CN115304600A - mTOR inhibitor, preparation method and application - Google Patents
mTOR inhibitor, preparation method and application Download PDFInfo
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- CN115304600A CN115304600A CN202211194474.5A CN202211194474A CN115304600A CN 115304600 A CN115304600 A CN 115304600A CN 202211194474 A CN202211194474 A CN 202211194474A CN 115304600 A CN115304600 A CN 115304600A
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to an mTOR inhibitor, a preparation method and application, and belongs to the technical field of chemical drugs. A compound having a structure shown in formula I or pharmaceutically acceptable salts thereof:
in the formula, R 1 Is selected from
、
、
、
；R 2 Is selected from C 1 ‑C 6 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
、
、
、
、
、
；R 3 Selected from H, OH, OCH 3 、OCH 2 CH 3 、OCH 2 CH 2 CH 3 、OCH(CH 3 ) 2 、
、
Description
Technical Field
The invention relates to an mTOR inhibitor, a preparation method and application, and belongs to the technical field of chemical drugs.
Background
Mammalian target of rapamycin (mTOR), which is a serine/threonine protein kinase, is widely present in biological cells as two complexes of mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2). mTOR plays an important role in cell growth, apoptosis and autophagy, and is an important component of multiple signal pathways in cells to participate in regulation of organism growth and metabolic balance, so that the mTOR inhibitor is widely applied to the fields of broad-spectrum antibiosis, antivirus, immunosuppression, antitumor and the like.
First generation mTOR inhibitors, such as rapamycin and its derivative analog "rapalogs", are mTORC1 inhibitors that prevent mTOR activation in a conformationally altered manner; for example, everolimus (everolimus) can be combined with an intracellular protein FKBP12 to form an inhibitory complex mTORC1, can inhibit the activity of mTOR, and the inhibition of an mTOR signaling pathway can lead to the reduction of the activities of a transcription regulatory factor S6 ribosomal protein kinase (S6K 1) and a eukaryotic elongation factor 4E-binding protein (4E-BP 1), thereby interfering the translation and synthesis of related proteins such as cell cycle, angiogenesis, glycolysis and the like. However, the compound activates the Akt feedback regulation pathway while inhibiting mTORC1, so that the wide clinical application of the compound is limited, and the drug resistance is generated. Therefore, in order to better meet the requirements of clinic and market, the development of a new mTOR inhibitor which is more effective and has better inhibitory activity has important economic and social benefits.
Disclosure of Invention
In view of the above-mentioned deficiencies of the prior art, the present invention aims to provide an mTOR inhibitor, a preparation method and a use thereof. The mTOR inhibitor provided by the invention is more effective and better in inhibitory activity, is used for preventing and/or treating malignant tumors, immune diseases, viral infection, neurological diseases and the like caused by the dysfunction of an mTOR signaling pathway, and has small side effects. The specific technical scheme is as follows:
in a first aspect, a compound having the structure shown in formula i:
in the formula, R 1 Is selected from
、
、
、
；
R 2 Is selected from C 1 -C 6 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
、
、
、
、
、
；
R 3 Selected from H, OH, OCH 3 、OCH 2 CH 3 、OCH 2 CH 2 CH 3 、OCH(CH 3 ) 2 、
、
。
In a second aspect, a method for preparing a compound having a structure shown in formula i or a pharmaceutically acceptable salt thereof comprises the following steps:
in the formula, R 1 、R 2 、R 3 Is as defined for the first aspect R 1 、R 2 、R 3 The definition of (2).
Step 1) Synthesis of Compound VII
Carrying out reduction reaction on the compound VIII and a reducing agent in a reaction solvent to obtain a compound VII;
further, in the step 1), the reaction temperature is 20 to 30 ℃, for example, the reaction temperature may be 20 ℃, 25 ℃, 30 ℃ or the like; when the reaction temperature is too low, the reaction rate is slow, and the reaction time is long; when the reaction temperature is too high, the stability of the compound VII (the compound represented by the formula VII) is affected. The reducing agent is at least one of iron powder, zinc powder, palladium carbon, ni and hydrogen, and preferably is the combination of palladium carbon and hydrogen. The reaction solvent is at least one of ethanol, methanol, dioxane and tetrahydrofuran, and preferably methanol.
The yield of the final compound VII can reach 61.2% by means of controlling the reaction temperature, selecting a specific reducing agent and the like.
Step 2), synthesis of Compound V
Reacting a compound VII and a compound VI in a reaction solvent to obtain a compound V;
further, in the step 2), the reaction temperature is 0-25 ℃; the temperature in the charging stage is controlled to be 0 to 5 ℃, so that the activity of the reactants is reduced, and side reactions are inhibited; if the reaction temperature of the main reaction is too low, the reaction rate is slow, and the reaction time is long; therefore, the temperature of the main reaction needs to be raised, but if the reaction temperature is too high, the side reaction cannot be inhibited, and the final yield is also affected; the optimal reaction temperature for the final main reaction was controlled at 25 ℃. The reaction solvent is at least one of N, N-dimethylformamide and tetrahydrofuran, and tetrahydrofuran is preferred.
By controlling the reaction temperature, the yield of the final compound V can reach 81.1 percent.
Step 3), synthesis of Compound IV
Carrying out reduction reaction on the compound V and a reducing agent in a reaction solvent to obtain a compound IV;
further, in the step 3), the reaction temperature is-30 ℃ to 0 ℃; the temperature in the charging stage is controlled to be-30 to-20 ℃, so as to reduce the activity of reactants and inhibit side reactions; however, if the reaction temperature of the main reaction is too low, the reaction rate is slow and the reaction time is long; therefore, the temperature of the main reaction needs to be raised, but if the reaction temperature is too high, side reactions cannot be inhibited, and the final yield is affected; the optimal reaction temperature for the final main reaction was controlled at-10 ℃. The reducing agent is at least one of (+) -diisopinocampheylchloroborane, sodium borohydride and sodium triacetyl borohydride, and the reducing agent is preferably (+) -diisopinocampheylchloroborane. The reaction solvent is at least one of N, N-dimethylformamide, tetrahydrofuran, toluene and N-methylpyrrolidone, and the reaction solvent is preferably tetrahydrofuran.
By means of controlling the reaction temperature, selecting a specific reducing agent and the like, the yield of the final compound IV can reach 71.1%.
Step 4) Synthesis of Compound III
Carrying out hydrolysis reaction on the compound IV and acid in a reaction solvent to obtain a compound III;
further, in the step 4), the reaction temperature is 0 ℃ to 60 ℃, for example, the reaction temperature may be 0 ℃,10 ℃, 20 ℃, 30 ℃, 40 ℃, 50 ℃ or 60 ℃ or the like; the acid is at least one of hydrochloric acid and trifluoroacetic acid, and is preferably trifluoroacetic acid. The reaction solvent is at least one of dichloromethane, methanol and ethanol, and dichloromethane is preferred. The Boc (abbreviation for t-butyloxycarbonyl) on deamination with trifluoroacetic acid is most efficient; in addition, to minimize the degree of racemization, it is desirable to use a lower reaction temperature, e.g., an optimal reaction temperature controlled at 0 ℃.
By means of controlling the reaction temperature, selecting specific acid and the like, the yield of the final compound III can reach 80.1%.
Step 5), synthesis of Compound II-1
Carrying out coupling reaction on a compound II-3, a compound II-2 and alkali in a reaction solvent at the temperature of 40-50 ℃, after the reaction is finished, adding acid, and continuing the reaction at the temperature of 10-40 ℃ (carrying out deprotection and ring closure reaction under an acidic condition) to obtain a compound II-1;
further, in the step 5), the base is at least one of triethylamine and diisopropylethylamine, and is preferably triethylamine; the acid is at least one of hydrochloric acid and trifluoroacetic acid, and is preferably hydrochloric acid; the reaction solvent is at least one of dichloromethane and N, N-dimethylformamide. In the coupling reaction, the triethylamine is adopted, the reaction efficiency is highest, and the reaction temperature can be 40 ℃, 43 ℃, 46 ℃ or 50 ℃ and the like, preferably 43 +/-3 ℃. The efficiency of performing ring closure reaction by adopting hydrochloric acid is highest; in addition, since a deprotection reaction is involved, a temperature reduction is required, for example, the optimum reaction temperature is controlled to 20. + -. 5 ℃.
By means of controlling the coupling reaction temperature, the deprotection group ring closing reaction temperature, selecting specific acid, alkali and the like, the yield of the compound II-1 can reach 84.0 percent.
Step 6), synthesis of Compound II
Carrying out hydrolysis reaction on the compound II-1 and alkali in a reaction solvent to obtain a compound II;
further, in step 6), the reaction temperature is 20 to 80 ℃, for example, the reaction temperature may be 20 ℃, 25 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃ or 80 ℃, preferably 25 ℃; the alkali is at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, potassium tert-butoxide and sodium methoxide, and is preferably sodium hydroxide; the reaction solvent is at least one of tetrahydrofuran, methanol, ethanol and dioxane, preferably ethanol.
By means of controlling the reaction temperature, selecting specific alkali and other measures, the yield of the compound II can reach 79.3 percent.
Step 7), synthesis of Compound I-1
Reacting the compound II, the compound III, an acid-binding agent and a condensing agent in a reaction solvent to obtain a compound I-1;
further, in the step 7), the reaction temperature is 0-60 ℃; when the compound II, the compound III and the acid-binding agent are added into a reaction solvent, the temperature is reduced to 0 ℃ to inhibit side reaction; however, if the reaction temperature of the main reaction is too low, the reaction rate is slow, and the reaction time is long; therefore, the temperature of the main reaction needs to be raised, but if the reaction temperature is too high, side reactions cannot be inhibited, and the final yield is affected; therefore, after the addition of the condensing agent, the main reaction temperature is raised to 25 ℃. The acid-binding agent is at least one of 4-dimethylamino pyridine and N, N-diisopropylethylamine, and preferably 4-dimethylamino pyridine. The condensing agent is at least one of 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, O-benzotriazole-tetramethylurea hexafluorophosphate, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and N, N '-dicyclohexylcarbodiimide, preferably N, N' -dicyclohexylcarbodiimide. The reaction solvent is at least one of N, N-dimethylformamide, dichloromethane and tetrahydrofuran, and dichloromethane is preferred.
By means of controlling the reaction temperature, selecting specific acid-binding agent, condensing agent and the like, the yield of the compound I-1 can reach 55.6 percent.
Further, when R is 3 Is selected from
The method comprises the following steps:
compound I-1, acetic anhydride（C 4 H 6 O 3 ) Reacting in a reaction solvent to obtain a compound I-2, wherein the compound I-2 and the compound I are the same compound;
the reaction temperature is 20 to 30 ℃, the reaction temperature is not too high, or by-products are increased, so the reaction temperature is preferably 20 ℃; the reaction solvent is at least one of N, N-dimethylformamide, dichloromethane, tetrahydrofuran and toluene, and toluene is preferred.
By means of controlling the reaction temperature, selecting acetic anhydride as an acylating agent and the like, the yield of the compound I-2 can reach 65.0 percent.
Further, when R is 3 Is selected from
The method comprises the following steps:
reacting a compound I-1, benzyl chloroformate (Cbz-Cl) and alkali in a reaction solvent to obtain a compound I-3, wherein the compound I-3 and the compound I are the same compound;
wherein the reaction temperature is 15-30 ℃, and the alkali is selected from at least one of cesium carbonate, potassium carbonate and sodium bicarbonate, preferably sodium bicarbonate; the reaction solvent is at least one of N, N-dimethylformamide, dichloromethane and tetrahydrofuran, and tetrahydrofuran is preferred.
By means of controlling the reaction temperature, selecting specific alkali and other measures, the yield of the compound I-3 can reach 78.3 percent.
Further, when R is 3 When selected from H, compound I-1 is the same compound as Compound I.
In a third aspect, an mTOR inhibitor, comprising: the compound has the structure shown in the formula I or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or diluents.
In a fourth aspect, the compound with the structure shown in formula I or pharmaceutically acceptable salt thereof is used for preparing a medicament for preventing and/or treating malignant tumor, immune diseases, viral infection and neurological diseases. Wherein the malignant tumor is glioblastoma, renal malignancy, gastric malignancy, malignant skin tumor, rhabdomyosarcoma, bladder malignancy, breast malignancy, uterine malignancy, lung malignancy, colon malignancy, prostate malignancy, ovarian malignancy, or pancreatic malignancy.
The invention has the beneficial effects that:
1) The compound shown in the formula I, the pharmaceutically acceptable salt and the pharmaceutical composition containing the compound as an active ingredient are used as mTOR inhibitors, are more effective and better in inhibitory activity, are used for preventing and/or treating malignant tumors, immune diseases, viral infections, neurological diseases and the like caused by dysfunction of mTOR signaling pathways, and have smaller side effects; therapeutic objectives can be achieved by administering to a patient in need of such prevention and/or treatment a therapeutically effective dose of one or more compounds of formula I.
2) The preparation method is simple, mild in condition, convenient to operate, low in requirement on equipment condition, easy to realize, simple in post-treatment, few in by-products, high in yield, suitable for industrial large-scale production and high in application value.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and do not limit the invention.
Definition of
"pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. The salt comprises: acid addition salts obtained by reaction of the free base of the parent compound with an inorganic acid or with an organic acid; such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid, and the like; such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, benzenesulfonic acid (benzenesulfonate), benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, malonic acid, or the like; preferably hydrochloric acid or (L) -malic acid; or when the acid proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or coordinated with an organic base, a salt is formed; such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
"pharmaceutically acceptable carrier" refers to a pharmaceutical carrier that is conventional in the pharmaceutical art, and that does not significantly stimulate an organism and does not abrogate the biological activity and properties of the administered compound, such as: diluents such as water and the like; fillers, such as starch, sucrose, and the like; binders such as cellulose derivatives, alginates, gelatin, polyvinylpyrrolidone; humectants, such as glycerol; disintegrating agents such as agar, calcium carbonate and sodium bicarbonate; absorption promoters, such as quaternary ammonium compounds; surfactants such as cetyl alcohol; adsorption carriers such as kaolin and bentonite clay; lubricants, such as talc, calcium stearate and magnesium stearate, and polyethylene glycol, and the like. In addition, other adjuvants such as flavoring agent and sweetener can also be added into the above medicinal composition.
The compounds of the invention may have one or more asymmetric centers; the compounds can thus be prepared as individual (R) -stereoisomers or (S) -stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or designation of a particular compound in the specification and claims is intended to include the individual enantiomers and racemic or other mixtures thereof. Methods for determining stereochemical configuration and separating stereoisomers are well known in the art (see the discussion in chapter 4 of "Advanced Organic Chemistry", 4 th edition, j. March, john Wiley and Sons, new York, 1992). Thus, the present invention also encompasses any stereoisomeric form, its corresponding enantiomers (d-and l-isomers or (+) and (-) isomers), and diastereomers thereof, and mixtures thereof, having mTOR inhibitory activity, and is not limited to any one stereoisomeric form.
"ambient temperature" has the meaning well known in the art and is typically 24 to 28 ℃.
Embodiments of the present invention provide a compound having the structure of formula i or a pharmaceutically acceptable salt thereof:
wherein when R is 3 Selected from H, R 1 Is selected from
、
Or
，R 2 Is selected from
、
、
Or
；
When R is 3 Is selected from
Or
When R is 1 Is selected from
，R 2 Is selected from
。
Further, the structure shown in formula I can be, but is not limited to, the following structure:
the present invention has been carried out several times in succession, and some of the results of the tests are now included as references to describe the invention in detail, which are described in detail below with reference to specific examples.
Example 1
The first step is as follows:
adding a compound VIII (31.3 g, 0.1mol) and palladium carbon (3.1 g) into methanol (300 mL), stirring, introducing hydrogen, keeping the pressure of the hydrogen at 40-50psi, heating to 25 ℃ after stirring, keeping the temperature for reaction for 12 hours, monitoring the reaction by TLC, filtering after the reaction is finished to obtain a first solid, adding the first solid into 500mL of methanol, heating to reflux, carrying out hot filtration to obtain a filtrate, carrying out reduced pressure concentration to obtain a second solid, adding the second solid into a mixed solution of 100mL of ethyl acetate and 100mL of petroleum ether, heating to reflux, cooling and crystallizing to obtain 17.3g of a yellow solid compound VII with the yield of 61.2%. The structural formula of the compound VIII is shown as the formula VIII, and the rest compounds are analogized in the same way.
The second step is that:
dissolving a compound VII (15.0 g, 0.05mol) and a compound VI (di-tert-butyl dicarbonate, 24.1g, 0.11mol) in tetrahydrofuran (400 mL), cooling to 0-5 ℃, raising to 25 ℃ after dissolution, preserving heat for 6 hours, monitoring the reaction by TLC, adding water (100 mL) after the reaction is finished, quenching the reaction, separating liquid, taking an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain 15.5g of oily substance, and purifying to obtain a gray solid compound V with the yield of 81.1%.
The third step:
dissolving a compound V (14.2g, 0.04mol) in tetrahydrofuran (400 mL), cooling to-30 ℃, dropwise adding (+) -diisopinocampheylchloroborane (19.2g, 0.06mol), and keeping the temperature at-20 to-30 ℃ in the dropwise adding process; heating to-10 deg.C, reacting for 16 hr, concentrating under reduced pressure, adding diethyl ether and diethanolamine (77.6 mL, 0.8mol), stirring at room temperature for 4 hr, filtering to obtain organic phase, concentrating, and performing column chromatography (eluent: dichloromethane/methanol = 20/1) to obtain 10.9g oily compound IV with yield of 71.1%.
The fourth step:
dissolving a compound IV (10.0 g, 0.03mol) in dichloromethane (100 mL), cooling to 0 ℃, dropwise adding trifluoroacetic acid (50 mL), heating to room temperature, stirring for reaction for 2 hours, monitoring the reaction by TLC, after the reaction is finished, concentrating under reduced pressure to remove dichloromethane and trifluoroacetic acid, adjusting the pH to 8-10, precipitating a solid, filtering, and drying to obtain 5.9g of a solid compound III, wherein the yield is 80.1%.
The fifth step:
dissolving the compound 1-II-3 (7.0 g, 0.02mol) and the compound 1-II-2 (5.1g, 0.02mol) in dichloromethane (100 mL), slowly adding dropwise triethylamine (1.0 g, 0.04mol) at 40-46 ℃, stirring for reaction for 3 hours, monitoring the reaction by TLC, cooling to 15-25 ℃ after the reaction is finished, adding 32mL of 6N hydrochloric acid aqueous solution dropwise, standing for layering after the reaction is finished, washing an organic phase with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, drying the organic phase, and concentrating to obtain 8.2g of solid compound 1-II-1 with the yield of 84.0%.
And a sixth step:
compound 1-II-1 (8.0 g, 0.02mol) was dissolved in ethanol (100 mL), an aqueous sodium hydroxide solution (1.6 g, 0.04mol) was added thereto at room temperature with stirring, the reaction was monitored by TLC, after completion of the reaction, concentration was performed under reduced pressure, a 2N aqueous hydrochloric acid solution was added to adjust the pH to 1 to 2, extraction was performed with ethyl acetate (100 mL. Times.2), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give 5.8g of Compound 1-II as a white solid with a yield of 79.3%.
The seventh step:
dissolving the compounds 1-II (3.6 g,7.9 mmol) in dichloromethane (10 mL), adding the compound III (2.3 g,7.9 mmol) and DMAP (4-dimethylaminopyridine, 1.1g,8.7 mmol) respectively, cooling to 0 ℃, adding DCC (N, N' -dicyclohexylcarbodiimide, 1.8g,8.7 mmol), slowly raising to room temperature, continuing to react for 2 hours, monitoring the reaction by TLC, adding ethyl acetate after the reaction is finished, filtering to obtain filtrate, concentrating the filtrate under reduced pressure to obtain oily matter, and performing column chromatography to obtain 3.2g of the compound 1 as a white solid with the yield of 55.6 percent and ESI (+) m/z = 728.8M H] + 。
Example 2
The first step is as follows:
dissolving the compound 2-II-3 (7.4g, 0.02mol) and the compound 1-II-2 (5.1g, 0.02mol) in dichloromethane (100 mL), slowly adding triethylamine (1.0 g, 0.04mol) dropwise at 40-46 ℃, stirring for reaction for 3 hours, monitoring the reaction by TLC, cooling to 15-25 ℃ after the reaction is finished, adding 32mL of 6N hydrochloric acid aqueous solution dropwise, standing for layering after the reaction is completed, washing an organic phase with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, drying the organic phase, and concentrating to obtain 8.2g of solid compound 2-II-1 with the yield of 82.1%.
The second step is that:
compound 2-II-1 (8.0 g,15.6 mmol) was dissolved in ethanol (100 mL), an aqueous sodium hydroxide solution (1.3 g,31.8 mmol) was added thereto at room temperature with stirring, the reaction was monitored by TLC, after completion of the reaction, the reaction mixture was concentrated under reduced pressure, a 2N aqueous hydrochloric acid solution was added to adjust the pH to 1 to 2, extraction was performed with ethyl acetate (100 mL. Times.2), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give 5.6g of compound 2-II as a white solid with a yield of 76.1%.
The third step:
dissolving compounds 2-II (3.8g, 8.0 mmol) in dichloromethane (20 mL), adding compound III (2.4g, 8.0 mmol) and DMAP (4-dimethylaminopyridine, 1.2g,8.0 mmol) respectively, cooling to 0 ℃, adding DCC (N, N' -dicyclohexylcarbodiimide, 1.8g,8.8 mmol), slowly raising the temperature to room temperature, continuing the reaction for 2 hours, monitoring the reaction by TLC, after the reaction is completed, adding ethyl acetate, filtering to obtain a filtrate, concentrating the filtrate under reduced pressure to obtain an oil, and performing column chromatography to obtain 2.7g of compound 2 as a white solid, wherein the yield is 45.1%, and ESI (+) m/z = 742.8M H] + 。
Example 3
The first step is as follows:
dissolving the compound 3-II-3 (0.7g, 1.89mmol) and the compound 1-II-2 (0.5g, 1.89mmol) in dichloromethane (10 mL), slowly adding dropwise triethylamine (0.4g, 3.8mol) at 40 to 46 ℃, stirring for reaction for 3 hours, monitoring the reaction by TLC, after the reaction is finished, cooling to 15 to 25 ℃, adding dropwise 5mL 6N hydrochloric acid aqueous solution, standing for layering after the reaction is finished, washing an organic phase with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, drying the organic phase, and concentrating to obtain 0.8g of the solid compound 3-II-1 with the yield of 84%.
The second step is that:
compound 3-II-1 (0.5g, 1mmol) was dissolved in ethanol (10 mL), an aqueous sodium hydroxide solution (0.12g, 3mmol) was added with stirring at room temperature, the reaction was monitored by TLC, after completion of the reaction, concentration was performed under reduced pressure, a 2N aqueous hydrochloric acid solution was added to adjust the pH to 1 to 2, extraction was performed with ethyl acetate (50 mL. Times.2), the organic layers were combined, dried over anhydrous sodium sulfate, and concentration was performed to obtain 0.34g of compound 3-II as an off-white solid in a yield of 72.1%.
The third step:
dissolving the compound 3-II (0.3 g,0.6 mmol) in dichloromethane (5 mL), adding the compound III (0.17g, 0.6 mmol) and DMAP (4-dimethylaminopyridine, 0.1g,0.7 mmol) respectively, cooling to 0 ℃, adding DCC (N, N' -dicyclohexylcarbodiimide, 0.14g,0.7 mmol), slowly raising to room temperature, continuing to react for 2 hours, monitoring the reaction by TLC, adding ethyl acetate after the reaction is finished, filtering to obtain filtrate, concentrating the filtrate under reduced pressure to obtain oil, and performing column chromatography to obtain 0.18g of compound 3 as a white solid, wherein the yield is 41.1%, ESI (+) m/z 742 =.8M H] + 。
Example 4
The first step is as follows:
dissolving the compound 4-II-3 (1.0g, 2.8mmol) and the compound 1-II-2 (0.7g, 2.8mmol) in dichloromethane (5 mL), slowly dropwise adding triethylamine (0.6 g,5.6 mol) at 40-46 ℃, stirring for reaction for 3 hours, monitoring the reaction by TLC, after the reaction is finished, cooling to 15-25 ℃, dropwise adding 4mL, 6N hydrochloric acid aqueous solution, standing for layering after the reaction is finished, washing an organic phase by using saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, drying the organic phase, and concentrating to obtain 1.1g of solid compound 4-II-1, wherein the yield is 80%.
The second step is that:
compound 4-II-1 (0.7g, 1.4 mmol) was dissolved in ethanol (5 mL), aqueous sodium hydroxide (0.17g, 4.2mmol) was added with stirring at room temperature, the reaction was monitored by TLC, after completion of the reaction, concentration was performed under reduced pressure, 2N aqueous hydrochloric acid was added to adjust pH to 1 to 2, extraction was performed with ethyl acetate (50 mL × 2), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 0.45g of compound 4-II as a white solid in a yield of 70%.
The third step:
dissolving compound 4-II (0.4 g,0.9 mmol) in dichloromethane (5 mL), adding compound III (0.26g, 0.9 mmol) and DMAP (4-dimethylaminopyridine, 0.12g, 1mmol) respectively, cooling to 0 ℃, adding DCC (N, N' -dicyclohexylcarbodiimide, 0.2g, 1mmol), slowly raising to room temperature, continuing to react for 2 hours, monitoring the reaction by TLC, after the reaction is completed, adding ethyl acetate, filtering to obtain filtrate, concentrating the filtrate under reduced pressure, and performing column chromatography to obtain 0.3g of compound 4 as solid, wherein the yield is 44.1%, and ESI (+) m/z =730.4[ [ M ] H + H ], [ 1 ]] + 。
Example 5
Compound 1 (0.3g, 0.4mmol) was dissolved in toluene (4 mL), warmed to 50 ℃ and stirred to dissolve, then cooled to 20 ℃ and acetic anhydride (C) was added dropwise 4 H 6 O 3 81.6mg,0.8 mmol), keeping the temperature for continuous reaction after finishing the dropwise addition, monitoring the reaction by TLC, adding an aqueous solution of sodium bicarbonate after the reaction is finished, stirring for 30 minutes, adding ethyl acetate, stirring for layering, and concentrating the organic phase under reduced pressure to obtain 0.2g of oily compound 5, wherein the yield is 65.0 percent, and ESI (+) m/z =770.8[ M ] +H ]] + 。
Example 6
Compound 1 (0.3g, 0.4 mmol) was dissolved in tetrahydrofuran (4 mL), sodium bicarbonate (67.2mg, 0.8mmol) and Cbz-Cl (benzyl chloroformate, 107.4mg,0.6 mmol) were added, the reaction was continued at room temperature, the reaction was monitored by TLC, after completion of the reaction, water was added and the mixture was stirred for 30 minutes, ethyl acetate was added and the layers were separated by stirring, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.27g of Compound 6 as an oil in 78.3% yield and ESI (+) m/z = 862.9M + H] + 。
Example 7
The first step is as follows:
dissolving a compound 7-II-3 (1.0g, 2.8mmol) and a compound 7-II-2 (730.8mg, 2.8mmol) in dichloromethane (5 mL), slowly dropwise adding triethylamine (0.6g, 5.6 mol) at 40-46 ℃, stirring for reaction for 3 hours, monitoring the reaction by TLC, cooling to 15-25 ℃ after the reaction is finished, dropwise adding 4mL of 6N hydrochloric acid aqueous solution, standing for layering after the reaction is completed, washing an organic phase by using a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, drying the organic phase, and concentrating to obtain 1.1g of solid compound 7-II-1 with the yield of 78%.
The second step:
compound 7-II-1 (0.7 g,1.4 mmol) was dissolved in ethanol (10 mL), an aqueous sodium hydroxide solution (0.17g, 4.2mmol) was added under stirring at room temperature, the reaction was monitored by TLC, after completion of the reaction, concentration was performed under reduced pressure, 2N aqueous hydrochloric acid was added to adjust pH to 1 to 2, extraction was performed with ethyl acetate (50 mL × 2), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 0.46g of compound 7-II as a white-like solid in a yield of 70%.
The third step:
dissolving the compound 7-II (0.4 g,0.9 mmol) in dichloromethane (5 mL), adding the compound III (0.26g, 0.9 mmol) and DMAP (4-dimethylaminopyridine, 0.12g, 1mmol) respectively, cooling to 0 ℃, adding DCC (N, N' -dicyclohexylcarbodiimide, 0.2g, 1mmol), slowly raising to room temperature, continuing to react for 2 hours, monitoring the reaction by TLC, after the reaction is completed, adding ethyl acetate, filtering to obtain filtrate, concentrating the filtrate under reduced pressure to obtain oil, and performing column chromatography to obtain 0.3g of solid compound 7 with the yield of 44.0% and the (+) m/z =733.2[ ESI M H ] H] + 。
Example 8
The structural formula of compound 8 is shown in formula 8, which is a white solid, ESI (+) m/z =716.8[ 2 ] M + H] + 。
Biological evaluation test
U87MG Human Glioblastoma(ATCC)
3 H Thymidine Incorporation Protocol
Growth medium: BRL essential Medium (500 mL) containing Earle Salts
+5mL BRL MEN non-essential amino acid (10 mM)
+5mL BRL penicillin and streptomycin (10000 microgram/mL )
+5mL BRL sodium pyruvate solution (100 mM)
+5mL BRL-glutamate (200 mM)
+50mL fetal bovine serum
The test procedure was as follows:
1. cells were trypsinized at a final volume of 10 in 200. Mu.l growth medium 4 The concentration of cells/well was placed in a 96-well flat bottom plate and adhered at 37 ℃ for 24 hours.
2. The medium was carefully removed with a pipette so as not to disturb the cell monolayer, 200. Mu.l of fresh growth medium was added to each well, 10. Mu.l of each of compounds 1 to 8 was added, and the mixture was further cultured at 37 ℃ for 48 hours.
3. At the end of the 5 hours of incubation, the plates were plated with 1. Mu. Ci 3 H-thymidine is used for calibration. Mu.l of 11. Mu. Ci in compounds 1 to 8 was added, and the plate was returned to the incubator for the last 5 hours.
4. The radioactive medium was carefully removed with a pipette so as not to disturb the cell monolayer. Add 50. Mu.l BRL 10 Xtrypsin to each well, followed by incubation at 37 ℃ for 10 minutes or until the monolayer is shed from the bottom well. Samples were harvested on glass fiber filter pads using a Skatron 96-well harvester and counted on a Wallac Betaplate counter. Calculating to obtain IC of the target compound 50 The values are shown in Table 1:
TABLE 1
As can be seen from Table 1, compounds 1 to 8 all have good inhibitory effects on mTOR, wherein the inhibitory activities of compounds 1 and 6 are the highest.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. A compound having the structure shown in formula I or a pharmaceutically acceptable salt thereof:
in the formula, R 1 Is selected from
、
、
、
；
R 2 Is selected from C 1 -C 6 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
、
、
、
、
、
；
R 3 Selected from H, OH, OCH 3 、OCH 2 CH 3 、OCH 2 CH 2 CH 3 、OCH(CH 3 ) 2 、
、
。
2. The compound or pharmaceutically acceptable salt thereof according to claim 1,
when R is 3 Selected from H, R 1 Is selected from
、
Or
，R 2 Is selected from
、
、
Or
；
When R is 3 Is selected from
Or
When R is 1 Is selected from
，R 2 Is selected from
。
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the following formulas 1-8, and has the following structural formula:
4. a process for the preparation of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, comprising the steps of:
in the formula, R 1 、R 2 、R 3 As defined in any one of claims 1 to 3 for R 1 、R 2 、R 3 The definition of (1);
step 1), synthesis of Compound VII
Reacting the compound VIII with a reducing agent in a reaction solvent to obtain a compound VII;
step 2), synthesis of Compound V
Reacting a compound VII and a compound VI in a reaction solvent to obtain a compound V;
step 3), synthesis of Compound IV
Reacting the compound V and a reducing agent in a reaction solvent to obtain a compound IV;
step 4) Synthesis of Compound III
Reacting the compound IV with acid in a reaction solvent to obtain a compound III;
step 5), synthesis of Compound II-1
Reacting the compound II-3, the compound II-2 and alkali in a reaction solvent, and adding acid to continue reacting after the reaction is finished to obtain a compound II-1;
step 6), synthesis of Compound II
Reacting the compound II-1 with alkali in a reaction solvent to obtain a compound II;
step 7), synthesis of Compound I-1
Reacting the compound II, the compound III, an acid-binding agent and a condensing agent in a reaction solvent to obtain a compound I-1;
when R is 3 Is selected from
When the temperature of the water is higher than the set temperature,
reacting the compound I-1 and acetic anhydride in a reaction solvent to obtain a compound I-2, wherein the compound I-2 and the compound I are the same compound;
when R is 3 Is selected from
When the temperature of the water is higher than the set temperature,
reacting the compound I-1, benzyl chloroformate and alkali in a reaction solvent to obtain a compound I-3, wherein the compound I-3 and the compound I are the same compound;
when R is 3 When selected from H, the compound I-1 is the same compound as the compound I.
5. The preparation method of claim 4, wherein in the step 1), the reaction temperature is 20 to 30 ℃, the reducing agent is at least one of iron powder, zinc powder, palladium carbon, ni and hydrogen, and the reaction solvent is at least one of ethanol, methanol, dioxane and tetrahydrofuran;
in the step 2), the reaction temperature is 0-25 ℃, and the reaction solvent is at least one of N, N-dimethylformamide and tetrahydrofuran;
in the step 3), the reaction temperature is-30 ℃ to 0 ℃, the reducing agent is at least one of (+) -diisopinocampheylchloroborane, sodium borohydride and sodium triacetyl borohydride, and the reaction solvent is at least one of N, N-dimethylformamide, tetrahydrofuran, toluene and N-methylpyrrolidone;
in the step 4), the reaction temperature is 0-60 ℃, the acid is at least one of hydrochloric acid and trifluoroacetic acid, and the reaction solvent is at least one of dichloromethane, methanol and ethanol;
in the step 5), reacting a compound II-3, a compound II-2 and alkali in a reaction solvent at the temperature of 40-50 ℃, adding acid, and continuing to react at the temperature of 10-40 ℃, wherein the alkali is at least one of triethylamine and diisopropylethylamine, the acid is at least one of hydrochloric acid and trifluoroacetic acid, and the reaction solvent is at least one of dichloromethane and N, N-dimethylformamide;
in the step 6), the reaction temperature is 20-80 ℃, the alkali is at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, potassium tert-butoxide and sodium methoxide, and the reaction solvent is at least one of tetrahydrofuran, methanol, ethanol and dioxane;
in the step 7), the reaction temperature is 0-60 ℃, the acid-binding agent is at least one of 4-dimethylaminopyridine and N, N-diisopropylethylamine, the condensing agent is at least one of 2- (7-azobenzotriazol) -N, N, N ', N ' -tetramethylurea hexafluorophosphate, O-benzotriazol-tetramethylurea hexafluorophosphate, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and N, N ' -dicyclohexylcarbodiimide, and the reaction solvent is at least one of N, N-dimethylformamide, dichloromethane and tetrahydrofuran.
6. The method according to claim 5, wherein when R is 3 Is selected from
In the preparation method, the compound I-1 and acetic anhydride react in a reaction solvent at a temperature of 20 to 30 ℃, wherein the reaction solvent is at least one of N, N-dimethylformamide, dichloromethane, tetrahydrofuran and toluene.
7. The method according to claim 5, wherein when R is 3 Is selected from
In the method, the compound I-1, benzyl chloroformate and base react in a reaction solvent at the temperature of 15-30 ℃, wherein the base is at least one of cesium carbonate, potassium carbonate and sodium bicarbonate, and the reaction solvent is at least one of N, N-dimethylformamide, dichloromethane and tetrahydrofuran.
8. An mTOR inhibitor, comprising: a compound as claimed in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or diluents.
9. Use of the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in preparation of medicines for preventing and/or treating malignant tumors, immune diseases, viral infections and neurological diseases.
10. Use of a compound according to claim 9 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and/or treatment of a malignancy, an immunological disorder, a viral infection, a neurological disorder, wherein the malignancy is glioblastoma, renal malignancy, gastric malignancy, malignant skin neoplasm, rhabdomyosarcoma, bladder malignancy, breast malignancy, uterine malignancy, lung malignancy, colon malignancy, prostate malignancy, ovarian malignancy, or pancreatic malignancy.
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Denomination of invention: MTOR inhibitors, preparation methods, and applications Effective date of registration: 20230829 Granted publication date: 20230113 Pledgee: Industrial Bank Co.,Ltd. Beijing Pinggu Branch Pledgor: BEIJING XINKAIYUAN PHARMACEUTICAL TECHNOLOGY CO.,LTD. Registration number: Y2023110000364 |