Use of sigma receptor ligands in post-herpetic pain

专利摘要:
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.
公开号:ES2701975A2
申请号:ES201990008
申请日:2017-07-11
公开日:2019-02-26
发明作者:Jesús Cebrecos-Perez；Carlos Ramón Plata-Salaman
申请人:Esteve Pharmaceuticals SA；
IPC主号:

专利说明:

[0001]
[0002] USE OF SIGMA RECEIVER LIGANDS IN POST-HERPETIC PAIN
[0003]
[0004] FIELD OF THE INVENTION
[0005] The present invention relates to the use of ligands of the sigma receptor 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.
[0006]
[0007] BACKGROUND OF THE INVENTION
[0008] The sigma receptor (a) is a receptor for the endoplasmic reticulum and the cell surface 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 psychoses and motor disorders, such as dystonia and tardive dyskinesia, and motor disorders. associated with Huntington's chorea or Tourette's syndrome; and in Parkinson's disease (Walker, JM et al., Pharmacological Reviews, 1990, 42, 355). It has been reported that rimcazole, a known ligand of the sigma receptor, has clinical effects in the treatment of psychosis (Hanner, M. et al., Proc. Natl. Acad. Sci., 1996, 93: 8072-8077; Snyder, SH , Largent, BL J. Neuropsychiatry 1989, 1, 7). The sigma binding sites have preferential affinity for the dextrorotatory isomers of certain opioid benzomorphanes, such as (+) SKF 10047, (+) cyclazocine and (+) pentazocine, and also by some narcoleptics such as haloperidol.
[0009]
[0010] The sigma receptor has at least two subtypes, which can be differentiated by stereoselective isomers of these pharmacoactive drugs. SKF 10047 has nanomolar affinity for the sigma 1 (a-1) site and has micromolar affinity for the sigma site (a-2). Haloperidol has similar affinities for both subtypes. The endogenous sigma ligands are not known, although it has been suggested that progesterone is one of them. Possible pharmacological effects mediated by a sigma site include modulation of glutamate receptor function, response to neurotransmitters, neuroprotection, behavior and intellectual functions (Quirion, R. et al., Trends Pharmacol. Sci., 1992, 13: 85-86). The existence of sigma receptors in the CNS, the immune system and the endocrine system has suggested the likelihood that they can serve as a link between the three systems.
[0011] The presence of the sigma-1 receptor (a1R) in the rat pancreas has been described using the a1R radiotracer, 18F-FTC-146 (James et al., J. Nucl Med. 2014, 55 (1), 147- 153).
[0012]
[0013] WO 2006/021462 describes a family of pyrazole derivatives which are particularly selective inhibitors of the sigma-1 receptor. This family has a pyrazole group characterized by the 3-position substitution with an alkoxy group directly attached to nitrogen.
[0014]
[0015] Post-herpetic neuralgia (NPH) is a nerve pain due to damage caused by the varicella-zoster virus. Typically, neuralgia is confined to the dermatomal area of the skin and accompanies an outbreak of herpes zoster (commonly known as shingles) in that same dermatomal area. Neuralgia typically begins when the herpes zoster vesicles have dried up and are beginning to heal, but may begin in the absence of herpes zoster, a condition called zoster sine herpete.
[0016]
[0017] Herpes zoster (HZ) or "shingles" (described as a burning or throbbing pain, sharp throbbing, electrical shock and allodynia) is caused by a reactivation of the varicella-zoster virus (VZV). Primary VZV infection produces chicken pox, after which VZV remains latent in the sensory ganglia throughout the entire neuroaxis. The subsequent reactivation of the latent varicella zoster virus in the dorsal root ganglia results in a localized cutaneous eruption called "herpes zoster" and extends from a single sensory ganglion to the neural tissue and the dermatome of the affected segment. The increasingly weak immune responses mediated by virus-specific cells, which happens naturally due to aging or induced by diseases or immunosuppressive treatments, increase the risk of shingles. The characteristic rash normally heals in two to four weeks and acute pain is typically the symptom that causes the most discomfort.
[0018]
[0019] The main clinical aspects of HZ are: the acute pain of the 1HZ rash persists for up to 4 weeks; Subacute herpetic neuralgia persists from 30 days to 4 months. The rash appears after 5 days and appears as small red spots that turn into blisters. The papules develop into vesicles in 1 to 2 days and continue to appear for 3 to 4 days. There can be injuries of all types and tend to be grouped. The pustulation of the vesicles begins after 1 week of the appearance of the rash and is accompanied 3 to 5 days later by the ulceration and drying of the lesion. The scabs disappear after 3 to 4 weeks, but there may be scars and hiccups or hyperpigmentation.
[0020] More than 90 percent of adults in the United States show serologic evidence of varicella zoster virus infection and are at risk of developing shingles.
[0021]
[0022] The annualized incidence of herpes zoster is approximately 1.5 to 3.0 cases per 1000 people. The increase in age is a key risk factor for the development of herpes zoster; The incidence of shingles among people over 75 years of age exceeds 10 cases per 1000 people per year. It is estimated that the risk of herpes zoster throughout life is 10 to 20 percent. The other well-defined risk factor for shingles is immunity mediated by altered cells. Patients with neoplastic diseases (especially lymphoproliferative cancers), those receiving immunosuppressive drugs (including corticosteroids) and recipients of organ transplants are at an increased risk of developing shingles.
[0023]
[0024] Postherpetic neuralgia (PHN) is the painful sequel to acute infection with the herpes zoster virus and its most frequent chronic complication. The main clinical aspects of PHN are defined as: continuous chronic pain that persists> 3 months after the lesions have healed. In the worst cases, NPH goes on for several years. The pain is described as "burning", "penetrating", "throbbing" or "throbbing". Approximately 20% of HZ patients> 50 years of age develop NPH. The pain may be severe in the area where the blisters were present and the affected skin may be very sensitive to heat and cold.
[0025]
[0026] The time threshold after clinical zoster rash to pain to be classified as post-herpetic neuralgia (PHN) is variable (30, 90 or 120 days or 6 months) among researchers; however, recent models support 90 days as the most appropriate time definition.
[0027]
[0028] The risk of PHN increases with age. The increase in age and severity of pain due to HZ are the most important risk factors for NPH. Therefore, risk factors for the development of NPH include herpes zoster infection at a later age, stronger acute pain, more severe rash and the presence of a painful prodrome.
[0029]
[0030] The cause of NPH is probably nerve damage as a result of herpes zoster infection. The damage causes the nerves in the dermatomal area of the skin to send abnormal electrical signals to the brain. These signals can transmit a very acute pain and may persist or reappear for months, years or throughout life.
[0031] A key factor in the neural plasticity that underlies neuropathic pain is altered gene expression in the neurons of the dorsal sensory root ganglion. Sensory nerve injury induces neurochemical, physiological and anatomical changes to afferent and central neurons, such as afferent terminal sprouting and inhibitory interneuronal loss. Pathological findings include the degeneration of the primary afferent neuronal body and the axon, spinal cord atrophy, scar formation in the dorsal root ganglia, and loss of epidermal innervations.
[0032]
[0033] Both the incidence and the duration of post-herpetic neuralgia are directly related to the age of the patient. The reported incidence of post-herpetic neuralgia varies from 8 to 70 percent and increases as age advances. In comparison with younger patients, those 50 years of age or older had a pain prevalence that was 15 to 27 times higher at 30 and 60 days, respectively. Each one-year increase was associated with increases of 9 and 12 percent in the prevalence of post-herpetic neuralgia 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; Haanpáá, M. et al., Pain: Clinical updates, 2015, 23 (4): 1-8; Gharibo, C. et al., Pain Medicine News, 2011; 1-7).
[0034]
[0035] Post-herpetic neuralgia is extremely difficult to treat and has been shown to cause a serious reduction in quality of life, similar to 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.
[0036]
[0037] In many situations opioid analgesics may also be suitable. Sporadically, there are some successful experimental treatments, such as rhizotomy (cutting or damaging the affected nerve to relieve pain) and TENS (a type of electrical pulse therapy).
[0038] The treatment for NPH depends on the type and characteristics of the pain experienced by the patient. Pain control is essential for patient care; ensures patient comfort. Currently, the possible options include:
[0039]
[0040] • Antiviral agents (administered at the time of onset of herpes zoster attacks to shorten the clinical course and to help prevent complications, however, do not play any role after the acute attack, once NPH has been established).
[0041]
[0042] • Analgesics applied locally as topical agents (such as lidocaine) or delivered systemically (opioids and non-opioids).
[0043]
[0044] • Pain modification therapy that includes:
[0045]
[0046] or Antidepressants. Low doses of tricyclic antidepressants seem to work best for severe deep pain. They do not eliminate pain, but they make it easier to tolerate. Other prescription antidepressants can be used for alternative purposes to those approved, as in post-herpetic neuralgia and are generally less effective, although they can be tolerated better than tricyclics.
[0047] ^o Anticonvulsants. These agents are used to control strong muscle spasms and provide sedation in neuralgia. They have central effects in the modulation of pain. Medications, such as phenytoin (Dilantin, Phenytek), used to treat seizures, can also reduce the pain associated with post-herpetic neuralgia. The medications stabilize the abnormal electrical activity in the nervous system caused by the injured nerves. Doctors often prescribe other anticonvulsants called carbamazepine (Carbatrol, Tegretol) for acute, throbbing pain. New anticonvulsants, such as gabapentin (Neurontin) and lamotrigine (Lamictal) are generally better tolerated and can help control burning and pain.
[0048]
[0049] • Other non-pharmacological treatments for NPH include acupuncture, moxibustion, relaxation techniques, heat therapy or transcutaneous electrical nerve stimulation.
[0050]
[0051] In some cases, the treatment of post-herpetic neuralgia provides complete pain relief. Although most people still suffer from pain and some do not get any relief even though some preventive measures have been established at the primary and secondary levels. Therefore, HZ and NPH present challenges to health systems because they are prevalent, cause suffering and disability and are difficult to treat satisfactorily, especially in societies with aging populations.
[0052] Sang et al., In Anesthesiology, 2002, May 96 (5); 1053-61 published a clinical trial with dextromethorphan, memantine and lorazepam in the treatment of diabetic neuropathy and post-herpetic neuralgia, concluding that dextromethorphan is effective in a dose-dependent manner for selected patients with diabetic neuropathy, but that it was not met for Post-herpetic neuralgia, which suggested a difference in the mechanism of pain, so selective methods of pain should be used.
[0053]
[0054] Nelso et al. in Neurology. 1997 May 48 (5): 1212-1218 also reported that a high dose of dextromethorphan decreased pain in diabetic neuropathy, but not in postherpetic neuralgia.
[0055]
[0056] These publications show that post-herpetic pain is a distinctive type of pain and that the effectiveness of an analgesic in this specific indication can not be anticipated.
[0057]
[0058] Therefore, there is a need to provide a new form of prevention and treatment for post-herpetic pain and especially for neuropathic pain, allodynia, hyperalgesia and peripheral neuropathy that develop as a result of herpes zoster.
[0059]
[0060] SUMMARY OF THE INVENTION
[0061] The inventors of the present invention have discovered and surprisingly demonstrated that the administration of the specific sigma receptor ligands according to the general formula (I) is highly effective for the prevention and / or treatment of post-herpetic pain.
[0062]
[0063] Therefore, in one aspect, the invention relates to a compound that binds to the sigma receptor, according to the general formula (I) for use in the prevention and / or treatment of post-herpetic pain:
[0064]
[0065] where
[0066] 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 arylalkyl, unsubstituted or substituted non-aromatic heterocyclyl, heterocyclyl substituted or unsubstituted aromatic, substituted or unsubstituted heterocyclylalkyl, -COR8, -C (O) OR8, -C (O) NR8R9, -CH = NR8, -CN, -OR8, -OC (O) R8, -S ( O) t-R8, -NR8R9, -NR8C (O) R9, -NO2, -N = CR8R9 and halogen;
[0067]
[0068] 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 arylalkyl, substituted or unsubstituted aromatic or non-aromatic heterocyclyl , substituted or unsubstituted heterocyclylalkyl, - COR8, -C (O) OR8, -C (O) NR8R9, -CH = NR8, -CN, -OR8, -OC (O) R8, -S (O) t-R8 , -NR8R9, -NR8C (O) R9, -NO2, -N = CR8R9 and halogen;
[0069]
[0070] 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 arylalkyl, aromatic or nonaromatic heterocyclyl, substituted or unsubstituted, substituted or unsubstituted heterocyclylalkyl, -COR8, -C (O) OR8, -C (O) NR8R9, -CH = NR8, -CN, -OR8, -OC (O) R8, -S (O ) t-R8, -NR8R9, -NR8C (O) R9, -NO2, -N = CR8R9, and halogen, or together form an optionally substituted fused ring system;
[0071]
[0072] 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 arylalkyl, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted, substituted or unsubstituted heterocyclylalkyl, -COR8, -C (O) OR8, -C (O) NR8R9, -CH = NR8, -CN, -OR8, -OC (O) R8, -S (O) t-R8, -NR8R9, -NR8C (O) R9, -NO2, -N = CR8R9, and halogen, or together form, with the nitrogen atom to which they are attached, a heterocyclyl group aromatic or non-aromatic, substituted or unsubstituted;
[0073]
[0074] n is selected from 1,2, 3, 4, 5, 6, 7 or 8;
[0075]
[0076] t is 1, 2 or 3;
[0077]
[0078] R 8 and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted, substituted alkoxy or unsubstituted, substituted or unsubstituted aryloxy and halogen;
[0079]
[0080] or one of its pharmaceutically acceptable salts, isomers, prodrugs or solvates.
[0081]
[0082] In another aspect, the invention relates to a pharmaceutical composition comprising at least one compound of general formula (I) as defined above for use in the prevention and / or treatment of post-herpetic pain, wherein the composition further comprises at least one pharmaceutically acceptable carrier, adjuvant and / or carrier.
[0083]
[0084] 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.
[0085]
[0086] Another aspect of the invention relates to a method of treating a patient suffering from post-herpetic pain which comprises administering to the patient in need of such treatment a therapeutically effective amount of a sigma ligand of formula (I) as defined above. .
[0087]
[0088] Another aspect of the invention relates to a compound of formula (I) as defined above, for use in the prevention and / or treatment of post-herpetic pain, wherein the compound is administered in combination with an anticonvulsant.
[0089] Another aspect of the invention relates to a compound of formula (I) as defined above, for use in the prevention and / or treatment of post-herpetic pain where patients have been and / or are being treated with an anticonvulsant .
[0090]
[0091] Another 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 who have been and / or are being treated with an anticonvulsant.
[0092]
[0093] Another aspect of the invention is a method of treating a patient suffering from post-herpetic pain, comprising administering to the patient in need of said 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.
[0094]
[0095] The preferences and embodiments mentioned above can be combined to obtain other preferred compounds or uses.
[0096]
[0097] These aspects and their preferred embodiments are also further defined below in the detailed description and claims.
[0098]
[0099] BRIEF DESCRIPTION OF THE FIGURES
[0100] Figure 1 : NPRS (Numeric Scale of Pain Classification).
[0101] Figure 2 : Study design.
[0102] Figure 3 : NPRS - Average pain reduction throughout the study (mean change).
[0103]
[0104] DETAILED DESCRIPTION OF THE INVENTION
[0105] The invention relates, in one aspect, to a compound that binds to the sigma receptor according to the general formula (I) for use in the prevention and / or treatment of postherpetic pain.
[0106]
[0107] The compounds of general formula (I) bind with high affinity to the sigma receptor, and are particularly selective inhibitors of the sigma-1 receptor subtype.
[0108]
[0109] The compounds of the invention can replace a ligand in competitive binding assays, preferably in competitive binding assays of radioligands such as those they are described, by way of example, in WO2006 / 021462, for example, in receptor binding assays performed as described (DeHaven-Hudkins et al., Eur. J. Pharmacol., 1992, 227, 371 ) or a2 receptor binding assays such as those described (Radesca et al., J. Med. Chem., 1991, 34, 3058). Preferably, the binding of the compounds of the invention, with respect to binding to the sigma-1 receptor subtype, is measured by competition with the binding of 3 [H] - (+) - pentazocine, for example, in radioligand assays such as those described in the art (for example, DeHaven-Hudkins et al., 1992). Preferably, the compounds of the invention when evaluated at a concentration of 10-7 M provided at least 25%, more preferably at least 45%, even more preferably at least 65%, even more preferably at least 75%. %, most preferably at least 85% binding to the sigma-1 receptor in radioligand 3 [H] - (+) - pentazocine assays as defined above.
[0110]
[0111] The compounds of the invention selectively bind to the sigma receptor and generally show a nanomolar affinity for their target while showing a percentage inhibition of less than 50%, when studied at a concentration of 1 micromolar in a set of other targets. non-specific, or when there is an affinity or functional activity a hundred times less for those non-specific targets.
[0112]
[0113] The term "post-herpetic pain" refers to a pain developed as a result of shingles. With the resolution of the herpes zoster rash, the expression "postherpetic pain" refers to a pain that continues for three months or more. Specifically, the term "post-herpetic pain" refers to post-herpetic neuralgia (PHN).
[0114]
[0115] Therefore, a first embodiment of the present invention relates to a compound of formula (I) that binds to the sigma receptor, preferably to the subtype of the sigma-1 receptor, or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof. , for use in the prevention and / or treatment of post-herpetic pain (post-herpetic neuralgia):
[0116]
[0117]
[0118] where
[0119] 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 arylalkyl, unsubstituted or substituted non-aromatic heterocyclyl, heterocyclyl substituted or unsubstituted aromatic, substituted or unsubstituted heterocyclylalkyl, -COR8, -C (O) OR8, -C (O) NR8R9, -CH = NR8, -CN, -OR8, -OC (O) R8, -S ( O) t-R8, -NR8R9, -NR8C (O) R9, -NO2, -N = CR8R9 and halogen;
[0120]
[0121] 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 arylalkyl, substituted or unsubstituted aromatic or non-aromatic heterocyclyl , substituted or unsubstituted heterocyclylalkyl, - COR8, -C (O) OR8, -C (O) NR8R9, -CH = NR8, -CN, -OR8, -OC (O) R8, -S (O) t-R8 , -NR8R9, -NR8C (O) R9, -NO2, -N = CR8R9 and halogen;
[0122]
[0123] 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 arylalkyl, aromatic or nonaromatic heterocyclyl, substituted or unsubstituted, substituted or unsubstituted heterocyclylalkyl, -COR8, -C (O) OR8, -C (O) NR8R9, -CH = NR8, -CN, -OR8, -OC (O) R8, -S (O ) t-R8, -NR8R9, -NR8C (O) R9, -NO2, -N = CR8R9, and halogen, or together form an optionally substituted fused ring system;
[0124]
[0125] R5 and R6 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted alkenyl or unsubstituted, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, unsubstituted or substituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR8, -C (O) OR8, -C (O) NR8R9, -CH = NR8, -CN, -OR8, -OC (O) R8, -S (O) tR8, -NR8R9, -NR8C (O) R9, -NO2, -N = CR8R9, and halogen, or together form, with the nitrogen atom to which they are attached, an aromatic or non-aromatic heterocyclyl group, substituted or unsubstituted;
[0126]
[0127] n is selected from 1,2, 3, 4, 5, 6, 7 or 8;
[0128]
[0129] t is 1, 2 or 3;
[0130]
[0131] R 8 and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted, substituted alkoxy or unsubstituted, substituted or unsubstituted aryloxy and halogen.
[0132]
[0133] In a preferred embodiment of the invention, the compound whose use is defined above, is characterized in that R1 is selected from H, -COR8 or substituted or unsubstituted alkyl, preferably selected from H, methyl or acetyl.
[0134]
[0135] In another preferred embodiment of the invention, the compound whose use is defined above, is characterized in that R1 is hydrogen.
[0136]
[0137] In another preferred embodiment of the invention, the compound whose use is defined above, is characterized in that R2 is H or alkyl, preferably methyl or H.
[0138]
[0139] In another embodiment of the invention, the compound whose use is defined above, is characterized in that R3 and R4 are located in the meta and para positions of the phenyl group.
[0140]
[0141] In another preferred embodiment of the invention, the compound whose use is 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.
[0142]
[0143] In a particularly preferred embodiment of the invention, the compound whose use is defined above, is characterized in that both R3 and R4 together with the phenyl group they form an optionally substituted condensed ring system. More preferably, said condensed ring system is selected from a substituted or unsubstituted fused aryl group and an aromatic or partially aromatic, substituted or unsubstituted fused heterocyclyl group. Said condensed 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 condensed ring system is naphthyl, especially a ring system of type 2 -naphthyl, substituted or unsubstituted.
[0144]
[0145] In a preferred embodiment of the invention, the compound whose use is defined above, is characterized in that n is selected from 2, 3 and 4, more preferably n is 2.
[0146]
[0147] In another preferred embodiment of the invention, the compound of which is defined above, is characterized in that R5 and R6, together, form a morpholin-4-yl group.
[0148]
[0149] In a preferred variant of the invention, the compound of general formula (I) whose use is defined above is selected from:
[0150] [1] 4- {2- (1- (3,4-Dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy) ethyl} morpholine,
[0151] [2] 2- [1- (3,4-Dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] -W hydrochloride, W-diethylethanamine, [3] 1- (3,4-dichlorophenyl) hydrochloride ) -5-methyl-3- [2- (pyrrolidin-1-yl) ethoxy] -1H-pyrazole,
[0152] [4] 1- (3,4-Dichlorophenyl) -5-methyl-3- [3- (pyrrolidin-1-yl) propoxy] -1H-pyrazole hydrochloride,
[0153] [5] 1- {2- [1- (3,4-Dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] ethyl} piperidine,
[0154] [6] 1- {2- [1- (3,4-Dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] ethyl} -1H-imidazole,
[0155] [7] 3- {1- [2- (1- (3,4-Dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy) ethyl] piperidin-4-yl} -3H-imidazo [4.5 -b] pyridine,
[0156] [8] 1- {2- [1- (3,4-Dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] ethyl} -4-methylpiperazine,
[0157] [9] ethyl 4- {2- [1- (3,4-dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] ethyl} piperazinecarboxylate, [10] 1- (4- (2- (1 - (3,4-dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy) ethyl) piperazin-1-yl) ethanone, [11] hydrochloride of 4- {2- [1- (4-methoxyphenyl) - 5-methyl-1H-pyrazol-3-yloxy] ethyl} morpholine,
[0158] [12] 1- (4-methoxyphenyl) -5-methyl-3- [2- (pyrrolidin-1-yl) ethoxy] -1H-pyrazole,
[0159] [13] 1- (4-methoxyphenyl) -5-methyl-3- [3- (pyrrolidin-1-yl) propoxy] -1H-pyrazole,
[0160] [14] 1- [2- (1- (4-methoxyphenyl) -5-methyl-1H-pyrazol-3-yloxy) ethyl] piperidine,
[0161] [15] 1- {2- [1- (4-methoxyphenyl) -5-methyl-1H-pyrazol-3-yloxy] ethyl} -1H-imidazole,
[0162] [16] 4- {2- [1- (3,4-Dichlorophenyl) -5-phenyl-1H-pyrazol-3-yloxy] ethyl} morpholine hydrochloride,
[0163] [17] 1- (3,4-dichlorophenyl) -5-phenyl-3- [2- (pyrrolidin-1-yl) ethoxy] -1H-pyrazole hydrochloride,
[0164] [18] 1- (3,4-dichlorophenyl) -5-phenyl-3- [3- (pyrrolidin-1-yl) propoxy] -1H-pyrazole,
[0165] [19] 1- {2- [1- (3,4-Dichlorophenyl) -5-phenyl-1H-pyrazol-3-yloxy] ethyl} piperidine,
[0166] [20] 1- {2- [1- (3,4-Dichlorophenyl) -5-phenyl-1H-pyrazol-3-yloxy] ethyl} -1H-imidazole hydrochloride, [21] 2- {2- hydrochloride] [1- (3,4-dichlorophenyl) -5-phenyl-1H-pyrazol-3-yloxy] ethyl} -1,2,3,4-tetrahydroisoquinoline,
[0167] [22] 4- {4- [1- (3,4-Dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] butyl} morpholine hydrochloride, [23] 1- (3,4-dichlorophenyl) - 5-methyl-3- [4- (pyrrolidin-1-yl) butoxy] -1 H-pyrazole,
[0168] [24] 1- {4- [1- (3,4-Dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] butyl} piperidine hydrochloride, [25] 1- [4- [1- (3,4-dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] butyl} -4-methylpiperazine,
[0169] [26] 1- {4- [1- (3,4-Dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] butyl} -1H-imidazole,
[0170] [27] 4- [1- (3,4-Dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] -N, N-diethylbutan-1-amine,
[0171] [28] 1- {4- [1- (3,4-Dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] butyl} -4-phenylpiperidine hydrochloride,
[0172] [29] 1- {4- [1- (3,4-Dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] butyl} -6,7-dihydro-1H-indole-4 (5H) -one ,
[0173] [30] 2- {4- [1- (3,4-Dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] butyl} -1,2,3,4-tetrahydroisoquinoline,
[0174] [31] 4- {2- [1- (3,4-Dichlorophenyl) -5-isopropyl-1H-pyrazol-3-yloxy] ethyl} morpholine hydrochloride, [32] 2- [1- (3,4- dichlorophenyl) -5-isopropyl-1H-pyrazol-3-yloxy] -N, N-diethylethanamine,
[0175] [33] 1- (3,4-Dichlorophenyl) -5-isopropyl-3- [2- (pyrrolidin-1-yl) ethoxy] -1H-pyrazole hydrochloride, [34] 1- (3,4-hydrochloride -dichlorophenyl) -5-isopropyl-3- [3- (pyrrolidin-1-yl) propoxy] -1 H -pyrazole, [35] 1- {2- [1- (3,4-dichlorophenyl) -5-isopropyl -1H-pyrazol-3-yloxy] ethyl} piperidine,
[0176] [36] 2- {2- [1- (3,4-Dichlorophenyl) -5-isopropyl-1H-pyrazol-3-yloxy] ethyl} -1,2,3,4-tetrahydroisoquinoline hydrochloride,
[0177] [37] 4- {2- [1- (3,4-Dichlorophenyl) -1H-pyrazol-3-yloxy] ethyl} morpholine,
[0178] [38] 2- [1- (3,4-dichlorophenyl) -1H-pyrazol-3-yloxy] -N, N-diethylethanamine,
[0179] [39] 1- (3,4-dichlorophenyl) -3- [2- (pyrrolidin-1-yl) ethoxy] -1H-pyrazole,
[0180] [40] 1- {2- [1- (3,4-dichlorophenyl) -1H-pyrazol-3-yloxy] ethyl} piperidine,
[0181] [41] 1- (3,4-dichlorophenyl) -3- [3- (pyrrolidin-1-yl) propoxy] -1H-pyrazole,
[0182] [42] 1- {2- [1- (3,4-Dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] ethyl} piperazine dihydrochloride, [43] 1- {2- [1- (3 , 4-dichlorophenyl) -5-methyl-1H-pyrazol-3-yloxy] ethyl} pyrrolidin-3-amine,
[0183] [44] 4- {2- [1- (3,4-Dichlorophenyl) -4,5-dimethyl-1H-pyrazol-3-yloxy] ethyl} morpholine,
[0184] [45] 2- [1- (3,4-Dichlorophenyl) -4,5-dimethyl-1H-pyrazol-3-yloxy] -N, N-diethylethanamine hydrochloride,
[0185] [46] 1- (3,4-dichlorophenyl) -4,5-dimethyl-3- [2- (pyrrolidin-1-yl) ethoxy] -1 H -pyrazole hydrochloride, [47] 1- (3-hydrochloride , 4-dichlorophenyl) -4,5-dimethyl-3- [3- (pyrrolidin-1-yl) propoxy] -1H-pyrazole,
[0186] [48] 1- {2- [1- (3,4-dichlorophenyl) -4,5-dimethyl-1H-pyrazol-3-yloxy] ethyl} piperidine,
[0187] [49] 4- {4- [1- (3,4-Dichlorophenyl) -1H-pyrazol-3-yloxy] butyl} morpholine hydrochloride,
[0188] [50] (2S, 6R) -4- {4- [1- (3,4-dichlorophenyl) -1H-pyrazol-3-yloxy] butyl} -2,6-dimethylmorpholine hydrochloride,
[0189] [51] 1- {4- [1- (3,4-Dichlorophenyl) -1H-pyrazol-3-yloxy] butyl} piperidine hydrochloride,
[0190] [52] 1- (3,4-Dichlorophenyl) -3- [4- (pyrrolidin-1-yl) butoxy] -1H-pyrazole hydrochloride,
[0191] [53] 4- [1- (3,4-Dichlorophenyl) -1H-pyrazol-3-yloxy] -N, N-diethylbutan-1-amine oxalate,
[0192] [54] N-benzyl-4- [1- (3,4-dichlorophenyl) -1H-pyrazol-3-yloxy] -N-methylbutan-1-amine oxalate, [55] oxalate of 4- [1- ( 3,4-dichlorophenyl) -1H-pyrazol-3-yloxy] -N- (2-methoxyethyl) -N-methylbutan-1-amine,
[0193] [56] 4- {4- [1- (3,4-Dichlorophenyl) -1H-pyrazol-3-yloxy] butyl} thiomorpholine oxalate,
[0194] [57] 1- [1- (3,4-Dichlorophenyl) -5-methyl-3- (2-morpholinoethoxy) -1H-pyrazol-4-yl] ethanone oxalate, [58] 1- [1-] oxalate (3,4-dichlorophenyl) -5-methyl-3- [2- (pyrrolidin-1-yl) ethoxy] -1H-pyrazol-4-yl} ethanone,
[0195] [59] 1- {1- (3,4-Dichlorophenyl) -5-methyl-3- [2- (piperidin-1-yl) ethoxy] -1H-pyrazol-4-yl} ethanone oxalate,
[0196] [60] 1- {1- (3,4-Dichlorophenyl) -3- [2- (diethylamino) ethoxy] -5-methyl-1H-pyrazol-4-yl} ethanone oxalate,
[0197] [61] 4- {2- [5-methyl-1- (naphthalen-2-yl) -1H-pyrazol-3-yloxy] ethyl} morpholine,
[0198] [62] N, N -diethyl-2- [5-methyl-1- (naphthalen-2-yl) -1 H -pyrazol-3-yloxy] ethanamine,
[0199] [63] 1- {2- [5-methyl-1- (naphthalen-2-yl) -1 H -pyrazol-3-yloxy] ethyl} piperidine hydrochloride,
[0200] [64] 5-Methyl-1- (naphthalen-2-yl) -3- [2- (pyrrolidin-1-yl) ethoxy] -1H-pyrazole hydrochloride,
[0201]
[0202] its salts, different alternative salts, solvates or pharmaceutically acceptable prodrugs.
[0203]
[0204] In a particularly preferred embodiment of the invention, the compound whose use is defined above, is 4- {2- [5-methyl-1- (naphthalen-2-yl) -1H-pyrazol-3-yloxy] ethyl} morpholine or a prodrug, solvates thereof or their pharmaceutically acceptable salts.
[0205]
[0206] In a still more preferred embodiment of the invention, the compound whose use is defined above, is 4- {2- [5-methyl-1- (naphthalen-2-yl) -1H-pyrazol-3-yloxy] hydrochloride] ethyl} morpholine or a prodrug or solvates thereof.
[0207] In another still more preferred embodiment of the invention, the compound whose use is defined above is a polymorph of 4- {2- [5-methyl-1 (naphthalen-2-yl) -1H-pyrazol-3-yloxy hydrochloride. ] ethyl} morpholine, preferably form I as disclosed in WO2011 / 095579.
[0208]
[0209] The term "alkyl" refers to a radical of the linear or branched hydrocarbon chain type consisting of carbon and hydrogen atoms, which does not contain unsaturation, having from one to eight carbon atoms and which is bound to the remainder by a linkage. simple, for example, methyl, ethyl, n-propyl, / -propyl, n-butyl, f-pentyl, n-pentyl, etc. The alkyl radicals may be optionally substituted with one or more substituents such as an aryl, halo, hydroxy, alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto, alkylthio, etc. If it is substituted with an aryl, it corresponds to an "arylalkyl or aralkyl" radical, such as benzyl and phenethyl.
[0210]
[0211] The term "alkenyl" refers to an alkyl radical having at least two carbon atoms and having one or more unsaturated bonds.
[0212]
[0213] The term "cycloalkyl" refers to a stable 3- to 10-membered mono- or bicyclic radical which is saturated or partially saturated, and which is composed solely of carbon and hydrogen atoms, such as cyclohexyl or adamantyl. The cycloalkyl radical may be optionally substituted with one or more substituents such as alkyl, halo, hydroxy, amino, cyano, nitro, alkoxy, carboxy, alkoxycarbonyl, etc.
[0214]
[0215] The term "aryl" refers to radicals of one or more rings, including the radicals of several rings containing separated and / or condensed aryl groups. Typical aryl groups contain from 1 to 3 separate or condensed rings and from 6 to about 18 ring carbon atoms, such as a phenyl, naphthyl, indenyl, phenanthryl or anthracyl radical. The aryl radical may be optionally substituted with one or more substituents such as hydroxy, mercapto, halo, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl, alkoxycarbonyl, etc.
[0216]
[0217] The term "heterocyclyl" refers to a 3 to 15 member ring radical composed of carbon atoms and one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, preferably a 4 to 8 member ring with one or more heteroatoms, more preferably a 5 or 6 membered ring with one or more heteroatoms. It can be aromatic or non-aromatic. For the purposes of this invention, the heterocycle may be a mono-, bi- or tricyclic ring system, which may include condensed rings; and the nitrogen, carbon or sulfur atoms of the heterocyclyl radical may be optionally oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclyl radical may be partially or completely saturated or aromatic. Examples of such heterocycles include, without limitation, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran, coumarin, morpholine; pyrrole, pyrazole, oxazole, isoxazole, triazole, imidazole, etc.
[0218]
[0219] The term "alkoxy" refers to a radical of the formula -ORa, wherein Ra is an alkyl radical as defined above, for example, methoxy, ethoxy, propoxy, etc.
[0220]
[0221] The term "amino" refers to a radical of formula -NH2, -NHRa or -NRaRb, optionally quaternized, where Ra and Rb are an alkyl radical as defined above, for example, methoxy, ethoxy, propoxy, etc.
[0222]
[0223] The term "halo" or "hal" refers to bromine, chlorine, iodine or fluorine.
[0224]
[0225] The term "condensed ring system" refers to a polycyclic ring system containing 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 can form fused ring systems. Therefore, the fused ring system may be aromatic, partially aromatic or non-aromatic and may contain heteroatoms. A spiro-type ring system is not a condensed polycyclic system according to this definition, but the condensed polycyclic ring systems of the invention may have spiro-type rings attached to them by a single ring atom of the system. Some examples of fused ring systems are, without limitation, adamantyl, naphthyl (eg, 2-naphthyl), indenyl, phenanthryl, anthracyl, pyrenyl, benzimidazole, benzothiazole, etc.
[0226]
[0227] Unless specifically indicated otherwise in the specification, all groups may be optionally substituted where appropriate. 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 with one or more suitable groups, for example, halogen such as fluorine, chlorine, bromine or iodo; cyano; hydroxyl; nitro; azido; alkanoyl such as a C 1-6 alkanoyl group, such as, for example, acyl and the like; carboxamido; alkyl groups that include those groups that have 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms and more preferably from 1 to 3 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated bonds and from 2 to about 12 carbons or from 2 to about 6 carbon atoms; alkoxy groups having one or more bonds with oxygen and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether type bonds 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 type bonds 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 type bonds 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; carbocyclic aryl having 6 or more carbons, in particular phenyl or naphthyl, and aralkyl such as benzyl. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position in the group and each substitution is independent of the others.
[0228]
[0229] Unless otherwise specified, it is also intended that the compounds of the invention include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the compounds that have the structures of the present document except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon with a carbon enriched in 13C or 14C or a nitrogen enriched in 15N are included in the scope of this invention.
[0230]
[0231] The term "pharmaceutically acceptable salts, solvates, prodrugs" refers to any salt, ester, solvate or any other pharmaceutically acceptable compound which, when administered to the recipient, is capable of providing (directly or indirectly) a compound such as those described in This document. However, it will be appreciated that salts that are not pharmaceutically acceptable also fall within the scope of the invention, since they 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.
[0232]
[0233] For example, pharmaceutically acceptable salts of the compounds provided herein are synthesized from the starting compound that contains a basic moiety. or acid by conventional chemical methods. In general, such salts are prepared, for example, by reacting the free acid or base forms of these compounds with a stoichiometric amount of the base or the appropriate acid in water or in an organic solvent or in a mixture of both. In general, non-aqueous media such as 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, sulfate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate , fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate. Examples of alkali addition salts include inorganic salts such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminum and lithium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, W, W-dialkylethanolamine, triethanolamine, glucamine and salts of basic amino acids.
[0234]
[0235] Preferred derivatives or prodrugs in particular are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., allowing an orally administered compound to be absorbed more easily and into the blood) or that increase the supply of the initial compound to a biological compartment (for example, the brain or the lymphatic system) with respect to the initial species.
[0236]
[0237] Any compound that is a prodrug of a compound of formula (I) is contemplated by the scope of the invention. The term "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo into the compounds of the invention. Such derivatives will be obvious 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 compounds herein: esters, amino acid esters, phosphate esters, sulfonate esters of salts metallic, carbamates and amides. Those skilled in the art will be familiar with examples of well known methods for producing a prodrug of a particular active compound and these can be consulted, for example, in Krogsgaard-Larsen et al. "Textbook of Drug Design and Discovery" Taylor and Francis (April 2002).
[0238]
[0239] The compounds for use according to the invention may be in crystalline form either as free compounds or as solvates and both forms are intended to be within the scope of the present invention. In general, solvation methods they are known in the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment, the solvate is a hydrate.
[0240]
[0241] The compounds of general formula (I) for use according to the invention or their salts or solvates are preferably in a pharmaceutically acceptable or substantially pure form. By the term "pharmaceutically acceptable form" it is meant, inter alia, that it has a pharmaceutically acceptable level of purity, excluding normal pharmaceutical additives such as diluents and carriers and not including a material considered to be toxic with normal dosage levels. The purity levels for the drug substance are preferably greater than 50%, more preferably greater than 70%, most preferably greater than 90%. In a preferred embodiment the level of purity of the drug is greater than 95% of the compound of formula (I) or its salts, solvates or prodrugs.
[0242]
[0243] The compounds for use according to the present invention represented by the general formula (I) described above may include enantiomers depending on the presence of chiral centers or isomers depending on the presence of multiple bonds (eg, Z, E). Enantiomers, diastereoisomers or individual isomers and their mixtures are within the scope of the present invention.
[0244]
[0245] The compounds of general formula (I) for use according to the present invention and their salts or solvates can be prepared as indicated in the above application WO2006 / 021462.
[0246]
[0247] The reaction products obtained can be purified, if desired, by conventional methods, such as crystallization and chromatography. When the methods described above for the preparation of the compounds of the invention produce mixtures of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. If there are chiral centers, the compounds can be prepared in racemic form or the individual enantiomers can be prepared by enantiospecific synthesis or by resolution.
[0248]
[0249] A preferred pharmaceutically acceptable form is the crystalline form, including said crystalline form in a pharmaceutical composition. In the case of salts and solvates, the additional solvent and ionic moieties must also be non-toxic. The compounds of the invention can present different polymorphic forms; it is intended that the invention encompass all these forms.
[0250]
[0251] As used herein, the terms "treat", "treatment" and the term "treating" include the eradication, elimination, recovery, relief, modification or control of post-herpetic pain (post-herpetic neuralgia). .
[0252]
[0253] As used herein, the terms "prevention", "preventing", "preventive", "preventing" and "prophylaxis" refer to the ability of a therapeutician to avoid, minimize or hinder the start or development of a disease or condition before it starts, in this case the post-herpetic pain (post-herpetic neuralgia).
[0254]
[0255] Another aspect of the present invention relates to a method for treating post-herpetic pain, wherein the method or methods comprise 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.
[0256]
[0257] Another aspect of the present invention relates to a method for preventing post-herpetic pain, wherein the method or methods comprise 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.
[0258]
[0259] In another aspect, the 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 post-herpetic pain.
[0260]
[0261] In another aspect, the invention relates to the use of a compound of general formula (I) as defined above in the preparation of a medicament for preventing post-herpetic pain.
[0262]
[0263] The present invention further provides pharmaceutical compositions comprising a compound of formula (I), or a salt, derivative, prodrug or stereoisomers pharmaceutically acceptable thereof, together with a pharmaceutically acceptable carrier, adjuvant or vehicle, for administration to a patient.
[0264]
[0265] In another aspect, the invention therefore relates 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 it further comprises a pharmaceutically acceptable carrier, adjuvant and / or carrier.
[0266]
[0267] Examples of pharmaceutical compositions include any solid composition (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) for oral, topical or parenteral administration.
[0268]
[0269] In a preferred embodiment, the pharmaceutical compositions are in oral form, either solid or liquid. Pharmaceutical forms suitable for oral administration may be tablets, capsules, syrups or solutions and may contain conventional excipients known in the art such as binding agents, for example, syrup, gum arabic, gelatin, sorbitol, tragacanth gum or polyvinylpyrrolidone; filling materials, for example, lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricants for forming tablets, for example, magnesium stearate; disintegrants, for example, starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.
[0270]
[0271] The solid oral compositions can be prepared by conventional methods of combination, filling or tabletting. Repeated combination operations can be used to distribute the active ingredient for all those compositions that employ large amounts of filler materials. Such operations are conventional in the art. The tablets can be prepared, for example, by wet or dry granulation and optionally can be coated according to methods well known in the usual pharmaceutical practice, in particular with an enteric coating.
[0272]
[0273] The pharmaceutical compositions can also be adapted for parenteral administration, such as solutions, suspensions or sterile lyophilized products in the appropriate unit dosage form. Suitable excipients may be used, such as dough-forming agents, buffering agents or surfactants.
[0274] The aforementioned compositions will be prepared using standard methods such as those described or referenced in the Spanish and United States Pharmacopoeias and similar reference texts.
[0275]
[0276] The administration of the compounds or compositions of the present invention can be carried out by any suitable method, such as intravenous infusion, oral preparations and intraperitoneal and intravenous administration. Oral administration is preferred because of the patient's convenience and the chronic nature of the diseases to be treated.
[0277]
[0278] In general, the effective amount administered of a compound of the invention will depend on the relative efficacy of the selected compound, the severity of the disorder being treated and the weight of the patient. However, the active compounds will normally be administered one or more times a day for example 1, 2, 3 or 4 times a day, with typical total daily doses in the range between 0.1 and 1000 mg / kg / day.
[0279]
[0280] In a preferred embodiment of the compounds of formula (I) for use according to the invention, said compounds, optionally in the form of a pharmaceutical composition, are administered once a day.
[0281]
[0282] 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 comprised between 100 mg and 600 mg per day. Even more preferably, the compound of general formula (I) is administered at a daily dose comprised between 200 mg and 400 mg per day.
[0283]
[0284] In a preferred embodiment of the invention, the compound for use in the treatment or prevention of post-herpetic pain (post-herpetic neuralgia) is 4- {2- [5-methyl-1 (naphthalen-2-yl) - 1H-pyrazol-3-yloxy] ethyl} morpholine or its pharmaceutically acceptable salts, solvates or prodrugs. It is preferably found orally. More preferably the compound is administered daily. Even more preferably it is administered at a daily dose of between 100 to 600 mg, particularly preferred is a daily dose of between 200 and 400 mg per day.
[0285]
[0286] In a still more preferred embodiment of the invention, the compound for use in the treatment or prevention of post-herpetic pain (post-herpetic neuralgia) is 4- {2- [5-methyl-1 (naphthalen-2-hydrochloride. -yl) -1H-pyrazol-3-yloxy] ethyl} morpholine or its solvates or prodrugs. It is preferably found orally. More preferably this compound is administered daily. Even more preferably it is administered in a daily dose of between 100 to 600 mg per day, particularly preferred is a daily dose of between 200 and 400 mg per day.
[0287]
[0288] In another more preferred embodiment of the invention, the compound for use in the treatment or prevention of post-herpetic pain (post-herpetic neuralgia) is a polymorph of 4- {2- [5-methyl-1 (naphthalene -2-yl) -1H-pyrazol-3-yloxy] ethyl} morpholine, preferably Form I as disclosed in WO2011 / 095579. Preferably this polymorph is in oral form. More preferably this polymorph is administered daily. Even more preferably it is administered in a daily dose of between 100 to 600 mg per day, particularly preferred is a daily dose of between 200 and 400 mg per day.
[0289]
[0290] The compounds and compositions of this invention can be used with other drugs to provide a combination therapy. The other drugs can be part of the same composition or can be provided as an independent composition that can be administered simultaneously or sequentially. By sequential administration it is understood that the compounds for use according to the present invention are administered before the other drugs, and / or after the other drugs, at different times.
[0291]
[0292] Therefore, another aspect of the invention relates to a compound of formula (I), as defined above, for use in the prevention and / or treatment of postherpetic pain, where the compound is administered in combination with an anticonvulsant. .
[0293]
[0294] 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.
[0295]
[0296] Another aspect of the invention is related 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.
[0297]
[0298] In the present description, the term "combination" means that the two or more active principles can be administered together, either in a single composition or in separate forms, or alternatively also sequentially or separately.
[0299] 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) -1H-pyrazole-3 -yloxy] ethyl} morpholine or its pharmaceutically acceptable salts, solvates or a prodrug thereof.
[0300]
[0301] 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) - hydrochloride 1H-pyrazol-3-yloxy] ethyl} morpholine, or solvates or a prodrug thereof.
[0302]
[0303] In another preferred embodiment of the invention, the compound to be used in the combination as defined above, is a polymorph of the hydrochloride of 4- {2- [5-methyl-1- (naphthalen-2-yl) -1H- pyrazol-3-yloxy] ethyl} morpholine, preferably form I as disclosed in WO2011 / 095579.
[0304]
[0305] Another aspect of the invention relates to a compound of formula (I) as defined above, for use in the prevention and / or treatment of post-herpetic pain in cases in which patients have been and / or are being treated. treated with an anticonvulsant.
[0306]
[0307] 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 from post-herpetic pain, where the patients have been and / or they are being treated with an anticonvulsant selected between Pregabalin and Gabapentin.
[0308]
[0309] Another aspect of this invention relates to a method for treating post-herpetic pain, wherein said method comprises administering to the patient in need of said treatment a therapeutically effective amount of a compound of general formula (I) as defined above, in combination with an anticonvulsant, preferably selected from Gabapentin and Pregabalin, or a pharmaceutical composition thereof.
[0310]
[0311] Another aspect of this invention relates to a method for the prevention of postherpetic pain, wherein said method comprises administering to the patient in need of said treatment a therapeutically effective amount of the compound of general formula (I), as defined above, in combination with an anticonvulsant, preferably selected from Gabapentin and Pregabalin, or a pharmaceutical composition thereof.
[0312]
[0313] In yet another aspect the invention relates to a method of prevention and / or treatment of a patient suffering from post-herpetic pain, which comprises administering to the patient in need of said treatment a therapeutically effective amount of a compound of formula (I) as defined above, and where said patient has been or is being treated with an anticonvulsant.
[0314]
[0315] In another aspect, the invention is directed to the use of the compounds of general formula (I) defined above, in combination with an anticonvulsant, preferably Gabapentin or Pregabalin, in the preparation of a medicament for the treatment of post-herpetic pain.
[0316]
[0317] In yet another aspect, the invention is directed to the use of the compounds of general formula (I) defined above, in combination with an anticonvulsant, preferably Gabapentin or Pregabalin, in the preparation of a medicament for the prevention of post-herpetic pain.
[0318]
[0319] The following examples are provided solely as a further illustration of the invention and should not be construed as a definition of the limits of the invention.
[0320] EXAMPLES
[0321] Example 1
[0322] Synthesis of 4- {2- [5-methy1- (naphthalen-2-yl) -1H-pyrazol-3-yloxy] ethyl} morpholine (compound 61) and its hydrochloride salt
[0323]
[0324]
[0325]
[0326]
[0327] The compound 61 can be prepared as described in the earlier application WO2006 / 021462. Your hydrochloride can be obtained according to the following procedure:
[0328]
[0329] Compound 61 (6.39 g) was dissolved in ethanol saturated with HCl, then the mixture was stirred for several minutes and evaporated to dryness. The residue was crystallized from isopropanol. From the mother liquors of the first crystallization a second crystallization was obtained by its concentration. Both combined crystallizations generated 5.24 g (63%) of the corresponding hydrochloride salt (m.p. = 197-199 ° C).
[0330]
[0331] 1 H-NMR (DMSO-de) 6 ppm: 10.85 (sa, 1H), 7.95 (m, 4H), 7.7 (dd, J = 2.2, 8.8 Hz, 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).
[0332]
[0333] Purity by HPLC: 99.8%.
[0334]
[0335] Clinical data
[0336] Example 2:
[0337] A Phase II, parallel group, placebo controlled, double-blind, randomized, and exploratory clinical trial to assess the efficacy and safety of Example 1 orally in patients with post-herpetic neuralgia (PHN).
[0338] Methodology:
[0339] The clinical study was a parallel-controlled, double-blind, randomized, multicenter, placebo-controlled concept-trial study. Patients who fulfilled all the inclusion criteria and none of the exclusion criteria were included in an initial period of one week. During this week, patients were asked to complete a diary to record pain intensities.
[0340]
[0341] After an initial one-week period, the patient returned to the center for visit 2. The investigator again checked the patient's eligibility and reviewed the patient's diary to confirm that the patient had an average score of 24 hours> 4 on the NPRS (Numerical Pain Rating Scale) during the 7 days of the initial period. To be eligible to enter the treatment period, patients must have filled out the NPRS of the diary for a minimum of five days. The duration of treatment was 28 days. The patients received a dose of Example 1 (400 mg) or placebo (following the randomization list) orally on day 1 of the study (day following visit 2) and once a day until day 28. They took conducted efficacy evaluations at different times during and after the treatment period. Between visits, the evaluations were carried out by means of a daily card. Patients were followed up for one more week at the end of the treatment period.
[0342]
[0343] The NPRS (Numeric Pain Rating Scale) is therefore defined as a one-dimensional measure of pain intensity in adults. The NPRS is a segmented numerical version of the visual analogue scale (VAS) in which the person selects a whole number (0-10) that best reflects the intensity of their pain. The format used is a horizontal bar (Figure 1). Similar to VAS, NPRS is defined by terms that describe severe extremes of pain. In the present methodology, the 11 degrees of NPRS range from '0' representing one extreme of pain ("painless") to "10" representing the opposite extreme of pain (eg, "as much pain as can be imagined" or "the worst pain imaginable ").
[0344]
[0345] Diagnosis and main inclusion criteria:
[0346] Males and adult women with a diagnosis of moderate to severe pain of post-herpetic neuralgia present for more than 3 months from the healing of the rash but no longer than 5 years, treated with stable doses of gabapentin or pregabalin (Table 1) for at least one month before the examination visit, they were able to continue taking the same doses for the duration of the study.
[0347] In general, the median age of the randomized patients was 73.0 years (range 34 to 80).
[0348] Table 1
[0349] Gabapentin and Pregabalin at the entrance to the study (Randomized patients).
[0350]
[0351]
[0352]
[0353]
[0354] Treatment duration:
[0355] The duration of treatment was 28 days. Patients received a dose of the study drug, example 1 (400 mg) or placebo (following the randomization list) in the morning orally on day 1 of the study and once a day until day 28. They took performed evaluations of efficacy at different times during and after the treatment period. Between visits, the evaluations were carried out by means of a daily card. The patient was followed one more week at the end of the treatment period.
[0356]
[0357] The general design of the study is shown in Figure 2.
[0358]
[0359] At the end of the study with 13 randomized patients (9 patients in the placebo arm and 4 patients in the branch of example 1) the results obtained (Figure 3) are shown in Table 2:
[0360] Table 2
[0361]
[0362]
[0363]
[0364] Day 35 * 4.74 (1.34) -1.11 (0.84) 3.54 (1.80) -1.60 (1.90)
[0365] * No treatment
[0366]
[0367] Where initial pain refers to the value of pain that was present before starting treatment in the corresponding treatment groups.
[0368]
[0369] Referring to the data obtained to evaluate the analgesic efficacy of example 1, a reduction in pain intensity, measured by the patient's diary, was observed between the group treated with example 1 and the group treated with placebo (1.53 and 0.85 points, respectively) after 28 days with the study treatment.
[0370]
[0371] The previous results are confirmed by those (Table 3 and Table 4) reflected by the short pain inventory in short form (Short Form-Brief Pain Inventory, SF-BPI), the standard questionnaire used to assess the severity of pain and its impact in daily functions.
[0372]
[0373] Table 3
[0374] SF-BPI pain interference
[0375]
[0376] I
[0377]
[0378] * No treatment
[0379] Table 4
[0380] SF-BPI Minimum pain in the last 24 hours
[0381]
[0382]
[0383] * No treatment
[0384]
[0385] The brief inventory of pain in short form (sf-BPI) is defined here as a 9-item self-questionnaire based on the brief inventory of pain (BPI). The BPI is a medical questionnaire used to measure pain developed by the Pain Research Group of the Collaborating Center with the WHO for the Evaluation of Symptoms in Cancer Care.
[0386]
[0387] The sf-BPI samples both the severity of pain [Low (1-4), Moderate (5-6) and Severe (7-10)] and the impact of pain on the patient (pain interference: general activity, work, ability to walk, encouragement, ability to relate to others, vital joy and dream). The interference scale can be broken down into the subscales related to activity and mood and are sensitive to the response to the treatment dose.

权利要求:
Claims (13)
[1]
A compound according to the 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:

[2]
2. The compound for use according to claim 1, wherein R1 is hydrogen.
[3]
3. The compound for use according to any of claims 1 or 2, wherein R2 is H or alkyl, preferably methyl or H.
[4]
4. The compound for use according to any of claims 1 to 3, wherein R3 and R4, together with the phenyl, form a naphthyl group.
[5]
The compound for use according to any one of claims 1 to 4, wherein n is selected from 2, 3, 4, preferably n is 2.
[6]
6. The compound for use according to any of claims 1 to 5, wherein R5 and R6, together, form a morpholin-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) -1H-pyrazol-3-yloxy] ethyl} morpholine or a pharmaceutically acceptable salt, solvate or prodrug thereof.
[8]
8. The compound for use according to claim 7, wherein the compound is 4- {2- [5-methyl-1- (naphthalen-2-yl) -1H-pyrazol-3-yloxy] ethyl hydrochloride} morpholine or solvates or a prodrug thereof.
[9]
9. The compound for use according to claim 8, wherein the compound is the form I polymorph of 4- {2- [5-methyl-1- (naphthalen-2-yl) -1H-pyrazole- 3-yloxy] ethyl} morpholine.
[10]
The compound for use according to any one of claims 1 to 9, wherein the compound is administered in combination with an anticonvulsant.
[11]
11. The compound for use according to claim 10, wherein the anticonvulsant is selected from Pregabalin and Gabapentin.
[12]
12. A pharmaceutical composition comprising a compound of formula (I) 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 carrier, adjuvant and / or pharmaceutically acceptable carrier.
[13]
A method for the treatment or prevention of post-herpetic pain which comprises administering to the 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

类似技术:

---

公开号 | 公开日 | 专利标题

---

ES2625817T3|2017-07-20|Dihydropyridophthalazinone-type poly | polymerase | inhibitors

---

TWI629060B|2018-07-11|Use of sigma ligands in bone cancer pain

---

ES2724275T3|2019-09-09|1,2,4-triazoles as modulators of nuclear transport and their uses

---

KR101708447B1|2017-02-20|Sigma ligands for use in the prevention and/or treatment of postoperative pain

---

CA2601509A1|2006-09-28|Alpha7 neuronal nicotinic receptor ligand and antipsychotic compositions

---

US20190192525A1|2019-06-27|Apilimod compositions and methods for using same

---

TW201536295A|2015-10-01|Use of sigma ligands for the prevention and treatment of pain associated to interstitial cystitis/bladder pain syndrome |

---

JPH0920659A|1997-01-21|Kappa opium preparation agonist for inflammatory abdominal disease

---

ES2796181T3|2020-11-26|Combination of pure 5-HT6 receptor antagonists with acetylcholinesterase inhibitors

---

BR112020026062A2|2021-03-23|benzodiazepine derivatives, compositions, and methods for the treatment of cognitive impairment

---

JP6629464B2|2020-01-15|Three combinations of pure 5-HT6 receptor antagonist, acetylcholinesterase inhibitor and NMDA receptor antagonist

---

KR102023748B1|2019-09-20|Combination of pure 5-HT6 receptor antagonists and NMDA receptor antagonists

---

TW201328695A|2013-07-16|Monoacylglycerol lipase inhibitors for the treatment of metabolic diseases and related disorders

---

ES2701975A2|2019-02-26|Use of sigma receptor ligands in post-herpetic pain

---

KR20170096130A|2017-08-23|Use of sigma receptor ligands in osteoarthritis

---

WO2019068771A1|2019-04-11|Use of sigma receptor ligands in age-related cognitive impairments

---

ES2707781T3|2019-04-05|Pyrazolone compounds for the treatment of cerebrovascular disorders

---

EP3368040A1|2018-09-05|Methods and compositions for recovery from stroke

---

ES2700448A2|2019-02-15|Sigma ligands for use in the treatment of diabetes and metabolic syndrome

---

US10835532B2|2020-11-17|Muscarinic agonists as cognitive enhancers

---

ES2810983T3|2021-03-10|Combination of histamine-3 receptor inverse agonists with acetylcholinesterase inhibitors

---

BR112019012821A2|2019-11-26|benzodiazepine derivatives, compositions and methods for the treatment of cognitive impairment

同族专利:

---

公开号 | 公开日

---

TW201806601A|2018-03-01|

---

ES2701975R1|2019-03-01|

---

WO2018011169A1|2018-01-18|

---

AR109024A1|2018-10-17|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

BRPI0514692A|2004-08-27|2008-06-17|Esteve Labor Dr|sigma receptor inhibitors|

---

JP5894086B2|2010-02-04|2016-03-23|ラボラトリオス・デル・ドクター・エステベ・ソシエテ・アノニム|4-[-2-[[5-Methyl-1- -1H-pyrazol-3-yl] oxy] ethyl] morpholine hydrochloride polymorphs and solvates|

---

EP2460519A1|2010-12-03|2012-06-06|Laboratorios Del. Dr. Esteve, S.A.|Use of sigma ligands in bone cancer pain|

---

EP2524694A1|2011-05-19|2012-11-21|Laboratorios Del. Dr. Esteve, S.A.|Use of sigma ligands in diabetes type-2 associated pain|

---

MA41177A|2014-12-15|2017-10-24|Esteve Labor Dr|USE OF SIGMA RECEPTOR LIGANDS IN ARTHROSIS|WO2020113094A1|2018-11-30|2020-06-04|Nuvation Bio Inc.|Pyrrole and pyrazole compounds and methods of use thereof|

法律状态:
2019-02-26| BA2A| Patent application published|Ref document number: 2701975 Country of ref document: ES Kind code of ref document: A2 Effective date: 20190226 |

---

2019-03-01| EC2A| Search report published|Ref document number: 2701975 Country of ref document: ES Kind code of ref document: R1 Effective date: 20190222 |

---

2019-07-02| FA2A| Application withdrawn|Effective date: 20190626 |

优先权:

---

申请号 | 申请日 | 专利标题

---

EP16382331|2016-07-12|

---

PCT/EP2017/067332|WO2018011169A1|2016-07-12|2017-07-11|Use of sigma receptor ligands in post-herpetic pain|

---