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CN108997394A - Benzoxaborole Polymorphs alkyl compound and preparation method thereof - Google Patents

Benzoxaborole Polymorphs alkyl compound and preparation method thereof Download PDF

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CN108997394A
CN108997394A CN201810602298.1A CN201810602298A CN108997394A CN 108997394 A CN108997394 A CN 108997394A CN 201810602298 A CN201810602298 A CN 201810602298A CN 108997394 A CN108997394 A CN 108997394A
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obtains
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吴忠
李静荣
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Guangzhou Baiting Pharmaceutical Technology Co Ltd
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    • A—HUMAN NECESSITIES
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Abstract

The present invention relates to benzoxaborole Polymorphs alkyl compound and its pharmaceutically acceptable salts or solvate.The compound structure is as follows:

Description

Benzoxaborole Polymorphs alkyl compound and preparation method thereof
Technical field
The present invention relates to phosphodiesterase PDE4 inhibiting effect benzoxaborole Polymorphs alkyl compound and its Preparation method.
Background technique
Phosphodiesterase (Phosphodiesterase, PDE) is intracellular loops adenosine phosphate (cAMP) and cyclic guanosine monophosphate (cGMP) specific hydrolase enzyme.PDE has 11 hypotypes, including PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10 and PDE11.These PDE hypotypes maintain body normal by the balance of regulation cAMP and cGMP level Function, therefore, the imbalance of PDE function will lead to the generation of many diseases, including chronic obstructive pneumonia, asthma, arthritis, Atopic dermatitis, allergic dermatitis, psoriasis, allergic rhinitis, Crohn disease, adult respiratory distress syndrome (ARDS), conjunctivitis, bone Arthritis etc. (Annu Rev Biochem.2007,76:481-511).PDE4 hypotype is the di(2-ethylhexyl)phosphate that main transmitting inflammation occurs Esterase, including tetra- hypotypes of PDE4A, PDE4B, PDB4E and PDB4D.PDB4 inhibitor clinically has been used for inflammation associated The treatment of disease, as chronic obstructive pneumonia, atopic dermatitis treatment (Expert Opin.Investig.Drugs 2015, 24:1597-1611).Roflumilast (Roflumilast) is PDE4 suppression of first listing for chronic obstructive pneumonia treatment Preparation, since with adverse reactions such as Nausea and vomitings, application clinically is very restricted.Gram vertical boron sieve It (crisaborole) is that first be approved listing by U.S. FDA on December 14th, 2016 is used to treat atopic dermatitis The non-steroid PDE4 inhibitor of external application, but (British is remained to be further improved to the clinical efficacy of specific skin inflammation Journal of Dermatology 2018,178:659-662).Therefore, it is based on the studies above background, needs to be further discovered that Higher to activity, tolerance is more preferable, and the smaller Novel PDE 4 inhibitors of adverse reaction are for clinic.
Summary of the invention
It is an object of the present invention to provide a kind of benzoxaborole Polymorphs alkanes with phosphodiesterase PDE4 inhibiting effect Compound and its pharmaceutically acceptable salt or solvate.And further provide for the preparation method of such compound.
Shown in the following general formula (i) of the compounds of this invention structure:
B is boron；X is selected from oxygen (O), sulphur (S), nitrogen hydrogen (NH), N-methyl (NMe) or nitrogen benzyl (NBn)；R1 is selected from hydrogen, Halogen or nitro；R2 is selected from hydrogen, methyl, halogen or nitro etc..
Its unrestricted pharmaceutically acceptable salt includes inorganic acid salt, acylate, alkylsulfonate and aryl sulphur Hydrochlorate；The inorganic acid salt includes but are not limited to hydrochloride, hydrobromate, nitrate, sulfate, phosphate；It is described organic Hydrochlorate includes but are not limited to formates, acetate, propionate, benzoate, maleate, fumarate, succinate, wine Stone hydrochlorate, citrate；The alkylsulfonate includes but are not limited to methyl sulfonate, ethyl sulfonate；The aryl sulphur Hydrochlorate includes but are not limited to benzene sulfonate, tosilate；
Its pharmaceutically acceptable solvate, unrestricted includes itself and water, ethyl alcohol, isopropanol, ether or acetone Solvate.
The present invention preferably descends the compound of table structure:
The compound of the present invention has phosphodiesterase PDE4 inhibiting effect, can pass through the release of inhibition proinflammatory cytokine And treat inflammation related disease.Such as dermatitis, atopic dermatitis, allergic dermatitis and psoriasis etc.；Inflammatory bowel disease, such as Crow Grace disease, ulcerative colitis and nonspecific colonitis etc. and rheumatic arthritis.
The compound of the present invention benzoxaborole heterocycle pentane is the molecular skeleton containing boron atom, boron-containing compound tool There are inhibition atopic dermatitis, effect (the Journal of Dermatological of allergic dermatitis and other diseases associated with inflammation Treatment.Utility of boron in dermatology.https://doi.org/10.1080/ 09546634.2017.1363850).Gram vertical boron sieve is PDE4 inhibitor approval the controlling for atopic dermatitis of first boracic Treat (Curr Opin Investig Drugs.2009 10:1236-1242；CN101420854A), in view of containing boron atom Importance of the PDE4 inhibitor compound in treatment diseases associated with inflammation, the present invention is with benzoxaborole heterocycle pentane for basic bone Frame carries out structure of modification, it was found that the new benzo oxygen of the structural units such as benzothiazole, benzoxazoles and benzimidazole Miscellaneous boron Polymorphs alkyl compound has the PDE4 inhibitory activity and curative effect for being significantly higher than the boron-containing compound listed.
Specific embodiment
The present invention is further elaborated combined with specific embodiments below.These embodiments are only the mesh for explanation , and do not limit the scope of the invention and essence.
Nuclear magnetic data BrukerThe measurement of 600 nuclear magnetic resonance spectrometers, all solvents are passed through again using preceding Distillation, used anhydrous solvent are to be dried to obtain by standard method.
The system of amyl- 1 (3H) -ol (S1) of embodiment 1:5- (benzothiazole -2- oxygroup) benzo [c] [1,2] oxa- boron heterocycle It is standby
Step 1: under nitrogen protection, by 0.402g, the bromo- 5- hydroxy benzaldehyde of the 2- of 2.0mmol) it is dissolved in 10mL N.N- In dimethylformamide, 0.339g, the 2- chloro benzothiazole and 5.5g of 2.0mmol, the potassium carbonate of 40mmol, mixing is then added Liquid is stirred overnight at 80 DEG C, is then cooled down, filtering, and filtrate successively adds water and methylene chloride to extract, organic phase concentration, residual solution warp Column chromatographic isolation and purification is crossed, obtains the bromo- 5- of 2- (benzothiophene -2- oxygroup)-benzaldehyde, 0.34 gram of white solid, yield 51%.
Step 2. under nitrogen protection, by 0.334g, 5- (benzothiophene -2- oxygroup) -2- bromobenzaldehyde of 1.0mmol, It is dissolved in 3mL Isosorbide-5-Nitrae-dioxane, is then added 0.279g, 1.1mmol duplex pinacol borate, 22mg, 0.03mmol's PdCl2(dppf)) it is stirred overnight at 80 DEG C, then cools down with 0.294g, 3.0mmol potassium acetate, mixed liquor, filter, filtrate is dense Contracting, residual solution pass through column chromatographic isolation and purification, obtain 5- (benzothiophene -2- oxygroup) -2- (4,4,5,5,-tetramethyl -1,3,2- Penta ring -2- base of dioxy boron) benzaldehyde, 0.24 gram of white solid, yield 63%.
Step 3. by 0.15g, 0.39mmol 5- (benzothiophene -2- oxygroup) -2- (4,4,5,5,-tetramethyl -1,3,2- Penta ring -2- base of dioxy boron) benzaldehyde is dissolved in 5mL methanol, then in 0 DEG C of addition 16.3mg, 0.43mmol sodium borohydride, mixing Liquid stirs 20 minutes at 0 DEG C, then continues stirring 1 hour in room temperature, the hydrochloric acid of 1mL water and 5mL, 3N is added, it is small to be stirred at room temperature 2 When, it is amyl- to obtain 5- (benzothiazole -2- oxygroup) benzo [c] [1,2] oxa- boron heterocycle for mixture concentration, column chromatographic isolation and purification 1 (3H) -ol (S1) 0.045g, yield 41%.1H NMR(CDCl3, 600MHz): δ 7.81 (d, J=7.8Hz, 1H), 7.76 (d, J =7.8Hz, 1H), 7.71 (d, J=7.8Hz, 1H), 7.42-7.39 (m, 1H), 7.38 (d, J=1.8Hz, 1H), 7.35 (dd, J =7.8,1.8Hz, 1H), 7.31-7.29 (m, 1H), 5.31 (s, 1H), 5.12 (s, 2H)13C NMR(CDCl3,150MHz):δ 171.5,157.1,156.0,148.8,132.3,132.2,126.4,124.3,121.8,121.4,119.9,113.3,70.9.
Amyl- 1 (3H) -ol (S2) of embodiment 2:5- (5- fluoro benzothiazole -2- oxygroup) benzo [c] [1,2] oxa- boron heterocycle Preparation
Under nitrogen protection, by 3.0g, the bromo- 5- hydroxy-benzaldehyde of the 2- of 14.9mmol is dissolved in 30mL Isosorbide-5-Nitrae-two to step 1. In six ring of oxygen, 5.68g, 22.35mmol duplex pinacol borate, 1.09g, 1.49mmol PdCl is then added2(dppf) and 4.4g, 44.7mmol potassium acetate, mixed liquor are stirred overnight at 80 DEG C, then cool down, filtering, and filtrate concentration, residual solution passes through column Chromatography purifying, obtains 5- hydroxyl -2- (4,4,5,5- tetramethyls -1,3, penta ring -2- base of 2- dioxy boron) benzaldehyde, and white is solid 1.89 grams of body, yield 51%.
Step 2. is by 1.89g, 7.6mmol 5- hydroxyl -2- (4,4,5,5- tetramethyls -1,3, penta ring -2- base of 2- dioxy boron) Benzaldehyde is dissolved in 30mL methanol, and then in 0 DEG C of addition 344.7mg, 9.12mmol sodium borohydride, mixed liquor is in 0 DEG C of stirring 30 Minute, 36mL, 2N hydrochloric acid is then added, mixture is concentrated, and filtration drying obtains benzo [c] [1,2] oxa- boron heterocycle amyl- 1,5 (3H)-glycol, white solid 0.71g, yield 62%.
Step 3: by 50mg, amyl- 1,5 (3H)-glycol of 0.33mmol benzo [c] [1,2] oxa- boron heterocycle is dissolved in 5mL N- In crassitude, 75mg, the chloro- 5- fluoro benzothiazole of 0.40mmol 2- and 162.9mg, 0.5mmol cesium carbonate is then added, Mixed liquor is stirred overnight at room temperature, and is then handled and is reacted with ammonium chloride, ethyl acetate extraction, and the washing of organic phase saturated common salt is dry, Concentration, residual solution are isolated and purified through preparing efficient liquid phase, obtain 5- (5- fluoro benzothiazole -2- oxygroup) benzo [c] [1,2] oxa- Boron heterocycle amyl- 1 (3H) -ol, 28 milligrams of white solid, yield 28%.1H NMR(DMSO-d6,600MHz):δ9.30(s,1H), 7.89 (dd, J=8.8,2.4Hz, 1H), 7.85 (d, J=8.0Hz, 1H), 7.72 (dd, J=8.8,4.8Hz, 1H), 7.51 (d, J=1.6Hz, 1H), 7.40 (dd, J=8.0,2.4Hz, 1H), 7.32-7.27 (m, 1H), 5.03 (s, 2H)13C NMR (CDCl3, 150MHz): δ 170.7,160.7 (d, J=243Hz), 157.1,156.1,145.3,133.1 (d, J=10.8Hz), 132.3,122.8 (d, J=9.0Hz), 119.9,114.6 (d, J=24.0Hz), 113.3,108.1 (d, J=27.2Hz), 70.9.
Amyl- 1 (3H) -ol (S3) of embodiment 3:5- (6- fluoro benzothiazole -2- oxygroup) benzo [c] [1,2] oxa- boron heterocycle Preparation
Step: by 50mg, amyl- 1,5 (3H)-glycol of 0.33mmol benzo [c] [1,2] oxa- boron heterocycle is dissolved in 5mL N- first In base pyrrolidines, 75mg, the chloro- 6- fluoro benzothiazole of 0.40mmol 2- and 162.9mg, 0.5mmol cesium carbonate is then added, mixes It closes liquid to be stirred overnight at room temperature, is then handled and reacted with ammonium chloride, ethyl acetate extraction, the washing of organic phase saturated common salt is dry, dense Contracting, residual solution are isolated and purified through preparing efficient liquid phase, obtain 5- (6- fluoro benzothiazole -2- oxygroup) benzo [c] [1,2] oxa- boron Heterocycle amyl- 1 (3H) -ol, 15 milligrams of white solid, yield 15%.1H NMR(DMSO-d6,600MHz):δ9.31(s,1H), 8.01-7.97 (m, 1H), 7.85 (d, J=8.4Hz, 1H), 7.58 (dd, J=10.0,2.8Hz, 1H), 7.52 (d, J= 1.6Hz, 1H), 7.41 (dd, J=8.0,2.0Hz, 1H), 7.26-7.21 (m, 1H), 5.02 (s, 2H)13C NMR(CDCl3, 150MHz): δ 173.3,162.7 (d, J=242Hz), 157.0,156.2,149.9 (d, J=12.2Hz), 132.2,129.9, 127.5,122.1 (d, J=11.3Hz), 120.0,113.4,112.6 (d, J=24.2Hz), 108.8 (d, J=24.7Hz), 70.9.
Amyl- 1 (3H) -ol of embodiment 4:5- (5- nitrobenzene thiazole -2- oxygroup) benzo [c] [1,2] oxa- boron heterocycle (S4) preparation
Step: by 100mg, amyl- 1,5 (3H)-glycol of 0.67mmol benzo [c] [1,2] oxa- boron heterocycle is dissolved in 8mL acetonitrile In, 172mg, the chloro- 5- nitrobenzene thiazole of 0.8mmol 2- and 329.1mg, 1.01mmol cesium carbonate, mixed liquor 50 is then added It DEG C is stirred overnight, is cooled to room temperature, then plus water, solid are precipitated, and crude product solid is isolated and purified through preparing efficient liquid phase, obtains 5- Amyl- 1 (3H) -ol of (5- nitrobenzene thiazole -2- oxygroup) benzo [c] [1,2] oxa- boron heterocycle, 15 milligrams of white solid, yield 6.8%.1H NMR(DMSO-d6, 600MHz): δ 9.35 (s, 1H), 9.04 (s, 1H), 8.28 (dd, J=9.2,2.4Hz, 1H), 7.89-7.87 (m, 2H), 7.58 (d, J=1.6Hz, 1H), 7.47 (dd, J=8.0,2.0Hz, 1H), 5.04 (s, 2H)13C NMR(DMSO-d6,150MHz):δ174.8,156.9,156.6,149.0,147.0,139.7,133.0,124.0,120.3, 119.2,116.4,114.5,70.2.HRMS(ESI):calcd.for C14H10BN2O5S+329.0398,found 329.0443.
Amyl- 1 (3H) -ol of embodiment 5:5- (6- nitrobenzene thiazole -2- oxygroup) benzo [c] [1,2] oxa- boron heterocycle (S5) preparation
Step: by 100mg, amyl- 1,5 (3H)-glycol of 0.67mmol benzo [c] [1,2] oxa- boron heterocycle is dissolved in 8mL second In nitrile, 172mg, the chloro- 6- nitrobenzene thiazole of 0.8mmol 2- and 329.1mg, 1.01mmol cesium carbonate, mixed liquor is then added 50 DEG C are stirred overnight, and are cooled to room temperature, and then plus water, solid are precipitated, and crude product solid is isolated and purified through preparing efficient liquid phase, is obtained Amyl- 1 (3H) -ol of 5- (5- nitrobenzene thiazole -2- oxygroup) benzo [c] [1,2] oxa- boron heterocycle, produces by 20 milligrams of white solid Rate 9.1%.1H NMR(DMSO-d6,600MHz):δ9.36(s,1H),8.49(s,1H),8.28-8.22(m,2H),7.88(d,J =8.4Hz, 1H), 7.58 (s, 1H), 7.47 (d, J=8.0Hz, 1H), 5.04 (s, 2H)13C NMR(DMSO-d6,150MHz): δ177.0,156.9,156.6,153.9,144.0,133.0,133.0,122.6,121.9,120.4,119.9,114.6, 70.2.
Amyl- 1 (3H) -ol of embodiment 6:5- (6- methylbenzothiazole -2- oxygroup) benzo [c] [1,2] oxa- boron heterocycle (S6) preparation
Step: by 200mg, amyl- 1,5 (3H)-glycol of 1.33mmol benzo [c] [1,2] oxa- boron heterocycle is dissolved in 15mL In Isosorbide-5-Nitrae-dioxane, 456mg, the bromo- 4- methyl PhNCS of 2.0mmol 2-, 368mg, 2.66mmol carbon is then added Sour potassium, 49mg, 0.27mmol 1,10- phenanthrolene, 51.4mg, 0.27mmol cuprous iodide, 60 DEG C of mixed liquor stirred Night is cooled to room temperature, is then handled and is reacted with ammonium chloride, ethyl acetate extraction, the washing of organic phase saturated common salt, and dry, concentration is residual Extraction raffinate is isolated and purified through preparing efficient liquid phase, and it is miscellaneous to obtain 5- (6- methylbenzothiazole -2- oxygroup) benzo [c] [1,2] oxa- boron Ring amyl- 1 (3H) -ol, 20 milligrams of white solid, yield 5.1%.1H NMR(DMSO-d6,600MHz):δ9.30(s,1H),7.84 (d, J=7.6Hz, 1H), 7.74 (s, 1H), 7.58 (d, J=8.4Hz, 1H), 7.50 (d, J=1.6Hz, 1H), 7.39 (dd, J =8.0,1.6Hz, 1H), 7.25 (dd, J=8.4,1.2Hz, 1H), 5.02 (s, 2H), 2.39 (s, 3H)13C NMR(CDCl3, 150MHz):δ170.5,157.3,156.2,146.7,134.3,132.4,132.2,127.7,121.4,121.3,119.9, 113.2,70.9,21.5.HRMS(ESI):calcd.for C15H13BNO3S+298.0704,found 298.0724
The system of amyl- 1 (3H) -ol (S7) of embodiment 7:5- (benzoxazoles -2- oxygroup) benzo [c] [1,2] oxa- boron heterocycle It is standby
Step: by 270mg, amyl- 1,5 (3H)-glycol of 1.8mmol benzo [c] [1,2] oxa- boron heterocycle is dissolved in 5mL N- In crassitude, 332mg, the chloro- benzoxazoles of 2.16mmol 2- and 880mg, 2.7mmol cesium carbonate, mixed liquor is then added 60 DEG C are stirred overnight, and are cooled to room temperature, are then handled and are reacted with ammonium chloride, ethyl acetate extraction, and the washing of organic phase saturated common salt is done Dry, concentration, residual solution is isolated and purified through preparing efficient liquid phase, obtains 5- (benzoxazoles -2- oxygroup) benzo [c] [1,2] oxa- Boron heterocycle amyl- 1 (3H) -ol, 35 milligrams of white solid, yield 7.2%.1H NMR(DMSO-d6,600MHz):δ9.32(s,1H), 7.85 (d, J=8.0Hz, 1H), 7.66-7.63 (m, 1H), 7.60 (d, J=1.2Hz, 1H), 7.54-7.52 (m, 1H), 7.48 (dd, J=8.0,2.0Hz, 1H), 7.33-7.30 (m, 2H), 5.04 (s, 2H)13C NMR(CDCl3,150MHz):δ162.0, 156.0,155.1,148.4,140.5,132.2,124.7,119.9,118.8,113.3,110.0,70.9.
The system of amyl- 1 (3H) -ol (S8) of embodiment 8:5- (benzimidazolyl-2 radicals-oxygroup) benzo [c] [1,2] oxa- boron heterocycle It is standby
Step 1: by 1.00g, 6.5mmol 2-Chlorobenzimidazole is dissolved in 15mL N.N- dimethylformamide, is adding Enter, 314mg, 60% sodium hydride of 13.1mmol, 1.2g, 7.2mmol2- (chloromethane epoxide) ethyl front three is added after stirring half an hour Base silane, mixed liquor are stirred at room temperature 2 hours, and then plus water, ethyl acetate extraction, washing, saturation are salt washings, and drying is concentrated, Then pass through column chromatographic isolation and purification, obtain the chloro- 1- of 2- (((3- methyl silicon) ethyoxyl) methyl) benzimidazole, colourless liquid 1.28 grams, yield 68%.
Step 2: under nitrogen protection, by 909mg, the bromo- 5- hydroxy benzaldehyde of 4.53mmol 2- and 1.28g, 5.36mmol The chloro- 1- of 2- (((3- methyl silicon) ethyoxyl) methyl) benzimidazole, is dissolved in 10mL N.N- dimethylformamide, is then added 60% sodium hydride of 199mg, 4.98mmol, mixed liquor are stirred overnight at 120 DEG C, then cool down, filtering, filtrate successively add water and Ethyl acetate extraction, organic phase concentration, residual solution pass through column chromatographic isolation and purification, obtain 5- ((((3- methyl silicon) ethyoxyl) first Base) -1H- benzimidazolyl-2 radicals)-oxygroup) -2- bromobenzaldehyde, 0.57 gram of white solid, yield 28%.
Step 3: by 570mg, 1.27mmol 5- ((((3- methyl silicon) ethyoxyl) methyl) -1H- benzimidazolyl-2 radicals)-oxygen Base) -2- bromobenzaldehyde, it is dissolved in methanol 5mL, 72mg, 1.91mmol sodium borohydride is then added, mixed liquor continues to stir in room temperature It mixes 1 hour, mixture concentration, ethyl acetate extraction, dry, concentration, then column chromatographic isolation and purification, obtains 5- ((((3- methyl Silicon) ethyoxyl) methyl) -1H- benzimidazolyl-2 radicals)-oxygroup) -2- bromobenzyl alcohol, white solid 0.045g, yield 79%.
Step 4: by 451mg, 1.0mmol 5- ((((3- methyl silicon) ethyoxyl) methyl) -1H- benzimidazolyl-2 radicals)-oxygen Base) -2- bromobenzyl alcohol, it is dissolved in methylene chloride 5mL, 142mmL, 1.51mmol acetic anhydride, 12mg, 0.10mmol 4- is then added Dimethylamino naphthyridine, 417mmL, 3.01mmol triethylamine, mixed liquor continue to be stirred overnight in room temperature, mixture concentration, acetic acid second Ester extraction, dry, concentration, then column chromatographic isolation and purification, obtains 5- ((((3- methyl silicon) ethyoxyl) methyl) -1H- benzo miaow Azoles -2)-oxygroup) -2- bromobenzyl yl acetate, white solid 0.0457g, yield 93%.
Step 5. under nitrogen protection, by 457mg, 0.93mmol 5- ((((3- methyl silicon) ethyoxyl) methyl) -1H- benzene And imidazoles -2)-oxygroup) -2- bromobenzyl yl acetate, it is dissolved in Isosorbide-5-Nitrae-dioxane 10mL, 283mg, 1.12mmol is then added Duplex pinacol borate, 68mg, 0.09mmol PdCl2(dppf) and 274mg, 2.79mmol potassium acetate, mixed liquor is at 80 DEG C It is stirred overnight, then cools down, filter, filtrate concentration, residual solution passes through column chromatographic isolation and purification, obtains 5- ((((3- methyl silicon) Ethyoxyl) methyl) -1H- benzimidazolyl-2 radicals)-oxygroup) -2- (4,4,5,5,-tetramethyl -1,3, penta ring -2- base of 2- dioxy boron) benzyl Yl acetate, 0.385 gram of white solid, yield 79%.
Step 6. is by 300mg, 0.55mmol 5- ((((3- methyl silicon) ethyoxyl) methyl) -1H- benzimidazolyl-2 radicals)-oxygen Base) -2- (4,4,5,5,-tetramethyl -1,3, penta ring -2- base of 2- dioxy boron) benzylacetic acid ester is dissolved in methanol 3mL, then adding Enter 154mg, 1.11mmol potassium carbonate, mixed liquor is stirred overnight, and mixture filtering is concentrated and dried, obtains 5- ((((3- methyl silicon) Ethyoxyl) methyl) -1H- benzimidazolyl-2 radicals)-oxygroup) amyl- 1 (3H) -ol of benzo [c] [1,2] oxa- boron heterocycle, yellow liquid 0.19g, yield 85.9%.
Step 7: by 190mg, 0.48mmol 5- ((((3- methyl silicon) ethyoxyl) methyl) -1H- benzimidazolyl-2 radicals)-oxygen Base) amyl- 1 (3H) -ol of benzo [c] [1,2] oxa- boron heterocycle, it is dissolved in methylene chloride 1mL, trifluoroacetic acid 2mL is then added, mix It closes liquid to be stirred overnight at room temperature, be concentrated, residual solution is isolated and purified through preparing efficient liquid phase, obtains 5- (benzimidazolyl-2 radicals-oxygroup) benzene And amyl- 1 (3H) -ol of [c] [1,2] oxa- boron heterocycle, 30 milligrams of white solid, yield 24%.1H NMR(600MHz,DMSO- d6): δ 7.81 (d, J=8.0Hz, 1H), 7.46 (s, 1H), 7.43-7.30 (m, 3H), 7.15-7.12 (m, 2H), 5.01 (s, 2H).13C NMR(MeOH-d4,150MHz):δ156.5,156.0,155.8,134.6,131.8,122.4,118.9,113.4, 112.7,70.7.
Embodiment 9:5- ((1- methyl-1 H- benzimidazolyl-2 radicals)-oxygroup) benzo [c] [1,2] oxa- boron heterocycle amyl- 1 The preparation of (3H) -ol (S9).
Step 1: by 1.00g, 6.5mmol 2-Chlorobenzimidazole is dissolved in tetrahydrofuran 15mL, adds 288mg, 0.60mL, 9.8mmol iodomethane is added after stirring half an hour in 7.2mmol60% sodium hydride, and mixed liquor is stirred at room temperature 2 hours, so Afterwards plus water, ethyl acetate extraction, washing, saturation are salt washings, and drying is concentrated, and then passes through column chromatographic isolation and purification, obtains 1- Methyl -2-Chlorobenzimidazole, 0.95 gram of weak yellow liquid, yield 88%.
Step 2: under nitrogen protection, by 1.20g, the bromo- 5- hydroxy benzaldehyde of 5.97mmol 2- and 1.00g, 6.00mmol 1- methyl -2-Chlorobenzimidazole is dissolved in N.N- dimethylformamide 10mL, and 60%, 264mg, 6.60mmol hydrogen is then added Change sodium solution, mixed liquor is stirred overnight at 120 DEG C, then cools down, and filters, and filtrate successively adds water and ethyl acetate to extract, organic It is mutually concentrated, residual solution passes through column chromatographic isolation and purification, obtains 5- ((1- methyl-1 H- benzimidazolyl-2 radicals)-oxygroup) -2- bromobenzene first Aldehyde, 0.99 gram of white solid, yield 50%.
Step 3: by 1.02mg, 3.08mmol 5- ((1- methyl-1 H- benzimidazolyl-2 radicals)-oxygroup) -2- bromobenzaldehyde is molten In methanol 5mL, 175mg, 4.62mmol sodium borohydride is then added, mixed liquor continues stirring 1 hour in room temperature, and mixture is dense Contracting, ethyl acetate extraction, dry, concentration, then column chromatographic isolation and purification, obtains 5- ((1- methyl-1 H- benzimidazolyl-2 radicals)-oxygen Base) -2- bromobenzyl alcohol, white solid 1.17g, yield 90%.
Step 4: by 610mg, 1.84mmol 5- ((1- methyl-1 H- benzimidazolyl-2 radicals)-oxygroup) -2- bromobenzyl alcohol is dissolved in In methylene chloride 5mL, it is then added 0.26mL, 2.76mmol acetic anhydride, 23mg, 0.20mmol 4-dimethylaminopyridine, 0.76mL, 5.52mmol triethylamine, mixed liquor continue to be stirred overnight in room temperature, mixture concentration, and ethyl acetate extraction is dry, Concentration, then column chromatographic isolation and purification, obtains 5- ((1- methyl-1 H- benzimidazolyl-2 radicals)-oxygroup) -2- bromobenzyl yl acetate, white Color solid 0.635g, yield 92%.
Step 5. under nitrogen protection, by 543mg, 1.45mmol 5- ((1- methyl-1 H- benzimidazolyl-2 radicals)-oxygroup)- 2- bromobenzyl yl acetate is dissolved in Isosorbide-5-Nitrae-dioxane 10mL, is then added 441mg, 1.62mmol duplex pinacol borate, 106mg,0.145mmol PdCl2(dppf) and 526mg, 5.36mmol potassium acetate, mixed liquor is stirred overnight at 80 DEG C, then cold But, it filters, filtrate concentration, residual solution passes through column chromatographic isolation and purification, obtains 5- ((1- methyl-1 H- benzimidazolyl-2 radicals)-oxygen Base) -2- (4,4,5,5,-tetramethyl -1,3, penta ring -2- base of 2- dioxy boron) benzylacetic acid ester, 0.52 gram of white solid, yield 86%.
Step 6. is by 270mg, 0.64mmol 5- ((1- methyl-1 H- benzimidazolyl-2 radicals)-oxygroup) -2- (4,4,5,5,-four Methyl-1,3,2- dioxy boron, penta ring -2- base) benzylacetic acid ester, it is dissolved in methanol 5mL, 177mg, 1.28mmol then is being added Potassium carbonate, mixed liquor are stirred overnight, and mixture filtering is concentrated and dried, and residual solution is isolated and purified through preparing efficient liquid phase, obtain 5- Amyl- 1 (3H) -ol of ((1- methyl-1 H- benzimidazolyl-2 radicals)-oxygroup) benzo [c] [1,2] oxa- boron heterocycle, white solid 39mg, Yield 22%.1H NMR(600MHz,DMSO-d6): δ 7.82 (d, J=8.0Hz, 1H), 7.48 (m, 2H), 7.42 (d, J= 8.0Hz, 1H), 7.37 (d, J=8.0Hz, 1H), 7.21-7.15 (m, 2H), 5.01 (s, 2H), 3.74 (s, 3H)13C NMR (CDCl3,150MHz):δ156.3,155.5,136.6,132.5,123.2,122.8,119.5,117.7,113.3,108.9, 70.8,28.8.
Embodiment 10:5- ((1- benzyl -1H- benzimidazolyl-2 radicals)-oxygroup) benzo [c] [1,2] oxa- boron heterocycle amyl- 1 The preparation of (3H) -ol (S10).
Step 1: by 1.00g, 6.5mmol 2-Chlorobenzimidazole is dissolved in tetrahydrofuran 15mL, and 174mg is being added, 1.2mL, 10.1mmol benzyl bromine is added after stirring half an hour in 60% sodium hydride of 12.1mmol, and mixed liquor is stirred at room temperature 2 hours, so Afterwards plus water, ethyl acetate extraction, washing, saturation are salt washings, and drying is concentrated, and then passes through column chromatographic isolation and purification, obtains 1- Benzyl -2-Chlorobenzimidazole, 1.34 grams of weak yellow liquid, yield 85%.
Step 2: under nitrogen protection, by 1.56mg, the bromo- 5- hydroxy benzaldehyde of 7.76mmol 2- and 1.88g, 7.75mmol 1- benzyl -2-Chlorobenzimidazole, is dissolved in N.N- dimethylformamide 10mL, 60%, 341mg is then added, 8.53mmol sodium hydride, mixed liquor are stirred overnight at 120 DEG C, then cool down, filtering, and filtrate successively adds water and ethyl acetate to extract It takes, organic phase concentration, residual solution passes through column chromatographic isolation and purification, obtains 5- ((1- benzyl -1H- benzimidazolyl-2 radicals)-oxygroup) -2- Bromobenzaldehyde, 0.95 gram of white solid, yield 30%.
Step 3: by 920mg, 2.26mmol 5- ((1- benzyl -1H- benzimidazolyl-2 radicals)-oxygroup) -2- bromobenzaldehyde is molten In methanol 10mL, 128mg, 3.38mmol sodium borohydride is then added, mixed liquor continues stirring 1 hour, mixture in room temperature Concentration, ethyl acetate extraction, dry, concentration, then column chromatographic isolation and purification, obtains the bromo- 5- of 2- ((1- benzyl -1H- benzo miaow Azoles -2)-oxygroup)-benzyl ethyl alcohol, white solid 0.32g, yield 35%.
Step 4: by 573mg, 1.4mmol 5- ((1- benzyl -1H- benzimidazolyl-2 radicals)-oxygroup) -2- bromobenzyl ethyl alcohol is molten In methylene chloride 5mL, it is then added 198uL, 2.1mmol acetic anhydride, 17.5mg, 0.14mmol 4-dimethylaminopyridine, 0.582mL, 4.2mmol triethylamine, mixed liquor continue to be stirred overnight in room temperature, mixture concentration, and ethyl acetate extraction is dry, Concentration, then column chromatographic isolation and purification, obtains 5- ((1- benzyl -1H- benzimidazolyl-2 radicals)-oxygroup) -2- bromobenzyl yl acetate, white Color solid 0.29g, yield 46%.
Step 5. under nitrogen protection, by 290mg, 0.64mmol 5- ((1- benzyl -1H- benzimidazolyl-2 radicals)-oxygroup) - 2- bromobenzyl yl acetate is dissolved in Isosorbide-5-Nitrae-dioxane 10mL, is then added 164mg, 0.65mmol duplex pinacol borate, 47mg,0.064mmol PdCl2(dppf) and 127mg, 1.29mmol potassium acetate, mixed liquor is stirred overnight at 80 DEG C, then cold But, it filters, filtrate concentration, residual solution passes through column chromatographic isolation and purification, obtains 5- ((1- benzyl -1H- benzimidazolyl-2 radicals)-oxygen Base) -2- (4,4,5,5,-tetramethyl -1,3, penta ring -2- base of 2- dioxy boron) benzylacetic acid ester, 0.14 gram of white solid, yield 44%.
Step 6. is by 140mg, 0.28mmol 5- ((1- benzyl -1H- benzimidazolyl-2 radicals)-oxygroup) -2- (4,4,5,5,-four Methyl-1,3,2- dioxy boron, penta ring -2- base) benzylacetic acid ester, it is dissolved in methanol 3mL, 78mg, 0.56mmol carbon then is being added Sour potassium, mixed liquor are stirred overnight, and mixture filtering is concentrated and dried, and residual solution is isolated and purified through preparing efficient liquid phase, obtain 5- Amyl- 1 (3H) -ol of ((1- benzyl -1H- benzimidazolyl-2 radicals)-oxygroup) benzo [c] [1,2] oxa- boron heterocycle, white solid 25mg, Yield 25%.1H NMR(600MHz,DMSO-d6): δ 9.27 (br, 1H), 7.80 (d, J=8.4Hz, 1H), 7.50-7.48 (m, 3H),7.47-7.42(m,6H),7.17-7.13(m,2H),5.44(s,2H),5.01(s,2H).13C NMR(DMSO-d6, 150MHz):δ156.5,156.2,155.4,139.7,137.1,133.6,132.4,129.3,128,2,127.8,122.2, 122.0,119.7,118.4,113.5,110.3,70.2,45.9.
Embodiment 11: measurement of the compound to PDE4B1 inhibitory activity
By U.S. BPS Bioscience, Inc. (6044Cornerstone Court West, Ste.E, San Diego, CA92121, USA) company's measurement.Concrete operations are as follows:
Experimental material:
(1) compound in the present invention；
(2) positive control medicine Crisaborole is synthesized by this laboratory；
(3) PDE measures buffer (BPS Bioscience production number: 60393)；
(4) PDE bonding agent (BPS Bioscience production number: 60390)；
(5) PDE bonding agent diluent (cAMP) (BPS Bioscience production number: 60391).
Determination condition:
(1) DMSO dissolved compound, mother liquid concentration 10mM, DMSO content is no more than 1% in end reaction system.
(2) enzyme reaction mixture acts on 60 minutes at room temperature, measures buffer containing PDE in 50ul reaction mixture, The FAM-cAMP of 100nM, PDE4B1 enzyme and experimental compound.
(3) the combination agent solution (diluting bonding agent by 1:100) of 100 μ l is added, the reaction was continued at room temperature 60 minutes.
(4) Tecan Infinite M1000microplate reader measures fluorescence intensity, excitation (excitation):485；Emit (emission): 528.
Data analysis:
(1) experiment sets multiple holes.Fluorescence intensity is transformed into fluorescence (fluore partially using Tecan Magellan6 software Scence polatization), and data are analyzed using Graphpad Prism software.Negative control hole is (without change Close object) fluorescence polarization (FPt) be set to 100% activity, the fluorescence polarization of blank well (without test compound and PDE4B1 enzyme) (FPb) it is set to 0% activity.The active % of compound is calculated with following formula: % activity=(FP-FPb)/(FPt-FPb) × 100%, the wherein fluorescence polarization value of each dosing holes of FP=.
(2) equation Y=B+ (T-B)/1+10 is used{(LogEC50-X)×hill Slope}Do S nonlinear regression analysis dosage-work Linearity curve, wherein Y=activity %, B=minimum activity %, T=maximum activity %, X=compound concentration logarithm, Hill Slope =slope factor or Hill coefficient.IC50Value is the compound concentration for inhibiting half enzymatic activity.Experimental result is as follows:
Embodiment 12: the inhibiting effect of the release of compounds on cytokine TNF-α described in patent
Compound in the measurement present invention inhibits the ability of inflammatory factor.Detection compound is to lipopolysaccharide-induced Freshman The effect of TNF-α cytokine release in peripheral blood mononuclear cells (PBMCs).The compound effects of various concentration are thin in PBMCs Born of the same parents, then stimulate cell with the lipopolysaccharides (LPS) of 1 μ g/ml, and induced cellular secretion inflammatory factor takes supernatant.Use ELISA Method measures the release of cell factor in supernatant.
The specific method is as follows:
Human peripheral blood mononuclear cell is provided by Guangzhou Randt Biotechnology Co., Ltd.Freshly extd human peripheral monokaryon Cell (PBMCs) is resuspended in the RPMI-1640 culture medium containing 10%FBS, according to 5 × 105/ hole is inoculated in 96 orifice plates, and will Cell is at 37 DEG C, 5%C02Continue to cultivate 4h in incubator.By the compound in the present invention, be dissolved in dimethyl sulfoxide (DMSO, 100%) 10mM sample mother liquor is prepared in.96 orifice plates are added to after 10mM compound sample is diluted with RPMI-1640 culture medium In, final compound concentration is 0.1-100 μM, and after sample and cell are incubated for 15-30 minutes jointly, addition lipopolysaccharides (LPS) is right Cell is induced, the final concentration of 1 μ g/ml of lipopolysaccharides.Crisaborole (gram vertical boron sieve) is used as positive control.LPS and chemical combination Object collective effect for 24 hours, extracts supernatant and is stored in -80 DEG C.Using the Human TNF-α Valukine of Novus companyTM ELISA kit detects the TNF α in supernatant.As a result as follows:

Claims (8)

1. a kind of benzoxaborole Polymorphs alkyl compound with di-phosphate ester enzyme inhibition and its pharmaceutically acceptable Salt or pharmaceutically acceptable solvate, the general structure of the compound is as follows:
Wherein, B is boron；X is selected from oxygen, sulphur, nitrogen hydrogen, N-methyl or nitrogen benzyl；R1 is selected from hydrogen, halogen or nitro；R2 is selected from Hydrogen, methyl, halogen or nitro.
2. compound as described in claim 1, which is characterized in that the compound including following molecular structure:
。
3. compound as described in claim 1, it is characterised in that: the pharmaceutically acceptable salt includes hydrochloride, hydrogen bromine Hydrochlorate, nitrate, sulfate, phosphate；Formates, acetate, propionate, benzoate, maleate, fumarate, amber Amber hydrochlorate, tartrate, citrate, alkylsulfonate and arylsulphonate.
4. compound as described in claim 1, it is characterised in that: the pharmaceutically acceptable solvate includes water, second Alcohol, isopropanol, ether or acetone are the solvate of solvent.
5. compound as claimed in claim 1 or 2 is in the release treatment anti-inflammatory drugs that preparation inhibits proinflammatory cytokine Using.
6. application as claimed in claim 5, which is characterized in that the inflammation is dermatitis or inflammatory bowel disease or arthritis.
7. application as claimed in claim 6, which is characterized in that the dermatitis includes atopic dermatitis, allergic dermatitis or silver Bits disease；The inflammatory bowel disease includes Crohn disease, ulcerative colitis or nonspecific colonitis；The arthritis includes wind Wet arthritis.
8. the preparation method of compound as claimed in claim 1 or 2, in which:
The reaction route of the preparation method of 8.1 compounds (S1) is as follows:
Include the following steps:
(1) chloro benzothiazole ii obtains compound iii with compound i generation substitution reaction in the presence of alkali,
(2) compound iii occurs substitution reaction through palladium metal catalyst in the presence of alkali and obtains compound iv,
(3) it is target compound S1 that compound iv, which obtains compound v through reduction reaction,；
The reaction route of the preparation method of 8.2 compounds (S6) is as follows:
Include the following steps: that compound vii and compound viii obtains target compound v-c under copper metal catalyst action and is S6；
The reaction route of the preparation method of 8.3 compounds (S8) is as follows:
Including the following steps: that compound v-d obtains target compound v-e under trifluoroacetic acid effect is S8；
The preparation method reaction route of compound shown in the 8.4 following v-b of structure is as follows:
Include the following steps:
(1) compound i occurs substitution reaction through palladium metal catalyst in the presence of alkali and obtains compound vi,
(2) compound vi obtains compound vii through reduction reaction,
(3) compound vii obtains compound v-b with compound ii-b generation substitution reaction in the presence of alkali；The definition of R1, R2 It is identical with corresponding claim；
The preparation method reaction route of compound shown in the 8.5 following v-d of structure is as follows:
Include the following steps:
(1) compound ii-d obtains compound iii-d with compound i generation substitution reaction in the presence of alkali,
(2) compound iii-d obtains compound ix-d through reduction reaction,
(3) compound ix obtains compound x-d with acetic acid anhydride reactant under alkali effect,
(4) compound x-d occurs substitution reaction through palladium metal catalyst in the presence of alkali and obtains compound xi-d,
(5) compound xi-d obtains target compound v-d in the presence of alkali.
CN201810602298.1A 2018-06-12 2018-06-12 Benzoxaborole Polymorphs alkyl compound and preparation method thereof Pending CN108997394A (en)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101420854A (en) * 2006-02-16 2009-04-29 安纳考尔医药公司 Little molecule as the boracic of antiinflammatory agent
WO2010028005A1 (en) * 2008-09-04 2010-03-11 Anacor Pharmaceuticals, Inc. Boron-containing small molecules
CN102014927A (en) * 2008-03-06 2011-04-13 安纳考尔医药公司 Boron-containing small molecules as anti-inflammatory agents
WO2011094450A1 (en) * 2010-01-27 2011-08-04 Anacor Pharmaceuticals, Inc Boron-containing small molecules
CN104768932A (en) * 2012-10-25 2015-07-08 泰特拉探索合伙有限责任公司 Heteroaryl inhibitors of PDE4
CN106831840A (en) * 2017-03-23 2017-06-13 合肥医工医药有限公司 One class has micromolecular compound, preparation method and its medicinal usage of anti-inflammatory activity

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101420854A (en) * 2006-02-16 2009-04-29 安纳考尔医药公司 Little molecule as the boracic of antiinflammatory agent
CN102014927A (en) * 2008-03-06 2011-04-13 安纳考尔医药公司 Boron-containing small molecules as anti-inflammatory agents
WO2010028005A1 (en) * 2008-09-04 2010-03-11 Anacor Pharmaceuticals, Inc. Boron-containing small molecules
WO2011094450A1 (en) * 2010-01-27 2011-08-04 Anacor Pharmaceuticals, Inc Boron-containing small molecules
CN104768932A (en) * 2012-10-25 2015-07-08 泰特拉探索合伙有限责任公司 Heteroaryl inhibitors of PDE4
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