Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1990-12-21
1993-06-15
Bond, Robert T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544125, 546 67, 546 69, C07D45706, C07D45702, A61K 3148
Patent
active
052198626
DESCRIPTION:
BRIEF SUMMARY
The invention relates to ergolines substituted in 2-, 6- and 8beta-positions, their production and their use as pharmaceutical agents.
The ergoline derivatives substituted according to the invention have a long-chain hydrocarbon radical in 6-position, which increases the dopaminergic agonistic activity in comparison with the 6-methyl ergoline derivatives. At the same time, the metabolic stability of the compounds is maintained or is improved.
The invention relates to compounds of the formula I ##STR3## in which R.sup.2 means optionally substituted C.sub.1-7 alkyl, C.sub.2-7 alkenyl, CH.sub.2 --S--C.sub.1-4 alkyl or CH.sub.2 --O--C.sub.1-4 alkyl cycloalkyl-C.sub.1-2 -alkyl and ##STR4## or CO--NR.sup.3 --CO--NHR.sup.4 in which X stands for CN, OCH.sub.3, SCH.sub.3 or CONH.sub.2, R.sup.1 stands for hydrogen, halogen, methyl or methoxy, and R.sup.3 and R.sup.4 each mean C.sub.1-4 alkyl or (CH.sub.2).sub.n --N(CH.sub.3).sub.2, in which n=1-4 as well as their acid addition salts.
By alkyl is meant a straight-chain or branched alkyl radical such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, heyxl, heptyl, 2,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 1-ethylbutyl, isopentyl, isoheptyl i.a.
Alkyl radical R.sup.2 can be substituted especially in 1-position with a hydroxy, a C.sub.1-4 alkoxy or a C.sub.2-5 acyloxy group according to the formula C(OR')R"R'", in which R" and R'" each mean hydrogen or alkyl radicals with a maximum of 6 carbon atoms and R' is especially hydrogen or acetyl.
Aliphatic carboxylic acids such as, for example, acetic acid, propionic acid, butyric acid, caproic acid and trimethylacetic acid i.a. each are suitable as acyl groups.
If R.sup.2 or R.sup.6 mean an alkenyl radical, the latter preferably contains only one double bond, and the double bond in radical R.sup.6 cannot be adjacent to a nitrogen atom. For example, vinyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-butenyl, methallyl are suitable as alkenyl radicals.
If R.sup.6 means a cycloalkyl-alkyl group, there is meant, for example, cyclopropylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl.
The carboxylic acid anilide radical R.sup.8 can be substituted singly or doubly in o-, m- or p-position and by halogen is meant fluorine, chlorine, bromine or iodine.
Radicals R.sup.3 and R.sup.4 are preferably alternating.
Compounds are preferred which have in 2-position an optionally hydroxylated C.sub.1-4 alkyl or C.sub.2-4 alkenyl radical or a CH.sub.2 --O--CH.sub.3 or CH.sub.2 --S--CH.sub.3 group. C.sub.2-4 alkyls, C.sub.3-4 alkenyls or cycloalkylalkyls with up to 5 carbon atoms are to be considered as preferred embodiment for R.sup.6.
The compounds of formula 1 can occur as E or Z isomers or, if a chiral center is present in radical R.sup.2, as diastereomers and as their mixtures. The isomers and isomer mixtures are also included in this invention. 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.
The compounds of formula I as well as their acid addition salts especially exhibit centrally dopaminergic effectiveness and are therefore usable as pharmaceutical agents. The dopaminergic agonistic action was determined with the method of the automatic recording of stereotypes on rats described by Horowski (Arzneim. Forsch. 12, 2281-2286, 1978): immediately after intraperitoneal administration of the test substance or vehicle, male Wistar rats (90-120 g) are placed individually in restricted cages of acrylic glass. The number of contacts on a steel bowl with a central metal rod as a result of stereotypical chewing, licking and gnawing movements during 60 minutes is recorded by an electrodynamic recording system applied in front of the head of the animals. Mean values .+-.SEM of the number of contacts during 60 minutes for the various treatment groups are calculated, and t
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Krepelka, et al. Chem. Abstracts, vol. 88, 1978 Abstract 121501q.
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Grant and Hackh's Chemical Dictionary (McGraw-Hill Books, New York, 1987) p. 14.
Brumby Thomas
Loschmann Peter A.
Sauer Gerhard
Turner Jonathan
Wachtel Helmut
Bond Robert T.
Schering Aktiengesellschaft
Ward E. C.
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