CN105130960A - 1,3,5-triazine derivatives and application - Google Patents
1,3,5-triazine derivatives and application Download PDFInfo
- Publication number
- CN105130960A CN105130960A CN201510468003.2A CN201510468003A CN105130960A CN 105130960 A CN105130960 A CN 105130960A CN 201510468003 A CN201510468003 A CN 201510468003A CN 105130960 A CN105130960 A CN 105130960A
- Authority
- CN
- China
- Prior art keywords
- imidazol
- difluoromethyl
- triazin
- benzo
- morpholinyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 125000001424 substituent group Chemical group 0.000 claims abstract description 9
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 38
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- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—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
- C07D403/04—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 directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to novel 1,3,5-triazine derivatives represented by the formula I, and pharmaceutically-acceptable salts, hydrates, solvate, and prodrug thereof; wherein the definitions of substituent R1 and substituent R2 are represented in the description. The invention also relates to a preparation method and an application of the derivatives represented by the formula (I) in antitumor drugs.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and relates to a 1,3, 5-triazine derivative and a preparation method thereof, and also relates to application of the derivative in preparation of a medicament for treating tumors.
Background
Cancer seriously threatens human life and health, is one of the leading death reasons of human beings, and has great treatment difficulty. Cancer incidence has been on the rise since the late 20 th century and patients have been on the down-age. According to the world health organization, there are about 500 million patients dying from cancer every year worldwide, and 2000 million new cancer cases are predicted to occur by 2020, wherein the number of deaths will reach 1200 million. Over the last century, the drug treatment of cancer has achieved remarkable results, dozens of antitumor drugs have been developed, the life of a patient is effectively prolonged or the life quality of the patient is improved, but most of the drugs are cytotoxic drugs, the selectivity is not high, and the drug resistance problem exists. Therefore, research and development of antitumor drugs still face huge challenges, and research of antitumor drugs is still one of the important tasks in the medical field. In order to improve the curative effect of tumor treatment and make new breakthrough progress, a pharmacist must further study the mechanism of tumor occurrence and development, so as to find a new target point of anti-tumor effect and design a new and more effective drug by taking the target point as a breakthrough. Recently, more and more studies have shown that the PI3K (phosphatidylinositol triphosphate kinase) pathway is one of the activated signaling pathways in cancer, and is associated with the occurrence and development of tumors and changes in the cell cycle of tumors, and the use of PI3K inhibitors to block this pathway would be a promising strategy for cancer treatment.
Through a large amount of screening, the 1,3, 5-triazine derivatives have good water solubility and excellent anti-tumor effect, and are potential anti-tumor drugs.
Disclosure of Invention
The invention aims to provide 1,3, 5-triazine derivatives and a preparation method thereof. The invention also provides the cell level and target level activity screening results of the compounds and anti-tumor application thereof.
The invention relates to a compound with a structure shown as a general formula I, a preparation method and application thereof, wherein the compound comprises pharmaceutically acceptable salts, and the general formula I is as follows:
wherein,
R1and R2The same or different, are respectively and independently selected from hydrogen and (C)1-C10) Alkyl, (C)3-C7) Cycloalkyl group, (C)2-C10) Alkenyl and (C)2-C10) Alkynyl, substituted (substituents are hydrogen, halogen, C)1-C4Alkyl) or unsubstituted (C)5-C8) Aryl, which may be substituted by 1 to 3 identical or different R3Optionally substituted;
or R1And R2Together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl or 5-10 membered heteroaryl group, said heterocyclyl and heteroaryl groups other than R1And R2Optionally containing 1-4 heteroatoms selected from N, O and S in addition to the attached nitrogen atom, except for R1And R2Said heterocyclyl optionally including 1 or 2 carbon-carbon double or triple bonds in addition to the nitrogen atom to which it is attached, said heterocyclyl and heteroaryl optionally being interrupted by 1 to 3 identical or different R4Substitution;
R3、R4is (C)1-C4) Alkyl, (C)1-C4) Alkoxy, halo, hydroxy, cyano, carboxy, (C)1-C10) An ester group;
the present invention preferably relates to compounds of the following structure and pharmaceutically acceptable salts thereof:
wherein,
R1and R2The same or different, are respectively and independently selected from hydrogen and (C)1-C4) Alkyl, (C)3-C7) Cycloalkyl group, (C)2-C4) Alkenyl and (C)2-C4) Alkynyl, substituted (substituents are hydrogen, halogen, C)1-C4Alkyl) or unsubstituted (C)5-C8) Aryl, which may be substituted by 1 to 3 identical or different R3Optionally substituted;
or R1And R2Together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl or 5-10 membered heteroaryl group, which heterocyclyl and heteroaryl groups may optionally be substituted by 1-3 identical or different R4Substitution;
except that R1And R2Said heterocyclyl and heteroaryl groups may optionally contain 1-4 heteroatoms selected from N, O and S in addition to the nitrogen atom to which they are attached;
R3、R4is (C)1-C4) Alkyl, (C)1-C4) Alkoxy, halo, hydroxy, cyano, carboxy, (C)1-C10) An ester group;
the present invention also preferably relates to compounds of the structure:
wherein,
R1and R2The same or different, are respectively and independently selected from hydrogen and (C)1-C4) Alkyl, substituted (substituents are hydrogen, halogen, C)1-C4Alkyl) or unsubstituted (C)5-C8) Aryl, which may be substituted by 1 to 3 identical or different R3Optionally substituted;
or R1And R2Together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl or 5-10 membered heteroaryl group, which heterocyclyl and heteroaryl groups may optionally be substituted by 1-3 identical or different R4Substitution;
except that R1And R2Said heterocyclyl and heteroaryl groups may optionally contain 1-4 heteroatoms selected from N, O and S in addition to the nitrogen atom to which they are attached;
R3、R4is (C)1-C4) Alkyl, (C)1-C4) Alkoxy, halo, hydroxy, cyano, carboxy, (C)1-C10) An ester group;
the present invention also preferably relates to compounds of the structure:
wherein,
R1and R2The same or different, are respectively and independently selected from hydrogen and (C)1-C4) Alkyl, hydroxy substituted (C)1-C4) Alkyl, halo-substituted phenyl;
or R1And R2Together with the nitrogen atom to which they are attached form morpholinyl, 4-piperidinonyl, 4-hydroxypiperidinyl, imidazolyl, piperidinyl, 4-methylpiperidinyl, 3-methylpiperidinyl, 2-methylpiperidinyl, 4-methyl-1-piperazinyl;
the present invention also preferably relates to compounds of the structure:
wherein,
R1and R2Each independently is methyl, ethyl, hydrogen, isopropyl, hydroxyethyl, 3-hydroxypropyl, 2, 3-dihydroxypropyl, 2-ethylamino, 4-chlorophenyl, 4-bromophenyl; or R1And R2Together with the nitrogen atom to which they are attached form a 4-hydroxypiperidinyl, imidazolyl, 4-piperidonyl group;
preferably, the first and second electrodes are formed of a metal,
when R is1And R2When the same, R1And R2Each independently is methyl or ethyl;
when R is1And R2Not simultaneously, R1R2Each independently is hydrogen, isopropyl, hydroxyethyl, 3-hydroxypropyl, 2, 3-dihydroxypropyl, 2-ethylamino, 4-chlorophenyl, 4-bromophenyl; preferably R1When it is hydrogen, R2Is isopropyl, hydroxyethyl, 3-hydroxypropyl, 2, 3-dihydroxypropyl, 2-ethylamino, 4-chlorophenyl, 4-bromophenyl or R2When it is hydrogen, R1Is isopropyl, hydroxyethyl, 3-hydroxypropyl, 2, 3-dihydroxypropyl, 2-ethylamino, 4-chlorophenyl, 4-bromophenyl.
The compounds of general formula i according to the invention and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs are preferably the following compounds, but these compounds are not meant to limit the invention in any way:
m-01: 1- {4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazin-2-yl } piperidin-4-one;
m-02: 1- {4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazin-2-yl } piperidin-4-ol;
m-03: 4- {4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6- (1H-imidazol-1-yl) -1,3, 5-triazin-2-yl } morpholine;
m-04: n, N-dimethyl-4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazin-2-amine;
m-05: n, N-diethyl-4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazin-2-amine;
m-06: n-isopropyl-4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazin-2-amine;
m-07: 2- ({4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazin-2-yl } amino) ethanol;
m-08: 2- ({4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazin-2-yl } amino) -1-propanol;
m-09: 2- ({4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazin-2-yl } amino) -1, 2-propanediol;
m-10: n' - {4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazin-2-yl } ethyl-1, 2-diamine;
m-11: n- (4-bromophenyl) -4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazin-2-amine;
m-12: n- (4-chlorophenyl) -4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazin-2-amine.
The 1,3, 5-triazine derivative provided by the invention, wherein the pharmaceutically acceptable salt refers to a salt formed by a compound and an acid, and comprises an inorganic acid and an organic acid; forming a salt with a base, wherein the base is an alkali metal hydroxide.
According to some common methods in the field of the present invention, the pharmaceutically acceptable addition salts of the 1,3, 5-triazine derivatives of formula I above of the present invention with acids include inorganic and organic acid addition salts, and the addition salts with the following acids are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are those of formula i which may themselves be less active or even inactive, but which, upon administration, are converted to the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis, or otherwise).
In the present invention, "halogen" means fluorine, chlorine, bromine or iodo; "alkyl" refers to straight or branched chain alkyl; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl; "heteroaryl" means a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, which ring system is aromatic, such as imidazolyl, pyridyl, pyrazolyl, (1,2,3) -and (1,2,4) -triazolyl, furyl, thienyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl and the like.
The invention can contain 1,3, 5-triazine derivatives of the formula I and pharmaceutically acceptable salts, hydrates or solvates thereof as active ingredients, and the active ingredients are mixed with pharmaceutically acceptable carriers or excipients to prepare a composition and prepare a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipients refer to any diluents, auxiliary agents and/or carriers which can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
The clinical dosage of the 1,3, 5-triazine derivatives of formula I of the present invention for a patient may be based on: the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolism and excretion rates and the age, sex, disease stage of the patient are suitably adjusted, although the daily dose for an adult should generally be 10-1000mg, preferably 50-500 mg. Therefore, when the pharmaceutical composition of the present invention is formulated into a unit dosage form, each unit preparation should contain 10 to 500mg of the above-mentioned 1,3, 5-triazine derivative, preferably 50 to 300mg, in view of the above-mentioned effective dose. These formulations may be administered in several doses (preferably one to six times) at regular intervals, according to the guidance of a doctor or pharmacist.
The pharmaceutical composition of the present invention can be formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field. The above-mentioned several dosage forms can adopt the dosage forms of injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, external liniment and ointment, etc.
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art, including: binder, lubricant, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, pigment-free, correctant, antiseptic, solubilizer, matrix, etc. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
The active compounds of the present invention or their pharmaceutically acceptable salts and solvates thereof may be used alone as the sole anti-proliferative agent or in combination with anti-proliferative agents now on the market for the treatment and/or prevention of proliferative diseases such as psoriasis, benign prostatic hypertrophy, atherosclerosis and restenosis.
We have found that the compounds of the present invention have activity in inhibiting the growth of tumor cells in vitro and therefore, it can be used for the preparation of a medicament for the treatment and/or prevention of cancers, such as breast, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, uterus, pancreas, bone marrow, testis, ovary, lymph, soft tissues, head and neck, thyroid, esophageal cancers and leukemias, neuroblastoma and the like.
The compound has obvious inhibition effect on lung cancer cells, colon cancer cells, breast cancer and nasopharyngeal cancer cells through in vitro inhibition of activity tests of a non-small cell lung cancer cell strain H1975, a human lung adenocarcinoma epithelial cell strain A549, a non-small cell lung cancer cell strain PC9, a human colon cancer cell strain HCT116, a human breast cancer cell strain BT549, a nasopharyngeal cancer cell strain CNE2 and a human colon cancer cell strain SW 945.
The active compound or the medicinal salt and the solvate thereof can be used alone as a unique antitumor medicament or can be used together with the antitumor medicaments (such as platinum medicament cisplatin, camptothecin medicament irinotecan, vinca base medicament novinova, deoxycytidine medicament gemcitabine, etoposide, taxol and the like) on the market at present. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations are not intended to limit the scope of the invention in any way.
The following synthetic scheme (scheme 1) describes the preparation of the derivatives of formula I of the present invention, all starting materials being prepared by the means described in these synthetic schemes, by methods well known to those of ordinary skill in the art of organic chemistry or being commercially available. All final derivatives of the invention are prepared by the methods described in these synthetic routes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variables used in these synthetic routes are as defined below or in the claims.
The derivatives of formula I according to the invention can be prepared in a manner according to scheme 1 by reacting the corresponding intermediates, the substituents R of which1And R2As defined in the claims.
The invention provides a series of novel 1,3, 5-triazine derivatives with novel structures and a preparation method thereof, and biological activity test is carried out on the synthesized compounds, and the compounds have anti-tumor properties. The partial derivatives have good antitumor activity, so that the compounds are deeply researched, and the aim of the invention is achieved.
Detailed Description
The examples are intended to illustrate, but not to limit, the scope of the invention.
Preparation of an intermediate:
(1) synthesis of intermediate 4- (4, 6-dichloro-1, 3, 5-triazin-2-yl) morpholine (2)
And (3) experimental operation: 10.60g (100mmol) of anhydrous sodium carbonate and 120mL of water are sequentially added into a 500mL three-necked bottle, stirred and dissolved, 18.44g (100mmol) of 2,4, 6-trichloro-1, 3, 5-triazine (1) is added at 0 ℃, stirred uniformly, then a water (25mL) solution containing 8.71g (100mol) of morpholine is slowly dripped into the system, the dripping is finished within 30min, the temperature is kept at 0-5 ℃, the reaction is carried out for 3h, reduced pressure filtration is carried out, a filter cake is washed by a small amount of water and dried, 18.54g of white powdery solid is obtained, and the yield of the crude product is 78.94%.
(2) Synthesis of intermediate 4- { 4-chloro-6- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -1,3, 5-triazin-2-yl } morpholine (4)
And (3) experimental operation: a500 mL single-neck bottle was charged with 11.33g (48.2mmol) of 4- (4, 6-dichloro-1, 3, 5-triazin-2-yl) morpholine (2), 6.66g (48.2mmol) of anhydrous potassium carbonate, and 150. 150mL g of DMF under stirring, and 8.10g (48.2mmol) of 2-difluoromethyl-1H-benzimidazole (3) was added to react at room temperature for 2H, 200mL of water was added, the mixture was allowed to stand, a solid was precipitated, filtered under reduced pressure, washed with a small amount of water, and dried to obtain 15.21g of a white powdery solid, with a crude yield of 86.03%.
(II) synthesis preparation of a target product:
the general synthesis method I comprises the following steps:
a100 mL single-necked flask was charged with 1.47g (4mmol) of 4- { 4-chloro-6- [2- (difluoromethyl) -1H-benzo [ d ]]Imidazol-1-yl]-1,3, 5-triazin-2-yl } morpholine (4), 1.27g (12mmol) Na2CO350mL of tetrahydrofuran, 8mmol of secondary amine or primary amine was added with stirring, and the reaction was refluxed for 1 hour.
Example 1: synthesis of 1- {4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazin-2-yl } piperidin-4-one (M-01)
Taking 4-piperidone hydrochloride monohydrate as a raw material, cooling to room temperature after the reaction is finished according to a synthetic method I, adding 25mL of water, standing, separating out a solid, filtering under reduced pressure, washing with a small amount of water, drying, and recrystallizing a crude product with 95% ethanol to obtain a white solid with the yield of 67.21%.1HNMR(400MHz,CDCl3)ppm8.28(d,J＝8.0Hz,1H),7.82(d,J＝7.8Hz,1H),7.50(t,JHF＝53.50Hz,1H),7.42-7.30(m,2H),4.10(brs,4H),3.84(brs,4H),3.74(brs,4H),2.56-2.46(m,4H)；MS(ESI)m/z430.21828[M+H]+。
Example 2: synthesis of 1- {4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazin-2-yl } piperidin-4-ol (M-02)
Taking 4-hydroxypiperidine as a raw material, cooling to room temperature after the reaction according to a synthetic method I, adding 25mL of water, standing, precipitating a solid, filtering under reduced pressure, washing with a small amount of water, drying, and recrystallizing a crude product with 95% ethanol to obtain a white solid with the yield of 72.34%.1HNMR(400MHz,CDCl3)ppm8.27(d,J＝8.0Hz,1H)，7.81(d,J＝7.8Hz,1H),7.51(t,JHF＝53.2Hz,1H),7.38-7.29(m,2H),4.26(m,2H),3.96(brs,1H),3.80(m,4H),3.65(m,4H),3.41(m,2H),2.06-1.73(m,4H)；MS(ESI)m/z432.23862[M+H]+。
Example 3: synthesis of 4- {4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6- (1H-imidazol-1-yl) -1,3, 5-triazin-2-yl } morpholine (M-03)
Using imidazole as a raw material, performing a first synthesis method, after the reaction is finished, concentrating under reduced pressure to dryness, adding 25mL of water, extracting with 25mL of dichloromethane multiplied by 3, combining dichloromethane layers, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to dryness, separating and purifying by silica gel column chromatography, wherein an eluent is petroleum ether/ethyl acetate which is 3:1, and obtaining 1.23g of white powdery solid with the yield of 77.52%.1HNMR(400MHz,CDCl3)ppm8.59(s,1H),8.38(d,J＝8.1Hz,1H),7.90(d,J＝7.9Hz,1H),7.83(s,1H),7.51(s,1H),7.49-7.41(m,2H),7.21(s,1H),4.07-3.97(m,4H),3.91-3.83(s,4H)；MS(ESI)m/z398.77556[M+H]+。
Example 4: synthesis of N, N-dimethyl-4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazinyl-2-amine (M-04)
Dimethylamine hydrochloride is used as a raw material, according to the synthesis method I, after the reaction is finished, the dimethylamine hydrochloride is cooled to room temperature, 25mL of water is added, the mixture is kept stand to precipitate a solid, the solid is filtered under reduced pressure, a small amount of water is used for washing, the drying is carried out, and the crude product is recrystallized by 95 percent ethanol to obtain 1.05g of a white solid with the yield of 70.10 percent.1HNMR(400MHz,CDCl3)ppm8.41(d,J＝7.72Hz,1H),7.88(d,J＝8.1Hz,1H),7.65(t,JHF＝53.52Hz,1H),7.45-7.35(m,2H),3.87(t,J＝4.21Hz,4H),3.78(t,J＝4.21Hz,4H),3.23(s,3H),3.18(s,3H)；MS(ESI)m/z376.1[M+H]+。
Example 5: synthesis of N, N-diethyl-4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazinyl-2-amine (M-05)
Using diethylamine as a raw material, according to a synthesis method I, after the reaction is finished, cooling to room temperature, adding 25mL of water, standing, precipitating a solid, filtering under reduced pressure, washing with a small amount of water, drying, and recrystallizing a crude product with 95% ethanol to obtain 1.27g of a white solid with a yield of 78.73%.1HNMR(400MHz,DMSO-d6)ppm8.37(d,J＝7.9Hz,1H),7.82(d,J＝7.8Hz,1H),7.74(t,JHF＝53.08Hz,1H),7.49-7.34(m,2H),3.81-3.65(m,8H),3.64-3.52(m,4H),1.22-1.13(m,6H).；MS(ESI)m/z404.23557[M+H]+。
Example 6: synthesis of N-isopropyl-4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazin-2-amine (M-06)
Using isopropylamine as a raw material, according to a synthesis method I, after the reaction is finished, cooling to room temperature, adding 25mL of water, standing, precipitating a solid, filtering under reduced pressure, washing with a small amount of water, drying, and recrystallizing a crude product with 95% ethanol to obtain 1.19g of a white solid with the yield of 76.55%.1HNMR(400MHz,CDCl3)ppm8.43(dd,J＝8.40Hz,1H),7.89(t,J＝8.08Hz,1H),7.68(t,JHF＝53.64Hz,1H),7.49-7.35(m,2H),4.23(m,1H),3.88(brs,4H),3.80(brs,4H),1.30(m,6H).；MS(ESI)m/z390.2[M+H]+。
Example 7: synthesis of 2- ({4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazin-2-yl } amino) ethanol (M-07)
Taking 2-aminoethanol as a raw material, carrying out the reaction according to the first synthesis method, concentrating under reduced pressure to dryness, adding 25mL of water, extracting with 25mL of dichloromethane multiplied by 3, combining dichloromethane layers, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to dryness, and carrying out silica gel column chromatography for purification, wherein an eluent is petroleum ether/ethyl acetate which is 3:1, so as to obtain 0.82g of white powdery solid, and the yield is 52.50%.1HNMR(400MHz,DMSO-d6)ppm8.41(d,J＝8.32Hz,1H),7.88(t,J＝7.24Hz,1H),7.65(t,JHF＝52.88Hz,1H),7.45-7.35(m,2H),4.55(m,2H),3.83(brs,4H),3.74(brs,4H),3.52-3.51(m,2H)；MS(ESI)m/z392.19510[M+H]+。
Example 8: synthesis of 2- ({4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazin-2-yl } amino) -1-propanol (M-08)
Using 3-aminopropanol as a raw material, performing synthetic method one, after the reaction is finished, concentrating under reduced pressure to dryness, adding 25mL of water, extracting with 25mL of dichloromethane multiplied by 3, combining dichloromethane layers, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to dryness, and performing silica gel column chromatography for purification, wherein an eluent is petroleum ether/ethyl acetate which is 3:1 to obtain 0.77g of white powdery solid, and the yield is 47.72%.1HNMR(400MHz,DMSO-d6)ppm8.36(d,J＝8.32Hz,1H),7.84(t,J＝7.24Hz,1H),7.74(t,JHF＝52.88Hz,1H),7.47-7.37(m,2H),4.55(dt,J＝19.4Hz,2H),3.76(brs,4H),3.69(brs,4H),3.52-3.51(m,2H),1.78-1.69(m,2H)；MS(ESI)m/z406.17556[M+H]+。
Example 9: synthesis of 2- ({4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazin-2-yl } amino) -1, 2-propanediol (M-09)
Using 3-amino-1, 2-propylene glycol as a raw material, performing synthetic method one, after the reaction is finished, concentrating under reduced pressure to dryness, adding 25mL of water, extracting with 25mL multiplied by 3 of dichloromethane, combining dichloromethane layers, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to dryness, separating and purifying by silica gel column chromatography, wherein an eluent is petroleum ether/ethyl acetate 2:1, and obtaining 0.79g of white powdery solid with the yield of 46.70%.1HNMR(400MHz,CDCl3)ppm8.26(br,1H),7.78-7.70(m,1H),7.45(t,JHF＝53.2Hz,1H),7.31-7.28(m,2H),4.03-3.92(m,1H),3.68(m,8H),3.46(brs,2H),2.36-1.67(m,2H)；MS(ESI)m/z422.21802[M+H]+。
Example 10: n is a radical of1- {4- [2- (difluoromethyl) -1H-benzo [ d ]]Imidazol-1-yl]Synthesis of (E) -6-morpholinyl-1, 3, 5-triazin-2-yl } ethyl-1, 2-diamine (M-10)
Using ethylenediamine as a raw material, according to a synthesis method I, firstly adding 10 times of ethylenediamine, then adding an intermediate 3, after the reaction is finished, concentrating under reduced pressure to dryness, adding 25mL of water, extracting with 25mL of dichloromethane multiplied by 3, combining dichloromethane layers, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to dryness, and performing silica gel column chromatography purification, wherein an eluent is petroleum ether/ethyl acetate (1: 3) to obtain 0.32g of white powdery solid, and the yield is 20.66%.1HNMR(400MHz,CDCl3)ppm8.32(d,J＝7.72Hz,1H),7.74(d,J＝8.1Hz,1H),7.60(t,JHF＝53.52Hz,1H),7.41-7.33(m,2H),3.80-3.65(m,12H)；MS(ESI)m/z391.2[M+H]+。
Example 11: synthesis of N- (4-bromophenyl) -4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazin-2-amine (M-11)
P-bromoaniline is used as a raw material, according to a synthetic method I, after the reaction is finished, the reaction product is cooled to room temperature, 25mL of water is added, the reaction product is kept stand to separate out a solid, the solid is filtered under reduced pressure, the solid is washed with a small amount of water and dried, and the crude product is recrystallized by 95% ethanol to obtain 1.56g of a white solid with the yield of 77.98%.1HNMR(400MHz,DMSO-d6)ppm10.09(s,1H),8.59(brs,1H),8.05-7.92(m,1H),7.82(d,J＝8.0Hz,1H)，7.67(brs,2H),7.52-7.46(m,2H),7.48-7.36(m,2H),3.79(s,4H),3.71(s,4H)；MS(ESI)m/z504.13928[M+H]+。
Example 12: synthesis of N- (4-chlorophenyl) -4- [2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl ] -6-morpholinyl-1, 3, 5-triazin-2-amine (M-12)
P-chloroaniline is used as a raw material, according to the synthetic method I, after the reaction is finished, the p-chloroaniline is cooled to room temperature, 25mL of water is added, the mixture is kept stand to separate out a solid, the solid is filtered under reduced pressure, the mixture is washed with a small amount of water and dried, and the crude product is recrystallized by 95% ethanol to obtain 1.42g of a white solid with the yield of 77.74%.1HNMR(400MHz,DMSO-d6)ppm10.09(s,1H),8.61(s,1H),8.05-7.92(m,1H),7.84(d,J＝8.0Hz,1H),7.73(brs,2H),7.56-7.31(m,5H),3.81(brs,4H),3.72(brs,4H)；MS(ESI)m/z458.17977[M+H]+。
Research on antitumor activity of product of the invention
In vitro antitumor cell Activity
The research method of the in vitro antitumor activity comprises the following steps: the MTT method is known as a tetramethylazozole salt (3- (4, 5-dimethylthizol-2-yl) -2,5-diphenyltetrazolium bromide) colorimetric method. The method is simple and rapid to operate, has high sensitivity, and is frequently used in-vitro anti-tumor activity experiments. We applied this method and performed anti-tumor activity tests on the synthesized 12 target compounds. Seven cells of a non-small cell lung cancer cell strain H1975, a human lung adenocarcinoma epithelial cell strain A549, a non-small cell lung cancer cell strain PC9, a human colon cancer cell strain HCT116, a human breast cancer cell strain BT549, a nasopharyngeal carcinoma cell strain CNE2 and a human colon cancer cell strain SW945 are selected.
The experimental principle is as follows: MTT colorimetry is a method used to detect cell survival and growth. MTT is a yellow dye that is readily dissolved in water and penetrates the cell membrane into the interior of the cell. In living cells, amber dehydrogenase in mitochondria can reduce MTT to form blue-violet crystalline Formazan (Formazan), which is insoluble in water and deposited in cells. In dead cells, the reduction reaction described above did not occur, and therefore formazan was not produced. Formazan crystal is soluble in organic solvents such as isopropyl alcohol acid and dimethyl sulfoxide, and the light absorbance (OD value) is measured at 490nm by an enzyme linked immunosorbent assay, and the light absorbance is indirectly related to the number of living cells because the amount of formazan crystal formed is proportional to the number of living cells.
The experimental method comprises the following steps: 1. adding the mixture into a 96-well plate to a concentration of 1X 105mu.g/mL of cell suspension, 100. mu.L per well, the plate was placed in 5% CO2Incubate at 37 ℃ for 24h in an incubator.
2. Solutions of the test target compounds at different concentrations were added to the well plate of the previous step and incubation was continued for 24 h.
3. The culture medium was discarded, and 100. mu.L of 0.05% MTT application solution was added to each well and cultured for 4 hours.
4. The culture medium was discarded, 100. mu.L of DMSO was added to each well, formazan particles were completely dissolved by shaking for 5min, and absorbance (OD value) at 490nm was measured.
The experimental data were processed as follows:
the formula: inhibition (%) (blank OD average-sample OD average degree)/blank OD average × 100%. Then the half Inhibition Concentration (IC) of the tested medicine to the growth of various tumor cells is obtained by software calculation50)。
(results are shown in Table 1)
TABLE 1 in vitro cytotoxic Activity results for partial Compounds of the invention
In vivo Activity assay of Compounds of the invention in animals
The breast cancer cell strain BT549 is subjected to in vitro conventional subculture, washed 3 times by sterile Phosphate Buffer Solution (PBS), and resuspended in PBS to the concentration of 108Single cell suspension/mL. Disinfecting mouse skin with 75% alcohol cotton ball, and mixing 2 × 107The single cell suspension of (0.2m1) is inoculated to the subcutaneous part of the right shoulder and the back of a nude mouse, a subcutaneous transplantation tumor model is established, and the growth condition of the subcutaneous tumor is observed. Measuring the diameter of the transplanted tumor of the nude mouse by using a vernier caliper until the tumor grows to 100-300 mm3Animals were then randomized into groups. The antitumor effect of the test object is dynamically observed by using a method for measuring the tumor size. Tumor diameters were measured 2 times per week, and mice were weighed at the same time for each measurement. The compound group was administered intraperitoneally 2 times a week, and the control group was administered with an equal amount of physiological saline at the same time. After 4 weeks of dosing, the mice were sacrificed and the tumor mass was surgically removed and weighed.
The formula: tumor inhibition (%) was calculated as (mean tumor weight in control group-mean tumor weight in treatment group)/mean tumor weight in control group × 100%.
(results are shown in Table 2)
Table 2 shows the inhibition of the growth of transplanted tumor of BT549 breast cancer nude mouse by each compound (X + -SD, n ═ 8)
And (4) conclusion: experimental results show that the 1,3, 5-triazine derivative has a certain growth inhibition effect on PANC-1 pancreatic cancer nude mouse transplanted tumors. Wherein, when the compound M-01 is administrated at a dose of 3.3mg/kg, the tumor inhibition rate of the compound M-01 on pancreatic cancer PANC-1 reaches 33.1 percent, and when the compound M-05 is administrated at a dose of 3.2mg/kg, the tumor inhibition rate of the compound M-05 on pancreatic cancer PANC-1 reaches 34.8 percent. In addition, the compound has certain inhibition effect on the weight increase of mice.
Water solubility study of the products of the invention
Weighing the test sample ground into fine powder or weighing the liquid test sample, and strongly shaking in a solvent with a certain volume at 25 +/-2 ℃ for 30 seconds every 5 minutes; dissolution was observed within 30 minutes, as no visible solute particles or droplets were present, i.e., complete dissolution was observed. The water solubility data of compounds M01-12 are shown in Table 3.
TABLE 3 Water solubility of Compounds M01-12
(III) typical preparation:
wherein the 1,3, 5-triazine derivative may have any one of the compounds as an active ingredient.
Example 1
Tablets containing 10mg of active ingredient per tablet were prepared as follows:
sieving active ingredients, starch and cellulose, mixing thoroughly, mixing polyvinylpyrrolidone solution with the above powder, sieving, making into wet granule, drying at 50-60 deg.C, sieving carboxymethyl starch sodium salt, magnesium stearate and pulvis Talci, adding into the above granule, and tabletting.
Example 2
Capsules containing 100mg of active ingredient per capsule were prepared as follows:
Claims (10)
1. General formula (VII)ⅠAnd pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein:
R1and R2The same or different, are respectively and independently selected from hydrogen and (C)1-C10) Alkyl, (C)3-C7) Cycloalkyl group, (C)2-C10) Alkenyl and (C)2-C10) Alkynyl, substituted (substituents are hydrogen, halogen, C)1-C4Alkyl) or unsubstituted (C)5-C8) Aryl, which may be substituted by 1 to 3 identical or different R3Optionally substituted;
or R1And R2Together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl or 5-10 membered heteroaryl group, said heterocyclyl and heteroaryl groups other than R1And R2Optionally containing 1-4 heteroatoms selected from N, O and S in addition to the attached nitrogen atom, except for R1And R2Said heterocyclyl optionally including 1 or 2 carbon-carbon double or triple bonds in addition to the nitrogen atom to which it is attached, said heterocyclyl and heteroaryl optionally being interrupted by 1 to 3 identical or different R4Substitution;
R3、R4is (C)1-C4) Alkyl, (C)1-C4) Alkoxy, halo, hydroxy, cyano, carboxy, (C)1-C10) An ester group.
2. The 1,3, 5-triazine compound shown in the general formula I in claim 1 and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
R1and R2The same or different, are respectively and independently selected from hydrogen and (C)1-C4) Alkyl, (C)3-C7) Cycloalkyl group, (C)2-C4) Alkenyl and (C)2-C4) Alkynyl, substituted (substituents are hydrogen, halogen, C)1-C4Alkyl) or unsubstituted (C)5-C8) Aryl, which may be substituted by 1 to 3 identical or different R3Optionally substituted;
or R1And R2Together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl or 5-10 membered heteroaryl group, which heterocyclyl and heteroaryl groups may optionally be substituted by 1-3 identical or different R4Substitution; except that R1And R2The heterocyclyl and heteroaryl groups may optionally contain 1-4 heteroatoms selected from N, O and S in addition to the nitrogen atom to which they are attached.
3. The 1,3, 5-triazine compound shown in the general formula I and the pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as claimed in claim 1 or 2,
wherein,
R1and R2The same or different, are respectively and independently selected from hydrogen and (C)1-C4) Alkyl, substituted (substituents are hydrogen, halogen, C)1-C4Alkyl) or unsubstituted (C)5-C8) Aryl, which may be substituted by 1 to 3 identical or different R3Optionally substituted;
or R1And R2Together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl or 5-10 membered heteroaryl group, which heterocyclyl and heteroaryl groups may optionally be substituted by 1-3 identical or different R4Substitution; except that R1And R2The heterocyclyl and heteroaryl groups may optionally contain 1-4 heteroatoms selected from N, O and S in addition to the nitrogen atom to which they are attached.
4. 1,3, 5-triazines of the general formula I as claimed in any one of claims 1 to 3, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein,
R1and R2The same or different, are respectively and independently selected from hydrogen and (C)1-C4) Alkyl, hydroxy substituted (C)1-C4) Alkyl, halo-substituted phenyl;
or R1And R2Together with the nitrogen atom to which they are attached form morpholinyl, 4-piperidinonyl, 4-hydroxypiperidinyl, imidazolyl, piperidinyl, 4-methylpiperidinyl, 3-methylpiperidinyl, 2-methylpiperidinyl, 4-methyl-1-piperazinyl.
5. The 1,3, 5-triazines of formula I as claimed in any one of claims 1 to 4, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein,
R1and R2Each independently is methyl, ethyl, hydrogen, isopropyl, hydroxyethyl, 3-hydroxypropyl, 2, 3-dihydroxypropyl, 2-ethylamino, 4-chlorophenyl, 4-bromophenyl; or R1And R2Together with the nitrogen atom to which they are attached form a 4-hydroxypiperidinyl, imidazolyl, 4-piperidonyl group.
6. The following general formulaⅠAnd pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof:
m-01: 1- {4- [2- (difluoromethyl) -1H-benzo [2 ]d]Imidazol-1-yl]-6-morpholinyl-1, 3, 5-triazin-2-yl } piperidin-4-one;
m-02: 1- {4- [2- (difluoromethyl) -1H-benzo [2 ]d]Imidazol-1-yl]-6-morpholinyl-1, 3, 5-triazin-2-yl } piperidin-4-ol;
m-03: 4- {4- [2- (difluoromethyl) -1H-benzo [2 ]d]Imidazol-1-yl]-6-(1H-imidazol-1-yl) -1,3, 5-triazin-2-yl } morpholine;
M-04：N,N-dimethyl-4- [2- (difluoromethyl) -1H-benzo [2 ]d]Imidazol-1-yl]-6-morpholinyl-1, 3, 5-triazin-2-amine;
M-05：N,N-diethyl-4- [2- (difluoromethyl) -1H-benzo [2 ]d]Imidazol-1-yl]-6-morpholinyl-1, 3, 5-triazin-2-amine;
M-06：N-isopropyl-4- [2- (difluoromethyl) -1H-benzo [2 ]d]Imidazol-1-yl]-6-morpholinyl-1, 3, 5-triazin-2-amine;
m-07: 2- ({4- [2- (difluoromethyl) -1H-benzo [2 ]d]Imidazol-1-yl]-6-morpholinyl-1, 3, 5-triazin-2-yl } amino) ethanol;
m-08: 2- ({4- [2- (difluoromethyl) -1H-benzo [2 ]d]Imidazol-1-yl]-6-morpholinyl-1, 3, 5-triazin-2-yl } amino) -1-propanol;
m-09: 2- ({4- [2- (difluoromethyl) -1H-benzo [2 ]d]Imidazol-1-yl]-6-morpholinyl-1, 3, 5-triazin-2-yl } amino) -1, 2-propanediol;
M-10：N’- {4- [2- (difluoromethyl) -1H-benzo [2 ]d]Imidazole-1-radical]-6-morpholinyl-1, 3, 5-triazin-2-yl } ethyl-1, 2-diamine;
M-11：N- (4-bromophenyl) -4- [2- (difluoromethyl) -1H-benzo [2 ]d]Imidazol-1-yl]-6-morpholinyl-1, 3, 5-triazin-2-amine;
M-12：N- (4-chlorophenyl) -4- [2- (difluoromethyl) -1H-benzo [2 ]d]Imidazol-1-yl]-6-morpholinyl-1, 3, 5-triazin-2-amine.
7. A pharmaceutical composition comprising a compound of any one of claims 1 to 6, and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as an active ingredient, in combination with a pharmaceutically acceptable excipient.
8. The use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or a pharmaceutical composition according to claim 7, for the manufacture of a medicament for the treatment and/or prophylaxis of proliferative diseases.
9. Use of a compound of any one of claims 1-6, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, or a composition of claim 7, for the manufacture of a medicament for the treatment and/or prevention of cancer.
10. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or a composition according to claim 7, for the manufacture of a medicament for the treatment and/or prophylaxis of lung, colon, nasopharyngeal, breast cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510468003.2A CN105130960B (en) | 2015-07-31 | 2015-07-31 | 1,3,5- triazine derivatives and its application |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111065397A (en) * | 2017-08-11 | 2020-04-24 | 密歇根大学董事会 | Inhibitors of the MEK/PI3K, JAK/MEK, JAK/PI3K/mTOR and MEK/PI3K/mTOR biological pathways and methods for improving lymphatic uptake, bioavailability and solubility of therapeutic compounds |
| AU2021202619B2 (en) * | 2016-07-06 | 2022-03-10 | The Regents Of The University Of Michigan | Multifunctional inhibitors of MEK/PI3K and mTOR/MEK/PI3K biological pathways and therapeutic methods using the same |
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| CN101137382A (en) * | 2005-03-11 | 2008-03-05 | 全药工业株式会社 | Immunosuppressive agent and anti-tumor agent comprising heterocyclic compound as active ingredient |
| WO2010110685A2 (en) * | 2009-03-27 | 2010-09-30 | Pathway Therapeutics Limited | Pyrimddinyl and 1,3,5-triazinyl benzimtoazole sulfonamides and their use in cancer therapy |
| CN103002899A (en) * | 2010-04-30 | 2013-03-27 | 巴塞尔大学 | Piperazinotriazines as PI3K inhibitors for use in the treatment antiproliferative disorders |
| CN103025725A (en) * | 2010-08-10 | 2013-04-03 | 安斯泰来制药有限公司 | Hetero ring compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101137382A (en) * | 2005-03-11 | 2008-03-05 | 全药工业株式会社 | Immunosuppressive agent and anti-tumor agent comprising heterocyclic compound as active ingredient |
| WO2010110685A2 (en) * | 2009-03-27 | 2010-09-30 | Pathway Therapeutics Limited | Pyrimddinyl and 1,3,5-triazinyl benzimtoazole sulfonamides and their use in cancer therapy |
| CN103002899A (en) * | 2010-04-30 | 2013-03-27 | 巴塞尔大学 | Piperazinotriazines as PI3K inhibitors for use in the treatment antiproliferative disorders |
| CN103025725A (en) * | 2010-08-10 | 2013-04-03 | 安斯泰来制药有限公司 | Hetero ring compound |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| AU2021202619B2 (en) * | 2016-07-06 | 2022-03-10 | The Regents Of The University Of Michigan | Multifunctional inhibitors of MEK/PI3K and mTOR/MEK/PI3K biological pathways and therapeutic methods using the same |
| CN111065397A (en) * | 2017-08-11 | 2020-04-24 | 密歇根大学董事会 | Inhibitors of the MEK/PI3K, JAK/MEK, JAK/PI3K/mTOR and MEK/PI3K/mTOR biological pathways and methods for improving lymphatic uptake, bioavailability and solubility of therapeutic compounds |
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