2-Hydroxyoctadecene-9-CIS-Oate for use in the treatment of oncological conditions and neuropathic pain

Abstract

The present invention relates to the compound 2-hydroxy-octadecene-9-cis-oate for use in the treatment of oncological conditions including grade IV glioblastoma, grade 3 glioma, embryonal tumor, pituitary tumor, meningioma, hemangiopericytoma, hemangioblastoma, mesothelioma, cholangiocarcinoma, exocrine pancreatic cancer, neuroendocrine pancreatic cancer, rectal cancer, urinary tract cancer, bladder adenocarcinoma, and esophageal cancer, as well as for use in the treatment of peripheral diabetic neuropathy, spinal cord injury, postherpetic neuralgia, chemotherapeutic agents, antitumor agents, cancer, fibromyalgia, or neuropathic pain caused by hepatitis. The present invention also relates to pharmaceutical compositions comprising 2-hydroxy-octadecene-9-cis-oate.

Description

[Technical Field]

[0001] The present invention relates to the use of 2-hydroxy-octadecene-9-cis-oate (HOCO), a derivative of a monounsaturated fatty acid hydroxylated at the alpha carbon, its salts, or esters, for the treatment of oncological conditions and related conditions of the central nervous system, as well as for the treatment of neuropathic pain caused by oncological conditions resulting from such treatment with antitumor agents and chemotherapeutic agents, and for the treatment of neuropathic pain following nerve or spinal cord injury resulting from peripheral diabetic neuropathy, postherpetic neuralgia, and fibromyalgia or hepatitis. [Background technology]

[0002] Dietary lipids, including fatty acids, can regulate the lipid composition of cell membranes. Changes in membrane lipid composition are known to affect cellular signaling, potentially leading to disease onset, disease improvement, and even disease prevention. Similarly, therapeutic, nutraceutical, or pharmacological interventions focused on regulating membrane lipid levels can prevent and improve (cure) pathological processes.

[0003] Currently, cell membranes are known to be involved in multiple cellular processes. On the one hand, they support proteins involved in cellular signaling that regulate important organic parameters. This signaling, mediated by numerous hormones, neurotransmitters, cytokines, and growth factors, activates membrane proteins (receptors), which propagate the signals received within the cell through other proteins (peripheral membrane proteins), some of which are also located in the membrane. (1) These systems function as an amplification cascade, and (2) membrane lipids can regulate the localization and function of such peripheral proteins (plasma membrane or inner membrane or active or inactive cytoplasm), and the lipid composition of the membrane can have a significant impact on cellular functionality. In particular, the interaction between certain peripheral proteins, such as G proteins, protein kinase C, and RAS proteins, and the cell membrane depends on its lipid composition. On the other hand, the lipid composition of the cell membrane is influenced by the type and amount of lipids ingested. As a result, lipid intake can regulate the lipid composition of the membrane, which in turn can control the interactions (and therefore the activity) of important cellular signaling proteins.

[0004] In recent research, studies are being conducted to demonstrate the therapeutic activity of 2-hydroxy-octadecene-9-cis-oate (HOCO), a derivative of monounsaturated fatty acid hydroxylated at the α-carbon, in the treatment of various diseases.

[0005] There are patients with various types of cancer with poor prognosis who have unmet medical needs. Similarly, there are patients with neuropathic pain for whom conventional analgesic treatment is not sufficiently effective, and therefore who have unmet medical needs. Considering this, there is a need to provide new treatments for these patients. Detailed Description of the Invention

[0006] Therefore, the term "pharmaceutically acceptable salt" refers to a salt or ester of a compound that also possesses the desired pharmacological activity of the parent compound from which it is derived.

[0007] The terms "maintenance treatment" or "maintenance therapy" are defined as treatments administered as a primary or complementary treatment or therapy to a primary treatment or therapy, with the aim of preventing or delaying relapse of a disease that has achieved complete or partial remission after treatment with a first-line treatment or therapy, or with the aim of delaying the onset of the disease after the completion of treatment with a first-line therapy.

[0008] The terms "effective amount" or "therapeutic effective amount" refer to the amount of drug that produces a therapeutic effect without causing unacceptable toxic effects in the patient. The effective amount or dose of a drug depends on the compound and the disease or illness being treated, such as the patient's age, weight, and clinical condition, the form of administration, the patient's medical history, the severity of the disease, and the potency of the compound being administered.

[0009] The term "RANO" (Response Assessment in Neuro-Oncology) refers to a set of criteria used in clinical trials and clinical practice to assess responses in neuro-oncology (Brandsma and van den Bent).

[0010] The term "RECIST" (Response Evaluation Criteria in Solid Tumors) refers to evaluation criteria for solid tumors used in patients with primary and / or metastatic cancer or recurrent metastatic disease (Lencioni et al.).

[0011] The term "PR" (Partial Response) refers to a partial response to treatment, corresponding to a reduction in tumor size or the extent of cancer within the body. It is also called partial remission.

[0012] The term "SD" (Stable Disease) refers to a stable disease in which cancer does not decrease or increase in severity.

[0013] The term "AE" (Adverse Event) refers to an adverse effect understood as an unexpected medical problem that occurs during treatment with a drug or other therapy. Side effects can be mild, moderate, or severe and may have causes other than the drug or therapy being administered. They are also called adverse events.

[0014] The term "NCI-CTCAE" (National Cancer Institute-Common Terminology Criteria for Adverse Events) refers to the common terminology criteria for adverse events established by the National Cancer Institute of the United States.

[0015] The challenge of cutting-edge technology is to provide compounds for use in the treatment of several types of cancer with poor prognosis and / or short life expectancy, as well as in the treatment of neuropathic pain caused by peripheral diabetic neuropathy, postherpetic neuralgia, spinal cord injury, chemotherapy agents, antitumor agents, cancer, fibromyalgia, or hepatitis.

[0016] This invention provides a solution to a technical problem.

[0017] This invention relates to glioblastoma, astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, oligoastrocytoma, oligodengroglioma, epidymoma, xanthastrocytoma, medulloblastoma, low-grade glioma, grade 3 glioma, pontine glioma, and epidymoma. Tumor), subependymoma, gliomatosis cerebri, embryonic tumour, atypical rhabdoid teratoid tumour, tumour of cranial and spinal nerves, mixed neuro-glial tumour, pituitary tumour, germ cell tumour, meningeal tumour, hemangiopericytoma, hemangioblastoma, tumour of the choroid plexus, papilloma of the choroid plexus, pineocytoma, pineoblastoma, mesothelioma, pleural mesothelioma, adenocarcinoma of the bile duct, exocrine pancreatic cancer, cancer of the neuroendocrine pancreas, metastatic lung adenomaadenocarcinoma of the lung, small cell lung cancer, adenocarcinoma of the colon, rectal cancer, cancer of the recto-sigmoid junction, rectal adenocarcinoma, metastatic rectal adenocarcinoma of the colon, colorectal adenocarcinoma, metastatic colorectal adenocarcinoma, urachal fistula cancer, urachal adenocarcinoma, adenocarcinoma of the endometrium, cancer of the neuroendocrine pancreas, adenocarcinoma of the The present invention provides compound 2-hydroxy-octadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, administered at doses of 500 mg / day to 16000 mg / day, for use in the treatment of oncological pathologies selected from the group consisting of uterine pancreas, chondrosarcoma of the uterus, adenocarcinoma of the intestine cecum, bladder adenocarcinoma, esophageal cancer, and metastatic small-cell esophageal cancer.

[0018] 2-Hydroxyoctadecene-9-cis-Oate (HOCO) is a monounsaturated fatty acid with the following formula: COOH-CHOH-(CH2)6-CH=CH-(CH2)7-CH3

[0019] The present invention also includes glioblastoma, astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, oligodendroglioma, oligodendroglioma, ependymoma, yellowatt astrocytoma, medulloblastoma, low-grade glioma, grade 3 glioma, pontine glioma, ependymoma, subependymoma, cerebral gliomatosis, germ cell tumor, atypical teratomatous rhabdoid tumor, tumors of the cranial and spinal nerves, mixed glial tumor, pituitary tumor, germ cell tumor, meningioma, meningioma, hemangiopericytoma, hemangioblastoma, choroid plexus tumor, choroid plexus papilloma, pineal cell tumor, pinealoblastoma, mesothelioma, pleural mesothelioma, cholangiocarcinoma, exocrine pancreatic cancer, neuroendocrine pancreatic This invention provides the use of the compound 2-hydroxy-octadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, for the manufacture of pharmaceuticals for the treatment of oncological conditions selected from the group consisting of cancer, metastatic lung adenocarcinoma, colon adenocarcinoma, rectal cancer, rectosigmoid junction cancer, rectal adenocarcinoma, metastatic rectal adenocarcinoma, metastatic sigmoid colon adenocarcinoma, colorectal adenocarcinoma, metastatic colorectal adenocarcinoma, urachal fistula cancer, urachal adenocarcinoma, endometrial adenocarcinoma, neuroendocrine pancreatic cancer, pancreatic, uterine chondrosarcoma, cecal adenocarcinoma, bladder adenocarcinoma, esophageal cancer, and metastatic small cell esophageal cancer, administered in doses of 500 mg / day to 16000 mg / day.

[0020] The present invention further includes glioblastoma, astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, oligodendroglioma, oligodendroglioma, ependymoma, yellowatt astrocytoma, medulloblastoma, low-grade glioma, grade 3 glioma, pontine glioma, ependymoma, subependymoma, cerebral gliomatosis, germ blastoma, atypical teratomatous rhabdoid tumor, tumors of the cranial and spinal nerves, mixed glial tumors, and pituitary gland. Tumors, germ cell tumors, meningeal tumors, meningiomas, hemangiopericytomas, hemangioblastomas, choroid plexus tumors, choroid plexus papillomas, pineal cell tumors, pineal blastomas, mesotheliomas, pleural mesotheliomas, cholangiocarcinomas, exocrine pancreatic cancers, neuroendocrine pancreatic cancers, metastatic lung adenocarcinomas, small cell lung cancers, colon adenocarcinomas, rectal cancers, rectosigmoid junction cancers, rectal adenocarcinomas, metastatic rectal adenocarcinomas, metastatic sigmoid colon adenocarcinomas (metastatic The present invention provides a method for treating oncological conditions selected from the group consisting of sigmoid adenocarcinoma of the colon, colorectal adenocarcinoma, metastatic colorectal adenocarcinoma, urachal fistula carcinoma, urachal adenocarcinoma, endometrial adenocarcinoma, neuroendocrine pancreatic carcinoma, pancreatic adenocarcinoma, chondrosarcoma of the uterus, cecal adenocarcinoma, bladder adenocarcinoma, esophageal carcinoma, and metastatic small cell esophageal carcinoma, the method comprising administering the compound 2-hydroxy-octadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, to the subject at a dose of 500 mg / day to 16000 mg / day.

[0021] In a Stage I clinical trial using the sodium salt of HOCO (HOCOS, COONa-CHOH-(CH2)6-CH=CH-(CH2)7-CH3) as monotherapy in patients with various types of cancer who had not responded to antitumor therapy, the safety and efficacy of the compound against these cancer types were observed (Example 1).

[0022] Brain tumors have different molecular and cellular characteristics, so their treatment varies depending on the type of tumor. Furthermore, pediatric brain tumors have proven to differ from adult tumors, mainly from a molecular standpoint, meaning that treatment differs from that applied to adult patients. When a brain tumor originates from glial cells, it is called a glioma and is classified into astrocytoma, ependymoma, and oligodendroglioma depending on the type of glial cells involved. Astrocytomas originate from connective cells called astrocytes. They are the most common intra-axial primary tumors. This is the most common type of glioma. Ependymomas arise from ependymal cells that line the ventricles. They account for 2% of all brain tumors. They are most commonly seen in children. Oligodendrogliomas form from oligodendroglial cells, which are the supporting cells of the brain. They account for 1% to 2% of all brain tumors. They are more common in adults.

[0023] Glioblastoma is an astrocytoma that develops in the brain, cerebellum, or spinal cord. Glioblastomas account for about 15% of all brain tumors. Therefore, they are one of the most common types of primary brain tumors. Glioblastomas can affect people of any age, but are more common in adults. Glioblastomas are very aggressive, grow rapidly, and can spread throughout the brain. They rarely spread outside the brain. Because of these characteristics, glioblastomas can be very difficult to treat and are usually incurable. In this sense, the mean overall survival (OS) of patients with glioblastoma is about 14 months with current standard treatment, which consists of radiation and temozolomide and has not changed in the last 20 years.

[0024] At the time when the human studies completed in the present invention, glioblastoma was considered to be high-grade gliomas (III and IV) defined by genetic and epigenetic changes. Glioblastoma multiforme of grade IV can have several mutations. The type of grade IV glioblastoma having the native isocitrate dehydrogenase (IDH) enzyme is the most aggressive, and currently there is no effective treatment for this subtype of glioblastoma.

[0025] In an embodiment of a compound, salt, or ester for use in the present invention, the oncological condition is selected from the group consisting of oligodendroglioma, glioblastoma, oligodendroglioma, epithelioma, xanthoastrocytoma, medulloblastoma, pilocytic astrocytoma, pontine glioma, epithelioma, subepithelioma, cerebral gliomatosis, germinoma, atypical teratoid / rhabdoid tumor, tumors of the cranial and spinal nerves, mixed glioma tumors, pituitary tumors, germ cell tumors, meningeal tumors, meningioma, perivascular cell tumors, hemangioblastoma, choroid plexus tumors, choroid plexus papilloma, pineocytoma, pineoblastoma, mesothelioma, pleural mesothelioma, bile duct adenocarcinoma, exocrine pancreatic cancer, neuroendocrine pancreatic cancer, metastatic lung adenocarcinoma, small cell lung cancer, rectal cancer, rectal sigmoid junction cancer, metastatic rectal adenocarcinoma, metastatic sigmoid colon adenocarcinoma, metastatic colorectal adenocarcinoma, urachal fistula cancer, urachal adenocarcinoma, endometrial adenocarcinoma, neuroendocrine pancreatic cancer, uterine chondrosarcoma, cecal adenocarcinoma, bladder adenocarcinoma, esophageal cancer, and metastatic small cell esophageal cancer.

[0026] In an embodiment of a compound, salt, or ester for use in the present invention, the glioblastoma is grade IV glioblastoma multiforme having the native isocitrate dehydrogenase (IDH) enzyme.

[0027] In an embodiment, the compound, salt, or ester for use in the present invention is for use in the treatment of native IDH grade IV glioblastoma multiforme in a subject having methylation of the promoter of the methylguanine methyltransferase (MGMT) gene.

[0028] In an embodiment of a compound, salt, or ester for use in the present invention, the salt is a sodium salt.

[0029] In an embodiment of a compound, salt, or ester for use in the present invention, the ester is a methyl ester or an ethyl ester.

[0030] In an embodiment of the present invention, the compound, salt, or ester is administered orally.

[0031] In an embodiment of the present invention, the compound, salt, or ester is administered at a dose selected from the group consisting of 500 mg / day, 1000 mg / day, 1050 mg / day, 2000 mg / day, 2100 mg / day, 3150 mg / day, 4000 mg / day, 4200 mg / day, 6000 mg / day, 6300 mg / day, 8000 mg / day, 10000 mg / day, 12000 mg / day, 12600 mg / day, 14000 mg / day, and 16000 mg / day. Preferably, the compound, salt, or ester of the present invention is administered at a dose of 2100 mg / day or 12000 mg / day.

[0032] In an embodiment of the present invention, the compound, salt, or ester is administered twice a day at a dose selected from the group consisting of 250 mg, 500 mg, 1000 mg, 2000 mg, 4000 mg, 6000 mg, and 8000 mg.

[0033] In an embodiment of the present invention, the compound, salt, or ester is administered three times a day at a dose selected from the group consisting of 1050 mg, 2100 mg, 4000 mg, and 4200 mg.

[0034] In an embodiment of the present invention, the compound, salt, or ester is administered three times a day at a dose of 2100 mg / day, with each dose being 700 mg.

[0035] In an embodiment of the present invention, the compound, salt, or ester is administered three times a day at a dose of 12000 mg / day, with each dose being 400 mg.

[0036] In embodiments of the present invention, a compound, salt, or ester is used as a first-line treatment.

[0037] In embodiments of the compounds, salts, or esters for use in the present invention, the first-line treatment comprises a 4-week cycle, each cycle comprising administering the compound, salt, or ester daily for the first three weeks of each cycle, with no treatment during the fourth week.

[0038] In embodiments of the present invention, compounds, salts, or esters are used as pre- or post-operative treatments to reduce tumor size.

[0039] In embodiments of the compounds, salts, or esters for use in the present invention, the subject to be treated has been previously treated in at least one and up to five different chemotherapy treatment lines.

[0040] In embodiments of the present invention, the compound, salt, or ester is used as a maintenance treatment.

[0041] In embodiments of the compound, salt, or ester for use in the present invention, the maintenance treatment comprises a 4-week cycle, each cycle comprising administering the compound, salt, or ester daily for the first three weeks of each cycle, with no treatment during the fourth week.

[0042] In a stage II / III clinical trial forming part of the present invention, the first-line treatment of HOCOS in combination with radiotherapy and temozolomide was investigated in patients with newly diagnosed spontaneous primary grade IV glioblastoma multiforme (Example 2). The treatment of various types of cancer with HOCOS in combination with various chemotherapeutic agents was investigated in cell line studies (Example 3).

[0043] In embodiments of compounds, salts, or esters for use in the present invention, the treatment is as follows: - A chemoradiotherapy phase lasting 6-7 weeks, with radiotherapy administered daily for 5 days a week, starting from the first day of radiotherapy at 75 mg / m². 2 The chemoradiotherapy phase includes administering a second chemotherapeutic agent at a daily dose, and administering a compound, salt, or ester at a dose of 12,000 mg / day for 3 to 4 weeks from the start of radiotherapy. - A 4-week break from treatment, - A maintenance period of 6 cycles over 4 weeks, with each cycle consisting of 150-200 mg / m² for the first 5 days of each cycle. 2 This includes administering a second chemotherapy agent at a daily dose of 12,000 mg / day of the compound, salt, or ester for the first three weeks of each cycle, with no treatment during the fourth week, forming a maintenance period. - A monotherapy phase consisting of four-week cycles, each cycle comprising administering the compound, salt, or ester at a dose of 12,000 mg / day during the first three weeks of each cycle, with no treatment during the fourth week, and the cycle continuing indefinitely as maintenance therapy.

[0044] In the embodiments described above and other subsequent embodiments, the specific daily dose is based on the body surface area of ​​the subject being treated, as is common in the current art, in mg / m². 2 It is represented as follows.

[0045] In preferred embodiments of compounds, salts, or esters for use in the present invention, the treatment is: - A chemoradiotherapy phase lasting 6-7 weeks, with radiotherapy administered daily for 5 days a week, starting from the first day of radiotherapy, at a dose of 75 mg / m². 2 The chemoradiotherapy phase includes administering temozolomide at a daily dose, and administering HOCOS at a dose of 12,000 mg / day for 3 to 4 weeks from the start of radiotherapy. - A 4-week treatment suspension period, - A maintenance period of 6 cycles over 4 weeks, with each cycle starting on the 5th day of the first cycle, administered at a dose of 150-200 mg / m². 2 The treatment includes administering temozolomide at a daily dose of 12,000 mg / day of HOCOS for the first three weeks of each cycle, with no treatment during the fourth week, and a maintenance period. - A monotherapy phase consisting of four-week cycles, each cycle comprising administering the compound, salt, or ester at a dose of 12,000 mg / day during the first three weeks of each cycle, with no treatment during the fourth week, and the cycle continuing indefinitely as maintenance therapy.

[0046] In the embodiments of the compounds, salts, or esters for use in the present invention, radiotherapy is administered at a daily dose of 2 Gy.

[0047] In embodiments, the compounds, salts, or esters of the present invention are intended for simultaneous, separate, or sequential use in combination with a second chemotherapeutic agent selected from the group consisting of temozolomide, thiamine, gemcitabine, fluorouracil, oxyplatin, irinotecan, etoposide, imatinib, folfirinox, erlotinib, and cisplatin.

[0048] In embodiments, the compounds, salts, or esters for use in the present invention are for simultaneous, separate, or sequential use in combination with temozolomide in the treatment of glioblastoma. Preferably, the glioblastoma is natural IDH-grade IV glioblastoma multiforme.

[0049] The present invention also provides the compound 2-hydroxy-octadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, for use in the treatment of neuropathic pain, which is administered in doses ranging from 500 mg / day to 16000 mg / day.

[0050] Neuropathic pain is not conventional pain triggered by specific analgesic pain receptors, as is characteristic of amputations, lumps, burns, etc. Neuropathic pain can result from a variety of events, including neuronal injury, nerve injury of the central and / or peripheral nervous systems, chemotherapy, antitumor agents, cancer, peripheral diabetic neuropathy, postherpetic neuralgia, fibromyalgia, and hepatitis.

[0051] Most patients suffering from this type of neuropathic pain are treated with several very potent and toxic drugs, resulting in very modest treatment outcomes. One example is spinal cord injury, which has been shown to be resistant to opioid treatment and is typically treated with a class of drugs that are very potent for other types of pain (Rodgers et al.). Thus, patients with neuropathic pain are administered anticonvulsants, anxiolytics, antidepressants, opioids, and even anesthetics, which make it only temporarily tolerable for the patient.

[0052] The present invention also provides the use of the compound 2-hydroxy-octadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, for the manufacture of pharmaceuticals for the treatment of neuropathic pain.

[0053] The present invention further provides a method for treating neuropathic pain, the method comprising administering an effective amount of the compound 2-hydroxy-octadecene-9-cis-oate or a pharmaceutically acceptable salt or ester thereof to a subject.

[0054] In embodiments of the compounds, salts, or esters for use in the present invention, neuropathic pain is caused by neuronal injury or nerve injury of the central and / or peripheral nervous systems. Preferably, the nerve injury is spinal cord injury.

[0055] In embodiments of the compounds, salts, or esters for use in the present invention, neuropathic pain is caused by a cause selected from the group consisting of chemotherapeutic agents, antitumor agents, and cancer. Preferably, the antitumor agent is an alkaloid. More preferably, the alkaloid is vincristine.

[0056] In embodiments of the compounds, salts, or esters for use in the present invention, neuropathic pain is caused by a cause selected from the group consisting of peripheral diabetic neuropathy, postherpetic neuralgia, spinal cord injury, chemotherapeutic agents, antitumor agents, cancer, fibromyalgia, and hepatitis.

[0057] In embodiments, the compounds, salts, or esters for use in the treatment of neuropathic pain of the present invention are administered in doses selected from the group consisting of 500 mg / day, 1000 mg / day, 1050 mg / day, 2000 mg / day, 2100 mg / day, 3150 mg / day, 4000 mg / day, 4200 mg / day, 6000 mg / day, 6300 mg / day, 8000 mg / day, 10000 mg / day, 12000 mg / day, 12600 mg / day, 14000 mg / day, and 16000 mg / day. Preferably, the compounds, salts, or esters of the present invention are administered in doses of 2100 mg / day or 4200 mg / day.

[0058] In preferred embodiments of the compounds, salts, or esters for use in the present invention, neuropathic pain is derived from a cause selected from the group consisting of diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, and hepatitis.

[0059] In embodiments, the compounds, salts, or esters of the present invention are intended for simultaneous, separate, or sequential use in combination with at least one other active ingredient selected from the group consisting of pregabalin, opioid analgesics, steroid analgesics, nonsteroidal analgesics, cannabinoid analgesics, anticonvulsants, anxiolytics, anesthetics, and antidepressants.

[0060] In embodiments, the compounds, salts, or esters of the present invention include lamotrigine, omeprazole, phenoxypentanoic acid, metformin, ibuprofen, dalcolac, alprazolam, diazepam, baclofen, macrogol, duloxetine, levofloxacin, gabapentin, ceftriaxone, enoxaparin, pantoprazole, paracetamol, ipratropium bromide, acetylcysteine, metoclopramide, metamisole, teicoplanin, dexketoprofen, oxybutynin, meropenem, beclomethasone dipropionate, and formoterol fumarate. fumarate), atorvastatin, calcifediol, paroxetine, cyanocobalamin, clonazepam, amlodipine, trazodone, flurazepam, thiazide, losartan, metamisole, sucralfate, lactitol, pancreatin, dimethicone, betancol, amitriptyline, lorazepam, vitamin D, lormetazepam, solifenacin, simvastatin, sinitaprid, quetiapine, betmiga, enalapril, metformin, lilatizanidine, trospium, tramadol, cerucoxib, citalopram, sildenafil, tamsulosin, loratadine, tizanidine, vortioxetine, zolpidem, bromazepam, For use separately or sequentially, or concurrently, in combination with at least one other active ingredient selected from the group consisting of dexamethasone, dexketoprofen, losartan, eslicarbazepine, pentoxifylline, mirabegron, fluoxetine, chlorazepic acid, mirtazapine, rosuvastatin, prednisone, beclamethasone, methylprednisone, acyclovir, lignocaine, nystatin, delorazepam, alendronate, carbamazepine, cortisone, hydrocortisone, cannabidiol, and tetrahydrocannabinol.

[0061] The present invention also covers glioblastoma, astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, oligodendroglioma, oligodendroglioma, ependymoma, yellowatt astrocytoma, medulloblastoma, low-grade glioma, grade 3 glioma, pontine glioma, ependymoma, subependymoma, cerebral gliomatosis, germ blastoma, atypical teratomatous rhabdoid tumor, tumors of the cranial and spinal nerves, mixed glial tumors, pituitary tumors, germ cell tumors, meningioma, meningioma, hemangiopericytoma, hemangioblastoma, choroid plexus tumor, choroid plexus papilloma, pineal cell tumor, pineoblastoma, mesothelioma, pleural mesothelioma, cholangiocarcinoma, neuroendocrine pancreatic cancer, metastatic lung adenocarcinoma, small cell lung cancer, colon adenocarcinoma, rectal cancer, rectosigmoid junction A pharmaceutical composition is provided comprising compound 2-hydroxy-octadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, together with at least one pharmaceutically acceptable excipient or carrier, for use in the treatment of oncological pathologies selected from the group consisting of cancer, rectal adenocarcinoma, metastatic rectal adenocarcinoma, metastatic sigmoid colon adenocarcinoma, colorectal adenocarcinoma, metastatic colorectal adenocarcinoma, urachal fistula cancer, urachal adenocarcinoma, endometrial adenocarcinoma, neuroendocrine pancreatic cancer, pancreatic adenocarcinoma, chondrosarcoma, bladder adenocarcinoma, esophageal cancer, and metastatic small cell esophageal cancer, wherein the compound, salt, or ester is administered in doses of 500 mg / day to 16000 mg / day.

[0062] In embodiments of the pharmaceutical composition of the present invention, the oncological pathologies include oligodendrocyte tumor, glioblastoma, oligodendroneal glioma, ependymoma, celery astrocytoma, medulloblastoma, pilocytic astrocytoma, pontine glioma, ependymoma, subependymal glioma, cerebral gliomatosis, germ cell tumor, atypical teratomatous rhabdoid tumor, tumors of the cranial and spinal nerves, mixed glioma, pituitary tumor, germ cell tumor, meningeal tumor, meningioma, angiopericytoma, hemangioblastoma, choroid plexus tumor, choroid plexus papilloma, and pineal gland tumor. The following are selected from the group consisting of cystoma, pinealoblastoma, mesothelioma, pleural mesothelioma, cholangiocarcinoma, exocrine pancreatic cancer, neuroendocrine pancreatic cancer, metastatic lung adenocarcinoma, small cell lung cancer, rectal cancer, rectosigmoid junction cancer, metastatic rectal adenocarcinoma, metastatic sigmoid colon adenocarcinoma, metastatic colorectal adenocarcinoma, ureterostoma, urachal adenocarcinoma, endometrial adenocarcinoma, neuroendocrine pancreatic cancer, uterine sarcoma, cecal adenocarcinoma, bladder adenocarcinoma, esophageal cancer, and metastatic small cell esophageal cancer.

[0063] In embodiments of the pharmaceutical composition of the present invention, the glioblastoma is a grade IV glioblastoma multiforme having the enzyme isocitrate dehydrogenase (IDH).

[0064] In embodiments, the pharmaceutical composition of the present invention is for use in the treatment of native test-grade IV glioblastoma multiforme in subjects having methylation of the promoter of the methyl guanine methyl transferase (Mgmt) gene.

[0065] In embodiments of the pharmaceutical composition of the present invention, the salt is a sodium salt (HOCOS).

[0066] In embodiments of the pharmaceutical composition of the present invention, the ester is a methyl ester or an ethyl ester.

[0067] In embodiments of the pharmaceutical composition of the present invention, the compound, salt, or ester is administered in doses selected from the group consisting of 500 mg / day, 1000 mg / day, 1050 mg / day, 2000 mg / day, 2100 mg / day, 3150 mg / day, 4000 mg / day, 4200 mg / day, 6000 mg / day, 6300 mg / day, 8000 mg / day, 10000 mg / day, 12000 mg / day, 12600 mg / day, 14000 mg / day, and 16000 mg / day. Preferably, the compound, salt, or ester of the present invention is administered in doses of 2100 mg / day or 12000 mg / day.

[0068] In embodiments, the pharmaceutical composition of the present invention further comprises a second chemotherapeutic agent selected from the group consisting of temozolomide, thiamine, gemcitabine, fluorouracil, oxyplatin, irinotecan, etoposide, imatinib, folfirinox, erlotinib, and cisplatin.

[0069] In embodiments, the pharmaceutical composition of the present invention further comprises temozolomide for use in the treatment of glioblastoma. Preferably, the glioblastoma is natural IDH-grade IV glioblastoma multiforme.

[0070] The present invention also provides a pharmaceutical composition for use in the treatment of neuropathic pain, comprising the compound 2-hydroxy-octadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, together with at least one pharmaceutically acceptable excipient or carrier, wherein the compound, salt, or ester is administered in doses of 500 mg / day to 16000 mg / day.

[0071] In embodiments of the pharmaceutical composition of the present invention, neuropathic pain is caused by nerve injury or nerve injury of the central nervous system and / or peripheral nervous system. Preferably, the nerve injury is spinal cord injury.

[0072] In embodiments of the pharmaceutical composition of the present invention, neuropathic pain is caused by a cause selected from the group consisting of chemotherapeutic agents, antitumor agents, and cancer agents. Preferably, the antitumor agent is an alkaloid. More preferably, the alkaloid is vincristine.

[0073] In embodiments of the pharmaceutical composition of the present invention, neuropathic pain is caused by a cause selected from the group consisting of diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, and hepatitis.

[0074] In embodiments of the pharmaceutical compositions of the present invention for use in the treatment of neuropathic pain, the compound, salt, or ester is administered in doses selected from the group consisting of 500 mg / day, 1000 mg / day, 1050 mg / day, 2000 mg / day, 2100 mg / day, 4000 mg / day, 4200 mg / day, 6000 mg / day, 8000 mg / day, 10000 mg / day, 12000 mg / day, 14000 mg / day, and 16000 mg / day. Preferably, the compound, salt, or ester of the present invention is administered in doses of 2100 mg / day or 4200 mg / day.

[0075] In embodiments, the pharmaceutical composition of the present invention further comprises pregabalin, at least one other active ingredient selected from the group consisting of opioid analgesics, steroid analgesics, nonsteroidal analgesics, cannabinoid analgesics, anticonvulsants, anxiolytics, anesthetics, and antidepressants.

[0076] In embodiments, the pharmaceutical composition of the present invention further includes lamotrigine, omeprazole, phenoxypentanoic acid, metformin, ibuprofen, dalcolac, alprazolam, diazepam, baclofen, macrogol, duloxetine, levofloxacin, gabapentin, ceftriaxone, enoxaparin, pantoprazole, paracetamol, ipratropium bromide, acetylcysteine, metoclopramide, metamisole, and teicoplanin. Dexketoprofen, oxybutynin, meropenem, beclomethasone dipropionate, formoterol fumarate, atorvastatin, calcifediol, paroxetine, cyanocobalamin, clonazepam, amlodipine, trazodone, flurazepam, thiazide, losartan, metamisole, sucralfate, lactitol, pancreatin, dimethicone, betanazole, amitriptyline, lorazepam, vitamin D, lormetazepam, Solifenacin, simvastatin, sinitaprid, quetiapine, betamiga, valproate, lacosamide, lidocaine, metamizole, finasteride, acetylsalicylic acid, enalapril, metformin, lilatizanidine, trospium, tramadol, cercoxib, citalopram, sildenafil, tamsulosin, loratadine, tizanidine, vortioxetine, zolpidem, bromazepam, dexamethasone, dexketoprofen, rosa It contains at least one other active ingredient selected from the group consisting of rutan, eslicarbazepine, pentoxifylline, mirabegron, fluoxetine, chlorazepic acid, mirtazapine, rosuvastatin, prednisone, beclamethazone, methylprednisone, acyclovir, lignocaine, nystatin, delorazepam, alendronate, carbamazepine, cortisone, hydrocortisone, cannabidiol, and tetrahydrocannabinol.

[0077] In embodiments, the pharmaceutical composition of the present invention further comprises 1-20% (w / w) of an antioxidant, 0.01-10% (w / w) of a sweetener, 0.1-20% (w / w) of a gelling agent, and 0.01-10% (w / w) of a flavoring agent, and the total proportion of all components in the pharmaceutical composition (including the active ingredient) is 100% (w / w).

[0078] In embodiments, the pharmaceutical composition of the present invention further comprises 20-80% (w / w) of a diluent, 0.1-20% (w / w) of an antioxidant, 0.01-10% (w / w) of a sweetener, 0.1-20% (w / w) of a gelling agent, and 0.01-10% (w / w) of a flavoring agent, and the total proportion of all components in the pharmaceutical composition (including the active ingredient) is 100% (w / w).

[0079] The pharmaceutical composition of the present invention may be in the form of a gastro-resistant compound to prevent the degradation of its components due to the low pH of the gastric environment. Pharmaceutically acceptable excipients or carriers include, but are not limited to, diluents, antioxidants, sweeteners, gelling agents, flavoring agents, fillers, or other vehicles such as colloidal anhydrous silica and glyceryl monostearate. The pharmaceutical composition may be in the form of capsules, powders, tablets, emulsions, suspensions, solutions, or any other pharmaceutical form packaged in blisters, bottles, paper, polyester, polyethylene and / or aluminum sachets, or any other type of container. Conventional techniques for preparing pharmaceutical compositions can be used to produce the pharmaceutical composition of the present invention. For example, the compounds, salts, or esters of the present invention disclosed herein may be mixed with a carrier, or diluted by a carrier, or encapsulated in a carrier which may be in the form of ampoules, capsules, envelopes, paper, polyethylene and / or aluminum, or other packaging. When the carrier is a diluent, the carrier may be a solid, semi-solid, or liquid material that functions as a vehicle, excipient, or medium for the active compound. Some examples of suitable diluents are water, saline solution, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, cellulose alkyl ether, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters of pentaerythrol, polyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone. Similarly, the carrier or diluent may contain any sustained-release material known in the art, such as glyceryl monostearate or glyceryl distearate, either alone or in combination with wax. The pharmaceutical composition of the present invention may also contain a humectant, an antioxidant, an emulsifier and a suspending agent, a preservative, a sweetener, and a flavoring agent.The pharmaceutical compositions of the present invention can be formulated to provide rapid release, sustained release, or delayed release of the compounds disclosed herein after administration to a patient using methods well known in the art.

[0080] The pharmaceutical composition of the present invention may be a solid composition or a liquid solution.

[0081] The pharmaceutical compositions of the present invention may be sterilized and, if desired, may be mixed with adjuvants, emulsifiers, salts affecting osmotic pressure, buffers, and / or colorants, which do not react adversely with the compounds disclosed above.

[0082] Throughout the detailed description and claims, the terms “comprising,” “that comprises,” and their variations are meant in a non-restrictive sense and should not preclude other technical features. The terms “comprises,” “comprising,” and their variations, in particular, throughout the description and claims, include the terms “consists of,” “consisting of,” and their variations.

[0083] As used herein and in the claims, the singular "the" includes a plural noun unless the context explicitly indicates otherwise.

[0084] Unless otherwise defined, all technical and scientific terms used throughout this specification and the claims have the same meaning as those conventionally understood by those skilled in the art of the present invention. [Brief explanation of the drawing]

[0085] [Figure 1]This graph shows the pharmacokinetic profiles of HOCOS at different doses. The graph displays steady-state serum log[HOCOS](ng / ml) in patients at steady state after the first dose on the first day of treatment (day 1, black) and at steady state on day 21 of treatment (day 21, gray) for oral doses of 500 mg / day (twice daily (bid)), 1000 mg / day (twice daily), 2000 mg / day (twice daily), 4000 mg / day (twice daily), 8000 mg / day (twice daily), 12000 mg / day (three times daily (tid)), and 16000 mg / day (twice daily). These daily doses were divided into two (twice daily) or three (three times daily) daily doses. These results demonstrate good absorption of HOCOS at different doses in patients with different types of cancer (see Table 2). [Figure 2] Antitumor efficacy during HOCOS monotherapy. Phase I / II clinical trials tested the safety and efficacy of HOCOS in patients with different types of cancer (Table 2). In these patients (specified by code), tumor volume was determined at the end of the clinical trial (volume %) relative to initial diagnosis. (A) Tumor volume of glioblastoma patients relative to baseline volume (0%) at time of recruitment. The dotted lines represent the upper and lower limits for considering tumor progression, stable disease, and tumor regression according to the RANO criteria. (B) Tumor volume of patients with non-glioblastoma tumors relative to baseline volume (0%). In both graphs, gray bars represent patients treated with HOCOS with stable disease or tumor regression who did not meet all RANO or RECIST criteria, and black bars represent patients treated with HOCOS with stable disease or tumor regression who met all RANO or RECIST criteria. [Figure 3]Examples of response to HOCOS treatment. (A) Resonance imaging (MRI) images of glioblastoma patients showing tumor size at baseline (first column from the left) and progression during the period HOCOS was administered as the sole treatment (Phase I / II clinical trial) at 4 months (second column from the left), 9 months (third column from the left), 21 months (fourth column from the left), and 32 months (fifth column from the left). The tumor appears as a white area within a white circle in the center of normal nerve tissue (gray). Patients showed sustained tumor regression over time over 3 years with monotherapy of HOCOS 500 mg orally twice daily (1000 mg orally (po), twice daily) (according to RANO criteria). Transverse brain (upper scan) and sagittal (lower scan) MRI scans show a reduction in glioblastoma (in white circles) throughout the HOCOS monotherapy treatment period. (B) Effect of HOCOS (black dots) on a mouse (immunodeficient mouse) model (MIAPaCa-2 cells) of human pancreatic cancer. The images show how the treatment slows the growth rate of pancreatic cancer compared to the control (white dots). [Figure 4]Efficacy of HOCOS as standard-of-care, in combination with temozolomide and radiotherapy, in patients with newly diagnosed native (native) trial-grade IV glioblastoma. Phase II / III clinical trials evaluated the safety and efficacy of HOCOS in combination with TMZ and other drugs. (A) Overall survival (OS) of patients, corresponding to the time between diagnosis and death. Treatment with HOCOS (black bars) significantly increased OS. (B) Progression-free survival (PFS) corresponds to the time (months) between diagnosis and tumor size increase according to RANO criteria. The gray bars represent survival in patients treated with the current standard of care (SoC), consisting of 6 weeks of radiotherapy and 6 months of temozolomide; the white bars represent survival in clinical trials using the current standard of care and HOCOS or placebo (approximately 50% of each treatment accompanying 6 months of temozolomide and subsequent monotherapy); and the black bars represent extrapolation of survival in patients treated with HOCOS and the standard of care, taking into account that in the clinical trials, patients were randomized in a 1:1 ratio between the group treated with HOCOS and the group treated with placebo. Furthermore, patients were administered other drugs mentioned in this invention during treatment. [Figure 5]Safety and efficacy of HOCOS in the treatment of neuropathic pain in patients with spinal cord injury. (A) To evaluate the pharmacological safety of the product, adverse effects (AEs) are tested to determine whether they are treatment-related. Medical researchers determined whether AEs were treatment-related. The Phase I / II clinical trial in patients with spinal cord injury consisted of four randomly assigned groups of patients. Group 1 received placebo (n=9), Group 2 received 1050 mg of HOCOS in three divided doses of 350 mg each (n=11), Group 3 received 2100 mg of HOCOS in three divided doses of 700 mg each (n=11), and Group 4 received 4200 mg of HOCOS in three divided doses of 1400 mg each. All patients also received pregabalin along with other drugs mentioned herein. The bars on the left show all adverse events in patients treated with placebo or different doses of HOCOS (Pw / AE). The bars on the right show adverse events in patients identified by the principal investigator as directly related to treatment with HOCOS or placebo (Pw / RTAE). (B) A visual analogue scale (VAS) was used to determine the efficacy of HOCOS versus placebo in patients with neuropathic pain caused by spinal cord injury. Pain in the entire patient population (Panel B) was determined during screening visits, during baseline visits (V1), at the end of 1 month (V2), 2 months (V3), and 3 months (V4) of treatment, as well as 1 month after treatment without treatment (V5, follow-up). The reduction between baseline and end of the trial in the entire patient population was calculated as V1-V4. After the completion of the clinical trial, V5-V4 were analyzed, which had to be positive in all cases, because an increase in pain was expected upon discontinuation of treatment, either due to the drug effect or the placebo effect. Graph B shows pain levels (VAS) in patients administered 0.0 (placebo), 1050, 2100, or 4200 milligrams of HOCOS daily. (C) Since the sensation of neuropathic pain can fluctuate over time, it can decrease and even disappear spontaneously, pain assessments were performed at the end of the study treatment period (V5).The trial lasted approximately six months between screening and V5, and it was observed that some patients showed a continuous trend of pain reduction that continued after the completion of the treatment (between V4 and V5). Between V4 and V5, an increase in pain perception (albeit less) was expected even in the placebo group. This anomalous behavior was excluded in the second analysis, and patients with pain reduction between V4 and V5, or other abnormalities such as erratic values, were censored. In this censored population, results were obtained that were very similar to the results of the whole population, but were statistically significant (two-way ANOVA, Fisher's test of least significance - Fisher's LSD). (D) Pain values ​​on the VAS scale were measured in responder patients, which is the population of uncensored patients who experienced pain reduction of more than 1 point on the pain scale (between V1 and V4) and showed an increase in pain after completion of the treatment (between V4 and V5). The results show the values ​​± mean for each group and each time point. Following two-sided ANOVA, Fisher post-hoc LSD analysis was used to determine the significance of the data. *p<0.05 (relative to baseline pain). (E) VAS scores were performed in all patients with a probability of having neuropathic pain greater than 90% based on the "PainDetect" test. Pain reduction was statistically significant at doses of 2100 mg / day and 4200 mg / day. The 2100 mg / day dose was the most appropriate, showing reduction from month 1, significant from month 2, and reaching its maximum by month 3 of treatment, with the VAS score decreasing from approximately 7 to approximately 3. (F) In a patient population with a probability of more than 90% of developing neuropathic pain, the percentage of patients who responded (a reduction of ≥1.5 points on the VAS scale) in the placebo group (treated with pregabalin and other drugs, but not with HOCOS) was only 25%.In contrast, all groups of patients treated with HOCOS had a response rate of over 40%, and the 2100 mg / day group again had the highest response rate at 80%. [Figure 6] The efficacy of HOCOS as measured against thermal hyperalgesia in vincristine-induced neuropathic pain, as measured by a "tail flick" test. (A) Animals were first treated with 0.0 (control), 0.5, 0.75, or 1 mg / kg of vincristine (cumulative dose over 10 days). Vincristine is a drug used in cancer chemotherapy and is associated with the development of neuropathic pain. The same animals were then treated orally with either saline (0 mg / kg HOCOS) or HOCOS (400 mg / kg) for 28 days. Latency time in the indicated animal groups was measured after 28 days of treatment. HOCOS was shown to increase latency in the tail flick test, which is interpreted as a reduction in neuropathic pain. Values ​​are expressed as a percentage of response time to stimulation at day 28 of treatment compared to baseline (day 1). (B) Effect of HOCOS on thermal hyperalgesia induced by vincristine (1 mg / kg) and measured by the tail flick test. Such hyperalgesia is a consequence of neuropathic pain, and response times to heat are shown in animals at day 1 and 7 weeks after HOCOS treatment. This shows a decrease in response time to vincristine-induced heat discomfort, which did not change the vehicle treatment, but was significant with HOCOS treatment from 5 weeks after treatment. Furthermore, at 7 weeks after treatment, animals treated with vincristine and subsequently with HOCOS showed no significant difference compared to animals that did not receive vincristine. [Figure 7]Efficacy of HOCOS for mechanical allodynia as measured by the "Von Frey" test for vincristine-induced neuropathic pain. To identify the effects of HOCOS on other types of neuropathic pain other than those caused by spinal cord injury, the effects were studied using the Von Frey test. (A) Threshold pressure (grams) inducing plantar reflex in animals previously treated with vincristine (VC, cumulative dose of 1 mg / kg over 10 days), as well as after treatment for 1, 14, 21, and 28 days in the absence (0 mg / kg) or presence of HOCOS (400 mg / kg). (B) Results in animals previously treated with vincristine at 0 (control), 0.5, 0.75, or 1 mg / kg, followed by treatment for 28 days in the absence (0 mg / kg) or presence (400 mg / kg) of HOCOS. The results were expressed as both grams of pressure and a percentage of pressure relative to the control. [Modes for carrying out the invention]

[0086] Example 1: Phase I / II clinical trial in patients with glioblastoma and other advanced cancers An open-label, multicenter Phase I / II trial (placebo-free) was conducted in patients with glioblastoma (spontaneous or mutant IDH-containing high-grade), high-grade glioma, and other advanced solid tumors in sequential growth stages. All enrolled patients provided written informed consent and received concomitant medications listed in this invention. The trial was conducted in accordance with the Declaration of Helsinki and the International Council on Harmonization Guidelines on Good Clinical Practice and was approved by the Institutional Review Boards or Ethics Committees of the participating institutions. The trial was designed by Laminar Pharmaceuticals SA in collaboration with the study researchers.

[0087] The first objective was to determine the safety and tolerability of HOCOS administered as monotherapy, to document the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT), and to identify the recommended dose for treatment. The second objective included characterizing the unique and steady-state pharmacokinetic profile of HOCOS in a continuous daily dosing schedule and to evaluate the preliminary antitumor efficacy of HOCOS.

[0088] The disease was recorded by computed tomography or magnetic resonance imaging. Tumors were evaluated at baseline and every two treatment cycles until disease progression, according to the RANO criteria for glioblastoma, glioma, and other neurological tumors, or RECIST 1.1 for solid tumors in other tissues and organs.

[0089] The inventors included patients over 18 years of age with histologically or cytologically confirmed progressive solid tumors, including glioblastoma and various types of high-grade gliomas that were refractory to standard treatment, or patients who had previously been treated with one or more (up to five) different lines of cancer treatment and no longer responded to conventional treatment (Table 2). The glioma cohort included patients with grade 3 or 4 malignant gliomas that had relapsed or progressed after standard first-line or second-line treatment, with progressive disease defined according to RANO criteria.

[0090] Key exclusion criteria included having received chemotherapy within four weeks prior to the initiation of treatment (six weeks for mitomycin and nitrosourea, and two weeks for palliative radiotherapy and surgery), being unresolved from previous chemotherapy, NCI-CTCAE grade > 1, gastrointestinal dysfunction that may alter drug absorption, a history of hyperlipidemia and / or need for lipid-lowering therapy, significant uncontrolled cardiovascular disease, and recent intracranial or intratumoral hemorrhage on computed tomography or magnetic resonance imaging.

[0091] HOCOS was administered in the form of a dry powder and reconstituted as an oral suspension in water 30 minutes to 2 hours after meals in a 21-day cycle, accompanied by a series of excipients (Table 1) in polyester, aluminum, and low-density polystyrene envelopes. The suspensions contained the amounts of HOCOS and excipients shown in Table 1 for different dose levels.

[0092] [Table 1]

[0093] The initial dose is 250 mg twice daily, i.e., 500 mg daily. A standard "3+3" dose escalation design was used in seven cohorts (total daily doses from 500 mg to 16000 mg, see Table 2). Daily doses of 500, 1000, 2000, 4000, 8000, and 16000 mg were obtained by twice-daily administration, while the daily dose of 12000 mg was obtained by 4000 mg three times daily administration. Three patients were enrolled per dose level and observed for any dose-limiting toxicity (DLT) during the first treatment cycle. If no DLT was observed in any patient, they were moved to a higher dose level. If one of the three patients experienced a DLT, an additional three patients were included at the given dose level. As a standard measure of safety, patients were admitted to the hospital (admitted) within each cohort, with an interval of at least one week between the first and second patient admissions.

[0094] To enable evaluation of dose escalation decisions, patients must take more than 80% of the study drug and have a dose-limiting trial (DLT) during the DLT observation period.

[0095] Cohort dose escalation decisions were also based on a clinical review of all relevant data available from current and previous dose cohorts. The maximum dose administered was defined as the dose level at which a dose limit (DLT) was observed during the treatment cycle in over 33% of evaluable patients, and the maximum tolerated dose (MTD) was defined as the highest dose level lower than the previous one.

[0096] Treatment was maintained until clinical or radiological disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision. Changes to the treatment schedule, dose delays of up to 14 days, and up to two dose reductions due to toxicity were permitted. Intra-patient dose increases were permitted if, at the discretion of the investigator and with the use of medical monitoring, the patient obtained clinical benefit at the initial or current dose level.

[0097] Pharmacokinetics were evaluated by MS-tandem HPLC to measure HOCOS concentrations. Pharmacokinetic profiles (pre-administration and 1, 2, 4, 6, and 8 hours post-administration) were measured on cycles 1, 1, and 21. This included hemopharmacological exposure (dose, concentration, maximal concentration [Cmax], time-plasma area under the curve [AUC]) and population pharmacokinetic parameters (volume of distribution [Vd] and clearance [CL]). In the dose-escalation cohort, pre-administration trough levels were also measured on days 8 and 15. In the extended safety cohort, only the pharmacokinetic profile on day 1 was measured. Final pharmacokinetic samples were collected at the final clinical trial visit.

[0098] The predicted maximum sample size was determined by modeling the dose escalation clinical stop criteria, and additional patients were included in two expanded safety cohorts.

[0099] The efficacy analysis population included all patients who received at least 80% of the dose administered in cycle 1 and who underwent at least one tumor assessment in the trial. Responses were descriptively summarized using frequency distributions. Median progression-free survival (PFS) was estimated by Kaplan-Meier analysis. Progression-free survival at 6 months (PFS, i.e., the proportion of patients surviving and progression-free at 180 days after the start of treatment) was also determined.

[0100] The pharmacokinetic analysis population included patients who underwent HOCOS and provided at least one blood sample for evaluable pre- and post-administration pharmacokinetics. Pharmacokinetic parameters were summarized using descriptive statistics. Individual and mean concentration-versus-time profiles were presented on linear and logarithmic scales. Dose proportionality was tested using a power model.

[0101] result Fifty-four patients were treated at five research centers in the UK and Spain (Table 2). No patients were discontinued due to adverse events (AEs) or serious adverse events (SAEs) during either the dose escalation or expansion phases of the study. Thirty-two patients (15 with glioblastoma / glioma and 17 with other advanced solid tumors) were treated in the first seven cohorts and included in the dose escalation phase of the study (500 mg / day to 16000 mg / day). Next, 22 patients (12 with glioma and 10 with advanced solid tumors) were included in the expanded cohort (Cohort 8), and all patients received the investigational drug at a dose of 12000 mg / day. Of these patients, 44 were evaluable for analyzing the efficacy of HOCOS, as patients had to undergo at least two radioanalyses to assess this parameter.

[0102] The mean cumulative dose was 318,571.4 mg (1,143–2,912,571 mg), and the mean duration of treatment was 41 days (2–989 mg). Dose escalation ranged from 500–16,000 mg / day. HOCOS was rapidly absorbed and associated with dose-proportional exposure (Figure 1). Promising activity was observed in patients with high-grade gliomas. None of the 21 patients with glioblastoma or high-grade glioma showed serious adverse effects, with a mean PFS of 40 days and a response of up to 3 years, making the clinical trial extremely positive. The 18-month PFS in these patients, whose life expectancy was several weeks, was a desirable 18.5%. On the other hand, patients with other solid tumors in different organs had a mean PFS of 42 days. In conclusion, HOCOS demonstrated a very favorable safety profile and promising preliminary activity in a patient population with malignant tumors of the brain and other organs that were difficult to treat and had extremely low life expectancy. It should be noted that, since these patients were in a state of continuous tumor progression and had already ceased responding to any type of treatment, both cessation of disease progression (stable disease, SD) and partial response (tumor reduction: partial response, PR) were considered positive responses to treatment.

[0103] In a group of patients with glioblastoma and glioma, a decrease in astroglia cell brain-specific protein (glial fibrillary acidic protein, GFAP) was observed in 12 out of 15 patients (80%) on day 8 of cycle 1 (4 hours after administration), with a median percentage change from baseline of -20.1%. In this context, GFAP levels correlated with tumor volume and constitute a potential glioma biomarker. This trend was less pronounced on day 1 (pre-administration) in cycle 2, with a decrease in GFAP observed in 8 out of 13 patients (61.5%), with a median percentage change from baseline of -10.51%.

[0104] Twenty-one patients with glioblastoma or glioma and other neurological tumors (Table 2) underwent radiological evaluation (MRI) at baseline and at least one point after baseline. In this patient population, both partial response (PR) and stable disease (SD) were observed according to RANO criteria (Figure 2A, Table 2). One patient experienced a sustained partial response of over 3 years with 1000 mg of HOCOS daily between cycle 1 and cycle 44, followed by 12000 mg of HOCOS daily between cycle 45 and cycle 48 (Figures 2A and 3A). All patients received two lines of treatment without bevacizumab. The mean SD was 40 days, and 18.5% of patients had a disease-free period of 6 months or longer.

[0105] Furthermore, 24 other patients with other progressive solid tumors were included in the study as part of the planned treatment population. In these patients, tumor size reduction was observed in some, and disease stabilization was observed in others (Figure 2B, Table 2), with a mean tumor stabilization of 42 days.

[0106] In this Phase 1 I / IIA human trial, HOCOS monotherapy was well-tolerated, with the most frequent adverse events being diarrhea, nausea, and vomiting, which occurred rarely and were manageable with medication. These events were dose-dependent and predictable, considering the health status of the patient population and the nature of the HOCOS oral suspension. There were no investigational drug-induced adverse events (AEs) or fatalities. Therefore, HOCOS was well-tolerated at a dose of 4000 mg three times daily (12 grams orally, three times daily).

[0107] HOCOS monotherapy demonstrated promising antitumor activity in patients with high-grade glioma (grade 3), glioblastoma (grade 4), and other cancers. Patients with glioblastoma, glioma, and other types of cancer experienced a partial response (PR) or stable disease (SD) according to RANO criteria, and five patients were observed to have a clinical benefit lasting more than 6 months, including patients with grade IV glioblastoma who had been pre-treated but were no longer responsive to any treatment and experienced a response lasting more than 3 years (Figure 3A). The 6-month progression-free survival (PFS) rate in the glioma population was 18.5%, which is remarkable for this type of patient, where the disease is progressing and death usually occurs within months of recurrence, and the patient is no longer responsive to any treatment.

[0108] The promising clinical responses observed in such populations with poor prognoses and clearly unmet medical needs support the therapeutic efficacy of this product.

[0109] [Table 2-1]

[0110] [Table 2-2]

[0111] [Table 2-3]

[0112] HOCOS monotherapy, prescribed as rescue treatment in cancer patients previously treated with other drugs, has shown promising antitumor activity along with a manageable safety profile and significantly lower toxicity than other chemotherapy regimens, making it an ideal candidate for first-line treatment of gliomas, naturally occurring grade IV glioblastoma, and other types of cancer.

[0113] HOCOS treatment has been proven effective not only in humans but also in animal models of various types of human cancer, including pancreatic cancer. Figure 3B shows the antitumor effect of HOCOS on the proliferation of human pancreatic cancer (MIAPaCa-2 cells) in immunocompromised mice. In this case, pancreatic cancer is a very aggressive type of cancer with a high mortality rate and a very short life expectancy. Thus, patients with distant pancreatic cancer have a 5-year survival rate of 3%. This survival rate is somewhat higher (16%) in patients with regional pancreatic cancer, and localized cancer has the best prognosis (44% with a 5-year life expectancy).

[0114] Inclusion criteria Patients with glioblastoma / glioma and other types of tumors were included in this Phase I / II clinical trial. These patients received HOCOS monotherapy at the doses shown in Table 2. The criteria for including these patients were as follows: - The capacity and willingness to give written informed consent, - Male or female patients aged ≥18 years, - These were histologically or cytologically confirmed advanced solid neoplasms that were unresponsive to standard treatment or for which there was no standard therapy.

[0115] Inclusion criteria for patients with neurological tumors - Diagnosis of glioblastoma, grade 3 or 4 malignant glioma, or similar neurological tumor that recurs or progresses after standard first-line or second-line treatment or subsequent lines of treatment. - A truly progressive disease confirmed according to RANO criteria. - Life expectancy is at least 12 weeks, - ECOG performance status is 0-2, - The ability to swallow and ingest oral medications. - Ability to receive appropriate tumor imaging by CT or MRI to evaluate the course of the disease. - Screening / baseline hematologic values: Hemoglobin ≥ 90 g / L (9 g / dL) or 5.6 mmol / L, absolute neutrophil count ≥ 1.5 × 10⁻¹⁰ 9 / L, platelets ≥100×10 9 / L, - Screening / baseline coagulation value: International Normalized Ratio (INR) ≤ 1.5, partial thromboplastin time (PTT) ≤ 2 × upper limit of normal (ULN), - Screening / baseline liver function test values: Total bilirubin ≤ 1.5 × ULN; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN, unless explained by a genetic syndrome such as Gilbert's syndrome. - Screening / baseline renal function test values: serum creatinine ≤ 1.5 × ULN, - There is no history of corrected QT interval prolongation (QTc), and the QTc interval at screening / baseline is normal (QTc ≤ 450 milliseconds). - Female patients who are not capable of procreating (defined as >2 years since the last menstruation or surgical sterilization) (or male patients whose partners are not capable of procreating), female patients who are capable of becoming pregnant, who have a negative serum pregnancy test within 7 or 14 days prior to the first dose of HOCOS, followed by a negative urine pregnancy test within 7 days prior to the first dose of HOCOS, and who use an effective, non-hormonal method of contraception (non-hormonal intrauterine contraceptive device, barrier contraceptive method with spermicidal gel) (if males are not surgically sterilized, their partners use such a method).

[0116] Inclusion criteria for patients with solid tumors other than glioblastoma / glioma. - The presence of a lesion suitable for biopsy (essential for non-glioma patients enrolled in the expanded safety cohort, and highly desirable for non-glioma patients enrolled in the dose escalation phase).

[0117] Example 2: First-line clinical trial in newly diagnosed glioblastoma patients with HOCOS in combination with temozolomide and radiotherapy. Following the good results of the Phase I / II clinical trial, a Phase II / III trial was conducted in patients newly diagnosed with glioblastoma. This clinical trial was conducted in a double-blind, placebo-controlled format. Twenty-seven patients were included. Fifty percent of all patients were randomly assigned to the placebo group, and the other half were assigned to the HOCOS group, but neither the physician nor the patient knew who was taking the placebo or the verum. Two of the recruited patients withdrew from the trial before treatment began and were not valid for analysis. Patients with newly diagnosed glioblastoma or grade IV glioma, with wild-type isocitrate dehydrogenase (IDH) enzyme and methylation of the MGMT gene promoter, were included in the trial. All patients received, in addition to temozolomide, the other drugs mentioned in the present invention simultaneously. Furthermore, the patients received chemotherapy according to the above protocol.

[0118] The treatment used in the clinical trial consisted of the following five steps: Step 1. Treatment of the patient by surgery for glioblastoma removal. Step 2. Subjecting the patient to chemoradiotherapy for 6 - 7 weeks, with radiotherapy at a fractionated dose of 2 Gy per day, 5 days per week, and administration of temozolomide at a dose of 75 mg / m 2 per day, HOCOS at a dose of 12,000 mg / day or placebo, administered simultaneously with radiotherapy. Step 3. A 4-week washout period during which HOCOS and temozolomide radiotherapy are discontinued. Step 4. A maintenance period of 6 cycles, each cycle having a duration of 4 weeks, and each cycle consisting of daily administration of temozolomide (150 - 200 mg / m 2 ) and HOCOS (12,000 mg / day) or placebo for the first 3 weeks of each cycle, followed by a 7-day rest without treatment for each cycle. Procedure 5.4-week maintenance monotherapy cycle, in which HOCOS (12000 mg / day) or placebo is administered daily for the first three weeks of each cycle, followed by a seven-day washout period without treatment, and the above cycle is continued indefinitely as maintenance therapy until the tumor progresses according to RANO criteria.

[0119] The clinical trial conducted was a randomized, double-blind, placebo-controlled, two-arm (1:1 ratio) trial to evaluate the efficacy and safety of HOCO sodium salt versus placebo in patients newly diagnosed with glioblastoma (grade IV glioma) and naturally occurring disease. In all groups, patients received standard treatment (temozolomide and radiotherapy) along with the different drugs cited herein, and were randomized to receive either placebo (group A) or a dose of 12,000 mg / day of HOCOS (group B).

[0120] This trial evaluates progression-free survival (PFS) as the period between the diagnosis of glioblastoma and the observation of tumor growth based on RANO criteria. In addition, it studies overall survival (OS), which is the period of survival from diagnosis.

[0121] result The survival (both OS and PFS) of 24 patients was monitored over a period of 36 months. Figure 4 shows the results of this trial. 1:1 randomization (one placebo-treated patient for each HOCOS-treated patient) means that half of the patients received the investigational product (HOCOS) and the other half received placebo. Figure 4A shows the overall survival (OS) (black bars: combinational HOCOS + temozolomide) of patients participating in the trial conducted in this invention, compared to standard treatment survival (SoC, gray bars: temozolomide only). As can be understood, the overall survival rate of patients in the mixed population treated with temozolomide + HOCOS or placebo was significantly higher than the survival rate of standard treatment with temozolomide as the sole chemotherapy (survival rates of 38%, 9.4%, and 1.4% at 17, 28, and 36 months post-diagnosis, respectively) (60%, 44%, and 36% at 17, 28, and 36 months post-diagnosis, respectively). A similar increase is observed in progression-free survival, considering that the percentages of PFS at 17, 28, and 36 months were 28%, 24%, and 8%, respectively, compared to 18%, 2.8%, and 0.35% with standard treatment (Figure 4B). These data clearly demonstrate that patients treated with HOCOS + temozolomide receive additional therapeutic benefits compared to treatment with temozolomide alone. Considering that approximately half of the patients are treated with HOCOS and the other half with placebo, the potential proportion of patients who would benefit from this novel chemical compound is as follows: 0.5×(%HOCOS)+0.5×(%SoC)=%MIN It was calculated as follows. In the formula, %MIN is the percentage of patients with survival (optionally PFS or OS) in a mixed population of patients treated with HOCOS and untreated patients in the study of the present invention; %SoC is the percentage of patients that appear in studies performed with standard treatment (temozolomide only); and %HOCOS is the percentage of patients with survival (optionally PFS or OS) that may occur if all patients with grade IV glioblastoma with native IDH were treated with HOCOS (+ temozolomide and the drugs cited herein). In this formula, %HOCOS is the only unknown. %MIN data were obtained from this study, and %SoC data were obtained from the literature (meta-analysis using all studies performed on patients with glioblastoma treated with temozolomide). The 36-month survival rates, i.e., OS and PFS values, were 70.6% and 15.7% with HOCOS + temozolomide, respectively, compared to only 1.4% and 0.35% with temozolomide alone. This calculation, demonstrating the therapeutic potential of HOCOS, clearly demonstrates the therapeutic benefit of this compound (Figure 4). These results indicate that HOCOS results in a significant and substantial increase in life expectancy for patients with natural IDH grade IV glioblastoma, and that its combination with temozolomide can save many lives. Furthermore, its oral administration and absence of adverse effects mean that HOCOS can be administered permanently as the sole antitumor maintenance therapy, while temozolomide can only be administered for 6 months due to its toxicity.

[0122] Example 3. Cell line assays using HOCOS in combination with other compounds for the treatment of various types of cancer. In addition to monotherapy treatments in both humans and human cancer cells, as well as in experimental animals, as shown in Figures 2A, 2B, 3A, and 3B, combination therapies with HOCOS and other compounds extend beyond those shown in Figure 4. This is possible for two reasons. First, HOCOS is a very harmless (non-toxic) compound and does not pose a risk of increasing the significant and dangerous adverse effects of other antitumor drugs. Second, the mechanism of action of HOCOS is entirely different from that of other drugs, and therefore its effects may be additive. To investigate the potential use of HOCOS in combination therapies, human glioblastoma cell lines U118, SNB19, SF268, human mesothelioma cells NCI-H2021, and pancreatic cancer cells BxPC-3 (pancreatic adenocarcinoma) and MIAPaCa-2 (neuroendocrine pancreatic cancer) were cultured in the presence or absence of different chemotherapeutic agents, and in the presence or absence of HOCOS in combination with the aforementioned compounds. The compounds used in this study were temozolomide, thiamine, gemcitabine, fluoroacyl, oxyplatin, irinotecan, etoposide, imatinib, FOLFIRINOX, erlotinib, and cisplatin. The results showed that the combination of HOCOS and temozolomide was approximately three times more potent than HOCOS alone (Table 3). Furthermore, all combinations used were observed to exhibit superior antitumor efficacy compared to the single drug in both glioblastoma and pancreatic cancer. Therefore, since HOCOS is non-toxic at therapeutic doses, has a different mechanism of action than the other antitumor compounds, and enhances their efficacy, it can be used in combination therapy with other drugs for the treatment of glioblastoma or other types of cancer.

[0123] [Table 3]

[0124] Example 4: Clinical trial in patients with neuropathic pain caused by spinal cord injury A clinical trial using HOCOS was conducted in individuals with spinal cord injury suffering from neuropathic pain. The objective of this trial was to demonstrate the pharmacological safety (absence of toxicity) and pharmacological efficacy of HOCOS for neuropathic pain in patients with nerve injury. In this clinical trial, the mean neuropathic pain of the patients participating in the study was between 7 and 8 on a VAS scale, where 10 is maximum pain and 0 is no pain. Therefore, this is a population with elevated chronic pain. The pain is not relieved despite the many analgesics they use because it is a different pathology from conventional pain.

[0125] In a group of 44 patients, patients were randomly divided into four groups (double-blind). HOCOS tablets were administered at doses of 0 (placebo), 1050, 2100, or 4200 milligrams per day (three doses, administered orally), and neuropathic pain was recorded according to a VAS scale as a measure of efficacy. In addition, all patients received the concomitant medications described in this invention. The composition of the tablets is shown in Table 4.

[0126] [Table 4]

[0127] Patients underwent a screening visit (SV) to select those who met the inclusion requirements for the clinical trial, primarily those with spinal cord injury, neuropathic pain, and receiving pregabalin treatment. Once selected for the trial, a first visit (V1) was conducted, where patients were informed about the trial, pain was quantified, patients received the necessary medication for one month, and blood samples were taken to assess the patient's baseline condition. Visits V2, V3, and V4 were conducted one, two, and three months after the treatment to evaluate the effectiveness of the treatment and to take blood samples, respectively. From V4 onwards, medication was discontinued, and patients visited again one month later without treatment (V5). Therefore, V5 was a visit where an increase in pain levels was expected in all patients, both in those who showed efficacy from the treatment and discontinued product intake, and in those who experienced a placebo effect. Pain was measured on a VAS scale at all visits, screenings, and V1-V5 (Table 5).

[0128] [Table 5-1]

[0129] [Table 5-2]

[0130] Measurement of HOCOS side effects In this clinical trial, HOCOS had fewer adverse events per patient (Pw / AE) than placebo, with 0.5 adverse events per patient treated with HOCOS compared to 1 adverse event per patient treated with placebo (Figure 5A). Furthermore, treatment-attributable adverse events were also higher in patients treated with placebo (0.44 adverse events per patient, placebo treatment-related, Pw / RTAE) than in patients treated with HOCOS at the optimal dose (2100 mg per day) (0.08 adverse events per patient, HOCOS treatment-related, Pw / RTAE). The more than 80% reduction in parameters in the group with the dose selected for subsequent treatment (2100 mg daily) suggests that HOCOS is safe (non-toxic) and, in addition, protects patients with spinal cord injury from systemic health problems and / or problems arising from other drug therapies referred to in this invention. Therefore, these data indicate that HOCOS has a positive effect on the overall health of patients with spinal cord injury (paraplegia and quadriplegia).

[0131] Measurement of the effectiveness of HOCOS for neuropathic pain The efficacy of HOCOS for neuropathic pain in patients with spinal cord injury was determined using a VAS scale (Haefeli and Elfering) consisting of a straight line with ends defining "no pain" (0 on the scale) and "worst possible pain" (10 on the scale). Patients were asked to mark the intensity of their pain between these two points. Length scales of 5–20 cm were used, but the best results were obtained with a length of 10–15 cm. In this clinical trial, the efficacy of HOCOS was evaluated in 44 patients with spinal cord injury and neuropathic pain using two baseline measurements: a screening visit (SV) and a first visit (V1), in which patients had not yet received any drug treatment. Oral treatment lasted for 3 months, and pain was evaluated at 1 month (V2), 2 months (V3), and 3 months (V4) after treatment. V4 was also called the End of Treatment (EoT) visit. The patients remained medication-free for one month and were then evaluated at a fifth visit (V5), also known as the End of Study (EoS) visit.

[0132] Efficacy analysis was performed in both the "Total Population" of the trial (44 patients: Figure 5B) and the "Censored Population" of patients with objectively persistent pain (34 patients in whom a withdrawal effect on HOCOS was observed along with an increase in pain when treatment was discontinued: Figure 5C). The parameter selected for discontinuing patients was pain behavior between visits 4 and 5. Since the clinical trial described in this invention lasted approximately 6 months from patient screening to EoS, it is possible that several patients entered a spontaneous and natural pain reduction cycle. Patients who showed a reduction in pain due to treatment experienced an increase in pain after the end of the treatment period, so patients whose pain decreased between V4 and V5 at the end of treatment were discontinued. This discontinuation was performed equally in all experimental groups. Furthermore, pain was analyzed in the group of responding censored patients, who had a pain reduction of more than 1 point on the VAS scale (Figure 5D). As can be seen from the figures, there is a significant reduction in patients treated with HOCOS, particularly in the 2.1 gram daily group (700 milligrams three times a day, Tables 4 and 5). This difference is significant between V4 and V5 when censored patients who did not experience an increase in pain are excluded. There was no significant difference in the absolute value of the reduction among the three analyses performed on (1) all patients (Figure 5B), (2) uncensored patients (Figure 5C), and (3) response-censored patients (Figure 5D), indicating that the overall pain reduction is not affected by this type of analysis. However, the statistical significance improved between these analyses, suggesting that a more homogeneous patient population should be tested.

[0133] As mentioned above, neuropathic pain differs from other types of hyperalgesic pain in that it is caused by different molecular and cellular mechanisms. The PDQ questionnaire allows for the determination of whether the pain a patient is experiencing is neuropathic. In a further post-hoc analysis, patients treated with 2100 mg / day and 4200 mg / day showed a significant reduction in neuropathic pain levels as measured by VAS (Figure 5E). In this case, the 2100 mg / day dose (oral, three times daily) was the most effective, with pain reduction evident from the first month of treatment and significant from the second month. Three months after treatment with 2100 mg / day, VAS scores in these patients with a high probability of developing neuropathic pain were approximately half of what they were at the start of treatment (Figure 5E). Furthermore, in this subpopulation of patients, the percentage of respondents in the placebo group (0 mg / day) was observed to be only 25% (Figure 5F). In contrast, 80% of patients treated with 2100 mg / day of HOCOS responded to the treatment, while 37% and 55% of patients treated with 1050 mg / day and 4200 mg / day, respectively, responded (Figure 5F).

[0134] These results demonstrate that HOCOS is effective in treating neuropathic pain. It is very important to consider that all patients in this trial were treated with pregabalin and other drug therapies, achieving only partial pain relief. The reduction observed in patients with HOCOS treatment is significant (up to 3 on the VAS scale) and occurs in addition to the effects of pregabalin and other drug therapies. Because HOCOS has a different mechanism of action than other compounds, it can induce this effect alone or in combination with other drugs. In fact, since patients in this trial received different drug combinations in each case, the efficacy is not limited to any particular combination. In other words, HOCOS may be effective as monotherapy or in combination with pregabalin, opioids, anticonvulsants, anxiolytics, anesthetics, antidepressants, etc.

[0135] In the uncensored group receiving 2100 milligrams daily (the most effective therapeutic dose), HOCOS demonstrated efficacy in 75% of patients, with an average effect of approximately 2 points on the VAS pain scale (Tables 5 and 6). In a previous clinical trial using pregabalin (Cardenas et al.), only approximately 50% of patients responded to the treatment, and an average reduction of 1.2 points on the VAS scale was observed. Therefore, it can be concluded that HOCOS is more effective than pregabalin, and furthermore, its effect overlaps with that of pregabalin and is additive to pregabalin and the remaining pharmaceuticals mentioned in this invention.

[0136] The additive effect of HOCOS in inducing a significant reduction in neuropathic pain, along with the remaining drugs, has several considerations of interest that must be emphasized. Firstly, this reduction is greater than that brought about by pregabalin (along with the other drugs mentioned herein), the reference drug for the treatment of neuropathic pain, which reduces neuropathic pain by only 1.2 points on the VAS scale (Cardenas et al.). On the other hand, the percentage of patients responding to pregabalin was 33% in the placebo group and 48% in the pregabalin group, with a difference of 0.82 points on the VAS scale between these groups (Cardenas et al.). In this study using a daily dose of 2.1 g of HOCOS, there was a 1.92-point pain reduction on the VAS scale between V1 and V4 across the entire population. Patient censoring did not result in a difference in absolute pain values, but it did result in significance of the trial according to the statistical tests used (two-way ANOVA, Fisher's LSD test). Regarding the proportion of patients responding to HOCOS treatment in the censored population, a reduction of more than 1 VAS point was observed in 55% of patients treated with 1050 mg / day, 75% of patients treated with 2100 mg / day, and 56% of patients treated with 4200 mg / day (Table 6). In contrast, only 17% of placebo-treated and censored patients showed a significant reduction in neuropathic pain (Table 6). These data clearly demonstrate that HOCOS is more effective than pregabalin. Furthermore, all patients in this trial received pregabalin treatment, and therefore the observed effect is additive to the effect of pregabalin. This additive effect is due to the difference in the mechanisms of action of the two compounds. In a subpopulation of patients with a high probability of having neuropathic pain, the effect of HOCOS at a dose of 2100 mg / day at 3 months was very pronounced and significant (Figure 5E). Furthermore, a significant difference in pain reduction was found at 4200 mg / day, but placebo or a low dose (1050 mg / day of HOCOS) did not produce a significant change in pain levels on the VAS scale in patients with neuropathic pain.This demonstrates that treatment with HOCOS produces a specific pharmacological effect on neuropathic pain in patients with spinal cord injury. Furthermore, the increase in the mean value on the VAS scale after the completion of treatment is also consistent with the specific effect of this compound. Finally, in the patient population with a high probability of having neuropathic pain (>90%) according to the PDQ, the percentage of treatment responders in the 2100 mg / day group was significantly higher than in the placebo group (25% and 80%, respectively: Figure 5F). Again, this result demonstrates that treatment with HOCOS is specific and concentration-dependent.

[0137] [Table 6]

[0138] Example 5. Efficacy of HOCOS for neuropathic pain in a vincristine-treated rat model. The efficacy of HOCOS for neuropathic pain was also investigated in a rat model treated with vincristine (0.5 mg / kg to 1 mg / kg), a drug used in cancer chemotherapy and associated with the development of neuropathic pain. This model induces peripheral neuropathy similar to that observed in other types of patients, such as those with fibromyalgia, chemotherapy pain, postherpetic neuralgia, or post-diabetes or post-hepatitis patients, but this is not due to traumatic nerve injury. Therefore, unlike the spinal cord injury model, this model is an example of the usefulness of HOCOS in other types of neuropathic pain besides nerve injury, generally speaking, especially in spinal cord injury. In experimental animals, pain levels were recorded using analgesia based on the reduction of hyperalgesia (worsening of pain caused by mild stimuli, such as pressure from a toothpick) or allodynia (non-painful stimuli, such as light pressure or friction on the skin from a sheet or finger). In this sense, two types of tests were performed: (1) The "tail flick" test allows for the measurement of thermal hyperalgesia and consists of applying a heat source to the tail with a laser beam or similar device and recording the time it takes for the animal to move its tail away from the light beam. The longer the animal tolerates the heat, the higher the temperature it can tolerate and the lower its pain threshold. This test measures the latency time or period (in seconds) between the onset of stimulation and the response to the stimulation in the animal, with lower latency values ​​corresponding to higher levels of neuropathic pain (Klazas et al.). In this sense, vincristine reduced the latency time in a dose-dependent manner, while HOCOS increased the latency time in treated animals, indicating that vincristine can improve neuropathic pain (Figure 6A). In addition to the dose-dependent effect of vincristine, treatment with HOCOS after treatment with vincristine (1 mg / kg) had a time-dependent effect (Figure 6B).In this way, HOCOS induced recovery of tail flick values, but the vehicle did not. These results demonstrate that HOCOS is highly effective in treating neuropathic pain caused by factors other than nerve damage. Similarly, these results demonstrate the potential use of HOCOS in treating cancer patients and patients exhibiting pain induced by antitumor chemotherapy agents such as various alkaloids, including vincristine.

[0139] In addition to measuring thermal hyperalgesia, mechanical allodynia was measured using the Von Frey test. In this test, a non-painful stimulus (e.g., plantar pressure using plastic fibers) is induced, and the animal's response to the stimulus is observed. Figure 5 shows that the effect of HOCOS, as measured by the Von Frey test, is very pronounced and significant, and simultaneously increases during the treatment period (0-28 days) and is maintained against high doses of cytotoxic agents (Figures 7A and 7B). Mechanical allodynia is a type of pain that frequently occurs in patients with fibromyalgia, chemotherapy pain, postherpetic neuralgia, or post-diabetes or post-hepatitis. Therefore, HOCOS is useful in treating these types of neuropathic pain.

[0140] The above tests and results demonstrate that HOCOS is effective in treating neuropathic pain caused by factors other than nerve or spinal cord injury.

[0141] reference Brandsma and van den Bent, Pseudoprogression and pseudoresponse in the treatment of gliomas. Curr Opin Neurol. 2009;22(6):633-8. doi:10.1097 / WCO.0b013e328332363e Cardenas et al., A randomized trial of pregabalin in patients with neuropathic pain due to spinal cord injury. Neurology. 2013;80(6):533-9. doi:10.1212 / WNL.0b013e318281546b Pain assessment by Haefeli and Elfering. Eur Spine J. 2006;15 Suppl 1(Suppl 1):S17-24. doi:10.1007 / s00586-005-1044-x Klazas et al., Gabapentin Increases Intra-Epidermal and Peptidergic Nerve Fibers Density and Alleviates Allodynia and Thermal Hyperalgesia in a Mouse Model of Acute Taxol-Induced Peripheral Neuropathy.Biomedicines.2022;10(12):3190.doi:10.3390 / biomedicines10123190. Lencioni et al., "Objective response by mRECIST as a predictor and potential surrogate endpoint of overall survival in advanced HCC." J Hepatol. 2017;66(6):1166-1172. doi:10.1016 / j.jhep.2017.01.012. Rodgersらによる、Morphine resistance in spinal cord injury-related neuropathic pain in rats is associated with alterations in dopamine and dopamine-related metabolomics.J Pain.2022;23(5):772-783.doi:10.1016 / j.jpain.2021.11.009.

Claims

1. Glioblastoma, astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, oligodendroglioma, oligodendroglioma, ependymoma, yellowatt astrocytoma, medulloblastoma, low-grade glioma, grade 3 glioma, pontine glioma, ependymoma, subependymoma, cerebral gliomatosis, germ blastoma, atypical teratomatous rhabdoid tumor, tumors of the cranial and spinal nerves, mixed glial tumor, pituitary tumor, germ cell tumor, meningeal tumor, meningioma, hemangiopericytoma, hemangioblastoma, choroid plexus tumor, choroid plexus papilloma, pineal cell tumor, pineoblastoma, mesothelioma, pleural mesothelioma, cholangiocarcinoma, exocrine pancreatic cancer, neuroendocrine pancreatic cancer, metastatic lung cancer Compound 2-hydroxyoctadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, administered at doses of 500 mg / day to 16000 mg / day, for use in the treatment of oncological conditions selected from the group consisting of adenocarcinoma, small cell lung cancer, colonic adenocarcinoma, rectal cancer, rectosigmoid junction cancer, rectal adenocarcinoma, metastatic rectal adenocarcinoma, metastatic sigmoid colon adenocarcinoma, colorectal adenocarcinoma, metastatic colorectal adenocarcinoma, urachal fistula cancer, urachal adenocarcinoma, endometrial adenocarcinoma, neuroendocrine pancreatic cancer, pancreatic adenocarcinoma, chondrosarcoma of the uterus, cecal adenocarcinoma, esophageal cancer, and metastatic small cell esophageal cancer.

2. The aforementioned oncological conditions include oligodendroglycytoma, glioblastoma, oligodendroglioma, ependymoma, celery astrocytoma, medulloblastoma, pilocytic astrocytoma, pontine glioma, ependymoma, subependymal glioma, cerebral glioma, germ cell tumor, atypical teratomatous rhabdoid tumor, tumors of the cranial and spinal nerves, mixed glial tumors, pituitary tumors, germ cell tumors, meningeal tumors, meningiomas, hemangiopericytoma, hemangioblastoma, choroid plexus tumor, choroid plexus papilloma, pineal cell tumor, pinealoblastoma, mesothelioma, and pleural mesothelioma. A compound, salt, or ester according to claim 1, selected from the group consisting of tumor, cholangiocarcinoma, exocrine pancreatic cancer, neuroendocrine pancreatic cancer, metastatic lung adenocarcinoma, small cell lung cancer, rectal cancer, rectosigmoid junction cancer, metastatic rectal adenocarcinoma, metastatic sigmoid colon adenocarcinoma, metastatic colorectal adenocarcinoma, urachal fistula cancer, urachal adenocarcinoma, endometrial adenocarcinoma, neuroendocrine pancreatic cancer, chondrosarcoma of the uterus, cecal adenocarcinoma, bladder adenocarcinoma, esophageal cancer, and metastatic small cell esophageal cancer.

3. The compound, salt, or ester according to claim 1 or 2, wherein the glioblastoma is a grade IV glioblastoma having the enzyme isocitrate dehydrogenase (IDH).

4. A compound, salt, or ester according to claim 3 for use in the treatment of natural IDH grade IV glioblastoma multiforme in subjects having methylation of the promoter of the methylguanine methyltransferase (MGMT) gene.

5. The compound, salt, or ester according to any one of claims 1 to 4, wherein the salt is a sodium salt.

6. The compound, salt, or ester according to any one of claims 1 to 5, wherein the ester is a methyl ester or an ethyl ester.

7. A compound, salt, or ester according to any one of claims 1 to 6, administered orally.

8. A compound, salt, or ester according to any one of claims 1 to 7, administered in doses selected from the group consisting of 500 mg / day, 1000 mg / day, 1050 mg / day, 2000 mg / day, 2100 mg / day, 3150 mg / day, 4000 mg / day, 4200 mg / day, 6000 mg / day, 6300 mg / day, 8000 mg / day, 10000 mg / day, 12000 mg / day, 12600 mg / day, 14000 mg / day, and 16000 mg / day.

9. A compound, salt, or ester according to any one of claims 1 to 8, administered at a dose of 2100 mg / day.

10. A compound, salt, or ester according to any one of claims 1 to 8, administered at a dose of 12,000 mg / day.

11. A compound, salt, or ester according to any one of claims 1 to 10, to be used as a first-line treatment.

12. The compound, salt, or ester according to claim 11, wherein the first-line treatment comprises a four-week cycle, each cycle comprising administering the compound, salt, or ester daily for the first three weeks of each cycle, and no treatment during the fourth week.

13. A compound, salt, or ester according to any one of claims 1 to 12, used as a pre- or post-operative treatment to reduce the size of a tumor.

14. The compound, salt, or ester according to any one of claims 1 to 12, wherein the subject receiving the aforementioned treatment has been previously treated in at least one to five different lines of chemotherapy.

15. A compound, salt, or ester according to any one of claims 1 to 10, 13, or 14, to be used as a maintenance treatment.

16. The compound, salt, or ester according to claim 15, wherein the maintenance treatment comprises a four-week cycle, each cycle comprising administering the compound, salt, or ester daily for the first three weeks of each cycle, and no treatment during the fourth week.

17. The above treatment - A chemoradiotherapy phase lasting 6 to 7 weeks, in which radiotherapy is administered daily for 5 days per week, and from the first day of the radiotherapy, the second chemotherapeutic agent is administered at a dose of 75 mg / m². ２ A chemoradiotherapy stage comprising administering the compound, salt, or ester at a daily dose of 12,000 mg / day for three to four weeks from the start of the radiotherapy, - A four-week treatment suspension period, - A maintenance period of 6 cycles of 4 weeks, in which each cycle is administered by administering the second chemotherapeutic agent at a dose of 150-200 mg / m² for the first 5 days of each cycle. ２ The treatment involves administering the compound, salt, or ester at a daily dose of 12,000 mg / day for the first three weeks of each cycle, with a maintenance period during the fourth week in which no treatment is administered. - A monotherapy phase in a four-week cycle, each cycle comprising administering the compound, salt, or ester at a dose of 12,000 mg / day for the first three weeks of each cycle, with no treatment during the fourth week, and the cycle continuing indefinitely as maintenance therapy, according to any one of claims 1 to 16.

18. A compound, salt, or ester according to any one of claims 1 to 17, for simultaneous, separate, or sequential use in combination with a second chemotherapeutic agent selected from the group consisting of temozolomide, thiamine, gemcitabine, fluorouracil, oxyplatin, irinotecan, etoposide, imatinib, folfirinox, erlotinib, and cisplatin.

19. The compound, salt, or ester according to claim 18, for simultaneous, separate, or sequential use in combination with temozolomide in the treatment of glioblastoma.

20. The compound, salt, or ester according to claim 19, wherein the glioblastoma is a natural IDH grade IV glioblastoma multiforme.

21. Compound 2-hydroxyoctadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, for use in the treatment of neuropathic pain, administered at doses of 500 mg / day to 16000 mg / day.

22. The compound, salt, or ester according to claim 21, wherein the neuropathic pain is caused by nerve damage or by nerve damage of the central nervous system and / or peripheral nervous system.

23. The compound, salt, or ester according to claim 22, wherein the nerve injury is spinal cord injury.

24. The compound, salt, or ester according to claim 21, wherein the neuropathic pain is caused by a cause selected from the group consisting of chemotherapeutic agents, antitumor agents, and cancer agents.

25. The compound, salt, or ester according to claim 24, wherein the antitumor agent is an alkaloid.

26. The compound, salt, or ester according to claim 25, wherein the alkaloid is vincristine.

27. The compound, salt, or ester according to claim 21, wherein the neuropathic pain is caused by a cause selected from the group consisting of peripheral diabetic neuropathy, postherpetic neuralgia, fibromyalgia, and hepatitis.

28. A compound, salt, or ester according to any one of claims 21 to 27, administered in doses selected from the group consisting of 500 mg / day, 1000 mg / day, 1050 mg / day, 2000 mg / day, 2100 mg / day, 3150 mg / day, 4000 mg / day, 4200 mg / day, 6000 mg / day, 6300 mg / day, 8000 mg / day, 10000 mg / day, 12000 mg / day, 12600 mg / day, 14000 mg / day, and 16000 mg / day.

29. A compound, salt, or ester according to any one of claims 21 to 28, administered at a dose of 2100 mg / day.

30. A compound, salt, or ester according to any one of claims 21 to 28, administered at a dose of 4200 mg / day.

31. A compound, salt, or ester according to any one of claims 21 to 30, for simultaneous, separate, or sequential use in combination with at least one other active ingredient selected from the group consisting of pregabalin, opioid analgesics, steroid analgesics, nonsteroidal analgesics, cannabinoid analgesics, anticonvulsants, anxiolytics, anesthetics, and antidepressants.

32. Lamotrigine, Omeprazole, Phenoxypentanoic acid, Metformin, Ibuprofen, Dalcolac, Alprazolam, Diazepam, Baclofen, Macrogol, Duloxetine, Levofloxacin, Gabapentin, Ceftriaxone, Enoxaparin, Pantoprazole, Paracetamol, Ipratropium bromide, Acetylcysteine, Metoclopramide, Metamisole, Teicoplanin, Dexketoprofen, Oxybutynin, Meropenem, Beclo Metasone dipropionate, formoterol fumarate, atorvastatin, calcifediol, paroxetine, cyanocobalamin, clonazepam, amlodipine, trazodone, flurazepam, thiazide, losartan, metamizole, sucralfate, lactitol, pancreatin, dimethicone, betanazole, amitriptyline, lorazepam, vitamin D, lormetazepam, solifenacin, simvastatin, sinitaprid, quetiapine, betamiga, bal Proate, Lacosamide, Lidocaine, Metamisole, Finasteride, Acetylsalicylic acid, Enalapril, Metformin, Lillatizanidine, Trospium, Tramadol, Sercoxib, Citalopram, Sildenafil, Tamsulosin, Loratadine, Tizanidine, Vortioxetine, Zolpidem, Bromazepam, Dexamethasone, Dexketoprofen, Losartan, Eslicarbazepine, Pentoxifylline, Mirabegron, Fluoxetine, Chlorazepate, A compound, salt, or ester according to any one of claims 21 to 31, for simultaneous, separate, or sequential use in combination with at least one other active ingredient selected from the group consisting of mirtazapine, rosuvastatin, prednisone, beclamethazone, methylprednisone, acyclovir, lignocaine, nystatin, delorazepam, alendronate, carbamazepine, cortisone, hydrocortisone, cannabidiol, and tetrahydrocannabinol.

33. Glioblastoma multiforme, astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, oligodendroglioma, oligodendroglioma, ependymoma, yellowatt astrocytoma, medulloblastoma, low-grade glioma, grade 3 glioma, pontine glioma, ependymoma, subependymoma, cerebral gliomatosis, germ cell tumor, atypical teratomatous rhabdoid tumor, tumors of the cranial and spinal nerves, mixed glial tumor, pituitary tumor, germ cell tumor, meningeal tumor, meningioma, hemangiopericytoma, hemangioblastoma, choroid plexus tumor, choroid plexus papilloma, pineal cell tumor, pineoblastoma, mesothelioma, pleural mesothelioma, cholangiocarcinoma, exocrine pancreatic cancer, neuroendocrine pancreatic cancer, metastatic lung adenocarcinoma, small cell lung cancer, colon adenocarcinoma, rectal cancer, rectosigmoid junction cancer, A pharmaceutical composition for use in the treatment of oncological pathologies selected from the group consisting of rectal adenocarcinoma, metastatic rectal adenocarcinoma, metastatic sigmoid colon adenocarcinoma, colorectal adenocarcinoma, metastatic colorectal adenocarcinoma, urachal fistula carcinoma, urachal adenocarcinoma, endometrial adenocarcinoma, neuroendocrine pancreatic carcinoma, pancreatic adenocarcinoma, chondrosarcoma of the uterus, cecal adenocarcinoma, bladder adenocarcinoma, esophageal carcinoma, and metastatic small cell esophageal carcinoma, comprising compound 2-hydroxy-octadecene-9-cis-oleate, or a pharmaceutically acceptable salt or ester thereof, together with at least one pharmaceutically acceptable excipient or carrier, wherein the compound, salt, or ester is administered in a dose of 500 mg / day to 16000 mg / day.

34. The aforementioned oncological conditions include oligodendroblastoma, glioblastoma, oligodendroglioma, ependymoma, celerypha astrocytoma, medulloblastoma, pilocytic astrocytoma, pontine glioma, ependymoma, subependymal glioma, cerebral glioma, germ cell tumor, atypical teratomatous rhabdoid tumor, tumors of the cranial and spinal nerves, mixed glial tumors, pituitary tumors, germ cell tumors, meningeal tumors, meningiomas, hemangiopericytoma, hemangioblastoma, choroid plexus tumor, choroid plexus papilloma, pineal cell tumor, pineoblastoma, mesothelioma, The pharmaceutical composition according to claim 33, selected from the group consisting of pleural mesothelioma, cholangiocarcinoma, exocrine pancreatic cancer, neuroendocrine pancreatic cancer, metastatic lung adenocarcinoma, small cell lung cancer, rectal cancer, rectosigmoid junction cancer, metastatic rectal adenocarcinoma, metastatic sigmoid colon adenocarcinoma, metastatic colorectal adenocarcinoma, urachal fistula cancer, urachal adenocarcinoma, endometrial adenocarcinoma, neuroendocrine pancreatic cancer, chondrosarcoma of the uterus, cecal adenocarcinoma, bladder adenocarcinoma, esophageal cancer, and metastatic small cell esophageal cancer.

35. The pharmaceutical composition according to claim 33 or 34, wherein the glioblastoma is a grade IV glioblastoma having the enzyme isocitrate dehydrogenase (IDH).

36. The pharmaceutical composition according to claim 35 for use in the treatment of natural IDH grade IV glioblastoma multiforme in subjects having methylation of the promoter of the methylguanine methyltransferase (Mgmt) gene.

37. The pharmaceutical composition according to any one of claims 33 to 36, wherein the salt is a sodium salt.

38. The pharmaceutical composition according to any one of claims 33 to 37, wherein the ester is a methyl ester or an ethyl ester.

39. The pharmaceutical composition according to any one of claims 33 to 38, wherein the compound, salt, or ester is administered in doses selected from the group consisting of 500 mg / day, 1000 mg / day, 1050 mg / day, 2000 mg / day, 2100 mg / day, 3150 mg / day, 4000 mg / day, 4200 mg / day, 6000 mg / day, 6300 mg / day, 8000 mg / day, 10000 mg / day, 12000 mg / day, 12600 mg / day, 14000 mg / day, and 16000 mg / day.

40. The pharmaceutical composition according to any one of claims 33 to 39, wherein the compound, salt, or ester is administered at a dose of 2100 mg / day.

41. The pharmaceutical composition according to any one of claims 33 to 39, wherein the compound, salt, or ester is administered at a dose of 12,000 mg / day.

42. The pharmaceutical composition according to any one of claims 33 to 41, further comprising a second chemotherapeutic agent selected from the group consisting of temozolomide, thiamine, gemcitabine, fluorouracil, oxyplatin, irinotecan, etoposide, imatinib, folfirinox, erlotinib, and cisplatin.

43. A pharmaceutical composition according to any one of claims 33 to 42, further comprising temozolomide for use in the treatment of glioblastoma.

44. The pharmaceutical composition according to claim 43, wherein the glioblastoma is a natural IDH grade IV glioblastoma multiforme.

45. A pharmaceutical composition for use in the treatment of neuropathic pain, comprising the compound 2-hydroxy-octadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, together with at least one pharmaceutically acceptable excipient or carrier, wherein the compound, salt, or ester is administered in a dose of 500 mg / day to 16000 mg / day.

46. The pharmaceutical composition according to claim 45, wherein the neuropathic pain is caused by nerve damage or nerve damage of the central nervous system and / or peripheral nervous system.

47. The pharmaceutical composition according to claim 46, wherein the nerve injury is spinal cord injury.

48. The pharmaceutical composition according to claim 45, wherein the neuropathic pain is caused by a cause selected from the group consisting of chemotherapeutic agents, antitumor agents, and cancer agents.

49. The pharmaceutical composition according to claim 48, wherein the antitumor agent is an alkaloid.

50. The pharmaceutical composition according to claim 49, wherein the alkaloid is vincristine.

51. The pharmaceutical composition according to claim 45, wherein the neuropathic pain is caused by a cause selected from the group consisting of diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, and hepatitis.

52. The pharmaceutical composition according to any one of claims 45 to 51, wherein the compound, salt, or ester is administered in doses selected from the group consisting of 500 mg / day, 1000 mg / day, 1050 mg / day, 2000 mg / day, 2100 mg / day, 4000 mg / day, 4200 mg / day, 6000 mg / day, 8000 mg / day, 10000 mg / day, 12000 mg / day, 14000 mg / day, and 16000 mg / day.

53. The pharmaceutical composition according to any one of claims 45 to 52, wherein the compound, salt, or ester is administered at a dose of 2100 mg / day.

54. The pharmaceutical composition according to any one of claims 45 to 52, wherein the compound, salt, or ester is administered at a dose of 4200 mg / day.

55. The pharmaceutical composition according to any one of claims 45 to 54, further comprising pregabalin, at least one other active ingredient selected from the group consisting of opioid analgesics, steroid analgesics, nonsteroidal analgesics, cannabinoid analgesics, anticonvulsants, anxiolytics, anesthetics, and antidepressants.

56. Lamotrigine, Omeprazole, Phenoxypentanoic acid, Metformin, Ibuprofen, Dalcolac, Alprazolam, Diazepam, Baclofen, Macrogol, Duloxetine, Levofloxacin, Gabapentin, Ceftriaxone, Enoxaparin, Pantoprazole, Paracetamol, Ipratropium bromide, Acetylcysteine, Metoclopramide, Metamisole, Teicoplanin, Dexketoprofen, Oxybutynin, Meropenem, beclomethasone dipropionate, formoterol fumarate, atorvastatin, calcifediol, paroxetine, cyanocobalamin, clonazepam, amlodipine, trazodone, flurazepam, thiazide, losartan, metamizole, sucralfate, lactitol, pancreatin, dimethicone, betanazole, amitriptyline, lorazepam, vitamin D, lormetazepam, solifenacin, simvastatin, sinita Prid, Quetiapine, Betamiga, Valproate, Lacosamide, Lidocaine, Metamizole, Finasteride, Acetylsalicylic acid, Enalapril, Metformin, Lilatizanidine, Trospium, Tramadol, Sercoxib, Citalopram, Sildenafil, Tamsulosin, Loratadine, Tizanidine, Vortioxetine, Zolpidem, Bromazepam, Dexamethasone, Dexketoprofen, Losartan, Eslicarbazepine, Pentoxin The pharmaceutical composition according to claim 55, further comprising at least one other active ingredient selected from the group consisting of sifilin, mirabegron, fluoxetine, chlorazepic acid, mirtazapine, rosuvastatin, prednisone, beclamethasone, methylprednisone, acyclovir, lignocaine, nystatin, delorazepam, alendronate, carbamazepine, cortisone, hydrocortisone, cannabidiol, and tetrahydrocannabinol.

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