CN107698464A - His analogue of Baily department with histon deacetylase (HDAC) inhibitory action and its application - Google Patents
His analogue of Baily department with histon deacetylase (HDAC) inhibitory action and its application Download PDFInfo
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- CN107698464A CN107698464A CN201710947655.3A CN201710947655A CN107698464A CN 107698464 A CN107698464 A CN 107698464A CN 201710947655 A CN201710947655 A CN 201710947655A CN 107698464 A CN107698464 A CN 107698464A
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- hydroxylaminos
- oxo
- acrylic
- benzamide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/36—Nitrogen atoms
Abstract
The present invention relates to his analogue of a kind of Baily department with histon deacetylase (HDAC) inhibitory action, its active ingredient at least compound containing the formula, its officinal salt, hydrate, prodrug or the metabolite for being metabolized formation in any form.Described his analogue of Baily department has obvious histon deacetylase (HDAC) inhibitory action and antitumor activity, prompts medicine of such compound with preparation and histon deacetylase (HDAC) relevant disease, prepares antineoplastic and shared with other antineoplastics or radiotherapy to treat the potential use of tumour.
Description
Technical field
The invention belongs to field of medicaments, be specifically a kind of Baily department with histon deacetylase (HDAC) inhibitory activity he
Analogue and its application.
Background technology
Histon deacetylase (HDAC) (histone deacetylase, HDAC) is that one kind can hydrolyze histone or non-
The protease family of acetyl group on histone terminal lysin residue, it can make nuclear chromatin become even closer, so as to suppress
Genetic transcription, i.e., by influenceing various cell functions on histone and nonhistones deacetylation.HDAC mutation and different
The generation of a variety of diseases, especially tumour can be caused by often expressing, and HDAC unconventionality expressions in tumour cell, histone is largely in low
Acetylation status, this makes HDAC become important anti-tumor target.The expression of normal gene can be recovered by suppressing HDAC, so as to
It can block the cell cycle of cancer cell, promote cell differentiation and natural death of cerebral cells.Therefore, the improper deacetylations of HDAC are blocked to make
Histon deacetylase (HDAC) inhibitor (histone deacetylase inhibitors, HDACIs) is as effective anti-
Tumour medicine just arises at the historic moment.
The HDACIs of the listing of U.S. FDA approval at present shares 4 medicines, respectively Vorinostat (vorinostat, 2006
Year), romidepsin (romidepsin, 2009), his (belinostat, 2014) and LBH589 of Baily department
(panobinostat, 2015), clinically for skin T cell lymphoma, lymphoma peripheral T cell or Huppert's disease
Treatment.Chinese FDA was in approval HDACIs chidamides (chidamide) listing in 2014, for treating periphery T cell lymph
Knurl.In addition, there are multiple HDACIs to be in clinical investigation phase at present.
Most of HDACIs structure all meets the Pharmacophore Model of classics, and the model is broadly divided into three parts：
Recognition group with the interaction of enzyme surface, go deep into the zincbinding groups group of enzyme bottom and connect the two parts
Hydrophobicity long-chain.Find by prior art documents, many listings or the HDACIs in clinical research know on surface
Amido link is contained in other area, and only Baily department he in surface cog region contain sulfonamide structure, current technology do not record by
Sulphonyl amine key in his structure of Baily department replaces with amido link to obtain HDACIs content.
The content of the invention
The present invention in view of the deficienciess of the prior art, provide Baily department that a kind of surface cog region contains amido link he
Analogue, it has obvious inhibitory action to HDAC, and part of compounds shows that he and Vorinostat are stronger than Baily department
HDAC inhibitory activity, thus available for the disease relevant with this enzyme treatment.Meanwhile this kind of compound is to breast cancer cell
Also there is preferable inhibitory activity with cervical cancer cell.
The present invention is achieved by the following technical solutions, described his analogue of Baily department, i.e. N- (substitution virtues
Base) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide, there is following structure formula：
R is 2- aminomethyl phenyls in formula, 3- aminomethyl phenyls, 4- aminomethyl phenyls, 2- methoxyphenyls, 3- methoxyphenyls, 4-
Methoxyphenyl, 2- aminophenyls, 4- dimethylamino phenyls, 2- bromophenyls, 3- bromophenyls, 4- bromophenyls, 2- fluorophenyls, 4- chlorine
Phenyl, 2- pyridine radicals, 2- thiazolyls.
Above-mentioned his analog of Baily department of the present invention is using m-bromobenzoic acid as raw material, through carrying out Heck with methyl acrylate
Reaction, methyl acrylate side chain is introduced, then the carboxyl chloro on aromatic ring is obtained into acyl chlorides, reacted with substituted aromatic amines, finally and azanol
React to obtain target compound.15 compounds, the structure of target compound altogether, which have been synthesized, with above method is shown in Table 1.
The structure of his analog of Baily department of table 1 (spectral data is shown in embodiment)
HDAC inhibitory activity test result indicates that, the suppression of nanomole rank is presented to HDAC for all compounds of the present invention
Activity, wherein compound 7d and 7g be better than comparison medicine Baily department he, compound 7b, 7d, 7e, 7g and 7k are better than comparison medicine Fu Linuo
He, experimental result is listed in Table 2 below.
The HDAC inhibitory activity of compound synthesized by the present invention of table 2
| Compound | IC50(nM) | Compound | IC50(nM) |
| 7a | 605 | 7j | 278 |
| 7b | 163 | 7k | 167 |
| 7c | 209 | 7l | 259 |
| 7d | 11.5 | 7m | 250 |
| 7e | 164 | 7n | 204 |
| 7f | 288 | 7o | 417 |
| 7g | 12.5 | Baily department he | 31 |
| 7h | 223 | Vorinostat | 180 |
| 7i | 222 |
Measuring growth of the part of compounds to human cervical carcinoma cell HeLa and human breast cancer cell MDA-MB-231
Inhibitory action, the results showed that, good inhibiting effect, wherein compound 7i are presented to these tumour cells for the compound of test
Effect to cervical cancer cell better than Baily department he, experimental result is listed in Table 3 below.
Inhibitory activity of the preferred compound of table 3 to tumour cell
Result above shows that his analogue of Baily department of the present invention has the treatment prepared with HDAC relevant diseases
Medicine, prepare antineoplastic and shared with other antineoplastics or radiotherapy to treat the potential use of tumour.
Brief description of the drawings
Fig. 1 is the compounds of this invention synthetic line figure.
Embodiment
Embodiments of the invention are elaborated below, these embodiments give detailed embodiment and specific
Operating process, it is only illustrative of the invention and is not intended to limit the scope of the invention.
In Fig. 1, target compound of the present invention is for raw material with m-bromobenzoic acid (1), is passed through with methyl acrylate (2)
Heck reaction synthesis 3- (2- (methoxycarbonyl base) vinyl) benzoic acid (3), then react to obtain 3- (2- (methoxy first with thionyl chloride
Acyl group) vinyl) chlorobenzoyl chloride (4), acyl chlorides (4) reacts to obtain acid amides (6) with substituted aromatic amines (5) again, finally again with azanol reaction
Obtain target compound (7).
Embodiment 1：
The synthesis of 3- (2- (methoxycarbonyl base) vinyl) benzoic acid (3)
M-bromobenzoic acid (3.0g, 15mmol) and methyl acrylate (6.45g, 75mmol) are dissolved in N, N- dimethyl formyls
In amine (50mL), triethylamine (202mg, 2mmol), palladium (67mg, 0.3mmol) and three (o-methyl-phenyl) phosphorus are added
(92mg,0.3mmol).Under nitrogen, reaction solution is warming up to 110 DEG C and reacted 5 hours.Then it is cooled to room temperature, pH is adjusted with watery hydrochloric acid
The solid of precipitation is filtered to 2 or so, 2.15 grams of white solid, yield 70% is obtained with acetone recrystallization by value.1H NMR
(400MHz,DMSO-d6) δ 8.20 (d, J=1.8Hz, 1H), 8.02-7.95 (m, 2H), 7.74 (d, J=16.1Hz, 1H),
7.56 (t, J=7.7Hz, 1H), 6.72 (d, J=16.1Hz, 1H), 3.74 (s, 3H)
Embodiment 2：
The synthesis of 3- (2- (methoxycarbonyl base) vinyl) chlorobenzoyl chloride (4)
3- (2- (methoxycarbonyl base) vinyl) benzoic acid 3 (1.03g, 5mmol) is dissolved in q. s. toluene, adds protochloride
Sulfone (1.1mL, 15mmol) and 1 drop N,N-dimethylformamide.It is sub- that 90 DEG C of reactions remove toluene and excess chlorination under reduced pressure after 1 hour
Sulfone, obtain acyl chlorides 4.Crude product is not purified to be directly used in next step.
Embodiment 3：
Method is led in the synthesis of 3- (3- (substituted aryl) carbamyl) cinnamic acid methyl esters (6)
Substituted aromatic amines 5a-o (5mmol) is dissolved in dichloromethane (20mL), and ice-water bath adds triethylamine after being cooled to 0 DEG C
(7mmol), the dichloromethane solution of compound 4 is then slowly added dropwise.Reaction solution is slowly warmed to room temperature, stirring 1-2 hours to change
Compound 4 disappears (TLC monitorings).After reaction terminates, pH value is adjusted to 2 or so with watery hydrochloric acid.Separate organic layer, dichloromethane extraction water
Layer, merge organic layer, washing, anhydrous magnesium sulfate is dried, and removes solvent under reduced pressure.Column chromatography for separation (petroleum ether：Ethyl acetate=3：
1) compound 6a-o, is obtained.
3- (3- (2- aminomethyl phenyls) carbamyl) cinnamic acid methyl esters (6a)
White solid, yield 35%.1H NMR(400MHz,DMSO-d6) δ 9.97 (s, 1H), 8.34 (d, J=1.7Hz,
1H), 8.02-7.95 (m, 2H), 7.77 (d, J=16.1Hz, 1H), 7.59 (t, J=7.7Hz, 1H), 7.41-7.13 (m, 4H),
6.80 (d, J=16.1Hz, 1H), 3.78 (s, 3H), 2.26 (s, 3H)
3- (3- (3- aminomethyl phenyls) carbamyl) cinnamic acid methyl esters (6b)
White solid, yield 51%.1H NMR(400MHz,DMSO-d6) δ 10.21 (s, 1H), 8.29 (t, J=1.8Hz,
1H), 8.01-7.92 (m, 2H), 7.76 (d, J=16.1Hz, 1H), 7.67-7.50 (m, 3H), 7.25 (t, J=7.8Hz, 1H),
7.04-6.89 (m, 1H), 6.80 (d, J=16.1Hz, 1H), 3.76 (s, 3H), 2.33 (s, 3H)
3- (3- (4- aminomethyl phenyls) carbamyl) cinnamic acid methyl esters (6c)
White solid, yield 50%.1H NMR(400MHz,DMSO-d6) δ 10.20 (s, 1H), 8.28 (t, J=1.8Hz,
1H), 8.00-7.90 (m, 2H), 7.76 (d, J=16.1Hz, 1H), 7.70-7.58 (m, 2H), 7.30 (t, J=7.8Hz, 1H),
7.08-6.93 (m, 2H), 6.80 (d, J=16.1Hz, 1H), 3.78 (s, 3H), 2.35 (s, 3H)
3- (3- (2- methoxyphenyls) carbamyl) cinnamic acid methyl esters (6d)
White solid, yield 55%.1H NMR(400MHz,DMSO-d6) δ 9.58 (s, 1H), 8.34 (d, J=1.8Hz,
1H), 8.04-7.96 (m, 2H), 7.80-7.68 (m, 2H), 7.58 (t, J=7.7Hz, 1H), 7.21 (dd, J=8.3,1.7Hz,
1H), 7.12 (dd, J=8.3,1.3Hz, 1H), 6.99 (td, J=7.6,1.4Hz, 1H), 6.81 (d, J=16.1Hz, 1H),
3.84(s,3H),3.76(s,3H).
3- (3- (3- methoxyphenyls) carbamyl) cinnamic acid methyl esters (6e)
White solid, yield 46%.1H NMR(400MHz,DMSO-d6) δ 10.27 (s, 1H), 8.28 (t, J=1.8Hz,
1H), 8.04-7.96 (m, 2H), 7.77 (d, J=16.1Hz, 1H), 7.59 (t, J=7.7Hz, 1H), 7.48 (t, J=2.2Hz,
1H), 7.38 (dd, J=8.1,1.0Hz, 1H), 7.28 (t, J=8.1Hz, 1H), 6.80 (d, J=16.1Hz, 1H), 6.71
(dd, J=8.2,0.9Hz, 1H), 3.77 (s, 3H), 3.76 (s, 3H)
3- (3- (4- methoxyphenyls) carbamyl) cinnamic acid methyl esters (6f)
White solid, yield 38%.1H NMR(400MHz,DMSO-d6) δ 10.20 (s, 1H), 8.30 (t, J=1.7Hz,
1H), 8.02-7.90 (m, 2H), 7.76 (d, J=16.1Hz, 1H), 7.73-7.64 (m, 2H), 7.58 (t, J=7.7Hz, 1H),
7.00-6.87 (m, 2H), 6.80 (d, J=16.0Hz, 1H), 3.77 (s, 6H)
3- (3- (2- aminophenyls) carbamyl) cinnamic acid methyl esters (6g)
Faint yellow solid, yield 58%.1H NMR(400MHz,DMSO-d6) δ 10.74 (s, 1H), 8.59 (t, J=
1.7Hz, 1H), 8.13 (d, J=8.0Hz, 1H), 7.96 (d, J=7.8Hz, 1H), 7.76 (d, J=16.1Hz, 1H), 7.67-
7.57(m,2H),7.56-7.51(m,1H),7.48-7.32(m,2H),7.04-6.87(m,2H),3.76(s,3H).
3- (3- (4- dimethylamino phenyls) carbamyl) cinnamic acid methyl esters (6h)
White solid, yield 47%.1H NMR(400MHz,DMSO-d6) δ 10.16 (s, 1H), 8.29 (t, J=1.8Hz,
1H), 8.05-7.86 (m, 2H), 7.82-7.50 (m, 4H), 6.95 (s, 2H), 6.79 (d, J=16.1Hz, 1H), 3.77 (s,
3H),2.94(s,6H).
3- (3- (2- bromophenyls) carbamyl) cinnamic acid methyl esters (6i)
White solid, yield 38%.1H NMR(400MHz,DMSO-d6) δ 10.14 (s, 1H), 8.36 (t, J=1.8Hz,
1H), 8.06-7.98 (m, 2H), 7.83-7.69 (m, 2H), 7.64-7.52 (m, 2H), 7.46 (td, J=7.7,1.5Hz, 1H),
7.30-7.20 (m, 1H), 6.79 (d, J=16.1Hz, 1H), 3.76 (s, 3H)
3- (3- (3- bromophenyls) carbamyl) cinnamic acid methyl esters (6j)
White solid, yield 35%.1H NMR(400MHz,DMSO-d6) δ 10.44 (s, 1H), 8.29 (d, J=1.9Hz,
1H), 8.10 (t, J=1.9Hz, 1H), 8.02-7.92 (m, 2H), 7.80-7.74 (m, 2H), 7.61 (t, J=7.7Hz, 1H),
7.40-7.29 (m, 2H), 6.80 (d, J=16.1Hz, 1H), 3.76 (s, 3H)
3- (3- (4- bromophenyls) carbamyl) cinnamic acid methyl esters (6k)
Faint yellow solid, yield 45%.1H NMR(400MHz,DMSO-d6) δ 10.25 (s, 1H), 8.31 (d, J=
1.9Hz, 1H), 8.08-7.99 (m, 2H), 7.78 (d, J=16.1Hz, 1H), 7.76-7.69 (m, 2H), 7.66 (t, J=
7.7Hz, 1H), 7.02-6.89 (m, 2H), 6.80 (d, J=16.1Hz, 1H), 3.78 (s, 3H)
3- (3- (2- fluorophenyls) carbamyl) cinnamic acid methyl esters (6l)
White solid, yield 42%.1H NMR(400MHz,DMSO-d6) δ 10.20 (s, 1H), 8.35 (t, J=1.7Hz,
1H), 8.04-797 (m, 2H), 7.76 (d, J=16.1Hz, 1H), 7.71-7.51 (m, 2H), 7.44-7.15 (m, 3H), 6.80
(d, J=16.1Hz, 1H), 3.76 (s, 3H)
3- (3- (4- chlorphenyls) carbamyl) cinnamic acid methyl esters (6m)
White solid, yield 43%.1H NMR(400MHz,DMSO-d6) δ 10.21 (s, 1H), 8.29 (d, J=1.8Hz,
1H), 8.03-7.94 (m, 2H), 7.75 (d, J=16.0Hz, 1H), 7.73-7.68 (m, 2H), 7.61 (t, J=8.0Hz, 1H),
7.00-6.84 (m, 2H), 6.77 (d, J=16.0Hz, 1H), 3.76 (s, 3H)
3- (3- (2- pyridine radicals) carbamyl) cinnamic acid methyl esters (6n)
White solid, yield 31%.1H NMR(400MHz,DMSO-d6) δ 10.26 (s, 1H), 8.38 (d, J=1.8Hz,
1H), 8.24-8.11 (m, 2H), 7.92 (d, J=7.7Hz, 1H), 7.80 (t, J=7.7Hz, 1H), 7.75 (d, J=16.0Hz,
1H), 7.55-7.41 (m, 2H), 7.16 (t, J=5.9Hz, 1H), 6.67 (d, J=16.0Hz, 1H), 3.76 (s, 3H)
3- (3- (2- thiazolyls) carbamyl) cinnamic acid methyl esters (6o)
Faint yellow solid, yield 40%.1H NMR(400MHz,DMSO-d6) δ 8.55 (t, J=1.8Hz, 1H), 8.17-
8.06 (m, 1H), 7.98-7.90 (m, 1H), 7.75 (d, J=16.0Hz, 1H), 7.68-7.55 (m, 2H), 7.32 (d, J=
3.6Hz, 1H), 6.84 (d, J=16.1Hz, 1H), 3.76 (s, 3H)
Embodiment 4：
N- (substituted aryl) -3- (3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7) synthesis lead to method
Compound 6a-o (2.5mmol) is dissolved in methanol (40mL) and dichloromethane (20mL), ice bath is cooled to 0 DEG C, adds
Enter azanol (75mmol) and sodium hydroxide (25mmol).Reaction solution is slowly warmed to room temperature, and is stirred overnight.After reaction terminates, it is evaporated off
Solvent, water is added, pH value is adjusted to 7 or so with watery hydrochloric acid.The solid of precipitation is filtered, compound 7a-o is obtained with acetone recrystallization.
N- (2- aminomethyl phenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7a)
White solid, yield 87%, mp 143-144 DEG C1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),8.18
(s, 1H), 7.93 (d, J=7.6Hz, 1H), 7.73 (d, J=7.6Hz, 1H), 7.54 (t, J=7.7Hz, 1H), 7.44 (d, J=
15.8Hz, 1H), 7.34 (d, J=7.5Hz, 1H), 7.28 (d, J=7.2Hz, 1H), 7.20 (d, J=6.9Hz, 2H), 6.61
(d, J=15.8Hz, 1H), 2.25 (s, 3H)13C NMR(100MHz,DMSO-d6)δ165.4,163.1,136.8,135.9,
135.6,134.2,131.0,130.8,129.5,128.6,127.1,126.5,126.5,126.5,121.7,18.4.HRMS
(ESI):m/z calcd for C17H15N2O3[M-H]:295.1083；found:295.1087.
N- (3- aminomethyl phenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7b)
Faint yellow solid, yield 80%, mp 160-161 DEG C1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),
8.12 (s, 1H), 7.98-7.85 (m, 1H), 7.77 (d, J=7.7Hz, 1H), 7.62-7.49 (m, 4H), 7.24 (t, J=
7.8Hz, 1H), 6.94 (d, J=7.5Hz, 1H), 6.60 (d, J=15.8Hz, 1H), 2.31 (s, 3H)13C NMR(100MHz,
DMSO-d6)δ165.6,162.9,139.4,138.3,138.1,136.1,135.4,132.7,131.1,129.6,129.0,
126.8,125.0,121.4,120.6,118.0,21.7.HRMS(ESI):m/z calcd for C17H15N2O3[M-H]:
295.1083；found:295.1090.
N- (4- aminomethyl phenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7c)
Faint yellow solid, yield 73%, mp 183-184 DEG C1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),
10.25 (s, 1H), 9.12 (s, 1H), 8.12 (s, 1H), 7.92 (d, J=6.8Hz, 1H), 7.76 (d, J=6.6Hz, 1H),
7.66 (d, J=7.7Hz, 2H), 7.54 (d, J=15.4Hz, 2H), 7.17 (d, J=7.7Hz, 2H), 6.59 (d, J=
15.8Hz,1H),2.28(s,3H).13C NMR(100MHz,DMSO-d6)δ165.4,162.9,138.0,137.0,136.1,
135.4,133.2,131.1,129.5,129.5,129.5,128.9,126.7,120.8,120.8,120.7,21.0.HRMS
(ESI):m/z calcd for C17H15N2O3[M-H]:295.1083；found:295.1084.
N- (2- methoxyphenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7d)
Faint yellow solid, yield 78%, mp 125-127 DEG C1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),
8.17 (s, 1H), 7.94 (d, J=7.7Hz, 1H), 7.83-7.66 (m, 2H), 7.62-7.41 (m, 2H), 7.21 (td, J=
7.8,1.8Hz, 1H), 7.12-7.08 (m, 1H), 6.99 (td, J=7.6,1.4Hz, 1H), 6.63 (d, J=15.8Hz, 1H),
3.84(s,3H).13C NMR(100MHz,DMSO-d6)δ165.2,162.9,152.2,137.8,135.6,135.6,131.1,
129.6,128.7,127.1,126.7,126.5,125.2,120.9,120.7,111.9,56.2.HRMS(ESI):m/z
calcd for C17H15N2O4[M-H]:311.1032；found:311.1010.
N- (3- methoxyphenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7e)
White solid, yield 80%, mp 142-144 DEG C1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.13
(s, 1H), 7.90 (d, J=7.7Hz, 1H), 7.74 (d, J=7.6Hz, 1H), 7.55 (t, J=7.7Hz, 1H), 7.50-7.42
(m, 2H), 7.39 (dd, J=7.9,1.7Hz, 1H), 7.26 (t, J=8.1Hz, 1H), 6.70 (dd, J=8.2,2.5Hz, 1H),
6.61 (d, J=15.8Hz, 1H), 3.76 (s, 3H)13C NMR(100MHz,DMSO-d6)δ165.7,163.1,159.9,
140.8,136.7,136.0,135.8,131.0,129.9,129.5,128.7,126.5,121.8,113.0,109.7,
106.5,55.5.HRMS(ESI):m/z calcd forC17H15N2O4[M-H]:311.1032；found:311.1030.
N- (4- methoxyphenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7f)
White solid, yield 63%, mp 172-174 DEG C1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),8.14
(s, 1H), 7.93 (d, J=7.6Hz, 1H), 7.78-7.68 (m, 3H), 7.62-7.45 (m, 2H), 6.93 (d, J=8.8Hz,
2H), 6.62 (d, J=15.8Hz, 1H), 3.74 (s, 3H)13C NMR(100MHz,DMSO-d6)δ165.2,162.9,156.1,
137.7,136.1,135.5,132.6,130.9,129.5,128.8,126.6,122.4,122.4,120.9,114.2,
114.2,55.6.HRMS(ESI):m/z calcd forC17H15N2O4[M-H]:311.1032；found:311.1035.
N- (2- aminophenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7g)
Faint yellow solid, yield 63%, mp 165-167 DEG C1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),
8.19 (s, 1H), 7.97 (d, J=7.8Hz, 1H), 7.76 (d, J=7.7Hz, 1H), 7.61-7.49 (m, 2H), 7.18 (d, J=
7.8Hz, 1H), 6.99 (t, J=7.6Hz, 1H), 6.80 (d, J=8.0Hz, 1H), 6.67-6.55 (m, 2H), 4.94 (s, 2H)
.13C NMR(100MHz,DMSO-d6)δ165.5,163.0,143.7,138.1,135.7,135.4,131.0,129.5,
129.1,127.2,127.1,126.9,123.5,120.6,116.7,116.5.HRMS(ESI):m/z calcd for
C16H14N3O3[M-H]:296.1035；found:296.1028.
N- (4- dimethylamino phenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7h)
Faint yellow solid, yield 71%, mp 175-177 DEG C1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),
10.10(s,1H),9.12(s,1H),8.12(s,1H),7.98-7.85(m,1H),7.73(s,1H),7.60-7.52(m,4H),
6.79 (d, J=6.1Hz, 2H), 6.60 (d, J=15.6Hz, 1H), 2.89 (s, 6H)13C NMR(100MHz,DMSO-d6)δ
164.8,163.0,147.8,138.2,136.3,135.4,130.8,129.5,129.3,128.9,126.6,122.3,
122.3,120.6,113.0,113.0,41.0,41.0.HRMS(ESI):m/z calcd for C18H18N3O3[M-H]:
324.1348；found:324.1351.
N- (2- bromophenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7i)
White solid, yield 69%, mp 107-109 DEG C1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.20
(s, 1H), 7.97 (d, J=7.8Hz, 1H), 7.79 (d, J=7.7Hz, 1H), 7.73 (d, J=7.9Hz, 1H), 7.64-7.51
(m, 3H), 7.48-7.40 (m, 1H), 7.24 (td, J=7.7,1.7Hz, 1H), 6.61 (d, J=15.8Hz, 1H)13C NMR
(100MHz,DMSO-d6)δ165.5,162.9,137.9,136.9,135.6,135.1,133.2,131.6,129.7,129.4,
128.9,128.6,128.6,126.6,121.1,120.8.HRMS(ESI):m/z calcd for C16H12BrN2O3[M-H]:
359.0031；found:359.0017.
N- (3- bromophenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7j)
Faint yellow solid, yield 71%, mp 160-162 DEG C1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),
8.14 (s, 1H), 8.11 (s, 1H), 7.93 (d, J=7.5Hz, 1H), 7.77 (d, J=5.4Hz, 2H), 7.63-7.50 (m,
2H), 7.37-7.27 (m, 2H), 6.61 (d, J=15.8Hz, 1H)13C NMR(100MHz,DMSO-d6)δ165.9,162.8,
141.2,137.8,135.6,131.4,131.1,129.6,129.0,126.8,123.0,121.9,120.9,119.4.HRMS
(ESI):m/z calcd for C16H12BrN2O3[M-H]:359.0031；found:359.0021.
N- (4- bromophenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7k)
White solid, yield 65%, mp 200-202 DEG C1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),
10.45 (s, 1H), 9.12 (s, 1H), 8.12 (s, 1H), 7.92 (d, J=7.6Hz, 1H), 7.77 (d, J=8.7Hz, 3H),
7.63-7.46 (m, 4H), 6.59 (d, J=15.8Hz, 1H)13C NMR(100MHz,DMSO-d6)δ165.8,163.0,
138.9,138.0,135.8,135.5,131.9,131.9,131.3,129.6,129.0,126.8,122.7,122.7,
120.7,115.9.HRMS(ESI):m/z calcd for C16H12BrN2O3[M-H]:359.0031；found:359.0034.
N- (2- fluorophenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7l)
White solid, yield 84%, mp 165-167 DEG C1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.19
(s, 1H), 7.97 (d, J=7.9Hz, 1H), 7.78 (d, J=8.0Hz, 1H), 7.67-7.46 (m, 4H), 7.40-7.19 (m,
4H), 6.65 (d, J=15.8Hz, 1H)13C NMR(100MHz,DMSO-d6) δ 164.2 (J=264.4Hz), 156.3 (J=
245.6Hz), 137.8,135.6,135.0,131.4,129.6,129.1,127.7,127.5 (J=7.6Hz), 126.9,
(126.1,126.0,124.8 J=3.5Hz), 120.9,116.3 (J=19.7Hz) .HRMS (ESI):m/z calcd for
C16H12FN2O3[M-H]:299.0832；found:299.0819.
N- (4- chlorphenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7m)
Faint yellow solid, yield 57%, mp 191-193 DEG C1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),
10.46 (s, 1H), 9.11 (s, 1H), 8.12 (s, 1H), 7.92 (d, J=6.7Hz, 1H), 7.80 (dd, J=17.0,7.7Hz,
3H), 7.56 (t, J=12.5Hz, 2H), 7.43 (d, J=8.3Hz, 2H), 6.60 (d, J=15.7Hz, 1H)13C NMR
(100MHz,DMSO-d6)δ165.7,162.9,138.5,138.0,135.8,135.5,131.3,129.6,129.0,129.0,
129.0,127.8,126.8,122.3,122.3,120.8.HRMS(ESI):m/z calcd for C16H12ClN2O3[M-H]:
315.0536；found:315.0546.
N- (2- pyridine radicals) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7n)
Faint yellow solid, yield 60%, mp 164-165 DEG C1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),
8.41 (d, J=4.5Hz, 1H), 8.28-8.16 (m, 2H), 7.99 (d, J=7.5Hz, 1H), 7.86 (t, J=7.8Hz, 1H),
7.77 (d, J=7.3Hz, 1H), 7.60-7.45 (m, 2H), 7.19 (t, J=5.9Hz, 1H), 6.64 (d, J=15.7Hz, 1H)
.13C NMR(100MHz,DMSO-d6)δ166.1,163.2,152.6,148.4,138.6,135.9,135.1,131.4,
129.5,128.9,126.8,121.9,120.4,115.2.HRMS(ESI):m/z calcd for C15H12N3O3[M-H]:
282.0879；found:282.0868.
N- (2- thiazolyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7o)
Faint yellow solid, yield 68%, mp 196-198 DEG C1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),
8.06 (d, J=7.7Hz, 1H), 7.71 (d, J=7.6Hz, 1H), 7.62-7.39 (m, 3H), 7.13 (s, 1H), 6.61 (d, J=
15.8Hz,1H).13C NMR(100MHz,DMSO-d6)δ166.1,163.0,162.3,138.0,137.8,135.5,135.4,
131.4,129.7,129.4,127.0,120.6,113.2.HRMS(ESI):m/z calcd for C13H10N3O3S[M-H]:
288.0443；found:288.0414.
Embodiment 5：
HDAC inhibitory activity is tested
Inhibitory action using Fluorometric assay compound to HDAC, its principle are to be acted on HDAC containing acetylation side
The substrate of chain makes its deacetylation, then hydrolyzed deacetylated product of the substrate generation with fluorescence.By the chemical combination of various concentrations
Thing detects fluorescence signal after being blended in incubation at room temperature a period of time with the buffer solution containing substrate and the HDAC solution prepared, swashs
Hair wavelength is 355nm, launch wavelength 460nm.The change of fluorescent absorption value can reflect the repressed situations of HDAC, according to number
The change of value can calculate the inhibiting rate of compound and try to achieve IC50Value.Positive control drug be Vorinostat and Baily department he, experiment knot
Fruit is shown in Table 2.
Embodiment 6：
Anti tumor activity in vitro is tested
Using the cytotoxicity of Alamar Blue method detection compounds, its principle is in proliferation process, into the cell
NADPH/NADP, FADH/FAD, FMNH/FMN and NADH/NAD ratio rise, in reducing environment.Resazurin is a kind of
Nontoxic, permeable membrane blue dyes, it is as a kind of oxidation-reduction indicator, after cell endocytic, in cytoplasm by more than
Metabolic Intermediate reduces, and its reduzate resorufin shows pink and has very strong fluorescence.Examined with fluophotometer
Survey fluorescence signal, excitation wavelength 560nm, launch wavelength 590nm.The inhibiting rate of compound can be calculated according to the change of numerical value
And try to achieve IC50Value.Positive control drug be Baily department he, experimental result is shown in Table 3.
Claims (5)
1. his analogue of Baily department with histon deacetylase (HDAC) inhibitory action, it is characterized in that：For N- (substitution virtues
Base) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) heterocyclic carbamate derivatives, general structure is as follows：
R is 2- aminomethyl phenyls, 3- aminomethyl phenyls, 4- aminomethyl phenyls, 2- methoxyphenyls, 3- methoxyphenyls, 4- methoxybenzenes
Base, 2- aminophenyls, 4- dimethylamino phenyls, 2- bromophenyls, 3- bromophenyls, 4- bromophenyls, 2- fluorophenyls, 4- chlorphenyls, 2-
Pyridine radicals, 2- thiazolyls.
2. his analogue of the Baily department according to claim 1 with histon deacetylase (HDAC) inhibitory action, its
Be characterised by, his analogue of described Baily department, its officinal salt, hydrate, prodrug or in any form metabolism formed
Metabolite, the compound is selected from：
N- (2- aminomethyl phenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7a);
N- (3- aminomethyl phenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7b);
N- (4- aminomethyl phenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7c);
N- (2- methoxyphenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7d);
N- (3- methoxyphenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7e);
N- (4- methoxyphenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7f);
N- (2- aminophenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7g);
N- (4- dimethylamino phenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7h);
N- (2- bromophenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7i);
N- (3- bromophenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7j);
N- (4- bromophenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7k);
N- (2- fluorophenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7l);
N- (4- chlorphenyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7m);
N- (2- pyridine radicals) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7n);
N- (2- thiazolyls) -3- ((3- hydroxylaminos) -3- oxo -1- acrylic) benzamide (7o).
3. his analogue of Baily department as claimed in claim 1 is in the disease for the treatment of histon deacetylase (HDAC) mediation
Using.
4. his purposes of the analogue in antineoplastic is prepared of Baily department as claimed in claim 1.
5. purposes according to claim 4, it is characterised in that described tumour is breast cancer, cervical carcinoma, oophoroma, preceding
Row gland cancer, lymph cancer, stomach cancer, intestinal cancer, liver cancer and lung cancer.
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| CN1378450A (en) * | 1999-09-08 | 2002-11-06 | 斯隆-凯特林癌症研究院 | Novel class of cytodifferentiating agents and histone deactylase inhibitors, and methods of use thereof |
| WO2003070188A2 (en) * | 2002-02-15 | 2003-08-28 | Sloan-Kettering Institute For Cancer Research | Method of treating trx mediated diseases |
| WO2003087066A1 (en) * | 2002-04-11 | 2003-10-23 | Sk Chemicals, Co., Ltd. | α,β-UNSATURATED HYDROXAMIC ACID DERIVATIVES AND THEIR USE AS HISTONE DEACETYLASE INHIBITORS |
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| CN1378450A (en) * | 1999-09-08 | 2002-11-06 | 斯隆-凯特林癌症研究院 | Novel class of cytodifferentiating agents and histone deactylase inhibitors, and methods of use thereof |
| WO2003070188A2 (en) * | 2002-02-15 | 2003-08-28 | Sloan-Kettering Institute For Cancer Research | Method of treating trx mediated diseases |
| WO2003087066A1 (en) * | 2002-04-11 | 2003-10-23 | Sk Chemicals, Co., Ltd. | α,β-UNSATURATED HYDROXAMIC ACID DERIVATIVES AND THEIR USE AS HISTONE DEACETYLASE INHIBITORS |
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