WO2006034604A1 - 5-membered-s-heterocyclic compounds and their use in preparing of medicines for treating or preventing the obesity-relating diseases - Google Patents

Abstract

The invention relates to 5-membered-S-heterocyclic compounds of formula (I), their racemates, optical isomers, medicinal salts or hydrates, wherein RI is C3-C18 straight- or branched-chain alkyl, C3-C18 straight- or branched-chain alkenyl, R2 is H, C1-C4 straight- or branched-chain alkyl, CF3, R3 is H, =CH2, =CX2, =CHX, X is C1-C3straight- or branched-chain alkyl, F, Cl, Br. The invention also :relates to method for the preparation of compounds of formula (I) and the use of these compounds in preparing medicines, which can reduce weight and anti-tumor.

Description

 Five-membered sulfur heterocyclic compound and use thereof for preparing a medicament for treating and preventing obesity-related diseases

 The present invention relates to a five-membered sulfur heterocyclic compound of the formula I, a process for the preparation thereof, a pharmaceutical composition comprising the above compound, and a compound for the treatment and/or prevention of obesity, non-insulin dependent diabetes mellitus and complications thereof The use of drugs for obesity complications such as coronary heart disease, hypertension, and hyperlipidemia, as well as tumors and their complications. Background technique

Obesity is a multifactorial chronic disease that is affected by factors such as biological behavior and environment. When the body eats more calories than the calories consumed, excess heat is stored in the body as fat, and the body mass index (BMI) increases due to increased body fat. BMI is defined as: BMI-weight (kg) / height ² (m ² ), and BMI greater than ²⁴ are obese patients. With the development of the economy and the improvement of people's living standards, the trend of obesity patients in the world is doubling every five years in recent years. At present, there are at least 2.5 million obesity patients in the world, accounting for the total population. 7% (Claude Β·, The New England Journa l of Medicine, 2000, 343: 1888-1889). Obesity not only affects aesthetics, but can also cause coronary heart disease, hypertension, hyperlipidemia, non-insulin-dependent diabetes mellitus and certain malignancies (Mus t A, et al., J. Am. Med. Assos, 1999, 282: 1523). ). Therefore, it has important clinical significance for the prevention and treatment of obesity.

At present, the drugs for treating obesity are mainly divided into three categories according to their mechanism of action. The first type is an appetite suppressant. The representative drug is Sibutramine, which is a central appetite suppressant that inhibits the reuptake of norepinephrine and serotonin, giving people a sense of fullness and reducing appetite. Reduce eating. Common side effects are dry mouth, nausea, anorexia, abdominal pain, constipation, insomnia, etc., and mild increase in blood pressure and heart rate. The second type is the digestion and absorption blocker, and the representative drug is orlistat. (Olistat), which blocks the breakdown of fat into small molecules of triglycerides by inhibiting pancreatic lipase. Common side effects include causing gastrointestinal dysfunction in patients and reducing the absorption of fat-soluble vitamins by patients. The third category is metabolic stimulators such as thyroxine, P 3 receptor agonists, etc. (Zhou Yuzhao, Huang Zhongyi, Chinese Pharmacy, 2000, 11 (4), 168-169).

 Recent studies have shown that Fatty acid synthase (FAS) can achieve weight loss by inhibiting fatty acid synthesis and suppressing appetite, while also improving non-insulin-dependent diabetes, lowering hypertension, and coronary artery embolism. And the incidence of other obesity complications (LoftusTM, Jaworsky DE, Frehywot GL, Towns end CA, Ronnett GV, Lane MD, Kuhajda FP, Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors, Science, 2000, 288: 2379-81). Studies on the mechanism of action of specific inhibitors of fatty acid synthase showed that fatty acid synthase inhibitors can reduce the synthesis of fatty acids, and the concentration of malonyl-CoA (malony) increases due to fatty acid synthesis. Acyl-CoA acts directly on the feeding center of the hypothalamus, inhibiting the secretion of neuropeptide Y (NPY) that promotes feeding, leading to inhibition of feeding. On the other hand, in peripheral tissues such as liver and adipose tissue, fatty acid synthase inhibitors can increase the activity of carophyllin palmitoyltransferase-l (CPT-1), thereby enhancing fatty acid Oxidation and energy consumption. Pharmacological experiments have also shown that fatty acid synthase specific inhibitors have less toxic side effects, and inhibition of appetite can produce their own feedback regulation (Thupari JN, Landree LE, Ronnett GV, Kuhajda FP, C75 increases peripheral energy utilization and fatty Acid oxidation in diet-induced obesity, Proc Natl Acad Sci, USA, 2002, 99: 9498-502)

Summary of the invention

The object of the present invention is to find and develop a role for fatty acid synthase (FAS) The small molecule inhibitor, through which the fatty acid synthase is inhibited, on the one hand, reduces the synthesis and enrichment of fatty acids; on the other hand, it increases the concentration of the substrate malonyl-CoA, directly acts on the feeding center of the hypothalamus, inhibits eating, through Compensatory consumption of excess fat in the body to achieve weight loss. It also improves the incidence of non-insulin-dependent diabetes, low blood pressure, coronary embolism, and other obesity complications. Since FAS is highly expressed in certain tumor tissues such as colon cancer, prostate cancer, ovarian cancer, breast cancer, etc., the present invention can further be used as an anticancer drug. Further, the compound of the present invention is applied to the rearing of livestock and poultry, and the fat content in the meat can be reduced.

 The present invention relates to a trans-membered five-membered sulfur heterocyclic compound of the formula I, a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt or hydrate thereof. The present inventors have found that compounds of formula I are useful in the treatment of obesity and the various concurrent diseases caused thereby.

among them:

^ is a C ₃ ~ C ₁₈ linear or branched alkyl group, a C ₃ ~ C ₁₈ straight or branched alkenyl group,

R ₂ is H, d ~ C ₄ linear or branched alkyl, CF ₃ ,

R ₃ is H, =CH ₂ , =CX ₂ , =CHX,

X is a d ~ C ₃ linear or branched alkyl group, F, CI, Br.

 Another aspect of the invention relates to a pharmaceutical composition comprising at least one racemate or optical isomer of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or subtractive agent.

Another aspect of the invention also relates to the preparation of novel synthetic detergents of the formula I and / or the compound of formula II. Another aspect of the invention also relates to a racemate or an optical isomer of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof for use in the manufacture of a medicament for the prevention and/or treatment of obesity and various diseases caused thereby the use of.

 The compound of the formula I according to the invention has a certain inhibitory or cytotoxic effect on certain tumor cells which are highly expressed by fatty acid synthase, and therefore, the compound of the formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof can be used for, for example, colon cancer, prostate Relief or treatment of tumors or symptoms of cancer, ovarian cancer, breast cancer, etc.

 The fatty acid synthase to which the compound disclosed by the present invention is applicable is not limited to the human body, and includes a fatty acid synthase in an animal, which can cause a decrease in fat level of livestock such as chickens, ducks, and the like, and thus the compound disclosed in the present invention The composition containing the compound can be used to raise poultry and livestock of low fat and high lean type.

 More specifically, the present invention relates to a trans five-membered sulfur heterocyclic compound of the formula I, including racemic or optical isomers thereof or a pharmaceutically acceptable salt or hydrate thereof.

among them:

^ is c ₃ ~ c ₁₈ straight or branched alkyl, c ₃ ~ c ₁₈ straight or branched alkenyl,

R ₂ is H, d ~ C ₄ linear or branched alkyl, CF ₃ ,

R ₃ is H, =CH ₂ , =CX ₂ , =CHX,

X is a d ~ C ₃ linear or branched alkyl group, F, CI, Br.

Preferred compounds of the invention are the trans isomers represented by Formula II, including racemates or optical isomers thereof, or pharmaceutically acceptable salts or hydrates thereof,

among them:

^ is c ₃ ~ c ₁₈ linear or branched alkyl, c ₃ ~ c ₁₈ straight or branched fluorenyl.

 Particularly preferred compounds of the invention, or pharmaceutically acceptable salts or hydrates thereof,

 Trans-2-oxo-3 -methylene-5-n-hexyl-tetrahydrothiophene-4-carboxylic acid

 Trans-2-oxo-3-methylene-5-n-heptyl-tetrahydrothiophene-4-carboxylic acid

 Trans-2-oxo-3-methylene-5-n-octyl-tetrahydrothiophene- 4-carboxylic acid

 Trans-2-oxo-3-methylene-5-n-decyl-tetrahydrothiophene- 4-carboxylic acid

 Trans-2-oxo-3-indenyl-5-n-decyl-tetrahydrothiophene- 4-carboxylic acid

Trans- ² -oxo-3-methyl-5-n-undecyl-tetrahydrothiophene-4-carboxylic acid Another aspect of the invention also relates to the novel synthesis of compounds of formula I and / or formula II Process, the compounds of the present invention are conveniently prepared from known starting materials according to the synthetic reaction schemes described below.

 1). Reverse the phosphonate derivative of formula III with an alkyl or alkenyl derivative of formula IV

R.CHO where the definition is the same as the compound of formula I,

Obtaining a compound of formula V,

 Wherein the definition is the same as the compound of formula I.

2). The compound of the formula V is reacted with thioacetic acid, hydrochloric acid and trifluoroacetic acid to obtain a compound of the formula VI, which comprises a stereoselective ring-closing process to give the trans isomer VI.

Wherein the definition is the same as the compound of formula I.

3). reacting a compound of the formula VI with a magnesium methyl carbonate test (CH ₃ OC0 ₂ MgOCH ₃ ) to obtain a compound of the formula VII,

Further, a compound of the formula VII is reacted with a Stock solution consisting of acetic acid, furfural, N-methylaniline and anhydrous sodium acetate to obtain a trans isomer compound of the formula II.

4). The compound of the general formula II is esterified with an alkyl or alkenyl alcohol R20H under the action of a catalyst such as thionyl chloride (S0 ₂ C1 ₂ ) or DCC, and is isolated and purified to obtain R3. a trans isomer of the formula I which is =CH ₂ ,

Wherein ^ and R ₂ are as defined in the formula I.

 The synthesis reaction of the compounds of formula I and formula I I is detailed in the following reaction routes.

III V

Wherein the substituents of R1 and R2 are the same as formula I

Reaction step 1: O

 Ft. A 1-NaHTHF

BO ² 2. BrCH ₂ C0 ₂ Et

 III V

Triethyl phosphate (Acros reagent), sodium hydride (NaH 60%; purchased by Beijing Reagent Co., Ltd.) in dry tetrahydrofuran under the protection of an inert gas such as nitrogen; Kunming suspension and ethyl bromoacetate (BrCH ₂ C0) ₂ Et, purchased by Beijing Reagent Co., Ltd.) Reaction, stirring at 0 °C - 50 °C for 2-48 hours, extraction with ethyl acetate, drying of organic layer, thick. The resulting orange liquid III is prepared with an alkyl or mercapto aldehyde (Acros reagent, or according to the method provided by Jendralla H, et al, Tetrahedron Lett, 1990, 31: 2545) in lithium diisopropylamide (LDA, Stir for 2 to 48 hours with Aldrich reagent or sodium hydride. It was concentrated to give a pale yellow liquid. It is reacted with trifluoroacetic acid/water (1:1 ~ 20:1) and sodium hydroxide in water. After acidification, liquid separation extraction, drying, and concentration, the obtained crude product was subjected to flash column chromatography (eluent: petroleum ether / ethyl acetate / glacial acetic acid system) to obtain compound (trans / cis = 2 8) . Wherein R1 is as defined in the formula I.

 Reaction step 2:

 V VI

 Compound V is reacted with deuterated acetic acid (Acros reagent) at 60-90 ° C for 30 minutes to 48 hours. The product is refluxed with aqueous hydrochloric acid and trifluoroacetic acid in the presence of nitrogen, and then treated to obtain a black oily liquid. Column chromatography (eluent: petroleum ether / ethyl acetate / glacial acetic acid system) gave compound VI. Wherein R1 is as defined in the general formula I.

Reaction step 3:

VI VII Compound VI was reacted with magnesium methyl carbonate reagent (Aldrich reagent, CH ₃ 0C0 ₂ Mg0CH ₃ 2.0M/DMF) in a nitrogen stream at 135-140 ° C for 24 hours to 168 hours in dichloromethane. The reaction with hydrochloric acid is carried out, and the obtained crude product is added to a stock solution (20 ml of acetic acid, 15 ral of 37% formaldehyde solution, 5.2 ml of N-methylaniline, 600 mg of anhydrous sodium acetate) under a nitrogen atmosphere for 20 minutes at 0 to 40 ° C. 4 hours. The reaction mixture was extracted with diethyl ether. The obtained crude product was subjected to flash column chromatography (eluent: petroleum ether / ethyl acetate / glacial acetic acid system) to give Compound II. Wherein R1 is as defined in the formula I.

 Reaction step 4:

II I The ester compound of the compound of the formula II is reacted with an alkyl or alkenyl alcohol R20H (Aldrich reagent) under the action of a catalyst such as thionyl chloride (S0 ₂ C1 ₂ ) or DCC, and is isolated and purified to obtain R3 as = a trans isomer of the formula I of CH ₂ , wherein

The definitions of ^ and R ₂ are the same as the definition of formula I.

We have unexpectedly discovered that in the synthesis of a compound of formula VI, a one-step selective ring-closing cyclization process allows stereoselective compounds of formula VI with the trans isomer as the main product. . The trans isomers of the compounds of formulas I and II can be stereoselectively synthesized in accordance with the novel synthetic methods of the compounds of formula I and formula II provided herein. The present invention can employ asymmetric synthesis to give a single optical isomer. However, resolution of the racemate is the primary means of obtaining optically pure compounds. There are four main methods of resolution: crystallization, chromatography, kinetics and enzymatic methods. For the resolution of the racemate of the compound of the present invention, a crystallization method of practical value is preferably used: a chiral base is added to a solution of a racemate in water, an organic solvent or a mixed solvent of water and an organic solvent. The component is a diastereomer, and one of the diastereomers is preferentially precipitated by utilizing the solubility of the diastereomer in the solvent. The preferred chiral base may be ephedrine or the like, and the chromatographic method is mainly carried out using an HPLC chiral column to obtain a single optical purity compound.

 Another aspect of the invention relates to a pharmaceutical composition comprising a racemate or an optical isomer of a compound of the invention and at least one pharmaceutically acceptable carrier which is useful for in vivo treatment and is biocompatible. The pharmaceutical compositions can be prepared in a variety of forms depending on the route of administration. The compounds mentioned in the present invention can also be prepared into various pharmaceutically acceptable salts.

 The pharmaceutical compositions of the present invention comprise an effective amount of a compound of formula I according to the invention, or a pharmaceutically acceptable salt or hydrate thereof, and one or more suitable pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate, saturated a mixture of partial glycerides of plant fatty acids, water, salt or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, Cellulose material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin.

The compound of the present invention is a type of fatty acid synthase inhibitor, and the compound of the present invention has better inhibitory activity of fatty acid synthase and more obvious weight loss effect and better stability than the compound C75 mentioned in U.S. Patent No. 5,981,575. Sex, especially suitable for industrial production and long-term storage. The compounds of the invention may be used, but are not limited to, for the treatment of obesity, type II diabetes and its complications, coronary heart disease, high blood Obesity complications such as pressure and hyperlipidemia.

 The present invention can also be extended to the use of a medicament for preparing an antitumor and a complication thereof. Since certain tumor cells have a high degree of FAS expression, the compounds of the present invention have a certain inhibitory or cytotoxic effect on certain tumor cells, and therefore, the compound of the formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof can be used, for example, for colon cancer. Relief or treatment of tumors or their symptoms of prostate cancer, ovarian cancer, breast cancer, etc. Further, the compound and the composition thereof disclosed in the present invention can be used for lowering the fat level of livestock such as chickens and ducks and pigs, and raising low-fat, high-lean-type poultry and livestock. The regimen containing the compound of the invention may vary depending on the use involved.

 The pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Inside, intraventricular, intrasternal and intracranial injection or input, or by means of an explant reservoir. Among them, oral, intraperitoneal or intravenous administration is preferred.

 When administered orally, the compounds of the invention may be formulated in any orally acceptable form including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions. Among them, the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as barium stearate may also be added. The diluent used in the capsule preparation generally comprises lactose and dried corn starch. Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier or suspension. If desired, some sweetening, aroma or coloring agents may be added to the above oral formulation.

In the case of topical administration, especially in the treatment of facial surfaces or organs easily accessible by topical application, such as eye, skin or lower intestinal neurological diseases, the compounds of the present invention can be formulated into different topical preparations according to different affected faces or organs. The form is specifically described as follows: When the eye is topically applied, the compound of the present invention can be formulated into a preparation form of a micronized suspension or solution, and the carrier used is an isotonic pH of sterile saline, which may or may not be added. Preservatives such as benzyl chloride alkoxide. For eye use, it can also The compound is formulated into a cream form such as a vaseline cream.

 When applied topically to the skin, the compounds of the invention may be in the form of a suitable ointment, lotion or cream preparation wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers which can be used for ointment preparations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; and detergents or creams which can be used include, but are not limited to, mineral oils. , sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.

 The compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile aqueous or oily suspension or sterile injection solutions. Among them, carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution. Alternatively, sterilized, fixed oils may be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.

 It should also be noted that the dosage and method of use of the compounds of the invention depends on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and Subjective judgment of the doctor. A preferred dosage is from 0.01 to 100 mg/kg body weight per day, wherein the optimal dose is from 1 mg/kg to 50 mg/kg body weight per day.

 DRAWINGS

 Figure 1 Compound S8 inhibits FAS activity-effect curve

 Figure 2 Compound S8 inhibits FAS activity-effect curve

 Fig. 3 Effect of compound S8 on ATP content in 3T3-L1 of preadipocytes Figure 4. Effect of compound S8 on feeding of (DI0) mice

 Figure 5. Effect of compound S8 on body weight changes in (DI0) mice

 detailed description

 The following examples are illustrative of preferred embodiments of the invention and are not intended to limit the invention in any way.

The melting point of the compound was determined by a SRY-1 type melting point apparatus and the temperature was not corrected. ^a H-NMR The spectra were determined by a Bruker ARX400 or US Var ian ^Unity Inova 600 NMR instrument, and the FAB quality was determined by the Zabspect high resolution grammar.

Example 1 : trans-2-oxo-3-methylene-5-n-octyl-tetrahydrothiophene-4-decanoic acid (compound S8)

Preparation 1, 2-octene-itaconic acid synthesis:

Under a nitrogen atmosphere, triethyl citrate (22.4 g, 0.1 mol, Acros reagent) was dissolved in 50 ml of dry tetrahydrofuran solution, and sodium hydride was slowly added dropwise at 0 ° C (60% 5. 0g 0. 125raol Beijing) The reagent company purchased) in a suspension of 120 ml of anhydrous THF, warmed to room temperature and stirred overnight. The reaction solution was lowered to 0 ° C, and ethyl bromoacetate (BrCH ₂ C0 ₂ Et 16.7 g, 0.1 mol of Beijing Reagent Co., Ltd.) was added dropwise to the above reaction solution, and the mixture was warmed to room temperature and stirred for 24 hours. The mixture was concentrated under reduced pressure. EtOAc was evaporated.

4.70 g of the compound III (15 mmol) was added dropwise to a solution of 30 ml of sodium hydride (60% 0. 6 g) in anhydrous tetrahydrofuran at 0 ° C under N2. The furfural (C ₉ H ₁₈ 0, 2.13 g, 15 mmol, Acros reagent) was dissolved in 10 ml of anhydrous tetrahydrofuran, and the mixture was added dropwise, and the mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of water (10 ml), and the solvent was evaporated. Add about 2.2 ml of trifluoroacetic acid/water (9:1), stir at room temperature for 3 hours, distill off trifluoroacetic acid under reduced pressure, and add the obtained black liquid to 25 ml of 10% NaOH solution and about 20 ml of ethanol, and reflux overnight. The reaction solution was cooled, acidified with concentrated hydrochloric acid, and then extracted with diethyl ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated, flash column chromatography ( petroleum ether: ethyl acetate: glacial acetic acid/10:3:0. The compound V (^/cis = 2) was 1.97 g, yield 57%. Trans compound V: MS [M]+=242.3 m/e; 'H-NMR (600 MHz, CDC1 ₃ ) δ 7.12 (t 1H); 3.36 (s 2H) 1.1-1.6 (m 14H) 0.88 (t 3H) .

Cis compound V: MS [M] + = 242.3 m/e; 'H-NMR (600 MHz, CDC1 ₃ ) δ 6.23 (t 1H) 3.30 (s 2H) 1.1-1.6 (m 14H) 0.88 (t 3H).

 Preparation 2, Synthesis of trans-2-n-octyl-5-0--3-carboxylic acid-tetrahydrothiophene

 V

 Compound V (2.42 g, 10 mmol) and 3 ml of thioacetic acid (Acros reagent, far excess) were reacted at 85-90 ° C overnight, and excess thioacetic acid was distilled off under reduced pressure. Under nitrogen, 6M was added. Hydrochloric acid (20 ml) was refluxed for 6-8 hours, cooled, and the aqueous layer was combined with ethyl acetate. EtOAc was evaporated. After 2-4 hours, trifluoroacetic acid was evaporated to dryness, and chloroform (20 ml×3×××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××× : 2: 0.07) Compound VI as a white solid, 703 mg, yield: 48.5%.

MS[M]+=258.4ra/e ; 'H-NMR (600MHz, CDC1 ₃ ) δ 4.12 (m , 1H); 3.10 (dt, 1H) 2.84-3.04 (m, 2H) 1.1-2.1 (m, 14H ) 0.86 (t, 3H).

 Preparation of trans-2-oxo-3-methyl-5-n-octyl-tetrahydrothiophene-4-carboxylic acid (S8)

^Vl VII s ₈ Compound VI (200 mg, 0.78 mmol) was reacted with magnesium sulfonate reagent (CH ₃ OC0 ₂ MgOCH ₃ , 1.8 M/DMF, 15 ml, Adlrich reagent) in a stream of nitrogen at 135-140 ° C for 72 hours. Add 10% aq. of hydrochloric acid in the presence of dichloromethane, separate the dichloromethane layer, wash with saturated brine, and distill off dichloromethane under reduced pressure at 30 ° C. The crude VII obtained is added under nitrogen. 5 ml Stock solution (20 ml acetic acid, 15 ml 37 °/form formaldehyde solution, 5.2 ml N-methylaniline, 600 mg anhydrous sodium acetate) was reacted at 20 ° C for 2 hours. The reaction mixture was extracted with diethyl ether. EtOAc (EtOAcjjjjjjjjjjj S8 solid 110 mg, yield 52.4%, mp: 79-81.5. C.

MS [M]+=270.4m/e; 'H-NMR (600MHz, CDC1 ₃ ) δ 6.16 (d, 1H); 5.58 (d, 1H) 4.08 (dt, 1H) 3.70 (m, 1H) 1.1-2.1 (m, 14H)

0.86 (t, 3H).

Example 2: trans-2-oxo-3-methyl-5-n-hexyl-tetrahydrothiophene-4-nonanoic acid The furfural was changed to n-heptanal by the preparation method of Example 1. Acros reagent) gave trans-2-oxo-3-methylene-5-n-hexyl-tetrahydrothiophene- 4-carboxylic acid compound, mp: 77-79.

MS [M] +=242.4 m/e; ^X H-NMR (600MHz, CDC1 ₃ ) δ 6.18 (d, 1H); 5.61 (d, 1H) 4.08 (dt, 1H) 3.71 (ra, 1H) 1.1-2.1 (m, 10H)

0.88 (t, 3H).

Example 3: Trans-2-oxo-3-methyl-5-n-decyl-tetrahydrothiophene-4-carboxylic acid The preparation method of Example 1 was carried out, wherein furfural was changed to n-nonanal (Acros Test ^) to give trans-2-oxo-3-methylene-5-n-decyl-tetrahydrothiophene-4-carboxylic acid compound: mp: 81-82.5 °C.

MS [M] + = 284.4 m/e; 'H-NMR (600 MHz, CDC1 ₃ ) δ 6.17 (d, 1H);

5.59(d, 1H) 4.08(dt, 1H) 3.72(m, 1H) 1.1-2.1 (m, 16H)

0.88 (t, 3H). Example 4: Formula 2-Oxo-3-methylene-5-n-decyl-tetrahydrothiophene-4-carboxylic acid The preparation method of Example 1 was used, wherein furfural was changed to n-undecaldehyde (Acros Test 'j) to give trans-2-oxo-3-methylene-5-n-decyl-tetrahydrothiophene-4-carboxylic acid compound: mp: 83-85 °C.

MS [M] +=298. 4m/e; 'H- MR (600MHz, CDC1 ₃ ) δ 6. 18 (d, 1H) ; 5. 61 (d, 1H) 4. 08 (dt , 1H) 3. 71 (m, 1H) 1. 1-2. 1 (m, 18H)

0. 89 (t, 3H).

Example 5: trans-2-oxo-3-methylene-5-n-undecyl-tetrahydrothiophene-4-carboxylic acid

 Using the preparation method of Example 1, wherein the furfural is changed to n-dodecaldehyde (Acros reagent) to obtain trans-2-oxo-3-methylene-5-n-undecyl-tetrahydrothiophene-4 - formate: mp: 85. 5-87 °C.

MS [M] += 312. 4m/e; 'H-NMR (600MHz, CDC1 ₃ ) δ 6. 18 (d, 1H) ; 5. 59 (d, 1H) 4. 08 (dt , 1H) 3. 71 (m, 1H) 1. 1-2. 1 (m, 2 OH)

0. 86 (t, 3H).

Example 6: Trans-2-oxo-3-methylene-5-n-octyl-tetrahydrothiophene-4-carboxylic acid (Compound S8) Test for inhibition of fatty acid synthase (FAS)

 Purification of fatty acid synthase (FAS) from rat liver

SD rats (200-250g) were fed with a fat-free high-sugar diet after two days of fasting, and induced high expression of FAS in the liver. After 3 days, the rats were acutely sacrificed, and the liver was placed in ice-cold 0.1 M phosphate buffer (PB). 1 mol / L PB (including 1 mmol / L MgC12, 0. lmraol / L EDTA, 10% glycerol, pH 7.5), wash away the blood, and cut off excess connective tissue, adding 5 volumes of 0.1 mol / L PB (including 2% rabbit serum, lmmol/LDTT) was homogenized by Polytron for 5 min. Add 25% PEG to a final concentration of 5%, stir for 10 min, and centrifuge at 9000 r/min for 30 min at 4 °C. The supernatant was collected and 25% PEG was added to give a final concentration of 11 °/. , stir lOmin, centrifuge at 9000r/min for 5min at 4 °C. The precipitate was retained, and 0.1 mol/LPB (2% rabbit serum, 1 mmol/LDTT, 2 mg/ml BSA) was added for secondary homogenization. Evenly Add ammonium sulfate (25g/ml) to the slurry and stir for 30min, centrifuge at 9000r/min for 30min at 4°C. _o Discard the supernatant and resuspend the pellet with 0.05mol/L PB (lmmol/L DTT, 2mg/ml BSA). Homogenate. Add 25% PEG to a final concentration of 10%, stir for 10 min, centrifuge at 9000 r/min for 30 min at 4 ° C, collect the supernatant, repeat the above procedure, combine the two supernatants, add 35% PEG, and let it end. The concentration was 15%, stirred for 10 min, centrifuged at 9000 r/min for 4 min at 4 ° C, and the precipitate was collected, and the precipitate was carefully washed with a small volume of double distilled water. Add 0. 05 mol/L PB (including 2 legs ol/L DTT). Resuspend the pellet, centrifuge at 9000r/min for 10 min at 4 °C, and take the supernatant for ion exchange column chromatography (DEAE. FF, Pharmacia). A gradient elution of 0· 05 mol/L PB (pH 7.5) of Na CI (O-lmol/L) was carried out, and the elution peak containing FAS was collected, concentrated by ammonium sulfate (21. 5 g/ml), and the protein was collected by centrifugation. With 0.

Reagent) Separation by gel column chromatography. The active components are collected. The size of FAS was determined by PAGE electrophoresis to be 260KD, the content of Lowery was determined, and the activity of FAS was determined by spectrophotometry. The results confirmed that FAS with the desired purity and certain activity was obtained for drug screening. Purified FAS was stored in -70 liters.

 Compound S8 has a four-factor effect on FAS

2摩尔/L. ₂ P0 (ρΗ7. 6), co-incubation at 37 °C for 30 minutes, adding 52 jLimol/L propionyl-CoA (Sigma reagent) to initiate the reaction, UV (340 nm) to detect the oxidation number of NADPH, and Calculate the activity of FAS. According to the activity change of FAS, the compound S8 (0-5 (^g/mL) dose-response curve (Fig. 1) was obtained, and the IC ₅ o of the compound S8 was found to be 6. 0 ± 0. lg/mL. According to the compound S8 lO The aging curve of g/mL showed that the inhibition of FAS by compound S8 increased with time in 0-15 min, and reached a plateau at 15-30 min (Fig. 2). The experiment showed the combination of compound S8 and FAS. Accompanied by the characteristics of the 'speed response.

Example 7: Synthesis of Endogenous Fatty Acids in HL60 Cells by Compound S8 Human anterior myeloid leukemia cell line HL60) was cultured in serum-free conditions of 1640 medium, and the cell density was 5 x 10 ⁵ molybdenum cells/ml. Experimental group: Solvent control group, compound S8 (2.5 g/ml, 5^g/ml, 10j1⁄2g/ml) _o Add compound S8 and incubate at 37 °C, 5% CO ₂ for 2 h, add 2 CL [U- ¹⁴ C Sodium acetate (Sigma) at 37. C, 5% C0 ₂ continued to incubate for 2 h. Discard the culture and add 2 ml of 2:1 chloroform:methanol mixture, homogenate for 5 min, and centrifuge (700 min, 15 min) to collect the supernatant. Add 20% of the volume of the initial extract and mix well. Centrifuge (2000 rpm, lOmin), remove the supernatant, and wash it with the washing solution 200j3⁄4l along the tube wall. Do not disturb the lower layer, gently rotate the tube to make the lotion and The remaining supernatant was mixed and removed, and repeated twice. Preparation of lotion: Mix chloroform, methanol and water in a volume ratio of 3:48:47, and make 0.02% CaCl ₂ , 0.017% MgCl ₂ and 0.29% NaCl ₀ in the washing solution. Add 150 μl of the above extracted lipid to 6 ml. In xylene scintillation solution (containing 0.5% PP0 and 0.03°/»POPOP), mix and count in liquid scintillation counter. The effect of FAS inhibitor S8 on endogenous fatty acid synthesis in HL60 cells is shown in Table 1. The results indicate that compound S8 can inhibit the synthesis of endogenous fatty acids in HL60 cells in a dose-dependent manner.

Table 1. Effect of FAS inhibitors on endogenous fatty acid synthesis in HL60 cells (cpm/5 x

10 ⁵ cells ) Solvent control S8 (l(^g/ml) S8 (5μ ₈ /ιη1) S8 (2.5 g/ml)

21586 ±1411 33±5 100±18 150±20 Example 8: Effect of compound S8 on ATP content in pre-adipocyte 3T3-L1 ATP standard curve

Preparation of a solution of luciferase-fluorescein (Shanghai Institute of Botany, Chinese Academy of Sciences) One photonase buffer powder was dissolved in 50 ml of distilled water to contain 50 mM glycylglycine (pH 7.6), 10 mmol/L MgS0 ₄ , 1 leg ol/LEDTA-Na ² buffer. Luciferase-fluorescein was dissolved in a luciferase buffer at a concentration of 3 mg/mL. Draw the standard curve, take freshly prepared ATP working solution 40)3⁄41, put it into 96-well fluorescent plate, quickly add 160μ1 of freshly prepared luciferase solution, scan and record the luminous intensity. Take the illuminance as the ordinate, and the concentration of ΑΤΡ dissolved in the night is the standard curve.

 Determination of the content of bismuth in the pre-adipocyte 3T3-L1 by compound S8

3T3-L1 cells were cultured in DMEM containing 10% calf serum into a monolayer, and then added for drug treatment for 2 h. Experimental group: solvent control group, S8 (10^g/ral, 25 _§ /ιη1, 50^g/ml ₀ Trypsin digestion of the harvested cells, take the cell suspension 50μί, add 450μl lOOmM Tr i s-HCl, boil for 2min, centrifuge at 2°C, l OOOg for 2min, and take the supernatant in the test tube for testing. 40 μl of the test sample to be tested was placed in a 96-well fluorescent plate, and the newly prepared luciferase solution was quickly added to 16 Ομΐ, and the luminescence intensity was scanned and recorded. Each sample was tested 6 times and its average value was taken as the luminescence value of this sample. The content of each group of sputum was calculated according to the standard curve. The results showed that the drug S8 could be added to the ATP in 3T3-L1 cells at a concentration of l (^g/ml, 25/*g/ml, 50^g/ml). The results of the test are shown in Figure 3.

Example 9: Compound S8 slimming effect test results

 C57BL/6J male mice (4-6 weeks old, purchased from the Experimental Animal Center of the Academy of Military Medical Sciences) were given nutrient feed for 3 months, resulting in a simple nutritional obesity (DI0) model. The composition of the nutrient feed: milk powder 5%, lard 20%, egg yolk powder 10%, sucrose 10 ° /. , peanut powder 5%, salt 2%, concentrated fish oil lmL/Kg, basic feed 48%, free drinking water. In the experiment, the dose was 10 mg/Kg, intraperitoneal injection (ip), continuous administration for 5 days, and the effect of the drug on the foraging and body weight of the (DI0) mice every 24 hours. The results showed that S8 significantly inhibited the feeding of mice (Fig. 4) and continued to decrease the body weight of the mice. On day 6, the body weight of the mice decreased by 17.3% (Fig. 5).

Claims

Rights request

A trans-membered five-membered sulfur heterocyclic compound of the formula I, a racemic quinone optical isomer thereof or a pharmaceutically acceptable salt or hydrate thereof,

 among them:

! ^ is a C ₃ ~ C ₁₈ linear or branched alkyl group, C ₃ ~ C ₁₈ straight or branched chain,

R ₂ is H, a linear or branched alkyl group, CF ₃ ,

R ₃ is H, =CH ₂ , =CX ₂ , =CHX,

 X is a C^Cs linear or branched alkyl group, F, CI, Br.

2. The compound of claim 1 which is a trans isomer represented by the formula II, a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt or hydrate thereof,

Wherein: the definition of the substituent is the same as claim 1.

3. A compound according to claim 1 or 2 selected from

 Trans-2-oxo-3-methyl-5-n-hexyl-tetrahydrothiophene-4-carboxylic acid

Trans-2-oxo-3-methylene-5-n-heptyl-tetrahydrothiophene-4-carboxylic acid Trans-2-oxo-3-methyl-5-n-octyl-tetrahydrothiophene-4-carboxylic acid trans-2-oxo-3-methylene-5-n-decyl-tetrahydrothiophene -4-carboxylic acid

 Trans-2-oxo-3-indolyl-5-n-decyl-tetrahydrothiophene- 4-carboxylic acid

 Trans-2-oxo-3-methylene-5-n-undecyl-tetrahydrothiophene-4-carboxylic acid.

4. A pharmaceutical composition comprising the compound of any one of claims 1 to 3, a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable carrier. A process for the preparation of a compound according to any one of claims 1 to 3 which comprises 1) a reaction of a phosphonate derivative of the formula I I I with an alkyl or alkenyl acid derivative of the formula IV

^CHO where the definition of claim 1 is

 To obtain a compound of formula V,

 Wherein the definition of claim 1

2) - reacting a compound of formula V with thioacetic acid, hydrochloric acid and trifluoroacetic acid to give formula VI a compound, the reaction comprising a stereoselective ring-forming process, the trans isomer VI is obtained,

 Wherein the definition of claim 1

3). reacting a compound of the formula VI with a magnesium methyl carbonate reagent CH ₃ OC0 ₂ MgOCH ₃ to obtain a compound of the formula VII,

 Wherein the definition of claim 1

 Further reacting a compound of the formula VII with a stock solution consisting of acetic acid, formaldehyde, N-mercaptoaniline and anhydrous sodium acetate to obtain a compound of the formula II,

4). The compound of the formula II is esterified with an alkyl or alkenyl alcohol R20H, and is isolated and purified to obtain a trans isomer compound of the formula I wherein R3 is = (3⁄4)

Wherein and the definition of 11 _{2 is} the same as claim 1.

6. Use of a compound according to any one of claims 1 to 3 for the preparation of a slimming drug.

7. Use of a compound according to any one of claims 1 to 3 for the preparation of an antitumor drug.