Use of pregnane-diones as analgesic agents

Details Use of pregnane-diones as analgesic agents Use of pregnane-diones as analgesic agents

1998-11-20

2004-09-07

Pryor, Alton (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C177S179000, C177S181000

Reexamination Certificate

active

06787530

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to compounds and compositions.
In a particular instance, the present invention relate 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
4
is H or Me, preferably Me and preferably in alpha conformation;
R
5
and R
6
, taken together, are O;
R
7
is H or Me, preferably H;
R
8
=H, OH, OAc, SH, SAc, Cl, Br, F
including solvates thereof, pharmaceutically acceptable derivatives thereof, prodrugs thereof, tautomers thereof, isomers thereof, and metabolites thereof.
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 O;
R
4
is H or Me, preferably Me and preferably in alpha conformation;
R
5
and R
6
, taken together, are O;
R
7
is H or Me, preferably H;
R
8
=H, OH, OAc, SH, SAc, Cl, Br, F
including solvates thereof, pharmaceutically acceptable derivatives thereof, prodrugs thereof, tautomers thereof, isomers thereof, and metabolites thereof.
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
and R
6
, taken together, are O;
R
7
is H or Me, preferably H;
R
8
=H, OH, OAc, SH, SAc, Cl, Br, F
including solvates thereof, pharmaceutically acceptable derivatives thereof, prodrugs thereof, tautomers thereof, isomers thereof, and metabolites, thereof
We have found unexpectedly that metabolites and prodrugs of compounds of Formula II are also active as analgesic agents. Therefore the invention further comprises a composition when used as an analgesic comprising a metabolite or a prodrug of a compound of Formula II wherein
R
1
is H or Me, preferably H;
R
2
is OH, preferably in the alpha conformation
R
3
is H
or R
2
and R
3
, taken together, are O;
R
4
is H or Me and preferably in the alpha conformation
R
5
and R
6
, taken together, are O;
R
7
is H or Me, preferably R;
R
8
=H, OH, Oac, SH, SAc, Cl, Cr, F.
In a further aspect of the invention there is disclosed a method of analgesia comprising administering an effective amount of a metabolite or a prodrug of a compound of Formula II wherein
R
1
is H or Me, preferably H;
R
2
is OH, preferably in the alpha conformation
R
3
is H
or R
2
and R
3
, taken together, are O;
R
4
is H or Me and preferably in the alpha conformation
R
5
and R
6
, taken together, are O;
R
7
is H or Me, preferably H;
R
8
=H, OH, Oac, SH, SAc, Cl, Cr, F.
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 May 16, 1973) to GLAXO;
German Patent Specification No. 2,255,108 (based on British Application No. 52465/71 filed Nov. 11, 1971) to GLAXO;
U.S. Pat. No. 3,558,608 (granted Jan. 27, 1971, filed Dec. 30, 1968) to SEARLE;
South African Patent Specification 70/03861 (filed Jan. 15, 1971 based on British Application filed Jun. 20, 1969) to GLAXO;
German Patent Specification No. 2,162,554 (filed Jun. 29, 1972, based on British Application No. 60,068/70 filed Dec. 17, 1970) to GEAXRO;
French Patent Specification No. 2,1187121 (filed Sep. 1, 1972, based on British Application 60,068/70 filed Dec. 17, 1970) to GLAXO and
German Patent Specification No. 2,162,593 (filed Jul. 6, 1972, based on British Application No. 60,067/70 filed Dec. 17, 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-11,20-dione which is of Formula III and which is commonly referred to as alphadolone acetate.
Further preferred compounds of the invention include metabolites of alphadolone acetate.
More preferably a compound for use in the invention is alphadolone glucuronide.
The compounds may be used individually or in mixtures with other compounds or metabolites/prodrugs of compounds of Formula II.
In addition, compounds and metabolites 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 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 intragastically, 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 70 kg human would be about a maximum of 2.00 grams of the compound of Formula II every 6 hours.
We have conducted further scientific trials (see Examples 2 to 5) which provides evidence indicating that metabolites of alphadolone produced in the liver are responsible for the pain relieving effect of alphadolone when given orally and intraperitoneally to rats and orally to man. We have therefore prepared the following detailed description of such further evidence which we have obtained from our experimental data shown in Examples 2 to 5.
Alphadolone has been marketed as an anaesthetic (Saffan; Althesin) formulated in combination with another neurosteroid called alphaxalone. It is generally accepted in the literature that both alphaxalone and alphadolone are intravenous anaesthetics, i.e. when they are given intravenously, they produce sedation and unconsciousness to a level sufficient for surgery. Since the basis of our claim for the analgesic properties of alphadolone is that it does not produce sedation and unconsciousness when given as described in the patent, we though it important to investigate whether alphadolone on its own does have anaesthetic properties. Such data, although alluded to in the literature, is not stated clearly with scientific evidence. Thus, we performed the experiments described in Example 2. Rats were given an intravenous injection of alphadolone. All of the rats became unconscious and surgically anaesthetised within 5 seconds of the intravenous injection. The dose given intravenously would be expected to achieve blood levels very similar to a blood level that might be achieved after intraperitoneal injection of the dose of alphadolone used for anaesthesia in combination with alphaxalone. Thus, it can be concluded that intravenous injection of alphadolone produces unconsciousness. However, alphadolone given by other routes does not produce unconsciousness (vide infra).
Experiments with orally administered alphadolone are shown in Example 3 where.

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