JP2001501584A - カルシリチック化合物 - Google Patents
カルシリチック化合物Info
- Publication number
- JP2001501584A JP2001501584A JP09536327A JP53632797A JP2001501584A JP 2001501584 A JP2001501584 A JP 2001501584A JP 09536327 A JP09536327 A JP 09536327A JP 53632797 A JP53632797 A JP 53632797A JP 2001501584 A JP2001501584 A JP 2001501584A
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- phenyl
- compound
- alk
- unsubstituted
- 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.)
- Ceased
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 313
- 230000001126 calcilytic effect Effects 0.000 title claims abstract description 50
- 238000000034 method Methods 0.000 claims abstract description 145
- 230000000694 effects Effects 0.000 claims abstract description 57
- 102000013830 Calcium-Sensing Receptors Human genes 0.000 claims abstract description 54
- 108010050543 Calcium-Sensing Receptors Proteins 0.000 claims abstract description 54
- 125000000217 alkyl group Chemical group 0.000 claims description 168
- -1 6-CN-2-pyridyl Chemical group 0.000 claims description 153
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 65
- 125000001424 substituent group Chemical group 0.000 claims description 63
- 125000003342 alkenyl group Chemical group 0.000 claims description 55
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 47
- 125000002947 alkylene group Chemical group 0.000 claims description 41
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 41
- 229910001424 calcium ion Inorganic materials 0.000 claims description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 39
- 201000010099 disease Diseases 0.000 claims description 37
- 125000003118 aryl group Chemical group 0.000 claims description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- 210000002966 serum Anatomy 0.000 claims description 29
- 125000003545 alkoxy group Chemical group 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 28
- 208000035475 disorder Diseases 0.000 claims description 27
- 210000000988 bone and bone Anatomy 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 230000002159 abnormal effect Effects 0.000 claims description 21
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 21
- 125000004450 alkenylene group Chemical group 0.000 claims description 19
- 229910052801 chlorine Inorganic materials 0.000 claims description 19
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- 230000003834 intracellular effect Effects 0.000 claims description 19
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims description 15
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000001624 naphthyl group Chemical group 0.000 claims description 14
- 125000004419 alkynylene group Chemical group 0.000 claims description 13
- 125000004076 pyridyl group Chemical group 0.000 claims description 13
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000001188 haloalkyl group Chemical group 0.000 claims description 10
- 125000004600 benzothiopyranyl group Chemical group S1C(C=CC2=C1C=CC=C2)* 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 230000001225 therapeutic effect Effects 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 7
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 208000001132 Osteoporosis Diseases 0.000 claims description 5
- 125000001475 halogen functional group Chemical group 0.000 claims description 5
- 230000004079 mineral homeostasis Effects 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- 229910052796 boron Inorganic materials 0.000 claims description 4
- 208000010392 Bone Fractures Diseases 0.000 claims description 3
- 206010017076 Fracture Diseases 0.000 claims description 3
- 208000010191 Osteitis Deformans Diseases 0.000 claims description 3
- 208000027868 Paget disease Diseases 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 230000035876 healing Effects 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 208000027202 mammary Paget disease Diseases 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- 201000008968 osteosarcoma Diseases 0.000 claims description 3
- 208000028169 periodontal disease Diseases 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 238000012216 screening Methods 0.000 claims description 3
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000005017 substituted alkenyl group Chemical group 0.000 claims 2
- YNSCKPCDFIDINW-UHFFFAOYSA-N 3-[[2-[[1-[2-(dimethylamino)acetyl]-6-methoxy-4,4-dimethyl-2,3-dihydroquinolin-7-yl]amino]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]amino]thiophene-2-carboxamide Chemical compound COC1=CC(C(CCN2C(=O)CN(C)C)(C)C)=C2C=C1NC(N=C1NC=CC1=1)=NC=1NC=1C=CSC=1C(N)=O YNSCKPCDFIDINW-UHFFFAOYSA-N 0.000 claims 1
- 208000037147 Hypercalcaemia Diseases 0.000 claims 1
- 230000036772 blood pressure Effects 0.000 claims 1
- 230000000148 hypercalcaemia Effects 0.000 claims 1
- 208000030915 hypercalcemia disease Diseases 0.000 claims 1
- 230000003211 malignant effect Effects 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 186
- 210000004027 cell Anatomy 0.000 description 82
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 67
- 239000007787 solid Substances 0.000 description 65
- 238000002360 preparation method Methods 0.000 description 55
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 53
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 102000003982 Parathyroid hormone Human genes 0.000 description 45
- 239000000199 parathyroid hormone Substances 0.000 description 45
- 108090000445 Parathyroid hormone Proteins 0.000 description 44
- 229960001319 parathyroid hormone Drugs 0.000 description 44
- 239000011575 calcium Substances 0.000 description 41
- 239000000243 solution Substances 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 36
- 235000002639 sodium chloride Nutrition 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 230000028327 secretion Effects 0.000 description 28
- 229910052791 calcium Inorganic materials 0.000 description 27
- 239000000203 mixture Substances 0.000 description 26
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 25
- 239000010410 layer Substances 0.000 description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- 125000004432 carbon atom Chemical group C* 0.000 description 22
- 238000004519 manufacturing process Methods 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- DUMKDWRRTLFHTA-UHFFFAOYSA-N 1-(4-methoxyphenyl)-2-methylpropan-2-amine Chemical compound COC1=CC=C(CC(C)(C)N)C=C1 DUMKDWRRTLFHTA-UHFFFAOYSA-N 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- 230000000849 parathyroid Effects 0.000 description 19
- 239000000047 product Substances 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000012458 free base Substances 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- FQYUMYWMJTYZTK-UHFFFAOYSA-N Phenyl glycidyl ether Chemical compound C1OC1COC1=CC=CC=C1 FQYUMYWMJTYZTK-UHFFFAOYSA-N 0.000 description 16
- 150000002430 hydrocarbons Chemical group 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 150000001412 amines Chemical class 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- 102000005962 receptors Human genes 0.000 description 12
- 108020003175 receptors Proteins 0.000 description 12
- 125000000304 alkynyl group Chemical group 0.000 description 11
- 150000003975 aryl alkyl amines Chemical class 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 11
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 239000012230 colorless oil Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 229940098773 bovine serum albumin Drugs 0.000 description 9
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 230000004044 response Effects 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
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- BXOCBNXPOIPDTL-UHFFFAOYSA-N 1-(4-methoxyphenyl)-2-methylpropan-2-amine;hydrochloride Chemical compound Cl.COC1=CC=C(CC(C)(C)N)C=C1 BXOCBNXPOIPDTL-UHFFFAOYSA-N 0.000 description 7
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 7
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 238000004007 reversed phase HPLC Methods 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- 238000010561 standard procedure Methods 0.000 description 7
- BGSZBHCYLIHECZ-UHFFFAOYSA-N 2-(4-methoxyphenyl)-n,n-dimethylethanamine Chemical compound COC1=CC=C(CCN(C)C)C=C1 BGSZBHCYLIHECZ-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 230000009286 beneficial effect Effects 0.000 description 6
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- 238000001727 in vivo Methods 0.000 description 6
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- 230000002401 inhibitory effect Effects 0.000 description 6
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- 238000012746 preparative thin layer chromatography Methods 0.000 description 6
- ZMQAAUBTXCXRIC-UHFFFAOYSA-N safrole Chemical compound C=CCC1=CC=C2OCOC2=C1 ZMQAAUBTXCXRIC-UHFFFAOYSA-N 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 6
- 208000020084 Bone disease Diseases 0.000 description 5
- 241000283690 Bos taurus Species 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
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- 239000002552 dosage form Substances 0.000 description 5
- XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
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- 229920006395 saturated elastomer Polymers 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- LTPVSOCPYWDIFU-UHFFFAOYSA-N 4-methoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1 LTPVSOCPYWDIFU-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- 102000055006 Calcitonin Human genes 0.000 description 4
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- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 108010081690 Pertussis Toxin Proteins 0.000 description 4
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- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 4
- 229960004015 calcitonin Drugs 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 239000012259 ether extract Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
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- 238000005259 measurement Methods 0.000 description 4
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- 102000004169 proteins and genes Human genes 0.000 description 4
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- 238000000926 separation method Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- QYYCPWLLBSSFBW-UHFFFAOYSA-N 2-(naphthalen-1-yloxymethyl)oxirane Chemical compound C=1C=CC2=CC=CC=C2C=1OCC1CO1 QYYCPWLLBSSFBW-UHFFFAOYSA-N 0.000 description 3
- QAZAWPCTVDEZCT-UHFFFAOYSA-N 2-chloro-6-hydroxybenzonitrile Chemical compound OC1=CC=CC(Cl)=C1C#N QAZAWPCTVDEZCT-UHFFFAOYSA-N 0.000 description 3
- FGLBSLMDCBOPQK-UHFFFAOYSA-N 2-nitropropane Chemical compound CC(C)[N+]([O-])=O FGLBSLMDCBOPQK-UHFFFAOYSA-N 0.000 description 3
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Classifications
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
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- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/58—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
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- Chemical & Material Sciences (AREA)
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- Veterinary Medicine (AREA)
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- Physical Education & Sports Medicine (AREA)
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- Rheumatology (AREA)
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- Immunology (AREA)
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- Endocrinology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyridine Compounds (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
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| US62960896A | 1996-04-09 | 1996-04-09 | |
| US08/629,608 | 1996-04-09 | ||
| US3226396P | 1996-12-03 | 1996-12-03 | |
| US60/032,263 | 1996-12-03 | ||
| PCT/US1997/005558 WO1997037967A1 (en) | 1996-04-09 | 1997-04-04 | Calcilytic compounds |
Publications (2)
| Publication Number | Publication Date |
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| JP2001501584A true JP2001501584A (ja) | 2001-02-06 |
| JP2001501584A5 JP2001501584A5 (enExample) | 2005-01-13 |
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| BR (1) | BR9708632A (enExample) |
| CA (1) | CA2251331C (enExample) |
| CO (1) | CO4820431A1 (enExample) |
| DE (1) | DE69733649T2 (enExample) |
| EA (1) | EA002984B1 (enExample) |
| IL (1) | IL126458A (enExample) |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004094362A1 (ja) * | 2003-04-23 | 2004-11-04 | Japan Tobacco Inc. | CaSRアンタゴニスト |
| US7285572B2 (en) | 2003-05-28 | 2007-10-23 | Japan Tobacco Inc. | CaSR antagonist |
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| DE4426245A1 (de) | 1994-07-23 | 1996-02-22 | Gruenenthal Gmbh | 1-Phenyl-3-dimethylamino-propanverbindungen mit pharmakologischer Wirkung |
| US7202261B2 (en) * | 1996-12-03 | 2007-04-10 | Nps Pharmaceuticals, Inc. | Calcilytic compounds |
| UY24949A1 (es) * | 1997-04-08 | 2001-04-30 | Smithkline Beecham Corp | Compuestos calcilíticos |
| AU2351699A (en) | 1998-01-30 | 1999-08-16 | Brigham And Women's Hospital | The human calcium-sensing receptor in the detection and treatment of cancer |
| US7262280B1 (en) | 1998-04-03 | 2007-08-28 | Nps Pharmaceuticals, Inc. | G-protein fusion receptors and constructs encoding same |
| AR018177A1 (es) | 1998-04-08 | 2001-10-31 | Smithkline Beecham Corp | Compuestos calciliticos, una composicion farmaceutica que los comprende y el uso de los mismos para la manufactura de un medicamento. |
| CA2245903A1 (en) * | 1998-09-28 | 2000-03-28 | Mcgill University | Use of pex in the treatment of metabolic bone diseases |
| PE20001456A1 (es) * | 1999-02-02 | 2001-01-28 | Smithkline Beecham Corp | Compuestos calcioliticos |
| CO5180628A1 (es) * | 1999-07-31 | 2002-07-30 | Smithkline Beecham Corp | Compuestos calcioliticos |
| AR030684A1 (es) * | 2000-01-24 | 2003-09-03 | Smithkline Beecham Corp | Compuestos calciliticos, uso de dichos compuestos en la manufactura de medicamentos, e intermediarios utiles en la preparacion de dichos compuestos |
| US20030018203A1 (en) * | 2002-07-17 | 2003-01-23 | Largo Maria Amparo | Calcilytic compounds |
| DE60131781T2 (de) * | 2000-07-21 | 2008-12-24 | Smithkline Beecham Corp. | Kalzilytische verbindungen |
| FR2812875B1 (fr) | 2000-08-08 | 2003-12-12 | Centre Nat Rech Scient | Nouvelles diamines possedant une activite modulatrice des casr et leur mode de preparation |
| US6916956B2 (en) | 2000-08-11 | 2005-07-12 | Japan Tobacco, Inc. | Calcium receptor antagonist |
| JP2004514659A (ja) * | 2000-10-25 | 2004-05-20 | スミスクライン・ビーチャム・コーポレイション | カルシライティック化合物 |
| MXPA04009959A (es) | 2002-04-12 | 2004-12-13 | Schering Corp | Ligandos del receptor acoplado a la proteina g y metodos. |
| US7176322B2 (en) | 2002-05-23 | 2007-02-13 | Amgen Inc. | Calcium receptor modulating agents |
| US6908935B2 (en) | 2002-05-23 | 2005-06-21 | Amgen Inc. | Calcium receptor modulating agents |
| FR2847250B1 (fr) * | 2002-11-15 | 2006-09-22 | Oreal | Composition, notamment cosmetique, comprenant une amine secondaire ou tertiaire |
| TWI316511B (en) | 2002-11-26 | 2009-11-01 | Smithkline Beecham Corp | Calcilytic compounds |
| WO2004069793A2 (en) * | 2003-01-28 | 2004-08-19 | Bristol-Myers Squibb Company | Novel 2-substituted cyclic amines as calcium sensing receptor modulators |
| US7205322B2 (en) * | 2003-02-12 | 2007-04-17 | Bristol-Myers Squibb Company | Thiazolidine compounds as calcium sensing receptor modulators |
| US7265145B2 (en) * | 2003-05-28 | 2007-09-04 | Bristol-Myers Squibb Company | Substituted piperidines and pyrrolidines as calcium sensing receptor modulators and method |
| WO2005065050A2 (ja) | 2003-12-25 | 2005-07-21 | Asahi Kasei Pharma Corporation | 2環化合物 |
| WO2005077892A1 (en) * | 2004-02-06 | 2005-08-25 | Smithkline Beecham Corporation | Calcilytic compounds |
| US7648965B2 (en) * | 2004-05-14 | 2010-01-19 | Unigene Laboratories Inc. | Method for fostering bone formation and preservation |
| US7531518B2 (en) | 2004-05-14 | 2009-05-12 | Unigene Laboratories Inc. | Method for fostering bone formation and preservation |
| PL1757582T3 (pl) | 2004-05-28 | 2016-04-29 | Mitsubishi Tanabe Pharma Corp | Aryloalkiloaminy i sposób ich wytwarzania |
| US20080069814A1 (en) * | 2005-01-05 | 2008-03-20 | Novacea, Inc. | Prevention of Thrombotic Disorders with Active Vitamin D Compounds or Mimics Thereof |
| BRPI0610077A2 (pt) * | 2005-04-22 | 2010-05-25 | Novacea Inc | tratamento, prevenção e atenuação de distúrbios pulmonares associados à quimioterapia ou radioterapia com compostos de vitamina d ativos ou miméticos destes |
| FR2885129B1 (fr) | 2005-04-29 | 2007-06-15 | Proskelia Sas | Nouveaux derives de l'ureee substituee parun thiazole ou benzothiazole, leur procede de preparation, leur application a titre de medicaments, les compositions pharmaceutiques les renfermant et utilisation. |
| US20060293667A1 (en) * | 2005-05-19 | 2006-12-28 | Agnes Vignery | Bone implant device and methods of using same |
| ES2400693T3 (es) | 2005-09-02 | 2013-04-11 | Amgen Inc. | Regulación del equilibrio de fluido intestinal usando calcimiméticos |
| DE602006010905D1 (de) | 2005-11-25 | 2010-01-14 | Galapagos Sas | Harnstoff-derivate als calcium-rezeptor-modulatoren |
| WO2009055631A1 (en) * | 2007-10-25 | 2009-04-30 | Smithkline Beecham Corporation | Calcilytic compounds |
| KR101479371B1 (ko) * | 2008-06-05 | 2015-01-05 | 아사히 가세이 파마 가부시키가이샤 | 술폰아미드 화합물 및 그 용도 |
| EP2196461A1 (de) | 2008-12-15 | 2010-06-16 | Bayer CropScience AG | 4-Amino-1,2,3-benzoxathiazin-Derivate als Pestizide |
| WO2010103429A1 (en) | 2009-03-10 | 2010-09-16 | Pfizer Inc. | 1,1-(Dimethyl-Ethylamino)-2-Hydroxy-Propoxy]-Ethyl}-3-Methyl-Biphenyl-4- Carboxylic Acid Derivatives As Calcium Receptor Antagonists |
| GB201217330D0 (en) | 2012-09-28 | 2012-11-14 | Univ Cardiff | Therapeutic for treating inflammatory lung disorders |
| CN103601645B (zh) * | 2013-11-07 | 2016-05-25 | 上海适济生物科技有限公司 | 1-(苯乙基氨基)丙烷-2-醇类化合物或其盐的制备方法 |
| WO2019153216A1 (zh) * | 2018-02-09 | 2019-08-15 | 北京梅尔森医药技术开发有限公司 | 取代芳基胺醇化合物及其制备方法和用途 |
| WO2021110859A1 (en) * | 2019-12-05 | 2021-06-10 | Syngenta Crop Protection Ag | One step process for the preparation of phenyl ethyl amine derivatives |
| CN116199605A (zh) * | 2023-02-27 | 2023-06-02 | 上海睿腾医药科技有限公司 | 一种5-氯-2-羟基-二甲基苯磺酰胺的合成方法 |
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| SE388849B (sv) * | 1974-02-14 | 1976-10-18 | Haessle Ab | Forfarande for framstellning av nya aminer med beta-receptorstimulerande verkan |
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1997
- 1997-04-04 AT AT97917848T patent/ATE298739T1/de not_active IP Right Cessation
- 1997-04-04 CA CA002251331A patent/CA2251331C/en not_active Expired - Lifetime
- 1997-04-04 AU AU26070/97A patent/AU726659B2/en not_active Expired
- 1997-04-04 NZ NZ332068A patent/NZ332068A/en not_active IP Right Cessation
- 1997-04-04 WO PCT/US1997/005558 patent/WO1997037967A1/en not_active Ceased
- 1997-04-04 PL PL329314A patent/PL191027B1/pl unknown
- 1997-04-04 US US08/832,984 patent/US6022894A/en not_active Expired - Fee Related
- 1997-04-04 SG SG9905132A patent/SG99290A1/en unknown
- 1997-04-04 CN CNB971953686A patent/CN1254465C/zh not_active Expired - Lifetime
- 1997-04-04 IL IL12645897A patent/IL126458A/en not_active IP Right Cessation
- 1997-04-04 DE DE69733649T patent/DE69733649T2/de not_active Expired - Lifetime
- 1997-04-04 JP JP09536327A patent/JP2001501584A/ja not_active Ceased
- 1997-04-04 EA EA199800913A patent/EA002984B1/ru not_active IP Right Cessation
- 1997-04-04 EP EP97917848A patent/EP0901459B1/en not_active Expired - Lifetime
- 1997-04-04 BR BR9708632-0A patent/BR9708632A/pt not_active Application Discontinuation
- 1997-04-08 CO CO97017849A patent/CO4820431A1/es unknown
- 1997-04-09 AR ARP970101400A patent/AR008586A1/es active IP Right Grant
- 1997-06-16 SA SA97180135A patent/SA97180135B1/ar unknown
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1998
- 1998-08-11 US US09/132,179 patent/US6521667B1/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004094362A1 (ja) * | 2003-04-23 | 2004-11-04 | Japan Tobacco Inc. | CaSRアンタゴニスト |
| US7304174B2 (en) | 2003-04-23 | 2007-12-04 | Japan Tobacco Inc. | CaSR antagonist |
| RU2315036C2 (ru) * | 2003-04-23 | 2008-01-20 | Джапан Тобакко Инк. | Антагонист casr |
| EP2189439A2 (en) | 2003-04-23 | 2010-05-26 | Japan Tobacco, Inc. | CaSR antagonist |
| EP2308828A2 (en) | 2003-04-23 | 2011-04-13 | Japan Tobacco Inc. | CaSR antagonist |
| US7285572B2 (en) | 2003-05-28 | 2007-10-23 | Japan Tobacco Inc. | CaSR antagonist |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2251331A1 (en) | 1997-10-16 |
| EP0901459B1 (en) | 2005-06-29 |
| NZ332068A (en) | 2001-03-30 |
| EA199800913A1 (ru) | 1999-06-24 |
| PL191027B1 (pl) | 2006-03-31 |
| IL126458A (en) | 2004-06-20 |
| SG99290A1 (en) | 2003-10-27 |
| ATE298739T1 (de) | 2005-07-15 |
| SA97180135B1 (ar) | 2006-06-12 |
| HK1018899A1 (en) | 2000-01-07 |
| CN1254465C (zh) | 2006-05-03 |
| DE69733649T2 (de) | 2006-05-18 |
| PL329314A1 (en) | 1999-03-15 |
| CA2251331C (en) | 2009-06-09 |
| CN1221401A (zh) | 1999-06-30 |
| BR9708632A (pt) | 2000-01-18 |
| EA002984B1 (ru) | 2002-12-26 |
| AR008586A1 (es) | 2000-02-09 |
| AU726659B2 (en) | 2000-11-16 |
| DE69733649D1 (de) | 2005-08-04 |
| AU2607097A (en) | 1997-10-29 |
| US6521667B1 (en) | 2003-02-18 |
| IL126458A0 (en) | 1999-08-17 |
| WO1997037967A1 (en) | 1997-10-16 |
| US6022894A (en) | 2000-02-08 |
| EP0901459A1 (en) | 1999-03-17 |
| CO4820431A1 (es) | 1999-07-28 |
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