CN110305138A - A kind of compound for the treatment of cancer and application thereof - Google Patents

A kind of compound for the treatment of cancer and application thereof Download PDF

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Publication number
CN110305138A
CN110305138A CN201910234144.6A CN201910234144A CN110305138A CN 110305138 A CN110305138 A CN 110305138A CN 201910234144 A CN201910234144 A CN 201910234144A CN 110305138 A CN110305138 A CN 110305138A
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compound
pharmaceutically acceptable
acceptable salt
solvate
formula
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CN110305138B (en
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杜武
温坤
李兴海
陈元伟
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Hinova Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

Compound shown in formula I or its optical isomer or its pharmaceutically acceptable salt or its hydrate or its solvate: R1‑R20It is respectively and independently selected from hydrogen, deuterium.Various compounds and its esters, hydrate or solvate provided by the invention, have anticancer activity and better metabolic stability.Especially there is significant curative effect to the cancer of NTRK fusion mutation.

Description

A kind of compound for the treatment of cancer and application thereof
Technical field
The present invention relates to compounds of a kind for the treatment of cancer and application thereof.
Background technique
Cancer is the general designation of a major class malignant tumour.The characteristics of cancer cell is to make patient's body without limitation, without end hyperplasia Interior nutriment is largely consumed；Cancer cell releases a variety of toxin, and human body is made to generate a series of symptoms；Cancer cell can also turn Move on to whole body growth and breeding everywhere, cause human body syntexis, inability, anaemia, loss of appetite, fever and serious organ function by Damage etc..Therefore, a kind of new drug for capableing of effective treating cancer is researched and developed, it appears particularly important.
Larotrectinib (LOXO-101) is a kind of potent, oral, selective tyrosine receptor kinase (TRK) inhibition Agent, structural formula are as follows:That first kinds of tumors takes orally targeted drug, for each age group and The curative effect of kinds of tumors patient is preferable.
Deuterated drug, which refers to, replaces with deuterium for the part hydrogen atom in drug molecule.Due to deuterium in drug molecule shape and Volume and hydrogen are close, and deuterated drug can generally retain the bioactivity and selectivity of original drug.More than c h bond due to C-D key Stablize, so that deuterated drug, in chemical reaction process, the more difficult fracture of C-D key, half-life period can extend.
But due to the metabolic process of biosystem complexity, the pharmacokinetic property of drug in vivo is by more Aspect factor influences, and also shows corresponding complexity.Compared with corresponding non-deuterated drug, deuterated drug pharmacokinetics The variation of matter shows great contingency and unpredictability.Not only the deuterated of certain sites cannot extend half-life period, instead It may be made to shorten (Scott L.Harbeson, Roger D.Tung.Deuterium in Drug Discovery and Development, P405-406.), deteriorate its pharmacokinetic property；On the other hand, on drug molecule certain positions hydrogen because Also be not easy for reasons such as steric hindrances it is deuterated, therefore, drug it is deuterated not follow one's bent, can deuterated site be can not be pre- Phase.
Present invention contemplates that it is deuterated by being carried out to Larotrectinib compound, it is good to obtain a kind of pharmacokinetic property Good, reduction dosage, reduces the deuterated drug of the metabolite of toxic side effect.
Summary of the invention
The purpose of the present invention is to provide compounds of a kind for the treatment of cancer and application thereof.
Present invention firstly provides Formulas I compound represented or its optical isomer or its pharmaceutically acceptable salt, Or its hydrate or its solvate:
Wherein, R1-R20It is respectively and independently selected from hydrogen, deuterium.
Further, the compound of formula I has structure shown in Formula II:
Further, the compound of formula I has structure shown in formula III:
Further, the compound of formula I has structure shown in formula IV:
Further, the compound of formula I has structure shown in Formula V:
Wherein, R1, R2, R4-R20It is respectively and independently selected from hydrogen, deuterium.
Further, the Formula V compound has structure shown in Formula IV:
Further, the compound is selected from following compounds:
Further, the pharmaceutically acceptable salt is phosphate, the d-camphorsulfonic acid salt of the compound, hydrochloric acid Salt, hydrobromate, hydrofluoride, sulfate, nitrate, formates, acetate, propionate, oxalates, malonate, amber Hydrochlorate, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, mesylate, benzene Mesylate, benzene sulfonate, aspartate or glutamate, preferably sulfate.
The present invention also provides above compound or its optical isomer or its pharmaceutically acceptable salt or its hydrations The purposes of object or its solvate in the drug of preparation treating cancer.
Further, the drug is the drug for the cancer that treatment has NTRK Gene Fusion.
Further, the cancer be salivary-gland carcinoma, sarcoma, infantilism fibrosarcoma, lung cancer, thyroid cancer, colon cancer, Melanoma, cholangiocarcinoma, gastrointestinal stromal tumor, kidney, bladder cancer or gastric cancer.
The present invention also provides above compound or its optical isomer or its pharmaceutically acceptable salt or its hydrations Object or its solvate are preparing the purposes in TRK inhibitor.
The present invention also provides a kind of anti-tumor drugs, it is with above-mentioned compound or its optical isomer or its medicine Acceptable salt or its hydrate or its solvate are active constituent on, along with prepared by pharmaceutically acceptable auxiliary material Made of preparation.
As used herein, " deuterated " refers to one or more hydrogen in compound or group replaced deuterium.It is deuterated to can be One replaces, two replace, polysubstituted or full substitution.In another preferred example, deuterium is big in the deuterium isotopic content of deuterium the position of substitution In natural deuterium isotopic content (0.015%), even more preferably greater than 50%, even more preferably greater than 75%, even more preferably greater than 95%, more preferably Ground is greater than 97%, even more preferably greater than 99%, even more preferably greater than 99.5%.In the compounds of this invention, D is expressed as deuterium.
Active constituent
As used herein, term " the compounds of this invention " refers to Formulas I compound represented.The term further includes and Formulas I chemical combination Various optical isomers, pharmaceutically acceptable salt, hydrate or the solvate of object.
As used herein, term " pharmaceutically acceptable salt " refers to that the compounds of this invention and acid or alkali are formed by suitable use Make the salt of drug.Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferred salt is the compounds of this invention and acid The salt of formation.The acid for suitably forming salt includes but is 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, third Diacid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzene methanesulfonic acid, benzene Sulfonic acid, aspartic acid or glutamic acid.
Further, the acid for forming pharmaceutically acceptable salt is sulfuric acid.
Pharmaceutically acceptable auxiliary material
The pharmaceutically acceptable auxiliary material, it have certain physiological activity, but the addition of the ingredient will not change it is above-mentioned The leading position of pharmaceutical composition in the course of disease treatment, and auxiliary effect is only played, these auxiliary effects are only pair The utilization of the ingredient known activity is the usual adjuvant treatment modality of field of medicaments.If by above-mentioned complementary ingredient and the present invention Pharmaceutical composition is used cooperatively, and still should belong to the scope of protection of the invention.
Various compounds and its esters, hydrate or solvate provided by the invention, have anticancer activity and preferably Metabolic stability.Especially there is significant curative effect to the cancer of NTRK fusion mutation.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention The technology realized all belongs to the scope of the present invention.
Specific embodiment
General synthetic routes:
Embodiment 1:N- (5- ((R) -2- (2,5- difluorophenyl) pyrroles -1- base) pyrazoles [1,5-a] pyrimidin-3-yl) -3- The synthesis of -3 deuteriums of hydroxyl-pyrrole radicals -1- amide (2)
Step 1: 1-Boc-3- hydroxyl -3- deuterium pyrroles (2-1)
Under nitrogen protection, 1- tertbutyloxycarbonyl -3- pyrrolidones (1.0g, 5.40mmol) is dissolved in 10mL methylene chloride In, under ice-water bath, four deuterium aluminium lithiums (339.0mg, 8.10mmol) are added portionwise.Under ice-water bath, 2h is stirred.Methanol is slowly added dropwise to quench It goes out reaction, the NaOH of 0.5mL15% is added, then is dry with anhydrous sodium sulfate, be spin-dried for, silica gel column chromatography purifying.Obtain oily liquid Body 1-Boc-3- hydroxyl -3- deuterium pyrroles (850.0mg, 4.49mmol).Yield: 83.2%.MS(ESI)m/e133.1(M-55)+。
Step 2: 3- hydroxyl -3- deuterium pyrroles (2-2)
1-Boc-3- hydroxyl -3- deuterium pyrrolidines (400.0mg, 2.12mmol) is dissolved in 2mL methylene chloride, 2mL tri- is added Fluoroacetic acid.1h is stirred at room temperature.Solvent in vacuo concentration, obtain crude product 3- hydroxyl -3- deuterium pyrroles trifluoroacetate (250.0mg, It 2.12mmol) is directly used in and reacts in next step.Yield: 100.0%.
Step 3: N- (5- ((R) -2- (2,5- difluorophenyl) pyrroles -1- base) pyrazoles [1,5-a] pyrimidin-3-yl) -3- hydroxyl - 3 deuteriums of base-pyrrole radicals -1- amide (2)
By (R) -5- (2- (2,5- difluorophenyl) pyrroles -1- base) pyrazoles [1,5- α] pyrimidine -3- amino (2-3) (100.0mg, 0.32mmol) and N, N'- carbonyl dimidazoles (CDI) (77.1mg, 0.48mmol) are added to 3mL methylene chloride, room Temperature stirring 2h.Triethylamine (96.2mg, 0.96mmol) and 3- hydroxyl -3- deuterium pyrroles trifluoroacetate (55.0mg, 0.64mmol) It is dissolved in 1mL methylene chloride to be added in reaction solution, 1h is stirred at room temperature.Solvent in vacuo concentration, silica gel column chromatography purifying, obtains white Solid N- (5- ((R) -2- (2,5- difluorophenyl) pyrroles -1- base) pyrazoles [1,5-a] pyrimidin-3-yl) -3 deuteriums of -3- hydroxyl-pyrrole Cough up -1- amide (105.0mg, 0.25mmol).Yield: 73.6%.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).
Embodiment 2:(S)-N-5- ((R) -2- (2,5- difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5- α] pyrimidine -3- Base) -3- hydroxyl pyrrolidine -1- formamide (3) and (R)-N-5- ((R) -2- (2,5- difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5- α] pyrimidin-3-yl) -3- hydroxyl pyrrolidine -1- formamide (4) preparation
The isolated compound 3 (121mg, ee=99.7%) of the chiral preparation HPLC of compound 2 (297mg) and chemical combination Object 4.Chiral separation condition: Prep-HPLC equipment: Prep-HPLC-Gilson；Chiral column: ART Cellulose-SB is chiral Column, 2cm × 25cm, 5um；Mobile phase: Hex:EtOH=80:20；Temperature: 25 DEG C；Flow velocity: 20ml/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)。
Beneficial effects of the present invention are verified with the mode of test example below:
The metabolic stability experiment of test example 1, the compounds of this invention
The present invention passes through detection Mouse Liver Microsomes and people's liver microsomal half-life t1/2Study the metabolism of the compounds of this invention Stability.For its detection method according to common detection methods, committed step is as follows:
Step 1: mother solution is prepared by the ingredient of following table 1 than column:
The preparation of table 1, mother solution
Reagent Concentration Volume Final concentration
Phosphate buffer 200mM 200μL 100mM
High purity water - 106μL -
MgCl2Solution 50mM 40μL 5mM
Step 2: carrying out following two experiments respectively:
A) add reduced Coenzyme II (NADPH): the hepatomicrosome and 40 μ L concentration that 10 μ L concentration are 20mg/mL are 10mM's NADPH is added in hatching test.The ultimate density of hepatomicrosome and NADPH are 0.5mg/mL and 1mM.
B the high purity water that hepatomicrosome and 40 μ L that NADPH:10 μ L concentration is 20mg/mL) is not added is added in hatching test. The ultimate density of hepatomicrosome is 0.5mg/mL.
Step 3: be added 4 μ L 200 μM of concentration positive control or the embodiment of the present invention 1 prepare compound 2 or It reacts and starts after compound 3 prepared by embodiment 2.Positive control in this experiment is Larotrectinib.Test compound Ultimate density be 2 μM.
Step 4: 0,15,30,45 and 60 minute time point by respectively taking out 50 μ L in reaction solution.Into reaction solution Be added 4 times of volumes acetonitrile and IS (labetalol of the alprazolam of 100nM concentration, 200nM concentration, 200nM concentration The ketoprofen of 2 μM of concentration of caffeine and).Sample is centrifuged 40 minutes under 3220 grammes per square metre power.100 μ L of supernatant 100 μ L high purity waters of middle addition are analyzed with LC-MS/MS.
Step 5: data are analyzed: determining peak area from the chromatography of ions figure of extraction.Slope value k passes through the surplus of parent drug The linear regression of remaining percentage and the natural logrithm of incubation time curve determines.
Vitro half-lives (external t1/2) determined by slope value: in vitro t1/2=-(0.693/k)
External inherence clearance rate (in vitro CLint, as unit of μ L/min/mg) and use following equation (replication Average value) by vitro half-lives t1/2(minute) conversion:
Amplify inherent clearance rate (Scale up CLint, as unit of mL/min/kg) and it (repeats to survey by using following formula Fixed average value) by external t1/2(minute) conversion:
Mouse and people's hepatomicrosome metabolic stability experimental result are shown in Table 2:
Table 2, mouse and people's hepatomicrosome metabolic stability experimental result
Larotrectinib is the anti-cancer agent for NTRK fusion of Loxo Oncology company, U.S. exploitation, mesh It is preceding to have listed.Data in table 2 show that metabolic stability of the compound of the present invention in hepatomicrosome compares reference compound Larorectinib is significantly increased, illustrate the compounds of this invention there is a strong possibility can to have preferably clinical medicine for power It learns.
Various compounds and its esters, hydrate or solvate provided by the invention, have anticancer activity and preferably Metabolic stability especially has significant curative effect to the cancer of NTRK fusion mutation, and application prospect is excellent.

Claims (13)

1. Formulas I compound represented or its optical isomer or its pharmaceutically acceptable salt or its hydrate or its solvent Close object:
Wherein, R1-R20It is respectively and independently selected from hydrogen, deuterium.
2. compound according to claim 1 or its optical isomer or its pharmaceutically acceptable salt or its hydration Object or its solvate, it is characterised in that: the compound of formula I has structure shown in Formula II:
3. compound according to claim 1 or its optical isomer or its pharmaceutically acceptable salt or its hydration Object or its solvate, it is characterised in that: the compound of formula I has structure shown in formula III:
4. compound according to claim 1 or its optical isomer or its pharmaceutically acceptable salt or its hydration Object or its solvate, it is characterised in that: the compound of formula I has structure shown in formula IV:
5. compound according to claim 1 or its optical isomer or its pharmaceutically acceptable salt or its hydration Object or its solvate, it is characterised in that: the compound of formula I has structure shown in Formula V:
Wherein, R1, R2, R4-R20It is respectively and independently selected from hydrogen, deuterium.
6. compound according to claim 5 or its optical isomer or its pharmaceutically acceptable salt or its hydration Object or its solvate, it is characterised in that: the Formula V compound has structure shown in Formula IV
7. compound according to claim 1 or its optical isomer or its pharmaceutically acceptable salt or its hydration Object or its solvate, it is characterised in that: the compound is selected from following compounds:
8. according to claim 1~7 described in any item compounds or its optical isomer or its pharmaceutically acceptable salt, Or its hydrate or its solvate, it is characterised in that: the pharmaceutically acceptable salt be the compound phosphate, D-camphorsulfonic acid salt, hydrochloride, hydrobromate, hydrofluoride, sulfate, nitrate, formates, acetate, propionate, grass Hydrochlorate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, hardship Sour salt, mesylate, benzene methanesulfonic acid salt, benzene sulfonate, aspartate or glutamate, preferably sulfate.
9. any one of claim 1~7 compound or its optical isomer or its pharmaceutically acceptable salt or its water Close the purposes of object or its solvate in the drug of preparation treating cancer.
10. purposes according to claim 9, it is characterised in that: the drug is the cancer that treatment has NTRK Gene Fusion Drug.
11. purposes according to claim 10, it is characterised in that: the cancer is salivary-gland carcinoma, sarcoma, baby's fiber type Sarcoma, lung cancer, thyroid cancer, colon cancer, melanoma, cholangiocarcinoma, gastrointestinal stromal tumor, kidney, bladder cancer or gastric cancer.
12. any one of claim 1~7 compound or its optical isomer or its pharmaceutically acceptable salt or its Hydrate or its solvate are preparing the purposes in TRK inhibitor.
13. a kind of anti-tumor drug, it is characterised in that: it is with the described in any item compounds of claim 1~7 or its light It learns isomers or its pharmaceutically acceptable salt or its hydrate or its solvate is active constituent, along with pharmaceutically The preparation that acceptable auxiliary material is prepared.
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