CN1086943C - 苯并噻吩衍生物在制备降低血清钙的药物中的用途 - Google Patents
苯并噻吩衍生物在制备降低血清钙的药物中的用途 Download PDFInfo
- Publication number
- CN1086943C CN1086943C CN96191671A CN96191671A CN1086943C CN 1086943 C CN1086943 C CN 1086943C CN 96191671 A CN96191671 A CN 96191671A CN 96191671 A CN96191671 A CN 96191671A CN 1086943 C CN1086943 C CN 1086943C
- Authority
- CN
- China
- Prior art keywords
- acid
- calcium
- chemical compound
- hypercalcemia
- raloxifene
- 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.)
- Expired - Fee Related
Links
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 239000011575 calcium Substances 0.000 title claims abstract description 29
- 229910052791 calcium Inorganic materials 0.000 title claims abstract description 29
- 210000002966 serum Anatomy 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title abstract description 18
- 230000003247 decreasing effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- -1 hexamethyleneimino Chemical group 0.000 claims abstract description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- 239000012453 solvate Substances 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims description 25
- 208000037147 Hypercalcaemia Diseases 0.000 claims description 17
- 230000000148 hypercalcaemia Effects 0.000 claims description 17
- 208000030915 hypercalcemia disease Diseases 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 5
- 201000002980 Hyperparathyroidism Diseases 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 230000001815 facial effect Effects 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 abstract 3
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 229960004622 raloxifene Drugs 0.000 description 16
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 16
- 229920002472 Starch Polymers 0.000 description 14
- 239000008107 starch Substances 0.000 description 14
- 235000019698 starch Nutrition 0.000 description 14
- 239000003826 tablet Substances 0.000 description 10
- 239000002775 capsule Substances 0.000 description 9
- 108090000445 Parathyroid hormone Proteins 0.000 description 7
- 229940011871 estrogen Drugs 0.000 description 7
- 239000000262 estrogen Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 102000055006 Calcitonin Human genes 0.000 description 5
- 108060001064 Calcitonin Proteins 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 229960004015 calcitonin Drugs 0.000 description 5
- 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 5
- 230000000694 effects Effects 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- BKXVVCILCIUCLG-UHFFFAOYSA-N raloxifene hydrochloride Chemical compound [H+].[Cl-].C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 BKXVVCILCIUCLG-UHFFFAOYSA-N 0.000 description 5
- 229960002119 raloxifene hydrochloride Drugs 0.000 description 5
- 102000003982 Parathyroid hormone Human genes 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000007963 capsule composition Substances 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 239000000199 parathyroid hormone Substances 0.000 description 4
- 229960001319 parathyroid hormone Drugs 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 230000003248 secreting effect Effects 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 208000006386 Bone Resorption Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 102100036893 Parathyroid hormone Human genes 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 230000024279 bone resorption Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000010513 Stupor Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 229940046836 anti-estrogen Drugs 0.000 description 2
- 230000001833 anti-estrogenic effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 2
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000002934 diuretic Substances 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000328 estrogen antagonist Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000013521 mastic Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 210000001685 thyroid gland Anatomy 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical class OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
- HQALDKFFRYFTKP-UHFFFAOYSA-N 2-[4-[4-(2-benzyl-1-benzothiophen-3-yl)phenyl]-2-bromo-6-(3-methoxyphenyl)phenoxy]acetic acid Chemical compound COC1=CC=CC(C=2C(=C(Br)C=C(C=2)C=2C=CC(=CC=2)C=2C3=CC=CC=C3SC=2CC=2C=CC=CC=2)OCC(O)=O)=C1 HQALDKFFRYFTKP-UHFFFAOYSA-N 0.000 description 1
- ZHPJDHNKDVBXAV-UHFFFAOYSA-N 2-acetyl-4-methoxybenzoic acid Chemical class COC1=CC=C(C(O)=O)C(C(C)=O)=C1 ZHPJDHNKDVBXAV-UHFFFAOYSA-N 0.000 description 1
- HMGCGUWFPZVPEK-UHFFFAOYSA-N 2-naphthalen-2-ylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=C(C=CC=C2)C2=C1 HMGCGUWFPZVPEK-UHFFFAOYSA-N 0.000 description 1
- OFJWFSNDPCAWDK-UHFFFAOYSA-N 2-phenylbutyric acid Chemical class CCC(C(O)=O)C1=CC=CC=C1 OFJWFSNDPCAWDK-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical class CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 1
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 208000000187 Abnormal Reflex Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010001367 Adrenal insufficiency Diseases 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 206010003671 Atrioventricular Block Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 208000010271 Heart Block Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010021089 Hyporeflexia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- BRGCOJCRLVNSBC-UHFFFAOYSA-N OC(C(=O)O)CCCCCCCCCCCCCCCCCCCC(=O)O Chemical compound OC(C(=O)O)CCCCCCCCCCCCCCCCCCCC(=O)O BRGCOJCRLVNSBC-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 206010033647 Pancreatitis acute Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical class OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 206010043458 Thirst Diseases 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- 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 1
- 206010047700 Vomiting Diseases 0.000 description 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 201000003229 acute pancreatitis Diseases 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 208000017515 adrenocortical insufficiency Diseases 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000002686 anti-diuretic effect Effects 0.000 description 1
- 239000003160 antidiuretic agent Substances 0.000 description 1
- 229940124538 antidiuretic agent Drugs 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 208000006218 bradycardia Diseases 0.000 description 1
- 230000036471 bradycardia Effects 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- JOYKCMAPFCSKNO-UHFFFAOYSA-N chloro benzenesulfonate Chemical compound ClOS(=O)(=O)C1=CC=CC=C1 JOYKCMAPFCSKNO-UHFFFAOYSA-N 0.000 description 1
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 229940035811 conjugated estrogen Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- VFNGKCDDZUSWLR-UHFFFAOYSA-L disulfate(2-) Chemical compound [O-]S(=O)(=O)OS([O-])(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-L 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- QTTMOCOWZLSYSV-QWAPEVOJSA-M equilin sodium sulfate Chemical compound [Na+].[O-]S(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4C3=CCC2=C1 QTTMOCOWZLSYSV-QWAPEVOJSA-M 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- JKKFKPJIXZFSSB-CBZIJGRNSA-N estrone 3-sulfate Chemical compound OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JKKFKPJIXZFSSB-CBZIJGRNSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 229910021485 fumed silica Inorganic materials 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 230000010247 heart contraction Effects 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical class OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- KQCYUUCXUXWWBT-UHFFFAOYSA-N hydroxy phosphono hydrogen phosphate Chemical compound OOP(O)(=O)OP(O)(O)=O KQCYUUCXUXWWBT-UHFFFAOYSA-N 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 206010020917 hypervitaminosis D Diseases 0.000 description 1
- TVZISJTYELEYPI-UHFFFAOYSA-N hypodiphosphoric acid Chemical compound OP(O)(=O)P(O)(O)=O TVZISJTYELEYPI-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 150000002500 ions Chemical group 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000001055 magnesium Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- 150000005342 methoxybenzoic acids Chemical class 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000002232 neuromuscular Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- HVZWVEKIQMJYIK-UHFFFAOYSA-N nitryl chloride Chemical compound [O-][N+](Cl)=O HVZWVEKIQMJYIK-UHFFFAOYSA-N 0.000 description 1
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 210000002990 parathyroid gland Anatomy 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- SGDMQXAOPGGMAH-UHFFFAOYSA-N phenol;thiophene Chemical compound C=1C=CSC=1.OC1=CC=CC=C1 SGDMQXAOPGGMAH-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229940063238 premarin Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 229940034208 thyroxine Drugs 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 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
- 210000004881 tumor cell Anatomy 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
Classifications
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
-
- 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
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
- A61P5/12—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH for decreasing, blocking or antagonising the activity of the posterior pituitary hormones
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Liquid Crystal Substances (AREA)
- Pyrrole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
本发明涉及一种降低血清钙含量的方法,该方法包括对需要这种治疗的患者使用有效量的式I化合物和其可药用盐和其溶剂化物,其中R1和R3分别是氢,-CH3,-CO-(C1-6烷基),或-CO-Ar,其中Ar是选择性被取代的苯基;R2选自吡咯烷基,六亚甲基亚氨基,和哌啶子基。
Description
钙是人体中最丰富和最重要的一种矿物质。钙也是在各种生物功能中如血凝结,维持正常心跳,神经肌肉发生和代谢活动发生中的重要阳离子。在这些过程中骨胳系统提供了重要的血钙储存器。人体中超过99%的钙作为羟磷灰石存在于骨胳中。各种疾病和代谢紊乱可以引起血清钙含量增高或降低,因此引起严重的生化和临床异常现象。
在控制钙和骨胳代谢的因素中,两种多肽激素,甲状旁腺激素和降血钙素被认为是最重要的。甲状旁腺激素(PTH)是84-氨基酸肽,它用于提高血钙和增加骨再吸收。降血钙素是32-氨基酸多肽,它用于降低骨再吸收和降低血钙。降血钙素在甲状腺中和也许在外甲状腺位置产生,甲状旁腺激素在甲状旁腺中产生。人体中降血钙素和甲状旁腺激素的半衰期可以以分钟测量。
血钙过多被定义为在血中有过量的钙。许多不同临床症状可以导致血钙过多,其中在循环血液中产生高浓度的游离钙离子。引起血钙过多的因素可以包括,例如,甲状旁腺机能亢进,癌症(有或没有骨迁移),维生素D过多症,肉样瘤病,甲状腺素症,不能动的状态,和肾上腺机能不全等。
血钙过多的许多表现对于其潜在的原因并非特异。严重的血钙过多导致昏迷和死亡。不严重的神经病学表现可以包括精神错乱,昏迷,虚弱,和反射减弱。血钙过多可以通过在心电图上缩短的QT间隔检测到。心率失常情况很少见,但心动过缓和一度心传导阻滞已有报道。急性血钙过多可以与明显的高血压相联系。胃肠表现形式包括便秘和厌食;症状严重时可以表现为恶心和呕吐。据报道急性胰腺炎与各种因素的血钙过多有关。血钙过多干扰抑制尿分泌的激素作用,因此导致多尿症和烦渴。与明显的血钙过多有关的肾功能可逆还原作用是分泌作用和作用。维生素D,1.25(OH)2D(二羟基胆骨化醇)的活性代谢抑制PTH的分泌作用和合成。1.25(OH)2D中的还原作用是有助于在肾衰竭中的增加的PTH分泌作用的主要因素。
目前血钙过多的治疗包括通过利尿的有力的静脉内水合作用以从患者体内清除钙。而且,人们有时也使用糖肾上腺皮质激素在这种通过利尿的静脉内水合作用中从患者体内清除钙。已经用于治疗血钙过多的其他方法包括给药光辉霉素(对肿瘤细胞有直接毒性的化学治疗剂,它可以降低血浆钙含量),给药降血钙素(来自甲状腺的激素,它可以抑制骨再吸收,因此降低血浆钙含量),羟二磷酸盐(结合磷酸钙表面的化合物,它抑制骨结晶再吸收)和给药磷酸盐。使用每一种上面讨论的方法的治疗结果具有相对短期的疗效,其结果是,停止进行上面讨论的每一种治疗之后血钙过多通常容易回复。
R2选自吡咯烷基,六亚甲基亚氨基,和哌啶子基。
本发明涉及这样一种发现,即一组经选则的式1的2-苯基-3-芳酰基苯并噻酚!可以用于降低血清钙含量。因此,本发明还提供了抑制血钙过多的方法和其作用,尤其是当这种症状由甲状旁腺机能亢进引起或与恶性肿瘤有关时。
通过对需要这种治疗的患者使用一定剂量的式I化合物或其可药用盐或其溶剂化物,将本发明提供的使用方法进行了实践,其表明式I化合物对降低血清钙含量是有效的。
术语“抑制”包括其通常被接受的含义,包括阻止,防止,制止,和减慢,停止或逆转。因此,本发明的方法包括适当的医药治疗和/或预防给药万法。
用于本发明的术语“血清钙含量”指在患者血浆中发现的钙离子含量,包括结合蛋白的钙和非扩散性的钙,以及扩散性的钙和以游离离子化形式和以配合形式存在的钙。确定血浆钙含量的适当的方法由Connerty,H.V.和Briggs,A.R.揭示于《美国临床病理学杂志》,第45卷,第290页(1986)。
雷洛昔芬是本发明的化合物,其中该化合物是式1化合物的盐酸盐,其中R1和R3是氢,和R2是1-哌啶基,该化合物是原子核规则的分子。雷洛昔芬已经被表明它结合雌激素受体,它最初被认为是具有抗-雌激素功能和药理学作用的分子,因为它阻滞雌激素活化子宫组织和活化与雌激素相关的乳腺癌的能力。的确,雷洛昔芬确实在某些细胞中阻滞雌激素作用;但是在其他细胞类型中,当雌激素确实显示相同的药理学,例如,骨质疏松症,血钙过多时,雷洛昔芬活化相同的基因。结果,雷洛昔芬已经被称为具有混合的激动剂-拮抗剂性质的抗-雌激素。雷洛昔芬显示的和不同于雌激素的唯一特征现在被认为是由于唯一的与通过雌激素-雌激素受体配合物的基因的活化作用和/或阻遏作用相反的通过雷洛昔芬-雌激素受体配合物的各种基因功能的活化作用和/或阻遏作用。因此,尽管雷洛昔芬和雌激素利用和竞争相同的受体,但是来自这两者的基因调控的药理学结果不容易被预测,并且对于它们中的每一个都是唯一的。
通常,该化合物用普通的赋形剂,稀释剂或载体配制,并压成片剂,或者配制成方便口服给药,或通过肌内或静脉内途径给药的酏剂或溶液剂。该化合物可以经表皮给药,可以配制成持续释放剂量形式等。
用于本发明方法中的化合物可以根据已知的方法,如美国专利US4133814,US4418068,和US4380635中详细描述的那些方法制备,所有这些专利被本文引用作为参考。通常,该方法从具有6-羟基和2-(4-羟基苯基)的苯并[b]噻酚开始。将起始化合物保护,酰化,和去保护以形成式I化合物。该化合物的制备实施例在上面讨论的美国专利中提供。选择性取代的苯基包括苯基和被C1-6烷基,C1-4烷氧基,羟基,硝基,氯,氟,或三(氯或氟)甲基取代一次或两次的苯基。
用于本发明方法中的化合物与各种有机和无机酸和碱形成可药用的酸和碱加成盐,包括通常被用于药物化学中的可药用盐。这种盐也是本发明的一部分。用于形成这种盐的典型的无机酸包括盐酸,氢溴酸,氢碘酸,硝酸,硫酸,磷酸,连二磷酸等等。也可以使用由有机酸,如脂肪单和二羧酸,苯基取代的链烷酸,羟基链烷酸和羟基烷二酸,芳族酸,脂肪和芳族磺酸衍生得到的盐。因此,这种可药用盐包括乙酸盐,苯乙酸盐,三氟乙酸盐,丙烯酸盐,抗坏血酸盐,苯甲酸盐,氯代苯甲酸盐,二硝基苯甲酸盐,羟基苯甲酸盐,甲氧基苯甲酸盐,甲基苯甲酸盐,邻-乙酰氧基苯甲酸盐,萘-2-苯甲酸盐,溴化物,异丁酸盐,苯基丁酸盐,β-羟基丁酸盐,丁炔-1,4-二酸盐,己炔-1,4-二酸盐,癸酸盐,辛酸盐,氯化物,肉桂酸盐,柠檬酸盐,甲酸盐,富马酸盐,乙醇酸盐,庚酸盐,马尿酸盐,乳酸盐,苹果酸盐,马来酸盐,羟基马来酸盐,丙二酸盐,扁桃酸盐,甲磺酸盐,烟酸盐,异烟酸盐,硝酸盐,草酸盐,邻苯二甲酸盐,对苯二甲酸盐,磷酸盐,磷酸一氢盐,磷酸二氢盐,偏磷酸盐,焦磷酸盐,丙炔酸盐,丙酸盐,苯基丙酸盐,水杨酸盐,癸二酸盐,琥珀酸盐,辛二酸盐,硫酸盐,硫酸氢盐,焦硫酸盐,亚硫酸盐,亚硫酸氢盐,磺酸盐,苯磺酸盐,对-溴苯磺酸盐,氯代苯磺酸盐,乙磺酸盐,2-羟乙基磺酸盐,甲磺酸盐,萘-1-磺酸盐,萘-2-磺酸盐,对-甲苯磺酸盐,二甲苯磺酸盐,酒石酸盐等等。优选的盐是盐酸盐。
可药用酸加成盐一般通过将式I化合物与等摩尔或过量的酸反应形成。反应物通常混入互溶剂如乙醚或苯中。盐通常在约1小时至10天的时间内从溶液中沉淀出来并且可以通过过滤分离,或者溶剂可以用常规的方法汽提。
通常用于成盐的碱包括氢氧化铵和碱金属和碱土金属氢氧化物,碳酸盐,以及脂族和伯、仲和叔胺,脂族二胺。在制备加合盐中特别有用的碱包括氢氧化铵,碳酸钾,甲胺,二乙胺,乙二胺和环己胺。
与经衍生得到它们的化合物相比,可药用盐通常具有增强的溶解特性,因此它们更适合于配制成液体制剂或乳化剂。
药物制剂可以通过本领域已知的方法制备。例如,化合物可以与常规的赋形剂,稀释剂,或载体配成制剂,形成片剂,胶囊,悬浮剂,粉剂等等。适用于这种制剂的赋形剂,稀释剂,和载体的实例包括:填料和填充剂如淀粉,糖,甘露醇,和硅酸衍生物;粘合剂如羧甲基纤维素和其他纤维素衍生物,藻酸盐,明胶,和聚乙烯吡咯烷酮;润湿剂如甘油;崩解剂如碳酸钙和碳酸氢钠;阻滞溶解剂如石蜡;再吸收促进剂如季铵化合物;表面活性剂如鲸蜡醇,甘油单硬脂酸酯;吸附载体如高岭土和膨润土;和润滑剂如滑石,硬脂酸钙和镁,和固体聚乙二醇。
该化合物也可以配制成酏剂或方便口服给药的溶液剂,或配制成适合于非肠道给药,例如通过肌内,皮下或静脉内途径给药的溶液剂。此外,该化合物很适于配制成持续释放剂量形式的制剂等等。该制剂可以被这样构成,以使得它们仅仅或优选地在肠道的特殊部位,可能要用一段时间释放活性成分。涂层材料,包衣材料和保护基质可以用,例如,聚合物或蜡制备。
根据本发明,降低血清钙含量所需的给药安排和式I化合物的具体剂量取决于症状的严重程度,给药途径,和由护理医生确定的有关因素。通常被接受的和有效的每日剂量是约0.1-约1000毫克/天,更典型的是约50-约600毫克/天,优选范围是200-600毫克/天。该剂量每天可以按一次至约三次的方式,或者如果需要可以按更多次的方式,对需要这种治疗的患者给药,让患者用药足够长的时间以有效地降低患者血清钙含量的。
通常优选以酸加成盐的形式将化合物I给药,通常以带有碱性基团,如哌啶子基环的药物给药。有利的还有通过口服途径将该化合物给药。为此目的,可以使用下列口服剂量形式。
制剂
在下列制剂中,“活性成分”指式I化合物。制剂1:明胶胶囊
使用下列成分制备硬明胶胶囊:成分 数量(毫克/胶囊)活性成分 0.1-1000淀粉,NF 0-650可流动淀粉粉末 0-650350厘沲硅氧烷流体 0-15
将各组分掺合,通过第45目U.S.筛,填充入硬明胶胶囊中。
已经制备的雷洛昔芬的具体胶囊制剂的实例包括下列胶囊:制剂2:雷洛昔芬胶囊成分 数量(毫克/胶囊)雷洛昔芬 1淀粉,NF 112可流动淀粉粉末 225.3350厘沲硅氧烷流体 1.7制剂3:雷洛昔芬胶囊成分 数量(毫克/胶囊)雷洛昔芬 5淀粉,NF 108可流动淀粉粉末 225.3350厘沲硅氧烷流体 1.7制剂4:雷洛昔芬胶囊成分 数量(毫克/胶囊)雷洛昔芬 10淀粉,NF 103可流动淀粉粉末 225.3350厘沲硅氧烷流体 1.7制剂5:雷洛昔芬胶囊成分 数量(毫克/胶囊)雷洛昔芬 50淀粉,NF 150可流动淀粉粉末 397350厘沲硅氧烷流体 3.0
上面具体的制剂可以根据所提供的合理的变化进行改变。
使用下列成分制备片剂:制剂6:片剂成分 数量(毫克/片)活性成分 0.1-1000微晶纤维素 0-650发烟二氧化硅 0-650硬脂酸 0-15
将各组分掺合并压成片剂。
另一方面,每片含有0.1-1000毫克活性成分的片剂根据下列制备:制剂7:片剂成分 数量(毫克/片)活性成分 0.1-1000淀粉 45微晶纤维素 35聚乙烯吡咯烷酮(作为在水中的 410%的溶液)羧甲基纤维素钠 4.5硬脂酸镁 0.5滑石 1
将活性成分,淀粉,和纤维素通过第45目U.S.筛并完全混合。将聚乙烯吡咯烷酮的溶液与得到的粉末混合,然后通过第14目U.S.筛。将如此制备的颗粒在50-60℃干燥并通过第18目U.S.筛。将羧甲基淀粉钠,硬脂酸镁,和滑石先通过第60目U.S.筛,然后加入到上面的颗粒中,混合后用压片机压成片剂。
每5毫升剂量含有0.1-1000毫克药物的混悬剂根据下列制备:制剂8:混悬剂成分 数量(毫克/5毫升)活性成分 0.1-1000毫克羧甲基纤维素钠 50毫克糖浆 1.25毫克苯甲酸溶液 0.10毫升香味剂 适量着色剂 适量纯净水加至 5毫升
将药物通过第45目U.S.筛并与羧甲基纤维素钠和糖浆混合形成调匀的膏体。将苯甲酸溶液,香味剂,和着色剂用适量水稀释,在搅拌下加入膏体中。然后加入足够的水至所需的体积。
试验步骤
在研究1中,将251位健康的绝经后妇女分成4组:第1组 雷洛昔芬盐酸盐, 200毫克/天;第2组 雷洛昔芬盐酸盐, 600毫克/天;第3组 马雌激素, 0.625毫克/天;或第4组 空白对照剂。
在研究2中,将167位健康的绝经后妇女随机地分成4组:第1组 空白对照剂;第2组 雷洛昔芬盐酸盐,200毫克/天;第3组 雷洛昔芬盐酸盐,50毫克/天;或第4组 雷洛昔芬盐酸盐,10毫克/天。
上述研究的给药周期是8周。在这两种研究中,临床实验安全评价包括血清CBC和化学专家小组在基线(0周),和每次回访(2,4和8周)时的评价。研究完全之后,将研究的数据进行统计分析。
上面的研究中使用的本发明的化合物对血清钙含量的影响证明了本发明化合物的效用。
Claims (5)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/380,881 US5512583A (en) | 1995-01-30 | 1995-01-30 | Methods of decreasing serum calcium levels |
US08/380,881 | 1995-01-30 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1172432A CN1172432A (zh) | 1998-02-04 |
CN1086943C true CN1086943C (zh) | 2002-07-03 |
Family
ID=23502813
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN96191671A Expired - Fee Related CN1086943C (zh) | 1995-01-30 | 1996-01-29 | 苯并噻吩衍生物在制备降低血清钙的药物中的用途 |
Country Status (19)
Country | Link |
---|---|
US (1) | US5512583A (zh) |
EP (1) | EP0723780B1 (zh) |
JP (1) | JPH10513184A (zh) |
KR (1) | KR19980701731A (zh) |
CN (1) | CN1086943C (zh) |
AT (1) | ATE216232T1 (zh) |
AU (1) | AU701262B2 (zh) |
CA (1) | CA2211530A1 (zh) |
CZ (1) | CZ286161B6 (zh) |
DE (1) | DE69620661T2 (zh) |
DK (1) | DK0723780T3 (zh) |
ES (1) | ES2172633T3 (zh) |
HU (1) | HUP9801335A3 (zh) |
NO (1) | NO973470L (zh) |
NZ (1) | NZ302546A (zh) |
PT (1) | PT723780E (zh) |
RU (1) | RU2176503C2 (zh) |
UA (1) | UA43389C2 (zh) |
WO (1) | WO1996023501A1 (zh) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5393763A (en) * | 1992-07-28 | 1995-02-28 | Eli Lilly And Company | Methods for inhibiting bone loss |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4133814A (en) * | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
US4418068A (en) * | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
US4380635A (en) * | 1981-04-03 | 1983-04-19 | Eli Lilly And Company | Synthesis of acylated benzothiophenes |
US5075321A (en) * | 1987-03-24 | 1991-12-24 | University Of Pennsylvania | Methods of treating diseases characterized by interactions of IgG-containing immune complexes with macrophage Fc receptors using antiestrogenic benzothiophenes |
US5395842A (en) * | 1988-10-31 | 1995-03-07 | Endorecherche Inc. | Anti-estrogenic compounds and compositions |
JP3157882B2 (ja) * | 1991-11-15 | 2001-04-16 | 帝国臓器製薬株式会社 | 新規なベンゾチオフエン誘導体 |
DE4320896A1 (de) * | 1993-06-24 | 1995-01-05 | Denecke Rainer Dr Med Vet | Präparat zur Therapie und Prophylaxe von Demenz-Erkrankungen |
US5478847A (en) * | 1994-03-02 | 1995-12-26 | Eli Lilly And Company | Methods of use for inhibiting bone loss and lowering serum cholesterol |
UA41909C2 (uk) * | 1994-07-22 | 2001-10-15 | Елі Ліллі Енд Компані | Використання комбінації сполук для інгібірування остеопорозу, фармацевтичний препарат |
-
1995
- 1995-01-30 US US08/380,881 patent/US5512583A/en not_active Expired - Fee Related
-
1996
- 1996-01-29 CZ CZ19972403A patent/CZ286161B6/cs not_active IP Right Cessation
- 1996-01-29 HU HU9801335A patent/HUP9801335A3/hu unknown
- 1996-01-29 WO PCT/US1996/001406 patent/WO1996023501A1/en not_active Application Discontinuation
- 1996-01-29 DE DE69620661T patent/DE69620661T2/de not_active Expired - Fee Related
- 1996-01-29 CN CN96191671A patent/CN1086943C/zh not_active Expired - Fee Related
- 1996-01-29 JP JP8523733A patent/JPH10513184A/ja not_active Withdrawn
- 1996-01-29 UA UA97074027A patent/UA43389C2/uk unknown
- 1996-01-29 DK DK96300610T patent/DK0723780T3/da active
- 1996-01-29 AU AU48622/96A patent/AU701262B2/en not_active Ceased
- 1996-01-29 NZ NZ302546A patent/NZ302546A/en unknown
- 1996-01-29 ES ES96300610T patent/ES2172633T3/es not_active Expired - Lifetime
- 1996-01-29 EP EP96300610A patent/EP0723780B1/en not_active Expired - Lifetime
- 1996-01-29 KR KR1019970705127A patent/KR19980701731A/ko not_active Application Discontinuation
- 1996-01-29 RU RU97114794/14A patent/RU2176503C2/ru active
- 1996-01-29 AT AT96300610T patent/ATE216232T1/de not_active IP Right Cessation
- 1996-01-29 CA CA002211530A patent/CA2211530A1/en not_active Abandoned
- 1996-01-29 PT PT96300610T patent/PT723780E/pt unknown
-
1997
- 1997-07-28 NO NO973470A patent/NO973470L/no not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5393763A (en) * | 1992-07-28 | 1995-02-28 | Eli Lilly And Company | Methods for inhibiting bone loss |
Also Published As
Publication number | Publication date |
---|---|
CZ240397A3 (cs) | 1998-01-14 |
ES2172633T3 (es) | 2002-10-01 |
NO973470D0 (no) | 1997-07-28 |
NZ302546A (en) | 2000-06-23 |
KR19980701731A (ko) | 1998-06-25 |
PT723780E (pt) | 2002-08-30 |
DK0723780T3 (da) | 2002-06-17 |
NO973470L (no) | 1997-07-28 |
WO1996023501A1 (en) | 1996-08-08 |
EP0723780B1 (en) | 2002-04-17 |
MX9705697A (es) | 1997-10-31 |
US5512583A (en) | 1996-04-30 |
DE69620661D1 (de) | 2002-05-23 |
JPH10513184A (ja) | 1998-12-15 |
DE69620661T2 (de) | 2002-11-14 |
HUP9801335A2 (hu) | 1999-05-28 |
AU701262B2 (en) | 1999-01-21 |
CN1172432A (zh) | 1998-02-04 |
HUP9801335A3 (en) | 2000-03-28 |
CA2211530A1 (en) | 1996-08-08 |
UA43389C2 (uk) | 2001-12-17 |
AU4862296A (en) | 1996-08-21 |
EP0723780A3 (zh) | 1996-09-11 |
RU2176503C2 (ru) | 2001-12-10 |
CZ286161B6 (cs) | 2000-01-12 |
EP0723780A2 (en) | 1996-07-31 |
ATE216232T1 (de) | 2002-05-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1049335C (zh) | 苯并噻吩类化合物的制药用途 | |
CN1058389C (zh) | 苯并噻吩类化合物的用途 | |
DE69515038T2 (de) | Verwendung von raloxifen und dessen analogen zur herstellung eines medikaments zur behandlung viraler erkrankungen | |
CN1108093A (zh) | 抑制血管舒缩症状和护理有关绝经后综合征心理障碍的方法 | |
CN1095663C (zh) | 抑制低密度脂蛋白氧化和动脉粥样硬化的方法 | |
CN1053102C (zh) | 苯并噻吩衍生物在制备抑制软骨退化的药物方面的用途 | |
CN1109752A (zh) | 抑制机能障碍性子宫出血的方法 | |
CN1108102A (zh) | 抑制自身免疫疾病的方法 | |
DE69428877T2 (de) | Hemmung einer Fehlentwicklung der Ovarien, verspüteter Pubertät oder sexuellem Infantilismus | |
CN1108099A (zh) | 抑制性早熟的方法 | |
CN1107332A (zh) | 抑制绝经后妇女的中枢神经系统问题的方法 | |
CN1108103A (zh) | 抑制特纳综合征的方法 | |
CN1108100A (zh) | 抑制乳房病症的方法 | |
CN1192141A (zh) | 抑制黑素瘤的方法 | |
AU3157001A (en) | Product for treating gynecomastia | |
CN1086943C (zh) | 苯并噻吩衍生物在制备降低血清钙的药物中的用途 | |
CN1169116A (zh) | 抑制环境雌激素的方法 | |
KR20010052852A (ko) | 근골격 허약을 치료하기 위한 선택적인 에스트로겐 수용체조절제 및 성장 호르몬 분비촉진제의 치료적 혼합물 | |
CN1177295A (zh) | 抑制生长激素作用的方法 | |
AU692155B2 (en) | Method and composition for treatment of osteoporosis | |
CN1108101A (zh) | 抑制男性不育症的方法 | |
MXPA97005697A (en) | Methods to reduce your calcium levels | |
AU694112B2 (en) | Method and composition for treatment of osteoporosis | |
CN1169679A (zh) | 抑制与舒缓激肽有关疾病的方法 | |
MXPA97001532A (en) | Procedure to increase testoster levels |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C19 | Lapse of patent right due to non-payment of the annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |