CN102838625B - Tetrahydropyridothiazole compounds, preparation method, drug compositions containing the same, and uses thereof - Google Patents
Tetrahydropyridothiazole compounds, preparation method, drug compositions containing the same, and uses thereof Download PDFInfo
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Abstract
The present invention relates to the field of pharmaceutical chemistry and drug treatment. Specifically the present invention relates to tetrahydropyridothiazole compounds represented by the following general formula I, a preparation method, drug compositions containing the same, and uses thereof. The compounds represented by the general formula I in the present invention are selective inhibitors acting on histonedeacetylase-6, and provide inhibition effects for deacetylation action of the histonedeacetylase, particularly for deacetylation action of the histonedeacetylase-6 so as to produce biological activities, such that the present invention further relates to applications of the compounds in preparation of drugs for treatment of histonedeacetylase-6 inhibitor mediated diseases, specifically in preparation of drugs for treatment of tumors, neurological diseases, and associated diseases.
Description
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field.Specifically, the present invention relates to tetrahydropyridine and thiazole compound, its preparation method and comprise the pharmaceutical composition of this compound; The invention still further relates to the application of this compounds in the medicine of the disease mediated by histon deacetylase (HDAC)-6 inhibitor for the preparation for the treatment of, be specifically related to it and preparing the application in treatment tumour, nervous system disease and relative disease medicine thereof.
Background technology
Cancer is one of principal disease threatening human health.World Health Organization's data show, cancer is that the whole world causes one of main causes of death, and within 2007, number of cancer deaths reaches 7,900,000, accounts for 13% of all death tolls.Antitumor drug mainly cytotoxic drug conventional clinically at present, this kind anti-cancer drugs has the shortcoming such as poor selectivity, the toxic side effect that are difficult to avoid and produces resistance etc. greatly, easily.Along with deeply and being rapidly in progress of life science, oncology mechanism of causing a disease and pathogenetic molecular biology research are that developmental function is laid a good foundation in the antitumor drug of the high-efficiency low-toxicity of specificity target spot.To the generation of tumour with to shift relevant protein classes various, and the albumen of whole biological meaning is had just most possibly to become the action target spot of wide spectrum low toxicity antitumor drug to growth of tumour cell regulation and control.Research shows, the acetylize of lysine residue that the generation of tumour and nucleosome core histone N-hold and the unbalance of deacetylation have close relationship.Histone modification (as methylate, acetylize, phosphorylation, ubiquitination etc.) play an important role in eukaryotic gene expression regulation.In these are modified, acetylation of histone/deacetylation is particularly important, and it affects genetic expression by changing electric charge or the reconstruction of participation chromatin configuration around chromatin.
Chromatinic fundamental unit nucleosome in karyocyte, is made up of core histones (H2A, H2B, H3 and H4), H1 and DNA.In nucleosome assembling process, first (H3/H4) tetramer is combined with DNA, with latter two H2A/H2B heterodimer, be attached to (H3/H4) 2 junction 5 and 3DNA on form nucleosome.It is DNA replication dna that nucleosomal structure is modified, transcribe, committed step in repair process.Before more than 30 years, Allfre etc. have found that core histones N-holds acetylize that multiple trans-acting factor can be regulated to be combined with nucleosome, thus affect genetic transcription.After this research deepens continuously, and finds that histone can have multiple modification mode: ubiquitination, phosphorylation, acetylize, to methylate, their separately (working in coordination with) regulatory gene transcribe.Wherein acetylation of histone removes the inhibiting main mechanism of nucleosome; by histone acetyltransferases (histoneacetyltransferase; and the regulation and control of histon deacetylase (HDAC) (histonedeacetylase, HDAC) HAT).
NSC 630176 (histone deacetylase inhibitor; HDACi) by regulating acetylize and the deacetylation of the lysine residue of histone N-end; activate cancer suppressor gene and suppress cancer gene; participate in cell cycle progression and differentiation; thus inhibition tumor cell growth, inducing apoptosis of tumour cell.With various diseases as the generation of cancer, acute myeloid leukaemia, virus and infection etc. is relevant with development, study the treatment of its inhibitor to above-mentioned disease significant.
Mankind HDAC family can be divided three classes: I class comprises HDAC1, HDAC2, HDAC3 and HDAC8, is only present in nucleus; II class comprises HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, HDAC10 and HDAC11, shuttles back and forth in signal transduction process between nucleus and tenuigenin, and wherein HDAC11 includes the catalytic site of I class and II class HDAC; III class and front 2 classes make a big difference, and its activity is not rely on Zn
2+, but rely on nadide (NAD), with the Sir2 homology of yeast, have 7 kinds of hypotypes at least, it can not suppress by I, II class hdac inhibitor.
But according to traditional drug target confirmation experience, HDAC also should not as a drug target, and reason is that the interior middle key factor of HDAC and cell has too many interaction to determine the complicacy of its biological action.Therefore, the discovery of hdac inhibitor is for fullying understand that the biological function of HDAC has very important effect.Have been found that the inhibitor for I, II, III class in HDAC at present, comprise natural product and synthetic compound is originated really have better that optionally compound is very limited.
Present Research for II class hdac inhibitor is that HDAC6 makes fast progress, there are some researches show HDAC6 can deacetylation nonhistones, as a-tubulin, cortactin and HSP90, and relevant with the stability of microtubule and cell movement.The growth of multiple myeloma cell can be made to be suppressed its suppression and not affect non-cancerous cells; also report HDAC6 is had to suppress relevant with neuroprotective; in the optionally HDAC6 inhibitor reported; the common feature that they have is all straight chain type compound; and zine ion combining site is in the majority with sulfydryl, as follows.
HDAC6：IC
50＝2nM HDAC3：IC
50＝0.42nM
HDAC1：IC
50＝271nM HDAC8：IC
50＝6851nM
HDAC2：IC
50＝252nM HDAC10：IC
50＝90.7nM
HDAC6：IC
50＝29nM HDAC6：IC
50＝36nM
HDAC1/HDAC6＝35～42 HDAC4/HDAC6＝32～37
HDAC6：IC
50＝2010nM HDAC10：IC
50＞30000nM
HDAC1：IC
50＝10800nM HDAC8：IC
50＝13900nM
HDAC2：IC
50＞30000nM
In recent years result of study display, to the suppression of HDAC activity growth capable of inhibiting cell and Cell differentiation inducing activity, produces anticarcinogenic effect in some tumour cells.Several development project relevant with hdac inhibitor starts, and the research of hdac inhibitor has become the very active research field of antitumor drug.Amount of activated higher hdac inhibitor enters clinical study at present, comprises MS275 (Bayer/syndax), MGCD-0103 (MethylGene), LBH-589 (Novartisd), PXD101 (Topotarget), SB-939 (S*Bio), CI-99 (Pfizer) etc.Hdac inhibitor further develops, and needs for HDAC systems biology function, and has more deep research to the biological action of independent HDAC hypotype.So far very clear and definite understanding is not also formed for the problems referred to above, have from pharmacological means, utilize the inhibitor of non-selectivity to produce HDAC many hypotypes simultaneously and suppress, thus study its biological function.But better means are that utilization has and has better optionally inhibitor for HDAC different subtype and study.And at present mainly RNAi technology is passed through for the biological function research means that gos deep into of each hypotype.Therefore find to have better optionally hdac inhibitor the biology and pharmacological effects furtheing investigate HDAC is significant.
Summary of the invention
One object of the present invention is to provide a class to act on the selective depressant of histon deacetylase (HDAC)-6; namely the tetrahydropyridine represented by general formula I thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvate, this compounds can be used for the relative disease for the treatment of, prevention and prohibition is mediated by histon deacetylase (HDAC)-6 inhibitor.
Another object of the present invention is that providing a kind of prepares the tetrahydropyridine the method for thiazole compound that are represented by general formula I.
Also object of the present invention is to provide a kind of tetrahydropyridine containing being represented by general formula I and the pharmaceutical composition of thiazole compound, its steric isomer and pharmacy acceptable salt, prodrug or its solvate.
Another object of the present invention is to provide the tetrahydropyridine that represented by general formula I and the purposes of thiazole compound, its steric isomer and pharmacy acceptable salt, prodrug or its solvate.The compound represented by general formula I is the selective depressant acting on histon deacetylase (HDAC)-6; it can suppress the deacetylation effect of histon deacetylase (HDAC), particularly suppresses the deacetylation effect of histon deacetylase (HDAC)-6 thus produces biological activity.Therefore, another aspect of the present invention uses the deacetylation effect of at least one compound of the present invention to histon deacetylase (HDAC)-6 to suppress; The method is particularly useful for treating the disease, illness and/or the obstacle that are regulated by histon deacetylase (HDAC) (particularly histon deacetylase (HDAC)-6) inhibitor.
Another object of the present invention there are provided the tetrahydropyridine that represented by general formula I and thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvate are used for the treatment of tumour, nervus retrogression class disease and diseases related etc. method thereof.
To achieve these goals, the invention provides a kind of tetrahydropyridine of being represented by following general formula I and thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvate,
Wherein:
W does not exist, or is-CH
2-,-CH
2-CH
2-or-CH=CH-;
R
1be selected from C
1-8alkyl, C
1-8alkoxyl group, C
3-10cycloalkyl, C
3-8alkenyl, list or two C
1-3alkylamino, list or two C
1-3alkylamidoalkyl, C
1-3alkyl sulphonyl, C
1-3in the phenyl of alkoxy carbonyl, hydroxyl, methylol, hydroxyethyl, methylthio group, trifluoromethylthio, trifluoromethyl, difluoro-methoxy, amino, amino-sulfonyl, phenyl, replacement, phenoxy group and heteroaryl; Preferably, R
1for C
1-6alkyl, C
3-6cycloalkyl, C
3-8the phenyl of alkenyl, phenyl, replacement or heteroaryl; More preferably, R
1for heteroaryl;
R
2for being selected from hydrogen atom, C
1-8alkyl, C
1-8alkoxyl group, list or two C
1-3alkylamino, list or two C
1-3alkylamidoalkyl, C
1-3alkyl sulphonyl, C
1-3in the phenyl of alkoxy carbonyl, hydroxyl, methylol, hydroxyethyl, methylthio group, trifluoromethylthio, trifluoromethyl, difluoro-methoxy, trifyl, amino, amino-sulfonyl, phenyl, replacement, phenoxy group, halogen, nitro and cyano group; Preferably, R
2for hydrogen atom;
R
3and R
4separately be selected from hydrogen atom, C
1-10alkyl, C
3-10cycloalkyl, C
1-6the C that alkoxy carbonyl replaces
3-10cycloalkyl, C
3-10the C of cycloalkyl substituted
1-4alkyl, C
3-8alkenyl, C
5-8cycloalkenyl group, adamantyl, C
6-20aryl, C
6-20the C that aryl replaces
1-4in alkyl, heteroaryl and heterocyclic radical; Preferably, R
3for hydrogen atom, R
4for hydrogen atom;
Described heteroaryl is the identical or different heteroatomic 5-10 first aromatic radical, such as thienyl, benzothienyl, furyl, benzofuryl, thiazolyl, benzothiazolyl, pyrazinyl, the pyrimidyl etc. that are selected from containing 1-3 in N, O and S;
Described heterocyclic radical is the identical or different heteroatomic 5-10 unit nonaro-maticity group be selected from containing 1-3 in N, O and S, such as piperidyl, piperazinyl, morpholinyl etc.;
Substituting group on the phenyl of described replacement is selected from C
1-8alkyl, C
1-8in alkoxyl group and halogen; Preferably, described substituting group is C
1-8alkyl.
In an embodiment of the invention, in above-mentioned general formula I, W is not for exist, and other substituent definition are same as described above.
In an embodiment of the invention, in above-mentioned general formula I, W is-CH
2-, other substituent definition are same as described above.
In an embodiment of the invention, in above-mentioned general formula I, W is-CH
2-CH
2-, other substituent definition are same as described above.
In an embodiment of the invention, in above-mentioned general formula I, W is-CH=CH-, and other substituent definition are same as described above.
Compound of the present invention can exist with the form of non-solvation with the form of pharmaceutically acceptable solvent (such as water, ethanol etc.) solvation.Usually, for the present invention, think that the form of solvation is equal to the form of non-solvation.
Whole specification sheets and claims are applicable to give a definition.Unless otherwise mentioned or point out, term " alkyl " represents straight or branched alkyl.The example of described alkyl comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.Preferred alkyl is methyl, ethyl, propyl group, sec.-propyl and the tertiary butyl.
Unless otherwise mentioned or point out, term " alkoxyl group " represents radical-O-alkyl, and wherein alkyl is as defined above.
Unless otherwise mentioned or point out, term " halogen " refers to fluorine, chlorine, bromine or iodine.
More preferably, the tetrahydropyridine represented by general formula I thiazole compound is selected from following compound:
And steric isomer under usable condition and pharmacy acceptable salt, prodrug or its solvate.
Invention additionally provides tetrahydropyridine the preparation method of thiazole compound that general formula I represents.
The compound with general structure I of the present invention synthesizes by following route of synthesis, and this approach comprises and to be similar in chemical field known, particularly states the method for declaratives according to this.Initial substance generally can from commercial source, such as Aldrich chemical company (University of Wisconsin-Madison pungent state Milwaukee) obtains, or by method well-known to those skilled in the art can prepare (as by following books summarize method preparation: " reagent for organic synthesis effect " 1-19 volume (USA New York Wiley company 1967-1999 version) of Louis F.Fieser and Mary Fieser; Or " Beilsteins Handbuch der organischen Chemie " Auf1. version the 4th and comprise supplement (Berlin, Germany Springer-Verlag company publish and also can obtain via Beilstein online material storehouse).
Except as otherwise noted, in following reaction scheme, each symbol of described compound has identical implication.Compound in reaction scheme comprises its salt, such as, as having the salt etc. of the compound definitions of structural formula I.
For illustrative purposes, following shown reaction process is provided for the possible approaches synthesizing compound of the present invention and key intermediate species.About the more detailed description of indivedual reactions steps, ask for an interview embodiment part described later.Understanding can use other route of synthesis to synthesize compound of the present invention by those skilled in the art.Although that show on stream and to touch upon specific initial substance and reagent in aftermentioned part, they can substitute with other initial substances and reagent easily, and provide multiple derivative and/or reaction conditions.In addition, in view of present disclosure, conventional chemical well-known to those skilled in the art can be used, and modify further and state numerous compounds prepared by method by this.
According to another object of the present invention, the invention provides a kind of tetrahydropyridine of being represented by general formula I and the preparation method of thiazole compound, the method comprises the following steps:
Step a: the carboxylic acid cpd represented by formula A1 carries out condensation reaction with the compound represented by formula A2 and prepares the compound represented by formula A3; The solvent that wherein condensation reaction is used is methylene dichloride, 1,2-ethylene dichloride, chloroform, DMF (DMF) or its any mixture, is preferably methylene dichloride; Condensation reaction condensing agent used is 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC), Diisopropylcarbodiimide (DIC), dicyclohexyl carbodiimide (DCC), phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus (PyBOP), O-benzotriazole-N, N, N, N '-tetramethyl--urine salt-hexafluorophosphate (HBTU), 1-hydroxyl-benzo-triazole (HOBt) or its any mixture; Condensation reaction organic bases used is triethylamine, 4-dimethylaminopyridine (DMAP), diisopropyl ethyl amine (DIPEA) or its any mixture, is preferably diisopropyl ethyl amine (DIPEA); Temperature of reaction is 0-200 DEG C, is preferably 0 DEG C-room temperature;
Or the compound represented by formula A2 carries out condensation reaction with the carboxylic acid halides of the carboxylic acid represented by formula A1 and prepares the compound represented by formula A3; The solvent that wherein condensation reaction is used is methylene dichloride, 1,2-ethylene dichloride, chloroform, DMF (DMF) or its any mixture, is preferably methylene dichloride; Condensation reaction organic bases used is pyridine, triethylamine, 4-dimethylaminopyridine (DMAP), diisopropyl ethyl amine (DIPEA) or its any mixture, is preferably triethylamine;
Step b: the compound represented by formula A3 carries out deprotection reaction and prepares the compound represented by formula A4; The solvent that wherein deprotection reaction is used is methylene dichloride, ethyl acetate, dioxane, ether or its any mixture, is preferably methylene dichloride; Deprotection reaction deprotecting regent used is trifluoroacetic acid (TFA), hydrogenchloride or its any mixture, is preferably trifluoroacetic acid; Temperature of reaction is 0-60 DEG C, is preferably 0 DEG C-room temperature;
Step c: the compound represented by formula A4 and the compound R represented by formula A5
1the carboxylic acid R that-W replaces
1-W-COOH carries out amidate action and prepares the compound represented by formula A6; The solvent that wherein amidate action is used is methylene dichloride, 1,2-ethylene dichloride, chloroform, DMF (DMF) or its any mixture; Amidate action condensing agent used is 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC), Diisopropylcarbodiimide (DIC), dicyclohexyl carbodiimide (DCC), phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus (PyBOP), O-benzotriazole-N, N, N, N '-tetramethyl--urine salt-hexafluorophosphate (HBTU), 1-hydroxyl-benzo-triazole (HOBt) or its any mixture; Amidate action organic bases used is triethylamine, 4-dimethylaminopyridine (DMAP), diisopropyl ethyl amine (DIPEA) or its any mixture; Temperature of reaction is 0-200 DEG C, is preferably 0 DEG C-room temperature;
Or, the compound represented by formula A4 and the compound R represented by formula A5
1the carboxylic acid halides R that-W replaces
1-W-COX reacts and prepares the compound represented by formula A6; The solvent wherein reacting used is methylene dichloride, 1,2-ethylene dichloride, chloroform, DMF (DMF) or its any mixture; The organic bases reacting used is pyridine, triethylamine, 4-dimethylaminopyridine (DMAP), diisopropyl ethyl amine (DIPEA) or its any mixture; Temperature of reaction is 0-200 DEG C, is preferably 0 DEG C-room temperature;
Steps d: the compound represented by formula A6 and R
3-NHOR
4carry out nucleophilic substitution reaction and prepare the compound represented by formula A7; The solvent that wherein nucleophilic substitution reaction is used is methyl alcohol, tetrahydrofuran (THF), acetonitrile or its any mixture; Nucleophilic substitution reaction mineral alkali used is sodium hydroxide, potassium hydroxide, lithium hydroxide or its any mixture; Temperature of reaction is 0-80 DEG C, is preferably 0 DEG C-40 DEG C;
Or the compound represented by the formula A6 reaction that is hydrolyzed generates corresponding acid, then with R
3-NHOR
4carry out condensation reaction and prepare the compound represented by formula A7; The mineral alkali that wherein hydrolysis reaction is used is lithium hydroxide, sodium hydroxide, potassium hydroxide, salt of wormwood or its any mixture; Hydrolysis reaction solvent used is methyl alcohol, ethanol, tetrahydrofuran (THF) or its any mixture; The temperature of hydrolysis reaction is 0-80 DEG C, is preferably 0 DEG C-40 DEG C; Condensation reaction solvent used is methylene dichloride, 1,2-ethylene dichloride, chloroform, DMF (DMF) or its any mixture; Condensation reaction organic bases used is pyridine, triethylamine, 4-dimethylaminopyridine (DMAP), diisopropyl ethyl amine (DIPEA) or its any mixture; The temperature of condensation reaction is 0-200 DEG C; Be preferably 0 DEG C-room temperature;
Wherein X is halogen, W, R
1, R
2, R
3and R
4definition the same.
Preliminary study shows, following disease, illness and/or obstacle mediated by NSC 630176: relieve chronic Lymphocytic leukemia, mammary cancer, prostate cancer, ovarian cancer, carcinoma mesothelial, T-cell lymphoma, cardiac hypertrophy, chronic heart failure, inflammation, cardiovascular disorder, thalassemia, CNS disease, autoimmune disorder, nerve degenerative diseases etc.
Therefore, find through research, compound of the present invention is suitable for disease, illness and/or the obstacle for the treatment of and being mediated by NSC 630176.
Another aspect provides a kind of method of the disease mediated by NSC 630176, illness and/or obstacle for the treatment of animal, described method comprises to the pharmaceutical composition of the compound of the present invention of the animal administering therapeutic significant quantity of this treatment of needs or the compound of the present invention containing treatment significant quantity and pharmaceutically acceptable vehicle, diluent or carrier.
Another embodiment of the invention is to provide a kind of pharmaceutical composition, and it comprises the compound of the present invention or its pharmacy acceptable salt, prodrug or its solvate and pharmaceutically acceptable vehicle, diluent or carrier for the treatment of significant quantity.Be to be understood that, pharmaceutical composition of the present invention can comprise one or more compounds of the present invention, i.e. 7a, 7b, 7c, 7d, 7e, 7f, 7g, 7h, 7i, 7j, 7k, 7l, 7m, 7n, 7o, 7p, 7q, 7r, 7s, 7t or 7u, and the arbitrary combination of these compounds.
Further, compound of the present invention can be used in single therapy or combination therapy.Time in for combination therapy, compound of the present invention uses usually with together with the therapy (such as He Saiting uncommon agate appropriate in profit) of micromolecular compound, radiation, antibody, gene therapy, cell therapy, hormonotherapy or cytokine therapy.
In a preferred embodiment of the invention, compound of the present invention can combine the treatment for cancer with other chemotherapy or antineoplastic agent.The example of other chemotherapy described or antineoplastic agent includes catharanthus alkaloid (as vincristine(VCR) and vinealeucoblastine(VLB)), anthracycline antibiotics (as Zorubicin and erythromycin), alkylating agent (as Chlorambucil), taxanes (as taxol), antifol (as Mexician scammony) and DNA methylation inhibitor.
Typical formula prepares it by mixing compound of the present invention and pharmaceutically acceptable carrier, thinner or vehicle etc.Suitable carrier, thinner or vehicle are well-known to those skilled in the art, comprise the material of such as carbohydrate, wax, water-soluble and/or swellability polymkeric substance, wetting ability or lyophobic dust, gelatin, oil, solvent, water etc.Specific support used, thinner or vehicle, by according to using the mode of compound of the present invention and object and determining.Generally by those skilled in the art think can be administered to safety (GRAS) mammal solvent based on, and selective solvent.Generally speaking, the solvent of safety is nontoxicity water-containing solvent such as water, and other water solubles or the non-toxic solvent miscible with water.Suitable water-containing solvent comprises water, ethanol, propylene glycol, polyoxyethylene glycol (as PEG400, PEG300) etc. and composition thereof.This formula also can comprise one or more buffer reagents, tranquilizer, tensio-active agent, wetting agent, lubricant, emulsifying agent, suspension agent, sanitas, antioxidant, opalizer, glidant, processing aid, tinting material, sweetener, perfume agent, seasonings and other known additives, with the appearance form providing one of this medicine graceful (that is compound of the present invention or its pharmaceutical compositions), or assist the manufacture of this pharmaceutical product (that is medicine).
This formula can use conventional dissolving combination process and prepare.Such as, under the existence of one or more above-mentioned vehicle, the stabilized form (complex compound as with cyclodextrin derivative or other known recombiners) of the drug substance of bulk (that is compound of the present invention or this compound) is dissolved in suitable solvent.Typically compound of the present invention is mixed with pharmaceutical formulation, to provide the appearance of this medicine manageable dosage, and provides a kind of easy to handle product to patient.
The pharmaceutical composition (or formula) Gong using according to the administering mode of this medicine, and can be packed in many ways.Generally speaking, comprise container for the object distributed, wherein deposit the pharmaceutical formulation of suitable form.Suitable container is well-known to those skilled in the art, comprises the material of such as bottle (plastics and vial), sachet, ampoule, plastics bag, metallic cylinder etc.In addition, container can be equipped with sign, so that the content of this container to be described.This mark also can comprise suitable warning message.
According to methods for the treatment of of the present invention, for needing the individuality of this treatment to give compound of the present invention, or giving the combination of compound of the present invention and at least one additional medicaments, being preferably a kind of form of pharmaceutical compositions.With regard to combined aspects of the present invention, other medicaments of compound of the present invention and at least one (as antineoplastic agent catharanthus alkaloid (as vincristine(VCR) and vinealeucoblastine(VLB)), anthracycline antibiotics (such as Zorubicin and erythromycin), alkylating agent (as Chlorambucil), taxanes (as taxol), antifol (as Mexician scammony) and DNA methylation inhibitor) can separate administration, or to comprise the pharmaceutical compositions administration of the two simultaneously.Generally speaking, oral administration is preferably.But, if the individuality for the treatment of cannot be swallowed, or be obstructed at oral administration or in other situations un-desired, then may be suitable for carrying out parenteral or transdermal administration.According to methods for the treatment of of the present invention, when one of compound of the present invention and other medicaments of at least one combine administration, this administering mode can sequentially or simultaneously carry out in time, and generally to carry out as preferably simultaneously.With regard to the administering mode sequentially carried out, compound of the present invention and this additional medicaments can with arbitrary order of administration.Generally speaking, this administering mode is preferably oral administration.The administration that this administering mode is particularly preferably oral and carries out simultaneously.When compound of the present invention and this additional medicaments are sequential administration, respective administration is undertaken by identical or different method.
According to method of the present invention, the combination (being referred to herein as " combination ") of compound of the present invention or compound of the present invention and other medicaments of at least one, preferably with the form administration of pharmaceutical composition.Therefore, compound of the present invention or combination can with in arbitrary known oral, rectum, transdermal, parenteral (such as intravenously, intramuscular or subcutaneous), brain pond, intravaginal, intraperitoneal, intravesical, locally (such as powder, ointment or drop), cheek or nose formulation, separate or be administered to sufferer together.
Be applicable to the pharmaceutical composition of parenteral injection, generally comprise pharmaceutically acceptable sterile, aqueous or non-aqueous solution, dispersion liquid, suspension or emulsion, and become aseptic syringeability solution or the sterilized powder of dispersion liquid for recombinating.Suitable moisture or nonaqueous carrier or thinner (comprising solvent and carrier), comprise water, ethanol, polyvalent alcohol (propylene glycol, polyoxyethylene glycol, glycerine etc.) and suitable mixture thereof; Vegetables oil (such as sweet oil); And syringeability organic ester such as ethyl oleate.Such as by using coating such as Yelkin TTS, when dispersion liquid, the particle size needed for maintenance, and by using tensio-active agent, and maintain suitable mobility.
These pharmaceutical compositions also can contain vehicle, such as sanitas, wetting agent, emulsifying agent and dispersion agent.By various bactericides and mycocide, such as metagin, butylene-chlorohydrin, phenol, Sorbic Acid etc., thus avoid microbial contamination said composition.Isoosmotic pressure agent such as carbohydrate, sodium-chlor etc. may also be desired.By using the medicament that can postpone to absorb, such as aluminum monostearate and gelatin, and extend the absorption of injection type pharmaceutical composition.
Solid dosage for oral administration can comprise capsule, tablet, powder and particle.In these solid dosages, compound of the present invention or combination mix with at least one inert excipient, diluent or carrier.Suitable vehicle, diluent or carrier comprise the material of such as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade, or (a) filler or extender (as starch, lactose, sucrose, mannitol, silicic acid etc.); (b) tackiness agent (as carboxymethyl cellulose, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose, gum arabic etc.); (c) wetting agent (as glycerine etc.); (d) disintegrating agent (as agar, calcium carbonate, potato or tapioca (flour), alginic acid, specific complex silicate, sodium carbonate etc.); (e) solution retarding agents (as paraffin etc.); F () accelerates absorption agent (as quaternary ammonium compound etc.); (g) wetting agent (as ethanoyl alcohol, glyceryl monostearate etc.); (h) sorbent material (as kaolin, wilkinite etc.); And/or (i) lubricant (as talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sodium Lauryl Sulphate BP/USP etc.).When capsule and tablet, this formulation also can comprise buffer reagent.The solid-state composition of similar type also can be used as soft with the filler in hard-filled gelatin capsules, and it uses lactose and high molecular weight polyethylene glycol etc. as vehicle.
The solid dosage of such as tablet, dragee, capsule and particle can be prepared, enteric film known in such as pharmacy preparation field or other coatings with coating or shell.They also can contain opalizer, and can be the composition that delayed mode disengages compound of the present invention and/or additional medicaments.The example of spendable embedded composition, comprises polymeric agents and wax.If suitable, this medicine is also also the microencapsulation form with upper one or more mentioned vehicle.
Liquid forms for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, liquid syrup and elixir.Except compound of the present invention or combination, this liquid forms can containing inert diluent conventional in this area, such as water or other solvents; Solubilizing agent and emulsifying agent, such as ethanol, isopropyl alcohol, ethyl-carbonate, ethyl acetate, benzylalcohol, phenylformic acid benzyl ester, propylene glycol, 1,3 butylene glycol, dimethyl formamide; Oils (as Oleum Gossypii semen, Peanut oil, Fructus Maydis oil, sweet oil, Viscotrol C, sesame wet goods); Glycerine; Tetrahydrofurfuryl alcohol; The fatty acid ester of polyoxyethylene glycol and sorbitan; Or the mixture etc. of these materials.
Except these inert diluents, said composition also can comprise vehicle, such as wetting agent, emulsifying agent and suspension agent, sweetener, seasonings and perfume agent.
With regard to suspension, except compound of the present invention or combination, carrier such as suspension agent can be contained further, as ethoxylated isostearyl alcohols, polyoxyethylene candy alcohol and anhydrosorbitol candy alcohol ester, Microcrystalline Cellulose, partially aluminium hydroxide, wilkinite, agar and tragacanth gum, or the mixture etc. of these materials.
Pharmaceutical composition for rectum or vagina administration preferably includes suppository, by compound of the present invention or combination are mixed with suitable non-irritating excipient or carrier and prepare, vehicle or carrier be cocoa butter, polyoxyethylene glycol or suppository wax such as, it is solid-state and at body temperature for liquid, therefore can dissolve in rectum or vagina and disengage active compound in general room temperature.
The combination of compound of the present invention and compound of the present invention and nervus retrogression class or tumour medicine is used for Topical dosage forms, can comprise ointment, powder, spray and inhalation.This pharmaceutical composition can aseptically with pharmaceutically acceptable vehicle, diluent or carrier and required arbitrary sanitas, buffer reagent or propellant mixing.Ophthalmic formulations, eye ointment, powder and solution, be also intended to be covered by scope of the present invention.
Knownly, compound of the present invention (or combination) can be inserted in drinking-water, takes in this compound of therapeutic dose whereby in company with the drinking water supply of every day.This compound can directly measure inserts in drinking-water, preferably with the form of liquid water-soluble concentrate (aqueous solution of such as water-soluble salt).
By being scattered in by medicine in a kind of pharmaceutically acceptable oil such as peanut oil, sesame oil, corn wet goods, and prepare pasty state formula.
By compound of the present invention or combination being mixed with thinner such as carbowax, palm wax etc., and preparation contains the pill of the compound of the present invention of significant quantity, pharmaceutical composition or combination; Also lubricant such as Magnesium Stearate or calcium stearate can be added, to promote pill processing procedure.
The present invention is also contained through isotope-labeled the compounds of this invention, except one or more atom by atomic mass or total mass number be different from one of atomic mass or total mass number atom common in nature except the fact of replacing, it is that not state person therewith identical.Can include the isotropic substance example in compound of the present invention in, comprise the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, iodine and chlorine, it is distinguished such as:
2hydrogen,
3hydrogen,
11carbon,
13carbon,
14carbon,
13nitrogen,
15nitrogen,
15oxygen,
17oxygen,
18oxygen,
31phosphorus,
32phosphorus,
35sulphur,
18fluorine,
123iodine,
125iodine and
36chlorine.
Some isotope-labeled compound of the present invention (use by example
3h and
14c mark those) for compound and/or substrate tissue distribution assays.Particularly preferably tritiate (namely
3h) and carbon-14 (namely
14c) isotropic substance, because their easy preparation and determination methods.And, heavier isotropic substance as deuterium (namely
2h) carrying out replacement and can provide some treatment advantage caused by larger metabolic stability (such as Half-life in vivo increases or volume requirements reduces), thus may be preferred in some cases.Positron emitting isotopes, such as
15o,
13n,
11c and
18f is used for positron emission tomography (PET) research, to check substrate receptor occupancy.Isotope-labeled compound of the present invention generally can be followed and be similar to method disclosed in scheme and/or Examples below, by substituting nonisotopically labelled reagent to prepare with isotope-labeled reagent.
Embodiment
By the following example, embodiment of the present invention are described.But should be appreciated that embodiment of the present invention are not limited to the specific detail in the following example, because in view of disclosure of the present invention, other changes are known and apparent to those of ordinary skill in the art.
There is provided following experimental example to illustrate the present invention further, but it does not form restriction on its scope.
Laboratory sample analyzes instrument and reagent
Nuclear magnetic resonance spectrum (
1h NMR,
13c NMR) by Mercury-300 or the Mercury-400 type nmr determination of Varian company, (solvent is CDCl
3, be inside designated as TMS).LC-MS is measured by Thermo Finnigan LCQDECA × P type mass spectrograph.Fusing point measures (thermometer reading is not calibrated) by the SGW X-4 type melting point apparatus of Shanghai Precision Scientific Apparatus Co., Ltd.Column chromatography for separation used silica gel is Haiyang Chemical Plant, Qingdao's product (200-300 order).TLC silica-gel plate is the HSF-254 thin-layer chromatography precoated plate of Yantai Chemical Manufacture, adopts ultraviolet lamp, and iodine cylinder develops the color.Ultraviolet lamp is Shanghai Gu Cun electric light instrument plant ZF-1 type ultraviolet analysis instrument for three purposed.In synthesis, raw materials used 1 is protected through BOC by the commercially available prod para-amino benzoic acid of Aldrich chemical company (University of Wisconsin-Madison pungent state Milwaukee) and obtains; raw material 2 is bought from Chinese Shao Yuan chemical reagents corporation; acyl chlorides used in reaction is all purchased from Aldrich chemical company commercially available prod, and part prepares corresponding acyl chlorides by the acid that Aldrich chemical company is commercially available by sulfur oxychloride.
Embodiment 1:
A) preparation of compound 3
Weigh Compound 1 (210mg, 0.89mmol) with compound 2 (200mg, 0.81mmol) in reaction tubes, be dissolved in 2 milliliters of N, after dinethylformamide (DMF), add diisopropylethylamine (DIPEA) (0.31mL, 1.77mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (170mg is added under nitrogen protection, 0.89mmol) with 1-hydroxyl-benzo-triazole (HoBt) (120mg, 0.89mmol), stirred overnight at room temperature, reaction solution directly uses 30 milliliters of extraction into ethyl acetate, organic layer uses 1N hydrochloric acid successively, saturated sodium bicarbonate, water and saturated brine are respectively washed once, with anhydrous sodium sulfate drying, crude product is obtained after pressure reducing and steaming solvent, crude by column chromatography separation and purification obtains product, elution requirement is sherwood oil: ethyl acetate=5: 1-3: 1, obtaining compound 3 is white, amorphous solid 293mg, yield 84.5%.
1H NMR(300MHz，CDCl
3)δ9.59(s，2H)，7.53(d，J＝8.1Hz，2H)，7.38(d，J＝8.1Hz，2H)，4.86(s，2H)，4.38-4.31(m，2H)，3.75(br s，2H)，2.93(br s，2H)，1.47(s，9H)，1.30(t，J＝7.2Hz，2H)
ESI-MS(m/z)：432.1(M+1，100％)
B) preparation of compound 4
Weigh Compound 3 (200mg, after 0.46mmol) being dissolved in the dichloromethane solution of 5 milliliter of 20% trifluoroacetic acid (TFA), stirring at room temperature three hours, pressure reducing and steaming solvent, adds 10mL saturated sodium bicarbonate reaction solution and alkalizes, with 20 milliliters of dichloromethane extractions twice, organic layer is respectively washed once with water and saturated brine respectively, anhydrous sodium sulfate drying, after pressure reducing and steaming solvent, obtaining compound 4 is colorless solid 135mg, yield 87.8%.
1H-NMR(300MHz，CDCl
3)δ7.19(d，J＝8.4Hz，2H)，6.55(d，J＝8.4Hz，2H)，5.58(s，2H)，4.83(s，2H)，4.37-4.30(m，2H)，3.79(d，J＝5.7Hz，2H)，2.93(d，J＝5.4Hz，2H)，1.30(t，J＝6.9Hz，3H)
ESI-MS(m/z)：332.1(M+1，100％)
C) preparation of compound 6a
Weigh Compound 4 (100mg, 0.30mmol) adds triethylamine (Et after being dissolved in 5 milliliters of methylene dichloride
3n) (0.052mL; 0.36mmol); Acetyl Chloride 98Min. 5a (0.026mL is added under nitrogen protection; 0.36mmol); stirring at room temperature 4h; reaction solution directly uses 30 milliliters of dichloromethane extractions; organic layer is respectively washed once with water and saturated brine respectively; anhydrous sodium sulfate drying; obtain crude product after pressure reducing and steaming solvent, crude by column chromatography separation and purification obtains product, and elution requirement is methylene dichloride: methyl alcohol=100: 1-20: 1; obtaining compound 6a is white, amorphous solid 95mg, yield 84.2%.
1H NMR(300MHz，CDCl
3)δ7.59(d，J＝8.4Hz，2H)，7.45(d，J＝8.4Hz，2H)，4.92(br s，2H)，4.52-4.45(m，2H)，3.85(br s，2H)，3.06(br s，2H)，2.22(s，3H)，1.44(t，J＝7.2Hz，3H)
LC-MS：m/z 374.1[M+1]
+
D) preparation of compound 7a
Taking oxammonium hydrochloride (2.64g, 38mmol) puts in 50mL reaction flask, then adds 20mL methyl alcohol, is heated to 40 DEG C, adds potassium hydroxide (2.12g, 38mmol) and reacts 10 minutes.After reaction solution is cooled to 0 DEG C, filter.Weigh Compound 6a (75mg, 2mmol) adds filtrate subsequently, and then adds KOH (250mg, 4.46mmol) and at room temperature reacts half an hour.
Reaction solution is extracted with ethyl acetate.The saturated NH of organic layer
4the Cl aqueous solution and saturated aqueous common salt wash, and then use anhydrous sodium sulfate drying, filter reconcentration.Middle product chromatographic column is extracted, and DCM: MeOH: NH
4oH=10: 1: 0.1 as elutriant, and obtained target compound 7a is white solid 37mg, yield 52%.
1H NMR(300MHz，DMSO-d
6)δ10.26(s，1H)，7.67(d，J＝8.1Hz，2H)，7.42-7.34(m，3H)，4.83(s，2H)，3.76(br s，2H)，2.89(br s，2H)，2.06(s，3H)
LC-MS：m/z 361.2[M+1]
+
E) preparation of compound 6b-6u
The preparation of compound 6b-6u is identical with the preparation method of compound 6a in embodiment 1, has obtained the midbody compound listed in Table 1.Just use butyryl chloride (5b) respectively, capryl(yl)chloride (5c), the rare acyl chlorides of 1-penta (5d), Benzoyl chloride (5e), phenyllacetyl chloride (5f), phenylpropyl alcohol acyl chlorides (5g), cyclohexyl acyl chlorides (5h), cyclopentylpropionyl chloride (5i), cyclohexyl propionyl chloride (5j), cinnamyl chloride (5k), 3-methoxycinnamate acyl chlorides (5l), 4-methoxycinnamate acyl chlorides (5m), 3-methylcinnamoyl chloride (5n), 4-methylcinnamoyl chloride (5o), 3-cinnamyl bromide acyl chlorides (5p), 4-cinnamoyl chloride chlorine (5q), 2-fluorine cinnamyl chloride (5r), 3-fluorine cinnamyl chloride (5s), furans cinnamyl chloride (5t) and thiophene cinnamyl chloride (5u) instead of the Acetyl Chloride 98Min. 5a in embodiment 1.The mass-spectrometric data of midbody compound 6b-6u sees the following form shown in 1.
Table 1: intermediate 6b-6u
F) preparation of target compound 7b-7u
After obtaining above-mentioned midbody compound, the preparation of compound 7b-7u is substantially identical with the preparation method of compound 7a in embodiment 1, just instead of the 6a in embodiment 1 with intermediate 6b-6u respectively, has obtained the target compound 7b-7u listed in the following table.The mass-spectrometric data of target compound 7b-7u sees the following form shown in 2.
Table 2: target compound 7b-7u
Pharmacological examples Example
The external measuring method for activity of histon deacetylase (HDAC)
Utilize insect baculovirus expression system to express people source restructuring HDAC family protein with His label and GST label, obtained by Ni affinity column protein purification and there is bioactive HDAC family recombinant protein.With Boc-lys (Ac)-AMC or Ac-Lys-Tyr-Lys (Ac)-AMC for substrate, adopt fluorescence detection, in black 384 hole flat bottom microtiter plate (OptiPlateTM-384F, PerkinElmer), detect enzymic activity.Substrate is after HDAC albumen deacetylation, and the product A MC utilizing pancreatin hydrolysis to obtain can be detected fluorescent signal under the 355nm of fluorescence detector excites 460nm utilizing emitted light.By detecting the change of fluorescent signal in time, calculate initial velocity of reaction.In brief, in the survey live body system of 25 μ L, comprise HDAC substrate (5-50 μM, 5 μ L), people source recombinant protein HDAC (20-200nM) and compound, all the components is all with Hepes damping fluid dilution (25mM Hepes, 137mM NaCl, 2.7mM KCl and 4.9mM MgCl
2, pH 8.0) etc.The HDAC6 reaction times is incubated at room 3 hours, HDAC1 and the HDAC3 reaction times is incubated at room 24 hours.Finally add 25 μ L trypsinase termination reactions, after room temperature places 30 minutes, detect 355nm with Envision (PerkinElmer) and excite fluorescent signal under 460nm utilizing emitted light, calculate HDAC activity.
Pharmacology data: so that will the Pharmacological test results of one group of the compounds of this invention that part embodiment 1 obtains be announced in following table 3; the contrast adopted in test is Mo Shadong (Merck & Co.; Inc) NSC 630176 (SAHA) medicine of first listing of company's exploitation, is used for the treatment of epithelial cell lymphatic cancer.
Table 3 embodiment bioassay data
As can be seen from the above table, positive compound is the NSC 630176 Vorinostat (SAHA) of bibliographical information, its IC on HDAC1
50value is 118 μMs, the IC on HDAC3
50value is 170 μMs, the IC on HDAC6
50value is 34 μMs, close with bibliographical information, and illustrate that the method can repeat literature method preferably, the Activity Results that this system obtains has higher confidence level.Can see from upper table; the molecular level test experiments of this compounds shows that compound of the present invention has very strong binding activities to histon deacetylase (HDAC)-6; and all embody certain selectivity; wherein the selectivity between HDAC1, HDAC3 and HDAC6 of some compound reaches 100 times, illustrates that this compounds is that a class effectively has optionally histon deacetylase (HDAC) 6 inhibitor.
Only illustratively, scope of the present invention is not limited thereto above-mentioned example.It is apparent for modifying to one skilled in the art, and the present invention is only by the restriction of claims scope.
Claims (13)
1. the tetrahydropyridine represented by following general formula I thiazole compound and a pharmacy acceptable salt thereof,
Wherein:
W does not exist, or is-CH
2-,-CH
2-CH
2-or-CH=CH-;
R
1be selected from C
1-8alkyl, C
3-10cycloalkyl, C
3-8in the phenyl of alkenyl, phenyl, replacement, heteroaryl;
R
2, R
3and R
4be hydrogen atom;
Described heteroaryl is the identical or different heteroatomic 5-10 unit aromatic radical be selected from containing 1-3 in N, O and S;
Substituting group on the phenyl of described replacement is selected from C
1-8alkyl, C
1-8in alkoxyl group and halogen.
2. the tetrahydropyridine that represented by general formula I according to claim 1 thiazole compound and pharmacy acceptable salt thereof, wherein, W does not exist.
3. the tetrahydropyridine that represented by general formula I according to claim 1 thiazole compound and pharmacy acceptable salt thereof, wherein, W is-CH
2-.
4. the tetrahydropyridine that represented by general formula I according to claim 1 thiazole compound and pharmacy acceptable salt thereof, wherein, W is-CH
2-CH
2-.
5. the tetrahydropyridine that represented by general formula I according to claim 1 thiazole compound and pharmacy acceptable salt thereof, wherein, W is-CH=CH-.
6. the tetrahydropyridine that represented by general formula I according to claim 1 thiazole compound and pharmacy acceptable salt thereof, wherein, R
1for C
1-6alkyl, C
3-6cycloalkyl, C
3-8the phenyl of alkenyl, phenyl, replacement, heteroaryl.
7. the tetrahydropyridine that represented by general formula I according to claim 6 thiazole compound and pharmacy acceptable salt thereof, wherein, R
1for heteroaryl.
8. the tetrahydropyridine that represented by general formula I according to claim 1 thiazole compound and pharmacy acceptable salt thereof, wherein, this compound is selected from and comprises in following compound 7a-7u:
9. the tetrahydropyridine that represented by following general formula I according to claim 1 a preparation method for thiazole compound, the method comprises the following steps:
Step a: the carboxylic acid cpd represented by formula A1 carries out condensation reaction with the compound represented by formula A2 and prepares the compound represented by formula A3; The solvent that wherein condensation reaction is used is methylene dichloride, 1,2-ethylene dichloride, chloroform, DMF or its any mixture; Condensation reaction condensing agent used is 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, Diisopropylcarbodiimide, dicyclohexyl carbodiimide, phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus, O-benzotriazole-N, N, N, N '-tetramethyl--urine salt-hexafluorophosphate, 1-hydroxyl-benzo-triazole or its any mixture; Condensation reaction organic bases used is triethylamine, 4-dimethylaminopyridine, diisopropyl ethyl amine or its any mixture; Temperature of reaction is 0-200 DEG C;
Or the compound represented by formula A2 carries out condensation reaction with the carboxylic acid halides of the carboxylic acid represented by formula A1 and prepares the compound represented by formula A3; The solvent that wherein condensation reaction is used is methylene dichloride, 1,2-ethylene dichloride, chloroform, DMF or its any mixture; Condensation reaction organic bases used is pyridine, triethylamine, 4-dimethylaminopyridine, diisopropyl ethyl amine or its any mixture;
Step b: the compound represented by formula A3 carries out deprotection reaction and prepares the compound represented by formula A4; The solvent that wherein deprotection reaction is used is methylene dichloride, ethyl acetate, dioxane, ether or its any mixture; Deprotection reaction deprotecting regent used is trifluoroacetic acid, hydrogenchloride or its any mixture; Temperature of reaction is 0-60 DEG C;
Step c: the compound represented by formula A4 and the compound R represented by formula A5
1the carboxylic acid R that-W replaces
1-W-COOH carries out amidate action and prepares the compound represented by formula A6; The solvent that wherein amidate action is used is methylene dichloride, 1,2-ethylene dichloride, chloroform, DMF or its any mixture; Amidate action condensing agent used is 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, Diisopropylcarbodiimide, dicyclohexyl carbodiimide, phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus, O-benzotriazole-N, N, N, N '-tetramethyl--urine salt-hexafluorophosphate, 1-hydroxyl-benzo-triazole or its any mixture; Amidate action organic bases used is triethylamine, 4-dimethylaminopyridine, diisopropyl ethyl amine or its any mixture; Temperature of reaction is 0-200 DEG C;
Or, the compound represented by formula A4 and the compound R represented by formula A5
1the carboxylic acid halides R that-W replaces
1-W-COX reacts and prepares the compound represented by formula A6; The solvent wherein reacting used is methylene dichloride, 1,2-ethylene dichloride, chloroform, DMF or its any mixture; The organic bases reacting used is pyridine, triethylamine, 4-dimethylaminopyridine, diisopropyl ethyl amine or its any mixture; Temperature of reaction is 0-200 DEG C;
Steps d: the compound represented by formula A6 and R
3-NHOR
4carry out nucleophilic substitution reaction and prepare the compound represented by formula A7; The solvent that wherein nucleophilic substitution reaction is used is methyl alcohol, tetrahydrofuran (THF), acetonitrile or its any mixture; Nucleophilic substitution reaction mineral alkali used is sodium hydroxide, potassium hydroxide, lithium hydroxide or its any mixture; Temperature of reaction is 0-80 DEG C;
Or the compound represented by the formula A6 reaction that is hydrolyzed generates corresponding acid, then with R
3-NHOR
4carry out condensation reaction and prepare the compound represented by formula A7; The mineral alkali that wherein hydrolysis reaction is used is lithium hydroxide, sodium hydroxide, potassium hydroxide, salt of wormwood or its any mixture; Hydrolysis reaction solvent used is methyl alcohol, ethanol, tetrahydrofuran (THF) or its any mixture; The temperature of hydrolysis reaction is 0-80 DEG C; Condensation reaction solvent used is methylene dichloride, 1,2-ethylene dichloride, chloroform, DMF or its any mixture; Condensation reaction organic bases used is pyridine, triethylamine, 4-dimethylaminopyridine, diisopropyl ethyl amine or its any mixture; The temperature of condensation reaction is 0-200 DEG C;
Wherein X is halogen, W, R
1, R
2, R
3and R
4identical with claim 1 of definition.
10. the application in the medicine of disease that mediated by histon deacetylase (HDAC)-6 inhibitor in preparation treatment of the tetrahydropyridine that represented by general formula I according to claim 1 thiazole compound and pharmacy acceptable salt thereof.
11. application according to claim 10; wherein, the described disease mediated by histon deacetylase (HDAC)-6 inhibitor comprises relieve chronic Lymphocytic leukemia, mammary cancer, prostate cancer, ovarian cancer, carcinoma mesothelial, T-cell lymphoma, cardiac hypertrophy, chronic heart failure, inflammation, cardiovascular disorder, thalassemia, CNS disease, autoimmune disorder and nerve degenerative diseases.
12. 1 kinds are used for the treatment of by the pharmaceutical composition of the disease of histon deacetylase (HDAC)-6 inhibitor mediation; it contains one or more tetrahydropyridines of being represented by general formula I according to claim 1 for the treatment of significant quantity and thiazole compound and pharmacy acceptable salt thereof, and one or more pharmaceutically acceptable vehicle, diluent or carriers.
13. pharmaceutical compositions according to claim 12; wherein, the described disease mediated by histon deacetylase (HDAC)-6 inhibitor comprises relieve chronic Lymphocytic leukemia, mammary cancer, prostate cancer, ovarian cancer, carcinoma mesothelial, T-cell lymphoma, cardiac hypertrophy, chronic heart failure, inflammation, cardiovascular disorder, thalassemia, CNS disease, autoimmune disorder and nerve degenerative diseases.
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