CN108794358A - Substitution benzenesulfonyl class compound and its purposes for preparing drug - Google Patents

Substitution benzenesulfonyl class compound and its purposes for preparing drug Download PDF

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CN108794358A
CN108794358A CN201710287968.0A CN201710287968A CN108794358A CN 108794358 A CN108794358 A CN 108794358A CN 201710287968 A CN201710287968 A CN 201710287968A CN 108794358 A CN108794358 A CN 108794358A
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amino
straight chain
branch
group
substitution
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CN108794358B (en
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郑灿辉
朱驹
王明萍
王重庆
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Second Military Medical University SMMU
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Second Military Medical University SMMU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to one kind replace benzenesulfonyl class compound, crystal form, pharmaceutically acceptable salt class, hydrate, solvate or prodrug, and preparation method thereof and pharmaceutical applications.Shown in the general structure of the compound such as formula (I).Experiments have shown that it has higher inhibitory activity to HDAC, especially part of compounds shows good selective inhibitory activity to HDAC6, while such compound shows broad-spectrum anti-tumor activity to human blood tumour (myeloma, leukaemia) and solid tumor (oophoroma, breast cancer, melanoma, lung cancer).It prompts such compound that there is the medicine prepared with the relevant disease of HDAC especially HDAC6 activity, prepares antitumor drug, and prepare synergist and shared with other antitumor drugs or radiotherapy to treat the potential use of tumour.

Description

Substitution benzenesulfonyl class compound and its purposes for preparing drug
Technical field
The present invention relates to pharmaceutical technology fields, more particularly it relates to a kind of replace benzenesulfonyl class compound, Further relate to the composition of such compound, preparation method and its active related with acetylation of histone enzyme (HDAC) preparing treatment Disease or the drug of symptom, antineoplastic and synergist in purposes.
Background technology
HDAC and acetylation of histone enzyme are the internal two groups enzymes with reverse functions, can be adjusted including histone A variety of cores inside and outside histone acetylation state, adjust genetic transcription, cell differentiation, cell cycle and Apoptosis etc. to play Multiple functions.HDAC includes four subfamilies, Zn2+The I types (HDAC1-3,8) of dependence, IIA (HDAC4,5,7,9), IIB (HDAC6,10) and IV (HDAC11) and NAD+The type III (sirtuins 1-7) of dependence.HDAC is proved and tumour, nerve The occurrence and development of the diseases such as systemic disease and inflammation and infection have substantial connection.Thus HDAC wide spectrums and selective small molecule press down Preparation is used for treatment and research (the Nat Rev Drug of the diseases such as tumour, the nervous system disease, inflammation and virus infection Discov 2014,13,673-91；Pharmacol Ther 2014,143,323-36.).
Albumen deacetylation increase is one of the characteristic feature of many tumours caused by HDAC high expression or activity improve, HDAC expression all can be observed in a variety of hematological system tumors and increase (Cancer Lett 2009,280,168-76).It is multiple Property myeloma be also unequivocally established the common high expression of I types HDAC (especially HDAC1), and it is closely related with poor prognosis (Epigenetics 2014,9,1511-20).Therefore, targeting HDAC is increasingly becoming one of research hotspot of oncotherapy (Lancet Oncol 2013,14,1038-9.).In recent years, the development of HDAC micromolecular inhibitors is very fast, includes mainly different Hydroximic acid, benzamides, cyclic peptide and short-chain fat acids etc..They show swollen for hematological system in vivo and in vitro Extensive antitumous effect (the Nat Rev Drug Discov 2014,13,673-91 of tumor, lung cancer and prostate cancer etc.；J Med Chem 2008,51,1505-29.).Three such drug Vorinostats of current foreign countries' approved listing (vorinostat, SAHA), romidepsin (romidepsin) (J Clin Invest 2014,124,30-9.) and Baily department he (belinostat, 2014.07 crowdes) (Br J Haematol 2015,168,811-9.), domestic just approval one drug of listing Chidamide (chidamide, 2015.01 approvals) (Cancer Chemother Pharmacol 2012,69,1413-22.), It is approved for the treatment of skin or lymphoma peripheral T cell.And multiple hdac inhibitors are shown very in clinical test Good anti-Huppert's disease effect, and shared with other antitumor drugs and can play notable synergistic effect, 2015.02 pas are than department His (panobinostat) is shared with bortezomib and dexamethasone for multiple myeloma (Lancet by FDA approvals Oncol 2014,15,1195-206.)。
In addition, since isoform selective inhibitors may have more preferable curative effect and lower side effect, it is increasingly becoming close Year research hotspot (Nat Rev Drug Discov 2014,13,673-91；Curr Pharm Des 2015,21,1472- 502.).Research confirms that newly discovered HDAC6 selective depressants (such as Rocilinostat, ACY-1215) can pass through influence Aggresomes formation participates in protein degradation systems, to the inhibitor bortezomib with another proteasome pathway of the system Play the role of synergistic treatment Huppert's disease, come into clinical test at present (Blood 2012,119, 2579-89；Br J Haematol.2015,169,423-34).HDAC6 selective depressants are also used for the nervous system disease Research (the Nat Rev Drug Discov of the disease treatments such as (neurodegenerative disease, alzheimer's disease etc.) and inflammation 2014,13,673-91.)。
In conclusion the inhibitor of research and development HDAC, especially isoform selective inhibitors, have the treatment of the diseases such as tumour It is significant.
Invention content
The object of the present invention is to provide the preparations of a kind of novel substitution benzenesulfonyl class compound and such compound Method, purposes and composition.
In the first aspect of the present invention, a kind of substitution benzenesulfonyl class compound, general structure such as formula (I) institute are provided Show：
Wherein：
R1Group is amino, hydroxyl, unsubstituted or substituted aromatic monocyclic；Wherein, substituent group is monosubstituted or polysubstituted, is C1~C5Straight chain, branch or cyclic alkane base, halogen；
Or R1Group isR4It is hydrogen atom, unsubstituted or substituted C1~C7Straight chain, branch or cyclic annular alkane Alkyl, unsubstituted or substituted C1~C7Straight chain, branch or cyclic olefin base；Wherein, substituent group is monosubstituted or polysubstituted, for not Substitution or substituted aroma monocycle, halogen；
Or R4Group isWherein, R5It is hydrogen atom ,-XR7(Ⅴ)；Wherein, X is R7It is hydrogen atom, unsubstituted or substituted aromatic monocyclic is unsubstituted or substituted Hydrogenated aromatic condensed ring, unsubstituted or substituted aromatic condensed ring, wherein substituent group is monosubstituted or polysubstituted, is C1~C5Straight chain, branch Chain or cyclic alkane base, halogen；
Or R7Group is-VR8(VI), wherein V is nitrogen, oxygen, R8It is hydrogen atom, C1~C7Straight chain, branch or cyclic alkane oxygen Base；
Or R7Group is-WR9(VII), wherein W is C1~C7Straight chain, branch or cyclic alkane base, C1~C7Straight chain, branch Or cyclic olefin base, R9It is hydrogen atom, unsubstituted or substituted aromatic monocyclic, wherein substituent group is monosubstituted or polysubstituted, is straight Chain, branch or cyclic alkane base, halogen；
R6The position of substitution is located at two or three-digit, is hydrogen atom, hydroxyl, amino, halogen, C1~C5Straight chain, branch or cyclic annular alkane Alkyl,
Or R6Group is-UR10(VIII), wherein U is O, N, S,R10It is hydrogen atom, aromatic monocyclic, Aromatic condensed ring, C1~C7Straight chain, branch or cyclic alkane base；
R2Group is Wherein, R8For C1~C5Straight chain, branch or cyclic alkane base,
Or R2Group is-ZYR11(Ⅸ), wherein Z is N, O, S,Y is C1~C10Straight chain, branch or Cyclic alkane base, C1~C10Straight chain, branch or cyclic olefin base, aromatic monocyclic, aromatic condensed ring, R11It is
Or Y is-QT- (Ⅹ), wherein Q is C1~C10Straight chain, branch or cyclic alkane base, C1~C10Straight chain, branch or ring Shape alkylene, T are aromatic monocyclic or aromatic condensed ring；
R3The position of substitution is located at two or three-digit, is hydrogen atom, nitro, trifluoromethyl, cyano, sulfonic group, carboxyl, C1~C5 Linear chain or branched chain alkyl, halogen, hydroxyl, amino.
As the present invention a preference,
R1Group is amino, hydroxyl, unsubstituted aromatic monocyclic,
R2Group is-ZYR11(Ⅸ), wherein Z is N, O, S, and Y is C1~C10Straight chain, branch or cyclic alkane base, C1~C10 Straight chain, branch or cyclic olefin base, aromatic monocyclic, aromatic condensed ring, R11It is
Or Y is-QT- (Ⅹ), wherein Q is C1~C10Straight chain, branch or cyclic alkane base, C1~C10Straight chain, branch or ring Shape alkylene, T are aromatic monocyclic or aromatic condensed ring；
R3The position of substitution is located at two or three-digit, is hydrogen atom, nitro, trifluoromethyl, cyano, sulfonic group, carboxyl, C1~C5 Linear chain or branched chain alkyl, halogen, hydroxyl, amino.
As the present invention a preference,
R1Group is amino, hydroxyl, unsubstituted aromatic monocyclic,
R2Group is-ZYR11(Ⅸ), wherein Z is N, O, S, and Y is C1~C7Straight chain, branch or cyclic alkane base, C1~C7Straight chain, branch or cyclic olefin base, aromatic monocyclic, R11It is
Or Y is-QT- (Ⅹ), wherein Q is C1~C4Straight chain, branch or cyclic alkane base, T are aromatic monocyclics；
R3The position of substitution is located at two or three-digit, be hydrogen atom, nitro, trifluoromethyl, cyano, sulfonic group, carboxyl, halogen, Hydroxyl, amino.
As the present invention a preference,
R1Group is amino, hydroxyl,
R2Group is-ZYR11(Ⅸ), wherein Z is N, O, S, and Y is C1~C7Linear paraffin base, R11It is
Or Y is-QT- (Ⅹ), wherein Q is C1~C4Linear paraffin base, T are aromatic monocyclics；
R3The position of substitution is located at two or three-digit, is nitro.
As the present invention a preference,
R1Group isR4Group is
Wherein, R5It is-XR7(Ⅴ)；Wherein, X isR7Group is-WR9 (VII), wherein W is C1~C7Straight chain, branch or cyclic alkane base, C1~C7Straight chain, branch or cyclic olefin base, R9It is substitution virtue Fragrant monocycle, wherein substituent group is monosubstituted or polysubstituted, is straight chain, branch or cyclic alkane base, halogen；
R6The position of substitution is located at two or three-digit, R6Group is-UR10(VIII), wherein U is O, N, S, R10It is hydrogen atom, fragrance Monocycle, aromatic condensed ring, C1~C7Straight chain, branch or cyclic alkane base；
R2Group is
R3The position of substitution is located at two or three-digit, is hydrogen atom, nitro, trifluoromethyl, cyano, sulfonic group, carboxyl, C1~C5 Linear chain or branched chain alkyl, halogen, hydroxyl, amino.
As the present invention a preference,
R1Group isR4Group is
Wherein, R5It is-XR7(Ⅴ)；Wherein, X isR7Group is-WR9 (VII), wherein W is C1~C4Straight chain, branch or cyclic olefin base, R9It is substituted aroma monocycle, wherein substituent group is monosubstituted Or it is polysubstituted, it is straight chain, branch or cyclic alkane base, halogen；
R6The position of substitution is located at two or three-digit, R6Group is-UR10(VIII), wherein U is O, N, S, R10It is aromatic monocyclic；
R2Group is
R3The position of substitution is located at two or three-digit, is hydrogen atom.
As the present invention a preference,
R1Group isR4Group is
Wherein, R5It is-XR7(Ⅴ)；Wherein, X isR7Group is-WR9(VII), wherein W is C1~C4Straight chain Alkylene, R9Substituted aroma monocycle, wherein substituent group be it is monosubstituted or polysubstituted, be straight chain, branch or cyclic alkane base, Halogen；
R6The position of substitution is located at two or three-digit, R6Group is-UR10(VIII), wherein U is O, R10It is aromatic monocyclic；
R2Group is
R3The position of substitution is located at two or three-digit, is hydrogen atom.
As the present invention a preference,
R1Group isR4Group is
Wherein, R5It is hydrogen atom ,-XR7(Ⅴ)；Wherein, X is R7It is unsubstituted or substituted aromatic condensed ring, wherein substituent group is monosubstituted or polysubstituted, is C1~C5Straight chain, branch Or cyclic alkane base, halogen；
Or R7Group is-WR9(VII), wherein W is C1~C7Straight chain, branch or cyclic alkane base, C1~C7Straight chain, branch Or cyclic olefin base, R9It is substituted aroma monocycle, wherein substituent group is monosubstituted or polysubstituted, is straight chain, branch or cyclic annular alkane Alkyl, halogen；
R6The position of substitution is located at two or three-digit, be hydrogen atom, hydroxyl, amino, halogen,
Or R6Group is-UR10(VIII), wherein U is O, N, S, R10It is aromatic monocyclic；
R2Group is-ZYR11(Ⅸ), wherein Z is N, O, S, and Y is C1~C10Straight chain, branch or cyclic alkane base, C1 ~C10Straight chain, branch or cyclic olefin base, aromatic monocyclic, aromatic condensed ring, R11It is
Or Y is-QT- (Ⅹ), wherein Q is C1~C10Straight chain, branch or cyclic alkane base, C1~C10Straight chain, branch or ring Shape alkylene, T are aromatic monocyclic or aromatic condensed ring；
R3The position of substitution is located at two or three-digit, be hydrogen atom, nitro, trifluoromethyl, cyano, sulfonic group, carboxyl, halogen, Hydroxyl, amino.
As the present invention a preference,
R1Group isR4Group is
Wherein, R5It is hydrogen atom ,-XR7(Ⅴ)；Wherein, X is R7It is unsubstituted or substituted aromatic condensed ring, wherein substituent group is singly to take In generation, is polysubstituted, is C1~C5Linear paraffin base；
Or R7Group is-WR9(VII), wherein W is C1~C4Linear alkene base, R9It is substituted aroma monocycle, wherein substitution Base is monosubstituted or polysubstituted, is straight chain, branch or cyclic alkane base, halogen；
R6The position of substitution is located at two or three-digit, be hydrogen atom, hydroxyl, amino, halogen,
Or R6Group is-UR10(VIII), wherein U is O, N, S, R10It is aromatic monocyclic；
R2Group is-ZYR11(Ⅸ), wherein Z is N, O, S, and Y is C1~C7Straight chain, branch or cyclic alkane base, R11It is
Or Y is-QT- (Ⅹ), wherein Q is C1~C4Straight chain, branch or cyclic alkane base, T are aromatic monocyclics；
R3The position of substitution is located at two or three-digit, be hydrogen atom, nitro, trifluoromethyl, cyano, sulfonic group, carboxyl, halogen, Hydroxyl, amino.
As the present invention a preference,
R1Group isR4Group is
Wherein, R5It is hydrogen atom ,-XR7(Ⅴ)；Wherein, X is
R7Group is-WR9(VII), wherein W is C1~C4Linear alkene base, R9It is substituted aroma monocycle, wherein substituent group It is monosubstituted, is linear paraffin base；
R6The position of substitution is located at two or three-digit, is hydrogen atom,
Or R6Group is-UR10(VIII), wherein U is O, N, S, R10It is aromatic monocyclic；
R2Group is-ZYR11(Ⅸ), wherein Z is N, O, S, and Y is C1~C7Linear paraffin base, R11It is
Or Y is-QT- (Ⅹ), wherein Q is C1~C4Linear paraffin base, T are aromatic monocyclics；
R3The position of substitution is located at two or three-digit, is hydrogen atom, nitro.
As the present invention a preference,
R1Group isR4Group is
Wherein, R5It is hydrogen atom ,-XR7(Ⅴ)；Wherein, X is
R7Group is-WR9(VII), wherein W is C1~C4Linear alkene base, R9It is substituted aroma monocycle, wherein substituent group It is monosubstituted, is linear paraffin base；
R6The position of substitution is located at two or three-digit, is hydrogen atom,
Or R6Group is-UR10(VIII), wherein U is O, R10It is aromatic monocyclic；
R2Group is-ZYR11(Ⅸ), wherein Z is N, and Y is C1~C7Linear paraffin base, R11It is
Or Y is-QT- (Ⅹ), wherein Q is C1~C4Linear paraffin base, T are aromatic monocyclics；
R3The position of substitution is located at two or three-digit, is hydrogen atom, nitro.
As the present invention a preference,
R1Group isR4Group is
Wherein, R5It is hydrogen atom,
R6The position of substitution is located at two or three-digit, be hydrogen atom, hydroxyl, amino, halogen,
Or R6Group is-UR10(VIII), wherein U is O, N, S, R10It is aromatic monocyclic；
R2Group is-ZYR11(Ⅸ), wherein Z is N, O, S, and Y is C1~C7Linear paraffin base, R11It is
Or Y is-QT- (Ⅹ), wherein Q is C1~C4Linear paraffin base, T are aromatic monocyclics；
R3The position of substitution is located at two or three-digit, is nitro.
As the present invention a preference,
R1Group isR4Group is
Wherein, R5It is hydrogen atom,
R6The position of substitution is located at two or three-digit, is hydrogen atom,
Or R6Group is-UR10(VIII), wherein U is O, R10It is aromatic monocyclic；
R2Group is-ZYR11(Ⅸ), wherein Z is N, and Y is C1~C7Linear paraffin base, R11It is
Or Y is-QT- (Ⅹ), wherein Q is C1~C4Linear paraffin base, T are aromatic monocyclics；
R3The position of substitution is located at two or three-digit, is nitro.
As the present invention a preference,
R1Group isR4Group is
Wherein, R5It is-XR7(Ⅴ)；Wherein, X isR7 It is unsubstituted or substituted aromatic condensed ring, wherein substituent group is monosubstituted or polysubstituted, is C1~C5Linear paraffin base；
R6The position of substitution is located at two or three-digit, be hydrogen atom, hydroxyl, amino, halogen,
R2Group is-ZYR11(Ⅸ), wherein Z is N, O, S, and Y is C1~C7Straight chain, branch or cyclic alkane base, R11It is
R3The position of substitution is located at two or three-digit, is hydrogen atom, nitro.
As the present invention a preference,
R1Group isR4Group is
Wherein, R5It is-XR7(Ⅴ)；Wherein, X isR7It is unsubstituted or substituted aromatic condensed ring, wherein substituent group It is monosubstituted or polysubstituted, is C1~C5Linear paraffin base；
R6The position of substitution is located at two or three-digit, is hydrogen atom,
R2Group is-ZYR11(Ⅸ), wherein Z is N, and Y is C1~C7Linear paraffin base, R11It is
R3The position of substitution is located at two or three-digit, is hydrogen atom, nitro.
As a preferred embodiment of the present invention, the substitution benzenesulfonyl class compound is selected from：
1) N- hydroxyls -2- (2- nitro -4- aminosulfonvlphenyls amino) acetamide
2) N- hydroxyls -3- (2- nitro -4- aminosulfonvlphenyls amino) propionamide
3) N- hydroxyls -4- (2- nitro -4- aminosulfonvlphenyls amino) butyramide
4) N- hydroxyls -5- (2- nitro -4- aminosulfonvlphenyls amino) pentanamide
5) N- hydroxyls -6- (2- nitro -4- aminosulfonvlphenyls amino) caproamide
6) N- hydroxyls -7- (2- nitro -4- aminosulfonvlphenyls amino) heptamide
7) N- hydroxyls -8- (2- nitro -4- aminosulfonvlphenyls amino) caprylamide
8) N- hydroxyls -4- ((2- nitro -4- aminosulfonvlphenyls amino) methyl) benzamide
9) N- (4- (Hydroxycarboamoyl) benzenesulfonyl) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) acryloyl group ammonia Base) benzamide
10) N- (4- (2- (hydroxyl amino) -2- oxos ethylamino) -3- nitrobenzenesulfonyls) -2- phenoxy groups -4- (3- (2- Aminomethyl phenyl) Acryloyl amino) benzamide
11) N- (4- (the third amino of 3- (hydroxyl amino) -3- oxos) -3- nitrobenzenesulfonyls) -2- phenoxy groups -4- (3- (2- Aminomethyl phenyl) Acryloyl amino) benzamide
12) N- (4- (4- (hydroxyl amino) -4- oxo fourths amino) -3- nitrobenzenesulfonyls) -2- phenoxy groups -4- (3- (2- Aminomethyl phenyl) Acryloyl amino) benzamide
13) N- (4- (penta amino of 5- (hydroxyl amino) -5- oxos) -3- nitrobenzenesulfonyls) -2- phenoxy groups -4- (3- (2- Aminomethyl phenyl) Acryloyl amino) benzamide
14) N- (4- (the own amino of 6- (hydroxyl amino) -6- oxos) -3- nitrobenzenesulfonyls) -2- phenoxy groups -4- (3- (2- Aminomethyl phenyl) Acryloyl amino) benzamide
15) N- (4- (7- (hydroxyl amino) -7- oxos amino in heptan) -3- nitrobenzenesulfonyls) -2- phenoxy groups -4- (3- (2- Aminomethyl phenyl) Acryloyl amino) benzamide
16) N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) -3- nitrobenzenesulfonyls) -2- phenoxy groups -4- (3- (2- Aminomethyl phenyl) Acryloyl amino) benzamide
17) N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) benzenesulfonyl) -2- phenoxy groups -4- (3- (2- methylbenzenes Base) Acryloyl amino) benzamide
18) N- (4- ((4- Hydroxycarboamoyls) benzylamino) -3- nitrobenzenesulfonyls) -2- phenoxy group -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzamide
19) N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) -3- nitrobenzenesulfonyls) -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzamide
20) N- (4- (the own amino of 6- (hydroxyl amino) -6- oxos) -3- nitrobenzenesulfonyls) -2- phenoxy benzamides
21) N- (4- (7- (hydroxyl amino) -7- oxos amino in heptan) -3- nitrobenzenesulfonyls) -2- phenoxy benzamides
22) N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) -3- nitrobenzenesulfonyls) -2- phenoxy benzamides
23) N- (4- ((4- Hydroxycarboamoyls) benzylamino) -3- nitrobenzenesulfonyls) -2- phenoxy benzamides
24) 2- (4- chlorophenoxies)-N- (4- (the own amino of 6- (hydroxyl amino) -6- oxos) -3- nitrobenzenesulfonyls) benzene Formamide
25) 2- (4- chlorophenoxies)-N- (4- (4- (Hydroxycarboamoyl) benzylamino) -3- nitrobenzenesulfonyls) benzene Formamide
26) N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) -3- nitrobenzenesulfonyls) benzamide
27) N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) -3- nitrobenzenesulfonyls) -4- (1- (3,5,5,8,8- Pentamethyl -5,6,7,8- naphthane -2- bases) vinyl) benzamide
28) N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) benzenesulfonyl) -4- (1- (3,5,5,8,8- pentamethyls - 5,6,7,8- naphthane -2- bases) vinyl) benzamide
In the second aspect of the present invention, provides the crystal form of the substitution benzenesulfonyl class compound, can pharmaceutically connect Inorganic acid salt or acylate, hydrate, solvate or the prodrug received.
In the third aspect of the present invention, a kind of pharmaceutical composition is provided, the pharmaceutical composition, which contains, pharmaceutically may be used The excipient or carrier of receiving and the substitution benzenesulfonyl class compound or the substitution benzenesulfonyl class compound Crystal form, pharmaceutically acceptable inorganic acid salt or acylate, hydrate, solvate or prodrug.
As a kind of specific implementation mode of the present invention, the pharmaceutical composition also contains other drugs active constituent.
As the preference of the present invention, the other drugs active constituent is bortezomib.
It is highly preferred that the molar ratio of substitution the benzenesulfonyl class compound and bortezomib described in the pharmaceutical composition For 187.5-3000.
In the fourth aspect of the present invention, the substitution benzenesulfonyl class compound or the substituted benzene sulphur are provided The crystal form of acyl compounds, pharmaceutically acceptable inorganic acid salt or acylate, hydrate, solvate or prodrug are being made Standby treatment and the purposes in the drug of the relevant disease of acetylation of histone enzyme (HDAC) activity or symptom.
As a kind of specific implementation mode of the present invention, the acetylation of histone enzyme is acetylation of histone enzyme 6 (HDAC6)。
In the fourth aspect of the present invention, the substitution benzenesulfonyl class compound or the substituted benzene sulphur are provided The crystal form of acyl compounds, pharmaceutically acceptable inorganic acid salt or acylate, hydrate, solvate or prodrug are being made Purposes in standby antineoplastic and synergist.
As a kind of specific implementation mode of the present invention, the tumour is selected from myeloma, leukaemia, oophoroma, mammary gland Cancer, melanoma or lung cancer.But it is not limited only to this.
In the fifth aspect of the present invention, the preparation method of the substitution benzenesulfonyl class compound, feature are provided It is, includes the following steps：Under alkaline condition, there is the carboxylic acid ester compound of different substitution benzenesulfonyls to occur with azanol Reaction generates the hydroxamic acid compound with different substitution benzenesulfonyls.
Herein, " prodrug " refers to that a reagent is converted into prototype medicine in vivo.Prodrug is typically useful, because at certain In the case of kind, they may administration easier than prototype medicine.Prodrug is typically the precursor of medicine, and next administration and absorption are converted For active material, or by some processes become the stronger type of activity, is such as converted by metabolic pathway.What some prodrugs had Chemical group keeps its activity relatively low and/or the dissolubility or some other properties of comparison prototype medicine.Once the chemical group of prodrug It is removed and/or it is modified, obtain active drug.
The pharmaceutically acceptable inorganic acid salt can be selected from hydrochloride, sulfate, phosphate, diphosphate, hydrogen bromine Hydrochlorate, nitrate, the pharmaceutically acceptable acylate can be selected from acetate, maleate, fumarate, tartaric acid Salt, succinate, lactate, tosilate, salicylate, oxalates.
Described pharmaceutical composition can be solid form or liquid form, and dosage form can be tablet, dispersible tablet, contain Piece, oral disintegrating tablet, sustained release tablets, capsule, soft capsule, dripping pill, granule, injection, powder-injection or aerosol etc..Work as the present invention It when compound is used for such use, can be mixed with one or more pharmaceutically acceptable carriers or excipient, such as solvent, dilution Agent etc., and can be administered orally with following form：Tablet, pill, capsule, dispersible powder, particle or suspension (contain Such as from about 0.05-5% suspending agents), syrup (containing such as from about 10-50% sugar) and elixir (contain about 20-50% ethyl alcohol), or in addition It is administered with mode：Ointment, gel, drug containing adhesive plaster etc., or with sterile injectable solution or suspension form (in isotonic medium In contain about 0.05-5% suspending agents) carry out parenteral routes.For example, these pharmaceutical preparations contain the pact mixed with carrier The active constituent of 0.01-99%, more preferably about 0.1-90% (weight).Suitable administration route includes but not limited to, take orally, Intravenous injection, rectum, aerosol, parenterai administration, ophthalmic administration, pulmonary administration, percutaneous dosing, vagina administration, duct administration, Nasal-cavity administration and local administration.
" pharmaceutically acceptable carrier " refers to：One or more biocompatible solids or liquid filler or gelatinous mass, They are suitble to people to use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " herein means generation be in composition Each component energy and the compound of the present invention and they between mutually admix, and the effect of significantly reduce compound.Pharmaceutically Acceptable carrier part example has sugared (such as glucose, sucrose, lactose), starch (such as cornstarch, potato starch), Cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate), gelatin, talcum powder, Gu Body lubricant (such as odium stearate, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame oil, peanut oil, olive oil) are more First alcohol (such as propylene glycol, glycerine, mannitol, sorbierite), emulsifier (such as Tweens), wetting agent (such as dodecyl sodium sulfonate Sodium), colorant, flavoring agent, stabilizer, antioxidant, preservative, apirogen water etc..
" synergist " refers to that a kind of and certain class compatibility of drugs is lived in use, enhancing such drug with specific mechanism Property drug, play synergistic effect., can be with other drugs drug combination as synergist, " administering drug combinations " refer to will be several Medicine selected by kind gives patient's medication, with identical or different administering mode in identical or different time administration. Term " collaboration ", " synergistic effect " or " synergy " refers to as used herein and there is inhibition HDAC or anti-tumor drug to script The effect of original Drug inhibition HDAC or antitumous effect can be enhanced when sharing another drug.
The invention has the advantages that：
1, substitution benzenesulfonyl class compound of the invention is shown to the higher inhibitory activity of HDAC, especially partization It closes object and good selective inhibitory activity is shown to HDAC6.Therefore these compounds, which have, prepares and HDAC especially HDAC6 The medicine of the relevant disease of activity, prepares antitumor drug, and prepare synergist and other antitumor drugs or radiation Treatment is shared to treat the potential use of tumour.
2, substitution benzenesulfonyl class compound of the invention is to human blood tumour (myeloma, leukaemia) and solid tumor (ovum Nest cancer, breast cancer, melanoma, lung cancer) show broad-spectrum anti-tumor activity.And it is shown preferably with existing drug combination Synergistic effect.Therefore, the compound of the present invention is expected have good development prospect.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment) It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution, i.e., of the invention It can be combined with each other between each substituent group, the new particular compound of composition is the part of the present invention.
Specific implementation mode
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are weight percent and weight Number.
Embodiment 1
The preparation of N- hydroxyls -8- (2- nitro -4- aminosulfonvlphenyls amino) caprylamide (compound 7 in table 1)：
1, the preparation of 8- (2- nitro -4- sulfonamidos phenylamino) ethyl caprilate
The fluoro- 3- nitrobenzene sulfonamides 0.5g (2.27mmol) of 4- are dissolved in the DMSO of 20ml, 8- amino is added thereto Ethyl caprilate 0.636g (3.4mmol), and the drops of DIEA 15 are instilled, after being stirred to react 8h under 80 DEG C of heating, solution is poured into ice water In, yellow solid, yield 90% is obtained by filtration.
2, the preparation of N- hydroxyls -8- (2- nitro -4- aminosulfonvlphenyls amino) caprylamide
8- (2- nitro -4- sulfonamidos phenylamino) ethyl caprilate 386mg (1mmol) is dissolved in the existing system of 10ml In the hydroxylamine hydrochloride methanol solution that 1.12mol/L potassium hydroxide dissociates, after 12h is stirred at room temperature, with diluted acid tune pH, it is obtained by filtration Crude product, column chromatography obtain yellow solid, yield 70%.
Embodiment 2-8
Embodiment 1 is repeated, difference is：Using different raw materials, to which compound 1-6 and 8 in table 1 be made.Specifically It is as follows：Use glycine ethyl ester, 3- alanines ethyl ester, 4-Aminobutanoicacid ethyl ester, 5- aminovaleric acids ethyl ester, 6-aminocaprolc acid second Ester, ethyl 7-aminoheptanoate and 4- aminomethyl benzoic acid ethyl esters replace raw material 8- aminocaprylic acid ethyl esters in embodiment 1, make respectively Obtain compound 1-6 and 8.
Embodiment 9
N- (4- (Hydroxycarboamoyl) benzenesulfonyl) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) acryloyl group ammonia Base) benzamide (compound 9 in table 1) preparation：
1, N- ((2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl) amino-sulfonyl) benzene first The preparation of acetoacetic ester
By 4- amino-sulfonyl ethyl benzoate 500mg (2.1mmol), 2- phenoxy groups -4- (3- (2- aminomethyl phenyls) propylene Acyl amino) benzoic acid 815mg (2.1mmol), 1- ethyls -3- (3- dimethylaminopropyls) carbodiimide hydrochloride (EDCI) 2.034g (10.5mmol), 4-dimethylaminopyridine 260.4mg (2.1mmol), using anhydrous DCM as solvent, normal-temperature reaction is for 24 hours Afterwards, the hydrochloric acid of 1M, saturated sodium bicarbonate, saturated common salt is used to wash successively, organic phase is concentrated to give solid 0.429g, yield 72.1%.
2, N- (4- (Hydroxycarboamoyl) benzenesulfonyl) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) acryloyl group ammonia Base) benzamide preparation
By N- ((2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl) amino-sulfonyl) benzene first Acetoacetic ester 292mg (0.5mmol) is dissolved in the hydroxylamine hydrochloride methanol solution that 1.12mol/L that 6ml now makes potassium hydroxide dissociates, After 12h is stirred at room temperature, with diluted acid tune pH, crude product is obtained by filtration, column chromatography obtains yellow solid, yield 70%.
Embodiment 10
N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) -3- nitrobenzenesulfonyls) -2- phenoxy groups -4- (3- (2- first Base phenyl) Acryloyl amino) benzamide (compound 16 in table 1) preparation：
1,8- (2- nitros -4- (N- (2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl) sulphurs Acylamino-) phenylamino) ethyl caprilate
By 8- (2- nitro -4- sulfonamidos phenylamino) ethyl caprilate 500mg (1.30mmol), 2- phenoxy group -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoic acid 485mg (1.30mmol), two Asia of 1- ethyls -3- (3- dimethylaminopropyls) carbon Amine hydrochlorate (EDCI) 1.25g (6.5mmol), 4-dimethylaminopyridine 160mg (0.4mmol), using anhydrous DCM as solvent, often After temperature reaction for 24 hours, the hydrochloric acid of 1M, saturated sodium bicarbonate, saturated common salt is used to wash successively, organic phase is concentrated to give solid, yield 60%.
2, N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) -3- nitrobenzenesulfonyls) -2- phenoxy groups -4- (3- (2- Aminomethyl phenyl) Acryloyl amino) benzamide preparation
By 8- (2- nitros -4- (N- (2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl) sulphurs Acylamino-) phenylamino) ethyl caprilate 300mg (0.4mmol) is dissolved in the salt that 1.12mol/L that 8ml now makes is dissociated with potassium hydroxide In sour azanol methanol solution, after 12h is stirred at room temperature, with diluted acid tune pH, crude product is obtained by filtration, column chromatography obtains yellow solid, production Rate 70%.
Embodiment 11-28
Embodiment 10 is repeated, difference is：Using different raw materials, to which compound 10-15 and 17- in table 1 be made 28.It is specific as follows：Use 2- (2- nitro -4- aminosulfonvlphenyls amino) ethyl acetate, 3- (2- nitro -4- aminosulfonyls Base phenyl amino) ethyl propionate, 4- (2- nitro -4- aminosulfonvlphenyls amino) ethyl butyrate, 5- (2- nitro -4- amino Sulfonvlphenyl amino) ethyl valerate, 6- (2- nitro -4- aminosulfonvlphenyls amino) ethyl hexanoate, 7- (2- nitros -4- Aminosulfonvlphenyl amino) cognac oil, 8- (4- aminosulfonvlphenyls amino) ethyl caprilates and 4- ((2- nitro -4- ammonia Base sulfonvlphenyl amino) methyl) ethyl benzoate replace embodiment 10 in raw material 8- (2- nitro -4- aminosulfonvlphenyls Amino) ethyl caprilate, compound 10-15 and 17-18 are made respectively；Use 4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzene Formic acid, 2- phenoxy benzoic acids, benzoic acid and 4- (1- (3,5,5,8,8- pentamethyl -5,6,7,8- naphthane -2- bases) ethylene Base) benzoic acid is instead of raw material 2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoic acid in embodiment 10, respectively Compound 19,22,26 and 27 is made；Raw material 2- phenoxy groups -4- (3- (2- in embodiment 10 are replaced using 2- phenoxy benzoic acids Aminomethyl phenyl) Acryloyl amino) benzoic acid, and 6- (2- nitro -4- aminosulfonvlphenyls amino) ethyl hexanoate, 7- (2- Nitro -4- aminosulfonvlphenyls amino) cognac oil and 4- ((2- nitro -4- aminosulfonvlphenyls amino) methyl) benzene first Acetoacetic ester replace raw material 8- (2- nitro -4- aminosulfonvlphenyls amino) ethyl caprilate, respectively be made compound 20-21 and 23；Raw material 2- phenoxy groups -4- (3- (2- aminomethyl phenyls) propylene in embodiment 10 is replaced using 2- (4- chlorphenyls) p-methoxybenzoic acid Acyl amino) benzoic acid, and 6- (2- nitro -4- aminosulfonvlphenyls amino) ethyl hexanoates and 4- ((2- nitro -4- amino Sulfonvlphenyl amino) methyl) ethyl benzoate replaces the sad second of raw material 8- (2- nitro -4- aminosulfonvlphenyls amino) Compound 24 and 25 is made in ester；Use 4- (1- (3,5,5,8,8- pentamethyl -5,6,7,8- naphthane -2- bases) vinyl) benzene Formic acid replaces raw material 2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoic acid in embodiment 10, and 8- (4- ammonia Base sulfonvlphenyl amino) ethyl caprilate replace raw material 8- (2- nitro -4- aminosulfonvlphenyls amino) ethyl caprilate, be made Compound 28.
The chemical constitution of target product is shown in Table 1-1, table 1-2 and table 1-3 in the general formula (I) that the present invention synthesizes.Nucleus magnetic hydrogen spectrum The chemical constitution of target product is characterized with mass spectrometer system, specific data are shown in Table 2.
Target compound structure in table 1-1 general formulas (I)
Target compound structure in table 1-2 general formulas (I)
Target compound structure in table 1-3 general formulas (I)
The hydrogen spectrum and mass spectrometric data of target compound in 2 general formula of table (I)
Embodiment 29HDAC inhibitory activity is tested
Inhibiting effect of the target compound to HDAC families is investigated using fluorescence method, basic principle is contained with HDAC catalysis There is the substrate of acylated chains to make its deacetylation, the substrate of trypsin hydrolysis deacetylation is then used to generate with fluorescence Hydrolysate.Series concentration target compound and the buffer solution containing substrate and trypsase and prepared HDAC is molten Liquid mixing is incubated at room temperature detection fluorescence signal (excitation wavelength 355nm, launch wavelength 460nm) after a period of time.Fluorescence The variation of light absorption value can reflect the suppressed situation of HDAC, and the inhibition IC of compound is calculated using its numerical value change50Value.It is positive Comparison medicine is Rocilinostat and SAHA.Experimental result is shown in Table 3.
The HDAC inhibitory activity of 3 target compound of table
The result shows that substitution benzenesulfonyl class compound of the invention show with the preferable inhibitory activity of HDAC, especially It is that part of compounds shows good selective inhibitory activity to HDAC6, it is selectively even better than clinical to HDAC6 to try The Rocilinostat (selectivity index 7.7) tested.Therefore these compounds, which have, prepares and HDAC especially HDAC6 activity phases The medicine of the disease of pass prepares antitumor drug, and prepares synergist and closed with other antitumor drugs or radiotherapy To treat the potential use of tumour.
30 anti tumor activity in vitro of embodiment is tested
1, experimental tumor strain
This experiment is respectively using tumour cell strain：RPMI-8226 (human myeloma cell), (human leukemia is thin by HL-60 Born of the same parents), U266 (human myeloma cell), SKOV3 (Proliferation of Human Ovarian Cell), MCF-7 (human breast cancer cell), A375 (human melanins Oncocyte) and NCI-H23 (human lung carcinoma cell) (being purchased from Shanghai Institute of Pharmaceutical Industry).
2, sample preparation
After being dissolved with DMSO (Merck), PBS (-) is added and is made into the solution of 1000 μ g/mL or uniform suspension, then With PBS (-) dilution containing DMSO.The ABT-737 and 4- that positive control drug is Rocilinostat, Abbott develops Benzamido-N- (3-nitro-4- (2- (phenylthio) ethylamino) phenylsulfonyl) benzamide is (right According to 1).3, test method
According to experiment detection and pertinent literature (Bioorg Med Chem Lett 2012,22,39-44； Nature.2005,437,677-681), using mtt assay.A concentration of 4~5 × 10 are added per hole for 96 orifice plates4The cell of a/mL is outstanding 100 μ L of liquid, set 37 DEG C, 5%CO2In incubator.After for 24 hours, addition sample liquid, 10 holes μ L/, if duplicate hole, 37 DEG C, 5%CO2Make Use 72h.The 20 μ L of MTT solution of 5mg/mL are added per hole, lysate is added after acting on 4h, 100 holes μ L/ are set in incubator, dissolving Afterwards 570nm OD values are surveyed with the full-automatic microplate reader of MK-2.Test result is shown in Table 4.
In-vitro multiplication inhibiting effect of the partial target compound to human body tumour cell in 4 general formula of table (I)
As known from Table 4, substitution benzenesulfonyl class compound of the invention shows wide spectrum to human blood tumour and solid tumor Antitumor activity, unlisted compound also show that preferable broad-spectrum anti-tumor activity, imply the compound of the present invention It is expected have good development prospect.
Embodiment 31 tests existing antitumor drug synergistic activity
Target compound is investigated on sensitive to existing medicine or drug resistant multiple myeloma cells to existing anti- The synergistic activity of tumour medicine.Target compound carries out growth of tumour cell inhibitory activity using mtt assay.Huppert's disease Cell strain uses H929 cells.The H929R cells of bortezomib drug resistant can be by being gradually increased bortezomib concentration (initially 0.5nM is incremented by by gradient of 0.2nM, is eventually increased to 15nM) culture medium in continuously cultivate and obtain.By tumour cell point Enter in 96 orifice plates, target compound or the combination of various concentration is added, with the medium culture 72 hours containing serum.It is added later MTT detects the trap of solution with microplate reader after being cultivated 4 hours at 37 DEG C, by with blank control relatively to evaluate it is thin Born of the same parents' Proliferation Ability situation.Based on target compound under various concentration and bortezomib independent medication to the inhibiting rate of tumour cell, With to the inhibiting rate of tumour cell, cooperateing with for target compound and bortezomib is calculated using CalcuSyn 2.1 when drug combination Index (combination index, CI), CI<0.9 shows with synergistic effect.Test result is shown in Table 5.
Partial target compound lives to the synergy of bortezomib in drug resistance and non-drug resistance H929 cells in 5 general formula of table (I) Property
As known from Table 5, substitution benzenesulfonyl class compound of the invention, either in non-drug resistance still in mdr cell On, all there is synergistic effect to existing antitumor drug, and (compound 16 is helped with boron in such as table 1 under a variety of concentration ratios Rice concentration ratio is 60 μM:80nM,60μM:160nM,120μM:40nM,120μM:80nM,120μM:160nM) its synergistic effect Highly significant, unlisted compound also show that significant synergistic effect, and it is good to imply that the compound of the present invention is expected to have Good development prospect.
Embodiment 32 inhibits to test to normal cell proliferation
Using normal cell strain WI-38 (people diploid fibroblast) and HEK-293, (human embryo kidney (HEK) epithelium is thin for this experiment Born of the same parents).Positive control drug is ACY-1215, SAHA and Panobinostat.Target compound is investigated to press down the proliferation of normal cell System activity is carried out using mtt assay, and a concentration of 4~5 × 10 are added per hole for 96 orifice plates4The 100 μ L of cell suspension of a/mL, set 37 DEG C, 5%CO2In incubator.After for 24 hours, addition sample liquid, 10 holes μ L/, if duplicate hole, 37 DEG C, 5%CO2Act on 72h.It is added per hole Lysate is added after acting on 4h in the 20 μ L of MTT solution of 5mg/mL, and 100 holes μ L/ are set in incubator, full-automatic with MK-2 after dissolving Microplate reader surveys 570nm OD values.Test result is shown in Table 6.
Inhibited proliferation of the partial target compound to normal cell in 6 general formula of table (I)
As known from Table 6, substitution benzenesulfonyl class compound of the invention, compared with positive control drug, to normal cell Proliferation Ability influence is smaller, and unlisted compound also shows that this advantage, implies that the compound of the present invention is expected There is good development prospect.

Claims (10)

1. a kind of substitution benzenesulfonyl class compound, which is characterized in that shown in its general structure such as formula (I)：
Wherein：
R1Group is amino, hydroxyl, unsubstituted or substituted aromatic monocyclic；Wherein, substituent group is monosubstituted or polysubstituted, is C1~ C5Straight chain, branch or cyclic alkane base, halogen；
Or R1Group isR4It is hydrogen atom, unsubstituted or substituted C1~C7Straight chain, branch or cyclic alkane Base, unsubstituted or substituted C1~C7Straight chain, branch or cyclic olefin base；Wherein, substituent group is monosubstituted or polysubstituted, not take Generation or substituted aroma monocycle, halogen；
Or R4Group isWherein, R5It is hydrogen atom ,-XR7(Ⅴ)；Wherein, X is R7It is hydrogen atom, unsubstituted or substituted aromatic monocyclic is unsubstituted or substituted Hydrogenated aromatic condensed ring, unsubstituted or substituted aromatic condensed ring, wherein substituent group is monosubstituted or polysubstituted, is C1~C5Straight chain, branch Chain or cyclic alkane base, halogen；
Or R7Group is-VR8(VI), wherein V is nitrogen, oxygen, R8It is hydrogen atom, C1~C7Straight chain, branch or cyclic alkane oxygroup；
Or R7Group is-WR9(VII), wherein W is C1~C7Straight chain, branch or cyclic alkane base, C1~C7Straight chain, branch or ring Shape alkylene, R9Hydrogen atom, unsubstituted or substituted aromatic monocyclic, wherein substituent group be it is monosubstituted or polysubstituted, be straight chain, Branch or cyclic alkane base, halogen；
R6The position of substitution is located at two or three-digit, is hydrogen atom, hydroxyl, amino, halogen, C1~C5Straight chain, branch or cyclic alkane Base,
Or R6Group is-UR10(VIII), wherein U is O, N, S,R10It is hydrogen atom, aromatic monocyclic, fragrance Condensed ring, C1~C7Straight chain, branch or cyclic alkane base；
R2Group isWherein, R8For C1~C5Straight chain, branch or cyclic alkane base,
Or R2Group is-ZYR11(Ⅸ), wherein Z is N, O, S,Y is C1~C10Straight chain, branch or ring-type Alkyl, C1~C10Straight chain, branch or cyclic olefin base, aromatic monocyclic, aromatic condensed ring, R11It is
Or Y is-QT- (Ⅹ), wherein Q is C1~C10Straight chain, branch or cyclic alkane base, C1~C10Straight chain, branch or cyclic annular alkene Alkyl, T are aromatic monocyclic or aromatic condensed ring；
R3The position of substitution is located at two or three-digit, is hydrogen atom, nitro, trifluoromethyl, cyano, sulfonic group, carboxyl, C1~C5Straight chain Or branched alkane alkyl, halogen, hydroxyl, amino.
2. substitution benzenesulfonyl class compound according to claim 1, which is characterized in that R1Group is amino, hydroxyl, not Substituted aroma monocycle,
R2Group is-ZYR11(Ⅸ), wherein Z is N, O, S, and Y is C1~C10Straight chain, branch or cyclic alkane base, C1~C10Straight chain, branch Chain or cyclic olefin base, aromatic monocyclic, aromatic condensed ring, R11It is
Or Y is-QT- (Ⅹ), wherein Q is C1~C10Straight chain, branch or cyclic alkane base, C1~C10Straight chain, branch or cyclic annular alkene Alkyl, T are aromatic monocyclic or aromatic condensed ring；
R3The position of substitution is located at two or three-digit, is hydrogen atom, nitro, trifluoromethyl, cyano, sulfonic group, carboxyl, C1~C5Straight chain Or branched alkane alkyl, halogen, hydroxyl, amino.
3. substitution benzenesulfonyl class compound according to claim 1, which is characterized in that
R1Group isR4Group is
Wherein, R5It is-XR7(Ⅴ)；Wherein, X isR7Group is-WR9(VII), Wherein, W is C1~C7Straight chain, branch or cyclic alkane base, C1~C7Straight chain, branch or cyclic olefin base, R9It is substituted aroma list Ring, wherein substituent group is monosubstituted or polysubstituted, is straight chain, branch or cyclic alkane base, halogen；
R6The position of substitution is located at two or three-digit, R6Group is-UR10(VIII), wherein U is O, N, S, R10It is hydrogen atom, fragrance is single Ring, aromatic condensed ring, C1~C7Straight chain, branch or cyclic alkane base；
R2Group is
R3The position of substitution is located at two or three-digit, is hydrogen atom, nitro, trifluoromethyl, cyano, sulfonic group, carboxyl, C1~C5Straight chain Or branched alkane alkyl, halogen, hydroxyl, amino.
4. substitution benzenesulfonyl class compound according to claim 1, which is characterized in that
R1Group isR4Group is
Wherein, R5It is hydrogen atom ,-XR7(Ⅴ)；Wherein, X is R7It is unsubstituted or substituted aromatic condensed ring, wherein substituent group is monosubstituted or polysubstituted, is C1~C5Straight chain, branch Or cyclic alkane base, halogen；
Or R7Group is-WR9(VII), wherein W is C1~C7Straight chain, branch or cyclic alkane base, C1~C7Straight chain, branch or ring Shape alkylene, R9It is substituted aroma monocycle, wherein substituent group is monosubstituted or polysubstituted, is straight chain, branch or cyclic alkane Base, halogen；
R6The position of substitution is located at two or three-digit, be hydrogen atom, hydroxyl, amino, halogen,
Or R6Group is-UR10(VIII), wherein U is O, N, S, R10It is aromatic monocyclic；
R2Group is-ZYR11(Ⅸ), wherein Z is N, O, S, and Y is C1~C10Straight chain, branch or cyclic alkane base, C1~ C10Straight chain, branch or cyclic olefin base, aromatic monocyclic, aromatic condensed ring, R11It is
Or Y is-QT- (Ⅹ), wherein Q is C1~C10Straight chain, branch or cyclic alkane base, C1~C10Straight chain, branch or cyclic annular alkene Alkyl, T are aromatic monocyclic or aromatic condensed ring；
R3The position of substitution is located at two or three-digit, be hydrogen atom, nitro, trifluoromethyl, cyano, sulfonic group, carboxyl, halogen, hydroxyl, Amino.
5. substitution benzenesulfonyl class compound according to claim 1, which is characterized in that the substitution benzenesulfonyl class Compound is selected from：
1) N- hydroxyls -2- (2- nitro -4- aminosulfonvlphenyls amino) acetamide
2) N- hydroxyls -3- (2- nitro -4- aminosulfonvlphenyls amino) propionamide
3) N- hydroxyls -4- (2- nitro -4- aminosulfonvlphenyls amino) butyramide
4) N- hydroxyls -5- (2- nitro -4- aminosulfonvlphenyls amino) pentanamide
5) N- hydroxyls -6- (2- nitro -4- aminosulfonvlphenyls amino) caproamide
6) N- hydroxyls -7- (2- nitro -4- aminosulfonvlphenyls amino) heptamide
7) N- hydroxyls -8- (2- nitro -4- aminosulfonvlphenyls amino) caprylamide
8) N- hydroxyls -4- ((2- nitro -4- aminosulfonvlphenyls amino) methyl) benzamide
9) N- (4- (Hydroxycarboamoyl) benzenesulfonyl) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) Benzamide
10) N- (4- (2- (hydroxyl amino) -2- oxos ethylamino) -3- nitrobenzenesulfonyls) -2- phenoxy groups -4- (3- (2- methyl Phenyl) Acryloyl amino) benzamide
11) N- (4- (the third amino of 3- (hydroxyl amino) -3- oxos) -3- nitrobenzenesulfonyls) -2- phenoxy groups -4- (3- (2- methyl Phenyl) Acryloyl amino) benzamide
12) N- (4- (4- (hydroxyl amino) -4- oxo fourths amino) -3- nitrobenzenesulfonyls) -2- phenoxy groups -4- (3- (2- methyl Phenyl) Acryloyl amino) benzamide
13) N- (4- (penta amino of 5- (hydroxyl amino) -5- oxos) -3- nitrobenzenesulfonyls) -2- phenoxy groups -4- (3- (2- methyl Phenyl) Acryloyl amino) benzamide
14) N- (4- (the own amino of 6- (hydroxyl amino) -6- oxos) -3- nitrobenzenesulfonyls) -2- phenoxy groups -4- (3- (2- methyl Phenyl) Acryloyl amino) benzamide
15) N- (4- (7- (hydroxyl amino) -7- oxos amino in heptan) -3- nitrobenzenesulfonyls) -2- phenoxy groups -4- (3- (2- methyl Phenyl) Acryloyl amino) benzamide
16) N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) -3- nitrobenzenesulfonyls) -2- phenoxy groups -4- (3- (2- methyl Phenyl) Acryloyl amino) benzamide
17) N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) benzenesulfonyl) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) third Enoylamino) benzamide
18) N- (4- ((4- Hydroxycarboamoyls) benzylamino) -3- nitrobenzenesulfonyls) -2- phenoxy groups -4- (3- (2- first Base phenyl) Acryloyl amino) benzamide
19) N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) -3- nitrobenzenesulfonyls) -4- (3- (2- aminomethyl phenyls) propylene Acyl amino) benzamide
20) N- (4- (the own amino of 6- (hydroxyl amino) -6- oxos) -3- nitrobenzenesulfonyls) -2- phenoxy benzamides
21) N- (4- (7- (hydroxyl amino) -7- oxos amino in heptan) -3- nitrobenzenesulfonyls) -2- phenoxy benzamides
22) N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) -3- nitrobenzenesulfonyls) -2- phenoxy benzamides
23) N- (4- ((4- Hydroxycarboamoyls) benzylamino) -3- nitrobenzenesulfonyls) -2- phenoxy benzamides
24) 2- (4- chlorophenoxies)-N- (4- (the own amino of 6- (hydroxyl amino) -6- oxos) -3- nitrobenzenesulfonyls) benzoyl Amine
25) 2- (4- chlorophenoxies)-N- (4- (4- (Hydroxycarboamoyl) benzylamino) -3- nitrobenzenesulfonyls) benzoyl Amine
26) N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) -3- nitrobenzenesulfonyls) benzamide
27) N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) -3- nitrobenzenesulfonyls) -4- (1- (five first of 3,5,5,8,8- Base -5,6,7,8- naphthane -2- bases) vinyl) benzamide
28) N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) benzenesulfonyl) -4- (1- (pentamethyl -5,6 3,5,5,8,8-, 7,8- naphthane -2- bases) vinyl) benzamide.
6. crystal form, the pharmaceutically acceptable inorganic acid salt or organic of substitution benzenesulfonyl class compound described in claim 1 Hydrochlorate, hydrate, solvate or prodrug.
7. a kind of pharmaceutical composition, which is characterized in that the pharmaceutical composition contains pharmaceutically acceptable excipient or load Substitution benzenesulfonyl class chemical combination described in body and substitution benzenesulfonyl class compound described in claim 1 or claim 6 The crystal form of object, pharmaceutically acceptable inorganic acid salt or acylate, hydrate, solvate or prodrug.
8. the substitution benzenesulfonyl class chemical combination described in substitution benzenesulfonyl class compound described in claim 1 or claim 6 The crystal form of object, pharmaceutically acceptable inorganic acid salt or acylate, hydrate, solvate or prodrug are in medicine preparation Purposes, the drug are used for：
A) treatment and the relevant disease of acetylation of histone enzymatic activity or symptom；
B) treatment and the relevant disease of 6 activity of acetylation of histone enzyme or symptom；
C) antitumor；Or
D) it is used as antitumor synergist.
9. purposes according to claim 8, which is characterized in that the tumour is myeloma, leukaemia, oophoroma, breast Gland cancer, melanoma or lung cancer.
10. the preparation method of substitution benzenesulfonyl class compound described in claim 1, which is characterized in that include the following steps： Under alkaline condition, the carboxylic acid ester compound with different substitution benzenesulfonyls reacts to generate with azanol to be taken with difference For the hydroxamic acid compound of benzenesulfonyl.
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