CN1112116A - 新的磺酰氨基二噁庚环及其制备方法,中间体,盐和用途 - Google Patents
新的磺酰氨基二噁庚环及其制备方法,中间体,盐和用途 Download PDFInfo
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- CN1112116A CN1112116A CN95102741A CN95102741A CN1112116A CN 1112116 A CN1112116 A CN 1112116A CN 95102741 A CN95102741 A CN 95102741A CN 95102741 A CN95102741 A CN 95102741A CN 1112116 A CN1112116 A CN 1112116A
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- 150000003839 salts Chemical class 0.000 title claims description 35
- 238000000034 method Methods 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title claims description 10
- 239000000543 intermediate Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- -1 hydroxylamino Chemical group 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 12
- 239000011707 mineral Substances 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 206010012601 diabetes mellitus Diseases 0.000 claims description 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000007524 organic acids Chemical class 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
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- QECVIPBZOPUTRD-UHFFFAOYSA-N N=S(=O)=O Chemical compound N=S(=O)=O QECVIPBZOPUTRD-UHFFFAOYSA-N 0.000 claims description 2
- 238000006136 alcoholysis reaction Methods 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000001118 alkylidene group Chemical group 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims 1
- 229920001577 copolymer Chemical group 0.000 claims 1
- 230000002218 hypoglycaemic effect Effects 0.000 abstract description 3
- ZHKJHQBOAJQXQR-UHFFFAOYSA-N 1H-azirine Chemical compound N1C=C1 ZHKJHQBOAJQXQR-UHFFFAOYSA-N 0.000 abstract 1
- HTJXZCZFMUOOFW-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-[1,3]dioxepino[5,6-d][1,3]oxazole Chemical compound C1OCOC=C2OCNC21 HTJXZCZFMUOOFW-UHFFFAOYSA-N 0.000 abstract 1
- XYYAFYBVUUMOTF-UHFFFAOYSA-N 3,5,8-trioxabicyclo[5.1.0]octane Chemical compound C1OCOCC2OC21 XYYAFYBVUUMOTF-UHFFFAOYSA-N 0.000 abstract 1
- AGNSCOWWQUDEGE-UHFFFAOYSA-N 6-amino-1,3-dioxepan-5-ol Chemical compound NC1COCOCC1O AGNSCOWWQUDEGE-UHFFFAOYSA-N 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 208000033641 Ring chromosome 5 syndrome Diseases 0.000 description 11
- 229960001413 acetanilide Drugs 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 235000010755 mineral Nutrition 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001733 carboxylic acid esters Chemical class 0.000 description 3
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 3
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 3
- 150000003457 sulfones Chemical class 0.000 description 3
- 150000003462 sulfoxides Chemical class 0.000 description 3
- 238000009834 vaporization Methods 0.000 description 3
- 230000008016 vaporization Effects 0.000 description 3
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229910052728 basic metal Inorganic materials 0.000 description 2
- 150000003818 basic metals Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- YFLKVSOKVKZERQ-UHFFFAOYSA-N 4-acetyl-4-aminocyclohexa-1,5-diene-1-sulfonyl chloride Chemical compound CC(=O)C1(N)CC=C(S(Cl)(=O)=O)C=C1 YFLKVSOKVKZERQ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- IZVRAXUGTRXXMC-UHFFFAOYSA-N C(C)(=O)NC1=CC=CC(=C1[As](O)(O)=O)O Chemical compound C(C)(=O)NC1=CC=CC(=C1[As](O)(O)=O)O IZVRAXUGTRXXMC-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000006704 dehydrohalogenation reaction Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002916 oxazoles Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 150000003112 potassium compounds Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
- C07D321/02—Seven-membered rings
- C07D321/04—Seven-membered rings not condensed with other rings
- C07D321/06—1,3-Dioxepines; Hydrogenated 1,3-dioxepines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
新的具有降血糖活性的0-取代或0-未取代的
6-磺酰氨基-1,3-二氧杂庚环-5-醇,它是由6-氨
基-1,3-二氧杂庚环-5-醇,四氢-6H-[1,3]-二氧杂
庚英并[5,6-d]噁唑,5,6-环氧-1,3-二氧杂庚环或
N-磺酰基-四氢-1H,4H-[1,3]-二氧杂庚环并[5,
6-b]丙啶作为起始原料得到的。
Description
本发明涉及新的磺酰氨基二噁庚环,其制备方法和中间体,其盐,以及含新化合物的药物制剂及它们的用途。
通式Ⅰ化合物及迄今未知的其生理上可接受的盐
其中
R1和R2表示氢原子,具有1-4个碳原子的直链或支链烷基或苯基,或
R1+R2一起表示具有4-6个碳原子的亚烷基
R3表示具有1-4个碳原子的直链或支链烷基,具有1-4个碳原子的直链或支链的单-至全氟代烷基,及邻,间或对位取代的苯基
其中
X表示氢原子,具有1-4个碳原子的直链或支链低级烷基,三氟甲基,原子序数为9-53的卤原子,羟基,烷氧基,氨基,烷基-或二烷基氨基,酰氨基或羟氨基,及
Y表示氢原子,具有1-4个碳原子的直链或支链低级烷基,苄基或磺酰基
-SO2-R3
其中
R3定义如上或表示酰基
-CO-R4
其中
R4表示具有1-4个碳原子的低级直链或支链烷基或苄基。
现已发现这些化合物具有有益的药理性能,特别是可降低血糖活性,其施用途径也是任意的,可通过静脉,皮下或口服施用,降血糖活性已通过对热血动物,如小鼠,的标准试验测定。
在通式Ⅰ化合物中,烷基和烷氧基表示甲基,乙基,丙基,异丙基,丁基,异丁基,仲丁基,和叔丁基,以及甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,仲丁氧基,叔丁氧基和异丁氧基,酰基是由脂肪酸,芳基脂肪酸,或芳香羧酸衍生得到的,所述酸例如甲酸,乙酸,丙酸,丁酸,苯乙酸或苯甲酸。
通式Ⅰ的新化合物与碱形成盐,这也是本发明的主题,这些盐的实例为碱金属和碱土金属盐,如钠盐,钾盐,镁盐或钙盐。
新的通式Ⅰ化合物可根据本发明的第一方法通式Ⅱ化合物
其中
R1,R2和Y定义如上
与通式Ⅲ的磺酸活性衍生物缩合而制备
其中
R3定义如上及
Z代表原子序数为9-17的卤原子或-OSO2R3,其中R3定义如上。
该反应是在与水混溶或与水不混溶的惰性有机溶剂中,有水或无水条件下,有或没有无机或有机酸结合剂情况下,在-50-+50℃,优选-10-+10℃,下进行,并且,任选的使用所得化合物与无机碱或金属醇化物反应转化成其药理上可接受的盐。
合适的惰性溶剂为例如,烃如甲苯和二甲苯,具有直到6个碳原子的低级醇如甲醇或乙醇,醚如二乙醚,二噁烷或四氢呋喃,氯代烃如二氯甲烷或氯仿,具有直到6个碳原子的低级酮如甲基乙基酮或甲基异丙基酮,羧酸酯如乙酸乙酯,羧酸酯如乙酸乙酯,羧酸腈如乙腈,酰胺如二甲基甲酰胺或HMPT,亚砜如二甲亚砜,砜如环丁砜。
合适的无机碱,可以使用碱金属和碱土金属的氢氧化物,碳酸氢盐,碳酸盐或磷酸盐,如可采用钠或钾及镁或钙的化合物,合适的有机碱为叔胺如三乙胺,二甲苯胺,吡啶,DBN或DBU。
合适的通式Ⅱ起始原料为根据通式Ⅰ中符号R1,R2和Y定义适当限定的化合物,其中一组起始原料为6-氨基-1,3-二氧杂庚环-5-醇,它们很容易制备,例如可通过水解适当的6-乙酰氨基-5-氯-1,3-二氧杂庚环(M.Sovak and R.Ranganathan,US 4389526)及氨解环氧-1,3二氧庚环(M.Sovak and R.Ranganathan,EP33426;A.V.Rama Rao et al,Indian J.Chem.22B(1983)419)而制备。
根据本发明的第二方法,新的通式Ⅰ化合物可通过通式Ⅳ的噁唑啉
其中
R1,R2和R4定义如上
与通式Ⅲ磺酸活性衍生物反应
其中
R3和Z定义如上,
该反应是在非水惰性有机溶剂中,在无机或有机酸结合剂存在下进行,并且任选的可水解或醇解所得的通式Ⅰ衍生物(Y=-COR4)制备通式Ⅰ衍生物(Y=H),及任选的使所得的化合物与无机碱或金属醇化物反应转化成其药物上可接受的盐,进行这个过程的方法与第一方法过程相同,只是本过程是在非水介质中进行的。
合适的通式Ⅳ起始原料为根据通式Ⅰ符号R1,R2和R4的定义适当限定的化合物。
它们可很容易的通过相应的6-酰氨基-5-氯-1,3-二氧庚环脱卤化氢成环(cyclisation)而制备,(M.Dumicet al.,Org Prep.Proced.Int.24,(1992)536 and ibid.25,(1992)373)。
根据本发明的第三种方法,新的通式Ⅰ化合物可通过通式Ⅴ的环氧化物
其中
R1和R2定义如上
与通式Ⅵ的磺酰氨反应而制备
其中
R3定义如上
该反应可通过在惰性有机溶剂存在或不存在的条件下,惰性有机溶剂例如,芳香烃如甲苯或二甲苯,氯代烃如二氯甲烷,氯仿或二氯乙烷,羧酸酯如乙酸乙酯,醚如二异丙基醚或二噁烷,酰胺如二甲基甲酰胺,二甲基乙酰氨或HMPT,亚砜如二甲亚砜或砜如环丁砜,在温度25-300℃和优选100-200℃下将两种反应物一起加热,并且,及任选的使用所得的化合物与无机碱或金属醇化物反应转化成其药理上可接受的盐。
合适的起始原料通式Ⅴ为根据通式Ⅰ符号R1和R2的定义适当限定的化合物,它们可很容易的通过适当的二氢二噁庚英(dihydrodioxepines)的环氧化反应制备。(J.Soukier et al.,C.R.Acad.Sci.Ser.C.280,(1975)601;W.J.Elliot et al.,J.Org.Chem.41,(1976)2469;A.J.Biloski,Synthesis 1980,810)。
根据本发明的第四种方法,新的通式Ⅰ化合物可通过通式Ⅶ的N-磺酰基-二噁庚因并丙啶(dioxepinoazirines)
其中
R1,R2和R3定义如上
在水或与水混溶的有机溶剂中,在无机碱的存在下,在0-150℃优选50-100℃温度下进行水解,并且,任选的,使所得的化合物与无机碱或金属醇化物反应转化成其药物上可接受的盐。
作为有机溶剂,可为具有多达6个碳原子的醇如甲醇或乙醇或叔丁醇,醚如二噁烷或四氢呋喃,氯代烃如二氯甲烷或氯仿,酮如丙酮,酰胺如二甲基甲酰胺或HMPT,胺如吡啶,亚砜如二甲亚砜,或砜如环丁砜。作为碱,可用碱金属的氢氧化物或碳酸盐,如锂,钠或钾化合物。
合适的起始原料通式Ⅶ为根据通式Ⅰ符号R1,R2和R3的定义适当限定的化合物,它们可通过适当的二噁庚英并丙啶的磺化制备。(M.Dumic at al.,Wo 9304967:Tetrahedron Lett.34(1993)3639)。
任选的,可将根据本发明方法(1-4)得到的新的通式Ⅰ化合物与等摩尔量的无机碱,碱金属氢氧化物如氢氧化钠,或碱金属醇化物如甲醇钠,在惰性有机溶剂如甲醇,乙醇,丙酮,甲苯,二异丙基醚中反应,转化成其药物上可接受的盐。
根据本发明方法得到的新的通式Ⅰ化合物及其药物上可接受的盐在由链尿菌素:(streptozotocine)引起的小鼠糖尿病模型中显示明显以致强烈的降血糖活性,其施用途径也是任意的,可通过静脉,皮下或口服施用。例如,在给由链尿菌素(streptozotocine)引起糖尿病的小鼠以20mg/kg剂量皮下施用顺-6-磺胺基-1,3-二噁庚环-5-醇4小时后,葡萄糖浓度降低16.6%,即其葡萄糖水平是对照组高血糖动物的83.4%
从以上看来,新的通式Ⅰ磺酰氨基二噁庚环及其药物上可接受的盐是有效的降血糖剂,并且通过普通的制药工艺,可将其转化成适当的药物制剂如片剂,丸剂,粉剂,胶囊剂,粒剂,及溶液等,它们对于糖尿病(diabetes mellitus)的治疗具有短期或长期活性。
通过下述实施例说明本发明而不是以任何方式限制本发明。
实施例1
将反-6-氨基-1,3-二氧杂庚环-5-醇(0.30g),4-乙酰基-氨基苯磺酰氯(0.58g),吡啶(0.40ml)和二氯甲烷(10.0ml)的混合物在0℃搅拌60分钟,减压蒸去溶剂后,蒸发后所得残留物在硅胶柱色谱上纯化,以乙酸乙酯洗脱。得到反-6-(4-乙酰氨基苯磺酰氨基)-1,3-二氧杂庚环-5-醇,M.P.210-211.℃/乙酸乙酯-甲醇(9.5∶0.5)。
实施例2
将顺-2-甲基-3a,4,8,8a-四氢-6H-[1,3]-二氧杂庚英并-[5,6-d]噁唑(1.00g),4-乙酰基-氨基苯磺酰氯(1.50g),吡啶(1.05ml)和二氯甲烷(60.0ml)的混合物在室温搅拌90分钟。加水(10.0ml),在同样温度下将反应混合物再搅拌15分钟,用二氯甲烷提取产物,提取物用无水硫酸钠干燥,减压蒸去二氯甲烷后,蒸发残留物在硅胶柱色谱上纯化,以乙酸乙酯/甲醇的混合物洗脱(9.8∶0.2)。
得到顺-6-(4-乙酰氨基苯磺酰氨基)-5-乙酰氧基-1,3-二氧杂庚环,M.P.184-186.℃/乙酸乙酯-甲醇(6∶1)。
将顺-6-(4-乙酰氨基苯磺酰氨基)-1,3-二氧杂庚环(0.150g),25%氨水(3.0ml)和96%乙醇(6.0ml)的混合物在室温下搅拌3小时,然后将所得的混合物减压蒸发至干,用乙酸乙酯/甲醇(1∶1)的混合物重结晶蒸发残留物,得到顺-6-(4-乙酰氨基苯磺酰氨基)-1,3-二氧杂庚环-5-醇,m.p.161-163℃。
实施例3
将5,6-环氧-1,3-二氧杂庚环(0.5g)和4-乙酰氨基苯磺酰胺(0.92g)的混合物在密闭的安瓿中于150℃加热15分钟,将所得混合物冷至室温,在硅胶柱色谱上纯化,以乙酸乙酯/甲醇(9.5∶0.5)的混合物洗脱,得到反-6-(4-乙酰氨基苯磺酰氨基)-1,3-二氧杂庚环-5-醇,M.P.208-210.℃/乙酸乙酯-甲醇(6∶1)。
实施例4
将1-(4-乙酰氨基苯磺酰基)-4,4-二甲基-,1a,2,6,6a-四氢-1H,4H-[1,3]-二氧杂庚英并[5,6-b]丙啶(0.33g),氢氧化钾(0.14g)和水(2.6ml)的混合物加热回流60分钟。将混合物冷至室温后,用稀盐酸酸化至PH 6.5并减压蒸发至干。在硅胶柱色谱上纯化残留物,以乙酸乙酯/甲醇(9.8∶0.2)的混合物洗脱。得到反-6-(4-乙酰氨基苯磺酰氨基)-2,2-二甲基-1,3-二氧杂庚环-5-醇,m.p.203-205.℃/二氯甲烷-甲醇(9∶1),及反-6-磺胺基-2,2-二甲基-1,3-二氧杂庚环-5-醇。
实施例5
将1-(4-乙酰氨基苯磺酰基)-1a,2,6,6a-四氢-1H,4H-[1,3]-二氧杂庚英并[5,6-b]丙啶(0.30g),氢氧化钾(0.10g)和水(2.5ml)的混合物加热回流60分钟。将混合物冷至室温后,用稀盐酸酸化至PH6.5并减压蒸发至干,在硅胶柱色谱上纯化残留物,以二氯甲烷-甲醇(10∶1)的混合物洗脱。
得到反-6-(4-乙酰氨基苯磺酰氨基)-1,3-二氧杂庚环-5-醇,m.p.209-211.℃/乙酸乙酯-甲醇(1∶1),及反-6-磺胺基-1,3-二氧杂庚环-5-醇.162-164.℃/乙酸乙酯-甲醇(1∶1)。
实施例6
向顺-6-氨基-1,3-二氧杂庚环-5-醇(0.30g)与吡啶(0.4ml)的二氯甲烷(10.0ml)的混合物中,于90分钟内0℃滴加入4-乙酰氨基苯磺酰氯(0.58g)的二氯甲烷溶液(35.0ml),随后在同样的温度下再搅拌混合物15分钟并减至蒸发至干,在硅胶柱色谱上纯化蒸发残留物,以二氯甲烷-甲醇(8∶2)的混合物洗脱。
得到顺-6-(4-乙酰氨基苯磺酰氨基)-1,3-二氧杂庚环-5-醇,m.p.159-161.℃/乙酸乙酯-甲醇(2∶1)。
Claims (19)
1、通式Ⅰ化合物及其生理上可接受的盐
其中
R1和R2表示氢原子,具有1-4个碳原子的直链或支链烷基或苯基,或
R1+R2一起表示具有4-6个碳原子的亚烷基,
R3表示具有1-4个碳原子的直链或支链烷基,具有1-4个碳原子的直链或支链的单至全氟代烷基,及邻,间或对位取代的苯基,
其中
X表示氢原子,具有1-4个碳原子的直链或支链低级烷基,三氟甲基,原子序数为9-53的卤原子,羟基,烷氧基,氨基,烷基一或二烷基氨基,酰氨基或羟氨基,及
Y表示氢原子,具有1-4个碳原子的直链或支链低级烷基,苄基或磺酰基
-SO2R3
其中
R3定义如上或表示酰基
-CO-R4
其中
R4表示具有1-4个碳原子的直链或支链低级烷基或苄基。
2、根据权利要求1的化合物及其药物上可接受的盐,其特征为R1=R2=H,顺式,Y=H,R3=4-CH3CONH-C6H4-。
3、根据权利要求1的化合物及其药物上可接受的盐,其特征为R1=R2=H,反式,Y=H,R3=4-CH3CONH-C6H4-。
4、根据权利要求1的化合物及其药物上可接受的盐,其特征为R1=R2=H,顺式,Y=H,R3=4-H2N-C6H4-。
5、根据权利要求1的化合物及其药物上可接受的盐,其特征为R1=R2=H,反式,Y=H,R3=4-H2N-C6H4-。
6、根据权利要求1的化合物及其药物上可接受的盐,其特征为R1=R2=H,顺式,Y=H,R3=C6H5-。
7、根据权利要求1的化合物及其药物上可接受的盐,其特征为R1=R 2 =H,反式,Y=H,R3=C6H5-。
8、根据权利要求1的化合物及其药物上可接受的盐,其特征为R1=R2=H,顺式,Y=H,R3=CH3-。
9、根据权利要求1的化合物及其药物上可接受的盐,其特征为R1=R2=H,反式,Y=H,R3=CH3-。
10、根据权利要求1的化合物及其药物上可接受的盐,其特征为R1=R2=CH3-,顺式,Y=H,R3=4-H2N-C6H4-
11、根据权利要求1的化合物及其药物上可接受的盐,其特征为R1=R2=CH3-,反式,Y=H,R3=4-H2N-C6H4-
12、根据权利要求1的化合物及其药物上可接受的盐,其特征为R1=R2=CH3-,顺式,Y=H,R3=4-H2N-C6H4-R3=4-CH3CONH-C6H4-
13、根据权利要求1的化合物及其药物上可接受的盐,其特征为R1=R2=CH3-,反式,Y=H,R3=4-H2N-C6H4-R3=4-CH3CONH-C6H4-
18、权利要求1-13化合物作为中间体合成降血糖剂的用途。
19、用于治疗糖尿病的药物制剂,其特征在于含有权利要求1-13通式Ⅰ磺酰氨化合物作为活性成分。
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EP1935879B1 (en) * | 2005-09-14 | 2016-05-11 | Daiichi Sankyo Company, Limited | Substituted cycloalkene derivative |
ES2688058T3 (es) * | 2011-11-10 | 2018-10-30 | Aratana Therapeutics Nv | Método para preparar derivados de ciclopropano |
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CN108787177B (zh) * | 2018-08-07 | 2024-03-15 | 中南大学 | 淤浆法制备黄原酸盐的方法及系统 |
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RU95102322A (ru) | 1996-12-20 |
CA2142920C (en) | 1999-08-17 |
RO113856B1 (ro) | 1998-11-30 |
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