Benzimidazole compounds as bradykinin antagonists

Details Benzimidazole compounds as bradykinin antagonists Benzimidazole compounds as bradykinin antagonists

1999-10-22

2001-02-27

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Silicon containing doai

C514S387000, C514S388000, C514S394000, C514S395000, C548S110000, C548S304400, C548S305100, C548S310700, C548S310100, C548S307100, C548S306400, C548S309400, C548S307400, C548S310400

Reexamination Certificate

active

06194396

ABSTRACT:

TECHNICAL FIELD
This invention relates to heterocyclic compounds and salts thereof which have activities as bradykinin antagonists and are useful for treating several diseases.
One object of this invention is to provide heterocyclic compounds and salts thereof which possess activities as bradykinin antagonists.
Another object of this invention is to provide processes for the preparation of said heterocyclic compounds and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said heterocyclic compounds and salts thereof.
Still further object of this invention is to provide an agent for the prevention and/or the treatment of bradykinin or its analogues mediated diseases such as allergy, inflammation, autoimmune disease, shock, pain, or the like, comprising said heterocyclic compounds and salts thereof as an active ingredient.
BACKGROUND ART
Heterocyclic compounds having activities as bradykinin antagonists have been known as described in EP-A-596,406 and EP-A-622,361.
DISCLOSURE OF THE INVENTION
The object heterocyclic compounds of this invention are new and can be represented by the following general formula [I]:
wherein
a group of the formula:
is a group of the formula:
X is O, S or N-R
5
R
1
is lower alkyl, halo(lower)alkyl, lower alkylamino(lower)alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, lower alkoxy, lower alkylthio, lower alkylamino, acyl(lower)alkyl, acyl, hydroxy, mercapto, aryl or ar(lower)alkyl, and
R
5
is hydrogen, lower alkyl, halo(lower)alkyl, lower alkylamino(lower)alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, lower alkoxy, lower alkylthio, lower alkylamino, acyl(lower)alkyl, acyl, aryl or ar(lower)alkyl, or
R
1
and R
5
are taken together to form lower alkylene optionally having O, S or N or lower alkenylene optopnally having O, S or N,
R
2
is hydrogen, halogen, lower alkyl or lower alkoxy,
R
3
is halogen, lower alkyl or lower alkoxy,
R
4
is amino optionally having suitable substituent(s),
R
8
is lower alkyl or acyl(lower)alkyl, and
A is lower alkylene.
The object compound [I] or its salt can be prepared by processes as illustrated in the following reaction schemes.
wherein R
a
1
is lower alkoxy,
R
6
is hydrogen or lower alkyl,
R
a
7
is acyl having amino,
R
b
7
is acyl having acylamino,
Y is a leaving group, and
a group of the formula:
R
2
, R
3
, R
4
, R
5
and A are each as defined above.
In the above and subsequent description of the present specification and claims, suitable examples of the various definitions to be included within the scope of the invention are explained in detail in the following.
The term “lower” is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
In this respect, the term “lower” in lower alkenyl moiety, lower alkynyl moiety, heterocyclic(lower)alkenyl moiety and ar(lower)alkenyl moiety in the various definitions is intended to mean a group having 2 to 6 carbon atoms.
Further, the term “lower” in lower alkenoyl moiety, lower alkynoyl moiety, cyclo(lower)alkyl moiety, cyclo(lower)alkenyl moiety, ar(lower)alkenoyl moiety, ar(lower)alkynoyl moiety and heterocyclic(lower)alkenoyl moiety in the various definitions is intended to mean a group having 3 to 6 carbon atoms.
Suitable “halogen” may be fluorine, chlorine, bromine and iodine.
Suitable “aryl” and aryl moiety in the term “ar(lower)alkenoyl” may be phenyl, naphthyl, phenyl substituted with lower alkyl [e.g. tolyl, xylyl, mesityl, cumenyl, di(tert-butyl)phenyl, etc.] and the like, in which preferable one is phenyl, naphthyl and tolyl.
Suitable “lower alkyl” and lower alkyl moiety in the terms “acyl (lower) alkyl”, “lower alkylamino(lower)alkyl”, “hydroxy(lower)alkyl”, “lower alkoxy(lower)alkyl”, “heterocyclic(lower)alkyl”, “lower alkylthio” and “lower alkylamino” may be straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or the like, in which preferable one is C
1
-C
4
alkyl such as methyl, ethyl, propyl, isobutyl or tert-butyl.
Suitable “lower alkoxy” and lower alkoxy moiety in the term “lower alkoxy(lower)alkyl” may be straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or the like, in which preferable one is C
1
-C
4
alkoxy such as methoxy, ethoxy or isopropoxy.
Suitable “lower alkylene” may be a straight or branched one such as methylene, ethylene, trimethylene, methylmethylene, tetramethylene, ethylethylene, propylene, pentamethylene, hexamethylene or the like, in which the most preferable one is methylene.
Suitable “lower alkenylene” may be a straight or branched C
2
-C
6
alkenylene such as vinylene, methylvinylene, propenylene, 1,3-butadienylene, pentenylene or the like.
Suitable “halo(lower)alkyl” may be chloromethyl, dichloromethyl, bromomethyl, fluoromethyl, trifluoromethyl, pentafluoroethyl, trifluoroethyl or the like.
Suitable “ar(lower)alkyl” may be benzyl, phenethyl, phenylpropyl, naphthylmethyl or the like, in which the most preferable one is benzyl.
Suitable “heterocyclic group” and all heterocyclic moieties in the various definitions mentioned in this specification and claims such as in the term “heterocyclic(lower)alkyl”, “hetrocyclic(lower)alkenyl”, “heterocyclic(lower)alkenoyl”, etc., may include saturated or unsaturated, monocyclic or polycyclic one containing at least one hetero atom such as oxygen atom, sulfur atom and/or nitrogen atom, preferably N, O and/or S containing heterocyclic group, in which preferable ones may be morpholinyl, piperazinyl, pyridyl, tetrahydropyridyl, pyrimidinyl, piperidyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, tetrazolyl, imidazolyl, pyrrolidinyl, pyrrolyl, quinolyl, tetrahydroquinolyl, isoquinolyl or the like.
Suitable “acyl” and acyl moiety in the term “acyl(lower)alkyl” may be substituted or unsubstituted alkanoyl such as alkanoyl [e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, 3,3-dimethylbutyryl, etc.], halo(lower)alkanoyl [e.g. chloroacetyl, trifluoroacetyl, bromoacetyl, bromobutyryl, heptafluorobutyryl, etc.], hydroxy(lower)alkanoyl [e.g. glycoloyl, lactoyl, 3-hydroxypropionyl, glyceroyl, etc.], lower alkylsulfonyloxy(lower)alkanoyl [e.g. mesyloxyacetyl, ethylsulfonyloxyacetyl, mesyloxypropionyl, etc.], lower alkoxy(lower)alkanoyl [e.g. methoxyacetyl, ethoxyacetyl, methoxypropionyl, ethoxypropionyl, propoxypropionyl, methoxybutyryl, etc.], lower alkylthio(lower)alkanoyl [e.g. methylthioacetyl, ethylthioacetyl, methylthiopropionyl, ethylthiopropionyl, propylthiopropionyl, methylthiobutyryl, etc.], lower alkanoyloxy(lower)alkanoyl [e.g. acetyloxyacetyl, acetyloxypropionyl, propionyloxyacetyl, etc.], aryloxy(lower)alkanoyl [e.g. phenyloxyacetyl, phenyloxypropionyl, tolyloxyacetyl, naphthyloxyacetyl, etc.], aroyl(lower)alkanoyl [e.g. phenyloxalyl, benzoylacetyl, benzoylpropionyl, etc.], carboxy(lower)alkanoyl [e.g. oxalo, carboxyacetyl, 3-carboxypropionyl, 3-carboxybutyryl, 4-carboxybutyryl, 4-carboxyvaleryl, etc.], esterified carboxy(lower)alkanoyl, for example, lower alkoxycarbonyl(lower)alkanoyl [e.g. methoxycarbonylacetyl, ethoxycarbonylacetyl, methoxycarbonylpropionyl, ethoxycarbonylpropionyl, etc.], carbamoyl(lower)alkanoyl [e.g. carbamoylacetyl, carbamoylpropionyl, etc.], lower alkylcarbamoyl(lower)alkanoyl [e.g. methylcarbamoylacetyl, methylcarbamoylpropionyl, ethylcarbamoylpropionyl, dimethylcarbamoylpropionyl, (N-methyl-N-ethylcarbamoyl)-propionyl, etc.], ar(lower)alkanoyl [e.g. phenylacetyl, tolylacetyl, naphthylacetyl, 2-phenylpropionyl, 3-phenylpropionyl, 4-phenylbutyryl, tritylcarbonyl, etc.], optionally substituted heterocyclic(lower)alkanoyl [e.g. morpholinoacetyl, thiomorpholinoacetyl, morpholinopropionyl, thiomorpholinopropionyl, piperidinopropionyl, piperazinylpropionyl, pyridylacetyl, pyrrolidinylpropionyl

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