US 2003/0191069 A1 · 2-oxoquinoline compounds and pharmaceutical uses thereof

Abstract

A 2-oxoquinoline compound or its pharmaceutically acceptable salt of general formula [I]: 1 (wherein each symbol in the formula is as determined in the description), and its pharmaceutical use. The compound [I] of the present invention and its pharmaceutically acceptable salts selectively act on cannabinoid receptors, particularly on peripheral type cannabinoid receptors, and have fewer side effects on the central nervous system, having great immunosuppressive action, anti-inflammatory action or antiallergic action. Therefore, these compounds are useful as cannabinoid receptors (particularly peripheral type cannabinoid receptors) modulator, immunosuppressants, anti-inflammatory agents, and antiallergic agents.

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Claims20

Dependent claims

A cannabinoid receptor modulator comprising, as an active ingredient, a 2-oxoquinoline compound represented by the following general formula [I] or its pharmaceutically acceptable salt:

112
where
W means —O—, —S(O)t—, —CR3R4—, —NR5—, —NR5CO—, —CONR5—, —COO— or —OCO— (where R3 and R4 may be identical or different and represent hydrogen atom or alkyl;
R5 represents hydrogen atom or alkyl;
and t indicates an integer, 0, 1 or 2);
R1 represents hydrogen atom, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl;
each group of R1, except hydrogen atom, may be substituted or unsubstituted with alkylamino, amino, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto, alkylthio, alkylsulfinyl or alkylsulfonyl;
each group, except hydrogen atom and alkyl, may be substituted or unsubstituted with alkyl;
R2 represents hydrogen atom, alkyl, —OR6 (where R6 represents hydrogen atom, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl), —NR7R8 (where R7 and R8 may be identical or different and represent hydrogen atom, alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl;
or R7 and R8, together with the adjacent nitrogen atom, can form a heteroaryl);
or —(CH2)u′—S(O)uR9 (where R9 represents hydrogen atom, alkyl, alkenyl or alkynyl, each of u and u′ independently represents an integer, 0, 1 or 2);
each group of R2, except hydrogen atom, may be substituted or unsubstituted with alkylamino, amino, hydroxy, alkoxy, alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto, alkylthio, alkylsulfinyl or alkyl sulfonyl;
each group, except hydrogen atom and alkyl, may be substituted or unsubstituted with alkyl;
Ra represents hydrogen atom or alkyl;
X represents —COORb, —CONH2, —CONRc-(Alka)r-R, —(CH2)p—OC(═Y)—NRd- (Alkb)g-R, —(CH2)q—NRe—C(=z)-(NRf)w-(Alkc)v-R, —(CH2)p—OH or —(CH2) q—NReRe′
(where each of Rb, Rc, Rd, and Rf independently represents hydrogen atom or alkyl;
each of Re and Re′ independently represents hydrogen atom or alkyl;
or Re and Re′, together with the adjacent nitrogen atom, can form a heteroaryl;
each of Alka, Alkb and Alkc independently represents alkylene or alkenylene;
each of the alkylene and alkenylene may be substituted or unsubstituted with hydroxy, carboxy, alkoxycarbonyl, alkyl (the alkyl may be substituted or unsubstituted with hydroxy, alkoxy or alkylthio) or —CONR10R11
(where R10 and R11 may be identical or different and represent hydrogen atom or alkyl;
or R10 and R11, together with the adjacent nitrogen atom, can form a heteroaryl);
R represents aryl, heteroaryl, cycloalkyl, benzene-condensed cycloalkyl or
113
where
A and B independently represent oxygen atom, nitrogen atom or sulfur atom;
k indicates an integer of 1-3;
each of the aryl and heteroaryl may be substituted or unsubstituted with an alkyl substituted or unsubstituted with hydroxy or may be substituted or unsubstituted with a hydroxy, alkoxy, alkenyloxy, acyl, acyloxy, halogen atom, nitro, amino, sulfonamide, alkylamino, aralkyloxy, pyridyl, piperidino, carboxy, alkoxycarbonyl, acylamino, aminocarbonyl, cyano or glucuronic acid residue;
the cycloalkyl may be substituted or unsubstituted with a hydroxy, alkoxy or ═O;
the benzene-condensed cycloalkyl may be substituted or unsubstituted with a hydroxy or alkoxy;
each of r, s, v and w independently represents 0 or 1;
each of Y and Z independently represents a nitrogen atom, oxygen atom or sulfur atom;
and each of p and q independently represents an integer of 1-4).

30 more elements

A 2-oxoquinoline compound as represented by the following general formula [I′] or its pharmaceutically acceptable salt:

115
where W means —O—, —S(O)t—, —CR3R4—, —NR5—, —NR5CO—, —CONR5—, —COO— or —OCO— (where R3 and R4 may be identical or different and represent hydrogen atom or alkyl;
R5 represents hydrogen atom or alkyl;
and t indicates an integer, 0, 1 or 2);
R1 represents hydrogen atom, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl;
each group of R1, except hydrogen atom, may be substituted or unsubstituted with alkylamino, amino, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto, alkylthio, alkylsulfinyl or alkylsulfonyl;
each group, except hydrogen atom and alkyl, may be substituted or unsubstituted with alkyl;
R2 represents hydrogen atom, alkyl, —OR6 (where R6 represents hydrogen atom, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl), —NR7R8 (where R7 and R8 may be identical or different and represent hydrogen atom, alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl;
or R7 and R8, together with the adjacent nitrogen atom, can form a heteroaryl);
or —(CH2)u′—S(O)uR9 (where R9 represents hydrogen atom, alkyl, alkenyl or alkynyl, each of u and u′ independently represents an integer, 0, 1 or 2);
each group of R2, except hydrogen atom, may be substituted or unsubstituted with alkylamino, amino, hydroxy, alkoxy, alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto, alkylthio, alkylsulfinyl or alkyl sulfonyl;
each group, except hydrogen atom and alkyl, may be substituted or unsubstituted with alkyl;
Ra represents hydrogen atom or alkyl;
X′ represents —CONRc-(Alka)r-R, —(CH2)p—OC(═y)—NRd-(Alkb)a-R or—(CH2)q—NRe—C (=Z)-(NRf)w-(Alkc)v-R,
where each of Rc, Rd, Re and Rf independently represents hydrogen atom or alkyl;
each of Alka, Alkband Alkc independently represents alkylene or alkenylene;
each of the alkylene and alkenylene may be substituted or unsubstituted with hydroxy, carboxy, alkoxycarbonyl, alkyl (the alkyl may be substituted or unsubstituted with a hydroxy, alkoxy or alkylthio);
or —CONR10R11 (where R10 and R11 may be identical or different and represent hydrogen atom or alkyl;
or R10 and R11, together with the adjacent nitrogen atom, can form a heteroaryl);
R represents aryl, heteroaryl, cycloalkyl, benzene-condensed cycloalkyl or
116
where
A and B independently represent oxygen atom, nitrogen atom or sulfur atom;
k indicates an integer of 1-3;
each of the aryl and heteroaryl may be substituted or unsubstituted with an alkyl substituted or unsubstituted with hydroxy or may be substituted or unsubstituted with a hydroxy, alkoxy, alkenyloxy, acyl, acyloxy, halogen atom, nitro, amino, sulfonamide, alkylamino, aralkyloxy, pyridyl, piperidino, carboxy, alkoxycarbonyl, acylamino, aminocarbonyl, cyano or glucuronic acid residue;
the cycloalkyl may be substituted or unsubstituted with a hydroxy, alkoxy or ═O;
the benzene-condensed cycloalkyl may be substituted or unsubstituted with a hydroxy or alkoxy;
each of r, s, v and w independently represents 0 or 1;
each of Y and Z independently represents a nitrogen atom, oxygen atom or sulfur atom;
and each of p and q independently represents an integer of 1-4,
provided that:
(a) when R2 is a hydrogen atom, then WR1 is substituted at position-j of 2-oxoquinoline;
and
(b) 1,2-dihydro-6,7-dimethoxy-2-oxo-N-(phenylmethyl)-3-quinolinecarboxamide and N-(1,2-dihydro-6,7-dimethoxy-2-oxo-3-quinolyl) benzamide are excluded.

31 more elements

Dependencies are inferred from the claim text.

Description18,080 words

Summary10,370 words

#The present invention relates to novel 2-oxoquinoline compounds and pharmaceutical uses thereof. In addition, the invention relates to novel uses of some types of 2-oxoquinoline compounds. More specifically, the invention relates to novel 2-oxoquinoline compounds that selectively act on cannabinoid receptors, particularly on peripheral cannabinoid receptors, and that have immunomodulating action, anti-inflammatory action, and antiallergic action with fewer side effects on the central nervous system and to pharmaceutical uses thereof.

#So far, a series of compounds named cannabinoids, which comprise C, H, and O, are known as constituents of cannabis. It has also been known that, among them, tetrahydrocannabinol (THC) is a major hallucinogen, and that a principal ingredient contained in the cannabis plant is Δ9-THC. It has been reported that Δ9-THC has actions including ataxia, increased sensitivity to stimulation, antiemetic action, analgesic action, hypothermic action, respiratory depression, catalepsy-inducing action, vasodilator action, immunosuppressive action, etc.

#The sites of these actions of Δ9-THC are roughly categorized into the central nervous system (Devane et al., Mol Pharmacol. 1988, 34, 605-613; Hollister et al., Pharmacol. Rev., 1986, 38, 1-20; Renu et al., Prog. Drug Res., 1991, 36, 71-114) and the peripheral tissues (Nye et al., J. Pharmacol. Exp. Ther., 1985, 234, 784-791; Flynn et al., Mol Pharmacol. 1992, 41, 736-742). There are reports suggesting that some of the actions on the central nervous system are medically applicable.

Detailed description7,710 words

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

#2-Amino-4-methoxy-3-pentyloxybenzaldehyde (1.675 g) obtained in Reference Example 2 was dissolved in toluene (16 ml), to which dimethyl malonate (2.40 ml), piperidine (1.04 ml), and benzoic acid (80 ml) were added, and the mixture was stirred 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 hydrogencarbonate (1600 ml) was added thereto to separate the organic layer, and the aqueous layer was extracted with toluene (30 ml). The combined organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered to remove the desiccating agent, and concentrated under reduced pressure. The residue was purified through silica-gel chromatography (eluent: a mixture of chloroform and ethyl acetate at a ratio of 1:1) to obtain the title compound (251 mg) (Table 5).

#7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid methyl ester (Example 1-1)

2-oxoquinoline compounds and pharmaceutical uses thereof

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2-oxoquinoline compounds and pharmaceutical uses thereof

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Abstract

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Claims20

Description18,080 words

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Description18,080 words

Classification9 codes

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