CN108976236A - A kind of deuterated PARP inhibitor, its salt, preparation method and the usage - Google Patents
A kind of deuterated PARP inhibitor, its salt, preparation method and the usage Download PDFInfo
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Abstract
The present invention provides a kind of deuterated compounds, its pharmaceutically acceptable salt, Preparation method and use.The compound is a new class of deuterated PARP inhibitor, the purposes the present invention also provides composition and the compound or composition containing the deuterated PARP inhibitor as anticancer drug.Pharmacokinetic trial shows that deuterated compound provided by the invention significantly improves blood concentration, extends drug half-life, extends the time that drug is detained in vivo, to reach better curative effect.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a new class of deuterated PARP inhibitor, its salt, preparation method
And purposes of the composition and the compound or composition containing the deuterated PARP inhibitor as anticancer drug.
Background technique
Currently, problem of many drugs due to the property difference of absorption, distribution, metabolism or excretion (ADME), and limit it
Application.Meanwhile this is also the main reason for clinical drug exploitation fails.Although using preparation technique and prodrug technologies, energy
The enough ADME property for improving drug to some extent, still, these methods can not fundamentally change the ADME property of drug.
For example, the problem that metabolism is fast, fast due to being metabolized, drug enters not to play a role also in vivo, is just fallen by organism metabolism, even if living
Property is high again, it does not have therapeutic effect yet.If it is desired to reach therapeutic effect it is necessary to increase dosage, to increase blood concentration, this
Sample not only increases medical expense, but also can bring more side effects.So how to pass through the transformation or adjustment of structure, especially
It is in the case where not influencing its active situation, is a urgent problem to improve the metabolic stability of drug.
Another ADME is limited in, and many drugs can generate the metabolin toxic to body in vivo, this makes patient
Injury of the toxic metabolite to human body is faced in medication.
Sometimes in order to change this situation, a kind of metabolic poison that can be quickly fallen by body metabolism can be introduced,
Such as the protease inhibitors class drug for treating HIV infection.U.S. FDA recommendation can combine when using this kind of drug and make
Use Ritonavir.Ritonavir is a kind of cytochrome P 450 enzymes 3A4 (CYP3A4) inhibitor, the enzyme be cause it is metabolic
Main cause (see Kempf, D.J.et al., Antimicrobial agents and chemotherapy, 1997,41 (3):
654-60).However, Ritonavir not only causes side effect, but also increase warp to patient HIV originally using " cocktail therapy "
Ji burden, and the increase of drug administration amount also reduces the compliance of patient.It is similar, CYP2D6 inhibitor quinidine and the right side
Dextromethorphan combination to reduce dextromethorphan tachymetabolism the problem of, still, quinidine generate side effect significantly limit it with
The potentiality for the treatment of are used in combination (see Wang, L et al., Clinical Pharmacology and in other drugs
Therapeutics,1994,56(6Pt 1):659-67；Or FDA is closed on the www.accessdata.fda.gov of its website
In the explanation of quinidine).
An effective way for improving drug metabolism is with the isotope deuterium of hydrogen come modified medicaments.
There are three types of isotopes for hydrogen: protium (1H, Hydrogen, Protium), deuterium (2H, Deuterium) and tritium (3H,
Tritium).Wherein deuterium (2H or D) be to obtain one of most widely used isotope, it be hydrogen present in nature (1H, protium)
A kind of stable isotope, it is "dead", be to be found in water for the first time by Urey in 1932.The atomic nucleus of deuterium is by a seed
It is formed with proton, and hydrogen (protium) only one proton.The content of deuterium in nature is about 0.015%, current a large amount of deuterium
Element is separated in the form of deuterated water from water, and content is up to 99.9%.Deuterated water is called heavy water, is most to pass through at present
The deuterium source helped and be easy to get.
Deuterated drug is to replace the protium (H) in drug molecule with deuterium (D), this due to the nuance of H and D
Replacing influences less on active, but since deuterium is than hydrogen weight, the chemical bond rupture of formation is difficult, therefore can produce to drug metabolism
Raw very big influence can improve medicine for effect well and can significantly mitigate side effect etc. when being particularly in metabolism site.Deuterium
For drug research report (Science 1961,133,102-104) from " science " impurity in 1961 since, achieve considerable
Development, wherein the companies such as Auspex, Concert, Deuteria/DeuteRx achieve much good grind in terms of deuterated drug
Study carefully achievement.The chorea therapeutic agent of Auspex: deuterated tetrabenazine (SD-809), by the deuterated of active site, from
And change metabolism, so that drug safety and validity are taken on a new look, clinical observation generation is depressed, sleepy, has a sleepless night and sits quietly
Difficult probability is very low, and due to its excellent clinical effectiveness, Teva spends 3,200,000,000 U.S. dollars to be put into the pocket.This event
So that the research of deuterated drug becomes field (the Nat.Rev.Drug Discov.2016,15,219- that everybody pays special attention to
221)。
Deuterium isotope and its deuterated compound are widely applied in numerous research fields, and deuterated compound not only can be with
As clinical medicine analysis internal standard, can be used for studying pharmacokinetics, drug-metabolic pathway and drug toxicology, in recent years
Come, deuterated compound itself can be used as better drug to develop.
The accretion rate of reduction drug is attempted by deuterated method, increases half-life period, or reduce by deuterated
The formation of unwanted metabolic products.The increase of bond energy can improve the ADME characteristic of drug after deuterated, so as to improve the drug effect of drug,
Safety and compliance.Simultaneously as the size and shape of D-atom and hydrogen atom are almost the same, hydrogen will not after being replaced by deuterium
Change the selectivity and biochemical activity of drug.
Polyadenylic acid diphosphonic acid phosphoribosynltransferase (PARP, poly ADP-ribose polymerase) is current treatment cancer
The novel target spot of disease, the effect of the enzyme are to be catalyzed ADP- ribose to be transferred to various receptor eggs from nicotinamide adenine dinucleotide
It is white, and single-stranded DNA can be repaired by base excision repair mode.In tumour cell, when PARP activity is suppressed
When, DNA damage reparation is easy error, and as DNA damage increases, tumour cell will be dead, to reach the mesh for the treatment of tumour
's.It is current research shows that (Han Wei etc., PARP inhibitor are used for the progress of oncotherapy, Chinese Journal of New Drugs, 2011,
20 (12), 1086-1091), PARP inhibitor is not only the sensitizer of chemicotherapy, and in BRCA1 and BRCA2 gene mutation
It can be used alone in breast cancer, selectivity kills the cancer cell that DNA repairs defect.
Rui Kapabu (English name: Rucaparib；Chemical name: the fluoro- 1,3,4,5- tetrahydro -2- of 8- [4- [(methylamino)
Methyl] phenyl] -6H- pyrrolo- [4,3,2-EF] [2] benzazepine -6- ketone), it is a kind of polyadenylic acid diphosphonic acid ribose turn
Enzyme inhibitor is moved, there is BRCA gene mutation for single therapy and received the advanced stage ovum of two kinds and the treatment of the above chemotherapy regimen
Nest cancer patient.
Currently, the research for Rui Kapabu is concentrated mainly on its own, as intermediate Study on Preparation (for example,
Geng Yuanshuo etc., the study on the synthesis of Poly adenosine diphosphate-ribose polymerase-1 inhibitor Rui Kapabu, fine-chemical intermediate, 2012,
42 (5), 48-52) and pharmacological research (for example, PARP and CHK inhibitors interact to cause DNA
Damage and cell death in mammary carcinoma cells, Cancer Biology&Therapy
(2013),14(5),458-465)。
But exploration is also lacked for the research of Rui Kapabu analog.Therefore, in the structure basis of Rui Kapabu,
Research and develop a kind of new drug for capableing of effective treating cancer, it appears particularly important.
Summary of the invention
The purpose of the present invention is to provide a kind of compounds and application thereof for treating tumour.
The present invention provides compound as follows or its pharmaceutically acceptable salts:
Wherein, X1、X2、X3、X4、X5It is separately selected from H or D, and at least one is selected from D.
It is further preferred that X1=X2。
It is further preferred that X1、X2When all hydrogen, X3、X4、X5All deuteriums,
It is further preferred that X1、X2When all hydrogen, X3、X4、X5Any two be deuterium, another be hydrogen.
It is further preferred that X1、X2When all hydrogen, X3、X4、X5One is deuterium, another two is hydrogen.
It is further preferred that X1、X2When all deuteriums, X3、X4、X5All hydrogen or two be hydrogen, one be deuterium or one
It is a be hydrogen, two be deuterium or all deuteriums.
The further preferably described compound is one of following compound:
Or its pharmaceutically acceptable salt.
Document Organic Process Research&Development, 2012,16 (12): 1897-1904 report
A kind of preparation method of Rucaparib as shown in Figure 1,
The compounds of this invention refers to above-mentioned preparation method, provides preparation method as shown in Figure 2,
Wherein, compound 1 can according to document Organic Process Research&Development, 2012,16
(12): 1897-1904 are prepared.
Compound 2 is selected from such as flowering structure:
Wherein, 2a can according to document Journal of the American Chemical Society (2000), 122
(14), 3358-3366 is prepared, and 2b is commercially available to be obtained.
Compound 4 is selected from such as flowering structure:
Wherein, 4a can be prepared according to patent WO2011113369,4b can according to document Synthesis (1971),
(12), 654-655 is prepared, and 4c can be according to document Journal of the American Chemical Society
(2005), 127 (26), 9641-9647 are prepared, and 4d is commercially available to be obtained.
The present invention also provides formula (I) compounds or its pharmaceutically acceptable salt in the purposes for preparing PARP inhibitor.
The present invention also provides a kind of pharmaceutical compositions.
A kind of pharmaceutical composition, it is active constituent that it, which is by above compound or its pharmaceutically acceptable salt, in addition medicine
The preparation that common auxiliary material or complementary ingredient are prepared on.
Compound shown in formula (I) of the present invention is repaired on the basis of keeping former compound well antitumor proliferation by deuterated
Decorations, so that pharmacokinetic property of the compound in blood plasma is more preferable, blood peak concentration of drug is high, and effective blood drug concentration is held time
It is long, it is smaller that administration dosage can be reduced, and then can further eliminate the bad metabolic problems of drug, reduce drug toxicity and
Other side effects.
Detailed description of the invention
Fig. 1 is the preparation flow figure of Rucaparib.
Fig. 2 is the synthesis flow of compound.
Fig. 3 is the synthetic schemes of compound 101.
Fig. 4 is the synthetic schemes of compound 102.
Fig. 5 is the synthetic schemes of compound 103.
Fig. 6 is the synthetic schemes of compound 104.
Fig. 7 is the synthetic schemes of compound 201.
Fig. 8 is the synthetic schemes of compound 202.
Fig. 9 is the synthetic schemes of compound 202.
Specific embodiment
In the present invention, the Chinese of abbreviation or English representative is as described below:
Pd(dppf)2Cl2[bis- (diphenylphosphino) ferrocene of 1,1'-] palladium chloride
DMAC DMAC N,N' dimethyl acetamide
MeOH methanol
Na2CO3Sodium carbonate
THF tetrahydrofuran
DCM methylene chloride
HCl hydrogen chloride
NaOH sodium hydroxide
DMSO-d6 hexadeuterated dimethyl sulfoxide
NaBH4Sodium borohydride
1H NMR nuclear magnetic resonance spectroscopy
ESI/MS electrospray ionisation liquid chromatography mass
Embodiment 1
101 synthesis as shown in figure 3,
Step 1: the synthesis of compound 3
Compound 1 (2.8g, 100mmol) is added in DMAC (30ml), Pd (dppf) is added2Cl2Methylene chloride network
It closes object (0.002g), 30min is stirred at room temperature, is again heated to 95 DEG C of heat preservation 1h, then cools to room temperature, add compound 2b
(1.5g, 100mmol) and Na2CO3(2.1g, 200mmol), water (10ml) is heated to 90 DEG C and is stirred to react 4h, and point board monitoring is anti-
It should be cooled to room temperature, be added water (150ml) completely, solid, filtering is precipitated, filter cake is washed with water, MeOH hot beating is then used again,
It is cooled to room temperature, filters, obtain light green solid compound 3 (2.77g, yield 90%).
δH(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: the synthesis of compound 5
Compound 3 (2.5g, 8.1mmol) is added in the mixture of MeOH (20ml) and THF (10ml), is added
Reaction 2h is stirred at room temperature in 4c, puts 3 fully reacting of board monitoring compound, is cooled to 0~5 DEG C, then be slowly added to NaBH in batches4
(0.65g, 17mmol), 10 DEG C of reaction 2h stirred below, is then warmed to room temperature again and is stirred to react 2h, puts board monitoring fully reacting,
The dilute hydrochloric acid (15ml) of 1N is slowly added dropwise, adds active carbon (5g), stirs 6h, filtering, water and acetic acid second is added in filtrate concentration
Ester extracts liquid separation, and organic phase is dry, is concentrated, and residue ethyl alcohol recrystallization is re-dissolved in DCM, is passed through dry HCl gas, filters,
Obtain off-white powder compound 5 (2.4g, yield 83%).
δH(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)+.
The synthesis of step 3:101
Compound 5 (2.2g, 6.1mmol) is added to NaOH-H2O-MeOH (0.48g NaOH+15ml H2O+5ml) molten
In liquid, 2h is stirred at room temperature, filters, filter cake is washed with water, is dried in vacuo, obtains off-white powder compound 101 (1.78g, yield
90%).
Embodiment 2
102 synthesis as shown in figure 4,
The synthesis step 1-3 of reference implementation example 1, is prepared compound 102.
δH(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)+.
Embodiment 3
103 synthesis as shown in figure 5,
The synthesis step 1-3 of reference implementation example 1, is prepared compound 103.
δH(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)+.
Embodiment 4
104 synthesis as shown in fig. 6,
The synthesis step 1-3 of reference implementation example 1, is prepared compound 104.
δH(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)+.
Embodiment 5
201 synthesis as shown in fig. 7,
The synthesis step 1-3 of reference implementation example 1, is prepared compound 201.
δH(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)+.
Embodiment 6
202 synthesis as shown in figure 8,
The synthesis step 1-3 of reference implementation example 1, is prepared compound 202.
δH(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=331 (M+H)+.
Embodiment 7
203 synthesis as shown in figure 9,
The synthesis step 1-3 of reference implementation example 1, is prepared compound 203.
δH(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)+.
Embodiment 8
Pharmacokinetic trial
102,202 and Rui Kapabu is taken to carry out pharmacokinetic studies.
Animal subject are as follows: male CD1 mouse, weight 18-22g.Animal subject 3-7 days a few days ago should be in test site in test
Adaptive feeding is carried out, male CD1 mouse is randomly divided into 3 groups, and stomach-filling is given by test agent respectively, fasting 12h before testing, from
By drinking water.Unified feed after administration.Single oral gavage gives the sample to be tested of 100mg/kg dosage, experimental group and positive controls
Sample to be tested uses Ethanol:PEG400: water (5:45:50, v/v/v) dissolution.Respectively upon administration 0.5,1.0,2.0,3.0,
It 5.0,8.0,10 and samples for 24 hours；3 mouse of per time point, it is quiet after eyeball of mouse after the above setting time point Animal Anesthesia
Arteries and veins clump extracting vein blood 0.3mL, sets in heparinised tubes, and 11000g is centrifuged 5min, and separated plasma freezes in -20 DEG C of refrigerators.Sample
When product examine is surveyed, plasma sample is after methanol extraction albumen using 102,202 and Rui Ka of compound in LC-MS/MS method measurement blood plasma
The concentration of Pabuk, the range of linearity are 30.0~30000ng/mL.
Main pharmacokinetic parameters (T after intragastric administration on mice administration is calculated using WinNonlin6.3 softwaremax, Cmax, AUC,
MRT and t1/2).Wherein, Cmax C is reachedmaxWith peak time TmaxFor measured value.
Lower area of blood concentration-time curve AUC0-tValue: it is calculated using trapezoidal method.
AUC0-∞=AUC0-t+Ct/ke,
Ct is that the last one can measure the blood concentration at time point, and ke is elimination rate constant；
Eliminate half-life period t1/2=0.693/ke；
Mean residence time MRT=AUMC/AUC.
102, the pharmacokinetic parameter of 202 and Rui Kapabu is shown in Table 1.
The pharmacokinetic parameter of 1 102,202 and Rui Kapabu of table
The experimental data from table 1 it is found that deuterated compound prepared by the present invention 102,202 TmaxWith the T of Rui Kapabumax
Identical, illustrating deuterated compound 102,202, absorbing state is similar in vivo with Rui Kapabu.But 102,202 CmaxRespectively
It is 1.31 times, 1.47 times of benznidazole；102,202 AUC0-tIt is 1.34 times, 1.42 times of Rui Kapabu respectively；102,202
Eliminate half-life period t1/2It is 1.28 times, 1.34 times of benznidazole, illustrates deuterated compound 102,202 provided by the invention, compared to auspicious
Kappa cloth significantly improves blood concentration, extends drug half-life, extends the time that drug is detained in vivo, to reach
To better curative effect.Meanwhile it can reasonably release compared to Rui Kapabu, the dosage of deuterated compound provided by the invention
It is smaller, and then the bad metabolic problems of drug can be further eliminated, reduce drug toxicity and other side effects.
Embodiment 9
Pharmaceutical composition
According to conventional method in that art, it is prepared into the phosphate of compound 202.
The phosphate 10g of compound 202
Starch 50g
Microcrystalline cellulose 45g
According to a conventional method, above-mentioned substance is packed into common gelatine capsule after mixing, 1000 capsules are made.
Claims (6)
1. a kind of deuterated compound, which is characterized in that shown in its structure such as formula (I):
And its pharmaceutically acceptable salt,
Wherein, X1、X2、X3、X4、X5It is separately selected from H or D, and at least one is selected from D.
2. a kind of deuterated compound according to claim 1, which is characterized in that formula (I) compound represented is selected from as follows
Structure:
And its pharmaceutically acceptable salt.
3. a kind of pharmaceutical composition, comprising therapeutically effective amount compound according to claim 1 or 2 or its can pharmaceutically connect
The salt and pharmaceutical acceptable carrier or diluent received.
4. any one of the claim 1-2 compound or its pharmaceutically acceptable salt are in the purposes for preparing PARP inhibitor.
5. purposes according to claim 4, which is characterized in that the drug is anti-tumor drug.
6. according to the described in any item purposes of claim 5-6, which is characterized in that the antitumor range includes: breast cancer, knot
It is intestinal cancer, uterine cancer, cancer of pancreas, lung cancer, gastric cancer, leukemia, lymph cancer, prostate cancer, liver cancer, cervical carcinoma, nerve metrocyte carcinoma, black
Melanoma, solid tumor or intracranial tumors.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109651377A (en) * | 2017-10-12 | 2019-04-19 | 成都海创药业有限公司 | A kind of compound for the treatment of cancer and application thereof |
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| CN109651377A (en) * | 2017-10-12 | 2019-04-19 | 成都海创药业有限公司 | A kind of compound for the treatment of cancer and application thereof |
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2018
- 2018-08-16 CN CN201810933066.4A patent/CN108976236B/en active Active
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| CN1342161A (en) * | 1999-01-11 | 2002-03-27 | 阿古龙制药公司 | Tricyclic inhibitors of poly(ADP-ribose) polymerases |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109651377A (en) * | 2017-10-12 | 2019-04-19 | 成都海创药业有限公司 | A kind of compound for the treatment of cancer and application thereof |
| CN109651377B (en) * | 2017-10-12 | 2020-10-20 | 成都海创药业有限公司 | Compound for treating cancer and application thereof |
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