WO2012068109A2 - Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof - Google Patents

Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof Download PDF

Info

Publication number
WO2012068109A2
WO2012068109A2 PCT/US2011/060791 US2011060791W WO2012068109A2 WO 2012068109 A2 WO2012068109 A2 WO 2012068109A2 US 2011060791 W US2011060791 W US 2011060791W WO 2012068109 A2 WO2012068109 A2 WO 2012068109A2
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
compound
alkyl
aryl
heteroaryl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2011/060791
Other languages
English (en)
French (fr)
Other versions
WO2012068109A3 (en
Inventor
John H. Van Duzer
Ralph Mazitschek
Yanbing Ding
Nan Yu
Yun Cao
Yong Liu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Acetylon Pharmaceuticals Inc
Original Assignee
Acetylon Pharmaceuticals Inc
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=46047943&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2012068109(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to KR1020137015474A priority Critical patent/KR20130115300A/ko
Priority to HK14102178.4A priority patent/HK1189002B/en
Priority to ES11840803.8T priority patent/ES2568260T3/es
Priority to PH1/2013/500964A priority patent/PH12013500964A1/en
Priority to AU2011329028A priority patent/AU2011329028B2/en
Priority to NZ610225A priority patent/NZ610225A/en
Priority to CA2818125A priority patent/CA2818125A1/en
Priority to EA201390711A priority patent/EA025345B1/ru
Priority to MX2013005392A priority patent/MX2013005392A/es
Priority to CN201180055168.7A priority patent/CN103429574B/zh
Priority to JP2013539949A priority patent/JP6041808B2/ja
Priority to BR112013011868A priority patent/BR112013011868A2/pt
Application filed by Acetylon Pharmaceuticals Inc filed Critical Acetylon Pharmaceuticals Inc
Priority to SG2013035498A priority patent/SG190211A1/en
Priority to EP11840803.8A priority patent/EP2640709B1/en
Publication of WO2012068109A2 publication Critical patent/WO2012068109A2/en
Publication of WO2012068109A3 publication Critical patent/WO2012068109A3/en
Priority to IL226326A priority patent/IL226326A0/en
Anticipated expiration legal-status Critical
Priority to PH12015500832A priority patent/PH12015500832A1/en
Priority to IL249594A priority patent/IL249594A0/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen 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
    • A61K31/495—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/04—Chelating agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D409/12—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 chain containing hetero atoms as chain links

Definitions

  • Ri is H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroarylalkyl, heteroaryl, heterocyclic, carbocyclic, -C(0)R 5 , or -S(0) P R 5 ; each of which may be optionally substituted; and
  • each R5 is independently H; optionally substituted alkyl, optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl;
  • cycloalkyl denotes a monovalent group derived from a monocyclic or polycyclic saturated or partially unsatured carbocyclic ring compound.
  • compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted. " In general, the term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
  • heteroaralkyl “optionally substituted heterocycloalkyl,” and any other optionally substituted group as used herein, refer to groups that are substituted or unsubstituted by independent replacement of one, two, or three or more of the hydrogen atoms thereon with substituents including, but not limited to:
  • This invention also encompasses pharmaceutical compositions containing, and methods of treating disorders through administering, pharmaceutically acceptable prodrugs of compounds of the invention.
  • compounds of the invention having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the invention.
  • phosphoryloxymethyloxy carbonyls as outlined in Advanced Drug Delivery Reviews, 1996, 19, 1 15.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
  • Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10.
  • Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities
  • R 2 is H.
  • each R A is indpendently alkyl, alkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, arylalkyl, heteroarylalkyl, haloalkyl, haloalkoxy, halo, OH, -N0 2 , -CN, or -NH 2 ; or two R A groups together with the atoms to which each is attached, can form an optionally substituted ring; and
  • each R A is indpendently alkyl, alkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, arylalkyl, heteroarylalkyl, haloalkyl, haloalkoxy, halo, OH, -N0 2 , -CN, or -NH 2 ; or two R A groups together with the atoms to which each is attached, can form an optionally substituted ring; and m is 0, 1 , or 2.
  • R X and R Y together with the carbon to which each is attached, forms a cycloalkyl or heterocycloalkyl, each of which is optionally substituted;
  • R X is ⁇ , methyl or pyridine
  • R Y is ⁇ .
  • a compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
  • the resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981).
  • the compounds of this invention may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
  • any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion. All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
  • methods for the treatment of cancer comprising administering a therapeutically effective amount of an inventive compound (i.e., of any of the formulae herein), as described herein, to a subject in need thereof.
  • an inventive compound i.e., of any of the formulae herein
  • the subject is identified as in need of such treatment.
  • a method for the treatment of cancer comprising
  • MM Multiple myeloma
  • Novel agents have recently been developed which target not only MM cells, but also the bone marrow (BM) microenvironment, and can overcome conventional drug resistance
  • bortezomib enhances sensitivity and can overcome resistance in MM cells to conventional
  • the present invention in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and a carrier suitable for coating said implantable device.
  • the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and a carrier suitable for coating said implantable device.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any of the formulae herein (e.g., formula I), or a pharmaceutically acceptable ester, salt, or prodrug thereof, together with a pharmaceutically acceptable carrier.
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • HDAC1 0.2 ng/ml
  • HDAC2 0.08 ng/ml
  • HDAC3 2 ng/ml
  • the final substrate concentrations used were 16 ⁇ (HDAC1), 10 ⁇ (HDAC2), 17 ⁇ (HDAC3) and 14 ⁇ (HDAC6).
  • Five ⁇ of compounds and 20 ⁇ of enzyme were added to wells of a black, opaque 384 well plate in duplicate. Enzyme and compound were incubated together at room temperature for 10 minutes. Five ⁇ of substrate was added to each well, the plate was shaken for 60 seconds and placed into a Victor 2 microtiter plate reader. The development of fluorescence was monitored for 60 min and the linear rate of the reaction was calculated.
  • the IC 50 was determined using Graph Pad Prism by a four parameter curve fit.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Immunology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pulmonology (AREA)
  • Dermatology (AREA)
  • Rheumatology (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Endocrinology (AREA)
  • Oncology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Addiction (AREA)
  • Emergency Medicine (AREA)
  • Transplantation (AREA)
  • Hospice & Palliative Care (AREA)
  • Obesity (AREA)
PCT/US2011/060791 2010-11-16 2011-11-15 Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof Ceased WO2012068109A2 (en)

Priority Applications (17)

Application Number Priority Date Filing Date Title
EP11840803.8A EP2640709B1 (en) 2010-11-16 2011-11-15 Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof
JP2013539949A JP6041808B2 (ja) 2010-11-16 2011-11-15 蛋白質脱アセチル化酵素抑制剤としてのピリミジン水酸基アミド化合物およびその利用方法
ES11840803.8T ES2568260T3 (es) 2010-11-16 2011-11-15 Compuestos de pirimidin hidroxi amida como inhibidores de proteína desacetilasa y métodos de uso de los mismos
PH1/2013/500964A PH12013500964A1 (en) 2010-11-16 2011-11-15 Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof
AU2011329028A AU2011329028B2 (en) 2010-11-16 2011-11-15 Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof
NZ610225A NZ610225A (en) 2010-11-16 2011-11-15 Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof
CA2818125A CA2818125A1 (en) 2010-11-16 2011-11-15 Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof
EA201390711A EA025345B1 (ru) 2010-11-16 2011-11-15 Гидроксиамидные соединения пиримидина в качестве ингибиторов деацетилаз белков и фармацевтические композиции для лечения заболевания, обусловленного hdac6, включающие эти соединения
MX2013005392A MX2013005392A (es) 2010-11-16 2011-11-15 Compuestos de hidroxiamida pirimidina como inhibidores de la proteina deacetilasa y metodo de uso de estos.
KR1020137015474A KR20130115300A (ko) 2010-11-16 2011-11-15 단백질 탈아세틸화 효소 억제제로서 피리미딘 하이드록시 아미드 화합물 및 그의 사용방법
BR112013011868A BR112013011868A2 (pt) 2010-11-16 2011-11-15 compostos de pirimidina hidróxi amida como inibidores da proteína desacetilase, composição farmacêutica e uso dos referidos compostos
HK14102178.4A HK1189002B (en) 2010-11-16 2011-11-15 Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof
CN201180055168.7A CN103429574B (zh) 2010-11-16 2011-11-15 作为蛋白质去乙酰化酶抑制剂的嘧啶羟基酰胺化合物和其使用方法
SG2013035498A SG190211A1 (en) 2010-11-16 2011-11-15 Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof
IL226326A IL226326A0 (en) 2010-11-16 2013-05-13 Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof
PH12015500832A PH12015500832A1 (en) 2010-11-16 2015-04-16 Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof
IL249594A IL249594A0 (en) 2010-11-16 2016-12-15 Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US41415810P 2010-11-16 2010-11-16
US61/414,158 2010-11-16
US201161503286P 2011-06-30 2011-06-30
US61/503,286 2011-06-30

Publications (2)

Publication Number Publication Date
WO2012068109A2 true WO2012068109A2 (en) 2012-05-24
WO2012068109A3 WO2012068109A3 (en) 2012-08-02

Family

ID=46047943

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2011/060791 Ceased WO2012068109A2 (en) 2010-11-16 2011-11-15 Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof

Country Status (19)

Country Link
US (3) US8614223B2 (enExample)
EP (2) EP3067346A1 (enExample)
JP (2) JP6041808B2 (enExample)
KR (1) KR20130115300A (enExample)
CN (2) CN103429574B (enExample)
AU (2) AU2011329028B2 (enExample)
BR (1) BR112013011868A2 (enExample)
CA (1) CA2818125A1 (enExample)
CL (1) CL2013001381A1 (enExample)
EA (2) EA201691121A1 (enExample)
ES (1) ES2568260T3 (enExample)
IL (2) IL226326A0 (enExample)
MX (1) MX2013005392A (enExample)
NZ (2) NZ710405A (enExample)
PH (2) PH12013500964A1 (enExample)
PL (1) PL2640709T3 (enExample)
PT (1) PT2640709T (enExample)
SG (2) SG10201509324QA (enExample)
WO (1) WO2012068109A2 (enExample)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8614223B2 (en) 2010-11-16 2013-12-24 Acetylon Pharmaceuticals, Inc. Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof
WO2015054175A1 (en) * 2013-10-11 2015-04-16 Acetylon Pharmaceuticals, Inc. Combinations of histone deactylase inhibitors and immunomodulatory drugs
WO2015054355A1 (en) * 2013-10-10 2015-04-16 Acetylon Pharmaceuticals, Inc. Hdac inhibitors, alone or in combination with pi3k inhibitors, for treating non-hodgkin's lymphoma
WO2015054099A1 (en) * 2013-10-08 2015-04-16 Acetylon Pharmaceuticals, Inc. Combinations of histone deacetylase inhibitors and either her2 inhibitors or pi3k inhibitors
WO2015061684A1 (en) 2013-10-24 2015-04-30 Mayo Foundation For Medical Education And Research Treatment of polycystic diseases with an hdac6 inhibitor
WO2016007423A1 (en) * 2014-07-07 2016-01-14 Acetylon Pharmaceuticals, Inc. Treatment of leukemia with histone deacetylase inhibitors
CN105939716A (zh) * 2013-12-03 2016-09-14 埃斯泰隆制药公司 组蛋白脱乙酰基酶抑制剂和免疫调节药物的组合
JP2016531163A (ja) * 2013-09-20 2016-10-06 アセチロン ファーマシューティカルズ インコーポレイテッドＡｃｅｔｙｌｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． Ｈｄａｃ６阻害物質を用いた、異常なリンパ球の機能に起因する疾患の治療
JP2016536354A (ja) * 2013-10-10 2016-11-24 アセチロン ファーマシューティカルズ インコーポレイテッドＡｃｅｔｙｌｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． 非ホジキンリンパ腫を治療するための、ｈｄａｃ阻害剤単独またはｂｔｋ阻害剤との組み合わせ
US10040769B2 (en) 2015-10-27 2018-08-07 Regenacy Pharmaceuticals, Llc HDAC inhibitors for the treatment of diabetic peripheral neuropathy
US10357493B2 (en) 2017-03-10 2019-07-23 Selenity Therapeutics (Bermuda), Ltd. Metalloenzyme inhibitor compounds
EP3569592A4 (en) * 2017-01-10 2020-08-12 Cstone Pharmaceutical (Suzhou) Co., Ltd. SELECTIVE HDAC6 INHIBITORS, THEIR METHOD OF PREPARATION AND THEIR APPLICATION
EP3755336A4 (en) * 2018-02-20 2021-12-01 Chong Kun Dang Pharmaceutical Corp. COMPOSITION TO PREVENT OR TREAT UVEITIS
JP7017309B2 (ja) 2013-12-20 2022-02-08 アセチロン ファーマシューティカルズ インコーポレイテッド 多発性骨髄腫におけるヒストン脱アセチル化酵素６（ｈｄａｃ６）バイオマーカー
RU2772274C2 (ru) * 2017-01-10 2022-05-18 Кстоун Фармасьютикалз (Сучжоу) Ко., Лтд. Селективные ингибиторы hdac6, способ их получения и их применение
US11571426B2 (en) 2017-11-24 2023-02-07 Chong Kun Dang Pharmaceutical Corp. Compositions for preventing or treating lupus
US11890356B2 (en) 2017-04-11 2024-02-06 The General Hospital Corporation HDAC6 inhibitors and imaging agents

Families Citing this family (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LT2526093T (lt) 2010-01-22 2016-10-10 Acetylon Pharmaceuticals, Inc. Grįžtamieji amido junginiai kaip baltymo deacetilazės inhibitoriai ir jų panaudojimo būdai
CA2868302A1 (en) 2012-03-23 2013-09-26 Dennis M. Brown Compositions and methods to improve the therapeutic benefit of indirubin and analogs thereof, including meisoindigo
HK1207403A1 (en) 2012-04-19 2016-01-29 Acetylon Pharmaceuticals, Inc. Biomarkers to identify patients that will respond to treatment and treating such patients
HK1213471A1 (zh) * 2012-10-12 2016-07-08 The Trustees Of The University Of Pennsylvania 作為蛋白脫乙酰基酶抑制劑的嘧啶羥基酰胺化合物及其使用方法
US9145412B2 (en) 2012-11-02 2015-09-29 Acetylon Pharmaceuticals, Inc. Selective HDAC1 and HDAC2 inhibitors
HK1220406A1 (zh) 2013-03-14 2017-05-05 Chdi Foundation, Inc. 组蛋白去乙酰酶抑制剂及组合物
WO2014159224A1 (en) 2013-03-14 2014-10-02 Chdi Foundation, Inc. Histone deacetylase inhibitors and compositions and methods of use thereof
EP3055299B1 (en) * 2013-10-10 2021-01-06 Acetylon Pharmaceuticals, Inc. Pyrimidine hydroxy amide compounds as histone deacetylase inhibitors
US9464073B2 (en) 2014-02-26 2016-10-11 Acetylon Pharmaceuticals, Inc. Pyrimidine hydroxy amide compounds as HDAC6 selective inhibitors
CN104974108B (zh) * 2014-04-04 2017-11-17 中国科学院上海药物研究所 一类2,2’‑串联双噻唑类化合物及其制备方法和用途
WO2015187542A1 (en) 2014-06-02 2015-12-10 Chdi Foundation Inc. Histone deacetylase inhibitors and compositions and methods of use thereof
WO2016090230A1 (en) * 2014-12-05 2016-06-09 Acetylon Pharmaceuticals, Inc. Pyrimidine hydroxy amide compounds for treating peripheral neuropathy
CA2969790A1 (en) 2014-12-05 2016-06-09 University of Modena and Reggio Emilia Combinations of histone deacetylase inhibitors and bendamustine
ES2816641T3 (es) 2014-12-12 2021-04-05 Regenacy Pharmaceuticals Inc Derivados de piperidina en calidad de inhibidores de HDAC1/2
CN104503831B (zh) * 2014-12-22 2017-10-13 北京奇虎科技有限公司 设备优化方法及装置
AR103598A1 (es) 2015-02-02 2017-05-24 Forma Therapeutics Inc Ácidos bicíclicos[4,6,0]hidroxámicos como inhibidores de hdac
AU2016215432B2 (en) 2015-02-02 2020-07-30 Valo Early Discovery, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
WO2016169417A1 (zh) * 2015-04-21 2016-10-27 成都金瑞长青生物科技有限公司 嘌呤基-n-羟基嘧啶甲酰胺衍生物及其制备方法和用途
US10272084B2 (en) 2015-06-01 2019-04-30 Regenacy Pharmaceuticals, Llc Histone deacetylase 6 selective inhibitors for the treatment of cisplatin-induced peripheral neuropathy
EP3303306B1 (en) 2015-06-08 2020-02-12 Acetylon Pharmaceuticals, Inc. Crystalline forms of a histone deacetylase inhibitor
WO2016200930A1 (en) 2015-06-08 2016-12-15 Acetylon Pharmaceuticals, Inc. Methods of making protein deacetylase inhibitors
JP2019515909A (ja) 2016-04-19 2019-06-13 アセチロン ファーマシューティカルズ インコーポレイテッドＡｃｅｔｙｌｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． 慢性リンパ性白血病の治療を目的とするｈｄａｃ阻害剤単独またはｂｔｋ阻害剤との配合物
EP3463366A4 (en) * 2016-06-07 2020-01-08 Dermavant Sciences GmbH TOPICAL FORMULATIONS OF PDE-4 INHIBITORS AND THEIR METHOD FOR USE THEREOF
EP3472131B1 (en) 2016-06-17 2020-02-19 Forma Therapeutics, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as hdac inhibitors
EP3496751B1 (en) 2016-08-08 2022-10-19 Acetylon Pharmaceuticals Inc. Pharmaceutical combinations of histone deacetylase 6 inhibitors and cd20 inhibitory antibodies and uses thereof
ES2969242T3 (es) 2016-11-10 2024-05-17 Acetylon Pharmaceuticals Inc Acidos fenil y piridinil hidroxámicos
JP7090611B2 (ja) 2016-11-23 2022-06-24 アセチロン ファーマシューティカルズ インコーポレイテッド ヒストン脱アセチル化酵素阻害剤とプログラム細胞死リガンド１（ｐｄ－ｌ１）阻害剤とを含む医薬組み合わせ物及びその使用方法
IT201700041723A1 (it) * 2017-04-14 2018-10-14 Italfarmaco Spa Nuovi inibitori selettivi di HDAC6
CN108299313B (zh) * 2018-01-16 2020-10-02 长沙霍滋生物科技有限公司 一种化合物及其在药学上的应用
CN108129367B (zh) * 2018-02-05 2020-10-02 南开大学 一种构建手性亚磺酰亚胺α位手性四级碳的构建方法及其产品与应用
EP3822267B1 (en) 2018-07-04 2023-08-30 Cstone Pharmaceuticals (Suzhou) Co., Ltd. Polymorph of hdac6-selective inhibitor and application thereof
JP2022504799A (ja) * 2018-10-12 2022-01-13 チョン クン ダン ファーマシューティカル コーポレーション ヒストン脱アセチル化酵素阻害剤およびメトトレキサートを含む薬学的組成物
CN111848454B (zh) * 2019-04-28 2021-05-07 山东大学 一种组蛋白去乙酰化酶6抑制剂及其制备方法和应用
WO2021110121A1 (zh) * 2019-12-05 2021-06-10 基石药业（苏州）有限公司 Hdac6选择性抑制剂及其组合疗法
CN114315736B (zh) * 2020-03-30 2025-11-18 甫康（上海）健康科技有限责任公司 二氢化茚胺类衍生物、其制备方法和用途
TWI864293B (zh) * 2020-06-08 2024-12-01 安基生技新藥股份有限公司 選擇性hdac6抑制劑及其用途
CN112029738B (zh) * 2020-08-18 2022-04-29 浙江省人民医院 人parkin蛋白乙酰化及其在药物制备中的应用
CN113024536B (zh) * 2021-03-12 2022-05-27 湖南师范大学 含嘧啶-哌嗪环的5-氨基噻唑甲酰胺类化合物及其制备方法和用途
US20250179065A1 (en) * 2022-02-03 2025-06-05 Eikonizo Therapeutics, Inc. Hdac6 inhibitors and uses thereof

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5304121A (en) 1990-12-28 1994-04-19 Boston Scientific Corporation Drug delivery system making use of a hydrogel polymer coating
US5837313A (en) 1995-04-19 1998-11-17 Schneider (Usa) Inc Drug release stent coating process
US5886026A (en) 1993-07-19 1999-03-23 Angiotech Pharmaceuticals Inc. Anti-angiogenic compositions and methods of use
US5891507A (en) 1997-07-28 1999-04-06 Iowa-India Investments Company Limited Process for coating a surface of a metallic stent
US6071305A (en) 1996-11-25 2000-06-06 Alza Corporation Directional drug delivery stent and method of use
US6099562A (en) 1996-06-13 2000-08-08 Schneider (Usa) Inc. Drug coating with topcoat
US6153252A (en) 1998-06-30 2000-11-28 Ethicon, Inc. Process for coating stents
US6203551B1 (en) 1999-10-04 2001-03-20 Advanced Cardiovascular Systems, Inc. Chamber for applying therapeutic substances to an implant device
US6231600B1 (en) 1995-02-22 2001-05-15 Scimed Life Systems, Inc. Stents with hybrid coating for medical devices
US6248127B1 (en) 1998-08-21 2001-06-19 Medtronic Ave, Inc. Thromboresistant coated medical device
US6251136B1 (en) 1999-12-08 2001-06-26 Advanced Cardiovascular Systems, Inc. Method of layering a three-coated stent using pharmacological and polymeric agents
US6258121B1 (en) 1999-07-02 2001-07-10 Scimed Life Systems, Inc. Stent coating
US6273913B1 (en) 1997-04-18 2001-08-14 Cordis Corporation Modified stent useful for delivery of drugs along stent strut
US6517889B1 (en) 2001-11-26 2003-02-11 Swaminathan Jayaraman Process for coating a surface of a stent

Family Cites Families (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3549633A (en) * 1968-11-20 1970-12-22 Merck & Co Inc Process for preparation of 1-h-imidazo (4,5-b)pyrazin-2-ones
US6777217B1 (en) 1996-03-26 2004-08-17 President And Fellows Of Harvard College Histone deacetylases, and uses related thereto
US20030129724A1 (en) 2000-03-03 2003-07-10 Grozinger Christina M. Class II human histone deacetylases, and uses related thereto
US7244853B2 (en) 2001-05-09 2007-07-17 President And Fellows Of Harvard College Dioxanes and uses thereof
AU2002363174B2 (en) 2001-11-01 2008-09-25 Janssen Pharmaceutica N.V. Amide derivatives as glycogen synthase kinase 3-beta inhibitors
ES2347544T3 (es) * 2002-03-13 2010-11-02 Janssen Pharmaceutica Nv Inhibidores de histona-desacetilasas.
NZ534771A (en) * 2002-03-13 2006-04-28 Janssen Pharmaceutica Nv Sulfonylamino-derivatives as novel inhibitors of histone deacetylase
US7154002B1 (en) 2002-10-08 2006-12-26 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7132425B2 (en) * 2002-12-12 2006-11-07 Hoffmann-La Roche Inc. 5-substituted-six-membered heteroaromatic glucokinase activators
US7169801B2 (en) 2003-03-17 2007-01-30 Takeda San Diego, Inc. Histone deacetylase inhibitors
AU2004261373B8 (en) * 2003-07-24 2010-11-04 Basf Se 2-substituted pyrimidines
EP1663953A1 (en) * 2003-09-24 2006-06-07 Methylgene, Inc. Inhibitors of histone deacetylase
AU2005230682B2 (en) 2004-04-05 2010-10-21 Merck Hdac Research, Llc Histone deacetylase inhibitor prodrugs
EP3354265A1 (en) 2005-03-22 2018-08-01 President and Fellows of Harvard College Treatment of solid tumors
GB0510204D0 (en) * 2005-05-19 2005-06-22 Chroma Therapeutics Ltd Enzyme inhibitors
JP2009509923A (ja) * 2005-08-26 2009-03-12 メシルジーン、インコーポレイテッド ヒストンデアセチラーゼのベンゾジアゼピン及びベンゾピペラジン類似体阻害薬
CN101379059A (zh) * 2006-02-07 2009-03-04 安斯泰来制药有限公司 N-羟基丙烯酰胺化合物
CN101400362B (zh) 2006-02-14 2016-10-12 哈佛大学校长及研究员协会 双官能组蛋白去乙酰化酶抑制剂
US8304451B2 (en) 2006-05-03 2012-11-06 President And Fellows Of Harvard College Histone deacetylase and tubulin deacetylase inhibitors
CN105481788A (zh) * 2006-10-28 2016-04-13 梅特希尔基因公司 组蛋白脱乙酰酶抑制剂
JP2011502133A (ja) * 2007-11-02 2011-01-20 メシルジーン インコーポレイテッド ヒストンデアセチラーゼの阻害剤
WO2009137503A1 (en) * 2008-05-05 2009-11-12 Envivo Pharmaceuticals, Inc. Hdac inhibitors and uses thereof
WO2009137462A2 (en) * 2008-05-05 2009-11-12 Envivo Pharmaceuticals, Inc. Methods for treating cognitive disorders using inhibitors of histone deacetylase
CA2729965A1 (en) * 2008-07-14 2010-01-21 Gilead Sciences, Inc. Fused heterocyclyc inhibitor compounds
CA2731730C (en) 2008-07-23 2017-06-13 President And Fellows Of Harvard College Deacetylase inhibitors and uses thereof
CA2749228C (en) * 2009-01-08 2016-05-17 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
WO2010099155A1 (en) 2009-02-26 2010-09-02 Arkema Inc. Rotational molded article formed from high molecular weight polyamides
WO2011011186A2 (en) * 2009-07-22 2011-01-27 The Board Of Trustees Of The University Of Illinois Hdac inhibitors and therapeutic methods using the same
WO2011019393A2 (en) 2009-08-11 2011-02-17 President And Fellows Of Harvard College Class- and isoform-specific hdac inhibitors and uses thereof
US20130040998A1 (en) 2010-01-08 2013-02-14 Dana-Farber Cancer Institute, Inc. Fluorinated hdac inhibitors and uses thereof
LT2526093T (lt) 2010-01-22 2016-10-10 Acetylon Pharmaceuticals, Inc. Grįžtamieji amido junginiai kaip baltymo deacetilazės inhibitoriai ir jų panaudojimo būdai
WO2012018499A2 (en) * 2010-08-05 2012-02-09 Acetylon Pharmaceuticals Specific regulation of cytokine levels by hdac6 inhibitors
JP6041808B2 (ja) 2010-11-16 2016-12-14 アセチロン ファーマシューティカルズ インコーポレイテッドＡｃｅｔｙｌｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． 蛋白質脱アセチル化酵素抑制剤としてのピリミジン水酸基アミド化合物およびその利用方法
EP2524918A1 (en) * 2011-05-19 2012-11-21 Centro Nacional de Investigaciones Oncológicas (CNIO) Imidazopyrazines derivates as kinase inhibitors
HK1207403A1 (en) 2012-04-19 2016-01-29 Acetylon Pharmaceuticals, Inc. Biomarkers to identify patients that will respond to treatment and treating such patients
US9145412B2 (en) 2012-11-02 2015-09-29 Acetylon Pharmaceuticals, Inc. Selective HDAC1 and HDAC2 inhibitors
US9139583B2 (en) 2013-02-01 2015-09-22 Acetylon Pharmaceuticals, Inc. Selective HDAC3 inhibitors
WO2014121062A1 (en) 2013-02-01 2014-08-07 Acetylon Pharmaceuticals, Inc. Selective hdac3 inhibitors
WO2014197471A1 (en) 2013-06-03 2014-12-11 Acetylon Pharmaceuticals, Inc. Histone deacetylase ( hdac) biomarkers in multiple myeloma
US9403779B2 (en) 2013-10-08 2016-08-02 Acetylon Pharmaceuticals, Inc. Combinations of histone deacetylase inhibitors and either Her2 inhibitors or PI3K inhibitors
ES2818933T3 (es) 2013-10-10 2021-04-14 Acetylon Pharmaceuticals Inc Inhibidores de la HDAC en combinación con los inhibidores de la pi3k, para el tratamiento del linfoma no Hodgkin
JP2016536354A (ja) 2013-10-10 2016-11-24 アセチロン ファーマシューティカルズ インコーポレイテッドＡｃｅｔｙｌｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． 非ホジキンリンパ腫を治療するための、ｈｄａｃ阻害剤単独またはｂｔｋ阻害剤との組み合わせ
EP3055299B1 (en) 2013-10-10 2021-01-06 Acetylon Pharmaceuticals, Inc. Pyrimidine hydroxy amide compounds as histone deacetylase inhibitors
EP3054939A4 (en) 2013-10-11 2017-12-13 Acetylon Pharmaceuticals, Inc. Combinations of histone deactylase inhibitors and immunomodulatory drugs
US9949972B2 (en) 2013-12-03 2018-04-24 Acetylon Pharmaceuticals, Inc Combinations of histone deacetylase inhibitors and immunomodulatory drugs

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5304121A (en) 1990-12-28 1994-04-19 Boston Scientific Corporation Drug delivery system making use of a hydrogel polymer coating
US5886026A (en) 1993-07-19 1999-03-23 Angiotech Pharmaceuticals Inc. Anti-angiogenic compositions and methods of use
US6231600B1 (en) 1995-02-22 2001-05-15 Scimed Life Systems, Inc. Stents with hybrid coating for medical devices
US5837313A (en) 1995-04-19 1998-11-17 Schneider (Usa) Inc Drug release stent coating process
US6099562A (en) 1996-06-13 2000-08-08 Schneider (Usa) Inc. Drug coating with topcoat
US6071305A (en) 1996-11-25 2000-06-06 Alza Corporation Directional drug delivery stent and method of use
US6273913B1 (en) 1997-04-18 2001-08-14 Cordis Corporation Modified stent useful for delivery of drugs along stent strut
US20010027340A1 (en) 1997-04-18 2001-10-04 Carol Wright Stent with therapeutically active dosage of rapamycin coated thereon
US5891507A (en) 1997-07-28 1999-04-06 Iowa-India Investments Company Limited Process for coating a surface of a metallic stent
US6153252A (en) 1998-06-30 2000-11-28 Ethicon, Inc. Process for coating stents
US6248127B1 (en) 1998-08-21 2001-06-19 Medtronic Ave, Inc. Thromboresistant coated medical device
US6258121B1 (en) 1999-07-02 2001-07-10 Scimed Life Systems, Inc. Stent coating
US6203551B1 (en) 1999-10-04 2001-03-20 Advanced Cardiovascular Systems, Inc. Chamber for applying therapeutic substances to an implant device
US6251136B1 (en) 1999-12-08 2001-06-26 Advanced Cardiovascular Systems, Inc. Method of layering a three-coated stent using pharmacological and polymeric agents
US6517889B1 (en) 2001-11-26 2003-02-11 Swaminathan Jayaraman Process for coating a surface of a stent

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
GROZINGER ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 96, 1999, pages 4868 - 4873
HASSIG ET AL., CURR. OPIN. CHEM. BIOL., vol. 1, 1997, pages 300 - 308
HIDESHIMA, T. ET AL., ONCOGENE, vol. 23, 2004, pages 8766 - 8776
HU ET AL., J. BIOL. CHEM., vol. 275, 2000, pages 15254 - 15264
JOHNSTONE ET AL., NATURE REVIEWS DRUG DISCOVERY, 2002, pages 287
KAO ET AL., GENES DEV., vol. 14, 2000, pages 55 - 66
MARKS ET AL., NATURE REVIEWS CANCER, vol. 7, 2001, pages 194
MITCHISON, CHEM. AND BIOL., vol. 15 3, 1994
SCHREIBER ET AL., J. AM. CHEM. SOC, vol. 112, 1990, pages 5583
See also references of EP2640709A4
TAUNTON ET AL., SCIENCE, vol. 272, 1996, pages 408 - 411
VENTER ET AL., SCIENCE, vol. 291, 2001, pages 1304 - 1351,6174-6177
WARRELL ET AL., J. NATL. CANCER INST., vol. 90, 1998, pages 1621 - 1625
YANG ET AL., J. BIOL. CHEM., vol. 272, 1997, pages 28001 - 28007
ZHOU ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 98, 2001, pages 10572 - 10577

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8614223B2 (en) 2010-11-16 2013-12-24 Acetylon Pharmaceuticals, Inc. Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof
JP2016531163A (ja) * 2013-09-20 2016-10-06 アセチロン ファーマシューティカルズ インコーポレイテッドＡｃｅｔｙｌｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． Ｈｄａｃ６阻害物質を用いた、異常なリンパ球の機能に起因する疾患の治療
JP2016536286A (ja) * 2013-10-08 2016-11-24 アセチロン ファーマシューティカルズ インコーポレイテッドＡｃｅｔｙｌｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． ヒストンデアセチラーゼ阻害剤とＨｅｒ２阻害剤またはＰＩ３Ｋ阻害剤のいずれかの組み合わせ
WO2015054099A1 (en) * 2013-10-08 2015-04-16 Acetylon Pharmaceuticals, Inc. Combinations of histone deacetylase inhibitors and either her2 inhibitors or pi3k inhibitors
US10722512B2 (en) 2013-10-08 2020-07-28 Acetylon Pharmaceuticals, Inc. Combinations of histone deacetylase inhibitors and either HER2 inhibitors or PI3K inhibitors
US9403779B2 (en) 2013-10-08 2016-08-02 Acetylon Pharmaceuticals, Inc. Combinations of histone deacetylase inhibitors and either Her2 inhibitors or PI3K inhibitors
WO2015054355A1 (en) * 2013-10-10 2015-04-16 Acetylon Pharmaceuticals, Inc. Hdac inhibitors, alone or in combination with pi3k inhibitors, for treating non-hodgkin's lymphoma
JP2016536354A (ja) * 2013-10-10 2016-11-24 アセチロン ファーマシューティカルズ インコーポレイテッドＡｃｅｔｙｌｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． 非ホジキンリンパ腫を治療するための、ｈｄａｃ阻害剤単独またはｂｔｋ阻害剤との組み合わせ
JP2016532668A (ja) * 2013-10-10 2016-10-20 アセチロン ファーマシューティカルズ インコーポレイテッドＡｃｅｔｙｌｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． 非ホジキンリンパ腫を治療するための、ｈｄａｃ阻害剤単独またはｐｉ３ｋ阻害剤との組み合わせ
WO2015054175A1 (en) * 2013-10-11 2015-04-16 Acetylon Pharmaceuticals, Inc. Combinations of histone deactylase inhibitors and immunomodulatory drugs
CN105722507A (zh) * 2013-10-11 2016-06-29 埃斯泰隆制药公司 组蛋白脱乙酰酶抑制剂与免疫调节药物的组合
JP2016532667A (ja) * 2013-10-11 2016-10-20 アセチロン ファーマシューティカルズ インコーポレイテッドＡｃｅｔｙｌｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． ヒストンデアセチラーゼ阻害薬及び免疫調節薬の組み合わせ
WO2015061684A1 (en) 2013-10-24 2015-04-30 Mayo Foundation For Medical Education And Research Treatment of polycystic diseases with an hdac6 inhibitor
JP2016534069A (ja) * 2013-10-24 2016-11-04 メイヨ・ファウンデーション・フォー・メディカル・エデュケーション・アンド・リサーチ Ｈｄａｃ６阻害剤での多嚢胞性疾患の治療
US11666569B2 (en) 2013-10-24 2023-06-06 National Institutes Of Health (Nih), U.S. Dept. Of Health And Human Services (Dhhs) U.S. Government Treatment of polycystic diseases with an HDAC6 inhibitor
JP2021073253A (ja) * 2013-10-24 2021-05-13 メイヨ・ファウンデーション・フォー・メディカル・エデュケーション・アンド・リサーチ Ｈｄａｃ６阻害剤での多嚢胞性疾患の治療
US10660890B2 (en) 2013-10-24 2020-05-26 National Institutes Of Health (Nih), U.S. Dept. Of Health And Human Services (Dhhs), U.S. Government Nih Division Of Extramural Inventions And Technology Resources (Deitr) Treatment of polycystic diseases with an HDAC6 inhibitor
CN105939716A (zh) * 2013-12-03 2016-09-14 埃斯泰隆制药公司 组蛋白脱乙酰基酶抑制剂和免疫调节药物的组合
US9949972B2 (en) 2013-12-03 2018-04-24 Acetylon Pharmaceuticals, Inc Combinations of histone deacetylase inhibitors and immunomodulatory drugs
JP7017309B2 (ja) 2013-12-20 2022-02-08 アセチロン ファーマシューティカルズ インコーポレイテッド 多発性骨髄腫におけるヒストン脱アセチル化酵素６（ｈｄａｃ６）バイオマーカー
US9833466B2 (en) 2014-07-07 2017-12-05 Acetylon Pharmaceuticals, Inc. Treatment of leukemia with histone deacetylase inhibitors
WO2016007423A1 (en) * 2014-07-07 2016-01-14 Acetylon Pharmaceuticals, Inc. Treatment of leukemia with histone deacetylase inhibitors
US10040769B2 (en) 2015-10-27 2018-08-07 Regenacy Pharmaceuticals, Llc HDAC inhibitors for the treatment of diabetic peripheral neuropathy
US10858323B2 (en) 2015-10-27 2020-12-08 Regenacy Pharmaceuticals, Llc HDAC inhibitors for the treatment of diabetic peripheral neuropathy
US10745389B2 (en) 2017-01-10 2020-08-18 Cstone Pharmaceuticals (Suzhou) Co., Ltd. HDAC6 selective inhibitors, preparation method therefor, and application thereof
RU2772274C2 (ru) * 2017-01-10 2022-05-18 Кстоун Фармасьютикалз (Сучжоу) Ко., Лтд. Селективные ингибиторы hdac6, способ их получения и их применение
EP3569592A4 (en) * 2017-01-10 2020-08-12 Cstone Pharmaceutical (Suzhou) Co., Ltd. SELECTIVE HDAC6 INHIBITORS, THEIR METHOD OF PREPARATION AND THEIR APPLICATION
US10357493B2 (en) 2017-03-10 2019-07-23 Selenity Therapeutics (Bermuda), Ltd. Metalloenzyme inhibitor compounds
US11938134B2 (en) 2017-03-10 2024-03-26 Eikonizo Therapeutics, Inc. Metalloenzyme inhibitor compounds
US12370194B2 (en) 2017-03-10 2025-07-29 Eikonizo Therapeutics, Inc. Metalloenzyme inhibitor compounds
US11890356B2 (en) 2017-04-11 2024-02-06 The General Hospital Corporation HDAC6 inhibitors and imaging agents
US12472271B2 (en) 2017-04-11 2025-11-18 The General Hospital Corporation HDAC6 inhibitors and imaging agents
US11571426B2 (en) 2017-11-24 2023-02-07 Chong Kun Dang Pharmaceutical Corp. Compositions for preventing or treating lupus
EP3755336A4 (en) * 2018-02-20 2021-12-01 Chong Kun Dang Pharmaceutical Corp. COMPOSITION TO PREVENT OR TREAT UVEITIS

Also Published As

Publication number Publication date
US8614223B2 (en) 2013-12-24
HK1189002A1 (zh) 2014-05-23
CN103429574B (zh) 2016-11-16
EP3067346A1 (en) 2016-09-14
AU2016266069A1 (en) 2016-12-22
PT2640709T (pt) 2016-07-13
WO2012068109A3 (en) 2012-08-02
CA2818125A1 (en) 2012-05-24
CN107011270A (zh) 2017-08-04
SG190211A1 (en) 2013-06-28
PH12013500964A1 (en) 2013-07-08
EP2640709B1 (en) 2016-04-06
CN103429574A (zh) 2013-12-04
BR112013011868A2 (pt) 2016-08-23
JP2013542994A (ja) 2013-11-28
JP6041808B2 (ja) 2016-12-14
PL2640709T3 (pl) 2016-10-31
EA025345B1 (ru) 2016-12-30
EP2640709A2 (en) 2013-09-25
US20140142104A1 (en) 2014-05-22
IL226326A0 (en) 2013-07-31
US9409890B2 (en) 2016-08-09
PH12015500832A1 (en) 2015-10-19
US20170096403A1 (en) 2017-04-06
AU2011329028A1 (en) 2013-05-30
NZ710405A (en) 2017-04-28
AU2011329028B2 (en) 2016-12-22
JP2017019820A (ja) 2017-01-26
NZ610225A (en) 2015-08-28
MX2013005392A (es) 2013-07-29
ES2568260T3 (es) 2016-04-28
IL249594A0 (en) 2017-02-28
CL2013001381A1 (es) 2014-04-11
EP2640709A4 (en) 2014-04-02
EA201691121A1 (ru) 2016-10-31
US20120121502A1 (en) 2012-05-17
KR20130115300A (ko) 2013-10-21
SG10201509324QA (en) 2015-12-30
EA201390711A1 (ru) 2014-03-31

Similar Documents

Publication Publication Date Title
EP2640709B1 (en) Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof
EP2526093B1 (en) Reverse amide compounds as protein deacetylase inhibitors and methods of use thereof
HK1228900A1 (en) Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof
HK1189002B (en) Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof
AU2011207289B2 (en) Reverse amide compounds as protein deacetylase inhibitors and methods of use thereof
HK1179254B (en) Reverse amide compounds as protein deacetylase inhibitors and methods of use thereof

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: 11840803

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 226326

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: MX/A/2013/005392

Country of ref document: MX

Ref document number: 12013500964

Country of ref document: PH

ENP Entry into the national phase

Ref document number: 2818125

Country of ref document: CA

Ref document number: 2013539949

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2013001381

Country of ref document: CL

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2011329028

Country of ref document: AU

Date of ref document: 20111115

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2011840803

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 201390711

Country of ref document: EA

ENP Entry into the national phase

Ref document number: 20137015474

Country of ref document: KR

Kind code of ref document: A

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112013011868

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: 12015500832

Country of ref document: PH

ENP Entry into the national phase

Ref document number: 112013011868

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20130513

WWE Wipo information: entry into national phase

Ref document number: 249594

Country of ref document: IL