CN110950881A - Tricyclic analogue, preparation method and application thereof - Google Patents
Tricyclic analogue, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a tricyclic analogue, the structure of which is shown as a formula I, and the definition of each substituent is described in the specification and the claims. The compound of the invention is a structural analogue of a simplified natural product Pyripyropene A, has the selective inhibitory activity of acyl coenzyme A cholesterol acyltransferase 2, and can be used for treating cardiovascular diseases such as atherosclerosis and the like.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a series of analogues with a natural product Pyripyropene A structure, a preparation method and application thereof, in particular to analogues of the natural product Pyripyropene A, a preparation method thereof and application of the analogues as inhibitors of acyl coenzyme A cholesterol acyltransferase 2(ACAT2) in treatment of cardiovascular diseases such as atherosclerosis.
Background
Cholesterol is present intracellularly as free cholesterol or as a cholesterol ester, as the predominant form of sterol in vertebrates. Free cholesterol in cells is an essential component of cell membranes and plays a key role in maintaining the fluidity of cell membranes and signal transduction of cells. In order for mammals to maintain their normal vital activities, elaborate regulatory mechanisms are necessary to maintain cholesterol metabolic balance. Intracellular free cholesterol mainly plays a functional role in the cytoplasmic membrane, is a cell membrane component essential for the life and activity of cells, including the survival or non-survival of cells, various functions of cells such as signal transduction, immunity, infection, etc., and is closely related to the dynamic equilibrium of free cholesterol in the cytoplasmic membrane, which is involved in the membranous vital structure of the cytoplasmic membrane, various protein or complex functions, etc.
The acyl coenzyme A Cholesterol Acyltransferase (ACAT) is the only enzyme which takes free cholesterol as a substrate to synthesize cholesterol ester in cells, is a key enzyme for regulating and controlling the metabolic balance of cholesterol in cells, and mainly participates in absorption, transportation and storage of living bodies to maintain the dynamic balance of cholesterol in cells. The intracellular ACAT activity is directly related to the functions of cell membrane micro-domain, the formation of foam cells of early-stage atherosclerotic lesions, and the like. ACAT is a membrane-bound protein located on the rough endoplasmic reticulum in tissue cells, and two subtypes have been discovered so far: ACAT1 and ACAT 2. They are both more differently organized. ACAT1 is present in almost every tissue and cell and regulates the cholesterol balance in tissues such as brain, macrophages and adrenal glands. ACAT2 is expressed only in liver and small intestine cells and is mainly responsible for the esterification synthesis of cholesterol in liver and small intestine. It has long been recognized that ACAT is closely related to the development of atherosclerosis. Therefore, inhibition of ACAT may not only decrease the absorption of cholesterol by the small intestine, but also inhibit the formation of various types of foam cells including those derived from macrophages, and is a very important target for the treatment of cardiovascular diseases.
The currently known ACAT inhibitors are broadly classified as follows: a. synthetic inhibitors: including ureas, amides, and imidazoles; b. a microbial inhibitor; c. a natural plant inhibitor. However, all ACAT inhibitors found to date have not been drugs because of the neglect of selectivity for the inhibitory activity of both ACAT subtypes. Different conclusions were later made regarding the effect of inhibiting ACAT1 on atherosclerosis. One laboratory thought that ACAT1 loss inhibited the development of atherosclerosis; another laboratory test showed that mice lacking ACAT1 had a greatly increased incidence of atherosclerosis. Analysis of the ACAT2 knockout mouse shows that ACAT-2-/-The mice have reduced cholesterol absorption and are resistant to lithiasis and food-induced hypercholesterolemia. Therefore, it is speculated that specific inhibition of ACAT1 disrupts intracellular cholesterol metabolic balance, leading to cholesterol cytotoxic effects, and is not beneficial in preventing the development of atherosclerosis. ACAT2 may be an effective target for preventing hyperlipidemia and atherosclerosis. Specific inhibition of ACAT2 will reduce cholesterol absorption and transport without affecting the intracellular cholesterol metabolic balance. In conclusion, it is important to develop highly selective inhibitors targeting ACAT 2.
However, only Pyripyropene A, which was a newly discovered ACAT inhibitor, had ACAT 2-specific inhibitory activity. Pyripyropenes was extracted from the fermentation broth of Aspergillus fumigates FO-1289 microorganism by Satoshi Omura et al 1993, and the natural isolation of Pyripyropenes is very difficult, complicated and less expensive. Moreover, natural Pyripyropenes has the defect of difficult preparation, the total synthesis route is as many as nineteen steps by taking carvone as a starting point, extremely harsh reaction conditions are used for many times, and the yield is extremely low. The doctor Zhan the drug institute has already carried out preliminary simplification on Pyripyropene A, opens the ring structure above the leftmost A ring in a natural product, removes two methylene groups and one aminomethyl group in the ring to obtain a series of compounds, and when the preparation is still complex, the field needs to synthesize a novel ACAT2 inhibitor which is simple, has better inhibitory activity and has higher selectivity.
Disclosure of Invention
The invention aims to provide a simplified Pyripyropene A analogue which can be used as an ACAT2 inhibitor and can be prepared into medicines for treating cardiovascular diseases such as atherosclerosis and the like.
Another object of the present invention is to provide a method for preparing the above-mentioned Pyripyropene a analogue.
It is a further object of the present invention to provide the use of the analogs of Pyripyropene a described above.
In a first aspect of the invention, there is provided a compound of formula I, tautomers, optical isomers and stereoisomers thereof, or pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
x is O, S, NH or C1-C6An alkylene group;
R4is a 4-8 membered heteroaryl;
w is hydrogen or hydroxy;
R1is hydrogen or C1-C6An alkyl group;
n is 0,1 or 2;
y, Z are each independently O, NH, S, -OC (═ O) -, -OC (═ O) O (C)1-C6Alkylene) -, -OC (═ O) (C)1-C6Alkylene) -, -O (C)1-C6Alkylene) -, -OC (═ O) (C)1-C6Alkylene) NHC(＝O)-、-OC(＝O)NH(C1-C6Alkylene) -or-OC (═ O) NH-;
R2and R3Each independently hydrogen, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C6-C12Aryl, substituted or unsubstituted 4-8 membered heteroaryl, substituted or unsubstituted C1-C6An alkoxy group;
each of the above substituents independently means having one or more substituents selected from the group consisting of: c1-C6Alkyl radical, C6-C12Aryl, 4-8 membered heteroaryl, C3-C8Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6Alkylamino, halogen, cyano, hydroxy, amino, -COC1-C6Alkyl, -COC3-C6Cycloalkyl, -COC6-C12And (4) an aryl group.
In another preferred embodiment, X is O.
In another preferred embodiment, R4Is a 5-7 membered heteroaryl group, preferably pyridine.
In another preferred embodiment, R1Is methyl, ethyl or propyl.
In another preferred embodiment, n is 1 or 2.
In another preferred embodiment, Y, Z are each independently O, NH, S, -OC (═ O) -, -OC (═ O) O (C)1-C4Alkylene) -, -OC (═ O) (C)1-C4Alkylene) -, -O (C)1-C4Alkylene) -, -OC (═ O) (C)1-C4Alkylene) NHC (═ O) -, -OC (═ O) NH (C)1-C4Alkylene) -or-OC (═ O) NH-.
In another preferred embodiment, R2And R3Each independently hydrogen, substituted or substituted C3-C6Cycloalkyl, substituted or substituted C6-C10Aryl, substituted or substituted 4-6 membered heteroaryl, substituted or unsubstituted C1-C6An alkoxy group;
each of the above substituents independently means having one or more substituents selected from the group consisting of: c1-C6Alkyl radical, C6-C10Aryl, 4-8 membered heteroaryl, C3-C6Cycloalkyl radical, C1-C4Alkoxy radical, C1-C4Alkylamino, halogen, cyano, hydroxy, amino, -COC1-C6Alkyl, -COC3-C6Cycloalkyl, -COC6-C10And (4) an aryl group.
In another preferred embodiment, the compound is:
the compound of the invention is a structural analogue of a simplified natural product Pyripyropene A, has the selective inhibitory activity of acyl coenzyme A cholesterol acyltransferase 2, and can be used for treating cardiovascular diseases such as atherosclerosis and the like.
In a second aspect of the present invention, there is provided a method for preparing a compound of the first aspect, wherein the structure of the compound of formula I is shown in formula Ia, formula Ib, formula Ic or formula Id, the method comprising the following steps:
n、Z、Y、R2、R3、R4same as before, PG1、PG2Is a hydroxyl protecting group which is a silicon ether, an ester group, a benzyl ether or an alkyl ether;
(1) ozonizing the double bond of the compound 14 to obtain a compound 15, and oxidizing the compound by Baeyer-Villiger to obtain the compound
Compound 16;
(2) removing acetyl from the compound 16, and then protecting hydroxyl by a protecting group to obtain a compound 17;
(3) reduction of compound 17DIBAL-H to give compound 18;
(4) carrying out coupling reaction on the compound 18, a compound 267 and an n-butyllithium reagent, oxidizing, and carrying out solvolysis reaction to obtain a compound 19;
(5) compound 19 is dehydroenolated by LHMDS, followed by neutralization of R4C-acylation and ring closure are carried out on COCl to obtain a compound 20;
(6) removing a protecting group from the compound 20, and reacting with acid anhydride, acyl chloride, isocyanate or chloroformate to obtain a compound Ia; performing Luche reduction reaction on the compound Ia to obtain a compound Ic;
or the compound 20 is reduced to obtain a compound Ib, and the compound Ib is subjected to deprotection and then reacts with acid anhydride, acyl chloride, isocyanate or chloroformate to obtain a compound Id.
In another preferred embodiment, the preparation method has one or more of the following characteristics:
the solvent used in the ozonization reaction in the step (1) is selected from: dichloromethane and methanol;
the reaction temperature of the ozonization reaction in the step (1) is-78 ℃ to room temperature;
the solvent used for DIBAL-H reduction in the step (3) is dichloromethane;
the reaction temperature of the DIBAL-H reduction reaction in the step (3) is-78-0 ℃;
the solvent used in the coupling reaction in the step (4) is an aprotic solvent, and is selected from diethyl ether and the like;
the reaction temperature of the coupling reaction in the step (4) is-78 ℃ to room temperature;
the solvent used in the solvolysis reaction in the step (4) is selected from: toluene and methanol;
the reaction temperature of the solvolysis reaction in the step (4) is 80 ℃;
the solvent used for C-acylation ring closing in the step (5) is an aprotic solvent selected from tetrahydrofuran;
the temperature of the C-acylation ring-closing reaction in the step (5) is 0 ℃ to room temperature;
the solvent used in the deprotection reaction and the acyl reaction in the step (6) is an aprotic solvent selected from dichloromethane;
the reaction temperature of the deprotection group reaction and the acyl group reaction in the step (6) is room temperature;
the solvent used in the Luche reduction reaction in the step (6) is selected from an alcohol solvent, preferably methanol or ethanol; the reaction temperature is-78 ℃ to room temperature.
In a third aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the first aspect or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable carrier.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
In a fourth aspect of the invention, there is provided the use of a compound of the first aspect, or a pharmaceutically acceptable salt thereof, for the preparation of: (i) agents that selectively inhibit ACAT 2; or (ii) a medicament for the prophylaxis and/or treatment of cardiovascular diseases.
In another preferred embodiment, the cardiovascular disease is selected from the group consisting of: hyperlipidemia, and atherosclerosis.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. For reasons of space, they will not be described in detail.
Detailed Description
Based on long-term and intensive research, the inventor continues to simplify the structure of Pyripyropenes A, constructs and removes the ring system which is synthesized in the mother nucleus of Pyripyropenes and consumes most energy, eliminates the o-diacyl structure of the leftmost ring system, changes the o-diacyl structure into a simpler structure which is easy to functionalize, removes the chiral center brought by the o-diacyl structure, simplifies the structure and the synthetic route, and solves the problem that the o-diacyl structure is poor in plasma stability and easy to metabolize in subsequent research. Thus, the target molecule with a brand new skeleton and a simplified structure is obtained, the structural complexity is greatly reduced, and the preparation method is easy to prepare from a simple natural raw material carvone. Compared with a natural product Pyripyropene A, the compound of the invention is simple and convenient to synthesize, has obviously better pharmacokinetic properties than Pyripyropene A in inhibiting ACAT2 activity and selectively inhibiting ACAT2, and is expected to become a novel medicine acting on the target spot for treating cardiovascular diseases such as atherosclerosis. On the basis of this, the present invention has been completed.
Term(s) for
In the present invention, the form is "C1-C6The expression "is intended to include the corresponding groups having 1, 2, 3, 4, 5, or 6 carbon atoms, e.g.," C1-C6Alkyl "refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms," C3-C6Cycloalkyl "refers to cycloalkyl having 3, 4, 5, or 6 carbon atoms.
In this context, the alkyl group is preferably an aliphatic alkyl group, and may be a straight-chain alkyl group, a branched-chain alkyl group, including without limitation: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl. Alkylene is a radical formed by an alkane having two hydrogen atoms removed, e.g. -CH2-、-CH2CH2-、-CH2CH2CH2-or-CH2CH2CH2CH2-。
Alkoxy means-O-alkyl, alkylamino means-NH (alkyl) or-N (alkyl), and alkyl is as defined above.
In this context, the cycloalkyl group may be a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably the cycloalkyl group comprises 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The aryl group refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring may be fused to a heterocyclyl, heteroaryl or cycloalkyl ring, non-limiting examples of which include benzimidazole, benzothiazole, benzoxazole, benzisoxazole, benzopyrazole, quinoline, benzindole, chroman.
The heteroaryl group refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5-or 6-membered, for example furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like. The heteroaryl group can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring.
Unless otherwise specified, the structural formulae depicted herein are intended to include all tautomeric, enantiomeric and stereoisomeric forms (e.g., enantiomers, diastereomers, geometric isomers or conformational isomers): for example, the R, S configuration containing an asymmetric center, the (Z), (E) isomers and the conformational isomers of (Z), (E) of the double bond. Thus, individual stereochemical isomers, tautomers or enantiomers, diastereomers or geometric isomers or conformational isomers or mixtures of tautomers of the compounds of the present invention are within the scope of the present invention.
Herein, the pharmaceutically acceptable salt is not particularly limited, and preferably includes: inorganic acid salts, organic acid salts, alkylsulfonic acid salts and arylsulfonic acid salts; the inorganic acid salt comprises hydrochloride, hydrobromide, nitrate, sulfate, phosphate and the like; the organic acid salt comprises formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate and the like; the alkyl sulfonate includes methyl sulfonate, ethyl sulfonate and the like; the aryl sulfonate includes benzene sulfonate, p-toluene sulfonate and the like.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures for the conditions not specified in the examples below are generally carried out according to conventional conditions (e.g.as described in Sambrook et al, molecular cloning: A laboratory Manual (New York: Cold Spring Harbor laboratory Press, 1989)) or according to the conditions as recommended by the manufacturer. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Examples of preparation of Compounds
In the following preparation examples, NMR was measured with a Mercury-Vx 300M instrument manufactured by Varian, and NMR was calibrated: delta H7.26ppm (CDCl)3)，2.50ppm(DMSO-d6)，3.15ppm(CD3OD); reagents are mainly provided by Shanghai chemical reagents company; TLC thin layer chromatography silica gel plate is produced by Shandong tobacco Taihuyou silica gel development Co., Ltd, model number HSGF 254; the normal phase column chromatography silica gel used for compound purification is produced by Shandong Qingdao ocean chemical plant, model zcx-11, 200-300 mesh.
Preparation example one (Compound No. ALY603)
Starting from the readily available starting material (S) -carvone from natural sources (20.0g,133.2mmol) and the lithium salt of L-proline (1.6g,13.3mmol) were placed in a round-bottomed flask, and further trimethylsilyl cyanide (35.4ml,266.4mmol) was slowly added and the resulting suspension stirred at room temperature for 24 h. TLC showed the starting material was almost completely reacted, diluted with 100ml THF and 100ml1M HCl, stirred at room temperature for 1h, then diluted with water, extracted with ether, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the crude product which was directly used in the next step. Chromium trioxide (18.8g, 106.6mmol) was slowly added to acetic anhydride (107ml), the mixture was stirred at room temperature until completely dissolved, and the resulting chromic acid reagent was then added dropwise to a-55 ℃ solution of the crude product from the previous step in dichloromethane, and stirred at this temperature for half an hour. TLC showed the starting material was reacted completely, quenched by addition of methanol, diluted with water, extracted with dichloromethane, the organic phase washed with saturated aqueous sodium bicarbonate solution and concentrated. Column chromatography (petroleum ether/ethyl acetate 10/1) gave the product 1 as a yellow oil (14.0g, 60% over two steps):1H NMR(CDCl3,300MHz)δ4.86(s,1H),4.78(s,1H),2.77-2.32(m,5H),2.05(s,3H),1.68(s,3H).
intermediate 1(162mg,0.93mmol) and cerous chloride heptahydrate (345mg,0.93mmol) were dissolved in methanol, cooled to an ice-water bath, sodium borohydride (35.0mg,0.93mmol) was added carefully and the mixture stirred for 30 mm of starting material to disappear. Quenching with acetone, diluting with ethyl acetate, washing the organic phase with water, washing with saturated brine, drying, concentrating, and separating and purifying by column chromatography (petroleum ether/ethyl acetate: 10/1) to obtain colorless transparent oily substance as product 2(131.0mg, yield 80%)1H NMR(CDCl3,300MHz)δ4.75(s,1H),4.70(s,1H),4.17(d,J＝5.7Hz,1H),3.01(d,J＝7.2Hz,1H),2.30-2.07(m,4H),2.04(s,3H),1.76(s,3H),1.45(dd,J＝12.6,22.8Hz,1H)。
Compound intermediate 2(131mg,0.74mmol) was dissolved in N, N-dimethylformamide, imidazole (100.7mg,1.48mmol) and dimethylaminopyridine (cat.) were added, and after stirring for 5min, tert-butyldimethylsilyl chloride (223.0mg,1.48mmol) was added, and the mixture was stirred at room temperatureAnd (4) at night. The next day, water was added to quench and ethyl acetate was extracted. The organic phase was washed with saturated brine, dried and concentrated. Column chromatography purification (petroleum ether/ethyl acetate 25/1) gave intermediate 3 as a colorless clear oil (213mg, 98% yield):1H NMR(CDCl3,300MHz)δ4.74(s,1H),4.72(s,1H),4.23(brs,1H),2.30-2.00(m,4H),2.00(s,3H),1.69(s,3H),1.49(dd,J＝12.6,22.8Hz,1H),0.89(s,9H),0.09(s,3H),0.07(s,3H)。
intermediate 3(4.4g,15mmol) was dissolved in Dichloromethane (DCM) (100ml) and MeOH (25ml), ozone was bubbled through at-78 ℃ until the reaction was complete, excess dimethyl sulfide was added, allowed to warm to rt and stir overnight, after concentration column chromatography (petroleum ether/ethyl acetate ═ 10/1) gave intermediate 4 as a clear oil (4.2g,14.3mmol, 95%):1H NMR(CDCl3,300MHz)δ4.23(m,1H),2.74-2.64(m,1H),2.39-2.38(m,2H),2.18(s,3H),2.03(s,3H),1.68-1.57(m,2H),0.89(s,9H),0.10(s,6H)。
intermediate 4(4.2g,14.3mmol) was dissolved in 200ml dichloromethane and m-chloroperoxybenzoic acid (9.9g,42.9mmol) was added at room temperature and warmed to reflux, maintaining the temperature at reflux for 12 h. Quenching by saturated sodium thiosulfate solution, extracting by ethyl acetate, washing an organic phase by saturated sodium carbonate solution, washing by saturated saline solution, drying and concentrating. Column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10:1) afforded compound 5 as a clear oil (1.37g,4.4mmol, 31%).1H NMR(CDCl3,300MHz)δ4.97-4.87(m,1H),4.28(m,1H),2.60-2.53(m,1H),2.24-2.19(m,2H),2.04(s,3H),2.03(s,3H),1.83-1.72(m,1H),0.90(s,9H),0.10(s,3H),0.09(s,3H)。
Intermediate 5(1.37g,4.4mmol) was dissolved in 30ml of methanol, anhydrous potassium carbonate (0.92g,6.65mmol) was added, stirred at room temperature for 2h, methanol was removed by rotation, diluted with ethyl acetate, washed with water, washed with brine, dried, concentrated, and separated by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give product 6(1g,3.74mmol, 85%).1H NMR(CDCl3,300MHz)δ4.22-4.20(m,1H),4.06(s,1H),2.42(s,2H),2.07(s,3H),2.02-1.92(m,2H),1.99-1.83(m,1H),1.59-1.22(m,1H),1.32-1.24(m,1H)0.90(s,9H),0.10(s,3H),0.09(s,3H)。
Intermediate 6(1g,3.74mmol) in DMF was added imidazole (509mg,7.48mmol), DMAP(cat.), stirring for 5min, adding TBSCl (1.13mg,7.48mmol), and the mixture stirring overnight at room temperature. The next day, water was added to quench and ethyl acetate was extracted. The organic phase was washed with saturated brine, dried and concentrated. Column chromatography purification (petroleum ether: ethyl acetate (v/v) ═ 25:1) afforded intermediate 6-1(1.14g,2.99mmol, 80% yield)1H NMR(CDCl3,300MHz)δ4.26-4.21(m,1H),3.86-3.76(m,1H),2.45-2.37(m,1H),2.28-2.11(m,2H),2.00(s,3H),1.70-1.59(m,1H),0.90(s,9H),0.88(s,9H),0.10-0.06(m,12H)。
Diisobutylaluminum hydride (DIBAL-H) (4.5ml,4.49mmol) was added dropwise to a solution of intermediate 6-1(1.14g,2.99mmol) in dry ice acetone bath, and after dropping, the mixture was warmed to room temperature and stirred for 2H. TLC monitored the end of the reaction of the starting material, quenched by addition of saturated aqueous sodium potassium tartrate solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (n-hexane/ethyl acetate (v/v) ═ 25/1) to give 6-2(1.03g,2.69mmol, 90% yield) as the product.1H NMR(CDCl3,300MHz)δ10.13(s,1H),4.34-4.29(m,1H),3.77-3.73(m,1H),2.66(dd,J＝18.0Hz,3.0Hz,1H),2.23-2.16(m,1H),2.14(s,3H),2.01-1.92(m,1H)1.71-1.50(m,1H)0.93-0.88(m,18H),0.14-0.06(m,12H)。
Intermediate 6-2(1.03g,2.69mmol) and iodide 267(1.08g,4.04mmol) were dissolved in dry ether, cooled to-78 deg.C, n-butyllithium (4.1ml,4.04mmol) was added dropwise, stirred at this temperature for 30min, and then quenched by addition of saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was dissolved in dichloromethane and dess-martin oxidant (DMP) (1.71g,4.04mmol) was added at 0 ℃ and stirred overnight at room temperature. The next day, the mixture was quenched with saturated sodium thiosulfate solution/saturated sodium bicarbonate solution (1/1), extracted with dichloromethane, washed with saturated brine, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give intermediate 6-3(0.48g, yield 33%). Intermediate 6-3(0.48g,0.89mmol) was dissolved in toluene (40ml) and methanol (10ml) and the reaction mixture was heated to ambient temperature at 80 ℃ under reflux overnight. The next day, column chromatography was concentrated (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give intermediate 6-4(0.45g,0.88mmol, 99% yield).1H NMR(CDCl3,300MHz)δ3.87–3.79(m,4H),3.72–3.63(m,1H),2.46–2.41(m,1H),2.22(s,3H),1.99–1.93(m,1H),1.55-1.42(m,2H),1.37–1.24(m,1H),1.24(s,3H),0.91–0.87(m,18H),0.12–0.05(m,12H)。
To a solution of LHMDS (8.8ml,8.8mmol) in THF at 0 deg.C was added dropwise a solution of intermediate 6-4(0.45g,0.88mmol) in THF, warmed to room temperature and stirred for 4h, nicotinoyl chloride hydrochloride was added rapidly and stirred for 2h at room temperature. TLC detects the material reaction, adds acetic acid to quench, water dilutes, extracts with dichloromethane, dries with anhydrous sodium sulfate, and concentrates. Column chromatography purification (petroleum ether/acetone (v/v) ═ 3/1) gave intermediate 6-5(195mg,0.41mmol, 47% yield).1H NMR(CDCl3,300MHz)δ9.04(s,1H),8.75(d,J＝3.0Hz,1H),8.19–8.16(m,1H),7.44(dd,J＝9.0,6.0Hz,1H),6.48(s,0.3H),6.42(s,0.7H),3.96(dd,J＝12.0,6.0Hz,1H),3.77–3.70(m,1H),2.60(dd,J＝12.0,3.0Hz,1H),2.37(d,J＝15.0Hz,1H),2.03–1.94(m,1H),1.53(d,J＝9.0Hz,1H),1.35(s,3H),1.21–1.14(m,1H),0.96–0.89(m,18H),0.19–0.07(m,12H)。
Acetyl chloride (37. mu.l, 0.52mmol) was added dropwise to 0.5ml of methanol, and the mixture was stirred at room temperature for 5min, followed by addition of a solution of intermediate 6-5(30mg,0.052mmol) in methanol and stirring at room temperature for 1 hour. Concentrated and directly used in the next step. The crude product was dissolved in dichloromethane and a catalytic amount of DMAP, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (50mg,0.26mmol) and p-cyanobenzoic acid (38mg,0.26mmol) were added and stirred at room temperature overnight. TLC monitored the reaction was complete, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to afford intermediate 6-6(20mg,0.033mmol, 63% yield) as a pale yellow solid.1H NMR(CDCl3,300MHz)δ9.08(s,1H),8.82(s,1H),8.23–7.99(m,4H),7.83–7.49(m,6H),6.53(s,0.5H),6.51(s,0.5H),5.70–5.59(m,1H),5.37–5.25(m,1H),3.19(dd,J＝9.0,3.0Hz,1H),2.99(dd,J＝12.0,3.0Hz,,1H),2.83–2.68(m,1H),2.22–2.13(m,1H),1.99–1.86(m,1H),1.74(s,2H),1.68(s,1H)。
Intermediate 6-6(20mg,0.033mmol) and cerous chloride heptahydrate (86mg,0.23mmol) were dissolved in methanol, sodium borohydride (9mg,0.23mmol) was added carefully as a solution cooled to-78 deg.C, and the mixture was stirred for 30 minutesThe raw material disappeared. Quenching with acetone, diluting with ethyl acetate, washing the organic phase with water, washing with saturated brine, drying, concentrating, and isolating and purifying by column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to give the final product ALY603(18mg, 90%):1H NMR(CDCl3,300MHz)δ9.03(s,1H),8.72(d,J＝3.0Hz,1H),8.13(d,J＝9.0Hz,1H),8.02–7.94(m,4H),7.62–7.54(m,4H),7.46–7.42(m,1H),6.52(s,1H),5.55(s,1H),5.46(s,1H),5.14(d,J＝6.0Hz,1H),2.89(s,1H),2.58–2.35(m,4H),1.26(s,3H)。
the following compounds were synthesized in the same manner:
compound ALY603R was prepared by replacing the compound S-carvone in preparation example one with R-carvone.
Preparation example two (Compound No. ALY578)
Starting from intermediate 6(270mg,1.01mmol) obtained in preparation example one, NaH (121mg,3.03mmol) was suspended in dry tetrahydrofuran, a dry THF solution of intermediate 6 was added dropwise, stirred at room temperature for 30min, a dry THF solution of p-methylbenzyl bromide (374mg,2.02mmol) was added dropwise, and the mixture was heated to 75 ℃ and refluxed for 2 h. TLC detection reaction was complete, water quenched, extracted with ethyl acetate, the organic phase washed with saturated brine, dried, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 25/1) to give intermediate 7-1(260mg,0.70mmol, 70% yield) as a clear oil:1H NMR(CDCl3,300MHz)δ7.24–7.15(m,4H),4.57–4.47(m,2H),4.21(s,1H),3.63–3.54(m,1H),2.64–2.56(m,1H),2.35–2.22(m,5H),2.00(s,3H),1.71–1.60(m,1H),0.91–0.89(m,9H),0.10(d,J＝3.0Hz,6H)。
DIBAL-H (1.05ml,1.05mmol) was added dropwise to a solution of compound 7-1(260mg,0.70mmol) in DCM under a dry ice acetone bath, and after completion of the addition, the mixture was warmed to room temperature and stirred for 2H. TLC monitored the end of the reaction of the starting material, quenched by addition of saturated aqueous sodium potassium tartrate solution, the mixture was allowed to warm to room temperature, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatographed (petroleum ether/ethyl acetate (v/v) ═ 25/1) to give product 7-2(160mg,0.43mmol, 61% yield).1H NMR(CDCl3,300MHz)δ10.15(s,1H),7.26–7.14(m,4H),4.55(dd,J＝15.0,12.0Hz,2H),4.30(s,1H),3.56–3.50(m,1H),2.92(d,J＝18.0Hz,1H),2.34(s,4H),2.15(s,3H),2.06–1.98(m,1H),1.73–1.62(m,1H),0.92(s,9H),0.13(d,J＝3.0Hz,6H)。
Intermediate 7-2(160mg,0.43mmol) and iodide 267(172mg,0.64mmol) were dissolved in dry ether, cooled to-78 deg.C, n-butyllithium (0.64ml,0.64mmol) was added dropwise, stirred at this temperature for 30 minutes, and then quenched by addition of saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was dissolved in dichloromethane and DMP (272mg,0.64mmol) was added at 0 deg.C, warmed to room temperature and stirred overnight. The next day, the mixture was quenched with saturated sodium thiosulfate solution/saturated sodium bicarbonate solution (1/1), extracted with dichloromethane, washed with saturated brine, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give intermediate 7-3(73mg, yield 33%). Intermediate 7-3(73mg,0.14mmol) was dissolved in toluene (10ml) and methanol (2ml) and the reaction mixture was heated to ambient temperature at 80 ℃ under reflux overnight. The next day, column chromatography was concentrated (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give intermediate 7-4(41mg,0.084mmol, 60% yield).1H NMR(CDCl3,300MHz)δ7.23–7.13(m,4H),4.60–4.44(m,2H),3.86–3.80(m,4H),3.49–3.39(m,1H),2.55(d,J＝15.0Hz,1H),2.38(dd,J＝15.0,6.0Hz,1H),2.34(s,3H),2.22(s,3H),2.15–2.09(m,1H),1.55–1.43(m,1H),1.25(s,3H),0.90(s,9H),0.10(d,J＝6.0Hz,6H)。
To a solution of LHMDS (0.6ml,0.59mmol) in THF at 0 deg.C was added dropwise the intermediateA solution of form 7-4(41mg,0.084mmol) in THF was warmed to room temperature and stirred for 4h, nicotinoyl chloride hydrochloride was added quickly and stirred for 2h at room temperature. TLC detects the material reaction, adds acetic acid to quench, water dilutes, extracts with dichloromethane, dries with anhydrous sodium sulfate, and concentrates. Column chromatography purification (petroleum ether/acetone (v/v) ═ 3/1) gave intermediate 7-5(10mg,0.018mmol, 23% yield).1H NMR(CDCl3,300MHz)δ9.05(s,1H),8.75(d,J＝3.0Hz,1H),8.18(d,J＝9.0Hz,1H),7.47–7.43(m,1H),7.25–7.14(m,4H),6.42(s,1H),4.63–4.46(m,2H),3.95(dd,J＝12.0,6.0Hz,1H),3.53–3.44(m,2H),2.66(d,J＝15.0Hz,1H),2.55(dd,J＝12.0,3.0Hz,1H),2.34(s,3H),2.19(d,J＝12.0Hz,1H),1.60–1.52(m,2H),1.25(s,3H),0.95–0.88(m,9H),0.16(d,J＝12.0Hz,6H)。
Acetyl chloride (13 μ l,0.18mmol) was added dropwise to 0.5ml of methanol and the mixture stirred at room temperature for 5min, followed by addition of a solution of intermediate 7-5(10mg,0.018mmol) in methanol and stirring at room temperature for 1 h. Concentrated and directly used in the next step. The crude product was dissolved in dichloromethane and a catalytic amount of DMAP, EDCI (10mg,0.053mmol) and p-cyanobenzoic acid (8mg,0.053mmol) were added and stirred at room temperature overnight. TLC monitored the reaction was complete, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to afford intermediates 7-6(5mg,0.009mmol, 50% yield) as pale yellow solids.1H NMR(CDCl3,300MHz)δ9.04(s,1H),8.74(s,1H),8.21–8.00(m,3H),7.82–7.79(m,1H),7.60(d,J＝9.0Hz,1H),7.44(s,1H),7.23–7.08(m,4H),6.48(s,0.3H),6.48(s,0.7H),5.50(dd,J＝12.0,6.0Hz,1H),4.63–4.35(m,2H),3.82–3.67(m,1H),3.11(dd,J＝9.0,3.0Hz,1H),2.76(d,J＝9.0Hz,1H),2.59–2.52(m,1H),2.34(s,3H),2.24–2.17(m,1H),2.04–1.94(m,1H),1.60(s,3H)。
Compounds 7-6(5mg,0.009mmol) and cerous chloride heptahydrate (20mg,0.063mmol) were dissolved in methanol, cooled to-78 deg.C and sodium borohydride (2mg,0.063mmol) was added carefully and the mixture stirred for 30 minutes until the starting material disappeared. Quenching with acetone, diluting with ethyl acetate, washing the organic phase with water, washing with saturated brine, drying, concentrating, and isolating and purifying by column chromatography (dichloromethane/methanol ═ 50/1) to afford ALY578(4mg, 77% yield) as a light yellow solid:1HNMR(500MHz,CDCl3)δ9.02–8.95(m,1H),8.71–8.66(m,1H),8.20–7.79(m,4H),7.47–7.347(m,2H),7.23–7.01(m,4H),6.51(s,0.3H),6.40(s,0.7H),5.30(dd,J＝10.0,5.0Hz,1H),4.61–4.44(m,2H),4.28(d,J＝10.0Hz,1H),3.96(s,1H),3.74–3.67(m,1H),2.79(d,J＝15.0Hz,1H),2.56–2.53(m,1H),2.35(d,J＝5.0Hz,3H),2.11–2.08(m,1H),1.92–1.88(m,1H),1.79–1.71(m,1H),1.48–1.40(m,3H)。
compound ALY578R was prepared by replacing compound S-carvone in the preparation examples with R-carvone.
The following compounds were synthesized in the same manner:
preparation example three (Compound No. ALY515)
Starting from compound 6-5 obtained in preparation example one, acetyl chloride (19. mu.l, 0.26mmol) was added dropwise to 0.5ml of methanol, and the mixture was stirred at room temperature for 5min, followed by addition of a solution of intermediate 6-5(15mg,0.026mmol) in methanol and stirring at room temperature for 1 h. Concentrated and directly used in the next step. The crude product was dissolved in dry DMF and a catalytic amount of DBU, dry triethylamine (15. mu.l, 0.104mmol), propyl isocyanate (15. mu.l, 0.156mmol) were added and stirred overnight at 80 ℃. TLC monitored the reaction was complete, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to afford intermediate 8-1(5mg,0.01mmol, 39% yield) as a clear oil.1H NMR(CDCl3,300MHz)δ9.06(s,1H),8.75(d,J＝3.0Hz,1H),8.19(d,J＝6.0Hz,1H),7.48–7.43(m,1H),6.55(s,0.5H),6.53(s,0.5H),5.26-5.17(m,1H),4.93–4.65(m,3H),3.25–3.09(m,4H),2.97-2.91(m,1H),2.82-2.78(m,1H),2.64-2.40(m,2H),2.17-2.14(m,1H),1.62-1.43(m,7H),1.00-0.85(m,6H)。
Intermediate 8-1(5mg,0.01mmol) and cerous chloride heptahydrate (25mg,0.07mmol) were dissolved in methanol and cooled to-78 deg.C with careful addition of borohydrideSodium (3mg,0.07mmol) was added and the mixture stirred for 30 minutes until the starting material disappeared. Quenching with acetone, diluting with ethyl acetate, washing the organic phase with water, washing with saturated brine, drying, concentrating, and isolating and purifying by column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to give the final product ALY515(4mg, 78%):1H NMR(500MHz,CDCl3)δ9.01(dd,J＝10.0,5.0Hz,1H),8.78–8.59(m,1H),8.11-8.08(m,1H),7.43-7.39(m,1H),6.49(s,1H),5.10–5.02(m,1H),4.83-4.75(m,2H),4.48(d,J＝10.0Hz,1H),4.61(s,1H)4.34(s,1H),3.22–3.12(m,4H),2.66-2.60(m,1H),2.45(s,1H),2.23(s,1H),2.04(s,1H),1.93–1.89(m,1H),1.59-1.49(m,4H),1.38(s,1.5H),1.31(s,1.5H),0.98-0.90(m,6H)。
the following compounds were synthesized in the same manner:
preparation example four (Compound No. ALY585-1, ALY585-2)
Starting from compound 6-5 obtained in preparation example one, acetyl chloride (37. mu.l, 0.52mmol) was added dropwise to 0.5ml of methanol, and the mixture was stirred at room temperature for 5min, followed by addition of a solution of intermediate 6-5(30mg,0.052mmol) in methanol and stirring at room temperature for 1 hour. Concentrated and directly used in the next step. The crude product was dissolved in methylene chloride, pyridine (42. mu.l, 0.52mmol) was added thereto, and the mixture was stirred at room temperature for 30min, and phenyl chloroformate (32. mu.l, 0.26mmol) was added thereto, and the mixture was stirred at room temperature overnight. TLC monitored the reaction was complete, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to afford intermediate 9-1(15mg,0.026mmol, 50% yield) as a clear oil.1H NMR (500MHz, CDCl3) δ 9.09(s,1H),8.76(d, J ═ 5.0Hz,1H), 8.21-8.18 (m,1H), 7.45-7.17 (m,11H),6.61(s,1H),5.24(dd, J ═ 15.0,5.0Hz,1H), 4.95-4.89 (m,1H),2.85(dd, J ═ 10.0,5.0Hz,1H), 2.79-2.73 (m,2H),1.90(q, J ═ 15.0Hz,1H),1.65(q, J ═ 15.0,1H),1.56(s, 3H). Intermediate 9-2(8mg,0.014mmol, 27% yield).1HNMR(500MHz,CDCl3)δ1H NMR(500MHz,CDCl3)δ9.04(s,1H),8.76(s,1H),8.19–8.16(m,1H),7.46–7.14(m,11H),6.53(s,1H),5.21–5.19(m,1H),5.05–5.00(m,1H),3.13(dd,J＝10.0,5.0Hz,1H),2.48-2.44(m,3H),2.13–2.08(m,1H),1.74(s,3H)。
Intermediate 9-1(15mg,0.026mmol) and cerous chloride heptahydrate (67mg,0.18mmol) were dissolved in methanol, sodium borohydride (7mg,0.18mmol) was added carefully as it cooled to-78 deg.C, and the mixture was stirred for 30 minutes until the starting material disappeared. Quenching with acetone, diluting with ethyl acetate, washing the organic phase with water, washing with saturated brine, drying, concentrating, and isolating and purifying by column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to give the final product ALY585-1(14mg, 92%):1H NMR(CDCl3,500MHz)δ9.03(S,1H),8.70(d,J＝5.0Hz,1H),8.16–8.06(m,1H),7.47–7.13(m,11H),6.54(s,1H),5.04(dd,J＝10.0,5.0Hz,1H),4.97–4.80(m,1H),4.56(d,J＝10.0Hz,1H),4.41(s,1H),2.85-2.82(m,1H),2.76–2.72(m,1H),2.00–1.90(m,2H),1.59-1.52(m,1H),1.45(s,3H).。
intermediate 9-2(8mg,0.014mmol) and cerous chloride heptahydrate (36mg,0.096mmol) were dissolved in methanol, sodium borohydride (4mg,0.096mmol) was added carefully as it cooled to-78 deg.C, and the mixture was stirred for 30 minutes until the starting material disappeared. Quenching with acetone, diluting with ethyl acetate, washing the organic phase with water, washing with saturated brine, drying, concentrating, and isolating and purifying by column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to give the final product ALY585-2(7mg, 85%):1H NMR(CDCl3,500MHz)δ9.01(s,1H),8.71(d,J＝5.0Hz,1H),8.17–8.06(m,1H),7.43–7.16(m,11H),6.49(s,1H),5.28(s,1H),5.09–5.05(m,2H),4.30(s,1H),2.79(s,1H),2.61(s,1H),2.44(d,J＝15.0Hz,1H),2.28(s,1H),2.00–1.90(m,1H),1.54(s,3H).。
the following compounds were synthesized in the same manner:
preparation example five (Compound No. ALY585)
Starting from compound 6-5 obtained in preparation example one, intermediate 6-5(25mg,0.044mmol) and cerous chloride heptahydrate (114mg,0.306mmol) were dissolved in methanol, sodium borohydride (12mg,0.306mmol) was added carefully as a cold to-78 ℃, and the mixture was stirred for 30min until the starting material disappeared. Quenching with acetone, diluting with ethyl acetate, washing the organic phase with water, washing with saturated brine, drying, concentrating, and purifying by column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to give intermediate 10-1(22mg,0.038mmol, 86%):1H NMR(CDCl3,300MHz)δ9.00(s,1H),8.70(s,1H),8.10(d,J＝6.0Hz,1H),7.41(dd,J＝9.0,6.0Hz,1H),6.46(s,0.4H),6.37(s,0.6H),4.47(d,J＝12.0Hz,1H),4.39(s,1H),3.77–3.71(m,2H),2.40(d,J＝15.0Hz,1H),1.99(d,J＝12.0Hz,1H),1.59–1.50(m,1H),1.39–1.14(m,4H),0.94–0.88(m,18H),0.15–0.08(m,12H)。
acetyl chloride (27 μ l,0.38mmol) was added dropwise to 0.5ml of methanol, and the mixture was stirred at room temperature for 5min, followed by addition of a solution of intermediate 10-1(22mg,0.038mmol) in methanol and stirring at room temperature for 1 hour. Concentrated and directly used in the next step. The crude product was dissolved in dichloromethane and a catalytic amount of DMAP, EDCI (36mg,0.19mmol) and p-cyanobenzoic acid (28mg,0.19mmol) were added and stirred at room temperature overnight. TLC monitored the reaction was complete, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to afford ALY585(10mg,0.017mmol, 45% yield) as a yellow solid.1H NMR(CDCl3,500MHz)δ8.97(s,1H),8.67(s,1H),8.21–8.08(m,5H),7.82–7.75(m,4H),7.38(s,1H),6.50(s,1H),6.41(s,1H),5.70(dd,J＝15.0,5.0Hz,1H),5.22–5.18(m,1H),3.02–2.98(m,1H),2.72–2.68(m,1H),2.08–2.01(m,1H),1.25(s,3H)。
Compound ALY585R was prepared by substituting R-carvone for S-carvone in the preparation examples.
The following compounds were synthesized in the same manner:
preparation example six (Compound No. ALY665)
Starting from intermediate 6(200mg,0.75mmol) obtained in preparation example one, this was dissolved in 0.5ml of ethyl vinyl ether, a catalytic amount of pyridinium p-toluenesulfonate was added and the mixture was stirred at room temperature for 2 h. TLC monitored the reaction was complete, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 25/1) to afford intermediate 11-1(251mg,0.74mmol, 99% yield) as a clear oil.1H NMR(CDCl3,300MHz)δ4.82–4.75(m,1H),4.30–4.25(m,1H),3.87–3.74(m,1H),3.66–3.42(m,2H),2.56-2.49(m,1H),2.34-2.17(m,2H),2.00(d,J＝3.0Hz,3H),1.73–1.57(m,1H),1.31(d,J＝6.0Hz,3H),1.22–1.17(m,3H),0.89(s,9H),0.10(d,J＝3.0Hz,6H).。
DIBAL-H (1.2ml,1.17mmol) was added dropwise to a solution of compound 11-1(265mg,0.78mmol) in DCM under a dry ice acetone bath, and after completion of the addition, the mixture was warmed to room temperature and stirred for 2H. TLC monitored the end of the reaction of the starting material, quenched by addition of saturated aqueous sodium potassium tartrate solution, the mixture was allowed to warm to room temperature, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatographed (petroleum ether/ethyl acetate (v/v) ═ 25/1) to give product 11-2(210mg,0.61mmol, 78% yield).
Intermediate 11-2(210mg,0.61mmol) and iodide 267(247mg,0.92mmol) were dissolved in dry diethyl ether, cooled to-78 deg.C, n-butyllithium (0.92ml,0.92mmol) was added dropwise, stirred at this temperature for 30min, and then quenched by addition of saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was dissolved in dichloromethane and DMP (390mg,0.92mmol) was added at 0 deg.C, warmed to room temperature and stirred overnight. The next day, the mixture was quenched with saturated sodium thiosulfate solution/saturated sodium bicarbonate solution (1/1), extracted with dichloromethane, washed with saturated brine, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give intermediate 11-3(170mg, 58% yield). Intermediate 11-3(170mg,0.35mmol) was dissolved in toluene (10ml) and methanol (2ml) and the reaction mixture was heated to the outsideReflux overnight at 80 ℃. The next day, column chromatography was performed (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give intermediate 11-4(120mg,0.26mmol, yield 74%).1H NMR(CDCl3,300MHz)δ4.80(dd,J＝9.0,6.0Hz,1H),3.90–3.79(m,1H),3.78(s,3H),3.64–3.58(m,3H),2.47–2.41(m,1H),2.22(s,3H),1.54–1.38(m,4H),1.30(d,J＝6.0Hz,3H),1.24(s,3H),1.21–1.16(m,3H),0.89–0.87(m,9H),0.10(d,J＝6.0Hz,6H)。
To a solution of LHMDS (1.8ml,1.82mmol) in THF at 0 deg.C was added dropwise a solution of intermediate 11-4(120mg,0.26mmol) in THF, warmed to room temperature and stirred for 4h, nicotinoyl chloride hydrochloride was added rapidly and stirred for 2h at room temperature. TLC detects the material reaction, adds acetic acid to quench, water dilutes, extracts with dichloromethane, dries with anhydrous sodium sulfate, and concentrates. Column chromatography purification (petroleum ether/acetone (v/v) ═ 3/1) gave intermediate 11-5(51mg,0.096mmol, 37% yield).1H NMR(CDCl3,300MHz)δ9.04(s,1H),8.74(d,J＝3.0Hz,1H),8.16(d,J＝9.0Hz,1H),7.44(dd,J＝9.0,6.0Hz,1H),6.48(s,0.2H),6.42(s,0.8H),4.83–4.80(m,1H),4.01–3.93(m,1H),3.81–3.38(m,3H),2.61–2.48(m,2H),2.09(s,1H),1.58-1.41(m,2H),1.34–1.17(m,9H),0.94-0.88(m,9H),0.18-0.13(m,5H).。
Intermediate 11-5(51mg,0.096mmol) was dissolved in 2ml of tetrahydrofuran at 0 deg.C, 2ml of 0.5N HCl was added dropwise, and stirring was continued for 4h at this temperature. TLC detects the reaction of raw materials, adds sodium carbonate saturated solution to quench, extracts with ethyl acetate, dries with anhydrous sodium sulfate, and concentrates. Column chromatography purification (dichloromethane/methanol (v/v) ═ 25/1) gave intermediate 11-6(30mg,0.065mmol, 68% yield).1H NMR(CDCl3,300MHz)δ9.06(s,1H),8.77(s,1H),8.18(d,J＝6.0Hz,1H),7.46(s,1H),6.43(s,1H),4.00(dd,J＝12.0,3.0Hz,1H),3.89-3.78(m,1H),2.64(dd,J＝12.0,3.0Hz,1H),2.49(d,J＝15.0Hz,1H),2.18(d,J＝15.0Hz,1H),1.81(s,1H),1.55–1.51(m,1H),1.37(d,J＝3.0Hz,3H),0.95(d,J＝3.0Hz,9H),0.20-0.14(m,6H)。
Intermediate 11-6(10mg,0.022mmol) was dissolved in dichloromethane, and a catalytic amount of DMAP, EDCI (9mg,0.044mmol), and Z-glycine (9mg,0.044mmol) were added and stirred at room temperature overnight. TLC to monitor the reaction completion, adding water to quench, ethyl acetate extraction, anhydrous sulfurSodium salt was dried and purified by column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to give intermediate 11-7(10mg,0.015mmol, 71% yield).1H NMR(CDCl3,300MHz)δ9.06(d,J＝3.0Hz,1H),8.76(dd,J＝6.0,3.0Hz,1H),8.20–8.16(m,1H),7.48-7.43(m,1H),7.36(s,5H),6.50(s,0.3H),6.43(s,0.7H),5.24(s,1H),5.14(s,2H),4.97–4.87(m,1H),4.06–3.97(m,3H),2.68(dd,J＝12.0,3.0Hz,1H),2.56-2.51(m,1H),2.22-2.17(m,1H),1.62(d,J＝6.0Hz,2H),1.38(s,3H),0.96–0.90(m,9H),0.21-0.25(m,5H).。
Acetyl chloride (10. mu.l, 0.15mmol) was added dropwise to 0.5ml of methanol, and the mixture was stirred at room temperature for 5min, followed by addition of a solution of intermediate 11-7(11mg,0.038mmol) in methanol and stirring at room temperature for 1 hour. Concentrated and directly used in the next step. The crude product was dissolved in dichloromethane and a catalytic amount of DMAP, EDCI (8mg,0.03mmol) and p-cyanobenzoic acid (5mg,0.03mmol) were added and stirred at room temperature overnight. TLC monitored the reaction was complete, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to afford intermediate 11-8(3mg,0.004mmol, 11% yield) as a colorless oil.1HNMR(CDCl3,300MHz)δ9.04(dd,J＝9.0,3.0Hz,1H),8.78-8.73(m,1H),8.20-8.12(m,3H),7.83–7.78(m,2H),7.49–7.35(m,6H),6.51(s,0.5H),6.48(s,0.5H),5.63–5.56(m,1H),5.25–5.10(m,3H),3.99(t,J＝6.0Hz,1H),3.84-3.78(m,1H),3.12–3.08(m,1H),2.92-2.88(m,1H),2.68-2.55(m,2H),2.37(s,1H),1.25(s,3H).。
Intermediate 11-8(3mg,0.004mmol) and cerous chloride heptahydrate (12mg,0.032mmol) were dissolved in methanol, sodium borohydride (2mg,0.032mmol) was added carefully after cooling to-78 deg.C, and the mixture was stirred for 30min until the starting material disappeared. Quenching with acetone, diluting with ethyl acetate, washing the organic phase with water, washing with saturated brine, drying, concentrating, and purifying by column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to give the final product ALY665(2mg, 75%):1H NMR(CDCl3,300MHz)δ8.99(d,J＝18.0Hz,1H),8.70(dd,J＝12.0,6.0Hz,1H),8.20–8.05(m,3H),7.81(d,J＝9.0Hz,2H),7.46–7.36(m,6H),6.50(s,0.5H),6.41(s,0.5H),5.41-5.36(m,2H),5.14–5.09(m,2H),4.55(d,J＝9.0Hz,1H),4.39(s,1H),3.98(d,J＝6.0Hz,1H),3.88–3.58(m,2H),2.78-2.68(m,1H),2.57-2.53(m,1H),2.28(s,1H),2.00(t,J＝12.0Hz,1H),1.87–1.75(m,1H),1.26(s,3H)。
the following compounds were synthesized in the same manner:
test example 1
Test examples for inhibition of ACAT2 Activity
1. The purpose of the test is as follows:
the inhibition of the ACAT2 activity by the Pyripyropene A structural analogues at the intact cell level was examined by measuring ACAT2 activity using fluorescently labeled sterols.
2. The test principle is as follows:
inhibition of ester synthesis with NBD 22-fluorescently labeled sterol with varying concentrations of compound, resulting in varying fluorescence intensity differences, was used to plot inhibition curves and IC was calculated50。
3. The experimental process comprises the following steps:
HepG2 cells at 1.5X 104After culturing each well for 24 hours in a 96-well plate, adding the cholesterol mixture, mixing well, continuing culturing for 24 hours, adding NBD 22-fluorescent labeled sterol with a final concentration of 0.5. mu.g/ml and compounds with a final concentration gradient of 0, 0.008, 0.04, 0.2, 1 and 5. mu.M, with three replicate wells for each concentration, after culturing for 6 hours, using a fluorescence analyzer (E488, A535) to measure the fluorescence intensity, plotting the fluorescence intensity values against different concentrations of compounds and obtaining IC50。
4. The experimental results are as follows: (the following compounds are exemplified but not limited to)
TABLE 1 inhibition of ACAT2 Activity by Compounds
| Compound numbering | IC50(μM) |
| Pyripyropene A | 0.179 |
| ALY603 | 0.115 |
| ALY578 | 0.148 |
| ALY564 | 0.224 |
| ALY621 | 0.303 |
| ALY727 | 0.146 |
| ALY585R | 0.442 |
| ALY515 | 0.383 |
| ALY619 | 0.281 |
| ALY585-1 | 0.136 |
| ALY665 | 0.478 |
Note: IC (integrated circuit)50The sample compounds were evaluated for 50% inhibition of ACAT2 activity.
The results show that the compounds have inhibitory activity on ACAT2, and the inhibitory activity of the ACAT2 inhibitor is obviously improved compared with that of only one specific inhibitor Pyripyropene A of ACAT 2.
Test example 2
Selectivity coefficient test example for inhibition of ACAT2 Activity
1. The purpose of the test is as follows:
the inhibition effect of the analogue with the Pyripyropene A structure on ACAT2 and ACAT1 at the whole cell level is detected by using a cholesterol oxidase method to measure the ACAT activity, so that the compound with high selectivity on ACAT2 is obtained.
2. The test principle is as follows:
IC was obtained by assaying the inhibitory effect of compounds of different concentrations on ACAT1 or ACAT2 activity using HepG2 cells50To calculate SI (ACAT 1-IC)50/ACAT2-IC50)。
3. The experimental process comprises the following steps:
HepG2 cells at 4X 105After 24 hours of incubation in 6-well plates at the initial density of each well, the medium was changed and 10. mu.g/ml Cholesterol and different concentrations of compounds were added and incubation was continued for 9 hours and the amount of cellular Cholesterol was determined using Cholesterol Assay kit.
4. The experimental results are as follows: (the following compounds are exemplified but not limited to)
The compounds of table 2 have ACAT1 inhibitory activity and SI:
| compound numbering | IC50(μM) | SI |
| PPPA | >20 | 200 |
| ALY603 | 56.31 | 477 |
| ALY578 | 8.747 | 61 |
| ALY564 | >10 | - |
| ALY621 | >10 | - |
| ALY727 | 12.90 | 88 |
| ALY515 | >10 | - |
| ALY619 | >10 | - |
| ALY582 | 13.80 | 76 |
| ALY585-1 | 34.53 | 254 |
The result shows that the compounds have high selectivity on inhibiting the ACAT2 activity.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A compound shown in a general formula I, a tautomer, an optical isomer and a stereoisomer thereof or pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
x is O, S, NH or C1-C6An alkylene group;
R4is a 4-8 membered heteroaryl;
w is hydrogen or hydroxy;
R1is hydrogen or C1-C6An alkyl group;
n is 0,1 or 2;
y, Z are each independently O, NH, S, -OC (═ O) -, -OC (═ O) O (C)1-C6Alkylene) -, -OC (═ O) (C)1-C6Alkylene) -, -O (C)1-C6Alkylene) -, -OC (═ O) (C)1-C6Alkylene) NHC (═ O) -, -OC (═ O) NH (C)1-C6Alkylene) -or-OC (═ O) NH-;
R2and R3Each independently hydrogen, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C6-C12Aryl, substituted or unsubstituted 4-8 membered heteroaryl, substituted or unsubstituted C1-C6An alkoxy group;
each of the above substituents independently means having one or more substituents selected from the group consisting of: c1-C6Alkyl radical, C6-C12Aryl, 4-8 membered heteroaryl, C3-C8Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6Alkylamino, halogen, cyano, hydroxy, amino, -COC1-C6Alkyl, -COC3-C6Cycloalkyl, -COC6-C12And (4) an aryl group.
2. The compound of claim 1, wherein: the compounds have one or more of the following characteristics:
(1) x is O;
(2)R4is a 5-7 membered heteroaryl group, preferably pyridine;
(3)R1is methyl, ethyl or propyl;
(4) n is 1 or 2.
3. The compound of claim 1, wherein: y, Z are each independently O, NH, S, -OC (═ O) -, -OC (═ O) O (C)1-C4Alkylene) -, -OC (═ O) (C)1-C4Alkylene) -, -O (C)1-C4Alkylene) -, -OC (═ O) (C)1-C4Alkylene) NHC (═ O) -, -OC (═ O) NH (C)1-C4Alkylene) -or-OC (═ O) NH-.
4. The compound of claim 1, wherein: r2And R3Each independently hydrogen, substituted or substituted C3-C6Cycloalkyl, substituted or substituted C6-C10Aryl, substituted or substituted 4-6 membered heteroaryl, substituted or unsubstituted C1-C6An alkoxy group;
each of the above substituents independently means having one or more selected from the group consisting ofSubstituent(s): c1-C6Alkyl radical, C6-C10Aryl, 4-8 membered heteroaryl, C3-C6Cycloalkyl radical, C1-C4Alkoxy radical, C1-C4Alkylamino, halogen, cyano, hydroxy, amino, -COC1-C6Alkyl, -COC3-C6Cycloalkyl, -COC6-C10And (4) an aryl group.
5. The compound of claim 1, wherein said compound is:
6. the method of claim 1, wherein the compound of formula I has the structure of formula Ia, formula Ib, formula Ic, or formula Id, and wherein the method comprises the steps of:
n、Z、Y、R2、R3、R4PG, as claimed in claim 11、PG2Is a hydroxyl protecting group which is a silicon ether, an ester group, a benzyl ether or an alkyl ether;
(1) ozonizing the double bond of the compound 14 to obtain a compound 15, and oxidizing by Baeyer-Villiger to obtain a compound 16;
(2) removing acetyl from the compound 16, and then protecting hydroxyl by a protecting group to obtain a compound 17;
(3) reduction of compound 17DIBAL-H to give compound 18;
(4) carrying out coupling reaction on the compound 18, a compound 267 and an n-butyllithium reagent, oxidizing, and carrying out solvolysis reaction to obtain a compound 19;
(5) compound 19 is dehydroenolated by LHMDS, followed by neutralization of R4C-acylation and ring closure are carried out on COCl to obtain a compound 20;
(6) removing a protecting group from the compound 20, and reacting with acid anhydride, acyl chloride, isocyanate or chloroformate to obtain a compound Ia; performing Luche reduction reaction on the compound Ia to obtain a compound Ic;
or the compound 20 is reduced to obtain a compound Ib, and the compound Ib is subjected to deprotection and then reacts with acid anhydride, acyl chloride, isocyanate or chloroformate to obtain a compound Id.
7. The method of claim 6, wherein the method has one or more of the following characteristics:
the solvent used in the ozonization reaction in the step (1) is selected from: dichloromethane and methanol;
the reaction temperature of the ozonization reaction in the step (1) is-78 ℃ to room temperature;
the solvent used for DIBAL-H reduction in the step (3) is dichloromethane;
the reaction temperature of the DIBAL-H reduction reaction in the step (3) is-78-0 ℃;
the solvent used in the coupling reaction in the step (4) is an aprotic solvent, and is selected from diethyl ether and the like;
the reaction temperature of the coupling reaction in the step (4) is-78 ℃ to room temperature;
the solvent used in the solvolysis reaction in the step (4) is selected from: toluene and methanol;
the reaction temperature of the solvolysis reaction in the step (4) is 80 ℃;
the solvent used for C-acylation ring closing in the step (5) is an aprotic solvent selected from tetrahydrofuran;
the temperature of the C-acylation ring-closing reaction in the step (5) is 0 ℃ to room temperature;
the solvent used in the deprotection reaction and the acyl reaction in the step (6) is an aprotic solvent selected from dichloromethane;
the reaction temperature of the deprotection group reaction and the acyl group reaction in the step (6) is room temperature;
the solvent used in the Luche reduction reaction in the step (6) is selected from an alcohol solvent, preferably methanol or ethanol; the reaction temperature is-78 ℃ to room temperature.
8. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable carrier.
9. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of: (i) agents that selectively inhibit ACAT 2; or (ii) a medicament for the prophylaxis and/or treatment of cardiovascular diseases.
10. The use of claim 9, wherein the cardiovascular disease is selected from the group consisting of: hyperlipidemia, and atherosclerosis.
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