CN1168099A - 3，4-二苯基苯并二氢吡喃在生产用于治疗或预防肥胖的药物组合物中的用途 - Google Patents
3，4-二苯基苯并二氢吡喃在生产用于治疗或预防肥胖的药物组合物中的用途 Download PDFInfo
- Publication number
- CN1168099A CN1168099A CN96191513A CN96191513A CN1168099A CN 1168099 A CN1168099 A CN 1168099A CN 96191513 A CN96191513 A CN 96191513A CN 96191513 A CN96191513 A CN 96191513A CN 1168099 A CN1168099 A CN 1168099A
- Authority
- CN
- China
- Prior art keywords
- purposes
- chemical compound
- aforementioned arbitrary
- obesity
- treatment
- 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
- 208000008589 Obesity Diseases 0.000 title claims abstract description 24
- 235000020824 obesity Nutrition 0.000 title claims abstract description 24
- 238000011282 treatment Methods 0.000 title claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 4
- 238000011321 prophylaxis Methods 0.000 title abstract 2
- 239000004305 biphenyl Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 22
- -1 methoxyl group Chemical group 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 11
- 230000002265 prevention Effects 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 230000003203 everyday effect Effects 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 230000003442 weekly effect Effects 0.000 claims description 5
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 3
- 239000007943 implant Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 abstract 1
- 125000001302 tertiary amino group Chemical group 0.000 abstract 1
- 229960003327 ormeloxifene Drugs 0.000 description 14
- 239000003925 fat Substances 0.000 description 13
- 239000003814 drug Substances 0.000 description 10
- XZEUAXYWNKYKPL-URLMMPGGSA-N ormeloxifene Chemical compound C1([C@@H]2[C@H](C3=CC=C(C=C3OC2(C)C)OC)C=2C=CC(OCCN3CCCC3)=CC=2)=CC=CC=C1 XZEUAXYWNKYKPL-URLMMPGGSA-N 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 230000037396 body weight Effects 0.000 description 8
- 235000013305 food Nutrition 0.000 description 7
- 230000036541 health Effects 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003405 delayed action preparation Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000002267 hypothalamic effect Effects 0.000 description 3
- 230000036186 satiety Effects 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 210000003710 cerebral cortex Anatomy 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 238000002651 drug therapy Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000003016 hypothalamus Anatomy 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 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
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical group CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- LLVWVIIOKIWERJ-UHFFFAOYSA-N 3,4-dihydro-2h-chromen-7-ol Chemical compound C1CCOC2=CC(O)=CC=C21 LLVWVIIOKIWERJ-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
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-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
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 238000005815 base catalysis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000001506 calcium phosphate Substances 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
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 206010016766 flatulence Diseases 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 235000019138 food restriction Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 208000020694 gallbladder disease Diseases 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 210000000088 lip Anatomy 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 238000009806 oophorectomy Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940127234 oral contraceptive Drugs 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000001009 osteoporotic effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000011421 subcutaneous treatment Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000002071 ventral thalamic nuclei Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 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
- A61K31/40—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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- 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
- A61P3/06—Antihyperlipidemics
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)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyrane Compounds (AREA)
Abstract
本发明提供通式(I)的化合物或其可药用盐与可药用的载体一起在生产用于治疗或预防肥胖的药物组合物中的新用途，其中R1、R4和R4彼此独立地是氢、羟基、卤素、三氟甲基、低级烷基、低级烷氧基或(叔氨基)(低级烷氧基)；R2和R3彼此独立地是氢或低级烷基。
Description
发明领域
本发明涉及通式I的化合物用于治疗肥胖患者以及预防肥胖的用途。本发明还包括含有这些化合物的药物组合物和这些化合物及其药物组合物的使用方法。
发明背景
众所周知，肥胖是发生许多常见病，例如动脉粥样硬化、高血压和糖尿病的危险因素。肥胖患者以及与肥胖有关的疾病的发生率在整个工业化的社会中正在逐渐增加。除运动、节食以及食物控制外，目前尚不存在令人信服的有效并可接受的降低体重的药物治疗。然而，由于肥胖是造成死亡及常见病的间接但却很重要的危险因素，所以寻找治疗肥胖的方法有非常重要的意义。
术语肥胖意指过量的脂肪组织。本文中，肥胖被认为是对健康形成威胁的任何程度的脂肪过量。正常与肥胖个体间的界限只能是近似的，但随着脂肪的增加，肥胖对健康形成的威胁是持续存在的。Framingham研究证实，超过适宜体重20％可明确地对健康形成威胁(Mann GV新英格兰医学杂志291：226，1974)。在美国，国家健康研究所对于肥胖一致认为，相对体重增加20％或体重指数(BMI＝以公斤表示的体重除以用米表示的身高)大于85％将对成年的青年构成健康威胁。通过使用这些标准，在美国有20至30％的成年男性和30至40％的成年女生为肥胖(NIH，内科纪事103：147，1985)。
即使中度肥胖也能增加夭折、糖尿病、高血压、动脉粥样硬化、胆囊疾病以及某些类型的癌症的危险性。在工业化的西方世界，肥胖在过去几十年内显著增加。由于肥胖及其引起的健康问题的高度流行，肥胖的预防和治疗应具有高度的公众健康优先权。
当能量的摄取超过消耗时，过量的能量被贮存于脂肪组织中，如果该净的正平衡持续下去，将会导致肥胖，即对于体重平衡有两个因素，任何一侧(摄取或消耗)出现异常均可导致肥胖。
对于进食行为的调节尚未完全理解。在一定程度上，食欲由下丘脑的稀疏区控制：下丘脑腹外侧核的摄食中枢(VLH)和下丘脑腹侧正中的饱食中枢(VMH)。大脑皮质从刺激进食的摄食中枢接受正向信号，而饱食中枢则通过向摄食中枢发出抑制性冲动来调节这一过程。许多调节性过程可以影响这些下丘脑中枢。饭后血浆葡萄糖和/或胰岛素的增加可以激活饱食中枢。食物诱导的胃扩张是另一个可能的抑制性因素。此外，下丘脑中枢对儿茶酚胺敏感，β-肾上腺素能的刺激可抑制进食行为。最终，大脑皮质控制进食行为，并且从摄食中枢传向大脑皮质的冲动是唯一的。心理、社会和遗传因素也会影响食物的摄取。
目前，多种技术都可用来影响最初的体重减轻。不幸的是，最初的体重减轻并不是最佳的治疗目的。而且，问题是大多数肥胖患者的体重最终又重新增加。建立和/或维持体重减轻的有效方法是现今治疗肥胖的主要目标。
星克罗曼是一种已知具有抗雌激素活性的非甾体化合物。它在印度被用作口服避孕药(参见，例如Salman等，美国专利说明书447622；Singh等，内分泌学报(Copenh)126(1992)，444-450；Grubb，Curr Opin ObstetGynecol 3(1991)，491-495；Sankaran等，避孕(1974)，279-289；印度专利说明书129187)。还将星克罗曼作为抗癌药物进行了研究，用于治疗进展期乳腺癌(Misra等，国际癌症杂志43(1989)，781-783)。最近发现，外消旋的星克罗曼是强效的降低胆固醇的药物，可以显著地降低血清浓度(S.D.Bain等，J Min Bon Res 9(1994)，S 394)。
美国专利5280040记载了用3，4-二芳基苯并二氢吡喃及其可药用盐降低骨质疏松的方法和药物组合物。
因此，现在仍需要可用于治疗或预防肥胖的组合物和方法。
本发明的一个目的是提供可有效地用于治疗或预防肥胖的化合物。
发明概述
我们惊奇地发现，权利要求1所述的通式I的化合物可用于治疗或预防肥胖。
发明详述
本发明部分是基于如下发现，即3，4-二芳基苯并二氢吡喃的代表性化合物星克罗曼(3，4-反-2，2-二甲基-3-苯-4-[p-(β-吡咯烷-1-基乙氧基)苯基]-7-甲氧基苯并二氢吡喃)可在兔子中有效地防治肥胖。星克罗曼是一个外消旋混合物。这些动物模型是肥胖的常用模型。这些数据表明式I的3，4-二芳基苯并二氢吡喃可以在哺乳动物，包括灵长类动物例如人中用作防治肥胖的治疗药物。
在本发明中，权利要求1所述的式I的化合物用于防治肥胖患者。式I中，R1、R4和R5彼此独立地是氢、卤素、三氟甲基、低级烷基、低级烷氧基或(叔氨基)(低级烷氧基)；R2和R3彼此独立地是氢或低级烷基。在此使用的术语“低级烷基”包括含有1至6个碳原子的直链和支链的烷基基团，例如甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基、仲戊基、正己基、2-乙基丁基、2，3-二甲基丁基等。术语“低基烷氧基”包括含有1至6个碳原子的直链和支链的烷氧基基团，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、正戊氧基、仲戊氧基、正己氧基、2-乙氧基丁氧基、2，3-二甲氧基丁氧基等。“卤素”包括氯、氟、溴和碘。叔氨基基团可以是N，N-二烷基胺，例如N，N-二甲氨基、N，N-二乙氨基、N，N-二丙氨基和N，N-二丁氨基；或环胺，例如哌啶、吡咯烷、N-甲基哌嗪或吗啉。文中的术语“(叔氨基)(低级烷氧基)”是被叔氨基取代的低级烷氧基。优选的化合物包括，其中R1是低级烷氧基；R2和R3是低级烷基，尤其是甲基；R4是氢；R5是环胺类型的(叔氨基)(低级烷氧基)。在特别优选的实施方案中，R1位于7位并且是低级烷氧基，特别是甲氧基；R2和R3均甲基，R4是氢，R5位于4位并且是(叔氨基)(低级烷氧基)基团，例如2-(吡咯烷-1-基)乙氧基。本发明包括所述式I化合物的所有可药用盐。
优选使用反式构型的式I化合物。这些化合物可以以外消旋混合物、或分离的立体异构体例如d-或1-对映体的形式使用。反-1-对映体最为优选。
用于本发明的特别优选的化合物是由1-星克罗曼和d-星克罗曼组成的星克罗曼。1-星克罗曼可能具有式IV的结构
3，4-二芳基苯并二氢吡喃可以根据已知的方法制备，例如美国专利说明书3340276(Carney等)和美国专利说明书3822287(Bolger)以及药物化学杂志19(1976)，276-279(Ray等)中记载的方法，在此将上述文献的内容引入本文作为参考。将顺式异构体转变为反式构型通过美国专利说明书3822287中公开的有机金属碱催化的重排反应来进行。光学活性的d-和1-对映体可以按照Salman等在美国专利说明书4447622(引入本文作为参考)中公开的方法，通过形成光学活性的酸式盐并将其碱水解生成所需的对映体进行制备。如果R2和R3不同并且R4和R5不同，则通式I包含了8个光学异构体。
在本发明中，可以将式I的3，4-二芳基苯并二氢吡喃制备成可药用盐，尤其是酸加成盐的形式，包括有机酸盐和无机酸盐。这些盐的例子包括有机酸，例如甲酸、富马酸、乙酸、丙酸、乙醇酸、乳酸、丙酮酸、草酸、琥珀酸、苹果酸、酒石酸、枸橼酸、苯甲酸、水杨酸等的盐。合适的无机酸加成盐包括盐酸、氢溴酸、硫酸和磷酸等的盐。酸加成盐可以作为化合物合成中的直接产物得到。或者，可以将游离碱溶于含有适当酸的合适溶剂中，然后通过蒸除溶剂或其它分离盐和溶剂的方法分离出盐。
式I的3，4-二芳基苯并二氢吡喃及其盐可用作人和兽用药，例如，用于治疗肥胖患者。为了用于本发明，可将式I的3，4-二芳基苯并二氢吡喃及其可药用盐和可药用的载体根据常规的方法配制成适于胃肠外、口服、鼻内、直肠内、皮下或皮内或透皮给药的药物。配方中还可另外含有一种或多种稀释剂、填料、乳化剂、防腐剂、缓冲剂、赋性剂等，并可制成溶液剂、粉末、乳剂、栓剂、脂质体、透皮贴剂、控释制剂、皮肤植入剂、片剂等剂型。本领域技术人员可以以适当的方式并根据公认的实践将化合物配制成药物，例如在Remingtons药物科学，Gennaro等，Mack出版公司，Easton，PA，1990中公开的方法。
口服给药为优选。因此将式I化合物制成适于口服给药的剂型，例如片剂或胶囊。通常，将式I化合物的可药用盐与载体混合并制成片剂的形状。合适的载体包括淀粉、糖、磷酸二钙、硬脂酸钙、硬脂酸镁等。这些组合物中还可另外含有一种或多种辅料，例如湿润剂、乳化剂、防腐剂、稳定剂、着色添加剂等。
含有式I化合物的药物组合物可以每日或每周给药一次或多次。该药物组合物的有效量为可以对肥胖产生有临床意义效果的量。该用量部分取决于所治疗的具体疾病、年龄、体重、患者的一般健康状况、以及对本领域技术人员显而易见的其它因素。
含有式I化合物的药物组合物可以以单位剂量形式每日或每周给药一次或多次。或者可以将其制成适于皮肤植入的控释制剂。植入剂可以在多达数年的所需时期内释放活性化合物。控释制剂记载于，例如Sanders等，药物科学杂志73(1964)，1294-1297，1984；美国专利说明书4489056；和美国专利说明书4210644，在此将以上文献引入本文作为参考。
式I化合物的优选例子是外消旋混合物形式以及1-星克罗曼和d-星克罗曼形式的星克罗曼。此外，3，4-反-2，2-二甲基-3-苯基-4-[4-(2-(吡咯烷-1-基)乙氧基)苯基]-7-羟基苯并二氢吡喃也是优选化合物。更优选的化合物是1-3，4-反-2，2-二甲基-3-苯基-4-[4-(2-(吡咯烷-1-基)乙氧基)苯基]-7-甲氧基苯并二氢吡喃。
通过以下实施例对本发明进行进一步的说明，然而，不应将这些实施例理解为对保护范围的限定。
在前面的描述以及如下实施例中所公开的特征(分别的及其任何组合形式的)可以作为以本发明的改变形式实现本发明的材料。实施例试验1
在用胆固醇饲养的兔子中研究了1-星克罗曼对兔子体重增加的影响。取30只性成熟的新西兰白兔(体重在3000-3550g的重量范围内)。将动物每笼一只关在35×45cm的笼子内并让其随意饮水。室温保持在18±0.5℃，最低相对温度为40％。
在药物治疗开始前一周，将动物在戊巴比妥的麻醉下进行两侧卵巢切除术。在经过一周的恢复期后分三组进行皮下处理：载体、17-β-雌二醇(0.5mg/kg)或1-星克罗曼7.5mg/kg。持续给药4周，每周三次。在整个实验过程中对动物进行食物限制，每日仅供给100g食物。所有动物每日均吃完其所有的食物。在开始时、治疗期间内以及实验结束时每周一次对兔子进行称重，测定出在整个期间内的体重增加。如表1所示，与用载体处理的动物和用雌激素处理的动物相比1-星克罗曼可显著地减少体重增加。表1.恒量喂食并用药物处理的兔子的体重增加
处理 体重增加(g)
安慰剂 255±20
雌激素 246±34
1-星克罗曼 38±28*
数值为平均值±SEM。*表示与用安慰剂处理的动
物相比体重增加显著减少；p＜0.001。
除已证实的化合物用于本发明的方法的有益效果外，未观察到有害的毒理学作用。试验2
从Mollegaards饲养中心(LI.Skensved，Denmark)购得28只遗传性肥胖的雄性小鼠(ob/ob小鼠)。将动物每笼3或4只一组关在金属吊笼中并让其随意接近食物和水，使其适应环境一周。室温维持在21℃±0.5℃，最低相对湿度为40％。屋内的光照时间为光照12小时黑暗12小时。
在一周的适应环境期后开始用试验化合物进行给药。化合物的给药量从0.001至100mg/天，给药期为1个月。化合物通过等渗注射液进行腹膜内给药，每周两次。每日测定食物消耗量并且在治疗期间内每周称重动物两次。试验3
使用与试验2相同的方法，不同的是给药期为3个月。试验4
使用与试验2相同的方法，不同的是给药期为6个月。试验5
对3到20个之间的肥胖(根据上述的标准)妇女给予本发明的化合物。化合物的给药量从0.1至1000mg/天，治疗期间为6个月。
在给药期直至停止给药后3个月内对这些妇女观察对其肥胖的作用。试验6
使用与试验5相同的方法，不同的是给药期为1年。试验7
使用与试验5相同的方法，不同的是用3到20个之间的肥胖男性进行试验。试验8
使用与试验7相同的方法，不同的是给药期为1年。
Claims (19)
1.通式I的化合物或其可药用盐与可药用的载体一起在生产用于治疗或预防肥胖的药物组合物中的用途，
其中R1、R4和R5彼此独立地是氢、羟基、卤素、三氟甲基、低级烷基、低级烷氧基或(叔氨基)(低级烷氧基)；R2和R3彼此独立地是氢或低级烷基。
2.根据权利要求1的用途，其中所述化合物具有通式III的结构：
其中R1、R2、R3、R4和R5均具有权利要求1所述的意义。
3.根据权利要求1或2的用途，其中R1是低级烷氧基，优选甲氧基。
4.根据前述任一权利要求的用途，其中R2是低级烷基，优选甲基。
5.根据前述任一权利要求的用途，其中R3是低级烷基，优选甲基。
6.根据前述任一权利要求的用途，其中R4是氢。
7.根据前述任一权利要求的用途，其中R5是(叔氨基)(低级烷氧基)，优选2-(吡咯烷-1-基)乙氧基。
8.根据前述任一权利要求的用途，其中所述的化合物是立体异构体，例如分离的d-或1-对映体。
9.根据前述任一权利要求的用途，其中所述的化合物是分离的1-对映体。
10.根据权利要求1的用途，其中所述化合物为3，4-反-2，2-二甲基-3-苯基-4-[4-(2-(吡咯烷-1-基)乙氧基)苯基]-7-甲氧基苯并二氢吡喃。
11.根据前述任一权利要求的用途，其中所述化合物为3，4-反-2，2-二甲基-3-苯基-4-[4-(2-(吡咯烷-1-基)乙氧基)苯基]-7-甲氧基苯并二氢吡喃的分离的d-或1-对映体。
12.根据权利要求11的用途，其中所述化合物为1-3，4-反-2，2-二甲基-3-苯基-4-[4-(2-(吡咯烷-1-基)乙氧基)苯基]-7-甲氧基苯并二氢吡喃。
13.根据前述任一权利要求的用途，其中所述组合物为适于口服给药的剂型。
14.根据前述任一权利要求的用途，其中所述化合物的给药剂量范围从大约0.001至75，优选从大约0.01至75，更优选从大约0.01至50并特别优选从大约0.1至25mg/kg患者/天。
15.根据前述任一权利要求的用途，其中所述组合物每日或每周给药一次或多次。
16.根据前述任一权利要求的用途，其中所述组合物为皮肤植入剂的形式。
17.治疗和预防肥胖的方法，包括向患者给予临床有效量的所述可用于任意前述用途权利要求的式I的抗肥胖化合物，或其用量足以治疗或预防肥胖的式I化合物的可药用盐。
18.一种治疗或预防肥胖的方法，该方法包括向需要该治疗的患者给予临床有效量的式I化合物或其盐以及含有该化合物的可药用组合物。
19.文中所述的任何新的特征或特征的组合。
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK0066/95 | 1995-01-20 | ||
| DK6695 | 1995-01-20 | ||
| DK77495 | 1995-06-30 | ||
| DK0774/95 | 1995-06-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1168099A true CN1168099A (zh) | 1997-12-17 |
Family
ID=26063228
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96191513A Pending CN1168099A (zh) | 1995-01-20 | 1996-01-10 | 3，4-二苯基苯并二氢吡喃在生产用于治疗或预防肥胖的药物组合物中的用途 |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US6008242A (zh) |
| EP (1) | EP0804187A1 (zh) |
| JP (1) | JPH10512270A (zh) |
| KR (1) | KR19980701547A (zh) |
| CN (1) | CN1168099A (zh) |
| AU (1) | AU4328996A (zh) |
| BR (1) | BR9606925A (zh) |
| CA (1) | CA2208837A1 (zh) |
| CZ (1) | CZ211997A3 (zh) |
| HU (1) | HUP9800334A3 (zh) |
| IL (1) | IL116826A (zh) |
| NO (1) | NO973340D0 (zh) |
| TW (1) | TW448046B (zh) |
| WO (1) | WO1996022092A1 (zh) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7910548B2 (en) * | 1997-06-06 | 2011-03-22 | Amylin Pharmaceuticals, Inc. | Methods for treating obesity |
| WO1999002152A1 (en) * | 1997-07-10 | 1999-01-21 | Novo Nordisk A/S | Use of 3,4-diphenylchromans for the manufacture of a pharmaceutical composition for increasing insulin sensitivity |
| AU1143899A (en) * | 1997-11-10 | 1999-05-31 | Novo Nordisk A/S | Transdermal delivery of 3,4-diarylchromans |
| CA2581316C (en) | 2004-09-21 | 2013-09-10 | Novogen Research Pty Ltd | Substituted chroman derivatives, medicaments and use in therapy |
| US8080675B2 (en) | 2004-09-21 | 2011-12-20 | Marshall Edwards, Inc. | Chroman derivatives, medicaments and use in therapy |
| ES2773753T3 (es) | 2010-11-01 | 2020-07-14 | Mei Pharma Inc | Compuestos isoflavonoides y métodos para el tratamiento del cáncer |
| PL2953938T3 (pl) | 2014-02-07 | 2017-12-29 | Novogen Ltd. | Funkcjonalizowane związki benzopiranowe i ich zastosowanie |
| AU2016215515B2 (en) | 2015-02-02 | 2020-04-30 | Mei Pharma, Inc. | Combination therapies |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3822287A (en) * | 1969-04-17 | 1974-07-02 | Rexall Drug Chemical | Process for preparation of substituted 3,4-(diphenyl)chromans |
| US4447622A (en) * | 1981-09-22 | 1984-05-08 | Council Of Scientific And Industrial Research Rafi Marg | Preparation of l- and d-isomers of dl-3,4-trans-2,2-disubstituted-3,4-diarylchromans and derivatives thereof |
| US5280040A (en) * | 1993-03-11 | 1994-01-18 | Zymogenetics, Inc. | Methods for reducing bone loss using centchroman derivatives |
-
1996
- 1996-01-09 TW TW085100184A patent/TW448046B/zh active
- 1996-01-10 WO PCT/DK1996/000011 patent/WO1996022092A1/en not_active Application Discontinuation
- 1996-01-10 JP JP8521977A patent/JPH10512270A/ja active Pending
- 1996-01-10 CA CA002208837A patent/CA2208837A1/en not_active Abandoned
- 1996-01-10 CZ CZ972119A patent/CZ211997A3/cs unknown
- 1996-01-10 AU AU43289/96A patent/AU4328996A/en not_active Abandoned
- 1996-01-10 HU HU9800334A patent/HUP9800334A3/hu unknown
- 1996-01-10 CN CN96191513A patent/CN1168099A/zh active Pending
- 1996-01-10 KR KR1019970704938A patent/KR19980701547A/ko not_active Application Discontinuation
- 1996-01-10 BR BR9606925A patent/BR9606925A/pt not_active Application Discontinuation
- 1996-01-10 EP EP96900092A patent/EP0804187A1/en not_active Withdrawn
- 1996-01-11 US US08/585,013 patent/US6008242A/en not_active Expired - Fee Related
- 1996-01-19 IL IL11682696A patent/IL116826A/xx active IP Right Grant
-
1997
- 1997-07-18 NO NO973340A patent/NO973340D0/no unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MX9705378A (es) | 1997-10-31 |
| NO973340L (no) | 1997-07-18 |
| NO973340D0 (no) | 1997-07-18 |
| BR9606925A (pt) | 1997-11-11 |
| CZ211997A3 (en) | 1997-12-17 |
| HUP9800334A2 (hu) | 1998-12-28 |
| IL116826A0 (en) | 1996-05-14 |
| TW448046B (en) | 2001-08-01 |
| JPH10512270A (ja) | 1998-11-24 |
| IL116826A (en) | 1999-11-30 |
| EP0804187A1 (en) | 1997-11-05 |
| HUP9800334A3 (en) | 1999-12-28 |
| WO1996022092A1 (en) | 1996-07-25 |
| CA2208837A1 (en) | 1996-07-25 |
| US6008242A (en) | 1999-12-28 |
| KR19980701547A (ko) | 1998-05-15 |
| AU4328996A (en) | 1996-08-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1196163B1 (en) | Pharmaceutical compositions for the treatment of insulin resistance | |
| AU2005218047B2 (en) | Derivatives of venlafaxine and methods of preparing and using the same | |
| CN1168096A (zh) | 3，4-二苯基苯并二氢吡喃在生产用于治疗或预防妇科疾病的药物组合物中的用途 | |
| CN1395488A (zh) | 用于激素替代治疗的屈螺酮 | |
| US5726202A (en) | Benign prostatic hypertrophy | |
| CN1168099A (zh) | 3，4-二苯基苯并二氢吡喃在生产用于治疗或预防肥胖的药物组合物中的用途 | |
| EP0873120A1 (en) | Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of menopausal symptoms | |
| US5756539A (en) | 3, 4-diphenyl chromans for inhibiting one or more psychiatric disorders | |
| EP0873119A1 (en) | Use of the l-enantiomer of centchroman for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of breast cancer | |
| CZ212397A3 (en) | Use of 3,4-diphenylchromans for preparing pharmaceutical preparations for treating or prophylaxis of hyperlipoproteinaemia, hypertriacylglycerolaemia, hyperlipidaemia, hypercholesterolaemia, arteriosclerosis and reduction of blood sedimentation | |
| AU702407B2 (en) | Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment of prophylaxis of idiopathic or physiologic gynaecomastia | |
| US5886021A (en) | Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for vasodilatory treatment or prophylaxis | |
| WO1998033499A1 (en) | Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for increasing libido in post-menopausal women | |
| MXPA97005378A (en) | Use of the 3,4-difenil-chromians for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of the obesi | |
| WO1998032437A1 (en) | Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for inhibiting one or more psychiatric disorders | |
| WO1998002156A1 (en) | Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for lowering intraocular pressure | |
| JP2000514441A (ja) | 月経前症候群の１又は複数の症状を抑制するための医薬組成物の製造のための３，４―ジフェニルクロマンの使用 | |
| WO1999002152A1 (en) | Use of 3,4-diphenylchromans for the manufacture of a pharmaceutical composition for increasing insulin sensitivity | |
| KR19980701384A (ko) | 측발성 또는 생리적 여성형유방의 치료 또는 예방용 약학적 조성물의 제조를 위한 3,4-디페닐크로만의 사용 | |
| JPH1135461A (ja) | 睡眠障害の治療剤 | |
| CN1207038A (zh) | 3,4－二苯基苯并二氢吡喃在生产预防或治疗绝经症状的药物组合物中的应用 | |
| WO1999048497A1 (en) | USE OF 3,4-DIPHENYLCHROMANS FOR THE MANUFACTURE OF A PHARMACEUTICAL COMPOSITION FOR LOWERING PLASMA LEVELS OF Lp(a) IN A HUMAN OR SUB-HUMAN PRIMATE |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |