CN103755595A - Hydroxamic acid derivative and application thereof - Google Patents

Hydroxamic acid derivative and application thereof Download PDF

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CN103755595A
CN103755595A CN201310726434.5A CN201310726434A CN103755595A CN 103755595 A CN103755595 A CN 103755595A CN 201310726434 A CN201310726434 A CN 201310726434A CN 103755595 A CN103755595 A CN 103755595A
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alkyl
cycloalkyl
heterocyclylalkyl
aryl
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余聂芳
宁澄清
刘瑞环
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Central South University
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Central South University
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Abstract

The invention relates to a hydroxamic acid derivative with a structural formula (I), wherein R1, R2, R3 and L are defined in the specification of the invention. The invention further relates to application of the hydroxamic acid derivative with the structural formula (I) as a histone deacetylase (HDAC) inhibitor or/and a PARP-1 (Poly-ADP-Ribose Polymerase-1) inhibitor.

Description

Hydroxamic acid derivatives and application thereof
Technical field
The present invention relates to field of medicaments, be specifically related to hydroxamic acid derivatives and application thereof.
Background technology
Cancer remains one of disease of high incidence high mortality.The cancer patient that China newly increases is every year 2,000,000, because the number of cancer mortality is 1,500,000.In various cancers, mammary cancer has become WomanHealth has been threatened to maximum disease.Chinese population association is in issue < in Beijing < China galactophore disease report of survey > > on February 1st, 2010, report show: in China along with socioeconomic development, the change of people life style and living environment, breast cancer incidence is increased year by year: the rate of growth of China's breast cancer incidence and mortality ratio exceeds national 1～2 percentage point occurred frequently, and be obvious rejuvenation trend.China is annual newly-increased more than 20 ten thousand patient with breast cancers now.
Aspect cancer clinical treatment, chemotherapy remains one of main method.Traditional cell toxicant anticarcinogen particularly acts on DNA or pathways metabolism kind anti-cancer drugs thing because the mechanism of action is clear, curative effect is determined, thereby still application clinically of diameter.And the research and development of targeted drug (particularly small-molecule drug) in recent years have become one of main direction of studying in cancer therapy drug research field.Through exploration for many years, in the fundamental research that " synthetic lethal theory " found at cancer therapy drug, obtained development faster.In numerous synthetic lethal genes, polyadenylic acid bisphosphate ribose transferring enzyme (Poly (ADP-ribose) polymerases, PARP), since within 1963, finding, has just attracted to note widely always.
PARP is DNA breach susceptor, and identification DNA single chain and double-strand break breach (especially DNA single splitting of chain breach) also participates in its reparation.The double-strand break breach reparation of mammalian cell mainly contains two approach: the one, and homologous recombination (homologous recombination, HR, main by this approach), another kind is non-homologous end joining (nonhomologous end joining, NHEJ).The Major Members of HR is cancer suppressor gene BRCA1 and BRCA2.
To the cell of BRCA1/BRCA2 producer sudden change, suppress the activity of cell PARP-1, just can cause mutant cell death, and normal cell is impregnable.Normal cell will be repaired the DNA damage by inductions such as oxidative stresss thousands of times every day, and this mainly gives the credit to the base excision reparation (Base excision repair, BER) that PARP activates.When PARP-1 activity inhibited, thereby because DNA damage fails to repair the accumulation that causes DNA double splitting of chain.Because the cell of BRCA1/BRCA2 sudden change, causes HR effectively not complete.The activity of PARP-1 be suppressed in this cell, can cause genomic highly unstable and finally cause necrocytosis.Famous " synthetic lethal theory " that Here it is.In test, the cell of BRCA1 or BRCA2 sudden change is Normocellular 1000 times to the susceptibility of PARP-1 inhibitor in vitro.
PARP-1 inhibitor can be used for treatment cancer patients, the especially BRCA1 of BRCA1 or BRCA2 defect or the patient with breast cancer of BRCA2 sudden change.BRCA1 or BRCA2 sudden change are mainly found in mammary cancer, ovarian cancer, prostate cancer and carcinoma of the pancreas.
HDAC (Histone Deacetylase) is the same with PARP-1, has participated in chromatin (Chromatin) running balance and has maintained the stable of gene pool (Genome).Hdac inhibitor, as epigenetics cancer therapy drug, has been obtained certain success.There are recently two compounds to obtain FDA approval listing: Vorinostat (SAHA obtains certification for 2006) (Marks, the P.A. of a Ge Shi Merck & Co., Inc.; Breslow, R.Nat.Biotechnol., 2007,25,84-90) and the Romidepsin(FK228 of Gloucester company, 2009) (Lansigan, F.; Foss, M.F.Drugs, 2010,70 (3), 273-286.).But, according to literature survey result, also there is no the difunctional inhibitor of PARP-1 and HDAC at present.
Summary of the invention
For the deficiency of existing cancer therapy drug, the invention provides a kind of hydroxamic acid derivatives and application.This hydroxamic acid derivatives can be used as hdac inhibitor or/and the application of PARP-1 inhibitor has good inhibition active.
Technical scheme of the present invention is:
A kind of hydroxamic acid derivatives, its chemical structure of general formula as shown in the formula (I):
Figure BDA0000446044920000021
In formula I:
R 1, R 2and R 3be selected from following one of two things:
Situation 1:R 1, R 2and R 3independently be selected from respectively one of following group: H, nitro, cyano group, halogen, haloalkyl, haloalkenyl group, hydroxyl, hydroxyalkyl, alkoxyl group, carbalkoxy, aryloxy, alkene oxygen base, alkynyloxy group, cycloalkyloxy, heterocycle alkoxyl group, amino, alkylamino, aminoalkyl group, amide group, alkyl amino-carbonyl, alkylsulfonyl, alkyl sulphonyl, alkyl sulphinyl, amino-sulfonyl, acyl group, cycloalkyl, cycloalkenyl group, Heterocyclylalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, the cycloalkyl alkyl of mixing, the Heterocyclylalkyl alkyl of mixing, the heteroaryl alkyl of mixing, the aryl alkyl of mixing,
Situation 2: at R 1, R 2and R 3in three substituting groups, any two adjacent replacements of substituting group, and two adjacent substituting groups connect into ring, are specially:
r 1, R 2and R 3in not the substituting group of Cheng Huan be selected from one of following group: H, nitro, cyano group, halogen, haloalkyl, haloalkenyl group, hydroxyl, hydroxyalkyl, alkoxyl group, carbalkoxy, aryloxy, alkene oxygen base, alkynyloxy group, cycloalkyloxy, heterocycle alkoxyl group, amino, alkylamino, aminoalkyl group, amide group, alkyl amino-carbonyl, alkylsulfonyl, alkyl sulphonyl, alkyl sulphinyl, amino-sulfonyl, acyl group, cycloalkyl, cycloalkenyl group, Heterocyclylalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, the cycloalkyl alkyl of mixing, the Heterocyclylalkyl alkyl of mixing, the heteroaryl alkyl of mixing, the aryl alkyl of mixing,
Wherein, R 4be selected from one of following group: H, nitro, cyano group, halogen, alkyl, assorted alkyl, haloalkyl, haloalkenyl group, hydroxyl, hydroxyalkyl, alkoxyl group, carbalkoxy, alkoxy aromatic yl, thiazolinyl, cycloalkyl, alkene oxygen base, alkynyloxy group, cycloalkyloxy, heterocycle alkoxyl group, amino, alkylamino, aminoalkyl group, amide group, alkyl amino-carbonyl, alkylsulfonyl, alkyl sulphonyl, alkyl sulphinyl, amino-sulfonyl, acyl group, cycloalkenyl group, Heterocyclylalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, the cycloalkyl alkyl of mixing, the Heterocyclylalkyl alkyl of mixing, the heteroaryl alkyl of mixing, the aryl alkyl of mixing,
X, Y and Z are identical or different, and be independently selected from C, N respectively, O, S;
L is-(CH 2=CH 2) n-, wherein n=0 or 1;
Wherein: " alkyl " is C1-C14 straight or branched aliphatic hydrocarbon group;
" halogen " refers to fluorine, chlorine, bromine or iodine;
The group that " assorted alkyl " refers to straight chain or contain branched-chain alkyl, and in main chain, at least contain one or more heteroatomss; Described " heteroatoms " refers to S, O or N atom;
" thiazolinyl " refers to the alkene of C2-C6;
" cycloalkyl " refers to the carbocyclic ring of monocycle, condensed ring or the volution of saturated or fractional saturation, is the ring of 3-9 carbon atom composition.
" cycloalkenyl group " refers to nonaro-maticity monocycle or encircles ring system more, wherein at least contain a carbon-to-carbon double bond and every ring and have 5-10 carbon atom;
" Heterocyclylalkyl " refers to and at least contains a heteroatomic cycloalkyl, and cycloalkyl is described above;
" aryl " represents the monocycle that can be optionally substituted or thick many rings, aromaticly comprises 5 to 12 carbon atom carbocyclic rings;
" heteroaryl " refers to the group that contains aromatic ring, and it has one or more heteroatoms in the annular atoms of aromatic ring, and heteroatoms is described above;
" cycloalkylalkyl " representative ring alkyl-alkyl, cycloalkyl, alkyl are described above;
" arylalkyl " refers to: (aryl-alkyl)-group, aryl, alkyl are described above;
" heteroarylalkyl " refer to (heteroaryl-alkyl)-group, heteroaryl, alkyl are described above;
" aryl mix alkyl " refer to (aryl-assorted alkyl)-group, aryl, assorted alkyl are described above;
" cycloalkyl mix alkyl " refer to (cycloalkyl-assorted alkyl)-group, cycloalkyl, assorted alkyl are described above;
" Heterocyclylalkyl mix alkyl " refer to (Heterocyclylalkyl-assorted alkyl)-group, Heterocyclylalkyl, assorted alkyl are described above;
" heteroaryl mix alkyl " refer to (heteroaryl-assorted alkyl)-group, heteroaryl, assorted alkyl are described above;
" aminoalkyl group " refer to (amino-alkyl)-group, alkyl is described above;
" alkoxyl group " refer to-O-alkyl, alkyl is described above;
" cycloalkyloxy " refer to-O-cycloalkyl, cycloalkyl is described above;
" alkene oxygen base " refer to-O-alkene-, wherein " alkene " refers to the alkene of C2-C6;
" alkynyloxy group ” Zhi – O-alkynes-, the wherein alkyne of alkynes C2-C6;
" aryloxy " refer to-O-aryl-, aryl is described above;
" heterocycle alkoxyl group " refer to-O-Heterocyclylalkyl-, Heterocyclylalkyl is described above.
Preferably, described R1, R2 and R3 are independently selected from respectively the alkoxyl group of haloalkenyl group, hydroxyl or the C1-C14 of haloalkyl, the C2-C6 of H, nitro, cyano group, halogen, C1-C14.
Preferably, described X, Y and Z are C.
Preferably, at R 1, R 2and R 3any two adjacent replacements and connect into ring in three substituting groups, are specially:
Figure BDA0000446044920000041
described R4 is selected from the cycloalkyl of H, phenyl, a 3-9 carbon atom, arbitrarily replacement or the Heterocyclylalkyl of a unsubstituted 3-9 carbon atom, the alkylene of C2-C6; Described " unsubstituted " represents that not having substituting group or only substituting group is hydrogen, described " optionally replacing " represents that this group can further replace or condense through one or more non-hydrogen substituting group, and described substituting group is: the cycloalkyl of the alkyl of a 1-6 carbon or 1-6 carbon; R 1, R 2and R 3in not the substituting group of Cheng Huan be H.
Further preferably, R1, R2 and R3 are independently selected from respectively H, nitro, halogen, haloalkyl; X, Y and Z are C.
Further preferably, at R 1, R 2and R 3any two adjacent replacements and connect into ring in three substituting groups, are specially:
Figure BDA0000446044920000051
r 1, R 2and R 3in not the substituting group of Cheng Huan be H; Described R 4be selected from the alkylene containing N Heterocyclylalkyl, C2-C6 of the cycloalkyl of H, phenyl, a 3-9 carbon atom, arbitrarily replacement or a unsubstituted 3-9 carbon atom; Described " optionally replacing " represents that this group can further replace or condense through one or more non-hydrogen substituting groups, and described substituting group is: the cycloalkyl of the alkyl of a 1-6 carbon or 1-6 carbon; X, Y and Z are C.
Further preferred, described R 4for have a substituent 3-9 carbon atom containing N Heterocyclylalkyl, wherein, described substituting group is the cycloalkyl of 1-6 carbon.
Described hydroxamic acid derivatives, comprises the pharmacy acceptable salt of the described compound of general formula (1), the pharmacy acceptable salt of prodrug, active metabolite and metabolite.
The application of described hydroxamic acid derivatives in preparation PARP-1 inhibitor and/or hdac inhibitor.
The application of described hydroxamic acid derivatives in preparation treatment cancer drug.
Described cancer is preferably mammary cancer, ovarian cancer, carcinoma of the pancreas, lung cancer, colorectal carcinoma, skin carcinoma or prostate cancer.
Below the present invention is further explained and is illustrated:
Prepare compound and pharmaceutical salt thereof described in general formula I, concrete grammar is as follows:
(1) in general formula I, as be preferably-(CH of L 2=CH 2) n-, and n=0, R 2=NO 2, R 3=H, when X, Y and Z are C, corresponding compound can synthesize by synthetic route 1.
Figure BDA0000446044920000052
Compound 1 is with oxammonium hydrochloride under the condition of triethylamine, and reaction gets final product to obtain the compound 2 in general formula I.Compound 3 is with R-XH under the condition of triethylamine, and reacting by heating obtains intermediate product 4, then gets final product to obtain the compound 5 in general formula I with oxammonium hydrochloride, sodium methylate low-temp reaction.
(2) work as R 1=H, X, Y and Z are C, and R 2and R 3be combined as ring
Figure BDA0000446044920000061
time, corresponding compound can synthesize by synthetic route 2.
Figure BDA0000446044920000062
3-nitrophthalic acid is as starting raw material, after acetic anhydride esterification, then obtains compound 8 with ammoniacal liquor hydrolysis, hofmann rearrangement.Compound 8 obtains compound 9 with methyl alcohol/sulphating, Raney's nickel hydro-reduction again.Compound 9 obtains benzimidizole derivatives 10 through condensation reaction, ring-closure reaction again, then reacts with azanol/sodium methylate, obtains the compound 11 in general formula I.
Term used herein " unsubstituted " represents that not having substituting group or only substituting group is hydrogen.
Term used herein " optionally replaces " and represents that this group can further replace or condense through one or more non-hydrogen substituting group.These substituting groups are independently selected from one or more group below: halogen ,=O ,=S ,-CN ,-NO 2,-CF 3,-OCF 3, alkyl, haloalkyl, assorted alkyl, cycloalkyl, cycloalkenyl group, Heterocyclylalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, the assorted alkyl of cycloalkyl, the assorted alkyl of Heterocyclylalkyl, the assorted alkyl of heteroaryl, the assorted alkyl of aryl, hydroxyl, alkoxyl group, hydroxyalkyl, amino, alkylamino, aminoalkyl group, acyl amino, alkyl sulphonyl and acyl group.
As the part of group or group, " alkyl " is C1-C14 straight or branched aliphatic hydrocarbon group, except being otherwise noted.
The group that " assorted alkyl " refers to straight chain or contain branched-chain alkyl, and in main chain, at least contain one or more S of being selected from, the heteroatoms of O and N.The preferential selection of assorted alkyl contains 2-14 atomchain.Assorted alkyl includes, but are not limited to: ethers, thioether class, alkyl esters, second or trialkyl amines, alkyl sulfinic acid class etc.
" cycloalkyl " refers to the carbocyclic ring of monocycle, condensed ring or the volution of saturated or fractional saturation.Ring take 3-9 carbon atom composition is selected as preferential.This group can be end group or bridged group.
" cycloalkenyl group " refers to nonaro-maticity monocycle or encircles ring system more.Wherein at least contain a carbon-to-carbon double bond and every ring and preferably there is 5-10 carbon atom.This group can be end group or bridged group.
" Heterocyclylalkyl " refers to and at least contains a heteroatomic cycloalkyl.Preferably contain 1-3 heteroatoms.Preferred ring is 3-14 ring, and the ring of more preferably selecting is 4-7 ring.Cycloalkyl, heteroatomic definition are described above.This group can be end group or bridged group.
" aryl " represents the monocycle that can be optionally substituted or thick many rings, aromatic carbocyclic ring (aromatic yl group can be replaced by one or more substituting groups), and every ring preferably comprises 5 to 12 carbon atoms (annular atoms is the atoll texture of carbon).This group can be end group or bridged group.
" heteroaryl " refers to the group that contains aromatic ring, and it has one or more heteroatoms in the annular atoms of aromatic ring.Heteroatomic definition is described above.This group can be end group or bridged group.Heteroaryl groups can be replaced by one or more substituting groups.
" cycloalkylalkyl " representative ring alkyl-alkyl, wherein cycloalkyl and moieties are described above, and this group can be end group or bridged group.
" arylalkyl " refers to: (aryl-alkyl)-group.Wherein, aryl is shown in relevant definition herein with alkyl.This group can be end group or bridged group.
" heteroarylalkyl " refer to (heteroaryl-alkyl)-group.Wherein, aryl is shown in relevant definition herein with moieties.This group can be end group or bridged group.
" aryl mix alkyl " refer to (aryl-assorted alkyl)-group.Wherein, aryl is shown in relevant definition herein with assorted alkyl, and this group can be end group or bridged group.
" cycloalkyl mix alkyl " refer to (cycloalkyl-assorted alkyl)-group.Wherein, cycloalkyl is shown in relevant definition herein with assorted alkyl.This group can be end group or bridged group.
" Heterocyclylalkyl mix alkyl " refer to (Heterocyclylalkyl-assorted alkyl)-group.Wherein, Heterocyclylalkyl is shown in relevant definition herein with assorted alkyl.This group can be end group or bridged group.
" heteroaryl mix alkyl " refer to (heteroaryl-assorted alkyl)-group.Wherein, heteroaryl is shown in relevant definition herein with assorted alkyl.This group can be end group or bridged group.
" aminoalkyl group " refer to (amino-alkyl)-group.Wherein, alkyl is shown in relevant definition herein.This group can be end group or bridged group.
" alkoxyl group " refer to-O-alkyl, wherein alkyl as defined herein.The preferred C1-C6 alkoxyl group of this alkoxyl group.This group can be end group or bridged group.
" cycloalkyloxy " refer to-O-cycloalkyl, wherein cycloalkyl as defined herein.This group can be end group or bridged group.
" alkene oxygen base " refer to-O-light alkene-, wherein light alkene is as defined herein.This group can be end group or bridged group.
" alkynyloxy group ” Zhi the rudimentary alkynes of – O--, the wherein alkyne of rudimentary alkynes C2-C6.This group can be end group or bridged group." aryloxy " refer to-O-aryl-, wherein aryl is as defined herein.This group can be end group or bridged group.
" heterocycle alkoxyl group " refer to-O-heterocycle alkoxyl group-, wherein Heterocyclylalkyl is as defined herein.This group can be end group or bridged group.
Except as otherwise noted, otherwise " alkylamino " refers to alkyl monosubstituted amino and dialkyl amido." alkyl monosubstituted amino " refer to-NH-alkyl, wherein alkyl as above defines." dialkyl amido " refer to-N(alkyl) 2, wherein each alkyl can be identical or different, and all meet the definition about alkyl herein.This group can be end group or bridged group.
Except non-designated, otherwise " arylamino " comprises single arylamino and ammonia diaryl base." single arylamino " expression aryl-NH-, wherein aryl as above defines.Ammonia diaryl base expression (aryl) 2n-, wherein each aryl can be identical or different, and all meet the definition to aryl herein.This group can be end group or bridged group.
" acyl group " represents alkyl-CO-, and wherein alkyl as defined herein.This group can be end group or bridged group.
" alkylsulfonyl " expression-S (O) 2-.This group can be end group or bridged group.
" acyl amino " represent (acyl group-amino)-group, wherein acyl group is as defined herein.This group can be end group or bridged group.
" amino-sulfonyl " represent (amino-alkylsulfonyl)-group, wherein alkylsulfonyl is as defined herein.This group can be end group or bridged group.
" alkyl sulphonyl " refer to-S (O) 2-alkyl, " alkyl sulphinyl " refer to-SO-alkyl, wherein alkyl is as defined herein.This group can be end group or bridged group.
The group of " hydroxyalkyl " refer to-alkyl-hydroxyl.Wherein alkyl as defined herein.
The present invention includes the represented compound of logical formula I and possible various isomery patterns thereof.Comprise: the geometrical isomer of non-mirror image isomer, mirror image isomer, tautomer and " E " or " Z " configurational isomer etc.Any chemist with certain basis all can be isolated the pure compound of above-mentioned optical purity or stereoisomerism.
The present invention includes the represented compound of logical formula I and possible raceme thereof or/and mirror image isomerism thing/or/and the mixture of non-mirror image isomerism thing.
In addition, the represented compound of logical formula I is also contained solvation and the non-solvated pattern of this compound in application.Therefore, the various compound with specified structure that includes, comprises its hydration and anhydrous mould assembly formula.
Except the represented compound of logical formula I, PARP-1 and the HDAC difunctional inhibitor of different specific embodiments comprise: pharmacy acceptable salt, the active metabolite of prodrug and these compounds, and the pharmacy acceptable salt of these metabolites.
Term " pharmacy acceptable salt " refers to that above-claimed cpd can keep original biological activity and be suitable for some salt of medicinal use.The pharmacy acceptable salt that leads to the represented compound of formula I has two kinds of formation forms: the one, with the salt of acid formation; Another is the salt forming with alkali or basic metal.Comprise mineral acid and organic acid with the acid of the represented compound formation pharmacy acceptable salt of logical formula I.Suitable mineral acid comprises: hydrochloric acid, sulfuric acid and phosphoric acid.Suitable organic acid can be selected from aliphatics, cycloaliphatic, aromaticity, heterocyclic carboxylic acid and sulphonic acids organic acid; The example includes but not limited to: formic acid, acetic acid, propionic acid, succsinic acid, glycolic acid, gluconic acid, lactic acid, oxysuccinic acid, tartrate, glycine, arginine, citric acid, FUMARIC ACID TECH GRADE, alkylsulphonic acid, virtue level sulfonic acid etc.Comprise with the basic metal of the represented compound formation pharmacy acceptable salt of logical formula I: lithium, sodium, potassium, magnesium, calcium, aluminium, zinc etc.; Comprise with the alkali of the represented compound formation pharmacy acceptable salt of logical formula I: choline, diethanolamine, morpholine etc.
" prodrug " is the represented derivative of a kind of logical formula I, by means of the mode of metabolism in vivo, it for example, become to the logical represented compound of formula I in vivo transforming (: by hydrolysis, reduce or oxidation).For example, compound and acid-respons represented logical formula I, that contain oh group can be prepared into corresponding ester.Corresponding ester is prodrug, can in vivo be hydrolyzed parent drug again.The acid that is applicable to preparing " prodrug " includes but not limited to: acetic acid, citric acid, lactic acid, tartrate, propanedioic acid, oxalic acid, Whitfield's ointment, succsinic acid, FUMARIC ACID TECH GRADE, maleic acid, methylene radical-bis-beta-hydroxyethyl base naphthoic acid, gentisinic acid, hydroxyethylsulfonic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, tosic acid etc.
Embodiment
In the following example, unless otherwise, all temperature units are degree Celsius.
Various starting raw materials and reagent are all from commercially available.Supplier includes but not limited to: Aldrich Chemical Company, Lancaster Synthesis Ltd etc.Unless otherwise, marketable material and reagent are all without being further purified direct use.
Oven drying and/or heat drying for glassware.(TLC) enterprising line trace of glass silica gel-60F254 flat board (0.25mm) for reaction.Analytical thin-layer chromatography is also launched with suitable solvent ratios (v/v).While exhausting take the upper reaction of TLC starting raw material as reaction end.
1h-NMR collection of illustrative plates is to measure and obtain with Bruker instrument (300MHz or 400MHz), and chemical shift represents with ppm.Use chloroform as reference standard (7.25ppm) or tetramethylsilane internal standard (0.00ppm).Optionally, also can use the solvent that other NMR is conventional. 1the method for expressing of H NMR: s=is unimodal, d=doublet, t=triplet, m=multiplet, br=widens, the doublet of dd=doublet, the doublet of dt=triplet.If when coupling constant is provided, its unit is Hz.
Mass spectrum is to measure and obtain with MS instrument, and ionization mode can be ESI or APCI.
Example is below only the synthetic method for the particular compound of inventing is described.But in synthetic method, do not have any restriction.Unlisted compound in an embodiment, also can use and same below synthetic route and synthetic method, selects suitable starting raw material, and in the place being necessary, the reaction conditions adjustment of suitable common-sense can be prepared a little.
Embodiment 1
Synthetic route one: 4-chloro-N-hydroxyl-3-nitrobenzamide (1)
Figure BDA0000446044920000101
In 50mL round-bottomed flask, add successively oxammonium hydrochloride (2.085g, 0.03mmol), triethylamine (6.2mL), methylene dichloride (15mL), stirring at room 5 minutes, ice bath.Be cooled to, after 0 ℃, add compound a (0.66g, 0.003mol), continue reaction after 1 hour, add 20mL water stopped reaction, extraction, collects dichloromethane layer, adds anhydrous sodium sulfate drying, vacuum-concentrcted, and HPLC separates, and freeze-drying obtains yellow solid 225mg. 1H?NMR(400MHz,DMSO-d 6):δ8.41(d,J=2.0Hz,1H),8.05(dd,J=8.4Hz,J=2.0Hz,1H),7.90(d,J=8.4Hz,1H)。MS(m/z):214.98[M+H] +。
Embodiment 2
4-trifluoromethyl-N-hydroxyl-3-nitrobenzamide (2)
Synthetic route is with embodiment 1. 1H?NMR(400MHz,DMSO-d 6):δ8.55(d,J=2.0Hz,1H),8.35(dd,J=8.0Hz,J=2.0Hz,1H),8.01(d,J=8.0Hz,1H)。MS(m/z):251.17[M+H] +。
Embodiment 3:
Synthetic route two
(R)-N-hydroxyl-2-(2-crassitude)-1H-h-benzimidazole-4-carboxamide (30)
Figure BDA0000446044920000102
In the dry there-necked flask of 1000ml, 30g compound a, with 400ml dissolve with methanol, with the constant pressure funnel dropping 45ml vitriol oil, is slowly warming up to 80 ℃, stir after 24h, while hot reaction solution is poured in appropriate mixture of ice and water, use saturated Na 2cO 3the aqueous solution is adjusted pH=8 left and right, suction filtration, and after gained solid drying, with dehydrated alcohol recrystallization, obtaining compound b is 22.6g.Productive rate: 70.1%; Purity by HPLC:98.7%; 1h-NMR (400MHz, DMSO-d 6): δ 8.35 (s, 2H), 8.34 (dd, J=1.6Hz, 8.3Hz, 1H), 8.22 (dd, J=1.6Hz, 7.8Hz, 1H), 6.75 (t, J=7.8Hz, 8.3Hz, 1H), 3.87 (s, 3H); 13c-NMR (100MHz, DMSO-d 6): δ 167.30,146.77,139.77,133.18,132.55,114.62,114.35,52.84.
Figure BDA0000446044920000103
In 500ml reaction flask, by 22.5g compound b with 200mlMeOH:AcOH=9: 1 mixed solution dissolves, and adds 44.2g SnCl 2.2H 2o, is slowly warming up to 70 ℃, stirs after 4h, and stopped reaction, with saturated Na 2cO 3the aqueous solution is adjusted pH=8 left and right, adds appropriate distilled water, with DCM extraction, and concentrated organic layer, obtaining brown solid compound c is 10.9g.Productive rate: 57.2%; Purity by HPLC:97.5%; 1h-NMR (400MHz, DMSO-d 6): δ 7.10 (dd, J=1.4Hz, 8.1Hz, 1H), 6.71 (dd, J=1.4Hz; 7.5Hz, 1H), 6.39 (t, J=7.5Hz, 8.1Hz, 1H); 6.20 (s, 2H), 4.77 (s, 2H), 3.77 (s, 3H); 13c-NMR (100MHz, DMSO-d 6): δ 169.11,140.05,136.31,119.15,117.78,115.78,109.36,51.74.
Figure BDA0000446044920000111
In dry reaction bottle, by compound d(1eq) with DMF:Pyridine=1:1(6vol) mixed solution dissolve, add CDI(1.1eq), 45 ℃ are stirred after 2h, and reaction solution is cooled to room temperature, add compound c(1eq), after 25 ℃ of stirring 18h of room temperature, be spin-dried for solvent, add AcOH(10vol), 80 ℃ are stirred after 3h, stopped reaction, concentrated, HPLC prepares separation, freeze-drying, obtains Verbindung.Productive rate: 56.4%, 1H-NMR (400MHz, DMSO-d6): δ 12.33 (s, 1H), 7.89 (dd, J=1.7Hz, 7.6Hz, 1H), 7.80 (dd, J=1.7Hz, 7.6Hz, 1H), 7.37-7.32 (m, 2H), 7.30-7.25 (m, 1H), 7.07 (t, J=7.4Hz, 1H), 6.92 (t, J=7.6Hz, 1H), 6.79 (d, J=7.5Hz, 1H), 5.29 (s, 2H), 5.06 (m, 1H), 3.95 (s, 3H), 3.71-3.66 (m, 1H), 3.54-3.48 (m, 1H), 2.36-2.27 (m, 1H), 2.12-2.02 (m, 1H), 1.97-1.92 (m, 2H), MS (m/z): 394.09[M+H] +, 402.05[M+Na] +.
Figure BDA0000446044920000112
In dry reaction bottle, with methyl alcohol (10vol), dissolve e, add after 10%Pd/C, first with N 2air in replacement(metathesis)reaction bottle three times, then with H 2n in replacement(metathesis)reaction bottle 2four times, after 25 ℃ of stirring 18h of room temperature, stopped reaction, with diatomite suction filtration reaction solution, is spin-dried for filtrate, with HPLC preparation, obtains compound f.Productive rate: 74.3%; 1h-NMR (400MHz, DMSO-d 6): δ 7.86 (d, J=7.2Hz, 1H), 7.79 (d; J=7.6Hz, 1H), 7.27 (t, J=7.8Hz; 1H), 4.46 (dd, J=6.5Hz, 1H); 3.96 (s, 3H), 3.04 (m, 1H); 2.91 (m, 1H), 2.18 (m, 1H); 2.04 (m, 1H), 1.78 (m, 2H); MS (m/z): 246.07[M+H] +, 268.05[M+Na] +.
Figure BDA0000446044920000121
In dry reaction bottle, with methyl alcohol (5vol), dissolve f (1eq), add after oxammonium hydrochloride (15eq), drip 30% sodium methylate (20eq), after 0 ℃ of reaction 15-30min, stopped reaction, adjusts pH=3 left and right with cryosel acid, filters, be spin-dried for solvent, with HPLC preparation, freeze-drying, obtains compound 30.Productive rate: 20.6%; 1h-NMR (400MHz, DMSO-d 6): δ 13.46 (s, 1H), 11.58 (s, 1H), 10.08 (s; 1H), 9.33 (s, 1H), 7.82 (d, J=7.4Hz; 1H), 7.78 (d, J=7.9Hz, 1H), 7.36 (t; J=7.8Hz, 1H), 5.09 (m, 1H); 3.46-3.40 (m, 2H), 2.56-2.48 (m, 1H); 2.24-2.17 (m, 1H), 2.16-2.04 (m, 2H); 13c-NMR (100MHz, DMSO-d 6): δ 163.01,158.77,151.73,137.84,122.89,122.44,119.84,117.66,56.04,45.80,39.31,30.70,23.88; MS (m/z): 247.05[M+H] +; HRMS (m/z): calcd for C 12h 14n 4o 2[M+H] +, 247.1192; Found, 247.1190.
Embodiment 4:
The activity test in vitro checking of the compounds of this invention:
By external enzyme inhibition activity, prove biological effectiveness of the present invention.The mensuration of the enzyme inhibition activity to PARP-1 and HDAC1, all adopts the related products of BIOMOL company and related assays method to measure.IC 50calculate with Graphic Prims4 mapping software.
Utilize compound experiment in vitro that srb assay (sulphonyl red bright staining, Sigma Pte Ltd) measures the present invention to each be the half growth inhibitory concentration of tumour cell.((Colo205 and HCT116), mankind mastopathy cell's strain MDA-MB231 and MDA-MB435, Human Lung Cancer cell line A549, Chinese hamster ovary cell strain CHO are available from ATCC for human colon's JEG-3.Co1o205 cell cultures is in containing 2mM paddy ammonia phthalein amine, 5%FBS, in the RPMI1640 of 1.0mM Sodium.alpha.-ketopropionate.The nutrient solution of A549 and MDA-MB231 cell is the RPMI164 containing 2mM L-glutaminate, 5%FBS; And the training liquid of MDA-MB435 cell is the DMEM of 2mM L-glutaminate, 5%FBS.HCT116 cell is incubated in the IMEM containing 2mML mono-glutamine, 5%FBS.Chinese hamster ovary celI, as the contrast of normal cell toxicity, is incubated at CHO special culture media.A549 and Co1o205 cell are inoculated in to 96 orifice plates, 100 μ L/ holes, every hole is respectively 5000 and 40000 cells.By MDA-MB435, HCT116, MDA-MB231, Chinese hamster ovary celI is inoculated in 96 orifice plates, every hole is 6000 cells, by 96 orifice plates in 370C, 5%CO2,100% relative humidity incubator preculture 24 hours, makes cell attachment.
In the time of every kind of cell strain zero control wells, add the 50%(mass/volume of 50 μ L precoolings) TCA fixed cell.It is 0.1 μ M that other holes add the compound 100 μ L(final concentrations of different concns, 1 μ M, 5 μ M, 10 μ M) act on different time span (24h, 48h, 72h), the each time point of each drug level is established 3 multiple holes, and establish blank (cell culture fluid, containing cell), without medicine control wells, (do not add medicine, add equivalent perfect medium), positive drug contrast and normal cell contrast (CHO), be placed in 37 ℃, 5%CO2 incubator and cultivate 48h under complete wet (100% relative humidity) condition.On nutrient solution liquid level, add the 50%(mass/volume of 50 μ L precoolings) TCA fixed cell.Then in 4 ℃, place 1h, abandon supernatant, deionized water wash 5 times of each hole, to remove TCA and serum protein etc.After air drying, every hole adds 0.4%SRB (with 1% acetic acid preparation) the approximately 100 μ L of q.s, and room temperature is placed 20～30min.Discard liquid in each hole, with 1% acetic acid washing 5 times, remove unconjugated dyestuff, until unconjugated dyestuff rinsing is clean fast.Air drying is until cannot see after moisture, with 200 μ L Tris base dissolvings, 5min or impact and mix up and down with Tip head vibrates on oscillator plate, and on multi-functional instrument (M5detection system, MD Group Ltd.) measure, the zeroing of 690nm blank, detection wavelength is 565nm.And then use XL-fit to draw dose response curve to measure its GI 50value.
Embodiment 1-2 is synthetic according to synthetic route 1.As shown in table 1, embodiment 1-2 can anticancer propagation.
The biologically active data of table 1 embodiment 1-2
Figure BDA0000446044920000131
Embodiment 3-35:
Compound in table 2 is all synthetic by above-mentioned synthetic road 2, and measures activity according to the method for embodiment 1-2, and data are as shown in table 2:
Compound and the activity data thereof with chemical structural formula (I) that table 2 can synthesize by method of the present invention
Figure BDA0000446044920000132
Figure BDA0000446044920000141
Figure BDA0000446044920000151
Figure BDA0000446044920000161
Figure BDA0000446044920000171
Figure BDA0000446044920000181
Figure BDA0000446044920000191
Figure BDA0000446044920000201
Figure BDA0000446044920000211
Figure BDA0000446044920000221
Figure BDA0000446044920000231
Figure BDA0000446044920000241
Figure BDA0000446044920000251
Figure BDA0000446044920000261
Figure BDA0000446044920000271

Claims (10)

1. a hydroxamic acid derivatives, its chemical structure of general formula as shown in the formula (I):
Figure FDA0000446044910000011
In formula I:
R 1, R 2and R 3be selected from following one of two things:
Situation 1:R 1, R 2and R 3independently be selected from respectively one of following group: H, nitro, cyano group, halogen, haloalkyl, haloalkenyl group, hydroxyl, hydroxyalkyl, alkoxyl group, carbalkoxy, aryloxy, alkene oxygen base, alkynyloxy group, cycloalkyloxy, heterocycle alkoxyl group, amino, alkylamino, aminoalkyl group, amide group, alkyl amino-carbonyl, alkylsulfonyl, alkyl sulphonyl, alkyl sulphinyl, amino-sulfonyl, acyl group, cycloalkyl, cycloalkenyl group, Heterocyclylalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, the cycloalkyl alkyl of mixing, the Heterocyclylalkyl alkyl of mixing, the heteroaryl alkyl of mixing, the aryl alkyl of mixing,
Situation 2: at R 1, R 2and R 3in three substituting groups, any two adjacent replacements of substituting group, and two adjacent substituting groups connect into ring, are specially:
Figure FDA0000446044910000012
r 1, R 2and R 3in not the substituting group of Cheng Huan be selected from one of following group: H, nitro, cyano group, halogen, haloalkyl, haloalkenyl group, hydroxyl, hydroxyalkyl, alkoxyl group, carbalkoxy, aryloxy, alkene oxygen base, alkynyloxy group, cycloalkyloxy, heterocycle alkoxyl group, amino, alkylamino, aminoalkyl group, amide group, alkyl amino-carbonyl, alkylsulfonyl, alkyl sulphonyl, alkyl sulphinyl, amino-sulfonyl, acyl group, cycloalkyl, cycloalkenyl group, Heterocyclylalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, the cycloalkyl alkyl of mixing, the Heterocyclylalkyl alkyl of mixing, the heteroaryl alkyl of mixing, the aryl alkyl of mixing,
Wherein, R 4be selected from one of following group: H, nitro, cyano group, halogen, alkyl, assorted alkyl, haloalkyl, haloalkenyl group, hydroxyl, hydroxyalkyl, alkoxyl group, carbalkoxy, alkoxy aromatic yl, thiazolinyl, cycloalkyl, alkene oxygen base, alkynyloxy group, cycloalkyloxy, heterocycle alkoxyl group, amino, alkylamino, aminoalkyl group, amide group, alkyl amino-carbonyl, alkylsulfonyl, alkyl sulphonyl, alkyl sulphinyl, amino-sulfonyl, acyl group, cycloalkenyl group, Heterocyclylalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, the cycloalkyl alkyl of mixing, the Heterocyclylalkyl alkyl of mixing, the heteroaryl alkyl of mixing, the aryl alkyl of mixing,
X, Y and Z are identical or different, and be independently selected from C, N respectively, O, S;
L is-(CH 2=CH 2) n-, wherein n=0 or 1;
Wherein: " alkyl " is C1-C14 straight or branched aliphatic hydrocarbon group;
" halogen " refers to fluorine, chlorine, bromine or iodine;
The group that " assorted alkyl " refers to straight chain or contain branched-chain alkyl, and in main chain, at least contain one or more heteroatomss; Described " heteroatoms " refers to S, O or N atom;
" thiazolinyl " refers to the alkene of C2-C6;
" cycloalkyl " refers to the carbocyclic ring of monocycle, condensed ring or the volution of saturated or fractional saturation, is the ring of 3-9 carbon atom composition.
" cycloalkenyl group " refers to nonaro-maticity monocycle or encircles ring system more, wherein at least contain a carbon-to-carbon double bond and every ring and have 5-10 carbon atom;
" Heterocyclylalkyl " refers to and at least contains a heteroatomic cycloalkyl, and cycloalkyl is described above;
" aryl " represents the monocycle that can be optionally substituted or thick many rings, aromaticly comprises 5 to 12 carbon atom carbocyclic rings;
" heteroaryl " refers to the group that contains aromatic ring, and it has one or more heteroatoms in the annular atoms of aromatic ring, and heteroatoms is described above;
" cycloalkylalkyl " representative ring alkyl-alkyl, cycloalkyl, alkyl are described above;
" arylalkyl " refers to: (aryl-alkyl)-group, aryl, alkyl are described above;
" heteroarylalkyl " refer to (heteroaryl-alkyl)-group, heteroaryl, alkyl are described above;
" aryl mix alkyl " refer to (aryl-assorted alkyl)-group, aryl, assorted alkyl are described above;
" cycloalkyl mix alkyl " refer to (cycloalkyl-assorted alkyl)-group, cycloalkyl, assorted alkyl are described above;
" Heterocyclylalkyl mix alkyl " refer to (Heterocyclylalkyl-assorted alkyl)-group, Heterocyclylalkyl, assorted alkyl are described above;
" heteroaryl mix alkyl " refer to (heteroaryl-assorted alkyl)-group, heteroaryl, assorted alkyl are described above;
" aminoalkyl group " refer to (amino-alkyl)-group, alkyl is described above;
" alkoxyl group " refer to-O-alkyl, alkyl is described above;
" cycloalkyloxy " refer to-O-cycloalkyl, cycloalkyl is described above;
" alkene oxygen base " refer to-O-alkene-, wherein " alkene " refers to the alkene of C2-C6;
" alkynyloxy group ” Zhi – O-alkynes-, the wherein alkyne of alkynes C2-C6;
" aryloxy " refer to-O-aryl-, aryl is described above;
" heterocycle alkoxyl group " refer to-O-Heterocyclylalkyl-, Heterocyclylalkyl is described above.
2. hydroxamic acid derivatives according to claim 1, is characterized in that, described X, Y and Z are C.
3. hydroxamic acid derivatives according to claim 1, is characterized in that, described R1, R2 and R3 are independently selected from respectively the alkoxyl group of haloalkenyl group, hydroxyl or the C1-C14 of haloalkyl, the C2-C6 of H, nitro, cyano group, halogen, C1-C14.
4. hydroxamic acid derivatives according to claim 1, is characterized in that, at R 1, R 2and R 3any two adjacent replacements and connect into ring in three substituting groups, are specially:
Figure FDA0000446044910000031
described R4 is selected from the cycloalkyl of H, phenyl, a 3-9 carbon atom, arbitrarily replacement or the Heterocyclylalkyl of a unsubstituted 3-9 carbon atom, the alkylene of C2-C6; Described " unsubstituted " represents that not having substituting group or only substituting group is hydrogen, described " optionally replacing " represents that this group can further replace or condense through one or more non-hydrogen substituting group, and described substituting group is: the cycloalkyl of the alkyl of a 1-6 carbon or 1-6 carbon; R 1, R 2and R 3in not the substituting group of Cheng Huan be H.
5. hydroxamic acid derivatives according to claim 1, is characterized in that, R1, R2 and R3 are independently selected from respectively H, nitro, halogen, haloalkyl; X, Y and Z are C.
6. hydroxamic acid derivatives according to claim 1, is characterized in that, at R 1, R 2and R 3any two adjacent replacements and connect into ring in three substituting groups, are specially:
Figure FDA0000446044910000032
r 1, R 2and R 3in not the substituting group of Cheng Huan be H; Described R 4be selected from the alkylene containing N Heterocyclylalkyl, C2-C6 of the cycloalkyl of H, phenyl, a 3-9 carbon atom, arbitrarily replacement or a unsubstituted 3-9 carbon atom; Described " optionally replacing " represents that this group can further replace or condense through one or more non-hydrogen substituting groups, and described substituting group is: the cycloalkyl of the alkyl of a 1-6 carbon or 1-6 carbon; X, Y and Z are C.
7. hydroxamic acid derivatives according to claim 6, is characterized in that described R 4for have a substituent 3-9 carbon atom containing N Heterocyclylalkyl, wherein, described substituting group is the cycloalkyl of 1-6 carbon.
8. according to the described hydroxamic acid derivatives of one of claim 1-7, it is characterized in that, comprise the pharmacy acceptable salt of the described compound of general formula (1), the pharmacy acceptable salt of prodrug, active metabolite and metabolite.
9. the application of the described hydroxamic acid derivatives of one of claim 1-7 in preparation PARP-1 inhibitor and/or hdac inhibitor.
10. application according to claim 9, is characterized in that, the application of described hydroxamic acid derivatives in preparation treatment cancer drug, and described cancer is preferably mammary cancer, ovarian cancer, carcinoma of the pancreas, lung cancer, colorectal carcinoma, skin carcinoma or prostate cancer.
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