CN1399545A - 治疗某些与体重增加有关的癌症 - Google Patents
治疗某些与体重增加有关的癌症 Download PDFInfo
- Publication number
- CN1399545A CN1399545A CN00807533A CN00807533A CN1399545A CN 1399545 A CN1399545 A CN 1399545A CN 00807533 A CN00807533 A CN 00807533A CN 00807533 A CN00807533 A CN 00807533A CN 1399545 A CN1399545 A CN 1399545A
- Authority
- CN
- China
- Prior art keywords
- formula
- chemical compound
- cyclobutyl
- chlorphenyl
- require
- 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
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 14
- 230000004584 weight gain Effects 0.000 title 1
- 235000019786 weight gain Nutrition 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 6
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 6
- 206010014759 Endometrial neoplasm Diseases 0.000 claims abstract description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 6
- 201000010175 gallbladder cancer Diseases 0.000 claims abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- 208000008589 Obesity Diseases 0.000 claims abstract description 4
- 235000020824 obesity Nutrition 0.000 claims abstract description 4
- 150000004682 monohydrates Chemical class 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 29
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 28
- 201000011510 cancer Diseases 0.000 claims description 12
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 10
- BMFVGAAISNGQNM-UHFFFAOYSA-N isopentylamine Chemical compound CC(C)CCN BMFVGAAISNGQNM-UHFFFAOYSA-N 0.000 claims description 7
- 201000008275 breast carcinoma Diseases 0.000 claims description 5
- 201000003914 endometrial carcinoma Diseases 0.000 claims description 5
- 201000007487 gallbladder carcinoma Diseases 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 206010014733 Endometrial cancer Diseases 0.000 abstract 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 abstract 1
- UWAOJIWUVCMBAZ-UHFFFAOYSA-N [1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-dimethylazanium;chloride Chemical compound Cl.C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UWAOJIWUVCMBAZ-UHFFFAOYSA-N 0.000 abstract 1
- 239000002552 dosage form Substances 0.000 description 10
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- 238000001802 infusion Methods 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 230000000407 monoamine reuptake Effects 0.000 description 4
- 229960004425 sibutramine Drugs 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 3
- 238000009505 enteric coating Methods 0.000 description 3
- 239000002702 enteric coating Substances 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000012053 oil suspension Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 2
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 206010019233 Headaches Diseases 0.000 description 2
- 206010026749 Mania Diseases 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 206010041349 Somnolence Diseases 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229960003914 desipramine Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229960002464 fluoxetine Drugs 0.000 description 2
- 238000001030 gas--liquid chromatography Methods 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- 238000004460 liquid liquid chromatography 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
- 210000000214 mouth Anatomy 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000012049 topical pharmaceutical composition Substances 0.000 description 2
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 2
- 229960004688 venlafaxine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- SFLSHLFXELFNJZ-CMIMLBRMSA-N 4-[(1r)-2-amino-1-hydroxy-1-tritioethyl]benzene-1,2-diol Chemical compound NC[C@@](O)([3H])C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-CMIMLBRMSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010012735 Diarrhoea Diseases 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
- 208000002705 Glucose Intolerance Diseases 0.000 description 1
- 206010021030 Hypomania Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 208000005946 Xerostomia Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 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 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000005978 brain dysfunction Effects 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
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 239000007766 cera flava Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000004531 microgranule Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 206010029410 night sweats Diseases 0.000 description 1
- 230000036565 night sweats Effects 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 231100000435 percutaneous penetration Toxicity 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000009466 transformation Effects 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
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Child & Adolescent Psychology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
将其中R1和R2独立为H或甲基的式I化合物或其药学上可接受的盐(例如任选以一水合物形式的N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺盐酸盐)用于治疗与肥胖有关的癌症,所述癌症包括结肠癌、乳癌、子宫内膜癌和胆囊癌。
Description
本发明涉及一种治疗某些与体重增加有关的癌症的方法。
可以用式I化合物有利地治疗的癌症包括结肠癌、乳癌、子宫内膜癌和胆囊癌。
式I的优选化合物为N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺或其盐,例如盐酸盐。该盐酸盐的优选形式为它的一水化物。
在英国专利说明书2098602和美国专利4,522,328中描述了治疗抑郁症的式I化合物,如N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺、N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N-甲胺和1-[1-(4-氯苯基)环丁基]-3-甲基丁胺及其盐的制备和使用。式I化合物如N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺及其盐在治疗帕金森氏病中的用途描述于公开的WO公开的PCT申请88/06444中。式I化合物如N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺及其盐在治疗大脑功能紊乱中的用途描述于美国专利4,939,175。N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺盐酸盐在治疗肥胖中的用途描述于公开的PCT申请WO90/06110中。该化合物特别优选的形式为N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺盐酸盐的一水化物(西布曲明盐酸盐),其被描述于欧洲专利号230742中。在公开的PCT申请WO95/20949中描述了N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺及其盐改善患有受损的葡萄糖耐受性或非胰岛素依赖性糖尿病患者的葡萄糖耐受性的用途。
本领域的技术人员应该理解式I化合物含有一个手性中心。当式I化合物含有一个单一的手性中心时,它可以存在两个对映异构体形式。本发明包括使用单独的对映体或对映体的混合物。通过本领域技术人员已知的方法可解析对映体,例如形成可以分离的非对映异构盐或复合物,如通过结晶作用分离;通过形成可以分离的非对映异构衍生物,如通过结晶作用、气-液色谱法或液相色谱法分离;一种对映体与对映异构的特殊试剂的选择性反应,例如酶氧化或还原反应,随后分离修饰的或未修饰的对映体;或在手性环境中通过气-液色谱法或液相色谱法分离,如在手性载体上如带有一个结合的手性配位体的硅胶或在手性溶剂的存在下分离。应该明白,用上述的分离方法中的一种将所需要的对映体转化为另一个化学实体,下一步要求释放出所需要的对映异构形式。或者,通过不对称合成,使用任选的活性试剂、底物、催化剂或溶剂可以合成特定的对映体,或通过不对称转变将一个对映体转化为另一个对映体合成特定的对映体。
式I的优选化合物为N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺、N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N-甲基胺和1-[1-(4-氯苯基)环丁基]-3-甲基丁胺,包括它们的外消旋体、单独的对映体和混合物,及其药学上可接受的盐。
可以通过对映体选择性的合成方法由任选的活性前体制备单独的对映体,或通过解析可以按照以上描述制备的外消旋化合物制备单独的对映体。式I的仲胺的对映体也可以通过以下方法制备,首先制备相应的伯胺的外消旋体,将后者解析为单独的对映体,然后用描述于英国专利说明书2098602的方法将旋光纯的伯胺对映体转化为所需的仲胺。
式I化合物的具体实例为:
(+)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N-甲基胺;
(-)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N-甲基胺;
(+)-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺;
(-)-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺;
(+)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N,N-二甲基胺;
(-)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N,N-二甲基胺。
在每种情况下皆优选盐酸盐,但游离碱和其它药学上可接受的盐也是适宜的。
可以以任何已知的药用剂型给予式I化合物。所给予的化合物的量将取决于许多因素,包括患者的年龄、疾病的严重性和患者过去的医疗史,并且所给予的化合物的量总是在主治医师的合理决定权范围内,但是一般设计所给予化合物的剂量在每天0.1到50mg,优选1到30mg的范围内,可一次或多次给药。
口服剂型为本发明使用的优选组合物并且这些剂型为此类给药方式的已知药用剂型,例如片剂、胶囊剂、颗粒剂、糖浆剂和水或油悬浮液。在制备这些组合物时使用的赋形剂为药剂师领域所熟悉的赋形剂。可以从活性化合物与如磷酸钙的填充剂、如玉米淀粉的崩解剂、如硬脂酸镁的润滑剂、如微晶纤维素或聚乙烯吡咯烷酮的粘合剂以及其它本领域已知的任选成分的混合物制备片剂,如通过已知的方法将该混合物压制成片。如果需要,可以用已知的方法和赋形剂将所述片剂包衣,所述包衣可以包括例如使用苯二甲酸羟丙基甲基纤维素的肠溶包衣。可以用本领域技术人员已知的方法配制片剂以便持续地释放出本发明的化合物。如果需要,可以用已知的方法给此类片剂提供肠溶包衣,如通过使用苯二甲酸醋酸纤维素包衣。类似地,可以用已知的方法制备含有活性化合物(加有或未加有赋形剂)的胶囊剂,例如硬或软明胶胶囊并且,如果需要,可以用已知的方法提供肠溶包衣。可以用已知的方法配制胶囊的内容物以便持续地释放出活性化合物。片剂和胶囊剂每片或每粒常规含有1到50mg的活性化合物。
例如,其它口服给药的剂型包括在无毒性的悬浮剂如羧甲基纤维素钠的存在下、在含水媒介中含有活性化合物的水性悬浮液和在适宜的植物油如花生油中含有本发明化合物的油悬浮液。可以将所述活性化合物与或不与添加的赋形剂配制成颗粒剂。患者可以直接摄入该颗粒剂或在摄入前将其加入到适宜的液体载体(如水)中。所述颗粒剂可以含有崩解剂,例如由一种酸与一种碳酸盐或碳酸氢盐形成的泡腾偶合物(effervescent couple)对以便促进在液体媒介中的分散。
可以将治疗性的式I活性化合物配制成为一种患者可以保留在口腔中的组合物以便通过口腔粘膜给予该活性化合物。
适宜直肠给药的剂型为此类给药方式的已知药用剂型,如含有可可脂或聚乙二醇基质的栓剂。
适宜胃肠外给药的剂型为此类给药方式的已知药用剂型,如在适宜溶剂中的无菌悬浮液或无菌溶液。
适宜局部给药的剂型可以包含一种基质,为了透皮给予所述化合物,将本发明的药用活性化合物分散在基质中以便该化合物保持与皮肤接触。可以通过使药用活性化合物与一种局部媒介物如矿物油、凡士林和/或一种蜡如石蜡或蜂蜡混合,与一种有效的透皮促进剂如二甲基亚砜或丙二醇一起制备适宜的透皮组合物。或者,可以将该活性化合物分散在药学上可接受的乳膏、凝胶或软膏基质中。在局部制剂中含有的活性化合物的量应该是打算将该局部制剂用于皮肤期间能够传递的化合物的治疗有效量。
可以将的式I治疗活性化合物配制为一种作为气雾剂分散进入到患者口腔或鼻腔的组合物。此类气雾剂可以由一种泵压包或含有挥发性抛射剂的加压包给药。
用于本发明方法的式I治疗活性化合物也可以通过从一个外源持续输注给药,如通过静脉输注给药或从一个放置在体内的化合物源持续给药。内源包括植入含有将要输注的化合物的储库,例如该化合物可以通过渗透持续释放,并且对于输注的化合物而言,植入物可以为(a)液体如待输注化合物的一种油悬浮液,一种很难溶于水的衍生物如十二烷酸盐或亲油性酯或(b)以植入载体形式存在的固体,如合成的树脂或蜡样物质。所述载体可以为含有所有化合物的单一实体(singlebody)或为一系列的若干个含有部分待传递的化合物的实体。内源中存在的活性化合物的量应该能够在长时间内释放治疗有效量的化合物。
在某些制剂中,以很小的粒径的微粒形式使用本发明的化合物可能是有益的,例如使用通过流能磨获得的微粒。
在本发明的组合物中,如果需要,该活性化合物可以与其它适配的药用活性成分组合。
另外,本发明提供式I化合物在生产治疗某些与肥胖有关的癌症如结肠癌、乳癌、子宫内膜癌和胆囊癌的药物中的用途。
另一方面,本发明进一步提供治疗结肠癌、乳癌、子宫内膜癌和胆囊癌的药用组合物,该组合物包括式I化合物与药学上可接受的稀释剂或载体。
单胺再摄取抑制剂一直用于治疗本发明描述的某些疾病。可是,已经知道这些化合物有许多缺点。首先,此类化合物不是对所有的病人有效。其次,有效的化合物不能彻底的治疗疾病。第三,该类型的化合物已知有许多不利的副作用。此类副作用包括恶心、性功能障碍、轻微头痛(headedness)、嗜睡、盗汗、颤动、口干、衰弱、失眠、腹泻、头痛、呕吐、焦虑、瞌睡、头昏、发烧、皮疹或过敏反应、关节痛、肌痛、痉挛、轻度躁狂和狂躁。
西布曲明(式I,R1=CH3,R2=CH3)具有一个药理学分布图,在单胺再摄取抑制剂中该分布图是唯一的。它的药理学活性代谢产物,(代谢产物1,在式I中R1=H,R2=CH3和代谢产物2,在式I中R1=H,R2=H)西布曲明抑制所有三个单胺的再摄取,这3种胺不同于5-羟色胺(5-HT)选择性再摄取抑制剂如氟苯氧丙胺、去甲肾上腺素选择性再摄取抑制剂如去甲丙咪嗪、多巴胺选择性再摄取抑制剂如丁氨苯丙酮,以及5-羟色胺-去甲肾上腺素再摄取抑制剂如文拉法辛(表1)。这是值独特的药理作用的联合,该联合作用使西布曲明和其它式I化合物有效地治疗某些与体重增加有关的癌症。
用类似于WO98/41528描述的方法进行以下分析。
表
实施例1和2
以及各种参照的单胺再摄取抑制剂在大鼠脑组织中 的体外单胺再摄取抑制分布比较
Ki(nM) | |||
[3H]去甲肾上腺素 | [3H]5-HT | [3H]多巴胺 | |
实施例1 | 3 | 18 | 24 |
实施例2 | 5 | 26 | 31 |
丁氨苯丙酮 | 2590 | 18312 | 409 |
去甲丙咪嗪 | 2 | 200 | 4853 |
氟苯氧丙胺 | 320 | 11 | 2025 |
文拉法辛 | 196 | 26 | 2594 |
所述结果为≥3次单独测定的平均值。
实施例1:在式I中R1=H,R2=CH3
实施例2:在式I中R1=H,R2=H
式I化合物在治疗某些癌症中的效果可以通过在确定的有关人群中进行临床试验证实。
用各种具体的实施方案描述了本发明。可是,可以进行许多改变和修饰而仍然在本发明的范围和精神内。
Claims (20)
2.权利要求1要求的方法,其中所述癌症为结肠癌、乳癌、子宫内膜癌或胆囊癌。
3.权利要求1或2要求的方法,其中所述式I化合物为N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺盐酸盐。
4.权利要求1或2要求的方法,其中所述式I化合物为一水合物形式的N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺盐酸盐。
5.权利要求1或2要求的方法,其中所述式I化合物为(+)-N-[1-[1-(4-氯苯基)环丁基]-3-甲基丁基]-N-甲胺。
6.权利要求1或2要求的方法,其中所述式I化合物为(-)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N-甲胺。
7.权利要求1或2要求的方法,其中所述式I化合物为(+)-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺。
8.权利要求1或2要求的方法,其中所述式I化合物为(-)-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺。
9.权利要求1或2要求的方法,其中所述式I化合物为(+)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N,N-二甲胺。
10.权利要求1或2要求的方法,其中所述式I化合物为(-)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N,N-二甲胺。
11.权利要求1或2要求的方法,其中所述式I化合物为(±)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N-甲胺。
12.权利要求1或2要求的方法,其中所述式I化合物为(±)-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺。
13.权利要求1或2要求的方法,其中所述式I化合物为(±)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N,N-二甲胺。
15.权利要求14要求的用途,其中所述癌症为结肠癌、乳癌、子宫内膜癌或胆囊癌。
16.权利要求14或15要求的用途,其中所述式I化合物为N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺盐酸盐。
17.权利要求14或15要求的用途,其中所述式I化合物为N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺盐酸盐一水合物。
18.一种治疗与肥胖有关的癌症的药用组合物,该组合物包括治疗有效量的式I化合物,包括其对映体和其药学上可接受的盐,以及药学上可接受的稀释剂或载体,其中R1和R2独立为H或甲基。
19.权利要求18要求的药用组合物,其中所述式I化合物为N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺盐酸盐。
20.权利要求18要求的药用组合物,其中所述式I化合物为N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺盐酸盐的一水合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12525099P | 1999-03-19 | 1999-03-19 | |
US60/125,250 | 1999-03-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1399545A true CN1399545A (zh) | 2003-02-26 |
Family
ID=22418838
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN00807533A Pending CN1399545A (zh) | 1999-03-19 | 2000-03-17 | 治疗某些与体重增加有关的癌症 |
Country Status (19)
Country | Link |
---|---|
EP (1) | EP1171106A1 (zh) |
JP (1) | JP2002539255A (zh) |
KR (1) | KR20010113765A (zh) |
CN (1) | CN1399545A (zh) |
AU (1) | AU3632000A (zh) |
BG (1) | BG105998A (zh) |
BR (1) | BR0009161A (zh) |
CA (1) | CA2367045A1 (zh) |
CZ (1) | CZ20013281A3 (zh) |
HU (1) | HUP0200497A2 (zh) |
IL (1) | IL145239A0 (zh) |
MX (1) | MXPA01009470A (zh) |
NO (1) | NO20014478L (zh) |
NZ (1) | NZ514012A (zh) |
PL (1) | PL351958A1 (zh) |
SK (1) | SK13372001A3 (zh) |
TR (1) | TR200102692T2 (zh) |
WO (1) | WO2000056323A1 (zh) |
ZA (1) | ZA200107687B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004096202A1 (en) * | 2003-04-28 | 2004-11-11 | Cipla Limited | Pharmaceutical formulation comprising anti-obesity agent and acidulant |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8531071D0 (en) * | 1985-12-17 | 1986-01-29 | Boots Co Plc | Therapeutic compound |
US5459164A (en) * | 1994-02-03 | 1995-10-17 | Boots Pharmaceuticals, Inc. | Medical treatment |
-
2000
- 2000-03-17 SK SK1337-2001A patent/SK13372001A3/sk unknown
- 2000-03-17 CA CA002367045A patent/CA2367045A1/en not_active Abandoned
- 2000-03-17 WO PCT/US2000/007361 patent/WO2000056323A1/en not_active Application Discontinuation
- 2000-03-17 EP EP00915015A patent/EP1171106A1/en not_active Withdrawn
- 2000-03-17 KR KR1020017011855A patent/KR20010113765A/ko not_active Application Discontinuation
- 2000-03-17 NZ NZ514012A patent/NZ514012A/xx not_active Application Discontinuation
- 2000-03-17 MX MXPA01009470A patent/MXPA01009470A/es unknown
- 2000-03-17 TR TR2001/02692T patent/TR200102692T2/xx unknown
- 2000-03-17 HU HU0200497A patent/HUP0200497A2/hu unknown
- 2000-03-17 BR BR0009161-8A patent/BR0009161A/pt not_active Application Discontinuation
- 2000-03-17 IL IL14523900A patent/IL145239A0/xx unknown
- 2000-03-17 AU AU36320/00A patent/AU3632000A/en not_active Abandoned
- 2000-03-17 JP JP2000606228A patent/JP2002539255A/ja not_active Withdrawn
- 2000-03-17 CN CN00807533A patent/CN1399545A/zh active Pending
- 2000-03-17 CZ CZ20013281A patent/CZ20013281A3/cs unknown
- 2000-03-17 PL PL00351958A patent/PL351958A1/xx not_active Application Discontinuation
-
2001
- 2001-09-14 NO NO20014478A patent/NO20014478L/no unknown
- 2001-09-18 ZA ZA200107687A patent/ZA200107687B/en unknown
- 2001-10-10 BG BG105998A patent/BG105998A/xx unknown
Also Published As
Publication number | Publication date |
---|---|
JP2002539255A (ja) | 2002-11-19 |
IL145239A0 (en) | 2002-06-30 |
BR0009161A (pt) | 2002-01-22 |
PL351958A1 (en) | 2003-07-14 |
TR200102692T2 (tr) | 2002-03-21 |
NO20014478D0 (no) | 2001-09-14 |
HUP0200497A2 (en) | 2002-08-28 |
MXPA01009470A (es) | 2004-03-19 |
NZ514012A (en) | 2001-09-28 |
CZ20013281A3 (cs) | 2002-07-17 |
AU3632000A (en) | 2000-10-09 |
NO20014478L (no) | 2001-10-29 |
BG105998A (en) | 2002-06-28 |
CA2367045A1 (en) | 2000-09-28 |
SK13372001A3 (sk) | 2002-07-02 |
KR20010113765A (ko) | 2001-12-28 |
WO2000056323A1 (en) | 2000-09-28 |
ZA200107687B (en) | 2002-12-18 |
EP1171106A1 (en) | 2002-01-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1188120C (zh) | 治疗饮食紊乱的方法 | |
CN1070698C (zh) | 医药治疗 | |
CN1173696C (zh) | 西布茶明类似物降低脂含量的用途 | |
KR20010033531A (ko) | 치료제 | |
US6376553B1 (en) | Treatment of pain | |
CN1161114C (zh) | 一种治疗睡眠障碍的化合物在制药中的用途 | |
US6376552B1 (en) | Treatment of gallstones | |
WO2000056318A1 (en) | Treatment of neuropathic pain or fibromyalgia | |
WO2000056149A1 (en) | Method of treating anxiety disorders | |
KR20020015357A (ko) | 시부트라민 및 올리스타트를 포함하는 제약 조성물 | |
CN1399545A (zh) | 治疗某些与体重增加有关的癌症 | |
WO2000056320A1 (en) | Treatment of menstrual function | |
CN1352552A (zh) | 关于骨关节炎的治疗 | |
CN1352553A (zh) | 怀孕后的减肥 | |
WO2000056148A1 (en) | Treatment of pharmacology of drug misuse and other addictive disorders | |
US6403650B1 (en) | Treatment of pulmonary hypertension | |
US20040198837A1 (en) | Treatment of neuropathic pain or fibromyalgia | |
CN1376061A (zh) | 关于食管裂孔疝的治疗 | |
WO2000056151A1 (en) | Method of treating obsessive-compulsive disorder | |
US20020132856A1 (en) | Treatment of premenstrual syndrome | |
WO2000056316A1 (en) | Treatment of gallstones |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |