Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-27
2004-01-06
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S300000, C514S414000, C514S256000, C514S415000, C514S383000, C514S364000, C514S323000, C546S113000, C546S277400, C548S466000, C548S511000, C548S266400, C548S131000, C544S333000, C544S350000
Reexamination Certificate
active
06673797
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an indole derivative and a mono- or diazaindole derivative that show an anti-inflammatory action and so forth and are useful as pharmaceuticals.
BACKGROUND
At present, the majority of medicines widely used as anti-inflammatory agents are non-steroid anti-inflammatory drugs (NSAIDs) that have, as the mechanism of action, an inhibitory action on cyclooxygenase (COX) that is involved in the biosynthesis of prostaglandin E2 (PGE2). However, since PGE2 synthesis activity is present in various tissues in the living body and governs the homeostasis thereof, various side effects are induced when NSAID is administered. For example, PGE2 demonstrates the action of maintaining blood flow in the stomach and kidneys, whereas administration of NSAIDs makes it difficult to maintain local blood flow, thereby causing gastric or renal disorders.
Under such circumstances, the presence of a COX isozyme has been confirmed. In order to distinguish it from the previously identified COX, the conventional type has been named COX-1, while the newly discovered isozyme has been named COX-2. In addition, this COX-2 has been clarified to be induced during inflammation and hardly be expressed at all under normal circumstances. It was also clarified that conventional NSAID are able to non-specifically inhibit both COX-1 and COX-2 enzymes. Therefore, the possibility arose of a compound having COX-2 inhibitory action being useful as a novel anti-inflammatory agent.
There are currently several compounds that are known to selectively inhibit only COX-2 without inhibiting COX-1 (Inflammation and Immunology, 3 (1), 29-36, 1995; Bioorganic & Med. Chem. Lett. 5 (8), 867-872, 1995, etc.). However, the actions of these compounds are not satisfactory and since some of them do not have an adequate water solubility or oral absorption, there is a need for a drug that demonstrates more effective COX-2 inhibitory action.
In addition, an indole derivative represented by the following formula:
(wherein, Ra represents a hydrogen atom, a straight or branched alkyl group having 1 to 7 carbon atoms, a straight or branched alkenyl group having 2 to 7 carbon atoms, a straight or branched alkynyl group having 2 to 7 carbon atoms, a cycloalkenyl group having 4 to 6 carbon atoms, an aryl group, a heteroaryl group, an alkylcarbonyl group in which the alkyl moiety is a straight or branched alkyl group having 1 to 7 carbon atoms, an alkenylcarbonyl group in which the alkenyl moiety is a straight or branched alkenyl group having 2 to 7 carbon atoms, an alkynylcarbonyl group in which the alkynyl moiety is a straight or branched alkynyl group having 2 to 7 carbon atoms, or —(CH
2
)
m
—Rd, where m represents an integer of 0 to 3 and Rd represents a cycloalkyl group having 3 to 6 carbon atoms which may be substituted with a straight or branched alkyl group having 1 to 3 carbon atoms; Rb represents —SO
2
—Re, where Re represents a straight or branched alkyl group having 1 to 3 carbon atoms; and Rc represents an aryl group which may have a substituent, a cycloalkyl group having 3 to 6 carbon atoms which may have a substituent, or a monocyclic heterocyclic group which may have a substituent) that selectively inhibits COX-2 is known from Japanese Patent Application Disclosure Hei No. 10-77266 (Japanese Patent Application Hei No. 9-24567).
The object of the present invention is to provide an indole derivative and a mono- or diazaindole derivative that have COX-2 inhibitory activity and are useful as pharmaceuticals, such as anti-inflammatory agents, etc.
As a result of conducting earnest research for the purpose of developing a compound that selectively or non-selectively inhibits COX-2 and has an anti-inflammatory action comparable to or higher than indometacin and other. existing NSAIDs, the inventors of the present application found that a compound represented by the general formula (1) has an excellent anti-inflammatory action and/or improved water solubility, making it useful as a pharmaceutical, thereby leading to completion of the present invention on the basis of this finding.
DISCLOSURE OF THE INVENTION
Accordingly, the present invention relates to a compound represented by the general formula (1):
wherein Het represents a heterocyclic group which may be substituted;
A
1
and A
2
each independently represent —CH═or —N═;
A
3
represents —CH
2
—, —(C═O)— or —SO
2
—;
R
1
represents a group selected from the following formulae:
wherein A
4
represents —O—, —S— or —NH—;
R
2
represents a straight or branched alkyl group having 1 to 3 carbon atoms;
n represents 0, 1 or 2, provided that when both A
1
and A
2
are —CH═, A
3
represents —CH
2
— or —SO
2
—,
or addition salts thereof with a pharmaceutically acceptable acid or base, or hydrates thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
In the definition of the compound represented by the general formula (1), a straight or branched alkyl group having 1 to 3 carbon atoms includes a methyl group, an ethyl group, an n-propyl group and an i-propyl group.
A heterocyclic group, which may be substituted, represented by Het is a 4- to 10-membered, monocyclic or condensed ring aliphatic or aromatic group containing 1, 2, 3 or 4 hetero atoms, which may be identical or different, such as an oxygen atom, a nitrogen atom and a sulfur atom. The substituent of the heterocyclic group includes, for example, a halogen atom, a straight or branched alkyl group having 1 to 4 carbon atoms (the group may be further substituted with a halogen atom), a straight or branched alkoxyl group having 1 to 4 carbon atoms (the group may be further substituted with a halogen atom), an oxo group, —S(O)
p
—R
3
(in which p is an integer of 0 to 2 and R
3
represents a straight or branched alkyl group having 1 to 3 carbon atoms), an amino group, a nitro group, a carboxyl group, —COOR
4
(in which R
4
represents a straight or branched alkyl group having 1 to 3 carbon atoms), —CONR
5
R
6
(in which R
5
and R
6
may be the same or different and each represent a hydrogen atom or a straight or branched alkyl group having 1 to 3 carbon atoms), a cyano group and a hydroxyl group. Among them, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, a t-butyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, an oxo group, a methylthio group, a methanesulfonyl group, an ethanesulfonyl group, an amino group, a nitro group, a carboxyl group, a methoxycarbonyl group, a methylaminocarbonyl group, a cyano group and a hydroxyl group are preferred and the fluorine atom, the carboxyl group, the methyl group, the methoxycarbonyl group and the methylaminocarbonyl group are particularly preferred. The above heterocyclic group may be further substituted with 1 to 3, preferably 1 heterocyclic group. The heterocyclic group as the substituent in this case includes heterocyclic groups listed below, which may be substituted, represented by Het in the compound of the general formula (1). Among them, tetrazolyl (particularly 5-tetrazolyl) and triazolyl (particularly 1,2,3-triazol-4-yl and 1,2,4-triazol-3-yl) are preferred.
While the heterocyclic group in the definition of Het can be substituted with the above substituent, a nitrogen atom of the heterocyclic group can further be bonded with an oxygen atom to form N-oxide. Moreover, a nitrogen atom and a carbon atom of the heterocyclic group may be substituted with a straight or branched alkyl group having 1 to 4 carbon atoms. Such alkyl group includes a methyl group.
In the definition of the compound of the formula (1), Het is the heterocyclic group which may be substituted with the above substituent, that is, a 4- to 10-membered, monocyclic or condensed cyclic aliphatic or aromatic group containing 1, 2, 3 or 4 identical or different hetero atoms, such as an oxygen atom, a nitrogen atom and a sulfur atom, preferably a 4- to 6-membered monocyclic aliphatic or aromatic group containing 1, 2, 3 or 4 identical or different hetero atoms, such a
Ishizawa Takenori
Kato Nobuaki
Maruyama Noriaki
Matsuoka Hiroharu
Suzuki Yukio
Browdy and Neimark PLLC
Chugai Seiyaku Kabushiki Kaisha
Liu Hong
Shah Mukund J.
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