Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-05-22
1994-11-22
Cintins, Marianne M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514307, 514319, 514326, 546114, 546146, 546205, 546206, 546208, C07D40106, C07D49504, A61K 3147, A61K 31445
Patent
active
053669819
DESCRIPTION:
BRIEF SUMMARY
This invention is concerned with novel substituted azacyclic compounds, processes for their preparation, and their use in medicine, particularly as analgesics.
Compounds which are kappa-receptor agonists act as analgesics through interaction with kappa opioid receptors. The advantage of kappa-receptor agonists over the classical .mu.-receptor agonists, such as morphine, lies in their ability to cause analgesia while being devoid of morphine-like behavioural effects and addiction liability.
European Published Patent Applications No. 0232612, discloses a group of azacyclic derivatives which exhibit kappa-receptor agonism without some of the behavioural effects of morphine and morphine analogues, and which are thus of potential therapeutic utility as analgesics.
A novel class of substituted azacyclic compounds has now been discovered which also exhibit potent kappa-receptor agonism without the aforementioned undesirable behavioural effects.
The novel class of compounds also possess diuretic activity which indicates that they are of potential use in the treatment of hyponatraemic disease states in mammals. The compounds are also of potential use in the treatment of cerebral ischaemia.
According to the present invention there is provided a compound, or a solvate or salt thereof, of formula (I): ##STR3## in which: (A) is ##STR4## p is 1, 2 or 3; ROC-- is an acyl group linked to the nitrogen atom of group (A) in which the group R contains a substituted or unsubstituted carbocyclic aromatic or heterocyclic aromatic ring; and are independently hydrogen or C.sub.1-6 alkyl; aromatic ring.
The C.sub.1-6 alkyl groups of R.sub.1 and R.sub.2 may be either straight or branched chain and examples are methyl, ethyl, propyl, n-butyl, n-pentyl or n-hexyl. R.sub.1 and R.sub.2 are preferably hydrogen or methyl, especially gem-dimethyl.
In (A), p is preferably 2 so that (A) has the character of a piperidine ring.
In the definition of ROC-- the term "carbocyclic aromatic" includes single or fused rings, having 6 to 12 ring carbon atoms, and the term "heterocyclic aromatic" includes single or fused rings having 5 to 12 ring atoms, comprising up to four hetero-atoms in the or each ring, selected from oxygen, nitrogen and sulphur. When the carbocyclic or heterocyclic group is a fused two ring system, one or both rings may be aromatic in character. Suitably, one of the rings is aromatic and the other is non-aromatic.
When R.sub.a forms a heterocyclic group, it may be a single ring having aromatic character, containing up to 6 ring atoms and comprising up to 2 hetero-atoms in the ring selected from oxygen, nitrogen and sulphur.
When R.sub.a forms an optionally substituted phenyl ring, examples of substituents are one or more of C.sub.1-6 alkyl, preferably methyl, halogen,, hydroxy, C.sub.1-6 alkoxy, thiol or C.sub.1-6 alkyl thio. Suitably R.sub.x represents thienyl, imidazolyl and unsubstituted phenyl.
The group R preferably has the formula (II): ##STR5## in which n is 0, 1 or 2; C.sub.1-6 alkyl, group, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.2-6 haloalkenyl, C.sub.2-6 haloalkynyl, optionally substituted phenyl, optionally substituted phenyl C.sub.1-6 alkyl, hydroxy, C.sub.1-6 alkoxy, thiol, C.sub.1-6 alkylthio, C.sub.1-6 haloalkoxy, C.sub.1-6 haloalkylthio, halogen, NO.sub.2, CN, CF.sub.3, --OCF.sub.3, --OCHF.sub.2, --OCF.sub.2 CF.sub.2 H, --OCCl.sub.2 CF.sub.3, --COOR.sub.9, --CONR.sub.10 R.sub.11, --SO.sub.3 R12, --SO.sub.2 NR.sub.13 R.sub.14 and --COR.sub.15 in which each of R.sub.9 to R.sub.15 is independently hydrogen, C.sub.1-6 alkyl, optionally substituted phenyl or optionally substituted phenyl C.sub.1-6 alkyl; group, and R.sub.7 is hydrogen or C.sub.1-6 alkyl, such as methyl or ethyl.
Preferred halogens are F, Cl and Br.
When two R.sub.6 's are linked they preferably form a fused cyclopentyl or cyclohexyl ring.
Preferably Ar is phenyl and R.sub.6 or R.sub.6.sup.a is preferably in the meta and/or para position.
Preferably R.sub.6 or R.sub.6.sup.a is bromine, chlorine, or CF.sub.3, particularly in the meta- or para-posit
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Colle Roberto
Dondio Giulio
Giardina Giuseppe
Vecchietti Vittorio
Cintins Marianne M.
Dr Lo Zambeletti S.p.A.
Kinzig Charles M.
Lentz Edward T.
Spivack Phyllis G.
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