WO2008087514A2 - Inhibiteurs d'hdac - Google Patents

Inhibiteurs d'hdac Download PDF

Info

Publication number
WO2008087514A2
WO2008087514A2 PCT/IB2008/000045 IB2008000045W WO2008087514A2 WO 2008087514 A2 WO2008087514 A2 WO 2008087514A2 IB 2008000045 W IB2008000045 W IB 2008000045W WO 2008087514 A2 WO2008087514 A2 WO 2008087514A2
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
piperazine
carboxylate
oxoprop
amino
Prior art date
Application number
PCT/IB2008/000045
Other languages
English (en)
Other versions
WO2008087514A3 (fr
Inventor
Virendra Kachhadia
Narayanaswamy Punthalir
Thanasekaran Ponpandian
Prabhu Daivasigamani
Akella Satya Visweswara Srinivas
Uma Ramachandran
Sriram Rajagopal
Gaddam Om Reddy
Sridahran Rajagopal
Abdul Raheem Keeri
Original Assignee
Orchid Research Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Orchid Research Laboratories Limited filed Critical Orchid Research Laboratories Limited
Publication of WO2008087514A2 publication Critical patent/WO2008087514A2/fr
Publication of WO2008087514A3 publication Critical patent/WO2008087514A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom

Definitions

  • novel compounds of the formula (I) their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof.
  • the present invention more particularly provides novel compounds of the general formula (I).
  • the present invention also provides a process for the preparation of the above said novel compounds of the general formula (I), their derivatives, analogs, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts pharmaceutical compositions, metabolites and prodrugs thereof.
  • the present invention relates to potentially pharmaceutical compositions and in particular to new molecules as active ingredients, that are used in particular as anticancer agents.
  • Compounds of the general formula (I), or pharmaceutically acceptable salts thereof according to the present invention have an ability of inhibiting histone deacetylating enzyme and of inducing differentiation and are useful as therapeutic or ameliorating agent for diseases that are involved in cellular growth such as malignant tumors, autoimmune diseases, skin diseases, infections etc.
  • novel compounds (I) of the present invention are useful for the treatment of cancer, which is one of the leading causes of death in the present society.
  • a great deal of effort has been underway to treat various forms of cancer for decades and until recently, chemoprevention of cancer is receiving its due share of attention.
  • Cancer may affect people at all ages, but risks tends to increase with age, due to the fact that DNA damage becomes more apparent in the aging DNA.
  • Cancer is one of the principal causes of death in developed countries, more than 11 million people are diagnosed with cancer every year, and it is estimated that there will be 16 million new cases every year by 2020. Cancer causes 7 million deaths every year or 12.5% of deaths worldwide. Cancer particularly affects major portion of people in industrialized world than in the non-industrialized world.
  • Cancer is a disease of multifactorial origin characterized by uncontrolled division of cells; when the cancer cell faces spatial restrictions, due to uncontrolled proliferation in an organ of the body, the ability of the cell to invade other distinct tissues occurs by a process defined as "metastasis" the stage in which cancer cells are transported through the bloodstream or the lymphatic system.
  • PKI 166 is a dual inhibitor of EGF receptor (HER 1) as well as erbB (HER 2).
  • EGF-receptor and PTK787 potent inhibitors of VEGF-receptor 2 (KDR) are able to suppress tumor growth via suppression of tumor angiogenesis and also these agents have entered clinical trials in tumor patients (Michal et.al., Drug Discovery Today, 10, 2005, 839-846)
  • KDR potent inhibitors of VEGF-receptor 2
  • Transcriptional regulation is a major event in cell differentiation, proliferation and apoptosis. Transcriptional activation of a set of genes determines cell destination and for this reason transcription is tightly regulated by a variety of factors.
  • One of its regulatory mechanisms, involved in the process is an alteration in the tertiary structure of DNA, which affects transcription factors to their target DNA regiments.
  • Nucleosomal integrity is regulated by the acetylating status of the core histone, with the result being permissiveness to transcription.
  • the regulations of transcription factor are thought to involve by changes in the structure of chromatin. Changing its affinity of histone proteins for coiled DNA in the nuclesome alters the structure of chromatin.
  • hypo acetylated histones are believed to have greater affinity to the DNA and form a tightly bound DNA-histone complex and render the DNA inaccessible to transcriptional regulation.
  • the acetylating status of the histone is governed by the balance activities of the histone acetyl transferase (HAT) and histone deacetylase (HDAC).
  • HAT histone acetyl transferase
  • HDAC histone deacetylase
  • HDACs histone deacetylases
  • HDACs histone deacetylases
  • RPD 3 class I includes HDAC I, 2, 3, 8, and 11
  • Hda 1 class II includes HDAC 4, 6, 7, 9, and 10
  • All of the HDACs have a highly conserved zinc dependent catalytic domain.
  • HDAC inhibitors are promising reagents for cancer therapy as effective inducers of apoptosis.
  • HDACIs structural classes of HDAC inhibitors
  • Zolinza Vorinostat, SAHA
  • This invention relates to immuno suppressants, process for their production, their uses and pharmaceutical compositions.
  • the invention provides a novel class of compounds useful in the treatment or prevention of diseases or disorders mediated by interactions, particularly diseases associated with EDG receptor mediated signal transduction, infectious diseases and cancer.
  • An alteration in the EDG receptor activity contributes to the pathology and/or symptomology of these diseases.
  • molecules that themselves alter the activity of EDG receptors are useful as therapeutic agents in the treatment of such diseases; wherein, n is chosen from 0, 1 and 2; m is chosen from 1, 2 and 3; R ⁇ represents C ⁇ -ioaryl, and Cs-ioheteroaryl etc; wherein aryl or heteroaryl of Ri is optionally substituted.
  • R 2 , R 3 , R 4 and R 5 are independently chosen from hydrogen, halo, hydroxy, Ci-ioalkyl etc.
  • A represents -XiC(O)OR 7 .
  • Xi represents B is CRgR ⁇ >; Rg and R 9 are independently hydrogen.
  • E represents CR 8 or N;
  • X represents -XiC(O)NR 7 X 2 -.
  • Xi and X 2 represent a bond, Ci- 3 alkylene and C 2-3 alkylene; R 7 is hydrogen and Ci- ⁇ alkyl; and heteroarylene of X is optionally substituted by halo and Ci -6 alkyl.
  • This invention relates to novel cross-linkable, photoactive silane derivatives of the formula I.
  • silane derivative of formula I and mixtures thereof are used as orientation layers for liquid crystals and for the production of unstructured or structured optical elements and multiplayer systems; wherein, X 1 , X 2 and X 3 denote alkyl, alkoxy or halogen, but atleast one of these radicals is either alkoxy or halogen.
  • L denotes a single bond or linking functional groups such as O, COO, OOC, NR 1 , NR 1 -CO-, CO-NR 1
  • Z denotes -O- or -NR 4 - and R 4 denotes hydrogen or lower alkyl.
  • Ring A denotes piperazin-1,4- diyl.
  • K is an alkyl-OCO group having 1-20 carbon atoms, which is optionally substituted by fluorine, chlorine, cyano or nitro etc. III.
  • US 2004/0077726 Al discloses certain active carbamic acid compounds which inhibit HDAC activity and which have the following formula I
  • A is an aryl group
  • Q 1 is a covalent bond or an aryl leader group
  • R1 is a sulfonamido substituent; and
  • Q 2 is an acid leader group; with the provision that if J is
  • Ql is an aryl leader group; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof.
  • This invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit proliferative conditions, such as cancer and psoriasis.
  • Q 1 is a covalent bond
  • J is 2
  • Q 2 is phenylene-meta-trans-ethylene
  • the compounds have the following formula II, wherein R B m is as defined in the patent.
  • Cancer is now believed to be the number one cause of premature death in industrialized countries.
  • the market for anti-cancer agents was estimated at about US $ 85.3billion in 2010 and continues to escalate. Befause of the need and the value of these drugs, many laboratories are intensively investigating the nature and vulnerability of cancerous cells, resulting in the development of novel screens and approaches.
  • Histone acetylation and deacetylation play an essential role in modifying the chromatin structure and regulating gene expression in eukaryotic cells.
  • Hyperacetylated histones are generally found in transcriptionally active genes and in the transcriptionally silent regions of the genome.
  • Key enzymes, which modify histone proteins and thereby regulate gene expression, are histone acetyl transferases (HATs) and histone deacetylases (HDACs).
  • HATs histone acetyl transferases
  • HDACs histone deacetylases
  • HDAC inhibitors such as Trichostatin A (TSA), Trapoxin (TPX), Suberoylanilide hydroxamic acid (SAHA), Sodium butyrate (NaB), Sodium valproate (VPA), Cyclic hydroxamic acid containing peptides (CHAPs), Depsipeptide FK-228 and MS-275 can de-repress these genes, resulting in antiproliferative effects in vitro and antitumor effects in vivo.
  • TSA Trichostatin A
  • TPX Trapoxin
  • SAHA Suberoylanilide hydroxamic acid
  • NaB Sodium butyrate
  • VPA Sodium valproate
  • CHAPs Cyclic hydroxamic acid containing peptides
  • Depsipeptide FK-228 and MS-275 can de-repress these genes, resulting in antiproliferative effects in vitro and antitumor effects in vivo.
  • HDACs are primarily responsible for the manifestation of the disease and can selective inhibitors be developed to address these specific diseases? It is clear that somewhat selective agents can be developed that distinguishes at least the histone and nonhistone protein deacetylation process. As these more selective agents advance into clinical trials their utility will become apparent, but as discussed, their approval (efficacy in a disease state) may depend on effective combinations with other therapeutics to maximize the desired pharmacological benefit.
  • novel compounds of the formula (I) their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, solvates, pharmaceutically acceptable salts and pharmaceutical compositions, metabolites and prodrugs thereof,
  • Q 2 represents optionally substituted groups such as aryl, aralkyl, heterocyclyl, heteroaryl and benzofused heteroaryl groups.
  • Ri represents hydrogen and alkyl.
  • R 2 represents hydrogen, -CN, -COOH, -COOCH 3 , -COOEt, -
  • R, R 3 and R 4 may be same or different and independently represent hydrogen, hydroxy, alkyl, alkoxy, acetyl, cycloalkyl, or optionally substituted aryl, aryloxy, benzyloxy, heteroaryl, heterocyclyl and benzofused heteroaryl groups; k, 1 and m are integers in the range of O to 2.
  • A represents saturated or unsaturated heterocyclyl groups containing one or more hetero atoms selected from O, S and N such as pyrrolidinyl, thiazolidinyl, oxazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl and pyridazinyl;
  • Qi represents a bond, -NH, -CO,
  • Suitable groups substituted on A, R, R 3 , R 4 and Q 2 may be selected from halogens such as fluorine, chlorine, bromine, iodine; hydroxy; nitro; cyano; azido; nitroso; hydrazine; formyl; alkyl; alkoxy; haloalkyl; haloalkoxy; cycloalkyl; aryl; aryloxy; acyl; acyloxy; acyloxyacyl; heterocyclyl; heteroaryl; amino; monoalkylamino; dialkylamino; acylamino; alkoxycarbonyl; aryloxycarbonyl; alkylsulfonyl; arylsulfonyl; alkylsulfinyl; arylsulflnyl; alkylthio; arylthio; sulfamoyl; alkoxyalkyl groups and carboxylic acids or its derivatives; Wherein
  • R, R 3 , R 4 and Q 2 which are cyclic rings represents substituted or unsubstituted 5 to 10 membered ring systems, and also the rings may be monocyclic or bicyclic, saturated or partially saturated or aromatic containing 1 to 4 hetero atoms selected from O, S, N and the like.
  • Pharmaceutically acceptable salts include base addition salts such as alkali metal salts like Li, Na, and K salts; alkaline earth metal salts like Ca and Mg, salts of organic bases such as lysine, arginine, guanidine, diethanolamine, ⁇ -phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline and the like, ammonium or substituted ammonium salts, aluminum salts. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc.
  • Salts may include acid addition salts where appropriate, which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • Pharmaceutically acceptable solvates may be hydrates or comprising of other solvents of crystallization such as alcohols.
  • analog includes a compound, which differs from the parent structure by one or more C, N, O or S atoms.
  • a compound in which one of the N atoms in the parent structure is replaced by an S atom is an analog of the former.
  • stereoisomer includes isomers that differ from one another in the way the atoms are arranged in space, but whose chemical formulas and structures are otherwise identical. Stereoisomers include enantiomers and diastereoisomers.
  • tautomers include readily interconvertible isomeric forms of a compound in equilibrium.
  • the enol-keto tautomerism is an example.
  • polymorphs include crystallographically distinct forms of compounds with chemically identical structures.
  • pharmaceutically acceptable solvates includes combinations of solvent molecules with molecules or ions of the solute compound.
  • derivative refers to a compound obtained from a compound according to formula (I), an analog, tautomeric form, stereoisomer, polymorph, hydrate, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, by a simple chemical process converting one or more functional groups, such as, by oxidation, hydrogenation, alkylation, esterification, halogenation, and the like.
  • Representative compounds include:
  • the compound of the general formula (I) is prepared by the following procedure (Scheme 1): Step (I): The condensation of the compound of formula (Ia), with 1,1'carbonyl diimidazole and primary or secondary amine is carried out in the presence of solvents selected from toluene, DMF, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethyl acetate, o-dichlorobenzene or a mixture thereof, in the presence of bases such as triethylamine, diethylamine, pyridine, DMAP and alkali carbonates such as sodium carbonate, potassium carbonate and the like to afford the compound of formula (Ib).
  • the reaction is carried out at a temperature in the range of O 0 C to room temperature.
  • solvents such as toluene, tetrahydrofuran, DMF, chloroform, dichloromethane, dichloroethane, ethylacetate, o- dichlorobenz
  • a primary or secondary amine e.g. hydroxylamine hydrochloride, N-methoxy hydroxylamine hydrochloride, Ophenylenediamine, or 2-aminothiazole
  • an acid activating reagent such as BOP, DCC, EDCI, isobutyl chloroformate and the like in the presence of solvents mentioned above to afford a compound of the formula (I).
  • any reactive group in the substrate molecule may be protected according to the conventional chemical practice.
  • Suitable protecting groups in any of the above-mentioned reactions are those used conventionally in the art.
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
  • the pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 10 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, tetrahydrofuran, methanol, t-butanol, dioxane, isopropanol, ethanol etc.
  • Organic bases such as diethanolamine, ⁇ -phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline, guanidine and the like, ammonium or substituted ammonium salts, aluminum salts.
  • Amino acids such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine etc may be used for the preparation of amino acid salts.
  • acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid, oxalic acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, tetrahydrofuran, dioxane etc. Mixture of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid
  • compounds of the invention may contain groups that may exist in tautomeric forms, and though one form is named, described, displayed and/or claimed herein, all the forms are intended to be inherently included in such name, description, display and/or claim.
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form, in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomeric form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or by using chiral bases such as brucine, cinchona alkaloids, their derivatives and the like.
  • Prodrugs of the compounds of formula (I) are also contemplated by this invention.
  • a prodrug is an active or inactive compound that is modified chemically through in-vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient.
  • the suitability and techniques involved in making and using prodrugs are well known to those skilled in the art.
  • polymorphs of the compounds of the general formula (I), forming part of this invention may be prepared by crystallization of the compounds of formula (I) under different conditions. For example, using different commonly used solvents, or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Heating or melting the compounds followed by cooling gradually or immediately, one can also obtain polymorphs.
  • the presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry and powder X-ray diffraction or other such techniques.
  • solvates of the compounds of the formula (I) forming part of this invention may be prepared by conventional methods such as dissolving the compounds of the formula (I) in solvents such as water, methanol, ethanol, mixture of solvents such as acetone:water, dioxane:water, N,N- dimethylformamide:water and the like, preferably water and recrystallization by using different crystallization techniques
  • the present invention also provides a pharmaceutical composition, containing one or more of the compounds of the general formula (I) as defined above, their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, metabolites, prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like, useful for the treatment of cancer, psoriasis, proliferative conditions and conditions mediated by HDAC.
  • a pharmaceutical composition containing one or more of the compounds of the general formula (I) as defined above, their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, metabolites, prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like, useful for the treatment of cancer, psoriasis, proliferative conditions and conditions mediated by HDAC.
  • the derivatives provided by the present invention can be employed as pharmaceutical compositions, for example, in the form of pharmaceutical compositions containing the derivatives together with appropriate, pharmaceutically acceptable carriers.
  • the products in accordance with the invention can be administered, for example, perorally, such as in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, or rectally, such as in the form of suppositories, etc.
  • the compositions may be sterilized and may contain auxiliary agents generally employed in the pharmaceutical art, such as sodium hydrogen carbonate, citric acid, propylene glycol, tween 80, etc.
  • the compounds can be used orally or parenterally.
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • the compositions may be prepared by processes known in the art, such as by combining the ingredients into a dosage form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and if desired, the usual pharmaceutical adjuvants.
  • the amount of the active ingredient in the composition may be less than 70% by weight.
  • Such compositions typically contain from 1 to 25%, preferably 1 to 15% by ⁇ weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents, excipients or solvents.
  • Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like.
  • the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or alkali or alkaline earth metal salts of the compounds.
  • the injectable solutions prepared in this manner can then be, administered intravenously, intraperitoneal Iy, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
  • the effective dose for treating a particular condition in a patient may be readily determined and adjusted by the physician during treatment to alleviate the symptoms or indications of the condition or disease.
  • a daily dose of active compound in the range of about 0.01 to 1000 mg/kg of body weight is appropriate for administration to obtain effective results.
  • the daily dose may be administered in a single dose or divided into several doses. In some cases, depending upon the individual response, it may be necessary to deviate upwards or downwards from the initially prescribed daily dose.
  • Typical pharmaceutical preparations normally contain from about 0.2 to about 500 mg of active compound of formula I and/or its pharmaceutically active salts or solvates per dose.
  • the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents.
  • the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
  • therapeutically effective amount or “effective amount” refers to that amount of a compound or mixture of compounds of Formula I that is sufficient to effect treatment, as defined below, when administered alone or in combination with other therapies to a mammal in need of such treatment.
  • the term "animal” as used herein is meant to include all mammals, and in particular humans. Such animals are also referred to herein as subjects or patients in need of treatment.
  • the therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound of Formula I chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can readily be determined by one of ordinary skill in the art.
  • treatment means any treatment of a disease in a mammal, including: a) Preventing the disease, that is, causing the clinical symptoms of the disease not to develop; b) Inhibiting the disease, that is, slowing or arresting the development of clinical symptoms; and/or c) Relieving the disease, that is, causing the regression of clinical symptoms.
  • Anti-cancer screen Experimental drugs are screened for anti-cancer activity in three cell lines for their GI 5 0, TGI and LC50 values (using five concentrations for each compound). The cell lines are maintained in DMEM containing 10% fetal bovine serum. 96 well micro titer plates are inoculated with cells in 100 ⁇ L for 24 hours at 37°C, 5% CO2, 95% air and 100% relative humidity. 5000 HCT 116 cells/well, 5000 NCIH 460 cells/well and 5000 U251 cells/well are plated. A separate plate with these cell lines is also inoculated to determine cell viability before the addition of the compounds (T 0 ). Addition of experimental drugs:
  • mice Following 24-hour incubation, experimental drugs are added to the 96 well plates. Each plate contains one of the above cell lines and the following in triplicate: five different concentrations (0.01, 0.1, 1, 10 and 100 ⁇ M) of four different compounds, appropriate dilutions of a cytotoxic standard and control (untreated) wells. Compounds are dissolved in DMSO to make 20 mM stock solutions on the day of drug addition and frozen at -20 0 C. Serial dilutions of these 20 mM stock solutions are made in complete growth medium such that 100 ⁇ L of these drug solutions in medium, of final concentrations equaling 0.01, 0.1, 1, 10 and 100 ⁇ M can be added to the cells in triplicate. Standard drugs whose anti-cancer activity has been well documented and which are regularly used are doxorubicin and SAHA. End-point measurement;
  • GI 50 is the concentration required to decrease % growth by 50%; TGI is the concentration required to decrease % growth by 100% and LC 50 is the concentration required to decrease % cell death by 50%.
  • Histone Deacetylase (HDAC) Inhibition Assay using Boc-Lys (Ac)-AMC Substrate Inhibition of HDAC has been implicated to modulate transcription and to induce apoptosis or differentiation in cancer cells.
  • the fluorometric assay provides a fast and fluorescence based method that eliminates radioactivity, extractions or chromatography, as used in traditional assays. The assay is based on two steps. First, the HDAC fluorometric substrate, which comprises an acetylated lysine side chain, is incubated with a sample containing HDAC activity (Mouse Liver Extract).
  • Deacetylation of the substrate sensitizes the substrate, in the second step; treatment with the Trypsin stop solution produces a fluorophore that can be easily analyzed using fluorescence plate reader.
  • Assay was done in 96 well black microplate and total volume of the assay is 100 ⁇ L.
  • Mouse liver enzyme is diluted 1:6 with HDAC buffer.
  • Enzyme cocktail made of 10 ⁇ L of diluted enzyme and 30 ⁇ L of HDAC buffer. 40 ⁇ L of enzyme cocktail dispensed into each well. 10 ⁇ L of different concentrations of inhibitor added in to each well, except enzyme control well. Preincubated the plate at 30 0 C for 5 minutes.
  • the HDAC reaction is started by adding 50 ⁇ L of HDAC substrate ( ⁇ oc-Lys (Ac)-AMC Substrate) solution. Incubated the plate at 30 0 C for 30 minutes. Adding 100 ⁇ L of Trypsin stop solution stops the reaction. The plate is incubated again at 30 0 C for 20-30 minutes. The release of AMC is monitored by measuring the fluorescence at excitation wavelength of 365 or 360 nm and emission wavelength of 440 or 460 nm. Buffer and substrate alone kept for blank subtraction. (Dennis Wegener et al, Anal. Biochem, 321, 2003, 202-208).

Abstract

L'invention concerne de nouveaux composés de formule (I), leurs dérivés, analogues, formes tautomères, stéréo-isomères, polymorphes, hydrates, solvates et sels pharmaceutiquement acceptables, ainsi que des compositions, des métabolites et des promédicaments contenant ceux-ci. Ces nouveaux composés peuvent inhiber les HDAC et sont utiles comme agent thérapeutique ou d'amélioration pour des maladies impliquées dans la croissance cellulaire, telles que tumeurs malignes, maladies auto-immunes, maladies de la peau, infections, inflammation, cancer, psoriasis, états prolifératifs et états à médiation par HDAC.
PCT/IB2008/000045 2007-01-17 2008-01-10 Inhibiteurs d'hdac WO2008087514A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN92CH2007 2007-01-17
IN92/CHE/2007 2007-01-17

Publications (2)

Publication Number Publication Date
WO2008087514A2 true WO2008087514A2 (fr) 2008-07-24
WO2008087514A3 WO2008087514A3 (fr) 2009-02-19

Family

ID=39636436

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2008/000045 WO2008087514A2 (fr) 2007-01-17 2008-01-10 Inhibiteurs d'hdac

Country Status (1)

Country Link
WO (1) WO2008087514A2 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2236503A1 (fr) * 2009-04-03 2010-10-06 NatureWise Biotech & Medicals Corporation Composants cinnamiques et dérivés de celui-ci pour l'inhibition de l'histone désacétylase
CN101857554A (zh) * 2009-04-03 2010-10-13 彦臣生技药品股份有限公司 抑制组蛋白去乙酰化酶的肉桂化合物和其衍生物
JP2011526936A (ja) * 2008-09-17 2011-10-20 エフ．ホフマン−ラ ロシュ アーゲー 癌の処理のための新規オルト−アミノアニリド
WO2013154870A1 (fr) 2012-04-10 2013-10-17 Annji Pharmaceutical Co., Ltd. Inhibiteurs d'histone désacétylases (hdac)
US9745253B2 (en) 2015-03-13 2017-08-29 Forma Therapeutics, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
WO2018213364A1 (fr) 2017-05-16 2018-11-22 Annji Pharmaceutical Co., Ltd. Inhibiteurs des histone désacétylases (hdac)
WO2021252475A1 (fr) 2020-06-08 2021-12-16 Annji Pharmaceutical Co., Ltd. Dérivés de quinazoline utiles en tant qu'inhibiteurs sélectifs de hdac6
CN116375698A (zh) * 2023-06-05 2023-07-04 中国林业科学研究院林产化学工业研究所 具有靶向抗肿瘤活性的新型漆酚基异羟肟酸型hdac抑制剂及其制备方法和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4894386A (en) * 1987-04-15 1990-01-16 Ici Americas Inc. Aliphatic carboxamides
WO2003073999A2 (fr) * 2002-03-01 2003-09-12 Pintex Pharmaceuticals, Inc. Composes de modulation de pin1 et procedes d'utilisation correspondant
WO2006016680A1 (fr) * 2004-08-09 2006-02-16 Astellas Pharma Inc. Composés d'hydroxyamide présentant une activité en tant qu'inhibiteurs d'histone désacétylase (hdac)

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4894386A (en) * 1987-04-15 1990-01-16 Ici Americas Inc. Aliphatic carboxamides
WO2003073999A2 (fr) * 2002-03-01 2003-09-12 Pintex Pharmaceuticals, Inc. Composes de modulation de pin1 et procedes d'utilisation correspondant
WO2006016680A1 (fr) * 2004-08-09 2006-02-16 Astellas Pharma Inc. Composés d'hydroxyamide présentant une activité en tant qu'inhibiteurs d'histone désacétylase (hdac)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011526936A (ja) * 2008-09-17 2011-10-20 エフ．ホフマン−ラ ロシュ アーゲー 癌の処理のための新規オルト−アミノアニリド
EP2236503A1 (fr) * 2009-04-03 2010-10-06 NatureWise Biotech & Medicals Corporation Composants cinnamiques et dérivés de celui-ci pour l'inhibition de l'histone désacétylase
CN101857554A (zh) * 2009-04-03 2010-10-13 彦臣生技药品股份有限公司 抑制组蛋白去乙酰化酶的肉桂化合物和其衍生物
JP2011020999A (ja) * 2009-04-03 2011-02-03 Genshin Seigi Yakuhin Kofun Yugenkoshi ヒストン脱アセチル化酵素を阻害するためのシナミック化合物とその誘導体
WO2013154870A1 (fr) 2012-04-10 2013-10-17 Annji Pharmaceutical Co., Ltd. Inhibiteurs d'histone désacétylases (hdac)
US9387209B2 (en) 2012-04-10 2016-07-12 Annji Pharmaceutical Co., Ltd. Histone deacetylases (HDACs) inhibitors
US9745253B2 (en) 2015-03-13 2017-08-29 Forma Therapeutics, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
US10266487B2 (en) 2015-03-13 2019-04-23 Forma Therapeutics, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
US10508077B2 (en) 2015-03-13 2019-12-17 Forma Therapeutics, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
US10988441B2 (en) 2015-03-13 2021-04-27 Valo Early Discovery, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
US11919839B2 (en) 2015-03-13 2024-03-05 Valo Health, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
WO2018213364A1 (fr) 2017-05-16 2018-11-22 Annji Pharmaceutical Co., Ltd. Inhibiteurs des histone désacétylases (hdac)
WO2021252475A1 (fr) 2020-06-08 2021-12-16 Annji Pharmaceutical Co., Ltd. Dérivés de quinazoline utiles en tant qu'inhibiteurs sélectifs de hdac6
CN116375698A (zh) * 2023-06-05 2023-07-04 中国林业科学研究院林产化学工业研究所 具有靶向抗肿瘤活性的新型漆酚基异羟肟酸型hdac抑制剂及其制备方法和应用
CN116375698B (zh) * 2023-06-05 2023-08-01 中国林业科学研究院林产化学工业研究所 具有靶向抗肿瘤活性的漆酚基异羟肟酸型hdac抑制剂及其制备方法和应用

Also Published As

Publication number Publication date
WO2008087514A3 (fr) 2009-02-19

Similar Documents

Publication Publication Date Title
RU2453536C2 (ru) Ингибиторы гистондезацетилазы
EP1786773B1 (fr) Derives d'isoindolin-1-one
WO2008087514A2 (fr) Inhibiteurs d'hdac
US20050209195A1 (en) Indolinone derivatives
US8263044B2 (en) Stilbene like compounds as novel HDAC inhibitors
EA011087B1 (ru) Соединения и фармацевтические композиции для лечения воспалительных заболеваний
PT1995242E (pt) Novos derivados de 1,2,3,4-tetra-hidroquinoxalina tendo actividade de ligação ao receptor de glucocorticóides
KR20030077551A (ko) 항종양제로서의 테트랄론 유도체
JP2009242437A (ja) スルホンアミド誘導体
WO2008113255A1 (fr) Dérivés de benzamide avec activité antiproliférative, leurs préparations pharmaceutiques
WO2007017728A2 (fr) Nouveaux composes heterocycliques
GB2441396A (en) Indoline sulfonamide compounds
WO2017045271A1 (fr) Dérivés de benzofuranne, leur procédé de préparation et leur utilisation thérapeutique
WO2007045962A2 (fr) Nouveaux inhibiteurs hdac
BRPI0915513B1 (pt) compostos derivados de ácido fenóxi-cromano carboxílico 6-substituído, composições farmacêuticas compreendendo os referidos compostos, uso dos mesmos, e processo para a preparação destes
CZ20014637A3 (cs) Substituované fenoxyoctové kyseliny
JP2011519966A (ja) 新規なｎ−（２−アミノ−フェニル）−アクリルアミド
CA2663943A1 (fr) Composes pour le traitement de troubles du metabolisme
TW201934547A (zh) 一種嘧啶類化合物、其製備方法及其醫藥用途
CA2787860C (fr) 2-imidazolidones substitues et analogues et leur utilisation contre le cancer
WO2022021683A1 (fr) Composé alcaloïde indolique, procédé de préparation associé et application associée
EP4008716A1 (fr) Nouveaux inhibiteurs des protéines de liaison de l'arnm du facteur de croissance 2 de type insuline
JP2007501833A (ja) 新規なオキサゾールと、その製造方法と、その薬剤としての利用法
WO2007113644A2 (fr) Nouveaux inhibiteurs d'hdac
KR100399364B1 (ko) 사이클린 의존 키나아제의 저해제로서 유용한3-히드록시-6-아미노-크로멘-4-온 유도체

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08702209

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08702209

Country of ref document: EP

Kind code of ref document: A2