WO2013075399A1 - 苯并五元不饱和杂环类化合物或其药用盐及其制备方法、药物组合物及其应用 - Google Patents
苯并五元不饱和杂环类化合物或其药用盐及其制备方法、药物组合物及其应用 Download PDFInfo
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- WO2013075399A1 WO2013075399A1 PCT/CN2012/001555 CN2012001555W WO2013075399A1 WO 2013075399 A1 WO2013075399 A1 WO 2013075399A1 CN 2012001555 W CN2012001555 W CN 2012001555W WO 2013075399 A1 WO2013075399 A1 WO 2013075399A1
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- WIPO (PCT)
- Prior art keywords
- group
- carboxylic acid
- ester
- dimethylamine
- substituted
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- 150000003839 salts Chemical class 0.000 title claims abstract description 29
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 13
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- 230000003262 anti-osteoporosis Effects 0.000 claims abstract description 6
- -1 isovaleryl Chemical group 0.000 claims description 126
- 125000004494 ethyl ester group Chemical group 0.000 claims description 80
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 63
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 41
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical class CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 125000005605 benzo group Chemical group 0.000 claims description 34
- 150000002391 heterocyclic compounds Chemical class 0.000 claims description 34
- 150000004702 methyl esters Chemical class 0.000 claims description 33
- 125000002252 acyl group Chemical group 0.000 claims description 31
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 28
- OFFSPAZVIVZPHU-UHFFFAOYSA-N 1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)=CC2=C1 OFFSPAZVIVZPHU-UHFFFAOYSA-N 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 23
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 22
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 20
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 20
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 19
- ZFQAAMGCGJKDSV-UHFFFAOYSA-N furo[2,3-f][1,3]benzodioxole-6-carboxylic acid Chemical compound C1=C2OC(C(=O)O)=CC2=CC2=C1OCO2 ZFQAAMGCGJKDSV-UHFFFAOYSA-N 0.000 claims description 19
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 19
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- DDYQAKGAKIASSJ-UHFFFAOYSA-N thieno[2,3-f][1,3]benzodioxole-6-carboxylic acid Chemical compound C1=C2SC(C(=O)O)=CC2=CC2=C1OCO2 DDYQAKGAKIASSJ-UHFFFAOYSA-N 0.000 claims description 15
- IQELKSYGXWBQJA-UHFFFAOYSA-N 6-methoxy-1-benzofuran-2-carboxylic acid Chemical compound COC1=CC=C2C=C(C(O)=O)OC2=C1 IQELKSYGXWBQJA-UHFFFAOYSA-N 0.000 claims description 14
- 238000010992 reflux Methods 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- DYSJMQABFPKAQM-UHFFFAOYSA-N 1-benzothiophene-2-carboxylic acid Chemical compound C1=CC=C2SC(C(=O)O)=CC2=C1 DYSJMQABFPKAQM-UHFFFAOYSA-N 0.000 claims description 13
- XTXMOIBADXDEKF-UHFFFAOYSA-N 6-methoxy-1-benzothiophene-2-carboxylic acid Chemical compound COC1=CC=C2C=C(C(O)=O)SC2=C1 XTXMOIBADXDEKF-UHFFFAOYSA-N 0.000 claims description 13
- 150000001412 amines Chemical class 0.000 claims description 13
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- YMZTUCZCQMQFMK-UHFFFAOYSA-N 3-methyl-1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2C(C)=C(C(O)=O)OC2=C1 YMZTUCZCQMQFMK-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 125000003277 amino group Chemical group 0.000 claims description 12
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- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000004185 ester group Chemical group 0.000 claims description 11
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
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- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 6
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- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 5
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- 125000003368 amide group Chemical group 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- QSJOOKNQBKWMAP-UHFFFAOYSA-N 1-benzofuran-2,6-dicarboxylic acid Chemical compound OC(=O)C1=CC2=CC=C(C=C2O1)C(O)=O QSJOOKNQBKWMAP-UHFFFAOYSA-N 0.000 claims description 4
- DHNVMKHYFMDCPG-UHFFFAOYSA-N 6-acetyl-1-benzofuran-2-carboxylic acid Chemical compound C(C)(=O)C1=CC2=C(C=C(O2)C(=O)O)C=C1 DHNVMKHYFMDCPG-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 239000012670 alkaline solution Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 125000005251 aryl acyl group Chemical group 0.000 claims description 4
- 150000007860 aryl ester derivatives Chemical class 0.000 claims description 4
- 150000003935 benzaldehydes Chemical class 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 239000012024 dehydrating agents Substances 0.000 claims description 4
- 150000008282 halocarbons Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 150000002440 hydroxy compounds Chemical class 0.000 claims description 4
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
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- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 239000001488 sodium phosphate Substances 0.000 claims description 4
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 4
- 125000003944 tolyl group Chemical group 0.000 claims description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 4
- ANSUPYBJVNMSJB-UHFFFAOYSA-N 5,6-dimethoxy-1-methylindole-2-carboxylic acid Chemical compound C1=C(OC)C(OC)=CC2=C1N(C)C(C(O)=O)=C2 ANSUPYBJVNMSJB-UHFFFAOYSA-N 0.000 claims description 3
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 3
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- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
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- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
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- 229910052708 sodium Inorganic materials 0.000 claims description 3
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- LOIHKMZAAYGFGR-UHFFFAOYSA-N (6-methoxy-1-benzofuran-2-carbonyl)oxymethylphosphonic acid Chemical compound P(=O)(O)(O)COC(=O)C=1OC2=C(C1)C=CC(=C2)OC LOIHKMZAAYGFGR-UHFFFAOYSA-N 0.000 claims description 2
- NQJCVIXMLHCDDC-UHFFFAOYSA-N (6-methoxy-1-benzothiophene-2-carbonyl)oxymethylphosphonic acid Chemical compound COC1=CC=C2C=C(C(=O)OCP(O)(O)=O)SC2=C1 NQJCVIXMLHCDDC-UHFFFAOYSA-N 0.000 claims description 2
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- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 claims description 2
- GSWKZAVAIDGPKF-UHFFFAOYSA-N 2-(6-methoxy-1-benzofuran-2-carbonyl)oxyethylphosphonic acid Chemical compound COC1=CC=C2C=C(C(=O)OCCP(O)(O)=O)OC2=C1 GSWKZAVAIDGPKF-UHFFFAOYSA-N 0.000 claims description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 2
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- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
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- 150000002611 lead compounds Chemical class 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
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- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
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- ZBELDPMWYXDLNY-UHFFFAOYSA-N methyl 9-(4-bromo-2-fluoroanilino)-[1,3]thiazolo[5,4-f]quinazoline-2-carboximidate Chemical compound C12=C3SC(C(=N)OC)=NC3=CC=C2N=CN=C1NC1=CC=C(Br)C=C1F ZBELDPMWYXDLNY-UHFFFAOYSA-N 0.000 description 1
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- 210000003098 myoblast Anatomy 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- YCJZWBZJSYLMPB-UHFFFAOYSA-N n-(2-chloropyrimidin-4-yl)-2,5-dimethyl-1-phenylimidazole-4-carboxamide Chemical compound CC=1N(C=2C=CC=CC=2)C(C)=NC=1C(=O)NC1=CC=NC(Cl)=N1 YCJZWBZJSYLMPB-UHFFFAOYSA-N 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000002188 osteogenic effect Effects 0.000 description 1
- 230000002138 osteoinductive effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
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- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229940088417 precipitated calcium carbonate Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 108010023714 recombinant human bone morphogenetic protein-2 Proteins 0.000 description 1
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- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 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 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 229940075554 sorbate Drugs 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
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- 235000000346 sugar Nutrition 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
- C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
- C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
- C07F9/655354—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Definitions
- Osteoporosis is a systemic bone mass characterized by microstructural destruction of bone tissue.
- osteoporosis caused by medication in HIV, cardiovascular disease and diabetes patients is becoming more and more serious. Osteoporosis and its complications have become a health problem that attracts the attention of the whole society. It is effective to prevent and treat osteoporosis. Drugs and treatments have also become research hotspots worldwide.
- osteoblasts obs
- osteoclasts ocs
- Osteoblast proliferation and differentiation are regulated by a variety of factors, including Bone Morphogenetic Protein-2 (BMP-2), which plays a key role in the differentiation of osteoblasts.
- BMP-2 also promotes the expression of other osteogenic factors, such as osteoinductive protein (OP), core binding factor al (Cbfal), alkaline phosphatase (ALP), and fatty acid coupling. Protein 4 (fabp4), etc.
- OP osteoinductive protein
- Cafal core binding factor al
- ALP alkaline phosphatase
- fabricp4 Protein 4
- BMP-2 not only has a stimulatory differentiation effect on bone tissue-derived cell lines, such as osteoblast precursor cells, ROB-C26 cells, MC3T3-EK osteoblasts, W-20 bone marrow stromal cells, etc.
- bone tissue-derived cell lines such as osteoblast precursor cells, ROB-C26 cells, MC3T3-EK osteoblasts, W-20 bone marrow stromal cells, etc.
- non-bone tissue-derived cell lines such as pluripotent fibroblasts C3H10T1/2 and C212 myoblasts, differentiate into osteoblasts, and induce differentiation of osteoblasts and remodeling of young bones in mesenchymal cells.
- rhBMP-2 Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2, INFUSE® Bone Graft) for its role in promoting bone deposition and repairing long bones
- the present invention provides a series of benzo five-membered unsaturated heterocyclic compounds having a structure of the formula I or a pharmaceutically acceptable salt thereof, which has an activity of up-regulating the expression of bone morphogenetic protein BMP-2 and can be used for the treatment of osteoporosis.
- the invention also provides a preparation method of the benzo five-membered unsaturated heterocyclic compound.
- the present invention also provides the use of the benzo five-membered unsaturated heterocyclic compound in the treatment of osteoporosis and related patients caused by osteoporosis.
- the present invention also provides a pharmaceutical composition for treating osteoporosis, which comprises the above-mentioned benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient.
- the benzo five-membered unsaturated heterocyclic ring of the present invention is a benzothiophene, benzofuran or an anthracene of a substituted 2-position carboxylic acid ester at a different position (3-, 4-, 5-, 6-, 7-) a compound of formula I which is a parent nucleus, a compound having a substituted ester group or a substituted amide group introduced at the 2-position, and a phenyl 5-membered unsaturated heterocyclic ring having an alkyl group, a halogen, an alkoxy group, an amino group, an acyl group Different substituents such as a carboxyl group and an ester group, and the effect of introducing a substituted ester group or a substituted amide group at the 2-position on the up-regulation of BMP-2 activity of the compound.
- the benzo five-membered unsaturated heterocyclic compound of the present invention has a structure represented by the formula I, wherein the benzene-unsaturated heterocyclic ring may have an alkyl group, a halogen, a decyloxy group, an amino group, an acyl group, a carboxyl group, an ester group or the like.
- Substituent; thiophene, furan ring or pyrrole moiety is a hydrocarbyl group, a carboxyl group, an acyl group, a decyloxy group, a sulfonic acid group, a phosphoric acid group, a sodium phosphate, a dihydrocarbylamine of 1 to 6 carbons, a morpholine, a piperidine, a N - Ethanylpiperazine, pyrrolidine, hydrocarbyl piperazine of 1 to 6 carbons, decahydropyrido[1,2 - ⁇ ]pyrazine, and the like.
- the present invention provides a benzo five-membered unsaturated heterocyclic compound having a structure represented by the formula I or a pharmaceutically acceptable salt thereof,
- X is selected from 0, S or NR 8 , wherein R 8 is selected from any one of H, a hydrocarbyl group, a halogenated hydrocarbyl group, a carbonyl hydrocarbyl group, a hydroxyhydrocarbyl group, an aminohydrocarbyl group, and a hydrocarbyloxy group;
- Y is selected from 0 or NR!'; wherein R!' is selected from any of H, -OH, a hydrocarbyl group, an acyl group, an alkoxy group, or a sulfonyl group; R 2 is selected from H or a C1-C6 dihydrocarbyl group;
- n 0-6 positive integer
- R 3 is selected from the group consisting of an anthracene, a hydrocarbon group, a halogen, an acyl group, a carboxyl group, an amino group, a substituted amino group, a sulfonic acid group, a nitrile group, and an acyl alkoxy group;
- R 5 , R 6 , and R 7 are each selected from the group consisting of H, a hydrocarbon group, an alkoxy group, a halogen group, a carboxyl group, an amino group, a substituted amino group, an acyl group, an ester group, and a sulfonic acid group;
- R 5 and R 6 are connected via a carbon, oxygen or nitrogen together, form a 5-7 membered ring structure or a 5-7 membered ring structure with a substituent group R 9, wherein, R 9 is selected from H, alkyl, haloalkyl Any one of a carbonyl hydrocarbon group, a hydroxy hydrocarbon group, an amino hydrocarbon group, and a hydrocarbyloxy group.
- the hydrocarbon group comprises a C1-C18 linear or branched alkyl group and a cycloalkyl group.
- the alkoxy group comprises a C1-C18 linear or branched alkoxy group.
- the acyl group comprises an acyl or aryl acyl group substituted by a linear or branched fluorenyl group of C1-C18.
- the ester group comprises an ester group or an aryl ester group substituted by a C1-C18 linear or branched fluorenyl group.
- the acylamino group comprises an acylamino or aryl acylamino group substituted by a C1-C18 linear or branched fluorenyl group.
- the C1-C18 linear or branched fluorenyl group comprises a C1-C18 linear or branched alkyl group selected from the group consisting of methyl, ethyl, isopropyl, n-propyl, Any of n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, or isohexyl.
- the cyclodecyl group includes any one of cyclopentane and cyclohexan.
- the C1-C18 linear or branched alkoxy group includes a methoxy group, an ethoxy group, an isopropoxy group, a n-propoxy group, a n-butoxy group, and an isobutoxy group. Any of a group, a sec-butoxy group, a tert-butoxy group, a n-pentyloxy group, an isopentyloxy group, a n-hexyloxy group, and an isohexyloxy group.
- the acyl group substituted by a C1-C18 linear or branched fluorenyl group includes a formyl group, an acetyl group, an isopropyl group, a n-propyl group, an allyl group, a cyclopropyl group. Any of an acyl group, an n-butyl acyl group, an isobutyl acyl group, a sec-butyl acyl group, a t-butyl acyl group, a n-pentyl acyl group, an isopentyl acyl group, an n-hexyl acyl group, and an isohexyl acyl group.
- the aryl acyl group includes any one of a phenyl acyl group and a tolyl acyl group.
- the ester group substituted by a C1-C18 linear or branched alkyl group includes a formyloxy group, an acetoxy group, an isopropyl acyloxy group, a n-propyl acyloxy group, Allyloxy, cyclopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, iso Any one of a pentyl acyloxy group, a n-hexyl acyloxy group, and an isohexyl acyloxy group.
- the aryl ester group includes any one of a phenyl acyloxy group and a tolyl acyloxy group.
- the acylamino group substituted by a C1-C18 linear or branched fluorenyl group includes a methyl amide group, an ethyl amide group, an isopropyl amide group, a propyl propyl amide group, an olefin group.
- the arylamido group includes any one of a phenylamido group and a tolylamino group.
- the hydrocarbon group is a C1-C6 linear or branched alkyl group.
- the hydrocarbon group in the halogenated hydrocarbon group, the carbonyl hydrocarbon group, the hydroxy hydrocarbon group, the amino hydrocarbon group or the alkoxy group is any one of C1 to C6 hydrocarbon groups.
- the substituent of the substituted amino group is a C2-C6 fluorenyl group.
- the substituent is selected from a C1-C6 lower fluorenyl group, a lower decyloxy group, Any one of halogen, amino or a combination thereof.
- the benzo five-membered unsaturated heterocyclic compound includes a substituted benzofuranyl-2-substituted carboxylic acid ester, a substituted benzothienyl-2-substituted carboxylic acid ester, and a substituted hydrazine. Any one of a mercapto-2-substituted carboxylic acid ester, a substituted phenylpropanyl-2-yl substituted amide, and a substituted phenylpropenyl-2-substituted amide.
- the substituted benzofuranyl group includes a methoxy group, a dimethoxy group, Any one or a combination of a fluorenyl group, a halogen, a carboxyl group, an acetyl group, a sulfonic acid group, a methyl carboxylate, a methylene dioxy group, a diamino group of C1-C18.
- the substituent in the substituted benzothienyl group includes a methoxysulfonic acid group, a methyl carboxylate, a methylene dioxy group, a substituted methylene dioxy group, a diamino group. Any one or a combination thereof.
- the substituent in the substituted indenyl group includes any one of a substituted methoxy group, a substituted dimethoxy group, a dimethoxy group, or a combination thereof.
- the substituent in the substituted phenylpropanyl group includes any one of a methylene dioxy group, a methyl carboxylate or a combination thereof.
- the substituted phenylpropenyl-2-substituted amide comprises a methylene dioxy group.
- the substituted carboxylic acid ester comprises a carboxylic acid (diethyl 2,-phosphonate), a carboxylic acid (dimethyl 2,-phosphonate), a carboxylic acid (2,- Dimethylamine) Ethyl ester, carboxylic acid (2,-dimethylamine) propyl ester, carboxylic acid pyrrolidine ethyl ester, carboxylic acid piperidinyl ethyl ester, carboxylic acid morpholine ethyl ester, carboxylic acid (1,1-dimethyl Ethyl-2-dimethylamine) Ethyl ester, carboxylic acid [4,-(2"-hydroxyethyl)]piperazine ethyl ester, carboxylic acid phosphonyl methyl ester, and carboxylic acid phosphonyl ethyl ester or Its combination.
- the substituted amide comprises carboxylic acid (2,-dimethylamine) ethylamine, carboxylic acid (2,-dimethylamine-N-methyl)ethylamine, carboxylic acid (4) , -phosphonoethylidene methylene benzene) Any one or combination of an amine, a carboxylic acid (4'-phosphono sodium methylene benzene) amine.
- the benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof comprises the following compounds:
- the benzo five-membered unsaturated heterocyclic compound having the structure of the formula I of the present invention is preferably improved in water solubility, metabolic stability and therapeutic activity, and has an activity of up-regulating BMP-2 protein expression and promoting bone formation.
- the activity becomes a novel anti-osteoporosis drug or its lead compound.
- the benzothiophene/furan or anthraquinone compound of the benzo five-membered unsaturated heterocyclic compound of the present invention or a pharmaceutically acceptable salt thereof has an effect of significantly upregulating the expression activity of bone morphogenetic protein BMP-2, and the anti-osteoporosis effect in vivo
- the results show that the compounds of the present invention have an effect of improving the symptoms of osteoporosis in SAMP6 mice.
- Another object of the present invention is to provide a process for the preparation of a benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof, comprising the steps of:
- Step 1) A substituted benzaldehyde having the structure shown in Formula II, a substituted ethyl acetate having the structure shown in Formula VI, is placed in an aprotic solvent, and an inorganic base is added at 0. After stirring at C-60 ° C, the intermediate III is obtained;
- Step 2) When Y in the structure of formula I is O, intermediate III is hydrolyzed in an aqueous alkaline solution, and heated under reflux with a substituted hydroxy compound under the action of a dehydrating agent. After completion of the reaction, separation and purification are carried out to obtain a target.
- Compound IV
- M is OH or N0 2 ;
- X is 0, S or NR 8 ;
- Rj , R 2 , R 3 , , R 5 , R 6 , R 7 , R 8 are as defined in claim 1;
- R 1() is a mercapto group or a halogen; a hydrocarbyloxy group selected from C1 to C18;
- the structural formula VI of the substituted ethyl acetate is:
- Another object of the present invention is to provide a process for the preparation of a benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof, comprising the steps of:
- Step 1) a substituted benzaldehyde having the structure shown in Formula II, a substituted ethyl acetate having the structure shown in Formula VI, is placed in an aprotic solvent, and an inorganic base is added, at 0 ° C to 60 ° C, Stirring reaction Thereafter, intermediate III is obtained;
- Step 2) When Y is 'in the structure of formula I, intermediate III is hydrolyzed in an aqueous alkaline solution, heated under reflux with thionyl chloride to form an acid chloride, and then added at 0 ° C. Obtaining a mixture; at room temperature, the mixture is reacted with a substituted amino compound, after completion of the reaction, separation and purification to obtain the target compound V;
- M is OH or N0 2 ;
- X is 0, S or NR 8 ;
- Ri , R 2 , R 3 , , R 5 , R 6 , R 7 , R 8 are as defined in claim 1;
- R 1Q is fluorenyl or Halogen;
- R n is selected from a C1-C18 alkoxy group; the substituted ethyl acetate has the structural formula VI:
- the aprotic solvent is DMF.
- the inorganic base is anhydrous K 2 C0 3 .
- the alkaline aqueous solution is an aqueous NaOH solution.
- the dehydrating agent is any one of DIC, DMAP or a combination thereof.
- the structure of the substituted hydroxy compound is as shown in Formula VII.
- the acid binding agent is any one of triethylamine and dichloromethane or a combination thereof.
- the structure of the substituted amino compound is as shown in Formula VIII.
- Another object of the present invention is to provide a pharmaceutical composition for anti-osteoporosis, which comprises a therapeutically effective amount of the benzo five-membered unsaturated heterocyclic compound of the present invention or a medicinal use thereof A salt and a pharmaceutically acceptable carrier.
- the benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof is contained in the pharmaceutical composition in an amount of 0.1 wt.% to 99.5 wt.%, preferably 0.5 wt.% to 95 wt. .%.
- compositions of the present invention may be in various dosage forms well known in the art, and the dosage form suitable for the present invention is selected from oral preparations, external preparations or injections, preferably oral preparations.
- Oral preparations are selected from the group consisting of tablets, capsules, granules, pills, powders, pills, syrups, lotions, lotions, effervescent, pastes, emulsions, teas, oral solutions, suspensions (dry suspensions or Suspension) or tea, etc.
- external preparations are selected from the group consisting of gels, ointments (sticks, ointments or ointments), tinctures, lotions, spreads, plasters, creams, ointments, suppositories, etc.
- Self-injection (injection) infusion or lyophilized powder needle.
- the compositions of the present invention can be prepared by formulation techniques well known in the art.
- composition of the present invention further comprises a pharmaceutically acceptable carrier, and the amount and type of the pharmaceutically acceptable carrier are determined according to factors such as the physical and chemical properties and content of the active ingredient in the composition, the type of the preparation, the formulation technique, and the like. .
- the pharmaceutically acceptable carriers of the present invention are conventional excipients or adjuvants well known in the art for preparing the above formulations.
- Excipients or excipients commonly used in oral or topical preparations include, but are not limited to, fillers (diluents), lubricants (glidants or anti-adhesives), dispersants, wetting agents, binders, conditioners, solubilizers , antioxidants, bacteriostatic agents, emulsifiers, disintegrators, etc.
- Binders such as syrup, gum arabic, gelatin, sorbitol, tragacanth, cellulose and its derivatives (eg microcrystalline cellulose, sodium carboxymethylcellulose, ethylcellulose or hydroxypropylmethylcellulose) ), gelatin paste, starch paddle or polyvinylpyrrolidone; fillers such as lactose, powdered sugar, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salts (such as calcium sulfate, calcium phosphate) , calcium hydrogen phosphate, precipitated calcium carbonate, etc., sorbitol or glycine; lubricants, such as micronized silica gel, magnesium stearate, talc, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, etc.; disintegrant , for example, starch and its derivatives (such as sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxyprop
- a buffer composed of (sodium), sodium citrate, sodium phosphate, and disodium hydrogen phosphate; an emulsifier such as polysorbate-80, sorbitan sorbate, pluronic F-68, lecithin , soy lecithin, etc.; solubilizers, such as Tween-80, bile, glycerin, etc.
- the active ingredient may be mixed with a pharmaceutically acceptable controlled release carrier according to the preparation requirements thereof, and then prepared according to a preparation method of a controlled release preparation well known in the art, such as adding a retarder coating or an active agent.
- a preparation method of a controlled release preparation well known in the art, such as adding a retarder coating or an active agent.
- the pellet is prepared into a pellet, such as a sustained-release pellet or a controlled-release pellet;
- the sustained-release carrier includes, but is not limited to, an oil-based admixture, a hydrophilic colloid or a coating retarder.
- the oleaginous incorporation agent is selected from any one or a combination of glyceryl monostearate, hydrogenated castor oil, mineral oil, polysiloxane or dimethyl siloxane; Any one or combination of sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, PVP, gum arabic, scutellaria or carbopol; the coating resistance
- the retardant is selected from the group consisting of ethyl cellulose (EC), hydroxypropylmethyl cellulose (HMPC), polyvinylpyrrolidone (PVP), cellulose acetate phthalate (CAP), acrylic resin, and the like. Or a combination thereof.
- the pharmaceutical composition is prepared in the form of a tablet, a suspension, a capsule, a granule, a pill, a powder, a pill, a syrup, a mixture, a lotion, an effervescent, and a paste.
- Agent emulsion, tea, powder, injection (injection), infusion, gel, plaster, plaster, cream, ointment, tincture, lotion, suppository, smear, ointment, ointment .
- Another object of the present invention is to provide the use of the benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the preparation of a medicament for treating osteoporosis.
- Example 20 6-carboxylic acid methyl ester benzofuran-2 -carboxylic acid (dimethyl 2,-phosphonate) ethyl ester
- 2-hydroxy-4-carboxylic acid methyl ester benzaldehyde (1.80 g, 10 mmol) and anhydrous K 2 C0 under ice bath 3 (1.66 g, 12 mmol) was dissolved in DMF (25 ml). After the dropwise addition was completed, the mixture was stirred at 0 ° C for 30 min, and then reacted in an oil bath at 60 ° C for 12 h.
- N,N-dimethylpropanolamine was used as a raw material and reacted according to the preparation method described in Example 20 to obtain 6-carboxylic acid methyl ester benzofuran-2-carboxylic acid (2'-dimethylamine) propyl ester. (Yield 47%).
- the morpholinoethanol was used as a raw material and reacted according to the preparation method described in Example 20 to give 6-carboxylic acid methyl ester benzofuran-2-carboxylic acid morpholine ethyl ester (yield: 55%).
- Example 26 6-carboxylic acid methyl ester benzofuran-2-carboxylic acid (1,1, -Dimethyl-2-dimethylamine)ethyl ester (Compound 26) was reacted with (1,1 '-dimethyl-2-dimethylamine) ethanol as a starting material according to the preparation method described in Example 20 to obtain Methyl 6-carboxylate benzofuran-2-carboxylic acid (1,1,-dimethyl-2-dimethylamine) ethyl ester (yield 37%).
- Example 27 6-Carboxylic acid methyl ester benzofuran-2-carboxylic acid [4,-(2"-hydroxyethyl) 1 piperazinyl ester (Compound 27) with [4'-(2"-hydroxyl The piperazine ethanol was used as a raw material and reacted according to the preparation method described in Example 20 to obtain 6-carboxylic acid methyl ester benzofuran-2-carboxylic acid [4,-(2"-hydroxyethyl)]piperazine. Ethyl ester (yield 41%).
- Example 29 5,6-Methylenedioxybenzofuran- 2-carboxylic acid (dimethyl 2,-phosphonate) ethyl ester (compound 29) was reacted with dimethyl 2-hydroxyethylphosphonate according to the preparation method described in Example 28 to give 5,6- Methylene dioxybenzofuran-2-carboxylic acid (dimethyl 2,-phosphonate) ethyl ester (yield 45%).
- Example 30 5,6-Methylenedioxybenzofuran-2 -carboxylic acid (2,-dimethylamine) ethyl ester (compound 30) The reaction was carried out according to the preparation method described in Example 28 using N,N-dimethylethanolamine as a starting material to obtain 5,6-methylenedioxybenzofuran-2-carboxylic acid (2,-dimethylamine). Ester (yield 50%).
- the compound 2 was used as a raw material, and then reacted according to the preparation method of Example 42 to give 6-methoxybenzofuran-2-carboxylic acid phosphonic acid ethyl ester (yield: 79%).
- Example 44 6- Methyl carboxylate benzothiophene-2-carboxylic acid (diethyl 2,-phosphonate) methyl ester (compound 44) 2-nitro-4-carboxylic acid methyl ester benzaldehyde (2.00) under ice bath g, 9.56 mmol) and anhydrous K 2 CO 3 (1.50 g, 11.4 mmol) were dissolved in DMF (25 ml), and ethyl acetate (1.15 g, 9.56 mmol) was slowly added dropwise o 0 ° C Stir for 30 min, then react in a 60 ° C oil bath for 10 h.
- Example 53 5,6-Methylenedioxybenzothiophene-2- Carboxylic acid (dimethyl 2,-phosphonate) Ethyl ester (Compound 53) Using dimethyl 2-hydroxyethylphosphonate as a starting material, the reaction was carried out in the same manner as in Example 52 to give 5,6-methylenedioxy Benzothiophene-2-carboxylic acid (dimethyl 2'-phosphonate) ethyl ester (yield 51%).
- Example 56 5,6-methylene Dioxybenzothiophene-2-carboxylic acid [4,-(2"-hydroxyethyl)]piperazine ethyl ester (Compound 56) Using [4,-(2"-hydroxyethyl)]piperazineethanol as a starting material, the reaction of Example 52 gave 5,6-methylenedioxybenzothiophene-2-carboxylic acid [4,- (2"-Hydroxyethyl)]piperazine ethyl ester (yield 39%).
- the morpholine ethyl ester was used as a starting material, and the mixture was subjected to the procedure of Example 52 to give 5,6-methylenedioxybenzothiophene-2-carboxylic acid morpholine ethyl ester (yield: 54%).
- N-methyl-5,6-dimethoxy-indole-2-carboxylic acid and morpholinoethanol were used as raw materials, and reacted according to the method of Example 64 to obtain N-methyl-5,6-dimethoxy.
- the base-B was introduced to the quinone-2-carboxylic acid morpholine ethyl ester (yield: 82%).
- Example 68 N- (2,- Hydroxyethyl)-5-methoxy-indole-2-carboxylic acid (2,-dimethylamine) ethyl ester (compound 68) with N-(2'-hydroxyethyl)-5-methoxy-
- the indole-2-carboxylic acid was used as a starting material, which was reacted according to the procedure of Example 64 to give N-(2,-hydroxyethyl)-5-methoxy-indole-2-carboxylic acid (2,-dimethylamine). Ethyl ester (yield 80%).
- Example 69 N-(2,-methoxy)-6-methoxy-indole-2-carboxylic acid (2,-dimethylamine) ethyl ester (Compound 69) with N-(2'-A The oxy)-6-methoxy-indole-2-carboxylic acid was used as a starting material, which was reacted according to the procedure of Example 64 to give N-(2,-methoxy)-6-methoxy-indole-2. - Carboxylic acid (2,-dimethylamine) ethyl ester (yield 80%).
- N-carboxymethyl-5-methoxy-indole-2-carboxylic acid was used as a starting material, and then reacted according to the method of Example 64 to give N-carboxymethyl-5-methoxy-indole.
- Carboxylic acid (2,-dimethylamine) ethyl ester yield 69%).
- Example 71 5,6-Methylenedioxyphenylpropan-2-carboxylate (2,-dimethylamine) Ethylamine (Compound 71)
- 2-Hydroxy-4,5-methylenedioxybenzaldehyde (3.32 g, 20 mmol) and anhydrous K 2 CO 3 (3.20 g, 24 mmol) were dissolved in DMF (50 ml), and bromoacetic acid B was slowly added dropwise. Ester (3.34 g, 20 mmol). After the dropwise addition was completed, the mixture was stirred at 0 ° C for 30 min, and then reacted in an oil bath at 60 ° C for 14 h.
- reaction mixture was poured into ice water, filtered, and chloroform dissolved solid, dried over anhydrous Na 2 S0 4 , filtered, and evaporated to dryness. After silica gel column chromatography, to obtain a yellow solid 4.00 g (86%).
- the compound 75 was used as a raw material, and reacted according to the method of Example 42 to obtain 5,6-methylenedioxybenzene.
- Example 86 6-Carboxylic acid methyl ester benzofuran-2-carboxylic acid phosphonium ethyl ester (Compound 86) The compound 21 was used as a starting material and reacted according to the method of Example 42 to give methyl 6-carboxylate benzofuran. 2-carboxylic acid phosphonoethyl ester (yield 79%).
- the compound 44 was used as a starting material to give 6-carboxylic acid methyl ester benzothiophene-2-carboxylic acid phosphonomethyl ester (yield: 41%).
- the compound of the present invention can be synthesized stably and reproducibly.
- Experiment 1 In vitro BMP-2 up-regulation activity screening
- a screening model for up-regulating BMP-2 was constructed, and plasmid PYJ was transiently transfected into MC3T3E1 cells.
- the specific process was as follows: 100 ⁇ 7 wells of MC3T3E1 cells were cultured in 96-well sterile plastic culture plates for 8 h. Dilute the appropriate amount of PYJ plasmid DNA in a sterile centrifuge tube with 25 ⁇ 7-well serum-free and anti-anti-DMEM medium. Dilute 0.5 ⁇ ! 7-well LF2000 in 25 ⁇ 7-well serum-free, anti-double-antibody DMEM medium in another sterile centrifuge tube.
- Reagent within 5 mm, combine the above two tubes, incubate for 20 min at room temperature, add the mixed transfection suspension to the above 96-well plate, mix well with each well 50 and then 96-well plate Placed in a 37 ° C carbon dioxide incubator, culture for a certain period of time and then add appropriate concentration of drug-acting cells before fluorescence detection;
- the measurement procedure was as follows: Discard the medium in the 96-well plate, gently rinse the cells with 200 PBS (pH 7.0), completely discard the PBS, add 25 ⁇ 7-well l xPLB, shake at room temperature for 15 min, and allow the cells to Completely lysate, completely aspirate the lysate into the corresponding well of a 96-well white plate for fluorescence analysis, and add 70 ⁇ 7-well analysis reagent LARII to the analysis white plate, immediately (within 5 min), place the analysis whiteboard on the Galaxy spectrophotometer.
- the detection conditions are: no excitation light wavelength, emission light wavelength is empty, Positioning delay is 1.0, Number of intervals 1, Interval time is 1.0s, the shaking mode is set before the instrument reading, and the shaking diameter is 1 mm.
- the up-regulation rate of the sample was calculated using the set positive control, blank control, and associated data and calculation formulas. The results are shown in Table 1.
- Up-regulation rate (sample luminescence - DMSO luminescence) / DMSO luminescence xl00%
- the present invention uses the above BMP-2 screening model to study the up-regulation rate of the compound of formula I of the present invention on BMP-2.
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Abstract
本发明提供了具有如通式I所示结构的苯并五元不饱和杂环化合物或其药用盐及其制备方法、药物组合物及其应用。实验表明,本发明所述的化合物具有上调骨形成蛋白BMP-2表达活性,抗体内抗骨质疏松作用,并具有改善SAMP6小鼠骨质疏松症状的效果;体外活性测试显示,本发明化合物表现出对骨形态发生蛋白BMP-2表达的明显上调作用。
Description
苯并五元不饱和杂环类化合物或其药用盐及其制备方法、 药物组合物及其应用 技术领域
本发明属于药物领域,涉及一类苯并五元不饱和杂环化合物或其药用盐及其 说
制备方法、 药物组合物及其用于制备抗骨质疏松的药物中的应用。 背景技术
骨质疏松症(osteoporosis)是一种以骨组织微结构破坏为特征的全身性骨量 书
显著减少的病症, 易导致骨骼脆性增加及病理性骨折, 极大地影响人们的生活质 量。 据统计, 目前全世界约有 2亿人患有骨质疏松症, 其发病率已跃居常见病、 多发病的第七位。 目前, 我国 50岁以上人群中骨质疏松症总患病率为 15.7%, 随着人口寿命的延长, 这一比例在逐步增加。 我国 70%-80%的中老年骨折是因 骨质疏松症引起的, 最常见的是椎体骨折。据不完全统计, 我国每年新发椎体骨 折病例约 181万例,髋部骨折病例为 23万例, 由此造成的医疗花费超过百亿元。 随着人口老龄化进程的加快, 其严重性也将加剧。 另外, HIV、 心血管疾病和糖 尿病病人因用药导致的骨质疏松也越来越严重,骨质疏松及其并发症已成为一个 引起全社会关注的健康问题,寻找预防和治疗骨质疏松的有效药物及治疗方法也 已成为世界范围内的研究热点。
在骨的形成过程中, 成骨细胞 (osteoblasts, obs) 和破骨细胞 (osteoclasts, ocs)相互协调, 使骨质的形成与溶解处于一种动态平衡, 维持骨质的不断更新。 当此协调失衡, 骨溶解超过骨形成时, 即导致骨质疏松。 以往的研究与治疗方案 大多针对破骨细胞以控制骨质的损失,但近年来的大量研究证明, 增强成骨细胞 的作用、改善骨质形成代谢、促进骨质的形成是治疗骨质疏松的新的更为重要的 途径。
成骨细胞的增殖和分化受多种因素的调节, 其中骨形态形成蛋白 (Bone Morphogenetic Protein-2, BMP-2)在成骨细胞的分化过程中起关键的作用。 BMP-2 除了直接促进成骨细胞的分化外,还能促进其它成骨因子的表达, 如骨诱导蛋白 (0P)、核心结合因子 a-l(Cbfal)、碱性磷酸酶 (ALP)、脂肪酸偶联蛋白 4(fabp4)等,
这些蛋白的表达在成骨细胞的分化中起着非常重要的作用。 实验证明, BMP-2 不但对骨组织来源的细胞株,如成骨细胞前体细胞、 ROB-C26细胞、 MC3T3-EK 成骨细胞、 W-20骨髓基质细胞等具有剌激分化作用, 还可诱导非骨组织来源的 细胞株, 如多潜能成纤维细胞 C3H10T1/2和 C212成肌细胞等分化为成骨细胞, 并能诱导间叶细胞中成骨细胞的分化及幼骨的重塑。
重组人 BMP-2 蛋白 (Recombinant Human Bone Morphogenetic Protein-2, rhBMP-2, INFUSE® Bone Graft) 因其促进骨沉积以及对长骨的修复作用, 在
2007年被美国 FDA批准用于自体骨移植以及局部牙槽嵴增高术, 在 2004年被 美国 FDA批准用于胫骨骨折的治疗, 在 2002年被 FDA批准用于脊柱融合术。 在德国,治疗胫骨骨折时,注射一针重组人 BMP-2蛋白的费用大约是 2970欧元, 且使用该药不能从健康保险公司获得偿付。 因此, 使用重组人 BMP-2蛋白将给 患者带来沉重的经济负担。 骨质疏松症治疗药物的研究虽取得了很大进展,但目前临床上使用的治疗药 物缺乏特异性, 普遍存在较严重的副作用。为获得组织特异性更强的改善体内骨 代谢平衡的治疗骨质疏松的新型药物和促进骨形成的新型药物,张月琴等人建立 了以 bmp-2启动子为药物作用靶点的促 BMP-2上调的抗骨质疏松筛选模型 (参 见中国专利申请 03104750.5 )用于筛选微生物来源及化学合成的化合物。研究发 现, 一类具有五元不饱和杂环结构的化合物具有明显上调 BMP-2的活性, 在卵 巢摘除模型大鼠和 SAMP6快速老化小鼠体内验证其确有改善骨质疏松症状的效 果 (参见中国专利 ZL 200610008114.6, 200910246709.9) 。 但是, 活性化合物 的结构特征中缺乏极性基团、强的亲脂和弱的亲水性质有可能导致其成药性较差 (如水溶性不足, 导致生物利用度低并影响代谢速率; 分子量小, 则存在产生中 枢神经毒性的风险等)。 为此, 需要进一步研究五元不饱和杂环类化合物的构效 关系, 通过结构改造和修饰以提高水溶性、 代谢稳定性和治疗活性。 发明内容
本发明还提供了所述苯并五元不饱和杂环类化合物的制备方法。
本发明还提供了所述苯并五元不饱和杂环类化合物在治疗骨质疏松症以及由 于骨质疏松所导致的相关病患方面的应用。
本发明还提供了可治疗骨质疏松症的药物组合物, 该药物组合物以上述苯并 五元不饱和杂环类化合物或其药用盐为活性组分。
本发明的苯并五元不饱和杂环在不同位置 (3-, 4-, 5-, 6-, 7- )为被取代的 2位羧 酸酯的苯并噻吩、苯并呋喃或吲哚为母核的式 I化合物,在 2-位引入带有取代酯 基或取代酰胺基的化合物, 并研究苯并五元不饱和杂环上连有烷基、 卤素、烷氧 基、 氨基、 酰基、 羧基、 酯基等不同取代基, 以及 2-位引入带有取代酯基或取代 酰胺基对化合物上调 BMP-2活性的影响。 本发明的苯并五元不饱和杂环化合物 结构如通式 I所示, 其中, 苯并不饱和杂环上可以带有烷基、 卤素、 垸氧基、 氨 基、 酰基、 羧基、 酯基等取代基; 噻吩、 呋喃环或吡咯结构部分的 为烃基、 羧基、 酰基、 垸氧基、 磺酸基、 磷酸基、 磷酸钠、 1-6个碳的二烃基胺、 吗啉、 哌啶、 N-乙醇基哌嗪、吡咯烷、 1-6个碳的烃基哌嗪、十氢吡啶并 [1,2 -α]吡嗪等。
本发明提供了具有如通式 I所示结构的苯并五元不饱和杂环化合物或其药 用盐,
R4
R5 、, 、、
R7 0 R2
I
式中,
X选自 0、 S或 NR8, 其中, R8选自 H、 烃基、 卤代烃基、 羰基烃基、 羟基烃基、 氨基烃基、 烃氧基的任一种;
Y选自 0 或 NR!'; 其中, R!' 选自 H、 -OH、 烃基、 酰基、 烷氧基、 磺 酰基的任一种;
R2选自 H或 C1-C6的二烃基;
n = 0-6正整数;
选自 H、 -OH、 烃基、 羧基、 酰基、 烷氧基、 磺酸基、 磷酸基、 磷酸 酯、磷酸钠、 C1-C6的二烃基胺、吗啉、哌啶、 N-乙醇基哌嗪、吡咯垸、 C1-C6 的烃基哌嗪、 十氢吡啶并 [1,2 -α]吡嗪的任一种;
R3选自 Η、 烃基、 卤素、 酰基、 羧基、 氨基、 取代的氨基、 磺酸基、 腈 基、 酰基烃氧基的任一种;
、 R5、 R6、 R7分别选自 H、 烃基、 烷氧基、 卤素、 羧基、 氨基、 取代 的氨基、 酰基、 酯基、 磺酸基的任一种;
R5与 R6通过碳、 氧或氮连接在一起, 形成 5-7元环结构或带有取代基 R9的 5-7元环结构, 其中, R9选自 H、 烃基、 卤代烃基、 羰基烃基、 羟基烃 基、 氨基烃基、 烃氧基的任一种。
本发明的优选方案中, 所述烃基包括 C1-C18的直链或支链的烷基和环烷 基。
本发明的优选方案中, 所述烷氧基包括 C1-C18的直链或支链的烷氧基。 本发明的优选方案中, 所述酰基包括由 C1-C18的直链或支链的垸基取代 的酰基或芳基酰基。
本发明的优选方案中, 所述酯基包括由 C1-C18的直链或支链的垸基取代 的酯基或芳基酯基。
本发明的优选方案中, 所述酰氨基包括由 C1-C18的直链或支链的垸基取 代的酰氨基或芳基酰氨基。
本发明的优选方案中, 所述 C1-C18的直链或支链的垸基包括 C1-C18的直 链或支链的烷基选自甲基、 乙基、 异丙基、 正丙基、 正丁基、 异丁基、 仲丁 基、 叔丁基、 正戊基、 异戊基、 正己基、 异己基的任一种。
本发明的优选方案中, 所述环垸基包括环戊烷、 环己垸的任一种。
本发明的优选技术方案中, 所述 C1-C18的直链或支链的烷氧基包括甲氧 基、 乙氧基、 异丙氧基、 正丙氧基、 正丁氧基、 异丁氧基、 仲丁氧基、 叔丁 氧基、 正戊氧基、 异戊氧基、 正己氧基、 异己氧基的任一种。
本发明的优选方案中, 所述由 C1-C18的直链或支链的垸基取代的酰基包括 甲酰基、 乙酰基、 异丙基酰基、 正丙基酰基、 烯丙基酰基、 环丙基酰基、 正 丁基酰基、 异丁基酰基、 仲丁基酰基、 叔丁基酰基、 正戊基酰基、 异戊基酰 基、 正己基酰基、 异己基酰基的任一种。
本发明的优选方案中,所述芳基酰基包括苯基酰基、甲苯基酰基的任一种。 本发明的优选方案中, 所述由 C1-C18的直链或支链的烷基取代的酯基包括 甲酰氧基、 乙酰氧基、 异丙基酰氧基、 正丙基酰氧基、 烯丙基酰氧基、 环丙基酰 氧基、 正丁基酰氧基、 异丁基酰氧基、 仲丁基酰氧基、 叔丁基酰氧基、 正戊基酰 氧基、 异戊基酰氧基、 正己基酰氧基、 异己基酰氧基的任一种。
本发明的优选方案中,所述芳基酯基包括苯基酰氧基、 甲苯基酰氧基的任一 种。
本发明的优选方案中, 所述由 C1-C18的直链或支链的垸基取代的酰氨基包 括甲基酰氨基、 乙基酰氨基、 异丙基酰氨基、 正丙基酰氨基、 烯丙基酰氨基、 环 丙基酰氨基、 正丁基酰氨基、 异丁基酰氨基、 仲丁基酰氨基、 叔丁基酰氨基、 正 戊基酰氨基、 异戊基酰氨基、 正己基酰氨基、 异己基酰氨基的任一种。
本发明的优选方案中, 所述芳基酰氨基包括苯基酰氨基、 甲苯基酰氨基的任 一种。
本发明的优选方案中, 所述烃基为 C1-C6的直链或支链的烷基。
本发明的优选方案中, 所述卤代烃基、 羰基烃基、 羟基烃基、 氨基烃基、 烃氧基中的烃基为 C1 -C6的烃基的任一种。
本发明的优选方案中, 所述取代的氨基的取代基为 C2-C6的垸基。
本发明的优选方案中,本发明的苯并五元不饱和杂环化合物或其药用盐中有 取代基团时, 所述取代基选自 C1-C6 的低级垸基、 低级垸氧基、 卤素、 氨基的 任一种或其组合。
本发明的优选方案中,所述苯并五元不饱和杂环化合物包括取代的苯并呋喃 基 -2-取代羧酸酯、 取代的苯并噻吩基 -2-取代羧酸酯、 取代的吲哚基 -2-取代羧酸 酯、 取代的苯丙呋喃基 -2-取代酰胺、 取代的苯丙噻吩基 -2-取代酰胺的任一种。
本发明的优选方案中, 所述取代的苯并呋喃基包括甲氧基、 二甲氧基、
C1-C18的垸基、 卤素、 羧基、 乙酰基、 磺酸基、 羧酸甲酯、 亚甲基二氧基、 二氨基的任一种或其组合。
本发明的优选方案中,所述取代的苯并噻吩基中的取代基包括甲氧基磺酸 基、 羧酸甲酯、 亚甲基二氧基、 取代的亚甲基二氧、 二氨基的任一种或其组 合。
本发明的优选方案中, 所述取代的吲哚基中的取代基包括取代的甲氧基、 取代的二甲氧基、 二甲氧基的任一种或其组合。
本发明的优选方案中,所述取代的苯丙呋喃基中的取代基包括亚甲基二氧 基、 羧酸甲酯的任一种或其组合。
本发明的优选方案中, 所述取代的苯丙噻吩基 -2-取代酰胺包括亚甲基二 氧基。
本发明的优选方案中, 所述取代羧酸酯包括羧酸 (2,-膦酸二乙酯) 甲酯、 羧酸 (2,-膦酸二甲酯) 乙酯、 羧酸 (2,-二甲胺) 乙酯、 羧酸 (2,-二甲胺) 丙酯、羧酸吡咯垸乙酯、羧酸哌啶乙酯、羧酸吗啉乙酯、羧酸(1,1-二甲基 -2- 二甲胺) 乙酯、 羧酸 [4,- ( 2"-羟乙基) ]哌嗪乙酯、 羧酸膦酰甲酯、 和羧酸膦 酰乙酯的任一种或其组合。
本发明的优选方案中, 所述取代酰胺包括羧酸酰 (2,-二甲胺) 乙胺、 羧 酸酰 (2,-二甲胺 -N-甲基) 乙胺、 羧酸酰 (4,-膦酰二乙酯亚甲基苯) 胺、 羧 酸酰 (4'-膦酰钠亚甲基苯) 胺的任一种或其组合。
本发明的优选方案中,所述苯并五元不饱和杂环化合物或其药用盐结构包括 如下化合物:
( 1 ) 6-甲氧基苯并呋喃 -2-羧酸 (2,-膦酸二乙酯) 甲酯;
(2) 6-甲氧基苯并呋喃 -2-羧酸 (2'-膦酸二甲酯) 乙酯;
(3 ) 6-甲氧基苯并呋喃 -2-羧酸 (2'-二甲胺) 乙酯;
(4) 6-甲氧基苯并呋喃 -2-羧酸 (2'-二甲胺) 丙酯;
(5 ) 6-甲氧基苯并呋喃 -2-羧酸吡咯垸乙酯;
(6) 6-甲氧基苯并呋喃 -2-羧酸哌啶乙酯;
(7) 6-甲氧基苯并呋喃 -2-羧酸吗啉乙酯;
(8) 6-甲氧基苯并呋喃 -2-羧酸 (1,1-二甲基 -2-二甲胺) 乙酯;
(9) 6-甲氧基苯并呋喃 -2-羧酸 [4,- (2"-羟乙基) ]哌嗪乙酯;
(10) 5-甲氧基苯并呋喃 -2-羧酸膦酰乙酯;
(11) 5, 6-二甲氧基苯并呋喃 -2-羧酸膦酰乙酯;
(12) 5-氟苯并呋喃 -2-羧酸膦酰乙酯;
(13) 6-甲基苯并呋喃 -2-羧酸膦酰乙酯;
(14) 6-辛基苯并呋喃 -2-羧酸膦酰乙酯;
(15) 6-羧基苯并呋喃 -2-羧酸膦酰乙酯;
(16) 5-羧基苯并呋喃 -2-羧酸膦酰乙酯;
(17) 6-羧基苯并呋喃 -2-羧酸 (2'-二甲胺) 乙酯;
(18) 6-乙酰基苯并呋喃 -2-羧酸 (2,-二甲胺) 乙酯;
(19) 5-磺酸基苯并呋喃 -2-羧酸 (2,-二甲胺) 乙酯;
(20) 6-羧酸甲酯苯并呋喃 -2-羧酸 (2,-膦酸二乙酯) 甲酯;
(21) 6-羧酸甲酯苯并呋喃 -2-羧酸 (2,-膦酸二甲酯) 乙酯;
(22) 6-羧酸甲酯苯并呋喃 -2-羧酸 (2'-二甲胺) 乙酯;
(23) 6-羧酸甲酯苯并呋喃 -2-羧酸 (2'-二甲胺) 丙酯;
(24) 6-羧酸甲酯苯并呋喃 -2-羧酸哌啶乙酯;
(25) 6-羧酸甲酯苯并呋喃 -2-羧酸吗啉乙酯;
(26) 6-羧酸甲酯苯并呋喃 -2-羧酸 (1,1,-二甲基 -2-二甲胺) 乙酯;
(27) 6-羧酸甲酯苯并呋喃 -2-羧酸 [4,- (2"-羟乙基) ]哌嗪乙酯;
(28) 5,6-亚甲基二氧苯并呋喃 -2-羧酸 (2'-膦酸二乙酯) 甲酯;
(29) 5,6-亚甲基二氧苯并呋喃 -2-羧酸 (2'-膦酸二甲酯) 乙酯;
(30) 5,6-亚甲基二氧苯并呋喃 -2-羧酸 (2,-二甲胺) 乙酯;
(31) 5,6-亚甲基二氧苯并呋喃 -2-羧酸 (2'-二甲胺) 丙酯;
(32) 5,6-亚甲基二氧苯并呋喃 -2-羧酸 [4,- (2"-羟乙基) ]哌嗪乙酉 ί
(33) 5,6-亚甲基二氧苯并呋喃 -2-羧酸吗啉乙酯;
(34) 6-羧酸乙酯苯并呋喃 -2-羧酸 (2'-二甲胺) 丙酯;
(35) 5,6-二氨基苯并呋喃 -2-羧酸 (2'-二甲胺) 丙酯;
(36) 6-甲氧基苯并噻吩 -2-羧酸 (2,-膦酸二乙酯) 甲酯;
(37) 6-甲氧基苯并噻吩 -2-羧酸 (2'-膦酸二甲酯) 乙酯;
(38) 6-甲氧基苯并噻吩 -2-羧酸 (2,-二甲胺) 乙酯;
(39) 6-甲氧基苯并噻吩 -2-羧酸 (2'-二甲胺) 丙酯;
(40) 6-甲氧基苯并噻吩 -2-羧酸吗啉乙酯;
(41 ) 6-甲氧基苯并噻吩 -2-羧酸 [4,- (2"-羟乙基) ]哌嗪乙酯;
(42) 6-甲氧基苯并呋喃 -2-羧酸膦酰甲酯;
(43 ) 6-甲氧基苯并呋喃 -2-羧酸膦酰乙酯;
(44) 6-羧酸甲酯苯并噻吩 -2-羧酸 (2,-膦酸二乙酯) 甲酯;
(45 ) 6-羧酸甲酯苯并噻吩 -2-羧酸 (2,-膦酸二甲酯) 乙酯;
(46) 6-羧酸甲酯苯并噻吩 -2-羧酸 (2,-二甲胺) 乙酯;
(47) 6-羧酸甲酯苯并噻吩 -2-羧酸 (2'-二甲胺) 丙酯;
(48) 6-羧酸甲酯苯并噻吩 -2-羧酸 [4,- (2"-羟乙基) ]哌嗪乙酯;
(49) 6-羧酸甲酯苯并噻吩 -2-羧酸吗啉乙酯;
(50) 6-磺酸基苯并噻吩 -2-羧酸 (2,-二甲胺) 乙酯;
(51 ) 6-二乙氨基-苯并噻吩 -2-羧酸 (2'-二甲胺) 乙酯;
(52) 5,6-亚甲基二氧苯并噻吩 -2-羧酸 (2,-膦酸二乙酯) 甲酯;
( 53 ) 5,6-亚甲基二氧苯并噻吩 -2-羧酸 (2,-膦酸二甲酯) 乙酯;
(54) 5,6-亚甲基二氧苯并噻吩 -2-羧酸 (2,-二甲胺) 乙酯;
(55 ) 5,6-亚甲基二氧苯并噻吩 -2-羧酸 (2,-二甲胺) 丙酯;
(56) 5,6-亚甲基二氧苯并噻吩 -2-羧酸 [4,- (2"-羟乙基) ]哌嗪乙酯;
(57) 5,6-亚甲基二氧苯并噻吩 -2-羧酸吗啉乙酯;
(58) 5,6-乙基亚甲基二氧苯并噻吩 -2-羧酸膦酰乙酯;
(59) 5,6-(2'-氯乙基)亚甲基二氧苯并噻吩 -2-羧酸膦酰乙酯;
(60) 5,6-(1,-羟乙基)亚甲基二氧苯并噻吩 -2-羧酸膦酰乙酯;
(61 ) 5,6-(1,-氨乙基)亚甲基二氧苯并噻吩 -2-羧酸膦酰乙酯;
(62) 5,6-(Γ-甲氧基乙基)亚甲基二氧苯并噻吩 -2-羧酸膦酰乙酯;
(63 ) 5,6-二甲氧基 -吲哚 -2-羧酸膦酰甲酯;
(64) N-乙酰基 -5,6-二甲氧基 -吲哚 -2-羧酸 (2,-二甲胺) 乙酯;
(65 ) N-甲基 -5,6-二甲氧基 -吲哚 -2-羧酸膦酰乙酯;
(66) N-甲基 -5,6-二甲氧基 -吲哚 -2-羧酸 (2'-二甲胺) 丙酯;
( 67 ) N-甲基 -5,6-二甲氧基 -吲哚 -2-羧酸吗啉乙酯;
(68) N- (2'-羟乙基) -5-甲氧基 -吲哚 -2-羧酸 (2'-二甲胺) 乙酯;
(69) N- (2,-甲氧乙基) -6-甲氧基 -吲哚 -2-羧酸 (2,-二甲胺) 乙酯;
(70) N- (乙酸甲酯) -5-甲氧基 -吲哚 -2-羧酸 (2'-二甲胺) 乙酯;
(71 ) 5,6-亚甲基二氧苯丙呋喃 -2-羧酸酰 (2'-二甲胺) 乙胺;
(72) 5,6-亚甲基二氧苯丙呋喃 -2-羧酸酰 (2'-二甲胺 -N-甲基) 乙胺;
(73 ) 5,6-亚甲基二氧苯丙噻吩 -2-羧酸酰 (2,-二甲胺) 乙胺;
(74) 5,6-亚甲基二氧苯丙噻吩 -2-羧酸酰 (2,-二甲胺 -N-甲基) 乙胺;
(75 ) 5,6-亚甲基二氧苯丙呋喃 -2-羧酸酰(4'-膦酰二乙酯亚甲基苯)胺;
(76) 5,6-亚甲基二氧苯丙呋喃 -2-羧酸酰 (4'-膦酰钠亚甲基苯) 胺;
(77) 5,6-亚甲基二氧苯丙噻吩 -2-羧酸酰(4,-膦酰二乙酯亚甲基苯)胺;
(78) 5,6-亚甲基二氧苯丙噻吩 -2-羧酸酰 (4'-膦酰钠亚甲基苯) 胺;
(79) 5,6-亚甲基二氧苯并呋喃 -2-羧酸膦酰甲酯;
(80) 5,6-亚甲基二氧苯并呋喃 -2-羧酸膦酰乙酯;
( 81 ) 6-甲氧基苯并噻吩 -2-羧酸膦酰甲酯;
(82) 6-甲氧基苯并噻吩 -2-羧酸膦酰乙酯;
( 83 ) 5,6-亚甲基二氧苯并噻吩 -2-羧酸膦酰甲酯;
(84) 5,6-亚甲基二氧苯并噻吩 -2-羧酸膦酰乙酯;
(85) 6-羧酸甲酯苯并呋喃 -2-羧酸膦酰甲酯;
(86) 6-羧酸甲酯苯并呋喃 -2-羧酸膦酰乙酯;
(87) 6-羧酸甲酯苯并噻吩 -2-羧酸膦酰甲酯;
( 88) 6-羧酸甲酯苯并噻吩 -2-羧酸膦酰乙酯。
本发明式 I所示结构的苯并五元不饱和杂环类化合物在水溶性、代谢稳定性 和治疗活性等方面得到较好改善, 并且, 具有上调 BMP-2蛋白表达的活性和促 骨形成的活性, 成为新型的抗骨质疏松药物或其先导化合物。
本发明的苯并五元不饱和杂环化合物或其药用盐中的苯并噻吩 /呋喃或吲哚 类化合物具有显著上调骨形成蛋白 BMP-2表达活性的效果, 体内抗骨质疏松作 用研究结果显示, 本发明的化合物有改善 SAMP6小鼠骨质疏松症状的效果。
本发明的另一目的在于提供苯并五元不饱和杂环化合物或其药用盐的制备 方法, 包括如下步骤:
步骤 1): 将结构如式 II所示的取代苯甲醛、 结构如式 VI所示的取代的 乙酸乙酯置于非质子溶剂中, 加入无机碱, 在 0。C -60°C条件下, 搅拌反应 后, 制得中间体 III;
R5
步骤 2): 当式 I结构中的 Y为 O时, 中间体 III在碱性水溶液中水解后, 在脱水剂的作用下, 与取代的羟基化合物加热回流反应, 反应完成后, 分离 纯化得到目标化合物 IV,
III IV
其中, M为 OH或 N02; X为 0、 S或 NR8; Rj , R2, R3, , R5, R6, R7, R8的定义同权利要求 1 ; R1()为巯基或卤素; 选自 C1-C18的烃氧基; 所述取代的乙酸乙酯的结构通式 VI为:
R3
R
R10 11
0 VL
本发明的另一目的在于提供苯并五元不饱和杂环化合物或其药用盐的制备 方法, 包括如下步骤:
步骤 1): 将结构如式 II所示的取代苯甲醛、 结构如式 VI所示的取代的 乙酸乙酯置于非质子溶剂中, 加入无机碱, 在 0°C -60°C条件下, 搅拌反应
后, 制得中间体 III;
II in
步骤 2): 当通式 I结构中 Y为 '时, 中间体 III在碱性水溶液中水解 后, 在二氯亚砜作用下, 加热回流形成酰氯, 再在 0°C下, 加入缚酸剂得到 混合液; 在常温下, 该混合液与取代的氨基化合物反应, 反应完成后, 分离 纯化得到目标化合物 V;
R4
R
3 V
其中, M为 OH或 N02; X为 0、 S或 NR8; Ri , R2, R3, , R5, R6, R7, R8的定义同权利要求 1 ; R1Q为巯基或卤素; Rn选自 C1-C18的烃 氧基; 所述取代的乙酸乙酯的结构通式 VI为:
R R
10 11
0 VI。
本发明的优选方案中: 所述非质子溶剂为 DMF。
本发明的优选方案中: 所述无机碱为无水 K2C03。
本发明的优选方案中: 所述碱性水溶液为 NaOH水溶液。
本发明的优选方案中: 所述脱水剂为 DIC、 DMAP的任一种或其组合。 本发明的优选方案中: 所述取代的羟基化合物的结构如通式 VII所示,
H〇、 ^R-|
n
R2 VII。
本发明的优选方案中, 所述缚酸剂为三乙胺、 二氯甲垸的任一种或其组 合<
R2 VIII。
本发明的另一目的在于提供一种用于抗骨质疏松的药物组合物, 所述药物 组合物中含有治疗有效量的本发明所述的苯并五元不饱和杂环化合物或其 药用盐与药学上可接受的载体。
本发明的优选技术方案中, 所述苯并五元不饱和杂环化合物或其药用盐 在药物组合物中的含量为 0.1wt.%-99.5wt.%, 优选为 0.5wt.%-95wt.%。
本发明组合物可为本领域熟知的各种剂型, 适合于本发明的剂型选自口 服制剂、 外用制剂或注射剂, 优选为口服制剂。 口服制剂选自片剂、 胶囊剂、 颗粒剂、 丸剂、 散剂、 滴丸、 糖浆剂、 合剂、 露剂、 泡腾剂、 糊剂、 乳剂、 茶剂、 口服液、 悬浮剂(干悬剂或悬浮液)或茶剂等; 外用制剂选自凝胶剂、 膏剂 (贴膏剂、 凝膏剂或软膏剂) 、 搽剂、 洗剂、 涂抹剂、 膏药、 霜剂、 软 膏剂、 栓剂等; 注射剂选自针剂 (注射剂) 、 输液或冻干粉针等。 可采用本 领域熟知的制剂技术手段制备得到本发明的组合物。
必要时, 本发明组合物中还包含药学上可接受的载体, 所述药学上可接 受的载体的用量、种类根据组合物中有效成分的理化性质和含量、制剂类型、 制剂技术等因素而定。
本发明所述药学上可接受的载体为本领域熟知的用于制备上述制剂的 常用赋形剂或辅料。 口服制剂或外用制剂常用的赋形剂或辅料包括但不仅限 于填充剂 (稀释剂) 、 润滑剂 (助流剂或抗粘着剂) 、 分散剂、 湿润剂、 粘 合剂、 调节剂、 增溶剂、 抗氧剂、 抑菌剂、 乳化剂、 崩解剂等。 粘合剂, 例 如糖浆、 阿拉伯胶、 明胶、 山梨醇、 黄芪胶、 纤维素及其衍生物 (如微晶纤 维素、 羧甲基纤维素钠、 乙基纤维素或羟丙甲基纤维素等) 、 明胶浆、 淀粉 桨或聚乙烯吡咯垸酮等; 填充剂, 例如乳糖、 糖粉、 糊精、 淀粉及其衍生物、 纤维素及其衍生物、 无机钙盐 (如硫酸钙、 磷酸钙、 磷酸氢钙、 沉降碳酸钙 等) 、 山梨醇或甘氨酸等; 润滑剂, 例如微粉硅胶、 硬脂酸镁、 滑石粉、 氢 氧化铝、硼酸、氢化植物油、聚乙二醇等; 崩解剂, 例如淀粉及其衍生物(如 羧甲基淀粉钠、 淀粉乙醇酸钠、 预胶化淀粉、 改良淀粉、 羟丙基淀粉、 玉米 淀粉等) 、 聚乙烯吡咯垸酮或微晶纤维素等; 湿润剂, 例如十二垸基硫酸钠、
水或醇等。
本发明所述注射剂常用的赋形剂或辅料包括但不仅限于: 抗氧剂, 例如 亚硫酸钠、 亚硫酸氢钠、 焦亚硫酸钠、 二丁基苯酸等; 抑菌剂, 例如 0. 5% 苯酚、 0. 3%甲酚、 0. 5%三氯叔丁醇; 调节剂, 例如盐酸、 枸橼酸、 氢氧化钾
(钠) 、 枸橼酸钠、 磷酸二氧钠和磷酸氢二钠组成的缓冲剂等; 乳化剂, 例 如聚山梨酯 -80、 没酸山梨坦、 普流罗尼克 F- 68, 卵磷酯、 豆磷脂等; 增溶 剂, 例如吐温 -80、 胆汁、 甘油等。
另外, 还可将活性成分与药学上可接受的缓控释载体按其制备要求加以 混合, 再按照本领域熟知的缓控释制剂的制备方法加以制备, 如加入阻滞剂 包衣或将活性成分微囊化后再制成微丸, 如缓释微丸或控释微丸; 所述的缓 控释载体包括但不仅限于油脂性掺入剂、 亲水胶体或包衣阻滞剂等, 所述的 油脂性掺入剂选自单硬脂酸甘油酯、 氢化蓖麻油、 矿油、 聚硅氧烷或二甲基 硅氧烷的任一种或其组合; 所述的亲水胶体选自羧甲基纤维素钠、 羟丙基纤 维素、 羟丙基甲基纤维素、 PVP、 阿拉伯胶、 西黄耆胶或卡波普等的任一种 或其组合;所述的包衣阻滞剂选自乙基纤维素(EC)、羟丙甲基纤维素 (HMPC)、 聚乙烯吡咯垸酮 (PVP ) 、 邻苯二甲酸醋酸纤维素 (CAP ) 、 丙烯酸类树脂等 的任一种或其组合。
本发明的优选方案中, 所述药物组合物的制剂形式选自片剂、 混悬液、胶囊 剂、 颗粒剂、 丸剂、 散剂、 滴丸剂、 糖浆剂、 合剂、 露剂、 泡腾剂、 糊剂、 乳剂、 茶剂、 粉剂、 针剂 (注射剂) 、 输液、 凝胶剂、 贴膏剂、 膏药、 霜剂、 软膏剂、 搽剂、 洗剂、 栓剂、 涂抹剂、 膏剂、 凝膏剂的任一种。
本发明的另一目的在于提供所述的苯并五元不饱和杂环化合物或其药用盐 或其药物组合物在制备治疗骨质疏松病症的药物中的应用。 具体实施方式
以下将结合实施例具体说明本发明,本发明的实施例仅用于说明本发明的技 术方案, 并非限定本发明的实质。
实施例 1 6·甲氧基苯并呋喃 -2-羧酸(2,-膦酸二乙酯) 甲酯(化合物 1)
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以 [4'- (2"-羟乙基) ]哌嗪乙醇为原料, 按照实施例 1所述的制备方法反应, 得到 6-甲氧基苯并呋喃 -2-羧酸 [4,- (2"-羟乙基) ]哌嗪乙酯 (收率为 37%) 。
1HNMR(CDC13)6: 1.13(s, IH), 2.37(d, J= 5.1 Hz, 4H), 2.64(d, J= 5.1 Hz, 4H), 2.72(t, J = 4.9 Hz, 2H), 2.94(t, J = 5.0 Hz, 2H 3.66(t, J = 4.9 Hz, 2H 3.92(s, 3H), 4.59(t, J = 5.0 Hz, 2H 6.94(s, IH), 7.20(s, IH), 7.5 l(s, IH), 7.58(s, IH). MS (EI+) m/z: 348 [M]+. 实施例 10 5-甲氧基苯并呋喃 -2-羧酸膦酰乙酯(化合物 10)
冰浴条件下,将 2-羟基 -5-甲氧基苯甲醛(3.0 g,20mmol)和无水 K2C03 (3.3g, 23.4mmol)溶解于 DMF(50ml)中, 缓慢滴加溴代乙酸乙酯 (3.3g, 20mmol)。 滴加完 毕, 0°C搅拌 30 min, 然后在 60°C油浴中, 反应 12h。 把反应液倒入冰水中, 过滤, 氯仿溶解固体, 无水 Na2S04干燥, 过滤, 旋干溶剂后, 以硅胶柱层析分 离, 得到黄色固体 3.24g (收率为 75%), 将其溶于二氧六环 (30ml) 中, 加入 1N 的氢氧化钠溶液 (15ml), 常温搅拌 2h, 将二氧六环蒸干, 剩余液体倾入冰水中, 用二氯甲垸洗涤, 调 PH值至 2, 过滤收集固体 2.68g (收率为 92%), 将其溶于二 氯甲垸(50ml),加入 DIC (1.51g, 11.98mmol),常温搅拌 lh后,加入 DMAP (0.24g, 1.96 mmol)与羟乙基膦酸二甲酯 (1.84g, 10.95mmol), 加热回流 6h后,用水与饱和 食盐水洗反应液, 无水硫酸镁干燥, 过滤后蒸干, 乙酸乙酯-石油醚体系重结晶, 得到 5-甲氧基苯并呋喃 -2-羧酸(2'-膦酸二甲酯) 甲酯 3.67g (收率为 77%) , 将 其溶于二氯甲垸 (50ml) , 加入三甲基溴硅垸 (9.85g, 64.8mmol)常温搅拌 3h, 用甲醇终止反应, 蒸干, 得到产物 5-甲氧基苯并呋喃 -2-羧酸膦酰乙酯 2.38g (收 率为 74%) 。
1HNMR(CDC13)6: 2.16(m, 2H), 3.88(s, 3H) 4.19(s, 2H), 4.46(t, J= 5.7 Hz, 2H), 7.02(dxd, J = 7.6 Hz, 1.7 Hz, 1H 7.45(s, 1H 7.50(d, J = 7.6 Hz, 1H 7.70(s, IH). MS (EI+) m/z: 300 [M]+. 实施例 11 5, 6-二甲氧基苯并呋喃 -2-羧酸膦酰乙酯 (化合物 11)
以 2-羟基 -4,5-二甲氧基苯甲醛为原料,按照实施例 10所述的制备方法反应, 得到 5, 6-二甲氧基苯并呋喃 -2-羧酸膦酰乙酯 (收率为 33%) 。
^MR (CDC13) δ: 2.13(m, 2H), 3.90(s, 3H 3.97(s, 3H 4.20(s, 2H), 4.46(t, J
= 4.8 Hz, 2H), 7.42(s, IH), 7.53(s, IH), 7.67(s, IH). MS (EI+) m/z: 330 [M]+.
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1HNMR(CDC13)6: 2.15(m, 2H), 4.36(s, 2H), 4.40(t, J= 7.5 Hz, 2H), 7.69(d, J= 7.5 Hz, IH), 7.72(s, 1H), 8.18(d, J= 7.5 Hz, IH), 8.43(s, IH), 12.49(s, IH). MS (EI+) m/z: 314 [M]+. 实施例 17: 6-羧基苯并呋喃 -2-羧酸(2,-二甲胺) 乙酯(化合物 17)
冰浴条件下,将 2-羟基 -4-甲氧基苯甲醛(2.2g, 13mmol)和无水 K2C03(2.2g, 15.6mmol)溶解于 DMFpOml)中, 缓慢滴加溴代乙酸乙酯 (2.2g, 13mmol)。 滴加完 毕, 0°C搅拌 30 min, 然后在 60°C油浴中, 反应 12h。 把反应液倒入冰水中, 过滤, 氯仿溶解固体, 无水 Na2S04干燥, 过滤, 旋干溶剂后, 经硅胶柱层析分 离后, 得到黄色固体 2.38 g (收率为 78%), 将其溶于二氧六环 (20ml) 中, 加入 1M/L的氢氧化钠溶液 (12ml), 常温搅拌 2 h, 将二氧六环蒸干, 剩余液体倾入冰 水中, 用二氯甲垸洗, 调 PH值至 2, 过滤收集固体 1.99g (收率为 95%), 将其溶 于二氯甲烷 (30ml ) , 加入 DIC (1.46g, 11.55mmol), 常温搅拌 lh后, 加入 DMAP(0.20g, 1.63mmol)与 N,N-二甲基乙醇胺 (0.94g, 10.59mmol), 加热回流 6h 后, 用水与饱和食盐水洗反应液, 无水硫酸镁干燥, 过滤后蒸干, 乙酸乙酯-石 油醚体系重结晶, 得到产物 6-羧基苯并呋喃 -2-羧酸(2'-二甲胺) 乙酯 2.33g (收 率为 87%) 。
^MR (CDC13) δ: 2.82(s, 6H), 3.35(t, J= 7.4 Hz, 2H), 4.60(t, J= 7.4 Hz, 2H), 7.68(s, IH), 7.76(d, J = 8.5 Hz, IH), 7.84(d, J = 8.5 Hz, 1H), 7.97(s, IH), 12.37(s, IH). MS (ΕΓ) m/z: 277 [M]+. 实施例 18: 6-乙酰基苯并呋喃 -2-羧酸(2,-二甲胺) 乙酯(化合物 18)
以 2-羟基 -4-乙酰基苯甲醛为原料, 按照实施例 17所述的制备方法反应, 得 到 6-乙酰基苯并呋喃 -2-羧酸 (2'-二甲胺) 乙酯 (收率为 51%) 。
iHNMR (CDCI3) δ: 2.5 l(s, 3H), 2.79(s, 6H), 3.34(t, J= 3.8 Hz, 2H), 4.65(t, J= 3.8 Hz, 2H), 7.3 l(s, IH), 7.70(d, J= 9.0 Hz, 1H), 7.83(d, J= 9.0 Hz, IH), 8.00(s, IH). MS (Ε ) m/z: 275 [M]+. 实施例 19: 5-磺酸基苯并呋喃 -2-羧酸(2,-二甲胺) 乙酯(化合物 19)
以 2-羟基 -5-磺酸基苯甲醛为原料, 按照实施例 17所述的制备方法反应, 得 到 5-磺酸基苯并呋喃 -2-羧酸 (2,-二甲胺) 乙酯 (收率为 44%) 。
1HNMR (CDCI3) δ: 2.82 (s, 6H), 3.34(t, J= 7.4 Hz, 2H), 3.56(s, IH), 4.60(t, J= 7.4 Hz, 2H), 7.72(m, 2H), 7.77(d, J = 7.5 Hz, IH), 8.19(s, IH). MS (EI+) m/z: 313 [M]+. 实施例 20: 6-羧酸甲酯苯并呋喃 -2-羧酸(2,-膦酸二甲酯) 乙酯(化合物 20) 冰浴条件下,将 2-羟基 -4-羧酸甲酯基苯甲醛(1.80g, lOmmol)和无水 K2C03 (1.66g, 12mmol)溶解于 DMF(25 ml)中, 缓慢滴加溴代乙酸乙酯 (1.67g, 10mmol)。 滴加完毕, 0°C搅拌 30min, 然后在 60°C油浴中, 反应 12 h。 把反应液倒入冰 水中, 过滤, 氯仿溶解固体, 无水 Na2S04干燥, 过滤, 旋干溶剂后, 经硅胶柱 层析分离后, 得到黄色固体 2.03 g(82%), 将其溶于四氢呋喃: 甲醇 =4:1的混合 溶液(20ml) 中, 加入氢氧化钠 (0.43g, lOJmmol), 常温搅拌 3h, 将溶液蒸干, 剩余液体倾入冰水中, 用二氯甲垸洗, 调 PH值至 2, 过滤, 收集固体, 用甲醇 重结晶,得到固体 1.42g (收率为 79%),将其溶于二氯甲垸 (25ml),加入 DIC (0.98g, 7.77mmol), 常温搅拌 lh后加入 DMAP (0.24g, 1.94mmol)与羟甲基膦酸二乙酯 (1.20g, 7.12mmol), 加热回流 6h后, 用水与饱和食盐水洗反应液, 无水硫酸镁干 燥, 过滤后, 蒸干, 乙酸乙酯-石油醚体系重结晶, 得到产物 6-羧酸甲酯苯并呋 喃 -2-羧酸 (2'-膦酸二甲酯) 乙酯 1.80g (收率为 75%) 。
'HNMR (CDC13) 5: 1.40 (t, J= 6.2 Hz, 6H), 3.87(s, 3H), 4.20(m, 4H), 4.45(d, J = 11.6 Hz, 2H), 7.56(s, IH), 7.75(d, J= 7.5 Hz, 1H), 7.88(d, J = 7.5 Hz, IH), 7.97(s, IH). MS (ΕΓ) m/z: 370 [M]+. 实施例 21: 6-羧酸甲酯苯并呋喃 -2-羧酸(2,-膦酸二乙酯) 甲酯(化合物 21) 以为 2-羟乙基膦酸二甲酯为原料, 按照实施例 20所述的制备方法反应, 得 到 6-羧酸甲酯苯并呋喃 -2-羧酸 (2,-膦酸二乙酯) 甲酯 (收率为 50%) 。
'HNMR (CDC13) δ: 2.14(m, 2H), 6.64(d, J= 12.0 Hz, 6H), 3.98(s, 3H), 4.45(t, J = 8.2 Hz, 2H), 8.05(s, 2H), 8.43(s, IH), 8.66(s, IH). MS (EI+) m/z: 356 [M]+. 实施例 22: 6-羧酸甲酯苯并呋喃 -2-羧酸(2,-二甲胺) 乙酯 (化合物 22)
以 N,N-二甲基乙醇胺为原料, 按照实施例 20所述的制备方法反应, 得到 6- 羧酸甲酯苯并呋喃 -2-羧酸 (2,-二甲胺) 乙酯 (收率为 45%)。
iH MR (CDCI3) δ: 2.81(s, 6H), 3.29(t, J= 3.9 Hz, 2H), 3.98(s, 3H), 4.62(t, J=
3.9 Hz, 2H), 7.73(s, IH), 7.76(d, J = 8.5 Hz, IH), 8.16(s, IH). MS (EI+) m/z: 291 岡 +. 实施例 23: 6-羧酸甲酯苯并呋喃 -2-羧酸(2'-二甲胺)丙酯 (化合物 23)
以 N,N-二甲基丙醇胺为原料, 按照实施例 20所述的制备方法反应, 得到 6- 羧酸甲酯苯并呋喃 -2-羧酸 (2'-二甲胺) 丙酯 (收率为 47%) 。
1HNMR( CDC13 )6: 1.90(m, 2H), 2.28(s, 6H), 2.52(t, J= 5.4 Hz, 2H), 3.98(s, 3H), 4.33(t, J = 5.4 Hz, 2H), 7.72(s, IH), 7.76(d, J= 9.0 Hz, IH), 8.10(d, J = 9.0 Hz, IH), 8.16(s, IH). MS (EI+) m/z: 305 [M]+. 实施例 24: 6-羧酸甲酯苯并呋喃 -2-羧酸哌啶乙酯 (化合物 24)
以哌啶乙醇为原料, 按照实施例 20所述的制备方法反应, 得到 6-羧酸甲酯 苯并呋喃 -2-羧酸哌啶乙酯 (收率为 53%) 。
'HNMR ( CDC13 ) δ: 1.50(m, 2H), 1.64(m, 4H), 2.36(t, J= 5.5 Hz, 2H), 2.75(t, J = 5.5 Hz, 2H), 2.94(t, J = 3.9 Hz, 2H), 3.98(s, 3H), 4.64(t, J = 3.9 Hz, 2H), 7.72(s, 1H), 7.76(d, J = 7.5 Hz, IH), 8.10(d, J= 7.5 Hz, IH), 8.15(s, IH). MS (EI+) m/z: 331 岡 +. 实施例 25: 6-羧酸甲酯苯并呋喃 -2-羧酸吗啉乙酯 (化合物 25)
以吗啉乙醇为原料, 按照实施例 20所述的制备方法反应, 得到 6-羧酸甲酯 苯并呋喃 -2-羧酸吗啉乙酯 (收率为 55%) 。
'HNMR ( CDC13 ) δ: 2.51(t, J= 4.7 Hz, 2H), 2.81(t, J= 4.7 Hz, 2H), 2.95(t, J = 3.9 Hz, 2H), 3.69(t, J= 4.7 Hz, 4H), 3.95(s, 3H), 4.66(t, J = 3.9 Hz, 2H), 7.70(s, IH), 7.74(d, J= 7.0 Hz, IH), 8.08(d, J= 7.0 Hz, IH), 8.17(s, IH). MS (EI+) m/z: 333 [M]+. 实施例 26: 6-羧酸甲酯苯并呋喃 -2-羧酸(1,1,-二甲基 -2-二甲胺)乙酯(化合物 26) 以 (1,1 '-二甲基 -2-二甲胺) 乙醇为原料, 按照实施例 20所述的制备方法反 应,得到 6-羧酸甲酯苯并呋喃 -2-羧酸(1,1,-二甲基 -2-二甲胺)乙酯(收率为 37%)。
'HNMR (CDC13 ) δ: 1.53(s, 6H), 2.36(s, 6H), 2.66(s, 2H), 3.98(s, 3H), 7.71(s, IH), 7.75(dxd, J - 7.5 Hz, 1.5 Hz, IH), 8.10(dxd, J = 7.5 Hz, 1.5 Hz, 1H), 8.17(d, J = 1.5 Hz, IH). MS (ΕΓ) m/z: 319 [M]+.
实施例 27: 6-羧酸甲酯苯并呋喃 -2-羧酸 [4,- (2"-羟乙基) 1哌嗪乙酯(化合物 27) 以 [4'- (2"-羟乙基) ]哌嗪乙醇为原料, 按照实施例 20所述的制备方法反应, 得到 6-羧酸甲酯苯并呋喃 -2-羧酸 [4,- (2"-羟乙基) ]哌嗪乙酯 (收率为 41%) 。
1HNMR (CDC13) δ: 2.30(m, 2H), 2.33(m, 2H), 2.39(t, J= 3.7 Hz, 2H), 2.56(t, J = 5.1 Hz, 2H), 2.61 (t, J = 5.1 Hz, 2H), 3.01 (t, J = 4.8 Hz, 2H), 3.56(t, J= 3.7 Hz, 2H), 3.97(s, 3H), 4.53(t, J= 4.8 Hz, 2H), 7.72(s, 1H), 7.75(d, J= 9.0 Hz, 1H), 8.03(d , J = 9.0 Hz, 1H), 8.22(s, 1H). MS (EI+) m/z: 376 [M]+. 实施例 28: 5,6-亚甲基二氧苯并呋喃 -2-羧酸(2,-膦酸二乙酯) 甲酯(化合物 28) 冰浴条件下,将 2-羟基 -4,5-亚甲基二氧苯甲醛(1.66g, lOmmol)和无水 K2C03 (1.66g, 12mmol)溶解于 DMF(25ml)中, 缓慢滴加溴代乙酸乙酯 (1.67g, 10mmol)。 滴加完毕, 0°C搅拌 30min, 然后在 60°C油浴中, 反应 12h。 把反应液倒入冰水 中, 过滤收集固体, 氯仿溶解固体, 无水 Na2S04干燥, 过滤, 旋干溶剂后, 经 硅胶柱层析分离后,得到黄色固体 2.04 g (收率为 87%),将其溶于二氧六环 (20ml) 中, 加入 1M/L的氢氧化钠溶液 (10ml), 常温搅拌 2h, 将二氧六环蒸干, 剩余液 体倾入冰水中, 用二氯甲烷洗, 调 PH值至 2, 过滤收集固体 1.30g (收率为 74%), 将其溶于二氯甲垸 (30ml) , 加入 DIC (0.87g, 6.90mmol), 常温搅拌 lh后加入 DMAP (0.23g, 1.88mmol)与羟甲基膦酸二乙酯 (1.16g, 6.90mmol), 加热回流 6h 后, 用水与饱和食盐水洗反应液, 无水硫酸镁干燥, 过滤后, 蒸干, 乙酸乙酯- 石油醚体系重结晶, 得到产物 5,6-亚甲基二氧苯并呋喃 -2-羧酸 (2'-膦酸二乙酯) 甲酯 1.72g (收率为 77%) 。
'HNMR (CDC13) δ: 1.40(t, J = 5.9 Hz, 6H), 4.2 l(m, 4H), 4.50(d, J= 11.9 Hz, 2H), 6.07(s, 2H), 7.48(s, 1H), 7.5 l(s, 1H), 7.68(s, 1H). MS (EI+) m/z: 356 [M]+. 实施例 29: 5,6-亚甲基二氧苯并呋喃 -2-羧酸(2,-膦酸二甲酯) 乙酯(化合物 29) 以 2-羟乙基膦酸二甲酯为原料, 按照实施例 28所述的制备方法反应, 得到 5,6-亚甲基二氧苯并呋喃 -2-羧酸 (2,-膦酸二甲酯) 乙酯 (收率为 45%) 。
1HNMR (CDC13) δ: 2,16(m, 2H), 3.66(d, J= 11.6 Hz, 6H), 4.42(t, J= 5.3 Hz, 2H), 6.05(s, 2H), 7.49(s, 1H), 7.50(s, 1H), 7.67(s, 1H). MS (EI+) m/z: 342 [M]+. 实施例 30: 5,6-亚甲基二氧苯并呋喃 -2-羧酸(2,-二甲胺) 乙酯(化合物 30)
以 N,N-二甲基乙醇胺为原料,按照实施例 28所述的制备方法反应,得到 5,6- 亚甲基二氧苯并呋喃 -2-羧酸 (2,-二甲胺) 乙酯 (收率为 50%) 。
'HNMR (CDC13 ) δ: 2.81(s, 6H), 3.31(t, J= 4.9 Hz, 2H), 4.60(t, J= 4.9 Hz, 2H), 6.08(s, 2H), 7.48(s, IH), 7.5 l(s, 1H), 7.66(s, IH). MS (EI+) m/z: 277 [M]+. 实施例 31: 5,6-亚甲基二氧苯并呋喃 -2-羧酸(2,-二甲胺) 丙酯(化合物 31)
以 N,N-二甲基丙醇胺为原料,按照实施例 28所述的制备方法反应,得到 5,6- 亚甲基二氧苯并呋喃 -2-羧酸 (2,-二甲胺) 丙酯 (收率为 52%) 。
'HNMR (CDC13 ) δ: 1.91(m, 2H), 2.29(s, 6H), 2.52(t, J= 5.6 Hz, 2H), 4.30(t, J=
5.6 Hz, 2H), 6.07(s, 2H), 7.46(s, IH), 7.49(s, IH), 7.67(s, IH). MS (EI+) m/z: 291 [M]+. 实施例 32: 5,6-亚甲基二氧苯并呋喃 -2-羧酸 [4,- (2"-轻乙基) I哌嗪乙酯(化合物 32)
以 [4'- (2"-羟乙基) ]哌嗪乙醇为原料, 按照实施例 28所述的制备方法反应, 得到 5,6-亚甲基二氧苯并呋喃 -2-羧酸 [4'- (2"-羟乙基)]哌嗪乙酯(收率为 33%)。
^MR (CDC13 ) δ: 1.16(s, IH), 2.33(t, J= 5.1 Hz, 4H), 2.53(m, 4H), 2.63(t, J=
4.7 Hz, 2H), 3.07(t, J= 4.7 Hz, 2H), 3.60(t, J = 4.7 Hz, 2H), 4.54(t , J = 4.7 Hz, 2H), 6.07(s, 2H), 7.48 (s, IH), 7.50(s, lH),7.67(s, IH). MS (EI+) m/z: 364 [M]+. 实施例 33: 5,6-亚甲基二氧苯并呋喃 -2-羧酸吗啉乙酯(化合物 33)
以吗啉乙醇为原料, 按照实施例 28所述的制备方法反应, 得到 5,6-亚甲基 二氧苯并呋喃 -2-羧酸吗啉乙酯 (收率为 53%) 。
'HNMR( CDC13 )6: 2.53(t, J= 4.7 Hz, 2H), 2.79(t, J =4.7 Hz, 2H), 2.88(t, J= 5.2 Hz, 2H), 3.70(t, J = 4.7 Hz, 4H), 4.08(t, J = 5.2 Hz, 2H), 6.06(s, 2H), 7.48(s, 1H), 7.50(s, IH), 7.67(s, IH). MS (EI+) m/z: 319岡 +·
实施例 34: 6-羧酸乙酯苯并呋喃 -2-羧酸(2'-二甲胺)丙酯 (化合物 34)
以 2-羟基 -4-羧酸乙酯基苯甲醛为原料,按照实施例 28所述的制备方法反应, 得到 6-羧酸乙酯苯并呋喃 -2-羧酸 (2,-二甲胺) 丙酯 (收率为 32%) 。
'HNMR (CDCI3) δ: 1.41(t, J= 6.0 Hz, 3H), 2.84(s, 6H), 3.33(t, J= 3.9 Hz, 2H), 4.34(q, J = 6.0 Hz, 2H), 7.67(s, IH), 7.77(dxd, J= 7.5 Hz, 1.6 Hz, IH), 8.10(dxd, J =
7.5 Hz, 1.6 Hz, 1H), 8.59(d, J= 1.6 Hz, IH). MS (EI+) m/z: 305 [M]+. 实施例 35: 5,6-二氨基苯并呋喃 -2-羧酸 (2'-二甲胺) 丙酯 (化合物 35)
以 2-羟基 -4,5-二氨基苯甲醛为原料, 按照实施例 28所述的制备方法反应, 得到 5,6-二氨基苯并呋喃 -2-羧酸 (2'-二甲胺) 丙酯 (收率为 61%) 。
'HNMR (CDC13) δ: 2.82(s, 6H), 3.27(t, J= 4.0 Hz, 2H), 4.35(s, 4H), 4.62(t, J=
4.0 Hz, 2H), 7.10(s, IH), 7.22(s, IH), 7.62(s, IH). MS (EI+) m/z: 263 [M]+. 实施例 36: 6-甲氧基苯并噻吩 -2-羧酸(2,-膦酸二乙酯) 甲酯 (化合物 36)
冰浴条件下,将 2-硝基 -4-甲氧基苯甲醛 (3.62g, 20mmol)和无水 K2C03 (3.31g, 24mmol)溶解于 DMF(50ml)中, 缓慢滴加巯基乙酸乙酯 (2.40g, 20mmol)。 滴加完 毕, 0°C搅拌 30 min, 然后在 60°C油浴中, 反应 8h。 把反应液倒入冰水中, 过 滤, 氯仿溶解固体, 无水 Na2S04干燥, 过滤, 旋干溶剂后, 以硅胶柱层析分离 后, 得到黄色固体 3.72 g (收率为 79%), 将其溶于二氧六环(30ml) 中, 加入 1N 的氢氧化钠溶液 (16ml), 常温搅拌 2h, 将二氧六环蒸干, 剩余液体倾入冰水中, 用二氯甲烷洗, 调 PH值至 2, 过滤收集固体 3.05g (收率为 93%), 将其溶于二氯 甲烷(40ml),加入 DIC (2.14g, 16.98mmol),常温搅拌 lh后,加入 DMAP (0.53g, 4.34 mmol)与羟甲基膦酸二乙酯 (2.71g,16.16mmol), 加热回流 5h后, 用水与饱和 食盐水洗反应液, 无水硫酸镁干燥, 过滤后, 蒸干, 乙酸乙酯-石油醚体系重结 晶, 得到产物 6-甲氧基苯并噻吩 -2-羧酸 (2'-膦酸二乙酯) 甲酯 2.23g (81%)
'HNMR(CDC13)5: 1.39(t, J= 6.6 Hz, 6H), 3.88(s, 3H), 4.16(m, 4H), 4.56(d,J = 11.9 Hz, 2H), 6.98(d, J = 7.7 Hz, IH), 7.50(s, IH), 7.84(d, J = 7.7 Hz, IH), 8.35(s, IH). MS (ΕΓ) m/z: 358 [M]+. 实施例 37: 6-甲氧基苯并噻吩 -2-羧酸(2,-膦酸二甲酯) 乙酯(化合物 37)
以 2-羟乙基膦酸二甲酯为原料, 按照实施例 36所述的制备方法反应, 得到 6-甲氧基苯并噻吩 -2-羧酸 (2'-膦酸二甲酯) 乙酯 (收率为 52%) 。
'HNMR (CDC13) δ: 2.12(m, 2H), 3.68(d, J= 12.0 Hz, 6H), 3.89(s, 3H), 4.42(t, J = 5.2 Hz, 2H), 6.99(d, J = 8.0 Hz, IH), 7.49(d, J = 2.0 Hz, IH), 7.85(d, J = 8.0 Hz, IH), 8.33(d, J= 2.0 Hz, IH). MS (EI+) m/z: 344 [M]+.
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60.00mmol), 常温搅拌 3h, 用甲醇终止反应, 蒸干, 得到 6-甲氧基苯并呋喃 -2- 羧酸膦酰甲酯 2.43g (收率为 85%) 。
!HNMR (CDC13) δ: 3.90(s, 3H), 4.35(s, 2H), 4.62(d, J= 11.90 Hz, 2H), 6.95(d, J = 7.50 Hz, 1H), 7.2 l(s, IH), 7.52(s, IH), 7.58(d, J - 7.50 Hz, 1H), MS (EI+) m/z: 286岡 +· 实施例 43: 6-甲氧基苯并呋喃 -2-羧酸膦酰乙酯(化合物 43)
以化合物 2为原料, 按照实施例 42所述的制备方法反应, 得到 6-甲氧基苯 并呋喃 -2-羧酸膦酰乙酯 (收率为 79%) 。
'HNMR (CDC13 ) δ: 1.98(m, 2H), 3.92(s, 3H), 4.24(t, J= 6.10 Hz, 2H), 4.35(s, 2H), 6.93(d, J = 7.0 Hz, IH), 7.19(s, IH), 7.58 (d, J = 7.0 Hz, IH), 8.20(s, IH). MS (EI+) m/z: 300 [M]+. 实施例 44: 6-羧酸甲酯苯并噻吩 -2-羧酸(2,-膦酸二乙酯) 甲酯(化合物 44) 冰浴条件下, 将 2-硝基 -4-羧酸甲酯基苯甲醛 (2.00g, 9.56mmol) 和无水 K2CO3(1.50g, 11.4mmol)溶解于 DMF(25 ml)中, 缓慢滴加巯基乙酸乙酯 (1.15g, 9.56mmol)o 滴加完毕, 0°C搅拌 30min, 然后在 60°C油浴中, 反应 10h。 把反 应液倒入冰水中, 过滤, 氯仿溶解固体, 无水 Na2S04干燥, 过滤, 旋干溶剂后, 经硅胶柱层析分离后, 得到黄色固体 2.22 g (收率为 88%), 将其溶于四氢呋喃: 甲醇 =4:1的混合溶液 (20ml) 中, 加入氢氧化钠 (0.43g, 10.7mmol), 常温搅拌 3h, 将溶液蒸干, 剩余液体倾入冰水中, 用二氯甲垸洗, 调 PH值至 2, 过滤收 集固体,用甲醇重结晶,得到固体 1.43g (收率为 72%),将其溶于二氯甲垸(25ml), 加入 DIC(0.91g, 7.26mmol), 常温搅拌 lh后加入 DMAP(0.22g, 1.80mmol)与羟甲 基膦酸二乙酯 (l.l lg, 6.26mmol), 加热回流 5h后, 用水与饱和食盐水洗反应液, 无水硫酸镁干燥, 过滤后, 蒸干, 乙酸乙酯-石油醚体系重结晶, 得到产物 6-羧 酸甲酯苯并噻吩 -2-羧酸 (2'-膦酸二乙酯) 甲酯 1.85g (收率为 80%) 。
1HNMR(CDC13)6: 1.13(t, J= 6.6 Hz, 6H), 3.98(s, 3H), 4.20(m, 4H), 4.67(d, J= 12.0 Hz, 2H), 8.02(s, IH), 8.04(s, IH), 8.42(s, 1H), 8.66(s, IH). MS (EI+) m/z: 386 岡 +· 实施例 45: 6-羧酸甲酯苯并噻吩 -2-羧酸(2'-膦酸二甲酯) 乙酯(化合物 45)
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加入 IN的氢氧化钠溶液 (10ml), 常温搅拌 2h, 将二氧六环蒸干, 剩余液体倾入 冰水中, 用二氯甲烷洗, 调 PH值至 2, 过滤收集固体 1.54g (收率为 88%),将其溶 于二氯甲垸( 30ml ),加入 DIC(1.19g, 9.44mmol), 常温搅拌 lh后加入 DMAP(0.15g, 1.23mmol)与羟甲基膦酸二乙酯 (1.32g, 7.85mmol), 加热回流 6h后, 用水与饱和 食盐水洗反应液, 无水硫酸镁干燥, 过滤后蒸干, 乙酸乙酯-石油醚体系重结晶, 得到产物 5,6-亚甲基二氧苯并噻吩 -2-羧酸 (2,-膦酸二乙酯) 甲酯 2.14g (收率为 73%) 。
1HNMR (CDC13 ) δ: 1.43(t, J = 6.2 Hz, 6H), 4.22(m, 4H), 4.59(d, J = 11.6 Hz, 2H), 6.08(s, 2H), 7.48(s, 1H), 8.10(s, 1H), 8.35(s, 1H). MS (EI+) m/z: 372 [M]+. 实施例 53: 5,6-亚甲基二氧苯并噻吩 -2-羧酸 (2,-膦酸二甲酯) 乙酯 (化合物 53) 以 2-羟乙基膦酸二甲酯为原料, 按照实施例 52的方法反应, 得到 5,6-亚甲 基二氧苯并噻吩 -2-羧酸 (2'-膦酸二甲酯) 乙酯 (收率为 51%) 。
'HNMR (CDC13) δ: 2.12(m, 2H), 3.67(d, J= 11.9 Hz, 6H), 4.45(t, J = 5.2 Hz, 2H), 6.03(s, 2H), 7.47(s, 1H), 8.10(s, 1H), 8.34(s, 1H). MS (EI+) m/z: 358 [M]+. 实施例 54: 5,6-亚甲基二氧苯并噻吩 -2-羧酸 (2,-二甲胺) 乙酯 (化合物 54)
以 Ν,Ν-二甲基乙醇胺为原料, 按照实施例 52的方法反应, 得到 5,6-亚甲基 二氧苯并噻吩 -2-羧酸 (2,-二甲胺) 乙酯 (收率为 57%)。
!HNMR (CDCI3) δ: 2.83(s, 6H), 3.33(t, J= 3.9 Hz, 2H), 4.59(t, J= 3.9 Hz, 2H), 6.07(s, 2H), 7.48(s, 1H), 8.1 l(s, 1H), 8.36(s, 1H). MS (EI+) m/z: 293 [M]+. 实施例 55: 5,6-亚甲基二氧苯并噻吩 -2-羧酸(2,-二甲胺) 丙酯 (化合物 55)
以 Ν,Ν-二甲基丙醇胺为原料, 按照实施例 52的方法反应, 得到 5,6-亚甲基 二氧苯并噻吩 -2-羧酸 (2'-二甲胺) 丙酯 (收率为 47%)。
1HNMR (CDC13 ) 6: 1.92(m, 2H), 2.27(s, 6H), 2.49(t, J= 7.7 Hz, 2H), 4.28(t, J= 7.7 Hz, 2H), 6.08(s, 2H), 7.50(s, 1H), 8.1 l(s, 1H), 8.38(s, 1H). MS (EI+) m/z: 307[M]+. 实施例 56: 5,6-亚甲基二氧苯并噻吩 -2-羧酸 [4,- (2"-羟乙基) ]哌嗪乙酯 (化合物 56)
以 [4,- (2"-羟乙基) ]哌嗪乙醇为原料,按照实施例 52的方法反应,得到 5,6- 亚甲基二氧苯并噻吩 -2-羧酸 [4,- (2"-羟乙基) ]哌嗪乙酯 (收率为 39%)。
'HNMR (CDC13 ) δ: 1.17(s, 1H), 2.35(t, J= 5.1 Hz, 2H), 2.56(t,J= 5.1 Hz, 2H), 2.58(t, J= 5.1 Hz, 2H), 2.65(t, J= 5.1 Hz, 2H), 2.66(t, J= 4.7 Hz, 2H), 3.07(t, J= 4.8 Hz, 2H), 3.62(t, J = 4.8 Hz, 2H), 4.53(t, J = 4.8 Hz, 2H), 6.07(s, 1H), 7.51(s, IH), 8.09(s, 1H), 8.52(s, IH). MS (EI+) m/z: 378 [M]+. 实施例 57: 5,6-亚甲基二氧苯并噻吩 -2-羧酸吗啉乙酯(化合物 57)
以吗啉乙酯为原料, 按照实施例 52的方法反应, 得到 5,6-亚甲基二氧苯并 噻吩 -2-羧酸吗啉乙酯 (收率为 54%)。
'HNMR (CDC13 ) δ: 2.53(t, J= 4.7 Hz, 2H), 2.76(t, J= 4.7 Hz, 2H), 3.03(t, J = 7.3 Hz, 2H), 3.68(t, J = 4.7 Hz, 4H), 6.06(s, 2H), 7.49(s, 1H), 8.10(s, IH), 8.37(s, IH). MS (EI+) m/z: 335岡 +.
实施例 58: 5,6-乙基亚甲基二氧苯并噻吩 -2-羧酸膦酰乙酯 (化合物 58)
冰浴条件下, 将 2-硝基 -4,5-乙基亚甲基二氧苯甲醛(2.23g,10mmol)和无水 K2C03 (1.66g, 12mmol)溶解于 DMF(25 ml)中, 缓慢滴加巯基乙酸乙酯 (L32g, l lmmol)。 滴加完毕, 0°C搅拌 30min, 然后在 80°C油浴中, 反应 14h。 把反应 液倒入冰水中, 过滤, 氯仿溶解固体, 无水 Na2S04干燥, 过滤, 旋干溶剂后, 经硅胶柱层析分离后, 得到黄色固体 2.25g (收率为 81%), 将其溶于二氧六环
(20ml ) 中, 加入 1N的氢氧化钠溶液 (8ml), 常温搅拌 2h, 将二氧六环蒸干, 剩余液体倾入冰水中, 用二氯甲垸洗, 调 PH值至 2, 过滤收集固体 1.82g (收率 为 90%),将其溶于二氯甲垸 (35ml) , 加入 DIC(U0g, 8.73mmol), 常温搅拌 lh 后加入 DMAP (0.15g, 1.23mmol)与羟乙基膦酸二甲酯 (U2g, 7.27mmol), 加热回 流 5h后, 用水与饱和食盐水洗反应液, 无水硫酸镁干燥, 过滤后蒸干, 乙酸乙 酯-石油醚体系重结晶,得到产物 2.13g (收率为 76%),将其溶于二氯甲烷 (30ml), 加入三甲基溴硅烷 (5.03g, 34.87mmol), 常温搅拌 3h, 用甲醇终止反应, 蒸干, 得到产物 5,6-乙基亚甲基二氧苯并噻吩 -2-羧酸膦酰乙酯 1.04g (收率为 88%)。
'HNMR( CDC13 ) 5: 0.99(t, J= 6.8 Hz, 3H), 2.12(t, J= 5.2 Hz, 2H), 2.14(m, 2H), 4.42(t, J = 5.2 Hz, 2H), 4.90(s 2H), 5.80(t, J = 5.9 Hz, IH), 7.49(s, 1H), 8.10(s, IH), 8.36(s, IH). MS (ΕΓ) m/z: 358 [M]+.
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'HNMR(CDC13)6: 1.92(m, 2H), 2.27(s, 6H), 2.48(t, J= 7.7 Hz, 2H), 3.90(s, 3H), 3.97(s, 3H), 4.03(s, 3H), 4.27(t, J= 7.7 Hz, 2H), 6.67(s, IH), 7.46(s, 1H), 7.52(s, IH). MS (EI+) m/z: 320岡 +.
实施例 67: N-甲基 -5,6-二甲氧基 -吲哚 -2-羧酸吗啉乙酯(化合物 67)
以 N-甲基 -5,6-二甲氧基 -吲哚 -2-羧酸与吗啉乙醇为原料, 按照实施例 64的 方法反应, 得到 N-甲基 -5,6-二甲氧基 -B引哚 -2-羧酸吗啉乙酯 (收率为 82%)。
'HNMRCCDCb )6: 2.53(t, J=4.7 Hz, 2H), 2.80(t, J= 4.7 Hz, 2H), 2.99(t, J= 3.8
Hz, 2H), 3.69(t, J= 4.7 Hz, 4H), 3.91(s, 3H), 3.96(s, 3H), 4.10(s, 3H), 4.60(t, J= 3.8
Hz, 2H), 6.72(s, IH), 7.49(s, IH), 7.74(s, IH). MS (EI+) m/z: 348 [M]+. 实施例 68: N- (2,-羟乙基) -5-甲氧基 -吲哚 -2-羧酸(2,-二甲胺)乙酯(化合物 68) 以 N- (2'-羟乙基) -5-甲氧基 -吲哚 -2-羧酸为原料, 按照实施例 64的方法反 应,得到 N- (2,-羟乙基) -5-甲氧基 -吲哚 -2-羧酸(2,-二甲胺)乙酯 (收率为 80%)。
'HNMR (CDC13) δ: 1.90(s, IH), 2.81(s, 6H), 3.30(t, J= 7.3 Hz, 2H), 3.87(t, J= 4.2 Hz, 2H), 3.96(s, 3H), 4.5 l(t, 4.2 1H), 4.60(t, J= 7.3 Hz, 2H), 4.76(t , J= 4.2 IH), 7.07(d, J = 8.5 Hz, IH), 7.44(d, J =8.5 Hz, 1H), 7.58(s, IH), 7.59(s, IH). MS (EI+) m/z: 306岡 +.
实施例 69: N- (2,-甲氧基) -6-甲氧基 -吲哚 -2-羧酸(2,-二甲胺)乙酯(化合物 69) 以 N- (2'-甲氧基) -6-甲氧基 -吲哚 -2-羧酸为原料, 按照实施例 64的方法反 应, 得到 N- (2,-甲氧基) -6-甲氧基 -吲哚 -2-羧酸(2,-二甲胺)乙酯 (收率为 80%)。
!HNMR (CDC13 ) δ: 2.82(s, 6H), 3.33(t, J= 4.4 Hz, 2H), 3.43(s, 3H), 3.75(t, J= 3.7 Hz, 2H), 3.98(s, 3H), 4.45(t, J = 3.7 Hz, 1H), 4.60(t, J = 4.6 Hz, 2H), 4.76(t, J = 3.7 Hz, IH), 7.03(d, J= 7.0 Hz, IH), 7.40(d, J=7.0 Hz, IH), 7.52(s, IH), 7.53(s, IH). MS (EI+) m/z: 320 [M]+. 实施例 70: N-羧甲基 -5-甲氧基 -H引哚 -2-羧酸(2,-二甲胺) 乙酯(化合物 70)
以 N-羧甲基 -5-甲氧基 -吲哚 -2-羧酸为原料, 按照实施例 64的方法反应, 得 到 N-羧甲基 -5-甲氧基 -Π引噪 -2-羧酸 (2,-二甲胺) 乙酯 (收率为 69%)。
,HNMR(CDC13)8: 2.80(s, 6H), 3.33(t, J= 7.0 Hz, 2H), 3.78(s, 3H), 3.89(s, 3H), 4.57(t, J = 7.0 Hz, 2H), 4.72(t, J = 7.7 Hz, 2H), 4.79(t, J= 7.7 Hz, 1H), 5.09(s, IH),
5.37(s, 1H), 7.04(d, J= 7.5 Hz, 1H), 7.41(d, J=7.5 Hz, 1H), 7.52(s, 1H), 7.53(s, 1H). MS (EI+) m/z: 334 [M]+. 实施例 71: 5,6-亚甲基二氧苯丙呋喃 -2-羧酸酰(2,-二甲胺) 乙胺(化合物 71) 冰浴条件下,将 2-羟基 -4,5-亚甲基二氧苯甲醛 (3.32g, 20mmol)和无水 K2C03 (3.20g, 24mmol)溶解于 DMF(50ml)中, 缓慢滴加溴代乙酸乙酯 (3.34g, 20mmol)。 滴加完毕, 0°C搅拌 30min, 然后在 60°C油浴中, 反应 14h。 把反应液倒入冰水 中, 过滤, 氯仿溶解固体, 无水 Na2S04干燥, 过滤, 旋干溶剂后, 经硅胶柱层 析分离后, 得到黄色固体 4.00g(86%), 将其溶于二氧六环 (35ml) 中, 加入 1N 的氢氧化钠溶液 (20ml), 常温搅拌 3h, 将二氧六环蒸干, 剩余液体倾入冰水中, 用二氯甲垸洗涤, 调 PH值至 2, 过滤, 得到固体 2.61g (收率为 75%),将其溶入二 氯亚砜 (20ml)中, 加热回流 lh, 减压蒸除多余二氯亚砜, 将其降温至 0°C, 加入 含有 Ν,Ν-二甲基乙二胺 (U2g, 12.72mmol) 和三乙胺 (1.53g, 15.14mmol)的二氯 甲烷溶液 (30 ml)中, 常温搅拌 4h, 得到 5,6-亚甲基二氧苯丙呋喃 -2-羧酸酰 (2'- 二甲胺) 乙胺 2.98g (收率为 85%) 。
'HNMR (CDC13) δ: 2.32(s, 6H), 2.62(t, J= 5.1 Hz, 2H), 3.41(t,J= 5.1 Hz, 1H), 3.43(t, J= 5.1 Hz, 1H), 6.06(s, 2H), 7.30(s, 1H), 7.48(s, 1H), 7.50(s, 1H), 7.57(s, 1H). MS (ΕΓ) m/z: 276 [M]+. 实施例 72: 5,6-亚甲基二氧苯丙呋喃 -2-羧酸酰(2,-二甲胺 -1,-甲基) 乙胺(化合 物 72)
以 Ν,Ν,Ν'-三甲基乙二胺为原料, 按照实施例 71的方法反应, 得到 5,6-亚甲 基二氧苯丙呋喃 -2-羧酸酰 (2,-二甲胺 -Γ-甲基) 乙胺 (收率为 46%) 。
1HNMR (CDC13) δ: 2.33(s, 6H), 2.67(t, J= 7.3 Hz, 2H), 3.13(t, J= 7.3 Hz, 1H), 3.34(s, 3H), 3.51(t, J = 7.3 Hz, 1 H), 6.06(s, 2 H), 7.48(s, 1H), 7.5 l(s, 1H), 7.56(s, 1H). MS (EI+) m/z: 290岡 +. 实施例 73: 5,6-亚甲基二氧苯丙噻吩 -2-羧酸酰(2,-二甲胺) 乙胺(化合物 73) 冰浴条件下,将 2-硝基 -4,5-亚甲基二氧苯甲醛(1.95g, lOmmol)和无水 K2C03 (2.85g, 12mmol)溶解于 DMF(25 ml)中, 缓慢滴加巯基乙酸乙酯 (1.32g, l lmmol)。 滴加完毕, 0°C搅拌 30 min, 然后在 60°C油浴中, 反应 10 h。 把反应液倒入冰
水中, 过滤, 氯仿溶解固体, 无水 Na2S04干燥, 过滤, 旋干溶剂后, 经硅胶柱 层析分离后, 得到黄色固体 2.01 g (收率为 76%), 将其溶于二氧六环(25ml) 中, 加入 1N的氢氧化钠溶液 (10ml), 常温搅拌 2h, 将二氧六环蒸干, 剩余液体倾入 冰水中, 用二氯甲垸洗, 调 PH值至 2, 过滤, 收集固体 1.62g (收率为 90%), 将 其溶入二氯亚砜 (15ml)中,加热回流 lh,减压蒸除多余二氯亚砜,将其降温至 0°C, 加入含有 N,N-二甲基乙二胺 (0.77g, 8.75mmol) 和三乙胺 (0.88g, 7.12mmol)的二 氯甲垸溶液 (20ml)中, 常温搅拌 4h, 得到 5,6-亚甲基二氧苯丙噻吩 -2-羧酸酰(2'- 二甲胺) 乙胺 1.89g (收率为 89%) 。
'HNMR (CDC13) δ: 2.34(s, 6H), 2.60(t, J= 5.0 Hz, 2H), 3.40(t, J= 5.0 Hz, 1H), 3.43(t, J= 5.0 Hz, 1H), 6.07(s 2H), 7.32(s, 1H), 7.47(s, 1H), 7.50(s, 1H), 7.58(s, 1H). MS (EI+) m/z: 292 [M]+. 实施例 74: 5,6-亚甲基二氧苯丙噻吩 -2-羧酸酰 (2,-二甲胺 -1,-甲基) 乙胺(化合 物 74)
以 Ν,Ν,Ν'-三甲基乙二胺为原料, 按照实施例 73的方法反应, 得到 5,6-亚甲 基二氧苯丙噻吩 -2-羧酸酰 (2,-二甲胺 -Γ-甲基) 乙胺 (收率为 48%) 。
'HNMR (CDC13) δ: 2.3 l(s, 6H), 2.69(t, J= 7.4 Hz, 2H), 3.13(t, J= 7.4 Hz, 1H), 3.36(s, 3H), 3.51(t, J= 7.4 Hz, 1H), 6.06(s, 2H), 7.49(s, 1H), 7.52(s, 1H), 7.56(s, 1H). MS (EI+) m/z: 306 [M]+. 实施例 75: 5,6-亚甲基二氧苯丙呋喃 -2-羧酸酰(4,-膦酰二乙酯亚甲基苯)胺 (化 合物 75)
以 4-氨基苄基磷酸二乙酯为原料, 按照实施例 71的方法反应, 得到 5,6-亚 甲基二氧苯丙呋喃 -2-羧酸酰 (4'-膦酰二乙酯亚甲基苯) 胺 (收率为 43%) 。
'HNMR ( CDC13) δ: 1.42(t, J= 6.0, 6H), 2.93(d, J= 11.8 Hz, 2H), 4.19(m, 4H), 6.67(s, 2H), 7.22(d, J= 7.5 Hz, 2H), 7.39(d, J= 7.5 Hz, 2H), 7.42(s, 1H), 7.45(s, 1H), 7.46(s, 1H), 9.43(s, 1H). MS (EI+) m/z: 431 [M]+. 实施例 76: 5,6-亚甲基二氧苯丙呋喃 -2-羧酸酰 (4,-膦酰钠亚甲基苯)胺 (化合物 76)
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实施例 86: 6-羧酸甲酯苯并呋喃 -2-羧酸膦酰乙酯(化合物 86) 以化合物 21为原料,按照实施例 42的方法反应,得到 6-羧酸甲酯苯并呋喃 -2-羧酸膦酰乙酯 (收率为 79%) 。
'HNMR (CDC13 ) δ: 2.19(m, 2H), 3.99(s, 3H), 4.18(s, 2H), 4.46(t, J= 8.0 Hz, 2H), 8.00(s, 2H), 8.49(s, 1H), 8.68(s, 1H). MS (ΕΫ) m/z: 328 [M]+. 实施例 87: 6-羧酸甲酯苯并噻吩 -2-羧酸膦酰甲酯 (化合物 87)
以化合物 44为原料,按照实施例 42的方法反应得到 6-羧酸甲酯苯并噻吩 -2- 羧酸膦酰甲酯 (收率为 41% ) 。
'HNMR (CDCI3) δ: 3.98(s, 3H), 4.20(s, 2H), 4.67(d, J= 12.0 Hz, 2 H), 8.02(s, 1H), 8.04(s, 1H), 8.42(s, 1H), 8.66(s, 1H). MS (Ef) m/z: 329 [M]+. 实施例 88: 6-羧酸甲酯苯并噻吩 -2-羧酸膦酰乙酯 (化合物 88)
以化合物 45为原料,按照实施例 42的方法反应得到 6-羧酸甲酯苯并噻吩 -2- 羧酸膦酰乙酯 (收率为 45% ) 。
'HNMR (CDC13 ) δ: 2.18(m, 2H), 3.98(s, 3H), 4.20(s, 2H), 4.46(t, J= 8.2 Hz, 2H), 8.02(s, 2H), 8.43(s, 1H), 8.66(s, 1H). MS (EI+) m/z: 344 [M]+. 药效实验
按照以上所说路线和方法, 能够稳定、 可重复性地合成得到本发明化合物。 实验一 体外 BMP-2上调活性筛选
参照中国专利申请 03104750.5的记载内容, 构建上调 BMP-2的筛选模型, 质粒 PYJ 瞬时转染 MC3T3E1 细胞, 具体过程为: 将 100 μΙ7孔适量浓度的 MC3T3E1 细胞在 96孔无菌塑料培养板内培养 8h, 用 25 μΙ7孔无血清无双抗 DMEM培养基稀释适量 PYJ质粒 DNA于无菌离心管中, 在另一个无菌离心管 中用 25 μΙ7孔无血清无双抗 DMEM培养基稀释 0.5 μ!7孔 LF2000 Reagent, 在 5 mm之内, 将上述两管合并混匀, 室温下再孵育 20 min, 将混合后的转染悬液加 到上述 96孔板内, 每孔 50 充分混匀后将 96孔板置于 37°C二氧化碳培养箱 内,培养一定时间然后加入适量浓度的药物作用细胞后再进行荧光检测; 具体检
测过程如下: 弃去 96孔板中的培养基, 用 200 的 PBS (pH 7.0) 轻轻漂 洗细胞后, 完全弃去 PBS, 加入 25 μΙ7孔的 l xPLB, 室温下振摇 15 min, 使细 胞完全裂解, 将裂解液完全吸出到荧光分析用 96孔白板相应孔内, 加入 70 μΙ7 孔的分析试剂 LARII于分析用白板内后, 立即 (5 min 内) 将分析用白板置于 Galaxy 分光光度计内; 检测条件为: 无激发光波长, 发射光波长为 empty, Positioning delay为 1.0, Number of intervals 1, Interval time为 1.0s, 设置仪器 读数前要为振摇模式, 振摇直径为 1毫米, 利用设置的阳性对照、 空白对照以及 相关的数据和计算公式, 计算样品的上调率。 结果见表 1。
上调率 = (样品发光数 - DMSO发光数) / DMSO发光数 xl00%
本发明采用上述 BMP-2筛选模型研究本发明的式 I化合物对 BMP-2上调率
(%)评价其活性。选用 0.1%DMSO为阴性对照, 0.4μΜ Lovastatin为阳性对照, 试验药物浓度为 4μΜ, 活性测定结果如表 1所示。 表 1给出了本发明的优选化 合物的结构, 但不以任何方式限制本发明。
表 1 本发明式 I化合物的结构及体外上调 ΒΜΡ-2的活性
体内抗骨质疏松作用研究结果显示: 本发明的化合物有改善 SAMP6小鼠骨 质疏松症状的效果。
体外活性测试显示: 本发明化合物表现出了对骨形态发生蛋白 BMP-2 表达 的明显上调作用。
Claims
式中,
X选自 0、 S或 NR8, 其中, 选自 H、 烃基、 卤代烃基、 羰基烃基、 羟基 烃基、 氨基烃基、 烃氧基的任一种;
Y选自 0 或 NR 其中, Ι 选自 H、 -OH、 烃基、 酰基、 垸氧基、 磺酰基 的任一种;
R2选自 H或 C1-C6的二烃基;
n = 0-6正整数; 选自 H、 -OH、 烃基、 羧基、 酰基、 垸氧基、 磺酸基、 磷酸基、 磷酸酯、 磷酸钠、 C1-C6的二烃基胺、 吗啉、 哌啶、 N-乙醇基哌嗪、 吡咯垸、 C1-C6的经 基哌嗪、 十氢吡啶并 [1,2 -α]吡嗪的任一种;
R3选自 Η、 烃基、 卤素、 酰基、 羧基、 氨基、 取代的氨基、 磺酸基、 腈基、 酰基烃氧基的任一种;
、 R5、 、 R7分别选自 H、 烃基、 垸氧基、 卤素、 羧基、 氨基、 取代的 氨基、 酰基、 酯基、 磺酸基的任一种;
R5与 通过碳、 氧或氮连接在一起, 形成 5-7元环结构或带有取代基 R9的 5-7元环结构, 其中, R9选自 H、 烃基、 卤代烃基、 羰基烃基、 羟基烃基、 氨基 烃基、 烃氧基的任一种。
2、 如权利要求 1所述的苯并五元不饱和杂环化合物或其药用盐, 其中, 所 述烃基包括 C1-C18的直链或支链的垸基和环垸基; 所述垸氧基包括 C1-C18的 直链或支链的烷氧基; 所述酰基包括由 C1-C18的直链或支链的垸基取代的酰基 或芳基酰基; 所述酯基包括由 C1-C18的直链或支链的垸基取代的酯基或芳基酯
基;所述酰氨基包括由 C1-C18的直链或支链的烷基取代的酰氨基或芳基酰氨基。
3、 如权利要求 2所述的苯并五元不饱和杂环化合物或其药用盐, 其中, 所 述 C1-C18的直链或支链的烷基选自甲基、 乙基、 异丙基、 正丙基、 正丁基、 异 丁基、 仲丁基、 叔丁基、 正戊基、 异戊棊、 正己基、 异己基的任一种; 所述环烷 基包括环戊垸、 环己垸的任一种;
所述 C1-C18的直链或支链的垸氧基选自甲氧基、 乙氧基、 异丙氧基、 正丙 氧基、 正丁氧基、 异丁氧基、 仲丁氧基、 叔丁氧基、 正戊氧基、 异戊氧基、 正己 氧基、 异己氧基的任一种;
所述由 C1-C18的直链或支链的垸基取代的酰基选自甲酰基、 乙酰基、 异丙 基酰基、 正丙基酰基、 烯丙基酰基、 环丙基酰基、 正丁基酰基、 异丁基酰基、 仲 丁基酰基、 叔丁基酰基、 正戊基酰基、 异戊基酰基、 正己基酰基、 异己基酰基的 任一种; 所述芳基酰基选自苯基酰基、 甲苯基酰基的任一种;
所述由 C1-C18的直链或支链的烷基取代的酯基选自甲酰氧基、 乙酰氧基、 异丙基酰氧基、 正丙基酰氧基、 烯丙基酰氧基、 环丙基酰氧基、 正丁基酰氧基、 异丁基酰氧基、 仲丁基酰氧基、 叔丁基酰氧基、 正戊基酰氧基、 异戊基酰氧基、 正己基酰氧基、异己基酰氧基; 所述芳基酯基包括苯基酰氧基、 甲苯基酰氧基的 任一种;
所述由 C1-C18的直链或支链的垸基取代的酰氨基选自甲基酰氨基、 乙基酰 氨基、 异丙基酰氨基、 正丙基酰氨基、 烯丙基酰氨基、 环丙基酰氨基、 正丁基酰 氨基、 异丁基酰氨基、 仲丁基酰氨基、 叔丁基酰氨基、 正戊基酰氨基、 异戊基酰 氨基、 正己基酰氨基、 异己基酰氨基; 所述芳基酰氨基包括苯基酰氨基、 甲苯基 酰氨基的任一种。
4、 如权利要求 3所述的苯并五元不饱和杂环化合物或其药用盐, 其中, 所 述烃基为 C1-C6的直链垸基或支链垸基。
5、 如权利要求 1所述的苯并五元不饱和杂环化合物或其药用盐, 其中, 所 述卤代烃基、 羰基烃基、 羟基烃基、 氨基烃基、 烃氧基中的烃基为 C1-C6烃 基; 所述取代的氨基的取代基为 C2-C6垸基。
6、 如权利要求 1-5任一项所述的苯并五元不饱和杂环化合物或其药用盐, 其中, 所述苯并五元不饱和杂环化合物选自取代的苯并呋喃基 -2-取代羧酸酯、 取代的苯并噻吩基 -2-取代羧酸酯、 取代的吲哚基 -2-取代羧酸酯、 取代的苯丙呋
喃基 -2-取代酰胺、 取代的苯丙噻吩基 -2-取代酰胺的任一种。
7、 如权利要求 6所述的苯并五元不饱和杂环化合物或其药用盐, 其中, 所 述取代的苯并呋喃基中的取代基选自甲氧基、 二甲氧基、 C1-C18的烷基、 卤素、 羧基、 乙酰基、 磺酸基、 羧酸甲酯、 亚甲基二氧基、 二氨基的任一种或其组合; 所述取代的苯并噻吩基中的取代基选自甲氧基磺酸基、羧酸甲酯、亚甲基二氧基、 取代的亚甲基二氧、二氨基的任一种或其组合; 所述取代的吲哚基中的取代基选 自取代的甲氧基、 取代的二甲氧基、 二甲氧基的任一种或其组合; 所述取代的苯 丙呋喃基中的取代基选自亚甲基二氧基、羧酸甲酯的任一种或其组合; 所述取代 的苯丙噻吩基 -2-取代酰胺包括亚甲基二氧基; 所述取代羧酸酯选自羧酸 (2'-膦 酸二乙酯) 甲酯、 羧酸 (2,-膦酸二甲酯) 乙酯、 羧酸 (2,-二甲胺) 乙酯、 羧酸
(2'-二甲胺)丙酯、羧酸吡咯垸乙酯、羧酸哌啶乙酯、羧酸吗啉乙酯、羧酸(1,1- 二甲基 -2-二甲胺) 乙酯、 羧酸 [4,- (2"-羟乙基) ]哌嗪乙酯、 羧酸膦酰甲酯、 和 羧酸膦酰乙酯的任一种或其组合; 所述取代酰胺选自羧酸酰 (2,-二甲胺) 乙胺、 羧酸酰 (2'-二甲胺 -N-甲基) 乙胺、 羧酸酰 (4,-膦酰二乙酯亚甲基苯) 胺、 羧酸 酰 (4,-膦酰钠亚甲基苯) 胺的任一种或其组合。
8、 如权利要求 7所述的苯并五元不饱和杂环化合物或其药用盐, 其中, 所 述苯并五元不饱和杂环化合物或其药用盐结构包括如下化合物:
( 1 ) 6-甲氧基苯并呋喃 -2-羧酸 (2,-膦酸二乙酯) 甲酯;
(2) 6-甲氧基苯并呋喃 -2-羧酸 (2'-膦酸二甲酯) 乙酯;
(3 ) 6-甲氧基苯并呋喃 -2-羧酸 (2'-二甲胺) 乙酯;
(4) 6-甲氧基苯并呋喃 -2-羧酸 (2'-二甲胺) 丙酯;
(5 ) 6-甲氧基苯并呋喃 -2-羧酸吡咯垸乙酯;
(6) 6-甲氧基苯并呋喃 -2-羧酸哌啶乙酯;
(7) 6-甲氧基苯并呋喃 -2-羧酸吗啉乙酯;
(8) 6-甲氧基苯并呋喃 -2-羧酸 (1,1-二甲基 -2-二甲胺) 乙酯;
(9) 6-甲氧基苯并呋喃 -2-羧酸 [4,- (2"-羟乙基) ]哌嗪乙酯;
( 10) 5-甲氧基苯并呋喃 -2-羧酸膦酰乙酯;
( 11 ) 5, 6-二甲氧基苯并呋喃 -2-羧酸膦酰乙酯;
( 12) 5-氟苯并呋喃 -2-羧酸膦酰乙酯;
( 13 ) 6-甲基苯并呋喃 -2-羧酸膦酰乙酯;
( 14) 6-辛基苯并呋喃 -2-羧酸膦酰乙酯;
( 15 ) 6-羧基苯并呋喃 -2-羧酸膦酰乙酯;
( 16) 5-羧基苯并呋喃 -2-羧酸膦酰乙酯;
( 17) 6-羧基苯并呋喃 -2-羧酸 (2'-二甲胺) 乙酯;
( 18) 6-乙酰基苯并呋喃 -2-羧酸 (2'-二甲胺) 乙酯;
( 19) 5-磺酸基苯并呋喃 -2-羧酸 (2'-二甲胺) 乙酯;
(20) 6-羧酸甲酯苯并呋喃 -2-羧酸 (2'-膦酸二乙酯) 甲酯;
(21 ) 6-羧酸甲酯苯并呋喃 -2-羧酸 (2,-膦酸二甲酯) 乙酯;
(22) 6-羧酸甲酯苯并呋喃 -2-羧酸 (2'-二甲胺) 乙酯;
(23 ) 6-羧酸甲酯苯并呋喃 -2-羧酸 (2'-二甲胺) 丙酯;
(24) 6-羧酸甲酯苯并呋喃 -2-羧酸哌啶乙酯;
(25 ) 6-羧酸甲酯苯并呋喃 -2-羧酸吗啉乙酯;
(26) 6-羧酸甲酯苯并呋喃 -2-羧酸 ( 1,1,-二甲基 -2-二甲胺) 乙酯;
(27) 6-羧酸甲酯苯并呋喃 -2-羧酸 [4'- (2"-羟乙基) ]哌嗪乙酯;
(28) 5,6-亚甲基二氧苯并呋喃 -2-羧酸 (2,-膦酸二乙酯) 甲酯;
(29) 5,6-亚甲基二氧苯并呋喃 -2-羧酸 (2,-膦酸二甲酯) 乙酯;
(30) 5,6-亚甲基二氧苯并呋喃 -2-羧酸 (2,-二甲胺) 乙酯;
(31 ) 5,6-亚甲基二氧苯并呋喃 -2-羧酸 (2,-二甲胺) 丙酯;
(32 ) 5,6-亚甲基二氧苯并呋喃 -2-羧酸 [4'- (2"-羟乙基) ]哌嗪乙酯;
(33 ) 5,6-亚甲基二氧苯并呋喃 -2-羧酸吗啉乙酯;
(34) 6-羧酸乙酯苯并呋喃 -2-羧酸 (2,-二甲胺) 丙酯;
(35) 5,6-二氨基苯并呋喃 -2-羧酸 (2'-二甲胺) 丙酯;
(36) 6-甲氧基苯并噻吩 -2-羧酸 (2,-膦酸二乙酯) 甲酯;
(37) 6-甲氧基苯并噻吩 -2-羧酸 (2'-膦酸二甲酯) 乙酯;
(38) 6-甲氧基苯并噻吩 -2-羧酸 (2'-二甲胺) 乙酯;
(39) 6-甲氧基苯并噻吩 -2-羧酸 (2'-二甲胺) 丙酯;
(40) 6-甲氧基苯并噻吩 -2-羧酸吗啉乙酯;
(41 ) 6-甲氧基苯并噻吩 -2-羧酸 [4'- (2"-羟乙基) ]哌嗪乙酯;
(42) 6-甲氧基苯并呋喃 -2-羧酸膦酰甲酯;
(43) 6-甲氧基苯并呋喃 -2-羧酸膦酰乙酯;
(44) 6-羧酸甲酯苯并噻吩 -2-羧酸 (2,-膦酸二乙酯) 甲酯;
(45 ) 6-羧酸甲酯苯并噻吩 -2-羧酸 (2'-膦酸二甲酯) 乙酯;
(46) 6-羧酸甲酯苯并噻吩 -2-羧酸 (2'-二甲胺) 乙酯;
(47) 6-羧酸甲酯苯并噻吩 -2-羧酸 (2'-二甲胺) 丙酯;
(48) 6-羧酸甲酯苯并噻吩 -2-羧酸 [4,- (2"-羟乙基) ]哌嗪乙酯;
(49) 6-羧酸甲酯苯并噻吩 -2-羧酸吗啉乙酯;
(50) 6-磺酸基苯并噻吩 -2-羧酸 (2'-二甲胺) 乙酯;
(51 ) 6-二乙氨基-苯并噻吩 -2-羧酸 (2'-二甲胺) 乙酯;
(52) 5,6-亚甲基二氧苯并噻吩 -2-羧酸 (2,-膦酸二乙酯) 甲酯;
(53 ) 5,6-亚甲基二氧苯并噻吩 -2-羧酸 (2,-膦酸二甲酯) 乙酯;
(54) 5,6-亚甲基二氧苯并噻吩 -2-羧酸 (2'-二甲胺) 乙酯;
(55 ) 5,6-亚甲基二氧苯并噻吩 -2-羧酸 (2,-二甲胺) 丙酯;
(56) 5,6-亚甲基二氧苯并噻吩 -2-羧酸 [4,- (2"-羟乙基) ]哌嗪乙酯;
(57) 5,6-亚甲基二氧苯并噻吩 -2-羧酸吗啉乙酯;
(58) 5,6-乙基亚甲基二氧苯并噻吩 -2-羧酸膦酰乙酯;
(59) 5,6-(2,-氯乙基)亚甲基二氧苯并噻吩 -2-羧酸膦酰乙酯;
(60) 5,6-(1,-羟乙基)亚甲基二氧苯并噻吩 -2-羧酸膦酰乙酯;
(61 ) 5,6-(1,-氨乙基)亚甲基二氧苯并噻吩 -2-羧酸膦酰乙酯;
(62) 5,6-(1,-甲氧基乙基)亚甲基二氧苯并噻吩 -2-羧酸膦酰乙酯;
(63 ) 5,6-二甲氧基 -吲哚 -2-羧酸膦酰甲酯;
(64) N-乙酰基 -5,6-二甲氧基 -吲哚 -2-羧酸 (2,-二甲胺) 乙酯;
(65 ) N-甲基 -5,6-二甲氧基 -U引哚 -2-羧酸膦酰乙酯;
(66) N-甲基 -5,6-二甲氧基 -吲哚 -2-羧酸 (2'-二甲胺) 丙酯;
( 67 ) N-甲基 -5,6-二甲氧基 -吲哚 -2-羧酸吗啉乙酯;
(68) N- (2'-羟乙基) -5-甲氧基 -吲哚 -2-羧酸 (2,-二甲胺) 乙酯;
(69) N- (2'-甲氧乙基) -6-甲氧基 -吲哚 -2-羧酸 (2,-二甲胺) 乙酯;
(70) N- (乙酸甲酯) -5-甲氧基 -吲哚 -2-羧酸 (2'-二甲胺) 乙酯;
(71 ) 5,6-亚甲基二氧苯丙呋喃 -2-羧酸酰 (2,-二甲胺) 乙胺;
(72) 5,6-亚甲基二氧苯丙呋喃 -2-羧酸酰 (2,-二甲胺 -N-甲基) 乙胺;
(73 ) 5,6-亚甲基二氧苯丙噻吩 -2-羧酸酰 (2'-二甲胺) 乙胺;
(74) 5,6-亚甲基二氧苯丙噻吩 -2-羧酸酰 (2,-二甲胺 -N-甲基) 乙胺;
(75) 5,6-亚甲基二氧苯丙呋喃 -2-羧酸酰(4'-膦酰二乙酯亚甲基苯)胺;
(76) 5,6-亚甲基二氧苯丙呋喃 -2-羧酸酰 (4,-膦酰钠亚甲基苯) 胺;
(77) 5,6-亚甲基二氧苯丙噻吩 -2-羧酸酰 (4,-膦酰二乙酯亚甲基苯)胺;
(78) 5,6-亚甲基二氧苯丙噻吩 -2-羧酸酰 (4,-膦酰钠亚甲基苯) 胺;
(79) 5,6-亚甲基二氧苯并呋喃 -2-羧酸膦酰甲酯;
(80) 5,6-亚甲基二氧苯并呋喃 -2-羧酸膦酰乙酯;
(81 ) 6-甲氧基苯并噻吩 -2-羧酸膦酰甲酯;
(82) 6-甲氧基苯并噻吩 -2-羧酸膦酰乙酯;
(83 ) 5,6-亚甲基二氧苯并噻吩 -2-羧酸膦酰甲酯;
(84) 5,6-亚甲基二氧苯并噻吩 -2-羧酸膦酰乙酯;
(85 ) 6-羧酸甲酯苯并呋喃 -2-羧酸膦酰甲酯;
(86) 6-羧酸甲酯苯并呋喃 -2-羧酸膦酰乙酯;
(87) 6-羧酸甲酯苯并噻吩 -2-羧酸膦酰甲酯;
(88) 6-羧酸甲酯苯并噻吩 -2-羧酸膦酰乙酯。
9、 一种权利要求 1-8任一项所述的苯并五元不饱和杂环化合物或其药用盐 的制备方法, 包括如下步骤:
步骤 1): 将结构如式 II所示的取代苯甲醛、 结构如式 VI所示的取代的乙酸 乙酯置于非质子溶剂中, 加入无机碱, 在 0°C -60°C条件下, 搅拌反应后, 制得 中间体 ΠΙ;
R4 R3
CHO R
Rio 11 R3
M O R
X 11
R R O
II III
III IV
其中, M为 OH或 N02; X为 0、 S或 NR8; , R2, R3, R4, R5, , R7, R8的定义同权利要求 1 ; R1Q为巯基或卤素; Rn选自 C1-C18的烃氧基; 所 述取代的乙酸乙酯的结构通式 VI为:
R3
R
R10、〜
0 VI。
10、 如权利要求 9所述的制备方法, 其中, 所述非质子溶剂为 DMF; 所述 无机碱为无水 K2C03 ; 所述碱性水溶液为 NaOH水溶液; 所述脱水剂为 DIC、 DMAP的任一种或其组合; 所述取代的羟基化合物的结构如通式 VII所示:
VII。
11、一种权利要求 1-8任一项所述的苯并五元不饱和杂环化合物或其药用盐 的制备方法, 所述方法包括如下步骤:
步骤 2):当通式 I结构中 Y为 '时,中间体 III在碱性水溶液中水解后, 在二氯亚砜作用下,加热回流形成酰氯,再在 0°C下,加入缚酸剂得到混合液; 在常温下, 该混合液与取代的氨基化合物反应, 反应完成后, 分离纯化得到 目标化合物 V,
R4
R5 R3
2:
base^ S02CI^ f¾ 」
Rfi X 、 N Re X
R7 O R,
R7
III V 其中, M为 OH或 N02; X为 0、 S或 NR8; , R2, R3, , R5, , R7, 的定义同权利要求 1 ; R1()为巯基或卤素; Rn选自 C1-C18的烃氧基; 所 述取代的乙酸乙酯的结构通式 VI为:
R3 N
Rio、 Rl 1
ο VI。
12、 如权利要求 11所述的制备方法, 其中, 步骤 1中, 所述非质子溶剂为 DMF; 所述无机碱为无水 K2C03 ; 所述碱性水溶液为 NaOH水溶液; 所述缚酸 剂为三乙胺、 二氯甲垸的任一种或其组合; 所述取代的氨基化合物的结构如通 式 VIII所示:
R2 VIII。
13、一种用于抗骨质疏松的药物组合物, 所述药物组合物中含有治疗有效量 的如权利要求 1-8任一项所述的苯并五元不饱和杂环化合物或其药用盐与药学上 可接受的载体。
14、 如权利要求 13所述的药物组合物, 所述苯并五元不饱和杂环化合物或 其药用盐在药物组合物中的含量为 0.1wt.%-99.5wt.%, 优选为 0.5wt.%-95wt.%。
15、权利要求 1-8任一项所述的苯并五元不饱和杂环化合物或其药用盐或权 利要求 13-14任一项所述的药物组合物在制备抗骨质疏松的药物中的应用。
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