Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-24
2002-02-12
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S431000, C514S450000, C514S510000, C540S594000, C540S595000, C549S009000, C549S355000, C564S237000
Reexamination Certificate
active
06346527
ABSTRACT:
TECHNICAL FIELD
This invention relates to new guanidine derivatives.
One object of this invention is to provide the new and useful guanidine derivatives and salts thereof which possess a strong inhibitory activity on Na
+
/H
+
exchange in cells.
Another object of this invention is to provide processes for preparation of the guanidine derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising said guanidine derivatives or a pharmaceutically acceptable salt thereof.
Still further object of this invention is to provide a use of said guanidine derivatives or a pharmaceutically acceptable salt thereof as a medicament for the treatment and/or prevention of cardiovascular diseases, cerebrovascular diseases, renal diseases, arteriosclerosis, shock and the like in human being and animals.
BACKGROUND ART
Some guanidine derivatives having pharmaceutical activities such as inhibitory activity on Na
+
/H
+
exchange in cells have been known as described in WO 98/55475.
DISCLOSURE OF INVENTION
The object guanidine derivatives of the present invention are novel and can be represented by the following general formula (I):
wherein
R
1
is hydrogen or halogen,
R
2
is hydroxy, acyl(lower)alkoxy, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, lower alkylthio(lower)alkyl, mono(or di or tri)halo(lower)alkyl, (ethoxycarbonyl)amino, sulfamoylamino, (dimethylsulfamoyl)amino, N,N-di(lower)alkylamino(lower)alkyl, hydroxyimino(lower)alkyl, lower alkoxyimino(lower)alkyl, acyl, lower alkylthio, cyano, acyl(lower)alkyl, acyl(lower)alkenyl, aryl which has one or more substituent(s) or a heterocyclic group which has one or more substituent(s), and
X is —CH
2
—, —S—, —SO
2
—, —O— or —NH—.
The object compound (I) of the present invention can be prepared by the following process.
Process (1)
wherein R
1
, R
2
and X are each as defined above.
The starting compound (II) can be prepared by the following processes or Preparations mentioned below, or similar manners thereto.
Process (A)
wherein
R
1
and R
2
are each as defined above,
R
3
is lower alkyl, and
R
4
is lower alkyl.
Salts of the object guanidine derivatives (I) are pharmaceutically acceptable, conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, 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; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, citrate, fumarate, isethionate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.).
In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.
The term “lower” is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.
Suitable “lower alkyl” and “lower alkyl” moiety in the terms “hydroxy(lower)alkyl”, “hydroxyimino(lower)alkyl”, “lower alkylthio”, etc. may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, and the like, preferably one having 1 to 4 carbon atom(s).
Suitable “lower alkenyl” and “lower alkenyl” moiety in the term “acyl(lower)alkenyl” may include vinyl, 1-(or 2-)propenyl, 1-(or 2- or 3-)butenyl, 1-(or 2- or 3- or 4-)pentenyl, 1-(or 2- or 3- or 4- or 5-)hexenyl, methylvinyl, ethylvinyl, 1-(or 2- or 3-)methyl-1-(or 2-)propenyl, 1-(or 2- or 3-)ethyl-1-(or 2-)propenyl, 1-(or 2- or 3- or 4-)methyl-1-(or 2- or 3-)butenyl, and the like, in which more preferable example may be C
2
-C
4
alkenyl.
Suitable “lower alkoxy” and “lower alkoxy” moiety in the terms “acyl(lower)alkoxy”, “lower alkoxy(lower)alkyl” and “lower alkoxyimino(lower)alkyl” may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like, in which the preferred one may be C
1
-C
4
alkoxy.
Suitable “halogen” may include fluorine, bromine, chlorine and iodine.
Mono(or di or tri)halo(lower)alkyl may include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 1 or 2-fluoroethyl, 1 or 2-bromoethyl, 1 or 2-chloroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl and the like, in which the preferred one is trifluoromethyl.
Suitable “aryl” may include phenyl, naphthyl and the like.
Suitable “acyl” and “acyl” moiety in the terms “acyl(lower)alkoxy”, “acylamino” and “acyl(lower)alkenyl” may include carboxy, carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.
Suitable example of said acyl may be illustrated as follows:
Carboxy; Carbamoyl; Thiocarbamoyl; Sulfamoyl;
Aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.);
lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.);
lower or higher alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.);
lower or higher alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl, etc.);
lower or higher alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl, etc.);
lower or higher alkoxysulfinyl (e.g., methoxysulfinyl, ethoxysulfinyl, etc.);
mono(or di or tri)halo(lower)alkylsulfonyl [e.g. fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, chloromethylsulfonyl, dichloromethylsulfonyl, trichloromethylsulfonyl, 1 or 2-fluoroethylsulfonyl, 1 or 2-chloroethylsulfonyl, etc.);
mono(or di or tri)halo(lower)alkylsulfinyl [e.g. fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, chloromethylsulfinyl, dichloromethylsulfinyl, trichloromethylsulfinyl, 1 or 2-fluoroethylsulfinyl, 1 or 2-chloroethylsulfinyl, etc.); or the like;
Aromatic acyl such as
aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.);
ar(lower)alkanoyl [e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl(lower)alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.]; ar(lower)alkenoyl [e.g., phenyl(lower)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.), naphthyl(lower)alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl, etc.), etc.];
ar(lower)alkoxycarbonyl [e.g., phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), etc.];
aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.);
aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.);
arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.);
arylsulfonyl (e.g., phenylsulfonyl, p-tolylsulfonyl, etc.);
arylsulfinyl (e.g., phenylsulfinyl, p-tolylsulfinyl, etc.); or the like;
Heterocyclic acyl such as
heterocycliccarbonyl;
heterocyclicsulfonyl;
heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl,
Akahane Atsushi
Inoue Yoshikazu
Minagawa Masatoshi
Takenaka Kohei
Fujisawa Pharmaceutical Co. Ltd.
Kifle Bruck
Liu Hong
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