CN108976236B

CN108976236B - Deuterated PARP inhibitor, salt thereof, preparation method and application thereof

Info

Publication number: CN108976236B
Application number: CN201810933066.4A
Authority: CN
Inventors: 阳杨; 许慧; 邓泽平; 成佳; 陈芳军
Original assignee: Hunan Huateng Pharmaceutical Co Ltd
Current assignee: Hunan Huateng Pharmaceutical Co Ltd
Priority date: 2018-08-16
Filing date: 2018-08-16
Publication date: 2020-11-10
Anticipated expiration: 2038-08-16
Also published as: CN108976236A

Abstract

The invention provides a deuterated compound, a pharmaceutically acceptable salt thereof, a preparation method and application. The compound is a novel deuterated PARP inhibitor, the invention also provides a composition containing the deuterated PARP inhibitor, and the application of the compound or the composition as an anti-cancer drug. Pharmacokinetic experiments show that the deuterated compound provided by the invention obviously improves the blood concentration, prolongs the half life of the medicament, and prolongs the time for which the medicament stays in vivo, thereby achieving better curative effect.

Description

Deuterated PARP inhibitor, salt thereof, preparation method and application thereof

Technical Field

The invention belongs to the field of medicinal chemistry, and particularly relates to a novel deuterated PARP inhibitor, a salt thereof, a preparation method thereof, a composition containing the deuterated PARP inhibitor, and application of the compound or the composition as an anti-cancer drug.

Background

Currently, many drugs are limited in their use due to problems with poor properties of absorption, distribution, metabolism or excretion (ADME). Meanwhile, it is also a main reason for the failure of clinical development of drugs. Although the ADME properties of drugs can be improved to some extent by using formulation techniques and prodrug techniques, these approaches do not fundamentally alter the ADME properties of drugs. For example, the problem of fast metabolism is that the drug is not effective when entering the body due to fast metabolism, and is metabolized by the body, and even if the activity is higher, the drug cannot achieve the treatment effect. If the treatment effect is to be achieved, the dosage is increased to increase the blood concentration, so that the treatment cost is increased and more side effects are brought. Therefore, how to improve the metabolic stability of the drug by modifying or adjusting the structure, especially without affecting the activity, is an urgent problem to be solved.

Another limitation of ADME is that many drugs produce toxic metabolites in the body, which exposes the patient to toxic metabolites that are harmful to the body when administered.

Sometimes to modify this condition, a metabolic inhibitor may be introduced which is rapidly metabolized by the body, such as protease inhibitors useful in the treatment of HIV infection. The U.S. FDA recommends that ritonavir be used in combination with such drugs. Ritonavir is an inhibitor of the cytochrome P450 enzyme 3A4(CYP3A4), which is the major cause of metabolism (see Kempf, D.J.et. al., antibodies and chemotherapy,1997,41(3): 654-60). However, ritonavir not only causes side effects, but also increases the economic burden on HIV patients who would otherwise use "cocktail therapy", and increases in the amount of drug administered also decrease patient compliance. Similarly, the CYP2D6 inhibitor, quinidine, is used in combination with dextromethorphan to reduce the problem of rapid metabolism of dextromethorphan, but the side effects produced by quinidine significantly limit its therapeutic potential for use in combination with other drugs (see Wang, L et al, Clinical Pharmacology and Therapeutics,1994,56(6Pt 1): 659-67; or FDA's instructions for quinidine at its website www.accessdata.fda.gov).

One effective way to improve drug metabolism is to modify the drug with deuterium, the isotope of hydrogen.

Hydrogen has three isotopes: protium (a)¹H, Hydrogen, titanium), deuterium (²H, Deuterium) and tritium (³H, Tritium). Wherein deuterium (²H or D) is one of the most widely used isotopes, which is hydrogen (C) occurring in nature¹H protium), non-radioactive, was first discovered by urea in 1932 in water. The nucleus of deuterium consists of one seed and a proton, whereas hydrogen (protium) has only one proton. Deuterium is present in nature in an amount of about 0.015%, and a large amount of deuterium is currently separated from water in the form of deuterated water, and the content of deuterium can reach 99.9%. Deuterium-substituted water, also called deuterium oxide, is currently the most economical and readily available source of deuterium.

The deuterium-substituted drug is prepared by replacing hydrogen (H) in drug molecules with deuterium (D), wherein the substitution has little influence on the activity due to the slight difference between H and D, but because deuterium is heavier than hydrogen, the formed chemical bond is difficult to break, so that the deuterium-substituted drug has great influence on the drug metabolism, and particularly when the deuterium-substituted drug is positioned at a metabolic site, the drug substitution effect can be well improved, the side effect can be remarkably reduced, and the like. Research on deuterated drugs has been greatly developed since the reports on impurities from Science 1961 (Science 1961,133,102-104), among which companies such as Auspex, Concert, Deuteria/DeuterRx have achieved many good results on deuterated drugs. Dancing medications by Auspex: deuterated tetrabenazine (SD-809) changes metabolism through deuteration of an active site, so that the safety and the effectiveness of the medicament are improved, the probability of depression, drowsiness, insomnia and difficulty in sitting in clinical observation is very low, and due to the excellent clinical effect, Teva spends 32 billion of dollars in burdening the Teva. This event also makes the study of deuterated drugs a very interesting area (nat. rev. drug discov.2016,15, 219-) -221).

Deuterium isotopes and deuterated compounds thereof are widely applied in a plurality of research fields, the deuterated compounds can be used as internal standards for clinical drug analysis and can be used for researching pharmacokinetics, drug metabolic pathways and drug toxicology, and in recent years, the deuterated compounds can be developed as better drugs.

The method of deuteration is used for trying to reduce the metabolic rate of the drug, increase the half-life, or reduce the formation of harmful metabolites through deuteration. The increase of bond energy after deuteration can improve ADME property of the medicine, thereby improving the efficacy, safety and compliance of the medicine. Meanwhile, as the size and the shape of the deuterium atom are basically consistent with those of the hydrogen atom, the selectivity and the biochemical activity of the medicine cannot be changed after the hydrogen is replaced by the deuterium.

Poly (ADP-ribose) transferase (PARP), which functions to catalyze the transfer of ADP-ribose from nicotinamide adenine dinucleotide to various receptor proteins and to repair single stranded DNA by means of base excision repair, is a novel target for cancer treatment today. In tumor cells, when PARP activity is inhibited, DNA damage repair is prone to error, and as DNA damage increases, tumor cells die, thereby achieving the goal of treating tumors. The current research shows that (Hanwe et al, research progress of PARP inhibitor for tumor treatment, China New medicine journal, 2011, 20(12), 1086-.

Ruipab (Invitrogen name: Rucaparib; chemical name: 8-fluoro-1, 3,4, 5-tetrahydro-2- [4- [ (methylamino) methyl ] phenyl ] -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one) is a poly (ADP-ribose) transferase inhibitor used for single drug treatment of patients with advanced ovarian cancer who have BRCA gene mutations and have been treated by two or more chemotherapy regimens.

Currently, research on Riclpa is mainly focused on itself, such as intermediate preparation process research (e.g., Gunn, et al, synthetic research of poly (adenosine diphosphate ribose) polymerase inhibitor Riclpa, fine chemical intermediates, 2012, 42(5), 48-52) and pharmacological research (e.g., PARP and CHK inhibitors intercation to cause DNA damageand cell death in mammary cells, Cancer Biology & Therapy (2013),14(5), 458-465).

However, research on the analogs of Riclpabu is still poorly explored. Therefore, it is very important to develop a new drug for effectively treating cancer based on the structure of the Ruipab.

Disclosure of Invention

The invention aims to provide a compound for treating tumors and application thereof.

The present invention provides a compound as shown below or a pharmaceutically acceptable salt thereof:

wherein, X₁、X₂、X₃、X₄、X₅Each independently selected from H or D, and at least one selected from D.

Further preferably, X₁＝X₂。

Further preferably, X₁、X₂When all are hydrogen, X₃、X₄、X₅All of the components are deuterium, and the total amount of deuterium,

further preferably, X₁、X₂When all are hydrogen, X₃、X₄、X₅Any two are deuterium and the other is hydrogen.

Further preferably, X₁、X₂When all are hydrogen, X₃、X₄、X₅One is deuterium and the other two are hydrogen.

Further preferably, X₁、X₂When all are deuterium, X₃、X₄、X₅All are hydrogen, or two are hydrogen, one is deuterium, or one is hydrogen, two are deuterium, or all are deuterium.

Further preferably the compound is one of the following compounds:

or a pharmaceutically acceptable salt thereof.

The document Organic Process Research & Development,2012,16(12): 1897-,

the compound of the present invention is prepared by the process shown in FIG. 2,

wherein, the compound 1 can be prepared according to the document Organic Process Research & Development,2012,16(12): 1897-1904.

Compound 2 is selected from the following structures:

among them, 2a can be prepared according to the Journal of the American Chemical Society (2000),122(14),3358-3366, and 2b can be commercially available.

Compound 4 is selected from the following structures:

among them, 4a can be prepared according to WO2011113369, 4b can be prepared according to the literature Synthesis (1971), (12), 654-.

The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a PARP inhibitor.

The invention also provides a pharmaceutical composition.

A pharmaceutical composition is a preparation prepared by taking the compound or the pharmaceutically acceptable salt thereof as an active ingredient and adding pharmaceutically common auxiliary materials or auxiliary ingredients.

On the basis of maintaining good antitumor proliferation of the original compound, the compound shown in the formula (I) is modified by deuteration, so that the pharmacokinetic property of the compound in blood plasma is better, the peak concentration of the blood drug is high, the effective blood drug concentration is maintained for a long time, the administration dosage can be reduced, the problem of poor metabolism of the drug can be further solved, and the drug toxicity and other side effects can be reduced.

Drawings

FIG. 1 is a scheme for the preparation of Rucaparib.

FIG. 2 is a scheme for the synthesis of compounds.

Figure 3 is a scheme for the synthesis of compound 101.

Figure 4 is a scheme for the synthesis of compound 102.

Figure 5 is a scheme for the synthesis of compound 103.

Figure 6 is a scheme for the synthesis of compound 104.

Figure 7 is a scheme for the synthesis of compound 201.

Figure 8 is a scheme for the synthesis of compound 202.

Figure 9 is a scheme for the synthesis of compound 202.

Detailed Description

In the present invention, the abbreviations or English-denoted Chinese names are as follows:

Pd(dppf)₂Cl₂[1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride

DMAC N, N-Dimethylacetamide

MeOH methanol

Na₂CO₃Sodium carbonate

THF tetrahydrofuran

DCM dichloromethane

HCl hydrogen chloride

NaOH sodium hydroxide

DMSO-d6 hexa-deuterated dimethyl sulfoxide

NaBH₄Sodium borohydride

¹H NMR hydrogen nuclear magnetic resonance spectrum

ESI/MS electrospray ionization liquid chromatography mass spectrometry

Example 1

The synthesis of 101 is shown in figure 3,

step 1: synthesis of Compound 3

Compound 1(2.8g, 100mmol) was added to DMAC (30ml), followed by addition of Pd (dppf)₂Cl₂Dichloromethane complex (0.002g), stirred at room temperature for 30min, heated to 95 deg.C and incubated for 1h, then cooled to room temperature, and Compound 2b (1.5g,100mmol) and Na were added₂CO₃(2.1g,200mmol) and water (10ml) were heated to 90 ℃ and stirred for 4h, the reaction was monitored by dot plate for completion, cooled to room temperature, water (150ml) was added, the solid precipitated, filtered, the filter cake washed with water, then slurried with hot MeOH, cooled to room temperature and filtered to give compound 3 as a pale green solid (2.77g, 90% yield).

H(400MHz,DMSO-d6)3.11(s,br,2H),3.42(s,br,2H),7.38(d,1H)7.47(d,1H),7.87(d,2H),8.06(d,2H),8.29(s,br,1H),10.06(s,br,1H)11.89(s,br,1H)；

ESI/MS：m/z＝309(M+H)+。

Step 2: synthesis of Compound 5

Adding compound 3(2.5g,8.1mmol) into a mixture of MeOH (20ml) and THF (10ml), adding 4c, stirring at room temperature for 2h, monitoring the completion of the reaction of compound 3 by a dot plate, cooling to 0-5 ℃, and then adding NaBH slowly in batches₄(0.65g,17mmol), stirring reaction at below 10 ℃ for 2h, then raising the temperature to room temperature and stirring reaction for 2h, monitoring the reaction completion by a dot plate, slowly dropwise adding 1N diluted hydrochloric acid (15ml), adding activated carbon (5g), stirring for 6h, filtering, concentrating the filtrate, adding water and ethyl acetate for extraction and liquid separation, drying and concentrating the organic phase, recrystallizing the residue with ethanol, dissolving in DCM, introducing dry HCl gas, and filtering to obtain an off-white solid compound 5(2.4g, yield 83%).

H(400MHz,DMSO-d6)2.53(t,br,3H),3.01-3.02(m,2H),3.35-3.37(m,2H),4.13(d,br,2H),7.33(dd,1H),7.40(dd,1H),7.65(s,4H),8.23(t,br,1H),9.38(s,br,1H),11.84(s,1H)。

ESI/MS：m/z＝325(M+H)+。

And step 3: 101 Synthesis

Compound 5(2.2g,6.1mmol) was added to NaOH-H2O-MeOH (0.48g NaOH +15ml H)₂O +5ml), stirred at room temperature for 2h, filtered, the filter cake washed with water and dried under vacuum to give compound 101 as an off-white solid (1.78g, yield 90%).

Example 2

The synthesis of 102 is shown in figure 4,

compound 102 was prepared by reference to synthesis steps 1-3 of example 1.

H(400MHz,DMSO-d6)2.53(t,br,3H),3.01-3.02(m,2H),3.35-3.37(m,1H),4.13(d,br,2H),7.33(dd,1H),7.40(dd,1H),7.65(s,4H),8.23(t,br,1H),9.38(s,br,1H),11.84(s,1H)。

ESI/MS：m/z＝326(M+H)+。

Example 3

The synthesis of 103 is shown in figure 5,

compound 103 was prepared by reference to synthesis steps 1-3 of example 1.

H(400MHz,DMSO-d6)2.53(t,br,3H),3.01-3.02(m,2H),4.13(d,br,2H),7.33(dd,1H),7.40(dd,1H),7.65(s,4H),8.23(t,br,1H),9.38(s,br,1H),11.84(s,1H)。

ESI/MS：m/z＝327(M+H)+。

Example 4

The composition of 104 is shown in figure 6,

compound 104 was prepared by reference to synthesis steps 1-3 of example 1.

H(400MHz,DMSO-d6)2.53(t,br,3H),3.01-3.02(m,3H),4.13(d,br,1H),7.65(s,3H),8.23(t,br,1H),9.38(s,br,1H),11.84(s,1H)。

ESI/MS：m/z＝329(M+H)+。

Example 5

The synthesis of 201 is shown in figure 7,

compound 201 was prepared by reference to synthesis steps 1-3 of example 1.

H(400MHz,DMSO-d6)2.53(t,br,3H),3.01-3.02(m,2H),4.13(d,br,1H),7.65(s,3H),8.23(t,br,1H),9.38(s,br,1H),11.84(s,1H)。

ESI/MS：m/z＝330(M+H)+。

Example 6

The synthesis of 202 is shown in figure 8,

compound 202 was prepared by reference to synthesis steps 1-3 of example 1.

ESI/MS：m/z＝331(M+H)+。

Example 7

The synthesis of 203 is shown in figure 9,

compound 203 was prepared by reference to synthesis steps 1-3 of example 1.

H(400MHz,DMSO-d6)2.53(t,br,3H),3.01-3.02(m,2H),7.65(s,3H),8.23(t,br,1H),9.38(s,br,1H),11.84(s,1H)。

ESI/MS：m/z＝332(M+H)+。

Example 8

Pharmacokinetic testing

Pharmacokinetic experiments were performed on 102, 202 and Ricapab.

The tested animals were: male CD1 mice, weighing 18-22 g. The test animals should be adaptively raised at the test site 3-7 days before the test day, and male CD1 mice are randomly divided into 3 groups, and are respectively administered with gastric lavage, fasted for 12h before the test and freely drunk. The administration was followed by a uniform meal. The samples to be tested are administrated by a single gavage with a dose of 100mg/kg, and the samples to be tested of the experimental group and the positive control group are dissolved by Ethanol, PEG400 and water (5:45:50, v/v/v). Samples were taken at 0.5, 1.0, 2.0, 3.0, 5.0, 8.0, 10 and 24h post-dose, respectively; at each time point, 0.3mL of venous blood was collected from retrobulbar venous plexus of mice after animal anesthesia at the above set time points, placed in heparinized tubes, centrifuged at 11000g for 5min, plasma was separated, and frozen in a refrigerator at-20 ℃. During sample detection, after protein is precipitated from a plasma sample through methanol, the concentrations of the

compounds

102 and 202 and the Ruipab in the plasma are determined by an LC-MS/MS method, and the linear range is 30.0-30000 ng/mL.

The WinNonlin6.3 software was used to calculate the major pharmacokinetic parameters (T) after gastric gavage in mice_max，C_maxAUC, MRT and t 1/2). Wherein the peak concentration C is reached_maxAnd time to peak T_maxIs an actual measurement value.

Area under plasma concentration-time curve AUC_0-tThe value: and calculating by adopting a trapezoidal method.

AUC_0-∞＝AUC_0-t+C_t/k_e，

Ct is the blood concentration at the last measurable time point, ke is the elimination rate constant;

elimination of half-life t_1/2＝0.693/k_e；

The mean residence time MRT is AUMC/AUC.

102. 202 and licarpb are shown in table 1.

Pharmacokinetic parameters of tables 1102, 202 and Ricapabu

From the experimental data in table 1, it can be seen that T of

deuterated compounds

102 and 202 prepared by the invention_maxT with Ruicapab_maxSimilarly,

deuterated compounds

102, 202 are shown to be absorbed in vivo similarly to Ricapab. However, C of 102, 202_max1.31 times and 1.47 times of the benznidazole respectively; 102. 202 AUC_0-tRespectively 1.34 times and 1.42 times of Ruipab; 102. 202 elimination half-life t_1/2Is 1.28 times and 1.34 times of the benznidazole, which shows that the

deuterated compounds

102 and 202 provided by the invention obviously improve the blood concentration, prolong the half-life period of the drug and prolong the time of the drug staying in the body compared with the Ruicapab, thereby achieving better curative effect. Meanwhile, compared with Ruicapa, the deuterated compound provided by the invention has smaller dosage, so that the problem of poor metabolism of the medicament can be further eliminated, and the toxicity and other side effects of the medicament can be reduced.

Example 9

Pharmaceutical composition

The phosphate salt of compound 202 was prepared according to conventional methods in the art.

Phosphate salt of Compound 202 10g

Starch 50g

Microcrystalline cellulose 45g

The materials are mixed evenly and put into common gelatin capsules according to the conventional method to prepare 1000 capsules.

Claims

1. A deuterated compound selected from the structures:

and pharmaceutically acceptable salts thereof.

2. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

3. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a PARP inhibitor.

4. The use of claim 3, wherein said PARP inhibitor is an anti-tumor drug.

5. Use according to claim 3 or 4, wherein the tumour is selected from: breast cancer, colon cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, blood cancer, lymph cancer, prostate cancer, liver cancer, cervical cancer, neuroblastoma, melanoma, solid tumor or intracranial tumor.