Substituted phenylamidines

Details Substituted phenylamidines Substituted phenylamidines

1999-07-14

2001-06-05

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S318000, C514S326000, C514S328000, C546S194000, C546S209000, C546S210000, C546S220000, C546S221000, C546S231000, C546S233000

Reexamination Certificate

active

06242466

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to novel substituted phenylamidines, their use as pharmaceutical agents, especially as antithrombotic agents, and methods for their synthesis.
BACKGROUND OF THE INVENTION
WO 96/33970 generically discloses phenylamidines of general formula
wherein inter alia R
1
denotes a C
1-4
-alkyloxycarbonyl group, an aryl-C
1-3
-alkyloxycarbonyl group or a group of formula
wherein
R
a
denotes a hydrogen atom or an alkyl group and R
b
denotes an alkyl group or a 3- to 7-membered cycloalkyl group.
DESCRIPTION OF THE INVENTION
It has now been found that the phenylamidines of general formula
wherein
R
6
denotes a C
1-18
-alkyloxycarbonyl or phenyl-C
1-4
-alkyloxycarbonyl group,
R
7
denotes a hydrogen atom, a C
1-8
-alkyl, C
4-7
-cycloalkyl, phenyl-C
1-4
-alkyl or R
8
—CO—OCHR
9
-group wherein
R
8
denotes a C
1-4
-alkyl, C
1-4
-alkoxy, C
3-7
-cycloalkyl or C
4-7
-cycloalkoxy group and
R
9
denotes a hydrogen atom or a C
1-4
-alkyl group,
the tautomers, stereoisomers and salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, have superior pharmacological properties, particularly as antithrombotic agents.
The present invention relates to the compounds of the above general formula I, the tautomers, stereoisomers and salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, their use and processes for preparing them.
Preferred compounds of the above general formula I are those wherein
the substituted amidino group is in the 4 position,
particularly those compounds wherein
R
6
denotes a C
1-18
-alkyloxycarbonyl or phenyl-C
1-4
-alkyloxycarbonyl group and
R
7
denotes a hydrogen atom, a C
1-8
-alkyl, C
5-7
-cycloalkyl or phenyl-C
1-4
-alkyl group,
the tautomers, stereoisomers and salts thereof.
Particularly preferred compounds of the above general formula I are those wherein
R
6
denotes a C
1-12
-alkyloxycarbonyl or phenyl-C
1-2
-alkyloxycarbonyl group and
R
7
denotes a C
1-8
-alkyl or C
5-7
-cycloalkyl group,
the tautomers, stereoisomers and salts thereof.
Most particularly preferred compounds of the above general formula I are those wherein
R
6
denotes a C
5-12
-akloxycarbonyl or benzyloxycarbonyl group and
R
7
denotes a C
1-4
-alkyl or C
5-6
-cycloalkyl group,
the tautomers, stereoisomers and salts thereof.
The following are mentioned as examples of particularly preferred compounds:
(1) 4-[2-[[4-(octyloxycarbonylamidino)phenyl]amino-carbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperidine,
(2) 4-[2-[[4-(hexyloxycarbonylamidino)phenyl]amino-carbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperidine,
(3) 4-[2-[[4-(hexyloxycarbonylamidino)phenyl]amino-carbonyl]-ethyl]-1-[(methoxycarbonyl)methyl]-piperidine and
(4) 4-[2-[[4-(octyloxycarbonylamidino)phenyl]amino-carbonyl]-ethyl]-1-[(methoxycarbonyl)methyl]-piperidine
and the salts thereof.
According to the invention the new compounds of general formula I are obtained, for example, by the following method:
reacting a compound of general formula
wherein
R
6
is as hereinbefore defined, with a compound of general formula
wherein
R
7
is as hereinbefore defined, or a reactive derivative thereof and
optionally subsequently converting the group R
7
into a hydrogen atom.
Examples of reactive derivatives of a compound of general formula III include the acid chlorides, acid azides, mixed anhydrides with aliphatic or aromatic carboxylic acids or monocarbonates, imidazolides and esters thereof such as the alkyl, aryl and aralkyl esters, e.g. the methyl, ethyl, isopropyl, pentyl, phenyl, nitrophenyl or benzyl esters.
The reaction is expediently carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, dimethylsulphoxide, benzene, toluene, chlorobenzene, tetrahydrofuran, pyridine, pyridine/methylene chloride, pyridine/dimethylformamide, benzene/tetrahydrofuran or dioxane, optionally in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N′-dicyclohexylcarbodiimide, N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide, 2-(1H-benzotriazolyl)-1,1,3,3-tetramethyl-uronium salts, N,N′-carbonyldiimidazole, N,N′-thionyldiimidazole, 2-chloro-1-methylpyridinium iodide or triphenylphosphine/carbon tetrachloride, optionally in the presence of dimethylaminopyridine or 1-hydroxy-benzotriazole and/or a base such as triethylamine, N-ethyl-diisopropylamine, pyridine or N-methyl-morpholine, expediently at temperatures between −10 and 180° C., preferably at temperatures between 0 and 120° C.
The subsequent conversion of the group R
7
into a hydrogen atom is expediently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, water/ethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran or water/dioxane at temperatures between −10 and 120° C., e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.
Moreover, the compounds of general formula I obtained may optionally be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
Thus, for example, the cis/trans mixtures obtained may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (−)-menthol and an optically active acyl group in amides, for example, may be a (+)- or (−)-menthyloxycarbonyl.
Furthermore, the compounds of formula I obtained may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, f

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