Bicyclic amino derivatives and PGD2, antagonist containing them

Details Bicyclic amino derivatives and PGD2, antagonist containing them Bicyclic amino derivatives and PGD2, antagonist containing them

2000-02-18

2002-05-07

Gerstl, Robert (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S468000, C514S539000, C514S562000, C560S041000, C562S450000

Reexamination Certificate

active

06384075

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to bicyclic amino derivatives and prostaglandin D
2
(hereinafter, referred to as PGD
2
) antagonist containing them.
BACKGROUND OF THE INVENTION
Some of bicyclic amino derivatives of the present invention have known to be useful as thromboxane A
2
(TXA
2
) antagonists (Japanese Patent Publication (KOKOKU) No. 79060/1993). However, the Japanese Patent Publication (KOKOKU) No. 79060/1993 only describes that the compounds are useful as TXA
2
antagonist, and does not suggest the usefulness thereof as PGD
2
antagonist as disclosed by the present invention.
Namely, the TXA
2
is known to have activities such as action against platelet agglutination, thrombogenesis, etc. The TXA
2
antagonist has therefore been considered to be useful as anti-thrombotic agent, and also in the treatment of myocardial infarction or asthma by antagonizing against TXA
2
.
On the other hand, the PGD
2
antagonist of the present invention is useful in the improvement of conditions due to excessive production of PGD
2
. Specifically, it is useful as a drug for treating diseases in which mast cell dysfunction is involved, for example, systemic mastocytosis and disorder of systemic mast cell activation, and also tracheal contraction, asthma, allergic rhinitis, allergic conjunctivitis, urticaria, injury due to ischemic reperfusion, and inflammation.
As is apparent from the above, the TXA
2
antagonist and the PGD
2
antagonist are completely different from each other in terms of the active site, mechanism of action, and application, and have quite different characteristics. Accordingly, it has never been expected that any compound could possess these activities simultaneously.
PGD
2
is produced through PGG
2
and PGH
2
from arachidonic acid by the action of cyclooxygenase activated by immunological or unimmunological stimulation and is the major prostanoid that is produced and released from mast cells. PGD
2
has various potent physiological and pathological activities. For example, PGD
2
can cause strong tracheal contraction, which leads to bronchial asthma, and, in a systemic allergic state, it can dilate the peripheral vessels, which leads to an anaphylactic shock. Especially, much attention has been paid on the idea that PGD
2
is one of the causal substances responsible to the onset of nasal occlusion in the allergic rhinitis. Therefore, it has been proposed to develop an inhibitor against the biosynthesis of PGD
2
or an antagonist of PGD
2
receptor as a drug for the reduction of nasal occlusion. However, the inhibitor of PGD
2
biosynthesis possibly affects greatly the synthesis of prostaglandins in other organisms, and therefore, it is desirable to develop an antagonist (blocker) specific to PGD
2
receptor.
DISCLOSURE OF THE INVENTION
The present inventors have studied intensively to develop PGD
2
receptor antagonists (blockers) specific to PGD
2
receptor, and found that compounds of the formula (I) below or its salt possess a potent activity as PGD
2
receptor antagonist, and are chemically and biochemically stable.
Accordingly, the present invention provides a PGD
2
antagonist which comprises a compound of the general formula (I) below or its salt or a hydrate thereof as an active ingredient:
wherein:
A is alkylene which optionally is intervened by hetero atom or phenylene, contains oxo group, and/or has an unsaturated bond;
B is hydrogen, alkyl, aralkyl or acyl;
R is COOR
1
, CH
2
OR
2
or CON(R
3
)R
4
;
R
1
is hydrogen or alkyl;
R
2
is hydrogen or alkyl;
R
3
and R
4
each are independently hydrogen, alkyl, hydroxy or alkylsulfonyl;
X
1
is a single bond, phenylene, naphtylene, thiophenediyl, indolediyl, or oxazolediyl;
X
2
is a single bond, —N═N—, —N═CH—, —CH═N—, —CH═N—N—, —CH═N—O—, —C═NNHCSNH—, —C═NNHCONH—, —CH═CH—, —CH(OH)—, —C(Cl)═C(Cl)—, —(CH
2
)n-, ethynylene, —N(R
5
)—, —N(R
51
)CO—, —N(R
52
)SO
2
—, —N(R
53
)CON(R
54
)—, —CON(R
55
)— —SO
2
N(R
56
)—, —O—, —S—, —SO—, —SO
2
—, —CO—, oxadiazolediyl, thiadiazolediyl or tetrazolediyl;
X
3
is alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclic group, cycloalkyl, cycloalkenyl, thiazolinylidenemethyl, thiazolidinylidenemethyl, —CH═NR
6
or —N═C(R
7
)R
3
;
R
5
, R
51
, R
52
, R
53
, R
54
, R
55
and R
56
each are hydrogen or alkyl;
R
6
is hydrogen, alkyl, hydroxy, alkoxy, carbamoyloxy, thiocarbamoyloxy, ureido or thioureido;
R
7
and R
8
each are independently alkyl, alkoxy or aryl;
n is 1 or 2;
Z is —SO
2
— or —CO—; and
m is 0 or 1;
wherein a cyclic substituent may has one to three substituents selected from the group consisting of nitro, alkoxy, sulfamoyl, substituted- or unsubstituted-amino, acyl, acyloxy, hydroxy, halogen, alkyl, alkynyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl, mesyloxy, cyano, alkenyloxy, hydroxyalkyl, trifluoromethyl, alkylthio, —N═PPh
3
, oxo, thioxo, hydroxyimino, alkoxyimino, phenyl and alkylenedioxy.
THE BEST EMBODIMENT FOR PRACTICING THE INVENTION
Specific examples of compounds usable as a PGD
2
antagonist above include a compound of the formula (I) wherein:
is
m is 0; and when Z is SO
2
, both X
1
and X
2
are a single bond; X
3
is alkyl, phenyl, naphthyl, stylyl, quinolyl or thienyl; and a cyclic substituent among these substituents optionally has one to three substituents selected from a group consisting of nitro, alkoxy, substituted- or unsubstituted-amino, halogen, alkyl and hydroxyalkyl, or its salt or hydrate thereof.
Similarly, specific examples include a compound of the formula (I) wherein:
when m is 1, both X
1
and X
2
are a single bond; and X
3
is phenyl optionally substituted with halogen, or its salt or hydrate thereof.
Similarly, specific examples include a compound of the formula (I) wherein:
when m is 1, X
1
is phenyl, X
2
is —CH
2
— or —N═N— and X
3
is phenyl, or its salt or hydrate thereof.
Similarly, examples of compounds of the formula (I) include those of the formula (Ia):
wherein A, B, R, X
1
, X
2
and X
3
are as defined above, or its salt or hydrate thereof, provided that those wherein (1) X
1
and X
2
are a single bond, and X
3
is substituted- or unsubstituted-phenyl, or naphthyl; and (2) A is 5-heptenylene, R is COOR
1
(R
1
is hydrogen or methyl), X
1
is 1,4-phenylene, X
2
is a single bond, and X
3
is phenyl are excluded.
Similarly, examples of compounds of the formula (I) include those of the formula (Ib):
wherein:
A, B, R, X
1
, X
2
and X
3
are as defined above, or its salt or hydrate thereof, provided that those wherein X
1
and X
2
are a single bond, and X
3
is phenyl, and wherein X
1
is a single bond, X
2
is —O—, and X
3
is benzyl are excluded.
More specifically, examples of compounds of the formula (I) include those of the formula (Ia) wherein X
1
and X
2
are a single bond, X
3
is isoxazolyl, thiadiazolyl, isothiazolyl, morpholyl, indolyl, benzofuryl, dibenzofuryl, dibenzodioxinyl, benzothienyl, dibenzothienyl, carbazolyl, xanthenyl, phenanthridinyl, dibenzoxepinyl, dibenzothiepinyl, cinnolyl, chromenyl, benzimidazolyl or dihydrobenzothiepinyl, or its salt or hydrate thereof.
Similarly, examples of compounds of the formula (I) include those of the formula (Ia) wherein X
1
is a single bond, X
2
is phenylene, X
3
is alkenyl, alkynyl, —CH═NR
6
or —N═C(R
7
)R
8
, or its salt or hydrate thereof.
Similarly, examples of compounds of the formula (I) include those of the formula (Ia) wherein R is COOR
1
, X
1
is phenylene or thiophenediyl, X
2
is a single bond, —N═N—, —CH═CH—, —CONH—, —NHCO— or ethynylene and X
3
is phenyl, thiazolinylidenemethyl, thiazolidinylidenemethyl or thienyl, or its salt or hydrate thereof.
More specifically, examples of the compound (I) of the present invention include those of the formula (Ib) wherein:
is
or its salt orhydrate thereof. Examples of more preferred compounds include those of the formula (Ib) wherein R is COOR
1
(R
1
is as defined above) or its salt or hydrate thereof.
Similarly, examples of compound (I) include those of the formula (Ib)

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