CN110054625A - The bis- target spot inhibitor of N- acyl group benzsulfamide hydroxamic acid Bcl-2, HDAC and preparation method and application - Google Patents
The bis- target spot inhibitor of N- acyl group benzsulfamide hydroxamic acid Bcl-2, HDAC and preparation method and application Download PDFInfo
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Abstract
The present invention relates to the bis- target spot inhibitor of a kind of N- acyl group benzsulfamide hydroxamic acid Bcl-2, HDAC and preparation method and application, compound has the structure as shown in general formula I.The compounds of this invention has anti-histone deacetylase and inhibits the activity of Bcl-2 albumen; the drug of related mammalian disease caused by can be used for preparing prevention or treating because of histon deacetylase (HDAC) abnormal expression and Bcl-2 protein abnormal expression, the invention further relates to the pharmaceutical applications of the composition with general formula I compound.
Description
Technical field
The present invention relates to the bis- target spot inhibitor of a kind of N- acyl group benzsulfamide hydroxamic acid Bcl-2, HDAC and its preparations
Method, pharmaceutical composition and medical usage, belong to pharmaceutical technology field.
Background technique
Apoptosis is the important homeostasis of multi-cell organism, it, which can actively be removed, does not need or abnormal cell,
To embryonic development, the normal physiologicals process such as homeostasis and resistance pathogen is maintained to play an important role.The mechanism
Disorder can induce various diseases, such as cancer, autoimmune disease, cardiovascular disease and neurodegenerative disease.Study table
Bright Bcl-2 protein family and apoptosis process are closely related, and are also the important target for the treatment of tumour.Bcl-2 family egg
It is white to have more than 20 kinds, anti-apoptotic proteins and pro apoptotic protein two major classes can be divided into according to function.These albumen are owned by 1~4
Bcl-2 homeodomain (Bcl-2homology domains, including BH1, BH2, BH3 and BH4).Anti-apoptotic proteins Bcl-2,
Bcl-xL, Bcl-W, Mcl-1, A1/Bfl-1 tumour cell can be made to escape apoptosis, structure generally wraps in conjunction with pro apoptotic protein
Containing tetra- structural domains of BH1-4.Pro apoptotic protein is divided into two class of BH3-only albumen and Multidomain albumen again, wherein Bim, Bad,
Bid, Puma and Noxa etc. belong to BH3-only albumen, and Bax and Bak belong to Multidomain pro apoptotic protein (also referred to as rush apoptosis
Effector).The spiral knot that anti-apoptotic proteins pass through its hydrophobic pocket (BH3 binding pocket) and the BH3 structural domain of pro apoptotic protein
It closes.Between Bcl-2 protein family member by protein-protein interaction (protein-protein interaction,
PPI), regulate and control mitochondrial apoptosis access jointly, carry out the apoptosis of inducing cell.Current only Venetoclax (ABT-199) one
Micromolecular inhibitor is approved by the FDA in the United States listing.
Histon deacetylase (HDAC) (HDAC) is most important and one of studies widest epigenetics target spot.In human body
Histon deacetylase (HDAC) and histone acetyltransferases (HAT) cooperation maintain normal acetylation of histone horizontal.Wherein,
Histon deacetylase (HDAC) becomes chromatin Structure closely by the acetyl group of removal histone ε-N- acetylated lysine,
Inhibit the generation of transcription.In tumour cell, histon deacetylase (HDAC) overexpression, so that the excessive deacetylation of histone,
Inhibit cell cycle inhibitors p21WAF1/CIP1Expression, reduce the stability and activity of tumor suppressor p53, promote
Cell factor hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) into Tumor Angiongesis express water
It is flat to increase.
The histon deacetylase (HDAC) of people has 18 hypotypes, is divided into Zn2+Dependent form (Class I, II, IV) and NAD+It relies on
Type (Class III): Class I (HDAC1~3,8), Class II (II a, HDAC4~5,7,9；II b, HDAC6,10),
Class II (SIRT1~7) and Class IV (HDAC11).The each not phase of each hypotype Tissue distribution in vivo and role
Together.
So far, U.S. FDA has had been approved by the general inhibitor listing of four histon deacetylase (HDAC)s: Vorinostat
(SAHA), Romidepsin (FK-228), Belinostat (PXD-101) and Panobinostat (LBH-589).Wherein,
Vorinostat and 3omidepsin is used for the treatment of cutaneous T-cell lymphomas, and Belinostat is used for peripheral t-Lymphocytes
The treatment of tumor, Panobinostat and other medicines combination treatment Huppert's disease.But the inhibitor listed still has very much
Deficiency, it is invalid to solid tumor especially under normal dose and there are cardiac toxics, so as to cause the clinical application of such drug
It is very limited.The part-structure of Bcl-2 inhibitor is introduced into previous HDACs inhibitor, histone may be made up
The deficiency of deacetylation inhibitor.Therefore, effectively double target spot inhibitor are that have to choose in anti-tumor drug research to Development of Novel
The project of war property and researching value.
Summary of the invention
The present invention provides a kind of bis- target spot inhibitor of N- acyl group benzsulfamide hydroxamic acid Bcl-2, HDAC, the present invention
The preparation method and application of the compound are also provided.
Technical scheme is as follows:
One, the bis- target spot inhibitor of N- acyl group benzsulfamide hydroxamic acid Bcl-2, HDAC
A kind of bis- target spot inhibitor of N- acyl group benzsulfamide hydroxamic acid Bcl-2, HDAC, have general formula I
Compound and its stereoisomer, pharmaceutically acceptable salt,
In general formula I, R is hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, carboxylic group substitution, C1-C12Alkane
Base, naphthenic base, or the C replaced by following one or more hydroxyls, halogen, nitro, cyano, carboxylic group1-C12Alkyl, cycloalkanes
Base contains identical or different one or more following substituent groups or the aryl, heteroaryl, the aryl alkyl, heteroaryl that do not replace
Base alkyl: hydroxyl, halogen, nitro, cyano, guanidine radicals, carboxyl, halogen C1-C12Alkyl, C1-C12Alkoxy, C1-C12Alkyl, C3-C12
Naphthenic base, aryl, heteroaryl；
In general formula I, X is carbon, nitrogen, oxygen, sulphur；
In general formula I, Z is aryl, heteroaryl, cyclohexyl, heterocycle, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group；
In general formula I, nlIt is 0-3, n2It is 0-5.
It is preferred according to the present invention, in general formula I,
R is hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, carboxylic group substitution；
X is carbon or nitrogen；
Z is methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；
n1It is 0-3；n2It is 0-5.
According to the present invention, it is further preferred that above-mentioned compound of Formula I is one of following:
2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((chloro- 5,5- dimethyl -3,4,5,6- of 4'-
Tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base)-N- ((4- ((2- (hydroxylamino) -2- oxoethyl) amino) -3-
Nitrobenzophenone) sulfonyl) benzamide (4A),
2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((chloro- 5,5- dimethyl -3,4,5,6- of 4'-
Tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base)-N- ((4- ((4- (Hydroxycarboamoyl) benzyl) amino) -3-
Nitrobenzophenone) sulfonyl) benzamide (4B),
1- (4- (N- (2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((chloro- 5,5- dimethyl of 4'-
3,4,5,6- tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base) benzoyl) sulfamoyl) -2- nitrobenzophenone) -
N- hydroxyl -4- formamide (4C),
1- (4- (N- (2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((chloro- 5,5- dimethyl of 4'-
3,4,5,6- tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base) benzoyl) sulfamoyl) -2- nitrobenzophenone) -
N- hydroxyl -3- formamide (4D),
(E) -2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((chloro- dimethyl -3,4 5,5- 4'-,
5-, 6- tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base)-N- ((4- (3- (hydroxyl amino) -3- oxo propyl- 1- alkene -
1- yl) phenyl) sulfonyl) benzamide (4E).
The above preferred compound, the number in subsequent bracket correspond to the compound in following reaction route and table 1
The number of structure.
Detailed description of the invention
Term and definition meaning used herein is as follows:
" aryl " refers to the aromatic hydrocarbons containing loop system, such as phenyl or naphthyl, optionally with it is Cycloalkylfused, it is described
Naphthenic base preferably has 5-7 annular atom, more preferably has 5-6 annular atom.Preferred aryl contains 5-15 carbon atom.
" heteroaryl " is aromatic heterocycle, can be monocycle or bicyclic radicals.They contain one or more, preferably 1-4,
More preferable 1-3, even more preferably 1-2 hetero atom, the hetero atom is independently selected from O, S and N.Heteroaryl includes oxidation
S or N, such as the N oxide of sulfinyl, sulfonyl and tricyclic nitrogen.Carbon atom or nitrogen-atoms are the tie points of Heteroaryl ring structures, by
This keeps stable aromatic ring.The example of heteroaryl includes but is not limited to pyridyl group, pyridazinyl, pyrazinyl, indolizine base, benzo
It is [b] thienyl, quinazolyl, purine radicals, indyl, quinolyl, pyrimidine radicals, pyrrole radicals, oxazolyl, thiazolyl, thienyl, different
Oxazolyl dislikes thiadiazolyl group, isothiazolyl, tetrazole radical, imidazole radicals, triazine radical, furyl, benzofuranyl and indyl.
" aryl alkyl " refers to C1-C6The aryl of alkylidene connection.
" heteroaryl alkyl " refers to C1-C6The heteroaryl of alkylidene connection.
" alkyl (Alkyl) ", individually or jointly, refers to the group derived from alkane, contains 1 to 20 carbon atom,
Preferably contain 1 to 12 carbon atom (if not specializing).It is straight chained alkyl or branched alkyl, and including containing
Cycloalkyl moiety or the straight chained alkyl or branched alkyl interrupted by cycloalkyl moiety.Straight chained alkyl or branched alkyl it is any can
And position (available point) connection is to generate stable compound.Its example includes but is not limited to 4- (isopropyl)-
Cyclohexyl-ethyl or 2- methyl-cyclopropylpentyl.In many embodiments, alkyl is containing 1 to 15 carbon atom, 1 to 8
Carbon atom, 1 to 6 carbon atom, 1 to 4 carbon atom or 1 to 2 carbon atom straight chained alkyl or branched alkyl, such as methyl, second
Base, propyl, isopropyl, butyl, tert-butyl and similar alkyl.
" alkylidene " is carbon atom groups derived from the alkane of divalent, is linear chain or branched chain, wherein, from identical carbon
Atom or different carbon atoms remove two hydrogen atoms.The example of alkylidene includes but is not limited to-CH2-、-CH2CH2And-
CH2CH(CH3)-。
" naphthenic base " is substituted or unsubstituted, saturated or unsaturated cyclic group, contains carbon atom and/or one
Or multiple hetero atoms.The ring can be monocycle or condensed ring, the ring system of bridged ring or loop coil.Annular atom number in each ring be 3-8,
More preferable 3-6, such as cyclopropyl, cyclopenta, cyclohexyl, adamantyl and similar group.
" alkoxy " indicates group-O-alkyl.
" halogen " individually or jointly, refers to all halogens, i.e. chlorine (Cl), fluorine (F), bromine (Br) or iodine (I).
" pharmaceutically acceptable salt " refers to that compound of Formula I has curative effect and nontoxic salt form.It can be by any acid
Property group (such as carboxyl) form anion salt, or cationic salts are formed by any basic group (such as amino).It is known in the art to be permitted
More such salt.The cationic salts formed on any acidic-group (such as carboxyl), or at any basic group (such as amino)
The anion salt of upper formation.These salt there are many be it is known in the art, as cationic salts include alkali metal (such as sodium and potassium) and
The salt and organic salt (such as ammonium salt) of alkaline-earth metal (such as magnesium and calcium).It can also be by using the I of corresponding acid processing alkaline form
Anion salt is easily obtained, such acid includes inorganic acid such as sulfuric acid, nitric acid, phosphoric acid etc.；Or organic acid for example acetic acid, propionic acid,
Hydroxyacetic acid, 2 hydroxy propanoic acid, Acetylformic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, winestone
Acid, 2- hydroxyl -1,2,3- the third three acid, methanesulfonic acid, ethanesulfonic acid, benzene methanesulfonic acid, 4- toluenesulfonic acid, cyclohexyl sulfinic acid, 2- hydroxyl
Yl benzoic acid, 4- amino-2-hydroxybenzoic acid etc..These salt are known to those of skill in the art, and those skilled in the art can make
Any salt provided by standby ability domain knowledge.In addition, those of skill in the art can according to solubility, stability, be easy preparation etc. because
Element takes certain salt and gives up another salt.The measurement of these salt and optimization are in the experience range of those of skill in the art.
" stereoisomer " used herein defines the compounds of this invention or its derivative physiologically is all possible
The form of stereoisomer.Unless otherwise directed, the chemical name of the compounds of this invention includes all possible spatial chemistry shape
The mixture of formula, affiliated mixture include all diastereomers of basic structure molecule and the sheet of enantiomer and substantially pure
The single isomeric forms of invention compound wherein contain lower than 10%, preferably shorter than 5%, especially less than 2%, optimal
Choosing is lower than 1% other isomers.The various stereoisomer forms of class peptide compounds of the present invention are obviously contained in of the invention
In range.
Compound of Formula I can by it is other it is protected in the form of or derivative in the form of exist, these forms are to this field
It is it will be apparent that should be included within the scope of the present invention for technical staff.
Substituent group itself as described above can be also substituted by one or more substituents.Such substituent group is included in
C.Hansch and A.Leo, Substituent Constants for Correlation Analysis in Chemistry
Substituent group those of is listed in and Biology (1979).Preferred substituent group includes alkyl, alkenyl, alkoxy, hydroxyl, oxygen
Base, nitro, amino, aminoalkyl (such as aminomethyl), cyano, halogen, carboxyl, carbonylic alkoxy (such as carbonyl ethyoxyl),
Sulfenyl, aryl, naphthenic base, heteroaryl, Heterocyclylalkyl (such as piperidyl, morpholinyl, pyrrole radicals etc.), imino group, hydroxyalkyl, aryl
Oxygroup, aryl alkyl and its combination.
" pharmaceutical composition (pharmaceutical composition) " refers to containing the active drug for treating upper significant quantity
The prepared product of agent, the form for being suitable for giving patient are produced.Therefore, the prepared product does not contain any one measured in this way
Component or various ingredients, that is, the medical implementer of Due Diligence has found that the prepared product is unsuitable for giving plain objects.In many
In the case of, this pharmaceutical composition is sterile prepared product.
" room temperature " involved in the present invention specific temperature range is 25-30 DEG C.
Two, the preparation method of the bis- target spot inhibitor of N- acyl group benzsulfamide hydroxamic acid Bcl-2, HDAC
A kind of preparation method of the bis- target spot inhibitor of N- acyl group benzsulfamide hydroxamic acid Bcl-2, HDAC, including step
It is rapid:
During the benzsulfamide 1A-1D that difference replaces is obtained with amino-compound generation nucleophilic substitution under reflux conditions
Mesosome 2A-2D, the benzsulfamide 1E that difference replaces react to obtain intermediate 2E, intermediate by the way that Heck occurs with benzsulfamide
2A-2E occurs amide condensed to obtain intermediate 3A-3E, methanol solution of the intermediate 3A-3E in azanol at room temperature with acid
Middle reaction obtains target compound 4A-4E.
Synthetic route is as follows:
Wherein, R, X, Z, nl、n2It is defined as above described in general formula I；
Reagent and condition: a) various amine, acetonitrile, n,N-diisopropylethylamine, 82 DEG C；B), 1- ethyl-(3- dimethylamino
Base propyl) phosphinylidyne diimmonium salt hydrochlorate, methylene chloride, room temperature；C) methanol solution of azanol, room temperature；D) triethylamine, palladium acetate,
Triphenylphosphine, n,N-Dimethylformamide.
Above-mentioned described various amine are glycine methyl ester, 4- (amino methyl) methyl benzoate, 4- piperidine carboxylic acid methyl esters, 3-
Piperidine carboxylate.
The structural formula of target compound is as shown in table 1 below in synthetic route:
The structural formula of 1 target compound of table
Preferred according to the present invention, the preparation method of the compounds of this invention is with 2- ((1H- pyrrolo- [2,3-b] pyridine -5-
Base) oxygroup) -4- (4- ((the chloro- 5,5- dimethyl -3,4,5,6- tetrahydro-of 4'- [1,1'- biphenyl] -2- base) methyl) piperazine -1-
Base) for-N- ((4- ((2- (hydroxylamino) -2- oxoethyl) amino) -3- nitrobenzophenone) sulfonyl) benzamide (4A), tool
Preparation step is as follows:
(1) synthesis of (2- nitro -4- aminosulfonylphenyl) glycine methyl ester (2A)
The chloro- 3- nitrobenzene sulfonyl chloride of 700mg 4- is dissolved in 20ml acetonitrile, 800mg glycine methyl ester hydrochloric acid is separately added into
Salt and 1.64g DIEA react 10 hours in 80 DEG C；It is cooled to room temperature and is diluted with ethyl acetate after reaction, organic phase 1M
Citric acid and saturated salt solution are washed twice respectively, and anhydrous magnesium sulfate is dry, are spin-dried for；Yellow solid 920mg is obtained through silica gel column purification,
Yield 76.7%；
(2) (4- (N- (2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((chloro- 5,5- diformazan of 4'-
Base -3-1,4,5,6- tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base) benzoyl) sulfamoyl) -2- nitrobenzene
Base) glycine ethyl ester (3A) synthesis
By 260mg 2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((the chloro- 5,5- dimethyl-of 4'-
3,4,5,6- tetrahydros-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base) benzoic acid is dissolved in 10ml methylene chloride, respectively plus
Enter 110mg DMAP, 140mg EDCI and 130mg 2A；It reacts under room temperature 12 hours, uses 1M lemon respectively after reaction
Twice, organic phase is dry with anhydrous magnesium sulfate for acid and saturated common salt washing, is spin-dried for, obtains yellow solid 180mg through silica gel column purification,
Yield 47.4%；
(3) 2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((chloro- dimethyl -3,4,5 5,5- 4'-,
6- tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base)-N- ((4- ((2- (hydroxylamino) -2- oxoethyl) amino) -
3- nitrobenzophenone) sulfonyl) benzamide (4A) synthesis
The preparation of azanol methanol solution:
Solution A: the dried hydroxylamine hydrochloride of 4.67g is dissolved in 24mL methanol to obtain the final product；
Solution B: 5.61g potassium hydroxide is dissolved in 14mL methanol to obtain the final product；
Solution B is added drop-wise in solution A at 0 DEG C, be added dropwise during be stirred continuously, after completion of dropwise addition 0 DEG C the reaction was continued
After 30min, it is removed by filtration solid and obtains colorless and transparent azanol methanol solution, drying for standby；
6mL azanol methanol solution is added into 30mg compound 3A, stirs 0.5h at room temperature；Rotation is except most of organic molten
A small amount of water is added in agent, adjusts pH to 5-7, filtering with 2M dilute hydrochloric acid；Filter cake is washed with water, and is dried to obtain target compound 4A, produces
Rate 84.8%.
The concrete operation step of the compound will will be described in detail in embodiment.
Those skilled in the art can change above-mentioned steps to improve yield, they can knowing substantially according to this field
Know the route for determining synthesis, such as selects reactant, solvent and temperature, it can be by using various GPF (General Protection False bases to avoid secondary anti-
The generation answered is to improve yield.These conventional guard methods can be found in such as T.Greene, Protecting Groups
in Organic Synthesis.
Three, the application of the bis- target spot inhibitor of N- acyl group benzsulfamide hydroxamic acid Bcl-2, HDAC
Screening active ingredients experiment display the compounds of this invention has anti-histone deacetylase and inhibits the work of Bcl-2 albumen
Property, therefore, the present invention also provides the series compounds in preparation prevention or to treat because of histon deacetylase (HDAC) abnormal expression
With the application in related mammalian disease medicament caused by Bcl-2 protein abnormal expression.In addition, the invention also includes one kind to fit
In the oral pharmaceutical composition for giving mammal, any compound and pharmaceutically acceptable carrier comprising above-mentioned general formula I,
It optionally include one or more pharmaceutically acceptable excipient.
In addition, the pharmaceutical composition that the invention also includes a kind of suitable for parenterally giving mammal, includes above-mentioned general formula I
Any compound and pharmaceutically acceptable carrier, optionally include one or more pharmaceutically acceptable excipient.
Using fluorescence polarization technology in the test experiments of Bcl-2 family protein micromolecular inhibitor, the specific survey of use
In amount system, fluorescent tag molecule is the Bid-BH3 polypeptide of 5-FAM label, can be with Bcl-2 family protein (Bcl-xL, Bcl-
2 and Mcl-1) it specifically binds, dissociation constant (Kd) in 30-60nM or so, the result that the two combines can generate higher
Polarization value.If untested compound can also compete in conjunction with these protein-specifics with fluorescent marker polypeptide,
Inhibit the combination of itself and albumen, so as to cause polarization value reduction.The polarization value and negative control that untested compound generates will be added
Compare with positive control, if polarization value is left with respect to the half for the difference that the reduction level of negative control reaches negative and positive value
It is right, then it is assumed that untested compound has obvious activity, can further its IC of Accurate Determining50Value, and then export its Reverse transcriptase
Constant Ki。
In external suppression enzyme experiment, Oligopeptide Substrates (the Color de Lys containing acetylated lysine side chainTM Substrate)
Under the action of HDAC, deacetylation effect occurs.Product sensibility after deacetylation increases, and detects and tries in acetylization reaction
Agent (Color de LysTMDeveloper under) inducing, absorbance value is generated at 405nm, is pressed down with the HDACs of untested compound
It makes of proportional.By measuring the 405nm absorbance of control group and untested compound group, the inhibition of untested compound can be calculated
Rate simultaneously acquires IC50Value.
External suppression enzyme experiment shows that the compound in the present invention has compared with strong inhibitory activity and selectivity Bcl-2, owns
The activity of compound is suitable with positive control ABT-263.Such compound has very big development prospect, and can be used for instructing to send out
Existing new and effective Bcl-2, the bis- target spot inhibitor of HDAC.
Specific embodiment
The present invention will be further explained with reference to the examples below, but not limited to this.
Embodiment 1.2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((chloro- 5,5- dimethyl-of 4'-
3,4,5,6- tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base)-N- ((4- ((2- (hydroxylamino) -2- oxoethyl)
Amino) -3- nitrobenzophenone) sulfonyl) and benzamide (4A) synthesis
The synthesis of (2- nitro -4- aminosulfonylphenyl) glycine methyl ester (2A)
The chloro- 3- nitrobenzene sulfonyl chloride of 700mg4- is dissolved in 20ml acetonitrile, glycine methyl ester hydrochloride is separately added into
800mg and DIEA 1.64g reacts 10 hours in 82 DEG C；It is cooled to room temperature and is diluted with ethyl acetate after reaction, organic phase
It is washed respectively twice with 1M citric acid and saturated salt solution, anhydrous magnesium sulfate is dry, is spin-dried for.Yellow solid is obtained through silica gel column purification
920mg, yield 76.7%.1H NMR (400MHz, DMSO) δ 7.93 (d, J=8.4Hz, 2H), 7.84 (d, J=8.4Hz, 2H),
7.72 (d, J=16.1Hz, 1H), 7.46 (s, 2H), 6.79 (d, J=16.1Hz, 1H), 3.75 (s, 3H)
The synthesis of compound 2B-2D is referring to 2A.
(4- (N- (2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((chloro- 5,5- dimethyl -3- of 4'-
1,4,5,6- tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base) benzoyl) sulfamoyl) -2- nitrobenzophenone) it is sweet
The synthesis of propylhomoserin ethyl ester (3A)
By 2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((chloro- dimethyl -3,4,5 5,5- 4'-,
6- tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base) benzoic acid 260mg is dissolved in 10ml methylene chloride, is separately added into
DMAP110mg, EDCI140mg and 2A130mg.It reacts 12 hours under room temperature.After reaction respectively with 1M citric acid and
Saturated common salt is washed twice.Organic phase is dry with anhydrous magnesium sulfate, is spin-dried for.Yellow solid 180mg, yield are obtained through silica gel column purification
47.4%.1H NMR (400MHz, DMSO) δ 11.68 (s, 1H), 11.40 (s, 1H), 8.78 (t, J=5.0Hz, 1H), 8.59
(d, J=1.9Hz, 1H), 8.04 (d, J=2.4Hz, 1H), 7.87-7.81 (m, 1H), 7.57-7.53 (m, 1H), 7.49 (dd, J
=5.8,2.8Hz, 2H), 7.34 (d, J=8.3Hz, 2H), 7.04 (d, J=8.3Hz, 2H), 6.99 (d, J=9.2Hz, 1H),
6.67 (dd, J=8.9,1.5Hz, 1H), 6.43-6.35 (m, 1H), 6.18 (d, J=1.5Hz, 1H), 4.33 (d, J=5.8Hz,
2H),3.72(s,3H),3.12–3.02(m,4H),2.76(s,2H),2.19(m,4H),2.16–2.11(m,2H)1.95(s,
2H), 1.38 (t, J=6.1Hz, 2H), 0.92 (s, 6H)
The synthesis of compound 3B-3E is referring to 3A.
2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((chloro- 5,5- dimethyl -3,4,5,6- of 4'-
Tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base)-N- ((4- ((2- (hydroxylamino) -2- oxoethyl) amino) -3-
Nitrobenzophenone) sulfonyl) benzamide (4A) synthesis
The preparation of azanol methanol solution:
Solution A: the dried hydroxylamine hydrochloride of 4.67g is dissolved in 24mL methanol to obtain the final product；
Solution B: 5.61g potassium hydroxide is dissolved in 14mL methanol to obtain the final product；
Solution B is added drop-wise in solution A at 0 DEG C, be added dropwise during be stirred continuously, after completion of dropwise addition 0 DEG C the reaction was continued
After 30min, it is removed by filtration solid and obtains colorless and transparent azanol methanol solution, drying for standby；
6mL azanol methanol solution is added into 30mg compound 3A, stirs 0.5h at room temperature；Revolving is removed most of organic
A small amount of water is added in solvent, adjusts pH to 5-7, filtering with 2M dilute hydrochloric acid；Filter cake is washed with water, and is dried to obtain target compound 4A,
Yield 84.8%.1H NMR(400MHz,DMSO)δ11.73(s,1H),10.86(s,1H),10.06(s,1H),9.02(s,
1H), 8.81 (t, J=4.9Hz, 1H), 8.59 (s, 1H), 8.05 (d, J=2.1Hz, 1H), 7.88-7.81 (m, 1H), 7.56
(s, 1H), 7.50 (d, J=8.7Hz, 2H), 7.36 (d, J=8.0Hz, 2H), 7.06 (d, J=7.9Hz, 2H), 6.87 (d, J=
9.2Hz, 1H), 6.69 (d, J=8.5Hz, 1H), 6.40 (s, 1H), 6.21 (s, 1H), 4.05 (d, J=5.2Hz, 2H), 3.19
(m,4H),2.98(s,2H),2.42(m,4H),2.21(s,2H),1.97(s,2H),1.40(s,2H),0.93(s,6H).
The synthesis of compound 4B-4E is referring to 4A.
Embodiment 2.2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((chloro- 5,5- dimethyl-of 4'-
3,4,5,6- tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base)-N- ((4- ((4- (Hydroxycarboamoyl) benzyl)
Amino) -3- nitrobenzophenone) sulfonyl) benzoyl (4B)
Intermediate and target compound preparation method such as embodiment 1.Yield: 82.2%.1H NMR(400MHz,DMSO)δ
10.63 (s, 1H), 10.07 (s, 1H), 9.20 (dd, J=12.5,6.5Hz, 1H), 8.60 (s, 1H), 8.04 (d, J=2.0Hz,
1H), 7.91 (d, J=7.9Hz, 1H), 7.72 (d, J=7.1Hz, 2H), 7.53 (d, J=6.1Hz, 2H), 7.48 (dd, J=
8.2,3.3Hz, 2H), 7.43 (d, J=7.8Hz, 1H), 7.36 (d, J=8.0Hz, 2H), 7.06 (d, J=7.9Hz, 2H),
6.91–6.80(m,1H),6.72–6.63(m,1H),6.43–6.35(m,1H),6.19(s,1H),4.83–4.66(m,2H),
3.25-3.12 (m, 4H), 2.99 (s, 2H), 2.40 (dd, J=28.8,5.5Hz, 3H), 2.21 (s, 2H), 1.97 (s, 2H),
1.40 (t, J=4.6Hz, 2H), 0.93 (s, 6H)
Embodiment 3.1- (4- (N- (2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((4'- chloro- 5,
5- dimethyl 3,4,5,6- tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base) benzoyl) sulfamoyl) -2- nitre
Base phenyl)-N- hydroxyl -4- formamide (4C)
Intermediate and target compound preparation method such as embodiment 1.Yield: 81.5%.1H NMR(400MHz,DMSO)δ
11.76 (s, 1H), 10.56 (s, 2H), 10.10 (s, 2H), 8.77 (s, 1H), 8.27 (d, J=1.6Hz, 1H), 8.06 (d, J=
2.1Hz, 1H), 7.84 (dd, J=8.8,1.5Hz, 1H), 7.57 (d, J=1.9Hz, 1H), 7.55-7.49 (m, 2H), 7.37
(d, J=8.1Hz, 2H), 7.26 (d, J=9.0Hz, 1H), 7.07 (d, J=8.1Hz, 2H), 6.69 (d, J=9.1Hz, 1H),
6.42 (s, 1H), 6.21 (s, 1H), 3.27 (s, 4H), 3.14 (s, 2H), 2.98 (dd, J=8.1,5.9Hz, 2H), 2.68-
2.54 (m, 3H), 2.26 (d, J=0.6Hz, 3H), 1.98 (s, 2H), 1.70 (d, J=0.8Hz, 4H), 1.41 (t, J=
5.7Hz,2H),0.93(s,6H).
Embodiment 4.1- (4- (N- (2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((4'- chloro- 5,
5- dimethyl 3,4,5,6- tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base) benzoyl) sulfamoyl) -2- nitre
Base phenyl)-N- hydroxyl -3- formamide (4D)
Intermediate and target compound preparation method such as embodiment 1.Yield: 80.1%.1H NMR(400MHz,DMSO)δ
11.74 (s, 1H), 10.55 (s, 1H), 10.04 (s, 1H), 8.81 (s, 1H), 8.26 (d, J=1.8Hz, 1H), 8.06 (d, J=
2.3Hz, 1H), 7.84 (dd, J=8.9,1.7Hz, 1H), 7.57 (d, J=2.1Hz, 1H), 7.52 (d, J=8.6Hz, 2H),
7.36 (d, J=8.2Hz, 2H), 7.29 (d, J=9.0Hz, 1H), 7.05 (d, J=8.2Hz, 2H), 6.74-6.63 (m, 1H),
6.42 (d, J=1.0Hz, 1H), 6.19 (s, 1H), 3.27 (d, J=12.5Hz, 2H), 3.17 (s, 4H), 3.12-3.01 (m,
2H), 2.95 (dd, J=14.7,6.8Hz, 2H), 2.47-2.32 (m, 4H), 2.25-2.14 (m, 2H), 1.97 (s, 2H), 1.81
(d, J=6.8Hz, 1H), 1.76-1.66 (m, 1H), 1.59 (ddd, J=35.1,18.1,6.9Hz, 2H), 1.40 (t, J=
5.9Hz,2H),0.93(s,6H).
Embodiment 5. (E) -2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((chloro- 5,5- diformazan of 4'-
Base -3,4,5,6- tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base)-N- ((4- (3- (hydroxyl amino) -3- oxo
Propyl- 1- alkene -1- base) phenyl) sulfonyl) benzamide (4E)
Intermediate and target compound preparation method such as embodiment 1.Yield: 84.1%.1H NMR(400MHz,DMSO)δ
11.81 (s, 1H), 11.06 (s, 1H), 10.88 (s, 1H), 10.34 (s, 5H), 10.12 (d, J=1.2Hz, 1H), 8.07 (d, J
=0.5Hz, 1H), 7.86 (d, J=7.9Hz, 2H), 7.66 (d, J=7.8Hz, 1H), 7.61-7.44 (m, 4H), 7.39 (d, J
=7.9Hz, 2H), 7.10 (d, J=7.9Hz, 2H), 6.72 (d, J=8.3Hz, 1H), 6.64 (s, 1H), 6.43 (s, 1H),
6.27 (s, 1H), 3.64 (dd, J=14.2,11.6Hz, 4H), 3.37-3.16 (m, 4H), 2.83-2.59 (m, 2H), 2.37 (s,
2H),2.01(s,2H),1.50–1.37(m,2H),0.94(s,6H).
Active evaluation test of 1. target compound of experimental example to Bcl-2 albumen
Experiment reagent:
N-terminal has carried out the Bid-BH3 polypeptide of fluorescent marker with 5-FAM
(5-FAM-QEDIIRNIARHLAQVGDSMDRSIPPG), is dissolved in 1 × PBS；
Test buffer: 1 × PBS；
Calibration solution: 1nM fluorescein, 10mM NaOH.
Laboratory apparatus: TECAN Infinite F200PRO multi-function microplate reader.
Experimental procedure:
1) target protein and small molecule compound to be measured are added in test buffer, room temperature, which is protected from light, after mixing is incubated for 30min.
The Bid BH3 polypeptide for adding fluorescent marker, making the total volume of each solution is 200 μ L, and room temperature is protected from light incubation after mixing
20min。
2) 60 μ L are respectively taken to be transferred in 384 orifice plate of black (parallel three groups) above-mentioned solution and calibration solution, immediately in enzyme
The detection that fluorescence polarization is carried out on instrument is marked, using 485nm as excitation wavelength, 535nm is launch wavelength, and the fluorescence of calibration solution is inclined
Vibration value is set to 20mP.
3) all compounds (1 μM, 10 μM, 50 μM) progress primary dcreening operation, each compound first under three typical concentrations exists
The parallel determination of 3 multiple holes is done on same plate, the measurement result of polarization value is averaged.According to negative control, positive control
And the measurement result of tested compounds polarization value calculates inhibiting rate.The target protein concentration generallyd use in measurement be 300~
500nM, fluorescent marker polypeptide use 5-FAM-Bid-BH3 polypeptide, and positive compound uses Gossypol or ABT-263.If
Test result shows that compound inhibiting rate under 50 μM of concentration is greater than 50%, and its inhibiting rate is in three concentration following tables of test
Reveal apparent dose-dependence, then it is assumed that the compound and target protein have specific binding, need further to measure ratio
Accurate IC50Numerical value.
4) to showing obvious active compound, (1nM, 10nM, 100nM, 1 μ under 7 various concentrations in primary dcreening operation
M, 10 μM, 50 μM, 100 μM) carry out the measurement of complete binding curve.Each compound does 3 multiple holes on same plate
It is measured in parallel, polarization value measurement result is averaged.With GraphPad Prism software data processing and figure is done, obtains the chemical combination
The IC of object50Value.
The total protein concentration according to used in measurement, the total concentration of fluorescent polypeptide, the dissociation of albumen-polypeptide complex are normal
Several and detection compound IC50Value, show that the Reverse transcriptase of detection compound is normal using the calculation method in following documents
Number Ki。
Experimental result is shown in Table 2.
2 target compound of table is to Bcl-2 body outer suppressioning experiment result
| Number | IC50(nM)a |
| ABT-263 | <10 |
| 4A | <10 |
| 4B | <10 |
| 4C | <10 |
| 4D | <10 |
| 4E | <10 |
aNumerical value is the average value of test result three times in table
Conclusion: as seen from the table, 5 compounds of the series are suitable with positive control drug to the inhibitory effect of Bcl-2 albumen.
Test result has critically important directive significance for further developing the higher Bcl-2 micromolecular inhibitor of activity.
2. target compound of experimental example inhibits test (In vitro) to histon deacetylase (HDAC)
Term explanation:
SAHA: Vorinostat.
MM: mM/l.
HeLa: cervical cancer cell.
Color de LysTMSubstrate: the Oligopeptide Substrates containing acetylated lysine side chain.
Color de Lys Developer: deacetylation detection reagent.
HDAC Assay Buffer: buffer, pH 8.0, Tris-HCl containing 50mM, 137mM NaCl, 2.7mM KCl,
1mM MgCl2。
Trichostatin A:HDAC inhibitor.
IC50: half-inhibitory concentration.
The stock solution of [1. material] target compound and positive control SAHA (50mM is dissolved in dimethyl sulfoxide)；Enzyme (HeLa
Cell extract, main component are HDAC1 and HDAC2)；Color de LysTMSubstrate；Color de Lys
Developer(Developer)；HDAC Assay Buffer(Buffer)；(TSA, 0.2mM are dissolved in Trichostatin A
Dimethyl sulfoxide)；96 orifice plates；Thermo Varioskan Flash all-wave length multi-function microplate reader.
2. [method] carries out Preparatory work of experiment according to the operation instructions of kit:
1) it dilutes enzyme: Hela cell extract and Buffer is diluted according to the volume ratio of 1:2；
2) it is dense eventually that compound (untested compound and positive control SAHA) diluted chemical compound: is diluted to 5x with Buffer
Degree；
3)Color de LysTMSubstrate: substrate is diluted into 50 times (1mM, 2x final concentration) with Buffer；
4)Color de LysTMDeveloper: the detection reagent configures in the 30min used.Firstly, with pre-cooling
Buffer is by Color de LysTMDeveloper dilutes 20 times (e.g., Buffer that 50 μ L add 950 μ L)；Then matched with fresh
By 100 times of TSA dilution, (such as 10 μ L are diluted to 1mL to the Developer solution set, and TSA concentration is 2 μM at this time, 2x final concentration, table
Show final concentration of 1 μM after being added to reaction system).
In 96 orifice plates, every hole is separately added into enzyme and 10 μ L untested compounds after 15 μ L dilution, adds after 37 DEG C of incubation 5min
Entering the substrate of 25 μ L, (blank well is not enzyme and compound, and Buffer is added to replace；Control wells compound is replaced with Buffer).By 96
Orifice plate is placed in 37 DEG C of shaking tables and is incubated for 30min.Then the Color de Lys that 50 μ L are now configured is added in every holeTMDeveloper,
Continue to be incubated for.The UV absorption under the conditions of 405nm is measured after 30min, in microplate reader, passes through measurement control group and target compound
The 405nm trap of group, can calculate the inhibiting rate of target compound and acquire IC50Value.Experimental result is shown in Table 3.
3 target compound of table is to HDAC body outer suppressioning experiment result
| Number | IC50(μM)a |
| SAHA | 0.319 |
| 4A | >1 |
| 4B | >1 |
| 4C | >1 |
| 4D | >1 |
| 4E | >1 |
aNumerical value is the average value of test result three times in table
Conclusion: as can be seen from the table, the activity of target compound is not highly desirable, but its test result is for into one
The higher bis- target spot inhibitor of Bcl-2, HDACs of step exploitation activity have good directive significance.
Claims (8)
1. a kind of bis- target spot inhibitor of N- acyl group benzsulfamide hydroxamic acid Bcl-2, HDAC, are the changes with general formula I
Object and its stereoisomer, pharmaceutically acceptable salt are closed,
In general formula I, R is hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, carboxylic group substitution, C1-C12Alkyl,
Naphthenic base, or the C replaced by following one or more hydroxyls, halogen, nitro, cyano, carboxylic group1-C12Alkyl, naphthenic base,
Contain identical or different one or more following substituent groups or the aryl, heteroaryl, aryl alkyl, the heteroaryl alkane that do not replace
Base: hydroxyl, halogen, nitro, cyano, guanidine radicals, carboxyl, halogen C1-C12Alkyl, C1-C12Alkoxy, C1-C12Alkyl, C3-C12Cycloalkanes
Base, aryl, heteroaryl；
In general formula I, X is carbon, nitrogen, oxygen, sulphur；
In general formula I, Z is aryl, heteroaryl, cyclohexyl, heterocycle, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group；
In general formula I, nlIt is 0-3, n2It is 0-5.
2. the bis- target spot inhibitor of N- acyl group benzsulfamide hydroxamic acid Bcl-2, HDAC as described in claim 1, feature
It is, in general formula I,
R is hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, carboxylic group substitution；
X is carbon or nitrogen；
Z is methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；
n1It is 0-3；n2It is 0-5.
3. the bis- target spot inhibitor of N- acyl group benzsulfamide hydroxamic acid Bcl-2, HDAC as claimed in claim 1 or 2, special
Sign is that compound of Formula I is one of following:
2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((chloro- 5,5- dimethyl -3,4,5,6- tetrahydro-of 4'-
[1,1'- biphenyl] -2- base) methyl) piperazine -1- base)-N- ((4- ((2- (hydroxylamino) -2- oxoethyl) amino) -3- nitrobenzene
Base) sulfonyl) benzamide (4A),
2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((chloro- 5,5- dimethyl -3,4,5,6- tetrahydro-of 4'-
[1,1'- biphenyl] -2- base) methyl) piperazine -1- base)-N- ((4- ((4- (Hydroxycarboamoyl) benzyl) amino) -3- nitro
Phenyl) sulfonyl) benzamide (4B),
1- (4- (N- (2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((the chloro- 5,5- dimethyl 3,4 of 4'-,
5,6- tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base) benzoyl) sulfamoyl) -2- nitrobenzophenone)-N- hydroxyl
Base -4- formamide (4C),
1- (4- (N- (2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((the chloro- 5,5- dimethyl 3,4 of 4'-,
5,6- tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base) benzoyl) sulfamoyl) -2- nitrobenzophenone)-N- hydroxyl
Base -3- formamide (4D),
(E) -2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((chloro- 5, the 5- dimethyl -3,4 of 4'-, 5-, 6-
Tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base)-N- ((4- (3- (hydroxyl amino) -3- oxo propyl- 1- alkene -1- base)
Phenyl) sulfonyl) benzamide (4E).
4. the system of the bis- target spot inhibitor of N- acyl group benzsulfamide hydroxamic acid Bcl-2, HDAC as claimed in claim 1 or 2
Preparation Method, which is characterized in that comprising steps of
The benzsulfamide 1A-1D that difference replaces occurs nucleophilic substitution with amino-compound under reflux conditions and obtains intermediate
2A-2D, the benzsulfamide 1E that difference replaces react to obtain intermediate 2E, intermediate 2A-2E by the way that Heck occurs with benzsulfamide
At room temperature with acid occur it is amide condensed obtain intermediate 3A-3E, intermediate 3A-3E reacts in the methanol solution of azanol
Obtain target compound 4A-4E；
Synthetic route is as follows:
Wherein, R, X, Z, nl、n2It is defined as above described in general formula I；
Reagent and condition: a) various amine, acetonitrile, n,N-diisopropylethylamine, 82 DEG C；B), 1- ethyl-(3- dimethylamino third
Base) phosphinylidyne diimmonium salt hydrochlorate, methylene chloride, room temperature；C) methanol solution of azanol, room temperature；D) triethylamine, palladium acetate, triphen
Base phosphine, n,N-Dimethylformamide；
Above-mentioned described various amine are glycine methyl ester, 4- (amino methyl) methyl benzoate, 4- piperidine carboxylic acid methyl esters, 3- piperidines
Carboxylic acid, ethyl ester.
5. 2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((the chloro- 5,5- of 4'- as claimed in claim 2
Dimethyl -3,4,5,6- tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base)-N- ((4- ((2- (hydroxylamino) -2- oxygen
For ethyl) amino) -3- nitrobenzophenone) sulfonyl) benzamide (4A) preparation method, comprising steps of
(1) synthesis of (2- nitro -4- aminosulfonylphenyl) glycine methyl ester (2A)
The chloro- 3- nitrobenzene sulfonyl chloride of 700mg 4- is dissolved in 20ml acetonitrile, be separately added into 800mg glycine methyl ester hydrochloride and
1.64g DIEA reacts 10 hours in 80 DEG C；It is cooled to room temperature and is diluted with ethyl acetate after reaction, organic phase is with 1M lemon
Acid and saturated salt solution are washed twice respectively, and anhydrous magnesium sulfate is dry, are spin-dried for；Yellow solid 920mg, yield are obtained through silica gel column purification
76.7%；
(2) (4- (N- (2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((chloro- 5,5- dimethyl -3- of 4'-
1,4,5,6- tetrahydro-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base) benzoyl) sulfamoyl) -2- nitrobenzophenone) it is sweet
The synthesis of propylhomoserin ethyl ester (3A)
By 260mg 2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((chloro- dimethyl -3,4 5,5- 4'-,
5,6- tetrahydros-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base) benzoic acid is dissolved in 10ml methylene chloride, is separately added into
110mg DMAP, 140mg EDCI and 130mg 2A；It reacts under room temperature 12 hours, uses 1M citric acid respectively after reaction
Twice with saturated common salt washing, organic phase is dry with anhydrous magnesium sulfate, is spin-dried for, obtains yellow solid 180mg through silica gel column purification, receives
Rate 47.4%；
(3) 2- ((1H- pyrrolo- [2,3-b] pyridine -5- base) oxygroup) -4- (4- ((the chloro- 5,5- dimethyl -3,4,5,6- four of 4'-
Hydrogen-[1,1'- biphenyl] -2- base) methyl) piperazine -1- base)-N- ((4- ((2- (hydroxylamino) -2- oxoethyl) amino) -3- nitre
Base phenyl) sulfonyl) benzamide (4A) synthesis
The preparation of azanol methanol solution:
Solution A: the dried hydroxylamine hydrochloride of 4.67g is dissolved in 24mL methanol to obtain the final product；
Solution B: 5.61g potassium hydroxide is dissolved in 14mL methanol to obtain the final product；
Solution B is added drop-wise in solution A at 0 DEG C, is stirred continuously during being added dropwise, 0 DEG C of the reaction was continued 30min after completion of dropwise addition
Afterwards, it is removed by filtration solid and obtains colorless and transparent azanol methanol solution, drying for standby；
6mL azanol methanol solution is added into 30mg compound 3A, stirs 0.5h at room temperature；Rotation adds except most of organic solvent
Enter a small amount of water, adjusts pH to 5-7, filtering with 2M dilute hydrochloric acid；Filter cake is washed with water, and is dried to obtain target compound 4A, yield
84.8%.
6. the bis- target spot inhibitor of N- acyl group benzsulfamide hydroxamic acid Bcl-2, HDAC a method according to any one of claims 1-3 exist
Related mammalian caused by preparation prevents or treats because of histon deacetylase (HDAC) abnormal expression and Bcl-2 protein abnormal expression
Application in disease medicament.
7. a kind of suitable for the oral pharmaceutical composition for giving mammal, comprising any compound of claim 1-3 and
One or more pharmaceutically acceptable carriers or excipient.
8. a kind of pharmaceutical composition suitable for parenterally giving mammal includes any compound of claim 1-3
With one or more pharmaceutically acceptable carriers or excipient.
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| CN111777626A (en) * | 2020-06-22 | 2020-10-16 | 沈阳药科大学 | Venetian-dihydroartemisinin split compound and preparation and application thereof |
| CN111777626B (en) * | 2020-06-22 | 2021-07-09 | 沈阳药科大学 | Venetian-dihydroartemisinin split compound and preparation and application thereof |
| CN114075187A (en) * | 2020-08-21 | 2022-02-22 | 山东大学 | Carbonyl pyrazole anti-tumor compound and preparation method and application thereof |
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