Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-01
2004-01-06
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S291000, C514S183000, C514S396000, C548S100000
Reexamination Certificate
active
06673807
ABSTRACT:
TECHNICAL FIELD
This invention relates to a new use of a compound possessing an inhibitory activity on the production of nitric oxide, which is useful in a medical field.
BACKGROUND ART
Various compounds possessing an inhibitory activity on the production of nitric oxide have already been known, for example, in EP 0 394 989-A2, WO96/16981, WO97/45425, WO98/27108, etc.
DISCLOSURE OF INVENTION
This invention relates to a new use of a compound possessing an inhibitory activity on the production of nitric oxide, for increasing an effect caused by interleukin 2 inhibitor (hereinafter, referred to IL-2 inhibitor).
Therefore, one object of the present invention is to provide a new use of a compound possessing an inhibitory activity on the production of nitric oxide, for increasing an effect caused by IL-2 inhibitor.
Another object of this invention is to provide a method for increasing an effect caused by IL-2 inhibitor by administering an effective amount of a compound possessing an inhibitory activity on the production of nitric oxide.
A further object of this invention is to provide a use of a compound possessing an inhibitory activity on the production of nitric oxide for manufacturing a medicament for increasing an effect caused by IL-2 inhibitor.
Still further object of this invention is to provide a composition comprising a compound possessing an inhibitory activity on the production of nitric oxide, for increasing an effect caused by IL-2 inhibitor.
In the present invention, the “compound possessing an inhibitory activity on the production of nitric oxide” should not be limited and be considered to mean any compounds which have an inhibitory activity on the production of nitric oxide. Preferable one is a compound possessing an inhibitory activity on the production of inducible nitric oxide synthase (iNOS), and the other preferable one is a compound possessing an iNOS-inhibitory activity.
The compound having the following formula (I) are exemplified as a preferable example of the above “compound possessing an inhibitory activity on the production of nitric oxide”.
wherein
R
1
is indolyl which may have a suitable substituent selected from the group consisting of lower alkyl, phenyl, halogen, lower alkoxy, and nitro, benzofuranyl, phenyl which may have one or two suitable substituent(s) selected from the group consisting of amino, acylamino, lower alkylamino, halogen, lower alkoxy and nitro, lower alkyl, quinoxalinyl, quinolyl, pyrrolyl, pyrimidinyl having benzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, indolinyl, anilino, phenylcarbamoyl or imidazolyl which may have one or two suitable substituent(s) selected from the group consisting of phenyl, lower alkyl and indolyl;
R
2
is hydrogen or phenyl(lower)alkyl;
R
4
is hydrogen, phenyl or pyridyl, each of which may have suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halogen, trihalomethyl, nitro, cyano, imidazolyl, optionally protected hydroxy, acyl, amino, acylamino, diacylamino, di(lower)alkyl-amino, amino(lower)alkyl, acylamino(lower)alkyl, pyrazolyl, morpholinyl, piperidyl, triazolyl, lower alkoxy(lower)alkoxy, hydroxy(lower)alkyl, lower alkylpiperazinyl, phenyl and carboxy, quinolyl or 3,4-methylenedioxyphenyl;
R
5
is hydrogen, imidazolyl, phenyl, nitrophenyl, phenyl(lower)- alkyl, optionally esterified carboxy or a group of the formula:
in which R
7
and R
8
are the same or different and each is hydrogen, phenyl, phenyl(lower)alkyl, lower alkyl or lower alkoxy; or
R
4
and R
5
in combination form a group of the formula:
—CH═CH—CH═CH—
Y is a group of the formula:
in which R
3
is hydrogen or a group of the formula:
—(CH
2
)
n
—R
6
in which R
6
is optionally protected hydroxy, acyl, carboxy, acylamino, lower alkoxy, phenyl(lower)alkoxy, lower alkylthio, phenyl which may have a suitable substituent selected from the group consisting of lower alkoxy, halogen, amino, acylamino, diacylamino and nitro, pyridyl which may have a suitable substituent selected from the group consisting of lower alkoxy and halogen, pyrazinyl, pyrimidinyl, furyl, imidazolyl, naphthyl, N-(lower)alkylindolyl or 3,4-methylenedioxyphenyl, and n is an integer of 0 to 3,
or a group of the formula:
in which R
11
is phenyl, phenoxy or phenyl(lower)alkoxy; or
R
2
and R
3
in combination form a group of the formula:
m is O or 1; and
X is S or NR
9
in which R
9
is hydrogen, lower alkyl, cyclo(lower)alkyl or a group of the formula:
in which R
10
is hydrogen, lower alkyl or lower alkoxy;
or a pharmaceutically acceptable salt thereof.
Suitable pharmaceutically acceptable salts of the compound (I) are conventional non-toxic salts and include, for example, a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, citrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); and a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid,gultamic acid, etc.).
In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.
The term “lower” is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.
Suitable “lower alkyl” and “lower alkyl moiety” in the terms “lower alkylthio”, “lower alkylthio(lower)alkyl”, “N-(lower)alkylindolyl”, “lower alkylamino”, “di(lower)alkylamino”, “phenyl(lower)alkyl”, “amino(lower)alkyl”, “acylamino(lower)alkyl”, “hydroxy(lower)alkyl” and “lower alkylpiperazinyl” include straight or branched onehaving 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl andhexyl, in which more preferred one is C1-C4 alkyl.
Suitable “lower alkoxy” and “lower alkoxy moiety” in the terms “lower alkoxy(lower)alkoxy” and “phenyl(lower)alkoxy” include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy and hexyloxy, in which more preferred one is C1-C4 alkoxy.
Suitable “halogen” includes, for example, fluorine, bromine, chlorine and iodine.
“Optionally esterified carboxy” includes carboxy and esterified carboxy. Suitable examples of said ester include lower alkyl ester(e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, tert-pentyl ester, hexyl ester, etc.); lower alkenyl ester (e.g., vinyl ester, allylester, etc.); lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.); lower alkoxy(lower)alkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.); mono(or di or tri)aryl(lower)alkyl ester, for example, mono(or di or tri)phenyl(lower)alkyl ester which may have one or more suitable substituent(s) [e.g.,benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester, etc.]; and aryl ester which may have one or more suitable substituent(s)such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc.).
Suitable “trihalo
Chida Noboru
Nakayama Osamu
Sakai Fumihiko
Yamazaki Harumi
Yokota Yoshihiro
Fujisawa Pharmaceutical Co. Ltd.
Leydig , Voit & Mayer, Ltd.
Low Christopher S. F.
Lukton David
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