CN101941948A - Histone deacetylase inhibitor with branched structure and synthesized through click chemistry - Google Patents

Histone deacetylase inhibitor with branched structure and synthesized through click chemistry Download PDF

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CN101941948A
CN101941948A CN2009100696939A CN200910069693A CN101941948A CN 101941948 A CN101941948 A CN 101941948A CN 2009100696939 A CN2009100696939 A CN 2009100696939A CN 200910069693 A CN200910069693 A CN 200910069693A CN 101941948 A CN101941948 A CN 101941948A
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王鹏
沈杰
尹正
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Nankai University
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Abstract

The invention relates to a histone deacetylase inhibitor with a branched structure and synthesized by utilizing click chemistry. The structural general formula of the histone deacetylase inhibitor is as shown in M1, wherein A is a C1-C6 alkyl chain; R1 and R2 are alkyl, naphthenic base, hetero alkyl, hetero naphthenic base, alkenyl, cycloalkenyl group, hetero alkenyl, hetero cycloalkenyl group, alkynyl, cycloalkynyl, hetero alkynyl, cyclo hetero alkynyl and aryl or heteroaryl; and R1 and R2 can be same and also be different. The invention also relates to a compound obtained by carrying out substituting derivatization or bridging derivatization on A, R1 and/or R2. The histone deacetylase inhibitor is a recently determined anticancer target protein; besides, the histone deacetylase inhibitor can be used for preparing drugs for treating cardiovascular diseases, immunological diseases and neurodegenerative diseases. The histone deacetylase inhibitor with the branched structure has better biological activity compared with the traditional unbranched compound.

Description

The synthetic inhibitors of histone deacetylase of click chemistry with branched structure
[technical field]: the invention belongs to the biological medicine technology field; be particularly related to the NSC 630176 that a kind of click chemistry synthetic has " branch " structure; such inhibitor can be used as preparation treatment cardiovascular disorder, the application of immune class disease and nerve degenerative diseases medicine.
[background technology]: the acetylize of lysine residue and deacetylation are that a pair of reversible protein is transcribed the back modification.Two enzymes of this reversing process of catalysis are respectively HDAC (histon deacetylase (HDAC), histone deacetylase) and HAT (histone acetyl based transferase, histone acetyltransferase).HAT and HDAC determine the degree of acetylation of substrate protein jointly by synergy, and then the interior numerous physical and chemical processes of regulating cell (glairy combination and transhipment, signal conduction and genetic expression etc.).The substrate protein of known HDAC/HAT comprises: histone, tubulin, Hsp90 and transcription factor (as p53, NF-B, Ku70 and Stat3) etc.Wherein, histone be research the earliest with maximum substrate proteins, the name of HDAC and HAT also comes therefrom.HDAC and HAT are a kind of important way of regulate gene expression in the epigenetics to the acetylation modification of histone.
Existing clinical study and pharmacological research show that HDAC is (potential) target spot of treatment numerous disease, and these diseases comprise: cancer, cardiovascular disorder, immune class disease and nerve degenerative diseases etc.Preclinical study shows that NSC 630176 is kill cancer cell optionally, and with many cancer therapy drugs good synergism is arranged.In October, 2006, the Vorinostat of being researched and developed by Merck company becomes the HDAC targeted drug that first is got permission.
We once delivered with the synthetic method with NSC 630176 of " non-branch " structure of click chemistry (Journal of Medicinal Chemistry, 2008,7417-7427).The structure of seven compounds that it is relevant is as follows:
Figure B2009100696939D0000011
In general, the biological activity of the NSC 630176 molecule of this class " non-branch " is relatively poor relatively.
[summary of the invention]: technical problem to be solved by this invention provides the NSC 630176 that a kind of new click chemistry synthetic has " branch " structure, and disclosed content comprises: the structure of compound, preparation method and application.Innovation of the present invention is: 1) by introducing the biological activity that " branch " structure strengthens NSC 630176; 2) by using chiral amino acid to come synthetic easily NSC 630176 with chirality " branch " structure.
The NSC 630176 (being the parent drug molecule) of utilizing the click chemistry synthetic to have " branch " structure provided by the invention, its general structure is M 1:
Figure B2009100696939D0000012
Wherein, A is the alkyl chain of a C1-C6, R 1And R 2Including, but not limited to various alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, or heteroaryl, R 1And R 2Can be the same or different;
The present invention includes, by to above-mentioned A, R 1And/or R 2The compound that replaces derivatize or bridge joint derivatize and obtain.Comprise A, R 1And/or R 2On some at least hydrogen atoms be substituted that base is replaced and the compound that obtains; Substituting group comprises alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl, halogen ,=O ,=S ,-CF 3,-OCF 3, carboxyl (COOH), sulfonic group (SO 3H), cyano group (CN), hydroxyl (OH), amino (NH 2), or nitro (NO 2);
Also be included in A, R 1And/or R 2Some at least singly-bounds in the middle of insert the bridge joint group and the compound that obtains; The bridge joint group comprises thioether group (S-), ether (O-), imino-(HN-), carbonyl ((CO)-), alkylsulfonyl ((SO 2)-), or sulfinyl ((SO)-);
The present invention also comprises through to A, R 1And/or R 2The substituting group that hockets is replaced and is inserted the bridge joint group and the compound that obtains.
General structure M provided by the invention 1One of preferred structure be formula M 2Structure, i.e. formula M 1In A in formula M 2In specifically be chosen to be methyne CH, R 2In formula M 2In specifically be chosen to be one one replacement, two replace or trisubstituted vinyl (R 3R 4C=CR 5),
Wherein, R 3, R 4And R 5Including, but not limited to hydrogen atom, alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, or heteroaryl, R 3, R 4And R 5Can be the same or different;
The present invention includes, by to R 3, R 4And/or R 5The compound that replaces derivatize or bridge joint derivatize and obtain.Comprise R 3, R 4And/or R 5On some at least hydrogen atoms be substituted that base is replaced and the compound that obtains; Substituting group comprises alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl, halogen ,=O ,=S ,-CF 3,-OCF 3, carboxyl (COOH), sulfonic group (SO 3H), cyano group (CN), hydroxyl (OH), amino (NH 2), or nitro (NO 2);
Also comprise R 3, R 4And/or R 5On some at least singly-bounds in the middle of insert the bridge joint group and the compound that obtains; The bridge joint group is including, but not limited to thioether group (S-), ether (O-), imino-(HN-), carbonyl ((CO)-), alkylsulfonyl ((SO 2)-), or sulfinyl ((SO)-);
The present invention includes by to R 3, R 4And R 5The substituting group that hockets is replaced and is inserted the bridge joint group and the compound that obtains.
General structure M provided by the invention 2One of preferred structure be formula M 3Structure, i.e. formula M 2In R 3In formula M 3In specifically be chosen to be (one replace an or polysubstituted) aromatic substituent (aryl or heteroaryl);
Figure B2009100696939D0000031
Wherein, X 1, X 2, X 3, X 4And X 5Be N or CH, can be the same or different;
The present invention includes, by to above-mentioned X 1, X 2, X 3, X 4And/or X 5The compound that replaces derivatize or bridge joint derivatize and obtain.Comprise, work as X 1, X 2, X 3, X 4And/or X 5During for CH, the some at least hydrogen atoms on it are substituted that base is replaced and the compound that obtains; Substituting group comprises alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl, halogen ,=O ,=S ,-CF 3,-OCF 3, carboxyl (COOH), sulfonic group (SO 3H), cyano group (CN), hydroxyl (OH), amino (NH 2), or nitro (NO 2);
Also comprise, work as X 1, X 2, X 3, X 4And/or X 5During for CH, at the middle compound that inserts the bridge joint group and obtain of C-H singly-bound; The bridge joint group comprises thioether group (S-), ether (O-), imino-(HN-), carbonyl ((CO)-), alkylsulfonyl ((SO 2)-), or sulfinyl ((SO)-);
The present invention includes by to X 1, X 2, X 3, X 4And X 5The substituting group that hockets is replaced and is inserted the bridge joint group and the compound that obtains.
According to formula M 3Described structure, its compound for reference are including, but not limited to molecule as follows:
Figure B2009100696939D0000041
Figure B2009100696939D0000051
General structure M provided by the invention 4Be formula M 1Another preferred structure, i.e. formula M 1In R 2In formula M 4In specifically be chosen to be the hetero-aromatic ring of a benzo,
Figure B2009100696939D0000061
Wherein, X 6, X 7, X 8And X 9Be N or CH, can be the same or different; Q 1Can be NH, S or O; Q 2Can be N or CH;
The present invention includes, by to Q 1, Q 2, X 6, X 7, X 8And/or X 9The compound that replaces derivatize or bridge joint derivatize and obtain.Comprise, work as Q 1Be NH, and Q 2, X 6, X 7, X 8And/or X 9During for CH, the some at least hydrogen atoms on it are substituted that base is replaced and the compound that obtains; Substituting group comprises alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl, halogen ,=O ,=S ,-CF 3,-OCF 3, carboxyl (COOH), sulfonic group (SO 3H), cyano group (CN), hydroxyl (OH), amino (NH 2), or nitro (NO 2);
Also comprise, work as Q 1Be NH, and Q 2, X 6, X 7, X 8And/or X 9During for CH, the middle compound that inserts the bridge joint group and obtain of the some at least singly-bounds on it; The bridge joint group comprises thioether group (S-), ether (O-), imino-(HN-), carbonyl ((CO)-), alkylsulfonyl ((SO 2)-), or sulfinyl ((SO)-).
The present invention includes by to Q 1, Q 2, X 6, X 7, X 8And X 9The substituting group that hockets is replaced and is inserted the bridge joint group and the compound that obtains.
Provided by the invention have a formula M 4The NSC 630176 of structure can be raw material with the chiral amino acid, through synthetic obtain (referring to the embodiment 1 and 2) of click chemistry.
According to formula M 4Described structure, the compound that it can be for reference are including, but not limited to molecule as follows:
Figure B2009100696939D0000071
Figure B2009100696939D0000081
The above parent drug molecule is at pharmaceutically acceptable various forms
The present invention also comprises corresponding pharmacy acceptable salt of above compound institute and prodrug, and medicinal activity metabolite and these metabolites are at pharmacy acceptable salt.The present invention also comprises the hydrate forms of all kinds of SOLVENTS form, particularly related compound of above all compounds.Also comprise above all compounds by with pharmaceutically acceptable dispersion agent or the carrier substance resulting mixture that combines, including, but not limited to liposome, nano particle, high molecular polymer, micro emulsion etc.The prodrugs that also comprises above all compounds, prodrug are meant that the mode by means of internal metabolism is converted into corresponding drug molecule with it in body.Specifically comprise:
The ester group prodrug:
A kind of ester group prodrug design based on above each described NSC 630176 (parent drug molecule), the general structure of this prodrug such as M 5Shown in,
Wherein, R 6Including, but not limited to hydrogen atom, alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, or heteroaryl;
The present invention includes R 6The compound that replaces derivatize or bridge joint derivatize and obtain.Specifically comprise R 6Some at least hydrogen atoms be substituted that base is replaced and the compound that obtains; Substituting group comprises alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl, halogen ,=O ,=S ,-CF 3,-OCF 3, carboxyl (COOH), sulfonic group (SO 3H), cyano group (CN), hydroxyl (OH), amino (NH 2), or nitro (NO 2);
Also comprise R 6Some at least singly-bounds in the middle of insert the bridge joint group and the compound that obtains; The bridge joint group comprises thioether group (S-), ether (O-), imino-(HN-), carbonyl ((CO)-), alkylsulfonyl ((SO 2)-), or sulfinyl ((SO)-).
The present invention includes by to R 6The substituting group that hockets is replaced and is inserted the bridge joint group and the compound that obtains.
The glycosyl prodrug:
A kind of design of glycosyl prodrugs, related glycosyl prodrug is that the sugar that above each described NSC 630176 (parent drug molecule) obtains as aglycone is sewed molecule, sew in the molecule at this sugar, hydrogen atom on the hydroxyl of the hydroximic acid functional group of former parent drug molecule is replaced by glycosyl, glycosyl includes but are not limited to glucose, semi-lactosi, lactose, maltose, sucrose, glucuronic acid, seminose, N-ethanoyl glucose, N-ethanoyl semi-lactosi, wood sugar, or sialic acid;
The present invention includes the compound that the hydrogen atom on the hydroxyl of glycosyl part is obtained by acyl substituted.
The aryl prodrug:
A kind of aryl prodrug design based on above each described NSC 630176 (parent drug molecule), the general structure of this prodrug such as M 6Shown in,
Figure B2009100696939D0000101
Wherein, Ar is an aryl or heteroaryl;
The present invention includes Ar is replaced derivatize or bridge joint derivatize and the compound that obtains.The some at least hydrogen atoms that comprise Ar are substituted that base is replaced and the compound that obtains; Substituting group comprises alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl, halogen ,=O ,=S ,-CF 3,-OCF 3, carboxyl (COOH), sulfonic group (SO 3H), cyano group (CN), hydroxyl (OH), amino (NH 2), or nitro (NO 2);
The middle compound that inserts the bridge joint group and obtain of some at least singly-bounds that also comprises Ar; The bridge joint group comprises thioether group (S-), ether (O-), imino-(HN-), carbonyl ((CO)-), alkylsulfonyl ((SO 2)-), or sulfinyl ((SO)-).
This claim comprises replaces and inserts the compound that the bridge joint group obtains to Ar by the substituting group that hockets.
The preferred structure of Ar is as follows:
Figure B2009100696939D0000102
Salt:
A kind of based on the corresponding pharmacy acceptable salt of above each described parent drug molecule or preceding drug compound institute, and medicinal activity metabolite and these metabolites are at pharmacy acceptable salt.Described pharmacy acceptable salt is meant that drug molecule can keep or partly keep original biological activity, and is applicable to some salt of medicinal use.
These salts comprise three kinds of forms:
The one, (these acid are including, but not limited to formic acid, acetate, propionic acid, succsinic acid for above-described parent drug molecule or preceding drug compound and certain acid, glycolic acid, gluconic acid, lactic acid, oxysuccinic acid, tartrate, glycine, arginine, citric acid, FUMARIC ACID TECH GRADE, FUMARIC ACID TECH GRADE, alkylsulphonic acid, aryl sulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, propanedioic acid, Whitfield's ointment, gentisinic acid etc.) the formed salt of pairing negatively charged ion;
Another kind is that (these positively charged ions are including, but not limited to ammonium, quaternary ammonium group positively charged ion, lithium ion for above-described parent drug molecule or preceding drug compound and certain positively charged ion, sodium ion, potassium ion, magnesium ion, calcium ion, aluminum ion, zine ion etc.) formed salt;
The third is the formed salt of positively charged ion that the protonated back of above-described parent drug molecule or preceding drug compound and organic amine forms, and these organic amines are including, but not limited to choline, ethylene glycol amine, morpholine etc.
Steric isomer:
The present invention also comprises the various isomeric form of all compounds that above-described parent drug molecule or preceding drug compound and salt thereof are represented.Comprise non-mirror image isomer, mirror image isomer, tautomer, the E/Z isomer of two keys.Any chemist with certain basis is all separable to go out above-mentioned optical purity or the pure compound of stereoisomerism.
The present invention also comprise the compound that above-described parent drug molecule or preceding drug compound and salt thereof are represented possible raceme or/and the mirror image isomerism thing or/and the mixture of non-mirror image isomerism thing.
A kind of pharmaceutical composition, it comprises: above each described parent drug molecule or preceding drug compound and pharmaceutically acceptable carrier.
The medical use of above-claimed cpd
The present invention includes above each described parent drug molecule, preceding drug compound, salt, steric isomer or composition as but be not limited to the acetylation of histone enzyme inhibitors; separately; perhaps with other medicines; thinner; vehicle and/or other medicines carrier are united use, are used as preparing the application of the medicine for the treatment of relative disease.These diseases existing many known relate to or part is regulated by HDAC is active.In the listed disease of next paragraph, known HDAC activity makes seizure of disease play the part of certain role for promoting, perhaps can be treated by compound of the present invention.
These illnesss include but not limited to proliferative disorders (as cancer), neurodegenerative disease (as, Huntington Chorea, polyglutamic acid amides disease, Parkinson's disease, alzheimer's disease, insane carbuncle outbreak, striatonigral degeneration, stein-leventhal syndrome, torsional tension are incomplete, spasmodic torticollis and dyskinesia, familial tremor is twitched the obscene words syndromes, Diffuse Lewy body disease, Pick's disease, intracranial hemorrhage primary lateral sclerosis, spinal cord muscular dystrophy, amyotrophic lateral sclerosis, matter polyneuropathy between hypertrophy, retinitis pigmentosa, hereditary optic atrophy, hereditary spastic paraplegia, carrying out property dystaxia and Shy-Drager syndrome etc.), metabolic disease (as, type ii diabetes), the eye degenerative disease (comprises, glaucoma, age-related macular degeneration, rubeotic glaucoma), inflammatory diseases and/or disorder of immune system (as, rheumatoid arthritis, osteoarthritis, JCA, graft versus host disease (GVH disease), psoriasis, asthma, spondyloarthropathy, Crohn's disease, inflammatory bowel, colonic ulcer, alcoholic hepatitis, diabetes, the Sjoegrens syndromes, multiple sclerosis, ankylosing spondylitis, membranous glomerulopathy, intervertebral disk pain, systemic lupus erythematosus etc.), relate to angiogenesis disease (as, cancer, psoriasis, rheumatoid arthritis etc.), mental illness (as, amphicheirality's neurological disorder, schizophrenia, mania, depression, dementia etc.), cardiovascular disorder (as, heart failure, restenosis, arteriosclerosis etc.), fibrotic disease (as, hepatic fibrosis, cystic fibrosis, hemangiofibroma etc.), infectious diseases (as, fungi infestation, viral infection, protozoan infection etc.), the hematopoiesis disease (as, Thalassemia, sicklemia etc.).
The present invention especially can be used as the application of the medicine of preparation treatment tumour, and tumor type is including, but not limited to breast cancer, lung cancer, ovarian cancer, prostate cancer, a cancer, neck cancer, the rectum cancer, cancer of the stomach, the cancer of the brain, leukemia etc.
More than the NSC 630176 of each described parent drug molecule, preceding drug compound, salt, steric isomer or composition can pass through stomach and intestine administration (oral or rectal administration); or parenteral introduction is (including, but not limited to subcutaneous; muscle, approach such as in intravenously and the skin).
The solid dosage of clothes administration is including, but not limited to capsule, lozenge, tablet, powder, particle and microcapsule.The NSC 630176 that contains above each described parent drug molecule, preceding drug compound, salt, steric isomer or composition and at least a inertia and pharmaceutically acceptable vehicle or supporting agent mix.These vehicle and supporting agent comprise Trisodium Citrate or Lin Suanergai, and/or: 1) weighting agent (as, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and Whitfield's ointment); 2) wedding agent (as, carboxymethyl cellulose, alginate, gelatin polyvinylpyrrolidone, sucrose and gum arabic); 3) disintegrating agent (as, agar glue, lime carbonate, potato or cassava starch, alginic acid, some silicate and yellow soda ash); 4) dissolving delayed-action activator (as, paraffin); 5) absorb accelerator (as, quaternary ammonium compound); 6) wetting agent (as, hexadecanol, glyceryl monostearate); 7) sorbent material (as, talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol).Solid dosage can be prepared into has coating or shell.
The liquid formulation of oral administration except active compound, also including, but not limited to pharmaceutically acceptable inert diluent (as, water or other solvent), stablizer and emulsifying agent (as, ethyl alcohol, ethyl-carbonate, ethyl acetate, phenylformic acid alcohol, phenylamino benzoic acid methyl esters, propylene glycol, 1,3 butylene glycol, dimethyl formamide, Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C, sesame oil, glycerine, tetrahydrofuran (THF) alcohol, the fatty acid ester of polyoxyethylene glycol and sorbitol anhydride etc.), suspension agent (as, ethoxyquin iso stearyl alcohols, polyoxyethylene sorbitol acid anhydride ester etc.), wetting agent, sweeting agent, spices and deodorant tune etc.
Be used for the preferred composition that rectum or vagina give and include but are not limited to suppository; Suppository can be mixed with suitable non-irritating excipient or carrier and got by above each described parent drug molecule, preceding drug compound, salt, steric isomer or composition.
The formulation that is used for topical is including, but not limited to powder, paster, spray, ointment and inhalation.More than each described parent drug molecule, preceding drug compound, salt, steric isomer or composition under aseptic condition, mix and get with pharmaceutically acceptable carrier and required any assistant agent.These assistant agents include but not limited to any sanitas, buffer reagent and/or mixture etc.
Non-enteron aisle injecting drug use prescription is including, but not limited to pharmaceutically aseptic aqua of acceptable or non-aqueous solvent, dispersion agent, suspension agent or emulsifying agent and use before just be made into the powder injection of injectable aseptic aqueous solution.
The preferential measures range of selecting is per kilogram of body weight about 0.01-300 milligram every day; Preferred measures range is per kilogram of body weight about 0.2-80 milligram every day.Also can select suitable metering repeatedly to divide the agent administration every day.
The implication of term involved in the present invention:
Alkyl: be meant straight chain or have the aliphatic hydrocarbon group of straight chain; Preferentially be chosen as the alkyl of C1-C14; The alkyl that is chosen as C1-C10 more preferably; The prepreerence C1-C6 that is chosen as.Embodiment is including, but not limited to methyl, ethyl, n-propyl, 2-propyl group, normal-butyl, isobutyl-, tertiary butyl, hexyl etc.
Cycloalkyl: the carbocyclic ring that is meant monocycle, condensed ring or the volution of saturated or fractional saturation.The ring of forming with 3-9 carbon atom is preferential the selection.Example includes, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
Assorted alkyl: be meant straight chain or contain the group of branched-chain alkyl, and in main chain, contain one or more S of being selected from least, the heteroatoms of O and N.Preferential selection contains 2-14 atomchain.Assorted alkyl includes, but are not limited to: ethers, thioether class, alkyl esters, second or trialkyl amines, alkyl sulfinic acid etc.
Heterocyclylalkyl: be meant that containing one at least is selected from N, S, the heteroatomic cycloalkyl of O.Preferably contain 1-3 heteroatoms.Preferred ring is 3-14 person's ring, and more preferably the ring of Xuan Zeing is 4-7 person's ring.Heterocyclylalkyl includes, but are not limited to: pyrrolidyl, pyrrolin base, Pyrrolidine base, pyrazoline base, piperidyl, morpholine tetrahydrofuran base, tetrahydrochysene thio-furan base, THP trtrahydropyranyl etc.
Alkenyl: be meant the aliphatic hydrocarbon group that contains a carbon-to-carbon double bond at least during as a group a part of, can be used as straight chain and also can have side chain.Preferential thiazolinyl of selecting to have C2-C14.C1-C12 is then better; What the most preferentially select is the thiazolinyl of C2-C6.This group can contain a plurality of pairs of keys and its conformation can respectively do for oneself E or Z in its main chain.The example of alkenyl group includes, but are not limited to: vinyl, propenyl etc.
Cycloalkenyl group: be meant that some at least carbon-carbon single bonds are replaced by a carbon-carbon double bond in the cycloalkyl.
Assorted thiazolinyl: be meant that some at least carbon-carbon single bonds are replaced by a carbon-carbon double bond in the assorted alkyl.
Heterocycloalkenyl: be meant that some at least carbon-carbon single bonds are replaced by a carbon-carbon double bond in the Heterocyclylalkyl.
Alkynyl group: be meant the aliphatic hydrocarbon group that contains a carbon-to-carbon triple bond at least during as a group a part of, can be used as straight chain and also can have side chain.Preferential alkynyl of selecting to have C2-C14.C1-C12 is then better; What the most preferentially select is the alkynyl of C2-C6.This group can contain a plurality of pairs of keys and its conformation can respectively do for oneself E or Z in its main chain.The example of alkynyl group includes, but are not limited to: ethynyl, proyl etc.
Cycloalkynyl radical: be meant that some at least carbon-carbon single bonds are replaced by a carbon carbon triple bond in the cycloalkyl.
Assorted alkynyl: be meant that some at least carbon-carbon single bonds are replaced by a carbon carbon triple bond in the assorted alkyl.
The heterocycle alkynyl: be meant that some at least carbon-carbon single bonds are replaced by a carbon carbon triple bond in the Heterocyclylalkyl.
Aryl: the part as a group or a group is meant: the monocycle or the condensed ring of (1) aromaticity: preferential aromaticity carbocyclic ring (annular atoms is the atoll texture of carbon) of selecting to have 5-12 carbon atom.The example of aryl includes, but are not limited to: phenyl, naphthyl; (2) can the saturated carbocyclic ring in connection portion, for example: phenyl and C5-7 cycloalkyl or C5-7 cycloalkenyl groups system condense mutually and form a ring texture.Example includes, but are not limited to: tetralyl, indenyl or hydrogen indenyl etc.Aromatic yl group can be replaced by one or more substituting groups.
Heteroaryl: be meant the many aromatic heterocyclics of monocycle or condensed.The preferential selection contained one or more N of being selected from, and O is or/and the heteroatoms 5-7 person aromatic nucleus of S.Typical heteroaryl substituting group comprises example, but is not limited to: furyl, thienyl, pyrroles, pyrazoles, triazole, thiazole, pyridine, pyrimidine, pyrazine, indoles, benzoglyoxaline etc.
Halogen: fluorine, chlorine, bromine and iodine.
Acyl group: be meant [R-CO-] group, R comprises alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl.The example of acyl group is including, but not limited to ethanoyl, propionyl, isobutyryl, benzoyl etc.
Substituted radical: including, but not limited to alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl, halogen ,=O ,=S ,-CF 3,-OCF 3, carboxyl (COOH), sulfonic group (SO 3H), cyano group (CN), hydroxyl (OH), amino (NH 2), nitro (NO 2).
Replace derivatize: the process that one or more hydrogen atoms of parent compound are replaced by " substituted radical ".
The bridge joint group: be meant that (A-), they can insert among a certain singly-bound X-Y substituting group with two connection site, form the new texture of X-A-Y.The bridge joint group is including, but not limited to thioether group (S-), ether (O-), imino-(HN-), carbonyl ((CO)-), alkylsulfonyl ((SO 2)-), sulfinyl ((SO)-).
The bridge joint derivatize: some substituting groups are bridged derivatize and are meant, are inserted into the process that " bridge joint group " obtains recruit's structure by some or a plurality of singly-bounds.The singly-bound that is inserted into the bridge joint group can be positioned at substituting group, or is positioned at other segmental junction of this substituting group and molecule.
NSC 630176: the IC50 value of inhibition of histone deacetylase is 100uM or lower compound.
Advantage of the present invention and positively effect:
The NSC 630176 with " branch " structure that the present invention proposes has better biological activity than existing overstepping one's bounds compound.Histon deacetylase (HDAC) is the anticancer target point protein of establishing recently; NSC 630176 also can be used as preparation treatment treatment cardiovascular disorder, the application of immune class disease and nerve degenerative diseases medicine.
[embodiment]:
The chemosynthesis example
Synthetic route that the present invention is used and method can be widely used in the synthetic of analogue.The following examples only are the synthetic methods that is used for illustrating the particular compound of being invented.But on synthetic method without any restriction.This paper embodiment does not have the synthetic of the compound that describes in detail, as long as change suitable original raw material, according to chemical general knowledge, changing when being necessary a little, reaction conditions gets final product, and for those skilled in the art, the synthetic of this compound is can realize fully in its ken of grasping.
React employed reagent and raw material mainly from but be not limited only to following supplier: Aldrich Chemical Company, Lancaster Synthesis Ltd etc.Reaction product is logical be with flash chromatography separate obtain target compound (J.Org.Chem., 1978,43:2923).Reaction product is used 1H-NMR proves conclusively structure; Usually, s represents unimodal, and d represents bimodal, and t represents triplet, and m represents multiplet, and br represents broad peak, and dd represents doublet, and dt represents the doublet of triplet; The unit of coupling constant is Hz.
(synthetic method of following enforcement 1 is shown in synthetic route one for synthetic route one.)
Figure B2009100696939D0000151
Embodiment 1, step 1: E-(2-methoxy (ethoxy) methyl) methyl-3-iodate acrylate
Containing the acrylic acid N of 5g E-iodate, N-dimethyl formyl acyl (DMF, 24mL) middle methoxy (ethoxy) methyl chloride (MEMCl) and the 4g K that adds 3.8mL 2CO 3, at room temperature stirred one hour.After reaction finishes, add the water of 24mL, use the extracted with diethyl ether three times of 24mL again.Organic phase is water, saturated common salt water washing again, uses anhydrous sodium sulfate drying.Ether is removed with the Rotary Evaporators underpressure distillation in dry intact back, crosses product E-(2-methoxy (ethoxy) methyl) methyl-3-iodate acrylate 3.193g that silicagel column (developping agent is a sherwood oil: ethyl acetate=10: 1, volume ratio) purifying obtains, and productive rate is 44.2%.
Step 2: (2-methoxy (ethoxy) methyl) methyl-(2E)-5-(trimethyl silicon based) penta-2-alkene-4-acetylenic acid ester
In the triethylamine of 40mL, add 3.09g product E-(2-methoxy (ethoxy) methyl) methyl-3-iodate acrylate; under nitrogen protection, add 0.62g triphenyl phosphorus palladium and 0.20g cuprous iodide catalyst; add 2.5mL trimethyl silicane alkynes again, stirred one hour under the room temperature.After having reacted, mixture is poured in the saturated aqueous ammonium chloride of 200mL, uses the extracted with diethyl ether three times of 100mL again.Organic phase saturated common salt water washing, use anhydrous sodium sulfate drying again, ether is removed in underpressure distillation, (developping agent is a sherwood oil: ethyl acetate=20: 1) purifying to cross silicagel column, obtain pale yellow oily liquid body (the 2-methoxy (ethoxy) methyl) methyl of 2.180g-(2E)-5-(trimethyl silicon based) penta-2-alkene-4-acetylenic acid ester, productive rate is 78.9%.
Step 3: E-5-(trimethyl silicon based) penta-2-alkene-4-acetylenic acid
The hydrochloric acid that in the 105mL tetrahydrofuran (THF), adds 2.12g (2-methoxy (ethoxy) methyl)-methyl-(2E)-5-(trimethyl silicon based) penta-2-alkynes-obtusilic acid ester and 8.3mL 3mol/L, stirred three days under the room temperature, with TLC (5% methanol dichloromethane solution, the Rf value of product point is about 0.1) some plate detection reaction degree.After having reacted, tetrahydrofuran (THF) is removed in underpressure distillation.Add again in the 200mL water, with 100mL dichloro four alkane extraction three times.Organic phase is used the saturated common salt water washing again, uses anhydrous sodium sulfate drying.Underpressure distillation obtains the orange red solid E-5-of 1.40g (trimethyl silicon based) penta-2-alkene-4-acetylenic acid, and productive rate is 95%.
Step 4: E-N-(to methoxy-benzyl oxygen)-5-(trimethyl silicon based) penta-2-alkene-4-ynamine
168mg E-5-(trimethyl silicon based) penta-2-alkene-4-acetylenic acid is dissolved in the 3mL methylene dichloride, adds the DMF of 0.13mL oxalyl chloride and trace again, stirred one hour under the room temperature, after having reacted, underpressure distillation obtains orange-red syrup.Add the 4mL methylene dichloride then, be cooled to 0 ℃, this is a solution A.In another Erlenmeyer flask B, add 285mgH 2NOPMBHCl, 0.51mL diisopropylethylamine (DIPEA) and 10mL methylene dichloride, and be cooled to 0 ℃.A solution slowly joins in the B solution, 0 ℃ of following stirring reaction half hour.After having reacted, add ice-cold 20mL 0.1mol/L hydrochloric acid soln and 20mL methylene dichloride.Organic phase is used anhydrous sodium sulfate drying again with 20mL 0.1mol/L hydrochloric acid soln extracting twice, and methylene dichloride is removed in underpressure distillation.Thick product is crossed silicagel column (developping agent sherwood oil: ethyl acetate=5: 1, volume ratio) purifying and is obtained white oily liquids 253mg, productive rate 84%.
Step 5: E-1-phenyl-1-alkene 3-enanthol
Add 1mL phenylacrolein (7.9mmol) in containing the dry round-bottomed flask of 30mL ether, nitrogen protection also drips the tetrahydrofuran solution (1.6M) of 10mL n-Butyl Lithium under condition of ice bath, and reaction solution is immediately from the colourless scarlet that becomes.Stirring reaction down spends the night.Dripped the 30mL saturated ammonium chloride solution in second day under condition of ice bath, reaction solution becomes yellow by scarlet.Use the separating funnel separatory.The upper strata is an ether layer, and lower floor is a water layer, twice of 50mL extracted with diethyl ether of water layer.The ether layer anhydrous sodium sulfate drying, ether is removed in underpressure distillation, and with silicagel column (developping agent sherwood oil: ethyl acetate=20: 1) purified product.Obtain the 1.38g weak yellow liquid, productive rate is 92.0%.
Step 6: E-1-phenyl-3-nitrine-1-heptene
In the round-bottomed flask that contains the 10mL dry toluene, add the E-1-phenyl-1-alkene-3-enanthol of 380mg (2mmol) and the DPPA of 0.65mL (3mmol).The DBU that under condition of ice bath, adds 0.45mL (3mmol).Ice bath stirred two hours down, and at room temperature reaction is spent the night then.Second day complete with TLC plate detection reaction.Reaction solution is poured in the 50mL water, and with 50mL ethyl acetate extraction three times.Ethyl acetate is removed in underpressure distillation, crosses silicagel column (the pure sherwood oil of developping agent, volume ratio) purified product, obtains the 350mg weak yellow liquid, and productive rate is 81.4%.
Step 7: (E)-N-(4-methoxybenzyloxy) 3-(1-((E)-1-phenylhept-1-en-3-yl)-1H-1,2,3-triazol-4-yl) acrylamide
In the round-bottomed flask that contains 10mL tetrahydrofuran (THF) and 10mL methyl alcohol, add E-N-(to methoxy-benzyl oxygen)-5-(trimethyl silicon based) penta-2-alkene-4-ynamine of 287mg (1mmol) and the cesium fluoride of 182mg (1.2mmol).Come the degree of detection reaction by a TLC plate.The polarity of intermediate of taking off TMS stronger than E.After the complete reaction, underpressure distillation removes and desolvates.Add in the saturated aqueous common salt of 100mL, use the dichloromethane extraction three times of 100mL again.Blended methylene dichloride anhydrous sodium sulfate drying, methylene dichloride is removed in underpressure distillation then.The white solid that obtains is dissolved in the 20mL tetrahydrofuran (THF), and in this solution, order adds the diisopropylethylamine of 280mg (1.3mmol) triazo-compound, 350mg (1mmol) catalyst P (OEt) 3CuI and 0.33mL (2mmol).At room temperature stir, reaction is spent the night, and reacts completely with the check of TLC plate.Underpressure distillation removes and desolvates, and remaining solid separates with the methylene dichloride of 100mL and the copper-bath of 100mL 1%.Water is used twice of the dichloromethane extraction of 100mL again.Blended methylene dichloride anhydrous sodium sulfate drying, methylene dichloride is removed in underpressure distillation then, crosses silicagel column (developping agent: methyl alcohol: methylene dichloride=1: 100, volume ratio) purified product, obtains the 315mg white solid, productive rate 73.4%.
Step 8: (E)-N-(4-methoxybenzyloxy)-3-(1-((E)-1-phenylhept-1-en-3-yl)-1H-1,2,3-triazol-4-yl) acrylamide
In the round-bottomed flask that contains the 20mL methylene dichloride, order adds the trifluoroacetic acid of P, 1mL (methylene chloride volume 5%) of 200mg (0.47mmol) and the tri isopropyl silane of 0.3mL (1.5mmol).Mixture at room temperature stirs, and with the degree of TLC plate detection reaction.After reacting completely, reaction mixture is dissolved in the 50mL acetonitrile, and neutralizes with DOWEXMARATHONE WBA anionite-exchange resin.The resin acetonitrile washed twice of 25mL.The underpressure distillation of blended acetonitrile obtains solid.Obtain white solid 70mg, productive rate 46.4% with C-18 reversed-phase column (developping agent water: acetonitrile=5: 1～1: 1, volume ratio) purified product.1H?NMR(400Hz，DMSO-d 6)：δ10.81(s，1H)，9.06(s，1H)，8.49(s，1H)，7.48-7.26(m，6H)，6.66-6.53(m，3H)，5.33(q，J＝7.0Hz，1H)，2.10-2.00(m，2H)，1.32-1.10(m，4H)，0.85(t，J＝7.0Hz，3H)。
(synthetic method that following examples 2 adopt is shown in synthetic route two for synthetic route two.)
Figure B2009100696939D0000171
Embodiment 2, step 1: synthetic compound D3
The hydrochloride of EDC (287 mg, 1.5mmol), 2-amino-phenol D1 (131mg, 1.2mmol), HOBt (270mg, 2.0mmol) and D2 (217mg 1mmol) joins under room temperature in the 5ml DMF solvent, add then triethylamine (144 μ l, 1.0mmol). the reaction at room temperature stirred 1 hour..Add the 25mL ethyl acetate in the mixture of reaction, use the hydrochloric acid soln of 25ml 1M then, 25mL saturated sodium bicarbonate solution and 25mL saturated sodium-chloride water solution wash successively.Organic phase solution with anhydrous magnesium sulfate drying after, remove solvent under reduced pressure.The gained crude product uses silicagel column to separate (moving phase: petrol ether/ethyl acetate=5/1), obtain yellow solid product D3 275mg (isolated yield 90%).
Step 2: synthetic compound D4
At room temperature, with acid amides D3 (100mg), triphenyl phosphorus (206mg, 0.79mmol) and 4A molecular sieve (4g/mmolD3) be dissolved in the 4mL tetrahydrofuran (THF), stirred 1 hour, temperature is reduced to 0 ℃ then, and dropping DIAD (0.16ml, tetrahydrofuran (THF) 0.79mmol) (1ml) solution.The temperature of reaction solution rises to room temperature gradually, and continues to stir 8 hours.Vacuum rotary steam removes and desolvates, and adds ether (5ml) then, and at room temperature stirs 1 hour.Filter, steaming desolventizes, and uses silicagel column to separate (moving phase: petrol ether/ethyl acetate=15/1) obtain white solid D4 79mg, isolated yield 74%.
Step 3: synthetic compound D5
(290mg, methylene dichloride 1mmol) (10mL) solution is cooled to 0 ℃, adds the trifluoroacetic acid of catalytic amount, allows temperature rise to room temperature gradually, continues to stir to disappear until raw material D4 with D4.Then, reaction solution washs with saturated sodium bicarbonate solution.Resulting organic phase solution is stand-by.
In another reaction flask, add the TfN of preparation just 3(3mmol) the copper sulfate solid and the sodium carbonate solution of the methylene dichloride of reagent (10mL) solution and catalytic amount.Aforesaid organic solution is added.Adding methyl alcohol, until water and the organic phase solution mutually that permeates mutually.At room temperature stir and spend the night.Steam except that desolvating in the decompression backspin, the dichloromethane solvent that adds 30mL then, and water (30mLX3) washing, dry back decompression backspin steams to remove and desolvates, use silicagel column to separate (moving phase: petroleum ether/ethyl ether=20/1) obtain colourless liquid D5 165mg, isolated yield 80%.
Step 4: synthetic compound D7
White solid D6 (1mmol) is dissolved in the 20mL tetrahydrofuran (THF), and in this solution, order adds 188mg (1.3mmol) triazo-compound D6,350mg (1mmol) catalyst P (OEt) 3The diisopropylethylamine of CuI and 0.33mL (2mmol).At room temperature stir, reaction is spent the night, and reacts completely with the check of TLC plate.Underpressure distillation removes and desolvates, and remaining solid separates with the methylene dichloride of 100mL and the copper-bath of 100mL 1%.Water is used twice of the dichloromethane extraction of 100mL again.Blended methylene dichloride anhydrous sodium sulfate drying, methylene dichloride is removed in underpressure distillation then, and (developping agent: methyl alcohol: purified product methylene dichloride=1: 100) obtains 325mg white solid D7, isolated yield 72% to cross silicagel column.
Step 5: synthetic compound D8
In the round-bottomed flask that contains the 20mL methylene dichloride, order adds the trifluoroacetic acid of 200mg D7,1mL (methylene chloride volume 5%) and the tri isopropyl silane of 0.3mL.Mixture at room temperature stirs, and with the degree of TLC plate detection reaction.After reacting completely, reaction mixture is dissolved in the 50mL acetonitrile, and neutralizes with DOWEX MARATHONE WBA anionite-exchange resin.Resin is with the acetonitrile washed twice of 25 mL.The underpressure distillation of blended acetonitrile obtains solid.With the C-18 reversed-phase column (developping agent water: acetonitrile=5: 1～1:: 1) purified product obtain white solid 120mg.1H?NMR(400Hz，DMSO-d 6)：δ10.8(s，1H)，9.5(s，1H)，8.65(s，1H)，7.8-7.6(m，2H)，7.5-7.2(m，3H)，6.54(d，J＝15.6Hz)，6.10(d，J＝7.0Hz，1H)，2.92(m，1H)，1.03(d，J＝6.8Hz，3H)，0.87(d，J＝6.8Hz，3H)。
The biological activity test method of NSC 630176
The histone deacetylase determination of activity
Enzyme activity determination can test with the HDACi test kit of BIOMOL company (referring to Journal of Medicinal Chemistry, 2008,7417-7427.).Test on 96 orifice plates and carry out.Experiment setting comprises blank, negative control, 5 dosage groups of positive control and compound (100nM, 200nM, 500nM, 1.0uM and 10uM).Measuring divides two stages to carry out.Reaction solution in the fs comprises: (15uL, 1U), the fluorescent polypeptide substrate of NSC 630176 solution (10uL) and HDAC enzyme melts liquid (25uL) to the HDAC enzyme solution.The buffered soln that these three solution all are Tris (comprising 50mM Tris pH 8.0,137mM sodium-chlor, 2.7mM Repone K, the BSA of 1mM magnesium chloride and 1mg/mL).This reaction solution reacted 45 minutes at 30 ℃.In subordinate phase, at first add " developer " solution 50uL in the test kit, at room temperature reacted then 30 minutes, on plate reading machine, read fluorescence data (absorb light: 350nm, emission light: 450nm) then.Operational analysis software Prism 4.0 obtains the IC50 value in a series of data.
The mensuration that suppresses the thin GI50 value of tumour
Medicine suppresses the mensuration of the GI50 value of growth of tumour cell:
1 tumor cell line that will be used to screen adds 5% foetal calf serum with the RPMI1640 substratum and the 2mM L-glutaminate is cultivated.
2 are seeded to 96 orifice plates with different clones respectively according to every hole 5000-40000 cell, and 96 orifice plates are placed 37 ° of C, 5%CO 2And 100% cultivated 24 hours under the relative humidity.
3 respectively get one from inoculation has 96 orifice plates of different clones, and with cell fixation, dyeing, measure light absorption value Tz, (concrete steps are seen below).
4 add medicine to be measured in each hole with different concns, at 37 ℃, and 5%CO 2And 100% cultivated 48 hours under the relative humidity.
Add cold TCA solution (for attached cell, the TCA final concentration is 10%, and suspension cell is 16%) in 5 every holes, fix 1 hour for 4 ℃.Discard liquid in the hole, dry after washing 5 times.
Add 0.4%SRB solution (containing 1% acetate) in 6 every holes, room temperature dyeing 10 minutes.Wash 5 times with 1% acetic acid solution, the unconjugated dyestuff of flush away also dries.
7 usefulness are buffered 10mM Tris solution dissolving bonded dyestuff not, measures the absorbance value of every hole under the 515nm wavelength, and establishing the contrast class value is C, and the experiment class value is Ti.
According to GI50=[(Ti-Tz)/(C-Tz)] formula of x100% calculates the GI50 value.

Claims (10)

1. NSC 630176 of utilizing the click chemistry synthetic to have " branch " structure, its general structure is M 1:
Figure F2009100696939C0000011
Wherein, A is the alkyl chain of a C1-C6, R 1And R 2Be alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, or heteroaryl, R 1And R 2Can be the same or different;
This claim also comprises A, R 1And/or R 2On some at least hydrogen atoms be substituted that base is replaced and the compound that obtains; Substituting group comprises alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl, halogen ,=O ,=S ,-CF 3,-OCF 3, carboxyl (COOH), sulfonic group (SO 3H), cyano group (CN), hydroxyl (OH), amino (NH 2), or nitro (NO 2);
This claim also is included in A, R 1And/or R 2Some at least singly-bounds in the middle of insert the bridge joint group and the compound that obtains; The bridge joint group comprises thioether group (S-), ether (O-), imino-(HN-), carbonyl ((CO)-), alkylsulfonyl ((SO 2)-), or sulfinyl ((SO)-);
This claim also comprises A, R 1And/or R 2The substituting group that hockets is replaced and is inserted the bridge joint group and the compound that obtains.
2. NSC 630176 according to claim 1 is characterized in that, general structure M 1One of preferred structure be formula M 2Structure, i.e. formula M 1In A in formula M 2In specifically be chosen to be methyne CH, R 2In formula M 2In specifically be chosen to be one one replacement, two replace or trisubstituted vinyl (R 3R 4C=CR 5),
Figure F2009100696939C0000012
Wherein, R 3, R 4And R 5Be hydrogen atom, alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, or heteroaryl, R 3, R 4And R 5Can be the same or different;
This claim also comprises R 3, R 4And/or R 5On some at least hydrogen atoms be substituted that base is replaced and the compound that obtains; Substituting group comprises alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl, halogen ,=O ,=S ,-CF 3,-OCF 3, carboxyl (COOH), sulfonic group (SO 3H), cyano group (CN), hydroxyl (OH), amino (NH 2), or nitro (NO 2);
This claim also comprises R 3, R 4And/or R 5On some at least singly-bounds in the middle of insert the bridge joint group and the compound that obtains; The bridge joint group is including, but not limited to thioether group (S-), ether (O-), imino-(HN-), carbonyl ((CO)-), alkylsulfonyl ((SO 2)-), or sulfinyl ((SO)-);
This claim comprises by to R 3, R 4And/or R 5The substituting group that hockets is replaced and is inserted the bridge joint group and the compound that obtains.
3. NSC 630176 according to claim 2 is characterized in that, general structure M 2One of preferred structure be formula M 3Structure, i.e. formula M 2In R 3In formula M 3In specifically be chosen to be an aromatic substituent;
Figure F2009100696939C0000021
Wherein, X 1, X 2, X 3, X 4And X 5Be N or CH, can be the same or different;
This claim also comprises, works as X 1, X 2, X 3, X 4And/or X 5During for CH, the some at least hydrogen atoms on it are substituted that base is replaced and the compound that obtains; Substituting group comprises alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl, halogen ,=O ,=S ,-CF 3,-OCF 3, carboxyl (COOH), sulfonic group (SO 3H), cyano group (CN), hydroxyl (OH), amino (NH 2), or nitro (NO 2);
This claim also comprises, works as X 1, X 2, X 3, X 4And/or X 5During for CH, at the middle compound that inserts the bridge joint group and obtain of C-H singly-bound; The bridge joint group comprises thioether group (S-), ether (O-), imino-(HN-), carbonyl ((CO)-), alkylsulfonyl ((SO 2)-), or sulfinyl ((SO)-);
This claim comprises by to X 1, X 2, X 3, X 4And/or X 5The substituting group that hockets is replaced and is inserted the bridge joint group and the compound that obtains.
4. NSC 630176 according to claim 1 is characterized in that, general structure M 4Be formula M 1Another preferred structure, i.e. formula M 1In R 2In formula M 4In specifically be chosen to be the hetero-aromatic ring of a benzo,
Figure F2009100696939C0000022
Wherein, X 6, X 7, X 8And X 9Be N or CH, can be the same or different; Q 1Can be NH, S or O; Q 2Can be N or CH;
This claim also comprises, works as Q 1Be NH, and Q 2, X 6, X 7, X 8And/or X 9During for CH, the some at least hydrogen atoms on it are substituted that base is replaced and the compound that obtains; Substituting group comprises alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl, halogen ,=O ,=S ,-CF 3,-OCF 3, carboxyl (COOH), sulfonic group (SO 3H), cyano group (CN), hydroxyl (OH), amino (NH 2), or nitro (NO 2);
This claim also comprises, works as Q 1Be NH, and Q 2, X 6, X 7, X 8And/or X 9During for CH, the middle compound that inserts the bridge joint group and obtain of the some at least singly-bounds on it; The bridge joint group comprises thioether group (S-), ether (O-), imino-(HN-), carbonyl ((CO)-), alkylsulfonyl ((SO 2)-), or sulfinyl ((SO)-).
This claim comprises by to Q 1, Q 2, X 6, X 7, X 8And/or X 9The substituting group that hockets is repeatedly replaced and is inserted the bridge joint group and the compound that obtains.
5. ester group prodrug design based on each described NSC 630176 in the claim 1 to 4, the general structure of this prodrug such as M 5Shown in,
Figure F2009100696939C0000031
Wherein, R 6Be hydrogen atom, alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, or heteroaryl;
This claim also comprises R 6Some at least hydrogen atoms be substituted that base is replaced and the compound that obtains; Substituting group comprises alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl, halogen ,=O ,=S ,-CF 3,-OCF 3, carboxyl (COOH), sulfonic group (SO 3H), cyano group (CN), hydroxyl (OH), amino (NH 2), or nitro (NO 2);
This claim also comprises R 6Some at least singly-bounds in the middle of insert the bridge joint group and the compound that obtains; The bridge joint group comprises thioether group (S-), ether (O-), imino-(HN-), carbonyl ((CO)-), alkylsulfonyl ((SO 2)-), or sulfinyl ((SO)-).
This claim comprises by to R 6The substituting group that hockets is replaced and is inserted the bridge joint group and the compound that obtains.
6. the design of a glycosyl prodrugs, related glycosyl prodrug is to be that the parent drug molecule is sewed molecule as the sugar that aglycone obtains with each described NSC 630176 in the claim 1 to 4, sew in the molecule at this sugar, hydrogen atom on the hydroxyl of the hydroximic acid functional group of former parent drug molecule is replaced by glycosyl, glycosyl comprises glucose, semi-lactosi, lactose, maltose, sucrose, glucuronic acid, seminose, N-ethanoyl glucose, N-ethanoyl semi-lactosi, wood sugar, or sialic acid;
This claim comprises the compound that the hydrogen atom on the hydroxyl of glycosyl part is obtained by acyl substituted.
7. aryl prodrug design based on each described NSC 630176 in the claim 1 to 4, the general structure of this prodrug such as M 6Shown in,
Figure F2009100696939C0000032
Wherein, Ar is an aryl or heteroaryl;
This claim comprises that some at least hydrogen atoms of Ar are substituted that base is replaced and the compound that obtains; Substituting group comprises alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl, halogen ,=O ,=S ,-CF 3,-OCF 3, carboxyl (COOH), sulfonic group (SO 3H), cyano group (CN), hydroxyl (OH), amino (NH 2), or nitro (NO 2);
This claim also comprises the middle compound that inserts the bridge joint group and obtain of some at least singly-bounds of Ar; The bridge joint group comprises thioether group (S-), ether (O-), imino-(HN-), carbonyl ((CO)-), alkylsulfonyl ((SO 2)-), or sulfinyl ((SO)-).
This claim comprises Ar is hocketed that substituting group is replaced and inserts the bridge joint group and the compound that obtains.
8. the various isomeric form of each described NSC 630176 or preceding drug compound in the claim 1 to 7 comprise non-mirror image isomer, mirror image isomer, tautomer, the E/Z isomer of two keys.
9. one kind based on the corresponding pharmacy acceptable salt of each described NSC 630176 or preceding drug compound institute in the claim 1 to 8, and medicinal activity metabolite, these metabolites are at pharmacy acceptable salt, and a kind of pharmaceutical composition; Said composition contains each described NSC 630176 or preceding drug compound and pharmaceutically acceptable carrier among the claim 1-8.
Among the claim 1-9 each described NSC 630176 or preceding drug compound or composition as the application of the medicine of the following disease of preparation treatment: with cytodifferentiation or the relevant disease of propagation, cardiovascular disorder, immune class disease and nerve degenerative diseases; The disease of preferential treatment is a cancer.
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