CN111087426B - 一种去甲基茴三硫衍生物及其制备方法和应用 - Google Patents
一种去甲基茴三硫衍生物及其制备方法和应用 Download PDFInfo
- Publication number
- CN111087426B CN111087426B CN201911012094.3A CN201911012094A CN111087426B CN 111087426 B CN111087426 B CN 111087426B CN 201911012094 A CN201911012094 A CN 201911012094A CN 111087426 B CN111087426 B CN 111087426B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- group
- liver
- diseases
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- RUVINXPYWBROJD-ONEGZZNKSA-N trans-anethole Chemical class COC1=CC=C(\C=C\C)C=C1 RUVINXPYWBROJD-ONEGZZNKSA-N 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 93
- 239000003814 drug Substances 0.000 claims abstract description 18
- 208000004930 Fatty Liver Diseases 0.000 claims abstract description 16
- -1 alkali metal cations Chemical class 0.000 claims abstract description 16
- 208000010706 fatty liver disease Diseases 0.000 claims abstract description 16
- 231100000240 steatosis hepatitis Toxicity 0.000 claims abstract description 16
- 206010019708 Hepatic steatosis Diseases 0.000 claims abstract description 15
- 206010013781 dry mouth Diseases 0.000 claims abstract description 12
- 208000007848 Alcoholism Diseases 0.000 claims abstract description 10
- 208000022309 Alcoholic Liver disease Diseases 0.000 claims abstract description 9
- 201000007930 alcohol dependence Diseases 0.000 claims abstract description 9
- 230000001154 acute effect Effects 0.000 claims abstract description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 7
- 208000031225 myocardial ischemia Diseases 0.000 claims abstract description 7
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 6
- 208000008964 Chemical and Drug Induced Liver Injury Diseases 0.000 claims abstract description 5
- 206010072268 Drug-induced liver injury Diseases 0.000 claims abstract description 5
- 231100000594 drug induced liver disease Toxicity 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- 239000007924 injection Substances 0.000 claims description 14
- 238000002347 injection Methods 0.000 claims description 14
- 208000019423 liver disease Diseases 0.000 claims description 14
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 10
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 9
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000002775 capsule Substances 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 239000003405 delayed action preparation Substances 0.000 claims description 4
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 3
- 208000006011 Stroke Diseases 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000000443 aerosol Substances 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 230000002490 cerebral effect Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000003086 colorant Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 239000002502 liposome Substances 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 229910001414 potassium ion Inorganic materials 0.000 claims description 2
- 229910001415 sodium ion Inorganic materials 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 239000000375 suspending agent Substances 0.000 claims description 2
- 230000002459 sustained effect Effects 0.000 claims description 2
- HBBGRARXTFLTSG-UHFFFAOYSA-N Lithium ion Chemical compound [Li+] HBBGRARXTFLTSG-UHFFFAOYSA-N 0.000 claims 1
- 239000006172 buffering agent Substances 0.000 claims 1
- 238000009472 formulation Methods 0.000 claims 1
- 229910001416 lithium ion Inorganic materials 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 18
- 229940079593 drug Drugs 0.000 abstract description 14
- 201000010099 disease Diseases 0.000 abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 11
- 208000005946 Xerostomia Diseases 0.000 abstract description 10
- 206010008118 cerebral infarction Diseases 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 7
- 201000006474 Brain Ischemia Diseases 0.000 abstract description 6
- 206010008120 Cerebral ischaemia Diseases 0.000 abstract description 6
- 208000011580 syndromic disease Diseases 0.000 abstract description 6
- 241000700159 Rattus Species 0.000 description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 18
- 210000004185 liver Anatomy 0.000 description 13
- 238000000465 moulding Methods 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 11
- 238000012360 testing method Methods 0.000 description 10
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 9
- 108010082126 Alanine transaminase Proteins 0.000 description 9
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 9
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 229960003180 glutathione Drugs 0.000 description 9
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 229940118019 malondialdehyde Drugs 0.000 description 8
- 230000001681 protective effect Effects 0.000 description 8
- 210000003462 vein Anatomy 0.000 description 8
- 238000005303 weighing Methods 0.000 description 8
- PKDBCJSWQUOKDO-UHFFFAOYSA-M 2,3,5-triphenyltetrazolium chloride Chemical compound [Cl-].C1=CC=CC=C1C(N=[N+]1C=2C=CC=CC=2)=NN1C1=CC=CC=C1 PKDBCJSWQUOKDO-UHFFFAOYSA-M 0.000 description 7
- 206010067125 Liver injury Diseases 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 210000001168 carotid artery common Anatomy 0.000 description 6
- 231100000753 hepatic injury Toxicity 0.000 description 6
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 6
- 229960003105 metformin Drugs 0.000 description 6
- 238000010186 staining Methods 0.000 description 6
- 240000001624 Espostoa lanata Species 0.000 description 5
- 235000009161 Espostoa lanata Nutrition 0.000 description 5
- 206010061216 Infarction Diseases 0.000 description 5
- 102000036639 antigens Human genes 0.000 description 5
- 108091007433 antigens Proteins 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 230000007574 infarction Effects 0.000 description 5
- 208000028867 ischemia Diseases 0.000 description 5
- 230000000302 ischemic effect Effects 0.000 description 5
- 210000003296 saliva Anatomy 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 108010024636 Glutathione Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 206010063837 Reperfusion injury Diseases 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 208000019425 cirrhosis of liver Diseases 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 210000005036 nerve Anatomy 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 4
- 230000010410 reperfusion Effects 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000003044 adaptive effect Effects 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000007963 capsule composition Substances 0.000 description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 3
- 210000000269 carotid artery external Anatomy 0.000 description 3
- 230000002354 daily effect Effects 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 230000035622 drinking Effects 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 238000002649 immunization Methods 0.000 description 3
- 230000003053 immunization Effects 0.000 description 3
- 230000035987 intoxication Effects 0.000 description 3
- 231100000566 intoxication Toxicity 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 210000000214 mouth Anatomy 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000007916 tablet composition Substances 0.000 description 3
- 239000001074 1-methoxy-4-[(E)-prop-1-enyl]benzene Substances 0.000 description 2
- 229910002012 Aerosil® Inorganic materials 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZIRCWPVSEKXWJX-UHFFFAOYSA-N COC1C=C(C(=S)C(=S)C1=S)O Chemical compound COC1C=C(C(=S)C(=S)C1=S)O ZIRCWPVSEKXWJX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 2
- 206010013774 Dry eye Diseases 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 206010019663 Hepatic failure Diseases 0.000 description 2
- 206010019728 Hepatitis alcoholic Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 241000220317 Rosa Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 231100000570 acute poisoning Toxicity 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 208000002353 alcoholic hepatitis Diseases 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 210000000702 aorta abdominal Anatomy 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000005013 brain tissue Anatomy 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 231100000739 chronic poisoning Toxicity 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 231100000234 hepatic damage Toxicity 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 2
- 230000008818 liver damage Effects 0.000 description 2
- 231100000835 liver failure Toxicity 0.000 description 2
- 208000007903 liver failure Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000011812 mixed powder Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 238000002203 pretreatment Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 1
- 206010049047 Chapped lips Diseases 0.000 description 1
- 206010008635 Cholestasis Diseases 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 206010051625 Conjunctival hyperaemia Diseases 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 206010013789 Dry throat Diseases 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- 206010024552 Lip dry Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000130764 Tinea Species 0.000 description 1
- 208000002474 Tinea Diseases 0.000 description 1
- 206010046274 Upper gastrointestinal haemorrhage Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 206010001584 alcohol abuse Diseases 0.000 description 1
- 208000025746 alcohol use disease Diseases 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 210000004004 carotid artery internal Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 231100000359 cholestasis Toxicity 0.000 description 1
- 230000007870 cholestasis Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 208000002925 dental caries Diseases 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000037336 dry skin Effects 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 229950009041 edaravone Drugs 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229960003699 evans blue Drugs 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 210000004013 groin Anatomy 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 208000023589 ischemic disease Diseases 0.000 description 1
- 229960003350 isoniazid Drugs 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 231100000832 liver cell necrosis Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 210000003657 middle cerebral artery Anatomy 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000024121 nodulation Effects 0.000 description 1
- 210000000956 olfactory bulb Anatomy 0.000 description 1
- RUVINXPYWBROJD-UHFFFAOYSA-N para-methoxyphenyl Natural products COC1=CC=C(C=CC)C=C1 RUVINXPYWBROJD-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000013077 scoring method Methods 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000007863 steatosis Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 210000001913 submandibular gland Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 210000001186 vagus nerve Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
- C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
-
- 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
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/12—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic the nitrogen atom of the amino group being further bound to hydrocarbon groups substituted by hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
- C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
- C07H5/06—Aminosugars
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Toxicology (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
技术领域
本发明属于医药技术领域,具体涉及一种去甲基茴三硫衍生物及其制备方法和应用。
背景技术
口干症是口腔内唾液缺乏所引起的一种症状。以口腔干燥为主要表现,口中苦涩,舌部运动不灵活,吞咽困难,***干裂、有鳞屑,口角易皲裂,常有严重进行性龋齿。同时还可伴有皮肤干燥、眼干、咽干、鼻腔干燥的症状。半数患者皮肤干燥,有鳞屑和痒感,因搔抓而苔癣化;眼干燥无泪,结膜充血,角膜干燥;上呼吸道黏膜萎缩,鼻黏膜干燥结痴。临床上口干症十分常见,尤其是老年人和化疗病人发病率更高,病人在病程中十分痛苦,且缓解病症的药物较少,防治口干症的药物属于临床未满足的需求。
脂肪肝是一种常见肝病变,是指各种原因引起的肝细胞内脂肪堆积,当脂肪含量超过肝重量(湿重)的5%,或在组织学上超过肝实质30%时,称为脂肪肝。从进程上可以将脂肪肝分为3期,第I期为单纯性脂肪肝,第II期为脂肪性肝炎,约有10%转化为III期,第III期则为脂肪性肝纤维化和肝硬化。脂肪肝在我国是仅次于肝炎的第二大肝病,并且发病率还在稳步提高。在欧美脂肪肝病人多于肝炎病人,也是十大常见死因之一,总之脂肪肝成为威胁人类生命健康的严重问题,防治脂肪肝的药物也是临床未满足的需求。
药物性肝病是指某些药物对肝的直接或间接损伤引起的疾病。由于药物或/及其代谢产物引起的肝脏损害。可以发生在以往没有肝病史的健康者或原来就有严重疾病的病人,在使用某种药物后发生程度不同的肝脏损害。目前至少有600多种药物可引起,其表现与人类各种肝病的表现相同,可以表现为肝细胞坏死、胆汁淤积、细胞内微脂滴沉积或慢性肝炎、肝硬化等。
酒精性肝病(Alcoholic Hepatitis)是由于长期大量饮酒导致的肝脏疾病。初期通常表现为脂肪肝,进而可发展成酒精性肝炎、肝纤维化和肝硬化。其主要临床特征是恶心、呕吐、黄疸、可有肝脏肿大和压痛。并可并发肝功能衰竭和上消化道出血等。严重酗酒时可诱发广泛肝细胞坏死,甚至肝功能衰竭。酒精性肝病是我国常见的肝脏疾病之一,严重危害人民健康。近年来酒精性肝病占同期肝病住院患者的比例在不断上升,防治酒精性肝病的药物属于临床未满足的需求。
酒精中毒俗称醉酒,是指患者一次饮大量酒精(乙醇)后发生的机体机能异常状态,对神经***和肝脏伤害最严重。医学上将其分为急性中毒和慢性中毒两种,前者可在短时间内给患者带来较大伤害,甚至可以直接或间接导致死亡。我国是饮酒大国,有文献报道我国急性酒精中毒患者占同期急诊患者的0.5%,占急性中毒患者的49%,治疗急性酒精中毒的药物属于临床未满足的需求。
心脑血管疾病是心脏血管疾病和脑血管疾病的统称,泛指由于高脂血症、血液黏稠、动脉粥样硬化以及高血压等所导致的心脏、大脑及全身组织发生的缺血性或出血性疾病。心脑血管疾病是一种严重威胁人类特别是50岁以上中老年人健康的常见病,其具有高患病率、高致残率和高死亡率的特点。目前,心脑血管疾病的治疗手段多种多样,但是即使应用目前最先进、完善的治疗手段,仍可有50%以上的心脑血管意外幸存者生活不能完全自理。据统计,全世界每年死于心脑血管疾病的人数高达1500万人,居各种死因首位。
发明内容
为了解决上述问题,本发明提供了一种去甲基茴三硫衍生物及其制备方法和应用。
本发明提供了一种式(I)所示化合物:
其中,
R1、R2分别或同时选自H、碱金属阳离子或有机胺阳离子;
X选自O、S或S=O。
进一步地,R1、R2分别或同时选自H或碱金属阳离子;所述碱金属阳离子为锂离子、钾离子、钠离子。
进一步地,所述化合物为:
进一步地,R1、R2分别选自H或有机胺阳离子,且R1、R2不同时为H;所述的有机胺阳离子如下所示:
进一步地,所述化合物为:
本发明还提供了前述的化合物在制备预防和/或治疗口干症、肝病、急性酒精中毒或心脑血管疾病的药物中的用途。
进一步地,所述肝病为脂肪肝、药物性肝病或酒精性肝病;和/或,所述心脑血管疾病为脑卒中或心肌缺血。
本发明还提供了一种药物组合物,它是以前述的化合物为活性成分,加上药学上可接受的辅料制备而成的制剂。
进一步地,所述药学上可接受的辅料选自稀释剂、填充剂、着色剂、助流剂、润滑剂、粘合剂、稳定剂、助悬剂或缓冲剂的任一种或多种。
进一步地,所述制剂是片剂、胶囊剂、口服液、注射剂、透皮剂、气雾剂固体制剂、脂质体制剂或缓控释制剂;优选地,所述制剂单位中含前述的化合物5-200mg/kg。
本发明中,室温为25±5℃;过夜为12±2h。
本发明中,碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀Ca~Cb烷基表明任何含“a”至“b”个碳原子的烷基,因此,例如,C1~C6烷基是指包含1~6个碳原子的烷基。
本发明化合物具有较好的水溶解度,且在防治口腔干燥综合征、脂肪肝、药物性肝病、酒精性肝病、急性酒精中毒、脑缺血、心脏缺血等疾病中具有优异的效果;本发明化合物可用于制备治疗前述疾病的药物,具有良好的应用前景。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为本发明化合物I-1-2的质谱图。
图2为本发明化合物的实验性脑缺血损伤大鼠NSS评分结果柱形图。
图3为各组的TTC染色测量法检测实验大鼠脑梗死体积柱形图。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
下面实施例中若无特殊说明,采用的方法为本领域常规方法。
实施例1、去甲基茴三硫(ADT)的制备
20克茴三硫(M1),58克无水吡啶盐酸盐混合均匀,氮气保护,缓慢加热到220摄氏度,固体全部溶解成均相体系,维持220摄氏度继续搅拌30分钟,自然冷却到室温。加200ml乙酸乙酯和200ml水加热至50摄氏度搅拌30分钟,过滤除去不溶物,所得滤液静置分层,取乙酸乙酯层,分别用40ml清水水洗两次,加50克无水硫酸钠和5克活性碳干燥脱色过夜。第二日过滤除去硫酸钠和活性碳,浓缩至有固体析出时加50ml石油醚搅拌结晶。结晶完全后过滤得橙黄色固体12克。收率63.7%。
1HNMR(DMSO,400MHz):δppm:7.77(m,2H),7.69(m,1H),6.90(m,2H)。
实施例2、本发明化合物I-1-1的制备
20克去甲基茴三硫(ADT)用200ml二氯甲烷溶解,加入吡啶21克,降温至-10摄氏度以下,缓慢滴加三氯氧磷27克,滴完三氯氧磷后于-5~0摄氏度反应5小时,去甲基茴三硫反应完全。加入200ml冰水,搅拌半小时后静置,所得化合物I-1-1粗品以油状物沉于瓶底。倾掉水和二氯甲烷,残留油状物分别用40ml 1N盐酸洗涤2次除吡啶盐酸盐。倾掉盐酸后所得产物用100ml四氢呋喃溶解,加30克无水硫酸钠干燥。过滤除去硫酸钠浓缩四氢呋喃至干得I-1-1化合物24克,收率88.6%。
ESI m/z:349.89[M+2Na+]。
实施例3、本发明化合物I-1-2、I-1-3的制备
12克化合物I-1-1用30ml无水乙醇溶解,室温搅拌下慢慢滴加甲醇钠的甲醇饱和溶液,直至pH值为7.5左右,约消耗甲醇钠2.5克。滴加完成后继续室温搅拌30分钟,过滤烘干得红褐色固体,即化合物I-1-2粗品11克,收率80%。
11克I-1-2粗品用44克纯净水加热到70摄氏度溶解,自然冷却到室温,慢慢加入88克无水乙醇产品结晶析出,继续搅拌1小时后过滤,烘干得化合物I-1-2浅红色固体7克,收率63.6%。本发明化合物I-1-2的质谱图如图1所示。
ESI m/z:394.00[M+2Na+]。
1HNMR(DMSO,400MHz):δppm:7.8(m,2H),7.7(m,1H),7.36(m,2H)。
同本实施例方法,消耗甲醇钠1.25克,可得去甲茴三硫磷酸酯单钠盐,即本发明化合物I-1-3浅红色固体6.7克。
实施例4、本发明化合物I-1-4的制备
3克化合物I-1-2用10毫升纯净水室温溶解,降温至内温0摄氏度,缓慢滴加10%双氧水3.5克,保持内温0摄氏度搅拌1小时,加入足量乙醇淬灭,过滤,烘干得化合物I-1-4深黄色固体2.5克,收率79.7%。
ESI m/z:411.84[M+2Na+]。
实施例5、本发明化合物I-1-5的制备
3克化合物I-1-2用10毫升纯净水室温溶解,降温至内温0摄氏度,缓慢滴加10%双氧水14.5克,保持内温0摄氏度搅拌过夜。带反应完全后,加入足量乙醇淬灭,过滤,烘干得化合物I-1-5深黄色固体2.4克,收率84%。
ESI m/z:379.92[M+2Na+]。
1HNMR(DMSO,400MHz):δppm:7.76(dd,J=8.8,3.3Hz,2H),7.67(d,J=3.5Hz,1H),7.34(dd,J=3.2Hz,2H)。
实施例6、本发明化合物药用片剂组合物的制备
化合物I-1-1的药用片剂组合物,其组成分别为I-1-1化合物1重量份,乳糖0.1-0.5重量份,羟丙纤维素0.05-0.08重量份,羧甲基淀粉钠0.008-0.014重量份,聚维酮K30适量,硬脂酸镁0.01-0.05重量份;按照上述比例制备成片剂,每片含化合物I-1-1为50毫克。
化合物I-1-2、I-1-3、I-1-4、I-1-5的药用片剂组合物制备方法同上述。
实施例7、本发明化合物药用胶囊组合物的制备
化合物I-1-2的药用胶囊剂组合物,含有25克化合物I-1-2、171克乳糖、4克微粉硅胶,共计200克及2号空心胶囊。制备方法为:
a,使用常规方法混合化合物I-1-2,乳糖和微粉硅胶,得混合粉末;
b,将混合粉末过120目筛后装填入2号胶囊并封口,共制1000粒。
其中,每粒胶囊含25毫克化合物I-1-2。
化合物I-1-1、I-1-3、I-1-4、I-1-5的药用胶囊剂组合物制备方法同上述。
实施例8、本发明化合物药用注射剂组合物的制备
化合物I-1-2的药用注射剂组合物,含有100克I-1-2、34克磷酸氢二钠及足量注射用水。制备方法为:
a,用二氧化碳饱和注射用水溶解磷酸氢二钠、I-1-2,用二氧化碳饱和注射用水配置到2000ml;
b,a步骤所得溶液滤过,分装于1000瓶2ml安瓿瓶中,熔封安瓿;
c,b中所得安瓿瓶流通蒸汽灭菌,检查。
化合物I-1-3、I-1-4、I-1-5的的药用注射剂组合物制备方法同上述。
以下通过具体的试验例证明本发明的有益效果。
试验例1、本发明化合物增加大鼠口腔干燥综合征唾液流量
Wistar大鼠,雄性,体重220-250g,由成都达硕实验动物有限公司提供,共计42只。将大鼠随机分组(其中2只留作抗原制备)每组8只,分别为:空白对照组、造模生理盐水组、化合物I-1-2、I-1-4、I-1-5给药组。
抗原的制备:取鼠颌下腺组织冰上匀浆,与同体积弗氏完全佐剂(CFA)充分混匀乳化,得到乳化蛋白抗原(质量浓度为600μg/ml)。
大鼠口腔干燥综合征造模:造模生理盐水组和给药组的大鼠进行造模处理,分别将乳化蛋白抗原多点注射大鼠两后脚掌与两侧腹股沟皮下,每只大鼠每次总剂量l ml。首次免疫后第21,35d,用乳化自身颌下腺蛋白抗原加强免疫2次,在自身免疫反应诱导开始后的第1,7,21,35天,每只鼠背部分别注射百白破疫苗0.2ml,共4次以增强免疫反应。空白对照组不进行造模。
各组给药:免疫7周后,空白对照组和造模生理盐水组每只口服灌胃生理盐水1ml/天;三个给药组分别口服灌胃化合物I-1-2、I-1-4、I-1-5,剂量为10mg/kg/天,化合物I-1-2、I-1-4、I-1-5用生理盐水配制,灌胃体积为1ml。给药周期为6周。
计算唾液流量:根据公式:唾液流量(mg)=棉球湿重-棉球干重,测得各组大鼠静息状态10min唾液流量,具体方法:用弯头镊子捡取小棉球,称质量为M0,然后置于大鼠舌下,并用镊子将其固定,10min后测小棉球质量为M1,(M1-M0)即为大鼠唾液流量。
实验结果如表1,本发明化合物I-1-2、I-1-4、I-1-5给药6周后,能明显增加唾液流量(与造模生理盐水组相比,**P<0.001),显示出改善口腔干燥综合征的作用。
表1本发明化合物增加实验大鼠唾液流量
组别 | 大鼠唾液流量(mg) |
空白对照组 | 35.6±2.3 |
造模生理盐水组 | 27.4±1.9 |
I-1-2组 | 34.8±1.7<sup>**</sup> |
I-1-4组 | 33.2±2.0<sup>**</sup> |
I-1-5组 | 34.1±1.9<sup>**</sup> |
试验例2、本发明化合物防治脂肪肝的动物实验研究
选雄性Wistar大鼠120只,体重180-220g,由成都达硕实验动物有限公司提供,分为6组,每组20只。本发明化合物实验时先用适量吐温研磨,再用0.5%的羧甲基纤维素钠混悬液(CMC)按设计浓度配制。
大鼠经适应性喂养3天后,每天上午各组大鼠给予30mg/kg(使用等量的0.5%CMC混悬液配制)化合物I-1-2、I-1-4、I-1-5和metformin(二甲双胍),空白组和模型组给予等量的0.5%CMC混悬液。下午除空白组外,其余各组大鼠隔天腹腔注射10%的CCl4菜籽油溶液,注射剂量为:0.08ml/100g,空白组以等容积生理盐水注射于相同部位。
于第18天末次给药后禁食16小时(不禁水),动物称重,股动脉取血,离心并分离血清,-30℃低温保存,待测血清中的生化指标。另摘取肝脏并称重,观察大体外观后,每只取肝左叶2块分别放于10%中性***溶液,待作肝组织病理学检查(固定后,石蜡包埋,切片,分别作HE染色和脂肪染色)。
各组大鼠生化指标记录如下表2。
表2各组大鼠血清生化指标
注:和metformin比较:**P<0.01,*P<0.05。
肝组织病理学检查分析结果如下表3。
表3各组大鼠肝组织病理学检查
注:和metformin比较:**P<0.01,*P<0.05。
肝脂肪染色评价结果如下表4。
表4各组大鼠肝脂肪染色结果
组别 | 给药剂量(mg/kg) | 评分 |
空白组 | N/A | 0 |
模型组 | N/A | 2.4 |
I-1-2 | 30 | 1.3* |
I-1-4 | 30 | 1.0** |
I-1-5 | 30 | 1.4* |
metformin | 30 | 1.6 |
注:和metformin比较:**P<0.01,*P<0.05。
上述实验表明,本发明化合物不仅可显著降低生化指标TG、CHOL、ALT、AST,而且针对肝脏病理损伤,尤其是肝细胞脂肪变性具有明显改善作用。
试验例3、本发明化合物对酒精性肝损伤大鼠的保护作用
SD大鼠,雄性,体重220-250g,共计36只。适应性喂养7天后,禁食12小时,随机分为3组:空白对照组12只,模型组12只和给药组12只。空白对照组给予常规词料,自由进食、饮水,每天灌胃给予等体积生理盐水;模型组和给药组每天给予56度高度白酒灌胃,剂量随时间延长而递增,第1周为8g/kg,第2周为10g/kg,第3周起至试验结束为12g/kg。酒精剂量(g)=白酒体积(ml)×白酒体积分数(0.56)×酒精相对密度。给药组于造模开始同时还灌胃化合物I-1-2(生理盐水配制,剂量为30mg/kg),上述各组同法饲养至实验结束。第24周所有动物禁食小时后腹主动脉取血,离心后取血清检测丙氨酸氨基转移酶(alaninetransaminase,ALT),天冬氨酸氨基转移酶(aspartate transaminase,AST),丙二醛(malondialdehyde,MDA),谷胱甘肽(glutathione,GSH)。结果见表5,化合物I-1-2给药后,能显著下降酒精引起ALT、AST、MDA以及GSH指标异常,与模型组相比,差异显著(**P<0.001),该结果显示本发明化合物对酒精导致大鼠的肝损伤有明显的保护作用。
表5酒精性肝损伤大鼠血清相关指标的影响
组别 | ALT(IU/L) | AST(IU/L) | MDA(nmol/ml) | GSH(mg/L) |
空白对照组 | 70.08±16.9 | 15.89±1.33 | 3.31±0.98 | 11.57±3.33 |
模型组 | 225.19±20.8 | 88.91±16.35 | 15.31±1.18 | 25.13±3.21 |
给药组 | 120.03±11.85<sup>**</sup> | 36.23±17.95<sup>**</sup> | 6.21±2.52<sup>**</sup> | 14.59±4.22<sup>**</sup> |
试验例4、本发明化合物对药物性肝损伤大鼠的保护作用
SD大鼠,雄性,体重220-250g,共计36只。适应性喂养7天后,禁食12小时,随机分为3组:空白对照组12只,模型组12只和给药组12只。空白对照组给予常规词料,自由进食、饮水,每天灌胃给予等体积生理盐水;模型组和给药组每天给予75mg/kg异烟肼,共给药14天。给药组于造模开始同时还灌胃化合物I-1-2(生理盐水配制,剂量为30mg/kg),上述各组同法饲养至实验结束。第24周所有动物禁食小时后腹主动脉取血,离心后取血清检测丙氨酸氨基转移酶(alanine transaminase,ALT),天冬氨酸氨基转移酶(aspartatetransaminase,AST),丙二醛(malondialdehyde,MDA),谷胱甘肽(glutathione,GSH)。结果见表6,化合物I-1-2给药后,能显著下降酒精引起ALT、AST、MDA以及GSH指标异常,与模型组相比,差异显著(**P<0.001),该结果显示本发明化合物对药物导致大鼠的肝损伤有明显的保护作用。
表6酒精性肝损伤大鼠血清相关指标的影响
组别 | ALT(IU/L) | AST(IU/L) | MDA(nmol/ml) | GSH(mg/L) |
空白对照组 | 67.78±17.4 | 16.21±2.33 | 3.55±1.03 | 12.31±2.32 |
模型组 | 263.01±23.1 | 113.19±15.41 | 21.00±1.68 | 32.07±3.13 |
给药组 | 166.29±23.04<sup>**</sup> | 51.37±14.75<sup>**</sup> | 4.34±1.15<sup>**</sup> | 15.19±4.08<sup>**</sup> |
试验例5、本发明化合物加快急性酒精中毒大鼠苏醒
SD大鼠,雄性,体重220-250g,共计24只。适应性喂养3天后,禁食12小时,随机分为2组,模型组和给药组各12只。模型组大鼠灌胃75%乙醇,剂量为10ml/kg,出现醉酒状态时尾静脉注射生理盐水(500μl);给药组大鼠灌胃75%乙醇,剂量为10ml/kg,出现醉酒状态时尾静脉注射化合物I-1-2,剂量为5mg/kg,化合物I-1-2为生理盐水配制,注射体积为500μl。记录醉酒时间以及醒酒时间:以1min内翻正反射小于3次确定醉酒状态;醒酒时间:翻正反射恢复时间。结果如表7,化合物I-1-2缩短了动物从醉酒状态到苏醒状态的时间间隔,与模型组相比具有明显的解酒作用(**P<0.001)。
表7本发明化合物缩短实验大鼠从醉酒状态到苏醒状态的时间间隔
组别 | 平均苏醒时间(h) |
模型组 | 8.3±2.2 |
给药组 | 5.1±1.5<sup>**</sup> |
试验例6、本发明化合物对实验性脑缺血损伤大鼠的保护作用
线栓法制备局灶性脑缺血(MCAO)大鼠模型:按线栓造模方法进行部分改良;10%水合氯醛3.5mL/kg腹腔注射麻醉,大鼠仰卧位固定于手术台上,常规消毒,颈部正中切口,暴露右侧颈总动脉和颈外动脉,小心分离与颈总动脉伴行的迷走神经,结扎颈总动脉和颈外动脉,在距离分叉处0.5cm左右用眼科剪将颈总动脉剪一小切口,将备用线栓送入切口,向内推行,将线栓沿颈总动脉、颈内动脉顺行至中动脉,遇到阻力时停止,从颈总动脉分叉处计算***深度(1.8±0.5)cm,造成大鼠大脑中动脉血供阻断,1小时后拔除栓线。
动物分组:(1)假手术组;(2)缺血再灌注模型组;(3)本发明化合物I-1-2(10mg/kg)干预组:生理盐水配制,造模后立即尾静脉注射给药一半剂量,栓线拔出后6小时尾静脉注射给药剩余一半剂量;(4)本发明化合物I-1-5(10mg/kg)干预组:生理盐水配制,造模后立即尾静脉注射给药一半剂量,栓线拔出后6小时尾静脉注射给药剩余一半剂量;(5)依达拉奉(Edaravone)(6mg/kg)阳性对照组,生理盐水配制,造模后立即给药,尾静脉注射;(6)羟基茴三硫(ADT)(10mg/kg)阳性对照组,玉米油溶解配制,缺血再灌注3小时后腹腔注射一半剂量,缺血再灌注10小时后腹腔注射剩余一半剂量。
分别于造模后、造模后24小时,进行神经功能评分,采用NSS评分法,分数越高代表神经功能损伤更严重。
2,3,5-氯化三苯四唑(TTC)染色测量脑梗死体积:缺血脑组织梗死率造模后25h,将大鼠断头处死,迅速取出大脑,用冷盐水冲洗后,快速于-20℃冰箱中放置10min,待脑组织稍硬后,取出,切掉嗅球、垂体、低位脑干,由前向后冠状切片,均匀切成2mm厚脑片,等分切成5片,置于1%TTC溶液中,37℃避光孵育30min,每隔5min左右翻动1次。TTC可与正常组织内的脱氢酶***反应被还原为玫瑰红色而使正常组织染呈玫瑰红色,梗死组织呈白色,且界限分明,眼科镊精确剥离梗死部位,电子天平精密称取总重并记录,计算脑梗死体积。
结果表明:NSS评分证明本发明化合物I-1-2与I-1-5的注射减轻了大鼠的神经神缺损(图2),造模后24h神经功能改善优于模型组,差异显著(*P≤0.05);造模后第24h,TTC染色测量脑梗死体积结果(图3)证明本发明化合物I-1-2及I-1-5明显减少梗死体积,与模型组相比差异显著(*P≤0.05)。
由上述数据可知,本发明提供的化合物与已见报道的羟基茴三硫(ADT)相比,水溶性强,配制操作简便,且在相同剂量下起到更强的治疗效果,差异显著(*P≤0.05)。
试验例7、本发明化合物对大鼠心脏缺血再灌注损伤的保护作用
将220~250g健康雄性SPF级SD大鼠,适应性喂养1周后,状态良好。
大鼠随机分为假手术(Sham)组、心脏缺血再灌注损伤(MI/R)组和本发明化合物预处理组(MI/R组和本发明化合物预处理组给药剂量均为5mg/kg),每组10只。本发明化合物预处理组术前尾静脉注射本发明化合物,而MI/R组术前给予等体积量0.900氯化钠溶液,预处理组、MI/R组给药14天后,给予心脏缺血再灌注手术;再灌注4h后,将冠状动脉左前降支原位重新结扎,由主动脉注入伊文思蓝,待心脏非缺血区分染成蓝色后,摘取心脏后用4℃盐水漂洗,切片,TTC液染色固定,染成蓝色的区域为非缺血区,红色区域(含白色区)为缺血区,白色区域为梗死区;各区域面积用Image ProPlus软件检测,心肌梗死面积以梗死区/缺血区×100%表示,结果如表8所示。
表8本发明化合物对大鼠心脏缺血再灌注损伤的保护作用
分组 | 给药剂量 | 心肌梗死面积(%) |
Sham | / | 0.7±0.2 |
MI/R | / | 70.8±12.1 |
I-1-2组 | 5mg/kg | 52.6±3.7* |
I-1-4组 | 5mg/kg | 53.0±4.7* |
I-1-5组 | 5mg/kg | 50.9±4.1* |
由表8可知,本发明化合物对大鼠心脏缺血再灌注损伤有明显保护作用,和MI/R组相比,梗死面积明显降低,差异显著(*P≤0.05)。
综上,本发明化合物具有较好的水溶解度,且在防治口腔干燥综合征、脂肪肝、药物性肝病、酒精性肝病、急性酒精中毒、脑缺血、心脏缺血等疾病中具有优异的效果;本发明化合物可用于制备治疗前述疾病的药物,具有良好的应用前景。
Claims (11)
2.根据权利要求1所述的化合物,其特征在于:R1、R2分别或同时选自H或碱金属阳离子;所述碱金属阳离子为锂离子、钾离子、钠离子。
6.权利要求1-5任一项所述的化合物在制备预防和/或治疗口干症、肝病、急性酒精中毒或心脑血管疾病的药物中的用途。
7.根据权利要求6所述的用途,其特征在于:所述肝病为脂肪肝、药物性肝病或酒精性肝病;和/或,所述心脑血管疾病为脑卒中或心肌缺血。
8.一种药物组合物,其特征在于:它是以权利要求1-5任一项所述的化合物为活性成分,加上药学上可接受的辅料制备而成的制剂。
9.根据权利要求8所述的药物组合物,其特征在于:所述药学上可接受的辅料选自稀释剂、填充剂、着色剂、助流剂、润滑剂、粘合剂、稳定剂、助悬剂或缓冲剂的任一种或多种。
10.根据权利要求8所述的药物组合物,其特征在于:所述制剂是片剂、胶囊剂、口服液、注射剂、透皮剂、气雾剂固体制剂、脂质体制剂或缓控释制剂。
11.根据权利要求10所述的药物组合物,其特征在于:所述制剂单位中含权利要求1-5任一项所述的化合物5-200mg/kg。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2018112389061 | 2018-10-23 | ||
CN201811238906 | 2018-10-23 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111087426A CN111087426A (zh) | 2020-05-01 |
CN111087426B true CN111087426B (zh) | 2021-02-02 |
Family
ID=70394099
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201911012094.3A Active CN111087426B (zh) | 2018-10-23 | 2019-10-23 | 一种去甲基茴三硫衍生物及其制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111087426B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110339200A (zh) * | 2019-08-23 | 2019-10-18 | 成都贝诺科成生物科技有限公司 | 一种茴三硫衍生物的应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009065926A2 (en) * | 2007-11-22 | 2009-05-28 | Sulfidris S.R.L. | New anticancer compounds |
CN101618222A (zh) * | 2008-06-30 | 2010-01-06 | 成都国嘉联合制药有限公司 | 茴三硫磷脂复合物及其制备方法 |
CN102690316A (zh) * | 2012-06-13 | 2012-09-26 | 中国药科大学 | 甘草次酸衍生物的制备方法和作为保肝药物的医药用途 |
WO2015185918A1 (en) * | 2014-06-02 | 2015-12-10 | University Of Exeter | Combinations of a photosensitizer with a hydrogen sulfide donor, thioredoxin inhibitor or nitroxide for use in photodynamic therapy |
-
2019
- 2019-10-23 CN CN201911012094.3A patent/CN111087426B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009065926A2 (en) * | 2007-11-22 | 2009-05-28 | Sulfidris S.R.L. | New anticancer compounds |
CN101618222A (zh) * | 2008-06-30 | 2010-01-06 | 成都国嘉联合制药有限公司 | 茴三硫磷脂复合物及其制备方法 |
CN102690316A (zh) * | 2012-06-13 | 2012-09-26 | 中国药科大学 | 甘草次酸衍生物的制备方法和作为保肝药物的医药用途 |
WO2015185918A1 (en) * | 2014-06-02 | 2015-12-10 | University Of Exeter | Combinations of a photosensitizer with a hydrogen sulfide donor, thioredoxin inhibitor or nitroxide for use in photodynamic therapy |
Also Published As
Publication number | Publication date |
---|---|
CN111087426A (zh) | 2020-05-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101848711B (zh) | 一种药物组合物及其在制备治疗脑血管病药物中的应用 | |
EP3458448B1 (en) | Fasn inhibitors for use in treating non-alcoholic steatohepatitis | |
WO2006034463A2 (en) | Herbal supplement to support weight loss | |
JP2683783B2 (ja) | シェーグレン症候群治療剤 | |
KR20190116416A (ko) | 원발 담즙성 담관염을 치료하기 위한 화합물 및 방법 | |
CN111087426B (zh) | 一种去甲基茴三硫衍生物及其制备方法和应用 | |
CN117017972A (zh) | 沉香成分对ampk的激活作用 | |
KR20100046188A (ko) | 지방간을 치료하기 위한 실로스타졸을 포함하는 카르보스티릴 유도체 | |
WO2021080129A1 (ko) | 하이드란제놀 또는 필로둘신을 유효성분으로 하는 피부장벽 강화 및 아토피 피부염 개선용 조성물 | |
KR20030085558A (ko) | 비구아나이드 유도체 | |
JPS6299323A (ja) | 高脂血症剤 | |
EA007952B1 (ru) | Применение ирбесартана для изготовления лекарств, которые пригодны для предупреждения или лечения лёгочной артериальной гипертензии | |
CN114929682B (zh) | 苯并硫代吡喃酮类化合物的盐及其制备方法和用途 | |
US20080132529A1 (en) | Method of improving bioavailability for non-sedating barbiturates | |
KR20210113240A (ko) | 신경 변성 질환의 예방 또는 치료약 | |
KR101423134B1 (ko) | 신규한 판카스타틴 화합물 및 그를 유효성분으로 포함하는 조성물 | |
US20030050274A1 (en) | Composition containing S-adenosylmethionine for treating or preventing insulin resistance syndrome | |
CN101735218A (zh) | 哌啶氨基甲酸酯衍生物及其应用 | |
CN109879839B (zh) | 6-哌嗪甲基-7-羟基苯并呋喃类化合物及其医药用途 | |
KR20110084514A (ko) | 피리딘-3-카르발데히드 o-(피페리딘-1-일-프로필)-옥심 유도체를 유효 성분으로서 함유하는 망맥락막 변성 질환의 치료제 | |
JPH0358922A (ja) | ビスフェノール誘導体での真性糖尿病処置法 | |
KR100504966B1 (ko) | 진세노사이드 Rg3 및 Rh2를 함유함을 특징으로 하는 항고혈압 조성물 | |
AU2006261296B2 (en) | Pharmaceutical composition comprising a 1-(3-chlorophenyl)-3-alkylpiperazine for treating apetite disorder | |
TW202333753A (zh) | 心腦血管藥物及其應用 | |
WO2014089646A1 (pt) | Uso de produtos de paullinia cupana na prevenção ou tratamento de fogacho |
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 |