Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2002-03-01
2003-05-13
Davis, Brian (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S154000, C564S157000, C564S158000, C546S308000, C514S352000, C514S616000
Reexamination Certificate
active
06563002
ABSTRACT:
This application is a Continuation of International application PCT/JP00/05914 Filed on Aug. 31, 2000.
BACKGROUND OF THE INVENTION
The present invention relates to agents for treating various inflammatory diseases:
It is known that various inflammatory diseases, rheumatism, immunoreactive diseases, cancerous metastasis and viral diseases are caused by the abnormal production of inflammatory cytokines or matrix metalloproteases or by an increase in the incidence of inflammatory cell adhesion molecules. Although various medicines for these diseases have been developed, the development of a highly safe medicine having a higher medicinal effect and only slight side effects is demanded.
It is supposed that various chronic inflammatory diseases are caused because inflammatory mediators such as various cytokines (in particular, IL-1, IL-2, IL-6, IL-8, TNF, etc. for inflammatory diseases), adhesion molecules and tissue destroying enzymes (such as matrix metalloproteases) are continuously produced by the continuous extracellular stimulation.
These inflammatory mediators are produced because the gene expression is activated by the extracellular stimulation. In this step, a transcription factor (TF) known as NF-kappa B plays the most important role. If the activation of NF-kappa B can be inhibited, the increase and chronicity of the inflammation can be prevented. This method will be a hopeful therapeutic method for inflammatory diseases such as rheumatoid arthritis and various autoimmune diseases.
Glucocorticoid hormone (GC) which strongly inhibits the activation of NF-kappa B in the cells is practically used as a powerful antiinflammatory agent or immunosuppressive agent. However, GC has various side effects caused by hormonal action thereof, and it also causes rebound phenomena. Therefore, the use of GC as a medicine is limited at present.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide new compounds having a high medicinal effect and less side effects and useful for the treatment of chronic inflammatory diseases.
Another object of the present invention is to provide a pharmaceutical composition containing the compound(s).
Still another object of the present invention is to provide an inflammatory cytokine production inhibitor, a matrix metalloprotease production inhibitor or an inhibitor of incidence of inflammatory cell adhesion molecules, each of which contains the above-described compound(s) as the active ingredient.
A further object of the present invention is to provide an antiinflammatory agent, an antirheumatic agent, an immunosuppressive agent, a cancerous metastasis inhibitor or an antiviral agent, each of which contains the above-described compound(s) as the active ingredient.
After intensive investigations made for the purpose of obtaining compounds having a strong activity of inhibiting NF-kappa B activation and useful as agents for treating chronic inflammatory diseases, the inventors have found compounds represented by general formula (I). The present invention has been completed on the basis of this finding.
Namely, the present invention provides biscyclopropanecarboxamide compounds represented by the following general formula (I) and pharmaceutically acceptable salts thereof:
wherein R
1
to R
4
, which may be the same or different from each other, each represent methyl group or chlorine atom, R
5
and R
6
, which may be the same or different from each other, each represent hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an aryl group which may have a substituent(s), and —A— represents one of the groups of the following general formulae (II), (III), (IV) and (V):
wherein B
1
to B
10
, which may be the same or different from each other, each represent an aromatic ring which may have a substituent(s) or an aromatic heterocyclic group having at least one hetero atom, which may have a substituent(s), —X
1
— to —X
6
—, which may be the same or different from each other, each represent an interatomic bond, —O—, —NR
7
—, —CR
8
R
9
—, —S—, —SO—, —SO
2
—, —CO—, —O—CO—, —CO—O—, —NR
10
—CO—or —CO—NR
11
—wherein R
7
represents hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an acyl group having 1 to 6 carbon atoms, R
8
to R
9
each represent hydrogen atom, hydroxyl group, a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, and R
10
to R
11
each represent hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
The present invention also provides a pharmaceutical composition containing the above-described biscyclopropanecarboxamide compound(s) or pharmaceutically acceptable salt(s) thereof.
The present invention provides NF-kappa B activation inhibitors, inflammatory cytokine production inhibitors, matrix metalloprotease production inhibitors and inhibitors of incidence of inflammatory cell adhesion molecules containing the above-described biscyclopropanecarboxamide compound(s) or pharmaceutically acceptable salt(s) thereof as the active ingredient. They are each usable as an antiinflammatory agent, an antirheumatic agent, an immunosuppressive agent, a cancerous metastasis inhibitor or an antiviral agent.
When —A— in the above-described compounds is benzene ring having a substituent, the biscyclopropanecarboxamide compounds or pharmaceutically acceptable salts thereof exhibit an excellent effect.
BEST MODE FOR CARRYING OUT THE INVENTION
The detailed description will be made below on the present invention.
The term “alkyl groups” in the present invention indicates linear or branched alkyl groups having 1 to 6 carbon atoms 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, tert-pentyl group, neopentyl group, 2-pentyl group, 3-pentyl group, n-hexyl group and 2-hexyl group. Methyl group, ethyl group, etc. are preferred.
The term “acyl groups” indicates linear or branched acyl groups having 1 to 6 carbon atoms or acyl groups having an aryl group, which may be substituted, such as formyl group, acetyl group, propionyl group, butyroyl group, isobutyroyl group, valeroyl group, isovaleroyl group, pivaloyl group, hexanoyl group, acryloyl group, methacryloyl group, crotonoyl group, isocrotonoyl group, benzoyl group and naphthoyl group.
The aryl groups include, for example, phenyl group, indenyl group, naphthyl group and fluorenyl group. Phenyl group is preferred.
The halogen atoms are, for example, fluorine atom, chlorine atom, bromine atom and iodine atom.
The alkoxyl groups are linear or branched alkoxyl groups having 1 to 6 carbon atoms such as methoxyl group, ethoxyl group, n-propoxyl group, isopropoxyl group, n-butoxyl group, isobutoxyl group, sec-butoxyl group and tert-butoxyl group. Methoxyl group, ethoxyl group, etc. are preferred.
The term “aromatic ring” in the definition of B
1
to B
10
includes, for example, benzene, indene, naphthalene and fluorene. Benzene is preferred.
The term “an aromatic heterocyclic ring having at least one hetero atom” in the definition of B
1
to B
10
means a 5- to 7-membered aromatic heterocyclic ring composed of carbon and nitrogen, oxygen, sulfur or selenium. They are, for example, pyridine, dihydropyran, pyridazine, pyrimidine, pyrazine, triazine, tetrazine, pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazole, triazole, pyrazole, furazane and thiadiazole.
The expression “which may have a substituent(s)” in “an aromatic ring which may have a substituent(s)” and “an aromatic heterocyclic group having at least one hetero atom, which may have a substituent(s)” in B
1
to B
10
indicates that the aromatic ring or the aromatic heterocyclic group may have 1 to 3 substituents which may be the same or different from each other and that the positions of the substituents are not particularly limited. Examples of them are halogen atoms, alkyl groups which may have a substituent(s), hydroxyl group, alkoxyl groups, carboxyl group, alkoxycarbonyl groups, cyano group, aralkyl groups which may have a substitu
Fujita Kohichi
Iino Yukio
Kobayashi Tsuyoshi
Takehana Kenji
Yamamoto Takashi
Ajinomoto Co. Inc.
Davis Brian
LandOfFree
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