Substituted tetrahydropyridin derivatives, method of...

Details Substituted tetrahydropyridin derivatives, method of... Substituted tetrahydropyridin derivatives, method of...

1999-06-04

2001-05-15

Fan, Jane (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S339000, C546S340000, C546S283700

Reexamination Certificate

active

06232319

ABSTRACT:

The present invention relates to new substituted tetrahydropyridine derivatives, to a process for preparing them and to pharmaceutical compositions containing them.
Many studies in the literature describe the synthesis of compounds derived from lobeline as alkaloids capable of interacting with nicotinic receptors. There may be mentioned especially Hootelé for the synthesis of sedinone and sedacrine (Hootelé C., Driessens F., Can. J. Chem., 1991, 69 (2), pp. 211-17) and Natsume for the synthesis of sedinine (Natsume M., Ogawa M., Hétérocyles [sic], 1985, 23 (4), pp. 831-4).
The compounds of the present invention are new and especially advantageous from a pharmacological standpoint for their specific interaction with nicotinic receptors, finding their application in the treatment of diseases associated with cerebral aging.
The aging of the population through an increase in life expectancy has given rise to a concomitant large increase in the incidence of neurodegenerative diseases associated with age, and in particular Alzheimer's disease. The main clinical manifestations of cerebral aging, and most particularly of neurodegenerative diseases, are the defects of mnestic and cognitive functions which can lead to dementia. It is widely demonstrated that, among the different neurotransmitters, acetylcholine has a preponderant place in memory functions, and that the cholinergic neuronal pathways are dramatically destroyed in certain neurodegenerative diseases or where there is a defect of activation during cerebral aging. Accordingly, numerous therapeutic approaches have been directed towards preventing destruction of the neuromediator via acetylcholinesterase or have sought to substitute themselves for the deficient neuromediator. In the latter case, the cholinergic agonists proposed have been of the muscarinic type, specific for the M1 postsynaptic receptors.
Recently, it has been shown that, in fact, the cholinergic impairment associated with Alzheimer's disease affected the neurons bearing the nicotinic receptors (N) more than those bearing the muscarinic receptors (Schroder et al., in “Alzheimer disease: therapeutic strategies”, ed. Birkhauser Boston, 1994, 181-185). Furthermore, numerous studies have shown that nicotine possesses memory-facilitating properties (Warburton, Prog. Neuropsychopharmacol, 1992, 16, 181-191) and that these properties exert their effect just as much on the mnestic functions (Levin and Torry, Psychopharmacol., 1996, 123, 88-97) as on the faculties of attention and of vigilance (Turchi et al., Psychopharmacol., 1995, 118, 195-205). Moreover, nicotine exerts neuroprotective effects with respect to excito-toxic agents such as glutamate (Akaike et al., Brain Res., 1994, 644, 181-187). These collective data are very probably to be linked to the epidemiological studies which have shown a lower incidence of Alzheimer's or Parkinson's disease among smokers.
Although the nicotinic receptors are not yet fully classified, it is nowadays well demonstrated that these receptors can be different in nature and, jointly, can have very diverse electrophysiological properties (for a review: Williams et al., Drug News Perspect., 1994, 7, 205-223). Accordingly, nicotine possesses both beneficial promnestic properties demonstrated in Alzheimer's patients (Wilson et al., 1995, 51, 509-514) and deleterious properties of habituation by activation of receptors having variable kinetics of inactivation.
Independently of nicotine itself, other nicotinic agonists have been described, including lobeline which possesses potent promnestic properties (Decker et al., Pharmacol. Biochem. Behav., 45, 571-576) but, contrary to nicotine, which binds preferentially to certain rapidly desensitizing receptor subtypes, designated &agr;7 (Marks et al., J. Pharmacol. Exp. Ther., 1986, 30, 427-436). Accordingly, lobeline is potentially without addictive potential.
The compounds of the present invention were hence synthesized as nicotinic ligands possessing promnestic properties for the treatment of memory defects associated with cerebral aging and with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Pick's disease, Korsakoff's disease and frontal and subcortical dementias.
More specifically, the present invention relates to the compounds of formula (I):
in which:
X represents a hydrogen atom,
Y represents a hydroxyl group,
or X and Y together form an oxo group,
R represents a linear or branched (C
1
-C
6
) alkyl group or a phenyl group optionally substituted with one or more halogen atoms or one or more linear or branched (C
1
-C
6
) alkyl, (C
1
-C
6
) alkoxy, linear or branched (C
1
-C
6
) polyhaloalkyl or hydroxyl groups,
R
1
represents a hydrogen atom or a group of formula (II):
in which:
X′ represents a hydrogen atom,
Y′ represents a hydroxyl group,
or X′ and Y′ simultaneously represent a linear or branched (C
1
-C
6
) alkoxy group,
or X′ and Y′ together form an oxo group or a linear or branched (C
1
-C
4
) alkylenedioxy group,
R
3
represents a linear or branched (C
1
-C
6
) alkoxy group or a phenyl group optionally substituted with one or more halogen atoms or one or more linear or branched (C
1
-C
6
) alkyl, (C
1
-C
6
) alkoxy, linear or branched (C
1
-C
6
) polyhaloalkyl or hydroxyl groups,
R
2
represents a hydrogen atom or a linear or branched (C
1
-C
6
) alkyl group optionally substituted with one or more, identical or different, optionally substituted aryl, linear or branched (C
1
-C
6
) alkoxy or hydroxyl groups,
on the understanding that, when R and R
2
simultaneously represent a methyl group, X represents a hydrogen atom,
Y represents a hydroxyl group and R
1
represents a group of formula (II) in which X′ represents a hydrogen atom and Y′ a hydroxyl group, then R
3
cannot represent a phenyl group,
their isomers as well as their addition salts with a pharmaceutically acceptable acid or base.
Optionally substituted aryl is understood to mean phenyl or naphthyl, each of these groups being optionally substituted with one or more halogen atoms or one or more linear or branched (C
1
-C
6
) alkyl, (C
1
-C
6
) alkoxy, linear or branched (C
1
-C
6
) polyhaloalkyl or hydroxyl groups.
Among pharmaceutically acceptable acids, there may be mentioned, without implied limitation, hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulfonic, camphoric, and the like, acids.
Among pharmaceutically acceptable bases, there may be mentioned, without implied limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, and the like.
The present invention relates preferentially to the compounds of formula (I) in which X represents a hydrogen atom and Y a hydroxyl group, and more especially the compounds of formula (I) in which X represents a hydrogen atom, Y a hydroxyl group and R
1
represents a hydrogen atom or a group of formula (II):
where X′, Y′ and R
3
are as defined above.
The invention also extends to the process for preparing the compounds of formula (I), wherein a compound of formula (III):
in which R
4
represents a linear or branched (C
1
-C
6
) alkyl or an aryl group, optionally substituted, is used as starting material,
which is reacted with sodium borohydride in the presence of sodium hydroxide to obtain the compound of formula (IV):
in which R
4
is as defined above,
which, subjected to the Reformatsky reagent BrZnCH
2
COOEt, yields the compound of formula (V):
in which R
4
has the same definition as above,
which is subjected successively to the action of dimethylthexylchlorosilane and then to that of lithium aluminum hydride to yield the compound of formula (VI):
in which R
4
is as defined above and Thex represents a (1,1,2)-trimethylpropyl group, which is subjected to Swern oxidation to yield the compound of formula (VII):
in which R
4
and Thex are defined as above,
which is subjected

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