WO2003076400A1 - New inhibitors of histone deacetylase - Google Patents

New inhibitors of histone deacetylase Download PDF

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Publication number
WO2003076400A1
WO2003076400A1 PCT/EP2003/002514 EP0302514W WO03076400A1 WO 2003076400 A1 WO2003076400 A1 WO 2003076400A1 EP 0302514 W EP0302514 W EP 0302514W WO 03076400 A1 WO03076400 A1 WO 03076400A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
amino
aminocι
alkyloxy
hydroxycι
Prior art date
Application number
PCT/EP2003/002514
Other languages
French (fr)
Inventor
Patrick René ANGIBAUD
Isabelle Noëlle Constance PILATTE
Sven Franciscus Anna Van Brandt
Bruno Roux
Peter Ten Holte
Marc Gustaaf Celine Verdonck
Lieven Meerpoel
Alexey Borisovich Dyatkin
Original Assignee
Janssen Pharmaceutica N.V.
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
Priority to JP2003574621A priority Critical patent/JP4644428B2/en
Priority to BR0308081-1A priority patent/BR0308081A/en
Application filed by Janssen Pharmaceutica N.V. filed Critical Janssen Pharmaceutica N.V.
Priority to EA200401201A priority patent/EA007272B1/en
Priority to EP03711980A priority patent/EP1485353B1/en
Priority to MXPA04008806A priority patent/MXPA04008806A/en
Priority to DK03711980.7T priority patent/DK1485353T3/en
Priority to NZ534834A priority patent/NZ534834A/en
Priority to AT03711980T priority patent/ATE521592T1/en
Priority to AU2003218736A priority patent/AU2003218736B2/en
Priority to CA2475764A priority patent/CA2475764C/en
Priority to KR10-2004-7011024A priority patent/KR20040090979A/en
Priority to US10/506,998 priority patent/US7816363B2/en
Priority to IL16400703A priority patent/IL164007A0/en
Publication of WO2003076400A1 publication Critical patent/WO2003076400A1/en
Priority to UA20041008334A priority patent/UA78031C2/en
Priority to HR20040799A priority patent/HRP20040799A2/en
Priority to IL164007A priority patent/IL164007A/en
Priority to NO20044194A priority patent/NO20044194L/en
Priority to US12/372,801 priority patent/US8268833B2/en
Priority to US12/372,785 priority patent/US8343988B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
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Definitions

  • This invention concerns compounds having histone deacetylase (HDAC) inhibiting enzymatic activity. It further relates to processes for their preparation, to compositions comprising them, as well as their use, both in vitro and in vivo, to inhibit HDAC and as a medicine, for instance as a medicine to inhibit proliferative conditions, such as cancer and psoriasis.
  • HDAC histone deacetylase
  • nucleosomes In all eukaryotic cells, genomic DNA in chromatine associates with histones to form nucleosomes. Each nucleosome consists of a protein octamer made up of two copies of each histones H2A, H2B, H3 and H4. DNA winds around this protein core, with the basic amino acids of the histones interacting with the negatively charged phosphate groups of the DNA. The most common posttranslational modification of these core histones is the reversible acetylation of the ⁇ -amino groups of conserved, highly basic N-terminal lysine residues.
  • Histone acetylation and deacetylation has long been linked to transcriptional control.
  • the recent cloning of the genes encoding different histone acetyltransferases and histone deacetylases provided a possible explanation for the relationship between histone acetylation and transcriptional control.
  • the reversible acetylation of histones can result in chromatin remodelling and as such act as a control mechanism for gene transcription.
  • histone deacetylation In general, hyperacetylation of histones facilitates gene expression, whereas histone deacetylation is correlated with transcriptional repression.
  • Histone acetyltransferases were shown to act as transcriptional coactivators, whereas histone deacetylases were found to belong to transcriptional repression pathways.
  • HDAC inhibitors can have great therapeutic potential in the treatment of cell proliferative diseases or conditions (Marks et al., Nature Reviews: Cancer 1: 194-202, 2001)
  • HDAC histone deacetylases
  • Trichostatin A has also been reported to be useful in the treatment of fibrosis, e.g. liver fibrosis and liver chirrhosis. (Geerts et al., European Patent Application EP 0 827 742, published 11 March, 1998).
  • Patent application WO01/38322 published on May 31, 2001 discloses amongst others inhibitors of histone deacetylase of general formula Cy-L 1 -Ar-Y 1 -C(O)-NH-Z, providing compositions and methods for treating cell proliferative diseases and conditions.
  • Patent application WO01/70675 published on 27 September, 2001 discloses inhibitors of histone deacetylase of formula Cy 2 -Cy 1 -X- Y ! -W and further provides compositions and methods for treating cell proliferative diseases and conditions.
  • the problem to be solved is to provide histone deacetylase inhibitors with high enzymatic activity and also show advantageous properties such as cellular activity and increased bioavailability, preferably oral bioavailability, and have little or no side effects.
  • novel compounds of the present invention solve the above described problem.
  • the compounds differ from the prior art in structure.
  • the compounds of the present invention show excellent in-vitro histone deacetylase inhibiting enzymatic activity.
  • the present compounds have advantageous properties with regard to cellular activity and specific properties with regard to inhibition of cell cycle progression at both Gl and G2 checkpoints (p21 induction capacity).
  • the compounds of the present invention show good metabolic stability and high bioavailability and more particular they show oral bioavailability.
  • This invention concerns compounds of formula (I)
  • N-oxide forms, the pharmaceutically acceptable addition salts and the stereo- chemically isomeric forms thereof wherein n is 0, 1, 2 or 3 and when n is 0 then a direct bond is intended; t is 0, 1, 2, 3 or 4 and when t is 0 then a direct bond is intended;
  • each Q is nitrogen or ⁇ * ;
  • each X is nitrogen or ⁇ ;
  • each Y is nitrogen or ⁇ ;
  • R 1 is -C(O) ⁇ R 7 R 8 , -NHC(O)R 9 , -C(O)-C,- 6 alkanediylSR 9 , -NR 10 C(O)N(OH)R 9 ,
  • R 9 is independently selected from hydrogen, Ci- ⁇ alkyl, -ealkylcarbonyl, arylCi- ⁇ alkyl, C ⁇ . 6 alkylpyrazinyl, pyridinone, pyrrolidinone or methylimidazolyl;
  • R 10 is independently selected from hydrogen or C ⁇ .6--lkyl
  • R 2 is hydrogen, halo, hydroxy, amino, nitro, d- 6 alkyl, C ⁇ - 6 alkyloxy, trifluoromethyl, di(C ⁇ - 6 alkyl)amino, hydroxyamino or naphtalenylsulfonylpyrazinyl;
  • -L- is a direct bond or a bivalent radical selected from C ⁇ - 6 alkanediyl, C ⁇ - alkyloxy, amino, carbonyl or aminocarbonyl;
  • each R 3 independently represents a hydrogen atom and one hydrogen atom can be replaced by a substituent selected from aryl;
  • R -4 i ⁇ s hydrogen, hydroxy, amino, hydroxyC ⁇ 6 alkyl, C ⁇ - 6 alkyl, Ci- ⁇ alkyloxy, arylC ⁇ alkyl, aminocarbonyl, hydroxycarbonyl, aminoC ⁇ - 6 alkyl, aminocarbonylC ⁇ . 6 alkyl, hydroxycarbonylCi- ⁇ alkyl, hydroxyaminocarbonyl, C ⁇ - 6 alkyloxycarbonyl, C ⁇ - 6 alkylaminoC ⁇ - 6 alkyl or di(C ⁇ . 6 alkyl)aminoC ⁇ - 6 alkyl;
  • - ⁇ is a radical selected from
  • each s is independently 0, 1, 2, 3, 4 or 5; each R 5 and R 6 are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaloC ⁇ - 6 alkyl; trihaloC ⁇ - 6 alkyloxy; C ⁇ - 6 alkyl; Ci.galkyl substituted with aryl and
  • each R 5 and R 6 can be placed on the nitrogen in replacement of the hydrogen;
  • aryl in the above is phenyl, or phenyl substituted with one or more substituents each independently selected from halo, C ⁇ - 6 alkyl, -ealkyloxy, trifluoromethyl, cyano or hydroxycarbonyl.
  • 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 a 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.
  • halo is generic to fluoro, chloro, bromo and iodo
  • C j.4 alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, e.g. methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like
  • C j.g alkyl includes C.
  • C 3 -iocycloalkyl includes cyclic hydrocarbon groups having from 3 to 10 carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl and the like.
  • another Zn-chelating group refers to a group, which is capable of interacting with a Zn-ion, which can be present at an enzymatic binding site.
  • Pharmaceutically acceptable addition salts encompass pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • the pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms, which the compounds of formula (I) are able to form.
  • the compounds of formula (I) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g.
  • hydrochloric or hydrobromic acid sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, trifluoroacetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, -toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids.
  • the compounds of formula (I) which have acidic properties may be converted in their pharmaceutically acceptable base addition salts by treating said acid form with a suitable organic or inorganic base.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • the term "acid or base addition salts" also comprises the hydrates and the solvent addition forms, which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
  • stereochemically isomeric forms of compounds of formula (I) defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures, which are not interchangeable, which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms, which said compound might possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of formula (I) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
  • N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those N-oxides wherein one or more of the piperidine-, piperazine or pyridazinyl-nitrogens are N-oxidized.
  • 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 ⁇ -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 and HDAC-10.
  • the histone deacetylase can also be derived from a protozoal or fungal source.
  • a first group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply: a) n is 1 or 2; b) t is 0, 1, 2 or 4; c) each Q is ⁇ ; d) R 1 is -C(O)NH(OH); e) R 2 is hydrogen or nitro; f) -L- is a direct bond or a bivalent radical selected from C ⁇ _ 6 alkanediyl; g) R 4 is hydrogen; h) -0 XX a radical selected from (a-l),(a-2), (a-3), (a-5), (a-6), (a-11), (a-18), (a-20), (a-21), (a-32), (a-33), (a-47) or (a-51); i) each s is independently 0, 1, 2, or 4; j) each R 5 and R 6 are independently selected from hydrogen; halo; trihaloC ⁇ - 6 alkyl; C ⁇ - 6 alkyl; C ⁇ _ 6
  • a second group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply: a) n is 1 ; b) t is 0, 1 or 2; c) each Q is ⁇ ; d) each X is nitrogen; e) each Y is nitrogen; f) R 1 is -C(O)NH(OH); g) R 2 is hydrogen; h) -L- is a direct bond; i) each R 3 independently represents a hydrogen atom; j) R 4 is hydrogen; k) ⁇ S is a radical selected from (a-6), (a-11), (a-20), (a-47) or (a-51); 1) each s is independently 0, 1, or 4; m) each R 5 andR 6 are independently selected from hydrogen; C ⁇ - 6 alkyl; C ⁇ _ 6 alkyloxy; naphtalenylsulf onyl; or phenyl substituted with hydroxyC 1 _ 4 alkyl or morpholinylC i .
  • a third group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply: a) R 1 is -C(O)NH(OH); b) -L- is a direct bond.
  • a fourth group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply: a) t is 1, 2, 3, or 4; b) R 1 is -C(O)NR 7 R 8 , -C(O)-Cj. 6 alkanediylSR 9 , -NR 10 C(O)N(OH)R 9 ,
  • R and R are each independently selected from hydrogen, hydroxy, hydroxyC ⁇ - 6 alkyl or amino -ealkyl; c) R 2 is hydrogen, halo, hydroxy, amino, nitro, C!- 6 alkyl, C ⁇ - 6 alkyloxy, trifluoromethyl or di(C ⁇ - 6 alkyl)amino; d) -L- is a direct bond or a bivalent radical selected from C ⁇ - 6 alkanediyl,
  • R 4 is hydrogen, hydroxy, amino, hydroxyC ⁇ . 6 alkyl, C ⁇ - 6 alkyl, C ⁇ - 6 alkyloxy, arylCi.galkyl, aminocarbonyl, aminoC ⁇ - 6 alkyl, C ⁇ _ 6 alkylaminoC ⁇ _ 6 alkyl or di(C ⁇ - 6 alkyl)aminoC ⁇ - 6 alkyl; f) — ⁇ -) is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-
  • each s is independently 0, 1, 2, 3 or 4;
  • R 5 is hydrogen; halo; hydroxy; amino; nitro; trihaloCi_ 6 alkyl; trihaloC ⁇ - 6 alkyloxy;
  • R 6 is hydrogen; halo; hydroxy; amino; nitro; trihaloC ⁇ _ alkyl; trihaloC ⁇ - 6 alkyloxy; C ⁇ .
  • alkyl C ⁇ repay 6 alkyloxy; C ⁇ - 6 alkylcarbonyl; C ⁇ - 6 alkyloxycarbonyl; C ⁇ - 6 alkylsulfonyl; hydroxyC ⁇ _ 6 alkyl; aryloxy; di(C ⁇ . 6 alkyl)amino; cyano; pyridinyl; phenyl; or phenyl substituted with one or two substituents independently selected from halo, C ⁇ - 6 alkyl, C ⁇ _ 6 alkyloxy or trifluoromethyl.
  • a group of preferred compounds consists of those compounds of formula (I) wherein t is 1, 2, 3, or 4; R 1 is -C(O)NR 7 R 8 , -C(O)-d- 6 alkanediylSR 9 , -NR 10 C(O)N(OH)R 9 ,
  • R 7 and R 8 are each independently selected from hydrogen, hydroxy, hydroxyC ⁇ - 6 alkyl or amino - ⁇ alkyl;
  • R 2 is hydrogen, halo, hydroxy, amino, nitro, Ci- ⁇ alkyl, d- 6 alkyloxy, trifluoromethyl or di(C ⁇ - 6 alkyl)amino;
  • -L- is a direct bond or a bivalent radical selected from C ⁇ - 6 alkanediyl, Ci-galkanediyloxy, amino or carbonyl;
  • R 4 is hydrogen, hydroxy, amino, hydroxyC ⁇ _ 6 alkyl, C h alk !, C ⁇ _ 6 alkyloxy, arylC ⁇ . 6 alkyl, aminocarbonyl, aminoCi.galkyl, C ⁇ . 6 alkylaminoC ⁇ . 6 alkyl or di(C ⁇ - 6 alkyl)aminoC ⁇ . 6 alkyl;
  • ⁇ is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9),
  • each s is independently 0, 1, 2, 3 or 4;
  • R 5 is hydrogen; halo; hydroxy; amino; nitro; trihaloC ⁇ _ 6 alkyl; trihaloC ⁇ profession 6 alkyloxy; C ⁇ . 6 alkyl; C ⁇ . 6 alkyloxy; C ⁇ . 6 alkylcarbonyl; C ⁇ _ 6 alkyloxycarbonyl;
  • C ⁇ - 6 alkyloxypiperidinyl pyrazolyl; pyrazolyl substituted with one or two substituents selected from C ⁇ - alkyl or trihaloC ⁇ galkyl; pyridinyl; pyridinyl substituted with C ⁇ _ 6 alkyloxy, aryloxy or aryl; pyrimidinyl; quinolinyl; indole; phenyl; or phenyl substituted with one or two substituents independently selected from halo, C ⁇ .
  • R 6 is hydrogen; halo; hydroxy; amino; nitro; trihaloC ⁇ 6 alkyl; trihaloCj-galkyloxy; Ci- ⁇ alkyl; Ci- ⁇ alkyloxy; C ⁇ _ 6 alkylcarbonyl; C ⁇ - 6 alkyloxycarbonyl; C ⁇ - 6 alkylsulfonyl; hydroxyC ⁇ - 6 alkyl; aryloxy; di(C ⁇ _ 6 alkyl)amino; cyano; pyridinyl; phenyl; or phenyl substituted with one or two substituents independently selected from halo, C ⁇ _ alkyl, C ⁇ _ alkyloxy or trifluoromethyl.
  • a further group of preferred compounds are those compounds of formula (I) wherein n is 1 or 2; t is 0, 1, 2 or 4; each Q is " ⁇ ; R 1 is -C(O)NH(OH); R 2 is hydrogen or nitro; -L- is a direct bond or a bivalent radical selected from C ⁇ - 6 alkanediyl; R 4 is hydrogen; -( ⁇ -2 ⁇ is a radical selected from (a-l),(a-2), (a-3), (a-5), (a-6), (a-11), (a-18), (a-20), (a-21), (a-32), (a-33), (a-47) or (a-51); each s is independently 0, 1,
  • each R 5 and R 6 are independently selected from hydrogen; halo; trihaloC ⁇ _ 6 alkyl; C ⁇ . 6 alkyl; C ⁇ - 6 alkyl substituted with aryl and C 3 _ ⁇ ocycloalkyl; C ⁇ - 6 alkyloxy; C ⁇ - 6 alkylcarbonyl; benzofuranyl; naphtalenylsulf onyl; pyridinyl substituted with aryloxy; phenyl; or phenyl substituted with one substituent independently selected from hydroxyC ⁇ alkyl or morpholinylC i ⁇ alkyl.
  • a group of more preferred compounds are those compounds of formula (I) wherein n is
  • each s is independently 0, 1, or 4; and each R 5 and R 6 are independently selected from hydrogen; C ⁇ _ 6 alkyl; C ⁇ _ 6 alkyloxy; naphtalenylsulfonyl; or aryl substituted with hydroxyC ⁇ alkyl or morpholinylC ⁇ _ 4 alkyl.
  • the compounds of formula (I) and their pharmaceutically acceptable salts and N-oxides and stereochemically isomeric forms thereof may be prepared in a conventional manner.
  • a general synthesis route is encompassed as example: a) Hydroxamic acids of formula (I) wherein R 1 is -C(O)NH(OH), said compounds being referred to as compounds of formula (I-a), may be prepared by reacting an intermediate of formula (II) with an appropriate acid, such as for example, trifluoro acetic acid. Said reaction is performed in an appropriate solvent, such as, for example, methanol.
  • intermediates of formula (II) may be prepared by reacting an intermediate of formula (III) with an intermediate of formula (IV) in the presence of appropriate reagents such as N-(ethylcarbonimidoyl)-N,N-dimethyl-l,3-propanediamine, monohydrochloride (EDC) and 1-hydroxy-lH-benzotriazole ( ⁇ OBT).
  • EDC monohydrochloride
  • ⁇ OBT 1-hydroxy-lH-benzotriazole
  • the reaction may be performed in a suitable solvent such as a mixture of DCM and T ⁇ F.
  • intermediates of formula (HI) may be prepared by reacting an intermediate of formula (V) with an appropriate base such as NaOH in the presence of a suitable solvent such as ethanol.
  • the compounds of formula (I) can also conveniently be prepared using solid phase synthesis techniques.
  • solid phase synthesis involves reacting an intermediate in a synthesis with a polymer support. This polymer-supported intermediate can then be carried on through a number of synthesis steps. After each step, filtering the resin and washing it numerous times with various solvents remove impurities. At each step the resin can be split up to react with various intermediates in the next step thus allowing for the synthesis of a large number of compounds. After the last step in the procedure the resin is treated with a reagent or process to cleave the resin from the sample.
  • the compounds of formula (I) and some of the intermediates may have at least one stereogenic centre in their structure. This stereogenic centre may be present in an R or an S configuration.
  • the compounds of formula (I) as prepared in the hereinabove described processes can be racemic mixtures of enantiomers, which can be separated from one another following art-known resolution procedures.
  • the racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated there from by alkali.
  • An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • said compound would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the compounds of formula (I), the pharmaceutically acceptable acid addition salts and stereoisomeric forms thereof have valuable pharmacological properties in that they have a histone deacetylase (HDAC) inhibitory effect.
  • HDAC histone deacetylase
  • This invention provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of the invention.
  • Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g. loss of contact inhibition). This includes the inhibition of tumour growth both directly by causing growth arrest, terminal differentiation and/or apoptosis of cancer cells, and indirectly, by inhibiting neovascularization of tumours.
  • This invention also provides a method for inhibiting tumour growth by administering an effective amount of a compound of the present invention, to a subject, e.g. a mammal (and more particularly a human) in need of such treatment.
  • this invention provides a method for inhibiting the growth of tumours by the administration of an effective amount of the compounds of the present invention.
  • tumours which may be inhibited, but are not limited to, lung cancer (e.g. adenocarcinoma and including non-small cell lung cancer), pancreatic cancers (e.g. pancreatic carcinoma such as, for example exocrine pancreatic carcinoma), colon cancers (e.g.
  • colorectal carcinomas such as, for example, colon adenocarcinoma and colon adenoma
  • prostate cancer including the advanced disease, hematopoietic tumours of lymphoid lineage (e.g. acute lymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid foUicular cancer, myelodysplastic syndrome (MDS), tumours of mesenchymal origin (e.g.
  • lymphoid lineage e.g. acute lymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma
  • myeloid leukemias for example, acute myelogenous leukemia (AML)
  • AML acute myelogenous leukemia
  • MDS myelodysplastic syndrome
  • tumours of mesenchymal origin e.g.
  • fibrosarcomas and rhabdomyosarcomas melanomas, teratocarcinomas, neuroblastomas, gliomas, benign tumour of the skin (e.g. keratoacanthomas), breast carcinoma (e.g. advanced breast cancer), kidney carcinoma, ovary carcinoma, bladder carcinoma and epidermal carcinoma.
  • the compound according to the invention may be used for other therapeutic purposes, for example: a) the sensitisation of tumours to radiotherapy by administering the compound according to the invention before, during or after irradiation of the tumour for treating cancer; b) treating arthropathies and osteopathological conditions such as rheumatoid arthritis, osteoarthritis, juvenile arthritis, gout, polyarthritis, psoriatic arthritis, ankylosing spondylitis and systemic lupus erythematosus; c) inhibiting smooth muscle cell proliferation including vascular proliferative disorders, atherosclerosis and restenosis; d) treating inflammatory conditions and dermal conditions such as ulcerative colitis, Crohn's disease, allergic rhinitis, graft vs.
  • the present invention discloses the compounds of formula (I) for use as a medicine as well as the use of these compounds of formula (I) for the manufacture of a medicament for treating one or more of the above mentioned conditions.
  • the compounds of formula (I), the pharmaceutically acceptable acid addition salts and stereoisomeric forms thereof can have valuable diagnostic properties in that they can be used for detecting or identifying a HDAC in a biological sample comprising detecting or measuring the formation of a complex between a labelled compound and a HDAC.
  • the detecting or identifying methods can use compounds that are labelled with labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances, etc.
  • labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances, etc.
  • the radioisotopes include 12S I, 131 1, 3 H and 14 C.
  • Enzymes are usually made detectable by conjugation of an appropriate substrate which, in turn catalyses a detectable reaction. Examples thereof include, for example, beta- galactosidase, beta-glucosidase, alkaline phosphatase, peroxidase and malate dehydrogenase, preferably horseradish peroxidase.
  • the luminous substances include, for example, luminol, luminol derivatives, luciferin, aequorin and luciferase.
  • Bio samples can be defined as body tissue or body fluids.
  • body fluids are cerebrospinal fluid, blood, plasma, serum, urine, sputum, saliva and the like.
  • the subject compounds may be formulated into various pharmaceutical forms for administration purposes.
  • compositions of this invention an effective amount of a particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets.
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, to aid solubility for example, may be included.
  • injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin.
  • Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment.
  • Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient, calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.
  • dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
  • a therapeutically effective amount would be from 0.005 g/kg to 100 mg/kg body weight, and in particular from 0.005 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.5 to 500 mg, and in particular 10 mg to 500 mg of active ingredient per unit dosage form.
  • a combination of a HDAC-inhibitor with another anticancer agent is envisaged, especially for use as a medicine, more specifically in the treatment of cancer or related diseases.
  • the compounds of the invention may be advantageously employed in combination with one or more other medicinal agents, more particularly, with other anti-cancer agents.
  • anti-cancer agents are:
  • platinum coordination compounds for example cisplatin, carboplatin or oxalyplatin;
  • - taxane compounds for example paclitaxel or docetaxel
  • topoisomerase I inhibitors such as camptothecin compounds for example irinotecan or topotecan;
  • topoisomerase II inhibitors such as anti-tumour podophyllotoxin derivatives for example etoposide or teniposide;
  • - anti-tumour vinca alkaloids for example vinblastine, vincristine or vinorelbine;
  • - anti-tumour nucleoside derivatives for example 5-fluorouracil, gemcitabine or capecitabine; alkylating agents such as nitrogen mustard or nitrosourea for example cyclophosphamide, chlorambucil, carmustine or lomustine;
  • anti-tumour anthracycline derivatives for example daunorubicin, doxorubicin, idarubicin or mitoxantrone;
  • trastuzumab for example trastuzumab
  • estrogen receptor antagonists or selective estrogen receptor modulators for example tamoxifen, toremifene, droloxifene, faslodex or raloxifene;
  • aromatase inhibitors such as exemestane, anastrozole, letrazole and vorozole;
  • - differentiating agents such as retinoids, vitamin D and retinoic acid metabolism blocking agents (RAMB A) for example accutane;
  • - DNA methyl transferase inhibitors for example azacytidine
  • - kinase inhibitors for example flavoperidol, imatinib mesylate or gefitinib
  • platinum coordination compound is used herein to denote any tumor cell growth inhibiting platinum coordination compound which provides platinum in the form of an ion.
  • taxane compounds indicates a class of compounds having the taxane ring system and related to or derived from extracts from certain species of yew (Taxus) trees.
  • topisomerase inhibitors is used to indicate enzymes that are capable of altering DNA topology in eukaryotic cells. They are critical for important cellular functions and cell proliferation. There are two classes of topoisomerases in eukaryotic cells, namely type I and type II. Topoisomerase I is a monomeric enzyme of approximately 100,000 molecular weight. The enzyme binds to DNA and introduces a transient single-strand break, unwinds the double helix (or allows it to unwind) and subsequently reseals the break before dissociating from the DNA strand. Topisomerase II has a similar mechanism of action which involves the induction of DNA strand breaks or the formation of free radicals.
  • camptothecin compounds is used to indicate compounds that are related to or derived from the parent camptothecin compound which is a water-insoluble alkaloid derived from the Chinese tree Camptothecin acuminata and the Indian tree
  • podophyllotoxin compounds is used to indicate compounds that are related to or derived from the parent podophyllotoxin, which is extracted from the mandrake plant.
  • anti-tumor vinca alkaloids is used to indicate compounds that are related to or derived from extracts of the periwinkle plant (Vinca rosea).
  • alkylating agents' 7 encompass a diverse group of chemicals that have the common feature that they have the capacity to contribute, under physiological conditions, alkyl groups to biologically vital macromolecules such as DNA. With most of the more important agents such as the nitrogen mustards and the nitrosoureas, the active alkylating moieties are generated in vivo after complex degradative reactions, some of which are enzymatic. The most important pharmacological actions of the alkylating agents are those that disturb the fundamental mechanisms concerned with cell proliferation in particular DNA synthesis and cell division. The capacity of alkylating agents to interfere with DNA function and integrity in rapidly proliferating tissues provides the basis for their therapeutic applications and for many of their toxic properties.
  • anti-tumour anthracycline derivatives comprise antibiotics obtained from the fungus Strep, Promotionicus var. caesius and their derivatives, characterised by having a tetracycline ring structure with an unusual sugar, daunosamine, attached by a glycosidic linkage.
  • Trastuzumab is a highly purified recombinant DNA-derived humanized monoclonal IgGl kappa antibody that binds with high affinity and specificity to the extracellular domain of the HER2 receptor.
  • estrogen receptor antagonists and “selective estrogen receptor modulators” are used to indicate competitive inhibitors of estradiol binding to the estrogen receptor (ER).
  • Selective estrogen receptor modulators when bond to the ER, induces a change in the three-dimensional shape of the receptor, inhibiting its binding to the estrogen responsive element (ERE) on DNA.
  • estrogen deprivation through aromatase inhibition or inactivation is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer.
  • antiestrogen agent is used herein to include not only estrogen receptor antagonists and selective estrogen receptor modulators but also aromatase inhibitors as discussed above.
  • the term "differentiating agents” encompass compounds that can, in various ways, inhibit cell proliferation and induce differentiation.
  • Vitamin D and retinoids are known to play a major role in regulating growth and differentiation of a wide variety of normal and malignant cell types.
  • Retinoic acid metabolism blocking agents RAMBA's
  • DNA methylation changes are among the most common abnormalities in human neoplasia. Hypermethylation within the promotors of selected genes is usually associated with inactivation of the involved genes.
  • DNA methyl transferase inhibitors is used to indicate compounds that act through pharmacological inhibition of DNA methyl transferase and reactivation of tumour suppressor gene expression.
  • kinase inhibitors comprises potent inhibitors of kinases that are involved in cell cycle progression and programmed cell death (apoptosis)
  • farnesyltransferase inhibitors is used to indicate compounds that were designed to prevent farnesylation of Ras and other intracellular proteins. They have been shown to have effect on malignant cell proliferation and survival.
  • HDAC inhibitors comprises but is not limited to:
  • - short-chain fatty acids for example butyrate, 4-phenylbutyrate or valproic acid;
  • hydroxamic acids for example suberoylanilide hydroxamic acid (SAHA), biaryl hydroxamate A-161906, bicyclic aryl-N-hydroxycarboxamides, pyroxamide, CG-1521, PXD-101, sulfonamide hydroxamic acid, LAQ-824, trichostatin A (TSA), oxamflatin, scriptaid, m-carboxy cinnamic acid bishydroxamic acid, or trapoxin-hydroxamic acid analogue;
  • SAHA suberoylanilide hydroxamic acid
  • biaryl hydroxamate A-161906 bicyclic aryl-N-hydroxycarboxamides, pyroxamide, CG-1521, PXD-101, sulfonamide hydroxamic acid, LAQ-824
  • TSA trichostatin A
  • oxamflatin scriptaid, m-carboxy cinnamic acid bishydroxamic
  • - cyclic tetrapeptides for example trapoxin, apidicin or depsipeptide
  • the compounds according to the present invention may be administered to a patient as described above, in conjunction with irradiation.
  • Irradiation means ionising radiation and in particular gamma radiation, especially that emitted by linear accelerators or by radionuclides that are in common use today.
  • the irradiation of the tumour by radionuclides can be external or internal.
  • the present invention also relates to a combination according to the invention of an anti-cancer agent and a HDAC inhibitor according to the invention.
  • the present invention also relates to a combination according to the invention for use in medical therapy for example for inhibiting the growth of tumour cells.
  • the present invention also relates to a combinations according to the invention for inhibiting the growth of tumour cells.
  • the present invention also relates to a method of inhibiting the growth of tumour cells in a human subject, which comprises administering to the subject an effective amount of a combination according to the invention.
  • This invention further provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a combination according to the invention.
  • the other medicinal agent and HDAC inhibitor may be administered simultaneously (e.g. in separate or unitary compositions) or sequentially in either order. In the latter case, the two compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved.
  • the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and HDAC inhibitor being administered, their route of administration, the particular tumour being treated and the particular host being treated. The optimum method and order of administration and the dosage amounts and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.
  • the platinum coordination compound is advantageously administered in a dosage of 1 to 500mg per square meter (mg/m 2 ) of body surface area, for example 50 to 400 mg/m 2 , particularly for cisplatin in a dosage of about 75 mg/m 2 and for carboplatin in about 300mg/m 2 per course of treatment.
  • the taxane compound is advantageously administered in a dosage of 50 to 400 mg per square meter (mg/m 2 ) of body surface area, for example 75 to 250 mg/m 2 , particularly for paclitaxel in a dosage of about 175 to 250 mg/m 2 and for docetaxel in about 75 to 150 mg/m 2 per course of treatment.
  • the camptothecin compound is advantageously administered in a dosage of 0.1 to 400 mg per square meter (mg/m ) of body surface area, for example 1 to 300 mg/m , particularly for irinotecan in a dosage of about 100 to 350 mg/m and for topotecan in about 1 to 2 mg/m 2 per course of treatment.
  • the anti-tumour podophyllotoxin derivative is advantageously administered in a dosage of 30 to 300 mg per square meter (mg/m 2 ) of body surface area, for example 50 to 250mg/m 2 , particularly for etoposide in a dosage of about 35 to 100 mg/m 2 and for teniposide in about 50 to 250 mg/m per course of treatment.
  • the anti-tumour vinca alkaloid is advantageously administered in a dosage of 2 to 30 mg per square meter (mg/m 2 ) of body surface area, particularly for vinblastine in a dosage of about 3 to 12 mg/m 2 , for vincristine in a dosage of about 1 to 2 mg/m 2 , and for vinorelbine in dosage of about 10 to 30 mg/m per course of treatment.
  • the anti-tumor nucleoside derivative is advantageously administered in a dosage of 200 to 2500 mg per square meter (mg/m 2 ) of body surface area, for example 700 tol500 mg/m , particularly for 5-FU in a dosage of 200 to 500mg/m , for gemcitabine in a dosage of about 800 to 1200 mg/m 2 and for capecitabine in about 1000 to 2500 mg/m 2 per course of treatment.
  • the alkylating agents such as nitrogen mustard or nitrosourea is advantageously administered in a dosage of 100 to 500 mg per square meter (mg/m 2 ) of body surface area, for example 120 to 200 mg/m 2 , particularly for cyclophosphamide in a dosage of about 100 to 500 mg m 2 , for chlorambucil in a dosage of about 0.1 to 0.2 mg/kg, for carmustine in a dosage of about 150 to 200 mg/m 2 , and for lomustine in a dosage of about 100 to 150 mg/m 2 per course of treatment.
  • mg/m 2 body surface area
  • cyclophosphamide in a dosage of about 100 to 500 mg m 2
  • chlorambucil in a dosage of about 0.1 to 0.2 mg/kg
  • carmustine in a dosage of about 150 to 200 mg/m 2
  • lomustine in a dosage of about 100 to 150 mg/m 2 per course of treatment.
  • the anti-tumor anthracycline derivative is advantageously administered in a dosage of 10 to 75 mg per square meter (mg/m 2 ) of body surface area, for example 15 to 60 mg/m 2 , particularly for doxorubicin in a dosage of about 40 to 75 mg/m 2 , for daunorubicin in a dosage of about 25 to 45mg/m 2 , and for idarubicin in a dosage of about 10 to 15 mg/m 2 per course of treatment.
  • Trastuzumab is advantageously administered in a dosage of 1 to 5mg per square meter (mg/m 2 ) of body surface area, particularly 2 to 4mg/m 2 per course of treatment.
  • the antiestrogen agent is advantageously administered in a dosage of about 1 to lOOmg daily depending on the particular agent and the condition being treated.
  • Tamoxifen is advantageously administered orally in a dosage of 5 to 50 mg, preferably 10 to 20 mg twice a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect.
  • Toremifene is advantageously administered orally in a dosage of about 60mg once a day, continuing the therapy for sufficient time to achieve and -21- maintain a therapeutic effect.
  • Anastrozole is advantageously administered orally in a dosage of about lmg once a day.
  • Droloxifene is advantageously administered orally in a dosage of about 20-100mg once a day.
  • Raloxifene is advantageously administered orally in a dosage of about 60mg once a day.
  • Exemestane is advantageously administered orally in a dosage of about 25mg once a day.
  • These dosages may be administered for example once, twice or more per course of treatment, which may be repeated for example every 7,14, 21 or 28 days.
  • the components of the combinations according to the invention i.e. the other medicinal agent and the HDAC inhibitor may be formulated into various pharmaceutical forms for administration purposes.
  • the components may be formulated separately in individual pharmaceutical compositions or in a unitary pharmaceutical composition containing both components.
  • the present invention therefore also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the other medicinal agent and the HDAC inhibitor together with one or more pharmaceutical carriers.
  • the present invention also relates to a combination according to the invention in the form of a pharmaceutical composition
  • a combination according to the invention in the form of a pharmaceutical composition
  • a pharmaceutical composition comprising an anti-cancer agent and a HDAC inhibitor according to the invention together with one or more pharmaceutical carriers.
  • the present invention further relates to the use of a combination according to the invention in the manufacture of a pharmaceutical composition for inhibiting the growth of tumour cells.
  • the present invention further relates to a product containing as first active ingredient a HDAC inhibitor according to the invention and as second active ingredient an anticancer agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.
  • EDC N-(ethylcarbonimidoyl)-N,N-dimethyl-l,3-propanediamine
  • DIEA diisopropylethylamine
  • DIPE diisopropyl ether
  • DMF dimethylformamide
  • EtOAc means ethyl acetate
  • IPrOff ' means isopropyl
  • MeOH means methanol
  • EtOH means ethanol
  • PyBrOP means bromo-tris-pyrrolidino- phosphonium hexafluorophosphate
  • TAA means triethylamine
  • THF trifluoroacetic acid
  • THF tetrahydrofuran.
  • Example Al a) A solution of hexahydro-lH-l,4-diazepine (0.20 mol) and l-fluoro-4-nitro-benzene (0.10 mol) in DCM (300 ml) was stirred at room temperature for 24 hours under nitrogen atmosphere. Yellow crystals precipitated. The precipitate was collected on filter, washed with ether and dried. The residue (21. lg, 87%) was taken up in water and treated with a 3 N NaO ⁇ solution.
  • intermediate 10 A mixture of intermediate 9 (0.03 mol) in EtO ⁇ (250 ml) was hydrogenated at 50 °C with Pd/C 10% (2 g) as a catalyst. After uptake of ⁇ 2 (1 equiv), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/(MeOH/NH 3 ) 90/10). The product fractions were collected and the solvent was evaporated, yielding 6.8 g (>96%) of intermediate 10.
  • Tetrakis (2-propanolato) titanium (0.0023 mol) was added to a mixture of l-(2- naphthalenylsulfonyl)- piperazine (0.0018 mol) and 4-oxo-l-piperidinecarboxylic acid, 1,1-dimethylethyl ester (0.0021 mol) in 1,2-dichloro- ethane (6ml) under N 2 flow.
  • the mixture was stirred at 50°C for 18 hours, then cooled to room temperature.
  • NaBH(OAc) 3 (0.0023 mol) was added portionwise. The mixture was stirred at room temperature for 4 hours. Water was added. The mixture was filtered over celite. The mixture was extracted with DCM. The filtrate was decanted.
  • N-cyclohexylcarbodiimide N' -methyl polystyrene (153mg) ( ⁇ ovaBiochem Cat. ⁇ r. 01-64-0211) was added N-acetyl-3,4,5-trimethoxy- anthranilic acid(0.2 mmol), dissolved in THF (0.5ml), followed by 1 -hydroxy- IH-benzotriazole, dissolved in T ⁇ F (0.5ml). This mixture was shaken for 10 minutes at room temperature.
  • intermediate 17 (0.1 mmol), dissolved in DCM (1ml) was added to the suspension after which the solvents were evaporated by means of a nitrogen flow at 50°C and subsequently, the neat reaction mixture was left overnight at 90°C under a flow of nitrogen.
  • the product was dissolved in dichloromethane (2 mL) and filtered through a glass filter. The residue was rinsed with DCM (2 x 2ml) and the filtrate was concentrated.
  • the product was then treated with a mixture of THF(lml) and aqueous sodium hydroxide (1ml, IN) for 48 hours at room temperature. Finally, the mixture was neutralized by the addition of aqueous HCI (1ml, IN), and dried at 70°C under a nitrogen flow, yielding intermediate 18.
  • intermediate 23 To intermediate 22 was subsequently added 1-hydroxy-lH-benzotriazole (0.13 mmol), dissolved in T ⁇ F (dry, 1ml), EDC (0.13 mmol), dissolved in DCM (dry, 1ml), and TEA (0.15 mmol). The mixture was stirred at room temperature for 10 minutes. O- (tetrahydro-2 ⁇ -pyran-2-yl)- hydroxylamine (0.13 mmol), dissolved in THF (dry 1ml) was added and the reaction mixture was stirred at room temperature overnight. The O 03/076400 36 solvents were evaporated and the product was purified using reverse phase-HPLC, yielding intermediate 23, melting point (219°C).
  • N-Fmoc-hydroxylamine 2-chlorotrityl resin (Novabiochem, 01-64-0165) was deprotected by 50% piperidine in DMF (RT, 24 hr). The resin was washed several times with DCM and DMF and swelled in DMF. Two equivalents of acid 1 , PyBrOP and 4 equivalents of DIEA were added as one portion. The mixture was shaken for 24 hr, liquid was drained and the resin was washed several times by DCM and DMF. The resin was swelled in DMF containing 2 equivalents of amine, was shaken 24 hr at RT, the liquid was drained and the resin was washed by DCM and DMF. The final product was cleaved by 5% TFA in DCM, analyzed by HPLC and MS and evaporated in the pre- weighted test-tubes. *. Based on the loading of the resin.
  • intermediate 28 A mixture of intermediate 10 (0.0042 mol) and 2-naphthalenecarboxaldehyde (0.005 mol) in 1,2-dichloro-ethane (10ml) was stirred at 50°C for 3 hours, then cooled to room temperature. NaBH(OAc) 3 (0.0055 mol) was added portionwise. The mixture was stirred at room temperature for 2 hours. Water was added. The mixture was extracted with DCM. The organic layer was separated, dried (MgSO ), filtered, and the solvent was evaporated till dryness. The residue (2g) was taken up in CH 3 CN/DIPE. The precipitate was filtered off and dried, yielding 1.2g (75%) of intermediate 28, melting point 147°C. Intermediate 28 was handled analogously as described in example [B4] to give 0.724g (88%) of compound 6 (.0.83 CF 3 COOH) , melting point > 260°C.
  • intermediate 29 A solution of 2-naphthaleneethanol, methanesulfonate (0.0029 mol) in acetonitrile (3ml) was added at 5°C to a mixture of intermediate 10 (0.0024 mol) and potassium carbonate (0.0048 mol) in acetonitrile (6ml). The mixture was stirred at room temperature for 18 hours, then stirred and refluxed overnight and cooled to room temperature. Water was added. The mixture was filtered, washed with water, then with diethyl ether and dried, yielding 0.45g (48%) of intermediate 29, melting point 128°C. Intermediate 29 was handled analogously as described in example [B4] to give 0.254g (86%) of compound 7 (.0.79 CF 3 COOH), melting point 209°C.
  • intermediate 30 A mixture of intermediate 20 (0.001 mol), morpholine (0.0013 mol) and potassium carbonate (0.002 mol) in acetonitrile (6ml) was stirred and refluxed overnight, then cooled, poured out into ice water and extracted with EtOAc. The organic layer was separated, dried (MgSO 4 ), filtered, and the solvent was evaporated. The residue (0.79g) was purified by column chromatography over silica gel (lO ⁇ m) (eluent: DCM/MeOH/NH OH 96/4/0.1). The pure fractions were collected and the solvent was evaporated. The residue (0.183g) was crystallized from DIPE.
  • Table F-l lists the compounds that were prepared according to one of the above Examples. The following abbreviations were used in the tables : .C2-HF O2 stands for the trifluoroacetate salt.
  • the in vitro assay for inhibition of histone deacetylase measures the inhibition of HDAC enzymatic activity obtained with the compounds of formula (I).
  • Kinetic solubility in aqueous media measures the ability of a compound to stay in aqueous solution upon dilution (see example C.3).
  • DMSO-stock solutions are diluted with a single aqueous buffer solvent in 3 consecutive steps. For every dilution turbidity is measured with a nephelometer.
  • a drug's permeability expresses its ability to move from one medium into or through another. Specifically its ability to move through the intestinal membrane into the blood stream and/or from the blood stream into the target. Permeability (see example C.4) can be measured through the formation of a filter-immobilized artificial membrane phospholipid bilayer.
  • a "sandwich” is formed with a 96-well microtitre plate and a 96-well filter plate, such that each composite well is divided into two chambers with a donor solution at the bottom and an acceptor solution at the top, separated by a 125 ⁇ m micro-filter disc (0.45 ⁇ m pores), coated with 2%(wt/v) dodecane solution of dioleoylphosphatidyl-choline, under conditions that multi-lamellar bilayers form inside the filter channels when the system contacts an aqueous buffer solution.
  • the permeability of compounds through this artificial membrane is measured in cm s.
  • the purpose is to look for the permeation of the drugs through a parallel artificial membrane at 2 different pH's: 4.0 and 7.4.
  • Compound detection is done with UV-spectrometry at optimal wavelength between 250 and 500 nm.
  • Metabolism of drugs means that a lipid-soluble xenobiotic or endobiotic compound is enzymatically transformed into (a) polar, water-soluble, and excretable metabolite(s).
  • the major organ for drug metabolism is the liver.
  • the metabolic products are often less active than the parent drug or inactive. However, some metabolites may have enhanced activity or toxic effects. Thus drug metabolism may include both "detoxication” and "toxication” processes.
  • One of the major enzyme systems that determine the organism's capability of dealing with drugs and chemicals is represented by the cytochrome P450 monooxygenases, which are NADPH dependent enzymes.
  • Metabolic stability of compounds can be determined in vitro with the use of subcellular human tissue (see example C.5). Here metabolic stability of the compounds is expressed as % of drug metabolised after 15 minutes incubation of these compounds with microsomes. Quantitation of the compounds was determined by LC-MS analysis.
  • the 21 kDa product of the WAF1 gene is found in a complex involving cyclins, cyclin dependent kinases (CDKs), and proliferating cell nuclear antigen (PCNA) in normal cells but not transformed cells and appears to be a universal inhibitor of CDK activity.
  • CDKs cyclin dependent kinases
  • PCNA proliferating cell nuclear antigen
  • Induction of p21WAFl in 1 response to cellular contact with a HDAC inhibitor is therefore a potent and specific indicator of inhibition of cell cycle progression at both the Gl and G2 checkpoints.
  • the capacity of the compounds to induce p21WAFl was measured with the p21WAFl enzyme linked immunosorbent assay (WAF1 ELISA of Oncogene).
  • the p21WAFl assay is a "sandwich" enzyme immunoassay employing both mouse monoclonal and rabbit polyclonal antibodies.
  • a rabbit polyclonal antibody, specific for the human WAF1 protein, has been immobilized onto the surface of the plastic wells provided in the kit. Any p21WAF present in the sample to be assayed will bind to the capture antibody.
  • the biotinylated detector monoclonal antibody also recognizes human p21WAFl protein, and will bind to any p21WAFl, which has been retained by the capture antibody.
  • the detector antibody is bond by horseradish peroxidase- conjugated streptavidin.
  • the horseradish peroxidase catalyses the conversion of the chromogenic substrate tetra-methylbenzidine from a colorless solution to a blue solution (or yellow after the addition of stopping reagent), the intensity of which is proportional to the amount of p21WAFl protein bond to the plate.
  • the colored reaction product is quantified using a spectrophotometer. Quantitation is achieved by the construction of a standard curve using known concentrations of p21WAFl (provided lyo ⁇ hilised)(see example C.6).
  • Example C.l In Vitro Assay for Inhibition of histone deacetylase :
  • HeLa nuclear extracts (supplier: Biomol) were incubated at 60 ⁇ g/ml with 2x10 M of radiolabeled peptide substrate.
  • a synthetic peptide i.e. the amino acids 14-21 of histone H4
  • the substrate is biotinylated at the NH 2 -terminal part with a 6-aminohexanoic acid spacer, and is protected at the COOH-terminal part by an amide group and specifically [ 3 Hjacetylated at lysine 16.
  • biotin-(6-aminohexanoic)Gly-Ala-([ 3 H]-acetyl-Lys-Arg- His-Arg-Lys-Val-NH 2 ) was added in a buffer containing 25 mM Hepes, 1 M sucrose, 0.1 mg/ml BSA and 0.01% Triton X-100 at pH 7.4. After 30 min the deacetylation reaction was terminated by the addition of HCI and acetic acid, (final concentration 0.035 mM and 3.8 mM respectively). After stopping the reaction, the free 3 H-acetate was extracted with ethylacetate.
  • Example C.3 Kinetic solubility in aqueous media
  • the first dilution step 10 ⁇ l of a concentrated stock-solution of the active compound, solubilized in DMSO (5mM), was added to 100 ⁇ l phosphate citrate buffer pH 7.4 and mixed.
  • an aliquot (20 ⁇ l) of the first dilution step was further dispensed in 100 ⁇ l phosphate citrate buffer pH 7.4 and mixed.
  • a sample (20 ⁇ l) of the second dilution step was further diluted in 100 ⁇ l phosphate citrate buffer pH 7.4 and mixed. All dilutions were performed in 96- well plates.
  • Example C.4 Parallel artificial membrane permeability analysis
  • the stock samples (aliquots of 10 ⁇ l of a stock solution of 5 mM in 100 % DMSO) were diluted in a deep-well or Pre-mix plate containing 2 ml of an aqueous buffer system pH 4 or pH 7.4 (PSR4 System Solution Concentrate (pION)). Before samples were added to the reference plate, 150 ⁇ l of buffer was added to wells and a blank UV-measurement was performed. Thereafter the buffer was discarded and the plate was used as reference plate. All measurements were done in UV-resistant plates (supplier: Costar or Greiner).
  • an acceptor filter plate 1 (supplier: Millipore, type:MAIP N45) was coated with 4 ⁇ l of the artificial membrane-forming solution (l,2-Dioleoyl-sn-Glycer-3-Phosphocholine in Dodecane containing 0.1% 2,6-Di-tert-butyl-4-methylphenol and placed on top of donor plate 1 to form a "sandwich". Buffer (200 ⁇ l) was dispensed into the acceptor wells on the top. The sandwich was covered with a lid and stored for 18h at room temperature in the dark.
  • the artificial membrane-forming solution l,2-Dioleoyl-sn-Glycer-3-Phosphocholine in Dodecane containing 0.1% 2,6-Di-tert-butyl-4-methylphenol
  • a blank measurement of acceptor plate 2 was performed through the addition of 150 ⁇ l of buffer to the wells, followed by an UV-measurement. After the blank measurement of acceptor plate 2 the buffer was discarded and 150 ⁇ l of acceptor solution was transferred from the acceptor filter plate 1 to the acceptor plate 2. Then the acceptor filter plate 1 was removed form the sandwich. After the blank measurement of donor plate 2 (see above), 150 ⁇ l of the donor solution was transferred from donor plate 1 to donor plate 2. The UN spectra of the donor plate 2, acceptor plate 2 and reference plate wells were scanned (with a SpectraMAX 190). All the spectra were processed to calculate permeability with the PSR4p Command Software. All compounds were measured in triplo.
  • Carbamazepine, griseofulvin, acycloguanisine, atenolol, furosemide, and chlorothiazide were used as standards in each experiment.
  • Compounds were ranked in 3 categories as having a low permeability (mean effect ⁇ 0.5 x 10 "6 cm s; score 1), a medium permeability (1 x 10 "6 cm s > mean effect > 0.5 x 10 "6 cm/s; score 2) or a high permeability (> 0.5 x 10 "6 cm/s; score 3).
  • Two compounds were tested and showed at least a score of 2 at one of the pH's measured.
  • Liver tissue was rinsed in ice-cold 0.1 M Tris-HCl (pH 7.4) buffer to wash excess blood. Tissue was then blotted dry, weighed and chopped coarsely using surgical scissors. The tissue pieces were homogenized in 3 volumes of ice-cold 0.1 M phosphate buffer (pH 7.4) using either a Potter-S (Braun, Italy) equipped with a Teflon pestle or a
  • Sorvall Omni-Mix homogeniser for 7 x 10 sec. In both cases, the vessel was kept in/on ice during the homogenization process.
  • Tissue homogenates were centrifuged at 9000 x g for 20 minutes at 4 °C using a Sorvall centrifuge or Beckman Ultracentrifuge. The resulting supernatant was stored at -80 °C and is designated 'S9'.
  • the S9 fraction can be further centrifuged at 100.000 x g for 60 minutes (4 °C) using a
  • the incubation mixture contained PBS (0.1M), compound (5 ⁇ M), microsomes (lmg/ml) and a NADPH-generating system (0.8 mM glucose-6- phosphate, 0.8 mM magnesium chloride and 0.8 Units of glucose-6-phosphate dehydrogenase).
  • Control samples contained the same material but the microsomes were replaced by heat inactivated (10 min at 95 degrees Celsius) microsomes. Recovery of the compounds in the control samples was always 100%.
  • a Quattro (supplier: Micromass, Manchester, UK) triple quadrupole mass spectrometer fitted with and ESI source was used as detector.
  • the source and the desolvation temperature were set at 120 and 350 °C respectively and nitrogen was used as nebuliser and drying gas.
  • Data were acquired in positive scan mode (single ion reaction). Cone voltage was set at 10 V and the dwell time was 1 sec.
  • Compound that had a metabolism between 20 and 70 % were defined as intermediately stable and compounds that showed a percentage metabolism higher than 70 were defined as low metabolic stable.
  • Cisapride was included as a compound with medium metabolic stability (% metabolism 45 %) and propanol was included as a compound with intermediate to high metabolic stability (25 % metabolism). These reference compounds were used to validate the metabolic stability assay.
  • Example C.6 p21 induction capacity
  • the following protocol has been applied to determine the p21 protein expression level in human A2780 ovarian carcinoma cells.
  • the A2780 cells (20000 cells /180 ⁇ l) were seeded in 96 microwell plates in RPMI 1640 medium supplemented with 2 mM L- glutamine, 50 ⁇ g/ml gentamicin and 10 % fetal calf serum. 24 hours before the lysis of the cells, compounds were added at final concentrations of 10 "5 , 10 "6 , 10 "7 and 10 "8 M. All compounds tested were dissolved in DMSO and further dilutions were made in culture medium. 24 hours after the addition of the compound, the supernatants were removed from the cells.
  • the lyophilised p21WAF standard was reconstituted with distilled H 2 O and further diluted with sample diluent (provided in the kit)
  • sample diluent provided in the kit
  • the samples were prepared by diluting them 1:4 in sample diluent.
  • the samples (100 ⁇ l) and the p21WAFl standards (100 ⁇ l) were pipetted into the appropriate wells and incubated at room temperature for 2 hours.
  • the wells were washed 3 times with lx wash buffer and then 100 ⁇ l of detector antibody reagent (a solution of biotinylated monoclonal p21WAFl antibody) was pipetted into each well.
  • detector antibody reagent a solution of biotinylated monoclonal p21WAFl antibody
  • the 400x conjugate (peroxidase streptavidine conjugate: 400-fold concentrated solution) was diluted and 100 ⁇ l of the lx solution was added to the wells. The wells were incubated at room temperature for 30 min and then washed 3 times with lx wash buffer and 1 time with distilled H 2 O. Substrate solution (chromogenic substrate)(100 ⁇ l) was added to the wells and the wells were incubated for 30 minutes in the dark at room temperature. Stop solution was added to each well in the same order as the previously added substrate solution. The absorbance in each well was measured using a spectrophotometric plate reader at dual wavelengths of 450/595 nm.
  • Table F-2 Table F-2 lists the results of the compounds that were tested according to example C.l, C.2, and C.3.
  • composition example Film-coated tablets

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Abstract

This invention comprises the novel compounds of formula (I) wherein n, t, R1, R2, R3, R4, L, Q, X, Y, Z and have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.

Description

NEW INHIBITORS OF fflSTONE DEACETYLASE.
This invention concerns compounds having histone deacetylase (HDAC) inhibiting enzymatic activity. It further relates to processes for their preparation, to compositions comprising them, as well as their use, both in vitro and in vivo, to inhibit HDAC and as a medicine, for instance as a medicine to inhibit proliferative conditions, such as cancer and psoriasis.
In all eukaryotic cells, genomic DNA in chromatine associates with histones to form nucleosomes. Each nucleosome consists of a protein octamer made up of two copies of each histones H2A, H2B, H3 and H4. DNA winds around this protein core, with the basic amino acids of the histones interacting with the negatively charged phosphate groups of the DNA. The most common posttranslational modification of these core histones is the reversible acetylation of the ε-amino groups of conserved, highly basic N-terminal lysine residues. The steady state of histone acetylation is established by the dynamic equilibrium between competing histone acetyltransferase(s) and histone deacetylase(s) herein referred to as "HDAC". Histone acetylation and deacetylation has long been linked to transcriptional control. The recent cloning of the genes encoding different histone acetyltransferases and histone deacetylases provided a possible explanation for the relationship between histone acetylation and transcriptional control. The reversible acetylation of histones can result in chromatin remodelling and as such act as a control mechanism for gene transcription. In general, hyperacetylation of histones facilitates gene expression, whereas histone deacetylation is correlated with transcriptional repression. Histone acetyltransferases were shown to act as transcriptional coactivators, whereas histone deacetylases were found to belong to transcriptional repression pathways.
The dynamic equilibrium between histone acetylation and deacetylation is essential for normal cell growth. Inhibition of histone deacetylase results in cell cycle arrest, cellular differentiation, apoptosis and reversal of the transformed phenotype. Therefore HDAC inhibitors can have great therapeutic potential in the treatment of cell proliferative diseases or conditions (Marks et al., Nature Reviews: Cancer 1: 194-202, 2001)
The study of inhibitors of histone deacetylases (HDAC) indicates that indeed these enzymes play an important role in cell proliferation and differentiation. The inhibitor Trichostatin A (TSA) causes cell cycle arrest at both Gl and G2 phases, reverts the transformed phenotype of different cell lines, and induces differentiation of Friend leukemia cells and others. TSA (and suberoylanilide hydroxamic acid SAHA) have been reported to inhibit cell growth, induce terminal differentiation, and prevent the formation of tumours in mice (Finnin et al., Nature, 401: 188-193, 1999).
Trichostatin A has also been reported to be useful in the treatment of fibrosis, e.g. liver fibrosis and liver chirrhosis. (Geerts et al., European Patent Application EP 0 827 742, published 11 March, 1998).
Patent application WO01/38322 published on May 31, 2001 discloses amongst others inhibitors of histone deacetylase of general formula Cy-L1-Ar-Y1-C(O)-NH-Z, providing compositions and methods for treating cell proliferative diseases and conditions.
Patent application WO01/70675 published on 27 September, 2001 discloses inhibitors of histone deacetylase of formula Cy2-Cy1-X- Y!-W and further provides compositions and methods for treating cell proliferative diseases and conditions.
The problem to be solved is to provide histone deacetylase inhibitors with high enzymatic activity and also show advantageous properties such as cellular activity and increased bioavailability, preferably oral bioavailability, and have little or no side effects.
The novel compounds of the present invention solve the above described problem. The compounds differ from the prior art in structure.
The compounds of the present invention show excellent in-vitro histone deacetylase inhibiting enzymatic activity. The present compounds have advantageous properties with regard to cellular activity and specific properties with regard to inhibition of cell cycle progression at both Gl and G2 checkpoints (p21 induction capacity). The compounds of the present invention show good metabolic stability and high bioavailability and more particular they show oral bioavailability. This invention concerns compounds of formula (I)
Figure imgf000005_0001
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo- chemically isomeric forms thereof, wherein n is 0, 1, 2 or 3 and when n is 0 then a direct bond is intended; t is 0, 1, 2, 3 or 4 and when t is 0 then a direct bond is intended;
each Q is nitrogen or ^* ;
each X is nitrogen or ^^ ;
each Y is nitrogen or ^^ ;
eac ,h r Zr i-s ni •trogen or — CET ^ ;
R1 is -C(O)ΝR7R8, -NHC(O)R9, -C(O)-C,-6alkanediylSR9, -NR10C(O)N(OH)R9,
-NR10C(O)C1-6alkanediylSR9, -NR10C(O)C=N(OH)R9 or another Zn-chelating- group wherein R7 and R8 are each independently selected from hydrogen, hydroxy,
Cj-ealkyl, hydroxy -galkyl, aminoCι-6alkyl or aminoaryl; R9 is independently selected from hydrogen, Ci-βalkyl, -ealkylcarbonyl, arylCi-όalkyl, Cι.6alkylpyrazinyl, pyridinone, pyrrolidinone or methylimidazolyl;
R10 is independently selected from hydrogen or Cι.6--lkyl;
R2 is hydrogen, halo, hydroxy, amino, nitro, d-6alkyl, Cι-6alkyloxy, trifluoromethyl, di(Cι-6alkyl)amino, hydroxyamino or naphtalenylsulfonylpyrazinyl;
-L- is a direct bond or a bivalent radical selected from Cι-6alkanediyl, Cι- alkyloxy, amino, carbonyl or aminocarbonyl;
each R3 independently represents a hydrogen atom and one hydrogen atom can be replaced by a substituent selected from aryl; R -4 i ■s hydrogen, hydroxy, amino, hydroxyCμ6alkyl, Cι-6alkyl, Ci-βalkyloxy, arylC^alkyl, aminocarbonyl, hydroxycarbonyl, aminoCι-6alkyl, aminocarbonylCι.6alkyl, hydroxycarbonylCi-βalkyl, hydroxyaminocarbonyl, Cι-6alkyloxycarbonyl, Cι-6alkylaminoCι-6alkyl or di(Cι.6alkyl)aminoCι-6alkyl;
-Θ is a radical selected from
Figure imgf000006_0001
(a-1) (a-2) (a-3) (a-4)
Figure imgf000006_0002
(a-5) (a-6) (a-7) (a-8)
Figure imgf000006_0003
(a-9) (a-10) (a-11) (a-12)
Figure imgf000006_0004
(a-13) (a-14) (a-15) (a-16)
Figure imgf000006_0005
Figure imgf000007_0001
(a-25) (a-26) (a-27) (a-28)
Figure imgf000007_0002
(a-29) (a-30) (a-31) (a-32)
Figure imgf000007_0003
(a-33) (a-34) (a-35) (a-36)
Figure imgf000007_0004
Figure imgf000007_0005
(a-37)
Figure imgf000007_0006
(a-39) (a-40)
Figure imgf000007_0007
-45) (a-46) (a-47) -48)
Figure imgf000008_0001
(a-49) (a-50) (a"51)
wherein each s is independently 0, 1, 2, 3, 4 or 5; each R5 and R6 are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaloCι-6alkyl; trihaloCι-6alkyloxy; Cι-6alkyl; Ci.galkyl substituted with aryl and
C3-ιocycloalkyl; Cι_6alkyloxy; Cι-6alkyloxyCι.6alkyloxy; Cι.6alkylcarbonyl;
Cι_6alkyloxycarbonyl; Cι-6alkylsulfonyl; cyanoCι-6alkyl; hydroxyCι-6alkyl; hydroxyCι.6alkyloxy; hydroxyCι_6alkylamino; aminoCi-6alkyloxy; di(Cι.6alkyl)aminocarbonyl; di(hydroxyCι-6alkyl)amino; (aryl)(Cι_6alkyl)amino; di(Cι_6alkyl)aminoCι_6alkyloxy; di(Cι-6alkyl)aminoCι.6alkylamino; di(Cι.6alkyl)aminoCι.6alkylaminoCι_6alkyl; arylsulfonyl; arylsulfonylamino; aryloxy; aryloxyCι.6alkyl; arylC2-6alkenediyl; di(Cι-6alkyl)amino; di(Cι-6alkyl)aminoCι_6alkyl; ch(Cι_6alkyl)amino(Cι_6alkyl)amino; di(Cμ6alkyl)amino(Cι-6alkyl)aminoCι-6alkyl; di(C i -6alkyl)aminoC ι.6alkyl(C \ -6alkyl)amino ; di(Cι_6alkyl)aminoCι_6alkyl(Cι_6alkyl)aminoCι_6alkyl; aminosulf onylamino(C i -6alkyl)amino ; aminosulfonylamino(Ci_6alkyl)aminoCi-6alkyl; di(C i _6alkyl)aminosulf onylamino(C i -6alkyl)amino ; di(Cι-6alkyl)aminosulfonylamino(Cι-6alkyl)aminoCι.6alkyl; cyano; thiophenyl; thiophenyl substituted with di(Cι_6alkyl)an-άnoCι.6alkyl(Cι_6alkyl)aminoCι_6alkyl, di(Cι-6alkyl)aminoCι_6alkyl, Cι-6alkylpiρerazinylCι.6alkyl, hydroxyC ι.6alkylpiperazinylC i .6alkyl , hydroxyC ι.6alkyloxyC i .βalkylpiperazinylC \ .6alkyl , di(Cι-6alkyl)aminosulfonylpiperazinylCι-6alkyl,
Cι-6alkyloxypiperidinyl, Cι-6alkyloxypiρeridinylCι_6alkyl, morpholinylCι.6alkyl, hydroxyCι-6alkyl(Cι.6alkyl)a-mnoCι_6alkyl, or di(hydroxyCι.6alkyl)aminoCι.6alkyl; furanyl; furanyl substituted with hydroxyCι„6alkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and Cι-6alkyl; Cι-6alkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; piperidinylCι-6alkyloxy; morpholinyl; Cι.6alkylmorpholinyl; morρholinylCι-6alkyloxy; morpholinylC i _6alkyl ; morpholinylC i .6alkylamino ; morpholinylCι-6alkylaminoCι-6alkyl; ρiρerazinyl; Ci-ealkylpiperazinyl; C i _6alkylpiperazinylC i .6alkyloxy ; piperazinylC ι-6alkyl ; naphtalenylsulf onylpiperazinyl ; naphtalenylsulf onylpiperidinyl ; naphtalenylsulf onyl ;
C i .^alkylpiperazinylC ι-6alkyl ; C i _6alkylpiperazinylC i _6alkylamino ;
C i _6alkylpiperazinylC ι-6alkylaminoC i _6alkyl ; C i .6alkylpiperazinylsulf onyl ; aminosulfonylpiρerazinylCι-6alkyloxy; aminosulf onylpiperazinyl; aminosulf onylpiperazinylC i -6alkyl ; di (C i .6alkyl)aminosulf onylpiperazinyl; di (C i .6alkyl)aminosulf onylpiperazinylC i -6alkyl ; hydroxyCi . alkylpiperazinyl ; hydroxyC i -βalkylpiperazinylC ι.6alkyl ; C ι_6alkyloxypiperidinyl ;
C ι_ alkyloxypiperidinylC ι_ alkyl ; piperidinylaminoC i -6alkylamino ; piperidinylaminoC i _6alkylaminoC i _6alkyl ;
(Cι.6alkylpiperidinyl)(hydroxyCι-6alkyl)aminoCi-6alkylamino;
(Cι.6alkylpiperio-inyl)(hydroxyC1- alkyl)aminoCι.6alkylaminoCι-.6alkyl; hydroxyC i _6alkyloxyCι - alkylρiperazinyl ; hydroxyC i .6alkyloxyCι.6alkylpiperazinylC i -βalkyl ; (hydroxyC i .6alkyl)(C ι.6alkyl)amino ; (hydroxyC ι.6alkyl)(C ι.6alkyl)aminoC ι-6alkyl ; hydroxyCι_6alkylaminoCι_6alkyl; di(hydroxyCι-6alkyl)aminoCι.6alkyl; pyrrolidinylCι_6alkyl; pyrrolidinylCι-6alkyloxy; pyrazolyl; thiopyrazolyl; pyrazolyl substituted with two substituents selected from Ci-galkyl or trihaloCι- alkyl; pyridinyl; pyridinyl substituted with Cμgalkyloxy, aryloxy or aryl; pyrimidinyl; tetrahydropyrimidinylpiperazinyl; tetrahydropyrimidinylpiperazinylCι-6alkyl; quinolinyl; indole; phenyl; phenyl substituted with one, two or three substituents independently selected from halo, amino, nitro, Cι-6alkyl, Cι-6alkyloxy, hydroxyCι-4alkyl, trifluoromethyl, trifluoromethyloxy, hydroxyCι_4alkyloxy, Cι_4alkylsulfonyl, Cι-4alkyloxyCι-4alkyloxy, Ci^alkyloxycarbonyl, aminoCi^alkyloxy, di(Cι.4alkyl)aminoCι-4alkyloxy, di(Cι_4alkyl)amino, di(Cι-4alkyl)aminocarbonyl, di(Cι-4alkyl)aminoCι_4alkyl, di(Cι-4alkyl)aminoCι.4alkylaminoCι-4alkyl, di(Cι-4alkyl)amino(Cι-4alkyl)amino, di(Cι_4alkyl)amino(Cι_4alkyl)aminoCι_4alkyl, di(Cι.4alkyl)aminoCι.4alkyl(Cι.4alkyl)amino, di(Ci.4alkyl)aminoCi.4alkyl(Ci_4alkyl)aminoCi-4alkyl, aminosulf onylamino(C i -4alkyl)amino , aminosulfonylamino(Cι-4alkyl)aminoCι-4alkyl, di(Cι-4alkyl)aminosulfonylamino(Cι-4alkyl)amino, di(Cι-4alkyl)aminosulfonylamino(Cι.4alkyl)aminoCι-6alkyl, cyano, piρeridinylC1.4alkyloxy, pyrrolidinylCι-4alkyloxy, aminosulf onylpiperazinyl, aminosulfonylpiperazinylCι-4alkyl, di(Cι-4alkyl)aminosulfonylpiperazinyl, di (C i -4alkyl)aminosulf onylpiperazinylC i -4alkyl , hydroxyCι_4alkylpiperazinyl , hydroxyC i -4alkylpiperazinylC i .4alkyl, C i _4alkyloxypiperidinyl , C i -4alkyloxypiperidinylC ι_4alkyl , hydroxyC ι_4alkyloxyC ι-4alkylpiperazinyl , hydroxyCι-4alkyloxyCι_4alkylpiperazinylCι_4alkyl,
(hydroxyCι.4alkyl)(Cι.4alkyl)amino, (hydroxyCι_4alkyl)(Cι_4alkyl)aminoCι_4alkyl, di(hydroxyCi-4alkyl)amino, di(hydroxyCι-4alkyl)aminoCι_4alkyl, furanyl, furanyl substituted with -CH=CH-CH=CH-, pyrrolidinylCι_4alkyl, pyrrolidinylCι-4alkyloxy, morpholinyl, morpholinylC ι_4alkyloxy, morpholinylCι_4alkyl, moιpholinylCι_4alkylamino, morpholinylCι-4alkylaminoCι.4alkyl, piperazinyl, C i _4alkylρiρerazinyl , C i .4alkylpiperazinylC ι-4alkyloxy , piperazinylC i -4alkyl, Cι.4alkylpiperazinylCι.4alkyl, Cι-4alkylpiperazinylCι-4alkylamino, Cι_4alkylpiperazinylCι_4alkylaminoCι_6alkyl, tetrahydropyrimidinylpiperazinyl, tetrahydropyrimichnylpiperazinylCι-4-dkyl, piperidinylaminoCi-4-ιlkylamino, piperidinylaminoCi.4alkylaminoCi.4alkyl, (Cι-4alkylpiperidinyl)(hydroxyCι-4alkyl)aminoCι-4alkylamino, (Cι-4alkylpiperidinyl)(hydroxyC1-4alkyl)aminoCi-4alkylaminoCι.4alkyl, ρyridinylCι-4alkyloxy, hydroxyCi.4alkylamino, hydroxyCι.4alkylaminoCι.4alkyl, di(Cι-4-dkyl)aminoCι-4-dkylamino, aminothiadiazolyl, aminosulfonylpiperazinylCi^alkyloxy, or thiophenylCι-4alkylamino; each R5 and R6 can be placed on the nitrogen in replacement of the hydrogen;
aryl in the above is phenyl, or phenyl substituted with one or more substituents each independently selected from halo, Cι-6alkyl, -ealkyloxy, trifluoromethyl, cyano or hydroxycarbonyl.
The term "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 a 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.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; Cj.4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, e.g. methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; Cj.galkyl includes C..4alkyl and the higher homologues thereof having 5 to 6 carbon atoms such as, for example, pentyl, 2-methyl- butyl, hexyl, 2-methylpentyl and the like; Cj_6alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof such as, 2- methylpentanediyl, 3-methylpentanediyl, 2,2-dimethylbutanediyl, 2,3- dimethylbutanediyl and the like; trihaloCι-6alkyl defines Cι-6alkyl containing three identical or different halo substituents for example trifluoromethyl; C2.6alkenediyl defines bivalent straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenediyl, 2-propenediyl, 3-butenediyl, 2-pentenediyl, 3-pentenediyl, 3-methyl-2-butenediyl, and the like; aminoaryl defines aryl substituted with amino;
C3-iocycloalkyl includes cyclic hydrocarbon groups having from 3 to 10 carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl and the like.
The term "another Zn-chelating group" refers to a group, which is capable of interacting with a Zn-ion, which can be present at an enzymatic binding site.
Pharmaceutically acceptable addition salts encompass pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms, which the compounds of formula (I) are able to form. The compounds of formula (I) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, trifluoroacetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, -toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids.
The compounds of formula (I) which have acidic properties may be converted in their pharmaceutically acceptable base addition salts by treating said acid form with a suitable organic or inorganic base. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. The term "acid or base addition salts" also comprises the hydrates and the solvent addition forms, which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The term "stereochemically isomeric forms of compounds of formula (I)", as used herein, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures, which are not interchangeable, which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms, which said compound might possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of formula (I) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those N-oxides wherein one or more of the piperidine-, piperazine or pyridazinyl-nitrogens are N-oxidized.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Whenever used hereinafter, the term "compounds of formula (I)" is meant to include also the pharmaceutically acceptable addition salts and all stereoisomeric forms.
As used herein, the terms "histone deacetylase" and "HDAC" are intended to refer to any one of a family of enzymes that remove acetyl groups from the ε-amino groups of lysine residues at the Ν-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 and HDAC-10. The histone deacetylase can also be derived from a protozoal or fungal source.
A first group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply: a) n is 1 or 2; b) t is 0, 1, 2 or 4; c) each Q is ^^ ; d) R1 is -C(O)NH(OH); e) R2 is hydrogen or nitro; f) -L- is a direct bond or a bivalent radical selected from Cι_6alkanediyl; g) R4 is hydrogen; h) -0 XX
Figure imgf000013_0001
a radical selected from (a-l),(a-2), (a-3), (a-5), (a-6), (a-11), (a-18), (a-20), (a-21), (a-32), (a-33), (a-47) or (a-51); i) each s is independently 0, 1, 2, or 4; j) each R5 and R6 are independently selected from hydrogen; halo; trihaloCι-6alkyl; Cι-6alkyl; Cι_6alkyl substituted with aryl and Cβ-iocycloalkyl; Cι_6alkyloxy; Cι_6alkylcarbonyl; benzofuranyl; naphtalenylsulf onyl; pyridinyl substituted with aryloxy; phenyl; or phenyl substituted with one substituent independently selected from hydroxyCι.4alkyl or morpholinylCi^alkyl.
A second group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply: a) n is 1 ; b) t is 0, 1 or 2; c) each Q is ^^ ; d) each X is nitrogen; e) each Y is nitrogen; f) R1 is -C(O)NH(OH); g) R2 is hydrogen; h) -L- is a direct bond; i) each R3 independently represents a hydrogen atom; j) R4 is hydrogen; k) ^S is a radical selected from (a-6), (a-11), (a-20), (a-47) or (a-51); 1) each s is independently 0, 1, or 4; m) each R5 andR6 are independently selected from hydrogen; Cι-6alkyl; Cι_6alkyloxy; naphtalenylsulf onyl; or phenyl substituted with hydroxyC 1_4alkyl or morpholinylC i .4alkyl .
A third group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply: a) R1 is -C(O)NH(OH); b) -L- is a direct bond.
A fourth group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply: a) t is 1, 2, 3, or 4; b) R1 is -C(O)NR7R8, -C(O)-Cj.6alkanediylSR9, -NR10C(O)N(OH)R9,
-NR10C(O)C1-6alkanediylSR9, -NR10C(O)C=N(OH)R9 or another Zn-chelating- group wherein R and R are each independently selected from hydrogen, hydroxy, hydroxyCχ-6alkyl or amino -ealkyl; c) R2 is hydrogen, halo, hydroxy, amino, nitro, C!-6alkyl, Cι-6alkyloxy, trifluoromethyl or di(Cι-6alkyl)amino; d) -L- is a direct bond or a bivalent radical selected from Cι-6alkanediyl,
Cι_6alkanediyloxy, amino or carbonyl; e) R4 is hydrogen, hydroxy, amino, hydroxyCι.6alkyl, Cι-6alkyl, Cι-6alkyloxy, arylCi.galkyl, aminocarbonyl, aminoCι-6alkyl, Cι_6alkylaminoCι_6alkyl or di(Cι-6alkyl)aminoCι-6alkyl; f) — ^-) is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42), (a-44),
(a-45), (a-46), (a-47), (a-48) and (a-51); g) each s is independently 0, 1, 2, 3 or 4; h) R5 is hydrogen; halo; hydroxy; amino; nitro; trihaloCi_6alkyl; trihaloCι-6alkyloxy;
Cμgalkyl; Cι_6alkyloxy; Cι- alkylcarbonyl; Ci-galkyloxycarbonyl; Cι.6alkylsulfonyl; hydroxyCi-6alkyl; aryloxy; di(Cι.6alkyl)amino; cyano; thiophenyl; furanyl; furanyl substituted with hydroxyCι-6alkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and Cι-6alkyl;
Cι-6alkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; morpholinyl;
C ι.6alkylmorpholinyl ; piperazinyl ; Ci-6alkylpiperazinyl; hydroxyC ι-6alkylρiperazinyl;
Cι-6alkyloxypiperidinyl; pyrazoly; pyrazolyl substituted with one or two substituents selected from Ci-βalkyl or trihaloCi-galkyl; pyridinyl; pyridinyl substituted with Cι_6alkyloxy, aryloxy or aryl; pyrimidinyl; quinolinyl; indole; phenyl; or phenyl substituted with one or two substituents independently selected from halo, Cι-6alkyl, Cι-6alkyloxy or trifluoromethyl; i) R6 is hydrogen; halo; hydroxy; amino; nitro; trihaloCι_ alkyl; trihaloCι-6alkyloxy; Cχ. alkyl; Cι„6alkyloxy; Cι-6alkylcarbonyl; Cι-6alkyloxycarbonyl; Cι-6alkylsulfonyl; hydroxyCι_6alkyl; aryloxy; di(Cι.6alkyl)amino; cyano; pyridinyl; phenyl; or phenyl substituted with one or two substituents independently selected from halo, Cι-6alkyl, Cι_6alkyloxy or trifluoromethyl.
A group of preferred compounds consists of those compounds of formula (I) wherein t is 1, 2, 3, or 4; R1 is -C(O)NR7R8, -C(O)-d-6alkanediylSR9, -NR10C(O)N(OH)R9,
-NR10C(O)Cι-6alkanediylSR9, -NR,0C(O)C=N(OH)R9 or another Zn-chelating- group wherein R7 and R8 are each independently selected from hydrogen, hydroxy, hydroxyCι-6alkyl or amino -όalkyl;
R2 is hydrogen, halo, hydroxy, amino, nitro, Ci-βalkyl, d-6alkyloxy, trifluoromethyl or di(Cι-6alkyl)amino; -L- is a direct bond or a bivalent radical selected from Cι-6alkanediyl, Ci-galkanediyloxy, amino or carbonyl; R4 is hydrogen, hydroxy, amino, hydroxyCι_6alkyl, Chalk !, Cι_6alkyloxy, arylCι.6alkyl, aminocarbonyl, aminoCi.galkyl, Cι.6alkylaminoCι.6alkyl or di(Cι-6alkyl)aminoCι.6alkyl;
^^ is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9),
(a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32),
(a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42), (a-44),
(a-45), (a-46), (a-47), (a-48) and (a-51); each s is independently 0, 1, 2, 3 or 4;
R5 is hydrogen; halo; hydroxy; amino; nitro; trihaloCι_6alkyl; trihaloCι„6alkyloxy; Cι.6alkyl; Cι.6alkyloxy; Cι.6alkylcarbonyl; Cι_6alkyloxycarbonyl;
Cι-6alkylsulfonyl; hydroxyCι- alkyl; aryloxy; di(Cι_6alkyl)amino; cyano; thiophenyl; furanyl; furanyl substituted with hydroxyC μ6alkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and Cι_ alkyl;
Cι-6alkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; morpholinyl; Cι_6alkylmorpholinyl; piperazinyl;
C i _6alkylpiperazinyl ; hydroxyC i -6alkylpiperazinyl ;
Cι-6alkyloxypiperidinyl; pyrazolyl; pyrazolyl substituted with one or two substituents selected from Cι- alkyl or trihaloCμgalkyl; pyridinyl; pyridinyl substituted with Cι_6alkyloxy, aryloxy or aryl; pyrimidinyl; quinolinyl; indole; phenyl; or phenyl substituted with one or two substituents independently selected from halo, Cι.6alkyl, Cι-6alkyloxy or trifluoromethyl; R6 is hydrogen; halo; hydroxy; amino; nitro; trihaloCμ6alkyl; trihaloCj-galkyloxy; Ci-βalkyl; Ci-βalkyloxy; Cι_6alkylcarbonyl; Cι-6alkyloxycarbonyl; Cι-6alkylsulfonyl; hydroxyC ι-6alkyl; aryloxy; di(Cι_6alkyl)amino; cyano; pyridinyl; phenyl; or phenyl substituted with one or two substituents independently selected from halo, Cι_ alkyl, Cι_ alkyloxy or trifluoromethyl.
A further group of preferred compounds are those compounds of formula (I) wherein n is 1 or 2; t is 0, 1, 2 or 4; each Q is "^ ; R1 is -C(O)NH(OH); R2 is hydrogen or nitro; -L- is a direct bond or a bivalent radical selected from Cι-6alkanediyl; R4 is hydrogen; -( ^-2^ is a radical selected from (a-l),(a-2), (a-3), (a-5), (a-6), (a-11), (a-18), (a-20), (a-21), (a-32), (a-33), (a-47) or (a-51); each s is independently 0, 1,
2, or 4; each R5 and R6 are independently selected from hydrogen; halo; trihaloCι_6alkyl; Cι.6alkyl; Cι-6alkyl substituted with aryl and C3_ιocycloalkyl; Cι-6alkyloxy; Cι-6alkylcarbonyl; benzofuranyl; naphtalenylsulf onyl; pyridinyl substituted with aryloxy; phenyl; or phenyl substituted with one substituent independently selected from hydroxyC^alkyl or morpholinylC i^alkyl.
A group of more preferred compounds are those compounds of formula (I) wherein n is
1; t is 0 or 1; each Q is ^* ; each X is nitrogen; each Y is nitrogen; R1 is -C(O)NH(OH); R2 is hydrogen; -L- is a direct bond; each R3 independently represents a hydrogen atom; R is hydrogen; -( ^-A^) is a radical selected from (a-
6), (a-11), (a-20), (a-47) or (a-51); each s is independently 0, 1, or 4; and each R5 and R6 are independently selected from hydrogen; Cι_6alkyl; Cι_6alkyloxy; naphtalenylsulfonyl; or aryl substituted with hydroxyC^alkyl or morpholinylCι_4alkyl.
Most preferred compounds are compounds No. 3, No. 4, No. 8, No. 5, No. 7, No. 6 and No 9.
Figure imgf000016_0001
Figure imgf000017_0001
The compounds of formula (I) and their pharmaceutically acceptable salts and N-oxides and stereochemically isomeric forms thereof may be prepared in a conventional manner. A general synthesis route is encompassed as example: a) Hydroxamic acids of formula (I) wherein R1 is -C(O)NH(OH), said compounds being referred to as compounds of formula (I-a), may be prepared by reacting an intermediate of formula (II) with an appropriate acid, such as for example, trifluoro acetic acid. Said reaction is performed in an appropriate solvent, such as, for example, methanol.
Figure imgf000017_0002
b) intermediates of formula (II) may be prepared by reacting an intermediate of formula (III) with an intermediate of formula (IV) in the presence of appropriate reagents such as N-(ethylcarbonimidoyl)-N,N-dimethyl-l,3-propanediamine, monohydrochloride (EDC) and 1-hydroxy-lH-benzotriazole (ΗOBT). The reaction may be performed in a suitable solvent such as a mixture of DCM and TΗF.
Figure imgf000018_0001
c) intermediates of formula (HI) may be prepared by reacting an intermediate of formula (V) with an appropriate base such as NaOH in the presence of a suitable solvent such as ethanol.
Figure imgf000018_0002
The compounds of formula (I) can also conveniently be prepared using solid phase synthesis techniques. In general, solid phase synthesis involves reacting an intermediate in a synthesis with a polymer support. This polymer-supported intermediate can then be carried on through a number of synthesis steps. After each step, filtering the resin and washing it numerous times with various solvents remove impurities. At each step the resin can be split up to react with various intermediates in the next step thus allowing for the synthesis of a large number of compounds. After the last step in the procedure the resin is treated with a reagent or process to cleave the resin from the sample. More detailed explanation of the techniques used in solid phase chemistry is described in for example "The Combinatorial Index" (B.Bunin, Academic Press) and Novabiochem's 1999 Catalogue & Peptide Synthesis Handbook (Novabiochem AG, Switzerland) both incorporated herein by reference. The compounds of formula (I) and some of the intermediates may have at least one stereogenic centre in their structure. This stereogenic centre may be present in an R or an S configuration.
The compounds of formula (I) as prepared in the hereinabove described processes can be racemic mixtures of enantiomers, which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated there from by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The compounds of formula (I), the pharmaceutically acceptable acid addition salts and stereoisomeric forms thereof have valuable pharmacological properties in that they have a histone deacetylase (HDAC) inhibitory effect.
This invention provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of the invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g. loss of contact inhibition). This includes the inhibition of tumour growth both directly by causing growth arrest, terminal differentiation and/or apoptosis of cancer cells, and indirectly, by inhibiting neovascularization of tumours.
This invention also provides a method for inhibiting tumour growth by administering an effective amount of a compound of the present invention, to a subject, e.g. a mammal (and more particularly a human) in need of such treatment. In particular, this invention provides a method for inhibiting the growth of tumours by the administration of an effective amount of the compounds of the present invention. Examples of tumours which may be inhibited, but are not limited to, lung cancer (e.g. adenocarcinoma and including non-small cell lung cancer), pancreatic cancers (e.g. pancreatic carcinoma such as, for example exocrine pancreatic carcinoma), colon cancers (e.g. colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), prostate cancer including the advanced disease, hematopoietic tumours of lymphoid lineage (e.g. acute lymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid foUicular cancer, myelodysplastic syndrome (MDS), tumours of mesenchymal origin (e.g. fibrosarcomas and rhabdomyosarcomas), melanomas, teratocarcinomas, neuroblastomas, gliomas, benign tumour of the skin (e.g. keratoacanthomas), breast carcinoma (e.g. advanced breast cancer), kidney carcinoma, ovary carcinoma, bladder carcinoma and epidermal carcinoma.
The compound according to the invention may be used for other therapeutic purposes, for example: a) the sensitisation of tumours to radiotherapy by administering the compound according to the invention before, during or after irradiation of the tumour for treating cancer; b) treating arthropathies and osteopathological conditions such as rheumatoid arthritis, osteoarthritis, juvenile arthritis, gout, polyarthritis, psoriatic arthritis, ankylosing spondylitis and systemic lupus erythematosus; c) inhibiting smooth muscle cell proliferation including vascular proliferative disorders, atherosclerosis and restenosis; d) treating inflammatory conditions and dermal conditions such as ulcerative colitis, Crohn's disease, allergic rhinitis, graft vs. host disease, conjunctivitis, asthma, ARDS, Behcets disease, transplant rejection, uticaria, allergic dermatitis, alopecia areata, scleroderma, exanthema, eczema, dermatomyositis, acne, diabetes, systemic lupus erythematosis, Kawasaki's disease, multiple sclerosis, emphysema, cystic fibrosis and chronic bronchitis; e) treating endometriosis, uterine fibroids, dysfunctional uterine bleeding and endometrial hyperplasia; f) treating ocular vascularisation including vasculopathy affecting retinal and choroidal vessels; g) treating a cardiac dysfunction; h) inhibiting immunosuppressive conditions such as the treatment of HIV infections; i) treating renal dysfunction; j) suppressing endocrine disorders; k) inhibiting dysfunction of gluconeogenesis; 1) treating a neuropathology for example Parkinson' s disease or a neuropathology that results in a cognitive disorder, for example, Alzheimer's disease or polyglutamine related neuronal diseases; m) inhibiting a neuromuscular pathology, for example, amylotrophic lateral sclerosis; n) treating spinal muscular atrophy; o) treating other pathologic conditions amenable to treatment by potentiating expression of a gene; p) enhancing gene therapy.
Hence, the present invention discloses the compounds of formula (I) for use as a medicine as well as the use of these compounds of formula (I) for the manufacture of a medicament for treating one or more of the above mentioned conditions.
The compounds of formula (I), the pharmaceutically acceptable acid addition salts and stereoisomeric forms thereof can have valuable diagnostic properties in that they can be used for detecting or identifying a HDAC in a biological sample comprising detecting or measuring the formation of a complex between a labelled compound and a HDAC.
The detecting or identifying methods can use compounds that are labelled with labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances, etc. Examples of the radioisotopes include 12SI, 1311, 3H and 14C. Enzymes are usually made detectable by conjugation of an appropriate substrate which, in turn catalyses a detectable reaction. Examples thereof include, for example, beta- galactosidase, beta-glucosidase, alkaline phosphatase, peroxidase and malate dehydrogenase, preferably horseradish peroxidase. The luminous substances include, for example, luminol, luminol derivatives, luciferin, aequorin and luciferase.
Biological samples can be defined as body tissue or body fluids. Examples of body fluids are cerebrospinal fluid, blood, plasma, serum, urine, sputum, saliva and the like.
In view of their useful pharmacological properties, the subject compounds may be formulated into various pharmaceutical forms for administration purposes.
To prepare the pharmaceutical compositions of this invention, an effective amount of a particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets.
Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, to aid solubility for example, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient, calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
Those skilled in the art could easily determine the effective amount from the test results presented hereinafter. In general it is contemplated that a therapeutically effective amount would be from 0.005 g/kg to 100 mg/kg body weight, and in particular from 0.005 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.5 to 500 mg, and in particular 10 mg to 500 mg of active ingredient per unit dosage form.
As another aspect of the present invention a combination of a HDAC-inhibitor with another anticancer agent is envisaged, especially for use as a medicine, more specifically in the treatment of cancer or related diseases.
For the treatment of the above conditions, the compounds of the invention may be advantageously employed in combination with one or more other medicinal agents, more particularly, with other anti-cancer agents. Examples of anti-cancer agents are:
- platinum coordination compounds for example cisplatin, carboplatin or oxalyplatin;
- taxane compounds for example paclitaxel or docetaxel;
- topoisomerase I inhibitors such as camptothecin compounds for example irinotecan or topotecan;
- topoisomerase II inhibitors such as anti-tumour podophyllotoxin derivatives for example etoposide or teniposide;
- anti-tumour vinca alkaloids for example vinblastine, vincristine or vinorelbine;
- anti-tumour nucleoside derivatives for example 5-fluorouracil, gemcitabine or capecitabine; alkylating agents such as nitrogen mustard or nitrosourea for example cyclophosphamide, chlorambucil, carmustine or lomustine;
- anti-tumour anthracycline derivatives for example daunorubicin, doxorubicin, idarubicin or mitoxantrone;
- HER2 antibodies for example trastuzumab;
- estrogen receptor antagonists or selective estrogen receptor modulators for example tamoxifen, toremifene, droloxifene, faslodex or raloxifene;
- aromatase inhibitors such as exemestane, anastrozole, letrazole and vorozole;
- differentiating agents such as retinoids, vitamin D and retinoic acid metabolism blocking agents (RAMB A) for example accutane;
- DNA methyl transferase inhibitors for example azacytidine; - kinase inhibitors for example flavoperidol, imatinib mesylate or gefitinib;
- farnesyltransferase inhibitors; or
- other HDAC inhibitors. The term "platinum coordination compound" is used herein to denote any tumor cell growth inhibiting platinum coordination compound which provides platinum in the form of an ion.
The term "taxane compounds" indicates a class of compounds having the taxane ring system and related to or derived from extracts from certain species of yew (Taxus) trees.
The term "topisomerase inhibitors" is used to indicate enzymes that are capable of altering DNA topology in eukaryotic cells. They are critical for important cellular functions and cell proliferation. There are two classes of topoisomerases in eukaryotic cells, namely type I and type II. Topoisomerase I is a monomeric enzyme of approximately 100,000 molecular weight. The enzyme binds to DNA and introduces a transient single-strand break, unwinds the double helix (or allows it to unwind) and subsequently reseals the break before dissociating from the DNA strand. Topisomerase II has a similar mechanism of action which involves the induction of DNA strand breaks or the formation of free radicals.
The term "camptothecin compounds" is used to indicate compounds that are related to or derived from the parent camptothecin compound which is a water-insoluble alkaloid derived from the Chinese tree Camptothecin acuminata and the Indian tree
Nothapodytes foetida.
The term "podophyllotoxin compounds" is used to indicate compounds that are related to or derived from the parent podophyllotoxin, which is extracted from the mandrake plant.
The term "anti-tumor vinca alkaloids" is used to indicate compounds that are related to or derived from extracts of the periwinkle plant (Vinca rosea).
The term "alkylating agents'7 encompass a diverse group of chemicals that have the common feature that they have the capacity to contribute, under physiological conditions, alkyl groups to biologically vital macromolecules such as DNA. With most of the more important agents such as the nitrogen mustards and the nitrosoureas, the active alkylating moieties are generated in vivo after complex degradative reactions, some of which are enzymatic. The most important pharmacological actions of the alkylating agents are those that disturb the fundamental mechanisms concerned with cell proliferation in particular DNA synthesis and cell division. The capacity of alkylating agents to interfere with DNA function and integrity in rapidly proliferating tissues provides the basis for their therapeutic applications and for many of their toxic properties.
The term "anti-tumour anthracycline derivatives" comprise antibiotics obtained from the fungus Strep, peuticus var. caesius and their derivatives, characterised by having a tetracycline ring structure with an unusual sugar, daunosamine, attached by a glycosidic linkage.
Amplification of the human epidermal growth factor receptor 2 protein (HER 2) in primary breast carcinomas has been shown to correlate with a poor clinical prognosis for certain patients. Trastuzumab is a highly purified recombinant DNA-derived humanized monoclonal IgGl kappa antibody that binds with high affinity and specificity to the extracellular domain of the HER2 receptor.
Many breast cancers have estrogen receptors and growth of these tumors can be stimulated by estrogen. The terms "estrogen receptor antagonists" and "selective estrogen receptor modulators" are used to indicate competitive inhibitors of estradiol binding to the estrogen receptor (ER). Selective estrogen receptor modulators, when bond to the ER, induces a change in the three-dimensional shape of the receptor, inhibiting its binding to the estrogen responsive element (ERE) on DNA.
In postmenopausal women, the principal source of circulating estrogen is from conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by the aromatase enzyme in peripheral tissues. Estrogen deprivation through aromatase inhibition or inactivation is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer.
The term "antiestrogen agent" is used herein to include not only estrogen receptor antagonists and selective estrogen receptor modulators but also aromatase inhibitors as discussed above.
The term "differentiating agents" encompass compounds that can, in various ways, inhibit cell proliferation and induce differentiation. Vitamin D and retinoids are known to play a major role in regulating growth and differentiation of a wide variety of normal and malignant cell types. Retinoic acid metabolism blocking agents (RAMBA's) increase the levels of endogenous retinoic acids by inhibiting the cytochrome P450- mediated catabolism of retinoic acids. DNA methylation changes are among the most common abnormalities in human neoplasia. Hypermethylation within the promotors of selected genes is usually associated with inactivation of the involved genes. The term "DNA methyl transferase inhibitors" is used to indicate compounds that act through pharmacological inhibition of DNA methyl transferase and reactivation of tumour suppressor gene expression.
The term "kinase inhibitors" comprises potent inhibitors of kinases that are involved in cell cycle progression and programmed cell death (apoptosis)
The term "farnesyltransferase inhibitors" is used to indicate compounds that were designed to prevent farnesylation of Ras and other intracellular proteins. They have been shown to have effect on malignant cell proliferation and survival.
The term "other HDAC inhibitors" comprises but is not limited to:
- short-chain fatty acids for example butyrate, 4-phenylbutyrate or valproic acid;
- hydroxamic acids for example suberoylanilide hydroxamic acid (SAHA), biaryl hydroxamate A-161906, bicyclic aryl-N-hydroxycarboxamides, pyroxamide, CG-1521, PXD-101, sulfonamide hydroxamic acid, LAQ-824, trichostatin A (TSA), oxamflatin, scriptaid, m-carboxy cinnamic acid bishydroxamic acid, or trapoxin-hydroxamic acid analogue;
- cyclic tetrapeptides for example trapoxin, apidicin or depsipeptide;
- benzamides for example MS-275 or CI-994, or
- depudecin.
For the treatment of cancer the compounds according to the present invention may be administered to a patient as described above, in conjunction with irradiation. Irradiation means ionising radiation and in particular gamma radiation, especially that emitted by linear accelerators or by radionuclides that are in common use today. The irradiation of the tumour by radionuclides can be external or internal.
The present invention also relates to a combination according to the invention of an anti-cancer agent and a HDAC inhibitor according to the invention.
The present invention also relates to a combination according to the invention for use in medical therapy for example for inhibiting the growth of tumour cells. The present invention also relates to a combinations according to the invention for inhibiting the growth of tumour cells.
The present invention also relates to a method of inhibiting the growth of tumour cells in a human subject, which comprises administering to the subject an effective amount of a combination according to the invention.
This invention further provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a combination according to the invention.
The other medicinal agent and HDAC inhibitor may be administered simultaneously (e.g. in separate or unitary compositions) or sequentially in either order. In the latter case, the two compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. It will be appreciated that the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and HDAC inhibitor being administered, their route of administration, the particular tumour being treated and the particular host being treated. The optimum method and order of administration and the dosage amounts and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.
The platinum coordination compound is advantageously administered in a dosage of 1 to 500mg per square meter (mg/m2) of body surface area, for example 50 to 400 mg/m2, particularly for cisplatin in a dosage of about 75 mg/m2 and for carboplatin in about 300mg/m2 per course of treatment.
The taxane compound is advantageously administered in a dosage of 50 to 400 mg per square meter (mg/m2) of body surface area, for example 75 to 250 mg/m2, particularly for paclitaxel in a dosage of about 175 to 250 mg/m2 and for docetaxel in about 75 to 150 mg/m2 per course of treatment.
The camptothecin compound is advantageously administered in a dosage of 0.1 to 400 mg per square meter (mg/m ) of body surface area, for example 1 to 300 mg/m , particularly for irinotecan in a dosage of about 100 to 350 mg/m and for topotecan in about 1 to 2 mg/m2 per course of treatment. The anti-tumour podophyllotoxin derivative is advantageously administered in a dosage of 30 to 300 mg per square meter (mg/m2) of body surface area, for example 50 to 250mg/m2, particularly for etoposide in a dosage of about 35 to 100 mg/m2 and for teniposide in about 50 to 250 mg/m per course of treatment.
The anti-tumour vinca alkaloid is advantageously administered in a dosage of 2 to 30 mg per square meter (mg/m2) of body surface area, particularly for vinblastine in a dosage of about 3 to 12 mg/m2, for vincristine in a dosage of about 1 to 2 mg/m2, and for vinorelbine in dosage of about 10 to 30 mg/m per course of treatment.
The anti-tumor nucleoside derivative is advantageously administered in a dosage of 200 to 2500 mg per square meter (mg/m2) of body surface area, for example 700 tol500 mg/m , particularly for 5-FU in a dosage of 200 to 500mg/m , for gemcitabine in a dosage of about 800 to 1200 mg/m2 and for capecitabine in about 1000 to 2500 mg/m2 per course of treatment.
The alkylating agents such as nitrogen mustard or nitrosourea is advantageously administered in a dosage of 100 to 500 mg per square meter (mg/m2) of body surface area, for example 120 to 200 mg/m2, particularly for cyclophosphamide in a dosage of about 100 to 500 mg m2, for chlorambucil in a dosage of about 0.1 to 0.2 mg/kg, for carmustine in a dosage of about 150 to 200 mg/m2, and for lomustine in a dosage of about 100 to 150 mg/m2 per course of treatment.
The anti-tumor anthracycline derivative is advantageously administered in a dosage of 10 to 75 mg per square meter (mg/m2) of body surface area, for example 15 to 60 mg/m2, particularly for doxorubicin in a dosage of about 40 to 75 mg/m2, for daunorubicin in a dosage of about 25 to 45mg/m2, and for idarubicin in a dosage of about 10 to 15 mg/m2 per course of treatment.
Trastuzumab is advantageously administered in a dosage of 1 to 5mg per square meter (mg/m2) of body surface area, particularly 2 to 4mg/m2 per course of treatment.
The antiestrogen agent is advantageously administered in a dosage of about 1 to lOOmg daily depending on the particular agent and the condition being treated. Tamoxifen is advantageously administered orally in a dosage of 5 to 50 mg, preferably 10 to 20 mg twice a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect. Toremifene is advantageously administered orally in a dosage of about 60mg once a day, continuing the therapy for sufficient time to achieve and -21- maintain a therapeutic effect. Anastrozole is advantageously administered orally in a dosage of about lmg once a day. Droloxifene is advantageously administered orally in a dosage of about 20-100mg once a day. Raloxifene is advantageously administered orally in a dosage of about 60mg once a day. Exemestane is advantageously administered orally in a dosage of about 25mg once a day.
These dosages may be administered for example once, twice or more per course of treatment, which may be repeated for example every 7,14, 21 or 28 days.
In view of their useful pharmacological properties, the components of the combinations according to the invention, i.e. the other medicinal agent and the HDAC inhibitor may be formulated into various pharmaceutical forms for administration purposes. The components may be formulated separately in individual pharmaceutical compositions or in a unitary pharmaceutical composition containing both components.
The present invention therefore also relates to a pharmaceutical composition comprising the other medicinal agent and the HDAC inhibitor together with one or more pharmaceutical carriers.
The present invention also relates to a combination according to the invention in the form of a pharmaceutical composition comprising an anti-cancer agent and a HDAC inhibitor according to the invention together with one or more pharmaceutical carriers.
The present invention further relates to the use of a combination according to the invention in the manufacture of a pharmaceutical composition for inhibiting the growth of tumour cells.
The present invention further relates to a product containing as first active ingredient a HDAC inhibitor according to the invention and as second active ingredient an anticancer agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.
Experimental part
The following examples are provided for purposes of illustration.
Hereinafter "EDC" means N-(ethylcarbonimidoyl)-N,N-dimethyl-l,3-propanediamine, monohydrochloride "DCM" means dichloromethane, "DIEA" means diisopropylethylamine, "DIPE" means diisopropyl ether, "DMF" means dimethylformamide, "EtOAc" means ethyl acetate, "iPrOff ' means isopropyl, "MeOH" means methanol, "EtOH" means ethanol, "PyBrOP" means bromo-tris-pyrrolidino- phosphonium hexafluorophosphate, "TEA"means triethylamine, "TFA" means trifluoroacetic acid and "THF" means tetrahydrofuran.
A. Preparation of the intermediates
Example Al a) A solution of hexahydro-lH-l,4-diazepine (0.20 mol) and l-fluoro-4-nitro-benzene (0.10 mol) in DCM (300 ml) was stirred at room temperature for 24 hours under nitrogen atmosphere. Yellow crystals precipitated. The precipitate was collected on filter, washed with ether and dried. The residue (21. lg, 87%) was taken up in water and treated with a 3 N NaOΗ solution. This mixture was extracted with DCM (3 x 500 ml), dried (Na2SO4), filtered, and the solvent was removed under reduced pressure and dried under vacuum at room temperature for 16 hours, yielding 18.3 g of hexahydro-l-(4- nitrophenyl)- lH-l,4-diazepine (interm. 1), melting point 115-116°C. b) Bis-(l,l-dimethylethyl)-dicarbonic acid, ester (0.090 mol) in DCM (100 ml) was added to a cooled (ice bath) solution of interm. 1 (0.090 mol) in DCM (200 ml), with stirring. Evolution of gas was observed. After the evolution of CO2 stopped, the ice- bath was removed and stirring was continued for 3 hours at room temperature. The reaction mixture was washed with a 1 N ΗC1 solution and water, then dried. The solvent was evaporated, yielding 20.5 g (70%) of hexahydro-4-(4-nitrophenyl)- 1H-1,4- diazepine-1-carboxylic acid, 1,1-dimethylethyl ester (interm.2), melting point 128- 130°C. c) Interm. 2 (0.047 mol) was added portionwise (over a 20-min period) to a refluxing mixture of hydrazine monohydrate (15 ml) in methanol (700 ml) and Raney Nickel (16.1 g). The reaction mixture was stirred and refluxed until the yellow color was discharged. The mixture was continued refluxing for an additional half an hour. The catalyst was removed by filtration. The solvent was evaporated, yielding 13.0 g of 4-(4- aminophenyl)hexahydro-lH-l,4-diazepine-l-carboxylic acid, 1,1-dimethylethyl ester (interm. 3). d) A mixture of interm. 3 (0.045 mol) and (l-ethoxyethylidene)-hydrazinecarboxylic acid, ethyl ester (0.090 mol) was heated neat on an oil bath at 130°C for 1 hour, with stirring. After additional two hours, the reaction mixture was cooled and 2-propanol
(about 100 ml) was added with trituration. The solid was filtered and dried to give 14 g of solid. This solid was triturated with ether, filtered off and dried, yielding 13.0 g (77%) of lH-l,4-diazepine-l-carboxylic acid, 4-[4-(l,5-dihydro-3-methyl-5-oxo-4H- l,2,4-triazol-4-yl)phenyl]hexahydro-lH-l,4-diazepine-l-carboxylic acid, 1,1- dimethylethyl ester (interm. 4) , melting point 238-240°C. e) Reaction under Ar atmosphere. l,l,l-Trimethyl-N-(trimethylsilyl)- silanamine, sodium salt (0.01 mol; 10 ml, 1 M/TΗF) was added (via syringe) to interm.4 (0.01 mol) in DMF (200 ml), at room temperature. Solid sodium salt started to form. It was stirred vigorously and additional DMF (200 ml) was added. A solution of 2-bromo- butane (0.02 mol) in DMF (100 ml) was added slowly at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The DMF solvent was removed (vacuum pump). Water was added to the residue and the resulting oily product was taken up with ether (500 ml). The ether solution was concentrated to give 2.70 g (oily material which solidified on standing; 62% yield) which was further purified by flash column chromatography over silica gel (eluent: 1% (10% ΝΗ4θΗ/CΗ3OΗ)/CΗ2Cl2) yielding 0.55 g of 4-[4-[l,5-dihydro-3-methyl-l-(l- methylpropyl)-5-oxo-4H-l,2,4-triazol-4-yl]phenyl]hexahydro-lH-l,4-diazepine-l- carboxylic acid, 1,1-dimethylethyl ester (interm. 5), melting point: 119-120°C. f) Interm. 5 (0.0014 mol) was added into a cooled solution of TFA (5 ml; ice-bath) for 30 min. The solvent was removed under reduced pressure. Water was added and the mixture was saturated with potassium carbonate. This mixture was extracted with ethylacetate (2 x 50 ml), dried over sodium sulfate, filtered and the solvent was removed, yielding 0.35 g (65%) of 4-[4-(hexahydro-lH-l,4-diazepin-l-yl)phenyl]-2,4- dihydro-5-methyl-2-(l-methylpropyl)~ 3H-l,2,4-triazol-3-one (interm. 6). g) A mixture of interm. 6 (0.00076 mol), 4-bromo-benzoic acid, methyl ester (0.00304 mol), (lR)-[l,r-binaphthalene]-2,2'-diylbis[diphenyl- phosphine (0.016 g), Pd2(dba)3 (0.008 g) and Cs2CO3 (0.40 g) in toluene (10 ml) was placed in a pressure tube (containing a small magnetic stirring bar) in a glove box under argon. The pressure tube was capped tightly and was heated in an oil bath at 120°C for 12 hours with stirring). More (lR)-[l,l'-binaphthalene]-2,2'-diylbis[diphenyl- phosphine (0.016 g), Pd2(dba)3 (0.008 g) and Cs2CO3 (0.40 g) were added. The mixture was heated at 120°C in the oil bath for 24 hours. The reaction mixture was filtered to remove the inorganic solid material and was washed with about 20 ml of CΗC13 . The filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography on silica gel (eluent: NHUOH/CHsOH/CH^k 0.1/0.9/99). The desired fractions were combined and the solvent was evaporated and dried at room temperature under vacuum for 16 hours, yielding 0.21 g (60%) of 4-[4-[4-[l,5-dihydro-3-methyl-l-(l- methylpropyl)-5-oxo-4H-l,2,4-triazol-4-yl]phenyl]hexahydro-lH-l,4-diazepin-l-yl]- benzoic acid, methyl ester (interm. 7), melting point 152°C-153°C. Example A2
A mixture of 4-[4-(phenylmethyl)-l-piperazinyl]- benzoic acid (0.0145 mol), O- (tetrahydro-2H-pyran-2-yl)- hydroxylamine (0.029 mol), N,N'-methanetetrayl- biscyclohexanamine (0.0145 mol) and 1-hydroxy-lH-benzotriazole (0.021 mol) in DCM p.a. (200 ml) was stirred at room temperature over the weekend. The reaction mixture was washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from EtOAc, filtered off and dried, yielding 3.5 g and another crop: 2.0 g , total yielding 5.5 g (95%) of 4-[4-(phenylmethyl)-l- piperazinyl]-N-[(tetrahydro-2H-pyran-2-yl)oxy]- benzamide (interm. 8).
Example A3 a) Preparation of
Figure imgf000032_0001
intermediate 9 A solution of l-(phenylmethyl)- piperazine (0.068 mol) in acetonitrile p.a. (135 ml) was added gradually to a solution of potassium carbonate (0.18 mol) and 2- (methylsulfonyl)- 5-pyrimidinecarboxylic acid, ethyl ester (0.082 mol) in acetonitrile p.a. (135 ml) and the reaction mixture was stirred for 45 min at room temperature. Then, the reaction mixture was stood overnight. DCM (400 ml) was added. Water (300 ml) was added and the organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (28g) was purified by column chromatography over silica gel (eluent: DCM/MeOΗ 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from acetonitrile, filtered off and dried in vacuo, yielding 15.1 g of intermediate 9. b) Preparation of
Figure imgf000032_0002
intermediate 10 A mixture of intermediate 9 (0.03 mol) in EtOΗ (250 ml) was hydrogenated at 50 °C with Pd/C 10% (2 g) as a catalyst. After uptake of Η2 (1 equiv), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/(MeOH/NH3) 90/10). The product fractions were collected and the solvent was evaporated, yielding 6.8 g (>96%) of intermediate 10. c) Preparation of
Figure imgf000033_0001
intermediate 11 Titanium tetrakis(ethoxide) (0.0029 mol) was added to a mixture of intermediate 10 (0.0022 mol) and 4-oxo-l-piperidinecarboxylic acid, 1,1-dimethylethyl ester (0.0027 mol) in 1,2-dichloro- ethane (6ml). The mixture was stirred at 50°C for 18 hours, then cooled to room temperature. NaBH(OAc)3 (0.0029 mol) was added portionwise. The mixture was stirred at room temperature for 2 hours. Water was added. The mixture was extracted with DCM and filtered over celite. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated till dryness. The residue (l.lg) was crystallized from diethyl ether DIPE. The precipitate was filtered off and dried, yielding 0.49g (51 %) of intermediate 11. d) Preparation of
Figure imgf000033_0002
.HCI intermediate 12
A mixture of intermediate 11 (0.0011 mol) in HCl/iPrOH (5ml) was stirred at 50°C for 1 hour, then cooled to room temperature. The precipitate was filtered, washed with EtOH, then with diethyl ether and dried, yielding 0.38g (94%) of intermediate 12 (HCI salt). e) Preparation of
Figure imgf000033_0003
A solution of 2-naphthalenesulfonyl chloride (0.0011 mol) in DCM (1ml) was added at 5°C to a mixture of intermediate 12 (0.001 mol) and TEA (0.0032 mol) in DCM (4ml) under N2 flow. The mixture was stirred at room temperature overnight. Potassium carbonate 10% was added. The mixture was extracted with DCM. The organic layer was separated, dried (MgSO ), filtered, and the solvent was evaporated till dryness. The residue (0.53g) was taken up in diethyl ether/DIPE. The precipitate was filtered off and dried yielding 0.42g (77%) of intermediate 13. Example A4 a) Preparation of
Figure imgf000034_0001
intermediate 14 Tetrakis (2-propanolato) titanium (0.0023 mol) was added to a mixture of l-(2- naphthalenylsulfonyl)- piperazine (0.0018 mol) and 4-oxo-l-piperidinecarboxylic acid, 1,1-dimethylethyl ester (0.0021 mol) in 1,2-dichloro- ethane (6ml) under N2 flow. The mixture was stirred at 50°C for 18 hours, then cooled to room temperature. NaBH(OAc)3 (0.0023 mol) was added portionwise. The mixture was stirred at room temperature for 4 hours. Water was added. The mixture was filtered over celite. The mixture was extracted with DCM. The filtrate was decanted. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated till dryness. The residue (1.3g) was purified by column chromatography over silica gel (70-200μm) (eluent: DCM 100 to DCM/MeOH 99/1). The pure fractions were collected and the solvent was evaporated, yielding 0.72g (86%) of intermediate 14. b) Preparation of
Figure imgf000034_0002
intermediate 15
A mixture of intermediate 14 (0.0014 mol) in HCl/iPrOH 5N (10ml) was stirred at 50°C for 18 hours, then cooled to room temperature, filtered, washed with diethyl ether and dried, yielding 0.53g (95%) of intermediate 15 (HCI salt), melting point 260°C.
Example A5 Preparation of
Figure imgf000034_0003
intermediate 16 A solution of 5-bromo-2-furancarboxaldehyde (0.0171 mol) in 1,2-dimethoxyethane (15ml) was added dropwise at room temperature to a solution of tetrakis(triphenylphosphine)- palladium (0.0045 mol) in 1,2-dimethoxyethane (50ml) under N2 flow. The mixture was stirred for 20 minutes. A suspension of [4- (hydroxymethyl)phenylj- boronic acid (0.0257 mol) in EtOH (18ml) was added. The mixture was stirred for 20 minutes. Sodiumcarbonate (0.15 mol) was added. The mixture was stirred and refluxed for 4 hours, then brought to room temperature. The organic layer was evaproated. The residue was taken up in DCM and washed with water. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (4.1g) was purified by column chromatography over silica gel (15-40μm) (eluent: DCM/MeOH 99/1). The pure fractions were collected and the solvent was evaporated, yielding 2.8g (82%) of intermediate 16.
Example A6 a) Preparation of
Figure imgf000035_0001
intermediate 17 A solution of 2-(methylsulfonyl)- 5-pyrimidinecarboxylic acid, ethyl ester (0.0434 mol) in acetonitrile (100ml) was added drop wise at 10°c to a solution of 4- piperidinemethanamine (0.0868 mol) and potassium carbonate (0.0434 mol) in acetonitrile (200ml) under N2 flow. The mixture was stirred at room temperature for 2 hours, poured out into ice water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (14.18g) was purified by column chromatography over silica gel (20-45 m) (eluent: DCM/MeOH/NHUOH 90/10/1 to 80/20/2). The pure fractions were collected and the solvent was evaporated, yielding 3.7g (32%) of intermediate 17. b) Preparation of
— o p intermediate 18
To N-cyclohexylcarbodiimide, N' -methyl polystyrene (153mg) (ΝovaBiochem Cat. Νr. 01-64-0211) was added N-acetyl-3,4,5-trimethoxy- anthranilic acid(0.2 mmol), dissolved in THF (0.5ml), followed by 1 -hydroxy- IH-benzotriazole, dissolved in TΗF (0.5ml). This mixture was shaken for 10 minutes at room temperature. Subsequently, intermediate 17 (0.1 mmol), dissolved in DCM (1ml) was added to the suspension after which the solvents were evaporated by means of a nitrogen flow at 50°C and subsequently, the neat reaction mixture was left overnight at 90°C under a flow of nitrogen. The product was dissolved in dichloromethane (2 mL) and filtered through a glass filter. The residue was rinsed with DCM (2 x 2ml) and the filtrate was concentrated. The product was then treated with a mixture of THF(lml) and aqueous sodium hydroxide (1ml, IN) for 48 hours at room temperature. Finally, the mixture was neutralized by the addition of aqueous HCI (1ml, IN), and dried at 70°C under a nitrogen flow, yielding intermediate 18. c) Preparation of
Figure imgf000036_0001
To product intermediate 18 (0.1 mmol) was added a solution of 1-hydroxy-lH- benzotriazole (0.1 mmol), EDC (0.1 mmol) and TEA (0.12 mmol) in a mixture of DCM/TΗF (3/4, 7ml). The reaction mixture was shaken for 5 minutes at room temperature, after which O-(tetrahydro-2Η-pyran-2-yl)- hydroxylamine (0.1 mmol) was added. The resulting solution was allowed to shake overnight at room temperature. The reaction mixture was then concentrated under a nitrogen flow at 50 °C to a volume of 5ml and then polymer supported methyl isocyanate (1.25 mmol/g, 0.25 mmol, Argonaut, Cat. Nr. 800261) and (polystyrylmethyl)trimethylammonium bicarbonate, (0.6 mmol) (NovaBiochem Cat. Nr. 01-64-0419) were added and this mixture was shaken for an additional 2 hours. The reaction mixture was filtered and the filtrate concentrated. Preparative HPLC purification of the product, yielded 29 mg of intermediate 19.
Example A7 Preparation of
Figure imgf000036_0002
intermediate 20 Methanesulfonyl chloride (0.006 mol) was added at 0°C to a solution of intermediate 27 (0.001 mol) and TEA (0.008 mol) in DCM (10ml) under N2 flow. The mixture was stirred at 0°C for 3 hours, poured out into ice water and extracted with DCM. The organic layer was separated, dried (MgSO ), filtered, and the solvent was evaporated, yielding 0.44g of intermediate 20. This product was used directly in the next reaction step. Example A8 a) Preparation of
Figure imgf000037_0001
intermediate 21 A sample of intermediate (0.1 mmol) and 2-phenyl-4H-3,l-benzoxazin-4-one (0.1 mmol) were weighed into a vessel and toluene (2ml) was added. The vessel was sealed and the mixture heated for 10 hours at 90°C. Next, the solvent was evaporated and the residue was taken up in DCM (4ml), followed by addition of ethanedioyl dichloride (1 mmol) and DMF (1 mmol). The resulting mixture was shaken overnight at 90°C. The reaction mixture was then washed with a 10% aqueous sodium bicarbonate solution (2 X 1ml), the phases were separated and the organic layer was concentrated, yielding intermediate 21. b) Preparation of
Figure imgf000037_0002
intermediate 22 Intermediate 21 (crude) was treated with a mixture of TΗF/1N aq. NaOΗZMeOΗ (1/1/0.2, 2.2ml) while stirred vigorously overnight at room temperature. Next, an aqueous ΗC1 (IN, 1ml) was added to neutralize the solution. The solvents were evaporated in vacuo, yielding intermediate 22. c) Preparation of
Figure imgf000037_0003
intermediate 23 To intermediate 22 was subsequently added 1-hydroxy-lH-benzotriazole (0.13 mmol), dissolved in TΗF (dry, 1ml), EDC (0.13 mmol), dissolved in DCM (dry, 1ml), and TEA (0.15 mmol). The mixture was stirred at room temperature for 10 minutes. O- (tetrahydro-2Η-pyran-2-yl)- hydroxylamine (0.13 mmol), dissolved in THF (dry 1ml) was added and the reaction mixture was stirred at room temperature overnight. The O 03/076400 36 solvents were evaporated and the product was purified using reverse phase-HPLC, yielding intermediate 23, melting point (219°C).
B. Preparation of final compounds Example Bl
N-Fmoc-hydroxylamine 2-chlorotrityl resin (Novabiochem, 01-64-0165) was deprotected by 50% piperidine in DMF (RT, 24 hr). The resin was washed several times with DCM and DMF and swelled in DMF. Two equivalents of acid1, PyBrOP and 4 equivalents of DIEA were added as one portion. The mixture was shaken for 24 hr, liquid was drained and the resin was washed several times by DCM and DMF. The resin was swelled in DMF containing 2 equivalents of amine, was shaken 24 hr at RT, the liquid was drained and the resin was washed by DCM and DMF. The final product was cleaved by 5% TFA in DCM, analyzed by HPLC and MS and evaporated in the pre- weighted test-tubes. *. Based on the loading of the resin.
Example B2 Preparation of
Figure imgf000038_0001
•H2O Compound 1 A mixture of interm. 7 (0.00075 mol), NH2OH/H2O 50% (5 ml), KCN (0.001 mol), MeOH (10 ml) and THF (10 ml) was stirred at room temperature for 48 hours. The solvent was evaporated. The residue was extracted with DCM and was washed with water. The solvent was removed and the oily residue (0.225 g) was purified by column chromatography over silica gel (eluent:
Figure imgf000038_0002
0.05/0.95/99; then with NH4OHyCH3OH/CH2Cl20.1/0.9/99). The pure fractions were collected and the solvent was evaporated, yielding 0.114 g of compound 1 .H2O, melting point 182- 184°C and 0.040 g of 4-[4-[4-[l,5-dihydro-3-methyl-l-(l-methylproρyl)-5-oxo-4H- l,2,4-triazol-4-yl]phenyl]hexahydro-lH-l,4-diazepin-l-yl]- benzoic acid, melting point 244-245°C. Example B3 Preparation of
Figure imgf000039_0001
Compound 2 Interm. 8 (0.000088 mol) was stirred in 5% TFA/MeOH (5 ml) for 24 hours at 25°C. Then, the reaction mixture was poured out into water (5 ml) + 1 equiv of NaHCO3. This mixture was extracted with DCM (5 ml, 2 x). The separated organic layer was dried (MgSO4), filtered and the solvent evaporated (blown dry under N2 flow at 50°C). The residue was dried (vacuum, 50°C), yielding 0.018 g (65%) of compound 2, melting point 196°C.
Example B4 a) Preparation of
Figure imgf000039_0002
A mixture of intermediate 13 (0.0008 mol) and sodium hydroxide (0.0016 mol) in EtOH (10ml) was stirred and refluxed for 2 hours, then cooled to room temperature.
The precipitate was filtered, washed with EtOH, then with diethyl ether and dried, yielding 0.425g (>100%) of intermediate 24 (sodium salt). b) Preparation of
Figure imgf000039_0003
EDC (0.001 mol) was added to a mixture of intermediate 24 (0.0008 mol), O- (tetrahydro-2H-pyran-2-yl)- hydroxylamine (0.001 mol) and 1 -hydroxy- IH- benzotriazole (0.001 mol) in DCM/TΗF (10ml) under N2 flow. The mixture was stirred at room temperature for 18 hours. The precipitate was filtered, washed with TΗF, then with diethyl ether and dried, yielding 0.4g (83%) of intermediate 25, melting point 260°C. c) Preparation of
Figure imgf000040_0001
TFA(0.5ml) was added to a mixture of intermediate 25 (0.0006 mol) in MeOH (10ml). The mixture was stirred at room temperature for 5 days. The precipitate was filtered, washed with diethyl ether and dried.. The residue was taken up in water, stirred for 30 5 minutes, filtered off and dried, yielding 0.143g (38%) of compound 3 (.0.91 CF3COOH), melting point 210°C.
Example B5 Preparation of
Figure imgf000040_0002
A mixture of intermediate 15 (0.0013 mol), 2-(methylsulfonyl)- 5- pyrimidinecarboxylic acid, ethyl ester (0.0017 mol) and potassium carbonate (0.0039 mol) in acetonitrile (10ml) was stirred at 80°C for 18 hours. Water was added. The mixture was extracted with DCM. The organic layer was separated, dried (MgSO4), 15 filtered and the solvent was evaporated till dryness. The residue (0.5g) was crystallized from CH3CN/DIPE. The precipitate was filtered off and dried, yielding 0.25g (37%) of intermediate 26.
Intermediate 26 was handled analogously as described in example [B4] to give 0.126g (74%) of compound 4 (.0.86 CF3COOH), melting point 230°C. 0
Figure imgf000040_0003
compound 4
Example B6 Preparation of
Figure imgf000041_0001
interme iate 27
A mixture of intermediate 10 (0.0015 mol) and intermediate 16 (0.0015 mol) in MeOH (6ml) was stirred at 60°C for 20 hours, then cooled to 0°C. Sodium hydroborate (0.0022 mol) was added. The mixture was brought to room temperature, then stirred for 4 hours, poured out into ice water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.8g) was purified by column chromatography over silica gel (15-40μm) (eluent: DCM/MeOH/NH^OH 97/3/0.1 to 95/5/0.1). The pure fractions were collected and the solvent was evaporated, yielding 0.28g (45%) of intermediate 27. Intermediate 27 was handled analogously as described in example [B4] to give 0.143g (89%) of compound 5 (.0.83 CF3COOH), melting point 219°C.
Figure imgf000041_0002
. 0.83 CF3COOH compound 5
Example B7 Preparation of
Figure imgf000041_0003
intermediate 28 A mixture of intermediate 10 (0.0042 mol) and 2-naphthalenecarboxaldehyde (0.005 mol) in 1,2-dichloro-ethane (10ml) was stirred at 50°C for 3 hours, then cooled to room temperature. NaBH(OAc)3 (0.0055 mol) was added portionwise. The mixture was stirred at room temperature for 2 hours. Water was added. The mixture was extracted with DCM. The organic layer was separated, dried (MgSO ), filtered, and the solvent was evaporated till dryness. The residue (2g) was taken up in CH3CN/DIPE. The precipitate was filtered off and dried, yielding 1.2g (75%) of intermediate 28, melting point 147°C. Intermediate 28 was handled analogously as described in example [B4] to give 0.724g (88%) of compound 6 (.0.83 CF3COOH) , melting point > 260°C.
Figure imgf000042_0001
.0.83 CF3COOH compound 6
Example B 8 Preparation of
Figure imgf000042_0002
intermediate 29 A solution of 2-naphthaleneethanol, methanesulfonate (0.0029 mol) in acetonitrile (3ml) was added at 5°C to a mixture of intermediate 10 (0.0024 mol) and potassium carbonate (0.0048 mol) in acetonitrile (6ml). The mixture was stirred at room temperature for 18 hours, then stirred and refluxed overnight and cooled to room temperature. Water was added. The mixture was filtered, washed with water, then with diethyl ether and dried, yielding 0.45g (48%) of intermediate 29, melting point 128°C. Intermediate 29 was handled analogously as described in example [B4] to give 0.254g (86%) of compound 7 (.0.79 CF3COOH), melting point 209°C.
Figure imgf000042_0003
.0.79 CF3COOH compound 7
Example B9 Preparation of
Figure imgf000042_0004
Intermediate 19 (0.05 mmol) was treated with TFA (2ml , in DCM/MeOH 1/1) for 10 days at room temperature. Next, the solvents were evaporated at room temperature under a flow of nitrogen, followed by addition of 1,4-dioxane and repeating the evaporation procedure. Then the sample was dried under a nitrogen flow overnight at 40°C, yielding compound 8 (.CF3COOH).
Example BIO Preparation of
Figure imgf000043_0001
intermediate 30 A mixture of intermediate 20 (0.001 mol), morpholine (0.0013 mol) and potassium carbonate (0.002 mol) in acetonitrile (6ml) was stirred and refluxed overnight, then cooled, poured out into ice water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.79g) was purified by column chromatography over silica gel (lOμm) (eluent: DCM/MeOH/NH OH 96/4/0.1). The pure fractions were collected and the solvent was evaporated. The residue (0.183g) was crystallized from DIPE. The precipitate was filtered off and dried, yielding 0.086g (47%) of intermediate 30, melting point 120°C. Intermediate 30 was handled analogously as described in example [B4] to give 0.432g (87%) of compound 9 (.0.47 H2O .1.99 CF3COOH), melting point 140°C .
Figure imgf000043_0002
compound 9 .0.47 H2O .1.99 CF3COOH
Example Bll Preparation of
Figure imgf000043_0003
compound 10 .CF3COOH A solution of TFA (5% in DCM/MeOH 1/1, 2ml) was added to intermediate 23 and the reaction mixture was stirred for 5 days at room temperature. Next, the solvents were evaporated at room temperature under a flow of nitrogen, followed by addition of 1,4- dioxane and the concentrating procedure was repeated. Then, the sample was dried under a nitrogen flow overnight at 40°C, yielding compound 10 (.CF3COOH).
Table F-l lists the compounds that were prepared according to one of the above Examples. The following abbreviations were used in the tables : .C2-HF O2 stands for the trifluoroacetate salt.
Table F-l
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
C. Pharmacological example:
The in vitro assay for inhibition of histone deacetylase (see example C.l) measures the inhibition of HDAC enzymatic activity obtained with the compounds of formula (I).
Cellular activity of the compounds of formula (I) was determined on A2780 tumour cells using a colorimetric assay for cell toxicity or survival (Mosmann Tim, Journal of Immunological Methods 65: 55-63, 1983)(see example C.2).
Kinetic solubility in aqueous media measures the ability of a compound to stay in aqueous solution upon dilution (see example C.3).
DMSO-stock solutions are diluted with a single aqueous buffer solvent in 3 consecutive steps. For every dilution turbidity is measured with a nephelometer.
A drug's permeability expresses its ability to move from one medium into or through another. Specifically its ability to move through the intestinal membrane into the blood stream and/or from the blood stream into the target. Permeability (see example C.4) can be measured through the formation of a filter-immobilized artificial membrane phospholipid bilayer. In the filter-immobilized artificial membrane assay, a "sandwich" is formed with a 96-well microtitre plate and a 96-well filter plate, such that each composite well is divided into two chambers with a donor solution at the bottom and an acceptor solution at the top, separated by a 125 μm micro-filter disc (0.45 μm pores), coated with 2%(wt/v) dodecane solution of dioleoylphosphatidyl-choline, under conditions that multi-lamellar bilayers form inside the filter channels when the system contacts an aqueous buffer solution. The permeability of compounds through this artificial membrane is measured in cm s. The purpose is to look for the permeation of the drugs through a parallel artificial membrane at 2 different pH's: 4.0 and 7.4. Compound detection is done with UV-spectrometry at optimal wavelength between 250 and 500 nm.
Metabolism of drugs means that a lipid-soluble xenobiotic or endobiotic compound is enzymatically transformed into (a) polar, water-soluble, and excretable metabolite(s). The major organ for drug metabolism is the liver. The metabolic products are often less active than the parent drug or inactive. However, some metabolites may have enhanced activity or toxic effects. Thus drug metabolism may include both "detoxication" and "toxication" processes. One of the major enzyme systems that determine the organism's capability of dealing with drugs and chemicals is represented by the cytochrome P450 monooxygenases, which are NADPH dependent enzymes. Metabolic stability of compounds can be determined in vitro with the use of subcellular human tissue (see example C.5). Here metabolic stability of the compounds is expressed as % of drug metabolised after 15 minutes incubation of these compounds with microsomes. Quantitation of the compounds was determined by LC-MS analysis.
The tumour suppressor p53 transcriptionally activates a number of genes including the WAF1/CIP1 gene in response to DNA damage. The 21 kDa product of the WAF1 gene is found in a complex involving cyclins, cyclin dependent kinases (CDKs), and proliferating cell nuclear antigen (PCNA) in normal cells but not transformed cells and appears to be a universal inhibitor of CDK activity. One consequence of p21WAFl binding to and inhibiting CDKs is to prevent CDK-dependent phosphorylation and subsequent inactivation of the Rb protein, which is essential for cell cycle progression. Induction of p21WAFl in1 response to cellular contact with a HDAC inhibitor is therefore a potent and specific indicator of inhibition of cell cycle progression at both the Gl and G2 checkpoints. The capacity of the compounds to induce p21WAFl was measured with the p21WAFl enzyme linked immunosorbent assay (WAF1 ELISA of Oncogene). The p21WAFl assay is a "sandwich" enzyme immunoassay employing both mouse monoclonal and rabbit polyclonal antibodies. A rabbit polyclonal antibody, specific for the human WAF1 protein, has been immobilized onto the surface of the plastic wells provided in the kit. Any p21WAF present in the sample to be assayed will bind to the capture antibody. The biotinylated detector monoclonal antibody also recognizes human p21WAFl protein, and will bind to any p21WAFl, which has been retained by the capture antibody. The detector antibody, in turn, is bond by horseradish peroxidase- conjugated streptavidin. The horseradish peroxidase catalyses the conversion of the chromogenic substrate tetra-methylbenzidine from a colorless solution to a blue solution (or yellow after the addition of stopping reagent), the intensity of which is proportional to the amount of p21WAFl protein bond to the plate. The colored reaction product is quantified using a spectrophotometer. Quantitation is achieved by the construction of a standard curve using known concentrations of p21WAFl (provided lyoρhilised)(see example C.6).
Example C.l: In Vitro Assay for Inhibition of histone deacetylase :
HeLa nuclear extracts (supplier: Biomol) were incubated at 60 μg/ml with 2x10 M of radiolabeled peptide substrate. As a substrate for measuring HDAC activity a synthetic peptide, i.e. the amino acids 14-21 of histone H4, was used. The substrate is biotinylated at the NH2-terminal part with a 6-aminohexanoic acid spacer, and is protected at the COOH-terminal part by an amide group and specifically [3Hjacetylated at lysine 16. The substrate, biotin-(6-aminohexanoic)Gly-Ala-([3H]-acetyl-Lys-Arg- His-Arg-Lys-Val-NH2), was added in a buffer containing 25 mM Hepes, 1 M sucrose, 0.1 mg/ml BSA and 0.01% Triton X-100 at pH 7.4. After 30 min the deacetylation reaction was terminated by the addition of HCI and acetic acid, (final concentration 0.035 mM and 3.8 mM respectively). After stopping the reaction, the free 3H-acetate was extracted with ethylacetate. After mixing and centrifugation, the radioactivity in an aliquot of the upper (organic) phase was counted in a β-counter. For each experiment, controls (containing HeLa nuclear extract and DMSO without compound), a blank incubation (containing DMSO but no HeLa nuclear extract or compound) and samples (containing compound dissolved in DMSO and HeLa nuclear extract) were run in parallel. In first instance, compounds were tested at a concentration of 10"5M. When the compounds showed activity at 10"5M, a concentration-response curve was made wherein the compounds were tested at concentrations between 10"5M and 10"12M. In each test the blank value was substracted from both the control and the sample values. The control sample represented 100% of substrate deactylation. For each sample the radioactivity was expressed as a percentage of the mean value of the controls. When appropriate IC5o-values (concentration of the drug, needed to reduce the amount of metabolites to 50% of the control) were computed using probit analysis for graded data. Herein the effects of test compounds are expressed as pIC5o (the negative log value of the IC5o-value). All tested compounds showed enzymatic activity at a test concentration of 10"5M and 28 compounds had a pIC50 ≥ 5 (see table F-2). Example C.2: Determination of antiproliferative activity on A2780 cells
All compounds tested were dissolved in DMSO and further dilutions were made in culture medium. Final DMSO concentrations never exceeded 0.1 % (v/v) in cell proliferation assays. Controls contained A2780 cells and DMSO without compound and blanks contained DMSO but no cells. MTT was dissolved at 5 mg/ml in PBS. A glycine buffer comprised of 0.1 M glycine and 0.1 M NaCl buffered to pH 10.5 with NaOH (1 N) was prepared (all reagents were from Merck). The human A2780 ovarian carcinoma cells (a kind gift from Dr. T.C. Hamilton [Fox Chase Cancer Centre, Pennsylvania, USA]) were cultured in RPMI 1640 medium supplemented with 2 mM L-glutamine, 50 μg/ml gentamicin and 10 % fetal calf serum. Cells were routinely kept as monolayer cultures at 37°C in a humidified 5 % CO2 atmosphere. Cells were passaged once a week using a trypsin/EDTA solution at a split ratio of 1:40. All media and supplements were obtained from Life Technologies. Cells were free of mycoplasma contamination as determined using the Gen-Probe Mycoplasma Tissue Culture kit (supplier: BioMerieux).
Cells were seeded in NUNC™ 96-well culture plates (Supplier: Life Technologies) and allowed to adhere to the plastic overnight. Densities used for plating were 1500 cells per well in a total volume of 200 μl medium. After cell adhesion to the plates, medium was changed and drugs and/or solvents were added to a final volume of 200 μl. Following four days of incubation, medium was replaced by 200 μl fresh medium and cell density and viability was assessed using an MTT-based assay. To each well, 25 μl MTT solution was added and the cells were further incubated for 2 hours at 37°C. The medium was then carefully aspirated and the blue MTT-formazan product was solubilized by addition of 25 μl glycine buffer followed by 100 μl of DMSO. The microtest plates were shaken for 10 min on a microplate shaker and the absorbance at 540 nm was measured using an Emax 96-well spectrophotometer (Supplier: Sopachem). Within an experiment, the results for each experimental condition are the mean of 3 replicate wells. For initial screening purposes, compounds were tested at a single fixed concentration of 10"6 M. For active compounds, the experiments were repeated to establish full concentration-response curves. For each experiment, controls (containing no drug and a blank incubation (containing no cells or drugs) were run in parallel. The blank value was subtracted from all control and sample values. For each sample, the mean value for cell growth (in absorbance units) was expressed as a percentage of the mean value for cell growth of the control. When appropriate, IC5o-values (concentration of the drug, needed to reduce cell growth to 50% of the control) were computed using probit analysis for graded data (Finney, D.J., Probit Analyses, 2nd Ed. Chapter 10, Graded Responses, Cambridge University Press, Cambridge 1962). Herein the effects of test compounds are expressed as pIC5o (the negative log value of the IC5o-value). Most of the tested compounds showed cellular activity at a test concentration of 10"6 M and 9 compounds had a pIC5o ≥ 5 (see table F-2)
Example C.3: Kinetic solubility in aqueous media
In the first dilution step, 10 μl of a concentrated stock-solution of the active compound, solubilized in DMSO (5mM), was added to 100 μl phosphate citrate buffer pH 7.4 and mixed. In the second dilution step, an aliquot (20 μl) of the first dilution step was further dispensed in 100 μl phosphate citrate buffer pH 7.4 and mixed. Finally, in the third dilution step, a sample (20 μl) of the second dilution step was further diluted in 100 μl phosphate citrate buffer pH 7.4 and mixed. All dilutions were performed in 96- well plates. Immediately after the last dilution step the turbidity of the three consecutive dilution steps were measured with a nephelometer. Dilution was done in triplicate for each compound to exclude occasional errors. Based on the turbidity measurements a ranking is performed into 3 classes. Compounds with high solubility obtained a score of 3 and for this compounds the first dilution is clear. Compounds with medium solubility obtained a score of 2. For these compounds the first dilution is unclear and the second dilution is clear. Compounds with low solubility obtained a score of 1 and for these compounds both the first and the second dilution are unclear. The solubility of 6 compounds was measured. From these compounds 3 showed a score of 3, 2 obtained a score of 2 and 1 demonstrated a score of 1 (see table F-2).
Example C.4: Parallel artificial membrane permeability analysis
The stock samples (aliquots of 10 μl of a stock solution of 5 mM in 100 % DMSO) were diluted in a deep-well or Pre-mix plate containing 2 ml of an aqueous buffer system pH 4 or pH 7.4 (PSR4 System Solution Concentrate (pION)). Before samples were added to the reference plate, 150 μl of buffer was added to wells and a blank UV-measurement was performed. Thereafter the buffer was discarded and the plate was used as reference plate. All measurements were done in UV-resistant plates (supplier: Costar or Greiner).
After the blank measurement of the reference plate, 150 μl of the diluted samples was added to the reference plate and 200 μl of the diluted samples was added to donorplate 1. An acceptor filter plate 1 (supplier: Millipore, type:MAIP N45) was coated with 4 μl of the artificial membrane-forming solution (l,2-Dioleoyl-sn-Glycer-3-Phosphocholine in Dodecane containing 0.1% 2,6-Di-tert-butyl-4-methylphenol and placed on top of donor plate 1 to form a "sandwich". Buffer (200 μl) was dispensed into the acceptor wells on the top. The sandwich was covered with a lid and stored for 18h at room temperature in the dark.
A blank measurement of acceptor plate 2 was performed through the addition of 150 μl of buffer to the wells, followed by an UV-measurement. After the blank measurement of acceptor plate 2 the buffer was discarded and 150 μl of acceptor solution was transferred from the acceptor filter plate 1 to the acceptor plate 2. Then the acceptor filter plate 1 was removed form the sandwich. After the blank measurement of donor plate 2 (see above), 150 μl of the donor solution was transferred from donor plate 1 to donor plate 2. The UN spectra of the donor plate 2, acceptor plate 2 and reference plate wells were scanned (with a SpectraMAX 190). All the spectra were processed to calculate permeability with the PSR4p Command Software. All compounds were measured in triplo. Carbamazepine, griseofulvin, acycloguanisine, atenolol, furosemide, and chlorothiazide were used as standards in each experiment. Compounds were ranked in 3 categories as having a low permeability (mean effect < 0.5 x 10"6 cm s; score 1), a medium permeability (1 x 10"6 cm s > mean effect > 0.5 x 10"6 cm/s; score 2) or a high permeability (> 0.5 x 10"6 cm/s; score 3). Two compounds were tested and showed at least a score of 2 at one of the pH's measured.
Example C.5: Metabolic stability
Sub-cellular tissue preparations were made according to Gorrod et al. (Xenobiotica 5:
453-462, 1975) by centrifugal separation after mechanical homogenization of tissue.
Liver tissue was rinsed in ice-cold 0.1 M Tris-HCl (pH 7.4) buffer to wash excess blood. Tissue was then blotted dry, weighed and chopped coarsely using surgical scissors. The tissue pieces were homogenized in 3 volumes of ice-cold 0.1 M phosphate buffer (pH 7.4) using either a Potter-S (Braun, Italy) equipped with a Teflon pestle or a
Sorvall Omni-Mix homogeniser, for 7 x 10 sec. In both cases, the vessel was kept in/on ice during the homogenization process.
Tissue homogenates were centrifuged at 9000 x g for 20 minutes at 4 °C using a Sorvall centrifuge or Beckman Ultracentrifuge. The resulting supernatant was stored at -80 °C and is designated 'S9'.
The S9 fraction can be further centrifuged at 100.000 x g for 60 minutes (4 °C) using a
Beckman ultracentrifuge. The resulting supernatant was carefully aspirated, aliquoted and designated 'cytosol'. The pellet was re-suspended in 0.1 M phosphate buffer (pH 7.4) in a final volume of 1 ml per 0.5 g original tissue weight and designated
'microsomes'.
All sub-cellular fractions were aliquoted, immediately frozen in liquid nitrogen and stored at -80 °C until use. For the samples to be tested, the incubation mixture contained PBS (0.1M), compound (5 μM), microsomes (lmg/ml) and a NADPH-generating system (0.8 mM glucose-6- phosphate, 0.8 mM magnesium chloride and 0.8 Units of glucose-6-phosphate dehydrogenase). Control samples contained the same material but the microsomes were replaced by heat inactivated (10 min at 95 degrees Celsius) microsomes. Recovery of the compounds in the control samples was always 100%.
The mixtures were preincubated for 5 min at 37 degrees Celsius. The reaction was started at timepoint zero (t = 0) by addition of 0.8 mM NADP and the samples were incubated for 15 min (t = 15). The reaction was terminated by the addition of 2 volumes of DMSO. Then the samples were centrifuged for 10 min at 900 x g and the supernatants were stored at room temperature for no longer as 24 h before analysis. All incubations were performed in duplo. Analysis of the supernatants was performed with LC-MS analysis. Elution of the samples was performed on a Xterra MS C18 (50 x 4.6 mm, 5 μm, Waters, US). An Alliance 2790 (Supplier: Waters, US) HPLC system was used. Elution was with buffer A (25 mM ammoniumacetate (pH 5.2) in
H2O/acetonitrile (95/5)), solvent B being acetonitrile and solvent C methanol at a flow rate of 2.4 ml/min. The gradient employed was increasing the organic phase concentration from 0 % over 50 % B and 50 % C in 5 min up to 100 % B in 1 min in a linear fashion and organic phase concentration was kept stationary for an additional 1.5 min. Total injection volume of the samples was 25 μl.
A Quattro (supplier: Micromass, Manchester, UK) triple quadrupole mass spectrometer fitted with and ESI source was used as detector. The source and the desolvation temperature were set at 120 and 350 °C respectively and nitrogen was used as nebuliser and drying gas. Data were acquired in positive scan mode (single ion reaction). Cone voltage was set at 10 V and the dwell time was 1 sec.
Metabolic stability was expressed as % metabolism of the compound after 15 min of incubation in the presence of active microsomes (E(act)) (% metabolism = 100 % -
„ Total Ion Current (TIC) of E(act) at t = 15 , 1 A _ , +, _ ,
(( — ) x 100). Compounds that had a
TIC of E(act) at t = 0 percentage metabolism less than 20 % were defined as highly metabolic stable. Compound that had a metabolism between 20 and 70 % were defined as intermediately stable and compounds that showed a percentage metabolism higher than 70 were defined as low metabolic stable. Three reference compounds were always included whenever a metabolic stability screening was performed. Verapamil was included as a compound with low metabolic stability (% metabolism = 73 %). Cisapride was included as a compound with medium metabolic stability (% metabolism 45 %) and propanol was included as a compound with intermediate to high metabolic stability (25 % metabolism). These reference compounds were used to validate the metabolic stability assay.
Three compounds were tested, one had a percentage metabolism less than 20 % and two had a metabolism between 20 and 70 %.
Example C.6: p21 induction capacity
The following protocol has been applied to determine the p21 protein expression level in human A2780 ovarian carcinoma cells. The A2780 cells (20000 cells /180 μl) were seeded in 96 microwell plates in RPMI 1640 medium supplemented with 2 mM L- glutamine, 50 μg/ml gentamicin and 10 % fetal calf serum. 24 hours before the lysis of the cells, compounds were added at final concentrations of 10"5, 10"6, 10"7 and 10"8 M. All compounds tested were dissolved in DMSO and further dilutions were made in culture medium. 24 hours after the addition of the compound, the supernatants were removed from the cells. Cells were washed with 200 μl ice-cold PBS. The wells were aspirated and 30 μl of lysisbuffer (50 mM Tris.HCl (pH 7.6), 150 mM NaCl, 1 % Nonidet p40 and 10 % glycerol) was added. The plates were incubated overnight at -70 °C. The appropriate number of microtiter wells were removed from the foil pouch and placed into an empty well holder. A working solution (lx) of the Wash Buffer (20x plate wash concentrate: 100 ml 20-fold concentrated solution of PBS and surfactant. Contains 2 % chloroacetamide) was prepared. The lyophilised p21WAF standard was reconstituted with distilled H2O and further diluted with sample diluent (provided in the kit) The samples were prepared by diluting them 1:4 in sample diluent. The samples (100 μl) and the p21WAFl standards (100 μl) were pipetted into the appropriate wells and incubated at room temperature for 2 hours. The wells were washed 3 times with lx wash buffer and then 100 μl of detector antibody reagent (a solution of biotinylated monoclonal p21WAFl antibody) was pipetted into each well. The wells were incubated at room temperature for 1 hour and then washed three times with lx wash buffer. The 400x conjugate (peroxidase streptavidine conjugate: 400-fold concentrated solution) was diluted and 100 μl of the lx solution was added to the wells. The wells were incubated at room temperature for 30 min and then washed 3 times with lx wash buffer and 1 time with distilled H2O. Substrate solution (chromogenic substrate)(100 μl) was added to the wells and the wells were incubated for 30 minutes in the dark at room temperature. Stop solution was added to each well in the same order as the previously added substrate solution. The absorbance in each well was measured using a spectrophotometric plate reader at dual wavelengths of 450/595 nm. For each experiment, controls (containing no drug) and a blank incubation (containing no cells or drugs) were run in parallel. The blank value was substracted from all control and sample values. For each sample, the value for ρ21WAFl induction (in absorbance units) was expressed as the percentage of the value for p21WAFl present in the control. Percentage induction higher than 130 % was defined as significant induction. Two compounds were tested in this assay, they both showed significant induction.
Table F-2: Table F-2 lists the results of the compounds that were tested according to example C.l, C.2, and C.3.
Figure imgf000057_0001
Figure imgf000058_0001
D. Composition example: Film-coated tablets
Prcp.ar on tablet c re
A mixture of 100 g of a compound of formula (I), 570 g lactose and 200 g starch is mixed well and thereafter humidified with a solution of 5 g sodium dodecyl sulphate and 10 g polyvinyl-pyrrolidone in about 200 ml of water. The wet powder mixture is sieved, dried and sieved again. Then there is added 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. The whole is mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of a compound of formula (I). Coating
To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanol there is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then there are added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol 10 g of polyethylene glycol is molten and dissolved in 75 ml of dichloromethane. The latter solution is added to the former and then there are added 2.5 g of magnesium octadecanoate, 5 g of polyvinyl- pyrrolidone and 30 ml of concentrated colour suspension and the whole is homogenated. The tablet cores are coated with the thus obtained mixture in a coating apparatus.

Claims

Claims
1. A compound of formula (I),
Figure imgf000059_0001
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein n is 0, 1, 2 or 3 and when n is 0 then a direct bond is intended; t is 0, 1, 2, 3 or 4 and when t is 0 then a direct bond is intended;
each Q is nitrogen or
each X is nitrogen or ^^ ;
each Y is nitrogen or ^^ ;
— CH" each Z is nitrogen or ^ ;
R1 is -C(O)ΝR7R8, -NHC(O)R9, -C(O)-Cι-6alkanediylSR9, -NR10C(O)N(OH)R9,
-NR10C(O)Cι-6alkanediylSR9, -NR10C(O)C=N(OH)R9 or another Zn-chelating- group wherein R7 and R8 are each independently selected from hydrogen, hydroxy,
Ci-βalkyl, hydroxyCi-βalkyl, aminoCι-6alkyl or aminoaryl;
R9 is independently selected from hydrogen, Cι-6alkyl, -όalkylcarbonyl, arylCι-6alkyl, C!-6alkylpyrazinyl, pyridinone, pyrrolidinone or methylimidazolyl;
R10 is independently selected from hydrogen or Cι-6alkyl;
R2 is hydrogen, halo, hydroxy, amino, nitro, Cι-6alkyl, C!-6alkyloxy, trifluoromethyl, di(Cι-6alkyl)amino, hydroxyamino or naphtalenylsulfonylpyrazinyl;
-L- is a direct bond or a bivalent radical selected from Cι-6alkanediyl, Cι-6alkanediyloxy, amino, carbonyl or aminocarbonyl; each R independently represents a hydrogen atom and one hydrogen atom can be replaced by a substituent selected from aryl;
R4 is hydrogen, hydroxy, amino, hydroxyCι-6alkyl, Ci-βalkyl, Cι.6alkyloxy, arylCi-ealkyl, aminocarbonyl, hydroxycarbonyl, aminoCi-galkyl, aminocarbonylCι_ alkyl, hydroxycarbonylCi.6alkyl, hydroxyaminocarbonyl, Cι.6alkyloxycarbonyl, Cι_6alkylaminoCι-6alkyl or di(Cι-6alkyl)aminoCι_6alkyl;
-Θ is a radical selected from
Figure imgf000060_0001
(a-1) (a-2) (a-3) (a-4)
Figure imgf000060_0002
(a-5) (a-6) (a"7> (a-8)
Figure imgf000060_0003
(a-9) (a-10) (a-11) (a"12)
Figure imgf000060_0004
(a-13) (a"14) (a~15) (a-16)
Figure imgf000061_0001
Figure imgf000061_0002
(a-25) (a-26) (a-27) (a-28)
Figure imgf000061_0003
-29) (a-30) (a-31) (a-32)
Figure imgf000061_0004
(a-33) (a-34) (a-35) (a-36)
Figure imgf000061_0005
Figure imgf000061_0006
(a-37)
Figure imgf000061_0007
(a-39) (a-40)
Figure imgf000062_0001
(a-49) (a-50) (a-51)
wherein each s is independently 0, 1, 2, 3, 4 or 5; each R5 and R6 are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaloCι_6alkyl; trihaloCι-6alkyloxy; Cι-6alkyl; Cι-6alkyl substituted with aryl and C3_ιocycloalkyl; Cι-6alkyloxy; Cι_6alkyloxyCι-6--lkyloxy; Cι-6alkylcarbonyl;
Cι_6alkyloxycarbonyl; Ci-βalkylsulfonyl; cyanoCι_6alkyl; hydroxyC ι.6alkyl; hydroxyCι-6alkyloxy; hydroxyCι_6alkylamino; aminoCι-6alkyloxy; di(Cι.6alkyl)aminocarbonyl; di(hydroxyCι-6alkyl)amino; (aryl)(Cι_6alkyl)amino; di(Ci-6alkyl)aminoCι-6alkyloxy; di(Cι.6alkyl)aminoCι_6alkylamino; di(Cι_6alkyl)aminoCι.6alkylaminoCι- alkyl; arylsulfonyl; arylsulfonylamino; aryloxy; aryloxyCι_6alkyl; arylC2-6alkenediyl; di(Cι-6alkyl)amino; di(Cι_6alkyl)aminoCι-6alkyl; di(Cι_6alkyl)amino(Cι.6alkyl)amino; di(Cι.6alkyl)amino(Cι.6alkyl)aminoCι_6alkyl; di(Cι.6alkyl)aminoCι.6alkyl(Cι.6alkyl)amino; di(Cι-6alkyl)aminoCι.6alkyl(Cι-6alkyl)aminoCι.6alkyl; aminosulfonylamino(Cι-6alkyl)amino; aminosulfonylamino(Cι_6alkyl)aminoCι-6alkyl; di(Ci_6alkyl)aminosulfonylamino(Ci-6alkyl)amino; di(Cι.6alkyl)aminosulfonylamino(Cι-6alkyl)aminoCι-6alkyl; cyano; thiophenyl; thiophenyl substituted with di(Cι.6alkyl)aminoCι-6alkyl(Cι-6alkyl)aminoC1-6alkyl, di(Cι-6alkyl)aminoCι-6alkyl, Cι-6alkylpiperazinylCι-6alkyl, hydroxyCι-6alkylpiperazinylCι-6alkyl, hydroxyC i .6alkyloxyC i .galkylpiperazinylC ι-6alkyl, di(Cι-6alkyl)aminosulfonylpiperazinylCι-6alkyl,
C i _6alkyloxypiperidinyl , C i -6alkyloxypiperidinylC ι_6alkyl, morpholinylC i .6alkyl , hydroxyCι_6alkyl(Cι.6alkyl)aminoCι.6alkyl, or di(hydroxyCι_6alkyl)aminoCι- alkyl; furanyl; furanyl substituted with hydroxyC ι.6alkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and Cι.6alkyl; Cι-6alkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; piperidinylCι-6alkyloxy; morpholinyl; Cι-6alkylmorpholinyl; morpholinylCι-6alkyloxy; morpholinylCi.6alkyl; morpholinylCi- alkylamino; morpholinylCι.6alkylaminoCι.6alkyl; piperazinyl; Cι.6alkylpiperazinyl; C i _6alkylρiperazinylC i-galkyloxy ; piperazinylC i-6alkyl ; naphtalenylsulfonylpiperazinyl; naphtalenylsulfonylpiperidinyl; naphtalenylsulfonyl;
Cι.6alkylpiperazinylCι_5alkyl; Cι_6alkylpiperazinylCι-6alkylamino;
C ι-6alkylpiperazinylC i .6alkylaminoC ι.6alkyl ; Cι-6alkylpiperazinylsulf onyl ; aminosulfonylpiperazinylCi-βalkyloxy; aminosulfonylpiperazinyl; aminosulfonylpiperazinylCi-galkyl; di(Cι-6alkyl)aminosulfonylpiperazinyl; di(Cι-6alkyl)aminosulfonylpiperazinylCι.6alkyl; hydroxyCι.6alkylpiperazinyl; hydroxyC i -6alkylpiperazinylC i-6alkyl ; C ι_6alkyloxypiperidinyl ;
C i .βalkyloxypiperidinylC ι_6alkyl ; piperidinylaminoC i - alkylamino; piperidinylaminoCι-6alkylaminoCι-6alkyl;
(Ci-ealkylpiperidinylXhyckoxy -ealkytyaminoCμgalkylamino;
(Cι.6alkylpiperidinyl)(hydroxyCι-6alkyl)aminoCι.6alkylaminoCι-6alkyl; hydroxyC ι-6alkyloxyC i .βalkylpiperazinyl ; hydroxyC \ .6alkyloxyC i -βalkylpiperazinylC ι.6alkyl ; (hydroxyCι_6alkyl)(Cι_6alkyl)amino; (hydroxyCι_6alkyl)(Cι.6alkyl)aminoCι-6alkyl; hydroxyCι-6alkylaminoCi-6alkyl; di(hydroxyCι_6alkyl)aminoCι_6alkyl; pyrrolidinylCi-galkyl; pyrrolidinylCi-ealkyloxy; pyrazolyl; thiopyrazolyl; pyrazolyl substituted with two substituents selected from Cι-6alkyl or trihaloCι_6alkyl; pyridinyl; pyridinyl substituted with Ci-galkyloxy, aryloxy or aryl; pyrimidinyl; tetrahydropyrimidinylpiperazinyl; tetrahydropyrimidinylpiperazinylCι-6alkyl; quinolinyl; indole; phenyl; phenyl substituted with one, two or three substituents independently selected from halo, amino, nitro, Ci-galkyl, Cι-6alkyloxy, hydroxyCι-4alkyl, trifluoromethyl, trifluoromethyloxy, hydroxyCι-4alkyloxy, Cι-4alkylsulfonyl, Cι.4alkyloxyCι_4alkyloxy, C^alkyloxycarbonyl, aminoCι-4alkyloxy, di(Cι.4alkyl)aminoCι.4alkyloxy, di(Cι-4alkyl)amino, di(Cι.4alkyl)aminocarbonyl, di(Cι-4alkyl)aminoCι-4alkyl, di(Cι-4alkyl)aminoCι.4alkylaminoCι-4alkyl, di(Cι- alkyl)amino(Cι-4alkyl)amino, di(Cι-4alkyl)amino(Cι.4alkyl)aminoCι-4alkyl, di (C ι-4alkyl)aminoC i _4alkyl(C i -4alkyl)amino, di (C i -4alkyl)aminoC i _4alkyl(C ι_4alkyl)aminoC i .4alkyl, aminosulfonylamino(Cι.4alkyl)amino, aminosulfonylamino(Cι_4alkyl)aminoCι_4alkyl, di(Cι.4alkyl)aminosulfonylamino(Cι.4alkyl)amino, di (C i -4-dkyl)aminosulfonylamino(C i -4alkyl)aminoC i^alkyl, cyano, piperidinylCι.4alkyloxy, pyrrolidinylCι.4alkyloxy, aminosulfonylpiperazinyl, aminosulfonylpiperazinylCι.4alkyl, di(Cι-4alkyl)aminosulfonylpiperazinyl, di(Cι.4alkyl)aminosulfonylpiperazinylCι-4alkyl, hydroxyC^alkylpiperazinyl, hydroxyCι.4alkylpiperazinylCi-4alkyl,
Figure imgf000064_0001
C i _4alkyloxypiperidinylCι _4alkyl, hydroxyC i -4alkyloxyC i .4alkylpiperazinyl, hydroxyC ι_4alkyloxyC i _4alkylpiperazinylC i _4alkyl ,
(hydroxyCι_4alkyl)(Cι.4alkyl)amino, (hydroxyCι-4alkyl)(Cι.4alkyl)aminoCι_4alkyl, di (hydroxyC ι.4alkyl)amino, di(hydroxyCι-4alkyl)aminoCι-4alkyl, furanyl, furanyl substituted with -CH=CH-CH=CH-, pyrrolidinylCι-4alkyl, pyrrolidinylCι.4alkyloxy, morpholinyl, morpholinylCi^alkyloxy, morpholinylC^alkyl, moφholinylCι.4alkylamino, morpholinylCι-4alkylaminoCι.4alkyl, piperazinyl, Cι-4alkylpiperazinyl, Cι.4alkylpiperazinylCι-4alkyloxy, ρiperazinylCι-4alkyl, Cι-4alkylpiperazinylCι_4alkyl, Cι-4alkylpiperazinylCι-4alkylamino, Cι-4alkylpiperazinylCι.4alkylaminoCι-6alkyl, tetrahydropyrimidinylpiperazinyl, tetrahydropyrirnidinylpiperazinylCi.4alkyl, piperidinylaminoCι.4alkylamino, piperidinylaminoCι-4alkylaminoCι_4alkyl, (Cι_4alkylpiperidinyl)(hydroxyCι_4alkyl)aminoCι-4alkylamino, (Cι.4alkylpiperidinyl)(hydroxyC1-4alkyl)aminoCι.4alkylaminoCι-4alkyl, pyridinylCι.4alkyloxy, hydroxyCι_4alkylamino, hydroxyCι.4alkylaminoCι_4alkyl, di(Cι_4alkyl)aπήnoCι-4alkylamino, aminothiadiazolyl, aminosulfonylpiperazinylCι.4alkyloxy, or thiophenylCi^alkylamino; each R and R can be placed on the nitrogen in replacement of the hydrogen;
aryl in the above is phenyl, or phenyl substituted with one or more substituents each independently selected from halo, Cι-6alkyl, -galkyloxy, trifluoromethyl, cyano or hydroxycarbonyl.
2. A compound as claimed in claim 1 wherein n is 1 or 2; t is 0, 1, 2 or 4; each Q is ^ ; R1 is -C(O)NH(OH); R2 is hydrogen or nitro; -L- is a direct bond or a
—( A) bivalent radical selected from Cι_6alkanediyl; R is hydrogen; ^-X is a radical selected from (a-l),(a-2), (a-3), (a-5), (a-6), (a-11), (a-18), (a-20), (a-21), (a-32), (a-33), (a-47) or (a-51); each s is independently 0, 1, 2, or 4; each R5 and R6 are independently selected from hydrogen; halo; trihaloCι-6alkyl; Ci-galkyl; Cι-6alkyl substituted with aryl and C3_ιocycloalkyl; Ci-galkyloxy; Cι_ alkylcarbonyl; benzofuranyl; naphtalenylsulf onyl; pyridinyl substituted with aryloxy; phenyl; or phenyl substituted with one substituent independently selected from hydroxyC ι_4alkyl or morpholinylC ι_4alkyl.
3. A compound as claimed in claim 1 wherein t is 1, 2, 3, or 4; R1 is -C(O)NR7R8, -C(O)-Cι-6alkanediylSR9, -NR10C(O)N(OH)R9,
-NR10C(O)C1-6alkanediylSR9, -NR10C(O)C=N(OH)R9 or another Zn-chelating- group wherein R7 and R8 are each independently selected from hydrogen, hydroxy, hydroxyCi-δalkyl or aminod-όalkyl; R2 is hydrogen, halo, hydroxy, amino, nitro, Cι-6alkyl, -6-ιlkyloxy, trifluoromethyl or
Figure imgf000065_0001
-L- is a direct bond or a bivalent radical selected from Cι_6alkanediyl,
Cι-6alkanediyloxy, amino or carbonyl; R4 is hydrogen, hydroxy, amino, hydroxyC ι-6alkyl, Cι_6alkyl, Ci-galkyloxy, arylCι_6alkyl, aminocarbonyl, aminoCi-galkyl, Cι_6alkylaminoCι-6alkyl or di(Cι_6alkyl)aminoCι_6alkyl;
X- is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-48) and (a-51); each s is independently 0, 1, 2, 3 or 4;
R5 is hydrogen; halo; hydroxy; amino; nitro; trihaloCι-6alkyl; trihaloCι-6alkyloxy; Cι_ alkyl; Cι-6alkyloxy; Cι_6alkylcarbonyl; Cι-6alkyloxycarbonyl; Cι.6alkylsulfonyl; hydroxyCι-6alkyl; aryloxy; di(Cι.6alkyl)amino; cyano; thiophenyl; furanyl; furanyl substituted with hydroxyCι- alkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and Cι-6alkyl; Cι_6alkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; morpholinyl; Cι_6alkylmorpholinyl; piρerazinyl; C i .6alkylpiperazinyl ; hydroxyC i .6alkylpiperazinyl ; Cι_6alkyloxypiperidinyl; pyrazoly; pyrazolyl substituted with one or two substituents selected from Cι-6alkyl or trihaloCi_6alkyl; pyridinyl; pyridinyl substituted with Cι-6alkyloxy, aryloxy or aryl; pyrimidinyl; quinolinyl; indole; phenyl; or phenyl substituted with one or two substituents independently selected from halo, Cι-6alkyl, Cι.6alkyloxy or trifluoromethyl; R6 is hydrogen; halo; hydroxy; amino; nitro; trihaloCi-galkyl; trihaloCi-galkyloxy; Cι.6alkyl; Ci-βalkyloxy; Ci-6alkylcarbonyl; Cι_ alkyloxycarbonyl; Cι-6alkylsulfonyl; hydroxyC ι-6alkyl; aryloxy; di(Cι_6alkyl)amino; cyano; pyridinyl; phenyl; or phenyl substituted with one or two substituents independently selected from halo, Ci-β lkyl, Cι-6alkyloxy or trifluoromethyl.
4. A compound as claimed in claim 1 and 2 wherein n is 1; t is 0 or 1; each Q is ^ ; each X is nitrogen; each Y is nitrogen; R1 is
-C(O)NH(OH); R2 is hydrogen; -L- is a direct bond; each R3 independently represents a hydrogen atom; R4 is hydrogen; -Θ v— is a radical selected from (a-6), (a-11), (a-20), (a-47) or (a-51); each s is independently 0, 1, or 4; and each R5 and R6 are independently selected from hydrogen; Cι.6alkyl; Cι_6alkyloxy; naphtalenylsulfonyl; or phenyl substituted with hydroxyC ι. alkyl or morpholinylC^alkyl.
5. A compound according to claim 1, 2 and 4 selected from compounds No. 3, No. 4, No. 8, No. 5, No. 7, No. 6 and No. 9.
Figure imgf000066_0001
Figure imgf000067_0001
6. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 1 to 5.
7. A process of preparing a pharmaceutical composition as claimed in claim 6 wherein the pharmaceutically acceptable carriers and a compound as claimed in claim 1 to 5 are intimately mixed.
8. A compound as claimed in any of claims 1 to 5 for use as a medicine.
9. Use of a compound as claimed in any of claims 1 to 5 for the manufacture of a medicament for the treatment of proliferative diseases.
10. A process for preparing a compound as claimed in claim 1, characterized by reacting an intermediate of formula (II) with an appropriate acid, such as for example, trifluoro acetic acid, yielding a hydroxamic acid of formula (I-a), wherein R1 is -C(O)NH(OH)
Figure imgf000068_0001
11. A method of detecting or identifying a HDAC in a biological sample comprising detecting or measuring the formation of a complex between a labelled compound as defined in claim (I) and a HDAC.
12. A combination of an anti-cancer agents and a HDAC inhibitor as claimed in any of claims 1 to 5.
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Cited By (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005011656A2 (en) 2003-07-30 2005-02-10 Xenon Pharmaceuticals Inc. Pyridyl derivatives and their use as therapeutic agents
WO2005011657A2 (en) 2003-07-30 2005-02-10 Xenon Pharmaceuticals Inc. Piperazine derivatives and their use as therapeutic agents
WO2005011654A2 (en) 2003-07-29 2005-02-10 Xenon Pharmaceuticals Inc. Pyridyl derivatives and their use as therapeutic agents
WO2005011655A2 (en) 2003-07-30 2005-02-10 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
WO2006034338A1 (en) 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as mediators of stearoyl-coa desaturase
WO2006082834A1 (en) * 2005-02-02 2006-08-10 Kowa Co., Ltd. Agent for prevention/therapy of disease caused by keratinocyte growth
WO2006086447A2 (en) 2005-02-09 2006-08-17 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
WO2006101521A2 (en) 2004-09-20 2006-09-28 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors
WO2006117548A1 (en) 2005-05-05 2006-11-09 Chroma Therapeutics Ltd Hydroxamic acid dervicatives as inhibitors of hdac enzymatic activity
WO2006130986A1 (en) * 2005-06-09 2006-12-14 Merck Frosst Canada Ltd. Azacyclohexane derivatives as inhibitors of stearoyl-coenzyme a delta-9 desaturase
WO2007009236A1 (en) * 2005-07-20 2007-01-25 Merck Frosst Canada Ltd. Heteroaromatic compounds as inhibitors of stearoyl-coenzyme a delta-9 desaturase
WO2007045962A2 (en) * 2005-10-18 2007-04-26 Orchid Research Laboratories Limited Novel hdac inhibitors
US7390813B1 (en) 2001-12-21 2008-06-24 Xenon Pharmaceuticals Inc. Pyridylpiperazines and aminonicotinamides and their use as therapeutic agents
JP2008530214A (en) * 2005-02-16 2008-08-07 シェーリング コーポレイション Piperazine substituted with a heterocyclic ring having CXCR3 antagonist activity
JP2008530219A (en) * 2005-02-16 2008-08-07 シェーリング コーポレイション Piperazine-piperidine substituted with amine-linked pyridyl and phenyl having CXCR3 antagonist activity
JP2009513599A (en) * 2005-10-27 2009-04-02 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Squaric acid derivatives as inhibitors of histone deacetylase
US7595343B2 (en) 2001-09-14 2009-09-29 Methylgene, Inc. Inhibitors of histone deacetylase
EP2167090A2 (en) * 2007-06-06 2010-03-31 University of Maryland, Baltimore Hdac inhibitors and hormone targeted drugs for the treatment of cancer
US7732475B2 (en) 2005-07-14 2010-06-08 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7767677B2 (en) 2004-09-20 2010-08-03 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US7777036B2 (en) 2004-09-20 2010-08-17 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
WO2010097586A1 (en) 2009-02-27 2010-09-02 Chroma Therapeutics Ltd. Enzyme inhibitors
US7829712B2 (en) 2004-09-20 2010-11-09 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase
US7838520B2 (en) 2001-09-14 2010-11-23 Methylgene, Inc. Inhibitors of histone deacetylase
US7868205B2 (en) 2003-09-24 2011-01-11 Methylgene Inc. Inhibitors of histone deacetylase
US7868204B2 (en) 2001-09-14 2011-01-11 Methylgene Inc. Inhibitors of histone deacetylase
EP2295410A1 (en) 2006-10-06 2011-03-16 Chroma Therapeutics Limited HDAC inhibitor
US7919496B2 (en) 2004-09-20 2011-04-05 Xenon Pharmaceuticals Inc. Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-CoA desaturase enzymes
EP2316826A1 (en) 2003-07-30 2011-05-04 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutics agents
US7947830B2 (en) 2004-07-28 2011-05-24 Janssen Pharmaceutica N.V. Substituted propenyl piperazine derivatives as novel inhibitors of histone deacetylase
US8030344B2 (en) 2007-03-13 2011-10-04 Methylgene Inc. Inhibitors of histone deacetylase
US8044052B2 (en) 2006-10-18 2011-10-25 Pfizer Inc. Biaryl ether urea compounds
US8071603B2 (en) 2004-09-20 2011-12-06 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US8088805B2 (en) 2004-03-26 2012-01-03 Methylgene Inc. Inhibitors of histone deacetylase
US8247562B2 (en) 2002-04-05 2012-08-21 Astrazeneca Ab Benzamide derivatives useful as histone deacetylase inhibitors
US8288373B2 (en) 2008-11-04 2012-10-16 Chemocentryx, Inc. Modulators of CXCR7
US8367663B2 (en) 2009-01-08 2013-02-05 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US8476289B2 (en) 2008-03-27 2013-07-02 Janssen Pharmaceutica Nv Aza-bicyclohexyl substituted indolyl alkyl amino derivatives as novel inhibitors of histone deacetylace
US8541457B2 (en) 2005-06-03 2013-09-24 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors
US8598168B2 (en) 2006-04-07 2013-12-03 Methylgene Inc. Inhibitors of histone deacetylase
US8609672B2 (en) 2010-08-27 2013-12-17 University Of The Pacific Piperazinylpyrimidine analogues as protein kinase inhibitors
US8664223B2 (en) 2006-01-19 2014-03-04 Janssen Pharmaceutica N.V Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase
US8710219B2 (en) 2011-04-01 2014-04-29 Curis, Inc. Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US8853202B2 (en) 2008-11-04 2014-10-07 Chemocentryx, Inc. Modulators of CXCR7
US8916554B2 (en) 2002-03-13 2014-12-23 Janssen Pharmaceutica, N.V. Amino-derivatives as novel inhibitors of histone deacetylase
US8962825B2 (en) 2006-10-30 2015-02-24 Glaxosmithkline Intellectual Property Development Limited Hydroxamates as inhibitors of histone deacetylase
US8980924B2 (en) 2010-11-24 2015-03-17 The Trustees Of Columbia University In The City Of New York Non-retinoid RBP4 antagonist for treatment of age-related macular degeneration and stargardt disease
US9133104B2 (en) 2005-05-05 2015-09-15 Chroma Therapeutics Ltd. Enzyme inhibitors
US9150543B2 (en) 2004-07-28 2015-10-06 Janssen Pharmaceutica N. V. Substituted indolyl alkyl amino derivatives as inhibitors of histone deacetylase
US9333202B2 (en) 2012-05-01 2016-05-10 The Trustees Of Columbia University In The City Of New York Non-retinoid antagonists for treatment of age-related macular degeneration and stargardt disease
US9434727B2 (en) 2014-04-30 2016-09-06 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
EP3116859A4 (en) * 2014-03-12 2017-02-08 Chong Kun Dang Pharmaceutical Corp. Novel compounds as histone deacetylase 6 inhibitors and pharmaceutical compositions comprising the same
US9598401B2 (en) 2013-07-29 2017-03-21 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use thereof
US9637450B2 (en) 2013-03-14 2017-05-02 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US9714232B2 (en) 2013-12-20 2017-07-25 Sunshine Lake Pharma Co., Ltd. Substituted piperazine compounds and methods of use thereof
US9856211B2 (en) 2005-05-13 2018-01-02 Topotarget Uk Limited Pharmaceutical formulations of HDAC inhibitors
US9938291B2 (en) 2013-03-14 2018-04-10 The Trustess Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US9944644B2 (en) 2013-03-14 2018-04-17 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US10273243B2 (en) 2013-03-14 2019-04-30 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US10584133B2 (en) 2018-03-30 2020-03-10 Biotheryx, Inc. Thienopyrimidinone compounds
US11234986B2 (en) 2018-09-11 2022-02-01 Curis, Inc. Combination therapy with a phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US11464786B2 (en) 2018-12-12 2022-10-11 Chemocentryx, Inc. CXCR7 inhibitors for the treatment of cancer
US11834452B2 (en) 2012-11-29 2023-12-05 Chemocentryx, Inc. CXCR7 antagonists

Families Citing this family (121)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6951862B2 (en) 1998-06-30 2005-10-04 Neuromed Technologies, Inc. Calcium channel blockers comprising two benzhydril moieties
US7186726B2 (en) 1998-06-30 2007-03-06 Neuromed Pharmaceuticals Ltd. Preferentially substituted calcium channel blockers
MXPA04007776A (en) 2002-03-13 2004-10-15 Janssen Pharmaceutica Nv Sulfonylamino-derivatives as novel inhibitors of histone deacetylase.
CN101450934B (en) * 2002-03-13 2012-10-10 詹森药业有限公司 Sulfonyl-derivatives as novel inhibitors of histone deacetylase
ATE398615T1 (en) 2002-03-13 2008-07-15 Janssen Pharmaceutica Nv PIPERAZINYL, PIPERIDINYL AND MORPHOLINYL DERIVATIVES AS NEW INHIBITORS OF HISTONE DEACETYLASE
ES2306858T3 (en) 2002-03-13 2008-11-16 Janssen Pharmaceutica Nv CARBONILAMINE DERIVATIVES AS NEW INHIBITORS OF HISTONADESACETILASAS.
DE60332367D1 (en) * 2002-08-20 2010-06-10 Astellas Pharma Inc HEMMER OF THE ABBAUS OF THE EXTRACELLULAR MATRIX OF ARTHRODIA CARTILAGE
WO2004024710A1 (en) * 2002-09-13 2004-03-25 Glaxo Group Limited Urea compounds active as vanilloid receptor antagonists for the treatment of pain
CA2499189A1 (en) * 2002-09-19 2004-04-01 University Of South Florida Method of treating leukemia with a combination of suberoylanilide hydromaxic acid and imatinib mesylate
AU2003296310A1 (en) * 2002-12-06 2004-06-30 University Of South Florida Histone deacetylase inhibitor enhancement of trail-induced apoptosis
US7723349B2 (en) 2003-04-24 2010-05-25 Incyte Corporation Aza spiro alkane derivatives as inhibitors of metalloproteases
BRPI0509715A (en) * 2004-04-09 2007-09-18 Neuromed Pharmaceuticals Ltd diarylamine derivatives as calcium blocking channels
EP1750712A2 (en) * 2004-05-19 2007-02-14 Solvay Pharmaceuticals GmbH Medicaments containing n-sulfamoyl-n'-arylpiperazines for the prophylaxis or treatment of obesity and related conditions
GB0412072D0 (en) * 2004-05-28 2004-06-30 Syngenta Participations Ag Chemical compounds
CN1980920A (en) 2004-06-14 2007-06-13 霍夫曼-拉罗奇有限公司 Thiophene derivatives, their manufacture and use as pharmaceutical agents
CN1964962A (en) 2004-06-14 2007-05-16 霍夫曼-拉罗奇有限公司 Thiophene hydroxamic acid derivatives and their use as HDAC inhibitors
SI1776358T1 (en) * 2004-07-28 2009-10-31 Janssen Pharmaceutica Nv Substituted propenyl piperazine derivatives as novel inhibitors of histone deacetylase
BRPI0515015A (en) 2004-08-11 2008-07-01 Kyorin Seiyaku Kk cyclic aminobenzoic acid derivative; medicine; ppar (alpha) agonist; ppar (alpha) double agonist, y; ppar double agonist (alpha), (delta); par modulator; lipid agent; prophylactic or therapeutic agent comprising at least one of the pharmaceutically acceptable cyclic derivatives of aminobenzoic acid or salt thereof
US20080167321A1 (en) 2004-09-20 2008-07-10 Xenon Pharmaceuticals Inc. Pyridine Derivatives For Inhibiting Human Stearoyl-Coa-Desaturase
GB0421908D0 (en) 2004-10-01 2004-11-03 Angeletti P Ist Richerche Bio New uses
WO2006050076A1 (en) * 2004-10-29 2006-05-11 Janssen Pharmaceutica, N.V. Pyrimidinyl substituted fused-pyrrolyl compounds useful in treating kinase disorders
EP2500063A1 (en) 2005-02-03 2012-09-19 TopoTarget UK Limited Combination therapy using HDAC inhibitors and melphalan for treating cancer
AU2006214319A1 (en) 2005-02-14 2006-08-24 Miikana Therapeutics, Inc. Fused heterocyclic compounds useful as inhibitors of histone deacetylase
WO2006099396A2 (en) * 2005-03-11 2006-09-21 The Regents Of The University Of Colorado Histone deacetylase inhibitors sensitize cancer cells to epidermal growth factor inhibitors
WO2006115833A1 (en) 2005-04-20 2006-11-02 Merck & Co., Inc. Benzothiophene hydroxamic acid derivatives with carbamate, urea, amide and sulfonamide substitutions
US7834034B2 (en) 2005-04-20 2010-11-16 Merck Sharp & Dohme Corp. Benzothiophene derivatives
AU2006240248A1 (en) 2005-04-20 2006-11-02 Merck Sharp & Dohme Corp. Benzothiophene hydroxamic acid derivatives
US8138198B2 (en) 2005-05-18 2012-03-20 Angibaud Patrick Rene Substituted aminopropenyl piperidine or morpholine derivatives as novel inhibitors of histone deacetylase
GB0510204D0 (en) * 2005-05-19 2005-06-22 Chroma Therapeutics Ltd Enzyme inhibitors
CA2608929C (en) * 2005-06-23 2014-01-28 Janssen Pharmaceutica N.V. Imidazolinone and hydantoine derivatives as novel inhibitors of histone deacetylase
JP2008546793A (en) 2005-06-24 2008-12-25 メルク エンド カムパニー インコーポレーテッド Modified malonic acid derivative
EP2258359A3 (en) 2005-08-26 2011-04-06 Braincells, Inc. Neurogenesis by muscarinic receptor modulation with sabcomelin
JP2009506069A (en) 2005-08-26 2009-02-12 ブレインセルス，インコーポレイティド Neurogenesis through modulation of muscarinic receptors
AU2006304787A1 (en) 2005-10-21 2007-04-26 Braincells, Inc. Modulation of neurogenesis by PDE inhibition
CA2625210A1 (en) 2005-10-31 2007-05-10 Braincells, Inc. Gaba receptor mediated modulation of neurogenesis
KR100696139B1 (en) * 2005-11-01 2007-03-20 한국화학연구원 Alkylcarbamoyl naphthalenyloxyoctenoylhydroxyamide derivatives having inhibitory activity against histone deacetylase and preparation thereof
EP1957056A2 (en) 2005-11-10 2008-08-20 TopoTarget UK Limited Histone deacetylase (hdac) inhibitors (pxdlol) for the treatment of cancer alone or in combination with chemotherapeutic agent
AR057579A1 (en) 2005-11-23 2007-12-05 Merck & Co Inc SPIROCICLICAL COMPOUNDS AS INHIBITORS OF ACETYLASE HISTONE (HDAC)
DK1981871T3 (en) 2006-01-19 2012-02-13 Janssen Pharmaceutica Nv Heterocyclyl alkyl derivatives as novel inhibitors of histone deacetylase
JP5137849B2 (en) * 2006-01-19 2013-02-06 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Substituted indolyl-alkyl-amino-derivatives as inhibitors of histone deacetylase
DK1981874T3 (en) 2006-01-19 2009-09-28 Janssen Pharmactuica N V Aminophenyl derivatives as novel inhibitors of histone deacetylase
CN101370789B (en) * 2006-01-19 2012-05-30 詹森药业有限公司 Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase
WO2007082880A1 (en) * 2006-01-19 2007-07-26 Janssen Pharmaceutica N.V. Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase
US20070202186A1 (en) 2006-02-22 2007-08-30 Iscience Interventional Corporation Apparatus and formulations for suprachoroidal drug delivery
WO2007100657A2 (en) 2006-02-28 2007-09-07 Merck & Co., Inc. Inhibitors of histone deacetylase
US20100216734A1 (en) 2006-03-08 2010-08-26 Braincells, Inc. Modulation of neurogenesis by nootropic agents
GB0605573D0 (en) * 2006-03-21 2006-04-26 Angeletti P Ist Richerche Bio Therapeutic Compounds
US8119685B2 (en) 2006-04-26 2012-02-21 Merck Sharp & Dohme Corp. Disubstituted aniline compounds
EP2026813A2 (en) 2006-05-09 2009-02-25 Braincells, Inc. 5 ht receptor mediated neurogenesis
EP2377531A2 (en) 2006-05-09 2011-10-19 Braincells, Inc. Neurogenesis by modulating angiotensin
US8119652B2 (en) 2006-05-18 2012-02-21 Merck Sharp & Dohme Corp. Aryl-fused spirocyclic compounds
EP2049124A4 (en) 2006-07-20 2010-02-10 Merck & Co Inc Phosphorus derivatives as histone deacetylase inhibitors
US7998971B2 (en) 2006-09-08 2011-08-16 Braincells Inc. Combinations containing a 4-acylaminopyridine derivative
US20100184806A1 (en) 2006-09-19 2010-07-22 Braincells, Inc. Modulation of neurogenesis by ppar agents
EP2099443A4 (en) * 2006-11-10 2010-05-05 Syndax Pharmaceuticals Inc Combination of er + ligands and histone deacetylase inhibitors for the treatment of cancer
CA2833209C (en) * 2007-04-27 2016-06-28 Purdue Pharma L.P. Piperidine and piperazine compounds as trpv1 antagonists
US7737175B2 (en) 2007-06-01 2010-06-15 Duke University Methods and compositions for regulating HDAC4 activity
JO2972B1 (en) 2007-06-08 2016-03-15 جانسين فارماسوتيكا ان. في Piperidine/Piperazine derivatives
AU2008258549B2 (en) 2007-06-08 2013-11-14 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
CA2687754C (en) 2007-06-08 2015-12-08 Janssen Pharmaceutica N.V. Piperidine, piperazine derivatives for use as dgat inhibitors
WO2008148851A1 (en) 2007-06-08 2008-12-11 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
CA2692153A1 (en) 2007-06-27 2009-01-08 Richard W. Heidebrecht, Jr. Pyridyl and pyrimidinyl derivatives as histone deacetylase inhibitors
US8389553B2 (en) 2007-06-27 2013-03-05 Merck Sharp & Dohme Corp. 4-carboxybenzylamino derivatives as histone deacetylase inhibitors
WO2009015237A1 (en) * 2007-07-23 2009-01-29 Syndax Pharmaceuticals, Inc. Novel compounds and methods of using them
US20100298270A1 (en) * 2007-07-23 2010-11-25 Syndax Pharmaceuticals, Inc. Novel Compounds and Methods of Using Them
BRPI0817211A2 (en) 2007-09-20 2017-05-16 Irm Llc compound compositions as modulators of gpr119 activity
JP2010540426A (en) 2007-09-25 2010-12-24 トポターゲット ユーケー リミテッド Method for synthesizing specific hydroxamic acid compounds
US20090149511A1 (en) * 2007-10-30 2009-06-11 Syndax Pharmaceuticals, Inc. Administration of an Inhibitor of HDAC and an mTOR Inhibitor
US20090131367A1 (en) * 2007-11-19 2009-05-21 The Regents Of The University Of Colorado Combinations of HDAC Inhibitors and Proteasome Inhibitors
WO2009126662A1 (en) * 2008-04-08 2009-10-15 Syndax Pharmaceuticals, Inc. Administration of an inhibitor of hdac, an inhibitor of her-2, and a selective estrogen receptor modulator
WO2009147170A2 (en) 2008-06-05 2009-12-10 Janssen Pharmaceutica Nv Drug combinations comprising a dgat inhibitor and a ppar-agonist
US8841287B2 (en) * 2008-06-12 2014-09-23 Janssen Pharmaceutica N.V. Diamino-pyridine, pyrimidine, and pyrazine modulators of the histamine H4 receptor
US8748458B2 (en) 2009-01-28 2014-06-10 Karus Therapeutics Limited Scriptaid isosteres and their use in therapy
US20100216805A1 (en) 2009-02-25 2010-08-26 Braincells, Inc. Modulation of neurogenesis using d-cycloserine combinations
WO2010118063A2 (en) 2009-04-06 2010-10-14 Agios Pharmaceuticals, Inc. Therapeutic compositions and related methods of use
ES2632954T3 (en) 2009-06-29 2017-09-18 Agios Pharmaceuticals, Inc. Quinoline-8-sulfonamide derivatives that have an anticancer activity
EP3520749A1 (en) 2010-10-15 2019-08-07 Clearside Biomedical, Inc. Device for ocular access
PT2640709T (en) 2010-11-16 2016-07-13 Acetylon Pharmaceuticals Inc Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof
EP2651898B1 (en) 2010-12-17 2015-12-09 Agios Pharmaceuticals, Inc. Novel n-(4-(azetidine-1-carbonyl)phenyl)-(hetero-)arylsulfonamide derivatives as pyruvate kinase m2 (pmk2) modulators
MX336022B (en) 2010-12-21 2016-01-06 Agios Pharmaceuticals Inc Bicyclic pkm2 activators.
TWI549947B (en) 2010-12-29 2016-09-21 阿吉歐斯製藥公司 Therapeutic compounds and compositions
US8404738B2 (en) * 2011-01-21 2013-03-26 Hoffmann-La Roche Inc. 4-amino-N-hydroxy-benzamides for the treatment of cancer
EP2683371B1 (en) 2011-03-09 2020-10-21 Cereno Scientific AB Compounds and methods for improving impaired endogenous fibrinolysis using histone deacetylase inhibitors
SG194697A1 (en) 2011-05-03 2013-12-30 Agios Pharmaceuticals Inc Pyruvate kinase activators for use in therapy
CN102807526B (en) * 2011-06-21 2015-12-02 寿光富康制药有限公司 The preparation method of NSC 630176 ZYJ-D08a and epimer thereof and application
UA113288C2 (en) 2011-06-22 2017-01-10 TRPV1 ANTAGONISTS CONTAINING DIGIDROXISMUSER AND THEIR APPLICATIONS
FR2976943B1 (en) * 2011-06-23 2013-07-12 Metabolys PIPERAZINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND USES THEREOF IN THE TREATMENT OF INSULIN RESISTANCE
US20150087687A1 (en) 2012-03-23 2015-03-26 Dennis Brown Compositions and methods to improve the therapeutic benefit of indirubin and analogs thereof, including meisoindigo
WO2013169858A1 (en) 2012-05-08 2013-11-14 The Broad Institute, Inc. Diagnostic and treatment methods in patients having or at risk of developing resistance to cancer therapy
NZ707366A (en) 2012-11-07 2018-11-30 Karus Therapeutics Ltd Novel histone deacetylase inhibitors and their use in therapy
WO2014124209A1 (en) 2013-02-08 2014-08-14 General Mills, Inc. Reduced sodium food products
WO2014179698A2 (en) 2013-05-03 2014-11-06 Clearside Biomedical, Inc. Apparatus and methods for ocular injection
AU2014264370B2 (en) 2013-05-10 2017-12-14 Karus Therapeutics Ltd Novel histone deacetylase inhibitors
US10188550B2 (en) 2013-06-03 2019-01-29 Clearside Biomedical, Inc. Apparatus and methods for drug delivery using multiple reservoirs
US9403779B2 (en) 2013-10-08 2016-08-02 Acetylon Pharmaceuticals, Inc. Combinations of histone deacetylase inhibitors and either Her2 inhibitors or PI3K inhibitors
WO2015054474A1 (en) * 2013-10-10 2015-04-16 Acetylon Pharmaceuticals, Inc. Pyrimidine hydroxy amide compounds as histone deacetylase inhibitors
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
CA2932411A1 (en) 2013-12-03 2015-06-11 Acetylon Pharmaceuticals, Inc. Combinations of histone deacetylase inhibitors and immunomodulatory drugs
US9464073B2 (en) 2014-02-26 2016-10-11 Acetylon Pharmaceuticals, Inc. Pyrimidine hydroxy amide compounds as HDAC6 selective inhibitors
CN107205988A (en) 2014-07-07 2017-09-26 埃斯泰隆制药公司 Leukaemia is treated using histone deacetylase inhibitor
US10722147B2 (en) 2014-08-13 2020-07-28 Nightbalance B.V. Activation by temperature sensor
GB201419228D0 (en) 2014-10-29 2014-12-10 Karus Therapeutics Ltd Compounds
GB201419264D0 (en) 2014-10-29 2014-12-10 Karus Therapeutics Ltd Compounds
AR102537A1 (en) * 2014-11-05 2017-03-08 Flexus Biosciences Inc IMMUNOMODULATING AGENTS
CA2969790A1 (en) 2014-12-05 2016-06-09 University of Modena and Reggio Emilia Combinations of histone deacetylase inhibitors and bendamustine
CN107835810A (en) * 2014-12-12 2018-03-23 瑞格纳西制药有限公司 Piperidine derivative as HDAC1/2 inhibitor
TWI698436B (en) 2014-12-30 2020-07-11 美商佛瑪治療公司 Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors
MA41291A (en) 2014-12-30 2017-11-07 Forma Therapeutics Inc PYRROLOTRIAZINONE AND IMIDAZOTRIAZINONE DERIVATIVES AS UBIQUE-SPECIFIC PROTEASE INHIBITORS No. 7 (USP7) FOR THE TREATMENT OF CANCER
WO2016126926A1 (en) 2015-02-05 2016-08-11 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
EP3253759A1 (en) 2015-02-05 2017-12-13 Forma Therapeutics, Inc. Isothiazolopyrimidinones, pyrazolopyrimidinones, and pyrrolopyrimidinones as ubiquitin-specific protease 7 inhibitors
US9932351B2 (en) 2015-02-05 2018-04-03 Forma Therapeutics, Inc. Thienopyrimidinones as ubiquitin-specific protease 7 inhibitors
US10272084B2 (en) 2015-06-01 2019-04-30 Regenacy Pharmaceuticals, Llc Histone deacetylase 6 selective inhibitors for the treatment of cisplatin-induced peripheral neuropathy
US11234976B2 (en) 2015-06-11 2022-02-01 Agios Pharmaceuticals, Inc. Methods of using pyruvate kinase activators
DK3398598T3 (en) * 2015-12-31 2022-07-11 Hitgen Inc SULFONAMIDE DERIVATIVE AND METHOD OF PREPARATION AND USE THEREOF
JP2019515909A (en) 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． HDAC inhibitor alone or in combination with a BTK inhibitor for the treatment of chronic lymphocytic leukemia
WO2017192565A1 (en) 2016-05-02 2017-11-09 Clearside Biomedical, Inc. Systems and methods for ocular drug delivery
IL264764B2 (en) 2016-08-12 2024-02-01 Clearside Biomedical Inc Devices and methods for adjusting the insertion depth of a needle for medicament delivery
AU2018342089A1 (en) 2017-09-26 2020-02-27 Dana-Farber Cancer Institute, Inc. Novel USP7 inhibitors for treating multiple myeloma
EP3870179A4 (en) * 2018-10-22 2022-11-23 Dana Farber Cancer Institute, Inc. Usp7 inhibition
WO2023222115A1 (en) * 2022-05-20 2023-11-23 四川汇宇制药股份有限公司 Hydroxyamide derivative and use thereof
CN117263936B (en) * 2023-11-21 2024-02-23 中国中医科学院医学实验中心 Imidazo [1,2-a ] pyridine derivative, preparation method thereof and application thereof in drug for inhibiting central nervous system penetrating HDAC6

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998055449A1 (en) * 1997-06-06 1998-12-10 The University Of Queensland Hydroxamic acid compounds having anticancer and anti-parasitic properties
WO2001038322A1 (en) * 1999-11-23 2001-05-31 Methylgene, Inc. Inhibitors of histone deacetylase
WO2003011851A2 (en) * 2001-06-15 2003-02-13 F. Hoffman-La Roche Ag Aromatic hydroxamic acid derivatives useful as hdac inhibitors

Family Cites Families (127)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB901749A (en) * 1957-12-06 1962-07-25 Ciba Ltd New 2-substituted pyrimidines
US2927924A (en) * 1958-04-03 1960-03-08 Lilly Co Eli Novel phenethyl-substituted piperazines
US3331845A (en) * 1963-04-04 1967-07-18 American Cyanamid Co 1-substituted-4-substituted amino alkylene piperazines
BE637271A (en) * 1963-04-04 1900-01-01
US3459731A (en) 1966-12-16 1969-08-05 Corn Products Co Cyclodextrin polyethers and their production
US3966743A (en) 1968-07-23 1976-06-29 Boehringer Mannheim G.M.B.H. Ortho fused cycloalkano-4-quinolone-3-carboxylic acid derivatives
US4049811A (en) 1968-07-23 1977-09-20 Boehringer Mannheim G.M.B.H. Compositions using cycloalkano-quinolone derivatives and their method of use
GB1345872A (en) 1970-09-03 1974-02-06 Wyeth John & Brother Ltd Amino-and acylamino-pyridine and hydropyridine derivatives
JPS5755714B2 (en) * 1972-03-18 1982-11-25
US4186199A (en) * 1978-11-02 1980-01-29 American Hoechst Corporation Indolo-,1,2-dihydroindolo-, and 1,2,6,7-tetrahydroindolo [1,7-ab][1,5] benzodiazepines
DE2939292A1 (en) 1979-09-28 1981-04-09 Boehringer Mannheim Gmbh, 6800 Mannheim N-PHENOXYALKYLPIPERIDINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
PH17194A (en) 1980-03-06 1984-06-19 Otsuka Pharma Co Ltd Novel carbostyril derivatives,and pharmaceutical composition containing the same
CA1183847A (en) 1981-10-01 1985-03-12 Georges Van Daele N-(3-hydroxy-4-piperidinyl)benzamide derivatives
JPS6143173A (en) * 1984-08-06 1986-03-01 Mitsui Petrochem Ind Ltd Novel pyrimidine drivative and preparation thereof
JPS6187672A (en) * 1984-10-08 1986-05-06 Mitsui Petrochem Ind Ltd Novel pyrimidine derivative
EP0188095A1 (en) 1984-12-13 1986-07-23 East Rock Technology Inc. Process for the manufacture of a toroidal ballast choke and machine for use in such process
JPS61140568A (en) * 1984-12-14 1986-06-27 Mitsui Petrochem Ind Ltd Quinazoline derivative, and hypotensor containing said derivative as active component
US4734418A (en) * 1984-12-14 1988-03-29 Mitsui Petrochemical Industries, Ltd. Quinazoline compounds and antihypertensives
US4840947A (en) * 1986-10-14 1989-06-20 Hoechst-Roussel Pharmaceuticals, Inc. Antiinflammatory and analgesic piperidin-4-yl-tetracyclic benzodiazepines and use thereas
HU206337B (en) 1988-12-29 1992-10-28 Mitsui Petrochemical Ind Process for producing pyrimidine derivatives and pharmaceutical compositions
JP2744663B2 (en) * 1988-12-29 1998-04-28 三井化学株式会社 Pyrimidines and their pharmaceutically acceptable salts
DE69009785T2 (en) * 1989-02-10 1994-11-03 Otsuka Pharma Co Ltd Carbostyril derivatives.
JP2664238B2 (en) 1989-03-01 1997-10-15 日清製粉株式会社 Nicotinic acid or its ester derivatives
US5342846A (en) 1990-12-05 1994-08-30 Synphar Laboratories, Inc. 7-substituted-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid compounds and 7-(substituted triazolyl pyrrolidin-1-yl) 4-oxoquinoline-3-carboxylic acid derivatives useful as antibacterial agents
EP0524146A1 (en) * 1991-07-19 1993-01-20 Ciba-Geigy Ag Aminosubstituted Piperazinederivatives
TW213903B (en) * 1991-08-16 1993-10-01 Boehringer Ingelheim Kg
DE4228792A1 (en) 1992-08-29 1994-03-03 Hoechst Ag New piperidinyl:amino-pyridine derivs. - useful as agricultural and technical fungicides.
US5338738A (en) 1993-04-19 1994-08-16 Bristol-Myers Squibb Company Cerebral function enhancers: acyclic amide derivatives of pyrimidinylpiperidines
US5459151A (en) 1993-04-30 1995-10-17 American Home Products Corporation N-acyl substituted phenyl piperidines as bronchodilators and antiinflammatory agents
FR2722788B1 (en) * 1994-07-20 1996-10-04 Pf Medicament NOVEL PIPERAZIDES DERIVED FROM ARYL PIPERAZINE, PROCESSES FOR THEIR PREPARATION, THEIR USE AS MEDICAMENTS AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME
US6083903A (en) 1994-10-28 2000-07-04 Leukosite, Inc. Boronic ester and acid compounds, synthesis and uses
ES2104509B1 (en) 1995-06-13 1998-07-01 Ferrer Int NEW COMPOUNDS DERIVED FROM 2- (3,4-DISSTITUTED-1-PIPERAZINYL) -5-FLUOROPYRIMIDINE.
JPH0959236A (en) * 1995-08-23 1997-03-04 Dai Ichi Seiyaku Co Ltd Benzamide
CZ154398A3 (en) 1995-11-23 1998-08-12 Janssen Pharmaceutica N.V. Solid mixtures of cyclodextrins prepared by melt extrusion
ZA9610745B (en) 1995-12-22 1997-06-24 Warner Lambert Co 4-Subsituted piperidine analogs and their use as subtype selective nmda receptor antagonists
US5952349A (en) * 1996-07-10 1999-09-14 Schering Corporation Muscarinic antagonists for treating memory loss
US5866702A (en) 1996-08-02 1999-02-02 Cv Therapeutics, Incorporation Purine inhibitors of cyclin dependent kinase 2
EP0827742A1 (en) 1996-09-04 1998-03-11 Vrije Universiteit Brussel Use of histone deacetylase inhibitors for treating fribosis or cirrhosis
SE9604786D0 (en) * 1996-12-20 1996-12-20 Astra Pharma Inc New compounds
FR2761960B1 (en) 1997-04-09 1999-05-28 Pechiney Emballage Flexible Eu POLYOLEFIN-BASED FILM FOR FORMING A FOLDING PACKAGE
EP0891930A1 (en) 1997-07-17 1999-01-20 Alusuisse Technology &amp; Management AG Sheet wrapping material
DE19743435A1 (en) 1997-10-01 1999-04-08 Merck Patent Gmbh Benzamidine derivatives
US6750228B1 (en) * 1997-11-14 2004-06-15 Pharmacia Corporation Aromatic sulfone hydroxamic acid metalloprotease inhibitor
ATE232521T1 (en) 1998-03-27 2003-02-15 Janssen Pharmaceutica Nv HIV-INHIBITING PYRIMIDINE DERIVATIVES
CA2328413A1 (en) * 1998-04-20 1999-10-28 Fujisawa Pharmaceutical Co., Ltd. Anthranilic acid derivatives as inhibitors of the cgmp-phosphodiesterase
JPH11335375A (en) * 1998-05-20 1999-12-07 Mitsui Chem Inc Benzamide derivative having histone deacetylase inhibiting action
RU2216541C2 (en) * 1998-08-04 2003-11-20 Астразенека Аб Derivatives of benzamide, method for their preparing and pharmaceutical composition based on thereof
GB9823873D0 (en) * 1998-10-30 1998-12-30 Pharmacia & Upjohn Spa 2-ureido-thiazole derivatives,process for their preparation,and their use as antitumour agents
BRPI9915552B8 (en) 1998-11-10 2021-05-25 Janssen Pharmaceutica Nv Hiv Reproduction Inhibiting Pyrimidines
EP1140792A1 (en) 1998-12-14 2001-10-10 American Home Products Corporation 3,4-diamino-3-cyclobutene-1,2-dione derivatives which inhibit leukocyte adhesion mediated by vla-4
WO2000039118A1 (en) * 1998-12-23 2000-07-06 Eli Lilly And Company Aromatic amides
CZ27399A3 (en) 1999-01-26 2000-08-16 Ústav Experimentální Botaniky Av Čr Substituted nitrogen heterocyclic derivatives process of their preparation, the derivatives employed as medicaments, pharmaceutical composition and a compound pharmaceutical preparation in which these derivatives are comprised as well as use of these derivatives for preparing medicaments
AU763030B2 (en) * 1999-03-03 2003-07-10 Samjin Pharmaceutical Co., Ltd. Piperazine derivatives and process for the preparation thereof
PT1041068E (en) 1999-04-01 2004-07-30 Pfizer Prod Inc COMPOUNDS FOR THE TREATMENT AND PREVENTION OF DIABETIC COMPLICATIONS
WO2000071515A2 (en) 1999-05-24 2000-11-30 Cor Therapeutics, Inc INHIBITORS OF FACTOR Xa
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
WO2000076980A1 (en) * 1999-06-10 2000-12-21 Yamanouchi Pharmaceutical Co., Ltd. Novel nitrogen-contaiing heterocyclic derivatives or salts thereof
GB9918035D0 (en) 1999-07-30 1999-09-29 Novartis Ag Organic compounds
EE200200095A (en) * 1999-09-01 2003-04-15 Aventis Pharma Deutschland Gmbh Sulfonylcarboxamide derivatives, their uses, pharmaceuticals and process for their preparation
US20030187261A1 (en) 2000-01-07 2003-10-02 Libor Havlicek Purine derivatives, process for their preparation and use thereof
US6608052B2 (en) 2000-02-16 2003-08-19 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
CA2404002A1 (en) 2000-03-24 2001-09-27 Methylgene, Inc. Inhibitors of histone deacetylase
DE10023484A1 (en) * 2000-05-09 2001-11-22 Schering Ag New 2-((cycloalkyl- or heterocyclyl-alkyl)-amino)-benzamide derivatives, are VEGF receptor, KDR kinase and FLT kinase inhibitors useful e.g. for treating tumors, psoriasis, arthritis or renal or ophthalmological diseases
WO2002000651A2 (en) 2000-06-27 2002-01-03 Bristol-Myers Squibb Pharma Company Factor xa inhibitors
AU2001280187A1 (en) 2000-08-28 2002-03-13 Toray Industries, Inc. Cyclic amine derivatives
ES2167276B1 (en) * 2000-10-20 2003-04-01 Esteve Labor Dr NEW DERIVATIVES OF CIANOARIL (OR CIANOHETEROARIL) -CARBONIL-PIPERAZINIL-PIRIMIDINAS, ITS PREPARATION AND ITS APPLICATION AS MEDICATIONS.
JO2409B1 (en) 2000-11-21 2007-06-17 شركة جانسين فارماسوتيكا ان. في Biphenylcarboxamides useful as lipid lowering agents
MXPA03009602A (en) * 2001-04-18 2004-04-02 Euro Celtique Sa Nociceptin analogs.
SE0101769D0 (en) * 2001-05-18 2001-05-18 Astrazeneca Ab Novel compounds
SE0101771D0 (en) * 2001-05-18 2001-05-18 Astrazeneca Ab Novel compounds
DE10130374A1 (en) 2001-06-23 2003-01-02 Boehringer Ingelheim Pharma Substituted N-acyl aniline derivatives, their preparation and their use as medicines
JO3429B1 (en) 2001-08-13 2019-10-20 Janssen Pharmaceutica Nv Hiv inhibiting pyrimidines derivatives
US6897220B2 (en) 2001-09-14 2005-05-24 Methylgene, Inc. Inhibitors of histone deacetylase
US7129034B2 (en) 2001-10-25 2006-10-31 Cedars-Sinai Medical Center Differentiation of whole bone marrow
GB0127929D0 (en) 2001-11-21 2002-01-16 Celltech R&D Ltd Chemical compounds
GB0229931D0 (en) 2002-12-21 2003-01-29 Astrazeneca Ab Therapeutic agents
CA2472711C (en) * 2002-01-18 2012-03-20 Yamanouchi Pharmaceutical Co., Ltd. 2-acylaminothiazole derivative or salt thereof
US20040091951A1 (en) 2002-02-07 2004-05-13 Axys Pharmaceuticals, Inc. Assay for measuring acetylation or deacetylation activity of an enzyme
WO2003068769A1 (en) * 2002-02-12 2003-08-21 Pfizer Inc. Non-peptide compounds affecting the action of gonadotropin-releasing hormone (gnrh)
EP1485378B1 (en) 2002-03-13 2008-06-18 Janssen Pharmaceutica N.V. Piperazinyl-, piperidinyl- and morpholinyl-derivatives as novel inhibitors of histone deacetylase
MXPA04007776A (en) 2002-03-13 2004-10-15 Janssen Pharmaceutica Nv Sulfonylamino-derivatives as novel inhibitors of histone deacetylase.
ATE398615T1 (en) 2002-03-13 2008-07-15 Janssen Pharmaceutica Nv PIPERAZINYL, PIPERIDINYL AND MORPHOLINYL DERIVATIVES AS NEW INHIBITORS OF HISTONE DEACETYLASE
CN101450934B (en) 2002-03-13 2012-10-10 詹森药业有限公司 Sulfonyl-derivatives as novel inhibitors of histone deacetylase
OA12790A (en) 2002-03-13 2006-07-10 Janssen Pharmaceutica Nv New inhibitors of histone deacetylase.
ES2306858T3 (en) 2002-03-13 2008-11-16 Janssen Pharmaceutica Nv CARBONILAMINE DERIVATIVES AS NEW INHIBITORS OF HISTONADESACETILASAS.
US6897307B2 (en) 2002-03-28 2005-05-24 Novartis Ag Process for preparing 2,6-diaminopurine derivatives
JP4606027B2 (en) 2002-04-03 2011-01-05 トポターゲット ユーケー リミテッド Carbamate compounds having piperazine bonds as HDAC inhibitors
TWI319387B (en) 2002-04-05 2010-01-11 Astrazeneca Ab Benzamide derivatives
GB0209715D0 (en) 2002-04-27 2002-06-05 Astrazeneca Ab Chemical compounds
DE10233412A1 (en) 2002-07-23 2004-02-12 4Sc Ag New compounds as histone deacetylase inhibitors
JP2005539001A (en) 2002-08-02 2005-12-22 アージェンタ・ディスカバリー・リミテッド Substituted thienyl hydroxamic acids as histone deacetylase inhibitors
ITMI20030025A1 (en) 2003-01-10 2004-07-11 Italfarmaco Spa HYDROXAMIC ACID DERIVATIVES FOR ANTI-INFLAMMATORY ACTIVITY.
TW200418806A (en) 2003-01-13 2004-10-01 Fujisawa Pharmaceutical Co HDAC inhibitor
US7465719B2 (en) 2003-01-17 2008-12-16 Topotarget Uk Limited Carbamic acid compounds comprising an ester or ketone linkage as HDAC inhibitors
TW200424174A (en) 2003-02-06 2004-11-16 Hoffmann La Roche New TP diamide
AU2003900608A0 (en) 2003-02-11 2003-02-27 Fujisawa Pharmaceutical Co., Ltd. Hdac inhibitor
US7244751B2 (en) 2003-02-14 2007-07-17 Shenzhen Chipscreen Biosciences Ltd. Histone deacetylase inhibitors of novel benzamide derivatives with potent differentiation and anti-proliferation activity
WO2004082638A2 (en) 2003-03-17 2004-09-30 Syrrx, Inc. Histone deacetylase inhibitors
TW200424187A (en) 2003-04-04 2004-11-16 Hoffmann La Roche New oxime derivatives and their use as pharmaceutically active agents
SI1611088T1 (en) 2003-04-07 2009-12-31 Pharmacyclics Inc Hydroxamates as therapeutic agents
EP1652842B1 (en) 2003-07-30 2012-04-11 Kyowa Hakko Kirin Co., Ltd. Indazole derivatives
TWI328038B (en) 2003-09-17 2010-08-01 Yeastern Biotech Co Ltd Fungal immunomodulatory protein (fip) prepared by microorganisms and uses thereof
US7781595B2 (en) 2003-09-22 2010-08-24 S*Bio Pte Ltd. Benzimidazole derivatives: preparation and pharmaceutical applications
SI1673349T1 (en) 2003-09-22 2010-10-29 S Bio Pte Ltd Benzimidazole derivatives: preparation and pharmaceutical applications
AU2004276337B2 (en) 2003-09-24 2009-11-12 Methylgene Inc. Inhibitors of histone deacetylase
JP2007509930A (en) 2003-10-27 2007-04-19 エス＊バイオ プライベート リミティッド Hydroxamates with acylureas and sulfonylureas
EP1682538A4 (en) 2003-10-27 2009-05-27 S Bio Pte Ltd Biaryl linked hydroxamates: preparation and pharmaceutical applications
GB0402496D0 (en) 2004-02-04 2004-03-10 Argenta Discovery Ltd Novel compounds
US20050197336A1 (en) 2004-03-08 2005-09-08 Miikana Therapeutics Corporation Inhibitors of histone deacetylase
JP5319113B2 (en) 2004-03-26 2013-10-16 メチルジーン インコーポレイテッド Inhibitors of histone deacetylase
RS51189B (en) 2004-07-28 2010-10-31 Janssen Pharmaceutica N.V. Substituted propenyl piperazine derivatives as novel inhibitors of histone deacetylase
SI1776358T1 (en) 2004-07-28 2009-10-31 Janssen Pharmaceutica Nv Substituted propenyl piperazine derivatives as novel inhibitors of histone deacetylase
WO2006010750A1 (en) 2004-07-28 2006-02-02 Janssen Pharmaceutica N.V. Substituted indolyl alkyl amino derivatives as novel inhibitors of histone deacetylase
US8138198B2 (en) 2005-05-18 2012-03-20 Angibaud Patrick Rene Substituted aminopropenyl piperidine or morpholine derivatives as novel inhibitors of histone deacetylase
CA2608929C (en) 2005-06-23 2014-01-28 Janssen Pharmaceutica N.V. Imidazolinone and hydantoine derivatives as novel inhibitors of histone deacetylase
CN101341138B (en) * 2005-06-30 2012-11-14 詹森药业有限公司 Cyclic anilino-pyridinotriazines as GSK-3 inhibitors
WO2007016532A2 (en) 2005-08-02 2007-02-08 Novartis Ag Mutations and polymorphisms of hdac4
WO2007048767A1 (en) 2005-10-27 2007-05-03 Janssen Pharmaceutica N.V. Squaric acid derivatives as inhibitors of histone deacetylase
DK1981874T3 (en) 2006-01-19 2009-09-28 Janssen Pharmactuica N V Aminophenyl derivatives as novel inhibitors of histone deacetylase
WO2007082874A1 (en) 2006-01-19 2007-07-26 Janssen Pharmaceutica N.V. Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase
DK1981871T3 (en) 2006-01-19 2012-02-13 Janssen Pharmaceutica Nv Heterocyclyl alkyl derivatives as novel inhibitors of histone deacetylase
CN101370789B (en) 2006-01-19 2012-05-30 詹森药业有限公司 Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase
JP5137849B2 (en) 2006-01-19 2013-02-06 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Substituted indolyl-alkyl-amino-derivatives as inhibitors of histone deacetylase
WO2007082880A1 (en) 2006-01-19 2007-07-26 Janssen Pharmaceutica N.V. Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase
AU2007296259A1 (en) 2006-09-15 2008-03-20 Janssen Pharmaceutica Nv Combinations of class-I specific histone deacetylase inhibitors with proteasome inhibitors
US20100270419A1 (en) * 2007-12-14 2010-10-28 Raphael Yoeli Redundancies and flows in vehicles
GB0901749D0 (en) 2009-02-03 2009-03-11 Oxford Nanopore Tech Ltd Adaptor method

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998055449A1 (en) * 1997-06-06 1998-12-10 The University Of Queensland Hydroxamic acid compounds having anticancer and anti-parasitic properties
WO2001038322A1 (en) * 1999-11-23 2001-05-31 Methylgene, Inc. Inhibitors of histone deacetylase
WO2003011851A2 (en) * 2001-06-15 2003-02-13 F. Hoffman-La Roche Ag Aromatic hydroxamic acid derivatives useful as hdac inhibitors

Cited By (112)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7868204B2 (en) 2001-09-14 2011-01-11 Methylgene Inc. Inhibitors of histone deacetylase
US7838520B2 (en) 2001-09-14 2010-11-23 Methylgene, Inc. Inhibitors of histone deacetylase
US7595343B2 (en) 2001-09-14 2009-09-29 Methylgene, Inc. Inhibitors of histone deacetylase
US7390813B1 (en) 2001-12-21 2008-06-24 Xenon Pharmaceuticals Inc. Pyridylpiperazines and aminonicotinamides and their use as therapeutic agents
US8916554B2 (en) 2002-03-13 2014-12-23 Janssen Pharmaceutica, N.V. Amino-derivatives as novel inhibitors of histone deacetylase
US9150560B2 (en) 2002-03-13 2015-10-06 Janssen Pharmaceutica Nv Inhibitors of histone deacetylase
US9556161B2 (en) 2002-03-13 2017-01-31 Janssen Pharmaceutica Nv Inhibitors of histone deacetylase
US9533979B2 (en) 2002-03-13 2017-01-03 Janssen Pharmaceutica Nv Amino-derivatives as novel inhibitors of histone deacetylase
US8247562B2 (en) 2002-04-05 2012-08-21 Astrazeneca Ab Benzamide derivatives useful as histone deacetylase inhibitors
WO2005011654A2 (en) 2003-07-29 2005-02-10 Xenon Pharmaceuticals Inc. Pyridyl derivatives and their use as therapeutic agents
US8383628B2 (en) 2003-07-29 2013-02-26 Xenon Pharmaceuticals Inc. Pyridyl derivatives and their use as therapeutic agents
WO2005011656A2 (en) 2003-07-30 2005-02-10 Xenon Pharmaceuticals Inc. Pyridyl derivatives and their use as therapeutic agents
EP2316828A1 (en) 2003-07-30 2011-05-04 Xenon Pharmaceuticals Inc. Piperazine derivatives and their use as therapeutic agents
WO2005011655A2 (en) 2003-07-30 2005-02-10 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
EP2316826A1 (en) 2003-07-30 2011-05-04 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutics agents
EP2316827A1 (en) 2003-07-30 2011-05-04 Xenon Pharmaceuticals Inc. Piperazine derivatives and their use as therapeutic agents
EP2316825A1 (en) 2003-07-30 2011-05-04 Xenon Pharmaceuticals Inc. Pyridyl derivatives and their use as therapeutic agents
EP3042895A1 (en) 2003-07-30 2016-07-13 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
US7335658B2 (en) 2003-07-30 2008-02-26 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
WO2005011657A2 (en) 2003-07-30 2005-02-10 Xenon Pharmaceuticals Inc. Piperazine derivatives and their use as therapeutic agents
US7868205B2 (en) 2003-09-24 2011-01-11 Methylgene Inc. Inhibitors of histone deacetylase
US8088805B2 (en) 2004-03-26 2012-01-03 Methylgene Inc. Inhibitors of histone deacetylase
US9150543B2 (en) 2004-07-28 2015-10-06 Janssen Pharmaceutica N. V. Substituted indolyl alkyl amino derivatives as inhibitors of histone deacetylase
US9636341B2 (en) 2004-07-28 2017-05-02 Janssen Pharmaceutica N.V. Substituted indolyl alkyl amino derivatives as novel inhibitors of histone deacetylase
US7947830B2 (en) 2004-07-28 2011-05-24 Janssen Pharmaceutica N.V. Substituted propenyl piperazine derivatives as novel inhibitors of histone deacetylase
US8426416B2 (en) 2004-07-28 2013-04-23 Janssen Pharmaceutica, N.V. Substituted propenyl piperazine derivatives as novel inhibitors of histone deacetylase
US7829712B2 (en) 2004-09-20 2010-11-09 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase
WO2006101521A2 (en) 2004-09-20 2006-09-28 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors
US7777036B2 (en) 2004-09-20 2010-08-17 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
EP2269610A2 (en) 2004-09-20 2011-01-05 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors
US7767677B2 (en) 2004-09-20 2010-08-03 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
WO2006034338A1 (en) 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as mediators of stearoyl-coa desaturase
US8026360B2 (en) 2004-09-20 2011-09-27 Xenon Pharmaceuticals Inc. Substituted pyridazines as stearoyl-CoA desaturase inhibitors
US8071603B2 (en) 2004-09-20 2011-12-06 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US7919496B2 (en) 2004-09-20 2011-04-05 Xenon Pharmaceuticals Inc. Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-CoA desaturase enzymes
US7951805B2 (en) 2004-09-20 2011-05-31 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase
JPWO2006082834A1 (en) * 2005-02-02 2008-06-26 興和株式会社 Prophylactic / therapeutic agent for diseases caused by keratinocyte proliferation
WO2006082834A1 (en) * 2005-02-02 2006-08-10 Kowa Co., Ltd. Agent for prevention/therapy of disease caused by keratinocyte growth
WO2006086447A2 (en) 2005-02-09 2006-08-17 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
JP2008530219A (en) * 2005-02-16 2008-08-07 シェーリング コーポレイション Piperazine-piperidine substituted with amine-linked pyridyl and phenyl having CXCR3 antagonist activity
JP2008530214A (en) * 2005-02-16 2008-08-07 シェーリング コーポレイション Piperazine substituted with a heterocyclic ring having CXCR3 antagonist activity
JP4688889B2 (en) * 2005-02-16 2011-05-25 シェーリング コーポレイション Piperazine-piperidine substituted with amine-linked pyridyl and phenyl having CXCR3 antagonist activity
JP2011126901A (en) * 2005-02-16 2011-06-30 Schering Corp Heterocyclic-substituted piperazine with cxcr3 antagonist activity
JP4873352B2 (en) * 2005-02-16 2012-02-08 シェーリング コーポレイション Piperazine substituted with a heterocyclic ring having CXCR3 antagonist activity
US9133104B2 (en) 2005-05-05 2015-09-15 Chroma Therapeutics Ltd. Enzyme inhibitors
WO2006117548A1 (en) 2005-05-05 2006-11-09 Chroma Therapeutics Ltd Hydroxamic acid dervicatives as inhibitors of hdac enzymatic activity
US9856211B2 (en) 2005-05-13 2018-01-02 Topotarget Uk Limited Pharmaceutical formulations of HDAC inhibitors
US9957227B2 (en) 2005-05-13 2018-05-01 Topotarget Uk Limited Pharmaceutical formulations of HDAC inhibitors
US8541457B2 (en) 2005-06-03 2013-09-24 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors
WO2006130986A1 (en) * 2005-06-09 2006-12-14 Merck Frosst Canada Ltd. Azacyclohexane derivatives as inhibitors of stearoyl-coenzyme a delta-9 desaturase
US7732475B2 (en) 2005-07-14 2010-06-08 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7741494B2 (en) 2005-07-14 2010-06-22 Takeda San Diego, Inc. Histone deacetylase inhibitors
WO2007009236A1 (en) * 2005-07-20 2007-01-25 Merck Frosst Canada Ltd. Heteroaromatic compounds as inhibitors of stearoyl-coenzyme a delta-9 desaturase
WO2007045962A3 (en) * 2005-10-18 2008-08-21 Orchid Res Lab Ltd Novel hdac inhibitors
WO2007045962A2 (en) * 2005-10-18 2007-04-26 Orchid Research Laboratories Limited Novel hdac inhibitors
JP2009513599A (en) * 2005-10-27 2009-04-02 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Squaric acid derivatives as inhibitors of histone deacetylase
US7884105B2 (en) 2005-10-27 2011-02-08 Janssen Pharmaceutica, N.V. Squaric acid derivatives as inhibitors of histone deacetylase
US8664223B2 (en) 2006-01-19 2014-03-04 Janssen Pharmaceutica N.V Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase
US9078896B2 (en) 2006-01-19 2015-07-14 Janssen Pharmaceutica, N.V. Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase
US8598168B2 (en) 2006-04-07 2013-12-03 Methylgene Inc. Inhibitors of histone deacetylase
US9725407B2 (en) 2006-10-06 2017-08-08 Glaxosmithkline Intellectual Property Development Limited HDAC inhibitors
US8637547B2 (en) 2006-10-06 2014-01-28 Chroma Therapeutics Ltd. Compounds which inhibit members of the histone deacetylase family of enzymes and their use in the treatment of cell proliferative diseases
US9273003B2 (en) 2006-10-06 2016-03-01 Glaxosmithkline Intellectual Property Development Limited Methods of treating lymphoma and rheumatoid arthritis with cyclopentyl (2S)-cyclohexyl[({6-[3-(hydroxyamino)-3-oxopropyl]pyridin-3-yl}methyl)amino]acetate
EP2295410A1 (en) 2006-10-06 2011-03-16 Chroma Therapeutics Limited HDAC inhibitor
US8044052B2 (en) 2006-10-18 2011-10-25 Pfizer Inc. Biaryl ether urea compounds
US8962825B2 (en) 2006-10-30 2015-02-24 Glaxosmithkline Intellectual Property Development Limited Hydroxamates as inhibitors of histone deacetylase
US8354445B2 (en) 2007-03-13 2013-01-15 Methylgene Inc. Inhibitors of histone deacetylase
US8030344B2 (en) 2007-03-13 2011-10-04 Methylgene Inc. Inhibitors of histone deacetylase
EP2167090A2 (en) * 2007-06-06 2010-03-31 University of Maryland, Baltimore Hdac inhibitors and hormone targeted drugs for the treatment of cancer
EP2167090A4 (en) * 2007-06-06 2010-08-25 Univ Maryland Hdac inhibitors and hormone targeted drugs for the treatment of cancer
US8110550B2 (en) 2007-06-06 2012-02-07 University Of Maryland, Baltimore HDAC inhibitors and hormone targeted drugs for the treatment of cancer
US8476289B2 (en) 2008-03-27 2013-07-02 Janssen Pharmaceutica Nv Aza-bicyclohexyl substituted indolyl alkyl amino derivatives as novel inhibitors of histone deacetylace
US8853202B2 (en) 2008-11-04 2014-10-07 Chemocentryx, Inc. Modulators of CXCR7
US8288373B2 (en) 2008-11-04 2012-10-16 Chemocentryx, Inc. Modulators of CXCR7
US8367663B2 (en) 2009-01-08 2013-02-05 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US11597732B2 (en) 2009-01-08 2023-03-07 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US8906909B2 (en) 2009-01-08 2014-12-09 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US10894795B2 (en) 2009-01-08 2021-01-19 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US11261195B2 (en) 2009-01-08 2022-03-01 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US8461157B2 (en) 2009-01-08 2013-06-11 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
WO2010097586A1 (en) 2009-02-27 2010-09-02 Chroma Therapeutics Ltd. Enzyme inhibitors
US8609672B2 (en) 2010-08-27 2013-12-17 University Of The Pacific Piperazinylpyrimidine analogues as protein kinase inhibitors
US8980924B2 (en) 2010-11-24 2015-03-17 The Trustees Of Columbia University In The City Of New York Non-retinoid RBP4 antagonist for treatment of age-related macular degeneration and stargardt disease
US11654136B2 (en) 2011-04-01 2023-05-23 Curis, Inc. Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US11135205B2 (en) 2011-04-01 2021-10-05 Curis, Inc. Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US8710219B2 (en) 2011-04-01 2014-04-29 Curis, Inc. Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US10543197B2 (en) 2011-04-01 2020-01-28 Curis, Inc. Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US9333202B2 (en) 2012-05-01 2016-05-10 The Trustees Of Columbia University In The City Of New York Non-retinoid antagonists for treatment of age-related macular degeneration and stargardt disease
US11834452B2 (en) 2012-11-29 2023-12-05 Chemocentryx, Inc. CXCR7 antagonists
US10273243B2 (en) 2013-03-14 2019-04-30 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US9637450B2 (en) 2013-03-14 2017-05-02 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US11919913B2 (en) 2013-03-14 2024-03-05 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US9938291B2 (en) 2013-03-14 2018-04-10 The Trustess Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US9944644B2 (en) 2013-03-14 2018-04-17 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US11028098B2 (en) 2013-03-14 2021-06-08 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US10421720B2 (en) 2013-03-14 2019-09-24 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US9926271B2 (en) 2013-03-14 2018-03-27 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US10570148B2 (en) 2013-03-14 2020-02-25 The Trustees Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US10787453B2 (en) 2013-03-14 2020-09-29 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US9598401B2 (en) 2013-07-29 2017-03-21 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use thereof
US9714232B2 (en) 2013-12-20 2017-07-25 Sunshine Lake Pharma Co., Ltd. Substituted piperazine compounds and methods of use thereof
EP3116859A4 (en) * 2014-03-12 2017-02-08 Chong Kun Dang Pharmaceutical Corp. Novel compounds as histone deacetylase 6 inhibitors and pharmaceutical compositions comprising the same
US10287255B2 (en) 2014-03-12 2019-05-14 Chong Kun Dang Pharmaceutical Corp. Compounds as histone deacetylase 6 inhibitors and pharmaceutical compositions comprising the same
US10407433B2 (en) 2014-04-30 2019-09-10 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10913746B2 (en) 2014-04-30 2021-02-09 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US11649240B2 (en) 2014-04-30 2023-05-16 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US9777010B2 (en) 2014-04-30 2017-10-03 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US9434727B2 (en) 2014-04-30 2016-09-06 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10072016B2 (en) 2014-04-30 2018-09-11 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10584133B2 (en) 2018-03-30 2020-03-10 Biotheryx, Inc. Thienopyrimidinone compounds
US11234986B2 (en) 2018-09-11 2022-02-01 Curis, Inc. Combination therapy with a phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US11464786B2 (en) 2018-12-12 2022-10-11 Chemocentryx, Inc. CXCR7 inhibitors for the treatment of cancer

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