WO2004110989A1 - Derives de n-hydroxy-7-(arylamino)heptanamide utiles pour traiter des maladies hyperproliferatives - Google Patents

Derives de n-hydroxy-7-(arylamino)heptanamide utiles pour traiter des maladies hyperproliferatives Download PDF

Info

Publication number
WO2004110989A1
WO2004110989A1 PCT/US2004/015465 US2004015465W WO2004110989A1 WO 2004110989 A1 WO2004110989 A1 WO 2004110989A1 US 2004015465 W US2004015465 W US 2004015465W WO 2004110989 A1 WO2004110989 A1 WO 2004110989A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
phenyl
optionally substituted
compound
substituents
Prior art date
Application number
PCT/US2004/015465
Other languages
English (en)
Inventor
Harold C. E. Kluender
Zhenqiu Hong
Gaetan H. Ladouceur
Xiao-Gao Liu
Uday Khire
Lei Wang
Original Assignee
Bayer Pharmaceuticals Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Pharmaceuticals Corporation filed Critical Bayer Pharmaceuticals Corporation
Publication of WO2004110989A1 publication Critical patent/WO2004110989A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to novel ⁇ /-hydroxy-7-(arylamino)heptanamide derivative compounds including salts, carbonates and O-acylated derivatives thereof, pharmaceutical compositions containing such compounds, and the use of those compounds or compositions for treating hyper-proliferative disorders.
  • Ar is selected from phenyl, 3-quinolyl, 5-indolyl, and 5-indazolyl;
  • R is selected from H, O-(CrC 6 )alkyl, thienyl, naphthyl, benzofuranyl, benzothiophenyl,
  • R 1 is selected from H, C(O)W, C(O)NHX, and S(O) 2 Y;
  • V is selected from NH, O and CH 2 , and when V is NH, N can be optionally substituted with (C r C 4 )alkyl;
  • W is selected from (C-rC 8 )alkyl optionally substituted with 2, (C 3 -C 6 )cycloalkyl, O-(C r C 4 )alkylphenyl, O-(C r C 4 )alkyl, naphthyl, thienyl, furyl, benzothienyl, phenyl said phenyl being optionally substituted with up to 3 substituents each independently selected from (CrC 4 )alkyl, O-(C r C 4 )alkyl, S-(C 1 -C 4 )alkyl, halo, CF 3 , 0-CF 3 , phenyl, O-phenyl, O-(C r C 4 )alkyl-phenyl, and isoxazolyl said isoxazolyl being optionally substituted with up to 2 independently selected (C- ⁇ -C 4 )alkyl groups; X is selected from (CrC 8 )alkyl optionally
  • Y is selected from (C r C 8 )alkyl optionally substituted with Z, (C 3 -C6)cycloalkyl, naphthyl, thienyl, furyl, benzothienyl, phenyl said phenyl being optionally substituted with up to 3 substituents each independently selected from (C r C 4 )alkyl, O-(C r C 4 )alkyl, S-(C r C 4 )alkyl, halo, CF 3 , 0-CF 3 , phenyl, O-phenyl, O-(C r C 4 )alkyl-phenyl, and isoxazolyl said isoxazolyl being optionally substituted with up to 2 independently selected (C r C 4 )alkyl groups; Z is selected from naphthyl, O-phenyl, O-(d-C 4 )alkyl, and phenyl said phenyl being optionally substituted with up to 2 substitu
  • a preferred embodiment of this invention is a compound of Formula I wherein W is selected from (C 3 -C 6 )cycloalkyl, O-(C- ⁇ -C 4 )alkylphenyl, naphthyl, thienyl, furyl, benzothienyl, (C-
  • X is selected from (C-i-C 4 )alkyl, (C 1 -C 4 )alkylphenyl, naphthyl, cyclohexyl, and phenyl said phenyl being optionally substituted with up to 3 substituents each selected independently from phenyl, O-phenyl, O-(CrC 4 )alkyl, S-(C r C 4 )alkyl, halo, CF 3 , and N[(C r C 4 )alkyl] 2 ;
  • Y is selected from naphthyl, thienyl, and phenyl said phenyl being optionally substituted with up to 2 substituents each selected independently from (C r C 4 )alkyl, O-(C r C 4 )alkyl, halo, CF 3 , OCF 3 , phenyl and NHC(O)(C r C 4 )alkyl; and Z is selected from O-(
  • Another preferred embodiment of this invention is a compound of Formula I wherein W is selected from (C 3 -C 4 )cycloalkyl, naphthyl, thienyl, furyl, benzothienyl,
  • (C- ⁇ -C 2 )alkyl optionally substituted with Z, and phenyl optionally substituted up to 2 substituents each selected independently from (C r C 2 )alkyl, O-(C r C 2 )alkyl, halo, CF 3 , phenyl, and N[(C-
  • X is selected from (CrC 4 )alkyl, (C- ⁇ -C 2 )alkylphenyl, naphthyl, cyclohexyl, and phenyl said phenyl being optionally substituted with up to 3 substituents each selected independently from phenyl, O-phenyl, O-(C- ⁇ -C 2 )alkyl, S-(C r C 2 )alkyl, halo, CF 3 , and Nf(C 1 -C 2 )BlRyI] 2 ;
  • Y is selected from naphthyl, thienyl, and phenyl said phenyl being optionally substituted with up to 2 substituents each selected independently from
  • Another preferred embodiment of this invention is a compound of Formula I wherein R 1 represents S(O) 2 Y.
  • Another preferred embodiment of this invention is a compound of Formula I wherein R 1 represents S(O) 2 Y and Y is thienyl.
  • Another preferred embodiment of this invention is a compound of Formula I wherein R 1 represents C(O)W.
  • Another preferred embodiment of this invention is a compound of Formula I wherein R 1 represents C(O)W and W is thienyl or benzothienyl.
  • Another preferred embodiment of this invention is a compound of Formula I wherein Ar is phenyl.
  • Another preferred embodiment of this invention is a compound of Formula I wherein Ar is 5-indolyl.
  • the present invention relates to a process of making a compound of formula (I), wherein
  • hydroxylamine hydrochloride preferably in the presence of a base, or
  • hydroxylamine such as (O-(tetrahydro-2H- pyran-2-yl)hydroxylamine, preferably in the presence of trimethylaluminum, and in a second step is deprotected, preferably under acidic conditions.
  • a compound of formula (V) is known or can be prepared as described infra.
  • (CrC 8 )alkyl and “(C r C 4 )alkyl” mean linear or branched saturated carbon groups having from about 1 to about 8 or about 4 C atoms, respectively. Such groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, ferf-butyl, and the like.
  • O-(C r C 4 )alkyl means an O atom substituted with a (CrC 4 )alkyl group, where the O-(C r C 4 )alkyl group is attached to the rest of the molecule at the group's O atom.
  • Such groups include methoxy, ethoxy, ⁇ -propoxy, f-butoxy and the like.
  • S-(C r C 4 )alkyl means an S atom substituted with a (CrC 4 )alkyl group, where the S-(C- ⁇ -C 4 )a!kyl group is attached to the rest of the molecule at the group's S atom.
  • groups include methylthio, ethylthio, n-propylthio, f-butylthio and the like.
  • O-(C r C 4 )alkylphenyl means an O atom substituted by a (C r C 4 )alkyl group said alkyl group being itself substituted by phenyl.
  • the O-(C- ⁇ -C 4 )alkylphenyl group is attached to the rest of the molecule at the group's O atom.
  • Such groups include benzyloxy, 2-phenethyloxy, 3-phenylpropoxy, 2-phenylbutyloxy and the like.
  • O-phenyl means phenoxy, the phenoxy group being attached to the rest of the molecule at the group's O atom.
  • C 3 -C 6 cycloalkyl means a saturated monocyclic alkyl group of from 3 to about 6 carbon atoms and includes such groups as cyclopropyl, cyclopentyl, cyclohexyl, and the like.
  • halo means an atom selected from Cl, Br, F, and I, where Cl and F are preferred.
  • each of the 2 alkyl groups is selected independently from the other so that they may be the same or different.
  • heterocyclic groups such as thienyl, furyl, naphthyl, benzofuranyl, benzothiophenyl, isoxazolyl, and the like, are each attached to the rest of the molecule through any available C atom. Substituents on such heterocycles may be attached to the heterocycle through any available C atom on the heterocycle.
  • the compounds of this invention may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms may be present in the (R) or (S) configuration or (R, S) configuration. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • Preferred compounds are those with the absolute configuration of the compound of this invention which produces the more desirable biological activity.
  • Separated, pure and partially purified isomers and racemic mixtures of the compounds of this invention are each included within the scope of the present invention.
  • the purification of said isomers and the separation of said isomeric mixtures can be accomplished by standard techniques known in the art.
  • compositions of these compounds are also within the scope of this invention.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts,” J. Pharm. ScL 66: 1-19, 1977.
  • Representative salts of the compounds of this invention include the conventional non-toxic salts and the quaternary ammonium salts that are formed, for example, from inorganic or organic acids or bases by means well known in the art.
  • acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate,
  • Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and ⁇ /-methyl-D-glucamine.
  • basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate
  • diamyl sulfates long chain halides such as decyl, lauryl
  • the term "pharmaceutically acceptable carbonate” refers to a relatively non-toxic carbonate derivative of a compound of the present invention where the H atom of an acid hydroxyl group of a compound of Table I has been replaced with a alkoxy-carbonyl group where said alkoxy may be substituted with phenyl, alkoxy, and the like.
  • the carbonates of the compounds of this invention include pharmaceutically acceptable carbonates such as methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl- or pentyl-carbonate.
  • O-acylated derivative refers to a relatively non-toxic O-acylated derivative of the present invention where the O atom of the hydroxamic acid group is substituted with an acyl group such as acetyl, propanoyl, butanoyl, benzoyl or toluoyl and the like.
  • carbonate and O-acylated derivative(s) may be hydrolyzed at physiological pH values or may be cleaved by endogenous esterases or lipases in vivo to release the parent compound as the active material for treating hyper-proliferative disorders.
  • endogenous esterases or lipases See, e.g., U.S. Patent No. 4,942,184, U.S. Patent No. 4,960,790, U.S. Patent No. 5,817,840, and U.S. Patent No. 5824701, all of which are incorporated herein by reference in their entirety, and references therein.
  • the compounds used in this invention may be prepared by standard techniques known in the art, by known processes analogous thereto, and/or by the processes described herein, using starting materials which are either commercially available or producible according to routine, conventional chemical methods.
  • the following preparative methods (Methods A-G) are presented in Reaction Schemes 1-3 to aid the reader in the synthesis of the compounds of the present invention.
  • compounds of Formula (I) can be prepared in a 3 or 4 step sequence starting from a substituted aniline, represented by
  • Method A the aniline of Formula (II) and the bromo ester of Formula (III) are allowed to react in a polar aprotic solvent such as DMF and in the presence of a base such as potassium carbonate, to provide the aryl amino ester of Formula (IV).
  • a polar aprotic solvent such as DMF
  • a base such as potassium carbonate
  • the compound of Formula (IV) may be converted to the N-substituted amino ester of Formula (V) by either Method B or Method D.
  • the Formula (IV) compound is treated with a sulfonyl chloride [ R 1 -CI, where R 1 is Y-SO 2 -] in the presence of a non-nucleophilic base such as DMAP, to give the compound of Formula (V).
  • the Formula (IV) compound is treated with a chloroformate [R 1 -Cl, where R 1 is W-C(O)-, and W is (C r C 4 )alkoxy or phenyl-(C-i-C 4 )alkyl-O-] in the presence of a base such as triethyl amine, in an aprotic solvent such as THF to give the Formula (V) compound.
  • Direct conversion of the Formula (V) compound to the invention compound of Formula (I) can be accomplished by the conditions designated as Method C, namely, treatment of the compound of Formula (V) with hydroxylamine hydrochloride in methanol in the presence of a base such as potassium hydroxide.
  • the Formula (I) compound can be prepared by a multi-step procedure designated as Method E. In the first step of Method E, the compound of Formula (V) is allowed to react with (O-
  • Compounds of Formula (I) where the R is naphthyl, thienyl, naphthyl, benzofuranyl, benzothiophenyl, or an optionally substituted phenyl group can be prepared from compounds of Formula (VII), as illustrated in Reaction Scheme 3.
  • the R group is introduced by a palladium-catalyzed coupling reaction of the bromo substituted compound of Formula (VII) with a boronic acid derivative, for example, R-B(OH) 2 , in the presence of a Pd catalyst, such as PdCI 2 (dppf), and a mild base such as NaHCO 3 , to produce the intermediate of Formula (V).
  • the Formula (V) compound can then be used to prepare the corresponding compound of Formula (I) using Methods C or E, as described in Reaction Scheme 1 , above.
  • Electron impact mass spectra were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Hewlett Packard 5890 Gas Chromatograph with a J & W DB-5 column (0.25 ⁇ M coating; 30 m x 0.25 mm). The ion source was maintained at 250 0 C and spectra were scanned from 50-800 amu at 2 sec per scan.
  • Step 1 Preparation of Ethyl 7-(1/-/-indol-5-ylamino)heptanoate
  • Step 1 of Example 1 constitutes General Method A for the preparation of aminoester intermediates used in the synthesis of various compounds of this invention as indicated in the table of all Examples.
  • Step 2 Preparation of Ethyl 7-ri/-/-lndol-5-yl(2-thienylsulfonyl)aminolheptanoate
  • Step 2 of Example 1 constitutes General Method B for the preparation of sulfonamide intermediates used in the synthesis of various compounds of this invention as indicated in the table of all Examples.
  • Step 3 Preparation of /V-Hvdroxy-7-HH-indol-5-yl(2-thienylsulfonyl)aminolheptanamide
  • Step 3 of Example 1 constitutes General Method C for the preparation of final hydroxamic acids of this invention as indicated in the table of all Examples.
  • Example 2
  • Step 1 Preparation of Ethyl 7-([4-(1-piperidinv ⁇ phenyllamino>heptanoate
  • Step 2 Preparation of Ethyl 7-(f(Benzyloxy)carbonyn[4-(1-piperidinyl)phenyllamino) heptanoate
  • Step 2 of Example 2 constitutes General Method D for the preparation of carbamate intermediates used in the synthesis of various compounds of this invention as indicated in the table of all Examples
  • Step 3 Preparation of Benzyl 7-Oxo-7-r(tetrahvdro-2/-/-pyran-2-yloxy)aminolheptylf4-(1- piperidinvPphenvUcarbamate
  • Ethyl 7-[(4-methoxyphenyl)amino]heptanoate was prepared from 4-methoxyaniline and ethyl 7-bromoheptanoate using General Method A as described in Example 1 , Step 1 above.
  • Step 2 of Example 3 constitutes General Method F for the preparation of amide intermediates used in the synthesis of various compounds of this invention as indicated in the table of all Examples.
  • Step 3 Preparation of ⁇ M7-(hvdroxyaminoV7-oxohepty ⁇ -/V-(4-metho ⁇ yphenvO-2- thiophenecarboxamide
  • Step 2 The above product of Step 2 was converted to the title compound using General Method C as found in Example 1 , Step 3 and purified either on a Biotage flash 40 silica column as in Example 1 or by reverse phase chromatography on C18 columns from YMC using gradient elution from 10 to 90 % acetonitrile in water with 0.5% trifluoroacetic acid.
  • Step 1 of Example 4 constitutes General Method G for the preparation of urea intermediates used in the synthesis of various compounds of this invention as indicated in the table of all Examples.
  • Step 2 Preparation of 7-rr(Benzylaminotoarbonyll(4-methoxyphenvnaminoy/V- hvdroxyheptanamide
  • Step 1 The above product of Step 1 was converted to the title compound using General Method C as found in Example 1 , Step 3 and purified as described above in Example 3.
  • Step 1 Ethyl 7-[(4-bromophenyl)amino]heptanoate was prepared from 4- bromoaniline and ethyl 7-bromoheptanoate using General Method A as described in Example 1 , Step 1 above.
  • Step 2 This material was then converted to ethyl 7-[(4-bromophenyl)(2- thienylsulfonyl)amino]heptanoate using General Method B as described in Example 1, Step 2.
  • Step 3 A mixture of ethyl 7-[(4-bromophenyl)(2-thienylsulfonyl)amino]heptanoate (103 mg, 0.22 mmol), benzofuran-2-boronic acid (53 mg, 0.33 mmol), and NaHCO 3 (55 mg,
  • Step 3 of Example 5 constitutes General Method H for the preparation of biaryl intermediates used in the synthesis of various compounds of this invention as indicated in the table of all Examples.
  • Step 4 The product of Step 3 was converted to the title compound using General Method C as described in Example 1 , Step 3.
  • Salts of the compounds identified herein can be obtained by isolating the compounds as hydrochloride salts, prepared by treatment of the free base with anhydrous
  • a desired salt of a compound of this invention can be prepared in situ during the final isolation and purification of a compound by means well known in the art.
  • a desired salt can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Carbonates of this invention in general may be made by conventional methods well known in the art.
  • the hydroxyl group of the hydroxamic acid moiety of a compound of Formula I may be converted to a carbonate by reacting the compound with, for example, an alkyl haloformate such as ethyl chloroformate in the presence of a base.
  • O-Acylated derivatives of this invention in general may be made by conventional methods well known in the art.
  • the hydroxyl group of the hydroxamic acid moiety of a compound of Formula I may be converted to an O-acylated derivative by reacting the compound with an acyl halide or anhydride, such as acetyl chloride or benzoic anhydride and the like, in the presence of a base such as triethylamine.
  • the compounds and prodrugs of this invention can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition.
  • the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, prodrug, or salt thereof, of the present invention.
  • a pharmaceutically acceptable carrier is any carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
  • a pharmaceutically effective amount of compound is that amount which produces a result or exerts an influence on the particular condition being treated.
  • the compounds of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, otically, sublingually, rectally, vaginally, and the like.
  • the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
  • the solid unit dosage forms can be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
  • the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
  • binders such as acacia, corn starch or gelatin
  • disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn star
  • Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
  • Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring and coloring agents described above, may also be present.
  • the pharmaceutical compositions of this invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
  • Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as s ⁇ y bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol.
  • the suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
  • sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
  • the compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1 ,1-dioxolane-4-methanol, ethers such as poly( ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such
  • Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.
  • Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
  • Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
  • suitable detergents include cationic detergents, for example di
  • compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile- lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulation ranges from about 5% to about 15% by weight.
  • the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
  • surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • the pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions.
  • Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca- ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions.
  • sterile fixed oils are conventionally employed as solvents or suspending media.
  • any bland, fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can be used in the preparation of injectables.
  • the invention relates to intravenous (i.v.) application of the active compound, e.g. as bolus injection (that is as single dose, e.g. per syringe), infusion over a short period of time (e.g. for up to one hour) or infusion over a long period of time
  • bolus injection that is as single dose, e.g. per syringe
  • infusion over a short period of time e.g. for up to one hour
  • a long period of time e.g. for up to one hour
  • the application can also be done by intermittent dosing.
  • the applied volume can vary dependent on the conditions and usually is 0.5 to 30, preferably 1 to 20 ml for bolus injection, 25 to 500, preferably 50 to 250 ml for infusion over a short period of time and 50 to 1000, preferably 100 to 500 ml for infusion over a long period of time.
  • the application forms have to be sterile and free of pyrogens. They can be based on aqueous solvents or mixtures of aqueous and organic solvents. Examples are ethanol, polyethyleneglycol (PEG) 300 or 400, aqueous solutions containing cyclodextrins or emulsifiers, such as lecithin, Pluronic F68®, Solutol HS15® or Cremophor®. Aqueous solutions are preferred.
  • the solutions are generally isotonic and euhydric, for example with a pH of 3 to 11 , preferably 6 to 8 and most preferred about 7.4.
  • Glass or plastic containers can be employed as packaging for i.v.-solutions, e.g. rubber seal vials. They can contain liquid volumes of 1 to 1000, preferably 5 to 50 ml.
  • the solution can directly be withdrawn from the vial to be applied to the patient.
  • it can be advantageous to provide the active compound in solid form (e.g. as lyophilisate) and dissolve by adding the solvent to the vial directly before administration.
  • Solutions for infusion can advantageously be packaged in containers made from glass or plastic, for example bottles or collapsible containers such as bags.
  • compositions of the invention can contain liquid volumes of 1 to 1000, preferably 50 to 500 ml.
  • a composition of the invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such material are, for example, cocoa butter and polyethylene glycol.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued
  • Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations which are known in the art. It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device.
  • the construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art.
  • Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier.
  • One such implantable delivery system used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,011 ,472, issued April 30, 1991.
  • compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired.
  • Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M. F. et al, "Compendium of Excipients for Parenteral Formulations” PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311 ; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics
  • Commonly used pharmaceutical ingredients which can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples.include but are not limited to carbon dioxide, CCI 2 F 2 , F 2 CIC-CCIF 2 and CCIF 3 ) air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben,
  • clarifying agents include but are not limited to bentonite
  • emulsifying agents include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate
  • encapsulating agents include but are not limited to gelatin and cellulose acetate phthalate
  • flavorants include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin
  • humectants include but are not limited to glycerol, propylene glycol and sorbitol
  • levigating agents include but are not
  • compositions according to the present invention can be illustrated as follows:
  • Composition 100-200 mg of the compound of Example 1 , 15 g polyethylenglykol 400 and 250-g water, in saline optionally with up to 15 % Cremophor EL, and optionally up to 15% ethyl alcohol, and optionally up to 2 equivalents of a pharmaceutically suitable acid such as lactic acid, citric acid or hydrochloric acid.
  • a pharmaceutically suitable acid such as lactic acid, citric acid or hydrochloric acid.
  • Example 1 The compound of Example 1 and the polyethylenglykol 400are dissolved in the water with stirring.
  • the solution is sterile filtered (pore size 0.22 ⁇ m) and filled into heat sterilized infusion bottles under aseptical conditions.
  • the infusion bottles are being sealed with rubber seals.
  • Intravenously administrable solution 2 Composition: 100-200 mg of the compound of Example 1 , saline solution, optionally with up to 15 % by weight of Cremophor EL, and optionally up to 15% by weight of ethyl alcohol, and optionally up to 2 equivalents of a pharmaceutically suitable acid such as lactic acid, citric acid or hydrochloric acid.
  • a pharmaceutically suitable acid such as lactic acid, citric acid or hydrochloric acid.
  • Example 1 The compound of Example 1 is dissolved in the saline solution with stirring. Optionally Cremophor EL, ethyl alcohol or acid are added. The solution is sterile filtered (pore size 0.22 ⁇ m) and filled into heat sterilized infusion bottles under aseptical conditions. The infusion bottles are being sealed with rubber seals
  • a 5 mg/mL solution of the desired compound of this invention is made using sterile, injectable water, and the pH is adjusted if necessary.
  • the solution is diluted for administration to 1 - 2 mg/mL with sterile 5% dextrose and is administered as an IV infusion over 60 minutes.
  • Lvophilized powder for IV administration A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lypholized powder, (ii) 32- 327 mg/mL sodium citrate, and (iii) 300 - 3000 mg Dextran 40.
  • the formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg/mL, and is administered either IV bolus or by IV infusion over 15 - 60 min.
  • Intramuscular suspension The following solution or suspension can be prepared, for intramuscular injection: 50 mg/mL of the desired, water-insoluble compound of this invention
  • Hard Shell Capsules A large number of unit capsules are prepared by filling standard two- piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
  • Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
  • Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
  • Immediate Release Tablets/Capsules These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication.
  • the active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
  • the drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
  • the present invention relates to a method of using the compounds described above, including salts and esters thereof and corresponding compositions thereof, to treat mammalian hyper-proliferative disorders.
  • This method comprises administering to a patient an amount of a compound of this invention, or a pharmaceutically acceptable salt thereof, which is effective to treat the patient's hyper-proliferative disorder.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular hyper-proliferative disorder.
  • Hyper-proliferative disorders include but are not limited to solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias.
  • breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
  • Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
  • Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, and urethral cancers.
  • Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to laryngeal / hypopharyngeal / nasopharyngeal / oropharyngeal cancer, and lip and oral cavity cancer.
  • Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • the utility of the compounds of the present invention can be illustrated, for example, by their activity in vitro in the in vitro tumor cell proliferation assay described below.
  • the link between activity in tumor cell proliferation assays in vitro and anti-tumor activity in the clinical setting has been very well established in the art.
  • taxol Silvestrini et al. Stem Cells 1993, 11(6), 528-35
  • taxotere Bissery et al. Anti Cancer Drugs 1995, 6(3), 339
  • topoisomerase inhibitors Edelman et al. Cancer Chemother. Pharmacol. 1996, 37(5), 385-93
  • the following assay is one of the methods by which compound activity relating to treatment of the disorders identified herein can be determined.
  • the adherent tumor cell proliferation assay used to test the compounds of the present invention involves a readout called Cell Titre-Glo developed by Promega (Cunningham, BA "A Growing Issue: Cell Proliferation Assays. Modern kits ease quantification of cell growth” The Scientist 2001 , -/5(13), 26, and Crouch, SP et al., "The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity" Journal of
  • HCT116 cells colon carcinoma, purchased from ATCC
  • A549 lung carcinoma, purchased from ATCC
  • test compounds are added over a final concentration range of 10 nM to 20 ⁇ M in serial dilutions at a final DMSO concentration of 0.2 %.
  • Cells are incubated for 72 h at 37 0 C in complete growth media after addition of the test compound.
  • the cells are lysed and 100 microliters of substrate/buffer mixture is added to each well, mixed and incubated at room temperature for 8 min.
  • the samples are read on a luminometer to measure the amount of ATP present in the cell lysates from each well, which corresponds to the number of viable cells in that well. Values read at 24 h incubation are subtracted as Day 0.
  • a linear regression analysis can be used to determine drug concentration which results in a 50% inhibition of cell proliferation using this assay format.
  • Representative compounds of this invention as shown in the table below, showed a significant inhibition of tumor cell proliferation in the assays with HCT116 cells and representative compounds were also studied with the A549 cells and found to be active.
  • MDA-MB-231 (breast adenocarcinoma, purchased from ATCC), LnCaP (prostate carcinoma, purchased from ATCC) 1 H460 (lung carcinoma, purchased from ATCC), or HeIa (cervix adenocarcinoma) cells can also be used in similar assays.
  • LnCaP prostate carcinoma, purchased from ATCC
  • 1 H460 lung carcinoma, purchased from ATCC
  • HeIa cervical adenocarcinoma
  • the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.
  • a unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day.
  • the daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from
  • the daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • the compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
  • the compounds of this invention can be combined with known anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof.
  • Optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11 th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6- mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednis
  • anti-hyper-proliferative agents suitable for use with this invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des nouveaux dérivés de N-hydroxy-7-(arylamino)heptanamide comprenant des sels, des carbonates et des dérivés O-acylés correspondants, des compositions pharmaceutiques contenant ces composés, ainsi que l'utilisation de ces composés ou de ces compositions pour traiter des maladies hyperprolifératives.
PCT/US2004/015465 2003-05-14 2004-05-13 Derives de n-hydroxy-7-(arylamino)heptanamide utiles pour traiter des maladies hyperproliferatives WO2004110989A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US47071303P 2003-05-14 2003-05-14
US60/470,713 2003-05-14

Publications (1)

Publication Number Publication Date
WO2004110989A1 true WO2004110989A1 (fr) 2004-12-23

Family

ID=33551421

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/015465 WO2004110989A1 (fr) 2003-05-14 2004-05-13 Derives de n-hydroxy-7-(arylamino)heptanamide utiles pour traiter des maladies hyperproliferatives

Country Status (1)

Country Link
WO (1) WO2004110989A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006117548A1 (fr) 2005-05-05 2006-11-09 Chroma Therapeutics Ltd Derives de l'acide hydroxamique servant d'inhibiteurs de l'activite enzymatique de la hdac
WO2010097586A1 (fr) 2009-02-27 2010-09-02 Chroma Therapeutics Ltd. Inhibiteurs d'enzymes
EP2295410A1 (fr) 2006-10-06 2011-03-16 Chroma Therapeutics Limited Inhibiteur de HDAC
JP2012521982A (ja) * 2009-03-27 2012-09-20 チョン・クン・ダン・ファーマシューティカル・コーポレーション 新規なヒドロキサメート誘導体、その作製方法、及びこれを含有する薬学的組成物
CN102731380A (zh) * 2011-04-14 2012-10-17 上海美迪西生物医药有限公司 7-(n-(2-吡啶基)磺酰胺基或酰胺基)-n-羟基庚酰胺衍生物及其制备方法和应用
CN103896837A (zh) * 2012-12-25 2014-07-02 上海美迪西生物医药有限公司 2-(n-(3-喹啉基)磺酰胺基或酰胺基)-n-羟基乙酰胺衍生物及其制备方法和应用
US8962825B2 (en) 2006-10-30 2015-02-24 Glaxosmithkline Intellectual Property Development Limited Hydroxamates as inhibitors of histone deacetylase
US9133104B2 (en) 2005-05-05 2015-09-15 Chroma Therapeutics Ltd. Enzyme inhibitors
JP2017081931A (ja) * 2007-06-12 2017-05-18 アカオゲン，インコーポレーテッド 抗菌剤
CN115636761A (zh) * 2021-07-20 2023-01-24 中国石油天然气股份有限公司 一种油溶性表面活性剂、驱油剂及其应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6462023B1 (en) * 1996-09-10 2002-10-08 British Biotech Pharmaceuticals, Ltd. Cytostatic agents

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6462023B1 (en) * 1996-09-10 2002-10-08 British Biotech Pharmaceuticals, Ltd. Cytostatic agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
STACY W. REMISZEWSKI ET AL.: "Inhibitors of Human Histone Deacetylase: Synthesis and Enzyme and Cellular Activity of Straight Chain Hydroxamates", JOURNAL OF MEDICINAL CHEMISTRY., vol. 45, no. 4, 14 February 2002 (2002-02-14), USAMERICAN CHEMICAL SOCIETY. WASHINGTON., pages 753 - 757, XP002303393 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006117548A1 (fr) 2005-05-05 2006-11-09 Chroma Therapeutics Ltd Derives de l'acide hydroxamique servant d'inhibiteurs de l'activite enzymatique de la hdac
US9133104B2 (en) 2005-05-05 2015-09-15 Chroma Therapeutics Ltd. Enzyme 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
EP2295410A1 (fr) 2006-10-06 2011-03-16 Chroma Therapeutics Limited Inhibiteur de HDAC
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
US9725407B2 (en) 2006-10-06 2017-08-08 Glaxosmithkline Intellectual Property Development Limited HDAC inhibitors
US8962825B2 (en) 2006-10-30 2015-02-24 Glaxosmithkline Intellectual Property Development Limited Hydroxamates as inhibitors of histone deacetylase
JP2017081931A (ja) * 2007-06-12 2017-05-18 アカオゲン，インコーポレーテッド 抗菌剤
WO2010097586A1 (fr) 2009-02-27 2010-09-02 Chroma Therapeutics Ltd. Inhibiteurs d'enzymes
JP2012521982A (ja) * 2009-03-27 2012-09-20 チョン・クン・ダン・ファーマシューティカル・コーポレーション 新規なヒドロキサメート誘導体、その作製方法、及びこれを含有する薬学的組成物
US8466161B2 (en) 2009-03-27 2013-06-18 Chong Kun Dang Pharmaceutical Corp. Hydroxamate derivative, a production method for the same, and a pharmaceutical composition comprising the same
CN102731380A (zh) * 2011-04-14 2012-10-17 上海美迪西生物医药有限公司 7-(n-(2-吡啶基)磺酰胺基或酰胺基)-n-羟基庚酰胺衍生物及其制备方法和应用
CN103896837A (zh) * 2012-12-25 2014-07-02 上海美迪西生物医药有限公司 2-(n-(3-喹啉基)磺酰胺基或酰胺基)-n-羟基乙酰胺衍生物及其制备方法和应用
CN115636761A (zh) * 2021-07-20 2023-01-24 中国石油天然气股份有限公司 一种油溶性表面活性剂、驱油剂及其应用
CN115636761B (zh) * 2021-07-20 2024-07-05 中国石油天然气股份有限公司 一种油溶性表面活性剂、驱油剂及其应用

Similar Documents

Publication Publication Date Title
EP2097381B1 (fr) 4-[4-({[4-chloro-3-(trifluorométhyl)phényl)]carbamoyl}amino)-3-fluorophénoxy]-n-méthylpyridine-2-carboxamide monohydraté
WO2003095448A1 (fr) Derives de pyridinyl amino pyrimidine utilises dans le traitement des troubles de l'hyperproliferation
US20100063112A1 (en) Polymorph iii of 4-[4-(amino)-3-fluorophenoxy]-n-methylpyridine-2-carboxamide
US20100113533A1 (en) Polymorph II of 4-[4-(Amino)-3- Fluorophenoxy]-N-Methylpyridine-2-Carboxamide
WO2004110989A1 (fr) Derives de n-hydroxy-7-(arylamino)heptanamide utiles pour traiter des maladies hyperproliferatives
JP4709757B2 (ja) 過剰増殖性障害の処置に有用なベンゾフラン誘導体
US20090143412A1 (en) Furopyridine and furopyrimidine derivatives for the treatment of hyper-proliferative disorders
EP2056817A1 (fr) Dérivés de benzofurane et de benzothiophène utiles dans le traitement de cancers du système nerveux central
WO2004094376A1 (fr) Acides hydroxamiques utilises pour traiter des troubles d'hyperproliferation
WO2004039359A2 (fr) Methode d'utilisation de derives de pyrimidine dans le traitement de troubles hyperproliferatifs
US20060142295A1 (en) Method of treating cancer with quinolone carboxylic acid derivatives
WO2005087778A1 (fr) Derives de furopyridine tricycliques utiles dans le traitement de maladies hyperproliferatives
US20070105851A1 (en) Indolyl-thienopyrazinone derivatives useful for treating hyperproliferative disorders and diseases associated with angiogenesis

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)
122 Ep: pct application non-entry in european phase