Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1990-07-12
1993-04-13
Waddell, Frederick E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514288, 514872, A01N 4360, A01N 4342
Patent
active
052023257
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a new therapeutic use of ergoline derivatives having the formula I ##STR2## wherein n is 1 or 2, R.sub.1 represents a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group, R.sub.2 represents a hydrogen atom and R.sub.3 represents a hydrogen atom or a hydroxy group or R.sub.2 and R.sub.3 together represent a chemical bond, R.sub.4 represents a hydrogen atom or a phenyl or C.sub.1 -C.sub.4 alkyl group, R.sub.3 represents a C.sub.1 -C.sub.4 alkyl group or an allyl group and R.sub.6 represents a hydrogen or halogen atom; and the pharmaceutically acceptable salts thereof.
The compounds of the formula I and their preparation are described in EP-A-0197241 or can be prepared by techniques analogous to those described in EP-A-0197241. EP-A-0197241 shows the functional anti-dopaminergic activity of certain ergoline derivatives in normal mice. The compounds are said to have moderate to good anti-hypertensive activity and to be useful as anxiolytic and antipsychotic agents.
It has been found that the ergoline derivatives of the formula I may be unexpectedly used in the treatment of other diseases different from psychosis and anxiety. The compounds of formula (I) block the emetic response induced by cytotoxic agents such as cisplatin and also by radiation treatment. The compounds are therefore of use in the treatment of nausea and vomiting associated with cancer therapy.
Accordingly, the present invention provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating emesis. The pharmaceutical composition containing the compound of formula I or salt thereof as active agent can therefore be prepared by a process characterised in that the active agent, which has been prepared in a known way, is admixed with a pharmaceutically acceptable carrier and/or diluent and then transformed into a pharmaceutical preparation suitable for treating emesis.
The invention further provides: a pharmaceutically acceptable salt thereof; and patient in need of said treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
In formula (I), a C.sub.1 -C.sub.4 alkyl group may be a methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or t-butyl group. R.sub.1 is generally a hydrogen atom or a methyl or iso-propyl group, preferably a hydrogen atom or a methyl group.
R.sub.4 is preferably methyl or hydrogen. R.sub.5 may be methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, iso-butyl or allyl. Preferably R.sub.5 is methyl. When R.sub.6 is halogen, it may be fluorine, chlorine or bromine. Preferably R.sub.6 is chlorine or bromine or hydrogen.
The wavy lines ( ) in formula I indicate that the substituents in the 8- or 9-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, or in both, i.e. a mixture thereof such as a diasteroisomer. Preferably the substituent in the 8-position is in the .beta.-configuration and the substituent in 9-position is in the .alpha.-configuration.
Preferred ergoline derivatives for use in the present invention are identified in Table I.
TABLE I ______________________________________
Laboratory
Code Chemical Name Reference
______________________________________
FCE 23884
6-Methyl-9,10-didehydro-
EP-A-197241
8.beta.-(3,5-dioxo-piperazin-
Example 5
1-yl-methyl)-ergoline
(I: R.sub.1 = R.sub.4 = R.sub.6 = H, R.sub.5 = CH.sub.3
R.sub.2 + R.sub.3 = bond, n = 1)
FCE 23952
1,5-Dimethyl-8.beta.-(3,5-
EP-A-197241
dioxo-piperazin-1-yl-
Example 2
methyl)-ergoline
(I: R.sub.2 = R.sub.3 = R.sub.4 = R.sub.6 = H,
R.sub.1 = R.sub.5 = CH.sub.3, n = 1)
FCE 23710
6-Methyl-8.beta.-(3,5-dioxo-4-
EP-A-197241
methyl-piperazin-1-yl-
Example 3
methyl)-ergoline
(I: R.sub.1 = R.sub.2 = R.sub.3 = R.sub.6 = H,
R.sub.4 = R.sub.5 = CH.sub.3, n = 1)
FCE 23308
6-Methyl-8.beta.-(3,5-dioxo-
EP-A-197241
REFERENCES:
patent: 4853390 (1989-08-01), Hilsher
patent: 4950672 (1990-08-01), Haefliger
Goodman & Gilman "The Pharmacological Basis . . . " p. 259 (1985).
Brambilla Enzo
Buonamici Metilde
Pegrassi Lorenzo
Rossi Alessandro
Farmitalia Carlo Erba S r l.
Hook Gregory
Waddell Frederick E.
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