Compounds with analgesic and local anaesthetic effect

Details Compounds with analgesic and local anaesthetic effect Compounds with analgesic and local anaesthetic effect

1995-03-24

1998-05-26

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514316, 514326, 546189, 546225, 546208, 546234, A61K 31445, C07D21132

Patent

active

057565201

DESCRIPTION:

BRIEF SUMMARY
This application is the national phase of PCT/SE95/00106, filed on Feb. 3, 1995 issued as WO95/21821 on Aug. 17, 1995.


FIELD OF THE INVENTION

The present invention is directed to new compounds having both local anaesthetic and analgesic effect, a process for their preparation and their use in the manufacture of pharmaceutical preparations.


BACKGROUND OF THE INVENTION

Pethidine is a frequently used analgesic, but its local anaesthetic effect is weak. The anaesthetic/analgesic effect of pethidine after spinal administration is often insufficient in both respects. Instead combinations of bupivacaine and fentanyl or morphine are being used. The opiate analgesics have several severe drawbacks, e.g. development of tolerance, addiction, risk for respiratory depression. There is, thus, a need for agents giving a local anaesthesia with a remaining analgesic effect having less side-effects than the currently used combinations. Such agents should be used after spinal or epidural injections as local anaesthetics intraoperatively. Thereafter the compounds would give good post-operative pain relief.


PRIOR ART

Hardy D. G. et al, describe in J.Med.Chem. 8, pp 847-851 (1965) the structure-activity relationship of certain analogues of pethidine, which are disclosed as having an analgesic activity. The Swedish patent 96980 describes 1-methyl-4-phenyl-piperidine-4-carboxylic acid and two amides thereof, but does not disclose any specific pharmaceutical effect, only that the compounds can be used in the manufacture of new drugs.
From WO SE90/00818 certain substituted 4-phenyl-piperidine-4-carboxamides are described as having both local anaesthetic and analgesic effects.


OUTLINE OF THE INVENTION

The novel compounds according to the present invention are defined by the following formulae (A): ##STR2## wherein Z is a group ##STR3## taken from the left to the right direction in formula (A) or a carbonyl group; and wherein: carbon atoms, and n is 3,4 or 5, or --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --; when Z is a carbonyl group, p is 2, as well as the
Preferred compounds according to the invention are those wherein R.sub.4 (in the benzene ring which is coupled to the group Z) is in the 2-position and wherein R.sub.2 are the same being an ethyl group; or methyl group and R.sub.2 is an ethyl group; or R.sub.1 and R.sub.2 together form a chain --(CH.sub.2)--.sub.4 ; or methyl group and R.sub.2 is an isopropyl group; or a methyl group and R.sub.2 is an ethyl group; or a methyl group and R.sub.2 is an ethyl group; or R.sub.2 are the same being an ethyl group.
Preferred salts according to the invention are pharmaceutically acceptable salts. The hydrochloride is especially preferred.
Citrate, methansulfonate and maleate are other examples of salts which can be used.
The compounds according to the present invention are more suitable to use in pain management, because they are less toxic and more effective as local anaesthetics and analgesics. Compounds of the formulae A and pharmaceutically acceptable salts thereof not only give an unexpectedly good effect as spinal and epidural anaesthetics, but also have an additional analgesic effect that lasts a long time after the anaesthetic effect has declined. Thus no combination of active compounds need to be given and the risks connected with these combinations can be avoided. The compounds also give an unexpectedly superior effect to the known compounds having this kind of combination effects.
The most preferred compounds according to the invention known at present, are the compounds according to Example 13 and Example 6A, i.e. compounds of the formula XIII, and compounds of the formula VI wherein H.sub.5 ; H.sub.5 ;


Preparation

For preparing the substituted piperidine-4-carboxamides of formula (A) according to the invention, the compounds could be divided into six groups which were prepared according to Schemes 1-5.
The first group, aromatically unsubstituted 1-(3-acetoxy-3-phenyl-propyl)-4-phenyl-piperidine-4-carboxamides (V), and the second group 1-(3-hydroxy-3-phenyl-propyl)-4-p

REFERENCES:
patent: 2951080 (1960-08-01), Pohland
patent: 3850935 (1974-11-01), Nakao et al.
Chemical Abstracts 101:749, abstr. # 191709Z (1984).
Hardy et al., "Structure-Activity Relationship of Some New Analogs of Pethidine," J. Med. Chem. 8:847-851 (1965).

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