CN107235958A - A kind of synthetic method for preparing PARP inhibitor Niraparib - Google Patents
A kind of synthetic method for preparing PARP inhibitor Niraparib Download PDFInfo
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
- C07D211/28—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms to which a second hetero atom is attached
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Abstract
A kind of new synthetic method for preparing PARP inhibitor Niraparib, this method is included with initiation material methyl anthranilate through diazo coupling, and cyclization, amidatioon, de- BOC, chiral resolution obtain the Niraparib that purity reaches 99.85%.The inventive method is easy, it is easy to operates, is a method which be suitable for industrial production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, it is related to a kind of synthetic method for preparing PARP inhibitor Niraparib.
Background technology
Niraparib is a kind of oral Poly ADP-ribose polymerase (PARP) inhibitor, can suppress cell to DNA damage
Reparation, it is adaptable to the cancer of BRCA1/2 gene mutations, such as oophoroma and breast cancer, by biotech company of the U.S.
Tesaro is researched and developed.For the cancer cell with BRCA gene mutations, if PARP activity is further suppressed, these are thin
Born of the same parents will produce a large amount of DNA damages when dividing, and cause cancer cell death.Niraparib chemical names are 2- [4- ((3S) -3- piperazines
Piperidinyl) phenyl] -2H- indazole -7- formamides, the III clinical trial phases that a key name is NOVA are completed, Niraparib shows
Extremely good curative effect.In experiment, researcher recruited more than 500 after platinum-based chemotherapy oophoroma there is the trouble recurred
Person, and whether BRCA gene mutations are carried according to reproduction cell, patient has been divided into two groups.It is mutated in reproduction cell with BRCA
Group in, median by the Niraparib patient's progression free survival phases treated is up to 21 months, than 5.5 of control group
The moon has obtained notable extension.
At present, the relevant patent document of synthetic method in the prior art for Niraparib includes Preparation
of pharmaceutically acceptable salts of (3S)-3-[4-[7-(aminocarbonyl)-2H-
indazol-2-yl]phenyl]piperidines as inhibitors of poly(ADP-ribose)polymerase
(PARP), Preparation of piperidinylphenylindazolylcarboxamide for useas poly
(ADP-ribose) polymerase inhibitors etc. a, it is disclosed that chemical synthesis route, as follows and right
Niraparib discovery procedure has carried out detailed discussion.
The synthetic route using 3- methyl -2- nitrobenzoic acids as initiation material, by with methanol under conditions of acyl chlorides ester
Change obtains compound A, A and is heated to reflux in benzoyl peroxide and NBS CCl4 solution 12 hours, and bromination obtains compound B.B with
Acetonitrile and the oxidation of N-methylmorpholine-N- oxide water solutions obtain compound C.The compound C and tert-butyl group -3- (4- aminophenyls)
Piperidines -1- carboxylic acid tert-butyl esters are stirred at reflux in ethanol solution obtains compound D.Compound D and sodium azide and DMF mixtures
Reaction, cyclization formed intermediate E .. compounds E be passed through in methanol solution 60 DEG C of NH3 heating it is acylated intermediate F. compounds
F adds hydrochloric acid in ethyl acetate Yu dioxane solutions, sloughs BOC groups and obtains intermediate G, through Chiralpak AS-H positives
Chiral chromatographic column splits and obtains target compound S type rotamers Niraparib.The synthetic route is longer, uses
Chiralpak AS-H positive chiral chromatographic columns split Niraparib is difficult to realize in large-scale industrial production, and reaction
Used sodium azide etc. unstable and difficult post processing raw material, limit industrialization safety in production.
The content of the invention
In order to overcome the above-mentioned deficiencies of the prior art, the purpose of the present invention is to improve one kind to prepare PARP inhibitor
Niraparib synthetic method, route is novel, and multiple brand-new intermediates, and the property of intermediate are obtained in building-up process
It is stable, it is easy to operate, it is easy to accomplish industrialized production.
To achieve these goals, implementation process of the invention is as follows：
A kind of synthetic method for preparing PARP inhibitor Niraparib, synthetic route is as follows：
Wherein compound (I) is PARP inhibitor Niraparib.
It the following specifically describes synthesis step：
The first step：
Methyl anthranilate is mixed with sulfuric acid solution, then natrium nitrosum, -10 DEG C to 10 of reaction temperature is slowly added dropwise
DEG C, with the tert-butyl group -3- Phenylpiperidine -1- t-butyl formates in 10% sodium hydroxide solution environment after the brownish red diazol of generation
Middle progress coupling reaction obtains intermediate (II), and intermediate (II) structure is
Second step:
Intermediate (II) is in the rhenium [Re of ten carbonyl two2(CO)10] and the catalysis of sodium acetate [NaOAc] under, catalytic intermediary
(II) azobenzene structure cyclization, cyclization forms indazole ring in the dicyandiamide solution of methanol, obtains intermediate (III), realizes one
The indazole structure constructed in intermediate (III) is walked, the structure of intermediate (III) is
3rd step：
Intermediate (III) is added to sodium methoxide, formamide afterwards in dry DMF is dissolved at 0 DEG C, 40 DEG C of reactions are warming up to
The amide structure formed after 3.5h, methyl esters ammonolysis in intermediate (IV), obtains crude intermediate (IV), then at room temperature by crude product
Intermediate (IV) is added to dioxane-water (volume ratio 8：1) in the mixed solvent, is warming up to 101 DEG C, the complete molten rear addition of solid
Activated carbon, backflow, suction filtration, filtrate, stand, suction filtration while hot, dry, obtain intermediate (IV), the structure of intermediate (IV) is：
4th step:
Intermediate (IV), with the de- BOC protection groups of trifluoroacetic acid reaction, solvent, thing is made with dichloromethane in dichloromethane
The mol ratio of matter is intermediate (IV)：Dichloromethane：Trifluoracetic acid=1:5:1, reaction in about 3 hours is stirred at room temperature completely, is evaporated
Racemization intermediate (V) is obtained, the structure of intermediate (V) is
5th step：
Racemization intermediate (V) is dissolved in organic solvent the dissolving that flows back, L- (+)-tartaric acid is added, cool crystallization, separation
Solid crystal, obtains Niraparib.L- (+)-tartrate, is dissolved in water, hydrogenation sodium hydroxide solution alkalization, then
Ethyl acetate extraction is added, washing is drying to obtain compound (I) PARP inhibitor Niraparib, its structural formula isThe mass ratio of described organic solvent and racemization intermediate (V) is 10~20:1；Described
The mass ratio of L- (+)-tartaric acid and Niraparib intermediates 4 is 0.5~5:1, preferably 3~4:1.
The organic solvent used in the 5th described step during racemization intermediate (V) chemical resolution is tetrahydrofuran, first
Alcohol, ethanol, acetone, ethyl acetate or several arbitrary proportion mixtures, preferred alcohol, ethyl acetate, recrystallization temperature are -10~0
℃。
The solvent used in BOC protection reaction preparation racemization intermediates (V) is taken off in the 4th described step and is selected from tetrahydrofuran, two
One or more in the ring of oxygen six, dichloromethane, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene, acetonitrile are appointed
Meaning scalemic thereof mixture, preferably dichloromethane, it is room temperature to take off BOC institutes temperature in use.
In the described first step by methyl anthranilate prepare diazol can be used potassium nitrite, calcium nitrite,
Silver nitrite, natrium nitrosum, barium nitrite, nitrous ether (ethyl nitrite), isoamyl nitrite, isobutyl nitrite, Isopropyl Nitrite,
Nitrite tert-butyl, nitrous acid straight butyl, n-propyl nitrite are carried out as the reagent of diazo-reaction, preferably natrium nitrosum.
The present invention compared with prior art, this have the advantage that：
1) the initiation material methyl anthranilate that the present invention is used synthesizes the original that field is generally used for organic drug
Material, it is cheap and be readily obtained；
2) synthetic route of the present invention is short, and step is simple.
3) present invention in each intermediate link only with such as：The operations such as extraction, dry, filtering, crystallization and recrystallization
Method, post processing is simple and convenient, is easier to realize large-scale production；
4) route of the present invention is novel, and multiple brand-new intermediates are obtained in building-up process, and the property of intermediate is stable,
It is easy to operate, it is easy to accomplish industrialized production.
Brief description of the drawings
Fig. 1 is the final thing Niraparib of present invention HPLC chromatogram.
Embodiment
The present invention is further discussed below with reference to embodiments, but the present invention is not limited to following examples.
Embodiment
Intermediate (II)Synthesis, the synthesis of intermediate (II) is divided into two steps
Carry out, the preparation of first step diazol：By 52mL (0.4mol) methyl anthranilates and the sulfuric acid of 170mL 20%
(0.62mol) is mixed, and when being cooled to 10 DEG C, the natrium nitrosums of 42mL 30% (0.4mol) solution is slowly added dropwise into reaction bulb.With
Starch potassium iodide paper examines excessive nitrous acid, determines reaction end.The brownish red diazol of generation carries out second step and uncle
The coupling reaction of butyl -3- Phenylpiperidine -1- t-butyl formates：Take 100g (0.4mol) tert-butyl group -3- Phenylpiperidine -1- formic acid
The tert-butyl ester is dissolved in the sodium hydroxide solutions of 500mL 10%, is stirred continuously in the lower above-mentioned diazol of instillation, stirs 5h, stand knot
Crystalline substance, suction filtration, and recrystallize in ethanol 127g intermediate (II), yield：78%.
1H-NMR(300MHz,DMSO-d6)(ppm)δ:8.52 (2H, d, J=7.6Hz), 8.25-8.11 (3H, m), 7.86
(1H, t), 7.51 (2H, d, J=7.6Hz), 3.91 (3H, s), 3.75-3.49 (2H, m), 3.38-3.32 (2H, m), 2.77-
2.67(1H,m),1.92-1.68(2H,m),1.58-1.43(2H,m),1.38(9H,s)；13C-NMR(75MHz,DMSO-d6)δ
(ppm):164.6,153.5,150.0,141.1,133.5,128.6,127.5,126.9,123.0,117.0,80.1,56.9,
51.3,49.2,40.3,30.8,28.2,22.9；MS(ESI)for(M+H)+:424.2.
Intermediate (III)Synthesis, take 82g (0.2mol) Niraparib
Intermediate 1 is mixed with 68mL (0.64mol) toluene and 16mL (0.4mol) methanol, stirring and dissolving, adds the rhenium of ten carbonyls of 6.5g two
([Re2(CO)10] 10mmol) and 5.4g sodium acetates (0.04mol) as catalyst, be heated to reflux 72 hours at 150 DEG C, while hot
Filtering, static crystallization, 40 DEG C of vacuum drying 4h obtain 51.2g intermediates (III), yield is 61%.
1H-NMR(300MHz,DMSO-d6)(ppm)δ:8.51 (1H, s), 8.13 (1H, d, J=7.1Hz), 7.95 (1H,
D, J=8.3Hz), 7.91 (2H, d, J=8.4Hz), 7.39 (2H, d, J=8.4Hz), 7.18 (1H, t, J=7.2Hz), 4.30-
4.10(2H,m),4.00(3H,s),2.85-2.70(3H,m),2.11-2.03(1H,m),1.83-1.75(1H,m),1.73-
1.53(2H,m overlapped to H2O signal),1.48(9H,s).
13CNMR(75MHz,DMSO-d6)δ(ppm):167.3,153.4,145.3,136.8,128.4,126.7,125.1,
124.1,120.8,112.0,80.0,57.0,51.3,49.0,40.3,30.5,28.1,22.8；MS(ESI)for(M+H)+:
436.2.
Intermediate (IV)Synthesis, at 0 DEG C by the middle of 17.2g (41mmol)
Body (III) is dissolved in 100mL dry DMFs, and 13mL (328mmol) formamide, 3.3g (62mmol) methanol are added into this solution
Sodium, is warming up to 40 DEG C of reaction 3.5h.Reaction solution is cooled to room temperature, is poured into 400mL water, 1h is stirred, suction filtration is dried, in obtaining
Mesosome (IV) crude product 17.23g (theoretical yield is 13.78g), yield is 87%.The crude product 10.0g of compound 3 is added at room temperature
To the in the mixed solvent of 80mL dioxane-water (volume ratio 8: 1), 101 DEG C, the complete molten rear addition 0.2g (quality of solid are warming up to
Fraction 2%) activated carbon, continue the 0.5h that flows back, while hot suction filtration, filtrate is cooled to 0 DEG C, stand 2h (precipitation white needle-like crystals),
Suction filtration, dries, obtains intermediate (IV).
1H-NMR(300MHz,DMSO-d6)(ppm)δ:9.04 (1H, br.s), 8.51 (1H, s), 8.31 (1H, d, J=
6.8Hz), 7.91 (1H, d, J=8.3Hz), 7.84 (2H, d, J=8.2Hz), 7.42 (2H, d, J=8.2Hz), 7.31-7.22
(1H,m),5.95(1H,br,s),4.40-4.05(2H,m),2.90-2.70(3H,m),2.15-2.00(1H,m),1.85-
1.75(1H,m),1.75-1.50(2H,moverlapped to H2O signal),1.48(9H,s)；
13CNMR(75MHz,DMSO-d6)δ(ppm):168.2,153.4,143.6,136.8,128.9,126.5,125.1,
124.3,120.8,115.1,80.0,57.0,49.3,40.5,30.7,28.4,22.5；MS(ESI)for(M+H)+:421.2
Intermediate (V)Synthesis, 18g intermediates (IV) (42mmol) add
Into 180mL dichloromethane, after being sufficiently mixed, gradually it is added dropwise after 50mL trifluoroacetic acid solutions, stirring 24h, adds 80mL hydrogen-oxygens
Change sodium water solution, stratification collects organic phase, with anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain 11.2g intermediates (V), mole
Yield is 83.33%.
1H-NMR (300MHz, DMSO-d6) (ppm) δ 9.28 (1H, s), 8.57 (1H, br, s), 8.06 (2H, d, J=
7.2Hz), 8.04 (2H, d, J=8.4Hz), 7.88 (2H, br.s), 7.49 (2H, d, J=8.4Hz), 7.27 (1H, dd, J=
8.4,7.2Hz),3.08-2.94(2H,m),2.77-2.67(1H,m),2.76-2.73(2H,m),1.75-1.47(4H,m).
13C-NMR(75MHz,DMSO-d6)δ(ppm):168.2,143.4,136.7,128.8,126.4,125.1,
123.9,120.9,115.2,52.2,48.8,43.5,30.8,25.1,
MS(ESI)for(M+H)+:321.2.
Compound (I) NiraparibSynthesis, 100g intermediates (V) are added to
In 1000mL absolute ethyl alcohols, 50g L- (+)-tartaric acid for heating to back flow reaction 0.5h are added, system is then cooled to -10~
0 DEG C of crystallization, is filtrated to get solid；Solid is refined with 200mL ethyl alcohol recrystallizations, Niraparib L- (+)-tartaric acid is obtained
Salt 66.89g, molar yield 45.5%.
Niraparib L- (+)-tartrate 4.5g is added in 22.5mL pure water, then added under the conditions of normal temperature water-bath
Enter sodium hydroxide solution 1.3g, ethyl acetate 45.0mL is added after being sufficiently mixed, 3h is stirred at room temperature to clarification.Stratification, water
Mutually extracted again with 45.0mL ethyl acetate, merge organic phase；Washed successively with 15mL water and saturated nacl aqueous solution 15mL, with nothing
Aqueous sodium persulfate is filtered after drying, and filtrate is concentrated into dilute crystalline substance, and compound (I) Niraparib 2.88g, the step are obtained after crystal is dried
The yield 94.2% of reaction, overall yield of reaction is 14.78%, and determining compound (I) Niraparib purity through HPLC is
99.85% (chromatogram is illustrated in fig. 1 shown below), uses Daicel companyAD-3 150mm × 2.1mm is chiral
It is 99.7% that post, which measures ee values,.1H-NMR(300MHz,DMSO-d6)(ppm)δ9.28(1H,s),8.57(1H,br,s),8.06
(2H, d, J=7.2Hz), 8.04 (2H, d, J=8.4Hz), 7.88 (2H, br.s), 7.49 (2H, d, J=8.4Hz), 7.27
(1H, dd, J=8.4,7.2Hz), and 3.08-2.94 (2H, m), 2.77-2.67 (1H, m), 2.76-2.73 (2H, m), 1.75-
1.47(4H,m).
13C-NMR(75MHz,DMSO-d6)δ(ppm):168.2,143.4,136.7,128.8,126.4,125.1,
123.9,120.9,115.2,52.2,48.8,43.5,30.8,25.1,MS(ESI)for(M+H)+:321.2.
Claims (9)
1. a kind of synthetic method for preparing PARP inhibitor Niraparib, synthetic route is as follows：
Wherein compound (I) is PARP inhibitor Niraparib.
2. a kind of synthetic method for preparing PARP inhibitor Niraparib according to right 1, it is characterised in that by adjacent ammonia
Yl benzoic acid methyl esters is mixed with sulfuric acid solution, then is slowly added dropwise natrium nitrosum, -10 DEG C to 10 DEG C of reaction temperature, generation it is reddish brown
Carry out in 10% sodium hydroxide solution environment with the tert-butyl group -3- Phenylpiperidine -1- t-butyl formates being coupled after color diazol anti-
Deserved intermediate (II), intermediate (II) structure is
3. a kind of synthetic method for preparing PARP inhibitor Niraparib according to claim 1, it is characterised in that in
Mesosome (II) is in the rhenium (Re of ten carbonyl two2(CO)10) and the catalysis of sodium acetate (NaOAc) under, the azobenzene of catalytic intermediary (II)
Structure cyclization, cyclization forms indazole ring in the dicyandiamide solution of methanol, obtains intermediate (III), realizes that a step constructs intermediate
(III) the indazole structure in, the structure of intermediate (III) is
4. a kind of synthetic method for preparing PARP inhibitor Niraparib according to claim 1, it is characterised in that 0
DEG C by intermediate (III) in dry DMF is dissolved in after add sodium methoxide, formamide, be warming up to 40 DEG C reaction 3.5h, methyl esters ammonolysis
The amide structure formed afterwards in intermediate (IV), obtains crude intermediate (IV), then at room temperature by crude intermediate (IV) plus
Enter to dioxane-water (volume ratio 8：1) in the mixed solvent, is warming up to 101 DEG C, the complete molten rear addition activated carbon of solid flows back,
Suction filtration, filtrate, stand, suction filtration while hot, dry, obtain intermediate (IV), the structure of intermediate (IV) is：
5. a kind of synthetic method for preparing PARP inhibitor Niraparib according to claim 1, it is characterised in that in
Mesosome (IV), with the de- BOC protection groups of trifluoroacetic acid reaction, solvent, the mol ratio of material is made with dichloromethane in dichloromethane
For intermediate (IV)：Dichloromethane：Trifluoracetic acid=1:5:1, reaction in about 3 hours is stirred at room temperature completely, is evaporated and obtains racemization
Intermediate (V), the structure of intermediate (V) is
6. a kind of synthetic method for preparing PARP inhibitor Niraparib according to claim 1, it is characterised in that will
Racemization intermediate (V) is dissolved in organic solvent the dissolving that flows back, and adds L- (+)-tartaric acid, and cool crystallization, separates solid crystal, obtains
To Niraparib.L- (+)-tartrate, it is dissolved in water, then hydrogenation sodium hydroxide solution alkalization adds acetic acid second
Ester is extracted, washing, is concentrated under reduced pressure and is drying to obtain compound (I) PARP inhibitor Niraparib, its structural formula isThe mass ratio of described organic solvent and Niraparib racemizations intermediate (V) for 10~
20:1；The mass ratio of described L- (+)-tartaric acid and Niraparib racemizations intermediate (V) is 0.5~5:1.
7. a kind of synthetic method for preparing PARP inhibitor Niraparib according to claim 1, it is characterised in that institute
The organic solvent used in the 5th step stated during racemization intermediate (V) chemical resolution is tetrahydrofuran, methanol, ethanol, third
Ketone, ethyl acetate or several arbitrary proportion mixtures, preferred alcohol, ethyl acetate, recrystallization temperature are -10~0 DEG C.
8. a kind of synthetic method for preparing PARP inhibitor Niraparib according to claim 1, it is characterised in that institute
The solvent used in BOC protection reaction preparation racemization intermediates (V) is taken off in the 4th step stated and is selected from tetrahydrofuran, dioxane, two
One or more of arbitrary proportions in chloromethanes, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene, acetonitrile are mixed
Polymer mixtures, preferably dichloromethane, it is room temperature to take off BOC institutes temperature in use.
9. a kind of synthetic method for preparing PARP inhibitor Niraparib according to claim 1, it is characterised in that institute
Potassium nitrite, calcium nitrite, silver nitrite, Asia can be used by the diazol for preparing of methyl anthranilate in the first step stated
The tertiary fourth of sodium nitrate, barium nitrite, nitrous ether (ethyl nitrite), isoamyl nitrite, isobutyl nitrite, Isopropyl Nitrite, nitrous acid
Ester, nitrous acid straight butyl, n-propyl nitrite are carried out as the reagent of diazo-reaction.
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| EA201992177A1 (en) | 2017-03-27 | 2020-02-25 | Тесаро, Инк. | COMPOSITIONS BASED ON NIRAPARIB |
| CN118271233A (en) * | 2017-04-24 | 2024-07-02 | 特沙诺有限公司 | Nilaparil manufacturing method |
| AU2018341479B2 (en) | 2017-09-26 | 2022-02-17 | Tesaro, Inc. | Niraparib formulations |
| CN109134351B (en) * | 2018-09-21 | 2022-03-11 | 武汉理工大学 | Synthesis method of S-3- (4-aminophenyl) piperidine |
| JP2022504228A (en) * | 2018-10-03 | 2022-01-13 | テサロ， インコーポレイテッド | Crystal form of niraparib free base |
| CN110156751B (en) * | 2019-05-28 | 2022-01-18 | 江苏食品药品职业技术学院 | Novel method for preparing nilapanib and intermediate thereof |
| CN110343088B (en) * | 2019-07-17 | 2021-05-11 | 东南大学 | Derivative based on PARP inhibitor Niraparib and preparation method and application thereof |
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| CN101578279A (en) * | 2007-01-10 | 2009-11-11 | P.安杰莱蒂分子生物学研究所 | Amide substituted indazoles as poly(ADP-ribose)polymerase (PARP) inhibitors |
-
2016
- 2016-09-14 CN CN201610825254.6A patent/CN106496187A/en not_active Withdrawn
-
2017
- 2017-07-21 CN CN201710598882.XA patent/CN107235958A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101578279A (en) * | 2007-01-10 | 2009-11-11 | P.安杰莱蒂分子生物学研究所 | Amide substituted indazoles as poly(ADP-ribose)polymerase (PARP) inhibitors |
Non-Patent Citations (3)
| Title |
|---|
| HUGO E. GOTTLIEB,ET AL.: "NMR Chemical Shifts of Common Laboratory Solvents as Trace Impurities", 《J. ORG. CHEM.》 * |
| PHILIP JONES，ET AL.: "Discovery of 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors", 《J. MED. CHEM.》 * |
| XIAOYU GENG ET AL.: "Rhenium-Catalyzed [4+1] Annulation of Azobenzenes and Aldehydes via Isolable Cyclic Rhenium(I) Complexes"", 《ORG. LETT.》 * |
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| CN106496187A (en) | 2017-03-15 |
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