Morphine derivatives with analgesic activity

Details Morphine derivatives with analgesic activity Morphine derivatives with analgesic activity

1998-12-08

2000-11-21

Rotman, Alan L.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

546 46, A61K 314355, C07D48900, C07D48902

Patent

active

061505242

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to new improved morphine derivatives, processes for preparing them and their use as analgesics for treating pain.


TECHNOLOGICAL BACKGROUND

Opiates are most commonly used as analgesics for treating severe chronic and acute pain. The opiate most frequently used at present for treating severe chronic or acute pain is morphine. An example of chronic pain is the pain which occurs in cancer. An example of acute pain is the pain which may occur after operations. The opiates used up until now for treating such pain are indeed highly effective but have a number of unpleasant and/or undesirable side effects, e.g. a short duration of activity, respiratory depression, nausea, constipation, diuresis and euphoria and they are also addictive.
Morphine hydrazone derivatives with analgesic activity are known from EP-A-0 242 417. EP-A-0 577 847 discloses 6-N-substituted morphine derivatives with analgesic and diuretic activity. EP-A-0 632 041 discloses 6-nicotinoylaminomorphine derivatives having analgesic activity.
A number of publications disclose preparations which attempt to avoid some of the known disadvantages of the opiates used up until now. EP-B-300 806 discloses the use of phospholipid vesicles for encapsulating opioid analgesics. EP-A-672 416, EP-A-647 448, EP-A-631 781 and WO 94/22431 disclose long-acting formulations of opiates in a hydrophobic matrix. All the formulations mentioned above have a duration of activity of from 12 to 24 hours. The disadvantages of these preparations are the delayed start of activity and the side effects, which still occur.


OBJECTIVE

There is therefore a need for compounds with powerful analgesic activity which can be taken orally, have a reduced side effects profile and wherein the analgesic activity starts quickly and is maintained throughout the desired period.
The object of the invention was therefore to provide new analgesically active compounds which, compared with known opiates, especially morphine, are more effective when administered orally and parenterally, begin their analgesic effect more rapidly, continue to act for the desired length of time and show a significant reduction in the typical side effects.
This object has been achieved by means of the new morphine derivatives of formula I.


DESCRIPTION OF THE INVENTION

The invention therefore relates to morphine derivatives (these compounds are referred to in the STN databases as morphians and this nomenclature is used in the claims) of the formula ##STR2## wherein D denotes a straight-chained or branched, optionally halogenated C.sub.1-4 -alkyl group, compounds are morphine derivatives or 7,8-dihydromorphine derivatives, (R.sub.2), --CO--N(L.sub.1) (L.sub.2) or --L.sub.3 --A.sub.1 --Q--A.sub.2 --B (R.sub.2)--C(R.sub.3) (R.sub.4)--B or --R.sub.1, (R.sub.2)--C(R.sub.3) (R.sub.4)--B hydrogen, a straight-chained or branched, saturated or unsaturated C.sub.1-4 -alkyl group or a group --(CH.sub.2).sub.x --OR.sub.7, --(CH.sub.2).sub.x --OC(O)R.sub.7, (CH.sub.2).sub.x --F, (CH.sub.2).sub.x --Cl, (CHF).sub.x --F, (CHCl).sub.x --Cl, (CF.sub.2).sub.x --F, (CCl.sub.2).sub.x --Cl --(CH.sub.2).sub.m --, unsaturated, mono- or bicyclic 5-10-membered ring system, substituted by R.sup.3 and/or R.sup.4, with the exception of 7, 8, 9 and 10-membered monocyclic groups, --OH, --(CH.sub.2).sub.n --CO.sub.2 R.sub.7, --(CH.sub.2).sub.n --CN, --(CH.sub.2).sub.n --CONR.sub.5 OR.sub.6, --(CH.sub.2).sub.n CONR.sub.5 R.sub.6, --(CH.sub.2).sub.n --OR.sub.5, --(CH.sub.2).sub.n --COR.sub.5, --(CH.sub.2).sub.n --OC(O)R.sub.7, --(CH.sub.2).sub.n --CONR.sub.5 OR.sub.6, --(CH.sub.2 O.sub.n --NR.sub.5 C(O)R.sub.6, --(CH.sub.2).sub.n --SR.sub.5, --(CH.sub.2).sub.n S(O)R.sub.5, --(CH.sub.2).sub.n --S(O).sub.2 NR.sub.5 R.sub.6, --(CH.sub.2).sub.n --NR.sub.5 R.sub.6, --(CH.sub.2).sub.n --NHC(O)R.sub.5, --(CH.sub.2).sub.n --NHS(O).sub.2 R.sub.5, --(CH.sub.2).sub.n --F, --(CH.sub.2).sub.n --Cl, --(CH.sub.2).sub.n Br, --(CH.sub.2).sub.n --NO.sub.2 or a straight-chained or branched C.sub.1-4 -alkyl group, a C.sub.1-4 -alkenyl gro

REFERENCES:
patent: 3131185 (1964-04-01), Lafon et al.
Progr. Drug Res., vol. 36, 1991, Basel. Boston. Berlin, pp. 49-70, XP002028172 KOLB, V.M.: "Opiate Receptors: Search for New Drugs" see the whole document.
Adv.Drug Res., vol. 16, 1987, London, pp. 281-307, XP002028173 KOLB, V.M.: "The Stereoelectronic Effects at the Opiate Receptor: Their Influence on Affinity and Intrinsic Activity" see the whole document.

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