
A compound that suppresses 2 and the following compounds and salts thereof are preferred. Salicylic acid derivatives with anti-inflammatory and analgesic effects such as aspirin, pyrazolone derivatives with anti-inflammatory and analgesic effects such as antipyrine, phenylbutazone, oxybutazone, sulfinpyrazone, acemethacin, aceclofenac, aluminoprofen, ampenac, ampiroxicam, butybufen, carprofen, diclofenac , Diflunisal, droxicam, etodolac, fenbufen, fenoprofen,
Flufenamic acid, flurbiprofen, ibuprofen, indomethacin, indomethacin farnesyl ester, ketoprofen, ketorolac, loxoprofen, mefenamic acid, meclofenamate, meloxicam, nabumetone, naproxen, oxaprozin, pyrazolac, piroxicam, pranoprofen, progourmetacin, Sarin duck, tenidup, tenoxicam,
Tiaprofenic acid, ticlopidine, tolmetin, tolfenamic acid, ximoprofen, zaltoprofen, nimesulide, furosulide,

3-Formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one, N- [2-cyclohexyloxy-4-
Nitrophenyl] methanesulfonamide, dihydro-
4-[[3,5-bis (1,1-dimethylmethyl) -4-
Hydroxyphenyl] methylene] -2-methyl-2H-
1,2-Oxazin-3 (4H) -one, 1- [4- (methylsulfonyl) phenyl] -3-tolufluoromethyl-5- (4-fluorophenyl) -1H-pyrazole, 1- [2- ( 4-Fluorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene, 5-bromo-2- (4-fluorophenyl) -3-
[4- (methylsulfonyl) phenyl] thiophene,
5-Methanesulfonamide-6- (2,4-difluorophenylthio) -1-indanone. Furthermore, international patent application publications WO95 / 15315, WO95 / 15316, W
Suitable compounds are the compounds described in O95 / 15317 and WO95 / 15318 and salts thereof. In particular, the compounds described in claim 16 of WO95 / 15315 [1
-[(4-alkylsulfonyl) phenyl] -3-substituted-
5-substituted-1H-pyrazole derivative and the like], that is, 1-
[4- (methylsulfonyl) phenyl] -5- (4-
Fluorophenyl) -3-trifluoromethyl-1H-
Pyrazole, 1- [4- (methylsulfonyl) phenyl] -5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazole, 1- [4- (methylsulfonyl) phenyl] -5- (4 -Bromophenyl)
-3- (trifluoromethyl) -1H-pyrazole, 1
-[4- (Methylsulfonyl) phenyl] -5- (4
-Iodophenyl) -3- (trifluoromethyl) -1
H-pyrazole,

1- [4- (methylsulfonyl) phenyl] -5- (phenyl) -3- (trifluoromethyl)
Pyrazole, 1- [4- (methylsulfonyl) phenyl] -5- (4-fluorophenyl) -3- (chlorodifluoromethyl) -1H-pyrazole, 1- [4- (methylsulfonyl) phenyl] -5- ( 4-chlorophenyl) -3- (chlorodifluoromethyl) -1H-pyrazole, 1- [4- (methylsulfonyl) phenyl]
-5- (4-Bromophenyl) -3- (chlorodifluoromethyl) -1H-pyrazole, 1- [4- (methylsulfonyl) phenyl] -5- (4-iodophenyl)
-3- (chlorodifluoromethyl) -1H-pyrazole, 1- [4- (methylsulfonyl) phenyl] -5
-(Phenyl) -3- (chlorodifluoromethyl) -1
H-pyrazole, 1- [4- (methylsulfonyl) phenyl] -5- (4-fluorophenyl) -3- (difluoromethyl) -1H-pyrazole, 1- [4- (methylsulfonyl) phenyl] -5 (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazole,
1- [4- (methylsulfonyl) phenyl] -5-
(4-Bromophenyl) -3- (difluoromethyl)-
1H-pyrazole, 1- [4- (methylsulfonyl)
Phenyl] -5- (4-iodophenyl) -3- (difluoromethyl) -1H-pyrazole, 1- [4- (methylsulfonyl) phenyl] -5- (phenyl) -3-
(Difluoromethyl) -1H-pyrazole, 1- [4-
(Methylsulfonyl) phenyl] -5- (fluorophenyl) -3- (pentafluoroethyl) -1H-pyrazole, 1- [4- (methylsulfonyl) phenyl]
-5- (4-chlorophenyl) -3- (pentafluoroethyl) -1H-pyrazole, 1- [4- (methylsulfonyl) phenyl] -5- (4-bromophenyl)-
3- (pentafluoroethyl) -1H-pyrazole,

1- [4- (methylsulfonyl) phenyl] -5- (4-iodophenyl) -3- (pentafluoroethyl) -1H-pyrazole, 1- [4- (methylsulfonyl) phenyl] -5- (Phenyl) -3-
(Pentafluoroethyl) pyrazole, 1- [4- (methylsulfonyl) phenyl] -5- (4-fluorophenyl) -3- (heptafluoropropyl) -1H-pyrazole, 1- [4- (methylsulfonyl) phenyl ] -5- (4-Chlorophenyl) -3- (heptafluoropropyl) -1H-pyrazole, 1- [4- (methylsulfonyl) phenyl] -5- (4-bromophenyl) -3- (heptafluoropropyl) -1H-pyrazole, 1- [4- (methylsulfonyl) phenyl]-
5- (4-iodophenyl) -3- (heptafluoropropyl) -1H-pyrazole, and 1- [4- (methylsulfonyl) phenyl] -5- (phenyl) -3-
(Heptafluoropropyl) -1H-pyrazole, and the compound [4- (optionally having substituents at the 3- and 5-positions-1H
-Pyrazol-1-yl) benzenesulfonamide derivative and the like], that is, ethyl 1- [4- (aminosulfonyl) phenyl] -5- (4-chlorophenyl) -1H
-Pyrazole-3-carboxylate, ethyl 1-
[4- (aminosulfonyl) phenyl] -5- (4-
Methylphenyl) -1H-pyrazole-3-carboxylate, isopropyl 1- [4- (aminosulfonyl) phenyl] -5- (4-chlorophenyl) -1H-
Pyrazole-3-carboxylate,

N- [4- (methylphenyl) -1- [4
-(Aminosulfonyl) phenyl) -5- (4-fluorophenyl) -1H-pyrazole-3-carboxamide, N- [3-chlorophenyl] -1- [4-aminosulfonyl) phenyl] -5- (4-fluoro Phenyl) -1H-pyrazole-3-carboxamide, N-
[3-Fluorophenyl] -1- [4-aminosulfonyl) phenyl] -5- (4-fluorophenyl) -1
H-pyrazole-3-carboxamide, N- [3-fluorophenyl] -1- [4-aminosulfonyl) phenyl] -5- (4-chlorophenyl) -1H-pyrazole-3-carboxamide, phenylmethyl N-[[ 1
-[4- (aminosulfonyl) phenyl] -5- (4
-Chlorophenyl) -1H-pyrazol-3-yl] carbonyl] glycinate, 4- [5- (4-bromophenyl) -3-cyano-1H-pyrazol-1-yl] benzenesulfonamide, 4- [3-cyano -5- (4
-Fluorophenyl) -1H-pyrazol-1-yl]
Benzenesulfonamide, 4- [5- (4-chlorophenyl) -3-cyano-1H-pyrazol-1-yl]
Benzenesulfonamide, 4- [3-cyano-5-
(4-Methoxyphenyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [3-cyano-5
-(4-Methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [3-cyano-5
-(4-Methylthiophenyl) -1H-pyrazole-1
-Yl] benzenesulfonamide, 4- [5- (5-
Chloro-4-methoxyphenyl) -3-cyano-1H-
Pyrazol-1-yl] benzenesulfonamide,

4- [5- (5-bromo-4-methoxyphenyl) -3-cyano-1H-pyrazol-1-yl]
Benzenesulfonamide, 4- [3-cyano-5-phenyl-1H-pyrazol-1-yl] benzenesulfonamide, 4- [4-chloro-5- (4-fluorophenyl) -1H-pyrazol-1-yl ] Benzenesulfonamide, 4- [4-chloro-5- (4-chlorophenyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [4-bromo-5- (4-chlorophenyl) -1H-pyrazole -1-yl] benzenesulfonamide, 4- [4-chloro-5-phenyl-1H
-Pyrazol-1-yl] benzenesulfonamide,
4- [4-chloro-5- (3,5-dichloro-4-methoxyphenyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [4-bromo-5- (4-methylphenyl)- 1H-pyrazol-1-yl] benzenesulfonamide, 4- [4-chloro-5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [4-chloro-5- ( 3-chloro-4-methoxyphenyl) -1H-pyrazole-1
-Yl] benzenesulfonamide, 4- [4-chloro-5- (4-methoxyphenyl) -1H-pyrazole-
1-yl] benzenesulfonamide, 4- [4-bromo-5- (4-methoxyphenyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [4-cyano-5- (4-methoxyphenyl) ) -1H-Pyrazol-1-yl] benzenesulfonamide, 4- [4-
Chloro-5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide,

4- [4-ethyl-5-phenyl-3-
(Trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [4-methyl-5
-Phenyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4-
[5- (4-methoxyphenyl) -4-methyl-3-
(Trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-chlorophenyl) -4-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] benzene Sulfonamide, 4- [5- (4-chlorophenyl) -4-ethyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [4-ethyl-5- (4- Methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [4-ethyl-5- (4-methoxy-3-methylphenyl) -3- (trifluoromethyl) ) -1H-Pyrazol-1-yl] benzenesulfonamide, 4- [4-ethyl-5- (4-methoxyphenyl) -3- (triflu) Romechiru)-1H-pyrazol-1-yl] benzenesulfonamide, 4- [4-
Ethyl-5- (3-fluoro-4-chlorophenyl)-
3- (trifluoromethyl) -1H-pyrazole-1-
Ile] benzenesulfonamide, 4- [5- (4-fluorophenyl) -4-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [4-methyl-5 -(4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [4-
Fluoro-5-phenyl-3- (trifluoromethyl)
-1H-pyrazol-1-yl] benzenesulfonamide, 4- [4-bromo-5- (4-chlorophenyl)
-3- (difluoromethyl) -1H-pyrazole-1-
Il] benzenesulfonamide,

4- [4-chloro-5- (3,5-dichloro-4-methoxyphenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [4-chloro -3- (difluoromethyl) -5-phenyl-1H-pyrazol-1-yl] benzenesulfonamide, 4- [4-bromo-3- (difluoromethyl) -5-phenyl-1H-pyrazole-
1-yl] benzenesulfonamide, 4- [4-chloro-3- (difluoromethyl) -5- (4-methoxyphenyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [4-chloro- 3-Cyano-5-phenyl-1H-pyrazol-1-yl] benzenesulfonamide, 4- [4-chloro-5- (4-chlorophenyl) -3-cyano-1H-pyrazol-1-yl] benzenesulfonamide , 4- [4-chloro-3-cyano-5- (4-fluorophenyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [4-bromo-3-cyano-5- (4-fluoro Phenyl) -1
H-pyrazol-1-yl] benzenesulfonamide, 4- [4-bromo-3-cyano-5-phenyl-1
H-pyrazol-1-yl] benzenesulfonamide, ethyl [1- (4-aminosulfonyl) phenyl] -4-bromo-5- (4-chlorophenyl) -1H
-Pyrazol-3-yl] carboxylate, methyl
[1- (4-Aminosulfonylphenyl] -4-chloro-5-phenyl-1H-pyrazol-3-yl] carboxylate, methyl [1- (4-aminosulfonylphenyl] -4-chloro-5- (4 -Chlorophenyl) -1H-pyrazol-3-yl] carboxylate,

Ethyl [1- (4-aminosulfonylphenyl) -4-chloro-5- (4-chlorophenyl)
-1H-pyrazol-3-yl] carboxylate, methyl [1- (4-aminosulfonylphenyl] -4
-Chloro-5- (4-fluorophenyl) -1H-pyrazol-3-yl] carboxylate, methyl [1-
(4-Aminosulfonylphenyl) -4-bromo-5
-(4-Fluorophenyl) -1H-pyrazole-3-
Iyl] carboxylate, methyl [1- (4-aminosulfonylphenyl] -4-chloro-5- (3-chloro-4-methoxyphenyl) -1H-pyrazole-3-
Iyl] carboxylate, methyl [1- (4-aminosulfonylphenyl] -4-chloro-5- (3,5-
Dichloro-4-methoxyphenyl) -1H-pyrazol-3-yl] carboxylate, methyl [1- (4-
Aminosulfonylphenyl] -5- (3-bromo-4
-Methoxyphenyl) -4-chloro-1H-pyrazol-3-yl] carboxylate, 4- [4-chloro-3
-Isopropyl-5-phenyl-1H-pyrazole-1
-Yl] benzenesulfonamide, 4- [4-chloro-3-methyl-5-phenyl-1H-pyrazole-1-
Il] benzenesulfonamide, 4- [4-chloro-
3-hydroxymethyl-5-phenyl-1H-pyrazol-1-yl] benzenesulfonamide, 4- [4-
Chloro-5- (chlorophenyl) -3-hydroxymethyl-1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazole-1- Il] benzenesulfonamide, 4- [5-phenyl-3-
(Trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide,

4- [5- (4-fluorophenyl) -3
-(Trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-cyanophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide , 4-
[5- (2,4-Difluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) ) -1H-Pyrazol-1-yl] benzenesulfonamide, 4- [5-
(3,4-Dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-bromophenyl) -3-
(Trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (2,4-
Dichlorophenyl) -3- (trifluoromethyl) -1
H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4 -Methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5-
(2-chlorophenyl) -3- (trifluoromethyl)
-1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (2-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-Aminophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5-
(2 Methylphenyl) -3- (trifluoromethyl)-
1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-fluoro-2-methylphenyl)
-3- (trifluoromethyl) -1H-pyrazole-1
-Yl] benzenesulfonamide,

4- [5- (3-methylphenyl) -3-
(Trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-ethoxyphenyl) -3- (trifluoromethyl) -1H-
Pyrazol-1-yl] benzenesulfonamide, 4,
-[5- (3,5-dimethylphenyl-4-methoxy)
-3- (trifluoromethyl) -1H-pyrazole-1
-Yl] benzenesulfonamide, 4- [5- (3-
Fluorophenyl) -3- (trifluoromethyl) -1
H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5-
(4-Methylthiophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-chloro-3-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5-
(4-ethylphenyl) -3- (trifluoromethyl)
-1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (2,4-dimethylphenyl) -3-
(Trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (2-methoxyphenyl) -3- (trifluoromethyl) -1H-
Pyrazol-1-yl] benzenesulfonamide, 4,
-[5- (4-Methoxy-3-methylphenyl) -3-
(Trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (3-bromo-4-methylthiophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] Benzenesulfonamide, 4- [5- (3-chloro-4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5-
(3,4-dimethoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide,

4- [5- (3-chloro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5
-(3-chloro-4-methoxy-5-methylphenyl)
-3- (trifluoromethyl) -1H-pyrazole-1
-Yl] benzenesulfonamide, 4- [5- (3-
Ethyl-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-fluoro-2-methoxyphenyl) -3- (trifluoromethyl) ) -1H-Pyrazol-1-yl] benzenesulfonamide, 4-
[5- (4-methoxy-3- (3-propynyl) phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5-
(3,4-dichloro-4-methoxyphenyl) -3-
(Trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (3-chloro-4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] Benzenesulfonamide, 4- [5- (3-fluoro-4-methylthiophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4-
[5- (3-methyl-4-methylthiophenyl) -3-
(Trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (3-chloro-4-methylthiophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] Benzenesulfonamide, 4- [5- (4- (N, N-dimethylamino) phenyl) -3- (trifluoromethyl) -1H-
Pyrazol-1-yl] benzenesulfonamide, 4,
-[5- (4-Methyl-3-nitrophenyl) -3-
(Trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide,

4- [5- (4- (N-methylamino) phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5
-(3-Amino-4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-chlorophenyl) -3- (difluoromethyl)- 1H-pyrazole-
1-yl] benzenesulfonamide, 4- [5- (4
-Methylthiophenyl) -3- (difluoromethyl)-
1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-methylphenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5-phenyl- 3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-methoxyphenyl) -3- (difluoromethyl) -1H-pyrazole-
1-yl] benzenesulfonamide, 4- [5- (3
-Fluoro-4-methoxyphenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-chlorophenyl)-
3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (2-fluoro-4-methoxyphenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] Benzenesulfonamide, 4- [5- (3-chloro-4-methylphenyl) -3- (difluoromethyl) -1H-pyrazole-
1-yl] benzenesulfonamide, 4- [5- (3
-Chloro-4-methoxyphenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-chloro-3-methylphenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5-
(3,4-dimethoxyphenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide,

4- [5- (3,5-dichloro-4-methoxyphenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4-
[5- (3,5-difluoro-4-methoxyphenyl)
-3- (difluoromethyl) -1H-pyrazole-1-
Il] benzenesulfonamide, 4- [5- (2-methoxyphenyl) -3- (difluoromethyl) -1H-
Pyrazol-1-yl] benzenesulfonamide, 4,
-[5- (3-Bromo-4-methoxyphenyl) -3-
(Difluoromethyl) -1H-pyrazol-1-yl]
Benzenesulfonamide, 4- [5- (4-methylsulfonylphenyl) -3- (difluoromethyl) -1
H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-chlorophenyl) -3- (heptafluoropropyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4 -Chlorophenyl) -3- (chloro-difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4-
[5- (4-chlorophenyl) -3- (pentafluoroethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-fluorophenyl)-
3- (3-hydroxypropyl) -1H-pyrazole-
1-yl] benzenesulfonamide, 4- [5-
(3,4-dichloro-4-methoxyphenyl) -3-
(3-Hydroxypropyl) -1H-pyrazole-1-
Il] benzenesulfonamide, 4- [5- (3-chloro-4-methoxyphenyl) -3- (chloromethyl)
-1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-chlorophenyl) -3- (cyanomethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [3- (chloro- Difluoromethyl) -5- (3-fluoro-4-methoxyphenyl)-
1H-pyrazol-1-yl] benzenesulfonamide, ethyl 3- [1- (4-aminosulfonylphenyl) -5- (phenyl) -1H-pyrazol-3-yl] 2-cyano-2-propenoate,

4- [5- (phenyl) -3- (fluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (5-bromo-2-thienyl) -3- (difluoro) Methyl) -1H-pyrazole-
1-yl] benzenesulfonamide, 4- [5- (5
-Chloro-2-thienyl) -3- (difluoromethyl)
-1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (1-cyclohexenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- ( 1-cyclohexyl) -3- (difluoromethyl) -1H-pyrazole-
1-yl] benzenesulfonamide, 4- [5-
(1,4-benzodioxan-6-yl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [3- (difluoromethyl)
-5- (4-methylcyclohexyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5-
(2-Benzofuranyl) -3- (difluoromethyl)-
1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (1,3-benzodioxol-5-yl) -3- (difluoromethyl) -1H-pyrazole-
1-yl] benzenesulfonamide, 4- [5- (2
-Benzofuryl-1-3- (trifluoromethyl) -1
H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (5-bromo-2-thienyl) -3-
(Trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (5-chloro-2-thienyl) -3- (trifluoromethyl) -1
H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (5-indanyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (5 -Methyl-2-thienyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide,

4- [5- (2,3-dihydrobenzofuran-2-yl) -3- (trifluoromethyl) -1H-
Pyrazol-1-yl] benzenesulfonamide, 4,
-[5- (1-Cyclohexenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (1,2,3,4-tetrahydronaphth-5- Yl) -3- (trifluoromethyl)
-1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (2-benzothienyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (3,4-Dihydro-2H-1-benzothiopyran-7-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-methyl-
1,3-benzodioxol-6-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-methyl-1,
3-benzodioxol-5-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, and the compound described in claim 7 of WO95 / 15317, ie, 4 -(4-Fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -1-phenyl-3- (trifluoromethyl) -1
H-pyrazole, 4- (4-chlorophenyl) -5-
[4- (methylsulfonyl) phenyl] -1-phenyl-3- (trifluoromethyl) -1H-pyrazole,
4- (4-Bromophenyl) -5- [4- (methylsulfonyl) phenyl] -1-phenyl-3- (trifluoromethyl) -1H-pyrazole, 4- (4-iodophenyl) -5- [4 -(Methylsulfonyl) phenyl] -1-phenyl-3- (trifluoromethyl) -1
H-pyrazole, 5- [4- (methylsulfonyl) phenyl] -1,4-diphenyl-3- (trifluoromethyl) -1H-pyrazole,

4- (4-methylphenyl) -5- [4-
(Methylsulfonyl) phenyl] -1-phenyl-3
-(Trifluoromethyl) -1H-pyrazole, 4-
(4-Methylthiophenyl) -5- [4- (methylsulfonyl) phenyl] -1-phenyl-3- (trifluoromethyl) -1H-pyrazole, 4- (4-methylsulfinylphenyl) -5- [4- (Methylsulfonyl) phenyl] -1-phenyl-3- (trifluoromethyl) -1H-pyrazole, 4- (4-hydroxyphenyl) -5- [4- (methylsulfonyl) phenyl]
-1-Phenyl-3- (trifluoromethyl) -1H-
Pyrazole, 4- (4-methoxyphenyl) -5- [4
-(Methylsulfonyl) phenyl] -1-phenyl-
3- (trifluoromethyl) -1H-pyrazole, 4-
(4-Nitrophenyl) -5- [4- (methylsulfonyl) phenyl] -1-phenyl-3- (trifluoromethyl) -1H-pyrazole, 4- (4-aminophenyl) -5- [4- ( Methylsulfonyl) phenyl]-
1-phenyl-3- (trifluoromethyl) -1H-pyrazole, 4- (4-N-methylaminophenyl) -5
-[4- (Methylsulfonyl) phenyl] -1-phenyl-3- (trifluoromethyl) -1H-pyrazole, 4- (4-N, N-dimethylaminophenyl) -5
-[4- (Methylsulfonyl) phenyl] -1-phenyl-3- (trifluoromethyl) -1H-pyrazole, 4- (4-trifluoromethylaminophenyl)-
5- [4- (methylsulfonyl) phenyl] -1-phenyl-3- (trifluoromethyl) -1H-pyrazole, 4- (4-acetamidophenyl) -5- [4- (methylsulfonyl) phenyl] -1-phenyl-3-
(Trifluoromethyl) -1H-pyrazole, 4- (4
-[N-acetylamino] methylphenyl) -5- [4
-(Methylsulfonyl) phenyl] -1-phenyl-
3- (trifluoromethyl) -1H-pyrazole,

1- (4-fluorophenyl) -5- [4
-(Methylsulfonyl) phenyl] -4-phenyl-
3- (trifluoromethyl) -1H-pyrazole, 1-
(4-chlorophenyl) -5- [4- (methylsulfonyl) phenyl] -4-phenyl-3- (trifluoromethyl) -1H-pyrazole, 1- (4-bromophenyl) -5- [4- (methyl Sulfonyl) phenyl]-
4-phenyl-3- (trifluoromethyl) -1H-pyrazole, 1- (4-iodophenyl) -5- [4-
(Methylsulfonyl) phenyl] -4-phenyl-3
-(Trifluoromethyl) -1H-pyrazole, 1-
(4-Methylphenyl) -5- [4- (methylsulfonyl) phenyl] -4-phenyl-3- (trifluoromethyl) -1H-pyrazole, 1- (4-methylthiophenyl) -5- [4- ( Methylsulfonyl) phenyl] -4-phenyl-3- (trifluoromethyl) -1
H-pyrazole, 1- (4-hydroxyphenyl) -5
-[4- (Methylsulfonyl) phenyl] -4-phenyl-3- (trifluoromethyl) -1H-pyrazole, 1- (4-methoxyphenyl) -5- [4- (methylsulfonyl) phenyl] -4- Phenyl-3- (trifluoromethyl) -1H-pyrazole, 1- (4-nitrophenyl) -5- [4- (methylsulfonyl) phenyl] -4-phenyl-3- (trifluoromethyl)
-1H-pyrazole, 1- (4-aminophenyl) -5
-[4- (Methylsulfonyl) phenyl] -4-phenyl-3- (trifluoromethyl) -1H-pyrazole, 1- (4-N-methylaminophenyl) -5- [4
-(Methylsulfonyl) phenyl] -4-phenyl-
3- (trifluoromethyl) -1H-pyrazole, 1-
(4-N, N-dimethylaminophenyl) -5- [4-
(Methylsulfonyl) phenyl] -4-phenyl-3
-(Trifluoromethyl) -1H-pyrazole, 1-
(4-Trifluoromethylphenyl) -5- [4- (methylsulfonyl) phenyl] -4-phenyl-3-
(Trifluoromethyl) -1H-pyrazole,

1- (4-acetamidophenyl) -5-
[4- (methylsulfonyl) phenyl] -4-phenyl-3- (trifluoromethyl) -1H-pyrazole,
4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -1-phenyl-3- (difluoromethyl) -1H-pyrazole, 4- (4-fluorophenyl) -5- [4- (Methylsulfonyl) phenyl] -1-phenyl-1H-pyrazole, 4- (4-fluorophenyl) -5- [4- (methylsulfonyl))
Phenyl] -1-phenyl-3- (methyl) -1H-pyrazole, 4- (4-fluorophenyl) -5- [4-
(Methylsulfonyl) phenyl] -1-phenyl-3
-(Cyano) -1H-pyrazole, 1,4-bis (4-
Fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-
Pyrazole, 5- [4- (methylsulfonyl) phenyl] -1,4-diphenyl-3- (difluoromethyl)
-1H-pyrazole, 4- [4- (4-fluorophenyl] -1-phenyl-3- (trifluoromethyl) -1
H-pyrazol-5-yl] benzenesulfonamide, 4- [4- (4-chlorophenyl] -1-phenyl-3- (trifluoromethyl) -1H-pyrazole-5
-Yl] benzenesulfonamide, 4- [4- (4-
Bromophenyl] -1-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide, 4- [4- (4-iodophenyl] -1
-Phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide, 1,4
-Diphenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide, 4-
[4- (4-methylphenyl) -1-phenyl-3-
(Trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide,

4- [4- (4-methylthiophenyl]-
1-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide, 4-
[4- (4-Methylsulfonylphenyl) -1-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide, 4- [4-
(4-Hydroxyphenyl] -1-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide, 4- [4- (4-methoxyphenyl] -1-phenyl-3- ( Trifluoromethyl)
-1H-pyrazol-5-yl] benzenesulfonamide, 4- [4- (4-nitrophenyl] -1-phenyl-3- (trifluoromethyl) -1H-pyrazole-
5-yl] benzenesulfonamide, 4- [4- (4
-Aminophenyl] -1-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide, 4- [4- (4-N-methylaminophenyl] -1-phenyl-3- (Trifluoromethyl)
-1H-pyrazol-5-yl] benzenesulfonamide, 4- [4- (4-N, N-dimethylaminophenyl] -1-phenyl-3- (trifluoromethyl) -1
H-pyrazol-5-yl] benzenesulfonamide, 4- [4- (4-trifluoromethylphenyl]-
1-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide, 4-
[4- (4-acetamidophenyl] -1-phenyl-3
-(Trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide, 4- [4- (4- [N
-Acetylamino] methylphenyl) -1-phenyl-
3- (trifluoromethyl) -1H-pyrazole-5-
Il] benzenesulfonamide, 4- [1- (4-fluorophenyl) -4-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide,

4- [1- (4-chlorophenyl) -4-
Phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide, 4- [1
-(4-Bromophenyl) -4-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide, 4- [1- (4-iodophenyl) -4-phenyl-3- (Trifluoromethyl) -1
H-pyrazol-5-yl] benzenesulfonamide, 4- [1- (4-methylphenyl) -4-phenyl-3- (trifluoromethyl) -1H-pyrazole-5
-Yl] benzenesulfonamide, 4- [1- (4-
Methylthiophenyl) -4-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide, 4- [1- (4-hydroxyphenyl) -4-phenyl-3- (trifluoromethyl) ) -1
H-pyrazol-5-yl] benzenesulfonamide, 4- [1- (4-methoxyphenyl) -4-phenyl-3- (trifluoromethyl) -1H-pyrazole-
5-yl] benzenesulfonamide, 4- [1- (4
-Nitrophenyl) -4-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide, 4- [1- (4-aminophenyl)-
4-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide, 4-
[1- (4-N-methylaminophenyl) -4-phenyl-3- (trifluoromethyl) -1H-pyrazole-
5-yl] benzenesulfonamide, 4- [1- (4
-N, N-dimethylaminophenyl) -4-phenyl-
3- (trifluoromethyl) -1H-pyrazole-5-
Il] benzenesulfonamide,

4- [1- (4-trifluoromethylphenyl) -4-phenyl-3- (trifluoromethyl)-
1H-pyrazol-5-yl] benzenesulfonamide, 4- [1- (4-acetamidophenyl) -4-phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide, 4- [4-
(4-Fluorophenyl) -1-phenyl-3- (difluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide, 4- [4- (4-fluorophenyl) -1-phenyl-1H-pyrazole- 5-yl] benzenesulfonamide, 4- [4- (4-fluorophenyl) -1-phenyl-3- (methyl) -1H-pyrazol-5-yl] benzenesulfonamide, 4-
[4- (4-fluorophenyl) -1-phenyl-3-
(Cyano) -1H-pyrazol-5-yl] benzenesulfonamide, 4- [1,4-bis (4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide , And 4
-[1,4-diphenyl-3- (difluorophenyl)
-1H-pyrazol-5-yl] benzenesulfonamide etc. are mentioned as a suitable thing.

As the cyclooxygenase inhibitor,
Further, the compounds described in JP-A-5-246997 or salts thereof can be mentioned. In particular, the Japanese Patent Application Laid-Open No. 5-2
The compounds mentioned in Examples 1 to 33 of JP-A-46997 can be mentioned as preferable examples. The publication (JP-A-5
The compounds described in JP-A-246997) are specifically represented by the following formula (IV):

Embedded image And a salt thereof. In the above formula (IV), R ⁵ is C _1-6 alkylthio, cyclo C _1-6 alkyl, hydroxy, hydroxy C _1-6 alkyl, cyano, C _1-6 alkylenedioxy, acyl, acyloxy, aryloxy and Optionally acyl or C
Been aryl substituted with a substituent selected from the group consisting of C _1-6 alkoxy optionally substituted with _1-6 alkoxy, R ⁶ is halogen, halo-C _1-6 alkyl, cyano or acyl, R ⁷ represents aryl substituted with nitro, hydroxy, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl or C _1-6 alkylsulfonyl (provided that R ⁷ is nitro, hydroxy or When it is aryl substituted with C _1-6 alkoxy,
R ⁵ is aryl substituted with C _1-6 alkylthio, C _1-6 alkylsulfinyl or C _1-6 alkylsulfonyl).

In the above formula (IV), R ⁵ is hydroxy, hydroxy C _1-6 alkyl, cyano, C _1-6 alkylenedioxy, acyl, acyloxy, aryloxy and optionally acyl or C _1-6 alkoxy. Phenyl substituted with a substituent selected from the group consisting of C _1-6 alkoxy which may be substituted with is particularly preferable phenyl substituted with cyano, C _1-6 alkanoyl or C _1-6 alkoxy. Preferable, more preferably phenyl substituted with cyano or methoxy. In the above formula (IV), R ⁶ is preferably halogen or haloC _1-6 alkyl, and particularly preferably bromine, difluoromethyl or trifluoromethyl. In the above formula (IV), R ⁷ is preferably phenyl substituted with alkylthio, C _1-6 alkylsulfinyl or C _1-6 alkylsulfonyl, and particularly phenyl substituted with methylthio, methylsulfinyl or methylsulfonyl. Preferred examples include:
As the compound represented by the above formula (IV), 3- (difluoromethyl) -1- (4-methoxyphenyl) -5- [4
-(Methylsulfonyl) phenyl] pyrazole, 3-
(Difluoromethyl) -1- (4-methoxyphenyl)
-5- [4- (methylsulfinyl) phenyl] pyrazole, 3- (difluoromethyl) -1- (4-methoxyphenyl) -5- [4- (methylthio) phenyl] pyrazole, 3-bromo-1- (4 -Methoxyphenyl)-
5- [4- (methylthio) phenyl] pyrazole, 3-
(Difluoromethyl) -1- [3,4- (methylenedioxy) phenyl] -5- [4- (methylthio) phenyl] pyrazole and the like are preferable, and especially 3- (difluoromethyl) -1- (4-methoxy Phenyl) -5-
[4- (Methylsulfonyl) phenyl] pyrazole or 3- (difluoromethyl) -1- (4-methoxyphenyl) -5- [4- (methylsulfinyl) phenyl] pyrazole is more preferred.

The central analgesic is a general term for narcotic or non-narcotic analgesics, and compounds such as morphine, codeine, ethylmorphine, oxycodeine, dihydrocodeine, pethidine, fentanyl, pentazocine and salts thereof are preferable. is there. The steroids are all corticosteroids having an anti-inflammatory effect, and compounds such as betamethasone, dexamethasone, fludrocortisone, hydrocortisone, methylprednisolone, prednisolone, triamcinolone, paramethasone and salts thereof are suitable. The anti-inflammatory enzyme agent is a generic term for proteins having an acute inflammation suppressing action and / or analgesic action, and bromersin, lysozyme, promerase, pronase, serrapeptase, streptokinase, chymotrypsin, amylase and the like are preferable. These fast-acting anti-inflammatory analgesics may be in the form of pharmaceutically acceptable salts as in the case of compound (I).

The pharmaceutical composition comprising the quinoline or quinazoline arthritis prophylactic / therapeutic agent of the present invention in combination with a fast-acting anti-inflammatory analgesic is a physiologically acceptable carrier or excipient containing these active ingredients separately or simultaneously. Mixed with agents, binders, diluents, etc., for example, granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions, solutions, etc. It can be administered parenterally. If the active ingredients are separately formulated at this time, those separately formulated can be mixed and administered using a diluent or the like at the time of use, but those separately formulated, separately, simultaneously, Alternatively, they may be administered to the same subject at different times.

The pharmaceutical agent of the present invention can be formulated according to a conventional method. In this specification, parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion and the like. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as an aqueous solution. As the vehicles or solvents that can be used, water,
Examples thereof include Ringer's solution and isotonic saline solution. In addition, sterile, fixed oils may be conventionally employed as a solvent or suspending medium. For this purpose, any non-volatile oil and fatty acid can be used, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural or synthetic or semi-synthetic mono- or di- or triglycerides. Suppositories for rectal administration consist of the drug and suitable nonirritating excipients, such as cocoa butter and polyethylene glycols, which are solid at room temperature but liquid at intestinal temperature and melt in the rectum. Can be manufactured by mixing with a substance that emits.

Examples of solid dosage forms for oral administration include powders, granules, tablets, pills and capsules described above. In such dosage forms, the active ingredient compound may comprise at least one additive, such as sucrose,
Lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginate, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic Can be mixed with the polymers or glycerides. Such dosage forms also
As usual, further additives can be included, such as inert diluents, lubricants such as magnesium stearate, preservatives such as parabens, sorbic acid, antioxidants such as ascorbic acid, α-tocopherol, cysteine and the like. Agents, disintegrants, binders, thickeners, buffering agents, sweeteners, flavoring agents, perfumes and the like. Tablets and pills can also be prepared with enteric coating. The liquid for oral administration is
Examples include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, solutions and the like, which may contain inert diluents commonly used in the art, such as water. The dose of each drug to be administered per day can be appropriately selected according to age, body weight, symptoms, administration time, dosage form, administration method, drug combination, etc., but quinoline or quinazoline arthritis prophylaxis -Therapeutic agent is usually a clinical dose of 5 to 1000 mg, preferably 10 to 200, per adult when orally administered.
In the case of parenteral administration, the dose can be selected in the range of 0.1 to 100 mg, preferably 1 to 100 mg. In the case of administration, the dose can be appropriately increased or decreased based on the clinically used dose. For example, in the case of a cyclooxygenase inhibitor, 1 to 5000 mg is orally administered,
The preferred range is 25 to 4500 mg, and the range for parenteral administration is 0.2 to 200 mg, preferably 1 to 100 mg. Specifically as the cyclooxygenase inhibitor, for example, in the case of aspirin, it is 10 in oral administration.
It can be selected in the range of 0 to 4500 mg, in the case of indomethacin can be selected in the range of 50 to 150 mg in the oral administration, and in the case of diclofenac, it can be selected in the range of 25 in the oral administration.
It can be selected in the range of ~ 75 mg, and in the case of loxoprofen,
In oral administration, it can be selected in the range of 60 to 180 mg. In the case of a central analgesic, the oral administration is 1-1000 mg, preferably 5-300 mg, and the parenteral administration is 0.1-300 mg, preferably 0.5-100.
You can select in the mg range. Specifically as the central analgesic, for example, in the case of morphine, 10 is orally administered.
-60 mg, and in parenteral administration, it can be selected in the range of 5-60 mg. Further, in the case of a steroid drug, it is orally administered in an amount of 0.1 to 400 mg, preferably 0.5 to 100 mg,
For parenteral administration, 0.1 to 100 mg, preferably 0.1.
It can be selected in the range of 5 to 25 mg. Specifically, as the steroid drug, for example, in the case of prednisolone, 5 to 100 mg for oral administration and 5 to 25 mg for parenteral administration
In the case of dexamethasone, for example, it can be selected in the range of 0.5 to 10 mg in the oral administration and in the range of 0.5 to 2.5 mg in the parenteral administration. Also,
In the case of an anti-inflammatory enzyme preparation, it can be selected in the range of 5 to 40 mg in oral administration, and in both oral administration and parenteral administration, it can be appropriately selected depending on the situation based on the clinical dose of each alone. . The frequency of administration is suitably 1 to 3 times a day. The toxicity of the concomitant drug in the present invention is low.

[0063]

BEST MODE FOR CARRYING OUT THE INVENTION 【Example】

Example 1 Effect on rat arthritis of arthritis Male Freund's complete adjuvant (0.5% tuberculosis death) in the footpad of the right hind leg of male Lewis rats (7 weeks old) consisting of 6 rats in each group The suspension was sensitized by injecting 0.05 ml of a liquid paraffin suspension)). 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester (hereinafter,
Compound A (abbreviated as A) (3.13 mg / kg) and indomethacin (0.25 mg / kg) are suspended in 0.5% methylcellulose and immediately before sensitization (0 days) to 30 days 5 to 6 times a week. Orally, alone or in combination of both agents. The volume of the left hind limb was measured immediately before sensitization (0th day), 14th day and 28th day, and the swelling suppression rate of the footpad in the non-sensitized rat was obtained. The body weight was measured immediately before the administration, and the weight increase rate (%) in the non-sensitized rat was calculated. Results are for each group (N = 6)
Is expressed as the mean ± standard error of the mean, and comparative test is performed by Student's t-test. Also, the risk rate is 5
Less than% was considered significant. As shown in [Table 1], the combined administration of Compound A and indomethacin showed a stronger effect in suppressing edema and weight gain as compared with single administration.

[0064]

[Table 1] As described above, the compound A / indomethacin combination group exhibited a remarkable swelling-inhibitory effect as compared with the group using Compound A or indomethacin alone, and as a result, a marked increase in body weight was observed. In particular, it is a direct indicator of anti-arthritic action 28
In the swelling suppression rate on the day, the combination group of compound A and indomethacin showed a remarkable effect more than the additive effect of both drugs,

[0065]

EFFECT OF THE INVENTION In an experimental model of adjuvant arthritis that develops arthritis similar to human rheumatoid arthritis, the concomitant agent of the present invention causes a significant swelling that is more than the additive effect of both agents as compared with the case of using each agent alone. An inhibitory effect was observed. Therefore, the combined drug (combination drug) provided by the present invention can be expected to have excellent fast-acting and continuous anti-inflammatory / analgesic effects on arthritis, particularly rheumatoid arthritis. Further, the combination drug according to the present invention, if the type of each drug, the administration method, the dose, etc. are appropriately selected depending on the symptoms,
Even for chronic arthritis, it exhibits an excellent fast-acting anti-inflammatory and analgesic effect from the beginning of the treatment, and even if it is administered for a long period of time, the side effects are extremely small, and the effect can be safely maintained.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location // C07D 215/22 C07D 215/38 215/38 239/80 239/80 A61K 37/54 ABG

Claims (20)

[Claims] 1. Prevention of quinoline or quinazoline arthritis
A medicine comprising a therapeutic agent and a fast-acting anti-inflammatory analgesic. 2. The medicine according to claim 1, wherein the fast-acting anti-inflammatory analgesic is a cyclooxygenase inhibitor. 3. The medicine according to claim 1, wherein the fast-acting anti-inflammatory analgesic agent is a central analgesic agent. 4. The medicine according to claim 1, wherein the fast-acting anti-inflammatory analgesic is a steroid drug. 5. The medicine according to claim 1, wherein the fast-acting anti-inflammatory analgesic agent is an anti-inflammatory enzyme agent. 6. Prevention of quinoline or quinazoline arthritis
The therapeutic agent has the general formula (I): [In the formula, Y represents a nitrogen atom or C-G (G represents a carboxyl group which may be esterified or amidated, an acyl group or a hydroxyalkyl group), and R represents a hydrocarbon which may be substituted. A residue or an optionally substituted heterocyclic group, X is an oxygen atom or an optionally oxidized sulfur atom, n is 0 or 1, and k is 0 or 1. G and R may combine with each other to form a ring. Ring A and ring B may each have a substituent. ] The pharmaceutical according to claim 1, which is a compound represented by the formula or a pharmaceutically acceptable salt thereof. 7. An optionally substituted hydrocarbon residue represented by R, wherein n is 0, is --CH ₂ --X ¹ --Z ¹ [wherein X ¹ is an oxygen atom or an oxidation group]. good sulfur or be - a (m is an integer of _{0~5), - (CH 2)} m
Z ¹ represents an optionally substituted hydrocarbon residue, an optionally substituted heterocyclic group or an optionally substituted amino group. ] The pharmaceutical according to claim 6, which is a group represented by: 8. The medicine according to claim 7, wherein X ¹ is — (CH ₂ ) _m — (m represents 0 or 1). 9. The medicine according to claim 7, wherein the optionally substituted heterocyclic group represented by Z ¹ is an aromatic 5-membered heterocyclic group containing 2 to 3 heteroatoms. 10. The medicine according to claim 6, wherein Y is CG. 11. The medicine according to claim 10, wherein G is a C _1-6 alkoxycarbonyl group. 12. The medicine according to claim 10, wherein G is an ethoxycarbonyl group. 13. The medicine according to claim 6, wherein ring A is substituted with at least one alkoxy group. 14. The pharmaceutical according to claim 6, wherein ring A is substituted with two methoxy groups. 15. The medicine according to claim 14, wherein the ring A is substituted with two methoxy groups at the 6-position and the 7-position of the quinoline ring or the quinazoline ring. 16. The medicine according to claim 6, wherein ring B is represented by at least one alkoxy group. 17. The medicine according to claim 6, wherein ring B is substituted with two alkoxy groups which are the same or different. 18. The medicine according to claim 6, wherein k is 0. 19. The compound represented by the general formula (I) is 6,7-dimethoxy-9-phenylfuro [3,4-b] quinolin-1 (3H) -one, 4- (3,4-dimethoxy). Phenyl) -6,7-dimethoxy-2-[(1-methylimidazol-2-yl) thiomethyl] quinoline-3-carboxylic acid ethyl ester, 4- (3,4-dimethoxyphenyl) -2- (2-hydroxy Ethylthiomethyl) -6,7-dimethoxyquinazoline, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(4-methyl-1,2,4-triazole-3
-Yl) thiomethyl] quinazoline, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(1-methylimidazol-2-yl) ethyl] quinoline-3-carboxylic acid ethyl ester, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-3-methoxycarbonylquinoline-2-acetic acid methyl ester, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2 , 4-Triazol-1-ylmethyl)
Quinoline-3-carboxylic acid ethyl ester, 4- (3-isopropoxy-4-methoxyphenyl)-
6,7-dimethoxy-2- (1,2,4-triazole-
1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, 4- (3-hydroxy-4-methoxyphenyl) -6,
7-dimethoxy-2- (1,2,4-triazole-1-
Ylmethyl) quinoline-3-carboxylic acid ethyl ester, 4- (4-hydroxy-3-methoxyphenyl) -6,
7-dimethoxy-2- (1,2,4-triazole-1-
Ylmethyl) quinoline-3-carboxylic acid ethyl ester, 7-hydroxy-6-methoxy-4- (3,4-dimethoxyphenyl) -2- (1,2,4-triazole-1-
Ylmethyl) quinoline-3-carboxylic acid ethyl ester, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl)
Quinoline-3-carboxylic acid ethyl ester 1-oxide or 2- (N, N-diethylaminomethyl) -4
The drug according to claim 6, which is-(3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylic acid ethyl ester. 20. A therapeutic agent for arthritis, which comprises a combination of a quinoline or quinazoline arthritis prophylactic / therapeutic agent and a fast-acting anti-inflammatory analgesic agent.