Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-12-13
2004-06-01
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S250000, C514S301000, C514S397000, C514S300000, C514S339000, C514S414000, C514S415000, C546S114000, C546S256000, C546S122000, C546S113000, C544S353000, C544S350000, C548S454000, C548S305100, C548S491000, C548S465000
Reexamination Certificate
active
06743793
ABSTRACT:
TECHNICAL FIELD
The present invention relates to indole derivatives.
More specifically, the present invention relates to indole derivatives represented by formula (I):
(wherein all symbols have the same meanings as described below), a process for the preparation of the same and use thereof.
BACKGROUND ART
Prostaglandin D (hereinafter referred to as “PGD”) are known as a metabolite in the arachidonic acid cascade, and are known to have effects of bronchoconstriction, vasodilatation or vasoconstriction and platelet aggregation inhibition. PGD is considered to be produced from mast cells, and the increase of PGD concentration has been recognized among systemic mastocytosis patients (
New Eng. J. Med.,
303, 1400-1404 (1980)). Also, PGD is considered to relate to neuro activities, especially, sleep and hormone secretion. Furthermore, there are reports suggesting participations in platelet aggregation, glycogen metabolism, ocular tension adjustment and the like.
PGD shows its effects by binding to a DP receptor which is a receptor thereof. A DP receptor antagonist binds to and is antagonistic to its receptor so that it can inhibit the function of PGD. Accordingly, it is considered to be useful for the prevention and/or treatment of diseases, for example, allergic diseases such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, etc.; systemic mastocytosis; disorders due to systemic mastocyte activation; anaphylactic shock; bronchoconstriction; urticaria; eczema; allergic bronchopulmonary aspergillosis; inflammatory paranasal sinus; nasal polyp; hypersensitive angitis; eosinophilia; contact dermatitis; diseases accompanied with itching, such as atopic dermatitis, urticaria, allergic conjunctivitis, allergic rhinitis, contact dermatitis, etc.; secondary diseases caused by behaviors (scratching behaviors, beating, etc.), such as cataract, retinal detachment, inflammation, infection, sleep disorder, etc.; inflammation; chronic obstructive pulmonary disease; ischemic reperfusion disorder; cerebrovascular disorder; pleuritis complicated by rheumatoid arthritis; ulcerative colitis; and the like. Moreover, it is considered to relate to sleeping and platelet aggregation and to be useful for these diseases.
Some DP receptor antagonists are known until now, and BW-A868C represented by formula (A) is considered to be the most selective:
Also, recently, DP receptor antagonists which are thromboxane derivatives have been published in WO 98/25915, WO 98/25919, WO 97/00853, WO 98/15502 and the like.
On the other hand, as a compound similar to the compound of the present invention, an indole compound represented by formula (B) is known as a synthetic intermediate (
J. Heterocyclic Chem.,
19, 1195 (1982)).
DISCLOSURE OF THE INVENTION
The present inventors intensively studied to find a compound which specifically binds to DP receptor and show an antagonistic activity and found that the object could be attained by indole derivatives represented by formula (I), and thus the present invention has been completed.
That is, the present invention relates to an indole derivative represented by formula (I):
wherein R
1
represents hydroxy, C1-6 alkoxy, or NR
8
R
9
, in which R
8
and R
9
each independently represents a hydrogen atom, C1-6 alkyl, or SO
2
R
13
, in which R
13
represents C1-6 alkyl, a C3-15 saturated or unsaturated carbocyclic ring or a 4- to 15-membered heterocyclic ring containing 1 to 5 nitrogen atom(s), sulfur atom(s) and/or oxygen atom(s);
R
2
represents a hydrogen atom, C1-6 alkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, a halogen atom, amino, trihalomethyl, cyano, hydroxy, benzyl, or 4-methoxybenzyl;
R
3
represents a hydrogen atom, C1-6 alkyl, C1-6 alkoxy, a halogen atom, trihalomethyl, cyano, or hydroxy;
R
4
and R
5
each independently represents a hydrogen atom, C1-6 alkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, a halogen atom, nitro, amino, trihalomethyl, cyano, or hydroxy;
D represents a single bond, C1-6 alkylene, C2-6 alkenylene, or C1-6 oxyalkylene;
in -G-R
6
,
1) G represents a single bond, C1-6 alkylene which may be substituted with 1 to 2 oxygen atom(s) and/or sulfur atom(s), C2-6 alkenylene which may be substituted with 1 to 2 oxygen atom(s) and/or sulfur atom(s), in which the alkylene and the alkenylene may be substituted with hydroxy or C1-4 alkoxy, —C(O)NH—, —NHC(O)—, —SO
2
NH—, —NHSO
2
—, or diazo;
R
6
represents a C3-15 saturated or unsaturated carbocyclic ring, or a 4- to 15-membered heterocyclic ring containing 1 to 5 nitrogen atom(s), sulfur atom(s) and/or oxygen atom(s), in which the ring may be substituted with 1 to 5 substituent(s) selected from C1-6 alkyl, C1-10 alkoxy, C2-6 alkoxyalkyl, a halogen atom, hydroxy, trihalomethyl, nitro, amino, phenyl, phenoxy, oxo, C2-6 acyl, C1-6 alkanesulfonyl and cyano,
2) G and R
6
are taken together to represent
(i) C1-15 alkyl which may be substituted with 1 to 5 oxygen atom(s) and/or sulfur atom(s);
(ii) C2-15 alkenyl which may be substituted with 1 to 5 oxygen atom(s) and/or sulfur atom(s); or
(iii) C2-15 alkynyl which may be substituted with 1 to 5 oxygen atom(s) and/or sulfur atom(s),
in which the alkyl, the alkenyl and the alkynyl may be substituted with 1 to 12 substituent(s) selected from C1-6 alkoxy, a halogen atom, hydroxy, cyano, oxo and NR
11
R
12
, in which R
11
and R
12
each independently represents a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, phenyl, benzoyl, naphthyl, phenyl substituted with C1-6 alkyl, or C1-6 alkyl substituted with phenyl or cyano;
n represents 1 to 3;
m represents 1 to 3;
i represents 1 to 4; and
represents a single bond or a double bond, or a non-toxic salt thereof;
(2) a process for the preparation thereof;
(3) a pharmaceutical agent comprising it as an active ingredient; and
(4) 2-methylindole-4-acetic acid which is a novel synthetic intermediate.
In formula (I), the C1-6 alkyl represented by R
2
, R
3
, R
4
, R
5
, R
6
, R
8
, R
9
, R
11
, R
12
or R
13
includes, methyl, ethyl, propyl, butyl, pentyl, hexyl, and isomers thereof.
In formula (I), the C1-6 alkoxy represented by R
1
, R
2
, R
3
, R
4
or R
5
includes methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, and isomers thereof.
In formula (I), the C1-10 alkoxy represented by R
6
includes methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, and isomers thereof.
In formula (I), the C1-15 alkyl represented by G and R
6
taken together includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, and isomers thereof.
In formula (I), the C1-15 alkyl which may be substituted with 1 to 5 oxygen atom(s) and/or sulfur atom(s) represented by G and R
6
taken together represents the above alkyl in which any 1 to 5 carbon atom(s) are substituted with an oxygen atom(s) and/or a sulfur atom(s).
In formula (I), the C2-15 alkenyl represented by G and R
6
which are taken together includes vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pehtadecenyl, and isomers thereof.
In formula (I), the C2-15 alkenyl which may be substituted with 1 to 5 oxygen atom(s) and/or sulfur atom(s) represented by G and R
6
which are taken together represents the above alkenyl in which any 1 to 5 carbon atom(s) are substituted with an oxygen atom(s) and/or a sulfur atom(s).
In formula (I), the C2-15 alkynyl represented by G and R
6
which are taken together includes ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl, and isomers thereof.
In formula (I), the C2-15 alkynyl which may be substituted with 1 to 5 oxygen atom(s) and/or sulfur atom(s) represented by G and R
6
which are taken together represents the above alkynyl in which any 1 to 5 carbon atom(s) are substituted with an oxygen atom(s) and/or a sulfur atom(s).
In formula (I), the C2-6 alkoxyalkyl represented by R
2
, R
4
, R
5
or R
6
includes methoxymethyl, methoxyethyl,
Kobayashi Kaoru
Nambu Fumio
Torisu Kazuhiko
Ono Pharmaceutical Co. Ltd.
Small Andrea D
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