WO2006029850A1 - Hydrazone derivatives and their use as beta secretase inhibitors - Google Patents

Hydrazone derivatives and their use as beta secretase inhibitors Download PDF

Info

Publication number
WO2006029850A1
WO2006029850A1 PCT/EP2005/009902 EP2005009902W WO2006029850A1 WO 2006029850 A1 WO2006029850 A1 WO 2006029850A1 EP 2005009902 W EP2005009902 W EP 2005009902W WO 2006029850 A1 WO2006029850 A1 WO 2006029850A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
cycloalkyl
aryl
compound according
substituted
Prior art date
Application number
PCT/EP2005/009902
Other languages
French (fr)
Inventor
Benno Schindelholz
Gerard Schmid
Alessandro Brigo
Dragana Milas
Gabriel Garcia
Original Assignee
The Genetics Company, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Genetics Company, Inc. filed Critical The Genetics Company, Inc.
Priority to JP2007530679A priority Critical patent/JP2008513364A/en
Priority to CA002579472A priority patent/CA2579472A1/en
Priority to EP05787258A priority patent/EP1791818A1/en
Publication of WO2006029850A1 publication Critical patent/WO2006029850A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with 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
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C07D213/77—Hydrazine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • 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
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D409/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/167—Purine radicals with ribosyl as the saccharide radical

Definitions

  • the present invention relates to novel hydrazone derivatives and the use of such hydrazone derivatives as beta-secretase inhibitors.
  • AD Alzheimer's disease
  • AD ⁇ -amyloid precursor protein
  • ⁇ -APP ⁇ -amyloid precursor protein
  • BACE beta-Amyloid Converting Enzyme
  • R 3 is selected from the group consisting of H, methyl and hydroxyalkyl
  • Z 1 and Z 2 are selected independently from one an ⁇ other from the group consisting of substituted or unsubstituted phenyl, naphtyl, pyridinyl, pyrazolyl, pyrimidinyl, pyrazid- inyl, quinolinyl, iso-quinolinyl, coumarinyl, indolyl, thia- zolyl and thiophenyl groups bearing substituents n R 1 and m R 2 ,
  • R 1 and R 2 which may be the same or are different from one another are selected from the group consisting of H, alkyl, cycloalkyl, -CO 2 R 4 , -CONHR 4 , -CR 4 O, -SO 2 R 4 , -NR 4 -CO-R 4 , alkoxy, alkylthio, -OH, -0-aryl, -0-cycloalkyl, -S-aryl, -S-cycloalkyl, hydroxyalkyl, halogen, haloalkyl, haloalkoxy, -CN, -NO 2 , hy- droxyalkylamine, aminoalkyl, alkylamine, aryl, heteroaryl and sulfonamide,
  • R 4 is selected from the group consisting of H, C 1 to C 6 branched or unbranched alkyl, aryl, cycloalkyl, alkoxy, hetero- cycloalkyl, -OH, -0-aryl, -0-alkyl, -0-cycloalkyl, aminoalkyl, alkylamine, aryl and heteroaryl,
  • n and m are the numbers of substituents R 1 and R 2 in Z 1 and Z 2 , respectively, which are in a range between 0 and 5,
  • R 1 and/or R 2 may form a fused aromatic or a carbocyclic or hetero ⁇ cyclic ring system
  • Zi and Z 2 are selected independently from one another from the group consisting of substituted or unsubstituted cyclic and acyclic alkyl, phenyl, naphthyl, pyridinyl, pyrrolyl, pyra- zolyl, pyrimidinyl, pyrazidinyl, quinolinyl, iso-quinolinyl, coumarinyl, indolyl, triazinyl (comprising 1,2,4 and 1,3,5 tri- azinyl) , imidazolyl, thiazolyl, thiophenyl and oxazolyl groups bearing substituents (Ri) n and (R 2 ) m , wherein the number of substituents in Z 1 and Z 2 , (Ri) n and (R 2 ) m is in a range between 0 and 5 and
  • R 1 , R 2 are selected from the group consisting of H, alkyl, cycloalkyl, -CO 2 R 4 , -CONHR 4 , -CR 4 O, -SO 2 R 4 , -NR 4 -CO-R 4 , alkoxy, alkylthio, -OH, -SH, -0-aryl, -0-cycloalkyl, -S-aryl, -S- cycloalkyl, hydroxyalkyl, halogen, haloalkyl, haloalkoxy, CN, NO 2 , hydroxyalkylamine, aminoalkyl, alkylamine, aryl or het- eroaryl, sulfone and sulfonamide
  • R x and R 2 may be the same or different from one another
  • R 1 and/or R 2 may form a fused aromatic or a carbocyclic or heterocyclic ring system
  • R 3 is selected from the group consisting of H, C 1 to C 6 branched or unbranched alkyl, aryl, heteroaryl; haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocycloalkyl.
  • R 4 is selected from the group consisting of H, C 1 to C 6 branched or unbranched alkyl, aryl, cycloalkyl, alkoxy, hetero ⁇ cycloalkyl, -OH, -0-aryl, -0-alkyl, -0-cycloalkyl, aminoalkyl, alkylamine, aryl or heteroaryl;
  • hydrazone derivatives which act as beta-secretase inhibitors having the general formula I
  • R 3 is selected from the group consisting of H, methyl and hydroxyalkyl
  • Zi and Z 2 are selected independently from one an ⁇ other from the group consisting of substituted or unsubstituted phenyl, naphtyl, pyridinyl, pyrazolyl, pyrimidinyl, pyrazid- inyl/ quinolinyl, iso-quinolinyl, coumarinyl, indolyl, thia- zolyl and thiophenyl groups bearing substituents n R 1 and m R 2 ,
  • Ri and R 2 which may be the same or are different from one another are selected from the group consisting of H, alkyl, cycloalkyl, -CO 2 R 4 , -CONHR 4 , -CR 4 O, -SO 2 R 4 , -NR 4 -CO-R 4 , alkoxy, alkylthio, -OH, -0-aryl, -0-cycloalkyl, -0-alkyl-aryl, -S-aryl, -S-cycloalkyl, hydroxyalkyl, halogen, haloalkyl, haloalkoxy, - CN, -NO 2 , hydroxyalkylamine, aminoalkyl, alkylamine, aryl, het- eroaryl and sulfonamide,
  • R 4 is selected from the group consisting of H, C 1 to Cs branched or unbranched alkyl, aryl, cycloalkyl, alkoxy, hetero- cycloalkyl, -OH, -0-aryl, -0-alkyl, -O-cycloalkyl, aminoalkyl, alkylamine, aryl and heteroaryl,
  • n and m are the numbers of substituents R 1 and R 2 in Z x and Z 2 , respectively, which are in a range between 0 and 5,
  • Ri and/or R 2 may form a fused aromatic or a carbocyclic or hetero- cyclic ring system, or a salt, or a physiologically functional derivative, or a prodrug thereof,
  • salts are, for example, alkali metal salts, in par ⁇ ticular sodium and potassium salts, or ammonium salts but not lim- ited thereto.
  • R 4 is selected from the group consisting of H, C 1 to C 4 branched or unbranched alkyl, aryl, cycloalkyl, alkoxy, heterocycloalkyl, -OH, -0-aryl, -0-alkyl, -O-cycloalkyl, aminoalkyl, alkylamine., aryl and heteroaryl.
  • Z x is a substituted phenyl group which is in a still more preferred embodiment substituted by at least one halogen atom or at least one hydroxyl group like in the examples no. 3, 18, 19, 20, 21, 23-26, 28-31, 33, 35, 39, 40, 46, 47, 55, 57-60, 63, 66-68, 75-77, 86-88, 91-96, 98, 100-104, 108, 111, 113, 114, 118 and 119.
  • Zi is a substi ⁇ tuted phenyl group which is substituted by at least two halogen at ⁇ oms and one hydroxyl group and in another preferred embodiment of the invention the hydroxyl group is in o-position relative to the bonding position of the hydrazone motif.
  • Zi is a sub ⁇ stituted phenyl group which bears at least a substituted or unsub- stituted aryl or heteroaryl ring or one or two terbutyl groups.
  • the phenyl group (Zl) is substi ⁇ tuted by another phenyl or heteroaryl group which are directly linked to the phenyl group (Zl) or via an ether bond.
  • the phenyl group is part of a fused ring sys ⁇ tem.
  • Zi is a substituted phenyl group which is in a still more preferred embodiment substituted by at least one halogen atom or at least one hydroxy group.
  • Zi bears two or three substituents which may be the same or different from one another, preferentially one substituent is in o-position rela- tive to the bonding position of the hydrazone motif.
  • Z 2 is selected from the group con ⁇ sisting of substituted or unsubstituted phenyl, pyridinyl and pyrimidinyl groups.
  • Z 2 is phenyl group which is pref- erably substituted by a benzyl group that is linked to the phenyl group via an ether bond like in the examples no. 4-6, 18-21 and 65.
  • the benzyl group which is linked to the phenyl group via an ether bond is a substi- tuted or unsubstituted benzyloxy group.
  • Z 2 is pyrimidyl ring bearing a substituted or unsubstitued cycloalkyl group or a disubstituted amino group like in the examples no. 3, 31, 74, 76-84, 86-102, 105- 110 and 112.
  • Z 2 is a pyridyl ring bearing a trifluoromethyl group, like in the examples no. 114-118.
  • Z 2 is an unsubstituted phenyl group.
  • Z 2 is a phenyl group bearing at least one halogen substituent.
  • Z 2 is a phenyl group bearing at least two halogen substituents, which may be the same or different from one another.
  • Z 2 is a phenyl group bearing at least one substituent selected from the group consisting of methyl, trifluoromethyl, hydroxy, carboxyl or an ether group which is in a still more preferred embodiment a substituted or un ⁇ substituted benzyloxy group.
  • one substituent in Z 2 is in o- position relative to the bonding position of the hydrazone motif. Additionally, in a further preferred embodiment the compound has one of the following formulas
  • the invention further relates to a compound of the formula
  • the invention further relates to the use of the compounds according to the invention as a medicament.
  • the invention further relates to the use of the compounds according to the invention for the manufacture of a pharmaceutical composition for the treatment or prevention of a condition or disorder which is mediated by beta-secretase.
  • the compounds according to the invention are useful as a medicament, especially as beta-secretase inhibitors.
  • Beta-secretase is inhibited very effectively and the compounds ac ⁇ cording to the invention have IC50 values of less than 120 ⁇ M, more preferred of less than 100 ⁇ M, still more preferred less than 50 ⁇ M and most preferred less than 20 ⁇ M.
  • the most potent compounds ac ⁇ cording to the invention have IC50 values of less than 10 ⁇ M, more preferred of less than 8 ⁇ M and most preferred less than 6 ⁇ M like for example compounds no. 60, 61, 74-81.
  • the invention further relates to the use of the compounds according to the invention for the manufacture of a pharmaceutical composition to inhibit the formation of beta-amyloid peptides from the amyloid precursor protein APP.
  • the compounds according to the invention are well suited for the inhibition of the formation of beta-amyloid pep ⁇ tides from the amyloid precursor protein APP. Therefore, the com ⁇ pounds according to the invention are suitable for the manufacture of a pharmaceutical composition for the treatment or prevention of conditions or diseases relying on beta-amyloid peptide formation as Alzheimer's disease, Down syndrome, cerebral amyloid angiopathy, He ⁇ reditary Cerebral Haemorrhage with Amylosis of the Dutch type (HCHWA-D) and other degenerative dementia.
  • the invention further relates to the use of the compounds according to the invention for the manufacture of a pharmaceutical composition for the treatment or prevention of Alzheimer's disease, neurodegen- eration, memory and attention deficits, dysfunction of cellular pro- liferation, or other disorders associated with or responsive to the inhibition of beta-amyloid peptides .
  • the invention further relates to the use of the compounds according to the invention for the manufacture of a pharmaceutical composition for the treatment or prevention of conditions or diseases selected from the group consisting of Alzheimer's disease, Down syndrome, cerebral amyloid angiopathy, Hereditary Cerebral Haemorrhage with Amylosis of the Dutch type (HCHWA-D) and other degenerative dementia characterized by beta-amyloid deposits.
  • a pharmaceutical composition for the treatment or prevention of conditions or diseases selected from the group consisting of Alzheimer's disease, Down syndrome, cerebral amyloid angiopathy, Hereditary Cerebral Haemorrhage with Amylosis of the Dutch type (HCHWA-D) and other degenerative dementia characterized by beta-amyloid deposits.
  • the invention further relates to a pharmaceutical composition com ⁇ prising a compound according to the invention or a pharmaceutically acceptable salt thereof.
  • the pharmaceu- -tical composition comprises a pharmaceutically acceptable carrier, diluent, and/or excipient.
  • the compounds according to the invention may be administered alone or in the form of a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound according to the invention or a pharmaceutically active salt thereof may further com ⁇ prise at least one pharmaceutically acceptable carrier, diluent or excipient. It is understood that in specific embodiments also fur ⁇ ther active compounds are contained within the composition.
  • the compounds according to the invention may be formulated for topi ⁇ cal, oral, transdermal, parenteral, sublingual, intranasal, in- trathecal, rectal, inhalative or intravenous administration in form of e.g. tablets, gel, capsules, patches, ointments, creams.
  • Par ⁇ enteral delivery can be carried out by depot, syringe, ampoule or vial.
  • the compounds of the invention may thus be placed into the form of phar ⁇ maceutical compositions and unit dosages thereof, and in such form may be employed as solids, liquids or in the form of sterile in ⁇ jectable solutions.
  • a solid carrier is used, the preparation may be tableted, placed in a hard gelatine capsule in powder or pellet form, or in form of a troche or lozenge.
  • the solid carrier may con ⁇ tain conventional excipients such as binding agents, tableting lu ⁇ bricants, fillers, disintegrants, wetting agents and the like. Tab ⁇ lets may be film coated by conventional techniques.
  • the preparation may be in form of syrup, emul ⁇ sion, soft gelatine capsule, sterile vehicle for injection, an aque ⁇ ous or non-aqueous liquid suspension, or may be a dry product for reconstitution with water or other suitable vehicles before use.
  • Liquid preparations may contain conventional additives such as sus- pending agents, emulsifying agents, wetting agents, non-aqueous ve ⁇ hicle (including edible oils), preservatives, as well as flavouring and /or colouring agents.
  • a vehicle normally will comprise sterile water, at least in large part, al ⁇ though saline solutions, glucose solutions and like may be utilized.
  • Injectable suspensions also may be used, in which case conventional suspending agents may be employed.
  • Conventional preservatives, buff ⁇ ering agents and the like also may be added to the parenteral dosage forms. Administration, however, can also be carried out rectally, e.g., in the form of suppositories, or vaginally, e.g. in the form of pessaries, tampons, creams, or percutaneously, e.g., in the form of ointments, creams or tinctures.
  • a suitable dose of compounds or pharmaceutical compositions accord ⁇ ing to the invention for a mammal, especially humans, suffering from, or likely to suffer from any condition as described herein is an amount of active ingredient from about O.l ⁇ g/kg (NB: there are few example of compounds that are delivered at lower dosis, eg some hormone) to 500mg/kg body weight.
  • the dose may be in the range of O.l ⁇ g/kg to 100mg/kg body weight for in ⁇ travenous administration.
  • the active ingredient will preferably be administered in equal doses from one to four times daily.
  • the com ⁇ pounds of Formula (I) can also be used in the form of a precursor (prodrug) or a suitably modified form that releases the active com ⁇ pound in vivo.
  • the administered dose will be gradually in ⁇ creased until the optimal effective dosage for the treated host is determined.
  • the optimal administered dosage will be determined by a physician or others skilled in the art, depending on the relevant circumstances including the condition to be treated, the choice of compound to be administered, the route of administration, the sex, age, weight, and the specific response of the treated individual in respect to the severity of the individual's symptoms.
  • compositions are prepared by conventional tech ⁇ niques appropriate to the desired preparation containing appropriate amounts of the active ingredient, i.e., the compounds of the present invention.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional pro- portions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the compounds of the invention are prepared by processes known in the art for the synthesis of hydrazones . Especially preferred is the reaction of an aldehyde or ketone of Formula II with a compound of Formula III to obtain the hydrazone derivative of general formula I according to the invention, whereby the substituents Z 1 , Z 2 and R 3 are defined as in the foregoing.
  • alkyl group denotes a linear or branched Ci-C 6 -alkyl, preferably a linear or branched chain of Ci-C 6 - atoms, a linear or branched Ci-C 6 -alkenyl or a linear or branched Ci- C ⁇ -alkinyl group, which can optionally be substituted by one or more substituents R 3 , wherein R 3 and R 4 are defined as above.
  • Ci-C ⁇ alkyl denotes in particular methyl, ethyl, propyl, butyl, pentyl, hexyl or the corresponding alkene and alkine homologues.
  • an alkyl group denotes a linear or branched d-C 4 -alkyl, a linear or branched Ci-C 4 -alkenyl group, which can be optionally be substituted by one or more substituents, which are defined as the residues R 3 or R 4 as men ⁇ tioned above.
  • C 1 -C 4 alkyl denotes in particular methyl, ethyl, pro ⁇ pyl, isopropyl, butyl, isobutyl, fc-butyl or the corresponding alkene homologues .
  • Ci-C 4 -alkyl and Ci-C 4 -alkenyl residue may include not limited to the following groups
  • a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to seven carbon atoms, wherein one or more of the carbon atoms in the ring can be substi ⁇ tuted by a group X, wherein X is selected from the group consisting of N, S, 0, SO, SO 2 , NR 4 and CO; the C 4 -C 7 -cycloalkyl residue may be selected from the group comprising -cyclo-C 3 H 5 , -cyclo-C 4 H 7 , -cyclo- C 5 H 9 , -CyCIo-C 6 H 11 , -cyclo-C 7 H 13 , the cycloalkyl group can optionally be substituted by one or more substituents R 3 , wherein R 3 and R 4 are defined as in the foregoing.
  • a cycloalkyl group de ⁇ notes a non-aromatic ring system containing three to six carbon at ⁇ oms, wherein one or more of the carbon atoms in the ring can be sub ⁇ stituted by a group X, wherein X is selected from the group consist- ing of N, S, 0, SO, SO 2 , NR 4 and CO; the C 4 -C 6 -cycloalkyl residue may be selected from the group comprising -cyclo-C 3 H 5 , -cyclo-C 4 H 7 , - cyclo-C 5 H 9 , -cyclo-C ⁇ Hu, the cycloalkyl group can optionally be sub ⁇ stituted by one or more substituents which are optionally defined as the residues R 3 and/or R 4 as stated in the foregoing.
  • alkoxy group denotes an 0-alkyl group, the alkyl group being de ⁇ fined as above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy group or a pentoxy group.
  • a haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably a -C(Rs) 3 , -CR 5 (R 5 ) 2 , -CR 5 (R 5 )R 5 , - C 2 (Rs) 5 , -CH 2 -C(Rs) 3 , -CH 2 -CR 5 (R 5 ) 2 , -CH 2 -CR 5 (R 5 )R 5 , -C 3 (R 5 ) 7 or -C 2 H 4 - C(Rs) 3 , wherein R 5 represents F, Cl, Br or I, preferably F or Cl and wherein R 5 may be the same or different.
  • a haloalkyl group denotes an alkyl group which is substituted by one to three halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably a -C(Rs) 3 , -CH(Rs) 2 , -CH 2 -CH(R 5 ) 2 , -CH 2 -C(R S ) 3 , - C 2 H 4 -CH(R 5 ) 2 or -C 2 H 4 -C (R 5 ) 3 , wherein R 5 represents F, Cl, Br or I, preferably F or Cl and wherein R 5 may be the same or different from one another.
  • a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group be ⁇ ing defined as above.
  • a haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyloxy group is preferably a -OC(R 5 ) 3 , -OCR 5 (R 5 )2, -
  • R 5 OCR 5 (R 5 )R 5 , -OC 2 (Rs) 5 , -OCH 2 -C(Rs) 3 , -OCH 2 -CR 5 (RS) 2 , -OCH 2 -CR 5 (R 5 )R 5 , - OC 3 (R 5 )v or -OC 2 H 4 -C(Rs) 3 , wherein R 5 represents F, Cl, Br or I, pref ⁇ erably F or Cl and wherein R 5 may be the same or different.
  • a haloalkoxy group denotes an alkoxy group which is substi- tuted by one to three halogen atoms, the alkyl group being as de ⁇ fined above; the haloalkyloxy group is preferably a -OC (R 5 )3, -OCH 2 - C(Rs) 3 , -OC 2 H 4 -C (R 5 ) 3 , wherein R 5 represents F, Cl, Br or I and wherein R 5 may be the same or different from one another.
  • a hydroxyalkylamino group denotes an (HO-alkyl) 2 -N- group or
  • a hydroxylakylamino group denotes an (0H-alkyl) 2 -N- group, HO-alkyl-NH- group or HO-alkyl-NR 4 - group, the alkyl and R 4 groups being defined as above.
  • a halogen group denotes chlorine, bromine, fluorine or iodine.
  • An aryl group denotes preferably an aromatic group having five to ten carbon and/or heteroatoms, which can optionally be substituted by one or more substituents wherein Ri and R 2 being as defined above.
  • an aryl group denotes an aromatic group having five to six carbon and/or heteroatoms, which can optionally be substi- tuted by one or more substituents which are optionally being defined as the residues Ri and/or R 2 as mentioned above.
  • a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom like O 7 N, S.
  • This heterocyc- lie group can be fused to another ring.
  • this group can be selected from an oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol- 2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, l,2,4-oxadiazol-3-yl, 1,2, 4-oxadiazol-5-yl, 1,2,4- thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2, 5-oxadiazol-3-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrrolyl, 2-pyr
  • a heteroaryl group denotes a 5- or 6-membered het ⁇ erocyclic group which contains at least one heteroatom like 0, N, S and is selected from the group consisting of a thiazol-2-yl, thia- zol-4-yl, thiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1, 2,4-thiadiazol-5- yl, 1,2, 5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 2-furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4- pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, in ⁇ dolyl, benzimidazolyl, benzothi
  • a hydrazine compound according to formula III ( ⁇ 100mg) , an alde ⁇ hyde according to general formula II (1 equivalent) , ca. 100 mg of Amberlyst 15 ion-exchange resin and molecular sieves in tetrahydro- furan (4ml) were placed in a G-12 flask. The reaction mixture was heated to reflux for 4 h. A TLC analysis (Hexane/EtOAc:1/1) showed that all hydrazine was reacted. The reaction mixture was filtered and the solution concentrated to a small volume (ca. 0.5 mL) . The resulting residue was suspended in methanol (ca. 1.5 mL) , sonicated, centrifuged and decanted. This process was repeated a second time. The white-yellowish solid formed was dried under vacuum.
  • Table 1 List of specific compounds according to general formula I HPLC /MS
  • One useful assay to test the inhibitory acitivity of the beta- secretase is based on the fluorescence resonance energy transfer (FRET) technology to monitor cleavage of a peptide substrate.
  • FRET fluorescence resonance energy transfer
  • An exemplary assay for the analysis of the inhibition of beta- secretase activity utilizes human embryonic kidney cell line HEK293
  • transgenic cell lines for example CHO or SH-SY5Y could be used as well.
  • the cells are incubated in the presence/absence of the inhibitory compound (diluted in DMSO; final concentration of DMSO: 0.05%) at the desired concentration, generally up to 100 ⁇ M.
  • conditioned media is analyzed for beta- secretase activity, for example, by analysis of cleavage fragments.
  • 25 A beta can be analyzed by immunoassay, using specific detection an ⁇ tibodies (HS40 ABeta kit from The Genetics Company) .
  • the enzymatic activity is measured in the presence and abs'ence of the compound in ⁇ hibitors to demonstrate specific inhibition of beta-secretase medi ⁇ ated cleavage of APP substrate.
  • Example 4 Determination of compound in the brain 0
  • mice C57/bl6 mice, designated "wt" mice, were obtained.
  • the mice were -treated with the phenylhydrazone Nr. 29. Dosing was administered ei- ther intraperitoneally or orally. The oral dose was administered via oral gavage. Intraperitoneally-treated animals received a single in ⁇ jection, or were dosed once or twice a day up to 8 days. In addi ⁇ tion, a group of age-matching wt mice were treated with the carrier vehicle only.
  • animal models can be used to screen for inhibition of beta- secretase activity.
  • animal models useful in the inven ⁇ tion include, but are not limited to, mouse, guinea pig, dog, and the like.
  • the animals used can be wild type, transgenic, or knockout models.
  • mammalian models can express mutation in APP, ⁇ such as APP695-SW and the like described herein. Examples of trans- genie non-human mammalian models are described in Hsiao et al. , 1996, Science 274, 99-102 and Kawarabayshi et al. , 2001, J Neuroscie 21, 372-381.
  • Tg2576 mice prepared as described in Hsiao et al. , 1996, Science 274, 99-102 are useful to analyze in vivo suppression of A beta release in the presence of putative inhibitory compounds.
  • Transgenic animals are administered an amount of the BACE inhibitor formulated in a carrier suitable for the chosen mode of administra- tion, as for example described in Chang et al. , 2004, J. Neurochem. 89, 1409-1416.
  • Control animals are untreated, treated with vehicle, or treated with an inactive compound.
  • Administration can be acute, i.e., single dose or multiple dose in one day, or can be chronic, i.e., dosing is repeated daily for a period of days.
  • brain tissue, cerebral fluid or blood is obtained from se ⁇ lected animals and analyzed for the presence of APP cleavage pep ⁇ tides, including A beta, for example, by immunoassay using specific antibodies for A beta detection.
  • treated transgenic animals e.g. Tg2576 mice
  • APP induced phenotypes as for example described in Hsiao et al. , 1996, Science 274, 99-102.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Neurosurgery (AREA)
  • Medicinal Chemistry (AREA)
  • Neurology (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Hospice & Palliative Care (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Indole Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to compounds having the general formula (I) wherein R3 is selected from the group consisting of H, methyl and hydroxyalkyl, and wherein Z1 and Z2 are selected independently from one another from the group consisting of substituted or un­substituted phenyl, naphtyl, pyridinyl, pyrazolyl, pyramidinyl, pyrazidinyl, quinolinyl, iso-quinolinyl, coumarinyl, indolyl, thiazolyl and thiophenyl groups bearing substituents n R1 and m R2, wherein R1 and R2 which may be the same or are different from one another are selected from the group consisting of H, alkyl, cycloalkyl, -C02R4, -CONHR4, -CR4O, -SO2R4, -NR4-CO-R4, alkoxy, al­kylthio, -OH, -O-aryl, -O-cycloalkyl, -S-aryl, -S-cycloalkyl, hy­droxyalkyl, halogen, haloalkyl, haloalkoxy, -CN, -NO2, hydroxyal­ kylamine, aminoalkyl, alkylamine, aryl, heteroaryl and sulfona­mide, wherein R4 is selected from the group consisting of H, C1 to C6 branched or unbranched alkyl, aryl, cycloalkyl, alkoxy, hetero­cycloalkyl, -OH, -O-aryl, -O-alkyl, -O-cycloalkyl, aminoalkyl, alkylamine, aryl and heteroaryl, and wherein n and m are the num­bers of the substituents R1 and R2 in Z1 and Z2, respectively, which are in a range between 0 and 5, with the proviso that if n and m are integers higher than 2, R1 and/or R2 may form a fused aromatic or a carbocyclic or heterocyclic ring system, or a salt, or a physiologically functional derivative, or a prodrug thereof.

Description

HYDRAZONE DERIVATIVES AND THEIR USE AS BETA SECRETASE INHIBITORS
' The present invention relates to novel hydrazone derivatives and the use of such hydrazone derivatives as beta-secretase inhibitors.
Alzheimer's disease (AD) is a very common form of dementia in humans and affects parts of the brain that control inter alia memory and language.
The occurrence of AD is associated with protein clusters in the brain, also termed "amyloid plaques" and "neurofibrillary tangles". These protein clusters comprise the β-amyloid precursor protein (β- APP) . β-APP is degraded by the β-Amyloid Converting Enzyme (BACE, also known under the name of beta-secretase) to produce β-amyloid peptide which is the main component of these clusters of amyloid plaques. It has been found out that the activity of BACE is an early step in the pathogenesis pathway for AD.
It has therefore been an object of the present invention to provide new compounds which serve as inhibitors for BACE and are thus thera¬ peutically useful in the treatment of AD.
This object is solved by providing hydrazone derivatives which act as beta-secretase inhibitors having the general formula I
Figure imgf000002_0001
wherein R3 is selected from the group consisting of H, methyl and hydroxyalkyl, and wherein Z1 and Z2 are selected independently from one an¬ other from the group consisting of substituted or unsubstituted phenyl, naphtyl, pyridinyl, pyrazolyl, pyrimidinyl, pyrazid- inyl, quinolinyl, iso-quinolinyl, coumarinyl, indolyl, thia- zolyl and thiophenyl groups bearing substituents n R1 and m R2,
wherein R1 and R2 which may be the same or are different from one another are selected from the group consisting of H, alkyl, cycloalkyl, -CO2R4, -CONHR4, -CR4O, -SO2R4, -NR4-CO-R4, alkoxy, alkylthio, -OH, -0-aryl, -0-cycloalkyl, -S-aryl, -S-cycloalkyl, hydroxyalkyl, halogen, haloalkyl, haloalkoxy, -CN, -NO2, hy- droxyalkylamine, aminoalkyl, alkylamine, aryl, heteroaryl and sulfonamide,
wherein R4 is selected from the group consisting of H, C1 to C6 branched or unbranched alkyl, aryl, cycloalkyl, alkoxy, hetero- cycloalkyl, -OH, -0-aryl, -0-alkyl, -0-cycloalkyl, aminoalkyl, alkylamine, aryl and heteroaryl,
wherein n and m are the numbers of substituents R1 and R2 in Z1 and Z2, respectively, which are in a range between 0 and 5,
with the proviso that if n and m are integers higher than 2, R1 and/or R2 may form a fused aromatic or a carbocyclic or hetero¬ cyclic ring system,
or a salt, or a physiologically functional derivative, or a prodrug thereof,
whereas the compounds
Figure imgf000004_0001
are not comprised within formula I.
The object is further solved by providing hydrazone derivatives which act as beta-secretase inhibitors having the general formula I
Figure imgf000004_0002
wherein
Zi and Z2 are selected independently from one another from the group consisting of substituted or unsubstituted cyclic and acyclic alkyl, phenyl, naphthyl, pyridinyl, pyrrolyl, pyra- zolyl, pyrimidinyl, pyrazidinyl, quinolinyl, iso-quinolinyl, coumarinyl, indolyl, triazinyl (comprising 1,2,4 and 1,3,5 tri- azinyl) , imidazolyl, thiazolyl, thiophenyl and oxazolyl groups bearing substituents (Ri)n and (R2)m, wherein the number of substituents in Z1 and Z2 , (Ri)n and (R2)m is in a range between 0 and 5 and
R1, R2are selected from the group consisting of H, alkyl, cycloalkyl, -CO2R4, -CONHR4, -CR4O, -SO2R4, -NR4-CO-R4, alkoxy, alkylthio, -OH, -SH, -0-aryl, -0-cycloalkyl, -S-aryl, -S- cycloalkyl, hydroxyalkyl, halogen, haloalkyl, haloalkoxy, CN, NO2, hydroxyalkylamine, aminoalkyl, alkylamine, aryl or het- eroaryl, sulfone and sulfonamide
whereby, Rx and R2 may be the same or different from one another
and wherein in the case that n and m are integers higher than 2, R1 and/or R2 may form a fused aromatic or a carbocyclic or heterocyclic ring system
R3 is selected from the group consisting of H, C1 to C6 branched or unbranched alkyl, aryl, heteroaryl; haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocycloalkyl.
R4 is selected from the group consisting of H, C1 to C6 branched or unbranched alkyl, aryl, cycloalkyl, alkoxy, hetero¬ cycloalkyl, -OH, -0-aryl, -0-alkyl, -0-cycloalkyl, aminoalkyl, alkylamine, aryl or heteroaryl;
and wherein compound
Figure imgf000005_0001
is not comprised within formula I,
or a salt, or a physiologically functional derivative, or a prodrug thereof. The object is further solved by providing hydrazone derivatives which act as beta-secretase inhibitors having the general formula I
Figure imgf000006_0001
wherein R3 is selected from the group consisting of H, methyl and hydroxyalkyl,
and wherein Zi and Z2 are selected independently from one an¬ other from the group consisting of substituted or unsubstituted phenyl, naphtyl, pyridinyl, pyrazolyl, pyrimidinyl, pyrazid- inyl/ quinolinyl, iso-quinolinyl, coumarinyl, indolyl, thia- zolyl and thiophenyl groups bearing substituents n R1 and m R2,
wherein Ri and R2 which may be the same or are different from one another are selected from the group consisting of H, alkyl, cycloalkyl, -CO2R4, -CONHR4, -CR4O, -SO2R4, -NR4-CO-R4, alkoxy, alkylthio, -OH, -0-aryl, -0-cycloalkyl, -0-alkyl-aryl, -S-aryl, -S-cycloalkyl, hydroxyalkyl, halogen, haloalkyl, haloalkoxy, - CN, -NO2, hydroxyalkylamine, aminoalkyl, alkylamine, aryl, het- eroaryl and sulfonamide,
wherein R4 is selected from the group consisting of H, C1 to Cs branched or unbranched alkyl, aryl, cycloalkyl, alkoxy, hetero- cycloalkyl, -OH, -0-aryl, -0-alkyl, -O-cycloalkyl, aminoalkyl, alkylamine, aryl and heteroaryl,
wherein n and m are the numbers of substituents R1 and R2 in Zx and Z2, respectively, which are in a range between 0 and 5,
with the proviso that if n and m are integers higher than 2, Ri and/or R2 may form a fused aromatic or a carbocyclic or hetero- cyclic ring system, or a salt, or a physiologically functional derivative, or a prodrug thereof,
whereas the compounds
Figure imgf000007_0001
are not comprised within formula I.
It is understood that general formula I comprises the corresponding isomeric forms, i.e. the E and the Z form thereof.
Examples of such salts are, for example, alkali metal salts, in par¬ ticular sodium and potassium salts, or ammonium salts but not lim- ited thereto.
It is understood that the compounds according to the invention may contain one or more asymmetric carbon atoms in R or S configuration and thus the compounds may be present as racemates or racemic mix¬ tures, pure enantiomers, diastereomic mixtures etc. In a preferred embodiment, R4 is selected from the group consisting of H, C1 to C4 branched or unbranched alkyl, aryl, cycloalkyl, alkoxy, heterocycloalkyl, -OH, -0-aryl, -0-alkyl, -O-cycloalkyl, aminoalkyl, alkylamine., aryl and heteroaryl.
In another preferred embodiment, Zx is a substituted phenyl group which is in a still more preferred embodiment substituted by at least one halogen atom or at least one hydroxyl group like in the examples no. 3, 18, 19, 20, 21, 23-26, 28-31, 33, 35, 39, 40, 46, 47, 55, 57-60, 63, 66-68, 75-77, 86-88, 91-96, 98, 100-104, 108, 111, 113, 114, 118 and 119.
In a further preferred embodiment of the invention Zi is a substi¬ tuted phenyl group which is substituted by at least two halogen at¬ oms and one hydroxyl group and in another preferred embodiment of the invention the hydroxyl group is in o-position relative to the bonding position of the hydrazone motif.
Aditionally, in a preferred embodiment of the invention Zi is a sub¬ stituted phenyl group which bears at least a substituted or unsub- stituted aryl or heteroaryl ring or one or two terbutyl groups.
In another preferred embodiment, the phenyl group (Zl) is substi¬ tuted by another phenyl or heteroaryl group which are directly linked to the phenyl group (Zl) or via an ether bond. In a further preferred embodiment, the phenyl group is part of a fused ring sys¬ tem.
In preferred embodiments, Zi is a substituted phenyl group which is in a still more preferred embodiment substituted by at least one halogen atom or at least one hydroxy group.
Further, in another preferred embodiment of the invention Zi bears two or three substituents which may be the same or different from one another, preferentially one substituent is in o-position rela- tive to the bonding position of the hydrazone motif. In another preferred embodiment Z2 is selected from the group con¬ sisting of substituted or unsubstituted phenyl, pyridinyl and pyrimidinyl groups.
In a further preferred embodiment, Z2 is phenyl group which is pref- erably substituted by a benzyl group that is linked to the phenyl group via an ether bond like in the examples no. 4-6, 18-21 and 65.
Further, in a preferred embodiment of the invention the benzyl group which is linked to the phenyl group via an ether bond is a substi- tuted or unsubstituted benzyloxy group.
In an additional preferred embodiment, Z2 is pyrimidyl ring bearing a substituted or unsubstitued cycloalkyl group or a disubstituted amino group like in the examples no. 3, 31, 74, 76-84, 86-102, 105- 110 and 112.
In a further preferred embodiment, Z2 is a pyridyl ring bearing a trifluoromethyl group, like in the examples no. 114-118.
Additionally, in another preferred embodiment Z2 is an unsubstituted phenyl group.
In another preferred embodiment Z2 is a phenyl group bearing at least one halogen substituent.
In a further preferred embodiment of the invention Z2 is a phenyl group bearing at least two halogen substituents, which may be the same or different from one another.
In another preferred embodiment of the invention Z2 is a phenyl group bearing at least one substituent selected from the group consisting of methyl, trifluoromethyl, hydroxy, carboxyl or an ether group which is in a still more preferred embodiment a substituted or un¬ substituted benzyloxy group.
In another preferred embodiment one substituent in Z2 is in o- position relative to the bonding position of the hydrazone motif. Additionally, in a further preferred embodiment the compound has one of the following formulas
Figure imgf000010_0001
The invention further relates to a compound of the formula
Figure imgf000010_0002
Other preferred compounds are those listed in table 1.
Other preferred compounds are those listed in table 2.
The invention further relates to the use of the compounds according to the invention as a medicament.
The invention further relates to the use of the compounds according to the invention for the manufacture of a pharmaceutical composition for the treatment or prevention of a condition or disorder which is mediated by beta-secretase. The compounds according to the invention are useful as a medicament, especially as beta-secretase inhibitors. Beta-secretase is inhibited very effectively and the compounds ac¬ cording to the invention have IC50 values of less than 120 μM, more preferred of less than 100 μM, still more preferred less than 50 μM and most preferred less than 20 μM. The most potent compounds ac¬ cording to the invention have IC50 values of less than 10 μM, more preferred of less than 8 μM and most preferred less than 6 μM like for example compounds no. 60, 61, 74-81.
The invention further relates to the use of the compounds according to the invention for the manufacture of a pharmaceutical composition to inhibit the formation of beta-amyloid peptides from the amyloid precursor protein APP. The compounds according to the invention are well suited for the inhibition of the formation of beta-amyloid pep¬ tides from the amyloid precursor protein APP. Therefore, the com¬ pounds according to the invention are suitable for the manufacture of a pharmaceutical composition for the treatment or prevention of conditions or diseases relying on beta-amyloid peptide formation as Alzheimer's disease, Down syndrome, cerebral amyloid angiopathy, He¬ reditary Cerebral Haemorrhage with Amylosis of the Dutch type (HCHWA-D) and other degenerative dementia.
The invention further relates to the use of the compounds according to the invention for the manufacture of a pharmaceutical composition for the treatment or prevention of Alzheimer's disease, neurodegen- eration, memory and attention deficits, dysfunction of cellular pro- liferation, or other disorders associated with or responsive to the inhibition of beta-amyloid peptides .
The invention further relates to the use of the compounds according to the invention for the manufacture of a pharmaceutical composition for the treatment or prevention of conditions or diseases selected from the group consisting of Alzheimer's disease, Down syndrome, cerebral amyloid angiopathy, Hereditary Cerebral Haemorrhage with Amylosis of the Dutch type (HCHWA-D) and other degenerative dementia characterized by beta-amyloid deposits.
The invention further relates to a pharmaceutical composition com¬ prising a compound according to the invention or a pharmaceutically acceptable salt thereof. In one preferred embodiment the pharmaceu- -tical composition comprises a pharmaceutically acceptable carrier, diluent, and/or excipient. The compounds according to the invention may be administered alone or in the form of a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound according to the invention or a pharmaceutically active salt thereof may further com¬ prise at least one pharmaceutically acceptable carrier, diluent or excipient. It is understood that in specific embodiments also fur¬ ther active compounds are contained within the composition.
The compounds according to the invention may be formulated for topi¬ cal, oral, transdermal, parenteral, sublingual, intranasal, in- trathecal, rectal, inhalative or intravenous administration in form of e.g. tablets, gel, capsules, patches, ointments, creams. Par¬ enteral delivery can be carried out by depot, syringe, ampoule or vial.
The compounds of the invention, together with a conventional adju¬ vant, carrier, or diluent, may thus be placed into the form of phar¬ maceutical compositions and unit dosages thereof, and in such form may be employed as solids, liquids or in the form of sterile in¬ jectable solutions. If a solid carrier is used, the preparation may be tableted, placed in a hard gelatine capsule in powder or pellet form, or in form of a troche or lozenge. The solid carrier may con¬ tain conventional excipients such as binding agents, tableting lu¬ bricants, fillers, disintegrants, wetting agents and the like. Tab¬ lets may be film coated by conventional techniques. If a liquid carrier is employed, the preparation may be in form of syrup, emul¬ sion, soft gelatine capsule, sterile vehicle for injection, an aque¬ ous or non-aqueous liquid suspension, or may be a dry product for reconstitution with water or other suitable vehicles before use. Liquid preparations may contain conventional additives such as sus- pending agents, emulsifying agents, wetting agents, non-aqueous ve¬ hicle (including edible oils), preservatives, as well as flavouring and /or colouring agents. For parenteral administration, a vehicle normally will comprise sterile water, at least in large part, al¬ though saline solutions, glucose solutions and like may be utilized. Injectable suspensions also may be used, in which case conventional suspending agents may be employed. Conventional preservatives, buff¬ ering agents and the like also may be added to the parenteral dosage forms. Administration, however, can also be carried out rectally, e.g., in the form of suppositories, or vaginally, e.g. in the form of pessaries, tampons, creams, or percutaneously, e.g., in the form of ointments, creams or tinctures.
A suitable dose of compounds or pharmaceutical compositions accord¬ ing to the invention for a mammal, especially humans, suffering from, or likely to suffer from any condition as described herein is an amount of active ingredient from about O.lμg/kg (NB: there are few example of compounds that are delivered at lower dosis, eg some hormone) to 500mg/kg body weight. For parenteral administration, the dose may be in the range of O.lμg/kg to 100mg/kg body weight for in¬ travenous administration. The active ingredient will preferably be administered in equal doses from one to four times daily. The com¬ pounds of Formula (I) can also be used in the form of a precursor (prodrug) or a suitably modified form that releases the active com¬ pound in vivo. Normally, the administered dose will be gradually in¬ creased until the optimal effective dosage for the treated host is determined. The optimal administered dosage will be determined by a physician or others skilled in the art, depending on the relevant circumstances including the condition to be treated, the choice of compound to be administered, the route of administration, the sex, age, weight, and the specific response of the treated individual in respect to the severity of the individual's symptoms.
The pharmaceutical compositions are prepared by conventional tech¬ niques appropriate to the desired preparation containing appropriate amounts of the active ingredient, i.e., the compounds of the present invention. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional pro- portions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The compounds of the invention are prepared by processes known in the art for the synthesis of hydrazones . Especially preferred is the reaction of an aldehyde or ketone of Formula II with a compound of Formula III to obtain the hydrazone derivative of general formula I according to the invention, whereby the substituents Z1, Z2 and R3 are defined as in the foregoing.
Figure imgf000014_0001
II III I A hydrazine of general formula III was reacted under appropriate conditions with an aldehyde or a ketone of general formula II under ion exchange resin catalysis and preferably at, but not limited to, room temperature to yield compound I.
In the compounds I and III of the reaction equation Z2 is preferably selected from the group consisting of substituted or unsubstituted phenyl, pyridinyl and pyrimidinyl groups .
The terms as used herein for the chemical entities are defined as follows:
An alkyl group, if not stated otherwise, denotes a linear or branched Ci-C6-alkyl, preferably a linear or branched chain of Ci-C6 - atoms, a linear or branched Ci-C6-alkenyl or a linear or branched Ci- Cδ-alkinyl group, which can optionally be substituted by one or more substituents R3, wherein R3 and R4 are defined as above. Ci-Cβ alkyl denotes in particular methyl, ethyl, propyl, butyl, pentyl, hexyl or the corresponding alkene and alkine homologues. Preferably, an alkyl group denotes a linear or branched d-C4-alkyl, a linear or branched Ci-C4-alkenyl group, which can be optionally be substituted by one or more substituents, which are defined as the residues R3 or R4 as men¬ tioned above. C1-C4 alkyl denotes in particular methyl, ethyl, pro¬ pyl, isopropyl, butyl, isobutyl, fc-butyl or the corresponding alkene homologues .
The Ci-C4-alkyl, Ci-C4-alkenyl and Ci-C4-alkinyl residue may include but is not limited to the following groups -CH3, -C2H5, -CH=CH2, -C≡CH, -C3H7, -CH (CH3) 2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡C-CH3, -CH2-C=CH, -C4H9, -CH2-CH (CH3) 2, -CH (CH3) -C2H5 , -CH2-CH (CH3) -CH3, -C(CH3)3, -C2H4-CH=CH2, -CH=CH-C2H5, -CH=C(CH3)2, -CH2- CH=CH-CH3, -CH2-C (CH3)=CH2, -C (CH3) =CH-CH3, -C (CH3) -CH=CH2, -CH=CH- CH=CH2, -C2H4-C=CH, -C=C-C2H5, -CH2-C=C-CH3, -C=C-CH=CH2, -CH=CH-C=CH, -C≡C-C≡CH.
Preferentially, the Ci-C4-alkyl and Ci-C4-alkenyl residue may include not limited to the following groups
-CH3, -C2H5, -CH=CH2, -C3H7, -CH(CH3)2, -CH2-CH=CH2, -C4H9, -CH2-CH(CH3)2, -CH(CH3) -C2H5, -CH2-CH(CH3) -CH3, -C(CH3J3-
A cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to seven carbon atoms, wherein one or more of the carbon atoms in the ring can be substi¬ tuted by a group X, wherein X is selected from the group consisting of N, S, 0, SO, SO2, NR4 and CO; the C4-C7-cycloalkyl residue may be selected from the group comprising -cyclo-C3H5, -cyclo-C4H7, -cyclo- C5H9, -CyCIo-C6H11, -cyclo-C7H13, the cycloalkyl group can optionally be substituted by one or more substituents R3, wherein R3 and R4 are defined as in the foregoing. Preferentially, a cycloalkyl group de¬ notes a non-aromatic ring system containing three to six carbon at¬ oms, wherein one or more of the carbon atoms in the ring can be sub¬ stituted by a group X, wherein X is selected from the group consist- ing of N, S, 0, SO, SO2, NR4 and CO; the C4-C6-cycloalkyl residue may be selected from the group comprising -cyclo-C3H5, -cyclo-C4H7, - cyclo-C5H9, -cyclo-CβHu, the cycloalkyl group can optionally be sub¬ stituted by one or more substituents which are optionally defined as the residues R3 and/or R4 as stated in the foregoing.
An alkoxy group denotes an 0-alkyl group, the alkyl group being de¬ fined as above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy group or a pentoxy group.
A haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably a -C(Rs)3, -CR5 (R5)2, -CR5 (R5)R5, - C2(Rs)5, -CH2-C(Rs)3, -CH2-CR5 (R5)2, -CH2-CR5(R5)R5, -C3(R5)7 or -C2H4- C(Rs)3, wherein R5 represents F, Cl, Br or I, preferably F or Cl and wherein R5 may be the same or different. Preferentially, a haloalkyl group denotes an alkyl group which is substituted by one to three halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably a -C(Rs)3, -CH(Rs)2, -CH2-CH(R5)2, -CH2-C(RS)3, - C2H4-CH(R5)2 or -C2H4-C (R5)3, wherein R5 represents F, Cl, Br or I, preferably F or Cl and wherein R5 may be the same or different from one another.
A hydroxyalkyl group denotes an HO-alkyl group, the alkyl group be¬ ing defined as above.
A haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyloxy group is preferably a -OC(R5)3, -OCR5 (R5)2, -
OCR5(R5)R5, -OC2(Rs)5, -OCH2-C(Rs)3, -OCH2-CR5(RS)2, -OCH2-CR5(R5)R5, - OC3(R5)v or -OC2H4-C(Rs)3, wherein R5 represents F, Cl, Br or I, pref¬ erably F or Cl and wherein R5 may be the same or different. Preferen¬ tially, a haloalkoxy group denotes an alkoxy group which is substi- tuted by one to three halogen atoms, the alkyl group being as de¬ fined above; the haloalkyloxy group is preferably a -OC (R5)3, -OCH2- C(Rs)3, -OC2H4-C (R5) 3, wherein R5 represents F, Cl, Br or I and wherein R5 may be the same or different from one another.
A hydroxyalkylamino group denotes an (HO-alkyl) 2-N- group or
HO-alkyl-NH- group, the alkyl group being as defined above. Prefer¬ entially, a hydroxylakylamino group denotes an (0H-alkyl)2-N- group, HO-alkyl-NH- group or HO-alkyl-NR4- group, the alkyl and R4 groups being defined as above.
A halogen group denotes chlorine, bromine, fluorine or iodine.
An aryl group denotes preferably an aromatic group having five to ten carbon and/or heteroatoms, which can optionally be substituted by one or more substituents wherein Ri and R2 being as defined above. Preferentially, an aryl group denotes an aromatic group having five to six carbon and/or heteroatoms, which can optionally be substi- tuted by one or more substituents which are optionally being defined as the residues Ri and/or R2 as mentioned above.
A heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom like O7 N, S. This heterocyc- lie group can be fused to another ring. For example, this group can be selected from an oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol- 2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, l,2,4-oxadiazol-3-yl, 1,2, 4-oxadiazol-5-yl, 1,2,4- thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2, 5-oxadiazol-3-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, indolyl, in- dolinyl, benzo- [b] -furanyl, benzo [b] thiophenyl, benzimidazolyl, ben- zothiazolyl, quinazolinyl, quinoxazolinyl, indolizin-yl, isoindolyl, 3H-indolyl, lH-indazolyl, purinyl, 4H-quinolizinyl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, quinolinyl, tetrahydroquinolinyl, iso- quinolinyl, tetrahydroisoquinolinyl, phthalazinyl, 1,8- naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phe- nothiazinyl, phenoxazinyl, indenyl, coumarinyl, naphthalinyl, fluo- renyl, anthracenyl group. This heterocyclic group can optionally be substituted by one or more substituents R1 or R2 which are defined as above.
Preferentially, a heteroaryl group denotes a 5- or 6-membered het¬ erocyclic group which contains at least one heteroatom like 0, N, S and is selected from the group consisting of a thiazol-2-yl, thia- zol-4-yl, thiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1, 2,4-thiadiazol-5- yl, 1,2, 5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 2-furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4- pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, in¬ dolyl, benzimidazolyl, benzothiazolyl, quinazolinyl, isoindolyl, 3H- indolyl, quinolinyl, isoquinolinyl, phtalazinyl, 1, 8-naphtyridinyl, coumarinyl and naphtalinyl group. This heterocyclic group can op- tionally be substituted by one or more substituents which are de¬ fined as the residues Ri and/or R2 as mentioned above.
The invention is further described by way of examples in a merely illustrative manner without limiting the scops of the invention.
Examples
Example 1: General synthetic procedure for the preparation of com¬ pounds of formula I
A hydrazine compound according to formula III ( ~100mg) , an alde¬ hyde according to general formula II (1 equivalent) , ca. 100 mg of Amberlyst 15 ion-exchange resin and molecular sieves in tetrahydro- furan (4ml) were placed in a G-12 flask. The reaction mixture was heated to reflux for 4 h. A TLC analysis (Hexane/EtOAc:1/1) showed that all hydrazine was reacted. The reaction mixture was filtered and the solution concentrated to a small volume (ca. 0.5 mL) . The resulting residue was suspended in methanol (ca. 1.5 mL) , sonicated, centrifuged and decanted. This process was repeated a second time. The white-yellowish solid formed was dried under vacuum.
This methodology is applicable for all compounds of general formula
1 according to the invention. However, other synthetic pathways are not excluded and are also within the knowledge of a person skilled in the art.
Specific compounds are shown in the following table 1.
Further specific compounds are shown in the following table 2.
Mass was determined by mass spectrometry. Compounds in Tables 1 and
2 show in-vitro activity below 50 μM. In-Vitro activities were de¬ termined as described in example 2.
Table 1: List of specific compounds according to general formula I HPLC /MS
Structure (ESI)
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000027_0002
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Table 2: List of further specific compounds according to general formula I
Figure imgf000036_0002
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Example 2 : Inhibition of Beta-Secretase Activity - FRET assay
Assays for determining APP cleavage at the beta-secretase cleavage site are well known in the art. Exemplary assays are described, for example, in U.S. Patent Nos. 5,744,346 and 5,942,400.
One useful assay to test the inhibitory acitivity of the beta- secretase is based on the fluorescence resonance energy transfer (FRET) technology to monitor cleavage of a peptide substrate. 5 μl/well of substrate (0.2 mM in 0.1 M Na-Ac pH=4.5; Bachem No. M- 2470) is pipetted into a black 96 well plate and stored in the dark. 5 μl/well of DMSO containing inhibitor compound (final concentration of compounds: between 1 nanomolar and 500 micromolar) are pipetted into 96 well transparent V-form plate, IQ M. of 0.1 M Na-Ac pH=4.5 and 20 μl rhBACEl (10 μg/ml in 0.1 M Na-Ac pH=4.5; R&D Systems No 931-AS) are added and incubated for 10 minutes at RT. 94 ml of each well are then transferred to the substrate in the black plate to start the reaction. Immediately after mixing time (T)=O is measured with a Wallacl420 plate reader (excitation 355nm, emission 486nm) . The reactions are measured again after incubation for 60 min at 370C with gentle shaking. Relative compound inhibition potency is deter- mined by calculating the concentration of compound that showed a » 5 fifty percent reduction in detected signal (IC50) compared to the en¬ zyme reaction signal in the control with no added compound.
Example 3 : Inhibition of Beta-Secretase Activity - Cellular Assay
10 An exemplary assay for the analysis of the inhibition of beta- secretase activity utilizes human embryonic kidney cell line HEK293
(ATCC Accession No. CRL-1573) transfected with APP751 containing the naturally occurring double mutation Lys651Met652 to Asn651Met652
(numbered for APP751) , commonly called the Swedish mutation and
15 shown to overproduce A beta (Citron et al . , 1992, Nature 360:672-
674), as described in U.S. Patent No. 5,604,102. However, other transgenic cell lines, for example CHO or SH-SY5Y could be used as well.
20 The cells are incubated in the presence/absence of the inhibitory compound (diluted in DMSO; final concentration of DMSO: 0.05%) at the desired concentration, generally up to 100 μM. At the end of the treatment period (24h) , conditioned media is analyzed for beta- secretase activity, for example, by analysis of cleavage fragments. 25 A beta can be analyzed by immunoassay, using specific detection an¬ tibodies (HS40 ABeta kit from The Genetics Company) . The enzymatic activity is measured in the presence and abs'ence of the compound in¬ hibitors to demonstrate specific inhibition of beta-secretase medi¬ ated cleavage of APP substrate. Relative compound inhibition potency
30 is determined by calculating the concentration of compound that showed a fifty percent reduction in detected signal (IC50) compared to the A beta 40 signal in the control with no added compound.
The following compounds showed IC50 values below 50 μM: 35
Nl, N8, NlO, N13, N15-N21, N23-N30, N40, N43, N58-N66, N69-N70, N76- N81, N83-N88, N90-N94, N96, N98-N100, N102, N108-N109, N114, N119.
Example 4 : Determination of compound in the brain 0
C57/bl6 mice, designated "wt" mice, were obtained. The mice were -treated with the phenylhydrazone Nr. 29. Dosing was administered ei- ther intraperitoneally or orally. The oral dose was administered via oral gavage. Intraperitoneally-treated animals received a single in¬ jection, or were dosed once or twice a day up to 8 days. In addi¬ tion, a group of age-matching wt mice were treated with the carrier vehicle only.
'Animals were sacrified between 0.5 and 24 h after the final dose. The brains were removed and stored at -800C. The brain was cut into 200 mg pieces, 800 μl of a Acetonitrile:Water solution (80:20; v:v) were added and the brain samples were sonicated for 2 min. Samples were vortexed for 2 min and insoluble particles were removed by cen- trifugation. The compound in the samples was detected by High Per¬ formance Liquid Chromatography at 254 or 360 nm. Concentrations were determined by adding an internal standard to the brain samples.
Following intraperitoneal administration of a single dose of 55 mg/kg, compound levels were detectable in the brain within 30 min, persist at this level for at least 5 h post administration and dis¬ play peak levels 2.5 h after injection. Upon treatment of mice once a day with the same dose for three consecutive days, the amount of the compound detected in the brain 24 h after the last injection was twice the peak level measured after single dosing. Similar levels of compound could be detected after treatment twice a day for 8 con¬ secutive days, indicating a saturation effect for the accumulation of the compound in the brain.
After single oral dose administration (100 mg/kg) the compound could be detected in the brain of "wt" mice arguing for oral absorption of the compound.
Example 5: Inhibition of Beta-Secretase in Animal Models of AD
'Various animal models can be used to screen for inhibition of beta- secretase activity. Examples of animal models useful in the inven¬ tion include, but are not limited to, mouse, guinea pig, dog, and the like. The animals used can be wild type, transgenic, or knockout models. In addition mammalian models can express mutation in APP, ^such as APP695-SW and the like described herein. Examples of trans- genie non-human mammalian models are described in Hsiao et al. , 1996, Science 274, 99-102 and Kawarabayshi et al. , 2001, J Neuroscie 21, 372-381.
For instance, Tg2576 mice, prepared as described in Hsiao et al. , 1996, Science 274, 99-102 are useful to analyze in vivo suppression of A beta release in the presence of putative inhibitory compounds.
Transgenic animals are administered an amount of the BACE inhibitor formulated in a carrier suitable for the chosen mode of administra- tion, as for example described in Chang et al. , 2004, J. Neurochem. 89, 1409-1416. Control animals are untreated, treated with vehicle, or treated with an inactive compound. Administration can be acute, i.e., single dose or multiple dose in one day, or can be chronic, i.e., dosing is repeated daily for a period of days. Beginning at time 0, brain tissue, cerebral fluid or blood is obtained from se¬ lected animals and analyzed for the presence of APP cleavage pep¬ tides, including A beta, for example, by immunoassay using specific antibodies for A beta detection. At the end of the test period, ani¬ mals are sacrificed and brain tissue, cerebral fluid or blood is analyzed for the presence of A beta and/or beta-amyloid plaques. Al¬ ternatively, treated transgenic animals (e.g. Tg2576 mice) can be monitored for changes in the APP induced phenotypes as for example described in Hsiao et al. , 1996, Science 274, 99-102.

Claims

1. Hydrazone derivative of the general formula I
Figure imgf000060_0001
wherein R3 is selected from the group consisting of H, methyl and hydroxyalkyl,
and wherein Z1 and Z2 are selected independently from one an- other from the group consisting of substituted or unsubstituted phenyl, naphtyl, pyridinyl, pyrazolyl, pyrimidinyl, pyrazid- inyl, quinolinyl, iso-quinolinyl, coumarinyl, indolyl, thia- zolyl and thiophenyl groups bearing substituents n R1 and m R2,
wherein R1 and R2 which may be the same or are different from one another are selected from the group consisting of H, alkyl, cycloalkyl, -CO2R4, -CONHR4, -CR4O, -SO2R4, -NR4-CO-R4, alkoxy, alkylthio, -OH, -0-aryl, -0-cycloalkyl, -S-aryl, -S-cycloalkyl, hydroxyalkyl, halogen, haloalkyl, haloalkoxy, -CN, -NO2, hy- droxyalkylamine, aminoalkyl, alkylamine, aryl, heteroaryl and sulfonamide,
wherein R4 is selected from the group consisting of H, C1 to Ce branched or unbranched alkyl, aryl, cycloalkyl, alkoxy, hetero- cycloalkyl, -OH, -0-aryl, -0-alkyl, -0-cycloalkyl, aminoalkyl, alkylamine, aryl and heteroaryl,
and wherein n and m are the numbers of the substituents R1 and R2 in Z1 and Z2, respectively, which are in a range between 0 and 5, with the proviso that if n and m are integers higher than 2, R1 and/or R2 may form a fused aromatic or a carbocyclic or hetero¬ cyclic ring system,
or a salt, or a physiologically functional derivative, or prodrug thereof,
whereas the compounds
Figure imgf000061_0001
are not comprised within formula I.
2. Compound according to claim 1, characterized in that Z1 is a substituted phenyl group which is substituted by at least two halogen atoms and one hydroxyl group.
3. Compound according to anyone of the preceding claims, charac¬ terized in that Z1 is a substituted phenyl group which bears at least a substituted or unsubstituted aryl or heteroaryl ring or one or two terbutyl groups.
4. Compound according to anyone of the preceding claims, charac¬ terized in that Z2 is a phenyl group which is preferably sub¬ stituted by a benzyl group that is linked to the phenyl group via an ether bond.
5. Compound according to one of the claims 1 to 3, characterized in that Z2 is a pyrimidyl ring bearing a substituted or unsub- stituted cycloalkyl group or a disubstituted amino group.
6. Compound according to claim 4, characterized that the benzyl group which is linked to the phenyl group via an ether bond is a substituted or unsubstituted benzyloxy group.
7. Compound according to claim 2, characterized in that the hy- droxyl group is in o-position relative to the bonding position of the hydrazone motif.
Compound according to one of the claims 1 to 3 and 7, charac¬ terized in that the compound has one of the following formulas
Figure imgf000062_0001
9. Compound of the formula
Figure imgf000062_0002
10. Compound according to one of the claims 1, 2, 3 and 7, charac¬ terized in that Z2 is selected from the group consisting of substituted or unsubstituted phenyl, pyridinyl and pyrimidinyl groups .
11. Use of a compound according to any one of the preceding claims as a medicament.
12. Use of a compound according to anyone of claims 1 to 10 for the manufacture of a pharmaceutical composition for the treat- ment or prevention of a condition or disorder which is medi¬ ated by beta-secretase.
13. Use of a compound according to anyone of the claims 1 to 10 for the manufacture of a pharmaceutical composition to inhibit the formation of beta-amyloid peptides from the amyloid pre¬ cursor protein APP.
14. Use of a compound according to anyone of the claims 1 to 10 for the manufacture of a pharmaceutical composition for the treatment or prevention of Alzheimer's disease, neurodegenera- tion, memory and attention deficits, dysfunction of cellular proliferation, or other disorders associated with or respon¬ sive to the inhibition of beta-amyloid peptides.
15. Use of a compound according to anyone of claims the 1 to 10 for the manufacture of a pharmaceutical composition for the treatment or prevention of conditions or diseases selected from the group consisting of Alzheimer's disease, Down syn¬ drome, cerebral amyloid angiopathy, Hereditary Cerebral Haem- orrhage with Amylosis of the Dutch type (HCHWA-D) and other degenerative dementia characterized by beta-amyloid deposits.
16. Pharmaceutical composition comprising a compound according to anyone of the claims 1 to 10 or a pharmaceutically acceptable salt thereof.
17. Pharmaceutical composition according to claim 16, further com¬ prising at least one pharmaceutically acceptable carrier, diluent or excipient.
PCT/EP2005/009902 2004-09-14 2005-09-14 Hydrazone derivatives and their use as beta secretase inhibitors WO2006029850A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2007530679A JP2008513364A (en) 2004-09-14 2005-09-14 Hydrazone derivatives and their use as beta-secretase inhibitors
CA002579472A CA2579472A1 (en) 2004-09-14 2005-09-14 Hydrazone derivatives and their use as beta secretase inhibitors
EP05787258A EP1791818A1 (en) 2004-09-14 2005-09-14 Hydrazone derivatives and their use as beta secretase inhibitors

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP04021840 2004-09-14
EP04021840.6 2004-09-14
EP04022088.1 2004-09-16
EP04022088 2004-09-16

Publications (1)

Publication Number Publication Date
WO2006029850A1 true WO2006029850A1 (en) 2006-03-23

Family

ID=35517447

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2005/009902 WO2006029850A1 (en) 2004-09-14 2005-09-14 Hydrazone derivatives and their use as beta secretase inhibitors

Country Status (4)

Country Link
EP (1) EP1791818A1 (en)
JP (1) JP2008513364A (en)
CA (1) CA2579472A1 (en)
WO (1) WO2006029850A1 (en)

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007065940A1 (en) * 2005-12-08 2007-06-14 Laboratoires Serono S.A. Antiproliferative pyrimidyl, fused pyrimidyl and pyrimidyl hydrazones
WO2008055945A1 (en) 2006-11-09 2008-05-15 Probiodrug Ag 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases
WO2008065141A1 (en) 2006-11-30 2008-06-05 Probiodrug Ag Novel inhibitors of glutaminyl cyclase
WO2008104580A1 (en) 2007-03-01 2008-09-04 Probiodrug Ag New use of glutaminyl cyclase inhibitors
WO2011026835A1 (en) * 2009-09-02 2011-03-10 Vifor (International) Ag Novel pyrimidine and triazine hepcidine antagonists
WO2011029920A1 (en) 2009-09-11 2011-03-17 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
EP2330906A1 (en) * 2008-08-15 2011-06-15 University Of Louisville Research Foundation, Inc. Compounds, their syntheses, and their uses
WO2011041737A3 (en) * 2009-10-02 2011-08-18 Fred Hutchinson Cancer Research Center Gain-of-function bcl-2 inhibitors
WO2011107530A2 (en) 2010-03-03 2011-09-09 Probiodrug Ag Novel inhibitors
WO2011110613A1 (en) 2010-03-10 2011-09-15 Probiodrug Ag Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (en) 2010-04-21 2011-10-27 Probiodrug Ag Novel inhibitors
US8183252B2 (en) 2003-12-15 2012-05-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
WO2012123563A1 (en) 2011-03-16 2012-09-20 Probiodrug Ag Benz imidazole derivatives as inhibitors of glutaminyl cyclase
US20120252839A1 (en) * 2009-10-02 2012-10-04 Fred Hutchinson Cancer Research Center Gain-of-function bcl-2 inhibitors
US8541408B2 (en) 2007-04-24 2013-09-24 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives substituted with a cyclic group
US8546380B2 (en) 2005-10-25 2013-10-01 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US8637504B2 (en) 2008-06-13 2014-01-28 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity
US8653067B2 (en) 2007-04-24 2014-02-18 Shionogi & Co., Ltd. Pharmaceutical composition for treating Alzheimer's disease
US8703785B2 (en) 2008-10-22 2014-04-22 Shionogi & Co., Ltd. 2-aminopyrimidin-4-one and 2-aminopyridine derivatives both having BACE1-inhibiting activity
US8883779B2 (en) 2011-04-26 2014-11-11 Shinogi & Co., Ltd. Oxazine derivatives and a pharmaceutical composition for inhibiting BACE1 containing them
US8927721B2 (en) 2010-10-29 2015-01-06 Shionogi & Co., Ltd. Naphthyridine derivative
US8999980B2 (en) 2009-12-11 2015-04-07 Shionogi & Co., Ltd. Oxazine derivatives
US9018219B2 (en) 2010-10-29 2015-04-28 Shionogi & Co., Ltd. Fused aminodihydropyrimidine derivative
EP2865670A1 (en) 2007-04-18 2015-04-29 Probiodrug AG Thiourea derivatives as glutaminyl cyclase inhibitors
US20150374694A1 (en) * 2013-02-22 2015-12-31 Emory University Tgf-beta enhancing compositions for cartilage repair and methods related thereto
US9540359B2 (en) 2012-10-24 2017-01-10 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity
EP3150589A1 (en) * 2007-06-08 2017-04-05 MannKind Corporation Ire-1a inhibitors
EP3461819A1 (en) 2017-09-29 2019-04-03 Probiodrug AG Inhibitors of glutaminyl cyclase
WO2021184097A1 (en) 2020-03-18 2021-09-23 Faculdades Católicas N-acyl-hydrazone compounds, use in the treatment of amyloid and non-amyloid degenerative aggregopathies, and pharmaceutical composition
EP3901139A4 (en) * 2018-12-19 2022-10-05 Korea Institute of Science and Technology Novel hydrazone derivative with aryl or heteroaryl group substituted at terminal amine group thereof and use thereof

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE561091A (en) *
NL7010689A (en) * 1970-07-18 1972-01-20 2-(3,4-dichlorophenyl)-4,4-dimethylsemicarbazide and its alkyl - derivs - selective herbicides
DE2118468A1 (en) * 1971-04-16 1972-10-26 Farbenfabriken Bayer Ag, 5090 Lever Kusen Fungicides
US3829492A (en) * 1972-02-04 1974-08-13 Rohm & Haas Fungicidal salicylaldehyde hydrazones and azines
US6503914B1 (en) * 2000-10-23 2003-01-07 Board Of Regents, The University Of Texas System Thienopyrimidine-based inhibitors of the Src family
WO2003049698A2 (en) * 2001-12-10 2003-06-19 Temple University - Of The Commonwealth System Of Higher Education Substituted hydrazones as inhibitors of cyclooxygenase-2
WO2003059346A1 (en) * 2002-01-18 2003-07-24 The Genetics Company Inc. Beta-secretase inhibitors
WO2004063196A1 (en) * 2003-01-14 2004-07-29 De Novo Pharmaceuticals Limited 1,2,4-triazin-3-yl-hydrazine or 5h-1,2,4-triazino’5,6-b!indol-3-yl-hydrazine compounds as inhibitors of bace useful in the treatment of alzheimer
WO2005037213A2 (en) * 2003-10-14 2005-04-28 Cornell Research Foundation, Inc. Antiinflammatory inhibitors of respiratory burst in adherent neutrophils
EP1612204A1 (en) * 2003-03-31 2006-01-04 Daiichi Pharmaceutical Co., Ltd. Hydrazone derivative

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE561091A (en) *
NL7010689A (en) * 1970-07-18 1972-01-20 2-(3,4-dichlorophenyl)-4,4-dimethylsemicarbazide and its alkyl - derivs - selective herbicides
DE2118468A1 (en) * 1971-04-16 1972-10-26 Farbenfabriken Bayer Ag, 5090 Lever Kusen Fungicides
US3829492A (en) * 1972-02-04 1974-08-13 Rohm & Haas Fungicidal salicylaldehyde hydrazones and azines
US6503914B1 (en) * 2000-10-23 2003-01-07 Board Of Regents, The University Of Texas System Thienopyrimidine-based inhibitors of the Src family
WO2003049698A2 (en) * 2001-12-10 2003-06-19 Temple University - Of The Commonwealth System Of Higher Education Substituted hydrazones as inhibitors of cyclooxygenase-2
WO2003059346A1 (en) * 2002-01-18 2003-07-24 The Genetics Company Inc. Beta-secretase inhibitors
WO2004063196A1 (en) * 2003-01-14 2004-07-29 De Novo Pharmaceuticals Limited 1,2,4-triazin-3-yl-hydrazine or 5h-1,2,4-triazino’5,6-b!indol-3-yl-hydrazine compounds as inhibitors of bace useful in the treatment of alzheimer
EP1612204A1 (en) * 2003-03-31 2006-01-04 Daiichi Pharmaceutical Co., Ltd. Hydrazone derivative
WO2005037213A2 (en) * 2003-10-14 2005-04-28 Cornell Research Foundation, Inc. Antiinflammatory inhibitors of respiratory burst in adherent neutrophils

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
"New therapeutic patents for Alzheimer's disease", EXPERT OPINION ON THERAPEUTIC PATENTS, ASHLEY PUBLICATIONS, GB, vol. 8, no. 12, 1998, pages 1751 - 1757, XP002240134, ISSN: 1354-3776 *
A.A.SCHILT ET AL.: "Snthesis and Chelation Properties of Hydrazones", ANAL.CHEM., vol. 56, 1984, pages 2860 - 2862, XP001026964 *
B.BOUTEAU ET AL.: "Synthesis and Salidiuretic Activity of 2,3-Dihydro- 8-(1-pyrrolyl)-1,2,4-triazolo[4,3-a]pyridines", CHEM.PHARM.BULL., vol. 39, no. 1, 1991, pages 81 - 85, XP001208232 *
B.PRESCOTT ET AL.: "Potential Antitumor Agents: Derivatives of 2-Hydrazino-5-nitropyridine", J.PHARM.SCI., vol. 59, no. 1, 1970, pages 101 - 104, XP009059936 *
DOVEY H F ET AL: "FUNCTIONAL GAMMA-SECRETASE INHIBITORS REDUCE BETA-AMYLOID PEPTIDE LEVELS IN BRAIN", JOURNAL OF NEUROCHEMISTRY, NEW YORK, NY, US, vol. 76, no. 1, 2001, pages 173 - 181, XP001147446, ISSN: 0022-3042 *
F.H.CASE: "Preparation of new 2-Pyridyl and Pyrazinylhydrazone containing Ferroin Group", J.CHEM.ENG.DATA, vol. 21, no. 1, 1976, pages 124 - 125, XP009059868 *
F.LIONS ET AL.: "Sexadentate Chlate Compounds", JACS, vol. 80, 1958, pages 3858 - 3865, XP002363974 *
M.F.ZADY ET AL.: "Structural Criteria for Hydrazone Photochromism in Solution", J.C.S.PERKIN I, 1975, pages 2036 - 2039, XP009059934 *
T.R.PRZYSTAL ET AL.: "2-Hydrazino-8-quinolinol and Derivatives", J.MED.CHEM., vol. 10, 1967, pages 981, XP002363975 *

Cited By (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8183252B2 (en) 2003-12-15 2012-05-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
US9029358B2 (en) 2005-10-25 2015-05-12 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US8633188B2 (en) 2005-10-25 2014-01-21 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US8546380B2 (en) 2005-10-25 2013-10-01 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US8815851B2 (en) 2005-10-25 2014-08-26 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
JP2009518364A (en) * 2005-12-08 2009-05-07 ラボラトワール セローノ ソシエテ アノニム Pyrimidyl, condensed pyrimidyl, pyridylhydrazone that suppresses growth
WO2007065940A1 (en) * 2005-12-08 2007-06-14 Laboratoires Serono S.A. Antiproliferative pyrimidyl, fused pyrimidyl and pyrimidyl hydrazones
US8288398B2 (en) 2005-12-08 2012-10-16 Merck Serono Sa Antiproliferative pyrimidyl, fused pyrimidyl and pyrimidyl hydrazones
AU2006323944B2 (en) * 2005-12-08 2012-08-16 Merck Serono Sa Antiproliferative pyrimidyl, fused pyrimidyl and pyrimidyl hydrazones
WO2008055945A1 (en) 2006-11-09 2008-05-15 Probiodrug Ag 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases
WO2008065141A1 (en) 2006-11-30 2008-06-05 Probiodrug Ag Novel inhibitors of glutaminyl cyclase
WO2008104580A1 (en) 2007-03-01 2008-09-04 Probiodrug Ag New use of glutaminyl cyclase inhibitors
EP2481408A2 (en) 2007-03-01 2012-08-01 Probiodrug AG New use of glutaminyl cyclase inhibitors
EP2865670A1 (en) 2007-04-18 2015-04-29 Probiodrug AG Thiourea derivatives as glutaminyl cyclase inhibitors
US8884062B2 (en) 2007-04-24 2014-11-11 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives substituted with a cyclic group
US8653067B2 (en) 2007-04-24 2014-02-18 Shionogi & Co., Ltd. Pharmaceutical composition for treating Alzheimer's disease
US8895548B2 (en) 2007-04-24 2014-11-25 Shionogi & Co., Ltd. Pharmaceutical composition for treating alzheimer's disease
US8541408B2 (en) 2007-04-24 2013-09-24 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives substituted with a cyclic group
EP3150589A1 (en) * 2007-06-08 2017-04-05 MannKind Corporation Ire-1a inhibitors
US9981901B2 (en) 2007-06-08 2018-05-29 Fosun Orinove Pharmatech, Inc. IRE-1α inhibitors
US9273053B2 (en) 2008-06-13 2016-03-01 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having Beta secretase inhibitory activity
US9650371B2 (en) 2008-06-13 2017-05-16 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity
US8637504B2 (en) 2008-06-13 2014-01-28 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity
EP2330906A4 (en) * 2008-08-15 2014-07-09 Univ Louisville Res Found Compounds, their syntheses, and their uses
US9061984B2 (en) 2008-08-15 2015-06-23 University Of Louisville Research Foundation, Inc. Compounds related to chalcones and benzothienopyrimidines, their synthesis, and uses to treat diseases
EP2330906A1 (en) * 2008-08-15 2011-06-15 University Of Louisville Research Foundation, Inc. Compounds, their syntheses, and their uses
US8703785B2 (en) 2008-10-22 2014-04-22 Shionogi & Co., Ltd. 2-aminopyrimidin-4-one and 2-aminopyridine derivatives both having BACE1-inhibiting activity
JP2013503833A (en) * 2009-09-02 2013-02-04 ヴィフォール （インターナショナル） アクチェンゲゼルシャフト Novel pyrimidine and triazine hepcidin antagonists
WO2011026835A1 (en) * 2009-09-02 2011-03-10 Vifor (International) Ag Novel pyrimidine and triazine hepcidine antagonists
WO2011029920A1 (en) 2009-09-11 2011-03-17 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
WO2011041737A3 (en) * 2009-10-02 2011-08-18 Fred Hutchinson Cancer Research Center Gain-of-function bcl-2 inhibitors
US20120252839A1 (en) * 2009-10-02 2012-10-04 Fred Hutchinson Cancer Research Center Gain-of-function bcl-2 inhibitors
US8865901B2 (en) 2009-10-02 2014-10-21 Fred Hutchinson Cancer Research Center Gain-of-function Bcl-2 inhibitors
US8999980B2 (en) 2009-12-11 2015-04-07 Shionogi & Co., Ltd. Oxazine derivatives
US9656974B2 (en) 2009-12-11 2017-05-23 Shionogi & Co., Ltd. Oxazine derivatives
US9290466B2 (en) 2009-12-11 2016-03-22 Shionogi & Co., Ltd. Oxazine derivatives
WO2011107530A2 (en) 2010-03-03 2011-09-09 Probiodrug Ag Novel inhibitors
WO2011110613A1 (en) 2010-03-10 2011-09-15 Probiodrug Ag Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (en) 2010-04-21 2011-10-27 Probiodrug Ag Novel inhibitors
US9018219B2 (en) 2010-10-29 2015-04-28 Shionogi & Co., Ltd. Fused aminodihydropyrimidine derivative
US8927721B2 (en) 2010-10-29 2015-01-06 Shionogi & Co., Ltd. Naphthyridine derivative
WO2012123563A1 (en) 2011-03-16 2012-09-20 Probiodrug Ag Benz imidazole derivatives as inhibitors of glutaminyl cyclase
US8883779B2 (en) 2011-04-26 2014-11-11 Shinogi & Co., Ltd. Oxazine derivatives and a pharmaceutical composition for inhibiting BACE1 containing them
US9540359B2 (en) 2012-10-24 2017-01-10 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity
US9758513B2 (en) 2012-10-24 2017-09-12 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity
US20150374694A1 (en) * 2013-02-22 2015-12-31 Emory University Tgf-beta enhancing compositions for cartilage repair and methods related thereto
US10322125B2 (en) * 2013-02-22 2019-06-18 Emory University TGF-beta enhancing compositions for cartilage repair and methods related thereto
EP3461819A1 (en) 2017-09-29 2019-04-03 Probiodrug AG Inhibitors of glutaminyl cyclase
EP3901139A4 (en) * 2018-12-19 2022-10-05 Korea Institute of Science and Technology Novel hydrazone derivative with aryl or heteroaryl group substituted at terminal amine group thereof and use thereof
WO2021184097A1 (en) 2020-03-18 2021-09-23 Faculdades Católicas N-acyl-hydrazone compounds, use in the treatment of amyloid and non-amyloid degenerative aggregopathies, and pharmaceutical composition

Also Published As

Publication number Publication date
CA2579472A1 (en) 2006-03-23
EP1791818A1 (en) 2007-06-06
JP2008513364A (en) 2008-05-01

Similar Documents

Publication Publication Date Title
WO2006029850A1 (en) Hydrazone derivatives and their use as beta secretase inhibitors
RU2690489C2 (en) Leukotriene a4-hydrolase inhibitors
EP0512901B1 (en) Aminated polycyclic compounds and their enantiomers, process for their preparation and pharmaceutical compositions containing them
US9458118B2 (en) Sodium channel modulators for the treatment of pain and diabetes
RU2696559C2 (en) Leukotriene a4-hydrolase inhibitors
TW200940526A (en) Pyridyl non-aromatic nitrogenated heterocyclic-1-carboxylate ester derivative
JP5649585B2 (en) Benzoarylureido compound and composition for preventing or treating neurodegenerative brain disease containing the same
EP0934290B1 (en) Aminothiazole derivatives, method of preparation and pharmaceutical compositions containing same
JP5253155B2 (en) MAO-B inhibitor useful for the treatment of obesity
CN1345309A (en) Diaryl derivatives and their use as medicaments
WO2018208855A1 (en) Sphingosine 1 phosphate receptor agonists for neuroprotection
JPH10279477A (en) Protein tyrosine kinase inhibitor for suppression of proliferation process in mammal cell, containing benzylidene-and cinnamylidene-malonic nitrile derivative as active ingredient
US11147802B2 (en) Substituted oxadiazole chemical compound and composition containing said chemical compound and use thereof
WO2007051333A1 (en) Triazine beta-secretase inhibitors
US7476754B2 (en) Biphenyl derived thiamides as calpain inhibitors
JP2005517008A (en) Urea linker derivatives for use as PPAR modulators
JP7250015B2 (en) Anti-HBV tetrahydroisoxazolo[4,3-c]pyridine class compounds
CN111386283A (en) Peptide antimicrobial complexes and methods of use thereof
JP2005523292A (en) Peroxisome proliferator-activated receptor modulator
FR2751650A1 (en) NOVEL N-BENZENESULFONYL-L-PROLINE COMPOUNDS, METHOD OF PREPARATION AND THERAPEUTIC USE
CN100560568C (en) Cyclin imide peptidyl metalloprotease inhibitor and application thereof
JP4550353B2 (en) Hematopoietic prostaglandin D2 synthase inhibitor
WO2006097809A2 (en) Novel tyrosine derivatives
US20020082254A1 (en) Compounds for treating disorders where a decreased level of plasma FFA is desired
CN1694870A (en) Acetyl 2-hydroxy-1, 3-diaminoalkanes

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 KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM 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): 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 IS IT LT LU LV 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
WWE Wipo information: entry into national phase

Ref document number: 2005787258

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2579472

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2007530679

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

WWP Wipo information: published in national office

Ref document number: 2005787258

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 2005787258

Country of ref document: EP