Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-02
2003-02-11
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S238800, C514S252160, C544S060000, C544S115000, C544S361000
Reexamination Certificate
active
06518265
ABSTRACT:
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 medicaments for preventive or therapeutic treatment of diseases of humans and animals in which a cytokine such as TNF, IL-1 is mediated, which include 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 (e.g., hemolytic anemia, anaplastic anemia, idiopathic thrombocythemia, etc.), autoimmune intestinal diseases (e.g., ulcerative colitis, Crohn's disease, etc.), autoimmune corneitis (e.g., keratoconjunctivitis sicca, spring catarrh, etc.), 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.
BACKGROUND ART
Some compounds having 1H-imidazoquinoline structure are known which are analogous to the compounds of the present invention. Journal of Medicinal Chemistry, Vol. 11, p. 87 (1968) discloses 1-(2-piperidinoethyl)-1H-imidazo[4,5-c]-quinoline, 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-c]quinoline as a compound having analgesic and anticonvulsant actions. However, 1H-imidazopyridine derivatives as those according to the present invention have never been known so far.
Moreover, 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). 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 never been known so far.
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 and IL-1 and the like are useful as medicaments.
The inventors of the present invention made intensive studies to achieve the object. As a result, they found novel 1H-imidazopyrdine derivatives which have an excellent inhibitory action against production of TNF or IL-1 and achieved the present invention.
Tile present invention thus relates to novel 1H-imidazopyridine derivatives represented by the following general formula (I) or salts thereof:
wherein R
1
represents hydrogen atom, 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 hydrogen atom, an alkyl group, a halogen atom, 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 substituted; ring A represents a homocyclic or heterocyclic ring which may be substituted with one or more alkyl groups, alkoxyl groups, or halogen atoms; R
3
represents a saturated nitrogen-containing heterocyclic group which may be substituted; and m represents an integer of from 0 to 3; provided that, when R
3
represents unsubstituted piperidino group, at least one of R
1
and R
2
is not hydrogen atom.
According to the second embodiment of the present invention, there are provided novel 1H-imidazopyridine derivatives represented by the following general formula (II) or salts thereof:
wherein R
1
, R
2
, ring A and m have the same meanings as those defined above; R
4
represents hydrogen atom, an alkyl group, benzyl group, triphenylmethyl group, an alkanoyl group which may be substituted, an alkoxycarbonyl group, benzyloxycarbonyl group, a thiocarbamoyl group which may be substituted, an alkanesulfonyl group, a benzenesulfonyl group which may be substituted, or amidino group; Y represents methylene group, oxygen atom, sulfur atom, nitrogen atom, a group represented by NH, or a single bond; and n represents an integer of from 0 to 2.
According to the third embodiment of the present invention, there are provided, among the compounds represented by the aforementioned general formulas (I) and (II), the compounds wherein ring A is a benzene ring or a thiophene ring, or the salts thereof.
According to another aspect, there is provided a medicament which comprises as an active ingredient the compound represented by the aforementioned general formula (I) or (II), or a pharmacologically acceptable salt thereof. The medicament is useful for preventive or therapeutic treatment of diseases of mammals including humans, in which a cytokine such as TNF, IL-1 is mediated, which include 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 (e.g., hemolytic anemia, anaplastic anemia, idiopathic thrombocythemia, etc.), autoimmune intestinal diseases (e.g., ulcerative colitis, Crohn's disease, etc.), autoimmune corneitis (e.g., keratoconjunctivitis sicca, spring catarrh, etc.), 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 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 or therapeutic treatment of diseases in which a cytokine such as TNF, IL-1 is mediated, which comprises the step of administering a preventively 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. In addition, the present invention provides an inhibitor against production of tumor necrotizing factor (TNF) or interleukin-1 (IL-1) which comprises as an active ingredient the compound represented by the aforementioned general formula (I) or (II), or a pharmacologically acceptable salt thereof.
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. The compounds represented by the aforementioned general formula (II) are characterized in that they have a specific saturated nitrogen-containing heterocyclic group which may have specific substituents as R
3
among the compounds represented by the aforementioned general formula (I). However, the scope of the present invention is not limited to the compounds represented by the aforementioned general formula (II), and it should be understood that any compounds having as R
3
a saturated nitrogen-containing heterocyclic group which may be substituted fall within the scope of the present invention.
In the aforementioned general formulas (I) and (II), examples of the alkyl group represented by R
1
, R
2
or R
4
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
Aoyama Makoto
Izumi Tomoyuki
Kato Hideo
Kato Ken-ichi
Sakaguchi Jun
Greenblum & Bernstein P.L.C.
Hokuriku Seiyaku Co. Ltd.
Robinson Binta
Seaman D. Margaret
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