EP1791818A1 - Derives d'hydrazone et leur utilisation comme inhibiteurs de la beta-secretase - Google Patents

Derives d'hydrazone et leur utilisation comme inhibiteurs de la beta-secretase

Info

Publication number
EP1791818A1
EP1791818A1 EP05787258A EP05787258A EP1791818A1 EP 1791818 A1 EP1791818 A1 EP 1791818A1 EP 05787258 A EP05787258 A EP 05787258A EP 05787258 A EP05787258 A EP 05787258A EP 1791818 A1 EP1791818 A1 EP 1791818A1
Authority
EP
European Patent Office
Prior art keywords
group
cycloalkyl
aryl
compound according
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05787258A
Other languages
German (de)
English (en)
Inventor
Benno Schindelholz
Gerard Schmid
Alessandro Brigo
Dragana Milas
Gabriel Garcia
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Genetics Co Inc
Genetics Company Inc
Original Assignee
Genetics Company Inc
Genetics Co 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 Genetics Company Inc, Genetics Co Inc filed Critical Genetics Company Inc
Priority to EP05787258A priority Critical patent/EP1791818A1/fr
Publication of EP1791818A1 publication Critical patent/EP1791818A1/fr
Withdrawn legal-status Critical Current

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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
  • 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.

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Abstract

L'invention porte sur des composés de la formule générale (1) dans laquelle R3 est choisi dans le groupe composé de H, méthyle et hydroxyalkyle, et dans laquelle Z1 et Z2 sont choisis indépendamment l'un de l'autre dans le groupe composé de groupes phényle, naphtyle, pyridinyle, pyrazolyle, pyramidinyle, pyrazidinyle, quinolinyle, iso-quinolinyle, coumarinyle, indolyle, thiazolyle et thiophényle substitués ou non substitués, portant les substituants n R1 et m R2, où R1 et R2, qui peuvent être les mêmes ou différents, sont choisis dans le groupe composé de H, alkyle, cycloalkyle, -C02R4, -CONHR4, -CR4O, -SO2R4, -NR4-CO-R4, alcoxy, alkylthio, -OH, -O-aryle, -O-cycloalkyle, -S-aryle, -S-cycloalkyle, hydroxyalkyle, halogène, haloalkyle, haloalcoxy, -CN, -NO2, hydroxyalkylamine, aminoalkyle, alkylamine, aryle, hétéroaryle et sulfonamide, où R4 est choisi dans le groupe composé de H, alkyle C1 à C6 ramifié ou non ramifié, aryle, cycloalkyle, alcoxy, hétérocycloalkyle, -OH, -O-aryle, -O-alkyle, -O-cycloalkyle, aminoalkyle, alkyleamine, aryle et hétéroaryle, et où n et m représentent les nombres de substituants R1 et R2 dans Z1 et Z2, respectivement, qui sont compris dans une plage de 0 à 5, à condition que si n et m sont des entiers supérieurs à 2, R1 et/ou R2 peuvent former un noyau aromatique fusionné ou un noyau carbocyclique ou hétérocyclique, ou un sel, ou un dérivé physiologiquement fonctionnel ou un promédicament de ces derniers.
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