WO1999002499A1 - Composes quinoline et utilisations de ceux-ci en medecine - Google Patents

Composes quinoline et utilisations de ceux-ci en medecine Download PDF

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Publication number
WO1999002499A1
WO1999002499A1 PCT/JP1998/003089 JP9803089W WO9902499A1 WO 1999002499 A1 WO1999002499 A1 WO 1999002499A1 JP 9803089 W JP9803089 W JP 9803089W WO 9902499 A1 WO9902499 A1 WO 9902499A1
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Prior art keywords
alkyl
heteroaryl
pharmaceutically acceptable
cycloalkyl
alkoxy
Prior art date
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PCT/JP1998/003089
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English (en)
Japanese (ja)
Inventor
Takashi Inaba
Tetsudo Kaya
Hiroyuki Iwamura
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Japan Tobacco Inc.
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Publication date
Application filed by Japan Tobacco Inc. filed Critical Japan Tobacco Inc.
Priority to KR1020007000255A priority Critical patent/KR20010021696A/ko
Priority to AU81279/98A priority patent/AU8127998A/en
Publication of WO1999002499A1 publication Critical patent/WO1999002499A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • 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.
  • a compound group consisting of a series of C, H, and 0 called cannapinoid was known as a cannabis component.
  • THC tetrahydrocannabinol
  • mu 9-THC mu 9-THC is the main component contained in cannabis.
  • Pharmacological effects of this ⁇ 9-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.
  • peripheral cell-type receptors such as those on macrophages (Munnro et al., Nature, 1993, 365, 61-65)
  • peripheral cell-type receptors have been shown to modulate the immune response to produce anti-inflammatory effects.
  • 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.
  • 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.
  • 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.
  • 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.).
  • the present invention is as follows (1) to (14).
  • 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
  • R 1 represents alkyl
  • 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 -.
  • 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 ⁇ optimum 2, dividing the hydrogen atoms in the R 2
  • 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 benzene-condensed cycloalkyl may be substituted by a hydroxyl group or an alkoxy, and r represents 0 or 1.
  • 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
  • w is —0—
  • R 1 is alkyl having 4 to 6 carbon atoms
  • R 2 ′ is alkoxy
  • 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.
  • m is 0 or an integer of 1 or 2.
  • a pharmaceutical composition comprising the compound according to any one of (2) to (6) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Alkyloxy 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.
  • Compound [1] can be produced, for example, as follows, but is not limited thereto. Production method
  • R 12 and R 13 are the same or different and represent hydrogen, alkyl, arylalkyl or cyano, and other symbols are as defined above.
  • 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.
  • the solvent examples 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.
  • 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
  • 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.
  • hydrocarbon solvents such as benzene, toluene, xylene and hexane
  • ether solvents such as getyl ether, 1,2-dimethylox
  • 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.
  • the compound [4] can be obtained by reducing the nitro group of the compound [3] by a conventional method.
  • Compound [4] can be condensed with malonic acid derivative [5] in the presence of a suitable acid or base to give compound [6].
  • suitable acid or base examples 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.
  • the solvent examples 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.
  • hydrocarbon solvents such as benzene, toluene, xylene, hexane, and heptane
  • ether solvents such as getyl ether, 1,2-dimethyloxetane, tetrahydrofuran, and diglyme
  • 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.
  • Compound [7] can be obtained by hydrolyzing compound [6] in a solvent in the presence of a suitable base.
  • a 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.
  • 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),
  • a base can be allowed to coexist if necessary.
  • the base include organic amines such as triethylamine, pyridine and N-methylmorpholine, and preferably triethylamine.
  • solvent examples 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a pharmacologically acceptable carrier 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 benzy
  • 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.
  • 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.
  • the compound of the present invention can also be applied as a veterinary medicine.
  • 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).
  • 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).
  • 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
  • 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.
  • mice 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.
  • 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].
  • 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.

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Abstract

L'invention concerne des composés représentés par la formule générale (1), ou des sels de ceux-ci, acceptables sur le plan pharmacologique. Dans cette formule, chaque symbole possède les notations données dans la description. Ces composés (1) et leurs sels agissent sélectivement sur les récepteurs cannabinoïdes, notamment sur les récepteurs périphériques, et possèdent d'excellents effets immunosuppresseurs, anti-inflammatoires, antiallergiques et thérapeutiques vis-à-vis des néphrites, et peu d'effets secondaires sur le système nerveux central. Aussi, ces composés sont utiles en tant qu'agonistes et antagonistes des récepteurs cannabinoïdes (notamment les récepteurs périphériques), en tant qu'immunosuppresseurs, agents anti-inflammatoires et antiallergiques, et en tant que médicaments destinés à soigner les néphrites.
PCT/JP1998/003089 1997-07-11 1998-07-09 Composes quinoline et utilisations de ceux-ci en medecine WO1999002499A1 (fr)

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KR1020007000255A KR20010021696A (ko) 1997-07-11 1998-07-09 퀴놀린 화합물 및 그의 의약용도
AU81279/98A AU8127998A (en) 1997-07-11 1998-07-09 Quinoline compounds and medicinal uses thereof

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