Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-31
2001-08-14
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S468000, C514S183000, C514S211100, C514S224200, C549S049000, C549S057000, C549S467000, C540S468000, C540S552000, C544S048000
Reexamination Certificate
active
06274619
ABSTRACT:
TECHNICAL FILED
The present invention relates to novel compounds and pharmaceutically acceptable salts thereof.
More particularly, it relates to novel amidino derivatives and pharmaceutically acceptable salts thereof, which are useful as urokinase inhibitors, to processes for the preparation thereof, to a pharmaceutical composition comprising the same, to a use of the same as a medicament and to a method of the therapeutic treatment of diseases in a human being or an animal.
Accordingly, one object of the present invention is to provide novel amidino derivatives and pharmaceutically acceptable salts thereof, which are useful as urokinase inhibitors.
Another object of the present invention is to provide processes for the preparation of novel amidino derivatives and salts thereof.
A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said amidino derivatives and pharmaceutically acceptable salts thereof.
Urokinase (urokinase-type Plasminogen Activator, uPA) is a multi-domain serine protease which is able to convert the inactive precursor plasminogen to active plasmine.
Among the family of plasminogen activators, tissue type plasminogen activator (tPA) is present both in normal and in malignant tissue, whereas uPA has been shown to be produced abundantly by several common malignancies such as melanoma and colon, breast and prostate cancers.
Cellular invasiveness initiated by urokinase causes many physiological processes such as angiogenesis, neovascularization, bone restructuring, embryo implantaion in the uterus (embryonic development), infiltration of immune cells into inflammatory sites, ovulation, trophoblast implantation, breast, uterine, and prostatic involution, spermatogenesis, tissue remodeling during wound repair (wound healing) and organ differentiation, fibrosis, local invasion of tumors into adjacent areas (tumor invasion), metastatic spread of tumor cells from primary to secondary sites (tumor metastasis), and tissue destruction in arthritis.
Inhibitors of urokinase therefore have mechanism-based anti-angiogenic, anti-arthritic, anti-inflammatory, anti-invasive, anti-metastatic, anti-osteoporotic, anti-retinopathic (for angiogenesis-dependent retinopathies), contraceptive, and tumoristatic activities.
DISCLOSURE OF INVENTION
The object amidino derivatives are novel and can be represented by the following general formula:
in which
R
1
is hydrogen, optionally substituted lower alkylcarbamoyl(lower)alkylidene, lower alkylidene, lower alkyl, optionally substituted ar(lower)alkyl, cyclo(lower)alkyl(lower)alkyl, protected carboxy(lower)alkyl, carboxy(lower)alkyl, hydroxy(lower)alkyl, optionally substituted lower alkylcarbamoyl(lower)alkyl, lower alkylthio(lower)alkyl, carboxy(lower)alkanoyl, protected carboxy(lower)alkanoyl, aroyl, lower alkanoyl, or optionally substituted arylcarbamoyl(lower)alkyl,
R
2
is hydrogen, carboxy, protected carboxy, formyl or N-(lower) alkyl-N-(lower) alkoxycarbamoyl,
R
3
is hydrogen or amidino-protective group,
A is lower alkylene or carbonyl,
X is
Y is lower alkylene, —S— or —SO
2
—,
Z is —S— or —O—, and
the line:
is a single bond or double bond,
or pharmaceutically acceptable salts thereof.
Suitable salts of the object compound (I) are pharmaceutically acceptable, conventional non-toxic salts and may include;
a salt with a base such as an inorganic base salt, for example, an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt, for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.);
a salt with an acid such as inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, etc.);
a salt with a basic or acidic amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.); and the like.
The object compound (I) and pharmaceutically acceptable salt thereof may include a solvate [e.g. enclosure compound (e.g., hydrate, etc.)].
It is to be noted that the compound (I) and the other compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixture thereof are included within the scope of this invention.
According to the present invention, the object compound (I) or pharmaceutically acceptable salts thereof can be prepared by the processes as illustrated by the following reaction schemes.
in which
R
1
, R
2
, R
3
, A, X, Y, Z and the line:
are each as defined above,
R
a
1
is optionally substituted lower alkylcarbamoyl(lower)alkylidene or lower alkylidene,
R
b
1
is optionally substituted lower alkylcarbamoyl(lower)alkyl or lower alkyl,
R
c
1
is protected carboxy(lower)alkyl or protected carboxy(lower)alkanoyl,
R
d
1
is carboxy(lower)alkyl or carboxy(lower)alkanoyl,
R
a
2
is protected carboxy,
R
b
2
is N-(lower)alkyl-N-(lower)alkoxycarbamoyl,
R
a
3
is amidino-protective group,
R
4
is ester residue,
X
a
is
The object compounds thus obtained can be converted to its salt by a conventional method.
The compound (II) used in the Process 1 may be new and can be prepared, for example, according to the following Preparations or by a conventional manner.
In the descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope thereof are explained in detail as follows.
The term “lower” is intended to mean 1 to 6 carbon atom(s), preferably 1 to 4 carbon atom(s), unless otherwise indicated.
Suitable “lower alkoxy” may include straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, and the like, and the most preferable example may be methoxy.
Suitable “lower alkyl” may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like, and the most preferable example may be ethyl and butyl for R
1
.
Suitable “ester residue” means a group substituted with the hydrogen atom in the “esterified carboxy” as mentioned below.
Suitable “optionally substituted arylcarbamoyl(lower)alkyl” means aforementioned lower alkyl substituted by arylcarbamoyl group such as phenylcarbamoyl, tolylcarbamoyl, xylylcarbamoyl, cumenylcarbamoyl, mesitylcarbamoyl, naphthylcarbamoyl, and the like, and said arylcarbamoyl group is optionally substituted by the group consisting of lower alkyl as mentioned above, lower alkoxy as mentioned above, and lower alkylenedioxy as mentioned below, in which more preferable example may be phenylcarbamoyl(lower)alkyl optionally substituted by lower alkylenedioxy, and the most preferable one may be 3,4-methylenedioxyphenylcarbamoylmethyl.
Suitable “halogen” may include fluorine, bromine, chlorine and iodine, in which more preferable example may be fluorine.
Suitable “cyclo(lower)alkyl(lower)alkyl” means aforementioned lower alkyl substituted by cyclo(lower)alkyl as mentioned below, in which the most preferable example may be cyclohexylmethyl.
Suitable “optionally substituted ar(lower)alkyl” means aforementioned lower alkyl substituted by aryl as mentioned below, in which said aryl group is optionally substituted by the group consisting of lower alkyl as mentioned above, lower alkoxy as mentioned above, and lower alkylenedioxy as mentioned below, wherein more preferable example may be C
6
-C
10
ar(lower)alkyl optionally substituted by one or two suitable substituents selected from the group consisting of lower alkoxy and lower alkylenedioxy, and the most preferable one may be benzyl, phenethyl, 3,4-dimethoxyphenethyl and 3,4-methylenedioxyphenethyl.
Suitable “lower alkylenedioxy” may include straight or branched one such as methylenedioxy, ethylenedioxy, trimethylenedioxy, tetramethylenedioxy, pe
Mizuno Hiroaki
Sakurai Minoru
Tanaka Akito
Fujisawa Pharmaceutical Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Rao Deepak R.
Shah Mukund J.
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