Optically active thiomorpholine derivatives

Details Optically active thiomorpholine derivatives Optically active thiomorpholine derivatives

1995-02-22

1997-10-21

Grumbling, Matthew V.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

544 60, C07D41706, A61K 3154

Patent

active

056796749

DESCRIPTION:

BRIEF SUMMARY
This is the national stage (35 USC 371) of PCT/JP93/01210, filed Aug. 27, 1993.


TECHNICAL FIELD

The present invention relates to optically active carboxamide derivatives having potent analgesic activity and low toxicity, or to pharmacologically acceptable salts thereof.
BACKGROUND ART
In the central nervous system, the presence of three kinds of receptors, .mu.-, k- and .delta.-receptors, participating in analgesic effect has been clarified. It is said that an agonist which has an affinity to k-receptor among these shows strong analgesic effect and does not show such side effects as addiction, tolerance formation, respiratory inhibition, inhibition of smooth muscle movement and so on which are observed, for example, in .mu.-receptor agonistic morphine etc. Accordingly, the development of a k-receptor agonist having a strong analgesic activity and fewer side effects has been desired.
The present inventors have synthesized a series of heterocyclic compounds and examined their pharmacological activities for many years. As a result, they have found carboxamide derivatives or their pharmacologically acceptable salts thereof having potent analgesic activity and filed a


BRIEF DESCRIPTION OF INVENTION

The present inventors have found that optically active carboxamide derivatives having specific stereochemical configuration of the compounds covered in the above application exhibit much strong analgesic activity as k-receptor agonist comparing with racemates and the other stereoisomers have fewer side effects and are practical as analgesic agents; and have accomplished the present invention.


DETAILED DESCRIPTION OF INVENTION

The optically active carboxamide derivatives of the present invention have general formula: ##STR2##
In the formula, R.sup.1 represents a hydrogen or halogen atom; R.sup.2 represents a halogen atom: R.sup.3 represents a pyrrolidino or piperidino group: Y represents a methylene or carbonyl group; and n is an integer of 1 or 2.
An analgesic agent or a k-receptor agonistic agent of the present invention comprises the above compounds or pharmacologically acceptable salts thereof as an active ingredient.
Halogen atoms represented by R.sup.1 and R.sup.2 include, for example, fluorine, chlorine, bromine and iodine atoms; preferably a fluorine or chlorine atom: and particularly preferably a chlorine atom.
The compounds having a general formula (I) described above can, if necessary, be converted to pharmacologically acceptable salts thereof by conventional means.
Examples of such salts include: for example, salts of mineral acids such as hydrochloric acid, hydroboromic acid, hydroiodic acid, sulfuric acid or phosphoric acid; and salts of organic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, mandelic acid, citric acid or tartaric acid; and preferably salts of hydrochloric acid, methanesulfonic acid, fumaric acid or succinic acid.
The preferred compounds of general formula (I) are those in which:
the more preferred compounds of general formula (I) are those in which:
the particularly preferred compounds of general formula (I) are those in which:
The preferred specific compounds are those of Compound No. 1, 2, 3, 4, 5, 6, 7, 8, 9, 17, 19, 33, 41, 42, 43, 44, 57 and 59 in which the Compound Number is same as in Table 3 described hereinafter.
And the more preferred specific compounds are those of rpholine; thiomorpholine; -naphthoyl!thiomorpholine; hthoyl!thiomorpholine; naphthoyl!thiomorpholine; and morpholine.
The compounds of a general formula (I) of the present invention can readily be prepared by the following method: ##STR3##
In the above formulae, R.sup.1, R.sup.2, R.sup.3, Y and n are as defined above.
Method A involves a method for preparing a compound of formula (I).
Step A1 is a step for preparing a compound of general formula (I) and is conducted by reacting a compound of general formula (II) or its reactive derivative with a compound of general formula (III) in an inert solvent

REFERENCES:
patent: 5021413 (1991-06-01), Terada et al.

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