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

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 application thereof in preparation of weight-losing medicine

Technical Field

The invention belongs to the field of medicines, and particularly relates to a novel aryl-containing cyclobutyl compound and pharmaceutically acceptable salts thereof. The invention also relates to a preparation method of the compound and the salt thereof, and application of the compound and the salt thereof in preparing medicaments for preventing and treating obesity.

Background

Due to the rapid development of science, improvement of material living conditions and unreasonable dietary structure, obesity has become an increasingly serious problem. The united states Federation of obesity has recognized obesity as a "global infectious disease" and is rising at a "startling rate". Estimated by the world health organization, more than 10 billion adults are overweight today, and at least 3 billion people are obese worldwide. The disease is not limited to developed industrial countries, but the rate of increase in the number of obese people is also dramatically increasing in developing countries. In the 11 th european obesity academic conference, china was first placed on a leaderboard of the incidence of obesity in the world. Obesity, AIDS, drug addiction to drugs and wine addiction are the four major medical social problems in the world, are the large enemies of human health and longevity, and can also induce or aggravate the morbidity of certain common chronic diseases, especially diabetes, cardiovascular and cerebrovascular system diseases, sleep apnea syndrome and the like. It is statistical that approximately 28-32.5 million people die of obesity and its complications in the United states each year over the last 10-20 years. In recent years, with the improvement of self-health care consciousness, weight reduction attracts more and more attention. People can lose weight through various ways, such as regular exercise, and are matched with healthy and balanced diet. However, these methods generally fail to achieve long-term results, and therefore weight-loss drugs are becoming more and more popular. Therefore, from the scientific research point of view, the research of safe and effective anti-obesity drugs has great social and economic benefits.

Sibutramine hydrochloride (Sibutramine hydrochloride) is a chemical synthetic drug with the efficacy of losing weight, and the chemical name of the Sibutramine hydrochloride is N- {1- [1- (4-chlorphenyl) cyclobutyl ] -3-methylbutyl } -N, N-dimethylamine hydrochloride monohydrate (with a chiral center). It was developed by Knoll of BASF corporation, Germany, as a 5-hydroxytryptamine and norepinephrine reuptake inhibitor. Sibutramine hydrochloride (Sibutramine hydrochloride) was approved by FDA as a weight-loss drug in 11 months 1997, marketed in the united states in 2 months 1998 under the trade name Meridia, sold in the year of $ 1.94 million, sold in 1999 in over $ 3 million, currently sold in more than 20 countries in europe and america, became the mainstream product in the europe and america weight-loss market, and thus became the BASF fourth largest product in germany. In 5 months of 2000, the drug is approved by the national drug administration (SDA) to be marketed in China and has the trade name of Qumei. Currently, 300 million people take sibutramine globally.

Sibutramine is a 5-hydroxytryptamine and norepinephrine reuptake inhibitor in vivo (Buckett, w.r., Thomas, P.C.&Luscombe, G.P (1988) neuropsychopharmacology-biology-psychiatric synopsis (prog. neuropsychopharmacol. biol. Psychiat)12575-.&Buckett, W.R, (1989) Neuropharmacology28,129-134). The study demonstrated that the compound lost body weight through a two-way effect; it can reduce food intake by increasing satiety (Fantino, M.&Souquet, a. -M. (1995) journal of international obesity (int.j. obecity)19，145；Halford，J.C.G.，Heal，D.J.&Blundell, J.E. (1995) J.England Pharmacol (Brit.J.Pharmacol)114387P; and Stricker-Krongrad, a., Souquet, a. -M.&Burlet, C. (1995) journal of International obesity (int.J. Obesity)19145) and it increases energy expenditure by stimulating thermogenesis (Connoley, i.p., Heal, D.J.&Stocl, M.J. (1995) British journal of pharmacology (Brit.J.Pharmacol)114388P; and Connoley, i.p., Frost, i.heal, d.j.&Stocl, M.J. (1996) J.Pharmacol, Brit.J.117170P). In addition, sibutramine can lower waist/hip ratio, reduce triglyceride, total cholesterol, and low density lipoprotein (LDL-ch), and increase high density lipoprotein (HDL-ch) (Li Zuifu, etc. [ J ]]Journal of chinese endocrine metabolism, 2002, 18 (3): 204-; wujian et al [ J]Journal of liberty military medicine, 2002, 27 (2): 172-176; and [ J]Journal of chinese endocrine metabolism, 2001, 18 (3): 201-202).

The prior art further discloses that sibutramine for treating obesity [ (10-30) mg/d ] can reduce 5-10% of basic body weight and can better maintain the basic body weight. The medicine has unobvious sedative, exciting and sympathomimetic effects, and good tolerance, and has common adverse effects of dry mouth, headache, anorexia, constipation, and insomnia. However, sibutramine cannot be used for patients with coronary artery disease, congestive heart failure, arrhythmia, stroke and severe impaired liver function, is forbidden for patients with hypertension and anorexia nervosa, who cannot control blood pressure, and is used with caution for patients with a history of hypertension, narrow-angle glaucoma and seizure.

The prior art also discloses that sibutramine and its demethylated compounds are effective in the treatment of neuropsychiatric disorders including obesity, insomnia, fatigue, depression, and the like; metabolic diseases; and cardiovascular diseases. For sibutramine, its optical isomers and demethylated compounds, PCT/US2000/007202 discloses that it reduces weight gain after pregnancy; PCT/US2000/007255 discloses that it reduces platelet adhesion; PCT/US2000/007122 discloses its use in the treatment of chronic fatigue; PCT/US2000/007123 discloses its therapeutic effect on metabolic syndrome; PCT/US2000/007361 discloses its treatment of obesity-related tumors; PCT/US2000/007124 discloses its use in the treatment of pulmonary hypertension; PCT/US2000/007177 discloses the treatment of sleep syndrome; PCT/US2000/001217 discloses its smoking cessation effect; US 6046242 discloses its effect in treating urinary incontinence. The prior art also discloses methods for large scale resolution of sibutramine (Tetra Asymm 2003; 14 (25): 3553-6). Further modification work was also done on sibutramine by researchers in the field of chemical synthesis. For example, methods for the asymmetric synthesis of R-sibutramine (Organic process research and development, 2006; 10 (2): 327) 333); a method for demethylation of sibutramine (US 6399826); a method for asymmetric synthesis of demethyl R-sibutramine (Tetra Lett; 2002; 43 (13): 2331-3). In the literature j.chem.soc.perkin trans.1; EN; 21; 1996; 2583-2590, modification of methyl, amino and cyclobutyl in the molecule of sibutramine demethyl compound, and preparation of pure optical isomers of the above derivatives were investigated. The following are several specific structural formulas of sibutramine derivatives:

in org.lett.; EN; 7; 13; 2005; 2599 in 2602, methyl and amino groups in the molecular structure of the sibutramine demethyl compound are modified, and the optical isomers of the derivatives are resolved, wherein the specific structural formula of the optical isomers of the derivatives is as follows:

although the sibutramine derivatives disclosed in the literature have many variations, only preliminary studies on the chemical form variations have been conducted, and further confirmation is needed whether they have the effect of reducing weight similar to that of sibutramine and can reduce the adverse reactions of sibutramine. Therefore, it is necessary to obtain sibutramine derivatives which can confirm the pharmaceutical activity and reduce the toxicity of the drugs.

Disclosure of Invention

The invention aims to provide a group of novel derivatives of sibutramine, which improve the physicochemical properties of active ingredients by multiple modification of the amino group of sibutramine on the premise of achieving the prior pharmaceutical activity so as to reduce the toxic and side effects of the sibutramine as a weight-losing medicament.

The invention provides a derivative which is a compound shown as a formula (I), and also comprises an enantiomer or diastereomer mixture, a racemic mixture and a pharmaceutically acceptable salt of the compound and the mixture:

wherein:

x is H, halogen, CF₃、C_1-3One of alkyl, alkoxy, thioalkyl and phenyl; preferably halogen, more preferably chlorine in the para position of the phenyl ring.

R₁Is H or is C₁～C₄Preferably isobutyl.

R₃Can be H, formyl, acetyl, haloacetyl, benzoyl, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), or with R₂and-HN-forming a 3-7 membered ring (which ring may be saturated or unsaturated, and may be substituted by one or more halogens, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy substituted); r₃Preferably H, formyl, acetyl, haloacetyl, benzoyl, benzyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), or with R₂and-HN-forms a 3-7 membered ring structure (the ring may be saturated or unsaturated, and the ring may be substituted with chloro, hydroxy, methyl, ethyl, propyl, isopropyl, butyl); r₃More preferably H, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc) or with R₂and-HN-forming five-membered saturated N-heterocyclic alkanes or 4-hydroxy substituted C_1-3An alkyl group.

When R is₃When R is H, formyl, acetyl, haloacetyl, benzoyl, benzyloxycarbonyl, tert-butoxycarbonyl (Boc), or 9-fluorenylmethoxycarbonyl₂The following groups may be mentioned: c_1-12Alkyl, benzyl, substituted benzyl, or R₄(CH₂)_n- (wherein: n ═ 1-4; R₄Can be hydroxyl, amino, mercapto, alkylthio, carboxylic acid, amide, ureido, pyridyl, thienyl, furyl, imidazolyl or indolyl), R₅R₆(CH)-(R₅May be C_1-12An alkyl group; r₆May be hydroxy, amino, mercapto), and R₃and-HN-forms a 3-7 membered ring; r₂Preferably methyl, ethyl, propyl,Isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, benzyl, halogen substituted benzyl, alkyl substituted benzyl, alkoxy substituted benzyl, hydroxy substituted benzyl, R₄(CH₂)_n- (wherein, if n is 1-2, then R₄Hydroxyl, amino, sulfydryl, methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, isobutylthio, carboxylic acid group, amide group, carbamido group, pyridyl, thienyl, furyl, imidazolyl, indolyl and hydrocarbon thio; if n is 3-4, R₄Is amino, carboxylic acid, amide, ureido), or R₅R₆(CH)-(R₅Is methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl or isobutyl; r₆Can be hydroxyl, amino, sulfhydryl); r₂Most preferably H, C_2-4Alkyl radical, R₄(CH₂)_n- (wherein: n ═ 1-4; R₄Is a hydroxyl group, a mercapto group, a hydrocarbon thio group, a carboxylic acid group, an amide group, an urea group, an imidazole group).

More preferably, when R is₃When is H, R₂More preferred are methyl, isopropyl, isobutyl, sec-butyl, benzyl, methylthioethyl, hydroxymethyl, R₄(CH₂)_nWhen n is 1, R₄Hydroxyl, sulfydryl, carboxylic acid group, amido, imidazolyl, p-hydroxyphenyl and indolyl; when n is 2, R₄Is methyl sulfide, carboxylic acid group and amide group; when n is 3, R₄Is a ureido group; when n is 4, R₄Is amino), R₅R₆(CH)-(R₅Is methyl, R₆Is a hydroxyl group).

In a particularly preferred embodiment, X is chloro at the para position of the phenyl ring; r₁Is an isobutyl group; r₃Is H, Cbz, Boc, or Fmoc; r₂Is isopropyl. This group of compounds is based on the compound of example 9 and the third group of compounds related thereto, further comprising compounds based on the compound of example 9 with Cbz or Fmoc instead of Boc protecting group.

In another particularly preferred embodiment, X is chloro at the para position of the phenyl ring; r₁Is an isobutyl group; r₃With NH and R₂Forming a pyrrole ring. This group of compounds is based on the compound of example 41 and the eighteenth group of compounds related thereto, or salts of these compounds.

The term "alkyl" in the present invention includes straight-chain and branched alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl and hexyl; the term "halogen" includes fluorine, chlorine, bromine and iodine.

It will be appreciated by those skilled in the art that the compounds of formula (I) contain at least 1 chiral centre. When the compound of formula (I) contains two chiral centers, it may exist in 4 enantiomeric forms. The pure optical isomers, enantiomeric mixtures, diastereomeric mixtures, racemic mixtures of the structures shown in formula (I), and the above compounds, mixtures and pharmaceutically acceptable salts thereof are all within the scope of the invention.

The invention adopts an obese rat model, takes sibutramine as a reference substance, observes the weight-losing effect of a test drug and the reference drug on the obese rat model, and carries out biochemical determination on blood fat and blood and pathological detection on important organs such as heart, liver, kidney and the like on a tested animal. The results prove that each experimental medicine contained in the formula (I) has the weight-losing effect of different degrees on obese model rats, can obviously reduce the final weight, the Lee coefficient, the weight of white adipose tissues around the kidney and the genitals and the white adipose cell count around the genitals of the obese model rats, and has the similar weight-losing effect with sibutramine; the experimental medicines have obvious reducing effect on serum cholesterol and triglyceride, but have no obvious influence on serum total protein and blood sugar of experimental animals, and have no obvious pathological damage to important tissues and organs. The compounds of the present invention are therefore suitable for the prevention and treatment of obesity and its related disorders.

The present invention provides the use of compounds of formula (I), including the pure enantiomers thereof, racemic mixtures thereof, diastereomeric mixtures thereof and pharmaceutically-acceptable salts thereof, in medicaments for the treatment of obesity and related disorders. The 'associated condition' refers to a medical condition known to those skilled in the art to be associated with obesity. The term includes, but is not limited to, the following diseases: hypertension; coronary thrombosis; stroke; depression; anxiety; psychosis (e.g., schizophrenia); tardive dyskinesia; drug addiction; drug abuse; cognitive disorders; alzheimer's disease; cerebral ischemia; dementia; parkinson's syndrome; amnesic syndrome; obsessive compulsive disorder; a panic attack; social phobia, eating disorders; lipid syndrome; hyperglycemia; hyperlipidemia; and stress responses in mammals, particularly humans.

Detailed Description

The compounds of the present invention can be achieved according to the following methods and procedures.

First, with reference to the method described in patent GB2098602A or elsewhere, a starting compound of formula (II) is prepared (see example 1) which contains a chiral centre, which can be resolved by a person skilled in the art by known methods, for example by formation of separable diastereomeric salts or complex crystals; formation of diastereomeric derivatives which can be separated, for example, by crystallization, gas-liquid chromatography or liquid chromatography; subjecting one enantiomer to a selective reaction, such as enzymatic oxidation or reduction, with an enantiomer-specific reagent, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, e.g., on a chiral support (e.g., silica gel with bound chiral ligand) or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted to another chemical entity by one of the separation methods described above, an additional step of releasing the desired enantiomeric form may be required.

R in the starting Compound represented by the formula (II)₁Is H or C_1-4An alkyl group; x is independently H, halogen, CF₃、C_1-3Alkyl, alkoxy, thioalkyl or phenyl.

After preparing the optical isomers of the starting compounds of formula (II), those skilled in the art can prepare the compounds of formula (I) of the present invention using the following two schemes.

The first scheme is as follows:

in this embodiment, R in the starting compound represented by the formula (III)₃Is H, formyl, acetyl, haloacetyl, benzoyl, carbobenzoxy (Cbz), tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc); r₂Is methyl, isopropyl, isobutyl, sec-butyl, benzyl, methylthioethyl, hydroxymethyl or is R₄(CH₂)_nWhen n is 1, R₄Hydroxyl, sulfydryl, carboxylic acid group, amido, imidazolyl, p-hydroxyphenyl and indolyl; when n is 2, R₄Is methyl sulfide, carboxylic acid group and amide group; when n is 3, R₄Is a ureido group; when n is 4, R₄Is an amino group), or is R₅R₆(CH)-(R₅Is methyl, R₆Is a hydroxyl group).

The optical isomer of the compound represented by the formula (I) of the present invention is produced by condensation reaction of the raw material compound represented by the formula (III) with a certain optical isomer, enantiomer, diastereomer, racemic mixture of the raw material compound represented by the formula (II).

Scheme II:

the rest is the same as scheme one except that R₃And R₂and-HN-forming a 3-7 membered ring (which ring may be saturated or unsaturated, and may be substituted by one or more halogens, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy substituted), R₂And R₃and-HN-forms a 3-7 membered ring. R₃And R₂and-HN-form a ring the compound of formula (I) has the following specific structure:

where n is 0-4, R₇Is one or more halogens, hydroxy, C_1-4Alkyl radical, C_1-4An alkoxy group.

As in the two schemes above, the preparation of the compound of formula (I) according to the invention involves a one-step condensation reaction, and the preparation of the compound can be carried out by a person skilled in the art by known methods using a condensing agent. The condensation reaction can be carried out, for example, by 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, etc.

The following specific examples are included to illustrate the invention by way of preparation of several groups of compounds and are not to be construed as limiting the disclosure. The reagents and intermediates used in the examples are either commercially available or can be readily prepared by those skilled in the art of organic synthesis according to standard literature procedures. Other methods of preparing the compounds of the present invention will be known to those skilled in the art.

Starting compound

Example 1: preparation of 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine and its optical isomer

1. Preparation of racemic 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine

According to the method of the reference literature (Chinese medicine industry journal, 2001; 32 (8): 337-9), p-chlorobenzonitrile and 1, 3-dibromopropane firstly carry out cyclization reaction to prepare a cyclobutyl intermediate, and the cyclobutyl intermediate is prepared by Grignard reaction and reduction reaction. The yield thereof was found to be 56.2%.

2. Splitting example: after 20.3g of racemic 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine prepared in step 1 was dissolved in 300ml of a mixed solution of acetone/water/methanol (volume ratio: 1: 0.13: 0.7), 12.1g of L (+) -tartaric acid was added and refluxed for 0.5 hour, and then cooled naturally, allowed to stand at room temperature for 2 to 4 days to cause crystal formation, filtered, washed with cold acetone/water (100ml/13ml), and dried to obtain 10.3g of a sample with a yield of 33%.

25g of the crystal product is taken, added with acetonitrile/water/ethanol 300ml/65ml/30ml and refluxed for 1 hour, cooled to room temperature and filtered to obtain 18g of white crystal product with the yield of 72 percent. Obtaining free alkali after alkali treatment. The optical purity was 99.7%. The product is (S) -1- [1- (4-chlorphenyl) cyclobutyl ] -3-methylbutylamine.

The mother liquor was resolved with D- (-) -tartaric acid as described above to give the other optical isomer in 75.2% yield. Obtaining free alkali after alkali treatment. The optical purity of the (R) -1- [1- (4-chlorphenyl) cyclobutyl ] -3-methylbutylamine is 99.4%.

Using chiral column (chiral column is ULTRON ES-OVM (150mmx4.6mm), mobile phase is 0.01MKH₂PO₄/CH₃The chiral purity of the optical isomers is measured by OH (70: 30) and the ultraviolet detection wavelength is 200nm, and the results show that the optical purity of the compounds is more than 99.0 percent.

First group

Example 2: preparation of 2- (Boc protected amino) -N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } acetamide and its isomers

250mg of the unresolved 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine obtained in example 1 and 210mg of N- (tert-butoxycarbonyl) -2-aminoacetic acid were taken and dissolved in 3ml of anhydrous THF. Then, 220mg of DCC was weighed out and dissolved in 25ml of anhydrous THF. A THF solution of DCC was added dropwise to the reaction solution. After the dropwise addition, the reaction was stirred at room temperature overnight, and a large amount of white precipitate was formed. The precipitate was filtered off and washed repeatedly with anhydrous ether for more than 3 times. Collecting the filtrate and ether used for washing the precipitate, spin-drying to obtain a crude product, and then separating and purifying by using a column chromatography method to obtain 2- (Boc protected amino) -N- {1- [1- (4-chlorphenyl) cyclobutyl ] -3-methylbutyl } acetamide.

The same reaction and treatment procedure as described above using resolved 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine gave two optical isomers of 2- (Boc protected amino) -N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } acetamide.

Example 3: preparation of 2-amino-N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } acetamide and its isomers

The product obtained in example 2, 2- (Boc protected amino) -N- {1- [1- (4-chlorophenyl) cyclobutyl]Addition of 3-methylbutyl } acetamide or an optical isomer thereof to CF₃COOH was dissolved in the solution. The solution was stirred at room temperature for one hour and the CF was removed₃COOH, a white turbidity was formed. It was dissolved in anhydrous ether and washed repeatedly with saturated sodium bicarbonate solution until the washed liquid became neutral. The ether solution was then washed 2 to 3 times with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Filtering to remove desiccant, evaporating under reduced pressure to remove solvent, separating and purifying the obtained crude product by column chromatography to obtain 2- (amino) -N- {1- [1- (4-chlorphenyl) cyclobutyl]-3-methylbutyl } acetamide or an optical isomer thereof.

Example 4: preparation of 2-amino-N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } acetamide hydrochloride:

the product 2- (amino) -N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } acetamide from example 3 is dissolved in a little absolute diethyl ether, diethyl hydrochloride is added and a large amount of white precipitated crystals, i.e. 2- (amino) -N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } acetamide hydrochloride, is formed.

Second group

Example 5: preparation of 2- (Boc-protected amino) -N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } propanamide and its isomers

This compound was prepared by the method of example 2 by reacting unresolved or resolved 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine with N- (tert-butoxycarbonyl) -2-amino-propionic acid to give the product.

Example 6: preparation of 2-amino-N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } propionamide and its isomers

The compound obtained in example 5 was reacted in CF by the method of example 3₃And removing the protecting group on the amino group in COOH to obtain the product.

Example 7: preparation of 2-amino-N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } propionamide hydrochloride

This salt was prepared as in example 4, to give the product.

Third group

Example 8: preparation of 2- (Boc protected amino) -N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3-methylbutyl-butanamide

This compound was prepared as in example 2 by reacting unresolved or resolved 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine with N- (tert-butoxycarbonyl) -2-amino-3-methylbutyric acid to give the product.

Example 9: preparation of 2-amino-N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3-methylbutyl-butanamide

The compound obtained in example 8 was reacted in CF as in example 3₃And removing the protecting group on the amino group in COOH to obtain the product. Molecular weight is 348.91 (C)₂₀H₂₉ClN₂O)；MS(ESI)：350(M+H⁺)。

Example 10: preparation of 2-amino-N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3-methylbutyl-butanamide hydrochloride

This salt was prepared as in example 4, to give the product.

Fourth group

Example 11: preparation of 2- (Boc protected amino) -N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -4-methylpentanamide

This compound was prepared by the method of example 2 by reacting unresolved or resolved 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine with N- (tert-butoxycarbonyl) -2-amino-4-methylpentanoic acid to give the product.

Example 12: preparation of 2-amino-N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -4-methylpentanamide

The compound obtained in example 11 was reacted in CF as in example 3₃And removing the protecting group on the amino group in COOH to obtain the product.

Example 13: preparation of 2- (Boc protected amino) -N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3-methylpentanamide

The product was obtained by reacting unresolved or resolved 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine with N- (tert-butoxycarbonyl) -2-amino-3-methylpentanoic acid as in example 2.

Example 14: preparation of 2-amino-N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3-methylpentanamide

The compound obtained in example 13 was reacted in CF as in example 3₃And removing the protecting group on the amino group in COOH to obtain the product.

Fifth group

Example 15: preparation of 2- (Boc protected amino) N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3-phenylpropanamide

This compound was prepared by the method of example 2 by reacting unresolved or resolved 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine with N- (tert-butoxycarbonyl) -2-amino-3-phenylpropionic acid to give the product.

Example 16: preparation of 2-amino-N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3-phenylpropanamide

The compound obtained in example 15 was reacted in CF as in example 3₃And removing the protecting group on the amino group in COOH to obtain the product.

Sixth group

Example 17: preparation of 2- (Boc-protected amino) -N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3-methylsulfanyl butyramide

This compound was prepared by reacting unresolved or resolved 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine with N- (tert-butoxycarbonyl) -2-amino-4-methylthiobutyric acid by the procedure of example 2, whereby the product was obtained.

Example 18: preparation of 2-amino-N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3-methylsulfanyl butyramide

The compound obtained in example 17 was reacted in CF as in example 3₃And removing the protecting group on the amino group in COOH to obtain the product.

Seventh group

Example 19: preparation of 2- (Boc protected amino) -N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3-hydroxypropionamide

This compound was prepared by the method of example 2 by reacting unresolved or resolved 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine with N- (tert-butoxycarbonyl) -2-amino-3-hydroxypropionic acid to give the product.

Example 20: preparation of 2-amino-N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3-hydroxypropionamide

The compound obtained in example 19 was reacted in CF as in example 3₃And removing the protecting group on the amino group in COOH to obtain the product.

Eighth group

Example 21: preparation of 2- (Boc protected amino) -N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3-hydroxybutyramide

This compound was prepared by reacting unresolved or resolved 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine with N- (tert-butoxycarbonyl) -2-amino-3-hydroxybutyric acid according to the procedure of example 2, to give the product.

Example 22: preparation of 2-amino-N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3-hydroxybutyramide

The compound obtained in example 21 was reacted in CF as in example 3₃And removing the protecting group on the amino group in COOH to obtain the product.

Ninth group

Example 23: preparation of 2- (Fmoc-protected amino) -N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3-mercaptopropionamide

250mg of undissociated or undissociated 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine and 410mg of N- (9-fluorenylmethoxycarbonyl) -2-amino-3-mercaptopropionic acid were dissolved in 5ml of anhydrous DMF, and 0.5ml of triethylamine was added thereto. Then 300mg BDP was weighed out and dissolved in 25ml anhydrous DMF. A DMF solution of BDP was added dropwise to the reaction solution. After the dropwise addition, the reaction was stirred at room temperature for half an hour, and a large amount of white precipitate was formed. The precipitate was filtered off and washed repeatedly with anhydrous ether for more than 3 times. Collecting filtrate and ether used for washing and precipitating, obtaining crude products after spin-drying, and then separating and purifying by a column chromatography method to obtain 2- (Fmoc protected amino) -N- {1- [1- (4-chlorphenyl) cyclobutyl ] -3-methylbutyl } -3-mercaptopropionamide.

Example 24: preparation of 2-amino-N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3-mercaptopropionamide

The product obtained in example 23, 2- (Fmoc-protected amino) -N- {1- [1- (4-chlorophenyl) cyclobutyl]-3-methylbutyl } -3-mercaptopropionamide was added to 0.05-0.1mol/L (n-Bu)₄N⁺F^-Is dissolved in DMF. The solution is stirred at room temperature and reacted for half an hour, then DMF is removedA white turbidity formed. It was dissolved in anhydrous ether and washed repeatedly with saturated sodium bicarbonate solution until the washed liquid became neutral. The ether solution was then washed 2 to 3 times with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Filtering to remove desiccant, evaporating under reduced pressure to remove solvent, separating and purifying the obtained crude product by column chromatography to obtain 2-amino-N- {1- [1- (4-chlorphenyl) cyclobutyl]-3-methylbutyl } -3-mercaptopropionamide.

Tenth group

Example 25: preparation of 3- (Fmoc-protected amino) -4- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine } -4-carbonyl-butyric acid

This compound was obtained by reacting unresolved or resolved 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine with N- (9-fluorenylmethoxycarbonyl) -2-aminosuccinic acid in the same manner as in example 23.

Example 26: preparation of 3-amino-4- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine } -4-carbonyl-butyric acid

According to the method of example 24, the compound obtained in example 23 is added to a solution of 0.05 to 0.1mol/L (n-Bu)₄N⁺F^-The protecting group on the amino group is removed from DMF to obtain the product.

Eleventh group

Example 27: 2- (Fmoc-protected amino) -N¹- {1- [1- (4-chlorophenyl) cyclobutyl]Preparation of (E) -3-methylbutyl-succinamide

This compound was prepared by reacting unresolved or resolved 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine with N- (9-fluorenylmethoxycarbonyl) -2-amino-4-amidopropionic acid as in example 23, whereby the product was obtained.

Example 28: 2-amino-N¹- {1- [1- (4-chlorophenyl) cyclobutyl]Preparation of (E) -3-methylbutyl-succinamide

By way of example 24, examples27 the obtained compound is present in an amount of 0.05-0.1mol/L (n-Bu)₄N⁺F^-The protecting group on the amino group is removed from DMF to obtain the product.

Twelfth group

Example 29: preparation of 4- (Fmoc-protected amino) -5- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine } -5-carbonylvaleric acid

This compound was prepared by reacting unresolved or resolved 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine with N- (9-fluorenylmethoxycarbonyl) -2-aminoglutaric acid as in example 23, whereby the product was obtained.

Example 30: preparation of 4-amino-5- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine } -5-carbonylvaleric acid

By the method of example 24, the compound obtained in example 29 was dissolved in 0.05 to 0.1mol/L (n-Bu)₄N⁺F^-The protecting group on the amino group is removed from DMF to obtain the product.

Group thirteen

Example 31: 2- (Fmoc-protected amino) -N¹- {1- [1- (4-chlorophenyl) cyclobutyl]Preparation of (E) -3-methylbutyl glutaramide

This compound was prepared by reacting unresolved or resolved 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine with N- (9-fluorenylmethoxycarbonyl) -2-amino-4-amidobutyric acid according to the procedure of example 23, thereby obtaining the product.

Example 32: 2-amino-N¹- {1- [1- (4-chlorophenyl) cyclobutyl]Preparation of (E) -3-methylbutyl glutaramide

By the method of example 24, the compound obtained in example 31 was dissolved in 0.05 to 0.1mol/L (n-Bu)₄N⁺F^-The protecting group on the amino group is removed from DMF to obtain the product.

Fourteenth group

Example 33: preparation of 1- {4- (Fmoc-protected amino) -5- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine } -5-carbonylpentyl } urea

This compound was prepared by the reaction of unresolved or resolved 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine with N- (9-fluorenylmethoxycarbonyl) -2-amino-5-hydrazinopentanoic acid as in example 23 to give the product.

Example 34: preparation of 1- { 4-amino-5- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine } -5-carbonylpentyl } urea

By the method of example 24, the compound obtained in example 33 was dissolved in 0.05 to 0.1mol/L (n-Bu)₄N⁺F^-The protecting group on the amino group is removed from DMF to obtain the product.

Fifth group

Example 35: preparation of 2- (Cbz-protected amino) -N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3- (1H-4-imidazole) propionamide

250mg of undissociated or undissociated 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine and 410mg of N- (benzyloxycarbonyl) -2-amino-3- (1H-4-imidazole) propionic acid were dissolved in 5ml of anhydrous DMF, and 0.5ml of triethylamine was added thereto. 400mg BOP was then weighed out and dissolved in 25ml of anhydrous DMF. A DMF solution of BDP was added dropwise to the reaction solution. After the dropwise addition, the reaction was stirred at room temperature for half a time, and a large amount of white precipitate was formed. The precipitate was filtered off and washed repeatedly with anhydrous ether for more than 3 times. Collecting filtrate and ether used for washing precipitate, and spin-drying to obtain crude product, and then separating and purifying by column chromatography to obtain 2- (Cbz protected amino) -N- {1- [1- (4-chlorphenyl) cyclobutyl ] -3-methylbutyl } -3- (1H-4-imidazole) propionamide.

Example 36: preparation of 2-amino-N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3- (1H-4-imidazole) propionamide

The product obtained in example 35, 2- (Cbz protected amino) -N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3- (1H-4-imidazole) propionamide, was dissolved in ethanol. Then, an appropriate amount of 10% Pd-C was added thereto. Adding hydrogen at normal temperature and normal pressure until hydrogen is not absorbed. The catalyst was filtered off, ethanol was removed by rotary filtration and a white turbid product formed. This was dissolved in anhydrous ether, and the ether solution was washed with a saturated aqueous sodium chloride solution 2 to 3 times and dried over anhydrous sodium sulfate. Filtering to remove the drying agent, evaporating the solvent under reduced pressure, and separating and purifying the obtained crude product by using a column chromatography method to obtain the 2-amino-N- {1- [1- (4-chlorphenyl) cyclobutyl ] -3-methylbutyl } -3- (1H-4-imidazole) propionamide.

Sixteenth group

Example 37: preparation of 2- (Cbz-protected amino) -N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3- (4-hydroxyphenyl) propionamide

This compound was prepared by the reaction of unresolved or resolved 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine with N- (benzyloxycarbonyl) -2-amino-3- (4-hydroxyphenyl) propionic acid as in example 35, whereby the product was obtained.

Example 38: preparation of 2-amino-N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3- (4-hydroxyphenyl) propionamide

The compound obtained in example 37 was deprotected at the amino group by the method of example 36 using 10% Pd-C in ethanol solution to obtain the product.

Seventeenth group

Example 39: preparation of 2- (Cbz-protected amino) -N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3- (1H-indolyl) propionamide

This compound is prepared by reacting unresolved or resolved 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine with N- (benzyloxycarbonyl) -2-amino-3- (1H-indolyl) propionamide according to the procedure of example 35, thereby obtaining the product.

Example 40: preparation of 2-amino-N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -3- (1H-indolyl) propionamide

The compound obtained in example 39 was deprotected at the amino group by the method of example 36 using 10% Pd-C in ethanol solution, to obtain the product.

Eighteenth group

Example 41: preparation of N- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } pyrrole-2-amide

This compound was prepared by reacting unresolved or resolved 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine with pyrrole-2-carboxylic acid according to the procedure of example 2, giving the product.

Example 42: n- {1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutyl } -4-hydroxypyrrole-2-amide

This compound was prepared by the method of example 2 by reacting unresolved or resolved 1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine with 4-hydroxypyrrole-2-carboxylic acid to give the product.

ESI mass spectrometry was performed on the products of the above examples, and the above-listed compounds all showed the expected molecular ion peaks in the ESI mass spectrum. See table 1 for relevant information:

TABLE 1 examples 2-42 related structures and ESI mass spectra information

The preparation of the compounds of formula (I) and their enantiomeric compounds of the invention is illustrated above by specific examples. The compounds encompassed by the present invention are not limited to those exemplified in the examples, but include pharmaceutically acceptable salts of the compounds or enantiomeric compounds thereof.

Pharmaceutically acceptable salts are particularly suitable for pharmaceutical applications because of their greater solubility in water than the starting or base compound. The compounds of the present invention have basic nitrogen and can therefore be prepared as salts by acid addition with pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid, and organic acids such as carbonic acid, acetic acid, oxalic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-bromobenzenesulfonic acid, succinic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, tartaric acid and trifluoroacetic acid, amino acids and the like. Thus, such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, acrylate, formate, isobutyrate, caprate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-butyne-1, 4-dioate, 3-cyclohexyne-2, 5-dioate, benzoate, chlorobenzoate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hippurate, beta-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, mesylate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, fumarate, maleate, 2-butyne-1, 4-dioate, 3-cyclohexyne-2, 5-dioate, benzoate, chlorobenzoate, phenylacetate, phenylbutyrate, tartrate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, glutamate, arginine, lysine, and the like. For medical purposes, the use of the hydrochloride is particularly preferred, and the process for the preparation of salts from the compounds already given in examples 4, 7 and 10 is likewise suitable for the compounds of the other examples.

On the other hand, the compounds of the present invention may also exist in various polymorphic forms, such as amorphous and crystalline forms. All crystalline forms of the compounds of the present invention are included within the scope of the present invention.

In the application aspect, the compound, the optical isomer, the medicinal salt and the crystal structure of the compound can be used as a medicinal active ingredient for preparing weight-reducing medicines. The pharmaceutical effect thereof is described below by experiments.

Toxicity test of weight-reducing drug

Method and device

1. Establishment of obese animal model

The freshly weaned SD rats were fed with abundant nutritional feed except for the blank control group, and the rats were allowed to eat food at will every day, so that an obese animal model was established rapidly.

2. Experimental groups, dose determination and dosing regimens

The freshly weaned SD rats 210 were randomly divided into 21 groups of 10 animals each, half of the animals and males, and provided abundant nutritional feed, and the rats of each group were fed ad libitum daily, with the following groups and dosages:

(1) blank control group: feeding with basal feed.

(2) Model group: feeding with nutritional feed without limitation.

The above two groups are administered with 1% carboxymethyl cellulose excipient, the rest experimental drug groups are fed with nutritional feed, and are administered with 1% carboxymethyl cellulose to corresponding drug concentration, the administration volume is 1ml/100g, and the administration is performed once a day for 30 days. The dosage design is obtained by converting the clinical dosage of the positive control medicament sibutramine of 10 mg/person/day according to the equivalent dosage of the person and the rat.

1) EXAMPLE 16 Compound drug bolus 0.11mg/ml

2) EXAMPLE 16 Compound drug Small dose 0.055mg/ml

3) EXAMPLE 22 Compound drug Large dose 0.11mg/ml

4) EXAMPLE 22 Compound drug Small dose 0.055mg/ml

5) EXAMPLE 12 Compound drug Large dose 0.11mg/ml

6) EXAMPLE 12 Compound drug Small dose 0.055mg/ml

7) EXAMPLE 26 Compound drug Large dose 0.11mg/ml

8) EXAMPLE 26 Compound drug Small dose 0.055mg/ml

9) EXAMPLE 14 Compound drug Large dose 0.11mg/ml

10) EXAMPLE 14 Compound drug Small dose 0.055mg/ml

11) EXAMPLE 2 Compound drug Large dose 0.11mg/ml

12) EXAMPLE 2 Compound drug Small dose 0.055mg/ml

13) EXAMPLE 40 Compound drug Large dose 0.11mg/ml

14) EXAMPLE 40 Compound drug Small dose 0.055mg/ml

15) EXAMPLE 41 Compound drug Large dose 0.11mg/ml

16) EXAMPLE 41 Compound drug Small dose 0.055mg/ml

17) EXAMPLE 9 Compound drug Large dose 0.11mg/ml

18) EXAMPLE 9 Compound drug Small dose 0.055mg/ml

19) Sibutramine 0.11mg/ml

3. Observation index

Weighing body weight every day, then dosing according to body weight, and observing stool and urine and general physical signs.

② the antemortem rats were fasted for 12h, body length (from nose to anus) and tail length were measured under ether anesthesia and the Lee index was calculated. The animals were then sacrificed.

(Lee) s index ═ { body weight (g) × 103}1/3 ÷ body length (cm)

Taking blood to measure total cholesterol, triglyceride, total protein and blood sugar;

taking fat around genitals, weighing, fixing with 2.5% formaldehyde ethanol for use, and calculating the number and size of fat cells in the whole visual field under a 400-fold microscope;

taking the heart, liver, kidney and genitals, fixing with 10% formaldehyde solution, and observing whether there is pathological change.

4. Statistical treatment the mean of each group is represented by x + -S and is subjected to t-test treatment.

Second, screening results

(1) The effects of the various drug groups on serum total protein, triglyceride, cholesterol and blood sugar of obese rats

The results are shown in table 2, and the serum total protein and the blood sugar of each drug group have no obvious statistical significance compared with the model group and the blank control group; compared with the model group, the groups of the medicines for serum cholesterol and triglyceride have difference or obvious difference. The experimental medicaments have no obvious influence on the total serum protein and the blood sugar of the obese rat, can obviously reduce the concentration of the monocholesterol and the triglyceride in the serum of the obese rat, and have similar action with sibutramine.

In addition, as compared with the sibutramine positive control group, the compound drug serum triglyceride in the large and small dose groups of example 2, example 41 and example 9 is equivalent to the sibutramine positive group in analysis of each drug group, which suggests that the compounds are likely to be weight-reducing drugs with better therapeutic effects.

It is presumed that the other two compounds (compounds of example 8 and example 10) of the group of example 9 have the same active structure as the compound of example 9, and thus have the same pharmacodynamic activity as the compound of example 9; and further that the substitution of the protecting group Boc with Cbz or Fmoc did not materially alter the pharmaceutical activity.

(2) Effect of each group on the body weight, Lee factor, the weight of perirenal and perigenital white adipose tissue, and the perigenital white adipose cell count (40X 10 visual field) in obese rats

The results are shown in table 3, and the model control group has significant differences in final body weight, Lee coefficient, weight of white adipose tissue around kidney and genitals, and white adipose cell count reduction around genitals compared to the blank control group, indicating that the model is successful; the compound medicine of example 41, the compound medicine of example 9 and sibutramine can obviously reduce the final body weight, Lee coefficient, the weight of white adipose tissues around kidney and genitals and the white adipose cell count around genitals of obese rats, and have difference or significant difference compared with a model group; the compound medicines in example 41 and the compound medicines in example 9 have no difference compared with sibutramine in the final body weight, Lee coefficient, white adipose tissue weight around kidney and genitals and white adipose cell count reduction of the periphery of genitals of obese rats, and the rest medicines have difference or obvious difference compared with the sibutramine group; compared with the blank control group, each medicine group has the weight-reducing effect with different degrees. From the above analysis, it can be seen that each experimental drug can reduce the final body weight, Lee coefficient, white adipose tissue weight around kidney and genitals, and white adipose cell count around genitals of obese rats, and has different weight-reducing effects, wherein the effect of the compound drug of example 41 and the compound drug of example 9 is the best, and the effect is similar to that of sibutramine.

(3) Changes of white fat cells around genitals and pathological sections of important organs in each drug group

And (3) observing pathological section photos (more pictures are provided, but comprehensive character description is given), wherein the white fat cells around the genitals of the normal control group have normal shapes and clear boundaries, and the number of the fat cells is normal in each 40X 10 times visual field. White fat cells around the genitals of the model group are obviously enlarged, the boundary is unclear, the outline is fuzzy, and the model group has a fusion tendency; in each 40 × 10-fold field, the number of adipocytes was significantly reduced, the diameter was increased, and the adipocyte count was statistically significantly different from that of the normal control group. The morphology of white fat cells around genitals of each group of the applied medicines is between that of a model group and that of a normal control group, wherein the white fat cell morphology of the compound medicine of the example 41 and that of the compound medicine of the example 9 are relatively small, the fat cell count is obviously different from that of the model control group, and the compound medicine of the example 9 has no statistical difference from that of sibutramine.

Pathological observation results of important organs: no obvious pathological changes are found in the heart, liver, kidney, ovary and testis of the normal control group animals; compared with a normal control group, the large-dose group of animals with the medicine has no obvious difference in heart, liver, kidney, ovary and testis, and shows that the medicine has no important organ damage except the weight-losing effect, thereby prompting that the medicine can be expected to reduce the toxic and side effect on organisms.

Third, conclusion

The weight-reducing effect of each medicine group is different, wherein the weight-reducing effect of the compound medicine of the group of the example 9 and the group of the example 41 is the best, and is similar to or better than that of sibutramine; compared with a normal control group, the heart, liver, kidney, ovary and testis of the animal in the model group and the compound drug high-dose group have no obvious pathological changes.

TABLE 2 Effect of the respective groups on serum Total protein, triglyceride, Cholesterol, blood glucose in obese rats

Group of	Total serum protein (g/l)	Serum triglycerides (mmol/l)	Serum cholesterol (mmol/l)	Blood sugar (mmol/l)
					Blank control group	76.34±7.99	0.95±0.17▲	2.71±0.25▲	4.14±0.50
Model set	72.26±7.83	2.77±0.07■★	4.04±0.58■★	4.06±0.55
					EXAMPLE 16 Large chemical dose	76.53±7.15	1.99±0.19▲■	2.76±0.20▲	4.29±0.49
EXAMPLE 16 Low dose of the Chemicals	75.45±7.11	2.21±0.36▲■★	2.91±0.17▲	4.06±0.78
					EXAMPLE 22 high dose of the Chemicals	75.37±7.23	1.63±0.27▲■	3.26±0.39▲□	4.20±1.35
EXAMPLE 22 Low dose of the Chemicals	75.58±5.34	2.10±0.32▲■	3.43±0.41△■	4.02±0.54
					EXAMPLE 12 high dose of the Chemicals	76.02±5.21	1.93±0.62▲■	2.81±0.24▲	4.08±0.80
EXAMPLE 12 Low dose of the Chemicals	77.66±8.19	1.78±0.44▲■	3.23±0.42△□	3.94±1.16
					EXAMPLE 26 Large chemical dose	73.90±5.74	1.71±0.12▲■☆	3.09±0.54▲	3.98±0.44
EXAMPLE 26 Low dose of the Chemicals	72.79±11.6	2.73±0.58▲■★	2.68±0.14▲	4.07±0.54
					EXAMPLE 14 Large chemical dose	73.39±7.73	2.69±0.43■★	2.64±0.16▲	4.05±0.70
Example 14 small dosage of chemical medicine	73.07±7.99	1.93±0.09▲■☆	2.99±0.15▲■	4.21±0.68
					EXAMPLE 2 high dose of the chemical	73.45±8.72	1.42±0.28▲■	2.86±0.20▲	4.19±0.60
EXAMPLE 2 Low dose of the chemical	75.66±10.3	1.44±0.03▲■	3.15±0.38▲■	3.92±0.60
					EXAMPLE 40 Large chemical dose	72.30±7.57	1.69±0.17▲■	2.92±0.46▲	4.16±0.98
EXAMPLE 40 Low dose of the chemical	75.09±7.23	1.95±0.38▲■☆	2.86±0.30▲	4.23±0.48
					EXAMPLE 41 high dose of the chemical	76.06±10.0	1.57±0.16▲■	2.60±0.20▲	4.51±0.65
EXAMPLE 41 Low dose of the chemical	75.37±6.93	1.91±0.12▲■☆	3.11±0.17▲■	4.18±1.10
					EXAMPLE 9 Large chemical dose	74.44±7.21	0.88±0.20▲	2.55±0.20▲	4.16±0.18
EXAMPLE 9 Small dose of the Chemicals	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

^△Compared with the model group, P is less than 0.05;^▲compared with the model group, P is less than 0.01;

^□compared with a blank control group, P is less than 0.05;^■p is less than 0.01 compared with the blank group;

^☆compared with the sibutramine group, P is less than 0.05;^★compared with the sibutramine group, P is less than 0.01;

TABLE 3 Effect of the individual drug groups on the body weight, Lee factor, the weight of perirenal and perigenital white adipose tissue, the perigenital white adipose cell count (40X 10 visual field) in obese rats

Group of	Final body weight (g)	Lee coefficient	Weight of white adipose tissue around kidney and genitalia (g)	Fat cell count (40X 10 field)
					Blank control group	189±19▲★	302.70±20.95▲★	2.21±0.23▲☆	117.90±13.71▲★
Model set	310±71■★	336.63±20.17■★	6.46±2.43■☆	30.60±6.06■★
					EXAMPLE 16 Large chemical dose	294±67■☆	307.23±19.87▲★	4.73±2.04■	49.70±6.33▲■★
EXAMPLE 16 Low dose of the Chemicals	282±71■	309.72±10.15▲	6.22±3.64■	46.60±10.74▲■☆
					EXAMPLE 22 high dose of the Chemicals	286±58■☆	307.09±11.74▲★	4.44±1.58△■	55.4±7.73▲■★
EXAMPLE 22 Low dose of the Chemicals	293±64■	312.05±23.26△	5.32±1.24■	54.60±10.74▲■
					EXAMPLE 12 high dose of the Chemicals	294±46■★	309.24±16.08▲	5.28±3.15■	48.7±11.66▲■
EXAMPLE 12 Low dose of the Chemicals	316±81■	313.57±16.21△	5.62±1.18■	53.60±9.57▲■
					EXAMPLE 26 Large chemical dose	294±58■★	310.09±25.66△★	4.82±1.51■	51.3±9.71▲■★
EXAMPLE 26 Low dose of the Chemicals	311±74■	315.22±13.43△★	5.54±2.37■	52.1±11.97▲■
					EXAMPLE 14 Large chemical dose	294±68■☆	312.65±14.65▲★	4.43±1.87■	48.10±8.39▲■★
EXAMPLE 14 Low dose of the Chemicals	293±54■	317.57±13.45△☆	6.62±1.59■	48.20±8.27▲■☆
					EXAMPLE 2 high dose of the chemical	295±62■★	314.12±14.08△★	4.23±0.81△■	50.02±8.28▲■★
EXAMPLE 2 Low dose of the chemical	292±61■	310.70±8.23▲	4.88±1.66■	48.00±12.43▲■
					Example 2 lower dose of the chemical	295±65■	315.31±18.92△	5.30±1.86■	47.10±9.79▲■
EXAMPLE 40 Large chemical dose	287±56■☆	318.94±19.49★	4.83±1.64■	450.10±9.09▲■★
					EXAMPLE 40 Low dose of the chemical	269±51■	315.68±17.00△	5.05±1.57■	48.40±10.99▲■
EXAMPLE 41 high dose of the chemical	251±34△■	294.54±15.23▲☆	4.00±0.66▲■	59.20±8.43▲■★
					EXAMPLE 41 Low dose of the chemical	292±70■	314.52±12.13▲	4.89±2.59■	52.20±6.75▲■
EXAMPLE 9 Large chemical dose	242±27△■	283.58±17.77▲□	3.87±2.08△□	68.2±7.93▲■
					EXAMPLE 9 Small dose of the Chemicals	295±64■	314.44±9.18▲☆	4.80±1.60■	54.80±5.45▲■
Sibutramine group	227±37▲■	276.31±13.72▲■	3.70±2.19▲□	72.50±10.19▲■

^△Compared with the model group, P is less than 0.05;^▲compared with the model group, P is less than 0.01;

^□compared with a blank control group, P is less than 0.05;^■p is less than 0.01 compared with the blank group;

^☆compared with the sibutramine group, P is less than 0.05;^★compared with the sibutramine group, P is less than 0.01.

The above experiments illustrate the use of the compounds of the present invention (including racemates, optical isomers and their salts) in the manufacture of medicaments. It is noted that the amount required to achieve the desired biological effect in an application will depend on a variety of factors, such as the particular compound selected, the intended use, the type of administration and the clinical condition of the patient. In general, the daily dose will be in the range 0.3mg to 100mg (usually 3mg to 50mg) per kg body weight per day, for example 3-10 mg/kg/day. Intravenous doses may range, for example, from 0.3mg to 1.0mg/kg, and may be administered by infusion in a suitable manner, at doses of from 10ng to 100ng per kilogram per minute. Infusion solutions suitable for these purposes may contain, for example, 0.1ng to 10mg, usually 1ng to 10mg per ml. A single dose may, for example, contain from 0.1ng to 10g of active compound. Thus, ampoules for injection may, for example, contain from 1mg to 100mg, and orally administrable single-dose preparations, such as tablets or capsules, may, for example, contain from 1.0 to 1000mg, usually from 10 to 600 mg. In the case of pharmaceutically acceptable salts, the above masses relate to the mass of the free compound on which the salt is based. The compounds for the prophylaxis or treatment of the above-mentioned conditions may be according to formula (I) as such, but they are preferably in the form of a pharmaceutical composition together with an acceptable carrier. The carrier must, of course, be compatible, that is, compatible with the other ingredients of the composition and not deleterious to the health of the patient. The carrier may be a solid or a liquid or both, and is preferably formulated with the compound as a single dose, for example, as a tablet, which may contain from 0.05 to 95% by weight of the active compound. Additional pharmaceutically active substances may also be present, including additional compounds according to formula (I). The pharmaceutical compositions of the present invention may be prepared according to any of the known pharmaceutical procedures which essentially comprise admixing the ingredients with pharmacologically acceptable carriers and/or adjuvants.

The pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (e.g. sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration in each individual case depends on the type and severity of the condition to be treated and on the type of compound according to formula (I) used in each case. Sugar coated formulations and sugar coated sustained release formulations are also included within the scope of the invention. Acid and gastric juice resistant formulations are preferred. Suitable gastro-resistant layers include anionic polymers of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and methyl crotonate.

Pharmaceutical compositions suitable for oral administration may be presented as discrete units, such as capsules, cachets, lozenges or tablets, in each case containing an amount of a compound according to formula (I); powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; or an oil-in-water or water-in-oil emulsion. As already mentioned, the compositions may be prepared according to any suitable pharmaceutical method including the step of contacting the active compound with a carrier which may contain one or more additional ingredients. In general, the compositions are prepared by uniformly and consistently mixing the active compound with liquid and/or finely divided solid carriers and then, if necessary, shaping the product. Thus, for example, tablets may be prepared by compressing or otherwise shaping a powder or granules of the compound (optionally together with one or more additional ingredients). Compressed tablets may be prepared by compressing in a suitable machine the compound(s) (e.g. in powder or granules), optionally mixed with a binder, mould release agent, inert diluent and/or one or more surfactant/dispersant(s). Molded tablets may be prepared by molding in a suitable machine the powdered compound moistened with an inert liquid diluent.

Pharmaceutical compositions suitable for oral (sublingual) administration include lozenges, which comprise a compound according to formula (I) and a flavoring agent, usually sucrose and acacia or tragacanth, and pastilles, which comprise the compound in an inert base, for example gelatin and glycerol or sucrose and acacia.

Pharmaceutical compositions suitable for parenteral administration preferably comprise sterile aqueous formulations of a compound according to formula (I), which are preferably isotonic with the blood of the intended recipient. These formulations are preferably administered intravenously, although they may also be administered subcutaneously, intramuscularly or intradermally as injections. The formulations are preferably prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with respect to blood. The injectable compositions of the invention generally contain from 0.1 to 5% by weight of active compound.

Pharmaceutical compositions suitable for rectal administration preferably present as single dose suppositories. They may be prepared by mixing a compound according to formula (I) with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.

Pharmaceutical compositions suitable for topical application to the skin preferably present as ointments, creams, lotions, pastes, sprays, aerosols or oils. Carriers which may be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. In general, the concentration of active compound is from 0.1 to 15%, for example from 0.5 to 2% by weight of the composition.

Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal administration may be presented as single patches adapted for long-term intimate contact with the epidermis of the patient. Such patches suitably contain an optionally buffered aqueous solution of the active compound, the compound being dissolved and/or dispersed in the adhesive or dispersed in the polymer. Suitable active compounds can be released by electron transport or iontophoresis, for example Pharmaceutical Research, 2 (6): 318 (1986).

The compounds of the invention are notable for beneficial effects on lipid metabolism, they are particularly suitable for weight loss and for maintaining reduced weight after weight loss in mammals, and for use as anorectic agents. The compounds are notable for their low toxicity and fewer side effects. The compounds may be used alone or in combination with other weight-reducing or appetite-reducing active compounds.

Additional anorectically active compounds of this type are described, for example, in rote list chapter 01, weight loss agents/appetite suppressants, and may also include active compounds that increase energy conversion in an organism, thereby causing a reduction in weight, or compounds that affect the general metabolism of the organism such that increased caloric intake does not result in an expansion of the fat stores in the organism, and normal caloric intake results in a reduction in fat stores. The compounds are suitable for the prevention, in particular the treatment, of overweight or obesity. The compounds are furthermore suitable for the prevention, in particular the treatment, of type II diabetes, arteriosclerosis, for the normalization of the lipid metabolism and for the treatment of hypertension. The compounds act as MCH antagonists and are also suitable for the treatment of sensory disorders and other psychiatric indications, such as depression, anxiety neurosis, schizophrenia, and disorders associated with circadian rhythms and the treatment of drug abuse.

In another aspect, the compounds of the present invention may be combined with one or more additional pharmacologically active substances to form a compound, which may be selected, for example, from the group consisting of antidiabetic agents, anti-fat agents, blood pressure lowering active compounds, lipid lowering agents and therapeutic and/or prophylactic active compounds for complications resulting from or associated with diabetes.

Suitable antidiabetic agents include insulin, amylin, GLP-1 and GLP-2 derivatives such as those disclosed in WO98/08871 by Novo Nordisk A/S, and orally hypoglycemic active compounds.

The oral hypoglycemic active compounds preferably include sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon receptor antagonists, GLP-1 agonists, potassium channel openers (such as those disclosed in WO 97/26265 and WO 99/03861 by Novo Nordisk A/S), insulin-sensitizers, insulin receptor kinase activators, inhibitors of hepatic enzymes involved in gluconeogenesis and/or glycogenolysis stimulation (such as glycogen phosphatase inhibitors), modulators of glucose uptake and glucose excretion, compounds that alter lipid metabolism (such as antihyperlipidemic active compounds and antilipidemic active compounds, such as HMGCoA reductase inhibitors), cholesterol transport/cholesterol uptake inhibitors, bile acid reabsorption inhibitors or microsomal triglyceride transfer protein (MTP) inhibitors, Compounds that reduce nutrient uptake, PPAR and RXR agonists, and active compounds that act on the ATP-dependent potassium channel of beta cells.

In one embodiment of the invention, the compounds of the invention are administered in combination with insulin.

In another embodiment, the compounds of the invention are formulated for co-administration with sulfonylureas, such as tolbutamide, glyburide, glibenclamide, glipizide, gliquidone, glipizide, glibornuride, or gliclazide.

In another embodiment, the compounds of the present invention are formulated with a biguanide for combined administration, for example, metformin.

In another embodiment, the compounds of the present invention are formulated with meglitinide for administration in combination, for example, with each of the classes of glinides.

In another embodiment, the compounds of the invention are formulated for co-administration with thiazolidinediones, such as troglitazone, ciglitazone, pioglitazone, rosiglitazone (rosiglitazone) or the compounds disclosed in WO 97/41097 by dr. reddy's research foundation, particularly 5- [ [4- [ (3, 4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl ] methyl ] -2, 4-thiazolidinedione.

In another embodiment, the compounds of the invention are formulated for co-administration with an α -glucosidase inhibitor, such as miglitol or acarbose.

In another embodiment, the compounds of the invention are combined for co-administration with active compounds that act on the ATP-dependent potassium channel of beta cells, such as tolbutamide, glibenclamide, glimepiride, glipizide, gliclazide or repaglinide.

In another embodiment, the compounds of the present invention are formulated for co-administration with an antihyperlipidemic or antilipidemic active compound, such as cholestyramine, colestipol, clofibrate, fenofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, atorvastatin (atorvastatin), cerivastatin, covastatin, probucol, ezetiib or dextrothyroxine.

In another embodiment, a compound of the invention is formulated for co-administration with one or more of the other pharmaceutical compounds described above, such as sulfonylurea and metformin, sulfonylurea and acarbose, repaglinide and metformin, insulin and sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, and the like.

In addition, the compounds of the present invention may be combined with one or more anti-adipogenic agents or appetite control active compounds for co-administration. Such active compounds may be selected from the group consisting of CART agonists, NPY antagonists, MC4 agonists, orexin (Oxexin) antagonists, H3 agonists, TNF agonists, CRF BP antagonists, urocortin (urocortin) agonists, beta 3 agonists, MSH (black cell stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotonin and norepinephrine reuptake inhibitors, 5HT modulators, MAO inhibitors, doll skin agonists, galanin antagonists, growth hormones, growth hormone releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, Leptin (Leptin) agonists, dopamine agonists (bromocriptine, Doprexin), esterase/amylase inhibitors, cannabinoid receptor 1 antagonists, Acylated Stimulating Protein (ASP) modulators, PPAR modulators, RXR modulators, hCNTF mimetics or TR-beta agonists.

In one embodiment of the invention, the anti-fat agent is leptin or modified leptin.

In another embodiment, the anti-fat agent is dextroamphetamine or amphetamine.

In another embodiment, the anti-fat agent is fenfluramine or dexfenfluramine.

In another embodiment, the anti-fat agent is sibutramine or mono-and di-demethylated active metabolites of sibutramine.

In another embodiment, the anti-fat agent is orlistat.

In another embodiment, the anti-fat agent is mazindol, bupropion, or phentermine.

In addition, the compounds of the present invention may be administered in combination with one or more antihypertensive active compounds. Examples of antihyperglycemic active compounds are beta blockers, such as alprenolol, atenolol, timolol, pindolol, and metoprolol, ACE (angiotensin converting enzyme) inhibitors, such as benazepril, captopril, enalapril, fosinopril, laninopril, and ramipril, calcium channel blockers, such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem, and verapamil, and alpha blockers, such as doxazosin, urapidil, prazosin, and terazosin. Furthermore, reference may be made to Remington: the Science and practice of Pharmacy, 19th edition, Gennaro, edition, Mack Publishing Co., Easton, PA, 1995.

It goes without saying that every suitable combination of a stereoisomer compound according to the invention with one or more of the above-mentioned compounds and optionally one or more other pharmacologically active substances should also be considered as being covered by the scope of protection of the present invention.

Claims (10)

1. An aryl cyclobutyl compound, including compounds represented by formula (I), stereoisomeric compounds thereof, compound crystals, and pharmaceutically acceptable salts of the compounds:

wherein,

x is H, halogen, CF₃、C_1-3Of alkyl, alkoxy, thioalkyl and phenyl groupsOne kind of the material is selected;

R₁is H or is C₁～C₄Linear or branched alkyl of (a);

R₃can be H, formyl, acetyl, haloacetyl, benzoyl, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), or with R₂and-HN-forming a 3-7 membered ring (which ring may be saturated or unsaturated, and may be substituted by one or more halogens, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy substituted);

when R is₃When R is H, formyl, acetyl, haloacetyl, benzoyl, benzyloxycarbonyl, tert-butoxycarbonyl (Boc), or 9-fluorenylmethoxycarbonyl₂Is the following group: c_1-12Alkyl, benzyl, substituted benzyl, or R₄(CH₂)_n- (wherein: n ═ 1-4; R₄Can be hydroxyl, amino, mercapto, alkylthio, carboxylic acid, amide, ureido, pyridyl, thienyl, furyl, imidazolyl or indolyl), R₅R₆(CH)-(R₅May be C_1-12An alkyl group; r₆May be hydroxy, amino, mercapto), and R₃and-HN-forms a 3-7 membered ring; r₂Preferably methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, benzyl, halogen atom-substituted benzyl, alkyl-substituted benzyl, alkoxy-substituted benzyl, hydroxy-substituted benzyl, R₄(CH₂)_n- (wherein, if n is 1-2, then R₄Hydroxyl, amino, sulfydryl, methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, isobutylthio, carboxylic acid group, amide group, carbamido group, pyridyl, thienyl, furyl, imidazolyl, indolyl and hydrocarbon thio; if n is 3-4, R₄Is amino, carboxylic acid, amide, ureido), or R₅R₆(CH)-(R₅Is methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl or isobutyl; r₆Can be hydroxyl, amino, sulfhydryl).

2. Aryl cyclobutyl compounds according to claim 1, characterized in that X is halogen, preferably chlorine in the para position of the phenyl ring.

3. Aryl cyclobutyl compounds according to claim 1 or 2, characterized in that R₁Is an isobutyl group.

4. Aryl cyclobutyl compounds according to claim 1, 2 or 3, characterized in that R₃Preferably, H, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), or 9-fluorenylmethoxycarbonyl (Fmoc).

5. Aryl cyclobutyl compounds according to claim 1, 2 or 3, characterized in that R₃Preferably with R₂and-HN-forming five-membered saturated N-heterocyclic alkanes or 4-hydroxy substituted C₁～C₃An alkyl group.

6. The aryl cyclobutyl compound of claim 4, wherein R is₂Preferably methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, benzyl, halogen atom-substituted benzyl, alkyl-substituted benzyl, alkoxy-substituted benzyl, hydroxy-substituted benzyl, R₄(CH₂)_n- (wherein, if n is 1-2, then R₄Hydroxyl, amino, sulfydryl, methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, isobutylthio, carboxylic acid group, amide group, carbamido group, pyridyl, thienyl, furyl, imidazolyl, indolyl and hydrocarbon thio; if n is 3-4, R₄Is amino, carboxylic acid, amide, ureido), or R₅R₆(CH)-(R₅Is methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl or isobutyl; r₆Can be hydroxyl, amino, sulfhydryl).

7. Aryl cyclobutylation compound according to claim 4The compound is characterized in that R₂Most preferably H, C_2-4Alkyl radical, R₄(CH₂)_n- (wherein: n ═ 1-4; R₄Is a hydroxyl group, a mercapto group, a hydrocarbon thio group, a carboxylic acid group, an amide group, an urea group, an imidazole group).

8. Aryl cyclobutyl compounds according to claim 5, characterized in that R₂Is with R₃and-HN-forming five-membered saturated N-heterocyclic alkanes or 4-hydroxy substituted C₁～C₃An alkyl group.

9. Aryl cyclobutyl compounds according to claim 1, characterized in that X is chlorine in the para-position of the phenyl ring and R is₁Is isobutyl, R₃Is H, Cbz, Boc or Fmoc, R₂Is isopropyl; or X is chlorine in the para-position of the phenyl ring, R₁Is isobutyl, R₃With NH and R₂Forming a pyrrole ring.

10. The use of an aryl cyclobutyl compound according to any of claims 1 to 9 for the preparation of a slimming medicament comprising a medicament with a single or complex compound as active ingredient, a compound medicament comprising the compound in combination with other medicaments or a pharmaceutical preparation comprising the compound in combination with pharmaceutical adjuvants.