CN111518048B - Magl抑制剂、制备方法和用途 - Google Patents
Magl抑制剂、制备方法和用途 Download PDFInfo
- Publication number
- CN111518048B CN111518048B CN202010058304.9A CN202010058304A CN111518048B CN 111518048 B CN111518048 B CN 111518048B CN 202010058304 A CN202010058304 A CN 202010058304A CN 111518048 B CN111518048 B CN 111518048B
- Authority
- CN
- China
- Prior art keywords
- disorders
- disease
- pharmaceutically acceptable
- condition
- pain
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 101710116393 Monoglyceride lipase Proteins 0.000 title claims abstract description 16
- 102100029814 Monoglyceride lipase Human genes 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title abstract description 4
- 238000000034 method Methods 0.000 title description 10
- 239000003112 inhibitor Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 208000002193 Pain Diseases 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 14
- 230000036407 pain Effects 0.000 claims abstract description 13
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 6
- 208000030886 Traumatic Brain injury Diseases 0.000 claims abstract description 5
- 230000009529 traumatic brain injury Effects 0.000 claims abstract description 5
- 201000011510 cancer Diseases 0.000 claims abstract description 4
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 4
- 230000036506 anxiety Effects 0.000 claims abstract description 3
- 230000001404 mediated effect Effects 0.000 claims abstract description 3
- 230000004968 inflammatory condition Effects 0.000 claims abstract 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 208000010877 cognitive disease Diseases 0.000 claims description 8
- 201000001119 neuropathy Diseases 0.000 claims description 7
- 230000007823 neuropathy Effects 0.000 claims description 7
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 6
- 208000028698 Cognitive impairment Diseases 0.000 claims description 6
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 6
- 206010048010 Withdrawal syndrome Diseases 0.000 claims description 6
- 208000035475 disorder Diseases 0.000 claims description 5
- 206010028813 Nausea Diseases 0.000 claims description 4
- 206010047700 Vomiting Diseases 0.000 claims description 4
- 230000002159 abnormal effect Effects 0.000 claims description 4
- 230000010261 cell growth Effects 0.000 claims description 4
- 230000004663 cell proliferation Effects 0.000 claims description 4
- 230000008693 nausea Effects 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 4
- 230000008673 vomiting Effects 0.000 claims description 4
- 208000031674 Traumatic Acute Stress disease Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 208000020925 Bipolar disease Diseases 0.000 claims description 2
- 206010010904 Convulsion Diseases 0.000 claims description 2
- 208000016192 Demyelinating disease Diseases 0.000 claims description 2
- 208000030814 Eating disease Diseases 0.000 claims description 2
- 208000019454 Feeding and Eating disease Diseases 0.000 claims description 2
- 208000016285 Movement disease Diseases 0.000 claims description 2
- 206010044565 Tremor Diseases 0.000 claims description 2
- 235000014632 disordered eating Nutrition 0.000 claims description 2
- 210000000987 immune system Anatomy 0.000 claims description 2
- 208000027866 inflammatory disease Diseases 0.000 claims description 2
- 208000017169 kidney disease Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 201000000980 schizophrenia Diseases 0.000 claims description 2
- 208000020431 spinal cord injury Diseases 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 208000026278 immune system disease Diseases 0.000 claims 2
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 230000008674 spewing Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 4
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 3
- 208000006011 Stroke Diseases 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 241000699670 Mus sp. Species 0.000 description 19
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- 239000000725 suspension Substances 0.000 description 9
- 208000033808 peripheral neuropathy Diseases 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 239000000935 antidepressant agent Substances 0.000 description 6
- 230000006399 behavior Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 230000001430 anti-depressive effect Effects 0.000 description 5
- 210000003169 central nervous system Anatomy 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 201000006417 multiple sclerosis Diseases 0.000 description 5
- 230000009182 swimming Effects 0.000 description 5
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 229940005513 antidepressants Drugs 0.000 description 4
- 150000002759 monoacylglycerols Chemical class 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 208000003174 Brain Neoplasms Diseases 0.000 description 3
- 108090000371 Esterases Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 102000004157 Hydrolases Human genes 0.000 description 3
- 108090000604 Hydrolases Proteins 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- 229940122357 Monoacylglycerol lipase inhibitor Drugs 0.000 description 3
- 208000018737 Parkinson disease Diseases 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 208000005017 glioblastoma Diseases 0.000 description 3
- 208000002551 irritable bowel syndrome Diseases 0.000 description 3
- 208000028867 ischemia Diseases 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 201000008482 osteoarthritis Diseases 0.000 description 3
- 201000000306 sarcoidosis Diseases 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- MRLGCTNJRREZHZ-UHFFFAOYSA-N 3-phenoxybenzaldehyde Chemical compound O=CC1=CC=CC(OC=2C=CC=CC=2)=C1 MRLGCTNJRREZHZ-UHFFFAOYSA-N 0.000 description 2
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 2
- 208000023890 Complex Regional Pain Syndromes Diseases 0.000 description 2
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 2
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 description 2
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010014967 Ependymoma Diseases 0.000 description 2
- 208000029523 Interstitial Lung disease Diseases 0.000 description 2
- 241000581650 Ivesia Species 0.000 description 2
- 208000008930 Low Back Pain Diseases 0.000 description 2
- 102000005398 Monoacylglycerol Lipase Human genes 0.000 description 2
- 108020002334 Monoacylglycerol lipase Proteins 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- GIYXAJPCNFJEHY-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-1-propanamine hydrochloride (1:1) Chemical compound Cl.C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 GIYXAJPCNFJEHY-UHFFFAOYSA-N 0.000 description 2
- 208000026301 Postoperative Cognitive Complications Diseases 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- 208000004078 Snake Bites Diseases 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 201000002661 Spondylitis Diseases 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000003542 behavioural effect Effects 0.000 description 2
- 229930003827 cannabinoid Natural products 0.000 description 2
- 239000003557 cannabinoid Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000007705 epithelial mesenchymal transition Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229960000389 fluoxetine hydrochloride Drugs 0.000 description 2
- 238000012048 forced swim test Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 208000027061 mild cognitive impairment Diseases 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 208000028173 post-traumatic stress disease Diseases 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000010410 reperfusion Effects 0.000 description 2
- 206010039083 rhinitis Diseases 0.000 description 2
- 208000019116 sleep disease Diseases 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 208000019206 urinary tract infection Diseases 0.000 description 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- YBADLXQNJCMBKR-UHFFFAOYSA-N (4-nitrophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C([N+]([O-])=O)C=C1 YBADLXQNJCMBKR-UHFFFAOYSA-N 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- PQDRWMYDXMMMBP-UHFFFAOYSA-N 2-oxoicosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCC(=O)C(O)=O PQDRWMYDXMMMBP-UHFFFAOYSA-N 0.000 description 1
- 208000037415 AIDS wasting syndrome Diseases 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 208000007788 Acute Liver Failure Diseases 0.000 description 1
- 206010000804 Acute hepatic failure Diseases 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 208000008811 Agoraphobia Diseases 0.000 description 1
- 201000011374 Alagille syndrome Diseases 0.000 description 1
- 206010053164 Alcohol withdrawal syndrome Diseases 0.000 description 1
- 208000003130 Alcoholic Neuropathy Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 206010003011 Appendicitis Diseases 0.000 description 1
- 206010003399 Arthropod bite Diseases 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000004020 Brain Abscess Diseases 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 208000032841 Bulimia Diseases 0.000 description 1
- 206010006550 Bulimia nervosa Diseases 0.000 description 1
- 206010006811 Bursitis Diseases 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000001387 Causalgia Diseases 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 206010008479 Chest Pain Diseases 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 208000030939 Chronic inflammatory demyelinating polyneuropathy Diseases 0.000 description 1
- 208000036166 Classic glucose transporter type 1 deficiency syndrome Diseases 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 208000013586 Complex regional pain syndrome type 1 Diseases 0.000 description 1
- 102000006311 Cyclin D1 Human genes 0.000 description 1
- 108010058546 Cyclin D1 Proteins 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 201000010374 Down Syndrome Diseases 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 208000014094 Dystonic disease Diseases 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000034846 Familial Amyloid Neuropathies Diseases 0.000 description 1
- 241001126309 Fasciolopsis Species 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 201000011240 Frontotemporal dementia Diseases 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 208000009139 Gilbert Disease Diseases 0.000 description 1
- 208000022412 Gilbert syndrome Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 108700006771 Glut1 Deficiency Syndrome Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 1
- 208000003577 HIV wasting syndrome Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000018565 Hemochromatosis Diseases 0.000 description 1
- 208000016988 Hemorrhagic Stroke Diseases 0.000 description 1
- 206010019646 Hepatic cyst Diseases 0.000 description 1
- 208000002972 Hepatolenticular Degeneration Diseases 0.000 description 1
- 206010019842 Hepatomegaly Diseases 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101001012646 Homo sapiens Monoglyceride lipase Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 208000006877 Insect Bites and Stings Diseases 0.000 description 1
- 208000005615 Interstitial Cystitis Diseases 0.000 description 1
- 206010065973 Iron Overload Diseases 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 208000034800 Leukoencephalopathies Diseases 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 206010027193 Meningioma malignant Diseases 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 1
- 206010028116 Mucosal inflammation Diseases 0.000 description 1
- 201000010927 Mucositis Diseases 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- 208000023178 Musculoskeletal disease Diseases 0.000 description 1
- 206010028570 Myelopathy Diseases 0.000 description 1
- 150000001200 N-acyl ethanolamides Chemical class 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000000693 Neurogenic Urinary Bladder Diseases 0.000 description 1
- 206010029279 Neurogenic bladder Diseases 0.000 description 1
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 206010030043 Ocular hypertension Diseases 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 208000003435 Optic Neuritis Diseases 0.000 description 1
- 206010061323 Optic neuropathy Diseases 0.000 description 1
- 206010069350 Osmotic demyelination syndrome Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 206010034912 Phobia Diseases 0.000 description 1
- 208000002151 Pleural effusion Diseases 0.000 description 1
- 206010035603 Pleural mesothelioma Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 208000024777 Prion disease Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- 206010037742 Rabies Diseases 0.000 description 1
- 201000001947 Reflex Sympathetic Dystrophy Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 206010061481 Renal injury Diseases 0.000 description 1
- 206010063897 Renal ischaemia Diseases 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 208000008765 Sciatica Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 206010040744 Sinus headache Diseases 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 206010041250 Social phobia Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000003589 Spider Bites Diseases 0.000 description 1
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 1
- 206010042496 Sunburn Diseases 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 206010043269 Tension headache Diseases 0.000 description 1
- 208000008548 Tension-Type Headache Diseases 0.000 description 1
- 208000000323 Tourette Syndrome Diseases 0.000 description 1
- 208000016620 Tourette disease Diseases 0.000 description 1
- 206010067722 Toxic neuropathy Diseases 0.000 description 1
- 231100000126 Toxic neuropathy Toxicity 0.000 description 1
- 206010044688 Trisomy 21 Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 206010047163 Vasospasm Diseases 0.000 description 1
- 206010047601 Vitamin B1 deficiency Diseases 0.000 description 1
- 208000018839 Wilson disease Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 231100000836 acute liver failure Toxicity 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 208000026345 acute stress disease Diseases 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 208000029650 alcohol withdrawal Diseases 0.000 description 1
- 208000020701 alcoholic polyneuropathy Diseases 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 206010003074 arachnoiditis Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 206010004398 benign neoplasm of skin Diseases 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 208000002894 beriberi Diseases 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 208000009885 central pontine myelinolysis Diseases 0.000 description 1
- 206010008129 cerebral palsy Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 201000001352 cholecystitis Diseases 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 201000005795 chronic inflammatory demyelinating polyneuritis Diseases 0.000 description 1
- 208000013507 chronic prostatitis Diseases 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 208000014439 complex regional pain syndrome type 2 Diseases 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 208000010118 dystonia Diseases 0.000 description 1
- 230000004406 elevated intraocular pressure Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 208000026663 encephalopathy due to GLUT1 deficiency Diseases 0.000 description 1
- 239000002621 endocannabinoid Substances 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 239000002329 esterase inhibitor Substances 0.000 description 1
- 239000004060 excitotoxin Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 208000030316 grade III meningioma Diseases 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000010370 hearing loss Effects 0.000 description 1
- 231100000888 hearing loss Toxicity 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 208000024798 heartburn Diseases 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- 208000007475 hemolytic anemia Diseases 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- QNYRAEKLMNDRFY-UHFFFAOYSA-N jzl195 Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(=O)N1CCN(CC=2C=C(OC=3C=CC=CC=3)C=CC=2)CC1 QNYRAEKLMNDRFY-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 208000037806 kidney injury Diseases 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 208000036546 leukodystrophy Diseases 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000002366 lipolytic effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 208000038015 macular disease Diseases 0.000 description 1
- 240000004308 marijuana Species 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000007538 neurilemmoma Diseases 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 208000027831 neuroepithelial neoplasm Diseases 0.000 description 1
- 230000003959 neuroinflammation Effects 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 208000020911 optic nerve disease Diseases 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- -1 organic acid salts Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 208000003154 papilloma Diseases 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 230000007918 pathogenicity Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 208000001297 phlebitis Diseases 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 201000000742 primary sclerosing cholangitis Diseases 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 206010036807 progressive multifocal leukoencephalopathy Diseases 0.000 description 1
- 208000023958 prostate neoplasm Diseases 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 206010039667 schwannoma Diseases 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 201000002859 sleep apnea Diseases 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 201000001716 specific phobia Diseases 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 208000006379 syphilis Diseases 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 206010044008 tonsillitis Diseases 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- 201000007905 transthyretin amyloidosis Diseases 0.000 description 1
- 208000009174 transverse myelitis Diseases 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 231100000611 venom Toxicity 0.000 description 1
- 208000009935 visceral pain Diseases 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/36—One oxygen atom
- C07D263/42—One oxygen atom attached in position 5
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Nutrition Science (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Psychology (AREA)
- Addiction (AREA)
- Rheumatology (AREA)
- Diabetes (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
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。
Description
技术领域
本发明涉及药物领域，特别涉及一种MAGL抑制剂及其制备方法和用途。
背景领域
单酰基甘油脂肪酸酶(Monoacylglycerol Lipase,MAGL)，又称甘油一酯酶，是一类促进脂肪分解成甘油和脂肪酸的丝氨酸水解酶，是α/β水解酶超家族的成员之一，系丝氨酸水解酶，在人侵袭性肿瘤细胞和原发性肿瘤细胞内高表达。MAGL广泛表达于脂肪组织、肌肉、肾、卵巢、睾丸和肝中。在脂质代谢组织中，MAGL可协同激素敏感性脂解酶将储存的三酰甘油分解为脂肪酸和甘油，为机体供能。在中枢神经系统中，MAGL可将2-花生四烯酸甘油(2-AG)水解成花生四烯酸和甘油，调节内源性大麻素系统。Numura等(Nomura DK,LombardiDP,Chang JW,et al.Monoacylglycerol Lipase Exerts Dual Control overEndocannabinoid and Fatty Acid Pathways to Support Prostate Cancer[J].ChemBiol,2011,18(7):846-56.)的研究显示，MAGL是上皮间质转化和肿瘤干细胞的基因表达标记的一部分。MAGL是上皮间质转化和肿瘤干细胞的基因表达标记，且可通过调节脂肪酸代谢网络、内源性大麻素系统和周期蛋白D1、Bcl-2的水平等，促进肿瘤的发生。高水平的MAGL可调节富含促癌信号脂质的脂肪酸网络，促进肿瘤转移、侵袭、存活以及在体内生长，能够通过提高自由脂肪酸的水平来维持肿瘤细胞的高致病性。MAGL已成为抗肿瘤药物研发的重要靶点，然而其具体机制尚不明确。
发明内容：
本发明提供式I化合物或其药学上可接受的盐：
本发明提供式I化合物的合成方法，具体步骤如下：醋酐中加入马尿酸，醋酸钠，间苯氧基苯甲醛，加热搅拌制得。所述加热温度为100℃-150℃，优选为120℃-140℃，最优选130℃。
本发明提供药物组合物，包含上述化合物或其药学上可接受的盐，和一种或多种药学上可接受的药用辅料。
本申请提供了一种药物组合物，其包含本申请所述的化合物或其药学可接受的盐和药学可接受的载体。所述药物组合物包括但不限于口服剂型、胃肠外给药剂型、外用剂型和直肠给药剂型。所述组合物可以是液体、固体、半固体、凝胶或气溶胶形式。在一些实施方式中，所述药物组合物可以是口服的片剂、胶囊、丸剂、粉剂、缓释制剂、溶液和悬浮液，用于胃肠外注射的无菌溶液、悬浮液或乳液，用于外用的软膏或乳膏，或者用于直肠给药的栓剂。在其它实施方式中，所述药物组合物为适合单次施予精确剂量的单位剂型
本发明提供了上述所有化合物或其药学上可接受的盐及其药物组合物，其作为单酰基甘油酯酶抑制剂的用途；或其用于制备治疗具有单酰基甘油酯酶代谢途径的病理学特征的疾病或病症的药物的用途。
本发明提供了上述所有化合物或其药学上可接受的盐及其药物组合物用于抑制单酰基甘油酯酶的方法。该方法包括体内和体外抑制单酰基甘油酯酶的方法。还提供了上述所有化合物或其药学上可接受的盐及其药物组合物用于治疗单酰基甘油酯酶介导的疾病或病症的方法。
其中所述病症选自：代谢紊乱(例如肥胖症)；肾病(例如急性炎症性肾损伤及糖尿病肾病)；呕吐或涌吐(例如化学疗法诱导的呕吐)；恶心(例如难治性恶心或化学疗法诱导的恶心)；进食障碍(例如厌食症或贪食症)；神经病变(例如糖尿病神经病变、糙皮病性神经病变、酒精性神经病变、脚气病神经病变)；烧灼样足综合征；神经变性病症[多发性硬化(MS)、帕金森病(PD)、亨廷顿病、痴呆、阿尔茨海默病、肌萎缩侧索硬化(ALS)、癫痫、额颞叶痴呆、睡眠障碍、克雅氏病(CJD)或朊病毒病]；心血管疾病(例如高血压、血脂异常、动脉粥样硬化、心律不齐或心肌缺血)；骨质疏松症；骨关节炎；精神分裂症；抑郁症；双相障碍；震颤；运动障碍；张力失常；痉挛状态；图雷特氏综合征；睡眠呼吸暂停；听力损失；眼疾病(例如青光眼、高眼压症、黄斑变性或源于眼内压升高的疾病)；恶病质；失眠；脑膜炎；睡眠病；进行性多灶性白质脑病；De Vivo病；脑水肿；大脑性瘫痪；戒断综合征[戒酒综合征、抗抑郁药停药综合征、抗精神病药停药综合征、苯并二氮停药综合征、大麻戒断、新生儿戒断、尼古丁戒断或阿片类戒断]；外伤性脑损伤；非外伤性脑损伤；脊髓损伤；癫痫发作；兴奋毒素暴露；缺血[中风、肝缺血或再灌注、CNS缺血或再灌注]；肝纤维化、铁超负荷、肝硬化；肺病症[哮喘、变态反应、COPD、慢性支气管炎、肺气肿、囊性纤维化、肺炎、结核病、肺水肿、肺癌、急性呼吸窘迫综合征、间质性肺病(ILD)、结节病、特发性肺纤维化、肺栓塞、胸腔积液或间皮瘤]；肝病症[急性肝衰竭、Alagille综合征、肝炎、肝肿大、吉尔伯特氏综合征、肝囊肿、肝血管瘤、脂肪肝疾病、脂肪性肝炎、原发性硬化性胆管炎、片形吸虫病、原发性胆管硬化、巴-希二氏综合征、血色素沉着病、威尔逊氏症或转甲状腺素相关遗传性淀粉样变性]、中风[例如缺血性中风、出血性中风]；蛛网膜下腔出血；脑内出血；血管痉挛；AIDS消耗综合征；肾缺血；与异常细胞生长或增殖有关的病症[例如良性肿瘤或癌症，例如良性皮肤肿瘤、脑瘤、乳头状瘤、前列腺肿瘤、脑肿瘤(胶质母细胞瘤、髓上皮瘤、髓母细胞瘤、神经母细胞瘤、星形细胞瘤、星形母细胞瘤、室管膜瘤、少突神经胶质瘤、丛肿瘤、神经上皮瘤、骨骺肿瘤、室管膜母细胞瘤、恶性脑膜瘤、肉瘤病、黑色素瘤、神经鞘瘤)、黑色素瘤、转移性肿瘤、肾癌、膀胱癌、脑癌、胶质母细胞瘤(GBM)、胃肠癌、白血病或血癌]；自身免疫病[例如银屑病、红斑狼疮、干燥综合征、强直性脊柱炎、未分化脊柱炎、贝赫切特氏病、溶血性贫血、移植物排斥]；炎症性病症[例如阑尾炎、滑囊炎、结肠炎、膀胱炎、皮炎、静脉炎、鼻炎、肌腱炎、扁桃体炎、血管炎、寻常痤疮、慢性前列腺炎、肾小球肾炎、超敏反应、IBS、盆腔炎性疾病、结节病、HIV脑炎、狂犬病、脑脓肿、神经炎症、中枢神经系统(CNS)炎症]；免疫系统病症(例如移植排斥或乳糜泻)；创伤后应激障碍(PTSD)；急性应激障碍；惊恐障碍；物质诱导性焦虑；强迫症(OCD)；广场恐怖症；特定恐怖症；社交恐怖症；焦虑症；注意缺陷障碍(ADD)；注意缺陷多动障碍(ADHD)；阿斯佩各综合征；疼痛[例如急性疼痛；慢性疼痛；炎症性疼痛；内脏痛；手术后疼痛；偏头痛；下腰痛；关节疼痛；腹痛；胸痛；乳房切除术后疼痛综合征；月经疼痛；子宫内膜异位症疼痛；由物理创伤所致的疼痛；头痛；窦性头痛；紧张性头痛、蛛网膜炎、疱疹病毒疼痛、糖尿病性疼痛；由选自以下的病症所致的疼痛：骨关节炎、类风湿性关节炎、骨关节炎、脊椎炎、痛风、阵痛、肌骨骼疾病、皮肤病、牙痛、胃灼热、烧伤、晒伤、蛇咬伤、毒蛇咬伤、蜘蛛咬伤、昆虫叮咬、神经源性膀胱、间质性膀胱炎、尿路感染(UTI)、鼻炎、接触性皮炎/超敏反应、发痒、湿疹、咽炎、黏膜炎、肠炎、肠易激综合征(IBS)、胆囊炎及胰腺炎；神经性疼痛(例如神经性腰痛、复杂性区域疼痛综合征、支柱三叉神经痛、灼性神经痛、中毒性神经病、反射性交感神经营养不良、糖尿病神经病变、化学治疗剂所致的慢性神经病变或坐骨神经痛疼痛)]；脱髓鞘病[例如多发性硬化(MS)、德维克氏病、CNS神经病变、脑桥中央髓鞘溶解、梅毒性脊髓病、脑白质病、脑白质营养不良症、格林-巴利综合征、慢性炎症性脱髓鞘性多神经病、抗髓磷脂相关糖蛋白(MAG)周围神经病变、夏科-马里-图思病、周围神经病变、脊髓病变、视神经病变、进展性炎症性神经病变、视神经炎、横贯性脊髓炎]；及认知损害[例如与唐氏综合征有关的认知损害；与阿尔茨海默病有关的认知损害；与PD有关的认知损害；轻度认知损害(MCI)、痴呆、化学疗法后认知损害(PCCI)、手术后认知功能障碍(POCD)]。
本文所用术语“药学可接受的盐”是指保留了指定化合物的游离酸和游离碱的生物效力，并且在生物学或其它方面上没有不良作用的盐。本申请化合物还包括药学可以接受的盐。药学可接受的盐是指把母体化合物中的碱基基团转换成盐的形式。药学可接受的盐包括，但不仅限于，碱基基团例如胺(氨)基的无机或有机酸盐类。本申请药学可接受的盐可以由母体化合物合成，即母体化合物中的碱性基团与1-4当量的酸在一个溶剂系统中反应。合适的盐列举在Remingtong’s Pharmaceutical Scicences,17th ed.,MackPublishing Company,Easton,Pa.,1985,p.1418和Journal of Pharmaceutical Science,66,2(1977)中。
除特别指示外，本申请中的盐指用有机酸/无机酸形成的酸式盐，以及用有机碱/无机碱形成的碱式盐。另外，当通式化合物的碱性官能团是吡啶或咪唑(但不限制于吡啶或咪唑)，酸性官能团是羧酸(但不限制于羧酸)时就会形成两性离子(内盐)，内盐也包括在本申请中的盐内。
具体实施方式：
下面结合具体的实施方式对本发明做进一步描述，但本发明并不受其限制。且本领域技术人员不需要付出创造性劳动即可得到的其它具体化合物，均在本发明范围内。
实施例1
1ml醋酐中加入马尿酸(156.3mg，1.335mmol)，醋酸钠(94.9mg，1.157mmol，)，间苯氧基苯甲醛(176mg，0.89mmol)，130℃搅拌1.5h。停止反应，加入饱和碳酸氢钠溶液淬灭，乙酸乙酯萃取3次，饱和氯化钠溶液洗3次，无水硫酸钠干燥，经柱层析分离纯化(石油醚：乙酸乙酯＝100:1)得到目标化合物黄色粉末143.4mg(54.2％)。
1HNMR(DMSOd6)δ(ppm):8.14(s,1H),7.87-7.96(m,2H),7.78-7.85(m,1H),7.70-7.78(m,1H),7.61-7.69(m,2H),7.48-7.58(m,3H),7.29-7.38(m,2H),7.15-7.26(m,3H)；MS测得分子量与理论值相符。
实施例A：MAGL酶分析
采用Cayman的MAGL抑制剂筛选试剂盒，根据其说明书，以4-硝基苯乙酸的乙醇溶液作为MAGL的底物，底物的终浓度为236UM.96孔板中每孔加入150微升的1Xassaybuffer，10微升的重组人MAGL蛋白,以及10微升的不同浓度的MAGLinhibitor(1nM-1000nM间的六个点).JZL195(阳性对照抑制剂)作为阳性对照孔，室温孵育5min后，每孔加入10微升的MAGL底物，将86孔震荡10秒，室温下放置10min，检测410nm的吸光值。其中，还要设置100％抑制对照孔(96孔板中每孔加入150微升的1Xassaybuffer，10微升的MAGL,以及10微升的DMSO,设置三个复孔)，背景孔(每孔加入160微升的1Xassay buffer以及10微升的DMSO,设置三个复孔)。然后采用graphad prism 5.0计算拟合各抑制剂的IC50曲线，得MAGLZ-III-12IC50为9.632μM。
实施例B：动物试验
1材料与方法
1.1实验动物
体重18～22g雄性ICR小鼠。动物在正常的12h光照，12h黑暗时间表下活动。环境温度和相对湿度分别保持在22±1℃和55±5％。
1.2实验方法
1.2.1动物分组和给药方法
3组实验小鼠，每组10只，设为对照组(生理盐水组)，阳性对照组(盐酸氟西汀胶囊，5mg/kg)，式I化合物给药处理组，给药浓度为5mg/kg。
所有药物通过灌胃以20mL/kg体重的剂量使用，1次/天，持续10天。最后一次给药1h后，开始进行动物行为学的检测。
1.2.2小鼠强迫游泳试验
小鼠强迫游泳实验根据Porsolt(Porsalt R D.Behavioural despair in mice:Aprimary screening test for antidepressants[J].Arch.Int.Pharmacolodyn.1977,229)建立的方法进行检测。小鼠单独在开放的圆柱形容器(直径10cm，高25cm)中强迫游泳，该容器水温25±1℃，水深19cm，每只动物在6分钟的过程中保持不动的总时间被记录为不动时间(以秒为单位)。每只小鼠在停止挣扎时被判定为不动，并且在水中保持悬浮不动，只做出必要的动作以保持头部高于水面。不动时间的减少表明具有抗抑郁作用。
1.2.3小鼠悬尾试验
尾部悬浮试验(TST)根据Porsolt等(Porsolt R D,Le Pichon M,JalfreM.Depression:a new animal model sensitive to antidepressant treatments[J].Nature,1977,266(5604):730-732)建立的方法进行检测。使用悬尾夹子，在距离盒子(250mm×250mm×300mm)尾部10mm，头部距离底部5cm处将小鼠分别悬挂在尾部。在具有最小背景的黑暗房间中测试噪声，每只小鼠悬挂6分钟，在最后4分钟间隔记录不动时间。判定标准是小鼠停止挣扎，完全静止不动。
1.2.4数据处理
所有数据以x±SD表示，组间比较采用单因素方差分析。
2结果
2.1式I化合物对小鼠强迫游泳行为的影响
式I化合物对小鼠强迫游泳行为影响实验表明阳性对照药盐酸氟西汀、式I化合物组均能明显缩短小鼠强迫游泳累积不动时间(P＜0.1)(表1)。
表1式I化合物对小鼠强迫游泳行为的影响
注：与对照组比较，P＜0.1，P＜0.05。
2.2式I系列化合物对小鼠悬尾行为的影响
与对照组相比，式I化合物式I各化合物组能明显缩短悬尾小鼠的累计不动时间(P＜0.1)(表2)。
表2式I化合物对小鼠悬尾行为的影响
注：与对照组比较，P＜0.1，P＜0.05。
3讨论
小鼠强迫游泳和小鼠悬尾是较为常用的、经典的抑郁症动物模型。模型所体现出的小鼠绝望、行为扭曲等状态是体外模拟抑郁症的显著特征，同时由于其对抗抑郁药物比较敏感且便于操作，因此是抗抑郁药物常用的筛选模型。本研究采用这两种经典的抑郁动物模型对式I化合物的抗抑郁活性进行进一步的评价与验证。结果表明，式I化合物能显著缩短小鼠强迫游泳和小鼠悬尾的累积不动时间，表明式I化合物具有明确的抗抑郁作用。
Claims (7)
1.一种药物组合物，其包含如所示化合物或其药学上可接受的盐及药学上可接受的载体。
2.如权利要求1所述的药物组合物，其特征在于，所述药学上可接受的载体为药学上可接受的辅料。
3.如权利要求1所述药物组合物在制备治疗MAGL介导的疾病或病症的药物中的用途。
4.如权利要求3所述的用途，其特征在于，其中所述疾病或病症选自：代谢紊乱，肾病，呕吐或涌吐或恶心，进食障碍，神经病变，精神分裂症，抑郁症，双相障碍，震颤，运动障碍，戒断综合征，外伤性脑损伤，非外伤性脑损伤，脊髓损伤，癫痫发作，与异常细胞生长或增殖有关的病症，炎症性病症，免疫系统病症，急性应激障碍，物质诱导性焦虑，强迫症，焦虑症，注意缺陷障碍，疼痛，脱髓鞘病，及认知损害。
5.如权利要求3所述的用途，其特征在于，所述疾病或病症选自代谢紊乱，抑郁症，戒断综合征，与异常细胞生长或增殖有关的病症例如良性肿瘤或癌症，炎症性病症，免疫系统病症，急性应激障碍，焦虑症，注意缺陷障碍。
6.如权利要求3所述的用途，其特征在于，所述疾病或病症选自抑郁症，与异常细胞生长或增殖有关的病症，炎症性病症，免疫系统病症，焦虑症，注意缺陷障碍。
7.如权利要求3所述的用途，其特征在于，所述疾病或病症为良性肿瘤或癌症。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910104696 | 2019-02-01 | ||
| CN2019101046965 | 2019-02-01 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111518048A CN111518048A (zh) | 2020-08-11 |
| CN111518048B true CN111518048B (zh) | 2024-04-30 |
Family
ID=71900390
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010058304.9A Active CN111518048B (zh) | 2019-02-01 | 2020-01-19 | Magl抑制剂、制备方法和用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111518048B (zh) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4612388A (en) * | 1984-04-10 | 1986-09-16 | Mitsui Toatsu Chemicals, Incorporated | Process for producing N-acylphenylalanines |
| GB2184120A (en) * | 1985-12-06 | 1987-06-17 | Budapesti Vegyimuevek | Novel azlactone derivatives, process for the preparation thereof and pesticides containing these compounds as active ingredient |
| CN1120533A (zh) * | 1994-05-02 | 1996-04-17 | 赫彻斯特股份公司 | N-酰基-α-氨基酸衍生物的制备方法 |
| WO2000024392A1 (fr) * | 1998-10-26 | 2000-05-04 | Sumitomo Pharmaceuticals Company, Limited | Inhibiteur de la formation de beta-amyloide |
-
2020
- 2020-01-19 CN CN202010058304.9A patent/CN111518048B/zh active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4612388A (en) * | 1984-04-10 | 1986-09-16 | Mitsui Toatsu Chemicals, Incorporated | Process for producing N-acylphenylalanines |
| GB2184120A (en) * | 1985-12-06 | 1987-06-17 | Budapesti Vegyimuevek | Novel azlactone derivatives, process for the preparation thereof and pesticides containing these compounds as active ingredient |
| CN1120533A (zh) * | 1994-05-02 | 1996-04-17 | 赫彻斯特股份公司 | N-酰基-α-氨基酸衍生物的制备方法 |
| WO2000024392A1 (fr) * | 1998-10-26 | 2000-05-04 | Sumitomo Pharmaceuticals Company, Limited | Inhibiteur de la formation de beta-amyloide |
Non-Patent Citations (2)
| Title |
|---|
| American Chemical Society（ACS）.CAS RN为297142-55-3的化合物.《STNext Registry 数据库》.2000,摘要. * |
| CAS RN为297142-55-3的化合物;American Chemical Society（ACS）;《STNext Registry 数据库》;摘要 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111518048A (zh) | 2020-08-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102015635B (zh) | 氮杂环丁烷衍生物 | |
| CN102333568A (zh) | 药物化合物 | |
| CA2554610A1 (fr) | Derives d'aryl- et d'heteroaryl-piperidinecarboxylates, leur preparation et leur application comme inhibiteurs de l'enzyme faah | |
| Liu et al. | Design, synthesis, and biological evaluation of novel (4-(1, 2, 4-oxadiazol-5-yl) phenyl)-2-aminoacetamide derivatives as multifunctional agents for the treatment of Alzheimer's disease | |
| CN111518020A (zh) | Magl抑制剂及其制备方法、用途 | |
| NZ573352A (en) | Substituted carboxamides as group i metabotropic receptor antagonists | |
| CN111518048B (zh) | Magl抑制剂、制备方法和用途 | |
| Noori et al. | Phenyl-quinoline derivatives as lead structure of cholinesterase inhibitors with potency to reduce the GSK-3β level targeting Alzheimer's disease | |
| EP2234966B1 (fr) | Derives d'azetidines, leur preparation et leur application en therapeutique | |
| CN111518049B (zh) | Magl抑制剂、制备方法及用途 | |
| US9688664B2 (en) | Modulators of fatty acid amide hydrolase | |
| CN111518047B (zh) | Magl抑制剂及制备方法和用途 | |
| EP2265580B1 (en) | Novel method for the production of sulphonylpyrroles as hdac inhibitors | |
| CN107556316A (zh) | 含桥环的咪唑衍生物 | |
| WO2021042911A1 (zh) | Magl抑制剂及其制备方法、用途 | |
| CN107556315A (zh) | 含四元环的咪唑衍生物 | |
| CN112552229A (zh) | Magl抑制剂及制备方法和用途 | |
| CN112552253A (zh) | Magl抑制剂及其制备方法和用途 | |
| CN112552227A (zh) | Magl抑制剂及其制备方法、用途 | |
| CN112552228A (zh) | Magl抑制剂及其用途 | |
| JP2020186182A (ja) | 標的蛋白質分解誘導化合物 | |
| FR2925051A1 (fr) | Derives d'azetidines,leur preparation et leur application en therapeutique | |
| WO2010146299A1 (fr) | Esters derives d'azetidines, leur preparation et leur application en therapeutique comme modulateurs des recepteurs cannabinoides | |
| KR20040047217A (ko) | 신규한 캐테콜 히드라자이드 유도체 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |