Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-02-24
1999-11-09
Davis, Zinna Northington
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546192, 568309, C07D21170, C07D40104, C07D21152, A61K 31445
Patent
active
059817542
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel 4-substituted 1-phenylalkyl-1,2,3,6-tetrahydropyridines with a neurotrophic and neuroprotective activity, to a process for their preparation and to pharmaceutical compositions in which they are present.
EP-0 458 696 describes the use of a 1-(2-naphthylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine for the preparation of drugs for the treatment of cerebral and neuronal disorders.
WO 93/11107 describes piperidines and tetrahydropyridines with a protective activity on the damage caused by hypoxic/ischemic states.
It has now been found that certain phenylalkyl-1,2,3,6-tetrahydropyridines substituted by a phenyl or pyridyl group exert a neurotrophic action on the nervous system which is similar to the action of nerve growth factor (NGF), and can restore function to cells which are damaged or exhibit anomalies in their physiological functions.
According to one of its features, the present invention therefore relates to the compounds of formula (I): ##STR2## in which Y is --CH-- or --N--; (C.sub.1-C.sub.4)alkoxy group; -C.sub.4)alkyl or (C.sub.1 -C.sub.4)alkoxy group; -C.sub.7) carboxyalkyl, a (C.sub.1 -C.sub.4)alkoxycarbonyl(C.sub.3 -C.sub.6)alkyl, a (C.sub.3 -C.sub.7)carboxyalkoxy or a (C.sub.1 -C.sub.4)alkoxycarbonyl(C.sub.3 -C.sub.6)alkoxy; -C.sub.7)cycloalkoxy, (C.sub.3 -C.sub.7)cycloalkylmethyl, (C.sub.3 -C.sub.7)cycloalkylamino and cyclohexenyl, it being possible for said radical to be substituted by a halogen, hydroxyl, (C.sub.1 -C.sub.4)alkoxy, carboxyl, (C.sub.1 -C.sub.4)alkoxycarbonyl, amino or mono- or di-(C.sub.1 -C.sub.4)alkylamino; or -C.sub.3)alkylphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl and styryl, it being possible for said group to be monosubstituted or polysubstituted on the phenyl group by a halogen, CF.sub.3, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, cyano, amino, mono- or di-(C.sub.1 -C.sub.4)alkylamino, (C.sub.1 -C.sub.4)acylamino, carboxyl, (C.sub.1 -C.sub.4)alkoxycarbonyl, aminocarbonyl, mono- or di-(C.sub.1 -C.sub.4)alkylaminocarbonyl, amino(C.sub.1 -C.sub.4)alkyl, hydroxy(C.sub.1 -C.sub.4)alkyl or halogeno(C.sub.1 -C.sub.4)alkyl, the salts and solvates thereof and the quaternary ammonium salts thereof.
In the present description the term "(C.sub.1 -C.sub.3)alkyl" denotes methyl, ethyl, n-propyl and i-propyl groups.
The term "(C.sub.1 -C.sub.4)alkyl" denotes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl groups.
The term "(C.sub.3 -C.sub.6)alkyl" denotes a saturated or unsaturated hydrocarbon radical containing from 3 to 6 carbon atoms, such as, for example, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, t-pentyl, n-hexyl, i-hexyl etc.
The term "alkoxy" denotes a hydroxyl group substituted by an alkyl, alkenyl or alkynyl group.
If X is a phenyl group, the nomenclature used for the biphenyl radical conforms to the IUPAC rules, i.e. the numbering of the positions of the two rings is as follows: ##STR3## and the radicals having this structure are named as follows: ##STR4##
The compounds of formula (I) in which X is in the 4-position of the phenyl group, and the salts thereof, especially those which are pharmaceutically acceptable, the solvates thereof and the quaternary ammonium salts thereof, are particularly advantageous compounds.
One preferred group of compounds among those of formula (I) in which X is a group (c) is represented by the compounds in which the phenyl is substituted by 1 to 3 halogen, 1 to 3 CF.sub.3, 1 to 3 (C.sub.1 -C.sub.4)alkyl, 1 to 3 (C.sub.1 -C.sub.4)alkoxy, 1 to 3 cyano, 1 to 3 amino, 1 to 3 mono- or di-(C.sub.1 -C.sub.4)alkylamino, 1 to 3 (C.sub.1 -C.sub.4)acylamino, 1 to 3 carboxyl, 1 to 3 (C.sub.1 -C.sub.4)alkoxycarbonyl, 1 to 3 aminocarbonyl, 1 to 3 mono- or di-(C.sub.1 -C.sub.4)alkylaminocarbonyl, 1 to 3 amino(C.sub.1 -C.sub.4)alkyl, 1 to 3 hydroxy(C.sub.1 -C.sub.4)alkyl or 1 to 3 halogeno(C.sub.1 -C.sub.4)alkyl.
Another preferred group consists of the compounds of formula (I
REFERENCES:
Rehse et al., Arch. Pharm., vol. 312, 1979, pp. 670-681.
El-Shafie et al., Sci. Pharm., vol. 62, 1994, pp. 389-403.
Sato et al., Chem. Pharm. Bull., vol. 29, 1981, pp. 3134-3144.
Saari et al., J. Med. Chem., vol. 27, No. 9, 1984, pp. 1182-1185.
Suzuki et al., Synthetic Communications, vol. 11, No. 7, 1981, pp. 513-519.
Galda et al., Synthesis, vol. 5, 1996, pp. 614-620.
Huth et al., Tetrahedron, vol. 45, No. 21, 1989, pp. 6679-6682.
Siegmann et al., Organometallics, vol. 8, No. 11, 1989, pp. 2659-2664.
Badone Domenico
Baroni Marco
Cardamone Rosanna
Fournier Jacqueline
Guzzi Umberto
Davis Zinna Northington
Sanofi
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