NZ542674A - 2-Propylidene-19-nor-vitamin D compounds - Google Patents
2-Propylidene-19-nor-vitamin D compoundsInfo
- Publication number
- NZ542674A NZ542674A NZ542674A NZ54267404A NZ542674A NZ 542674 A NZ542674 A NZ 542674A NZ 542674 A NZ542674 A NZ 542674A NZ 54267404 A NZ54267404 A NZ 54267404A NZ 542674 A NZ542674 A NZ 542674A
- Authority
- NZ
- New Zealand
- Prior art keywords
- hydroxy
- compound
- group
- hydrogen
- hydroxypropylidene
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 113
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 64
- 239000001257 hydrogen Substances 0.000 claims abstract description 64
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 11
- 208000029725 Metabolic bone disease Diseases 0.000 claims abstract description 9
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 7
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 6
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims abstract description 5
- 150000003431 steroids Chemical class 0.000 claims abstract description 5
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 4
- 208000013725 Chronic Kidney Disease-Mineral and Bone disease Diseases 0.000 claims abstract description 4
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 4
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 4
- 208000000453 Skin Neoplasms Diseases 0.000 claims abstract description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 4
- 201000006409 renal osteodystrophy Diseases 0.000 claims abstract description 4
- 201000000849 skin cancer Diseases 0.000 claims abstract description 4
- 206010009900 Colitis ulcerative Diseases 0.000 claims abstract description 3
- 208000011231 Crohn disease Diseases 0.000 claims abstract description 3
- 206010039984 Senile osteoporosis Diseases 0.000 claims abstract description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 claims abstract description 3
- 230000008416 bone turnover Effects 0.000 claims abstract description 3
- 230000001054 cortical effect Effects 0.000 claims abstract description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 3
- 206010025135 lupus erythematosus Diseases 0.000 claims abstract description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 3
- 208000005368 osteomalacia Diseases 0.000 claims abstract description 3
- 208000001685 postmenopausal osteoporosis Diseases 0.000 claims abstract description 3
- 208000030136 Marchiafava-Bignami Disease Diseases 0.000 claims abstract 8
- 230000037118 bone strength Effects 0.000 claims abstract 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 67
- 239000000203 mixture Substances 0.000 claims description 67
- 150000002431 hydrogen Chemical class 0.000 claims description 45
- 125000000217 alkyl group Chemical group 0.000 claims description 42
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 40
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 claims description 39
- 239000003814 drug Substances 0.000 claims description 33
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 18
- 125000001153 fluoro group Chemical group F* 0.000 claims description 18
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 17
- 210000000988 bone and bone Anatomy 0.000 claims description 17
- 229910052805 deuterium Inorganic materials 0.000 claims description 17
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 16
- 125000004043 oxo group Chemical group O=* 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 14
- 150000003254 radicals Chemical class 0.000 claims description 10
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 8
- 125000001118 alkylidene group Chemical group 0.000 claims description 8
- 125000005345 deuteroalkyl group Chemical group 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000004434 sulfur atom Chemical group 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 238000007911 parenteral administration Methods 0.000 claims description 6
- 208000032839 leukemia Diseases 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000011200 topical administration Methods 0.000 claims description 2
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 153
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 141
- -1 vitamin D compounds Chemical class 0.000 description 68
- 239000000243 solution Substances 0.000 description 44
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 42
- 238000005481 NMR spectroscopy Methods 0.000 description 41
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 37
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 35
- 230000000694 effects Effects 0.000 description 35
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
- 101150041968 CDC13 gene Proteins 0.000 description 29
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
- 229960005084 calcitriol Drugs 0.000 description 27
- 239000011575 calcium Substances 0.000 description 26
- 229910052791 calcium Inorganic materials 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 24
- 239000012267 brine Substances 0.000 description 24
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
- 229930003316 Vitamin D Natural products 0.000 description 23
- 239000011710 vitamin D Substances 0.000 description 23
- 235000019166 vitamin D Nutrition 0.000 description 23
- 229940046008 vitamin d Drugs 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 21
- 229910052786 argon Inorganic materials 0.000 description 21
- 239000002904 solvent Substances 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 19
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 18
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 17
- 238000010828 elution Methods 0.000 description 16
- 238000000034 method Methods 0.000 description 16
- 239000011734 sodium Substances 0.000 description 16
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 230000000968 intestinal effect Effects 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- 238000003756 stirring Methods 0.000 description 14
- 125000000746 allylic group Chemical group 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- 230000032258 transport Effects 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 230000004069 differentiation Effects 0.000 description 12
- 238000003818 flash chromatography Methods 0.000 description 12
- 238000011282 treatment Methods 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- 150000002576 ketones Chemical class 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 125000002252 acyl group Chemical group 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 238000000926 separation method Methods 0.000 description 10
- 239000000284 extract Substances 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- MPQXHAGKBWFSNV-UHFFFAOYSA-N oxidophosphanium Chemical class [PH3]=O MPQXHAGKBWFSNV-UHFFFAOYSA-N 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 150000003710 vitamin D derivatives Chemical class 0.000 description 9
- 230000027455 binding Effects 0.000 description 8
- 230000024245 cell differentiation Effects 0.000 description 8
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 229930194542 Keto Natural products 0.000 description 7
- 150000004808 allyl alcohols Chemical class 0.000 description 7
- 239000000538 analytical sample Substances 0.000 description 7
- 239000012230 colorless oil Substances 0.000 description 7
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- 238000007239 Wittig reaction Methods 0.000 description 6
- 230000004071 biological effect Effects 0.000 description 6
- FNIATMYXUPOJRW-UHFFFAOYSA-N cyclohexylidene Chemical group [C]1CCCCC1 FNIATMYXUPOJRW-UHFFFAOYSA-N 0.000 description 6
- 230000037213 diet Effects 0.000 description 6
- 235000005911 diet Nutrition 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 230000027425 release of sequestered calcium ion into cytosol Effects 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- 229940088594 vitamin Drugs 0.000 description 6
- 229930003231 vitamin Natural products 0.000 description 6
- 235000013343 vitamin Nutrition 0.000 description 6
- 239000011782 vitamin Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 230000000125 calcaemic effect Effects 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 150000002596 lactones Chemical class 0.000 description 5
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 5
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- PKFBWEUIKKCWEW-WEZTXPJVSA-N (1r,3r)-5-[(2e)-2-[(1r,3as,7ar)-1-[(2r)-6-hydroxy-6-methylheptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]cyclohexane-1,3-diol Chemical class C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1C[C@@H](O)C[C@H](O)C1 PKFBWEUIKKCWEW-WEZTXPJVSA-N 0.000 description 4
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 4
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 4
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- PMOIAJVKYNVHQE-UHFFFAOYSA-N phosphanium;bromide Chemical compound [PH4+].[Br-] PMOIAJVKYNVHQE-UHFFFAOYSA-N 0.000 description 4
- 150000004714 phosphonium salts Chemical class 0.000 description 4
- 238000011321 prophylaxis Methods 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
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- 230000004044 response Effects 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 4
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 3
- AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- AAWZDTNXLSGCEK-UHFFFAOYSA-N Cordycepinsaeure Natural products OC1CC(O)(C(O)=O)CC(O)C1O AAWZDTNXLSGCEK-UHFFFAOYSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
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- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
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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 3
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- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 3
- 150000003722 vitamin derivatives Chemical class 0.000 description 3
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- ATMUYWZMPLKPEJ-XLMAVXFVSA-N (1r,3ar,7ar)-7a-methyl-1-[(2r)-6-methylheptan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-one Chemical compound O=C1CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]21 ATMUYWZMPLKPEJ-XLMAVXFVSA-N 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- JWUBBDSIWDLEOM-UHFFFAOYSA-N 25-Hydroxycholecalciferol Natural products C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2C1=CC=C1CC(O)CCC1=C JWUBBDSIWDLEOM-UHFFFAOYSA-N 0.000 description 2
- JWUBBDSIWDLEOM-DCHLRESJSA-N 25-Hydroxyvitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C/C=C1\C[C@@H](O)CCC1=C JWUBBDSIWDLEOM-DCHLRESJSA-N 0.000 description 2
- JWUBBDSIWDLEOM-NQZHSCJISA-N 25-hydroxy-3 epi cholecalciferol Chemical compound C1([C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=CC=C1C[C@H](O)CCC1=C JWUBBDSIWDLEOM-NQZHSCJISA-N 0.000 description 2
- RQFUZUMFPRMVDX-UHFFFAOYSA-N 3-Bromo-1-propanol Chemical compound OCCCBr RQFUZUMFPRMVDX-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
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- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 1
- 208000032349 type 2B vitamin D-dependent rickets Diseases 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
-
- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
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- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Diabetes (AREA)
- Dermatology (AREA)
- Pulmonology (AREA)
- Hematology (AREA)
- Transplantation (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Cardiology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Urology & Nephrology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Furan Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US46195803P | 2003-04-10 | 2003-04-10 | |
| PCT/US2004/011059 WO2004092118A2 (en) | 2003-04-10 | 2004-04-09 | 2-propylidene-19-nor-vitamin d compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ542674A true NZ542674A (en) | 2009-03-31 |
Family
ID=33299883
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ542674A NZ542674A (en) | 2003-04-10 | 2004-04-09 | 2-Propylidene-19-nor-vitamin D compounds |
Country Status (14)
| Country | Link |
|---|---|
| US (3) | US20060293291A1 (https=) |
| EP (1) | EP1613588B1 (https=) |
| JP (1) | JP5005340B2 (https=) |
| KR (1) | KR20050120787A (https=) |
| CN (2) | CN101293894B (https=) |
| AT (1) | ATE556999T1 (https=) |
| AU (1) | AU2004230948A1 (https=) |
| BR (1) | BRPI0409194A (https=) |
| CA (1) | CA2516233C (https=) |
| MX (1) | MXPA05009336A (https=) |
| MY (1) | MY146504A (https=) |
| NZ (1) | NZ542674A (https=) |
| WO (1) | WO2004092118A2 (https=) |
| ZA (1) | ZA200506204B (https=) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA200506204B (en) * | 2003-04-10 | 2006-10-25 | Wisconsin Alumni Res Found | 2-propylidene-19-nor-vitamin D compounds |
| US7713951B2 (en) * | 2004-04-09 | 2010-05-11 | Wisconsin Alumni Research Foundation | 2-alkylidene-18,19-dinor-vitamin D compounds |
| DK1848442T3 (da) * | 2005-02-11 | 2012-05-29 | Wisconsin Alumni Res Found | 2-methylene-19-nor-(20s-24epi)-1alfa,25-dihydroxyvitamine-d2 |
| WO2006086613A2 (en) * | 2005-02-11 | 2006-08-17 | Wisconsin Alumni Research Foundation | 2-METHYLENE-19-NOR- (20S-24S) - 1α, 25-D IHYDROXYVITAMIN-D2 |
| US8114393B2 (en) | 2005-09-14 | 2012-02-14 | Wisconsin Alumni Research Foundation | Methods and compositions for phosphate binding |
| US20090281340A1 (en) * | 2006-04-05 | 2009-11-12 | Deluca Hector F | 1alpha-hydroxy-2-(3'-hydroxypropylidene)-19-nor-vitamin d compounds and methods of making and treatment thereof |
| NZ571896A (en) | 2006-04-05 | 2011-09-30 | Wisconsin Alumni Res Found | 1-Alpha.-hydroxy-2-(3'-hydroxypropylidene)-19-nor-vitamin D compounds and methods of making and use thereof |
| NZ570711A (en) | 2006-04-06 | 2012-10-26 | Wisconsin Alumni Res Found | 2-Substituted-1alpha, 25-dihydroxy-19,26,27-trinor vitamin D analogs and uses thereof |
| EP2021321B1 (en) * | 2006-04-06 | 2012-06-20 | Wisconsin Alumni Research Foundation | 2-methylene-1alpha,25-dihydroxy-18,19,21-trinorvitamin d3 and uses thereof |
| MX2008012912A (es) * | 2006-04-06 | 2008-11-26 | Wisconsin Alumni Res Found | Analogos de 2-metilen-1a,25-dihidroxi-19,21-dinorvitamina d3 y sus usos. |
| EP2001860A2 (en) * | 2006-04-06 | 2008-12-17 | Wisconsin Alumni Research Foundation | 19-nor-vitamin d analogs with 1,2,or 3,2 heterocyclic ring |
| WO2008035207A2 (en) * | 2006-04-06 | 2008-03-27 | Wisconsin Alumni Research Foundation | 2-methylene-1alpha-hydroxy-19,21-dinorvitamin d3 analogs and uses thereof |
| NZ570712A (en) * | 2006-04-06 | 2011-11-25 | Wisconsin Alumni Res Found | 2-methylene-1alpha-hydroxy-18,19,21-trinorvitamin D3 analogs and uses thereof |
| EP2004597B1 (en) * | 2006-04-10 | 2011-01-26 | Wisconsin Alumni Research Foundation | 1alpha-hydroxy-2-(3'-hydroxypropylidene)-19-nor-vitamin d compounds with a 1,1-dimethylpropyl side chain |
Family Cites Families (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL67153A (en) | 1981-11-02 | 1986-12-31 | Res Inst Medicine Chem | Intermediates in the production of vitamin d analogues and method for their production |
| US4666634A (en) * | 1984-12-05 | 1987-05-19 | Chugai Seiyaku Kabushiki Kaisha | vitamin D3 derivatives having a substituent at 2-position |
| GB8904154D0 (en) | 1989-02-23 | 1989-04-05 | Leo Pharm Prod Ltd | Chemical compounds |
| NZ232734A (en) | 1989-03-09 | 1991-11-26 | Wisconsin Alumni Res Found | 19-nor vitamin d derivatives and pharmaceutical compositions |
| CA1333616C (en) * | 1989-03-09 | 1994-12-20 | Hector F. Deluca | 19-nor-vitamin d compounds |
| US5246925A (en) * | 1989-03-09 | 1993-09-21 | Wisconsin Alumni Research Foundation | 19-nor-vitamin D compounds for use in treating hyperparathyroidism |
| AU649057B2 (en) | 1990-08-24 | 1994-05-12 | Wisconsin Alumni Research Foundation | Methods and compositions containing vitamin D compounds for improvement of skin conditions |
| ES2123505T3 (es) | 1990-09-07 | 1999-01-16 | Wisconsin Alumni Res Found | Nuevo uso de compuestos de 19-nor-vitamina d 1alfa-hidroxilada para tratar la psoriasis. |
| AU650751B2 (en) | 1991-05-28 | 1994-06-30 | Wisconsin Alumni Research Foundation | Novel synthesis of 19-nor vitamin D compounds |
| US5086191A (en) * | 1991-05-28 | 1992-02-04 | Wisconsin Alumni Research Foundation | Intermediates for the synthesis of 19-nor vitamin D compounds |
| JP3213092B2 (ja) * | 1991-11-01 | 2001-09-25 | 中外製薬株式会社 | ２β位に置換基を有するビタミンＤ誘導体 |
| EP0619306B1 (en) * | 1993-04-05 | 1996-09-11 | Wisconsin Alumni Research Foundation | 19-Nor-vitamin D3 compounds with substituent at 2-position |
| US5565589A (en) * | 1993-11-03 | 1996-10-15 | Wisconsin Alumni Research Foundation | 17-formyl-5,6-trans-vitamin D compounds |
| US5428029A (en) * | 1993-11-24 | 1995-06-27 | Hoffmann-La Roche Inc. | Vitamin D3 fluorinated analogs |
| WO1996001811A1 (en) * | 1994-07-11 | 1996-01-25 | The Johns-Hopkins University | 2-substituted 1,25-dihydroxyvitamin d3 derivatives |
| DE69507714D1 (de) * | 1994-11-21 | 1999-03-18 | Wisconsin Alumni Res Found | 18,19-dinor-vitamin-d-derivate |
| US5877168A (en) * | 1995-02-10 | 1999-03-02 | Chugai Seiyaku Kabushiki Kaisha | Vitamin D derivative with substituent at the 2β-position |
| IL118156A (en) * | 1995-05-09 | 2001-08-26 | Duphar Int Res | Vitamin d compounds, their preparation and pharmaceutical compositions containing them |
| US5843928A (en) * | 1997-03-17 | 1998-12-01 | Wisconsin Alumni Research Foundation | 2-alkylidene-19-nor-vitamin D compounds |
| US5945410A (en) * | 1997-03-17 | 1999-08-31 | Wisconsin Alumni Research Foundation | 2-alkyl-19-nor-vitamin D compounds |
| US6392071B1 (en) * | 1997-03-17 | 2002-05-21 | Wisconsin Alumni: Research Foundation | 26,27-homologated-20-EPI-2-alkylidene-19-nor-vitamin D compounds |
| GB9915839D0 (en) * | 1999-07-06 | 1999-09-08 | Textron Automotive U K | Valve assembly for vehicle washing system |
| EP1524264A3 (en) * | 2000-05-31 | 2010-01-20 | Wisconsin Alumni Research Foundation | 2-ethylidene-19-nor-vitamin D compounds |
| NZ522909A (en) | 2000-05-31 | 2004-09-24 | Wisconsin Alumni Res Found | 2-ethyl and 2-ethylidene-19-nor-vitamin D compounds |
| US6846811B2 (en) * | 2002-04-22 | 2005-01-25 | Wisconsin Alumni Research Foundation | (20S) 1α-hydroxy-2α-methyl and 2β-methyl-19-nor-vitamin D3 and their uses |
| ZA200506204B (en) * | 2003-04-10 | 2006-10-25 | Wisconsin Alumni Res Found | 2-propylidene-19-nor-vitamin D compounds |
| EP1694333A2 (en) * | 2003-11-25 | 2006-08-30 | Deltanoid Pharmaceuticals, Inc. | Methods for reducing body fat using vitamin d compounds |
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2004
- 2004-04-09 ZA ZA200506204A patent/ZA200506204B/en unknown
- 2004-04-09 AT AT04749961T patent/ATE556999T1/de active
- 2004-04-09 MX MXPA05009336A patent/MXPA05009336A/es active IP Right Grant
- 2004-04-09 AU AU2004230948A patent/AU2004230948A1/en not_active Abandoned
- 2004-04-09 US US10/544,163 patent/US20060293291A1/en not_active Abandoned
- 2004-04-09 NZ NZ542674A patent/NZ542674A/en not_active IP Right Cessation
- 2004-04-09 CN CN2008101302056A patent/CN101293894B/zh not_active Expired - Fee Related
- 2004-04-09 US US10/821,479 patent/US7241747B2/en not_active Expired - Lifetime
- 2004-04-09 CA CA2516233A patent/CA2516233C/en not_active Expired - Fee Related
- 2004-04-09 BR BRPI0409194-9A patent/BRPI0409194A/pt not_active Application Discontinuation
- 2004-04-09 EP EP04749961A patent/EP1613588B1/en not_active Expired - Lifetime
- 2004-04-09 CN CNB2004800096206A patent/CN100534981C/zh not_active Expired - Fee Related
- 2004-04-09 WO PCT/US2004/011059 patent/WO2004092118A2/en not_active Ceased
- 2004-04-09 KR KR1020057019087A patent/KR20050120787A/ko not_active Abandoned
- 2004-04-09 JP JP2006509883A patent/JP5005340B2/ja not_active Expired - Fee Related
- 2004-10-14 MY MYPI20044250A patent/MY146504A/en unknown
-
2007
- 2007-05-17 US US11/750,172 patent/US7531527B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP5005340B2 (ja) | 2012-08-22 |
| MY146504A (en) | 2012-08-15 |
| WO2004092118A3 (en) | 2005-01-27 |
| HK1086817A1 (zh) | 2006-09-29 |
| ATE556999T1 (de) | 2012-05-15 |
| US20040229851A1 (en) | 2004-11-18 |
| JP2006523239A (ja) | 2006-10-12 |
| KR20050120787A (ko) | 2005-12-23 |
| CA2516233A1 (en) | 2004-10-28 |
| US20070213546A1 (en) | 2007-09-13 |
| US7531527B2 (en) | 2009-05-12 |
| US7241747B2 (en) | 2007-07-10 |
| MXPA05009336A (es) | 2005-11-04 |
| CN1771226A (zh) | 2006-05-10 |
| AU2004230948A1 (en) | 2004-10-28 |
| WO2004092118A2 (en) | 2004-10-28 |
| EP1613588B1 (en) | 2012-05-09 |
| BRPI0409194A (pt) | 2006-04-11 |
| EP1613588A2 (en) | 2006-01-11 |
| CN100534981C (zh) | 2009-09-02 |
| CN101293894A (zh) | 2008-10-29 |
| CN101293894B (zh) | 2011-04-06 |
| US20060293291A1 (en) | 2006-12-28 |
| ZA200506204B (en) | 2006-10-25 |
| CA2516233C (en) | 2011-09-20 |
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