CN103271904B - 一种一氧化氮供体型内皮素受体拮抗剂和其制备方法及其应用 - Google Patents
一种一氧化氮供体型内皮素受体拮抗剂和其制备方法及其应用 Download PDFInfo
- Publication number
- CN103271904B CN103271904B CN201310182180.5A CN201310182180A CN103271904B CN 103271904 B CN103271904 B CN 103271904B CN 201310182180 A CN201310182180 A CN 201310182180A CN 103271904 B CN103271904 B CN 103271904B
- Authority
- CN
- China
- Prior art keywords
- preparation
- nitric oxide
- methylenedioxyphenyl
- grams
- endothelin
- 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.)
- Expired - Fee Related
Links
- 239000002308 endothelin receptor antagonist Substances 0.000 title claims abstract description 23
- 229940118365 Endothelin receptor antagonist Drugs 0.000 title claims abstract description 20
- 239000002840 nitric oxide donor Substances 0.000 title claims abstract description 4
- 238000002360 preparation method Methods 0.000 title claims description 50
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 8
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 6
- 208000006673 asthma Diseases 0.000 claims abstract description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 5
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 30
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims description 20
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 claims description 12
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 7
- -1 salt compounds Chemical class 0.000 claims description 7
- 229940081310 piperonal Drugs 0.000 claims description 6
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 238000003403 chloroformylation reaction Methods 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 4
- 208000017169 kidney disease Diseases 0.000 claims description 4
- 239000001117 sulphuric acid Substances 0.000 claims description 4
- 235000011149 sulphuric acid Nutrition 0.000 claims description 4
- 210000001685 thyroid gland Anatomy 0.000 claims description 4
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 230000029936 alkylation Effects 0.000 claims description 2
- 238000005804 alkylation reaction Methods 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 102000010180 Endothelin receptor Human genes 0.000 abstract description 4
- 108050001739 Endothelin receptor Proteins 0.000 abstract description 4
- 210000002216 heart Anatomy 0.000 abstract description 3
- 230000003042 antagnostic effect Effects 0.000 abstract description 2
- 206010020850 Hyperthyroidism Diseases 0.000 abstract 1
- 206010029164 Nephrotic syndrome Diseases 0.000 abstract 1
- 230000002490 cerebral effect Effects 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 abstract 1
- 208000009928 nephrosis Diseases 0.000 abstract 1
- 231100001027 nephrosis Toxicity 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000002585 base Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 9
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000011734 sodium Substances 0.000 description 7
- 239000013078 crystal Substances 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 229960004756 ethanol Drugs 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- WLDWSGZHNBANIO-UHFFFAOYSA-N 2',5'-Dihydroxyacetophenone Chemical compound CC(=O)C1=CC(O)=CC=C1O WLDWSGZHNBANIO-UHFFFAOYSA-N 0.000 description 4
- 230000008485 antagonism Effects 0.000 description 4
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 206010019280 Heart failures Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 229940044551 receptor antagonist Drugs 0.000 description 3
- 239000002464 receptor antagonist Substances 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 0 *C1=C(*)c(cc(cc2)O)c2C=CC1*1=CCC=C2OCOC2=C1 Chemical compound *C1=C(*)c(cc(cc2)O)c2C=CC1*1=CCC=C2OCOC2=C1 0.000 description 2
- RUECLZIBZIPGTM-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yl)-6-propan-2-yloxy-2,3-dihydrochromen-4-one Chemical compound C1=C2OCOC2=CC(C2OC3=CC=C(C=C3C(=O)C2)OC(C)C)=C1 RUECLZIBZIPGTM-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 102000002045 Endothelin Human genes 0.000 description 2
- 108050009340 Endothelin Proteins 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 102000006240 membrane receptors Human genes 0.000 description 2
- 108020004084 membrane receptors Proteins 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000010813 municipal solid waste Substances 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 238000002531 positive electrospray ionisation time-of-flight mass spectrometry Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- IPEYJIFDNBWURW-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yl)-6-phenylmethoxy-2,3-dihydrochromen-4-one Chemical compound C1C(OC2=C(C1=O)C=C(C=C2)OCC3=CC=CC=C3)C4=CC5=C(C=C4)OCO5 IPEYJIFDNBWURW-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 206010059245 Angiopathy Diseases 0.000 description 1
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 238000007445 Chromatographic isolation Methods 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- 102000048186 Endothelin-converting enzyme 1 Human genes 0.000 description 1
- 108030001679 Endothelin-converting enzyme 1 Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229940122985 Peptide agonist Drugs 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- MOTJMGVDPWRKOC-QPVYNBJUSA-N atrasentan Chemical compound C1([C@H]2[C@@H]([C@H](CN2CC(=O)N(CCCC)CCCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1 MOTJMGVDPWRKOC-QPVYNBJUSA-N 0.000 description 1
- 229950010993 atrasentan Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229960003065 bosentan Drugs 0.000 description 1
- GJPICJJJRGTNOD-UHFFFAOYSA-N bosentan Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 GJPICJJJRGTNOD-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- GLCKXJLCYIJMRB-UPRLRBBYSA-N enrasentan Chemical compound C1([C@H]2[C@@H]([C@H](C3=CC=C(C=C32)OCCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1OCCO GLCKXJLCYIJMRB-UPRLRBBYSA-N 0.000 description 1
- 229950006561 enrasentan Drugs 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000001286 intracranial vasospasm Diseases 0.000 description 1
- XMBWDFGMSWQBCA-RNFDNDRNSA-M iodine-131(1-) Chemical compound [131I-] XMBWDFGMSWQBCA-RNFDNDRNSA-M 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- TUYWTLTWNJOZNY-UHFFFAOYSA-N n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(2h-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]-5-propan-2-ylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C2=NNN=N2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 TUYWTLTWNJOZNY-UHFFFAOYSA-N 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- AAZYNPCMLRQUHI-UHFFFAOYSA-N propan-2-one;2-propan-2-yloxypropane Chemical compound CC(C)=O.CC(C)OC(C)C AAZYNPCMLRQUHI-UHFFFAOYSA-N 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229960002578 sitaxentan Drugs 0.000 description 1
- PHWXUGHIIBDVKD-UHFFFAOYSA-N sitaxentan Chemical compound CC1=NOC(NS(=O)(=O)C2=C(SC=C2)C(=O)CC=2C(=CC=3OCOC=3C=2)C)=C1Cl PHWXUGHIIBDVKD-UHFFFAOYSA-N 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229950000584 tezosentan Drugs 0.000 description 1
- 230000001971 thyroidal effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种具有通式(1)结构的一氧化氮供体型内皮素受体拮抗剂(1),其中,R1代表-CH(CH3)2、 或R2代表Cl或R3代表H或-(CH2)4ONO2。本发明化合物具有很强的内皮素受体拮抗活性,可用于制备治疗心脑血管、肿瘤、糖尿病、肾病、哮喘以及甲状腺亢进的药物。
Description
技术领域
本发明属于医药化工领域,具体涉及一种一氧化氮供体型内皮素受体拮抗剂,还涉及上述一氧化氮供体型内皮素受体拮抗剂的制备方法,最后涉及上述一氧化氮供体型内皮素受体拮抗剂的应用。
背景技术
心脑血管疾病的死亡率居各类疾病之首,其最终死因绝大多数是心肌肥大,心力衰竭(心衰)、脑卒中及致死性心律失常。尤其近年来严重心衰的病死率居高不下,已形成国际医药界的一个难题。这些疾病目前均缺乏有效的治疗药物。
内皮素(endothclin,ET)是由血管内皮细胞、心肌、平滑肌等合成及分泌的一种含有21个氨基酸的活性多肽,具有强大的缩血管和促血管平滑肌细胞增殖作用,是一种内源性损伤因子,在许多心、脑、肺、肾和血管疾病的发病中都具有重要意义。ET有3种形式的异型体,分别称为ET-1,ET-2和E-3,ET经内皮素转换酶(ECEs)作用而激活,激活的ET与其受体结合而发挥作用,其中ET1既有强烈而持久的血管收缩作用,又具有促进细胞生长和有丝分裂特性,是引起多种疾病的炎性因子。由于内皮素拮抗剂蕴藏的潜在的治疗价值,世界各大制药公司都积极地投入到内皮素拮抗剂的研究与开发中,内皮素拮抗剂的研究现已成为热点。已发现的作用较强的肽类ET拮抗剂有BQ123、BQ160、FR2139317等,但由于肽类拮抗剂的口服生物利用率低而限制了其在须长期用药的心血管疾病中的应用。许多制药公司致力于有口服活性的非肽类ET拮抗剂的研究。已经上市的内皮素受体拮抗剂有波生坦、替唑生坦、恩拉生坦、西他生坦、阿曲生坦及安贝生坦,在治疗高血压、肺动脉高压、肿瘤、糖尿病并发症、心肌梗死及脑血管痉挛等方面取得很好效果。
发明内容
本发明所要解决的技术问题是提供一种一氧化氮供体型内皮素受体拮抗剂。
本发明还要解决的技术问题是提供一种一氧化氮供体型内皮素受体拮抗剂的制备方法。
本发明最后要解决的技术问题是提供上述内皮素受体拮抗剂及其盐类化合物作为制备治疗心脑血管、肿瘤、糖尿病、肾病、哮喘以及甲状腺亢进药物中的应用。
为解决上述技术问题,本发明所采用的技术方案如下:
一种内皮素受体拮抗剂,具有通式(1)的结构:
其中,R1代表—CH(CH3)2、 或R2代表Cl或R3代表H或—(CH2)4ONO2。
上述一氧化氮供体型内皮素受体拮抗剂的制备方法,对苯二酚在浓硫酸催化下与乙酸酐反应生成对苯二酚二乙酸酯,在无水三氯化铝作用下发生Fries重排,生成2,5-二羟基苯乙酮,2,5-二羟基苯乙酮经选择性烷基化生成5-烷氧基-2-羟基苯乙酮,5-烷氧基-2-羟基苯乙酮在碱性条件下与胡椒醛发生缩合反应,缩合反应后的产物在POCl3和DMF环境中发生氯甲酰化反应,氯甲酰化反应的产物与4-取代苯酚在NaH的DMF悬浮液中进行反应,该反应后的产物先经过选择性氧化再与一氧化氮供体缩合即得到目标化合物,目标化合物通过柱层析分离纯化或有机溶剂重结晶精制。一氧化氮供体型内皮素受体拮抗剂的合成路线:
上述一氧化氮供体型内皮素受体拮抗剂及其盐类化合物作为制备治疗心脑血管、肿瘤、糖尿病、肾病、哮喘以及甲状腺亢进药物中的应用。
上述一氧化氮供体型内皮素受体拮抗剂或其药学上可接受的盐类化合物可以单独或与至少一种药学上可接受的载体组合成制剂以供给药,如针剂、输液、滴丸、片剂、胶囊剂、颗粒剂、口服液等。
有益效果:相比于现有技术,本发明的化合物具有很强的内皮素受体拮抗活性,可用于制备治疗心脑血管、肿瘤、糖尿病、肾病、哮喘以及甲状腺亢进的药物,且治疗效果显著。
具体实施方式
在本发明中所使用的术语,除非另有说明,一般具有本领域普通技术人员通常理解的含义。在以下实施例中,未详细描述的各种过程和方法是本领域中公知的常规方法。
其中,在下述实施例中,这些基团的名称为:4-甲基苄氧基;苄氧基;4-氯苄氧基;4-甲氧基苄氧基;[(4-甲氧基)苯氧基]。
熔点采用b形管熔点管测定;红外光谱仪为Nicolet Impact410型,KBr压片;核磁共振仪采用Bruker-AV300型,TMS为内标;元素分析用Carlo Erba1106型元素分析仪测定;质谱用finnigan FTMS-2000型及HP1100LC/MSD型质谱仪测定。
2,5-二羟基苯乙酮的制备:在1升的烧杯中加入110克(1.0mol)的对苯二酚,206克(2.02mol)的乙酸酐和2mL浓硫酸,手工搅拌反应混合物,反应很快进行并放热,继续搅拌十分钟后,将反应混合物转移到2升的盛有200克碎冰的烧杯中,搅拌,待冰完全融化后,抽滤,水洗,烘干,得白色固体粉末170克,用无水乙醇重结晶得白色晶体对苯二酚二乙酸酯140克,收率72%,Mp.120-122℃;向配有带氯化钙干燥管的回流冷凝管的500mL圆底烧瓶中,加入50克(0.257mol)的对苯二酚二乙酸酯和116克(0.87mol)粉状无水三氯化铝,混匀,在油浴上缓慢加热,使外温在110℃维持一小时,产生大量烟雾,将外温升到160-165℃,保温三小时,撤去油浴,反应物冷至室温,加入350mL的冰盐酸溶液,充分搅拌,使过量的三氯化铝水解,过滤,用冷水洗涤(2×100mL),得粗品35克,收率89%,用乙醇重结晶得绿色针状晶体2,5-二羟基苯乙酮,Mp.198-200℃;
5-异丙氧基-2-羟基苯乙酮的制备:称取15.2克(0.1mol)2,5-二羟基苯乙酮,36.92克(0.3mol)2-溴丙烷,3.7克碘化钾,16.6克(0.12mol)碳酸钾,加入到150mL的磨口锥形瓶中,再加入60mL的丙酮,搅拌下回流24小时,过滤,滤液旋干,残余物过柱(以石油醚:乙酸乙酯=10:1的混合溶剂为洗脱液),得黄色油状物13.6克,收率70%;5-苄氧基-2-羟基苯乙酮的制备:称取1.9克(12.5mmol)2,5-二羟基苯乙酮,3.45克(25mmol)碳酸钾,1.6克(12.5mmol)的苄氯,3.7克碘化钾,加入到150mL的磨口锥形瓶中,再加入60mL的丙酮,慢慢的滴加含有1.6克(12.5mmol)的苄氯的丙酮溶液,加毕,搅拌下回流24小时,过滤,滤液旋干,残余物过柱(以石油醚:乙酸乙酯=10:1的混合溶剂为洗脱液),得黄色油状物13.6克,收率70%;5-(4-甲基苄氧基)-2-羟基苯乙酮、5-(4-甲氧基苄氧基)-2-羟基苯乙酮、5-(4-氯苄氧基)-2-羟基苯乙酮的制备方法均可参照5-苄氧基-2-羟基苯乙酮的制备方法,5-取代-2-羟基苯乙酮化合物的合成可参照化合物5-异丙氧基-2-羟基苯乙酮或5-苄氧基-2-羟基苯乙酮的合成方法,结果见如下表1:
表1
2-(3,4-亚甲二氧基苯基)-6-异丙氧基-2,3-二氢-4-色酮的制备:称取4.4g(23mmol)的5-异丙氧基-2-羟基苯乙酮,3.4g(23mmol)的胡椒醛,加入到50mL的锥形瓶中,再加入10mL甲醇,搅拌下滴加2M的NaOH溶液45mmol(1.8gNaOH,22mLH2O),加毕,室温搅拌72h,丙酮稀释,过滤,乙醇重结晶,得黄色针状结晶2.5g,收率33%。Mp.112-114℃;2-(3,4-亚甲二氧基苯基)-6-苄氧基-2,3-二氢-4-色酮的制备:称取2.42g(10mmol)的5-苄氧基-2-羟基苯乙酮,1.5g(10mmol)的胡椒醛,加入到50mL的锥形瓶中,再加入10mL甲醇,搅拌下滴加2M的NaOH溶液20mmol(将0.8gNaOH溶于10mLH2O中配成的溶液),加毕,室温搅拌72h,丙酮稀释,过滤,甲醇重结晶,得黄色粉末2.0g,收率53%,Mp.132-134℃;同理,2-(3,4-亚甲二氧基苯基)-6-(4-甲基苄氧基)-2,3-二氢-4-色酮、2-(3,4-亚甲二氧基苯基)-6-(4-甲氧基苄氧基)-2,3-二氢-4-色酮、2-(3,4-亚甲二氧基苯基)-6-(4-氯苄氧基)-2,3-二氢-4-色酮的制备方法均可参照2-(3,4-亚甲二氧基苯基)-6-苄氧基-2,3-二氢-4-色酮的制备方法,结果见如下表2:
表2
实施例1:2-(3,4-亚甲二氧基苯基)-4-氯-6-异丙氧基-2H-色烯-3-羧酸的制备
第一步,制备2,5-二羟基苯乙酮:
在1升的烧杯中加入110克(1.0mol)的对苯二酚,206克(2.02mol)的乙酸酐和2mL浓硫酸,手工搅拌反应混合物,反应很快进行并放热,继续搅拌十分钟后,将反应混合物转移到2升的盛有200克碎冰的烧杯中,搅拌,待冰完全融化后,抽滤,水洗,烘干,得白色固体粉末170克,用无水乙醇重结晶得白色晶体对苯二酚二乙酸酯140克,收率72%,Mp.120-122℃;向配有带氯化钙干燥管的回流冷凝管的500mL圆底烧瓶中,加入50克(0.257mol)的对苯二酚二乙酸酯和116克(0.87mol)粉状无水三氯化铝,混匀,在油浴上缓慢加热,使外温在110℃维持一小时,产生大量烟雾,将外温升到160-165℃,保温三小时,撤去油浴,反应物冷至室温,加入350mL的冰盐酸溶液,充分搅拌,使过量的三氯化铝水解,过滤,用冷水洗涤(2×100mL),得粗品35克,收率89%,用乙醇重结晶得绿色针状晶体2,5-二羟基苯乙酮,Mp.198-200℃;
第二步,制备5-异丙氧基-2-羟基苯乙酮:
称取15.2克(0.1mol)2,5-二羟基苯乙酮,36.92克(0.3mol)2-溴丙烷,3.7克碘化钾,16.6克(0.12mol)碳酸钾,加入到150mL的磨口锥形瓶中,再加入60mL的丙酮,搅拌下回流24小时,过滤,滤液旋干,残余物过柱(以石油醚:乙酸乙酯=10:1的混合溶剂为洗脱液),得黄色油状物13.6克,收率70%;
第三步,制备2-(3,4-亚甲二氧基苯基)-6-异丙氧基-2,3-二氢-4-色酮:
称取4.4g(23mmol)的5-异丙氧基-2-羟基苯乙酮,3.4g(23mmol)的胡椒醛,加入到50mL的锥形瓶中,再加入10mL甲醇,搅拌下滴加2M的NaOH溶液45mmol(1.8gNaOH,22mLH2O),加毕,室温搅拌72h,丙酮稀释,过滤,乙醇重结晶,得黄色针状结晶2.5g,收率33%。Mp.112-114℃;
第四步,制备2-(3,4-亚甲二氧基苯基)-4-氯-6-异丙氧基-2H-色烯-3-羧酸:
将21g(0.137mol)的POCl3于0℃下,滴加到41.60mL(0.54mol)的DMF中形成混合物,于0℃下搅拌30min,另将18g(0.05mol)的2-(3,4-亚甲二氧基苯基)-6-异丙氧基-2,3-二氢-4-色酮溶于70mLDMF中,在0℃下滴加到上述混合物中,加完后在室温下搅拌48h,充分反应后,将反应后的混合物倾入到200mL冰水中,搅拌10min.,过滤,干燥,以丙酮-异丙醚重结晶,得黄色结晶性粉末15g,收率80%,Mp.114-115℃;
称取2.2g(0.023mol)的氨基磺酸溶于13mL水中,向其中加入含有3.5g(0.0094mol)上述产物的甲苯溶液,形成混合溶液,冷却至0℃,将2.14g(0.0023mol)NaClO2溶于18mL冰水中,于0℃下滴加到上述混合溶液中,搅拌30min.,在搅拌的过程中再依次加入亚硫酸钠溶液(1.2gNaSO3溶于10mL水中),氢氧化钠溶液(1.6gNaOH溶于35mL水中),添加完成后搅拌10min.,过滤,水洗,干燥,乙醇重结晶,得黄色粉末2-(3,4-亚甲二氧基苯基)-4-氯-6-异丙氧基-2H-色烯-3-羧酸3.4g,收率89%,Mp.173-174℃,MS(TOF MS ES+):411.1[M+Na]+
1H-NMR(CDCl3)δ(ppm):1.32-1.44(d,6H),4.43-4.51(m,1H),5.92(d,2H),6.09(s,1H),6.69-6.75(t,2H),6.81-6.86(m,3H),7.18-7.30(t,1H).IR(cm-1):3425.44,2973.67,1692.82,1668.94,1597.80,1567.61,1501.42,1482.87,1286.25,1252.05。
实施例2:2-(3,4-亚甲二氧基苯基)-4-[(4-甲氧基)苯氧基]-6-异丙氧基-2H-色烯-3-羧酸的制备
第一步,制备2,5-二羟基苯乙酮:
参照实施例1中的第一步步骤操作;
第二步,制备5-异丙氧基-2-羟基苯乙酮:
参照实施例1中的第二步步骤操作;
第三步,制备2-(3,4-亚甲二氧基苯基)-6-异丙氧基-2,3-二氢-4-色酮:
参照实施例1中的第三步步骤操作;
第四步,制备2-(3,4-亚甲二氧基苯基)-4-氯-6-异丙氧基-2H-色烯-3-羧酸:
参照实施例1中的第四步步骤操作;
第五步,制备目标产物:
将2-(3,4-亚甲二氧基苯基)-4-氯-6-异丙氧基-2H-色烯-3-羧酸4g(0.01mol)加入到250mL的锥形瓶中,加入50mL的无水DMF溶解,搅拌下加入1.5g60%的NaH,室温搅拌30分钟,再加入1.3g(0.01mol)对甲氧基苯酚,于室温下搅拌6小时,将反应混合物倾入300mL冰水中,乙酸乙酯萃取三次(300mL×3),无水硫酸镁干燥,过柱(石油醚:乙酸乙酯=10:1),制得黄色固体粉末,收率50%,Mp.180--182℃.MS(TOF MS ES+):499.1[M+Na]+1H-NMR(CDCl3)δ(ppm):0.99-1.01(d,3H),1.23-1.28(d,3H),3.75s,3H),4.09-4.17(m,1H),5.91(s,2H),6.34(s,1H),6.62-6.98(m,10H).IR(cm-1):3437.79,2975.24,1664.21,1630.30,1575.19,1503.79,1486.59,1442.61,1246.23,1234.38,1209.46。
实施例3:2-(3,4-亚甲二氧基苯基)-4--[(4-甲氧基)苯氧基]-6-苄氧基-2H-色烯-3-羧酸的制备
第一步,制备2,5-二羟基苯乙酮:
参照实施例1中的第一步步骤操作;
第二步,制备5-苄氧基-2-羟基苯乙酮:
称取1.9克(12.5mmol)2,5-二羟基苯乙酮,3.45克(25mmol)碳酸钾,1.6克(12.5mmol)的苄氯,3.7克碘化钾,加入到150mL的磨口锥形瓶中,再加入60mL的丙酮,慢慢的滴加含有1.6克(12.5mmol)的苄氯的丙酮溶液,加毕,搅拌下回流24小时。过滤,滤液旋干,残余物过柱(以石油醚:乙酸乙酯=10:1的混合溶剂为洗脱液),得黄色油状物13.6克,收率70%;
第三步,制备2-(3,4-亚甲二氧基苯基)-6-苄氧基-2,3-二氢-4-色酮:
称取2.42g(10mmol)的5-苄氧基-2-羟基苯乙酮,1.5g(10mmol)的胡椒醛,加入到50mL的锥形瓶中,再加入10mL甲醇,搅拌下滴加2M的NaOH溶液20mmol(将0.8gNaOH溶于10mLH2O中配成的溶液),加毕,室温搅拌72h,丙酮稀释,过滤,甲醇重结晶,得黄色粉末2.0g,收率53%,Mp.132-134℃;
第四步,制备2-(3,4-亚甲二氧基苯基)-4-氯-6-苄氧基-2H-色烯-3-羧酸:
参照实施例1中的第四步操作步骤;
第五步,制备目标产物:
参照实施例2中的第五步操作步骤,得到黄色固体粉末,收率83%,Mp.174-176℃。MS(ESI-):523.2[M-H]-1H-NMR(CDCl3)δ(ppm):3.74(s,3H),4.75(q,2H),5.89(s,2H),6.29(s,1H),6.67-6.92(m,5H),7.23-7.31(m,br,6H)。IR(cm-1):3432.31,2947.96,2903.83,1702.47,1691.18,1665.40,1631.12,1573.18,1502.06,1485.93,1442.81,1239.89,1201.92。
实施例4:2-(3,4-亚甲二氧基苯基)-4-氯-6-(4-甲基苄氧基)-2H-色烯-3-羧酸的制备
参照实施例12-(3,4-亚甲二氧基苯基)-4-氯-6-异丙氧基-2H-色烯-3-羧酸的制备方法,得到黄色固体粉末,收率45%,Mp.167-169℃。MS(ESI-):499.0[M-H]-1H-NMR(CDCl3)δ(ppm):2.35(s,3H),4.98(s,2H),5.89(s,2H),6.25(s,1H),6.68-6.89(m,5H),7.02-7.36(m,5H),IR(cm-1):3442.70,3433.06,3068.53,3020.32,2954.74,2918.10,2889.17,1693.38,1668.31,1600.81,1566.09,1485.09,1442.66,1377.08,1317.29,1259.43,1240.14,1188.07,1039.58。
实施例5:2-(3,4-亚甲二氧基苯基)-4-氯-6-(4-甲氧基苄氧基)-2H-色烯-3-羧酸的制备
参照实施例12-(3,4-亚甲二氧基苯基)-4-氯-6-异丙氧基-2H-色烯-3-羧酸的制备方法,得到黄色固体粉末,收率80%,Mp.156-158℃。MS ESI(-):465[M-H]-1H-NMR(CDCl3)δ(ppm):3.82(s,3H),4.95(s,2H),5.91(s,2H),6.26(s,1H),6.69-6.93(m,6H),7.27-7.35(m,3H),IR(cm-1):3450.41,2999.10,2900.74,1695.31,1620.09,1571.88,1488.94,1452.30,1380.94,1278.72,1249.79,1184.21,1031.85。
实施例6:2-(3,4-亚甲二氧基苯基)-4-氯-6-苄氧基-2H-色烯-3-羧酸的制备
参照实施例12-(3,4-亚甲二氧基苯基)-4-氯-6-异丙氧基-2H-色烯-3-羧酸的制备方法,得黄色固体粉末,收率57%,Mp.145-148℃。MS(ESI-):435.0[M-H]-1H-NMR(CDCl3)δ(ppm):5.00(s,2H),5.98(s,2H),6.2(s,1H),6.67-6.88(m,5H),7.24-7.42(m,6H)。IR(cm-1):3082.70,3058.35,2928.61,2897.32,2876.65,1705.07,1685.02,1621.34,1570.71,1503.06,1483.20,1442.05,1423.01,1379.32。
实施例7:2-(3,4-亚甲二氧基苯基)-4-氯-6-(4-氯苄氧基)-2H-色烯-3-羧酸的制备
参照实施例12-(3,4-亚甲二氧基苯基)-4-氯-6-异丙氧基-2H-色烯-3-羧酸的制备方法制得黄色固体粉末,收率67%,Mp.158-160℃。MS(ESI+):471.2(M+)1H-NMR(CDCl3)δ(ppm):2.79-2.86(dd,1H),2.98-3.08(m,1H),5.31-5.36(dd,1H),5.98(s,2H),6.81(s,1H),6.84-7.41(m,10H)。IR(cm-1):3450.41,3080.11,2898.81,1676.03,1618.17,1488.94,1440.73,1407.94,1379.01,1342.36,1286.43,1232.43,1193.85,1126.35,1091.63,1062.70,1033.77,1010.63,929.63,871.76,815.83。
实施例8:2-(3,4-亚甲二氧基苯基)-4-氯-6-异丙氧基-2H-色烯-3-羧酸-4’-亚硝氧基丁酯的制备
称取1.5g(3.86mmol)2-(3,4-亚甲二氧基苯基)-4-氯-6-异丙氧基-2H-色烯-3-羧酸(由上述实施例1制得)和3.75(17.4mol)的1,4-二溴丁烷,加入100mL的锥形瓶中,边搅拌边滴加含有1mL三乙胺的丙酮溶液(加入的丙酮溶液为50mL),滴加完成,回流10h,过滤,丙酮洗涤滤饼,将滤液旋干,过柱(以石油醚:乙酸乙酯=20:1的混合溶剂为洗脱液),得黄色粘稠液体3g,收率60%。MS(TOF MS ES+):528.1M+Na]+
1H-NMR(CDCl3)δ(ppm):1.25-1.38(d,6H),1.65-1.76(m,br,4H),4.26-4.30(m,2H),4.37-4.41(M,2H),4.6-4.72(M,1H),6.07(s,2H),6.88-6.91(d,1H),7.18-7.58(m,5H)。IR(cm-1):2972.10,2933.53,2900.74,1685.67,1631.67,1623.95,1571.88,1490.87,1440.73,1392.51,1361.65,1332.72,1284.50,1215.07,1134.07,1031.85,993.27。
实施例9:2-(3,4-亚甲二氧基苯基)-4-[(4-甲氧基)苯氧基]-6-异丙氧基-2H-色烯-3-羧酸-4’-亚硝氧基丁酯的制备
参照实施例92-(3,4-亚甲二氧基苯基)-4-氯-6-异丙氧基-2H-色烯-3-羧酸-4’-亚硝氧基丁酯的制备方法,由2-(3,4-亚甲二氧基苯基)-4-[(4-甲氧基)苯氧基]-6-异丙氧基-2H-色烯-3-羧酸(由上述实施例2制得)最终得到黄色粘稠物,收率80%。
MS(TOF MS ES+):616.2[M+Na]+,632.2[M+K]+
1H-NMR(CDCl3)δ(ppm):1.07-1.09(d,3H),1.18-1.20(d,3H),1.47-1.60(m,4H),1.60-1.88(m,1H),3.74(s,3H),4.03-4.13(m,2H),4.20-4.25(m,3H),4.48-4.49(m,1H),5.91(s,1H),6.26(s,1H),6.70--6.94(m,10H)。
IR(cm-1):2968.60,2936.51,2901.59,1691.05,1639.45,1631.34,1503.38,1486.17,1443.64,1278.76,1207.20,864.45。
实施例10:2-(3,4-亚甲二氧基苯基)-4-氯-6-苄氧基-2H-色烯-3-羧酸-4’-亚硝氧基丁酯的制备
参照实施例92-(3,4-亚甲二氧基苯基)-4-氯-6-异丙氧基-2H-色烯-3-羧酸-4’-亚硝氧基丁酯的制备方法,由2-(3,4-亚甲二氧基苯基)-4-氯-6-苄氧基-2H-色烯-3-羧酸(由上述实施例6制得)最终得到黄色粘稠物,收率41%。
MS:ESI(+):577.1[M+Na]+,
1H-NMR(CDCl3)δ(ppm):1.66-1.79(br,4H),4.16-4.28(m,2H),4.37-4.41(m,2H),5.02(s,2H),5.91(s,2H),6.20(s,1H),6.68-6.87(m,4H),7.25-7.40(m,6H)。
IR(cm-1):3450.41,2956.67,2896.88,1693.38,1627.81,1571.88,1490.87,1440.73,1382.87,1315.36,1276.79,1245.93,1190.00,1134.07,1091.63,1033.77,1006.77,927.70,860.19。
实施例11:2-(3,4-亚甲二氧基苯基)-4-氯-6-(4-甲基苄氧基)-2H-色烯-3-羧酸--4’-亚硝氧基丁酯的制备
参照实施例92-(3,4-亚甲二氧基苯基)-4-氯-6-异丙氧基-2H-色烯-3-羧酸-4’-亚硝氧基丁酯的制备方法,由2-(3,4-亚甲二氧基苯基)-4-氯-6-(4-甲基苄氧基)-2H-色烯-3-羧酸(由上述实施例4制得)最终得到黄色固体,收率83%。Mp.85-87℃.
MS(ESI+):590.0[M+Na]+,606.1[M+K]+
1H-NMR(CDCl3)δ(ppm):1.66-1.79(br,4H),4.16-4.28(m,2H),4.37-4.41(m,2H),5.02(s,2H),5.91(s,2H),6.20(s,1H),6.68-6.87(m,4H),7.25-7.40(m,6H)。
IR(cm-1):3074.32,2956.67,2920.03,2896.88,1693.38,1627.81,1571.88,1488.94,1442.66,1382.87,1315.36,1276.79,1245.93,1191.93,1134.07,1120.56,1091.63,1033.77,1006.77,985.56,927.70,860.19。
实施例12:2-(3,4-亚甲二氧基苯基)-4-氯-6-(4-甲氧基苄氧基)-2H-色烯-3-羧酸-4’-亚硝氧基丁酯的制备
参照实施例92-(3,4-亚甲二氧基苯基)-4-氯-6-异丙氧基-2H-色烯-3-羧酸-4’-亚硝氧基丁酯的制备方法,由2-(3,4-亚甲二氧基苯基)-4-氯-6-(4-甲氧基苄氧基)-2H-色烯-3-羧酸(由上述实施例5制得)最终得到黄色固体,收率82%。Mp.77-79℃.
MS(ESI+):606[M+Na]+,622[M+K]+
1H-NMR(CDCl3)δ(ppm):1.68-1.76(m,br,4H),3.81(s,3H),4.18-4.20(m,1H),4.23-4.27(m,1H),4.38-4.41(s,2H),4.94(s,2H),5.91(s,2H),6.20(s,1H),6.68-6.91(m,5H),7.25-7.34(m,5H)。
IR(cm-1):3450.41,2968.24,2898.81,1716.53,1629.74,1569.95,1512.09,1479.30,1440.73,1382.87,1282.57,1245.93,1217.00,1182.28。
表3本发明一氧化氮供体型内皮素受体拮抗剂
实施例13:放射受体分析法筛选内皮素受体拮抗剂
采用放射受体分析法,利用125I-ET1与大鼠左心室膜受体的结合,对本发明所述化合物进行筛选,具体操作如下:
材料:125I-ET1:由北京北方生物技术研究所标记,放射比活度为1750Ci/mmol。Tris-Hcl缓冲液(50mM,PH7.4),自行配制。BSA:购自建成生物技术公司。ET1:购自sigma公司。49#玻璃纤维滤膜:购自上海虹光公司。
动物:雄性SD大鼠,230~250g。
方法:大鼠脱颈椎处死,迅速取心脏,分离左心,加入Tris缓冲液制成10%匀浆,经3次不同转速离心,提取膜受体蛋白。以测得的cpm值折算配体受体结合量。
筛选结果见表4。结果表明化合物Ⅰ01-Ⅰ12对内皮素受体具有不同程度的拮抗作用。
表4ET受体拮抗剂(10-7M)竞争结合(M±SD)
化合物 | B%(n) |
I01 | 38.4±10.0(6) |
I02 | 31.1±9.5(6) |
I03 | 40.9±17.2(6) |
I04 | 95.0±25.1(2) |
I05 | 89.2±12.4(2) |
I06 | 63.8±22.6(2) |
I07 | 98.9±25.5(2) |
I08 | 60.5±20.2(5) |
I09 | 37.2±7.3(6) |
I10 | 77.5±17.6(6) |
I11 | 100.0±22.5(2) |
I12 | 88.45±27.4(2) |
B%:表示放射性碘代内皮素与心肌受体的结合百分率;M为平均值,SD为标准偏差。
:实施例14:ET受体拮抗剂对ETAR和ETBR的竞争结合
采用实施例13的125I-ET1竞争受体配基结合试验。在进行对ETAR选择性作用时,加入ETBR激动剂S6C饱和对ETBR的结合。进行ETBR选择性时,加入ETA选择性阻断剂PD156707,与ETAR饱和结合,考察化合物Ⅰ03和Ⅰ09对ETAR和ETBR的竞争结合情况,结果如表5所示。结果表明化合物Ⅰ03和Ⅰ09对ETAR和ETBR有双重拮抗作用。
表5ET受体拮抗剂对ETAR和ETBR的竞争结合(M±sd,n=3)
综上,125I-ET1竞争受体配基结合试验结果表明,化合物Ⅰ01-Ⅰ12对内皮素受体具有不同程度的拮抗作用。其中化合物Ⅰ03和Ⅰ09对ETAR和ETBR有双重拮抗作用。
Claims (3)
1.一种一氧化氮供体型内皮素受体拮抗剂,具有通式(1)的结构:
其中,R1代表–CH(CH3)2、 R2代表Cl或R3代表—(CH2)4ONO2。
2.权利要求1所述一氧化氮供体型内皮素受体拮抗剂的制备方法,其特征在于:对苯二酚在浓硫酸催化下与乙酸酐反应生成对苯二酚二乙酸酯,在无水三氯化铝作用下发生Fries重排,生成2,5-二羟基苯乙酮,2,5-二羟基苯乙酮经选择性烷基化生成5-烷氧基-2-羟基苯乙酮,5-烷氧基-2-羟基苯乙酮在碱性条件下与胡椒醛发生缩合反应,缩合反应后的产物在POCl3和DMF环境中发生氯甲酰化反应,氯甲酰化反应的产物与4-取代苯酚在NaH的DMF悬浮液中进行反应,该反应后的产物先经过选择性氧化再与一氧化氮供体缩合即得到目标化合物。
3.权利要求1所述一氧化氮供体型内皮素受体拮抗剂及其盐类化合物作为制备治疗心脑血管、肿瘤、糖尿病、肾病、哮喘以及甲状腺亢进药物的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310182180.5A CN103271904B (zh) | 2013-05-15 | 2013-05-15 | 一种一氧化氮供体型内皮素受体拮抗剂和其制备方法及其应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310182180.5A CN103271904B (zh) | 2013-05-15 | 2013-05-15 | 一种一氧化氮供体型内皮素受体拮抗剂和其制备方法及其应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103271904A CN103271904A (zh) | 2013-09-04 |
CN103271904B true CN103271904B (zh) | 2014-11-12 |
Family
ID=49054131
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201310182180.5A Expired - Fee Related CN103271904B (zh) | 2013-05-15 | 2013-05-15 | 一种一氧化氮供体型内皮素受体拮抗剂和其制备方法及其应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103271904B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103539760B (zh) * | 2013-10-23 | 2016-04-13 | 东南大学 | 苯氧苯乙酸类内皮素拮抗剂及其制备方法与应用 |
-
2013
- 2013-05-15 CN CN201310182180.5A patent/CN103271904B/zh not_active Expired - Fee Related
Non-Patent Citations (4)
Title |
---|
Natsuki Ishizuka等.Structure-Activity Relationships of a Novel Class of Endothelin-A Receptor Antagonists and Discovery of Potent and Selective Receptor Antagonist......(S-1255). 1. Study on Structure-Activity Relationships and Basic Structure Crucial for ETA Antagonism.《Journal of Medicinal Chemistry》.2002,第45卷(第10期),第2041-2055页. * |
Structure-Activity Relationships of a Novel Class of Endothelin-A Receptor Antagonists and Discovery of Potent and Selective Receptor Antagonist......(S-1255). 1. Study on Structure-Activity Relationships and Basic Structure Crucial for ETA Antagonism;Natsuki Ishizuka等;《Journal of Medicinal Chemistry》;20020409;第45卷(第10期);第2041-2055页 * |
一氧化氮供体最新研究进展及应用前景;李松 等;《中国生化药物杂志》;20061231;第27卷(第6期);第374-378页 * |
李松 等.一氧化氮供体最新研究进展及应用前景.《中国生化药物杂志》.2006,第27卷(第6期),第374-378页. * |
Also Published As
Publication number | Publication date |
---|---|
CN103271904A (zh) | 2013-09-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103097340B (zh) | 治疗活性组合物及其使用方法 | |
CN105008335B (zh) | 合成甲状腺激素类似物及其多形体的方法 | |
EP2074114B1 (en) | Pyrimidinones as casein kinase ii (ck2) modulators | |
US20080200524A1 (en) | Amide compounds as ion channel ligands and uses thereof | |
CN101772494B (zh) | 4-嘧啶磺酰胺衍生物 | |
CN101148418B (zh) | 一枝蒿酮酸衍生物及其用途 | |
CN86104539A (zh) | 羟基和烷氧基嘧啶类 | |
CN111518031B (zh) | 一种含有异羟肟酸的化合物及其制备方法、应用 | |
AU2016246068A1 (en) | Xanthine-substituted alkynyl carbamates/reverse carbamates as A2b antagonists | |
CN101717359B (zh) | 吲达帕胺的合成方法 | |
CN112062712A (zh) | 一种2-(5-溴-3-甲基吡啶-2-基)乙酸盐酸盐的制备方法 | |
CN106336396A (zh) | 一种苯甲酸阿格列汀的制备方法 | |
CN102558097A (zh) | 一种改进的雷诺嗪合成方法 | |
CN108373468B (zh) | 一种n-2-吡啶-5-嘧啶甲胺的制备方法 | |
CN103271904B (zh) | 一种一氧化氮供体型内皮素受体拮抗剂和其制备方法及其应用 | |
CN103539659B (zh) | 2,4-二苄氧基苯甲酸衍生物及其制备方法与应用 | |
CN103467445B (zh) | 苯甲酸阿格列汀的制备方法 | |
CN108727238A (zh) | 一种urat1抑制剂及其制备方法和用途 | |
CN103588712B (zh) | 一种嘧啶类化合物及其制备方法、和应用 | |
CN107216271B (zh) | 酒石酸匹莫范色林杂质及其制备方法 | |
CN105622452A (zh) | Ahu-377结晶型游离酸及其制备方法和应用 | |
CN104926807B (zh) | 一种利伐沙班相关物质“二胺”及其合成方法 | |
CN111116493B (zh) | 一种制备Apabetalone的方法、中间体及其中间体的制备方法 | |
CN107266442A (zh) | 具有抗肿瘤活性的哌啶并吡啶类化合物的制备方法 | |
CN103130674B (zh) | 预防和治疗阿尔兹海默症的潜在药物gx50,gx51,gx52,gx180的化学合成方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20141112 |
|
CF01 | Termination of patent right due to non-payment of annual fee |