Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Acyclic nitrogen double bonded to acyclic nitrogen – acyclic...
Reexamination Certificate
2001-03-12
2004-03-09
Davis, Brian (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Acyclic nitrogen double bonded to acyclic nitrogen, acyclic...
C514S354000, C514S415000, C514S421000, C514S423000, C514S517000, C514S535000, C514S544000, C514S563000, C514S603000, C514S616000, C514S624000, C546S323000, C548S476000, C548S513000, C548S537000, C558S050000, C558S404000, C560S251000, C562S433000, C564S086000, C564S153000, C564S154000, C564S155000, C564S156000, C564S157000, C564S158000, C564S190000
Reexamination Certificate
active
06703379
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to benzene derivatives useful for the treatment of various inflammatory diseases and pharmaceutical compositions containing them.
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 necrotizing 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 (V. C. Foletta et al., [Journal of Leukocyte Biology, 63, 139-152, 1998], P. J. Barnes et al., [The new England Journal of Medicine, 336, 1066-1071, 1997] and M. J. Suto et al., [Current Pharmaceutical Design, 3, 515-528, 1997]).
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
The object of the present invention is to provide benzene derivatives having a remarkable medicinal effect and only a slight side effect and useful for the treatment of chronic inflammatory diseases.
Another object of the present invention is to provide a pharmaceutical composition containing the benzene derivative.
The above-described and other objects of the present invention will be apparent from the following description and Examples.
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.
Namely, the present invention relates to benzene derivatives of the following general formula (I) or pharmaceutically acceptable salts thereof:
wherein
R
1
represents a cycloalkyl group having a substituent or a cycloalkenyl group having a substituent, R
2
represents hydrogen atom or an alkyl group, R
3
to R
10
, which may be the same or different from each other, represent hydrogen atom, a halogen atom, hydroxyl group, mercapto group, nitro group, cyano group, trifluoromethyl group, an alkyl group, an alkoxyl group, an alkylthio group, an amino group which may be substituted with an alkyl group or an amino-protecting group, an acyloxy group, an acyl group, carboxyl group, an alkoxycarbonyl group or carbamoyl group,
−Y represents a group of following general formula (II), (III) or (IV):
wherein
R
11
and R
13
each represent hydrogen atom or an alkyl group, R
12
and R
14
each represent an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, a cycloalkenyl group which may have a substituent, an aryl group which may have a substituent, an aromatic heterocyclic group having one or more hetero atom, which may have a substituent, or a saturated heterocyclic group having one or more hetero atoms, which may have a substituent, and R
15
and R
16
each represent an alkyl group or an aryl group which may form a ring together, and n and m each represent an integer selected from among 0 to 6, and
—X— represents an interatomic bond, or any of —O—, —O—CHR
17
—, —O—CHR
18
—O—, —O—CO—, —CO—O—, —O—CS—, —CS—O—, —S—, —SO—, —SO
2
—, —S—CHR
19
—, —CHR
20
—S—, —S—CO—, —CO—S—, —S—CS—, —CS—S—, —SO
2
—NR
21
—, —NR
22
—SO
2
—, —NR
23
—, —NR
24
—CHR
25
—, —CHR
26
—NR
27
—CO—, —C(═NOR
28
)—, —C(═CHR
29
)—, —CO—CHR
30
—, —CHR
31
—CO—, —CO—NR
32
—, —NR
33
—CO—, —CR
34
R
35
—, —CHR
36
—CHR
37
— and —CR
38
═CR
39
— wherein R
17
, R
18
, R
19
, R
20
, R
21
, R
22
, R
25
, R
26
, R
29
, R
30
, R
31
, R
32
, R
33
, R
34
, R
38
and R
39
each represent hydrogen atom or an alkyl group, R
23
, R
24
, R
27
and R
28
each represent hydrogen atom, an alkyl group or an acyl group, R
36
and R
37
each represent hydrogen atom, hydroxyl group or an alkyl group, and R
35
represents hydrogen atom, hydroxyl group, mercapto group, cyano group, an alkyl group, which may have a substituent, an alkoxyl group, an alkylthio group, an acyloxy group, an amino group which may be substituted with an alkyl group or an amino-protecting group, carboxyl group, an alkoxycarbonyl group or carbamoyl group.
The present invention provides a pharmaceutical composition, particularly AP-1 and NF-kappa B activation inhibitor, inflammatory cytokine production inhibitor, matrix metalloprotease production inhibitor and inflammatory cell adhesion molecule expression inhibitor. They can be used as anti-inflammatory agent, antirheumatic agent, immunosuppressant, cancerous metastasis inhibitor, remedy for arteriosclerosis and antiviral agent, which contains the above-described benzene derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The detailed description of the present invention will be made below.
The term “halogen atoms” include fluorine atom, chlorine atom, bromine atom and iodine atom.
The term “hetero atoms” herein indicates oxygen atom, sulfur atom and nitrogen atom. Among them, nitrogen atom is preferred.
The term “cycloalkyl groups” herein indicates cyclic alkyl groups of 3 to 6 carbon atoms such as cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group. Among them, cyclopropyl group is preferred.
The term “cycloalkenyl groups” herein indicates cyclic alkenyl groups having 3 to 6 carbon atoms such as cyclopropenyl group, cyclobutenyl group, cyclopentenyl group and cyclohexenyl group.
The term “alkyl groups” herein 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. Among them, methyl group and ethyl group are preferred.
The term “alkoxyl groups” herein indicates linear or branched alkoxyl groups having 1 to 6 carbon atoms such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group and tert-butoxy group. Among them, methoxy group and ethoxy group are preferred.
The term “alkylthio groups” indicates linear or branched alkylthio groups having 1 to 6 carbon atoms such as methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, sec-butylthio group and tert-butylthio group.
The term “amino groups which may be substituted with an alkyl group” indicates unsubstituted amino groups or amino groups mono- or di-substituted with alkyl group(s). The al
Fujita Kohichi
Iino Yukio
Kobayashi Tsuyoshi
Kodaira Ariko
Takehana Kenji
Ajinomoto Co. Inc.
Davis Brian
LandOfFree
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