MXPA01001378A - 1h-imidazopyridine derivatives - Google Patents

Abstract

1H-Imidazopyridine derivatives represented by general formula (I);or salts thereof (wherein R1 is hydrogen, hydroxyl, alkyl, cycloalkyl, styryl or aryl;R2 is hydrogen, alkyl, halogeno, hydroxyl, amino, cyclic amino or phenoxy;A is an optionally substituted homo- or hetero-cycle;R3 is a saturated nitrogenous heterocyclic group;and m is an integer of 0 to 3). The above compounds exhibit excellent production-inhibiting activities against TNF or IL-1, thus being extremely useful as preventive or therapeutic agents for diseases due to these cytokines.

Description

1H-IMIDAZOPIRIDINE DERIVATIVES DESCRIPTION OF THE INVENTION The present invention relates to novel 1H-imidazopyridine derivatives or salts thereof having a potent inhibitory action against production of tumor necrotizing factor (TNF) or interleukin-1 (IL-). 1) and are useful as medicaments for preventive or therapeutic treatment of human and animal diseases, in which a cytokine such as TNF, IL-1 is mediated, which includes chronic inflammatory diseases (e.g. rheumatic arthritis, osteoarthritis, etc.). ), allergic rhinitis, atopic dermatitis, contact dermatitis, asthma, sepsis, septic shock, various autoimmune diseases [autoimmune hemic diseases (eg, hemolytic anemia, anaplastic anemia, idiopathic thrombocythemia, etc.), autoimmune intestinal diseases) for example, ulcerative colitis, Crohn's disease, etc.), autoimmune corneitis (for example, keratoconjunctivitis sicca, spring catarrh , etc.), endocrine ophthalmopathy, Graves disease, sarcoid granuloma, multiple sclerosis, systemic erythematodes, multiple chondritis, pachydermia, chronic active hepatitis, mastelia gravis, psoriasis, interstitial pulmonary fibrosis and the like], diabetes, cancer cachexia, infectious cachexia HIV and similar.

Some compounds having the structure of 1H-imidazoquinoline are known to be analogous to the compounds of the present invention. Journal of Medicinal Chemistry, Vol. 11, p. 87 (1968) describes l- (2-piperidinoethyl) -lH-imidazo [4,5-c] quinoline, Japanese Unexamined Patent Publication (KOKAI) No. SHO 60-123488 / 1985 describes 1-isobutyl-H-imidazo [4,5-c] quinolin-4-amine (general name: imiquimod) as a compound having an antiviral action, and Hungarian Patent Publication No. 34479 (Patent No. 190109) discloses 1- (2-diethylamino- ethyl-H-imidazo [4,5-c] quinoline as a compound having analgesic and anticonvulsant actions, however, lH-imidazopyridine derivatives such as those according to the present invention have never been known until now. imiquimod mentioned above has been known to have an induction action of a few classes of cytokines such as interferon (IFN) TNF, IL-1 and the like, which are described in Journal of Interferon Research, Vol. 14, p.81 ( 1994) However, the derivatives of lH-imidazoporidine or derivatives of 1H-imidazoquinoline that have as an action Inhibitor against the production of TNF or IL-1, whose action is totally opposite to that taught by the aforementioned techniques, have never been known before.

It is an object of the present invention to provide novel compounds which have excellent inhibitory actions against the production of cytokines such as TNF and IL-1, the like being useful as medicaments. Intense studies have been done to achieve the object. As a result, novel 1H-imidazopyridine derivatives having excellent inhibitory action against the production of TNF or IL-1 were found and the present invention is achieved. The present invention thus relates to the novel IH-imidazopyridine derivatives represented by the following general formula (I) or salts thereof. wherein R1 represents a hydrogen atom, a hydroxyl group, an alkyl group which may have one or more substituents, a cycloalkyl group which may be substituted, a styryl group which may be substituted, or an aryl group which may be substituted have one or more substituents; R 2 represents a hydrogen atom, an alkyl group, a halogen atom, a hydroxyl group, an amino group which may have one or two substituents, a cycloamino group which may be substituted, or a phenoxy group which may be substituted; ring A represents a homocyclic or heterocyclic ring which may be substituted with one or more alkyl groups, alkoxy groups, or halogen atoms; R3 represents a heterocyclic group containing saturated nitrogen which may be substituted; and m represents an integer from 0 to 3; with the proviso that, when R3 represents an unsubstituted piperidino group, at least one of R1 and R2 is not a hydrogen atom. According to the second embodiment of the present invention, novel lH-imidazopyridine derivatives represented by the following general formula (II) or salts thereof are provided: wherein R1, R2, ring A and m have the same meanings as those defined above; R4 represents a hydrogen atom, an alkyl group, a benzyl group, a triphenylmethyl group, an alkanoyl group which may be substituted, an alkoxycarbonyl group, a benzyloxycarbonyl group, a thiocarbamoyl group which may be substituted, an alkanesulfonyl group, a group benzenesulfonyl which may be substituted, or an amidino group; Y represents a methylene group, an oxygen atom, a sulfur atom, a nitrogen atom, a group represented by NH, or a single bond; and n represents an integer from 0 to 2. According to the third embodiment of the present invention, among the compounds represented by the general formulas (I) and (II) mentioned above, the compounds wherein ring A is a benzene ring, or thiophene ring, or the salts thereof. According to another aspect, a medicament is provided which comprises as an active ingredient the compound represented by the general formula (I) or (II) mentioned above, or a pharmacologically acceptable salt thereof. The medicament is useful for preventive or therapeutic treatment or diseases of mammals including humans, in which a cytokine such as TNF, IL-1 is mediated, which includes chronic inflammatory diseases (e.g., rheumatic arthritis, osteoarthritis, etc.), allergic rhinitis, atopic dermatitis, contact dermatitis, asthma, sepsis, septic shock, various autoimmune diseases [autoimmune hemic diseases (eg, hemolytic anemia, anaplastic anemia, idiopathic thrombocythemia, etc.), autoimmune intestinal diseases (eg, ulcerative colitis) , Crohn's disease, etc.), autoimmune corneitis (for example, keratoconjunctivitis sicca, spring catarrh, etc.), endocrine ophthalmopathy, Graves disease, sarcoid granuloma, multiple sclerosis, systemic erythematoses, multiple chondritis, pachydermia, chronic active hepatitis , graft misenance, psoriasis, interstitial pulmonary fibrosis and the like], diabetes, cachexia can waxy, HIV infectious cachexia and the like. According to another aspect, there is provided a use of the compound represented by the general formula (I) or (II) mentioned above, or a pharmacologically acceptable salt thereof for the manufacture of the aforementioned medicament; and a method for the preventive or therapeutic treatment of diseases in which a cytokine such as TN, IL-1 is mediated, comprising the step of administering a preventive or therapeutically effective amount of the compound represented by the general formula (I) or ( II) mentioned above, a pharmacologically acceptable salt thereof, to a mammal including a human. In addition, the present invention provides an inhibitor against the production of tumor necrotizing factor (TNF) or interleukin-1 (IL-1) which comprises as an active ingredient the compound represented by the general formula (I) or (II) mentioned above, or a pharmacologically acceptable salt thereof. Specific explanations of the compounds of the above-mentioned general formulas (I) and (II) of the present invention will be given below. The compounds represented by the above-mentioned general formula (II) are characterized in that they have a specific saturated nitrogen containing heterocyclic group which may have specific substituents such as R3 among the compounds represented by the general formula (I) mentioned above. However, the scope of the present invention is not limited to the compounds represented by the general formula (II) mentioned above, and it should be understood that any compounds having as R3 a heterocyclic group containing saturated nitrogen which may be substituted fall within the scope of the present invention. In the general formulas (I) and (II) mentioned above examples of alkyl groups represented by R 1, R 2 or R 4 include, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a n-group -butyl, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, an n-hexyl group and the like.

Examples of the cycloalkyl group represented by R 1 include, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like. Examples of the aryl group, represented by R 1 include, for example, a phenyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 3-pyridazinyl group, a 4-pyridazinyl group, a 2-group pyrimidinyl, a 4-pyrimidinyl group, a 5-pyrimidinyl group, a pyrazinyl group, a 2-furyl group, a 3-furyl group, a 2-thienyl group, a 3-thienyl group, a 1-pyrrolyl group, a 2-pyrrolyl group, a 3-pyrrolyl group, a 1-imidazolyl group, a 2-imidazolyl group, a 4-imidazolyl group, a 1-pyrazolyl group, a 3-pyrazolyl group, a 4-pyrazolyl group, a group 5 -pyrazolyl, a 2-oxazolyl group, a 4-oxazolyl group, a 3-isoxazolyl group, a 4-isoxazolyl group, a 5-isoxazolyl group, a 2-thiazolyl group, a 4-thiazolyl group, a 5-thiazolyl group , a 3-isothiazolyl group, a 4-isothiazolyl group, a 5-isothiazolyl group, a 1,2,3-triazol-1-yl group, a 1, 2, 3-triazol-4-yl group, a 1 group , 2, 3-triazol-5-yl, a 1,2,4-triazol-1-yl group, a group 1, 2, 4-triazol-3-yl, a 1,2-triazol-5-yl group, a 1-tetrazolyl group, a 5-tetrazolyl group, a 1, 2, 5-thiadiazole-3 group ilo, a 1-indolyl group, a 2-indolyl group, a 3-indolyl group and the like.

Examples of the halogen atom represented by R 2 include, for example, fluorine atom, chlorine atom, bromine atom and iodine atom. Examples of the amino group which may have one or two substituents represented by R2 include, for example, an amino group, a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, a cyclopropylamino group, a group cyclobutylamino, a cyclopentylamino group, a cyclohexylamino group, a dimethylamino group, a diethylamino group, an anilino group, a pyridylamino group, a 4-pyridylmethylamino group, a benzylamino group, a p-methoxybenzylamino group, a dibenzylamino group and the like. Examples of the cycloamino group represented by R 2 include, for example, a 1-aziridinyl group, a 1-azeitidinyl group, a 1-pyrrolidinyl group, a piperidino group, a 1-piperazinyl group, a hexahydro-1 H-azepin-1 group ilo, a hexahydro-lH-1,4-diazepin-1-yl group, a morpholino group, a 4-thiomorpholino group and the like. Examples of the homocyclic or heterocyclic ring represented by ring A in the general formulas (I) and (II) mentioned above, include, for example, a benzene ring, a cyclopentene ring, a cyclohexene ring, a cycloheptene ring, a cyclooctene ring, a cycloheptadiene ring, a thiophene ring, a furan ring, a pyridine ring, a pyrazine ring, a pyrrole ring, a thiazole ring, an oxazole ring, an azepine ring and the like. Examples of the alkyl group which may be substituted on the homocyclic or heterocyclic ring include, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec group -butyl, a tert-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, an n-hexyl group and the like. Examples of the alkoxy group which may be substituted on the ring include, for example, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentyloxy group, an isopentyloxy group, a neopentyloxy group, an n-hexyloxy group and the like. Example of the halogen atom which may be substituted on the ring include, for example, fluorine atom, chlorine atom, bromine atom and iodine atom. The number and kind of these substituents are not particularly limited, and when two or more substituents exist, they may be the same or different. In the general formula (I) mentioned above, the heterocyclic group containing saturated nitrogen represented by R3 means a heterocyclic group containing saturated nitrogen which has one or more nitrogen atoms as atoms constituting the ring, and that can also have one or more oxygen atoms or sulfur atoms as atoms that make up the ring. Examples include a 1-aziridinyl group, a 2-aziridinyl group, a 1-azetidinyl group, a 2-azetidinyl group, a 3-azetidinyl group, a 1-pyrrolidinyl group, a 2-pyrrolidinyl group, a 3-pyrrolidinyl group , a pyrazolidinyl group, imidazolinyl group, a piperidino group, a 2-piperidyl group, a 3-piperidyl group, a 4-piperidyl group, a 1-piperazinyl group, a 2-piperazinyl group, a hexahydro-lH-azepinyl group 1-yl, a hexahydro-lH-azepin-2-yl group, a hexahydro-lH-azepin-3-yl group, a hexahydro-lH-azepin-4-yl group, a hexahydro-lH-1, 4- group diazepin-1-yl, a hexahydro-lH-1,4-diazepin-2-yl group, a hexahydro-lH-1,4-diazepin-5-yl group, a hexahydro-lH-1,4-diazepin- 6-yl, a 2-morpholinyl group, a 3-morpholinyl group, a morpholino group, a 2-thiomorpholinyl group, a 3-thiomorpholinyl group, a 4-thiomorpholinyl group, a 3-isoxazolidinyl group, a 3-isothiazolidinyl group, a 1,2,3-triazolidin-4-yl group, a 1,2,4-triazolidin-3-yl group, or n group 1, 2, 5-thiadiazolin-3-yl and the like, and preferred groups include, for example, a 3-piperidyl group, a 4-piperidyl group, a 1-piperazinyl group, a 2-piperazinyl group, a group 3-pyrrolidinyl, a 2-azetidinyl group, a 3-azetidinyl group, a 2-morpholinyl group, a 2-thiomorpholino group and the like.

In the general formula (II) mentioned above, examples of alkanoyl group, which may be substituted which are represented by R 4 include, for example, a formyl group, an acetyl group, a propionyl group, an n-butyryl group, an isobutyryl group , a valeryl group, an isovaleryl group, a pivaloyl group, a fluoroacetyl group, a difluoroacetyl group, a trifluoroacetyl group, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group and the like. Examples of the alkoxycarbonyl group represented by R 4 include, for example, a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a ter butoxycarbonyl, an n-pentyloxycarbonyl group, an n-hexyloxycarbonyl group and the like. Examples of the thiocarbamoyl group which may be substituted which are represented by R 4 include, for example, a thiocarbamoyl group, a methylthiocarbamoyl group, an ethylthiocarbamoyl group, an n-propylthiocarbamoyl group, an isopropylthiocarbamoyl group, an n-butylthiocarbamoyl group, an isobutylthiocarbamoyl group, a sec-butylthiocarbamoyl group, a tert-butylthiocarbamoyl group and the like. Examples of the alkanesulfonyl group represented by R 4 include, for example, a methanesulfonyl group, an ethanesulfonyl group, an n-propanesulfonyl group, an n-butanesulfonyl group and the like. In the present specification, with respect to the substitution / bonding position of the terms "the aryl group", "the homocyclic or heterocyclic ring" and "heterocyclic group containing saturated nitrogen", the terms used herein encompass any groups in their meanings which can be substituted / linked to any position in a substitutable / linkable element between the atoms constituting the ring, as large as the substitution / link position is not particularly limited, as shown in some examples above. In the above-mentioned general formulas (I) and (II) of the present invention, when certain functional groups are preferred as "that can be substituted" or "which can have substituents" the substituent can be any group as large as it can substitute in the functional groups. The number and kind of the substituent are not particularly limited, and when two or more substituents exist, they may be the same or different. Examples include halogen atoms such as fluorine atom, chlorine atom, and bromine atom; hydroxyl group; alkyl groups such as methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group and an n-hexyl group; a trifluoromethyl group; aryl groups such as a phenyl group, a naphthyl group, and a pyridyl group; alkoxy groups such as a methoxy group; an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and tert-butoxy group; aryloxy groups such as a phenoxy group; amino groups which may be substituted such as an amino group, a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, a cyclopropylamino group, a cyclobutylamino group, a cyclopentylamino group, a cyclohexylamino group, a dimethylamino group, a diethylamino group, an anilino group, a pyridylamino group, a benzylamino group, a dibenzylamino group, an acetylamino group, a trifluoroacetylamino group, a tert-butoxycarbonylamino group, a benzyloxycarbonylamino group, a benzhydrylamino group, and a triphenylmethylamino group; a formyl group; alkanoyl groups such as an acetyl group, a propionyl group, an n-butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a fluoroacetyl group, a difluoroacetyl group, a trifluoroacetyl group, a chloroacetyl group, a dichloroacetyl group, and a trichloroacetyl group; alkoxycarbonyl groups such as a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, an isobutoxybonbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group, an n-pentyloxycarbonyl group, and an n-hexyloxycarbonyl group; a benzyloxycarbonyl group; a carbamoyl group; alkylcarbamoyl groups such as a methylcarbamoyl group, an ethylcarbamoyl group, an n-propylcarbamoyl group, an isopropylcarbamoyl group, an n-butylcarbamoyl group, an isobutylcarbamoyl group, a sec-butylcarbamoyl group, and a tert-butylcarbamoyl group; a thiocarbamoyl group; alkylthiocarbamoyl groups such as a methylthiocarbamoyl group, an ethylthiocarbamoyl group, an n-propylthiocarbamoyl group, an isopropylthiocarbamoyl group, an n-butylthiocarbamoyl group, an isobutylthiocarbamoyl group, a sec-butylthiocarbamoyl group, and tert-butylthiocarbamoyl group; an amidino group; alkylthio groups such as a methylthio group; alcansulfinyl groups such as a methanesulfinyl group; alkanesulfonyl groups such as a methanesulfonyl group, an ethanesulfonyl group, an n-propanesulfonyl group and n-butanesulfonyl group; arylsulfonyl groups such as p-toluenesulfonyl group, a p-methoxybenzenesulfonyl group, and a p-fluorobenzenesulfonyl group; aralkyl groups such as a benzyl group, a naphthyl group, a pyridylmethyl group, a furfuryl group, and a triphenylmethyl group; a nitro group; a cyano group; a sulfamoyl group; an oxo group; a hydroxyimino group; alkoxyimino groups such as a methoxyimino group, an ethoxyimino group, an n-propoxyimino group, and an isopropoxyimino group; ethylenedioxy group and the like. The compounds represented by the above-mentioned general formulas (I) and (II) of the present invention can be converted into salts, preferably pharmacologically acceptable salts, if desired; or free bases that can be generated from the resulting salts. Examples of the salts, preferably the pharmacologically acceptable salts, of the compounds represented by the above-mentioned general formulas (I) and (II) of the present invention include acid addition salts, for example, salts with mineral acids such as acid hydrochloric, hydrobromic acid, hydriodic acid, nitric acid, sulfuric acid and phosphoric acid; and salts with organic acids such as acetic acid, propionic acid, butyric acid, formic acid, valeric acid, maleic acid, fumaric acid, citric acid, oxalic acid, malic acid, succinic acid, lactic acid, methanesulfonic acid, ethanesulfonic acid, acid benzenesulfonic acid, p-toluenesulfonic acid, mandelic acid, 10-camphorsulfonic acid, tartaric acid, stearic acid, gluconic acid, nicotinic acid, trifluoroacetic acid and benzoic acid.

Among the compounds represented by the above-mentioned general formulas (I) and (II) of the present invention, optical isomers may exist for compounds having asymmetric carbons. These optical active compounds and mixtures thereof fall within the scope of the present invention. The compounds represented by the general formulas (I) and (II) or salts thereof according to the present invention can exist as any crystalline form depending on the manufacturing conditions, or exist as any hydrate or solvate. These crystalline forms, hydrates or solvates, and mixtures thereof, fall within the scope of the present invention. Preferred compounds of the present invention include, for example, the following compounds and salts thereof; however, the present invention is not limited to those examples: (1) 4-chloro-l- [2- (4-piperidyl) ethyl] -lH-imidazo [4, 5 c] quinoline; 0 (2) 4, 8-dichloro-l- [2- (4-piperidyl) ethyl] -lH-imidazo [4, 5 c] quinoline; (3) 4-chloro-8-methyl-1- [2- (4-piperidi1) ethyl] -lH-imidazo [4, 5 c] quinoline; (4) 4-chloro-8-methoxy-1- [2 - '(4-piperidyl) ethyl] -IH-imidazo [4,5- 5 c] quinoline; (5) 4-chloro-2-phenyl-l- [2- (4-piperidyl) ethyl] -lH-imidazo [4, 5-c] quinoline; (6) 4,8-dichloro-2-phenyl-l- [2- (4-piperidyl) ethyl] -1H-imidazo [4, 5-c] quinoline; (7) 4-chloro-8-methyl-2-phenyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [4, 5-c] quinoline; (8) 4-chloro-8-methoxy-2-phenyl-l- [2- (4-piperidyl) ethyl] -1H-imidazo [4, 5-c] quinoline; (9) 4-chloro-l- [2- (4-piperidyl) ethyl] -2-trifluoromethyl-lH-imidazo [4, 5-c] quinoline; (10) 4, 8-dichloro-l- [2- (4-piperidyl) ethyl] -2-trifluoromethyl-lH-imidazo [4, 5-c] quinoline; (11) 4-chloro-8-methyl-1- [2- (4-piperidyl) ethyl] -2-trifluoromethyl-lH-imidazo [4,5-c] quinoline; (12) 4-Chloro-8-methoxy-1- [2- (4-piperidyl) ethyl] -2-trifluoromethyl-1H-imidazo [4, 5-c] quinoline; (13) 4-chloro-2- (4-methylphenyl) -1- [2- (4-piperidyl) ethyl] -1H-imidazo [4, 5-c] quinoline; (14) 4-chloro-2- (4-methoxyphenyl) -1- [2- (4-piperidyl) ethyl] -1H-imidazo [4, 5-c] quinoline; (15) 4-chloro-2- (4-fluorophenyl) -1- [2- (4-piperidyl) ethyl] -1H-imidazo [4, 5-c] quinoline; (16) 4-chloro-l- [2- (4-piperidyl) ethyl] -2- (4-trifluoromethylphenyl) -lH-imidazo [4,5-c] quinoline; (17) 4-chloro-2- (2-furyl) -1- [2- (4-piperidyl) ethyl] -1H-imidazo [4, 5-c] quinoline; (18) 4-Chloro-l- [2- (4-piperidyl) ethyl] -2- (2-thienyl) -1H-imidazo [4, 5-c] quinoline; (19) 4-chloro-2- (2-imidazolyl) -1- [2- (4-piperidyl) ethyl] -1H-imidazo [4, 5-c] quinoline; (20) 4-chloro-l- [2- (4-piperidyl) ethyl] -2- (2-thiazolyl) -1H-imidazo [4, 5-c] quinoline; (21) 4-chloro-2- (5-methyl-2-thienyl) -l- [2- (4-piperidyl) ethyl] -1H-imidazo [4, 5-c] quinoline; (22) 4-Chloro-l- [2- (4-piperidyl) ethyl] -2- (2-pyrrolyl) -lH-imidazo [, 5-c] quinoline; (23) 4-methyl-2-phenyl-1- [2- (4-piperidyl) ethyl] -lH-imidazo [, 5-c] quinoline; (24) 2- (4-fluorophenyl) -4-methyl-1- [2- (4-piperidi1) ethyl] -1H-imidazo [4,5-c] quinoline; (25) 4 -methyl-1- [2- (4-piperidyl) ethyl] -2- (4-trifluoromethylphenyl) -lH-imidazo [4,5-c] quinoline; (26) 2- (2-furyl) -4-methyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [4, 5-c] quinoline; (27) 4-methyl-l- [2- (4-piperidyl) ethyl] -2- (2-thienyl) -1H-imidazo [4, 5-c] quinoline; (28) 2- (2-imidazolyl) -4-methyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [4, 5-c] quinoline; (29) 4-methyl-l- [2- (4-piperidyl) ethyl] -2- (2-thiazolyl) -1H-imidazo [4, 5-c] quinoline; (30) 4-methyl-2- (3-methyl-2-thienyl) -1- [2- (4-piperidyl) ethyl] -1H-imidazo [4, 5-c] quinoline; (31) 4-Methyl-2- (5-methyl-2-thienyl) -l- [2- (4-piperidyl) ethyl] -lH-imidazo [4, 5-c] quinoline; (32) 4-Methyl-1- [2- (4-piperidyl) ethyl] -2- (2-pyrrolyl) -1H-imidazo [4, 5-c] quinoline; (33) 4-methyl-2- (1-methyl-2-pyrrolyl) -l- [2- (4-piperidyl) ethyl] -lH-imidazo [4, 5-c] quinoline; (34) 4-chloro-6,7,8,9-tetrahydro-2-phenyl-1- [2- (4-piperidyl) ethyl] -lH-imidazo [4,5-c] quinoline; (35) 4-chloro-6,7-dihydro-2-phenyl-1- [2- (4-piperidyl) ethyl] -1H-imidazo [5, 4-c] cyclopenta [b] pyridine; (36) 4-chloro-2-phenyl-l- [2- (4-piperidyl) ethyl] -lH-imidazo [5,4-d] thieno- [3,2- b] pyridine; (37) 4-chloro-2-phenyl-l- [2- (3-piperidyl) ethyl] -lH-imidazo [4,5-c] quinoline; (38) 4-chloro-1- [2- (2-morpholinyl) ethyl] -2-phenyl-lH-imidazo [4,5-c] quinoline; (39) 4-chloro-2-phenyl-l- [2- (1-piperazinyl) ethyl] -1H-imidazo [4, 5-c] quinoline; (40) 4, 6, 7, 8, 9-pentachloro-2-ethoxymethyl-1- [2- (4-thiomorpholinyl) ethyl] -lH-imidazo [4,5-c] quinoline; (41) 4-chloro-6, 7, 8, 9-tetrahydro-2-hydroxymethyl-1- [2- (1-piperazinyl) ethyl] -IH-imidazo [5, 4-d] cyclohepta [b] pyridine; Y (42) 4-chloro-2- (3-methyl-2-thienyl-l- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline The novel lH-imidazopyridine derivatives represented by the general formula (I) or (II) mentioned above according to the present invention can be prepared by various methods, however, the methods of preparation of the compounds of the present invention are not limited thereto. Following preparation methods, specific explanations of the compounds represented by the general formula (I) mentioned above, will be given, and it will be obvious that these methods of preparation include the compounds represented by the general formula (II) mentioned above. For the synthesis of the compounds of the present invention, the following synthetic method can be used according to the method described in Japanese Unexamined Patent Publication (KOKAI) No. Hei 3-206078 / 1991 or Tetrahedron, Vol. 51, p. 581 3 (1995): (IX) (X) wherein R5 represents hydroxyl group or an alkyl group; R6 represents a chlorine atom or an alkyl group; R1 has the same meaning as that defined by R1 (except for the hydroxyl group), and R3, m and ring A have the same meanings as those defined above. In Step 1, the compound of the general formula (IV) can be obtained by allowing the compound represented by the general formula (III) to react with a nitrating agent such as a concentrated nitric acid and fuming nitric acid in the presence or absence of acetic acid, sulfuric acid and the like at a temperature which varies from 0 ° C to 200 ° C. In Step 2, the compound of the general formula (V) can be obtained by allowing the compound of the general formula (IV) to react with a suitable chlorinating agent, for example, phosphorous oxychloride, thionyl chloride, phosgene, oxalyl chloride, phosphorous pentachloride or the like, in the presence or absence of a solvent such as toluene at a temperature ranging from 0 ° C to 200 ° C. In Step 3, the compound of the general formula (VII) can be obtained by reacting the amine represented by the general formula (VI) with the compound of the general formula (V) in a solvent such as N, N-dimethylformamide and toluene in the presence or absence of a base such as triethylamine and potassium carbonate at a temperature ranging from -10 ° C to the reflux temperature of a solvent. In Step 4, the compound of the general formula (VIII) can be obtained by reducing the nitro group in the compound of the general formula (VII) according to an appropriate reduction method, for example, catalytic reduction using a metal catalyst such as platinum, Raney nickel, and palladium / carbon; reduction using nickel chloride and sodium borohydride; reduction using iron powder and hydrochloric acid and the like. The reduction can be carried out in a solvent such as water, methanol, ethanol and tetrahydrofuran, as well as a mixed solvent thereof, at a temperature ranging from 0 ° C to the reflux temperature of the solvent.

In Step 5, the compound of the general formula (IX) can be obtained by reacting the compound of the formula (VIII) with a compound represented by the following general formula (XI), (XII) or (XIII): R ^ COX (XII) (R1 | CO) 20 (XIII) wherein R represents a lower alkyl group; X represents a halogen atom; R1 'has the same meaning as that defined for R1 (except for the hydroxyl group), in the presence or absence of a basic catalyst such as triethylamine, or an acid catalyst such as hydrochloric acid and p-toluenesulfonic acid, in the presence or absence of a solvent such as N, N-dimethylformamide, tetrahydrofuran, acetonitrile, xylene and toluene, at a temperature ranging from 0 ° C to 200 ° C. In Stage 6, as a method instead of the Stage , the compound of the general formula (IX) can be obtained by reacting the compound of the general formula (VIII) with a compound represented by the following general formula (XIV): R1'CHO (XIV) wherein R1 'has the same meaning as that defined by R1 (except for the hydroxyl group), in the presence of 2,3-dichloro-5,6-dicyanyl-1-benzoquinone in a solvent such as acetonitrile, 1,4-dioxane and tetrahydrofuran a a temperature that varies from 0 ° C to the reflux temperature of the solvent. In Step 7, as a method in place of Step 5 or 6, the compound of the general formula (X) can be obtained by reacting the above-mentioned compound of the general formula (VIII) with a compound represented by the following formula general (XV): R C00H (XV) wherein R1 'has the same meaning as that defined by R1 (except for the hydroxyl group), in the presence or absence of an acid catalyst such as hydrochloric acid and sulfuric acid, in the presence or absence of a solvent such as N, N-dimethylformamide and toluene, at a temperature ranging from 0 ° C to 200 ° C. Further, when R5 represents hydroxyl group in the general formula (X), the compound of the general formula (IX) can be obtained by carrying out chlorination in Step 8. The chlorination is carried out by protecting the compound of the general formula (X), if desired, to the nitrogen atom not attached to the group (CH2) m, which is adjacent to the saturated nitrogen-containing heterocyclic group represented by R3, with a protecting group such as alkanoyl groups in a conventional manner, then reacting with an appropriate chlorinating agent, for example, phosphorous oxychloride, thionyl chloride, phosgene, oxalyl chloride, phosphorous pentachloride or the like in the presence or absence of a solvent such as toluene at a temperature ranging from 0 ° C to 200 ° C, and additional deprotection in a conventional manner, if desired, to obtain the compound of the general formula (IX) wherein R6 is a chlorine atom. In the second synthetic method of the compounds of the present invention, the compound of the general formula (XVI): wherein R3, R6, m and ring A have the same meanings as those defined above, can be obtained by allowing the compound of the general formula (VIII) to react together with triphosgene in the presence of a base such as triethylamine and potassium carbonate in a solvent such as 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran, N, N-dimethylformamide and toluene at a temperature ranging from 0 ° C to the reflux temperature of a solvent. In the third synthetic method of the compounds of the present invention, the compound of the general formula (XVII): wherein Z represents an aromatic ring; the symbol "a" represents an integer of 1 or 2; and R3, R6, m and ring A have the same meanings as those defined above, can be obtained by carrying out adequate oxidation of the compound of the general formula (IX) having an aryl group substituted with a methylthio group such as R1 ', then of protection; if desired, the nitrogen atom not bound to the (CH2) m group which is adjacent to the saturated nitrogen-containing heterocyclic group represented by R3, with a protecting group such as alkanoyl groups in a conventional manner, and additional deprotection in a manner conventional, if desired. The oxidation can be carried out in various ways according to the desired product. More specifically, the preparation can be done, when the symbol "a" represents an integer of 1, by reacting with an oxidizing agent, for example, chromic acid, hydrogen peroxide, m-chloroperbenzoic acid, sodium periodate, periodate of potassium or the like, or when the symbol "a" represents an integer of 2, with an oxidizing agent, for example, chromic acid, hydrogen peroxide, m-chloroperbenzoic acid, osmium tetraoxide, ruthenium tetraoxide or the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dichloroethane, methanol, acetone and water, as well as a mixed solvent thereof, at a varying temperature from 0 ° C to the reflux temperature of a solvent. In the fourth synthetic method of the compounds of the present invention, the compound of the general formula (I) wherein R2 is a hydroxyl group can be obtained by allowing a compound of the general formula (I) wherein R2 is a chlorine to react with water and an appropriate acid or base in a solvent that varies from 0 ° C to the reflux temperature of a solvent. Examples of the appropriate acid include, for example, organic acids such as formic acid, acetic acid, and trifluoroacetic acid, and mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid. Examples of suitable base include, for example, hydroxides, carbonates and alkali metal acid carbonate such as sodium and potassium and alkaline earth metal such as magnesium and calcium and the like. Examples of the solvents include, for example, alcohols such as methanol, ethanol and n-propanol, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran and the like and solvents containing water thereof.

In the fifth synthetic method of the compounds of the present invention, the compound of the general formula (I) wherein R 2 is a fluorine atom, bromine atom, or iodine atom and R 1 is R 1 'can be obtained by allowing a compound which is obtained to react the compound of the general formula (I) wherein R2 is a chlorine atom and R1 is R1 'or wherein R2 is a hydroxyl group and R1 is R1' with trifluoromethanesulfonic anhydride, methanesulfonyl chloride or p-toluenesulfonyl chloride to react with a metal halide (eg, potassium fluoride, sodium fluoride, lithium fluoride, potassium bromide, sodium bromide, potassium iodide, sodium iodide, etc.), an aprotic solvent such as dimethylsulfoxide, N, N-dimethylformamide, and acetonitrile in the presence or absence of a phase transferred catalyst such as tetraphenylphosphonium bromide, hexadecyltributylphosphonium bromide, and 18-crowns-6 at a temperature ranging from 0 ° C. to reflux temperature of a solvent. In the sixth synthetic method of the compounds of the present invention, the compound of the general formula (I), wherein R 3 is a heterocyclic group containing saturated nitrogen from which the nitrogen atom which is not bound to the group (CH 2) m adjacent is unprotected, can be obtained by subjecting the compound of the general formula (I), wherein R3 is a heterocyclic group containing saturated nitrogen having a protecting group such as alkanoyl groups, alkoxycarbonyl groups, a benzyl group and a trifluoromethyl group in the nitrogen atom that is not bound to the adjacent (CH2) m group, for deprotection with an acid or alkali, or for catalytic reduction with a metal catalyst, according to the type of the nitrogen atom protection group. Deprotection by using an acid or alkali can be carried out with an appropriate acid or base in the presence or absence of a cation scavenger such as anisole and thioanisole in a solvent. Examples of the solvent used include, for example, ethyl acetate, methylene chloride, 1,2-dichloroethane, 1,4-dioxane, methanol, ethanol, n-propanol, N, N-dimethylformamide, tetrahydrofuran and water, as well as a mixed solvent thereof. Examples of the acid used include, for example, hydrochloric acid, a solution of ethyl acetate of acid chloride, an ethanolic solution of acid chloride, sulfuric acid, hydrobromic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, formic acid, acid acetic and similar. Examples of the base include, for example, hydroxides, carbonates and alkali metal acid carbonate such as sodium and potassium, and alkaline earth metal such as magnesium and calcium and the like. The reaction can be carried out at a temperature ranging from 0 ° C to the reflux temperature of a solvent. The catalytic reduction can be carried out using an appropriate metal catalyst such as platinum, palladium / carbon, Raney nickel, Pearlman's reagent in water, an alcohol such as methanol, ethanol and n-propanol, and acetic acid, as well as a mixed solvent thereof in the presence or absence of an acid such as hydrochloric acid at a temperature ranging from room temperature to the reflux temperature of the solvent under a pressure ranging from normal pressure to 200 kg / cm 2. In the seventh synthetic method of the compounds of the present invention, the compound of the general formula (I) wherein R2 is a phenoxy group which may be substituted may be obtained by reacting the compound of the general formula (I) wherein R2 is a chlorine atom with a phenol derivative which may be substituted in the presence of a base such as sodium hydroxide and potassium hydroxide in the presence or absence of a solvent such as N, N-dimethylformamide and toluene at a temperature which It varies from 0 ° C to 200 ° C. In the eighth synthetic method of the compounds of the present invention, the compound of the general formula (I) wherein R2 is an amino group which can be obtained by subjecting the compound of the general formula (I) wherein R2 is a phenoxy group which may be substituted, which is obtained by the seventh method synthetic, to react together with ammonium acetate in the presence or absence of a solvent such as N, N-dimethylformamide and toluene at a temperature ranging from 0 ° C to 200 ° C. In the ninth synthetic method of the compounds of the present invention, the compound of the general formula (I) wherein R 2 is an amino group, which may have one or two substituents or a cyclic amino group which may be substituted may be obtained by subjecting the compound of the general formula (I) wherein R2 is a chlorine atom to be reacted together with an amine derivative which may have one or two substituents or a cyclic amine derivative which may be substituted in the presence or absence of a base such as triethylamine, potassium carbonate and sodium hydroxide in the presence or absence of a solvent such as water, alcohols including methanol, ethanol and n-propanol, methylene chloride, 1,2-dichloroethane, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran and toluene at a temperature ranging from 0 ° C to 200 ° C under normal pressure or a pressurized condition. In the tenth synthetic method of the compounds of the present invention, the compound of the general formula (I) wherein R2 is an amino group can be obtained by subjecting the compound of the general formula (I) wherein R2 is a benzylamino group, a dibenzylamine group, or p-methoxybenzylamine group, which is obtained, in the ninth synthetic method, by catalytic reduction using an appropriate metal catalyst, or by subjecting the compound of the general formula (I) wherein R is a p-group methoxybenzylamine for deprotection using an acid. The catalytic reduction can be carried out with a metal catalyst such as palladium / carbon and Pearlman reagent in a solvent such as alcohols, including methanol and ethanol, and water, as well as a mixed solvent thereof at a temperature ranging from the ambient temperature at the reflux temperature of a solvent in the presence or absence of an acid such as hydrochloric acid, acetic acid and formic acid, ammonium formate, cyclohexene, and cyclohexadiene under a pressure ranging from normal pressure to 200 kg / cm2. The deprotection using an acid can be carried out with an acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid and trifluoromethanesulfonic acid in a solvent such as alcohols including methanol and ethanol, methylene chloride, 1,2-dichloroethane, 1,4- dioxane, tetrahydrofuran, toluene and N, N-dimethylformamide in the presence or absence of a cation scavenger such as anisole and thioanisole at a temperature ranging from 0 ° C to the reflux temperature of a solvent.

In the eleventh synthetic method of the compounds of the present invention, the compound of the general formula (I) wherein R3 is a heterocyclic group containing saturated nitrogen which is substituted with an oxo group which can be obtained by reacting the compound of the general formula (I) wherein R3 is a heterocyclic group containing saturated nitrogen which is substituted with an ethylendioxy group, with an acid such as hydrochloric acid, a solution of ethyl acetate of acid chloride, sulfuric acid, hydrobromic acid, acid trifluoroacetic acid, p-toluenesulfonic acid, formic acid and acetic acid in the presence or absence of a solvent such as ethyl acetate, methylene chloride, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, n-propanol and N, N- dimethylformamide, or a solvent containing water thereof at a temperature ranging from 0 ° C to 200 ° C. In the twelfth synthetic method of the compounds of the present invention, the compound of the general formula (I) wherein R3 is a heterocyclic group containing saturated nitrogen which is substituted with a hydroxyimino group or an alkoxyimino group can be obtained by reacting the compound of the general formula (I) wherein R3 is a heterocyclic group containing saturated nitrogen which is substituted with an oxo group, which is obtained by the eleventh synthetic method, with a compound represented by the following general formula (XVIII) : R7-0-NH2 (XVIII) wherein R7 represents a hydrogen atom or an alkyl group, in the presence or absence of a base such as triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and acetate of sodium in a solvent such as alcohols including methanol, ethanol and n-propanol, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, and toluene at a temperature of e varies from 0 ° C to the reflux temperature of a solvent. In the thirteenth synthetic method of the compounds of the present invention, the compound of the general formula (I) wherein R 2 is a hydrogen atom can be obtained by subjecting the compound of the general formula (I) wherein R 2 is an atom of chlorine for catalytic reduction using a metal catalyst such as platinum and palladium / carbon in the presence or absence of an acid such as hydrochloric acid and acetic acid in an alcohol solvent such as methanol and ethanol or a solvent containing water thereof , under normal pressure at a temperature that varies from room temperature to the reflux temperature of a solvent. In a fourteenth synthetic method of the compounds of the present invention, the compound of the general formula (I), wherein R3 is a heterocyclic group containing saturated nitrogen, having an appropriate substituent on the nitrogen atom that is not bound to the adjacent (CH2) m group, can be obtained by reacting an appropriate reagent with the compound of the general formula (I) wherein R3 is a heterocyclic group containing saturated nitrogen that does not have a protecting group at the nitrogen atom that it is not linked to the adjacent (CH2) m group. The reaction can be carried out in the presence or absence of a solvent such as N, N-dimethylformamide, methylene chloride, tetrahydrofuran, toluene, pyridine, nitrobenzene, 1,2-dichloroethane, 1,4-dioxane, methanol, ethanol, n-propanol and water, as well as a mixed solvent thereof, in the presence or absence of a base such as triethylamine and potassium carbonate at a temperature ranging from 0 ° C to 200 ° C. Examples of the appropriate reagent include, for example, alkyl halides, triphenylmethyl chloride, benzyl chloride, benzhydryl chloride, a mixture of formic acid and formalin, acetyl chloride, acetic anhydride, trifluoroacetic anhydride, benzoyl chloride, benzyl chlorocarbonate. , ethyl chlorocarbonate, di-tert-butyl dicarbonate, sodium cyanate, alkyl isocyanates, sodium thiocyanate, alkyl isothiocyanates, lH-pyrazole-1-carboxyamidine, methanesulfonyl chloride, p-toluenesulfonyl chloride, p-fluorobenzenesulfonyl chloride, urethanes, alkylurethanes, thiourethanes, alkylthiourethanes and the like. In the fifteenth synthetic method of the compounds of the present invention, the compound of the general formula (I), wherein R 3 is a heterocyclic group containing saturated nitrogen substituted with an alkoxycarbonyl group or a benzyloxycarbonyl group at the nitrogen atom which is not bound to the adjacent (CH2) m group can be obtained by reacting the compound of the general formula (I) wherein R3 is a heterocyclic group containing saturated nitrogen substituted with an alkyl group or benzyl group at the nitrogen atom which is not bound to the adjacent (CH 2) m group with an alkyl chlorocarbonate or benzyl chlorocarbonate in the presence or absence of a solvent such as methylene chloride and toluene in the presence or absence of a base such as triethylamine and potassium carbonate a a temperature that varies from 0 ° C to 200 ° C. Some of the compounds represented by the general formulas (III) to (VIII) which are synthetic starting materials or intermediates in the preparations of the compounds of the present invention are known compounds, which are described in, for example, Journal of Medicinal Chemistry , Vol. 18, p. 726 (1975); Vol. 33, p. 1880 (1990); and Vol. 40, p. 1779 (1997); International Patent Publication No. 97/20820; European Patent Publication No. 223124 (1987) and the like, and may be prepared according to the method described herein. The preparations of some novel compounds will be described in reference examples. Medicaments comprising as an active ingredient the novel lH-imidazopyridine derivative represented by the general formula (I) or (II) mentioned above or a salt thereof are generally administered as oral preparations in the forms of capsules, tablets, granules fines, granules, powders, syrups, dry syrups and the like, or as parenteral preparations in the forms of injections, suppositories, eye drops, eye ointments, eardrops, nose drops, skin preparations, inhalations and the like. These formulations can be manufactured according to conventional methods by the addition of pharmacologically and pharmaceutically acceptable additives. For example, in oral preparations and suppositories, pharmaceutical ingredients can be used such as excipients such as lactose, D-mannitol, corn starch, and crystalline cellulose; disintegrators such as carboxymethylcellulose and calcium carboxymethylcellulose; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone; lubricants such as magnesium stearate and talc; coating agents such as hydroxypropylmethylcellulose, sucrose, and titanium oxide; bases such as polyethylene glycol and hard fat and the like. In injections or drops for eyes and ears and the like, the pharmaceutical ingredients may be used such as solubilizing or solubilizing aids which may constitute aqueous preparations or those dissolved until use such as distilled water for injection, physiological saline, and propylene glycol; pH modifiers such as inorganic or organic acids or bases; isotonicites such as sodium chloride, glucose and glycerin; stabilizers and the like; and in eye ointments and skin preparations, pharmaceutical ingredients that are suitable for ointments, creams and patches such as white petrolatum, macrogols, glycerin and cotton fabrics. A dose of the compounds of the present invention to a patient under therapeutic treatment is generally from about 0.1 to 1,000 mg in oral administration, and from about 0.01 to 500 mg in parenteral administration for an adult, which may depend on the symptoms of the patient. The dose mentioned above can be administered once a day or several times a day as divided portions. However, it is desirable that the aforementioned dose can suitably be increased or decreased according to a purpose of a therapeutic or preventive treatment, part or type of a disease, and the age or symptoms of a patient. EXAMPLES The present invention will be explained with reference to the Reference Examples and Working Examples. However, the scope of the present invention is not limited to these examples. The abbreviations in the tables have the following meanings: Ph, phenyl; Bn, benzyl; Boc, tert-butoxycarbonyl; Ac, acetyl; Ms, methanesulfonyl; Ts, p-toluenesulfonyl; Me, methyl; Et, ethyl; n-Bu, n-butyl. Reference Example 1 Ethyl N-triphenylmethyl-4-piperidinecarboxylate To a solution of 76.5 g of ethyl isonipecotate and 81.5 ml of triethylamine in 750 ml of methylene chloride, 149 g of triphenylmethyl chloride was added in portions divided into three portions. at room temperature, and the mixture was stirred for 16 hours. The reaction mixture was added with water and extracted with methylene chloride. The extract was washed successively with water and saturated brine, and dried, and then the solvent was evaporated. The resulting brown liquid was added with diisopropyl ether, and the precipitated crystals were collected by filtration and washed with diisopropyl ether to give 184 g of pale yellow crystals. Recrystallization from ethanol gave colorless prisms having the melting point from 147.5 to 148.5 ° C. Elemental analysis for C2H2gN02 Calculated% C, 81.17; H, 7.32; N, 3.51. Found% C, 81.19; H, 7.22; N, 3.44. Reference Example 2 N-Trifenilmeti1-4-piperidinmethanol To a suspension of 10.6 g of lithium-aluminum hydride in 300 ml of tetrahydrofuran was added dropwise a solution of 112 g of n-triphenylmethyl-4-piperidine carboxylate. ethyl acetate in 400 ml of tetrahydrofuran under cooling, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was added dropwise with a mixture of tetrahydrofuran and 10% aqueous sodium hydroxide solution under cooling. An insoluble matter was filtered and washed with tetrahydrofuran. The filtrate was combined and concentrated to give a colorless solid. The colorless solid was washed with methanol to give 84.2 g of colorless crystals. Recrystallization from methanol gave colorless crystals having the melting point from 92 to 99.5 ° C. Elemental analysis for C2sH27NO Calculated% C, 83.99; H, 7.61; N, 3.92 Found% C, 83.79; H, 7.74; N, 3.94 According to the method of Reference Example 2, the compound of Reference Example 3 was obtained. Reference Example 3 N-Trifenylmethyl-4-piperidinyl ethanol Appearance: colorless liquid NMR spectrum (CDCl 3) ppm: 1.26 (1H, brs), 1.36 (2H, brs), 1.45-1.58 (4H, m), 1.67 (2H, d, J = 12Hz), 3.05 (2H, brs), 3.74 (2H, t, J = 6Hz), 7.14 (3H, t, J = 7.5Hz), 7.24 (6H, t, J = 7.5Hz), 7.46 (6H, brs) IR spectrum v (liquid) cm "1: 3416 Mass spectrum m / z: 371 (M +) Reference Example 4 (N-Trifenylmethyl-4-piperidinyl) methyl methanesulfonate To a solution of 84.0 g of N-triphenylmethyl-4-piperidinemethanol and 36.2 ml of triethylamine in 420 ml of tetrahydrofuran, 18.3 ml of methanesulfonyl chloride was added dropwise under cooling, and the mixture was stirred at room temperature for 5.5 hours. The extract was washed successively with water and saturated brine, and dried, and then the solvent was evaporated, the resulting residue was added with a mixture of isopropanol and methanol, and the precipitated crystals were added. were collected by filtration and washed with methanol to give 90.4 g of colorless crystals.

Recrystallization from a mixture of methylene chloride and methanol gave colorless prisms having the melting point from 129.5 to 134 ° C. Elemental analysis for C26H29N03S. Calculated% C, 71.69; H, 6.71; N, 3.22 Found% C, 71.68; H, 6.47; N, 3.19 According to the method of Reference Example 4, the compound of Reference Example 5 was obtained. Reference Example 5 2- (N-Trifenylmethyl-4-piperidyl) ethyl methansulfonate Appearance: colorless crystals Recrystallization solvent: methanol-diethylether mp: 111.5-114 ° C Elemental analysis for C27H3? N03S Calculated% C, 72.13; H, 6.95; N, 3.12 Found% C, 72.03; H, 7.12; N, 3.14 Reference Example 6 4-Azidomethyl-N-triphenylmethylpiperidine A suspension of 60.0 g of (N-triphenylmethyl-4-piperidyl) methyl methanesulfonate and 17.9 g of sodium azide in 300 ml of dry N, N-dimethylformamide are added. stirred at 70 ° C for 17 hours. After the reaction, an insoluble matter was filtered and the filtrate was concentrated. The resulting residue was added with water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried, and then the solvent was evaporated. The resulting solid was washed successively with ethanol and n-hexane to give 42.6 g of colorless crystals. Recrystallization from a mixture of methanol and diethyl ether gave colorless crystals having melting point from 103.5 to 105.5 ° C. Elemental analysis for C25H26N Calculated% C, 78.50; H, 6.85; N, 14.65 Found% C, 78.45; H, 6.74; N, 14.82 Reference Example 7 2- (2-Azidoethyl) -1-piperidinecarboxylate terbutyl To a solution of 46.7 g of tert-butyl 2- (2-hydroxyethyl) -1-piperidinecarboxylate and 31.3 ml of triethylamine in 300 ml of dry tetrahydrofuran, 15.8 ml of methanesulfonyl chloride was added dropwise under cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with water and extracted with diethyl ether. The extract was washed successively with water and saturated brine, and dried, and then the solvent was evaporated. The resulting solid was washed with n-heptane to give 54.4 g of colorless crystals. And then, 22.9 g of sodium azide and 220 ml of N, N-dimethylformamide were added to the resulting crystals, and the mixture was stirred at 70 ° C for 4 hours.

After the reaction, an insoluble matter was filtered and the filtrate was concentrated. The resulting residue was added with water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried, and then the solvent was evaporated to give 43.2 g of a yellow liquid. NMR spectrum d (DMSO-d6) ppm: 1.20-1.32 (HH, m), 1.40 (9H, s), 1.48-1.58 (5H, m), 1.60-1.68 (HH, m), 1.88-1.96 (H, m) 2.71-2.78 (ÍH, m), 3.28 (2H, t, J = 6.5Hz), 3.80-3.86 (ÍH, 10 m), 4.19-4.25 (ÍH, m). IR spectrum v (liquid) cm "1: 2104, 1692 Reference example 8 4 -oxo-1-piperidinacetonitrile A suspension of 25.0 g of monohydrate 4-1-piperidinone monohydrate, 11.5 ml of chloroacetonitrile and 57.0 ml of diisopropylethylamine in 250 ml Tetrahydrofuran was refluxed for 10 hours.After the reaction, an insoluble matter was filtered.The filtrate was added with saturated aqueous sodium hydrogen carbonate solution and extracted with a mixture of ethyl acetate and methanol (10: 1) .The extract was dried, and the solvent was evaporated to give brown crystals.The crystals were washed with a mixture of ethyl acetate and n-heptane to give 15.7 g of pale brown crystals. ni ltri JUttrif niiHII 'II l í NMR spectrum d (CDCl3) ppm: 2.53 (4H, t, J = 6Hz), 2.91 (4H, t, J = 6Hz), 3.66 (2H, s) IR spectrum v (KBr) cpf1: 2232, 1714 Mass spectrum m / z: 138 (M +) According to the method of Reference Example 8, the compound of Reference Example 9 was obtained. Reference Example 9 4- (tert-Butoxycarbonylamino) -1-piperidineacetonitrile Appearance: colorless needles Recrystallization solvent: methanol mp: 147-148 ° C Elemental analysis for Ci2H2? N302 Calculated% C, 60.23; H, 8.84; N, 17.56 Found% C, 60.08; H, 8.63; N, 17.55 Reference Example 10 N-Trifenylmethyl-4-piperidineacetonitrile A suspension of 90.4 g of (N-triphenylmet-l-4-piperidyl) methyl methanesulfonate, 3.50 g of potassium iodide and 20.3 g of sodium cyanide in 400 ml of dry dimethylsulfoxide was stirred at 90 ° C for 5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried, and the solvent was evaporated to give a yellow liquid. The liquid was added with methanol, and the precipitated crystals were collected by filtration and washed with methanol to give 70.0 g of colorless crystals. Recrystallization from a mixture of methylene chloride and methanol gave colorless crystals having melting point from 138 to 139 ° C. Elemental analysis for C2gH26N2. Calculated% C, 85.21; H, 7.15; N, 7.64 Found% C, 85.35; H, 7.26; N, 7.62 According to the method of Reference Example 10, the compounds of Reference Examples 11 to 13.

Reference Example 14 N-Trifenylmethyl-4-piperidineacetic acid A suspension of 21.2 g of N-triphenylmethyl-4-piperidineacetonitrile, 127 ml of 10% aqueous sodium hydroxide solution and 312 ml of ethanol was refluxed for 74 hours. hours. The reaction mixture was neutralized with 10% hydrochloric acid under cooling, and then adjusted to pH 4-5 with 10% aqueous citric acid solution. The precipitated crystals were collected by filtration, and washed successively with water and methanol to give 23.6 g of colorless crystals. Recrystallization from a mixture of methanol and ethyl acetate gave colorless needles having the melting point from 197 to 209 ° C (decomposition). Elemental analysis for C2gH27N02 Calculated% C, 81.01; H, 7.06; N, 3.63 Found% C, 80.85; H, 7.17; N, 3.70 Reference Example 15 Ethyl N-triphenylmethyl-4-piperidineacetate A suspension of 23.6 g of N-triphenylmethyl-4-piperidineacetic acid, 16.9 g of potassium carbonate and 5.0 ml of ethyl bromide in 230 ml of N , Dried N-dimethylformamide was stirred at 90 ° C for 5 hours. After cooling, the reaction mixture was added with water and ethyl acetate, and the precipitated crystals were collected by filtration and -aatt "-. A». »; .- • were washed with water to give 20.6 g of colorless crystals. Recrystallization from a mixture of methanol and tetrahydrofuran gave colorless crystals having melting point from 165 to 166 ° C. Elemental analysis for C2ßH3? N02 Calculated% C, 81.32; H, 7.56; N, 3.39 Found% C, 81.08; H, 7.69; N, 3.43 Reference example 16 4, 4-Ethylenedioxy-1-piperidineacetonitrile A solution of 10.0 g of 4-oxo-1-piperidineacetonitrile, 22.6 g of ethylene glycol and 0.62 g of anhydrous p-toluenesulfonic acid in 100 ml of toluene was carried refluxed for 6 hours with Dean-stark dehydration apparatus. After cooling, the reaction mixture was added with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was dried, and the solvent was evaporated to give a pale brown liquid. The resulting liquid was purified by alumina column chromatography using ethyl acetate-n-heptane (1: 3) as an eluting solvent to give 12.8 g of a colorless liquid. NMR spectrum d (CDCl3) ppm: 1.78 (4H, t, J = 6Hz), 2.69 (4H, t, J = 6Hz), 3.52 (2H, s), 3.96 (4H, s) IR spectrum v (liquid) cm "1: 2230, 1094 Mass spectrum m / z: 182 (M +) Reference example 17 4-Aminomethyl-N-triphenylmethylpiperidine To a suspension of 4.70 g of lithium-aluminum hydride in 250 ml of dry tetrahydrofuran, was added in drops a solution of 47.7 g of 4-azidomethyl-N-triphenylmethylpiperidine in 250 ml of dry tetrahydrofuran under cooling, and the mixture was stirred at room temperature for 4 hours.The reaction mixture was added dropwise with a mixture of tetrahydrofuran and solution of 10% aqueous sodium hydroxide under cooling.An insoluble matter in the mixture was filtered, and washed with tetrahydrofuran.The filtrate and washings were combined and concentrated to give 48.1 g of a colorless liquid.D NMR spectrum (CDCl3) ppm: 1.14 (ÍH, brs), 1.36 (2H, brs), 1.48 (2H, qd, J = 5.2.5Hz), 1.68 (2H, d, J = 11.5Hz), 2.59 (2H, d, J = 6Hz), 3.10 (2H, brs) , 7.14 (3H, t, J = 7.5Hz), 7.25 (6H, t, J = 7.5Hz), 7.47 (6H, brs). IR spectrum v (liquid) cm "1: 3056,3028 High resolution mass spectrum: Analysis for C25H28N2 Calculated m / z: 356.2252 Found m / z: 356.2250 Reference example 18 4- (2-Aminoethyl) -N-triphenylmethylpiperidine To a suspension of 21.7 g of lithium aluminum hydride in 300 ml of dry tetrahydrofuran, a solution of 28.1 g of concentrated sulfuric acid in 100 ml of dry tetrahydrofuran was added dropwise under cooling, and the mixture was stirred for 30 minutes. And then, a solution of 70.0 g of N-triphenylmethyl-4-piperidineacetonitrile in 300 ml of dry tetrahydrofuran was added dropwise to the mixture under cooling, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was added dropwise with a mixture of tetrahydrofuran and 10% aqueous sodium hydroxide solution under cooling. An insoluble matter was filtered into the mixture, and the filtrate was concentrated. The resulting residue was added with water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried, and the solvent was evaporated to give 71.4 g of a colorless liquid. NMR spectrum d (CDCl3) ppm: 1.18 (HH, brs), 1.35 (2H, brs), 1.40 (2H, q, J = 7.5Hz), 1.48 (2H, qd, J = 11.5.3Hz), 1.63 (2H) , d, J = 11.5Hz), 2.67 (2H, t, J = 7.5Hz), 3.05 (2H, brs), 7.14 (3H, t, J = 7.5Hz), 7.24 (6H, t, J = 7.5Hz ), 7.47 (6H, brs). IR spectrum v (liquid) cm "1: 3060,3032 High resolution mass spectrum: Analysis for C26H3oN2 Calculated m / z: 370.2409 Found m / z: 370.2400 According to the method of Reference Example 18 the compound of Example reference 19 was obtained Reference example 19 4- (3-Aminopropyl) -N-triphenylmethylpiperidine Appearance: colorless liquid NMR spectrum d (DMSO-d6) ppm: 0.95-1.05 (H, m), 1.19-1.35 (6H, m ), 1.41 (2H, q, J = 11.5Hz), 1.62 (2H, d, J = 11.5Hz), 2.47 (2H, t, J = 6.5Hz) 2.93 (2H, d, J = 11.5Hz), 7.15 (3H, t, J = 7.5Hz), 7.28 (6H, t, J = 7.5Hz), 7.38 (6H, d, J = 7.5Hz) IR spectrum v (liquid) cm "1: 2972.2920 Example of reference 20 2- (2-Aminoethyl) -1-piperidinecarboxylate terbutyl A suspension of 43.0 g of tert-butyl 2- (2-azidoethyl) -1-piperidinecarboxylate and 2.15 g of palladium on 5% carbon in 215 ml of methanol was catalytically hydrogenated at room temperature for 9 hours.

After the reaction, the catalyst was filtered, and the filtrate was concentrated to give 37.2 g of a colorless liquid. NMR spectrum d (DMSO-d6) ppm: 1.20-1.30 (H, m), 1.38 (9H, s), 1.45-1.58 (4H, m), 1.72-1.82 (HH, m), 2.34-2.47 (2H, m), 2.65-2.76 (HH, m), 3.18 (2H, t, J = 6Hz) 3.78-3.85 (ÍH, m), 4. 13-4.20 (ÍH, m) IR spectrum v (liquid) cm "1: 2976, 2936, 1692 Reference example 21 1- (2-Aminoethyl) -4,4-ethylenedioxypiperidine A suspension of 12.7 g of 4, 4- Ethylenedioxy-1-piperidineacetonitrile, 1.3 ml of Raney nickel and 113 ml of 2% methanolic ammonia solution was catalytically hydrogenated at room temperature under 50 atmospheres for 20 hours After the reaction, the catalyst was filtered, and the filtrate was concentrated The resulting pale green liquid was purified by alumina column chromatography [eluting solvent: ethyl acetate- ^ ethyl acetate-methanol (10: 1)] to give 10.1 g of a colorless liquid NMR spectrum: d (DMSO -d6) ppm: 1.58 (4H, t, J = 6Hz), 2.37 (2H, t, J = 6.5Hz), 2.42 (4H, t, J = 6Hz), 2.57 (2H, t, J = 6.5Hz) , 3.84 (4H, s) IR spectrum v (liquid) cm_12956, 2884, 1094 According to the method of Reference Example 21, the compounds of Reference Examples 22 to 25 were obtained.

Reference Example 26 5,7-Dichloro-6-nitrothieno [2,3-b] pyridine A mixture of 24.8 g of 4,5-dihydro-7-hydroxy-6-nitrothieno [3,2-b] pyridine-5 -one and 87 ml of phosphorous oxychloride was stirred at 60 ° C for 24 hours. The reaction solution was concentrated and the residue was dissolved in a mixture of methylene chloride and methanol (10: 1) and then the solution was poured into water. An insoluble matter was filtered, and the organic solvent layer was separated. In addition, the aqueous layer was extracted with a mixture of methylene chloride and methanol (10: 1). The combined organic solvent layer was dried, and the solvent was evaporated to give brown crystals. The resulting brown crystals were purified by column chromatography on silica gel using ethyl acetate-n-hexane (1: 3) as a solvent in elution to give 10.6 g of pale brown crystals. Recrystallization from n-hexane gave pale brown crystals having the melting point from 96 to 97 ° C. NMR spectrum d (CDCl3) ppm: 7.61 (ΔI, d, J = 5.5Hz), 8.07 (ΔI, d, J = 5.5Hz) IR spectrum v (KBr) cm "1: 1540, 1368 Mass spectrum m / z : 248,250,252 (M +, 9: 6: 1) According to the method of Reference Example 16, the compounds of Reference Examples 27 to 32 were obtained.

J = 9.2.

H.d, J = H H.d, J = 9 Reference example 33 2-Chloro-3-nitro-4- [2- (N-triphenylmethyl-4-piperidinyl) ethylamino] quinoline To a solution of 22.6 g of 2,4-dichloro-3-nitroquinoline and 13.0 ml of triethylamine in 60 ml of N, N-dimethylformamide, a solution of 23.0 g of 4- (2-aminoethyl) -N-triphenylmethylpiperidine in 40 ml of N, N-dimethylformamide was added dropwise with stirring under cooling. The mixture was stirred at room temperature for 1 hour. The reaction mixture was added with ethyl acetate and water. The precipitated crystals were collected by filtration, and washed successively with ethyl acetate and diethylether to give 26. 9 g of yellow crystals. Recrystallization from a mixture of N, N-dimethylformamide and ethyl acetate gave yellow crystals having the melting point from 223.5 to 231 ° C (decomposition). Elemental analysis for C35H33C1N402 Calculated% C, 72.84; H, 5.76; N, 9.71 Found% C, 72.64; H, 5.80; N, 9.82 According to the method of Reference Example 33, the compounds of Reference Examples 34 to 60 were obtained. (2 H.t.J Reference Example 61 3-Amino-2-chloro-4- [2- (N-triphenylmethyl-4-piperidyl) ethylamino] quinoline To a solution of 6.56 g of nickel chloride hexahydrate and 22.3 ml of methanol in 100 ml of tetrahydrofuran, 2. 09 g of sodium borohydride was added in portions under cooling, and then a suspension of 31.9 g of 2-chloro-3-nitro-4- [2-N-triphenylmethyl-4-piperidyl) ethylamino] quinoline in 300 ml of tetrahydrofuran was added to the mixture.

Successively, 8.35 g of sodium borohydride divided into four portions was added in portions, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added with 50 ml of water and an insoluble matter was filtered, and then the extract was concentrated. The residue was added with water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried, and then the solvent was evaporated. The resulting pale green liquid was solidified with a mixture of ethyl acetate and diisopropyl ether, and the solid was washed successively with isopropanol and diisopropyl ether to give 20.1 g of pale green crystals. Recrystallization from isopropanol gave pale green crystals having the melting point from 116 to 121 ° C. Elemental analysis for C 35 H 35 C 1 N 4 Calculated% C, 76.83; H, 6.45; N, 10.24 Found% C, 76.64; H, 6.54; N, 10.17 According to the method of Reference Example 61, the compounds of Reference Examples 62 to 88 were obtained. * i. - -, i i. »? SS ^ c- Example 1 4-Chloro-l- [2- (N-triphenylmethyl-4-p? Peridyl) ethyl] -1H-imidazo [4,5-c] -quinoline A solution of 19.9 g of 3-amino-2-chloro -4- [2- (N-triphenylmethyl-4-piperidyl) -ethylamino) quinoline, 24.1 ml of ethyl orthoformate and 0.68 g of p-toluenesulfonic acid monohydrate in 200 ml of toluene was refluxed for 6 hours. After cooling, the precipitated crystals were collected by filtration, and washed with diisopropyl ether to give 16.4 g of colorless crystals. Recrystallization from a mixture of methanol and tetrahydrofuran gave colorless crystals having melting point from 229 to 234.5 ° C (decomposition). Elemental analysis for C36H33C1N Calculated% C, 77.61; H, 5.97; N, 10.06 Found% C, 77.50; H, 5.98; N, 9.95 Example 2 4-Chloro-2-trifluoromethyl-1- [2- (N-triphenylmethyl-4-pipe idyl) ethyl] -lH-imidazo [4, 5-c] quinoline To a solution of 2.50 g of -amino-2-chloro-4- [2- (N-triphenylmethyl-4-piperidyl) ethylamino] quinoline and 0.76 ml of triethylamine in 60 ml of dry tetrahydrofuran, a solution of 0.63 ml of trifluoroacetic anhydride in 40 ml of dry tetrahydrofuran it was added dropwise under cooling, and the mixture was stirred at room temperature for 2 hours. The solvent in the reaction mixture was evaporated, and the residue was added with water and saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried, and then the solvent was evaporated. A solution of 3.03 g of the resulting pale yellow solid and 0.30 g of p-toluenesulfonic acid monohydrate in 100 ml of toluene was refluxed for 20 hours. After the reaction, the solvent was evaporated, and the residue was added with methanol and acetone. The precipitated crystals were collected by filtration to give 1.79 g of colorless crystals. NMR spectrum d (DMSO-d6) ppm: 1.35-1.55 (3H, m), 1.59 (2H, q, J = llHz), 1.77 (2H, d, J = llHz), 1.80-1.90 (2H, m), 2.98 (2H, brs), 4.75 (2H, t, J = 8.5Hz), 7.17 (3H, t, J = 8Hz), 7.30 (6H, t, J = 8Hz), 7.41 (6H, brs), 7.84 ( ÍH, td, J = 7.5, 2Hz), 7.87 (ÍH, td, J = 7.5, 2Hz), 8.16 (ÍH, dd, J = 7.5, 2Hz), 8.34 (ÍH, dd, J = 7.5, 2Hz). Example 3 4- [2- (4-Methyl-2-phenyl-1H-imidazo [4, 5-c] quinolin-1-yl) ethyl] 1-piperidinecarboxylic acid tert-butyl A solution of 0.65 g of 4- [ 2- [(3-amino-2-methylquinolin-4-yl) amino] -ethyl] -1-piperidinecarboxylic acid tert-butyl ester, 0.29 g of benzaldehyde and 0.08 g of 2,3-dichloro-5,6-dicyano- 1, 4-benzoquinone in 5 ml of tetrahydrofuran was stirred at room temperature for 3 days. The reaction mixture was added with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated to give a reddish-brown liquid. The resulting liquid was purified through column chromatography on silica gel using ethyl acetate-n-heptane (1: 1) as an eluting solvent, and washed with I diisopropylether to give 0.55 g of a colorless solid. Recrystallization from diisopropyl ether gave colorless crystals having melting point from 146 to 146. 5 ° C. Elemental analysis for C29H34N402 Calculated% C, 74.01; H, 7.28; N, 11.91 Found% C, 73.95; H, 7.54; N, 11.84. According to the methods of Examples 1 to 3, the compounds of Examples 4 to 72 were obtained.

J & AJL? Al * '? F'g Jito- - - ¿S ?.

H.d, H.d, J Example 73 4- [2- (4-Chloro-2-hydroxy-1H-imidazo [4, 5-c] quinolin-1-yl) -ethyl] -1-piperidinecarboxylic acid tert-butyl ester * n ^^ To a solution of 0.60 g of 4- [2- (3-amino-2-chloro-4-quinolylamino) -ethyl] -1-piperidinecarboxylic acid tert-butyl ester and 0.44 g of triphos in 10 ml of 1 , 2-dichloroethane, 0.41 ml of triethylamine was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with saturated aqueous sodium hydrocarbonate solution, and extracted with 1,2-dichloroethane. The extract was washed with saturated brine, and dried, and the solvent was evaporated. The residue was washed with diisopropyl ether to give 0.57 g of colorless crystals. Recrystallization from 1,2-dichloroethane gave colorless crystals having melting point from 222 to 223 ° C. Elemental analysis for C22H27C1N403 Calculated% C, 61.32; H, 6.32; N, 13.00 Found% C, 61.15; H, 6.34; N, 13.00 Example 74 4- [2- [4-chloro-2- (4-methansphonylphenyl) -1H-imidazo [4, 5-c] -quinolin-1-yl] ethyl] -1-piperidinecarboxylic acid tert-butyl ester To a suspension of 0.63 g of 4- [2- [4-chloro-2- (4-methylthiophenyl) -lH-imidazo [4, 5-c] quinolin-1-yl] ethyl] -1-piperidinecarboxylate ter- Butyl in 18 ml of 1,4-dioxane, a solution of 0.38 g of sodium periodate in 6 ml of water was added dropwise, and the mixture was stirred at 50 ° C for 13 hours. The reaction solution was concentrated, and the residue was purified through silica gel column chromatography using 1,2-dichloroethane-methanol (10: 1) as a solvent in elution to give 0.47 g of a colorless solid. Recrystallization from a mixture of isopropanol and water gave colorless crystals having melting point from 183 to 186 ° C. Elemental analysis for C29H33C1N403S • 1/4 H20 Calculated% C, 62.46; H, 6.06; N, 10.05 Found% C, 62.33; H, 5.90; N, 9.91 Example 75 4- [2- [4-Chloro-2- (4-methanesulfonylphenyl) -1H-imidazo [4, 5-c] -quinolin-1-yl] ethyl] -1-piperidinecarboxylic acid tert-butyl ester To a solution of 0.40 g of 4- [2- [4-chloro-2- (4-methylthiophenyl) -lH-imidazo [4,5-c] quinolin-1-yl] ethyl] -l-piperidinecarboxylate ter- Butyl in 20 ml of 1,2-dichloroethane, 0.40 g of m-chloroperbenzoic acid was added in portions little by little, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 10% aqueous sodium hydroxide solution, and extracted with 1,2-dichloroethane. The extract was washed with saturated aqueous sodium hydrocarbonate solution and dried, and then the solvent was evaporated. The residue was washed with a mixture of diisopropyl ether and diethylether to give 0.42 g of colorless crystals. Recrystallization from methanol gave colorless crystals, having melting point from 149 to 156 ° C. Elemental analysis for C29H33C1N404S • 1 / 4H20 Calculated% C, 60.72; H, 5.89; N, 9.77 Found% C, 60.72; H, 5.81; N, 9.67 Example 76 4-Hydroxy-2-phenyl-l- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline A solution of 871 mg of 4-chloro-2-phenyl -1- [2- (4-piperidyl) ethyl] -lH-imidazo [4, 5-c] quinoline and 2.5 ml of 6N hydrochloric acid in 8 ml of 1,4-dioxane was refluxed for 3 hours. The reaction mixture was adjusted to pH 10 with 10% aqueous sodium hydroxide solution, and added with potassium carbonate, and then extracted with 1,2-dichloroethane. The extract was dried, and the solvent was evaporated.

The resulting residue was washed with ethyl acetate to give 522 mg of pale brown crystals. Recrystallization from methanol gave pale brown crystals having melting point from 242.5 to 244 ° C. Elemental analysis for C23H24N40 • 1 / 4H20 Calculated% C, 73.28; H, 6.55; N, 14.86 Found% C, 73.32; H, 6.45; N, 14.77 According to the method of Example 76, the compounds of Examples 77 to 79 were obtained.

Example 80 4- [2- (4-phenoxy-1H-imidazo [4,5-c] quinolin-1-yl) ethyl] -1-piperidinecarboxylic acid tert-butyl ester A mixture of 4.46 g of 4- [2- ( 4-Chloro-1H-imidazo [4, 5-c] quinolin-1-yl) ethyl] -1-piperidinecarboxylate of tert-butyl, 10.1 g of phenol and 1.80 g of potassium hydroxide were stirred at 120 ° C for 7 hours. hours. The reaction mixture was adjusted to pH 10 with 10% aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed successively with 10% aqueous sodium hydroxide solution and saturated brine, and dried, and then the solvent was evaporated to give a brown liquid. The resulting brown liquid was purified through silica gel column chromatography using ethyl acetate as a solvent in elution to give 3.59 g of a colorless solid. Recrystallization from a mixture of ethyl acetate and n-hexane gave colorless crystals having melting point from 130.5 to 132.5 ° C. Elemental analysis for C2ßH32N403 15 Calculated% C, 71.16; H, 6.83; N, 11.86. Found% C, 71.10; H, 7.10; N, 11.69 According to the method of Example 80, the compounds of Examples 81 to 87 were obtained.

"M. ¡Ki¿í? 8 '? ^ £ i ^, Example 88 4- [2- (4-amino-lH-imidazo [4, 5-c] quinolin-1-yl) ethyl] -1-piperidinecarboxylic acid tert-butyl ester A mixture of 4.40 g of 4- [2- ( 4-phenoxy-1H-imidazo [4, 5-c] -quinolin-1-yl) ethyl] -1-piperidinecarboxylic acid tert -butyl ester and 34.5 g of ammonium acetate were stirred at 140 ° C for 3 hours. The reaction mixture was added with water, adjusted to pH 9 with 10% aqueous sodium hydroxide solution, and extracted with methylene chloride. The extract was washed with saturated brine, and dried, and then the solvent was evaporated. The resulting residue was purified by column chromatography on alumina using methylene chloride methanol (100: 1 to 20: 1) as solvents in elution, and washed with diisopropyl ether to give 1.88 g of colorless crystals. Recrystallization from ethyl acetate gave colorless crystals having melting point from 193 to 193.5 ° C. Elemental analysis for C22H29N502 Calculated% C, 66.81; H, 7.39; N, 17.71 Found% C, 66.93; H, 7.48; N, 17.66 According to the method of Example 88, the compounds of Examples 89 to 92 were obtained.

Example 93 4- [2- (4-dimethylamino-2-phenyl-1H-imidazo [4, 5-c] quinolin-1-yl) -ethyl] -1-piperidinecarboxylic acid tert-butyl ester A mixture of 0.69 g of 4 - [2- (4-chloro-2-phenyl) -1H-imidazo [4, 5-c] quinolin-1-yl) ethyl] -1-piperidinecarboxylic acid tert-butyl ester and 7 ml of aqueous 50% dimethylamine solution % was stirred in a sealed tube at 80 ° C external temperature for 2 hours. The reaction solution was added with water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried, and the solvent was evaporated. The residue was washed successively with isopropanol and diisopropyl ether to give 0.52 g of colorless crystals. Recrystallization from isopropanol gave colorless crystals having melting point from 170.5 to 171.5 ° C. Elemental analysis for C3oH3 Ns02 Calculated% C, 72.12; H, 7.46; N, 14.02 Found% C, 71.95; H, 7.72; N, 13.83 Example 94 4- [2- [4- (4-methyl-piperazin-1-yl) -2-phenyl-1H-imidazo [4, 5-c] -quinolin-1-yl] ethyl] -1-piperidinecarboxylate of tert-butyl A mixture of 0.80 g of 4- [2- (4-chloro-2-phenyl-1H-imidazo- [4,5- c] quinolin-1-yl) ethyl] -1-piperidinecarboxylate ter- butyl and 1 ml of N-methylpiperazine was stirred at 80 ° C for 6 hours. The reaction mixture was added with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract dried, and the solvent was evaporated. The residue was purified through alumina column chromatography using ethyl acetate-n-heptane (1: 3 to 1: 1) as solvents in elution, and washed with a mixture of diisopropyl ether and n-heptane to give 0.74 g of colorless crystals. Recrystallization from ethyl acetate gave colorless needles having the melting point from 140 to 141 ° C. Elemental analysis for C33H42N602 Calculated% C, 71.45; H, 7.63; N, 15.15 Found% C, 71.23; H, 7.65; N, 14.99 According to the methods of Examples 93 and 94, the compounds of Examples 95 to 102 were obtained.

EXAMPLE 103 4-Amino-2-phenyl-1- [2- (4-piperidyl) ethyl] -IH-imidazo [4, 5-c] quinoline trifluoroacetate A mixture of 0.30 g of 4- [2- [4- (4-methoxybenzylamino) -2-phenyl-1H-imidazo [4, 5-c] quinolin-1-yl] ethyl] -1-piperidinecarboxylic acid tert-butyl ester and 9 ml of trifluoroacetic acid was stirred at 65 ° C outside for 6 hours. The reaction solution was concentrated, and the residue was added with isopropanol. The precipitated crystals were collected by filtration, and washed with diisopropyl ether to give 0.31 g of pale yellow crystals. Recrystallization from a mixture of ethanol and isopropanol gave colorless crystals having melting point from 223 to 224 ° C. Elemental analysis for C23H25N5 • 2CF3C02H • H20 Calculated% C, 52.51; H, 4.73; N, 11.34 Found% C, 52.61; H, 4.45; N, 11.61 EXAMPLE 104 1- [2- (4-Chloro-2-phenyl-1H-imidazo [4, 5-c] quinol-1-yl) ethyl] -4-piperidinone A mixture of 0.39 g of 1- [ 2- (4-Chloro-2-phenyl-1H-imidazo [4, 5-c] quinolin-1-yl) ethyl] -4,4-ethylenedioxypiperidine and 4 ml of concentrated sulfuric acid was stirred at room temperature for 30 minutes . The reaction mixture was poured into ice water, adjusted to pH 11 with 10% aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and dried, and then the solvent and evaporated to give 0.42 g of a colorless liquid. The resulting liquid was purified through column chromatography on alumina using ethyl acetate-n-heptane (1: 1) as a solvent in elution to give 0.32 g of colorless crystals. Recrystallization from isopropanol gave colorless needles having melting point from 163 to 165 ° C. Elemental analysis for C23H2? ClN40 Calculated% C, 68.23; H, 5.23; N, 13.84. Found% C, 68.26; H, 5.31; N, 13.78 Example 105: 1- [2- (4-Chloro-2-phenyl-1H-imidazo [4, 5-c] quinolin-1-yl) ethyl] -4-piperidinone oxime A mixture of 0.20 g of 1 - [2- (4-chloro-2-phenyl-lH-imidazo [4, 5-c] quinolin-1-yl) ethyl] -4-piperidinone, 0.04 g of hydroxylamine hydrochloride, 0.09 g of sodium acetate and 4 ml of methanol was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was added with aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, and dried, and the solvent was evaporated to give 0.25 g of a colorless solid. Recrystallization from ethyl acetate gave colorless crystals having melting point from 201 to 207 ° C (decomposition). Elemental analysis for C23H22C1N50 • 1 / 2H20 Calculated% C, 64.41; H, 5.40; N, 16.33 Found% C, 64.75; H, 5.32; N, 16.09 Example 106 4- [2- (2-phenyl-lH-imidazo [4, 5-c] quinolin-1-yl) ethyl] -1-piperidinecarboxylic acid tert-butyl A suspension of 0.80 g of 4- [ 2- (4-Chloro-2-phenyl-1H-imidazo- [4, 5-c] quinolin-1-yl) ethyl] -1-piperidinecarboxylic acid tert-butyl ester and 0.30 g of palladium on 5% carbon in 80% ml of methanol was catalytically hydrogenated at ordinary temperature under atmospheric pressure for 12 hours. After the reaction, the catalyst was filtered, and the filtrate was concentrated. The residue was purified through silica gel column chromatography using ethyl acetate-n-heptane (1: 1 to 4: 1) as solvents in elution and washed with diisopropyl ether to give 0.49 g of pale yellow crystals.

Recrystallization from diisopropyl ether gave colorless crystals having melting point from 138 to 139 ° C. Elemental analysis for C2gH32N402 Calculated% C, 73. 66; H, 7 06; N, 12 27 Found% C, "73. 46; H, 7, 21; N, 12. 17 According to the method of Example 106, the compounds of Examples 107 to 109 were obtained.

EXAMPLE 110 4-Chloro-2-phenyl-1- [2- (4-piperidyl) ethyl] -IH-imidazo [4,5-c] quinoline hydrochloride and fumarate A mixture of 3.64 g of 4-chloro-2- phenyl-1- [2- (N-triphenylmethi-4-piperidi1) ethyl] -IH-imidazo [4, 5-c] quinoline, 30 ml of methanol and 10 ml of trifluoroacetic acid was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was washed successively with ethyl acetate and diethylether to give pale brown crystals (trifluoroacetate). The resulting crystals were added with ethyl acetate, and extracted with water. The aqueous layer was adjusted to pH 11 with 10% aqueous sodium hydroxide solution, and extracted with a mixture of 1,2-dichloromethane and methanol. The extract was washed with saturated brine, and dried, and then the solvent was evaporated to give 1.74 g of a colorless liquid. A part of the colorless liquid was converted to the hydrochloride in a conventional method. Recrystallization from methanol gave colorless crystals having melting point from 257 to 265 ° C (decomposition) In the same way, the fumarate was prepared in a conventional method. Recrystallization from methanol gave colorless crystals having melting point from 185.5 to 186.5 ° C (decomposition). Hydrochloride: Elemental analysis for C23H23C1N • HCl • H20 Calculated% C, 62.02; H, 5.88; N, 12.58 Found% C, '62.08; H, 5.77; N, 12.60 Fumarate: Elemental analysis for C23H23C1N • C4H40 • H20 Calculated% C, 61.77; H, 5.57; N, 10.67 Found% C, 62.04; H, 5.40; N, 10.70 Example 111 4-Phenoxy-l- [2- (4-piperidyl) ethyl] -lH-imidazo [4, 5-c] quinoline trifluoroacetate To a solution of 0.30 g of 4- [2- (4- Phenoxy-lH-imidazo [4,5-c] -quinoln-1-yl) ethyl] -1-piperidinecarboxylic acid tert-butyl ester in 10 ml of methylene chloride, 1 ml of trifluoroacetic acid was added at room temperature, and the The mixture was stirred for 1.5 hours. The reaction solution was concentrated. The resulting pale yellow solid was washed successively with isopropanol and diisopropyl ether to give 0. 36 g of colorless crystals. Recrystallization from a mixture of methylene chloride and ethanol gave colorless crystals having the melting point from 211 to 216 ° C. Elemental analysis for C23H24N 0 • CF3C02H • 1 / 8H20 Calculated% C, 61. 44; H, 5 twenty-one; N, 11 46 Found% C, 61. 26; H, 5 05; N, 11 47 Example 112 4-Chloro-2-phenyl-1- [2- (1-piperazinyl) ethyl] -IH-imidazo [4, 5-c] quinoline methanesulfonate To a solution of 1.20 g of 4- [2- (4-Chloro-2-phenyl-1H-imidazo- [4, 5-c] quinolin-1-yl) ethyl] -1-piperazinecarboxylic acid tert-butyl ester in 12 ml of 1,2-dichloroethane, 1.2 ml of acid methanesulfonic acid was added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was added with isopropanol and ethanol, and the precipitated crystals were collected by filtration to give 1.24 g of colorless crystals. Recrystallization from methanol gave colorless crystals having melting point from 256 to 270 ° C (decomposition). Elemental analysis for C22H22CIN5 • 2CH3S03H Calculated% C, 49.35; H, 5.18; N, 11.99 Found% C, 49.60; H, 5.11; N, 12.16 Example 113 4-Amino-l- [2- (4-piperidyl) ethyl] -1H-imidazo [4, 5-c] quinoline hydrochloride A mixture of 1.57 g of 4- [2- (4-amino -lH-imidazo [4, 5-c] quinolin-1-yl) ethyl] -1-piperidinecarboxylic acid tert-butyl ester and 40 ml of an ethyl acetate solution of acid chloride were stirred at room temperature for 5 hours. The reaction mixture was added with water, adjusted to pH 10 with 10% aqueous sodium hydroxide solution, and extracted with methylene chloride. The extract was dried, and the solvent was evaporated. The residue was washed with ethyl acetate to give 1.01 g of pale brown crystals. The resulting crystals were purified by column chromatography on alumina using methylene chloride-methanol (40: 1 to 20: 1) as solvents in elution, and washed with diisopropyl ether to give colorless crystals. The hydrochloride was prepared in a conventional method. Recrystallization from ethanol gave colorless crystals having melting point from 243 to 244 ° C (decomposition). Elemental analysis for C? 7H2? N5 • HCl • 3 / 4H20 Calculated% C, 59.12; H, 6.86; N, 20.28 Found% C, 59.10; H, 6.83; N, 20.30 According to the methods of Examples 110 to 113 the compounds of Examples 114 to 186 were obtained. i ^ HMU¡KÉrfMgM ^ ^^^^ t¿? h? i ^ li Example 187 1- [2- (Nn-Butyl-4-piperidyl) ethyl] -4-chloro-lH-imidazo [4, 5-c] quinoline hydrochloride To a suspension of 1.20 g of 4-chloro-1-trifluoroacetate - [2- (4-piperidyl) ethyl] -lH-imidazo- [4,5-c] quinoline and 0.77 g of potassium carbonate in 6 ml of N, N-dimethylformamide, 0.30 ml of n-butyl bromide are added dropwise at room temperature, and the mixture was stirred for 5 hours. The reaction mixture was adjusted to pH with 10% aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried, and then the solvent was evaporated to give 0.92 g of a pale brown liquid. The resulting liquid was dissolved in tetrahydrofuran. The solution was filtered on silica gel, and the filtrate was concentrated to give 0.87 g of a colorless solid. The hydrochloride was prepared in a conventional method. Recrystallization from a mixture of methanol and ethyl acetate gave colorless crystals having melting point from 144 to 158 ° C. Elemental analysis for C2? H27ClN4 • 2HC1 • 1 / 2H20 Calculated% C, 55.70; H, 6.68; N, 12.37 Found% C, 55.80; H, 6.65; N, 12.44 Example 188 1- [2- (N-Acetyl-4-piperidyl) ethyl] -4-chloro-lH-imidazo [4, 5-c] quinoline To a solution of 0.60 g of 4-chloro-trifluoroacetate 1 [2- (4-piperidi1) ethyl] -lH-imidazo- [4, 5-c] quinoline in 4 ml of pyridine, 2 ml of acetic anhydride was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was evaporated. The residue was added with isopropanol and diisopropyl ether, and the precipitated crystals were collected by filtration, and washed with diisopropyl ether to give 0.45 g of colorless crystals. Recrystallization from a mixture of methylene chloride and diisopropyl ether gave colorless crystals having melting point from 183 to 186.5 ° C. Elemental analysis for C? 9H? ClN40 Calculated% C, 63.95; H, 5.93; N, 15.70 Found% C, 63.81; H, 5.87; N, 15.61 According to the methods of Examples 187 and 188, the compounds of Examples 189 to 194 were obtained. 11. 67 Example 195 4-Chloro-l- [2- [N- (4-fluorophenylsulfonyl) -4-piperidyl] ethyl] -lH-imidazo- [4,5-c] quinoline To a suspension of 0.50 g of trifluoroacetate from 4- chloro-1- [2- (4-piperidyl) ethyl] -IH-imidazo [4, 5-c] quinoline and 0.32 g of potassium carbonate in 2 ml of N, N-dimethylformamide, a solution of 0.23 g of chloride of p-fluorobenzenesulfonyl in 3 ml of N, N-dimethylformamide was added dropwise at room temperature, and the mixture was stirred for 5 hours. The reaction mixture was adjusted to pH 10 with 10% aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried, and then the solvent was evaporated to give 0.35 g of a colorless solid. Recrystallization from a mixture of methanol, ethanol and water gave colorless crystals having the melting point from 175 to 178.5 ° C. Elemental analysis for C23H22C1FN402S Calculated% C, 58.41; H, 4.69; N, 11.85 Found% C, 58.43; H, 4.52; N, 11.88 Example 196 1- [2- (N-Methanesulfonyl-4-piperidyl) ethyl] -4-phenoxy-1H-imidazo [4,5-c] quinoline To a solution of 1.00 g of 4-phenoxy-trifluoroacetate 1 [2- (4-piperidyl) ethyl] -lH-imidazo- [4, 5-c] quinoline and 0.57 ml of triethylamine in 10 ml of methylene chloride, 0.16 ml of methanesulfonyl chloride was added dropwise at room temperature , and the mixture was stirred for 1.5 hours. The reaction mixture was added with water, and extracted with methylene chloride. The extract was washed with water, and dried, and then the solvent was evaporated to give a colorless liquid. The resulting colorless liquid was solidified with ethyl acetate, and the solid was washed with diethyl ether to give 0.80 g of colorless crystals. Recrystallization from a mixture of methylene chloride and ethyl acetate gave colorless crystals having the melting point from 173. 5 to 176 ° C. Elemental analysis for C24H26N403S Calculated% C, 63.98; H, 5.82; N, 12.44 Found% C, 64.01; H, 5.96; N, 12.28 According to the method of Example 196, the compounds of Examples 197 to 199 were obtained.

Example 200 4- [2- (4-Amino-lH-imidazo [4, 5-c] quinolin-1-yl) ethyl] -N-methyl-1-piperidine-carbothioamide A suspension of 0.50 g of 4-amino -l- [2- (4-piperidyl) ethyl] -IH-imidazo [4, 5-c] quinoline and 0.37 g of methylisothiocyanate in 10 ml of methylene chloride was stirred at room temperature for 1 hour and then the crystals precipitated they were collected by filtration to give 0.56 g of colorless crystals. Recrystallization from a mixture of methylene chloride and methanol gave colorless crystals having the melting point from 216 to 218 ° C. Elementary analysis for • 1 / 2H20 Calculated% C, 60.45; H, 6.67; N, 22.26 Found% C, 60.79; H, 6.66; N, 21.97 According to the method of Example 200, the compound of Example 201 was obtained. Example 201 4- [2- (4-Chloro-2-phenyl-1H-imidazo [4, 5-c] quinolin-1-yl) ethyl] -N-methyl-1-piperidinecarbothioamide Appearance: colorless crystals Recrystallization solvent: methanol mp: 215-220 ° C (decomposition) Elemental analysis for C25H26C1N5S Calculated% C, 64.71; H, 5.65; N, 15.09 Found% C, 64.80; H, 5.62; N, 14.96 Example 202 1- [2- (1-Amidino-4-piperidyl) ethyl] -4-chloro-2-phenyl-1H-imidazo [4, 5-c] quinoline hydrochloride A solution of 0.75 g of 4 -chloro-2-phenyl-1- [2- (4-piperidyl) ethyl] -lH-imidazo- [4,5-c] quinoline, 0.40 g of lH-pyrazole-1-carboxamidine hydrochloride and 0.39 ml of triethylamine in 5 ml of N, N-dimethylformamide was stirred at room temperature for 19 hours. The reaction solution was concentrated and the residue was added with ethanol, and then the precipitated crystals were collected by filtration to give 0.51 g of colorless crystals. Recrystallization from ethanol gave colorless crystals having melting point from 270 to 273 ° C (decomposition). Elemental analysis for C24H25C1N6 • HCl • 1 / 2H20 Calculated% C, 60.25; H, 5.69; N, 17.57 Found% C, 60.47; H, 5.61; N, 17.36 As an example of the excellent effects of the compounds according to the present invention, the experimental results of inhibitory actions against the production of TNF-α and IL-1β in human cells will be shown later. 1. Preparation of blood cells for culture Approximately 50 mL of whole blood was collected from healthy adult volunteers by vein puncture in a plastic tube which contains 170 μL of Novo-heparin 1000 (Novo-Nordisk A / S). Then, PBMCs (Peripheral Blood Mononuclear Cells) were prepared using a cell separation tube, LeucoPREP ™ (Becton Dickinson) and cultured with RPMI-1640 medium (Nissui Pharmaceutical Co.) containing 2 mM L-glutamine (Life Technologies), 2.5 U / ml of penicillin-2.5 μg / mL of streptomycin solution (Life Technologies) supplemented with 10% fetal bovine serum (Intergen Company) at lxlO6 cells / mL. 2. Preparation of the test compounds The test compounds were dissolved in distilled ultra pure water, dimethyl sulfoxide, or 0.1 N hydrochloric acid at 20 μM, and then sequentially diluted with se and used. The compounds were examined at concentrations ranging from 10 ~ 10 M to 10 ~ 5 M. 3. Treatment of cells with drugs 10 μL of 1 μg / mL of lipopolysaccharide (LPS) was added to a 96 well plate (flat bottom) for cell culture, MicroTest III ™ tissue culture plate (Becton Dickinson), containing 180 μL of PBMCs in the aforementioned medium. After 30 minutes, 10 μL of the test compound solution or solvent was added additionally to each well, and the plate was covered with a plastic lid and incubated at 37 ° C for 16 hours in a 5% atmosphere of C02 4. Determination of human TNF-α and human ß-IL-1 An enzyme immunoassay by the sandwich method was performed to determine human TNF-α and human ß-IL-1 in the culture supernatant. The anti-cytokine antibody (the first antibody) was diluted and placed in 96-well microtiter plates for coating. After the wells were washed, the supernatant culture was properly diluted and then added to each well and incubated. Then the second antibody against the cytokine and the third body against the second antibody were added in succession while washing processes were applied between the operations. After the final washing process, a solution of tetramethylbenzidine (DAKO) was added to each well to initiate the color reaction. The color reaction was abruptly quenched with 1 N sulfuric acid, and then the absorbance at 450 nm of each well was measured by microplate reader, M-Vmax ™ (Molecular Devices). The concentrations of the cytokines were determined by software quantification, Softmax ™ (Molecular Devices), in comparison with the cration curves obtained using the recombinant cytokines as the standards. For determination of human TNF-a, the anti-human monoclonal TNF-a (ENDOGEN), polyclonal rabbit anti-human TNF-a (Pharma Biotechnology Hannover), peroxidase conjugated donkey anti-rabbit IgG (Jackson ImmunoRes.Labs.) And recombinant human TNF-a (INTERGEN Company) were used for the first, second and third antibodies and the standard for the cration curve , respectively. For the determination of human IL-1β, monoclonal anti-human IL-1β (Cistron), polyclonal sheep anti-human IL-1β (biogenesis), HRP conjugate anti-donkey goat (Chemicon International) , and recombinant human IL-1β (R & D Systems) were used for the first, second and third antibodies and the standard for the cration curve, respectively. In both cases for TNF-α and IL-1β, the activities of each test compound were shown as percentages (%) of the amount of the cytokine induced by the LPS treatment together with the test compound against the amount of cytokine induced by treatment only with LPS. The results shown in tables 1 and 2. Table 1. Inhibitory action against the production of TNF-a in human cells Table 2: Inhibitory Action against the production of IL-1β in human cells These results clearly indicated that the compounds of the present invention have excellent inhibitory actions against the production of TNF and IL-1. Industrial Applicability The compounds of the present invention have excellent inhibitory actions against the production of TNF or IL-1 and are extremely useful as preventive or therapeutic agents of diseases mediated by these cytokines.

Claims (5)

1. CLAIMS 1. An iH-imidazopyridine derivative represented by the following general formula or a salt thereof: characterized in that R1 represents a hydrogen atom, a hydroxyl group, an alkyl group, which may have one or more substituents, a cycloalkyl group which may be substituted, a styryl group, which may be substituted, or an aryl group which may have one or more substituents; R 2 represents a hydrogen atom, an alkyl group, a halogen atom, a hydroxyl group, an amino group which may have one or two substituents, a cyclic amino group which may be substituted, or a phenoxy group which may be replaced; Ring A represents a homocyclic or heterocyclic ring which may be substituted with one or more alkyl groups, alkoxy groups, or halogen atoms; R3 represents a heterocyclic group containing saturated nitrogen which may be substituted; and m represents an integer from 0 to 3; with the proviso that when R3 represents an unsubstituted piperidino group, at least one of R1 and R2 is not a hydrogen atom.
2. 2. An lH-imidazopyridine derivative represented by the following general formula or salt thereof: characterized in that R1 represents a hydrogen atom, a hydroxyl group, an alkyl group which may have one or more substituents, a cycloalkyl group which may be substituted, a styryl group, which may be substituted, or an aryl group which may be substituted. have one or more substituents; R 2 represents a hydrogen atom, an alkyl group, a halogen atom, a hydroxyl group, an amino group which may have one or two substituents, a cyclic amino group which may be substituted, or a phenoxy group which may be replaced; Ring A represents a homocyclic or heterocyclic ring which may be substituted with one or more alkyl groups, alkoxy groups, or halogen atoms; m represents an integer from 0 to 3; R4 represents a hydrogen atom, an alkyl group, a benzyl group; a triphenylmethyl group, an alkanoyl group which may be substituted, an alkoxycarbonyl group, a benzyloxycarbonyl group, a thiocarbamoyl group which may be substituted, or an alkanesulfonyl group, a benzenesulfonyl group which may be substituted, or an amidino group; Y represents a methylene group, oxygen atom, sulfur atom, nitrogen atom, a group represented by NH, or a single bond; and n represents an integer from 0 to 2.
3. The compound of the salt thereof according to claim 1 or claim 2, characterized in that ring A is a benzene ring or a thiophene ring.
4. 4. The medicament which is characterized in that it comprises as an active ingredient the 1H-imidazopyridine derivative or a pharmaceutically acceptable salt thereof according to claim 1 or claim 2.
5. 5. The medicament according to claim 4, characterized because it is used for preventive or therapeutic treatment of a disease in which a cytokine is mediated.