ZA200206698B

ZA200206698B - 1H-Imidazopyridine derivatives.

Info

Publication number: ZA200206698B
Application number: ZA200206698A
Authority: ZA
Inventors: Hideo Kato; Jun Sakaguchi; Tomoyuki Izumi; Ken-Ichi Kato
Original assignee: Horkuriku Seiyaku Co Ltd
Priority date: 2000-02-09
Filing date: 2002-08-21
Publication date: 2003-08-21

Description

£d4QUc/ 0090 - . , " . :

SPECIFICATION

1H-Imidazopyridine derivatives

Technical Field :

The present invention relates to novel 1H-imidazopyridine derivatives or salts thereof which have a potent inhibitory action against production of tumor necrotizing factor (TNF) or interleukin-1 (IL-1) and are useful as active ingredients of medicaments. :

Background Art

Some compounds having 1H-imidazoquinoline structure are known which are analogous to the compounds of the present invention. For example, Journal of

Medicinal Chemistry, Vol. 11, p. 87 (1968) discloses 1-(2-piperidinoethyl)-1H-imidazo- [4,5-c]lquinoline, Japanese Patent Unexamined Publication (KOKAI) No. Sho 60-123488/1985 discloses 1-isobutyl-1H-imidazo[4,5-c]quinoline-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)-1H-imidazo[4,5-clquinoline as a compound having analgesic and anticonvulsant actions. However, 1H-imidazopyridine derivatives as those according to the present invention have not been known so far. :

The aforementioned imiquimod has been known to have an inducing action of a few kinds of cytokines such as interferon (IFN), TNF, IL-1 and the like, which is described in Journal of Interferon Research, Vol. 14, p. 81 (1994). In addition, as compounds having IFN-inducing activity, International Publication W099/29693 discloses imidazonaphthylidine derivatives and Japanese Patent Unexamined

Publication (KOKAI) No. Heil1-80156/1999 discloses imidazopyridine derivatives.

However, 1H-imidazopyridine derivatives or 1H-imidazoquinoline derivatives having an inhibitory action against production of TNF or IL-1, which action is totally opposite to those taught by the aforementioned prior arts, have not been known so far. :

.

Ye

Disclosure of the Invention

An object of the present invention is to provide novel compounds which have : excellent inhibitory actions against production of cytokines such as TNF, IL-1 and the like and are useful as medicaments.

The inventors of the present invention made intensive studies to achieve the object. As a result, they found novel 1H-imidazopyridine derivatives which have an excellent inhibitory action against production of TNF or IL-1 and achieved the present invention. © The present invention thus relates to novel 1H-imidazopyridine derivatives represented by the following general formula (I) or salts thereof:

R—(CH KF — ahd nN" OR? (I) wherein R! represents hydrogen atom, an alkyl group which may be substituted, a cycloalkyl group which may be substituted, or an aryl group which may be substituted; R2 represents a cycloalkyl group which may be substituted, an alkyl group which may be substituted, an aryl group which may be substituted, cyano group, mercapto group, carboxyl group, or carbamoyl group; ring A represents a homocyeclic or heterocyclic ring which may be substituted; R3 represents an amino group which may be substituted or a saturated nitrogen-containing heterocyclic group which may be substituted; and k represents an integer of from 0 to 3; provided that the compound wherein R3 represents a saturated nitrogen-containing heterocyclic group which may be substituted and R? is a non-substituted alkyl group is excluded.

According to a preferred embodiment of the present invention, provided are novel 1H-imidazopyridine derivatives represented by the following general formula (II) or salts thereof:

) '

Ya

RP—(CHe. FR —

NOR? (I) wherein R!, R2, ring A and k have the same meanings as those defined above; R¥ represents a group represented by the following formula (III)

CH

"\ Y | ig

N— or os” ge ACH Tg ALAC an

R4, R5, R¢ may be the same or different and represent hydrogen atom, an alkyl group which may be substituted, a benzyl group which may be substituted, triphenylmethyl group, an acyl group which may be substituted, an alkoxycarbonyl group which may be substituted, a benzyloxycarbonyl group which may be substituted, a thiocarbamoyl group which may be substituted, an alkanesulfonyl group which may be substituted, a benzenesulfonyl group which may be substituted, or an amidino group which may be substituted; Y represents oxygen atom, sulfur atom, or nitrogen atom, a group represented by CHz, CH, or NH, or a single bond; and m and n may be the same or different and represent an integer of from 0 to 2, provided that when R3 represents a group represented by the following formula (IV): (CHa)

CCl =8 _N_ACHa)y RS AN {CHa vy

R? does not represent a non-substituted alkyl group. The compound represented by the aforementioned general formula (II) fall within the scope of the aforementioned general formula (I), i.e., they are characterized to have, as R3 of the aforementioned general formula (I), the amino group which may have a specific substituent or the saturated nitrogen-containing heterocyclic group which may have a specific

' w, substituent represented by R3.

According to another preferred embodiment of the present invention, provided are the compounds or salts thereof represented by the aforementioned general formula (I) and formula (II) wherein the ring Aisa benzene ring which may be substituted or a thiophene ring which may be substituted.

According to still another preferred embodiment, provided are the compounds or salts thereof represented by the aforementioned general formula (I) and formula (II) wherein R2 is trifluoromethyl! group.

From another aspect, there is provided a medicament which comprises the compound represented by the aforementioned general formula (I) or (I), or a pharmacologically acceptable salt thereof as an active ingredient. The medicament is useful for preventive and/or therapeutic treatment of diseases of humans and animals, in which a cytokine such as TNF or IL-1 is involved, which include chronic inflammatory diseases (e.g., rheumatic arthritis, osteoarthritis and the like), allergic rhinitis, atopic dermatitis, contact dermatitis, urticaria, eczema, pruritus cutaneus, prurigo, asthma, sepsis, septic shock, various autoimmune diseases [autoimmune hemic diseases (e.g., hemolytic anemia, anaplastic anemia, idiopathic thrombocythemia and the like), autoimmune intestinal diseases (e.g., ulcerative : colitis, Crohn's disease and the like), autoimmune corneitis (e.g., keratoconjunctivitis sicca, spring catarrh and the like), endocrine ophthalmopathy, Graves disease, sarcoid granuloma, multiple sclerosis, systemic erythematodes, multiple chondritis, pachydermia, active chronic hepatitis, myasthenia gravis, psoriasis, interstitial pulmonary fibrosis and the like], diabetes, cancerous cachexia, HIV-infectious cachexia and the like.

According to a further aspect, there are provided an inhibitor against production of a cytokine which comprises the compound represented by the aforementioned general formula (I) or (II), or a pharmacologically acceptable salt thereof as an active ingredient. As an preferred embodiment, provided is the inhibitor against production of tumor necrotizing factor (TNF) or interleukin-1 (IL-1).

Furthermore, according to the present invention, provided are a use of the compound represented by the aforementioned general formula (I) or (II), or a pharmacologically acceptable salt thereof for the manufacture of the aforementioned

“ . medicament; and a method for the preventive and/or therapeutic treatment of diseases in which a cytokine is involved, which comprises the step of administering a preventively and/or therapeutically effective amount of the compound represented by the aforementioned general formula (I) or (II) or a pharmacologically acceptable salt thereof to a mammal including a human.

Best Mode for Carrying Out the Invention

Specific explanations of the compounds of the aforementioned general formulas (I) and (II) of the present invention will be given below. In the aforementioned general formulas (I) and (II), examples of the alkyl group represented by R1, R2, R¢, R5, and R® defined as an alkyl group which may be substituted, include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group and the like.

Examples of the cycloalkyl group represented by R! and R?, defined as a cycloalkyl group which may be substituted, include, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and the like.

Examples of the aryl group represented by R! and R?, defined as an aryl group which may be substituted, include, for example, phenyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 3-pyridazinyl group, 4-pyridazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, pyrazinyl group, 2-furyl group, 3-furyl group, 2-thienyl group, 3-thienyl group, 1-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 1-pyrazolyl group, 3-pyrazolyl group, 4-pyrazolyl group, 2-oxazolyl group, 4-oxazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 1,2,3-triazol-1-yl group, 1,2,3-triazol-4-yl group, 1,2,3-triazol-5-yl group, 1,2,4-triazol-1-yl group, 1,2,4-triazol-3-yl group, 1,2,4-triazol-5-yl group, 1-tetrazolyl group, 5-tetrazolyl group, 1,2,5-thiadiazol-3-yl group, 1-naphthyl group, 2-naphthyl group, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 1-indolyl group, 2-indolyl group, 3-indolyl group and the like.

Examples of the homocyclic or heterocyclic ring represented by ring A in the aforementioned general formulas (I) and (II), defined as a homocyclic or heterocyclic ring which may be substituted, include, for example, benzene ring, cyclopentene ring, cyclohexene ring, cycloheptene ring, cyclooctene ring, cycloheptadiene ring, thiophene ring, furan ring, pyridine ring, pyrazine ring, pyrimidine ring, pyrrole ring, thiazole ring, oxazole ring, azepine ring, naphthalene ring, quinoline ring and the like.

Preferred ring includes benzene ring, thiophene ring or the like.

The saturated nitrogen-containing heterocyclic group represented by R3 in the aforementioned general formula (I), which may be substituted, includes where R¥ in the aforementioned general formula (II) is the saturated nitrogen-containing heterocyclic group represented by the general formula (IV) which may be substituted.

The saturated nitrogen-containing heterocyclic group includes those having one or more nitrogen atoms as ring-constituting atom(s), and further optionally having one or more oxygen atoms or sulfur atoms as ring-constituting atom(s). Examples include 1-aziridinyl group, 2-aziridinyl group, 1-azetidinyl group, 2-azetidinyl group, 3-azetidinyl group, 1-pyrrolidinyl group, 2-pyrrolidinyl group, 3-pyrrolidinyl group, pyrazolidinyl group, imidazolidinyl group, piperidino group, 2-piperidyl group, 3-piperidyl group, 4-piperidyl group, 1-piperazinyl group, 9-piperazinyl group, hexahydro-1,2-diazin-3-yl group, hexahydro-1,3-diazin-2-yl group, hexahydro-1H-azepin-1-yl group, hexahydro-1H-azepin-2-yl group, hexahydro-1H-azepin-3-yl group, hexahydro-1H-azepin-4-yl group, hexahydro-1H-1,4-diazepin-1-yl group, hexahydro-1H-1,4-diazepin-2-yl group, hexahydro-1H-1,4-diazepin-5-yl group, hexahydro-1H-1,4-diazepin-6-yl group, 2-morpholinyl group, 3-morpholinyl group, morpholino group, 2-thiomorpholinyl group, 3-thiomorpholinyl group, 4-thiomorpholinyl group, 3-oxazolidinyl group, 3-isoxazolidinyl group, 3-thiazolidinyl group, 3-isothiazolidinyl group, tetrahydro-1,2,4-oxadiazol-3-yl group, tetrahydro-1,2,5-oxadiazol-3-yl group, 1,2,3-triazolidin-4-yl group, 1,2,4-triazolidin-3-yl group, tetrahydro-1,2,4-thiadiazol-3-yl group, 1,2,5-thiadiazolin-3-yl group, decahydroquinolyl group, 8-azabicyclo[3.2.1]Joctan-3-yl group, 9-azabicyclo[3.3.1]nonan-3-yl group and the like, and preferred groups include, for example, 3-piperidyl group, 4-piperidyl group, 1-piperazinyl group, 2-piperazinyl group, 3-pyrrolidinyl group, 9-azetidinyl group, 3-azetidinyl group, 2-morpholinyl

. Po group, 2-thiomorpholinyl group and the like.

In the aforementioned formula (II), examples of the acyl group represented by R4, RS, and RS, defined as an acyl group which may be substituted, include, for example, formyl group, acetyl group, propionyl group, n-butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, benzoyl group, 2-pyridylearbonyl group, nicotinoyl group, isonicotinoyl group, 3-pyridazinylcarbonyl group, 4-pyridazinylcarbonyl group, 2-pyrimidinylcarbonyl group, 4-pyrimidinyl- carbonyl group, 5-pyrimidinylcarbonyl group, pyrazinylcarbonyl group, 2-furylcarbonyl group, furoyl group, thenoyl group, 3-thienylcarbonyl group, 1-pyrrolylcarbonyl group, 2-pyrrolylcarbonyl group, 3-pyrrolylcarbonyl group, 1-imidazolylcarbonyl group, 2-imidazolylcarbonyl group, 4-imidazolylcarbonyl group, 1-pyrazolylcarbonyl group, 3-pyrazolylcarbonyl group, 4-pyrazolylcarbonyl group, 2-oxazolylcarbonyl group, 4-oxazolylcarbonyl group, 3-isoxazolylcarbonyl group, 4-isoxazolylcarbonyl group, 5-isoxazolylcarbonyl group, 2-thiazolylcarbonyl group, ) 4-thiazolylcarbonyl group, 5-thiazolylcarbonyl group, 3-isothiazolylcarbonyl group, 4-isothiazolylcarbonyl group, 5-isothiazolylcarbonyl group, 1,2,3-triazol-1-ylcarbonyl group, 1,2,3-triazol-4-ylcarbonyl group, 1,2,3-triazol-5-ylcarbonyl group, 1,2,4-triazol-1-ylcarbonyl group, 1,2,4-triazol-3-ylcarbonyl group, 1,2,4-triazol-5- ylcarbonyl group, 1-tetrazolylcarbonyl group, 5-tetrazolylcarbonyl group, 1,2,5-thiadiazol-3-ylcarbonyl group, 1-naphthoyl group, 2-naphthoyl group, 2-quinolylcarbonyl group, 3-quinolylcarbonyl group, 4-quinolylcarbonyl group, 1-indolylcarbonyl group, 2-indolylcarbonyl group, 3-indolylcarbonyl group, cyclohexylacetyl group, acryloyl group, phenylacetyl group and the like. Examples of the alkoxycarbonyl group represented by R4, R5, and RS, defined as an alkoxycarbonyl group which may be substituted, include, for example, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, n-pentyloxycarbonyl group, n-hexyloxycarbonyl group and the like. Examples of the alkanesulfonyl group represented by R¢, R5, and RS, defined as an alkanesulfonyl group which may be substituted, include, for example, methanesulfonyl group, ethanesulfonyl group, n-propanesulfonyl group, n-butanesulfonyl group and the like.

In the compounds of aforementioned general formulas (I) and (II) of the present invention, when certain functional groups are referred to as “which may be substituted,” the substituent may be any group so long as it can substitute on the functional groups.

The number, kind, and substituting position of the substituent are not particularly limited, and when two or more substituents exist, they may be the same or different.

Examples of substitutable functional groups include halogen atoms such as fluorine atom, chlorine atom, bromine atom, or iodine atom; hydroxyl group; alkyl groups such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, and n-hexyl group; trifluoromethyl group; aryl groups such as phenyl group, naphthyl group, and pyridyl group; alkoxyl groups such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, and tert-butoxy group; aryloxy groups such as phenoxy group, pyridyloxy group, naphthyloxy group; amino groups which may be substituted such as amino group, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, cyclopropylamino group, cyclobutylamino group, cyclopentylamino group, cyclohexylamino group, dimethylamino group, diethylamino group, anilino group, pyridylamino group, benzylamino group, - dibenzylamino group, acetylamino group, trifluoroacetylamino group, } tert-butoxycarbonylamino group, benzyloxycarboxylamino group, benzhydrylamino group, and triphenylmethylamino group; acyl groups which may be substituted such as formyl group, acetyl group, propionyl group, n-butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, dichloroacetyl group, and trichloroacetyl group; alkoxycarbonyl groups such as methoxycarbenyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, n-pentyloxycarbonyl group, and n-hexyloxycarbonyl group; benzyloxycarbonyl group; carbamoyl group; alkylcarbamoyl groups such as methylcarbamoyl group, ethylcarbamoyl Jr— n-propylcarbamoyl group, isopropylcarbamoyl group, n-butylcarbamoyl group, isobutylcarbamoyl group, sec-butylcarbamoyl group, and tert-butylcarbamoyl group; thiccarbamoy! group; :

'C alkylthiocarbamoyl groups such as methylthiocarbamoyl group, ethylthiocarbamoyl group, n-propylthiocarbamoyl group, isopropylthiocarbamoyl group, n-butylthiocarbamoyl group, isobutylthiocarbamoyl group, sec-butylthiocarbamoyl group, and tert-butylthiocarbamoyl group; amidino group; alkylthio groups such as methylthio group, ethylthio group, and n-propylthio group; alkanesulfinyl groups such as methanesulfinyl group, ethanesulfinyl group, and n-propanesulfinyl group; alkanesulfonyl groups such as methanesulfonyl group, ethanesulfonyl group, n-propanesulfonyl group, and n-butanesulfonyl group; arylsulfonyl groups which may be substituted such as p-toluenesulfonyl group, p-methoxybenzenesulfonyl group, and p-fluorobenzenesulfonyl group; aralkyl groups such as benzyl group, naphthylmethyl group, pyridylmethyl group, furfuryl group, and triphenylmethyl group; nitro group; cyano group; azido group; sulfamoyl group; oxo group; hydroxyimino group; alkoxyimino groups such as methoxyimino group, ethoxyimino group, n-propoxyimino group, and isopropoxyimino group; ethylenedioxy group and the like.

In the specification, some examples are given with respect to the substituting/binding position of an aryl group of “the aryl group”, “the homocyclic or heterocyclic ring”, "the acyl group”, "the aryloxy group”, "the amino group which may be substituted”, "the arylsulfonyl group”, and "the aralkyl group”. However, the aforementioned groups may substitute/bind at any position unless a substituting/binding position is specifically limited.

The compounds represented by the aforementioned general formulas (I) and (II) of the present invention can be converted into salts, preferably, pharmacologically acceptable salts, if desired; or free bases can be generated from the resulting salts.

Examples of the salts, preferably the pharmacologically acceptable salts of the compounds represented by the aforementioned general formulas (I) and (II) of the present invention include acid-addition salts, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; and salts with organic acids such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, : trifluoroacetic acid, acrylic acid, oleic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, malonic acid, lactic acid, glutaric acid, sebacic acid, gluconic acid, lauric acid, myristic acid, stearic acid, undecanoic

« ) acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, benzoic acid, phthalic acid, terephthalic acid, cinnamic acid, p-toluenesulfonic acid, nicotinic acid, picric acid, adipic acid, aspartic acid, glutamic acid, 10-camphorsulfonic acid, enantiomers thereof and the like.

Among the compounds represented by the aforementioned general formulas (I) and (II) of the present invention, optical isomers or diastereomers may exist for compounds having one or more asymmetric carbons. These optical isomers and mixtures thereof, racemates or salts thereof also fall within the scope of the present invention.

The compounds represented by the aforementioned general formulas (I) and (II) or the salts thereof according to the present invention can exist as any crystalline form depending on manufacturing conditions, or exist as any hydrate or solvate.

These crystalline forms, hydrates or solvates, and mixtures thereof also 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 these examples: (1) 1-[2-(4-Piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo[4,5-c]lquinoline (2) 2-Phenyl-1-[2-(4-piperidyl)ethyl]l-4-trifluoromethyl-1H-imidazo[4,5-c]quinoline 3) 8-Chloro-2-phenyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo[4,5-c]- quinoline 4) 8-Methyl-2-phenyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo[4,5-c]- quinoline (5) 8-Methoxy-2-phenyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo[4,5-c]- quinoline (6) 1-[2-(4-Piperidyl)ethyl]-2,4-ditrifluoromethyl-1H-imidazo[4,5-c]quinoline (7) 2-Cyclopentyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo(4,5-c]- quinoline N (8) 2-Cyclohexyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo{4,5-c]lquinoline (9) 2-tert-Butyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo[4,5-clquinoline (10) 2-(4-Methylphenyl)-1-[2-(4-piperidyl)ethyi]-4-trifluoromethyl-1H-imidazo[4,5-cl- quinoline

(11) 2-(4-Methoxyphenyl)-1-[2-(4-piperidyl)ethyl]l-4-trifluoromethyl-1H-imidazol[4,5-c]-

quinoline

12) 2-(4-Fluorophenyl)-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo[4,5-cl-

quinoline

{13) 1-[2-(4-Piperidyl)ethyl]-4-triflucromethyl-2-(4-trifluoromethylphenyl)-1H-

imidazo[4,5-c]quinoline

(14) 2-(4-Iodophenyl)-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo[4,5-c]-

quinoline

(15) 1-[2-(4-Piperidyl)ethyl]-2-(2-pyrrolyl)-4-trifluoromethyl-1H-imidazo[4,5-c]-

quinoline

(16) 2-(2-1H-Imidazolyl)-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo[4,5-c]-

quinoline an 1-[2-(4-Piperidyl)ethyl]-2-(2-thiazolyl)-4-trifluoromethyl-1H-imidazo[4,5-c]-

quinoline (18) 1-[2-(4-Piperidyl)ethyl]-2-(2-thienyl)-4-trifluoromethyl-1H-imidazo[4,5-c]-

quinoline

(19) 2-(5-Methyl-2-thienyl)-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo-

[4,5-cJquinoline

(20) 2-(3-Methyl-2-thienyl)-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline

(21) 2-(2-Furyl)-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo[4,5-clquinoline

(22) 7-Chloro-2-phenyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo-

[4,5-clquinoline

(23) 7-Chloro-1-[2-(4-piperidyl)ethyl]-2-(2-pyrrolyl)-4-trifluoromethyl-1H-imidazo-

[4,5-c]lquinoline

(24) 7-Chloro-1-[2-(4-piperidyl)ethyl]-2-(2-thiazolyl)-4-trifluoromethyl-1H-imidazo-

[4,5-c]quinoline

(25) 7-Chloro-2-(2-1H-imidazolyl)-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-

imidazo[4,5-c]quinoline

(26) T-Chloro-2-(2-furyl)-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo-

[4,5-c]quinoline

(27) 7-Chloro-1-[2-(4-piperidyl)ethyl]-2-(2-thienyl)-4-trifluoromethyl-1H-imidazo-

- [4,5-clquinoline (28) 7-Chloro-2-cyclopentyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo- ; [4,5-clquinoline 29) 7 -Chloro-2-cyclohexyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline (30) 7-Fluoro-2-phenyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo[4,5-c]- quinoline 31) 7 -Fluoro-1-[2-(4-piperidyl)ethyl]-2-(2-pyrrolyl)-4-trifluoromethyl-1H-imidazo- [4,5-c]lquinoline (32) 7-Fluoro-1-[2-(4-piperidyl)ethyl]-2-(2-thiazolyl)-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline (33) 7-Fluoro-2-(2-1H-imidazolyl)-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H- imidazo[4,5-clquinoline (34) 7-Fluoro-2-(2-furyl)-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline (85) 7-Fluoro-1-[2-(4-piperidyl)ethyl]-2-(2-thienyl)-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline (36) 2-Cyclopentyl-7-fluoro-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo- [4,5-¢]quinoline (37) 2-Cyclohexyl-7 -fluoro-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline (38) 7-Methyl-2-phenyl-1-{2-(4-piperidylethyl]-4-trifluoromethyl-1H-imidazo[4,5-c]- quinoline (39) 7-Methyl-1-[2-(4-piperidyl)ethyl]-2-(2-pyrrolyl)-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline (40) 7-Methyl-1-[2-(4-piperidyl)ethyl]l-2-(2-thiazolyl)-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline (41) 9-(2-1H-Imidazolyl)-7-methyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H- imidazo[4,5-c]lquinoline (42) 2-(2-Furyl)-7-methyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline (43) 7-Methyl-1-[2-(4-piperidyl)ethyl]-2-(2-thienyl)-4-trifluoromethyl-1H-imidazo-

[4,5-c]quinoline

(44) 2-Cyclopentyl-7 -methyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo-

[4,5-c]quinoline

(45) 2-Cyclohexyl-7-methyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo-

[4,5-clquinoline

(46) 6-Methyl-2-phenyl-1-[2-(4-piperidyl)ethyl}-4-trifluoromethyl-1H-imidazo-

[4,5-clquinoline

47) 6-Methyl-1-[2-(4-piperidyl)ethyl]-2-(2-pyrrolyl)-4-trifluoromethyl-1H-imidazo-

[4,5-c]quinoline

(48) 6-Methyl-1-[2-(4-piperidyl)ethyl]-2-(2-thiazolyl)-4-trifluoromethyl-1H-imidazo-

[4,5-c]lquinoline

49) 9-(2-1H-Imidazolyl)-6-methyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-

imidazo[4,5-clquinoline

(50) 2-(2-Furyl)-6-methyl-1-[2-(4-piperidyl)ethyl]-4-trifinoromethyl-1H-imidazo-

[4,5-c]lquinoline

(51) 6-Methyl-1-[2-(4-piperidyl)ethyl]-2-(2-thienyl)-4-trifluoromethyl-1H-imidazo-

[4,5-c]lquinoline

(52) 2-Cyclopentyl-6-methyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo-

[4,5-c]lquinoline .

(53) 2-Cyclohexyl-6-methyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo-

[4,5-c]lquinoline -

(54) 7 -Methoxy-2-phenyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline

(55) 9-Phenyl-1-[2-(4-piperidyl)ethyl]-4,7-ditrifluoromethyl-1H-imidazo[4,5-c]-

quinoline

(56) 7 -Chloro-2-phenyl-1-[2-(1-piperazinyl)ethyl]-4-trifluoromethyl-1H-imidazo-

[4,5-c]lquinoline

(57) 7-Chloro-1-[2-(1-piperazinyl)ethyl]-2-(2 -pyrrolyl)-4-trifluoromethyl-1H-imidazo-

[4,5-c]quinoline

(58) 7.Chloro-1-[2-(1-piperazinyl)ethyl]-2-(2-thiazolyl)-4-trifluoromethyl-1H-

imidazol4,5-clquinoline

(59) 7-Chloro-2-(2-1H-imidazolyl)-1-[2-( 1-piperazinyl)ethyl]-4-trifluoromethyl-1H-

imidazo[4,5-c]quinoline (60) 7-Chloro-2-(2-furyl)-1-[2-(1-pip erazinyl)ethyl]-4-trifluoromethyl-1H-imidazo- [4,5-c]quinoline

(61) 7-Chloro-1-[2-(1-piperazinyl)ethyl]-2 -(2-thienyl)-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline

(62) 7-Chloro-2-cyclopentyl-1-[2-( 1-piperazinyl)ethyll-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline (63) 7-Chloro-2-cyclohexyl-1-[2-( 1-piperazinyl)ethyll-4-trifluoromethyl-1H-imidazo- [4,5-c]lquinoline

(64) 7-Fluoro-2-phenyl-1-[2-( 1-piperazinyl)ethyl]-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline

(65) 7-Fluoro-1-[2-(1-piperazinyl)ethyl]}-2-(2-pyrrolyl)-4-trifluoromethyl-1H-imidazo- [4,5-c]lquinoline

(66) 7-Fluoro-1-[2-(1-piperazinyl)ethyl]-2 -(2-thiazolyl)-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline

(67) 7-Fluoro-2-(2-1H-imidazolyl)-1-[2-( 1-piperazinyl)ethyl]-4-trifluoromethyl-1H- imidazo[4,5-clquinoline (68) 7-Fluoro-2-(2-furyl)-1-[2-( 1-piperazinyl)ethyl]-4-trifluoromethyl-1H-imidazo- [4,5-clguinoline

(69) 7-Fluoro-1-[2-(1-piperazinyl)ethyl]-2 -(2-thienyl)-4-trifiluoromethyl-1H-imidazo- [4,5-c]quinoline

(70) 2-Cyclopentyl-7-fluoro-1-[2-(1-piperazinyl)ethyl] -4-trifluoromethyl-1H-imidazo- [4,5-clquinoline

(71) 2-Cyclohexyl-7-fluoro-1-[2-( 1-piperazinyl)ethyll-4-trifluoromethyl-1H-imidazo- [4,5-c]lquinoline

(72) 7-Methyl-2-phenyl-1-[2-(1-piperazinyl)ethyll-4-trifluoromethyl-1H-imidazo- [4,5-c]quinoline

(73) T-Methyl-1-[2-(1-piperazinyl)ethyl]-2-(2-pyrrolyl)-4-trifluoromethyl-1H-imidazo- [4,5-c]quinoline

(74) T-Methyl-1-[2-(1-piperazinyl)ethyl]-2-(2-thiazolyl)-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline

(75) 2-(2-1H-Imidazolyl)-7-methyl-1-[2-(1-piperazinyli)ethyl]-4-triflucromethyl-1H-

imidazo[4,5-clquinoline

(76) 2-(2-Furyl)-7-methyl-1-[2-( 1-piperazinyl)ethyl]-4-trifluoromethyl-1H-imidazo- [4,5-c]quinoline (77) 7-Methyl-1-[2-(1-piperazinyl)ethyl]-2-(2-thienyl)-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline

(78) 2-Cyclopentyl-7-methyl-1-[2-( 1-piperazinyl)ethyl]-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline

(79) 2-Cyclohexyl-7-methyl-1-[2-( 1-piperazinyl)ethyl]-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline

(80) 6-Methyl-2-phenyl-1-[2-( 1-piperazinyl)ethyll-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline

(81) 6-Methyl-1-[2-( 1-piperazinyl)ethyl]-2-(2-pyrrolyl)-4-trifluoromethyl-1H-imidazo- [4,5-c]lquinoline

(82) 6-Methyl-1-[2-(1-piperazinyl)ethyl]-2 -(2-thiazolyl)-4-trifluoromethyl-1H-imidazo- [4,5-c]lquinoline

(83) 2-(2-1H-Imidazolyl)-6-methyl-1-[2-( 1-piperazinyl)ethyl]-4-trifluoromethyl-1H- imidazo[4,5-clquinoline

(84) 2-(2-Furyl)-6-methyl-1-[2-(1-piperazinyl)ethyll-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline

(85) 6-Methyl-1-[2-( 1-piperazinyl)ethyl]-2-(2-thienyl)-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline

(86) 2-Cyclopentyl-6-methyl-1-[2-( 1-piperazinyl)ethyl]-4-trifluoromethyl-1H-imidazo- [4,5-c]quinoline

(87) 2-Cyclohexyl-6-methyl-1-{2-(1-piperazinyl)ethyl]-4-trifluoromethyl- 1H-imidazo- [4,5-c]quinoline

(88) 7-Chloro-1-[2-(2-morpholinyl)ethyl]-2-phenyl-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline

(89) 7-Chloro-1-[2-(2-morpholinyl)ethyl]-2-(2-pyrrolyl)-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline (90) 7-Chloro-1-[2-(2-morpholinyl)ethyl]-2-(2-thiazolyl)-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline

(91) 7-Chloro-2-(2-1H-imidazolyl)-1-[2-(2-morpholinyl)ethyl]-4-trifluoromethyl-1H- }

imidazo[4,5-c]quinoline

(92) 7-Chloro-2-(2-furyl)-1-[2-(2-morpholinyl)ethyl]-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline

(93) 7-Chloro-1-[2 -(2-morpholinyl)ethyl]-2-(2-thienyl)-4-trifluoromethyl-1H-imidazo-

[4,5-clquinoline (94) 7-Chloro-2-cyclopentyl-1-[2-(2-morpholinyl)ethyl]-4-trifluoromethyl-1H-imidazo-

[4,5-c]lquinoline

(95) 7-Chloro-2-cyclohexyl-1-[2-(2-morpholinyl)ethyl]-4-trifluoromethyl-1H-imidazo-

[4,5-clquinoline

(96) 7-Fluoro-1-[2-(2-morpholinyl)ethyl]-2-phenyl-4-trifluoromethyl-1H-imidazo-

[4,5-c]lquinoline

(97) 7-Fluoro-1-[2-(2-morpholinyl)ethyl]-2-(2-pyrrolyl)-4-trifluoromethyl-1H-imidazo-

[4,5-clquinoline

(98) 7-Fluoro-1-[2-(2-morpholinyl)ethyl]-2-(2-thiazolyl)-4-trifluoromethyl-1H-imid azo-

[4,5-c]lquinoline

(99) 7-Fluoro-2-(2-1H-imidazolyl)-1-[2-(2-morpholinyl)ethyl]-4-trifluoromethyl-1H-

imidazo[4,5-clquinoline

(100) 7 -Fluoro-2-(2-furyl)-1-[2 -(2-morpholinyl)ethyl]-4-trifluoromethyl-1H-imidazo-

[4,5-clquinoline

(101) 7-Fluoro-1-[2-(2-morpholinyl)ethyl]-2-(2-thienyl)-4-triflucromethyl-1H-imidazo- :

[4,5-clquinoline

(102) 2-Cyclopentyl-7 -fluoro-1-[2-(2-morpholinyl)ethyll-4-trifluoromethyl-1H-imidazo-

[4,5-c]lquinoline

(103) 2-Cyclohexyl-7-fluoro-1-[2-(2-morpholinyl)ethyl]-4-trifluoromethyl-1H-imidazo-

[4,5-c]lquinoline

(104) 7-Methyl-1-[2-(2-morpholinyl)ethyl]-2-phenyl-4-trifluoromethyl-1H-imidazo-

[4,5-clquinoline

(105) 7-Methyl-1-[2-(2-morpholinyl)ethyl]-2-(2-pyrrolyl)-4-triflucromethyl-1H-

imidazol[4,5-clquinoline

(106) 7-Methyl-1-[2-(2-morpholinyl)ethyl]-2-(2-thiazolyl)-4-triflucromethyl-1H-

imidazol4,5-clquinoline

(107) 2-(2-1H-Imidazolyl)-7-methyl-1-{2-(2-morpholinyl)ethyl]-4-trifluoromethyl-1H-

imidazo[4,5-clquinoline (108) 2-(2-Furyl)-T-methyl-1-[2 -(2-morpholinyl)ethyll-4-trifluoromethyl-1H-imidazo- {4,5-c]lquinoline (109) 7-Methyl-1-[2-(2-morpholinyl)ethyl] -2-(2-thienyl)-4-trifluoromethyl-1H-imidazo- [4,5-c]lquinoline (110) 2-Cyclopentyl-7-methyl-1-[2 -(2-morpholinyl)ethyl]-4-trifluoromethyl-1H- imidazo[4,5-ciquinoline (111) 2-Cyclohexyl-7 -methyl-1-[2-(2-morpholinyl)ethyl]-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline 112) 6-Methyl-1-[2-(2-morpholinyl)ethyll-2-phenyl-4-trifluoromethyl-1H-imidazo- [4,5-clquinoline (113) 6-Methyl- 1-02 -(2-morpholinyl)ethyl]-2-(2-pyrrolyl)-4-trifluoromethyl- 1H- imidazo[4,5-clquinoline (114) 6-M ethyl-1-[2-(2-morpholinyl)ethyl]-2-(2-thiazolyl)-4-trifluoromethyl-1H- imidazo[4,5-clquinoline (115) 2-(2-1H-Imidazolyl)-6-methyl-1-[2 -(2-morpholinyl)ethyl]l-4-trifluoromethyl-1H- imidazo[4,5-clquinoline (116) 2-(2-Furyl)-6-methyl-1-[2 -(2-morpholinyl)ethyl]-4-trifluoromethyl-1H-imidazo- [4,5-c]lquinoline (117) 6-Methyl-1-[2-(2-morpholinyl)ethyl]-2-(2 -thienyl)-4-trifluoromethyl-1H- imidazo[4,5-clquinoline (118) 2-Cyclopentyl-6-methyl-1-[2 -(2-morpholinyl)ethyl}-4-trifluoromethyl-1H- imidazo[4,5-c]quinoline (119) 2-Cyclohexyl-6-methyl-1-{2 -(2-morpholinyl)ethyl]-4-trifluoromethyl-1H- imidazo[4,5-clquinoline (120) 4-Cyclopropyl-2-phenyl-1-[2 ~(4-piperidyl)ethyl]-1H-imidazo[4,5-clquinoline (121) 4-Cyclopropyl-1-[2-(4-piperidyl)ethyl]-2 -(2-pyrrolyl)-1H-imidazo[4,5-c]lquinoline (122) 2 4-Diphenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5 -c]quinoline (123) 4-Phenyl-1-[2-(4-piperidyl)ethyl]-2 -(2-pyrrolyl)-1H-imidazo[4,5-c]Jquinoline (124) 4-(2-Furyl)-2-phenyl-1-[2-(4-piperidyl)ethyl]- 1H-imidazo(4,5-clquinoline (125) 2-Phenyl-1-[2-(4-piperidyl)ethyl]-4-(2-thienyl)-1H-imidazo[4,5-clquinoline (126) 4-Cyano-2-phenyl-1-{2-(4-piperidyl)ethyll-1H-imidazo[4,5-clquinoline

(127) 4-Mercapto-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-clquinoline : (128) 9-Phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-clquinoline-4-carboxylic acid (129) 2-Phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-clquinoline-4-carboxamide (130) 2-Phenyl-1-[2-(1-piperazinyl)ethyl]-4-trifluoromethyl-1H-imidazo[4,5-c]- quinoline (131) 1-[2-(1-Piperazinyl)ethyl]-2-(2-pyrrolyl)-4-trifluoromethyl-1H-imidazo[4,5-c]- quinoline (132) 2-Phenyl-1-[2-(3-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo[4,5-clquinoline (133) 1-[2-(3-Piperidyl)ethyl]-2-(2-pyrrolyl)-4-trifluoromethyl-1H-imidazo[4,5-c]- quinoline (134) 1-[2-(2-Morpholinyl)ethyl}-2-phenyl-4-trifluoromethyl-1H-imidazo[4,5-cl- quinoline (135) 1-[2-(2-Morpholinyl)ethyl]-2-(2-pyrrolyl)-4-trifluoromethyl-1H-imidazo[4,5-c]- quinoline (136) 9-Ethoxymethyl-1-[2-(2-thiomorpholinyl)ethyl]-4-trifluoromethyl-1H-imidazo- [4,5-c]quinoline (137) 1-[2-(8-Azabicyclo[3.2.1]octan-3-yl)ethyl]-2-phenyl-4-trifluoromethyl-1H- imidazo[4,5-clquinoline : : (138) 1-[2-(8-Azabicyclo[3.2.1]octan-3-yl)ethyl]-2-(2-pyrrolyl)-4-trifluoromethyl-1H- imidazo[4,5-clquinoline (139) 12-Aminoethyl)-2-phenyl-4-trifluoromethyl-1H-imidazo[4,5-clquinoline (140) 1-(2-Aminoethyl)-2-(2-pyrrolyl)-4-trifluoromethyl-1H-imidazo[4,5-c]quinoline (141) 1-(2-Dimethylaminoethyl)-2-phenyl-4-trifluoromethyl-1H-imidazo[4,5-c]- quinoline (142) 1-(2-Dimethylaminoethyl)-2-(2-pyrrolyl)-4-trifluoromethyl-1H-imidazo[4,5-cl- quinoline (143) 9-Phenyl-1-[2-(3-pyrrolidinyl)ethyl]-4-trifluoromethyl-1H-imidazo[4,5-cl- quinoline (144) 1-[2-(3-Azetidinyl)ethyl]-2-(2-pyrrolyl)-4-trifluoromethyl-1H-imidazo[4,5-c]- quinoline (145) 6,7,8,9-Tetrahydro-2-phenyl-1-[2-(4-piperidyl)ethyl]-4-trifiuoromethyl-1H- imidazo[4,5-c]quinoline

(146) 6,7-Dihydro-2-phenyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo- [5,4-d]cyclopentalblpyridine (147) 6,7-Dihydro-1-[2-(4-piperidyl)ethyl]-2-(2-pyrrolyl)-4-trifluoromethyl-1H- imidazo[5,4-d]cyclopentalblpyridine (148) 8,7-Dihydro-1-[2-(4-piperidyl)ethyl]-2-(2-thiazolyl)-4-trifluoromethyl-1H- imidazo[5,4-d]cyclopenta[blpyridine (149) 6,7-Dihydro-2-(2-1H-imidazolyl)-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H- imidazo[5,4-d]cyclopenta[b]pyridine (150) 2-(2-Furyl)-6,7-dihydro-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo- [5,4-d]lcyclopenta[b]pyridine (151) 6,7-Dihydro-1-[2-(4-piperidyl)ethyl]-2-(2-thienyl)-4-trifluoromethyl-1H-imidazo- [5,4-d]eyclopenta[blpyridine (152) 2-Cyclopentyl-6,7-dihydro-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H- imidazo[5,4-d]leyclopentalblpyridine (153) 2-Cyclohexyl-6,7-dihydro-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo- [5,4-d]cyclopenta[b]pyridine (154) 2-Phenyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H-imidazo[5,4-d]thieno- [3,2-blpyridine (155) 2-Phenyl-1-[2-(4-piperidyl)ethyl]l-4-trifluoromethyl-1H-imidazo[4,5-c][1,5]- naphthyridine (156) 2-Phenyl-1-(4-piperidyl)-4-trifluoromethyl-1H-imidazo[4,5-c]quinoline (187) 2-Phenyl-1-[3-(4-piperidyl)propyl]-4-trifluoromethyl-1H-imidazo[4,5-c]quinoline (158) 1-[2-(n-Butylamino)ethyl]-4-methyl-2-phenyl-1H-imidazo[4,5-clquinoline (159) 1-[2-(Benzylamino)ethyl]-4-methyl-2-phenyl-1H-imidazo[4,5-clquinoline (160) 4-Methyl-2-phenyl-1-[2-(triphenylmethylamino)ethyl]-1H-imidazo[4,5-c]- quinoline (161) Benzyl N-[2-(4-methyl-2-phenyl-1H-imidazo[4,5-c]lquinolin-1-yl)ethyllcarbamate (162) N-[2-(4-Methyl-2-phenyl-1H-imidazo[4,5-clquinolin-1-yl)ethyllacetamide (163) N-Methyl-N’-[2-(4-methyl-2-phenyl-1H-imidazo[4,5-c]lquinolin-1-yl)ethyl]- _ thiourea (164) N-[2-(4-Methyl-2-phenyl-1H-imidazo[4,5-clquinolin-1-yl)ethyllmethane- sulfonamide i

(165) N-[2-(4-Methyl-2-phenyl-1H-imidazo[4,5-c]lquinolin-1-yl)ethyl] p-toluene- sulfonamide

(166) 1-(2-Guanidinoethyl)-4-methyl-2-phenyl-1H-imidazo[4,5-c]lquinoline (167) 2-Methylamino-N-[2-(2-phenyl-4-trifluoromethyl-1H-imidazo[4,5-clquinolin-1- ylethyl]lacetamide . (168) 9-Methylamino-N-[2-[2-(2-pyrrolyl)-4-trifluoromethyl-1H-imidazo[4,5-cJquinolin- 1-yllethyllacetamide (169) 2-Dimethylamino-N-[2-(2-phenyl-4-trifluoromethyl-1H-imidazo[4,5-c]lquinolin-1- yl)ethyllacetamide (170) 2-Dimethylamino-N-[2-[2-(2-pyrrolyl)-4-trifluoromethyl-1H-imidazo[4,5-c]- quinolin-1-yllethyl]lacetamide (171) 2-Amino-N-[2-(2-phenyl-4-trifluoromethyl-1H-imidazo[4,5-c]quinolin-1-yl)- ethyllacetamide 172) 2-Amino-N-[2-[2 -(2-pyrrolyl)-4-trifluoromethyl-1H-imidazo[4,5-c]quinolin-1- yllethyllacetamide (178) 1-Acetyl-4-[2-(2-phenyl-4-trifluoromethyl-1H-imidazo[4,5-clquinolin-1-yl)ethyl]- piperidine (174) 1-[2-(1-Benzyl-4-piperidyl)ethyl]-2-phenyl-4-trifluoromethyl-1H-imidazo[4,5-¢]- quinoline (175) 7-Chloro-2-(2-hydroxyphenyl)-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H- imidazo(4,5-clquinoline (176) 7-Chloro-2-(2-methoxyphenyl)-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H- imidazo[4,5-clquinoline (177) 7-Chloro-2-(3-hydroxyphenyl)-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H- imidazo[4,5-clquinoline (178) 7-Chloro-2-(3-methoxyphenyl)-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H- imidazo[4,5-clquinoline (179) 7-Chloro-2-(4-hydroxyphenyl)-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H- imidazol4,5-clquinoline (180) 7-Chloro-2-(4-methoxyphenyl)-1-{2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H- imidazol4,5-c]lquinoline (181) 2-(2-Hydroxyphenyl)-7-methyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H- )

imidazo[4,5-clquinoline (182) 2-(2-Methoxyphenyl)-7-methyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H- imidazo[4,5-c]quinoline (183) 2-(3-Hydroxyphenyl)-7-methyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H- imidazo(4,5-clquinoline (184) 2-(3-Methoxyphenyl)-7-methyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H- imidazo[4,5-clquinoline (185) 2-(4-Hydroxyphenyl)-7-methyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H- imidazo[4,5-c]quinoline (186) 2-(4-Methoxyphenyl)-7-methyl-1-[2-(4-piperidyl)ethyl]-4-trifluoromethyl-1H- imidazo{4,5-clquinoline

The novel 1H-imidazopyridine derivatives represented by the aforementioned general formula (I) or (II) according to the present invention can be prepared by, for example, various methods such as exemplified below; however, the preparation methods of the compounds of the present invention are not limited thereto. In the following preparation methods, specific explanations for the compounds represented by the aforementioned general formula (I) will be given, and it is obvious that these preparation methods include the preparation methods of the compounds represented by the aforementioned general formula (II).

As the first synthetic method of the compounds of the present invention, the following preparation can be carried out in accordance with the method disclosed in

Japanese Patent Unexamined Publication (KOKAI) No. Hei 3-206078/1991 or

Tetrahedron, Vol. 51, p. 5813 (1995):

R®—(CH,)

OH Cl z “NH

NO, NO, NO,

Xx Step 1 x Step 2 ES lL Al R3—(CH)—NH Al

N~ TR’ N~ TR’ 2 N" TR’ ) (VD (VID (VID)

R®—(CH,) R*—(CHa)« R' ~N “nH N—(

NH, N

Step 3 = Steps 4 or5 =

RA | Pr ~

ZN ZN

N R N R

(Ix) LY)

wherein R7 represents a cycloalkyl group which may be substituted, an alkyl group which may be substituted, or an aryl group which may be substituted;, and R, R3, k, and ring A have the same meanings as those defined above.

In Step 1, the compound of the general formula (VI) can be obtained by allowing the compound represented by the general formula (V) to react with a chlorinating agent, for example, phosphorus oxychloride, thionyl chloride, phosgene, oxalyl chloride, phosphorus pentachloride or the like, in the presence or absence of a solvent such as toluene and N,N-dimethylformamide at a temperature ranging from 0°C to 200°C.

In Step 2, the compound of the general formula (VIII) can be obtained by reacting the amine represented by the general formula (VII) with the compound of the general formula (VI) 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 3, the compound of the general formula (IX) can be obtained by reducing the nitro group of the compound of the general formula (VIII) according to an ordinarily-used reducing 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.

In Step 4, the compound of the general formula (X) can be obtained by reacting the compound of the general formula (IX) with a compound represented by the following general formula (XI), (XII), (XIII), or (XIV):

R1C(OR)s (XD

R1COX (XII) (R1CO)20 (XIII)

R1CO2H (XIV) wherein R represents a lower alkyl group; X represents a halogen atom; R! has the same meaning as that defined above, in the presence or absence of a basic catalyst such as triethylamine,

N,N-diisopropylethylamine, pyridine, sodium carbonate, and potassium carbonate, or an acid catalyst such as hydrochloric acid, sulfuric acid, and p-toluenesulfonic acid, in the presence or absence of a solvent such as N,N-dimethylformamide, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, xylene, and toluene, at a temperature ranging from 0°C to 200°C.

As an alternate step for Step 4, the compound of the general formula (X) can be obtained in Step 5 by reacting the compound of the general formula (IX) with a compound represented by the following general formula (XV):

RICHO (XV) wherein R! has the same meanings as that defined above, in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in a solvent such as acetonitrile, 1,4-dioxane, tetrahydrofuran, 1,2-dichloroethane, and toluene at a temperature ranging from 0°C to the reflux temperature of the solvent.

According to the second synthetic method of the compounds of the present invention, the compound of the following general formula (XVII): 3 R!

R* (CHa) —

N xX

GLY

N (XVID 0" wherein R1, R3, k, and ring A have the same meanings as those defined above, can be obtained by reacting the compound of the following general formula (XVI) which can be synthesized by the method disclosed in Japanese Patent Unexamined

Publication(KOKAI) No. Sho 60-123488/1985: 3 R'

R*—(CH,)~_

N=

N op

N XVI wherein RL, R3, k, and ring A have the same meanings as those defined above, with an oxidizing agent such as hydrogen peroxide, m-chloroperbenzoic acid, meta sodium periodate, meta potassium periodate or the like in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, acetone, and water, or a mixed solvent thereof, at a temperature ranging from 0°C to the reflux temperature of a solvent, after protecting at need the nitrogen atom of the amino group represented by R3 which may be substituted or the saturated nitrogen-containing heterocyclic group represented by R3 whose nitrogen atom not bound to the adjacent (CHz)x group which may be substituted, with a protecting group such as alkanoyl groups in a conventional manner, and furthermore deprotecting at need the protecting group such as alkanoyl groups in a conventional manner.

Then, the compound of the general formula (I) wherein R? is cyano group can be obtained by treating the compound of the general formula (XVII) with cyanotrimethylsilane in the presence of 1,8-diazabicyclo[5.4.0]-7-undecene in a solvent such as N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dichloroethane, acetonitrile, and toluene at a temperature ranging from 0°C to the reflux temperature of a solvent.

According to the third synthetic method of the compounds of the present invention, the compound of the general formula (I) wherein R? is mercapto group can be obtained by treating the compound of the following general formula (XVIII) obtainable from a starting material wherein R7 of the compound of the aforementioned general formula (V) is replaced with a chlorine atom in a similar manner to the first synthetic method:

R—(CHa)e, —

GX nN" Cl (XVIII) wherein R1, R3, k, and ring A have the same meanings as those defined above, with thiourea in a solvent such as methanol, ethanol, n-propanol,

N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, or the aforementioned solvent containing water at a temperature ranging from room temperature to the reflux temperature of a solvent.

Claims

“y . What is claimed is:

1. A 1H-imidazopyridine derivative represented by the following general formula (I) or a salt thereof: R—(CHah N Nr aL NRE (1) wherein R! represents hydrogen atom, an alkyl group which may be substituted, a cycloalkyl group which may be substituted, or an aryl group which may be substituted; R2 represents a cycloalkyl group which may be substituted, an alkyl group which may be substituted, an aryl group which may be substituted, cyano group, mercapto group, carboxyl group, or carbamoyl group; ring A represents a homocyelic or heterocyclic ring which may be substituted; R3 represents an amino group which may be substituted or a saturated nitrogen-containing heterocyclic group which may be substituted; and k represents an integer of from 0 to 3; provided that the compound wherein R3 represents a saturated nitrogen-containing heterocyclic group which may be substituted and R2? is a non-substituted alkyl group is excluded.

2. A 1H-imidazopyridine derivative represented by the following general formula (II) or a salt thereof: . R—(CHe, KN Nn one NOR (on) wherein R! represents hydrogen atom, an alkyl group which may be substituted, a cycloalkyl group which may be substituted, or an aryl group which may be substituted; R2 represents a cycloalkyl group which may be substituted, an alkyl group which may be substituted, an aryl group which may be substituted, cyano group, mercapto group, carboxyl group, or carbamoyl group; ring A represents a

« Y a Co homocyeclic or heterocyclic ring which may be substituted; k represents an integer of . from O to 3; R3 represents a group represented by the following general formula (III)

. I ¥ Ny & | or 9 RS J ’ RS AN _ (CHa), RS _N (CH2)n (1) R4, R5, R6 may be the same or different and represent hydrogen atom, an alkyl group which may be substituted, a benzyl group which may be substituted, triphenylmethyl group, an acyl group which may be substituted, an alkoxycarbonyl group which may be substituted, a benzyloxycarbonyl group which may be substituted, a thiocarbamoyl group which may be substituted, an alkanesulfonyl group which may be substituted, a benzenesulfonyl group which may be substituted, or an amidino group which may be substituted; Y represents oxygen atom, sulfur atom, or nitrogen atom, a group represented by CHz, CH, or NH, or a single bond; and m and n may be the same or different and represent an integer of from 0 to 2, provided that when R3 represents a group represented by the following general formula (IV): (CHp)m Ch = AT RS AN _ACHa), RS NL ACHD (ry R2? does not represent a non-substituted alkyl group.

3. The compound or a salt thereof according to claim 1 or claim 2, wherein the ring A is a benzene ring which may be substituted or a thiophene ring which may E be substituted.

4. The compound or a salt thereof according to any one of claims 1 to 3, wherein R2 is trifluoromethyl group.

5. A medicament which comprises the compound or a pharmacologically acceptable salt thereof as an active ingredient according to any one of claims 1 to 4.

6. The medicament according to claim 5, which is used for preventive and/or therapeutic treatment of a disease in which a cytokine is involved.

“gy : 200

7. The medicament according to claim 6, wherein the cytokine is tumor necrotizing factor (TNF) or interleukin-1 (IL-1).

8. An inhibitor against production of a cytokine which comprises the compound or a pharmacologically acceptable salt thereof as an active ingredient according to any one of claims 1 to 4.

9. A method for a preventive and/or therapeutic treatment of a disease in which a cytokine is involved, which comprises the step of administering a preventively and/or therapeutically effective amount of the compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 4 to a mammal including a human.

10. A use of the compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 4 for manufacture of the medicament according to any one of claims 5 to 7.