WO1999002499A1

WO1999002499A1 - Quinoline compounds and medicinal uses thereof

Info

Publication number: WO1999002499A1
Application number: PCT/JP1998/003089
Authority: WO
Inventors: Takashi Inaba; Tetsudo Kaya; Hiroyuki Iwamura
Original assignee: Japan Tobacco Inc.
Priority date: 1997-07-11
Filing date: 1998-07-09
Publication date: 1999-01-21
Also published as: AU8127998A; KR20010021696A

Abstract

Compounds represented by general formula (1) or pharmaceutically acceptable salts thereof, wherein each symbol is as defined in the specification. The compounds (1) and pharmaceutically acceptable salts thereof act selectively on cannabinoid receptors, in particular, peripheral receptors and exhibit excellent immunosuppressive, anti-inflammatory, antiallergic and nephritis-treating effects with little side effects on the central system. Thus, they are useful as agonists and antagonists to cannabinoid receptors (in particular, the peripheral ones), immunosuppressants, anti-inflammatory agents, antiallergic agents and remedies for nephritis.

Description

Description Quinoline compounds and their pharmaceutical uses

TECHNICAL FIELD The present invention relates to a novel compound which selectively acts on cannapinoy dressing, particularly peripheral type dressing, and a pharmaceutical use thereof. More specifically, the present invention relates to a novel compound having few central side effects and having an immunoregulatory action, an anti-inflammatory action, an anti-allergic action, and a therapeutic effect on nephritis, and a pharmaceutical use thereof. Background art

Heretofore, a compound group consisting of a series of C, H, and 0 called cannapinoid was known as a cannabis component. Of these, tetrahydrocannabinol (THC) is the main hallucinogen, and it is known that mu 9-THC is the main component contained in cannabis. Pharmacological effects of this Δ9-THC include ataxia, increased irritability, antiemetic, analgesic, hypothermic, hypopnea, respiratory depression, hepatic hepatic elicitation, vasodilation, immunosuppression, etc. I have.

The mechanisms of these pharmacological actions include the central nervous system (Devane et al., Mol Pharmacol. 1988, 34, 605-613; Hollister et al., Pharmacol. Rev., 1986, 38, l-20; Renv et al., Prog. Drug. Exp. Ther., 1991, 36, 71-114) and peripheral cell lines (Nye et al., J. Pharmacol. Exp. Ther., 1985, 234, 784-791; Flynn et al., Mol Pharmacol. 1992, 42, 736-742. ), And some of the effects via the central nervous system have been reported for medical applications.

In particular, the discovery of peripheral cell-type receptors, such as those on macrophages (Munnro et al., Nature, 1993, 365, 61-65), has been shown to modulate the immune response to produce anti-inflammatory effects. The development of an agonist of peripheral cell-type receptor, which has both an antiallergic effect and a therapeutic effect on nephritis and also has an immunomodulatory effect, is expected.

For the agonists of Cannabinoy Dresep Yuichi, pyrazolyl derivatives Hei 6-73014, EP 656354, EP 658546), THC derivatives (JP-A-3-209377), benzoxazine derivatives (US 5 112820), indole derivatives (US 508 1122), fatty acids Derivatives (WO 94/12466) are known.

Also, various quinoline derivatives have been reported. For example, J. Pharm. Sci., 1984, 73, 11, 1652-1653 discloses benzylamido, which is useful as a central nervous system stimulant, 6,7-dimethoxy-2--2-oxo-1,2-dihydroquinoline-13-carboxylate. Sodium, Khim. Geterotsikl. Soedin., 1993, 8, 1101-1104 states that 4-hydroxy-12-oxo-1,1,2-dihydroquinoline-13-carboxylic acid (pyridine) is useful as an anti-inflammatory agent. — 2-yl) amide is disclosed, and Synthesis, 1995, 11, 1362-1364 discloses 2-oxo-11,2-dihydroquinoline-13-carboxylic acid cyclohexylamide. In addition, Japanese Patent Publication No. 4-1500373 discloses a quinoline compound useful as an immunomodulator, and French Published Patent Application No. 23 77400 discloses a quinoline compound useful as an analgesic. Publication WO 96/05166 discloses a quinoline compound useful as a 5-HT ₄ receptor agonist. However, these documents do not disclose the pharmacological action based on the mechanism of action mediated by Cannapinoy Drecept Yuichi. Disclosure of the invention

An object of the present invention is to provide a novel compound which selectively acts on cannapinoy drecept, particularly a peripheral receptor, and a medicinal use thereof.

More specifically, it is an object of the present invention to selectively act on cannabinoid dresses, especially peripheral cell lines, and to act on the central nervous system (ie, excitement, hallucinations, ataxia, increased irritability, body temperature). To provide a novel compound which has low side effects such as lowering of blood pressure, respiratory depression, stimulating action of tallepsy, lowering of blood pressure, etc., and also has an immunomodulatory action, an anti-inflammatory action, an anti-allergic action and a therapeutic effect on nephritis, and its pharmaceutical use. .

As a result of intensive studies by the present inventors to achieve the above object, the novel compound of the present invention has a selective affinity for cannabinoid receptors, in particular, peripheral cell line receptors. Medical areas known to be involved, especially It has been found that it has a pharmaceutical effect in medical fields involving peripheral cell-based tissues (immune diseases, various inflammations, allergic diseases, nephritis, etc.).

That is, the present invention is as follows (1) to (14).

(1) General formula (1)

[Where W is one 0—, -S (0) _t , one CR ³ R ⁴ —, one NR ⁵ —, -N ⁵ C 0—, — C0NR ⁵ —, — C00— or — 0C0— ( In the formula, R ³ and R ⁴ are the same or different and each represents a hydrogen atom or alkyl, R ⁵ represents a hydrogen atom or alkyl, t represents 0 or an integer of 1 to 2, and R ¹ represents alkyl. , Alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl, wherein each group in R ¹ is alkyl, alkylamino, amino, hydroxyl, alkoxy, alkoxy, aryloxycarbonyl, Ashiru, Ashiruokishi, Ashiruchio, mercapto, alkyl Chio, alkylsulfinyl or alkylsulfonyl may be substituted by, R ² is a hydrogen atom, an alkyl, one oR ⁶ ( Wherein, R ⁶ is a hydrogen atom, an alkyl, Aruke, alkynyl, Ariru, § reel alkyl, Heteroariru, Heteroari -. Showing Ruarukiru, cycloalkyl or cycloalkylalkyl), -NR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom, an alkyl, an alkenyl, alkynyl, Ashiru, Ariru, § reel alkyl, Heteroariru, Heteroari one Ruarukiru, or a cycloalkyl or cycloalkylalkyl, or H ⁷ and R ⁸ May form a heteroaryl with an adjacent nitrogen atom), or — (CH ₂ ) _U .S (0) _U R ⁹ wherein R ⁹ is a hydrogen atom, alkyl, alkenyl or alkynyl the, u is 0 or an integer of 1 to 2, U 'represents shown.) an integer of 0 or 1乃optimum 2, dividing the hydrogen atoms in the R ² Each group, Alkyl, alkylamino, amino, hydroxyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto, alkylthio, alkylsulfinyl, alkylsulfinyl, alkylsulfonyl may be substituted, and Alk represents alkylene or alkenylene. Alkylene and alkenylene at 1 k are each a hydroxyl group; a carboxyl; an alkoxycarbonyl; an alkyl optionally substituted by a hydroxyl group, an alkoxy or an alkylthio;-CONR ^ R ¹¹ (wherein ¹¹ ^[] and ^{11 1} may be the same or different and each represents a hydrogen atom or an alkyl, or R ^{1 Q} and R ¹¹ may be taken together with an adjacent nitrogen atom to form a heteroaryl. R may be aryl, heteroaryl, cycloalkyl or benzene-condensed cycloalkyl, and the aryl and heteroaryl may be alkyl, hydroxyl, alkoxy, and alkoxy, respectively, which may be substituted with a hydroxyl group. It may be substituted with lucenyloxy, acetyl, acryloxy, halogen atom, nitro, amino, sulfonic acid amide, alkylamino, aralkyloxy, pyridyl, biperidino, ruboxyl, alkoxyl-ponyl, acylamino, aminoamino, cyano. The cycloalkyl may be substituted by a hydroxyl group, an alkoxy, and = 0. The benzene-condensed cycloalkyl may be substituted by a hydroxyl group or an alkoxy, and r represents 0 or 1. ] Or a pharmaceutically acceptable salt thereof as an active ingredient.

(2) General formula (1 ')

(Where W is — 0—, one S (0) _t , — CR ³ R ⁴ —, one NR ⁵ —, —NR ⁵ C 0—, one C0NR ⁵ —, — C00— or one 0C0— ( wherein the R ³ and R ⁴ are the same or different which it hydrogen atom or alkyl, R ⁵ is a hydrogen atom or alkyl, t denotes a.) represents an integer of 0 or 1 to 2, R ¹ ' Is alkyl having 4 to 6 carbon atoms, Alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl;

Each R ^1, each group of alkyl, Arukiruamino, Amino, hydroxyl, alkoxy, alkoxycarbonyl, Ashiru, Ashiruokishi, Ashiruchio, mercapto, alkylthio, alkylsulfinyl or alkylsulfonyl may be substituted by, R ² ' Is alkyl, —OR ⁶ (wherein R ⁶ represents a hydrogen atom, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl), — NR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom, an alkyl, an alkenyl, an alkynyl, an acyl, an aryl, an arylalkyl, a heteroaryl, a heteroarylalkyl, a cycloalkyl or a cycloalkyl Alkyl Or R ⁷ and R ⁸ may combine with an adjacent nitrogen atom to form a heteroaryl.) Or — (CH ₂ ) _u .S (0) _U R ⁹ (wherein , R ⁹ is a hydrogen atom, an alkyl, alkenyl or alkynyl, u is 0 or an integer of 1 to 2, u, represents shown.) 0 or an integer of 1 to 2, each of groups into the R ² ' Each may be substituted with alkyl, alkylamino, amino, hydroxyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto, alkylthio, alkylsulfinyl, alkylsulfonyl, and R is aryl, heteroaryl, cycloalkyl or A benzene-fused cycloalkyl, wherein the aryl and the heteroaryl are each an alkyl optionally substituted with a hydroxyl group, a hydroxyl group, Si, alkenyloxy, acyl, acyloxy, halogen atom, nitro, amino, sulfonic acid amide, alkylamino, aralkyloxy, pyridyl, biperidino, carboxyl, alkoxycarbonyl, acylamino, aminocarbonyl, cyano may be substituted. The cycloalkyl may be substituted with a hydroxyl group, alkoxy, and = 0, the benzene-condensed cycloalkyl may be substituted with a hydroxyl group, alkoxy, and m represents 0 or an integer of 1 to 5. Or a pharmaceutically acceptable salt thereof.

(3) w is —0—, R ¹ is alkyl having 4 to 6 carbon atoms, R ² ′ is alkoxy, and R is aryl or heteroaryl (where And heteroaryl are alkyl, hydroxyl, alkoxy, alkenyloxy, acyl, acylyl, halogen atom, nitro, amino, sulfonic acid amide, alkylamino, aralkyloxy, pyridyl, piperidino, carboxyl, respectively, which may be substituted with a hydroxyl group. It may be substituted by alkoxycarbonyl, acylamino, aminocarbonyl, or cyano. And m is 0 or an integer of 1 or 2. The compound according to (2) or a pharmaceutically acceptable salt thereof.

(4) The compound or a pharmaceutically acceptable salt thereof according to (3), wherein the substitution position of WR ¹ ′ is the j-position of the benzene ring, and the substitution position of R ² , is the i-position of the benzene ring.

(5) The compound or a pharmaceutically acceptable salt thereof according to (4), wherein aryl in R is phenyl and heteroaryl is pyridine.

(6) 7-Methoxy-1-2-oxo-1-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-pyridine-14-ylethyl) amide, 7-methoxy-12-oxo-8- Pentyloxy 1,2-dihydroquinoline-13-carbonic acid (4-aminobenzyl) amide, 7-methoxy-2-oxo-1 8-pentyloxy-1,1,2-dihydroquinoline-13-capronic acid [2_ ( 4-Aminophenyl) ethyl] amide and a compound according to (5), which is selected from 7-methoxy-l-2-oxo-l 8-pentyloxy-l, 2-dihydroquinoline-l-carboxylic acid (4-aminophenyl) amide A pharmaceutically acceptable salt thereof.

(7) A pharmaceutical composition comprising the compound according to any one of (2) to (6) or a pharmaceutically acceptable salt thereof as an active ingredient.

(8) A cannabinoid dressing receptor agonist or antagonist comprising the compound according to any one of (2) to (6) or a pharmaceutically acceptable salt thereof as an active ingredient.

(9) The cannabinoid dressep is a peripheral cannabinoid dressp, and the compound or pharmaceutically acceptable salt thereof according to any of (2) to (6) is contained as an active ingredient. Agonist or antagonist.

(10) A cannabinoid dressing receptor agonist or antagonist comprising, as an active ingredient, the compound according to any one of (2) to (6) or a pharmaceutically acceptable salt thereof, which is an immunomodulator.

(1 1) The compound according to any one of (2) to (6), which is a therapeutic agent for an autoimmune disease. A cannabinoid dressing agonist or antagonist comprising a substance or a pharmaceutically acceptable salt thereof as an active ingredient.

(12) An activator or antagonist of cannabinoid dressepep comprising the compound according to any of (2) to (6) or a pharmaceutically acceptable salt thereof as an active ingredient, which is an anti-inflammatory agent.

(13) A cannabinoid dressepceptor agonist or antagonist comprising as an active ingredient the compound according to any one of (2) to (6) or a pharmaceutically acceptable salt thereof, which is an antiallergic agent.

(14) A cannabinoid dressev yuichi agonist or antagonist comprising as an active ingredient the compound according to any of (2) to (6) or a pharmaceutically acceptable salt thereof, which is a therapeutic agent for nephritis.

Each group used in the present specification is described below.

“Alkyl” is a straight or branched chain having 1 to 10 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, Pentyl, isopentyl, neopentyl, t-pentyl, hexyl, isohexyl, neohexyl, heptyl and the like.

R ² , R ² ′, R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ preferably have 1 to 7 carbon atoms, and in R ⁶ , more preferably methyl. R ³ and R ⁴ preferably have 1 to 4 carbon atoms. R ¹ and R preferably have 4 to 6 carbon atoms. In R ¹⁰ and R ¹¹ are preferably those having a carbon number of 1-4. R ¹² and R ¹³ preferably have 1 to 4 carbon atoms.

“Alkenyl” is a straight or branched chain having 2 to 10 carbon atoms, specifically, vinyl, aryl, crotyl, 2-pentenyl, 3-pentenyl, 21-hexenyl, 3 —Hexenyl, heptenyl and the like.

R ⁶ , R ⁷ , R ⁸ and R ^g preferably have 2 to 7 carbon atoms. ! ^ And ¹ 'preferably have 4 to 7 carbon atoms.

“Alkynyl” is a straight or branched chain having 2 to 10 carbon atoms, specifically, ethynyl, provinyl, butynyl, 2-pentynyl, 3-pentynyl Hexyl, 2-hexynyl, 3-hexynyl, heptynyl and the like.

R ⁶ , R ⁷ , R ⁸ and R ⁹ preferably have 2 to 7 carbon atoms.

R ¹ and R preferably have 4 to 7 carbon atoms.

The “alkylene” in Alk is a linear or branched one having 1 to 4 carbon atoms, and specific examples include methylene, ethylene, trimethylene, and tetramethylene. More preferably, it is of ethylene.

“Alkenylene” in Alk is a straight-chain or branched-chain having 2 to 4 carbon atoms, and specific examples thereof include vinylene, propenylene, and butenylene.

The “alkoxy” for R ² ′ means that the alkyl moiety has 1 to 4 carbon atoms among the alkyls defined above, and specifically, methoxy, ethoxy, propoxy, isopropyloxy, butyloxy, t —Butoxy and the like.

“Cycloalkyl” is a monocyclic saturated cyclic alkyl having 3 to 8 carbon atoms, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexyl.

RR ′ R ⁶ , R ⁷ and R ⁸ preferably have 3 to 6 carbon atoms. R preferably has 3 to 7 carbon atoms, more preferably cyclohexyl.

RR ^l "Cycloalkylalkyl" in R ^6, R ⁷ and R ^8, der those 3-6 carbon atoms a cycloalkyl cycloalkyl portion is as defined above their is, alkyl portion is as defined above alkyl Among those having 1 to 4 carbon atoms. Specific examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl and the like.

“Aryl” in R II ¹ , R ⁶ , R ⁷ , R ⁸ and R specifically includes aromatic hydrocarbons such as phenyl, naphthyl and biphenyl, and is preferably phenyl.

RR ¹ ′ “aryl alkyl” in R ⁶ , R ⁷ , R ⁸ , R ¹² and R ¹³ means that the aryl part is an aryl as defined above, and the alkyl part is as defined above. It is an alkyl having 1 to 4 carbon atoms. Specific examples include benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl, biphenylmethyl and the like, and preferably benzyl.

The “heteroaryl” in RR ¹ R ⁶ , R ⁷ , R ⁸ and R may be saturated with a hydrogen atom. , Oxosazolyl, isoxazolyl, tetrazolyl, thiadiazolyl, oxaziazolyl, triazinyl, triazolyl, chenyl, pyrrolyl, pyrrolinyl, furyl, azepinyl, penzopyranyl, benzozoenyl, benzotriazolyl, indolyl, isoindolyl, isoindolyl, isoindolyl, isoindolyl, isoindolyl Quinazolinyl, quinoxalinyl, 1,8-naphthyridyl, 1,7-naphthyridyl, 1,6-naphthyridyl, 1,5-naphthyridyl, pyrido [2,3-d] pyrimidyl, thi [2,3-b] pyridyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperidino, piperazinyl, morpholino, hydroazepinyl, hydroindolyl, hydroisoindolyl, hydroquinolyl, hydroisoquinolyl, etc., preferably pyridyl, chenyl, Imidazolyl and morpholino.

The “heteroaryl formed by R ⁷ and R ⁸ together with an adjacent nitrogen atom” is a heteroaryl having one or more nitrogen atoms among the heteroaryls defined above. Specifically, pyrrolidinyl, imidazolidinyl, biperidino, biradizinyl, morpholino, pyrazolyl, imidazolyl, tetraVlyl, triazolyl, pyrrolyl, pyrrolinyl, indolyl, hydroazepinyl, hydroindolyl, hydroisoindolyl, hydroquinolyl, hydroquinolyl And morpholino, biperidino, pyrrolidinyl and imidazolyl.

RR ′ The term “heteroarylalkyl” in R ⁶ , R ⁷ and R ⁸ means that the heteroaryl portion is as defined above, and the alkyl portion has 1 to 4 carbon atoms among the alkyls defined above. Things. Specific examples include 2-phenylmethyl, 3-furylmethyl, 4-pyridylmethyl, 2-quinolylmethyl, 3-isoquinolylmethyl and the like, and preferably 4-pyridylmethyl.

The “benzene-condensed cycloalkyl” in R means that the cycloalkyl moiety is Cycloalkyl as defined above, specifically, for example, tetrahydronaphthylene, indane, or the like, preferably tetrahydronaphthalene.

The `` acyl '' in R ⁷ and R ⁸ is a carbonyl substituted with the above-defined alkyl or aryl as defined above, and specifically includes, for example, formyl, acetyl, propylionyl, benzoyl, naphthoyl and the like. Can be

Further, each group which may be substituted may be substituted with one or more substituents. The group used as the substituent will be described below.

"Halogen atom" is fluorine, chlorine, bromine and iodine.

“Alkyl”, “alkoxy” and “acyl” are as defined above for “alkyl”, “alkoxy” and “acyl”, respectively.

“Alkoxycarbonyl” means an alkyl moiety having 1 to 4 carbon atoms among the alkyls defined above. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like, and preferably ethoxycarbonyl.

“Alkylamino” means that the alkyl moiety has 1 to 4 carbon atoms among the alkyls defined above. Specific examples include methylamino, ethylamino, propylamino, butylamino, dimethylamino, and getylamino.

“Alkylthio” means that the alkyl moiety has 1 to 4 carbon atoms among the alkyls defined above. Specific examples include methylthio, ethylthio, propylthio, and butylthio.

“Alkylsulfinyl” means that the alkyl moiety has 1 to 4 carbon atoms among the alkyls defined above. Specific examples include methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl and the like.

“Alkylsulfonyl” means that the alkyl moiety has 1 to 4 carbon atoms among the alkyls defined above. Specific examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, and the like.

“Alkenyoxy” means that the alkenyl part thereof has 2 to 4 carbon atoms among the alkyls defined above. Specific examples include ethenyloxy, propenyloxy, butenyloxy and the like. “Asiloxy” has the above-defined acyl portion, and specific examples include formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy and the like, with acetyloxy being preferred.

The term "acylthio" has the above-defined acyl moiety, and specific examples include formylthio, acetylthio, propionylthio, butyrylthio, isoptyrylthio, and the like. Preferred is acetylsilthio.

“Acylamino” has the above-defined acyl portion, and specific examples include formylamino, acetylamino, propionylamino, butyrylamino, and the like, with acetylamino being preferred.

"Aralkyloxy" means that the aralkyl moiety is arylalkyl as defined above. Specific examples include benzyloxy, phenyloxy, phenylpropyloxy, phenylbutyloxy, naphthylmethyloxy, biphenylmethyloxy and the like.

"Heteroaryl formed by R ^{1 Q} and R ¹¹ together with an adjacent nitrogen atom" is defined as "heteroaryl formed by R ⁷ and R ⁸ together with an adjacent nitrogen atom." Is synonymous with

“Pharmaceutically acceptable salts” include, specifically, sodium metal salts, potassium salts, cesium salts and other alkaline metal salts; calcium salts, magnesium salts and other alkaline earth metal salts; Organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt; hydrochloride, hydrobromide, sulfate And inorganic salts such as phosphates; organic salts such as formate, acetate, trifluoroacetate, maleate and tartrate; sulfones such as methanesulfonate, benzenesulfonate and p-toluenesulfonate Acid salts; examples include, but are not limited to, amino acid salts such as arginine, aspartate, and glutamate.

In the present invention, various isomers, prodrugs, metabolites, hydrates, and solvates of each compound are also included.

Compound [1] can be produced, for example, as follows, but is not limited thereto. Production method

1st step

2nd step 3rd step ₂ R ¹³ [5]

4th step

Step 5 H ₂ N— (Alk) _r — R [8]

N Alk) `` R

H-I (

H [1]

(In the formula, R ¹² and R ¹³ are the same or different and represent hydrogen, alkyl, arylalkyl or cyano, and other symbols are as defined above.)

1st step

This step is a method of nitrating the ortho position of the formyl group on the benzene ring of the compound [2] to obtain the compound [3].

The compound [2] is reacted with fuming nitric acid in a solvent in the presence of concentrated sulfuric acid to give a nitro compound.

Examples of the solvent include ether solvents such as getyl ether, 1,2-dimethoxetane, tetrahydrofuran, and diglyme; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; Ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and isopropyl alcohol; acid solvents such as acetic acid and acetic anhydride; and preferably acetic acid. is there.

The reaction temperature is usually from −50 to 200 ° C., preferably from 110 to 60 ° C. The reaction time is generally 15 minutes to 48 hours, preferably 1 to 8 hours. The compound [3] can be obtained by reacting the obtained nitro compound with an alkyl compound such as bromopentane in a suitable solvent in the presence of a base. Suitable bases include, for example, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, n-butyllithium, s-butyllithium Tert-butyllithium, lithium diisopropylamide, and the like, and a carbon dioxide lime is preferable.

Suitable solvents include, for example, hydrocarbon solvents such as benzene, toluene, xylene and hexane; ether solvents such as getyl ether, 1,2-dimethyloxetane, tetrahydrofuran and diglyme; dichloromethane, chloroform and Halogen solvents such as carbon tetrachloride and 1,2-dichlorobenzene; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile, and acetone; methanol And alcoholic solvents such as ethanol, isopropyl alcohol and t-butanol. It is dimethylformamide.

The reaction temperature is usually from 110 to 200 ° C, preferably from 0 to 60 ° C. The reaction time is usually 15 minutes to 48 hours, preferably 1 to 8 hours.

Second step

The compound [4] can be obtained by reducing the nitro group of the compound [3] by a conventional method.

3rd step

Compound [4] can be condensed with malonic acid derivative [5] in the presence of a suitable acid or base to give compound [6]. Examples of the malonic acid derivative include getyl malonate, dimethyl malonate, dibenzyl malonate, ethyl cyanoacetate, and methyl cyanoacetate, and preferably dimethyl malonate is used. Suitable acids include, for example, benzoic acid, p-toluenesulfonic acid, acetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid and the like, preferably benzoic acid. Examples of the base include sodium hydride, potassium t-butoxide, sodium ethoxide, sodium methoxide, ammonium acetate, sodium acetate, piperidine, pyridine, pyrrolidine, n-methylmorpholine, morpholine, and triethylamine, and are preferable. Is biperazine.

Examples of the solvent include hydrocarbon solvents such as benzene, toluene, xylene, hexane, and heptane; ether solvents such as getyl ether, 1,2-dimethyloxetane, tetrahydrofuran, and diglyme; ethyl acetate, acetic acid Ester solvents such as methyl and ethyl acetate; polar solvents such as dimethylformamide, dimethyl sulfoxide, acetate nitrile, and acetone; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and t-butyl alcohol; And preferably toluene.

The reaction temperature is usually 0 to 150 ° C, preferably 120 ° C. The reaction time is generally 2 hours to 48 hours, preferably 24 hours.

4th step

Compound [7] can be obtained by hydrolyzing compound [6] in a solvent in the presence of a suitable base. Examples of the solvent include alcoholic solvents such as methanol, ethanol, isopropyl alcohol, and toluene, or water or a mixed solvent thereof.

Suitable bases include, for example, sodium carbonate, lithium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, n-butyllithium, s-butyl Lithium, t-butyllithium, lithium diisopropylamide and the like are preferred, and lithium carbonate is preferred.

Step 5

The target compound [1] can be obtained by reacting the compound [7] with the compound [8] as an activated carboxylic acid derivative.

Examples of the activated carboxylic acid derivative include, for example, an acid halide obtained by treating a carboxylic acid with thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, etc .; Triazole, N-hydroxysuccinimide, etc., dicyclohexylcarbodiimide (DCC),

1-Ethyl 3- (3-dimethylaminopropyl) carbodiimide (WSC) Active ester obtained by condensing with a condensing agent such as hydrochloride; carboxylic acid is converted to ethyl ethyl carbonate, And mixed acid anhydrides obtained by reaction with isobutyl carbonate and the like. Preferably, an active ester obtained from N-hydroxybenzotriazole using WSC hydrochloride as a condensing agent is used.

In the above reaction, a base can be allowed to coexist if necessary. Examples of the base include organic amines such as triethylamine, pyridine and N-methylmorpholine, and preferably triethylamine.

Examples of the solvent include hydrocarbon solvents such as benzene, toluene, hexane and xylene; ether solvents such as getyl ether, 1,2-dimethyloxetane, tetrahydrofuran and diglyme; dichloromethane, chloroform and tetrachloride Carbon, 1,

Halogen solvents such as 2-dichlorobenzene; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile, acetone and the like. Dimethylformamide It is.

The reaction temperature is generally 0 to 100 ° C, preferably 0 to 30 ° C. The reaction time is generally 15 minutes to 24 hours, preferably 1 to 12 hours.

The compound [1] produced as described above can be separated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, chromatography and the like.

Further, a pharmaceutically acceptable salt of compound [1] and various isomers of compound [1] can be produced by a conventionally known method.

Compound [1] and a pharmaceutically acceptable salt thereof are useful for mammals in the medical field in which cannabinoid drecept is known to be involved, particularly in the medical field involving peripheral cell-based tissues (immune diseases, It has medicinal effects in various inflammations, allergic diseases, nephritis, etc.

That is, the compound [1] and a pharmaceutically acceptable salt thereof selectively act on cannabinoid dress, especially peripheral receptors, have few central side effects, and have excellent immunomodulatory and anti-inflammatory properties. It has action, antiallergic action, and nephritis treatment effect. Accordingly, compound [1] and a pharmaceutically acceptable salt thereof are cannabinoid dressup (in particular, peripheral cannabinoid dressup) agonists and antagonists, immunomodulators, therapeutic agents for autoimmune diseases, anti-inflammatory agents, anti-inflammatory agents, It is useful as an allergic or nephritis treatment. When the compound [1] or a pharmaceutically acceptable salt thereof is used as a pharmaceutical preparation, usually, a pharmacologically acceptable carrier, excipient, diluent, bulking agent, disintegrant, Stabilizers, preservatives, buffers, emulsifiers, fragrances, coloring agents, sweeteners, thickeners, flavoring agents, solubilizing agents, and other additives, specifically water, vegetable oils, ethanol or benzyl Alcohols such as alcohol, polyethylene glycol, glycerol triacetate, gelatin, lactose, starch, etc., carbohydrates, magnesium stearate, talc, lanolin, petrolatum, etc. , Granules, suppositories, injections, eye drops, liquids, capsules, troches, aerosols, elixirs, suspensions, emulsions, syrups It forms a Do score and the can be administered orally or parenterally.

The dosage depends on the type and degree of the disease, the compound to be administered and the administration route, the age of the patient, It can vary depending on gender, weight, etc. In the case of oral administration, the compound [1] 0.1 to L: O mg, preferably 1 to 30 mg per day is administered to an adult in one or several divided doses.

In addition, the compound of the present invention can also be applied as a veterinary medicine. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.

Reference Example 1 (1st step)

4-Methoxy-1- 2-nitro-3-pentyloxybenzaldehyde

A suspension of a mixture of isovanillin (200 g), acetic acid (700 ml), and concentrated sulfuric acid (0.2 ml) was cooled to 0 ° C, and an acetic acid solution (200 ml) of fuming nitric acid (57.2 ml) was added for 30 minutes. It was dropped. After stirring for 40 minutes, water (400 ml) was added, and the crystals were collected by filtration to give 3-hydroxy-14-methoxy-2-nitrobenzenesaldehyde and 3-hydroxy-14-methoxy-6--2. A mixture with trobenzaldehyde (56.4 g) was obtained. Dimethylformamide (700 ml) was mixed with the obtained mixture, and potassium carbonate (136.7 g) and bromopentane (127.7 ml) were sequentially added to this solution. After stirring at 100 ° C. for 4 hours, the reaction solution was filtered, and water (600 ml) and hexane: ethyl acetate = 1: 1 (600 ml) were added to carry out liquid separation. The aqueous layer was extracted with hexane: ethyl acetate = 1: 1 (600 ml), the organic layers were combined, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the crystals formed by concentration under reduced pressure were filtered. Further, the filtrate is concentrated, and the generated crystals are collected by filtration. The filtrate is again concentrated, and the generated crystals are collected by filtration. The filtrate is concentrated to obtain 4-methoxy-12-nitro-13- Pentyloxybenzaldehyde was obtained as a red oil (117g). The crystals collected by filtration were combined to give 4-methoxy-6-nitro-13-pentyloxybenzaldehyde as yellow crystals (90. lg) (see Table 1).

Reference Example 2 (2nd step)

2-Amino 4- 4-Methoxy 3-Pentyloxy pentazaldehyde

4-Methoxy 2-Nitro-3-pentyloxybenza obtained in Reference Example 1 Rudehydride (2.213 g) was dissolved in ethanol (22 ml), stannic chloride dihydrate (9.34 g) was added, and the mixture was heated under reflux for 4 hours. The reaction solution was ice-cooled, and a saturated aqueous solution of sodium hydrogen carbonate was added to make an alkaline solution, followed by extraction with ethyl acetate (50 ml). The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 5: 1). 2-Amino-4-methoxy-3-pentyloxybenzaldehyde (1.675 g) was obtained (see Table 1).

Reference Example 3 (3rd step)

7 —Methoxy 2-oxo-1 8 —Pentyloxy 1,2 —dihydroquinoline —3-Rubonic acid methyl ester

The 2-amino-4-methoxy-13-pentyloxybenzaldehyde (1.675 g) obtained in Reference Example 2 was dissolved in toluene (16 ml), and dimethyl malonate (2.40 ml) and piperidine were added to this solution. (1.04 ml) and benzoic acid (80 ml) were added, and the mixture was heated with stirring at an external temperature of 120 ° C. for 27 hours. After the reaction solution was cooled to room temperature, a saturated aqueous solution of sodium hydrogen carbonate (1600 ml) was added thereto, and the organic layer was separated. The aqueous layer was extracted with toluene (30 ml). The organic layers were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. The drying agent is filtered off, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel chromatography (closure form: ethyl acetate = 1: 1) to give 7-methoxy-12-oxo-8-pentyloxy. There was obtained 1,1,2-dihydroquinoline-l-3-rubutyric acid methyl ester (251 mg) (see Table 1).

Reference Example 4 (4th step)

7-Methoxy 2-oxo-1 8-pentyloxy 1,2-dihydroquinoline-3-carboxylic acid

7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-13-carboxylic acid methyl ester (240 mg) obtained in Reference Example 3 was dissolved in methanol (7 ml) and water (3 ml). Sodium oxide (120 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction vessel was cooled on ice, concentrated hydrochloric acid was added to make an acid solution, and the mixture was extracted with ethyl acetate (20 ml). The organic layer is dried over anhydrous sodium sulfate, the desiccant is filtered off, and the solution is concentrated under reduced pressure. 7-Methoxy_2-oxo-8-pentyloxy 1,2-dihydroxy Norin-3-carboxylic acid (228 ml) was obtained (see Table 2).

Example 1

7-Methoxy 2-oxo- 8-pentyloxy 1,2-dihydroquinoline-l-3-carboxylic acid (2-pyridine-14-ylethyl) amide

7-Methoxy-2-oxo-1-8-pentyloxy-1,2-dihydroxyquinoline-3-carboxylic acid (30.0 mg) obtained in Reference Example 4 and 2-pyridine-14-ylethylamine (36.0 mg) and 1-hydroxybenzo Triazole hydrate (17.3 mg) was dissolved in dimethylformamide (2 ml), and 1-ethyl-13- (3-dimethylaminopropyl) carbodiimid hydrochloride (24.5 mg) was added to this solution under ice-cooling. Added in. After stirring at room temperature for 5 hours, ethyl acetate (3 ml) and saturated aqueous sodium hydrogen carbonate solution (3 ml) were added to the reaction solution to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, and the desiccant was filtered. After the separation, the residue obtained by concentrating the solvent under reduced pressure is purified by column chromatography (cloth form: methanol = 25: 1) to give 7-methoxy-1-oxo-one. 8-Pentyloxy-1,2-dihydroquinoline-13-caprolubonic acid (2-pyridine-4-ylethyl) amide (35 mg) was obtained as colorless crystals (see Table 3).

Example 2

7-Methoxy-1- 2-oxo-8-pentyloxy 1,2-dihydroquinoline-3-carboxylic acid (4-aminobenzyl) amide

Example 3

7-Methoxy-1- 2-oxo-8-pentyloxy-1,2-dihydroquinoline-13-carboxylic acid [2-4-aminophenyl) ethyl] amide

Example 4

7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylate (4-aminophenyl) amide hydrochloride

The compounds shown in Examples 2 to 4 were obtained in the same manner as in Example 1 above. Tables 3 and 4 show the physical properties of the compound. Shu) B ind i ng ass ay (nvitro) The specimens used were rat cerebellar membrane fraction and spleen cells as cannabinoid central (CB1) and peripheral (CB2) receptor rich tissues (Male SD rat, 7-9 Weeks). Specimen on round bottom 24 well plate (cerebellar membrane fraction: 5 μg / g

1, spleen ^{cells: 1 X 1 0 7 ce 1} 1 s / ml), labeled ligand ^([3 H] W in 5 5 2 1 2- 2 , 2 nM) and unlabeled W in 5 5 2 1 2- 2 Alternatively, a test substance was added, and the cerebellar membrane fraction was incubated at 30 ° C for 90 minutes, and the spleen cells were incubated at 4 ° C for 360 minutes. Assay buffer used was a 50 mM MT ris solution containing 0.2% BSA for the cerebellar membrane fraction, and 50 mM Tris-HBSS containing 0.2% BSA for spleen cells. After the incubation, the sample was filtered through a filter (Packard, Unifilter 24 GF / B), dried scintilation solution (Packard, Microsint-20) was added, and the radioactivity of the sample was measured (Packard, Top count). A9912V). Non-specific binding is obtained by adding an excess amount of WiN 5 52 1 2 -2 (1 μΜ), and specificity is obtained by subtracting non-specific binding from total binding obtained by adding only labeled ligand. Target binding was calculated. The test substance was dissolved in DMS 0 so that the final concentration of DMS 0 was 0.1%. Bound analyte, seeking IC 5 ₀ values from a percentage of specific binding, is calculated K i values of the test substance from which the ^[3 H] W in 5 5 2 1 2- 2 of K d values did.

[II] Force lagenin-induced paw edema model (inv ivo)

Female ddy mice (6-8 weeks old) were used. The volume of the right leg before administration was measured (Unicom, Prethysumometer TK-101), and 2 hours later, the test compound dissolved in olive oil was orally administered at 10 ml / kg. One hour after the administration, 50% of 1% carrageenin dissolved in physiological saline was intradermally administered to the right heel. Three hours later, the volume of the right foot was measured and compared with that before administration.

In test [II], the test compound was dissolved in DMSO and diluted with olive oil before use (final concentration of DMSO was 1%).

Table 5 shows the results of the tests [I] and [II].

Formulation examples are shown below, but are not limited thereto.

Formulation example

(a) 10 g of the compound of Example 1 (b) Lactose 50 g

(c) 15 g corn starch

(d) Sodium carboxymethyl cellulose 44 g

(e) Magnesium stearate l g

The total amount of (a), (b) and (c) and 30 g of (d) are kneaded with water, dried in vacuo and granulated. The granulated powder is mixed with 14 (d) and 1 g (e), and the mixture is made into tablets using a tableting machine to produce 1000 tablets each containing 1 Omg of (a). Industrial applicability

The compound [1] of the present invention and a pharmaceutically acceptable salt thereof can selectively act on cannabinoid dresses, especially peripheral receptors, have few central side effects, and have excellent immunomodulatory and anti-inflammatory effects. It has an antiallergic effect and a therapeutic effect on nephritis. Therefore, it is useful as a cannabinoid dressep (in particular, peripheral cannabinoid dressep) agonists and antagonists, immunomodulators, therapeutic agents for autoimmune diseases, anti-inflammatory agents, antiallergic agents, and therapeutic agents for nephritis.

twenty four

Table 3

9Z

€ 0 / 86df / IDd 66W0 / 66 OW Table 5

Ki value (nM) ED ₅₀ (mg / kg: po)

Central receptor Peripheral receptor Power-lagenin induction

C / S

(C) (S) Foot edema model

1 140 <0.4> 350 0.1

2 700 g 0.4> 1750 0.04

Claims

The scope of the claims

-General formula (1)

Wherein, W is - 0-, - S (0) t one, -C ³ R ⁴ - _S one ^{^{NR 5 -, -NR 5 C 0-}} , one CONR ⁵ -, -C_rei_0- or - OCO — (Wherein, R ³ and R ⁴ are the same or different and each represents a hydrogen atom or alkyl, R ⁵ represents a hydrogen atom or alkyl, and t represents 0 or an integer of 1 or 2), and R ¹ Represents alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl, and each group in R ¹ is alkyl, alkylamino, amino, hydroxyl, alkoxy, alkoxy, alkoxide aryloxycarbonyl, Ashiru, Ashiruokishi, Ashiruchio, mercapto, alkyl Chio, alkylsulfinyl or alkylsulfonyl may be substituted by, R ² is a hydrogen atom, an alkyl, one oR ⁶ (wherein In the formula, R ⁶ represents a hydrogen atom, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl., One NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ is the same or different and each represents a hydrogen atom, alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl, or R ⁷ and R ⁸ May form a heteroaryl with an adjacent nitrogen atom) or (CH ₂ ) _u , — S (0) _U ⁹ , wherein R ⁹ is a hydrogen atom, alkyl, alkenyl or alkynyl the, U is 0 or an integer of 1 to 2, u, represents shown.) an integer of 0 or 1乃Itaru 2, hydrogen atoms in the R ² Except for alkyl, alkylamino, amino, hydroxyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto, alkylthio, alkyl May be substituted with sulfinyl or alkylsulfonyl, Alk represents alkylene or alkenylene, and the alkylene and alkenylene in Alk are each a hydroxyl group; a carboxyl; an alkoxycarbonyl; a hydroxyl group, an alkoxy or an alkylthio which may be alkyl; in over CONR R ¹¹ (wherein, 11 ^{1 ()} and 1 ^ ¹ or ¹ indicates a hydrogen atom or an alkyl the same or different, or R ^{1 (5} and R ¹¹ are adjacent R may represent aryl, heteroaryl, cycloalkyl or benzene-fused cycloalkyl, and the aryl and heteroaryl may be each substituted with a nitrogen atom to form a heteroaryl. , Alkyl which may be substituted with a hydroxyl group, hydroxyl group, alkoxy, alkenyloxy, , Acyloxy, halogen atom, nitro, amino, sulfonamide, alkylamino, aralkyloxy, viridyl, biperidino, carbonyl, alkoxycarbonyl, acylamino, aminocarbonyl, cyano, and the cycloalkyl is a hydroxyl group. , Alkoxy, = 0, and the benzene-condensed cycloalkyl may be substituted with a hydroxyl group or alkoxy, and r represents 0 or 1.] or a pharmaceutically acceptable compound thereof. A cannabinoid dressing agonist or antagonist comprising a salt to be used as an active ingredient.

2. —General formula [1 ']

[Where W is — 0—, — S (0) _t- one, one CR ³ R ⁴ —, — NR ⁵ —, -NR ⁵ C 0—, — CONR ⁵ —, — C00— or one 0C0— ( wherein, R ³ and R ⁴ are each hydrogen atom or an alkyl identical or different, R ⁵ is a hydrogen atom or alkyl, t denotes shown.) 0 or an integer of 1 to 2, R ¹ 'is C4 to C6 alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl; Each group in R ", alkyl, Arukiruamino, Amino, hydroxyl, alkoxy, alkoxycarbonyl, Ashiru, Ashiruokishi, Ashiruchio, mercapto, alkylthio, alkylsulfinyl or alkylsulfonyl may be substituted by, R ^2, is alkyl, (in the formula, R ⁶ is a hydrogen atom, alkyl Le, alkenyl, alkynyl, Ariru, § reel alkyl, Heteroariru, to Teroari one Ruarukiru, cycloalkyl or cycloalkylalkyl.) -OR ^6, - N ⁷ R ⁸ (wherein, R ⁷ and R ⁸ are the same or different and each independently represents a hydrogen atom, an alkyl, an alkenyl, an alkynyl, an acyl, an aryl, an arylalkyl, a heteroaryl, a heteroarylalkyl, a cycloalkyl or a cycloalkylalkyl Show Or R ⁷ and R ⁸ may form a heteroaryl connexion such together with the adjacent nitrogen atom.), Or one _{_{(CH 2) U .- S (}} 0) U R 9 ( wherein, R ⁹ is a hydrogen atom, an alkyl, alkenyl or alkynyl, u a is 0 or 1 to 2 integer, u 'denotes a.) represents an integer of 0 or 1 to 2, the R ^2' each respective group in, May be substituted with alkyl, alkylamino, amino, hydroxyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, acylsil, mercapto, alkylthio, alkylsulfinyl, alkylsulfonyl, and R is aryl, heteroaryl, cycloalkyl or benzene condensation Represents cycloalkyl, and the aryl and heteroaryl are each an alkyl, a hydroxyl group, an alkoxy group which may be substituted with a hydroxyl group. Si, alkenyloxy, acyl, acyloxy, halogen atom, nitro, amino, sulfonic acid amide, alkylamino, aralkyloxy, pyridyl, biperidino, carboxyl, alkoxycarbonyl, acylamino, aminocarbonyl, cyano may be substituted. The cycloalkyl may be substituted with a hydroxyl group, alkoxy, = 0, the benzene-condensed cycloalkyl may be substituted with a hydroxyl group, alkoxy, and m represents 0 or an integer of 1 to 5. Or a pharmaceutically acceptable salt thereof.

3. W is —0—, R ¹ is alkyl having 4 to 6 carbon atoms, R ² is alkoxy, and R is aryl or heteroaryl (where the aryl and heteroaryl are It may be substituted with an alkyl group which may be substituted with a hydroxyl group, a hydroxyl group, an alkoxy, an alkenyloxy, an acyl, an acyloxy, a halogen atom, a nitro, It may be substituted with amino, sulfonic acid amide, alkylamino, aralkyloxy, pyridyl, biperidino, carboxyl, alkoxycarbonyl, acylamino, aminocarbonyl, or cyano. 3. The compound according to claim 2, wherein m is 0 or an integer of 1 to 2, or a pharmaceutically acceptable salt thereof.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein the substitution position of WR is at the j-position of the benzene ring, and the substitution position of R ² is at the i-position of benzene.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 4, wherein aryl in R is phenyl and heteroaryl is pyridine.

6.7 —Methoxy 1 2 —Oxo 1 8 —Pentyloxy 1,2-dihydroquinoline 1 —3-Rubonic acid (2-Pyridine 1-ylethyl) amide, 7—Methoxy 2 —Oxo 1 8 — Pentyloxy 1,2-dihydroquinoline 1-3-carboxylic acid (4-aminobenzyl) amide, 7-methoxy-12-oxo-1 8-pentyloxy 1,2-dihydroquinoline-13-carboxylic acid [2- (4 -Aminophenyl) ethyl] amide and a compound according to claim 5, which is selected from 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-13-potassium (4-aminophenyl) amide. Or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising the compound according to any one of claims 2 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.

8. A cannabinoid receptor agonist or antagonist comprising the compound according to any one of claims 2 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.

9. Cannabinoid dressing comprising the compound according to any one of claims 2 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the cannabinoid dressing is a peripheral cannabinoid dressing. Drug or antagonist.

10. A cannabinoid dressing receptor agonist or antagonist comprising the compound according to any one of claims 2 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient, which is an immunomodulator.

11. A cannapinoid dressing inhibitor or antagonist comprising the compound according to any one of claims 2 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient, which is a therapeutic agent for an autoimmune disease.

12. A cannabinoid dressing receptor agonist or antagonist comprising the compound according to any one of claims 2 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient, which is an anti-inflammatory agent.

13. A cannabinoid dressing agonist or antagonist comprising the compound according to any one of claims 2 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient, which is an antiallergic agent.

14. A cannabinoid dressing receptor agonist or antagonist comprising as an active ingredient the compound according to any one of claims 2 to 6 or a pharmaceutically acceptable salt thereof as a therapeutic agent for nephritis.