Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-03-12
1995-03-28
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 67, 546 68, C07D45712, A61K 3148
Patent
active
054017483
DESCRIPTION:
BRIEF SUMMARY
The invention relates to new 2,14-disubstituted ergolines, their production and use in pharmaceutical agents.
2-Substituted ergolines, which exhibit affinity for central dopamine receptors and have .alpha..sub.2 -receptor-blocking action, are known from EP-A-160 842. The new 2,14-disubstituted ergolines show a good or increased dopaminergic agonist activity and simultaneously an improvement of the metabolic stability and thus an increase of action.
The invention relates to compounds of formula I ##STR2## in which R.sup.2 is C.sub.1-4 alkyl, cycloalkyl-C.sub.1-2 alkyl, R.sup.3, R.sup.4 and R.sup.5 each mean hydrogen or C.sub.1-5 alkyl, substituted C.sub.1-7 alkyl as well as their acid addition salts or isomers.
The physiologically compatible acid addition salts are derived from the known inorganic and organic acids, such as, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, citric acid, maleic acid, fumaric acid, tartaric acid, i.a.
By alkyl is understood respectively a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, 2,2-dimethylpropyl, 2-methylbutyl, isopentyl, heptyl, isoheptyl.
If R.sup.6 means an alkenyl radical, the latter can be straight-chain or branched and contains preferably only one double bond, and the double bond cannot be adjacent to the nitrogen atom. As alkenyl radicals, for example, 2-propenyl, 1-methyl-2-propenyl, 2-butenyl, methallyl are suitable.
If R.sup.6 means a cycloalkyl-alkyl group, radicals with up to 5 carbon atoms, for example, cyclopropylmethyl, cyclopropylethyl and cyclobutylmethyl, are preferred.
As alkyl radicals R, methyl, ethyl, isopropyl, tert-butyl, ethyl-methyl-propyl are especially suitable. As substituents of the alkyl radicals, methoxy, acetoxy, halogen and especially fluorine are suitable.
The compounds of formula I can occur, if a chiral center is present, as diastereomers and as their mixtures. The isomers and mixtures of isomers are also encompassed by this invention.
The compounds of formula I as well as their acid addition salts are usable as pharmaceutical agents because of their agonistic affinity for central dopamine receptors.
The compounds are suitable because of their agonistic activity on central dopamine receptors especially for treatment of Parkinson's disease and hyperprolactinemia.
The dopaminergic agonistic effect is determined, for example, with the help of method, described by Horowski and Wachtel, of the registration of stereotypies by observation of behavior (Eur. J. Pharmacol. 36: 373-383, 1976):
Immediately after intraperitoneal test substance or vehicle administration, female Wistar rats (90-110 g) are placed individually in observation cages made from transparent acrylic glass (25.times.19.times.13.5 cm). At 30, 60, 120, 240, 360 and 480 minutes after pretreatment, the presence of behavior stereotypies (chewing, licking, gnawing) is registered by observation of the animals for 2 minutes (i.e., of 30th-32nd, 60th-62nd, 120th-122nd minutes, etc.). Animals which during the 2-minute observation period show continuous chewing, licking and gnawing movements (longer than 30 seconds) are considered stereotypic.
The number of animals per treatment group with behavior stereotypies is determined during the various observation times. The different treatment groups consist of n=8 animals each. Average effective dose (ED.sub.50) is determined with 95% range of confidence for the various observation times with the help of probit analysis. The results are represented in table 1.
The compounds according to the invention are introduced in a dose of 0,001 to 10 mg of active substance in a physiologically compatible vehicle. The use of the compounds according to the invention takes place in a dose of 0.00001 to 0.1 mg/kg/day, preferably 0.001 to 0.1 mg/kg/day analogously to the known agent bromocryptine.
TABLE 1 ______________________________________
Time behavior of the stereotypy-triggering activity of 2,14-
disubstituted ergolines
REFERENCES:
patent: 4731367 (1988-03-01), Sauer et al.
patent: 4847262 (1989-07-01), Sauer et al.
patent: 4863929 (1989-09-01), Sauer et al.
patent: 5037832 (1991-08-01), Brumby et al.
Loschmann Peter A.
Sauer Gerhard
Wachtel Helmut
Peabody John
Richter Johann
Schering Aktiengesellschaft
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