CN101723896B - Tyrosine derivative histone deacetylases inhibitor and application thereof - Google Patents
Tyrosine derivative histone deacetylases inhibitor and application thereof Download PDFInfo
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Abstract
The invention relates to a tyrosine derivative histone deacetylases inhibitor and a preparation method and an application thereof. The invention further provides a kind of powerful histone deacetylases inhibitor, which can effectively treat the disease of abnormal expression of the activity of the histone deacetylases. In particular, the invention relates to a compound having the structure of formula (I) and further relates to various optical isomers, pharmaceutically acceptable salts, solvates and prodrugs of the compound. The invention further relates to a medicament composition and pharmaceutical use of the compound containing the structure of formula (I).
Description
Technical field
The present invention relates to one type of tyrosine derivative histone deacetylases inhibitor, belong to technical field of chemistry.
Background technology
Histon deacetylase (HDAC) (HDACs) is the complicated lytic enzyme of one type of function.In nucleus, the nucleosome that the octameric histone that is being twined by the DNA chain constitutes is to constitute chromosomal structural unit, and histon deacetylase (HDAC) (HDACs) can fall (like reaction formula II) with the ethanoyl hydrolysis on the lysine residue terminal amino group in the histone; Thereby cause the positive charge density of histone to increase, cause that then the avidity of histone and electronegative DNA strengthens, genetic transcription is suppressed; (referring to Christian; A.H., et al.Curr.Opin.Chem.Biol., 1997; 1,300; Kouzarides, T., Curr.Opin.Genet.Dev., 1999,9,40); Wolffe, A.P.Sci.Washington, 1996,272,371.In addition, the deacetylation of nucleosome histone is also assembled with chromatin, and DNA repairs with reorganization closely related, (referring to Polo, S.E., et al.Cancer Lett., 2005,220,1; Vidanes, G.M., etal.Cell, 2005,121,973).Recently, the increasing nonhistones substrate that is proved to be HDACs, like transcription factor, cytoskeletal protein, Chaperones Molecular etc., (referring to Glozak, M.A., et al.Gene, 2005,363,15).Have the function of complicacy like this just because of HDACs, its expression is closely related with numerous disease with active imbalance, comprising: cancer, neurodegenerative disease; Virus infection, inflammation, white blood disease; Malaria and mellitus etc., wherein, cancer is the disease the most serious to human life's health threat beyond doubt.Research shows that HDACs and tumour cell incidence and development are closely related, as: suppress tumour cell differentiation and apoptosis; Promote tumor cell proliferation, migration and vasculogenesis strengthen tumour cell to the resistibility of chemotherapeutics etc.; (referring to Witt, O., et al.Cancer Letter.; 2009,277,8).
Reaction formula II
Found in human body that at present there are 18 members in HDACs family, according to its structure, the different of function and distribution are divided into four types.Wherein, I class (HDAC1,2,3 and 8), II class (IIa:HDAC4,5,7 and 9; IIb:HDAC6,10), IV class (HDAC11) belongs to zine ion dependency lytic enzyme, and III class HDACs (SIRT 1-7) is NAD
+Dependent.Research shows that closely-related with tumour mainly is zine ion dependency HDACs, and hdac inhibitor (HDACs Inhibitors, HDACi) effectively breed, and promotes apoptosis by anticancer.And it is wide that HDACi has antitumor spectra, the advantage that toxic side effect is low, and they are to solid tumor, and white blood disease, lymphoma all have the good restraining activity.Therefore, be the focus that the agent of target spot design with suppressed has become antitumor drug research to HDACs.
The HDACi pharmacophore of report mostly comprises following three parts at present: zine ion chelation group (ZBG), hydrophobic long-chain (Linker) and protein surface cog region (Surface Recognition Domain).The zine ion chelation group can chelating HDACs active site zine ion, thereby the activity of inhibitory enzyme.Present known activity is the strongest, and using the widest zine ion chelation group is hydroxamic acid group, and therefore, it is the zine ion chelation group that the present invention also adopts hydroxamic acid group.(S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is called for short (S)-Tic, is a kind of non-albumen a-amino acid.(S)-how much conformations of specific molecule that Tic had and specific biological activity received people's very big concern, it has been used as the peptide class and a type peptide inhibitor of synthetic plurality of enzymes as the key chiral raw material, as angiotensin-converting enzyme (ACE) suppressor factor (referring to Hayashi, K., et al.Chem.Pharm.Bull., 1985; 33,2011.), and matrix metalloproteinase-8 (MMP-8) suppressor factor (referring to Matter, H., etal.Bioorg.Med.Chem., 2002; 10,3529.), and farnesyl transferase (FTase) suppressor factor (referring to Kotha, S., et al.Eur.J.Org.Chem.; 2001,17,3375), and prolyl endopeptidase (PEPs) suppressor factor (referring to Vendeville, S.; Et al.Bioorg.Med.Chem., 2002,10,1719), and opioid receptor (Opioid Receptor) selective agonist and antagonist etc. are (referring to Balboni; G., et al.J.Med.Chem., 2002,45,5556 and Balboni; G., et al.J.Med.Chem., 2002,45,713.).Yet, (S)-design that Tic is used for HDACi as yet the someone report that therefore, the present invention is with optically pure 3,5-two iodo-L-tyrosine are material construction (S)-Tic structure fragment, and the design of using it for HDACi is with synthetic.In addition, consider the flexibility of compound, we also replace the synthetic HDACi of (S)-Tic frame design with the tyrosine skeleton.
Summary of the invention
The present invention is directed to the deficiency of prior art, a kind of tyrosine derivative histone deacetylases inhibitor is provided.
Technical scheme of the present invention is following:
Compound with general formula I, with and optical isomer, diastereomer and racemic mixture, its pharmacy acceptable salt, solvate or prodrug,
Wherein,
R
1Be aryl, heteroaryl, aryl C1-6 alkyl, heteroaryl C1-9 alkyl, aryl C2-6 thiazolinyl; Heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl, C1-6 alkyl, assorted alkyl or cycloalkyl; Optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyanic acid, halogen C1-8 alkyl; The C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy, aryl C1-8 carbalkoxy;
R
2Be hydrogen, the acyl group of each seed amino acid preparation, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl; The C1-6 alkyloyl, the cycloalkanes acyl group, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl or heteroaryl C1-9 alkane alkylsulfonyl, optional by one or more following groups replacements: hydroxyl; Halogen, nitro, cyanic acid, carboxyl, halogen C1-8 alkyl, C1-8 alkoxyl group; The C1-6 alkyl-carbonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy, aryl, heteroaryl, aryl C1-6 alkyl, heteroaryl C1-9 alkyl; Aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl, C1-6 alkyl, assorted alkyl; Naphthenic base is preferably replaced by one or more following groups: hydroxyl, halogen, nitro, cyanic acid; Halogen C1-8 alkyl, C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy, aryl C1-8 carbalkoxy;
R
3Be the hydroxamic acid base, carboxyl, methoxycarbonyl, carboxamido-group or hydrazide group;
N is 1 or 2;
M is 0 or 1;
* be that steric configuration is S or R optical purity or its raceme.
Preferably, above-claimed cpd (I) is one of following:
(S)-and 2-tertbutyloxycarbonyl-7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-phenyl-carboxamido-group)-1,2,3,4-tetrahydroisoquinoline (7a);
(S)-and 2-tertbutyloxycarbonyl-7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-benzyl-carboxamido-group)-1,2,3,4-tetrahydroisoquinoline (7b);
(S)-and 2-tertbutyloxycarbonyl-7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(1-styroyl)-carboxamido-group)-1,2,3,4-Tetrahydroisoquinoli-(7c);
(S)-and 2-tertbutyloxycarbonyl-7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-p-methoxyphenyl-carboxamido-group)-1,2,3,4-tetrahydroisoquinoline (7d);
(S)-and 2-tertbutyloxycarbonyl-7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-p-methylphenyl-carboxamido-group)-1,2,3,4-tetrahydroisoquinoline (7e);
(S)-and 2-tertbutyloxycarbonyl-7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-o-methyl-phenyl--carboxamido-group)-1,2,3,4-tetrahydroisoquinoline (7f);
(S)-and 2-tertbutyloxycarbonyl-7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(aminomethyl phenyl-carboxamido-group between N-)-1,2,3,4-tetrahydroisoquinoline (7g);
(S)-and 2-tertbutyloxycarbonyl-7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-is to fluorophenyl-carboxamido-group)-1,2,3,4-tetrahydroisoquinoline (7h);
(S)-and 2-tertbutyloxycarbonyl-7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(chloro-phenyl--carboxamido-group between N-)-1,2,3,4-tetrahydroisoquinoline (7i);
(S)-and 2-tertbutyloxycarbonyl-7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(2, the 4-3,5-dimethylphenyl)-carboxamido-group)-1,2,3,4-tetrahydroisoquinoline (7j);
(S)-and 2-tertbutyloxycarbonyl-7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(3-chloro-4-fluorophenyl)-carboxamido-group)-1,2,3,4-tetrahydroisoquinoline (7k);
(S)-and 2-tertbutyloxycarbonyl-7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(1-naphthyl)-carboxamido-group)-1,2,3,4-tetrahydroisoquinoline (7l);
(S)-and 2-tertbutyloxycarbonyl-7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(1-xenyl)-carboxamido-group)-1,2,3,4-tetrahydroisoquinoline (7m);
(S)-and 2-tertbutyloxycarbonyl-7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(1-amyl group)-carboxamido-group)-1,2,3,4-tetrahydroisoquinoline (7n);
(S)-and 2-tertbutyloxycarbonyl-7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(1-hexyl)-carboxamido-group)-1,2,3,4-tetrahydroisoquinoline (7o);
(S)-and 2-tertbutyloxycarbonyl-7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(the N-tertiary butyl-carboxamido-group)-1,2,3,4-tetrahydroisoquinoline (7p);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-phenyl-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8a);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-benzyl-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8b);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(1-styroyl)-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8c);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-p-methoxyphenyl-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8d);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-p-methylphenyl-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8e);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-o-methyl-phenyl--carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8f);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(aminomethyl phenyl-carboxamido-group between N-)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8g);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-is to fluorophenyl-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8h);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(chloro-phenyl--carboxamido-group between N-)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8i);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(2, the 4-3,5-dimethylphenyl)-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8j);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(3-chloro-4-fluorophenyl)-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8k);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(1-naphthyl)-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8l);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(1-xenyl)-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8m);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(1-amyl group)-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8n);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(1-hexyl)-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8o);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(the N-tertiary butyl-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8p);
(S)-benzyl 3-(4-(2-(azanol base)-2-carbonyl oxyethyl group) phenyl)-1-oxygen-1-(anilino) propane-2-base-carbamate (13a);
(S)-benzyl 3-(4-(2-(azanol base)-2-carbonyl oxyethyl group) phenyl)-1-oxygen-1-(benzamido group) propane-2-base-carbamate (13b);
(S)-benzyl 3-(4-(2-(azanol base)-2-carbonyl oxyethyl group) phenyl)-1-oxygen-1-(P-nethoxyaniline base) propane-2-base-carbamate (13c) or
(S)-benzyl 3-(4-(2-(azanol base)-2-carbonyl oxyethyl group) phenyl)-1-oxygen-1-(amylamine base) propane-2-base-carbamate (13d).
The class peptide compounds midbody for preparing above-mentioned general formula (I) is: (S)-7-hydroxyl-6,8-two iodo-1,2,3; 4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride, (S)-2-tertiary butyloxycarbonyl-7-hydroxyl-6,8-two iodo-1,2; 3,4-tetrahydroisoquinoline-3-carboxylic acid, (S)-2-tertiary butyloxycarbonyl-7-hydroxyl-1; 2,3,4-tetrahydroisoquinoline-3-carboxylic acid or (S)-N-carbobenzoxy-(Cbz)-tyrosine.
The present invention also provides the application in the medicine of prevention or the treatment mammalian diseases relevant with the active unconventionality expression of histon deacetylase (HDAC) of these compounds.Described related mammalian disease with the active unconventionality expression of histon deacetylase (HDAC) comprises: cancer, neurodegenerative disease, virus infection, inflammation, white blood disease, malaria and mellitus etc.Therefore, the invention still further relates to the pharmaceutical composition that contains (I) structural compounds.
In addition, the present invention also comprises a kind of mammiferous pharmaceutical composition of orally give that is suitable for, and comprises arbitrary compound of above-mentioned general formula (I), and pharmaceutically acceptable carrier, optional one or more pharmaceutically acceptable vehicle that comprises.
In addition, the present invention comprises that also a kind of parenteral that is suitable for gives mammiferous pharmaceutical composition, comprises arbitrary compound of above-mentioned general formula (I), and pharmaceutically acceptable carrier, optional one or more pharmaceutically acceptable vehicle that comprises.
Detailed Description Of The Invention
Used definition and term
Term and definition implication used among this paper is following:
" aryl " is meant the aromatic carbocyclic group.Preferred aromatic ring contains 6-10 carbon atom.
" heteroaryl " is aromatic heterocycle, can be monocycle or bicyclic radicals.Preferable heteroaryl comprises, thienyl for example, furyl, pyrryl, pyridyl, pyrazinyl, thiazolyl, pyrimidyl, quinolyl and tetrazole base, benzothiazolyl, benzofuryl, indyl etc.
" assorted alkyl " refers to saturated or unsaturated, carbon atoms and at least one heteroatomic chain, and wherein any heteroatoms is non-conterminous.Contain 2-15 atom (carbon atom) in the assorted alkyl, preferably contain 2-10 atom.Assorted alkyl can be direct-connected or side chain, replacement or unsubstituted.
" naphthenic base " is replacement or unsubstituted, saturated or undersaturated cyclic group, and it contains carbon atom and/or one or more heteroatoms.This ring can be monocycle or condensed ring, the ring system of bridged ring or volution.Monocycle has 3-9 atom usually, preferably has 4-7 atom, and many rings contain 7-17 atom, preferably contain 7-13 atom.
" halogen ", or " halogen " comprises fluorine, chlorine, bromine or iodine, preferred fluorine and chlorine.
" acyl group of each seed amino acid preparation " is meant the group that various amino acid whose carboxyls are obtained after acidylate, preferred hydrophobic amino acid, and like glycocoll, L-Ala, Xie Ansuan, leucine, Isoleucine, phenylalanine(Phe), proline(Pro).
" aroyl " is meant that the aromatic carbon ring end is connected with the group of carbonyl, and preferred aromatic ring contains 6-10 carbon atom.
" 4-hetaroylpyrazol " refers to that the aromatic heterocycle end is connected with the group of carbonyl, can be monocycle or bicyclic radicals.Preferable heteroaryl comprises thienyl, furyl, pyrryl, pyridyl, pyrazinyl, thiazolyl, pyrimidyl, quinolyl and tetrazole base, benzothiazolyl, benzofuryl, indyl etc.
" cycloalkanes acyl group " refers to replace or for substituted, saturated or undersaturated annular termination is connected with the group of carbonyl, and it contains carbon atom and/or one or more heteroatoms.This ring can be monocycle or condensed ring, the ring system of bridged ring or volution.Monocycle has 3-9 atom usually, preferably has 4-7 atom, and many rings contain 7-17 atom, preferably contain 7-13 atom.
" pharmacy acceptable salt " is meant that formula (I) compound has curative effect and nontoxic salt form.It can form anion salt by arbitrary acidic-group (like carboxyl), or forms cationic salts by arbitrary basic group (like amino).A lot of such salt known in the art.Go up the cationic salts that forms at any acidic-group (like carboxyl), or go up the anion salt that forms at any basic group (like amino).It is known in the art that these salt have many, comprises the salt and the organic salt (like ammonium salt) of basic metal (like sodium and potassium) and earth alkali metal (like magnesium and calcium) like cationic salts.Also can obtain anion salt easily through (I) that uses corresponding s.t. alkaline form, such acid comprises mineral acid such as sulfuric acid, nitric acid, phosphoric acid etc.; Or organic acid such as acetate, propionic acid, oxyacetic acid, 2 hydroxy propanoic acid, 2-oxo propionic acid, oxalic acid, propanedioic acid, succsinic acid, toxilic acid, fumaric acid, oxysuccinic acid, tartrate, 2-hydroxyl-1; 2,3-the third three acid, methylsulfonic acid, ethyl sulfonic acid, benzene methanesulfonic acid, 4-toluene sulfonic acide, cyclohexyl-sulfinic acid, 2 hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid etc.These salt are that those of skill in the art know, and those skilled in the art can prepare any salt that this area knowledge is provided.In addition, those of skill in the art can get certain salt according to factors such as solubleness, stability, easy preparations and give up another kind of salt.The mensuration of these salt and optimization are in those of skill in the art's experience scope.
" solvate " is the title complex that solute (like inhibitors of metalloproteinase) and solvent (like water) are combined to form.Referring to J.Honig etc., The Van Nostrand Chemist ' s Dictionary, p.650 (1953).The pharmaceutically acceptable solvent that the present invention adopts comprises bioactive those solvents of not disturbing inhibitors of metalloproteinase (for example water, ethanol, acetate, N, dinethylformamide, DMSO 99.8MIN. and the solvent that these those skilled in the art knew or confirm easily).
" optical isomer " used herein, " enantiomorph ", " diastereomer ", " raceme " etc. have defined the form of The compounds of this invention or all possible steric isomer of its physiological verivate.Only if indication is arranged in addition; The chemical name of The compounds of this invention comprises the mixture of all possible stereochemical form, and affiliated mixture comprises all diastereomers and the enantiomorph of substruction molecule, and the single isomeric forms of the The compounds of this invention of substantially pure; Promptly wherein contain and be lower than 10%; Preferably be lower than 5%, particularly be lower than 2%, most preferably be lower than other isomer of 1%.The various stereoisomer forms of class peptide compounds of the present invention all obviously are contained in the scope of the present invention.
The form of all right other protected form of formula (I) compound or verivate exists, and these forms will be apparent to those skilled in the art, and all should be contained in the scope of the present invention.
Aforesaid substituting group self also can be replaced by one or more substituting groups.Such substituting group is included in C.Hansch and A.Leo, those substituting groups of listing among the Substituent Constants for Correlation Analysis in Chemistry and Biology (1979).Preferred substituted comprises, alkyl for example, thiazolinyl, alkoxyl group, hydroxyl, oxygen base, nitro; Amino, aminoalkyl group (like aminomethyl etc.), cyanic acid, halogen, carboxyl, carbonylic alkoxy (like carbonyl oxyethyl group etc.); Sulfenyl, aryl, naphthenic base, heteroaryl, Heterocyclylalkyl (like piperidyl, morpholinyl; Pyrryl etc.), imino-, hydroxyalkyl, aryloxy, arylalkyl, and combine.
The preparation method of said compound, reactions step and reaction formula are following:
The preparation method comprises the steps:
Synthetic route 1: with optically pure 3,5-two iodo-L-tyrosine are raw material, in succession through the Pictet-Spengler cyclization, and the protection secondary amine, hydro-reduction takes off iodine, and the polypeptide condensation connects R
1Group with the methyl bromoacetate nucleophilic reaction, is made hydroximic acid at last and is taken off Boc protection base and obtain end product.Reaction formula is following:
Synthetic route 1:
Wherein, R
1Be aryl, heteroaryl, aryl C1-6 alkyl, heteroaryl C1-9 alkyl, aryl C2-6 thiazolinyl; Heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl, C1-6 alkyl, assorted alkyl; Naphthenic base, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyanic acid; Halogen C1-8 alkyl, C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy, aryl C1-8 carbalkoxy.
Reagent in said synthesis route 1 reaction formula: (a) Paraformaldehyde 96,37% hydrochloric acid, glycol dimethyl ether, reacted 18 hours by 72-75 ℃; (b) dimethyl dicarbonate butyl ester, 1mol/L sodium hydroxide solution, THF; (c) 10% palladium carbon, hydrogen, methyl alcohol; (d) various amines, NSC 57182,1-hydroxy benzo triazole, anhydrous tetrahydro furan; (e) methyl bromoacetate, salt of wormwood, anhydrous N, dinethylformamide; (f) azanol potassium, anhydrous methanol; (g) the saturated ethyl acetate solution of hydrogenchloride.
The structural formula of the target compound of synthetic route 1 is as follows:
Synthetic route 2: with L-tyrosine is raw material, and through the protection amido, the polypeptide condensation connects R
1Group with the methyl bromoacetate nucleophilic reaction, is made hydroximic acid at last.Reaction formula is following:
Synthetic route 2:
Wherein, R
1Be aryl, heteroaryl, aryl C1-6 alkyl, heteroaryl C1-9 alkyl, aryl C2-6 thiazolinyl; Heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl, C1-6 alkyl, assorted alkyl; Naphthenic base, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyanic acid; Halogen C1-8 alkyl, C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy, aryl C1-8 carbalkoxy.
Reagent in said synthesis route 2 reaction formula: (h) chloroformic acid benzyl ester, 1mol/L sodium hydroxide solution; (i) various amines, NSC 57182,1-hydroxy benzo triazole, anhydrous tetrahydro furan; (j) methyl bromoacetate, salt of wormwood, anhydrous N, dinethylformamide; (k) azanol potassium, anhydrous methanol.
The structural formula of the target compound of synthetic route 2 is as follows:
The concrete operations step of said compound will specify in an embodiment.
Those skilled in the art can change to improve yield above-mentioned steps; They can confirm the synthetic route according to the ABC of this area; Like the selective reaction thing, solvent and temperature, thus can improve yield with the generation of avoiding side reaction through using various GPF (General Protection False bases.These conventional guard methods can be referring to for example T.Greene, Protecting Groups in OrganicSynthesis.
Obviously, above-mentioned route is that stereoselectivity is synthetic, also can prepare its optically active type of peptide compounds through above-mentioned route.For example with raw material 3,5-two iodo-L-tyrosine or L-tyrosine replace with its optical isomer (D configuration).Those skilled in the art can obtain various other isomer easily, and can be through conventional separation means purifying, like chirality salt or chirality chromatography column etc.
Because the high homology of each hypotype catalytic center of zine ion dependency histon deacetylase (HDAC) (HDACs), we select histon deacetylase (HDAC) 8 hypotypes (HDAC8) of present known X-diffraction crystal structure to carry out the enzymic activity test.HDACs active fluoro analytical procedure (two-step approach), it is active, simple to operate, highly sensitive fast, conveniently to detect HDACs.The first step, (Boc-Lys (acetyl)-AMC) is hatched with the HDAC8 sample that contains expression, makes the substrate deacetylate, activates substrate to contain the Methionin HDACs fluorogenic substrate of an acetylize side chain.Second step; Use pancreatin hydrolysis Boc-Lys-AMC, produce this fluorophor of AMC (being chromophoric group), measure fluorescence intensity in emission wavelength/excitation wavelength (390nm/460nm); Thereby the fluorescence intensity according to suppressor factor group and control group is calculated inhibiting rate, and asks and calculate the IC50 value.The enzymic activity test philosophy is seen the reaction formula III.
Thiazolyl blue detection method (mtt assay), human colon cancer cell strain (HCT116), human oophoroma cell line (SKOV3) are used in the test of the cytoactive of compound; The cell suspension of people's acute leukemia cells strain (HL60) is inoculated in 96 orifice plates respectively, adds the substratum that contains the different concns compound in every hole, after hatching; With MTT dyeing, after continuing to hatch, on ELIASA at 570nm place the absorbancy (OD value) in the every hole of mensuration; Calculate inhibitory rate of cell growth, thereby confirm the activity of compound.
It is a kind of tyrosine derivative histone deacetylases inhibitor that the class peptide compounds of general formula (I) external presses down this compounds of enzyme test proof.
Tyrosine derivative of the present invention spatially is complementary with the avtive spot of histon deacetylase (HDAC), has therefore shown that external higher inhibition is active.
The reaction formula III
Histone deacetylase is a histon deacetylase (HDAC) in the reaction formula III, and Trypsin is a trypsinase, and 4-amino-7-methylcoumarin is 4-amino-7-methylcoumarin.
The pharmaceutical composition that contains The compounds of this invention
Part verivate of the present invention can free form or is existed with salt form.Pharmacy acceptable salt of the known chemical compound lot type of those skilled in the art and preparation method thereof.Pharmacy acceptable salt comprises conventional avirulent salt, comprises such compound alkali and quaternary ammonium salt inorganic or that organic acid forms.
Compound of the present invention can form hydrate or solvate.The one skilled in the art known with compound formed hydrate or form the method for solvate when in solution, concentrating during with the water freeze-drying with appropriate organic solvent.
The present invention comprises the medicine that contains the therapeutic dose The compounds of this invention and the pharmaceutical composition of one or more pharmaceutically acceptable carriers and/or vehicle.Carrier comprises like salt solution, BS, and glucose, water, glycerine, ethanol and their binding substances, hereinafter is discussed in more detail.If desired, said composition can also comprise wetting agent or emulsifying agent in a small amount, or the pH buffer reagent.Said composition can be liquid, suspension-s, emulsion, tablet, pill, capsule, extended release preparation or powder.Said composition can be mixed with suppository with traditional tamanori and carrier such as triglyceride.Oral prepns can comprise the mannitol of standard vector such as medicine grade, lactose, starch, Magnesium Stearate, soluble saccharin, Mierocrystalline cellulose and magnesiumcarbonate or the like.Preparation and deciding optionally, preparation can design mixing, granulation and compression or solvent components.In another approach, said composition can be mixed with nano particle.
The pharmaceutical carrier that uses can be solid or liquid.
The typical solid carrier comprises lactose, terra alba, sucrose, talcum, gel, agar, pectin, gum arabic, Magnesium Stearate, Triple Pressed Stearic Acid or the like.Solid carrier can comprise that one or more maybe be simultaneously as sweetener, lubricant, solubilizing agent, suspension agent, filler, glidant, compression aid, the material of tackiness agent or tablet-disintegrating agent; It can also be an encapsulating material.In powder, carrier is pulverizing solid, and it mixes with pulverizing activeconstituents.Activeconstituents and the carrier with necessary compression property are with suitable mixed, with the shape and the size compression of needs in tablet.Powder and tablet preferably comprise 99% activeconstituents at the most.Suitable solid carrier comprises, for example, and calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gel, Mierocrystalline cellulose, methylcellulose gum, sodium carboxymethyl-cellulose, Vinylpyrrolidone polymer alkane ketone, low melt wax and ion exchange resin.
Exemplary of liquid carriers comprises syrup, peanut oil, sweet oil, water or the like.Liquid vehicle is used to prepare solution, suspension-s, emulsion, syrup, the compsn of tincture and sealing.Activeconstituents can dissolve or be suspended in pharmaceutically acceptable liquid vehicle such as water, organic solvent, the mixture of the two or pharmaceutically acceptable oils or fat.Liquid vehicle can comprise other suitable medicated premix such as solubilizing agent, emulsifying agent, and buffer reagent, sanitas, sweetener, sweetener, suspension agent, thickening material, pigment, viscosity modifier is stablized shape or osmotic pressure-regulator.The suitable example that is used for the liquid vehicle of oral and administered parenterally comprises that water (partly comprises as above-mentioned additive; Derivatived cellulose for example; The preferably carboxymethyl cellulose sodium salt solution); Alcohol (comprising monohydroxy-alcohol and polyvalent alcohol, for example terepthaloyl moietie) and their verivate, and oils (for example fractionated coconut oil and peanut oil).The carrier that is used for administered parenterally can also be grease such as OE and sec.-propyl myristate.Aseptic liquid vehicle is used for the aseptic fluid composition of administered parenterally.The liquid vehicle that is used for pressurized compositions can be halohydrocarbon or other pharmaceutically acceptable propelling agents.Sterile solution or aaerosol solution composition of liquid medicine can be used for, for example, and intravenously, intramuscular, intraperitoneal or subcutaneous injection.But single pushes or injection gradually during injection, goes into 30 minutes the interior perfusion of passages through which vital energy circulates.This compound can also be with the form oral administration of liquid or solids compsn.
Carrier or vehicle can comprise time lag material known in the art, like glyceryl monostearate or distearin, also can comprise wax, TKK 021, Vltra tears, methyl methacrylate or the like.When preparation is used for when oral; Generally acknowledge PHOSALPG-50 (phosphatide (phospholipid) and 1; The 2-Ucar 35 concentrates; A.Nattermann & Cie.GmbH) 0.01% tween 80 in is used for the preparation of the acceptable oral preparation of other compounds, can be adapted to the preparation of all cpds of the present invention.
Can use medicament forms miscellaneous when giving The compounds of this invention.If the use solid carrier, preparation can be tablet, is placed into powder or piller form or lozenge or lozenge form in the hard capsule.The amount of solid carrier changes to a great extent, but preferably from about 25mg to about 1.0g.If the use liquid vehicle, preparation can be syrup, emulsion, soft capsule, aseptic injectable solution or suspension-s in the liquid suspension of ampoule or bottle or non-water.
In order to obtain stable water miscible formulation, can compound or its pharmacy acceptable salt be dissolved in the organic or inorganic aqueous acid, 0.3M succsinic acid or citric acid solution.Optionally, the tart verivate can be dissolved in suitable basic soln.If can not get soluble form, can compound be dissolved in suitable cosolvent or their combination.The example of suitable cosolvent like this includes but are not limited to, and concentration range is from the ethanol of 0-60% TV, Ucar 35, Liquid Macrogol, polysorbate 80, glycerine, polyoxyethylene fatty acid ester, Fatty Alcohol(C12-C14 and C12-C18) or glycerine hydroxy fatty acid ester or the like.
Various release systems are known and can be used for the administration of compound or other various preparations, and these preparations comprise tablet, capsule, and injectable solution, the capsule in the liposome, particulate, microcapsule, or the like.The method of introducing includes, but are not limited to skin, intracutaneous, intramuscular, endoperitoneal, intravenous, subcutaneous, nasal cavity, lung, peridural, eyes with (preferred usually) oral route.Compound can through any easily or other suitable administration; For example through injecting or bolus injection; Through epithelium or the mucous membrane circuit (for example; Oral mucosa, rectum and intestines mucosa, or the like) absorb or the support through carrying medicament and can be in other biological promoting agent administration together.Can whole body or topical.Be used for nose, when the treatment of segmental bronchus or lung disease or prevention, preferred route of administration is oral, nasal administration or segmental bronchus smoke substance or atomizer.
Compound 13a among the present invention, 7d, 8l; 7i; 7a is superior to positive control drug to the inhibition activity of histon deacetylase (HDAC) 8 hypotypes (HDAC8), has the excellent development prospect, and can be used as the lead compound of finding new and effective NSC 630176.In addition, compound 7d, 7i and 8l demonstrate the activity that is superior to positive control Vorinostat (SAHA) in the test of extracorporeal anti-tumor cell proliferation, have the excellent development prospect.
Description of drawings
Fig. 1 is compound (S)-2-tertbutyloxycarbonyl-7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-p-methoxyphenyl-carboxamido-group)-1; 2; 3,4-tetrahydroisoquinoline (7d) passes through Sybyl7.3 with the 3-D display synoptic diagram with the result of docking of the active region of histon deacetylase (HDAC) 8 hypotypes.
Embodiment
Below in conjunction with embodiment the present invention is done further explanation, but be not limited thereto.
Synthesizing of embodiment 1. The compounds of this invention
With (7a), (8a) with (13a) be example:
1) (S)-and 7-hydroxyl-6,8-two iodo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride 2
In the 250mL concentrated hydrochloric acid, add 3, and 5-two iodo-L-tyrosine (1,30.0g, 69.3mmol), (7.8g 260.0mmol), and is warming up to 72 ℃ gradually for glycol dimethyl ether (20mL) and Paraformaldehyde 96.0.5 after hour, add concentrated hydrochloric acid (50mL) again, (5.2g, 173.3mmol), the oil bath temperature control continues reaction 18 hours at 72-75 ℃ for glycol dimethyl ether (10mL) and Paraformaldehyde 96.The cooling of reaction suspension ice bath is also filtered, and filter cake spent glycol dme thorough washing gets 19.41g white powder 2 after the drying.Productive rate: 58.17%, ESI-MS m/z:446.2 [M+H
+],
1H-NMR (DMSO-d
6) δ 3.07 (dd, J=16.8Hz, 10.8Hz, 1H), 3.22 (dd, J=16.8Hz, 4.8Hz; 1H), 4.02 (d, J=16.2Hz, 1H), 4.15 (d, J=16.2Hz, 1H); 4.32 (dd, J=4.8Hz, 10.8Hz, 1H), 7.73 (s, 1H); 9.68 (s, 1H), 10.00 (br s, 2H), 14.17 (br s, 1H).
2) (S)-and 2-tertbutyloxycarbonyl-7-hydroxyl-6,8-two iodo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 3
(4.81g 10.0mmol) is dissolved in the sodium hydroxide solution of 22mL1mol/L compound 2, and adds 5mL dimethyl dicarbonate butyl ester (2.40g, tetrahydrofuran solution 11.0mmol).Control reaction solution pH at 9-11 with the sodium hydroxide solution of 1mol/L in the reaction process.Behind the room temperature reaction 6 hours; Steam the THF that removes in the reaction solution, with sherwood oil reaction solution is extracted 3 times again, and be acidified to pH4-5 with the citric acid solution of 1mol/L; Use ethyl acetate extraction then three times; Organic phase merges the back and uses the saturated common salt water washing, anhydrous magnesium sulfate drying, and solvent evaporated gets 4.99g buff powder 3.Productive rate: 91.56%,
1H-NMR (DMSO-d
6) δ 1.34+1.40 (s, 9H, cis/trans), 2.87-3.00 (m, 2H), 4.13-4.41 (m, 2H), 4.61-4.75 (m, 1H), 7.57 (s, 1H), 9.41 (br s, 1H), 12.71 (br s, 1H).
3) (S)-and 2-tertbutyloxycarbonyl-7-hydroxyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 4
(2.73g 5.0mmol) is dissolved in the 30mL anhydrous methanol compound 3, and (1.11g is 11.0mmol) with 10% palladium carbon (0.23g) to wherein adding triethylamine.Feed hydrogen reaction after 5 hours, use the zeyssatite filtration catalizer, steam and remove methyl alcohol; The citric acid solution that adds 1mol/L is used ethyl acetate extraction three times then to pH4-5, uses the saturated common salt water washing behind the combined ethyl acetate layer; Anhydrous magnesium sulfate drying, solvent evaporated get 1.10g buff powder 4.Productive rate: 75.32%,
1H-NMR (DMSO-d
6) δ 1.39+1.45 (s, 9H, cis/trans), 2.92-3.04 (m, 2H), 4.26-4.51 (m, 2H), 4.57-4.82 (m, 1H), 6.52 (s, 1H), 6.57 (d, J=8.4Hz, 1H), 6.97 (d, J=8.4Hz, 1H), 9.28 (s, 1H), 12.60 (s, 1H).
4) (S)-and 2-tertbutyloxycarbonyl-7-hydroxyl-3-(N-phenyl-carboxamido-group)-1,2,3,4-tetrahydroisoquinoline 5a
(2.93g, 10.0mmol) (1.49g 11.0mmol) is dissolved in the 40mL anhydrous tetrahydro furan compound 4, drips NSC 57182 (2.27g, tetrahydrofuran solution 11.0mmol) under the condition of ice bath with the 1-hydroxy benzo triazole.After 30 minutes, (1.02g 11.0mmol) continues room temperature reaction and spends the night to add aniline.After reaction finishes; Steam to remove THF, add ETHYLE ACETATE, put into refrigerator and cooled and freeze to spend the night NSC 30023 (DCU) is fully separated out; Filtering NSC 30023 (DCU); Filtrating is used saturated sodium carbonate solution successively, the hydrochloric acid soln of 1mol/L and saturated nacl aqueous solution washing, and steaming desolventizes and obtains 2.55g yellow powder 5a behind the anhydrous magnesium sulfate drying.Productive rate: 69.29%, ESI-MS m/z:369.5 [M+H
+],
1H-NMR (DMSO-d
6) δ 1.30+1.45 (s, 9H, cis/trans), 2.85-3.11 (m, 2H), 4.27-4.52 (m, 2H); 4.55-4.74 (m, 1H), 6.57-6.64 (m, 2H), 6.96-7.04 (m, 2H), 7.25-7.30 (m; 2H), 7.49-7.56 (m, 2H), 9.29 (s, 1H), 9.96 (s, 1H).
5) (S)-and 2-tertbutyloxycarbonyl-7-(2-(methoxyl group)-2-carbonyl oxyethyl group)-3-(N-phenyl-carboxamido-group)-1,2,3,4-tetrahydroisoquinoline 6a.
(2.55g, 40mLN 6.93mmol) add potassium carbonate powder (1.91g in the dinethylformamide solution to compound 5a; 13.86mmol) and methyl bromoacetate (2.12g, 13.86mmol), stirring at room is reacted after 3 hours in the reaction solution impouring 300mL water; There are a large amount of depositions to separate out; With ethyl acetate extraction three times, use the saturated common salt water washing behind the combined ethyl acetate layer, anhydrous magnesium sulfate drying; Solvent evaporated gets the product bullion, and this bullion separates (sherwood oil: ETHYLE ACETATE=3: 1) get 1.16g colorless oil 6a with silicagel column.Productive rate: 38.10%, ESI-MS m/z:441.6 [M+H
+],
1H-NMR (DMSO-d
6) δ 1.33+1.47 (s, 9H, cis/trans), 2.93-3.16 (m, 2H), 3.70 (s, 3H), 4.34-4.58 (m; 2H), 4.62-4.88 (m, 1H), 4.78 (s, 2H), 6.72-6.90 (m, 2H), 7.02-7.16 (m; 2H), 7.26-7.31 (m, 2H), 7.49-7.56 (m, 2H), 10.00 (s, 1H).
6) (S)-and 2-tertbutyloxycarbonyl-7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-phenyl-carboxamido-group)-1,2,3,4-tetrahydroisoquinoline 7a
Azanol potassium (NH
2OK) preparation of solution: the saturated absolute methanol solution of 14mL Pottasium Hydroxide is added drop-wise in the absolute methanol solution that 24mL contains 4.67g (67mmol) oxammonium hydrochloride; Temperature is lower than 40 ℃ in the control, dropwises cooling reaction liquid; The airtight preservation of filtrating of filtering white Repone K deposition, gained is subsequent use.
Compound 6a (0.88g, 2.0mmol) be dissolved in the 10mL anhydrous methanol after, to wherein adding the above-mentioned azanol potassium of 3.5mL (NH
2OK) solution.0.5 after hour, steam and remove methyl alcohol, the hydrochloric acid soln of 2mol/L is acidified to pH3-4; Use ethyl acetate extraction then, use the saturated common salt water washing behind the combined ethyl acetate layer, through anhydrous magnesium sulfate drying; Solvent evaporated gets bullion, and bullion gets 0.23g white powder 7a through ETHYLE ACETATE/ethyl alcohol recrystallization.Productive rate: 26.05%, mp:179-181 ℃;
1H-NMR (DMSO-d
6) δ 1.30+1.46 (s, 9H, cis/trans), 2.89-3.19 (m, 2H), 4.34-4.65 (m, 2H); 4.44 (s, 2H), 4.57-4.80 (m, 1H), 6.70-6.88 (m, 2H); 7.01-7.17 (m, 2H), 7.24-7.32 (m, 2H), 7.49-7.56 (m, 2H); 8.97 (s, 1H), 10.01 (s, 1H), 10.81 (s, 1H); HRMS (AP-ESI) m/z calcd for C
23H
28N
3O
6[M+H]
+442.1978 found 442.1980.
7) (S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-phenyl-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt 8a
Compound 7a (0.15g, 0.34mmol) be dissolved in the 5mL anhydrous ethyl acetate after, to wherein adding the saturated ethyl acetate solution of 10mL hydrogenchloride.In the reaction process gradually adularescent deposition separate out, will precipitate filtering after 8 hours, use the ether thorough washing, must 0.12g white powder 8a after the drying.Productive rate: 91.35%, mp:187-189 ℃;
1H-NMR (DMSO-d
6) δ 2.98-3.37 (m, 2H), 4.28-4.30 (m, 2H), 4.32-4.37 (m, 1H), 4.45 (s; 2H), and 6.89-6.92 (m, 2H), 7.12-7.23 (m, 2H), 7.36-7.41 (m, 2H); 7.65-7.67 (m, 2H), 9.00 (br s, 1H), 9.60 (br s, 1H); 9.81 (br s, 1H), 10.77 (s, 1H), 10.87 (s, 1H); HRMS (AP-ESI) m/z calcd for C
18H
20N
3O
4[M+H]
+342.1454 found 342.1459.
8) (S)-N-carbobenzoxy-(Cbz)-tyrosine 10
With compound 2 (1.81g 10.0mmol) is dissolved in the sodium hydroxide solution of 11mL1mol/L, drip under the cryosel bath condition chloroformic acid benzyl ester (1.87,11.0mmol).Control reaction solution pH at 9-11 with the sodium hydroxide solution of 1mol/L in the reaction process.Behind the room temperature reaction 2 hours, with reaction solution extraction 3 times, the citric acid solution with 1mol/L is acidified to pH4-5 again with sherwood oil; Use ethyl acetate extraction then three times; Organic phase merges the back and uses the saturated common salt water washing, and through anhydrous magnesium sulfate drying, solvent evaporated gets 2.95g brown oil 10.Productive rate: 93.65%, ESI-MS m/z:316.2 [M+H
+].
9) (S)-benzyl 3-(4-hydroxy phenyl)-1-oxygen-1-(anilino) propane-2-base-carbamate 11a
The compound method of compound 11a is consistent with 5a's.Different is: with (S)-N-carbobenzoxy-(Cbz)-tyrosine (compound 10) is raw material, products obtained therefrom (S)-benzyl 3-(4-hydroxy phenyl)-1-oxygen-1-(anilino) propane-2-base-carbamate 11a, and productive rate: 93.65%, ESI-MS m/z:391.5 [M+H
+].
10) (S)-benzyl 3-(4-(2-(methoxyl group)-2-carbonyl oxyethyl group) phenyl)-1-oxygen-1-(anilino) propane-2-base-carbamate 12a
The compound method of compound 12a is consistent with 6a's.Different is: with (S)-benzyl 3-(4-hydroxy phenyl)-1-oxygen-1-(anilino) propane-2-base-carbamate (compound 11a) is raw material; Products obtained therefrom (S)-benzyl 3-(4-(2-(methoxyl group)-2-carbonyl oxyethyl group) phenyl)-1-oxygen-1-(anilino) propane-2-base-carbamate 12a; Productive rate: 63.67%
1H-NMR (DMSO-d
6) δ 2.78 (dd, J=13.8Hz, 10.8Hz, 1H), 2.96 (dd, J=13.8Hz, 4.8Hz, 1H); 3.69 (s, 3H), 4.36 (dd, J=10.8Hz, 4.8Hz, 1H), 4.75 (s, 2H); 4.97 (s, 2H), 6.84-6.85 (m, 2H), 7.05-7.07 (m, 1H), 7.24-7.35 (m; 9H), 7.59-7.60 (m, 2H), 7.67-7.68 (m, 1H), 10.11 (s, 1H).
11) (S)-benzyl 3-(4-(2-(azanol base)-2-carbonyl oxyethyl group) phenyl)-1-oxygen-1-(anilino) propane-2-base-carbamate 13a
The compound method of compound 13a is consistent with 7a's.Different is: (4-(2-(azanol base)-2-carbonyl oxyethyl group) phenyl)-1-oxygen-1-(anilino) propane-2-base-carbamate (compound 12a) is a raw material with (S)-benzyl 3-; Products obtained therefrom (S)-benzyl 3-(4-(2-(azanol base)-2-carbonyl oxyethyl group) phenyl)-1-oxygen-1-(anilino) propane-2-base-carbamate 13a; Productive rate: 27.46%
1H-NMR (DMSO-d
6) δ 2.78 (dd, J=13.8Hz, 10.8Hz, 1H), 2.96 (dd, J=13.8Hz, 4.8Hz, 1H); 4.36 (dd, J=10.8Hz, 4.8Hz, 1H), 4.41 (s, 2H), 4.97 (s, 2H); 6.86-6.87 (m, 2H), 7.05-7.07 (m, 1H), 7.24-7.36 (m, 9H), 7.59-7.60 (m, 2H); 7.66-7.67 (m, 1H), 8.96 (s, 1H), 10.11 (s, 1H), 10.81 (s, 1H); HRMS (AP-ESI) m/z calcd for C
25H
26N
3O
6[M+H]
+464.4904 found 464.4910.
Embodiment 2 target compound inhibition of histone deacetylase activity tests (In vitro)
Histon deacetylase (HDAC) (HDACs) active fluoro analytical procedure is mainly in two steps: the first step; The Methionin HDACs fluorogenic substrate (Boc-Lys (acetyl)-AMC) that contains an acetylize side chain; Histon deacetylase (HDAC) 8 hypotypes (HDAC8) sample with containing expression is hatched; Make the substrate deacetylate, activate substrate.Second step, use pancreatin hydrolysis Boc-Lys-AMC, produce this fluorophor of AMC (being chromophoric group), measure fluorescence intensity in emission wavelength/excitation wavelength (390nm/460nm), thereby calculate inhibiting rate, and ask and calculate IC according to the fluorescence intensity of suppressor factor group and control group
50Value.The enzymic activity test philosophy is seen patent specification part correlation content.Experimental result is seen table 1.
The external enzyme test result that presses down of table 1. compound (I)
aNumerical value is the MV of three tests in the table, the numeric representation standard deviation after " ± ".
The SAHA commodity are called Zolinza, and general Vorinostat by name is the NSC 630176 of U.S. food Drug Administration (FDA) in approval listing in 2006.
Above-mentioned test result shows that the tyrosine derivative compounds all shows the stronger inhibition of histon deacetylase (HDAC) 8 hypotypes (HDAC8) active, wherein compound 13a; 7d; 8l, 7i, 7a is superior to positive control drug Vorinostat (SAHA) to the inhibition activity of histon deacetylase (HDAC) 8 hypotypes (HDAC8); Have the excellent development prospect, and can be used as the lead compound of finding new and effective NSC 630176.
Embodiment 3 target compounds suppress the activity test (In vitro) of cell proliferation
Choose enzymic activity compound 7d preferably, 7i, 8l carries out the activity test of vitro inhibition cancer cell multiplication, and the result sees table 2.
The term explanation:
HCT116: human colon cancer cell strain.
SKOV3: human oophoroma cell line.
HL60: people's acute leukemia cells strain.
SAHA: commodity are called Zolinza, and general Vorinostat by name is the NSC 630176 of U.S. food Drug Administration (FDA) in approval listing in 2006.
DMSO: DMSO 99.8MIN..
IC
50: half-inhibition concentration.
1. [material] HCT116, SKOV3, HL60 cell strain, the blue MTT of tetramethyl-azo azoles, 10% foetal calf serum, 96 orifice plates
2. [method]
Cell cultures HCT116, SKOV3, three kinds of tumor cell lines of HL60 adopt conventional the cultivation.All use the logarithmic phase cell during experiment.
The cell growth detects (mtt assay) HCT116, SKOV3, and the HL60 cell suspension all is adjusted to 1 * 10
5/ ml is inoculated in 96 orifice plates (50 μ l/ hole) respectively, 5000 cells/well.Behind the bed board 4h; Add the substratum that 50ul contains the different concns compound in every hole; 1000,200,40,8,1.6,0.32ug/ml make that the compound final concentration is respectively in the hole:, each concentration is established three multiple holes, does blank when not adding the hole reading of cell; Add the hole that cell do not add compound and make the compound blank well, SAHA makes the compound positive control.In 37 ℃, hatch 48h in 5% carbonic acid gas, every hole adds the MTT staining fluid of 10 μ l0.5%, after continuing to hatch 4h, 2500rpm, centrifugal 30min abandons substratum in the plate hole then, adds DMSO 99.8MIN., the 200ul/ hole.Measure the absorbancy OD value in every hole on the ELIASA in the 570nm place, inhibitory rate of cell growth is calculated as follows:
Table 2 cell proliferation experiment result
| Compound | IC 50(mM) HCT116 | IC 50(mM) SKOV3 | IC 50(mM) HL60 |
| 7d | 0.048±0.0071 | 0.42±0.037 | ＞2.12 |
| 7i | 0.49±0.016 | 0.68±0.075 | 0.96±0.052 |
| 8l | 0.17±0.027 | 0.75±0.036 | 0.98±0.047 |
| SAHA | 0.79±0.019 | 1.66±0.21 | ＞3.78 |
aNumerical value is the MV of three tests in the table, the numeric representation standard deviation after " ± ".
Last table test data shows that compound 7d, 7i and 8l demonstrate the activity that is superior to positive control SAHA in the test of extracorporeal anti-tumor cell proliferation, have the excellent development prospect.
Claims (6)
1. the compound that has general formula I,
Wherein,
R
1Be aryl, heteroaryl, aryl C1-6 alkyl, heteroaryl C1-9 alkyl, C1-6 alkyl;
R
2Be hydrogen, the acyl group of each seed amino acid preparation, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl;
R
3Be the hydroxamic acid base, carboxyl or methoxycarbonyl;
N is 1 or 2;
M is 0 or 1;
* be that steric configuration is S or R optical purity or its raceme;
Described " aryl " is meant the aromatic carbocyclic group that contains 6-10 carbon atom;
Described " heteroaryl " is aromatic heterocycle, and monocycle or bicyclic radicals are thienyls, furyl, pyrryl, pyridyl, pyrazinyl, thiazolyl, pyrimidyl, quinolyl, tetrazole base, benzothiazolyl, benzofuryl or indyl;
Described " acyl group of each seed amino acid preparation " is meant the group that various amino acid whose carboxyls are obtained after acidylate, be selected from glycocoll, L-Ala, Xie Ansuan, leucine, Isoleucine, phenylalanine(Phe) or proline(Pro);
Described " aroyl " is meant that the aromatic carbon ring end is connected with the group of carbonyl, and aromatic ring contains 6-10 carbon atom;
Described " 4-hetaroylpyrazol " refers to that the aromatic heterocycle end is connected with the group of carbonyl, is monocycle or bicyclic radicals; Be thienyl, furyl, pyrryl, pyridyl, pyrazinyl, thiazolyl, pyrimidyl, quinolyl and tetrazole base, benzothiazolyl, benzofuryl or indyl.
2. compound as claimed in claim 1 is characterized in that it being one of following compound:
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-phenyl-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8a);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-benzyl-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8b);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(1-styroyl)-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8c);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-p-methoxyphenyl-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8d);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-p-methylphenyl-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8e);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-o-methyl-phenyl--carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8f);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(aminomethyl phenyl-carboxamido-group between N-)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8g);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-is to fluorophenyl-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8h);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(chloro-phenyl--carboxamido-group between N-)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8i);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(2, the 4-3,5-dimethylphenyl)-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8j);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(3-chloro-4-fluorophenyl)-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8k);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(1-naphthyl)-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8l);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(1-xenyl)-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8m);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(1-amyl group)-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8n);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(N-(1-hexyl)-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8o);
(S)-and 7-(2-(azanol base)-2-carbonyl oxyethyl group)-3-(the N-tertiary butyl-carboxamido-group)-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (8p).
3. the preparation method of the said compound of claim 1 is characterized in that comprising the steps:
Synthetic route 1: with optically pure 3,5-two iodo-L-tyrosine are raw material, in succession through the Pictet-Spengler cyclization, and the protection secondary amine, hydro-reduction takes off iodine, and the polypeptide condensation connects R
1Group with the methyl bromoacetate nucleophilic reaction, is made hydroximic acid at last and is taken off Boc protection base and obtain end product; Reaction formula is following:
Synthetic route 1:
Wherein, R
1With claim 1;
Reagent in said synthesis route 1 reaction formula: (a) Paraformaldehyde 96,37% hydrochloric acid, glycol dimethyl ether, reacted 18 hours by 72-75 ℃; (b) dimethyl dicarbonate butyl ester, 1mol/L sodium hydroxide solution, THF; (c) 10% palladium carbon, hydrogen, methyl alcohol; (d) various amines, NSC 57182,1-hydroxy benzo triazole, anhydrous tetrahydro furan; (e) methyl bromoacetate, salt of wormwood, anhydrous N, dinethylformamide; (f) azanol potassium, anhydrous methanol; (g) the saturated ethyl acetate solution of hydrogenchloride.
4. claim 1 or the 2 described compounds application in the medicine for preparing prevention or the treatment mammalian diseases relevant with the active unconventionality expression of histon deacetylase (HDAC); Described related mammalian disease with the active unconventionality expression of histon deacetylase (HDAC) is: cancer, neurodegenerative disease, virus infection, inflammation, malaria and mellitus.
5. one kind is suitable for the mammiferous pharmaceutical composition of orally give, comprises the compound and one or more pharmaceutically acceptable carriers or vehicle of claim 1 or 2.
6. one kind is suitable for parenteral and gives mammiferous pharmaceutical composition, comprises the compound and one or more pharmaceutically acceptable carriers or vehicle of claim 1 or 2.
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| CN102807526B (en) * | 2011-06-21 | 2015-12-02 | 寿光富康制药有限公司 | The preparation method of NSC 630176 ZYJ-D08a and epimer thereof and application |
| CN102659617B (en) * | 2012-04-27 | 2014-05-21 | 天津医科大学 | L-tyrosine derivative, medicine compound and application thereof |
| CN102746213B (en) * | 2012-05-18 | 2014-06-18 | 潍坊博创国际生物医药研究院 | Cinnamamide histone deacetylase inhibitor, preparation method thereof, and application thereof |
| CN103172540B (en) * | 2013-03-18 | 2015-07-01 | 潍坊博创国际生物医药研究院 | Phenylglycine histone deacetylase inhibitor as well as preparation method and applications thereof |
| CN103880745B (en) * | 2014-02-26 | 2018-12-04 | 南通大学 | A kind of chemical synthesis process of the bromo- 1,2,3,4- tetrahydroisoquinoline -1- formic acid of 6- |
| CN109666045A (en) * | 2017-10-13 | 2019-04-23 | 中蓝晨光化工研究设计院有限公司 | A kind of preparation method of DOPO methylolated derivatives DOPO-CH2OH |
| CN109020846B (en) * | 2018-07-25 | 2020-12-29 | 山东大学 | O-substituted tyrosine Bcl-2 protein inhibitor, preparation method and application thereof |
| CN109776414B (en) * | 2019-01-02 | 2022-04-22 | 山东大学 | Bcl-2 protein inhibitor and preparation method and application thereof |
| CN113527206B (en) * | 2020-04-17 | 2022-12-30 | 上海中泽医药科技有限公司 | Benzoazaheterocycle compound, preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999064442A1 (en) * | 1998-06-10 | 1999-12-16 | Istituto Di Ricerche Di Biologia Molecolare P Angeletti S.P.A. | Peptide inhibitors of hepatitis c virus ns3 protease |
| CN1832920A (en) * | 2003-08-08 | 2006-09-13 | 特兰斯泰克制药公司 | Aryl and heteroaryl compounds, compositions, and methods of use |
| WO2006095922A1 (en) * | 2005-03-10 | 2006-09-14 | Kyoto Pharmaceutical Industries, Ltd. | Tetrahydroisoquinoline compound and medicinal use thereof |
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| SI1776358T1 (en) * | 2004-07-28 | 2009-10-31 | Janssen Pharmaceutica Nv | Substituted propenyl piperazine derivatives as novel inhibitors of histone deacetylase |
| CN101723896B (en) * | 2009-11-03 | 2012-10-31 | 山东大学 | Tyrosine derivative histone deacetylases inhibitor and application thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999064442A1 (en) * | 1998-06-10 | 1999-12-16 | Istituto Di Ricerche Di Biologia Molecolare P Angeletti S.P.A. | Peptide inhibitors of hepatitis c virus ns3 protease |
| CN1832920A (en) * | 2003-08-08 | 2006-09-13 | 特兰斯泰克制药公司 | Aryl and heteroaryl compounds, compositions, and methods of use |
| WO2006095922A1 (en) * | 2005-03-10 | 2006-09-14 | Kyoto Pharmaceutical Industries, Ltd. | Tetrahydroisoquinoline compound and medicinal use thereof |
Non-Patent Citations (4)
| Title |
|---|
| Kane Timothy R. et al.Solid-Phase Synthesis of 1 |
| Kane, Timothy R. et al.Solid-Phase Synthesis of 1,2,3,4-Tetrahydroisoquinoline Derivatives Employing Support-Bound Tyrosine Esters in the Pictet-Spengler Reaction.《Journal of Combinatorial Chemistry》.2004,564-572. * |
| Ontoria, Jesus M. et al.The Design and Enzyme-Bound Crystal Structure of Indoline Based Peptidomimetic Inhibitors of Hepatitis C Virus NS3 Protease.《Journal of Medicinal Chemistry》.2004,6443-6446. * |
| 焦杰 等.一组新的N－羟基肉桂酰胺类组蛋白去乙酰化酶抑制剂的合成和初步活性研究.《中国药物化学杂志》.2008,250-253. * |
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