CN101648891A - Aryl cyclobutyl compound and application thereof in preparing weight-losing medicine - Google Patents

Aryl cyclobutyl compound and application thereof in preparing weight-losing medicine Download PDF

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CN101648891A
CN101648891A CN200910092011A CN200910092011A CN101648891A CN 101648891 A CN101648891 A CN 101648891A CN 200910092011 A CN200910092011 A CN 200910092011A CN 200910092011 A CN200910092011 A CN 200910092011A CN 101648891 A CN101648891 A CN 101648891A
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compound
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cyclobutyl
amino
phenyl
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CN101648891B (en
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陈小平
温守明
阎亚矢
赵锋
孙占国
丁浩
孟小平
张洁青
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YinGu Pharmaceutical Co Ltd
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BEIJING JIASHI LIANBO MEDICAL SCIENCE AND TECHNOLOGY Co Ltd
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Abstract

The invention provides a novel aryl cyclobutyl compound and medical application thereof. The compound comprises an antipode or a non-antipode mixture, a racemic mixture and pharmaceutically acceptablesalts of the compound and the mixture. The novel compound is used for preparing medicines for treating adiposit and relevant symptoms. Through the experiment, the compound not only can reach the weight-losing effect like a traditional weight-losing medicine of sibutramine, but also can obviously reduce serum cholesterol and triglyceride. The invention has no damage to visceral organs and can be used as a novel safe weight-losing medicine with multi-functions.

Description

Aryl cyclobutyl compound and the application in the preparation slimming medicine thereof
Technical field
The invention belongs to field of medicaments, be specifically related to a class new compound that contains aryl cyclobutyl and pharmacy acceptable salt thereof.The invention still further relates to preparation method and this compounds and the application of salt in the medicine of the fat disease of preparation control thereof of this compounds and salt thereof.
Background technology
Because the develop rapidly of science, the improvement of material life condition and dietary structure unreasonable, obesity has become serious day by day problem.The fat alliance organization of the U.S. thinks that obesity is " a kind of transmissible disease of the whole world ", and just rises with " making us terrified speed ".Estimate that according to the World Health Organization whole world is overweight above 1,000,000,000 adults now, at least 3 hundred million people's obesities.This disease is not limited only to flourishing industrial country, and in developing country, gathering way of fat number also significantly risen.In the 11st the fat academic conference in Europe, China is put into world's incidence of obesity ranking list first.Obesity and AIDS, malicious anaesthetic addiction and alcoholophilia are listed as the world's four big medical science social concerns, be the formidable enemy of human health longevity, also can bring out or increase the weight of sickness rate, especially diabetes, diseases of cardiovascular and cerebrovascular systems, sleep apnea syndrome of certain common chronic disease etc.According to statistics, in the past in the period of 10～20 annual nearly 28～32.5 ten thousand people of the U.S. die from obesity and complication thereof.In recent years, along with the raising of people's self health consciousness, fat-reducing more and more causes people's attention.Though people can lose weight by all means,, be equipped with health, isostatic diet simultaneously as regular exercise.But these methods all can't reach secular effect usually, so slimming medicine more and more is subjected to people's favor.Therefore from the scientific research angle, develop anti-obesity medicine safely and effectively, have important social and economic benefit.
Sibutramine hydrochloride (Sibutramine Hydrochlofide) is exactly the chemical synthetic drug that a class has curative effect on obesity, its chemistry N-{1-[1-(4-chloro-phenyl-) cyclobutyl by name]-the 3-methyl butyl }-N, N dimethylamine hydrochloric acid monohydrate (chiral centre is arranged).It is a kind of serotonin and NRI by the Knoll company exploitation of German BASF AG.Sibutramine hydrochloride (Sibutramine Hydrochlofide) obtains the FDA approval in November, 1997 as diet pill, and go on the market in the U.S. in February, 1998, trade(brand)name Meridia, sell 1.94 hundred million dollars then, 1999 annual sales amounts have surpassed 300,000,000 dollars, American-European more than 20 countries of situation of selling well at present become the American-European mainstream product in the market of losing weight, and therefore become the fourth-largest product of German BASF.In May, 2000, this medicine obtains National Drug Administration (SDA) approval in China's listing, and commodity are called Qu Mei.That at present, sibutramine is taken in the whole world is 3,000,000 people.
Sibutramine is a kind of serotonine and norepinephrine reuptake inhibitor (Buckett, W.R., Thomas, P.C.﹠amp in vivo; Luscombe, G.P. (1988) " neural psychopharmacology-biology-psychiatry outline " (Prog.Neuropsychopharmacol.Biol.Psychiat) 12, 575-584 and Luscombe, G.P., Hopcroft, R.H., Thomas, P.C.﹠amp; Buckett, W.R. (1989) " neuropharmacology " (Neuropharmacology) 28, 129-134).Studies confirm that this compound is by the two-way function weight reduction; It can reduce picked-up (Fantino, M.﹠amp to food by improving satiety; Souquet, A.-M. (1995) " international fat magazine " (Int.J.Obesity) 19, 145; Halford, J.C.G., Heal, D.J.﹠amp; Blundell, J.E. (1995) " Britain's pharmacology magazine " (Brit.J.Pharmacol) 114, 387P; And Stricker-Krongrad, A., Souquet, A.-M.﹠amp; Burlet, C. (1995) " international fat magazine " (Int.J.Obesity) 19, 145), and it increases energy expenditure (Connoley, I.P., Heal, D.J.﹠amp by stimulating heat production; Stocl, M.J. (1995) " Britain's pharmacology magazine " (Brit.J.Pharmacol) 114, 388P; And Connoley, I.P., Frost, I.Heal, D.J.﹠amp; Stocl, M.J. (1996) " Britain's pharmacology magazine " (Brit.J.Pharmacol) 117, 170P).In addition, sibutramine can also reduce waist/stern ratio, reduces triglyceride, total cholesterol, low-density lipoprotein (LDL-ch) in the blood, high density lipoprotein increasing (HDL-ch) (the Chinese endocrine metabolism magazine of Li Qifu etc. [J], 2002,18 (3): 204-205; Wu Jian etc. [J]. PLA's medical journal, 2002,27 (2): 172-176; [J]. Chinese endocrine metabolism magazine, 2001,18 (3): 201-202).
Prior art further discloses, and sibutramine-treated obesity [(10-30) mg/d] can reduce the basic body weight of 5%-10%, and can keep preferably.The calmness of this medicine, excitement, sympatheticomimetic action and not obvious, tolerance is better, and its common untoward reaction is dry, headache, apocleisis, constipation, insomnia.But sibutramine can not be used for coronary artery disease, congestive heart failure, arrhythmia, apoplexy, serious liver function damage patient, forbid in out of contior hypertensive patient of blood pressure and anorexia nervosa patient, history of hypertension, angle closure glaucoma, the careful usefulness of epileptic seizures history person are arranged.
Prior art also discloses, and sibutramine and demethylation compound thereof can effectively be treated neuropsychiatric disease, comprise obesity, insomnia, fatigue, depression etc.; Metabolic trouble; And cardiovascular disorder.For sibutramine, its optical isomer and demethylation compound thereof, PCT/US2000/007202 discloses it can reduce the increase of conceived back body weight; PCT/US2000/007255 discloses it can reduce the platelet adhesion reaction effect; PCT/US2000/007122 discloses its treatment chronic fatigue syndrome; PCT/US2000/007123 discloses its treatment metabolic syndrome effect; PCT/US2000/007361 discloses the fat relevant tumour of its treatment; PCT/US2000/007124 discloses its treatment pulmonary hypertension; PCT/US2000/007177 discloses treatment sleep syndromes; PCT/US2000/001217 discloses its smoking cessation effect; US 6046242 discloses its treatment urinary incontinence effect.Existing document has also disclosed method (the Tetra Asymm 2003 of extensive fractionation sibutramine; 14 (25): 3553-6).The field of chemical synthesis researchist has also done further modification work to sibutramine.For example, the method for asymmetric synthesis R-sibutramine (Organic processresearch and development, 2006; 10 (2): 327-333); The method of sibutramine demethylation (US6399826); Method (the Tetra Lett of asymmetric synthesis demethyl R-sibutramine; 2002; 43 (13): 2331-3).At document J.Chem.Soc.Perkin Trans.1; EN; 21; 1996; Among the 2583-2590, respectively methyl, amino, cyclobutyl in the sibutramine demethylation adduct molecule are modified, also the pure optically active isomer of said derivative is prepared simultaneously and done research.Below be several concrete sibutramine derivant structure formulas:
Figure G2009100920116D00031
At document Org.Lett.; EN; 7; 13; 2005; Among the 2599-2602 methyl, amino in the sibutramine demethyl molecular structure of compounds have been done modification, and said derivative is split out optically active isomer, concrete derivative optically active isomer structural formula is as follows:
Figure G2009100920116D00032
Though the sibutramine derivative that discloses in the document has a variety of versions, but only chemical species is changed and carried out preliminary study, whether they are had the fat-reducing drug effect similar to sibutramine, and the untoward reaction that whether can alleviate sibutramine also needs further conclusive evidence.Therefore, it is very necessary to obtain the sibutramine derivative that can prove conclusively its pharmaceutical activity and lower drug toxicity.
Summary of the invention
The object of the invention is to provide the derivative of one group of new sibutramine, by the multiple modification to sibutramine amino, under the prerequisite that reaches existing pharmaceutical active, improves the physico-chemical property of activeconstituents, to reduce its toxic side effect as slimming medicine.
The derivative that the invention provides is a compound shown in the formula (I), also comprises its enantiomorph or non-enantiomer mixture, its racemic mixture, and above-claimed cpd and mixture pharmacy acceptable salt:
Figure G2009100920116D00041
Wherein:
X is H, halogen, CF 3, C 1-3A kind of in alkyl, alkoxyl group, alkylthio and the phenyl; Be preferably halogen, be more preferably the chlorine in the phenyl ring contraposition.
R 1Be H or for C 1～C 4The straight or branched alkyl, be preferably isobutyl-.
R 3Can be H, formyl radical, ethanoyl, halo ethanoyl, benzoyl, carbobenzoxy-(Cbz) (Cbz), tertbutyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc) or and R 2With-HN-form 3-7 unit ring (this ring can be saturated also can be undersaturated, also may be by one or more halogen, hydroxyl, C 1-4Alkyl, C 1-4Alkoxyl group replaces); R 3Preferably H, formyl radical, ethanoyl, halo ethanoyl, benzoyl, carbobenzoxy-(Cbz), tertbutyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc) or and R 2With-HN-form the 3-7 ring structure (this ring can be saturated also can be undersaturated, this ring also can be replaced by chlorine, hydroxyl, methyl, ethyl, propyl group, sec.-propyl, butyl); R 3More preferably H, carbobenzoxy-(Cbz) (Cbz), tertbutyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc) or and R 2Five yuan of saturated N heterocycle alkane or 4 hydroxyls of forming with-HN-replace C 1-3Alkyl.
Work as R 3When being H, formyl radical, ethanoyl, halo ethanoyl, benzoyl, carbobenzoxy-(Cbz), tertbutyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl, R 2Can be following radicals: C 1-12Alkyl, benzyl, substituted benzyl or R 4(CH 2) n-(wherein: n=1-4; R 4Can be that hydroxyl, amino, sulfydryl, sulfenyl, hydrocarbon are for sulfenyl, carboxylic acid group, amide group, urea groups, pyridyl, thienyl, furyl, imidazolyl or indyl), R 5R 6(CH)-(R 5Can be C 1-12Alkyl; R 6Can be hydroxyl, amino, sulfydryl) and R 3With-HN-formation 3-7 unit ring; R 2Be preferably methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, sec-butyl, isobutyl-, benzyl, halogen atom substituted benzyl, alkyl substituted benzyl base, alkoxyl group substituted benzyl, hydroxyl substituted benzyl, R 4(CH 2) n-(wherein: if n=1-2, then R 4Be hydroxyl, amino, sulfydryl, methylthio group, ethylmercapto group, rosickyite base, iprotiazem base, butylthio, uncle's butylthio, isobutyl sulfenyl, carboxylic acid group, amide group, urea groups, pyridyl, thienyl, furyl, imidazolyl, indyl, sulfenyl; If n=3-4, then R 4Be amino, carboxylic acid group, amide group, urea groups) or R 5R 6(CH)-(R 5Be methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, isobutyl-; R 6Can be hydroxyl, amino, sulfydryl); R 2Most preferably be H, C 2-4Alkyl, R 4(CH 2) n-(wherein: n=1-4; R 4Be hydroxyl, sulfydryl, sulfenyl, carboxylic acid group, amide group, urea groups, imidazolyl).
More preferred, work as R 3When being H, R 2Be more preferably methyl, sec.-propyl, isobutyl-, sec-butyl, benzyl, methylthio ethyl, methylol, R 4(CH 2) n-(during n=1, R 4Be hydroxyl, sulfydryl, carboxylic acid group, amide group, imidazolyl, p-hydroxybenzene, indyl; During n=2, R 4Be first sulphur, carboxylic acid group, amide group; During n=3, R 4Be urea groups; During n=4, R 4Be amido), R 5R 6(CH)-(R 5Be methyl, R 6Be hydroxyl).
In particularly preferred embodiments, be chlorine in the contraposition of X phenyl ring; R 1It is isobutyl-; R 3Be H, Cbz, Boc or Fmoc; R 2It is sec.-propyl.This group compound is based on the compound of embodiment 9 and the 3rd group of relevant therewith compound, also comprises the compound that substitutes the Boc protecting group based on the compound of embodiment 9 with Cbz or Fmoc.
In another particularly preferred embodiment, be chlorine in the contraposition of X phenyl ring; R 1It is isobutyl-; R 3With NH and R 2Form pyrrole ring.This group compound is based on the compound of embodiment 41 and the 18 group of relevant therewith compound, or the salt of these compounds.
Term among the present invention " alkyl " has comprised the alkyl group of straight chain and side chain, as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, amyl group and hexyl; Term " halogen " comprises fluorine, chlorine, bromine and iodine.
One skilled in the art will appreciate that in formula (I) compound and contain 1 chiral centre at least.When containing two chiral centres in formula (I) compound, can there be 4 enantiomeric forms in it.Pure optically active isomer, mixture of enantiomers, non-enantiomer mixture, racemic mixture and above-claimed cpd thereof, mixture and the pharmacy acceptable salt of structure all belong to scope of the present invention shown in the formula (I).
The present invention adopts the endomorphy type rat model, is contrast with the sibutramine, viewing test medicine and the antiobesity action of contrast medicine to the endomorphy type rat model, and the examination animal is carried out vitals pathology such as blood fat, blood biochemical mensuration and the heart, liver, kidney detect.The result confirms, each experimental drug that is included in the formula (I) all has in various degree antiobesity action to fat rat model, final body weight, Lee coefficient, the kidney that can obviously reduce the endomorphy type rat reach sexual organ white adipose tissue weight, sexual organ white adipose cell counting on every side on every side on every side, and be similar to the antiobesity action of sibutramine; Each experimental drug has tangible reduction effect to serum cholesterol, triglyceride, but laboratory animal total serum protein, blood sugar are not had tangible influence, and important histoorgan is not had obvious pathology infringement.Therefore The compounds of this invention is suitable for prevention and treatment obesity and associated conditions thereof.
The invention provides formula (I) compound and comprise its pure enantiomorph, its raceme mixture, its non-enantiomer mixture and its pharmacologically acceptable salt purposes in the medicine of treatment obesity and associated conditions.Described ' associated conditions ' is meant the medical conditions that well known to a person skilled in the art with fat relevant.This term includes but are not limited to following disease: hypertension; Coronary thrombosis; Apoplexy; Dysthymia disorders; Anxiety; Psychosis (for example schizophrenia); Tardive dyskinesia; Drug habit; Drug abuse; Cognitive disorder; Alzheimer's disease; Cerebral ischemia; Dull-witted; Parkinsonism; Amnestic syndrome; Obsession; Panic attack; Social phobia, eating disorder; The lipid syndromes; Blood sugar is too high; Blood fat is too high; With the intravital stress reaction of Mammals, particularly people.
Embodiment
The compounds of this invention can be accomplished according to following method and step.
At first, the starting compound (referring to embodiment 1) of the method preparation formula of introducing with reference to patent GB2098602A or other document (II), this starting compound contains chiral centre, those skilled in the art can split it by known method, for example, by forming separable non-mapping salt or complex crystal; Formation can be carried out isolating non-enantiomer derivative by for example crystallization, gas liquid chromatography or liquid chromatography; A kind of enantiomorph and enantiomorph specific reagent are carried out selective reaction, for example oxydasis or reduction, the enantiomorph of separation modification and unmodified then; Perhaps in chiral environment, for example in chiral environment, for example chiral support (for example having the silica gel in conjunction with chiral ligand) goes up or carry out gas liquid chromatography or liquid chromatography in the presence of chiral solvent.Be appreciated that when required enantiomorph changes into another kind of chemical entities by one of above-mentioned separation method, also need to discharge in addition the step of required enantiomeric form.
R shown in the formula (II) in the starting compound 1Be H or C 1-4Alkyl; X independently is H, halogen, CF 3, C 1-3Alkyl, alkoxyl group, alkylthio or phenyl.
After the optical isomer of starting compound was ready to shown in the formula (II), those skilled in the art can adopt following two schemes to prepare compound shown in the formula of the present invention (I).
Scheme one:
Figure G2009100920116D00061
In this programme, the R shown in the formula (III) in the starting compound 3For being H, formyl radical, ethanoyl, halo ethanoyl, benzoyl, carbobenzoxy-(Cbz) (Cbz), tertbutyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc); R 2For methyl, sec.-propyl, isobutyl-, sec-butyl, benzyl, methylthio ethyl, methylol or be R 4(CH 2) n-(during n=1, R 4Be hydroxyl, sulfydryl, carboxylic acid group, amide group, imidazolyl, p-hydroxybenzene, indyl; During n=2, R 4Be first sulphur, carboxylic acid group, amide group; During n=3, R 4Be urea groups; During n=4, R 4Be amido) or be R 5R 6(CH)-(R 5Be methyl, R 6Be hydroxyl).
The a certain optical isomer of starting compound shown in starting compound shown in the above-mentioned formula (III) and the formula (II), enantiomorph, diastereomer, raceme mixture generate the optical isomer of compound shown in the formula of the present invention (I) by condensation reaction.
Scheme two:
All the other are all identical with scheme one, just R 3With R 2With-HN-form 3-7 unit ring (this ring can be saturated also can be undersaturated, also may be by one or more halogen, hydroxyl, C 1-4Alkyl, C 1-4Alkoxyl group replaces), R 2With R 3With-HN-formation 3-7 unit ring.R 3With R 2To form compound concrete structure shown in the formula (I) of ring as follows with-HN-:
Figure G2009100920116D00062
This moment n=0-4, R 7Be one or more halogen, hydroxyl, C 1-4Alkyl, C 1-4Alkoxyl group.
As above-mentioned two schemes, relate to a step condensation reaction shown in the formula of the present invention (I) in the preparation of compound, those skilled in the art can utilize condensing agent to carry out the preparation of this compound by known method.For example utilize DCC, DIC, BDP, BOP, EDC, AOP, PyAOP, PPAA, TOTU, HATU, HAPyU, HAMDU, HBTU, HBTyU, HBMDU, HBPyU, DEPBT, HOAT, HOBT, PyBOP, TATU, TBTU, PyBrop, PyCloP, CIP, TFFH, BTFFH, PyCIU, CDTP, BOP-C1, DPPA, DEPC, BOMI, BDMP to wait and realize this condensation reaction.
The specific embodiment that below comprises illustrates the present invention with the preparation of several groups of compounds, does not constitute the restriction to the disclosure of invention.Agents useful for same and intermediate or can be provided by commerce in the example perhaps can easily be prepared according to the normative document method by those skilled personnel of organic synthesis field.Those persons skilled in the art of this area also have other to prepare the method for The compounds of this invention as can be known.
Starting compound
Embodiment 1:1-[1-(4-chloro-phenyl-) cyclobutyl]-preparation of 3-methylbutylamine and optical isomer thereof
1, racemic 1-[1-(4-chloro-phenyl-) cyclobutyl]-preparation of 3-methylbutylamine
The method of reference literature (Chinese Journal of Pharmaceuticals, 2001; 32 (8): 337-9), by p-chlorobenzyl cyanide and 1, the 3-dibromopropane annulation of going ahead of the rest, preparation cyclobutyl intermediate prepares through Grignard reaction and reduction reaction again.Yield 56.2%.
2, split example: racemic 1-[1-(4-chloro-phenyl-) cyclobutyl that step 1 is prepared]-3-methylbutylamine 20.3g is with the mixed solution 300ml dissolving of acetone/methyl alcohol=1: 0.13: 0.7 (volume ratio), adding L (+)-tartrate 12.1g then refluxed 0.5 hour, naturally cooling, room temperature left standstill 2-4 days, there is crystallization to generate, filters, wash with cold acetone (100ml/13ml), get sample 10.3g, yield 33% after drying.
Get above-mentioned crystallized product 25g, add acetonitrile/water/ethanol 300ml/65ml/30ml and refluxed 1 hour, be cooled to room temperature filter white crystals product 18g, yield 72%.After alkaline purification, get free alkali.Optical purity 99.7%.This product is (S)-1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methylbutylamine.
Same as above, mother liquor is obtained another kind of optically active isomer, yield 75.2% with D-(-)-tartrate fractionation.After alkaline purification, get free alkali.Optical purity 99.4% is (R)-1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methylbutylamine.
(chiral column is ULTRON ES-OVM (150mmx4.6mm), and moving phase is 0.01MKH with chiral column 2PO 4/ CH 3OH (70: 30), ultraviolet detection wavelength are 200nm) measure the chiral purity of optical isomer, the result shows that the optical purity of these compounds is all greater than 99.0%.
First group
Embodiment 2:2-(Boc protect amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl } preparation of ethanamide and isomer thereof
Get 1-[1-(4-chloro-phenyl-) cyclobutyl that obtains among the embodiment 1 without fractionation]-3-methylbutylamine 250mg and the anhydrous THF dissolving of 3ml of 210mg N-(tertbutyloxycarbonyl)-2-Padil.And then take by weighing 220mg DCC, with the anhydrous THF dissolving of 25ml.The THF drips of solution of DCC is added in the reaction soln.Dropwise back stirring at room reaction and spend the night, have a large amount of white precipitates to generate.The filtering precipitation, and should precipitate more than 3 times with the anhydrous diethyl ether repetitive scrubbing.Collect filtrate and the used ether of washing precipitation, get thick product after being spin-dried for, obtain 2-(Boc protects amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl with the column chromatography method separation and purification then]-the 3-methyl butyl } ethanamide.
Adopt 1-[1-(4-chloro-phenyl-) cyclobutyl split]-the 3-methylbutylamine carries out above-mentioned same reaction and treating processes, can obtain 2-(Boc protects amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl } two kinds of optical isomers of ethanamide.
Embodiment 3:2-amino-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl } preparation of ethanamide and isomer thereof
With embodiment 2 products therefrom 2-(Boc protect amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl } ethanamide or its optical isomer join CF 3Dissolve among the COOH.This solution is stirring reaction Ex-all CF after hour at room temperature 3COOH, the muddy shape thing of adularescent generates.It is dissolved in the anhydrous diethyl ether, and with the saturated sodium bicarbonate solution repetitive scrubbing till the liquid that washes out becomes neutrality.Wash this diethyl ether solution 2-3 time with saturated sodium-chloride water solution then, and use anhydrous sodium sulfate drying.The filtering siccative removes solvent under reduced pressure, and the gained crude product obtains 2-(amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl with the column chromatography method separation and purification then]-the 3-methyl butyl } ethanamide or its optical isomer.
Embodiment 4:2-amino-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl } preparation of acetamide hydrochloride:
With embodiment 3 products therefrom 2-(amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl ethanamide with the dissolving of a little anhydrous diethyl ether after, add the salt acid ether, should have a large amount of white precipitate crystallizations to produce, this crystallization is 2-(amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl } acetamide hydrochloride.
Second group
Embodiment 5:2-(Boc protect amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl } preparation of propionic acid amide and isomer thereof
Pressing embodiment 2 methods will be without 1-[1-(4-chloro-phenyl-) cyclobutyl that splits or split]-3-methylbutylamine and N-(tertbutyloxycarbonyl)-2-amino-this compound of propionic acid prepared in reaction, thus product obtained.
Embodiment 6:2-amino-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl } preparation of propionic acid amide and isomer thereof
Press embodiment 3 methods, with gained compound among the embodiment 5 at CF 3Protecting group among the COOH on the deaminize, thus product obtained.
Embodiment 7:2-amino-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl } preparation of propionamide hydrochloride
Prepare this salt by embodiment 4 methods, thereby obtain product.
The 3rd group
Embodiment 8:2-(Boc protect amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-methylbutyryl amine
Pressing embodiment 2 will be without 1-[1-(4-chloro-phenyl-) cyclobutyl that splits or split]-3-methylbutylamine and N-(tertbutyloxycarbonyl)-2-amino-this compound of 3 Methylbutanoic acid prepared in reaction, thus product obtained.
Embodiment 9:2-amino-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-methylbutyryl amine
Press embodiment 3 methods, with embodiment 8 gained compounds at CF 3Protecting group among the COOH on the deaminize, thus product obtained.Molecular weight is 348.91 (C 20H 29ClN 2O); MS (ESI): 350 (M+H +).
Embodiment 10:2-amino-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-methylbutyryl amine hydrochlorate
Prepare this salt by embodiment 4 methods, thereby obtain product.
The 4th group
Embodiment 11:2-(Boc protect amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 4-methylpent acid amides
Pressing embodiment 2 methods will be without 1-[1-(4-chloro-phenyl-) cyclobutyl that splits or split]-3-methylbutylamine and N-(tertbutyloxycarbonyl)-2-amino-this compound of 4-methylvaleric acid prepared in reaction, thus product obtained.
Embodiment 12:2-amino-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 4-methylpent acid amides
Press embodiment 3 methods, with embodiment 11 gained compounds at CF 3Protecting group among the COOH on the deaminize, thus product obtained.
Embodiment 13:2-(Boc protect amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-methylpent acid amides
Pressing embodiment 2 methods will be without 1-[1-(4-chloro-phenyl-) cyclobutyl that splits or split]-3-methylbutylamine and N-(tertbutyloxycarbonyl)-2-amino-3 methylvaleric acid react, thereby obtain product.
Embodiment 14:2-amino-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-methylpent acid amides
Press embodiment 3 methods, with embodiment 13 gained compounds at CF 3Protecting group among the COOH on the deaminize, thus product obtained.
The 5th group
Embodiment 15:2-(Boc protect amino) N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-Phenylpropionamide
Pressing embodiment 2 methods will be without 1-[1-(4-chloro-phenyl-) cyclobutyl that splits or split]-3-methylbutylamine and N-(tertbutyloxycarbonyl)-2-amino-this compound of 3-phenylpropionic acid prepared in reaction, thus product obtained.
Embodiment 16:2-amino-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-Phenylpropionamide
Press embodiment 3 methods, with embodiment 15 gained compounds at CF 3Protecting group among the COOH on the deaminize, thus product obtained.
The 6th group
Embodiment 17:2-(Boc protect amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-methylthio group butyramide
Pressing embodiment 2 methods will be without 1-[1-(4-chloro-phenyl-) cyclobutyl that splits or split]-3-methylbutylamine and N-(tertbutyloxycarbonyl)-2-amino-this compound of 4-methylmercapto butyric acid prepared in reaction, thus product obtained.
Embodiment 18:2-amino-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-methylthio group butyramide
Press embodiment 3 methods, with embodiment 17 gained compounds at CF 3Protecting group among the COOH on the deaminize, thus product obtained.
The 7th group
Embodiment 19:2-(Boc protect amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-hydroxyl propionic acid amide
Pressing embodiment 2 methods will be without 1-[1-(4-chloro-phenyl-) cyclobutyl that splits or split]-3-methylbutylamine and N-(tertbutyloxycarbonyl)-2-amino-this compound of 3-hydroxy-propionic acid prepared in reaction, thus product obtained.
Embodiment 20:2-amino-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-hydroxyl propionic acid amide
Press embodiment 3 methods, with embodiment 19 gained compounds at CF 3Protecting group among the COOH on the deaminize, thus product obtained.
The 8th group
Embodiment 21:2-(Boc protect amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-maloyl group amine
Pressing embodiment 2 methods will be without 1-[1-(4-chloro-phenyl-) cyclobutyl that splits or split]-3-methylbutylamine and N-(tertbutyloxycarbonyl)-this compound of 2 amino 3 hydroxybutyric acid prepared in reaction, thus product obtained.
Embodiment 22:2-amino-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-maloyl group amine
Press embodiment 3 methods, with embodiment 21 gained compounds at CF 3Protecting group among the COOH on the deaminize, thus product obtained.
The 9th group
Embodiment 23:2-(Fmoc protect amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-sulfydryl propionic acid amide
Get without 1-[1-(4-chloro-phenyl-) cyclobutyl that splits or split]-3-methylbutylamine 250mg and the 5ml dry DMF dissolving of 410mg N-(9-fluorenylmethyloxycarbonyl)-2-amino-3-mercaptopropionic acid, to wherein adding the 0.5ml triethylamine.And then take by weighing 300mg BDP, with the dissolving of 25ml dry DMF.The DMF drips of solution of BDP is added in the reaction soln.Dropwise the back stirring at room and react half hour, have a large amount of white precipitates to generate.The filtering precipitation, and should precipitate more than 3 times with the anhydrous diethyl ether repetitive scrubbing.Collect filtrate and the used ether of washing precipitation, get thick product after being spin-dried for, obtain 2-(Fmoc protects amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl with the column chromatography method separation and purification then]-the 3-methyl butyl }-3-sulfydryl propionic acid amide.
Embodiment 24:2-amino-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-sulfydryl propionic acid amide
With embodiment 23 products therefrom 2-(Fmoc protect amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-3-sulfydryl propionic acid amide joins 0.05-0.1mol/L (n-Bu) 4N +F -DMF in dissolve.This solution is stirring reaction Ex-all DMF after half hour at room temperature, and the muddy shape thing of adularescent generates.It is dissolved in the anhydrous diethyl ether, and with the saturated sodium bicarbonate solution repetitive scrubbing till the liquid that washes out becomes neutrality.Wash this diethyl ether solution 2-3 time with saturated sodium-chloride water solution then, and use anhydrous sodium sulfate drying.The filtering siccative removes solvent under reduced pressure, and the gained crude product obtains 2-amino-N-{1-[1-(4-chloro-phenyl-) cyclobutyl with the column chromatography method separation and purification then]-the 3-methyl butyl }-3-sulfydryl propionic acid amide.
The tenth group
Embodiment 25:3-(Fmoc protects amino)-4-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methylbutylamine }-the butyro-preparation of 4-carbonyl
Pressing embodiment 23 methods will be without 1-[1-(4-chloro-phenyl-) cyclobutyl that splits or split]-3-methylbutylamine and N-(9-fluorenylmethyloxycarbonyl)-this compound of 2-amino-succinic acid prepared in reaction, thus this product obtained.
Embodiment 26:3-amino-4-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methylbutylamine }-the butyro-preparation of 4-carbonyl
Press embodiment 24 methods, with embodiment 23 gained compounds at 0.05-0.1mol/L (n-Bu) 4N +F -DMF in protecting group on the deaminize, thereby obtain product.
The 11 group
Embodiment 27:2-(Fmoc protects amino)-N 1The preparation of-{ 1-[1-(4-chloro-phenyl-) cyclobutyl]-3-methyl butyl } succinic diamide
Pressing embodiment 23 methods will be without 1-[1-(4-chloro-phenyl-) cyclobutyl that splits or split]-3-methylbutylamine and N-(9-fluorenylmethyloxycarbonyl)-this compound of 2-amino 4-amide group propionic acid prepared in reaction, thus this product obtained.
Embodiment 28:2-amino-N 1The preparation of-{ 1-[1-(4-chloro-phenyl-) cyclobutyl]-3-methyl butyl } succinic diamide
Press embodiment 24 methods, with embodiment 27 gained compounds at 0.05-0.1mol/L (n-Bu) 4N +F -DMF in protecting group on the deaminize, thereby obtain product.
The 12 group
Embodiment 29:4-(Fmoc protect amino)-5-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methylbutylamine }-preparation of 5-carbonyl valeric acid
Pressing embodiment 23 methods will be without 1-[1-(4-chloro-phenyl-) cyclobutyl that splits or split]-3-methylbutylamine and N-(9-fluorenylmethyloxycarbonyl)-this compound of 2 aminopentanedioic acid prepared in reaction, thus this product obtained.
Embodiment 30:4-amino-5-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methylbutylamine }-preparation of 5-carbonyl valeric acid
Press embodiment 24 methods, with embodiment 29 gained compounds at 0.05-0.1mol/L (n-Bu) 4N +F -DMF in protecting group on the deaminize, thereby obtain product.
The 13 group
Embodiment 31:2-(Fmoc protects amino)-N 1The preparation of-{ 1-[1-(4-chloro-phenyl-) cyclobutyl]-3-methyl butyl } glutaramide
Pressing embodiment 23 methods will be without 1-[1-(4-chloro-phenyl-) cyclobutyl that splits or split]-3-methylbutylamine and N-(9-fluorenylmethyloxycarbonyl)-this compound of 2-amino 4-amide group butyric acid prepared in reaction, thus this product obtained.
Embodiment 32:2-amino-N 1The preparation of-{ 1-[1-(4-chloro-phenyl-) cyclobutyl]-3-methyl butyl } glutaramide
Press embodiment 24 methods, with embodiment 31 gained compounds at 0.05-0.1mol/L (n-Bu) 4N +F -DMF in protecting group on the deaminize, thereby obtain product.
The 14 group
Embodiment 33:1-{4-(Fmoc protect amino)-5-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methylbutylamine }-5-carbonyl amyl group } preparation of urea
Pressing embodiment 23 methods will be without 1-[1-(4-chloro-phenyl-) cyclobutyl that splits or split]-3-methylbutylamine and N-(9-fluorenylmethyloxycarbonyl)-this compound of 2-amino 5-diazanyl valeric acid prepared in reaction, thus this product obtained.
Embodiment 34:1-{4-amino-5-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methylbutylamine }-5-carbonyl amyl group } preparation of urea
Press embodiment 24 methods, with embodiment 33 gained compounds at 0.05-0.1mol/L (n-Bu) 4N +F -DMF in protecting group on the deaminize, thereby obtain product.
The 15 group
Embodiment 35:2-(Cbz protect amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-(1H-4-imidazoles) propionic acid amide
Get without 1-[1-(4-chloro-phenyl-) cyclobutyl that splits or split]-3-methylbutylamine 250mg and the 5ml dry DMF dissolving of 410mg N-(carbobenzoxy-(Cbz))-2-amino-3-(1H-4-imidazoles) propionic acid, to wherein adding the 0.5ml triethylamine.And then take by weighing 400mg BOP, with the dissolving of 25ml dry DMF.The DMF drips of solution of BDP is added in the reaction soln.Dropwise back stirring at room reaction half, have a large amount of white precipitates to generate.The filtering precipitation, and should precipitate more than 3 times with the anhydrous diethyl ether repetitive scrubbing.Collect filtrate and the used ether of washing precipitation, get thick product after being spin-dried for, obtain 2-(Cbz protects amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl with the column chromatography method separation and purification then]-the 3-methyl butyl }-3-(1H-4-imidazoles) propionic acid amide.
Embodiment 36:2-amino-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-(1H-4-imidazoles) propionic acid amide
With embodiment 35 products therefrom 2-(Cbz protect amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-3-(1H-4-imidazoles) propionic acid amide joins in the ethanol and dissolves.Then to wherein adding an amount of 10%Pd-C.Hydrogenation is to not inhaling till the hydrogen under the normal temperature and pressure.Leach catalyzer, revolve except that ethanol, the muddy shape thing of adularescent generates.It is dissolved in the anhydrous diethyl ether, washs this diethyl ether solution 2-3 time with saturated sodium-chloride water solution then, and use anhydrous sodium sulfate drying.The filtering siccative removes solvent under reduced pressure, and the gained crude product obtains 2-amino-N-{1-[1-(4-chloro-phenyl-) cyclobutyl with the column chromatography method separation and purification then]-the 3-methyl butyl }-3-(1H-4-imidazoles) propionic acid amide.
The 16 group
Embodiment 37:2-(Cbz protect amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-(4-hydroxy phenyl) propionic acid amide
Pressing embodiment 35 methods will be without 1-[1-(4-chloro-phenyl-) cyclobutyl that splits or split]-3-methylbutylamine and this compound of N-(carbobenzoxy-(Cbz))-2-amino-3-(4-hydroxy phenyl) propionic acid prepared in reaction, thus this product obtained.
Embodiment 38:2-amino-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-(4-hydroxy phenyl) propionic acid amide
Press embodiment 36 methods, with embodiment 37 gained compounds in ethanolic soln with the protecting group on 10% the Pd-C deaminize, thereby obtain product.
The 17 group
Embodiment 39:2-(Cbz protect amino)-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-(1H-indyl) propionic acid amide
Pressing embodiment 35 methods will be without 1-[1-(4-chloro-phenyl-) cyclobutyl that splits or split]-3-methylbutylamine and this compound of N-(carbobenzoxy-(Cbz))-2-amino-3-(1H-indyl) propionic acid amide prepared in reaction, thus this product obtained.
Embodiment 40:2-amino-N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-preparation of 3-(1H-indyl) propionic acid amide
Press embodiment 36 methods, with embodiment 39 gained compounds in ethanolic soln with the protecting group on 10% the Pd-C deaminize, thereby obtain product.
The 18 group
Embodiment 41:N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl } preparation of pyrroles-2-acid amides
Will be by embodiment 2 methods without 1-[1-(4-chloro-phenyl-) cyclobutyl that splits or split]-3-methylbutylamine and pyrroles-2-carboxylic acid reaction prepare this compound, thereby obtain product.
Embodiment 42:N-{1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-methyl butyl }-4-hydroxyl pyrroles-2-acid amides
Will be by embodiment 2 methods without 1-[1-(4-chloro-phenyl-) cyclobutyl that splits or split]-3-methylbutylamine and 4-hydroxyl pyrroles-2-carboxylic acid reaction prepare this compound, thereby obtain product.
Above embodiment product is carried out the ESI mass spectroscopy, enumerate compound all shows expection in the ESI mass spectrum molecular ion peak above the result.Relevant information is referring to table 1:
Table 1 embodiment 2～42 dependency structures and ESI mass spectrum information
Figure G2009100920116D00141
Figure G2009100920116D00151
Figure G2009100920116D00161
Figure G2009100920116D00171
Figure G2009100920116D00181
Figure G2009100920116D00191
Figure G2009100920116D00201
More than with specific embodiment the preparation of formula of the present invention (I) compound and enantiomer compound thereof has been described.The compound that the present invention is contained is not limited to the content that embodiment enumerates, and comprises that also compound or its enantiomer compound are at pharmacy acceptable salt.
Pharmacy acceptable salt is particularly suitable for medical applications, because compare with initial or basic compound, their solubleness in water is bigger.There is basic nitrogen in The compounds of this invention, therefore can prepare salify by sour addition with pharmaceutically acceptable mineral acid and organic acid, mineral acid is hydrochloric acid for example, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid, organic acid is carbonic acid for example, acetate, oxalic acid, Phenylsulfonic acid, tosic acid, to bromo-benzene sulfonic acid, Succinic Acid, phenylformic acid, Citric Acid, ethyl sulfonic acid, fumaric acid, glyconic acid, oxyacetic acid, isethionic acid, lactic acid, lactobionic acid, toxilic acid, oxysuccinic acid, methylsulfonic acid, succsinic acid, tosic acid, tartrate and trifluoroacetic acid, amino acid etc.Therefore, this class pharmacy acceptable salt comprises vitriol, pyrosulphate, hydrosulfate, sulphite, hydrosulphite, phosphoric acid salt, monohydric phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate salt, muriate, bromide, iodide, acetate, propionic salt, octylate, acrylate, formate, isobutyrate, hydrochlorate more, caprate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-butyne-1, the 4-diacid salt, 3-cyclohexyne-2, the 5-diacid salt, benzoate, chloro-benzoate, phenylacetate, phenpropionate, benzenebutanoic acid salt, Citrate trianion, lactic acid salt, hippurate, beta-hydroxy-butanoic acid salt, glycollate, maleate, tartrate, mesylate, propanesulfonic acid salt, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, mandelate, glutaminate, arginic acid salt, lysine salt etc.With regard to medical purpose, particularly preferred use hydrochloride has provided by the salifiable method of compound among the embodiment 4,7,10, and this method is suitable equally for the compound among other embodiment.
On the other hand, can also there be various polymorphics in The compounds of this invention, for example amorphous forms and crystal type.All crystal formations of The compounds of this invention all comprise within the scope of the invention.
In application facet, The compounds of this invention, its optical isomer, pharmaceutical salts, crystalline structure all can be used as the preparation that active constituents of medicine is used for slimming medicine.Its pharmacy effect below is described by experiment.
The active toxicity test of slimming medicine
One, method
1. the foundation of fat animal model
Will be just from newborn SD rat except that the blank group, give abundant nutrient fodder and feed, allow rat ad libitum access every day, to such an extent as to set up fat animal model rapidly.
2. experiment grouping, dosage are determined and dosage regimen
To just be divided into 21 groups at random from 210 of newborn SD rats, 10 every group, male and female half and half provide abundant nutrient fodder, and each organizes rat ad libitum access every day, and grouping and dosage are as follows:
(1) blank group: give basal feed and feed.
(2) model group: give nutrient fodder and feed, quantity-unlimiting.
More than two groups all irritate stomach with 1% carboxymethyl cellulose excipient, all the other are respectively tested the medicine group and all give and the nutrient fodder nursing, and are made into corresponding drug level with 1% carboxymethyl cellulose and gavage, the administration volume is 1ml/100g, once a day, gavages 30 days continuously.Dosage design is according to clinical dosage 10mg/ people/sky of positive control medicine sibutramine, according to the dose,equivalent conversion of people and rat and get.
1) the heavy dose of 0.11mg/ml of embodiment 16 compound medicines
2) the low dose of 0.055mg/ml of embodiment 16 compound medicines
3) the heavy dose of 0.11mg/ml of embodiment 22 compound medicines
4) the low dose of 0.055mg/ml of embodiment 22 compound medicines
5) the heavy dose of 0.11mg/ml of embodiment 12 compound medicines
6) the low dose of 0.055mg/ml of embodiment 12 compound medicines
7) the heavy dose of 0.11mg/ml of embodiment 26 compound medicines
8) the low dose of 0.055mg/ml of embodiment 26 compound medicines
9) the heavy dose of 0.11mg/ml of embodiment 14 compound medicines
10) the low dose of 0.055mg/ml of embodiment 14 compound medicines
11) the heavy dose of 0.11mg/ml of embodiment 2 compound medicines
12) the low dose of 0.055mg/ml of embodiment 2 compound medicines
13) the heavy dose of 0.11mg/ml of embodiment 40 compound medicines
14) the low dose of 0.055mg/ml of embodiment 40 compound medicines
15) the heavy dose of 0.11mg/ml of embodiment 41 compound medicines
16) the low dose of 0.055mg/ml of embodiment 41 compound medicines
17) the heavy dose of 0.11mg/ml of embodiment 9 compound medicines
18) the low dose of 0.055mg/ml of embodiment 9 compound medicines
19) sibutramine 0.11mg/ml
3. observation index
1. weigh every day,, and observe stool and urine and general signs then by the body weight administration.
2. respectively organize rat fasting 12h before putting to death, it is long and calculate Li Shi (Lee) index under etherization to survey body long (from nose to anus) and tail.Put to death animal then.
(Lee) family name's index={ body weight (g) * 103}1/3 ÷ body long (cm)
3. get hematometry blood total cholesterol, triglyceride level, total protein, blood sugar;
Get around the sexual organ fat and weigh, fixing standby with 2.5% formaldehyde ethanol, adipocyte number and size under 400 power microscopes in the full visual field of calculating;
5. core, liver, kidney, sexual organ, and fixing standby with 10% formaldehyde solution, observe and have or not pathological change.
4. statistical treatment is respectively organized equal number average and is represented with x ± S, and does the t check and handle.
Two, The selection result
(1) each medication group is to the influence of obese rat total serum protein, triglyceride level, cholesterol, blood sugar
The result is as shown in table 2, and each medication group total serum protein, blood sugar are compared no obvious statistical significance with model group, blank group; Serum cholesterol, each medication group of triglyceride level are compared variant or significant difference with model group.Illustrate that respectively testing medicine does not have obvious influence to obese rat total serum protein, blood sugar, each tests the concentration that medicine can obviously reduce endomorphy type rat serum inventory cholesterol, triglyceride level, to sibutramine similar effect is arranged.
In addition, compare analysis from each medication group with the sibutramine positive controls, embodiment 2 large and small dosage groups, embodiment 41 heavy dose of groups, embodiment 9 large and small dosage group compound medicine serum triglycerides and the positive group of sibutramine quite point out these compounds to become the more excellent slimming medicine of result of treatment probably.
Can know by inference, two kinds of compounds (embodiment 8 and embodiment 10 compounds) in addition of embodiment 9 place groups have identical active structure with the compound of embodiment 9, therefore have and the same drug activity of embodiment 9 compounds; And further know by inference, blocking group Boc replaces can not having essence to change to pharmaceutical activity with Cbz or Fmoc.
(2) each medication group is to reaching the sexual organ influence of white adipose tissue weight, sexual organ white adipose cell counting (40 * 10 visual field) on every side on every side around obese rat body weight, Lee coefficient, the kidney
The result is as shown in table 3, and model control group is compared with the blank group, white adipose tissue weight around final body weight, Lee coefficient, the kidney and around the sexual organ, reduce sexual organ around white adipose cytometer number average there were significant differences, show that model is successful; Final body weight, Lee coefficient, kidney that embodiment 41 compound medicines, embodiment 9 compound medicines, sibutramine can obviously reduce obese rat reach sexual organ white adipose tissue weight, the white adipose cell counting on every side of minimizing sexual organ on every side on every side, compare variant or significant difference with model group; Embodiment 41 compound medicines, embodiment 9 compound medicines reach sexual organ white adipose tissue weight, the white adipose cell counting on every side of minimizing sexual organ on every side on every side to final body weight, Lee coefficient, the kidney of obese rat, compare indifference with sibutramine, all the other each medication groups are compared all variant or significant difference with the sibutramine group; Compare with the blank group, each medication group all has antiobesity action in various degree.As seen from the above analysis, each is tested medicine and can reduce around the final body weight, Lee coefficient, kidney of obese rat and white adipose tissue weight around the sexual organ, reduce white adipose cell counting around the sexual organ, antiobesity action is in various degree arranged, wherein, similar effect is arranged to sibutramine with embodiment 41 compound medicines, embodiment 9 compound medicine drug effects fruit the best.
(3) white adipose cell around each medication group sexual organ, the change of important organ pathological section
Pathological section photo (picture is more, does not provide one by one for this reason among the present invention, but provides comprehensive text description) is provided, and the white adipose cellular form is normal around the normal control group sexual organ, clear border, and in each 40 * 10 times of visual field, the number of adipocyte is normal.The white adipose cell obviously increases around the model group sexual organ, obscure boundary, and soft edge has the tendency of fusion; In each 40 * 10 times of visual field, the number of adipocyte obviously reduces, and diameter increases, and the adipocyte counting has statistically-significant difference with the normal control group.The white adipose cellular form was between model group and normal control group around sexual organ were respectively organized in medication, wherein, the white adipose cellular form of embodiment 41 compound medicines, embodiment 9 compound medicines is less relatively, adipocyte counting compares with model control group that there were significant differences, and embodiment 9 compound medicines are compared no difference of science of statistics with sibutramine.
Important organ pathological observation result: the normal control treated animal heart, liver, kidney, ovary, testis there is no obvious pathological change; The heavy dose of treated animal heart of medicine of the present invention, liver, kidney, ovary, testis are compared no significant difference with the normal control group, and medicine shown in the demonstration is not seen the vitals infringement except that antiobesity action, point out medicine of the present invention to be expected to alleviate toxic side effect to body.
Three, conclusion
Each medication group has antiobesity action in various degree, and is wherein with compound medicine antiobesity action the best of embodiment 9 place groups and embodiment 41 place groups, similar to sibutramine or more excellent; Model group, the heavy dose of treated animal heart of The compounds of this invention medicine, liver, kidney, ovary, testis are compared with the normal control group, do not see obvious pathological change.
Each medication group of table 2 is to the influence of obese rat total serum protein, triglyceride level, cholesterol, blood sugar
Group Total serum protein (g/l) Serum triglyceride (mmol/l) Serum cholesterol (mmol/l) Blood sugar (mmol/l)
The blank group ??76.34±7.99 ??0.95±0.17 ▲ ??2.71±0.25 ▲ ??4.14±0.50
Model group ??72.26±7.83 ??2.77±0.07 ■★ ??4.04±0.58 ■★ ??4.06±0.55
Embodiment 16 chemical drug heavy doses ??76.53±7.15 ??1.99±0.19 ▲■ ??2.76±0.20 ▲ ??4.29±0.49
Embodiment 16 chemical drug low doses ??75.45±7.11 ??2.21±0.36 ▲■★ ??2.91±0.17 ▲ ??4.06±0.78
Embodiment 22 chemical drug heavy doses ??75.37±7.23 ??1.63±0.27 ▲■ ??3.26±0.39 ▲□ ??4.20±1.35
Embodiment 22 chemical drug low doses ??75.58±5.34 ??2.10±0.32 ▲■ ??3.43±0.41 △■ ??4.02±0.54
Embodiment 12 chemical drug heavy doses ??76.02±5.21 ??1.93±0.62 ▲■ ??2.81±0.24 ▲ ??4.08±0.80
Embodiment 12 chemical drug low doses ??77.66±8.19 ??1.78±0.44 ▲■ ??3.23±0.42 △□ ??3.94±1.16
Embodiment 26 chemical drug heavy doses ??73.90±5.74 ??1.71±0.12 ▲■☆ ??3.09±0.54 ▲ ??3.98±0.44
Embodiment 26 chemical drug low doses ??72.79±11.6 ??2.73±0.58 ▲■★ ??2.68±0.14 ▲ ??4.07±0.54
Embodiment 14 chemical drug heavy doses ??73.39±7.73 ??2.69±0.43 ■★ ??2.64±0.16 ▲ ??4.05±0.70
Embodiment 14 chemical drug low doses ??73.07±7.99 ??1.93±0.09 ▲■☆ ??2.99±0.15 ▲■ ??4.21±0.68
Embodiment 2 chemical drug heavy doses ??73.45±8.72 ??1.42±0.28 ▲■ ??2.86±0.20 ▲ ??4.19±0.60
Embodiment 2 chemical drug low doses ??75.66±10.3 ??1.44±0.03 ▲■ ??3.15±0.38 ▲■ ??3.92±0.60
Embodiment 40 chemical drug heavy doses ??72.30±7.57 ??1.69±0.17 ▲■ ??2.92±0.46 ▲ ??4.16±0.98
Embodiment 40 chemical drug low doses ??75.09±7.23 ??1.95±0.38 ▲■☆ ??2.86±0.30 ▲ ??4.23±0.48
Embodiment 41 chemical drug heavy doses ??76.06±10.0 ??1.57±0.16 ▲■ ??2.60±0.20 ▲ ??4.51±0.65
Embodiment 41 chemical drug low doses ??75.37±6.93 ??1.91±0.12 ▲■☆ ??3.11±0.17 ▲■ ??4.18±1.10
Embodiment 9 chemical drug heavy doses ??74.44±7.21 ??0.88±0.20 ▲ ??2.55±0.20 ▲ ??4.16±0.18
Embodiment 9 chemical drug low doses ??72.34±7.84 ??1.01±0.06 ▲ ??3.01±0.30 ▲□ ??4.19±0.47
Sibutramine ??74.44±8.39 ??1.24±0.31 ▲ ??3.07±0.27 ▲ ??4.36±0.69
△Compare P＜0.05 with model group; ▲Compare P＜0.01 with model group;
Compare P＜0.05 with the blank group; ■Compare P＜0.01 with the blank group;
☆Compare P＜0.05 with the sibutramine group; ★Compare P＜0.01 with the sibutramine group;
Each medication group of table 3 is to reaching the sexual organ influence of white adipose tissue weight, sexual organ white adipose cell counting (40 * 10 visual field) on every side on every side around obese rat body weight, Lee coefficient, the kidney
Group Final body weight (g) The Lee coefficient Reach sexual organ white adipose tissue weight (g) on every side around the kidney Adipocyte counting (40 * 10 visual field)
The blank group ??189±19 ▲★ ??302.70±20.95 ▲★ ??2.21±0.23 ▲☆ ??117.90±13.71 ▲★
Model group ??310±71 ■★ ??336.63±20.17 ■★ ??6.46±2.43 ■☆ ??30.60±6.06 ■★
Embodiment 16 chemical drug heavy doses ??294±67 ■☆ ??307.23±19.87 ▲★ ??4.73±2.04 ■ ??49.70±6.33 ▲■★
Embodiment 16 chemical drug low doses ??282±71 ■ ??309.72±10.15 ▲ ??6.22±3.64 ■ ??46.60±10.74 ▲■☆
Embodiment 22 chemical drug heavy doses ??286±58 ■☆ ??307.09±11.74 ▲★ ??4.44±1.58 △■ ??55.4±7.73 ▲■★
Embodiment 22 chemical drug low doses ??293±64 ■ ??312.05±23.26 △ ??5.32±1.24 ■ ??54.60±10.74 ▲■
Embodiment 12 chemical drug heavy doses ??294±46 ■★ ??309.24±16.08 ▲ ??5.28±3.15 ■ ??48.7±11.66 ▲■
Embodiment 12 chemical drug low doses ??316±81 ■ ??313.57±16.21 △ ??5.62±1.18 ■ ??53.60±9.57 ▲■
Embodiment 26 chemical drug heavy doses ??294±58 ■★ ??310.09±25.66 △★ ??4.82±1.51 ■ ??51.3±9.71 ▲■★
Embodiment 26 chemical drug low doses ??311±74 ■ ??315.22±13.43 △★ ??5.54±2.37 ■ ??52.1±11.97 ▲■
Embodiment 14 chemical drug heavy doses ??294±68 ■☆ ??312.65±14.65 ▲★ ??4.43±1.87 ■ ??48.10±8.39 ▲■★
Embodiment 14 chemical drug low doses ??293±54 ■ ??317.57±13.45 △☆ ??6.62±1.59 ■ ??48.20±8.27 ▲■☆
Embodiment 2 chemical drug heavy doses ??295±62 ■★ ??314.12±14.08 △★ ??4.23±0.81 △■ ??50.02±8.28 ▲■★
Embodiment 2 chemical drug low doses ??292±61 ■ ??310.70±8.23 ▲ ??4.88±1.66 ■ ??48.00±12.43 ▲■
Embodiment 2 chemical drug smaller doses ??295±65 ■ ??315.31±18.92 △ ??5.30±1.86 ■ ??47.10±9.79 ▲■
Embodiment 40 chemical drug heavy doses ??287±56 ■☆ ??318.94±19.49 ★ ??4.83±1.64 ■ ??450.10±9.09 ▲■★
Embodiment 40 chemical drug low doses ??269±51 ■ ??315.68±17.00 △ ??5.05±1.57 ■ ??48.40±10.99 ▲■
Embodiment 41 chemical drug heavy doses ??251±34 △■ ??294.54±15.23 ▲☆ ??4.00±0.66 ▲■ ??59.20±8.43 ▲■★
Embodiment 41 chemical drug low doses ??292±70 ■ ??314.52±12.13 ▲ ??4.89±2.59 ■ ??52.20±6.75 ▲■
Embodiment 9 chemical drug heavy doses ??242±27 △■ ??283.58±17.77 ▲□ ??3.87±2.08 △□ ??68.2±7.93 ▲■
Embodiment 9 chemical drug low doses ??295±64 ■ ??314.44±9.18 ▲☆ ??4.80±1.60 ■ ??54.80±5.45 ▲■
The sibutramine group ??227±37 ▲■ ??276.31±13.72 ▲■ ??3.70±2.19 ▲□ ??72.50±10.19 ▲■
△Compare P＜0.05 with model group; ▲Compare P＜0.01 with model group;
Compare P＜0.05 with the blank group; ■Compare P＜0.01 with the blank group;
☆Compare P＜0.05 with the sibutramine group; ★Compare P＜0.01 with the sibutramine group.
Above description of test the application of The compounds of this invention (comprising racemize, optical isomer and their salt) in pharmacy.Need to prove that in application, in order to reach required biology effect, needed amount depends on multiple factor, the type of for example selected specific compound, desired use, administration and patient's clinical state.Generally speaking, every day dosage in 0.3mg to 100mg scope (usually 3mg to 50mg) every day every kg body weight, for example 3-10mg/kg/ days.Intravenous dosages for example can be in 0.3mg to 1.0mg/kg scope, can be by the mode infusion administration that is fit to, and dosage is the every kg p m of 10ng to 100ng.The infusion solution that is suitable for these purposes for example can contain every milliliter of 0.1ng to 10mg, common 1ng to 10mg.Single dose for example can contain 0.1ng to 10g active compound.Thereby the injection ampoule for example can contain 1mg to 100mg, the single dose preparation of Orally-administrable---for example tablet or capsule---, and for example can contain 1.0 to 1000mg, common 10 to 600mg.Under the situation of pharmacy acceptable salt, above-mentioned quality relates to the quality as the free cpds on salt basis.The compound that is used for prevention of above-mentioned illness or treatment can be according to the compound of formula (I) itself, but they preferably present the form of pharmaceutical composition with acceptable carrier.Certainly carrier must be compatible, that is to say that other compositions of it and described composition are compatible, and is harmless to patient's health.Carrier can be that solid or liquid or the two all are, preferably is mixed with single dose with compound, and for example tablet wherein can contain 0.05 to 95 weight % active compound.Can also there be other pharmaceutically active substances, comprises other compound according to formula (I).Pharmaceutical composition of the present invention can be prepared according to any known method of pharmacy, and these methods comprise in itself mixes acceptable carrier on each composition and the pharmacology and/or auxiliary agent.
Pharmaceutical composition of the present invention is to be suitable for those of oral, rectum, part, per os (for example hypogloeeis) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenously) administration, but optimal administering mode depends on the type of the illness that will treat and seriousness in each single case and the used type of compounds according to formula (I) in each case.Sugar-coated preparation and sugar-coat sustained release preparation are also included within the scope of the invention.Preferred acidproof and resistant to gastric juice preparation.The resistant to gastric juice way layer that is fit to comprises Cellacefate, poly-acetate O-phthalic vinyl acetate, hydroxypropylmethylcellulose phthalate and the anionic polymer of M Cr.
The medicinal compositions that is suitable for oral administration can present independently unit, and for example capsule, cachet, lozenge or tablet contain the compound according to formula (I) of a certain amount in each case; Pulvis or granule; Solution in water-based or non-aqueous liquid or suspension; Perhaps oil-in-water-type or water-in-oil emulsion.As mentioning, described composition can be prepared according to any suitable method of pharmacy, comprises the step that active compound is contacted with carrier (can comprise one or more other components).Generally speaking, composition is like this preparation, with mixing of the solid carrier uniformity of active compound and liquid and/or fine dispersion, then if necessary, makes the product moulding.Thereby for example, tablet can prepare like this, suppresses the powder or the particle of compound (taking the circumstances into consideration and one or more other components) or makes it moulding.Compressed tablet can prepare like this, suppresses the free-flowing form (for example powder or particle) of compound (taking the circumstances into consideration to be mixed with tackiness agent, releasing agent, inert diluent and/or one or more surfactant/dispersant) in suitable machine.Matrix band can prepare like this, uses the moistening powdered compounds moulding of inert liquid diluent in suitable machine.
Be fit to comprise lozenge with the pharmaceutical composition of per os (hypogloeeis) administration, it contains the compound and the correctives of with good grounds formula (I), is generally sucrose and gum arabic or tragacanth gum, and pastille, it comprises compound in inert base, matrix for example is gelatin and glycerine or sucrose and gum arabic.
The pharmaceutical composition that is suitable for administered parenterally preferentially comprises the sterilized water type preparation according to the compound of formula (I), and they are isoosmotic with the expection person's that is subjected to the medicine blood preferentially.These preparations are intravenous administration preferably, but they also can be used as that injection is subcutaneous, intramuscular or intradermal administration.Under preparation can preferably prepare like this, compound is mixed with water, aseptic the closing in blood etc. of gained solution oozed.Injectable composition of the present invention generally contains 0.1 to 5 weight % active compound.
The pharmaceutical composition that is suitable for rectal administration preferentially presents single dose suppository.They can prepare like this, will mix according to the compound of formula (I) and one or more conventional solid carriers theobroma oil for example, make the gained mixture forming.
The pharmaceutical composition that is suitable for the local skin medication preferably presents ointment, creme, lotion, paste, sprays, aerosol or finish.Operable carrier is the combination of Vaseline, lanolin, polyoxyethylene glycol, alcohols and two or more these materials.Generally speaking, the concentration of active compound accounts for 0.1 to 15% of composition weight, and for example 0.5 to 2%.
Transdermal administration also is possible.The pharmaceutical composition that is suitable for transdermal administration can present single patch, and they are fit to closely contact for a long time with patient's epidermis.This class patch is fit to contain the optional aqueous solution that is cushioned of active compound, compound dissolution and/or be dispersed in the tackiness agent or be dispersed in the polymkeric substance.The active compound that is fit to can be released by electrical operation or iontophoresis, Pharmaceutical Research for example, and 2 (6): 318 (1986) is described.
Compound of the present invention is because of remarkable to the beneficial effect of lipid metabolism, and they are particularly suitable for keeping behind Mammals loss of weight and the loss of weight weight that reduced and as anoretics.Compound is remarkable because of their hypotoxicity and less side effect.Can adopt independent compound or with other losss of weight or subtract the combination of appetite active compound.
The appetite active compound that subtracts that this type is other is for example stated in Roten Liste the 01st chapter loss of weight agent/appetite-inhibiting agent, can also comprise such active compound, they increase biological energy transformation, thereby cause the minimizing of weight, perhaps such compound, they influence the general metabolism of described biology, and consequently the calorie intake that is increased can not cause the expansion of described biological fat depot, and normal calorie intake causes the minimizing of fat depot.This compound is suitable for overweight or fat prevention, particularly treatment.This compound is suitable for type ii diabetes, arteriosclerotic prevention in addition, and particularly treatment is suitable for the normalizing and the hypertensive treatment of lipid metabolism.Compound serves as the MCH antagonist, and also being suitable for sensory disturbance and other psychosis indications must treat, for example depression, anxiety neurosis, schizophrenia, and the treatment of the treatment of the obstacle relevant with diel rhythm and drug abuse.
On the other hand, compound of the present invention can be united the formation compound medicines with one or more other pharmacological active substances, the latter for example can be selected from by antidiabetic, the agent of lipotropism fat, blood pressure reduce active compound, lipid lowering agent and by diabetes caused or with the group that active compound is formed that treats and/or prevents of diabetes complications associated with arterial system.
The antidiabetic that is fit to comprises Regular Insulin, amylin, GLP-1 and GLP-2 derivative, for example is disclosed among the WO98/08871 those and oral hypoglycemic activity compound by Novo NordiskA/S.
Described oral hypoglycemic activity compound preferentially comprises sulfonylurea, biguanides, meglitinide oxadiazole alkane diketone, thiazolidinedione, the heteroside enzyme inhibitors, the glucagon receptor antagonist, the GLP-1 agonist, potassium channel openers (for example being disclosed among WO 97/26265 and the WO 99/03861 those) by Novo Nordisk A/S, Regular Insulin is to quick dose, the insulin receptor kinase activator, the inhibitor (for example glycogen phosphorylase inhibitor) of the liver enzyme that involved in sugar heteroplasia and/or glycogenolysis stimulate, glucose uptake and glucose excretory modulator, change the compound (for example hyperlipidemia active compound and hyperlipemia active compound, for example HMGCoA reductase inhibitor) of lipid metabolism, cholesterol running/cholesterol uptake inhibitor, cholic acid cell reabsorption inhibitor or microsomal triglyceride transfer protein (MTP) inhibitor, reduce the compound of nutrition agent picked-up, PPAR and rxr agonist and the active compound that acts on β cell ATP dependency potassium channel.
A kind of embodiment of the present invention is that The compounds of this invention and Regular Insulin share with Combined Preparation.
In another embodiment, The compounds of this invention is composite in order to Combined Preparation with sulfonylurea, and for example tolbutamide, Glyburide, lattice row do not have urea, Glipizide, gliquidone, glisoxepide, glibornuride or gliclazide.
In another embodiment, The compounds of this invention and biguanides are composite in order to Combined Preparation, for example N1,N1-Dimethylbiguanide.
In another embodiment, The compounds of this invention is composite in order to Combined Preparation with meglitinide, and for example auspicious all kinds of row how.
In another embodiment, The compounds of this invention is composite in order to Combined Preparation with thiazolidinedione, for example troglitazone, ciglitazone, pioglitazone, rosiglitazone (rosiglitazone) or be disclosed in compound among the WO 97/41097 by Dr.Reddy ' s ResearchFoundation, 5-[[4-[(3 particularly, 4-dihydro-3-methyl-4-oxo-2-quinazolyl methoxyl group) phenyl] methyl]-2, the 4-thiazolidinedione.
In another embodiment, The compounds of this invention is composite in order to Combined Preparation with alpha-glucosidase inhibitor, for example miglitol or acarbose.
In another embodiment, The compounds of this invention is composite in order to Combined Preparation with the active compound that acts on β cell ATP dependency potassium channel, tolbutamide for example, Glyburide, glimepiride, Glipizide, gliclazide or repaglinide.
In another embodiment, The compounds of this invention is composite in order to Combined Preparation with lipidemia active compound or hyperlipemia active compound, and for example Colestyramine, colestipol, chlorine Bei Te, luxuriant and rich with fragrance nobert, lucky luxuriant and rich with fragrance Betsy, lovastatin, Pravastatin, Simvastatin, holder are cut down his spit of fland (atorvastatin), simvastatin (cerivastatin), chlorine and cut down his spit of fland, probucol, ezetimibe or dextrothyroxine.
In another embodiment, a kind of compound is composite with Combined Preparation with more than one above-mentioned other drug compounds among the present invention, for example sulfonylurea and N1,N1-Dimethylbiguanide, sulfonylurea and acarbose, repaglinide and N1,N1-Dimethylbiguanide, Regular Insulin and sulfonylurea, Regular Insulin and N1,N1-Dimethylbiguanide, Regular Insulin and troglitazone, Regular Insulin and lovastatin etc.
In addition, The compounds of this invention can be composite with Combined Preparation with one or more lipotropism fat agent or appetite control active compound.This class active compound can be selected from the agonist by CART; the NPY antagonist; the MC4 agonist; aricine (Oxexin) antagonist; the H3 agonist; the TNF agonist; the CRF agonist; CRF BP antagonist; urine cortin (urocotin) agonist; β 3 agonists; MSH (black cell stimulation hormone) agonist; the CCK agonist; serotonin reuptake inhibitors; mixed type thrombotonin and NRI; the 5HT modulator; the MAO inhibitor; the plain agonist of Han Wa skin; the galanin antagonist; tethelin; growth hormone releasing compounds; the TRH agonist; uncoupling protein 2 or 3 modulators; RMETHU LEPTIN (Leptin) agonist; dopamine agonist (bromocriptine; Doprexin); esterase/amylase inhibitor; Cannabined receptor 1 antagonist; acidylate stimulatory protein(SP) (ASP) modulator; the PPAR modulator; the RXR modulator; the group that hCNTF stand-in or TR-beta-agonists are formed.
In one embodiment of the invention, the agent of lipotropism fat is RMETHU LEPTIN or modification RMETHU LEPTIN.
In another embodiment, the agent of lipotropism fat is Dextroamphetamine or amphetamine.
In another embodiment, the agent of lipotropism fat is Phenfluoramine or Isomeride.
In another embodiment, the agent of lipotropism fat be sibutramine or sibutramine list-with two-demethylation active metabolite.
In another embodiment, the agent of lipotropism fat is an orlistat.
In another embodiment, the agent of lipotropism fat is Mazindol, Diethylpropion or phentermine.
In addition, The compounds of this invention can with one or more antihypertensive active compound Combined Preparation.The example of anti-high blood medicine active compound has beta-blocker, alprenolol for example, atenolol USP 23, timolol, pindolol, Proprasylyte and Mei Tuogeer, ACE (angiotensin-converting enzyme) inhibitor, for example benazepril, captopril, enalapril, fosinopril, Lenno Puli and Ramipril, calcium channel blocker, for example nifedipine, felodipine, nicardipine, Isrodipine, nimodipine, Odizem and verapamil, and alpha blocker, Doxazosin for example, urapidil, Prazosin and terazosin.In addition, can be with reference to Remington:The Science andPractice of Pharmacy, 19th edition, Gennaro, editor, Mack Publishing Co., Easton, PA, Combined Preparation is carried out in 1995 introduction.
Self-evident, steric isomer compound of the present invention and one or more above-claimed cpds and choose any one kind of them or every kind of suitable combination of multiple other pharmacological active substance also all should be considered as being covered by protection domain of the present invention.

Claims (10)

1, aryl cyclobutyl compound comprises the compound shown in the formula (I), its Stereoisomeric compounds, compound crystal and compound pharmacy acceptable salt:
Wherein,
X is H, halogen, CF 3, C 1-3A kind of in alkyl, alkoxyl group, alkylthio and the phenyl;
R 1Be H or for C 1～C 4The straight or branched alkyl;
R 3Can be H, formyl radical, ethanoyl, halo ethanoyl, benzoyl, carbobenzoxy-(Cbz) (Cbz), tertbutyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc) or and R 2With-HN-form 3-7 unit ring (this ring can be saturated also can be undersaturated, also may be by one or more halogen, hydroxyl, C 1-4Alkyl, C 1-4Alkoxyl group replaces);
Work as R 3When being H, formyl radical, ethanoyl, halo ethanoyl, benzoyl, carbobenzoxy-(Cbz), tertbutyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl, R 2Be following radicals: C 1-12Alkyl, benzyl, substituted benzyl or R 4(CH 2) n-(wherein: n=1-4; R 4Can be that hydroxyl, amino, sulfydryl, sulfenyl, hydrocarbon are for sulfenyl, carboxylic acid group, amide group, urea groups, pyridyl, thienyl, furyl, imidazolyl or indyl), R 5R 6(CH)-(R 5Can be C 1-12Alkyl; R 6Can be hydroxyl, amino, sulfydryl) and R 3With-HN-formation 3-7 unit ring; R 2Be preferably methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, sec-butyl, isobutyl-, benzyl, halogen atom substituted benzyl, alkyl substituted benzyl base, alkoxyl group substituted benzyl, hydroxyl substituted benzyl, R 4(CH 2) n-(wherein: if n=1-2, then R 4Be hydroxyl, amino, sulfydryl, methylthio group, ethylmercapto group, rosickyite base, iprotiazem base, butylthio, uncle's butylthio, isobutyl sulfenyl, carboxylic acid group, amide group, urea groups, pyridyl, thienyl, furyl, imidazolyl, indyl, sulfenyl; If n=3-4, then R 4Be amino, carboxylic acid group, amide group, urea groups) or R 5R 6(CH)-(R 5Be methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, isobutyl-; R 6Can be hydroxyl, amino, sulfydryl).
2, according to the described aryl cyclobutyl compound of claim 1, it is characterized in that described X is a halogen, preferably the chlorine in the phenyl ring contraposition.
3, according to claim 1 or 2 described aryl cyclobutyl compounds, it is characterized in that R 1It is isobutyl-.
4, according to claim 1 or 2 or 3 described aryl cyclobutyl compounds, it is characterized in that R 3Be preferably H, carbobenzoxy-(Cbz) (Cbz), tertbutyloxycarbonyl (Boc) or 9-fluorenylmethyloxycarbonyl (Fmoc).
5, according to claim 1 or 2 or 3 described aryl cyclobutyl compounds, it is characterized in that R 3Be preferably and R 2Five yuan of saturated N heterocycle alkane or 4 hydroxyls of forming with-HN-replace C 1～C 3Alkyl.
6, according to the described aryl cyclobutyl compound of claim 4, it is characterized in that R 2Be preferably methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, sec-butyl, isobutyl-, benzyl, halogen atom substituted benzyl, alkyl substituted benzyl base, alkoxyl group substituted benzyl, hydroxyl substituted benzyl, R 4(CH 2) n-(wherein: if n=1-2, then R 4Be hydroxyl, amino, sulfydryl, methylthio group, ethylmercapto group, rosickyite base, iprotiazem base, butylthio, uncle's butylthio, isobutyl sulfenyl, carboxylic acid group, amide group, urea groups, pyridyl, thienyl, furyl, imidazolyl, indyl, sulfenyl; If n=3-4, then R 4Be amino, carboxylic acid group, amide group, urea groups) or R 5R 6(CH)-(R 5Be methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, isobutyl-; R 6Can be hydroxyl, amino, sulfydryl).
7, according to the described aryl cyclobutyl compound of claim 4, it is characterized in that R 2Most preferably be H, C 2-4Alkyl, R 4(CH 2) n-(wherein: n=1-4; R 4Be hydroxyl, sulfydryl, sulfenyl, carboxylic acid group, amide group, urea groups, imidazolyl).
8, according to the described aryl cyclobutyl compound of claim 5, it is characterized in that R 2Be and R 3Five yuan of saturated N heterocycle alkane or 4 hydroxyls of forming with-HN-replace C 1～C 3Alkyl.
According to the described aryl cyclobutyl compound of claim 1, it is characterized in that 9, X is the chlorine in the phenyl ring contraposition, R 1Be isobutyl-, R 3Be H, Cbz, Boc or Fmoc, R 2It is sec.-propyl; Or X is the chlorine in the phenyl ring contraposition, R 1Be isobutyl-, R 3With NH and R 2Form pyrrole ring.
10, the arbitrary described aryl cyclobutyl compound of claim 1 to 9 is in the application of preparation in the slimming medicine, and slimming medicine comprises that with single or complex chemical compound be the pharmaceutical preparation that the compound medicine that combines of medicine, compound and the other medicines of activeconstituents or compound and excipient substance combine.
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