CN1045106A - 含硫杂环化合物 - Google Patents
含硫杂环化合物 Download PDFInfo
- Publication number
- CN1045106A CN1045106A CN89109626A CN89109626A CN1045106A CN 1045106 A CN1045106 A CN 1045106A CN 89109626 A CN89109626 A CN 89109626A CN 89109626 A CN89109626 A CN 89109626A CN 1045106 A CN1045106 A CN 1045106A
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- CN
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- Prior art keywords
- compound
- phenyl
- group
- substituted
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 Sulfur heterocyclic compound Chemical class 0.000 title claims abstract description 135
- 229910052717 sulfur Inorganic materials 0.000 title claims abstract description 13
- 239000011593 sulfur Substances 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 124
- 238000000034 method Methods 0.000 claims abstract description 90
- 150000003839 salts Chemical class 0.000 claims abstract description 76
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 26
- 238000002360 preparation method Methods 0.000 claims abstract description 23
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 16
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
- 239000001257 hydrogen Substances 0.000 claims abstract description 11
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical group 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 230000003647 oxidation Effects 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 6
- 230000009435 amidation Effects 0.000 claims 2
- 238000007112 amidation reaction Methods 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 210000000988 bone and bone Anatomy 0.000 abstract description 31
- 238000010521 absorption reaction Methods 0.000 abstract description 7
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 80
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 74
- 238000006243 chemical reaction Methods 0.000 description 63
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- 239000002904 solvent Substances 0.000 description 46
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
- 239000000203 mixture Substances 0.000 description 44
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 36
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 36
- 238000001035 drying Methods 0.000 description 35
- 239000010410 layer Substances 0.000 description 35
- 238000004458 analytical method Methods 0.000 description 34
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 33
- 238000005406 washing Methods 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
- 229910052760 oxygen Inorganic materials 0.000 description 30
- 239000001301 oxygen Substances 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- 238000003756 stirring Methods 0.000 description 29
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 28
- 239000002585 base Substances 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- 238000003810 ethyl acetate extraction Methods 0.000 description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 23
- 239000003513 alkali Substances 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 150000002148 esters Chemical class 0.000 description 21
- 235000019441 ethanol Nutrition 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 18
- 238000001953 recrystallisation Methods 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 17
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- 125000002252 acyl group Chemical class 0.000 description 15
- 239000000460 chlorine Substances 0.000 description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- 238000010025 steaming Methods 0.000 description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 12
- 239000011575 calcium Substances 0.000 description 12
- 125000000623 heterocyclic group Chemical group 0.000 description 12
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 11
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 10
- 238000009835 boiling Methods 0.000 description 10
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 10
- 229920004449 Halon® Polymers 0.000 description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 9
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 9
- 229910052500 inorganic mineral Inorganic materials 0.000 description 9
- 235000010755 mineral Nutrition 0.000 description 9
- 239000011707 mineral Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 8
- 125000003710 aryl alkyl group Chemical group 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 8
- 235000008504 concentrate Nutrition 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 230000035484 reaction time Effects 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 229910052791 calcium Inorganic materials 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 230000032050 esterification Effects 0.000 description 6
- 238000005886 esterification reaction Methods 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 150000007530 organic bases Chemical class 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 235000015320 potassium carbonate Nutrition 0.000 description 6
- 235000011118 potassium hydroxide Nutrition 0.000 description 6
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 6
- 239000008096 xylene Substances 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- 241000790917 Dioxys <bee> Species 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- 150000003462 sulfoxides Chemical class 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 229940073608 benzyl chloride Drugs 0.000 description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- 229910052698 phosphorus Inorganic materials 0.000 description 4
- 239000011574 phosphorus Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 150000003222 pyridines Chemical class 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 210000000689 upper leg Anatomy 0.000 description 4
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000005864 Sulphur Substances 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 125000004423 acyloxy group Chemical group 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000004898 kneading Methods 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 3
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- 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 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 125000003944 tolyl group Chemical group 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- WIHIUTUAHOZVLE-UHFFFAOYSA-N 1,3-diethoxypropan-2-ol Chemical compound CCOCC(O)COCC WIHIUTUAHOZVLE-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- YNWXVXXRJDFANW-UHFFFAOYSA-N C[SiH](C)C.I(=O)(=O)O Chemical compound C[SiH](C)C.I(=O)(=O)O YNWXVXXRJDFANW-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
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- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
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- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 1
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- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
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- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
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- 210000000115 thoracic cavity Anatomy 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 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
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- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- 239000011710 vitamin D Substances 0.000 description 1
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- 230000003442 weekly effect Effects 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
-
- 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
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- 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
-
- 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
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- 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
- A61P3/02—Nutrients, e.g. vitamins, minerals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D335/08—Naphthothiopyrans; Hydrogenated naphthothiopyrans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
- C07D337/02—Seven-membered rings
- C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D337/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
-
- 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
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Abstract
本发明提供通式(I)代表的含硫杂环化合物或其相应盐。
其中,环A为可被取代的苯环,R为氢或可被取代的烃基;B为可被酯化或酰胺化的羧基,X为-CH(OH)-或-CO-;K为0或1,K′为0,1或2。
同时,也提供了制备化合物(I)或其相应盐和用于治疗骨质疏松症的含有化合物(I)或其相应盐的制剂的方法。
化合物(I)及相应盐具有极好的骨重吸收抑制活性。
Description
本发明涉及用于治疗骨质疏松症的含硫杂环化合物及其相应的盐。
本发明中的化合物及其盐具有骨重吸收抑制活性,它们可抑制由于钙从骨向血中释放而造成的骨的定量消耗。
骨质疏松症是一种由于骨中的钙流失到血中而造成骨质减少的疾病,它使得骨质脆弱,易于骨折。
骨质疏松症的主要症状是驼背及胸椎骨,腰椎骨、股骨颈、桡骨远端、肋骨、肱骨近端等的骨折,引起这些疾病的原因可从内分泌不调到营养不调。这种病例所用的药物为:雌激素,降钙素(钙调节激素),维生素D,钙制剂等。
然而,这些治疗方法并不能对这些症状充分有效,可治疗的病人有限,而且它们不能确实有效地防止或减轻骨质损失。
(1)通式(Ⅰ)含硫的杂环化合或其药用盐
其中环A是可取代的苯环;R是氢原子或可取代的烃;B是可酯化或酰化的羧基,X是-CH(OH)-或-CO-;K是0或1;K′是0,1或2。
(2)制备式(Ⅰ)或其药用盐方法,其特征为:
(ⅰ)将通式(Ⅱ)化合物或其药用盐
其中,B′是酯化的羧基;Y是羟基或卤原子,其它符号如上所述,进行环化,如需要,可进一步氧化或水解,随后通过酰化水解或通过酰化和氧化水解,从而制成通式(Ⅰa)的含硫杂环化合物
其中式中每一符号如上定义,或
(ⅱ)还原上面的通式(Ⅰa)化合物或其药用盐,从而制成式(Ⅰb)含硫杂环化合物,
其中,式中每一符号如上定义。
(3)用于治疗骨质疏松症的药物制剂,该制剂包括有效量的抗骨质疏松症的化合物(Ⅰ)或其药用盐。
在式(Ⅰ)中,取代基或在环A上的取代基,(例如:可被取代的苯环)包括:卤素、硝基,可被取代的烷基,可被取代的羟基,可被取代的硫羟基,氨基,酰基,单或二烷氧磷酰基,膦酰基,可被取代的烷氧基,可被取代的芳烷基或可被取代的芳香杂环基,苯环可为1~4个取代基所取代,优选为1~2个取代基取代,取代基可相同或不同。
以上提到的卤素包括氟、氯、溴、碘。烷基或被取代烷基的烷基部分,优选含有1~10个碳原子的直链或支链的烷基,例如:甲基,乙基,丙基,异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基、庚基、辛基、壬基、癸基等;含有3~7碳的环烷基,如环丙基、环丁基、环乙基、环庚基等,这些基团可为1~3个取代基取代,这些取代基包括卤素(氟、氯、溴、碘),羟基,1~6碳的烷氧基(甲氧基、乙氧基、丙氧基、丁氧基和己氧基),单或二(1~6碳烷氧)磷酰基,膦酰基等。
被取代了烷基的特例包括:三氟甲基,三氟乙基,三氯甲基,羟甲基,2-羟乙基,甲氧乙基,1-甲氧乙基,2-甲氧乙基,2,2-二乙氧乙基,2-二乙氧磷酰乙基,2-膦酰乙基等。
被取代的羟基,包括:烷氧基、烯氧基、芳烷氧基、酰氧基和芳香氧基,以上提到的烷氧基优选:含1~10碳的直链或支链的烷氧基,(如:甲氧基,乙氧基,丙氧基,丁氧基,叔丁氧基,戊氧基,己氧基,庚氧基,壬氧基等);或4~6碳的环烷氧基,(如:环丁氧基,环戊氧基,环己氧基等);以上所提到的烯氧基优选2~10碳的烯氧基,(如烯丙氧基,丁烯氧基,2-戊烯氧基,3-己烯氧基,2-环戊烯甲氧基,2-环己烯氧基等);芳烷氧基优选6~19碳的芳烷氧基,更优先者为C6-14芳基-C1-4烷氧基,(如苄氧基,苯乙氧基等);酰氧基优选:C2-10的脂肪酰氧基,(如乙酰氧基、丙酰氧基、n-丁酰氧基、己酰氧基等);芳氧基优选C6-14的芳氧基,(如:苯酚基,二苯氧基等)。这些基团可进一步被1~3个取代基所取代,这些取代基如上述的卤素、羟基C1-6烷氧基,及单或二(C1-6烷氧)磷酰基。这些被取代羟基的特例包括:三氟甲基,2,2,2-三氟乙氧基,二氟甲氧基,2-甲氧乙氧基,4-氯苄氧基,2-(3,4-二甲氧苯)-乙氧基等。
可被取代的硫基包括:烷硫基、芳烷硫基及酰硫基。烷硫基优选C1-10的直链或支链的烷硫基,(如:甲硫基、乙硫基、丙硫基、丁硫基、戊硫基、己硫基、庚硫基、壬硫基等);或C4-6的环烷硫基(如:环丁硫基、环戊硫基、环己硫基等);芳烷硫基优选:C7-19的芳烷硫基,更优选C6-14芳基-C1-4烷硫基(如苄硫基,苯乙硫基等);酰硫基优选C2-10的烷酰硫基(如:乙酰硫基、丁酰硫基,n-丁酰硫基、己酰硫基等),这些基团可进一步为1~3个取代基所取代,如上面提到过的卤素、羟基,C1-6烷氧基,或:单或二(C1-6烷氧)磷酰基。被取代了硫基的特例包括:三氟甲硫基,2,2,2-三氟乙硫基,2-甲氧乙硫基,4-氯苄硫基,3,4-二氯苄硫基,4-氟苄硫基,2-(3,4-二甲氧苯基)乙硫基等。
上述的被取代氨基的取代基包括:以上所提到的C1-10烷基,C2-10烯基(如:烯丙基、乙烯基、2-戊-1-烯基,3-戊-1-烯基,2-己-1-烯基,3-己-1-烯基,2-环己烯基,2-环戊烯基,2-甲基-2-丙-1-烯基,3-甲基-2-丁-1-烯基等);C6-14芳基和C7-19芳烷基。这些取代基可相同或不同,取代基数目为1或2。这些取代基可进一步被各种取代基取代,如上面提到过的卤素,C1-3烷氧基,单或二(C1-6烷氧基)磷酰基及膦酰基。氨基被取代的特例包括:甲氨基、二甲氨基、乙氨基、二乙氨基、二丁氨基、二烯丙氨基、环己氨基、苯氨基、N-甲基-N-苯基氨基、N-甲基-N-(4-氯苄基)氨基,N,N-二(2-甲氧乙基)氨基等。
酰基基团包括从有机羧酸或从含有C1-6烃基的磺酸衍生出的酰基。这些C1-6烃基包括如甲基、乙基、n-丙基、己基、苯基等)。从有机羧酸衍生出的酰基包括:甲酰基,C1-10烷酰基(如乙酰基,丙酰基,丁酰基,戊酰基,新戊酰基,己酰基,辛酰基,环丁烷羰基,环己烷羰基,环庚烷羰基等);C2-10烯基酰基(如:巴豆酰基,2-环己烯酰基等);C6-14芳香酰基(如:苯甲酰氧基等);C7-19芳烷酰基(如:苯甲酰基,二苯甲酰基等);5或6元芳香杂环乙酰基(如:3-吡啶乙酰基,4-噻唑乙酰基等);从具有C1-6烃基的磺酸中衍生出的酰基,包括:甲磺酰基,乙磺酰基等。这些基团可进一步被1~3个取代基所取代,如上面提到过的卤素,羟基,C1-6烷氧基及氨基。被取代的酰基的特例为:三氟乙酰基、三氯乙酰基,4-甲氧基丁酰基,3-环己氧丙酰基,4-氯苯甲酰基,3,4-二甲氧-苯甲酰基等。
前面提到过的单或二烷氧磷酰基优选二-低级烷氧磷酰基,如:二甲氧磷酰基,二乙氧磷酰基,二丙氧磷酰基,二异丙氧磷酰基,亚乙二氧磷酰氧,二丁氧磷酰基等。
前述的被取代芳基的芳基部分,优选C6-14芳基,如苯基,萘基,蒽基等。这些基团均可被1~3个取代基所取代,如前面提到的:C1-6烷基,卤素,羟基,及C1-6烷氧基。被取代芳基的特例,包括:4-氯苯基,3,4-二甲氧苯基,4-环乙基苯基,5,6,7,8-四氢-2-萘基等。
可被取代的芳烷基的芳烷基,优选C7-19芳烷基,如:苄基、萘乙基、三苯甲基等。这些基团可被1~3个取代基核上取代,如前面提过的C1-6烷基,卤素、羟基及C1-6烷氧基。被取代的芳烷基的特例包括:4-氯苄基,3,4-二甲氧基苄基,4-环己苄基,2-(5,6,7,8-四氢-2-萘)乙基等。
可被取代的芳香杂环基团的芳香杂环,优选含有1~4个氮、氧或硫的5-或6-芳香杂环基团,如:呋喃基,噻吩基,咪唑基,噻唑基,恶唑基,噻二唑基等。这些基团可被1~3个取代基所取代,如前面提及的C1-6烷基,卤素、羟基及C1-6烷氧基。
当苯环被两个烷基邻位取代时,这些基团可形成分子式为-(CH2)m-的亚烷基,其中m为3~5的整数(如亚丙基、亚丁基、亚戊基)。当苯环被两个烷氧基邻位取代时,其可以形成用分子式为-O-(CH2)n-O-的二氧亚烷基,n为1~3的整数(如:二氧次甲基,二氧乙氧基及三氧亚丙基)。此时,和苯环的碳原子形成5~7元环。
可被取代的烃基基团的烃基R,包括前面提到的烷基(优选C1-10烷基),烯基(优选C2-10烯基),芳香(优选C6-14芳香),及芳烷基(优选C7-19芳烷基),这些烃基的取代基包括前面提及的5或6元的芳香杂环基,卤素,二烷氧磷酰基,膦酰基等。
R的优选例为非取代的C1-6烷基,如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、新戊基、己基等。
酯化的羧基B,包括:烷氧酰基,优选:C1-10烷氧酰基(如甲氧酰基,乙氧酰基,丙氧酰基,丁氧酰基等);芳氧酰基,优选C6-14芳氧酰基(如苯氧酰基等);及芳烷氧酰基,优选C7-19芳烷氧酰基(如:苄氧酰基等)。
酰胺化的羧基B优选分子式为-CONR1R2的氨基甲酰基,其中R1、R2各为氢原子、被取代烃基或5-或7-元杂环基团。
前面述及的可被取代的烃基基团中的烃基R1,R2,包括烷基(优选C1-10烷基),烯基(优选C2-10烯基);芳基(优选C6-14芳基);芳烷基(优选C7-19芳烷基)。这些基团可被1~3个取代基所取代,如:卤素(氟、氯、溴、碘),羟基,C1-6烷氧基、可被C1-6烷基取代的氨基(如二甲氨基,二乙氨基,二丙氨基等),酰基(如:C1-10烷酰基)取代的氨基(如:乙酰胺基、丙酰胺基,苯甲酰胺基等);可被C1-6烷基取代的氨基甲酰基(如二甲基氨基甲酰基,乙氧基氨基甲酰基,二丙基氨基甲酰基等);C1-6烷氧酰基(如:甲氧酰基,乙氧酰基,丙氧酰基等);单或二烷氧磷酰基(如:二甲氧磷酰基);膦酰基及芳香杂环基。
可被取代的5-到7-元杂环基团的5-到7-元杂环,R1,R2包括含一个硫、氮、或氧原子的5-到7-元杂环,含2~4个氮原子的5-或6-元杂环,含1-2个氮原子,和1个硫或氧原子的5-或6-元杂环。这些杂环中的每一个都可稠合到最多含有2个氮原子的六元环、苯环或含有一个硫原子的五元环。
上述的5-到7-元杂环的优选例,包括:吡啶基,嘧啶基,吡嗪基,哒嗪基,吡唑基,咪唑基,噻唑基,恶唑基,吡啶〔2,3-d〕并嘧啶基,苯并吡喃基,1,8-二氮杂萘基,喹啉基,噻吩〔2,3-d〕并吡啶基,四唑基,噻二唑基,恶二唑基,三嗪基,三唑基,噻吩基,吡咯基,吡咯啉基,呋喃基,吡咯烷基,苯并噻吩基,吲哚基,咪唑啉基,呱啶基,呱啶子基,呱嗪基,吗啉基,吗啉代基等。
取代的烷基R1,R2的特例,包括:三氟甲基,三氟乙基,二氟甲基,三氯甲基,2-羟乙基,2-甲氧乙基,2-乙氧乙基,2,2-二甲氧乙基,2,2-二乙氧乙基,2-吡啶甲基,3-吡啶甲基,4-吡啶甲基,2-(2-噻吩)-乙基,3-(3-呋喃)丙基,2-吗啉乙基,3-吡咯丁基,2-呱啶子乙基,2-(N,N-二甲基-氨基)乙基,2-(N-甲基-N-乙基氨基)乙基,2-(N,N-二异丙基-氨基)乙基,5-(N,N-二甲氨基)戊基,N,N-二甲氨基甲酰乙基,N,N-二甲氨基甲酰戊基,乙氧酰甲基,异丙氧酰乙基,叔丁氧酰丙基,2-乙氧磷酰乙基,3-二丙氧磷酰丙基,4-二丁氧丁酰丁基,二氧亚乙基磷酰甲基,2-膦酰乙基,3-膦酰乙基等。取代芳烷基R1或R2的特例为,4-氯苄基,3-(2-氟苯基)丙基,3-甲氧苄基,3,4-二甲氧苯乙基,4-乙基苄基,4-(3-三氟甲基苯基)丁基,4-乙酰胺基苄基,4-二甲基氨基苯乙基,4-二乙氧磷酰苄基,2-(4-二丙氧磷酰甲基苯基)乙基等。被取代芳基R1或R2的特例,包括4-氯苯基,4-环己基苯基,5,6,7,8-四氢-2-萘基,3-三氟甲基苯基,4-羟苯基,3,4,5-三甲氧苯基,6-甲氧-2-萘基,4-(4-氯苄氧基)苯基,3,4-二氧次甲基苯基,4-(2,2,2-三氟乙氧)苯基,4-丙炔苯基,4-环己酰苯基,4-二甲氨基苯基,4-苯甲酰胺基苯基,4-二乙氧氨基甲酰苯基,4-叔丁氧酰苯基,4-二乙氧磷酰苯基,4-二乙氧磷酰甲苯基,4-(2-二乙氧磷酰乙基)苯基,2-二乙氧磷酰甲苯基,3-二乙氧磷酰甲苯基,4-二丙氧磷酰苯基,4-(2-膦酰乙基)苯基,4-膦酰甲苯基,4-膦酰苯基等。被取代的五到六元杂环R1,R2的特例包括:5-氯-2-吡啶基,3-甲氧-2-吡啶基,5-甲基-2-苯并噻唑基,5-甲基-4-苯基-2-噻唑基,3-苯基-5-异恶唑基,4-(4-氯苯基)-5-甲基-2-恶唑基,3-苯基-1,2,4-噻二唑-5-基,5-甲基-1,3,4-噻二唑-2-基,5-乙酰胺基-2-嘧啶基,3-甲基-2-噻吩基,4,5-二甲基-2-呋喃基,4-甲基-2-吗啉基等。在以上提到的种类中,环A优选卤素、烷基,或烷氧基取代的苯环。
取代基B优选烷氧酰基,或通式为-CONR1R2的基团,其中R1,R2可为氢原子,可被取代的烃基或可被取代的五到七元杂环。
取代基R优选氢原子,C1-10烷基,或苯基。
化合物Ⅰ或其盐可由下列常规方法制备,
例如,可用下列方法(A-E),下面所提到的盐与化合物(Ⅰ)的盐相似或相同。
(1)方法A
通式(Ⅰa′)的化合物
其中B′为一酯化的羧基,其它符号分别与以前定义相同。通式(Ⅰa′)所代表的化合物或其相应的盐可由通式(Ⅱ)的化合物或其相应的盐经环化反应制备。
酯化的羧基B′可与B的定义相同,因此,B′优选烷基酯,尤其是具有C1-6烷基的酯(如甲基,乙基,丙基,异丙基,丁基,叔丁基,戊基,新戊基,己基等);或芳烷基酯,尤其是含有C7-19芳烷基的酯(如苄基,苯乙基,3-苯丙基等)。
环合反应与通常的Friedel-Crafts反应方法相同。
因此,该环合反应可以通过下列书中所述的方法进行:““Organic Reactions,Vol 2,page 114,John Wiley & Sons,Inc,New Yozk,1962”和“Shin Jikken Kagaku Kbza 14,《有机化合物Ⅱ的合成与反应》Maruzen,1977”,例如,具体说,反应可按下列方法进行。
该反应通常在不干扰反应的溶剂中或是不用溶剂来进行。
上述溶剂包括:芳香烃类(如苯、甲苯、二甲苯等);卤化烃(如:氯仿,二氯甲烷,1,2-二氯乙烷,1,1,2,2-四氯乙烷等);醚(如:乙醚,二恶烷,四氢呋喃等);硝基苯,硝基甲烷和二硫化碳,以及其各种混合溶剂。
该反应在路易斯酸存在下进行,
路易斯酸的例子包括:氢氟酸、硫酸、磷酸、五氧化二磷、三氯化铝、四氯化锡及氯化锌。
这些路易斯酸的比例优选为:每摩尔化合物(Ⅱ)或其盐用2-10摩尔路易斯酸。在任何情况下,反应温度在大约-20℃-200℃范围内,优选:0℃~100℃。反应时间通常为大约30分钟~约100小时,优选1~30小时。
(2)方法B
通式(Ⅰa″)的化合物
(其中各符号均与前述定义相同)及其相应的盐可以化合物(Ⅰa′)及其相应的盐通过水解反应制备。
该水解反应按常规方法在水溶液或水中进行。
上述水溶液包括:例如:水与醇(如甲醇、乙醇等),水与醚(如:四氢呋喃、二恶烷等);水与酰胺(如N,N-二甲基甲酰胺等);亚砜(如二甲基亚砜等)或水与酮(如:丙酮,丁酮等)的混合物。
该反应在碱或酸存在下进行反应。
上述碱可以是无机碱,如碱金属碳酸盐,(如碳酸钾,碳酸钠等),碱金属的氢氧化物(如:氢氧化钾,氢氧化钠,氢氧化锂等);或有机碱如各种烷氧化物(如甲氧基钠,乙氧基钠,叔丁氧基钾等)。酸可以是无机酸,如盐酸、硫酸、氢溴酸等,有机酸如醋酸,三氟醋酸等。优选相对于化合物(Ⅰa′)过量的酸或碱。碱的优选比例为化合物(Ⅰa′)的1。2-6倍当量数,酸的优选比例为化合物(Ⅰa′)的2-50倍当量数。
该反应通常在大约-20℃-150℃间进行,优选温度为大约-10℃-100℃。
(3)方法C
通式(Ⅰc)的化合物,
(其中B″为一酰胺化的羧基,其它符号同前述定义),及其盐可由化合物(Ⅰa″)及其盐,通过酰胺化反应制备。
该反应通过化合物(Ⅰa″)或盐与胺基化合物反应进行。
该胺基化合物优选下列通式(Ⅲ)的化合物
其中各符号都与以前的定义相同。化合物(Ⅰa″)或其盐与胺基化合物之间的反应是以与肽合成中常用的缩合反应相同的方法进行的。
因此,该反应可以按下列书中所述的各种已知的方法进行,“M.Bodansky and M.A.Ondetti:pePtide Syuthesis,Interscienle,New Yozk,1966,”“F.M.Finn and K.Hofmaun:The proteins,Vol 2,edited by H.Nenrath & R.L.Hill,Academic press New Yozk,1976,”和“Noluo Izumiya et al:pePtide Gosei no Kiso to Zikken,Marnzen,1985,”例如,酰叠氮法、酰氯法、酸酐法、混合脱水法、二环己基碳二亚胺(DCC)法,活化酯法、伍德瓦德试剂K法、酰基二咪唑法,氧化还原法,DCC/HONB法等。
因此,反应可在下例的反应条件下进行。
起始胺基化合物与化合物(Ⅰa″)或其相应盐的摩尔比大约为1~10。
反应在不干扰反应的溶剂中进行。
这些溶剂包括,例如:酰胺(如二甲基甲酰胺等);亚砜(如二甲基亚砜等);吡啶类(如:吡啶,甲基吡啶,二甲基吡啶等);卤化烃(如氯仿、二氯甲烷等);醚(如四氢呋喃等),腈类(如乙腈等),以及这些溶剂的适宜的混合物。这些溶剂可在无水或有水条件下使用。
反应温度通常在大约-20℃~50℃,优选约为:-10℃~30℃。反应时间约为1~100小时,优选约为2~40小时。
(4)方法D
通式(Ⅰd)的化合物
(其中“K”为1或2,其它符号均同前述)或其相应的盐可由化合物(Ⅰa′),(Ⅰa″)或(Ⅰc)(其中K′始终为0)或相应的盐,通过氧化反应制备。
该反应按使用氧化剂的通常的氧化方法进行。
用于该反应的氧化剂为基本上不影响含硫杂环化合物骨架结构的温和氧化剂,如过苯甲酸,间氯过苯甲酸,过氧化氢,过酸酯,偏高碘酸钠,苯基二氯碘化物,臭氧,过氧化氢与次氯酸钠,以上提到的为几个优选例。
该反应在不干扰反应的有机溶剂中进行。
上述之溶剂包括:芳烃(如苯、甲苯、二甲苯等);卤化烃(如氯仿、二氯甲烷、1,2-二氯乙烷,1,1,2,2-四氯乙烷等);醚(乙醚,二恶烷,四氢呋喃等);醇(如甲醇,乙醇,丙醇等),以及以上溶剂的各种混合溶剂。
当使用上述氧化剂的量与化合物(Ⅰa′),(Ⅰa″)或(Ⅰc)(K′为0)或其相应盐的量(摩尔数)相等或几乎相等时,主要形成K″为1的化合物(Ⅰd)。当所用的氧化剂过量时,K″为1的化合物(Ⅰd)进一步被氧化,形成K″为2的化合物(Ⅰd)。
该反应在室温或低于室温下进行(30~20℃),优选反应温度为大约-50℃~20℃。
反应时间为大约30分钟到10小时。
(5)方法E
通式(Ⅰb)的化合物或相应盐,可由化合物(Ⅰa′),(Ⅰa″),(Ⅰc)或(Ⅰd),或其盐通过还原反应制备。
该反应的起始反应物为方法A-D中任一反应所制备的具有通式(Ⅰ)的化合物,其中X为-CH(OH)-,即化合物(Ⅰb)及其相应的盐。
该反应可按已知的还原方法进行,如在“Shin Jikken Kagaku Koza,15-Qxidation and Reduction〔Ⅱ〕,Maruzen,1977”一书中所述的方法。
例如:该反应通过用还原剂来处理化合物(Ⅰa′),(Ⅰa″)(Ⅰc)或(Ⅰd)来进行。
所用还原剂可以是金属及金属盐,例如金属氢复合物(如碱金属硼氢化物:如硼氢化钠,硼氢化锂等);金属氢化物(如氢化钠等),有机锡(如:氢化三苯锡等),镍和锌化合物,以及由金属转移催化剂(如钯、铂、铑等)与氢结合而形成的催化还原体系。
该反应在不干扰反应的有机溶剂中进行。
上述有机溶剂,包括芳香烃(苯、甲苯、二甲苯等);卤化烃(如氯仿、二氯甲烷,1,2-二氯乙烷,1,1,2,2-四氯乙烷等);醚(如乙醚,二恶烷,四氢呋喃,乙烯甘醇单甲醚等);醇(如乙醇、甲醇、丙醇等);酰胺(如二甲基甲酰胺等)。这些溶剂根据使用的还原剂的类型而选择使用。
反应温度为0~130℃,优选10~100℃。
反应时间大约为1~24小时。
(6)方法F
该方法为通过方法A-E中合成的含有单烷氧磷酰基或双烷氧磷酰基的化合物,制备含有膦酰基的化合物的方法。
该反应用无机酸(如盐酸、氢溴酸等),或三烷基硅烷卤化物,在不干扰反应的溶剂中进行。
当使用无机酸时(如:盐酸、氢溴酸),溶剂可以是醇(如甲醇、乙醇、2-甲氧乙醇,1,2-亚乙基二醇、丙醇、丁醇等),水,或其混合物。酸通常大量过量。反应温度通常为10~150℃,优选30~100℃。反应时间为1~50小时。
当使用卤化硅烷时(如氯化三甲基硅烷,溴化三甲基硅烷,碘化三甲基硅烷等),溶剂可为卤化烃(如:四氯化碳,氯仿,二氯甲烷,1,2-二氯乙烷、1,1,2,2-四氯乙烷等)或乙腈,或溶剂混合物。
卤化硅烷对含单烷氧或双烷氧磷酰基的化合物的比例通常为1~10当量比,优选2~5当量比。反应温度为-30℃~100℃,优选-10℃~50℃。反应时间为30~100小时。
所得到的含硫杂环化合物可以利用通常的分离、纯化方法分离和提纯,如离心、减压离心、溶剂提纯、结晶、重结晶、再分配、层析等。同样的分离提纯方法也适用于下述的起始化合物的制备。
本发明的起始化合物(Ⅱ)可通过已知方法或与之类似的方法制备,如下列方法:
在上式中,Z为离去基团;Y′为卤原子,其余符号均同前述。
反应步骤1
在这步反应中,化合物(Ⅴ)或相应的盐与化合物(Ⅵ)及相应盐在碱存在下,生成化合物(Ⅱa)或相应盐。
所说的离去基团Z,包括卤素(优选:氯、溴、碘);酯化的活性羟基(如有机磺酸基:如对甲苯磺酰氧基,C1-4烷磺酰氧基如亚甲基磺酰氧基);及有机磷酸基(如二苯磷酰氧基,二苄磷酰氧基,二甲磷酰氧基等)。
化合物(Ⅴ)或相应的盐与化合物(Ⅵ)或相应的盐的反应在不干扰反应的溶剂中进行。
溶剂包括,芳烃(如苯、甲苯、二甲苯等);醚(如二恶烷、四氢呋喃、二甲氧基乙烷等),醇(如甲醇、乙醇、丙醇等);酯(如乙酸乙酯等);腈(如乙腈等),吡啶类(如吡啶,二甲基吡啶等);酰胺(如N,N-二甲基甲酰胺等);亚砜(如二甲基亚砜等);卤化烃(如氯仿,二氯甲烷,1,2-二氯乙烷,1,1,2,2-四氯乙烷等);酮(如丙酮、2-丁酮等),以及这些溶剂的混合物。
反应在碱存在下进行,无机碱如氢氧化钠,氢氧化钾,碳酸钾,碳酸钠,碳酸氢钠等;有机碱如:氨,吡啶,三乙胺,N,N-二甲基苯胺等。
优选的碱与化合物(Ⅴ)或其盐的摩尔比为1~5。
反应通常在-20℃~150℃间进行,优选温度为-10~100℃。
反应物(Ⅴ)或其盐可按下列书中所述方法进行,“Chem pharm Bull 30,3580(1982)”,“Chem pharm Bull 30,3601(1982)”
反应步骤2
在这步反应中,化合物(Ⅱa)或其相应盐被卤化得到化合物(Ⅱb)或其相应盐。
该反应可按下列步骤进行。
例如,该反应可按下列书中方法进行。
“Shin Zikken Kagaku Koza 14,Syntheses and Reactions of Organic ComPounds〔Ⅱ〕,Maruzen,1977”
因此,例如,该反应通过化合物(Ⅱa)或其盐与卤化剂,如:氯化剂(如:五氯化磷,亚硫酰氯,乙二酰氯等)反应来进行。
反应可在不干扰反应的溶剂中或不需溶剂进行。
上述溶剂包括:芳烃(如苯,甲苯、二甲苯等);醚(如二恶烷,四氢呋喃,二甲氧基乙烷等);腈(如乙腈等);酰胺(如N,N-二甲基甲酰胺等);卤化烃(如:氯仿,二氯甲烷,1,2-二氯乙烷,1,1,2,2-四氯乙烷等),以及上述溶剂的混合物。此反应在加热条件下进行(35℃~120℃),反应时间约为1~20小时。
反应步骤3
在这步反应中,化合物(Ⅱb)或其盐经氧化反应,生成化合物(Ⅱa)或其盐。
该反应以与方法D同样方法进行。
化合物(Ⅱa)也可通过下列步骤合成。
在上式中,R1为低级烷基,其它符号均同前述。
反应步骤1
在这步反应中,化合物(Ⅴ)与化合物(Ⅶ)或其盐在碱存在下,反应生成化合物(Ⅷ)。
离去基团Z包括,例如前面述及的基团。低级烷基R1的例子为:C1-4烷基,如甲基,乙基,丙基,异丙基,丁基,异丁基。
化合物(Ⅴ)与化合物(Ⅶ)或其盐的反应在不影响反应的溶剂中进行。
溶剂包括,例如:芳烃(如苯、甲苯、二甲苯等);醚(如二恶烷,四氢呋喃,二甲氧基乙烷等);酯(如乙酸乙酯等);酰胺(如N,N-二甲基甲酰胺等);亚砜(如:二甲基亚砜等);卤化烃(如:氯仿,二氯甲烷,1,2-二氯乙烷,1,1,2,2-四氯乙烷等);酮(如丙酮,2-丁酮等);以及溶剂的混合物。
该反应在碱存在下进行,这些碱包括无机碱,(如氢氧化钠,氢氧化钾,碳酸钾,碳酸氢钠等);有机碱(如吡啶,三乙胺,N,N-二甲基苯胺等)。
反应中碱与化合物(Ⅴ)的摩尔比优选1~5。
该反应通常在-20℃~150℃间进行。优选:大约-10℃~100℃。反应时间通常为30分钟~10小时。
反应步骤2
在此反应步骤中,化合物(Ⅷ)在碱存在下水解生成化合物(Ⅸ)。
该反应在不干扰反应的溶剂中进行,这些溶剂包括:醇(如:甲醇、乙醇、丙醇、异丙醇、2-甲氧基乙醇等,以及水与这些醇的混合物),四氢呋喃,丙酮,N,N-二甲基甲酰胺,二甲基亚砜等。
该反应在碱存在下进行,包括无机碱(如:氢氧化钠,氢氧化钾,碳酸钾等),氨水,或:有机碱(二级胺,如二甲胺、二乙胺、吗啉呱啶等),等等。
碱与化合物(Ⅷ)的优选摩尔比为1~10。
该反应通常在-20℃~150℃进行,优选约为-10℃~80℃。
反应步骤3
在这步反应中,化合物(Ⅸ)或其盐与化合物(Ⅹ)或其盐在碱存在下反应生成化合物(Ⅱa)及其盐。
离去基团Z的例子为被卤素(主要为氯、溴、或碘)活化了的羟基,或被酯化,如有机磺酸基(如对甲苯磺酰氧基)活化的羟基,C1-4烷基磺酰氧基,(如甲磺酰氧基),及有机磷酸基(如二苯磷酰氧基,二苄磷酰氧基,二甲磷酰氧基等)。
化合物(Ⅸ)或其盐与化合物(Ⅹ)或其盐的反应在不干扰反应的溶剂中进行。
这些溶剂的例子为:芳烃(如苯、甲苯、二甲苯等);醚(如:二恶烷、四氢呋喃、二甲氧基乙烷等);醇(如:甲醇、乙醇、丙醇等);酯(如乙酸乙酯);腈(如:乙腈等),吡啶类(如:吡啶、二甲基吡啶等);酰胺(如N,N-二甲酰胺等);亚砜(如二甲基亚砜等);卤化烃(如氯仿,二氯甲烷,1,2-二氯乙烷,1,1,2,2-四氯乙烷等);酮(如:丙酮,2-丁酮等);以及这些溶剂的适当的混合物。
该反应是在碱存在下进行的,包括无机碱(如氢氧化钠,氢氧化钾,碳酸钾,碳酸钠,碳酸氢钠等);有机碱(叔胺,如吡啶,三乙胺,N,N-二甲基苯胺等)。
碱与化合物(Ⅸ)的摩尔比优选1~5。
该反应通常在-20℃~150℃间进行,优选约为-10℃~100℃。
本发明中化合物(Ⅰ)的盐,优选药剂上可接受的盐,这些盐包括无机碱盐,有机碱盐,有机酸盐,具有碱性或酸性氨基酸的盐。无机碱基包括碱金属(如钠、钾等),碱土金属(如钙、镁等);有机碱基包括:三甲胺、三乙胺、吡啶、甲基吡啶、N,N-二苄基乙烯二胺、二乙醇胺等;无机酸包括:盐酸、氢溴酸、氢碘酸、磷酸、硝酸硫酸等;有机酸包括甲酸、乙酸、三氟乙酸、乙二酸、酒石酸、富马酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸、橡缘酸等;碱性或酸性氨基酸如精氨酸,赖氨酸,天冬氨酸,谷氨酸等,这里仅列举了部分。
上述的各类盐中,所说的碱基盐为,当化合物(Ⅰ)在B上含有羧基,或/和,环A上或在取代基B或R中含有酸性基团(如羧基或磺基)时,所形成的任何一种及所有盐。所谓的酸性盐是指那些化合物(Ⅰ)在环A上或在取代基B或R中含有碱性基时所形成的盐。
化合物(Ⅰ)或其盐的毒性很低,例如,在实例18和22中合成的化合物,以300mg/kg的剂量给小鼠口服用药时,无一例死亡。本发明中的化合物(Ⅰ)和盐,具有极好的骨重吸收抑制活性。因此,它们能有效地抑制人体中骨的溶解和减少。此外,化合物(Ⅰ)或其盐具有骨形成促进作用。
因此,本发明中的化合物(Ⅰ)或其盐可以完全地用于人及家畜,防止和治疗由于骨重吸收引起的疾病,如骨质疏松症。
化合物(Ⅰ)或其盐,可通过口服或其它方式(如肌注或静注)给药。
常用的口服制剂包括液体或固体剂型,如片剂(包括:糖衣片或膜衣片),丸剂,颗粒剂,粉剂,胶囊(包括软胶囊),糖浆,酏剂,乳剂,混悬剂等。
这些口服制剂,可以按已知方法,用药剂工作中常用的载体或辅料稀释化合物(Ⅰ)或药剂学上可接受的盐来制备。
例如,这些载体或辅料,包括粘合剂(如:糖浆,阿拉伯胶,明胶,山梨醇,黄蓍胶,聚乙烯吡咯烷酮等);填充剂(如:乳糖,蔗糖,及其它糖类,玉米淀粉,磷酸钙,甘氨酸等);润滑剂(如:硬脂酸镁,滑石,聚乙二醇,二氧化硅等);崩解剂(如:马铃薯淀粉);润滑剂(如:十二烷基磺酸钠)等等。
非肠道给药的剂型,包括:各种注射剂,(如:皮下,皮内,肌注、及其它注射剂)及栓剂等。
注射剂的制备可按下列已知方法进行,如:化合物(Ⅰ)或其盐在无菌的水或油介质中混悬或乳化,注射用水性介质包括:生理盐水及各种等渗溶液,必要时,可在注射剂中使用助悬剂如缩甲基纤维素钠或非离子型表面活性剂。油性介质包括:芝麻油,大豆油等,苯甲酸苄酯、苄醇也可作为助溶剂使用,如此制备的注射剂装于适宜的安瓿中。
也可以在制剂中加入具有骨重吸收抑制活性的其它活性成份(如Ipriflavone,依吡黄酮),以得到具有更强骨重吸收抑制活性的产品。
化合物(Ⅰ)或其盐,可用作骨重吸收引起的疾病(如:骨质疏松症)的预防和治疗剂,化合物(Ⅰ)及其盐的每日剂量,取决于患者的病情与体重,给药方式及其它因素。体重大约为50kg的成年人的口服剂量为1~500mg,优选15~300mg。活性成份(化合物(Ⅰ)或其盐)和其制剂每天给药1~3次。
本发明所提供的化合物(Ⅰ)及其相应盐,具有很强的骨重吸收抑制,骨代谢促进和骨形成促进活性,其可用于预防和治疗人及动物由于骨重吸收引起的疾病(如骨质疏松症)。
化合物(Ⅰ)或其盐具有微弱毒性,可以安全使用。
下列实验,参考实例与工作实例,意在进一步说明本发明,并非限制本发明的范围。
实验1,骨重吸收抑制的研究
骨重吸收抑制活性根据Raisz的方法测定“Journal of Clinical Investigation(J.Clin Invesf)44,103~116(1965)”。
因此,一只SPrague-Dawley种大鼠,在怀孕第19天,皮下注射50μCi的45Ca(钙的放射性同位素,以CaCl2的形式)。次日,动物被剖腹,无菌地取出胚胎。大鼠胚胎左右两侧肱骨(桡骨和尺骨)被离体,并在显微镜下解剖,尽可能剥离除去结缔组织及软骨,以准备骨组织样本。每块骨均在Fitton-Jackson改进的含有2mg/ml牛血清白蛋白的0.6ml BGJ培养基(由GIBCO实验室而得商品名)中于37℃培养1小时,当试验化合物以最终所加浓度为10μg/ml加到上述培养基中后,再继续培养2小时,测定培养基及骨中的45Ca放射活性,从骨中释放到培养基中的45Ca的比率(%)根据下式计算。
A= (B)/(B+C) ×100
A=45Ca从骨释放到培养基中的比率(%)
B=培养基中45Ca的量
C=骨中45Ca的量。
同一动物的胚胎骨不加试验化合物进行2天类似的培养做为对照。
每组五块骨的数据取平均,治疗组与空白组的数据的比率(%)可测出,结果列于表1。
注:1)2-氧化物 注:2)2,2-二氧化物
表1表明,本发明的化合物与对照组对比可抑制45Ca的释放44~88%,因此具有极好的骨重吸收抑制活性。
试验2 骨质疏松症治疗的研究
为10周的Sprague-Dawley种大鼠进行卵巢切除术,并从术后即日,给大鼠口服试验化合物,剂量为每周6天共3周,或共给药18天。最后一次用药的次日,每只大鼠的右侧股骨被切除,并用软X-射线装置进行X-射线拍摄(Softex CSM,Softex)。利用显微密度仪(pDM-5,Konica Medical),对软X-射线胶片上的股骨横断面从距远端及从密度波形十五分之一点进行扫描。根据Inoue等人在〔Journal of JaPanese OrthoPedic Association(J.JPn OrthoP Ass)57 1923(1983)〕中描述的显微密度仪法,计算出骨密度。
软X-射线拍照后,股骨远端三分之一与长轴成直角切除,用清洗泵洗掉骨髓后,股骨部分放于磁坩埚中,于烤箱中110℃干燥24小时,称量干重。
含有骨的磁坩埚转入马福炉中(Fp-41,Yamato Chemical)于500℃加热3小时,800℃加热2小时,称量钙化骨及灰重。
每组7只大鼠右侧股骨测量的平均值±标准误差可测出,结果见表2-4。
从表2到表4可明显地看出,本发明的化合物可有效地预防骨质损失并抑制体内钙从骨中释出。
下列参考及工作实例中所用符号具有下列意:
S:单峰,d:双峰,t:三重峰,q:四重峰,dd:双、双峰,m:多重峰,br:宽峰,J:偶合常数,THF:四氢呋喃,DMF:N,N-二甲基甲酰胺。
参考实例1
于冰浴冷却的含有48.0g三氯化铝的二氯甲烷溶液(500ml)中,依次滴加48.0g草酰氯和48.0g苯基环己烷,混合物冰浴搅拌30分钟,反应混合物倒入冰水中,分离出有机层,水层用氯仿提取,提取物与有机层合并,水洗,MgSO4干燥,减压蒸馏浓缩得4-环己基苯基乙醛酰乙酯。(68.0g,收率87%),沸点:163~165℃/0.3mmHg。NMR(δpPm,CDCl3)1.40(3H,t,J=7Hz),1.4-2.1(8H,m),2.60(1H,m),4.43(2H,q,J=7Hz),7.34(2H,d,J=9Hz),7.96(2H,d,J=7Hz)。
参考实例2
与参考实例1同样方法,得5,6,7,8-四氢-2-萘乙醛酰乙酯,收率80%,沸点:152~154℃/0.5mmHg。NMR(δppm,CDCl3):1.41(3H,t,J=7Hz),1.8(4H,m),2.8(4H,m),4.44(2H,q,J=7Hz),7.18(1H,q,J=9Hz),7.7(2H,m)。
参考实例3
与参考实例1同样方法,得3,4-二甲氧苯基乙醛酰乙酯,收率78%,沸点:158~160℃/0.1mmHg。NMR(δppm CDCl3):1.38(3H,t,J=7Hz),3.93(3H,S),3.95(3H,s),4.41(2H,q,J=7Hz),6.91(1H,d,J=8Hz),7.5-7.7(2H,m)。
参考实例4
同参考实例1的方法,得到3,4-二氧亚乙基苯基乙醛酰乙酯,收率:86%,沸点:172~175℃/0.5mmHg。
参考实例5
同参考实例1的方法,得到4-己基苯基乙醛酰乙酯,收率84%,沸点:160~162℃/0.5mmHg。NMR(δppm,CDCl3):0.87(3H,t,J=7Hz),1.40(3H,t,J=7Hz),1.2~1.8(8H,m),2.67(2H,t,J=7Hz),4.33(2H,q,J=7Hz),7.28(2H,d,J=9Hz),7.90(2H,d,J=9Hz)。
参考实例6
于含有2.0g硼氢化钠的100ml乙醇溶液中,滴加冰浴冷却的含有5,6,7,8-四氢-2-萘乙醛酰乙酯34.5g的乙醇溶液200ml,滴加完后,加入6ml冰醋酸,反应混合物倒入水中,用氯仿提取,氯仿层水洗,MgSO4干燥,蒸除溶剂,得到:油状的2-羟基-2(5,6,7,8-四氢-2-萘)乙酸乙酯。(34.5g,收率99%)。
NMR(δppm,CDCl3):1.22(3H,t,J=7Hz),1.8(4H,m),2.7(4H,m),3.32(1H,d,J=6Hz),4.0-4.4(2H,m),7.1(3H,m)。
参考实例7
同参考实例6的方法,得到2-羟基-2-(4-环己基苯基)乙酸乙酯,收率:83%
沸点:85~86℃(乙醇)
元素分析:C16H22O3
理论值:C,73.25;H,8.45
实际值:C,73.26;H,8.46
参考实例8
同参考实例6的方法,得到油状的2-羟基-2-(3,4-二甲氧基苯基)乙酰乙酯,收率82%
NMR(δppm,CDCl3):1.21(3H,t,J=7Hz),3.10(1H,d,J=6Hz),3.87(6H,S)4.21(2H,q,J=7Hz),5.07(1H,d,J=6Hz),6.7-7.0(3H,m)。
参考实例9
同参考实例6的方法,得到2-羟基-2-(3,4-二氧亚乙基苯基)乙酰乙酯油状物,收率:74%。
NMR(δppm,CDCl3):1.24(3H,t,J=7Hz)3.41(1H,d,J=6Hz),4.1-4.4(2H,m),4.26(4H,S),5.04(1H,d,J=6Hz),6.8-7.0(3H,m)。
参考实例10
同参考实例6的方法,得到2-羟基-2-(4-己基苯基)乙酸乙酯油状物。收率98%。
NMR(δppm,CDCl3):0.86(3H,t,J=7Hz)1.24(3H,t,J=7Hz),1.1-1.8(8H,m),2.60(2H,t,J=7Hz),4.0-4.4(2H,m),5.11(1H,S),7.13(2H,d,J=9Hz),7.32(2H,d,J=9Hz)。
参考实例11
于52g的2-羟基-2-(4-环己基苯基)-乙酸乙酯中,加入100ml亚磺酰氯,混合物回流一小时,反应混合物减压浓缩,残留的油状物用水稀释,乙醚提取,醚层用水洗,MgSO4干燥、减压蒸馏得:2-氯-2-(4-环己基苯基)乙酸乙酯,(50g,收率89%)。沸点:160-162℃/0.5mmHg。
NMR(δPPm,CDCl3):1.24(3H,t,J=7Hz)1.2-2.0(10H,m),2.5(1H,m),4.21(2H,q,J=7Hz),5.3(1H,S),7.18(2H,d,J=9Hz),7.40(2H,d,J=9Hz)
参考实例12
同参考实例11的方法,得到2-氯-2-(5,6,7,8-四氢-2-萘基)乙酸乙酯油状物,收率89%
沸点:139~141℃/0.5mmHg。
NMR(δppm,CDCl3):1.24(3H,t,J=7Hz)1.8(4H,m),2.7(4H,m),4.21(2H,q,J=7Hz),5.26(1H,S),7.0-7.2(3H,m)
参考实例13
同参考实例11的方法,得到2-氯-2-(3,4-二氧亚乙基苯基)乙酸乙酯油状物,收率90%,
沸点:165-167℃/0.3mmHg
NMR(δppm,CDCl3):1.27(3H,t,J=7Hz)4.1-4.4(2H,m),4.27(4H,S),5.25(1H,S),6.8-7.1(3H,m)。
参考实例14
同参考实例11的方法,得到2-氯-2-(4-己基苯基)乙酸乙酯油状物。沸点:152-155℃/0.5mmHg
NMR(δppm,CDCl3):0.88(3H,t,J=7Hz)1.26(3H,t,J=7Hz),1.1-1.8(8H,m),2.60(2H,t,J=7Hz),4.1-4.4(2H,m),5.33(1H,S),7.19(2H,d,J=9Hz),7.40(2H,d,J=9Hz)。
参考实例15
于含有19.5g的2-羟基-2-(3,4-二甲氧基苯基)乙酸乙酯的200ml苯溶液中,于50℃滴加三溴化硼8.18ml,反应混合物于60℃搅拌1小时,随后依次用水,饱和NaHCO3水溶液、及水洗涤,用MgSO4干燥,蒸除苯,其余部分经硅胶层析,从乙酸乙酯-正己烷(1∶3,V/V)洗脱液中,得油状物:
2-溴-2-(3,4-二甲氧苯基)乙酸乙酯,(18.5g,收率75%)。NMR(δppm,CDCl3):1.27(3H,t,J=7Hz),3.86(3H,S),3.89(3H,S),4.23(2H,q,J=7Hz),5.31(1H,S),6.80(1H,d,J=8Hz),7.0-7.2(2H,m)。
参考实例16
于400ml丙酮中溶入50g的4-环己基苯胺,加入147g47%的HBr水溶液,随后在0~5℃滴加含有21.6gNaNO2的30ml水溶液。混合物于5℃继续搅拌30分钟,随后加热到15℃,加入147g丙烯酸甲酯,剧烈搅拌,将1gCu2o分次少量加入,剧烈反应并放出氮气,当氮气释放完后,反应混合物继续搅拌2小时,浓缩,残余物用水稀释,乙酸乙酯提取。乙酸乙酯层用水洗,MgSO4干燥,蒸去溶剂,得到2-溴-3-(4-环己基苯基)丙酰甲酯油状物(91g,收率98%)
NMR(δppm.CDCl3):1.2-2.0(10H,m),2.5(1H,m),3.15(1H,d,d,J=14和7Hz),3.43(1H,d,d,J=14和17Hz),3.70(3H,S),4.37(1H,t,J=7Hz),7.10(4H,S)
参考实例17
于含有2-氯-2-(5,6,7,8-四氢2-萘基)乙酸乙酯(32g)的丙酮溶液(50ml)中,加入巯基乙酸(14g),K2CO3(52.7g)和丙酮(250ml)的混合物,回流5小时后,减压浓缩,剩余物倒入水中并用乙醚提取,水层经浓盐酸酸化,乙酸乙酯提取,乙酸乙酯层经水洗、MgSO4干燥,再经浓缩,残余物经硅胶层析,从氯仿-乙酸乙酯-甲醇(20∶2∶1V/V)洗脱液中,得到:乙氧甲酰(5,6,7,8-四氢-2-萘基)-甲基硫代乙酸油状物。(31.8g,收率81%)
NMR(δppm,CDCl3):1.23(3H,t,J=7Hz)1.8(4H,m),2.7(4H,m),3.07(1H,d,J=15Hz),3.30(1H,d,J=15Hz),4.18(2H,q,J=7Hz),4.79(1H,S),6.9-7.2(3H,m)。
参考实例18
同参考实例17的方法,得到:乙氧甲酰(3,4-二甲氧苯基)-甲硫基乙酸。收率98%。
NMR(δppm,CDCl3):1.23(3H,t,J=7Hz)3.18(2H,dd,J=21和15Hz),3.87(6H,S),4.20(2H,q,J=7Hz),4.81(1H,S),6.7-7.1(3H,m),9.40(1H,宽峰)。
参考实例19
同参考实例17的方法,得到:乙氧甲酰(4-环己基苯基)甲硫基乙酸油状物,(收率85%)。
NMR(δppm,CDCl3):1.23(3H,t,J=7Hz),1.2-2.0(8H,m),2.5(1H,m)3.18(2H,dd,J=21和15Hz),4.18(2H,q,J=7Hz),4.83(1H,S),7.17(2H,d,J=9Hz),7.38(2H,d,J=9Hz)。
参考实例20
46.5g三乙胺,滴加到冰浴冷却的,20.8g巯基乙酸,58g 2-氯-2-(4-正己基苯基)乙酸乙酯及250ml DMF的混合物中,滴加完后,冰浴冷却下继续搅拌1小时,所得到的反应混合物倒入水中,并用乙醚提取,水层经浓盐酸酸化,乙酸乙酯提取,乙酸乙酯层水洗,MgSO4干燥,浓缩,得乙氧甲酰(4-己基苯基)甲硫基乙酸63.5g,收率92%。
NMR(δppm,CDCl3):0.83(3H,t,J=7Hz),1.26(3H,t,J=7Hz),1.1-1.8(8H,m),2.59(2H,t,J=7Hz),3.11(1H,d,J=15Hz),3.30(1H,d,J=15Hz),4.1-4.4(2H,m),4.84(1H,S),7.26(2H,d,J=9Hz),7.35(2H,d,J=9Hz)。
参考实例21
同参考实例20的方法,得到甲氧甲酰基苯基甲硫基乙酸油状物,收率98%。
NMR(δppm,CDCl3):3.11(1H,d,J=15Hz),3.31(1H,d,J=15Hz),3.75(3H,S),4.90(1H,S),7.3-7.5(5H,m)。
参考实例22
同参考实例20的方法,得到甲氧甲酰基(4-氯苯基)甲硫基乙酸油状物,收率87%。
NMR(δppm,CDCl3):3.03(1H,d,J=15Hz)3.35(1H,d,J=15Hz),3.67(3H,S),4.81(1H,S),7.1-7.5(4H,m)。
参考实例23
同参考实例20的方法,得到:乙氧甲酰(3,4-二氧亚乙基苯基)甲硫基乙酸油状物,收率97%。
NMR(δppm,CDCl3):1.26(3H,t,J=7Hz),3.13(1H,d,J=15Hz),3.30(1H,d,J=15Hz),4.1-4-4(2H,m),4.26(4H,S),4.78(1H,S),6.8-7.1(3H,m)。
参考实例24
同参考实例20的方法,得到2-〔乙氧甲酰(4-环己基苯基)甲硫基〕丙酸油状物。收率89%。
NMR(δppm,CDCl3):1.1-2.0(16H,m),2.5(1H,m),3.49(2H,q,J=7Hz),4.1-4.4(2H,m),4.88(1H,S),7.1-7.4(4H,m)。
参考实例25
同参考实例20的方法,得到2-甲酰甲硫基-3-(4-环己基苯基)丙酸油状物,收率84%。
NMR(δppm,CDCl3):1.2-1.9(10H,m),2.5(1H,m),2.96(1H,d.d,J=15和7Hz)3.35(1H,d,J=16Hz),3.49(1H,d,J=16Hz),3.52(1H,d.d,J=15和7Hz),3.68(3H,S),3.6-3.8(1H,m),7.12(4H,S)。
参考实例26-41
与参考实例1基本相同方法,得表5中的化合物。
参考实例42-57
与参考实例6基本相同的方法,得表6中化合物。
参考实例58-73
与参考实例11基本相同的方法,得表7中化合物,
表7(续)
-47-
参考实 R1,R2收率 熔点
施例号 (%) (℃/mmHg)
68 2-CH3,4-CH393 115-118/0.5
69 3-CH3,4-CH390 118-120/0.7
70 3-C2H5,4-C2H5定量 注3)
71 2-(CH3)2CH-,4-(CH3)2CH- 95 129-132/0.5
72 3,4-(CH2)3- 92 128-132/0.3
73 3,4-(CH2)5- 89 145-148/0.2
注:
1)NMR(δppm,CDCl3):1.26(3H,t,J=7),2.36(3H,s),4.1-4.3(2H,m),5.32(1H,s),7.19(2H,d,J=9),7.38(2H,d,J=9)
2)NMR(δppm,CDCl3):1.24(3H,t,J=7),1.3-2.1(12H,m),2.7(1H,m),4.20(2H,q,J=7),5.30(1H,s),7.18(2H,d,J=9),7.40(2H,d,J=9)
3)NMR(δppm,CDCl3):1.20(6H,t,J=7),1.26(3H,t,J=7),2.66(4H,q,J=7),4.23(2H,q,J=7),5.31(1H,s),7.1-7.3(3H,m)
参考实例74-90
与参考实例20基本相同方法,得表8中的化合物。
参考实例91
硫代醋酸钾(CH3COSK,8.31g),分少量多次加到含有2-氯-2-(3,4-二甲基苯基)乙酸乙酯(15g)的DMF(80ml)溶液中,混合物室温搅拌2小时,随后,倒入水中,用乙酸乙酯提取,乙酸乙酯层水洗,MgSO4干燥,蒸除溶剂,得到:2-乙酰硫基-2-(3,4-二甲苯基)乙酰乙酯油状物16.5g,收率94%。
NMR(δppm,CDCl3):1.22(3H,t,J=7Hz),2.21(6H,S),2.30(3H,S),4.0-4.35(2H,m),5.2(1H,S),7.05-7.2(3H,m)。
参考实例92
将21.6g吗啉于室温下,滴加到含2-乙酰硫基-2-(3,4-二甲苯基)乙酸乙酯16.5g的甲醇溶液中(80ml)。于同样温度下继续搅拌2小时,反应混合物倒入水中,用2N-HCl酸化,乙酸乙酯提取,乙酸乙酯层水洗,MgSO4干燥,蒸去溶剂,残余物经硅胶层析,氯仿-正己烷(1∶3,V/V)洗脱,得到:2-硫-2-(3,4-二甲苯基)乙酸乙酯油状物(8.8g,63%)
NMR(δppm,CDCl3):1.23(3H,t,J=7Hz),2.23(6H,宽单峰),2.53(1H,d,J=7.5Hz),4.17(2H,q,J=7Hz),
4.60(1H,d,J=7.5Hz),7.0-7.3(3H,m)。
参考实例93
4.5g的2-硫-2-(3,4-二甲苯基)乙酸乙酯,3.3g2-溴丁酸,5.5g碳酸钾,及30mlDMF的混合物于室温下搅拌1小时,随后倒入水中,并用醚提取,水层经浓盐酸酸化,醚提取,醚层用水洗,MgSO4干燥,蒸除溶剂,得到2-〔2氧甲酰基-(3,4-二甲苯基)甲硫基〕丁酸油状物。(5.5g,89%)NMR(δppm,CDCl3):0.9-1.1(3H,m),1.1-1.3(3H,m),1.6-2.0(2H,m),2.25(6H,S),2。97(1H×1/2,t,J=7Hz),3。38(1H×1/2,t,J=7Hz),4.1-4.3(2H,m),4.78(1H×1/2,S),4.80(1H×1/2,S),7.0-7.3(3H,m)。
参考实例94-97
与参考实例93基本相同的方法,得到表9的油状化合物。
实施例1
在溶有71g甲氧甲酰(4-氯苯基)甲基硫代乙酸的400mlTHF中,加入39g草酸氯后,加入5滴DMF,于室温放置过夜,浓缩,剩余物溶于100ml CH2Cl2,在冰浴冷却时,将之滴加入含有AlCl3(69g)的CH2Cl2(400ml)混悬液中,滴加完后,混合物于室温搅拌3小时,倒入冰水中,分出有机层,水层用氯仿提取,与有机层合并,水洗,MgSO4干燥,蒸去溶剂,剩余物硅胶层析,乙醚-正己烷(1∶1,V/V)洗脱得结晶6-氯-3,4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰甲酯27g,乙酸乙酯-正己烷重结晶得无色片状结晶。熔点:
118~119℃。元素分析:C11H9O3SCl
计算值:C 51.47 H 3.53
实际值:C 51.40 H 3.58
在混悬有21.5g6-氯-3。4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰甲酯的甲醇(100ml)中,加入70ml 2N-KOH,室温搅拌1小时,反应液倒入水中,酸化,乙酸乙酯提取,酯层水洗MgSO4干燥,蒸去溶剂,得6-氯-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酸(18.8g,收率93%)乙酸乙酯重结晶得无色棱晶,熔点:220~221℃
元素分析:C10H7O3SCl
计算值:C.49.49,H.2.91
实际值:C.49.51,H.2.91
实施例2
在溶有63g乙氧甲酰(4-正己苯基)甲基硫乙酸的500ml乙醚中,加入33g亚硫酰氯,5滴吡啶,混合物回流30分钟,浓缩,剩余物溶于50mlCH2Cl2中,滴加到冰浴冷却的含有50gAlCl3的CH2Cl2(350ml)混悬液中,滴加完后反应物在冰浴下继续搅拌3小时,倒入冰水中,分离有机层,水层用氯仿提取,氯仿层与有机层合并,水洗,MgSO4干燥,蒸去溶剂,剩余物硅胶层析,乙醚-正己烷(1∶2,V/V)洗脱,得油状物6-正己基-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰乙酯(42g,收率70%)。
NMR(δppm,CDCl3):0.83(3H,t,J=7Hz),1.2-1.7(8H,m),1.30(3H,t,J=7Hz),2.64(2H,t,J=7Hz),3.27(1H,d,d,J=16和1Hz),4.24(2H,q,J=7Hz)4.27(1H,dd,J=16和1Hz),4.41(1H,S),7.1-7.4(2H,m),7.94(1H,d,J=2Hz)。
在混悬有41g的6-正己基-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰乙酯的150ml甲醇中,加入150ml2N-KOH,室温搅拌1小时,反应液倒入水中,酸化,乙酸乙酯提取,酯层水洗,MgSO4干燥,蒸去溶剂,得6-正己基-3,4-二氢-1H-2-苯并噻喃-4-酮-1-甲酸27.5g,
收率:74%,乙醚-己烷重结晶,得无色片晶,
熔点:66~67℃
元素分析:C16H20O3S
计算值:C,65.72;H,6.89
实际值:C,65.73;H,6.90
实施例3
与实施例2同样方法,得6-环己基-3.4-二氢-1H-2-苯并噻喃-4-酮-1甲酰乙酯
收率:69%,正己烷重结晶,得无色棱晶。
熔点:51~52℃
元素分析:C18H22O3S
计算值:C 67.89;H 6.96。
实际值:C 68.08;H 7.01。
在混悬有52g6-环己基-3,4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰乙酯的200ml甲醇中,加入100ml 2N-KOH,反应室温搅拌1小时,倒入水中,酸化,乙酸乙酯提取,酯层水洗MgSO4干燥,蒸去溶剂,得6-环己基-3,4-二氢-1H-2-苯并噻喃-4-酮-1-甲酸(33g,收率73%),乙酸乙酯-正己烷重结晶,得无色片晶,
熔点:171-172℃
元素分析:C16H18O3S
计算值:C,66.18;H,6.25,
实际值:C,66.16;H,6.28。
实施例4
与实施例2同样方法,得油状物3、4、6、7、8、9-六氢-1H-萘并〔2,3-C〕噻喃-4-酮-1-甲酰乙酯。
收率81%。
NMR(δppm,CDCl3):1.27(3H,t,J=7Hz)1.75(4H,m),2.75(4H,m),3.19(1H,d,J=16Hz),4.18(1H,d,J=16Hz),4.19(2H,q,J=7Hz),4.31(1H,S),6.87(1H,S),7.81(1H,S)。
在混悬有2.9g3,4,6,7,8,9-六氢-1H-萘并〔2,3-C〕噻喃-4-酮-1-甲酰乙酯的20ml甲醇中,加入10ml 2N-KOH,室温搅拌1小时,倒入水中,酸化,乙酸乙酯提取,酯层水洗,MgSO4干燥,蒸去溶剂,得3,4,6,7,8,9-六氢-1H-萘并〔2,3-C〕噻喃-4-酮-甲酸(2.3g,收率89%),乙酸乙酯重结晶,得无色棱晶
熔点 204~205℃
元素分析 C14H14O3S
计算值:C,64.10;H,5.38,
实际值:C,64.38;H,5.40。
实施例5
与实施例2同样方法,得油状物,6.7-二氧亚乙基-3,4-二氯-1H-2-苯并噻喃-4-酮-1-甲酰乙酯,收率73%。
NMR(δppm,CDCl3):1.31(3H,t,J=7Hz)3.21(1H,dd,J=16和1Hz),4.15-4.35(6H,m),6.72(1H,S),7.66(1H,S)。
在混悬有55g 6.7-二氧亚乙基-3,4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰乙酯的200ml乙醇中加入200ml 2N-NaOH,室温搅拌1小时,反应液倒入水中,酸化,乙酸乙酯提取,酯层水洗,MgSO4干燥,蒸去溶剂得6.7-亚乙二氧-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酸(32.5g,收率:65%)。乙酸乙酯重结晶得无色棱晶,熔点:207~208℃
元素分析 C12H10O5S
计算值:C,54.13,H,3.79,
实际值:C,54.37,H,3。82。
实施例6
同实施例2同样方法,得油状物3,4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰甲酯,收率73%。
NMR(δppm,CDCl3):3.25(1H,d,J=24Hz)3.77(3H。S),4.26(1H,d,J=24Hz),4.47(1H,S),7.0-7.5(5H,m),7.9-8.1(1H,m)。
在混悬有32g 3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰甲酯的150ml甲醇中,加入150ml 2N-KOH,室温搅拌1小时,反应液倒入水中,酸化,乙酸乙酯提取,酯层水洗,MgSO4干燥蒸去溶剂得3.4-二氯-1H-2-苯并噻喃-4-酮-1-甲酸,(22g,收率73%),乙酸乙酯-正己烷重结晶,得无色棱晶。
熔点:124-125℃
元素分析:C10H6O3S
计算值:C,57.68;H,3.87。
实际值:C,57.88,H,3.90。
实施例7
与实施例2同样方法,得6,7-二甲氧-3。4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰乙酯,收率69%,甲醇重结晶,得无色棒晶。
熔点:82-83℃
元素分析:C14H16O5S
计算值:C,56.74,H,5.44,
实际值:C,56.95,H,544。
在混悬有6g的6,7-二甲氧-3,4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰乙酯的20ml甲醇中加入15ml 2N.KOH,混合物室温搅拌1小时,反应液倒入水中,酸化,乙酸乙酯提取,酯层水洗,MgSO4干燥,蒸去溶剂,得6.7-二甲氧-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酸,(4.4g,收率82%),甲醇重结晶,得无色棱晶,
熔点:212-213℃
元素分析:C12H12O5S
计算值:C,53.72;H,4.51
实际值:C,53.76,H,4.61
实施例8
NMR(δppm,CDCl3):1.2-2.0(10H,m),2.55(1H,m),3.21(1H,d.d,J=14和5Hz)3.4(1H,m),3.41(1H,d,J=18Hz),3.63(1H,d,d,J=14和5Hz),3.81(3H,S)4.00(1H,d,J=18Hz),7.15(1H,d,J=8Hz),7.36(1H,d,d,J=8和2Hz),7.77(1H,d,J=2Hz)。
在混悬有40g7-环己基-1,2,4,5-四氢-3-苯并噻
-5-酮-2-甲酰甲酯的150ml甲醇中加入100ml 2N-KOH,混合物室温下搅拌1小时,反应物倒入水中,酸化,乙酸乙酯提取,酯层水洗,MgSO4干燥,蒸去溶剂,得7-环己基-1,2,4,5-四氢-3-苯并噻
-5-酮-2-甲酸(27.5g。收率72%)。乙酸乙酯重结晶得无色片晶,
熔点:210-211℃
元素分析:C17H20O3S
计算值:C,67.08,H,6.62。
实际值:C,67.25,H,6.63。
实施例9
与实施例2同样方法,得6-环己基-t-3-甲基-3,4-二氢-1H-2-苯并噻喃-4-酮-r-1-甲酰乙酯,收率80%NMR(δppm,CDCl3):1.32(3H,t,J=7Hz)1.45(3H,d,J=7Hz),1.2-1.9(10H,m)2.55(1H,m),4.26(2H,q,J=7Hz)4.43(1H,q,J=7Hz),4.43(1H,S),7.12(1H,d,J=8Hz)7.36(1H,dd,J=8和2Hz),7.91(1H,d,J=2Hz)。
在混悬含有11.5g6-环己基-3-甲基-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰乙酯的50ml甲醇中,加入40ml 2N-KOH,混合物于室温搅拌1小时,反应液倒入水中,酸化,乙酸乙酯提取,酯层水洗,MgSO4干燥,蒸去溶剂,得6-环己基-3-甲基-3.4-二氢-1H-2-苯并噻喃-4-酮-r-1-甲酸(7.4g,收率70%)乙酸乙酯重结晶,得无色片晶,
熔点:185-186℃
元素分析:C17H20O3S
计算值:C,67.08,H,6.62。
实际值:C,67.33,H,6.68。
实施例10
在溶有500mg 6-环己基-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酸的10ml DMF中加入365mg 85%的二乙基磷酸氰酯,混合物在冰浴中搅拌30分钟,然后加入160mg 3-氨基吡啶和202mg三乙胺,在冰浴冷却下进一步搅拌1小时,倒入水中,乙酸乙酯提取,酯层水洗,MgSO4干燥蒸去溶剂,得6-环己基-N-(3-吡啶基)-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰胺(490mg,收率79%)。乙酸乙酯-正己烷重结晶,得无色片晶。
熔点:194-195℃。
元素分析:C21H22N2O2S
计算值:C,68.82,H,6.05,N,7.64。
实际值:C,68.59,H,5.90,N,7.63。
实例11-55
与实例10同样方法,得表10中化合物。
注1)1,3-反式异构体
2)氯化氢
实例56
1.0g7-环己基-1,2,4,5-四氢-3-苯并噻
-5-酮-2-甲酸和2ml亚硫酰氯混和物加热回流30分钟,然后浓缩,剩余油状物溶于5mlCH2Cl2中,于室温滴加到含有757mg4-二乙氧磷酰苯胺的吡啶(10ml)溶液中,室温搅拌30分钟,浓缩,剩余物用1NHCl 50ml稀释,乙酸乙酯提取,酯层水洗,MgSO4干燥,蒸除溶剂,得7-环己基-N-(4-二乙氧磷酰苯基)-1,2,4,5-四氢-3-苯并噻
-5-酮-2-甲酰胺(760mg,收率45%)。己醇重结晶,得无色棱晶。
熔点:222-223℃
元素分析:C27H34NO5pS
计算值:C,62.90,H,6.65,N,2.72。
实际值:C,62.79,H,6.55,N,2.71。
实例57-58
与实例56同样方法,得表11中化合物。
实例59
102mg硼氢化钠加到含有7-环己基-N-(3,4-二氧次甲基苯基)-3,4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰胺(1.1g)的乙醇(20ml)溶液中,室温搅拌2小时,加1ml醋酸,反应液倒入水中,乙酸乙酯提取,酯层依次用水,饱和NaHCO3溶液和水洗涤,MgSO4干燥,蒸除溶剂,得7-环己基-N-(3。4-二氧次甲基苯基)-C-4-羟基-3.4-二氢-1H-2-苯并噻喃-r-1-甲酰胺(0.97g,收率88%)。乙酸乙酯重结晶,得无色棱晶,
熔点:208-209℃
元素分析:C23H25NO4S
计算值:C,67.13,H,6.12,N,3.40
实际值:C,66.91,H,6.19,N,3.15
实例60-62
与实例59相同方法,得表12中化合物。
注:1粉末,1,4-顺-和反-异构体的2∶1混合物
2粉末,1,4-顺-和反-异构体的3∶1混合物
3重结晶,2,5-顺-和反-异构体的2∶1混合物
实例63
间氯过苯甲酸(70%,662mg)的氯仿溶液(5ml)加到冰浴冷却的7-环己基-N-(3.4-二氧次甲基苯基)-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰胺(1.1g)的氯仿(15ml)溶液中,冰浴冷却下,搅拌1小时,反应液依次用水,饱和NaHCO3溶液,水洗涤,MgSO4干燥,蒸除溶剂,剩余物硅胶层析,乙酸乙酯-正己烷(2∶3,V/V)洗脱,蒸去溶剂,从第一洗脱带中得7-环己基-N-(3.4-二氧次甲基苯基)-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰胺-2.2-二氧化物(0.28g,收率23%)。乙酸乙酯-正己烷重结晶,得无色针晶。
熔点:224-225℃
元素分析:C23H23NO6S
计算值:C,62.57;H,5.25;N,3.17。
实际值:C,62.41,H,5.23,N,3.21。
从第二洗脱带中得7-环己基-N-(3.4-二氧次甲基苯基)-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰胺-2-氧化物(1,2-顺和反异构体6∶4混合物)(0.58g,收率53%),乙醇重结晶,得无色棱晶。
熔点:208-209℃
元素分析:C23H23NO5S
计算值:C.64.92;H.5.45;N.3.29。
实际值:C.64.57;H.5.28;N.3.45。
实例64-67
与实例63同样方法,得表13中化合物。
注:1顺和反异构体1∶1(ca.)混合物
2粉末,顺和反异构体的1∶1(ca.)混合物
3粉末
实例68
在7-环己基-N-(4-二乙氧磷酰甲基苯基)-1,2,4,5-四氢-3-苯并噻
-5-酮-2-甲酰胺(0.53g)的氯仿溶液(10ml)中,滴加间氯过苯甲酸(80% 0.6478)的氯仿溶液10ml,于室温放置过夜,反应混合物依次用K2CO3溶液,及水洗涤,MgSO4干燥,蒸除溶剂得7-环己基-N-(4-二乙氧磷酰甲基苯基)-1,2,4,5-四氢-3-苯并噻
-5-酮-2-甲酰胺-3.3-二氧化物(0.49g,收率87%),氯仿-乙醇重结晶,得无色片晶,
熔点:237-238℃
元素分析:C28H38NO7pS
计算值:C.59.88;H.6.46;N.2.49。
实际值:C.59.77;H.6.53;N.2.66。
实例69-70
与实例68基本相同方法,得表14中化合物。
实例71
6-甲基-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰乙酯-2,2-二氧化物(0.565g),2N-KOH(10ml)和甲醇(10ml)的混合物室温搅拌30分钟后,用2N-HCl酸化,乙酸乙酯提取,酯层水洗,MgSO4干燥,蒸除溶剂,剩余物加入2ml亚硫酰氯,回流30分钟,然后减压浓缩,油状剩余物溶于5ml二氯甲烷中,并于室温滴加到4-氨基苯基磷酰二乙酯(0.487mg)的吡啶(10ml)溶液中,混合物室温搅拌30分钟,倒入水中,乙酸乙酯提取,乙酸乙酯层依次用2N-HCl和水洗涤,MgSO4干燥,蒸除溶剂,得N-(4-二乙氧磷酰甲基苯基)-6-甲基-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰胺-2.2-二氧化物(0.32g,33%),乙醇重结晶,得无色针晶,
熔点:212-213℃
元素分析:C22H26NO7pS
计算值:C.55.11;H.5.47;N.2.92。
实际值:C.55.37;H.5.62;N.2.89。
实例72
与实例71基本同样方法,得N-(二乙氧磷酰苯基)-6-甲基-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰胺-2.2-二氧化物,收率55%,乙酸乙酯-正己烷重结晶,得无色棱晶,
熔点:129-130℃
元素分析:C21H24NO7pS
计算值:C.54.19;H.5.20;N.3.01。
实际值:C.54.14;H.5.39;N.2.92。
实例73
在溶有66g2-乙氧羰基(3,4-二甲苯基)甲硫基乙酸的300ml乙醚中,加入41.7g亚硫酰氯,再加入0.1ml吡啶,混合物于室温搅拌1小时,然后回流30分钟,减压浓缩,油状残余物溶于100ml二氯甲烷,在1小时内滴加到冰浴冷却的三氯化铝(64.4g)的二氯甲烷(300ml)混悬液中,反应液进一步在冰浴冷却下搅拌1小时,然后倒入冰水(1升)中,分出有机层,水洗,MgSO4干燥,蒸出溶剂,得6.7-二甲基-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰乙酯(49.5g,收率80%),正己烷重结晶,得无色片晶,熔点68-69℃。
元素分析:C14H16O3S
计算值:C.63.61;H.6.10。
实际值:C.63.68;H.6.15。
实例74-88
与实例73基本同样方法,得表15中化合物。
实例89
在溶有40.5g的2-〔乙氧羰基(3.4-二甲苯基)甲硫基丙酸的300ml乙醚中,加入24.4g亚硫酰氯,再加入0.1ml吡啶,混合物于室温搅拌1小时后,回流30分钟,减压浓缩,油状残余物溶于80ml二氯甲烷(CH2Cl2)在1小时内此溶液滴加到冰浴冷却的三氯化铝(AlCl3)(38.4g)的二氯甲烷(CH2Cl2)(300ml)混悬液中,反应物于冰浴冷却下进一步搅拌1.5小时后,倒入1升冰水中,分离有机层,水洗,MgSO4干燥,蒸除溶剂,油状残余物溶于乙氧化钠乙醇(由0.315g钠和200ml乙醇制备),回流15分钟,反应物倒入水中,1N,HCl酸化,乙醚提取,乙醚层水洗,MgSO4干燥,蒸除溶剂,残余物硅胶层析,乙醚-正己烷(1∶3)洗脱,得6.7-二甲基-t-3-甲基-3.4-二氢-1H-2-苯并噻喃-4-酮-r-1-甲酰乙酯(23.5g,收率62%),正己烷重结晶,得无色棱晶,熔点83-84℃。
元素分析:C15H18O3S
计算值:C 64.72;H 6.52
实际值:C 64.90;H 6.55
实例90-94
与实例89基本同样方法,得表16中化合物
实例95
21g6,7-二甲基-t-3-甲基-3.4-二氢-1H-2-苯并噻喃-4-酮-r-甲酸乙酯,100ml2N-KOH,和100ml甲醇混合物于50℃搅拌30分钟后,1N-HCl酸化,乙酸乙酯提取,酯层水洗,MgSO4干燥,减压浓缩,得6.7-二甲基-t-3-甲基-3.4-二氢-1H-2-苯并噻喃-4-酮-r-1-甲酸(16.5g,收率87%),乙酸乙酯重结晶,得无色棱晶,熔点203-204℃。
元素分析:C13H4O3S
计算值:C 62.38;H 5.64
实际值:C 62.67;H 5.67
实例96-116
与实例95基本同样方法,得表17中化合物
实例200
在溶有0.945g6.7-二甲基-3.4-二氢-1H-2-苯并噻喃-4-酮-甲酸的10mlTHF中,加入0.609g草酰氯和2滴DMF,于室温下搅拌1小时。另外,在冰浴冷却下,4.9g二乙氧磷酰胺,0.32g60%的氢化钠油溶液和30mlTHF混合搅拌30分钟,加入以上溶液,混合物在冰浴冷却下搅拌30分钟,倒入水中,乙酸乙酯提取,乙酸乙酯层水洗,MgSO4干燥,蒸除溶剂得N-二乙氧磷酰-6.7-二甲基-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰胺(0.29g,收率19%)。乙酸乙酯重结晶,得无色棱晶,熔点192-193℃,
元素分析:C16H22NO5pS
计算值:C 51.74;H 5.97;N 3.77
实际值:C 51.71;H 5.86;N 3.74
实例201
与实例200基本同样方法,合成6-环己基-N-二乙氧磷酰-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰胺,收率36%。乙酸乙酯重结晶,得无色针晶,熔点163-164℃
元素分析:C20H28NO5pS
计算值:C 56.46;H 6.63;N 3.29。
实际值:C 56.37;H 6.65;N 3.09。
实例202
在溶有0.473g的6.7-二甲基-3.4-二氢-1H-苯并噻喃-4-酮-1-甲酸的10mlTHF中,加入0.305g草酸氯和1滴DMF,于室温搅拌2小时,加入到20ml氨水-40ml乙酸乙酯中,再于室温下搅拌30分钟,乙酸乙酯被分离出,水洗,MgSO4干燥,蒸除溶剂,得6.7-二甲基-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰胺(0.38g,收率81%)乙酸乙酯重结晶,得无色片晶,熔点197-198℃。
元素分析:C12H13NO2S
计算值:C 61.25;H 5.57;N 5.95。
实际值:C 61.20;H 5.53;N 6.00。
实例203
0.5g6,7-二甲基-t-3-甲基-3.4-二氢-1H-2-苯并噻喃-4-酮-r-1-甲酸和2ml亚硫酰氯混合物回流搅拌1小时,浓缩,残余物溶入3ml氯仿,往混合物中加20ml氨水-30ml乙酸乙酯,室温搅拌30分钟,乙酸乙酯层分离,水洗,MgSO4干燥,蒸除溶剂,得6.7-二甲基-t-3-甲基-3.4-二氢-1H-2-苯并噻喃-4-酮-r-1-甲酰胺(0.305g,收率61%),乙酸乙酯重结晶,得无色针晶,熔点190-191℃。
元素分析:C13H15NO2S
计算值:C 62.62;H 6.06;N 5.06。
实际值:C 62.69;H 6.12;N 5.63。
实例204
1.6g碘化三甲基硅烷加到冰浴冷却的1.8gN-(4-二乙氧磷酰苯基)-6-环己基-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰胺和30ml四氯甲烷混合物中,室温搅拌30分钟,反应混合物浓缩,依次加入30ml甲醇,100ml2N-HCl,乙酸乙酯提取,乙酸乙酯层水洗,MgSO4干燥,蒸除溶剂,得6-环己基-N-(4-磷酰)-3.4-二氢-1H-2-苯并噻喃-4-酮-甲酰胺(0.92g,收率56%)乙酸乙酯-甲醇重结晶,得无色棱晶,熔点232-233℃。
元素分析:C22H24NO5pS
计算值:C 59.32;H 5.43;N 3.14。
实际值:C 58.90;H 5.31;N 3.02。
实例205
与实例204基本同样方法,得6.7-二甲基-(4-膦酰苯基)-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰胺,收率70%。乙酸乙酯-甲醇重结晶,得无色棱晶,熔点262-264℃。
元素分析:C18H18NO5pS
计算值:C 55.25;H 4.64;N 3.58。
实际值:C 55.06;H 4.72;N 3.35。
实例206
3.1g溴化三甲基硅烷加到含有2.6g6-环己基-N-(4-二乙氧磷酰甲基苯基)-3,4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰胺的50ml乙腈溶液中,室温搅拌12小时,反应液倒入水中,乙酸乙酯提取,乙酸乙酯层水洗,MgSO4干燥,蒸去溶剂,得6-环己基-N-(4-膦酰甲基苯基)-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰胺(0.91g,收率40%)。乙酸乙酯-甲醇重结晶,得无色棱晶,熔点226-227℃。
元素分析:C23H26NO5pS
计算值:C 60.12;H 5.70;N 3.05。
实际值:C 59.71;H 5.59;N 2.98。
实例207
与实例206基本同样方法,合成6.7-二甲基-N-(4-膦酰甲基苯基)-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰胺,乙酸乙酯-甲醇重结晶,得无色棱晶,熔点244-245℃。
元素分析:C19H20NO5pS
计算值:C 56.29;H 4.97;N 3.45。
实际值:C 55.97;H 4.87;N 3.34。
实例208
与实例59基本同样方法,得N-(4-氯苯基)-6,7-二甲基-c-4-羟基-3.4-二氢-1H-2-苯并噻喃-r-1-甲酰胺,收率78%,乙醇-氯仿重结晶,得无色棱晶,熔点244-245℃。
元素分析:C18H18NO2SCl
计算值:C 62.15;H 5.22;N 4.03。
实际值:C 62.02;H 5.18;N 4.06。
实例209
与实例59基本同样方法,得N-(4-二乙氧磷酰苯基)-6.7-二甲基-e-4-羟基-3,4-二氢-1H-2-苯并噻喃-r-1-甲酰胺,乙酸乙酯-正己烷重结晶,得无色棱晶,熔点162-163℃。
元素分析:C23H30NO5pS
计算值:C 59.60;H 6.52;N 3.20。
实际值:C 59.07;H 6.55;N 2.99。
制备实例1 片剂
每片成分:
1)化合物(实例22合成的化合物) 50mg
2)玉米淀粉 30mg
3)乳糖 113.4mg
4)羟丙基纤维素 6mg
5)水 0.03ml
6)硬脂酸镁 0.6mg
上述成分中的(1),(2),(3)和(4)混合,用(5)将其揉制成团,并于40℃真空干燥16小时。
将揉制之团料粉碎,过16目筛制粒,并混入成分(6),随后在旋转制片机(Kiktisui Seisakusho Co Ltd生产)上压片,制备200mg片。
制备实例2 肠溶衣片剂
1)化合物(实例33合成) 50mg
2)玉米淀粉 30mg
3)乳糖 113.4mg
4)羟基纤维素 6mg
5)水 0.03ml
6)硬脂酸镁 0.6mg
7)邻苯二甲酸乙酸纤维素 10mg
8)丙酮 0.2ml
上述成分中的(1),(2),(3),(4),(5)及(6)用制备实例1的方法制片,用(7)的丙酮溶液于条状涂料器(Freund生产)中包膜衣,制备的210mg肠衣片。
制备实例3 胶囊
1)化合物(实例35合成) 30mg
2)玉米淀粉 40mg
3)乳糖 74mg
4)羟丙基纤维素 6mg
5)水 0.02ml
上述成分中的(1),(2),(3)和(4)混合,用(5)揉制成团,并于40℃真空干燥16小时,干燥团料被粉碎,过16目筛制粒。用胶囊填充机(Zanassi,Italy制造)将颗粒填充于3号明胶胶囊,得到胶囊。
制备实例4 注射剂
1)化合物(实例23合成) 5mg
2)水杨酸钠 50mg
3)氯化钠 180mg
4)偏亚硫酸氢钠 20mg
5)羟苯甲酸甲酯 36mg
6)对羟苯甲酸丙酯 4mg
7)注射用水 2ml
上述成分中的(2),(3),(4),(5)及(6)溶于半量上述注射用水中,于80℃搅拌,所得溶液冷至40℃,将(1)溶入溶液,于溶液中加入剩余量的注射用水,使达到指定体积,用适宜的滤纸无菌过滤,得到无菌注射液。
Claims (15)
2、权利要求1中的化合物,其中,环A为可被1或2个相同或不同取代基取代的苯环,取代基包括卤素,C1-10烷基和C1-6烷氧基。
3、权利要求1中的化合物,其中,环A为可被1或2个相同或不同的C1-10烷基取代的苯环。
4、权利要求1中的化合物,其中,环A为可被C3-7环烷基取代的苯环。
5、权利要求1中的化合物,其中,R为氢,C1-10烷基或苯基。
6、权利要求1中的化合物,其中,R为氢,或甲基。
7、权利要求1中的化合物,其中,B为C1-10烷氧羰基或结构式-CONR1R2代表的基团,其中,R1和R2可为氢,可被取代的羟基或可被取代的5-7元杂环基。
8、权利要求1中的化合物,其中,B为结构式-CONR1R2代表的基团,其中,R1和R2可为氢,可被取代的烃基或可被取代的5-7元杂环基。
9、权利要求8中的化合物,其中,R1为氢,R2为结构式-C6H5(CH2)nP(O)(OR′)2代表的化合物,其中n为0或1,R′为C1-6烷基。
10、权利要求1中的化合物,其中,环A为可被1或2个相同或不同取代基取代的苯环。这些取代基有卤素,C1-10烷基,和C1-6烷氧基;R为氢;C1-10烷基或苯基;B为C1-10烷氧羰基或结构式-CONR1R2代表的基团,其中,R1和R2可为氢,可被取代的烃基,或可被取代的5-7元杂环基,K,K′都为0。
11、权利要求1中的化合物,命名为,6-环己基-N-(4-二乙氧磷酰甲基苯基)-3。4-二氯-1H-2-杂并噻喃-4-酮-1-甲酰胺。
12、权利要求1中的化合物,命名为,6。7-二甲基-N-(4-二乙氧磷酰苯基)-3,4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰胺。
13、权利要求1中的化合物,命名为6。7-二甲基-N-(4-二乙氧磷酰甲基苯基)-3.4-二氢-1H-2-苯并噻喃-4-酮-1-甲酰胺。
15、含有权利要求1中的抗骨质疏松有效量的化合物或其药用盐和药用载体或稀释剂的用于治疗骨质疏松症的制剂。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP335240/88 | 1988-12-28 | ||
JP33524088 | 1988-12-28 | ||
JP335240-88 | 1988-12-28 | ||
JP30360389 | 1989-11-21 | ||
JP303603/89 | 1989-11-21 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1045106A true CN1045106A (zh) | 1990-09-05 |
CN1032470C CN1032470C (zh) | 1996-08-07 |
Family
ID=26563567
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN89109626A Expired - Fee Related CN1032470C (zh) | 1988-12-28 | 1989-12-28 | 制备含硫杂环化合物的方法 |
Country Status (16)
Country | Link |
---|---|
US (1) | US5071841A (zh) |
EP (1) | EP0376197B1 (zh) |
JP (1) | JP2924033B2 (zh) |
KR (1) | KR0142429B1 (zh) |
CN (1) | CN1032470C (zh) |
AT (1) | ATE112770T1 (zh) |
AU (1) | AU623722B2 (zh) |
CA (1) | CA2006723C (zh) |
DE (1) | DE68918827T2 (zh) |
DK (1) | DK656789A (zh) |
ES (1) | ES2060735T3 (zh) |
FI (1) | FI102896B1 (zh) |
HK (1) | HK17396A (zh) |
HU (1) | HU209453B (zh) |
NO (1) | NO179977C (zh) |
NZ (1) | NZ231939A (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9617232B2 (en) | 2013-04-24 | 2017-04-11 | Daiichi Sankyo Company, Limited | Dicarboxylic acid compound |
US10053437B2 (en) | 2014-09-26 | 2018-08-21 | Daiichi Sankyo Company, Limited | Salt of dicarboxylic acid compound |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5158943A (en) * | 1988-11-21 | 1992-10-27 | Takeda Chemical Industries, Ltd. | Sulfur-containing heterocyclic compounds |
ES2157887T3 (es) * | 1990-05-30 | 2001-09-01 | Takeda Chemical Industries Ltd | Compuestos heterociclicos que contienen azufre. |
CN1151744A (zh) * | 1994-07-04 | 1997-06-11 | 武田药品工业株式会社 | 膦酸化合物及其制备和应用 |
TW403757B (en) | 1994-12-28 | 2000-09-01 | Takeda Chemical Industries Ltd | Optically active benzothiepin derivative, its preparation and use |
US5910492A (en) * | 1995-06-05 | 1999-06-08 | Takeda Chemical Industries, Ltd. | Osteogenic promoting pharmaceutical composition |
WO1997003989A1 (en) * | 1995-07-24 | 1997-02-06 | Takeda Chemical Industries, Ltd. | Production of optically active benzothiepin salts |
EP0949927B1 (en) | 1996-08-26 | 2002-10-16 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition containing osteogenesis-promoting substance and a polyethylene glycol |
WO1998015263A2 (en) * | 1996-10-09 | 1998-04-16 | Takeda Chemical Industries, Ltd. | A method for producing a microparticle |
US6344209B1 (en) | 1997-04-24 | 2002-02-05 | Takeda Chemical Industries, Ltd. | Apatite-coated solid composition |
WO1999065474A2 (en) * | 1998-06-15 | 1999-12-23 | Takeda Chemical Industries, Ltd. | Compositions for treating cartilage disease comprising certain sulfur-containing heterocyclic compounds |
US6355672B1 (en) | 1998-08-07 | 2002-03-12 | Takeda Chemical Industries, Ltd. | Benzothiepin derivatives, process for the preparation of the same and uses thereof |
TW557298B (en) * | 2000-08-14 | 2003-10-11 | Ciba Sc Holding Ag | A compound, a photopolymerizible composition, a process for producing coatings and a method for causing a photoinitiator to accumulate at the surface of coatings |
US6723736B2 (en) | 2000-10-10 | 2004-04-20 | Theracos, Inc. | Tricyclic compounds and uses thereof |
JP4843797B2 (ja) | 2006-01-18 | 2011-12-21 | 国立大学法人 東京医科歯科大学 | 骨形成促進物質とナノゲルを含有する骨形成用生体材料 |
CN101959875B (zh) | 2008-02-29 | 2013-10-16 | 日产化学工业株式会社 | 噻吩化合物及其中间体的制造方法 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1935685A1 (de) * | 1969-07-10 | 1971-01-14 | Schering Ag | Neue antimikrobiell wirksame Verbindungen |
US3636049A (en) * | 1969-11-26 | 1972-01-18 | Pfizer | Isothiochroman carboxamides |
FR2621038B1 (fr) * | 1987-09-28 | 1989-12-29 | Rhone Poulenc Sante | Derives d'alcadienes, leurs preparations, les medicaments les contenant et produits intermediaires |
-
1989
- 1989-12-21 DK DK656789A patent/DK656789A/da not_active Application Discontinuation
- 1989-12-21 NZ NZ231939A patent/NZ231939A/xx unknown
- 1989-12-22 EP EP89123794A patent/EP0376197B1/en not_active Expired - Lifetime
- 1989-12-22 DE DE68918827T patent/DE68918827T2/de not_active Expired - Fee Related
- 1989-12-22 AT AT89123794T patent/ATE112770T1/de not_active IP Right Cessation
- 1989-12-22 ES ES89123794T patent/ES2060735T3/es not_active Expired - Lifetime
- 1989-12-27 HU HU896790A patent/HU209453B/hu not_active IP Right Cessation
- 1989-12-27 JP JP1342280A patent/JP2924033B2/ja not_active Expired - Fee Related
- 1989-12-27 NO NO895267A patent/NO179977C/no not_active IP Right Cessation
- 1989-12-27 CA CA002006723A patent/CA2006723C/en not_active Expired - Fee Related
- 1989-12-27 FI FI896289A patent/FI102896B1/fi not_active IP Right Cessation
- 1989-12-28 US US07/458,094 patent/US5071841A/en not_active Expired - Lifetime
- 1989-12-28 AU AU47320/89A patent/AU623722B2/en not_active Ceased
- 1989-12-28 CN CN89109626A patent/CN1032470C/zh not_active Expired - Fee Related
- 1989-12-28 KR KR1019890019906A patent/KR0142429B1/ko not_active IP Right Cessation
-
1996
- 1996-02-01 HK HK17396A patent/HK17396A/xx not_active IP Right Cessation
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9617232B2 (en) | 2013-04-24 | 2017-04-11 | Daiichi Sankyo Company, Limited | Dicarboxylic acid compound |
US9670173B2 (en) | 2013-04-24 | 2017-06-06 | Daiichi Sankyo Company, Limited | Dicarboxylic acid compound |
US10053437B2 (en) | 2014-09-26 | 2018-08-21 | Daiichi Sankyo Company, Limited | Salt of dicarboxylic acid compound |
Also Published As
Publication number | Publication date |
---|---|
FI102896B (fi) | 1999-03-15 |
KR900009624A (ko) | 1990-07-05 |
CA2006723C (en) | 1998-08-25 |
NO179977B (no) | 1996-10-14 |
EP0376197B1 (en) | 1994-10-12 |
HU896790D0 (en) | 1990-03-28 |
AU623722B2 (en) | 1992-05-21 |
ATE112770T1 (de) | 1994-10-15 |
US5071841A (en) | 1991-12-10 |
HU209453B (en) | 1994-06-28 |
HK17396A (en) | 1996-02-09 |
CA2006723A1 (en) | 1990-06-28 |
AU4732089A (en) | 1990-07-19 |
NZ231939A (en) | 1991-07-26 |
NO179977C (no) | 1997-01-22 |
NO895267D0 (no) | 1989-12-27 |
CN1032470C (zh) | 1996-08-07 |
DE68918827T2 (de) | 1995-02-16 |
FI102896B1 (fi) | 1999-03-15 |
JP2924033B2 (ja) | 1999-07-26 |
JPH03232880A (ja) | 1991-10-16 |
FI896289A0 (fi) | 1989-12-27 |
EP0376197A1 (en) | 1990-07-04 |
DE68918827D1 (de) | 1994-11-17 |
DK656789A (da) | 1990-06-29 |
KR0142429B1 (ko) | 1998-06-01 |
DK656789D0 (da) | 1989-12-21 |
NO895267L (no) | 1990-06-29 |
ES2060735T3 (es) | 1994-12-01 |
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