CN116478141A - Deuterated KRAS inhibitor drug and application thereof - Google Patents
Deuterated KRAS inhibitor drug and application thereof Download PDFInfo
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- CN116478141A CN116478141A CN202310727689.7A CN202310727689A CN116478141A CN 116478141 A CN116478141 A CN 116478141A CN 202310727689 A CN202310727689 A CN 202310727689A CN 116478141 A CN116478141 A CN 116478141A
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- pharmaceutically acceptable
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- acceptable salts
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- kras
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- 229940124785 KRAS inhibitor Drugs 0.000 title claims abstract description 12
- 239000003814 drug Substances 0.000 title claims description 12
- 229940079593 drug Drugs 0.000 title description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 229910052805 deuterium Inorganic materials 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- -1 inhalants Substances 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims 1
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 claims 1
- 150000003840 hydrochlorides Chemical class 0.000 claims 1
- 150000002688 maleic acid derivatives Chemical class 0.000 claims 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims 1
- 235000021317 phosphate Nutrition 0.000 claims 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims 1
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 9
- 101150040459 RAS gene Proteins 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 102000016914 ras Proteins Human genes 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 102200006538 rs121913530 Human genes 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102100030708 GTPase KRas Human genes 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 108700042226 ras Genes Proteins 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 230000007730 Akt signaling Effects 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 102000013446 GTP Phosphohydrolases Human genes 0.000 description 1
- 102100029974 GTPase HRas Human genes 0.000 description 1
- 102100039788 GTPase NRas Human genes 0.000 description 1
- 108091006109 GTPases Proteins 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000584633 Homo sapiens GTPase HRas Proteins 0.000 description 1
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 101150105104 Kras gene Proteins 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- QTBSBXVTEAMEQO-GUEYOVJQSA-N acetic acid-d4 Chemical compound [2H]OC(=O)C([2H])([2H])[2H] QTBSBXVTEAMEQO-GUEYOVJQSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 230000036438 mutation frequency Effects 0.000 description 1
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a deuterated KRAS inhibitor, which is shown in the following formula I, and relates to the deuterated KRAS inhibitor, a pharmaceutical composition and application thereof.
Description
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to a deuterated KRAS inhibitor medicine and application thereof.
Background
RAS is the first oncogene found in the human body and has been the focus of research in drug development. There are three RAS genes in humans, HRAS, KRAS, and NRAS. RAS has GTPase activity, and is in an active state when RAS binds GTP, and is in an inactive state when RAS binds GDP, and its molecular switch functions during RAS-mediated cell signaling (RAS/RAF/MEK/ERK and PI3K/AKT signaling pathways), thereby regulating cell differentiation, proliferation and apoptosis processes. In human tumorigenesis, more than 30% are related to activation of RAS genes, and the most common mode of RAS gene activation during point mutation of RAS, wherein KRAS gene mutation frequency is highest, inhibitor drugs targeting KRAS are of great significance.
The deuterated medicine not only replaces one or more carbon-hydrogen bonds of the medicine molecules with carbon-deuterium bonds, but also overcomes the defects of easy metabolism, large side effect and the like of the original medicine by improving the pharmacokinetics property of the original medicine.
Disclosure of Invention
The invention provides a deuterated compound of a KRAS inhibitor and pharmaceutically acceptable salts thereof, which can further improve the pharmacokinetic properties of the deuterated compound of the KRAS inhibitor and pharmaceutically acceptable salts thereof, and reduce the dosage and possible toxic and side effects.
To achieve the above object, the present invention provides a deuterated compound of KRAS inhibitor having the formula i:
the deuterated compound of the KRAS inhibitor and pharmaceutically acceptable salt thereof comprise the following structures:
deuterated compounds of KRAS inhibitors and pharmaceutically acceptable salts thereof according to the present invention are selected from mesylate, maleate, hydrochloride or phosphate salts.
The deuterated compound and the pharmaceutically acceptable salt thereof disclosed by the invention comprise the application of the deuterated compound in preparation of antitumor drugs.
The deuterated compound and the pharmaceutically acceptable salt thereof provided by the invention comprise the deuterated compound and the pharmaceutically acceptable salt thereof as active ingredients and pharmaceutically acceptable carriers.
The deuterated compound and the pharmaceutical composition of the pharmaceutically acceptable salt thereof are selected from capsules, powder, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories or patches.
The beneficial effects are that: compared with the prior art, the invention has the following advantages:
the invention provides deuterated compounds and pharmaceutically acceptable salts thereof, which further improve the pharmacokinetic properties of KRAS inhibitors and reduce the dosage and possible toxic and side effects.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 1
Synthesis method
Intermediate 1 can be prepared by reference to example 1a of patent WO2021120890 A1;
synthesis of intermediate 2
To a solution of 0.626g of intermediate 1 (1 mmol) in N, N-dimethylformamide (10 mL) was added potassium hydroxide (4 mmol,4 eq) and elemental iodine (2 mmol,2 eq), the reaction was completed at room temperature for 3 hours, TLC was monitored, saturated sodium sulfite was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (10 ml x 2), washed with water (20 ml x 2), dried over anhydrous sodium sulfate with saturated salt (20 mL) water, and column chromatography was concentrated to give 0.544g of intermediate 2 in 62% yield.
Synthesis of intermediate 3
Sodium acetate (1 mmol,2 eq) was added to 0.44g of intermediate 2 (0.5 mmol) in deuterated acetic acid (8 mL), the reaction was completed for 2 hours, room temperature was carried out for 24 hours, TLC detection was complete, concentration was performed under reduced pressure, and column chromatography gave 0.25g of intermediate 3 in 79% yield.
Example 1 Synthesis of Compounds
0.25g of intermediate 3 (0.4 mmol) was added to dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added dropwise thereto, the reaction was completed by TLC at room temperature for 2 hours, and the compound of example 1 was obtained in a yield of 0.16g and 77% by HPLC purification after filtration and concentration under reduced pressure. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.6 (s, 1H), 7.52 (s, 1H), 7.47 - 7.39 (m, 2H), 7.25 (d, 1H), 6.39- 6.32 (m, 1H), 6.21 - 6.18 (m, 1H), 5.87 - 5.81 (m, 1H), 4.77 - 4.70 (m, 1H), 4.47 (s, 1 H), 4.33 (s, 1 H), 4.08 (s, 1H), 4.01 (s, 1 H), 3.99 (s, 3H), 2.93-2.81 (m, 2H), 2.80-2.68 (m, 2H), 2.40 (s, 3H), 2.09 (s, 3H).
Example 2
Synthesis method of example 2
Intermediate 6 is prepared from intermediate 1 as starting material by reference to the synthesis of intermediate 3.
Intermediate 7,8 can be prepared by reference to the synthetic route of example 1a of patent WO2021120890 A1.
0.125g of intermediate 8 (0.2 mmol) was added to dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added dropwise, the reaction was completed by TLC at room temperature for 2 hours, and the mixture was filtered and concentrated under reduced pressure. HPLC purification produced 0.056g of example 2 compound in 53% yield. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.0 (s, 1H), 7.70 (s, 1H), 7.51 - 7.41 (m, 3H), 7.24 (d, 1H), 6.44 - 6.38 (m, 1H), 6.19 - 6.16 (m, 1H), 5.85 - 5.81 (m, 1H), 4.79 - 4.71 (m, 1H), 4.46 (s, 1 H), 4.32 (s, 1 H), 4.08 (s, 1H), 4.01 (s, 1 H), 3.98 (s, 3H), 2.93 - 2.82 (m, 2H), 2.77 - 2.68 (m, 2H), 2.40 (s, 3H), 2.09 (s, 3H).
Example 3
Synthesis method of example 3
With reference to the synthetic procedure of example 2, HPLC purification afforded example 3 in 49% yield. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.2 (s, 1H), 7.58 (s, 1H), 7.49 - 7.41 (m, 3H), 7.24 (d, 1H), 6.37 - 6.29 (m, 1H), 6.20 - 6.13 (m, 1H), 5.84 - 5.80 (m, 1H), 4.77 - 4.71 (m, 1H), 4.47 (s, 1 H), 4.33 (s, 1 H), 4.08 (s, 1H), 4.00 (s, 1 H), 3.97 (s, 3H), 2.98 - 2.84 (m, 2H), 2.82 - 2.69 (m, 2H), 2.40 (s, 3H), 2.09 (s, 3H).
Test example 1: KRAS G12C Inhibition Activity test
Reagent and consumable
Name supplier number
Reagent KRASG12C, available from Cisbio under the trade designation: 63ADK000CB16PEG;
reagent 384-well plate, available from Perkin Elmer under the designation: 6007290.
(II) instruments
Centrifuge (manufacturer: eppendorf type 5430)
Enzyme label instrument (manufacturer: perkin Elmer, model: enVision)
(III) Experimental methods
The test example 1-3 and the control (Nohua JDQ-443) were each formulated with DMSO, diluted in proportion and added to 384 wells, a 4-fold final concentration of Tag1-SOS1 solution was formulated with a volume buffer, 2.5. Mu.L of a 4-fold final concentration of Tag1-SOS1 solution was added to 384 wells, a 4-fold final concentration of Tag2-KRAS-G12C solution was formulated with a volume buffer, centrifuged at 1000rpm for 30 seconds in 384 wells, and incubated at room temperature for 15 minutes after shaking. A1-fold final concentration of Anti-Tag1-Tb3+ solution and a 1-fold final concentration of Anti-Tag2-XL665 solution were prepared with a Detection buffer, and after mixing, 5. Mu.L was added to each well. The 384-well plate is centrifuged at 1000rpm for 30 seconds, and after shaking uniformly, incubated for 2 hours at room temperature, and read by an enzyme-labeled instrument, em665/620.
TABLE 1 KRAS G12C Inhibitory Activity test results
| Compounds of formula (I) | KRAS G12C IC 50 (nM) |
| Example 1 | 7.2 |
| Example 2 | 5.5 |
| Example 3 | 10 |
| JDQ-443 | 17 |
The example compounds all showed excellent KRAS G12C The inhibitor activity was nearly twice as high as that of the compound of example 2, and the activity gain was remarkable as compared with the positive drug JDQ-443.
Test example 2: pharmacokinetic experiments of Compounds
Experimental apparatus and materials
The high-speed refrigerated centrifuge, vortex shaker (Vortex Genius 3), high-speed centrifuge (Eppendorf 5415D), disposable syringe, pipette (Eppendorf), SD male rats used in the experiments were all purchased from university of dulcimer, EDTA-K2 vacuum blood collection tube, physiological saline. All oral rats were fasted for 12 hours prior to dosing, were free to drink water, and were fed freely during dosing.
(II) Experimental procedure
The compound of example 1 and JDQ-443 were dissolved using DMSO/solvent/water (10/10/80), respectively, to prepare clear solutions, and the dose of the compound administered by gavage was 25 mg/kg, and the dose of the compound administered by tail vein was 5 mg/kg. 2 min, 10 min, 30 min, 1 h, 2h, 3 h, 5 h, 8 h, 12h, 16 h, 24 h following tail vein administration, 0.5mL blood was continuously drawn from the fundus venous plexus into heparin tubes, 5min, 15min, 30 min, 1 h, 2h, 3 h, 5 h, 8 h, 12h, 16 h, 24 h blood was continuously drawn from the fundus venous plexus into 0.5mL heparin tubes following intragastric administration. After centrifugation of the sample at 8000 r for 10 min at 4℃the upper plasma layer was taken and stored at-20℃for 0.15. 0.15 mL, after which LC-MS/MS analysis was performed. The data were analyzed by the WinNolin non-compartmental model to obtain key pharmacokinetic parameters.
(III) results of experiments
TABLE 2 pharmacokinetic parameters
Compared with the positive drug JDQ-443, the half-life period of the oral administration of the embodiment 1 is doubled, the peak concentration is doubled, the oral bioavailability is obviously improved, and the administration dosage of the JDQ-443 can be effectively improved, so that the toxic and side effects of the high-dosage JDQ-443 are reduced.
Finally, it should be noted that the above describes in detail specific embodiments of the invention, but is only exemplary and the invention is not limited to the above described specific embodiments. Any equivalent modifications and substitutions for the present invention will occur to those skilled in the art, and are also within the scope of the present invention. Accordingly, equivalent changes and modifications are intended to be included within the scope of the present invention without departing from the spirit and scope thereof.
Claims (6)
1. Deuterated compound of KRAS inhibitor shown in formula I and pharmaceutically acceptable salt thereof,
;
wherein R is 1 ，R 2 Independently selected from hydrogen or deuterium, and R 1 ，R 2 Except for hydrogen.
2. The deuterated compound and pharmaceutically acceptable salts thereof according to claim 1 wherein the compound is selected from the following structures:
。
3. deuterated compound according to claim 1 and pharmaceutically acceptable salts thereof characterized in that the pharmaceutically acceptable salts are selected from the group consisting of methanesulfonates, maleates, hydrochlorides or phosphates.
4. Use of the deuterated compound and pharmaceutically acceptable salts thereof according to claim 1 in the preparation of an anti-tumor medicament.
5. The pharmaceutical composition of deuterated compound and pharmaceutically acceptable salts thereof according to claim 1, wherein the pharmaceutical composition consists of the deuterated compound and pharmaceutically acceptable salts thereof as an active ingredient and a pharmaceutically acceptable carrier.
6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is selected from the group consisting of capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories, and patches.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310727689.7A CN116478141B (en) | 2023-06-20 | 2023-06-20 | Deuterated KRAS inhibitor drug and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310727689.7A CN116478141B (en) | 2023-06-20 | 2023-06-20 | Deuterated KRAS inhibitor drug and application thereof |
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| Publication Number | Publication Date |
|---|---|
| CN116478141A true CN116478141A (en) | 2023-07-25 |
| CN116478141B CN116478141B (en) | 2023-10-24 |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107207474A (en) * | 2014-12-11 | 2017-09-26 | 齐尼思表观遗传学有限公司 | Substituted heterocycle is used as bromine domain inhibitor |
| CN108026046A (en) * | 2015-07-22 | 2018-05-11 | 亚瑞克西斯制药公司 | The purposes of substituted quinazoline compound and its inhibitor as G12C mutant KRAS, HRAS and/or NRAS protein |
| US20190144444A1 (en) * | 2017-11-15 | 2019-05-16 | Mirati Therapeutics, Inc. | Kras g12c inhibitors |
| WO2022157629A1 (en) * | 2021-01-19 | 2022-07-28 | Lupin Limited | Pharmaceutical combinations of sos1 inhibitors for treating and/or preventing cancer |
| CN114929342A (en) * | 2019-12-20 | 2022-08-19 | 诺华股份有限公司 | Pyrazolyl derivatives as anticancer agents |
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