CN108794358B - Substituted benzenesulfonyl compounds and application thereof in preparing medicines - Google Patents
Substituted benzenesulfonyl compounds and application thereof in preparing medicines Download PDFInfo
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- CN108794358B CN108794358B CN201710287968.0A CN201710287968A CN108794358B CN 108794358 B CN108794358 B CN 108794358B CN 201710287968 A CN201710287968 A CN 201710287968A CN 108794358 B CN108794358 B CN 108794358B
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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
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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
- C07C311/50—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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Abstract
The invention relates to a substituted benzenesulfonyl compound, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, a preparation method and a pharmaceutical application thereof. The structural general formula of the compound is shown as a formula (I). Tests show that the compound has higher inhibiting activity on HDAC, particularly, part of compounds show good selective inhibiting activity on HDAC6, and simultaneously, the compounds show broad-spectrum antitumor activity on human blood tumors (myeloma and leukemia) and solid tumors (ovarian cancer, breast cancer, melanoma and lung cancer). The compound has potential application in preparing medicaments for treating diseases related to HDAC (Histone data Access), particularly HDAC6 activity, preparing antitumor medicaments, preparing synergists and preparing potential application in treating tumors by combining with other antitumor medicaments or radiotherapy.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to substituted benzenesulfonyl compounds, a composition of the substituted benzenesulfonyl compounds, a preparation method of the substituted benzenesulfonyl compounds, and application of the substituted benzenesulfonyl compounds in preparation of medicines, antitumor drugs and synergists for treating diseases or symptoms related to histone acetyltransferase (HDAC) activity.
Background
HDAC and histone acetylase are two groups of enzymes with opposite functions in vivo, and can regulate acetylation states of various extranuclear proteins including histone, thereby playing roles in regulating gene transcription, cell differentiation, and cellCycle and apoptosis. HDAC includes four subfamilies, Zn 2+ Dependent type I (HDAC1-3, 8), IIA (HDAC4, 5, 7, 9), IIB (HDAC6, 10) and IV (HDAC11), and NAD + Form III of dependence (sirtuins 1-7). HDACs have been shown to be closely related to the development and progression of tumors, nervous system diseases, and inflammatory and infectious diseases. HDAC broad-spectrum and selective small molecule inhibitors are thus used in the treatment and study of tumors, neurological diseases, inflammation and viral infections (Nat Rev Drug Discov 2014,13, 673-91; Pharmacol Ther 2014,143,323-36.).
Increased deacetylation of proteins due to increased expression or activity of HDAC is one of the typical features of many tumors, and increased expression of HDAC is observed in a variety of hematological tumors (Cancer Lett 2009,280,168-76). Multiple myeloma has also been clearly demonstrated to be commonly highly expressed in class I HDACs (HDAC1 in particular) and to be closely associated with poor prognosis (epidemics 2014,9, 1511-20). Therefore, targeting HDACs is becoming one of the research hotspots for tumor therapy (Lancet Oncol 2013,14, 1038-9.). In recent years, HDAC small molecule inhibitors have been rapidly developed, mainly including hydroxamic acids, benzamides, cyclic peptides, short chain fatty acids, and the like. They exhibit a broad antitumor effect against hematological tumors, lung cancer, prostate cancer and the like in vitro and in vivo (Nat Rev Drug Discov 2014,13, 673-91; J Med Chem 2008,51, 1505-29.). Three of the drugs vorinostat (vorinostat, SAHA), romidepsin (romidepsin) (J Clin Invest 2014,124,30-9.) and belinostat (belinostat, 2014.07 lot) (Br J haematal 2015,168,811-9.) are currently approved abroad and one drug cidamide (chidamide, 2015.01 approval) (Cancer Chemother Pharmacol 2012,69,1413-22.) just marketed in China, approved for the treatment of cutaneous or peripheral T-cell lymphoma. However, a plurality of HDAC inhibitors have shown good anti-multiple myeloma effects in clinical trials and can play a role in significant synergism when being combined with other anti-tumor drugs, 2015.02 panobinostat (panobinostat) is approved by FDA to be combined with bortezomib and dexamethasone for multiple myeloma treatment (Lancet Oncol 2014,15, 1195-.
In addition, subtype-selective inhibitors are becoming the focus of recent research because of their potential for better therapeutic efficacy and lower side effects (Nat Rev Drug Discov 2014,13, 673-91; Curr Pharm Des 2015,21, 1472-. Studies have shown that newly discovered selective inhibitors of HDAC6 (e.g., Rocilinostat, ACY-1215) can be involved in the protein degradation system by affecting the formation of aggresome, thereby acting synergistically with bortezomib, an inhibitor of another proteasome pathway in this system, to treat multiple myeloma, and have now entered clinical trials (Blood 2012,119,2579-89; Br J haematol.2015,169, 423-34). HDAC6 selective inhibitors have also been used in the study of diseases such as neurological diseases (neurodegenerative diseases, alzheimer's disease, etc.) and the treatment of inflammation (Nat Rev Drug Discov 2014,13, 673-91).
In summary, the development of inhibitors of HDAC, especially subtype-selective inhibitors, is of great importance for the treatment of diseases such as tumor.
Disclosure of Invention
The invention aims to provide a novel substituted phenylsulfonyl compound, and a preparation method, application and composition of the compound.
In a first aspect of the present invention, there is provided a substituted phenylsulfonyl compound having a general structural formula as shown in formula (i):
wherein:
R 1 the group is amino, hydroxy, unsubstituted or substituted aromatic monocyclic ring; wherein the substituent is mono-or polysubstituted and is C 1 ～C 5 Linear, branched or cyclic alkyl, halogen;
or R 1 The radical is
R 4 Is a hydrogen atom, unsubstituted or substituted C 1 ～C 7 Straight, branched or cyclic alkyl, unsubstituted or substituted C 1 ～C 7 Straight chain, branched chainA chain or cyclic alkylene group; wherein, the substituent is mono-substituted or multi-substituted, is unsubstituted or substituted aromatic monocyclic ring, and is halogen;
or R 4 The radical is
Wherein R is 5 Is a hydrogen atom, -XR 7 (V); wherein X is
R 7 Is hydrogen atom, unsubstituted or substituted aromatic monocyclic ring, unsubstituted or substituted hydrogenated aromatic condensed ring, unsubstituted or substituted aromatic condensed ring, wherein the substituent is monosubstituted or polysubstituted and is C 1 ～C 5 Linear, branched or cyclic alkyl, halogen;
or R 7 The group being-VR 8 (VI) wherein V is nitrogen, oxygen, R 8 Is a hydrogen atom, C 1 ～C 7 Linear, branched or cyclic alkyloxy;
or R 7 The radical is-WR 9 (VII) wherein W is C 1 ～C 7 Straight, branched or cyclic alkyl radical, C 1 ～C 7 Linear, branched or cyclic alkylene radical, R 9 Is hydrogen atom, unsubstituted or substituted aromatic monocyclic ring, wherein the substituent is mono-substituted or poly-substituted, and is straight chain, branched chain or cyclic alkyl, halogen;
R 6 the substitution position is 2-position or 3-position and is hydrogen atom, hydroxyl, amino, halogen, C 1 ～C 5 A straight-chain, branched-chain or cyclic alkyl group,
or R 6 The radical being-UR 10 (VIII), wherein U is O, N, S,
R 10 is a hydrogen atom, an aromatic monocyclic ring, an aromatic condensed ring, C 1 ～C 7 A linear, branched or cyclic alkyl group;
R 2 the radical is
Wherein R is 8 Is C 1 ～C 5 A straight-chain, branched-chain or cyclic alkyl group,
or R 2 The radical being-ZYR 11 (IX), wherein Z is N, O, S,
y is C 1 ～C 10 Straight, branched or cyclic alkyl radical, C 1 ～C 10 Straight, branched or cyclic alkenyl, aromatic monocyclic ring, aromatic fused ring, R 11 Is that
Or Y is-QT- (X), wherein Q is C 1 ～C 10 Straight, branched or cyclic alkyl radical, C 1 ～C 10 A linear, branched or cyclic alkylene group, T is an aromatic monocyclic ring or an aromatic fused ring;
R 3 the substitution position is 2-position or 3-position, and is hydrogen atom, nitro, trifluoromethyl, cyano, sulfonic group, carboxyl, C 1 ～C 5 Straight-chain or branched-chain alkyl, halogen, hydroxyl and amino.
As a preferred example of the present invention,
R 1 the radicals are amino, hydroxy, unsubstituted aromatic monocyclic rings,
R 2 the radical being-ZYR 11 (IX) wherein Z is N, O, S, Y is C 1 ～C 10 Straight, branched or cyclic alkyl radical, C 1 ～C 10 Straight, branched or cyclic alkenyl, aromatic monocyclic ring, aromatic fused ring, R 11 Is that
Or Y is-QT- (X), wherein Q is C 1 ～C 10 Straight, branched or cyclic alkyl radical, C 1 ～C 10 A linear, branched or cyclic alkylene group, T is an aromatic monocyclic ring or an aromatic fused ring;
R 3 the substitution position is 2-position or 3-position, and is hydrogen atom, nitro, trifluoromethyl, cyano, sulfonic group, carboxyl, C 1 ～C 5 Straight-chain or branched-chain alkyl, halogen, hydroxyl and amino.
As a preferred example of the present invention,
R 1 the radicals are amino, hydroxy, unsubstituted aromatic monocyclic rings,
R 2 the radical being-ZYR 11 (IX) wherein Z is N, O, S, Y is C 1 ～C 7 Straight, branched or cyclic alkyl radical, C 1 ～C 7 Linear, branched or cyclic alkenyl, aromatic monocyclic ring, R 11 Is that
Or Y is-QT- (X), wherein Q is C 1 ～C 4 A linear, branched or cyclic alkyl group, T is an aromatic monocyclic ring;
R 3 the substitution position is 2-position or 3-position, and is hydrogen atom, nitryl, trifluoromethyl, cyano, sulfonic group, carboxyl, halogen, hydroxyl and amino.
As a preferred example of the present invention,
R 1 the radicals are amino, hydroxyl,
R 2 the radical being-ZYR 11 (IX) wherein Z is N, O, S, Y is C 1 ～C 7 Straight chain alkyl radical, R 11 Is that
Or Y is-QT- (X), wherein Q is C 1 ～C 4 A straight chain alkyl group, T is an aromatic monocyclic ring;
R 3 the substitution position is positioned at 2-position or 3-position and is nitro.
As a preferred example of the present invention,
R 1 the radical is
R 4 The radical is
Wherein R is 5 is-XR 7 (V); wherein X is
R 7 The group being-WR 9 (VII) wherein W is C 1 ～C 7 Straight, branched or cyclic alkyl radical, C 1 ～C 7 Linear, branched or cyclic alkylene radical, R 9 Is a substituted aromatic monocyclic ring, wherein the substituent is mono-substituted or multi-substituted, is a straight chain, branched chain or cyclic alkyl, and is halogen;
R 6 the substitution position being in the 2-or 3-position, R 6 The radical being-UR 10 (VIII) wherein U is O, N, S, R 10 Is a hydrogen atom, an aromatic monocyclic ring, an aromatic condensed ring, C 1 ～C 7 A linear, branched or cyclic alkyl group;
R 2 the radical is
R 3 The substitution position is 2-position or 3-position, and is hydrogen atom, nitro, trifluoromethyl, cyano, sulfonic group, carboxyl, C 1 ～C 5 Straight-chain or branched-chain alkyl, halogen, hydroxyl and amino.
As a preferred example of the present invention,
R 1 the radical is
R 4 The radical is
Wherein R is 5 is-XR 7 (V); wherein X is
R 7 The radical is-WR 9 (VII) wherein W is C 1 ～C 4 Linear, branched or cyclic alkylene radical, R 9 Is a substituted aromatic monocyclic ring, wherein the substituent is mono-substituted or multi-substituted, is a straight chain, branched chain or cyclic alkyl, and is halogen;
R 6 the substitution position being in the 2-or 3-position, R 6 The radical being-UR 10 (VIII) wherein U is O, N, S, R 10 Is an aromatic monocyclic ring;
R 2 the radical is
R 3 The substitution position is at the 2-position or 3-position and is a hydrogen atom.
As a preferred example of the present invention,
R 1 the radical is
R 4 The radical is
Wherein R is 5 is-XR 7 (V); wherein X is
R 7 The group being-WR 9 (Ⅶ) Wherein W is C 1 ～C 4 Straight-chain alkylene radical, R 9 Is a substituted aromatic monocyclic ring, wherein the substituent is mono-substituted or multi-substituted, is a straight chain, branched chain or cyclic alkyl, and is halogen;
R 6 the substitution position being in the 2-or 3-position, R 6 The radical being-UR 10 (VIII) wherein U is O, R 10 Is an aromatic monocyclic ring;
R 2 the radical is
R 3 The substitution position is at the 2-position or 3-position and is a hydrogen atom.
As a preferred example of the present invention,
R 1 the group is
R 4 The radical is
Wherein R is 5 Is a hydrogen atom, -XR 7 (V); wherein X is
R 7 Is an unsubstituted or substituted aromatic condensed ring, wherein the substituent is mono-substituted or poly-substituted and is C 1 ～C 5 Linear, branched or cyclic alkyl, halogen;
or R 7 The group being-WR 9 (VII) wherein W is C 1 ～C 7 Straight, branched or cyclic alkyl radical, C 1 ～C 7 Linear, branched or cyclic alkylene radical, R 9 Is a substituted aromatic monocyclic ring, wherein the substituent is mono-substituted orPolysubstituted, straight-chain, branched-chain or cyclic alkyl, halogen;
R 6 the substitution position is positioned at 2-position or 3-position and is hydrogen atom, hydroxyl, amino, halogen,
or R 6 The radical being-UR 10 (VIII) wherein U is O, N, S, R 10 Is an aromatic monocyclic ring;
R 2 the radical being-ZYR 11 (IX) wherein Z is N, O, S, Y is C 1 ～C 10 Straight, branched or cyclic alkyl radical, C 1 ～C 10 Straight, branched or cyclic alkenyl, aromatic monocyclic ring, aromatic fused ring, R 11 Is that
Or Y is-QT- (X), wherein Q is C 1 ～C 10 Straight, branched or cyclic alkyl radical, C 1 ～C 10 A linear, branched or cyclic alkylene group, T is an aromatic monocyclic ring or an aromatic fused ring;
R 3 the substitution position is 2-position or 3-position, and is hydrogen atom, nitryl, trifluoromethyl, cyano, sulfonic group, carboxyl, halogen, hydroxyl and amino.
As a preferred example of the present invention,
R 1 the group is
R 4 The radical is
Wherein R is 5 Is a hydrogen atom, -XR 7 (V); wherein X is
R 7 Is an unsubstituted or substituted aromatic condensed ring, wherein the substituent is mono-substituted or poly-substituted and is C 1 ～C 5 A straight chain alkyl group;
or R 7 The group being-WR 9 (VII) wherein W is C 1 ～C 4 Straight-chain alkylene radical, R 9 Is a substituted aromatic monocyclic ring, wherein the substituent is mono-substituted or multi-substituted, is a straight chain, branched chain or cyclic alkyl, and is halogen;
R 6 the substitution position is positioned at 2-position or 3-position and is hydrogen atom, hydroxyl, amino, halogen,
or R 6 The radical being-UR 10 (VIII) wherein U is O, N, S, R 10 Is an aromatic monocyclic ring;
R 2 the radical being-ZYR 11 (IX) wherein Z is N, O, S, Y is C 1 ～C 7 Straight, branched or cyclic alkyl radicals, R 11 Is that
Or Y is-QT- (X), wherein Q is C 1 ～C 4 A linear, branched or cyclic alkyl group, T is an aromatic monocyclic ring;
R 3 the substitution position is 2-position or 3-position, and is hydrogen atom, nitryl, trifluoromethyl, cyano-group, sulfonic group, carboxyl, halogen, hydroxyl and amino.
As a preferred example of the present invention,
R 1 the radical is
R 4 The radical is
Wherein R is 5 Is a hydrogen atom, -XR 7 (V); wherein X is
R 7 The group being-WR 9 (VII) wherein W is C 1 ～C 4 Straight-chain alkylene radical, R 9 Is a substituted aromatic monocyclic ring, wherein the substituent is monosubstituted, being a linear alkyl radical;
R 6 the substitution position is at the 2-position or 3-position, and is a hydrogen atom,
or R 6 The radical being-UR 10 (VIII) wherein U is O, N, S, R 10 Is an aromatic monocyclic ring;
R 2 the radical being-ZYR 11 (IX) wherein Z is N, O, S, Y is C 1 ～C 7 Straight-chain alkyl radical, R 11 Is that
Or Y is-QT- (X), wherein Q is C 1 ～C 4 A straight chain alkyl group, T is an aromatic monocyclic ring;
R 3 the substitution position is positioned at 2 position or 3 position and is hydrogen atom or nitryl.
As a preferred example of the present invention,
R 1 the radical is
R 4 The radical is
Wherein R is 5 Is a hydrogen atom, -XR 7 (V); wherein X is
R 7 The radical is-WR 9 (VII) wherein W is C 1 ～C 4 Linear alkenyl, R 9 Is a substituted aromatic monocyclic ring, wherein the substituent is monosubstituted, being a linear alkyl radical;
R 6 the substitution position is at the 2-or 3-position, a hydrogen atom,
or R 6 The radical being-UR 10 (VIII) wherein U is O, R 10 Is an aromatic monocyclic ring;
R 2 the radical being-ZYR 11 (IX) wherein Z is N and Y is C 1 ～C 7 Straight-chain alkyl radical, R 11 Is that
Or Y is-QT- (X), wherein Q is C 1 ～C 4 A straight chain alkyl group, T is an aromatic monocyclic ring;
R 3 the substitution position is positioned at 2 position or 3 position and is hydrogen atom or nitryl.
As a preferred example of the present invention,
R 1 the radical is
R 4 The radical is
Wherein R is 5 Is a hydrogen atom, and is a hydrogen atom,
R 6 the substitution position is positioned at 2-position or 3-position and is hydrogen atom, hydroxyl, amino, halogen,
or R 6 The radical being-UR 10 (VIII) wherein U is O, N, S, R 10 Is an aromatic monocyclic ring;
R 2 the radical being-ZYR 11 (IX) wherein Z is N, O, S, Y is C 1 ～C 7 Straight chain alkyl radical, R 11 Is that
Or Y is-QT- (X), wherein Q is C 1 ～C 4 A straight chain alkyl group, T is an aromatic monocyclic ring;
R 3 the substitution position is positioned at 2-position or 3-position and is nitro.
As a preferred example of the present invention,
R 1 the radical is
R 4 The radical is
Wherein R is 5 Is a hydrogen atom, and is a hydrogen atom,
R 6 the substitution position is at the 2-position or 3-position, and is a hydrogen atom,
or R 6 The radical being-UR 10 (VIII) wherein U is O, R 10 Is an aromatic monocyclic ring;
R 2 the radical being-ZYR 11 (IX) wherein Z is N and Y is C 1 ～C 7 Straight chain alkyl radical, R 11 Is that
Or Y is-QT- (X), wherein Q is C 1 ～C 4 A straight chain alkyl group, T is an aromatic monocyclic ring;
R 3 the substitution position is positioned at 2-position or 3-position and is nitro.
As a preferred example of the present invention,
R 1 the radical is
R 4 The radical is
Wherein R is 5 is-XR 7 (V); wherein X is
R 7 Is an unsubstituted or substituted aromatic condensed ring, wherein the substituent is mono-substituted or poly-substituted and is C 1 ～C 5 A straight chain alkyl group;
R 6 the substitution position is positioned at 2-position or 3-position and is hydrogen atom, hydroxyl, amino, halogen,
R 2 the radical being-ZYR 11 (IX) wherein Z is N, O, S, Y is C 1 ～C 7 Straight, branched or cyclic alkyl radicals, R 11 Is that
R 3 The substitution position is positioned at 2 position or 3 position and is hydrogen atom or nitryl.
As a preferred example of the present invention,
R 1 the radical is
R 4 The radical is
Wherein R is 5 is-XR 7 (V); wherein X is
R 7 Is an unsubstituted or substituted aromatic condensed ring, wherein the substituent is mono-substituted or poly-substituted and is C 1 ～C 5 A straight chain alkyl group;
R 6 the substitution position is at the 2-position or 3-position, and is a hydrogen atom,
R 2 the radical being-ZYR 11 (IX) wherein Z is N and Y is C 1 ～C 7 Straight chain alkyl radical, R 11 Is that
R 3 The substitution position is positioned at 2 position or 3 position and is hydrogen atom or nitryl.
In a preferred embodiment of the present invention, the substituted benzenesulfonyl compound is selected from the group consisting of:
1) n-hydroxy-2- (2-nitro-4-aminosulfonylphenylamino) acetamides
2) N-hydroxy-3- (2-nitro-4-aminosulfonylphenylamino) propanamide
3) N-hydroxy-4- (2-nitro-4-aminosulfonylphenylamino) butanamide
4) N-hydroxy-5- (2-nitro-4-aminosulfonylphenylamino) pentanamide
5) N-hydroxy-6- (2-nitro-4-aminosulfonylphenylamino) hexanamide
6) N-hydroxy-7- (2-nitro-4-aminosulfonylphenylamino) heptanamide
7) N-hydroxy-8- (2-nitro-4-aminosulfonylphenylamino) octanoyl amides
8) N-hydroxy-4- ((2-nitro-4-aminosulfonylphenylamino) methyl) benzamide
9) N- (4- (hydroxycarbamoyl) benzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
10) N- (4- (2- (hydroxyamino) -2-oxoethylamino) -3-nitrobenzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
11) N- (4- (3- (hydroxyamino) -3-oxopropanylamino) -3-nitrobenzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
12) N- (4- (4- (hydroxyamino) -4-oxobutylamino) -3-nitrobenzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
13) N- (4- (5- (hydroxyamino) -5-oxopentylamino) -3-nitrobenzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
14) N- (4- (6- (hydroxyamino) -6-oxohexylamino) -3-nitrobenzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
15) N- (4- (7- (hydroxyamino) -7-oxoheptylamino) -3-nitrobenzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
16) N- (4- (8- (hydroxyamino) -8-oxooctylamino) -3-nitrobenzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
17) N- (4- (8- (hydroxyamino) -8-oxooctylamino) benzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
18) N- (4- ((4-hydroxycarbamoyl) benzylamino) -3-nitrobenzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
19) N- (4- (8- (hydroxyamino) -8-oxooctylamino) -3-nitrobenzenesulfonyl) -4- (3- (2-methylphenyl) acryloylamino) benzamide
20) N- (4- (6- (hydroxyamino) -6-oxohexylamino) -3-nitrobenzenesulfonyl) -2-phenoxybenzamide
21) N- (4- (7- (hydroxyamino) -7-oxoheptylamino) -3-nitrobenzenesulfonyl) -2-phenoxybenzamide
22) N- (4- (8- (hydroxyamino) -8-oxooctylamino) -3-nitrobenzenesulfonyl) -2-phenoxybenzamide
23) N- (4- ((4-hydroxycarbamoyl) benzylamino) -3-nitrobenzenesulfonyl) -2-phenoxybenzamide
24)2- (4-chlorophenoxy) -N- (4- (6- (hydroxyamino) -6-oxohexylamino) -3-nitrobenzenesulfonyl) benzamide
25)2- (4-chlorophenoxy) -N- (4- (4- (hydroxycarbamoyl) benzylamino) -3-nitrobenzenesulfonyl) benzamide
26) N- (4- (8- (hydroxyamino) -8-oxooctylamino) -3-nitrobenzenesulfonyl) benzamide
27) N- (4- (8- (hydroxyamino) -8-oxooctylamino) -3-nitrobenzenesulfonyl) -4- (1- (3,5,5,8, 8-pentamethyl-5, 6,7, 8-tetrahydronaphthalen-2-yl) ethenyl) benzamide
28) N- (4- (8- (hydroxyamino) -8-oxooctylamino) benzenesulfonyl) -4- (1- (3,5,5,8, 8-pentamethyl-5, 6,7, 8-tetrahydronaphthalen-2-yl) vinyl) benzamide
In a second aspect of the present invention, there is provided a crystalline form, a pharmaceutically acceptable salt of an inorganic acid or an organic acid, a hydrate, a solvate, or a prodrug of the substituted phenylsulfonyl compound.
In a third aspect of the present invention, a pharmaceutical composition is provided, where the pharmaceutical composition contains a pharmaceutically acceptable excipient or carrier, and the substituted phenylsulfonyl compound or a crystal form, a pharmaceutically acceptable inorganic acid salt or organic acid salt, a hydrate, a solvate, or a prodrug of the substituted phenylsulfonyl compound.
As a specific embodiment of the present invention, the pharmaceutical composition further comprises other pharmaceutically active ingredients.
As a preferred example of the invention, the other pharmaceutical active ingredient is bortezomib.
More preferably, the molar ratio of the substituted phenylsulfonyl compound to bortezomib in the pharmaceutical composition is 187.5-3000.
In the fourth aspect of the present invention, the substituted phenylsulfonyl compound, or the crystal form, the pharmaceutically acceptable inorganic acid salt or organic acid salt, the hydrate, the solvate or the prodrug of the substituted phenylsulfonyl compound is provided for use in preparing a medicament for treating a disease or a symptom associated with histone acetyltransferase (HDAC) activity.
In one embodiment of the present invention, the histone acetylase is histone acetylase 6(HDAC 6).
In the fourth aspect of the invention, the substituted benzenesulfonyl compounds, or the crystal forms, pharmaceutically acceptable inorganic acid salts or organic acid salts, hydrates, solvates or prodrugs of the substituted benzenesulfonyl compounds are provided for use in preparing antitumor agents and synergists.
In one embodiment of the present invention, the tumor is selected from myeloma, leukemia, ovarian cancer, breast cancer, melanoma or lung cancer. But is not limited thereto.
In a fifth aspect of the present invention, there is provided a method for preparing the substituted phenylsulfonyl-based compound, comprising the steps of: under the alkaline condition, carboxylic ester compounds with different substituted benzenesulfonyl groups react with hydroxylamine to generate hydroxamic acid compounds with different substituted benzenesulfonyl groups.
As used herein, "prodrug" refers to an agent that is converted in vivo to the proto-drug. Prodrugs are often useful because, in some cases, they may be easier to administer than the proto-drug. Prodrugs are generally precursors to drugs which, following administration and absorption, are converted to the active species or, by some process, are converted to more active species, such as by metabolic pathways. Some prodrugs have chemical groups that make them less active and/or less soluble than the proto-drug or some other property. Once the chemical groups of the prodrug are removed and/or modified, the active drug is obtained.
The pharmaceutically acceptable inorganic acid salt can be selected from hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate, and the pharmaceutically acceptable organic acid salt can be selected from acetate, maleate, fumarate, tartrate, succinate, lactate, p-toluenesulfonate, salicylate and oxalate.
The pharmaceutical composition can be in solid form or liquid form, and can be in the dosage forms of tablets, dispersible tablets, buccal tablets, orally disintegrating tablets, sustained release tablets, capsules, soft capsules, dripping pills, granules, injections, powder injections or aerosols and the like. When the compounds of the present invention are used for the above-mentioned purpose, they may be mixed with one or more pharmaceutically acceptable carriers or excipients, such as solvents, diluents, etc., and may be orally administered in the form of: tablets, pills, capsules, dispersible powders, granules or suspensions (containing, for example, from about 0.05 to 5% suspending agent), syrups (containing, for example, from about 10 to 50% sugar), and elixirs (containing, for example, from about 20 to 50% ethanol), or by external administration: ointments, gels, medicated plasters, etc., or parenterally in the form of sterile injectable solutions or suspensions (containing about 0.05-5% suspending agent in an isotonic medium). For example, these pharmaceutical preparations may contain from about 0.01% to about 99%, more preferably from about 0.1% to about 90%, by weight of the active ingredient in admixture with a carrier. Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, auditory, nasal, and topical administration.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant that the components of the composition are capable of being blended with the compounds of the present invention and with each other without significantly diminishing the efficacy of the compounds. Examples of the pharmaceutically acceptable carrier moiety are sugars (e.g., glucose, sucrose, lactose, etc.), starches (e.g., corn starch, potato starch, etc.), celluloses and derivatives thereof (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., sodium stearate, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., tweens), wetting agents (e.g., sodium dodecylsulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
The synergist is a medicine which enhances the activity of a certain medicine by a specific mechanism when the synergist is compatible with the medicine for use, and plays a synergistic effect. As a potentiator, the agent may be administered in combination with other agents, where "co-administration" means administration of several selected therapeutic agents to a patient, either in the same or different modes of administration, at the same or different times. The term "synergistic", "synergism" or "potentiation", as used herein, refers to the effect on an agent that inhibits HDAC or an anti-tumor agent when the agent is present in combination with another agent to enhance the effect of the agent on inhibiting HDAC or the anti-tumor agent.
The invention has the advantages that:
1. the substituted benzenesulfonyl compound disclosed by the invention shows high inhibiting activity on HDAC (high-order fatty acid), and particularly, part of the compound shows good selective inhibiting activity on HDAC 6. Therefore, the compounds have potential application in preparing therapeutic drugs for diseases related to HDAC, particularly HDAC6 activity, preparing antitumor drugs, and preparing synergists for treating tumors by combining with other antitumor drugs or radiotherapy.
2. The substituted benzenesulfonyl compound shows broad-spectrum antitumor activity on human blood tumors (myeloma and leukemia) and solid tumors (ovarian cancer, breast cancer, melanoma and lung cancer). And the composition shows better synergistic effect when being used together with the existing medicaments. Therefore, the compound of the invention is expected to have good development prospect.
It is to be understood that within the scope of the present invention, each of the above-described features of the present invention and each of the features described in detail below (e.g., in the examples) may be combined with each other to form new or preferred embodiments, i.e., each of the substituent groups of the present invention may be combined with each other to form new specific compounds which are part of the present invention.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
Example 1
Preparation of N-hydroxy-8- (2-nitro-4-aminosulfonylphenylamino) octanoamide (compound 7 in Table 1):
1. preparation of ethyl 8- (2-nitro-4-sulfonylamino-phenylamino) -octanoate
0.5g (2.27mmol) of 4-fluoro-3-nitrobenzenesulfonamide was dissolved in 20ml of DMSO, 0.636g (3.4mmol) of ethyl 8-aminocaprylate was added thereto dropwise, 15 drops of DIEA were added dropwise, and after stirring and reacting for 8 hours at 80 ℃ with heating, the solution was poured into ice water and filtered to obtain a yellow solid with a yield of 90%.
2. Preparation of N-hydroxy-8- (2-nitro-4-aminosulfonylphenylamino) octanoyl amide
386mg (1mmol) of ethyl 8- (2-nitro-4-sulfonylaminophenylamino) octanoate is dissolved in 10ml of the 1.12mol/L hydroxylamine hydrochloride methanol solution which is prepared in the prior art and is dissociated by potassium hydroxide, after stirring for 12h at room temperature, the pH is adjusted by diluted acid, the crude product is obtained by filtration, and the crude product is obtained by column chromatography, and the yield is 70 percent.
Examples 2 to 8
Example 1 was repeated, with the difference that: different starting materials were used to prepare compounds 1-6 and 8 in Table 1. The method comprises the following specific steps: compounds 1 to 6 and 8 were prepared, respectively, using ethyl glycinate, ethyl 3-aminopropionate, ethyl 4-aminobutyrate, ethyl 5-aminopentanoate, ethyl 6-aminocaproate, ethyl 7-aminoheptanoate and ethyl 4-aminomethylbenzoate instead of the ethyl 8-aminocaprylate used as the starting material in example 1.
Example 9
Preparation of N- (4- (hydroxycarbamoyl) benzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide (compound 9 in Table 1):
1. preparation of ethyl N- ((2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzoyl) sulfamoyl) benzoate
Ethyl 4-aminosulfonylbenzoate 500mg (2.1mmol), 2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzoic acid 815mg (2.1mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI)2.034g (10.5mmol), 4-dimethylaminopyridine 260.4mg (2.1mmol) were reacted at room temperature for 24 hours in the presence of anhydrous DCM as a solvent, followed by washing with 1M hydrochloric acid, saturated sodium bicarbonate, saturated brine and concentrating the organic phase to obtain a solid 0.429g, in a yield of 72.1%.
2. Preparation of N- (4- (hydroxycarbamoyl) benzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
292mg (0.5mmol) of ethyl N- ((2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzoyl) sulfamoyl) benzoate was dissolved in 6ml of a 1.12mol/L hydroxylamine hydrochloride methanol solution free from potassium hydroxide prepared in the prior art, stirred at room temperature for 12 hours, adjusted in pH with a dilute acid, filtered to obtain a crude product, and subjected to column chromatography to obtain a yellow solid with a yield of 70%.
Example 10
Preparation of N- (4- (8- (hydroxyamino) -8-oxooctylamino) -3-nitrobenzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide (compound 16 in Table 1):
1. 8- (2-Nitro-4- (N- (2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzoyl) sulfonylamino) phenylamino) octanoic acid ethyl ester
500mg (1.30mmol) of ethyl 8- (2-nitro-4-sulfonylaminophenylamino) octanoate, 485mg (1.30mmol) of 2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzoic acid, 1.25g (6.5mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), 160mg (0.4mmol) of 4-dimethylaminopyridine were reacted at room temperature for 24 hours in the presence of anhydrous DCM as a solvent, and then washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated common salt in this order, and the organic phase was concentrated to give a solid in a yield of 60%.
2. Preparation of N- (4- (8- (hydroxyamino) -8-oxooctylamino) -3-nitrobenzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
300mg (0.4mmol) of ethyl 8- (2-nitro-4- (N- (2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzoyl) sulfonamido) phenylamino) octanoate is dissolved in 8ml of 1.12mol/L potassium hydroxide-free hydroxylamine hydrochloride methanol solution prepared in situ, stirred for 12h at room temperature, then the pH is adjusted with dilute acid, the crude product is obtained by filtration and column chromatography to obtain a yellow solid with a yield of 70%.
Examples 11 to 28
Example 10 was repeated, except that: different starting materials were used to prepare compounds 10-15 and 17-28 in Table 1. The method comprises the following specific steps: ethyl 2- (2-nitro-4-aminosulfonylphenylamino) acetate, ethyl 3- (2-nitro-4-aminosulfonylphenylamino) propionate, ethyl 4- (2-nitro-4-aminosulfonylphenylamino) butyrate, ethyl 5- (2-nitro-4-aminosulfonylphenylamino) pentanoate, ethyl 6- (2-nitro-4-aminosulfonylphenylamino) hexanoate, ethyl 7- (2-nitro-4-aminosulfonylphenylamino) heptanoate, ethyl 8- (4-aminosulfonylphenylamino) octanoate and ethyl 4- ((2-nitro-4-aminosulfonylphenylamino) methyl) benzoate were used instead of the starting material ethyl 8- (2-nitro-4-aminosulfonylphenylamino) benzoate in example 10 Phenylsulfonyl phenylamino) ethyl octanoate to produce compounds 10-15 and 17-18, respectively; using 4- (3- (2-methylphenyl) acryloylamino) benzoic acid, 2-phenoxybenzoic acid, benzoic acid and 4- (1- (3,5,5,8, 8-pentamethyl-5, 6,7, 8-tetrahydronaphthalen-2-yl) vinyl) benzoic acid instead of the starting material 2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzoic acid in example 10, compounds 19, 22, 26 and 27 were respectively prepared; compounds 20 to 21 and 23 were prepared, respectively, using 2-phenoxybenzoic acid instead of the starting material 2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzoic acid in example 10 and ethyl 6- (2-nitro-4-aminosulfonylphenylamino) hexanoate, ethyl 7- (2-nitro-4-aminosulfonylphenylamino) heptanoate and ethyl 4- ((2-nitro-4-aminosulfonylphenylamino) methyl) benzoate instead of the starting material ethyl 8- (2-nitro-4-aminosulfonylphenylamino) octanoate; compounds 24 and 25 were prepared using 2- (4-chlorophenyl) oxybenzoic acid instead of the raw material 2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzoic acid in example 10, and ethyl 6- (2-nitro-4-aminosulfonylphenylamino) hexanoate and ethyl 4- ((2-nitro-4-aminosulfonylphenylamino) methyl) benzoate instead of the raw material ethyl 8- (2-nitro-4-aminosulfonylphenylamino) octanoate; compound 28 was obtained by using 4- (1- (3,5,5,8, 8-pentamethyl-5, 6,7, 8-tetrahydronaphthalen-2-yl) vinyl) benzoic acid in place of the starting material 2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzoic acid in example 10, and ethyl 8- (4-aminosulfonylphenylamino) octanoate in place of the starting material ethyl 8- (2-nitro-4-aminosulfonylphenylamino) octanoate.
The chemical structures of the target products in the general formula (I) synthesized by the invention are shown in tables 1-1, tables 1-2 and tables 1-3. The nuclear magnetic hydrogen spectrum and the mass spectrum system characterize the chemical structure of the target product, and specific data thereof are shown in Table 2.
TABLE 1-1 structures of target compounds in general formula (I)
TABLE 1-2 structures of target compounds in general formula (I)
Tables 1-3 structures of target compounds of general formula (I)
TABLE 2 Hydrogen and Mass Spectroscopy data for the target Compounds of formula (I)
Example 29HDAC inhibitory Activity assay
The inhibition of the HDAC family by the target compound was examined by fluorescence, which is based on the principle that HDAC catalyzes deacetylation of a substrate containing an acetylated side chain, and trypsin hydrolyzes the deacetylated substrate to form a fluorescent hydrolysate. Fluorescence signals (excitation wavelength 355nm, emission wavelength 460nm) were detected after incubation for a period of time at room temperature by mixing a range of concentrations of the target compound with a buffer containing substrate and trypsin, and a formulated HDAC solution. The change of fluorescence absorbance can reflect the inhibition of HDAC, and the inhibition IC of the compound can be calculated by using the change of the fluorescence absorbance 50 The value is obtained. Positive control drugs were Rocilinostat and SAHA. The results are shown in Table 3.
TABLE 3 HDAC inhibitory Activity of target Compounds
The results show that the substituted benzenesulfonyl compound of the invention shows better inhibitory activity with HDAC, particularly part of the compound shows good selective inhibitory activity on HDAC6, and the selectivity on HDAC6 is even better than Rocilinostat in clinical tests (the selectivity index is 7.7). Therefore, the compounds have potential application in preparing therapeutic drugs for diseases related to HDAC, particularly HDAC6 activity, preparing antitumor drugs, and preparing synergists for treating tumors by combining with other antitumor drugs or radiotherapy.
Example 30 in vitro antitumor Activity assay
1. Experimental tumor strains
The tumor cell lines used in this experiment were: RPMI-8226 (human myeloma cell), HL-60 (human leukemia cell), U266 (human myeloma cell), SKOV3 (human ovarian cancer cell), MCF-7 (human breast cancer cell), A375 (human melanoma cell), and NCI-H23 (human lung cancer cell) (purchased from Shanghai pharmaceutical industry, Inc.).
2. Sample preparation
After dissolution in DMSO (Merck), PBS (-) was added to make a 1000. mu.g/mL solution or a homogeneous suspension, which was then diluted with DMSO-containing PBS (-). The positive control drugs were Rocilinostat, ABT-737 developed by Yapei corporation, and 4-benzamid-N- (3-nitro-4- (2- (phenylthio) ethyl) phenylsulfonyl) benzamid (control 1). 3. Test method
MTT method was used according to experimental tests and related literature (Bioorg Med Chem Lett 2012,22, 39-44; Nature.2005,437, 677-681). The adding concentration of each hole of the 96-hole plate is 4-5 multiplied by 10 4 Cell suspension 100. mu.L/mL, at 37 ℃ in 5% CO 2 In the incubator. After 24h, the sample solution was added at 10. mu.L/well in duplicate wells at 37 ℃ with 5% CO 2 The reaction is carried out for 72 hours. Adding 20 mu L of MTT solution of 5mg/mL into each hole, adding a dissolving solution after reacting for 4h, placing the solution into each hole of 100 mu L, placing the solution into an incubator, and measuring the OD value of 570nm by using an MK-2 full-automatic enzyme standard instrument after dissolving. The test results are shown in Table 4.
TABLE 4 inhibition of in vitro proliferation of human tumor cells by partial target compounds of general formula (I)
As can be seen from Table 4, the substituted benzenesulfonyl compounds of the present invention show broad-spectrum antitumor activities against human hematological tumors and solid tumors, and the compounds not listed also show good broad-spectrum antitumor activities, indicating that the compounds of the present invention are expected to have good development prospects.
Example 31 synergistic Activity test for existing antitumor drugs
And (3) investigating the synergistic activity of the target compound on the existing anti-tumor medicine on the multiple myeloma cells sensitive or resistant to the existing therapeutic medicine. The growth inhibition activity of the target compound on the tumor cells is carried out by adopting an MTT method. The multiple myeloma cell strain adopts H929 cells. Bortezomib-resistant H929R cells were obtained by continuous culture in media with increasing bortezomib concentrations (initially 0.5nM, increasing in a gradient of 0.2nM, and finally increasing to 15 nM). Tumor cells were divided into 96-well plates, different concentrations of the compound or combination of interest were added, and cultured with serum-containing medium for 72 hours. Thereafter, MTT was added, and after incubation at 37 ℃ for 4 hours, the absorbance of the solution was measured by a microplate reader, and the inhibition of cell proliferation was evaluated by comparison with a blank control. Based on the inhibition rate of the target compound and bortezomib on tumor cells when the target compound and bortezomib are used independently under different concentrations and the inhibition rate of the target compound and bortezomib on tumor cells when the target compound and bortezomib are used jointly, a Combination Index (CI) of the target compound and bortezomib is calculated by adopting Calcusyn 2.1, and the CI is less than 0.9, so that the synergistic effect is achieved. The test results are shown in Table 5.
TABLE 5 synergistic Activity of some target Compounds of general formula (I) on Bortezomib on drug-resistant and non-drug-resistant H929 cells
As can be seen from Table 5, the substituted benzenesulfonyl compounds of the present invention, whether on non-drug-resistant cells or drug-resistant cells, have synergistic effects on existing anti-tumor drugs, and have very significant synergistic effects at various concentration ratios (e.g., the concentration ratios of compound 16 to bortezomib in Table 1 are 60. mu.M: 80nM, 60. mu.M: 160nM, 120. mu.M: 40nM, 120. mu.M: 80nM, and 120. mu.M: 160nM), and the compounds not listed show significant synergistic effects, indicating that the compounds of the present invention are expected to have good development prospects.
Example 32 inhibition of Normal cell proliferation assay
Normal cell lines WI-38 (human diploid fibroblasts) and HEK-293 (human embryonic kidney epithelial cells) were used in this experiment. The positive control drugs were ACY-1215, SAHA and Panobinostat. Examination of proliferation inhibitory Activity of target Compound on Normal cells MT is usedThe T method is carried out, and the adding concentration of each hole of a 96-hole plate is 4-5 multiplied by 10 4 Cell suspension 100. mu.L/mL, at 37 ℃ in 5% CO 2 In the incubator. After 24h, the sample solution was added at 10. mu.L/well in duplicate wells at 37 ℃ with 5% CO 2 The reaction is carried out for 72 hours. Adding 20 mu L of MTT solution of 5mg/mL into each hole, adding a dissolving solution after reacting for 4h, placing the solution into each hole of 100 mu L, placing the solution into an incubator, and measuring the OD value of 570nm by using an MK-2 full-automatic enzyme standard instrument after dissolving. The test results are shown in Table 6.
TABLE 6 inhibition of proliferation of normal cells by a portion of the target compounds of general formula (I)
As can be seen from table 6, the substituted benzenesulfonyl compounds of the present invention have a smaller effect on inhibiting the proliferation of normal cells than the positive control drugs, and the compounds not shown also show such an advantage, indicating that the compounds of the present invention are expected to have a good development prospect.
Claims (7)
1. A substituted phenylsulfonyl compound is characterized by having a structural general formula shown as a formula (I):
wherein:
R 1 the radicals are amino, hydroxyl,
R 2 the radical being-ZYR 11 (IX) wherein Z is N, O, S, Y is a C1-C7 linear alkylene group, R 11 Is that
Or Y is-QT- (X) wherein Q is a C1-C4 linear alkylene radical and T is an aromatic monocyclic ring,
R 3 the substitution position is positioned at 2-position or 3-position and is nitro;
or alternatively
R 1 The radical is
R 4 The radical is
Wherein R is 5 is-XR 7 (V); wherein X is
R 7 The group being-WR 9 (VII) in which W is a C1-C4 linear alkenylene group, R 9 Is a substituted aromatic monocyclic ring, wherein the substituent is mono-substituted or multi-substituted, is a straight chain, branched chain or cyclic alkyl, and is halogen;
R 6 the substitution position being in the 2-or 3-position, R 6 The radical being-UR 10 (VIII) wherein U is O, R 10 Is an aromatic monocyclic ring;
R 2 the radical is
R 3 The substitution position is at the 2-position or the 3-position and is a hydrogen atom;
or
R 1 The radical is
R 4 The radical is
Wherein R is 5 Is a hydrogen atom, -XR 7 (V); wherein X is
R 7 The group being-WR 9 (VII) in which W is a C1-C4 linear alkenylene group, R 9 Is a substituted aromatic monocyclic ring, wherein the substituent is monosubstituted, being a linear alkyl radical;
R 6 the substitution position is at the 2-position or 3-position, and is a hydrogen atom,
or R 6 The radical being-UR 10 (VIII) wherein U is O, R 10 Is an aromatic monocyclic ring;
R 2 the radical being-ZYR 11 (IX) wherein Z is N, Y is a C1-C7 linear alkylene radical, R 11 Is that
Or Y is-QT- (X) wherein Q is a C1-C4 linear alkylene radical and T is an aromatic monocyclic ring;
R 3 the substitution position is positioned at 2 or 3 position and is hydrogen atom or nitryl;
or
R 1 The radical is
R 4 The radical is
Wherein R is 5 is-XR 7 (V); wherein X is
R 7 Is an unsubstituted or substituted aromatic condensed ring, wherein the substituent is mono-substituted or poly-substituted and is C 1 ～C 5 A straight chain alkyl group;
R 6 the substitution position is at the 2-position or 3-position, and is a hydrogen atom,
R 2 the radical being-ZYR 11 (IX) wherein Z is N, Y is a C1-C7 linear alkylene radical, R 11 Is that
R 3 Substitution positionAt the 2-position or the 3-position, is a hydrogen atom or a nitro group.
2. A substituted benzenesulfonyl compound is characterized in that the substituted benzenesulfonyl compound is selected from the following compounds:
1) n-hydroxy-2- (2-nitro-4-aminosulfonylphenylamino) acetamides
2) N-hydroxy-3- (2-nitro-4-aminosulfonylphenylamino) propanamide
3) N-hydroxy-4- (2-nitro-4-aminosulfonylphenylamino) butanamide
4) N-hydroxy-5- (2-nitro-4-aminosulfonylphenylamino) pentanamide
5) N-hydroxy-6- (2-nitro-4-aminosulfonylphenylamino) hexanamide
6) N-hydroxy-7- (2-nitro-4-aminosulfonylphenylamino) heptanamide
7) N-hydroxy-8- (2-nitro-4-aminosulfonylphenylamino) octanoyl amides
8) N-hydroxy-4- ((2-nitro-4-aminosulfonylphenylamino) methyl) benzamide
9) N- (4- (hydroxycarbamoyl) benzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
10) N- (4- (2- (hydroxyamino) -2-oxoethylamino) -3-nitrobenzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
11) N- (4- (3- (hydroxyamino) -3-oxopropanylamino) -3-nitrobenzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
12) N- (4- (4- (hydroxyamino) -4-oxobutylamino) -3-nitrobenzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
13) N- (4- (5- (hydroxyamino) -5-oxopentylamino) -3-nitrobenzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
14) N- (4- (6- (hydroxyamino) -6-oxohexylamino) -3-nitrobenzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
15) N- (4- (7- (hydroxyamino) -7-oxoheptylamino) -3-nitrobenzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
16) N- (4- (8- (hydroxyamino) -8-oxooctylamino) -3-nitrobenzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
17) N- (4- (8- (hydroxyamino) -8-oxooctylamino) benzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
18) N- (4- ((4-hydroxycarbamoyl) benzylamino) -3-nitrobenzenesulfonyl) -2-phenoxy-4- (3- (2-methylphenyl) acryloylamino) benzamide
19) N- (4- (8- (hydroxyamino) -8-oxooctylamino) -3-nitrobenzenesulfonyl) -4- (3- (2-methylphenyl) acryloylamino) benzamide
20) N- (4- (6- (hydroxyamino) -6-oxohexylamino) -3-nitrobenzenesulfonyl) -2-phenoxybenzamide
21) N- (4- (7- (hydroxyamino) -7-oxoheptylamino) -3-nitrobenzenesulfonyl) -2-phenoxybenzamide
22) N- (4- (8- (hydroxyamino) -8-oxooctylamino) -3-nitrobenzenesulfonyl) -2-phenoxybenzamide
23) N- (4- ((4-hydroxycarbamoyl) benzylamino) -3-nitrobenzenesulfonyl) -2-phenoxybenzamide
24)2- (4-chlorophenoxy) -N- (4- (6- (hydroxyamino) -6-oxohexylamino) -3-nitrobenzenesulfonyl) benzamide
25)2- (4-chlorophenoxy) -N- (4- (4- (hydroxycarbamoyl) benzylamino) -3-nitrobenzenesulfonyl) benzamide
26) N- (4- (8- (hydroxyamino) -8-oxooctylamino) -3-nitrobenzenesulfonyl) benzamide
27) N- (4- (8- (hydroxyamino) -8-oxooctylamino) -3-nitrobenzenesulfonyl) -4- (1- (3,5,5,8, 8-pentamethyl-5, 6,7, 8-tetrahydronaphthalen-2-yl) ethenyl) benzamide
28) N- (4- (8- (hydroxyamino) -8-oxooctylamino) benzenesulfonyl) -4- (1- (3,5,5,8, 8-pentamethyl-5, 6,7, 8-tetrahydronaphthalen-2-yl) vinyl) benzamide.
3. A pharmaceutically acceptable salt of an inorganic acid or an organic acid of the substituted phenylsulfonyl-based compound according to claim 1 or 2.
4. A pharmaceutical composition, comprising a pharmaceutically acceptable excipient or carrier, and a pharmaceutically acceptable salt of an inorganic acid or an organic acid of the substituted phenylsulfonyl compound of claim 1 or 2 or the substituted phenylsulfonyl compound of claim 3.
5. Use of a substituted phenylsulfonyl-based compound according to claim 1 or 2, or a pharmaceutically acceptable salt of an inorganic or organic acid of a substituted phenylsulfonyl-based compound according to claim 3, for the preparation of a medicament for:
a) treating a disease or condition associated with histone acetylase activity;
c) anti-tumor; or
d) Can be used as antitumor synergist.
6. The use according to claim 5, wherein the neoplasm is myeloma, leukemia, ovarian cancer, breast cancer, melanoma or lung cancer.
7. Use of the substituted phenylsulfonyl-based compound of claim 1 or 2, or the pharmaceutically acceptable inorganic or organic acid salt of the substituted phenylsulfonyl-based compound of claim 3 for the preparation of a medicament for:
b) treating a disease or condition associated with histone acetylase 6 activity.
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| CN107033043A (en) * | 2016-02-04 | 2017-08-11 | 中国人民解放军第二军医大学 | N- replaces benzenesulfonyl-substituted benzene formyl amine compound and its prepares the purposes of medicine |
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