CN112538069A - Azole derivative or pharmaceutically acceptable salt thereof, and preparation method and application thereof - Google Patents
Azole derivative or pharmaceutically acceptable salt thereof, and preparation method and application thereof Download PDFInfo
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention discloses an azole derivative or a pharmaceutically acceptable salt thereof and a preparation method thereof, wherein the structure of the azole derivative is shown as follows, compared with the prior art, the azole derivative is an azole compound which has a novel structure and a function of inhibiting CRM1 protein, and can block the proliferation of tumor cells and induce the apoptosis of the tumor cells when being used as a CRM1 protein inhibitor, so that the azole derivative can be used for treating and preventing various diseases of human and animals such as malignant tumor, and has obvious effectIt is superior.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a nuclear transport regulator derivative, a preparation method and an application thereof in pharmacy.
Background
Currently, malignant tumors remain one of the major life-threatening diseases. Cancer treatment, while much progress has been made, has not been able to treat cancer at all. Although the anticancer drugs on the market at present have certain curative effect, most of them are cytotoxic drugs and have serious toxic and side effects. Therefore, it is urgent to develop a novel anticancer drug targeting from an effective tumor target to study targeting.
Most studies on CRM1 have used the natural product CRM1 inhibitor leptomycin b (lmb). Has high toxicity to tumor cells, but is difficult to accept by animals due to obvious gastrointestinal toxicity. Inhibitors of nuclear export can have beneficial effects on neoplastic disorders and other hyperplastic disorders. To date, however, drug-like CRM1 inhibitors for small molecules for use in vitro and in vivo are still not common. CRM1 can inhibit tumor suppressor proteins, export several key proteins associated with many inflammatory processes, mediate retinoid X receptor a (rxra) transport, inhibit activation of a range of transcription factors like ICp27, E2F4, KL5, YAP1, ZAP to affect gene expression, mediate transport of key neuroprotective proteins, CRM1 controls nuclear localization and thus the activity of various DMA metabolisms, CRM1 is also associated with other disorders. Complete maturation of many viruses also requires complete nuclear export, mediated primarily by CRM 1.
In view of the above, the present invention provides a nuclear transport modulator derivative or a pharmaceutically acceptable salt thereof, an azole compound having a novel structure and a function of inhibiting CRM1 protein, which is a CRM1 protein inhibitor, can block tumor cell proliferation, induce tumor cell apoptosis, and is useful for treating various diseases, disorders or conditions associated with abnormal cellular responses triggered by inappropriate nuclear transport.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides the azole derivative or the pharmaceutically acceptable salt thereof. In order to achieve the purpose, the invention adopts the technical scheme that: an azole derivative or a pharmaceutically acceptable salt thereof, wherein the azole derivative has a structure of formula I:
wherein:
x, Y, Z is selected from-C (H) -or-N-;
r2 is selected from optionally substituted heteroaryl and optionally substituted aryl;
r1 is selected from hydrogen, deuterium, C1-10 alkyl, C3-6 cycloalkyl, heterocycloalkyl, heterocyclyl, aryl or benzyl, wherein the C1-10 alkyl, C3-6 cycloalkyl, heterocycloalkyl, heterocyclyl, aryl or benzyl is optionally substituted or unsubstituted by C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, cyano, nitro, hydroxy, mercapto, amino or halogen.
In a preferred embodiment of the present invention, the azole derivative is selected from table a:
TABLE A
In a preferred embodiment of the present invention, the synthesis is performed as follows:
in a preferred embodiment of the present invention, the method comprises the following steps:
s1, enabling cyano of the compound 1 to obtain thiocarboxamide under the action of sodium hydrosulfide and magnesium chloride, and reacting under the conditions of hydrazine hydrate and formic acid to generate triazole 2;
s2, triazole 2 and (Z) -3-ethyl iodoacrylate are coupled under the catalytic action of triethylene diamine to generate a compound 3;
s3, performing addition reaction on the double bond part of the compound 3 and liquid bromine, and removing one molecule of bromine under the action of triethylamine to obtain a key intermediate 4;
s4, under the catalytic action of bis (triphenylphosphine) palladium dichloride, the intermediate 4 and a plurality of nitrogen-containing aryl groups with boric acid structures are subjected to Suzuki coupling respectively to generate compounds 5a-5i connected with different nitrogen-containing aryl groups;
the ester bonds of S5 and 5a-5i are hydrolyzed into carboxylic acid under the action of lithium hydroxide, and the carboxylic acid further generates a positive drug KPT-8602 and a target compound 6b-6i under the atmosphere of ammonia gas under the catalysis of isobutyl chloroformate and N-methylmorpholine.
In a preferred embodiment of the present invention, the azole derivative or the pharmaceutically acceptable salt thereof, and the pharmaceutical composition are each capable of receiving a carrier.
In a preferred embodiment of the invention, the pharmaceutical composition is applied to preparation of a drug for inhibiting CRM1 protein.
In a preferred embodiment of the invention, the composition is used for preparing a medicament for treating inflammation, cancer or a hyperproliferative disease.
In a preferred embodiment of the invention, the composition is used for preparing a medicament for treating immune-related diseases.
In a preferred embodiment of the invention, the composition is used for preparing a medicament for modifying various antigenic peptides produced by proteasomes in an organism.
In a preferred embodiment of the invention, the composition at least comprises an azole compound capable of inhibiting the function of CRM1 protein, and the azole compound is used as a ZCCRM 1 protein inhibitor to block the proliferation of tumor cells and induce the apoptosis of the tumor cells.
The invention solves the defects in the background technology, and has the following beneficial effects:
(1) the nuclear transport regulator provided by the invention is an azole compound which has a novel structure and a function of inhibiting CRM1 protein, and the azole compound serving as a CRM1 protein inhibitor can block the proliferation of tumor cells and induce the apoptosis of the tumor cells, so that the nuclear transport regulator has obvious effects of treating and preventing various diseases of human and animals such as malignant tumors. The amount of compound in the compositions of the invention that is effective to moderately inhibit CRM1 in a biological sample or patient is of great use in the treatment of a variety of diseases, disorders, or conditions associated with aberrant cellular responses triggered by inappropriate nuclear transport.
(2) In order to prolong the effect of the medicine, the invention needs to slow the absorption rate of the medicine injected subcutaneously or intramuscularly. Absorption of the parenterally administered drug is delayed by dissolving or suspending the drug in an oil vehicle. The actual dosage level of the active ingredient of the pharmaceutical composition of the present invention is varied so as to obtain an effective amount of the active ingredient to achieve the desired therapeutic response without poisoning the patient for the particular patient, composition and mode of administration.
(3) The concentration of the compound of this embodiment in a pharmaceutically acceptable mixture of the invention will vary depending on a number of factors, including the dose of the compound administered, the pharmacokinetic characteristics of the compound used, and the route of administration. Another aspect of the invention provides combination therapy wherein one or more additional therapeutic agents are administered with the proteasome inhibitor of the present invention. Such combination therapy may be achieved by the simultaneous, sequential or separate administration of the treatment components.
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The invention is further explained below with reference to the figures and examples;
FIG. 1 is a scheme of a series 1 of compounds of the example of the present invention;
figure 2 is a scheme of a series 2 of compounds of example one of the present invention.
Detailed Description
The invention will now be described in further detail with reference to the accompanying drawings and examples, which are simplified schematic drawings and illustrate only the basic structure of the invention in a schematic manner, and thus show only the constituents relevant to the invention.
Example one
One embodiment of the invention is that the compounds of the invention or pharmaceutically acceptable salts thereof specifically include processes for the preparation of the compounds and routes of administration.
The following are methods for the synthesis of series 1 drug compounds and series 2 drug compounds.
As shown in fig. 1, the present example is a series 1 of compounds for the route design and synthesis. The synthesis method of the series 1 compound comprises the following steps: cyano of a compound 1 generates thiocarboxamide under the action of sodium hydrosulfide and magnesium chloride, the thiocarboxamide reacts under the conditions of hydrazine hydrate and formic acid to generate triazole 2, the triazole 2 is coupled with (Z) -3-iodoethyl acrylate under the catalytic action of triethylene diamine to generate a compound 3, then, a double bond part of the compound 3 is added with liquid bromine, one molecule of bromine is removed under the action of triethylamine to obtain a key intermediate 4, the intermediate 4 is subjected to Suzuki coupling with a plurality of nitrogen-containing aromatic groups with boric acid structures under the catalytic action of bis (triphenylphosphine) palladium dichloride to generate compounds 5a-5i connected with different nitrogen-containing aromatic groups, finally, ester bonds of the 5a-5i are hydrolyzed into carboxylic acid under the action of lithium hydroxide, and the carboxylic acid is further catalyzed by isobutyl chloroformate and azomethylmorpholine, generating positive drug KPT-8602 and target compound 6b-6i under the atmosphere of ammonia gas.
Specifically, the synthesis method of compound 3 of ethyl (Z) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) acrylate is as follows:
a250 mL eggplant-shaped bottle was charged with 3, 5-bis (trifluoromethyl) benzonitrile 1(10g, 41.8mmol), dissolved in DMF (50mL), and treated with NaSH (7.8g, 83.7mmol) and MgCl2(8.5g, 41.8mmol) in this order. The reaction was then stirred at room temperature for a further 3 h. After completion of the reaction was monitored by TLC, the reaction solution was poured into a mixed solution of ice and water (500 mL). Extraction with ethyl acetate (100 mL. times.3) and combined organic phases and washed with saturated sodium chloride solution (100 mL. times.1), dried over anhydrous Na2SO4, filtered and the solvent evaporated under reduced pressure to give crude 3, 5-bis (trifluoromethyl) benzenemethanesulphonamide (10.9g, 95.1% yield, 84% purity) as a yellow oily liquid which was used directly in the next step.
To a 250mL eggplant-shaped bottle was added 3, 5-bis (trifluoromethyl) phenylmethylthioamide (10.9g, 39.8mmol), dissolved in DMF (30mL), and 80% hydrazine hydrate (5.1mL, 83.6mmol) was added dropwise thereto at room temperature. The mixture was stirred for an additional 1h, then formic acid (30mL) was added dropwise thereto. The reaction was then stirred at 90 ℃ for a further 3 h. After completion of the reaction monitored by TLC, the reaction was allowed to cool to room temperature and the reaction was poured into purified water (600 mL). Extraction with ethyl acetate (100 mL. times.3) and combining the organic phases and washing with saturated sodium bicarbonate solution (300 mL. times.3) and saturated sodium chloride solution (100 mL. times.1), drying over anhydrous Na2SO4, filtering and evaporation of the solvent under reduced pressure gave the crude compound. Stirred with n-hexane (200 mL. times.3), filtered, and dried to give relatively pure 3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazole 2(8.5g, 76.0% yield, 90% purity) as a white solid.
To a 250mL eggplant-shaped bottle was added 3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazole 2(8.5g, 30.2mmol), dissolved in DMF (40mL), and DABCO (8.5g, 75.5mmol) was added thereto. After the mixture was further stirred at room temperature for 30min, ethyl (Z) -3-iodoacrylate (7.5g, 33.2mmol) was added dropwise to the reaction solution. The reaction was then stirred at room temperature for a further 3 h. After completion of the reaction monitored by TLC, the reaction solution was poured into a mixed solution of ice and water (400 mL). Extraction with ethyl acetate (80 mL. times.3) and combined organic phases and washed with saturated sodium chloride solution (100 mL. times.1), dried over anhydrous Na2SO4, filtered and the solvent evaporated under reduced pressure to give the crude compound. The resulting crude product was purified by column chromatography (PE/EtOAc ═ 25: 1) to give the compound ethyl (Z) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) acrylate 3(7.9g, yield 68.2%, purity 98%) as a white solid.
Specifically, the synthesis method of the intermediate 4 of the ethyl (Z) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazole-1-yl) -2-bromoacrylate comprises the following steps:
in a 250mL round bottom flask, ethyl (Z) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) acrylate 3(7.9g, 20.6mmol) obtained above was dissolved in dichloromethane (40 mL). Liquid bromine (6.6g, 41.2mmol) was slowly added dropwise over 30min, and the reaction was then stirred at room temperature for an additional 8 h. After completion of the reaction monitored by TLC, the reaction solution was poured into a mixed solution of ice and water (100 mL). Extraction with dichloromethane (50 mL. times.3) and the combined organic phases were washed with saturated sodium bisulfite solution (100 mL. times.3) and saturated sodium chloride solution (50 mL. times.1), dried over anhydrous Na2SO4, filtered and the solvent was evaporated under reduced pressure.
Purification by column chromatography (PE/EtOAc ═ 50: 1) separation afforded ethyl 3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) -2, 3-dibromopropionate (10.3g, 92.7% yield, 95% purity) as a white solid.
The intermediate ethyl 3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) -2, 3-dibromopropionate obtained in the previous step (10.3g, 19.1mmol) was weighed into a 250mL eggplant-shaped bottle, dissolved in tetrahydrofuran (40mL), stirred for 10min on ice bath, and triethylamine (3.9g, 38.2mmol) was added dropwise to the reaction mixture and further stirred for 30 min. The reaction was then allowed to warm to room temperature and stirring was continued for 6 h. After completion of the reaction was monitored by TLC, a mixed ice-water solution (100mL) was added to the reaction solution. Extraction with ethyl acetate (50 mL. times.3) and the combined organic phases were washed with saturated sodium chloride solution (50 mL. times.1), dried over anhydrous Na2SO4, filtered and the solvent was evaporated under reduced pressure. Purification by column chromatography (PE/EtOAc ═ 50: 1) gave ethyl (Z) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) -2-bromoacrylate 4(7.7g, yield 88.2%, purity 96%) as a white solid.
Specifically, the synthesis method of the compound (5a) of ethyl (E) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) -2- (pyrimidin-5-yl) acrylate is as follows:
a25 mL three-necked flask was taken and the important intermediate 4(200mg, 0.44mmol) and 5-pyrimidineboronic acid (81.9mg, 0.66mmol) were weighed out separately and dissolved in a mixed solution of dioxane (5mL) and water (1 mL). Subsequently, sodium acetate (86.4mg, 0.88mmol) was weighed into the reaction solution, and the reaction was stirred at room temperature after replacing nitrogen gas for 3 times. Then, Pd (PPh3) Cl2(30.9mg, 0.04mmol) was added to the reaction solution, and the reaction was again replaced with nitrogen gas for 3 times and then stirred at 80 ℃ overnight. After completion of the reaction was monitored by TLC, the reaction was allowed to cool to room temperature, and purified water (50mL) was added to the reaction solution. Extraction with ethyl acetate (15 mL. times.3) and combining the organic phases and washing with saturated sodium chloride solution (20 mL. times.1), drying over anhydrous Na2SO4, filtration and evaporation of the solvent in vacuo afforded the crude compound. Purification by column chromatography (PE/EtOAc ═ 8: 1) gave ethyl (E) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) -2- (pyrimidin-5-yl) acrylate 5a (125.3mg, yield 62.3%, purity 93%) as a white solid.
Specifically, the synthesis method of (E) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) -2- (pyrimidine-5-yl) acrylamide (6a) comprises the following steps:
in a 25mL eggplant-shaped bottle, 5a (125.3mg, 0.27mmol) was dissolved in tetrahydrofuran (3 mL). After stirring for 10min while cooling on ice, a solution of LiOH. H2O (45.3mg, 1.08mmol) in water (1mL) was added dropwise to the reaction mixture. After stirring was continued for 30min, the reaction was allowed to warm to room temperature and stirred overnight. After completion of the reaction was monitored by TLC, a mixed solution of ice and water (10mL) was poured into the reaction solution, and the pH of the solution was adjusted to 2-3 with 4N hydrochloric acid. Extraction was carried out with ethyl acetate (5 mL. times.3), the organic phases were combined and washed with saturated sodium chloride solution (20 mL. times.1), dried over anhydrous Na2SO4, filtered and the solvent was distilled off under reduced pressure. The relatively pure compound (E) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) -2- (pyrimidin-5-yl) acrylic acid (99.4mg, yield 85.8%, purity 89%) was obtained as a white solid. Directly used in the next step.
In a 25mL round bottom flask, the compound (E) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) -2- (pyrimidin-5-yl) acrylic acid (99.4mg, 0.23mmol) obtained in the previous step was dissolved in tetrahydrofuran (3 mL). After stirring for 10min under ice bath, isobutyl chloroformate (50.3mg, 0.37mmol) and N-methylmorpholine (35.4mg, 0.35mmol) were added to the reaction mixture, respectively. After the reaction was stirred at room temperature for 1h, and after TLC monitoring substrate reaction was complete, the reaction mixture was filtered and ammonia gas was purged through the filtrate at 0 ℃ for 1 h. After completion of the reaction monitored by TLC, the reaction solution was poured into a mixed solution of ice and water (10 mL). Extraction was carried out with ethyl acetate (5 mL. times.3), the organic phases were combined and washed with saturated sodium chloride solution (20 mL. times.1), dried over anhydrous Na2SO4, filtered and the solvent was distilled off under reduced pressure. Purification by column chromatography (PE/EtOAc ═ 2: 1) separation afforded the final product (E) -3- (3- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 4-triazol-1-yl) -2- (pyrimidin-5-yl) acrylamide (73.0mg, 74.2% yield, 98% purity) as a white solid.
As shown in fig. 2, the present example is a series 2 of compounds for the route design and synthesis. The synthesis method of the specific series 2 compound comprises the following steps: the compound 7 is coupled with (Z) -3-iodoethyl acrylate under the catalysis of triethylene diamine to generate a compound 8, and the yield is 54%. Compound 8 was subjected to Suzuki coupling with 1-iodo-3, 5-bis (trifluoromethyl) benzene in the presence of palladium bis (triphenylphosphine) dichloride under the basic condition of potassium acetate to give compound 9 in 49% yield. Then, the double bond site of the compound 9 was added with liquid bromine first, and then one molecule of bromine was eliminated under the action of triethylamine to obtain a compound 10 with a yield of 55%. The ester bond of the compound 10 is hydrolyzed into carboxylic acid under the action of lithium hydroxide, and the carboxylic acid further generates a key intermediate 11 under the catalysis of isobutyl chloroformate and N-methylmorpholine under the atmosphere of ammonia gas, and the yield is 59%. Finally, the intermediate 11 is respectively subjected to Suzuki coupling with a plurality of nitrogen-containing aromatic groups with boric acid structures under the catalytic action of bis (triphenylphosphine) palladium dichloride to obtain the target compounds 12a-12d with the yield of 21% -40%.
Specifically, the synthesis method of the compound 9 of ethyl (Z) -3- (4- (3, 5-bis (trifluoromethyl) phenyl) -1H-pyrazol-1-yl) acrylate comprises the following steps:
to a 250mL eggplant-shaped bottle was added pyrazole-4-boronic acid pinacol ester 7(10g, 51.8mmol), dissolved in DMF (40mL), and DABCO (14.5g, 129.5mmol) was added thereto. After the mixture was further stirred at room temperature for 30min, ethyl (Z) -3-iodoacrylate (12.9g, 57.0mmol) was added dropwise to the reaction solution. The reaction was then stirred at room temperature for a further 3 h. After completion of the reaction monitored by TLC, the reaction solution was poured into a mixed solution of ice and water (400 mL). Extraction with ethyl acetate (80 mL. times.3) and combined organic phases and washed with saturated sodium chloride solution (100 mL. times.1), dried over anhydrous Na2SO4, filtered and the solvent evaporated under reduced pressure to give the crude compound. The resulting crude product was purified by column chromatography (PE/EtOAc ═ 50: 1) to give the compound (Z) -ethyl 3- (4-boronic acid pinacol ester-1H-pyrazol-1-yl) acrylate 8(8.1g, yield 53.5%, purity 94%) as a white solid.
Synthesis of Compound 9 and workup with Compound 5a, Compound (Z) -ethyl 3- (4- (3, 5-bis (trifluoromethyl) phenyl) -1H-pyrazol-1-yl) acrylate 9(5.1g, yield 48.6%, purity 93%) was synthesized from intermediate 8(8.1g, 27.7mmol) and 1-iodo-3, 5-bis (trifluoromethyl) benzene (11.3g, 33.3mmol) as a white solid.
Specifically, the synthesis method of compound 10 of ethyl (Z) -3- (4- (3, 5-bis (trifluoromethyl) phenyl) -1H-pyrazol-1-yl) -2-bromoacrylate is as follows:
synthesis of Compound 10 and workup with Compound 4, intermediate 9(5.1g, 13.5mmol) was reacted with liquid bromine (4.3g, 26.9mmol) to give ethyl 3- (4- (3, 5-bis (trifluoromethyl) phenyl) -1H-pyrazol-1-yl) -2, 3-dibromoacrylate (5.3g, yield 74.2%, purity 90%) as a white solid. Intermediate ethyl 3- (4- (3, 5-bis (trifluoromethyl) phenyl) -1H-pyrazol-1-yl) -2, 3-dibromoacrylate (5.3g, 9.9mmol) was debrominated with triethylamine (2.0g, 19.9mmol) to yield ethyl (Z) -3- (4- (3, 5-bis (trifluoromethyl) phenyl) -1H-pyrazol-1-yl) -2-bromoacrylate 10(3.4g, yield 74.4%, purity 94%) as a white solid.
Specifically, the synthesis method of (Z) -3- (4- (3, 5-bis (trifluoromethyl) phenyl) -1H-pyrazol-1-yl) -2-bromoacrylamide (11) comprises the following steps:
synthesis of Compound 11 and workup Compound 6a, Compound 10 was subjected to ester hydrolysis in LiOH. H2O solution to give intermediate (Z) -3- (4- (3, 5-bis (trifluoromethyl) phenyl) -1H-pyrazol-1-yl) -2-bromoacrylic acid (2.5g, yield 80.1%, purity 92%) as a white solid.
Intermediate (Z) -3- (4- (3, 5-bis (trifluoromethyl) phenyl) -1H-pyrazol-1-yl) -2-bromoacrylic acid was treated successively with isobutyl chloroformate and N-methylmorpholine under an ammonia atmosphere to give compound (Z) -3- (4- (3, 5-bis (trifluoromethyl) phenyl) -1H-pyrazol-1-yl) -2-bromoacrylamide 11(1.9g, yield 74.1%, purity 97%) as a white solid.
Specifically, the synthesis method of the (Z) -3- (1- (3, 5-bis (trifluoromethyl) phenyl) -1H-pyrazol-4-yl) ethyl acrylate (15) comprises the following steps:
a150 mL pressure resistant tube was taken, CuI (14.2g, 7.5mmol), DMF (30mL), 1-iodo-3, 5-bis (trifluoromethyl) benzene (6.1g, 17.9mmol) were added thereto in this order, and after stirring at room temperature for 10min, intermediate 14(2.5g, 14.9mmol) and CsCO3(9.7g, 29.8mmol) were added to the reaction solution, and the reaction solution was transferred to a 120 ℃ oil pan and reacted for 24 h. After the reaction was monitored by TLC to completion, the reaction mixture was cooled to room temperature and poured into a mixed ice-water solution (300 mL). Extraction with ethyl acetate (60 mL. times.3) and the combined organic phases were washed with saturated sodium chloride solution (80 mL. times.1), dried over anhydrous Na2SO4, filtered and the solvent was evaporated under reduced pressure. The resulting crude product was isolated and purified by column chromatography (PE/EtOAc ═ 20: 1) to give the compound ethyl (Z) -3- (1- (3, 5-bis (trifluoromethyl) phenyl) -1H-pyrazol-4-yl) acrylate 15(3.4g, yield 60.3%, purity 95%) as a white solid.
Specifically, the synthesis method of (Z) -3- (1- (3, 5-bis (trifluoromethyl) phenyl) -1H-pyrazol-4-yl) -2-ethyl bromoacrylate (17) comprises the following steps:
synthesis of Compound 17 and workup with Compound 4, intermediate 15(3.4g, 9.0mmol) was reacted with liquid bromine (2.9g, 18.0mmol) to give ethyl 3- (1- (3, 5-bis (trifluoromethyl) phenyl) -1H-pyrazol-4-yl) -2, 3-dibromopropionate 16(4.7g, yield 98.3%, purity 98%) as a white solid. Compound 16(4.7g, 8.8mmol) is debrominated under the action of triethylamine (1.8g, 17.7mmol) to form two isomers with different structures. The compound ethyl (Z) -3- (1- (3, 5-bis (trifluoromethyl) phenyl) -1H-pyrazol-4-yl) -2-bromoacrylate 17(2.7g, yield 67.1%, purity 95%) as a white solid.
The specific compounds synthesized and their names are given in the table below.
A composition prepared according to this example, comprising a compound of this example, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the composition of this example is such that it is effective to moderately inhibit CRM1 in a biological sample or patient. This example, a composition formulated for administration to a patient in need of such composition.
In this embodiment, "patient" means an animal, which may be a veterinary patient (non-human mammal patient), or a human.
Pharmaceutically acceptable carriers in this embodiment refer to pharmaceutically acceptable materials, ingredients or vehicles, such as liquid or solid fillers, diluents, excipients, solvents or encapsulating materials. All carriers must be "acceptable", i.e., compatible with the other formulation ingredients of the formulation and not deleterious to the patient. Some examples of pharmaceutically acceptable carriers that can be used include: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch, potato starch, and substituted or unsubstituted beta-cyclodextrins; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc powder; (8) excipients, such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) a phosphate buffer solution; (21) other non-toxic compatible substances used in pharmaceutical formulations. The pharmaceutical composition of this example is non-pyrogenic, i.e., does not cause a significant increase in body temperature after administration to a patient.
By "pharmaceutically acceptable salts" in this example is meant the relatively non-toxic inorganic and organic acid addition salts of the inhibitors. These salts can be prepared in situ during the final isolation and purification of the inhibitor, or the purified inhibitor in the form of the free base can be reacted separately with a suitable organic or inorganic acid and the salt thus formed isolated. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, laurylsulfonate, and amino acid salts and the like.
The compositions of this embodiment can be administered orally, parenterally (including tap, intramuscular, intravenous, and intradermal), by inhalation mist, topically, rectally, transluminally, buccally, vaginally, or via an implanted reservoir.
The formulations for oral administration of this embodiment may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as liquid emulsions in oil-in-water or water-in-oil, or as elixirs or syrups, or as pastilles (using an inert base such as gelatin and glycerin, or sucrose and acacia) and/or as mouthwashes and the like, all containing a predetermined amount of the inhibitor as the active ingredient. The composition may also be administered in the form of a bolus, granule or paste. The active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate and/or any of the following: (1) fillers or extenders, such as starches, cyclodextrins, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato starch, tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retarders, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as acetol and glycerol monostearate; (8) adsorbents such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; (10) a colorant. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
Oral liquid dosage forms of this embodiment include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (especially cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, and mixtures thereof. The oral composition of this embodiment may also include adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, coloring agents, flavoring agents and preserving agents.
Formulations for rectal or vaginal administration in accordance with the present embodiments may be presented as a suppository, which may be prepared by mixing one or more inhibitors with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or salicylate, and which is solid at room temperature and liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent. Formulations suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
Regardless of the route of administration chosen, the inhibitors of the invention (which may be used in their appropriate hydrated forms) and/or the pharmaceutical compositions of the invention may be formulated into pharmaceutically acceptable dosage forms by conventional methods known in the art.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Various antibacterial and antifungal agents can be added to prevent the action of microorganisms, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Tonicity adjusting agents such as sugars, sodium chloride, and the like may also be required in the composition. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the addition of agents delaying absorption, for example, aluminum monostearate and gelatin.
In order to prolong the effect of the drug, this embodiment requires slowing the rate of absorption of the drug by subcutaneous or intramuscular injection. For example, absorption of a parenterally administered drug is delayed by dissolving or suspending the drug in an oil vehicle. This example allows for variations in the actual dosage level of the active ingredient of the pharmaceutical composition of the invention to achieve an effective amount of the active ingredient to achieve the desired therapeutic response without poisoning the patient for the particular patient, composition, and mode of administration.
The concentration of the compound of this embodiment in a pharmaceutically acceptable mixture will vary depending on a number of factors, including the dose of the compound administered, the pharmacokinetic characteristics of the compound used, and the route of administration. In another aspect of this embodiment, combination therapy is provided wherein one or more additional therapeutic agents are administered with the proteasome inhibitor of the present invention. Such combination therapy may be achieved by the simultaneous, sequential or separate administration of the treatment components.
Example two
Another embodiment of the invention is a method for treating a plurality of diseases, disorders or conditions associated with CRM1 activity in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt or composition thereof.
The cell line inhibitory activity assay was as follows:
1. cell cryopreservation
(1) After harvesting the cells, the cells were centrifuged at 1000 rpm for 5min and rinsed with PBS.
(2) 1640 medium containing 7% DMSO and 10% fetal bovine serum was resuspended.
(3) And (3) respectively loading into a freezing tube, placing into a cell freezing box, carrying out overnight treatment at-80 ℃, and then preserving by liquid nitrogen.
2. Cell recovery and culture:
(1) the frozen tube was taken out from the liquid nitrogen tank and put into warm water at 37 ℃ to shake gently to thaw the cell sap quickly.
(2) Transferring into a sterile centrifuge tube, adding 1640 culture solution containing 10% fetal calf serum, and gently blowing and beating into suspension.
(3) Centrifuging at 1000 r/v for 5min, discarding the supernatant, adding 10% culture medium 1640 containing fetal calf serum, and gently blowing to obtain suspension.
(4) Transferring into a culture bottle, and culturing in an incubator containing 5% CO2 at 37 deg.C and saturated humidity for 1-2 days.
3. Cell passage:
discarding the original culture medium, adding sterile PBS to wash once, adding 1mL of 0.25% pancreatin to incubate for about 1 minute, observing under a mirror, carefully sucking the pancreatin after most cells begin to become round, adding a fresh culture medium to stop digestion, blowing and beating the cells into a uniform cell suspension, and transferring the cell suspension into a cell incubator to continue culture.
4. Cytotoxicity test
(1) RPMI8226 cells in logarithmic growth phase were added to 384 well plates at 1000/well in a volume of 18. mu.L/well and incubated at 37 ℃ under 5% CO2 for 24 h.
(2) Test compounds at stock concentration of 10mM were diluted 10-fold with DMSO and 100-fold with 1640 medium without serum to give 10 μ M working concentration with 1% DMSO, followed by 2-fold gradient dilution with 10-fold dilution with 1% DMSO serum-free 1640 medium, and the tenth concentration point was the solvent control (no drug). Pipette 2 μ L of diluted compound per well into plated cell plates to give a final concentration of compound of 1000nM, 2-fold gradient dilution, 10 concentration gradients, 4 replicates per concentration. 1% DMSO was used as a solvent control and KPT-8602 as a positive control.
(3) After incubation at 37 ℃ for 72h, 10. mu.L of Cell-Titer detection reagent was added to each well, followed by incubation in a Cell incubator for 10 min.
(4) After shaking and mixing, Cell-Titer program detection was performed on a microplate reader, and inhibition% and IC50 value (nM) were calculated using GraphPad Prism 5.
The results for some of the compounds are given in the following table:
| numbering | RPMI8226 | Numbering | RPMI8226 |
| 6 | 128.1 | 21 | 1411 |
| 7 | 76.5 | 22 | 1336 |
| 8 | 1657 | 23 | NA |
| 9 | 1473 | 24 | |
| 10 | NA | 25 | 3259 |
| 11 | 259.0 | 26 | 2255 |
| 12 | 645.7 | 27 | NA |
| 13 | 1313 | 28 | NA |
| 14 | 1207 | 29 | NA |
| 15 | 1433 | 30 | NA |
| 16 | 880.5 | 31 | NA |
| 17 | 1922 | 32 | NA |
| 18 | NA | 33 | NA |
| 19 | 2751 | 34 | NA |
| 20 | 1472 | 35 | NA |
NA: has no activity
In light of the foregoing description of the preferred embodiment of the present invention, it is to be understood that various changes and modifications may be made by one skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.
Claims (10)
1. An azole derivative or a pharmaceutically acceptable salt thereof, wherein the azole derivative has a structure of formula I:
wherein:
x, Y, Z is selected from-C (H) -or-N-;
r2 is selected from optionally substituted heteroaryl and optionally substituted aryl;
r1 is selected from hydrogen, deuterium, C1-10 alkyl, C3-6 cycloalkyl, heterocycloalkyl, heterocyclyl, aryl or benzyl, wherein the C1-10 alkyl, C3-6 cycloalkyl, heterocycloalkyl, heterocyclyl, aryl or benzyl is optionally substituted or unsubstituted by C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, cyano, nitro, hydroxy, mercapto, amino or halogen.
2. The azole derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein the azole derivative is selected from table a:
TABLE A
3. The azole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, which is synthesized by the following scheme:
4. the process for producing an azole derivative or a pharmaceutically acceptable salt thereof according to claim 3, which comprises the steps of:
s1, enabling cyano of the compound 1 to obtain thiocarboxamide under the action of sodium hydrosulfide and magnesium chloride, and reacting under the conditions of hydrazine hydrate and formic acid to generate triazole 2;
s2, triazole 2 and (Z) -3-ethyl iodoacrylate are coupled under the catalytic action of triethylene diamine to generate a compound 3;
s3, performing addition reaction on the double bond part of the compound 3 and liquid bromine, and removing one molecule of bromine under the action of triethylamine to obtain a key intermediate 4;
s4, under the catalytic action of bis (triphenylphosphine) palladium dichloride, the intermediate 4 and a plurality of nitrogen-containing aryl groups with boric acid structures are subjected to Suzuki coupling respectively to generate compounds 5a-5i connected with different nitrogen-containing aryl groups;
the ester bonds of S5 and 5a-5i are hydrolyzed into carboxylic acid under the action of lithium hydroxide, and the carboxylic acid further generates a positive drug KPT-8602 and a target compound 6b-6i under the atmosphere of ammonia gas under the catalysis of isobutyl chloroformate and N-methylmorpholine.
5. A pharmaceutical composition based on any one of the azole derivatives or pharmaceutically acceptable salts thereof as claimed in claims 1 to 2, wherein both the azole derivative or pharmaceutically acceptable salt thereof and the pharmaceutical composition are capable of receiving a carrier.
6. The pharmaceutical composition of an azole derivative or a pharmaceutically acceptable salt thereof according to claim 5, wherein: the application of the pharmaceutical composition in preparing a drug for inhibiting CRM1 protein.
7. The pharmaceutical composition of an azole derivative or a pharmaceutically acceptable salt thereof according to claim 5, wherein: the use of said composition for the preparation of a medicament for the treatment of inflammation, cancer or a hyperproliferative disease.
8. The pharmaceutical composition of an azole derivative or a pharmaceutically acceptable salt thereof according to claim 5, wherein: the application of the composition in preparing a medicament for treating immune-related diseases.
9. The pharmaceutical composition of an azole derivative or a pharmaceutically acceptable salt thereof according to claim 5, wherein: the use of said composition for the preparation of a medicament for modifying various antigenic peptides produced by the proteasome in an organism.
10. The pharmaceutical composition of an azole derivative or a pharmaceutically acceptable salt thereof according to claim 5, wherein: the composition at least comprises an azole compound capable of inhibiting the function of CRM1 protein, and is used as a ZCCRM 1 protein inhibitor to block the proliferation of tumor cells and induce the apoptosis of the tumor cells.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113248474A (en) * | 2021-05-24 | 2021-08-13 | 王能能 | Five-membered azole heterocyclic derivative and preparation method and application thereof |
| WO2023036217A1 (en) * | 2021-09-08 | 2023-03-16 | 南京明德新药研发有限公司 | Acrylamide compound and use thereof |
| WO2023072248A1 (en) * | 2021-10-29 | 2023-05-04 | 正大天晴药业集团股份有限公司 | Pyridyl-containing compound |
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2020
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113248474A (en) * | 2021-05-24 | 2021-08-13 | 王能能 | Five-membered azole heterocyclic derivative and preparation method and application thereof |
| WO2023036217A1 (en) * | 2021-09-08 | 2023-03-16 | 南京明德新药研发有限公司 | Acrylamide compound and use thereof |
| WO2023072248A1 (en) * | 2021-10-29 | 2023-05-04 | 正大天晴药业集团股份有限公司 | Pyridyl-containing compound |
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