CN110339200A - A kind of application of Anethol Trithione derivative - Google Patents
A kind of application of Anethol Trithione derivative Download PDFInfo
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- CN110339200A CN110339200A CN201910783373.3A CN201910783373A CN110339200A CN 110339200 A CN110339200 A CN 110339200A CN 201910783373 A CN201910783373 A CN 201910783373A CN 110339200 A CN110339200 A CN 110339200A
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- anethol trithione
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- anethol
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- RUVINXPYWBROJD-UHFFFAOYSA-N para-methoxyphenyl Natural products COC1=CC=C(C=CC)C=C1 RUVINXPYWBROJD-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 239000001074 1-methoxy-4-[(E)-prop-1-enyl]benzene Substances 0.000 title claims abstract description 51
- RUVINXPYWBROJD-ONEGZZNKSA-N trans-anethole Chemical compound COC1=CC=C(\C=C\C)C=C1 RUVINXPYWBROJD-ONEGZZNKSA-N 0.000 title claims abstract description 36
- 208000026106 cerebrovascular disease Diseases 0.000 claims abstract description 21
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 17
- 230000002526 effect on cardiovascular system Effects 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 15
- 230000002265 prevention Effects 0.000 claims abstract description 9
- 229940079593 drug Drugs 0.000 claims description 12
- 238000002347 injection Methods 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 239000002552 dosage form Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 5
- 208000006011 Stroke Diseases 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 230000002490 cerebral effect Effects 0.000 claims description 4
- 208000031225 myocardial ischemia Diseases 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000002270 dispersing agent Substances 0.000 claims description 3
- 239000000284 extract Substances 0.000 claims description 3
- 239000003349 gelling agent Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 239000000829 suppository Substances 0.000 claims description 3
- 239000000375 suspending agent Substances 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- 239000000443 aerosol Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 239000011805 ball Substances 0.000 claims 1
- -1 demethyl Anethol Chemical compound 0.000 abstract description 17
- 230000000694 effects Effects 0.000 abstract description 5
- 241000700159 Rattus Species 0.000 description 12
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- 206010008118 cerebral infarction Diseases 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 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
- 229910019142 PO4 Inorganic materials 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 230000000302 ischemic effect Effects 0.000 description 6
- 235000021317 phosphate Nutrition 0.000 description 6
- 101800004637 Communis Proteins 0.000 description 5
- 206010063837 Reperfusion injury Diseases 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- 239000010452 phosphate Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 206010061216 Infarction Diseases 0.000 description 4
- 229910003202 NH4 Inorganic materials 0.000 description 4
- 230000007574 infarction Effects 0.000 description 4
- 208000028867 ischemia Diseases 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
- 239000011734 sodium Substances 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- 201000006474 Brain Ischemia Diseases 0.000 description 3
- 206010008120 Cerebral ischaemia Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000220317 Rosa Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 210000000941 bile Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 210000000232 gallbladder Anatomy 0.000 description 2
- 239000004519 grease Substances 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 230000010410 reperfusion Effects 0.000 description 2
- 239000004575 stone Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 208000019553 vascular disease Diseases 0.000 description 2
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- SWWQQSDRUYSMAR-UHFFFAOYSA-N 1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol;hydrochloride Chemical group Cl.C1=CC(O)=CC=C1CC1C2=CC(O)=C(O)C=C2CCN1 SWWQQSDRUYSMAR-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CNVMQWQGBYHHGM-UHFFFAOYSA-N 2,3,5-trichloro-1h-tetrazol-1-ium;chloride Chemical class [Cl-].ClN1[NH2+]C(Cl)=NN1Cl CNVMQWQGBYHHGM-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010003068 Aptyalism Diseases 0.000 description 1
- 201000001320 Atherosclerosis 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
- 206010008089 Cerebral artery occlusion Diseases 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 240000006927 Foeniculum vulgare Species 0.000 description 1
- 235000004204 Foeniculum vulgare Nutrition 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 208000005946 Xerostomia Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229940011037 anethole Drugs 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000003809 bile pigment Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 201000008247 brain infarction Diseases 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 210000000269 carotid artery external Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000013189 cholangiography Methods 0.000 description 1
- 201000001352 cholecystitis Diseases 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 description 1
- 229950009041 edaravone Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229960003699 evans blue Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- 208000023589 ischemic disease Diseases 0.000 description 1
- 238000009940 knitting Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 201000007309 middle cerebral artery infarction Diseases 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 210000000956 olfactory bulb Anatomy 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000009993 protective function 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
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000001186 vagus nerve Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
-
- 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
-
- 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
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides application of one kind Anethol Trithione derivative as shown in formula (I) in preparation prevention and/or treatment cardiovascular and cerebrovascular diseases medicament；Anethol Trithione derivative provided by the present application in Anethol Trithione group by introducing new group, and making it be applied to the prevention and treatment of cardiovascular and cerebrovascular disease has preferable effect, has significant difference compared to demethyl Anethol Trithione.
Description
Technical field
The present invention relates to pharmaceutical technology field more particularly to a kind of applications of Anethol Trithione derivative.
Background technique
Cardiovascular and cerebrovascular disease is the general designation of cardiovascular disease and cranial vascular disease, is referred to since hyperlipidemia, blood are glutinous
The ischemic or hemorrhagic disease that heart caused by thick, atherosclerosis and hypertension etc., brain and body tissue occur
Disease.Cardiovascular and cerebrovascular disease is a kind of common disease for seriously threatening the mankind and being especially 50 years old or more middle-aged and the old's health, has height
The characteristics of illness rate, high disability rate and high mortality.Currently, the treatment means of cardiovascular and cerebrovascular disease are varied, but even if
Using treatment means most advanced, perfect at present, can still there be 50% or more cardiovascular and cerebrovascular accident survivor life cannot be complete
It takes care of oneself.According to statistics, the number that cardiovascular and cerebrovascular disease is died of in the whole world every year is up to 15,000,000 people, and it is the first to occupy the various causes of the death.
Anethol Trithione is obtained by anethole and sulphur through cyclization.Clinically Anethol Trithione is bile component secernent；Its energy
Promote bile, cholic acid, the secretion of BILE PIGMENTS, activating liver cell, increases the function of detoxification of liver；It can also be used in cholecystitis, gallbladder
The treatment of stone disease, acute, chronic hepatitis etc. has the result of enhancing gall-bladder and cholangiography；And it can be with other drugs partner treatment jaundice
Property hepatitis, can also treat asialia.Anethol Trithione structure contains the segment that can release hydrogen sulfide: bis- sulphur ring penta of 3-H-1,2-
Alkene -3- thioketones, hydrogen sulfide have important adjustment effect to body physiological function as a kind of signal of interest molecule.Literature research
Therapeutic effect of the 3-H-1,2- dithiacyclopentene -3- thio-ketone derivative in such as headstroke class field；Such as
CN102807557 reports the analog derivative and prevents and treats the application in headstroke class disease medicament in preparation.But for one
There is preferable water soluble drug to carry out non-mouth for a little Patients with Cardiovascular/Cerebrovascular Diseases, especially cerebral apoplexy or myocardial ischemia class disease
Clothes administration is also very important.
In view of above-mentioned status, to meet the needs of in cardiovascular and cerebrovascular diseases, Anethol Trithione derivative and its application are widened
Range is very necessary.
Summary of the invention
Present invention solves the technical problem that being to provide a kind of application of Anethol Trithione derivative, Anethol Trithione provided by the present application
Derivative can be applied on the drug of preparation prevention and/or treatment cardiovascular and cerebrovascular disease.
In view of this, this application provides the Anethol Trithione derivatives as shown in formula (I) in preparation prevention and/or treatment heart and brain
Application in vascular diseases drug,
Wherein, R1And R2It is independently selected from H, Na, K or NH4 +。
Preferably, the cardiovascular and cerebrovascular disease is cerebral apoplexy or myocardial ischemia.
Preferably, the Anethol Trithione derivative is selected from such as formula (I 1), formula (I 2), formula (I 3), formula (I 4), formula (I 5), formula (I
And one of formula (I 7) compound represented or a variety of 6)；
Preferably, the dosage of the Anethol Trithione derivative is 200 μ g~200mg.
Preferably, including the Anethol Trithione derivative as shown in formula (I) and pharmaceutically acceptable auxiliary material；
Wherein, R1And R2It is independently selected from H, Na, K or NH4 +。
Preferably, the dosage form of the drug is oral preparation, injection, suppository or inhalant.
Preferably, the dosage form of the drug is tablet, capsule, granule, pill, soft extract, suspending agent, dispersing agent, sugar
Starch agent, gelling agent or aerosol.
This application provides the Anethol Trithione derivatives as shown in formula (I) in preparation prevention and/or treatment cardiovascular and cerebrovascular disease
Application in drug, Anethol Trithione derivative provided by the present application make it by introducing new group in Anethol Trithione group
Prevention and treatment applied to cardiovascular and cerebrovascular disease have preferable effect, have conspicuousness poor compared to demethyl Anethol Trithione
It is different.
Detailed description of the invention
Fig. 1 is the experimental cerebral ischemia injury rats NSS appraisal result column diagram of 2 derivative I b of the embodiment of the present invention；
Fig. 2 is that the TTC of the various experimental groups of the embodiment of the present invention 2 dyes mensuration test experience rat cerebral infarction volume cylindricality
Figure.
Specific embodiment
For a further understanding of the present invention, the preferred embodiment of the invention is described below with reference to embodiment, still
It should be appreciated that these descriptions are only further explanation the features and advantages of the present invention, rather than to the claims in the present invention
Limitation.
In view of the application direction of Anethol Trithione in the prior art, it is derivative that this application provides the Anethol Trithiones as shown in formula (I)
Application of the object in preparation prevention and/or treatment cardiovascular and cerebrovascular diseases medicament,
Wherein, R1And R2It is independently selected from H, Na, K or NH4 +。
Anethol Trithione derivative provided by the present application further increases-R on the basis of demethyl Anethol Trithione1R2-PO3Base
Group, the group not only have a preferable water solubility, can also further such that Anethol Trithione derivative there is prevention and/or control
The characteristic of cardiovascular disease is treated, and there is better effect relative to demethyl Anethol Trithione.
Heretofore described Anethol Trithione derivative is preventing and/or is treating to apply preferred pin pair on cardiovascular and cerebrovascular disease
Be cerebral apoplexy or myocardial ischemia；These two types of Diseases often lose the ability being independently administered orally, need using it is non-oral to
Medicine approach, such as intravenous injection etc., thus above-mentioned Anethol Trithione derivative it is preferable water-soluble to above-mentioned two classes disease have compared with
Good effect.In the application, the Anethol Trithione derivative is specifically to be selected from such as formula (I 1), formula (I 2), formula (I 3), formula (I 4), formula
One of (I 5), formula (I 6) and formula (I 7) compound represented are a variety of；
In practical application, the dosage of the Anethol Trithione derivative is 200 μ g~200mg.
Herein described drug specifically includes the Anethol Trithione derivative as shown in formula (I) and pharmaceutically acceptable auxiliary material；
Wherein, R1And R2It is independently selected from H, Na, K or NH4 +。
Auxiliary material described in said medicine is auxiliary material well known to those skilled in the art, is not limited particularly this application
System.
The dosage form of herein described drug specifically can be selected from oral preparation, injection, suppository or inhalant；More specifically,
The dosage form of the preparation is tablet, capsule, granule, pill, soft extract, suspending agent, dispersing agent, syrup, gelling agent or gas
Mist agent.
For a further understanding of the present invention, below with reference to embodiment to the application of Anethol Trithione derivative provided by the invention into
Row is described in detail, and protection scope of the present invention is not limited by the following examples.
Chemical reagent in following embodiment is purchased from Chengdu Ke Long chemical reagent factory.
The preparation of 1 demethyl Anethol Trithione derivative of embodiment
The preparation of the double ammonium salts (Ia) of demethyl Anethol Trithione phosphate: 20 grams of Anethol Trithiones and 58 grams of anhydrous pyridine hydrochloride mixing
Uniformly, nitrogen protection is heated slowly to 220 degrees Celsius, and solid is all dissolved into homogeneous system, maintains 220 degrees Celsius and continues to stir
It mixes 30 minutes, naturally cools to room temperature；Add 200ml ethyl acetate and 200ml water to be heated to 50 degrees Celsius to stir 30 minutes, filtering
Remove insoluble matter, gained filtrate stratification, ethyl acetate use respectively 40ml clear water washing twice, add 50 grams of anhydrous sodium sulfates and
The dry decoloration of 5 grams of activated carbon is overnight；Second day is filtered to remove sodium sulphate and activated carbon, and 50ml stone is added when being concentrated into solid precipitation
Oily ether stirred crystallization, filtering after crystallizing completely, obtains 12 grams of demethyl Anethol Trithione；
10 grams of demethyl Anethol Trithiones (ADT) are dissolved with 100ml methylene chloride, are added 10.5 grams of pyridine, it is Celsius to be cooled to -10
Degree reacts 5 hours, demethyl fennel three after dripping off phosphorus oxychloride in -5~0 degree Celsius hereinafter, be slowly added dropwise 13.5 grams of phosphorus oxychloride
Reaction of Salmon-Saxl is complete；100ml ice water is added, is stood after stirring half an hour, gained demethyl Anethol Trithione phosphate crude product is with grease
It is sunken to bottom of bottle, inclines and falls water and methylene chloride, residual grease removes pyridine hydrochloride with 20ml 1N salt acid elution 2 times respectively, inclines and
Products therefrom 50ml tetrahydrofuran dissolves after hydrochloric acid, adds 15 grams of anhydrous sodium sulfates to dry, filter and removes sodium sulphate concentration tetrahydro
Furans to obtain 12 grams of demethyl Anethol Trithione phosphate to dry；
10 grams of demethyl Anethol Trithione phosphates 30ml dehydrated alcohol dissolves, and is cooled under 6 degrees Celsius of stirrings and is slowly added dropwise
Concentrated ammonia liquor continues to be stirred at room temperature 30 minutes after being added dropwise to complete, filtering drying obtains red brown solid, i.e., until pH value is 7.5 or so
As formula (I 7) compound represented Ia is 9.2 grams total.ESI m/z:362.97 [M+Na+]。1HNMR (DMSO, 400MHz): δ ppm:
7.79 (m, 2H), 7.71 (m, 1H), 7.37 (m, 2H).
Demethyl Anethol Trithione phosphate double sodium salt (Ib): the preparation method of similar Ia replaces dense ammonia with sodium hydroxide solution
The double sodium salt as shown in formula (I 3) is prepared in water.ESI m/z:394.00 [M+2Na+]。
The double sylvite (Ic) of demethyl Anethol Trithione phosphate: the preparation method of similar Ia replaces dense ammonia with potassium hydroxide solution
Double sylvite as shown in formula (I 5) are prepared in water.ESI m/z:427.82 [M+2Na+]。
Protective effect of the 2 demethyl Anethol Trithione derivative I b of embodiment to experimental cerebral ischemia injury rats
Line brush prepares focal cerebral ischemia (MCAO) rat model: carrying out part improvement by line bolt modeling method；10%
Chloraldurate 3.5mL/kg intraperitoneal injection of anesthesia, rat dorsal position are fixed on operating table, routine disinfection, neck median incision,
Exposure right carotid and external carotid artery, careful separation and arteria carotis communis ligature arteria carotis communis and neck with the vagus nerve of row
Arteria carotis communis is being cut a small notch with eye scissors apart from crotch 0.5cm or so by outer artery, and siding bolt is sent into notch,
Inwardly carry out, by line bolt along arteria carotis communis, internal carotid direct motion to middle artery, stopping when meeting obstructions, from arteria carotis communis bifurcated
Place calculates insertion depth (1.8 ± 0.5) cm, causes intraluminal middle cerebral artery occlusion in rats blood supply to block, pulls out bolt line after 1 hour.
Animal packet: 1) sham-operation group；2) ischemia-reperfusion injury model group；3) derivative I b (10mg/kg) intervention group: physiology
Saline, a half-value dose, 6 hours tail vein injection administration residues one after bolt line is extracted is administered in tail vein injection immediately after modeling
Half-value dose；4) Edaravone (6mg/kg) positive controls, normal saline are administered immediately after modeling, tail vein injection；5)
Hydroxyl Anethol Trithione (ADT) (10mg/kg) positive controls, corn oil dissolution are prepared, and ischemia-reperfusion was injected intraperitoneally one after 3 hours
A remaining half-value dose is injected intraperitoneally in half-value dose after ischemia-reperfusion 10 hours.
After modeling, 24 hours after modeling, Neuroscore is carried out, using NSS point system, score gets over Gao Daibiao
Nervous function damage is more serious.
2,3,5- trichlorotetrazole chlorides (TTC) dyeing measurement cerebral infarction volume: 25h after ischemic tissue of brain infarct rate modeling,
By rat sacrificed by decapitation, brain is taken out rapidly, after being rinsed with cool brine, quickly 10min is placed in -20 DEG C of refrigerators, to brain group
Knit it is slightly hard after, take out, cut away olfactory bulb, hypophysis, low brain stem, from the front to the back coronal section, be uniformly cut into 2mm thickness brain piece, equal part
5 are cut into, is placed in 1%TTC solution, 37 DEG C are protected from light incubation 30min, stir 1 time every 5min or so.TTC can be with normal group
Dehydrogenase system response in knitting is reduced to rose and normal tissue dye is made to be in rose, and infarction tissue is white,
And clear-cut, ophthalmic tweezers accurately remove infarct location, electronic balance precision weighs gross weight and records, and calculates cerebral infarction volume.
The result shows that: NSS scoring proves that the injection of derivative I b alleviates the refreshing defect (attached drawing 1) of nerve of rat, modeling
Nervous function improves and is better than model group for 24 hours afterwards, significant difference (*P≤0.05)；The for 24 hours after modeling, TTC dyeing measurement cerebral infarction
Volume result (attached drawing 2) proves that derivative I b significantly reduces Infarction volume, significant difference (*P≤0.05)。
By above-mentioned data it is found that compound Ib provided by the invention is compared with reported hydroxyl Anethol Trithione (ADT), water
Dissolubility is strong, and formulation operations are easy, and stronger therapeutic effect is played under same dose, significant difference (*P≤0.05)。
Protective effect of 3 demethyl Anethol Trithione derivative I a, Ib, the Ic of embodiment to rat heart ischemical reperfusion injury
It is in good condition after adaptable fed 1 week by 220~250g SPF grades of sD rats of healthy male.
It is pre- that rat is randomly divided into sham-operation (Sham) group, heart ischemia reperfusion damage (MI/R) group and derivative low dosage
Processing group (5mg/kg), every group 10.The preoperative tail vein injection derivative of derivative pretreated group, and MI/R group is preoperative gives
0.900 sodium chloride solution of volume after pretreated group, MI/R group are administered 14 days, gives heart ischemia reperfusion operation；Reperfu- sion
After 4h, coronary artery left anterior descending branch is ligatured again in situ, Evans blue is injected by aorta, dyed to the non-ischemic differentiation of heart
After blue, win after heart with 4 DEG C of saline rinses, slice, TTC liquid dyeing is fixed, and the region for dying blue is non-ischemic region, red
Color region (containing white area) is ischemic region, and white area is infarcted region；Each region area Image ProPlus software detection,
Myocardial infarction area indicates that the results are shown in Table 1 with infarcted region/ischemic region × 100%；
Protective effect of 1 derivative of table to rat heart ischemical reperfusion injury
| Grouping | Dosage | Myocardial infarction area (%) |
| Sham | / | 0.8±0.3 |
| MI/R | / | 71.2±11.7 |
| Ia low dose group | 5mg/kg | 52.9±4.6* |
| Ib low dose group | 5mg/kg | 50.1±6.9* |
| Ic low dose group | 5mg/kg | 51.7±7.0* |
As shown in Table 1, derivative has obvious protective function to compare with MI/R group rat heart ischemical reperfusion injury,
Infarct size is substantially reduced, significant difference (*P≤0.05)。
The above description of the embodiment is only used to help understand the method for the present invention and its core ideas.It should be pointed out that pair
For those skilled in the art, without departing from the principle of the present invention, the present invention can also be carried out
Some improvements and modifications, these improvements and modifications also fall within the scope of protection of the claims of the present invention.
The foregoing description of the disclosed embodiments enables those skilled in the art to implement or use the present invention.
Various modifications to these embodiments will be readily apparent to those skilled in the art, as defined herein
General Principle can be realized in other embodiments without departing from the spirit or scope of the present invention.Therefore, of the invention
It is not intended to be limited to the embodiments shown herein, and is to fit to and the principles and novel features disclosed herein phase one
The widest scope of cause.
Claims (7)
1. application of the Anethol Trithione derivative as shown in formula (I) in preparation prevention and/or treatment cardiovascular and cerebrovascular diseases medicament,
Wherein, R1And R2It is independently selected from H, Na, K or NH4 +。
2. application according to claim 1, which is characterized in that the cardiovascular and cerebrovascular disease is cerebral apoplexy or myocardial ischemia.
3. application according to claim 1, which is characterized in that the Anethol Trithione derivative be selected from as formula (I 1), formula (I 2),
One of formula (I 3), formula (I 4), formula (I 5), formula (I 6) and formula (I 7) compound represented are a variety of；
4. application according to claim 1, which is characterized in that the dosage of the Anethol Trithione derivative be 200 μ g~
200mg。
5. application according to claim 1, which is characterized in that including Anethol Trithione derivative and pharmacy as shown in formula (I)
Upper acceptable auxiliary material；
Wherein, R1And R2It is independently selected from H, Na, K or NH4 +。
6. application according to claim 5, which is characterized in that the dosage form of the drug is oral preparation, injection, suppository
Or inhalant.
7. application according to claim 6, which is characterized in that the dosage form of the drug is tablet, capsule, granule, ball
Agent, soft extract, suspending agent, dispersing agent, syrup, gelling agent or aerosol.
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