CN113956233B - Amide compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof - Google Patents
Amide compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof Download PDFInfo
- Publication number
- CN113956233B CN113956233B CN202111230609.4A CN202111230609A CN113956233B CN 113956233 B CN113956233 B CN 113956233B CN 202111230609 A CN202111230609 A CN 202111230609A CN 113956233 B CN113956233 B CN 113956233B
- Authority
- CN
- China
- Prior art keywords
- compound
- pharmaceutically acceptable
- organic solvent
- acceptable salt
- amide compound
- 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
Images
Classifications
-
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The application discloses an amide compound or pharmaceutically acceptable salt thereof, and a preparation method and application thereof. The structural formula of the amide compound is shown as a formula (I), and the amide compound can combine with E3 ubiquitination ligase to recruit target proteins and cause ubiquitination and degradation of target proteins, and can specifically degrade KRASG12C by degrading KRASG12C proteins, so that the anti-tumor activity is generated, and the anti-tumor activity effect is good.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to an amide compound or pharmaceutically acceptable salt thereof, and a preparation method and application thereof.
Background
Murine sarcoma virus oncogene (RAS) proteins are an important member of the gtpase family, including NRAS, HRAS and KRAS. These enzymes play an important role in extracellular signal transduction, proliferation, apoptosis and differentiation. KRAS binds to Guanosine Triphosphate (GTP) in an active conformation and Guanosine Dinucleotide Phosphate (GDP) in an inactive conformation. The tight binding of mutated KRAS proteins to GTP places the KRAS proteins in an abnormal sustained activation conformation, resulting in sustained activation of downstream signaling pathways. KRAS inhibitors block KRAS/GEF interactions by recognizing mutant KRAS, inhibiting KRAS downstream effectors and thus generating antitumor activity. However, targeting KRAS becomes very difficult due to the high levels of GTP and the strong binding forces of KRAS to GTP in vivo. Furthermore, KRAS proteins are an elongated flat pocket, which makes KRAS drug-based design difficult. KRAS is known as a "non-patentable target".
In recent years, research into KRAS mutations has focused mainly on KRAS G12C, with mutated cysteines enabling drugs to be designed by means of covalent binding. KRAS G12C inhibitors inhibit downstream proteins, including RAS-MEK-ERK signaling, by undergoing michael addition to Cysteine (CYS), resulting in a conformational change in the protein, thus allowing KRASG12C to stay in an inactive KRAS-GDP conformation, producing an antitumor effect. Currently KRAS G12C inhibitors AMG510, MRTX849, etc. have entered the clinic and are expected to be the next weight drug. Although KRAS G12C inhibitors develop rapidly, there are problems with some resistance, mainly activation of the KRAS bypass signal in tumor cells.
Therefore, there is a need to provide a compound having a better antitumor effect.
Disclosure of Invention
The present invention aims to solve at least one of the above technical problems in the prior art. For this purpose, the invention provides an amide compound or a pharmaceutically acceptable salt thereof.
The invention also provides a preparation method of the amide compound or the pharmaceutically acceptable salt thereof.
The invention also provides application of the amide compound or pharmaceutically acceptable salt thereof.
The first aspect of the invention provides an amide compound or pharmaceutically acceptable salt thereof, wherein the structural formula of the amide compound is shown as the formula (I):
the invention relates to a technical scheme of amide compounds or pharmaceutically acceptable salts thereof, which has at least the following beneficial effects:
the amide compound disclosed by the invention can be combined with E3 ubiquitination ligase to recruit target proteins and cause ubiquitination and degradation of target proteins, and can specifically degrade KRASG12C by degrading KRASG12C proteins, so that the anti-tumor activity is generated, and the anti-tumor activity effect is good.
The second aspect of the present invention provides a method for preparing an amide compound or a pharmaceutically acceptable salt thereof, comprising the steps of:
s1, adding a compound 1, BOC-hexamethylenediamine and N, N-diisopropylethylamine into a first organic solvent to react to obtain a compound 2, and obtaining a compound 3 under an acidic condition;
s2, adding a compound 4 and 2, 5-dichlorobenzoic acid into a second organic solvent, and reacting under the condition of a palladium catalyst and inorganic base to obtain a compound 5; compound 5 gave compound 6 under acidic conditions;
s3, reacting the compound 6, maleic anhydride and N, N-diisopropylethylamine in a third organic solvent to obtain a compound 7;
s4, reacting the compound 7, the compound 3, the 1-hydroxybenzotriazole and triethylamine in a fourth organic solvent to obtain a compound shown in a formula (I);
the structural formula of the compounds 1 to 7 is as follows:
according to some embodiments of the invention, the compound 1 is prepared by:
3-fluorophosphoric anhydride and 3-amino-2, 6-piperidinedione are added into a solvent and organic alkali for heating reaction, and then the compound 1 is obtained.
According to some embodiments of the invention, the compound 4 is prepared by:
adding 4-chloro-5-iodo-2-methoxybenzoic acid, BOC piperazine and N, N-diisopropylethylamine into a fifth organic solvent for reaction to obtain a compound 4.
According to some embodiments of the invention, the first organic solvent, the second organic solvent, the third organic solvent, the fourth organic solvent, and the fifth organic solvent are each independently selected from at least one of N, N-dimethylformamide, toluene, or 1,4 dioxane.
According to some embodiments of the invention, the palladium catalyst in step S2 is one of tetrakis triphenylphosphine palladium or [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex.
According to some embodiments of the invention, the inorganic base in step S2 is at least one of sodium carbonate, potassium carbonate or potassium phosphate.
According to some embodiments of the invention, the solvent is glacial acetic acid.
According to some embodiments of the invention, the organic base is potassium acetate or sodium acetate.
According to some embodiments of the invention, the pH of the solvent is adjusted to less than 7 under acidic conditions. Including but not limited to adding hydrochloric acid, sulfuric acid, or nitric acid to a solvent.
The third aspect of the invention provides an application of an amide compound in preparing a KRASG12C degradation agent or an anticancer drug.
The fourth aspect of the present invention also provides a pharmaceutical composition comprising an amide compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
General terms
As used herein, "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic or other untoward reactions upon administration to an animal or human, and "pharmaceutically acceptable excipients" as used herein include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, such excipients being well known in the art for use of pharmaceutically active substances.
The "pharmaceutically acceptable salts" as used herein include base addition salts and acid addition salts.
Pharmaceutically acceptable base addition salts may be formed with metals or amines (e.g., alkali and alkaline earth metals or organic amines). Pharmaceutically acceptable salts of the compounds may also be prepared with pharmaceutically acceptable cations. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkali metal cations, alkaline earth metal cations, ammonium cations and quaternary ammonium cations. Carbonates or bicarbonates are also possible. The metals used as cations are sodium, potassium, magnesium, ammonium, calcium, ferric iron, or the like. Suitable amines include isopropylamine, trimethylamine, histidine, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.
Pharmaceutically acceptable acid addition salts include inorganic acid salts or organic acid salts. Suitable acid salts include hydrochloride, formate, acetate, citrate, salicylate, nitrate, phosphate. Other suitable pharmaceutically acceptable salts are well known to those skilled in the art and include, for example, formic acid, acetic acid, citric acid, oxalic acid, tartaric acid or mandelic acid, hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; salts with organic carboxylic, sulphonic or phosphoric acids or N-substituted sulfamic acids, for example acetic, trifluoroacetic, propionic, glycolic, succinic, maleic, hydroxymaleic, methylmaleic, fumaric, malic, tartaric, lactic, oxalic, gluconic, glucaric, glucuronic, citric, benzoic, cinnamic, mandelic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, pamoic, nicotinic or isonicotinic acid; and 20 alpha amino acids which are involved in protein synthesis in nature, for example glutamic acid or aspartic acid, and salts with phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane 1, 2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene 2-sulfonic acid, naphthalene 1, 5-disulfonic acid, 2-phosphoglyceric acid or 3-phosphoglyceric acid, glucose 6-phosphoric acid, N-cyclohexylsulfamic acid (for the formation of cyclohexanesulfonate), or other acidic organic compounds, for example ascorbic acid.
The pharmaceutical compositions containing the invention can be manufactured in a conventional manner, for example by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. The appropriate formulation depends on the route of administration selected.
Drawings
FIG. 1 is a graph of concentration versus time for degradation of KRAC C12C by amide-based compounds prepared in example 1;
FIG. 2 is a graph showing the degradation effects of the compound prepared IN example 1, KRAS G12C-IN-3 of comparative example 1 and Pomalidomide of comparative example 2;
FIG. 3 is a graph showing the effect of the amide compound prepared in example 1 on the degradation of KRASC12C and KRASG 13D;
FIG. 4 example 1 is a graph of amide compounds at various concentrations versus H358 tumor cells inhibiting KRASG12C mutation;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of the amide-based compound prepared in example 1;
FIG. 6 is a mass spectrum of the amide-based compound prepared in example 1.
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of comparative example 2.
Detailed Description
Unless otherwise specified, the raw materials, reagents and solvents used in the present invention are commercially available without any treatment or may be prepared by literature methods. In order to more clearly illustrate the present invention, the present invention will be further described with reference to preferred embodiments. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and that this invention is not limited to the details given herein.
RPMI-1640 medium was purchased from Gibco; fetal bovine serum was purchased from Capricorn Scientific; dimethyl sulfoxide (DMSO), tetramethylazoblue (MTT) were all purchased from Sigma. Cells were purchased from Changsha Youze Biotechnology Co., ltd, and all of the purchased cells were identified by STR.
Example 1
Example 1 provides an amide compound, wherein the structural formula of the amide compound is shown as formula (I):
the preparation method comprises the following steps:
preparation of Compound 1:
dissolving 167mg of 3-fluorophosphoric anhydride and 164mg of 3-amino-2, 6-piperidinedione in 5mL of glacial acetic acid, adding 82mg of potassium acetate, refluxing at 80 ℃ overnight, and adding water to obtain a compound 1;
s1, adding a compound 1 (276 mg), BOC-hexamethylenediamine (167 mg) and N, N-diisopropylethylamine (90 mg) into N, N-dimethylformamide to react to obtain a compound 2, removing BOC from the compound 2 under the condition of hydrochloric acid, and spinning to dry a solvent to obtain a compound 3;
preparation of Compound 4:
4-chloro-5-iodo-2-methoxybenzoic acid (311 mg) and BOC piperazine (186 mg) were dissolved in DMF, DIPEA (90 mg) was added to react at 90℃and water was added to precipitate compound 4.
S2, adding a compound 4 (480 mg) and 2, 5-dichlorobenzoboric acid (190 mg) into N, N-dimethylformamide, reacting under the condition of 7mg of tetraphenylphosphine palladium and 300mg of sodium carbonate, and obtaining a compound 5 through a column chromatography; removing BOC from the compound 5 under the condition of hydrochloric acid to obtain a compound 6;
s3, reacting a compound 6 (368 mg), maleic anhydride (98 mg) and N, N-diisopropylethylamine (90 mg) in N, N-dimethylformamide to obtain a compound 7;
s4, reacting compound 7 (497 mg), compound 3 (316 mg), 1-hydroxybenzotriazole (440 mg) and triethylamine (90 mg) in N, N-dimethylformamide to obtain a compound of formula (I);
the structural formula of the compounds 1 to 7 is as follows:
the structure of the obtained product was confirmed by nuclear magnetic resonance:
N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)-4-oxo-4-(4-(2',5',6-trichloro-4-methoxy-[1,1'-biphenyl]3-carbonyl) piperazin-1-yl) but-2-enamide (compound of formula (I)) Yellow oil. YIeld:12%. 1 H NMR(400MHz,CDCl3)δ8.34(d,J＝7.4Hz,1H),7.51(t,J＝7.2Hz,1H),7.42(d,J＝8.5Hz,1H),7.36–7.29(m,2H),7.17(s,1H),7.09(dd,J＝13.0,7.4Hz,2H),6.90(d,J＝8.6Hz,1H),6.35(dd,J＝20.5,12.4Hz,1H),6.24(s,1H),6.09(d,J＝12.3Hz,1H),4.93(m,1H),3.91(s,3H),3.71(m,3H),3.57(m,1H),3.48–3.22(m,7H),2.93–2.70(m,3H),2.15(m,1H),1.60–1.53(m,2H),1.41(m,4H).MS calculated for C 41 H 41 Cl 3 N 6 O 8 Na[M+Na] + 873.9,found 873.9.IR(KBr)νmax＝3387,2921,2855,1698,1616,1451,1360,1256,1189,1100,1016,844,742cm -1 .
Comparative example 1
Comparative example 1 is KRAS G12C-IN-3 with the structural formula
Comparative example 2
Comparative example 2 Pomalidomide (3-amino-N- (2, 6-dioxo-3-piperidyl) phthalimide) of the formula
Purchased from InvivoChem.
Performance testing
Application example 1
The amide compound prepared IN example 1 was subjected to KRASG12C degradation effect study with KRAS G12C-IN-3 of comparative example 1 and Pomalidomide of comparative example 2; the specific test method is as follows:
1. total cell protein extraction
(1) 0.4uL PMSF (100X) and 0.4uL phosphatase inhibitor (100X) were added to each 40uL RIPA lysate and mixed well.
(2) The cells were cultured, medium was discarded, washed with PBS, and transferred to a 1.5ML EP tube after being blown up with 40ul RIPA lysate.
(3) 1.5ML EP tube was shaken on ice for 30min, centrifuged at 12000g for 20min at 4℃and the supernatant was transferred to a fresh 1.5ML EP tube.
BCA assay for determining Total protein concentration
3.4 Xloading buffer was diluted with protein sample to 1X loading buffer,100 ℃for denaturation for 5min, and packaged in 1.5mL EP tube for direct use or preservation at-40 ℃. The final protein loading amount is 20-50ug;
SDS-PAGE preparation: 12% separation gel and concentration gel (5%) were used depending on the molecular weight of the protein of interest.
5. Electrophoresis: 1 XTris-Gly electrophoresis buffer pre-cooled overnight at 4℃was poured into the electrophoresis tank. Protein samples were added to each lane on an equal mass and equal volume basis, with 3ul protein markers on both sides. And (3) carrying out constant-voltage electrophoresis for 20min at 80V, increasing the voltage to 120V, and continuing the electrophoresis until bromophenol blue reaches the bottom of the separation gel for about 90min.
6. Transferring: preparing sponge, filter paper and PVDF membrane, pouring 1X transfer buffer solution and methanol which are pre-cooled overnight at 4 ℃ into a enamel tray and an incubation box respectively, soaking the PVDF membrane in the methanol for 3min, then soaking the PVDF membrane in the transfer solution, and fully soaking the sponge and the filter paper in the transfer solution. Cutting off redundant separating gel according to the size of target protein, and placing in membrane transferring liquid. The transfer tank was placed in a foam box filled with crushed ice. And (3) switching on a power supply, transferring the PVDF film from the sealing liquid to TBST for 75min by 100V constant voltage transfer or 300mA constant current transfer, rinsing for 5 times by TBST for 5min each time, and then cutting the strip according to the molecular weight of the target protein.
7. Closing: 5% skimmed milk powder is prepared, poured into an incubation box after being fully and evenly mixed, and slowly shaken on a shaking table to be sealed for 1h.
8. Preparing an anti-reaction liquid: the strips were placed in a centrifuge tube containing primary antibody, and incubated overnight with shaking at 4 ℃.
TBST was washed 5 times for 10min each.
10. Preparing a secondary antibody reaction solution: the antibodies were prepared with 1xTBST according to the dilution ratio noted in the antibody specification, mixed upside down and placed on ice. The strips were placed in a centrifuge tube containing the secondary antibody reaction solution and incubated for 1h at room temperature with shaking. 1xTBST was washed 5 times for 10min each.
11. And (5) exposing.
FIG. 1 is a graph showing the concentration and time relationship of the degradation of KRAC 12C by the amide compound prepared in example 1 according to the above in vitro experiment results; we can see from figure 1 that the compound prepared in example 1 of the present application is able to degrade KRASG12C and is concentration-dependent and time-dependent; FIG. 2 is a graph showing the degradation effects of the compound prepared IN example 1, comparative example 2KRAS G12C-IN-3 and comparative example 3 Pomalidomide; as can be seen from fig. 2, the degradation effect of the compounds of the present application on KRASG12C is significantly better than that of comparative examples 1 and 2; FIG. 3 is a graph showing the effect of the amide compound prepared in example 1 on the degradation of KRASC12C and KRASG 13D; as can be seen from fig. 3, the compounds prepared herein selectively degrade KRASG12C in H358 and H23 cells but not KRASG13D in HCT116 cells.
Application example 2
The anti-tumor activity of the amide compound prepared in the example 1 and the compounds in the comparative examples 1 and 2 on H358 lung cancer cells is studied, and the inhibition effect of the compounds on tumor cell proliferation is detected by adopting an MTT method.
Experimental principle: MTT colorimetric method is a method for detecting cell survival and growth, and the principle is that succinic dehydrogenase in mitochondria of living cells can reduce exogenous MTT into water-insoluble blue-violet crystalline formazan and deposit in cells, while dead cells lack this function. Dimethyl sulfoxide (DMSO) can dissolve formazan in living cells, an enzyme-linked immunosorbent assay (ELISA) is used for detecting an absorbance value (OD value) at 570nM, the number of living cells can be reacted according to the absorbance value, and the smaller the OD value is, the weaker the cell activity is, and the better the proliferation inhibition effect of the drug is.
Reagent preparation
1、MTT
50mL of centrifugal tube is wrapped with tinfoil paper to avoid light, 250mg of MTT powder is precisely weighed, added into a centrifugal tube, 50mL of PBS is added to completely dissolve the MTT powder, and the MTT powder is filtered and sterilized by a filter membrane with the aperture of 0.22 mu m and split charging and stored in a dark place at the temperature of minus 20 ℃.
2. Example 1 Compound configuration
The high-pressure EP tube was used to weigh the compound, and a corresponding amount of DMSO was added to the EP tube to give a 20mM stock solution, and the stock solution was diluted 1 with a corresponding amount of medium to give working solutions at concentrations of 5. Mu.M, 10. Mu.M, 25. Mu.M, 50. Mu.M, and 100. Mu.M.
The experimental steps are as follows:
(1) Taking cells in logarithmic growth phase, digesting, and adjusting cell number concentration to 2.5X10 4 Per mL, 100 μl/well was seeded into 96-well plates. At 37 ℃,5% CO 2 The cells were cultured overnight in a cell incubator until the cells adhered to the wall.
(2) The original medium was aspirated and each group was added with different concentrations of the compound of example 1, 5. Mu.M, 10. Mu.M, 25. Mu.M, 50. Mu.M, 100. Mu.M, respectively. The culture was continued in the cell incubator for 48 hours with 0.1% DMSO as a control group.
(3) mu.L of MTT solution was added to each well, and incubated in an incubator for 4 hours.
(4) The medium was discarded, 100 μl DMSO was added per well and the formazan crystals were fully dissolved by shaking for 15 min.
(5) Absorbance at 570nm was measured with an enzyme-linked immunosorbent assay.
(6) The cell growth inhibition was calculated according to the following formula:
inhibition ratio = [ (As-Ab)/(Ac-Ab) ]x100%;
as: absorbance of the experimental wells (cell, MTT, compound of example 1);
ac: absorbance of control wells (containing cells, MTT, no compound of example 1);
ab: absorbance of blank wells (cell free and compound of example 1, MTT containing);
the compounds of comparative example 1 and comparative example 2 were used in place of the compound of example 1 of the present application and were retested twice, respectively, in the same manner as described above.
The data obtained according to the above test are shown in table 1:
table 1 data for examples and comparative examples
| H358 cells (IC) 50 ) | |
| The compound prepared in example 1 of the present application | 17.41±0.45μM |
| Comparative example 1 | >50μM |
| Comparative example 2 | >100μM |
From the above results of in vitro experiments, it can be seen from FIG. 4 that the compound of example 1 is effective in inhibiting H358 cell growth, IC 50 17.41.+ -. 0.45. Mu.M. Plate formation experiments demonstrated that the compound of example 1 was effective in inhibiting H358 cell growth at 5. Mu.M, 10. Mu.M, 15. Mu.M, 20. Mu.M. We can conclude that the compound of example 1 described herein is capable of inhibiting the growth of KRASG12C mutated H358 tumor cells and has significantly better activity than KRAS G12C-IN-3 of comparative example 1 and Pomalidomide of comparative example 2.
The present invention has been described in detail with reference to the embodiments, but the present invention is not limited to the embodiments, and various changes can be made within the knowledge of those skilled in the art without departing from the spirit of the present invention.
Claims (9)
1. An amide compound or pharmaceutically acceptable salt thereof, which is characterized in that the structural formula of the amide compound is shown as the formula (I):
formula (I).
2. The method for producing an amide compound or a pharmaceutically acceptable salt thereof according to claim 1, comprising the steps of:
s1, adding a compound 1, BOC-hexamethylenediamine and N, N-diisopropylethylamine into a first organic solvent to react to obtain a compound 2, and obtaining a compound 3 under an acidic condition;
s2, adding a compound 4 and 2, 5-dichlorobenzoic acid into a second organic solvent, and reacting under the condition of a palladium catalyst and inorganic base to obtain a compound 5; compound 5 gave compound 6 under acidic conditions;
s3, reacting the compound 6, maleic anhydride and N, N-diisopropylethylamine in a third organic solvent to obtain a compound 7;
s4, reacting the compound 7, the compound 3, the 1-hydroxybenzotriazole and triethylamine in a fourth organic solvent to obtain a compound shown in a formula (I);
the first organic solvent, the second organic solvent, the third organic solvent and the fourth organic solvent are respectively and independently selected from at least one of N, N-dimethylformamide, toluene or 1,4 dioxane;
the structural formula of the compounds 1-7 is as follows:
3. the method for preparing an amide compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the compound 1 is prepared by the steps of:
3-fluorophthalic anhydride and 3-amino-2, 6-piperidinedione are added into a solvent and organic alkali for heating reaction, and then the compound 1 is obtained.
4. The method for preparing an amide compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the compound 4 is prepared by the steps of:
adding 4-chloro-5-iodo-2-methoxybenzoic acid, BOC piperazine and N, N-diisopropylethylamine into a fifth organic solvent for reaction to obtain a compound 4;
the fifth organic solvent is independently selected from at least one of N, N-dimethylformamide, toluene, or 1,4 dioxane.
5. The method for preparing an amide compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the palladium catalyst in step S2 is one of tetrakis triphenylphosphine palladium or [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex.
6. The method for preparing an amide compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the inorganic base in step S2 is at least one of sodium carbonate, potassium carbonate or potassium phosphate.
7. A process for the preparation of an amide compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein the solvent is glacial acetic acid.
8. The use of an amide compound according to claim 1 in the preparation of KRASG12C degrading agents or anticancer drugs producing antitumor activity by degrading KRASG12C protein.
9. A pharmaceutical composition comprising an amide compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111230609.4A CN113956233B (en) | 2021-10-22 | 2021-10-22 | Amide compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111230609.4A CN113956233B (en) | 2021-10-22 | 2021-10-22 | Amide compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113956233A CN113956233A (en) | 2022-01-21 |
| CN113956233B true CN113956233B (en) | 2023-06-06 |
Family
ID=79466000
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111230609.4A Active CN113956233B (en) | 2021-10-22 | 2021-10-22 | Amide compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113956233B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115259511B (en) * | 2022-06-08 | 2023-10-10 | 聊城市鲁西化工工程设计有限责任公司 | Polyol ketone residue recycling system and method |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105189456A (en) * | 2013-03-15 | 2015-12-23 | 亚瑞克西斯制药公司 | Covalent inhibitors of KRAS G12C |
| CN107949387A (en) * | 2015-04-06 | 2018-04-20 | 卡利泰拉生物科技公司 | With glutamine ihibitors for treatment lung cancer |
| CN109928956A (en) * | 2019-02-27 | 2019-06-25 | 杭州偶联医药科技有限公司 | A kind of compound of targeting ubiquitination degradation EGFR albumen and its pharmaceutical composition and application |
| CN112714646A (en) * | 2018-07-05 | 2021-04-27 | 西奈山伊坎医学院 | Protein tyrosine kinase 6(PTK6) degradation/disruption compounds and methods of use |
| WO2021086069A1 (en) * | 2019-10-31 | 2021-05-06 | 재단법인 대구경북첨단의료산업진흥재단 | Compound comprising ezh2 inhibitor and e3 ligase binder and pharmaceutical composition for preventing or treating ezh2-associated disease comprising same as active ingredient |
-
2021
- 2021-10-22 CN CN202111230609.4A patent/CN113956233B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105189456A (en) * | 2013-03-15 | 2015-12-23 | 亚瑞克西斯制药公司 | Covalent inhibitors of KRAS G12C |
| CN107949387A (en) * | 2015-04-06 | 2018-04-20 | 卡利泰拉生物科技公司 | With glutamine ihibitors for treatment lung cancer |
| CN112714646A (en) * | 2018-07-05 | 2021-04-27 | 西奈山伊坎医学院 | Protein tyrosine kinase 6(PTK6) degradation/disruption compounds and methods of use |
| CN109928956A (en) * | 2019-02-27 | 2019-06-25 | 杭州偶联医药科技有限公司 | A kind of compound of targeting ubiquitination degradation EGFR albumen and its pharmaceutical composition and application |
| WO2021086069A1 (en) * | 2019-10-31 | 2021-05-06 | 재단법인 대구경북첨단의료산업진흥재단 | Compound comprising ezh2 inhibitor and e3 ligase binder and pharmaceutical composition for preventing or treating ezh2-associated disease comprising same as active ingredient |
Non-Patent Citations (5)
| Title |
|---|
| Discovery of a Highly Potent and Selective Degrader Targeting Hematopoietic Prostaglandin D Synthase via In Silico Design;Hidetomo Yokoo et al.;《Journal of Medicinal Chemistry》;第64卷;15868-15882 * |
| Discovery of KRas G12C-IN-3 and Pomalidomide-based PROTACs as degraders of endogenous KRAS G12C with potent anticancer activity;Ling Li et al.;《Bioorganic Chemistry》;第117卷;第105447页 * |
| Discovery of Novel PDEδ Degraders for the Treatment of KRAS Mutant Colorectal Cancer;Junfei Cheng et al.;《Journal of Medicinal Chemistry》;第63卷;7892-7905 * |
| PROTACs 靶向蛋白质降解技术及其在合理药物设计中的应用;梁倩倩等;《中国新药杂志》;第28卷(第4期);442-450 * |
| 蛋白降解靶向嵌合体( PROTAC) 的研究进展;王瑞峰等;《中国药物化学杂志》;第29卷(第3期);234-240 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113956233A (en) | 2022-01-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101739243B1 (en) | Substituted piperidyl-ethyl-pyrimidine as ghrelin o-acyl transferase inhibitor | |
| AU2008289037B2 (en) | 5- (4- (haloalkoxy) phenyl) pyrimidine-2-amine compounds and compositions as kinase inhibitors | |
| Liu et al. | Design, synthesis and structure-activity relationships of novel 4-phenoxyquinoline derivatives containing 1, 2, 4-triazolone moiety as c-Met kinase inhibitors | |
| Liu et al. | Design, synthesis and biological evaluation of novel thieno [3, 2-d] pyrimidine derivatives containing diaryl urea moiety as potent antitumor agents | |
| TW201906825A (en) | Compound and method of use thereof | |
| EA027012B1 (en) | Cdc7 inhibitors | |
| JP2016500107A (en) | Glutamase inhibitor and method of use thereof | |
| RU2720810C2 (en) | Salts of a quinazoline derivative and a method for production thereof | |
| CN109689641B (en) | Crystal form and salt form of substituted 2-hydrogen-pyrazole derivative and preparation method thereof | |
| JP6092376B2 (en) | Inhibitors of JAK1 and JAK2 | |
| US10479789B2 (en) | Pyrido[1,2-A]pyrimidone analog, crystal form thereof, intermediate thereof and preparation method therefor | |
| US20240025916A1 (en) | Kras g12c inhibitors | |
| CN113956233B (en) | Amide compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof | |
| JP2013529641A (en) | Polymorph of OSI-906 | |
| WO2018059534A1 (en) | Crystal form and salt form of and preparation method for tyrosine kinase inhibitor | |
| WO2019114741A1 (en) | Salt serving as akt inhibitor and crystal thereof | |
| CN113527195B (en) | 5-aryl nicotinamide LSD1/HDAC double-target inhibitor, preparation method and application thereof | |
| CN115667241B (en) | Trka inhibitors | |
| JP7118349B2 (en) | CRYSTALLINE AND SALT FORM OF C-MET INHIBITORS AND METHODS OF PREPARATION | |
| CN114539293B (en) | Thienopyrimidine compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof | |
| RU2794977C2 (en) | Lsd1 inhibitor salt and its polymorphic form | |
| WO2022135580A1 (en) | Crystal form of pyridopyrrole compound, and preparation method therefor and use thereof | |
| Xiaoa et al. | D-dopachrome tautomerase inhibitor suppresses the proliferation of non-small cell lung cancer cells | |
| Liu et al. | Synthesis and In Vitro Antitumor Activity Evaluation of Gefitinib-1, 2, 3-Triazole Derivatives | |
| CN114989195A (en) | Thienopyrimidine compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof |
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 |