CN1365287A - Pharmaceutical composition containing enantioners and lipase inhibitor - Google Patents
Pharmaceutical composition containing enantioners and lipase inhibitor Download PDFInfo
- Publication number
- CN1365287A CN1365287A CN00810544A CN00810544A CN1365287A CN 1365287 A CN1365287 A CN 1365287A CN 00810544 A CN00810544 A CN 00810544A CN 00810544 A CN00810544 A CN 00810544A CN 1365287 A CN1365287 A CN 1365287A
- Authority
- CN
- China
- Prior art keywords
- chemical compound
- lipase inhibitor
- formula
- methyl
- enantiomer
- 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.)
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- 239000007900 aqueous suspension Substances 0.000 description 1
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- 201000011510 cancer Diseases 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
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- 125000002091 cationic group Chemical group 0.000 description 1
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- MVCQKIKWYUURMU-UHFFFAOYSA-N cetilistat Chemical compound C1=C(C)C=C2C(=O)OC(OCCCCCCCCCCCCCCCC)=NC2=C1 MVCQKIKWYUURMU-UHFFFAOYSA-N 0.000 description 1
- 229950002397 cetilistat Drugs 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
- 229940099898 chlorophyllin Drugs 0.000 description 1
- 235000019805 chlorophyllin Nutrition 0.000 description 1
- 201000001883 cholelithiasis Diseases 0.000 description 1
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- 238000000576 coating method Methods 0.000 description 1
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- 208000010877 cognitive disease Diseases 0.000 description 1
- 102000005311 colipase Human genes 0.000 description 1
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- 230000000593 degrading effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
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- 239000006185 dispersion Substances 0.000 description 1
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- 239000003623 enhancer Substances 0.000 description 1
- 239000010696 ester oil Substances 0.000 description 1
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 125000004387 flavanoid group Chemical group 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 108010091264 gastric triacylglycerol lipase Proteins 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 150000002332 glycine derivatives Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 210000000088 lip Anatomy 0.000 description 1
- 229940040461 lipase Drugs 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
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- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N n-hexadecanoic acid Natural products CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
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- 231100000252 nontoxic Toxicity 0.000 description 1
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- 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
- 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
- 239000003883 ointment base Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- HGVVOUNEGQIPMS-UHFFFAOYSA-N procyanidin Chemical compound O1C2=CC(O)=CC(O)=C2C(O)C(O)C1(C=1C=C(O)C(O)=CC=1)OC1CC2=C(O)C=C(O)C=C2OC1C1=CC=C(O)C(O)=C1 HGVVOUNEGQIPMS-UHFFFAOYSA-N 0.000 description 1
- 229920002414 procyanidin Polymers 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 229960000380 propiolactone Drugs 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000036186 satiety Effects 0.000 description 1
- 235000019627 satiety Nutrition 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 210000000582 semen Anatomy 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
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 201000002859 sleep apnea Diseases 0.000 description 1
- 230000005586 smoking cessation Effects 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
- 235000019710 soybean protein Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical class O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000375 suspending agent Substances 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
- 229960003080 taurine Drugs 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
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 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
- 229940116269 uric acid Drugs 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
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000011680 zucker rat Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Obesity (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Child & Adolescent Psychology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
A method for the treatment of obesity and associated co-morbid conditions in a human in need of such treatment which comprises administration to the human of a therapeutically effective amount of a compound of formula (I), including enantiomers and pharmaceutically acceptable salts thereof, in which R1 and R2 are independently H or methyl, and a therapeutically effective amount of a lipase inhibitor with the exception of orlistat; wherein the compound of formula (I) and the lipase inhibitor are administered simultaneously, separately or sequentially.
Description
The present invention relates to treat fat and the method for associated conditions and product and the pharmaceutical composition that is applicable to this method.More particularly, the present invention relates to treat fat and the method for associated conditions and product and the compositions that contains these chemical compounds by using sibutramine or its salt or metabolite and lipase inhibitor.
Sibutramine is reuptake inhibitor (Buckett, W.R., Thomas, the P.C.﹠amp of interior 5-hydroxy tryptamine of body and norepinephrine; Luscombe, G.P. (1988) .Prog.Neuro-Psychopharmacol.Biol.Psychiat.12,575-584 and Luscombe, G.P., Hopcroft, R.H., Thomas, P.C.﹠amp; Buckett, W.R. (1989) .Neuropharmacology, 28,129-134.).Studies show that it can lose weight by the dual function pattern; It can increase satiety and reduce picked-up (Fantino, the M.﹠amp of food; Souquet, A.-M. (1995) .Int.J.Obesity, 19,145; Halford, J.C.G., Heal, D.J.﹠amp; Blundell, J.E. (1995) .Brit.J.Pharmacol.114,387P; And Stricker-Krongrad, A., Souquet, A.-M.﹠amp; Burlet, C. (1995) .Int.J.Obesity, 19,145.), and can increase consumption (Connoley, I.P., Heal, the D.J.﹠amp of energy by stimulating heat production; Stock, M J. (1995) .Brit.J.Pharmacol.114,388P; And Connoley, I P., Frost, I., Heal, D.J.﹠amp; Stock, M.J. (1996) .Brit.J.Pharmacol.117,170P).The U.S. and at least 20 other state approvals in the world the use sibutramine treat obesity.
Lipase be responsible for degrading picked-up fat (Borgstrom, B. (1988) .Biochem.Biophys.Acta.962 (3), 308-316); Consequently, unabsorbed fat is discharged in feces.A kind of lipase inhibitor wherein, orlistat, it is fat to be approved for treatment at US and European, its chemical name be (2S, 3S, 5S)-5-[(S)-2-formamido group-4-methylpent acyloxy]-2-hexyl-3-hydroxy hexadecylic acid lactone.This material be also referred to as " N-formoxyl-L-leucine, with (3S, 4S)-the 3-hexyl-4-[(2S)-2-hydroxyl-tridecyl]-ester of 2-oxetanone ", (-)-tetrahydrochysene presses down lipstatin (lipstatin), tetrahydrochysene presses down lipstatin and orlistat.The extraction and the purposes in control or prevention of obesity and hyperlipemia thereof of orlistat in United States Patent (USP) 4598089 (Hoffmann-La Roche Inc.), have been put down in writing.In United States Patent (USP) 4983746 (Hoffmann-La Roche Inc.), put down in writing the preparation method of orlistat.In EP638317 (Hoffmann-La Roche AGF), put down in writing the compositions that contains orlistat and acarbose.
It is reported, can not be with orlistat and appetite suppressant coupling (The New York Times1997 May 15).Common pending application PCT/EP98/08249 discloses formula I chemical compound described below and orlistat coupling has been treated obesity.Surprisingly, having now found that can be to the generation beneficial effect that loses weight with Sibutramine hydrochloride monohydrate and lipase inhibitor co-administered.
Therefore, the invention provides the method for treatment obesity and associated conditions in mammal, the particularly people of needs treatments, this method comprises, to the formula I chemical compound of mammal, particularly people's administering therapeutic effective dose of needs treatment
Comprise its enantiomer and officinal salt, wherein R
1And R
2Be H or methyl independently of one another, and the lipase inhibitor of treatment effective dose, condition is that described lipase inhibitor is not an orlistat; Wherein, formula I chemical compound and lipase inhibitor while, difference or order administration.
The present invention has following advantage.At first, the value that the maximum that loses weight that is reached is reached when using formula I chemical compound or lipase inhibitor separately.Secondly, can reach collaborative losing weight, wherein, by losing weight of using to first test group that formula I chemical compound and lipase inhibitor reached greater than losing weight of using to second test group that formula I chemical compound reached and use the summation that loses weight that lipase inhibitor reaches to the 3rd test group.The 3rd, after using formula I chemical compound or lipase inhibitor, lose weight reach maintenance level after, can reach further and lose weight by using another kind of chemical compound.The 4th, can use the lower formula I chemical compound and the dosage of lipase inhibitor in the present invention, thereby reduce the side effect relevant with the above-claimed cpd of using higher dosage.The 5th, compare the improvement that when treating with the present invention, can obtain to work in coordination with fat relevant disease with individually dosed each chemical compound.
Preferred formula I chemical compound is N-{1-[1-(4-chlorphenyl) cyclobutyl]-the 3-methyl butyl]-N, N-dimethyl amine or its salt, for example hydrochlorate is called the sibutramine hydrochlorate.The preferred form of this hydrochlorate is its monohydrate, is called Sibutramine hydrochloride monohydrate.
In british patent specification 2098602, put down in writing for example N-{1-[1-(4-chlorphenyl) cyclobutyl of formula I chemical compound]-the 3-methyl butyl }-N, the preparation of N-dimethyl amine and salt thereof and the application in the treatment depression thereof.In disclosed PCT application WO 88/06444, put down in writing for example N-{1-[1-(4-chlorphenyl) cyclobutyl of formula I chemical compound]-the 3-methyl butyl }-N, the application in the treatment Parkinson's disease of N-dimethyl amine and salt thereof.In United States Patent (USP) 4939175, put down in writing N-{1-[1-(4-chlorphenyl) cyclobutyl]-the 3-methyl butyl }-N, the application in the treatment disordered brain function of N-dimethyl amine and salt thereof.In european patent number 397831, put down in writing N-{1-[1-(4-chlorphenyl) cyclobutyl]-the 3-methyl butyl }-N, the application of N-dimethyl amine hydrochlorate in the treatment obesity.The particularly preferred form of this chemical compound is N-{1-[1-(4-chlorphenyl) cyclobutyl]-the 3-methyl butyl }-N, N-dimethyl amine hydrochloride monohydrate (Sibutramine hydrochloride monohydrate), it is recorded in the european patent number 230742.In disclosed PCT application WO95/20949, put down in writing N-{1-[1-(4-chlorphenyl) cyclobutyl]-the 3-methyl butyl }-N, N-dimethyl amine and salt thereof are used to improve the purposes of the people's who has impaired glucose tolerance or non-insulin-dependent diabetes mellitus glucose tolerance.
It will be understood by those skilled in the art that formula I chemical compound contains a chiral centre.When formula I chemical compound contained a chiral centre, it can exist with two kinds of enantiomeric forms.Present invention includes the purposes of single enantiomer and mixture of enantiomers.Enantiomer can split by method known to those skilled in the art, for example, can carry out isolating diastereoisomeric salt or coordination compound by for example crystallization by forming; Formation can be carried out isolating non-enantiomer derivative by for example crystallization, gas liquid chromatography or liquid chromatograph; A kind of enantiomer and the specific reagent of enantiomer are optionally reacted for example oxydasis or reduction, the enantiomer of separation modification and unmodified then; Perhaps in chiral environment, for example go up or in the presence of chiral solvent, carry out gas liquid chromatography or liquid chromatograph in chiral support (silica gel that for example has bonded chiral ligand).Be appreciated that when required enantiomer is changed into another kind of chemical entities by one of above-mentioned separation method, also need the step of the required enantiomeric form of other release.Perhaps, can synthesize specific enantiomer with optically active reagent, substrate, catalyst or solvent, perhaps a kind of enantiomer be changed into another kind of enantiomer by asymmetric conversion by asymmetric synthesis.The second month in a season of formula I and the enantiomer of tertiary amine can also split into that optically pure primary amine enantiomer that its one enantiomer will suit then changes into the required second month in a season or the tertiary amine product prepares by preparation primary amine racemic modification, with this mixture.
Preferred formula I chemical compound is N-{1-[1-(4-chlorphenyl) cyclobutyl]-the 3-methyl butyl }-N, N-dimethyl amine, N-{1-[1-(4-chlorphenyl) cyclobutyl]-the 3-methyl butyl }-N-methyl amine and N-1-[1-(4-chlorphenyl) cyclobutyl]-3-methyl butyl amine, comprise its racemic modification, one enantiomer and mixture and their officinal salt.The concrete enantiomer of formula I is (+)-N-{1-[1-(4-chlorphenyl) cyclobutyl]-the 3-methyl butyl }-N, the N-dimethyl amine, (-)-N-{1-[1-(4-chlorphenyl) cyclobutyl]-the 3-methyl butyl }-N, the N-dimethyl amine, (R)-(+)-N-{1-[1-(4-chloro-phenyl) cyclobutyl]-the 3-methyl butyl }-the N-methyl amine, (S)-(-)-N-{1-[1-(4-chlorphenyl)-cyclobutyl]-the 3-methyl butyl }-the N-methyl amine, (R)-(+)-1-[1-(4-chlorphenyl) cyclobutyl]-3-methyl butyl amine and (S)-(-)-1-[1-(4-chlorphenyl) cyclobutyl]-3-methyl butyl amine.
Suitable lipase inhibitor comprises pancreatic lipase inhibitor, gastric lipase inhibitor and carboxyl ester lipase inhibitor, and it includes but are not limited to: the caulerpenin that puts down in writing among patent No. JP10203974A2, the application number 97JP-0014334; J.Chem.Soc., Perkin Trans.1 (1998), (8), the panclicins A-E that puts down in writing among the 1373-1382; Tetrahedron (1997), 53 (48), (-) that puts down in writing among the 16471-16488-panclicin D; Procyanidin that puts down in writing among the WO9723210 and analog; Put down in writing among patent No. JP04321700A2, the application number 91JP-0110814 from frumentum or the isolated lipase inhibitor of beans; The 4-of the following formula of putting down in writing among the EP-444482 (acyloxy ethyl) oxetanes-2-ketone
Wherein Q is the group of following formula
(R
3，R
4)NCO(X)
n-CO-?Q
1
(R
3, R
4) NCO-X
1Q
2 R
1And R
2By 1 to 3 halogen atom or contain maximum 20 carbon atoms (and optionally by 1, the 4-arlydene is interrupted, optionally replaced by aryl in the ω position and optionally by aryl-C
1-4-alkyl replaces) alkyl of maximum 18 carbon atoms of replacing of alkyl, alkenyl, alkynyl group or alkadienyl; Thereby R
1Can be on other position except that the α position of unsaturated carbon atom be interrupted, perhaps R by O or S atom or by sulfinyl or sulfonyl
1Be aryl-NH-or aryl-C
1-4-alkyl-OCONH-group, R
3And R
4Be hydrogen or C
1-4-alkyl; or the nitrogen-atoms that is connected with them lumps together 3 to 6 yuan of saturated rings of formation; this ring optionally contains an O or S atom on other position except that the α position of nitrogen-atoms; n is 1 or 0; X is the alkylidene that contains maximum 6 carbon atoms, and it is optionally by O or S atom or by sulfinyl or sulfonyl is interrupted and optionally by hydroxyl, sulfydryl, aryl, aryloxy group, arylthio, aryl-C
1-4-alkyl, aryl-C
1-4-alkoxyl, aryl-C
1-4-alkylthio group, aryl-C
1-4-alkylidene, C
3-7-cycloalkylidene or C
1-6-alkylidene replaces or by one or two C
1-6-alkyl, C
1-6-alkoxyl or C
1-6Alkylthio group replaces, thus two C on same carbon atom or two adjacent carbon atoms
1-6-alkyl, C
1-6-alkoxyl or C
1-6It must be that perhaps X is the group of following formula on other position the alpha-position of sulfinyl that removes O that selectivity exists or S atom or selectivity existence or sulfonyl that alkylthio group can form unsaturated carbon atom that hydroxyl that optionally monounsaturated 3 to 7 yuan of rings and selectivity exist or sulfydryl or selectivity exist
＝CHN(R，R
0) or-CHN (R, R0)CH
2-R and R0Hydrogen, C1-4-alkyl, C1-4-alkyl (CO or OCO)-, aryl, aryl (CO or OCO)-, aryl-C1-4-alkyl or aryl-C1-4-alkyl (CO or OCO)-and X1Be the alkylidene that contains maximum 6 carbon atoms, it can be by C1-4-alkoxyl, aryl, aryloxy group, arylthio, aryl-C1-4-alkyl, aryl-C1-4-alkoxyl or aryl-C1-4-alkylthio group replaces or by one or two C1-6-alkyl replaces, thereby is connected to two C on adjacent carbon atom1-6-alkyl can form 3 to 7 rings, particularly be selected from following compound: (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxa-cyclobutyl (oxetanyl)] methyl] lauryl (S)-2-isopropyl propionamide acid esters, (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxa-cyclobutyl] methyl] lauryl (S or R)-2-carbamoyl-valerate, (whole Z, S)-1-[[(2S, 3S)-3-ethyl-4-oxo-2-oxa-cyclobutyl] methyl] 9, 12-18 carbon dialkylenes (S)-2-isopropyl propionamide acid esters, (S)-1-[[(2S, 3S or 2R, 3R)-4-oxo-3-penta sulfenyl-2-oxa-cyclobutyl] methyl] lauryl (S)-2-isopropyl propionamide acid esters, (S)-1-[[(2S, 3S or 2R, 3R)-4-oxo-3-penta sulfenyl-2-oxa-cyclobutyl] methyl] lauryl [S: R (2: 1)-2-isopropyl propionamide acid esters, (S)-1-[[(2S, 3S)-3-ethyl-4-oxo-2-oxa-cyclobutyl]-methyl] octadecyl (S or R)-2-tert-butyl group propionamide acid esters, (S)-1-[[(2S, 3S)-3-ethyl-4-oxo-2-oxa-cyclobutyl] methyl] octadecyl 1-carbamoyl cyclopentane-carboxylic acid ester, (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxa-cyclobutyl] methyl] lauryl (RS)-2-benzyl propionamide acid esters, (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxa-cyclobutyl] methyl] lauryl (3-[(2-carbamoyl ethyl) sulfenyl] propionic ester, 5-oxo-D-PROLINE (S)-1-[[(2S, 3S)-3-ethyl-4-oxo-2-oxa-cyclobutyl] methyl] the octadecyl ester, Pidolidone (S)-1-[[(2S, 3S)-3-ethyl-4-oxo-2-oxa-cyclobutyl] methyl] the octadecyl ester, (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxa-cyclobutyl] methyl] lauryl (S or R)-2-isopropyl propionamide acid esters, (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxa-cyclobutyl] methyl] lauryl (RS)-2-carbamoyl valerate (epimer 1: 1), (whole Z, S)-1-[[(2S, 3S)-3-ethyl-4-oxo-2-oxa-cyclobutyl] methyl] 9, 12-18 carbon dialkylenes (S or R)-2-isopropyl propionamide acid esters, (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxa-cyclobutyl] methyl] lauryl (RS)-2-carbamoyl-4-methylpent acid esters (epimer 1: 1), (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxa-cyclobutyl] methyl] lauryl 1-carbamoyl naphthenic acid ester, (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxa-cyclobutyl] methyl] lauryl (RS)-2-methyl propanamide acid esters, (epimer 1: 1), (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxa-cyclobutyl] methyl] lauryl (RS)-2-ethyl propionamide acid esters, (epimer 1: 1), (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxa-cyclobutyl] methyl] lauryl (RS)-2-butyl propionamide acid esters, (epimer 1: 1), (S)-1-[[(2S, 3S)-3-ethyl-4-oxo-2-oxa-cyclobutyl] methyl] octadecyl 1-carbamoyl naphthenic acid ester, (S)-1-[[(2S, 3S or 2R, 3R)-4-oxo-3-penta sulfenyl-2-oxa-cyclobutyl] methyl] lauryl [S: R or R: S (2: 1)-2-isopropyl propionamide acid esters, (S)-1-[[(2R, 3R)-3-benzyl-4-oxo-2-oxa-cyclobutyl] methyl] lauryl [S or R)-2-isopropyl-propionamide acid esters, the N-formoxyl leucine 1-of the following formula of putting down in writing in US4931463, US5175186 and US5246960 (oxa-ring bytyry methyl) Arrcostab and analog thereof
R wherein1And R2C independently of one another1-17Alkyl, it is that other locational O or S atom saturated or that optionally by maximum 8 two keys or three key, be interrupted and/or optionally be present in except the alpha-position of unsaturated carbon atom are interrupted; Or phenyl, benzyl or by maximum 3 C1-6-alkyl-(O or S)1 or 0Group replaces-C6H
4-X-C
6H
5Ring, X is oxygen, sulphur or (CH2)
0-3，
R
3Hydrogen, C1-3-alkyl or C1-3Alkanoyl, R4Hydrogen or C1-3-alkyl, R5Hydrogen, Ar or Ar-C1-3Alkyl or the C that optionally by Y, is interrupted and optionally by Z, is replaced1-7-alkyl, perhaps R4And R5Form the saturated rings of 4 to 6 yuan, Y is oxygen, sulphur or group N (R6)、
C(O)N(R
6) or N (R6) C (O), Z is group-(O or S)-R7、-N(R
7，R
8)、
-C(O)N(R
7，R
8) or-N (R7)C(O)R
8, n is 1 or 0, condition is R when n is 15Be hydrogen, Ar is unsubstituted or by 3 radicals R9Or OR9The phenyl that replaces, R6、R
7、R
8And R9Hydrogen or C independently of one another1-3-alkyl, condition are to work as R3Formoxyl and R5Isobutyl group or R3Acetyl group and R5Carbamyl ylmethyl and while R2Undecyl or 2,5-hendecane dialkylene and R1R while being n-hexyl4not hydrogen, its enantiomer or diastereomer or its pharmaceutically acceptable acid addition salts, particularly be selected from following compound: N-formoxyl-(S)-leucine (S)-1-[[(2S, 3S)-3-ethyl-4-oxo-2-oxa-cyclobutyl] methyl] octadecyl ester or its pharmaceutically acceptable acid addition salts, particularly: N-formoxyl-L-Leu 1-[(is anti--3-ethyl-4-oxo-2-oxa-cyclobutyl) methyl] lauryl ester N-formoxyl-L-Leu 1-[(is anti--3-pi-allyl-4-oxo-2-oxa-cyclobutyl) methyl] lauryl ester N-formoxyl-S-leucine (S, 9Z, 12Z)-1-[(2S, 3S)-3-ethyl-4-oxo-2-oxa-cyclobutyl] methyl]-9, 12-18 carbon dialkylene ester N-formoxyl-S-leucine (S, Z)-1-[[(2S, 3S)-3-ethyl-4-oxo-2-oxa-cyclobutyl] methyl]-9-octadecyl ester N-formoxyl-S-leucine (R)-α-[[(2S, 3S)-3-ethyl-4-oxo-2-oxa-cyclobutyl] methyl]-p-phenoxy group-benzyl ester, or its pharmaceutically acceptable acid addition salts, Helv.Chim.Acta (1987), 70 (5), the tetrahydrochysene of putting down in writing in 1412-18 suppresses pancreas fat rhzomorph analog, wherein R=ethyl
The oxa-cyclobutanone compounds of the following formula of putting down in writing in EP-189577
X wherein1Undecyl or 2Z, 5Z-11 carbon dialkylenes, C6Be n-hexyl, Y is isobutyl group and Z is formoxyl or Y is carbamyl ylmethyl and Z is acetyl group; Chem.Pharm.Bull. (1986), 34 (3), the 2-alkane ketone derivative that the 1-that puts down in writing in 1118-27 replaces; J.Lipid Res. (1984), 25 (11), the soybean protein of putting down in writing in 1214-21; Taurine and the glycine derivative of the following formula of record in US 4104285
Wherein R=H, alkanoyloxy, BzO; R1＝CO
2H, alkoxyl carbonyl, CH2SO
3H； M, n=0,1); J.Pharm.Sci. (1976), 65 (8), put down in writing in 1243-5 1,2-dioleoyl-3-(α-1-adamantane acyl group)-sn-glycerine and 1-adamantanecarboxylic acid; The peptide that obtains from wheat of putting down in writing in JP07330794 A; The insertion of putting down in writing in WO9830588 comprise the peptide of the pancreatic lipase C terminal fragment of colipase recognition site; The flavonoids of putting down in writing in JP09143070A (flavanoids) and glucoside thereof; The triterpenoid of putting down in writing in JP09040689A; The chamenol of putting down in writing in JP08268882A; The flavonoids of putting down in writing in JP07061927A; (metal replaces) chlorophyllin compound of putting down in writing in JP05252898A; The 2-oxa-cyclobutanone derivatives of the formula I that puts down in writing in EP443449A:R wherein1And R2Contain maximum 17 carbon atoms and optionally except α-or β-position
The alkyl that is interrupted by oxygen atom on other position; Or optionally the ring on by 1 to
3 C
1-6-alkyl or C
1-6The benzyl that-alkoxyl replaces, X is hydrogen or formula (R
3, R
4) NCH (R
5) (CH
2)
nThe radicals R of-CO-
3Be hydrogen, C
1-3-alkyl or C
1-3-alkanoyl, R
4Be hydrogen or C
1-3-alkyl R
5Be hydrogen, group Ar or Ar-C
1-3-alkyl or optionally be interrupted and select by Y
The C that property ground is replaced by Z
1-7-alkyl, perhaps R
4And R
5The nitrogen-atoms that is connected with them lumps together and forms 4 to 6 yuan of rings, and Y is oxygen, sulfur or group N (R
6), C (O) N (R
6) or N (R
6) C (O), Z is group-(O or S)-R
7, N (R
7, R
8) or N (R
7) C (O) R
8, n is 1 or 0, R when n is 1
5Be hydrogen, Ar is by 1 to 3 R
9Or OR
9The phenyl that group replaces, R
6To R
9Be hydrogen or C
1-3-alkyl, and wherein X is not the salt of oxetanone chemical compound with formula I of weakly acidic hydrogen; But that put down in writing among the EP129748A lipstatin and tetrahydrochysene suppress pancreas fat streptozotocin derivative, but do not comprise orlistat; The cationic derivative that can not absorb of alkene-maleic acid of putting down in writing among the US 4211765A; Bile acid of putting down in writing among the GB1286949 and triglyceride absorb resin; And chemical compound for example ATL-962 and analog, it is recorded in the patent application that covers this chemical compound and covers in the patent application of its analog.
In the method for the invention, formula I chemical compound and lipase inhibitor can be simultaneously or for example to be used for simultaneously, respectively or the parallel administration of the form of the independently dosage unit that uses in order.
On the other hand, the invention provides formula I chemical compound, comprise its enantiomer and officinal salt (R wherein
1And R
2Be H or methyl independently of one another) and lipase inhibitor (not comprising orlistat) is used for simultaneously, respectively or use in order and treat obesity and associated conditions.
On the other hand, the invention provides formula I chemical compound, comprise its enantiomer and officinal salt (R wherein
1And R
2Be H or methyl independently of one another) and lipase inhibitor (not comprising orlistat) be used for simultaneously, respectively or use in order and treat obesity and associated conditions as the preparation of associating.
On the other hand, the invention provides and contain formula I chemical compound, comprise its enantiomer and officinal salt (R wherein
1And R
2Be H or methyl independently of one another) and lipase inhibitor (not comprising orlistat) be used for simultaneously, respectively or use in order and treat the product of obesity and associated conditions as combination formulations.
On the other hand, the invention provides formula I chemical compound, comprise its enantiomer and officinal salt (R wherein
1And R
2Be H or methyl independently of one another) be used for also accepting the purposes in the medicine of patient's treatment obesity of the lipase inhibitor treatment except that orlistat and associated conditions in production.
On the other hand, the invention provides the method for the fat and associated conditions of treatment, this method comprises, the patient who treats to needs uses and comprises the formula I chemical compound for the treatment of effective dose and the complementary therapy of the lipase inhibitor except that orlistat.
The present invention also provides above-mentioned drug combinations to be used for the treatment of purposes in the medicine of fat and associated conditions in production.In addition, the present invention also provides and has been used for the treatment of fat cooperative programs.
Term used herein " associated conditions " is meant well known by persons skilled in the art with fat relevant medical conditions.This term includes but are not limited to: the diabetes among mammal, the particularly mankind comprise non-insulin-dependent diabetes mellitus, impaired glucose tolerance; Depression, anxiety, psychosis (for example schizophrenia), tardive dyskinesia, drug dependence, drug dependence, cognitive disorder, presenile dementia, cerebral ischaemia, obsession, panic attack, social phobia, eating disorders for example bulimia nerovsa, anorexia, eat a piece and the diet of rejoicing with wild excitement, hyperglycemia, hyperlipemia and anxiety.
In addition, the present invention also can be used for the disease for the treatment of or preventing metabolic disease and causing thus, metabolic rate, sexual dysfunction, sleep apnea, premenstrual tension syndrome, the urinary incontinence of for example non-mobility's heat production and increase comprise tonicity urinary incontinence, hyperkinetic syndrome, hiatal hernia and reflux esophagitis, pain, particularly neuropathic pain, weight increase, chronic fatigue syndrome, osteoarthritis and the gout relevant with Drug therapy, cancer, menoxenia, cholelithiasis, orthostatic hypotension and the pulmonary hypertension relevant with weight increase.
The present invention can be used for angiocardiopathy preventing and reduces hematoblastic adhesion, is used to help losing weight after the losing weight, reducing craving for tobacco and helping smoking cessation after the pregnancy.The present invention also is used in mammal, particularly philtrum uric acid reducing level.
The dosage of each chemical compound depends on multiple factor, comprise the order of severity of patient's age, disease and the medication history in patient's past and can decide by the attending doctor usually, but it has been generally acknowledged that, the dosage of formula I chemical compound can be 0.1 to 50mg, in preferred 1 to the 30mg/ day scope, in single or divided doses, more preferably 10mg, 15mg, 20mg, 25mg or 30mg/ every day, first-selected 20mg.The dosage of lipase inhibitor can be in 5 to 2000mg scope, in single or divided doses, preferred every day 3 times, and more preferably in 50 to 1500mg, first-selected 100 to 1000mg scope.Formula 1 chemical compound, preferred Sibutramine hydrochloride monohydrate can be with the administrations of any known drug dosage form.The administration of lipase inhibitor preferred oral.
Of the present invention one preferred aspect, Sibutramine hydrochloride monohydrate is administered once every day, preferably do as first thing in morning, lipase inhibitor administration every day 3 times is when being at table or the preceding administration of having a meal.The dosage of preferred Sibutramine hydrochloride monohydrate is 20mg or 30mg, and be administered once every day, and the dosage of lipase inhibitor is 50mg, 100mg, 120mg or 150mg, and administration every day 3 times is when being at table or the preceding administration of having a meal.First-selected with Sibutramine hydrochloride monohydrate administration before administration first time lipase inhibitor, preferably before administration first time lipase inhibitor 30 minutes to 3 hours, for example before 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours or 3 hours.
On the other hand, the invention provides a kind of pharmaceutical composition, said composition contains formula I chemical compound
Comprise its enantiomer and officinal salt, wherein R
1And R
2Be H or methyl and the lipase inhibitor except that orlistat and pharmaceutically acceptable diluent or carrier independently of one another.
Peroral dosage form is to be used for preferred composition of the present invention, and these dosage forms are the known drug forms that are used for oral administration, for example tablet, capsule, granule, syrup and moisture and oil suspension.Used excipient is the known excipient in pharmacists field when preparing these compositionss.Tablet can be from reactive compound and filler calcium phosphate for example; Disintegrating agent is corn starch for example; Lubricant is magnesium stearate for example; Binding agent is microcrystalline Cellulose or polyvinylpyrrolidone and other the mixture preparation that can mixture be made the optional member of tablet by known method known in the art for example.As needs, tablet can be carried out coating with known method and excipient, comprise and use for example enteric coating of phthalic acid hydroxypropyl methylcellulose.Tablet can be prepared with mode well known by persons skilled in the art so that can slow release chemical compound of the present invention.As needs, can be by known method, for example provide enteric coating to this tablet with cellulose acetate phthalate.Equally, capsule, for example contain reactive compound and contain or do not contain the hard or Perle of the excipient of interpolation, can prepare by known method, and as need, can provide enteric coating by known way.Capsular content can be with the known method preparation so that can the slow release reactive compound.Tablet and capsule can contain 1 to 50mg formula I chemical compound and 1 to 1000mg lipase inhibitor usually.
Other dosage form that is used for oral administration comprises, for example nontoxic suspending agent for example sodium carboxymethyl cellulose in the presence of in aqueous vehicle, contain the aqueous suspension of reactive compound, and for example contain the oil suspension of reactive compound in the Oleum Arachidis hypogaeae semen at suitable vegetable oil.Reactive compound can be mixed with the granule that contains or do not contain the excipient of interpolation.These granules can directly be taken for the patient, perhaps it can be joined appropriate liquid carrier (for example in the water) and take then.Granule can contain disintegrating agent, and for example the effervescent couple that is formed by acid plus carbonate or bicarbonate is to promote the dispersion in liquid vehicle.
Formula I chemical compound can be mixed with the patient and it can be retained in intraoral compositions, thereby reactive compound through port transmucosal is absorbed.
The dosage form that is applicable to the formula I chemical compound of rectally is the known pharmaceutical forms that is used for described administration, for example contains the suppository of cocoa butter or Polyethylene Glycol substrate.
The dosage form that is applicable to the formula I chemical compound of parenteral is the known pharmaceutical forms that is used for described administration, for example sterile suspension in suitable solvent or sterile solution.
The dosage form that is used for the formula I chemical compound of topical can contain the substrate that is dispersed with pharmacologically active chemical compounds of the present invention therein, thereby makes chemical compound and contact skin so that make the chemical compound can transdermal administration.Suitable transdermal composition can by with the excipient of pharmaceutical active compounds and local usefulness for example mineral oil, vaseline and/or wax for example paraffin or Cera Flava and transdermal enhancer for example dimethyl sulfoxine or propylene glycol mixture prepare.Perhaps, reactive compound can be dispersed in pharmaceutically useful cream, gel or the ointment base.The amount of each contained reactive compound should be the amount that can carry the treatment effective dose of each chemical compound in the period when local preparation this section on skin in the topical formulations.
Formula I chemical compound can be mixed with the form of aerosol compositions to patient oral cavity or nasal cavity administration.Described aerosol can be from pump packing or from the packing administration of the pressurization that contains volatile propellant.
Also can be with the mode of formula I chemical compound by continuous infusion from external source (for example passing through intravenous infusion) or from being positioned at intravital chemical compound source administration.Inner source comprises the drug-reservoir of the implantation that contains the chemical compound that needs infusion, described chemical compound discharges continuously by for example osmosis, and implant, this implant can be (a) liquid, for example the chemical compound that needs infusion of the derivative form that water solublity is very little for example laruate or lipophilic ester oil suspension or (b) need the carrier solid of synthetic resin or waxy substance form for example of implantation of the chemical compound of infusion.Carrier can be a plurality of objects that contain the single object of all chemical compounds or contain some chemical compound that need carry respectively.In the inner source amount of contained reactive compound should be able to be in long-time each chemical compound of delivering therapeutic effective dose.
In some preparations, may preferably use the The compounds of this invention of the very little particle form of particle diameter, for example the granule that makes by fluid energy mill.
In compositions of the present invention,, reactive compound can be combined with the pharmacologically active principles of other compatibility as needs.Optionally with the vitamin fortification agent with chemical compound administration of the present invention.
The pharmaceutical composition that has mixed formula I chemical compound and lipase inhibitor simultaneously is an important embodiment of the present invention.This pharmaceutical composition contains each chemical compound for the treatment of effective dose.Each dosage unit can contain dosage every day of two kinds of chemical compounds, perhaps can contain the part of dosage every day, and for example 1/3rd of dosage.Perhaps, each dosage unit can contain a kind of whole dosage of chemical compound and the part dosage of another kind of chemical compound.In this case, the patient should take the once dosage unit of associating every day, and takes the dosage unit that one or many only contains another kind of chemical compound.
By following description the application of The compounds of this invention in producing pharmaceutical composition has been described.In this manual, if not otherwise stated, term " reactive compound " is meant any one or two kinds of chemical compounds of the present invention simultaneously.A) capsule
When the preparation capsule, the reactive compound of 10 weight portions and the lactose of 240 weight portions are pulverized mixing then.Mixture is filled in the hard gelatin capsule, and every capsules contains the reactive compound of the part of a unit dose or a unit dose.B) tablet
Prepare tablet with following composition.
Weight portion reactive compound 10 lactose 190 corn starchs 22 polyvinylpyrrolidones 10 magnesium stearate 3
Reactive compound, lactose and a part of starch are pulverized, mixed and the mixture that forms is granulated with the alcoholic solution of polyvinylpyrrolidone.Dried granules is mixed with magnesium stearate and remaining starch.Then mixture tabletting in pelleter is obtained the tablet of the reactive compound of an every part that contains a unit dose or a unit dose.The tablet of enteric coating
Prepare tablet by the method for describing in above (b).This tablet is used in a usual manner the ethanol of 20% cellulose acetate phthalate and 3% diethyl phthalate: dichloromethane (1: 1) solution carries out enteric coating.D) suppository (only formula I chemical compound)
In preparation during suppository, 100 weight portion reactive compounds are incorporated into then this mixture are made every in the 1300 weight portion triglyceride suppository bases and contain the suppository form for the treatment of effective amount of actives.Preparation 1
Prepare hard gelatin capsule with following composition:
The following composition of preparation 2 usefulness prepares tablet:
| Amount (mg/ capsule) | |
| Sibutramine hydrochloride monohydrate | ????20 |
| Lipase inhibitor | 50,100,120 or 150 |
| Starch | ????200 |
| Magnesium stearate | ????10 |
| Total amount | ????350 |
| Amount (mg/ tablet) | |
| Sibutramine hydrochloride monohydrate | ????10 |
| Lipase inhibitor | 50,100,120 or 150 |
| Microcrystalline Cellulose | ????400 |
| Silicon dioxide | ????10 |
| Stearic acid | ????5 |
| Total amount | ????545 |
Each composition mixing is pressed into tablet then.
The advantage of The compounds of this invention can be by as the next item down or multinomial studies confirm that.Research 1
Each is organized normal bull Sprague-Dawley CD rat (n=8-12) carry out a) the 1st group of following treatment; Administration every day Sibutramine hydrochloride monohydrate (1,3 or the 10mg/kg mouth
Clothes)+excipient (oral) of lipase inhibitor.B) the 2nd group; Every day twice (bidaily) oral administration lipase inhibitor (for example 10,20,
30,40,50,100 or 150mg/kg oral, preferred 10 or 20mg/kg)+western cloth
The excipient of Qu Ming (oral).C) the 3rd group; Control with Sibutramine hydrochloride monohydrate and lipase inhibitor Combined with Oral
Treat.D) the 4th group; Contrast, the excipient of oral administration sibutramine and lipase inhibitor.
Make rat arbitrarily near high-fat food.Measure food intake, water intake amount and body weight every day, the persistent period of treatment is 15,21 or 28 days.Research 2
The fat female Zucker rat (n=8-12) of each group that keeps high fat diet is carried out a) the 1st group of following treatment; Can obvious slimming dosage to compare with the contrast that excipient is handled
(1,3 or 10mg/kg oral) every day the oral administration Sibutramine hydrochloride monohydrate,
Totally 14 days.At sibutramine hydrochlorate one water of using same dose 14 day every day subsequently
The lipase inhibitor of compound (oral)+doses (for example 10,20,30,40,50,
100 or 150mg/kg, preferred 10 or 20mg/kg) treat.B) the 2nd group; Every day the oral administration Sibutramine hydrochloride monohydrate, totally 14 days.With
After 14 day every day with the excipient (oral) of sibutramine (oral) and lipase inhibitor
Treat.C) the 3rd group; Every day the oral administration Sibutramine hydrochloride monohydrate excipient, totally 14
My god, then subsequently 14 days excipient with Sibutramine hydrochloride monohydrate (mouthful
Clothes) and the excipient (oral) of lipase inhibitor carry out therapeutic alliance.Research 3
Each is organized normal bull Sprague-Dawley CD rat (n=8-12) carry out following treatment: a) the 1st group; Administration Sibutramine hydrochloride monohydrate (1,3 or 10mg/kg oral)
The excipient of+lipase inhibitor (oral) b) the 2nd group; The excipient of oral administration lipase inhibitor+sibutramine (oral) c) the 3rd group; The excipient of oral administration lipase inhibitor+sibutramine (oral) d) the 4th group; The excipient of the excipient+sibutramine of oral administration lipase inhibitor (mouthful
Clothes)
Sibutramine is administered once every day, maximum 3 times of lipase inhibitor administration every day (with appropriate dosage).1st, 3 and 4 groups can be optionally near high-fat food in institute is free.The 2nd group with sibutramine-treated group (the 1st group) feeding in couples, that is, give sibutramine-treated group pro-edible food (food rich in fat) amount in 24 hour time to animal.Measure food intake and body weight every day, the persistent period of treatment is 4-5 days.
The more resulting result of statistics between each treated animal body weight in one or the multinomial above-mentioned research has been confirmed advantage of the present invention.
Claims (8)
1, the method for treatment obesity and associated conditions in the people of needs treatment, this method comprises, to the formula I chemical compound of this person's administering therapeutic effective dose
Comprise its enantiomer and officinal salt, wherein R
1And R
2Be H or methyl independently of one another, and the lipase inhibitor except that orlistat of treatment effective dose; Wherein, formula I chemical compound and lipase inhibitor while, difference or order administration.
2, the formula I chemical compound that the process of claim 1 wherein is N-{1-[1-(4-chlorphenyl) cyclobutyl]-the 3-methyl butyl }-N, N-dimethyl amine or its salt.
3, the method for claim 2, the administration before administration lipase inhibitor 30 minutes to 3 hours of formula I chemical compound wherein.
4, formula I chemical compound, comprise its enantiomer and officinal salt, wherein R
1And R
2Be that H or methyl and the lipase inhibitor except that orlistat are used for simultaneously, respectively or use in order and treat obesity and associated conditions independently of one another.
5, formula I chemical compound, comprise its enantiomer and officinal salt, wherein R
1And R
2Being H or methyl and the lipase inhibitor except that orlistat independently of one another is used for simultaneously, respectively or use in order and treat obesity and associated conditions as the preparation of associating.
6, contain formula I chemical compound, comprise its enantiomer and officinal salt, wherein R
1And R
2Being H or methyl and the lipase inhibitor except that orlistat independently of one another is used for simultaneously, respectively or use in order and treat the product of obesity and associated conditions as combination formulations.
7, formula I chemical compound, comprise its enantiomer and officinal salt, wherein R
1And R
2Being H or methyl independently of one another is used for also accepting purposes in the medicine of patient's treatment obesity of the lipase inhibitor treatment except that orlistat and associated conditions in production.
8, pharmaceutical composition, it contains formula I chemical compound
Comprise its enantiomer and officinal salt, wherein R
1And R
2Be H or methyl and the lipase inhibitor except that orlistat independently of one another.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9914742.3A GB9914742D0 (en) | 1999-06-24 | 1999-06-24 | Therapeutic agents |
| GB9914742.3 | 1999-06-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1365287A true CN1365287A (en) | 2002-08-21 |
Family
ID=10855953
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00810544A Pending CN1365287A (en) | 1999-06-24 | 2000-06-16 | Pharmaceutical composition containing enantioners and lipase inhibitor |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP1189638A2 (en) |
| JP (1) | JP2003503344A (en) |
| KR (1) | KR20020012293A (en) |
| CN (1) | CN1365287A (en) |
| AU (1) | AU5815100A (en) |
| BG (1) | BG106209A (en) |
| BR (1) | BR0011884A (en) |
| CA (1) | CA2376213A1 (en) |
| CZ (1) | CZ20014614A3 (en) |
| GB (1) | GB9914742D0 (en) |
| HK (1) | HK1050476A1 (en) |
| HU (1) | HUP0201880A3 (en) |
| IL (1) | IL147078A0 (en) |
| MX (1) | MXPA01013023A (en) |
| NO (1) | NO20016301L (en) |
| PL (1) | PL352387A1 (en) |
| SK (1) | SK18822001A3 (en) |
| TR (1) | TR200103704T2 (en) |
| WO (1) | WO2001000187A2 (en) |
| ZA (1) | ZA200110046B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101890017A (en) * | 2009-05-22 | 2010-11-24 | 北京奥萨医药研究中心有限公司 | Medicament composition containing sibutramine and stanin fat-reducing medicament and application thereof |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6399826B1 (en) * | 1999-08-11 | 2002-06-04 | Sepracor Inc. | Salts of sibutramine metabolites, methods of making sibutramine metabolites and intermediates useful in the same, and methods of treating pain |
| US7089666B2 (en) * | 2003-06-06 | 2006-08-15 | The Regents Of The University Of California | Microfabricated vertical comb actuator using plastic deformation |
| US7989500B2 (en) | 2006-09-15 | 2011-08-02 | Reviva Pharmaceuticals, Inc. | Synthesis, methods of using, and compositions of cycloalkylmethylamines |
| WO2012003501A2 (en) | 2010-07-02 | 2012-01-05 | Reviva Pharmaceuticals, Inc. | Compositions, synthesis, and methods of using cycloalkylmethylamine derivatives |
| AU2012362105B2 (en) | 2011-12-30 | 2017-09-07 | Reviva Pharmaceuticals, Inc. | Compositions, synthesis, and methods of using phenylcycloalkylmethylamine derivatives |
-
1999
- 1999-06-24 GB GBGB9914742.3A patent/GB9914742D0/en not_active Ceased
-
2000
- 2000-06-16 WO PCT/EP2000/005544 patent/WO2001000187A2/en not_active Application Discontinuation
- 2000-06-16 PL PL00352387A patent/PL352387A1/en unknown
- 2000-06-16 AU AU58151/00A patent/AU5815100A/en not_active Abandoned
- 2000-06-16 BR BR0011884-2A patent/BR0011884A/en not_active IP Right Cessation
- 2000-06-16 IL IL14707800A patent/IL147078A0/en unknown
- 2000-06-16 MX MXPA01013023A patent/MXPA01013023A/en unknown
- 2000-06-16 EP EP00943819A patent/EP1189638A2/en not_active Withdrawn
- 2000-06-16 CN CN00810544A patent/CN1365287A/en active Pending
- 2000-06-16 HU HU0201880A patent/HUP0201880A3/en unknown
- 2000-06-16 SK SK1882-2001A patent/SK18822001A3/en unknown
- 2000-06-16 CA CA002376213A patent/CA2376213A1/en not_active Abandoned
- 2000-06-16 TR TR2001/03704T patent/TR200103704T2/en unknown
- 2000-06-16 KR KR1020017016577A patent/KR20020012293A/en not_active Application Discontinuation
- 2000-06-16 CZ CZ20014614A patent/CZ20014614A3/en unknown
- 2000-06-16 JP JP2001505897A patent/JP2003503344A/en active Pending
-
2001
- 2001-12-06 ZA ZA200110046A patent/ZA200110046B/en unknown
- 2001-12-11 BG BG06209A patent/BG106209A/en unknown
- 2001-12-21 NO NO20016301A patent/NO20016301L/en not_active Application Discontinuation
-
2003
- 2003-02-20 HK HK03101311.7A patent/HK1050476A1/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101890017A (en) * | 2009-05-22 | 2010-11-24 | 北京奥萨医药研究中心有限公司 | Medicament composition containing sibutramine and stanin fat-reducing medicament and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| BR0011884A (en) | 2003-08-12 |
| TR200103704T2 (en) | 2002-05-21 |
| BG106209A (en) | 2002-09-30 |
| WO2001000187A3 (en) | 2001-11-15 |
| EP1189638A2 (en) | 2002-03-27 |
| SK18822001A3 (en) | 2003-04-01 |
| NO20016301D0 (en) | 2001-12-21 |
| ZA200110046B (en) | 2003-03-06 |
| HUP0201880A3 (en) | 2003-03-28 |
| JP2003503344A (en) | 2003-01-28 |
| NO20016301L (en) | 2001-12-21 |
| GB9914742D0 (en) | 1999-08-25 |
| IL147078A0 (en) | 2002-08-14 |
| HUP0201880A2 (en) | 2002-12-28 |
| AU5815100A (en) | 2001-01-31 |
| KR20020012293A (en) | 2002-02-15 |
| PL352387A1 (en) | 2003-08-25 |
| CZ20014614A3 (en) | 2004-02-18 |
| CA2376213A1 (en) | 2001-01-04 |
| WO2001000187A2 (en) | 2001-01-04 |
| MXPA01013023A (en) | 2003-08-01 |
| HK1050476A1 (en) | 2003-06-27 |
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