WO2012039657A1

WO2012039657A1 - Novel chromane compound for the treatment of pain disorders

Info

Publication number: WO2012039657A1
Application number: PCT/SE2010/051021
Authority: WO
Inventors: Carl-Johan Aurell; Yevgeni Besidski; Inger Kers; Martin Nylöf
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2010-09-22
Filing date: 2010-09-22
Publication date: 2012-03-29
Anticipated expiration: 2013-03-22

Abstract

The present invention relates to the compound N-[(3S)-5-(5-methoxypyrazin-2-yl)-3,4- dihydro-2H-chromen-3-yl]-6-[(2,2,2-trifluoroethoxy)methyl]pyridine-3-carboxamide, or a pharmaceutical composition comprising said compound and to the use of said compounds in therapy.

Description

Novel chromane compound for the treatment of pain disorders Field of the invention

The present invention relates to a novel compound, to a pharmaceutical composition comprising said compound and to the use of said compound in therapy.

Background

The current treatment regimes for pain conditions utilise compounds which exploit a limited range of pharmacological mechanisms. One class of compounds, the opioids, stimulates the endogenous endorphine system; an example from this class is morphine. Compounds of the opioid class have several drawbacks that limit their use, e.g. emetic and constipatory effects and negative influence on respiratory capability. The second major class of analgesics, the non-steroidal antiinflammatory analgesics of the COX-1 or COX-2 types, also have liabilities such as insufficient efficacy in severe pain conditions and at long term use the COX-1 inhibitors cause ulcers of the mucosa. Mechanisms of analgesic effects of other currently used medicines are insufficiently characterized and/or have limited therapeutic potential.

Local anesthetics, that are known to block voltage-gated sodium channels, in a nonselective fashion, are useful for relieving pain in various areas of the human body and for blocking nerve conduction from the periphery to the central nervous system. They can also be used in the last-mentioned way to block sensory signalling by instilling solutions of local anesthetics at the spinal cord. Due to their high toxicity, in particular side effects of the cardiovascular and central-nervous systems, they can not, however, be used for systemic administration as generally useful analgesics. There remains thus a need for selective modulators of sodium channels involved in pain signal conduction, e.g. for the treatment of post herpetic neuropathy and post herpetic neuralgia.

Nine sodium channel subtypes have been cloned and functionally expressed to date.

(Wood JN, Baker M.. Current Opinion in Pharmacology 2001, 1, 17-21). They are differentially expressed throughout muscle and nerve tissues and show distinct biophysical properties. All voltage-gated sodium channels (NaV:s) are characterized by a high degree of selectivity for sodium over other ions and by their voltage-dependent gating. By applying genetic analysis it has been shown that a mutation in the gene coding for sodium channel NaV1.7, making this protein non-functional, can make a human become almost insensitive to pain (Cox JJ et al. Nature 2006, 444, 894-898 and Ahmad et al, Human Molecular Genetics, 2007, 17, 2114-2121).

It is well known that the voltage-gated sodium channels in nerves play a critical role in neuropathic pain (Baker MD and Wood JN. Trends in Pharmacological Sciences 2001, 22, 27-31). Injuries of the peripheral nervous system often result in neuropathic pain persisting long after the initial injury resolves. Examples of neuropathic pain include, but are not limited to, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias. It has been shown in human patients as well as in animal models of neuropathic pain, that damage to primary afferent sensory neurons can lead to neuroma formation and spontaneous activity, as well as evoked activity in response to normally innocuous stimuli. NaV1.7 is expressed in human neuromas, which may be responsible for the abnormal neural activity in chronic pain states {Acta Neurochirurgica 2002, 144, 803-810).

In rat models of peripheral nerve injury, ectopic activity in the injured nerve corresponds to the behavioral signs of pain. In these models, intravenous application of the sodium channel blocker and local anesthetic lidocaine can suppress the ectopic activity and reverse the tactile allodynia at concentrations that do not affect general behavior and motor function (Mao J and Chen LL, Pain, 2000, 87, 7-17).

In addition to neuropathic pain, sodium channel blockers have clinical uses in the treatment of epilepsy and cardiac arrhythmias. Recent evidence from animal models suggests that sodium channel blockers may also be useful for neuroprotection under ischaemic conditions caused by stroke or neural trauma and in patients with multiple sclerosis (MS). WO2008/130320 discloses certain chroman compounds exhibiting voltage-gated sodium channel inhibiting activity, especially Nav 1.7 blocking activity.

Disclosure of the invention

An aspect of the present invention is the compound N-[(3S)-5-(5-methoxypyrazin-2- yl)chroman-3-yl]-6-(2,2,2-trifluoroethoxymethyl)pyridine-3-carboxamide of the formula

One embodiment of the invention is the compound N-[(3S)-5-(5-methoxypyrazin-2- yl)chroman-3-yl]-6-(2,2,2-trifluoroethoxymethyl)pyridine-3-carboxamide in amorphous form.

Yet an embodiment of the invention is the compound N-[(3S)-5-(5-methoxypyrazin-2- yl)chroman-3-yl]-6-(2,2,2-trifluoroethoxymethyl)pyridine-3-carboxamide in crystalline form.

Synthesis

General Methods

All solvents used were of analytical grade and commercially available anhydrous solvents were routinely used for reactions. Starting materials used were available from commercial sources, such as methyl 6-(hydroxymethyl)pyridine-3-carboxylate, 2,2,2-trifluoroethanol, 2-bromo-5-methoxypyrazine, or prepared according to procedures disclosed in the patent literature. NMR spectroscopy was performed on a Bruker DPX400 NMR spectrometer operating at 400 MHz for 1H, 376 MHz for ¹⁹F, and 100 MHz for ¹³C, equipped with a 4-nucleus probe- head with Z-gradients. Alternatively, NMR spectroscopy was performed on a Bruker 500 MHz Avance III NMR spectrometer, operating at 500 MHz for ¾ equipped with a 5 mm TCI cryogenically cooled probe-head with Z-gradients.

The following reference signals were used: the middle line of (CD₃)₂SO δ 2.50

CDC1₃ δ 7.26 if the solvent contained 0.03% to 0.05% v/v tetramethylsilane, δ 0.00

(1H and ¹³C); unless otherwise indicated.

LC-MS analyses are recorded on a Waters LCMS system equipped with a Waters X-Terra MS, C8-column, (3.5 μιη, 100 mm x 3.0 mm i.d.). The mobile phase system consists of A: 10 mM ammonium acetate in water/MeCN (95:5) and B: MeCN. A linear gradient is applied running from 0% to 100% B in 4-5 minutes with a flow rate of 1.0 mL/min. The mass spectrometer is equipped with an electrospray ion source (ESI) operated in a positive or negative ion mode. The capillary voltage was 3 kV and the mass spectrometer is typically scanned between m/z 100-700. Alternatively, LC-MS HPLC conditions are as follows: Column: Agilent Zorbax SB-C8 2mm ID X 50mm Flow: 1.4 mL/minGradient: 95% A to 90% B over 3 min. hold 1 minute ramp down to 95% A over 1 minute and hold 1 minute. Where A = 2% MeCN in water with 0.1% formic acid and B = 2% water in MeCN with 0.1% formic acid. UV-DAD 210-400 nm.

Or, LC-MS analyses are performed on a LC-MS consisting of a Waters sample manager 2777C, a Waters 1525 μ binary pump, a Waters 1500 column oven, a Waters ZQ single quadrupole mass spectrometer, a Waters PDA2996 diode array detector and a Sedex 85 ELS detector. The mass spectrometer is configured with an atmospheric pressure chemical ionisation (APCI) ion source which is further equipped with atmospheric pressure photo ionisation (APPI) device. The mass spectrometer scanned in the positive mode, switching between APCI and APPI mode. The mass range is set to m/z 120-800 using a scan time of 0.3 s. The APPI repeller and the APCI corona are set to 0.86 kV and 0.80 μΑ, respectively. In addition, the desolvation temperature (300°C), desolvation gas (400 L/Hr) and cone gas (5 L/Hr) are constant for both APCI and APPI mode. Separation is performed using a Gemini column CI 8, 3.0 mm x 50 mm, 3 μιη, (Phenomenex) and run at a flow rate of 1 ml/min. A linear gradient is used starting at 100 % A (A: 10 mM ammonium acetate in 5% MeOH) and ending at 100% B (MeOH). The column oven temperature is set to 40 °C. Or, LC-MS analyses are performed on a LC-MS system consisting of a Waters Alliance 2795 HPLC, a Waters PDA 2996 diode array detector, a Sedex 75 ELS detector and a ZQ single quadrupole mass spectrometer. The mass spectrometer is equipped with an ES ion source operated in positive or negative ion mode. The capillary voltage was set to 3.2 kV and the cone voltage to 30 V, respectively. The mass spectrometer was scanned between m/z 100-700 with a scan time of 0.3 seconds. The diode array detector scans from 200-400 nm. The temperature of the ELS detector was adjusted to 40°C and the pressure ia set to 1.9 bar. Separation is performed on an X-Terra MS C8, 3.0 mm x 50 mm; 3.5 μιη (Waters) run at a flow rate of 1 mL/min. A linear gradient is applied starting at 100% A (A: lOmM NH₄OAc in 5% MeCN, or 8 mM HCOOH in 5% MeCN) ending at 100% B (B: MeCN). The column oven temperature ia set to 40°C.

Compounds have been named using either ACD/Name, version 10.06, software from Advanced Chemistry Development, Inc. (ACD/Labs), Toronto ON, Canada,

www.acdlabs.com, or Lexichem, version 1.4, software from OpenEye.

Rotamers may or may not be denoted in spectra depending upon ease of interpretation of spectra. Unless otherwise stated, chemical shifts are given in ppm with the solvent as internal standard.

Abbreviations

br broadened

δ chemical shift in parts per million (ppm) downfield from the standard

DCM dichloromethane

dppf (diphenylphosphino)ferrocene

EtOAc ethyl acetete

MeCN acetonitrile

MeOH methanol o.n. over night

r.t. room temperature or ambient temperature (ca 21-25 °C)

One aspect of the invention is a pharmaceutically acceptable salt of the compound N-[(3S)- 5 -(5 -methoxypyrazin-2-yl)chroman-3 -yl] -6-(2,2,2-trifluoroethoxymethyl)pyridine-3 - carboxamide.

One embodiment of the invention is a pharmaceutically acceptable salt of the compound N-[(3S)-5-(5-methoxypyrazin-2-yl)chroman-3-yl]-6-(2,2,2- trifluoroethoxymethyl)pyridine-3 -carboxamide in amorphous form.

Yet an embodiment of the invention is a pharmaceutically acceptable salt of the compound N-[(3S)-5-(5-methoxypyrazin-2-yl)chroman-3-yl]-6-(2,2,2- trifluoroethoxymethyl)pyridine-3 -carboxamide in crystalline form.

Salts for use in pharmaceutical formulations will be pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts that may be useful in an aspect of the invention are for example an acid-addition salt such as a salt formed with an inorganic or organic acid, such as any one of hydrochloride, tartrate, or oxalate salts.

Still other pharmaceutically acceptable salts useful in accordance with the invention and methods of preparing these salts may be found in, for example, Remington's

Pharmaceutical Sciences (18^th Edition, Mack Publishing Co.).

Pharmaceutical compositions

According to one embodiment of the present invention there is provided a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound N-[(3S)-5-(5-methoxypyrazin-2-yl)chroman-3-yl]-6-(2,2,2- trifluoroethoxymethyl)pyridine-3-carboxamide, or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers. One embodiment of the present invention is a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound N-[(3S)-5-(5- methoxypyrazin-2-yl)chroman-3 -yl] -6-(2,2 ,2-trifluoroethoxymethyl)pyridine-3 - carboxamide in amorphous form, or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.

One embodiment of the present invention is a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound N-[(3S)-5-(5- methoxypyrazin-2-yl)chroman-3 -yl] -6-(2,2 ,2-trifluoroethoxymethyl)pyridine-3 - carboxamide in crystalline form, or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.

The pharmaceutical composition may be in a form suitable for oral administration, for example as a tablet, pill, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration e.g. as an ointment, patch or cream or for rectal administration e.g. as a suppository.

In general the above compositions may be prepared in a conventional manner using one or more conventional excipients, pharmaceutical acceptable diluents and/or inert carriers.

The typical daily dose of the active ingredient varies within a wide range and will depend on various factors such as the relevant indication, severity of the illness being treated, the route of administration, the age, weight and sex of the patient and the particular compound being used, and may be determined by a physician. Medical Use

The compound N-[(3S)-5-(5-methoxypyrazin-2-yl)chroman-3-yl]-6-(2,2,2- trifluoroethoxymethyl)pyridine-3 -carboxamide, in base form, amorphous form, crystalline form or in any other form as claimed herein in accordance with the invention, is contemplated to be useful in therapy. The compound N-[(3S)-5-(5-methoxypyrazin-2- yl)chroman-3-yl]-6-(2,2,2-trifluoroethoxymethyl)pyridine-3-carboxamide as herein described and claimed, or a pharmaceutically acceptable salt thereof, exhibit a high degree of potency at the sodium channel NaVl .7 and also selectivity for this channel compared to other voltage-gated sodium channels. Accordingly, the compound N-[(3S)-5-(5- methoxypyrazin-2-yl)chroman-3 -yl] -6-(2,2 ,2-trifluoroethoxymethyl)pyridine-3 - carboxamide of the present invention is expected to be useful in the treatment of conditions associated with expression of NaVl .7 and other voltage-gated sodium channels.

The compound N-[(3S)-5-(5-methoxypyrazin-2-yl)chroman-3-yl]-6-(2,2,2- trifluoroethoxymethyl)pyridine-3 -carboxamide of the invention may be used to produce an inhibitory effect of sodium channels in mammals, including man.

One embodiment of the invention relates to the use of the compound N-[(3S)-5-(5- methoxypyrazin-2-yl)chroman-3 -yl] -6-(2,2 ,2-trifluoroethoxymethyl)pyridine-3 - carboxamide as hereinbefore defined, in the manufacture of a medicament for the treatment of NaVl .7 mediated disorders.

The compound N-[(3S)-5-(5-methoxypyrazin-2-yl)chroman-3-yl]-6-(2,2,2- trifluoroethoxymethyl)pyridine-3 -carboxamide according to the invention is

expected to be useful for the treatment of a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies, post traumatic neuropathy, and post herpetic neuralgia; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout. Still an aspect of the invention is the use of the compound N-[(3S)-5-(5- methoxypyrazin-2-yl)chroman-3 -yl] -6-(2,2 ,2-trifluoroethoxymethyl)pyridine-3 - carboxamide, for the treatment of a vascular headache such as migraine.

Yet an aspect of the invention is the use of the compound N-[(3S)-5-(5-methoxypyrazin-2- yl)chroman-3-yl]-6-(2,2,2-trifluoroethoxymethyl)pyridine-3-carboxamide, for the treatment of pain conditions related to erythermalgia, paroxysmal extreme pain disorder, psoriasis, emesis, urinary incontinence and hyperactive bladder.

Still an embodiment of the present invention is the use of the compound N-[(3S)-5-(5- methoxypyrazin-2-yl)chroman-3 -yl] -6-(2,2 ,2-trifluoroethoxymethyl)pyridine-3 - carboxamide, for the treatment of epilepsy.

One embodiment of the invention relates to the use of the compound N-[(3S)-5-(5- methoxypyrazin-2-yl)chroman-3 -yl] -6-(2,2 ,2-trifluoroethoxymethyl)pyridine-3 - carboxamide, as hereinbefore defined, for the treatment of pain conditions related to arthritis, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis or ischeamic pain.

One embodiment of the invention relates to the use of the compound N-[(3S)-5-(5- methoxypyrazin-2-yl)chroman-3 -yl] -6-(2,2 ,2-trifluoroethoxymethyl)pyridine-3 - carboxamide, as hereinbefore defined, in therapy.

Still an embodiment of the invention relates to the use of the compound N-[(3S)-5- (5-methoxypyrazin-2-yl)chroman-3-yl]-6-(2,2,2-trifluoroethoxymethyl)pyridine-3- carboxamide, as hereinbefore defined, for the manufacture of a medicament for the treatment of a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout. Still an aspect of the invention is the use of the compound N-[(3S)-5-(5- methoxypyrazin-2-yl)chroman-3 -yl] -6-(2,2 ,2-trifluoroethoxymethyl)pyridine-3 - carboxamide, for the manufacture of a medicament for use in the treatment of a vascular headache such as migraine.

Yet an aspect of the invention is the use of the compound N-[(3S)-5-(5-methoxypyrazin-2- yl)chroman-3-yl]-6-(2,2,2-trifluoroethoxymethyl)pyridine-3-carboxamide, for the manufacture of a medicament for use in the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder.

Still an embodiment of the present invention is the use of the compound N-[(3S)-5-(5- methoxypyrazin-2-yl)chroman-3 -yl] -6-(2,2 ,2-trifluoroethoxymethyl)pyridine-3 - carboxamide, for the manufacture of a medicament for use in the treatment of epilepsy.

Still an embodiment of the invention relates to a method for the treatment of any one of the following pain disorders such as: acute pain; chronic pain;

neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain;

pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout;

whereby the compound N-[(3S)-5-(5-methoxypyrazin-2-yl)chroman-3-yl]-6-(2,2,2- trifluoroethoxymethyl)pyridine-3-carboxamide, as hereinbefore defined, is

administered to a subject in need of such treatment.

Still an aspect of the invention is a method for the treatment of a vascular headache such as migraine, whereby the compound N-[(3S)-5-(5-methoxypyrazin-2- yl)chroman-3-yl]-6-(2,2,2-trifluoroethoxymethyl)pyridine-3-carboxamide, as

hereinbefore defined, is administered to a subject in need of such treatment.

Yet an aspect of the invention is a method for the treatment of pain conditions

related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder, whereby the compound N-[(3S)-5-(5-methoxypyrazin-2-yl)chroman-3-yl]- 6-(2,2,2-trifluoroethoxymethyl)pyridine-3-carboxamide, as hereinbefore defined, is administered to a subject in need of such treatment.

Still an embodiment of the present invention is a method for the treatment of epilepsy, whereby the compound N-[(3S)-5-(5-methoxypyrazin-2-yl)chroman-3-yl]-6-(2,2,2- trifluoroethoxymethyl)pyridine-3-carboxamide, as hereinbefore defined is administered to a subject in need of such treatment.

Yet an embodiment of the invention is the N-[(3S)-5-(5-methoxypyrazin-2- yl)chroman-3-yl]-6-(2,2,2-trifluoroethoxymethyl)pyridine-3-carboxamide, as

hereinbefore defined, for use in the treatment of a pain disorder such as: acute pain;

chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout.

Still an aspect of the invention is the compound N-[(3S)-5-(5-methoxypyrazin-2- yl)chroman-3-yl]-6-(2,2,2-trifluoroethoxymethyl)pyridine-3-carboxamide, as

hereinbefore defined, for use in the treatment of a vascular headache such as

migraine.

Yet an aspect of the invention is the compound N-[(3S)-5-(5-methoxypyrazin-2- yl)chroman-3-yl]-6-(2,2,2-trifluoroethoxymethyl)pyridine-3-carboxamide, as

hereinbefore defined, for use in the treatment of pain conditions related to

erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder.

Still an embodiment of the present invention is the compound N-[(3S)-5-(5- methoxypyrazin-2-yl)chroman-3 -yl] -6-(2,2 ,2-trifluoroethoxymethyl)pyridine-3 - carboxamide, as hereinbefore defined, for use in the treatment of epilepsy. Still an embodiment of the present invention is the use of the compound N-[(3S)-5-(5- methoxypyrazin-2-yl)chroman-3 -yl] -6-(2,2 ,2-trifluoroethoxymethyl)pyridine-3 - carboxamide, in anaesthesia.

In the context of the present specification, the term "therapy" and "treatment" includes prevention and prophylaxis, unless there are specific indications to the contrary. The terms "treat","therapeutic" and "therapeutically" should be construed accordingly.

In this specification, unless stated otherwise, the term "inhibitor" and "antagonist" mean a compound that by any means, partly or completely, blocks the transduction pathway leading to the production of a response by the ligand.

The term "disorder", unless stated otherwise, means any condition and/or disease associated with NaVl .7 activity.

Combinations

Pain treatment as defined herein may be applied as a sole therapy or may involve, in addition to a compound according to the invention, administration of other analgesics or adjuvant therapy. Such therapy may for example include in combination with the compound N-[(3S)-5-(5-methoxypyrazin-2-yl)chroman-3-yl]-6-(2,2,2- trifluoroethoxymethyl)pyridine-3-carboxamideof the present invention, one or more of the following categories of pain-relieving ingredients: a) opioid analgesics, for example morphine, ketobemidone or fentanyl;

b) analgesics of the NSAID or COX- 1/2 class, for example ibuprofene, naproxene, celecoxib or acetylsalicylic acid, and their analogues containing nitric oxide- donating groups;

c) analgesic adjuvants such as amitriptyline, imipramine, duloxetine or mexiletine; d) NMD A antagonists for example ketamine or dextrometorfan;

e) sodium channel blocking agents, for example lidocaine; f) anticonvulsants, for example carbamazepine, topiramate or lamotrigine;

g) anticonvulsant/analgesic amino acids such as gabapentin or pregabalin;

h) cannabinoids.

Each active compound of such a combination may be administered simultaneously, separately or sequentially.

EXAMPLES

The invention will now be illustrated by the following non-limiting examples. Example 1-1

Preparation of methyl 6-{[(methylsulfonyl)oxylmethyl}pyridine-3-carboxylate

In a 50 mL round-bottomed flask, 4-(dimethylamino)pyridine (0.037 g, 0.30 mmol) and methyl 6-(hydroxymethyl)pyridine-3-carboxylate (0.5 g, 2.99 mmoll) were dissolved in DCM (20 mL) under argon. Triethylamine (0.625 mL, 4.49 mmol) was added and the mixture was cooled to -78 °C. Methanesulfonyl chloride (0.301 mL, 3.89 mmol) was added dropwise and the mixture was stirred at low temperature. The reaction mixture was poured into ice-water after lh. The organics were extracted with DCM (3 x 50 mL). The combined organic phase was washed with water (1 x 100 mL), brine (1 x 100 mL), dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and dried in vacuum at r.t. The title compound was obtained in 87% yield (635 mg) as a yellow solid.

1H NMR (400 MHz, CDC1₃) δ ppm 3.14 (s, 3 H) 3.98 (s, 3 H) 5.40 (s, 2 H) 7.59 (dd, J=8.08, 0.51 Hz, 1 H) 8.38 (dd, J=8.08, 2.02 Hz, 1 H) 9.20 (d, J=1.52 Hz, 1 H).

MS (APPI/APCI) m/z 245.9 [M+H⁺] Example 1-2

Preparation of 6-[(2,2,2-trifluoroethoxy)methyll yridine-3-carboxylic acid

In an inerted 5 L reactor with potassium hydroxide (224 g, 3986.56 mmol) in DCM (700 mL) at 20 °C (outer temperature), aliquat 336 (45.6 mL, 99.66 mmol) was added under stirring, the flask was rinse washed with DCM (200 mL) and added to the reactor. 2,2,2- Trifluoroethanol (217 mL, 2989.92 mmol) was added slowly via a syringe, time 15 min, with the mixture temperature being <30 °C when charging was complete. Methyl 6- {[(methylsulfonyl)oxy]methyl}pyridine-3-carboxylate (244 g, 996.64 mmol) was added and a yellow-beige slurry was obtained. Full conversion was observed after 15 min. Water (1 L) was added and the temperature raised 50 °C and the mixture was stirred o.n.. The phases were separated and the organic phase was discharged, another wash with DCM (0.7 L) was done. The organic phase was discharged and the aqueous phase was clear filtered and put back into the reactor. At outer temperature 20 °C hydrochloric acid (150 mL) was charged and a slurry was obtained, which was stirred at outer temperature 0°C 1 h and was then vacuum filtrated, washed with water (2 x 90 mL) and dried in a vacuum oven at 45 °C o.n. to give the title compound (169 g, 72.1%) as a beige solid.

1H NMR (400 MHz, DMSO-t/₆) δ ppm 4.26 (q, 2 H) 4.83 (s, 2 H) 7.56 (dd, 1 H) 8.32 (dd, 1 H) 9.02 (dd, 1 H) 13.44 (br. s., 1 H).

Example 1-3

Pre aration of (3S)-3-amino-3,4-dihvdro-2H-chromen-5-ol

Scalemic (S)-5-methoxychroman-3 -amine (17.8 g, 54.05 mmol), as the D-tartaric acid salt was partitioned between DCM (200 mL) and 1M NaOH (150 mL). The layers were separated and the aqueous layer was extracted with additional dichloromethane (50 mL). The combined organic layer was dried over Na₂SC>4 and concentrated in vacuum to give approximately 8.8 g of the free base, which was redissolved in DCM (100 mL) and cooled to -70 °C. Tribromoborane (10.22 mL, 108.1 1 mmoL) was added over 15 min under nitrogen. The cooling bath was replaced by an ice-bath and the obtained suspension was stirred at 0 °C for 30 min. The mixture was cooled to -10 °C. Water (25 mL) was slowly added followed by slow addition of 4 M NaOH (approx 90 mL) until pH 10-1 1. The precipitated material was filtered off and washed with one portion of water and dried o.n. in a vacuum oven at 55 °C to give the title compound (10.70 g, 120%) as a beige solid.

1H NMR (400 MHz, DMSO-t/₆) δ ppm 9.40 (br. s., 1 H), 6.85 (t, 1 H), 6.31 - 6.39 (m, 1 H), 6.22 (d, 1 H), 3.96 - 4.06 (m, 1 H), 3.59 (dd, 1 H), 3.12 - 3.21 (m, 1 H), 2.81 (dd, 1 H), 2.24 (dd, 1 H).

MS (APPI/APCI) m/z 166 [M+H⁺]

The title compound: (3S)-3-amino-3,4-dihvdro-2H-chromen-5-ol was also synthesized according to the procedure described below:

To a solution of (S)-5-methoxychroman-3 -amine (48.8 g, 279.3 mmol) in acetic acid (50 ml) heated at 120 °C hydrogen bromide 48% in water (320 ml, 480g, 2.85 mol) was added over 15 min. The reaction mixture was stirred at this temperature for 6 h, then cooled to 10 °C and stirred overnight. The reaction mixture was transferred to a 1L reactor and the outer temperature was held at 15 °C. Ammonia 14.8 M (370 ml, 5.5 moles) was added slowly to the mixture outer temperature being held between -5°C and 15°C. After 1.5 h the addition was complete while pH value turned to 10. The reaction mixture was cooled to 0 °C and was held at that temperature overnight. The slurry formed was filtered to leave a solid product which was dried in vacuum overnight to yield the title compound (43.8 g, 97 %).

Example 1-4

Preparation of (3S)-3-[(tert-butoxycarbonyl)aminol-3.,4-dihvdro-2H-chromen-5-yl trifluoromethanesulfonate

A suspension of (3S)-3-amino-3,4-dihydro-2H-chromen-5- ol (8.93 g, 54.045 mmol) and triethylamine (18.03 mL, 129.71 mmol) in DCM (190 mL) was cooled to 0 °C and di-tert- butyl dicarbonate (12.97 g, 59.45 mmol) was added. The reaction mixture was allowed to warm up to rt and it was stirred for 2h, followed by cooling again to 0 °C and a second portion of triethylamine (18.03 mL, 129.71 mmol) was added. After 5 min

trifluoromethanesulfonic anhydride (11.82 mL, 70.26 mmol) was slowly added over 45 min. The obtained reaction mixture was stirred at 0 °C for 10 min. The reaction mixture was stirred at r.t. o.n., it was washed with water and the organic layer was dried over Na₂S0₄, filtered and concentrated in vacuum. The crude was added to a prepacked Redisep 120 g column and automatically eluted by an ISCO-system with a gradient of EtOAc in heptane (0-30%, detecting at 230 nm). The title compound (12.13 g, 56.5%) was obtained as an oil, which solidified upon standing.

1H NMR (400 MHz, CDC1₃) δ ppm 7.21 (t, 1 H), 6.90 (dd, 2 H), 4.79 (d, 1 H), 4.25 (br. s., 1 H), 4.15 (d, 2 H), 3.06 (dd, 1 H), 2.85 (dd, 1 H), 1.45 (s, 9 H).

MS (APPI/APCI) m/z 298 (M-Boc) The title compound: (3S)-3-[(tert-butoxycarbonyl)aminol-3.,4-dihvdro-2H-chromen-5- yl trifluoromethanesulfonate was also synthesized according to the procedure described below:

To a solution of (3S)-3-amino-3,4-dihydro-2H-chromen-5- ol (40.0 g, 242.3 mmol) in isopropyl acetate (260 ml) a solution of Di-t-butyldicarbonate (58.81 g, 269.46 mmol) in isopropyl acetate (100 ml) was added over lh at 45 °C. The reaction mixture was stirred at 45 °C for 4.5 h and then at 10 °C overnight. The reaction mixture was cooled to -10 ° and triethylamine (103 ml, 740 mmol) was added followed by an addition of

trifluoromethanesulfonic anhydride (49 ml, 291 mmol) over 1.5 h. The reaction mixture was stirred for 30 min at -10 ° and then heated to 30 °C. A solution of sodium bisulfate monohydrate (53.56 g, 387.90 mmol) in water (160 ml) was added at room temperature. The layers were separated (aqueous phases pH=4) and the organic phase was washed with water (200 ml). The organic layer was concentrated in vacuo and the residue was crystallized from a mixture of ethanol and water (2: 1). The crystallized product was filtered off and washed twice with a cold (0 °) mixture of water (100 ml) and ethanol (100 ml) before it was dried in vacuum oven at 40 °C to yield the title compound (77.9 g, 81%).

Example 1-5

Preparation of tert-butyl [(3S)-5-( 5,5-tetramethyl-1.3,2-dioxaborolan-2-yr)-3.,4- dihydr -2H-chromen-3-yll carbamate

A mixture of (3S)-3-[(tert-butoxycarbonyl)amino]-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate (5.00 g, 12.58 mmol), potassium acetate (3.70 g, 37.75 mmol) and bis(pinacolato)diboron (6.39 g, 25.17 mmol) in dioxane was stirred under a stream of argon for a circa 2 minutes. PdCl₂(dppf)-CH₂Cl₂ (0.822 g, 1.01 mmol) was added and the reaction mixture was heated to reflux for 2.5h. The reaction mixture was allowed to cool and it was filtered through a pad of celite which was rinsed with MeOH. The filtrate was concentrated in vacuum and the crude was partitioned between EtOAc and 1M NaOH. The organic layer was dried over Na₂S0₄ and concentrated in vacuum. The crude was added to a pre packed Redisep 80 g column and was eluted by an ISCO-system with a gradient of EtOAc in heptane (0-30%, detecting at 240 nm). A sticky colorless oil was obtained, which was used in the subsequent step without further analysis or purification.

Example 1-6

Preparation of tert-butyl [(3S)-5-( -methoxypyrazin-2-yl)-3,4-dihvdro-2H-chromen- 3-yll carbamate

A mixture of tert-butyl [(3S)-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-3,4-dihydro- 2H-chromen-3-yl] carbamate (4.72 g, 12.58 mmol), 2-bromo-5-methoxypyrazine (2.378 g, 12.58 mmol, commercially available) and potassium carbonate (18.87 mL, 37.74 mmol) in DMF (45 mL) was stirred under nitrogen for a circa 2 minutes. PdCl₂(d f)-CH₂Cl₂ adduct (0.719 g, 0.88 mmol) was added and the mixture was heated to 120 °C under N₂ for 55 min. The mixture was allowed to cool. EtOAc (100 mL) and brine (50 mL) were added. The organic layer was washed with additional brine, dried over Na₂S0₄ and concentrated in vacuum. The crude was purified by column chromatography using a pre packed Redisep 80 g column and eluation by an ISCO-system with a gradient of EtOAc in heptane (0- 40%). Concentration and drying in vacuum yielded the tite compound (3.04 g, 67.6%) as a white solid.

1H NMR (400 MHz, DMSO-ifc) δ ppm 8.38 (d, 1 H), 8.33 (d, 1 H), 7.21 (t, 1 H), 6.93 - 7.02 (m, 2 H), 6.85 - 6.91 (m, 1 H), 4.12 (d, 1 H), 3.96 (s, 3 H), 3.78 (d, 2 H), 2.78 - 2.87 (m, 1 H), 2.74 (d, 1 H), 1.35 (s, 9 H).

MS (APPI/APCI) m/z 358 [M+H⁺] Example 1-7

Preparation of (3S)-5-(5-methoxypyrazin-2-yl)-3.,4-dihvdro-2H-chromen-3-amine

Trifluoroacetic acid (21.21 mL, 275.32 mmol) was added in portions to an ice-cooled solution of tert-butyl [(3S)-5-(5-methoxypyrazin-2-yl)-3,4-dihydro-2H-chromen-3- yljcarbamate (4.92 g, 13.77 mmol) in DCM (120 mL) . The ice-bath was removed and the obtained solution was stirred at r.t. for 45 min and then stored in a refridgerator (circa 4 °C) o.n.. Volatiles were removed in vacuum and the residue was partitioned between 1M NaOH, NaCl (s) and EtOAc. The aqueous layer was extracted with additional 3 portions of EtOAc and the combined organic layers was dried over Na₂SC>4 and concentrated in vacuum to yield the title compound (4.28 g, 121%).

1H NMR (400 MHz, DMSO-t/₆) δ ppm 8.40 (d, 1 H), 8.35 (d, 1 H), 7.22 (t, 1 H), 7.01 (d, 1 H), 6.89 (d, 1 H), 4.62 (br. s., 2 H), 4.15 (d, 1 H), 3.96 (s, 3 H), 3.81 (dd, 1 H), 3.21 - 3.32 (m, 1 H), 2.92 (dd, 1 H), 2.63 (dd, 1 H).

MS (APPI/APCI) m/z 258 [M+H⁺]

Example 1 - Final compound

Preparation of N-[(3S)-5-(5-methoxypyrazin-2-yl)-3.,4-dihvdro-2H-chromen-3-yll-6- [(2,2,2-trifluoroethoxy)methyllpyridine-3-carboxamide

1 , l'-Carbonyldiimidazole (2.317 g, 14.29 mmol) was added to a stirred suspension of 6- [(2,2,2-trifluoroethoxy)methyl]pyridine-3-carboxylic acid (3.21 g, 13.64 mmol) in EtOAc (30 mL). The solution was stirred under nitrogen at 60 °C for 20 min and then allowed to cool to r.t. A solution of (3S)-5-(5-methoxypyrazin-2-yl)-3,4-dihydro-2H-chromen-3- amine (32.5 mL, 12.99 mmol) in ethyl acetate was added and the reaction mixture was stirred at r.t. o.n.. The mixture was washed with 1M NaOH (50 mL) and brine (50 mL). The organic layer was dried over Na₂SC>4 and concentrated in vacuum. The crude was dissolved in chloroform and added to a prepacked Redisep 120 g column and was eluted by an ISCO-system with a gradient of EtOAc in heptane (0-100%). After concentration and drying 3.95 g (64%) of amorphous title compound was obtained.

1H NMR (400 MHz, CDC -d) δ ppm 8.89 (d, 1 H), 8.27 (d, 1 H), 8.21 (d, 1 H), 8.11 (dd, 1 H), 7.55 (d, 1 H), 7.23 - 7.31 (m, 1 H), 7.04 (dd, 1 H), 7.00 (d, 1 H), 6.53 (d, 1 H), 4.86 (s, 2 H), 4.66 - 4.74 (m, 1 H), 4.24 - 4.37 (m, 2 H), 4.02 (s, 3 H), 3.97 (q, 2 H), 3.37 (dd, 1 H), 2.87 (d, 1 H).

MS (APPI/APCI) m/z 475 [M+H⁺] Example 2

Preparation of N- [(3 S)-5-(5-methoxypyrazin-2-yl)chroman-3-yll -6-(2,2,2- trifluoroethoxymethyl)pyridine-3-carboxamide crystalline Form A

4 mg of amorphous title compound was suspended in 1.5 mL hexane at r.t, followed by warming to 50 °C. The sample was then quickly cooled in a dry-ice/MeOH bath. The resulting solid did not redissolve upon warming to 50 °C and yielded crystalline form A.

To a slurry of amorphous title compound in iso-propanol were added a few seeding crystalls of form A, which resultated in spontaneous precipitation as form A.

X-Ray Powder Diffraction (XRPD) patterns were collected on a PANalytical X'Pert PRO MPD theta-theta system using long-fine-focus Cu Κα-radiation, wavelength of X-rays 1.5418 A, at 40 kV and 50 mA . A programmable divergence slit and a programmable anti- scatter slit giving an irradiated length of 10 mm were used. 0.02 radian Soller slits were used on the incident and on the diffracted beam path. A 20 mm fixed mask was used on the incident beam path and a Nickel-filter was placed in front of a PIXcel- detector using 255 active channels. Thin flat samples were prepared on flat silicon zero background plates using a spatula. The plates were mounted in sample holders and rotated in a horizontal position during measurement. Diffraction patterns were collected between 2°2theta and 40 or 50°2theta in a continuous scan mode. Total time for a scan between 2 and 40°2theta was approximately 10 minutes.

Figure 1 is an X-ray power diffraction (XPRD) for N-[(3S)-5-(5-methoxypyrazin-2- yl)chroman-3-yl]-6-(2,2,2-trifluoroethoxymethyl)pyridine-3-carboxamide crystalline Form A. Example 3

Preparation of N- [(3 S)-5-(5-methoxypyrazin-2-yl)chroman-3-yl] -6-(2,2,2- trifluoroethoxymethyl)pyridine-3-carboxamide crystalline Form B

The product in the last step of the synthesis and purification of N-[(3S)-5-(5- methoxypyrazin-2-yl)chroman-3 -yl] -6-(2,2 ,2-trifluoroethoxymethyl)pyridine-3 - carboxamide was isolated as an oil.

The oil was dissolved in a temperature controlled vessel of 100 L by adding filtered toluene ((5.8 L/kg); 67.89 moles; 7.18 L)). The temperature of the toluene solution was set to 70°C followed by adding filtered heptanes ((4L/kg) 33.78 moles 4.95L; 3.39kg), where a relatively clear solution appeared. The solution was cooled to 50°C and the crystallization of form B was started by seeding the solution with 2 g. of form B. The temperature was kept at 50 °C until a solution with crystals was obtained. The reaction vessel was cooled to 10°C and the slurry was filtered. The crystals were washed with a mixture of cold clear filtered toluene/heptane solution (2.9 L/kg-bulk-LR); 33.95 moles; 3.59 L; 3.13 kg;) and Heptane (2 L/kg-bulk-LR; 16.89 moles; 2.48 L; 1.69 kg;)). The product was dried under reduced pressure and 45°C until the toluene content was low enough to meet the set limits.

Spontaneous precipitation of form B (seeds)

The first precipitation of form B occurred during re-crystallization. The first step was an attempt to dissolve N-[(3S)-5-(5-methoxypyrazin-2-yl)chroman-3-yl]-6-(2,2,2- trifluoroethoxymethyl)pyridine-3 -carboxamide (16.3 gr) in 16.3 ml Toluene (1 mL/g-bulk- LR) and heptane (1 mL/g-bulk-LR) 24.45 ml followed by a raise in temperature to 37 °C. No clear solution was obtained. However, a solution was obtained by elevation of the temperature to 50°C in combination with addition of 30 ml Toluene (1 mL/g-bulk-LR). 15ml. of heptanes was added and the first crystal appeared. The crystallization was increased by adding 15 ml of heptanes. A viscous slurry was observed after 52 minutes. The filtration was facilitated by addition of 40ml of Toluene/Heptane, 25/75. An additional 40 ml of Toluene/Heptane, 25/75 was used to rinse the crystals on the filter. The crystals were finally rinsed with pure heptanes. The N-[(3S)-5-(5-methoxypyrazin-2-yl)chroman-3- yl]-6-(2,2,2-trifluoroethoxymethyl)pyridine-3-carboxamide was dried under reduced pressure at 45°C until the organic solvent residues were low enough to meet the set limits. X-Ray Powder Diffraction (XRPD) patterns were collected on a PANalytical X'Pert PRO MPD theta-theta system using long-fine-focus Cu Κα-radiation, wavelength of X-rays 1.5418 A, at 40 kV and 50 mA . A programmable divergence slit and a programmable anti- scatter slit giving an irradiated length of 10 mm were used. 0.02 radian Soller slits were used on the incident and on the diffracted beam path. A 20 mm fixed mask was used on the incident beam path and a Nickel-filter was placed in front of a PIXcel- detector using 255 active channels. Thin flat samples were prepared on flat silicon zero background plates using a spatula. The plates were mounted in sample holders and rotated in a horizontal position during measurement. Diffraction patterns were collected between 2°2theta and 40 or 50°2theta in a continuous scan mode. Total time for a scan between 2 and 40°2theta was approximately 10 minutes.

Figure 2 is an X-ray power diffraction (XPRD) for N-[(3S)-5-(5-methoxypyrazin-2- yl)chroman-3-yl]-6-(2,2,2-trifluoroethoxymethyl)pyridine-3-carboxamide crystalline Form B.

BIOLOGICAL EVALUATION

The ability of the compound of the invention to modulate specific voltage-gated sodium channels of interest e.g. NaVl .7, NaVl .2 or NaVl .5, may be determined by the following tests.

Cell lines

Stable cell lines expressing the full-length protein of the voltage-gated sodium channels NaV 1.7, NaV 1.2 or NaV 1.5, with or without one beta- 1 , beta-2, beta-3 or beta-4 subunit, are created by transfecting CHO cells or HEK293 cells, or any other suitable cell line, with a vector construct containing the complete open reading frame under a suitable promoter, as well known in the art. In vitro Electrophysiology

Electrophysiological studies can be performed with automated patch-clamp

electrophysiology platforms like Ion Works HT and Ion Works Quattro (Molecular Devises Corp.), as described by (Schroeder K et al. Journal of Biomolecular Screening 2003, 8 (1), 50-64) 1, or any other suitable system. Buffers for such experiments could have the following composition (mM): Internal solution; K-gluconate 100, KC1 40, MgCl 3.2 Hepes 5 and EGTA 3, pH 7.2-7.25. To this amphotericin B is added to final concentration of 0.1 mg/ml to generate access solution. External solution; Dulbecco's Phosphate buffered saline (D-PBS) NaCl 137.93, KC1 2.67, KH₂P04 1.47, Na₂HP04 8.06, CaCl₂ 0.90 and MgCl₂ 0.49, D-Glucose 5.56, Sodium Pyruvate 0.33.. The buffers may also have other compositions. Prior to the experiment cells expressing the voltage-gated ion channel of interest are detached from the tissue culture flasks, centrifuged, and resuspended in D-PBS. Compounds are prepared and serially diluted in DMSO, and finally diluted 1 : 100 in D- PBS. Cells are exposed to compounds through the pipetting system integrated into the platform, and the voltage-gated channel of interest is activated with specific voltage stimulation protocols. A suitable stimulation protocol may consist of eight voltage pulses, stepping from the holding potential of -90 mV to -20 mV for 50 ms at a frequency of 3 Hz (resting-state protocol), or from -65 mV to -20mV for 30 ms at a frequency of 3 Hz (steady-state protocol), but may also have other suitable parameters. Pre- and post-reads are separated by compound addition followed by 3 min incubation.

Electrophysiological studies can also be performed using the whole cell configuration of the standard patch clamp technique as described in the literature. In this assay, cells expressing the human voltage-gated sodium channel of interest are exposed to the compounds by conventional microperfusion systems and suitable voltage stimulus protocol is used to activate the voltage-gated sodium channels.

Ref: Schroeder, K., Neagle, B., Tresize, D.J., Worley, J., Journal of Biomolecular

Screening 8 (1), 2003, 50-64. Ex vivo and in vivo electrophysiology

The compound of the invention may reduce the abnormal neuronal firings induced in dorsal root ganglion neurons or neuroma in rats with Chung nerve lesion (reference see below). The inhibition on abnormal neuroal activities may be observed by perfusion a compound with accumlative concentrations in a organ bath where injured dorsal root ganglion is located (ex vivo) or by intravenous administration (in vivo anaesthetized rat).

In vivo experiments

The compound of the invention when given by systemic administration to mice or rats may specifically reduce pain behavior in the formalin test. This test is an accepted model of clinical pain in man, involving elements of nociceptor activation, inflammation, peripheral sensitization and central sensitization (A Tjolsen et al. Pain 1992, 51, 5). It can therefore be inferred that a compound of the present invention is useful as a therapeutic agent to relieve pain of various origins.

The compound of the invention may show analgesic activity in a rat model of

inflammatory pain induced by FCA (Freund's complete adjuvant) (Ladarola et al. Brain Research 1988, 455, 205-12) and in a model for neuropathic pain like the Chung nerve lesion model (Kim and Chung. Pain 1992, 50, 355).

In vitro metabolic stability test in microsomes

Rat liver tissue was homogenized in ice-cold buffer (10 mM Na/K phosphate, 1,14% KCl pH 7.4; volume (mL) of buffer is 2-4 x liver weight (g)) and centrifuged for 20 min at 14000 g. The supernatant was centrifuged for 80 min at 105.000 g. The pellet was washed with ice-cold buffer (approx. 100 mL for 250g liver) and again centrifuged at 105.000 g. The microsomes were resuspended in a 50 mM phosphate buffer (pH 7.4) using 20 ml Buffer per lOOg liver. Human liver microsomes were purchased from BD Gentest (lot 63103), protein concentration 20 mg/mL. Microsomes were stored until use in an 0₂ free atmosphere at -80°C. The test compound was dissolved in dimethyl sulphoxide (DMSO) to reach a concentration of 1 mM. The compound was diluted with a 50 mM phosphate buffer (pH 7.4) and microsomes and NAPDH were added to reach final concentrations of 1 μΜ compound, 0.5 mg microsomal protein/ml, and 1 mM of NADPH. The total incubation volume was 600 μί. The incubation mixture was kept 10 min at 37 °C before NADPH was added. At 0, 10, 30 and 45 min after addition of NADPH ice cold acetonitrile (1 : 1) + Internal standard 10% v/v was added to stop the reaction. A check for non-specific binding was conducted by adding compound to boiled microsomes. Also, incubations as above were performed in parallel with a cocktail containing 6 known substrates to assure that the six main CYP450 are functional. The cocktail consisted of S-mephenytoin, phenacetin, diclofenac, clomethiazole, midazolam and (+/-)-bufuralol. Following precipitation, the samples were centrifuged for 10 min at 1900 g. The supernatant was transferred to analysis vials and analysed on LC-MS/MS. The concentration of the compound was fitted to the following equation: C = Co-e ^kAt, where C is the measured concentration; Co is the concentration at time zero; and k is the elimination constant. Intrinsic clearance was calculated according to Cli_nt = k- V, in which F is the volume of the incubation. CIM was converted to hepatic extraction ratio using the well-stirred model.

The following results were obtained:

Table 1

Metabolic Metabolic

Compound Stability in Rat Stability in

Microsomes Human EH [%] Microsomes

EH [%]

N-[(3S)-5-(5-methoxypyrazin-2-yl)chroman-3-yl]-

6-(2,2,2-trifluoroethoxymethyl)pyridine-3- < 27 < 34 carboxamideof "EH" in Table 1 means "Hepatic Extraction Ratio", which is a measure for the metabolic stability. A Hepatic Extraction Ratio value of 0% means no metabolism, and a Hepatic Extraction Ratio value of 100% means 100 % metabolism.

Selectivity

The selectivity of human NaVl .7 channel blocking by the compound of the invention against other ion channels was measured using a automated patch-clamp electrophysiology technique based on Ion Works HT platform.

The following results were obtained:

Table 2

Based on potency values in table 2, the selectivity of the compound (S)-N-(5-(5- Methoxypyrazin-2-yl)chroman-3-yl)-6-((2,2,2-trifluoroethoxy)methyl)nicotinamide, for NaVl .7 over NaVl .5 can be calculated to 200-fold, and the selectivity of for NaVl .7 over NaVl .2 can be calculated to >500-fold.

Claims

1. The compound N-[(3S)-5-(5-methoxypyrazin-2-yl)chroman-3-yl]-6-(2,2,2- trifluoroethoxymethyl)pyridine-3-carboxamide of the formula

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 in crystalline form.

3. The compound according to claim 1, for use in therapy.

4. Use of the compound according to claim 1, for the manufacture of a medicament for use in the treatment of a pain disorder.

5. The compound according to claim 1, for use in the treatment of a pain disorder.

6. A method for the treatment of a pain disorder, whereby the compound according to claim 1 is administered to a subject in need of such pain treatment.

7. A pharmaceutical formulation comprising the compound according to claim 1 as an active ingredient, together with a pharmacologically and pharmaceutically acceptable carrier. A compound selected from any one of

• (3S)-3-[(tert-butoxycarbonyl)amino]-3,4-dihydro-2H-chromen-5-yl

trifluoromethanesulfonate;

• tert-butyl [(3S)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydro chromen-3-yl]carbamate;

• tert-butyl [(3S)-5-(5-methoxypyrazin-2-yl)-3,4-dihydro-2H-chromen-3- yljcarbamate; and

• (3S)-5-(5-methoxypyrazin-2-yl)-3,4-dihydro-2H-chromen-3-amine.