Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-26
2001-12-11
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06329381
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel heterocyclic compounds having inducing activity for biosynthesis of interferon. The heterocyclic compounds of the present invention induce biosynthesis of endogenous interferon in a living body, and are useful for medicines, such as antiviral agents, anticancer agents and therapeutic agents for immunologic diseases.
BACKGROUND OF THE ART
It has been recently determined that endogenous interferon plays not only central role to bio-defensive mechanism against virus infections and microbial infections, but also an important role dn antitumor and immune modulator. Mass production of interferon is established. Namely, it is possible to obtain of natural interferon by cell culture and also to produce a large amount of recombinant interferon from
E. coli
transferred with a gene of interferon and therefore, many research achievements on these interferons have accumulated. For example, many kinds of biological activity on interferon, such as antiviral activity, prevention of cell growth and immune modulation have been confirmed and interferon is practiced on clinics as treating agents for virus infected diseases, such as hepatitis C and hepatitis B, anticancer agents and therapeutic agents for immunologic disease. Furthermore, it is suggested that interferon will prevent carcinogenesis by hepatitis C and hepatitis B.
Since there is no therapeutic method for almost of the above diseases, interferon is especially made much of.
DISCLOSURE OF INVENTION
The object of the present invention is to provide novel low molecular weight compounds having inducing activity for biosynthesis of interferon, and interferon inducers, antiviral agents, anticancer agents and therapeutic agents for immunologic diseases comprising these compounds as active ingredients.
Viruses of many kinds of animals, microbes such as mycobacteria and protozoa, extracts of them, mitogen, specific antigens and immunopotenciators are known as inducers for biosynthesis of interferon. It is known that for example, many kinds of natural double strand RNAS, synthesized double strand RNAs such as poly-I:C, and anionic high molecular compounds such as polyacrylic acid and oxyamylose oxidized with chlorite have inductive activity of interferon.
On the other hand, among low molecular weight compounds have been found fluorenones, pyrimidine derivatives, anthraquinones, acridines and so on having inductive activity of interferon (Stringfollow, D. A.: Methods in Enzymology, 1981, 78, 262).
However, when these compounds are used in clinical trial, their inducing activity of interferon is unexpectedly low and these compounds have side effects or by administering them repeatedly, their inducing activity of interferon decreases and therefore, development on these compounds has not succeeded. Furthermore, imidazo-quinolines are known as interferon inducers among low molecular compounds. However, it is known that these compounds are inferior in selective interferon inducing activity and simultaneously induce cytokines such as IL-6, TNF-&agr;, etc (Testerman, T. L., et al.: J. Leukocyte Biol., 1995, 58, 365).
As the result of extensive investigation of interferon biosynthesis inducers among low molecules, the present inventors have found that the heterocyclic compounds of the present invention have excellent interferon biosynthesis inducing activity.
The present invention relates to a heterocyclic compound of the following general formula (I):
wherein X is sulfur atom, oxygen atom, —NR
3
— (in which R
3
is hydrogen atom, alkyl group or substituted alkyl, or may form a heterocyclic ring or a substituted heterocyclic ring together with R
1
via the nitrogen atom),
R
1
is alkyl group, substituted alkyl group, aryl group, substituted aryl group, heterocyclic group or substituted heterocyclic group, and
R
2
is hydrogen atom, or one or more substituents on the benzene ring, and said substituent is the same or different and is hydroxy group, lower alkyl group, substituted lower alkyl group, lower alkoxy group, substituted lower alkoxy group, lower alkanoyl group, substituted lower alkanoyl group, aroyl group, substituted aroyl group, carboxyl group, lower alkoxycarbonyl group, substituted lower alkoxycarbonyl group, amino group, lower alkylamino group, di(lower alkyl)amino group, carbamoyl group, lower alkylcarbamoyl group, di(lower alkyl)carbamoyl group, halogen atom, nitro group or cyano group; or a pharmaceutically acceptable salt thereof.
Further, the present invention relates to a pharmaceutical composition comprising a heterocyclic compound of the above formula (I) or its pharmaceutically acceptable salt as an active ingredient.
Further, the present invention relates to an interferon inducer, an antiviral agent, an anticancer agent and a therapeutic agent for immunologic diseases comprising a heterocyclic compound of the above formula (I) or its pharmaceutically acceptable salt as an active ingredient.
Furthermore, the present invention relates to a process for preparing a heterocyclic compound of the above formula (I) or its pharmaceutically acceptable salt.
Groups R
1
, R
2
and R
3
in the formula (I) are explained below.
In R
1
alkyl group includes straight or branched C
1-10
alkyl group (e.g. methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, 1-methylpropyl, 3-methylbutyl or hexyl), C
3-7
cycloalkyl group (e.g. cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl), and alkyl-substituted C
3-7
cycloalkyl group, preferably straight or branched C
1-6
alkyl group (e.g. methyl, ethyl, propyl, butyl or pentyl), and C
5-7
cycloalkyl group (e.g. cyclopentyl or cyclohexyl).
In R
1
substituted alkyl group means the above alkyl substituted by the same or different and one or more substituents.
Said substituents include cycloalkyl group (C
3-6
cycloalkyl group, such as cyclopropyl, cyclopentyl or cyclohexyl), hydroxy group, lower alkoxy group (C
1-6
alkoxy such as methoxy, ethoxy, propoxy, butoxy or pentoxy), substituted lower alkoxy group (substituted C
1-6
alkoxy group, such as methoxyethoxy, ethoxyethoxy, hydroxyethoxy or chloroethoxy), amino group, alkylamino group, cyano group, nitro group, acyl group, carboxyl group, lower alkoxycarbonyl group (C
2-7
alkoxycarbonyl group, such as methoxycarbonyl or ethoxycarbonyl), halogen atom, such as fluorine atom, chlorine atom or bromine atom, mercapt group, lower alkylthio group (C
1-6
alkylthio group, such as methylthio, ethylthio, propylthio or butylthio), substituted lower alkylthio group (substituted C
1-6
alkylthio group, such as methoxyethylthio, methylthioethylthio, hydroxyethylthio or chloroethylthio), aryl group (C
6-10
monocyclic or fused cyclic aryl group, such as phenyl or naphthyl), substituted aryl group (substituted C
6-10
monocyclic or fused cyclic aryl group, such as 4-hydroxyphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl or 3,4-dichlorophenyl), and heterocyclic group (5-6 membered saturated heterocyclic group containing nitrogen atoms from 0-2 and oxygen atoms from 0-2, such as piperidyl, piperazinyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolinyl or 1,3-dioxolanyl, 5-6 membered unsaturated heterocyclic group, such as furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, pyridyl or pyrimidinyl, or bicyclic unsaturated heterocyclic group, such as indolyl, isoindolyl, quinolyl, benzothiazolyl, chromanyl, benzofuranyl or phthalimino).
In R
1
aryl group means C
6-10
monocyclic or fused cyclic aryl group, such as phenyl or naphthyl.
In R
1
substituted aryl group means the above aryl group substituted by the same or different and one or more substituents.
Said substituent includes lower alkyl group (C
1-6
alkyl group, such as methyl, ethyl, propyl, butyl, cyclopentyl or cyclohexyl), hydroxy lower alkyl group (hydroxy C
1-6
alkyl group, such as hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl), lower alkoxy lower alkyl group (C
1-6
alkoxy C
1-6
alkyl group, such as 2-methoxyethyl, 2-ethoxyethyl or 3-methoxypropyl), hydroxy group, lower alkoxy group (C
1-6
alkoxy group, such as met
Kawakami Hajime
Kurimoto Ayumu
Ogino Tetsuhiro
Birch & Stewart Kolasch & Birch, LLP
McKenzie Thomas C
Shah Mukund J.
Sumitomo Pharmaceuticals Company Limited
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