WO2018011169A1

WO2018011169A1 - Use of sigma receptor ligands in post-herpetic pain

Info

Publication number: WO2018011169A1
Application number: PCT/EP2017/067332
Authority: WO
Inventors: Jesús CEBRECOS-PÉREZ; Carlos-Ramón PLATA-SALAMAN
Original assignee: Laboratorios Del Dr. Esteve, S.A.
Priority date: 2016-07-12
Filing date: 2017-07-11
Publication date: 2018-01-18
Also published as: ES2701975A2; AR109024A1; ES2701975R1; TW201806601A

Abstract

The invention relates to compounds of general formula (I) having pharmacological activity towards the sigma receptor, for use in the prevention and/or treatment of post-herpetic pain.

Description

USE OF SIGMA RECEPTOR LIGANDS IN POST-HERPETIC PAIN FIELD OF THE INVENTION

The present invention relates to the use of sigma receptor ligands, and more particularly to some pyrazole derivatives, and to the use of pharmaceutical compositions comprising them in the prevention and/or treatment of post-herpetic pain.

BACKGROUND OF THE INVENTION

The sigma (σ) receptor is a cell surface and endoplasmic reticulum receptor expressed in the central nervous system (CNS) among other tissues. From studies of the biology and function of sigma receptors, evidence has been presented that sigma receptor ligands may be useful in the treatment of psychosis and movement disorders such as dystonia and tardive dyskinesia, and motor disturbances associated with Huntington's chorea or Tourette's syndrome and in Parkinson's disease (Walker, J.M. et al, Pharmacological Reviews, 1990, 42, 355). It has been reported that the known sigma receptor ligand rimcazole clinically shows effects in the treatment of psychosis (Hanner, M. et al. Proc. Natl. Acad. Sci., 1996, 93:8072-8077; Snyder, S.H., Largent, B.L. J. Neuropsychiatry 1989, 1 , 7). The sigma binding sites have preferential affinity for the dextrorotatory isomers of certain opiate benzomorphans, such as (+)SKF 10047, (+)cyclazocine, and (+)pentazocine and also for some narcoleptics such as haloperidol.

The sigma receptor has at least two subtypes, which may be discriminated by stereoselective isomers of these pharmacoactive drugs. SKF 10047 has nanomolar affinity for the sigma 1 (σ-1 ) site, and has micromolar affinity for the sigma (σ-2) site. Haloperidol has similar affinities for both subtypes. Endogenous sigma ligands are not known, although progesterone has been suggested to be one of them. Possible sigma- site-mediated drug effects include modulation of glutamate receptor function, neurotransmitter response, neuroprotection, behavior, and cognition (Quirion, R. et al. Trends Pharmacol. Sci., 1992, 13:85-86). The existence of sigma receptors in the CNS, immune and endocrine systems have suggested a likelihood that it may serve as link between the three systems.

The presence of sigma-1 receptor (a1 R) in rat pancreas by using the a1 R radiotracer 18F-FTC-146 has been described (James et al., J Nucl Med. 2014, 55(1 ): 147-153). WO 2006/021462 discloses a family of pyrazole derivatives which are particularly selective inhibitors of the sigma-1 receptor. This family presents a pyrazole group which is characterized by the substitution at position 3 by an alkoxy group directly bounded to nitrogen.

Post-Herpetic Neuralgia (PHN) is a nerve pain due to damage caused by the varicella zoster virus. Typically, the neuralgia is confined to a dermatomic area of the skin, and follows an outbreak of herpes zoster (commonly known as shingles) in that same dermatomic area. The neuralgia typically begins when the herpes zoster vesicles have crusted over and begun to heal, but can begin in the absence of herpes zoster— a condition called zoster sine herpete.

Herpes Zoster (HZ) or "shingles" (described as burning or throbbing pain, sharp stabs, electric shocks, and allodynia) is caused by a reactivation of varicella zoster virus (VZV). VZV primary infection causes varicella (chickenpox) after which VZV becomes latent in sensory ganglia along the entire neuraxis. Subsequent reactivation of latent varicella-zoster virus in dorsal root ganglia results in a localized cutaneous eruption termed "herpes zoster" and its spread from a single sensory ganglion to the neural tissue and dermatome of the affected segment. Declining virus- specific cell-mediated immune responses, which occur naturally as a result of aging or are induced by immunosuppressive illness or medical treatments, increase the risk of shingles. The characteristic rash usually heals within two to four weeks, and acute pain is typically the most distressing symptom.

Main clinical aspects of HZ are: acute pain of HZ rash persists up to 4 weeks; subacute herpetic neuralgia persists from 30 days to 4 months. Rash appears after 5 days and presents as small, red spots that become blisters. Papules develop into vesicles within 1 to 2 days and continue to appear for 3 to 4 days. Lesions of all types may be present and tend to be grouped. Pustulation of vesicles begins within 1 week of the onset of rash and is followed 3 to 5 days later by lesion ulceration and crusting. Crusts usually resolve within 3 to 4 weeks, but scarring and hypo- or hyperpigmentation may persist.

Over 90 percent of adults in the United States have serologic evidence of varicella- zoster virus infection and are at risk for herpes zoster. The annualized incidence of herpes zoster is about 1 .5 to 3.0 cases per 1000 persons. Increasing age is a key risk factor for the development of herpes zoster; the incidence of shingles among persons older than 75 years of age exceeds 10 cases per 1000 person-years. The lifetime risk of herpes zoster is estimated to be 10 to 20 percent. The other well-defined risk factor for herpes zoster is altered cell-mediated immunity. Patients with neoplastic diseases (especially lymphoproliferative cancers), those receiving immunosuppressive drugs (including corticosteroids), and organ-transplant recipients are at increased risk for shingles.

Post Herpetic Neuralgia (PHN) is the painful sequelae of acute herpes zoster virus infection and its most frequent chronic complication. Main clinical aspects of PHN are: defined as continuous, chronic pain that persists ≥3 months after lesions have resolved. In the worst cases, PHN continues for many years. Pain described as "burning," "shooting," "stabbing," or "throbbing". About 20% of HZ patients≥50 years old develop PHN. Pain may be severe in the area where the blisters were present, and affected skin may be very sensitive to heat and cold.

The time threshold after the clinical eruption of zoster for pain to be classified as Post- Herpetic Neuralgia (PHN) is variable (30, 90, or 120 days or 6 months) across researchers; however, recent models support 90 days as the most appropriate time point definition.

PHN risk increases with age. Advancing age and the severity of acute HZ pain are the strongest risk factors for PHN. Thus, risk factors for PHN development include herpes zoster infection at older age, worse acute pain, more severe rash, and the presence of a painful prodrome.

The cause of PHN is presumably nerve damage resulting from herpes zoster infection. The damage causes nerves in the affected dermatomic area of the skin to send abnormal electrical signals to the brain. These signals may convey excruciating pain, and may persist or recur for months, years, or for life.

A key factor in the neural plasticity underlying neuropathic pain is altered gene expression in sensory dorsal root ganglia neurons. Injury to sensory nerves induces neurochemical, physiological and anatomical modifications to afferent and central neurons, such as afferent terminal sprouting and inhibitory interneuron loss. Pathologic findings include primary afferent neuronal body and axon degeneration, atrophy of the spinal cord, scarring of the dorsal root ganglion, and loss of epidermal innervations.

Both the incidence and the duration of post herpetic neuralgia are directly correlated with the patient's age. The reported incidence of postherpetic neuralgia ranges from 8 to 70 percent and increases with advancing age. As compared with younger patients, those who were 50 years of age or older had a prevalence of pain that was 15 and 27 times as high at 30 and 60 days, respectively. Each one-year increment in age was associated with 9 and 12 percent increases in the prevalence of post herpetic neuralgia at 30 and 60 days, respectively (Gnann J, Whitley Ft., N. Engl. J. Med., 2002, 347: 340- 346; Sampathkumar, P. et al., Mayo Clin. Proc, 2009, 84(3):274-280; Solomon C, N. Engl. J. Med., 2014; 371 :1526-1533; Haanpaa, M. et al., Pain: Clinical updates, 2015, 23(4):1 -8; Gharibo, C. et al.; Pain Medicine News; 201 1 ; 1 -7).

Post herpetic neuralgia is exceedingly difficult to treat and has been shown to cause severe impairment in quality of life similar to many other systemic diseases. Current therapies include antidepressants (such as tricyclic antidepressants), anticonvulsant agents (such as gabapentin, pregabalin, or topiramate), gabapentin enacarbil (a prodrug of gabapentin) and a variety of oral and topical analgesics (such as lidocaine patches or capsaicin lotion); however, these therapies are only partially effective in relieving pain, and the adverse effects of these medications can be additive, especially in elderly patients.

Opioid analgesics may also be appropriate in many situations. There are some sporadically successful experimental treatments, such as rhizotomy (severing or damaging the affected nerve to relieve pain) and TENS (a type of electrical pulse therapy).

Treatment for PHN depends on the type and characteristics of pain experienced by the patient. Pain control is essential to quality patient care; it ensures patient comfort. Currently, possible options include: • Antiviral agents (given at the onset of attacks of herpes zoster to shorten the clinical course and to help prevent complications; however, they have no role to play following the acute attack once PHN has become established).

• Analgesics locally applied topical agents (as Lidocaine) or systemically delivered (opioids and non-opioids).

• Pain modification therapy which includes:

o Antidepressants. Low dosages of tricyclic antidepressants, seem to work best for deep, aching pain. They do not eliminate the pain, but they may make it easier to tolerate. Other prescription antidepressants may be off-label used in postherpetic neuralgia and generally prove less effective, although they may be better tolerated than the tricyclics, o Anticonvulsants. These agents are used to manage severe muscle spasms and provide sedation in neuralgia. They have central effects on pain modulation. Medications such as phenytoin (Dilantin, Phenytek), used to treat seizures, also can lessen the pain associated with postherpetic neuralgia. The medications stabilize abnormal electrical activity in the nervous system caused by injured nerves. Doctors often prescribe another anticonvulsant called carbamazepine (Carbatrol, Tegretol) for sharp, jabbing pain. Newer anticonvulsants, such as gabapentin (Neurontin) and lamotrigine (Lamictal), are generally tolerated better and can help control burning and pain.

• Other non-pharmacological treatments for PHN include acupuncture, moxibustion, relaxation techniques, heat therapy or transcutaneous electrical nerve stimulation.

In some cases, treatment of post-herpetic neuralgia brings complete pain relief. But most people still experience some pain, and some do not receive any relief even some preventive measures at primary and secondary level has been established. Thus, HZ and PHN present challenges to health care systems, as they are prevalent, cause suffering and impaired function and are difficult to treat satisfactorily, especially in societies with aging populations.

Sang et al. in Anesthesiology, 2002, May 96(5): 1053-61 report a clinical trial of dextromethorphan, memantine and lorazepam in the treatment of diabetic neuropathy and postherpetic neuralgia, concluding that dextromethorphan is effective in a dose- related fashion in selected patients with diabetic neuropathy, but that this was not true for postherpetic neuralgia, suggesting a difference in pain mechanisms, so that selective approaches to pain should be used. Nelso et al. in Neurology, 1997 May 48(5):1212-1218 also report that high dose oral dextromethorphan decreased pain in diabetic neuropathy but not in postherpetic neuralgia.

These reports show that Postherpetic pain is a distinct type of pain and that effectiveness of an analgesic in this specific indication cannot be anticipated.

Therefore, there is a need to provide a new form of prevention and treatment for postherpetic pain, and especially for neuropathic pain, allodynia, hyperalgesia and peripheral neuropathy, developing as a consequence of a Herpes Zoster.

SUMMARY OF THE INVENTION

The inventors of the present invention have surprisingly found and demonstrated that the administration of the specific sigma receptor ligands according to general formula (I) is highly effective for the prevention and/or treatment of post-herpetic pain.

Therefore, in one aspect, the invention is directed to a compound binding to the sigma- receptor according to general formula (I) for use in the prevention and/or treatment of post-herpetic pain:

wherei Ri is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyi, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR₈, -C(0)OR₈,

-C(0)NR₈R₉, -CH=NR₈, -CN, -OR₈, -OC(0)R₈, -S(0),-R₈, -NR₈R₉, -NR₈C(0)R₉, -NO₂, - N=CR₈R₉, and halogen;

R₂ is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyi, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, - COR₈, -C(0)OR₈, -C(0)NR₈R₉, -CH=NR₈, -CN, -OR₈, -OC(0)R₈, -S(0)_t-R₈, -NR₈R₉ , -NR₈C(0)R₉ , -N0₂, -N=CR₈R₉ , and halogen ;

R₃ and R₄ are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyi, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR₈, -C(0)OR₈, - C(0)NR₈R₉, -CH=NR₈, -CN, -OR₈, -OC(0)R₈, -S(0)_t-R₈, -NR₈R₉, - NR₈C(0)R₉, -NO₂, -N=CR₈R₉, and halogen, or together they form an optionally substituted fused ring system;

R₅ and R₆ are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyi, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR₈, -C(0)OR₈, -

C(0)NR₈R₉, -CH=NR₈, -CN, -OR₈, -OC(0)R₈, -S(0),-R₈, -NR₈R₉, -NR₈C(0)R₉, -NO₂, -N=CR₈R₉, and halogen, or together form, with the nitrogen atom to which they are attached, a substituted or unsubstituted, aromatic or non-aromatic heterocyclyl group; n is selected from 1 , 2, 3, 4, 5, 6, 7 or 8; t is 1 ,2 or 3; R₈ and R₉ are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, and halogen; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

In another aspect, the invention is directed to a pharmaceutical composition comprising at least a compound of general formula (I) as defined above for the use in the prevention and/or treatment of post-herpetic pain, wherein the composition further comprises at least a pharmaceutically acceptable carrier, adjuvant and/or vehicle.

Another aspect of the invention relates to the use of a compound of formula (I) as defined above in the manufacture of a medicament for the prevention and/or treatment of post-herpetic pain.

Another aspect of the invention relates to a method of treatment of a patient suffering post-herpetic pain, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand of formula (I) as defined above.

A further aspect of the invention relates to a compound of formula (I) as defined above, for the use in the prevention and/or treatment of post-herpetic pain, wherein the compound is administered in combination with an anticonvulsant.

A yet further aspect of the invention relates to a compound of formula (I) as defined above, for the use in the prevention and/or treatment of post-herpetic pain wherein patients have been and/or are being treated with an anticonvulsant. A yet further aspect of the invention relates to the use of a compound of formula (I) as defined above for the manufacture of a medicament for the prevention and/or treatment of post-herpetic pain in patients that have been and/or are being treated with an anticonvulsant.

A still further aspect of the invention is a method of treatment of a patient suffering post-herpetic pain, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a compound of formula (I) as defined above, and wherein said patient has been or is being treated with an anticonvulsant.

The above mentioned preferences and embodiments can be combined to give further preferred compounds or uses.

These aspects and preferred embodiments thereof are additionally also defined hereinafter in the detailed description and in the claims.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 : NPRS (Numeric Pain Rating Scale)

Figure 2: Study design.

Figure 3: NPRS - Average pain decreasing throughout the study (mean change).

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed, in one aspect, to a compound binding to the sigma-receptor according to general formula (I) for use in the prevention and/or treatment of post- herpetic pain.

The compounds of general formula (I) bind with high affinity to the sigma-receptor, and they are particularly selective inhibitors of the sigma-1 receptor subtype. The compounds of the invention can replace a ligand in competitive binding assays, preferably in competitive radioligand-binding assays as exemplary described in WO2006/021462, e.g. in binding assays for the σ1 -receptor performed as described (DeHaven-Hudkins et al., Eur J Pharmacol, 1992, 227, 371 ) or binding assays for σ2- receptor as described (Radesca et al., J Med C ?em,1991 , 34, 3058). Preferably, binding of the compounds of the invention, with respect to binding to the sigma-1 receptor subtype, is measured by competing with the binding of ³[H]-(+)-pentazocine, e.g. in radioligand-assays as described in the art (e.g. in DeHaven-Hudkins et al., 1992). Preferably, compounds of the invention when assayed at a concentration of 10^" ⁷M yield at least 25%, more preferably at least 45%, even more preferably at least 65%, yet even more preferably at least 75%, most preferably at least 85% binding to the sigma- 1 receptor in ³[H]-(+)-pentazocine radioligand-assays as defined above.

The compounds of the invention bind selectively to the Sigma receptor and generally show nanomolar affinity for its target while showing either a percentage of inhibition less than 50% when tested at 1 micromolar in a panel of other non-specific targets or when there is one hundred times less affinity or functional activity for those non-specific targets.

The term "post-herpetic pain" relates to pain developed as a consequence of Herpes Zoster. With resolution of the Herpes Zoster eruption, the term "post-herpetic pain" relates to pain that continues for three months or more. Specifically the term "postherpetic pain" refers to postherpetic neuralgia (PHN).

Thus, a first aspect of the present invention relates to a compound of formula (I) binding to the sigma-receptor, preferably to the sigma- 1 receptor subtype, or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, for use in the prevention and/or treatment of post-herpetic pain (postherpetic neuralgia):

(I) wherein Ri is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyi, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR₈, -C(0)OR₈,

C(0)NR₈R₉, -CH=NR₈, -CN, -OR₈, -OC(0)R₈, -S(0),-R₈, -NR₈R₉, -NR₈C(0)R₉, -NO₂, -N=CR₈R₉, and halogen, or together form, with the nitrogen atom to which they are attached, a substituted or unsubstituted, aromatic or non-aromatic heterocyclyl group; n is selected from 1 , 2, 3, 4, 5, 6, 7 or 8;

t is 1 ,2 or 3;

R₈ and R₉ are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, and halogen. In a preferred embodiment of the invention, the compound for use as defined above is characterized in that

selected from H, -COR₈, or substituted or unsubstituted alkyl, preferably it is selected from H, methyl or acetyl.

In another preferred embodiment of the invention, the compound for use as defined above is characterized in that R^ is hydrogen.

In another preferred embodiment of the invention, the compound for use as defined above is characterized in that R₂ is H or alkyl, preferably methyl or H. In a further embodiment of the invention, the compound for use as defined above is characterized in that R₃ and R₄ are situated in the meta and para positions of the phenyl group.

In a further preferred embodiment of the invention, the compound for use as defined above is characterized in that R₃ and R₄ are independently selected from halogen, or substituted or unsubstituted alkyl, more preferably selected from halogen or haloalkyl.

In a particularly preferred embodiment of the invention, the compound for use as defined above is characterized in that both R₃ and R₄ together with the phenyl group form an optionally substituted fused ring system. More preferably, said fused ring system is selected from a substituted or unsubstituted fused aryl group and a substituted or unsubstituted aromatic or partially aromatic fused heterocyclyl group. Said fused ring system preferably contains two rings and/or from 9 to about 18 ring atoms, more preferably 9 or 10 ring atoms. Even more preferably, the fused ring system is naphthyl, especially a 2-naphthyl ring system, substituted or unsubstituted. In a yet further preferred embodiment of the invention, the compound for use as defined above is characterized in that n is selected from 2, 3, 4, more preferably n is 2. In a still further preferred embodiment of the invention, the compound for use as defined above is characterized in that R₅ and R₆, together, form a morpholin-4-yl group.

In a preferred variant of the invention the compound of general formula (I) for use as defined above is selected from:

[I ] 4-{2-(1 -(3,4-Dichlorophenyl)-5-methyl-1 H pyrazol-3-yloxy)ethyl} morpholine, [2] 2-[1 -(3,4-Dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]-N,N-diethylethanamine hydrochloride,

[3] 1 -(3,4-Dichlorophenyl)-5-methyl-3-[2-(pyrrolidin-1 -yl)ethoxy]-1 H-pyrazole hydrochloride,

[4] 1 -(3,4-Dichlorophenyl)-5-methyl-3-[3-(pyrrolidin-1 -yl)propoxy]-1 H-pyrazole hydrochloride,

[5] 1 -{2-[1 -(3,4-Dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]ethyl}piperidine,

[6] 1 -{2-[1 -(3,4-dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]ethyl}-1 H-imidazole, [7] 3-{1 -[2-(1 -(3,4-Dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy)ethyl]piperidin-4- yl}-3H-imidazo[4,5-b]pyridine,

[8] 1 -{2-[1 -(3,4-Dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]ethyl}-4- methylpiperazine,

[9] Ethyl 4-{2-[1 -(3,4-dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]ethyl}piperazine carboxylate,

[10] 1 -(4-(2-(1 -(3,4-dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy)ethyl)piperazin-1 - yl)ethanone,

[I I ] 4-{2-[1 -(4-Methoxyphenyl)-5-methyl-1 H-pyrazol-3-yloxy]ethyl}morpholine hydrochloride,

[12] 1 -(4-Methoxyphenyl)-5-methyl-3-[2-(pyrrolidin-1 -yl)ethoxy]-1 H-pyrazole,

[13] 1 -(4-Methoxyphenyl)-5-methyl-3-[3-(pyrrolidin-1 -yl)propoxy]-1 H-pyrazole,

[14] 1 -[2-(1 -(4-Methoxyphenyl)-5-methyl-1 H-pyrazol-3-yloxy)ethyl]piperidine,

[15] 1 -{2-[1 -(4-Methoxyphenyl)-5-methyl-1 H-pyrazol-3-yloxy]ethyl}-1 H-imidazole, [16] 4-{2-[1 -(3,4-Dichlorophenyl)-5-phenyl-1 H-pyrazol-3-yloxy]ethyl}morpholine hydrochloride, [17] 1 -(3,4-Dichlorophenyl)-5-phenyl-3-[2-(pyrrolidin-1 -yl)ethoxy]-1 H-pyrazole hydrochloride,

[18] 1 -(3,4-Dichlorophenyl)-5-phenyl-3-[3-(pyrrolidin-1 -yl)propoxy]-1 H-pyrazole, [19] 1 -{2-[1 -(3,4-Dichlorophenyl)-5-phenyl-1 H-pyrazol-3-yloxy]ethyl}piperidine, [20] 1 -{2-[1 -(3,4-Dichlorophenyl)-5-phenyl-1 H-pyrazol-3-yloxy]ethyl}-1 H-imidazole hydrochloride,

[21 ] 2-{2-[1 -(3,4-dichlorophenyl)-5-phenyl-1 H-pyrazol-3-yloxy]ethyl}-1 , 2,3,4- tetrahydroisoquinoline hydrochloride,

[22] 4-{4-[1 -(3,4-Dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]butyl}morpholine hydrochloride,

[23] 1 -(3,4-Dichlorophenyl)-5-methyl-3-[4-(pyrrolidin-1 -yl)butoxy]-1 H-pyrazole, [24] 1 -{4-[1 -(3,4-Dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]butyl}piperidine hydrochloride,

[25] 1 -{4-[1 -(3,4-Dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]butyl}-4- methylpiperazine dihydrochloride,

[26] 1 -{4-[1 -(3,4-Dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]butyl}-1 H-imidazole, [27] 4-[1 -(3,4-Dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]-N,N-diethylbutan-1 - amine,

[28] 1 -{4-[1 -(3,4-dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]butyl}-4- phenylpiperidine hydrochloride,

[29] 1 -{4-[1 -(3,4-dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]butyl}-6,7-dihydro- 1 H-indol-4(5H)-one,

[30] 2-{4-[1 -(3,4-dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]butyl}-1 ,2,3,4- tetrahydroisoquinoline,

[31 ] 4-{2-[1 -(3,4-dichlorophenyl)-5-isopropyl-1 H-pyrazol-3-yloxy]ethyl}morpholine hydrochloride,

[32] 2-[1 -(3,4-Dichlorophenyl)-5-isopropyl-1 H-pyrazol-3-yloxy]-N,N- diethylethanamine,

[33] 1 -(3,4-Dichlorophenyl)-5-isopropyl-3-[2-(pyrrolidin-1 -yl)ethoxy]-1 H-pyrazole hydrochloride,

[34] 1 -(3,4-Dichlorophenyl)-5-isopropyl-3-[3-(pyrrolidin-1 -yl)propoxy]-1 H-pyrazole hydrochloride,

[35] 1 -{2-[1 -(3,4-Dichlorophenyl)-5-isopropyl-1 H-pyrazol-3-yloxy]ethyl}piperidine, [36] 2-{2-[1 -(3,4-dichlorophenyl)-5-isopropyl-1 H-pyrazol-3-yloxy]ethyl}-1 ,2,3,4- tetrahydroisoqui-noline hydrochloride, [37] 4-{2-[1 -(3,4-dichlorophenyl)-1 H-pyrazol-3-yloxy]ethyl}morpholine,

[38] 2-[1 -(3,4-dichlorophenyl)-1 H-pyrazol-3-yloxy] N,N-diethylethanamine,

[39] 1 -(3,4-dichlorophenyl)-3-[2-(pyrrolidin-1 -yl)ethoxy]-1 H-pyrazole,

[40] 1 -{2-[1 -(3,4-dichlorophenyl)-1 H-pyrazol-3-yloxy]ethyl}piperidine,

[41 ] 1 -(3,4-dichlorophenyl)-3-[3-(pyrrolidin-1 -yl)propoxy]-1 H-pyrazole,

[42] 1 -{2-[1 -(3,4-Dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]ethyl}piperazine dihydrochloride,

[43] 1 -{2-[1 -(3,4-Dichlorophenyl)-5-methyl-1 H-pyrazol-3-yloxy]ethyl}pyrrolidin-3- amine,

[44] 4-{2-[1 -(3,4-Dichlorophenyl)-4,5-dimethyl-1 H-pyrazol-3-yloxy]ethyl}morpholine, [45] 2-[1 -(3,4-Dichlorophenyl)-4,5-dimethyl-1 H-pyrazol-3-yloxy]-N,N- diethylethanamine hydrochloride,

[46] 1 -(3,4-Dichlorophenyl)-4,5-dimethyl-3-[2-(pyrrolidin-1 -yl)ethoxy]-1 H-pyrazole hydrochloride,

[47] 1 -(3,4-Dichlorophenyl)-4,5-dimethyl-3-[3-(pyrrolidin-1 -yl)propoxy]-1 H-pyrazole hydrochloride,

[48] 1 -{2-[1 -(3,4-Dichlorophenyl)-4,5-dimethyl-1 H-pyrazol-3-yloxy]ethyl}piperidine, [49] 4-{4-[1 -(3,4-dichlorophenyl)-1 H-pyrazol-3-yloxy]butyl}morpholine hydrochloride,

[50] (2S,6R)-4-{4-[1 -(3,4-dichlorophenyl)-1 H-pyrazol-3-yloxy]butyl}-2,6- dimethylmorpholine hydrochloride,

[51 ] 1 -{4-[1 -(3,4-Dichlorophenyl)-1 H-pyrazol-3-yloxy]butyl}piperidine hydrochloride, [52] 1 -(3,4-Dichlorophenyl)-3-[4-(pyrrolidin-1 -yl)butoxy]-1 H-pyrazole hydrochloride, [53] 4-[1 -(3,4-dichlorophenyl)-1 H-pyrazol-3-yloxy]-N,N-diethylbutan-1 -amine oxalate,

[54] N-benzyl-4-[1 -(3,4-dichlorophenyl)-1 H-pyrazol-3-yloxy]-N-methylbutan-1 - amine oxalate,

[55] 4-[1 -(3,4-dichlorophenyl)-1 H-pyrazol-3-yloxy]-N-(2-methoxyethyl)-N- methylbutan-1 -amine oxalate,

[56] 4-{4-[1 -(3,4-dichlorophenyl)-1 H-pyrazol-3-yloxy]butyl}thiomorpholine oxalate,

[57] 1 -[1 -(3,4-Dichlorophenyl)-5-methyl-3-(2-morpholinoethoxy)-1 H-pyrazol-4- yl]ethanone oxalate,

[58] 1 -{1 -(3,4-dichlorophenyl)-5-methyl-3-[2-(pyrrolidin-1 -yl)ethoxy]-1 H-pyrazol-4- yljethanone oxalate, [59] 1 -{1 -(3,4-dichlorophenyl)-5-methyl-3-[2-(piperidin-1 -yl)ethoxy]-1 H-pyrazol-4- yljethanone oxalate,

[60] 1 -{1 -(3,4-dichlorophenyl)-3-[2-(diethylamino)ethoxy]-5-methyl-1 H-pyrazol-4- yljethanone oxalate,

[61 ] 4-{2-[5-Methyl-1 -(naphthalen-2-yl)-1 H-pyrazol-3-yloxy]ethyl}morpholine,

[62] N,N-Diethyl-2-[5-methyl-1 -(naphthalen-2-yl)-1 H-pyrazol-3-yloxy]ethanamine, [63] 1 -{2-[5-Methyl-1 -(naphthalen-2-yl)-1 H-pyrazol-3-yloxy]ethyl}piperidine hydrochloride,

[64] 5-Methyl-1 -(naphthalen-2-yl)-3-[2-(pyrrolidin-1 -yl)ethoxy]-1 H-pyrazole hydrochloride, their salts, different alternative pharmaceutically acceptable salts, solvates or prodrugs. In a particularly more preferred embodiment of the invention, the compound for use as defined above is 4-{2-[5-methyl-1 -(naphthalen-2-yl)-1 H-pyrazol-3- yloxy]ethyl}morpholine or its pharmaceutically acceptable salts, solvates or a prodrug thereof. In a still more particularly preferred embodiment of the invention, the compound for use as defined above is 4-{2-[5-methyl-1 -(naphthalen-2-yl)-1 H-pyrazol-3- yloxy]ethyl}morpholine hydrochloride or solvates or a prodrug thereof.

In a further preferred embodiment of the invention, the compound for use as defined above is a polymorph of 4-{2-[5-methyl-1 -(naphthalen-2-yl)-1 H-pyrazol-3- yloxy]ethyl}morpholine hydrochloride, preferably form I as disclosed in WO201 1 /095579.

"Alkyl" refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, having one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e. g., methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, etc. Alkyl radicals may be optionally substituted by one or more substituents such as a aryl, halo, hydroxy, alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto, alkylthio, etc. If substituted by aryl it corresponds to an "arylalkyl or aralkyl" radical, such as benzyl and phenethyl.

"Alkenyl" refers to an alkyl radical having at least two carbon atoms and having one or more unsaturated bonds.

"Cycloalkyi" refers to a stable 3-to 10-membered monocyclic or bicyclic radical which is saturated or partially saturated, and which consist solely of carbon and hydrogen atoms, such as cyclohexyl or adamantyl. The cycloalkyi radicalmay be optionally substituted by one or more substituents such as alkyl, halo, hydroxy, amino, cyano, nitro, alkoxy, carboxy, alkoxycarbonyl, etc.

"Aryl" refers to single and multiple ring radicals, including multiple ring radicals that contain separate and/or fused aryl groups. Typical aryl groups contain from 1 to 3 separated or fused rings and from 6 to about 18 carbon ring atoms, such as phenyl, naphthyl, indenyl, fenanthryl or anthracyl radical. The aryl radical may be optionally substituted by one or more substituents such as hydroxy, mercapto, halo, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl, alkoxycarbonyl, etc. "Heterocyclyl" refers to a stable 3-to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, preferably a 4-to 8-membered ring with one or more heteroatoms, more preferably a 5-or 6-membered ring with one or more heteroatoms. It may be aromatic or not aromatic. For the purposes of this invention, the heterocycle may be a monocyclic, bicyclic or tricyclic ring system, which may include fused ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidised; the nitrogen atom may be optionally quaternized ; and the heterocyclyl radical may be partially or fully saturated or aromatic. Examples of such heterocycles include, but are not limited to, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran, coumarine, morpholine; pyrrole, pyrazole, oxazole, isoxazole, triazole, imidazole, etc.

"Alkoxy" refers to a radical of the formula -ORa where Ra is an alkyl radical as defined above, e. g., methoxy, ethoxy, propoxy, etc. "Amino" refers to a radical of the formula-NH₂, -NHRa or -NRaRb, optionally quaternized, wherein Ra and Rb is an alkyl radical as defined above, e. g., methoxy, ethoxy, propoxy, etc. "Halo" or "hal" refers to bromo, chloro, iodo or fluoro.

"Fused ring system" refers to a polycyclic ring system that contains fused rings. Typically, the fused ring system contains 2 or 3 rings and/or up to 18 ring atoms. As defined above, cycloalkyl radicals, aryl radicals and heterocyclyl radicals may form fused ring systems. Thus, fused ring system may be aromatic, partially aromatic or not aromatic and may contain heteroatoms. A spiro ring system is not a fused-polycyclic by this definition, but fused polycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the system. Examples of fused ring systems are, but are not limited to, adamantyl, naphthyl (e.g. 2-naphthyl), indenyl, fenanthryl, anthracyl, pyrenyl, benzimidazole, benzothiazole, etc.

Unless otherwise stated specifically in the specification, all the groups may be optionally substituted, if applicable. References herein to substituted groups in the compounds of the present invention refer to the specified moiety that may be substituted at one or more available positions by one or more suitable groups, e. g., halogen such as fluoro, chloro, bromo and iodo ; cyano; hydroxyl ; nitro ; azido ; alkanoyl such as a C_1-6 alkanoyl group such as acyl and the like; carboxamido; alkyl groups including those groups having 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1 -3 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages and from 1 to about 12 carbon atoms or 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those moieties having one or more sulfinyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms ; alkylsulfonyl groups including those moieties having one or more sulfonyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; aminoalkyl groups such as groups having one or more N atoms and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; carbocylic aryl having 6 or more carbons, particularly phenyl or naphthyl and aralkyl such as benzyl. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other. Unless otherwise stated, the compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon or ¹⁵N-enriched nitrogen are within the scope of this invention.

The term "pharmaceutically acceptable salts, solvates, prodrugs" refers to any pharmaceutically acceptable salt, ester, solvate, or any other compound which, upon administration to the recipient is capable of providing (directly or indirectly) a compound as described herein. However, it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the invention since those may be useful in the preparation of pharmaceutically acceptable salts. The preparation of salts, prodrugs and derivatives can be carried out by methods known in the art. For instance, pharmaceutically acceptable salts of compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two. Generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Examples of the acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulphonate and p-toluenesulphonate. Examples of the alkali addition salts include inorganic salts such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminium and lithium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, Ν,Ν-dialkylenethanolamine, triethanolamine, glucamine and basic aminoacids salts. Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.

Any compound that is a prodrug of a compound of formula (I) is within the scope of the invention. The term "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Examples of well-known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al. "Textbook of Drug design and Discovery" Taylor & Francis (april 2002).

The compounds for use according to the invention may be in crystalline form either as free compounds or as solvates and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment the solvate is a hydrate.

The compounds of general formula (I) for use according to the invention or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels. Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment purity levels for the drug substance is above 95% of the compound of formula (I), or of its salts, solvates or prodrugs.

The compounds for use according to the present invention represented by the above described general formula (I) may include enantiomers depending on the presence of chiral centres or isomers depending on the presence of multiple bonds (e.g. Z, E). The single isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention. The compounds of general formula (I) for use according to the present invention and their salts or solvates can be prepared as disclosed in the previous application WO2006/021462.

The obtained reaction products may, if desired, be purified by conventional methods, such as crystallisation and chromatography. Where the above described processes for the preparation of compounds of the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. If there are chiral centers the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.

One preferred pharmaceutically acceptable form is the crystalline form, including such crystalline form in pharmaceutical composition. In the case of salts and solvates the additional ionic and solvent moieties must also be non-toxic. The compounds of the invention may present different polymorphic forms, it is intended that the invention encompass all such forms.

As used herein, the terms "treat", "treating" and "treatment" include the eradication, removal, reversion, alleviation, modification, or control of post-herpetic pain (postherpetic neuralgia).

As used herein, the terms "prevention", "preventing", "preventive" "prevent" and "prophylaxis" refers to the capacity of a therapeutic to avoid, minimize or difficult the onset or development of a disease or condition before its onset, in this case post- herpetic pain (postherpetic neuralgia).

Another aspect of this invention relates to a method of treating post-herpetic pain, which method(s) comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of general formula (I) as above defined or a pharmaceutical composition thereof. Another aspect of this invention relates to a method of preventing post-herpetic pain, which method(s) comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of general formula (I) as above defined or a pharmaceutical composition thereof.

In another aspect, the invention is directed to a use of a compound of general formula (I) as above defined in the preparation of a medicament for the treatment of postherpetic pain.

In another aspect, the invention is directed to a use of a compound of general formula (I) as above defined in the preparation of a medicament for preventing the postherpetic pain. The present invention further provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt, derivative, prodrug or stereoisomers thereof together with a pharmaceutically acceptable carrier, adjuvant, or vehicle, for administration to a patient. In another aspect, the invention is thus directed to a pharmaceutical composition comprising a compound of formula (I) as defined above for use in the prevention and/or treatment of post-herpetic pain, wherein the composition further comprises a pharmaceutically acceptable carrier, adjuvant and/or vehicle. Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration.

In a preferred embodiment of the invention, the pharmaceutical compositions are in oral form, either solid or liquid. Suitable dose forms for oral administration may be tablets, capsules, syrops or solutions and may contain conventional excipients known in the art such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art. The tablets may for example be prepared by wet or dry granulation and optionally coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.

The pharmaceutical compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the appropriate unit dosage form. Adequate excipients can be used, such as bulking agents, buffering agents or surfactants.

The mentioned compositions will be prepared using standard methods such as those described or referred to in the Spanish and US Pharmacopoeias and similar reference texts. Administration of the compounds or compositions of the present invention may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration. Oral administration is preferred because of the convenience for the patient and the chronic character of the diseases to be treated.

Generally an effective administered amount of a compound of the invention will depend on the relative efficacy of the compound chosen, the severity of the disorder being treated and the weight of the sufferer. However, active compounds will typically be administered once or more times a day for example 1 , 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 1000 mg/kg/day.

In a preferred embodiment of the compounds of general formula (I) for use according to the invention, said compounds, optionally in the form of a pharmaceutical composition, are administered once daily. In a preferred embodiment of the compounds of general formula (I) for use according to the invention, said compound is administered at a daily dose of from to 100 mg to 600 mg per day. Even more preferably, the compound of general formula (I) is administered at a daily dose of from 200 mg to 400 mg per day.

In a preferred embodiment of the invention, the compound for use in the treatment or prevention of postherpetic pain (postherpetic neuralgia) is 4-{2-[5-methyl-1 - (naphthalen-2-yl)-1 H-pyrazol-3-yloxy]ethyl}morpholine or its pharmaceutically acceptable salts, solvates or a prodrug thereof. Preferably it is in oral form. More preferably this compound is administered daily. Even more preferably it is administered at a daily dose of from 100 mg to 600 mg per day, particularly preferred is a daily dose of from 200 mg to 400 mg per day.

In a still more particularly preferred embodiment of the invention, the compound for use in the treatment or prevention of postherpetic pain (postherpetic neuralgia) is 4-{2-[5- methyl-1 -(naphthalen-2-yl)-1 H-pyrazol-3-yloxy]ethyl}morpholine hydrochloride or solvates or a prodrug thereof. Preferably it is in oral form. More preferably this compound is administered daily. Even more preferably it is administered at a daily dose of from 100 mg to 600 mg per day, particularly preferred is a daily dose of from 200 mg to 400 mg per day.

In a further preferred embodiment of the invention, the compound for use in the treatment or prevention of postherpetic pain (postherpetic neuralgia) is a polymorph of 4-{2-[5-methyl-1 -(naphthalen-2-yl)-1 H-pyrazol-3-yloxy]ethyl}morpholine hydrochloride, preferably form I as disclosed in WO201 1/095579. Preferably this polymorph is in oral form. More preferably this polymorph is administered daily. Even more preferably it is administered at a daily dose of from 100 mg to 600 mg per day, particularly preferred is a daily dose of from 200 mg to 400 mg per day. The compounds and compositions of this invention may be used to provide with other drugs a combination therapy. The other drugs may form part of the same composition, or be provided as a separate composition for simultaneous administration or for sequential administration. By sequential administration it is meant that compounds for use according to the present invention are administrated before the other drugs, and/or after the other drugs, at different time. Thus, a further aspect of the invention relates to a compound of formula (I) as defined above, for the use in the prevention and/or treatment of post-herpetic pain, wherein the compound is administered in combination with an anticonvulsant.

In a preferred embodiment, a compound of formula (I) as defined above, for use in the prevention and/or treatment of post-herpetic pain, is combined with an anticonvulsant selected from Pregabalin and Gabapentin. Another aspect of the invention relates to a combination for use in the prevention and/or treatment of post-herpetic pain, said combination comprising a compound of formula (I) as defined above and an anticonvulsant. In a preferred embodiment, the anticonvulsant is selected from Pregabalin and Gabapentin. In the present description, the term "combination" means that the two or more active ingredients can be administered together, either in a single composition or as separate forms, or alternatively also in a sequential or separate manner.

In a preferred embodiment of this aspect of the invention, the compound for use in the combination as defined above is 4-{2-[5-methyl-1 -(naphthalen-2-yl)-1 H-pyrazol-3- yloxy]ethyl}morpholine or its pharmaceutically acceptable salts, solvates or a prodrug thereof.

In a still more particularly preferred embodiment of this aspect of the invention, the compound for use in the combination as defined above is 4-{2-[5-methyl-1 -(naphthalen- 2-yl)-1 H-pyrazol-3-yloxy]ethyl}morpholine hydrochloride or solvates or a prodrug thereof.

In a further preferred embodiment of the invention, the compound for use in the combination as defined above is a polymorph of 4-{2-[5-methyl-1 -(naphthalen-2-yl)-1 H- pyrazol-3-yloxy]ethyl}morpholine hydrochloride, preferably form I as disclosed in WO201 1/095579. Another aspect of the invention relates to a compound of formula (I) as defined above, for the use in the prevention and/or treatment of post-herpetic pain wherein patients have been and/or are being treated with an anticonvulsant. In a preferred embodiment the compound of formula (I) as defined above, for use in the prevention and/or treatment of post-herpetic pain in patients suffering post-herpetic pain, wherein patients have been and/or are being treated with an anticonvulsant selected from Pregabalin and Gabapentin. A further aspect of this invention relates to a method of treating post-herpetic pain, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of general formula (I) as above defined in combination with an anticonvulsant, preferably selected from Gabapentin and Pregabalin, or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of preventing post-herpetic pain, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of general formula (I) as above defined in combination with an anticonvulsant, preferably selected from Gabapentin and Pregabalin, or a pharmaceutical composition thereof.

A still further aspect of the invention related to a method of prevention and/or treatment of a patient suffering post-herpetic pain, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a compound of formula (I) as defined above, and wherein said patient has been or is being treated with an anticonvulsant.

A further aspect, the invention is directed to a use of the compounds of general formula (I) as above defined in combination with an anticonvulsant, preferably Gabapentin or Pregabalin, in the preparation of a medicament for the treatment of post-herpetic pain.

In yet another aspect, the invention is directed to a use of the compounds of general formula (I) as above defined in combination with an anticonvulsant, preferably Gabapentin or Pregabalin, in the preparation of a medicament for preventing the post- herpetic pain. The following examples are given only as further illustration of the invention; they should not be taken as a definition of the limits of the invention. EXAMPLES

Example 1

Synthesis of 4-{2-[5-Methyl-1 -(naphthalen-2-yl)-1 H-pyrazol-3-yloxy]ethyl} morpholine (compound 61) and its hydrochloride salt

c<m*poun<i ·ι Exampf · 1

Compound 61 can be prepared as disclosed in the previous application WO2006/021462. Its hydrochloride can be obtained according the following procedure:

Compound 61 (6,39 g) was dissolved in ethanol saturated with HCI, the mixture was stirred then for some minutes and evaporated to dryness. The residue was crystallized from isopropanol. The mother liquors from the first crystallization afforded a second crystallization by concentrating. Both crystallizations taken together yielded 5.24 g (63 %) of the corresponding hydrochloride salt (m.p. = 197-199 ⁵C).

1 H-NMR (DMSO-d6) 6 ppm: 10,85 (bs, 1 H), 7,95 (m, 4H), 7,7 (dd, J=2,2, 8,8 Hz,1 H), 7,55 (m, 2H), 5,9 (s, 1 H), 4,55 (m, 2H), 3,95 (m, 2H), 3,75 (m, 2H), 3,55-3,4 (m, 4H), 3,2 (m, 2H), 2,35 (s, 3H).

HPLC purity: 99.8%.

Clinical Data

Example 2: An exploratory, randomized, double blind, placebo controlled, parallel groups Phase II clinical trial to evaluate the efficacy and safety of Example 1 by oral route, in patients with post-herpetic neuralgia (PHN). Methodology:

The clinical study was a multicenter, randomized, double blind, parallel group, placebo- controlled, proof-of-concept study. Patients meeting all inclusion and none of the exclusion criteria were included in a run-in period of one week. During this week, patients were asked to complete a diary daily to register the pain intensities.

After the one-week run-in period, patient returned to the center for visit 2. The investigator re-checked the patient eligibility and reviewed the patient's diary to confirm that the patient had a mean 24 hour average score≥ 4 on the NPRS (Numerical Pain Rating Scale) over 7 days of the run-in period. To be eligible to enter the treatment period, patients must have completed the NPRS of the diary a minimum of five days. Treatment duration was 28 days. Patients received one dose of Example 1 (400 mg) or placebo (following randomization list) by oral route on day 1 of the study (next day to visit 2) and once daily up to day 28. During and after the treatment period, efficacy assessments were performed at different time points. In between visits, assessments were done through a diary card. At the end of the treatment period, the patients were followed one week more.

The NPRS (Numerical Pain Rating Scale) is hereby defined as a unidimensional measure of pain intensity in adults. The NPRS is a segmented numeric version of the visual analog scale (VAS) in which a respondent selects a whole number (0-10 integers) that best reflects the intensity of his/her pain. The used format is a horizontal bar (Figure 1 ). Similar to the VAS, the NPRS is anchored by terms describing pain severity extremes. In the present methodology the 1 1 -item NPRS is used from '0' representing one pain extreme (e.g. "no pain") to '10' representing the other pain extreme (e.g. "pain as bad as you can imagine" or "worst pain imaginable").

Diagnosis and main criteria for inclusion:

Male and female adults with a diagnosis of moderate to severe pain of postherpetic neuralgia present for more than 3 months since the resolution of rash but no more than 5 years, treated with stable doses of gabapentin or pregabalin (Table 1 ) for at least one month prior to the screening visit, who were able to continue taking the same doses for the duration of the study.

Overall, the median age of the patients randomized was 73.0 (range from 34 to 80) years.

Table 1

Gabapentin and Pregabalin at study entry (Randomized patients)

Duration of treatment:

Treatment duration was 28 days. Patients received one dose of study drug Example 1 (400 mg) or placebo (following randomization list) in the morning by oral route on day 1 of the study and once daily up to day 28. During and after the treatment period, efficacy assessments were performed at different time points. In between visits, assessments were done through a diary card. At the end of the treatment period, the patient was followed one week more. The overall study design is shown in Figure 2.

At the end of the study with 13 patients randomized (9 patients in the placebo arm and 4 patients in Example 1 arm) the obtained results (Figure 3) are shown in Table 2:

Table 2

Day 7 4.30 (1 .02) -1.55 (1 .56) 4.69 (1 .27) -0.48 (0.98)

Day 14 4.84 (1 .45) -1 .01 (0.97) 4.67 (1 .37) -0.48 (1 .26)

Day 21 5.00 (1 .40) -0.85 (0.84) 4.29 (1 .69) -0.85 (1 .81 )

Day 28 4.32 (1 .04) -1.53 (1 .73) 4.29 (1 .90) -0.85 (1 .79)

Day 35^* 4 74 (1 .34) -1.1 1 (0.84) 3.54 (1 .80) -1 .60 (1 .90)

^* off-treatment

Wherein baseline pain stands for pain value which was present before starting treatment in the corresponding treatment groups.

Regarding data obtained to assess the analgesic efficacy of Example 1 , a decrease in the pain intensity, measured by the patient diary, between the group treated with Example 1 and the group treated with placebo was observed (1 .53 and 0.85 points, respectively) after 28 days with study treatment.

The above results are confirmed by the ones (Table 3 and Table 4) reflected through the Short Form-Brief Pain Inventory (SF-BPI), the standard questionnaire used to assess the severity of pain and its impact on daily functions.

Table 3

SF-BPI Pain Interference

Day 35* Mean (SD) 6..75 (4.30) -1..70 4.51 (3.83) 4..00

(SD: 4.28) (SD: 2..33)

(Mm, Max.) (1.60, 1 1.20) (0.20, 10.80)

¹ .

Table 4

SF-BPI Least pain in last 24 hours

The Short Form-Brief Pain Inventory (sf-BPI) hereby is defined as a 9 item self- administered questionnaire based in the Brief Pain Inventory (BPI). The BPI is a medical questionnaire used to measure pain developed by the Pain Research Group of the WHO Collaborating Centre for Symptom Evaluation in Cancer Care.

The sf-BPI sample both pain severity [Mild (1 -4), Moderate (5-6) and Severe (7-1 0)] and the impact of pain on the patient (pain interference: general activity, work, ability to walk, mood, ability to relate to others, enjoyment of life and sleep). The interference scale can be decomposed into activity-related and mood-related subscales and are sensitive to dose treatment response.

Claims

A compound according to general formula (I) or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, for use in the prevention and/or treatment of post-herpetic pain:

(I)

wherein

R is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyi, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR₈, -C(0)OR₈, -C(0)NR₈R₉, -CH=NR₈, -CN, -OR₈, - OC(0)R₈, -S(0)t-R₈, -NR₈R₉ , -NR₈C(0)R₉, -N0₂, - N=CR₈R₉, and halogen ;

R₂ is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyi, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, - COR₈, -C(0)OR₈, - C(0)NR₈R₉ , -CH=NR₈, -CN, -OR₈, -OC(0)R₈, -S(0)t-R₈, -NR₈ R₉ , - NR₈C(0) R₉ , -N0₂ , - N=CR₈ R₉ , and halogen ;

R₃ and R₄ are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyi, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, - COR₈, -C(0)OR₈, -C(0)NR₈R₉, -CH=NR₈, -CN, -OR₈, -OC(0)R₈, -S(0)t-R₈, - NR₈R₉, -NR₈C(0)R₉, -N0₂, -N=CR₈R₉, and halogen, or together they form an optionally substituted fused ring system;

R₅ and R₆ are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyi, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, - COR₈, -C(0)OR₈, -C(0)NR₈R₉, -CH=NR₈, -CN, -OR₈, -OC(0)R₈, -S(0)t-R₈, - NR₈R₉, -NR₈C(0)R₉, -N0₂, -N=CR₈R₉, and halogen, or together form, with the nitrogen atom to which they are attached, a substituted or unsubstituted, aromatic or non-aromatic heterocyclyl group; n is selected from 1 , 2, 3, 4, 5, 6, 7 or 8; t is 1 ,2 or 3;

R₈ and R₉ are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, and halogen.

2. The compound for use according to claim 1 , wherein is hydrogen.

3. The compound for use according to any of claims 1 or 2, wherein R₂ is H or alkyl, preferably methyl or H.

4. The compound for use according to any of claims 1 to 3, wherein R₃ and R₄ together with the phenyl forms a naphthyl group.

5. The compound for use according to any of claims 1 to 4, wherein n is selected from 2, 3, 4, more preferably n is 2.

6. The compound for use according to any of claims 1 to 5, wherein R₅ and R₆, together, form a morpholine-4-yl group.

7. The compound for use according to any of claims 1 to 6, wherein the compound is 4-{2-[5-Methyl-1 -(naphthalen-2-yl)-1 H-pyrazol-3-yloxy]ethyl}morpholine or a pharmaceutically acceptable salt, solvate or prodrug thereof.

8. The compound for use according to claim 7, wherein the compound is 4-{2-[5- Methyl-1 -(naphthalen-2-yl)-1 H-pyrazol-3-yloxy]ethyl}morpholine hydrochloride or a solvate or prodrug thereof.

The compound for use according to claim 8, wherein the compound is polymorph form I of 4-{2-[5-methyl-1 -(naphthalen-2-yl)-1 H-pyrazol-3- yloxy]ethyl}morpholine hydrochloride.

The compound for use according to any of claims 1 to 9, wherein the compound is administered in combination with an anticonvulsant.

1 1 . The compound for use according to claim 10, wherein the anticonvulsant is selected from Pregabalin and Gabapentin. 12. Pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1 to 9, for use in the prevention and/or treatment of post-herpetic pain, wherein the composition further comprises a pharmaceutically acceptable carrier, adjuvant and/or vehicle. 13. A method for the treatment or prevention of post-herpetic pain, comprising the administration to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand of formula (I) as defined in any of claims 1 to 9.