WO2008130323A1

WO2008130323A1 - Novel 8-piperazine-tetrahydronaphtalene derivatives for the treatment of pain

Info

Publication number: WO2008130323A1
Application number: PCT/SE2008/050462
Authority: WO
Inventors: Yevgeni Besidski; Ylva Gravenfors; Istvan Macsari
Original assignee: Astrazeneca Ab
Priority date: 2007-04-23
Filing date: 2008-04-22
Publication date: 2008-10-30

Abstract

The present invention relates to new compounds and pharmaceutically-acceptable salts thereof, and to new intermediates used in the preparation thereof, pharmaceutical compositions containing said compounds and to the use of said compounds in therapy.

Description

NOVEL β-PIPERAZINE-TETRAHYDRONAPHTALENE DERIVATIVES FOR

THE TREATMENT OF PAIN

Field of the Invention

The present invention relates to new compounds, to pharmaceutical composition containing said compounds and to the use of said compounds in therapy. The present invention further relates to processes for the preparation of said compounds and to new intermediates useful in the preparation thereof.

Background

Voltage-gated sodium channels are critical elements in the control of electrical excitability of various cell types, including muscle and neuronal cells. In muscle and neuronal cells voltage-gated sodium channels are mainly responsible for the rising phase of the action potential. Voltage-gated sodium channels are composed of a single alpha subunit and one or two beta subunits. There are 10 known alpha subunit proteins, of which nine are functional as an ion channel. The different alpha subunit proteins are herein referenced to as Navl.x, with x being an integer between 1 and 9. This labelling is in accordance with the conventions of the International Pharmacological Association (REF). Alpha subunits are large proteins of an approximate weight of 260 kDA (~ 2000 amino acids), and are functional as voltage-gated sodium channels as monomeric structures. Four beta subunits are known at present. Beta subunits are smaller proteins of an approximate weight of 33-36 kDa. Beta subunits can modulate functional expression, as well as the characteristics of channel opening and closing (gating) of alpha subunits.

Five major lines of evidence support the notion that voltage-gated sodium channels are important therapeutic targets: a) the biophysical characteristics of voltage-gated sodium channels, b) the tissue expression pattern of voltage-gated sodium channels, c) evidence from preclinical research, d) the association between several congenital diseases and channelopathies of voltage-gated sodium channels, and e) evidence from the usage of pharmacological agents active at voltage-gated sodium channels in the clinic.

A main biophysical characteristic of voltage-gated sodium channels is the fast opening and closing (activation and inactivation) of the channel upon an appropriate voltage stimulus.

These features make voltage-gated sodium channels absolutely essential in the generation of the upstroke of the action potential in most neuronal and muscle cells, and thereby central to the functionality of such tissue. Thus, inhibitory pharmacological interference with the activity of NaVs is expected to have dampening effects on excitability of such tissue. Such agents may thus be useful in the treatment of diseases that involve hyperactivity of neuronal or muscle tissue.

As outlined above, there are nine functional alpha subunits of voltage-gated sodium channels. Each of these alpha subunits has a characteristic tissue expression pattern. Tissue-specific up- or down-regulation of the expression of several of the voltage-gated sodium channels in human diseases or preclinical disease models in animals strongly supports a central role for specific voltage-gated sodium channels in distinct diseases.

Navl.7 is expressed in human neuromas, which are swollen and hypersensitive nerves and nerve endings that are often present in chronic pain states (Acta Neurochirurgica (2002) 144(8) 803-810). Navl.7 is also expressed in dorsal root ganglion neurons and contributes to the small tetrodoxin (TTX) sensitive component seen in these cells. Navl.7 may thus be a potential pain target in addition to its role in neuroendocrine excitability (EMBO Journal (1995) 14(6) 1084-1090).

The present invention relates to a novel group of compounds that exhibit NaVl.7 inhibiting activity, and are therefore expected to be useful in the prophylaxis and treatment of different acute and chronic pain conditions.

WO 97/34883, WO 99/14212, WO 99/05135 and WO 99/14213 describe compounds for use in treatment of pain. The compounds described in these prior art documents bind to serotonine receptors. The compounds of the present invention have little to none activity towards the serotonine receptor. The compounds of the present invention also are contemplated to have an improved pharmacokinetic profile compared to the compounds in the prior art, including a higher oral bioavailability, a decreased clearance and a decreased volume of distribution. Without being bound to any theory, the difference in pharmacokinetic profile is believed to be due to the fact that the right hand side of the molecule is aromatic in the compounds of the present invention while this is not the case for the known compounds.

Disclosure of the Invention According to the invention there is provided compounds of formula I,

wherein:

Ri is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be independently mono- or di-substituted with R₂ and/or R_3, R₂ and R₃ are independently selected from Ci-C₆ alkyl, halogen, CF₃, OH, Ci-C₃ alkoxy, OCF₃, SO₃CH₃, SO₃CF₃, phenyl, phenyl-Ci-C₆ alkyl and Ci-C₆ alkyl phenyl; with the proviso that when Ri is phenyl with one substituent R₂ which is Ci-C₆ alkyl, halogen, or CF₃, then Ri also has a second substituent R_3, as (7?j-enantiomers, (Sj-enantiomers or a racemate in the form of a free base or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention there is provided compounds of formula I wherein Ri is pyrazolyl, thiophenyl or pyridinyl.

In another embodiment of the invention there is provided compounds of formula I wherein Ri is phenyl. In yet another embodiment of the invention there is provided compounds of formula I wherein Ri is phenyl, pyrazolyl, thiophenyl or pyridinyl which may be independently mono- or di-substituted with R₂ and/or R₃,

R₂ and R₃ are independently selected from Ci-C₆ alkyl, halogen, CF₃, OH, Ci-C₃ alkoxy, OCF₃, SO₃CF₃ and phenyl; with the proviso that when Ri is phenyl with one substituent R₂ which is Ci-C₆ alkyl, halogen, or CF₃, then Ri also has a second substituent R_3, as (7?j-enantiomers, (Sj-enantiomers or a racemate in the form of a free base or a pharmaceutically acceptable salt thereof.

In another embodiment of the invention there is provided compounds of formula I wherein R₂ and R₃ are independently selected from Ci-C₆ alkyl, halogen, CF₃, Ci-C₃ alkoxy, OCF₃, SO₃CF₃, or phenyl.

In a further embodiment of the invention there is provided compounds of formula I wherein R₂ and R₃ are independently selected from CH₃, C(CH₃)₃, F, Cl, CF₃, OCH₃, OCH₂CH₃, OCH₂(CH₃)₂, OCF₃, SO₃CF₃, or phenyl.

In one embodiment the invention there is provided compounds of formula Ia,

(Ia) wherein

Ri is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be mono- or di-substituted with R₂ and/or R_3, wherein R₂ is Ci-C₆ alkyl, halogen, CF₃, OH, Ci-C₃ alkoxy, OCF₃, SO₃CH₃, SO₃CF₃, phenyl, phenyl-Ci-C₆ alkyl, Ci-C₆ alkyl phenyl, R₃ is OH, CF₃, OCF₃, halogen, Ci-C₆ alkyl or Ci-C₃ alkoxy; with the proviso that when Ri is phenyl with one substituent R₂ which is Ci-C₆ alkyl, halogen, or CF₃, then Ri also has a second substituent R_3, as (7?j-enantiomers, (Sj-enantiomers or a racemate in the form of a free base or a pharmaceutically acceptable salt thereof.

Definitions

For the avoidance of doubt it is to be understood that where in this specification a group is qualified by 'hereinbefore defined', 'defined hereinbefore' or 'defined above' the said group encompasses the first occurring and broadest definition as well as each and all of the other definitions for that group.

For the avoidance of doubt it is to be understood that in this specification Ci-C₆ means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.

In this specification, unless stated otherwise, the term "alkyl" includes both straight and branched chain alkyl groups and may be, but are not limited to methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl or i-hexyl. The term having 1 to 4 carbon atoms and may be but are not limited to methyl, ethyl, n-propyl, i-propyl or t-butyl.

The term "alkoxy", unless stated otherwise, refers to radicals of the general formula -O-R, wherein R is selected from a hydrocarbon radical. The term "alkoxy" may include, but is not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy or isobutoxy.

The term "amine" or "amino" refers to radicals of the general formula -NRR', wherein R and R' are independently selected from hydrogen or a hydrocarbyl radical. The term "aromatic" refers to hydrocarbyl radicals having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n + 2 delocalized electrons) and comprising 6 up to about 14 carbon atoms.

The term "aryl" used alone or as suffix or prefix, refers to a hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms, wherein the radical is located on a carbon of the aromatic ring.

The term 'alkylphenyl' refers to a phenyl group which is mono-, di-, or tri-substituted with alkyl such as for example methylphenyl in example 4.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine radicals.

The term "heterocycle" or "heterocyclic" or "heterocyclic ring" refers to ring-containing monovalent and divalent radicals having one or more heteroatoms, independently selected from N, O, P and S, as part of the ring structure and comprising at least 3 and up to about 20 atoms in the rings preferably 5 and 6 membered rings. Heterocyclic ring may be saturated or unsaturated and contain one or more double bonds.

The term "heteroaryl" refers to heterocyclic monovalent and divalent radicals having aromatic character.

The term "heteroaromatic" refers to heterocyclic monovalent and divalent radicals having aromatic character and may be, but is not limited to oxazolyl, isoxazol, furyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl, indazolyl, pyridonyl or benzothienyl. Heteroaryl may also be quinolinyl, quinoxalinyl, naphthyridinyl, isoquinolinyl or thiazolyl.

The term "hydrocarbyl" refers to any structure comprising only carbon and hydrogen atoms up to 14 carbon atoms.

For the avoidance of doubt a group R₃ substituted with a group SO₃CF₃, is an R₃ substituted with trifiuoromenthanesulfonic acid.

It will be appreciated that throughout the specification, the number and nature of substituents on rings in the compounds of the invention will be selected so as to avoid sterically undesirable combinations. The term "mammal" includes any of various warm-blooded vertebrate animals of the class Mammalia, including but not limited to humans, generally characterized by a covering of hair on the skin.

Another embodiment of the invention relates to compounds selected from the group consisting of

5-Methyl-N-[(2R)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-l- phenyl- 1 H-pyrazole-4-carboxamide,

N-[(2R)-8-(4-Methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]biphenyl-3- carboxamide,

5-tert-Butyl-N-[(2R)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]thiophene-2-carboxamide,

N-[(2S)-8-(4-Methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-4-

(trifluoromethoxy)benzamide, 4- { [(2S)-8-(4-Methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl]carbamoyl}phenyl trifluoromethanesulfonate,

2,4-Dimethoxy-N-[(2R)-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydronaphthalen-2- yljbenzamide,

N-[(2R)-8-(4-Methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-3,5- bis(trifluoromethyl)benzamide,

3-Fluoro-N-[(2R)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-4-

(trifluoromethyl)benzamide,

6-Isopropoxy-N-[(2R)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]nicotinamide, 2-Fluoro-N-[(2R)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-5-

(trifluoromethyl)benzamide,

4-Ethoxy-N-[(2R)-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydronaphthalen-2- yljbenzamide,

N-[(2R)-8-(4-Methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-2,5- bis(trifluoromethyl)benzamide,

2,4-Dichloro-N-[(2R)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzamide, 2-Fluoro-N-[(2R)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-4- (trifluoromethyl)benzamide,

3-Fluoro-4-methyl-N-[(2R)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzamide, 3-Chloro-4-fluoro-N-[(2R)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzamide, and

N-[(2R)-8-(4-Methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-6- (trifluoromethyl)nicotinamide, and pharmaceutically acceptable salts thereof.

For the avoidance of doubt the present invention relates to any one of the specific compounds mentioned above.

The present invention relates to the compounds of formula I or Ia as hereinbefore defined as well as to pharmaceutical acceptable salts thereof. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I or Ia.

A suitable pharmaceutically acceptable salt of the compounds of the invention is, for example, an acid-addition salt, for example a salt with an inorganic or organic acid. In addition, a suitable pharmaceutically acceptable salt of the compounds of the invention is an alkali metal salt, an alkaline earth metal salt or a salt with an organic base.

Other pharmaceutically acceptable salts and methods of preparing these salts may be found in, for example, Remington's Pharmaceutical Sciences (18th Edition, Mack Publishing

Co.). The compounds of the present invention may also exists as solvents, solvated hydrates or cocrystals.

The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.

The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric esters by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.

Compounds of the present invention have been named with the aid of computer software (ACDLabs 8.0 or 9.0/Name(IUPAC)).

Process

Another object of the invention relates to processes (a) or (b) for the preparation of compounds of general Formula I and salts thereof.

(a) acylation of a compound of formula II, with an acylating reagent such as a compound of formula III, wherein halo is fluoro, chloro or bromo and Ri is as defined in Formula I or

Ia.

The reaction may be carried out using a suitable acylating reagent such as an acyl chloride, in a suitable solvent such as dichloromethane, chloroform, toluene or acetonitrile at a temperature between -20 ⁰C and reflux. The reaction is advantageously effected by the presence of a base. A suitable base may be an organic amine base such as pyridine, 2,6-lutidine, collidine, triethylamine, N,N-diisopropylethylamine, morpholine, 7V-methylmorpholine, diazabicyclo[5.4.0]undec-7-ene or tetramethylguanidine or an alkali metal or an alkaline earth metal carbonate or hydroxide such as sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide. The reaction may be aided by the presence of 4-dimethylaminopyridine.

(b) acylation of a compound of formula II, with a suitable carboxylic acid IV, wherein Ri is as defined in Formula I or Ia.

The transformation may be performed using a suitable activating reagent such as 2-(1H- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate or N,N'- carbonyldiimidazole with a suitable base such as triethylamine or N ,N- diisopropylethylamine. The reaction may be performed in a suitable solvent such as dimethylformamide, acetonitrile or dichloromethane at a temperature between -20 ⁰C and reflux.

Protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore.

Protecting groups may be removed in accordance with techniques which are well known to those skilled in the art and as described hereinafter.

The use of protecting groups is fully described in "Protective Groups in Organic Chemistry", edited by J.W.F. McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 3^rd edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1999).

Persons skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative, and, on some occasions, more convenient manner, the individual process steps mentioned herein may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those associated hereinbefore with a particular reaction). This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis.

It will also be appreciated by those skilled in the art that, although certain protected derivatives of compounds of formula I, which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, they may be administered parenterally or orally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Moreover, certain compounds of formula I may act as prodrugs of other compounds of formula I.

All prodrugs of compounds of formula I are included within the scope of the invention.

Medical use

The compounds of the invention exhibit voltage-gated sodium channel inhibiting activity, especially Navl .7 blocking activity, for example as demonstrated in the test described below. The present invention relates to the compounds of formula I or Ia, which inhibit any sodium channel. Modulation of voltage-gated sodium channels by pharmacological or genetical tools points to a central role for distinct voltage-gated sodium channels in several disease models. A mouse line has been generated which through advanced molecular biology technologies eliminates the functional expression of Navl.7 in DRG neurons that express Navl.8 (Proceedings of the National Academy of Sciences USA (2004) 101(34) 12706-12711). This mouse line shows greatly reduced pain responses in several pain behaviour models. Likewise, Herpes-vector mediated knockdown of Navl.7 in primary afferents of wildtype mice results in a decrease in inflammatory hyperalgesia (Human Gene Therapy (2005) 16(2) 271-277).

Antagonists of NaV channels have been shown to be useful for treating a variety of conditions, including acute and chronic nociceptive, visceral, inflammatory, central and peripheral neuropathic pain. More specifically, modulators of NaV activity are currently used or being tested in the clinic as anaesthetics, including local anaesthetics (Pain (2000) 87(1) 7-17), neuropathic pain reliefers (European Journal of Pain (2002) 6(Supplement 1) 61-68), acute pain reliefers (The Cochrane Database of Systematic Reviews (2005) 3), chronic pain reliefers (Pharmacotherapy (2001) 21(9) 1070-1081), inflammatory pain reliefers (Proceedings of the National Academy of Sciences USA (1999) 96(14) 7645- 7649), headache reliefers (Headache (2001) 41(Supplement 1) S25-S32). The compounds of the invention are thus expected to be useful in both the prophylaxis and the treatment of a condition which is effected or facilitated by inhibition of voltage-gated sodium channels, in particular pain, such as acute and chronic pain disorders including but not limited to widespread pain, localized pain, nociceptive pain, inflammatory pain, central pain, central and peripheral neuropathic pain, central and peripheral neurogenic pain, central and peripheral neuralgia, low back pain, postoperative pain, visceral pain, pelvic pain, allodynia, anesthesia dolorosa, causalgia, dysesthesia, fibromyalgia, hyperalgesia, hyperesthesia, hyperpathia, ischemic pain, sciatic pain, pain associated with cystitis, including but not limited to interstitial cystitis, pain associated with multiple sclerosis, pain associated with arthritis, pain associated with osteoarthritis, pain associated with rheumatoid arthritis and pain associated with cancer.

Other indications that may be treated with the compounds of the inventions are, but not limited to, migraine, pruritus, fibromyalgia, tinnitus and epilepsy.

The compounds of the present invention may be administered alone or in combination with other compounds, especially therapeutically active compounds.

The compounds of the present invention may for example be combined with one or more of the following therapeutically active compounds: proton pump inhibitors such as omeprazole, lansoprazole, rabeprazole, tentorpazole, pantoprazole, esomeprazole, revaprazan or sorprazan. Thus one embodiment of the invention relates to a combination wherein a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester, solvates, hydrated solvates, hydrates or co crystals thereof, or a pharmaceutical composition or formulation comprising a compound of formula (I) or (Ia) is administered concurrently, simultaneously, sequentially or separately with another pharmaceutically active compound or compounds selected from the following:

(i) antidepressants such as agomelatine, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, pro trip tyline, ramelteon, reboxetine, robalzotan, sertraline, sibutramine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof, (ii) atypical antipsychotics including for example quetiapine and pharmaceutically active isomer(s) and metabolite(s) thereof. (iii) antipsychotics including for example amisulpride, aripiprazole, asenapine, benzisoxidil, bifeprunox, carbamazepine, clozapine, chlorpromazine, debenzapine, divalproex, duloxetine, eszopiclone, haloperidol, iloperidone, lamotrigine, loxapine, mesoridazine, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenylbutylpiperidine, pimozide, prochlorperazine, risperidone, sertindole, sulpiride, suproclone, suriclone, thioridazine, trifluoperazine, trimetozine, valproate, valproic acid, zopiclone, zotepine, ziprasidone and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.

(iv) anxiolytics including for example alnespirone, azapirones,benzodiazepines, barbiturates such as adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, zolazepam and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof. (v) anticonvulsants including for example carbamazepine, valproate, lamotrogine, gabapentin and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof. (vi) Alzheimer's therapies including for example donepezil, memantine, tacrine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.

(vii) Parkinson's therapies including for example deprenyl, L-dopa, Requip, Mirapex,

MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.

(viii) migraine therapies including for example almotriptan, amantadine, bromocriptine, butalbital, cabergoline, dichloralphenazone, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pramipexole, rizatriptan, ropinirole, sumatriptan, zolmitriptan, zomitriptan, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.

(ix) stroke therapies including for example abciximab, activase, NXY-059, citicoline, crobenetine, desmoteplase,repinotan, traxoprodil and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof. (x) urinary incontinence therapies including for example darafenacin, falvoxate, oxybutynin, propiverine, robalzotan, solifenacin, tolterodine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.

(xi) neuropathic pain therapies including for example gabapentin, lidoderm, pregablin and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof. (xii) nociceptive pain therapies such as celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, paracetamol and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.

(xiii) GABAb modulators such as baclofen, and equivalents and pharmaceutically active salts and metabolite(s) thereof. (xiv) Glutamate receptor antagonists and equivalents and pharmaceutically active salts and metabolite(s) thereof.

(xv) insomnia therapies including for example agomelatine, allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol, etomidate, glutethimide, halazepam, hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital, phenobarbital, propofol, ramelteon, roletamide, triclofos,secobarbital, zaleplon, Zolpidem and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.

(xvi) mood stabilizers including for example carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, verapamil, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.

Such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active compound or compounds within therapeutically active dosage ranges and/or the dosage described in the publication reference.

One embodiment of the invention relates to compounds of formula I or Ia as defined above, or any of the specific compounds mentioned above, or pharmaceutically acceptable salts thereof, or any of the specific salts mentions for these compounds, for use in therapy.

Another embodiment relates to the use of compounds of formula I or Ia as defined above, or any of the specific compounds mentioned above, or pharmaceutically acceptable salts thereof, or any of the specific salts mentions for these compounds, in the manufacture of a medicament for treatment of pain. A further embodiment relates to the use of compounds of formula I or Ia as defined above, or any of the specific compounds mentioned above, or pharmaceutically acceptable salts thereof, or any of the specific salts mentions for these compounds, in the manufacture of a medicament for treatment of acute or chronic nociceptive pain, visceral pain, inflammatory pain, and/or central or peripheral neuropathic pain.

One embodiment relates to a method of treatment of pain, or acute or chronic nociceptive pain, visceral pain, inflammatory pain, and/or central or peripheral neuropathic pain in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compounds of formula I or Ia as defined above, or any of the specific compounds mentioned above, or pharmaceutically acceptable salts thereof, or any of the specific salts mentions for these compounds, or a pharmaceutical composition comprising said compounds. An agent for the treatment of pain, or acute or chronic nociceptive pain, visceral pain, inflammatory pain, and/or central or peripheral neuropathic pain, which comprises as active ingredient a compounds of formula I or Ia as defined above , or any of the specific compounds mentioned above, or pharmaceutically acceptable salts thereof, or any of the specific salts mentions for these compounds, or a pharmaceutical composition comprising said compounds.

Pharmaceutical compositions The compounds of the invention will normally be administered orally, subcutaneously, intravenously, intraarterially, transdermally, intranasally, by inhalation, or by any other parenteral route, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or a non-toxic organic or inorganic acid addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated, as well as the route of administration, the compositions may be administered at varying doses.

One embodiment relates to a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound of formula I or Ia as defined above, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.

Another embodiment relates to said pharmaceutical composition according, for use in the treatment of pain or acute or chronic nociceptive pain, visceral pain, inflammatory pain, and/or central or peripheral neuropathic pain.

Suitable daily doses of the compounds of the invention in therapeutic treatment of humans are about 0.005 to 25.0 mg/kg body weight at oral administration and about 0.005 to 10.0 mg/kg body weight at parenteral administration. Example of ranges of daily doses of the compounds of the invention in therapeutic treatment of humans are about 0.005 to 10.0 mg/kg body weight at oral administration and about 0.005 to 5.0 mg/kg body weight at parenteral administration. Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, be longer acting than, produce fewer side effects than, be more easily absorbed than, or that they may have other useful pharmacological properties over, compounds known in the prior art.

The invention is illustrated by way of the following examples.

Examples

General Methods

Starting materials used were available from commercial sources, or prepared according to literature procedures.

Microwave irradiation was performed in a Creator^™, Initiator^™ or Smith Synthesizer^™ Single -mode microwave cavity producing continuous irradiation at 2450 MHz.

Mass spectra were recorded on one of the following instruments: a Perkin-Elmer SciX API 150ex spectrometer; a VG Quattro II triple quadrupole; a VG Platform II single quadrupole; or a Micromass Platform LCZ single quadrupole mass spectrometer (the latter three instruments were equipped with a pneumatically assisted electrospray interface (LC- MS)).

Prep-HPLC: Preparative chromatography was run on Waters auto purification HPLC with a diode array detector. Column: XTerra MS C8, 19 x 300 mm, 10 μm. Gradient with acetonitrile/0.1 M ammonium acetate in 5 % acetonitrile in MiIIiQ Water, typically run from 20% to 60% acetonitrile, in 13 min. Flow rate: 20 mL/min. Alternatively, purification was achieved on a semi preparative Shimadzu LC-8A HPLC with a Shimadzu SPD-IOA UV- vis. -detector equipped with a Waters Symmetry^® column (C 18, 5 μm, 100 mm x 19 mm). Gradient with acetonitrile/0.1 % trifiuoroacetic acid in MiIIiQ Water, typically run from 35% to 60% acetonitrile in 20 min. Flow rate: 10 mL/min. Alternatively, another column was used; Atlantis C18 19 x 100 mm, 5 μm column. Gradient with acetonitrile/0.1 M ammonium acetate in 5% acetonitrile in MiIIiQ Water, run from 0% to 35-50% acetonitrile, in 15 min. Flow rate: 15 mL/min. NMR spectra were recorded on a Varian Unity+ 400 NMR Spectrometer, operating at 400 MHz for proton and 100 MHz for carbon- 13, and equipped with a 5 mm BBO probe with Z-gradients; or on a Bruker av400 NMR spectrometer operating at 400 MHz for proton and 100 MHz for carbon-13, and equipped with a 3 mm flow injection SEI ¹HZD-¹³C probehead with Z-gradients, using a BEST 215 liquid handler for sample injection; or on a Bruker DPX400 NMR spectrometer, operating at 400 MHz for proton and 100 MHz for carbon-13, and equipped with a 4-nucleus probe with Z-gradients. The following reference signals were used: TMS δ 0.00, or the residual solvent signal of DMSO-J₆ δ 2.49, CD₃OD δ 3.31 or CDCl₃ δ 7.25 (unless otherwise indicated). Resonance multiplicities are denoted s, d, t, q, m and br for singlet, doublet, triplet, quartet, multiplet and broad, respectively. Column chromatography was performed using Merck Silica gel 60 (0.040-0.063 mm), or employing a Combi Flash^® Companion^™ system using RediSep^™ normal-phase flash columns. Compounds have been named using ACD/Name, version 9.0, software from Advanced Chemistry Development, Inc. (ACD/Labs), Toronto ON, Canada, www.acdlabs.com, 2004.

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.

Reactants

Following reactants, either new (see synthetic procedures described below), commercially available or described in the literature, were used for the preparation of the target compounds (table 1):

Amines:

Amine 2: (2R)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-amine,

Amine 8 : (2S)-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydronaphthalen-2-amine,

Acyl chlorides: Acyl chloride 1 : 4-(trifiuoromethoxy)benzoyl chloride,

Acyl chloride 2: 3-fluoro-4-(trifluoromethyl)benzoyl chloride,

Acyl chloride 3: 2-fluoro-4-(trifluoromethyl)benzoyl chloride, Acyl chloride 6: 2,4-dimethoxybenzoyl chloride,

Acyl chloride 7: 3,5-bis(trifluoromethyl)benzoyl chloride,

Acyl chloride 8: 2-fluoro-5-(trifluoromethyl)benzoyl chloride,

Acyl chloride 9: 4-ethoxybenzoyl chloride, Acyl chloride 10: 2,5-bis(trifluoromethyl)benzoyl chloride,

Acyl chloride 11 : 2,4-dichlorobenzoyl chloride,

Acyl chloride 12: 3-fluoro-4-methylbenzoyl chloride,

Acyl chloride 13: 3-chloro-4-fluorobenzoyl chloride,

Acyl chloride 15: 6-(trifluoromethyl)nicotinoyl chloride, Car boxy Hc acids:

Acid 3: 5-methyl-l -phenyl- lH-pyrazole-4-carboxylic acid,

Acid 4: biphenyl-3-carboxylic acid,

Acid 5: 5-tøt-butylthiophene-2-carboxylic acid,

Acid 27: 4- {[(trifluoromethyl)sulfonyl]oxy} benzoic acid, Acid 32: 6-isopropoxynicotinic acid.

General methods of synthesis. Method A:

To a solution of the amine (1 mole equivalents) and triethylamine (1.2 mole equivalents) in anhydrous dichloromethane the acid chloride (1.2 mole equivalents) was added. The reaction mixture was stirred at ambient temperature for 5-30 min and concentrated in vacuo. The crude product was purified using preparative HPLC. Method B:

7V,7V'-Carbonyldiimidazole (1.2 mole equivalent) was added to a solution of the carboxylic acid (1.2 mole equivalent) in anhydrous dimethylformamide followed by addition of a solution of the amine (1 mole equivalent) in anhydrous dimethylformamide. The reaction mixture was heated at 80 ⁰C for 2-12 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated in vacuo to yield the crude product. Purification by preparative HPLC. Method C:

Triethylamine (3 mole equivalent) and 2-(lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafiuorophosphate (1.5 mole equivalent) were added to a solution of the carboxylic acid (1 mole equivalent) in anhydrous acetonitrile and he reaction mixture was stirred for 10 min. A solution of the amine (1 mole equivalent) in anhydrous acetonitrile was added and the reaction mixture was stirred at ambient temperature for 1 h. The volatiles were removed in vacuo and the crude residue was purified by preparative HPLC.

Table 1. The following compounds were prepared according to Methods A-C, using the reactants mentioned above: amines and counterparts which are either carboxylic acids or secondary amines.

Biological tests

Expression of voltage-gated sodium channel in cell lines:

Gene(s) encoding the full-length protein of the voltage-gated sodium channel of interest are cloned and expressed under a suitable promoter in a suitable cell line, as well known in the art. The so constructed stable cell lines are used in screening assays to identify suitable compounds active on voltage-gated sodium channels. Suitable screening assays are as follows.

Li⁺ influx assay The cell line expressing the voltage-gated sodium channel of interest is plated in conventional 96 or 384 well tissue plates at a suitable cell density (for example 40000 cells/well in 96 well plate, or 20000 cells/well in 384 well plate). The cells are then repeatedly washed with a suitable Na free buffer using a suitable commercially available washer (for example EL-405 washer) until all tissue culture medium is removed from the wells. A suitable Na-free buffer could have the composition (mM) Choline chloride 137, KCl 5.4, MgSO₄ 0.81, CaCl₂ 0.95, glucose 5.55 and HEPES 25 at pH 7.4, but may also have other suitable composition. After completion of all wash steps, cells are incubated in the suitable Na free buffer for 15 min. Then, the Na free buffer is removed and cells are incubated with a buffer rich in LiCl for 60 min at 37⁰C. The LiCl buffer is also enriched in potassium ions, causing a depolarizing stimulus to the cells. Such a buffer may have the composition (mM): LiCl 100, KCl 50, MgSO₄ 0.81, CaCl₂ 0.95, glucose 5.55 and HEPES 25 at pH 7.4, but may also have other suitable composition. To enhance signal-to-noise ratio, an effective concentration (for example 100 μM) of the voltage-gated sodium channel opener veratridine, or any other suitable voltage-gated sodium channel opener, may be added to the medium to enhance signal detection. Furthermore, and also to enhance signal-to-noise ratio, an effective concentration (for example 10 μg/ml) of suitable scorpion venom may also be added to the medium to delay channel inactivation. In order to find a modulator of the voltage-gated sodium channel of interest, the assay can be complemented with compounds from a compound library. Compounds of interest are added to the Li-rich solution, one in each well. At the end of the incubation period cells are repeatedly washed with Na free buffer until all extracellular LiCl is removed. Cell lysis is obtained through incubation of cells with triton (1%) for 15 min, or any other suitable method. The resulting cell lysate is then introduced into an atomic absorption spectrophotometer, thus quantifying the amount of Li-influx during the procedure described above.

The described assay can be run with any atomic absorption spectrophotometer using plates of 96-well format, 384-well format, or any other conventional plate format. The described assay can be applied to cell lines expressing any given one or more of the voltage-gated sodium channel alpha subunits, as well as any given combination of one of the voltage- gated alpha subunits with any one or more beta subunit.

If needed the cell line of choice can be further hyperpolarised by expression of a suitable potassium leak ion channel, for example TREK-I, either by transient co-transfection or through establishment of a stable co-transfected cell line. The successful expression of a leak K current can be verified using traditional intracellular electrophysiology, either in whole cell patch-clamp, perforated patch-clamp or conventional two-electrode voltage- clamp. A cell line of choice modified to successfully express a voltage-gated sodium channel of interest together with a suitable potassium leak ion channel transfected can then be used for screening using atomic absorptions spectrometry, as described above.

Whole-cell voltage clamp electrophysiology assay

Electrophysiological recordings of sodium currents in cells stably expressing the voltage- gated sodium channel of interest confirms activity and provides a functional measure of the potency of compounds that specifically inhibit such channels.

Electrophysiological studies can be performed using automated patch-clamp electrophysiology platforms, like IonWorks HT, Ion Works Quattro, PatchXpress, QPatch or any other suitable platform. The cell line expressing the voltage-gated sodium channel of interest is appropriately prepared as suggested by the manufacturer of the automated patch-clamp platforms. Suitable extracellular and intracellular buffer for such experiments are applied according to the instructions given by the manufacturer of the automated patch- clamp platforms. Cells that express the voltage-gated sodium channel protein of interest are exposed to drugs through the pipetting system integrated in the platforms. A suitable voltage stimulus protocol is used to activate the voltage-gated sodium channel proteins of interest through depolarisation from a defined holding potential.

Electrophysiological studies can also be performed using the whole cell configuration of the standard patch clamp technique. In this assay, cells that express the voltage-gated sodium channel protein of interest are exposed to the drugs by conventional microperfusion systems and a suitable voltage stimulus protocol is used to activate the voltage-gated sodium channels.

Example

Title compounds of the above Examples were tested in the Whole-cell voltage clamp electrophysiology assay described above and were found to exhibit IC50 values as shown in the table below.

Claims

1. A compounds of formula I,

wherein: Ri is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be independently mono- or di-substituted with R₂ and/or R_3, R₂ and R₃ are independently selected from Ci-C₆ alkyl, halogen, CF₃, OH, Ci-C₃ alkoxy, OCF₃, SO₃CH₃, SO₃CF₃, phenyl, phenyl-Ci-C₆ alkyl and Ci-C₆ alkyl phenyl; with the proviso that when Ri is phenyl with one substituent R₂ which is Ci-C₆ alkyl, halogen, or CF₃, then Ri also has a second substituent R_3, as (7?j-enantiomers, (Sj-enantiomers or a racemate in the form of a free base or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein Ri is phenyl.

3. The compound according to any one of claims 1 to 2 wherein Ri is pyrazolyl, thiophenyl or pyridinyl.

4. The compound according to any one of claims 1 to 3 wherein R₂ and R₃ are independently selected from Ci-C₆ alkyl, halogen, CF₃, Ci-C₃ alkoxy, OCF₃, SO₃CF₃, or phenyl.

5. The compound according to any one of claims 1 to 3 wherein R₂ and R₃ are independently selected from CH₃, C(CH₃)₃, F, Cl, CF₃, OCH₃, OCH₂CH₃, OCH₂(CH₃)₂,

OCF₃, SO₃CF₃, or phenyl.

6. Compounds selected from the group consisting of 5-Methyl-N-[(2R)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-l- phenyl- 1 H-pyrazole-4-carboxamide,

N-[(2R)-8-(4-Methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]biphenyl-3- carboxamide, 5-tert-Butyl-N-[(2R)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]thiophene-2-carboxamide,

N-[(2S)-8-(4-Methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-4-

(trifluoromethoxy)benzamide,

4-{[(2S)-8-(4-Methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]carbamoyl}phenyl trifluoromethanesulfonate,

N-[(2R)-8-(4-Methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-3,5- bis(trifluoromethyl)benzamide, 3-Fluoro-N-[(2R)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-4-

(trifluoromethyl)benzamide,

6-Isopropoxy-N-[(2R)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]nicotinamide,

2-Fluoro-N-[(2R)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-5- (trifluoromethyl)benzamide,

N-[(2R)-8-(4-Methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-2,5- bis(trifluoromethyl)benzamide, 2,4-Dichloro-N-[(2R)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzamide,

2-Fluoro-N-[(2R)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-4-

(trifluoromethyl)benzamide,

3-Fluoro-4-methyl-N-[(2R)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzamide,

3-Chloro-4-fluoro-N-[(2R)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzamide, and N-[(2R)-8-(4-Methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-6-

(trifluoromethyl)nicotinamide, and pharmaceutically acceptable salts thereof.

7. The compound according to any one of claims 1 to 6 or a pharmaceutically-acceptable salts thereof, for use in therapy.

8. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically- acceptable salts thereof, for the manufacture of a medicament for treatment of acute or chronic nociceptive pain, visceral pain, inflammatory pain, and/or central or peripheral neuropathic pain.

9. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound according to any one of claims 1 to 6 or a pharmaceutically-acceptable salts thereof, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.

10. A method of treatment of pain disorders or acute or chronic nociceptive pain, visceral pain, inflammatory pain, and/or central or peripheral neuropathic pain, comprising administering to a mammal, including man in need of such treatment, a therapeutically effective amount of the compound according to any one of claims 1 to 6 or a pharmaceutically-acceptable salts thereof.