Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-11-16
2001-10-09
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S558000, C548S559000, C548S452000, C514S412000
Reexamination Certificate
active
06300366
ABSTRACT:
DESCRIPTION OF THE PRIOR ART
Compounds having a 2-aminopyrroline structure have been described for their anti-diarrhoal (EP 0155653) or antiparasitic (DE 2029297) properties.
BACKGROUND OF THE INVENTION
The compounds of the present invention have a novel structure which is characterised by the presence of a cyclopropyl group associated with the aminopyrroline ring. That structure gives them valuable pharmacological properties. In particular, tests have shown them to be capable of inducing a fall in arterial pressure, in cardiac frequency, as well as in disorders of cardiac rhythm. Accordingly, the compounds of the invention are used in the treatment of cardiovascular diseases, especially arterial hypertension, arrhythmia and associated disorders.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds of formula (I):
in which:
n is 1 or 2,
X represents an alkylene, alkenylene or alkynylene group, or an optionally substituted arylene group, or an optionally substituted heteroarylene group,
R
10
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group and R
11
, and R
12
together form a bond, or alternatively R
12
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group and R
10
and R
11
together form a bond,
R
2
, R
3
and R
4
each independently of the others represents; a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group, a linear or branched (C
1
-C
6
)hydroxyalkyl group, a linear or branched (C
1
-C
6
)alkoxy group, a linear or branched (C
1
-C
6
)alkoxycarbonyl group, an optionally substituted aryl group, an optionally substituted arylalkyl group in which the alkyl moiety is linear or branched and has from 1 to 6 carbon atoms, or an optionally substituted aryloxyalkyl group in which the alkyl moiety is linear or branched and has from 1 to 6 carbon atoms, or alternatively two of R
2
, R
3
and R
4
, with the carbon atoms carrying them, form a (C
5
-C
7
)cycloalkyl group,
wherein:
the term alkylene denotes a linear or branched divalent group containing from 1 to 6 carbon atoms,
the term alkenylene denotes a linear or branched divalent group containing from 2 to 6 carbon atoms and from 1 to 3 double bonds,
the term alkynylene denotes a linear or branched divalent group containing from 2 to 6 carbon atoms and from 1 to 3 triple bonds,
the term aryl represents a phenyl or naphthyl group, and the term arylene represents a divalent group of the same type,
the term heteroaryl denotes a mono- or bi-cyclic unsaturated or partially unsaturated group having from 4 to 11 ring members and from 1 to 5 hetero atoms selected from nitrogen, oxygen and sulphur, and the term heteroarylene represents a divalent group of the same type,
the term substituted associated with the expressions cryl, arylene, arylalkyl, aryloxyalkyl, heteroaryl and heteroarylene means that the groups in question are substituted in the aromatic moiety by one or more groups selected from halogen atoms or linear or branched (C
1
-C
6
)alkyl groups, linear or branched (C
1
-C
6
)alkoxy groups, hydroxy groups, cyano groups, nitro groups or amino groups (optionally substituted by one or two linear or branched (C
1
-C
6
)alkyl groups),
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
An advantageous aspect of the invention relates to compounds in which X represents an optionally substituted arylene group or an optionally substituted heteroarylene group. Of those compounds, very special preference will be given to those in which X represents an optionally substituted arylene group, for example a phenylene group.
Another advantageous aspect of the invention relates to compounds in which X represents an alkylene, alkenylene or alkynylene group, more especially an alkylene group.
Preferred compounds of the invention are those in which R
11
and R
12
together form a bond, R
10
preferably being a hydrogen atom.
Other preferred compounds of the invention are those in which each of R
2
, R
3
and R
4
represents a hydrogen atom.
An especially advantageous aspect of the invention relates to compounds of formula (I) in which X represents an alkylene group or an optionally substituted arylene group, R
10
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group, R
11
and R
12
together form a bond, and R
2
, R
3
and R
4
each independently of the others represents a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group, a linear or branched (C
1
-C
6
)-hydroxyalkyl group, a linear or branched (C
1
-C
6
)alkoxycarbonyl group, a linear or branched (C
1
-C
6
)alkoxy group, an optionally substituted aryl group, or an optionally substituted aryloxyalkyl group in which the alkyl moiety is linear or branched and has from 1 to 6 carbon atoms.
The preferred arylene group of the invention is the phenylene group.
Of the preferred compounds of the invention, special mention may be made of:
N-(2-cyclopropylphenyl)-3,4-dihydro-2H-pyrrol-5-amine, and addition salts thereof with a pharmaceutically acceptable acid,
N-(dicyclopropymethyl)-3,4-dihydro-2H-pyrrol-5-amine, and addition salts thereof with a pharmaceutically acceptable acid,
N-(2-Cyclopropylphenyl)-2-methyl-3,4-dihydro-2H-pyrrol-5-amine, and addition salts thereof with a pharmaceutically acceptable acid.
The invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that there is used as starting material a compound of formula (II):
in which R
2
, R
3
and R
4
are as defined in formula (I), R′
12
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group, and A represents an oxygen atom or a sulphur atom,
which is reacted:
either with an aromatic amine of formula (III):
in which n is as defined in formula (I), X
a
represents an arylene or heteroarylene group, and R′
10
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group,
to yield a compound of formula (I/a):
a particular case of the compounds of formula (I) in which R
2
, R
3
, R
4
and n are as defined above, X
a
represents an arylene or heteroarylene group, and R
10
, R
11
and R
12
are as defined in formula (I),
or with a methylating agent, such as, for example dimethyl sulphate or methyl iodide, to yield, after treatment in a basic medium, an intermediate which is treated directly in an alcoholic medium with an amine hydrochloride (IV):
in which R
1
and n are as defined in formula (I), X
b
represents an alkylene, alkenylene or alkynylene group, and R′
10
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group,
to yield a compound of formula (I/b):
a particular case of the compounds of formula (I) in which R
1
, R
2
, R
3
, R
4
and n are as defined above and X
b
represents an alkylene, alkenylene or alkynylene group,
which compounds (I/a) and (I/b) form the totality of the compounds of formula (I), and:
which may, where appropriate, be purified according to a conventional purification technique,
which are separated, where appropriate, into their stereoisomers according to a conventional separation technique,
which are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.
Of the pharmaceutical compositions according to the invention, special mention may be made of those which are suitable for oral, parenteral and nasal administration, tablets, dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, etc.
The dosage used varies according to the age and weight of the patient, the nature and severity of the disorder, and the route of administration, which may be oral, nasal, rectal or parenteral. In general, the unit dose ranges from 0.1 to 500 ml for a treatment in from 1 to 3 doses per 24 hours.
RE
Bousquet Pascal
Bruban Véronique
Ehrhardt Jean-Daniel
Feldman Josiane
Pfeiffer Bruno
Adir et Compagnie
Ramsuer Robert W.
Saeed Kamal
Sage G. Patrick
The Firm of Hueschen and Sage
LandOfFree
Aminopyrroline compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Aminopyrroline compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Aminopyrroline compounds will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2609458