CN105017140B - Anthranilamide compound and its production and use - Google Patents
Anthranilamide compound and its production and use Download PDFInfo
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- CN105017140B CN105017140B CN201410175341.2A CN201410175341A CN105017140B CN 105017140 B CN105017140 B CN 105017140B CN 201410175341 A CN201410175341 A CN 201410175341A CN 105017140 B CN105017140 B CN 105017140B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
Abstract
The invention belongs to pharmaceutical synthesis field, be related to the Anthranilamide compound of formula (I), more particularly to a kind of Anthranilamide compound and pyridine analogs containing piperidines or piperazine, and preparation method thereof and application medically.The compound of the present invention is tested by the target gene Gli inhibitory activity in external Hedgehog signal paths, is as a result shown, described compound has good Hedgehog signal path inhibitory activity, can further prepare new antineoplastic.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, is related to new Anthranilamide compound, preparation method and application.Specifically
Be related to a kind of Anthranilamide compound and pyridine analogs containing piperidines or piperazine, and preparation method thereof and medically
Application.
Background technology
Report display, malignant tumour turn into the common disease for seriously endangering people's life health.According to incompletely statistics, full generation
Boundary there are about 20,000,000 new cases every year；The annual new cases in China are about 160-200 ten thousand, and dead 1,300,000.Research is aobvious
Show, due to tumour ability of the early stage with transfer, about 50% patient has produced amphi position transfer in clinical diagnosis primary tumo(u)r, swells
Oncocyte increases fast, easily variation, so as to produce multidrug resistance, causes chemotherapy to fail, according to the relevent statistics, wherein more than 90% with it is swollen
The multidrug resistance of oncocyte is related, and the antineoplastic clinically applied at present is far from the requirement for meeting treatment.
The research of molecular targeted antineoplastic is the main trend and trend of current antineoplastic medicine research field.In recent years
Come, the antineoplastic of targeting Hedgehog (Hh) signal path turns into the new study hotspot in this field.Hedgehog(Hh)
Signal path plays an important role in the occurrence and development of tumour, has close contact with the tumour of the mankind about 1/3.Have
Research report, abnormal activation Hh signal transductions, will cause medulloblastoma, breast cancer, prostate cancer, lung cancer, colon cancer, bladder
The generation of the kinds of tumors such as cancer, oophoroma.Hedgehog is a kind of merism base found in the growth course of research drosophila
Cause, Hh signals are mainly mediated to intracellular transmission by transmembrane protein Ptch and Smo.During without Hh signals, Ptch is combined with Smo,
Suppress Smo effect, cause the suppression of transcription factor Gli transcriptional activities downstream.When there is Hh signals, Hh is combined with Ptch,
Inhibitory action of the Ptch to Smo is released, the Smo of activity recovery is passed on by level signal, activates Gli transcriptional activities, starts Hh
The transcript and expression of target gene.
At present in the antineoplastic research of targeting Hh signal paths, existing multiple medicines are listed or ground into clinic
Study carefully, as Genentech companies of the U.S. Vismodegid (GDC-0449) in 2012 by FDA ratify list, for skin
The treatment of cancer.In addition, Erismodegid (LDE225, Norvatis companies of Switzerland), LEQ-506 (Norvatis companies of Switzerland)
Clinical II phases and III phases are carried out with LY-2940680 (Lilly companies of the U.S.) etc., clinical studies show is to cutaneum carcinoma, brain
Cancer, medulloblastoma and other solid tumors are evident in efficacy.
More significantly, Hedgehog signal pathway inhibitors are being treated to tyrosine kinase inhibitor Imatinib
In non-small cell lung cancer (CML) patient procedure for producing resistance, the quantity of CML cells can not only be reduced, moreover it is possible to reduce Nai Yima
For the growth of Buddhist nun's CML cells, and it is the important difficulty that clinical therapy of tumor faces to have the problem of antineoplastic drug resistance at present
Topic.Therefore, the antineoplastic of targeting Hh signal path of the research and development with China's independent intellectual property right, suffer to improving China's tumour
The financial burden of person, clinical therapy of tumor effect is improved, is had great importance.
The content of the invention
It is an object of the invention to provide the new anthraniloyl with good Hedgehog signal paths inhibitory action
Amines, and in particular to a kind of Anthranilamide compound and its pyridine analogs containing piperidines or piperazine.
It is a further object of the present invention to provide the preparation method of above-mentioned Anthranilamide compound, more particularly to prepare
The method of Anthranilamide compound and its pyridine analogs containing piperidines or piperazine.
The Anthranilamide compound of the present invention has the structure of following formulas (I)：
Wherein：
X=C or N
Y=C or N
R2=H or or benzyl
R3=H or F or CF3Or 2- hydroxyl -2- isopropyls or 3- hydroxyl -3- isopentyl or ester group
In the present invention, preferable compound has the structure of following compounds 1,2,3,4,5,6,7,8,9：
By taking compound 5 as an example, the preparation process of compound of the invention is as follows：
Compound of the present invention is tested by external Hedgehog signal paths inhibitory activity, is as a result shown, described
Compound there is good Hedgehog signal path inhibitory activity, can further develop as new Hedgehog letters
Number pathway inhibitor and antineoplastic.
The present invention is tested external Hedgehog signal paths inhibitory activity, is as a result shown, compound is shown in the present invention
Go out preferable Hedgehog signal paths inhibitory activity, wherein compound 4 and 8 presses down for the target gene Gli in Hh signal paths
Make active IC50Value is less than 0.1 μM.The compound of the present invention can further prepare Hedgehog signal pathway inhibitors.
Used pharmacodynamics test method, it is method well-known to those skilled in the art in the present invention；
In the present invention, used NIH3T3 cells and Dual-Luciferase report detection kit is those skilled in the art
It can be obtained by approach purchased in market.
The Anthranilamide compound containing piperazine or piperidines and pyridine analogs of the present invention can especially be prepared
Hedgehog signal pathway inhibitors and antineoplastic.In view of abnormal activation Hh signal transductions, will cause medulloblastoma, breast
The generation of the kinds of tumors such as gland cancer, prostate cancer, lung cancer, colon cancer, carcinoma of urinary bladder, oophoroma.Malignant tumour of the present invention
Including the related neoplasms caused by Hedgehog signal path abnormal activations, including medulloblastoma, breast cancer, prostate cancer, lung
Cancer, colon cancer, carcinoma of urinary bladder, oophoroma, cutaneum carcinoma.
Embodiment
Embodiment 1：Synthesize compound 1,6- [4- [2- (dibenzyl amido) benzoyl] piperazine -1- bases]-ethyl nicotinate
1) 6- piperazinyl ethyl nicotinates are synthesized
6- chlorine apellagrins ethyl ester (12g, 0.06mol, 1.00equiv), piperazine (8.35g, 0.10mol, 1.50equiv) dissolving
In acetonitrile (100ml).Potassium carbonate (17.87g, 0.13mol, 2.00equiv) is added, under nitrogen protection, is flowed back at 100 DEG C
12h.TLC monitoring reactions are complete, filter, are evaporated filtrate.Ethyl acetate, moisture liquid are added, a small amount of washing twice, merges organic
Layer, saturated sodium-chloride are washed, anhydrous sodium sulfate drying, are stood.Filtrate is spin-dried for, and produces product 11.63g (Off-white solid) yield：
86.6%.MS(ESI)m/z([M+H]+):236.1。
2) N, N- dibenzyl -2- amido benzoic acid are synthesized
Ortho-aminobenzoic acid (10.0g), benzyl chloride (15.4g) are added in water (200ml), are added potassium carbonate (40.2g), are added
Heat backflow 12h, cooling, obtained alkaline solution is extracted with DCM (200ml × 3) removes unnecessary benzyl chloride, with dense under water layer ice bath
Hydrochloric acid adjusts pH ethyl acetate (200ml × 3) extraction, to merge organic layer, saturated sodium-chloride is washed, and anhydrous sodium sulfate is done to being approximately equal to 4
Dry, decompression boils off solvent and obtains product 18.2g, yield 79%.MS(ESI)m/z([M+H]+):316.1.
3) 6- [4- [2- (dibenzyl amido) benzoyl] piperazine -1- bases]-ethyl nicotinate is synthesized.
N, N- dibenzyl -2- amido benzoic acid 2.0g, EDC/HCl (2.4g) are added in THF (50ml), are stirred at room temperature
30min, 6- piperazinyl ethyl nicotinate 1.5g are added, argon gas protection, 2h are stirred at room temperature, TLC monitoring reactions are complete, and decompression boils off
THF, adds ethyl acetate and each 50ml of saturated aqueous common salt shakes layering, water layer EA (50ml × 3) extractions, merges organic layer, satisfies
Washed with sodium chloride, anhydrous sodium sulfate drying, decompression boils off solvent, the product 1.8g that ethyl alcohol recrystallization must purify, yield 55%.MS
(ESI)m/z([M+H]+):535.1。1HNMR (400MHz, CDCl3) δ 8.80 (d, J=1.8Hz, 1H), 8.05 (dd, J=9.0,
2.3Hz, 1H), 7.32-7.14 (m, 12H), 7.04 (t, J=7.2Hz, 2H), 6.54 (d, J=9.0Hz, 1H), 4.34 (q, J=
7.1Hz,2H),4.24(m,5H),3.97(m,1H),3.80–3.69(m,1H),3.50(m,2H),3.31–3.19(m,2H),
3.18-3.09 (m, 1H), 1.37 (t, J=7.1Hz, 3H).
Embodiment 2：Compound 2 is synthesized, [1- [2- (benzylamino) benzoyl] -4- [5- (2- hydroxy propane -2- bases) -
Pyridine -2- bases]] piperazine
1) [1- [2- (dibenzyl amido) benzoyl] -4- [5- (2- hydroxy propane -2- bases)-pyridine -2- bases]] is synthesized
Piperazine.
500mg6- [4- [2- (dibenzyl amido) benzoyl] piperazine -1- bases]-ethyl nicotinate, is dissolved in THF (15ml)
In, argon gas protection, -10 DEG C are cooled to, the grignard reagent (CH of iodomethane is added with syringe3MgI, 3ml, 3.0M/L), it is natural
Room temperature is warming up to, stirs 2h at room temperature, TLC monitoring reactions are complete, and reaction is quenched in saturated ammonium chloride solution (50ml), layering, water
Layer is extracted with ethyl acetate (50ml × 3), merges organic layer, and saturated sodium-chloride is washed, anhydrous sodium sulfate drying, and decompression boils off molten
Agent, crude product 420mg is obtained, take 100mg to prepare thin layer and separate the product 40mg that must be purified.MS(ESI)m/z([M+H]+):
521.1。
2) [1- [2- (benzylamino) benzoyl] -4- [5- (2- hydroxy propane -2- bases)-pyridine -2- bases]] piperazine is synthesized
Piperazine
500mg [1- [2- (dibenzyl amido) benzoyl] -4- [5- (2- hydroxy propane -2- bases)-pyridine -2- bases]] piperazine
Piperazine is dissolved in ethanol (20ml), and argon gas is replaced three times, adds Pd/C (50mg, Pd content 10%), and hydrogen is exchanged three times, room temperature
24h is reacted, TLC monitoring reactions are complete, filter out Pd/C, and decompression boils off ethanol, and obtaining light brown residue, directly to prepare thin layer pure
Change the product 110mg that must be purified.MS(ESI)m/z([M+H]+):431.1。1HNMR(600MHz,CDCl3)δ8.34(s,1H),
7.70 (d, J=7.4Hz, 1H), 7.35 (m, 4H), 7.26-7.10 (m, 3H), 6.80-6.57 (m, 3H), 4.38 (s, 2H),
4.15(s,1H),3.69(br,8H),1.60(s,6H)。
Embodiment 3：Synthesize compound 3, [1- [2- (dibenzyl amido) benzoyl] -4- [5- (3- hydroxyl pentanes -3-
Base)-pyridine -2- bases]] piperazine
500mg6- [4- [2- (dibenzyl amido) benzoyl] piperazine -1- bases]-ethyl nicotinate, be dissolved in THF (20ml,
It is super dry) in, argon gas protection, -10 DEG C are cooled to, the grignard reagent (C of bromoethane is added with syringe2H5MgI, 3ml, 3.0M/L),
Room temperature is warmed naturally to, stirs 2h at room temperature, TLC monitoring reactions are complete, and reaction is quenched in saturated ammonium chloride solution (50ml), point
Layer, aqueous layer with ethyl acetate (50ml × 3) extraction, merges organic layer, and saturated sodium-chloride is washed, anhydrous sodium sulfate drying, and decompression is steamed
Solvent is removed, obtains crude product 320mg, takes 100mg to prepare thin layer and separates the product 32mg that must be purified.MS(ESI)m/z([M+H]+):
549.1。1HNMR (400MHz, CDCl3) δ 8.19 (d, J=2.4Hz, 1H), 7.55 (dd, J=8.8,2.5Hz, 1H), 7.30-
7.14 (m, 12H), 7.07-6.97 (m, 2H), 6.60 (d, J=8.8Hz, 1H), 4.36-4.16 (m, 5H), 3.89-3.79 (m,
1H),3.62(m,1H),3.47(m,1H),3.38–3.23(m,2H),3.24–3.15(m,1H),3.12–3.04(m,1H),
1.89-1.71 (m, 4H), 1.61 (s, 1H), 0.78 (t, J=7.4Hz, 6H).
Embodiment 4：Synthesize compound 4, [1- (2- benzylaminos-nicotinoyl base) -4- [5- (2- hydroxy propane -2- bases)-pyrroles
Pyridine -2- bases]] piperazine
1) 6- [4- (2- chloronicotinoyls base) piperazine -1- bases]-ethyl nicotinate is synthesized.
1.0g2- chlorine apellagrins, 2.4gEDC/HCl are added in THF (50ml), and 30min is stirred at room temperature, and add DMAP
(155mg) and 1.5g6- piperazinyl ethyl nicotinates, argon gas protection, 12h is stirred at room temperature, TLC monitoring reactions are complete, and decompression boils off
THF, adds ethyl acetate and each 50ml of saturated aqueous common salt shakes layering, the extraction of water layer ethyl acetate, merges organic layer, saturation chlorine
Change sodium to wash, anhydrous sodium sulfate drying, decompression boils off solvent, column chromatography purifying, PE:EA=1:1 elutes the product 2.1g that must be purified.
Yield 92%.MS(ESI)m/z([M+H]+):375.0。
2) [1- (the chloro- nicotinoyl bases of 2-) -4- [5- (2- hydroxy propane -2- bases)-pyridine -2- bases]] piperazine is synthesized.
300mg6- [4- (2- chloronicotinoyls base) piperazine -1- bases]-ethyl nicotinate is dissolved in THF (15ml), argon gas protection,
- 10 DEG C are cooled to, the grignard reagent (CH of iodomethane is added with syringe3MgI, 3ml, 3.0M/L), 12h is stirred at -10 DEG C,
TLC monitoring reactions are complete, and reaction is quenched in saturated ammonium chloride solution (50ml), layering, aqueous layer with ethyl acetate (50ml × 3) extraction
Take, merge organic layer, saturated sodium-chloride is washed, anhydrous sodium sulfate drying, and decompression boils off solvent, and column chromatography purifies to obtain product 160mg.
MS(ESI)m/z([M+H]+):361.0。
3) [1- (2- benzylaminos-nicotinoyl base) -4- [5- (2- hydroxy propane -2- bases)-pyridine -2- bases]] piperazine is synthesized.
160mg [1- (the chloro- nicotinoyl bases of 2-) -4- [5- (2- hydroxy propane -2- bases)-pyridine -2- bases]] piperazine dissolved is in benzyl
Amine (5ml), argon gas are protected, and 24h is stirred at 90 DEG C, and decompression (40mmHg) distillation removes benzylamine, obtains residue and directly prepare thin layer
Purified product 32mg.MS(ESI)m/z([M+H]+):432.1。1HNMR (400MHz, CDCl3) δ 8.31 (d, J=2..5Hz,
1H), 8.21 (d, J=4.2Hz, 1H), 7.68 (dd, J=8.8,2.4Hz, 1H), 7.34 (m, 5H), 7.23 (s, 1H), 6.67-
6.56 (m, 2H), 6.16 (t, J=5.3Hz, 1H), 4.66 (d, J=5.3Hz, 2H), 3.73 (s, 4H), 3.66-3.49 (m,
4H),2.03(s,1H),1.57(s,6H).。
Embodiment 5：Synthesize compound 5,1- [2- (base of 2- methylpyrazoles -3) amido]-benzoyl) -4- (2- fluoroforms
The fluoro- benzoyls of base -4-)-piperazine
1) 1- (the iodo- benzoyls of 2-) -4- tbutyloxycarbonyl-piperazins are synthesized
3.0g2- iodo-benzoic acids, 4.6gEDC/HCl are added in THF (50ml), and 30min is stirred at room temperature, and add Boc piperazines
(2.3g), argon gas protection, 12h is stirred at room temperature, TLC monitoring reactions are complete, and decompression boils off THF, add ethyl acetate and saturation food
Each 50ml of salt solution shakes layering, water layer ethyl acetate (50ml × 3) extraction, merges organic layer, saturated sodium-chloride is washed, anhydrous slufuric acid
Sodium is dried, and decompression boils off solvent, column chromatography purifying, PE:EA=1:1 elutes the product 2.5g that must be purified.White solid, yield
50%.MS(ESI)m/z([M+H]+):417.1。
2) 1- (the iodo- benzoyls of 2-)-piperazine hydrochloride is synthesized
1- (the iodo- benzoyls of 2-) -4- tbutyloxycarbonyl-piperazins (2.0g), are placed in 50ml eggplant-shape bottles, add 8%
HCl/EA (20ml), 2h being stirred at room temperature, TLC monitoring reactions are complete, directly remove solvent under reduced pressure, obtain white solid 2.2g, without
Purifying is directly used in reacts in next step.
3) 1- (the iodo- benzoyls of 2-) -4- (the fluoro- benzoyls of 2- trifluoromethyls -4-)-piperazine is synthesized
It is obtained in the previous step that (1- (the iodo- benzoyls of 2-)-piperazine hydrochloride (2.2g) is dissolved in THF (50ml), adds three
Ethamine (3.5ml), stirring 30min are standby.2- trifluoromethyl -4- fluobenzoic acids (1.0g) are dissolved in THF (50ml), add EDC/
HCl (1.9g), stirs 30min at room temperature, adds (1- (the iodo- benzoyls of 2-)-piperazine THF solution, the argon gas guarantor of above-mentioned preparation
Shield, 12h being stirred at room temperature, TLC monitoring reactions are complete, and decompression boils off THF, add EA and each 100ml of saturated aqueous common salt and shake layering,
Water layer EA (50ml × 3) is extracted, and merges EA layers, and saturated sodium-chloride is washed, anhydrous sodium sulfate drying, and decompression boils off solvent, column chromatography
Purifying, PE:EA=1:1 elutes the product 1.9g that must be purified.White solid, yield 79%.MS(ESI)m/z([M+H]+):
508.1。1HNMR (400MHz, CDCl3) δ 7.84 (dd, J=28.0,8.0Hz, 1H), 7.49-7.26 (m, 4H), 7.24-7.02
(m,2H),4.14–3.62(m,4H),3.26(m,4H).
4) 1- [2- (base of 2- methylpyrazoles -3) amido]-benzoyl is synthesized) -4- (the fluoro- benzoyls of 2- trifluoromethyls -4-
Base)-piperazine
In 5ml microwave tube, sequentially add 1- (the iodo- benzoyls of 2-) -4- (the fluoro- benzoyls of 2- trifluoromethyls -4-) -
Piperazine (100mg), dimethylbenzene (2ml), 1- methyl -6- amidopyrazoles (23mg), BINAP (25mg), t-BuOK (56mg), argon gas
Stream blows microwave tube 2min, adds Pd (dba) 2 (18mg), and argon gas stream blows microwave tube 2min, seals, microwave reaction (120 DEG C, 1h).
TLC monitoring reactions are complete, remove solvent under reduced pressure, directly prepare thin layer and purify to obtain product 66mg.MS(ESI)m/z([M+H]+):
476.0。1HNMR(600MHz,CDCl3) δ 7.52-7.32 (m, 4H), 7.19 (d, J=6.3Hz, 2H), 6.94-6.73 (m, 2H),
6.05(s,1H),4.00(m,3H),3.72(s,6H),3.60(s,1H),3.28(s,2H).。
Embodiment 6：Synthesize compound 6,1- [2- (base of 2- methylpyrazoles -3) amido]-nicotinoyl base) -4- (2- trifluoromethyls -
The fluoro- benzoyls of 4-)-piperazine
1) 1- (the chloro- nicotinoyl bases of 2-) -4- tbutyloxycarbonyl-piperazins are synthesized
2.0g2- chlorine apellagrin compounds, 4.8gEDC/HCl are added in THF (100ml), and 30min is stirred at room temperature, and are added
DMAP (155mg) and Boc piperazines (2.4g), argon gas protection, 12h being stirred at room temperature, TLC monitoring reactions are complete, and decompression boils off THF,
Add EA and each 100ml of saturated aqueous common salt and shake layering, water layer EA (50ml × 3) extractions, merge organic layer, saturated sodium-chloride
Wash, anhydrous sodium sulfate drying, decompression boils off solvent, column chromatography purifying, PE:EA=1:1 elutes the product 2.1g that must be purified.Yield
50%.MS(ESI)m/z([M+H]+):326.0
2) 1- (the chloro- nicotinoyl bases of 2-)-piperazine hydrochloride is synthesized
1- (the chloro- nicotinoyl bases of 2-) -4- tbutyloxycarbonyl-piperazins (2.0g), are placed in 50ml eggplant-shape bottles, add 8%HCl/
EA (20ml), 2h, TLC (PE is stirred at room temperature:EA=1:1) monitoring reaction is complete, directly removes solvent under reduced pressure, obtains white solid
2.2g, it is directly used in without purifying and reacts in next step.
3) 1- (the chloro- nicotinoyl bases of 2-) -4- (the fluoro- benzoyls of 2- trifluoromethyls -4-)-piperazine is synthesized
1- (the chloro- nicotinoyl bases of 2-)-piperazine hydrochloride (2.2g) obtained in the previous step is dissolved in THF (50ml), adds three second
Amine (3.7ml), stirring 30min are standby.2- trifluoromethyl -4- fluobenzoic acids (1.2g) are dissolved in THF (50ml), add EDC/
HCl (1.9g), stirs 30min at room temperature, adds 1- (the chloro- nicotinoyl bases of 2-)-piperazine THF solution of above-mentioned preparation, and argon gas is protected,
12h is stirred at room temperature, TLC monitoring reactions are complete, and decompression boils off THF, add EA and each 100ml of saturated aqueous common salt and shake layering, water
Layer EA (50ml × 3) extractions, merge organic layer, and saturated sodium-chloride is washed, anhydrous sodium sulfate drying, and decompression boils off solvent, column chromatography
Purifying, PE:EA=1:3 elute the product 1.7g that must be purified.White solid, yield 49%.MS(ESI)m/z([M+H]+):
417.0。
4) 1- [2- (base of 2- methylpyrazoles -3) amido]-nicotinoyl base is synthesized) -4- (the fluoro- benzoyls of 2- trifluoromethyls -4-
Base)-piperazine
In 5ml microwave tube, 1- (the chloro- nicotinoyl bases of 2-) -4- (the fluoro- benzoyls of 2- trifluoromethyls -4-)-piperazine is sequentially added
Piperazine (60mg), dimethylbenzene (2ml), 1- methyl -6- amidopyrazoles (17mg), BINAP (19mg), t-BuOK (42mg), argon gas stream
Microwave tube 2min is blown, adds Pd (dba) 2 (14mg), argon gas stream blows microwave tube 2min, seals, microwave reaction (120 DEG C, 1h).
TLC monitoring reactions are complete, remove solvent under reduced pressure, directly prepare thin layer purifying, DCM:MeOH=20:1 expansion, obtain the product of purifying
37mg。MS(ESI)m/z([M+H]+):477.0。1HNMR(600MHz,CDCl3)δ8.29(s,1H),8.22(s,1H),7.49
(m,3H),7.37(s,2H),6.82(s,1H),6.33(s,1H),4.04(s,1H),3.85(s,1H),3.77(s,3H),
3.74–3.51(m,4H),3.30(s,2H)。
Embodiment 7：Synthesis compound 7, N- [1- (2- trifluoromethyl -4- fluoro benzoyls) piperidin-4-yl]-N- methyl -
1- (2- (base of 2- methylpyrazoles -3) amido]-phenyl) formamide
1) N- (1- t-butoxycarbonylpiperidin -4- bases)-N- methyl isophthalic acids-(2- iodophenyls) formamide is synthesized.
2- iodo-benzoic acids (1.2g), EDC/HCl (1.8g) are added in THF (50ml), and 30min is stirred at room temperature, and add N-
Boc-4- amine methyl piperidine (1.0g), argon gas protection, 12h is stirred at room temperature, TLC monitoring reactions are complete, and decompression boils off THF, add
Ethyl acetate and each 50ml of saturated aqueous common salt shake layering, water layer EA (50ml × 3) extractions, merge organic layer, saturated sodium-chloride
Wash, anhydrous sodium sulfate drying, decompression boils off solvent, column chromatography purifying, PE:EA=1:1 elutes the product 0.6g that must be purified.White
Solid, yield 28%.MS(ESI)m/z([M+H]+):445.1。
2) N- (piperidin-4-yl)-N- methyl isophthalic acids-(2- iodophenyls) carboxamide hydrochloride is synthesized
N- (1- t-butoxycarbonylpiperidin -4- bases)-N- methyl isophthalic acids-(2- iodophenyls) formamide (0.5g), is placed in 50ml eggplants
In shape bottle, 8%HCl/EA (10ml) is added, 2h is stirred at room temperature, TLC monitoring reactions are complete, directly remove solvent under reduced pressure, obtain white
Solid 0.7g, it is directly used in without purifying and reacts in next step.
3) N- [1- (2- trifluoromethyl -4- fluoro benzoyls) piperidin-4-yl]-N- methyl isophthalic acids-(2- iodophenyls) first are synthesized
Acid amides
N- (piperidin-4-yl)-N- methyl isophthalic acids-(2- iodophenyls) carboxamide hydrochloride (0.5g) obtained in the previous step is dissolved in
THF (20ml), adds triethylamine (0.9ml), and stirring 30min is standby.2- trifluoromethyl -4- fluobenzoic acids (0.25g) are dissolved in
THF (50ml), EDC/HCl (0.5g) is added, 30min is stirred at room temperature, adds N- (piperidin-4-yl)-N- first of above-mentioned preparation
Base -1- (2- iodophenyls) formamide THF solution, argon gas protection, 12h is stirred at room temperature, TLC monitoring reactions are complete, and decompression boils off
THF, add EA and each 50ml of saturated aqueous common salt and shake layering, water layer EA (50ml × 3) extractions, merge organic layer, saturation chlorination
Sodium is washed, anhydrous sodium sulfate drying, and decompression boils off solvent, column chromatography purifying, PE:EA=1:1 elutes the product 0.36g that must be purified.
White solid, yield 60%.MS(ESI)m/z([M+H]+):536.1。1HNMR (400MHz, CDCl3) δ 7.82 (d, J=
7.3Hz, 1H), 7.47-7.36 (m, 2H), 7.36-7.24 (m, 2H), 7.20 (s, 1H), 7.08 (t, J=7.6Hz, 1H),
4.94m, 2H), 3.45 (m, 1H), 3.30-3.10 (m, 1H), 3.08-2.76 (m, 2H), 2.69 (d, J=15.9Hz, 2H),
1.80(br,2H),1.37–1.14(m,3H).
4) N- [1- (2- trifluoromethyl -4- fluoro benzoyls) piperidin-4-yl]-N- methyl isophthalic acids-(2- (2- methyl pyrroles are synthesized
The base of azoles -3) amido]-phenyl) formamide
In 5ml microwave tube, N- [1- (2- trifluoromethyl -4- fluoro benzoyls) piperidin-4-yl]-N- first is sequentially added
Base -1- (2- iodophenyls) formamide (100mg), dimethylbenzene (2ml), 1- methyl -6- amidopyrazoles (22mg), BINAP (24mg),
T-BuOK (53mg), argon gas stream blow microwave tube 2min, add Pd (dba) 2 (18mg), and argon gas stream blows microwave tube 2min, seal, micro-
Ripple reacts (120 DEG C, 1h).TLC monitoring reactions are complete, remove solvent under reduced pressure, directly prepare thin layer and purify to obtain product 37mg.MS
(ESI)m/z([M+H]+):504.0。1HNMR(400MHz,CDCl3)δ7.43(m,2H),7.40–7.28(m,2H),7.23(d,J
=7.8Hz, 1H), 7.15 (m, 2H), 6.85 (t, J=7.5Hz, 1H), 6.78 (dd, J=8.2,4.1Hz, 1H), 6.01 (s,
1H), 4.93 (t, J=14.6Hz, 1H), 3.68 (s, 3H), 3.43 (m, 1H), 3.14 (br, 1H), 2.95 (d, J=14.4Hz,
3H),2.82(br,1H),1.87(m,2H),1.64(br,3H).。
Embodiment 8：Synthesize compound 8, N- [1- [2- (2- methylpyrazole -3- bases) amido] phenyl]-N- methyl isophthalic acids-(2-
Trifluoromethyl -4- fluorophenyls) formamide
1) N- (1- t-butoxycarbonylpiperidin -4- bases)-N- methyl isophthalic acids-(2- trifluoromethyl -4- fluorophenyls) formamide is synthesized.
2- trifluoromethyl -4- fluobenzoic acids (4.0g) are dissolved in THF (100ml), add EDC/HCl (7.3g), at room temperature
30min is stirred, DMAP (460mg) is added, argon gas protection, 20h is stirred at room temperature, TLC monitoring reactions are complete, and decompression boils off THF, adds
Enter ethyl acetate and each 50ml of saturation NaHCO3 shake layering, water layer EA (50ml × 3) extractions, merge organic layer, saturation chlorination
Sodium is washed, anhydrous sodium sulfate drying, and decompression boils off solvent, column chromatography purifying, PE:EA=2:1 elutes the product 4.3g that must be purified.In vain
Color solid, yield 56%.MS(ESI)m/z([M+Na]+):427.0。
2) N- (piperidin-4-yl)-N- methyl isophthalic acids-(2- trifluoromethyl -4- fluorophenyls) carboxamide hydrochloride is synthesized.
N- (1- t-butoxycarbonylpiperidin -4- bases)-N- methyl isophthalic acids-(2- trifluoromethyl -4- fluorophenyls) formamide (4.3g),
It is placed in 50ml eggplant-shape bottles, adds 8%HCl/EA (20ml), 2h is stirred at room temperature, TLC monitoring reactions are complete, directly remove under reduced pressure
Solvent, white solid 5.1g is obtained, be directly used in without purifying and react in next step.
3) N- [1- (2- iodobenzoyls) piperidin-4-yl]-N- methyl isophthalic acids-(2- trifluoromethyl -4- fluorophenyls) first is synthesized
Acid amides
N- (piperidin-4-yl)-N- methyl isophthalic acids obtained in the previous step-(2- trifluoromethyl -4- fluorophenyls) carboxamide hydrochloride
(0.5g) is dissolved in THF (20ml), adds triethylamine (0.7ml), and stirring 30min is standby.The iodo- benzoic acid of 2- (0.4g) is dissolved in
THF (50ml), EDC/HCl (0.6g) is added, 30min is stirred at room temperature, adds N- (piperidin-4-yl)-N- first of above-mentioned preparation
Base -1- (2- trifluoromethyl -4- fluorophenyls) formamide THF solution, argon gas protection, 12h being stirred at room temperature, TLC monitoring reactions are complete,
Decompression boils off THF, adds ethyl acetate and each 50ml of saturated aqueous common salt shakes layering, water layer EA (50ml × 3) extractions, be associated with
Machine layer, saturated sodium-chloride are washed, anhydrous sodium sulfate drying, and decompression boils off solvent, column chromatography purifying, PE:EA=1:1 elutes and must purify
Product 0.36g.White solid, yield 46%.MS(ESI)m/z([M+H]+):536.1。
4) N- [1- [2- (2- methylpyrazole -3- bases) amido] phenyl]-N- methyl isophthalic acids-(2- trifluoromethyl -4- fluorobenzene are synthesized
Base) formamide
In 5ml microwave tube, N- [1- (2- iodobenzoyls) piperidin-4-yl]-N- methyl isophthalic acids-(2- trifluoros are sequentially added
Methyl -4- fluorophenyls) formamide (100mg), dimethylbenzene (2ml), 1- methyl -6- amidopyrazoles (22mg), BINAP (24mg),
T-BuOK (53mg), argon gas stream blow microwave tube 2min, add Pd (dba) 2 (18mg), and argon gas stream blows microwave tube 2min, seal, micro-
Ripple reacts (120 DEG C, 1h).TLC monitoring reactions are complete, remove solvent under reduced pressure, directly prepare thin layer and purify to obtain product 65mg.MS
(ESI)m/z([M+H]+):504.0。1HNMR (400MHz, CDCl3) δ 8.27 (t, J=7.9Hz, 1H), 7.51 (dd, J=7.4,
1.5Hz, 1H), 7.44 (dd, J=14.3,5.5Hz, 2H), 7.33 (s, 1H), 7.24-7.04 (m, 1H), 6.78 (m, 1H),
6.31(s,1H),4.88(m,1H),4.38(br,2H),3.74(s,3H),3.13(br,2H),2.68(s,3H),1.90(m,
2H),1.69(m,2H).。
Embodiment 9：Synthesize compound 9, N- [1- [2- (2- methylpyrazole -3- bases) amido] pyridin-3-yl] piperidines -4-
Base]-N- methyl isophthalic acids-(2- trifluoromethyl -4- fluorophenyls) formamide
1) N- [1- (2- chloronicotinoyls base) piperidin-4-yl]-N- methyl isophthalic acids-(2- trifluoromethyl -4- fluorophenyls) formyl is synthesized
Amine.
N- (piperidin-4-yl)-N- methyl isophthalic acids-(2- trifluoromethyl -4- fluorophenyls) carboxamide hydrochloride (0.5g) is dissolved in
THF (20ml), triethylamine (0.7ml) is added, stir 30min, it is standby.The chloro- nicotinic acid of 2- (0.3g) is dissolved in THF (50ml), adds
Enter EDC/HCl (0.6g), stir 30min at room temperature, add N- (piperidin-4-yl)-N- methyl isophthalic acids-(2- trifluoros of above-mentioned preparation
Methyl -4- fluorophenyls) formamide THF solution, argon gas protection, 12h is stirred at room temperature, TLC monitoring reactions are complete, and decompression boils off THF,
Add ethyl acetate and each 50ml of saturated aqueous common salt shakes layering, water layer EA (50ml × 3) extractions, merge organic layer, saturation chlorine
Change sodium to wash, anhydrous sodium sulfate drying, decompression boils off solvent, column chromatography purifying, PE:EA=1:1~1:3 elute the product that must be purified
0.29g.White solid, yield 43%.MS(ESI)m/z([M+H]+):416.0。
2) N- [1- [2- (2- methylpyrazole -3- bases) amido] pyridin-3-yl] piperidin-4-yl is synthesized]-N- methyl isophthalic acids-(2-
Trifluoromethyl -4- fluorophenyls) formamide.
In 5ml microwave tube, N- [1- (2- chloronicotinoyls base) piperidin-4-yl]-N- methyl isophthalic acids-(2- fluoroforms are sequentially added
Base -4- fluorophenyls) formamide (100mg), dimethylbenzene (2ml), 1- methyl -6- amidopyrazoles (27mg), BINAP (29mg), t-
BuOK (65mg), argon gas stream blow microwave tube 2min, add Pd (dba) 2 (21mg), and argon gas stream blows microwave tube 2min, seal, microwave
React (120 DEG C, 1h).TLC monitoring reactions are complete, remove solvent under reduced pressure, directly prepare thin layer purifying, PE:EA=1：3 expansion 2
It is secondary, obtain the product 44mg of purifying.MS(ESI)m/z([M+H]+):505.0。1HNMR(600MHz,CDCl3)δ7.43(m,4H),
7.24(s,2H),6.86(br,2H),6.05(s,1H),4.90(s,1H),3.74(s,3H),3.31–2.51(m,5H),1.99
(m,4H)。
Embodiment 10：External Hedgehog signal paths inhibitory activity test
Transcription factor Gli luciferase reporter gene experiment：NIH3T3 cells are seeded to 48 orifice plates, after 24h with
Lipo2000 transfection reagents transfection Gli-firefly luciferase reporter and TK-Renilla luciferase
Reporter carriers are to NIH3T3 cells.After transfecting 36h, SHH and medicine to be measured that mouse source is recombinated add to 48 orifice plates (every group set
3 multiple holes；N=3).After cellar culture 36h, cell is washed 1 time with PBS, and with Dual-Luciferase report detection kit, (Promega is public
Department) measure Gli-luciferase activity, as judging Hh pathway activity indexs；
As a result show (as shown in table 1), compound shows that preferable Hedgehog signal paths suppress to live in the present invention
Property, wherein compound 4 and 8 is for the target gene Gli inhibitory activity IC in Hh signal paths50Value is less than 0.1 μM.The change of the present invention
Compound can further develop Hedgehog signal pathway inhibitors, as new type antineoplastic medicine.
Table 1 is the external inhibitory activity result of the Hedgehog signal paths of the compounds of this invention.
Table 1
Claims (9)
1. the Anthranilamide compound of logical formula (I) structure, it is characterized in that, described compound is containing piperidines or piperazine
Anthranilamide compound and pyridine analogs,
Wherein：
X=C or N
Y=C or N
R2=H
R3=H or F or CF3。
2. Anthranilamide compound according to claim 1, it is characterized in that, described compound is with following
The compound 5 of structure,
3. Anthranilamide compound according to claim 1, it is characterized in that, described compound is with following
The compound 6 of structure,
4. Anthranilamide compound according to claim 1, it is characterized in that, described compound is with following
The compound 7 of structure,
5. Anthranilamide compound according to claim 1, it is characterized in that, described compound is with following
The compound 8 of structure,
6. Anthranilamide compound according to claim 1, it is characterized in that, described compound is with following
The compound 9 of structure,
7. purposes of the Anthranilamide compound of claim 1 in Hedgehog signal pathway inhibitors are prepared.
8. the Anthranilamide compound of claim 1 is preparing the purposes in treating malignant tumor medicine.
9. the purposes according to claim 8, it is characterised in that described malignant tumour is Hedgehog signal paths abnormal activation institute
The related neoplasms of cause, it is medulloblastoma, breast cancer, prostate cancer, lung cancer, colon cancer, carcinoma of urinary bladder, oophoroma, cutaneum carcinoma.
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