CN105669556A - 3-substituted pyrazole-5-amide compounds having antitumor activity and applications thereof - Google Patents
3-substituted pyrazole-5-amide compounds having antitumor activity and applications thereof Download PDFInfo
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- CN105669556A CN105669556A CN201610004748.8A CN201610004748A CN105669556A CN 105669556 A CN105669556 A CN 105669556A CN 201610004748 A CN201610004748 A CN 201610004748A CN 105669556 A CN105669556 A CN 105669556A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention belongs to the technical field of medicine, relates to thio compounds having antitumor activity, and in particular, relates to thio-containing 3-substituted pyrazole-5-amide compounds and pharmaceutically acceptable salts and hydrates thereof and a drug composition with the compounds as active ingredients, and applications thereof for preparation of histone deacetylase inhibitors and for treatment and/or prevention of cancer. The compound represented by the general formula I and the pharmaceutically acceptable salts and hydrates thereof have the structure described in the specification, wherein R1 and R2 are described in the claims and specification.
Description
Technical field:
The invention belongs to medical art; relate to a kind of sulphur base compounds with anti-tumor activity; it is specifically related to the 3-substituted pyrazolecarboxylic-5-amides containing sulphur base; and pharmacy acceptable salt, hydrate; with the pharmaceutical composition taking this compound as activeconstituents, and in preparation NSC 630176 and be used for the treatment of and/or purposes in preventing cancer.
Background technology:
Epigenetic research is just becoming the hope that the mankind capture tumour. Epigenetic change mostly occurs in early days tumorigenic, and now human body is not yet caused material injury by tumour cell, now intervenes, it is more likely that strangled in cradle. In addition, comparing genetic modification is almost impossible reverse, and epigenetic modification can reverse extremely, and tumour cell is recovered as standard state. Thus, epigenetic research has more wide application prospect.
Histone modification is a kind of important way of epigenetic modification, and the most tumour cell of the mankind all exists histone and modifies abnormal, and this kind of exception can cause cancer suppressor gene silence to cause tumour to be formed. Histon deacetylase (HDAC) (Histonedeacetylase, HDAC) it is an enzyme family comprising multiple member, there will be a known 18 kinds of hypotypes at present, by its germline and different from yeast homology be divided into following four classes: with yeast Rpd3, HoS1, the I class of HoS2 homology, comprises HDAC1,2,3,8; With yeast Hda1, the IIa class of HoS3 homology comprises HDAC4,5,7,9, IIb class and comprises HDAC6,10; With the Group III of yeast Sir2 homology, comprise SIRT1～SIRT7; Homoeology is had with I and II class HDAC, but the IV class that its germline is different, there is HDAC11. Wherein I, II, IV class is classical Zn2+The HDACs relied on, and Group III belongs to Sirtuin family, is NAD+The HDACs relied on. Research shows, I and II class HDACs can inhibition tumor cell differentiation and wither and die, promote tumor cell proliferation etc., its generation with tumour, develop closely related, be that the inhibitor of target spot is studied and become one of focus that antitumor drug studies taking HDACs.
The present invention, on the basis of reference, has designed and synthesized a series of 3-substituted pyrazolecarboxylic-5-amides containing sulphur base, and anti tumor activity in vitro test result shows, it has good anti-tumor activity, and shows excellent HDAC restraining effect.
Summary of the invention:
It is an object of the invention to provide a kind of have anti-tumor activity sulphur base compounds; be specially the 3-substituted pyrazolecarboxylic-5-amides containing sulphur base and its preparation method, and this compounds as NSC 630176 prevention and/or treatment tumour in application.
The present invention relates to the compound shown in general formula I and pharmacy acceptable salt thereof, hydrate:
Wherein,
R1Independently it is selected from following substituting group: H, C1-C4Alkyl, C3-C6Cycloalkyl, substituted or unsubstituted C6～C10Aryl or heteroaryl, described substituting group can be C1-C4Alkoxyl group, C1-C4Alkyl, C6～C10Aryl, described heteroaryl contains 1-3 N, the heteroatoms of O or S;
R2Independently it is selected from following substituting group: H, C1-C4Alkyl, C1-C4Acyl group, C1-C4Alkene base oxygen carbonyl, carbobenzoxy-(Cbz), C6-C12Artyl sulfo, oleic acid base, 3-pyridyl-1H-pyrazoles-5-amide group-1,6-own base-sulphur base; Preferred H, methyl, ethanoyl, propionyl, positive butyryl radicals, isobutyryl, the third alkenyloxycarbonyl, carbobenzoxy-(Cbz), pyridine thio, oleic acid base, 3-pyridyl-1H-pyrazoles-5-amide group-1,6-own base-sulphur base;
Preferably, R1Independently it is selected from following substituting group: H, C1-C4Alkyl, C3-C6Cycloalkyl, substituted or unsubstituted phenyl, naphthyl, pyridyl, pyrazinyl, indyl, described substituting group is C1-C4Alkoxyl group, phenyl; Preferred H, cyclohexyl, methyl, p-methoxy-phenyl, xenyl, naphthyl, pyridyl, pyrazinyl, indyl.
The present invention preferably relates to and defines such as the compound of general formula I and pharmacy acceptable salt thereof, hydrate:
R1Independently it is selected from following substituting group: H, cyclohexyl, methyl, p-methoxy-phenyl, xenyl, 6～10 yuan of aryl;
R2Independently it is selected from following substituting group: H, C1-C4Alkyl, C1-C4Acyl group, C1-C4Alkene base oxygen carbonyl, carbobenzoxy-(Cbz), C6-C12Artyl sulfo, oleic acid base, 3-pyridyl-1H-pyrazoles-5-amide group-1,6-own base-sulphur base;
The present invention preferably relates to and defines such as the compound of general formula I and pharmacy acceptable salt thereof, hydrate:
Wherein,
R1Independently it is selected from following substituting group: H, cyclohexyl, methyl, phenyl, p-methoxy-phenyl, xenyl, naphthyl, pyridyl, pyrazinyl, indyl;
R2Independently it is selected from following substituting group: H, C1-C4Alkyl, C1-C4Acyl group, C1-C4Alkene base oxygen carbonyl, carbobenzoxy-(Cbz), C6-C12Artyl sulfo, oleic acid base, 3-pyridyl-1H-pyrazoles-5-amide group-1,6-own base-sulphur base.
Specifically, the present invention is preferably as follows compound:
3-methyl-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-cyclohexyl-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-phenyl-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(4-p-methoxy-phenyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(3.4-Dimethoxyphenyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(3,4,5-trimethoxyphenyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(4-xenyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(1-naphthyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(2-naphthyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(2-pyridyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(3-pyridyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(4-pyridyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(2-pyrazinyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(3-indyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-methyl mercapto)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides;
N-(6-(2-pyridyldithiol) own base)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-propionyl sulfydryl)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the 6-positive butyryl own base of sulfydryl)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-isobutyryl sulfydryl)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-third alkenyloxycarbonyl sulfydryl)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-carbobenzoxy-(Cbz) sulfydryl)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the 6-oleic acid own base of base sulfydryl)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-acetyl mercapto)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-methyl mercapto)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides;
N-(6-(2-pyridyldithiol) own base)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-propionyl sulfydryl)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the 6-positive butyryl own base of sulfydryl)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-isobutyryl sulfydryl)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-third alkenyloxycarbonyl sulfydryl)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-carbobenzoxy-(Cbz) sulfydryl)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the 6-oleic acid own base of base sulfydryl)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-acetyl mercapto)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides;
N, N '-(two 1,6-own base disulfide group)-(two 3-(4-pyridyl)-1H-pyrazoles-5-acid amides);
N, N '-(two 1,6-own base disulfide group)-(two 3-(3-pyridyl)-1H-pyrazoles-5-acid amides).
In addition, the present invention also comprises the front medicine of the compounds of this invention. According to the present invention, front medicine is the compound of general formula I, they self may have more weak activity or even not have activity, but upon administration, are converted to corresponding biologically active form (such as by metabolism, solvolysis or other mode) in physiological conditions.
The present invention comprises pharmaceutical composition, and said composition contains the sulphur base compounds containing 3 (5)-substituted-phenyl-5 (3)-amide group fragments of formula I and pharmaceutically acceptable excipient. Described pharmaceutically acceptable excipient refers to any thinner, auxiliary and/or the carrier that can be used for pharmaceutical field. The compound of the present invention can combinationally use with other activeconstituentss, such as, as long as they do not produce other disadvantageous effect, anaphylaxis.
The pharmaceutical composition of the present invention can be mixed with several formulation, wherein containing some excipient conventional in pharmaceutical field, such as, and oral preparations (such as tablet, capsule, solution or suspension); The preparation of injectable (such as solution or the suspension of injectable, or the dried powder of injectable, adding water for injection before the injection can use immediately); Topical formulations (such as ointment or solution).
Carrier for pharmaceutical composition of the present invention is available common type in pharmaceutical field, comprising: the tackiness agent of oral preparations, lubricant, disintegrating agent, solubility promoter, thinner, stablizer, suspension agent, pigment, correctives etc.; The sanitas of injectable formulation, solubilizing agent, stablizer etc.; The matrix of topical formulations, thinner, lubricant, sanitas etc. Pharmaceutical preparation can oral administration or parenteral (such as intravenously, subcutaneous, intraperitoneal or local) administration, if some drugs is unstable when stomach, enteric coated tablets can be mixed with.
By external press down enzyme test screening, we find the compounds of this invention can inhibition of histone deacetylation enzyme activity, therefore, the compounds of this invention can be used for the application in the disease relevant to histone deacetylase activity unconventionality expression, such as various cancer.
Screened and pharmacodynamic study in body by external activity, we find that the compounds of this invention has anti-tumor activity, therefore the compounds of this invention may be used for preparing the medicine treating and/or preventing various cancer, such as mammary gland, lung, colon, rectum, stomach, prostate gland, bladder, uterus, pancreas and ovarian cancer.
Active compound of the present invention can be used as unique cancer therapy drug use, or with one or more other antitumor drug conbined usage. Combination therapy by by each therapeutic component simultaneously, order or separate administration and realize.
The compounds of this invention and its preparation method are illustrated and illustrated to the embodiment hereinafter provided and preparation example further. It is to be understood that the scope of following embodiment and preparation example and limit the scope of the invention never in any form.
Synthetic route below describes the preparation of the formula I of the present invention, and all raw materials are all the methods by describing in these routes, prepared by the method known by organic chemistry filed those of ordinary skill or commercially available. Whole finalization compounds of the present invention are all the methods by describing in these routes or are prepared by similar method, and these methods are that organic chemistry filed those of ordinary skill is known. In these routes, the whole variable factor of application is such as definition hereafter or such as the definition in claim.
According to the formula I of the present invention, R2During for H, according to the obtained target compound of the method for route one. Each substituting group as Summary define.
According to the formula I of the present invention, R2During for methyl, according to the obtained target compound of the method for route two. Each substituting group as Summary define.
According to the formula I of the present invention, R2During for pyridine thio, according to the obtained target compound of the method for route three. Each substituting group as Summary define.
According to the formula I of the present invention, R2During for 3-pyridyl-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-amide group, according to the obtained target compound of the method for route four. Each substituting group as Summary define.
According to the formula I of the present invention, R2During for other substituting groups, according to the obtained target compound of the method for route four. Each substituting group as Summary define.
Preparation method of the present invention is simple to operate, mild condition, and gained compound all has histon deacetylase (HDAC) inhibit activities, and antitumor action is remarkable.
Embodiment
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary enforcement modes and object are only used for enumerating the present invention; not the real protection scope of the present invention is formed any type of any restriction, more non-protection scope of the present invention is confined to this.
The preparation of embodiment 1:3-methyl-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides
Steps A: the preparation of 2,4-dioxo methyl valerate
In 1g sodium, the methyl alcohol adding 20ml drying is dripped at 0 DEG C, it is stirred to sodium all to dissolve, under room temperature, this solution is dropped in the 150ml diethyl ether solution of 2.1g (36mmol) acetone and 4.3g (36mmol) dimethyl oxalate, reaction 4h, take out filter, filtration cakes torrefaction. Obtaining white solid, receipts rate is 99.2%..
The preparation of step B:3-methyl isophthalic acid H-pyrazoles-5-methyl-formiate
150ml acetic acid is added, stirring and dissolving in 5.1g (35.7mmol) 2,4-dioxo methyl valerate, add 2.14ml (43.2mmol) 98% hydrazine hydrate, back flow reaction 2h, reaction solution is poured in a large amount of cold water, precipitate out solid, take out filter, filtration cakes torrefaction. Obtaining white solid, receipts rate is 99.7%.
The preparation of step C:3-methyl isophthalic acid H-pyrazoles-5-carboxylic acid
In 10.1g (71.8mmol) 3-methyl isophthalic acid H-pyrazoles-5-methyl-formiate, add 75ml methyl alcohol, stirring and dissolving, add the 150ml aqueous solution of 4.4g (110mmol) sodium hydroxide, after 50 DEG C of reaction 2h, regulate pH=2 with 2M hydrochloric acid, precipitate out solid, take out filter, filtration cakes torrefaction. Obtaining white solid, receipts rate is 99.8%.
The preparation of step D:N-(the own base of 6-bromine)-3-methyl isophthalic acid H-pyrazoles-5-acid amides
1.2g (9.7mmol) 3-methyl isophthalic acid H-pyrazoles-5-carboxylic acid is dissolved in 50ml tetrahydrofuran (THF), 0.5ml triethylamine is added at 0 DEG C, 1.6g (11.6mmol) 1-hydroxy benzo triazole (HOBt), stirring and dissolving, add the own amine of 3.0g (11.6mmol) 6-bromine, stir 10min, add 2.3g (12.0mmol) 1-ethyl-3 (3-dimethyl propylamine) carbodiimide (EDCI), 50ml water is added after room temperature reaction 24h, extraction into ethyl acetate 2 times, merge organic layer, organic layer 0.5M salt pickling 1 time, wash 1 time, saturated sodium bicarbonate aqueous solution washes 1 time, saturated sodium-chloride water solution washes 2 times, organic layer anhydrous sodium sulfate drying. filtering, filtrate concentrates to obtain brown solid, and receipts rate is 79.4%.
Step e: the preparation of 3-methyl-N-(the own base of 6-acetyl mercapto)-1H-pyrazoles-5-acid amides
2.9g (10mmol) N-(the own base of 6-bromine)-3-methyl isophthalic acid H-pyrazoles-5-acid amides is dissolved in 100ml ethanol, add 3.42g (30mmol) thioacetic acid potassium, cross after being warming up to 60 DEG C of reaction 4h and filter out insolubles, steam dry filtrate, methylene dichloride dissolves, dichloromethane layer washes 2 times, and saturated sodium-chloride water solution washes 2 times, anhydrous sodium sulfate drying. After concentrated, crude product is through column chromatography for separation (silica gel, petrol ether/ethyl acetate, 5/1), obtains brown solid, and receipts rate is 71.5%.
Step F: the preparation of 3-methyl-N-(the own base of 6-acetyl mercapto)-1H-pyrazoles-5-acid amides
2.8g (10mmol) S-(6-(5-(4-fluorophenyl)-1H-pyrazoles-3-amide group) own base) acetyl thioesters is dissolved in 100ml ethanol; the LiOH aqueous solution of 25ml1.2mol/L is added under nitrogen protection; steam after room temperature reaction 4h except ethanol; add 100ml water; 2M hydrochloric acid adjusts pH=2, extraction into ethyl acetate 2 times, collected organic layer; organic layer saturated sodium-chloride water solution washes 2 times, anhydrous sodium sulfate drying. After concentrated, crude product is through column chromatography for separation (silica gel, petrol ether/ethyl acetate, 5/1), obtains white solid, and receipts rate is 65.2%.
According to the preparation method of embodiment 1, select suitable raw material, the compound of obtained embodiment 2-embodiment 15.
The preparation of embodiment 2:N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides
The preparation of embodiment 3:3-cyclohexyl-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides
LC-MSm/z:335.1[M+H]+.
The preparation of embodiment 4:3-phenyl-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides
LC-MSm/z:338.2[M+H]+.
The preparation of embodiment 5:3-(4-p-methoxy-phenyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides
LC-MSm/z:308.4[M+H]+.
The preparation of embodiment 6:3-(3.4-Dimethoxyphenyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides
LC-MSm/z:304.2[M+H]+.
The preparation of embodiment 7:3-(3,4,5-trimethoxyphenyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides
LC-MSm/z:320.3[M+H]+.
The preparation of embodiment 8:3-(4-xenyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides
LC-MSm/z:359.3[M+H]+.
The preparation of embodiment 9:3-(1-naphthyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides
The preparation of embodiment 10:3-(2-naphthyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides
LC-MSm/z:359.5[M+H]+
The preparation of embodiment 11:3-(2-pyridyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides
LC-MSm/z:334.6[M+H]+
The preparation of embodiment 12:3-(3-pyridyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides
LC-MSm/z:358.3[M+H]+
The preparation of embodiment 13:3-(4-pyridyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides
LC-MSm/z:370.2[M+H]+
The preparation of embodiment 14:3-(2-pyrazinyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides
LC-MSm/z:370.6[M+H]+
The preparation of embodiment 15:3-(3-indyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides
LC-MSm/z:370.1[M+H]+
The preparation of embodiment 16:N-(the own base of 6-methyl mercapto)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides
3.5g (10mmol) N-(the own base of 6-bromine)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides is dissolved in 100ml ethanol, add 1.4g (30mmol) sulfydryl methane, cross after being warming up to 60 DEG C of reaction 4h and filter out insolubles, steam dry filtrate, methylene dichloride dissolves, dichloromethane layer washes 2 times, and saturated sodium-chloride water solution washes 2 times, anhydrous sodium sulfate drying.After concentrated, crude product is through column chromatography for separation (silica gel, petrol ether/ethyl acetate, 5/1), obtains brown solid, and receipts rate is 64.1%
LC-MSm/z:366.2[M+H]+
The preparation of embodiment 17:N-(6-(2-pyridyldithiol) own base)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides
1.7g (5mmol) 3-(4-pyridyl)-N-(the own base of 6-acetyl mercapto)-1H-pyrazoles-5-acid amides is dissolved in 100mlDMF, add 1ml ethamine, drip and add 3.3g (15mmol) 2,2 '-dimercapto pyridine, room temperature reaction 12h. Stopped reaction, adds 200ml water, extraction into ethyl acetate 3 times, concentrated, prepares liquid phase separation fast, obtains white solid. Receipts rate 37.8%.
LC-MSm/z:376.5[M+H]+
The preparation of embodiment 18:N-(the own base of 6-propionyl sulfydryl)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides
1.5g (5mmol) 3-(4-pyridyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides is dissolved in 100ml methylene dichloride, drip at 0 DEG C and add 0.46g (5mmol) propionyl chloride, drip the complete room temperature that is transferred to and continue reaction 1h. Stopped reaction, adds 200ml water, dichloromethane extraction 3 times, concentrated, prepares liquid phase separation fast, obtains white solid. Receipts rate 76.3%.
LC-MSm/z:322.7[M+H]+
According to the preparation method of embodiment 18, select suitable raw material, the compound of obtained embodiment 19-embodiment 24.
The preparation of embodiment 19:N-(the 6-positive butyryl own base of sulfydryl)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides
LC-MSm/z:336.2[M+H]+
The preparation of embodiment 20:N-(the own base of 6-isobutyryl sulfydryl)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides
LC-MSm/z:348.4[M+H]+
The preparation of embodiment 21:N-(the own base of 6-third alkenyloxycarbonyl sulfydryl)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides
LC-MSm/z:291.5[M-H]-
The preparation of embodiment 22:N-(the own base of 6-carbobenzoxy-(Cbz) sulfydryl)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides
LC-MSm/z:294.2[M-H]-
The preparation of embodiment 23:N-(the 6-oleic acid own base of base sulfydryl)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides
LC-MSm/z:264.3[M-H]-
The preparation of embodiment 24:N-(the own base of 6-acetyl mercapto)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides
LC-MSm/z:308.8[M+H]+
According to the preparation method of embodiment 16, select suitable raw material, the compound of obtained embodiment 25.
The preparation of embodiment 25:N-(the own base of 6-methyl mercapto)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides
LC-MSm/z:366.5[M+H]+
According to the preparation method of embodiment 17, select suitable raw material, the compound of obtained embodiment 26.
The preparation of embodiment 26:N-(6-(2-pyridyldithiol) own base)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides
LC-MSm/z:376.0[M+H]+
According to the preparation method of embodiment 18, select suitable raw material, obtained embodiment 27 compound.
The preparation of embodiment 27:N-(the own base of 6-propionyl sulfydryl)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides
LC-MSm/z:322.9[M+H]+
According to the preparation method of embodiment 27, select suitable raw material, obtained embodiment 28-embodiment 33 compound.
The preparation of embodiment 28:N-(the 6-positive butyryl own base of sulfydryl)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides
LC-MSm/z:336.0[M+H]+
The preparation of embodiment 29:N-(the own base of 6-isobutyryl sulfydryl)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides
LC-MSm/z:348.1[M+H]+
The preparation of embodiment 30:N-(the own base of 6-third alkenyloxycarbonyl sulfydryl)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides
LC-MSm/z:291.7[M-H]-
The preparation of embodiment 31:N-(the own base of 6-carbobenzoxy-(Cbz) sulfydryl)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides
LC-MSm/z:294.3[M-H]-
The preparation of embodiment 32:N-(the 6-oleic acid own base of base sulfydryl)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides
LC-MSm/z:264.1[M-H]-
The preparation of embodiment 33:N-(the own base of 6-acetyl mercapto)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides
LC-MSm/z:308.5[M+H]+
Embodiment 34:N, N ' preparation of-(two 1,6-own base disulfide group)-(two 3-(4-pyridyl)-1H-pyrazoles-5-acid amides)
1.9g (5mmol) N-(6-(2-pyridyldithiol) own base)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides is dissolved in 100mL methylene dichloride; 1.8g (5mmol) 3-(4-pyridyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides is added, examination room temperature reaction 24h under nitrogen protection.Stopped reaction, adds 200mL water, 80mL dichloromethane extraction 3 times, concentrated, prepares liquid phase separation fast, obtains white solid. Receipts rate 61.2%.
LC-MSm/z:607.8[M+H]+
According to the preparation method of embodiment 34, select suitable raw material, the compound of obtained embodiment 35.
Embodiment 35:N, N ' preparation of-(two 1,6-own base disulfide group)-(two 3-(3-pyridyl)-1H-pyrazoles-5-acid amides)
LC-MSm/z:608.0[M+H]+
Embodiment 36. product pharmacological research of the present invention
Blank group (not dosing) and positive controls (Vorinostat) are established in experiment. By testing compound and Hela nuclear extract or HDAC1 or HDAC6 preculture 15min under room temperature, add fluorogenic substrate Boc Lys (Ac) AMC. After cultivating 60min at 37 DEG C, add terminator (containing Trypsin and SAHA) termination reaction. After 15min, application the multi-functional microplate reader of all-wave length excite be respectively 355nm and 460nm with emission wavelength time fluorescence intensity, calculate inhibiting rate. HDACs enzyme inhibition activity is shown in Tab.1 by target compound.
Tab.1 embodiment 1-15 is to HDACs, HDAC1, HDAC6 inhibit activities
The vitro inhibition activity test of inhibition of cell proliferation
1. cell recovery
From liquid nitrogen, carefully take out cell (cryopreservation tube) all melt rapidly in 37～40 DEG C of water-baths, make cell cross rapidly very easily impaired 0～5 DEG C temperature range. Aseptically putting into centrifuge tube with shifting liquid rifle sucking-off cell, centrifugal 3min under 1300r/min, adds nutrient solution after abandoning supernatant gently, and the mixed even and fine born of the same parents of piping and druming, move into and put into CO2gas incubator cultivation in culturing bottle, change liquid once after 4h.
2. passage
Need subculture 2-3 time can test after it is stable after cell recovery, go down to posterity every time and stick bottom culturing bottle 90% with cell and be as the criterion.
3. cell buried plate
Cell growth makes it digest bottom culturing bottle with trypsin solution (0.25%) when sticking bottom culturing bottle. Adding 10mL nutrient solution after abandoning trypsin solution gently, the mixed even and fine born of the same parents of piping and druming, draw 10uL cell suspension and add counting in cell counting count board, adjustment cell concn is 3.5 × 104Individual/hole. Except A1 hole is that blank well does not add extracellular in 96 orifice plates, all the other all add 100uL cell suspension. 96 orifice plates are put into incubator and cultivates 24h.
4. cell dosing
First with 50 μ LDMSO dissolved substances. Then add appropriate nutrient solution, make medicine dissolution become 2mmol/mL liquid. Then in 96 orifice plates, medicine dissolution is become 100,50,25,12.5,6.25 μm of ol/mL. Each concentration adds 3 holes, and wherein around two row two row cell growing ways are affected by environment relatively big, only use as blank cell hole. 96 orifice plates are put into incubator and cultivates 24h.
MTT test determination method
By cell by 1.5～3 × 104Cell density buries 96 orifice plates, and every hole 100uL, cell attachment 24h add the medicine (100uL/ hole) of different concns, MTT is added after medicine and cell incubation 96h, after putting into incubator 4h, abandon MTT (tetrazole) solution, add DMSO200uL. On magnetic force vibrator, vibration makes survivaling cell and MTT reaction product first fully dissolve, and puts into microplate reader and reads OD value at 570nm wavelength place. It is calculated as follows inhibiting rate:
Take SAHA as positive control drug, the vitro inhibition activity test of the inhibition of cell proliferation of target compound. Test-results is shown in Tab.2.
Tab.2 embodiment 1-23 is to breast cancer cell MCF-7 growth in vitro inhibit activities
Above-mentioned test-results shows, the compound of the general formula that the present invention to be protected has good anti-tumor activity and HDAC restraining effect.The compound of the present invention has good prospects for commercial application.
Claims (9)
1. compound as shown in general formula I and pharmacy acceptable salt thereof or hydrate:
Wherein,
R1Independently it is selected from following substituting group: H, C1-C4Alkyl, C3-C6Cycloalkyl, substituted or unsubstituted C6~C10Aryl or heteroaryl, described substituting group can be C1-C4Alkoxyl group, C1-C4Alkyl, C6~C10Aryl, described heteroaryl contains 1-3 N, the heteroatoms of O or S;
R2Independently it is selected from following substituting group: H, C1-C4Alkyl, C1-C4Acyl group, C1-C4Alkene base oxygen carbonyl, carbobenzoxy-(Cbz), C6-C12Artyl sulfo, oleic acid base, 3-pyridyl-1H-pyrazoles-5-amide group-1,6-own base-sulphur base.
2. compound according to claim 1 and pharmacy acceptable salt thereof or hydrate:
Wherein,
R1Independently it is selected from following substituting group: H, C1-C4Alkyl, C3-C6Cycloalkyl, substituted or unsubstituted phenyl, naphthyl, pyridyl, pyrazinyl, indyl, described substituting group is C1-C4Alkoxyl group, phenyl.
3. compound described in claim 1 or 2 and pharmacy acceptable salt thereof or hydrate:
Wherein,
R1Independently it is selected from following substituting group: H, cyclohexyl, methyl, p-methoxy-phenyl, xenyl, naphthyl, pyridyl, pyrazinyl, indyl.
4. compound described in any one and pharmacy acceptable salt thereof or hydrate in claim 1-3:
Wherein,
R2Independently it is selected from following substituting group: H, methyl, ethanoyl, propionyl, positive butyryl radicals, isobutyryl, the third alkenyloxycarbonyl, carbobenzoxy-(Cbz), pyridine thio, oleic acid base, 3-pyridyl-1H-pyrazoles-5-amide group-1,6-own base-sulphur base.
5., according to the compound of claim 1-4 described in any one and pharmacy acceptable salt thereof or hydrate, it is selected from:
3-methyl-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-cyclohexyl-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-phenyl-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(4-p-methoxy-phenyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(3.4-Dimethoxyphenyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(3,4,5-trimethoxyphenyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(4-xenyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(1-naphthyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(2-naphthyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(2-pyridyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(3-pyridyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(4-pyridyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(2-pyrazinyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
3-(3-indyl)-N-(the own base of 6-sulfydryl)-1H-pyrazoles-5-acid amides;
N-(6-(2-pyridyldithiol) own base)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-methyl mercapto)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-acetyl mercapto)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-propionyl sulfydryl)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the 6-positive butyryl own base of sulfydryl)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-isobutyryl sulfydryl)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-third alkenyloxycarbonyl sulfydryl)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-carbobenzoxy-(Cbz) sulfydryl)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the 6-oleic acid own base of base sulfydryl)-3-(4-pyridyl)-1H-pyrazoles-5-acid amides;
N,N'-(two 1,6-own base disulfide group)-(two 3-(4-pyridyl)-1H-pyrazoles-5-acid amides);
N-(6-(2-pyridyldithiol) own base)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-methyl mercapto)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-acetyl mercapto)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-propionyl sulfydryl)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the 6-positive butyryl own base of sulfydryl)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-isobutyryl sulfydryl)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-third alkenyloxycarbonyl sulfydryl)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the own base of 6-carbobenzoxy-(Cbz) sulfydryl)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides;
N-(the 6-oleic acid own base of base sulfydryl)-3-(3-pyridyl)-1H-pyrazoles-5-acid amides;
N,N'-(two 1,6-own base disulfide group)-(two 3-(3-pyridyl)-1H-pyrazoles-5-acid amides).
6. a pharmaceutical composition, it is characterised in that: comprise in claim 1-6 any one compound and pharmacy acceptable salt thereof or hydrate, and pharmaceutically acceptable vehicle.
7. the application of pharmaceutical composition described in any one compound and pharmacy acceptable salt thereof or hydrate or claim 6 in the disease medicament that preparation is relevant to histone deacetylase activity unconventionality expression in claim 1-5.
8. in claim 1-5 pharmaceutical composition described in any one compound and pharmacy acceptable salt thereof or hydrate or claim 6 in the application prepared in antitumor drug.
9. apply as claimed in claim 8, it is characterised in that, described tumour is prostate cancer, mammary cancer, cervical cancer or leukemia.
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| CN110283067A (en) * | 2019-06-27 | 2019-09-27 | 湖北大学 | A kind of synthetic method of 2,4- dihydroxy -3,3- acid dimethyl |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107445896A (en) * | 2017-08-08 | 2017-12-08 | 沈阳药科大学 | It is a kind of with the benzohydroxamic acid class compound of antitumor activity and its application |
| CN107445896B (en) * | 2017-08-08 | 2021-03-05 | 沈阳药科大学 | Phenyl hydroxamic acid compound with anti-tumor activity and application thereof |
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| CN113754587A (en) * | 2021-09-22 | 2021-12-07 | 沈阳药科大学 | Phenylpyrazole compound and application thereof |
| CN116768795A (en) * | 2023-08-16 | 2023-09-19 | 湖南速博生物技术有限公司 | Synthesis method of cyenopyrafen intermediate |
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