CN105712937B

CN105712937B - A kind of compound and application thereof for treating metastatic tumo(u)r

Info

Publication number: CN105712937B
Application number: CN201610106954.XA
Authority: CN
Inventors: 李健
Original assignee: Hebei Ningge Biomedical Technology Co Ltd
Current assignee: Hebei Ningge Biomedical Technology Co., Ltd.
Priority date: 2016-02-28
Filing date: 2016-02-28
Publication date: 2019-02-22
Anticipated expiration: 2036-02-28
Also published as: CN105712937A

Abstract

The invention discloses a kind of compound and application thereof for treating metastatic tumo(u)r, compounds shown in formula I, wherein R1-R8 is respectively and independently selected from the alkyl or part deuteroalkyl of H, D, C1-C3.The compound is a kind of new drug for treating metastatic tumo(u)r developed on the basis of veliparib structure, and the activity of PARP can be effectively suppressed.The compound can be used as the drug for the treatment of uterine cancer, lung cancer, gastric cancer, melanoma, breast cancer, prostate cancer, colon cancer or intracranial tumors.

Description

A kind of compound and application thereof for treating metastatic tumo(u)r

Technical field

The present invention relates to a kind of compounds and application thereof for treating metastatic tumo(u)r.

Background technique

Polyadenylic acid diphosphonic acid phosphoribosynltransferase (PARP) is the novel target spot for the treatment of cancer in recent years.PARP inhibitor is logical It crosses inhibition DNA of tumor cell injury repair, promote tumour cell that apoptosis occurs, so as to enhance radiotherapy and alkylating agent and platinum class The curative effect of chemotherapy.Attack is unfolded in " deadly defect " of this drug utilization hereditary breast cancer.This weakness is by being referred to as Caused by gene defect for " BRCA1 ", the ability that cancer cell repairs damaged dna is limited.Curative effect in addition to chemotherapeutic can be improved Outside, the patient that PARP inhibitor is mutated BRCA as single medicine is also effective.Patient gene's recombination function of BRCA mutation is scarce It loses, then inhibits the reparation of DNA by PARP inhibitor, then can kill tumour cell, concept clinical research by double action In have proven to this theoretical hypothesis.PARP inhibitor not only can produce synergistic effect with BRCA1 or BRCA2 mutation, it is also possible to There is also Synergistic killing effects for many also not found gene mutations.

Veliparib is the benzimidazoles compound of novel high selection inhibition PARP a kind of, and inside and outside experiment shows this Product have the significant inhibition active effect of PARP.It is swollen in treatment metastatic breast cancer, colon cancer, metastasis melanin tumor and brain Significant effect is obtained in terms of tumor, it is clinical to enter the III phase with the research that Temozolomide is combined treatment breast cancer.Perhaps Mostly novel veliparib is studied, and (for example, Xu Xiuchun, Shi Yu etc., novel PARP inhibitor veliparib is modern with application Drug and clinical, 2013,28 (1): 69-73.

But for the research of veliparib class drug also in the exploratory stage, therefore in the structure base of veliparib A kind of new drug that can effectively treat tumour is researched and developed on plinth, it is particularly important.

Summary of the invention

The object of the present invention is to provide a kind of compounds and application thereof for treating metastatic tumo(u)r.

The present invention provides Formulas I compound represented:

Formulas I

Wherein, R1-R8 is respectively and independently selected from the alkyl or part deuteroalkyl of H, D, C1-C3.

Further, the R1-R8 is respectively and independently selected from the alkyl or part deuteroalkyl of H, D, C1-C3.

Further, at least one in the R1-R8 is deuterium.

The present invention also provides purposes of the compound shown in Formulas I in preparation treatment metastatic tumo(u)r drug.

Further, the drug is PARP inhibitor class drug.

Further, the drug is the drug for treating uterine cancer, lung cancer, gastric cancer, melanoma or breast cancer.

Further, the drug is the drug for treating prostate cancer, colon cancer or intracranial tumors.

Specific embodiment

Below by specific embodiment, the present invention is further elaborated, but the present invention is not limited thereto.

Experimental method described in following embodiments is unless otherwise specified conventional method；The reagent and material, such as Without specified otherwise, commercially obtain.

The compound that the present invention treats metastatic tumo(u)r is selected from following any compound:

C1:

C2:

C3:

C4:

The synthesis of embodiment 1:2,3- diaminobenzene formamide

Into 500mL there-necked flask be added N,N-dimethylformamide (DMF) 80ml, 2,3- diaminobenzoic acid (9.1g, 60mmol), it stirs, thionyl chloride 10g is added dropwise in constant pressure funnel, and 30 DEG C are heated to after being added dropwise overnight, is then heated to 50 DEG C, ammonia aqueous solution 75g is added dropwise, reacts 3h, water 100ml is added, stirs 2h, is cooled to room temperature overnight, filtering product is used in combination 500ml water washing 5 times, 50ml isopropanol wash 1 time, room temperature in vacuo it is dry crude product 5.6g.Mass spectrum: 152.2(M+H⁺).

The synthesis of the deuterated benzamide of embodiment 2:2,3- diamino -5,6- two

Heavy water 20mL is added into 50ml Schlenk pipe, 2,3- diaminobenzene formamide 2g, saleratus 3g are added Palladium carbon 50mg, hydrogen substitution gas is three times.100 DEG C of heating water bath 72h, the reversed column column chromatographic purifying of alkalinity obtain target product 1.3g, yield 65%.Mass spectrum: 154.2(M+H⁺).

Embodiment 3: the synthesis of compound C1

The deuterated benzamide (1.6g, 10mmol) of 2,3- diamino -5,6- two is added into the there-necked flask of 100ml, adds 2- Methylimidazole (0.95g, 11mmol), sulphur powder (3.2g, 100mmol) stir 6h at 170 DEG C, methylene chloride are added after cooling 60ml dissolution, silica gel mixed sample concentration, silica gel chromatographic column, column chromatography for separation obtain target product 0.21g, yield 9%.Mass spectrum: 234.1(M+H⁺).¹H NMR (CD₃OD, 400 MHz, TMS): 7.82 (s,1H, Ph-H), 5.43 (s, 1H, Ph- H), 2.60 (m, 2H,-CH₂-), 2.52 (m, 2H,-CH₂-)。:

Embodiment 4: the synthesis of compound C2

The deuterated benzamide (1.6g, 10mmol) of 2,3- diamino -5,6- two is added into the there-necked flask of 100ml, adds 2- Two deuterated imidazoles (0.95g, 11mmol) of methyl -4,4-, sulphur powder (3.2g, 100mmol) stir 6h at 170 DEG C, are added after cooling Methylene chloride 60ml dissolution, silica gel mixed sample concentration, silica gel chromatographic column, column chromatography for separation obtain target product 0.18g, yield 7.6%.Mass spectrum: 236.2(M+H⁺).¹H NMR (CD₃OD, 400 MHz, TMS): 7.82 (s,1H, Ph-H) , 5.52 (s, 1H, Ph-H), 2.58 (m, 2H,-CH₂-)。

Embodiment 5: the synthesis of compound C3

The deuterated benzamide (1.6g, 10mmol) of 2,3- diamino -5,6- two is added into the there-necked flask of 100ml, is added The deuterated imidazoles (0.95g, 11mmol) of 2- methyl -4,4,5,5- four, sulphur powder (3.2g, 100mmol) stir 6h at 170 DEG C, cooling Methylene chloride 60ml dissolution, silica gel mixed sample concentration are added afterwards, silica gel chromatographic column, column chromatography for separation obtains target product 0.12g, receives Rate 5%.Mass spectrum: 238.2(M+H⁺).¹H NMR (CD₃OD, 400 MHz, TMS): 7.82 (s,1H, Ph-H), 5.45 (s, 1H, Ph-H)。

Embodiment 6: the synthesis of compound C4

2,3- diaminobenzene formyl (3.2g, 20mmol) is added into the there-necked flask of 100ml, methyl -4,4,5 2- are added, Tetra- deuterated imidazoles (0.95g, 11mmol) of 5-, sulphur powder (3.2g, 100mmol) stir 6h at 170 DEG C, dichloromethane are added after cooling Alkane 60ml dissolution, silica gel mixed sample concentration, silica gel chromatographic column, column chromatography for separation obtain target product 0.12g, yield 5%.Mass spectrum: 236.2(M+H⁺).¹H NMR (CD₃OD, 400 MHz, TMS): 7.95 (d, J = 8.8 Hz, 1H, Ph-H), 7.82 (t, J = 8.4 Hz , 1H, Ph-H), 7.63 (d, J = 8.8 Hz, 1H, =CH-), 5.72 (s, 1H, Ph- H)。

Purposes and its beneficial of the compound of the present invention in treatment metastatic tumo(u)r is illustrated below by way of experimental example Effect.

Experimental example a: the pharmacokinetics of the compounds of this invention

Rabbit 10, weight 1kg-1.5kg.Test preceding fasting for 24 hours, free water.Each testedization of stomach-filling 5mg/mg respectively Close object, compound with 5%DMSO, 5% Tween-80,90% 0.5%CMC-Na prepare, administered volume 10mL/kg.After administration 3h is unified to feed.After administration 0.25,0.5,1.0,2.0,4.0,6.0,12, and for 24 hours, each time point randomly selects 3 rabbits Son is placed in EDTA test tube at the time point set above in auricular vein extracting vein blood 0.5mL, 12000rpm centrifugation 10min, separated plasma are sealed in -20 DEG C of refrigerator-freezers.It goes 100 μ L serum into clean centrifuge tube with liquid-transfering gun, is added Acetonitrile (CH₃CN it) dilutes, and is centrifuged.Extracting centrifugal liquid detects drug concentration with LC-MS, the results are shown in Table 1.

Table 1 the result shows that, the peak concentration of drug of the compounds of this invention is high, drug absorption degree is preferable, eliminates half-life period and is better than The drug effect of clinical use can be improved in veliparib, reduces dosage rate.

Experimental example b: external activity experiment

It is being 8.0) 1mM DTT and 4 mM MgCl containing 50mM Tris(pH₂Enzyme assay is carried out in buffer solution. PARP is reacted comprising 1.5 μm of [3M]-NAD+ (1.6 μ Ci/mmol), 200nM biotin histone h1,200nM slDNA, and 1nM PARP or 4nM PARP-2 enzyme.SPA detection is carried out on 96 orifice plates added with 100 μ L reaction solutions.Contain PARP in 50uL With 50 μ L 2 × NAD+ substrate mixtures are added in 2 × enzyme solution mixture of DNA, reaction starts.150 μ L 1.5mM this first are added Amide reaction stops.170 μ L reaction terminating liquids are transferred on the coated flash plate of Streptavidin, are incubated 1 hour, use is miniature Plate scintillation counter counts.Ki data by under various concentration test-compound inhibiting rate curve determine.

The external activity of the compounds of this invention

It is concluded that the compound of the present invention has good rejection ability, wherein compound to PARP enzyme from table C2 is better than control drug Veliparib.

Comprehensive Experiment statistics indicate that, compound peak concentration of drug prepared by the present invention is high, drug absorption degree is preferable, can be used as PARP inhibitor has anti-tumor activity, especially has to metastatic gastric carcinoma, lung cancer, column gland cancer, colon cancer or intracranial tumors etc. good Good therapeutic activity, provides new selection for clinical application.

Claims

1. a kind of synthetic method for the compound for treating metastatic tumo(u)r, the compound in C2, C3, C4 compound one Kind, it is characterised in that: the synthetic method step of C2, C3, C4 compound are as follows: 1) 2,3- diamino -5,6-, bis- deuterated benzene The synthesis of formamide

Heavy water 20mL is added into 50ml Schlenk pipe, 2,3- diaminobenzene formamide 2g, saleratus 3g add palladium carbon 50mg, three times, 100 DEG C of heating water bath 72h, the reversed column column chromatographic purifying of alkalinity obtains target product 1.3g to hydrogen substitution gas, receives Rate 65%, mass spectrum: 154.2(M+H⁺)；2) synthesis of compound C2

2,3- diamino -5,6- bis- deuterated benzamide 1.6g, 10mmol are added into the there-necked flask of 100ml, adds methyl -4 2-, 4- bis- deuterated imidazoles 0.95g, 11mmol stirs 6h at 3.2g, 100mmol, 170 DEG C of sulphur powder, methylene chloride is added after cooling 60ml dissolution, silica gel mixed sample concentration, silica gel chromatographic column, column chromatography for separation obtain target product 0.18g, yield 7.6%, mass spectrum: 236.2(M+H⁺),¹H NMR (CD₃OD, 400 MHz, TMS): 7.82 (s,1H, Ph-H) , 5.52 (s, 1H, Ph- H), 2.58 (m, 2H,-CH₂-)；On connect 1) step, the synthetic method of compound C3 be,

2,3- diamino -5,6- bis- deuterated benzamide 1.6g, 10mmol are added into the there-necked flask of 100ml, 2- first is added Base -4,4,5,5- tetra- deuterated imidazoles 0.95g, 11mmol stir 6h at 3.2g, 100mmol, 170 DEG C of sulphur powder, are added after cooling Methylene chloride 60ml dissolution, silica gel mixed sample concentration, silica gel chromatographic column, column chromatography for separation obtain target product 0.12g, yield 5%, Mass spectrum: 238.2(M+H⁺),¹H NMR (CD₃OD, 400 MHz, TMS): 7.82 (s,1H, Ph-H), 5.45 (s, 1H, Ph-H)；The synthetic method of compound C4 is,

It is added 2,3- diaminobenzene formamide 3.2g, 20mmol into the there-necked flask of 100ml, is added 2- methyl -4,4,5,5- tetra- Deuterated imidazoles 0.95g, 11mmol, 6h is stirred at 3.2g, 100mmol, 170 DEG C of sulphur powder, and it is molten that methylene chloride 60ml is added after cooling Solution, silica gel mixed sample concentration, silica gel chromatographic column, column chromatography for separation obtain target product 0.12g, yield 5%, mass spectrum: 236.2(M+H⁺),¹H NMR (CD₃OD, 400 MHz, TMS): 7.95 (d, J = 8.8 Hz, 1H, Ph-H), 7.82 (t, J = 8.4 Hz , 1H, Ph-H), 7.63 (d, J = 8.8 Hz, 1H, =CH-), 5.72 (s, 1H, Ph-H)。