CN110386901B - Compound containing sulfonanilide pyrimidine structure and application thereof as antitumor drug - Google Patents
Compound containing sulfonanilide pyrimidine structure and application thereof as antitumor drug Download PDFInfo
- Publication number
- CN110386901B CN110386901B CN201810364564.1A CN201810364564A CN110386901B CN 110386901 B CN110386901 B CN 110386901B CN 201810364564 A CN201810364564 A CN 201810364564A CN 110386901 B CN110386901 B CN 110386901B
- Authority
- CN
- China
- Prior art keywords
- phenyl
- fluorophenyl
- cyclopropyl
- compound
- oxy
- 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.)
- Active
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Pharmacological experiments show that the compound has multi-target inhibition activity, has good multi-target inhibition activity (nM level) on c-Met, VEGFR-2 and EGFR simultaneously, has weak inhibition effect on normal cells while effectively inhibiting a plurality of tumor cells, shows better selective inhibition activity, has better safety and potential cardiotoxicity, has stronger antitumor activity and smaller toxic and side effects, can overcome the drug resistance of tumor cells, is easier to use as an antitumor drug, and can be used for preparing the antitumor drug. For therapeutic gene expressionDiseases caused by abnormal expression, such as: endocrine disorders, immune system diseases, genetic diseases and neurological diseases may also have better therapeutic effects. The compound containing the sulfonanilide pyrimidine structure is a compound shown as a formula (I) or pharmaceutically acceptable salt thereof:
Description
Technical Field
The invention relates to a compound containing a sulfonanilide pyrimidine structure and application of the compound in treating malignant tumors and diseases related to differentiation and proliferation.
Background
Malignant tumor cells have the characteristics of persistent proliferation signals, escape from growth inhibition, resist cell death, constantly replicate, angiogenesis, activate invasion, metastasis, restart energy metabolism, avoid immune destruction, recruit tumor microenvironment, and the like. Receptor tyrosine kinases transmit extracellular signals into cells and mediate the signal network control of many essential cellular functions. Dysregulation of receptor tyrosine kinase activity is a key factor in the development and progression of tumors and has been demonstrated in the development of a variety of receptor tyrosine kinase-type drugs.
More than 50 receptor tyrosine kinases are found at present, and the following are mainly studied: (1) Platelet-derived growth factor receptor (PDGFR), a representative drug such as pazopanib and regorafenib; (2) Epidermal Growth Factor Receptor (EGFR), which represents drugs such as gefitinib, erlotinib, afatinib, and the like; (3) VEGFR (Vascular endothelial growth factor receptor) has three subtypes of VEGFR-1/VEGFR-2/VEGFR-3, representing drugs such as axitinib, sorafenib, sunitinib and the like; (4) Hepatocyte Growth Factor Receptor (HGFR), including two types of c-Met/HGFR and RON (Receptor d's origininal/MSPR), represents drugs such as cabozantinib and crizotinib; (5) Fibroblast Growth Factor Receptors (FGFR) have four types of FGFR1/FGFR2/FGFR3/FGFR4, and represent medicines such as lenvatinib. There are also the Insulin receptor family (IR), the leukocyte tyrosine kinase family (LTK), and the like. These RTKs families typically have an extracellular ligand-binding domain (which binds to a particular ligand), a hydrophobic single-pass transmembrane domain, and an intracellular kinase catalytic domain and regulatory sequences. Research shows that PTKs play an important role in the development process of malignant tumors, promote cell proliferation, resist apoptosis and promote the occurrence and development of tumors. Since the first small molecule tyrosine kinase inhibitor (imatinib, used to treat chronic myelogenous leukemia CML) was approved by the FDA for marketing in 2001, a total of 23 small molecule TKIs were approved by the FDA for the treatment of various types of malignancies. In addition, some small molecular TKIs are used in different stages of clinical trials for the treatment of malignant tumors. The development and study of PTKs inhibitors (particularly RTKs inhibitors) has become an important area of research in recent years.
With the continuous emergence of target PTKs small-molecule inhibitors, the research and development of antitumor drugs are already in a brand-new stage when applied to clinical treatment, but the problem of the sequentially generated antitumor drug resistance also becomes a significant obstacle in tumor treatment.
Taking c-Met resistance as an example, the drug resistance mechanism of c-Met mainly comes from autocrine and paracrine, namely, HGF ligand is continuously secreted by the tumor to improve the drug resistance of the tumor. In addition, tumor signals activate EGFR, FGFR, VEGFR and other pathways through feedback to achieve the purpose of drug resistance. At the same time, MET signaling is also upregulated by other pathways such as resistance to EGFR. Studies have shown that MET expansion occurs in about 2% to 5% of the initial cases of non-small cell lung cancer (NSCLC), typically. Interestingly, the incidence of MET expansion increased to 5% to 22% in NSCLC patients treated with erlotinib/gefitinib. HGF/MET expansion has also been reported to occur frequently in NSCLC brain metastases patients. Furthermore, in certain clinical cases of tumors with acquired resistance to EGFR-TKI (including erlotinib and gefitinib), signal interference between MET and EGFR and amplification of MET/HGF signal has been observed. These evidence suggests that multi-target inhibition against c-Met and EGFR kinase may potentially overcome the problem of clinical resistance of existing antineoplastic drugs.
Cabozantinib (Cabozantinib) original name XL184, developed by Exelixis biopharmaceutical, usa. MET and VEGFR2 tyrosine kinase related to prostate cancer growth and spread are mainly taken as targets, tumor metastasis and angiogenesis are inhibited, and EGFR kinase inhibition activity is weak. The results of a phase II trial published on the ASCO annual meeting in 2014 showed that erlotinib + cabozantinib combination therapy had anti-tumor activity and that the growth rate of tumors was significantly reduced in 85% of patients with EGFR-positive non-small cell lung cancer whose disease progressed following prior monotherapy with erlotinib (EGFR inhibitor). This indicates that targeting c-Met/VEGFR-2/EGFR simultaneously may provide better treatment for patients resistant to EGFR tyrosine kinase inhibitors. If derivatization is carried out on the cabozantinib structure, scientific validation is required if active molecules simultaneously targeting c-Met/VEGFR-2/EGFR are available.
The inventor discovers that a substituted arylamino aromatic heterocyclic compound I-a (patent application number: 201610803077.1) has strong activity on target enzymes c-Met and VEGFR-2, but shows a certain inhibitory activity on EGFR kinase. For example, compound V-24 had the best inhibitory activity against c-Met and VEGFR-2 enzymes in vitro, with IC50 values of 7.28nM and 27.4nM, respectively, and inhibitory activity against the EGFR enzyme of only 2.15. Mu.M. How to obtain the three-target inhibitor which has higher activity to EGFR and simultaneously has high activity of c-Met and VEGFR-2 on the basis of structural modification of substituted arylamine aromatic heterocyclic compounds at the earlier stage of the inventor is a technical difficulty to be solved by the invention.
Has strong activity to target enzymes c-Met and VEGFR-2, but only shows certain inhibitory activity to EGFR kinase. For compound V-24, the inhibitory activity on c-Met and VEGFR-2 enzymes was optimized in vitro with IC50 values of 7.28nM and 27.4nM, respectively, whereas the inhibitory activity on EGFR enzyme was only 2.15. Mu.M.
In order to further improve the inhibitory activity of the compound on EGFR kinase, the inventor carries out a great deal of synthesis and pharmacological research, and finally successfully discovers a compound containing sulfonanilide pyrimidine with a novel structure, and the compound shows nM level activity on c-Met, VEGFR-2 and EGFR kinase in vitro, and compared with the compound in the patent 201610803077.1, the inhibitory activity on EGFR enzyme is obviously improved. Further patent medicine research shows that the compound of the invention has good inhibitory activity on various tumor cells, has low toxicity on normal cells and low potential cardiotoxicity, and is suitable for being used as a broad-spectrum, high-efficiency and low-toxicity antitumor drug.
In conclusion, the sulfonanilide pyrimidine structural compound has obvious structural novelty, obtains unexpected technical effects, has substantive characteristics and remarkable progress, and has creativity.
Disclosure of Invention
The invention aims to disclose a compound containing a sulfonanilide pyrimidine structure and application thereof as an anti-tumor medicament so as to discover a novel multi-target anti-tumor compound capable of effectively resisting tumor medicament resistance and meet the requirement of clinical application.
The compound containing the structure of the sulfonyl aniline pyrimidine is a compound shown as a formula (I) and pharmaceutically acceptable salt thereof:
wherein R is 1 Selected from amino, C 1 -C 4 Alkyl, trifluoromethyl, C 1 -C 3 Aminoalkyl radical, C 1 -C 3 Alkylamino, heterocyclic or substituted heterocyclic;
R 2 、R 3 is selected from C 1 -C 4 Alkyl, H, F or Cl;
n is selected from 0 or 1.
Preferably, said C 1 -C 4 Alkyl is methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl or isobutyl;
preferably, said C 1 -C 3 Aminoalkyl is aminomethyl, aminoethyl, 1-aminopropyl or 2-aminopropyl;
preferably, said C 1 -C 3 Alkylamino is N-methylamino, N-ethylamino or N-isopropylamino;
preferably, the heterocyclic ring is a saturated or unsaturated five-membered heterocyclic ring or six-membered heterocyclic ring containing 1 or 2 heteroatoms; the heteroatom is nitrogen, oxygen or sulfur;
preferably, the substituent of the substituted heterocycle refers to halogen, amino, hydroxyl, cyano, C 1 -C 4 Alkyl, trifluoromethyl, C 1 -C 3 Aminoalkyl or C 1 -C 3 An alkylamino group;
preferably, the compound containing the structure of the sulfonanilide pyrimidine includes, but is not limited to, the following compounds:
1N- (3-fluoro-4- ((2- ((3-sulfonamido) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1, 1-dimethylamide, 2N- (4-fluorophenyl) -N- (4- ((2- ((3-sulfonamidophenyl) amino) pyrimidine) -4-oxy) phenyl);
1-3N- (3-fluoro-4- ((2- ((3- (methylsulfonamido) phenyl) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1-4N- (4- ((2- ((3- (cyclopropylsulfonamido) phenyl) amino) pyrimidine) -4-oxy) -3-fluorophenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1-5N- (3-fluoro-4- ((2- ((3- (sulfonamido) phenyl) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1-6N- (3-fluoro-4- ((2- ((3- ((4-methylpiperazine) -1-sulfonyl) phenyl) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1-7N- (4-fluorophenyl) -N- (4- ((2- ((3- ((4-methylpiperazine) -1-sulfonyl) phenyl) amino) pyrimidine) -4-oxy) phenyl) cyclopropyl-1, 1-dicarboxamide;
1-8N- (4-fluorophenyl) -N- (4- ((2- ((3- (morpholinosulfonyl) phenyl) amino) pyrimidine) -4-oxy) phenyl) cyclopropyl-1, 1-dicarboxamide;
1-9N- (4-fluorophenyl) -N- (4- ((2- ((3- (4-methylpiperazine-1-sulfonylamino) phenyl) amino) pyrimidine) -4-oxy) phenyl) cyclopropyl-1, 1-dicarboxamide;
1-10N- (3-fluoro-4- ((2- ((3- (4-methylpiperazine-1-sulfonylamino) phenyl) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1-11N- (3-fluoro-4- ((2- ((3- (N-methylsulfonyl) phenyl) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1-12N- (4- ((2- ((3- ((aminomethyl) sulfonyl) phenyl) amino) pyrimidine) -4-oxy) -3-fluorophenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1-13N- (3-fluoro-4- ((2- ((3- ((N-carboxamido) amino) phenyl) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1-14N- (3-fluoro-4- ((2- ((3- ((1-methylpiperazine) -4-sulfonyl) phenyl) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1-15N- (4-fluorophenyl) -N- (4- ((2- ((3- ((trifluoromethyl) sulfonyl) phenyl) amino) pyrimidine) -4-oxy) phenyl) cyclopropyl-1, 1-dicarboxamide;
1-16N- (4-fluorophenyl) -N- (4- ((2- ((3- (piperazine-1-sulfonyl) phenyl) amino) pyrimidine) -4-oxy) phenyl) cyclopropyl-1, 1-dicarboxamide;
1-17N- (3-chloro-4- ((2- ((3-sulfonylphenyl) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
I-18N- (4- ((2- ((3- (methylsulfonylamino) phenyl) amino) pyrimidine) -4-oxy) phenyl) -N-phenylcyclopropyl-1, 1-dicarboxamide.
The structural formula of the compound is shown in the following table:
the salt is a chemically acceptable anion salt containing a drug;
preferred salts are acid salts, hydrobromide, sulphate, acetate, trifluoroacetate, citrate, tartrate, maleate, fumarate, methanesulphonate, malate, p-toluenesulphonate or oxalate;
the compounds of the invention can be prepared by the following general synthetic method:
Reagents and conditions:(a)SOCl 2 triethylamine/THF, 0 ℃,2h; (b) EDCI/DMF, r.t.,4h; (c) K is 2 CO 3 /DMF,90℃,6h；(d)PTSA/DMF,90℃,10h.
The general synthesis method and the specific operation method are as follows:
dissolving cyclopropane-1, 1-dicarboxylic acid (13.01g, 0.10mol) in THF 120mL, stirring for 15min under nitrogen protection, slowly dropwise adding triethylamine (10.12g, 0.10mol) at 0 ℃, and slowly dropwise adding SOCl 2 (9.95g, 0.10 mol), the temperature was maintained, and stirring was continued for 30min. 60mL of a THF solution containing aniline or 4-fluoroaniline (0.11 mol) was added dropwise thereto, and the reaction was completed under ice bath conditions. Adjusting the pH of the reaction solution to 9.0 by using 10% sodium hydroxide solution, stirring for 10min, adjusting the pH to 5.0 by using 1N HCl, separating out a solid, stirring for 15min, filtering, washing with water, and drying in vacuum to obtain a white solid 1-1.
P-aminophenol or 3-fluoro-4-aminophenol (5.38 mmol) and intermediate 1-1 (4.48 mmol) were dissolved in DMF15mL, EDC.HCl (1.03g, 5.38mmol) was added thereto, and the reaction was stirred at room temperature for 3h. After the reaction is finished, adding water into the reaction solution to separate out a white solid, adding 1N HCl to adjust the pH value to 4.0-5.0, stirring for 15min, filtering, washing a filter cake to be neutral, and drying in vacuum to obtain an intermediate 1-2.
Intermediate 1-2 (10 mmol) and the starting material 2, 4-dichloropyrimidine (10 mmol) were dissolved in DMF15mL, and potassium carbonate (1.52g, 11mmol) was added thereto, and the reaction was carried out at 90 ℃ for 6 hours. After the reaction is finished, cooling to room temperature, slowly adding 60mL of water in an ice water bath to precipitate a white solid, stirring for 30min, filtering, and drying to obtain an off-white to white solid 1-3.
The intermediate 1-3 (11 mmol), substituted aniline (10 mmol) and p-toluenesulfonic acid monohydrate (7.60g, 40mmol) are dissolved in DMF 20mL and heated to 90 ℃ for reaction for 10h. And after the reaction is finished, cooling to room temperature, slowly dropping the reaction solution into ice water to separate out a viscous solid, stirring for 20min, gradually solidifying the solid from the viscous state, filtering to obtain a light white solid, recrystallizing with ethyl acetate/methanol, filtering, and drying to obtain the target compound (1).
The compound comprising the structure of the formula (I) obtained by the preparation route and the method can further react with inorganic acid and organic acid in a solvent, and the salt of the corresponding compound having the structure of the formula (I) is separated out by cooling.
The raw materials, compounds and reagents used in the above-mentioned production methods can be purchased from commercial sources.
Pharmacological experiments show that the compound has the following beneficial effects:
1) The compound has multi-target inhibition activity, has good multi-target inhibition activity (nM level) on c-Met, VEGFR-2 and EGFR, and has important significance for overcoming drug resistance of tumor cells.
2) Compared with the marketed contrast medicament, the compound disclosed by the invention has weak inhibition effect on normal cells while effectively inhibiting multiple tumor cells, shows better selective inhibition activity and has good anti-tumor clinical application prospect.
3) Compared with a positive control medicament in a clinical period, the compound has better safety and smaller potential cardiotoxicity, and has a value of deep research.
In conclusion, when the compound is applied as an anti-tumor medicament, the compound has stronger anti-tumor activity and smaller toxic and side effects, can overcome the drug resistance of tumor cells, is easier to be used as the anti-tumor medicament, and can be used for preparing the anti-tumor medicament;
the compound has stronger inhibitory activity on three targets of c-Met, VEGFR-2 and EGFR, is used as an anti-tumor active molecule of a new action mechanism, and has novel, creative and substantial scientific progress.
The compound of the invention can be applied to mammals (including human beings) needing tumor treatment in the form of composition by oral administration, injection and the like; especially, oral administration is preferred. The dosage is 0.0001 mg/kg-200 mg/kg body weight per day. The optimum dose depends on the individual, and usually the dose is initially smaller and then gradually increased.
The invention also relates to a composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier;
the carrier refers to a carrier which is conventional in the pharmaceutical field, such as: diluents, excipients such as water, etc.; binders such as cellulose derivatives, gelatin, polyvinylpyrrolidone, etc.; fillers such as starch and the like; disintegrating agents such as calcium carbonate, sodium bicarbonate; in addition, other adjuvants such as flavoring agents and sweeteners may also be added to the composition.
The composition can be prepared into conventional solid preparations, such as tablets, capsules and the like, and is used for oral administration; it can also be made into injection.
The compound has the advantages of multi-target inhibition activity on tumor cell signal transduction pathways, stronger multi-target inhibition effect on target enzymes c-Met, VEGFR-2 and EGFR, lower toxicity on normal cells, small potential cardiotoxicity and suitability for being used as broad-spectrum, high-efficiency and low-toxicity antitumor drugs.
The invention has the advantages that the compound and the medicinal preparation thereof can be used for treating diseases caused by abnormal gene expression, such as: endocrine disorders, immune system diseases, genetic diseases and neurological diseases may also have better therapeutic effects.
Detailed Description
The content of the invention is further elucidated with reference to examples, without the scope of protection of the invention being limited to these examples.
Example 1
Preparation of N- (3-fluoro-4- ((2- ((3-sulfonamido) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide (I-1) and salts thereof
The preparation method is carried out according to a general synthesis method, and comprises the following specific operations:
preparation of intermediate 1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxylic acid (1-1):
dissolving cyclopropane-1, 1-dicarboxylic acid (13.01g, 0.10mol) in THF 120mL, stirring for 15min under nitrogen protection, slowly dropwise adding triethylamine (10.12g, 0.10mol) at 0 ℃, and slowly dropwise adding SOCl 2 (9.95g, 0.10 mol), the temperature was maintained, and stirring was continued for 30min. 60mL of a THF solution containing 4-fluoroaniline (12.22g, 0.11mol) was added dropwise thereto, and the reaction was completed under ice bath conditions. Adjusting the pH of the reaction solution to 9.0 by using 10% sodium hydroxide solution, stirring for 10min, adjusting the pH to 5.0 by using 1N HCl, separating out a solid, stirring for 15min, filtering, washing with water, and drying in vacuum to obtain 1-1 white solid, 14.71g and 65.9% yield. The product is not required to be purified and can be directly used for the next reaction. ESI-MS (m/z) 224.5[ 2 ], [ M + H ]] + .
Preparation of intermediates 1-2:
3-fluoro-4-aminophenol (0.68g, 5.38mmol) and intermediate 1-1 (1 g, 4.48mmol) were dissolved in 15mL of DMF, EDC.HCl (1.03g, 5.38mmol) was added thereto, and the reaction was stirred at room temperature for 3 hours. After the reaction is finished, adding water into the reaction solution to separate out a white solid, adding 1N HCl to adjust the pH value to 4.0-5.0, stirring for 15min, filtering, washing a filter cake to be neutral, and performing vacuum drying to obtain a white body 1-2: white solid, 81.4%, ESI-MS (m/z): 333.12, (+) M + H]+. 1 H NMR(400MHz,DMSO-d6)δppm:10.14(s,1H,CONH),9.64(s,1H,CONH),9.13(s,1H,OH),6.61～7.82(m,7H,Ar-H),1.44(s,4H,CH 2 CH 2 ).
Preparation of intermediates 1-3:
intermediate 1-2 (3.14g, 10mmol) and raw material 2, 4-dichloropyrimidine (10 mmol) were dissolved in 15mL of DMF, and potassium carbonate (1.52g, 11mmol) was added thereto, and the temperature was raised to 90 ℃ to conduct reaction for 6 hours. And after the reaction is finished, cooling to room temperature, slowly adding 60mL of water in an ice water bath to separate out a white solid, stirring for 30min, filtering, and drying to obtain an off-white solid 1-3: white solid, yield 82.0%, ESI-MS (m/z): 445.11[ M ] +H] + .
Preparation of N- (3-fluoro-4- ((2- ((3-sulfonamido) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide (I-1):
the intermediate 1-3 (4.89g, 11mmol), 3-aminobenzenesulfonamide (10 mmol) and p-toluenesulfonic acid monohydrate (7.60g, 40mmol) were dissolved in DMF 20mL, heated to 90 ℃ and reacted for 10h. And after the reaction is finished, cooling to room temperature, slowly dropping the reaction solution into ice water to separate out a viscous solid, stirring for 20min, gradually solidifying the solid from the viscous state, filtering to obtain a light white solid I-1, recrystallizing with ethyl acetate/methanol, filtering, and drying to obtain the target compound white solid. The yield thereof was found to be 70%. ESI-MS (m/z) 581.14[ m ] +H]+. 1 H NMR(400Hz,DMSO-d 6 )δppm:10.36(s,1H,NH),10.05(s,1H,NH),9.93(s,1H,NH),8.42(d,1H,J＝4.0Hz,ArH),8.04(s,1H,ArH),7.81(m,1H,ArH),7.73(d,1H,J＝8.0Hz,ArH),7.65(m,2H,ArH),7.46(d,1H,J＝8.0Hz,ArH),7.30(m,5H,ArH),7.16(m,2H,NH 2 ),6.60(d,1H,J＝8.0Hz,ArH),1.47(d,4H,J＝8.0Hz,CH 2 ).
Preparation of hydrochloride salt of Compound I-1:
compound I-1 (0.3 g) and a 5% aqueous hydrochloric acid solution (0.8 mmol) were added to ethanol (10 mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 0.3g of a white I-1 hydrochloride solid.
Preparation of compound I-1 mesylate:
compound T-1 (0.3 g) and methanesulfonic acid aqueous solution (0.8 mmol) were added to ethanol (10 mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 0.28g of a white I-1 methanesulfonate solid.
Preparation of compound I-1 hydrobromide salt:
compound I-1 (0.3 g) and a 5% aqueous hydrobromic acid solution (0.8 mmol) were added to ethanol (10 mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 0.34g of a white I-1 hydrobromic acid salt solid.
Preparation of compound I-1 oxalate salt:
compound I-1 (0.3 g) and oxalic acid dihydrate (0.8 mmol) were added to ethanol (10 mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 0.35g of a white I-1 oxalate solid.
Example 2
Preparation of N- (4-fluorophenyl) -N- (4- ((2- ((3-sulfonamidophenyl) amino) pyrimidine) -4-oxy) phenyl) cyclopropyl-1, 1-dicarboxamide (I-2) and salts thereof
Operating according to the general synthesis method, the target compound I-2 is prepared with the yield of 56%, ESI-MS (m/z): 563.15[ 2 ], [ M + H ]]+. 1 H NMR(400Hz,DMSO-d 6 )δppm:10.31(s,1H,NH),10.12(s,1H,NH),9.90(s,1H,NH),8.42(d,1H,J＝4.0Hz,ArH),8.04(s,1H,ArH),7.81(m,1H,ArH),7.73(d,1H,J＝8.0Hz,ArH),7.65(m,4H,ArH),7.30(m,5H,ArH),7.16(m,2H,NH 2 ),6.60(d,1H,J＝8.0Hz,ArH),1.47(d,4H,J＝8.0Hz,CH 2 ).
Preparation of compound I-2 hydrobromide salt:
starting from compound I-2 (2.0 mmol) and 5% aqueous hydrobromic acid (2.1 mmol), 0.9g of a white solid I-2 hydrobromide was obtained using the preparation of compound I-1 hydrobromide.
Example 3
Preparation of N- (3-fluoro-4- ((2- ((3- (methylsulfonylamino) phenyl) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide (I-3) and salts thereof
According to the general synthetic procedure, the target compound I-3 was prepared in 43% yield and ESI-MS (m/z): 595.11
[M+H] + . 1 H NMR(400Hz,DMSO-d 6 )δppm:10.36(s,1H,NH),10.05(s,1H,NH),9.93(s,1H,NH),8.42(d,1H,J＝4.0Hz,ArH),8.04(s,1H,ArH),7.81(m,1H,ArH),7.73(d,1H,J＝8.0Hz,ArH),7.65(m,2H,ArH),7.46(d,1H,J＝8.0Hz,ArH),7.30(m,5H,ArH),7.11(m,1H,NH),6.60(d,1H,J＝8.0Hz,ArH),2.93(s,3H,CH 3 )，1.41(d,4H,J＝8.0Hz,CH 2 ).
Preparation of compound I-3 malate:
adding compound I-1 (0.1 mmol) and malic acid (0.8 mmol) into ethanol (10 mL), refluxing for dissolution, cooling to precipitate white solid, and filtering to obtain 0.12g white I-3 malate solid.
Example 4
Preparation of N- (4- ((2- ((3- (cyclopropylsulfonamido) phenyl) amino) pyrimidine) -4-oxy) -3-fluorophenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide (I-4) and salts thereof
Operating according to the general synthesis method, the target compound I-4 is prepared with the yield of 51%, ESI-MS (m/z): 621.10[ 2 ] M + H] + . 1 H NMR(400Hz,DMSO-d 6 )δppm:10.33(s,1H,NH),10.12(s,1H,NH),9.93(s,1H,NH),8.46(d,1H,J＝4.0Hz,ArH),8.04(s,1H,ArH),7.81(m,1H,ArH),7.73(d,1H,J＝8.0Hz,ArH),7.65(m,2H,ArH),7.46(d,1H,J＝8.0Hz,ArH),7.30(m,5H,ArH),7.11(m,1H,NH),6.60(d,1H,J＝8.0Hz,ArH),2.93(m,2H,CH 2 )，1.41(d,4H,J＝8.0Hz,CH 2 ),0.88(d,4H,J＝8.0Hz,CH 2 ).
Preparation of fumarate salt of Compound T-4:
1.0g of white solid was obtained by using the compound T-4 (2.3 mmol) and fumaric acid (2.4 mmol) as starting materials and the method for producing oxalate of the compound T-1.
Example 5
Preparation of N- (3-fluoro-4- ((2- ((3- (sulfonamido) phenyl) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide (I-5) and salts thereof
According to the general synthesis operation, the target compound I-5 is prepared with yield 61%, ESI-MS (m/z): 596.14[ M ] +H] + . 1 H NMR(400Hz,DMSO-d 6 )δppm:10.36(s,1H,NH),10.05(s,1H,NH),9.93(s,1H,NH),8.42(d,1H,J＝4.0Hz,ArH),8.04(s,1H,ArH),7.81(m,1H,ArH),7.73(d,1H,J＝8.0Hz,ArH),7.65(m,2H,ArH),7.46(d,1H,J＝8.0Hz,ArH),7.30(m,5H,ArH),7.11(m,1H,NH),6.60(d,1H,J＝8.0Hz,ArH),2.03(s,2H,NH 2 )，1.41(d,4H,J＝8.0Hz,CH 2 ).
Preparation of compound I-5 oxalate salt:
1.0g of white solid was obtained by the method for producing oxalate of compound I-1 using compound T-5 (2.0 mmol) and tartaric acid (2.1 mmol) as starting materials.
Example 6
Preparation of N- (3-fluoro-4- ((2- ((3- ((4-methylpiperazine) -1-sulfonyl) phenyl) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide (I-6) and salts thereof
According to the general synthesis operation, the target compound I-6 is prepared with the yield of 52 percent, ESI-MS (m/z): 664.21[ m ] +H] + . 1 H NMR(400Hz,DMSO-d 6 )δppm:10.45(s,1H,NH),10.05(s,1H,NH),9.83(s,1H,NH),8.41(d,1H,J＝4.0Hz,ArH),8.04(s,1H,ArH),7.80(m,1H,ArH),7.79(d,1H,J＝8.0Hz,ArH),7.68(m,2H,ArH),7.46(d,1H,J＝8.0Hz,ArH),7.30(m,5H,ArH),7.11(m,1H,NH),6.60(d,1H,J＝8.0Hz,ArH),3.31(m,4H,CH 2 ),2.93(s,3H,CH 3 ),2.37(m,4H,CH 2 ),1.39(d,4H,J＝8.0Hz,CH 2 ).
Preparation of hydrochloride salt of Compound I-6:
using compound I-6 (1.8 mmol) and 5% aqueous hydrochloric acid (1.9 mmol) as starting materials, 0.85g of a white solid was obtained by the method for producing the compound I-1 hydrobromide.
Example 7
Preparation of N- (4-fluorophenyl) -N- (4- ((2- ((3- ((4-methylpiperazine) -1-sulfonyl) phenyl) amino) pyrimidine) -4-oxy) phenyl) cyclopropyl-1, 1-dicarboxamide (I-7) and salts thereof
Operating according to the general synthesis method, the target compound I-7 is prepared with the yield of 60 percent, ESI-MS (m/z) 646.17[ 2 ], [ M + H ]] + . 1 H NMR(400Hz,DMSO-d 6 )δppm:10.55(s,1H,NH),9.98(s,1H,NH),9.83(s,1H,NH),8.41(d,1H,J＝4.0Hz,ArH),8.04(s,1H,ArH),7.83(m,1H,ArH),7.79(d,1H,J＝8.0Hz,ArH),7.68(m,3H,ArH),7.46(d,1H,J＝8.0Hz,ArH),7.30(m,5H,ArH),7.11(m,1H,NH),6.60(d,1H,J＝8.0Hz,ArH),3.31(m,4H,CH 2 ),2.91(s,3H,CH 3 ),2.37(m,4H,CH 2 ),1.34(d,4H,J＝8.0Hz,CH 2 ).
Preparation of compound I-7 hydrobromide:
using compound I-7 (1.9 mmol) and 5% aqueous hydrobromic acid (2.0 mmol) as starting materials, the preparation of compound I-1 hydrobromic acid salt was carried out in the same manner as described above, whereby 0.93g of a white solid was obtained.
Example 8
Preparation of N- (4-fluorophenyl) -N- (4- ((2- ((3- (morpholinosulfonyl) phenyl) amino) pyrimidine) -4-oxy) phenyl) cyclopropyl-1, 1-dicarboxamide (I-8) and salts thereof
According to the general synthesis operation, the target compound I-8 is prepared with the yield of 66%, ESI-MS (m/z): 596.14[ M ] +H] + . 1 H NMR(400Hz,DMSO-d 6 )δppm:10.36(s,1H,NH),10.05(s,1H,NH),9.93(s,1H,NH),8.42(d,1H,J＝4.0Hz,ArH),8.04(s,1H,ArH),7.81(m,1H,ArH),7.73(d,1H,J＝8.0Hz,ArH),7.65(m,2H,ArH),7.46(d,1H,J＝8.0Hz,ArH),7.30(m,5H,ArH),7.11(m,1H,NH),6.60(d,1H,J＝8.0Hz,ArH),2.03(s,2H,NH 2 )，1.41(d,4H,J＝8.0Hz,CH 2 ).
Preparation of the oxalate salt of Compound I-8:
1.2g of white solid is obtained by using the compound I-8 (2.4 mmol) and oxalic acid dihydrate (2.5 mmol) as raw materials and adopting the preparation method of the oxalate compound I-1, and the yield is 85%.
Example 9
Preparation of N- (4-fluorophenyl) -N- (4- ((2- ((3- (4-methylpiperazine-1-sulfonamido) phenyl) amino) pyrimidine) -4-oxy) phenyl) cyclopropyl-1, 1-dicarboxamide (I-9) and salts thereof
By operating according to the general synthesis method, the target compound I-9 is prepared with the yield of 53%, ESI-MS (m/z): 661.22[ 2[ M ] +H] + . 1 H NMR(400Hz,DMSO-d 6 )δppm:10.43(s,1H,NH),10.19(s,1H,NH),9.83(s,1H,NH),8.40(d,1H,J＝4.0Hz,ArH),8.04(s,1H,ArH),7.80(m,1H,ArH),7.79(d,1H,J＝8.0Hz,ArH),7.62(m,2H,ArH),7.43(d,1H,J＝8.0Hz,ArH),7.30(m,6H,ArH),7.12(m,1H,NH),6.60(d,1H,J＝8.0Hz,ArH),4.25(s,1H,NH),3.30(m,4H,CH 2 ),2.91(s,3H,CH 3 ),2.37(m,4H,CH 2 ),1.37(d,4H,J＝8.0Hz,CH 2 ) 1.1g of a white solid was obtained by a method for producing a hydrobromide of the compound I-1 using the compound I-9 (2.2 mmol) and glacial acetic acid (2.3 mmol) as raw materials.
Example 10
Preparation of N- (3-fluoro-4- ((2- ((3- (4-methylpiperazine-1-sulfonylamino) phenyl) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide (I-10) and salts thereof
According to the general synthesis method, the target compound I-10 is prepared with the yield of 61%, ESI-MS (m/z): 678.22[ M ] +H] + . 1 H NMR(400Hz,DMSO-d 6 )δppm:10.67(s,1H,NH),10.21(s,1H,NH),9.83(s,1H,NH),8.41(d,1H,J＝4.0Hz,ArH),8.04(s,1H,ArH),7.80(m,1H,ArH),7.79(d,1H,J＝8.0Hz,ArH),7.68(m,2H,ArH),7.43(d,1H,J＝8.0Hz,ArH),7.30(m,5H,ArH),7.12(m,1H,NH),6.60(d,1H,J＝8.0Hz,ArH),4.25(s,1H,NH),3.31(m,4H,CH 2 ),2.91(s,3H,CH 3 ),2.37(m,4H,CH 2 ),1.33(d,4H,J＝8.0Hz,CH 2 ) Preparation of hydrochloride salt of Compound I-10
Using compound I-10 (2.3 mmol) and 5% aqueous hydrochloric acid (2.4 mmol) as starting materials, 0.9g of a white solid was obtained by the method for producing the compound I-1 hydrobromide.
Example 11
Preparation of N- (3-fluoro-4- ((2- ((3- (N-methylsulfonyl) phenyl) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide (I-11) and salts thereof
According to the general synthesis operation, the target compound I-11 is prepared with the yield of 71 percent, ESI-MS (m/z): 595.15[ m ] +H] + . 1 H NMR(400Hz,DMSO-d 6 )δppm:10.44(s,1H,NH),10.15(s,1H,NH),9.97(s,1H,NH),8.42(d,1H,J＝4.0Hz,ArH),8.04(s,1H,ArH),7.90(m,1H,ArH),7.73(d,1H,J＝8.0Hz,ArH),7.65(m,2H,ArH),7.46(d,1H,J＝8.0Hz,ArH),7.32(m,5H,ArH),7.16(m,1H,NH),6.60(d,1H,J＝8.0Hz,ArH),3.12(d,3H,J＝8.0Hz,CH 3 ),1.41(d,4H,J＝8.0Hz,CH 2 ).
Preparation of compound I-11 maleate salt
1.22g of a white solid was obtained by the method for producing a hydrobromide of the compound I-11 using the compound I-11 (2.1 mmol) and maleic acid (2.2 mmol) as raw materials.
Example 12
Preparation of N- (4- ((2- ((3- ((aminomethyl) sulfonyl) phenyl) amino) pyrimidine) -4-oxy) -3-fluorophenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide (I-12) and salts thereof
Preparing the target compound I according to the general synthesis method12, yield 61%, ESI-MS (m/z) 595.16[ M ] +H] + . 1 H NMR(400Hz,DMSO-d 6 )δppm:10.31(s,1H,NH),10.12(s,1H,NH),9.93(s,1H,NH),8.42(d,1H,J＝4.0Hz,ArH),8.04(s,1H,ArH),7.81(m,1H,ArH),7.73(d,1H,J＝8.0Hz,ArH),7.60(m,2H,ArH),7.46(d,1H,J＝8.0Hz,ArH),7.21(m,5H,ArH),7.16(m,2H,NH 2 ),6.50(d,1H,J＝8.0Hz,ArH),3.12(d,2H,J＝8.0Hz,CH 3 ),1.41(d,4H,J＝8.0Hz,CH 2 ).
1.O2g of white solid was obtained from compound I-12 (2.2 mmol) and methanesulfonic acid (2.3 mmol) as the starting materials by the method for the preparation of compound I-1 hydrobromide.
Example 13
Preparation of N- (3-fluoro-4- ((2- ((3- ((N-carboxamido) amino) phenyl) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide (I-13) and salts thereof
According to the general synthesis operation, the target compound I-13 is prepared with the yield of 51%, ESI-MS (m/z): 610.16[ m ] +H] + . 1 H NMR(400Hz,DMSO-d 6 )δppm:11.01(s,1H,NH),10.05(s,1H,NH),9.94(s,1H,NH),8.41(d,1H,J＝4.0Hz,ArH),8.04(s,1H,ArH),7.81(m,1H,ArH),7.73(d,1H,J＝8.0Hz,ArH),7.65(m,2H,ArH),7.46(d,1H,J＝8.0Hz,ArH),7.30(m,5H,ArH),7.11(m,1H,NH),6.60(d,1H,J＝8.0Hz,ArH),3.11(d,3H,J＝8.0Hz,CH 3 ),2.19(s,1H,NH)，1.41(d,4H,J＝8.0Hz,CH 2 ).
Preparation of Compound I-13 p-toluenesulfonate:
1.35g of a white solid was obtained by the method for producing a hydrobromide of the compound I-1 using the compound I-13 (2.4 mmol) and p-toluenesulfonic acid (2.5 mmol) as raw materials.
Example 14
Preparation of N- (3-fluoro-4- ((2- ((3- ((1-methylpiperazine) -4-sulfonyl) phenyl) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide (I-14) and salts thereof
According to the operation of the general synthesis method, the target compound I-15 is prepared with the yield of 65%, ESI-MS (m/z): 663.21[ M ] +H] + . 1 H NMR(400Hz,DMSO-d 6 )δppm:10.62(s,1H,NH),10.05(s,1H,NH),9.83(s,1H,NH),8.41(d,1H,J＝4.0Hz,ArH),8.04(s,1H,ArH),7.80(m,1H,ArH),7.79(d,1H,J＝8.0Hz,ArH),7.68(m,2H,ArH),7.46(d,1H,J＝8.0Hz,ArH),7.30(m,5H,ArH),7.11(m,1H,NH),6.60(d,1H,J＝8.0Hz,ArH),3.31(m,4H,CH 2 ),3.11(m,1H,CH),2.93(s,3H,CH 3 ),2.37(m,4H,CH 2 ),1.39(d,4H,J＝8.0Hz,CH 2 ).
1.1g of white solid was obtained by using compound T-14 (2.0 mmol) and tartaric acid (2.1 mmol) as raw materials and the method for producing oxalate of compound I-1.
Example 15
Preparation of N- (4-fluorophenyl) -N- (4- ((2- ((3- ((trifluoromethyl) sulfonyl) phenyl) amino) pyrimidine) -4-oxy) phenyl) cyclopropyl-1, 1-dicarboxamide (I-15) and salts thereof
According to the general synthesis operation, the target compound I-15 is prepared with the yield of 51%, ESI-MS (m/z): 616.14[ m ] +H] + . 1 H NMR(400Hz,DMSO-d 6 )δppm:10.52(s,1H,NH),10.12(s,1H,NH),9.90(s,1H,NH),8.42(d,1H,J＝4.0Hz,ArH),8.04(s,1H,ArH),7.81(m,1H,ArH),7.73(d,1H,J＝8.0Hz,ArH),7.65(m,4H,ArH),7.30(m,5H,ArH),6.60(d,1H,J＝8.0Hz,ArH),1.45(d,4H,J＝8.0Hz,CH 2 ).
1.3g of white solid is obtained by using a preparation method of a compound I-1 oxalate and taking a compound I-15 (2.0 mmol) and citric acid (2.1 mmol) as raw materials.
Example 16
Preparation of N- (4-fluorophenyl) -N- (4- ((2- ((3- (piperazine-1-sulfonyl) phenyl) amino) pyrimidine) -4-oxy) phenyl) cyclopropyl-1, 1-dicarboxamide (I-16) and salts thereof
According to the general synthesis operation, the target compound I-16 is prepared with the yield of 50%, ESI-MS (m/z): 632.20[ M ] +H] + . 1 H NMR(400Hz,DMSO-d 6 )δppm:10.69(s,1H,NH),10.13(s,1H,NH),9.83(s,1H,NH),8.41(d,1H,J＝4.0Hz,ArH),8.04(s,1H,ArH),7.84(m,1H,ArH),7.79(d,1H,J＝8.0Hz,ArH),7.61(m,3H,ArH),7.46(d,1H,J＝8.0Hz,ArH),7.32(m,5H,ArH),7.11(m,1H,NH),6.60(d,1H,J＝8.0Hz,ArH),3.31(m,4H,CH2),2.37(m,4H,CH2),1.92(m,1H,NH),1.34(d,4H,J＝8.0Hz,CH2).
1.3g of white solid is obtained by using a preparation method of a compound I-1 oxalate and taking a compound T-16 (2.0 mmol) and malic acid (2.1 mmol) as raw materials.
Example 17
Preparation of N- (3-chloro-4- ((2- ((3-sulfonylphenyl) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide (I-17) and salts thereof
According to the general synthesis operation, the target compound I-17 is prepared with the yield of 55%, ESI-MS (m/z): 597.10[ M ] +H] + . 1 H NMR(400Hz,DMSO-d 6 )δppm:110.35(s,1H,NH),10.04(s,1H,NH),9.93(s,1H,NH),8.42(d,1H,J＝4.0Hz,ArH),8.04(s,1H,ArH),7.80(m,1H,ArH),7.73(d,1H,J＝8.0Hz,ArH),7.65(m,2H,ArH),7.46(d,1H,J＝8.0Hz,ArH),7.30(m,5H,ArH),7.12(m,2H,NH 2 ),6.60(d,1H,J＝8.0Hz,ArH),1.43(d,4H,J＝8.0Hz,CH 2 ).
0.8g of white solid is obtained by using a preparation method of compound I-1 oxalate and taking compound I-17 (2.0 mmol) and trifluoroacetic acid (2.1 mmol) as raw materials.
Example 18
Preparation of N- (4- ((2- ((3- (methylsulfonylamino) phenyl) amino) pyrimidine) -4-oxy) phenyl) -N-phenylcyclopropyl-1, 1-dicarboxamide (I-18) and salts thereof
Operating according to the general synthesis method, the target compound I-18 is prepared with a yield of 51%, ESI-MS (m/z): 559.18[ 2 ], [ M + H ]] + . 1 H NMR(400Hz,DMSO-d 6 )δppm:10.28(s,1H,NH),10.05(s,1H,NH),9.93(s,1H,NH),8.42(d,1H,J＝4.0Hz,ArH),8.04(s,1H,ArH),7.81(m,1H,ArH),7.70(d,1H,J＝8.0Hz,ArH),7.55(m,4H,ArH),7.46(d,1H,J＝8.0Hz,ArH),7.30(m,5H,ArH),7.11(m,1H,NH),6.60(d,1H,J＝8.0Hz,ArH),2.95(s,3H,CH3),1.41(d,4H,J＝8.0Hz,CH2).
1.0g of a white solid was obtained by a method for producing hydrochloride of the compound I-1 using the compound I-18 (2.0 mmol) and phosphoric acid (2.1 mmol) as raw materials.
Example 19 Compounds in vitro assay for c-Met, VEGFR-2 and EGFR enzyme inhibitory Activity
Selecting a MET enzyme (Cat: 14-526) kit produced by Millipore to test the inhibitory activity of the compound on c-Met; VEGFR-2enzyme (Cat: K2643) kit from Sigma and EGFR (Cat: PV 3872) kit from Invitrogen were selected for the test of the inhibitory activity of VEGFR-2 and EGFR. The experimental operation is carried out according to the kit instruction, and the experimental result is shown in the table.
* Compounds I-2 and I-24 of patent 201610803077.1
As can be seen from the above table, the tested compounds of the present invention show better inhibitory activity on c-Met, VEGFR2 and EGFR, and the inhibitory activity is equivalent to or better than that of a positive control drug Cabozantinib, especially the inhibitory activity on EGFR enzyme is significantly better than that of Cabozantinib and the active compound I-2 in the patent 201610803077.1 * And I-24 * . Wherein, the compounds I-1, I-3, I-6 and I-11-I-14 have stronger inhibitory activity (IC) on the three target enzymes c-Met, VEGFR2 and EGFR 50 <100nM)。
EXAMPLE 20 Compound anti-proliferative Activity in vitro on tumor cells and on human Normal cells
The antiproliferative activity of partial compounds of the invention on human colorectal cancer cell strain HCT116, human renal clear cell carcinoma skin metastasis cell strain Caki-1, human pancreatic cancer cell strain PANC-1, human liver cancer cell strain HepG2, human prostate cancer cell strain PC-3 and MRC-5 human normal embryonic lung fibroblasts was determined. IC50 values were determined by the CCK-8 method (Cat # CK04-13, dojindo) with Cabozantinib and ACS Med.chem.Lett.2014,5,673-678, compound 3h being selected as a control. The specific results are shown in the table (unit: μ M):
* Compound 3h in ACS Med.chem.Lett.2014,5,673-678
As can be seen from the table above, compared with the positive control drug Cabozantinib and the control compound for 3h, the compound of the invention shows good in vitro anti-tumor cell proliferation activity on various tumor cells; the anti-tumor cell proliferation activity of part of the compounds is better than that of positive control drugs Cabozantinib and 3h. Wherein, the compounds I-1, I-3, I-6, I-11, I-12 and I-14 have higher inhibitory activity on human colorectal cancer cell strain HCT116, human renal clear cell carcinoma skin metastasis cell strain Caki-1, human pancreatic cancer cell strain PANC-1 and human liver cancer cell strain HepG2, are superior to positive control drugs Cabozantinib and 3h, and have the characteristic of broad-spectrum efficient anti-tumor cell proliferation.
Compared with the control compound 3h, the active compounds I-1, I-3, I-6, I-11, I-12 and I-14 of the invention contain at least one O atom or N atom on the sulfonyl side chain in addition to sulfonyl groups, and the introduction of the O atom or N atom is presumed to increase the hydrogen bond interaction between the compound of the invention and the action target according to the pharmacological test result so as to improve the biological activity of the compound, and the introduction of the O atom or N atom can also adjust the solubility and the acid-base property of the compound and enhance the tumor cell membrane permeability of the compound.
Meanwhile, compared with a reference medicament Cabozantinib, the tested compound has weaker inhibitory activity on normal embryonic lung fibroblasts of MRC-5 human, and has lower toxic and side effects.
EXAMPLE 21 Effect of Compounds on hERG Potassium channel
The in vitro potential cardiotoxic side effects of the compounds I-1, I-3, I-6, I-11, I-12 and I-14 were preliminarily investigated by the hERG potassium ion channel inhibition test. The results of the experiment are as follows:
| Compd | hERGIC 50 (μM) |
| Cabozantinib | >30 |
| I-1 | >30 |
| I-3 | >30 |
| I-6 | >30 |
| I-11 | >30 |
| I-12 | >30 |
| I-14 | >30 |
the hERG experiment result shows that the inhibitory activity of the tested compounds I-1, I-3, I-6, I-11, I-12, I-14 and Cabozantinib on the hERG potassium ion channel is more than 30 mu M, which indicates that the compound has low potential cardiotoxicity.
EXAMPLE 22 maximum tolerated dose toxicity test for intragastric administration of Compounds
40 ICR mice were divided into 4 groups of 10 animals each, half of which had weights of 18-20 g. After fasting for 6 hours, test samples were each individually removed from each group by sterile plastic syringes and gavaged orally at a volume of 0.3ml/10 g. General signs of the animals and mortality of the animals were recorded at 1, 2, and 4 hours post-dose. Animals were observed and recorded daily for 14 days of continuous observation after dosing, body weight and signs of death. And (3) dissecting dead animals, observing whether the visceral organs of the animals have macroscopic pathological changes, and carrying out pathological examination on suspicious tissues and organs.
The experimental results show that: the maximum tolerance of the compounds I-1, I-3, I-6, I-11, I-12 and I-14 to the intragastric administration of mice is more than 500mg/kg, and the animal tolerance is better.
EXAMPLE 23 composition tablet preparation
The preparation method comprises the following steps: mixing the compound of any of examples 1-18 with sucrose and corn starch, moistening with water, stirring, drying, pulverizing, sieving, adding calcium stearate, mixing, and tabletting. Each tablet weighs 200mg, and the content of active ingredients is 10mg.
EXAMPLE 24 preparation of injectable compositions
Example 1-18 Compound 20mg
Water for injection 80mg
The preparation method comprises the following steps: dissolving active ingredient in water for injection, mixing, filtering, and packaging the obtained solution under aseptic condition into ampoule bottles with 10mg of active ingredient content of 2 mg/bottle.
Although the present invention has been described with reference to the preferred embodiments, it is not intended to limit the present invention, and those skilled in the art can make variations and modifications of the present invention without departing from the spirit and scope of the present invention by using the methods and technical contents disclosed above.
Claims (8)
1. A compound containing a sulfonanilide pyrimidine structure is characterized by being a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof:
wherein R is 1 Selected from amino, C 1 -C 4 Alkyl, difluoromethyl, C 1- C 3 Aminoalkyl radical, C 1 -C 3 Alkylamino, heterocyclic or substituted heterocyclic;
the heterocyclic ring is a saturated or unsaturated five-membered heterocyclic ring or six-membered heterocyclic ring containing 1 or 2 heteroatoms, and the heteroatoms are nitrogen, oxygen or sulfur;
the substituent of the substituted heterocycle refers to halogen, amino, hydroxyl, cyano, C 1 -C 4 Alkyl, trifluoromethyl, C 1 -C 3 Aminoalkyl or C 1 -C 3 An alkylamino group;
R 2 、R 3 is selected from C 1 -C 4 Alkyl, H, F or C1;
n is selected from 0 or 1.
2. The compound containing a sulfonanilide pyrimidine structure according to claim 1, wherein C is 1 -C 4 Alkyl is methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl or isobutyl.
3. The compound containing a sulfonanilide pyrimidine structure according to claim 1, wherein C is 1 -C 3 Aminoalkyl is aminomethyl, aminoethyl, 1-aminopropyl or 2-aminopropyl.
4. The compound of claim 1, wherein C is C 1 -C 3 The alkylamino group is N-methylamino, N-ethylamino or N-isopropylamino.
5. The compound containing the sulfonanilide pyrimidine structure is characterized in that the compound containing the sulfonanilide pyrimidine structure is as follows:
1-1N- (3-fluoro-4- ((2- ((3-sulfonamido) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1-2N- (4-fluorophenyl) -N- (4- ((2- ((3-sulfonamidophenyl) amino) pyrimidine) -4-oxy) phenyl) cyclopropyl-1, 1-dicarboxamide;
1-3N- (3-fluoro-4- ((2- ((3- (methylsulfonylamino) phenyl) aminopyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1-4N- (4- ((2- ((3- (cyclopropylsulfonamido) phenyl) aminopyrimidine) -4-oxy) -3-fluorophenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1-5N- (3-fluoro-4- ((2- ((3- (sulfonamido) phenyl) aminopyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1-6N- (3-fluoro-4- ((2- ((3- ((4-methylpiperazine) -1-sulfonyl) phenyl) aminopyrimidine) -4-oxy) phenyl) Λ/- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1-7N- (4-fluorophenyl) -N- (4- ((2- ((3- ((4-methylpiperazine) -1-sulfonyl) phenyl) aminopyrimidine) -4-oxy) phenyl) cyclopropyl-1, 1-dicarboxamide;
1-10N- (3-fluoro-4- ((2- ((3- (4-methylpiperazine-1-sulfonylamino) phenyl) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1-11N- (3-fluoro-4- ((2- ((3- (N-methylsulfonyl) phenyl) amino) pyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1-12N- (4- ((2- ((3- ((aminomethyl) sulfonyl) phenyl) amino) pyrimidine) -4-oxy) -3-fluorophenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1-13N- (3-fluoro-4- ((2- ((3- ((N-carboxamido) amino) phenyl) aminopyrimidine) -4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1-14N- (3-fluoro-4- ((2- ((3- ((l-methylpiperazine) -4-sulfonyl) phenyl) aminopyrimidine) -4-oxy) phenyl) a N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide;
1-16N- (4-fluorophenyl) -N- (4- ((2- ((3- (piperazine-1-sulfonyl) phenyl) aminopyrimidine) 4-oxy) phenyl) cyclopropyl-1, 1-dicarboxamide;
1-17N- (3-chloro-4- ((2- ((3-sulfonylphenyl) aminopyrimidine) 4-oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide.
6. According to claim
Any one of the salts of the compound having a structure of sulfanilide pyrimidine is characterized in that the salt is a pharmaceutically acceptable anion salt.
7. The method of
Any one of the compounds containing the structure of the sulfadiazine is applied to the preparation of antitumor drugs.
8. A composition comprising a therapeutically effective amount of the composition of claim
Any one of the compounds or salts containing a sulfonanilide pyrimidine structure and a pharmaceutically acceptable carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810364564.1A CN110386901B (en) | 2018-04-23 | 2018-04-23 | Compound containing sulfonanilide pyrimidine structure and application thereof as antitumor drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810364564.1A CN110386901B (en) | 2018-04-23 | 2018-04-23 | Compound containing sulfonanilide pyrimidine structure and application thereof as antitumor drug |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110386901A CN110386901A (en) | 2019-10-29 |
| CN110386901B true CN110386901B (en) | 2022-11-25 |
Family
ID=68284418
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810364564.1A Active CN110386901B (en) | 2018-04-23 | 2018-04-23 | Compound containing sulfonanilide pyrimidine structure and application thereof as antitumor drug |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110386901B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114394940B (en) * | 2022-01-26 | 2024-01-16 | 武汉工程大学 | Cyclopropyl-1, 1 diamide compound and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006137706A1 (en) * | 2005-06-24 | 2006-12-28 | B & C Biopharm. Co., Ltd. | 6-(4-substituted-anilino)pyrimidine derivatives, method for preparing thereof and antiviral pharmaceutical composition comprising the same |
| CN107286140A (en) * | 2016-04-12 | 2017-10-24 | 上海医药工业研究院 | Substituted aromatic amines base heteroaromatic class compound and its application as antineoplastic |
| CN107793363A (en) * | 2016-09-06 | 2018-03-13 | 上海医药工业研究院 | A kind of substituted aromatic amines base heteroaromatic class compound and its application as antineoplastic |
-
2018
- 2018-04-23 CN CN201810364564.1A patent/CN110386901B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006137706A1 (en) * | 2005-06-24 | 2006-12-28 | B & C Biopharm. Co., Ltd. | 6-(4-substituted-anilino)pyrimidine derivatives, method for preparing thereof and antiviral pharmaceutical composition comprising the same |
| CN107286140A (en) * | 2016-04-12 | 2017-10-24 | 上海医药工业研究院 | Substituted aromatic amines base heteroaromatic class compound and its application as antineoplastic |
| CN107793363A (en) * | 2016-09-06 | 2018-03-13 | 上海医药工业研究院 | A kind of substituted aromatic amines base heteroaromatic class compound and its application as antineoplastic |
Non-Patent Citations (3)
| Title |
|---|
| Combining Similarity Searching and Network Analysis for the Identification of Active Compounds;Ryo Kunimoto et al.;《ACS Omega》;20180403;第3卷;第3768-3777页 * |
| Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity;Zhengsheng Zhan et al.;《ACS Medicinal Chemistry Letters》;20140326;第5卷;说明书第674页，摘要，第673页左栏第2段 * |
| 新型c-Met抑制剂的设计合成及生物活性研究;黄道伟等;《中国药物化学杂志》;20160430;第26卷(第2期);第90-97页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110386901A (en) | 2019-10-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110582483B (en) | Compound containing o-amino heteroaromatic alkynyl and preparation method and application thereof | |
| CN103124730B (en) | Heterocyclic alkynyl benzene compounds and medical compositions and uses thereof | |
| CN106866571B (en) | Heterocyclic urea compound and its pharmaceutical composition and application | |
| CN105601573B (en) | 2-aminopyrimidine compound and pharmaceutical composition and application thereof | |
| WO2016026445A1 (en) | Indazole compounds as fgfr kinase inhibitor, preparation and use thereof | |
| WO2017136315A1 (en) | Aminothiazole compounds and use thereof | |
| RU2618423C2 (en) | Antitumor effect amplifyer containing imidazooxaazine compound | |
| AU2018226922B2 (en) | Urea-substituted aromatic ring-linked dioxane-quinazoline and -linked dioxane-quinoline compounds, preparation method therefor and use thereof | |
| WO2012098416A1 (en) | Diarylacetylene hydrazide containing tyrosine kinase inhibitors | |
| WO2014082578A1 (en) | Heteroaryl alkyne compound and application thereof | |
| TW200916458A (en) | Heterocyclic compounds and methods of use thereof | |
| KR20200054096A (en) | Compound inhibiting YAP-TEAD interaction and pharmaceutical composition for treating or preventing cancer comprising the same as an active ingredient | |
| CA2958741C (en) | Quinazoline derivatives | |
| CN109575045B (en) | Thienopyrimidine compound, preparation method thereof, medicinal composition and application thereof | |
| CN110386901B (en) | Compound containing sulfonanilide pyrimidine structure and application thereof as antitumor drug | |
| CN103664734B (en) | Heterocycle hydroximic acid compound and medicinal compositions thereof and application | |
| CN107793363B (en) | Substituted arylamino aromatic heterocyclic compound and application thereof as antitumor drug | |
| WO2012154879A2 (en) | Autophagy inhibitors | |
| WO2017202311A1 (en) | Polycrystalline form of 2-aminopyrimidine | |
| CN109476634B (en) | Crystal of salt of quinazoline derivative | |
| CN106916112B (en) | Pyrimidine derivative, preparation method and medical application thereof | |
| CA3195465A1 (en) | Succinate and crystal form thereof as therapeutics | |
| US11479559B2 (en) | Urea-substituted aromatic ring-linked dioxinoquinoline compounds, preparation method and uses thereof | |
| WO2021180008A1 (en) | Tri-aromatic ring compound containing urea structure and use thereof | |
| CN101423513B (en) | Amine pyrimidine derivates, and production method thereof, and medicament composition and use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |