N-acyl-substituted azacyclic compounds, processes for their prep

Details N-acyl-substituted azacyclic compounds, processes for their prep N-acyl-substituted azacyclic compounds, processes for their prep

1992-05-22

1994-06-21

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514318, 514320, 514324, 514326, 546146, 546193, 546196, 546202, 546208, 546209, 546226, 546227, A61K 3147, A61K 31445, C07D21706, C07D40106

Patent

active

053228480

DESCRIPTION:

BRIEF SUMMARY
This invention is concerned with novel substituted azacyclic derivatives, 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.
EP-A-330461, 330467 AND 330469 (Glaxo Group Ltd) disclose groups of azacyclic derivatives which are stated to exhibit kappa-receptor agonism, and which are said to be of potential therapeutic utility in the treatment of pain and cerebral ischaemia.
A novel class of structurally related substituted azacyclic derivatives has now been discovered which also exhibit potent kappa-receptor agonism without some of the undesirable behavioural effects of morphine and morphine analogues.
Furthermore, this novel class of derivatives tend to show improved duration of action over corresponding unsubstituted azacyclic derivatives, while maintaining effective analgesic activity.
The novel class of derivatives also possess diuretic activity which indicates that they are of potential use in the treatment of hyponatraemic disease states in mammals.
The novel class of derivatives 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): ##STR2## in which W, which may be attached to the same or different carbon atom as R.sub.1, is hydroxy, C.sub.1-6 alkoxy (preferably methoxy), halogen (preferably fluorine), thiol, C.sub.1-6 alkylthio, hydroxy C.sub.1-6 alkyl, methylidene, hydroxycarbonyl, aminocarbonyl, C.sub.1-3 alkoxycarbonyl, NHR.sub.1a or NHCOR.sub.1a where R.sub.1a is H or C.sub.1-6 alkyl; (preferably methyl) or together with W forms a keto-group or a cyclic ether or thioether containing from 1 to 4 carbon atoms; ##STR3## in which each of R.sub.2 and R.sub.3, which may be attached to the same or different carbon atom, is hydrogen, C.sub.1-6 alkyl, hydroxy, thiol, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio or halogen (preferably fluorine); group optionally substituted by one or two C.sub.1-6 alkyl groups and attached to the same or different carbon atom; heterocyclic group, preferably having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from oxygen, nitrogen and sulphur; group in which the group R contains a substituted or unsubstituted carbocyclic aromatic or heterocyclic aromatic ring, ##STR4## , R represents a tetralone moiety, or W is halogen or C.sub.1-6 alkoxy, or R.sub.1 is other than hydrogen or a keto group with W; hydroisoquinoline group, R represents a tetralone moiety or R.sub.1 is other than hydrogen or a keto group with W, or W is halogen or C.sub.1-6 alkoxy; tetrahydro isoquinoline group, substitution only occurs in the --(CH.sub.2).sub.3 -- group formed by R.sub.4 and R.sub.5.
Preferably, the R tetralone moiety is of formula (IIa), (IIb), (IIc) or (IId) as hereinafter defined.
Preferably, W and R.sub.1 are attached to the same carbon atom on the azacyclic ring, in the 3-position with respect to the nitrogen.
Preferably, one of R.sub.2 and R.sub.3 is halogen (preferably fluorine), C.sub.1-6 alkoxy, thiol, C.sub.1-6 alkylthio, or both R.sub.2 and R.sub.3 are other than hydrogen. In a particularly preferred embodiment, R.sub.2 and R.sub.3 are attached to the same carbon atom in the azacyclic ring. In the latter case, preferred groups are alkyl, thereby providing a gem di-alkyl substitution pattern.
Examples of W are hydroxy, fluoro and methoxy, and examples of R.sub.1 are hydrogen, methyl and fluoro.
It is also preferred that when R.sub.x forms the remainder of a phenyl ring and R.sub.4 and R.sub.5 form a --(CH.sub.2).sub.3 -- group, the latter is substituted, particularly by two C.sub.1-6 alkyl groups on the same carbon atom of the -

REFERENCES:
patent: 4954509 (1990-09-01), Vecchietti
patent: 4999359 (1991-05-01), Vecchietti
patent: 5030649 (1991-07-01), Vecchietti
patent: 5089507 (1992-02-01), Vecchietti
Gottschlich et al "Preparation of 2-Acyl-1-Pyrrolidinomethyl 1,2,3,4-Tetrahydro Isoquinolines and Analogs and Drugs" CA 113:211862x (1990).
T. Mukaiyama et al., "Enantioface-Differentiating (Asymmetric) Addition of Alkyllithium and Dialkylmagnesium to Aldehydes by Using (2S,2'S)-2-Hydroxymethyl-1-((1-alkylpyrrolidin-2-yl)-methyl)pyrrolidines as Chiral Ligands", J. Am. Chem. Soc., vol. 101, No. 6, 1979, pp. 1455-1460.

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