Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-31
2004-09-21
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252010, C514S253030, C514S275000, C514S277000, C514S345000, C514S352000, C514S351000, C514S247000, C544S224000, C544S239000, C544S315000, C544S330000, C546S001000, C546S290000, C546S304000
Reexamination Certificate
active
06794378
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a therapeutic agent for various kinds of inflammatory disease.
It is known that various inflammatory diseases, rheumatoid diseases, immunoreactive diseases, cancer metastasis and viral diseases are caused by the abnormal production of inflammatory cytokines and matrix metalloprotease and also by the increase in the expression of inflammatory cell adhesion molecules.
Although various medicines for these diseases were developed in the prior art, further development of a medicine having a stronger efficiency, higher safety and weaker side effects is demanded.
The pathophysiological states of various chronic inflammatory diseases are considered to be caused by the continuous production of inflammation mediators such as cytokines particularly, inflammatory cytokines including IL-1, IL-2, IL-6, IL-8 and tumor necrosis factor (TNF)], adhesion molecules, tissue destroying enzymes (such as matrix metalloprotease), etc. by the continuous extracellular stimulation.
The inflammatory mediators are produced because the gene expression is activated by the extracellular stimulation. A substance having the most important role in this step is a transcription factor known as AP-1 or NF-kappa B. Namely, it is expected that when the activation of AP-1/NF-kappa B can be inhibited, the development of inflammation and the advance thereof into chronic stage can be prevented and that such a method will be a hopeful treatment of inflammatory diseases such as rheumatoid arthritis and various autoimmune diseases.
Glucocorticoid hormone (GC) which strongly inhibits the activation of intracellular AP-1 and NF-kappa B has been used as a powerful anti-inflammatory agent and immunosuppressant. However, the use of GC as a medicine is limited because it has various side effects due to hormonic action thereof and it causes rebound phenomenon.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a new compound effective to cure chronic inflammatory disease with high activity and fewer side effects.
Another object of the present invention is to provide a pharmaceutical composition comprising corresponding new compound.
After intensive investigations made for the purpose of finding compounds having a strong activity of inhibiting the activation of AP-1 and NF-kappa B and useful as a strong remedy for chronic inflammatory diseases, the inventors have found that compounds of general formula (I) which will be described below have this effect. The present invention has been completed on the basis of this finding.
That is, the present invention provides a heterocyclic compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.
wherein R
1
is a cycloalkyl group, a cycloalkyl group having a substituent(s), a cycloalkenyl group or a cycloalkenyl group having a substituent(s); each R
2
and R
3
is a hydrogen atom or an alkyl group; R
4
is an alkyl group, an alkyl group having a substituent(s), an alkenyl group, an alkenyl group having a substituent(s), a cycloalkyl group, a cycloalkyl group having a substituent(s), a cycloalkenyl group, a cycloalkenyl group having a substituent(s), an aryl group, an aryl group having a substituent(s), an aromatic heterocyclic group having at least one hetero-atom within a ring or an aromatic heterocyclic group having a substituent(s) and at least one hetero-atom within a ring; A is a heterocyclic ring or a heterocyclic ring having a substituent(s); B is an aromatic ring, an aromatic ring having a substituent(s), a heterocyclic ring or a heterocyclic ring having a substituent(s); n is an integer selected from 0 to 6; —Y— is an interatomic bond, —CO—, —CO—O—, —CO—NR
5
—, —CS—NR
6
—, —SO—, —SO
2
— wherein each R
5
and R
6
is a hydrogen atom or an alkyl group; and —X— is an interatomic bond, —O—, —O—CHR
7
—, —CHR
8
—O—, —O—CO—, —CO—O—, —O—CS—, —CS—O—, —S—, —SO—, —SO
2
—, —S—CHR
9
—, —CHR
10
—S—, —S—CO—, —CO—S—, —S—CS—, —CS—S—, —SO
2
—NR
11
—, —NR
12
—SO
2
—, —NR
13
—, —NR
14
—CHR
15
—, —CHR
16
—NR
17
—, —CO—, —C(═NOR
18
)—, —C(═CHR
19
)—, —CO—CHR
20
—, —CHR
21
—CO—, —CO—NR
22
—, —NR
23
—CO—, —CR
24
R
25
—, —CHR
26
—CHR
27
—, —CR
28
═CR
29
—, —O—CHR
30
—CHR
31
— wherein each R
7
, R
8
, R
9
, R
10
, R
15
, R
16
, R
20
, R
21
, R
24
, R
28
, R
29
, R
30
and R
31
is either of a hydrogen atom or an alkyl group; each of R
11
, R
12
, R
13
, R
14
, R
17
, R
18
, R
19
, R
22
and R
23
is either of a hydrogen atom, an alkyl group or an acyl group; each of R
26
and R
27
is either of a hydrogen atom, a hydroxy group or an alkyl group; and R
25
is a hydrogen atom, a hydroxy group, an alkyl group, an alkyl group having a substituent(s), a mercapto group, an alkoxy group, an alkylthio group, an acyloxy group, an amino group, an alkylamino group, an amino group substituted with an amino protective group, a carboxyl group, an alkoxycarbonyl group, an aminocarbonyl group, or a cyano group.
Further, the present invention provides an AP-1 or NF-kappaB activation inhibitor, an inflammatory cytokine production inhibitor, a matrix-metalloprotease production inhibitor and an inflammatory cell adhesion factor expression inhibitor, each of which comprises, as an active ingredient, the above-described heterocyclic compound or a pharmaceutically acceptable salt thereof, and these can be used as an anti-inflammatory agent, an anti-rheumatism agent, an immuno-suppressive agent, a cancer metastasis inhibitor, an antiviral agent or a curative agent for arterial sclerosis.
It is to be noted that a heterocyclic compound or a pharmaceutically acceptable salt thereof according to the present invention, in which R
1
is a cycloalkyl group having a substituent(s), may be more effective. Among these, compounds wherein R
1
is a cyclopropyl group having a substituent(s), more specifically either of a 2,2-dimethylcyclopropyl group or a 2,2-dichlorocyclopropyl group are of high activity. Among these, higher activity can be obtained by compounds wherein R
4
is 2,2-dimethylcyclopropyl group or 2,2-dichlorocyclopropyl group, —Y— is —CO— and n=0; or compounds wherein R
4
is an aryl group or an aryl group having a substituent(s), —Y— is —CO— and n=1; or compounds wherein R
4
is an aryl group or an aryl group having a substituent(s), —Y— is an interatomic bond and n is 1 or 2.
BEST MODE FOR CARRYING OUT THE PRESENT INVENTION
Examples of the halogen atom in the present invention include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
The alkyl group means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a tert-pentyl group, a neopentyl group, a 2-pentyl group, a 3-pentyl group, a n-hexyl group and a 2-hexyl group, wherein the methyl group and the ethyl group are preferable.
The alkenyl group means a straight-chain or branched-chain alkenyl group having 1 to 6 carbon atoms such as a 1-propenyl group, an allyl group, an isopropenyl group, a 1-butenyl group and a 2-butenyl group.
The cycloalkyl group means a cyclic alkyl group having 3 to 6 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group, wherein the cyclopropyl group is a preferable cycloalkyl group.
The cycloalkenyl group means a cyclic alkenyl group having 3 to 6 carbon atoms such as a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group and a cyclohexenyl group.
The hetero atom means specifically, for example, an oxygen atom, a sulfur atom and a nitrogen atom, wherein nitrogen atom is preferable.
The an aryl group means specifically, for example, a phenyl group, an indenyl group, a naphthyl group and a fluorenyl group, wherein phenyl group is preferable.
The aromatic heterocyclic group having at least one hetero atom means specifically, for example, a pyranyl group, a pyridyl group, a pyridazyl group, a pyrimidyl
Fujita Koichi
Hatanaka Toshihiro
Iino Yukio
Kobayashi Tsuyoshi
Kodaira Ariko
Ajinomoto Co. Inc.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Patel Sudhaker B.
Raymond Richard L.
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