Spiro imidazoline compounds

Details Spiro imidazoline compounds Spiro imidazoline compounds

1999-12-17

2001-01-09

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...

C514S400000, C548S301100

Reexamination Certificate

active

06172097

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new Spiro imidazoline compounds, and to their use as &agr;2-adrenergic antagonists and monoamine reuptake blockers.
DESCRIPTION OF THE PRIOR ART AND BACKGROUND OF THE INVENTION
The adrenergic nervous system plays an important role at a number of levels, for example at arterial, venous, cardiac and renal level, and at the level of the central and peripheral autonomic nervous systems. Compounds capable of interacting with adrenergic receptors can thus induce a large number of physiological responses, such as vasoconstriction, vasodilation, an increase or decrease in cardiac rhythm, variation in the strength of contraction of the cardiac muscle and variation in metabolic activities. Various adrenergic compounds have been used in the past to modify these or other physiological responses.
Spiro imidazoline compounds for use as &agr;1- or &agr;2-adrenergic agonists or partial agonists are found in the prior art (EP 635 495, EP 635 496, EP 635 497).
In addition to the fact that the compounds described in the present invention are new, they have an &agr;2-adrenergic antagonist and monoamine reuptake-blocking profile, rendering them of use in the treatment of depression (Drug News & Perspectives, 4 (4), 1991). The main problem posed by antidepressants is that they take a long time to become effective, associated with their particular manner of action. Studies have demonstrated that the association of an &agr;2-adrenergic antagonist with an inhibitor of monoamine (serotonin and/or noradrenaline) reuptake made it possible to reduce that length of time (Commun. Psychopharmacol, 4, pp. 95-100, 1980). The combination of those two effects in a single compound could give rise to a new generation of much more effective antidepressants. Among those compounds, napamezole (U.S. Pat. No. 5,017,584) is described as having both an &agr;2-adrenergic antagonist activity and a monoamine reuptake-blocking activity.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention, which have a new structure, have a selective &agr;2-adrenergic antagonist profile and at the same time the ability to inhibit monoamine reuptake.
The present invention relates more especially to compounds of formula (I):
wherein:
A represents a benzene ring unsubstituted or substituted by from 1 to 4 identical or different groups selected from linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, hydroxy, polyhalo-(C
1
-C
6
)alkyl in which the alkyl moiety is linear or branched, cyano, nitro, amino, alkylamino, dialkylamino, thioalkyl, sulphonylalkyl, sulphinylalkyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, formyl, carbamoyl, carboxamide, phenyl, benzyl, and halogen atoms,
B represents an imidazoline ring as represented in formulae (Ia) and (Ib):
wherein R represents a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group, or a benzyl group,
it being understood that “alkyl” is understood to mean a linear or branched (C
1
-C
6
)alkyl group,
their tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The preferred compounds of the invention are those wherein R represents a hydrogen atom.
Advantageously the invention relates to compounds of formula (I) wherein B represents a ring of formula (Ia).
Preferably, the invention relates to compounds of formula (I) wherein A is unsubstituted.
When the ring A is substituted by from 1 to 4 identical or different groups, the preferred substituents are linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, hydroxy, polyhalo-(C
1
-C
6
)alkyl in which the alkyl moiety is linear or branched, and halogen atoms.
Very advantageously, the invention relates to compounds of formula (I) having a trans ring junction.
More especially still, the invention relates to spiro[(1,3-diazacyclopent-1-ene)-5:2′-(trans-1′,2′,3′,4′,4′a,9′,9′a,10′-octahydroanthracene)] and, preferably, to the mixture composed of spiro[(1,3-diazacyclopent-1-ene)-5:2′(S)-(trans-1′,2′,3′,4′,4′a(R),9′,9′a(S),10′-octahydroanthracene)] and its enantiomer, and to the mixture composed of spiro[(1,3-diazacyclopent-1-ene)-5:2′(S)-(trans-1′,2′,3′,4′,4′a(S),9′,9′a(R),10′-octahydroanthracene)] and its enantiomer.
The tautomers, enantiomers and diastereoisomers and addition salts with a pharmaceutically acceptable acid or base of the preferred compounds of the invention form an integral part of the invention.
The invention relates also to a process for the preparation of compounds of formula (I) characterised in that there is used as starting material a compound of formula (II):
wherein A is as defined hereinbefore,
which is condensed with 1,4-cyclohexanedione mono-ethylene acetal enolate in order to obtain a compound of formula (III):
wherein A is as defined hereinbefore,
which is subjected to the action of methyl(triphenyl)phosphonium iodide to yield a compound of formula (IV):
wherein A is as defined hereinbefore,
which is cyclised in the presence of tributyltin hydride and AIBN to yield a compound of formula (V):
wherein A is as defined hereinbefore
which is subjected, in succession, to the action of an acidic medium followed by a Strecker reaction to obtain a compound of formula (VI):
wherein A is as defined hereinbefore,
which is subjected to the action of a reducing agent, such as LiAIH
4
for example, to yield a compound of formula (VII):
wherein A is as defined hereinbefore
which is reacted with formamidine acetate to obtain a compound of formula (I/a), a particular case of the compounds of formula (I):
wherein A is as defined hereinbefore and B′ represents an unsubstituted imidazoline ring as represented in formulae (Ia/a) and (Ib/a):
which may be subjected, in the presence of a base, to the action of a compound of formula (VIII):
R′-J  (VIII)
wherein R′ represents a linear or branched (C
1
-C
6
)alkyl group or a benzyl group and J represents a leaving group, such as a halogen atom or a tosyl group, to yield a compound formula (I/b), a particular case of the compounds of formula (I):
wherein A is as defined hereinbefore and B″ represents a substituted imidazoline ring as represented in formulae (Ia/b) and (Ib/b):
wherein R′ is as defined hereinbefore,
which compounds of formulae (I/a) and (I/b) constitute the totality of the compounds of formula (I) and may be purified according to a conventional separation technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base, and are separated, where appropriate, into their isomers according to a conventional separation technique.
The compounds of the invention and pharmaceutical compositions containing them have proved to be of use in the treatment of depression.
In fact, the compounds of the present invention are specific &agr;2-adrenergic antagonists and also act as powerful inhibitors of serotonin and/or noradrenaline reuptake.
As such, they can be used therapeutically in the treatment of depression, obesity, panic attacks, anxiety, obsessive-compulsive disorders, cognitive disorders, phobias, impulsive disorders associated with the abuse of drugs and withdrawal therefrom, sexual dysfunctions and Parkinson's disease.
The present invention relates also to pharmaceu

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