WO2008052444A1

WO2008052444A1 - Compounds with a six-membered heterocyclic ring, their preparing method and pharmaceutical use

Info

Publication number: WO2008052444A1
Application number: PCT/CN2007/003119
Authority: WO
Inventors: Song Li; Xiaokui Wang; Lili Wang; Hongying Liu; Junhai Xiao; Zhibing Zheng; Wu Zhong; Guoming Zhao; Qi Jin
Original assignee: Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A.
Priority date: 2006-11-02
Filing date: 2007-11-02
Publication date: 2008-05-08
Also published as: CN101172978A

Abstract

The present invention provides compounds of formula (I) with a six-membered heterocyclic ring, pharmaceutically acceptable salts, solvates or geometrical isomers thereof, and pharmaceutical compositions comprising the said compounds, wherein all substituents have the same meaning as defined in the description. The invention also provides a method for preparing the compounds of formula I and use of these compounds in producing weight reducing medicines and antineoplastic medicines.

Description

Six-membered heterocyclic compound, preparation method thereof and medical use thereof

The present invention relates to a six-membered heterocyclic compound of the formula I, a process for the preparation thereof, a pharmaceutical composition comprising the above compound, and a compound of the same for use in the preparation of a medicament for the treatment and/or prevention of obesity, non-insulin dependent diabetes and complications, crown The use of drugs for obesity complications such as 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 it consumes, the excess calories are stored in the body in the form of fat, which increases the body mass index (BMI) due to increased body fat. BMI is defined as: BMI = weight (kg) / height ² (m ² ), and those with a BMI greater than 24 are obese. 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 about 7 of the total population. % (Claude B., The New England Journal Of Medicine, 2000, 343: 1888-1889) „ Obesity not only affects aesthetics, but also causes 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, the prevention and treatment of obesity is of great clinical significance.

At present, the drugs for treating obesity are mainly divided into three categories according to their mechanism of action. The first category is an appetite suppressant. The representative drug is Sibutramine, which is a central food 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, which represents the drug is Olissi tat. It inhibits pancreatic lipase and blocks the breakdown of fat into small molecules of triglycerides. 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 scorpion stimulating hormone, 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 appetite suppression, while also improving non-leaven-dependent diabetes, lowering hypertension, coronary Incidence of embolism and other obesity complications ( Loftus TM, 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 have shown that fatty acid synthase inhibitors can reduce the synthesis of fatty acids, which are hindered by fatty acid synthesis, leading to an increase in the concentration of malonyl-CoA, malonyl-CoA. 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 carnitine palmitoyltransferase-1 (CPT-1), thereby enhancing fatty acid Oxidation and energy consumption. Pharmacological experiments have shown that fatty acid synthase-specific inhibitors have less toxic side effects, and inhibition of appetite can produce feedback regulation of white body (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).

The object of the present invention is to find and develop a hydrazine that acts on fatty acid synthase (FAS)! Molecular inhibitors, through which fatty acid synthase is inhibited, on the one hand, reduce the synthesis and enrichment of fatty acids; on the one hand, increase the concentration of the substrate malonyl-CoA, directly on the feeding center of the hypothalamus, inhibit eating, and compensate Sexual consumption of excess fat in the body to achieve weight loss goals. It also improves non-insulin-dependent diabetes and reduces the incidence of hypertension, coronary embolism and other obesity complications. Since the FAS enzyme is highly expressed in certain tumor tissues such as colon cancer, prostate cancer, ovarian cancer, breast cancer, and the like, 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 inventors have discovered that compounds of formula I are useful in the treatment or prevention of obesity and its complications as well as tumors.

Accordingly, in one aspect, the invention provides a compound of formula I, or a pharmaceutically acceptable salt, solvate thereof or geometric isomer thereof,

among them:

Is a C ₁₈ linear or branched alkyl group, a C ₃ - C ₁₈ straight or branched alkenyl group having a chain selective of 3⁄4, nitro, hydroxy, hydroxymethyl, -CN, trifluoromethyl , trifluoromethoxy, phenoxy, benzyloxy, 0 or S,

112 is C, ~ (: ₆ linear or branched alkyl, benzyl, trifluoromethyl,

R3 is H, sulfhydryl,

X is an oxygen or sulfur atom;

A is a 5- to 6-membered aromatic carbocyclic or heterocyclic substituent, wherein the aromatic carbocyclic ring contains 6 to 14 carbon atoms, such as phenyl, benzyl or naphthyl, and the heterocyclic ring includes 1 to 4 From the following heteroatoms: 0, S, N, such as pyrrole, pyridine, piperidine, pyrrolidine, or morpholine; aromatic carbocyclic or heterocyclic ring may be unsubstituted, or may be substituted by 1 to 5 selected from Base substitution: halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, phenoxy, benzyloxy, CN, carboxy or amino;

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, comprising at least one compound of formula I, a pharmaceutically acceptable salt, solvate or geometric isomer thereof, and a pharmaceutically acceptable carrier or Shape agent.

In another aspect, the invention relates to a process for the synthesis of a compound of formula I and / or a compound of formula I I or a pharmaceutically acceptable salt thereof or a solvate thereof.

In another aspect, the invention relates to the use of a compound of formula I, a pharmaceutically acceptable salt, solvate or geometric isomer thereof, for the manufacture of a medicament for the prevention and/or treatment of obesity and various diseases caused thereby .

In a further aspect, the compounds of formula I according to the invention have a certain inhibitory or cytotoxic effect on certain tumor cells which are highly expressed by fatty acid synthase, therefore, the compounds of formula I and their pharmaceutically acceptable salts and solvates It can be used for the relief and treatment of tumors such as colon cancer, prostate cancer, ovarian cancer, breast cancer or the like.

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, a preferred compound of the invention is a structure represented by the formula π, a racemate or an optical isomer thereof, a pharmaceutically acceptable salt or solvate thereof or a geometric isomer thereof,

I I

among them:

111 is ( ₃ ~ c ₁₈ linear or branched alkyl, c ₃ ~ c ₁₈ straight or branched alkenyl,

R3 is H, sulfhydryl,

A is phenyl, 1,3 -dimercaptopyrrolyl,

X is selected from the group consisting of 0, S atoms.

According to the invention, the term "C ₃ -C ₁₈ straight or branched alkyl" is preferably a C ₆ -C„ straight or branched alkyl group, such as hexyl, octyl, decyl, decyl, undecyl, etc. ; the term "C ₃ -C ₁₈ straight or branched alkenyl" is preferably C ₆ -C„ straight or branched alkenyl, such as hexenyl, octenyl, nonenyl, decenyl, undecane Alkenyl and the like. The term "geometric isomer" refers to a cis or trans isomer.

Particularly preferred compounds of the invention include:

Trans-6-n-hexyl-1,3,7-trimethyl-4-oxo-1,4,6,7-tetrahydropyran [4,3-b]pyrrole-7-carboxylic acid;

Trans-6-n-heptyl-1,3,7-trimethyl-4-oxo-1,4,6,7-tetrahydropyran[4,3-b]pyrrole-7-carboxylic acid;

Trans-6-n-octyl-1,3,7-trimethyl-4-oxo-1,4,6,7-tetrahydropyran[4,3-b]pyrrol-7-carboxylic acid;

Trans-6-n-decyl-1,3,7-trimethyl-4-oxo-1,4,6,7-tetrahydropyran[4,3-b]pyrrole-7-carboxylic acid;

Trans-6-n-decyl-1,3,7-trimethyl-4-oxo-1,4,6,7-tetrahydropyran[4,3-b]pyrrole-7-carboxylic acid; Trans-6-n-undecyl-1,3 trimethyl-4-oxo-•1, 4, 6, 7-tetrahydropyran [ 4, 3-b ] pyrrole-7

Cis--6-n-hexyl-1,3,7-tridecyl-4-oxo-1,4,6,7-tetrahydropyran[4,3--b]pyrrol-7-carboxylic acid ;

Cis--6-n-heptyl-1,3,7-tridecyl-4-oxo-1,4,6,7-tetrahydropyran[4,3·-b]pyrrol-7-carboxylate Acid

Cis-6-n-octyl-1, 3, 7-trimethyl-4-oxo-1, 4, 6, ^7-- tetrahydropyran [4, 3- -b] pyrrole carboxylic -7- acid;

Cis--6-n-decyl-1,3,7-trimethyl-4-oxo-1,4,6,7-tetrahydropyran[4,3·-b]pyrrol-7-carboxylate Acid

Cis--6-n-decyl-1,3,7-trimethyl-4-oxo-1,4,6,7-tetrahydropyran[4,3--b]pyrrol-7-carboxylate Acid

Cis--6-n-undecyl-1,3,7-trimethyl-4-oxo-,1,4,6,7-tetrahydropyran [4,3-b]pyrrole-7 -carboxylic acid;

Trans--3-n-hexyl-1-oxo-isobenzotetrahydropyran-4-carboxylate

Trans--3-n-heptyl-1-oxo-isobenzotetrahydropyran-4-carboxyl

Trans--3-n-octyl-1-oxo-isobenzotetrahydropyran-4-carboxyl

Trans--3-n-decyl-1-oxo-isobenzotetrahydropyran-4-carboxyl

Trans--3-n-undecyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; cis--3-n-hexyl-1-oxo-isobenzotetrahydropyridyl Methyl-4-carboxylic acid;

Cis--3-n-heptyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid;

Cis--3-n-octyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid;

Cis--3-n-decyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid;

Cis--3-n-undecyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; trans--3-n-hexyl-4-mercapto-1-oxo-iso Benzotetrahydropyran-4 Trans-3-n-heptyl-4-methyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; trans-3-n-octyl-4-methyl-1-oxo -isobenzotetrahydropyran-4-carboxylic acid; trans-3-n-decyl-4-methyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; trans-3 - n-decyl-4-methyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; trans-3-n-undecyl-4-methyl-1-oxo-iso Benzotetrahydropyran-4-carboxylic acid;

Cis-3-n-hexyl-4-mercapto-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; cis-3-n-heptyl-4-methyl-1-oxo- Isobenzotetrahydropyran-4-carboxylic acid; cis-3-n-octyl-4-methyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; cis-3- n-Mercapto-4-methyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; cis-3-n-decyl-4-mercapto-1-oxo-isobenzotetra Hydropyran-4-carboxylic acid; cis-3-n-undecyl-4-methyl-1-oxo-isobenzotetrahydropyran-4-carboxytrans-3-n-hexyl-4 -methyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; trans-3-n-heptyl-4-methyl-1-oxo-isobenzotetrahydropyran-4 -carboxylic acid; trans-3-n-octyl-4-mercapto-1-oxo-isobenzotetrahydrothiopyran-4-carboxylic acid; trans-3-n-decyl-4-indenyl- 1-oxo-isobenzotetrahydropyran-4-carboxylic acid; trans-3-n-decyl-4-mercapto-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; Trans-3-n-undecyl-4-methyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid;

Cis-3-n-hexyl-4-mercapto-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; cis-3-n-heptyl-4-methyl- 1-oxo- Isobenzotetrahydropyran-4-carboxylic acid; cis-3-n-octyl-4-methyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; cis-3- n-Mercapto-4-methyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; cis-3-n-decyl-4-mercapto-1-oxo-isobenzo-4- Hydrothiazol-4-carboxylic acid; cis-3-n-undecyl-4-methyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; And a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the invention also relates to a novel process for the synthesis of compounds of formula I and / or formula II, which are conveniently prepared from known starting materials in accordance with the following synthetic scheme:

1) the compound of formula III reacts with decyl alcohol under the catalysis of concentrated sulfuric acid,

Obtaining a compound of formula IV,

Wherein A is defined in the same manner as claim 1,

2) The compound of the formula IV is reacted with decane (CH ₃ I) in the presence of a base such as sodium hydride (NaH) or lithium diisopropylamide (LDA) to give a compound of the formula V.

Where A is defined in the same way as claim 1.

3) reacting a compound of the formula IV with NaH, R1CH0 to give a compound of the formula VI,

Wherein, A is a phenyl group, and R1 is as defined in claim 1.

4) reacting a compound of formula V with LDA, R1CH0 to give a compound of formula VII (cis and trans),

Wherein, A and Rl are as defined in claim 1; R3 is a methyl group, and X is an oxygen atom.

5) reacting a compound of the formula IV with lithium diisopropylamide (LDA), triisopropoxytitanium chloride ((i-PrO) ₃ TiCl ), R1CH0 to give a compound of the formula VII (cis and trans),

Wherein A is a phenyl group, X is an oxygen atom, and R3 is H, and R1 is as defined in claim 1.

6) reacting a compound of formula VI with thioacetic acid, hydrochloric acid and trifluoroacetic acid to give a compound of formula VII (cis and trans),

Wherein A is a phenyl group, X is a sulfur atom, and R3 is H, and R1 is as defined in claim 1.

7) reacting a compound of the formula VII with an aqueous lithium hydroxide solution to give a compound of the formula II,

II

Wherein, A, X, Rl, and R3 are defined as claimed in

8) esterifying a compound of the formula II with an alkyl or alkenyl alcohol R20H, and purifying to obtain a compound of the formula I,

Wherein, A, X, Rl, R3 are as defined in claim 1,

The synthesis scheme of the compounds of the formula I and the formula II is detailed in the following reaction scheme: Reaction step one:

The raw material diacid III (0.1 mol) was dissolved in 200 ml of decyl alcohol, a catalytic amount of concentrated sulfuric acid was added, and refluxed overnight. Concentrate, and distill off most of the decyl alcohol. Add about 200 ml of ethyl acetate to the residue, wash with water, saturated NaHC0 ₃ solution, and saturated brine to dryness, dry over anhydrous Na ₂ SO ₄ , and concentrate. Compound IV, yield 80-90%.

Wherein A is defined in the same way as claim 1.

Reaction step two: H

Compound IV (46 leg ol) was dissolved in 200 ml of anhydrous tetrahydrofuran in the presence of N ₂ , cooled to -78 ° C, and slowly dropped into 48 ml of LDA solution (2M, 96mmo), and maintained at -78 for 2 hours. Methyl iodide (6.82 g, 48 mmo) was dissolved in 20 ml of anhydrous THF and 20 ml of anhydrous DMF. The solution was added dropwise to the above reaction solution, and the reaction was kept at -78 X for 1 hour, and the temperature was slowly raised until the reaction was continued for 1 hour. clarification, reaction was stopped. the reaction solution was poured into H ₂ S0 ₄ in solution (6N, 40ml), and extracted (300ml / 3 times) with ethyl acetate, the organic layers were combined and washed 3 times with saturated brine, dried over anhydrous MgS04 Concentrated to a brown liquid. Column chromatography (petroleum ether: ethyl acetate: water acetic acid = 10:3: 0.07) to give compound V (oil yield: 85 - 95%).

Wherein A is defined in the same way as claim 1.

Reaction step three:

IV

Compound IV (0.02 mol) was dissolved in 30 ml of dry THF solution in the presence of N ₂ , and a suspension of NaH (60%, 1. 0 g, 0.025 mol) in 200 ml of anhydrous THF was slowly added dropwise. The reaction was changed to 0 hr for 2 hr, and the reaction solution became an emulsion. The aldehyde R1CH0 (20 mmol) was dissolved in 20 ml of anhydrous THF, and the above reaction solution was added dropwise thereto, and the reaction was continued at 0 ° C for 5 hours. After the reaction was over, the reaction was quenched with 20 ml of 6M hydrochloric acid. The mixture was extracted with ethyl acetate (100 ml / 3×), and the organic layer was combined and washed three times with saturated brine, dried over anhydrous EtOAc.

Wherein A is a phenyl group and R1 is as defined in claim 1.

Reaction step four:

Compound V (10 hr) was dissolved in 200 ml of anhydrous tetrahydrofuran in the presence of N ₂ , cooled to -78X, slowly added dropwise 5.5 ml of LDA solution (2M, llmmol), and maintained at -78 °C for 2 hours, The aldehyde R1CH0 (llmmol) was dissolved in 20 ml of anhydrous THF, and the solution was added dropwise to the reaction mixture. The solution became pale yellow, and the reaction was maintained at -78 TC for 2 hours and then slowly warmed to room temperature for 4 hours. With a 6N H ₂ S0 ₄ solution (20ml) quenched. After extraction with ethyl acetate (100 ml / 3), the organic layer was combined and washed three times with brine, dried over anhydrous Column chromatography (petroleum ether: ethyl acetate = 10:2) gave the cis and trans products of compound VII as oils.

Wherein, A and R1 are as defined in claim 1; R3 is a methyl group, and X is an oxygen atom. Reaction step five:

In the presence of N ₂ , compound IV (1 Ommol) was dissolved in 200 ml of anhydrous tetrahydrofuran, cooled to -78, and slowly dropped into 5 ml of LDA solution (2M, 10 leg. 1), and after -78 reaction for 1 hour, 12 ml of (i-Pr0) ₃ TiCl solution (1 M, 12 mmol) was added dropwise and the reaction was continued for 1 hour. The aldehyde R1CH0 (10 mmol) was dissolved in 15 ml of anhydrous THF, and the above reaction mixture was added dropwise thereto, and the reaction was maintained at -78 for 2 hours, and then the temperature was slowly raised to OX reaction overnight. The reaction was quenched with 6N of 11 ₂ 30 ₄ (201111). The mixture was extracted with EtOAc (EtOAc (EtOAc) (EtOAc) VII Both the formula and the trans isomer are oily.

Wherein A is a phenyl group, X is an oxygen atom, and R3 is H, and R1 is as defined in claim 1. Reaction step six:

10ml of compound VI (l Ommol) and thioacetic acid (large excess) of anhydrous pyridine and 5 drops of co-react for 3 days at 85-90, diluted with 100ml ethyl acetate was added, washed until no odor with a saturated aqueous solution of NaHC0 ₃ The ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated In the presence of N ₂ , 6 M of HCl was added to a solution of about 40 ml of HCl for 6-8 hours, and the mixture was cooled. The aqueous layer was extracted with ethyl acetate. The organic layer was combined and washed with saturated brine and dried over anhydrous magnesium sulfate. The oily liquid was refluxed with 10 ml of TFA for 2 hours, and then evaporated to dryness. EtOAc was evaporated. EtOAc EtOAc EtOAc EtOAc. The cis and trans isomers of the compound VI I are obtained.

Reaction step seven:

The cis and trans isomers of the compound VI I were separately dissolved in an appropriate amount of methanol, and an equimolar amount of a 1N aqueous solution of LiOH was added thereto, and stirred at room temperature overnight. 6N after the reaction The aqueous solution of HCl was acidified and extracted with EtOAc (EtOAc (EtOAc:EtOAc) The cis and trans isomers of the corresponding compound of formula II are obtained separately.

Wherein, A, X, R1, and R3 are as defined in claim 1.

Reaction step eight:

The compound of the formula II is subjected to an esterification reaction with an alkyl group or an alkenyl alcohol R20H under the action of a catalyst such as thionyl chloride, DCC or EDC to obtain a corresponding compound of the formula I.

Wherein, A, X, R1, and R3 are as defined in claim 1.

The compounds of the invention may also be used in the form of their pharmaceutically acceptable salts or solvates. Physiologically acceptable salts of the compound of formula I or formula I I include conventional salts formed from pharmaceutically acceptable inorganic or organic bases, and acid addition salts of quaternary ammonium. More specific examples of suitable base salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, strontium, Ν'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. Diamine, guanidine-methylglucamine and procaine salts. Hereinafter, when referring to the compound of the present invention, the compound of the formula I or the formula I I and pharmaceutically acceptable salts and solvates thereof are included.

The present invention also encompasses prodrugs of the compounds of the invention, which are those which, upon administration, undergo chemical conversion by metabolic processes, and then become active drugs. Typically, such prodrugs are functional derivatives of the compounds of the invention which are readily converted in vivo to the desired compound of formula (I). Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Des ign Of Prodrugs", H Bund Saard, El Sevier, ed., 1985.

The invention also includes an active metabolite of a compound of the invention, which refers to the invention A compound of the defined formula which still has the activity of the invention after being metabolized in vivo. Another aspect of the invention relates to a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier of a compound of the invention, which is useful for in vivo treatment and is biocompatible. The pharmaceutical composition can be prepared in various forms depending on the route of administration.

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, or a geometric isomer 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 plants. Partial glyceride mixture of fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, fiber Substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin.

The compound of the present invention is a type of fatty acid synthase inhibitor, and a US patent

Compared with the compound C75 mentioned in US Pat. No. 5,981,575, the compound of the present invention not only has a better inhibitory activity of a fatty acid synthase but also has a good stability, and is particularly 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 I diabetes and its complications, coronary heart disease, hypertension, and hyperlipidemia.

The invention can also be extended to the use of a medicament for the preparation of 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, whereby the compound of formula I and / or formula II or a pharmaceutically acceptable salt thereof or a solvate thereof It can be used for the relief or treatment of tumors such as colon cancer, prostate cancer, ovarian cancer, breast cancer or the like. Further, the compound containing the present invention and the composition containing the same 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 Intra, 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 magnesium stearate may also be added. The diluent used in the capsule formulation generally comprises lactose and dried cornstarch. 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.

When applied topically, especially in the treatment of facial or organs easily accessible by topical application, such as eye, skin or lower intestinal neurological diseases, the compounds of the invention may 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 ophthalmic use, the compound can also be formulated into a bone form such as vaseline.

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

The compounds of the invention may also be administered in the form of a sterile injectable preparation, including sterile injection Water or oil suspension or sterile injectable solution. Among them, carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, 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 5 mg/kg to 10 mg/kg body weight per day. detailed description

The invention is further illustrated by the following intermediates and examples which are not intended to limit the invention.

The melting point of the compound was determined by a YRT-3 type melting point apparatus, and the temperature was not corrected. The 'H-NMR spectrum was measured by a Bruker ARX 400 type nuclear magnetic instrument. FAB mass spectra were determined by a Zabspect high resolution magnetic mass spectrometer.

Example

Example 1 Synthesis of 3-hexyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid (compound PH6)

Preparation 1: Synthesis of 2-methoxycarbonylhydrazino-benzoic acid oxime ester

The raw material 2-carboxymethylene-benzoic acid 18 g (0.1 mol) was dissolved in 200 ml of methanol, and a catalytic amount of concentrated sulfuric acid was added thereto, followed by reflux overnight. Concentrated to remove most Yue alcohol was distilled, adding about 200ml of ethyl acetate to the residue, washed with water, saturated NaHC0 ₃ solution, and saturated brine until neutral, dried over anhydrous Na ₂ S0 _4, and concentrated to give the title compound as a 5克。 Oily material 18. 5g. The yield was 89%.

Preparation 2: Synthesis of 3-hexyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid (compound PH6)

In the presence of N ₂ , 2.08 g of 2-methoxycarbonylindenyl-benzoic acid methyl ester (10 mmol) was dissolved in 200 ml of anhydrous tetrahydrofuran, cooled to -78 Torr, and slowly added dropwise 5 ml of LDA solution (2M, 10 mmol) After maintaining -78 for 1 hour, 12 ml of (i-PrO) ₃ TiCl solution (1 M, 12 mmol) was added dropwise, and the reaction was continued for 1 hour. n-Heptanal (1.14 g, 10 mmol) was dissolved in 15 ml of anhydrous THF, and the solution was added dropwise to the reaction mixture. The solution became pale yellow, and the mixture was allowed to react for 2 hours and then slowly warmed to 0 C overnight. With a 6N H ₂ S0 ₄ solution (20ml) quenched. After extraction with ethyl acetate (100 ml / 3 ), the organic layer was combined and washed three times with saturated brine, dried over anhydrous MgSO. Column chromatography (petroleum ether: ethyl acetate = 10:2) gave cis compound 6a (650 mg) and trans compound 6b (638 mg) as oil. Compound 6a/6b was dissolved in an appropriate amount of decyl alcohol, and an equimolar amount of a 1N aqueous solution of LiOH was added thereto, and the mixture was stirred at room temperature for 1 hour, and the reaction was completed. The mixture was acidified with EtOAc (EtOAc) (EtOAc:EtOAcEtOAc The cis compound compound (PH6A) and the trans compound (PH6B) were obtained, respectively.

PH6A: 285mg Yield 10.3 % mp 76.5-77.5 FAB MS [M+l] ⁺ : m/z=277.1

'HNMR (400MHz, CD ₃ C1) δ = 8.16 (d, 1H, J = 6.72Hz); 7.59 (m, 1H); 7.50 (m, 1H); 7.33 (d, 1H, J = 7.28Hz); 4.61 (m, 1H); 3.85 (d, 1H, J=3.08Hz); 1.98 (m, 1H); 1.82 (m, 1H); 1.62 (m, 1H); 1.49 (m, 1H); 1.2-1.4 ( m, 6H) ; 0.88 (t, 3H, J = 6.74 Hz).

PH6B: 240mg Yield 8.7% mp 78-801: FAB MS [M+l] ⁺ : m/z=277.1

^NMR (400MHz, CD ₃ C1) δ = 8.15 (d, 1H, J = 7.56Hz); 7.62 (m, IH); 7.50 (m, IH); 7.32 (d, 1H, J=7.56); 4.92 ( m, IH); 3.90 (d, IH, J=5.32Hz); 1.78 (m, IH); 1.61 (m', IH); 1.1-1.5 (m, 8H); 0.86(t, 3H, J=6.72 Hz) ₀

Example 2: Synthesis of 3-heptyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid (compound PH7)

Using the preparation method of Example 1, except that n-heptanal was replaced with n-octanal, the title compounds PH7A (cis) and PH7B (trans) were obtained.

PH7A: 580mg Yield 20.1% mp 75-77 FAB MS [M+l] ⁺ : m/z=291.1

'HNMR (400MHz, CD ₃ C1) δ = 8.16 (d, IH, J = 6.56Hz); 7.58 (m, IH); 7.50 (m, IH); 7.33 (d, 1H, J = 7.28Hz); 4.61 (m, IH); 3.84 (d, 1H, J=3.08Hz); 1.97 (m, IH); 1.82 (m, IH); 1.62 (m, IH); 1.48 (m, IH); 1.2-1.4 ( m, 8H) ; 0.88 (t, 3H, J = 6.88 Hz).

PH7B: 604mg Yield 20.8% mp 79-82. FAB MS [M+l] ⁺ : m/z=291.3

NMR NMR (400MHz, CD ₃ C1) δ = 8.15 (d, IH, J = 7.88 Hz); 7.62 (m, IH); 7.50 (m, IH); 7.32 (d, IH, J = 7.56); 4.92 ( m, IH); 3.90 (d, 1H, J=5.32Hz); 1.78 (m, IH) ; 1.61 (m, IH) ; 1.1-1.5 (m, 10H); 0.87(t, 3H, J=6.86Hz ).

Example 3: Synthesis of 3-octyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid (compound PH8)

Using the preparation method of Example 1, except that n-heptanal was replaced with n-nonanal to give the title compounds PH8A (cis) and PH8B (trans).

PH8A: 540mg yield 17.7% mp 75-77 FAB MS[M+1] ⁺ : m/z=305.1

'HNMR (400MHz, CD ₃ C1) δ = 8.16 (d, 1H, J = 6.72Hz); 7.59 (m, IH); 7.50 (m, IH); 7.34 (d, 1H, J = 7.28Hz); 4.61 (m, IH); 3.84 (d, IH, J-3.08Hz); 1.98 (m, IH); 1.83 (m, IH); 1.63 (m, IH); 1.49 (m, IH); 1.2-1.4 ( m, 10H); 0.88 (t, 3H, J = 6.74 Hz).

Anal.Calcd for C ₁₈ H ₂₄ 0 ₄ (304.39): C, 71.03; H, 7.95

Found: C, 71.39; H, 8.21

PH8B: 616mg Yield 20.3% mp 79-82. FAB MS [M+l] ⁺ : m/z=305.3

'HNMR (400MHz, CD ₃ C1) δ = 8.15 (d, IH, J = 7.70Hz); 7.62 (m, IH); 7.50 (m, IH); 7.33 (d, 1H, J = 7.88); 4.92 ( m, IH); 3.91 (d, 1H, J=5.32Hz); 1.78 (m, IH); 1.61 (m, IH) ; 1.1-1.5 (m, 12H); 0.87(t, 3H, J=6.86Hz ).

Anal.Calcd for C ₁₈ H ₂₄ 0 ₄ (304.39): C, 71.03; H, 7.95

Found: C, 71.37; H, 8.18

Example 4: Synthesis of 3-mercapto-1-oxo-isobenzotetrahydropyran-4-carboxylic acid (compound PH9)

Using the preparation method of Example 1, except that n-heptanal was replaced with n-nonanal to give the title compounds PH9A (cis) and PH9B (trans).

PH9A: 640mg Yield 20.1% mp 75-77 FAB MS[M+1] ⁺ : m/z=319.1

'H MR (400MHz, CD ₃ C1) δ = 8.15 (d, IH, J = 7.56Hz); 7.58 (m, IH); 7.50 (m, IH); 7.32 (d, 1H, J = 7.56Hz); 4.61 (m, IH); 3.84 (d, 1H, J=3.08Hz); 1.97 (m, IH); 1.83 (m, IH); 1.60 (m, IH); 1.45 (m, IH); 1.0-1.4 (m, 12H); 0.87 (t, 3H, J = 6.74 Hz).

PH9B: 600mg yield 18.8% mp 79-82.5 FAB MS [M+l] ⁺ : m/z=319.3 N2007/003119

'H MR (400MHz, CD ₃ C1) δ = 8.15 (d, IH, 1 = 6.72Hz); 7.62 (m, IH); 7.50 (m, IH); 7.32 (d, 1H, J=7.92); 4.92 (m, IH); 3.91(d, 1H, J=5.32Hz); 1.80 (m, IH) ; 1.62 (m, IH); 1.1-1.5 (m, 14H); 0.87 (t, 3H, J=6.86 Hz).

Example 5: Synthesis of 3-mercapto-1-oxo-isobenzotetrahydropyran-4-carboxylic acid (compound PH10)

The preparation method of Example 1 was carried out except that n-heptanal was replaced with n-undecaldehyde to give the title compounds PH10A (cis) and PH10B (trans).

PHIOA: 616mg Yield 18.5% mp 75-77 FAB MS [M+l] ⁺ : m/ z=333.1

'HNMR (400MHz, CD ₃ C1) δ = 8.15 (d, IH, J = 7.00Hz); 7.58 (m, IH); 7.50 (m, IH); 7.32 (d, 1H, J = 7.56Hz); 4.61 (m, IH); 3.84 (d, IH, J=3.08Hz); 1.98 (m, IH); 1.83 (m, IH); 1.60 (m, IH); 1.49 (m, IH); 1.0-1.4 ( m, 14H); 0.87 (t, 3H, J=6.86Hz) _β

PH10B: 610mg yield 18.6% mp 79-82.5 FAB MS [M+l] ⁺ : m/ z=333.1

NMR NMR (400MHz, CD ₃ C1) δ =8.11 (d, 1H, J=7.88Hz); 7.59 (m, IH); 7.46 (m, IH); 7.31 (d, 1H, J=6.44) ; 4.90 ( b, IH); 3.85(b, IH, J=5.32Hz); 1.75 (m, IH); 1.56 (m, IH); 1.1-1.5 (m, 16H); 0.87(t, 3H, J=6.72Hz ).

Example 6: Synthesis of 3-undecyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid (Compound PH11)

The preparation method of Example 1 was carried out except that n-glycolate was changed to n-dodecaldehyde to obtain the title compounds PH11A (cis) and PH11B (trans).

PH11A: 600mg Yield 17.3% mp 75-77Ό FAB MS [M+l] ⁺ : m/z=347.1

NMR NMR (400MHz, CD ₃ C1) δ =8.16 (d, 1H, J=6.72Hz); 7.59 (m, 1H); 7.50 (m, 1H); 7.34 (d, 1H, J-7.56Hz); 4.61 (m, 1H); 3.85 (d, 1H, J=5.60Hz); 1.99 (m, 1H); 1.83 ( m, 1H); 1.62 (m, 1H); 1.49 (m, 1H); 1.0-1.4 (m, 16H); 0.88 (t, 3H, J = 6.76 Hz).

PHllB: 596mg Yield 17%, 2% mp 79-82.5°C FAB MS [M+l] ⁺ : m/z=347.1

^{_{! H NMR (400MHz, CD 3}} C1) δ = 8.15 (d, 1H, J = 6.72Hz); 7.62 (m, 1H); 7.50 (m, 1H); 7.32 (d, 1H, J = 7.84); 4.91 (b, 1H); 3.91 (b, 1H, J=5.32Hz); 1.79 (m, 1H); 1.62 (m, 1H); 1.1-1.5 (m, 18H); 0.87(t, 3H, J=6.72 Hz). Example 7: Synthesis of 3-hexyl-4-mercapto-1-oxo-isobenzotetrahydropyran-4-carboxylic acid (MPH6)

Preparation 1: Synthesis of 2-(1-methoxycarbonyl-ethyl)-benzoic acid methyl ester

In the presence of N ₂ , 9.6 g of 2-methoxycarbonylindenyl-benzoic acid oxime ester (46 mmol) was dissolved in 200 ml of anhydrous tetrahydrofuran, cooled to -78, and slowly dropped into 48 ml of LDA solution (2M, 96 mmol). The reaction was kept for 2 hours. Iodine ( 6.82 g, 48 mmol) was dissolved in 20 ml of anhydrous THF and 20 ml of anhydrous DMF. The solution was added dropwise to the above reaction solution, and the solution became a pale yellow suspension, and the reaction was maintained at -78 TC for 1 hour. The temperature was raised to -60 C and the reaction was continued for 1 hour. The solution became clear and the reaction was stopped. The reaction solution was poured into H ₂ S0 ₄ solution (6N, 40ml) in, (300ml / 3 times) and extracted with ethyl acetate, the organic layers were combined and washed 3 times with saturated brine, dried over anhydrous MgS04, and concentrated to give a brown liquid . Column chromatography (petroleum ether: ethyl acetate: glacial acetic acid - 10:3: 0.07). That is, the title compound was 10.6 g (yield of oil, 90.4%).

Preparation 2: Synthesis of 3-hexyl-4-methyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid (MPH6)

In the presence of N ₂ , 2.22 g of 2-(1-indoxycarbonyl-ethyl)-benzoic acid decyl ester (10 mmol) was dissolved in 200 ml of anhydrous tetrahydrofuran, cooled to -78 Torr, and slowly dropped into 5.5 ml of LDA solution ( 2M, 11 let ol), hold - 78 After 2 hours of reaction, n-heptanal (1.25 g, 11 匪ol) was dissolved in 20 ml of anhydrous THF, and the above reaction solution was added dropwise, and the solution turned pale yellow, maintaining -78 reaction. After 2 hours, the temperature was slowly raised to room temperature for 4 hours. With a 6N H ₂ S0 ₄ solution (20ml) quenched. The organic layer was combined and washed with brine brine (3××××××××××××××××××××× Column chromatography (petroleum ether: ethyl acetate = 10:2) gave compound 6a (400 mg) and 6b (478 mg) as oil. Compound 6a/6b was dissolved in an appropriate amount of methanol, and an equimolar amount of a 1N aqueous solution of LiOH was added thereto, and stirred at room temperature overnight. After completion of the reaction, the mixture was acidified with EtOAc (EtOAc) (EtOAc) (EtOAc) 0.05). The cis compound MPH6A and the trans compound MPH6B were obtained, respectively.

MPH6A: 230mg Yield 7.93 % mp 76.5-77.5 FAB MS [M+l] ⁺ : m/z=291.1

^{_{! HNMR (400MHz, CD 3 C1}} ) δ = 8.14 (d, 1H, J = 6.72Hz); 7.62 (m, 1H); 7.47 (m, 1H); 7.27 (d, 1H, J = 6.72Hz); 4.88 (m, 1H); 1.74 (m, 2H); 1.1-1.6 (m, 8H); 1.50 (s, 3H); 0.88 (t, 3H, J = 6.86 Hz).

Anal.Calcd for C ₁₇ H ₂₂ 0 ₄ (290.36): C, 70.32; H, 7.64

Found: C, 70.01; H, 7.91

MPH6B: 307mg yield is 10.59% mp 78- 80 FAB MS [M+l] ⁺ : m/z=291.1

^{_{! H NMR (400MHz, CD 3}} C1) δ = 8.17 (d, 1H, J = 6.16Hz); 7.61 (m, IH); 7.35-7.50 (m, 2H); 4.30 (m, IH); 1.82 (m, 2H); 1.1-1.5 (m, 8H); 1.64 (s, 3H); 0.88 (t, 3H, J= 6.72Hz)„

Anal.Calcd for C ₁₇ H ₂₂ 0 ₄ (290.36): C, 70.32; H, 7.64

Found: C, 70.07; H, 7.92

Example 8: Synthesis of 3-heptyl-4-indenyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid (MPH7)

Using the preparation method of Example 7, except that n-heptanal was replaced by n-octanal, the title compounds MPH7A (cis) and MPH7B (trans) were obtained.

MPH7A: 270mg Yield 8.88% mp 75-771: FAB MS [M+l] ⁺ : m/z=305.1

'H NMR (400MHz, CD ₃ C1) δ = 8.15 (d, 1H, J = 7.7 Hz); 7.62 (m, IH); 7.47 (m, IH); 7.28 (d, IH, J = 7.84 Hz); 4.88 (m, IH); 1.74 (m, 2H); 1.1-1.6 (m, 10H); 1.50 (s, 3H); 0.88 (t, 3H, J = 6.86 Hz).

MPH7B: 300mg Yield 9.87% mp 79-82.5° FAB MS [M+l] ⁺ : m/z-305.1

NMR NMR (400MHz, CD ₃ C1) δ=8.14 (d, 1H, J=7.88Hz); 7.60 (m, IH); 7.42-7.47 (m, 2H) ; 4.29 (m, IH); 1.80 (m, 2H) ; 1.1-1.5 (m, 10H); l, 63 (s, 3H); 0.88 (t, 3H, J-6.86 Hz).

Example 9: Synthesis of 3-octyl-4-methyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid (MPH8)

Using the preparation method of Example 7, except that n-heptanal was replaced with n-nonanal to give the title compounds MPH8A (cis) and MPH8B (trans).

MPH8A: 207mg Yield 6.51% mp 75-77 FAB MS [M+l] ⁺ : m/z=319.1

NMR NMR (400MHz, CD ₃ C1) δ = 8.15 (d, 1H, J = 7.84Hz); 7.61 (m, IH); 7.47 (m, IH); 7.26 (d, 1H, J = 7.28Hz); 4.88 (m, IH); 1.75 (m, 2H); 1.1-1.6 (m, 12H); 1.50 (s, 3H); 0.88 (t, 3H, J = 6.86 Hz). MPH8B: 310mg yield 9.75% mp 79-82.5 FAB MS [M+l] ⁺ : m/z-319.1

NMR NMR (400MHz, CD ₃ C1) δ = 8.17 (d, IH, J = 7.84Hz); 7.61 (m, IH); 7.44-7.49 (m, 2H); 4.31 (m, IH); 1.83 (m, 2H) ; 1.1-1.5 (m, 12H); 1.65 (s, 3H); 0.88 (t, 3H, J-6.72 Hz).

Example 10: Synthesis of 3-mercapto-4-indolyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid (MPH9)

Using the preparation method of Example 7, except that n-glycolate was changed to n-nonanal, the title compounds MPH9A (cis) and MPH9B (trans) were obtained.

MPH9A: 200mg Yield 6.01% mp 75-771; FAB MS[M+1] ⁺ : m/ z=333.1

NMR NMR (400MHz, CD ₃ C1) δ = 8.15 (d, IH, J = 7.84Hz); 7.61 (m, IH); 7.47 (m, IH); 7.26 (d, 1H, J = 7.00Hz); 4.88 (m, IH); 1.76 (m, 2H); 1.1-1.6 (m, 14H); 1.50 (s, 3H); 0.88 (t, 3H, J = 6.86 Hz).

MPH9B: 273mg Yield 8.20% mp 79-82. FAB MS [M+l] ⁺ : m/z=333.1

NMR NMR (400MHz, CD ₃ C1) δ =8.17 (d, 1H, J=7.84Hz); 7.61 (m, IH); 7.44-7.49 (m, 2H); 4.32 (m, IH); 1.83 (m, 2H) ; 1.1-1.5 (m, 14H); 1.64 (s, 3H); 0.88 (t, 3H, J-6.82 Hz).

Example 11: Synthesis of 3-mercapto-4-indolyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid (MPH10)

Using the preparation method of Example 7, except that n-heptanal was replaced with n-undecaldehyde, the title compounds MPH10A (cis) and MPH10B (trans) were obtained.

MPH10A: 240mg Yield 6.94% mp 75-77 FAB MS [M+l] ⁺ : m/z=347.1

NMR NMR (400MHz, CD ₃ C1) δ=8.15 (d, IH, J=7.84Hz); 7.61 (m, IH); 7.47 (m, IH); 7.26 (d, IH, J=7.84Hz); 4.88 (m, IH); 1.76 (m, 2H); 1.1-1.6 (m, 16H); 1.50(s, 3H); 0.88 (t, 3H, J=6.86Hz) „ Anal.Calcd for C ₂₁ H ₃₀ O ₄ (346.47) : C, 72.80; H , 8.73 Found: C, 72.51; H, 8.98

MPH10B: 310mg Yield 8.96 % mp 79-82.5 Γ FAB MS [M+l] ⁺ : m/z=347.1

^{_{! H NMR (400MHz, CD 3}} C1) δ = 8.17 (d, 1H, J = 7.84Hz); 7.61 (m, IH); 7.44-7.49 (m, 2H); 4.31 (m, IH); 1.82 (m , 2H); 1.1-1.5 (m, 16H); 1.65 (s, 3H); 0.88 (t, 3H, J = 6.86 Hz).

Anal.Calcd for C ₂₁ H ₃₀ O ₄ (346.47) : C, 72.80; H, 8.73

Found: C, 72.51; H, 8.98

Example 12: Synthesis of 3-undecyl-4-methyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid (MPH11)

The preparation method of Example 7 was carried out except that n-heptanal was replaced with n-dodecaldehyde to obtain the title compounds MPH11A (cis) and MPH11B (trans).

MPHllA: 230mg Yield 6.39% mp 75-77*C FAB MS [M+l] ⁺ : m/z=361.1

^{_{! H NMR (400MHz, CD 3}} C1) δ = 8.15 (d, IH, J = 7.84Hz); 7.61 (m, IH); 7.47 (m, IH); 7.26 (d, 1H, J = 6.20Hz); 4.88 (m, IH); 1.76 (m, 2H); 1.1-1.6 (m, 18H); 1.50 (s, 3H); 0.88 (t, 3H, J-6.88 Hz).

MPH11B: 270mg Yield 7.50% mp 79-82.5 Γ FAB MS [M+l] ⁺ : m/z=361.1

NMR NMR (400MHz, CD ₃ C1) δ =8.17 (d, 1H, J=7.84Hz); 7.61 (m, IH); 7.44-7.49 (m, 2H) ; 4.31 (m, IH) ; 1.83 (m, 2H) ; 1.1-1.5 (m, 18H); 1.65 (s, 3H); 0.88 (t, 3H, J = 6.86 Hz).

Example 13: 6-Hexyl-1,3,7-trimethyl-4-oxo-1,4,6,7-tetrahydropyran[4,3-b]-pyrrole-7-carboxylic acid (PMN6) )Synthesis

Preparation 1: 2-(1-methoxycarbonyl-ethyl)-1,4-dimethyl-1H-pyrrole-3 - Synthesis of methyl carboxylate

The synthesis method is the same as that of 2-(1-oxocarbonyl-ethyl)-benzoic acid methyl ester, except that the starting material is changed from 2-methoxycarbonylmethylene-benzoic acid decyl ester to 2-hydrazine. Oxylcarbonylindenyl-1,4-dimercapto-1H-pyrrole-3-carboxylic acid decyl ester, yield 87.6%.

FAB MS [M+l] ⁺ : m/z = 240.1 NMR (400 MHz, CD ₃ C1) δ = 6.28 (s, 1H); 4.67 (t, 1H, J = 7.32 Hz); 3.77 (s, 3H) ;3.6(s, 3H); Synthesis of 4-Oxo-1,4,6,7-tetrahydropyran[4,3-b]-pyrrole-7-carboxylic acid (PMN6)

The synthesis method of such a compound is the same as that of the synthesis method of Example 7, except that the starting material 2-(1-oximeoxycarbonyl-ethyl)-benzoic acid methyl ester is changed to 2-(1-methoxycarbonyl-ethyl)- 1, 4-Dimethyl-1H-pyrrole-3-carboxylate. The n-heptanal was used to obtain the title compounds PMN6A (cis) and PMN6B (trans).

PMN6A: 230mg Yield 7.93 % mp 76.5-77.5 FAB MS [M+l] ⁺ : m/z=308.1

NMR NMR (400MHz, CD ₃ C1) δ =6.32 (d, 1H, J=l.12Hz); 4.72 (dd, 1H, J=10.36, 1.4Hz); 3.47 (s, 3H) ; 2.26 (d, 3H , J = 0.84 Hz); 1.80 (m, 2H); 1.2-1.5 (m, 8H); 1.41 (s, 3H); 0.88 (t, 3H, J = 6.72 Hz).

PMN6B: 307mg yield is 10.59% mp 78-80X FAB MS [M+l] ⁺ : m/z=308.1

NMR NMR (400MHz, CD ₃ C1) δ = 6.34 (d, 1H, J = 0.84 Hz); 4.27 (dd, 1H, J = 9.24, 2.52 Hz); 3.60 (s, 3H); 2.26 (d, 3H, J=l.12Hz); 1.76(m, 2H) ; 1.65 (s, 3H) ; 1.2-1.5 (m , 8H) ; 0.88 (t , 3H, J=7.00Hz) ₀

Example 14: 6-Heptyl-1,3,7-trimethyl-4-oxo-1,4,6,7-tetrahydropyran[4,3-b]-pyrrole-7-carboxylic acid ( Synthesis of PMN7)

Prepared as in Example 13 except that n-heptanal was replaced by n-octanal to give the title compounds PMN7A (cis) and PMN7B (trans).

PMN7A: 270mg yield 8.88% mp 75- 77 FAB MS [M+l] ⁺ : m/z=322.1

NMR NMR (400MHz, CD ₃ C1) δ = 6.32 (s , 1H); 4.72 (d, 1H, J = 10.64 Hz); 3.47 (s, 3H) ; 2.26 (s, 3H) ; 1.80 (m, 2H) ; 1.2-1.5 (m, 10H); 1.40(s, 3H); 0.88 (t, 3H, J=6.72Hz) _β

PMN7B: 300mg Yield 9.87% mp 79-82. FAB MS [M+l] ⁺ : m/z=322.1

NMR NMR (400MHz, CD ₃ C1) δ = 6.34 (s, 1H); 4.27 (dd, 1H, J=9.24, 2.8Hz); 3.60(s, 3H); 2.27(s, 3H); 1.76 (m, 2H); 1.65 (s, 3H); 1.2-1.5 (m, 10H); 0.88 (t, 3H, J-6.72 Hz).

Example 15: 6-octyl-1,3,7-trimethyl-4-oxo-1,4,6,7-tetrahydropyran[4,3-b]-pyrrole-7-carboxylic acid ( Synthesis of PMN8)

Prepared as in Example 13 except that n-heptanal was converted to n-furfural to give the title compound PMN8A (cis) and PMN8B (trans).

PMN8A: 207mg Yield 6.51% mp 75-77Ό FAB MS[M+1] ⁺ : m/ z=336.1

NMR NMR (400MHz, CD ₃ C1) δ =6.31 (d, 1H, J=0.84Hz); 4.72 (d, 1H, J=10.64Hz); 3.47(s, 3H) ; 2.25 (d, 3H, J= 0.84Hz) ; 1.80 (m, 2H); 1.2-1.5 (m, 12H); 1.40 (s, 3H); 0.88 (t, 3H, J-7.00 Hz). Anal. Calcd for C ₁₉ H ₂₉ N0 ₄ (335.45): C, 68.03; H, 8.71; N,

4.18

Found: C, 68.41; H, 8.98; N, 4.01

PMN8B: 310mg Yield 9.75% mp 79-82. FAB MS [M+l] ⁺ : m/z=336.1

NMR NMR (400MHz, CD ₃ C1) δ =6.33 (s , 1H); 4.25 (d, 1H, J=9.56Hz); 3.60(s, 3H) ; 2.25(s, 3H) ; 1.76 (m, 2H) ; 1.2-1.5 (m, 12H); 1.64 (s, 3H); 0.88(t, 3H, J=6.88Hz) ₀

Anal. Calcd for C ₁₉ H ₂₉ N0 ₄ (335.45): C, 68.03; H, 8.71; N,

4.18

Found: C, 68.47; H, 8.98; N, 3.98

Example 16: 6-Mercapto-1,3,7-trimethyl-4-oxo-1,4,6,7-tetrahydropyran[4,3-b]-pyrrole-7-carboxylic acid ( Synthesis of PMN9)

Prepared as in Example 13 except that n-heptanal was converted to n-furfural to give the title compound PMN9A (cis) and PMN9B (trans).

PMN9A: 200mg Yield 6.01% mp 75-77 FAB MS [M+l] ⁺ : m/z=350.1

NMR NMR (400MHz, CD ₃ C1) δ =6.32 (d, 1H, J=0.84Hz); 4.72 (d, 1H, J=10.36Hz); 3.47(s, 3H) ; 2.26 (d, 3H, J= 0.84Hz); 1.80 (m, 2H); 1.2-1.5(m, 14H); 1.40(s, 3H) ; 0.88(t, 3H, J=6.86 Hz)

PMN9B: 273mg yield 8.20% mp 79-82.5V FAB MS [M+l] ⁺ : m/z=350.1

^{_{! H NMR (400MHz, CD 3}} C1) δ = 6.34 (d, 1H, J = 0.84Hz); 4.27 (dd, 1H, J = 8.96, 2.80Hz); 3.60 (s, 3H); 2.26 (d, 3H , J = 0.84 Hz); 1.76 (m, 2H); 1.65 (s, 3H); 1.2-1.5 (m, 14H); 0.88 (t, 3H, J = 6.88 Hz). Example 17: 6-Mercapto-1,3,7-trimethyl-4-oxo-1,4,6,7-tetrahydropyran[4,3-b]-pyrrole-7-carboxylic acid ( Synthesis of PMN10)

Prepared as in Example 13 except that n-heptanal was converted to n-decanoaldehyde to give the title compounds PMN10A (cis) and PMN10B (trans).

PMNIOA: 240mg yield 6.94% mp 75-77Γ FAB MS [M+l] ⁺ : m/z=364.1

NMR NMR (400MHz, CD ₃ C1) δ =6.31 (d, 1H, J=0.84Hz); 4.72 (dd, 1H, J=9.24, 1.4Hz); 3.47(s, 3H) ; 2.25 (d, 3H, J = 0.84 Hz); 1.80 (m, 2H); 1.2 - 1.5 (m, 16H); 1.40 (s, 3H); 0.88 (t, 3H, J = 6.86 Hz).

PMN10B: 310mg Yield 8.96 % mp 79-82.5 X: FAB MS [M+l] ⁺ : m/z=364.1

NMR NMR (400MHz, CD ₃ C1) δ =6.33 (d, 1H, J=0.84Hz); 4.27 (dd, 1H, J=9.24, 2.56Hz); 3.59 (s, 3H) ; 2.26 (d, 3H, J = 1.12 Hz); 1.76 (m, 2H); 1.64 (s, 3H); 1.2-1.5 (m, 16H); 0.88 (t, 3H, J = 6.86 Hz).

Example 18: 6-undecyl-1,3,7-trimethyl-4-oxo-1,4,6,7-tetrahydropyran[4,3-b]-pyrrole-7-carboxylate Synthesis of acid (PMN11)

Prepared as in Example 13 except that n-heptanal was converted to n-dodecaldehyde to give the title compounds PMN11A (cis) and PMN11B (trans).

PMNllA: 230mg yield 6.39% mp 75-77X FAB MS [M+l] ⁺ : m/z=378.1

NMR NMR (400MHz, CD ₃ C1) δ =6.32 (d, 1H, J=l.12Hz); 4.72 (dd, 1H, J=8.96, 1.4Hz); 3.46(s, 3H) ; 2.26 (d, 3H , J = 0.84 Hz); 1.80 (m, 2H); 1.2-1.5 (m, 18H); 1.40 (s, 3H); 0.88 (t, 3H, J = 6.66 Hz).

Anal. Calcd for C ₂₂ H ₃₅ N0 ₄ (377.53): C, 69.99; H, 9.34; N, 3.71

Found: C, 69.47; H, 9.78; N, 3.98

PMN11B: 270mg Yield 7.50% mp 79-82.5 Ό FAB MS [M+l] ⁺ : m/z=378.1

'H NMR (400MHz, CD ₃ C1) δ =6.34 (d, 1H, J=0.84Hz); 4.27 (d, 1H, J=8.96Hz); 3.60(s, 3H) ; 2.26 (d, 3H, J = 0.84 Hz); 1.76 (m, 2H); 1.65 (s, 3H); 1.2-1.5 (m, 18H); 0.88 (t, 3H, J = 6.86 Hz).

Anal. Calcd for C ₂₂ H ₃₅ N0 ₄ (377.53): C, 69.99; H, 9.34; N,

3.71

Found: C, 69.55; H, 9.69; N, 3.99

Example 19: Synthesis of 3-hexyl-1-oxo-isobenzotetrahydrothiopyran-4-carboxylic acid (PHS6)

Preparation 1: Synthesis of 2-(1-曱-oxycarbonyl-octane-1-ene)-benzoic acid methyl ester

In the presence of N ₂ , 2-oxocarbonylcarbonylindenyl-benzoic acid methyl ester ( 4.16 g,

0.02 mol) dissolved in 30 ml of dry THF solution, slowly dropping NaH (60%, 0)

A suspension of 1.0 g, 0.025 mol) in 200 ml of anhydrous THF was kept at 0 for 2 hr, and the reaction mixture became an emulsion. Heptanal (2.28 g, 20 awake ol) was dissolved in 20 ml of anhydrous THF, and the above reaction solution was added dropwise, and the solution became a pale yellow clear liquid, and the reaction was continued for 5 hours. After the reaction was over, the reaction was quenched with 20 ml of 6M hydrochloric acid. The mixture was extracted with EtOAc (EtOAc) (EtOAc m.

Preparation 2: Synthesis of 3-hexyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid (PHS6)

3.04 g (10 mmol) of methyl 2-(l-methoxycarbonyl-dodecan-1-ene)-benzoate and 10 ml of thioacetic acid (large excess) and 5 drops of anhydrous pyridine were reacted at 85-90X. days, diluted with ethyl acetate 100ml was added, washed until no odor with saturated aqueous NaHC0 _3, the ethyl acetate layer was dried over anhydrous sodium sulfate, and concentrated to give a black oil. In the presence of N ₂ , 6 M of HCl was added to a solution of about 40 ml of HCl for 6-8 hours, and the mixture was cooled. The aqueous layer was extracted with ethyl acetate. The organic layer was combined and washed with saturated brine and dried over anhydrous magnesium sulfate. The oily liquid was refluxed with 10 ml of TFA for 2 hours, and then evaporated to dryness. EtOAc was evaporated. EtOAc EtOAc EtOAc EtOAc The cis-trans isomer compound 6A/6B was obtained. Compound 6a/6b was dissolved in an appropriate amount of decyl alcohol, and an equimolar amount of a 1N aqueous solution of LiOH was added thereto, and stirred at room temperature overnight. After completion of the reaction, the mixture was acidified with EtOAc (EtOAc) (EtOAc) (EtOAc) 0.05). The title compounds PHS6A (cis) and PHS6B (trans) were obtained, respectively.

PHS6A: 420mg Yield 14.38% mp 75-771: FAB MS [M+l] ⁺ : m/z=293.1

NMR NMR (400MHz, CD ₃ C1) δ = 7.98 (dd, 1H, J=7.84, 1.40Hz); 7.53 (m, 1H); 7.47 (m, 1H) ; 7.27 (d, 1H, J=9.52Hz) 4.10(d, 1H, J=3.08Hz); 3.93 (m, 1H); 1.99 (m, 1H); 1.84 (m, 1H); 1.1-1.6 (m, 8H); 0.88(t, 3H, J =6.72Hz)„ Anal. Calcd for C ₁₆ H ₂₀ O ₃ S (292.40): C, 65.72; H, 6.89; S, 10.97

Found: C, 65.47; H, 7.11; S, 11.27

PHS6B: 332mg yield 11.37% mp 75-77 FAB MS [M+l] ⁺ : m/z=293.1

'HNMR (400MHz, CD ₃ G1) δ=7.98 (d, 1H, J=6.72Hz); 7.57 (m, 1H); 7.49 (m, 1H); 7.25 (d, 1H, J=6.16Hz); 4.06 (d, 1H, J = 3.36 Hz); 3.83 (m , 1H); 1.63 (m , 2H) ; 1.1-1.6 (m , 8H) ; 0.88 (t , 3H, J = 6.72 Hz).

Example 20: Synthesis of 3-heptyl-1-oxo-isobenzotetrahydrothiopyran-4-carboxylic acid (PHS7)

Prepared as in Example 19 except that n-heptanal was replaced by octanal to give the title compounds PHS7A (cis) and PHS7B (trans).

PHS7A: 395mg yield 12.91% mp 75-77 FAB MS [M+l] ⁺ : m/z=307.1

NMR NMR (400MHz, CD ₃ C1) δ =7.98 (dd, 1H, J=7.84, 1.68Hz); 7.53 (m, 1H); 7.47 (m, 1H); 7.28 (d, 1H, J=l.12Hz 4.10(d, 1H, J=3.08Hz); 3.93 (m, 1H); 1.99 (m, 1H); 1.83(m, 1H); 1.1-1.6 (m, 10H); 0.87 (t, 3H, J=6.88Hz) ₀

PHS7B: 342mg yield 11.18% mp 75-77Γ FAB MS [M+l] ⁺ : m/z=307.1

'HNMR (400MHz, CD ₃ C1) δ=7.98 (d, 1H, J=7.84Hz); 7.57 (m, 1H); 7.48 (m, 1H); 7.25 (d, 1H, J=6.16Hz); 4.07 (d, 1H, J=3.36Hz); 3.83 (m, 1H); 1.63 (m, 2H) ; 1.1-1.6 (m, 10H); 0.85 (t , 3H, J=6.88Hz) ₀

Example 21: Synthesis of 3-octyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid (PHS8) Prepared as in Example 19 except that n-heptanal was converted to furfural to give the title compound, </RTI><RTIgt;

PHS8A: 259mg yield 8.09% mp 75-77 X FAB MS[M+1] ⁺ : m/z=321.1

'HNMR (400MHz, CD ₃ C1) δ = 7.98 (d, 1H, J = 6.76Hz); 7.53 (m, 1H); 7.47 (m, 1H); 7.28 (d, 1H, J = 7.84Hz); 4.10 (d, 1H, J=3.08Hz); 3.92 (m, 1H); 1.99 (m, 1H); 1.83 (m, 1H); 1.1-1.6 (m, 12H); 0.87 (t, 3H, J=6.88 Hz).

PHS8B: 246mg yield 7.69% mp 75-77 FAB MS[M+1] ⁺ : m/z=321.1

_{'HNMR (400MHz, CD 3 C1} ) δ = 7.98 (dd, 1H, J = 7.88, 1.12Hz); 7.56 (m, 1H); 7.48 (m, 1H); 7.24 (d, 1H, J = 8.72Hz) ; 4.07 (d, 1H, J=3.36Hz); 3.83 (m, 1H) ; 1.63 (m, 2H) ; 1.1-1.6 (m, 12H);

0.85(t, 3H, J=6.86Hz)„

Example 22: Synthesis of 3-mercapto-1-oxo-isobenzotetrahydrothiopyran-4-carboxylic acid (PHS9)

Prepared as in Example 19 except that n-heptanal was replaced by furfural to give the title compounds PHS9A (cis) and PHS9B (trans).

PHS9A: 306mg yield 9.16% mp 75-77Γ FAB MS [M + 1] +: m / z = 335.1

NMR NMR (400MHz, CD ₃ C1) δ = 7.98 (dd, 1H, J = 6.56, 1.12Hz); 7.53 (m, 1H); 7.47(m, 1H) ; 7.28(d, 1H, J=7.84Hz) ;410 (m, 1H);

1.1-1.6 (m, 14H); 0.87 (t, 3H, J = 6.86 Hz).

PHS9B: 321mg Yield 9.61% mp 75-77 FAB MS[M+1] ⁺ : m/ z=335.1

_{'HNMR (400MHz, CD 3 C1} ) δ = 7.98 (dd, 1H, J = 7.88, 1.40Hz); 7.57 (m, IH); 7.49 (m, IH); 7.26 (d, 1H, J = 6.16 Hz); 4.07 (d, IH, J = 3.36 Hz); 3.83 (m, IH); 1.63 (m, 2H) ); 1.1-1.6 (m, 14H);

0.86 (t, 3H, J = 7.00 Hz).

Example 23: Synthesis of 3-mercapto-1-oxo-isobenzotetrahydrothiopyran-4-carboxylic acid (PHS10)

Prepared as in Example 19 except that n-heptanal was converted to the undecalaldehyde to give the title compound, PHS10A (cis) and PHS10B (trans).

PHSIOA: 380mg Yield 10.92% mp 75-77 FAB MS [M+l] ⁺ : m/z=349.1

'HNMR (400MHz, CD ₃ C1) δ =7.99 (dd, 1H, J=7.56, 1.40Hz); 7.53 (m, IH); 7.47 (m, IH); 7.28 (d, 1H, J=7.84Hz) ;411 (m, IH);

1.1-1.6 (m, 16H); 0.87 (t, 3H, J = 6.88 Hz).

Anal. Calcd for C ₂₀ H ₂₈ O ₃ S (348.51): C, 68.93; H, 8.10; S,

9.20

Found: C, 68.67; H, 8.48; S, 8.97

PHS10B: 330mg yield 9.48% mp 75-77X FAB MS [M+l] ⁺ : m/z=349.1

_{Ή NMR (400MHz, CD 3 C1} ) δ = 7.98 (d, 1H, J = 7.84Hz); 7.57 (m, IH); 7.48 (m, IH); 7.24 (d, 1H, J = 5.88Hz); 4.07 (d, 1H, J = 3.36 Hz); 3.83 (m, IH); 1.64 (m, 2H); 1.1-1.6 (m, 16H); 0.86 (t, 3H, J = 6.86 Hz).

Anal. Calcd for C ₂₀ H ₂₈ O ₃ S (348.51): C, 68.93; H, 8.10; S,

9.20

Found: C, 68.72; H, 8.39; S, 9.00

Example 24: Synthesis of 3-undecyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid (PHS11) Prepared as in Example 19 except that n-heptanal was replaced with dodecanal to give the title compound, PHS11A (cis) and PHS11B (trans).

PHS11A: 354mg yield 9.78% mp 75-77 FAB MS [M+l] ⁺ : m/z=363.1

'H MR (400MHz, CD ₃ C1) δ =7.99 (dd, 1H, J=7.56, 1.40Hz); 7.54 (m, 1H); 7.47 (m, 1H); 7.27 (d, 1H, J=7.56Hz 4.11 (d, 1H, J=3.36Hz); 3.93 (m, 1H); 1.99 (m, 1H); 1.84 (m, 1H); 1.1-1.6 (m, 18H); 0.87(t, 3H, J = 6.86 Hz).

PHS11B: 250mg yield 6.91% mp 75-77 FAB MS [M+l] ⁺ : m/z=363.1

^NMR (400MHz, CD ₃ C1) δ =7.98 (dd, 1H, J=7.56, 1.12Hz); 7.57 (m, 1H); 7.48 (m, 1H); 7.24 (d, 1H, J=6.16Hz) ; 4.07 (d, 1H, J=3.36Hz); 3.83 (m, 1H) ; 1.63 (m, 2H) ; 1.1-1.6 (m, 18H); 0.87 (t, 3H, J=7.00Hz) _o

Example 25: Inhibition test of compound for fatty acid synthase activity:

1) Preparation of fatty acid synthase

Male Sprague-Dawley rats weighing 220-250 g, fasted for two days, then given high-sugar and low-fat diets, fed for three days, quickly sacrificed the diet-induced fatty acid high expression rat model, took the liver, and used ice-cold phosphate The liver was lavaged with salt buffer (0.1 M; pH 7.5). (Note: The above steps are all performed at 4). After weighing, it was paddled with a phosphate buffer of 0.1 M in a volume of 5 ml/mg and a pH of 7.2. After full slurrying, 25% (w/v) polyethylene glycol (Mr6000) was added to a concentration of 5%, stirred for 10 minutes, 9000 rpm, and centrifuged for 30 minutes. The supernatant was filtered through a large filter, and its volume was measured, 25% of PEG was added thereto to a final concentration of 11%, stirred for 10 minutes, and then centrifuged for 15 minutes at a rotational speed of 9000 rpm. After centrifugation, the supernatant was discarded, and the surface of the precipitate was gently washed with ice-cold distilled water, and the surface of the PEG was washed as much as possible. With 0.1M phosphate buffer salt (pH 7.2, including lmMDTT, 2% rabbit serum, 2mg/ml bovine blood The albumin was slurried on the sediment, and the volume was 1/4 of the volume before the last centrifugation. After the slurry was slurried, ammonium sulfate (25 g 00 ml) was added while stirring, and the mixture was stirred for 30 minutes and centrifuged at 9000 rpm for 30 minutes. The pellet was slurried with 0.05 M phosphate buffered saline (pH 7.2, containing 1 mM DTT, 2 mg/ml bovine serum albumin), and the final volume was the same as in the previous step. Then, adding 25% PEG to the homogenate to a final concentration of 10%, stirring for 10 minutes, centrifuging at 9000 rpm for 15 minutes, collecting and storing the supernatant, repeating the precipitation, and collecting the two supernatants together. 35% of PEG was added thereto to a final concentration of 15%, stirred for 10 minutes, centrifuged at 9Q00 rpm for 30 minutes, and a precipitate was collected. The precipitate was dissolved in 0.05 M phosphate buffered saline (pH 7.5, containing 2 mM DTT), centrifuged for 5 minutes at 3000 rpm, and the supernatant was collected. 5Mphosphate buffer salt. The buffer was 0. 05M phosphate buffer salt. The collected liquid was centrifuged and concentrated by an ultrafiltration concentrating tube at a rotation speed of 3000 g to a final volume of about 2 ml, and the concentrated product was added to a gel chromatography exchange column for further separation and purification. The buffer was 0.1 M phosphate buffered saline (pH 7.5, containing 5 mM DTT), and the active peak was collected. The collected liquid is concentrated, in the same manner as above, and stored, and can be stored or stored. The above steps are all in progress.

2) Inhibition test of compound on fatty acid synthase activity

The drug concentration was 60μιηο1 and NADPH (200ηΜ); acetyl-CoA (66nM); phosphate buffer (580ml, 0. ΙΜ, ΡΗ 7. 0); purified fatty acid synthase 24ul. Incubate for 30 min under 37, and add propionyl-CoA (200 nM) to initiate the reaction. The amount of NADPH oxidized at 340 nm was measured using a S500P spectrophotometer, and 83 compounds were initially identified by drug inhibition of the enzyme. A dose-response curve was obtained for a drug whose inhibition was close to or better than that of the positive compound C75, and the IC50 value was determined. Propionyl-CoA and acetyl-CoA are products of SIGMA, and NADPH is a product of ROCHE.

3) Experimental results Table 1 Initial screening results of compound inhibitory activity (60μπιο1)

悴土 SD 士 SD

PH6A 7.25 ± 1.02 ΜΡΗ6Α 3.62 ±4.53 P N6A 31.51 ± 3.14 PHS6A 18.03 ± 3.76

PH6B 15.94 ± 1.26 ΜΡΗ6Β 3.62 soil 2.51 PMN6B 6.16 ± 1.19 PHS6B 43.44 ±4.26

PH7A 9.42 士 2.51 ΜΡΗ7Α 9.42 ±4.53 Painting A 24.66 士 1.19 PHS7A 11.59 ±4.53

PH7B 13.77 ± 3.32 ΜΡΗ7Β 10.87 ±4.35 PM 7B 19.18 ± 3.14 PHS7B 50 ±2.84

PH8A 33.77 ± 0.25 ΜΡΗ8Α 4 oo7.25士 1.34 Painting A 42.32 soil 1.25 PHS8A 40.16士 1. 2

PH8B 21.01 soil 3.32 ΜΡΗ8Β 11.59 ± 1.26 PMN8B 8.7±5 PHS8B 13.93 ±6.51

PH9A 14.49 ± 3.32 ΜΡΗ9Α 18.84 soil 3.32 hidden A 21.92 ± 5.44 PHS9A 93.48 ± 6

PH9B 30.43 ± 2.48 ΜΡΗ9Β 19.57 ±2.17 Country B 5.47 ± 2.05 PHS9B 97.54 ± 2. 6

PHI OA 28.99 ±4.53 MPH10A 90.58 ± 3.32 P N10A 38.36 ±4.11 PHS10A 99.18 ± 1.42

PHI OB 34.06 ± 1.26 MPH10B 89.13 ±2.17 FM 10B 30.82 ±6.61 PHS10B 90.98士 3.76

PH11A 50.72 ± 5· 47 MPH11A 89.86 ± 3.32 FMN11A 71.92 ± 3.14 PHS11A 95.65 soil 3

PHI IB 86.23 soil 5.47 MPH11B 97.83 ±2.17 wake up IB 96.58 ± 1.19 PHS11B 96.72 ± 1.42

C75 42.75士 2.51 Table 4.2 Preferred compounds IC50 determination results

Compound IC50(uM) 95% confidence interval Compound IC50(uM) 95% confidence interval No.

PHS9A 36.73 24.96-54.06 MPH10A 34.15 23.88-48.82

PHS9B 26.86 19.88-36.31 MPH10B 34.50 22.82-52.17

PHS10A 12.32 8.69-17.49 MPH11B 6.47 4.18-10.02

PHS10B 8.29

PMN11A 27.20 19.43-38.07

PHS11A 4.11 2.08-8.10 PMN11B 11.23 6.31-20.00

PHS11B 3.62 2.44-5.37 C75 15.53 6.83-35.32 The results show that the compound of the present invention has strong inhibitory activity against the enzyme at a concentration of 60 μm ηο1. Positive control C75 or equivalent, and some of the compounds have IC50 values less than the positive control C75. Example 26: Preferred compound cytotoxicity test

2.1 MTT method experiment principle

Thiazole blue (MTT) can enter the cell through the cell membrane. The succinyl dehydrogenase in the mitochondria of living cells can reduce the exogenous MTT to the blue-purple Formazan crystal which is insoluble in water and deposit in the cell. It is dissolved by dimethyl sulfoxide (DMS0), and its light absorption value is measured by an enzyme-linked immunosorbent detector at a wavelength of 490 nm, which can indirectly reflect the number of cells.

2.2 Experimental method:

Normally passaged human embryonic lung fibroblasts (HLF) were resuspended in 1040 FCS 1640 medium at a concentration of 3-5 x l OVml, seeded in 96-well flat bottom plate, ΙΟΟμΙ/well; Gradiently diluted each small molecule compound to be tested, ΙΟμΙ/well. A solvent control and a positive drug C75 control were also provided. Incubate in 5% C0 ₂ , 37t; cultured in a cell culture incubator for 48 hours, add MTT (5mg/ml) l (μl per well, shake for 3-5min, place in 5% C0 ₂ , 37 cell culture incubator to continue culture 4-6 hours, DMS0 ΙΟΟμΙ was added to each well, and after shaking for 3-5 min, the optical density value at 490 nm was measured on an enzyme-linked instrument. The TC50 value of the compound was converted according to the optical density value.

2.3 Experimental results

Table 4.3 Cytotoxicity test results of preferred compounds Compound FAS inhibition HLF Cytotoxicity Therapeutic index

IC50 (μΜ) 50(μΜ) (TC50/IC50)

C75 15.53 (6.83-35.32) 87.09 3. 6(1. 98 -10.24)

MPH11B 6.47 (4.18-10.02) 54.21 8. 4(5. 4- 13)

PHS11A 4.11 (2.08-8.10) 7. 9(4. 0- •15.7)

PHS10A 12.32 (8.69-17.49) 64.18 5. 2 (3. 7- 7.4)

PHS10B 8.29 (3.88-17.72) 33.9 4. 0 (1. 9- 8.7)

PMN11A 27.20 (19.43-38.07) 146.3 5. 4(3. 8- 7.5)

PMNllB 11.23 (6.31-20.00) 72.11 6. 4 (3.6- 11.4) The results indicate that the representative compounds of the present invention (PHS10A, PHS10B, PMN11A, PMNllB) have TC50 values greater than or close to the positive control, and their therapeutic index is calculated ( TC50/IC50) are both greater or closer to the positive control.

Claims

A six-membered heterocyclic compound of the formula I, or a pharmaceutically acceptable salt thereof, a solvate or a geometric isomer thereof,

among them:

R1 is a C ₃ -C ₁₈ linear or branched alkyl group, a C ₃ -C ₁₈ linear or branched alkenyl group, which is selectively bonded to the halogen, nitro, hydroxy, hydroxymethyl, -CN, trifluoro Methyl, trifluoromethoxy, phenoxy, benzyloxy, 0 or S,

112 is a linear or branched alkyl group of 11, d ~, benzyl, trifluoromethyl,

R3 is H, sulfhydryl,

X is an oxygen or sulfur atom;

A is a 5- to 6-membered aromatic carbocyclic or heterocyclic substituent, wherein the aromatic carbocyclic ring contains 6 to 14 carbon atoms, such as phenyl, benzyl or naphthyl, and the heterocyclic ring includes 1 to 4 selected from below. Heteroatoms: 0, S, N, such as pyrrole, pyridine, piperidine, pyrrolidine, or morpholine; aromatic carbocyclic or heterocyclic ring may be unsubstituted or substituted by 1 to 5 substituents selected from : 素, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, phenoxy, benzyloxy, CN, carboxy or amino;

2. The compound of claim 1 which is a compound of formula I which is a six-membered heterocyclic compound represented by formula II, or a pharmaceutically acceptable salt, solvate thereof or geometric isomer thereof,

among them:

a ~ c ₁₈ straight or branched alkyl group, c ₃ ~ c ₁₈ straight or branched alkenyl,

R3 is H, methyl,

A is phenyl, 1, 3-dimethylpyrrolyl,

X is selected from the group consisting of 0, S atoms.

3. A compound according to claim 1 or 2 which is selected from the group consisting of:

Trans-6-n-hexyl-1,3,7-tridecyl-4-oxo-1,4,6,7-tetrahydropyran [4,3-b]pyrrole-7-carboxylic acid;

Trans-6-n-octyl-1,3,7-trimethyl-4-oxo-1,4,6,7-tetrahydropyran[4,3-b]pyrrole-7-carboxylic acid;

Trans-6-n-undecyl-1,3,7-trimethyl-4-oxo-1, 4, 6, 7-tetrahydropyran[4,3-b]pyrrol-7-carboxylate Acid

Cis-6-n-hexyl-1,3,7-trimethyl-4-oxo-1,4,6,7-tetrahydropyran [4,3-b]pyrrole-7-carboxylic acid;

Cis-6-n-heptyl-1,3,7-trimethyl-4-oxo-1, 4, 6, 7-tetrahydropyridyl Butyl [ 4, 3-b ] pyrrole-7-carboxylic acid;

Cis-6-n-octyl-1,3,7-trimethyl-4-oxo-1,4,6,7-tetrahydropyran[4,3-b]pyrrole-7-carboxylic acid;

Cis-6-n-decyl-1,3,7-trimethyl-4-oxo-1,4,6,7-tetrahydropyran[4,3-b]pyrrole-7-carboxylic acid;

Cis-6-n-undecyl-1,3,7-tridecyl-4-oxo-1,4,6,7-tetrahydropyran[4,3-b]pyrrole-7-carboxylate Acid; trans-3-n-hexyl-1-oxo-iso-p-tetrahydropyran-4-carboxylic acid

Trans-3-n-heptyl-1-oxo-iso-p-tetrahydropyran-4-carboxylic acid

Trans-3-n-octyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid

Trans-3-n-decyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid

Trans-3-n-undecyl-1-oxo-isobenzotetrahydropyran-4- cis-3-n-hexyl-1-oxo-isobenzotetrahydropyran-4-carboxylate Acid

Cis-3-n-heptyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid

Cis-3-n-octyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid

Cis-3-n-decyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid

Cis-3-n-undecyl-1-oxo-isobenzotetrahydropyran-4-trans-3-n-hexyl-4-mercapto-1-oxo-isobenzotetrahydropyridyl -4--4-carboxylic acid trans-3-n-heptyl-4-mercapto-1 -oxo-isobenzotetrahydropyran-4-carboxylic acid trans-3-n-octyl-4-fluorenyl - 1 -oxo-isobenzotetrahydropyran-4-carboxylic acid trans-3-n-decyl-4-mercapto-1 -oxo-isobenzotetrahydropyran-4-carboxylic acid Trans-3-n-decyl-4-methyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; trans-3-n-undecyl-4-methyl-1 Oxo-isobenzotetrahydropyran-4-carboxylic acid;

Cis-3-n-hexyl-4-mercapto-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; cis-3-n-heptyl-4-methyl-1-oxo- Isobenzotetrahydropyran-4-carboxylic acid; cis-3-n-octyl-4-mercapto-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; cis-3- N-decyl-4-mercapto-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; cis-3-n-decyl-4-mercapto- 1-oxo-isobenzotetra Hydropyran-4-carboxylic acid; cis-3-n-undecyl-4-methyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; trans-3-n-hexyl 4-methyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; trans-3-n-heptyl-4-methyl-1-oxo-isobenzotetrahydrothiopyran 4-carboxylic acid; trans-3-n-octyl-4-methyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; trans-3-n-decyl-4-methyl 1--1-oxo-isobenzotetrahydrothiopyran-4-carboxylic acid; trans-3-n-decyl-4-methyl-1-oxo-isobenzotetrahydrothiopyran-4-carboxylate Acid; trans-3-n-undecyl-4-indolyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid;

Cis-3-n-hexyl-4-mercapto- 1-oxo-isobenzotetrahydropyran-4-carboxylic acid; cis-3-n-heptyl-4-methyl- 1 -oxo- Isobenzotetrahydropyran-4-carboxylic acid; cis-3-n-octyl-4-mercapto-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; cis-3- n-Mercapto-4-methyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid; cis-3-n-decyl-4-methyl-1-oxo-isobenzotetra Hydrothiat-4-carboxylic acid; cis-3-n-undecyl-4-methyl-1-oxo-isobenzotetrahydropyran-4-carboxylic acid;

And a pharmaceutically acceptable salt or solvate thereof.

4. A pharmaceutical composition comprising the compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.

5. A method of preparing the compound of any one of claims 1 to 3, comprising:

Obtaining a compound of formula IV,

Wherein A is defined in the same manner as claim 1,

2) The compound of the formula IV is reacted with methyl iodide (CH ₃ I) in the presence of a base such as sodium hydride (NaH) or lithium diisopropylamide (LDA) to give a compound of the formula V.

Where A is defined in the same way as claim 1.

Wherein, A is a phenyl group, and R1 is as defined in claim 1.

4) reacting a compound of formula V with LDA, R1CH0 to give a compound of formula VI I (cis and trans),

Wherein, A and Rl are as defined in claim 1; R3 is a fluorenyl group, and X is an oxygen atom;

5) The compound of formula IV with lithium diisopropylamide (LDA), titanium triisopropoxide ((i- PrO chloride) ₃ TiCl), R1CH0 reaction, to give a compound of formula VII (cis and trans),

II

Wherein, A, X, Rl, and R3 are defined as claimed in

I

Wherein, A, X, R1, and R3 are as defined in 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 anti-tumor drug.