CN103936752A - Isatin histone deacetylase inhibitors as well as preparation method and applications thereof - Google Patents

Isatin histone deacetylase inhibitors as well as preparation method and applications thereof Download PDF

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CN103936752A
CN103936752A CN201410184672.2A CN201410184672A CN103936752A CN 103936752 A CN103936752 A CN 103936752A CN 201410184672 A CN201410184672 A CN 201410184672A CN 103936752 A CN103936752 A CN 103936752A
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methyl
reaction
indoline
spiral shell
compound
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徐文方
金康
张颖杰
王学建
黄永学
侯金宁
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Weifang Bochuang International Biological Medical Research Institute
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Weifang Bochuang International Biological Medical Research Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to isatin histone deacetylase inhibitors as well as a preparation method and applications thereof. The series of compounds have a structure as shown in the general formula I in the specification. Activity screening experiments shows that the histone deacetylase inhibitors have excellent in-vitro and in-vivo activity and can be used for preparing medicines for treating diseases with abnormal expression of histone deacetylase activity. The invention also relates to a medicine composition containing the compounds with a structure as shown in the formula I, as well as an application of the composition in medicine preparation.

Description

Isatin histone deacetylases inhibitor and its preparation method and application
Technical field
The invention belongs to organic compound and synthesize and medical applications technical field, be specifically related to a kind of derivative isatin histone deacetylases inhibitor and preparation method thereof and application.
Background technology
Histon deacetylase (HDAC) (HDACs) is a kind of zine ion dependent form or NDA +dependent form enzyme; histon deacetylase (HDAC) (HDACs) can be by the ethanoyl hydrolysis (as reaction formula II) on the lysine residue terminal amino group of range protein substrate; such as histone etc.; thereby cause the positive charge density of histone to increase; then the avidity that causes histone and electronegative DNA strengthens, and genetic transcription is suppressed.Recently, the increasing nonhistones substrate that is proved to be HDACs, as transcription factor, cytoskeletal protein, molecular chaperoneses etc., have the function of complexity like this just because of HDACs, its expression and active imbalance are closely related with numerous disease, comprising: cancer, nervous system disease, virus infection, inflammation, leukemia, malaria and diabetes etc., wherein, cancer, makes the disease the most serious to human life's health threat undoubtedly.Research shows, it is closely related that development occurs for HDACs and tumour cell, as: inhibition tumor cell differentiation and apoptosis, promote tumor cell proliferation, migration and vasculogenesis, strengthen the resistibility of tumour cell to chemotherapeutics etc.
In human body, found that at present there are 18 members in HDACs family, according to its structure, the difference of function and distribution can be divided into four classes.Wherein, I class (HDAC1,2,3 and 8), II class (II a:HDAC4,5,7 and 9; II b:HDAC6,10), IV class (HDAC11) belongs to zine ion dependency lytic enzyme, and III class HDACs (SIRT1-7) is NAD +dependent.Research shows, closely-related with tumour is mainly zine ion dependency HDACs, and hdac inhibitor is anticancer propagation effectively, promotes apoptosis.And it is wide that HDACi has antitumor spectra, the advantage that toxic side effect is low, they are to solid tumor, leukemia, lymphoma has good inhibition active, therefore, is the focus that shot design inhibitor has become antitumor drug research for HDACs.The Inhibiting enzyme activity of existing NSC 630176 and cell antitumor activity are all undesirable.
Summary of the invention
The object of the invention is to; overcome the deficiencies in the prior art; a kind of isatin histone deacetylases inhibitor is provided; histon deacetylase (HDAC) HDACs is had to stronger inhibition activity; there is good DEVELOPMENT PROSPECT, and can be used as the lead compound of finding new and effective NSC 630176.The present invention also provides the preparation method and application of isatin histone deacetylases inhibitor.
For solving the problems of the technologies described above, technical scheme of the present invention is:
isatin histone deacetylases inhibitor
Isatin histone deacetylases inhibitor or its pharmacy acceptable salt, solvate or prodrug, have the structure shown in formula I:
Wherein,
R 1hydrogen, halogen F, Cl, Br, I, aryl, heteroaryl, aryl C1-8 alkyl, heteroaryl C1-9 alkyl, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl, C1-8 alkyl, assorted alkyl or cycloalkyl, optional one or more following group replaces: halogen, hydroxyl, cyano group, nitro, C1-9 alkoxyl group, halogen C1-9 alkyl, C1-8 alkyl-carbonyl, C1-8 carbalkoxy, aryl C1-6 carbalkoxy;
R 2aryl, heteroaryl, aryl C1-8 alkyl, heteroaryl C1-8 alkyl, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl, C1-8 alkyl, assorted alkyl or cycloalkyl;
R 3azanol base, hydroxyl, methoxyl group, O-Phenylene Diamine base;
M is 1,2 or 3;
N is 0,1 or 2.
preferably, R 1hydrogen, halogen F, Cl, Br, nitro and hydroxyl; R 2c1-5 alkyl, phenyl, styryl;
more preferred, the compound of above-mentioned formula I is one of following:
2-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl)-N-(2-(azanol base)-2-ethoxycarbonyl) ethanamide (8a);
4-(2-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) acetamido)-N-maloyl group amine (8b);
6-(2-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxyl hexanamide (8c);
(E)-3-(4-(2-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) kharophen)-phenyl)-N-hydroxyl acryl acid amides (8d);
4-(2-(5 '-fluoro-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (16a);
4-(2-(5 '-chloro-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (16b);
4-(2-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (16c);
4-(2-(2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (16d);
4-(2-(5 '-methyl-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (16e);
4-(2-(5 '-nitro-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (16f);
4-(2-(5 '-chloro-2 '-oxo spiral shell [[1,3] dioxane-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (21a);
4-(2-(5 '-chloro-2 '-oxo spiral shell [[1,3] dioxepin-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (21b);
4-(2-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxane-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (21c);
4-(2-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxepin-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (21d);
4-(3-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxane-2,3 '-indoline]-1 '-yl) propionamido-)-N-hydroxybenzamide (25a);
4-(4-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxane-2,3 '-indoline]-1 '-yl) amide-based small)-N-hydroxybenzamide (25b);
N-(2-aminophenyl)-4-(2-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxane-2,3 '-indoline]-1 '-yl) acetone amino) benzamide (27).
the preparation method of isatin histone deacetylases inhibitor
The preparation method of isatin histone deacetylases inhibitor of the present invention is one of following:
synthetic route 1:, react with ethylene ketal through Sandmeyer reaction taking para-bromoaniline as raw material, with methyl bromoacetate nucleophilic reaction, hydrolysis reaction, polypeptide condensation connects R 2group, finally makes hydroximic acid and obtains end product; Synthetic route 1 reaction formula is as follows:
Wherein, R 2described in above-mentioned formula I;
Reagent in said synthesis route 1 reaction formula: (a) Chloral Hydrate, oxammonium hydrochloride, sodium sulfate, 85 DEG C; (b) vitriol oil, 90 DEG C; (c) ethylene glycol, tosic acid, toluene, 130 DEG C; (d) methyl bromoacetate, Tetrabutyl amonium bromide, salt of wormwood, potassiumiodide, acetone, 60 DEG C; (e) ethanol, potassium hydroxide, hydrochloric acid; (f) the amino methyl hexyl hydrochloride of glycine methyl ester hydrochloride or γ-aminobutyric acid methyl ester hydrochloride or 6-or to amino-cinnamic acid methyl ester hydrochloride, isobutyl chlorocarbonate, N-methylmorpholine, tetrahydrofuran (THF) ,-20 DEG C; (g) azanol potassium, methyl alcohol.
The structural formula of the target compound in synthetic route is as follows:
synthetic route 2:taking the aniline of different para-orientation as raw material, through Sandmeyer reaction, react with ethylene ketal, with methyl bromoacetate nucleophilic reaction, hydrolysis reaction, polypeptide condensation connection methyl p-aminobenzoate group, finally makes hydroximic acid and obtains end product; Synthetic route 2 reaction formula are as follows:
Wherein, R 1described in above-mentioned formula I;
Reagent in said synthesis route 2 reaction formula: (a) Chloral Hydrate, oxammonium hydrochloride, sodium sulfate, 85 DEG C; (b) vitriol oil, 90 DEG C; (c) ethylene glycol, tosic acid, toluene, 130 DEG C; (d) methyl bromoacetate, Tetrabutyl amonium bromide, salt of wormwood, potassiumiodide, acetone, 60 DEG C; (e) ethanol, potassium hydroxide, hydrochloric acid; (f ') methyl p-aminobenzoate hydrochloride, isobutyl chlorocarbonate, N-methylmorpholine, tetrahydrofuran (THF) ,-20 DEG C; (g) azanol potassium, methyl alcohol.
The structural formula of the target compound in synthetic route is as follows:
synthetic route 3:taking 5 different isatin that replace as raw material, through ketal reaction, with methyl bromoacetate nucleophilic reaction, hydrolysis reaction, polypeptide condensation connects methyl p-aminobenzoate group, finally makes hydroximic acid and obtains end product; Synthetic route 3 reaction formula are as follows:
Wherein, R 1, n is with described in above-mentioned formula I;
Reagent in said synthesis route 3 reaction formula: (h) ethylene glycol, 1,3-PD, BDO, tosic acid, toluene, 130 DEG C; (d) methyl bromoacetate, Tetrabutyl amonium bromide, salt of wormwood, potassiumiodide, acetone, 60 DEG C; (e) ethanol, potassium hydroxide, hydrochloric acid; (f ') methyl p-aminobenzoate hydrochloride, isobutyl chlorocarbonate, N-methylmorpholine, tetrahydrofuran (THF) ,-20 DEG C; (g) azanol potassium, methyl alcohol.
The structural formula of the target compound in synthetic route is as follows:
synthetic route 4:taking the intermediate compound 17c in synthetic route 3 as raw material, through ketal reaction, with methyl bromoacetate or methyl bromide c nucleophilic reaction, hydrolysis reaction, polypeptide condensation connects methyl p-aminobenzoate group, finally makes hydroximic acid and obtains end product; Synthetic route 4 reaction formula are as follows:
Wherein, m is with described in above-mentioned formula I;
Reagent in said synthesis route 4 reaction formula: (i) methyl bromoacetate or methyl bromide c, Tetrabutyl amonium bromide, salt of wormwood, potassiumiodide, acetone, 60 DEG C; (e) ethanol, potassium hydroxide, hydrochloric acid; (f ') methyl p-aminobenzoate hydrochloride, isobutyl chlorocarbonate, N-methylmorpholine, tetrahydrofuran (THF) ,-20 DEG C; (g) azanol potassium, methyl alcohol.
The structural formula of the target compound in synthetic route is as follows:
synthetic route 5:taking intermediate compound 20c in synthetic route 3 as raw material, through hydrolysis reaction, obtain end product with the condensation reaction of O-Phenylene Diamine, synthetic route 5 reaction formula are as follows:
Reagent in said synthesis route 5 reaction formula: (e) ethanol, potassium hydroxide, hydrochloric acid; (j) O-Phenylene Diamine, isobutyl chlorocarbonate, N-methylmorpholine, tetrahydrofuran (THF) ,-20 DEG C.
The structural formula of the target compound in synthetic route is as follows:
R in following table is the R in general formula I 3,
The concrete operation step of described compound will be described in detail in an embodiment.
Those skilled in the art can change to improve yield to above-mentioned steps; they can determine synthetic route according to the ABC of this area; as selective reaction thing, solvent and temperature, thus can be by using various GPF (General Protection False bases to improve yield with the generation of avoiding side reaction.These conventional guard methods can be referring to for example T. Greene, Protecting Groups in Organic Synthesis.
the pharmaceutical composition that contains the compounds of this invention and application
The present invention also provides the application of these compounds in the medicine of preparing the mammalian diseases that prevention or treatment are relevant to the active unconventionality expression of histon deacetylase (HDAC).The described related mammalian disease with the active unconventionality expression of histon deacetylase (HDAC) comprises: cancer, neurodegenerative disease, virus infection, inflammation, leukemia.Malaria and diabetes etc.Therefore, the invention still further relates to the pharmaceutical composition that contains I structural compounds.
In addition, the present invention also comprises that one is suitable for the oral mammiferous pharmaceutical composition that gives, and the arbitrary compound that comprises above-mentioned formula I, and pharmaceutically acceptable carrier, optionally comprise one or more pharmaceutically acceptable vehicle.
In addition, the present invention also comprises that one is suitable for parenteral and gives mammiferous pharmaceutical composition, and the arbitrary compound that comprises above-mentioned formula I, and pharmaceutically acceptable carrier, optionally comprise one or more pharmaceutically acceptable vehicle.
Term and definition implication used in the present invention is as follows:
" aryl " refers to aromatic carbocyclic group.Preferably aromatic ring contains 6-10 carbon atom.
" heteroaryl " is aromatic heterocycle, can be monocycle or bicyclic radicals.Preferably heteroaryl comprises, such as thienyl, furyl, pyrryl, pyridyl, pyrazinyl, thiazolyl, pyrimidyl, quinolyl and tetrazole base, benzothiazolyl, benzofuryl, indyl etc.
" assorted alkyl " refers to saturated or unsaturated, carbon atoms and at least one heteroatomic chain, and wherein any one heteroatoms is non-conterminous.In assorted alkyl, contain 2-15 atom (carbon atom), preferably contain 2-10 atom.Assorted alkyl can be straight or branched, replacement or unsubstituted.
" cycloalkyl " is replacement or unsubstituted, saturated or undersaturated cyclic group, and it contains carbon atom and/or one or more heteroatoms.This ring can be monocycle or condensed ring, the ring system of bridged ring or volution.Monocycle has 3-9 atom conventionally, preferably 4-7 atom, and many rings contain 7-17 atom, preferably contain 7-13 atom.
" halogen " or " halogen " comprises fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine.
" pharmacy acceptable salt " refers to that (I) compound has curative effect and nontoxic salt form.It can form anion salt by arbitrary acidic-group (as carboxyl), or forms cationic salts by arbitrary basic group (as amino).Much such salt known in the art.At the upper cationic salts forming of any acidic-group (as carboxyl), or at the upper anion salt forming of any basic group (as amino).It is known in the art that these salt have many, as cationic salts comprises salt and the organic salt (as ammonium salt) of basic metal (as sodium and potassium) and alkaline-earth metal (as magnesium and calcium).Also can obtain easily anion salt by (I) that use corresponding acid treatment alkaline form, such acid comprises that electrodeless acid is as sulfuric acid, nitric acid, phosphoric acid etc.; Or organic acid is as acetic acid, propionic acid, carboxyl acetic acid, 2 hydroxy propanoic acid, Acetylformic acid, oxalic acid, propanedioic acid, succsinic acid, toxilic acid, fumaric acid, oxysuccinic acid, tartrate, 2-hydroxyl-1,2,3-the third three acid, methylsulfonic acid, ethyl sulfonic acid, this methylsulfonic acid, 4-toluene sulfonic acide, cyclohexyl-sulfinic acid, 2 hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid etc.These salt are that those of skill in the art know, and those skilled in the art can prepare any salt that this area knowledge provides.In addition, those of skill in the art can get certain salt according to factors such as solubleness, stability, easy preparations and give up another kind of salt.The mensuration of these salt and optimization are within the scope of those of skill in the art's experience.
" solvate " is the title complex that solute (as inhibitors of metalloproteinase) and solvent (as water) are combined to form.Referring to J.Honig etc., The Van Nostrand Chemist ' s Distionary, P.650 (1953).The pharmaceutically acceptable solvent that the present invention adopts comprises bioactive those solvents (for example, known to water, ethanol, acetic acid, DMF, dimethyl sulfoxide (DMSO) and this those skilled in the art or easy definite solvent) that do not disturb inhibitors of metalloproteinase.
Formula I compound can also exist with the form of other protected forms or derivative, and these forms will be apparent to those skilled in the art, and all should be contained in scope of the present invention.
Substituting group as above self also can be replaced by one or more substituting groups.Such substituting group is included in C.Hansch and A.Leo, those substituting groups of listing in Substituent Constants for Correlation Analysis in Chemistry and Biology (1979).Preferred substituting group comprises, for example alkyl, thiazolinyl, alkoxyl group, hydroxyl, oxygen base nitro, amino, aminoalkyl group (as aminomethyl etc.), cyano group, halogen, carboxyl, hydroxy alkoxy base (as carbonyl oxyethyl group etc.), sulfenyl, aryl, cycloalkyl, heteroaryl, Heterocyclylalkyl (as piperidyl, morpholinyl, pyrryl etc.), imino-, hydroxyalkyl, aryloxy, arylalkyl, and combination.
Due to the high homology of each hypotype catalytic center of zine ion dependency histon deacetylase (HDAC) (HDACs); we have selected the HDACs extracting from hela cell core to carry out enzymic activity test; HDACs active fluoro analytical procedure (two-step approach); can fast, conveniently detect HDACs activity; simple to operate; highly sensitive; the first step; containing the Methionin HDACs fluorogenic substrate (Boc-Lys (acetyl)-AMC) of an acetylize side chain; with the HDACs sample incubation containing expressing; make substrate deacetylate, activate substrate.Second step pancreatin hydrolysis Boc-Lys-AMC, produce this fluorophor of AMC (being chromophoric group), measure fluorescence intensity in emission wavelength/excitation wavelength (390nm/460nm), thereby calculate inhibiting rate according to the fluorescence intensity of inhibitor group and control group, and ask and calculate IC50 value.Enzymic activity test philosophy is shown in reaction formula III.
The test of the cytoactive of compound is used Thiazolyl blue detection method (mtt assay), human colon cancer cell strain (HCT116), the isocellular cell suspension of people's acute leukemia cells strain (HL60) is inoculated in respectively 96 orifice plates, the substratum that does not add different concns compound in hole, after hatching, dye with MTT, after continuing to hatch, in microplate reader, measure the absorbancy (OD value) that does not have hole at 570nm place, calculate inhibitory rate of cell growth, thus the activity of deterministic compound.
The class peptide compounds of formula I external press down enzyme test prove that this compounds is a kind of isatin histone deacetylases inhibitor.
Isatin analog derivative of the present invention spatially matches with the avtive spot of histon deacetylase (HDAC), has therefore shown in vitro higher inhibition activity.
In reaction formula III, Histone deacetylase is histon deacetylase (HDAC), and Trypsin is trypsinase, and 4-amino-7-methylcoumarin is 4-amino-7-methylcoumarin.
Isatin compounds all shows the inhibition activity stronger to histon deacetylase (HDAC) HDACs; especially the Inhibiting enzyme activity that designs synthetic compound 21a-d and 25a-b series in the present invention has improved nearly a hundred times than the positive control drug SAHA having gone on the market; the antitumor activity of some knurl strain has been improved to nearly 10 times; wherein compound 25a is the highest to the inhibition activity of HDACs; and be better than positive control drug SAHA; there is good DEVELOPMENT PROSPECT, and can be used as the lead compound of finding new and effective NSC 630176.Compound 27 is hdac inhibitors of a non-hydroxamic acid, and Inhibiting enzyme activity and cell antitumor activity all have obvious advantage compared with positive control drug SAHA.
Brief description of the drawings
Fig. 1 is compound 4-(4-(5 '-bromo-2 '-oxo spiral shell [[1; 3] dioxane-2; 3 '-indoline]-1 '-yl) amide-based small) and-N-hydroxybenzamide and histone deacetylase 8 hypotype active region dock result by Sybyl7.3 with 3-D display schematic diagram; in figure, " Zinc Ion " is " zine ion ", and " Pocket X " is " pocket X ".
Embodiment
Below in conjunction with embodiment, the present invention is described further, but be not limited to this.
embodiment 1.the compounds of this invention 8a's is synthetic
(1) 5-bromoisatin 3
In the three-necked bottle that electric stirring, thermometer and constant voltage dropper are housed, add the water of 40mL, when warm, add anhydrous sodium sulphate (90g), starting electric stirring makes it even, add Chloral Hydrate (0.06mol) aqueous solution of 20ml, then slowly drip para-bromoaniline (1) (0.04mol), the solution of concentrated hydrochloric acid (10mL) and water (70mL) preparation, along with the people of dripping of para-bromoaniline will produce a large amount of flockss.Drip subsequently the aqueous solution (40mL) of oxammonium hydrochloride (O.13mol).After dropwising, be warming up to 85 DEG C, monitor reaction process, stopped reaction after 1.5-2.5h with TLC.Reaction system is cooled to rapidly to room temperature, and suction filtration, dries, and obtaining thick product is brown solid.Water recrystallization, all obtains rice white needle-like crystal 3.
5 '-bromine spiral shell [[1,3] dioxolane-2,3 '-indoles]-2-ketone 4
To 150mL compound 3(6.21mmol) toluene solution in add ethylene glycol (31.05mmol) and tosic acid (6.21mmol), under the condition of 130 DEG C, stirring reaction 5 hours, reaction finishes rear steaming and desolventizes, remaining mixture acetic acid ethyl dissolution, obtain compound 4. 1H NMR (600 MHz through column chromatography purification, DMSO) δ 10.60 (s, 1H), 7.43 (d, J=2.2 Hz, 1H), 7.39 (dd, J=8.3, 2.2 Hz, 1H), 6.85 (d, J=8.3 Hz, 1H), 4.34 – 4.25 (m, 4H).
2-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) methyl acetate 5
To 50mL compound 4(2.2mmol) acetone soln in add methyl bromoacetate (2.64mmol), Tetrabutyl amonium bromide (0.22mmol), potassiumiodide (0.22mmol), salt of wormwood (2.64mmol).Under room temperature, stir and spend the night.Reaction finishes rear steaming and desolventizes, and uses acetic acid ethyl dissolution mixture, obtains product 5. 1H NMR (600 MHz, DMSO) δ 7.53 (d after column chromatography purification, J=2.0 Hz, 1H), 7.49 (dd, J=8.4,2.1 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 4.55 (s, 2H), 4.37 – 4.29 (m, 4H), 3.68 (s, 3H).
Compound 5 is dissolved in the ethanol/water solution of potassium hydroxide to stirring reaction 2 hours, obtains carboxylic acid cpd 6, for next step reaction.
2-(2-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) ethanamide methyl acetate 7a
Isobutyl chlorocarbonate (1.8mmol) is splashed into compound 6(1,5mmol) and in the tetrahydrofuran solution of N-methylmorpholine (3.3mmol), under-15 DEG C of conditions, react 30 minutes, then glycine methyl ester (1.65mmol) is added in reaction solution, continue reaction and spend the night.Reaction finishes rear steaming and desolventizes, and uses acetic acid ethyl dissolution mixture, obtains product 7a. 1H NMR (600 MHz after column chromatography purification, DMSO) δ 7.63 – 7.59 (m, 2H), 6.88 (d, J=8.1 Hz, 1H), 4.35 (s, 2H), 4.34 (d, J=6.7 Hz, 2H), 4.31 (d, J=3.8 Hz, 2H), 3.89 (d, J=5.8 Hz, 2H), 3.63 (s, 3H).
2-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxolane-2.3 '-indoline]-1 '-yl)-N-(2-(azanol base)-2-oxoethyl) ethanamide 8a
Compound 7a is dissolved in the azanol potassium solution just having prepared and is reacted 2 hours.After reaction finishes, add saturated citric acid solution modulation acid, the crude product of the compound 8a being then extracted with ethyl acetate, after column chromatography purification, obtain product 8a. 1H NMR (600 MHz, DMSO) δ 10.57 (s, 1H), 8.86 (d, J=1.3 Hz, 1H), 8.57 (t, J=5.8 Hz, 1H), 7.61 – 7.56 (m, 2H), 6.92 – 6.90 (m, 1H), 4.35 – 4.32 (m, 4H), 4.32 – 4.30 (m, 2H), 3.65 (d, J=5.8 Hz, 2H).
embodiment 2.the compounds of this invention 8b's is synthetic
Preparation method is with compound 8a, and difference is that the glycine methyl ester 4-Aminobutanoicacid methyl esters in reaction reagent replaces.1H?NMR?(600?MHz,?DMSO)?δ?10.36?(s,?1H),?8.70?(s,?1H),?8.27?(t,?J?=?5.5?Hz,?1H),?7.60?(dd,?J?=?6.8,?2.0?Hz,?2H),?6.90?–?6.87?(m,?1H),?4.33?(dd,?J?=?4.1,?2.7?Hz,?2H),?4.32?–?4.30?(m,?2H),?4.25?(s,?2H),?3.05?(dd,?J?=?12.9,?6.7?Hz,?2H),?1.96?(t,?J?=?7.5?Hz,?2H),?1.66?–?1.60?(m,?2H).
embodiment 3.the compounds of this invention 8csynthetic
Preparation method is with compound 8a, and difference is that the glycine methyl ester 6-aminocaprolc acid methyl esters in reaction reagent replaces. 1H?NMR?(600?MHz,?DMSO)?δ?10.34?(s,?1H),?8.67?(s,?1H),?8.23?(t,? J?=?5.5?Hz,?1H),?7.62?–?7.58?(m,?2H),?6.87?(d,? J?=?8.3?Hz,?1H),?4.34?–?4.32?(m,?2H),?4.32?–?4.30?(m,?2H),?4.24?(s,?2H),?3.05?(dd,? J?=?12.7,?6.7?Hz,?2H),?1.94?(t,? J?=?7.4?Hz,?2H),?1.51?–?1.44?(m,?2H),?1.40?(dt,? J?=?14.6,?7.1?Hz,?2H),?1.27?–?1.20?(m,?2H).
embodiment 4.the compounds of this invention 8dsynthetic
Preparation method is with compound 8a, and difference is that the glycine methyl ester in reaction reagent is used amino-cinnamic acid methyl esters is replaced. 1H?NMR?(600?MHz,?DMSO)?δ?10.71?(s,?1H),?10.19?(s,?1H),?9.00?(s,?1H),?7.64?(d,? J?=?8.4?Hz,?2H),?7.52?(d,? J?=?8.3?Hz,?2H),?7.45?(d,? J?=?2.4?Hz,?1H),?7.40?(d,? J?=?15.7?Hz,?1H),?7.36?(dd,? J?=?8.7,?2.4?Hz,?1H),?6.49?(d,? J?=?8.8?Hz,?1H),?6.37?(d,? J?=?15.8?Hz,?1H),?4.17?(t,? J?=?6.8?Hz,?2H),?4.07?(t,? J?=?6.9?Hz,?2H),?3.94?(s,?2H).
embodiment 5.the compounds of this invention 16asynthetic
Preparation method is with compound 8a, and difference is that the para-bromoaniline para-fluoroaniline in reaction reagent replaces, and glycine methyl ester replaces with methyl p-aminobenzoate. 1H?NMR?(600?MHz,?DMSO)?δ?11.12?(s,?1H),?10.72?(s,?1H),?10.63?(s,?1H),?7.90?(d,? J?=?8.8?Hz,?1H),?7.70?(dd,? J?=?22.7,?8.8?Hz,?2H),?7.63?(d,? J?=?8.8?Hz,?1H),?7.36?(dd,? J?=?7.6,?2.8?Hz,?1H),?7.27?(td,? J?=?9.1,?2.7?Hz,?1H),?7.09?–?7.05?(m,?1H),?4.55?(d,? J?=?8.7?Hz,?2H),?4.36?(dd,? J?=?4.6,?2.7?Hz,?2H),?4.32?(dd,? J?=?4.7,?2.6?Hz,?2H).
embodiment 6.the compounds of this invention 16bsynthetic
Preparation method is with compound 8a, and difference is that the para-bromoaniline p-Chlorobenzoic acid amide in reaction reagent replaces, and glycine methyl ester replaces with methyl p-aminobenzoate. 1H?NMR?(600?MHz,?DMSO)?δ?11.12?(s,?1H),?10.70?(s,?1H),?10.61?(s,?1H),?7.90?(d,? J?=?8.8?Hz,?1H),?7.72?(d,? J?=?8.8?Hz,?1H),?7.68?(d,? J?=?8.8?Hz,?1H),?7.62?(d,? J?=?8.8?Hz,?1H),?7.52?(dd,? J?=?4.3,?2.2?Hz,?1H),?7.49?(dd,? J?=?8.4,?1.9?Hz,?1H),?7.10?(dd,? J?=?8.4,?5.6?Hz,?1H),?4.56?(d,? J?=?8.6?Hz,?2H),?4.35?(dd,? J?=?4.2,?2.8?Hz,?2H),?4.33?(d,? J?=?3.7?Hz,?2H).
embodiment 7.the compounds of this invention 16csynthetic
Preparation method is with compound 8a, and difference is that the glycine methyl ester methyl p-aminobenzoate in reaction reagent replaces.H?NMR?(600?MHz,?DMSO)?δ?11.12?(s,?1H),?10.62?(s,?1H),?8.95?(s,?1H),?7.72?(d,? J?=?8.5?Hz,?2H),?7.63?(dd,? J?=?20.6,?8.2?Hz,?4H),?7.04?(d,? J?=?8.1?Hz,?1H),?4.54?(s,?2H),?4.34?(d,? J?=?5.3?Hz,?4H).
embodiment 8.the compounds of this invention 16dsynthetic
Preparation method is with compound 8a, and difference is that the para-bromoaniline aniline in reaction reagent replaces, and glycine methyl ester replaces with methyl p-aminobenzoate. 1H?NMR?(600?MHz,?DMSO)?δ?11.12?(s,?1H),?10.72?(s,?1H),?10.62?(s,?1H),?7.90?(d,? J?=?8.8?Hz,?1H),?7.72?(d,? J?=?8.8?Hz,?1H),?7.69?(d,? J?=?8.8?Hz,?1H),?7.63?(d,? J?=?8.8?Hz,?1H),?7.43?–?7.38?(m,?2H),?7.10?(t,? J?=?7.5?Hz,?1H),?7.03?(dd,? J?=?8.4,?4.7?Hz,?1H),?4.54?(d,? J?=?8.9?Hz,?2H),?4.39?–?4.36?(m,?2H),?4.31?(dd,? J?=?4.5,?2.3?Hz,?2H).
embodiment 9.the compounds of this invention 16esynthetic
Preparation method is with compound 8a, and difference is that the para-bromoaniline para-totuidine in reaction reagent replaces, and glycine methyl ester replaces with methyl p-aminobenzoate..? 1H?NMR?(600?MHz,?DMSO)?δ?11.12?(s,?1H),?10.69?(s,?1H),?10.60?(s,?1H),?7.90?(d,? J?=?8.8?Hz,?1H),?7.72?(d,? J?=?8.8?Hz,?1H),?7.70?–?7.67?(m,?1H),?7.63?(d,? J?=?8.8?Hz,?1H),?7.24?–?7.18?(m,?2H),?6.91?(dd,? J?=?8.0,?5.1?Hz,?1H),?4.51?(d,? J?=?8.9?Hz,?2H),?4.36?(dd,? J?=?4.0,?2.4?Hz,?2H),?4.30?–?4.28?(m,?2H),?2.28?(s,?3H).
embodiment 10.the compounds of this invention 16fsynthetic
Preparation method is with compound 8a, and difference is that the para-bromoaniline p-Nitroaniline in reaction reagent replaces, and glycine methyl ester replaces with methyl p-aminobenzoate. 1H?NMR?(600?MHz,?DMSO)?δ?11.21?(s,?1H),?10.81?(s,?1H),?10.13?(s,?1H),?8.24?(d,? J?=?2.8?Hz,?1H),?8.10?(dd,? J?=?9.2,?2.8?Hz,?1H),?7.96?(dd,? J?=?8.7,?3.6?Hz,?1H),?7.93?(d,? J?=?8.8?Hz,?1H),?7.82?(d,? J?=?8.8?Hz,?1H),?7.79?(dd,? J?=?8.8,?3.9?Hz,?1H),?7.76?–?7.73?(m,?1H),?4.24?(d,? J?=?5.4?Hz,?1H),?4.12?(dd,? J?=?4.6,?2.6?Hz,?1H),?4.06?(dd,? J?=?4.6,?2.4?Hz,?1H),?4.03?(dd,? J?=?14.2,?7.1?Hz,?1H),?3.82?(s,?2H).
embodiment 11.the compounds of this invention 21asynthetic
Preparation method is with compound 16b, and difference is that the ethylene glycol 1,3-PD in reaction reagent replaces. 1H?NMR?(600?MHz,?DMSO)?δ?11.13?(s,?1H),?10.71?(s,?1H),?10.22?(s,?1H),?7.90?(d,? J?=?8.7?Hz,?1H),?7.73?(d,? J?=?8.7?Hz,?1H),?7.70?(d,? J?=?8.8?Hz,?1H),?7.64?(d,? J?=?8.8?Hz,?1H),?7.47?–?7.42?(m,?2H),?7.07?–?7.05?(m,?1H),?4.72?(dt,? J?=?19.5,?9.8?Hz,?2H),?4.58?(d,? J?=?8.7?Hz,?2H),?3.96?(dd,? J?=?9.7,?5.2?Hz,?2H),?2.24?–?2.14?(m,?1H),?1.73?–?1.67?(m,?1H).
embodiment 12.the compounds of this invention 21bsynthetic
Preparation method is with compound 16b, and difference is that the ethylene glycol BDO in reaction reagent replaces. 1H?NMR?(600?MHz,?DMSO)?δ?11.13?(s,?1H),?10.69?(s,?1H),?10.23?(s,?1H),?7.73?(s,?1H),?7.71?(dd,? J?=?4.7,?2.6?Hz,?2H),?7.70?–?7.68?(m,?1H),?7.63?(d,? J?=?8.8?Hz,?1H),?7.44?(dd,? J?=?8.4,?1.4?Hz,?1H),?7.07?(dd,? J?=?6.1,?2.3?Hz,?1H),?4.56?(s,?2H),?4.27?(d,? J?=?3.0?Hz,?2H),?4.03?(d,? J?=?4.3?Hz,?2H),?1.73?(d,? J?=?3.9?Hz,?4H).
embodiment 13.the compounds of this invention 21csynthetic
Preparation method is with compound 16c, and difference is that the ethylene glycol 1,3-PD in reaction reagent replaces. 1H?NMR?(600?MHz,?DMSO)?δ?11.12?(s,?1H),?10.75?(s,?1H),?10.66?(s,?1H),?7.90?(d,? J?=?8.7?Hz,?1H),?7.72?(d,? J?=?8.7?Hz,?1H),?7.69?(d,? J?=?8.8?Hz,?1H),?7.63?(d,? J?=?8.8?Hz,?1H),?7.52?(d,? J?=?2.2?Hz,?1H),?7.50?–?7.48?(m,?1H),?7.11?–?7.09?(m,?1H),?4.56?(d,? J?=?8.6?Hz,?2H),?4.34?(d,? J?=?6.5?Hz,?4H),?1.19?(dd,? J?=?28.9,?14.1?Hz,?2H).
embodiment 14.the compounds of this invention 21dsynthetic
Preparation method is with compound 16c, and difference is that the ethylene glycol BDO in reaction reagent replaces..? 1H?NMR?(600?MHz,?DMSO)?δ?10.74?(s,?1H),?10.65?(s,?1H),?10.18?(s,?1H),?7.90?(d,? J?=?8.7?Hz,?1H),?7.81?(d,? J?=?2.0?Hz,?1H),?7.72?(d,? J?=?8.8?Hz,?1H),?7.69?–?7.67?(m,?1H),?7.63?(d,? J?=?8.8?Hz,?1H),?7.57?(dd,? J?=?8.4,?2.0?Hz,?1H),?7.05?–?7.01?(m,?1H),?4.56?(d,? J?=?8.7?Hz,?2H),?4.27?(d,? J?=?12.2?Hz,?2H),?4.04?–?4.01?(m,?2H),?1.73?(s,?4H).
embodiment 15.the compounds of this invention 25asynthetic
Preparation method is with compound 21c, and difference is that the methyl bromoacetate methyl bromide c in reaction reagent replaces. 1H?NMR?(600?MHz,?DMSO)?δ?11.11?(s,?1H),?10.39?(s,?1H),?10.23?(s,?1H),?7.88?–?7.86?(d,? J?=?8.8?Hz,?1H),?7.71?–?7.66?(dd,? J?=?8.4,?20.4?Hz,?2H),?7.61?–?7.60?(m,?2H),?7.51?(s,?1H),?7.16–?7.14?(d,? J?=?7.8?Hz,?1H),?4.72–?4.68?(t,? J?=?9.6?Hz,?2H),?3.85–?3.82?(t,? J?=?7.2?Hz,?4H),?2.69–?2.67?(t,? J?=?7.2?Hz,?2H),?2.17–?2.15?(t,? J?=?7.2?Hz,?1H),?1.69–?1.66?(d,? J?=13.2?Hz,?1H).
embodiment 16.the compounds of this invention 25bsynthetic
Preparation method is with compound 21c, and difference is that the methyl bromoacetate bromo-butyric acid methyl esters in reaction reagent replaces. 1H?NMR?(600?MHz,?DMSO)?δ11.09?(s,?1H),?10.15?(s,?1H),?10.11?(s,?1H),?7.70?–?7.68?(d,? J?=?8.4?Hz,?2H),?7.64?–?7.62?(d,? J?=?8.4?Hz,?3H),?7.53?(s,?1H),?7.13?–?7.12?(d,? J?=?7.8?Hz,?1H),?4.73–?4.70?(t,? J?=?10.2?Hz,?2H),?3.92?–?3.91?(d,? J?=?8.4?Hz,?2H),?3.69–?3.67?(t,? J?=?6.6?Hz,?2H),?2.43?–?2.39?(dd,? J?=?10.2,?15.6?Hz,?2H),?2.17–?2.15?(t,? J?=?6.6?Hz,?1H),?1.88–?1.85?(t,? J?=?13.8?Hz,?2H),?1.69?–?1.67?(d,? J?=?12.0?Hz,?1H).
embodiment 17.the compounds of this invention 20csynthetic
Preparation method is with compound 21c. 1H?NMR?(600?MHz,?DMSO)?δ?10.75?(s,?1H),?7.93?(d,? J?=?8.8?Hz,?2H),?7.71?(d,? J?=?8.8?Hz,?2H),?7.58?(dd,? J?=?8.4,?2.1?Hz,?1H),?7.54?(d,? J?=?2.0?Hz,?1H),?7.03?(d,? J?=?8.4?Hz,?1H),?4.72?(dd,? J?=?11.8,?9.3?Hz,?2H),?4.57?(s,?2H),?3.98?–?3.93?(m,?2H),?3.82?(s,?3H),?2.23?–?2.15?(m,?1H),?1.69?(d,? J?=?13.5?Hz,?1H).
embodiment 18.the compounds of this invention 26synthetic
Preparation method is with compound 6. 1H?NMR?(600?MHz,?DMSO)?δ?12.69?(d,? J?=?69.0?Hz,?1H),?10.71?(s,?1H),?7.90?(d,? J?=?8.6?Hz,?2H),?7.68?(d,? J?=?8.6?Hz,?2H),?7.58?(dd,? J?=?8.4,?1.4?Hz,?1H),?7.54?(s,?1H),?7.02?(t,? J?=?8.4?Hz,?1H),?4.72?(t,? J?=?10.8?Hz,?2H),?4.57?(s,?2H),?3.98?–?3.92?(m,?2H),?2.23?–?2.16?(m,?1H),?1.70?(d,? J?=?13.4?Hz,?1H).
embodiment 19.the compounds of this invention 27synthetic
Isobutyl chlorocarbonate (1.8mmol) is splashed into compound 26(1,5mmol) and in the tetrahydrofuran solution of N-methylmorpholine (3.3mmol), under-15 DEG C of conditions, react 30 minutes, then O-Phenylene Diamine (1.65mmol) is added in reaction solution, continue reaction and spend the night.Reaction finishes rear steaming and desolventizes, and uses acetic acid ethyl dissolution mixture, obtains product 27. after column chromatography purification 1h NMR (600 MHz, DMSO) δ 10.67 (s, 1H), 9.59 (s, 1H), 7.97 (d, j=8.2 Hz, 2H), 7.69 (d, j=8.4 Hz, 2H), 7.62 – 7.57 (m, 1H), 7.55 (s, 1H), 7.15 (d, j=7.6 Hz, 1H), 7.04 (d, j=8.4 Hz, 1H), 6.96 (t, j=7.5 Hz, 1H), 6.78 (d, j=7.9 Hz, 1H), 6.59 (t, j=7.4 Hz, 1H), 4.88 (s, 2H), 4.73 (t, j=10.8 Hz, 2H), 4.58 (s, 2H), 3.96 (d, j=7.5 Hz, 2H), 2.24 – 2.15 (m, 1H), 1.70 (d, j=13.3 Hz, 1H).
embodiment 20. target compound histon deacetylase (HDAC) activity test always (in vitro)
Histon deacetylase (HDAC) (HDACs) active fluoro analytical procedure is mainly in two steps: the first step; containing the Methionin HDACs fluorogenic substrate (Boc-Lys (acetyl)-AMC) of an acetylize side chain; with the histon deacetylase (HDAC) HDACs sample incubation containing expressing; be substrate deacetylate, activate substrate.Second step, use pancreatin hydrolysis Boc-Lys-AMC, produce this fluorophor of AMC (being chromophoric group), measure fluorescence intensity in emission wavelength/excitation wavelength (390nm/460nm), thereby calculate inhibiting rate according to the fluorescence intensity of inhibitor group and control group, and ask and calculate IC50 value.Enzymic activity test philosophy is shown in patent specification part associated viscera.Experimental result is in Table 1-5.
In a table, numerical value is the mean value of three tests, the numeric representation standard deviation after " ± ".
SAHA commodity are called Zolinza, and general Vorinostat by name, for U.S. food Drug Administration (FDA) is in the NSC 630176 of approval listing in 2006.
Above-mentioned test result shows; isatin compounds all shows the inhibition activity stronger to histon deacetylase (HDAC) HDACs; wherein compound 25a is the highest to the inhibition activity of HDACs; and be better than positive control drug SAHA; there is good DEVELOPMENT PROSPECT, and can be used as the lead compound of finding new and effective NSC 630176.
embodiment 21. target compound suppresses the activity test of cell proliferation
Choose the good compound 21a-d of enzymic activity, 25a-b, 27 carry out the activity test of vitro inhibition cancer cell multiplication, the results are shown in Table 6.
Term explanation:
PC-3: human prostate cancer cell line.
MDA-MB-231: breast carcinoma cell strain.
K562: the former leukemia cell line of chronic marrow.
U937: human leukemia cell line.
DMSO: dimethyl sulfoxide (DMSO).
IC50: half-inhibition concentration.
1. [material] PC-3, MDA-MB-231, K562, U937 cell strain, the blue MTT of tetramethyl-azo azoles, 10% foetal calf serum, 96 orifice plates.
2. [method]
Cell cultures PC-3, MDA-MB-231, K562, tetra-kinds of tumor cell lines of U937 all adopt cellar culture.When experiment, all use logarithmic phase cell.
Growth of Cells detects (mtt assay) PC-3, MDA-MB-231, and K562, U937 cell suspension is all adjusted to 1 × 105/ml, is inoculated in respectively 96 orifice plates (50 microlitres/hole), 5000 cells/well.After bed board 4 hours, in every hole, add the substratum of 50 microlitres containing different concns compound, compound final concentration in hole is respectively: 1000,200,40,8.1.6,0.32 microgram/ml, each concentration is established three multiple holes.While not adding the hole reading of cell, do blank, add the hole that cell do not add compound and do compound blank well, SAHA does compound positive control.In 37 DEG C, in 5% carbonic acid gas, to hatch 48 hours, every hole adds the MTT staining fluid of 10 microlitres 10.5%, continues to hatch 4 hours, 2500rpm, centrifugal 30 minutes, then abandon substratum in plate hole, add dimethyl sulfoxide (DMSO), 200 microlitres/hole.Microplate reader and 570nm place measure the absorbancy OD value in every hole, and inhibitory rate of cell growth is calculated as follows:
Inhibiting rate (%)=[(the average OD value of the average OD value-experimental port of control wells) the average OD value of/control wells] × 100%
In a table, numerical value is the mean value of three tests, the numeric representation standard deviation after " ± ".
Upper table test data shows, compound 21a-d, and 25a-b, 27 demonstrate the activity that is better than or is equivalent to positive control SAHA in the experiment of anti-tumour cell proliferative in vitro, have good DEVELOPMENT PROSPECT.

Claims (10)

1. the isatin histone deacetylases inhibitor shown in formula I, or its pharmacy acceptable salt, solvate or prodrug,
Wherein,
R 1hydrogen, halogen F, Cl, Br, I, aryl, heteroaryl, aryl C1-8 alkyl, heteroaryl C1-9 alkyl, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl, C1-8 alkyl, assorted alkyl or cycloalkyl, optional one or more following group replaces: halogen, hydroxyl, cyano group, nitro, C1-9 alkoxyl group, halogen C1-9 alkyl, C1-8 alkyl-carbonyl, C1-8 carbalkoxy, aryl C1-6 carbalkoxy;
R 2aryl, heteroaryl, aryl C1-8 alkyl, heteroaryl C1-8 alkyl, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl, C1-8 alkyl, assorted alkyl or cycloalkyl;
R 3azanol base, hydroxyl, methoxyl group or O-Phenylene Diamine base;
M is 1,2 or 3;
N is 0,1 or 2.
2. compound as claimed in claim 1, is characterized in that: described R 1hydrogen, halogen F, Cl, Br, nitro or hydroxyl.
3. compound as claimed in claim 1, is characterized in that: described R 2c1-5 alkyl, phenyl or styryl.
4. compound as claimed in claim 1, is characterized in that: be one of following compounds:
2-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl)-N-(2-(azanol base)-2-ethoxycarbonyl) ethanamide (8a);
4-(2-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) acetamido)-N-maloyl group amine (8b);
6-(2-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxyl hexanamide (8c);
(E)-3-(4-(2-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) kharophen)-phenyl)-N-hydroxyl acryl acid amides (8d);
4-(2-(5 '-fluoro-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (16a);
4-(2-(5 '-chloro-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (16b);
4-(2-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (16c);
4-(2-(2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (16d);
4-(2-(5 '-methyl-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (16e);
4-(2-(5 '-nitro-2 '-oxo spiral shell [[1,3] dioxolane-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (16f);
4-(2-(5 '-chloro-2 '-oxo spiral shell [[1,3] dioxane-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (21a);
4-(2-(5 '-chloro-2 '-oxo spiral shell [[1,3] dioxepin-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (21b);
4-(2-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxane-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (21c);
4-(2-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxepin-2,3 '-indoline]-1 '-yl) acetamido)-N-hydroxybenzamide (21d);
4-(3-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxane-2,3 '-indoline]-1 '-yl) propionamido-)-N-hydroxybenzamide (25a);
4-(4-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxane-2,3 '-indoline]-1 '-yl) amide-based small)-N-hydroxybenzamide (25b);
N-(2-aminophenyl)-4-(2-(5 '-bromo-2 '-oxo spiral shell [[1,3] dioxane-2,3 '-indoline]-1 '-yl) acetone amino) benzamide (27).
5. the preparation method of the compound as described in claim 1,2,3 or 4, is characterized in that synthetic route is as follows:
synthetic route 1:, react with ethylene ketal through Sandmeyer reaction taking para-bromoaniline as raw material, with methyl bromoacetate nucleophilic reaction, hydrolysis reaction, polypeptide condensation connects R 2group, finally makes hydroximic acid and obtains end product; Synthetic route 1 reaction formula is as follows:
Wherein, R 2described in above-mentioned formula I;
Reagent in said synthesis route 1 reaction formula: (a) Chloral Hydrate, oxammonium hydrochloride, sodium sulfate, 85 DEG C; (b) vitriol oil, 90 DEG C; (c) ethylene glycol, tosic acid, toluene, 130 DEG C; (d) methyl bromoacetate, Tetrabutyl amonium bromide, salt of wormwood, potassiumiodide, acetone, 60 DEG C; (e) ethanol, potassium hydroxide, hydrochloric acid; (f) the amino methyl hexyl hydrochloride of glycine methyl ester hydrochloride or γ-aminobutyric acid methyl ester hydrochloride or 6-or to amino-cinnamic acid methyl ester hydrochloride, isobutyl chlorocarbonate, N-methylmorpholine, tetrahydrofuran (THF) ,-20 DEG C; (g) azanol potassium, methyl alcohol.
6. the preparation method of the compound as described in claim 1,2,3 or 4, is characterized in that synthetic route is as follows:
synthetic route 2:taking the aniline of different para-orientation as raw material, through Sandmeyer reaction, react with ethylene ketal, with methyl bromoacetate nucleophilic reaction, hydrolysis reaction, polypeptide condensation connection methyl p-aminobenzoate group, finally makes hydroximic acid and obtains end product; Synthetic route 2 reaction formula are as follows:
Wherein, R 1described in above-mentioned formula I;
Reagent in said synthesis route 2 reaction formula: (a) Chloral Hydrate, oxammonium hydrochloride, sodium sulfate, 85 DEG C; (b) vitriol oil, 90 DEG C; (c) ethylene glycol, tosic acid, toluene, 130 DEG C; (d) methyl bromoacetate, Tetrabutyl amonium bromide, salt of wormwood, potassiumiodide, acetone, 60 DEG C; (e) ethanol, potassium hydroxide, hydrochloric acid; (f ') methyl p-aminobenzoate hydrochloride, isobutyl chlorocarbonate, N-methylmorpholine, tetrahydrofuran (THF) ,-20 DEG C; (g) azanol potassium, methyl alcohol.
7. the preparation method of the compound as described in claim 1,2,3 or 4, is characterized in that synthetic route is as follows:
synthetic route 3:taking 5 different isatin that replace as raw material, through ketal reaction, with methyl bromoacetate nucleophilic reaction, hydrolysis reaction, polypeptide condensation connects methyl p-aminobenzoate group, finally makes hydroximic acid and obtains end product; Synthetic route 3 reaction formula are as follows:
Wherein, R 1, n is with described in above-mentioned formula I;
Reagent in said synthesis route 3 reaction formula: (h) ethylene glycol, 1,3-PD, BDO, tosic acid, toluene, 130 DEG C; (d) methyl bromoacetate, Tetrabutyl amonium bromide, salt of wormwood, potassiumiodide, acetone, 60 DEG C; (e) ethanol, potassium hydroxide, hydrochloric acid; (f ') methyl p-aminobenzoate hydrochloride, isobutyl chlorocarbonate, N-methylmorpholine, tetrahydrofuran (THF) ,-20 DEG C; (g) azanol potassium, methyl alcohol.
8. the preparation method of the compound as described in claim 1,2,3 or 4, is characterized in that synthetic route is one of following:
synthetic route 4:taking the intermediate compound 17c in synthetic route 3 as raw material, through ketal reaction, with methyl bromoacetate or methyl bromide c nucleophilic reaction, hydrolysis reaction, polypeptide condensation connects methyl p-aminobenzoate group, finally makes hydroximic acid and obtains end product; Synthetic route 4 reaction formula are as follows:
Wherein, m is with described in above-mentioned formula I;
Reagent in said synthesis route 4 reaction formula: (i) methyl bromoacetate or methyl bromide c, Tetrabutyl amonium bromide, salt of wormwood, potassiumiodide, acetone, 60 DEG C; (e) ethanol, potassium hydroxide, hydrochloric acid; (f ') methyl p-aminobenzoate hydrochloride, isobutyl chlorocarbonate, N-methylmorpholine, tetrahydrofuran (THF) ,-20 DEG C; (g) azanol potassium, methyl alcohol;
synthetic route 5:taking intermediate compound 20c in synthetic route 3 as raw material, through hydrolysis reaction, obtain end product with the condensation reaction of O-Phenylene Diamine, synthetic route 5 reaction formula are as follows:
Reagent in said synthesis route 5 reaction formula: (e) ethanol, potassium hydroxide, hydrochloric acid; (j) O-Phenylene Diamine, isobutyl chlorocarbonate, N-methylmorpholine, tetrahydrofuran (THF) ,-20 DEG C.
9. the application of the compound described in claim 1,2,3 or 4 in the medicine of preparing the mammalian diseases that prevention or treatment are relevant to the active unconventionality expression of histon deacetylase (HDAC); The described relevant mammalian diseases to the active unconventionality expression of histon deacetylase (HDAC) comprises: cancer, neurodegenerative disease, virus infection, inflammation, leukemia, malaria and diabetes.
10. be suitable for a mammiferous pharmaceutical composition, comprise the compound described in any one and one or more pharmaceutically acceptable carriers or vehicle in claim 1-4, this pharmaceutical composition is oral gives and/or parenteral gives.
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US9745253B2 (en) 2015-03-13 2017-08-29 Forma Therapeutics, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
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