Methods for the Treatment of Neurological Disorders

Abstract

Cisplatin is a potent chemotherapeutic drug that is widely used to treat various solid cancers. However, its clinical effectiveness is strongly limited by frequent and severe adverse effects such as nephrotoxicity. Therefore, there is an urgent medical need to identify novel strategies to limit cisplatin-induced pain. Here, the inventors have identified adenosine A, which is approved by the US Food and Drug Administration. 2A We provide evidence that the receptor antagonist istradefylline (KW-6002) significantly protects against cisplatin-induced neuropathy in a subchronic cisplatin treatment experimental model. In particular, the present invention provides a therapeutically effective dose of selective A 2A Adenosine receptor (A 2A The present invention relates to a method for the treatment of neuropathy (e.g. chemotherapy-induced neuropathy) in a subject in need thereof comprising administering to said subject an R) antagonist.

Description

[Technical field]

[0001] Field of the invention: The present invention relates to a method for the treatment of a neurological disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective A2A adenosine receptor (A2AR) antagonist.

[0002] Background of the invention: Neuropathy is defined by the International Association for the Study of Pain (IASP) as a functional disorder or pathological changes in one or several nerves (mononeuropathy or polyneuropathy, respectively). Neuropathy may be accompanied or not by pain (painless neuropathy or painful neuropathy, respectively). Neuropathy is induced by several factors, including but not limited to metabolic disorders (diabetic neuropathy), injuries or diseases affecting the nervous system (neurotrauma, stroke), hereditary (Guillain-Barre syndrome, Charcot-Marie-Tooth disease), viral infections and antiretroviral drugs (human immunodeficiency virus, herpes simplex virus), and cancer chemotherapy. The latter is called chemotherapy-induced peripheral neuropathy (CIPN). CIPN may limit the dose and choice of cytostatic drugs, delay further treatment cycles, or lead to the discontinuation of cytostatic therapy. Therefore, optimal chemotherapy treatment is altered and the survival chances of cancer patients are reduced. Symptoms range from early post-treatment pain such as paclitaxel to paresthesias, sensory ataxia, paresthesias (loss of sensation), tingling, and mechanical and cold allodynia. The extremities of the body are primarily affected, but neuropathy can progress along the limbs during repeated treatments. Substances that cause CIPN include the commonly used taxanes, platinum derivatives, and vinca alkaloids, as well as the more rarely used ixabepilone, bortezomib, and thalidomide.

[0003] There are no treatments for CIPN approved by the U.S. Food and Drug Administration (FDA). Preventive or curative interventions and identification of the underlying mechanisms causing CIPN will be important steps in improving adherence to cancer treatment and the quality of life of cancer survivors.

[0004] Platinum-based compounds, such as cisplatin, carboplatin, and oxaliplatin, bind to and damage DNA in rapidly dividing cells (e.g., cancer cells), triggering cell death. These drugs are used for nearly all types of solid tumors. All three are known to cause the classical symptoms of CIPN, but the incidence is higher for cisplatin and oxaliplatin. CIPN caused by cisplatin is more often irreversible than oxaliplatin cases. CIPN is the dose-limiting toxicity for both cisplatin and oxaliplatin. A number of candidate neuroprotective agents have been tested to reduce CIPN induced by cisplatin, but none of these agents have demonstrated the ability to prevent or limit cisplatin neurotoxicity.

[0005] Cisplatin is a potent antitumor agent that is widely used to treat various solid tumors, such as lung, ovarian, or testicular cancer, as well as certain forms of lymphoma (1). The antitumor effect of cisplatin requires its intracellular bioactivation by replacement of chloride with a water molecule, resulting in the formation of highly reactive molecules that bind to DNA and induce cytotoxic lesions in tumors (2). However, the unwanted accumulation of cisplatin in healthy cells may also trigger genotoxicity. Indeed, the clinical use of cisplatin is limited by a variety of severe adverse effects, including chemotherapy-induced peripheral neuropathy (CIPN) (3-5).

[0006] In clinical practice, CIPN is often considered a frequent but unavoidable adverse effect of cisplatin chemotherapy that should be tolerated by patients. (12) Therefore, there is an urgent medical need to alleviate peripheral neuropathy without interfering with the effectiveness of cisplatin in controlling tumor growth.

[0007] Adenosine plays a major role in intracellular and tissue homeostasis (13-15). Its physiological functions rely on four G protein-coupled receptors, namely A1, A2A, A2B, and A3 (16-19). Adenosine is important for several aspects of physiological functions. In this study, using a mouse model of acute and subchronic cisplatin administration, we unexpectedly observed that the US Food and Drug Administration-approved A2A receptor antagonist istradefylline (also known as KW-6002) attenuates pain hypersensitivity associated with CIPN while not altering but rather enhancing the antitumor properties of cisplatin. These data support the repurposing of istradefylline as a valuable preventive approach in patients undergoing treatment with cisplatin.

[0008] Summary of the invention: The present invention relates to a method for the treatment of chemotherapy-induced peripheral neuropathy (CIPN) in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a selective A2A adenosine receptor (A2AR) antagonist. In particular, the present invention is defined by the claims.

[0009] Detailed description of the invention: Cisplatin is a powerful chemotherapeutic drug that is widely used to treat various solid cancers. However, its clinical effectiveness is strongly limited by frequent and severe adverse effects, such as chemotherapy-induced peripheral neuropathy (CIPN). Therefore, there is an urgent medical need to identify novel strategies to limit neuropathy. Here, we provide evidence that the US Food and Drug Administration-approved adenosine A2A receptor antagonist istradefylline (KW-6002) significantly protects against neuropathic pain in a subchronic cisplatin intoxication experimental model. Importantly, we also demonstrate that the antitumor properties of cisplatin are not altered and can even be enhanced at the molecular level by istradefylline in tumor-bearing mice. Together, our results support the use of istradefylline as a novel and valuable preventive approach for the clinical management of patients undergoing treatment with cisplatin.

[0010] The present invention relates to a therapeutically effective amount of selective A 2A Adenosine receptor (A 2A The present invention relates to a method for the treatment of a neurological disorder in a subject in need thereof, comprising the step of administering to said subject an R) antagonist.

[0011] The present invention also provides a therapeutically effective amount of selective A 2A Adenosine receptor (A 2A The present invention also relates to a method for the treatment of chemotherapy-induced peripheral neuropathy (CIPN) in a subject in need thereof, comprising the step of administering to said subject an anti-cancer drug (ADR) antagonist.

[0012] The present invention relates to a method for the treatment of a neurological disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of istradefylline (KW-6002) or a derivative thereof.

[0013] The present invention also relates to a method for the treatment of chemotherapy-induced peripheral neuropathy (CIPN) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of istradefylline (KW-6002) or a derivative thereof.

[0014] The present invention also provides a selective A inhibitor for use in a subject in need thereof for the treatment of a neurological disorder. 2A Adenosine receptor (A 2A R) relating to antagonists.

[0015] In some embodiments, the present invention provides a selective ADP-1 inhibitor for use in a subject in need thereof for the treatment of chemotherapy-induced peripheral neuropathy. 2A Concerning adenosine receptor antagonists.

[0016] In some embodiments, the present invention relates to istradefylline (KW-6002) or a derivative thereof for use in a subject in need thereof for the treatment of a neurological disorder.

[0017] In some embodiments, the present invention relates to istradefylline (KW-6002) or a derivative thereof for use in a subject in need thereof for the treatment of chemotherapy-induced peripheral neuropathy.

[0018] The term "subject" as used herein refers to mammals, such as rodents, cats, dogs, and primates. In particular, the subject according to the present invention is a human. In particular, the subject according to the present invention is an adult. In particular, the subject according to the present invention is a child. In particular, the subject according to the present invention is a teenager. In particular, the subject according to the present invention is a newborn. The term "subject" as used herein includes "patient".

[0019] In some embodiments, the subject of the present invention is suffering from a neurological disorder.

[0020] The term "neuropathy" as used herein, also known as "peripheral neuropathy", refers to diseases that affect peripheral nerves, meaning nerves beyond the brain and spinal cord. Injury to peripheral nerves can induce pain or impair sensory, motor, glandular or organ function, depending on which nerve is affected; in other words, neuropathy affecting motor, sensory, or autonomic nerves causes different symptoms. More than one type of nerve may be affected at the same time. Peripheral neuropathy can be acute (with sudden onset, rapid progression) or chronic (symptoms begin subtly and progress slowly) and can be reversible or permanent. Common causes include systemic disease (e.g. diabetes or leprosy), hyperglycemia-induced glycation, vitamin deficiencies, medications (e.g. chemotherapy, or commonly prescribed antibiotics such as metronidazole and the fluoroquinolone antibiotics (e.g. ciprofloxacin, levofloxacin, moxifloxacin)), traumatic injury (including ischemia), radiation therapy, excessive alcohol consumption, immune system disorders, celiac disease, non-celiac gluten sensitivity, or viral infections. It may also be hereditary (present from birth) or idiopathic (with unknown cause).

[0021] In certain embodiments, the neuropathy is neuropathic pain or painless neuropathy.

[0022] Neuropathic pain, also known as painful neuropathy, is currently defined as pain initiated or caused by primary lesion or dysfunction in the nervous system.Nerve damage can be caused by trauma and disease, and therefore the term "neuropathic pain" encompasses many disorders with diverse etiologies.These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, CIPN, postherpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, immunodeficiency virus neuropathy, phantom limb pain, carpal tunnel syndrome, central poststroke pain, and chronic alcoholism-related pain, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy, and vitamin deficiency.Neuropathic pain is pathological because it has no protective role. Neuropathic pain is often present even after the original cause has disappeared, generally lasting for several years, and importantly reduces the patient's quality of life (Woolf and Mannion, 1999, Lancet, 353, 1959-1964). Neuropathic pain symptoms are difficult to treat because they are often heterogeneous even among patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). They include spontaneous pain (which may be persistent) and paroxysmal or abnormally evoked pain, such as hyperalgesia (increased sensitivity to noxious stimuli) and allodynia (sensitivity to normally non-noxious stimuli).

[0023] Neuropathies that affect only one nerve are called "mononeuropathy," while neuropathy involving nerves in roughly the same area on both sides of the body is called "symmetric polyneuropathy" or simply "polyneuropathy." When two or more (typically a few, but sometimes many) separate nerves in different areas of the body are affected, it is called "multiple mononeuritis," "multifocal mononeuropathy," or "multiple mononeuropathy."

[0024] Neuropathies can cause painful muscle spasms, fasciculations (fine muscle contractions), muscle loss, bone degeneration, and changes in the skin, hair, and nails.Furthermore, motor neuropathy can cause impaired balance and coordination, most commonly muscle weakness;sensory neuropathy can cause numbness to touch and vibration, decreased position sense causing worse coordination and balance, decreased sensitivity to temperature changes and pain, spontaneous tingling or burning pain, or cutaneous allodynia (severe pain from normally painless stimuli such as light touch);and autonomic neuropathy can produce a variety of symptoms depending on the glands and organs affected, but common symptoms are poor bladder control, abnormal blood pressure or heart rate, and decreased ability to sweat normally.

[0025] Treatment can be for any purpose, including therapeutic treatment of subjects suffering from neuropathy (e.g., chemotherapy-induced painful neuropathy), as well as prophylactic treatment of subjects not suffering from pain (e.g., subjects identified as being at high risk for pain).

[0026] In some embodiments, the subject of the present invention suffers from chemotherapy-induced peripheral neuropathy.

[0027] In certain embodiments, the methods of the present invention are suitable for the treatment of chemotherapy-induced peripheral neuropathy (CIPN).

[0028] In certain embodiments, the methods of the present invention are suitable for treating painful neuropathy associated with chemotherapy-induced peripheral neuropathy (CIPN).

[0029] The term "chemotherapy-induced peripheral neuropathy (CIPN)" as used herein refers to peripheral neuropathy induced by antitumor drugs, often referred to as cancer chemotherapy. The International Association for the Study of Pain defines neuropathy as a functional disorder or pathological change in one of several nerves, which may spread bilaterally. CIPN is primarily a sensory neuropathy that may involve motor and autonomic changes. CIPN symptoms usually appear late, i.e., weeks or months after the completion of chemotherapy, and their severity is usually proportional to the cumulative dose of the drug. Some patients experience a paradoxical worsening and / or intensification of symptoms after treatment cessation, as well as a phenomenon known as "coasting," in which mild neuropathy worsens or new CIPN develops. Pain and paresthesia may continue for months or even years after chemotherapy cessation.

[0030] Clinically, CIPN manifests as sensory, motor and / or autonomic dysfunction of varying intensity. Sensory symptoms usually occur first, affecting the feet and hands, and generally present with a classic "stocking-glove" neuropathy, with the most distal limbs generally exhibiting the greatest impairment. Symptoms include paresthesia, tingling, altered tactile sensations, vibration disturbances, paresthesias and dysesthesia, induced by touch and warm or cold temperatures. In addition, painful sensations (including spontaneous burning, lancinating or electric shock-like pain, as well as mechanical or thermal allodynia or hyperalgesia) occur frequently. In severe cases, these symptoms may progress to loss of sensory perception. Motor symptoms occur less frequently than sensory symptoms and are generally assumed to be in the form of distal muscle weakness, gait and balance disorders, and movement disorders. These symptoms have a significant and often underappreciated impact on quality of life and safety, e.g. cancer patients with CIPN are three times more likely to fall. In severe cases, CIPN can lead to motor paralysis, which can result in immobility and severe disability of the patient. Sensory neuropathy occurs more frequently than autonomic neuropathy, which usually includes orthostatic hypotension, constipation, and changes in sexual or urinary function (77).

[0031] The term "cancer" as used herein has its general meaning in the art and refers to a group of diseases involving abnormal cell growth that has the ability to invade or spread to other parts of the body. The term "cancer" further includes both primary and metastatic cancers. Examples of cancers that can be treated by the methods and compositions of the present invention include, but are not limited to, cancer cells originating from the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, digestive tract, gums, head, kidney, liver, lung, nasopharynx, cervix, ovary, prostate, skin, stomach, testes, tongue, or uterus. Furthermore, cancer may be classified as any of the following histological types, in particular: malignant neoplasm; cell carcinoma; undifferentiated cell carcinoma; giant cell and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial cell carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; malignant gastrinoma; cholangiocarcinoma; hepatocellular carcinoma; mixed hepatocellular and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenomatous intrapolypoid adenocarcinoma; familial polyposis coli adenocarcinoma; solid cell carcinoma; malignant carcinoma bronchiolar and alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe cell carcinoma; eosinophilic cell carcinoma; eosinophilic adenocarcinoma; basophilic cell carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma; Endometrioid carcinoma; skin adnexal carcinoma; apocrine carcinoma; sebaceous gland carcinoma; auditory canal adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma; papillary cystadenocarcinoma; papillary serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma; invasive ductal carcinoma; medullary carcinoma; lobular carcinoma; inflammation foetal carcinoma; Paget's disease of the breast; pancreatic acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma with squamous metaplasia; malignant thymoma; malignant ovarian stromal tumor; malignant theca cell tumor; malignant granulosa cell tumor; and malignant neuroblastoma; Sertoli cell carcinoma; malignant Leydig cell tumor; malignant lipid cell tumor; malignant paraganglioma; malignant extramammary paraganglioma; pheochromocytoma; malignant glomus tumor; malignant melanoma; amelanotic melanoma; superficial spreading malignant melanoma; malignant melanoma in giant pigmented nevus tumor;epithelioid cell malignant melanoma;malignant blue nevus;sarcoma;fibrosarcoma;malignant fibrous histiocytoma;myxosarcoma;liposarcoma;leiomyosarcoma;rhabdomyosarcoma;embryonal rhabdomyosarcoma;alveolar rhabdomyosarcoma;stromal sarcoma;malignant mixed tumor;Müllerian mixed tumor;nephroblastoma;hepatoblastoma;carcinosarcoma;malignant mesenchymoma;malignant Brenner tumor;malignant phyllodes tumor;synovial sarcoma;malignant mesothelioma;dysgerminoma;embryonal carcinoma;malignant teratoma;malignant ovarian goiter;choriocarcinoma;malignant mesonephroma;angiosarcoma;Malignant hemangioendothelioma;Kaposi's sarcoma;Malignant hemangiopericytoma;Lymphangiosarcoma;Osteosarcoma;Parocytic osteosarcoma;Chondrosarcoma;Malignant chondroblastoma;Mesenchymal chondrosarcoma;Giant cell tumor of bone;Ewing's sarcoma;Malignant odontogenic tumor;Ameloblastic sarcoma;Malignant ameloblastoma;Ameloblastic fibrosarcoma;Malignant pinealoma;Chordoma;Malignant glioma;Ependymoma;Protoplasmic astrocytoma;Fibrillary astrocytoma;Astroblastoma;Medulloblastoma;Glioblastoma;Oligodendroglioma;Oligodendroglioma;Anaplastic neuroectodermal tumor;Cerebellar sarcoma;Ganglioblastoma;Neuroblastoma;Retinoblastoma;Olfactory neurogenic tumor;Malignant meningioma;Neurofibrosarcoma;Malignant The tumor may be, but is not limited to, schwannoma; malignant granular cell tumor; malignant lymphoma; Hodgkin's disease; Hodgkin's lymphoma; lateral granuloma; small lymphocytic lymphoma; diffuse large cell malignant lymphoma; follicular malignant lymphoma; mycosis fungoides; other specified non-Hodgkin's lymphoma; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphocytic leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia.

[0032] As used herein, the terms "treatment", "treat" and "treating" refer to reversing, alleviating, inhibiting the progression of a disease or disorder (i.e., pain) as described herein, or delaying, eliminating or reducing the occurrence or onset of a disorder or disease as described herein, compared to what would occur if no action was taken. As used herein, the terms "prevention" or "prophylactic use" and "prophylactic treatment" refer to any medical or public health procedure whose purpose is to prevent a disease (i.e., pain) as disclosed herein. As used herein, the terms "prevent", "prevention" and "preventing" refer to the reduction of the risk of acquiring or developing a given condition (i.e., pain), or the reduction or suppression of recurrence or the condition (i.e., pain) in a subject who is not ill but has been ill or has been in close proximity to a subject who has the condition (i.e., pain).

[0033] In some embodiments, the prophylactic methods of the present invention are particularly suitable for subjects identified as being at high risk for neuropathy and / or CIPN.Typically, subjects at risk for pain include patients who will undergo emergency surgery.

[0034] The compound of the present invention can be used as a drug.The compound is useful for treating neuropathy, such as chemotherapy-induced peripheral neuropathy (CIPN).

[0035] As used herein, "A 2A Adenosine receptor receptors (A 2A The term adenosine receptor (ADR), also called ADORA2A or RDC8, refers to the adenosine receptor and also refers to the human gene encoding it. The protein is a member of the G protein-coupled receptor (GPCR) family, with seven transmembrane α-helices and an extracellular N-terminus and an intracellular C-terminus. The protein plays an important role in many biological functions, such as regulating heart rate and circulation, cerebral and renal blood flow, immune function, pain, and sleep. It is also involved in pathophysiological conditions, such as inflammatory diseases and disorders.

[0036] As used herein, the term "antagonist" or "inhibitor" refers to an agent (i.e., a molecule) that inhibits or blocks the activity of a receptor. For example, an antagonist refers to a molecule that inhibits or blocks the activity of a receptor.

[0037] As used herein, A 2A The term "biological activity" of adenosine receptors refers to cisplatin-induced pain hypersensitivity associated with significant downregulation of Tnf in the spinal cord, and IL6 and tumor necrosis factor expression in the dorsal root ganglion (DRG).

[0038] Option A 2A Tests for determining the ability of a compound to be an A R antagonist are well known to those skilled in the art. In a preferred embodiment, the selective antagonist is 2Ain a manner sufficient to inhibit the biological activity of R. 2A Binds specifically to R. A 2A Bonds to R and A 2A Inhibition of the biological activity of R can be determined by any competitive assay known in the art. For example, the assay can be performed using a selective A 2A As an R antagonist, the substance to be tested is an A 2A The binding ability can consist of determining the ability of the antibody to bind to R. The binding ability is reflected by measuring Kd. As used herein, the term "KD" is meant to refer to the dissociation constant, which is obtained from the ratio of Kd to Ka (i.e., Kd / Ka) and expressed as a molar concentration (M). The KD value for binding to a biomolecule can be determined using methods well established in the art. In a specific embodiment, the binding ability of the antibody "A" is determined by measuring the binding ability of the antibody "A". 2A A selective antagonist that specifically binds to human Aβ with a KD of 1 μM or less, 100 nM or less, 10 nM or less, or 3 nM or less. 2A A competitive assay is then set up to determine whether the substance is an inhibitor of A 2A The ability of the selective A to inhibit the biological activity of R may be determined. Functional assays such as the assessment of the ability to reduce cisplatin-induced pain hypersensitivity associated with significant downregulation of Tnf in the spinal cord and expression of IL6 and Tnf in the dorsal root ganglion (DRG) may be considered. 2A R antagonist, A 2A Neutralizing, blocking, inhibiting, eliminating, reducing or interfering with the biological activity of R can be readily determined.

[0039] In some embodiments, the selective antagonists of the present invention (i.e., selective A 2A R antagonist) is A 2A It acts through direct interaction with adenosine receptors.

[0040] As used herein, the term "neuropathy-reducing agent" refers to a pharma- ceutically acceptable compound or composition that, when administered to a subject, can reduce at least one parameter selected therefrom. In some instances, the neuropathy-reducing agent is a selective A 2A It is an adenosine receptor (A2AR) antagonist.

[0041] As used herein, "A 2A Adenosine receptor (A 2A The term "R) antagonist" is used in 2A In some embodiments, the selective A of the present invention is 2A Receptor antagonists can be used to reduce pain (e.g., neuropathy).These selective antagonists can be used to reduce the neuropathy induced by a single dose of chemotherapy drugs as described above; the drugs are active for several days after administration.

[0042] As used herein, the term "selective antagonist" refers to a selective A 2A The selective antagonist according to the present invention is an abbreviation of "adenosine receptor antagonist". 2A Refers to an antagonist that specifically targets adenosine receptors.

[0043] As used herein, the term "derivative" refers to a derivative that is a derivative of the base compound (i.e., selective A 2A antagonists), meaning that they share a core structural component.

[0044] As used herein, the term "analog" refers to a compound that is structurally and functionally related to another compound; the compound and the analog share a high degree of structural similarity and have similar biological functions.

[0045] In some embodiments, the selective A 2AThe adenosine receptor antagonist is preferably selected from among istradefylline (KW-6002) or a derivative thereof, MSX-3, SCH-58261, NIR178 (also known as PBF-509), ciforadenant, AB928, AZD4635, EOS100850, inupadenant (EOS-850), EXS21546, TT-10 and TT-53, and pharma- ceutically acceptable salts thereof. Preferably, in all embodiments, the selective A 2A The adenosine receptor antagonist is preferably selected from among istradefylline (KW-6002) or a derivative thereof, MSX-3, SCH-58261, tozadenant (SYN115), preladenant (SCH-420814), NIR178 (also known as PBF-509), ciforadenant, AB928, AZD4635, EOS100850, inupadenant (EOS-850), EXS21546, TT-10 and TT-53. 2A Receptor (A 2A Examples of substituted purine compounds that act as R) antagonists or derivatives thereof also include compounds disclosed in International Patent Application No. WO2021179074. For example, WO2021179074 includes the following compounds: [ka] [ka] [ka]

[0046] These selective antagonists have demonstrated their effectiveness in reducing neurological damage. They can be used alone, sequentially or in a mixture of at least two antagonists.

[0047] In some embodiments, the present invention also relates to a selective A inhibitor selected from among istradefylline (KW-6002) or a derivative thereof, MSX-3, SCH-58261, NIR178 (also known as PBF-509), ciforadenant, AB928, AZD4635, EOS100850, inupadenant (EOS-850), EXS21546, TT-10 and TT-53 for use as a neuropathy reducing agent in the treatment of chemotherapy-induced painful neuropathy. 2A Concerning adenosine receptor antagonists.

[0048] As used herein, the term "KW-6002," also known as istradefylline, refers to 8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione. KW-6002 has the following CAS number: 155270-99-8 and the following chemical formula: [ka] It has.

[0049] As used herein, the term "MSX-3" refers to 3,7-dihydro-8-[(1E)-2-(3-methoxyphenyl)ethenyl]-7-methyl-3-[3-(phosphonooxy)propyl-1-(2-propynyl)-1H-purine-2,6-dione disodium salt hydrate. MSX-3 has the following CAS number: 261717-23-1 and the following chemical formula: [ka] It has.

[0050] As used herein, the term "SCH-58261" refers to 2-(2-furanyl)-7-(2-phenylethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine. SCH-58261 has the following CAS number: 160098-96-4 and the following chemical formula: [ka] It has.

[0051] As used herein, the term "tozadenant" refers to 4-hydroxy-N-(4-methoxy-7-morpholin-4-yl-1,3-benzothiazol-2-yl)-4-methylpiperidine-1-carboxamide. Tozadenant has the following CAS number: 870070-55-6 and the following chemical formula: [ka] It has.

[0052] As used herein, the term "preladenant" refers to 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine. Preladenant has the following CAS number: 377727-87-2 and the following chemical formula: [ka] It has.

[0053] As used herein, the term "NIR178," also known as "taminadenanth" or "PBF-509," refers to 5-bromo-2,6-di(pyrazol-1-yl)pyrimidin-4-amine. NIR178 has the following CAS number: 1337962-47-6 and the following chemical formula: [ka] It has.

[0054] As used herein, the term "sifoladenant" refers to (S)-7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine. Sifoladenant has the following CAS number: 1202402-40-1 and the following chemical formula: [ka] It has.

[0055] As used herein, the term "etrmadenant," also known as "AB928," refers to 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile. AB928 has the following CAS number: 2239273-34-6 and the following chemical formula: [ka] It has.

[0056] As used herein, the term "imaladennant," also known as "AZD4635," refers to 6-(2-chloro-6-methyl-4-pyridinyl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine. Imaladenant has the following CAS number: 1321514-06-0 and the following chemical formula: [ka] It has.

[0057] As used herein, the term "EOS100850" refers to (+)-5-amino-3-{2-[4-(2,4-difluoro-5-{2-[(S)-methanesulfinyl]ethoxy}phenyl)piperazin-1-yl]ethyl}-8-(furan-2-yl)[1,3]thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one hydrochloride. EOS100850 has the following CAS number: 2411004-22-1 and the following chemical formula: [ka] It has.

[0058] As used herein, the term "inupadenant", also known as "ES-850", refers to 7-amino-10-[2-[4-[2,4-difluoro-5-[2-[(S)-methylsulfinyl]ethoxy]phenyl]piperazin-1-yl]ethyl]-4-(furan-2-yl)-12-thia-3,5,6,8,10-pentazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7-tetraen-11-one. Inupadenant has the following CAS number: 2246607-08-7 and the following chemical formula: [ka] It has.

[0059] As used herein, the term "TT-10" refers to (2-(allylamino)-4-aminothiazol-5-yl)(5-fluorothiophen-2-yl)methanone. TT-10 has the following CAS number: 2230640-94-3 and the following chemical formula: [ka] It has.

[0060] As used herein, the term "EXS21546" refers to an A2AR selective antagonist that does not penetrate the central nervous system, manufactured by Exscientia, Inc. (Proof-of-Concept Identifier: NCT04727138).

[0061] As used herein, the term "TT-53" refers to a selective adenosine receptor antagonist manufactured by Tarus therapeutics.

[0062] The present invention also relates to a selective A combination with a chemotherapeutic agent. 2A Use of adenosine receptor antagonists In some embodiments, the therapeutic use of chemotherapeutic agents induces the development of CIPN associated with pain hypersensitivity.

[0063] The term "chemotherapy" as used herein has its general meaning in the art and refers to treatment consisting of administering to a patient a chemotherapeutic agent. Chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylmelamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; acetogenins (particularly bullatacin and bullatacinone); camptothecins (such as the synthetic analog topotecan); bryostatins; kallistatin; CC-1065 (e.g., its adozelesin, carzelesin, and bizelesin synthetic analogs); cryptophycins (especially cryptophycin I and cryptophycin 8); dolastatins; duocarmycins (e.g., synthetic analogues, such as KW-2189 and CBI-TMI; eleutherobin; pancratistatin; sarcodictyin; spongiostatin; nitrogen mustards, such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novoenbiquine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitroureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics, such as enediyne antibiotics (e.g. calicheamicin, especially calicheamicin gamma 11 and calicheamicin omega 11; dynemicins, such as dynemicin A; bisphosphonates, such as clodronate; esperamicin;and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carubicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (e.g. morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, Esorubicin, Idarubicin, Marcelomycin, Mitomycins such as Mitomycin C, Mycophenolic acid, Nogalamycin, Olivomycin, Peplomycin, Potfilomycin, Puromycin, Querramycin, Lodorubicin, Streptonigrin, Streptozocin, Tubercidin, Ubenimex, Zinostatin, Zorubicin; Antimetabolites such as Methotrexate and 5-Fluorouracil (5-FU); Folic acid analogues such as Denopterin, Methotrexate, Pteropterin, Trimetrexate; Purine analogues such as Fludarabi purines, 6-mercaptopurine, thiamiprine, thioguanine;pyrimidine analogues, e.g. ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens, e.g. calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone;antiadrenal drugs, e.g. aminoglutethimide, mitotane, trilostane;folic acid supplements, e.g. folinic acid;aceglatone;aldophosphamide glycosides;aminolevulinic acid;eniluratone Sil; Amsacrine; Bestravsil; Bisantrene; Edatrexate; Defofamine; Demecolcine; Diaziquone; Eflornithine; Elliptinium acetate; Epothilone; Etoglucide; Gallium acetate; Hydroxyurea; Lentinan; Lonidamine; Maytansinoids, such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidamol: Nitracrine; Pentostatin; Phenamet; Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK polysaccharide complex); Razoxane; Rhizoxin;Schizofuran;spirogermanium;tenuazonic acid;triaziquone;2,2',2''-trichlorotriethylamine;trichothecenes (especially T-2 toxin, verrucarin A, roridin A, and anguidin);urethane;vindesine;dacarbazine;mannomustine;mitobronitol;mitolactol;pipobroman;gacytosine;arabinosides ("Ara-C");cyclophosphamide;thiotepa;taxoids, such as paclitaxel and docetaxel;chlorambucil;gemcitabine;6-thioguanine;mercaptopurine;methotrexate;platinum coordination complexes, such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitors RFS2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0064] As used herein, the term "chemotherapeutic agent" refers to any pharma- ceutically acceptable composition that is therapeutically or pharma- ceutical effective in treating cancer. A chemotherapeutic agent can be, for example, a DNA alkylating agent.

[0065] In some embodiments, the chemotherapeutic agent is selected from among DNA alkylating agents, particularly from among platinum-containing chemotherapeutic agents, more particularly from among cisplatin, carboplatin, oxaliplatin, and pharma- ceutically acceptable salts thereof.

[0066] In particular, the therapeutic use of cisplatin is the development of cisplatin-induced pain hypersensitivity (CIPN, in particular pain hypersensitivity).

[0067] As used herein, the term "cisplatin" refers to cis-diamminedichloroplatinum(II), a drug used in chemotherapy primarily because it blocks DNA synthesis and induces apoptosis through a p53-mediated mechanism of action. Cisplatin has the following CAS number: 15663-27-1 and the following chemical formula: [ka] It has.

[0068] As used herein, the term "oxaliplatin" refers to [(1R,2R)-cyclohexane-1,2-diamine](ethanedioate-O,O')platinum(II). Oxaliplatin has the following CAS number: 63121-00-6 and the following chemical formula: [ka] It has.

[0069] As used herein, the term "carboplatin" refers to cis-diammine(cyclobutane-1,1-dicarboxylate-O,O')platinum(II). Carboplatin has the following CAS number: 41575-94-4 and the following chemical formula: [ka] It has.

[0070] As used herein, "A 2A The term "capable of inducing overexpression of adenosine receptors" refers to a drug that, when administered in a given amount and in a pharmacologic effective amount or dose, e.g., can induce overexpression of adenosine receptors. 2A Relative expression of adenosine receptors means 1-fold or greater, more particularly 1.1-fold or greater.

[0071] As used herein, the term "administering" or "administration" refers to administering a substance (as it exists outside the body) (e.g., selective A 2A Adenosine receptor (A 2A R) antagonist) to a subject, for example, by mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery, and / or any other physical delivery method described herein or known in the art. When a disease or its symptoms are treated, the administration of the substance is typically performed after the onset of the disease or its symptoms. When a disease or its symptoms are prevented, the administration of the substance is typically performed before the onset of the disease or its symptoms.

[0072] "Therapeutically effective amount" refers to an amount effective at a dosage and for a period of time necessary to achieve a desired therapeutic result. The therapeutically effective amount of a drug may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of the drug to elicit a desired response in the individual. A therapeutically effective amount is also an amount in which any toxic or adverse effects of the antibody or portion of the antibody are outweighed by the therapeutically beneficial effects. The effective dose and dosage regimen for a drug depends on the disease or condition to be treated and can be determined by one of ordinary skill in the art. A physician of ordinary skill in the art can easily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician can start a dose of a drug used in a pharmaceutical composition at a level lower than required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved. In general, an appropriate dose of the composition of the present invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect according to a particular dosage regimen. Such an effective dose will generally depend on the factors described above. For example, a therapeutically effective amount for therapeutic use can be measured by its ability to stabilize the progression of a disease. Those skilled in the art will be able to determine such amounts based on such factors as the patient's size, the severity of the subject's symptoms, and the specific composition or route of administration selected. An exemplary, non-limiting range for a therapeutically effective amount of a drug is about 0.1-100 mg / kg, such as about 0.1-50 mg / kg, such as about 0.1-20 mg / kg, such as about 0.1 mg-10 mg / kg, such as about 0.5, such as about 0.3, about 1, about 3 mg / kg, about 5 mg / kg, or about 8 mg / kg. Administration can be, for example, intravenous, intramuscular, intraperitoneal, or subcutaneous, and can be administered, for example, near the target site. The dosage regimen in the above methods of treatment and use is adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus can be administered, or several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. In some embodiments, the effectiveness of treatment is monitored, eg, at predetermined time points, during therapy.As a non-limiting example, the treatment according to the present invention may be carried out in an amount of about 0.1 to 100 mg / kg per day, e.g., 0.2, 0.5, 0.9, 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg / kg per day, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg / kg per day, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 1 A single or divided dose may be provided every 24, 12, 8, 6, 4 or 2 hours, or any combination thereof, on at least one day of the 5th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, 36th, 37th, 38th, 39th or 40th day, or alternatively for at least one week of the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th or 20th week, or any combination thereof.

[0073] In some embodiments, the selective A 2A The therapeutically effective amount of the adenosine receptor antagonist may be equal to or greater than 10 mg, and may be equal to or less than 350 mg, in particular equal to 20 mg, 21 mg, 30 mg, 35 mg, 40 mg, 60 mg, 70 mg, 100 mg, or 120 mg, 160 mg, 180 mg, 210 mg, or 240 mg. 2A When the adenosine receptor antagonist is KW-6002 or a derivative thereof, its therapeutically effective amount is preferably below the maximum value, which may be equal to 60 mg or more to 230 mg, more preferably 70 mg or more, or equal to 210 mg or less. As explained later in this specification, when the amount of this particular selective antagonist exceeds a threshold value, it is no longer active as a pain reducer (e.g., neuropathy reducer), particularly in reducing cisplatin-induced pain (e.g., cisplatin-induced neuropathy).

[0074] In some embodiments, the therapeutically effective amount of the chemotherapeutic agent can be equal to 80 mg or more and equal to 1400 mg or less, particularly 140 mg, 147 mg, 630 mg, 692 mg, and 700 mg. When the chemotherapeutic agent contains cisplatin as an active compound, particularly when the drug contains cisplatin as the only active compound, particularly suitable values ​​are 140 mg, 700 mg, and 1400 mg.

[0075] The term "combination" as used herein is intended to refer to all dosage forms that provide a first drug together with other (second, third) drugs. The drugs may be administered simultaneously, separately, or sequentially in any order. According to the present invention, the drug is administered to the subject using any suitable method that allows the drug to reach the chondrocytes of the bone growth plate. In some embodiments, the drug is administered to the subject systemically (i.e., via systemic administration). Thus, in some embodiments, the drug is administered to the subject so that it enters the circulatory system and is distributed throughout the body. In some embodiments, the drug is administered to the subject by local administration, for example, by local administration to growing bone.

[0076] As used herein, the term "combination treatment," "combination therapy," or "combination of therapies" refers to treatment using more than one drug therapy. The combination therapy can be a dual therapy or a two-drug combination therapy.

[0077] As used herein, the term "concurrent administration" refers to administration of two active ingredients by the same route at the same time or substantially the same time. The term "separate administration" refers to administration of two active ingredients by different routes at the same time or substantially the same time. The term "sequential administration" refers to administration of two active ingredients at different times, where the routes of administration are the same or different.

[0078] In some embodiments, the selective A 2AThe adenosine receptor antagonist will be administered prior to administration of the chemotherapeutic agent, at least one hour prior to administration of the chemotherapeutic agent.

[0079] In some embodiments, the chemotherapy drug can be administered in one dose. In this case, the selective antagonist can be administered before, preferably at least 1 hour before, the administration of the chemotherapy drug. It can also be administered before or after the administration of the chemotherapy drug. For example, it can be administered at least once, the day after the administration of the chemotherapy drug, for example, once a day, for 1, 2, 5, or 8 days after the administration of the chemotherapy drug. In particular, when the chemotherapy drug contains cisplatin as an active compound, preferably as the only anticancer active compound and as the only active compound, the chemotherapy drug is administered several times, once a day for several days, for example (for example, once a day for a week), and the selective antagonist is preferably administered before, for example, at least 1 hour before, each administration of the chemotherapy drug. The selective antagonist can also be administered once a day, after the last administration of the chemotherapy drug, in particular for at least 1 or 2 days after the last administration of the chemotherapy drug, for example, for 5 days after the last administration of the chemotherapy drug.

[0080] The present invention provides a therapeutically effective amount of a selective A 2A Adenosine receptor (A 2A R) The present invention also relates to combinations of antagonists with chemotherapeutic agents.

[0081] In a particular embodiment, the present invention relates to a therapeutically effective amount of KW-6002 or a derivative thereof in combination with cisplatin for use in the treatment of neurological disorders (eg, CIPN).

[0082] The present invention also provides a method for treating neurological disorders (e.g., CIPN) comprising administering to a patient a therapeutically effective amount of at least one of the following compounds: 2A Adenosine receptor (A 2A R) antagonists and ii) chemotherapeutic agents.

[0083] In a particular embodiment, the present invention relates to i) KW-6002 or a derivative thereof and ii) cisplatin for simultaneous, separate or sequential use in the treatment of neurological disorders (eg, CIPN).

[0084] The present invention also provides a therapeutically effective amount of selective A 2A Adenosine receptor (A 2A The present invention relates to a pharmaceutical composition comprising a selective A R antagonist and a chemotherapeutic agent. 2A Adenosine receptor (A 2A R) The antagonist is KW-6002 or a derivative thereof and the chemotherapeutic agent is cisplatin.

[0085] More particularly, the pharmaceutical compositions according to the present invention are suitable for treating neuropathy, such as chemotherapy-induced painful neuropathy.

[0086] Option A as defined above 2A Adenosine receptor (A 2A The R) antagonist and / or chemotherapeutic agent, as well as the pharmaceutical composition according to the invention as described above, may be combined with a pharma- ceutically acceptable excipient, optionally with a sustained release matrix, such as a biodegradable polymer, to form a pharmaceutical composition.

[0087] Selection A as above 2A Adenosine receptor (A 2AR) antagonists and / or chemotherapeutic agents may be formulated with pharma- ceutically acceptable excipients, optionally with sustained release matrices, such as biodegradable polymers, to form pharmaceutical compositions. "Pharmaceutically" or "pharmaceutical acceptable" refers to molecular entities and compositions that do not produce adverse, allergic or other undesirable reactions when administered appropriately to a mammal, particularly a human. A pharma- ceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any kind. In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, parenteral, topical or rectal administration, the active ingredient may be administered to animals and humans, alone or in combination with another active ingredient, in unit dosage form, in admixture with conventional pharmaceutical supports. Suitable unit dosage forms include oral route dosage forms, such as tablets, gel capsules, powders, granules, and oral suspensions or solutions, sublingual and buccal dosage forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal, parenteral, and intranasal dosage forms, and rectal dosage forms. Typically, pharmaceutical compositions contain a vehicle that is pharma- ceutically acceptable for injectable formulations. These may be, in particular, isotonic and sterile saline solutions (such as monosodium or di-sodium phosphate, sodium chloride, potassium chloride, calcium chloride or magnesium chloride, or mixtures of such salts), or dried, in particular lyophilized, compositions that allow the reconstitution of an injection solution when sterile water or saline is added, as the case may be. Pharmaceutical dosage forms suitable for injection use include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the dosage form must be sterile and fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. Solutions containing the compounds of the present invention as free bases or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, as well as in oils. Under normal conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms. The polypeptide (or the nucleic acid encoding it) may be formulated into the composition in neutral or salt form. Pharmaceutically acceptable salts include acid addition salts (formed with the free amino groups of the protein), which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acid, or organic acids such as acetic, oxalic, tartaric, mandelic acid. Salts formed with free carboxyl groups may also be derived from inorganic bases such as, for example, sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, or ferric hydroxide, and organic bases such as isopropylamine, trimethylamine, histidine, procaine, and the like. The carrier may also be a solvent or dispersion medium, including, for example, water, ethanol, polyol (such as, for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of injectable compositions can be brought about by including in the composition substances that delay absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active polypeptide in the required amount in the appropriate solvent with several other ingredients as enumerated above, as required, followed by sterilization filtration. In general, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle that contains the basic dispersion medium and the other ingredients as enumerated above.In the case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods are vacuum drying and freeze-drying techniques, which produce a powder of the active ingredient and any additional desired ingredients from the solution thereof that has previously been sterile filtered. When formulated, the solution will be administered in a manner compatible with the dosage formulation and in a therapeutically effective amount. The formulation is easily administered in a variety of dosage forms, such as the types of injectable solutions described above, although drug release capsules and the like may also be used. For parenteral administration in aqueous solutions, for example, the solution should be suitably buffered if necessary, and the liquid diluent should first be made isotonic with sufficient saline or dextrose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. In this regard, the sterile aqueous media that can be used will be known to those of skill in the art in light of the present disclosure. For example, one dose can be dissolved in 1 ml of isotonic NaCl solution and added to 1000 ml of liquid for subcutaneous infusion therapy, or injected at the proposed infusion site. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person administering will, in any event, determine the appropriate dose for the individual subject.

[0088] The present invention will be further illustrated by the following figures and examples, which should not, however, be construed as limiting the scope of the present invention in any way. [Brief description of the drawings]

[0089] [Figure 1]Prophylactic treatment with KW-6002 reduces pain hypersensitivity and cytokine upregulation induced by cisplatin. (A) Mechanical sensitivity measured by von Frey hairs in mice in response to cisplatin and / or KW6002 in the subchronic paradigm described in Figure 2. Arrows indicate injection of cisplatin and / or PBS. Data and results are presented as mean ± SEM. ***p<0.001 vs. cisplatin (n=5 / group; 2-way ANOVA followed by Tukey post-hoc test). IL6 and tumor necrosis factor mRNA levels in spinal cord (B-C) and dorsal root ganglion (D-E) 8 days after the start of cisplatin treatment. Data and results are presented as mean ± SEM. *p<0.05 vs. cisplatin (n=5 / group; 1-way ANOVA followed by Tukey post-hoc test). (F and G) mRNA levels of IL1b (F) and Ccl2 (G) in dorsal root ganglia 8 days after the start of cisplatin treatment. Data are means ± SEM. *p<0.05 vs. vehicle; **p<0.01 vs. cisplatin; two-way ANOVA (n=5 / group). [Diagram 2] Illustrated animal procedure. Dosing schedule of KW-6002 in the subchronic model. C57BL6 / J 8-week-old male mice were randomized into four groups: vehicle, KW-6002, cisplatin, or KW-6002 / cisplatin. Cisplatin was administered (3 mg / kg) for 6 days and sacrificed 72 hours after the last injection. The first dose of KW-6002 (3 mg / kg) was administered 5 days before treatment with cisplatin and was administered once daily until sacrifice. [Diagram 3]KW6002 prevents nephrotoxicity and neurotoxicity without attenuating the antitumor properties of cisplatin in a mEERL syngeneic in vivo mouse model. (A-C) KW6002 attenuated cisplatin-induced nephrotoxicity as estimated by mRNA levels of KIM1 (A) and the inflammatory markers tumor necrosis factor and IL6 (B and C). *p<0.05 and ***p<0.001 vs. vehicle; *p<0.01 and **p<0.01 vs. cisplatin; one-way ANOVA (n=5-6 mice / group). (D) Mechanical sensitivity measured by von Frey hairs in mice in response to cisplatin and / or KW6002. Arrows indicate injection of cisplatin and / or PBS. Data and results are mean ± SEM. ***p<0.001 vs. vehicle; ***p<0.001 vs. cisplatin; two-way ANOVA (n=5 animals / group). (E) Absolute tumor size in different groups of animals. Results are shown as mean ± SEM. ***p<0.001 vs. vehicle; *p<0.05 vs. cisplatin; two-way ANOVA (n=5-6 animals / group).

[0090] Working Example: Materials and Methods Animals and treatments Animal experiments were adapted from 63–63. Animal procedures were performed on 8–10 week old male C57Bl6 / J mice (Janvier Institute, Jackson Laboratory, except for pain experiments). Mice were fed standard laboratory chow with water and food ad libitum and kept under constant environmental conditions with a 12-h light / dark cycle. Istradefylline (KW-6002; Tocris) was dissolved in a carrier solution consisting of 15% DMSO, 15% Cremophor (Sigma), and 70% saline solution (vehicle). Cisplatin (Accord Healthcare) was dissolved in saline solution. Neuropathy resulting from subchronic cisplatin was evaluated after six intraperitoneal injections of cisplatin (3 mg / kg) once a day starting on day 0, and mice were sacrificed 72 h after the last injection of cisplatin (day 8). KW-6002 was administered intraperitoneally once daily from day −5 to day 7 ( Fig. 2 ).

[0091] mEERL in vivo tumor model We used a validated human papillomavirus-positive oropharyngeal squamous cell carcinoma mouse model (not for sale) as previously described (80). This model consists of oropharyngeal epithelial cells derived from C57Bl / 6 male mice stably expressing human papillomavirus 16 viral oncogenes E6 and E7, H-Ras, and luciferase (mEERL cells). mEERL cells were grown to confluence in T75 flasks, after which the cells were trypsinized, harvested, washed three times with sterile PBS, and resuspended in 1 mL of sterile PBS to the appropriate concentration. Mice were injected subcutaneously into the right flank with 20 μL of a solution containing either 1,000,000 mEERL cells or PBS (vehicle). The day of injection of mEERL cells is indicated as day -14. Tumor volumes were monitored using Vernier digital calipers. Tumors with a volume of 100 mm were cultured at 100°C for 1 h. 3 Once this was reached, mice were randomly assigned to one of three experimental groups (vehicle; cisplatin; or cisplatin plus KW6002).

[0092] Behavioral assessment Mechanical pain sensitivity, a classical readout of CIPN in rodents, was assessed using von Frey filaments as previously described (65-66). Briefly, mice were placed in opaque boxes (10 × 10 × 10 cm). After a 30 min rearing period, von Frey filaments were applied and paw withdrawal thresholds were calculated using the "up and down" method. Behavioral testing was performed by an experimenter blinded to treatment and genotype.

[0093] Sample collection Lumbar dorsal root ganglion (DRG) and spinal cord tissues were rapidly dissected and snap frozen in liquid nitrogen.

[0094] RNA extraction For dorsal root ganglion and spinal cord tissues, total RNA was extracted with phenol / chloroform followed by precipitation in isopropanol as previously described ( 71 ).

[0095] Quantitative reverse transcription PCR Reverse transcription was performed on 1 μg of RNA using the High Capacity cDNA Reverse Transcription Kit (Thermo Fisher) according to the manufacturer's recommendations. Real-time PCR was performed on a StepOne instrument using the Taqman Gene Expression Master Mix (Thermo Fisher) according to the manufacturer's recommendations. Expression levels of the following genes were assessed using the comparative CT method (2ΔCT): tumor necrosis factor alpha (TNFα, assay identification number Mm00443258_m1), interleukin-6 (IL6, assay identification number Mm00446190_m1), IL1b (assay identification number Mm00434228_m1), chemokine (CC motif) ligand 2 (Ccl2, assay identification number Mm00441242_m1). Transcription levels of PPIA (peptidyl propyl isomerase A) (Mm02342430_m1) were used as an endogenous control.

[0096] statistics All data are presented as mean ± SEM. Differences between groups were assessed using two-tailed Student's t-test, one-way ANOVA followed by multiple comparison Tukey post-hoc test, or repeated measures two-way ANOVA using Prism (GraphPad Software). Differences were considered statistically significant at p<0.05. Numbers of biologically independent experiments, sample sizes, p-values, and statistical tests are all indicated in the text or figure legends.

[0097] result Antagonism of A2A receptors limits cisplatin-induced pain hypersensitivity An important limitation in the therapeutic use of cisplatin is the occurrence of chemotherapy-induced peripheral neuropathy, especially pain hypersensitivity (Sisignano, 2014; Krukowski et al., 2017). To evaluate whether KW-6002 reduces cisplatin-induced pain hypersensitivity and associated proinflammatory cytokines in the DRG and spinal cord, mice were treated with cisplatin and KW-6002 as described above (Figure 2). Interestingly, treatment with KW-6002 significantly alleviated pain hypersensitivity (Figure 1A). When we determined the effect of A2A receptor antagonists on cisplatin-induced IL6 and tumor necrosis factor expression in the dorsal root ganglion and spinal cord, we found that KW-6002 significantly downregulated tumor necrosis factor expression in the spinal cord as well as tumor necrosis factor expression in the dorsal root ganglion (Figure 1B to Figure 1E). We found that treatment with KW-6002 significantly reversed the upregulation of IL1b and Ccl2 in dorsal root ganglia (Figures 1F and 1G), two cytokines known to contribute to chemotherapy-induced peripheral neuropathy (78, 79).

[0098] A2A receptor antagonism protects against cisplatin-induced nephrotoxicity and CIPN while enhancing tumor growth control in a syngeneic model of human papillomavirus-positive squamous cell carcinoma We used an additional cancer mouse model to verify the renal and neuroprotective effects of KW6002 in the context of tumors (80). Subcutaneous mEERL cells were injected into C57Bl6 / J mice, which were then treated with cisplatin alone or in combination with KW6002. Administration of KW6002 to tumor-bearing mice limited the expression of cisplatin-induced indicators of nephrotoxicity (KIM-1, Figure 3A) and the inflammatory cytokines tumor necrosis factor and IL6 (Figures 3B and 3C). KW6002 also reduced cisplatin-induced pain hypersensitivity in this model (Figure 3D). Finally, KW6002 significantly enhanced tumor control by cisplatin (Figure 3E). In summary, using this additional model with a different cancer etiology, the renal protective effects, reduced pain hypersensitivity, and enhanced tumor control were restored, which suggests that A 2A Highlight the promising therapeutic potential of receptor inhibition.

[0099] These data supported that KW-6002 could also alleviate cisplatin-induced peripheral neuropathy.

[0100] References: Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into this disclosure. [Table 1] TIFF2025508035000020.tif248165 TIFF2025508035000021.tif241165 TIFF2025508035000022.tif241165 TIFF2025508035000023.tif241165 TIFF2025508035000024.tif242165 TIFF2025508035000025.tif44165

Claims

1. A method for the treatment of a neurological disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective A2A adenosine receptor (A2AR) antagonist.

2. 2. The method of claim 1, wherein the neuropathy is chemotherapy-induced peripheral neuropathy (CIPN).

3. The method of claim 2, wherein the CIPN is induced by a chemotherapeutic agent.

4. 3. The method of claim 2, wherein the chemotherapeutic agent is cisplatin.

5. 2. The method of claim 1, wherein the selective A2A adenosine receptor antagonist is selected from among istradefylline (KW-6002) or a derivative thereof, MSX-3, SCH-58261, tozadenant (SYN115), and preladenant (SCH-420814), NIR178 (PBF-509), ciforadenant, AB928, AZD4635, EOS100850, inupadenant (EOS-850), EXS21546, TT-10 and TT-53, and pharma- ceutically acceptable salts thereof, more particularly from among istradefylline (KW-6002) or a derivative thereof, MSX-3 and SCH-58261.

6. The method of claim 1, wherein the selective A2A adenosine receptor antagonist is KW-6002.

7. 2. The method of claim 1, wherein the selective A2A adenosine receptor antagonist is administered orally or parenterally.

8. A pharmaceutical composition comprising a therapeutically effective amount of a selective A2A adenosine receptor (A2AR) antagonist and a chemotherapeutic agent.

9. The pharmaceutical composition according to claim 9, wherein the selective A2A adenosine receptor (A2AR) antagonist is KW-6002 or a derivative thereof.

10. 9. The pharmaceutical composition of claim 8, wherein the chemotherapeutic agent is cisplatin.

11. A pharmaceutical composition comprising a compound according to any one of claims 8 to 10 and one or more pharma- ceutically acceptable excipients.

12. A selective A2A adenosine receptor (A2AR) antagonist for use in the treatment of neurological disorders.

13. 13. A selective A2A adenosine receptor antagonist for use according to claim 12, wherein the neuropathy is chemotherapy-induced peripheral neuropathy (CIPN).

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