CN113288899A - Application of heterocyclic thiol compound in preparation of antitumor drugs - Google Patents
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
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- C07D251/22—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to two ring carbon atoms
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- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
- C07D251/40—Nitrogen atoms
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Abstract
The heterocyclic thiol compound provided by the invention shows better activity against liver cancer cells, human breast cancer cells or human non-small cell lung cancer cells, lays a foundation for screening and developing new drugs, and has better practical value.
Description
(I) technical field
The invention relates to an application of heterocyclic thiol compounds in preparing antitumor drugs.
(II) background of the invention
Malignant tumor is one of common diseases seriously threatening human health and all diseases, so the development of novel anti-tumor drugs has important practical significance. Heterocycles are basic parent nuclei of medicines and natural products, and a large number of documents report that the compounds have good biological activity, so that the further research on the application of heterocyclic thiol compounds in the preparation of antitumor medicines has certain social significance.
Disclosure of the invention
In order to obtain an active component of a novel antitumor drug, the invention adopts the following technical scheme:
an application of heterocyclic thiol compounds shown as formula (I), (II) or (III) in preparing antineoplastic agent is disclosed:
in the formula (I), R1、R2Each independently is C1～C10Alkyl or R1And R2Are connected into a ring and are combined with N between the two to form C containing N or N, O4～C8A heterocycle; r3、R4Each independently is C1～C10Alkyl or R3And R4Are connected into a ring and are combined with N between the two to form C containing N or N, O4～C8A heterocycle; preferably R1、R2Each independently is methyl or R1And R2Are connected to form a ring and are combined with N between the two to form a piperidine ring, a pyrrolidine ring or a morpholine ring; r3、R4Each independently is methyl or R3And R4Are connected to form a ring and are combined with N between the two to form a piperidine ring, a pyrrolidine ring or a morpholine ring;
in the formula (II), R5Is C1～C10Alkyl or two R5Are connected into a ring and are combined with N between the two to form C containing N4～C8A heterocycle; preferably R5Is methyl or two R5Are connected to form a ring and are combined with N between the two to form a piperidine ring;
in the formula (III), R6Is C6～C8Aryl, preferably phenyl.
Further, the heterocyclic thiol compound is preferably one of the following compounds:
furthermore, the tumor cell is human liver cancer cell (HEPG2), human breast cancer cell (T47D) or human non-small cell lung cancer cell (A549).
Furthermore, when the tumor is human liver cancer cell (HEPG2), the compound (I-1) or (II-2) has better anti-tumor activity; when the tumor is a human breast cancer cell (T47D), the compound (II-1), (II-2) or (III-1) has better anti-tumor activity; when the tumor is human non-small cell lung cancer cell (A549), the compound (I-6), (II-1) or (III-1) has better anti-tumor activity.
The invention relates to a preparation method of heterocyclic thiol compounds shown in formula (I), which mainly comprises the steps of preparing 2-chloro-1, 3, 5-triazine intermediates shown in formula (IV) under the condition of room temperature by using cyanuric chloride and secondary amine (dimethylamine, piperidine, tetrahydropyrrole or morpholine) under the action of triethylamine, then reacting the intermediates with thiourea at 110 ℃, and treating the intermediates with sodium hydroxide to obtain the heterocyclic thiol compounds shown in formula (I). Wherein the ratio of the amounts of substances of cyanuric chloride to secondary amine is 1: 1-2: 1; the mass ratio of the 2-chloro-1, 3, 5-triazine intermediate shown in the formula (IV) to the thiourea to the sodium hydroxide is 1: 2: 1.
r in the formula (IV)1、R2、R3、R4Are respectively connected with R in the formula (I)1、R2、R3、R4The same is true.
The invention relates to a preparation method of heterocyclic mercaptan compound shown in formula (II), which is mainly characterized in that dicyandiamide sodium and amine react at 90 ℃ in the presence of hydrochloric acid to obtain cyanoguanidine shown in formula (V); then reacting with sodium thiosulfate at room temperature under the action of hydrochloric acid to obtain amidinothiourea shown in formula (VI); finally, condensing with methyl formate under the action of sodium methoxide to obtain the heterocyclic thiol compound shown in the formula (II). Wherein the mass ratio of the amine to the substances of dicyandiamide sodium and hydrochloric acid is 1: 1: 1; the mass ratio of aniline, hydrochloric acid and sodium thiosulfate is 1: 1.8: 0.9; the mass ratio of guanylthiourea, sodium and ethyl formate is 1: 3: 4
R in the formulae (V), (VI)5And R in the formula (II)5The same is true.
The invention relates to a preparation method of heterocyclic thiol compound shown in formula (III), which is mainly characterized in that arylformyl isothiocyanate shown in formula (VII) and arylformamidine shown in formula (VIII) react at room temperature under the action of sodium hydroxide to prepare the heterocyclic thiol compound shown in formula (III). Wherein, the mass ratio of the arylformyl isothiocyanate to the arylformamidine and the sodium hydroxide is 1: 1: 4;
r in the formulae (VII), (VIII)6And R in the formula (III)6The same is true.
Compared with the prior art, the invention has the beneficial effects that: the heterocyclic thiol compound provided by the invention shows better activity against liver cancer cells, human breast cancer cells (T47D) or human non-small cell lung cancer cells, lays a foundation for screening and developing new drugs, and has better practical value.
Detailed Description
The invention will now be further illustrated by the following examples, without limiting the scope of the invention thereto.
Example 1: preparation of Compound (I-1)
Cyanuric chloride (5.00g,27.11mmol) was added to acetone (50mL), morpholine (4.7mL,53.94mmol) and triethylamine (11.2mL,80.54mmol) were added under ice-bath conditions, the reaction was carried out at room temperature for 2h, after completion of the reaction, an appropriate amount of ice water was added, the mixture was filtered, and the compound (IV-1) (6.90g) was obtained by drying.
The above-mentioned compound (IV-1) (6.90g, the amount of theoretical substance: 24.18mmol) and thiourea (3.78g,49.65mmol) were added to dioxane (50mL) and reacted at 110 ℃ for 13 hours, the reaction solution was cooled to room temperature, filtered, the cake was dissolved in ethyl acetate (60mL), and sodium hydroxide (1.0g,25mmol) was further added to react at room temperature for 3 hours. Filtering after the reaction is finished, washing a filter cake by ethyl acetate, and recrystallizing by methanol to obtain a compound (I-1) ((I-1))3.51g,yield:51％)。1H NMR(500MHz,DMSO-d6)δ11.42(m,1H),3.81-3.65(m,8H),3.62-3.59(m,8H)。
Example 2: preparation of Compound (I-2)
The operation was carried out in the same manner as in example 1 except that morpholine was changed to piperidine (1.8mL,18.18mmol), the amount of cyanuric chloride was changed to (1.78g,9.65mmol), the amount of triethylamine was changed to (4.7mL,33.81mmol), the compound (IV-1) was changed to the compound (IV-2) (1.73g,6.14mmol), and the amount of thiourea was changed to (1.03g,13.53mmol), whereby the compound (I-2) (0.57g, yield: 33%) was obtained.1H NMR(500MHz,DMSO-d6)δ11.42(m,1H),3.81-3.65(m,8H),3.62-3.59(m,8H)。
Example 3: preparation of Compound (I-3)
The operation was carried out in the same manner as in example 1 except that morpholine was changed to an aqueous dimethylamine solution (10mL,60.20mmol), the amount of cyanuric chloride was changed to (5.56g,30.15mmol), the amount of triethylamine was changed to (13mL,93.92mmol), the compound (IV-1) was changed to the compound (IV-3) (5.21g,25.91mmol), the amount of thiourea was changed to (3.95g,51.86mmol), and the compound (I-3) (3.62g, yield: 70%)
Example 4: preparation of Compound (I-4)
The same operation as in example 1 was conducted except that the amount of morpholine was changed to (1.4mL,16.26mmol), the amount of cyanuric chloride was changed to (2.98g,16.26mmol), and the amount of triethylamine was changed to (7.0mL,50.26mmol), thereby obtaining compound (VII-1) (2.36 g); the same operation as in example 1 was repeated, except that morpholine was changed to tetrahydropyrrole (0.8mL,10.00mmol), cyanuric chloride was changed to compound (VII-1) (2.36g,10mmol), the amount of triethylamine was changed to compound (IV-1) (30.00 mmol), compound (IV-1) was changed to compound (IV-1)-4) (1.01g,3.74mmol) and the amount of thiourea was changed to (0.58g,7.62mmol) to obtain compound (I-4) (0.39g, yield: 39%);1H NMR(500MHz,DMSO-d6)δ11.27(s,1H),3.79-3.67(m,4H),3.63-3.58(m,4H),3.51-3.44(m,4H)。
example 5: preparation of Compound (I-5)
The same operation as in example 4 was carried out except that morpholine was changed to piperidine (3.0mL,30.30mmol), the amount of cyanuric chloride was changed to (6.00g,32.54mmol), and the amount of triethylamine was changed to (15.0mL,107.92mmol), to give compound (VII-2) (3.38 g); the same operation as in example 1 was carried out except that the amount of morpholine was changed to (1.3mL,14.92mmol), the amount of cyanuric chloride was changed to compound (VII-2) (3.38g,14.50mmol), the amount of triethylamine was changed to (6.1mL,43.86mmol), the amount of compound (IV-4) was changed to compound (IV-5) (3.20g,11.28mmol), the amount of thiourea was changed to (1.77g,23.25mmol), giving compound (I-5) (1.49g, yield: 47%);1H NMR(500MHz,DMSO-d6)δ11.14(s,1H),3.84–3.60(m,4H),3.52–3.40(m,4H),1.96–1.76(m,4H),1.65–1.56(m,2H),1.52–1.42(m,4H)。
example 6: preparation of Compound (I-6)
The operation was carried out in the same manner as in example 5 except that the amount of the compound (VII-2) was changed to (2.81g,12.05mmol), that of morpholine was changed to tetrahydropyrrole (1.0mL,12.05mmol), that of triethylamine was changed to (5.4mL,38.85mmol), that of the compound (IV-5) was changed to the compound (IV-6) (1.99g,7.40mmol), and that of thiourea was changed to (1.13g,14.80mmol), whereby the compound (I-6) (1.43g, yield: 73%);1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),3.76–3.66(m,4H),3.51–3.42(m,4H),1.95–1.79(m,4H),1.65–1.58(m,2H),1.53–1.44(m,4H)
example 7: preparation of Compound (II-1)
Dimethylamine hydrochloride (10.00g,122.64mmol) was added to water (60mL), sodium dicyandiamide (12.00g,134.90mmol) was added, and the mixture was heated to 90 ℃ for reaction for 34 h. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with water and dried to obtain compound (V-1).
The compound (V-1) was added to acetone (75mL), concentrated hydrochloric acid (12 mL,144mmol) and sodium thiosulfate pentahydrate (16.00g,82.35mmol) were added, the mixture was reacted at room temperature for 2 hours, after completion of the reaction, aqueous ammonia was added to adjust PH to 9, the mixture was concentrated, and the mixture was subjected to column chromatography (eluent was dichloromethane: methanol 40:1 by volume) to give compound (VI-1) (7.65 g).
After sodium (1.06g,43.48mmol) was added to methanol (25mL), and the compound (VI-1) (2.52g,17.24mmol) was added after sodium was completely dissolved, the reaction mixture was reacted at room temperature for 3 hours, ethyl formate (4.5mL,75.69mmol) was added, the reaction mixture was reacted at room temperature for 21 hours, and after completion of the reaction, the reaction solution was concentrated, water was added, extraction was performed with dichloromethane for 3 times, organic layers were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and separation was performed by column chromatography (eluent dichloromethane: methanol: 40:1, volume ratio) to obtain compound (II-1) (1.41g, 53%).1H NMR(500MHz,DMSO-d6)δ12.90(s,1H),8.07(s,1H),3.16(s,3H),3.13(s,3H)。
Example 8: preparation of Compound (II-2)
The same procedure as in example 8 was repeated, except that dimethylamine hydrochloride was changed to piperidine (10.00g,117.43mmol) and dilute hydrochloric acid (117.43mL,117.43mmol), and the amount of sodium dicyandiamide was changed to (10.5g,117.94mmol), to give compound (V-2).
The amount of concentrated hydrochloric acid was changed to (5mL,60mmol) and the amount of sodium thiosulfate pentahydrate was changed to (5.50g,28.31mmol), giving compound (VI-2) (3.75g)
The amount of sodium was changed to (0.50g,21.73mmol), the amount of compound (VI-1) was changed to compound (VI-2) (1.50g,8.05mmol), and the amount of methyl formate was changed to (2.0mL,32.20mmol), giving compound (II-2) (1.38g, 87%)。1H NMR(500MHz,DMSO-d6)δ12.85(s,1H),8.06(s,1H),3.80–3.76(m,4H),1.66–1.61(m,2H),1.56–1.51(m,4H)
Example 9: preparation of Compound (III-1)
To a solution of benzamidine hydrochloride (0.48g,3.06mmol) in toluene (4mL) and water (8mL) was added a solution of sodium hydroxide (0.49g,12.25mmol) in water (3mL), followed by addition of benzoyl isothiocyanate (0.4mL,3.06mmol) and reaction at room temperature for 30 minutes, the reaction solution PH was adjusted to 6 using hydrochloric acid, water was added, extraction was performed 3 times with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (eluent: dichloromethane: methanol: 40:1, volume ratio) to obtain compound (III-1) (0.41g, 51%).1HNMR(500MHz,DMSO-d6)δ14.40(s,1H),8.45–8.41(m,4H),7.75–7.71(m,2H),7.65–7.60(m,4H)
Example 10: biological activity test of anti-human liver cancer cell (HEPG2), human breast cancer cell (T47D) or human non-small cell lung cancer cell (A549)
In vitro anti-human liver cancer cell (HEPG2), human breast cancer cell (T47D) or human non-small cell lung cancer cell (A549) activity test method: MTT method
The experimental steps are as follows:
1) preparation of samples: for soluble samples, each 1mg was dissolved in 20. mu.L DMSO, 2. mu.L was diluted with 1000. mu.L of culture medium to a concentration of 100. mu.g/mL, and then the culture medium was serially diluted to the use concentration.
2) Culture of cells
2.1) preparation of culture medium, wherein each 1000mL of culture medium contains 80 ten thousand units of penicillin, 1.0g of streptomycin and 10% of inactivated fetal calf serum.
2.2) culture of cells: inoculating tumor cells into culture medium, standing at 37 deg.C and 5% CO2Culturing in an incubator, and carrying out passage for 3-5 days.
3) Determination of the inhibition of tumor cell growth by samples
The cells were digested with EDTA-pancreatin digest and diluted to 1X 10 with medium5Perml, 100 uL/well in 96-well cell culture plates, 37 ℃ 5% CO2Culturing in an incubator. After 24h of inoculation, samples diluted with medium were added, 100. mu.L per well, 3 wells per concentration, and placed at 37 ℃ in 5% CO2The culture was performed in an incubator, 5mg/mL MTT was added to the cell culture wells after 72h, 10. mu.L per well, incubated at 37 ℃ for 4h, DMSO was added, 150. mu.L per well, shaken with a shaker, and formazan was completely solubilized and colorimetric at a wavelength of 570nm using a microplate reader. The tumor cell inhibition rate of the samples was calculated by using cells cultured in the medium containing no sample and the same concentration of DMSO as a control under the same conditions, and the results are shown in Table 1.
The inhibition effect of 9 samples of the compounds (I-1) - (I-6), (II-1) - (II-2) and (III-1) on the growth of liver cancer cells, human breast cancer cells or non-small cell lung cancer cells in vitro was determined by taking human liver cancer cells (HEPG2), human breast cancer cells (T47D) or human non-small cell lung cancer cells (A549) as models (the results are detailed in Table 1).
TABLE 1.60. mu. mol/L inhibition ratio (%) (for human hepatoma cells (HEPG2), human breast cancer cells (T47D) or human non-small cell lung cancer cells (A549) of each compound
| Compound (I) | HEPG2 | T47D | A549 |
| (I-1) | 71.17 | 29.01 | <10 |
| (I-2) | <10 | 24.61 | 31.73 |
| (I-3) | <10 | 69.80 | 19.06 |
| (I-4) | 11.93 | 34.60 | 65.06 |
| (I-5) | <10 | 19.35 | 36.85 |
| (I-6) | 24.36 | 20.26 | 21.57 |
| (II-1) | 11.30 | 30.45 | 50.24 |
| (II-2) | 60.66 | 79.73 | 25.77 |
| (III-1) | <10 | 60.73 | 85.68 |
Claims (10)
1. An application of heterocyclic thiol compounds shown as formula (I), (II) or (III) in preparing antineoplastic agent is disclosed:
in the formula (I), R1、R2Each independently is C1～C10Alkyl or R1And R2Are connected into a ring and are combined with N between the two to form C containing N or N, O4～C8A heterocycle; r3、R4Each independently is C1～C10Alkyl or R3And R4Are connected into a ring and are combined with N between the two to form C containing N or N, O4～C8A heterocycle;
in the formula (II), R5Is C1～C10Alkyl or two R5Are connected into a ring and are combined with N between the two to form C containing N4～C8A heterocycle;
in the formula (III), R6Is C6～C8And (4) an aryl group.
2. The use of a heterocyclic thiol compound of formula (I) according to claim 1 in the preparation of an anti-tumor medicament, wherein:
R1、R2each independently is methyl or R1And R2Are connected to form a ring and are combined with N between the two to form a piperidine ring, a pyrrolidine ring or a morpholine ring; r3、R4Each of which isIndependently is methyl or R3And R4Linked to form a ring and combined with the N between the two to form a piperidine ring, a tetrahydropyrrole or a morpholine ring.
3. The use of a heterocyclic thiol compound of formula (II) according to claim 1 in the preparation of an anti-tumor medicament, wherein: r5Is methyl or two R5Are connected to form a ring and are combined with N between the two to form a piperidine ring;
4. the use of a heterocyclic thiol compound of formula (III) according to claim 1 in the preparation of an anti-tumor medicament, wherein: r6Is phenyl.
5. The use of a heterocyclic thiol compound of formula (I), (II) or (III) as defined in claim 1 in the preparation of an anti-tumor medicament, wherein:
the heterocyclic thiol compound is one of the following compounds:
6. the use of a heterocyclic thiol compound of formula (I), (II) or (III) as defined in claim 1 in the preparation of an anti-tumor medicament, wherein: the tumor cell is human liver cancer cell, human breast cancer cell or human non-small cell lung cancer cell.
7. The use of a heterocyclic thiol compound of formula (I), (II) or (III) as defined in claim 1 in the preparation of an anti-tumor medicament, wherein: the tumor is HEPG2 cell, T47D cell or A549 cell.
8. The use of a heterocyclic thiol compound of formula (I), (II) or (III) as defined in claim 7 in the preparation of an anti-tumor medicament, wherein: the tumor is HEPG2 cells, and the heterocyclic thiol compound is (I-1) or (II-2).
9. The use of a heterocyclic thiol compound of formula (I), (II) or (III) as defined in claim 7 in the preparation of an anti-tumor medicament, wherein: the tumor is T47D cells, and the heterocyclic thiol compound is (II-1), (II-2) or (III-1).
10. The use of a heterocyclic thiol compound of formula (I), (II) or (III) as defined in claim 7 in the preparation of an anti-tumor medicament, wherein: the tumor is A549 cells, and the heterocyclic thiol compound is (I-6), (II-1) or (III-1).
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