TW201806601A - Use of sigma receptor ligands in post-herpetic pain - Google Patents

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 pain after herpes

The present invention relates to the use of sigma receptor ligands, more particularly to some pyrazole derivatives, and to the use of pharmaceutical compositions containing the same in the prevention and / or treatment of pain caused by herpes.

In other tissues, sigma receptors are cell surface receptors and endoplasmic reticulum receptors expressed in the central nervous system (CNS). Through biological and functional studies of sigma receptors, there is evidence that sigma receptor ligands can be used to treat psychiatric and dyskinesias such as dystonia and delayed dyskinesia, as well as with Huntington's chorea or Toure Dyskinesia-related dyskinesia and Parkinson's disease (Walker, JM et al., Pharmacological Reviews, 1990, 42, 355). It has been reported that the known sigma receptor ligand lincarbazole clinically shows a role in treating psychosis (Hanner, M. et al. Proc. Natl. Acad. Sci., 1996, 93: 8072-8077; Snyder , SH, Largent, BLJ Neuropsychiatry 1989, 1, 7). The sigma binding site for certain opioid phenylmorphine dextroisomers such as (+) SKF 10047, (+) Cyclozoxine and (+) Pentazocin and certain narcotics such as fluoropyridoxine have preferential affinity.

Sigma receptors have at least two subtypes, which can be distinguished by stereoselective isomers of these pharmacologically active drugs. SKF 10047 has a nanomolar affinity for the σ-1 site and a slight molar affinity for the σ-2 site. Fluroxidine has similar affinity for the two subtypes. The endogenous sigma ligand is unknown, although progesterone is considered 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 presence of sigma receptors in the CNS, immune and endocrine systems suggests that it may serve as a link between the three systems.

The detection of the presence of sigma-1 receptors (sigma 1R) in rat pancreas by using the sigma 1R 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, especially selective inhibitors of sigma-1 receptors. There is a pyrazole group in this family, which is characterized by substitution at the 3-position through an alkoxy group directly bonded to nitrogen.

Herpes sequelae neuralgia (PHN) is neuralgia caused by varicella zoster virus damage. Usually, neuralgia is limited to the skin area of the skin, and then herpes zoster (commonly called herpes zoster) erupts in the same skin area. Neuralgia usually occurs when herpes zoster vesicles have formed a skin and started to heal, but it can also occur without herpes zoster. This is a type called "zoster sine herpete." "Disease.

Herpes zoster (HZ) or "shingles" (described as burning or throbbing pain, severe tingling, electric shock, and allodynia) is restarted by the varicella zoster virus (VZV) caused. VZV primary infection causes chickenpox (chickenpox), after which VZV lurks in the sensory ganglia along the entire nerve axis. The re-activation of latent varicella-zoster virus in the dorsal root ganglion leads to a localized rash called "zoster" that spreads from a single sensory ganglion to the nerve tissue and skin area of the affected part. Declining virus-specific cell-mediated immune responses occur naturally due to aging or induction by immunosuppressive diseases or medical treatment, increasing the risk of herpes zoster. Idiopathic rashes usually heal within two to four weeks, and acute pain is usually the most distressing symptom.

The main clinical manifestations of herpes zoster are: acute pain of HZ rash lasts 4 weeks; subacute herpes neuralgia lasts 30 days to 4 months. The rash appeared after 5 days, and appeared as small red spots, which turned into blisters. Within 1 to 2 days, papules develop into vesicles, which continue to appear for 3 to 4 days. All types of lesions may exist and tend to be grouped. The formation of pustules of vesicles begins within 1 week after the onset of the rash, and then progresses to lesion ulcers and crusts after 3 to 5 days. Crusting is usually completed within 3 to 4 weeks, but scars and hypopigmentation or hyperpigmentation may persist.

More than 90% of American adults have serological evidence of varicella-zoster virus infection and are at risk of herpes zoster.

The annual incidence of shingles is about 1.5 to 3.0 cases per 1,000 people. Increasing age is a key risk factor for the development of herpes zoster; among people over 75 years old, the incidence of herpes zoster exceeds 10 cases per 1,000 people per year on. The lifetime risk of herpes zoster is estimated to be 10% to 20%. Another clear risk factor for herpes zoster is altered cell-mediated immunity. Patients with tumor diseases (especially lymphoproliferative cancers), patients receiving immunosuppressive drugs (including corticosteroids), and recipients of organ transplants have an increased risk of herpes zoster.

Postherpetic neuralgia (PHN) is the pain sequelae of acute herpes zoster virus infection and the most common chronic complication. The main clinical aspects of PHN are: defined as continuous chronic pain that persists after treatment of the lesion 3 months. In the worst case, PHN lasts for many years. Pain is described as "burning", "shock", "stinging" or "throbbing". Approximately 20% of HZ patients over 50 years old develop PHN. Where blisters occur, the pain may be severe, and the affected skin may be very sensitive to heat and cold.

The threshold of pain time after clinical outbreak of herpes zoster classified as herpetic neuralgia (PHN) is variable for researchers (30, 90, or 120 days or 6 months), however, recent models Support 90 days as the most suitable time point definition.

The risk of PHN increases with age. The increasing age and severity of acute HZ pain are the biggest risk factors for PHN. Therefore, the risk factors for the development of PHN include herpes zoster infection in old age, more severe acute pain, more severe rash, and the presence of prodromal symptoms of pain.

The cause of PHN may be nerve damage caused by herpes zoster infection. The damage causes nerves in the affected skin area to send abnormal electrical signals to the brain. These signals may convey distressing pain and may last or relapse for months, years or life.

A key factor in the neuroplasticity of neuropathic pain is to alter gene expression in sensory dorsal root ganglion neurons. Sensory nerve damage causes neurochemical, physiological, and anatomical changes to afferent neurons and central neurons, such as afferent nerve germination and inhibitory interneuron loss. Pathological findings include primary afferent neurons and axonal degeneration, spinal cord atrophy, dorsal root ganglion scar formation, and loss of epidermal nerve distribution.

The incidence and duration of herpetic neuralgia are directly related to the patient's age. The incidence of herpes zoster neuralgia is reported to be between 8% and 70%, and increases with age. Compared with younger patients, the incidence of pain in patients over the age of 50 at 30 and 60 days was 15 and 27 times, respectively. For each year of age, the incidence of herpetic neuralgia increases by 9% and 12% at 30 and 60 days, respectively (Gnann J, Whitley R., 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; Haanpää, M. Et al., Pain: Clinical updates, 2015, 23 (4): 1-8; Gharibo, C., etc .; Pain Medicine News; 2011; 1-7).

Herpetic neuralgia is very difficult to treat and, similar to many other systemic diseases, has been shown to cause severe impairment of quality of life. Current therapies include antidepressants (such as tricyclic antidepressants), anticonvulsants (such as gabapentin, pregabalin or topiramate), gabapentin (a prodrug of gabapentin) and various oral and local analgesics (such as lidocaine) Because of patches or capsaicin lotions); however, these therapies are only partially effective in relieving pain, and the side effects of these drugs are increased, especially in elderly patients.

Opioid analgesics may also be suitable in many cases. There are occasionally successful experimental treatments, such as nerve root excision (cutting or damaging the affected nerve to relieve pain) and TENS (a type of electrical pulse therapy).

The treatment of PHN depends on the type and characteristics of the pain experienced by the patient. Pain control is essential for quality patient care; it ensures patient comfort. Currently, possible options include:

˙Antiviral drugs (administered during the onset of herpes zoster to shorten the clinical process and help prevent complications, but once PHN has occurred, they cannot play a role after acute onset.)

˙ Analgesics are administered topically (lidocaine) or delivered systemically (opioids and non-opioids).

˙Pain modification therapy includes:

○ Antidepressants. Low-dose tricyclic antidepressants seem to be best for deep soreness. They cannot eliminate pain, but they can make it more bearable. Other prescription antidepressant drugs may be drugs for post-herpetic neuralgia that have not been approved by clinical trials and usually prove to be less effective, although they may be better tolerated than tricyclic drugs.

○ Anticonvulsant drugs. These drugs are used to treat severe muscle spasms and provide a sedative effect in neuralgia. They have a central role in pain regulation. Medications used to treat seizures, such as phenytoin (Dilantin, phenytoin), can also reduce the pain associated with postherpetic neuralgia. Drugs can stabilize abnormal electrical activity in the nervous system caused by damaged nerves. Doctors often prescribe another An anticonvulsant drug called carbamazepine (carbamazepine, imidamine) is used for severe pain and tingling. Newer anticonvulsants, such as gabapentin (Geurpentin (Neurontin)) and lamotrigine (Libiton) are generally better tolerated and can help control burning pain and pain.

˙Other non-pharmacological treatments for PHN include acupuncture, moxibustion, relaxation techniques, hyperthermia or transcutaneous electrical nerve stimulation.

In some cases, the treatment of herpetic neuralgia can completely relieve the pain. But most patients still experience some pain, and some people do not get any relief, even if preventive measures have been established in primary and secondary conditions. Therefore, HZ and PHN pose challenges to the health care system because they are ubiquitous, causing pain and impaired function, and are difficult to treat satisfactorily, especially among the elderly patient population.

Sang et al. Reported in Anesthesiology, 2002, May 96 (5): 1053-61 clinical trials of dextromethorphan, memantine, and lorazepam in the treatment of diabetic neuropathy and herpes zoster neuralgia. Conclusion: In selected diabetic neuropathy patients, dextromethorphan is effective in a dose-dependent manner, but it is not true for herpes zoster neuralgia, which indicates that the pain mechanism is different, so the choice should be used Sexual treatment of pain.

Nelso et al., Neurology, 1997 May 48 (5): 1212-1218 also reported that high-dose oral dextromethorphan reduced pain in diabetic neuropathy, but did not reduce postherpetic neuralgia.

These reports show that the pain after herpes zoster is a different kind of pain Pain, and the effectiveness of analgesics in this particular indication cannot be expected.

Therefore, there is a need to provide a new form of prevention and treatment of postherpetic pain, especially for neuropathic pain, allodynia, hyperalgesia, and peripheral neuropathy that develop as a result of shingles.

The inventors of the present invention have unexpectedly discovered and demonstrated that the administration of specific sigma receptor ligands according to general formula (I) is very effective for preventing and / or treating herpes sequelae pain.

Therefore, in one aspect, the present invention relates to a compound according to general formula (I) or a pharmaceutically acceptable salt, isomer, medicament thereof bound to a sigma-receptor for preventing and / or treating postherpetic pain Precursor or solvate:

Where R _{1 is} selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Arylalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted heterocyclic group alkyl, -COR ₈ , -C (O ) OR ₈ , -C (O) NR ₈ R ₉ , -CH = NR ₈ , -CN, -OR ₈ , -OC (O) R ₈ , -S (O) _t -R ₈ , -NR ₈ R ₉ , -NR ₈ C (O) R ₉ , -NO ₂ , -N = CR ₈ R ₉ and halogen; R _{2 is} selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted ring Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aromatic or non-aromatic heterocyclic, substituted or Unsubstituted heterocyclic alkyl, -COR ₈ , -C (O) OR ₈ , -C (O) NR ₈ R ₉ , -CH = NR ₈ , -CN, -OR ₈ , -OC (O) R ₈ , -S (O) _t -R ₈ , -NR ₈ R ₉ , -NR ₈ C (O) R ₉ , -NO ₂ , -N = CR ₈ R ₉ and halogen; R ₃ and R ₄ Are selected from hydrogen, substituted or Unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted Aromatic or non-aromatic heterocyclic groups, substituted or unsubstituted heterocyclic alkyl groups, -COR ₈ , -C (O) OR ₈ , -C (O) NR ₈ R ₉ , -CH = NR ₈ , -CN, -OR ₈ , -OC (O) R ₈ , -S (O) _t -R ₈ , -NR ₈ R ₉ , -NR ₈ C (O) R ₉ , -NO ₂ , -N = CR ₈ R ₉ and halogen, or they together form an optionally substituted fused ring system; R ₅ and R ₆ are selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aromatic or non-aromatic heterocyclic group, substituted or unsubstituted heterocyclic Cycloalkyl, -COR ₈ , -C (O) OR ₈ , -C (O) NR ₈ R ₉ , -CH = NR ₈ , -CN, -OR ₈ , -OC (O) R ₈ , -S (O) _t -R ₈ , -NR ₈ R ₉ , -NR ₈ C (O) R ₉ , -NO ₂ , -N = CR ₈ R ₉ and halogen, or they are together with the attached nitrogen atom shape A substituted or unsubstituted aromatic or non-aromatic heterocyclic group; is selected from n-7 or 8; t is 1, 2 or 3; R ₈ and R ₉ each 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 heterocyclic group, substituted or unsubstituted alkoxy group, substituted or unsubstituted aryloxy group and halogen.

In another aspect, the invention relates to a pharmaceutical composition comprising at least one compound of the general formula (I) as defined above for the prevention and / or treatment of postherpetic pain, wherein the composition further comprises at least one pharmaceutically acceptable Accepted carriers, adjuvants and / or excipients.

Another aspect of the invention relates to the use of a compound of formula (I) as defined above in the preparation of a medicament for the prevention and / or treatment of pain caused by herpes.

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

Another aspect of the present invention relates to a compound of formula (I) as defined above for use in the prevention and / or treatment of pain after herpes, wherein the compound is administered in combination with an anticonvulsant.

Another aspect of the invention relates to compounds of formula (I) as defined above, Its use for the prevention and / or treatment of pain caused by herpes, in which the patient has been and / or is being treated with anticonvulsants.

Another aspect of the invention relates to the use of a compound of formula (I) as defined above for the preparation of a medicament for the prevention and / or treatment of herpes sequelae pain in patients who have been and / or are being treated with anticonvulsants.

Another aspect of the invention relates to a method of treating a patient suffering from postherpetic pain, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) as defined above and wherein the patient has or is taking Treat with anticonvulsants.

The above preferred and embodiments can be combined to obtain better compounds or uses.

These aspects and their preferred embodiments are further defined below, in the detailed description, and in the scope of patent applications.

Figure 1: NPRS (Digital Pain Scoring Table); Figure 2: Experimental design; Figure 3: NPRS-mean pain reduction (mean change) throughout the study.

In one aspect, the present invention relates to a compound according to general formula (I) that binds to a sigma receptor for use in the prevention and / or treatment of pain caused by herpes.

The compounds of general formula (I) have a high affinity for sigma receptors, and they are in particular selective inhibitors of the sigma-1 receptor subtype.

The compound of the present invention can replace the ligand in the competitive binding test, preferably the competitive radiation ligand binding test exemplarily described in WO2006 / 021462, for example, the binding test of σ-1 receptor such as (DeHaven-Hudkins, etc., Eur J Pharmacol, 1992, 227, 371) or the sigma-2 receptor binding test as (Radesca et al., J Med Chem, 1991, 34, 3058). Preferably, the binding of the compound of the present invention is determined by competition with the binding of ³ [H]-(+)-pentazoline relative to binding to the σ-1 receptor subtype, for example in the prior art (eg DeHaven -Hudkins et al., 1992) described the radiation ligand test. Preferably, when tested at a concentration of 10 ^-7 M, in the ³ [H]-(+)-pentazoline radiation ligand test as defined above, the compound of the present invention is at least 25% bound to σ The -1 receptor is more preferably at least 45%, even more preferably at least 65%, still more preferably at least 75%, and most preferably at least 85%.

The compounds of the invention selectively bind to sigma receptors and usually show nanomolar affinity for their targets, when tested at 1 micromolar in other groups of non-specific targets, or when When the non-specific targeting affinity or functional activity is one hundred times smaller, it also shows a percentage of inhibition of less than 50%.

The term "pain after herpes" refers to pain caused by herpes zoster. With the treatment of herpes zoster, the term "pain after herpes" refers to pain that lasts for more than three months. Specifically, the term "herpetic pain" refers to herpes zoster neuralgia (PHN).

Therefore, the first aspect of the present invention relates to a compound according to the general formula (I) or a pharmaceutically acceptable compound thereof for the prevention and / or treatment of postherpetic pain (herpes zoster neuralgia) binding to a sigma receptor Accepted salts, isomers, prodrugs or solvates:

Where R _{1 is} selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Arylalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted heterocyclic group alkyl, -COR ₈ , -C (O ) OR ₈ , -C (O) NR ₈ R ₉ , -CH = NR ₈ , -CN, -OR ₈ , -OC (O) R ₈ , -S (O) _t -R ₈ , -NR ₈ R ₉ , -NR ₈ C (O) R ₉ , -NO ₂ , -N = CR ₈ R ₉ and halogen; R _{2 is} selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted ring Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aromatic or non-aromatic heterocyclic, substituted or Unsubstituted heterocyclic alkyl, -COR ₈ , -C (O) OR ₈ , -C (O) NR ₈ R ₉ , -CH = NR ₈ , -CN, -OR ₈ , -OC (O) R ₈ , -S (O) _t -R ₈ , -NR ₈ R ₉ , -NR ₈ C (O) R ₉ , -NO ₂ , -N = CR ₈ R ₉ and halogen; R ₃ and R ₄ Selected from hydrogen, substituted Unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted Aromatic or non-aromatic heterocyclic groups, substituted or unsubstituted heterocyclic alkyl groups, -COR ₈ , -C (O) OR ₈ , -C (O) NR ₈ R ₉ , -CH = NR ₈ , -CN, -OR ₈ , -OC (O) R ₈ , -S (O) _t -R ₈ , -NR ₈ R ₉ , -NR ₈ C (O) R ₉ , -NO ₂ , -N = CR ₈ R ₉ and halogen, or they together form an optionally substituted fused ring system; R ₅ and R ₆ are selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aromatic or non-aromatic heterocyclic group, substituted or unsubstituted heterocyclic Cycloalkyl, -COR ₈ , -C (O) OR ₈ , -C (O) NR ₈ R ₉ , -CH = NR ₈ , -CN, -OR ₈ , -OC (O) R ₈ , -S (O) _t -R ₈ , -NR ₈ R ₉ , -NR ₈ C (O) R ₉ , -NO ₂ , -N = CR ₈ R ₉ and halogen, or they are together with the attached nitrogen atom shape A substituted or unsubstituted aromatic or non-aromatic heterocyclic group; is selected from n-7 or 8; t is 1, 2 or 3; R ₈ and R ₉ Selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic Or a non-aromatic heterocyclic group, substituted or unsubstituted alkoxy group, substituted or unsubstituted aryloxy group and halogen.

In a preferred embodiment of the present invention, the compound for use is characterized in that R _{1 is} selected from H, —COR ₈ , or substituted or unsubstituted alkyl, preferably selected from H, methyl, or acetyl .

In another preferred embodiment of the present invention, the compound for use is characterized in that R ₁ is hydrogen.

In another preferred embodiment of the present invention, the compound for use is characterized in that R ₂ is hydrogen or alkyl, preferably methyl or H.

In another embodiment of the invention, the compound of the use as defined above is characterized in that R ₃ and R ₄ are substituted in the meta and para positions of the phenyl group.

In another preferred embodiment of the present invention, the compound for the use as defined above is characterized in that R ₃ and R ₄ are each selected from halogen or substituted or unsubstituted alkyl, more preferably from halogen or haloalkyl.

In a particularly preferred embodiment of the present invention, the compound for the use as defined above is characterized in that R ₃ and R ₄ together with phenyl form an optionally substituted fused ring system. More preferably, the fused ring system is selected from substituted or unsubstituted fused aryl groups, and substituted or unsubstituted aromatic or partially aromatic fused heterocyclic groups. The fused ring system preferably contains two rings and / or 9 to about 18 ring atoms, more preferably 9 or 10 ring atoms. Even better, the fused ring system is a naphthyl group, especially a 2-naphthyl ring system, substituted or unsubstituted.

In another preferred embodiment of the present invention, the compound for use is characterized in that n is selected from 2, 3, and 4, more preferably, n is 2.

In another preferred embodiment of the present invention, the compound for use is characterized in that R ₅ and R ₆ together form morpholin-4-yl.

In a preferred variant of the invention, the compound of general formula (I) for use as described above is selected from: [1] 4- {2- (1- (3,4-dichlorophenyl) -5- Methyl-1H pyrazol-3-yloxy) ethyl} morpholine, [2] 2- [1- (3,4-dichlorophenyl) -5-methyl-1Hpyrazol-3-yl Oxy] -N, N-diethylethylamine hydrochloride, [3] 1- (3,4-dichlorophenyl) -5-methyl-3- [2- (pyrrolidin-1-yl ) Ethoxy] -1H-pyrazole hydrochloride, [4] 1- (3,4-dichlorophenyl) -5-methyl-3- [3- (pyrrolidin-1-yl) propoxy Group] -1H-pyrazole hydrochloride, [5] 1- {2- [1- (3,4-dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] ethyl Yl} pyridine, [6] 1- {2- [1- (3,4-dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] ethyl} -1H-imidazole , [7] 3- {1- [2- (1- (3,4-dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] ethyl] pyridin-4- Yl} -3H-imidazole [4,5-b] pyridine, [8] 1- {2- [1- (3,4-dichlorophenyl) -5-methyl-1H-pyrazol-3-yl Oxy] ethyl} -4-methylpyrazine, [9] ethyl 4- {2- [1- (3,4-dichlorophenyl) -5-methyl-1H-pyrazole-3- Yloxy] ethyl} pyrazine carboxylate, [10] 1- (4- (2- (1- (3,4-dichlorophenyl) -5-methyl-1H-pyrazole-3- Yloxy] ethyl) pyrazin-1-yl) ethanone, [11] 4- {2- [1- (4-methoxyphenyl) -5-methyl-1H-pyrazol-3-yloxy] ethyl} morpholine hydrochloride, [12] 1- (4-methoxyphenyl) -5-methyl-3- [2- (pyrrolidin-1-yl) ethoxy] -1H-pyrazole, [13] 1- (4 -Methoxyphenyl) -5-methyl-3- [3- (pyrrolidin-1-yl) propoxy] -1H-pyrazole, [14] 1- [2- (1- (4- Methoxyphenyl) -5-methyl-1H-pyrazol-3-yloxy) ethyl] pyridine, [15] 1- {2- [1- (4-methoxyphenyl)- 5-methyl-1H-pyrazol-3-yloxy] ethyl} -1H-imidazole, [16] 4- {2- [1- (3,4-dichlorophenyl) -5-phenyl -1H-pyrazol-3-yloxy] ethyl} morpholine hydrochloride, [17] 1- (3,4-dichlorophenyl) -5-phenyl-3- [2- (pyrrolidine -1-yl) ethoxy] -1H-pyrazole hydrochloride, [18] 1- (3,4-dichlorophenyl) -5-phenyl-3- [3- (pyrrolidine-1- Group) propoxy] -1H-pyrazole, [19] 1- {2- [1- (3,4-dichlorophenyl) -5-phenyl-1H-pyrazol-3-yloxy] Ethyl} pyridine, [20] 1- {2- [1- (3,4-dichlorophenyl) -5-phenyl-1H-pyrazol-3-yloxy] ethyl} -1H- Imidazole hydrochloride, [21] 2- {2- [1- (3,4-dichlorophenyl) -5-phenyl-1H-pyrazol-3-yloxy] ethyl} -1,2 , 3,4-Tetrahydroisoquinoline hydrochloride, [22] 4- {4- [1- (3,4-dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy Yl] butyl} morpholine hydrochloride, [23] 1- (3,4-dichlorophenyl) -5-methyl-3- [4- (pyrrolidin-1-yl) butoxy ] -1H- pyrazole, [24] 1- {4- [1- (3,4-dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] butyl} pyridinium hydrochloride, [25] 1- {4- [1- (3,4-dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] butyl} -4-methylpyrazine dihydrochloride, [26] 1- {4- [1- (3,4-dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] butyl} -1H-imidazole, [27] 4 -[1- (3,4-dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] -N, N-diethylbutan-1-amine, [28] 1- {4- [1- (3,4-dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] butyl} -4-phenylpyridinium hydrochloride, [29] 1- {4- [1- (3,4-dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] butyl} -6,7-dihydro-1H-indole -4 (5H) -one, [30] 2- {4- [1- (3,4-dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] butyl}- 1,2,3,4-tetrahydroisoquinoline, [31] 4- {2- [1- (3,4-dichlorophenyl) -5-isopropyl-1H-pyrazol-3-yl Oxy] ethyl} morpholine hydrochloride, [32] 2- [1- (3,4-dichlorophenyl) -5-isopropyl-1H-pyrazol-3-yloxy] -N , N-diethylethylamine, [33] 1- (3,4-dichlorophenyl) -5-isopropyl-3- [2- (pyrrolidin-1-yl) ethoxy] -1H -Pyrazole hydrochloride, [34] 1- (3,4-dichlorophenyl) -5-isopropyl-3- [3- (pyrrolidin-1-yl) propoxy] -1H-pyridine Azole hydrochloride , [35] 1- {2- [1- (3,4-dichlorophenyl) -5-isopropyl -1H- pyrazol-3-yloxy] ethyl} piperidine, [36] 2- {2- [1- (3,4-dichlorophenyl) -5-isopropyl-1H-pyrazol-3-yloxy] ethyl} -1,2,3,4 -Tetrahydroisoquinoline hydrochloride, [37] 4- {2- [1- (3,4-dichlorophenyl) -1H-pyrazol-3-yloxy] ethyl} morpholine, [ 38] 2- [1- (3,4-dichlorophenyl) -1H-pyrazol-3-yloxy] N, N-diethylethylamine, [39] 1- (3,4-di Chlorophenyl) -3- [2- (pyrrolidin-1-yl) ethoxy] -1H-pyrazole, [40] 1- {2- [1- (3,4-dichlorophenyl)- 1H-pyrazol-3-yloxy] ethyl} pyridine, [41] 1- (3,4-dichlorophenyl) -3- [3- (pyrrolidin-1-yl) propoxy] -1H-pyrazole, [42] 1- {2- [1- (3,4-dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] ethyl} pyrazinedi Hydrochloride, [43] 1- {2- [1- (3,4-dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] ethyl} pyrrolidine-3- Amine, [44] 4- {2- [1- (3,4-dichlorophenyl) -4,5-dimethyl-1H-pyrazol-3-yloxy] ethyl} morpholine, [ 45] 2- [1- (3,4-dichlorophenyl) -4,5-dimethyl-1H-pyrazol-3-yloxy] -N, N-diethylamine hydrochloride, [ 46] 1- (3,4-dichlorophenyl) -4,5-dimethyl-3- [2- (pyrrolidin-1-yl) ethoxy] -1H-pyrazole hydrochloride, [ 47] 1- (3,4-dichlorophenyl) -4,5-dimethyl-3- [3- (pyrrolidin-1-yl) propoxy] -1H-pyrazole hydrochloride, [48] 1- {2- [1- (3,4-dichlorophenyl) -4,5-dimethyl-1H-pyrazol-3-yloxy] ethyl} pyridine, [49] 4- {4- [1- (3,4-dichlorophenyl) -1H-pyrazol-3-yloxy] butyl} morpholine hydrochloride, [50] (2S, 6R) -4- {4- [1- (3,4-Dichlorophenyl) -1H-pyrazol-3-yloxy] butyl} -2,6-dimethylmorpholine hydrochloride, [51] 1- {4- [1- (3,4-dichlorophenyl) -1H-pyrazol-3-yloxy] butyl} pyridine hydrochloride, [52] 1- (3,4-dichlorobenzene Yl) -3- [4- (pyrrolidin-1-yl) butoxy] -1H-pyrazole hydrochloride, [53] 4- [1- (3,4-dichlorophenyl) -1H- Pyrazol-3-yloxy] -N, N-diethylbutan-1-amine oxalate, [54] N-benzyl-4- [1- (3,4-dichlorophenyl) -1H-pyrazol-3-yloxy] -N-methylbutan-1-amine oxalate, [55] 4- [1- (3,4-dichlorophenyl) -1H-pyrazole- 3-yloxy] -N- (2-methoxyethyl) -N-methylbutan-1-amine oxalate, [56] 4- {4- [1- (3,4-dichloro Phenyl) -1H-pyrazol-3-yloxy] butyl} thiomorpholine oxalate, [57] 1- [1- (3,4-dichlorophenyl) -5-methyl- 3- (2-morpholinylethoxy) -1H-pyrazol-4-yl] ethanone oxalate, [58] 1- {1- (3,4-dichlorophenyl) -5-methyl Yl-3- [2- (pyrrolidin-1-yl) ethoxy] -1H-pyrazol-4-yl} ethanone oxalate, [59] 1- {1- (3,4-di Phenyl) -5-methyl-3- [2- (piperidin-1-yl) ethoxy] -1H- pyrazol-4-yl} ethanone oxalate, [60] 1- {1- (3,4-dichlorophenyl) -3- [2- (diethylamino) ethoxy] -5-methyl-1H-pyrazol-4-yl} ethyl Ketone oxalate, [61] 4- {2- [5-methyl-1- (naphthalen-2-yl) -1H-pyrazol-3-yloxy] ethyl} morpholine, [62] N , N-diethyl-2- [5-methyl-1- (naphthalen-2-yl) -1H-pyrazol-3-yloxy] ethylamine, [63] 1- {2- [5- Methyl-1- (naphthalen-2-yl) -1H-pyrazol-3-yloxy] ethyl} pyridinium hydrochloride, [64] 5-methyl-1- (naphthalen-2-yl) -3- [2- (pyrrolidin-1-yl) ethoxy] -1H-pyrazole hydrochloride, their salts, different alternative pharmaceutically acceptable salts, solvates or prodrugs.

In a more preferred embodiment of the present invention, the compound for the use as defined above is 4- {2- [5-methyl-1- (naphthalen-2-yl) -1H-pyrazol-3-yloxy Radical] ethyl} morpholine or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In a more preferred embodiment of the present invention, the compound for the use as defined above is 4- {2- [5-methyl-1- (naphthalen-2-yl) -1H-pyrazol-3-yloxy Radical] ethyl} morpholine hydrochloride, or solvate or prodrug.

In another preferred embodiment of the present invention, the compound for use as defined above is 4- {2- [5-methyl-1- (naphthalen-2-yl) -1H-pyrazol-3-yl The polycrystalline compound of oxy] ethyl} morpholine hydrochloride is preferably Form I as disclosed in WO2011 / 095579.

"Alkyl" refers to a straight-chain or branched-chain hydrocarbon radical composed of carbon and hydrogen atoms, There is no saturation, with 1 to 8 carbon atoms, which are connected to the rest of the molecule through a single bond, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl Wait. The alkyl radical can be optionally substituted by one or more substituents, such as aryl, halogen, hydroxy, alkoxy, carboxy, cyano, carbonyl, acetyl, alkoxycarbonyl, amino, nitro, Mercapto, alkylthio, etc. If substituted by an aryl group, it corresponds to an "alkylaryl 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.

"Cycloalkyl" refers to a stable 3- to 10-membered monocyclic or bicyclic free radical, which is saturated or partially saturated, and is composed only of carbon and hydrogen atoms, such as cyclohexyl or adamantyl. The cycloalkyl radical can be optionally substituted with one or more substituents, such as alkyl groups, halogen atoms, hydroxyl groups, amino groups, cyano groups, nitro groups, alkoxy groups, carboxyl groups, alkoxycarbonyl groups, and the like.

"Aryl" refers to monocyclic or polycyclic free radicals, including polycyclic free radicals containing individual and / or fused aryl groups. Typical aryl groups contain 1 to 3 individual or fused rings, and 6 to about 18 carbon ring atoms, such as phenyl, naphthyl, indenyl, fenanthryl, or anthracenyl radicals. The aryl radical can be optionally substituted with one or more substituents, such as hydroxyl, mercapto, halogen atom, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, amino Alkyl, acetyl, alkoxycarbonyl, etc.

"Heterocyclyl" refers to a stable 3 to 15-membered ring radical consisting of carbon atoms and 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. It is preferably a 4- to 8-membered ring having one or more heteroatoms, and more preferably a 5- or 6-membered ring having one or more heteroatoms. It can be aromatic or non-aromatic. For the purposes of the present invention, the heterocycle may be a monocyclic, bicyclic or tricyclic system, which may include a fused ring system; and the nitrogen, carbon or sulfur atoms in the heterocyclic radical may be optionally oxidized; the nitrogen atom It may optionally be quaternized; and the heterocyclic radicals may be partially or fully saturated or aromatic. Examples of the heterocyclic ring include but are not limited to: azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, pyridine, pyrazine, purine, quinoline, thiadiazole, tetrahydrofuran , Coumarin, morpholine, pyrrole, pyrazole, oxazole, isoxazole, triazole, imidazole, etc.

"Alkoxy" refers to a radical having the general formula -ORa, where Ra is an alkyl radical as defined above, such as methoxy, ethoxy, propoxy, and the like.

"Amino" refers to a radical having the general formula -NH ₂ , -NHRa or -NRaRb, optionally quaternized, where Ra and Rb are alkyl radicals as defined above, such as methoxy, ethoxy, Propoxy etc.

"Halogen" or "halogen atom" refers to bromine, chlorine, iodine or fluorine.

"Fused ring system" refers to a multi-ring system containing a fused ring. Typically, fused ring systems contain 2 or 3 rings and / or up to 18 ring atoms. As defined above, cycloalkyl radicals, aryl radicals and heterocyclic radicals can form a fused ring system. Thus, the fused ring system may be aromatic, partially aromatic, or non-aromatic, and may contain heteroatoms. A spiro ring system is defined as a non-fused polycyclic ring, but the fused polycyclic ring system of the present invention may be a spiro ring that itself has a single ring atom connected to it through the system. Examples of fused ring systems include but are not limited to adamantyl, naphthyl (eg 2-naphthyl), Indenyl, phenanthryl, anthracenyl, pyrenyl, benzimidazole, benzthiazole, etc.

Unless otherwise indicated in this specification, all groups can be optionally substituted if necessary. The substituent groups referred to in the compounds of the present invention refer to specific moieties substituted by one or more suitable groups at one or more available positions, such as halogens, such as fluorine, chlorine, bromine and iodine; Hydroxy; nitro; azido; lower alkanol, such as C _1-6 lower alkanol, such as acyl, etc .; methylamino; alkyl, including having 1 to about 12 carbon atoms or 1 Groups of up to about 6 carbon atoms and more preferably 1-3 carbon atoms; alkenyl and alkynyl groups, having one or more unsaturated bonds and 2 to about 12 carbon atoms or 2 to about 6 carbon atoms; Alkoxy, having one or more oxygen bonds and 1 to about 12 carbon atoms or 1 to about 6 carbon atoms; aryloxy, such as phenoxy; alkylthio, including having one or more thioether bonds And a portion of 1 to about 12 carbon atoms or 1 to about 6 carbon atoms; alkylsulfinyl, including one or more sulfinyl bonds and 1 to about 12 carbon atoms or 1 to about 6 A portion of carbon atoms; alkylsulfonyl groups, including those having one or more sulfonamide bonds and 1 to about 12 carbon atoms or 1 to about 6 carbon atoms Aminoalkyl, for example, a group having one or more nitrogen atoms and 1 to about 12 carbon atoms or 1 to about 6 carbon atoms; carbocyclic aryl group, having 6 or more carbon atoms, in particular Are phenyl or naphthyl and aralkyl, for example benzyl. Unless otherwise indicated, the optional substituent may have a substituent at each substitutable position of the group, and each substitution is independent of each other.

Unless otherwise indicated, the compounds of the invention are also intended to include compounds that differ only in the presence of one or more isotope-rich atoms. For example, the present invention includes compounds having this structure except for deuterium or tritium instead of hydrogen, or carbon atoms rich in ¹³ C or ¹⁴ C instead of carbon or nitrogen atoms rich in ¹⁵ N.

The term "pharmaceutically acceptable salt, solvate, prodrug" refers to any pharmaceutically acceptable salt, ester, solvate, or any other compound as long as it can be administered to the recipient (directly or indirectly) ) Provides compounds as described herein. However, it will be understood that non-pharmaceutically acceptable salts also fall within the scope of the present invention because they can be used to prepare pharmaceutically acceptable salts. The preparation of salts, prodrugs and derivatives can be carried out by methods known in the art.

For example, the pharmaceutically acceptable salts of the compounds provided herein are synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts are prepared, for example, by reacting the free acid or benzine forms of these compounds with the appropriate stoichiometric amounts of benign or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Examples of acid addition salts include inorganic acid addition salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts, such as acetate, male Salt, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate. Examples of benzyl addition salts include inorganic salts such as sodium, potassium, calcium, ammonium, magnesium, aluminum, and lithium salts, and organic benzyl salts such as ethylenediamine, ethanolamine, N, N-dia Alkylethanolamine, triethanolamine, Glucosamine and basic amino acid salts.

Particularly preferred derivatives or prodrugs are those that increase the bioavailability of the compound of the present invention when the compound is administered to a patient (for example by allowing oral administration of the compound for easier absorption into the blood), or relative to the mother , Enhance the delivery of the parent compound to the biological membrane (such as the brain or lymphatic system).

Any compound of the prodrug of the compound of general formula (I) is within the scope of the present invention. The term "prodrug" is used in the broadest sense and includes those derivatives that are transformed into compounds of the invention in vivo. Such derivatives are easily understood by those skilled in the art, and depending on the functional groups present in the molecule, the compounds of the present invention include but are not limited to the following derivatives: esters, amino acid esters, phosphate esters, metal salt sulfonic acids Esters, carbamates and amino compounds. Examples of known methods for preparing prodrugs of a given active compound are known to those skilled in the art, and see, for example, Krogsgaard-Larsen et al. "Textbook of Drug design and Discovery" Taylor & Francis (April 2002).

The compound used in the present invention may be in a crystalline form, or a free compound or a solvate, and the scope of the present invention is intended to include both forms. Solvation methods are known in the prior art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment, the solvate is a hydrate.

The compound of general formula (I) or its salt or solvate used according to the present invention is preferably a pharmaceutically acceptable or substantially pure compound. Among them, the pharmacologically acceptable form refers to the pharmacologically acceptable purity The level does not include conventional pharmaceutical additives such as diluents and carriers, and does not include materials that are considered toxic at normal dosage levels. The purity level of the drug is preferably higher than 50%, more preferably higher than 70%, and most preferably higher than 90%. In a preferred embodiment, the compound of general formula (I) or a salt, solvate or prodrug thereof has a purity higher than 95%.

The compound of the present invention represented by the general formula (I) as described above may include an enantiomer depending on the presence of a chiral center, or an isomer depending on the presence of a multiple bond (for example, Z, E). Individual isomers, enantiomers or diastereomers and mixtures thereof fall within the scope of the present invention.

The compounds of general formula (I) according to the invention and their salts or solvates can be prepared according to the disclosure in the prior application WO2006 / 021462.

If necessary, the obtained reaction product can be purified by conventional methods, such as crystallization and chromatography. The method described above for preparing the compounds of the present invention produces a mixture of stereoisomers, which can be separated by conventional techniques, such as preparative chromatography. If a chiral center exists, the compound can be prepared in racemic form, or the individual enantiomers can be prepared by enantiomer synthesis or resolution.

A preferred pharmaceutically acceptable form is a crystalline form, including crystalline forms in pharmaceutical compositions. In the case of salts and solvates, other ionic and solvent moieties must also be non-toxic. The compounds of the present invention may exist in different polymorphic forms, which are intended to include all such forms in the present invention.

As used herein, the term "treat, treating, "Treatment" includes elimination, removal, recovery, relief, alteration or control of herpes sequelae pain (herpes zoster neuralgia).

As used herein, the term "prevention", "prevention", "preventive", "preventive", "prophylaxis" refers to the ability of a therapeutic agent to prevent, minimize, or have difficulty attacking or developing a disease or condition before the onset of disease, which is blister in this application Post-rash pain (herpes zoster neuralgia).

Another aspect of the present invention relates to a method for treating pain after herpes, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of general formula (I) as defined above or a pharmaceutical composition thereof.

Another aspect of the present invention relates to a method for preventing pain caused by herpes, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of general formula (I) as defined above or a pharmaceutical composition thereof.

In another aspect, the present invention relates to the use of a compound of general formula (I) as defined above in the preparation of a medicament for the treatment of pain caused by herpes.

In another aspect, the present invention relates to the use of the compound of general formula (I) as defined above in the preparation of a medicament for preventing pain caused by herpes.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, derivative, prodrug or stereoisomer thereof and a pharmaceutically acceptable carrier for administration to a patient , Adjuvant or excipient.

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined above for preventing and / or treating pain caused by herpes, wherein the composition further comprises a pharmaceutically acceptable carrier, adjuvant and / or Or excipients.

Examples of pharmaceutical compositions include any solid (tablet, pill, capsule, granule, etc.) or liquid (solution, suspension, or emulsion) composition for oral, topical, or parenteral administration.

In a preferred embodiment of the present invention, the pharmaceutical composition is in oral form, solid or liquid. Suitable dosage forms for oral administration may be tablets, capsules, syrups or solutions, and may contain conventional excipients known in the art, such as binders, such as syrup, gum arabic, gelatin, sorbitol , Tragacanth or polyvinylpyrrolidone; fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tableting lubricants such as magnesium stearate; disintegrants such as starch, polyvinylpyrrolidone, starch Sodium glycolate or microcrystalline cellulose; or a pharmaceutically acceptable wetting agent, such as sodium lauryl sulfate.

Solid oral compositions can be prepared by conventional methods of blending, filling or tabletting. The mixing operation can be repeated to distribute the active agent in compositions using large amounts of fillers. Such operations are routine in the art. Tablets can be prepared, for example, by wet or dry granulation, and optionally coated according to methods well known in normal pharmaceutical practice, especially with an enteric coating.

The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms. Sufficient excipients such as fillers, buffers or surfactants can be used.

The mentioned compositions are prepared using standard methods as described or referenced in the Spanish and US Pharmacopeias and similar references.

The compound or composition of the present invention can be administered by any suitable method, such as intravenous injection, oral preparation, and intraperitoneal and intravenous administration. mouth Administration is preferred because it is convenient for the chronic features of the patient and the disease to be treated.

Generally, the effective amount of the compound of the present invention depends on the relative efficacy of the selected compound, the severity of the condition to be treated and the weight of the patient. However, the active compound is usually administered one or more times per day, for example once, twice, three times or four times per day, and usually the total daily dose is 0.1-1000 mg / kg / day.

In a preferred embodiment of the compound of general formula (I) used according to the invention, said compound, optionally in the form of a pharmaceutical composition, is administered once a day.

In a preferred embodiment of the compound of general formula (I) used according to the invention, the compound is administered in a daily dose of 100 mg to 600 mg per day. Even more preferably, the compound of general formula (I) is administered in a daily dose of 200 mg to 400 mg per day.

In a preferred embodiment of the present invention, the compound for treating or preventing herpes sequelae pain (herpes zoster neuralgia) is 4- {2- [5-methyl-1- (naphthalen-2-yl ) -1H-pyrazol-3-yloxy] ethyl} morpholine or a pharmaceutically acceptable salt, solvate or prodrug thereof. The oral form is preferred. More preferably, the compound is administered daily. Even more preferably, it is administered at a daily dose of 100 mg to 600 mg per day, and particularly preferably at a daily dose of 200 mg to 400 mg per day.

In a more preferred embodiment of the present invention, the compound for treating or preventing herpes sequelae pain (herpes zoster neuralgia) is 4- {2- [5-methyl-1- (naphthalene-2- Group) 1H-pyrazol-3-yloxy] ethyl} morpholine hydrochloride or Solvates or their prodrugs. The oral form is preferred. More preferably, the compound is administered daily. Even more preferably, it is administered at a daily dose of 100 mg to 600 mg per day, and particularly preferably at a daily dose of 200 mg to 400 mg per day.

In another preferred embodiment of the present invention, the compound for treating or preventing herpes sequelae pain (herpes zoster neuralgia) is 4- {2- [5-methyl-1- (naphthalene-2 -Yl) -1H-pyrazol-3-yloxy] ethyl} morpholine hydrochloride polycrystalline compound, preferably Form I disclosed in WO2011 / 095579. Preferably, the polycrystalline compound is in oral form. More preferably, the polycrystalline compound is administered daily. Even more preferably, it is administered at a daily dose of 100 mg to 600 mg per day, and particularly preferably at a daily dose of 200 mg to 400 mg per day.

The compounds and compositions of the present invention can be used to provide combination therapy with other drugs. The other drugs may be part of the composition or provided as separate compositions for simultaneous or sequential administration. For sequential administration, it means that the compound according to the use according to the invention is administered before and / or after other drugs at different times.

Therefore, another aspect of the present invention relates to a compound of formula (I) as defined above for use in the prevention and / or treatment of pain after herpes, wherein the compound is administered in combination with an anticonvulsant.

In a preferred embodiment, the compound of formula (I) as defined above for the prevention and / or treatment of postherpetic pain is combined with an anticonvulsant drug selected from pregabalin and gabapentin.

Another aspect of the present invention relates to a combination for preventing and / or treating herpes sequelae pain, said combination comprising a compound of formula (I) as defined above and Anticonvulsants. In a preferred embodiment, the anticonvulsant is selected from pregabalin and gabapentin.

In the present specification, the term "combination" means that two or more active ingredients can be administered together, administered as a composition or separately, or sequentially or separately.

In a preferred embodiment of this aspect of the invention, the compound used in the above combination is 4- {2- [5-methyl-1- (naphthalen-2-yl) -1H-pyrazol-3-yloxy ] Ethyl} morpholine or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In a more preferred embodiment of this aspect of the invention, the compound used in the above combination is 4- {2- [5-methyl-1- (naphthalen-2-yl) -1H-pyrazol-3-yl Oxy] ethyl} morpholine hydrochloride or its solvate or its prodrug.

In another preferred embodiment of the present invention, the compound used in the above combination is 4- {2- [5-methyl-1- (naphthalen-2-yl) -1H-pyrazol-3-yloxy ] A polycrystalline compound of ethyl} morpholine hydrochloride, preferably Form I as disclosed in WO2011 / 095579.

Another aspect of the present invention relates to a compound of formula (I) as defined above for use in the prevention and / or treatment of pain caused by herpes, in which the patient has been and / or is being treated with an anticonvulsant.

In a preferred embodiment, the compound of formula (I) as defined above is used to prevent and / or treat patients suffering from postherpetic pain, where the patient has and / or is using anticonvulsants selected from pregabalin and gabapentin Medicine treatment.

Another aspect of the invention relates to a method for treating pain caused by herpes Method, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) as defined above, which is administered in combination with an anticonvulsant drug, preferably selected from gabapentin and pregabalin, Or its pharmaceutical composition.

Another aspect of the present invention relates to a method for preventing postherpetic pain, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) as defined above in combination with an anticonvulsant drug, said anticonvulsant The convulsant is preferably selected from gabapentin and pregabalin, or a pharmaceutical composition thereof.

Another aspect of the invention relates to a method of preventing and / or treating patients suffering from postherpetic pain, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) as defined above, and wherein The patient has been or is being treated with anticonvulsants.

In another aspect, the present invention relates to the use of a compound of the general formula (I) as defined above in combination with an anticonvulsant drug of preferably gabapentin or pregabalin in the preparation of a medicament for the treatment of pain caused by herpes.

In another aspect, the present invention relates to the use of a compound of formula (I) as defined above in combination with an anticonvulsant drug of preferably gabapentin or pregabalin in the preparation of a medicament for the prevention of postherpetic pain.

The examples given below serve only as a further illustration of the invention; they should not be considered as limiting the scope of the invention.

Example 1 4- {2- [5-methyl-1- (naphthalen-2-yl) -1H-pyrazol-3-yloxy] ethyl} morpholine (Compound 61) and the synthesis of its hydrochloride

Compound 61 can be prepared according to the disclosure of the previous application WO2006 / 021462. Its hydrochloride salt can be obtained according to the following procedure: Compound 61 (6.39 g) is dissolved in an ethanol solution saturated with HCl, and then the mixture is stirred for several minutes and evaporated to dryness. The residue is crystallized from isopropanol. The mother liquor of the first crystallization is concentrated to perform the second crystallization. The two crystallizations produced a total of 5.24 g (63%) of the corresponding hydrochloride salt (m.p. = 197-199 ° C).

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

An exploratory, randomized, double-blind, placebo-controlled, parallel group phase II clinical trial was conducted to evaluate the efficacy and safety of Example 1 through oral route in patients with postherpetic neuralgia (PHN).

method:

The clinical study is a multi-center, randomized, double-blind, parallel group, placebo-controlled proof of concept study. Patients who meet all the inclusion criteria and exclusion criteria will undergo a one-week break-in period. During this week, the patient was asked to complete a diary daily to record the pain intensity.

After a week of running-in period, the patient returned to the center for follow-up2. Investigators re-examined the patient ’s eligibility and reviewed the patient ’s diary to confirm the patient ’s average 24-hour average NPRS (Digital Pain Score) score during the 7-day break-in period 4. In order to be eligible for treatment, patients must complete a NPRS log for at least 5 days. The treatment time is 28 days. Patients received a dose of the oral route of Example 1 (400 mg) or placebo (randomized list) on the first day of the study (the second day of follow-up 2) once a day to day 28. The efficacy evaluation during and after the treatment was performed at different time points. Between experiments, the evaluation is done through a log card. At the end of treatment, patients were followed for more than one week.

NPRS (Digital Pain Score Table) is defined as a one-dimensional measure of pain intensity in adults. NPRS is a segmented digital version of the Visual Analogue Scale (VAS), in which the subject chooses the integer (0- 10 integer). The format used is a level chart (Figure 1). Similar to VAS, NPRS is defined by terms describing the severity of pain. In this method, 11 items of NPRS are used from "0" for one pain limit (eg "no pain") to "10" for another pain limit (eg "pain you can imagine" or "most imaginable most" Poor pain ").

Diagnosis and main criteria:

Male and female adults diagnosed with moderate to severe painful herpes zoster neuralgia more than 3 months but not more than 5 years since treatment of the rash, use a stable dose of gabapentin or pregabalin before the screening test After at least one month of treatment (Table 1), they were able to continue taking the same dose during the study.

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

Treatment time:

The treatment time is 28 days. Patients received a dose of study drug Example 1 (400 mg) or placebo (randomized list) by oral route on the morning of the first day of the study until day 28. During and after treatment, the evaluation of efficacy was conducted at different time points. Between experiments, the evaluation is done through a log card. At the end of treatment, patients were followed for more than one week.

The overall research design is shown in Figure 2.

At the end of the randomized 13-patient study (9 patients in the placebo group and 4 patients in the example 1 group), the results (Figure 3) are shown in Table 2:

The baseline pain represents the pain value that existed before the corresponding treatment group started treatment.

Regarding the data obtained to evaluate the analgesic effect of Example 1, between the group treated in Example 1 and the group treated with the placebo, the decrease in pain intensity measured through the patient log was observed after the 28-day treatment study (respectively: 1.53 and 0.85 points).

The above results are confirmed by the results (Table 3 and Table 4) reflected in the short form Condensed Pain Scale (SF-BPI), a standard questionnaire for assessing the severity of pain and its effect on daily function.

The short form Condensed Pain Scale (sf-BPI) is defined as 9 self-filled questionnaires based on the Condensed Pain Scale (BPI). BPI is a medical questionnaire for pain measurement developed by the Pain Research Group of the WHO Collaborating Center for cancer care symptom evaluation.

The sf-BPI sample includes the severity of pain [mild (1-4), moderate (5-6) and severe (7-10)] and the effect of pain on the patient (pain interference: general activity, work, walking ability, Emotions, ability to get along with others, enjoy life and sleep). The interference scale can be decomposed into activity-related and emotion-related subscales, and it is sensitive to dose treatment response.

Claims (13)

A compound for preventing and / or treating pain caused by herpes or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, wherein the compound has the general formula (I): Where R _{1 is} selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Arylalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted heterocyclic group alkyl, -COR ₈ , -C (O ) OR ₈ , -C (O) NR ₈ R ₉ , -CH = NR ₈ , -CN, -OR ₈ , -OC (O) R ₈ , -S (O) _t -R ₈ , -NR ₈ R ₉ , -NR ₈ C (O) R ₉ , -NO ₂ , -N = CR ₈ R ₉ and halogen; R _{2 is} selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted ring Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aromatic or non-aromatic heterocyclic, substituted or Unsubstituted heterocyclic alkyl, -COR ₈ , -C (O) OR ₈ , -C (O) NR ₈ R ₉ , -CH = NR ₈ , -CN, -OR ₈ , -OC (O) R ₈ , -S (O) _t -R ₈ , -NR ₈ R ₉ , -NR ₈ C (O) R ₉ , -NO ₂ , -N = CR ₈ R ₉ and halogen; R ₃ and R ₄ Are selected from hydrogen, substituted or Unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted Aromatic or non-aromatic heterocyclic groups, substituted or unsubstituted heterocyclic alkyl groups, -COR ₈ , -C (O) OR ₈ , -C (O) NR ₈ R ₉ , -CH = NR ₈ , -CN, -OR ₈ , -OC (O) R ₈ , -S (O) _t -R ₈ , -NR ₈ R ₉ , -NR ₈ C (O) R ₉ , -NO ₂ , -N = CR ₈ R ₉ and halogen, or they together form an optionally substituted fused ring system; R ₅ and R ₆ are selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aromatic or non-aromatic heterocyclic group, substituted or unsubstituted heterocyclic Cycloalkyl, -COR ₈ , -C (O) OR ₈ , -C (O) NR ₈ R ₉ , -CH = NR ₈ , -CN, -OR ₈ , -OC (O) R ₈ , -S (O) _t -R ₈ , -NR ₈ R ₉ , -NR ₈ C (O) R ₉ , -NO ₂ , -N = CR ₈ R ₉ and halogen, or they are together with the attached nitrogen atom shape A substituted or unsubstituted aromatic or non-aromatic heterocyclic group; is selected from n-7 or 8; t is 1, 2 or 3; R ₈ and R ₉ each 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 heterocyclic group, substituted or unsubstituted alkoxy group, substituted or unsubstituted aryloxy group and halogen. The compound according to claim 1, wherein R ₁ is hydrogen. The compound according to claim 1 or 2, wherein R ₂ is hydrogen or alkyl, preferably methyl or hydrogen. The compound according to any one of claims 1 to 3, wherein R ₃ and R ₄ together with phenyl form a naphthyl group. The compound for use according to any one of claims 1 to 4, wherein n is selected from 2, 3, 4, and n is more preferably 2. The compound according to any one of claims 1 to 5, wherein R ₅ and R ₆ together form morpholin-4-yl. The compound according to any one of claims 1 to 6, wherein the compound is 4- {2- [5-methyl-1- (naphthalen-2-yl) -1H-pyrazol-3-yloxy Radical] ethyl} morpholine or a pharmaceutically acceptable salt, solvate or prodrug thereof. The compound according to claim 7, wherein the compound is 4- {2- [5-methyl-1- (naphthalen-2-yl) -1H-pyrazol-3-yloxy] ethyl} morpholine hydrochloride or a solvate or prodrug thereof. The compound according to claim 8, wherein the compound is 4- {2- [5-methyl-1- (naphthalen-2-yl) -1H-pyrazol-3-yloxy] ethyl} Morpholine hydrochloride polycrystalline compound Form I. The compound for use according to any one of claims 1 to 9, wherein the compound is administered in combination with an anticonvulsant. The compound for use according to claim 10, wherein the anticonvulsant is selected from pregabalin and gabapentin. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 9 for preventing and / or treating pain caused by herpes, wherein the composition further comprises a pharmaceutically acceptable Carriers, adjuvants and / or excipients. A method for treating or preventing pain caused by herpes, comprising administering to a patient in need of such treatment a therapeutically effective amount of a sigma ligand of formula (I) as defined in any one of claims 1 to 9.