WO1999022730A1

WO1999022730A1 - Use of (+)-6-carboxamido-3-methylamino-1,2,3,4-tetrahydrocarbazole for treating hyperalgesia

Info

Publication number: WO1999022730A1
Application number: PCT/GB1998/003234
Authority: WO
Inventors: Andrew Alexander Parsons
Original assignee: Vanguard Medica Limited
Priority date: 1997-10-31
Filing date: 1998-10-29
Publication date: 1999-05-14
Also published as: GB9723061D0; ZA989890B; AU9637398A

Abstract

(+)-6-Carboxamido-3-methylamino-1,2,3,4-tetrahydrocarbazole or a physiologically acceptable salt, solvate or hydrate thereof for use in the treatment of conditions involving enhanced or exaggerated sensitivity to pain.

Description

USE OF (+)-6-CARBOXAMIDO-3-METHYLAMINO-l,2,3,4-TETRAHYDROCARBAZOLE FOR TREAΗNG HYPER- ALGESIA

The present invention relates to the treatment of hyperalgesia. In particular the invention relates to the use of (+)-6-carboxamido-3- methylamino- 1,2,3,4- tetrahydrocarbazole (VML 251) in the treatment of conditions involving enhanced or exaggerated sensitivity to pain, such as hyperalgesia, causalgia and allodynia.

PCT patent specification WO 93/00086 describes certain carbazole derivatives as 5-HTι-like receptor agonists having anti-migraine activity. Of these compounds (+)-6- carboxamido-3- methylarnino-l,2,3,4-tetrahydrocarbazole, in the form of its succinate salt, described in PCT patent specification WO 94/14772 has been found to be particularly effective and is currently under clinical investigation as a potential therapy for migraine under the approved name frovatriptan (code number VML 251). This compound has a long duration of action and produces low incidence of side effects in migraine patients (Ryan & Keywood, 1997, Cephalalgia 17, 418). The receptor designation '5-HTι-like' has more recently been superseded by the term '5-HTIB/JD'. The exact mechanism by which 5-HTJB/JD receptor agonists exert their therapeutic effects in migraine is not known; current hypotheses suggest it involves constriction of cerebral arteries and or a direct inhibitory effect on release of neuropeptide from primary afferent nerve terminals. Conditions involving enhanced or exaggerated sensitivity to pain, may occur in a variety of situations, eg following nerve or tissue damage. In general, hyperalgesia refers to conditions wherein a painful stimulus is rendered more painful and allodynia to conditions wherein a non-painful stimulus is perceived to be painful.

It has recently been reported that sumatriptan, a 5-HT\γ /\τ) receptor agonist commercially available for the treatment of migraine, possesses anti-hyperalgesic properties following morphine withdrawal (Ghelardini et al., 1996, Fund Clin Pharmacol 10, 192). However, in a clinical study of patients with facial pain sumatriptan was found to reduce pain but at a level which was not considered to be of clinical benefit (Harrison et al, 1997, Eur. Neuropsycholpharmacology 7: 83-88) . Furthermore, in this study, patients treated with sumatriptan experienced a variety of side effects, including: feelings of heaviness, warm/hot sensations, dryness of mouth, neck pain/stiffness and nausea and vomiting.

It has now been found that frovatriptan exhibits antihyperalgesic activity in an animal model of carrageenan-induced thermal hyperalgesia. The present invention provides use of (+)-6-carboxamido-3- methylamino- 1,2,3, 4- tetrahydrocarbazole (frovatriptan) and physiologically acceptable salts, solvates and hydrates thereof in the treatment of conditions involving enhanced or exaggerated sensitivity to pain. Conditions involving enhanced or exaggerated sensitivity to pain include, but are not limited to, ongoing pain conditions such as atypical facial pain, neuropathic pain, back pain, complex regional pain syndromes I and II, arthritic pain, sports injury pain, pain related to infection e.g. HEN, post-polio syndrome, post-herpetic neuralgia, phantom limb pain, labour pain, cancer pain, post-chemotherapy pain, post-stroke pain, post-operative pain, neuralgia, tolerance to narcotics or withdrawal from narcotics.

It is believed that the properties of frovatriptan produce a pharmacological profile which will provide clinically relevant pain relief in conditions involving enhanced or exaggerated sensitivity to pain. In contrast to sumatriptan, frovatriptan has a selective anti-vasodilatory effect against cerebral vasculature, not affecting coronary vasculature to any significant degree. Furthermore, the longer half-life of frovatriptan, which results in a longer duration of action, make it particularly suitable for use in conditions of ongoing or long-lasting pain.

According to a further feature of the present invention we provide the use of (+)-6- carboxamido-3 - methylamino- 1 ,2,3 ,4-tetrahydrocarbazole (frovatriptan) and physiologically acceptable salts, solvates and hydrates thereof in the manufacture of a medicament for use in conditions involving enhanced or exaggerated sensitivity to pain. According to a further feature of the present invention we provide a method for the treatment or prophylaxis of conditions involving enhanced or exaggerated sensitivity to pain in a subject which comprises administering to the subject an effective amount of (+)- 6-carboxamido-3- methylamino- 1, 2,3, 4-tetrahydrocarbazole (frovatriptan) or a physiologically acceptable salt, solvate or hydrate thereof.

(+)-6-Carboxamido-3- methylamino- 1,2,3 ,4-tetrahydrocarbazole and its physiologically acceptable salts, solvates and hydrates may be prepared by methods known in the art for the preparation of tetrahydrocarbazoles, for example as described in PCT patent specification WO 93/00086 or WO 94/14772.

For use in medicine, (+)-6-carboxamido-3- methylamino- 1,2,3 ,4- tetrahydrocarbazole and its physiologically acceptable salts, solvates and hydrates are usually administered as a standard pharmaceutical composition comprising a compound of the invention and a physiologically acceptable carrier.

The compounds for use according to the invention may be administered by any convenient method, for example by oral, parenteraL, buccal, inhalation, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly. The compounds for use according to the invention when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt, solvate or hydrate in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule. Typical parenteral compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

Compositions suitable for transdermal administration include ointments, gels and patches. Preferably the composition is in unit dose form such as a tablet, capsule or ampoule.

Each dosage unit for oral administration contains preferably from 0.1 to 250 mg, eg 1 to 250 mg (and for parenteral administration contains preferably from 0.01 to 25 mg, eg 0.1 to 25 mg) of a compound of the invention.

The physiologically acceptable compounds for use according to the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 0.1 and 500 mg, eg between 1 mg and 500 mg, preferably between 1 and 40 mg, eg between 1 and 10 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of the invention, the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.

The following Examples illustrate the preparation of pharmaceutical formulations which may be employed in accordance with the present invention in which the active ingredient is frovatriptan.

Pharmaceutical formulations

Example A

A tablet for oral administration is prepared by combining.

Mg Tablet Active ingredient 2.5 lactose 153 starch 33 crospovidone 12 microcrystalline cellulose 30 magnesium stearate 2

into a 9 mm tablet.

Example B

An injection for parenteral administration is prepared from the following:

% w:w Active ingredient 0,50% (w:v)

1M citric acid 30% (v:v) sodium hydroxide (qs) to pH 3.2 water for injection BP to 100 ml The active ingredient is dissolved in the citric acid and the pH slowly adjusted to pH 3.2 with the sodium hydroxide solution. The solution is then made up to 100 ml with water, sterilised by filtration and sealed into appropriately sized ampoules and vials.

Experimental

Test Methods

Carrageenan-induced Thermal Hyperalgesia

Mice were placed in the test apparatus, for 10 min, once a day for three days for habituation. Withdrawal latencies of the left foot, to a focused, thermal stimulus (plantar test) were measured on separate days and the last measurement taken as a baseline. Carrageenan (2% w/v in saline, 0.25mls) was injected into the plantar surface of the left foot and withdrawal latencies measured (240 min post carrageenan). Three experiments were performed: frovatriptan (3, 10, 30 and 100 ug/kg ip) or vehicle was given 15 or 90 min pre-plantar test, 225 or 150 min post carrageenan (n=15 per group) and frovatriptan (0.3, 3 and 30 ug/kg ip) or vehicle was given 90 min pre plantar test, 150 min post carrageenan (n=18-19 per group).

Carrageenan-induced inflammation

The effect of frovatriptan (30ug/kg ip) on the carrageenan-induced increase in paw volume was measured. Frovatriptan was given 30 min, before intraplantar carrageenan, 150 min and 225 min post-carrageenan (n=15 per group). Control animals were given saline (ip) 180 min post carrageenan (carrageenan control). Paw volume was measured 240min post-carrageenan for all groups. The mean paw volume was calculated for the carrageenan control group and volumes for each animal in each test group expressed as a percentage of this mean. The percentage (%) inhibition of paw was calculated using the following formula.

(l-(test volume/carrageenan control, mean volume)) x 100 Results

Carrageenan-induced Thermal Hyperalgesia

Frovatriptan 15 min pre-test

Before drug administration baseline latencies to the thermal stimulus were similar for all groups (vehicle=8.17 ± 0.58 s, 3ug/kg=8.24 ± 0.63 s, 10ug/kg=8.27 ± 0.65 s, 30ug/kg=8.14 ± 0.61 s and 100ug/kg=8.18 ± 0.59 s, n=15 per group). Carrageenan evoked an inflammation of the injected foot characterised by oedema and hyperalgesia. 1.76 ± 0.34 s (n=15), indicating thermal hyperalgesia. Frovatriptan given ip 15 min pre- test (225min post-carrageenan) had no effect on withdrawal latencies at 3ug/kg (2.18 ± 0.36 s) or lOug/kg (1.75 ± 0.31 s) but at 30ug/kg significantly attenuated thermal hyperalgesia (3.47 ± 0.48 s, p<0.05 ANONA followed by Dunnett's test compared to vehicle). At lOOug/kg the effect was no longer significant (2.25 ± 0.28 s)

Frovatriptan 90 min pre-test

When frovatriptan was given 90 min before test, baseline latencies were similar for all groups (vehicle=8.02 ± 0.58 s, 3ug/kg=8.04 ± 0.59, 10ug/kg=8.10 ± 0.63 s, 30ug/kg=8.12 ± 0.62 s and 100ug/kg=8.05 ± 0.55 s, n=15 per group). Four hours after administration of carrageenan, in vehicle treated animals, the withdrawal latency to the thermal stimulus was reduced to 1.96 ± 0.24 s (n=15). Frovatriptan given ip 90 min before test (150 min post- carrageenan) had no significant effect on thermal hyperalgesia at any dose although the withdrawal latencies recorded were similar to those observed when it was given 15 min pre-test (3ug/kg= 2.96 ± 0.36 s, 10ug/kg=2.37 ± 0.22 s, 30ug/kg=2.51 ± 0.31 and 100ug/kg=2.80 ± 0.53 s, n=15 per group).

This study was repeated using an increased number of animals to increase the power. Once again baseline latencies were similar in all groups (vehicle=7.71 ± 0.60 s, 0.3ug kg=7.71 ± 0.57 s, 3ug kg=7.76 ± 0.59 s and 30ug/kg=7.92 ± 0.60 s, n=19 per group). In vehicle- treated mice the withdrawal latency to the thermal stimulus was reduced to 2.17 ± 0.19 s (n=19). Frovatriptan given given ip 90 min before test (150 min post-carrageenan, n=18- 19) had no significant effect on the latency to response at 0.3ug/kg (3.22 ± 0.55 s) but significantly attenuated thermal hyperalgesia at 3ug/kg (3.51 ± 0.44 s) and 30ug/kg (3.61 ± 0.48 s) (p<0.05 AΝOVA followed by Duncan's test compared to vehicle). Carrageenan-induced inflammation

Paw volume was measured 240 min post intraplantar injection of saline or carrageenan. In animals which received saline ip, 180 min post intra-planatar injection of saline paw volume was 141.3 ± 7.4 ul. In the carrageenan control group the paw volume was 276.0 ± 7.98 ul. Frovatriptan (30ug/kg ip) had no significant effect, at any time point, on the increase in paw volume induced by carrageenan. (Frovatriptan given 30 min pre- carrageenan, paw volume =258.0 ± 8.2 ul, 150 min post carrageenan paw volume =287.3 ± 10.2 and 225min post carrageenan=285.3 ± 8.4 ul.

Frovatriptan was also tested in a mouse model of thermal nociception but was found to have no effect in that test.

Claims

Claims:

1. (+)-6-Carboxar do-3-methylarnino- 1 ,2,3 ,4-tetrahydrocarbazole or a physiologically acceptable salt, solvate or hydrate thereof for use in the treatment of a condition involving enhanced or exaggerated sensitivity to pain.

2. (+)-6-Carboxamido-3-methylamino-l,2,3,4-tetrahydrocarbazole or a physiologically acceptable salt, solvate or hydrate thereof for use according to claim 1, wherein the condition is hyperalgesia, causalgia or allodynia.

3. (+)-6-Carboxamido-3-methylamino- 1 ,2,3 ,4-tetrahydrocarbazole or a physiologically acceptable salt, solvate or hydrate thereof for use according to claim 1 or claim 2 wherein the condition is selected from atypical facial pain, neuropathic pain, back pain, complex regional pain syndromes I and II, arthritic pain, sports injury pain, pain related to infection, post-polio syndrome, post-herpetic neuralgia, phantom limb pain, labour pain, cancer pain, post-chemotherapy pain, post-stroke pain, post-operative pain, neuralgia, tolerance to narcotics or withdrawal from narcotics.

4. The use of (+)-6-carboxamido-3 -methylamino- 1,2,3, 4-tetrahydrocarbazole or a physiologically acceptable salt, solvate or hydrate thereof in the manufacture of a medicament for use in the treatment of a condition involving enhanced or exaggerated sensitivity to pain.

5. Use according to claim 4, wherein the condition is hyperalgesia, causalgia or allodynia.

6. Use according to claim 4 or claim 5 wherein the condition is selected from atypical facial pain, neuropathic pain, back pain, complex regional pain syndromes I and LI, arthritic pain, sports injury pain, pain related to infection, post-polio syndrome, post- herpetic neuralgia, phantom limb pain, labour pain, cancer pain, post-chemotherapy pain, post-stroke pain, post-operative pain, neuralgia, tolerance to narcotics or withdrawal from narcotics.

7. A method for the treatment or prophylaxis of conditions involving enhanced or exaggerated sensitivity to pain in a subject which comprises administering to the subject an effective amount of (+)-6-carboxamido-3 -methylamino- 1,2,3, 4- tetrahydrocarbazole or a physiologically acceptable salt, solvate or hydrate thereof.

8. Method of treatment according to claim 7, wherein the condition is hyperalgesia, causalgia or allodynia.

9. Method of treatment according to claim 7 or claim 8 wherein the condition is selected from atypical facial pain, neuropathic pain, back pain, complex regional pain syndromes I and II, arthritic pain, sports injury pain, pain related to infection, post-polio syndrome, post-herpetic neuralgia, phantom limb pain, labour pain, cancer pain, post- chemotherapy pain, post-stroke pain, post-operative pain, neuralgia, tolerance to narcotics or withdrawal from narcotics.