CN110305138B - Compound for treating cancer and application thereof - Google Patents
Compound for treating cancer and application thereof Download PDFInfo
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- CN110305138B CN110305138B CN201910234144.6A CN201910234144A CN110305138B CN 110305138 B CN110305138 B CN 110305138B CN 201910234144 A CN201910234144 A CN 201910234144A CN 110305138 B CN110305138 B CN 110305138B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
A compound represented by formula I, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof: r1‑R20Each independently selected from hydrogen and deuterium. The compounds and salts, hydrates or solvates thereof provided by the invention have anticancer activity and better metabolic stability. Especially has obvious curative effect on NTRK fusion mutation cancer.
Description
Technical Field
The invention relates to a compound for treating cancer and application thereof.
Background
Cancer is a general term for a large group of malignant tumors. Cancer cells are characterized by unlimited and endless proliferation, so that nutrients in a patient body are greatly consumed; the cancer cells release various toxins, so that a series of symptoms are produced by a human body; cancer cells can also be transferred to all parts of the body to grow and reproduce, which causes emaciation, weakness, anemia, inappetence, fever, serious organ function impairment and the like. Therefore, it is very important to develop a new drug capable of effectively treating cancer.
Larotrectinib (LOXO-101) is a potent, oral, selective Tyrosine Receptor Kinase (TRK) inhibitor having the structural formula:
is the first oral targeted medicine for various tumors, and has better curative effect on patients with various tumors in all ages.
Deuterated drugs refer to replacement of a portion of the hydrogen atoms in a drug molecule with deuterium. Because deuterium is close to hydrogen in shape and volume in a drug molecule, deuterated drugs generally retain the biological activity and selectivity of the original drug. Because the C-D bond is more stable than the C-H bond, the C-D bond is less prone to break and the half-life period of the deuterated drug is prolonged in the chemical reaction process.
However, due to the complex metabolic processes of biological systems, the pharmacokinetic properties of drugs in the body are influenced by various factors and show corresponding complexity. The change in pharmacokinetic properties of deuterated drugs represents a great chance and unpredictability compared to corresponding non-deuterated drugs. Deuteration at some sites, not only does not prolong half-life, but may shorten it (Scott l. harbeson, Roger d. tung. deuterium in Drug Discovery and Development, P405-406.), deteriorating its pharmacokinetic properties; on the other hand, hydrogen at some positions on a drug molecule is also not easily deuterated due to steric hindrance and the like, so that the deuteration of the drug is not random and a site capable of deuteration is unpredictable.
The invention expects to obtain a class of deuterated drugs of metabolites with good pharmacokinetic properties, reduced dosage and reduced toxic and side effects by carrying out deuteration on the Larotrectinib compound.
Disclosure of Invention
The invention aims to provide a compound for treating cancer and application thereof.
The invention firstly provides a compound shown in formula I, or an optical isomer, or a pharmaceutically acceptable salt, or a hydrate, or a solvate thereof:
wherein R is1-R20Each independently selected from hydrogen and deuterium.
Further, the compound of formula I has the structure shown in formula II:
further, the compound of formula I has the structure shown in formula III:
further, the compound of formula I has the structure shown in formula IV:
further, the compound of formula I has the structure shown in formula V:
wherein R is1，R2，R4-R20Each independently selected from hydrogen and deuterium.
Further, the compound of formula V has the structure of formula VI:
further, the compound is selected from the following compounds:
further, the pharmaceutically acceptable salt is a phosphate, a d-camphorsulfonate, a hydrochloride, a hydrobromide, a hydrofluoride, a sulfate, a nitrate, a formate, an acetate, a propionate, an oxalate, a malonate, a succinate, a fumarate, a maleate, a lactate, a malate, a tartrate, a citrate, a picrate, a methanesulfonate, a benzylsulfonate, a benzenesulfonate, an aspartate or a glutamate of the compound, preferably a sulfate.
The invention also provides application of the compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof in preparing a medicament for treating cancer.
Further, the medicament is a medicament for treating cancer with NTRK gene fusion.
Further, the cancer is salivary gland cancer, sarcoma, infant fibrosarcoma, lung cancer, thyroid cancer, colon cancer, melanoma, cholangiocarcinoma, gastrointestinal stromal tumor, renal cancer, bladder cancer or stomach cancer.
The invention also provides application of the compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof in preparing a TRK inhibitor.
The invention also provides an antitumor drug which is a preparation prepared by taking the compound, or the optical isomer, or the pharmaceutically acceptable salt, or the hydrate, or the solvate as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
As used herein, "deuterated" refers to a compound or group in which one or more hydrogens are replaced with deuterium. Deuterium can be mono-, di-, poly-, or fully substituted. In another preferred embodiment, the deuterium isotope content of deuterium at the deuterium substitution position is greater than the natural deuterium isotope content (0.015%), more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably greater than 97%, more preferably greater than 99%, more preferably greater than 99.5%. In the compounds of the present invention, D represents deuterium.
Active ingredient
As used herein, the term "compounds of the invention" refers to compounds of formula I. The term also includes various optical isomers, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.
As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed by reacting a compound of the present invention with an acid. Suitable acids for forming the salts include, but are not limited to:
phosphoric acid, d-camphorsulfonic acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, aspartic acid, or glutamic acid.
Further, the acid that forms a pharmaceutically acceptable salt is sulfuric acid.
Pharmaceutically acceptable auxiliary materials
The pharmaceutically acceptable auxiliary material has certain physiological activity, but the addition of the component does not change the dominance of the medicinal composition in the process of treating diseases, but only plays an auxiliary effect, and the auxiliary effects are only the utilization of the known activity of the component and are auxiliary treatment modes which are commonly used in the field of medicine. If the auxiliary components are used in combination with the pharmaceutical composition of the present invention, the protection scope of the present invention should still be included.
The compounds and salts, hydrates or solvates thereof provided by the invention have anticancer activity and better metabolic stability. Especially has obvious curative effect on NTRK fusion mutation cancer.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
General synthetic route:
example 1: synthesis of N- (5- ((R) -2- (2, 5-difluorophenyl) pyrrol-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3-hydroxy-3 deuterium-pyrrolyl-1-amide (2)
The first step is as follows: 1-Boc-3-hydroxy-3-deuteropyrrole (2-1)
1-tert-Butoxycarbonyl-3-pyrrolidone (1.0g,5.40mmol) was dissolved in 10mL of dichloromethane under nitrogen, and lithium aluminum tetradeuteride (339.0mg,8.10mmol) was added in portions under an ice-water bath. Stirring for 2h under ice-water bath. The reaction was quenched slowly by dropwise addition of methanol, 0.5mL of 15% NaOH was added, and the mixture was dried over anhydrous sodium sulfate, spun-dried, and purified by silica gel column chromatography. 1-Boc-3-hydroxy-3-deuteropyrrole was obtained as an oily liquid (850.0mg,4.49 mmol). Yield: 83.2 percent. MS (ESI) M/e133.1(M-55)+。
The second step is that: 3-hydroxy-3-deuteropyrrole (2-2)
1-Boc-3-hydroxy-3-deuterium pyrrolidine (400.0mg,2.12mmol) was dissolved in 2mL of dichloromethane and 2mL of trifluoroacetic acid was added. Stir at room temperature for 1 h. The solvent was concentrated in vacuo to give crude 3-hydroxy-3-deuteropyrrole trifluoroacetate (250.0mg,2.12mmol) which was used directly in the next reaction. Yield: 100.0 percent.
In the third step, N- (5- ((R) -2- (2, 5-difluorophenyl) pyrrol-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3-hydroxy-3 deuterium-pyrrolyl-1-amide (2)
Reacting (R) -5- (2- (2, 5-difluorophenyl) pyrrole-1-yl) pyrazole [1, 5-alpha]Pyrimidine-3-amino (2-3) (100.0mg,0.32mmol) and N, N' -Carbonyldiimidazole (CDI) (77.1mg,0.48mmol) were added to 3mL of dichloromethane, and stirred at room temperature for 2 h. Triethylamine (96.2mg,0.96mmol) and 3-hydroxy-3-deuteropyrrole trifluoroacetate (55.0mg,0.64mmol) were dissolved in 1mL of dichloromethane and added to the reaction solution, which was stirred at room temperature for 1 h. Concentrating the solvent in vacuum, purifying by silica gel column chromatography to obtain white solid N- (5- ((R) -2- (2, 5-difluorophenyl) pyrrole-1-yl) pyrazole [1,5-a]Pyrimidin-3-yl) -3-hydroxy-3 deuterium-pyrrole-1-amide (105.0mg,0.25 mmol). Yield: 73.6 percent. MS (ESI) M/e 430.1(M + H)+。
1H NMR(400MHz,DMSO-d6)δ8.50(s,1H),7.81(s,1H),7.28(s,1H),7.13(s,1H),6.93(s,1H),6.44–5.83(m,1H),5.37(s,1H),4.95(s,1H),3.95(d,J＝4.5Hz,1H),3.69(s,1H),3.40(d,J＝8.6Hz,2H),3.24(d,J＝10.6Hz,1H),2.50(s,2H),2.19–1.53(m,4H)。
Example 2: preparation of (S) -N-5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5- α ] pyrimidin-3-yl) -3-hydroxypyrrolidine-1-carboxamide (3) and (R) -N-5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5- α ] pyrimidin-3-yl) -3-hydroxypyrrolidine-1-carboxamide (4)
Compound 2(297mg) was isolated by chiral preparative HPLC to give compound 3(121mg, ee-99.7%) and compound 4. Chiral separation conditions: Prep-HPLC equipment, Prep-HPLC-Gilson; chiral column: ART Cellulose-SB chiral column, 2cm × 25cm, 5 um; mobile phase: hex: EtOH 80: 20; the temperature is 25 ℃; the flow rate was 20 ml/min. Compound 3 MS (ESI) M/e 430.1(M + H)+.1H NMR(400MHz,CDCl3)δ8.24(s,1H),8.13(s,1H),7.11–6.98(m,1H),6.92(s,1H),6.74(s,1H),5.94(s,1H),5.29(s,1H),3.89(d,J＝5.1Hz,1H),3.71(d,J＝8.3Hz,1H),3.57(s,3H),2.47(dd,J＝10.3,6.7Hz,2H),2.10–1.92(m,4H)。
Compound 4 MS (ESI) M/e 430.1(M + H)+.1H NMR(400MHz,CDCl3)δ8.28(s,1H),8.16(s,1H),7.04(d,J＝12.0Hz,1H),6.92(s,1H),6.76(s,1H),6.15–5.78(m,1H),5.54–5.20(m,1H),3.93(s,1H),3.83–3.45(m,4H),2.49(s,1H),2.32(s,2H),2.13–2.05(m,3H)。
The beneficial effects of the invention are verified by means of the test examples as follows:
test example 1 Metabolic stability test of Compound of the present invention
The invention detects half-life period t of mouse liver microsome and human liver microsome1/2The metabolic stability of the compounds of the invention was investigated. The detection method is based on a conventional detection method, and comprises the following key steps:
the first step is as follows: the mother solution was prepared according to the ingredient ratio of table 1 below:
TABLE 1 preparation of mother solutions
| Reagent | Concentration of | Volume of | Final concentration |
| Phosphate buffer | 200mM | 200μL | 100mM |
| High purity water | - | 106μL | - |
| MgCl2Solutions of | 50mM | 40μL | 5mM |
The second step is that: the following two experiments were performed separately:
A) reduced coenzyme II (NADPH): 10 μ L of liver microsomes at a concentration of 20mg/mL and 40 μ L of NADPH at a concentration of 10mM were added to the incubation experiments. The final concentrations of liver microsomes and NADPH were 0.5mg/mL and 1 mM.
B) Without addition of NADPH: 10 μ L of liver microsomes at a concentration of 20mg/mL and 40 μ L of high purity water were added to the incubation test. The final concentration of liver microsomes was 0.5 mg/mL.
The third step: the reaction started after the addition of 4. mu.L of a positive control at a concentration of 200. mu.M, or Compound 2 prepared in example 1 of the present invention or Compound 3 prepared in example 2. The positive control in this experiment was Larotrectinib. The final concentration of test compound was 2 μ M.
The fourth step: 50. mu.L of each was removed from the reaction solution at time points 0,15,30,45 and 60 minutes. To the reaction solution were added 4 volumes of acetonitrile and IS (alprazolam at 100nM concentration, labetall at 200nM concentration, caffeine at 200nM concentration and ketoprofen at 2. mu.M concentration). The sample was centrifuged at 3220 g for 40 minutes. mu.L of the supernatant was added to 100. mu.L of high purity water and analyzed by LC-MS/MS.
The fifth step: and (3) data analysis: peak areas were determined from the extracted ion chromatograms. The slope value k is determined by linear regression of the remaining percentage of parent drug versus the natural logarithm of the incubation time curve.
Half life in vitro (in vitro t)1/2) Determined by the slope value: in vitro t1/2＝-(0.693/k)
Intrinsic clearance in vitro (in vitro CL)intIn μ L/min/mg) from the in vitro half-life t using the following equation (mean of repeated determinations)1/2Conversion in (minutes):
amplification of intrinsic clearance (Scale up CL)intIn mL/min/kg) from in vitro t by using the following formula (average of repeated measurements)1/2Conversion in (minutes):
the results of the mouse and human liver microsome metabolic stability experiments are shown in table 2:
TABLE 2 results of metabolic stability experiments on mouse and human liver microsomes
Larotrectinib is a new antitumor drug developed by Loxo Oncology corporation in the United states and aiming at NTRK fusion, and is currently on the market. The data in table 2 show that the compounds of the invention have significantly improved metabolic stability in liver microsomes compared to the reference compound, larorecetiib, indicating that the compounds of the invention are highly likely to have better clinical pharmacokinetics.
The compounds and salts, hydrates or solvates thereof provided by the invention have anticancer activity and better metabolic stability, especially have obvious curative effect on NTRK fusion mutation cancers, and have good application prospect.
Claims (8)
1. A compound, or a pharmaceutically acceptable salt thereof, characterized by: the compound is selected from the following compounds:
2. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: the pharmaceutically acceptable salt is phosphate, d-camphorsulfonate, hydrochloride, hydrobromide, hydrofluoride, sulfate, nitrate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, methanesulfonate, toluenesulfonate, benzenesulfonate, aspartate or glutamate of the compound.
3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein: the pharmaceutically acceptable salt is a sulfate salt of the compound.
4. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
5. Use according to claim 4, characterized in that: the medicament is a medicament for treating cancer with NTRK gene fusion.
6. Use according to claim 5, characterized in that: the cancer is salivary gland cancer, infantile fibrosarcoma, lung cancer, thyroid cancer, colon cancer, melanoma, cholangiocarcinoma, renal cancer, bladder cancer or gastric cancer.
7. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the preparation of a TRK inhibitor.
8. An antitumor agent characterized by: the compound or the pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 is used as an active ingredient, and a pharmaceutically acceptable auxiliary material is added to prepare the preparation.
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| CN111138437B (en) * | 2019-12-04 | 2021-03-05 | 杭州华东医药集团新药研究院有限公司 | Substituted pyrazolo [1,5-a ] pyrimidine amino acid derivatives and uses thereof |
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| CN102264736A (en) * | 2008-10-22 | 2011-11-30 | 阵列生物制药公司 | Substituted pyrazolo[1,5-a]pyrimidine compounds as trk kinase inhibitors |
| CN104211683A (en) * | 2013-05-29 | 2014-12-17 | 成都海创药业有限公司 | Imidazoldione compound and use thereof |
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