HK1066534B - Urea-compounds active as vanilloid receptor antagonists for the treatment of pain - Google Patents

Description

This invention relates to a novel compound, being a urea derivative having pharmacological activity, a process for its preparation, to compositions containing the compound and to the use of the compound in medicine, especially in the treatment of various disorders.

Vanilloids are a class of natural and synthetic compounds that are characterised by the presence of a vanillyl (4-hydroxy 3-methoxybenzyl) group or a functionally equivalent group. Vanilloid Receptor (VR-1), whose function is modulated by such compounds, has been widely studied and is extensively reviewed by Szallasi and Blumberg (The American Society for Pharmacology and Experimental Therapeutics, 1999, Vol. 51, No. 2.).

A wide variety of Vanilloid compounds of different structures are known in the art, for example those disclosed in European Patent Application Numbers, EP 0 347 000 and EP 0 401 903 , UK Patent Application Number GB 2226313 and International Patent Application, Publication Number WO 92/09285 . Particularly notable examples of vanilloid compounds or vanilloid receptor modulators are capsaicin or trans 8-methyl-N-vanillyl-6-nonenamide which is isolated from the pepper plant, capsazepine (Tetrahedron, 53, 1997, 4791) and olvanil or - N-(4-hydroxy-3-methoxybenzyl)oleamide (J. Med. Chem., 36, 1993, 2595).

US Patent Numbers, US 3,424,760 and US 3,424,761 both describe a series of 3-Ureidopyrrolidines that are said to exhibit analgesic, central nervous system, and pyschopharmacologic activities. These patents specifically disclose the compounds 1-(1-phenyl-3-pyrrolidinyl)-3-phenyl urea and 1-(1-phenyl-3-pyrrolidinyl)-3-(4-methoxyphenyl)urea respectively.

International Patent Applications, Publication Numbers WO 02/08221 , WO 02/16317 , WO 02/16318 and WO 02/16319 each disclose certain vanilloid receptor antagonists and their use in the treatment of diseases associated with the activity of the vanilloid receptor.

Co-pending International Patent Application Number PCT/EP02/04802 discloses a series of urea derivatives and their use in the treatment of diseases associated with the activity of the vanilloid receptor.

According to a first aspect of the present invention, there is provided the compound N-(2-Bromophenyl)-N'-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea, having the formula: or a pharmaceutically acceptable salt or solvate thereof.

The compound of the invention can exist in various tautomeric forms and it is to be understood that the invention encompasses all such tautomeric forms.

As indicated above, the compound of the invention can form salts, especially pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts are those use conventionally in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts.

Suitable pharmaceutically acceptable salts include acid addition salts.

Suitable pharmaceutically acceptable acid addition salts include salts with inorganic acids such, for example, as hydrochloric acid, hydrobromic acid, orthophosphoric acid or sulphuric acid, or with organic acids such, for example as methanesulphonic acid, toluenesulphonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid or acetylsalicylic acid.

The salts and/or solvates of the compound of the invention which are not pharmaceutically acceptable may be useful as intermediates in the preparation of pharmaceutically acceptable salts and/or solvates of compound of the invention or the compound itself, and as such form another aspect of the present invention.

The compound of the invention may be prepared in crystalline or non-crystalline form, and if crystalline, may be optionally hydrated or solvated. This invention includes in its scope stoichiometric hydrates as well as compounds containing variable amounts of water.

Suitable solvates include pharmaceutically acceptable solvates, such as hydrates.

Solvates include stoichiometric solvates and non-stoichiometric solvates.

The present invention also provides a process for the preparation of the compound of the invention or a pharmaceutically acceptable salt or solvate thereof, which process comprises coupling 2-bromophenyl isocyanate with (R)-1-(5-Trifluoromethylpyridin-2-yl)-pyrrolidin-3-ylamine with 2-bromophenyl isocyanate with (R)-1-(5-Trifluoromethylpyridin-2-yl)-pyrrolidin-3-ylamine, and optionally thereafter preparing a salt or a solvate of the compound so formed.

Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.

The compound of the invention and pharmaceutically acceptable salts thereof have Vanilloid receptor antagonist (VR1) activity and are believed to be of potential use for the treatment or prophylaxis of certain disorders, or treatment of the pain associated with them, such as: pain, chronic pain, neuropathic pain, postoperative pain, postrheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, dental pain, headache, migraine, neuropathies, carpal tunnel syndrome, diabetic neuropathy, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, neuritis, sciatica, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, broncho constriction, inflammatory disorders, oesophagitis, heart bum, Barrett's metaplasia, dysphagia, gastroeosophageal reflux disorder (GERD), stomach and duodenal ulcers, functional dyspepsia, irritable bowel syndrome, inflammatory bowel disease, colitis, Crohn's disease, pelvic hypersensitivity, pelvic pain, menstrual pain, renal colic, urinary incontinence, cystitis, bums, itch, psoriasis, pruritis, emesis (hereinafter referred to as the "Disorders of the Invention").

Accordingly, the invention also provides the compound of the invention or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance, in particular in the treatment and/or prophylaxis of the Disorders of the Invention.

In particular, the invention provides the compound or a pharmaceutically acceptable salt or solvate thereof for use in the treatment or prophylaxis of pain.

The invention further provides a method for the treatment or prophylaxis of disorders in which antagonism of the Vanilloid (VR1) receptor is beneficial, in particular the Disorders of the Invention, in mammals including humans, which comprises administering to a mammal in need thereof a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt or solvate thereof.

The invention provides for the use of the compound of the invention or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of disorders in which an antagonist of the Vanilloid (VR1) receptor is beneficial, particularly the Disorders of the Invention.

In order to use the compound of the invention in therapy, it will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. Thus, the present invention also provides a pharmaceutical composition, which comprises the compound of the invention or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or excipient therefor.

A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral, rectal administration or intravesical administration to the bladder and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions, suspensions or suppositories. Orally administrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.

For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.

The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. For systemic administration, dosage levels from 0.01 mg to 100mg per kilogramme of body weight are useful in the treatment of pain. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20, 20 to 250, or 0.1 to 500.0 mg, for example 0.2 to 5 and 0.1 to 250 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.5 to 1000 mg; and such therapy may extend for a number of weeks or months.

No unacceptable toxicological effects are indicated with compounds of the invention when administered in accordance with the invention.

The following Descriptions and Examples illustrate the preparation of the compound of the invention.

Abbreviations

• MgSO4 - Magnesium sulfate
• DCM - dichloromethane

Description 1 [(R)-1-(5-Trifluoromethylpyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (D1)

To a solution of 2-chloro-5-trifluoromethylpyridine (7.3g, 0.04mol) and 3R-(+)-3-(tert-butyloxycarbonylamino)pyrrolidine (7.5g, 0.04mol) in dry dimethylformamide (100ml) was added powdered potassium carbonate (6.6g, 0.05mol) and the reaction heated at 100°C for 7h and cooled. Solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was separated, dried (MgSO₄) and filtered. Removal of solvent under reduced pressure gave a solid. Chromatography on silica gel eluting with ethyl acetate and DCM (gradient elution, 20% maximum) afforded the title compound as a white solid.

Description 2 (R)-1-(5-Trifluoromethylpyridin-2-yl)-pyrrolidin-3-ylamine (D2)

A solution of D1 (11.5g, 0.04mol) in DCM (80ml) was cooled (ice-bath) and trifluoroacetic acid (excess, 50ml) was added. Reaction was warmed to ambient temperature, stirred for 3h and partitioned between ethyl acetate and aqueous sodium hydroxide. The organic phase was separated, dried (MgSO₄) and filtered. Removal of solvent under reduced pressure afforded the crude product as a yellow oil. Bulb to bulb distillation under reduced pressure initially afforded the title compound as an oil which crystallised on standing.

Example 1 N-(2-Bromophenyl)-N'-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea (E1)

A solution of 2-bromophenyl isocyanate (Aldrich Chemical Company) (27.4ml, 0.222mol) in dry diethyl ether (65ml) was added dropwise over 0.5h to an efficiently stirred solution of D2 (51.4g, 0.222mol) in dry diethyl ether (0.8L) under argon at ambient temperature. After stirring for 18h, a white precipitate was filtered off and washed with dry diethyl ether (2 x 150ml). The solid was crushed to a fine powder and then re-stirred with diethyl ether (470ml) for 4h at ambient temperature. The insoluble product was filtered off, washed with diethyl ether (100ml) and dried at 50°C/vacuum/24h to afford title compound as a white solid.

¹H NMR (d₆-DMSO, 400MHz) δ 1.94-1.98 (1H, m), 2.19-2.28 (1H, m), 3.31-3.41 (1 H, m), 3.56 (2H, br, s), 3.67-3.71 (1 H, m), 4.34-4.36 (1 H, m), 6.62 (1H, d, J 9.0Hz), 6.89 (1 H, t, J 7.8Hz), 7.28 (1 H, t, J 8.5Hz), 7.47 (1 H, d, J 6.7Hz), 7.55 (1 H, dd, J 8.0, 1.4Hz), 7.76-7.79 (2H, m), 8.12 (1 H, dd, J 8.3, 1.4Hz), 8.41 (1H, s). MH⁺ 429, 431.

Pharmacological Data (a) In vitro assay

As referenced above, the compound of the invention is a vanilloid receptor (VR1) antagonists and hence have useful pharmaceutical properties. Vanilloid receptor (VR1) antagonist activity can be confirmed and demonstrated for any particular compound by use of conventional methods, for example those disclosed in standard preference texts such as D. Le Bars, M. Gozarin and S. W. Cadden, Pharmacological Reviews, 2001, 53(4), 597-652] or such other texts mentioned herein.

The screen used for the compounds of this invention was based upon a FLIPR based calcium assay, similar to that described by Smart et al. (British Journal of Pharmacology, 2000, 129, 227-230). Transfected astrocytoma 1321N1 cells, stably expressing human VR1, were seeded into FLIPR plates at 25,000cells/well (96-well plate) and cultured overnight.

The cells were subsequently loaded in medium containing 4µM Fluo-3 AM (Molecular Probes) for 2 hours, at room temperature, in the dark. The plates were then washed 4 times with Tyrode containing 1.5mM calcium, without probenecid. The cells were pre-incubated with compound or buffer control at room temperature for 30 minutes. Capsaicin (Sigma) was then added to the cells. Compounds having antagonist activity against the human VR1 were identified by detecting differences in fluorescence when measured after capsaicin addition, compared with no compound buffer controls. Thus, for example, in the buffer control capsaicin addition results in an increase in intracellular calcium concentration resulting in fluorescence. A compound having antagonist activity blocks the capsaicin binding to the receptor, there is no signalling and therefore no increase in intracellular calcium levels and consequently lower fluorescence. pKb values are generated from the IC₅₀ values using the Cheng-Prusoff equation.

All compounds tested by the above methodology had pKb > 6, preferred compounds having a pKb > 7.0.

(b) FCA-induced hyperalgesia in the Guinea pig

100µl of 1 mg/ml FCA was injected intraplantar into the left paw of 4 groups of 8 male Dunkin Hartley guinea-pigs (batch: 6282434, average weight 340g). 24 hours later compounds were administered orally at 0 (vehicle), 3, 10 30mg/kg with vehicle as 1 %methylcellulose and dosing volume being 2ml/kg and dosing straight into the stomach. The methylcellulose was added gradually to the compound into the pestle and mortar and ground together.

Behavioural readouts of mechanical hyperalgesia were obtained before FCA administration (naïve reading), after FCA but before drug administration (predose reading) and 1 hour after drug administration. The readout used was paw pressure (Randall-Sellito) and the end point was paw withdrawal. The paw pressure equipment also had one silver disc placed on the point to increase the markings by a factor of 2.

Compounds having a pKb > 7.0 in vitro, according to model (a) above, were tested in this model and shown to be active.

Claims (7)

1. The compound N-(2-Bromophenyl)-N'-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea, having the formula: or a pharmaceutically acceptable salt or solvate thereof.
2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or excipient therefor.
3. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof for use as an active therapeutic substance.
4. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof for use in the treatment and/or prophylaxis of pain.
5. Use of the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of disorders in which antagonism of the Vanilloid (VR1) receptor is beneficial.
6. Use according to claim 5, wherein said disorders are selected from pain, chronic pain, neuropathic pain, postoperative pain, postrheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, dental pain, headache, migraine, neuropathies, carpal tunnel syndrome, diabetic neuropathy, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, neuritis, sciatica, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, broncho constriction, inflammatory disorders, oesophagitis, heart bum, Barrett's metaplasia, dysphagia, gastroeosophageal relux disorder (GERD), stomach and duodenal ulcers, functional dyspepsia, irritable bowel syndrome, inflammatory bowel disease, colitis, Crohn's disease, pelvic hypersensitivity, pelvic pain, menstrual pain, renal colic, urinary incontinence, cystitis, burns, itch, psoriasis, pruritis and emesis.
7. A process for the preparation of the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, which process comprises coupling 2-bromophenyl isocyanate with (R)-1-(5-Trifluoromethylpyridin-2-yl)-pyrrolidin-3-ylamine, and optionally thereafter preparing a salt or a solvate of the compound so formed.