CN1109752A - 抑制机能障碍性子宫出血的方法 - Google Patents
抑制机能障碍性子宫出血的方法 Download PDFInfo
- Publication number
- CN1109752A CN1109752A CN94119734A CN94119734A CN1109752A CN 1109752 A CN1109752 A CN 1109752A CN 94119734 A CN94119734 A CN 94119734A CN 94119734 A CN94119734 A CN 94119734A CN 1109752 A CN1109752 A CN 1109752A
- Authority
- CN
- China
- Prior art keywords
- dysfunctional uterine
- uterine bleeding
- acid
- salt
- chemical compound
- 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.)
- Pending
Links
- 206010027514 Metrorrhagia Diseases 0.000 title claims abstract description 20
- 206010013908 Dysfunctional uterine bleeding Diseases 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title abstract description 16
- 230000002401 inhibitory effect Effects 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- -1 hexamethylenemino Chemical group 0.000 claims abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 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 4
- 239000012453 solvate Substances 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 4
- 230000002265 prevention Effects 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 abstract 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 19
- 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 18
- 229960004622 raloxifene Drugs 0.000 description 18
- 208000032843 Hemorrhage Diseases 0.000 description 15
- 239000002775 capsule Substances 0.000 description 12
- 239000000262 estrogen Substances 0.000 description 11
- 229940011871 estrogen Drugs 0.000 description 10
- 229920002472 Starch Polymers 0.000 description 8
- 239000008107 starch Substances 0.000 description 8
- 235000019698 starch Nutrition 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 description 5
- 230000009969 flowable effect Effects 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- 229920001296 polysiloxane Polymers 0.000 description 5
- 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 4
- 208000034158 bleeding Diseases 0.000 description 4
- 231100000319 bleeding Toxicity 0.000 description 4
- 230000000740 bleeding effect Effects 0.000 description 4
- 230000001076 estrogenic effect Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010014759 Endometrial neoplasm Diseases 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
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound 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
- 230000002159 abnormal effect Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 2
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 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
- DGXRZJSPDXZJFG-UHFFFAOYSA-N docosanedioic acid Chemical compound OC(=O)CCCCCCCCCCCCCCCCCCCCC(O)=O DGXRZJSPDXZJFG-UHFFFAOYSA-N 0.000 description 2
- 201000003914 endometrial carcinoma Diseases 0.000 description 2
- 210000004696 endometrium Anatomy 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
- 238000009472 formulation Methods 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
- 238000009802 hysterectomy Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000016087 ovulation Effects 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 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
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000583 progesterone congener Substances 0.000 description 2
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 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
- 238000004804 winding Methods 0.000 description 2
- 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
- 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
- BTHAMNJTBJFIQX-UHFFFAOYSA-N 4-(1-benzothiophen-2-yl)phenol Chemical compound C1=CC(O)=CC=C1C1=CC2=CC=CC=C2S1 BTHAMNJTBJFIQX-UHFFFAOYSA-N 0.000 description 1
- PXACTUVBBMDKRW-UHFFFAOYSA-M 4-bromobenzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-M 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000005995 Aluminium silicate Substances 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
- 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
- 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
- 206010013786 Dry skin Diseases 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 239000004606 Fillers/Extenders Substances 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
- NMJREATYWWNIKX-UHFFFAOYSA-N GnRH Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CC(C)C)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 NMJREATYWWNIKX-UHFFFAOYSA-N 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 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
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 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
- 206010067572 Oestrogenic effect Diseases 0.000 description 1
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 101000857870 Squalus acanthias Gonadoliberin Proteins 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
- 206010066901 Treatment failure Diseases 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
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000556 agonist Substances 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
- 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
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 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
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 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
- 239000008112 carboxymethyl-cellulose Substances 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
- 230000001684 chronic effect Effects 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000003745 diagnosis Methods 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
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 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
- VFNGKCDDZUSWLR-UHFFFAOYSA-L disulfate(2-) Chemical compound [O-]S(=O)(=O)OS([O-])(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-L 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 201000006828 endometrial hyperplasia Diseases 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 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
- TVZISJTYELEYPI-UHFFFAOYSA-N hypodiphosphoric acid Chemical compound OP(O)(=O)P(O)(O)=O TVZISJTYELEYPI-UHFFFAOYSA-N 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical class OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-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
- 201000010260 leiomyoma Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000002101 lytic effect Effects 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
- 230000007257 malfunction Effects 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
- 230000009245 menopause Effects 0.000 description 1
- 208000007106 menorrhagia Diseases 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- 150000005342 methoxybenzoic acids Chemical class 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
- 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
- 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
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000032696 parturition Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class 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
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003405 preventing effect Effects 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 229940095055 progestogen systemic hormonal contraceptives Drugs 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229960001860 salicylate Drugs 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
- 208000012788 shakes Diseases 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide 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
- 239000002904 solvent Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 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
- 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
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 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
- 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
- 229950004288 tosilate Drugs 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
- 238000002604 ultrasonography Methods 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 210000004291 uterus Anatomy 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
- 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
- A61K31/395—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
- A61K31/40—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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
抑制机能障碍性子宫出血的方法，该方法包括给
需要治疗的患者施用有效剂量的I式化合物或其药
学上适用的盐或溶剂化物，
其中R1和R3独立地为氢、
烷基)或
这里Ar为任意取代的苯基；
R2系选自吡咯烷子基、六亚甲基亚氨基和哌啶子基。
Description
机能障碍性子宫出血是妇科学中临床上常见的问题。在生殖和以后的年月里任一妇女均可能受到影响。机能障碍性出血其特征在于经血过多（过量的周期出血，每一周期出血多于或等于80ml）（Greesen等，Eur J Obstet Gynecol Reprod Biol，48（3），207～214（1993））、子宫出血（周期异常频率）、除正常周期之外的出血或不经正常周期的出血。
异常出血可能的原因是多种多样的，包括生理学上的变化（如绝经）、妊振、子宫内膜癌或纤维肌瘤，因此机能障碍性子宫出血的诊断必须在仔细的观察之后确定，以便排除其他的原因（Galle等，Postgrad Med.93（2），73～76（1993））。
在大多数病例中，机能障碍性子宫出血与排卵停止有关（Bayer等，JAMA，269（14），1823～1828（1993））。不排卵的出血在青春期和更年期频繁出现，并且可能与生理上雌激素水平变化有关（文献同前）。但是出血可能由于继发于无拮抗的雌激素分泌的慢性排卵停止（它导致子宫内膜增生）所引起，并且与增加的子宫内膜癌的危险有关（文献同前）。不适当的雌激素水平，不管是过量的雌激素还是没有被合适的孕激素类（孕甾酮）拮抗的雌激素水平，均被认为是许多机能障碍性子宫出血病例的可能原因。
治疗不排卵的出血通常目的是减少出血，更具体地说是止住急性出血、防止出血复发和预防长期并发症（文献同前）。首选的治疗方法是药物，下面将现有选择方案的应用范围和限制列表说明。
治疗 目的 限制
a)GnRH 在垂体轴阻止 ·通过注射
激动剂1雌激素分泌 ·促进骨质疏松症
·限于手术前应用
·副作用
2)周期性口服孕 纠正雌激素- ·有限的效果
激素类药物2,3孕激素比例 ·副作用
3)非甾族的抗炎 局部子宫内膜 ·有限的效果
药物 作用 ·非特效的药物
·副作用
1.Thomas等，Br J Obstet Gynaecol，98（11），1155-1159（1991）。
2.Fraser，Aust NZ J Obstet Gynaecol，30（4），353～356（1990）。
3.Bonduelle，Postgrad Med J，67（791），833-836（1991）。
如果上述治疗失败，那么通常需要进行外科手术。所述外科手术一般是子宫内膜的部分切除或子宫切除，但是这些方法涉及大量的花费并有副作用（Thomas等，同上；Perino，Acta Eur Ferti，21（6），313-317（1990）），有时失败的比例高到20%（Fraser，同上；Hellen，Histopathology，22（4），361-365（1993））。为了治疗机能障碍性子宫出血，在美国每年有多达50000名妇女进行子宫切除（Perino，同上）。
本发明提供了抑制机能障碍性子宫出血的方法，该方法包括给需要治疗的患者施用有效量的式Ⅰ化合物或其药学上适用的盐或溶剂化物，
其中R1和R3各自独立地为氢、-CH3、
（C1-C6烷基）或
，这里Ar为任意取代的苯基，
R2系选自吡咯烷子基（Pyrrolidino）、六亚甲基亚氨基和哌啶子基。
本发明涉及发现用于抑制机能障碍性子宫出血的式Ⅰ化合物。本发明提供的治疗方法通过给妇女施用一定剂量的能有效地抑制机能障碍性子宫出血的式Ⅰ化合物或其药学上适用的盐或溶剂化物来实施。
术语“抑制机能障碍性子宫出血”通常是指减少出血次数和/或出血量，无论该出血是在正常周期之内或正常周期之外，或是没有周期，或与不正常周期有关；或者是指抑制子宫出血。本发明方法还包括治疗和/或预防性治疗。
雷洛昔芬（式Ⅰ化合物的盐酸盐，其中R1为氢，R2为1-哌啶基，R3为氢）具有与雌激素受体结合的能力，因为雷洛昔芬具有抑制雌激素激活子宫组织和抑制依赖雌激素的乳房癌的能力，因此原先认为其分子的功能和药理学是抗雌激素。雷洛昔芬确实在一些细胞中具有抑制雌激素的作用，但是在另一些类型的细胞中雷洛昔芬可激活如雌激素所激活的相同的基因，并且显示出相同的药理作用（如骨质疏松、血脂过多）。雷洛昔芬所显示和不同于雌激素的独特性质，现在认为是由于与通过雌激素-雌激素受体复合物激活和/或抑制各种基因功能相反，雷洛昔芬通过雷洛昔芬-雌激素受体复合物独特地激活和/或抑制各种基因功能。因此，虽然雷洛昔芬与雌激素利用和竞争同一受体，但是由两者的基因调节所引起的药理学结果不易被预测，并且各自是独特的。
一般来讲，本发明化合物可以与常用的赋形剂、稀释剂或载体进行配方并且可压制成片剂，或者也可以配制成方便口服给药的酏剂或溶液剂，或通过肌内或静脉途径给药。本发明化合物还可以经皮给药或阴道内给药，并且可以配制缓释剂型等。
可以按照已有的方法制备本发明方法中使用的化合物，如按美国专利4，133，814、4，418，068和4，380，635所述方法进行制备，所有这些文献均收编在本发明中作为参考。一般来讲，该方法从带有6-羟基和2-（4-羟基苯基）基团的苯并[b]噻吩开始。起始化合物的羟基被保护，3位进行酰化，并将产物进行脱保护，生成式Ⅰ化合物。以上美国专利叙述了制备上述化合物的实施例。术语“任意取代的苯基”包括苯基和用C1～C6烷基、C1～C4烷氧基、羟基、硝基、氯、氟或三（氯或氟）甲基一次或二次取代的苯基。
用于本发明方法的化合物可以与多种有机和无机酸、碱生成药学上适用的酸和碱加成盐，药学上适用的酸和碱加成盐包括通常用于药物化学上的生理上适用的盐。所述盐也包括在本发明的范围内。用于生成上述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。可以应用由有机酸生成的盐，有机酸例如有脂肪族一或二羧酸、苯基取代的链烷酸、羟基链烷酸和羟基链烷二酸，以及芳香族酸、脂肪族和芳香族磺酸。所述药学上适用的盐因此包括乙酸盐、苯基乙酸盐、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、羟基乙酸盐、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、乙烷磺酸盐、2-羟基乙烷磺酸盐、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。优选的盐是盐酸盐。
药学上适用的酸加成盐一般可通过式Ⅰ化合物与等摩尔或过量的酸反应制得。反应物通常于互溶剂如乙醚或苯中进行反应。盐一般在约1小时～10天内从溶液中析出，并且可以经过滤分离，或者按常规方法除去溶剂。
通常用于生成盐的碱包括氢氧化铵、碱金属和碱土金属氢氧化物、碳酸盐，以及脂肪族的伯、仲、叔胺和脂肪族二胺。用于制备加成盐的碱尤其包括氢氧化钠、氢氧化钾、氢氧化铵、碳酸钾、甲胺、二乙胺、乙二胺和环己胺。
与化合物（由该化合物衍生得到盐）相比较，药学上适用的盐一般具有提高溶解度的性质，因此它们通常更适用于配制液剂或乳剂。
药物制剂可以按本技术领域已知的方法制备。例如，将化合物与常用的赋形剂、稀释剂或载体一起配制，并可配制成片剂、胶囊剂、混悬液剂、粉剂等。适用于上述制剂的赋形剂、稀释剂和载体包括：填充剂和增量剂如淀粉、糖、甘露糖醇以及硅衍生物；粘合剂如羧甲基纤维素和其他的纤维素衍生物，藻酸盐、明胶和聚乙烯吡咯烷酮；湿润剂如甘油；崩解剂如碳酸钙和碳酸氢钠；阻滞溶解剂如石蜡；吸收促进剂如季铵化合物；表面活性剂如鲸蜡醇、单硬脂酸甘油酯；吸附载体如高岭土和膨润土；以及润滑剂如滑石、硬脂酸钙和硬脂酸镁以及固体聚乙二醇。
本发明化合物也可以配制成方便口服的酏剂或溶液剂，或者配制成适于非经胃肠道（如经肌内、皮下或静脉途径）给药的溶液剂。另外，本发明化合物还非常适用于配制成缓释剂型等。缓释制剂可以这样构成，以使它们仅仅或最好在肠道的特定部位并可能在一定时间内释放活性成分。包衣材料、包袋材料和保护材料可以由例如聚合物质或蜡制得。
为抑制机能障碍性子宫出血需应用的本发明式Ⅰ化合物的具体剂量将取决于由主治医师决定的患者的身体状况、给药途径以及有关的因素。一般来讲，每天接受的有效剂量为约0.1～1000mg，更一般的是约30～600mg。该剂量每天将对需治疗的患者一次或分大约三次给药。
通过口服途径服用上述化合物也是有益的。为此，可利用下述口服剂型的药物。
制剂
在下述制剂中“活性成分”是指式Ⅰ化合物。
制剂1：明胶胶囊剂
硬明胶胶囊剂按下面方法制备：
成分 量(mg/胶囊)
活性成分 0.1-1000
淀粉,NF 0-650
可流动的淀粉粉末 0-650
聚硅氧烷流体(350厘沲) 0-15
将上述成分混合，通过美国45号筛并将其装入硬明胶胶囊。
已经制备的雷洛昔芬胶囊剂实施例包括下述制剂：
制剂2：雷洛昔芬胶囊剂
成分 量(mg/胶囊)
雷洛昔芬 1
淀粉,NF 112
可流动的淀粉粉末 225.3
聚硅氧烷流体(350厘沲) 1.7
制剂3:雷洛昔芬胶囊剂
成分 量(mg/胶囊)
雷洛昔芬 5
淀粉,NF 108
可流动的淀粉粉末 225.3
聚硅氧烷流体(350厘沲) 1.7
制剂4:雷洛昔芬胶囊剂
成分 量(mg/胶囊)
雷洛昔芬 10
淀粉,NF 103
可流动的淀粉粉末 225.3
聚硅氧烷流体(350厘沲) 1.7
制剂5:雷洛昔芬胶囊剂
成分 量(mg/胶囊)
雷洛昔芬 50
淀粉,NF 150
可流动的淀粉粉末 397
聚硅氧烷流体(350厘沲) 3.0
按照合理的改变，还可以将上述具体的制剂进行变化。
用下述成分制备含有雷洛昔芬的片剂：
制剂6：片剂
成分 量(mg/片)
雷洛昔芬 0.1～1000
微晶纤维素 0～650
煅制的二氧化硅 0～650
硬脂酸 0～15
将上述成分混合并压制成片剂。
另外，每片含0.1～1000mg活性成分的片剂可以按下法制备：
制剂7：片剂
成分 量(mg/片)
活性成分 0.1～1000
淀粉 45
微晶纤维素 35
聚乙烯吡咯烷酮(为10%的水溶液) 4
羧甲基纤维素钠 4.5
硬脂酸镁 0.5
滑石 1
将活性成分、淀粉和纤维素通过美国45号筛，并充分地混合。使聚乙烯吡咯烷酮溶液与得到的粉末混合，然后再通过美国14号筛。得到的颗粒于50～60℃干燥并通过美国18号筛。将预先通过美国60号筛的羧甲基纤维素钠、硬脂酸镁和滑石加到颗粒中，在混合以后将其在压片机上压制成片剂。
每5ml剂量含0.1～1000mg药物的各个混悬液剂可按下法制备：
制剂8：混悬液剂
成分 量(mg/5ml)
活性成分 0.1～1000mg
羧甲基纤维素钠 50mg
糖浆 1.25mg
苯甲酸溶液 0.10ml
调味剂 适量
着色剂 适量
纯水 加至 5ml
将药物通过美国45号筛并与羧甲基纤维素钠和糖浆混合，得到调匀的糊状物。用一些水将苯甲酸溶液、调味剂、着色剂稀释，然后于搅拌下加入。再加入足量的水至所需体积。
试验方法
至少选择5名妇女进行临床研究。这些妇女患有机能障碍性子宫出血。因为所涉及症状具有特异反应性和主观特性，所以本研究设安慰剂对照组，即将受试妇女分成两组，一组接受本发明的活性成分，另一组接受安慰剂。在本研究开始之前，根据患者的机能障碍性子宫出血的特点（血液损失、出血时间等）进行鉴定。鉴定还包括用组织学评定进行子宫活组织检查、“动情性记分”，以及用超声波检查、放射成象、NMR或CAT扫描进行子宫内膜厚度测定。试验组的妇女每天口服30～600mg药物。连续治疗3～12个月。进行精确的记录，以便将两组机能障碍性子宫出血的情况以及在研究结束时将上述结果进行比较。将每组成员之间的结果进行比较，并将每个患者的结果与试验开始前每个患者所述的症状进行比较。
本发明化合物对患者机能障碍性子宫出血具有正性效果，表明了本发明化合物的效用。
Claims (4)
1、适用于抑制机能障碍性子宫出血的药物组合物，该组合物含有下述式Ⅰ化合物或其药学上适用的盐或溶剂化物作为活性成分，
其中R1和R3各自独立地为氢、-CH3、
或
，这里Ar为任意取代的苯基，
R2选自吡咯烷子基、六亚甲基亚氨基和哌啶子基。
2、权利要求1的药物组合物，其中所述化合物为其盐酸盐。
3、权利要求1的药物组合物，其中所述组合物适用于预防给药。
4、权利要求1的药物组合物，其中所述化合物为下式化合物或其盐酸盐，
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/171,391 US5446053A (en) | 1993-12-21 | 1993-12-21 | Methods of inhibiting dysfunctional uterine bleeding |
| US171,391 | 1993-12-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1109752A true CN1109752A (zh) | 1995-10-11 |
Family
ID=22623570
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94119734A Pending CN1109752A (zh) | 1993-12-21 | 1994-12-19 | 抑制机能障碍性子宫出血的方法 |
Country Status (20)
| Country | Link |
|---|---|
| US (2) | US5446053A (zh) |
| EP (1) | EP0659417B1 (zh) |
| JP (1) | JPH07215858A (zh) |
| KR (1) | KR950016726A (zh) |
| CN (1) | CN1109752A (zh) |
| AT (1) | ATE168887T1 (zh) |
| AU (1) | AU692490B2 (zh) |
| CA (1) | CA2138510A1 (zh) |
| CZ (1) | CZ321094A3 (zh) |
| DE (1) | DE69412049T2 (zh) |
| DK (1) | DK0659417T3 (zh) |
| ES (1) | ES2119094T3 (zh) |
| GR (1) | GR3027706T3 (zh) |
| HU (1) | HUT71469A (zh) |
| IL (1) | IL112037A (zh) |
| NO (1) | NO944930L (zh) |
| NZ (1) | NZ270167A (zh) |
| PH (1) | PH31099A (zh) |
| RU (1) | RU94044456A (zh) |
| ZA (1) | ZA9410080B (zh) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6515009B1 (en) | 1991-09-27 | 2003-02-04 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US5811447A (en) | 1993-01-28 | 1998-09-22 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US6251920B1 (en) | 1993-05-13 | 2001-06-26 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies |
| US5770609A (en) | 1993-01-28 | 1998-06-23 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies |
| US5847007A (en) | 1993-05-13 | 1998-12-08 | Neorx Corporation | Prevention and treatment of pathologies associated with abnormally proliferative smooth muscle cells |
| US6491938B2 (en) | 1993-05-13 | 2002-12-10 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US5595722A (en) | 1993-01-28 | 1997-01-21 | Neorx Corporation | Method for identifying an agent which increases TGF-beta levels |
| US5856340A (en) * | 1995-02-28 | 1999-01-05 | Eli Lilly And Company | Method of treating estrogen dependent cancers |
| AU6277396A (en) | 1995-06-07 | 1996-12-30 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies with tamoxifen analogues |
| IL120266A (en) | 1996-02-28 | 2005-05-17 | Pfizer | Use of estrogen antagonists and estrogen agonists in the preparation of medicaments for inhibiting pathological conditions |
| TW442286B (en) * | 1996-02-28 | 2001-06-23 | Pfizer | New therapeutic uses of estrogen agonists |
| AU6959898A (en) * | 1997-04-11 | 1998-11-11 | David J. Grainger | Compounds and therapies for the prevention of vascular and non-vascular pathol ogies |
| US6054446A (en) | 1997-12-24 | 2000-04-25 | Sri International | Anti-estrogenic steroids, and associated pharmaceutical compositions and methods of use |
| KR20010080254A (ko) * | 1998-11-26 | 2001-08-22 | 야마구찌 다까시 | 주기 투여용 의약조성물 |
| CA2372720C (en) | 1999-05-04 | 2007-09-11 | John Antony Kanis | Androgen glycosides and androgenic activity thereof |
| IN191020B (zh) | 2000-03-28 | 2003-09-13 | Dabur Res Foundation | |
| WO2002094788A1 (en) * | 2001-05-22 | 2002-11-28 | Eli Lilly And Company | 2-substituted 1,2,3,4-tetrahydroquinolines and derivatives thereof, compositions and methods |
| JP2004531559A (ja) * | 2001-05-22 | 2004-10-14 | イーライ・リリー・アンド・カンパニー | エストロゲン欠乏または内因性エストロゲンに対する異常な生理反応に関連する疾患を抑制するためのテトラヒドロキノリン誘導体 |
| BR0312054A (pt) * | 2002-06-25 | 2005-10-18 | Wyeth Corp | Uso de derivados de tio-oxindol na preparação de medicamentos úteis no tratamento de condições relacionadas com hormÈnio, e kit farmacêutico |
| KR102295878B1 (ko) | 2021-06-16 | 2021-08-31 | 최경선 | 셀프용 등 지압기 |
Family Cites Families (7)
| 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 |
| US4859585A (en) * | 1986-04-17 | 1989-08-22 | Trustees Of Tufts College | In-vitro methods for identifying compositions which are agonists and antagonists of estrogens |
| 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 |
-
1993
- 1993-12-21 US US08/171,391 patent/US5446053A/en not_active Expired - Lifetime
-
1994
- 1994-12-19 IL IL11203794A patent/IL112037A/en not_active IP Right Cessation
- 1994-12-19 ZA ZA9410080A patent/ZA9410080B/xx unknown
- 1994-12-19 ES ES94309475T patent/ES2119094T3/es not_active Expired - Lifetime
- 1994-12-19 AT AT94309475T patent/ATE168887T1/de not_active IP Right Cessation
- 1994-12-19 RU RU94044456/14A patent/RU94044456A/ru unknown
- 1994-12-19 AU AU81561/94A patent/AU692490B2/en not_active Ceased
- 1994-12-19 KR KR1019940034917A patent/KR950016726A/ko not_active Application Discontinuation
- 1994-12-19 PH PH49597A patent/PH31099A/en unknown
- 1994-12-19 CZ CZ943210A patent/CZ321094A3/cs unknown
- 1994-12-19 EP EP94309475A patent/EP0659417B1/en not_active Expired - Lifetime
- 1994-12-19 NZ NZ270167A patent/NZ270167A/xx unknown
- 1994-12-19 NO NO944930A patent/NO944930L/no unknown
- 1994-12-19 CA CA002138510A patent/CA2138510A1/en not_active Abandoned
- 1994-12-19 DE DE69412049T patent/DE69412049T2/de not_active Expired - Fee Related
- 1994-12-19 DK DK94309475T patent/DK0659417T3/da active
- 1994-12-19 HU HU9403663A patent/HUT71469A/hu unknown
- 1994-12-19 CN CN94119734A patent/CN1109752A/zh active Pending
- 1994-12-19 JP JP6314590A patent/JPH07215858A/ja active Pending
-
1995
- 1995-04-14 US US08/422,388 patent/US5552416A/en not_active Expired - Lifetime
-
1998
- 1998-08-20 GR GR980401883T patent/GR3027706T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0659417A2 (en) | 1995-06-28 |
| EP0659417B1 (en) | 1998-07-29 |
| RU94044456A (ru) | 1996-10-10 |
| JPH07215858A (ja) | 1995-08-15 |
| US5446053A (en) | 1995-08-29 |
| ATE168887T1 (de) | 1998-08-15 |
| ZA9410080B (en) | 1996-06-19 |
| AU692490B2 (en) | 1998-06-11 |
| IL112037A (en) | 1999-03-12 |
| NO944930D0 (no) | 1994-12-19 |
| EP0659417A3 (en) | 1995-09-06 |
| NO944930L (no) | 1995-06-22 |
| IL112037A0 (en) | 1995-03-15 |
| US5552416A (en) | 1996-09-03 |
| HU9403663D0 (en) | 1995-02-28 |
| KR950016726A (ko) | 1995-07-20 |
| ES2119094T3 (es) | 1998-10-01 |
| DE69412049D1 (de) | 1998-09-03 |
| PH31099A (en) | 1998-02-05 |
| CZ321094A3 (en) | 1995-08-16 |
| CA2138510A1 (en) | 1995-06-22 |
| AU8156194A (en) | 1995-06-29 |
| GR3027706T3 (en) | 1998-11-30 |
| NZ270167A (en) | 1997-08-22 |
| DE69412049T2 (de) | 1999-01-14 |
| DK0659417T3 (da) | 1998-12-07 |
| HUT71469A (en) | 1995-11-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1109752A (zh) | 抑制机能障碍性子宫出血的方法 | |
| CN1049335C (zh) | 苯并噻吩类化合物的制药用途 | |
| CN1079671C (zh) | 抑制骨损失的组合疗法 | |
| 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 | |
| CN1058389C (zh) | 苯并噻吩类化合物的用途 | |
| CN1109753A (zh) | 抑制肺动脉高血压病的方法 | |
| CN1108102A (zh) | 抑制自身免疫疾病的方法 | |
| CN1107705A (zh) | 提高绝经后妇女性欲的方法 | |
| CN1106260A (zh) | 抑制软骨退化的药用组合物 | |
| CN1108091A (zh) | 抑制妇女生育力的方法 | |
| CN1107332A (zh) | 抑制绝经后妇女的中枢神经系统问题的方法 | |
| CN1107702A (zh) | 抑制卵巢发育不全、青春发育延迟或性幼稚型的方法 | |
| CN1109884A (zh) | 抑制髓过氧化物酶活性的方法 | |
| CN1108103A (zh) | 抑制特纳综合征的方法 | |
| CN1108100A (zh) | 抑制乳房病症的方法 | |
| CN1108099A (zh) | 抑制性早熟的方法 | |
| CN1156406A (zh) | 关于防治假骨变性的方法 | |
| CN1199337A (zh) | 抑制血纤维蛋白溶酶原激活剂抑制剂1的方法 | |
| CN1177295A (zh) | 抑制生长激素作用的方法 | |
| CN1108101A (zh) | 抑制男性不育症的方法 | |
| KR19980702553A (ko) | 난소암의 억제 방법 | |
| CZ52297A3 (en) | Pharmaceutical preparation for inhibiting primary endometrial hyperplasia | |
| CN1169678A (zh) | 防治原发性子宫内膜增生的方法 | |
| CN1169679A (zh) | 抑制与舒缓激肽有关疾病的方法 | |
| CN1156405A (zh) | 骨治疗和骨折修复方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| AD01 | Patent right deemed abandoned | ||
| C20 | Patent right or utility model deemed to be abandoned or is abandoned |