Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-08-02
2004-11-02
Chang, Celia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S318000, C546S187000, C546S188000, C546S193000
Reexamination Certificate
active
06812235
ABSTRACT:
TECHNICAL FIELD
The present invention relates to &bgr;-alanine derivatives and their use as receptor antagonists. More particularly, it relates to 2-acylamino-&bgr;-alanine derivatives and a pharmaceutically acceptable salt thereof and their use as fibrinogen receptor antagonists.
BACKGROUND ART
European Patent Application No. 512,831 A1 discloses fibrinogen receptor antagonists. European Patent Application No. 445,796 A2 discloses inhibitors of blood platelets aggregation. International Patent Publication Nos. WO95/08536, WO96/29309 and WO97/33869 disclose N-(3-piperidylcarbonyl)-&bgr;-alanine derivatives as platelet-activating factor (PAF) antagonists.
DISCLOSURE OF INVENTION
The present invention relates to &bgr;-alanine derivatives and their use as fibrinogen receptor antagonists.
The &bgr;-alanine derivatives of the present invention can be represented by the following formula (I):
wherein
R
1
is hydrogen atom or an amino protective group;
A is a lower allylene group or a lower alkenylene group;
R
2
is hydrogen atom or an amino group which may be substituted with an acyl group selected from the group consisting of
a lower alkanoyl group which may be substituted with amino, lower alkanoylamino, ar(lower)alkoxycarbonylamino, aryl, aroylamino, carboxy, lower alkoxycarbonylamino, ar(lower)alkoxy, lower alkoxycarbonyl, lower alkanoyloxy, lower alkoxy or hydroxy group, among which the aryl and aroylamino may further be substituted with carboxy, lower alkoxy or lower alkoxycarbonyl,
a lower alkoxycarbonyl group which may be substituted with lower alkoxy, aryl or cyclo(lower)alkyl,
a lower alkenyloxylcarbonyl group,
a di(lower)alkylaminosulfonyl group,
a cycloalkanoyl group which may be substituted with lower alkoxy,
an aroyl group which may be substituted with (C
3
-C
6
) alkoxy, carbamoyl(lower)alkoxy, N-(lower)alkylcarbamoyl(lower)alkoxy, N,N-di(lower))alkylcarbamoyl(lower)alkoxy, lower alkoxycarbonyl, nitro, cyano, carboxy, carboxy(lower)alkoxy, ar(lower)alkoxy, lower alkoxycarbonyl(lower)alkoxy, cyclo(lower)alkoxy, lower alkoxycarbonylamino, cyclo(lower)alkyl(lower)alkoxy, lower alkanoylamino or lower alkylcarbamoyl,
an aryloxycarbonyl group,
a heterocyclylcarbonyl group,
a protected carboxycarbonyl group and
a heterocyclyloxycarbonyl group;
R
3
is hydrogen atom or an aryl or aralkyl group which may be substituted with one or more of hydroxy and/or lower alkoxy; a moiety represented by the formula:
is a bivalent N-containing 6- to 8-membered heterocyclic group;
provided that
(1) when R
2
is hydrogen atom, then the moiety of
is a bivalent N-containing 7- or 8-membered heterocyclic group and A, R
1
and R
3
are as defined above, or R
3
is hydroxy- or isobutoxy-substituted phenyl group and A, R
1
and the moiety of
are as defined above,
(2) when R
2
is unsubstituted amino group, then the amino protective group for R
1
is a lower alkoxycarbonyl group and A, R
3
and the moiety of
are as defined above, or A is a lower alkenylene group and R
1
, R
3
and the moiety of
are as defined above,
(3) when R
2
is amino group substituted with an actyl group, then the moiety of
is a bivalent N-containing 7-membered heterocyclic group and A, R
1
and R
3
are as defined above, and
(4) when R
2
is an amino group substituted with a cycloalkanoyl group which may be substituted with lower alkoxy, then R
1
is hydrogen atom and A, R
3
and the moiety of
are as defined above.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope are explained in detail in the following.
The term “lower” is intended to mean a group having 1 to 7 carbon atom(s), unless otherwise indicated.
Suitable lower alkyl moieties in the terms of the lower alkanoyl, lower alkanoylamino, ar(lower)alkoxycarbonylamino, lower alkoxycarbonylanino, ar(lower)alkoxy, lower alkoxycarbonyl, lower alkanoyloxy, lower alkoxy, di(lower)alkylaminosulfonyl, carbamoyl(lower)alkoxy, N-(lower)alkylcarbamoyl(lower)alkoxy, N,N-di(lower)alkylcarbamoyl(lower)alkoxy, carboxy(lower)alkoxy, lower alkoxycarbonyl(lower)alkoxy, cyclo(lower)alkyl(lower)alkoxy and lower alkylcarbamoyl groups may be straight or branched ones having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl or the like, more suitably the ones having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.
Suitable examples of the lower alkenyl moieties in the term of lower alkenyloxylcarbonyl groups include straight or branched ones having 2 to 6 carbon atoms, such as vinyl, propenyl (i.e., allyl or 1-propenyl), butenyl, isobutenyl, pentenyl or hexenyl.
Suitable cycloalkyl moieties in the term of cyclo(lower)alkyl, cycloalkanoyl, cyclo(lower)alkoxy and cyclo(lower)alkyl(lower)alkoxy groups include the ones having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
Suitable aryl groups and aryl moieties in the terms of the ar(lower)alkoxycarbonylamino, aroylamino, aroyl, ar(lower)alkoxy, aryloxycarbonyl and aralkyl groups may be aromatic hydrocarbon residues having 6 to 12 carbon atoms. Suitable examples are phenyl and naphthyl.
Suitable heterocyclic groups in the term of the heterocyclylcarbonyl and heterocyclyloxycarbonyl groups may include mono- or poly-cyclic groups containing at least one hetero atom selected from nitrogen, sulfur and oxygen atoms, such as
(1) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl or 2H-1,2,3-triazolyl], tetrazolyl [e.g., 1H-tetrazolyl or 2H-tetrazolyl] or the like.;
(2) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing an oxygen atom, for example, furyl, pyranyl or the like;
(3) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms, for example, thienyl, thiopyranyl or the like;
(4) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or 1,2,5-oxadiazolyl] or the like;
(5) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl or 1,2,5-thiadiazolyl] or the like;
(6) unsaturated condensed heterocyclic groups containing 1 to 2 nitrogen atoms, for example, indolyl, indazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, benzimidazolyl or the like;
(7) unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms, for example, benzofuryl, benzopyranyl or the like;
(8) unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms, for example, benzo[b]thienyl or the like;
(9) unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, phenoxazinyl or the like;
(10) unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, benzothiazolyl, benzoisothiazolyl, phenothiazinyl or the like.
Suitable amino protective groups may include conventional amino protecting groups such as lower alkanoyls (e.g., acetyl or propionyl) and aroyls (e.g., benzoyl or naphthoyl) as explained below, ar(lower)alkyls which may have 1 to 3 suitable substituents (e.g., benzyl, 4-nitorobenzyl, phenethyl, 1-phenethyl, benzhydryl or trityl), lower alkoxy carbonyls (e.g., tert-butoxycarbonyl), ar(lower)alkoxy carbonyls (e.g., benzyloxycarbonyl or fluore
Aoki Toshiaki
Harada Kayoko
Kuroda Satoru
Minagawa Masatoshi
Nakamura Hideko
Chang Celia
Fujisawa Pharmaceutical Co. Ltd.
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