阅读说明：本技术 Magl抑制剂、制备方法和用途 (MAGL inhibitor, preparation method and application ) 是由 张贵民 李�杰 肖贺 支卓尔 于 2020-01-19 设计创作，主要内容包括：本发明属于药物领域,涉及一种化合物及其药学上可接受的盐；其制备方法；及含有这样的化合物或盐的组合物；及其用于治疗MAGL介导的疾病及病症(包括例如疼痛、炎症性病症、创伤性脑损伤、抑郁症、焦虑症、阿尔茨海默病、代谢紊乱、中风或癌症等)的用途。(The invention belongs to the field of medicines, and relates to a compound and pharmaceutically acceptable salts thereof; a process for the preparation thereof; and compositions containing such compounds or salts; and their use for the treatment of MAGL mediated diseases and disorders including, for example, pain, inflammatory disorders, traumatic brain injury, depression, anxiety, alzheimer's disease, metabolic disorders, stroke, or cancer.)

1. A compound of formula I:

2. a method for synthesizing a compound shown as a formula I comprises the following specific steps: hippuric acid reacts with m-phenoxybenzaldehyde under the condition of alkaline heating.

3. The synthesis process according to claim 2, characterized in that the reaction is carried out at a temperature of heating comprised between 100 ℃ and 150 ℃, preferably between 120 ℃ and 140 ℃, most preferably 130 ℃.

4. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of claim 1 and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition of claim 4, wherein the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable adjuvant or other pharmaceutical ingredient.

6. The pharmaceutical composition of claim 4, for use in the preparation of a medicament for treating a disease or disorder mediated by MAGL.

7. The use of claim 6, wherein the disease or condition is selected from the group consisting of: metabolic disorders, renal diseases, emesis or vomiting or nausea, eating disorders, neuropathy, schizophrenia, depression, bipolar disorder, tremor, movement disorders, withdrawal syndrome, traumatic brain injury, non-traumatic brain injury, spinal cord injury, seizures, conditions associated with abnormal cell growth or proliferation, inflammatory conditions, immune system conditions, acute stress disorders, substance-induced anxiety, obsessive-compulsive disorders, anxiety disorders; attention deficit disorder, attention deficit hyperactivity disorder, pain; demyelinating disease, and cognitive impairment.

8. Use according to claim 6, wherein the disease or condition is selected from metabolic disorders, depression, withdrawal syndrome, conditions associated with abnormal cell growth or proliferation such as benign tumors or cancer, inflammatory conditions, immune system disorders, acute stress disorders, anxiety disorders; attention deficit disorder, attention deficit hyperactivity disorder.

9. Use according to claim 6, wherein the disease or condition is selected from depression, conditions associated with abnormal cell growth or proliferation such as benign tumours or cancer, inflammatory conditions, immune system conditions, anxiety; attention was paid to the deficit disorder.

10. A method of inhibiting MAGL comprising contacting the MAGL with a compound or pharmaceutically acceptable salt of claim 1.

Technical Field

The invention relates to the field of medicines, and in particular relates to a MAGL inhibitor, and a preparation method and application thereof.

Background field of the invention

Monoacylglycerol Lipase (MAGL), also known as monoglyceride, is a serine hydrolase that promotes the breakdown of fats into glycerol and fatty acids, is one of the members of the α/β hydrolase superfamily, is a serine hydrolase that is highly expressed in human invasive tumor cells and primary tumor cells. MAGL is widely expressed in adipose tissue, muscle, kidney, ovary, testis, and liver. In lipid metabolism tissues, MAGL can cooperate with hormone sensitive lipolytic enzymes to break down stored triacylglycerols into fatty acids and glycerol, providing energy to the body. In the central nervous system, MAGL hydrolyzes 2-arachidonic acid glycerol (2-AG) to arachidonic acid and glycerol, regulating the endocannabinoid system. Numura et al (Nomura DK, LombardDP, Chang JW, et al, Monoacylglycerol Lipase Exerts Dual Control over Endocosanoids and fat Acid Pathways to Support State Cancer [ J ]. ChemBiol,2011,18(7):846-56.) showed that MAGL is part of the gene expression signature of epithelial mesenchymal transition and tumor stem cells. MAGL is a gene expression marker of epithelial-mesenchymal transition and tumor stem cells, and can promote tumorigenesis by regulating fatty acid metabolic networks, endogenous cannabinoids system, and the levels of cyclin D1, Bcl-2, and the like. High levels of MAGL modulate the fatty acid network rich in oncogenic signaling lipids, promote tumor metastasis, invasion, survival and growth in vivo, and can maintain high pathogenicity of tumor cells by increasing the levels of free fatty acids. The MAGL has become an important target for the research and development of anti-tumor drugs, but the specific mechanism of the MAGL is not clear.

The invention content is as follows:

the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

the invention provides a synthesis method of a compound shown in a formula I, which comprises the following steps: adding hippuric acid, sodium acetate and m-phenoxybenzaldehyde into acetic anhydride, and heating and stirring. The heating temperature is 100 ℃ to 150 ℃, preferably 120 ℃ to 140 ℃, and most preferably 130 ℃.

The invention provides a pharmaceutical composition, which comprises the compound or the pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable pharmaceutic adjuvants.

The present application provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition includes, but is not limited to, oral dosage forms, parenteral dosage forms, topical dosage forms, and rectal dosage forms. The composition may be in the form of a liquid, solid, semi-solid, gel, or aerosol. In some embodiments, the pharmaceutical composition may be tablets, capsules, pills, powders, sustained release formulations, solutions and suspensions for oral administration, sterile solutions, suspensions or emulsions for parenteral injection, ointments or creams for topical use, or suppositories for rectal administration. In other embodiments, the pharmaceutical composition is in unit dosage form suitable for single administration of a precise dose

The invention provides all the compounds or pharmaceutically acceptable salts and pharmaceutical compositions thereof, and application thereof as monoacylglycerol esterase inhibitors; or for the manufacture of a medicament for the treatment of a disease or condition characterised by a pathology of a monoacylglycerol esterase metabolic pathway.

The present invention provides methods for inhibiting monoacylglycerol esterases with all of the above compounds or their pharmaceutically acceptable salts and pharmaceutical compositions thereof. The methods include methods of inhibiting monoacylglycerol esterases in vivo and in vitro. Also provided are methods of using all of the above compounds, or pharmaceutically acceptable salts and pharmaceutical compositions thereof, for treating monoacylglycerol esterase-mediated diseases or conditions.

Wherein the disorder is selected from: metabolic disorders (e.g., obesity); renal diseases (e.g., acute inflammatory kidney injury and diabetic nephropathy); emesis or emesia (e.g., chemotherapy-induced emesis); nausea (e.g., refractory nausea or chemotherapy-induced nausea); eating disorders (e.g., anorexia or bulimia); neuropathy (e.g., diabetic neuropathy, pellagra neuropathy, alcoholic neuropathy, beriberi neuropathy); burn foot syndrome; neurodegenerative disorders [ Multiple Sclerosis (MS), Parkinson's Disease (PD), huntington's disease, dementia, alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), epilepsy, frontotemporal dementia, sleep disorders, creutzfeldt-jakob disease (CJD), or prion disease ]; cardiovascular diseases (e.g., hypertension, dyslipidemia, atherosclerosis, arrhythmia, or myocardial ischemia); osteoporosis; osteoarthritis; schizophrenia; depression; bipolar disorder; shaking; movement disorders; tension disorder; spasticity; tourette's syndrome; sleep apnea; hearing loss; eye diseases (e.g., glaucoma, ocular hypertension, macular degeneration or diseases resulting from elevated intraocular pressure); cachexia; insomnia; meningitis; sleep disorders; progressive multifocal leukoencephalopathy; de Vivo disease; cerebral edema; cerebral palsy; withdrawal syndrome [ withdrawal syndrome, antidepressant withdrawal syndrome, antipsychotic withdrawal syndrome, benzodiazepine withdrawal syndrome, cannabis withdrawal, neonatal withdrawal, nicotine withdrawal or opioid withdrawal ]; traumatic brain injury; non-traumatic brain injury; spinal cord injury; seizures; excitotoxin exposure; ischemia [ stroke, hepatic ischemia or reperfusion, CNS ischemia or reperfusion ]; liver fibrosis, iron overload, cirrhosis; pulmonary disorders [ asthma, allergy, COPD, chronic bronchitis, emphysema, cystic fibrosis, pneumonia, tuberculosis, pulmonary edema, lung cancer, acute respiratory distress syndrome, Interstitial Lung Disease (ILD), sarcoidosis, idiopathic pulmonary fibrosis, pulmonary embolism, pleural effusion or mesothelioma ]; liver disorders [ acute liver failure, Alagille syndrome, hepatitis, hepatomegaly, gilbert's syndrome, liver cysts, hepatic hemangiomas, fatty liver disease, steatohepatitis, primary sclerosing cholangitis, fascioliasis, primary biliary cirrhosis, barren-hilgard syndrome, hemochromatosis, wilson's disease, or transthyretin-associated hereditary amyloidosis ], stroke [ e.g., ischemic stroke, hemorrhagic stroke ]; subarachnoid hemorrhage; intracerebral hemorrhage; vasospasm; AIDS wasting syndrome; renal ischemia; a disorder associated with abnormal cell growth or proliferation [ e.g., a benign tumor or cancer, e.g., a benign skin tumor, brain tumor, papilloma, prostate tumor, brain tumor (glioblastoma, medulloblastoma, astrocytoma, ependymoma, oligodendroglioma, plexus tumor, neuroepithelioma, epiphyseal tumor, ependymoma, malignant meningioma, sarcoidosis, melanoma, schwannoma), melanoma, metastatic tumor, kidney cancer, bladder cancer, brain cancer, Glioblastoma (GBM), gastrointestinal cancer, leukemia, or blood cancer ]; autoimmune diseases [ e.g. psoriasis, lupus erythematosus, sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, behcet's disease, hemolytic anemia, graft rejection ]; inflammatory disorders [ e.g., appendicitis, bursitis, colitis, cystitis, dermatitis, phlebitis, rhinitis, tendonitis, tonsillitis, vasculitis, acne vulgaris, chronic prostatitis, glomerulonephritis, hypersensitivity, IBS, pelvic inflammatory disease, sarcoidosis, HIV encephalitis, rabies, brain abscess, neuroinflammation, Central Nervous System (CNS) inflammation ]; immune system disorders (e.g., transplant rejection or celiac disease); post-traumatic stress disorder (PTSD); acute stress disorder; panic disorder; substance-induced anxiety; obsessive Compulsive Disorder (OCD); agoraphobia; specific phobias; social phobia; anxiety disorders; attention Deficit Disorder (ADD); attention Deficit Hyperactivity Disorder (ADHD); asper's syndrome; pain [ e.g., acute pain; chronic pain; inflammatory pain; visceral pain; post-operative pain; migraine headache; low back pain; joint pain; abdominal pain; chest pain; post-mastectomy pain syndrome; menstrual pain; endometriosis pain; pain due to physical trauma; headache; sinus headache; tension headache, arachnoiditis, herpes virus pain, diabetic pain; pain resulting from a condition selected from: osteoarthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, labor, musculoskeletal diseases, skin diseases, toothache, heartburn, burn, sunburn, snake bite, venomous snake bite, spider bite, insect bite, neurogenic bladder, interstitial cystitis, Urinary Tract Infection (UTI), rhinitis, contact dermatitis/hypersensitivity, itching, eczema, pharyngitis, mucositis, enteritis, Irritable Bowel Syndrome (IBS), cholecystitis, and pancreatitis; neuropathic pain (e.g., neuropathic low pain, complex regional pain syndrome, pillar trigeminal neuralgia, causalgia, toxic neuropathy, reflex sympathetic dystrophy, diabetic neuropathy, chronic neuropathy caused by chemotherapeutic agents, or sciatica pain); demyelinating diseases [ e.g. Multiple Sclerosis (MS), veryke's disease, CNS neuropathy, central pontine myelination, syphilitic myelopathy, leukoencephalopathy, leukodystrophy, guillain-barre syndrome, chronic inflammatory demyelinating polyneuropathy, anti-myelin-associated glycoprotein (MAG) peripheral neuropathy, charcot-marie-tooth-tree disease, peripheral neuropathy, myelopathy, optic neuropathy, progressive inflammatory neuropathy, optic neuritis, transverse myelitis ]; and cognitive impairment [ e.g., cognitive impairment associated with down's syndrome; cognitive impairment associated with alzheimer's disease; cognitive impairment associated with PD; mild Cognitive Impairment (MCI), dementia, post-chemotherapy cognitive impairment (PCCI), post-operative cognitive dysfunction (POCD) ].

As used hereinThe term "pharmaceutically acceptable salt" refers to salts that retain the biological potency of the free acid and free base of the specified compound, and that are biologically or otherwise not adversely affected. The compounds of the present application also include pharmaceutically acceptable salts. Pharmaceutically acceptable salts refer to the form in which the base group in the parent compound is converted to a salt. Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amine (amino) groups. Pharmaceutically acceptable salts of the present application can be synthesized from the parent compound by reacting a basic group in the parent compound with 1-4 equivalents of an acid in a solvent system. Suitable salts are listed in Remingtong's Pharmaceutical sciences, 17^thed., MackPublishing Company, Easton, Pa.,1985, p.1418 and Journal of Pharmaceutical Science,66,2 (1977).

Unless otherwise indicated, salts in this application refer to acid salts formed with organic/inorganic acids, as well as basic salts formed with organic/inorganic bases. In addition, when the basic functional group of the compound of formula (la) is pyridine or imidazole (but not limited to pyridine or imidazole) and the acidic functional group is carboxylic acid (but not limited to carboxylic acid), zwitterions (inner salts) are formed and are included in the salts herein.

The specific implementation mode is as follows:

the present invention will be further described with reference to specific embodiments, but the present invention is not limited thereto. And other specific compounds that are available to those skilled in the art without inventive effort are within the scope of this invention.