NEW USE OF PREGNANE-DIONES AS ANALGESIC AGENTS

Abstract: The present invention provides: the new use of compounds of formula (II) wherein R<1> is H or Me, preferably H; R<2> is OH, preferably in alpha conformation; R<3> is H, or R<2> and R<3>, taken together, are O; R<4> is H or Me, preferably Me, and preferably in alpha conformation; R<5> is H; R<6> is H; or R<5> and R6, taken together, are O; R<7> is H or Me, preferably H; R<8> is H, Me or -CH2 O CO CH3. The present invention also provides a method of analgesia comprising administering an effective amount of a compound of formula (II) wherein R<1> est H or Me, preferably H; R<2> is OH, preferably in alpha conformation; R<3> is H, or R<2> and R<3>, taken together, are O; R<4> is H or Me, preferably Me, and preferably in alpha conformation; R<5> is H; R<6> is H; or R<5> and R<6>, taken together, are O; R<7> is H or Me, preferably H; R<8> is H, Me or -CH2 O CO CH3. The present invention also provides an analgesic composition comprising a compound of formula (II) wherein R<1> is H or Me, preferably H; R<2> is OH, preferably in alpha conformation; R<3> is H, or R<2> and R<3>, taken together, are O; R<4> is H or Me, preferably Me, and preferably in alpha conformation; R<5> is H; R<6> is H; or R<5> and R<6>, taken together, are O; R<7> is H or Me, preferably H; R<8> is H, Me or -CH2 O CO CH3 together with a pharmaceutically acceptable diluent.

Description: TITLE : New Use of Pregnane-diones as analgesic agents FIELD OF THE INVENTION This invention relates to compounds and compositions. In a particular instance, the present invention relates to analgesia, methods of analgesia and analgesic compositions. SUMMARY OF THE INVENTION The present invention provides:- the new use of compounds of Formula II as shown in the accompanying drawings wherein R 1 is H or Me, preferably H; R 2 is OH, preferably in alpha conformation; R 3 is H; or R 2 and R 3 , taken together, are O; R* is H or Me, preferably Me and preferably in alpha conformation; R 5 is H; R 6 is H; or R 5 and R 6 , taken together, are O; R 7 is H or Me, preferably H; R β is H, Me or -CH 2 0 CO CH 3 . The present invention also provides a method of analgesia comprising administering an effective amount of a compound of Formula II wherein R 1 is H or Me, preferably H; R 2 is OH, preferably in alpha conformation; R 3 is H; or R 2 and R 3 , taken together, are 0; R 4 is H or Me, preferably Me and preferably in alpha conformation; R 5 is H; R 6 is H; or R 5 and R 6 , taken together, are 0; R 7 is H or Me, preferably H; R β is H, Me or -CH 2 0 CO CH 3 . The present invention also provides an analgesic composition comprising a compound of Formula II wherein R 1 is H or Me, preferably H; R 2 is OH, preferably in alpha conformation; R 3 is H; or R 2 and R 3 , taken together, are 0; R* is H or Me, preferably Me and preferably in alpha conformation; R 5 is H; R 6 is H; or R 5 and R 6 , taken together, are 0; R 7 is H or Me, preferably H; R β is H, Me or -CH 2 0 CO CH 3 together with a pharmaceutically acceptable diluent. PREFERRED ASPECTS OF THE INVENTION The compounds of the invention are related to pregnane-dione which is shown in Formula I. The following Patent Specifications describe some of the compounds and their method of preparation:- British Patent Specification No. 1,317,185 (Application No. 33162/72 filed 16th May, 1973) to GLAXO; German Patent Specification No. 2,255,108 (based on British Application No. 52465/71 filed 11th November, 1971) to GLAXO; USA Patent Specification No. 3,558,608 (granted 27th January, 1971, filed 30th December, 1968) to SEARLE; South African Patent Specification 70/03861 (filed 15th January, 1971 based on British Application filed 20th June, 1969) to GLAXO; German Patent Specification No. 2,162,554 (filed 29th June, 1972, based on British Application No. 60,068/70 filed 17th December, 1970) to GLAXO; French Patent Specification No. 2,118,121 (filed 1st September, 1972, based on British Application 60,068/70 filed 17th December, 1970) to GLAXO; and German Patent Specification No. 2,162,593 (filed 6th July, 1972, based on British Application No. 60,067/70 filed 17th December, 1970) to GLAXO. The whole of the subject matter of those specifications together with items 105627c and 9285v of Chemical Abstracts, Vol. 77, 1972; 64113v, 64114w, 20793n of Chemical Abstract 5, Vol. 75, 1971; 115783f and 66672h of Chemical Abstracts Vol 79, 1973; and 1020345 of Chemical Abstracts Vol 78, 1973 is to be considered included and imported hereinto. A preferred compound for use is 21-acetoxy-3alpha-hydroxy-5alpha-pregnane-ll,20-dione which is of Formula III and which is commonly referred to as alphadolone. Other compounds which may be suitable for use include: 3alpha-hydroxy-5alpha-pregnan-20-one and 3alpha-hydroxy-5beta-pregnan-20-one which are of Formula IV. The compounds may be used individually or in mixtures with other compounds of Formula II. In addition, compounds of Formula II may be used concurrently with other analgesic drugs such as opioids to potentiate or increase the analgesic effects of those drugs. Suitable opioids for this use include morphine. The compounds for use in this invention may be provided in free acid form or as a salt. It is preferred that the compounds are provided as either sulphate or methane sulphonate salts. The compositions of this invention may be prepared for administration by various routes including intravenous. intramuscular, peritoneal and any other convenient route. However, the applicant has found that effective results are obtained when a compound of Formula II is administered into the intestines particularly intragastrically, and in a particular instance via an oral route. Accordingly, in a preferred aspect, the present invention provides a composition in a form suitable for oral administration. That form may include tablet, capsule or lozenge or a liquid form. It is preferred that the composition contains a surfactant and/or a solubility improver. One solubility improver is water-soluble polyoxyethylated castor oil. A suitable surfactant is Cremophor EL. A suitable dosage in a 70kg human would be about a maximum of 2.00 grams of the compound of Formula II every 6 hours. BRIEF DESCRIPTION OF THE VIEW OF THE DRAWINGS Figure 1 is a graph showing results obtained. Figure 2 is a graph showing results obtained, and Figure 3 is formula drawings. Examples Example 1 We performed a pilot experiment on one drug naive male Wistar rat that weighed approximately 200g. We measured the nociceptive (pain) threshold in the tail using electrical current as the noxious stimulus. We measured the electrical current threshold for pain (ECT) in the tail every five minutes until the readings stabilised. We then gave 150 mg alphadolone suspended in 1% Cremophor EL, 99% saline, intragastrically. Subsequent ECT measurements as shown in Figure 1 showed a significant rise in tail pain thresholds which lasted a long time after drug administration. Example 2 We performed a more controlled series of experiments with intragastric alphadolone (150 mg dissolved in 1.0 ml 20% Cremophor EL to 200g male wistar rats). We measured ECT in the neck and the tail every 5 minutes for 15 minutes before and for some time after drug administration. Five rats received on two successive days at random either alphadolone in Cremophor EL followed by Cremophor alone on the next day or vice versa. These experiments were also performed double blind. By that we mean that, at the time of the experiment the person making the measurements did not know what the rat received, drug plus Cremophor or just Cremophor alone. These results are shown in figure 2 which is a time response curve showing the mean of the responses in all five rats to the drug with vehicle and vehicle (Cremophor) alone. In all cases alphadolone caused rises in ECT pain thresholds in the neck and tail whereas the vehicle alone had no effect. In all of these experiments bicuculline 10 pmol was given intrathecally 30 minutes after the intragastric drug or vehicle. By giving bicuculline intrathecally to the lumbrosacral spinal cord we were able to test the theory that the antinociception or pain relief following intragastric alphadolone was due to an action of that drug on spinal cord GABA A receptors. Bicuculline is a selective GABA A receptor antagonist. In confining bicuculline to the part of the spinal cord responsible for tail innervation we would expect tail GABA-mediated responses to be reversed but those responsible for neck sensations to be unaffected. That is the result shown in Figure 2. Thus the conclusion from this is that alphadolone causes analgesia by acting on GABA λ receptors in the spinal cord even when the drug is given into the stomach. The vehicle had no effect the rats were not sedated or exhibited any disturbances in consciousness in any way. The claims and drawings form part of the disclosure of this specification as does the description, claims, illustrations, photographs and drawings of any associated provisional or parent specification or of any priority document, if any, all of which are imported herelnto as part of the record hereof. Finally it is to be understood that various alterations, modifications and/or additions may be incorporated into the various constructions and arrangements or parts without departing from the spirit and ambit of the invention.

Claims: THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:- 1. An analgesic composition comprising a compound of Formula II wherein R 1 is H or Me, R 2 is OH, R 3 is H; or R 2 and R 3 , taken together, are 0; R 4 is H or Me, R s is H; R 6 is H; or R 5 and R 6 , taken together, are O; R 7 is H or Me, R β is H, Me or -CH 2 0 CO CH 3 together with a pharmaceutically acceptable diluent. 2. An analgesic composition according to Claim 1, wherein R 1 is H; R 2 is OH in alpha conformation, R 4 is Me and R 7 is H. 3. An analgesic composition according to Claim 2 wherein R 4 is Me in alpha conformation. 4. An analgesic composition according to Claim 1 comprising alphadolone. 5. An analgesic composition according to Claim 1 comprising 3alpha-hydroxy-5alpha-pregnan-20-one. 6. An analgesic composition according to Claim 1 comprising 3alpha-hydroxy-5beta-pregnan-20-one. 7. An analgesic composition according to Claim 1 comprising more than one compound according to Formula II. 8. An analgesic composition according to Claim 1 comprising an additional analgesic drug. 9. An analgesic composition according to Claim 8 comprising an opioid drug. 10. An analgesic composition according to Claim 9 comprising morphine. 11. An analgesic composition according to Claim 1 in a form suitable for oral administration. 12. An analgesic composition according to Claim 11 in a liquid form. 13. An analgesic composition according to Claim 11 in the form of a tablet, capsule or lozenge. 14. An analgesic composition according to Claim 1 comprising a surfactant and/or a solubility improver. 15. An analgesic composition according to claim 14 in which the surfactant is Cremophor EL. 16. An analgesic composition according to Claim 14 in which the solubility improver is water-soluble polyoxyethylated castor oil. 17. A method of analgesia comprising administering an effective amount of a compound of Formula II wherein: R 1 is H or Me, R 2 is OH, R 3 is H; or R 2 and R 3 , taken together, are 0; R 4 is H or Me, R 5 is H; R 6 is H; or R 5 and R 6 , taken together, are 0; R 7 is H or Me, R β is H, Me or -CH 2 0 CO CH 3 18. A method according to Claim 17 wherein R 1 is H; R 2 is OH in alpha conformation, R 4 is Me and R 7 is H. 19. A method according to Claim 18 wherein R 4 is Me in alpha conformation. 20. A method according to Claim 17 wherein the compound of Formula II is alphadolone. 21. A method according to Claim 17 wherein the compound of Formula II is 3alpha-hydroxy-5alpha-pregnan-20-one. 22. A method according to Claim 17 wherein the compound of Formula II is 3alpha-hydroxy-5beta-pregnan-20-one. 23. A method according to Claim 17 comprising administering effective amounts of more than one compound according to Formula II. 24. A method according to Claim 17 comprising an additional analgesic drug. 25. A method according to Claim 24 wherein the additional analgesic drug is an opioid drug. 26. A method according to Claim 25 wherein the opioid drug is morphine. 27. A method according to Claim 17 in which the compound is administered by the intravenous, intramuscular or peritoneal route. 28. A method according to Claim 17 in which the compound is administered into the intestines. 29. A method according to Claim 28 in which the compound is administered intragastrically. 30. A method according to Claim 29 in which the compound is administered via an oral route. 31. A method according to Claim 17 in which the compound of Formula II is administered up to a maximum dose of 2.00 grams/70kg human every 6 hours. 32. The new use as an analgesic agent of a compound of Formula II wherein R 1 is H or Me, R 2 is OH, R 3 is H; or R 2 and R 3 , taken together, are 0; R 4 is H or Me, R 5 is H; R 6 is H; or R 5 and R 6 , taken together, are 0; R 7 is H or Me, R 8 is H, Me or -CH 2 0 CO CH 3 33. The new use as an analgesic agent of a compound according to Claim 32 wherein R 1 is H; R 2 is OH in alpha conformation, R 4 is Me and R 7 is H. 34. The new use as an analgesic agent of a compound according to Claim 33 wherein R 4 is Me in alpha conformation. 35. The new use as an analgesic agent of alphdolone. 36. The new use as an analgesic agent of 3alρha-hydroxy- 5alpha-pregnan-20-one. 37. The new use as an analgesic agent of 3alpha-hydroxy- 5beta-pregnan-20-one. 38. The new use as an analgesic agent of a mixture of more than one compound according to Claim 32. 39. The new use of a compound of Formula II wherein R 1 is H or Me, R 2 is OH, R 3 is H; or R 2 and R 3 , taken together, are 0; R 4 is H or Me, R 5 is H; R 6 is H; or R 5 and R 6 , taken together, are 0; R 7 is H or Me, R 8 is H, Me, or -CH 2 0 CO CH 3 to potentiate the effect of an analgesic drug. 40. The new use of a compound of Formula II according to Claim 39 to potentiate the analgesic effect of an opioid drug. 41. The new use of a compound of Formula II according to Claim 40 to potentiate the analgesic effect of morphine. 42. An analgesic composition substantially as hereinbefore described with reference to the examples. 43. A method of analgesia substantially as hereinbefore described with reference to the examples. 44. The new use as an analgesic agent of a compound of Formula II substantially as hereinbefore described with reference to the examples. 45. The steps, features, compositions and compounds referred to or indicated in the specification and/or claims of this application, individually or collectively, and any and all combinations or any two or more of said steps or features.

Inventors: GOODCHILD COLIN STANLEY, GOODCHILD, COLIN, STANLEY
Applicants: GOODCHILD COLIN STANLEY, GOODCHILD, COLIN, STANLEY
Application year: 1996
Main classification: A61K31
IPC codes: A61K31