Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-12-28
2000-05-09
Kight, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 68, 546 67, A61K 3148, C07D45702
Patent
active
060604832
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the treatment of neurodegenerative diseases employing ergoline derivatives, to new ergoline derivatives for such a treatment, to a process for preparing them and to their pharmaceutical acceptable salts.
The present invention relates to the therapeutic use, in the treatment of neurodegenerative diseases, of ergoline derivatives of formula I ##STR2## wherein R.sub.1 represents a hydrogen atom or a linear or branched C.sub.1 -C.sub.5 alkyl or C.sub.2 -C.sub.5 alkenyl group optionally substituted with a C.sub.3 -C.sub.7 cycloalkyl, a hydroxy group or a R.sub.3 - substituted phenyl group wherein R.sub.3 is a hydroxy or a hydroxymethyl group; alkyl or a C.sub.2 -C.sub.5 alkenyl group optionally substituted with a hydroxy group, a R.sub.3 -substituted phenyl group wherein R.sub.3 is as above defined, or with a C.sub.1 -C.sub.5 alkoxy group; the symbols--at positions 2,3 and 8, 9 independently denote a single or double chemical bond and Z represents a group (CH.sub.2).sub.n OH, wherein n is 0 or an integer from 1 to 3, or a group C(R.sub.4).sub.2 OH wherein R.sub.4 is a C.sub.1 -C.sub.5 alkyl or a phenyl group, or a pharmaceutically acceptable salt thereof.
The wavy line (.about..about.) in formula I indicates that the substituent in the 8- or 10-position may be either in the .alpha.-configuration, i.e. below the plane of the ring, or in the .beta.-configuration, i.e. above the plane of the ring.
In a further aspect of the present invention, there are provided novel ergoline derivatives of formula I as above defined, characterised in that the following compounds are excluded:
More preferably there are provided ergoline derivatives of formula I as above depicted, characterised in that Z is not a hydroxy, hydroxymethyl or hydroxyethyl group, when R.sub.1 is hydrogen, or a methyl group, R.sub.2 is hydrogen or a methyl, propyl, isopropyl group, --at 2, 3 position is a double bond and--at 8,9 position represents a single or a double bond.
In the present specification, the term C.sub.1 -C.sub.5 alkyl group includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl groups and the term C.sub.2 -C.sub.5 alkenyl group includes 2-propenyl, 1-butenyl, 1,1-dimethylallyl, 1-pentenyl, 2-pentenyl. The term C.sub.3 -C.sub.6 cycloalkyl group includes cyclopropyl, cyclopentyl and cyclohexyl groups.
The R.sub.3 substituent on the phenyl group in the meanings of R.sub.1 and R.sub.2 may be in orto, meta or para position.
Pharmaceutical acceptable salts, which may be used in the acid addition salt formation, include maleic, citric, tartaric, fumaric, methanesulphonic, acetic, benzoic, succinic, gluconic, glutamic, malic, mucoic, ascorbic as organic acids or hydrochloric, hydrobromic, sulphuric, or phosphoric as inorganic acids. Among the addition salts obtained by employing acids, hydrochloric, methanesulphonic, citric and tartaric are the most preferred.
In the present invention, R.sub.1 is preferably hydrogen atom, methyl, 2 hydroxyethyl or (2-hydroxy-2-phenyl)ethyl group; R.sub.2 is preferably hydrogen atom or methyl, 1-methylethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl group, Z is preferably a group (CH.sub.2).sub.n OH, or C(R.sub.4).sub.2 OH, n is preferably O, 1 or 2, R.sub.4 is preferably methyl or phenyl group.
Specific examples of the preferred compounds of the present invention are those listed hereinunder: (2-hydroxy-2-phenyl)ethyl-8.beta.-hydroxymethyl-10.alpha.-methoxy-ergoline 2,3-dihydro-6-methyl-8.beta.-(2-hydroxy)ethyl-10.alpha.-methoxy-ergoline, 2,3-dihydro-6-methyl-8.beta.-dimethylhydroxymethyl-10.alpha.-methoxy-ergol ine, 2,3-dihydro-6-methyl-8.beta.-dimethylhydroxymethyl-10.alpha.-hydroxy-ergol ine, 6-methyl-8.alpha.-diphenylhydroxymethyl-10.alpha.-methoxy-ergoline.
The invention provides also a process for preparing compounds of formula I of the present invention, depending on the nature of the substituents, starting from known ergolines by appropriate chemical modifications.
Processes for preparing compounds of formula I and pharmaceutically ac
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Yuzo, M. et al.: Inhibitory action of nicergoline and its major metabolites on acetylcholinesterase activity in rat and mouse brain. Adv. Behav. biol. 38B ( Basic clin. , Ther, Aspects Alzheimer's and parkinson's dis. ), vol. 2, pp. 415-419, 1990.
Brambilla Enzo
Carfagna Nicola
Mantegani Sergio
Varasi Mario
Aulakh Charanjit S.
Kight John
Pharmacia & Upjohn S.p.A.
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