Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-09-10
2002-05-07
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S307000, C514S308000, C514S316000, C514S318000, C514S326000, C514S330000, C546S140000, C546S146000, C546S187000, C546S189000, C546S192000, C546S193000, C546S194000, C546S208000
Reexamination Certificate
active
06384028
ABSTRACT:
TECHNICAL FIELD
The present invention relates to &bgr;-alanine derivative and a pharmaceutically acceptable salt thereof. More particularly, it relates to &bgr;-alanine derivative and a salt thereof which is glycoprotein IIb/IIIa antagonist, inhibitor of blood platelets aggregation and inhibitor of the binding of fibrinogen to blood platelets.
BACKGROUND ART
In European Patent Application No. 512,831 A1, there are disclosed fibrinogen receptor antagonists.
In European Patent Application No. 445,796 A2, there are disclosed inhibitor of blood platelets aggregation.
DISCLOSURE OF INVENTION
The present invention relates to &bgr;-alanine derivative and a salt thereof. More particularly, it relates to &bgr;-alanine derivative and a salt thereof which is glycoprotein IIb/IIIa antagonist and inhibitor of platelet aggregation, and useful as:
a drug for the prevention and/or the treatment of diseases caused by thrombus formation such as arterial thrombosis; arterial sclerosis; ischemic heart diseases [e.g. angina pectoris (e.g. stable angina pectoris, unstable angina pectoris including imminent infarction, etc.), myocardial infarction (e.g. acute myocardial infarction, etc.), coronary thrombosis, etc.]; ischemic brain diseases [e.g. cerebral infarction {e.g. cerebral thrombosis (e.g. acute cerebral thrombosis, etc.), cerebral embolism, etc.}, transient cerebral ischemia (e.g. transient ischemic attack, etc.), cerebrovascular spasm after cerebral hemorrhage (e.g. cerebrovascular spasm after subarachnoid hemorrhage, etc.), etc.]; pulmonary vascular diseases (e.g. pulmonary thrombosis, pulmonary embolism etc.); peripheral circulatory disorder [e.g. arteriosclerosis obliterans, thromboangiitis obliterans (i.e. Burger's disease), Raynaud's disease, complication of diabetes mellitus (e.g. diabetic angiopathy, diabetic neuropathy, etc.), phlebothrombosis (e.g. deep vein thrombosis, etc.), etc.] or the like;
a drug for the prevention and/or the treatment of restenosis and/or reocclusion such as restenosis and/or reocclusion after percutaneous transluminal coronary angioplasty (PTCA), restenosis and/or reocclusion after the administration of thrombolytic drug (e.g. tissue plasminogen activator (TPA), etc.) or the like;
a drug for the adjuvant therapy with thrombolytic drug (e.g. TPA, etc.) or anticoagulant (e.g. heparin, etc.);
a drug for the prevention and/or the treatment of the thrombus formation in case of vascular surgery, valve replacement, extracorporeal circulation [e.g. surgery (e.g. open heart surgery, pump-oxygenator, etc.) hemodialysis, etc.], transplantation, or the like;
a drug for the prevention and/or the treatment of disseminated intravascular coagulation (DIC), thrombotic thrombocytopenia, essential thrombocytosis, inflammation (e.g. nephritis, etc.), immune diseases, or the like;
a drug for inhibiting of metastasis; or the like.
The &bgr;-alanine derivative of the present invention is expected to be useful as an inhibitor of cell adhesion and so is expected to be useful as
a drug for the prevention and/or the treatment of disseminated intravascular coagulation (DIC), thrombotic thrombocytopenia, essential thrombocytosis, inflammation (e.g. nephritis, etc.), immune diseases, or the like;
a drug for inhibiting of metastasis; or the like.
The object &bgr;-alanine derivative of the present invention can be shown by the following formula (I):
wherein R
1
is piperidyl, piperidyl having amino protective group, tetrahydropyridyl, tetrahydropyridyl having amino protective group, azetidinyl, azetidinyl having amino protective group, tetrahydroisoquinolyl or tetrahydroisoquinolyl having amino protective group,
R
2
is carboxy or protected carboxy,
A
1
is lower alkylene, lower alkanyl-ylidene, lower alkenylene, cyclo(lower)alkylene or arylene,
A
2
is lower alkylene which may have one or more suitable substituent(s) or arylene,
is piperidinediyl or
tetrahydroisoquinolinediyl, and
m is an integer of 0 or 1,
with proviso that
when R
1
is piperidyl,
A
1
is lower alkylene, and
A
2
is lower alkylene which may have one or more suitable substituent(s) except 5 or 6-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), which may have one or more lower alkyl; ar(lower)alkoxy(lower)alkyl; hydroxy(lower)alkyl; lower alkoxy(lower)alkyl; cyclo(lower)alkyl; aroylamino(lower)alkyl; lower alkanoylamino(lower)alkyl which may have halogen; lower alkanoylamino having halogen; and aroylamino having halo(lower)alkyl;
then R
2
is pentyloxycarbonyl, isopentyloxycarbonyl, isohexyloxycarbonyl, phenethyloxycarbonyl, aryloxycarbonyl or indanyloxycarbonyl,
or a salt thereof.
The object compound (I) or a salt thereof can be prepared by the following processes.
wherein R
1
, R
2
, A
1
, A
2
,
and m are each as defined above,
R
a
1
is piperidyl having amino protective group, tetrahydropyridyl having amino protective group, azetidinyl having amino protective group or tetrahydroisoquinolyl having amino protective group,
R
b
1
is piperidyl, tetrahydropyridyl, azetidinyl or tetrahydroisoquinolyl,
R
a
2
is protected carboxy, and
is piperidyl or tetrahydroisoquinolyl.
The starting compound (IV) or a salt thereof is novel and can be prepared by the following schemes.
wherein R
1
, A
1
,
and m are each as defined above,
R
5
is protected carboxy, and
is piperidyl or tetrahydroisoquinolyl.
Among the starting compounds (II), (III), (V), (VI) and (VII), there are novel compounds. They can be prepared from the known compounds in a conventional manner in this field of the art or the similar manners to those disclosed in Preparations and/or Examples mentioned later in the present specification.
Suitable salts of the object compound (I) are pharmaceutically acceptable salts such as conventional non-toxic salts and include a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.] and an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.] an ammonium salt, an organic base salt [e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt dicyclohexylamine salt, N,N-dibenzylethylenediamine salt, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.], a salt with an amino acid [e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc.] and the like.
In the above and subsequent descriptions of this specification, suitable examples of the various definitions are explained in detail as follows:
The term “lower” is intended to mean 1 to 6 carbon atom(s), unless otherwise indicated.
The term “higher” is used to intend a group having 7 to 20 carbon atoms, unless otherwise provided.
The preferable number of the “one or more” in the term “one or more suitable substituent(s)” may be 1 to 3.
Suitable “lower alkyl” may be straight or branched ones such as methyl, ethyl, isopropyl, propyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl, isohexyl or the like.
Suitable “protected carboxy” may be carboxy protected by a conventional protecting group such as an esterified carboxy group, or the like, and concrete examples of the ester moiety in said esterified carboxy group may be the ones such as lower alkyl ester [e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, isopentyl ester, hexyl ester, isohexyl ester, 1-cyclopropylethyl ester, etc.] which may have suitable substituent(s), for example, lower alkanoyloxy(lower)alkyl ester [e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 1-acetoxyethyl ester, 1-propionyloxyethyl ester, pivaloyloxyethyl ester, 2-propionyloxyethyl ester, hexanoyloxymethyl ester, etc.], lower-a
Kato Masayuki
Ohkubo Mitsuru
Takahashi Fumie
Yamanaka Toshio
Coleman Brenda
Fujisawa Pharmaceutical Co. Ltd.
LandOfFree
N-acylpiperidinylcarbonylaminocarboxylic acids and their use... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with N-acylpiperidinylcarbonylaminocarboxylic acids and their use..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and N-acylpiperidinylcarbonylaminocarboxylic acids and their use... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2867274