[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2012117421A1 - Inhibiteurs de l'histone désacétylase - Google Patents

Inhibiteurs de l'histone désacétylase Download PDF

Info

Publication number
WO2012117421A1
WO2012117421A1 PCT/IN2012/000147 IN2012000147W WO2012117421A1 WO 2012117421 A1 WO2012117421 A1 WO 2012117421A1 IN 2012000147 W IN2012000147 W IN 2012000147W WO 2012117421 A1 WO2012117421 A1 WO 2012117421A1
Authority
WO
WIPO (PCT)
Prior art keywords
carboxamide
hydroxy
fluorophenyl
acryloyl
tetrahydroisoquinoline
Prior art date
Application number
PCT/IN2012/000147
Other languages
English (en)
Inventor
Sridharan Rajagopal
Narasimhan Kilambi
Virendra Kachhadia
Suresh Rathinasamy
Gopalan Balasubramanian
Umamaheswari Mani
Nirmala RAJAGOPALAN
Judy Auxcilia PUSHPARAJ
Anshu Mittal Roy
Lolaknath Santosh Vishwakarma
Shridhar Narayanan
Vadivel KALIYAMOORTHY
Ponpandian Thanasekaran
Rama THATAVARTHY KRISHNA
Kalaivani KANNAN
Jayanarayan Kulathingal
Jeyamurugan Mookkan
Srinivasan Chidambaram Venkateswaran
Fakrudeen AHAMED ALI
Original Assignee
Orchid Research Laboratories Ltd
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 Ltd filed Critical Orchid Research Laboratories Ltd
Publication of WO2012117421A1 publication Critical patent/WO2012117421A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Described herein are compounds as isoform selective histone deacetylase inhibitors, their derivatives, analogs, tautomeric forms, stereoisomers, geometrical isomers, diastereomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, metabolites, intermediates and prodrugs thereof, the preparation of these compounds, the pharmaceutical compositions comprising these compounds and the use of these compounds for treating various diseases.
  • Transcriptional regulation is a major event in cell differentiation, proliferation and apoptosis.
  • Particularly the regulations of transcription factor are thought to involve by changes in the structure of chromatin. Changing the affinity of histone proteins for coiled DNA in the nucleosome alters the structure of chromatin. Hypoacetylated 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 balancing activities of the histone acetyl transferase (HAT) and histone deacetylase (HDAC).
  • HAT histone acetyl transferase
  • HDAC histone deacetylase
  • HDACs Human HDACs are classified into two distinct classes, the HDACs and sirtuins.
  • the HDACs are further divided into two subclasses based on their similarity to yeast histone deacetylases, Rpd3 (class I includes HDAC 1, 2, 3, 8 and 1 1) and Hdal (class II includes HDAC 4, 5, 6, 7, 9 and 10).
  • Rpd3 class I includes HDAC 1, 2, 3, 8 and 1 1
  • Hdal class II includes HDAC 4, 5, 6, 7, 9 and 10
  • Biochemically all of these HDACs have a highly conserved zinc dependent catalytic domain, while Class- Ill (SIRTl -7) are dependent on nicotinamide adenine dinucleotide (NAD+) (Langley B., et al., Current Drug Targets-CNS & Neurological Disorders, 2005, 4, 41-50).
  • NAD+ nicotinamide adenine dinucleotide
  • SAHA Suberoylanilide hydroxamic acid
  • CCL cutaneous T-cell lymphoma
  • FDA Food and Drug Administration
  • HDAC inhibitors in clinical trials are Entinostat (MS-275), Belinostat (PXD101), Resminostat (4SC-201), Mocetinostat (MGCD0103), Panobinostat (LBH589), Sodium butyrate (NaB), Sodium valproate (VPA), Cyclic hydroxamic acid containing peptides (CHAPs), PCI-24781, J J-26481585 etc. (Tan J., et al., Journal of Hematology & Oncology, 2010, 3(5), 1-13).
  • HDAC inhibitors were shown to have both pro- and antiinflammatory effects in a wide range of inflammation relevant cell types. These inhibitors have shown promising effects in animal models in variety of inflammatory diseases such as arthritis, inflammatory bowel disease, septic shock, granuloma, airways inflammation and asthma. ITF2357 is found to reduce the production of proinflammatory cytokines in vitro and systemic inflammation in vivo (Halili M.A., et al., Current Topics in Medicinal Chemistry, 2009, 9, 309-319; Bonfils C, et al., Expert Opinion on Drug Discovery, 2008, 3, 1041-1065).
  • EDP-0334 is in the late preclinical stage for the treatment of Alzheimer's disease and other related CNS disorders (Hahnen E., et al., Expert Opinion on Investigational Drugs, 2008, 17(2), 169-184; Kazantsev A.G., et al., Nature Reviews Drug Discovery, 2008, 7, 854-868; Bonfils C, Expert Opinion on Drug Discovery, 2008, 3, 1041-1065).
  • pan-HDAC inhibitors Most of the above mentioned compounds are pan-HDAC inhibitors. At present, isoform selective HDAC inhibitors are gaining importance in treating various diseases such as inflammation, CNS disorders etc., since these might have better toxicological profile and more disease specific (Butler .V., et al., Current Pharmaceutical Design, 2008, 14, 505-528; Hahnen E., et al., Expert Opinion on Investigational Drugs, 2008, 17(2), 169-184).
  • HDACl mostly involves in cancer related problems/diseases.
  • the over-expression of HDACl mediates the reduction in the expression of p53 and pVHL (von Hippel Lindau protein), which results in the over-expression of HIF- ⁇ and its transcriptional target Vascular endothelial growth factor (VEGF).
  • VEGF Vascular endothelial growth factor
  • TSA HDACi Trichostatin-A
  • Some of the examples of HDACl selective inhibitors are trapoxin-A, SB-429201, MS275 and MGCD0103.
  • HDAC3 is another isoform which is involved in inflammatory diseases (Zhu H., et al., Journal of Biological Chemistry, 2010, 285, 9429-9436) and CNS disorders.
  • Triazol-4-ylphenyl bearing benzamide compounds are found to be HDAC3 selective inhibitors (He R., et al., Journal of Medicinal Chemistry, 2010, 53, 1347-1356).
  • Repligen Corporation disclosed the SAR and HDAC3 activity of the compounds including pimelic acid derivatives as HDAC inhibitors (WO2010028193A1). Recently in 2010, Repligen Corporation received orphan drug approval for their HDAC3 isoform selective compound (RG2833) to treat Friedreich's ataxia.
  • HDAC6 which is a cytoplasmic enzyme that mediates wide range of cellular functions including microtubule-dependent trafficking and signalling, ubiquitin level sensing, regulation of chaperone levels and responses to oxidative stress.
  • Over expression of HDAC6 has been identified in a variety of cancer cell lines and mouse tumor models. The up-regulation of HDAC6 in diverse tumors and cell lines are widely investigated (Aldana-Masangkay G.I., et al., Journal of Biomedicine and Biotechnology, 2011, ID875824, 1-10).
  • the miss folded protein clearance by formation of aggresomes and autophagy with the help of ubiquitin-binding HDAC6 looks promising for developing small isoform selective molecules for treating cancer.
  • Inhibition of HDAC6 can promote survival and regeneration of neurons.
  • HDAC6 a potential non-toxic therapeutic target for ameliorating CNS injury characterized by oxidative stress induced neurodegeneration and insufficient axonal regeneration (Rivieccio M.A., et al., Proceedings of the National Academy of Sciences, 2009, 106(46), 19599-19604).
  • a selective HDAC6 inhibitor, Tubastatin-A exhibited promising neuroprotective activity.
  • HDAC8 Another important isoform HDAC8, which belongs to Class-I family, have clinical relevance in neuroblastoma biology, a highly malignant embryonal childhood cancer (Oehme I., et al., Expert Opinion on Investigational Drugs, 2009, 18(1 1), 1605- 1617).
  • Linkerless hydroxamic acids are found to be HDAC8 isoform selective (Butler K.V., et al., Current Pharmaceutical Design, 2008, 14, 505-528).
  • WO2005108367A1 discloses the compounds for treatment of neurodegenerative diseases
  • WO2006010749A2 and WO2007082874A1 discloses following compounds, which have histone deacetylase inhibiting enzymatic activity,
  • One objective herein is to provide compound of the formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, geometrical isomers, diastereomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, metabolites, intermediates and prodrugs thereof for the treatment of various cancers viz. liquid or solid tumours such as cancer of colon, pancreas, breast, etc.
  • Another objective herein is to provide a method of preventing or treating proliferative diseases or cancers.
  • Yet another objective herein is to provide a method of preventing or treating CNS disorders including but not limited to Huntington's disease, Parkinson's disease, Alzheimer's disease, Friedreich's ataxia and stroke by administering a therapeutic amount of compound of the formula (I).
  • Another objective is to provide a method of preventing or treating immune & inflammatory conditions.
  • Another objective herein is to provide a pharmaceutical composition containing compounds described herein.
  • Another objective herein is to provide a process for the preparation of compounds described herein.
  • Another object of the present invention is to provide a compound of potent isoform selective/ pan HDAC inhibitor; and/or an improved method for inhibiting HDACs in a cell; and/or an improved method for the treatment of a condition mediated by HDACs; and/or a method of treatment and/or prevention of proliferative condition or cancer; and/or a method of treatment and/or prevention of inflammatory disorders; and/or a method of treatment and/or prevention of neurodegenerative disorders; and/or a method of treatment and/or prevention of cancer induced bone pain; or at least to provide the public with a useful choice.
  • a X fp CONH R (I) its derivatives, analogs, tautomeric forms, stereoisomers, geometrical isomers, diastereomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, metabolites, intermediates and prodrugs thereof.
  • Ar represents substituted or unsubstituted groups selected from (C 6 -Ci4)aryl, 5- 15 membered heterocyclyl and 5-15 membered heteroaryl;
  • Ar 1 represents optionally substituted groups selected from (C 6 -Ci4)aryl, 5-15 membered heterocyclyl and 5-15 membered heteroaryl;
  • Ar 2 represents substituted or unsubstituted groups selected from (Ci- C 6 )alkylene, (Ce-C ⁇ arylene and 5-15 membered heteroarylene;
  • B represents hydrogen, -COOR 1 , -CONR'R 2 , -CH S NR'R 2 , -CH S OR 1 , -CH 2 OCONR'R 2 , -CH 2 NR'C0R 2 , substituted or unsubstituted groups selected from (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -Ci 4 )aryl and (C 3 -Ci 2 )cycloalkyl;
  • B 1 represents hydrogen, -COOR 1 , -CONR , -CH Z NR'R, -CH 2 0R', -CH 2 0C0NR'R 2 , -CH ⁇ R ⁇ OR 2 , substituted or unsubstituted groups selected from (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -Ci 4 )aryl and (C 3 -Ci 2 )cycloalkyl;
  • D represents hydrogen, -COOR 1 , -CONR ! R 2 , -CHbNR ⁇ , -CH 2 0R 1 , -CH 2 0C0NR 1 R 2 , -CH ⁇ R ⁇ OR 2 , substituted or unsubstituted groups selected from (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -Ci 4 )aryl and (C 3 -Ci 2 )cycloalkyl;
  • R 1 represents hydrogen, substituted or unsubstituted groups selected from (Cj- C 6 )alkyl, (C 3 -C 12 )cycloalkyl, 5-15 membered heterocyclyl, (C 6 -Ci4)aryl, (C 6 - (C 6 -Ci 4 )aryl(C 2 -C 6 )alkenyl, (C 6 -Ci 4 )aryl(C 2 -C 6 )alkynyl, 5-15 membered heteroaryl, 5-15 membered heteroaryl(Ci-C 6 )alkyl, 5-15 membered heteroaryl(C 2 -C 6 )alkenyl and 5-15 membered heteroaryl(C 2 -C6)alkynyl;
  • R 2 represents hydrogen, substituted or unsubstituted groups selected from (Q- C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -Ci 2 )cycloalkyl, 5-15 membered heterocyclyl, (C 6 -C I4 )aryl, (C 6 -Ci 4 )aryl(Ci-C 6 )alkyl, (C 6 -Ci 4 )aryl(C 2 -C 6 )alkenyl, (C 6 - Ci4)aryl(C 2 -Ce)alkynyl, 5-15 membered heteroaryl, 5-15 membered heteroaryl(Ci- C 6 )alkyl, 5-15 membered heteroaryl(C 2 -C 6 )alkenyl and 5-15 membered heteroaryl(C 2 - C 6 )alkynyl; or R 1 and R 2 combine together to form substitute
  • B 1 or D when one of B 1 or D is hydrogen or unsubstituted alkyl, the other is neither of hydrogen nor of unsubstituted alkyl;
  • X represents a bond, -CO-, -S0 2 -, -CS-, -CH 2 -, -CONR 3 -, -CONR 3 CH 2 -, -CH 2 OCO-, -CONR 3 CO-, -CH 2 NR 3 CO-, -CH 2 NR 3 - or -CH 2 NR 3 CH 2 -; wherein R 3 represents hydrogen or substituted or unsubstituted groups selected from (Ci-C 6 )alkyl and (C3-Ci 2 )cycloalkyl; re resents substituted or unsubstituted groups selected from
  • W, W 1 , W 2 , W 3 and W 4 independently represent C or N;
  • ring Q 1 is a substituted or unsubstituted 4 to 8 membered heterocyclyl ring;
  • R 4 represents hydrogen, halogen, hydroxy, nitro, amino, cyano or substituted or unsubstituted (Ci-C6)alkyl, amino(Ci-C 6 )alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy and halo(C i -C 6 )alkoxy;
  • R represents -OH, ortho substituted aniline or substituted or unsubstituted group selected from aminoaryl and hydroxyaryl;
  • provided herein is the method of inhibiting the histone deacetylase enzyme comprising administering therapeutically effective amount of compound of formula (I).
  • composition comprising compound of formula (I).
  • the compound of formula (I) for use in the treatment of proliferative conditions or cancer in combination with other clinically relevant cytotoxic agents or non-cytotoxic agents or radiation or monoclonal antibodies.
  • the compound of formula (I) for use in the treatment of proliferative conditions or cancer selected from lung cancer, non- small-cell lung cancer (NSCLC), small cell lung cancer (SCLC), colon cancer, fibrosarcoma, kidney cancer, lymphoma, leukemia, skin cancer, pancreatic cancer, breast cancer, prostate cancer, bone cancer, oral cancer, multiple myeloma, brain cancer, head and neck cancer, ovarian cancer, gastric cancer, liver cancer, cervical cancer, solid tumors, cutaneous T-cell lymphoma (CTCL), acute myeloid leukemia, chronic lymphocytic leukemia and acute lymphoblastic leukemia.
  • NSCLC non- small-cell lung cancer
  • SCLC small cell lung cancer
  • colon cancer fibrosarcoma
  • kidney cancer lymphoma
  • leukemia skin cancer
  • pancreatic cancer breast cancer
  • prostate cancer prostate cancer
  • oral cancer multiple myeloma
  • brain cancer head and neck cancer
  • ovarian cancer gastric cancer
  • liver cancer cervical
  • the compound of formula (I) for use in the treatment of the inflammatory diseases, comprising rheumatoid arthritis, inflammatory bowel disease, psoriasis, dermatitis, granuloma, uveitis, chronic obstructive pulmonary disease (COPD), ulcerative colitis, Crohn's disease, multiple sclerosis and sepsis.
  • inflammatory diseases comprising rheumatoid arthritis, inflammatory bowel disease, psoriasis, dermatitis, granuloma, uveitis, chronic obstructive pulmonary disease (COPD), ulcerative colitis, Crohn's disease, multiple sclerosis and sepsis.
  • the compound of formula (I) for use in the treatment of neurodegenerative disorders selected from Huntington's disease, Alzheimer's disease, Parkinson's disease, Friedreich's ataxia and stroke.
  • the compound of formula (I) described herein is efficiently transported across the blood brain barrier (BBB).
  • BBB blood brain barrier
  • A represents
  • Ar represents substituted or unsubstituted groups selected from (C 6 - Ci4)aryl or 5-15 membered heteroaryl;
  • Ar represents substituted or unsubstituted (C6-C )4 )aryl
  • Ar represents substituted or unsubstituted 5-15 membered heterocyclyl or 5-15 membered heteroaryl
  • X represents -CO-, -CH 2 - -CONR 3 -, -CONR 3 CH 2 - -S0 2 - or -NR 3 CO-;
  • X represents -CO- -CH 2 - -CONR 3 - or -CONR 3 CH 2 -; In one embodiment, X represents -CO- or -CH 2 -;
  • X represents -CO-, -CONR -, -NR CO- -CONR 3 CH 2 -;
  • ring Q 1 represents piperidinyl, piperazinyl, pyrrolidinyl azepan
  • the group is selected from,
  • R represents OH or
  • Ar represents phenyl, naphthyl, benzo[d][l,3]dioxolyl, indolyl, pyridyl, quinolinyl or thienyl;
  • Ar 1 represents phenyl, naphthyl, benzo[d][l,3]dioxolyl, indolyl, pyridyl, quinolinyl or thienyl;
  • X represents -CO-, -CH 2 - -CONH- or -CONHCH 2 -;
  • A represents ;
  • Ar a represents substituted or unsubstituted groups selected from (C6-Cio)aryl, 5- 10 membered heterocyclyl and 5-10 membered heteroaryl;
  • Ar la represents optionally substituted groups selected from (C 6 -Qo)aryl, 5-10 membered heterocyclyl and 5-10 membered heteroaryl;
  • Ar 2a represents substituted or unsubstituted groups selected from (C 6 -
  • B represents hydrogen, substituted or unsubstituted groups selected from (Ci- C 6 )alkyl and (C 3 -C 6 )cycloalkyl;
  • B l represents hydrogen, -CONR la R 2a , substituted or unsubstituted groups selected from (Ci-C 6 )alkyl and (C 3 -C 6 )cycloalkyl;
  • D a represents hydrogen, -COOR la , -CONR ,a R 2a , substituted or unsubstituted groups selected from (Ci-Ce)alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -Ci 0 )aryl and (C 3 -C 6 )cycloalkyl;
  • B la or D a when one of B la or D a is hydrogen or unsubstituted alkyl, the other is neither of hydrogen nor of unsubstituted alkyl;
  • R la represents hydrogen, substituted or unsubstituted groups selected from (Ci-C 6 )alkyl and (C 3 -C 6 )cycloalkyl;
  • R 2 represents hydrogen, substituted or unsubstituted groups selected from (Ci-C 6 )alkyl and (C 3 -C 6 )cycloalkyl; or R Ia and R 2a combine together to form substituted or unsubstituted 3-7 membered ring having 0-3 heteroatoms selected from O, S and N;
  • X a represents a bond, -CO-, -CH 2 -, -CONR 3a -, -CONR 3a CH 2 - or -CH 2 NR 3a -;
  • 3 a represents hydrogen, (Ci-C 6 )alkyl or (C3-C6)cycloalkyl;
  • T represents C, S, O or N
  • W lb represents C, S, O or N
  • W 2b represents C or N
  • W 3b represents C or N
  • a is an integer selected from 1 and 2;
  • b at each occurence is independently selected from an interger 0 and 1 ;
  • R 4 represents hydrogen, halogen, hydroxy, nitro, amino, cyano or substituted or unsubstituted groups selected from (Ci-C6)alkyl, amino(C]-C6)alkyl, halo(C]-C 6 )alkyl, (Ci-C6)alkoxy and halo(Ci-Ce)alkoxy;
  • R x represents OH or
  • substituents are one or more groups, selected from halogens, hydroxy, nitro, cyano, amino, formyl, (Ci-Ce)alkyl, halo(Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, halo(Ci-C 6 )alkoxy, (C 6 -Ci4)arylalkoxy, (C3-Ci )cycloalkyloxy, (C6-Ci 4 )aryl, (C 6 -Ci 4 )aryloxy, (Ci-C 6 )alkylamino, -COOR a , -C(0)R b , -C(0)NR a R b , -NR a C(0)NR b R c , -NR a C(S) R b R°, -N(R a )SOR b , -N(R a )S0 2 R b , -NR a C(0)
  • a a represents In another embodiment, A represents ;
  • Ar 2a represents (C6-Ci 0 )arylene
  • T represents C, O, S or N;
  • W la represents C, O, S or N;
  • W 2a represents C or N
  • a is an integer selected from 1 and 2;
  • b at each occurence is independently selected from integer 0 and 1;
  • W 3a represents C or N
  • described herein is the compound of formula (Ila), (lib), (lie), (lid), (He), (Ilf) or (Ilg), derived from compound of formula (I).
  • the hydrogen atom in -CH-, -CH 2 -, -NH- optionally be replaced with the groups, not limited to, halogen, hydroxy, nitro, cyano, amino, formyl, substituted or unsubstituted groups selected from (C[-C6)alkyl, halo(Q- C 6 )alkyl, (Ci-C6)alkoxy, halo(C 1 -C6)alkoxy, (C6-Ci4)arylalkoxy, (C 3 -Ci 2 )cycloalkyl, (C6-Ci 4 )aryl, (C6-Ci4)aryloxy and the like.
  • the -CH 2 - groups can be alkylene chain such as -CH 2 - -CH 2 -CH 2 - -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH(CH 3 )-, -CH 2 -CH(CH 3 )-CH 2 - and the like.
  • the ⁇ - ⁇ or ⁇ - ⁇ can have zero, one or more substituents.
  • (Ci-C6)alkyl refers to straight or branched aliphatic hydrocarbon groups having the specified number of carbon atoms, which are attached to the rest of the molecule by a single atom, which may be optionally substituted by one or more substituents. Examples include, without limitation, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, t-butyl, pentyl and hexyl.
  • (Ci-C 6 )alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, which may be optionally substituted by one or more substituents. Examples include, without limitation, methylene, ethylene, isopropylene, n-propylene, n-butylene, isobutylene, t-butylene, pentylene and hexylene.
  • (C6-Ci4)aryl refers to aromatic radicals having 6 to 14 carbon atoms, which may be optionally substituted by one or more substituents.
  • “(C6-Ci4)aryl” moiety is (C6-Cio)aryl. Examples include, without limitation, phenyl, naphthyl, indanyl and biphenyl.
  • heterocyclyl refers to a stable 5 to 15 membered ring radical, which consists of carbon atoms and one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be monocyclic, bicyclic, tricyclic or polycyclic ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated.
  • heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure, which may be optionally substituted by one or more substituents.
  • “5-15 membered heterocyclyl” moiety includes 5-10 membered heterocyclyl.
  • Examples include, without limitation, azetidinyl, acridinyl, benzodioxolyl, benzo[d][l,3]dioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, homopiperazinyl, 2-oxoazepinyl, azepinyl, pyrrolyl
  • 5-15 membered heterocyclyl are selected from benzo[d][l,3]dioxolyl, benzothiazolyl, benzoxazolyl, thienyl, furyl, pyrrolyl, thiazolyl, indolyl, isoindolyl, mo holinyl, quinolyl, isoquinolyl, oxazolyl, pyridinyl and pyrimidinyl.
  • 5-15 membered heteroaryl refers to an aromatic heterocyclyl ring radical as defined above.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of stable structure.
  • “5-15 membered heteroaryl” moiety is 5-10 membered heteroaryl.
  • (C 6 -Ci4)arylene or “5-15 membered heteroarylene” refers to bivalent aryl or heteroaryl respectively.
  • arylene include, without limitation, phenylene, naphthylene and indanylene.
  • heteroarylene include, without limitation, benzo[d][l,3]dioxolylene, benzothiazolylene, benzoxazolylene, thienylene, furylene, pyrrolylene, thiazolylene, indolylene, isoindolylene, morpholinylene, quinolylene, isoquinolylene, oxazolylene, pyridinylene and pyrimidinylene.
  • (C3-Ci2)cycloalkyl refers to non-aromatic mono or polycyclic ring system of about 3 to 12 carbon atoms, which may be optionally substituted by one or more substituents.
  • the polycyclic ring denotes hydrocarbon systems containing two or more ring systems with one or more ring carbon atoms in common i.e. a spiro, fused or bridged structures.
  • “(C 3 -Ci 2 )cycloalkyl” moiety is "(C 3 -C6)cycloalkyl”.
  • Examples include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, perhydronaphthyl, adamantyl, homoadamantyl, noradamantyl and norbornyl groups, bridged cyclic groups and spirobicyclic groups e.g spiro [4.4] non-2-yl.
  • (Ci-C 6 )alkoxy refers to an alkyl group attached via an oxygen linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Examples include, without limitation, -OCH 3j -OC 2 Hs and -OC3H7.
  • (C 1 -C 6 )alkylamino refers to an alkyl group as defined above attached via amino linkage to the rest of the molecule, which may be optionally substituted by one or more substituents.
  • Preferred alkylamino groups include, without limitation -NHCH 3 , -N(CH 3 ) 2 and -NHCH 2 CH 3 .
  • (C 2 -C 6 )alkenyl refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched chain having about 2 to 6 carbon atoms, which may be optionally substituted by one or more substituents. Examples include, without limitation, ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl and pentenyl.
  • (C2-C6)alkynyl refers to a straight or branched hydrocarbyl radicals having at least one carbon-carbon triple bond and having in the range of 2-6 carbon atoms, which may be optionally substituted by one or more substituents. Examples include, without limitation, ethynyl, propynyl, butynyl and pentynyl.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • halo(C] -C6)alkyl refers to halogen group attached via an alkyl linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Examples include, without limitation, -CH 2 C1, -C 2 H 4 C1, trifluoromethyl, tribromomethyl and trichloromethyl.
  • halo(Ci-C6)alkoxy refers to a group resulting from the replacement of one or more hydrogen atoms from an alkoxy group with one or more halogen atoms, which can be the same or different, which may be optionally substituted by one or more substituents. Examples include, without limitation, chloromethoxy, chloroethoxy, trifluoromethoxy, trifluoroethoxy and trichloromethoxy.
  • (C 6 -C 1 4)aryl(Ci-C6)alkoxy refers to an alkoxy group attached to aryl substituent, which may be substituted by one or more substituents.
  • Preferred arylalkoxy groups include, without limitation, benzyloxy and phenylethoxy.
  • (C3-Ci 2 )cycloalkyloxy refers to a cycloalkyl group attached via an oxygen linkage to the rest of the molecule, which may be substituted. Examples include, without limitation -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl and -O- cyclohexyl.
  • amino(Ci-C 6 )alkyl refers to an amino group attached via alkyl linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Examples include, without limitation -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 NHCH 3 and -CH 2 N(CH 3 ) 2 .
  • (C6-Ci 4 )aryl(Ci-C 6 )alkyl refers to an aryl group directly bonded to an alkyl group, which may be optionally substituted by one or more substituents. Examples, include, without limitation, -CH 2 C 6 H 5 and -C 2 H 4 C 6 H 5 .
  • (C6-C 14 )aryl(C 2 -C6)alkenyl refers to an aryl group directly bonded to an alkenyl group, which may be optionally substituted by one or more substituents. Examples, include, without limitation, -C 2 H 2 C 6 H5 and -C3H5C6H5.
  • (C6-Ci 4 )aryl(C 2 -C6)alkynyl refers to an aryl group directly bonded to an alkynyl group, which may be optionally substituted by one or more substituents. Examples, include, without limitation, -C 2 C 6 H5 and -C 3 H 2 C 6 H5.
  • heteroaryl(Ci-C6)alkyl refers to a heteroaryl group directly bonded to an alkyl group, which may be optionally substituted by one or more substituents. Examples include, without limitation, -CH 2 -pyridinyl and -C 2 H4-furyl.
  • heteroaryl(C 2 -C6)alkenyl refers to a heteroaryl group directly bonded to an alkenyl group, which may be optionally substituted by one or more substituents. Examples include, without limitation, -C 2 H 2 -pyridinyl and - C 3 H 5 -furyl.
  • heteroaryl(C 2 -C6)alkynyl refers to a heteroaryl group directly bonded to an alkynyl group, which may be optionally substituted by one or more substituents. Examples include, without limitation, -C 2 -pyridinyl and -C 3 H 2 - furyl.
  • aminoaryl refers to aryl group substituted with amino group.
  • hydroxyaryl refers to aryl group substituted with hydroxy group.
  • R a , R b or R c can also combine to form a substituted or unsubstituted 3-10 membered heterocyclic rings including spiro-fused heterocyclic ring having 0-3 heteroatoms; the substituents are optionally further substituted by one or more substituents as defined above.
  • substitutents refers to one or more groups selected from halogens, hydroxy, nitro, cyano, amino, formyl, (C]-C6)alkyl, halo(Ci- C 6 )alkyl, (C,-C 6 )alkoxy, (C 6 -Ci 4 )aryl, (C 6 -Ci 4 )aryloxy, (d-C 6 )alkylamino, -COOR 3 , -C(0)NR a R b , -SR a , -SOR a and -S0 2 R , wherein R a , R b or R c in each of the above groups represent hydrogen, optionally substituted groups selected from (Ci-C 6 )alkyl, (C3-C 12 )cycloalkyl, (C6-C 14 )aryl; the substituents are optionally further substituted by one or more substituents as defined above.
  • the compounds described herein can be either E or Z geometrical isomers and in some cases mixtures can also be present. In cases where two or more double bonds are present in formula (I), then it can give rise to more than two geometrical isomers and in these cases the invention is said to cover all the isomers.
  • stereoisomers are isomers that differ in the arrangement of their atoms in space.
  • Compounds disclosed herein may exist as single stereoisomers, racemates and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the subject matter described.
  • solvates includes combinations of solvent molecules with molecules or ions of the solute compound.
  • derivatives refers to a chemical compound or molecule made from a parent compound by one or more chemical reactions such as, by oxidation, hydrogenation, alkylation, esterification, halogenation and the like.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • metabolic refers to compounds that result from a metabolic process either by breakdown or modifications of parent compound through phase I or phase II metabolism. Examples of metabolism on the compounds of the present invention include addition of -OH, hydrolysis and cleavage.
  • analog refers to a chemical compound that is structurally similar to another compound but differs slightly in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group.
  • An analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, cream, suspensions, aerosols, and the like, may contain flavorants, sweeteners, excipients etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • 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.
  • Suitable routes of administration includes, not limited to, oral, transdermal, rectal, nasal, topical, sublingual, intrathecal, intra-articular, intracisternal, intravaginal, ophthalmic, epidural, intracerebral, intracerebroventricular, intravesical, intravitreal, intracavernous intrauterine transmucosal or parenteral administration such as subcutaneous, intramuscular, intravenous, intraperitoneal and intradermal routes.
  • parenteral administration the compounds can be combined with a 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, intraperitoneally, subcutaneously or intramuscularly.
  • phrases “pharmaceutically acceptable” refers to compounds or compositions that are physiologically tolerable and do not typically produce allergic or similar untoward reaction, including but not limited to gastric upset or dizziness when administered to mammal.
  • Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts; salts of organic bases such as N, N'-diacetylethylenediamine, glucamine, triethylamine, choline, dicyclohexylamine, benzylamine, trialkylamine, thiamine, guanidine, diethanolamine, a-phenylethylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, ammonium, substituted ammonium salts and the like.
  • inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts
  • salts of organic bases such as N, N'-diacetylethylenediamine, glucamine, triethylamine, choline, dicycl
  • 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.
  • prodrugs refers to any pharmacologically inactive or less active compound which, when metabolized or chemically transformed by a mammalian system is converted into a pharmacologically active compound of formula (I) of the present invention.
  • some of the prodrugs are esters of the compound of formula (I), during metabolism the ester group is cleaved to form the active compound of formula (I).
  • a general overview of prodrug is provided in H Surya Prakash Rao, Resonance, 2003, 8, 19-27.
  • the compounds described herein can also be prepared in any solid or liquid physical form, for example the compound can be in a crystalline form, in amorphous form and have any particle size.
  • the compound particles may be micronized or nanoized, or may be agglomerated, or in the form of particulate granules, powders, oils, oily suspensions or any other form of solid or liquid physical forms.
  • the compounds described herein may also exhibit polymorphism.
  • This invention further includes different polymorphs of the compounds of the present invention.
  • polymorph refers to a particular crystalline state of a substance, having particular physical properties such as X-ray diffraction, IR spectra, melting point and the like.
  • histone deacetylase inhibitor or "inhibitor of histone deacetylase” is used to identify a compound, which is capable of interacting with a histone deacetylase and inhibiting its activity, more particularly its enzymatic activity. Inhibiting histone deacetylase enzymatic activity means reducing the ability of a histone deacetylase to remove an acetyl group from a histone. Preferably, such inhibition is specific, i.e. the histone deacetylase inhibitor reduces the ability of histone deacetylase to remove an acetyl group from a histone at a concentration that is lower than the concentration of the inhibitor that is required to produce some other, unrelated biological effect.
  • histone deacetylase and "HDAC” are intended to refer to any one of a family of enzymes that remove acetyl groups from the ⁇ -amino groups of lysine residues at the N-terminus of a histone. Unless otherwise indicated by context, the term “histone” is meant to refer to any histone protein, including HI, H2A, H2B, H3, H4 and H5, from any species.
  • Human HDAC proteins or gene products include but are not limited to, HDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, HDAC- 10 and HDAC-11.
  • the histone deacetylase can also be derived from a protozoal or fungal source.
  • isoform selective/specific HDAC inhibitors are one which affects a single HDAC isoform and the term “class selective/specific HDAC inhibitors” are one which affects several isoforms within a single class.
  • the compounds described herein are used in the treatment or prevention of cancer.
  • the cancer includes solid tumors or hematologic malignancies. Examples include, without limitation, multiple myeloma, lung cancer, breast cancer, prostate cancer, colon cancer and fibrosarcoma.
  • the present invention provides a method of treatment of a disorder caused by, associated with or accompanied by disruptions of cell proliferation and/or angiogenesis including administration of a therapeutically effective amount of a compound of formula (I).
  • described herein is the use of the compound of formula (I) for treating cancer, without limitation, tumors, sarcomas, lymphomas, carcinomas, leukemias, myelomas and melanomas.
  • the present invention provides a method of treatment of a disorder, disease or condition that can be treated by the inhibition of HDAC enzymes including administration of therapeutically effective amount of compound of formula (I).
  • proliferative diseases include, for example, a tumor disease and/or metastasis.
  • the proliferative disease may furthermore be a hyperproliferative condition such as leukemia, fibrosis, angiogenesis, psoriasis, atherosclerosis and smooth muscle proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.
  • the compounds described herein are selectively toxic or toxic to rapidly proliferating cells than to normal cells, including, for example, human cancer cells, e.g. cancerous tumors, the compounds have significant antiproliferative effects and promotes differentiation, e.g., cell cycle arrest and apoptosis.
  • the compounds induce p21, cyclin-CDK interacting protein, which includes either apoptosis or Gl arrest in variety of cell lines.
  • a method of treatment and/or prevention of inflammatory diseases which are mediated by HDAC's comprising rheumatoid arthritis (RA), inflammatory bowel disease (IBD), pelvic inflammatory disease (PID), human airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), cancer-induced bone pain (CIBP), atherosclerosis, endometriosis, granuloma, sepsis, multiple sclerosis, organ transplant rejection and other systemic inflammatory diseases, comprising administering to a subject suffering from the inflammatory diseases, a therapeutically effective amount of a compound of formula (I) (Bonfils C, et al., Expert Opinion on Drug Discovery, 2008, 3, 1041-1065).
  • a method of treatment and/or prevention of neurodegenerative disorders/CNS disorders including but not limited to Huntingtons's disease, Alzheimer's disease, Parkinson's disease, Friedreich's ataxia, stroke, spinal muscle atrophy, anxiety, traumatic brain injury, cerebral palsy, schizophrenia, spinocerebellar ataxia, Rett syndrome, fragile X disease, seizure disorders, depression, unipolar depression, bipolar disorder, amyotrophic lateral sclerosis, ischemia, Rubinstein-taybi syndrome, AIDS dementia, dementia, Korsakoff s syndrome, brain cancers, Wilson disease, Tay-Sach's disease, Tourette's disease, epilepsy and the like comprising administering to a subject suffering from the CNS disorder, a therapeutically effective amount of a compound of formula (I).
  • a method of treatment and/or prevention of CIBP comprising administering to a subject suffering from such a disorder, a therapeutically effective dose of compound of formula (I).
  • the present invention provides a method of treatment of various fungal diseases by the inhibition of fungal HDAC enzymes, comprising administration of therapeutically effective amount of compound of formula (I).
  • the present invention also provides a method of treatment and/or prevention of human immunovirus (HIV) latent disease, comprising, administering a therapeutically effective amount of a compound of formula (I).
  • HAV human immunovirus
  • the compounds described herein are also used for the treatment and/or prevention of protozoal infections such as malaria by inhibiting protozoal HDAC, comprising administering therapeutically effective amount of compound of formula (I).
  • Compounds disclosed herein are also used to treat Gaucher disease by inhibiting HDAC enzyme.
  • terapéuticaally effective amount or “effective amount” is an amount sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations.
  • An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
  • the compound may be administered in combination therapy by combining the compound of formula (I) with one or more separate agents, not limited to targets such as HDAC, DNA methyltransferase, heat shock proteins (e.g. HSP90), kinase, matrix metalloproteinases, proteasome inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors or other known HDAC inhibitors.
  • targets such as HDAC, DNA methyltransferase, heat shock proteins (e.g. HSP90), kinase, matrix metalloproteinases, proteasome inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors or other known HDAC inhibitors.
  • Combination therapy includes the administration of the subject compounds in further combination with other biologically active ingredients (such as, but are not limited to, different antineoplastic agent) and non-drug therapies (such as, but are not limited to, surgery or radiation treatment).
  • biologically active ingredients such as, but are not limited to, different antineoplastic agent
  • non-drug therapies such as, but are not limited to, surgery or radiation treatment.
  • the compounds described herein can be used in combination with other pharmaceutically active compounds, preferably, which will enhance the effect of the compounds of the invention.
  • the compounds can be administered simultaneously or sequentially to the other drug therapy.
  • cytotoxic agents are those which possesses a specific destructive action on certain cells or that may be genotoxic, oncogenic, mutagenic, teratogenic, or hazardous to cells in any way and includes most anti-cancer drugs substances. It acts by killing the cell or inhibiting the growth or proliferation of cells.
  • non-cytotoxic agents are substances that can be employed in treatment of cancers, which are more often cytostatic than cytotoxic (no tumor regression but inhibition of tumor progression). Examples include but not limited to tyrosine kinase inhibitors, angiogenesis inhibitors etc.,
  • the compound of formula (I) described herein may be coadministered with the other cytotoxic agents/non-cytotoxic agents, selected from but not limited to, bortezomib, disulfiram, salinosporamide A and carfilzomib, afatinib, axitinib, bevacizumab, cetuximab, crizotinib, dasatinib, erlotinib, fostamatinib, gefitinib, imatinib, lapatinib, lenvatinib, mubritinib, nilotinib, panitumumab, pazopanib, pegaptanib, ranibizumab, ruxolitinib, sorafenib, sunitinib, trastuzumab, vandetanib and vemurafenib, raloxifene, tamoxifen and related analogs
  • the subject compounds may be combined with the antineoplastic agents (e.g. small molecules, monoclonal antibodies, antisense R A and fusion proteins) that inhibit one or more biological targets.
  • antineoplastic agents e.g. small molecules, monoclonal antibodies, antisense R A and fusion proteins
  • Such combination may enhance therapeutic efficacy over the efficacy achieved by any of the agents alone and may prevent or delay the appearance of resistant variants.
  • HDAC6 in another aspect, described herein is inhibiting HDAC6, in a biological sample includes in vitro, in vivo, ex vivo, cell cultures, blood and other body fluids.
  • subject refers to animals including, not limited to mammals, and in particular humans, 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.
  • the term "transported across the blood-brain barrier” refers to targeting moiety that is able to cross the BBB.
  • the permeability will be determined by the BBB uptake parameters like K p , Kpu etc.
  • prophylaxis or "prevention” means preventing the disease, i.e, causing the clinical symptoms of the disease not to develop.
  • treatment'V'treating mean any treatment of a disease in a mammal, including: (a) Inhibiting the disease, i.e, slowing or arresting the development of clinical symptoms; and/or (b) Relieving the disease, i.e, causing the regression of clinical symptoms.
  • a beneficial outcome of the treatment may include, but not limited to either a decrease in the severity of systems or delay in the onset of symptoms or a substantial reversal of the symptom or condition.
  • compound(s) for use embrace any one or more of the following: (1) use of compound(s), (2) method of use of compound(s), (3) use in the treatment of, (4) the use for the manufacture of pharmaceutical composition / medicament for treatment/treating or (5) method of treatment / treating/ preventing / reducing / inhibiting comprising administering an effective amount of the active compound to a subject in need thereof.
  • Y -COOH or -S0 2 CI or -CHO or CH 2 OH;
  • R Y Methyl or ethyl
  • the pharmaceutically acceptable salts of the compounds of formula (I) are also prepared.
  • Acid addition salts are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p- toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, fumaric acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, tetrahydrofuran (THF), dioxane, etc. Mixture of solvents may also be used.
  • Step A 4-Cyanomethyl-benzoic acid methyl ester
  • TMSCN trimethylsilylcyanide
  • TBAF tetra-M- butylammonium fluoride
  • 4-Bromethyl benzoic acid methyl ester (20 g, 87.3 mmol) dissolved in acetonitrile (100 mL) was added drop wise over a period of 30 minutes, the reaction temperature was increased to 80 °C and stirring continued for another 30 minutes.
  • solvent was distilled out under reduced pressure, the crude material obtained was purified by column chromatography to give the pure title compound (10 g, Yield 68.7 %).
  • Step D Methyl 2-(2,2,2-trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline-7-carboxylate
  • Step E Methyl l,2,3,4-tetrahydroisoquinoline-7-carboxylate
  • Step A tert-Butyl 4-chloro-3-formyl-5,6-dihydropyridine-l(2H)-carboxylate
  • Step B 5-tert-Butyl 2-ethyl 6,7-dihydrofuro[3,2-c]pyridine-2,5(4H)-dicarboxylate
  • Step C Ethyl 4,5,6,7-tetrahydrofuro[3,2-c]pyridine-2-carboxylate
  • Step A 5-tert-butyl 2-ethyl oxylate
  • a solution of tert-Butyl 4-chloro-5-formyl-3,6-dihydropyridine-l(2H)- carboxylate (10 g, 40.9 mmol) in DCM was added triethylamine (11.8 mL, 81.8 mmol) and ethyl mercaptoacetate (7.8 g, 65.4 mmol) at room temperature.
  • the reaction mixture was refluxed for 2 hours, quenched with water and extracted with ethyl acetate (2 x 100 mL).
  • the organic layer was separated, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to afford the crude product.
  • the crude product obtained on purification by column chromatography affords the title compound. (4.0 g, Yield 35%).
  • Step B Ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
  • Step C te -Butyl 4-(pyrrolidin-l-yl)-5,6-dihydropyridine-l(2H)-carboxylate
  • Step D 5-tert-Butyl 3-ethyl 7a-(pyrrolidin-l-yl)-3a,4,7,7a-tetrahydroisoxazolo[4,5- c]pyridine-3,5(6H)-dicarboxylate
  • Step E Ethyl 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-carboxylate
  • Step A (E)-3-(4-(methoxycarbonyl)phenyl)acrylic acid
  • Methyl 4-formyl benzoate (5.0 g, 30.5 mmol), malonic acid (9.5 g, 91.5 mmol) and piperidine (0.5 mL, mmol) were added to a solution of pyridine (30 mL) and refluxed at 100 °C for 4 hours. The reaction mixture was cooled, neutralised with concentrated HC1 and filtered to obtain the crude product (4.5 g, Yield 59 %).
  • Step B (E)-Methyl 4-(3-amino-3-oxoprop-l-enyl)benzoate
  • Step C (E)-Methyl 4-(2-cyanovinyl)benzoate (£ ⁇ -Methyl 4-(3-amino-3-oxoprop-l-enyl)benzoate (1.0 g, 4.8 mmol) was dissolved in THF (50 mL). To this triethylamine (2.56 mL, 18.4 mmol) was added and cooled to 0 °C. Trifluoro acetic anhydride (1.2 mL, 8.8 mmol) was added slowly to the reaction mixture and stirred at room temperature for 1 hour.
  • reaction mixture was poured into ice mixture and the resultant precipitate was filtered which was further purified by silica column chromatography eluting with acetone/hexane solvent mixture to get the title compound (0.35 g, Yield 38.5 %).
  • Step E Methyl 4-(3-(2,2,2-trifluoroacetamido)propyl)benzoate
  • Methyl 4-(3-aminopropyl)benzoate (10 g, 43.66 mmol) was added portion wise to the well stirred trifluoroacetic anhydride (30 mL). This was further stirred for 3 hours at room temperature. The reaction mixture was poured into 100 mL of ice cold water and stirred for another 30 minutes. The resulting solid was filtered, washed with hexane and dried under vacuum to get the title compound (9 g, Yield 71.3 %).
  • Step F Methyl 2-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lH-benzo[c]azepine-8- carboxylate
  • Methyl 4-(3-(2,2,2-trifluoroacetamido)propyl)benzoate (5.0 g, 18.18 mmol) was stirred at room temperature with paraformaldehyde (2.1 g, 72.7 mmol), acetic acid (25mL) and cone. H 2 S0 4 (38 mL) for 18 hours. The clear solution was added to cold water (100 mL) and extracted with ethyl acetate (2x 100 mL). The organic layer was washed with 50 mL of saturated sodium bicarbonate solution, water (200 mL) and dried over anhydrous sodium sulphate, concentrated under vacuum to get the title compound (3.0 g, Yield 52.5 %).
  • Methyl 2-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-lH-benzo[c]azepine-8- carboxylate (3 g, 9.9 mmol) was dissolved in methanol (20 mL) and added to potassium carbonate (4.18 g, 29.9 mmol) and water (2 mL) and then stirred at room temperature for 3 hours. Methanol was removed from the reaction mixture and water (100 mL) was added, extracted with ethyl acetate (100 mL), followed by washing with water (100 mL). The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get colourless solid (1.23 g, Yield 60.6 %).
  • Step B Ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate
  • Step C Ethyl 2-(4-(tert-butoxycarbonyl)piperazin-l-yl)pyrimidine-5-carboxylate
  • Step D Ethyl 2-(piperazin-l-yl)pyrimidine-5-carboxylate
  • Step-I Methyl 2-(2,3-Diphenylacryloyl)- 1 ,2,3,4-tetrahydroisoquinoline-7-carboxylate
  • Step-II 2-(2,3-Diphenylacryloyl)-N-hydroxy- 1 ,2,3,4-tetrahydroisoquinoline-7- carboxamide
  • Example 154 2-(2-(4-Fluorophenyl)-3-phenylallyl)-N-hydroxy-l,2,3,4-tetrahydro isoquinoline-7-carboxamide
  • Step A 2-(4-fluorophenyl)-3-phenylprop-2-en-l-ol
  • Step B 2-(4-fluorophenyl)-3-phenylallyl methanesulfonate
  • Step C Methyl 2-(2-(4-fluorophenyl)-3-phenylallyl)-l,2,3,4-tetrahydroisoquinoline-7- carboxylate
  • Step D 2-(2-(4-Fluorophenyl)-3-phenylallyl)-N-hydroxy-l,2,3,4-tetrahydro isoquinoline-7-carboxamide
  • step II Methyl 2-(2-(4- fluorophenyl)-3-phenylallyl)- 1 ,2,3,4-tetrahydroisoquinoline-7-carboxylate was converted to title compound (0.2 g, 57 %).
  • Step-I 2-(2,3-Diphenylacryloyl)-l,2,3,4-tetrahydroisoquinoline-7-carboxylic acid
  • 2-(2,3-Diphenylacryloyl)-l,2,3,4-tetrahydroisoquinoline-7- carboxylic acid methyl ester (0.300 g, 0.7 mmol) in methanol (15 mL) was added aqueous LiOH (0.090 g, 3.7 mmol in 2 mL of water) solution.
  • the reaction mixture was stirred at room temperature for 4 hours and diluted with 100 mL of cold water.
  • Step-II N-(2-Aminophenyl)-2-(2,3-diphenylacryloyl)-l,2,3,4-tetrahydroisoquinoline-
  • HDAC Histone Deacetylase
  • rhHDACl or rhHDAC6 The Histone Deacetylase (HDAC) inhibitory activity of molecules to specific isoforms (rhHDACl or rhHDAC6) were assayed with Boc-Lys (q-Ac)-AMC substrate, (Bachem 1-1875) which has been previously described as a small -molecule screening method for HDAC enzymes in vitro.
  • the total HDAC assay volume was 100 /L and the assay components were diluted in HDAC buffer (50 mM Tris-HCl, 137 mM NaCl, 2.7 mM KCl and 2 mM MgCl 2 , pH 8.0). The reaction was carried out in black 96-well plates (Nunc).
  • the HDAC assay mixture contained HDAC substrate (37.5 ⁇ , 40 ⁇ ,), rhHDACl or rhHDAC6 enzymes (final concentration 30 ⁇ , diluted to 10 //L final volumes) and inhibitor (2X, the required assay concentration, diluted to 50 ⁇ , final volume).
  • HDAC1 inhibitory activity the assay components were incubated at 37 °C for 3 Hours, whereas for HDAC6 the components were incubated for 1 hour.
  • Positive control termed as total activity (TA) contained all the above components except the inhibitor.
  • the negative control or blank contained neither enzyme nor inhibitor. In each case inhibitor volumes were replaced with an equivalent volume of buffer.
  • ICso values of the test compounds were computed by analyzing dose-response inhibition curves (Graph Pad prism, 4) (Bonfils C, et al., Clinical Cancer Research, 2008, 14, 3441 - 3449).
  • test compounds were screened for HDAC6 enzyme inhibitory activity.
  • the compounds whose IC50 values in the range of less than 1 nM to 50 nM are 1, 4, 5, 6, 7, 8, 9, 10, 12, 11, 14, 17, 19, 20, 21, 22, 23, 24, 25, 29, 32, 43, 44, 45, 46, 48, 49, 52, 53, 54, 55, 59, 62, 64, 69, 70, 71, 72, 76, 77, 78, 80, 85, 87, 88, 28, 86, 152 and 153.
  • a few of the compounds showed greater than 2000 fold selectivity for HDAC6 over HDAC1. In another embodiment some of the compounds showed greater than 1000 fold selectivity for HDAC6 over HDAC1. Several compounds have greater than 100 fold selectivity for HDAC6 over HDAC 1.
  • test compounds were screened in ten cancer cell lines for cell viability using Sulforhodamine B (SRB) cell viability assay (Vichai V. et al., Nature Protocols, 2006, 1(3), 1112-1116) and CCK8 assay.
  • SRB Sulforhodamine B
  • the cell lines - MCF7 and MDA MB231 human breast cancer cell lines
  • NCIH460 human lung cancer cell line
  • HCT116 human colon cancer cell line
  • PC3 human prostate cancer cell line
  • HT1080 human fibrosarcoma cell line
  • DMEM Dulbecco's modified eagle's medium
  • test compounds were added to the plates in triplicates with appropriate dilutions along with the cytotoxic standard and control (untreated) wells.
  • Test compounds were dissolved in dimethyl sulfoxide (DMSO) to prepare 100 mM stock solutions on the day of drug addition and serial dilutions were carried out in complete growth medium at 5x strength such that 50 iL added to wells gave final concentrations of 0.0064, 0.032, 0.16, 0.8, 4, 20 and 100 uM in the well.
  • DMSO dimethyl sulfoxide
  • the plates were then incubated for 72 hours at 37 °C, 5 % C0 2 , 95 % air and 100 % relative humidity.
  • TCA ice-cold trichloroacetic acid
  • Percent growth was calculated relative to the control and zero measurement wells (T 0 ) as followsj.
  • PG (OD530test - OD530T 0 ) / (OD530T 0 ) x 100 (If OD530test ⁇ OD530T 0 ).
  • GI50 the concentration required to decrease PG by 50 % vs control
  • PC- 12 pheochromocytoma
  • a semi suspension cells were seeded in Poly -D Lysine coated plate and incubated overnight at 37 °C and 5% C0 2 . After 24 hours, the cells were treated with test compounds along with 3-Nitropropionic acid and kept for 48 hours incubation at 37 °C, 5% C0 2 . Lactate dehydrogenase (LDH) in the cell supernatant was estimated using an LDH kit for cytotoxicity (Roche, Cat. No.11644793001). To determine the LDH activity of supematants, 100 reaction mixture was added to each well and incubated for 30 minutes at 25 °C and the absorbance of the samples measured at 490 nm. The results obtained were tabulated below.
  • LDH Lactate dehydrogenase
  • RAW 264.7 cells were seeded in a 24 well plate and incubated for 48 hours. After 48 hours, the cells were treated with various concentrations of the test compounds for 24 hours followed by lipopolysaccharide (LPS) stimulation (10 ng/mL) for 3 hours. TNF-a in the cell supernatant was estimated using an ELISA kit (R&D Systems) as per manufacturer's instructions.
  • LPS lipopolysaccharide
  • RAW 264.7 cells were seeded in a 24 well plate and incubated for 48 hours. After 48 hours the cells were treated with various concentrations of the test compounds for 24 hours followed by LPS stimulation (100 ng/mL) for 3 hours. IL-6 in the cell supernatant was estimated using an ELISA kit (R&D Systems) as per manufacturer's instructions.
  • THP1 cells were seeded in a 24 well plate along with phorbol myristate acetate (PMA) (32 nM) and incubated for 24 hours. After 24 hours, the media were changed and cells were incubated for another 24 hours. Then cells were treated with various concentrations of the test compounds for 24 hours followed by LPS stimulation (10 ng/mL) for 4 hours. TNF-a in the cell supernatant was estimated using an ELISA kit (R&D Systems) as per manufacturer's instructions.
  • PMA phorbol myristate acetate
  • THP1 cells were seeded in 24 well plates along with PMA (32 nM) and incubated for 24 hours. After 24 hours media were changed and cells were incubated for another 24 hours. Then cells were treated with various concentrations of the test compounds for 24 hours followed by LPS stimulation (100 ng/mL) for 8 hours. IL-6 in the cell supernatant was estimated using an ELISA kit (R&D Systems) as per manufacturer's instructions.
  • Metabolic stability is defined as the percentage of parent compound lost over time in the presence of liver microsomes, liver S9, or hepatocytes, depending on the goal of the assay.
  • the stock solutions of test compound were prepared using DMSO or water.
  • Incubation of reaction mixture including cryopreserved mouse or human liver microsomes (1 mg/mL), test compound (50 ⁇ ), and nicotinamide adenine dinucleotide phosphate (NADPH) for different time points, e.g. 10, 15, 30, and 60 minutes or single time points, e.g. 60 minutes.
  • Reaction is started by the addition of NADPH and stopped either immediately or after 60 minutes for screening assay or at 5, 15, 30 and 60 minutes for a more precise estimate of clearance by addition of ice- cold acetonitrile, followed by sample preparation. Determination of loss of parent compound (compared to zero time point control and/or no NADPH-control) was done using HPLC or LC-MS methods. Metabolism was expressed as percentage of test compound metabolized after a certain time. A marker reaction and marker substrate (e.g. testosterone) was employed as quality criteria of the metabolic capability of the microsomes. (Rodrigues, A.D., et al. Biochemical Pharmacology, 1994, 48(12): 2147- 2156).
  • Metabolic stability was expressed as % metabolism of the compound after 30 minutes of incubation in the presence of active microsomes.
  • Compound that had a % metabolism less than 30 % were defined as highly stable.
  • Compound that had a metabolism between 30 % and 60 % were defined as moderately stable and compounds that showed a % metabolism higher than 60 % were defined as less stable. Some of the test compounds were found to be moderately stable.
  • Dialysis membranes Cellulose acetate membranes with 12,000-14,000 molecular weight cut-off were charged by serially wetting in distilled water and distilled water containing 20 % ethanol for 60 and 20 minutes, respectively. Charged dialysis membranes were rinsed with distilled water three times and stored in isotonic sodium phosphate buffer until use.
  • the 96-well dialysis apparatus was assembled by following the manufacturers instructions using the charged membranes 0.15 mL of sodium phosphate buffer (pH 7.4) was placed on the dialysate side of each well and 0.15 mL of plasma spiked with the test compound (predetermined concentrations) on the other side, and the plate was completely sealed with adhesive membrane and incubated in a shaking dry incubator preset at 100 rpm at 37 °C to equilibrate for 8 hours (as determined previously). All samples were incubated in triplicates at predetermined concentrations. At the end of equilibration time, the volume of plasma and the buffer was measured for each well. 80 of plasma and the buffer was diluted with an equal volume of acetonitrile and centrifuged for 10 minutes to precipitate the proteins. The supernatant was analyzed using HPLC. The test compound shows moderate plasma protein binding.
  • test compounds were administered to separate sets of two animals for each time point at 15 mg/kg dose intravenously to check for its blood-brain barrier permeability.
  • Cerebrospinal fluid (CSF) was collected by direct cisterna-magna (CM) puncture at the specified time points from anesthetized rats.
  • mice were housed in individually ventilated cages (IVC), maintained in 12 hours light dark cycle with standard laboratory chow diet and water ad libitum in controlled room temperature (22 + 3 ° C) and humidity (50 ⁇ 20 %).
  • IVC individually ventilated cages
  • the animals were grouped based on body weight and treated with test compound at 50 mg/kg i.p for seven days. After the treatment period, the animals were observed for 14 days, during which body weight and clinical symptoms were recorded. Mean changes in body weight was calculated as compared to the control. On the day of termination, the animals were sacrificed using C0 2 asphyxiation and gross pathological examination carried out. Organs of interest were collected and subjected to histopathological analysis.
  • mice were housed in IVC, maintained in 12 hours light dark cycle with standard laboratory chow diet and water ad libitum in controlled room temperature (22 + 3 ° C) and humidity (50 ⁇ 20 %).
  • Tumors rose from cells obtained from ATCC, USA and maintained in vivo by subcutaneous (s.c.) passage of tumor fragments (-30 mg) in healthy mice according to standard reporting procedures.
  • Each experimental group included 6-8 mice bearing s.c tumors. Tumors were implanted into the auxiliary region using precision trochar and tumor growth was monitored by measuring diameters with a vernier caliper.
  • Tumor volume (TV) was calculated according to the formula:
  • L and W are the longest diameter and shortest diameter of the tumor respectively.
  • Test compound treatment started when tumors were palpable (-100 mm 3 ). Test compound was administered by per oral or by intra peritoneal once daily for a period of 21 days. Control mice were administered with vehicle at equivalent volume. Tumor size was measured twice a week and body weight taken daily prior to dosing. Parameters such as survival, change in the tumor volume, body weight and clinical symptoms were observed and recorded. Test compound efficacy was assessed by calculating tumor volume with respect to vehicle control
  • T/C % (1-TVtreatment / TV control) X 100
  • Oxazolone induced dermatitis in mice was performed using the protocol described in Tamura T., et al., European Journal of Pharmacology, 2005, 524, 149- 154.
  • Balb/C mice were acclimatized to laboratory conditions five to seven days prior to the start of the experiment. They were randomly distributed to various groups based on body weight. The abdomen of animals was shaved using a small animal clipper. All the animals were sensitized with 15 % oxazolone by application to the clipped abdomen (20 ⁇ ,) 7 days before challenge. On 7 th day, the animals were challenged with 2 % oxazolone at the ears (20 uL per ear). Test compounds were applied over the ears of sensitized mice 30 minutes before and 4 hours after challenge.
  • ear thickness was measured using a thickness gauge. Animals were sacrificed after 24 hours and ears collected by punch biopsy for ear weight and histopathology. Percent reduction in the ear thickness and ear weight was calculated using the following equation.
  • Ear thickness ⁇ ar thick* 1658 in Oxazolone group - Ear thickness in Treatment group

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des inhibiteurs d'histone désacétylase sélectifs isoformes de formule (I), leurs dérivés, analogues, formes tautomères, stéréo-isomères, polymorphes, hydrates, métabolites, pro-médicaments, solvates, sels pharmaceutiquement acceptables et des compositions de ceux-ci. Ces composés sont des inhibiteurs sélectifs isoformes d'HDAC et sont utiles en tant qu'agent thérapeutique ou d'amélioration destiné à des maladies affectant la croissance cellulaire, telles que le cancer, les tumeurs malignes, les maladies auto-immunes, les maladies de la peau, les infections fongiques, les infections par des protozoaires, le VIH, l'inflammation et les troubles du SNC.
PCT/IN2012/000147 2011-03-02 2012-03-01 Inhibiteurs de l'histone désacétylase WO2012117421A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN613/CHE/2011 2011-03-02
IN613CH2011 2011-03-02

Publications (1)

Publication Number Publication Date
WO2012117421A1 true WO2012117421A1 (fr) 2012-09-07

Family

ID=46172833

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2012/000147 WO2012117421A1 (fr) 2011-03-02 2012-03-01 Inhibiteurs de l'histone désacétylase

Country Status (1)

Country Link
WO (1) WO2012117421A1 (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9273043B2 (en) 2011-06-22 2016-03-01 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
WO2016168598A1 (fr) * 2015-04-17 2016-10-20 Forma Therapeutics, Inc. Tétralines d'acide 3-spirocycliques-6-hydroxamiques en tant qu'inhibiteurs d'hdac
US9505776B2 (en) 2013-03-14 2016-11-29 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US9604922B2 (en) 2014-02-24 2017-03-28 Alkermes Pharma Ireland Limited Sulfonamide and sulfinamide prodrugs of fumarates and their use in treating various diseases
US9745253B2 (en) 2015-03-13 2017-08-29 Forma Therapeutics, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
KR20170122759A (ko) * 2015-02-02 2017-11-06 포르마 세라퓨틱스 인크. Hdac 억제제로서의 3-알킬-4-아미도-바이사이클릭 [4,5,0] 하이드록삼산
US10029995B2 (en) 2015-09-03 2018-07-24 Forma Therapeutics, Inc. [6,6] fused bicyclic HDAC8 inhibitors
CN108358853A (zh) * 2018-02-09 2018-08-03 中山大学 一种抗神经炎症的二苯乙烯类似物及其制备方法和应用
WO2018213364A1 (fr) 2017-05-16 2018-11-22 Annji Pharmaceutical Co., Ltd. Inhibiteurs des histone désacétylases (hdac)
US10183934B2 (en) 2015-02-02 2019-01-22 Forma Therapeutics, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
CN109415373A (zh) * 2016-06-08 2019-03-01 方济各安吉利克化学联合股份有限公司 新的抗菌化合物
WO2019189731A1 (fr) 2018-03-30 2019-10-03 住友化学株式会社 Composé hétérocyclique et agent de lutte contre les arthropodes nuisibles le contenant
CN110325508A (zh) * 2017-01-20 2019-10-11 加利福尼亚大学董事会 雄激素受体的n-末端结构域的抑制剂
US10555935B2 (en) 2016-06-17 2020-02-11 Forma Therapeutics, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors
CN112292370A (zh) * 2018-04-20 2021-01-29 瓦洛早期发现股份有限公司 作为hdac抑制剂的异吲哚啉
EP3694528A4 (fr) * 2017-10-13 2021-07-28 The Regents of the University of California Modulateurs de mtorc1
CN113816903A (zh) * 2021-09-22 2021-12-21 蚌埠医学院 一种四氢异喹啉二苯乙烯类化合物及其制备方法、应用
US11230548B2 (en) 2013-03-14 2022-01-25 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2103119A1 (en) * 1971-01-23 1972-07-27 Farbwerke Hoechst AG, vormals Meister Lucius & Brüning, 6000 Frankfurt N-substd-2,3-diphenyl-allylamines - prepn from the corresp alcohol via the bromide
WO2005108367A1 (fr) 2004-05-03 2005-11-17 Envivo Pharmaceuticals, Inc. Composes pour traiter les maladies neurodegeneratives
WO2006010749A2 (fr) 2004-07-28 2006-02-02 Janssen Pharmaceutica N.V. Derives de piperazine de propenyle substituee comme nouveaux inhibiteurs de l'histone deacetylase
WO2007054776A2 (fr) * 2005-11-10 2007-05-18 Orchid Research Laboratories Limited Composes semblables au stilbene comme inhibiteurs hdac atypiques
WO2007082874A1 (fr) 2006-01-19 2007-07-26 Janssen Pharmaceutica N.V. Dérivés de pyridine et de pyrimidine en tant qu'inhibiteurs d'histone désacétylase
WO2009047615A2 (fr) * 2007-10-10 2009-04-16 Orchid Research Laboratories Limited Nouveaux inhibiteurs des histone désacétylases
WO2009053808A2 (fr) * 2007-10-22 2009-04-30 Orchid Research Laboratories Limited Inhibiteurs d'histone désacétylase
WO2010028193A1 (fr) 2008-09-03 2010-03-11 Repligen Corporation Composés comprenant des dérivés d'acide pimélique en tant qu'inhibiteurs de hdac
WO2010151317A1 (fr) 2009-06-22 2010-12-29 Millennium Pharmaceuticals, Inc. Acides hydroxamiques substitués et leurs utilisations
WO2010151318A1 (fr) 2009-06-22 2010-12-29 Millennium Pharmaceuticals, Inc. Acides hydroxamiques substitués et leurs utilisations
US20110300134A1 (en) 2010-01-22 2011-12-08 Acetylon Pharmaceuticals Reverse amide compounds as protein deacetylase inhibitors and methods of use thereof

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2103119A1 (en) * 1971-01-23 1972-07-27 Farbwerke Hoechst AG, vormals Meister Lucius & Brüning, 6000 Frankfurt N-substd-2,3-diphenyl-allylamines - prepn from the corresp alcohol via the bromide
WO2005108367A1 (fr) 2004-05-03 2005-11-17 Envivo Pharmaceuticals, Inc. Composes pour traiter les maladies neurodegeneratives
WO2006010749A2 (fr) 2004-07-28 2006-02-02 Janssen Pharmaceutica N.V. Derives de piperazine de propenyle substituee comme nouveaux inhibiteurs de l'histone deacetylase
WO2007054776A2 (fr) * 2005-11-10 2007-05-18 Orchid Research Laboratories Limited Composes semblables au stilbene comme inhibiteurs hdac atypiques
WO2007082874A1 (fr) 2006-01-19 2007-07-26 Janssen Pharmaceutica N.V. Dérivés de pyridine et de pyrimidine en tant qu'inhibiteurs d'histone désacétylase
WO2009047615A2 (fr) * 2007-10-10 2009-04-16 Orchid Research Laboratories Limited Nouveaux inhibiteurs des histone désacétylases
WO2009053808A2 (fr) * 2007-10-22 2009-04-30 Orchid Research Laboratories Limited Inhibiteurs d'histone désacétylase
WO2010028193A1 (fr) 2008-09-03 2010-03-11 Repligen Corporation Composés comprenant des dérivés d'acide pimélique en tant qu'inhibiteurs de hdac
WO2010151317A1 (fr) 2009-06-22 2010-12-29 Millennium Pharmaceuticals, Inc. Acides hydroxamiques substitués et leurs utilisations
WO2010151318A1 (fr) 2009-06-22 2010-12-29 Millennium Pharmaceuticals, Inc. Acides hydroxamiques substitués et leurs utilisations
US20110300134A1 (en) 2010-01-22 2011-12-08 Acetylon Pharmaceuticals Reverse amide compounds as protein deacetylase inhibitors and methods of use thereof

Non-Patent Citations (25)

* Cited by examiner, † Cited by third party
Title
ALDANA-MASANGKAY G.I. ET AL., JOURNAL OF BIOMEDICINE AND BIOTECHNOLOGY, vol. ID875824, 2011, pages 1 - 10
BONFILS C. ET AL., CLINICAL CANCER RESEARCH, vol. 14, 2008, pages 3441 - 3449
BONFILS C. ET AL., EXPERT OPINION ON DRUG DISCOVERY, vol. 3, 2008, pages 1041 - 1065
BONFILS C., EXPERT OPINION ON DRUG DISCOVERY, vol. 3, 2008, pages 1041 - 1065
BUTLER K.V. ET AL., CURRENT PHARMACEUTICAL DESIGN, vol. 14, 2008, pages 505 - 528
BUTLER K.V. ET AL., JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 132, no. 31, 2010, pages 10842 - 10846
ELLIS L. ET AL., PHARMACEUTICALS, vol. 3, 2010, pages 2441 - 2469
H SURYA; PRAKASH RAO, RESONANCE, vol. 8, 2003, pages 19 - 27
HAHNEN E. ET AL., EXPERT OPINION ON INVESTIGATIONAL DRUGS, vol. 17, no. 2, 2008, pages 169 - 184
HALILI M.A. ET AL., CURRENT TOPICS IN MEDICINAL CHEMISTRY, vol. 9, 2009, pages 309 - 319
HE R. ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 53, 2010, pages 1347 - 1356
HIDESHIMA T. ET AL., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 102, no. 24, 2005, pages 8567 - 8572
KAZANTSEV A.G. ET AL., NATURE REVIEWS DRUG DISCOVERY, vol. 7, 2008, pages 854 - 868
KELLY HUBER, JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 286, no. 25, 2011, pages 22211 - 22218
LANGLEY B. ET AL., CURRENT DRUG TARGETS-CNS & NEUROLOGICAL DISORDERS, vol. 4, 2005, pages 41 - 50
OEHME I. ET AL., EXPERT OPINION ON INVESTIGATIONAL DRUGS, vol. 18, no. 11, 2009, pages 1605 - 1617
OHSUMI K ET AL: "Novel combretastatin analogues effective against murine solid tumors: design and structure-activity relationships.", JOURNAL OF MEDICINAL CHEMISTRY 30 JUL 1998 LNKD- PUBMED:9685242, vol. 41, no. 16, 30 July 1998 (1998-07-30), pages 3022 - 3032, XP002680008, ISSN: 0022-2623 *
RIVIECCIO M.A. ET AL., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 106, no. 46, 2009, pages 19599 - 19604
RODRIGUES, A.D. ET AL., BIOCHEMICAL PHARMACOLOGY, vol. 48, no. 12, 1994, pages 2147 - 2156
SANTO L. ET AL., BLOOD, 2011
TAMURA T. ET AL., EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 524, 2005, pages 149 - 154
TAN J. ET AL., JOURNAL OF HEMATOLOGY & ONCOLOGY, vol. 3, no. 5, 2010, pages 1 - 13
TANNOUS P. ET AL., CIRCULATION, vol. 117, no. 24, 2008, pages 3070 - 3078
VICHAI V. ET AL., NATURE PROTOCOLS, vol. 1, no. 3, 2006, pages 1112 - 1116
ZHU H. ET AL., JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 285, 2010, pages 9429 - 9436

Cited By (76)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9273043B2 (en) 2011-06-22 2016-03-01 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US9630959B2 (en) 2011-06-22 2017-04-25 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US10450308B2 (en) 2011-06-22 2019-10-22 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US12076306B2 (en) 2013-03-14 2024-09-03 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US9505776B2 (en) 2013-03-14 2016-11-29 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US11905298B2 (en) 2013-03-14 2024-02-20 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US10596140B2 (en) 2013-03-14 2020-03-24 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US11083703B2 (en) 2013-03-14 2021-08-10 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US11230548B2 (en) 2013-03-14 2022-01-25 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US11679092B2 (en) 2013-03-14 2023-06-20 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US10406133B2 (en) 2013-03-14 2019-09-10 Alkermes Pharma Ireland Limited Prodrugs of fumarates and their use in treating various diseases
US9604922B2 (en) 2014-02-24 2017-03-28 Alkermes Pharma Ireland Limited Sulfonamide and sulfinamide prodrugs of fumarates and their use in treating various diseases
US10421731B2 (en) 2015-02-02 2019-09-24 Forma Therapeutics, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10450283B2 (en) 2015-02-02 2019-10-22 Forma Therapeutics, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10214500B2 (en) 2015-02-02 2019-02-26 Forma Therapeutics, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10214501B2 (en) 2015-02-02 2019-02-26 Forma Therapeutics, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US11274084B2 (en) 2015-02-02 2022-03-15 Valo Health, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10239845B2 (en) 2015-02-02 2019-03-26 Forma Therapeutics, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US11279681B2 (en) 2015-02-02 2022-03-22 Valo Health, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US11274085B2 (en) 2015-02-02 2022-03-15 Valo Health, Inc. 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10377726B2 (en) 2015-02-02 2019-08-13 Forma Therapeutics, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10407418B2 (en) 2015-02-02 2019-09-10 Forma Therapeutics, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
US10112915B2 (en) 2015-02-02 2018-10-30 Forma Therapeutics, Inc. 3-aryl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10414738B2 (en) 2015-02-02 2019-09-17 Forma Therapeutics, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10870645B2 (en) 2015-02-02 2020-12-22 Valo Early Discovery, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
US10421732B2 (en) 2015-02-02 2019-09-24 Forma Therapeutics, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10428031B2 (en) 2015-02-02 2019-10-01 Forma Therapeutics, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
CN114057765A (zh) * 2015-02-02 2022-02-18 瓦洛健康股份有限公司 作为hdac抑制剂的3-芳基-4-酰氨基-二环[4,5,0]异羟肟酸
US11702412B2 (en) 2015-02-02 2023-07-18 Valo Health, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
US10442776B2 (en) 2015-02-02 2019-10-15 Forma Therapeutics, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
KR20170122759A (ko) * 2015-02-02 2017-11-06 포르마 세라퓨틱스 인크. Hdac 억제제로서의 3-알킬-4-아미도-바이사이클릭 [4,5,0] 하이드록삼산
US10183934B2 (en) 2015-02-02 2019-01-22 Forma Therapeutics, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
US10450284B2 (en) 2015-02-02 2019-10-22 Forma Therapeutics, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10457652B2 (en) 2015-02-02 2019-10-29 Forma Therapeutics, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10464909B2 (en) 2015-02-02 2019-11-05 Forma Therapeutics, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10464910B2 (en) 2015-02-02 2019-11-05 Forma Therapeutics, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10472337B2 (en) 2015-02-02 2019-11-12 Forma Therapeutics, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10479772B2 (en) 2015-02-02 2019-11-19 Forma Therapeutics, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10494354B2 (en) 2015-02-02 2019-12-03 Forma Therapeutics, Inc. 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10494352B2 (en) 2015-02-02 2019-12-03 Forma Therapeutics, Inc. 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10494353B2 (en) 2015-02-02 2019-12-03 Forma Therapeutics, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10494351B2 (en) 2015-02-02 2019-12-03 Forma Therapeutics, Inc. 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10501424B2 (en) 2015-02-02 2019-12-10 Forma Therapeutics, Inc. 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
KR102633628B1 (ko) 2015-02-02 2024-02-02 포르마 세라퓨틱스 인크. Hdac 억제제로서의 3-알킬-4-아미도-바이사이클릭 [4,5,0] 하이드록삼산
US10513501B2 (en) 2015-02-02 2019-12-24 Forma Therapeutics, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10988450B2 (en) 2015-02-02 2021-04-27 Valo Early Discovery, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US11891365B2 (en) 2015-02-02 2024-02-06 Valo Health, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10822316B2 (en) 2015-02-02 2020-11-03 Valo Early Discovery, Inc. 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10829462B2 (en) 2015-02-02 2020-11-10 Valo Early Discovery, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10829461B2 (en) 2015-02-02 2020-11-10 Valo Early Discovery, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10266487B2 (en) 2015-03-13 2019-04-23 Forma Therapeutics, 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
US10988441B2 (en) 2015-03-13 2021-04-27 Valo Early Discovery, Inc. Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
US9745253B2 (en) 2015-03-13 2017-08-29 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
WO2016168598A1 (fr) * 2015-04-17 2016-10-20 Forma Therapeutics, Inc. Tétralines d'acide 3-spirocycliques-6-hydroxamiques en tant qu'inhibiteurs d'hdac
US9630922B2 (en) 2015-04-17 2017-04-25 Forma Therapeutics, Inc. 3-spiro-7-hydroxamic acid tetralins as HDAC inhibitors
US9637453B2 (en) 2015-04-17 2017-05-02 Forma Therapeutics, Inc. 3-spirocyclic-6-hydroxamic acid tetralins as HDAC inhibitors
US10829460B2 (en) 2015-09-03 2020-11-10 Valo Early Discovery, Inc. [6,6] fused bicyclic HDAC8 inhibitors
US10029995B2 (en) 2015-09-03 2018-07-24 Forma Therapeutics, Inc. [6,6] fused bicyclic HDAC8 inhibitors
US11414392B2 (en) 2015-09-03 2022-08-16 Valo Health, Inc. [6,6] fused bicyclic HDAC8 inhibitors
US10370343B2 (en) 2015-09-03 2019-08-06 Forma Therapeutics, Inc. [6,6] Fused bicyclic HDAC8 inhibitors
CN109415373A (zh) * 2016-06-08 2019-03-01 方济各安吉利克化学联合股份有限公司 新的抗菌化合物
US11730721B2 (en) 2016-06-17 2023-08-22 Valo Health, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors
US10555935B2 (en) 2016-06-17 2020-02-11 Forma Therapeutics, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors
US10874649B2 (en) 2016-06-17 2020-12-29 Valo Early Discovery, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors
CN110325508B (zh) * 2017-01-20 2023-06-30 加利福尼亚大学董事会 雄激素受体的n-末端结构域的抑制剂
CN110325508A (zh) * 2017-01-20 2019-10-11 加利福尼亚大学董事会 雄激素受体的n-末端结构域的抑制剂
WO2018213364A1 (fr) 2017-05-16 2018-11-22 Annji Pharmaceutical Co., Ltd. Inhibiteurs des histone désacétylases (hdac)
EP3694528A4 (fr) * 2017-10-13 2021-07-28 The Regents of the University of California Modulateurs de mtorc1
CN108358853A (zh) * 2018-02-09 2018-08-03 中山大学 一种抗神经炎症的二苯乙烯类似物及其制备方法和应用
CN108358853B (zh) * 2018-02-09 2021-06-25 中山大学 一种抗神经炎症的二苯乙烯类似物及其制备方法和应用
WO2019189731A1 (fr) 2018-03-30 2019-10-03 住友化学株式会社 Composé hétérocyclique et agent de lutte contre les arthropodes nuisibles le contenant
CN112292370A (zh) * 2018-04-20 2021-01-29 瓦洛早期发现股份有限公司 作为hdac抑制剂的异吲哚啉
CN113816903A (zh) * 2021-09-22 2021-12-21 蚌埠医学院 一种四氢异喹啉二苯乙烯类化合物及其制备方法、应用
CN113816903B (zh) * 2021-09-22 2023-11-14 蚌埠医学院 一种四氢异喹啉二苯乙烯类化合物及其制备方法、应用

Similar Documents

Publication Publication Date Title
WO2012117421A1 (fr) Inhibiteurs de l'histone désacétylase
CA3122317C (fr) Compose d'isoindoline, procede de preparation, composition pharmaceutique et utilisation du compose d'isoindoline
JP5798115B2 (ja) 置換ヒドロキサム酸およびその使用
WO2016131381A1 (fr) Composés à cycles fusionnés, composition pharmaceutique et utilisations associées
KR20170018913A (ko) 리신 특이적 데메틸라제-1의 억제제
EP2443092A1 (fr) Composes bicycliques et tricycliques utilises en tant qu'inhibiteurs de kat ii
WO2012012322A1 (fr) Acides hydroxamiques substitués et leurs utilisations
EA027533B1 (ru) Конденсированные тетра- или пентациклические дигидродиазепинокарбазолоны в качестве ингибиторов parps
CN107835810A (zh) 作为hdac1/2抑制剂的哌啶衍生物
AU2006228787A1 (en) Substituted aminoalkyl- and amidoalkyl-benzopyran derivatives
KR20130046436A (ko) 안드로겐 수용체 길항제, 항암제로서 사이클릭 n,n''-다이아릴티오우레아 및 n,n''-다이아릴우레아, 이의 제조방법 및 이의 용도
US11319326B2 (en) Tricyclic fused derivatives of 1-(cyclo)alkyl pyrtdin-2-one useful for the treatment of cancer
KR102720992B1 (ko) 피롤리딘 화합물
JP2014144947A (ja) 新規ヒストンデアセチラーゼインヒビター
US20180237453A1 (en) Tricyclic fused pyridin-2-one derivatives and their use as brd4 inhibitors
WO2017083756A1 (fr) Composés hétérocycliques pour le traitement de maladies
EP2280940A1 (fr) Nouveaux n-(2-amino-phényl)-acrylamides
CN113166148B (zh) 作为cdk-hdac双通路抑制剂的杂环化合物
CA3178647A1 (fr) Amides tricycliques substitues, analogues de ceux-ci et procedes les mettant en oeuvre
US10323043B2 (en) Derivatives of macrocyclic N-aryl-tricyclopyrimidine-2-amine polyethers as inhibitors of FTL3 and JAK
US20240299400A1 (en) Transcription Factor GLI1 Inhibitors and Uses Thereof
CN115515943B (zh) 噁二唑衍生物
KR20190104195A (ko) 치환된 3-디알킬아미노메틸-피페리딘-4-일-벤즈아미드 및 이를 제조 및 사용하는 방법
CA3181590A1 (fr) Amides d'isoquinolinylmethyle substitues, analogues de ceux-ci et procedes les utilisant
EA044023B1 (ru) Замещенный 3,4,12,12а-тетрагидро-1н-[1,4]оксазино[3,4-c]пиридо[2,1-f][1,2,4]триазин-6,8-дион, фармацевтическая композиция, способы их получения и применения

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: 12723930

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12723930

Country of ref document: EP

Kind code of ref document: A1