Antithrombotic phenylalkyl derivatives

Details Antithrombotic phenylalkyl derivatives Antithrombotic phenylalkyl derivatives

1999-12-09

2001-10-09

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S314000, C514S224200, C514S230500, C514S230800, C514S249000, C514S235200, C514S307000, C514S309000, C514S637000, C544S051000, C544S052000, C544S105000, C544S353000, C544S354000, C544S128000, C546S165000, C546S141000, C546S146000, C546S148000, C564S244000

Reexamination Certificate

active

06300342

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to phenylalkyl derivatives, their use as pharmaceuticals, especially as antithrombotic agents, and methods for preparing such compounds.
DESCRIPTION OF THE INVENTION
The present invention relates to phenylalkyl derivatives of general formula
the tautomers, the stereoisomers and mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acid or bases, which have valuable properties.
The compounds of the above general formula I, wherein R
b
denotes a hydrogen atom, a nitro or cyano group, are valuable intermediate products for producing the other compounds of general formula I, and the compounds of the above general formula I, wherein R
b
denotes one of the optionally substituted aminomethyl or amidino groups mentioned below, and the tautomers and stereoisomers thereof have valuable pharmacological properties, particularly a thrombin-inhibiting activity, the effect of prolonging the thrombin time and an inhibitory effect on thrombocyte aggregation.
Thus, the present application relates to the new compounds of the above general formula I and the preparation thereof, pharmaceutical compositions containing the pharmacologically active compounds and their use.
In the above general formula I
R
a
denotes a hydrogen atom, a carboxy, C
1-3
-alkoxycarbonyl, benzoyl, phenylsulphonyl, nitro, R
1
NR
2
, R
1
NR
2
—X— or (R
3
X)NR
1
— group wherein
R
1
denotes a hydrogen atom, a C
1-5
-alkyl group, which may be substituted by a phenyl, carboxy, C
1-4
-alkoxycarbonyl or aminocarbonyl group, whilst the amino group of the aminocarbonyl group may additionally be mono- or disubstituted by C
1-4
-alkyl, phenyl-C
1-3
-alkyl, phenyl, carboxy-C
1-3
-alkyl- or C
1-3
-alkoxycarbonyl-C
1-3
-alkyl groups and the substituents may be identical or different, or a straight-chained C
2-3
-alkyl group, which is terminally substituted by amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl)amino, C
1-4
-alkanoylamino, phenylamino, N-benzyloxycarbonyl-phenylamino, pyrrolidino, piperidino or morpholino group,
R
2
denotes a hydrogen atom, a C
1-3
-alkyl group optionally substituted by one or two phenyl groups or by a naphthyl group, or a phenyl group which may be substituted by a fluorine, chlorine or bromine atom or by a straight-chained C
2-3
-alkyl group, which is terminally substituted by an amino, C
1-3
-alkylamino, C
1-3
-alkanoylamino, di-(C
1-3
-alkyl)amino, pyrrolidino, piperidino or morpholino group,
R
1
and R
2
together with the nitrogen atom between them denote a pyrrolidino or piperidino group optionally substituted by a C
1-3
-alkyl, carboxy or C
1-3
-alkoxycarbonyl group, a pyrrolidino or piperidino group substituted by two C
1-3
-alkyl groups or a morpholino group,
R
3
denotes a straight-chained or branched C
1-7
-alkyl group, which may be substituted in the 1, 2 or 3 position by a phenyl group or in the 2 to 7 position by a fluorine, chlorine or bromine atom, by a carboxy or C
1-3
-alkoxycarbonyl group, a trifluoromethyl group, a phenyl, naphthyl or chromanyl group which may be substituted in each case by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C
1-3
-alkyl, C
1-3
-alkoxy, amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl)amino or aminocarbonyl group, whilst the abovementioned phenyl, naphthyl or chromanyl groups may additionally be substituted by one to three methyl groups, a phenyl or aminophenyl group substituted by two chlorine or bromine atoms, a thienyl group optionally substituted by a chlorine or bromine atom or by a methyl group, a C
3-8
-cycloalkyl, C
8-12
-bicycloalkanone, quinolyl, isoquinolyl or benzimidazolyl group or
R
1
and R
3
together denote an n-alkylene group with 3 to 5 carbon atoms, wherein an ethylene group linked to the SO
2
— or CO— group may be replaced by a 1,2-phenylene group, and
X denotes a carbonyl or sulphonyl group,
or R
a
may also denote a C
2-3
-alkanoyl group, which is substituted in the alkyl moiety by a carboxy-C
1-3
-alkyl or C
1-3
-alkoxycarbonyl-C
1-3
-alkyl group and a benzoyl, naphthoyl, phenylsulphonyl or naphthylsulphonyl group,
R
b
denotes an amidino group optionally substituted by a C
1-10
-alkoxycarbonyl or phenyl-C
1-3
-alkoxycarbonyl group, a cyano or aminomethyl group,
R
c
and R
d
, which may be identical or different, each denote a hydrogen, fluorine, chlorine, bromine or iodine atom, a methyl, methoxy, nitro, amino or aminocarbonyl group or an amino group optionally substituted by a straight-chained C
2-4
-alkanoyl group, wherein the alkanoyl moiety may be terminally substituted by a carboxy or C
1-3
-alkoxycarbonyl group,
A denotes an ethylene, ethenylene, n-propylene or n-butylene group optionally substituted by one or two C
1-3
-alkyl groups, whilst a methylene group of an ethylene or n-propylene group optionally substituted by one or two C
1-3
-alkyl groups, which is
(i) linked to the nitrogen atom, may be replaced by a carbonyl group, or
(ii) linked to the phenyl nucleus, may be replaced by an oxygen or sulphur atom, by a sulphinyl or sulphonyl group or by an imino group optionally substituted by a C
1-3
-alkyl group,
B denotes a bond, a methylene, ethylene, ethenylene or n-propylene group optionally substituted by one or two C
1-3
-alkyl groups, whilst
(iii) in the abovementioned methylene, ethylene or n-propylene groups, if Y denotes a carbonyl or thiocarbonyl group, a methylene group may be replaced by an oxygen atom or by an imino group optionally substituted by a C
1-3
-alkyl group, or
(iv) in the abovementioned ethylene or n-propylene groups, if Y denotes a methylene group, a methylene group in the 3 or 4 position relative to the nitrogen atom may be replaced by an oxygen atom or by an imino group optionally substituted by a C
1-3
-alkyl group,
W denotes a methine group or a nitrogen atom and
Y denotes a methylene, carbonyl or thiocarbonyl group.
Preferred compounds of the above general formula I however are those wherein
R
a
, R
c
, R
d
, A, B, W and Y are as hereinbefore defined and
R
b
denotes an amidino group optionally substituted by a C
1-10
-alkoxycarbonyl or phenyl-C
1-3
-alkoxycarbonyl group,
the optical antipodes and the salts thereof.
Particularly preferred compounds of the above general formula I however are those wherein
R
a
denotes an R
1
NR
2
, R
1
′NR
2
′—X or (R
3
X)NR
1
— group wherein
R
1
denotes a hydrogen atom, a C
1-4
-alkyl group, which may be substituted by a phenyl, carboxy, C
1-2
-alkoxycarbonyl or aminocarbonyl group, whilst the amino group of the aminocarbonyl group may additionally be mono or disubstituted by C
1-4
-alkyl, phenyl, benzyl, carboxy-C
1-2
-alklyl or C
1-2
-alkoxycarbonyl-C
1-2
-alkyl groups and the substituents may be identical or different, or an ethyl group, which is terminally substituted by an amino, acetylamino, morpholino, phenylamino or N-benzyloxycarbonyl-phenylamino group,
R
2
denotes a hydrogen atom, a C
1-3
-alky group optionally substituted by one or two phenyl groups or by a naphthyl group, a cyclohexyl group, or a phenyl group optionally substituted by a chlorine atom, by a 2-aminoethyl or 2-acetylamino group,
R
1
′ and R
2
′ have the meanings given hereinbefore for R
1
and R
2
or together with the nitrogen atom between them denote a pyrrolidino or piperidino group optionally substituted by a methyl, carboxy or C
1-2
-alkoxycarbonyl group, a pyrrolidino or piperidino group substituted by two methyl groups, or a morpholino group,
R
3
denotes a straight-chained or branched C
1-5
-alkyl group, which may be substituted in the 1, 2 or 3 position by a phenyl, carboxy or C
1-3
-alkoxycarbonyl group or in the 2 or 3 position by a chlorine atom, a trifluoromethyl group, a phenyl or naphthyl group, which may be substituted in each case by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C
1-3
-alkyl, C
1-3
-alkoxy, amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl)amino or aminocarbonyl group, whilst the abovementioned phenyl groups may additionally be substituted by one to three methyl groups, a phenyl or aminophenyl gro

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