CN102838625A - 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.Particularly, 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 this compounds and be used for treating application, be specifically related to its application in preparation treatment tumour, nervous system disease and relative disease medicine thereof by the medicine of the disease of histon deacetylase (HDAC)-6 suppressor factor mediation in preparation.
Background technology
Cancer is one of principal disease that threatens human health.World Health Organization's data show that cancer is that the whole world causes one of main causes of death, and the cancer mortality number reached 7,900,000 in 2007, accounted for 13% of all death tolls.Antitumor drug commonly used clinically at present mainly is a cytotoxic drug, and this kind anti-cancer drugs has shortcoming such as poor selectivity, big, the easy generation resistance of toxic side effect etc. that are difficult to avoid.Along with life science deeply with progress at full speed, about tumour 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.The albumen relevant with transfer with the generation of tumour is of a great variety, and regulation and control have the albumen of general biological significance just most possibly to become the action target spot of wide spectrum low toxicity antitumor drug to growth of tumour cell.Research shows, the acetylize of the lysine residue of the generation of tumour and nucleosome core histone N-end and deacetylation unbalance has confidential relation.Histone modification (as methylate, acetylize, phosphorylation, ubiquitinization etc.) plays an important role in the eukaryotic gene expression regulation.In these were modified, acetylation of histone/deacetylation was particularly important, and it is rebuild through electric charge around the change chromatin or participation chromatin configuration influences genetic expression.
Chromatinic fundamental unit nucleosome in the karyocyte is made up of core histones (H2A, H2B, H3 and H4), H1 and DNA.In the nucleosome assembling process, (H3/H4) tetramer at first combines with DNA, and with latter two H2A/H2B heterodimer, 5 and the 3DNA that is attached to (H3/H4) 2 junctions goes up and form nucleosome.It is dna replication dna that nucleosomal structure is modified, transcribe, the committed step in the repair process.Before more than 30 years, Allfre etc. have found that core histones N-holds acetylize can regulate multiple trans-acting factor and combines with nucleosome, thereby influence genetic transcription.After this research deepens continuously, and finds that histone can have multiple modification mode: ubiquitinization, phosphorylation, acetylize, methylate etc., their separately (working in coordination with) regulatory gene transcribe.Wherein acetylation of histone is to remove the inhibiting main mechanism of nucleosome, receive the histone acetyl based transferase (histoneacetyltransferase, HAT) and histon deacetylase (HDAC) (histonedeacetylase, regulation and control HDAC).
NSC 630176 (histone deacetylase inhibitor; HDACi) acetylize and the deacetylation of the lysine residue through regulating histone N-end; Activate cancer suppressor gene and suppress the cancer gene; Participate in cell cycle progression and differentiation, thereby suppress growth of tumour cell, inducing apoptosis of tumour cell.Relevant with development with the generation of multiple disorders such as cancers, acute myeloid leukaemia, virus and infection etc., it is significant to above-mentioned treatment of diseases to study its suppressor factor.
Mankind HDAC family can be divided three classes: the I class comprises HDAC1, HDAC2, HDAC3 and HDAC8, only is present in the nucleus; The II class comprises HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, HDAC10 and HDAC11, in the signal transduction process, shuttles back and forth between nucleus and tenuigenin, and wherein HDAC11 includes the catalytic site of I class and II class HDAC; III class and preceding 2 types have very big difference, and its activity is not to rely on Zn
2+, but rely on nicotinamide adenine dinucleotide (NAD), and with zymic Sir2 homology, having 7 kinds of hypotypes at least, it can not be suppressed by I, II class hdac inhibitor.
Yet according to traditional drug target conclusive evidence experience, HDAC also should not be as a drug target, and reason is that middle key factor has too many interaction to determine the complicacy of its biological action in HDAC and the cell.Therefore, the discovery of hdac inhibitor has important effect for the biological function of overall understanding HDAC.Have been found that the suppressor factor to I, II, III class among the HDAC at present, comprise that natural product and synthetic compound originate, it is very limited really to have a better selectivity compound.
Present Research for II class hdac inhibitor is that HDAC6 makes fast progress, and there are some researches show that HDAC6 ability deacetylation is nonhistones, like a-tubulin, cortactin and HSP90, and relevant with the stability and the cell movement of microtubule.The growth of multiple myeloma cell is suppressed and does not influence non-cancer cells its inhibition; Also there is report HDAC6 to suppress relevant with neuroprotective; In the optionally HDAC6 suppressor factor of having reported; The common feature that they have is all to be the straight chain type compound, and the zine ion combining site is in the majority with sulfydryl, and is 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 shows, to the active inhibition of HDAC growth capable of inhibiting cell and inducing cell differentiation, in some tumour cells, produces anticarcinogenic effect.Several development projects relevant with hdac inhibitor start, and the research of hdac inhibitor has become very active research field of antitumor drug.The active higher H DAC suppressor factor of part has got into clinical study at present, comprises MS275 (Bayer/syndax), MGCD-0103 (MethylGene), LBH-589 (Novartisd), PXD101 (Topotarget), SB-939 (S*Bio), CI-99 (Pfizer) etc.The further development of hdac inhibitor then need be for HDAC systems biology function, and the biological action that reaches independent HDAC hypotype has more deep research.So far also form very clear and definite understanding for the problems referred to above, have, utilize the suppressor factor of non-selectivity simultaneously many hypotypes of HDAC to be produced inhibition, thereby study its biological function from pharmacological means.Yet better means have the better selectivity suppressor factor for utilization has for the HDAC different subtype and study.And the biological function research means that gos deep into for each hypotype mainly is through the RNAi technology at present.Therefore find that having the better selectivity hdac inhibitor is significant for biology and the pharmacology function of furtheing investigate HDAC.
Summary of the invention
One object of the present invention is the selective depressant that provides one type to act on histon deacetylase (HDAC)-6; Tetrahydropyridine and thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvolyte promptly represented by general formula I, this compounds can be used for treating, preventing and suppress the relative disease by the mediation of histon deacetylase (HDAC)-6 suppressor factor.
Another object of the present invention is to provide the tetrahydropyridine that a kind of preparation represented by general formula I and the method for thiazole compound.
Also purpose of the present invention is to provide a kind of tetrahydropyridine represented by general formula I and pharmaceutical composition of thiazole compound, its steric isomer and pharmacy acceptable salt, prodrug or its solvolyte of containing.
Another purpose of the present invention is to provide the tetrahydropyridine represented by general formula I and the purposes of thiazole compound, its steric isomer and pharmacy acceptable salt, prodrug or its solvolyte.The compound of being represented by general formula I is the selective depressant that acts on histon deacetylase (HDAC)-6; It can suppress the deacetylation effect of histon deacetylase (HDAC), thereby particularly the deacetylation effect of histon deacetylase (HDAC)-6 is suppressed to produce biological activity.Therefore, another aspect of the present invention is to use at least a compound of the present invention to come the deacetylation effect of histon deacetylase (HDAC)-6 is suppressed; This method is particularly useful for disease, illness and/or the obstacle that treatment is regulated by histon deacetylase (HDAC) (particularly histon deacetylase (HDAC)-6) suppressor factor.
A further object of the present invention is to provide the tetrahydropyridine represented by general formula I and thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvolyte to be used to treat tumour, nervus retrogression class disease and diseases related etc. method thereof.
To achieve these goals, the present invention provides a kind of tetrahydropyridine and thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvolyte of being represented by following general formula I,
Wherein:
W does not exist, and perhaps is-CH
2-,-CH
2-CH
2-or-CH=CH-;
R
1Be selected from C
1-8Alkyl, C
1-8Alkoxyl group, C
3-10Naphthenic base, C
3-8Alkenyl, list or two C
1-3Alkylamino, list or two C
1-3Alkylamidoalkyl, C
1-3Alkyl sulphonyl, C
1-3In alkoxy carbonyl, hydroxyl, methylol, hydroxyethyl, methylthio group, trifluoromethylthio, trifluoromethyl, difluoro-methoxy, amino, amino-sulfonyl, phenyl, substituted phenyl, phenoxy and the heteroaryl; Preferably, R
1Be C
1-6Alkyl, C
3-6Naphthenic base, C
3-8Alkenyl, phenyl, substituted phenyl or heteroaryl; More preferably, R
1Be heteroaryl;
R
2For being selected from Wasserstoffatoms, 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 alkoxy carbonyl, hydroxyl, methylol, hydroxyethyl, methylthio group, trifluoromethylthio, trifluoromethyl, difluoro-methoxy, trifyl, amino, amino-sulfonyl, phenyl, substituted phenyl, phenoxy, halogen, nitro and the cyanic acid; Preferably, R
2Be Wasserstoffatoms;
R
3And R
4Be independently selected from Wasserstoffatoms, C respectively
1-10Alkyl, C
3-10Naphthenic base, C
1-6The substituted C of alkoxy carbonyl
3-10Naphthenic base, C
3-10The C of cycloalkyl substituted
1-4Alkyl, C
3-8Alkenyl, C
5-8Cycloalkenyl group, adamantyl, C
6-20Aryl, C
6-20The substituted C of aryl
1-4In alkyl, heteroaryl and the heterocyclic radical; Preferably, R
3Be Wasserstoffatoms, R
4Be Wasserstoffatoms;
Said heteroaryl is to contain 1-3 the first aromaticity group of identical or different heteroatomic 5-10 that is selected among N, O and the S, for example thienyl, benzothienyl, furyl, benzofuryl, thiazolyl, benzothiazolyl, pyrazinyl, pyrimidyl etc.;
Said heterocyclic radical is to contain 1-3 identical or different heteroatomic 5-10 first non-aromaticity group, for example piperidyl, piperazinyl, the morpholinyl etc. that are selected among N, O and the S;
Substituting group on the said substituted phenyl is selected from C
1-8Alkyl, C
1-8In alkoxyl group and the halogen; Preferably, said substituting group is C
1-8Alkyl.
In an embodiment of the invention, in the above-mentioned general formula I, W is not for existing, and other substituent definition are same as described above.
In an embodiment of the invention, in the above-mentioned general formula I, W is-CH
2-, other substituent definition are same as described above.
In an embodiment of the invention, in the 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 the above-mentioned general formula I, W is-CH=CH-that other substituent definition are same as described above.
Compound of the present invention can exist with the form of solvation not with the form of pharmaceutically acceptable solvent (for example water, ethanol etc.) solvation.Usually, for the present invention, think that the form of solvation is equal to the not form of solvation.
Be applicable to whole specification sheets and claims to give a definition.Unless otherwise mentioned or point out, term " alkyl " expression straight or branched alkyl.The example of said 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 " expression group-O-alkyl, wherein alkyl as above defines.
Unless otherwise mentioned or point out that term " halogen " is meant fluorine, chlorine, bromine or iodine.
More preferably, tetrahydropyridine and the thiazole compound represented by general formula I are selected from the following compound:
And the steric isomer under usable condition and pharmacy acceptable salt, prodrug or its solvolyte.
The present invention provides the tetrahydropyridine that general formula I representes and the preparation method of thiazole compound in addition.
Compound with general structure I of the present invention can be synthetic through following route of synthesis, and this approach comprises and is similar in the chemical field to be known, and particularly states the method for bright part according to this.Starting substance generally can be from commercial source; Obtain such as Aldrich chemical company (the hot state of University of Wisconsin-Madison Milwaukee), or the method for being known by one of skill in the art can prepare (as preparing through the method for being summarized in the following books: " reagent that is used for the organic synthesis effect " 1-19 volume (the USA New York Wiley 1967-1999 of company version) of Louis F.Fieser and Mary Fieser; Or " Beilsteins Handbuch der organischen Chemie " the 4th of Auf1. version and comprise supplement (Berlin, Germany Springer-Verlag company publish and also can obtain) via Beilstein online material storehouse.
Except as otherwise noted, in the reactions route, each symbol of described compound has identical implication.Compound in reaction scheme comprises its salt, for example, as has the salt etc. of compound in structural formula I definition.
For the usefulness of explaining, the reaction process shown in following is provided for the possible approach of synthetic compound of the present invention and key intermediate species.The more detailed explanation of relevant indivedual reactions step, the embodiment part of stating after asking for an interview.Those skilled in the art will understand and can use other route of synthesis to synthesize compound of the present invention.Though that show on stream and after state part touch upon specific starting substance and reagent, they can be alternative with other starting substances and reagent easily, and multiple verivate and/or reaction conditions is provided.In addition,, can use conventional chemical well-known to those skilled in the art, state the prepared numerous compounds of method through this and further modify in view of present disclosure.
According to another object of the present invention, the invention provides a kind of tetrahydropyridine of representing by general formula I and the preparation method of thiazole compound, this method may further comprise the steps:
Step a: carry out condensation reaction and prepare the compound of representing by formula A3 by formula A1 carboxylic acid cpd of representing and the compound of representing by formula A2; Wherein the used solvent of condensation reaction is a methylene dichloride, 1,2-ethylene dichloride, chloroform, N, and dinethylformamide (DMF) or its any mixture are preferably methylene dichloride; The used condensing agent of condensation reaction is 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC), di-isopropyl carbodiimide (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; The used organic bases of condensation reaction is triethylamine, 4-dimethyl amine pyridine (DMAP), diisopropyl ethyl amine (DIPEA) or its any mixture, is preferably diisopropyl ethyl amine (DIPEA); Temperature of reaction is 0-200 ℃, is preferably 0 ℃-room temperature;
Perhaps, the carboxylic acid halides by formula A2 compound of representing and the carboxylic acid of being represented by formula A1 carries out condensation reaction and prepares the compound of being represented by formula A3; Wherein the used solvent of condensation reaction is a methylene dichloride, 1,2-ethylene dichloride, chloroform, N, and dinethylformamide (DMF) or its any mixture are preferably methylene dichloride; The used organic bases of condensation reaction is pyridine, triethylamine, 4-dimethyl amine pyridine (DMAP), diisopropyl ethyl amine (DIPEA) or its any mixture, is preferably triethylamine;
Step b: the compound of being represented by formula A3 carries out deprotection reaction and prepares the compound of being represented by formula A4; Wherein the used solvent of deprotection reaction is methylene dichloride, ETHYLE ACETATE, dioxane, ether or its any mixture, is preferably methylene dichloride; The used deprotecting regent of deprotection reaction is trifluoroacetic acid (TFA), hydrogenchloride or its any mixture, is preferably trifluoroacetic acid; Temperature of reaction is 0-60 ℃, is preferably 0 ℃-room temperature;
Step c: by formula A4 compound of representing and the compound R of representing by formula A5
1The substituted carboxylic acid R of-W
1-W-COOH carries out amidate action and prepares the compound of being represented by formula A6; Wherein the used solvent of amidate action is a methylene dichloride, 1,2-ethylene dichloride, chloroform, N, dinethylformamide (DMF) or its any mixture; The used condensing agent of amidate action is 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC), di-isopropyl carbodiimide (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; The used organic bases of amidate action is triethylamine, 4-dimethyl amine pyridine (DMAP), diisopropyl ethyl amine (DIPEA) or its any mixture; Temperature of reaction is 0-200 ℃, is preferably 0 ℃-room temperature;
Perhaps, by formula A4 compound of representing and the compound R of representing by formula A5
1The substituted carboxylic acid halides R of-W
1-W-COX reaction and compound that preparation is represented by formula A6; The solvent that wherein reacts used is a methylene dichloride, 1,2-ethylene dichloride, chloroform, N, dinethylformamide (DMF) or its any mixture; The organic bases that reacts used is pyridine, triethylamine, 4-dimethyl amine pyridine (DMAP), diisopropyl ethyl amine (DIPEA) or its any mixture; Temperature of reaction is 0-200 ℃, is preferably 0 ℃-room temperature;
Steps d: the compound and the R that represent by formula A6
3-NHOR
4Carry out nucleophilic substitution reaction and prepare the compound of representing by formula A7; Wherein the used solvent of nucleophilic substitution reaction is methyl alcohol, THF, acetonitrile or its any mixture; The used mineral alkali of nucleophilic substitution reaction is sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate or its any mixture; Temperature of reaction is 0-80 ℃, is preferably 0 ℃-40 ℃;
Perhaps, the compound of being represented by the formula A6 reaction that is hydrolyzed generates corresponding acid, again with R
3-NHOR
4Carry out condensation reaction and prepare the compound of representing by formula A7; Wherein the used mineral alkali of hydrolysis reaction is Lithium Hydroxide MonoHydrate, sodium hydroxide, Pottasium Hydroxide, salt of wormwood or its any mixture; The used solvent of hydrolysis reaction is methyl alcohol, ethanol, THF or its any mixture; The temperature of hydrolysis reaction is 0-80 ℃, is preferably 0 ℃-40 ℃; The used solvent of condensation reaction is a methylene dichloride, 1,2-ethylene dichloride, chloroform, N, dinethylformamide (DMF) or its any mixture; The used organic bases of condensation reaction is pyridine, triethylamine, 4-dimethyl amine pyridine (DMAP), diisopropyl ethyl amine (DIPEA) or its any mixture; The temperature of condensation reaction is 0-200 ℃; Be preferably 0 ℃-room temperature;
Wherein X is a halogen, W, R
1, R
2, R
3And R
4Definition the same.
Preliminary study shows that following disease, illness and/or obstacle are 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, through discovering, compound of the present invention is to be suitable for disease, illness and/or the obstacle of treating by NSC 630176 mediated.
Another aspect of the present invention provides a kind of method by disease, illness and/or obstacle that NSC 630176 mediated of treating animal, and said method comprises to the compound of the present invention of the animal administering therapeutic significant quantity of this treatment of needs or contains the compound of the present invention of treating significant quantity and the pharmaceutical composition of pharmaceutically acceptable vehicle, diluent or carrier.
Another embodiment of the invention provides a kind of pharmaceutical composition, and it comprises the compound of the present invention of treating significant quantity or its pharmacy acceptable salt, prodrug or its solvolyte and pharmaceutically acceptable vehicle, diluent or carrier.Be to be understood that; Pharmaceutical composition of the present invention can comprise one or more compounds of the present invention; Be 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 the combination therapy.When being used for combination therapy, compound of the present invention uses with therapy (for example He Saiting and sharp appropriate uncommon agate), gene therapy, cell therapy, hormonotherapy or cytokine therapy based on micromolecular compound, radiation, antibody usually.
In a preferred embodiment of the invention, compound of the present invention can be united with other chemotherapy or antineoplastic agent and is used for treatment for cancer.The instance of said other chemotherapy or antineoplastic agent has comprised catharanthus alkaloid (like vincristine(VCR) and vinealeucoblastine(VLB)), anthracycline antibiotics (like Zorubicin and Oxacyclotetradecane,erythromycin deriv), alkylating agent (like TV), taxanes (like taxol), antifol (like Mexician scammony) and dna methylation inhibitor.
Typical prescription is through mixing compound of the present invention and pharmaceutically acceptable carrier, thinner or vehicle etc. prepare it.Suitable carrier, thinner or vehicle are well-known to those skilled in the art, comprise the material such as glucide, wax, water-soluble and/or swellability polymkeric substance, wetting ability or lyophobic dust, gelatin, oil, solvent, water etc.Used specific support, thinner or vehicle will be according to the mode of using compound of the present invention and purposes and decide.Generally think that with those skilled in the art but the solvent that safety is administered to mammal (GRAS) is the basis, and selective solvent.Generally speaking, the solvent of safety be the nontoxicity water-containing solvent such as water, and other water solubles or the nontoxicity solvent miscible with water.Suitable water-containing solvent comprises water, ethanol, Ucar 35, polyoxyethylene glycol (like PEG400, PEG300) etc. and composition thereof.This prescription also can comprise one or more buffer reagents, tranquilizer, tensio-active agent, wetting agent, lubricant, emulsifying agent, suspension agent, sanitas, inhibitor, opalizer, glidant, processing aid, tinting material, sweetener, perfume agent, seasonings and other known additives; Providing one of this medicine graceful appearance form (that is compound of the present invention or its pharmaceutical compositions), or assist the manufacturing of this pharmaceutical product (that is medicine).
This prescription can use conventional dissolving combination process and prepare.For example, in the presence of one or more above-mentioned vehicle, with the stabilized form of blocky drug substance (that is compound of the present invention or this compound) (as with the complex compound of cyclodextrin derivative or other known recombiners) be dissolved in the The suitable solvent.Typically compound of the present invention is mixed with pharmaceutical formulation,, and a kind of easy to handle product is provided to the patient with the dosage of easy control that this medicine is provided.
The pharmaceutical composition of the confession using (or prescription) can be complied with the administering mode of this medicine, and packs in many ways.Generally speaking, the object that is used to distribute comprises container, wherein deposits the pharmaceutical formulation of suitable form.Suitable container is well-known to those skilled in the art, comprises the material such as bottle (plastics and vial), sachet, ampoule, plastics bag, metallic cylinder etc.In addition, on 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 treat-ment of the present invention, give compound of the present invention for the individuality of this treatment of needs, or give the combination of compound of the present invention and at least a additional medicaments, be preferably a kind of form of pharmaceutical compositions.With regard to combined aspects of the present invention; Compound of the present invention and at least a other medicaments (like antineoplastic agent catharanthus alkaloid (like vincristine(VCR) and vinealeucoblastine(VLB)), anthracycline antibiotics (for example Zorubicin and Oxacyclotetradecane,erythromycin deriv), alkylating agent (like TV), taxanes (like taxol), antifol (like Mexician scammony) and dna methylation inhibitor) but separate administration, or to comprise the pharmaceutical compositions administration of the two simultaneously.Generally speaking, be preferably oral administration.Yet, if the individuality of being treated can't swallow, or oral administration be obstructed or non-other situation of desiring under, possibly suit to carry out parenteral or transdermal administration.According to treat-ment of the present invention, when one of compound of the present invention and at least a other medicaments were combined administration, this administering mode can carry out in time in regular turn or simultaneously, and generally to carry out simultaneously to preferably.With regard to the administering mode that carries out in regular turn, compound of the present invention and this additional medicaments can be with arbitrary order administrations.Generally speaking, this administering mode is preferably oral administration.This administering mode is preferably administration oral and that carry out simultaneously especially.When compound of the present invention and this additional medicaments were administration in regular turn, administration separately can be carried out through identical or different method.
According to method of the present invention, the combination of compound of the present invention or compound of the present invention and at least a other medicaments (being referred to herein as " combination ") is 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 (for example intravenously, intramuscular or subcutaneous), the brain pond, intravaginal, intraperitoneal, intravesical, part (for example powder, ointment or drop), cheek or nose formulation, separate or be administered to sufferer together.
Be applicable to non-pharmaceutical composition, generally comprise pharmaceutically acceptable aseptic moisture or non-aqueous solution, dispersion liquid, suspension-s or emulsion, and be used to recombinate and become the aseptic syringeability solution or the sterilized powder of dispersion liquid through enteral administration.Suitable moisture or nonaqueous carrier or thinner (comprising solvent and carrier) comprise water, ethanol, polyvalent alcohol (Ucar 35, polyoxyethylene glycol, glycerine etc.) and suitable mixture thereof; Vegetables oil (such as sweet oil); And the syringeability organic ester is such as OE.For example can under the situation of dispersion liquid, keep required particle size through using coating such as Yelkin TTS, and through the use tensio-active agent, and keep suitable flowability properties.
These pharmaceutical compositions also can contain vehicle, such as sanitas, wetting agent, emulsifying agent and dispersion agent.Can pass through various bactericide and mycocide, for example metagin, butylene-chlorohydrin, phenol, Sorbic Acid etc., thus avoid the microbial contamination said composition.Isoosmotic pressure agent such as carbohydrate, sodium-chlor etc. possibly also be what desired.The medicament that can postpone absorption through use, such as aluminum monostearate and gelatin, and the absorption that prolongs the injection type pharmaceutical composition.
The solid dosage that is used for oral administration can comprise capsule, tablet, powder and particle.In these solid dosages, compound of the present invention or combination are to mix with at least a inert excipient, diluent or carrier.Suitable vehicle, diluent or carrier comprise the material such as Trisodium Citrate or Lin Suanergai, or (a) filler or extender (like starch, lactose, sucrose, mannitol, silicic acid etc.); (b) tackiness agent (like CMC 99.5, alginate, gelatin, PVP K120, sucrose, gum arabic etc.); (c) wetting agent (like glycerine etc.); (d) disintegrating agent (like agar, lime carbonate, yam or tapioca(flour), alginic acid, specific complex silicate, yellow soda ash etc.); (e) solution retarding agent (like paraffin etc.); (f) quicken absorption agent (like quaternary ammonium compound etc.); (g) wetting agent (like ethanoyl alcohol, glyceryl monostearate etc.); (h) sorbent material (like kaolin, wilkinite etc.); And/or (i) lubricant (like talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sodium Lauryl Sulphate BP/USP etc.).Under the situation of capsule and tablet, this formulation also can comprise buffer reagent.The solid-state composition of similar type also can be used as the filler in the soft and rigid filling gelatine capsule, and it uses lactose and high molecular weight polyethylene glycol etc. as vehicle.
Can prepare such as tablet, dragee, capsule and particulate solid dosage, such as the enteric film of being known in the pharmacy preparation field or other coatings with coating or shell.They also can contain opalizer, and can be the compsn that delayed mode disengages compound of the present invention and/or additional medicaments.The instance of spendable embedded compsn comprises polymerizability material and wax.If suitable, this medicine also also is the microencapsulation form with last mentioned one or more vehicle.
The liquid formulation that is used for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension-s, liquid syrup and elixir.Except compound of the present invention or combination, this liquid state formulation can contain inert diluent commonly used in this area, such as water or other solvents; Solubilizing agent and emulsifying agent are such as ethanol, isopropyl alcohol, ethyl-carbonate, ETHYLE ACETATE, benzylalcohol, phenylformic acid benzyl ester, Ucar 35,1,3 butylene glycol, N; Oils (like Oleum Gossypii semen, Peanut oil, Fructus Maydis oil, sweet oil, Viscotrol C, sesame wet goods); Glycerine; Tetrahydrofurfuryl alcohol; The fatty ester of polyoxyethylene glycol and sorbitan; Or the mixture of these materials etc.
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-s; Except compound of the present invention or combination; Can further contain carrier such as suspension agent; Like ethoxylation isooctadecanol, T 46155 pear oligose alcohol and dehydration pear oligose alcohol ester, Microcrystalline Cellulose, inclined to one side white lake, wilkinite, agar and tragacanth gum, or the mixture of these materials etc.
The pharmaceutical composition that is used for rectum or vagina administration preferably includes suppository; Can prepare through compound of the present invention or combination are mixed with non-irritating excipient that suits or carrier; Vehicle or carrier such as cocoa butter, polyoxyethylene glycol or suppository wax; Its general room temperature be solid-state and at body temperature for liquid, therefore can in rectum or vagina, dissolve and disengage active compound.
The combination of compound of the present invention and compound of the present invention and nervus retrogression class or tumour medicine is used for the topical formulation, can comprise ointment, powder, spray and inhalation.This pharmaceutical composition can be under aseptic condition and pharmaceutically acceptable vehicle, diluent or carrier and needed arbitrary sanitas, buffer reagent or propellant mixing.Ophthalmic formulations, eye also are intended to be covered by in the scope of the present invention with ointment, powder and solution.
Known ground, compound of the present invention (or combination) can be inserted in the 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 and insert in the drinking-water, preferably with the form of liquid water-soluble concentrate (such as the aqueous solution of water-soluble salt).
Can be through medicine being scattered in a kind of pharmaceutically acceptable oil such as peanut oil, til, the corn wet goods, and preparation pasty state prescription.
Can pass through compound of the present invention or combination are mixed such as carbowax, palm wax etc. with thinner, and preparation contains the pill of compound of the present invention, pharmaceutical composition or the combination of significant quantity; Also can add lubricant such as Magnesium Stearate or calcium stearate, to promote the pill processing procedure.
The present invention is also contained through isotope-labeled The compounds of this invention, and except one or more atoms are different from one of atomic mass common in the nature or the total mass number atom institute metathetical fact by atomic mass or total mass number, it is that not state the person therewith identical.Can include the isotropic substance instance in the compound of the present invention in, comprise the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, iodine and chlorine, its respectively such as:
2Hydrogen,
3Hydrogen,
11Carbon,
13Carbon,
14Carbon,
13Nitrogen,
15Nitrogen,
15Oxygen,
17Oxygen,
18Oxygen,
31Phosphorus,
32Phosphorus,
35Sulphur,
18Fluorine,
123Iodine,
125Iodine reaches
36Chlorine.
Some isotope-labeled compound of the present invention (use by example
3H with
14Those of C mark) be used for compound and/or substrate tissue distribution assays.Preferred especially tritiate (promptly
3H) and carbon-14 (promptly
14C) isotropic substance is because their preparation and detections easily.And heavier isotropic substance such as deuterium are (promptly
2H) replace some treatment advantage of being caused by bigger metabolic stability (for example the transformation period increases or dose requirements reduces in the body) can be provided, thereby possibly be preferred in some cases.The positron radiation isotropic substance, for example
15O,
13N,
11C with
18F is used for positron emission tomography (PET) research, with inspection substrate acceptor occupancy.Isotope-labeled compound of the present invention generally can be followed the disclosed method in scheme and/or hereinafter embodiment that is similar to, and prepares through substituting nonisotopically labelled reagent with isotope-labeled reagent.
Embodiment
Through the following example explanation embodiment of the present invention.Yet, should be appreciated that embodiment of the present invention are not subject to the specific detail in the following example, because in view of disclosure of the present invention, other change those of ordinary skills is known and conspicuous.
Provide following experimental example further illustrating the present invention, but it does not constitute the restriction to its scope.
Laboratory sample is analyzed used instrument and reagent
Nuclear magnetic resonance spectrum (
1H NMR,
13C NMR) (solvent is CDCl by the Mercury-300 of Varian company or Mercury-400 type nmr determination
3, in be designated as TMS).LC-MS is measured by Thermo Finnigan LCQDECA * P type mass spectrograph.Fusing point is measured (thermometer reading is not calibrated) by the SGW X-4 type fusing point appearance of Shanghai Precision Scientific Apparatus Co., Ltd.The column chromatography for separation used silica gel is Haiyang Chemical Plant, Qingdao's product (a 200-300 order).The TLC silica-gel plate is the HSF-254 thin-layer chromatography precoated plate of Yantai Chemical Manufacture, adopts uv lamp, the colour developing of iodine cylinder.Uv lamp is the Shanghai ZF-1 of a Gu Cun electric light instrument plant type ultraviolet analysis instrument for three purposed.The raw materials used 1 commercially available prod para-amino benzoic acid by Aldrich chemical company (the hot state of University of Wisconsin-Madison Milwaukee) gets through the BOC protection in synthetic; Raw material 2 is bought from the splendid chemical reagents corporation far away of China; Acyl chlorides used in the reaction is all available from Aldrich chemical company commercially available prod, and part prepares corresponding acyl chlorides by the commercially available acid of Aldrich chemical company through sulfur oxychloride.
Embodiment 1:
A) preparation of compound 3
Take by weighing compound 1 (210mg, 0.89mmol) (200mg is 0.81mmol) in reaction tubes with compound 2; Be dissolved in 2 milliliters of N, behind the dinethylformamide (DMF), add diisopropylethylamine (DIPEA) (0.31mL; 1.77mmol), nitrogen protection adds 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) down, and (170mg is 0.89mmol) with 1-hydroxyl-benzo-triazole (HoBt) (120mg; 0.89mmol), stirred overnight at room temperature, reaction solution is directly used 30 milliliters of ethyl acetate extractions; Organic layer is used anhydrous sodium sulfate drying after respectively washing once with 1N hydrochloric acid, saturated sodium bicarbonate, water and saturated brine successively, gets crude product behind the pressure reducing and steaming solvent; Crude product gets product through column chromatographic isolation and purification; Elution requirement is a sherwood oil: ETHYLE ACETATE=5: 1-3: 1, and getting 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
Take by weighing compound 3 (200mg, 0.46mmol) be dissolved in the dichloromethane solution of 5 milliliter of 20% trifluoroacetic acid (TFA) after, stirring at room three hours; The pressure reducing and steaming solvent adds 10mL saturated sodium bicarbonate reaction solution and alkalizes, with twice of 20 milliliters of dichloromethane extraction; Organic layer is after water and saturated brine are respectively washed once respectively, and anhydrous sodium sulfate drying is behind the pressure reducing and steaming solvent; Getting 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
Take by weighing compound 4 (100mg, 0.30mmol) be dissolved in 5 milliliters of methylene dichloride after, add triethylamine (Et
3N) (0.052mL, 0.36mmol), adding Acetyl Chloride 98Min. 5a under the nitrogen protection (0.026mL, 0.36mmol); Stirring at room 4h, reaction solution directly use 30 milliliters of dichloromethane extractions, and organic layer is after water and saturated brine are respectively washed once respectively; Anhydrous sodium sulfate drying gets crude product behind the pressure reducing and steaming solvent, crude product gets product through column chromatographic isolation and purification; Elution requirement is a methylene dichloride: methyl alcohol=100: 1-20: 1, and getting 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
(2.64g 38mmol) puts in the 50mL reaction flask, adds 20mL methyl alcohol then, is heated to 40 ℃, and (2.12g, 38mmol) reaction is 10 minutes to add Pottasium Hydroxide to take by weighing oxammonium hydrochloride.After reaction solution is cooled to 0 ℃, filter.(75mg 2mmol) adds filtrating, and (250mg 4.46mmol) at room temperature reacts half a hour and then to add KOH to take by weighing compound 6a subsequently.
Reaction solution is used ethyl acetate extraction.Organic layer is used saturated NH
4The Cl aqueous solution and saturated aqueous common salt wash, and use anhydrous sodium sulfate drying then, filter reconcentration.Middle product extracts DCM with chromatographic column: MeOH: NH
4OH=10: making target compound 7a was white solid 37mg, yield 52% as elutriant in 1: 0.1.
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 among the embodiment 1, has made the midbody compound of in table 1, listing.Just use butyryl chloride (5b) respectively; Capryl(yl)chloride (5c); 1-penta rare acyl chlorides (5d); Benzoyl chloride 99min. (5e); Phenyllacetyl chloride (5f); Phenylpropyl alcohol acyl chlorides (5g); Cyclohexyl acyl chlorides (5h); Cyclopentyl propionyl chloride (5i); Cyclohexyl propionyl chloride (5j); Cinnamyl chloride (5k); 3-methoxyl group cinnamyl chloride (5l); 4-methoxyl group cinnamyl chloride (5m); 3-methyl cinnamyl chloride (5n); 4-methyl cinnamyl 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) have replaced the Acetyl Chloride 98Min. 5a among the embodiment 1.The mass-spectrometric data of midbody compound 6b-6u sees the following form shown in 1.
Table 1: midbody 6b-6u
F) preparation of target compound 7b-7u
After obtaining above-mentioned midbody compound, the preparation method of compound 7a is basic identical among the preparation of compound 7b-7u and the embodiment 1, has just replaced the 6a among the embodiment 1 with midbody 6b-6u respectively, has made the target compound 7b-7u that in following table, lists.The mass-spectrometric data of target compound 7b-7u sees the following form shown in 2.
Table 2: target compound 7b-7u
Pharmacological testing embodiment
The external measuring method for activity of histon deacetylase (HDAC)
Utilize insect baculovirus expression system to express to have the people source reorganization HDAC family protein of His label and GST label, through the HDAC family recombinant protein of Ni affinity column protein purification acquisition biologically active.With Boc-lys (Ac)-AMC or Ac-Lys-Tyr-Lys (Ac)-AMC is substrate, adopts fluorescence detection, the flat microwell plate in black 384 holes (OptiPlateTM-384F, PerkinElmer) the middle enzymic activity that detects.Substrate is behind HDAC albumen deacetylation, and the product A MC that utilizes pancreatin hydrolysis to obtain excites under the 460nm emission light at the 355nm of fluorescence detector and can be detected fluorescent signal.Through detecting the variation of fluorescent signal in time, calculate initial velocity of reaction.In brief, in the survey live body of the 25 μ L system, comprise HDAC substrate (5-50 μ M; 5 μ L), people source recombinant protein HDAC (20-200nM) and compound; All the components all is with the dilution of Hepes damping fluid (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, and HDAC1 and HDAC3 reaction times are incubated at room 24 hours.Add 25 μ L trypsinase termination reactions at last, room temperature was placed after 30 minutes, detected 355nm with Envision (PerkinElmer) and excited the fluorescent signal under the 460nm emission light, and it is active to calculate HDAC.
Pharmacology data: the pharmacology test result that will announce one group of The compounds of this invention that part obtains with embodiment 1 in the following table 3; The contrast of adopting in the test is Mo Shadong (Merck Co.; Inc) NSC 630176 (SAHA) medicine of first listing of company's exploitation is used to treat the epithelial cell lymphatic cancer.
Table 3 embodiment bioassay data
Can find out that from last table positive compound is the NSC 630176 Vorinostat (SAHA) of bibliographical information, its IC on HDAC1
50Value is 118 μ M, the IC that HDAC3 is last
50Value is 170 μ M, the IC that HDAC6 is last
50Value is 34 μ M, and close with bibliographical information explains that this method can repeat literature method preferably, and resulting active result has higher confidence level on this system.Can see from last table; The molecular level test experiments of this compounds shows that compound of the present invention has very strong combination activity to histon deacetylase (HDAC)-6; And all embody certain selectivity; Wherein the selectivity between the HDAC1 of some compound, HDAC3 and the HDAC6 reaches 100 times, explains that this compounds is one type and effectively has optionally histon deacetylase (HDAC) 6 suppressor factor.
Above-mentioned example is only as illustrative purposes, and scope of the present invention is not so limited.It is conspicuous making amendment to one skilled in the art, and the present invention only receives the restriction of accompanying claims scope.
Claims (17)
1. tetrahydropyridine and thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvolyte of representing by following general formula I,
Wherein:
W does not exist, and perhaps is-CH
2-,-CH
2-CH
2-or-CH=CH-;
R
1Be selected from C
1-8Alkyl, C
1-8Alkoxyl group, C
3-10Naphthenic base, C
3-8Alkenyl, list or two C
1-3Alkylamino, list or two C
1-3Alkylamidoalkyl, C
1-3Alkyl sulphonyl, C
1-3In alkoxy carbonyl, hydroxyl, methylol, hydroxyethyl, methylthio group, trifluoromethylthio, trifluoromethyl, difluoro-methoxy, amino, amino-sulfonyl, phenyl, substituted phenyl, phenoxy and the heteroaryl;
R
2For being selected from Wasserstoffatoms, 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 alkoxy carbonyl, hydroxyl, methylol, hydroxyethyl, methylthio group, trifluoromethylthio, trifluoromethyl, difluoro-methoxy, trifyl, amino, amino-sulfonyl, phenyl, substituted phenyl, phenoxy, halogen, nitro and the cyanic acid;
R
3And R
4Be independently selected from Wasserstoffatoms, C respectively
1-10Alkyl, C
3-10Naphthenic base, C
1-6The substituted C of alkoxy carbonyl
3-10Naphthenic base, C
3-10The C of cycloalkyl substituted
1-4Alkyl, C
3-8Alkenyl, C
5-8Cycloalkenyl group, adamantyl, C
6-20Aryl, C
6-20The substituted C of aryl
1-4In alkyl, heteroaryl and the heterocyclic radical;
Said heteroaryl is to contain 1-3 the first aromaticity group of identical or different heteroatomic 5-10 that is selected among N, O and the S;
Said heterocyclic radical is to contain 1-3 the identical or different non-aromaticity group of heteroatomic 5-10 unit that is selected among N, O and the S;
Substituting group on the said substituted phenyl is selected from C
1-8Alkyl, C
1-8In alkoxyl group and the halogen.
2. tetrahydropyridine and thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvolyte of being represented by general formula I according to claim 1, wherein, W does not exist.
3. tetrahydropyridine and thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvolyte of being represented by general formula I according to claim 1, wherein, W is-CH
2-.
4. tetrahydropyridine and thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvolyte of being represented by general formula I according to claim 1, wherein, W is-CH
2-CH
2-.
5. tetrahydropyridine and thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvolyte of being represented by general formula I according to claim 1, wherein, W is-CH=CH-.
6. tetrahydropyridine and thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvolyte of representing by general formula I according to claim 1, wherein, R
1Be C
1-6Alkyl, C
3-6Naphthenic base, C
3-8Alkenyl, phenyl, substituted phenyl or heteroaryl.
7. tetrahydropyridine and thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvolyte of representing by general formula I according to claim 6, wherein, R
1Be heteroaryl.
8. according to each described tetrahydropyridine and thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvolyte of representing by general formula I among the claim 1-7, wherein, R
2Be Wasserstoffatoms.
9. according to each described tetrahydropyridine and thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvolyte of representing by general formula I among the claim 1-7, wherein, R
3Be Wasserstoffatoms.
10. according to each described tetrahydropyridine and thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvolyte of representing by general formula I among the claim 1-7, wherein, R
4Be Wasserstoffatoms.
11. according to each described tetrahydropyridine and thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvolyte of representing by general formula I among the claim 1-7, wherein, R
2, R
3And R
4Be Wasserstoffatoms.
12. tetrahydropyridine and thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvolyte of being represented by general formula I according to claim 11, wherein, this compound is selected from and comprises among the following compound 7a-7u:
13. the described tetrahydropyridine of being represented by following general formula I of a claim 1 and the preparation method of thiazole compound, this method may further comprise the steps:
Step a: carry out condensation reaction and prepare the compound of representing by formula A3 by formula A1 carboxylic acid cpd of representing and the compound of representing by formula A2; Wherein the used solvent of condensation reaction is a methylene dichloride, 1,2-ethylene dichloride, chloroform, N, dinethylformamide (DMF) or its any mixture; The used condensing agent of condensation reaction is 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC), di-isopropyl carbodiimide (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; The used organic bases of condensation reaction is triethylamine, 4-dimethyl amine pyridine (DMAP), diisopropyl ethyl amine (DIPEA) or its any mixture; Temperature of reaction is 0-200 ℃;
Perhaps, the carboxylic acid halides by formula A2 compound of representing and the carboxylic acid of being represented by formula A1 carries out condensation reaction and prepares the compound of being represented by formula A3; Wherein the used solvent of condensation reaction is a methylene dichloride, 1,2-ethylene dichloride, chloroform, N, dinethylformamide (DMF) or its any mixture; The used organic bases of condensation reaction is pyridine, triethylamine, 4-dimethyl amine pyridine (DMAP), diisopropyl ethyl amine (DIPEA) or its any mixture;
Step b: the compound of being represented by formula A3 carries out deprotection reaction and prepares the compound of being represented by formula A4; Wherein the used solvent of deprotection reaction is methylene dichloride, ETHYLE ACETATE, dioxane, ether or its any mixture; The used deprotecting regent of deprotection reaction is trifluoroacetic acid (TFA), hydrogenchloride or its any mixture; Temperature of reaction is 0-60 ℃;
Step c: by formula A4 compound of representing and the compound R of representing by formula A5
1The substituted carboxylic acid R of-W
1-W-COOH carries out amidate action and prepares the compound of being represented by formula A6; Wherein the used solvent of amidate action is a methylene dichloride, 1,2-ethylene dichloride, chloroform, N, dinethylformamide (DMF) or its any mixture; The used condensing agent of amidate action is 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC), di-isopropyl carbodiimide (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; The used organic bases of amidate action is triethylamine, 4-dimethyl amine pyridine (DMAP), diisopropyl ethyl amine (DIPEA) or its any mixture; Temperature of reaction is 0-200 ℃;
Perhaps, by formula A4 compound of representing and the compound R of representing by formula A5
1The substituted carboxylic acid halides R of-W
1-W-COX reaction and compound that preparation is represented by formula A6; The solvent that wherein reacts used is a methylene dichloride, 1,2-ethylene dichloride, chloroform, N, dinethylformamide (DMF) or its any mixture; The organic bases that reacts used is pyridine, triethylamine, 4-dimethyl amine pyridine (DMAP), diisopropyl ethyl amine (DIPEA) or its any mixture; Temperature of reaction is 0-200 ℃;
Steps d: the compound and the R that represent by formula A6
3-NHOR
4Carry out nucleophilic substitution reaction and prepare the compound of representing by formula A7; Wherein the used solvent of nucleophilic substitution reaction is methyl alcohol, THF, acetonitrile or its any mixture; The used mineral alkali of nucleophilic substitution reaction is sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate or its any mixture; Temperature of reaction is 0-80 ℃;
Perhaps, the compound of being represented by the formula A6 reaction that is hydrolyzed generates corresponding acid, again with R
3-NHOR
4Carry out condensation reaction and prepare the compound of representing by formula A7; Wherein the used mineral alkali of hydrolysis reaction is Lithium Hydroxide MonoHydrate, sodium hydroxide, Pottasium Hydroxide, salt of wormwood or its any mixture; The used solvent of hydrolysis reaction is methyl alcohol, ethanol, THF or its any mixture; The temperature of hydrolysis reaction is 0-80 ℃; The used solvent of condensation reaction is a methylene dichloride, 1,2-ethylene dichloride, chloroform, N, dinethylformamide (DMF) or its any mixture; The used organic bases of condensation reaction is pyridine, triethylamine, 4-dimethyl amine pyridine (DMAP), diisopropyl ethyl amine (DIPEA) or its any mixture; The temperature of condensation reaction is 0-200 ℃;
Wherein X is a halogen, W, R
1, R
2, R
3And R
4Definition and claim 1 in identical.
14. described tetrahydropyridine and the application of representing by general formula I in the medicine of the disease that the preparation treatment is mediated by histon deacetylase (HDAC)-6 suppressor factor of thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvolyte of claim 1.
15. application according to claim 14; Wherein, said disease by the mediation of histon deacetylase (HDAC)-6 suppressor factor 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.
16. one kind is used to treat the pharmaceutical composition by the disease of histon deacetylase (HDAC)-6 suppressor factor mediation; It contains described tetrahydropyridine and thiazole compound, its steric isomer and pharmacy acceptable salt thereof, prodrug or its solvolyte of being represented by general formula I of one or more claims 1 of treating significant quantity, and one or more pharmaceutically acceptable vehicle, diluent or carrier.
17. application according to claim 16; Wherein, said disease by the mediation of histon deacetylase (HDAC)-6 suppressor factor 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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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103191412A (en) * | 2013-04-01 | 2013-07-10 | 北京师范大学 | Degradation of PA200 and acetylation-mediated core histones through proteasome |
| US10112915B2 (en) | 2015-02-02 | 2018-10-30 | Forma Therapeutics, Inc. | 3-aryl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors |
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| CN103191412A (en) * | 2013-04-01 | 2013-07-10 | 北京师范大学 | Degradation of PA200 and acetylation-mediated core histones through proteasome |
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