CN107157976A - Application of the compound of thioether acids structure in medicament for resisting platelet aggregation is prepared - Google Patents
Application of the compound of thioether acids structure in medicament for resisting platelet aggregation is prepared Download PDFInfo
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- CN107157976A CN107157976A CN201710534867.9A CN201710534867A CN107157976A CN 107157976 A CN107157976 A CN 107157976A CN 201710534867 A CN201710534867 A CN 201710534867A CN 107157976 A CN107157976 A CN 107157976A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 38
- 208000010110 spontaneous platelet aggregation Diseases 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 title claims abstract description 12
- QGFORSXNKQLDNO-UHFFFAOYSA-N erdosteine Chemical compound OC(=O)CSCC(=O)NC1CCSC1=O QGFORSXNKQLDNO-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229960003262 erdosteine Drugs 0.000 claims abstract description 14
- JZKHUBWXBZINMO-UHFFFAOYSA-N 1,3-thiazinan-3-ium-4-carboxylate Chemical compound OC(=O)C1CCSCN1 JZKHUBWXBZINMO-UHFFFAOYSA-N 0.000 claims abstract description 6
- WSYVIAQNTFPTBI-UHFFFAOYSA-N ethyl 3-[2-[(2-methoxyphenoxy)methyl]-1,3-thiazolidin-3-yl]-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)N1CCSC1COC1=CC=CC=C1OC WSYVIAQNTFPTBI-UHFFFAOYSA-N 0.000 claims abstract description 6
- IKOCLISPVJZJEA-UHFFFAOYSA-N letosteine Chemical compound CCOC(=O)CSCCC1NC(C(O)=O)CS1 IKOCLISPVJZJEA-UHFFFAOYSA-N 0.000 claims abstract description 6
- UVZICZIVKIMRNE-UHFFFAOYSA-N thiodiacetic acid Chemical compound OC(=O)CSCC(O)=O UVZICZIVKIMRNE-UHFFFAOYSA-N 0.000 claims abstract description 6
- FXPSJTKESYQXLX-HQVZTVAUSA-N (2r)-2-acetamido-3-(2-methyl-3-oxo-3-phenylpropyl)sulfanylpropanoic acid Chemical compound CC(=O)N[C@H](C(O)=O)CSCC(C)C(=O)C1=CC=CC=C1 FXPSJTKESYQXLX-HQVZTVAUSA-N 0.000 claims abstract description 5
- UGHACTSHTBCZGG-PHDIDXHHSA-N (4s)-3-[2-[[(2r)-2-sulfanylpropanoyl]amino]acetyl]-1,3-thiazolidine-4-carboxylic acid Chemical compound C[C@@H](S)C(=O)NCC(=O)N1CSC[C@@H]1C(O)=O UGHACTSHTBCZGG-PHDIDXHHSA-N 0.000 claims abstract description 5
- XVAYJUBRRZOANH-UHFFFAOYSA-N 2-(1,3-thiazolidine-3-carbonyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)N1CSCC1 XVAYJUBRRZOANH-UHFFFAOYSA-N 0.000 claims abstract description 5
- DXSXAJGKYKXYMX-UHFFFAOYSA-N 2-[2-[(2-methyl-4-oxo-1,3-benzodioxin-2-yl)sulfanyl]propanoylamino]acetic acid Chemical compound C1=CC=C2OC(SC(C)C(=O)NCC(O)=O)(C)OC(=O)C2=C1 DXSXAJGKYKXYMX-UHFFFAOYSA-N 0.000 claims abstract description 5
- MLLYDWHLZFTQBY-UHFFFAOYSA-N 3-(carboxymethylsulfanyl)propanoic acid Chemical compound OC(=O)CCSCC(O)=O MLLYDWHLZFTQBY-UHFFFAOYSA-N 0.000 claims abstract description 5
- KINWYTAUPKOPCQ-YFKPBYRVSA-N Fudosteine Chemical compound OC(=O)[C@@H](N)CSCCCO KINWYTAUPKOPCQ-YFKPBYRVSA-N 0.000 claims abstract description 5
- GBFLZEXEOZUWRN-VKHMYHEASA-N S-carboxymethyl-L-cysteine Chemical compound OC(=O)[C@@H](N)CSCC(O)=O GBFLZEXEOZUWRN-VKHMYHEASA-N 0.000 claims abstract description 5
- ULHWZNASVJIOEM-ZETCQYMHSA-N S-prenyl-L-cysteine Chemical compound CC(C)=CCSC[C@H](N)C(O)=O ULHWZNASVJIOEM-ZETCQYMHSA-N 0.000 claims abstract description 5
- 229950001938 bencisteine Drugs 0.000 claims abstract description 5
- 229960004399 carbocisteine Drugs 0.000 claims abstract description 5
- 229950003369 cartasteine Drugs 0.000 claims abstract description 5
- HSPYGHDTVQJUDE-LURJTMIESA-N dacisteine Chemical compound CC(=O)N[C@H](C(O)=O)CSC(C)=O HSPYGHDTVQJUDE-LURJTMIESA-N 0.000 claims abstract description 5
- 229950007177 dacisteine Drugs 0.000 claims abstract description 5
- 229950002395 danosteine Drugs 0.000 claims abstract description 5
- 230000002526 effect on cardiovascular system Effects 0.000 claims abstract description 5
- 229950006783 fudosteine Drugs 0.000 claims abstract description 5
- 229950002628 guaisteine Drugs 0.000 claims abstract description 5
- 229950006447 isalsteine Drugs 0.000 claims abstract description 5
- 229960004870 letosteine Drugs 0.000 claims abstract description 5
- 229950001125 midesteine Drugs 0.000 claims abstract description 5
- 229950009623 moguisteine Drugs 0.000 claims abstract description 5
- 229950008125 omonasteine Drugs 0.000 claims abstract description 5
- 229950003826 prenisteine Drugs 0.000 claims abstract description 5
- MKTVMEMIKNBVHI-UHFFFAOYSA-N s-[1-oxo-1-[(2-oxothiolan-3-yl)amino]propan-2-yl] thiophene-2-carbothioate Chemical compound C1CSC(=O)C1NC(=O)C(C)SC(=O)C1=CC=CS1 MKTVMEMIKNBVHI-UHFFFAOYSA-N 0.000 claims abstract description 5
- DUTQZUMFFDWHBC-UHFFFAOYSA-N s-[2-[2-[(2-methoxyphenoxy)methyl]-1,3-thiazolidin-3-yl]-2-oxoethyl] ethanethioate Chemical compound COC1=CC=CC=C1OCC1N(C(=O)CSC(C)=O)CCS1 DUTQZUMFFDWHBC-UHFFFAOYSA-N 0.000 claims abstract description 5
- XBJWOGLKABXFJE-YFKPBYRVSA-N telmesteine Chemical compound CCOC(=O)N1CSC[C@H]1C(O)=O XBJWOGLKABXFJE-YFKPBYRVSA-N 0.000 claims abstract description 5
- 229960002384 telmesteine Drugs 0.000 claims abstract description 5
- QLOBGRBOWVVKIE-NSHDSACASA-N (2r)-2-acetamido-3-(2-acetyloxybenzoyl)sulfanylpropanoic acid Chemical compound CC(=O)N[C@H](C(O)=O)CSC(=O)C1=CC=CC=C1OC(C)=O QLOBGRBOWVVKIE-NSHDSACASA-N 0.000 claims abstract description 4
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 4
- 208000026106 cerebrovascular disease Diseases 0.000 claims abstract description 4
- 229950009469 nesosteine Drugs 0.000 claims abstract description 4
- 229950011165 salmisteine Drugs 0.000 claims abstract description 4
- JJXDGYJCYKWEAI-UHFFFAOYSA-N taurosteine Chemical compound OS(=O)(=O)CCNC(=O)C1=CC=CS1 JJXDGYJCYKWEAI-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229950008172 taurosteine Drugs 0.000 claims abstract description 4
- 239000002253 acid Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims 18
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 239000005864 Sulphur Substances 0.000 claims 1
- 230000002265 prevention Effects 0.000 abstract description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 22
- 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 20
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 20
- 239000008101 lactose Substances 0.000 description 20
- 235000019359 magnesium stearate Nutrition 0.000 description 20
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 20
- 238000007873 sieving Methods 0.000 description 18
- 238000012360 testing method Methods 0.000 description 17
- 210000001772 blood platelet Anatomy 0.000 description 12
- 230000000144 pharmacologic effect Effects 0.000 description 12
- 239000002775 capsule Substances 0.000 description 11
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 9
- 229960003009 clopidogrel Drugs 0.000 description 9
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 9
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 7
- 229960001138 acetylsalicylic acid Drugs 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 150000003384 small molecules Chemical class 0.000 description 6
- 241000700159 Rattus Species 0.000 description 4
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000007710 freezing Methods 0.000 description 4
- 239000003292 glue Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- -1 Acyl cysteine Chemical compound 0.000 description 3
- 208000032843 Hemorrhage Diseases 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 229940127219 anticoagulant drug Drugs 0.000 description 3
- 230000000740 bleeding effect Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 230000003285 pharmacodynamic effect Effects 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 241001597008 Nomeidae Species 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- 230000003187 abdominal effect Effects 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 229940127218 antiplatelet drug Drugs 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical group C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 210000004623 platelet-rich plasma Anatomy 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- CFPHMAVQAJGVPV-UHFFFAOYSA-N 2-sulfanylbutanoic acid Chemical group CCC(S)C(O)=O CFPHMAVQAJGVPV-UHFFFAOYSA-N 0.000 description 1
- 206010061623 Adverse drug reaction Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 239000005465 B01AC22 - Prasugrel Substances 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 1
- 101000610548 Homo sapiens Proline-rich protein 4 Proteins 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- 206010060840 Ischaemic cerebral infarction Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- 206010068052 Mosaicism Diseases 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 102100040122 Proline-rich protein 4 Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- YTGJWQPHMWSCST-UHFFFAOYSA-N Tiopronin Chemical compound CC(S)C(=O)NCC(O)=O YTGJWQPHMWSCST-UHFFFAOYSA-N 0.000 description 1
- 108010058907 Tiopronin Proteins 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000002429 anti-coagulating effect Effects 0.000 description 1
- 230000006502 antiplatelets effects Effects 0.000 description 1
- 229940127217 antithrombotic drug Drugs 0.000 description 1
- 208000025870 aspirin resistance Diseases 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229960002433 cysteine Drugs 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000007887 hard shell capsule Substances 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000009149 molecular binding Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229960004197 prasugrel Drugs 0.000 description 1
- DTGLZDAWLRGWQN-UHFFFAOYSA-N prasugrel Chemical compound C1CC=2SC(OC(=O)C)=CC=2CN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 DTGLZDAWLRGWQN-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000003765 sex chromosome Anatomy 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- MZMXYAPUAIKOGR-UHFFFAOYSA-M sodium;2-(1,3-thiazolidine-3-carbonyl)benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1C(=O)N1CSCC1 MZMXYAPUAIKOGR-UHFFFAOYSA-M 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 229960004402 tiopronin Drugs 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 208000004043 venous thromboembolism Diseases 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Emergency Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides application of the compound of thioether acids structure in the medicine for treatment or prevention cardiovascular and cerebrovascular disease as caused by platelet aggregation is prepared.Wherein include carbocisteine, Fudosteine, Erdosteine, Moguisteine, Letosteine, Prenisteine, Nesosteine, Midesteine, Isalsteine, Taurosteine, Telmesteine, Salmisteine, Omonasteine, dacisteine, cartasteine, danosteine, guaisteine, Bencisteine and thiodiglycolic acid.
Description
Technical field
The invention belongs to pharmaceutical field, specifically, prepared the present invention relates to the compound of thioether acids structure for controlling
Application in the medicine for the treatment of or the prevention cardiovascular and cerebrovascular disease as caused by platelet aggregation.
Background technology
As China human mortality aging degree is increasingly sharpened, on the cardiovascular and cerebrovascular disease as caused by thrombus sex chromosome mosaicism is continuous
Rise, often show as myocardial infarction, apoplexy, Ischemic Cerebral Infarction, VTE etc., the people of such disease is died from the whole world every year
Number is close to a quarter of the total death toll in the world, therefore anti-thrombotic drugs are developed into global major drugmakers competitively
The focus of exploitation, representational medicine has an aspirin and clopidogrel, wherein clopidogrel in 2015 market at home
Consumption sum is up to 9,200,000,000 yuan, and this medicine has come the first place position of national various medicine oral medications for successive years.But
It is excessive by the adverse drug reaction of representative of aspirin and clopidogrel, to cause based on hemorrhage of digestive tract and cerebral hemorrhage otherwise
Good reaction, more unfortunately clopidogrel antiplatelet effects can not make all patients be benefited, some patientss are to clopidogrel
Cardiovascular protective effect there is clopidogrel Resistant, similarly there are some patientss to produce aspirin for aspirin
Resistance.Therefore in the market needs the chemicals of more brand news to improve the deficiency of existing kind.
Clopidogrel and prasugrel are a precursor medicine, it is necessary to be metabolized Viability product after ring-opening oxidation in vivo
Pharmacological action is played, its effective active group is sulfydryl butenoic acid structure, we set about analysis from the sulfydryl of activity and found, Hen Duohan
There is the less small molecule polar compound of molecular weight of exposed sulfydryl, there is the pharmacological action of certain platelet aggregation-against, such as second
Acyl cysteine, Tiopronin and captopril etc., but these micromolecular compounds have not been used to platelet aggregation-against disease
Treatment, thus it is speculated that its reason is probably that its exposed sulfydryl and protein molecular binding ability are too strong, and adverse reaction is excessive, bleeding
Rate is too high, these molecules be not merely can platelet aggregation-against can also reach the pharmacological action of thrombolysis sometimes, and this is for length
The patient of phase medication is extremely disadvantageous, and the risk for the rate that can cause bleeding is greatly increased, the exploitation side of medicament for resisting platelet aggregation
To being how to reduce Bleeding rate to greatest extent while drug effect is ensured, and these contain the small molecule polarity of exposed sulfydryl
Compound is clearly unsuitable long-term prescription.We herein basis on, expect find the small molecule polarity containing sulfide based structural
Compound attempts the exploitation for anticoagulant, it is contemplated that the compound of the sulfide based structural and binding ability of albumen is weak much reaches
Active less than sulfydryl, thus it is speculated that possible result is probably the pharmacological action without anti-freezing, we, which retrieved pertinent literature, does not have
There is the small molecule polar compound for finding sulfide based structural to be used for the document report of platelet aggregation-against.We also simply arbitrarily do individual
Attempt, but result of the test, considerably beyond our expectation.It was found that multiple small molecule polar compounds containing thioether acids structure
There is good anti-freezing pharmacological action.
The content of the invention
Take charge of in the treatment that smooth class compound is widely used in respiratory disorder, the treatment of particularly many phlegm, its molecular structure
Contain sulfide based structural mostly, and seldom contain exposed sulfydryl, we retrieve the relevant smooth class compound of department to it is hematoblastic related
Document, finds only one of which Erdosteine（erdosteine）Compound be reported with blood platelet interact two texts
Offer, this two documents are published on same periodical Human ＆ Experimental Toxicology by same author Arica
Influence about Erdosteine to hematological function, but their result of the test, which is Erdosteine unexpectedly, lifting blood platelet
Quantity and the pharmacological action for promoting hemostasis, which results in our interest, their experimental method is in 180-200g by body weight
Rat 28 be only randomly divided into 4 groups, blank group awards physiological saline, in addition three groups to give strategic point respectively by high, normal, basic three dosage more
Smooth 3mg/kg/day, 10mg/kg/day, 30mg/kg/day are taken charge of, successive administration takes blood after three days, determine platelet counts, knot
Fruit is that middle dose group platelet counts are more slightly higher than blank group, and the platelet counts of low dosage and high dose group are far above middle dose group
（P<0.05）, and the platelet counts of low dose group and high dose group are essentially identical.That is Erdosteine has on earth
Anastalsis is promoted still to have anticoagulant effect to be ambiguous.
We set about from Erdosteine, and its active metabolite in vivo is the sulfydryl fourth after hydrolysis during for resolving sputum
Sour structure, and the active metabolite sulfydryl butenoic acid structure of clopidogrel in vivo are a little approached, and we are repeating Arica reality
In testing, their experimentation and experimental result can not be repeated out, be drawn by contrast in our experimentation
Erdosteine has the experiment conclusion of certain platelet aggregation-against.Then it is presumed that the function of Erdosteine platelet aggregation-against
Be by Erdosteine active metabolite in vivo be hydrolysis after mercaptobutyric acid structure in action, for deep checking
Pharmacological action of the Erdosteine in platelet aggregation-against, we directly carry out testing in vitro with rat plasma, and discovery is not passed through
Crossing the Erdosteine of hydrolysis also has the pharmacological action of preferably reduction platelet aggregation, thus speculates that it can play reduction blood small
The active group of pharmacological action of plate aggregation should be thioether acetic acid structure, and then we are by oxalic acid thioether（Thiodiglycolic acid）
Applied to platelet aggregation-against experiment, as a result its antiplatelet drug action is three times of the aspirin of Isodose unexpectedly
Action effect！This is very magical.We are again the carboxylic first department with thioether acetic acid structure and thioether propionic acid structure
Smooth to be applied to platelet aggregation-against experiment, as a result its antiplatelet drug action is equal to aspirin, can only speculate landing
The active group of the pharmacological action of low platelet aggregation should be thioether acetic acid or thioether propionic acid structure, and then we are possible to
The obtained compound containing thioether acetic acid or thioether propionic acid structure such as carbocisteine, Fudosteine, mecrysteine, E Duosi
Smooth, Moguisteine, Letosteine, Prenisteine, Nesosteine, Midesteine, Isalsteine, Taurosteine, Telmesteine, sand
Meter Si Tan, Omonasteine, dacisteine, cartasteine, danosteine, guaisteine, Bencisteine and thiodiglycolic acid etc., and together
Isodose aspirin has done the system Pharmacodynamics screening in terms of platelet aggregation-against, and experimental result is these compounds
Aspirin contrast with same concentration has the pharmacological action of preferable platelet aggregation-against, particularly thiodiglycolic acid to have more preferable
Platelet aggregation-against pharmacological action.That is the small molecule polarization compound with thioether fatty acid structure is treating small by blood
There is good therapeutic effect in terms of disease caused by plate aggregation.
Embodiment
Pharmacodynamics test 1:
A, hematoblastic preparation：Rat is anaesthetized through the ml/kg of 10% chloraldurate 4, abdominal aortic blood, 3.2% sodium citrate anti-freezing
（Blood is 9 with anti-coagulants volume ratio:1）, 1200 rpm, 10 min of centrifugation, separation platelet rich plasma（PRP）；3500 rpm from
The min of the heart 10, separation platelet poor plasma (PPP).
B, PAR measure：With PPP as substrate, PRP is measured.170 μ L PPP are added in plastic testing cup
TCH test channel is put into 30 μ L water, PPP keys is pressed and carries out substrate measurement；170 μ LPRP are added in another test cup and 20 μ L are to be measured
Medicine（Final concentration of 100 μ g/ml）, plus a magnetic bead, test cup is put into 37 DEG C of pre-temperature passages and incubates 3min, will after terminating
Test cup moves into TCH test channel, is measured by start button, derivant AA10 μ L (final concentration of 1 mM) is added, by Born ratios
Turbid method records maximum platelet aggregation rate in 5 min, and calculates its inhibiting rate.
C, data processing：
Assemble the % of inhibiting rate=(control group PAR-test group PAR)/control group PAR × 100.
D, experimental result are as follows：
The inhibitory action one of the compounds on platelet aggregation of thioether acids structure
Pharmacodynamics test 2：
SD rats 42 by body weight at 210-230 grams, are randomly divided into 7 groups, i.e. negative control group (0.9% physiological saline, 5ml/
Kg), Erdosteine group (50mg/kg), Moguisteine group (50mg/kg), Letosteine group (50mg/kg), Nesosteine group (sodium
Salt, 50mg/kg), Omonasteine group (50mg/kg), positive controls (clopidogrel, 50mg/kg).Gastric infusion is used,
Administered volume is 5ml/kg.Once a day, it is administered within continuous three days.Through the ml/ of 10% chloraldurate 4 after being administered 2 hours for the last time
Kg is anaesthetized, abdominal aortic blood, 3.2% sodium citrate anti-freezing（Blood is 9 with anti-coagulants volume ratio:1）, 1200 rpm centrifugations 10
Min, separates platelet rich plasma（PRP）；3500 rpm centrifuge 15 min, separation platelet poor plasma (PPP).Use blood platelet
Calculating instrument is determined after the platelet count in PRP, and PRP platelet count is adjusted to 250 × 10 by PPP9Individual/L or so.Adjust blood
Platelet assembles instrument, adds the sample that 200 μ L are regulated, plus a magnetic bead in plastic testing cup, test cup is put into 37 DEG C
3 min are incubated in pre-temperature passage, test cup is moved into TCH test channel after terminating, the μ L (final concentration of 45 of derivant ADP 3 are added
μM), it is measured, maximum platelet aggregation rate in 5 min of record, by the results contrast with negative control group, calculates its suppression
Rate processed, calculates every group of L-Arginine, as a result as follows：
Embodiment 1
Carbocisteine 750mg
Lactose 1000mg
Microcrystalline cellulose 240mg
Magnesium stearate 10mg
After above-mentioned material is mixed, cross 60 mesh sieves, by tabletting machine, the tablet that every piece weight is 200mg is made.According to need
This tablet can be coated.
Embodiment 2
Carbocisteine 500mg
Lactose 1200mg
Microcrystalline cellulose 290mg
Magnesium stearate 10mg
After above-mentioned material is mixed, 60 mesh sieves are crossed, are fitted into hollow hard shell capsules, the capsule that every grain weight is 200mg is made.
Embodiment 3
By 50mg thiodiglycolic acid, 120mg lactose, 29mg microcrystalline celluloses, 1mg magnesium stearates, tabletting system after mixing sieving
Into 200mg tablet.
Embodiment 4
By 50mg Fudosteine, 100mg lactose, 49mg microcrystalline celluloses, 1mg magnesium stearates, tabletting is made after mixing sieving
200mg tablet.
Embodiment 5
By 50mg Bencisteine, 80mg lactose, 69mg microcrystalline celluloses, 1mg magnesium stearates, tabletting is made after mixing sieving
200mg tablet.
Embodiment 6
By 50mg Erdosteine, 80mg lactose, 69mg microcrystalline celluloses, 1mg magnesium stearates, tabletting is made after mixing sieving
200mg tablet.
Embodiment 7
By 50mg Moguisteine, 80mg lactose, 69mg microcrystalline celluloses, 1mg magnesium stearates, tabletting is made after mixing sieving
200mg tablet.
Embodiment 8
By 50mg Letosteine, 80mg lactose, 69mg microcrystalline celluloses, 1mg magnesium stearates, tabletting is made after mixing sieving
200mg tablet.
Embodiment 9
By 50mg Prenisteine, 80mg lactose, 69mg microcrystalline celluloses, 1mg magnesium stearates, tabletting is made after mixing sieving
200mg tablet.
Embodiment 10
By 50mg Nesosteine sodium, 80mg lactose, 69mg microcrystalline celluloses, 1mg magnesium stearates, glue is encased in after mixing sieving
In capsule, 200mg capsule is made.
Embodiment 11
By 20mg Midesteine, 105mg lactose, 74mg microcrystalline celluloses, 1mg magnesium stearates, glue is encased in after mixing sieving
In capsule, grain weight 200mg capsule is made
Embodiment 12
By 50mg Isalsteine, 80mg lactose, 69mg microcrystalline celluloses, 1mg magnesium stearates, glue is encased in after mixing sieving
In capsule, 200mg capsule is made.
Embodiment 13
By 50mg Taurosteine, 90mg lactose, 59mg microcrystalline celluloses, 1mg magnesium stearates, capsule is encased in after mixing sieving
In, 200mg capsule is made.
Embodiment 14
By 25mg Telmesteine, 100mg lactose, 74mg microcrystalline celluloses, 1mg magnesium stearates, glue is encased in after mixing sieving
In capsule, 200mg capsule is made.
Embodiment 15
By 25mg Salmisteine, 105mg lactose, 69mg microcrystalline celluloses, 1mg magnesium stearates, tabletting is made after mixing sieving
200mg tablet.
Embodiment 16
By 25mg Omonasteine, 105mg lactose, 69mg microcrystalline celluloses, 1mg magnesium stearates, tabletting is made after mixing sieving
200mg tablet.
Embodiment 17
By 25mg dacisteine, 105mg lactose, 69mg microcrystalline celluloses, 1mg magnesium stearates, tabletting is made after mixing sieving
200mg tablet.
Embodiment 18
By 25mg cartasteine, 105mg lactose, 69mg microcrystalline celluloses, 1mg magnesium stearates, tabletting is made after mixing sieving
200mg tablet.
Embodiment 19
By 50mg danosteine, 80mg lactose, 69mg microcrystalline celluloses, 1mg magnesium stearates, tabletting is made after mixing sieving
200mg tablet.
Embodiment 20
By 25mg guaisteine, 105mg lactose, 69mg microcrystalline celluloses, 1mg magnesium stearates, tabletting is made after mixing sieving
200mg tablet.
Claims (20)
1. the compound of thioether acids structure is being prepared for treating or preventing the cardiovascular and cerebrovascular disease as caused by platelet aggregation
Application in medicine.
2. application according to claim 1, it is characterised in that：The compound of described thioether acids structure is selected from：Carboxylic first department
Smooth, Fudosteine, Erdosteine, Moguisteine, Letosteine, Prenisteine, Nesosteine, Midesteine, Isalsteine, ox
Sulphur department is smooth, Telmesteine, Salmisteine, Omonasteine, dacisteine, cartasteine, danosteine, guaisteine, Bencisteine
And thiodiglycolic acid.
3. application according to claim 2, it is characterised in that：The compound of described thioether acids structure is carbocisteine,
Or its pharmaceutically acceptable salt.
4. application according to claim 2, it is characterised in that：The compound of described thioether acids structure is Fudosteine,
Or its pharmaceutically acceptable salt.
5. application according to claim 2, it is characterised in that：The compound of described thioether acids structure is Moguisteine,
Or its pharmaceutically acceptable salt.
6. application according to claim 2, it is characterised in that：The compound of described thioether acids structure is Letosteine,
Or its pharmaceutically acceptable salt.
7. application according to claim 2, it is characterised in that：The compound of described thioether acids structure is Prenisteine,
Or its pharmaceutically acceptable salt.
8. application according to claim 2, it is characterised in that：The compound of described thioether acids structure is Nesosteine,
Or its pharmaceutically acceptable salt.
9. application according to claim 2, it is characterised in that：The compound of described thioether acids structure is Midesteine,
Or its pharmaceutically acceptable salt.
10. application according to claim 2, it is characterised in that：The compound of described thioether acids structure is Isalsteine,
Or its pharmaceutically acceptable salt.
11. application according to claim 2, it is characterised in that：The compound of described thioether acids structure is Taurosteine,
Or its pharmaceutically acceptable salt.
12. application according to claim 2, it is characterised in that：The compound of described thioether acids structure is Telmesteine,
Or its pharmaceutically acceptable salt.
13. application according to claim 2, it is characterised in that：The compound of described thioether acids structure is Salmisteine,
Or its pharmaceutically acceptable salt.
14. application according to claim 2, it is characterised in that：The compound of described thioether acids structure is Omonasteine,
Or its pharmaceutically acceptable salt.
15. application according to claim 2, it is characterised in that：The compound of described thioether acids structure is dacisteine,
Or its pharmaceutically acceptable salt.
16. application according to claim 2, it is characterised in that：The compound of described thioether acids structure is cartasteine,
Or its pharmaceutically acceptable salt.
17. application according to claim 2, it is characterised in that：The compound of described thioether acids structure is danosteine,
Or its pharmaceutically acceptable salt.
18. application according to claim 2, it is characterised in that：The compound of described thioether acids structure is guaisteine,
Or pharmaceutically acceptable salt.
19. application according to claim 2, it is characterised in that：The compound of described thioether acids structure is Bencisteine, or
Its pharmaceutically acceptable salt.
20. application according to claim 2, it is characterised in that：The compound of described thioether acids structure is thio diethyl
Acid, or its pharmaceutically acceptable salt.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710534867.9A CN107157976A (en) | 2017-07-03 | 2017-07-03 | Application of the compound of thioether acids structure in medicament for resisting platelet aggregation is prepared |
| PCT/CN2018/000238 WO2019007015A1 (en) | 2017-07-03 | 2018-07-03 | Application of compound of thioether acid structure in preparing anti-platelet aggregation drugs |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710534867.9A CN107157976A (en) | 2017-07-03 | 2017-07-03 | Application of the compound of thioether acids structure in medicament for resisting platelet aggregation is prepared |
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| WO2019007015A1 (en) * | 2017-07-03 | 2019-01-10 | 北京北朋科技有限公司 | Application of compound of thioether acid structure in preparing anti-platelet aggregation drugs |
| CN109248319A (en) * | 2017-07-14 | 2019-01-22 | 郜建敏 | Contain the pharmaceutical composition for taking charge of smooth class compound and aspirin |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109248319A (en) * | 2017-07-14 | 2019-01-22 | 郜建敏 | Contain the pharmaceutical composition for taking charge of smooth class compound and aspirin |
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| CN106176642B (en) * | 2016-07-19 | 2019-08-13 | 山东罗欣药业集团股份有限公司 | A kind of Disket and preparation method thereof for treating respiratory disease |
| CN107157976A (en) * | 2017-07-03 | 2017-09-15 | 北京北朋科技有限公司 | Application of the compound of thioether acids structure in medicament for resisting platelet aggregation is prepared |
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| CN109248319A (en) * | 2017-07-14 | 2019-01-22 | 郜建敏 | Contain the pharmaceutical composition for taking charge of smooth class compound and aspirin |
Non-Patent Citations (3)
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| ANTONIO MACCIÒ等: "Carbocysteine: clinical experience and new perspectives in the treatment of chronic inflammatory diseases", 《EXPERT OPIN. PHARMACOTHER.》 * |
| 张晗等: "心脑血管疾病痰瘀互结证述析", 《天津中医药》 * |
| 赵平: "黏痰调节剂（司坦类）的药理学进展及其临床应用评价", 《中国医院用药评价与分析》 * |
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| WO2019007015A1 (en) * | 2017-07-03 | 2019-01-10 | 北京北朋科技有限公司 | Application of compound of thioether acid structure in preparing anti-platelet aggregation drugs |
| CN109248319A (en) * | 2017-07-14 | 2019-01-22 | 郜建敏 | Contain the pharmaceutical composition for taking charge of smooth class compound and aspirin |
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