CN108794516A - Boric acid and boric acid ester compound and its preparation method and application - Google Patents
Boric acid and boric acid ester compound and its preparation method and application Download PDFInfo
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Abstract
The present invention provides a kind of boric acid and boric acid ester compound as shown in Formulas I and Formula II, preparation method, purposes and pharmaceutical composition.The boric acid and boric acid ester compound have the function of protease inhibition body, can be used in treating Huppert's disease.
Description
Technical field
The invention belongs to field of medicaments, and in particular, to a kind of boric acid and boric acid ester compound and preparation method thereof and
Purposes.
Background technology
Huppert's disease (multiple myeloma, MM) is a kind of thick liquid cell cancer, sees marrow.Huppert's disease
In, one group of thick liquid cell (or myeloma cell) is converted into cancer cell and hyperplasia, and the number of thick liquid cell is made to be higher than normal level.Due to
Thick liquid cell extensive migration in vivo, it is possible to involve most bone in vivo, may cause compression fracture, bone dissolubility lesion and
It is ache related.Huppert's disease can lead to several serious health problems, involve the red of bone, immune system, kidney and individual
Cell count, more typically symptom includes skeleton pain and tired for part, and tired is the symptom of anaemia.Huppert's disease belongs to rare
Cancer, the annual new cases about 11.4 ten thousand in the whole world.
Proteasome is the proteasome for having more active sites, be responsible for include cell cycle regulating protein with
The degradation of intracellular most protein including apoptosis protein.Preclinical study shows that proteasome inhibitor has
The effects that inducing cell apoptosis, chemoradiotherapy enhanced sensitivity.Very it is interesting that research finds the cell that vicious transformation occurs to protease
Body inhibits more more sensitive than non-malignant cell.Therefore, protease inhibition body becomes a kind of oncotherapy approach got a good chance of.Egg
White enzyme body inhibitor part has by lowering Nuclear factor kappa B (NF κ B) or cell cycle regulation albumen and Apoptosis access
There is antitumor action.
The boric acid class proteasome inhibitor for treating Huppert's disease listed at present have bortezomib and
Ai Shazuo meter.Bortezomib is the reversible inhibitor of 26S proteasomes chymotrypsinlike activity in mammalian cell, in 2003
On May 19, in, with Velcade (Bortezomib) trade name list marketing, preparation type was pulvis by the quick examination of U.S. FDA.
Ai Shazuo meter is preferentially combined and the activity of 5 subunits of β of inhibition chymotrypsin-sample 20S proteasomes, in November, 2015
Ratify to list by FDA within 20th, Ai Shazuo meter citrates joint lenalidomide and dexamethasone were for previously having received at least
A kind of MM patient of therapeutic scheme, preparation type are capsule.
In administration route, the bortezomib of oral Ai Shazuo meter relative injections has obviously advantage.However,
It is only 58% to analyze mean absolute oral bioavailbilty according to group PK.Clinically Ai Shazuo meter still has diarrhea, constipation,
Decrease of platelet, peripheral neuropathy, nausea, periphery oedema, the toxic side effects such as vomiting.
Therefore, there is still a need for exploitations for this field has more preferable pharmacodynamics performance and pharmacokinetics performance to Huppert's disease
Compound.
Invention content
The object of the present invention is to provide a kind of new compounds and application thereof with proteosome enzyme inhibition.The present invention
It was unexpectedly observed that deuterated boric acid provided by the present invention or boric acid ester compound be compared with corresponding non-deuterated compound,
With significantly superior different pharmacodynamics performance and pharmacokinetics performance, it is specifically embodied in drug half-life and bioavilability
On have the raising of highly significant, therefore be more suitable for protesome inhibitors, and then more applicable preparation treatment albumen body enzyme
The drug of inhibitor class relevant disease.The present invention is completed on this basis.
First aspect present invention provides a kind of boric acid ester compound shown in formula I or its crystal form, can pharmaceutically connect
Salt, hydrate or the solvate received,
Wherein, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、
R22、R23It is to be each independently selected from hydrogen or deuterium, and at least one is deuterium.
In another preferred example, R7、R8、R9、R14、R15Separately it is selected from hydrogen or deuterium.
In another preferred example, the compound is selected from the group：
In another preferred example, the compound is selected from：
Second aspect of the present invention provides one kind boric acid compound as shown in Formula II or its crystal form, can pharmaceutically connect
Salt, hydrate or the solvate received,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25It is each
From independently selected from hydrogen or deuterium, and at least one is deuterium.
In another preferred example, R7、R8、R9、R14、R15It is separately to be selected from hydrogen or deuterium.
In another preferred example, the compound is selected from the group：
In another preferred example, the compound is selected from：
Third aspect present invention provides a kind of preparation method of pharmaceutical composition, by first aspect present invention and second party
Compound or its crystal form, pharmaceutically acceptable salt, hydrate or solvate described in face and pharmaceutically acceptable
Carrier is mixed, to form pharmaceutical composition.
Fourth aspect present invention provides a kind of pharmaceutical composition, contains (1) first aspect present invention and second aspect institute
The compound stated or its crystal form, pharmaceutically acceptable salt, hydrate or solvate；(2) pharmaceutically acceptable carrier.
In another preferred example, described pharmaceutical composition also contains other medicine；Preferably, described other
Medicine is the drug for treating Huppert's disease.
Fifth aspect present invention provides compound or its crystal form, medicine described in first aspect present invention and second aspect
The purposes of acceptable salt, hydrate or solvate on, they are used as protesome inhibitors, or are used to prepare treatment
Inhibit the drug for there are related disorders with proteosome enzyme is prevented.
In another preferred example, the disease is selected from Huppert's disease.
In another preferred example, the pharmaceutical composition is injection, wafer, tablet, pill, powder or granule.
Sixth aspect present invention provides a kind of therapy, including step：To object in need for the treatment of, using the present invention
Compound described in first aspect or second aspect or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, or
Pharmaceutical composition described in fourth aspect present invention.
In another preferred example, with the people for having related disorders with the inhibition of proteosome enzyme when the object.
The present invention also provides a kind of preparation method of the compound of formula I described in first aspect present invention,
Wherein, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、
R22、R23Definition it is as described in claim 1；
R24、R25、R26、R27Independently selected from hydrogen or deuterium；
R28、R29It is borate protecting group, is each independently selected from alkyl or R28、R29It is jointly formed ring protection base.
Specifically, which includes the following steps：
1) Formula IX compound represented is obtained by imines condensation reaction as shown in Formula VII with Formula X compound represented
Compound；The reaction preferably carries out in acid condition；
2) Formula VII compound represented obtains changing as shown in Formula IV with Formula VIII compound represented by addition reaction
Close object；The condition of the reaction preferably carries out under the catalysis of copper reagent；
3) Formula IV compound represented obtains such as formula IV compound represented by hydrolysis or its is pharmaceutically acceptable
Salt；The reaction preferably carries out in acid condition；
4) formula IV compound represented or its pharmaceutically acceptable salt and compound shown as a formula V or its pharmaceutically
Amidation process occurs under the action of condensing agent and obtains such as formula III compound represented for acceptable salt；
5) formula III compound represented is obtained by boric acid ester hydrolysis such as Formula II compound represented；The reaction condition
It is preferred that carrying out under acid or alkaline conditions；
6) Formula II compound represented with citric acid or deuterated citric acid by being condensed to form chemical combination shown in formula I
Object.
The present invention also provides the preparation methods of the compound of formula I described in another first aspect present invention, pass through chemical combination
Object II carries out esterification with citric acid or deuterated citric acid and is made；The reaction is heated preferably in ethyl acetate to be issued
It is raw.
Wherein, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、
R22、R23、R24、R25、R26、R27It is to be each independently selected from hydrogen or deuterium, and at least one is deuterium.
In yet other embodiments, comprise the following steps：
Dissolved compound II, citric acid are in organic solvent, reaction heating reaction 2-48h at 40~95 DEG C, allow its slowly
It is cooled to room temperature, white solid is filtered, ethyl acetate washing obtains compound as white solid I.
The preferred methyl acetate of organic solvent described in the program, ethyl acetate, isopropyl acetate, butyl acetate etc..
The present invention also provides a kind of preparation method of the compound as shown in Formula II B, compound IIB passes through compound IIA
Hydrogen/deuterium exchange system occurs under alkaline condition to obtain；Using the preferred deuterated reagent of reagent.
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R19、R20、R21、R22、R23、R24、R25It is respective
Independently selected from hydrogen or deuterium.
In yet other embodiments, compound IID is by such as Formula II C compounds represented in acid or alkali
Property under the conditions of, in deuterated reagent occur hydrogen deuterium exchange system obtain,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R20、R21、R22、R23、R24、R25It is respective independence
Ground is selected from hydrogen or deuterium.
In yet other embodiments, comprise the following steps：
Acid or alkali is added in deuterated reagent in dissolved compound IIC at room temperature, and reaction stirs 12- at 0~35 DEG C
72h, NMR show that the reaction was complete, are reacted with 1N hydrochloric acids, and dichloromethane extraction purifies to obtain compound IID after concentration.
The preferred CD of deuterated reagent described in the program3OD, CH3OD, D2O, AcOD, CD3CCOOD etc..
The preferred sodium methoxide of alkali described in the program, sodium ethoxide, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine
Deng.
The preferred acetic acid of acid, trifluoroacetic acid, p-methyl benzenesulfonic acid, camphorsulfonic acid, Loprazolam, hydrochloric acid, sulfuric acid described in the program
Deng.
The present invention also provides the preparation method of another boric acid compound as shown in Formula II, compound II passes through such as formula
III compounds represented occur boric acid ester hydrolysis reaction and are made,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25It is each
From independently selected from hydrogen or deuterium, and at least one is deuterium；
R28、R29It is borate protecting group, is each independently selected from alkyl or R28、R29It is jointly formed ring protection base.
In yet other embodiments, comprise the following steps：
Dissolved compound III is added in acid or alkali, reaction mixture stirs 2-24 at 20~40 DEG C in alcohols solvent
Hour, TLC shows that the reaction was complete, and normal heptane, sodium hydroxide and dichloromethane wash successively, and compound II is purified to obtain after concentration.
The preferred methanol of alcohols solvent described in the program, ethyl alcohol, isopropanol, n-butanol etc.；
Acid or the preferred hydrochloric acid of alkali, sulfuric acid, phosphoric acid, boric acid, alkylboronic acids, aryl boric acid, sodium hydroxide, hydrogen described in the program
Potassium oxide, lithium hydroxide etc..
The present invention also provides a kind of such as formula III compound represented,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23It is respective independence
Ground is selected from hydrogen or deuterium, and at least one is deuterium；
R28、R29It is borate protecting group, is each independently selected from alkyl or R28、R29It is jointly formed ring protection base.
The present invention also provides a kind of preparation method such as formula III compound represented, compound III passes through as shown in formula IV
Compound or its pharmaceutically acceptable salt, with compound shown as a formula V or its pharmaceutically acceptable salt by being condensed
Reaction is made,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R28、R29As changed
It closes defined in object III；
In yet other embodiments, comprise the following steps：
At -20~10 DEG C, dissolved compound IV, compound V, condensing agent is in organic solvent.Alkali is added dropwise thereto, reacts
Be slowly increased to 0~35 DEG C stirring 2~for 24 hours, TLC show that the reaction was complete, add water quenching reaction, ethyl acetate extraction, after concentration obtain
Crude Compound III.
The preferred dimethylformamide of organic solvent described in the program, tetrahydrofuran, dichloromethane, ethyl acetate, toluene, two
Methylacetamide, acetonitrile etc.；
The preferred 1- ethyls-of condensing agent described in the program (3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate
(EDC.HCl), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), O- benzotriazole-tetramethylurea six
Fluorophosphoric acid ester (HBTU), 2- (7- aoxidizes benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid esters (HATU), O- benzos
Triazole-N, N, N ', N '-tetramethylurea tetrafluoro boric acid esters (TBTU), 2- (interior -5- norbornene -2,3- dicarboximide) -1,
1,3,3- tetramethylurea tetrafluoroborate (TNTU), 6- Chloro-Benzotriazoles -1,1,3,3- tetramethylurea tetrafluoro boric acid ester salt
(TCTU), hexafluorophosphoric acid benzotriazole -1- oxygroups three (dimethylamino) phosphorus (BOP), hexafluorophosphoric acid benzotriazole -1- bases-oxygroup
Tripyrrole alkyl phosphorus (PyBOP), three (dimethylamino) phosphine hexafluorophosphate (PyAOP) of 7- azepine benzo triazol-1-yls oxygroup, N,
At least one of N '-carbonyl dimidazoles (CDI) and 4- (4,6- dimethoxy-triazine) -4- methyl morpholine hydrochlorides (DMTMM).
The present invention also provides a kind of such as formula IV compound represented or its pharmaceutically acceptable salt
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16It is to be each independently selected from hydrogen or deuterium, and at least one
A is deuterium；
R28、R29It is borate protecting group, is each independently selected from alkyl or R28、R29It is jointly formed ring protection base.
The present invention also provides a kind of such as formula IV compounds represented or the preparation method of its pharmaceutically acceptable salt, change
Object IV is closed to be made by deprotection base under acid condition by such as Formula IV compound represented,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R28、R29As defined in compound IV.
In yet other embodiments, comprise the following steps：
Crude Compound VI is dissolved in organic solvent, the organic solvent solution of 1~6M HCl is added, and is reacted 0~40
After stirring 1-4h at DEG C, it is concentrated to give white solid, is filtered, compound IV is obtained after organic solvent washing.
The preferred methanol of organic solvent described in the program, ethyl alcohol, isopropanol, ethyl acetate , dioxanes, tetrahydrofuran, methyl
Tertbutyl ether, n-hexane, acetone etc..
The present invention also provides a kind of such as Formula IV compound represented,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16It is to be each independently selected from hydrogen or deuterium, and at least one
A is deuterium；
R28、R29It is borate protecting group, is each independently selected from alkyl or R28、R29It is jointly formed ring protection base.
The present invention also provides a kind of preparation method such as Formula IV compound represented, compound VI passes through as shown in Formula VII
Compound with as Formula VIII compound represented under the catalysis of copper reagent by addition reaction be made,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R28、R29As defined in compound VI.
In yet other embodiments, comprise the following steps：
At 0 DEG C, dissolved compound VII, copper reagent, PCy3·HBF4, benzylamine is in organic solvent/water, addition compound
VIII, after reaction stirs 1-8h at 0~50 DEG C, TLC shows that the reaction was complete, ethyl acetate extraction, crude Compound after concentration
VI。
Copper reagent preferably sulfuric acid copper, copper chloride, copper bromide, cuprous iodide etc. described in the program；
The preferred tetrahydrofuran of organic solvent described in the program, toluene, ethyl acetate, acetone, acetonitrile, n-hexane etc..
The present invention also provides a kind of such as Formula VII compound represented,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16It is to be each independently selected from hydrogen or deuterium, and at least one
A is deuterium.
The present invention also provides a kind of preparation method such as Formula VII B compounds represented, compound VIIB passes through such as Formula VII A
Compound represented is made by hydrogen/deuterium exchange reaction,
Wherein, R7、R9、R10、R11、R12、R13、R14、R15、R16As compound VII is defined.
In yet other embodiments, comprise the following steps：
Alkali is added in deuterated reagent in dissolved compound VIIA at room temperature, and 12-72h, NMR are stirred in reaction at 0~35 DEG C
The reaction was complete for display, is reacted with 1N hydrochloric acids, and dichloromethane extraction purifies to obtain compound VIIB after concentration.
The preferred CD of deuterated reagent described in the program3OD, CH3OD, D2O, AcOD, CD3CCOOD etc..
The preferred sodium methoxide of alkali described in the program, sodium ethoxide, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine
Deng.
The present invention also provides a kind of preparation methods such as Formula VII compound represented, which is characterized in that passes through such as Formula IX institute
The compound shown is made with compound represented by a formula X by condensation reaction,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16As defined in compound VII.
In yet other embodiments, comprise the following steps：
In organic solvent lewis acid is added, reaction mixture is at 20~80 DEG C in dissolved compound IX, compound X
2-24h is stirred, after TLC shows that the reaction was complete, water quenching reaction, ethyl acetate extraction is added to purify to obtain compound VII after concentration.
The preferred dichloromethane of organic solvent described in the program, toluene, ethyl acetate, tetrahydrofuran, methyl tertiary butyl ether(MTBE) etc.；
The preferred p-methyl benzenesulfonic acid of lewis acid described in the program, para-methylbenzenepyridinsulfonate sulfonate, tetraisopropoxy titanium, tri-chlorination
Aluminium, ferric trichloride, magnesium sulfate etc..
The present invention also provides a kind of such as Formula IX compound represented,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16It is to be each independently selected from hydrogen or deuterium, and at least one
A is deuterium.
The present invention also provides a kind of preparation method such as Formula IX B compounds represented, compound IXB passes through such as Formula IX A institutes
The compound shown is obtained by hydrogen/deuterium exchange system,
Wherein, R7、R9、R10、R11、R12、R13、R14、R15、R16It is to be each independently selected from hydrogen or deuterium.
In yet other embodiments, comprise the following steps：
Alkali is added in deuterated reagent in dissolved compound IXA at room temperature, and 12-72h, NMR are stirred in reaction at 0~35 DEG C
The reaction was complete for display, is reacted with 1N hydrochloric acids, and dichloromethane extraction purifies to obtain compound IXB after concentration.
The preferred CD of deuterated reagent described in the program3OD, CH3OD, D2O, AcOD, CD3CCOOD etc..
The preferred sodium methoxide of alkali described in the program, sodium ethoxide, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine
Deng.
A kind of preparation method of such as Formula IX compound represented of the present invention, compound IX pass through such as Formula XI compound represented
It is made by hydrolysis,
Wherein, R7For deuterium；
R8、R9、R10、R11、R12、R13、R14、R15、R16Separately it is selected from hydrogen or deuterium；
R30And R31It independently is alkyl or R30And R31It is jointly formed cyclic compound.
In yet other embodiments, comprise the following steps：
At 0 DEG C, dissolved compound XI, PhI (OAc)2In acetonitrile/water, reaction is stirred at room temperature 1~6 hour, and TLC is aobvious
Show that the reaction was complete, water quenching reaction is added into reaction system, methyl tertiary butyl ether(MTBE) extraction purifies after concentration and obtains compound
IX。
The present invention also provides a kind of such as Formula XI A compounds represented,
Wherein, R8、R9、R10、R11、R12、R13、R14、R15、R16Separately it is selected from hydrogen or deuterium；
R30And R31It independently is alkyl or R30And R31It is jointly formed cyclic compound.
The present invention also provides a kind of preparation methods such as Formula XI A compounds represented, which is characterized in that passes through such as Formula XI B
Compound represented occurs hydrogen/deuterium exchange system and obtains under alkaline condition,
Wherein, R8、R9、R10、R11、R12、R13、R14、R15、R16Separately it is selected from hydrogen or deuterium；
R30And R31It independently is alkyl or R30And R31It is jointly formed cyclic compound.
In yet other embodiments, comprise the following steps：
N-BuLi hexane solution, reaction mixing is added dropwise in tetrahydrofuran solution in dissolved compound XIB at -70 DEG C
Liquid is slowly increased to be stirred at room temperature 2 hours, and deuterated reagent is added dropwise, and reaction mixture is stirred at room temperature 0.5 hour, TLC display reactions
After completely, saturated ammonium chloride quenching reaction is added, ethyl acetate extraction purifies to obtain compound XIA after concentration.
The preferred CD of deuterated reagent described in the program3OD, CH3OD, D2O, AcOD, CD3CCOOD etc..
The present invention also provides a kind of compound shown as a formula V,
Wherein, R18、R19、R20、R21、R22、R23It is to be each independently selected from hydrogen or deuterium, and at least one is deuterium.
The present invention also provides a kind of preparation method such as Formula V B compounds represented, compound VB passes through as shown in Formula V A
Compound is obtained by hydrogen/deuterium exchange system,
Wherein, R19、R20、R21、R22、R23It is to be each independently selected from hydrogen or deuterium.
In yet other embodiments, comprise the following steps：
Acid or alkali is added in deuterated reagent in dissolved compound VA at room temperature, and reaction stirs 12-72h at 0~35 DEG C,
NMR shows that the reaction was complete, is reacted with 1N hydrochloric acids, and dichloromethane extraction purifies to obtain compound VB after concentration.
The preferred CD of deuterated reagent described in the program3OD, CH3OD, D2O, AcOD, CD3CCOOD etc..
The preferred sodium methoxide of alkali described in the program, sodium ethoxide, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine
Deng.
The preferred acetic acid of acid, trifluoroacetic acid, p-methyl benzenesulfonic acid, camphorsulfonic acid, Loprazolam, hydrochloric acid, sulfuric acid described in the program
Deng.
If commercially available, it is possible to use the portion of product in above-mentioned reaction step, which is made according to more short-circuit line shown in Formulas I, to be changed
Close object；Such as it can be by buying intermediate shown in previously described formula IV, formula III, then according to offer the step of system in the above method
Obtain Formula II or Formulas I compound represented.
Term used in the present invention has following meaning in addition to having opposite statement：
" alkyl " refers to the aliphatic hydrocarbon group of saturation, includes the straight chain and branched group of 1 to 10 carbon atom, preferably includes 1
To 6 carbon atoms.Non-limiting embodiment include but not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group,
Tertiary butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl propyls, 2,2- dimethyl propyls, 1- ethyl propyls,
2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls propyl, 1,1,2- thmethylpropyl, 1,1- dimethyl butyrates
Base, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- dimethylbutyls, 2- ethyl-butyls, 2- methyl amyls, 3- methyl
Amyl, 4- methyl amyls, 2,3- dimethylbutyls etc..Alkyl can be substituted or unsubstituted, when substituted, substituent group
It can be substituted on any workable tie point, preferably one or more following groups, independently selected from alkyl, alkene
Base, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl,
Heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo.
" cyclic compound ", which refers to, replaces either non-substituted full carbocyclic ring or heterocyclic compound.Cyclic annular chemical combination in the present invention
Object is preferably five-membered ring, hexatomic ring, heptatomic ring.
As used herein, " deuterated " refers to one or more of compound or group hydrogen and is replaced by deuterium.It is deuterated to be
One substitution, two substitutions, polysubstituted or full substitution.
In another preferred example, deuterium is greater than natural deuterium isotopic content in the deuterium isotopic content of deuterium the position of substitution
(0.015%), even more preferably greater than 50%, even more preferably greater than 75%, even more preferably greater than 95%, even more preferably greater than 97%, more preferably
More than 99%, even more preferably greater than 99.5%.
As used herein, term " pharmaceutically acceptable salt " refers to the compounds of this invention and acid or alkali is formed by suitable use
Make the salt of drug.Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferred salt is the compounds of this invention and acid
The salt of formation.The acid for suitably forming salt includes but is not limited to：Hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid etc. are inorganic
Acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid,
The organic acids such as picric acid, methanesulfonic acid, toluenesulfonic acid, benzene sulfonic acid；And the acidic amino acids such as aspartic acid, glutamic acid.
Abbreviations table：
| Abbreviation | Full name |
| TBTU | O- benzotriazole-N, N, N ', N '-tetramethylurea tetrafluoro boric acid esters |
| HATU | 2- (7- aoxidizes benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid esters |
| HBTU | O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester |
| PhI(OAc)2 | Diacetyl iodobenzene |
| PCy3·HBF4 | Tricyclohexyl phosphine tetrafluoroborate |
| B2pin2 | Join pinacol borate |
Following table is the structural formula of compound involved in embodiment
Specific implementation mode
The present invention is explained in detail below with reference to specific example so that those of ordinary skill in the art are more fully understood
The present invention, specific example are only used to illustrate the technical scheme of the present invention, and do not limit the present invention in any way.
Embodiment 1：Prepare compound XIa
Isopentyl aldehyde (15.07g, 175mmol) is dissolved, 1,3- dimercaptopropane (37.87g) is in dichloromethane (304mL), instead
It answers mixed liquor to be cooled to 0 degrees centigrade, boron trifluoride ether (49.67g) is added dropwise, it is small that reaction mixture is stirred at room temperature 20
When, TLC display reactions are complete, and saturated sodium bicarbonate solution quenching reaction, ethyl acetate extraction is added, and concentration post-processes to change
Close object XIa (36g).
MS(ESI)m/z：177(M+H+)
1H NMR (400MHz, CDCl3) δ 4.07 (t, J=7.5Hz, 1H), 2.97-2.77 (m, 4H), 2.20-1.84 (m,
3H), 1.59 (t, J=7.3Hz, 2H), 0.94 (d, J=6.6Hz, 6H)
Embodiment 2：Prepare compound XIb
The positive fourths of 1.6M are added dropwise in tetrahydrofuran solution (125mL) in dissolved compound XIa (8.8g, 50mmol) at -70 DEG C
Base lithium hexane solution (140mL), reaction mixture are slowly increased to be stirred at room temperature 2 hours, and deuterated water (21mL) is added dropwise, and reaction is mixed
It closing liquid to be stirred at room temperature 0.5 hour, after TLC shows that the reaction was complete, saturated ammonium chloride quenching reaction is added, ethyl acetate extracts,
Compound XIb (8.4g) is purified to obtain after concentration.
MS(ESI)m/z：178(M+H+)。
1H NMR(CDCl3, 400MHz) δ 2.95-2.80 (m, 4H), 2.16-1.88 (m, 3H), 1.61 (t, J=7.3Hz,
2H), 0.94 (d, J=6.6Hz, 6H)
Embodiment 3：Prepare compound IXa
At 0 DEG C, dissolved compound XIb (8.4g, 47mmol), PhI (OAc)2(43g) is in acetonitrile/water (20mL/20mL)
In, reaction is stirred at room temperature 1 hour, and TLC shows that the reaction was complete, and water quenching reaction, methyl tertbutyl are added into reaction system
Ether extracts, and is purified after concentration and obtains compound IXa (7.8g).
MS(ESI)m/z：88(M+H+)。
Embodiment 4：Prepare compound IXa
At 0 DEG C, dissolved compound XIb (8.4g, 47mmol), PhI (OAc)2(43g) is in acetonitrile/water (20mL/20mL)
In, reaction is stirred at room temperature 6 hours, and TLC shows that the reaction was complete, and water quenching reaction, methyl tertbutyl are added into reaction system
Ether extracts, and is purified after concentration and obtains compound IXa (7.9g).
Embodiment 5：Prepare compound IXb
10% palladium charcoal (1g) is added in n-hexane (50mL) in dissolved compound XII (5g), reacts room temperature under a hydrogen atmosphere
4h is stirred, after TLC shows that the reaction was complete, diatomite filtering, n-hexane washing purifies to obtain compound IXb (4.2g) after concentration.
MS(ESI)m/z：93(M+H+)。
Embodiment 6：Prepare compound IXd
Dissolved compound IXc (10g, 0.12mol) is in CD3In OD (50mL), CH is added3ONa (0.6g) reacts at 0 DEG C
12h is stirred, after nuclear-magnetism shows that the reaction was complete, oxalic acid quenching reaction, distillation obtains compound IXd (6g).
MS(ESI)m/z：89(M+H+)。
Embodiment 7：Prepare compound VIIa
Dissolved compound VIId (2.6g, 13.7mmol) is in CD3In OD (5mL), CH is added3ONa (3.2g) is reacted 50
4h is stirred at DEG C, after TLC shows that the reaction was complete, 1N hydrochloric acids reaction, ethyl acetate extraction purifies to obtain compound after concentration
VIIa(2.3g)。
MS(ESI)m/z：192(M+H+)。
1H NMR (400MHz, CDCl3)：δ 7.94 (s, 1H), 2.11-1.93 (m, 1H), 1.12 (s, 9H), 0.94 (dd, J
=6.8,4.2Hz, 6H),
Embodiment 8：Prepare compound VIIa
Dissolved compound IXd (5g, 57mmol), compound X (15.2g) is in ethyl acetate (50mL), magnesium sulfate
(30g), reaction mixture stirs 24 hours at 20 DEG C, after TLC shows that the reaction was complete, water quenching reaction, ethyl acetate is added to extract,
Compound VIIa (9.2g) is purified to obtain after concentration.
Embodiment 9：Prepare compound VIIb
Dissolved compound IXa (4g, 46mmol), compound X (12.2g) is in dichloromethane (40mL), p-methyl benzenesulfonic acid
Pyridiniujm (0.6g), reaction mixture stirs 24 hours at 20 DEG C, after TLC shows that the reaction was complete, adds water quenching reaction, acetic acid second
Ester extracts, and compound VIIb (7.7g) is purified to obtain after concentration.
MS(ESI)m/z：191(M+H+)。
Embodiment 10：Prepare compound VIIc
Dissolved compound IXb (2.8g, 32mmol), compound X (8.5g) are in toluene (28mL), four isopropyl oxygen titaniums
(0.4g), reaction mixture stirs 2 hours at 80 DEG C, after TLC shows that the reaction was complete, water quenching reaction, ethyl acetate is added to extract,
Compound VIIc (5.1g) is purified to obtain after concentration.
MS(ESI)m/z：196(M+H+)。
Embodiment 11：Prepare compound VIa
At 0 DEG C, dissolved compound VIIa (362mg, 1.9mmol), CuSO4(3.6mg), PCy3·HBF4(8.4mg), benzyl
B2pin2 (961mg) is added in amine (10mg) (5mL/1mL) in toluene/water, and after reaction stirs 6h at 25 DEG C, TLC is shown instead
Should be complete, ethyl acetate extraction, crude Compound VIa (648mg) after concentration is directly used in and reacts in next step.
MS(ESI)m/z：320(M+H+)。
Embodiment 12：Prepare compound VIb
At 0 DEG C, dissolved compound VIIa (2.7g, 14.2mmol), CuBr2(27mg), PCy3·HBF4(63mg), benzylamine
B is added in (76mg) in tetrahydrofuran/water (10mL/5mL)2pin2(7.21g), after reaction stirs 1h at 50 DEG C, TLC is shown
The reaction was complete, and ethyl acetate extraction, crude Compound VIb (5.6g) after concentration is directly used in and reacts in next step.
MS(ESI)m/z：319(M+H+)。
Embodiment 13：Prepare compound VIc
At 0 DEG C, dissolved compound VIIc (633mg, 3.25mmol), CuCl2(4.5mg), PCy3·HBF4(12.7mg),
B is added in benzylamine (15mg) (6mL/2mL) in ethyl acetate/water2pin2(1.2g), after reaction stirs 8h at 0 DEG C, TLC is aobvious
Show that the reaction was complete, ethyl acetate extraction, crude Compound VIc (1.3g) after concentration is directly used in and reacts in next step.
MS(ESI)m/z：324(M+H+)。
Embodiment 14：Prepare compound Vb
Dissolved compound Va (2g) is in CD3In OD (15mL), CH is added at room temperature3ONa (60mg), reaction are stirred at 25 DEG C
48h is mixed, NMR shows that the reaction was complete, is reacted with 1N hydrochloric acids, and dichloromethane extraction purifies to obtain compound Vb after concentration
(1.6g)。
MS(ESI)m/z：251(M+H+)。
Embodiment 15：Prepare compound IVa
Crude Compound VIa (648mg) is dissolved in methanol (4mL), and the ethyl acetate solution of 4M HCl is added at room temperature
(1mL) is concentrated to give white solid after 1h is stirred at room temperature in reaction, filters, and compound IVa is obtained after methyl tertiary butyl ether(MTBE) washing
(429mg)。
MS(ESI)m/z：216(M-HCl+H+)。
1H NMR (400MHz, DMSO) δ 7.70 (s, 2H), 2.71 (t, J=8.8Hz, 1H), 1.68 (dt, J=13.3,
6.7Hz, 1H), 1.26 (d, J=2.4Hz, 12H), 0.88 (d, J=6.4Hz, 6H)
Embodiment 16：Prepare compound IVb
Crude Compound VIb (5.6g) is dissolved in ethyl alcohol (56mL), and 6M HCl dioxane solutions are added at 0 DEG C
(10mL) is concentrated to give white solid after reaction stirs 4h at 0 DEG C, filters, and compound IVb is obtained after ethyl acetate washing
(2.83g)。
MS(ESI)m/z：215(M-HCl+H+)。
1H NMR(CDCl3, 400MHz) and δ 8.22 (s, 3H), 1.93-1.61 (m, 3H), 1.27 (d, J=2.4Hz, 12H),
0.96 (d, J=6.4Hz, 6H)
Embodiment 17：Prepare compound IVc
Crude Compound VIc (1.3g) is dissolved in acetone (10mL), and the tetrahydrofuran solution of 1M HCl is added at 40 DEG C
(2mL) is concentrated to give white solid after reaction stirs 2h at 40 DEG C, filters, and compound IVc (729mg) is obtained after acetone washing.
MS(ESI)m/z：220(M-HCl+H+)。
Embodiment 18：Prepare compound IIIa
At -20 DEG C, dissolved compound IVa (300mg, 1.2mmol), compound Va (248mg), TBTU (385mg) is in four
In hydrogen furans (10mL).Diisopropyl ethyl amine (323mg) is added dropwise thereto, reaction is slowly increased to 0 DEG C of stirring for 24 hours, and TLC is shown
The reaction was complete, and water quenching reaction, ethyl acetate extraction is added to obtain crude Compound IIIa (550mg) after concentration, be used for without further purification
It reacts in next step.
MS(ESI)m/z：445(M+H+)。
Embodiment 19：Prepare compound IIIb
At -10 DEG C, dissolved compound IVb (501mg, 2mmol), compound Va (496mg), HATU (620mg) is in dichloro
In methane (10mL).Diisopropyl ethyl amine (774mg) is added dropwise thereto, reaction is slowly increased to 25 DEG C and stirs 12h, and TLC is shown
The reaction was complete, and water quenching reaction, ethyl acetate extraction is added to obtain crude Compound IIIb (830mg) after concentration, be used for without further purification
It reacts in next step.
MS(ESI)m/z：444(M+H+)。
Embodiment 20：Prepare compound IIIc
At -10 DEG C, dissolved compound IVc (703mg, 2.75mmol), compound Va (680mg), HBTU (1.03g) is in two
In methylformamide (20mL).Diisopropyl ethyl amine (986mg) is added dropwise thereto, reaction is slowly increased to 35 DEG C of stirrings 2h, TLC
The reaction was complete for display, and water quenching reaction, ethyl acetate extraction is added to obtain crude Compound IIIc (1.2g) after concentration, without further purification
For reacting in next step.
MS(ESI)m/z：449(M+H+)。
Embodiment 21：Prepare compound IIId
At -10 DEG C, dissolved compound IVd (630mg, 2.46mmol), compound Vb (612mg), TBTU (0.93g) is in two
In methylformamide (20mL).Triethylamine (887mg) is added dropwise thereto, reaction is slowly increased to 35 DEG C of stirring 2h, TLC display reactions
Completely, water quenching reaction, ethyl acetate extraction is added to obtain crude Compound IIId (1.08g) after concentration, be used for without further purification next
Step reaction.
MS(ESI)m/z：445(M+H+)。
Embodiment 22：Prepare compound IIa
Crude Compound IIIa (0.55g) is dissolved in methanol (6mL), is added in dilute hydrochloric acid (1N, 3.3mL), and reaction is mixed
It closes liquid to stir 2 hours at 40 DEG C, TLC shows that the reaction was complete, normal heptane, and sodium hydroxide and dichloromethane wash successively, concentration
After purify to obtain compound IIe (0.36g).
MS(ESI)m/z：345(M-H2O+H+)。
1H NMR (400MHz, MeOD) δ 7.63 (t, J=1.4Hz, 1H), 7.51 (d, J=1.4Hz, 2H), 4.26 (s,
2H), 2.79 (s, 1H), 1.72-1.65 (m, 1H), 0.96 (d, J=6.6Hz, 6H).
Embodiment 23：Prepare compound IIa
Crude Compound IIIa (0.55g) is dissolved in methanol (6mL), is added in sodium hydroxide (1N, 5mL), and reaction is mixed
It closes liquid to stir 12 hours at 20 DEG C, TLC shows that the reaction was complete, normal heptane, and sodium hydroxide and dichloromethane wash successively, concentration
After purify to obtain compound IIe (0.38g).
Embodiment 24：Prepare compound IIb
Dissolved compound IIa (0.23g) is in CD3In OD (3mL), CH is added at room temperature3ONa (13mg) reacts at 35 DEG C
12h is stirred, NMR shows that the reaction was complete, is reacted with 1N hydrochloric acids, and dichloromethane extraction purifies to obtain compound IIb after concentration
(0.2g)。
MS(ESI)m/z：347(M-H2O+H+)。
Embodiment 25：Prepare compound IIc
Dissolved compound IIm (722mg) is in D2In O (5mL), at 0 DEG C, CH is added3ONa (27mg) reactions are stirred at 0 DEG C
After 72 hours, NMR shows that the reaction was complete, is reacted with 1N hydrochloric acids, and dichloromethane extraction purifies to obtain compound IIc after concentration
(630mg)。
MS(ESI)m/z：345(M-H2O+H+)。
1H NMR (400MHz, MeOD) δ 7.62 (t, J=1.4Hz, 1H), 7.51 (d, J=1.4Hz, 2H), 2.87-2.75
(m, 1H), 1.73-1.65 (m, 1H), 1.48-1.35 (m, 2H), 0.96 (d, J=6.6Hz, 6H)
Embodiment 26：Prepare compound IIc
Dissolved compound IIId (1.08g) is in methanol (10mL), at room temperature, phenyl boric acid (2.6g), dilute hydrochloric acid is added
(1N, 6mL), after reaction is stirred 24 hours at 20 DEG C, TLC shows that the reaction was complete, normal heptane, sodium hydroxide and dichloromethane according to
Secondary washing purifies to obtain compound IIc (720mg) after concentration.
Embodiment 27：Prepare compound IIe
Crude Compound IIIb (0.45g, 1mmol) is dissolved, isobutaneboronic acid (0.630g) is ethyl alcohol (6.6mL), positive heptan
In alkane (6.6mL) and dilute hydrochloric acid (1N, 3.3mL), reaction mixture is stirred at room temperature 2 hours, and TLC shows that the reaction was complete, just
Heptane, sodium hydroxide and dichloromethane wash successively, and compound IIe (0.16g) is purified to obtain after concentration.
MS(ESI)m/z：344(M-H2O+H+)。
1H NMR (MeOD, 400MHz) δ 7.62 (s, 1H), 7.50 (d, 2H), 4.25 (s, 2H), 1.69-1.68 (m, 1H),
1.35 (d, 2H), 0.97 (d, J=6.6Hz, 6H)
Embodiment 28：Prepare compound IIf
P-methyl benzenesulfonic acid (8mg) is added in AcOD (1mL) in dissolved compound IIe (100mg) at room temperature, reacts 35
It is stirred at DEG C for 24 hours, NMR shows that the reaction was complete, is reacted with 1N hydrochloric acids, and dichloromethane extraction purifies to obtain compound after concentration
IIf(86mg)。
MS(ESI)m/z：346(M-H2O+H+)。
Embodiment 29：Prepare compound IIh
Crude Compound IIIc (1.2g) is dissolved in isopropanol (10mL), is added in sodium hydroxide (1N, 5mL), reaction
Mixed liquor stirs 2 hours at 40 DEG C, and TLC shows that the reaction was complete, normal heptane, and sodium hydroxide and dichloromethane wash successively, dense
Compound IIh (0.65g) is purified to obtain after contracting.
MS(ESI)m/z：349(M-H2O+H+)。
Embodiment 30：Prepare compound IIi
NaOH (51mg) is added in MeOD (10mL) in dissolved compound IIh (300mg) at room temperature, reacts at 30 DEG C
12h is stirred, NMR shows that the reaction was complete, is reacted with 1N hydrochloric acids, and dichloromethane extraction purifies to obtain compound IIi after concentration
(210mg)。
MS(ESI)m/z：351(M-H2O+H+)。
Embodiment 31：Prepare compound Ia
Dissolved compound IIa (50mg), citric acid (66mg) react the 2h that flows back at 90 DEG C, allow it in 4mL ethyl acetate
It is slowly cooled to room temperature, after being stirred overnight, white solid is filtered, ethyl acetate washing obtains compound as white solid Ia
(40mg)。
MS(ESI)m/z：345
1H NMR (400MHz, DMSO) δ 12.15 (s, 2H), 10.72 (s, 1H), 9.14 (s, 1H), 7.67 (s, 1H),
7.57 (d, J=1.2Hz, 2H), 4.28 (s, 2H), 2.89-2.68 (m, 4H), 1.69-1.67 (m, 1H), 0.87 (d, J=
6.4Hz, 6H)
Embodiment 32：Prepare compound Ib
In 4mL ethyl acetate, reaction is heated in reaction at 60 DEG C for dissolved compound IIb (50mg), citric acid (66mg)
12h allows it to be slowly cooled to room temperature, and white solid is filtered, and ethyl acetate washing obtains compound as white solid Ib
(51mg)。
MS(ESI)m/z：347
Embodiment 33：Prepare compound Ic
In 4mL ethyl acetate, reaction is heated in reaction at 40 DEG C for dissolved compound IIc (50mg), citric acid (66mg)
48h allows it to be slowly cooled to room temperature, and white solid is filtered, and ethyl acetate washing obtains compound as white solid Ic
(36mg)。
MS(ESI)m/z：345
1H NMR (400MHz, DMSO) δ 12.16 (s, 2H), 10.73 (s, 1H), 9.13 (s, 1H), 7.67 (s, 1H),
7.57 (d, 2H), 3.38 (s, 2H), 3.00-2.55 (m, 4H), 1.68 (s, 1H), 1.30-1.18 (d, J=24.1Hz, 2H),
0.97 (d, J=6.4Hz, 6H)
Embodiment 34：Prepare compound Ie
Dissolved compound IIe (50mg), citric acid (66mg) are in 4mL ethyl acetate, reaction heating reaction 9h at 80 DEG C,
It allows it to be slowly cooled to room temperature, white solid is filtered, ethyl acetate washing obtains compound as white solid Ie (45mg).
MS(ESI)m/z：344
1H NMR (DMSO, 400MHz) δ 12.17-12.13 (m, 2H), 10.70 (s, 1H), 9.14 (s, 1H), 7.67 (s,
1H), 7.57 (d, J=1.4Hz, 2H), 4.25 (s, 1H), 2.70-2.60 (m, 4H), 1.66-1.61 (m, 1H), 1.40-1.31
(d, J=24.1Hz, 2H), 0.97 (d, J=6.4Hz, 6H)
Embodiment 35：Prepare compound If
Dissolved compound IIf (50mg), citric acid (66mg) are in 4mL butyl acetates, reaction heating reaction 1h at 95 DEG C,
It allows it to be slowly cooled to room temperature, and continues to stir 6h, white solid is filtered, ethyl acetate washing obtains white solid chemical combination
Object If (53mg).
MS(ESI)m/z：346
Embodiment 36：Prepare compound Ih
In 4mL isopropyl acetates, reaction is heated in reaction at 90 DEG C for dissolved compound IIh (50mg), citric acid (66mg)
2h allows it to be slowly cooled to room temperature, and continues to stir 12h, and white solid is filtered, and ethyl acetate washing obtains white solid
Compound Ih (46mg).
MS(ESI)m/z：349
Embodiment 37：Prepare compound Ii
Dissolved compound IIi (50mg), citric acid (66mg) are in 4mL butyl acetates, reaction heating reaction 2h at 90 DEG C,
It allows it to be slowly cooled to room temperature, and continues to stir 12h, white solid is filtered, ethyl acetate washing obtains white solid chemical combination
Object Ii (49mg).
MS(ESI)m/z：351
Embodiment 38：Prepare compound In
Dissolved compound IIm (50mg), D2Citric acid (66mg) heats reaction in 4mL butyl acetates, reaction at 90 DEG C
2h allows it to be slowly cooled to room temperature, and continues to stir 12h, and white solid is filtered, and ethyl acetate washing obtains white solid
Compound In (51mg).
MS(ESI)m/z：343
Embodiment 39：Prepare compound Io
Dissolved compound IIi (50mg), D4Citric acid (66mg) heats reaction in 4mL butyl acetates, reaction at 90 DEG C
2h allows it to be slowly cooled to room temperature, and continues to stir 12h, and white solid is filtered, and ethyl acetate washing obtains white solid
Compound Io (53mg).
MS(ESI)m/z：343
Embodiment 40：External activity test
Activity suppression of the detection compound to the proteasome subunit CTL of cellular level：
Cell culture
Culture medium：MEM culture mediums (Gibco, 11095-080)+10%FBS
Condition of culture：37 DEG C, 5%CO2
First, the Calu-6 cells (Chinese Academy of Sciences's cell, TCHu144) of logarithmic growth phase, are digested, fresh cultured with pancreatin
After base weight is outstanding, spread into 384 porocyte culture plates (Cat.3707, Corning) according to the density of 2000 cells in every hole, per hole 20
20 μ L culture mediums (being free of cell) are added in background signal hole, is put into incubator and continues overnight incubation for μ L cell culture fluids.
Untested compound is diluted to 2mM with DMSO, then 3 times of doubling dilutions, totally 10 concentration points.Again with fresh training
Base is supported by 40 times of the diluted chemical compound of gradient dilution, DMSO a concentration of 2.5%.
The compound that 5 μ L have diluted is added into sample well.Untested compound initial concentration is 10 μM, 3 times of doubling dilutions.
Isometric solvent (2.5%DMSO) is added in full control wells living and background signal hole, DMSO is a concentration of in final system
0.5%.
Continue after cultivating 2hr, 25 μ L Proteasome-Glo are added per holeTM Cell-Based Reagent
(Promega, G1200) vibrates 10min, and Luminescence is read with microplate reader (PE, envision 2104).
Each hole is calculated by complete active hole (untested compound is not added) and background signal hole (not having cell)
Inhibiting rate, multiple holes are averaged, while being inhibited to each untested compound with the picture analysis software PRISM 5.0 of profession
The diagram of rate.
Inhibiting rate is calculated with following formula：
Inhibiting rate=(RLU100%-RLUsample)/(RLU100%-RLUbackground) 100%
The results are shown in Table 2.The result shows that：Compared with control compound Im or IIm, the compound of the present invention is to Calu-6
The active rejection abilities of Cellular proteasomes CT-L are similar.
Table 2
Embodiment 41：The Pharmacokinetic Evaluation of rat
From Shanghai, western Poole-Bi Kai experimental animals Co., Ltd buys male SPF grades of medical fitness, healthy SD without exception
Rat.It takes a blood sample through jugular puncture, each sample collection about 0.2mL, heparin sodium anti-freezing, blood sampling time point is as follows：
Before administration, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h after administration, for 24 hours and 48h.
Blood specimen collection is placed on ice, centrifugal separation plasma (centrifugal condition：8000 revs/min, 6 minutes, 2-8
℃).- 80 DEG C are deposited in before the plasma analysis of collection.
Blood sample is analyzed by experiment mechanism analysis department using LC-MS/MS.
According to the plasma drug concentration data of drug, the non-compartment models of pharmacokinetics software for calculation WinNonlin5.2 point are used
Not Ji Suan test sample pharmacokinetic parameter AUC0-∞、MRT0-∞、Cmax、Tmax、T1/2With the parameters such as Vd and its average value and
Standard deviation.In addition, bioavilability (F) will be calculated by following formula.
F=(AUC(0-∞)(PO)×Dose(IV))/(AUC(0-∞)(IV)×Dose(PO)) × 100%
It is less than the sample of lower limit of quantitation for concentration, when carrying out pharmacokinetic parameter calculating, before reaching Cmax
The sample of sampling should be calculated with zero, and sample point sample should be calculated with no standard measure (BLQ) after reaching Cmax.
Deuterated compound and the pharmacokinetic parameter of non-deuterated compound such as following table.According to experimental result it is found that this hair
Bright deuterated compound IIc, IIa, compared with corresponding non-deuterated compound IIm, drug Half-life in vivo, AUC and biology profit
Expenditure is all significantly improved.The half-life period of wherein compound IIc improves at least 70%, bioavilability improve to
Few 80%.
Table 3
PO(1mg/Kg)
Due to describing the present invention according to its specific embodiment, certain modifications and equivalent variations are general for this field
Logical technical staff is obvious and is included within the scope of the invention.
Claims (30)
1. a kind of boric acid ester compound shown in formula I or its crystal form, pharmaceutically acceptable salt, hydrate or solvent close
Object,
Wherein, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、
R23It is to be each independently selected from hydrogen or deuterium, and at least one is deuterium.
2. boric acid ester compound as described in claim 1 or its crystal form, pharmaceutically acceptable salt, hydrate or solvent
Close object, which is characterized in that work as R1、R2、R3、R4、R5、R6、R10、R17、R20、R21、R22、R23For hydrogen when, R7、R8、R9、R11、R12、
R13、R14、R15、R16、R18、R19It is separately to be selected from hydrogen or deuterium, and at least one is deuterium.
3. boric acid ester compound as described in claim 1 or its crystal form, pharmaceutically acceptable salt, hydrate or solvent
Close object, which is characterized in that the compound is selected from the group：
4. a kind of boric acid compound as shown in Formula II or its crystal form, pharmaceutically acceptable salt, hydrate or solvent close
Object,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25It is respectively only
It is on the spot selected from hydrogen or deuterium, and at least one is deuterium.
5. boric acid compound as claimed in claim 4 or its crystal form, pharmaceutically acceptable salt, hydrate or solvent close
Object, which is characterized in that work as R10、R17、R20、R21、R22、R23、R24、R25For hydrogen when, R7、R8、R9、R11、R12、R13、R14、R15、R16、
R18、R19It is separately to be selected from hydrogen or deuterium, and at least one is deuterium.
6. boric acid compound as claimed in claim 4 or its crystal form, pharmaceutically acceptable salt, hydrate or solvent close
Object, which is characterized in that the compound is selected from the group：
7. a kind of preparation method of pharmaceutical composition, which is characterized in that will in claim 1-6 any compound or
Its crystal form, pharmaceutically acceptable salt, hydrate or solvate and pharmaceutically acceptable carrier are mixed, to be formed
Pharmaceutical composition.
8. a kind of pharmaceutical composition, which is characterized in that containing (1) claim 1-6 any compound or its crystal form,
Pharmaceutically acceptable salt, hydrate or solvate；(2) pharmaceutically acceptable carrier.
9. a kind of method for the treatment of cancer, it includes to needing any one of this patient's administration claim 1-6 treated describedization
Close object or its crystal form, pharmaceutically acceptable salt, hydrate or solvate or pharmaceutical composition according to any one of claims 8.
10. a kind of preparation method of boric acid ester compound shown in formula I, which is characterized in that pass through the boron as shown in Formula II
Acid compound is made with citric acid or the condensation of deuterated citric acid,
Wherein, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、
R23、R24、R25、R26、R27It is to be each independently selected from hydrogen or deuterium, and at least one is deuterium.
11. a kind of preparation method of the boric acid compound as shown in Formula II B, which is characterized in that by changing as shown in Formula II A
Object generation hydrogen/deuterium exchange system is closed to obtain,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R19、R20、R21、R22、R23、R24、R25It is respective independence
Ground is selected from hydrogen or deuterium.
12. preparation method as claimed in claim 11, which is characterized in that pass through hydrogen/deuterium by such as Formula II C compounds represented
The standby such as Formula II D compounds represented of exchange system,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R20、R21、R22、R23、R24、R25It is to select each independently
From hydrogen or deuterium.
13. a kind of preparation method of the boric acid compound as shown in Formula II, which is characterized in that by changing as shown in formula III
Object generation boric acid ester hydrolysis reaction is closed to be made,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25It is respectively only
It is on the spot selected from hydrogen or deuterium, and at least one is deuterium；
R28、R29It is borate protecting group, is each independently selected from alkyl or R28、R29It is jointly formed ring protection base.
14. a kind of such as formula III compound represented,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23It is to select each independently
From hydrogen or deuterium, and at least one is deuterium；
R28、R29It is borate protecting group, is each independently selected from alkyl or R28、R29It is jointly formed ring protection base.
15. a kind of preparation method such as formula III compound represented, which is characterized in that by such as formula IV compound represented or
Its pharmaceutically acceptable salt is made with compound shown as a formula V or its pharmaceutically acceptable salt by condensation reaction,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R28、R29Definition such as
Described in claim 14.
16. a kind of such as formula IV compound represented or its pharmaceutically acceptable salt
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R28、R29Definition it is as claimed in claim 14.
17. a kind of such as formula IV compound represented or the preparation method of its pharmaceutically acceptable salt, which is characterized in that pass through
If Formula IV compound represented is made by deprotection base,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R28、R29Definition it is as claimed in claim 14.
18. a kind of such as Formula IV compound represented,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R28、R29Definition it is as claimed in claim 14.
19. a kind of preparation method such as Formula IV compound represented, which is characterized in that by such as Formula VII compound represented and
If Formula VIII compound represented is made by addition reaction,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R28、R29Definition it is as claimed in claim 14.
20. a kind of such as Formula VII compound represented,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16It is to be each independently selected from hydrogen or deuterium, and at least one is
Deuterium.
21. a kind of preparation method of such as Formula VII compound represented, which is characterized in that pass through such as Formula VII A compounds represented
It is made by hydrogen/deuterium exchange reaction,
Wherein, R7、R9、R10、R11、R12、R13、R14、R15、R16Definition it is as claimed in claim 20.
22. a kind of preparation method such as Formula VII compound represented, which is characterized in that by such as Formula IX compound represented and
Compound represented by a formula X is made by condensation reaction,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16Definition it is as claimed in claim 20.
23. a kind of such as Formula IX compound represented,
Wherein, R7、R8、R9、R10、R11、R12、R13、R14、R15、R16Definition it is as claimed in claim 20.
24. a kind of preparation method of such as Formula IX B compounds represented, which is characterized in that pass through such as Formula IX A compounds represented and pass through
Hydrogen/deuterium exchange system is crossed to obtain,
Wherein, R7、R9、R10、R11、R12、R13、R14、R15、R16Definition it is as claimed in claim 20.
25. a kind of preparation method of such as Formula IX compound represented, which is characterized in that pass through such as Formula XI compound represented and pass through
Hydrolysis is made,
Wherein, R7For deuterium；
R8、R9、R10、R11、R12、R13、R14、R15、R16Separately it is selected from hydrogen or deuterium；
R30And R31It independently is alkyl or R30And R31It is jointly formed cyclic compound.
26. a kind of such as Formula XI A compounds represented,
Wherein, R8、R9、R10、R11、R12、R13、R14、R15、R16Separately it is selected from hydrogen or deuterium；
R30And R31It independently is alkyl or R30And R31It is jointly formed cyclic compound.
27. a kind of preparation method of such as Formula XI A compounds represented, which is characterized in that existed by such as Formula XI B compounds represented
Hydrogen/deuterium exchange system occurs under alkaline condition to obtain,
Wherein, R8、R9、R10、R11、R12、R13、R14、R15、R16Separately it is selected from hydrogen or deuterium；
R30And R31It independently is alkyl or R30And R31It is jointly formed cyclic compound.
28. a kind of compound shown as a formula V or its pharmaceutically acceptable salt
Wherein, R18、R19、R20、R21、R22、R23It is to be each independently selected from hydrogen or deuterium, and at least one is deuterium.
29. a kind of preparation method of such as Formula V B compounds represented, which is characterized in that pass through such as Formula V A compounds represented and pass through
Hydrogen/deuterium exchange system obtains,
Wherein, R19、R20、R21、R22、R23It is to be each independently selected from hydrogen or deuterium.
30. a kind of preparation method of compound shown in formula I, it is characterised in that include the following steps,
1) Formula IX compound represented obtains the chemical combination as shown in Formula VII with Formula X compound represented by imines condensation reaction
Object；
2) Formula VII compound represented obtains the chemical combination as shown in Formula IV with Formula VIII compound represented by addition reaction
Object；
3) Formula IV compound represented obtains such as formula IV compound represented by hydrolysis or its is pharmaceutically acceptable
Salt；
4) formula IV compound represented or its pharmaceutically acceptable salt and compound shown as a formula V or its can pharmaceutically connect
The salt received is condensed to yield such as formula III compound represented；
5) formula III compound represented is obtained by boric acid ester hydrolysis such as Formula II compound represented；
6) Formula II compound represented with citric acid or deuterated citric acid by being condensed to form compound shown in formula I.
Wherein, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、
R23Definition it is as described in claim 1；
R24、R25、R26、R27Independently selected from hydrogen or deuterium；
R28、R29It is borate protecting group, is each independently selected from alkyl or R28、R29It is jointly formed ring protection base.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109251218A (en) * | 2017-12-05 | 2019-01-22 | 深圳市塔吉瑞生物医药有限公司 | A kind of preparation method and its crystal form of substituted boric acid ester compound |
| CN111689993A (en) * | 2019-03-11 | 2020-09-22 | 凯特立斯（深圳）科技有限公司 | Novel preparation method of chiral alpha-amino boric acid ester as key intermediate of boron-containing zomib drug |
Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002059131A1 (en) * | 2001-01-25 | 2002-08-01 | Millennium Pharmaceuticals, Inc. | Formulation of boronic acid compounds |
| US20090076031A1 (en) * | 2007-09-17 | 2009-03-19 | Protia, Llc | Deuterium-enriched bortezomib |
| CN101772507A (en) * | 2007-08-06 | 2010-07-07 | 米伦纽姆医药公司 | Proteasome inhibitor |
| CN102066386A (en) * | 2008-06-17 | 2011-05-18 | 米伦纽姆医药公司 | Boronate ester compounds and pharmaceutical compositions thereof |
| US20110301124A1 (en) * | 2007-08-06 | 2011-12-08 | Millennium Pharmaceuticals, Inc. | Proteasome inhibitors |
| CN103030656A (en) * | 2011-09-30 | 2013-04-10 | 北京大学 | Synthetic method of proteasome inhibitor bortezomib and analogs |
| WO2013180149A1 (en) * | 2012-05-30 | 2013-12-05 | 富山化学工業株式会社 | Deuterated nitrogenated heterocyclic carboxamide derivative or salt thereof |
| US20150166601A1 (en) * | 2012-07-13 | 2015-06-18 | Concert Pharmaceuticals Inc. | Deuterated carfilzomib |
| CN105732683A (en) * | 2016-03-25 | 2016-07-06 | 南京林业大学 | Dipeptide boric acid composed of carboxylic acid and alpha-amino acid as well as ester compound thereof, and preparation method and application of dipeptide boric acid and ester compound thereof |
| CN106496259A (en) * | 2015-09-08 | 2017-03-15 | 成都贝斯凯瑞生物科技有限公司 | A kind of boracic intermediate and its application in medical industry |
| CN106916177A (en) * | 2017-03-23 | 2017-07-04 | 南京师范大学 | A kind of deuterated dipeptide boronic acid or its ester type compound and its synthetic method and purposes |
| CN108368134A (en) * | 2016-07-25 | 2018-08-03 | 深圳市塔吉瑞生物医药有限公司 | A kind of substituted boronic acid compounds and the medical composition and its use comprising the compound |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3896064A1 (en) * | 2015-07-06 | 2021-10-20 | Gilead Sciences, Inc. | 4,6-diamino-quinoline-3-carbonitrile derivatives as cancer osaka thyroid (cot) modulators for treating crohn's disease and ulcerative colitis |
-
2017
- 2017-04-26 CN CN201710284493.XA patent/CN108794516A/en not_active Withdrawn
-
2018
- 2018-04-26 WO PCT/CN2018/084623 patent/WO2018196812A1/en active Application Filing
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002059131A1 (en) * | 2001-01-25 | 2002-08-01 | Millennium Pharmaceuticals, Inc. | Formulation of boronic acid compounds |
| CN101772507A (en) * | 2007-08-06 | 2010-07-07 | 米伦纽姆医药公司 | Proteasome inhibitor |
| US20110301124A1 (en) * | 2007-08-06 | 2011-12-08 | Millennium Pharmaceuticals, Inc. | Proteasome inhibitors |
| US20090076031A1 (en) * | 2007-09-17 | 2009-03-19 | Protia, Llc | Deuterium-enriched bortezomib |
| CN102066386A (en) * | 2008-06-17 | 2011-05-18 | 米伦纽姆医药公司 | Boronate ester compounds and pharmaceutical compositions thereof |
| CN103030656A (en) * | 2011-09-30 | 2013-04-10 | 北京大学 | Synthetic method of proteasome inhibitor bortezomib and analogs |
| WO2013180149A1 (en) * | 2012-05-30 | 2013-12-05 | 富山化学工業株式会社 | Deuterated nitrogenated heterocyclic carboxamide derivative or salt thereof |
| US20150166601A1 (en) * | 2012-07-13 | 2015-06-18 | Concert Pharmaceuticals Inc. | Deuterated carfilzomib |
| CN106496259A (en) * | 2015-09-08 | 2017-03-15 | 成都贝斯凯瑞生物科技有限公司 | A kind of boracic intermediate and its application in medical industry |
| CN105732683A (en) * | 2016-03-25 | 2016-07-06 | 南京林业大学 | Dipeptide boric acid composed of carboxylic acid and alpha-amino acid as well as ester compound thereof, and preparation method and application of dipeptide boric acid and ester compound thereof |
| CN108368134A (en) * | 2016-07-25 | 2018-08-03 | 深圳市塔吉瑞生物医药有限公司 | A kind of substituted boronic acid compounds and the medical composition and its use comprising the compound |
| CN106916177A (en) * | 2017-03-23 | 2017-07-04 | 南京师范大学 | A kind of deuterated dipeptide boronic acid or its ester type compound and its synthetic method and purposes |
Non-Patent Citations (2)
| Title |
|---|
| YUEXIAN LI ET AL,: "Synthesis of four isotopically labeled forms of a proteasome inhibitor, bortezomib", 《JOURNAL OF LABBELED COMPOUNDS AND RADIOPHARMACEUTICALS》 * |
| 刘洁: "氘代药物进展", 《氘代药物进展》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109251218A (en) * | 2017-12-05 | 2019-01-22 | 深圳市塔吉瑞生物医药有限公司 | A kind of preparation method and its crystal form of substituted boric acid ester compound |
| WO2019109802A1 (en) * | 2017-12-05 | 2019-06-13 | 深圳市塔吉瑞生物医药有限公司 | Preparation method of substituted borate compound and crystal form of same |
| CN109251218B (en) * | 2017-12-05 | 2021-08-24 | 深圳市塔吉瑞生物医药有限公司 | Preparation method and crystal form of substituted boric acid ester compound |
| CN113603713A (en) * | 2017-12-05 | 2021-11-05 | 深圳市塔吉瑞生物医药有限公司 | Preparation method and crystal form of substituted boric acid ester compound |
| CN111689993A (en) * | 2019-03-11 | 2020-09-22 | 凯特立斯（深圳）科技有限公司 | Novel preparation method of chiral alpha-amino boric acid ester as key intermediate of boron-containing zomib drug |
| CN111689993B (en) * | 2019-03-11 | 2023-04-14 | 凯特立斯（深圳）科技有限公司 | Novel method for preparing chiral alpha-amino boric acid ester as key intermediate of boron-containing zomib drug |
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