Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-08-17
2000-07-11
Rotman, Alan L.
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, A61K 37437, C07D45700, C07D47104
Patent
active
06087371&
DESCRIPTION:
BRIEF SUMMARY
This application claims priority from British Patent Application No. 9603226.3, the contents of which are incorporated herein by reference.
This invention relates to new heterocyclic-ergoline derivatives, to a process for their preparation, to their use as medicaments and to a pharmaceutical composition containing them.
The novel compounds act upon the central nervous system by binding to 5-HT.sub.1A receptors and hence can be used for the management of central nervous system pathologies. The said compounds can be employed for the treatment of various disorders associated with serotoninergic disfunctions, such as impairment of thermoregulation, memory function, sleep disorders, satiety control (i.e. food and beverage consumption), drugs addiction, control of drug withdrawal, hypertension, hyperemesis, depression, anxiety, psychosis and ischemic insult.
More particularly, the present invention relates to compounds of formula I: ##STR2## wherein R.sub.1 is hydrogen atom or C.sub.1-4 alkyl group; R.sub.2 is hydrogen, chlorine, or bromine atom, methyl or C.sub.1-4 alkylthio group; n is 0, 1 or 2; three heteroatoms which are the same or different and which are selected from the group consisting of sulfur, oxygen and nitrogen atom and X is hydrogen, chlorine or bromine or fluorine atom, or a pharmaceutically acceptable acid addition salt thereof.
The invention also provides a pharmaceutical formulation comprising a compound of formula I or suitable pharmaceutically acceptable acid addition salts including salts with both organic and inorganic acids in combination with a pharmaceutically acceptable excipient.
In the present specification, the term C.sub.1-4 alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl and tertbutyl groups.
The aromatic 5-membered heterocyclic ring in particular contains one or more nitrogen atoms and up to one sulphur or one oxygen atom but not together.
Preferably, these 5-membered heterocyclic rings include oxadiazole, thiadiazole, triazole which are linked to the ergolinyl and pyridinyl residues through the carbon atoms as illustrated below: ##STR3##
Pharmaceutically acceptable acids, which may be used in the acid addition salt formation, include maleic, citric, tartaric, fumaric, methane sulphonic, acetic, benzoic, succinic, gluconic, lactic, malic, mucoic, glutammic, ascorbic as organic acids or hydrochloric, hydrobromic, sulphuric or phosphoric as inorganic acids.
Among the addition salts obtained by employing acids hydrochloric, sulphoric, methanesulphoric, citric and succinic salts are the most preferred.
The compounds of formula I may be prepared using as starting material an appropriate derivative of the carboxylic function at position 8 of the ergoline framework and a suitable 3-substituted pyridine via well-known reactions of heterocyclic chemistry for obtaining penta-atomic heterocyclic rings having three heteroatoms.
The present invention also provides a process tor the preparation the compounds of formula I or the acid addition salts thereof, which process comprises: ##STR4## wherein R.sub.1, R.sub.2 and n are as above defined with a compound of formula III ##STR5## wherein X is as defined above; or (i') reacting the compound of the formula II as defined above with hydrazine hydrate and then reacting the resultant hydrazide derivative with a compound of formula III' ##STR6## wherein X is as above defined; (ii) reacting the resultant compound of formula IV ##STR7## wherein R.sub.1, R.sub.2, n and X are as defined above, with a dehydrating agent, affording a compound of formula I wherein Het represents a group of the formula ##STR8## or (ii') reacting the resultant compound of formula IV with a sulphurating agent such as P.sub.2 S.sub.5 or the like affording a compound of the formula I wherein Het represents a group of formula ##STR9## or (i") reacting an activated derivative of a compound of the formula II as defined above with a compound of formula III" ##STR10## wherein X is as defined above to afford a compound of formula I, wherein Het represents a group of the formu
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Bandiera Tiziano
Caccia Carla
Mantegani Sergio
Meroni Maurizio
Varasi Mario
Pharmacia & Upjohn S.p.A.
Rotman Alan L.
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