CN107721937B - Preparation method and application of compound containing pyrimidone skeleton - Google Patents
Preparation method and application of compound containing pyrimidone skeleton Download PDFInfo
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Abstract
The invention relates to pyrimidone compounds shown as a general formula I, geometric isomers thereof, pharmaceutically acceptable salts, solvates or prodrugs thereof, preparation methods thereof, pharmaceutical compositions containing the compounds, and substituent groups R1Have the meanings given in the description. The invention also relates to the use of compounds of general formula (I) for the preparation of a medicament for the treatment and/or prophylaxis of cancer and other proliferative diseases.
Description
Technical Field
The invention relates to a novel morpholine pyrimidinone compound, a geometric isomer thereof, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, a preparation method thereof and a pharmaceutical composition containing the compound. The invention also relates to application of the compounds in preparing and/or preventing medicaments for cancers and other proliferative diseases.
Background
Cancer (cancer), a malignant tumor, is a fatal disease that seriously harms human health. Around the world, there are 1400 new cancer cases and 820 ten thousand cancer deaths worldwide. 180 ten thousand cases of lung cancer and 159 ten thousand deaths are seen. Thus, malignancies have become second-class killers in humans after cardiovascular disease.
The PI3K-Akt-mTOR signal pathway (PI3K pathway) composed of Phosphoinositide-3-kinase (PI3K) and Protein kinase B (Akt/PKB) and rapamycin target Protein (Mammalian target of rapamycin, mTOR) at the downstream of the PI 3-Akt-mTOR signal pathway plays an important role in the biological process of tumor cells, and is closely related to the cell cycle, angiogenesis, tumorigenesis and invasion. Over-expression of this signaling pathway can lead to abnormal cellular proliferation, transcription, translation, and metabolic processes, leading to tumorigenesis. Therefore, small molecule inhibitors targeting key molecules in the PI3K/Akt signaling pathway have become hot spots for research on current antitumor drugs.
Phosphatidylinositol-3 kinase is a kind of specific Receptor Tyrosine Kinases (RTKs), PI3K is a heterodimer composed of regulatory subunit p85 and catalytic subunit p110, and is classified into type I, type II and type III according to the difference of substrate and catalytic subunit p110 structure, and type I can be further classified into type IAClass I and IBClass, known as the PI3Ks family, includes several phosphatidylinositol kinases and DNA-dependent protein kinases such as ATM, ATR and DNA-PK etc., which phosphorylate the third hydroxyl group of phosphatidylinositol, producing the inositol substance phosphatidylinositol-3-phosphate (PIP3) with a second messenger role. The second messenger, PIP3, can bind PI3K to downstream effector (especially AKt) pairs, leading to membrane recruitment and phosphorylation. The research shows that: the PI3K family is associated with numerous processes such as cell proliferation, anti-apoptosis, cell migration, bubble transport, and cancerous transformation of cells, and these biological effects are mediated primarily by the "anchor" molecule 3-phosphoinositide (PIP, PIP2, PIP3) catalyzed by PI 3K. The research finds that the PI3K pathway is universally disregulated in a wide range of human tumor spectrums, and the dysfunction or deletion caused by the mutation of certain genes in the pathway can cause the transformation of normal cells, promote the proliferation and survival of tumor cells and mediate the invasion and migration of the tumor cells, so the PI3K is a better acting target of a small molecule inhibitor and provides an opportunity for treating cancers.
Mammalian target of rapamycin (mTOR) is the only phosphorylated protein substrate of the serine/threonine phosphatidylinositol-3-kinase related kinase family member (PIKK), has an apoptosis inhibiting effect, and is frequently overexpressed in tumor cells. Two protein complexes are distinguished by functional and structural differences: mTORC1 and mTORC 2. Wherein, mTORC1 is sensitive to rapamycin, and can promote ribosome synthesis, mRNA translation and autophagy; mTORC2 is insensitive to rapamycin and promotes cell entry into the cell cycle, cell survival, cytoskeletal remodeling and metabolism. mTOR is a downstream effector molecule of AKt, and activated AKt can indirectly activate mTORC1, which in turn phosphorylates ribosomal protein p and the translation inhibitory molecule e binding protein. Meanwhile, mTORC2 up-regulates the activity of PI3K/Akt/mTOR signaling pathway by phosphorylating the Ser473 site of Akt, further stimulating the growth of tumor cells.
Currently, many compounds targeting type i PI3K (PI3K α) have entered clinical research phase, such as: the natural products of wortmannin, Buparlisib, Alpelisib, PI-103, BEZ-235, PKI-587 and the like.
The GDC-0941 reported in the literature is developed by gene tack research, belongs to morpholinopyrimidone compounds, is a selective I-type phosphatidylinositol 3-kinase (PI3K) inhibitor obtained by virtually screening compounds, and has an IC50 of 3nM for inhibiting PI3K P110 alpha subtype in vitro.
The inventor designs and synthesizes a series of morpholine pyrimidone derivatives on the basis of reference documents, and results show that the morpholine pyrimidone derivatives have antitumor activity after screening antitumor activity of a plurality of tumor cell strains in vitro.
The invention relates to a morpholine pyrimidone compound shown in a general formula (I) and pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein the content of the first and second substances,
R1is selected from the group consisting of:
preference is given to
R2Is phenyl, (C)3-C6) Cycloalkyl, 5-10 membered heteroaryl, 5-10 membered saturated or partially saturated heterocyclyl, said heteroaryl and heterocyclyl containing 1-3 heteroatoms independently selected from O, N and S, and R2Optionally 1 to 3R3Substitution;
R3is 1-3 same or different groups selected from hydrogen, hydroxyl, halogen, nitro, amino, cyano, azido, mercapto, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy group, (C)1-C6) Alkanemercapto, allyl, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl group.
The invention also preferably relates to the morpholine pyrimidinone compounds shown in the general formula (I) and geometric isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein R is2Is phenyl, a 5-to 10-membered heteroaryl group containing 1 to 3 heteroatoms optionally selected from O, N and S, and R2Optionally 1 to 3R3Substitution;
R3is 1-3 same or different groups selected from hydrogen, hydroxyl, halogen, nitro, amino, cyano, (C)1-C4) Alkyl, ethenyl, propenyl, 2-methylpropenyl, ethynyl, (C)1-C4) Alkoxy, trifluoromethyl, trifluoromethoxy, allyl, mono-or di (C)1-C4Alkyl) substituted amino, (C)1-C4) Alkylamide group, carboxyl group, (C)1-C4) Alkylsulfinyl, sulfonyl, (C)1-C4) Substituents for alkanoyl, carbamoyl, 4- (dimethylamino) -1-piperidinylcarbonyl;
the invention particularly preferably relates to morpholinopyrimidinone compounds represented by general formula (I) and geometric isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein,
R2is phenyl, benzothiazolyl, benzoxazolyl, pyridyl, furyl, thienyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, triazolyl, and R2Optionally 1 to 3R3Substitution;
R3is 1 to 3 identical or different substituents from the group consisting of hydrogen, hydroxy, fluorine, chlorine, bromine, iodine, nitro, amino, cyano, methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, propenyl, 2-methylpropenyl, ethynyl, methoxy, ethoxy, cyclopropoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, allyl, methylamino, ethylamino, dimethylamino, carboxamido, acetylamino, propionylamino, cyclopropylamino, carboxy, methylsulfinyl, sulfonyl, methanesulfonyl, formyl, acetyl, propionyl, cyclopropanoyl, carbamoyl, 4- (dimethylamino) -1-piperidinylcarbonyl.
The morpholinopyrimidinone compounds represented by the general formula (i) of the present invention and geometric isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof are preferably the following compounds, but these compounds are not meant to limit the present invention in any way:
1-phenyl-3- [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (2-chlorophenyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (3-chlorophenyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (4-chlorophenyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (p-tolyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- [4- (trifluoromethyl) phenyl ] -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (4-bromophenyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (4-fluorophenyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (2, 4-Dimethoxyphenyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (4-Nitrophenyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (4-acetylphenyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (2, 4-dichlorophenyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (2, 4-dimethylphenyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- [3- (trifluoromethyl) phenyl ] -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- [2- (trifluoromethyl) phenyl ] -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- [4- (trifluoromethoxy) phenyl ] -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
(E) -2- (4-methoxybenzylidene) -N- [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] amino-1-carboxylic acid hydrazide
(E) -2- [4- (trifluoromethoxy) benzylidene ] -N- [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] amino-1-carboxylic acid hydrazide
(E) -2- (3-methoxybenzylidene) -N- [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] amino-1-carboxylic acid hydrazide
Furthermore, the morpholinopyrimidinone skeleton-containing compound of the above formula I can form a pharmaceutically acceptable salt with an acid according to the present invention by a conventional method in the art. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with the following acids being 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 derivatives of formula I which may themselves have poor or no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) to the corresponding biologically active form.
"halogen" in the present invention means fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl; "aryl" refers to phenyl with no substituents or with substituents; "heteroaryl" means a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, the ring system being 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; "saturated or partially saturated heterocyclyl" refers to monocyclic or polycyclic ring systems containing one or more heteroatoms selected from N, O, S, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, thiazolinyl, and the like.
The compound containing the morpholinopyrimidone skeleton and pharmaceutically acceptable salts and solvates thereof which are shown in the formula I can be used as active ingredients, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition and prepared into a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier 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 compound of the invention having the morpholinopyrimidinone skeleton of formula I above for use in a patient may be according to: 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 10-500mg, preferably 50-300 mg. Therefore, when the pharmaceutical composition of the present invention is formulated into a unit dosage form, 10 to 500mg of the compound having morpholinopyrimidone skeleton of the above formula I, preferably 50 to 300mg, per unit formulation should be contained in consideration of the above 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.
Through in vitro inhibition activity tests of lung cancer cells H460, colon cancer cells HT-29, human breast cancer cells MDA-MB-231, human gastric cancer cells MKN-45 and human lung adenocarcinoma cells A549, the compounds of the invention are found to have remarkable anti-tumor activity, so that the compounds of the invention can be used for preparing medicaments for treating and/or preventing various 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, esophagus, leukemia, neuroblastoma and the like. In particular to the preparation of the medicine for treating and/or preventing lung cancer and liver cancer.
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 is not intended to limit the scope of the present invention in any way.
The following synthetic schemes describe the preparation of the derivatives of formula I of the present invention, all starting materials being prepared by the methods described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry or commercially available. All of the final compounds of the present invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All the variable factors applied in these routes are as defined below or in the claims.
The derivatives of general formula I according to the invention can be prepared according to the methods of the first and second routes, wherein the compound T1 is prepared from the compound I and different substituted isocyanates, and the compound T2 is prepared from the compound I, benzyl chloroformate, hydrazine hydrate and different substituted aldehydes through a series of reactions, wherein the substituents T1-T2 are defined as the compounds of general formula I.
Route one:
and a second route:
the specific implementation mode is as follows:
the following examples are intended to illustrate, but not limit, the scope of the invention. NMR of the compounds was measured using Bruker ARX-300 and Mass Spectroscopy was measured using Agilent 1100LC/M (S) D; all reagents used were analytically or chemically pure.
EXAMPLE 11 preparation of phenyl-3- [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
Synthesis of 1.14-nitrobenzonitrile (M2)
100g (0.66mol) of p-nitrobenzaldehyde, 60g (0.86mol) of hydroxylamine hydrochloride and 100mL of DMSO were put in a three-necked flask and reacted for 4 hours under reflux. The reaction solution was cooled to room temperature, poured into 500mL of ice water, filtered under suction to give a yellow solid, which was dried to give 88.91g of a pale yellow solid with a yield of 90.7%.
1.24 Synthesis of Ethyl nitrobenzyl imidate (M3)
80g (0.54mol) of p-nitrobenzonitrile were dissolved in 86mL (1.62mol) of absolute ethanol and 800mL of dry 1, 4-dioxane in the presence of dry HCl gas and reacted at room temperature for 12 h. The solvent was evaporated to dryness to give a yellow sticky solid, 52ml of 2.5% NaOH solution was poured in, the pH was adjusted to neutral, suction filtration was carried out, and drying was carried out to give 43.48g of a yellow solid with a yield of 71.4%.
Synthesis of N-methyl-4-nitrobenzamidine (M4)
5g of ethyl 4-nitrobenzyl imidate (0.026mol) and 2g (0.030mol) of methylamine hydrochloride were dissolved in 50mL of a mixed solvent of methanol/water (9:1), and the mixture was stirred at 45 ℃ for 5 hours. The solvent was evaporated to dryness to obtain a yellow solid. Dissolving in 20mL of water, adjusting pH to 12 with 3.4mL of 2.5% NaOH solution, filtering, and drying to obtain dark white solid 2.6g with a yield of 57%.
1.46 Synthesis of hydroxy-3-methyl-2- (4-nitrophenyl) -4(3H) -pyrimidinone (M5)
2.6g N-methyl-4-nitrobenzamidine (0.016mol) and 3.5mL (0.033mol) of dimethyl malonate are dissolved in 6mL of anisole, the temperature is raised to 130 ℃ for reaction for 12 hours, and the yellow solid 2.6g is obtained after suction filtration and drying, and the yield is 57%.
Synthesis of 56-chloro-3-methyl-2- (4-nitrophenyl) -4(3H) -pyrimidinone (M6)
8.8g (0.036mol) 6-hydroxy-3-methyl-2- (4-nitrophenyl) -4(3H) -pyrimidinone are dissolved in 44mL phosphorus oxychloride and stirred at 80 ℃ for 5H. The phosphorus oxychloride was evaporated off, the obtained solid was slowly added to ice water, the pH was adjusted to 12 with 15% NaOH solution, filtered and dried to obtain 7.6g of yellow solid with a yield of 80.8%.
Synthesis of 63-methyl-6-morpholinyl-2- (4-nitrophenyl) -4(3H) -pyrimidinone (M7)
4g (0.015mol) 6-chloro-3-methyl-2- (4-nitrophenyl) -4(3H) -pyrimidinone are added to 4mL (0.045mol) morpholine and 40mL DMAF and the mixture is stirred for 3.5H at 80 ℃. The reaction solution was poured into 20mL of ice water, the pH was adjusted to 12 with 3.0mL of 15% NaOH solution, filtered with suction, and dried to give 3.9g of a yellow solid with a yield of 87.9%.
Synthesis of 72- (4-aminophenyl) -3-methyl-6-morpholinyl-4 (3H) -pyrimidinone (I)
5g (0.089mol) of iron powder was added to 0.9mL of concentrated hydrochloric acid and 60mL of 90% ethanol, and stirred at room temperature for 30 min. The temperature was raised to 60 ℃ and 4g (0.013mol) of 3-methyl-6-morpholinyl-2- (4-nitrophenyl) -4(3H) -pyrimidinone were added. The reaction was refluxed at 80 ℃ for 5 h. Slightly cooling, adding 0.2g (0.017mol) of activated carbon for decolorization, and heating to reflux and stirring for 30 min. Suction filtration is carried out while hot, cooling is carried out, the pH is adjusted to 10 with 3.6mL of 10% NaOH solution, extraction is carried out with 3X 30mL of dichloromethane, the organic phases are combined and dried. The organic solvent was evaporated to give a pale yellow powder with a yield of 55.25%.
1.81 Synthesis of phenyl-3- [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
0.05mol of phenyl isocyanate was dissolved in 5mL of methylene chloride, and 0.05mol of intermediate I was added to the solution to react at room temperature for about 5 hours. After the reaction was completed, 0.13g of off-white solid was obtained by suction filtration, and the yield was 75.6%.
MS(ESI)m/z(％):406.3[M+H]+；1H-NMR(400MHz,Chloroform-d)δ8.77(s,1H),8.46(s,1H),7.56(d,J＝8.2Hz,2H),7.42(d,J＝7.7Hz,4H),7.25(s,1H),7.02(d,J＝7.7Hz,1H),5.47(s,1H),3.70(s,4H),3.49(s,4H),3.42(s,3H)
Prepared by the method of example 1 by reacting the intermediate I as a raw material with various phenyl isocyanates
Compounds of examples 1 to 16 (see Table 1)
EXAMPLE 17 Synthesis of (E) -2- (4-methoxybenzylidene) -N- [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] amino-1-carbohydrazide
17.1 Synthesis of intermediate phenyl N- [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] amino-1-carboxylic acid phenyl ester (II)
1.4g (0.0049mol) of 2- (4-aminophenyl) -3-methyl-6-morpholinyl-4 (3H) -pyrimidinone is dissolved in 5mL of dichloromethane, 8.2mL (0.015mol) of phenyl chloroformate is slowly dropped under the ice bath condition, 5mL of chloroform is added after dropping, and the temperature is raised to 35 ℃ for reaction for 3H. The reaction solution was cooled to room temperature, left to stand overnight, and filtered with suction to give 1.92g of a white solid with a yield of 90.14%.
17.2 Synthesis of N- [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] amino-1-carboxylic acid hydrazide (III)
1.0g (0.0025mol) phenyl [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] carbamate was dissolved in 1.5mL (0.025mol) hydrazine hydrate and 10mL toluene and reacted at 80 ℃ for 5 h. The reaction solution was cooled to room temperature, the solvent was concentrated, 15mL of isopropyl alcohol-isopropyl ether (1:5) was added, stirred, filtered, and dried to obtain 0.4g of a white solid with a yield of 47.6%.
17.3 Synthesis of (E) -2- (4-methoxybenzylidene) -N- [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] amino-1-carbohydrazide
0.05mol of 4-methoxybenzaldehyde was dissolved in 5mL of anhydrous ethanol, and 0.05mol of intermediate (III) was added thereto, followed by reflux reaction at elevated temperature. After the reaction was completed, the reaction mixture was cooled to room temperature, and 0.13g of an off-white solid was obtained by suction filtration, with a yield of 76.8%.
MS(ESI)m/z(％):463.2[M+H]+(see Figure 37);1H-NMR(400MHz,DMSO-d6)δ10.77(s,1H),9.15(s,1H),7.93(s,1H),7.81(t,J＝8.3Hz,4H),7.63-7.54(m,2H),7.05-6.96(m,2H),5.44(s,1H),3.81(s,3H),3.64(t,J＝4.8Hz,4H),3.46(t,J＝4.8Hz,4H),3.28(s,3H)
prepared by the method of example 17, starting from intermediate III, by reaction with various substituted benzaldehydes
Compounds of examples 17 to 19 (see Table 1)
TABLE 1
In vitro anti-tumor cell activity of the product of the invention
The morpholine pyrimidone skeleton compound of the formula I is screened for inhibiting the activity of human lung cancer cells H460, human colon cancer cells HT-29, human breast cancer cells MDA-MB-231, human stomach cancer cells MKN-45 and human lung adenocarcinoma cells A549 in vitro. The control GDC-0941 was prepared according to the methods described in the literature (j.med. chem.2008,51(18), pp 5522-5532).
(1) After cells were thawed and passaged for 2-3 stabilities, they were digested from the bottom of the flask with trypsin solution (0.25%). After pouring the cell digest into the centrifuge tube, the culture medium is added to stop the digestion. Centrifuging the centrifuge tube at 800r/min for 10min, discarding supernatant, adding 5mL culture solution, blowing and beating the mixed cells, sucking 10 μ L cell suspension, adding into cell counting plate, counting, and adjusting cell concentration to 104Per well. 100. mu.L of the cell suspension was added to the 96-well plate except that the A1 well was a blank well and no cells were added. The 96-well plate was placed in an incubator for 24 h.
(2) The test sample was dissolved in 50. mu.L of dimethyl sulfoxide, and then an appropriate amount of culture medium was added to dissolve the sample to 2mg/mL of the liquid, and then the sample was diluted to 20, 4, 0.8, 0.16, 0.032. mu.g/mL in a 24-well plate.
3 wells were added for each concentration, two columns of cells surrounding each, which were greatly affected by the environment, and only used as blank wells. The 96-well plate was placed in an incubator for 72 h.
(3) The drug-containing culture medium in the 96-well plate was discarded, the cells were washed twice with Phosphate Buffered Saline (PBS), 100. mu.L of MTT (0.5mg/mL) was added to each well, and the mixture was placed in an incubator for 4 hours, and then the MTT solution was discarded, and 100. mu.L of dimethyl sulfoxide was added thereto. And oscillating on a magnetic oscillator to fully dissolve the viable cells and the MTT reaction product formazan, and putting the formazan into an enzyme labeling instrument to measure the result. Determination of drug IC by Bliss method50The value is obtained.
The results of the partial compounds on inhibiting the activity of human lung cancer cells H460, human colon cancer cells HT-29, human breast cancer cells MDA-MB-231, human stomach cancer cells MKN-45 and human lung adenocarcinoma cells A549 are shown in Table 2.
TABLE 2
From the above experimental results, it is clear that the compound of formula I to be protected by the present invention has good in vitro anti-tumor activity, comparable to or due to GDC-0941, which is a positive control drug.
Claims (8)
1. Compounds of general formula (I) and pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
R1is selected from the group consisting of:
R2is phenyl, and R2Optionally 1 to 3R3Substitution;
R3is 1-3 same or different selected from hydrogen, halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, halogenated (C)1-C6) Alkyl or (C)1-C6) Alkoxy group, (C)1-C6) An alkyl acyl group.
2. A compound of formula (I) according to claim 1,
wherein the content of the first and second substances,
R2is phenyl, and R2Optionally 1 to 3R3Substitution;
R3is 1-3 same or different selected from hydrogen, halogen, (C)1-C4) Alkyl, (C)1-C4) Alkoxy, trifluoromethyl, trifluoromethoxy, (C)1-C4) An alkylamide group.
3. A compound of formula (I) according to claim 2, wherein,
R3is 1 to 3 same or different compounds selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, cyclopropoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, formyl, acetyl, propionyl.
4. The following compounds and their pharmaceutically acceptable salts,
1-phenyl-3- [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (2-chlorophenyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (3-chlorophenyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (4-chlorophenyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (p-tolyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- [4- (trifluoromethyl) phenyl ] -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (4-bromophenyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (4-fluorophenyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (2, 4-Dimethoxyphenyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (4-acetylphenyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (2, 4-dichlorophenyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- (2, 4-dimethylphenyl) -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- [3- (trifluoromethyl) phenyl ] -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- [2- (trifluoromethyl) phenyl ] -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
N- [4- (trifluoromethoxy) phenyl ] -N' - [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl ] urea
(E) -2- (4-methoxybenzylidene) -N- [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl]Amino-1-carboxylic acid hydrazides
(E) -2- [4- (trifluoromethoxy) benzylidene]-N- [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl]Amino-1-carboxylic acid hydrazides
(E) -2- (3-methoxybenzylidene) -N- [4- (1-methyl-4-morpholinyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) phenyl]Amino-1-carboxylic acid hydrazides.
5. A pharmaceutical composition comprising a compound of any one of claims 1 to 4 and pharmaceutically acceptable salts thereof as an active ingredient together with pharmaceutically acceptable excipients.
6. The use of a compound according to any one of claims 1 to 4, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment and/or prevention of proliferative diseases.
7. The use of a compound according to any one of claims 1 to 4, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
8. The use of a compound according to any one of claims 1 to 4, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of lung cancer, liver cancer, stomach cancer, colon cancer, breast cancer.
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| WO2010120994A2 (en) * | 2009-04-17 | 2010-10-21 | Wyeth Llc | Ureidoaryl-and carbamoylaryl-morpholino- pyrimidine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their synthesis |
| CN103172577A (en) * | 2012-01-13 | 2013-06-26 | 沈阳药科大学 | 4-aminoquinoline and 4-aminoquinoline compound and applications of compound |
| CN104230952A (en) * | 2014-08-16 | 2014-12-24 | 沈阳药科大学 | Compound containing pyrimidine skeleton, and preparation method and use of compound |
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| WO2010120994A2 (en) * | 2009-04-17 | 2010-10-21 | Wyeth Llc | Ureidoaryl-and carbamoylaryl-morpholino- pyrimidine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their synthesis |
| CN103172577A (en) * | 2012-01-13 | 2013-06-26 | 沈阳药科大学 | 4-aminoquinoline and 4-aminoquinoline compound and applications of compound |
| CN104230952A (en) * | 2014-08-16 | 2014-12-24 | 沈阳药科大学 | Compound containing pyrimidine skeleton, and preparation method and use of compound |
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