Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-08-21
2001-12-04
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06326404
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to the use of O-desmethyl-N-mono-desmethyl-tramadol for the production of pharmaceutical compositions for the treatment of pain and various related indications as well as pharmaceuticals comprising O-desmethyl-N-mono-desmethyl-tramadol.
The treatment of pain conditions is of great importance in medicine. There is currently a world-wide need for additional pain therapy. The pressing requirement for a target-oriented treatment of pain conditions which is right for the patient which is to be understood as the successful and satisfactory treatment of pain for the patients is documented in the large number of scientific works which have recently and over the years appeared in the field of applied analgesics or on basic research on nociception.
SUMMARY OF THE INVENTION
The underlying object of the present invention was to provide a substance useful in the treatment of pain and also related indications, as well as pharmaceutical compositions for such treatment.
It has now been found that O-desmethyl-N-mono-desmethyl-tramadol is useful in the treatment of pain and also related indications.
One main aspect of the invention is therefore the use of O-desmethyl-N-mono-desmethyl-tramadol as a racemate, a mixture of its enantiomers or a single enantiomer in the form of its base or salts of physiologically acceptable acids for the production of a pharmaceutical composition for the treatment of pain.
O-desmethyl-N-mono-desmethyl-tramadol (sometimes referred to as MS in the literature and in the following text) is known as one of the in vivo metabolites of Tramadol (1RS,2RS)-2[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol; Lintz et al. Arzneim.-Forsch./Drug Res. 31(11), 1932-1943, 1981).
Tramadol assumes a special position amongst centrally acting analgesics. Since this active ingredient acts as a strong inhibitor of pain without the side effects which are known for opioids (J. Pharmacol. Exp. Ther. 267, 331 (1993)). Tramadol is a racemate and consists of equal amounts of (+) and (−) enantiomers. It is a centrally acting analgesic with an opiod and a non-opioid mechanism of action. The opioid properties are derived from &mgr;-opioid receptor interaction, whereas the inhibition of neuronal re-uptake of monoamines (norepinephrine (NE) and serotonin (5-HT)) is responsible for the non-opioid activity. The opioid receptor affinity of tramadol is very low, but the compound is extensively metabolized by O- and N-demethylation.
In the prior art, the metabolite M
5
is not described as having analgesic properties. The recent and surprising findings of the inventors leading to this patent application were on the one hand, the fact that M
5
has a strong &mgr;-opioid receptor affinity which was strong enough to induce in vivo analgesic activity as proven after direct administration into a brain ventricle, and on the other hand, the fact that M
5
shows a poor penetration of the blood brain barrier or even seemed to be unable to penetrate it.
The fact that peripherally applied M
5
does not—at least not noticably—act in the central nervous system (CNS) makes M
5
an ideal compound for a peripheral treatment of pain avoiding any analgesic action on the CNS. Therefore the use of O-desmethyl-N-mono-desmethyl-tramadol as a racemate, a mixture of its enantiomers or as a single enantiomer in the form of its base or salts of physiologically acceptable acids for the production of a pharmaceutical composition for the peripheral treatment of pain is a preferred embodiment of this invention.
Kinds of pain which stem from a peripheral cause and/or which may be treated peripherally include inter alia burn pain, wound pain, visceral pain, soft-tissue pain, articular pain, and cancer pain, which are therefore preferred indications for the use of M
5
. The usefulness of M
5
to treat peripheral pain is believed due to the high &mgr;-opioid receptor affinity. So another aspect of the invention is the use of O-desmethyl-N-mono-desmethyl-tramadol as a racemate, as a mixture of its enantiomers or as a single enantiomer in the form of its base or salts of physiologically acceptable acids for the production of a pharmaceutical composition for the treatment of burn pain, wound pain, visceral pain, soft-tissue pain, articular pain and/or cancer pain.
Surprisingly it was further shown that O-desmethyl-N-mono-desmethyl-tramadol is also usable for the treatment of urinary incontinence and/or pruritus and for the treatment diarrhea. These therapeutic activities may also be due to the high &mgr;-opioid receptor affinity. Therefore, a further object of the invention is the use of O-desmethyl-N-mono-desmethyl-tramadol as a racemate, a mixture of its enantiomers or a single enantiomer in the form of its base or salts of physiologically acceptable acids for the production of a pharmaceutical for the treatment of urinary incontinence, diarrhea and/or pruritus.
The racemate of M
5
is very effective for the treatment in the above mentioned indications. Surprisingly, however, the (+)-enentiomer of M
5
((+)-O-desmethyl-N-mono-desmethyl-tramadol) showed a very pronounced activity as well. Therefore, a highly preferred embodiment of the invention is the use of (+)-O-desmethyl-N-mono-desmethyl-tramadol in the form of its base or salts of physiologically acceptable acids for the production of a pharmaceutical and for treatment of any of the above mentioned indications.
In some of the above-mentioned indications, especially in pain associated with burns or wounds (but with sore and itching skin as well), the skin is damaged leading to an elevated risk of infection. To prevent or treat an infection, an anti-infective agent such as an antibiotic or disinfectant such as polyvidon-iodine is used. Especially in these indications it is useful to combine antibiotics or disinfectants such as polyvidon-iodine with O-desmethyl-N-mono-desmethyl-tramadol. Therefore, another preferred aspect of the invention is the use of O-desmethyl-N-mono-desmethyl-tramadol in combination with an anti-infective agent.
Salts of physiologically acceptable acids according to this invention include both salts with inorganic and with organic acids. The hydrochloride salt is especially preferred.
A further object of the invention is to provide pharmaceutical compositions comprising O-desmethyl-N-mono-desmethyl-tramadol as a racemate, a mixture of its enantiomers or a single enantiomer in the form of its base or salts of physiologically acceptable acids as active ingredient.
Another aspect of the invention is to provide pharmaceutical compositions comprising the (+)-enantiomer of O-desmethyl-N-mono-desmethyl-tramadol in the form of its base or salts of physiologically acceptable acids as active ingredient.
As these above mentioned pharmaceutical compositions according to the invention seem to be especially useful in the above mentioned indications, another aspect of the invention is to provide pharmaceutical compositions according to the invention for the treatment of urinary incontinence, diarrhea, pruritus and/or especially pain, particularly burn pain, wound pain, visceral pain, soft tissue pain, articular pain, and/or cancer pain.
Another aspect of the invention is to provide pharmaceutical compositions which comprise in addition to O-desmethyl-N-mono-desmethyl-tramadol as a racemate, a mixture of its enantiomers, or a single enantiomer especially the (+)-enantiomer of O-desmethyl-N-mono-desmethyl-tramadol in the form of its base or salts of physiologically acceptable acids at least one additional active ingredient. This additional active ingredient can be any suitable pharmaceutical substance. A preferred additional active ingredient for the above mentioned special indications is at least one anti-infective agent, such as an antibiotic or a disinfectant like polyvidon-iodine.
In addition to O-desmethyl-N-mono-desmethyl-tramadol as a racemate, a mixture of its enantiomers, or a single enantiomer, especially the (+)-enantiomer of O-desmethyl-N-mono-desmethyl-tramadol
Englberger Werner
Friderichs Elmar
Hennies Hagen-Heinrich
Koegel Babette
Crowell & Moring LLP
Gruenenthal GmbH
Jarvis William R. A.
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