CA2579472A1 - Hydrazone derivatives and their use as beta secretase inhibitors - Google Patents
Hydrazone derivatives and their use as beta secretase inhibitors Download PDFInfo
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- CA2579472A1 CA2579472A1 CA002579472A CA2579472A CA2579472A1 CA 2579472 A1 CA2579472 A1 CA 2579472A1 CA 002579472 A CA002579472 A CA 002579472A CA 2579472 A CA2579472 A CA 2579472A CA 2579472 A1 CA2579472 A1 CA 2579472A1
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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
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- 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
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- 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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- 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
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- 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
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- 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
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- 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
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- C07D285/01—Five-membered rings
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- 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
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- 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
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- 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
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- C07H19/16—Purine radicals
- C07H19/167—Purine radicals with ribosyl as the saccharide radical
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 Z2are selected independently from one another from the group consisting of substituted or un~substituted 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, al~kylthio, -OH, -O-aryl, -O-cycloalkyl, -S-aryl, -S-cycloalkyl, hy~droxyalkyl, halogen, haloalkyl, haloalkoxy, -CN, -NO2, hydroxyal~ kylamine, aminoalkyl, alkylamine, aryl, heteroaryl and sulfona~mide, wherein R4 is selected from the group consisting of H, C1 to C6 branched or unbranched alkyl, aryl, cycloalkyl, alkoxy, hetero~cycloalkyl, -OH, -O-aryl, -O-alkyl, -O-cycloalkyl, aminoalkyl, alkylamine, aryl and heteroaryl, and wherein n and m are the num~bers 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 R2may 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 (3-amyloid precursor protein ((3-APP). (3-APP is degraded by the (3-Amyloid Converting Enzyme (BACE, also known under the name of beta-secretase) to produce (3-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
Z1 NN\Z 2 I
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 R,_ 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, -CR40, -S02R4, -NR4-CO-R4, alkoxy, alkylthio, -OH, -0-aryl, -0-cycloalkyl, -S-aryl, -S-cycloalkyl, hydroxyalkyl, halogen, haloalkyl, haloalkoxy, -CN, -NOZ, 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 H
CI ,N \
OH
CI
H O~N+;O
I
CI
O", + / F
OH N
CI p F
H CI
CI ,N
I
COH CI
CI
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
H
z Z2 wherein Z1 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 (R1)n and (R2)m, wherein the number of substituents in Zl and Z2 ,(Rl)n and (R2)m is in a range between 0 and 5 and R1, R2are selected from the group consisting of H, alkyl, cycloalkyl, -C02R4, -CONHR4, -CR40, -S02R4, -NR4-CO-R4, alkoxy, alkylthio, -OH, -SH, -0-aryl, -0-cycloalkyl, -S-aryl, -S-cycloalkyl, hydroxyalkyl, halogen, haloalkyl, haloalkoxy, CN, NOz, hydroxyalkylamine, aminoalkyl, alkylamine, aryl or het-eroaryl, sulfone and sulfonamide whereby, R, 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 H
CI
OH
CI
is not comprised within formula I, or a salt, or a physiologically functional derivative, or a prodrug thereof.
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 (3-amyloid precursor protein ((3-APP). (3-APP is degraded by the (3-Amyloid Converting Enzyme (BACE, also known under the name of beta-secretase) to produce (3-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
Z1 NN\Z 2 I
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 R,_ 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, -CR40, -S02R4, -NR4-CO-R4, alkoxy, alkylthio, -OH, -0-aryl, -0-cycloalkyl, -S-aryl, -S-cycloalkyl, hydroxyalkyl, halogen, haloalkyl, haloalkoxy, -CN, -NOZ, 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 H
CI ,N \
OH
CI
H O~N+;O
I
CI
O", + / F
OH N
CI p F
H CI
CI ,N
I
COH CI
CI
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
H
z Z2 wherein Z1 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 (R1)n and (R2)m, wherein the number of substituents in Zl and Z2 ,(Rl)n and (R2)m is in a range between 0 and 5 and R1, R2are selected from the group consisting of H, alkyl, cycloalkyl, -C02R4, -CONHR4, -CR40, -S02R4, -NR4-CO-R4, alkoxy, alkylthio, -OH, -SH, -0-aryl, -0-cycloalkyl, -S-aryl, -S-cycloalkyl, hydroxyalkyl, halogen, haloalkyl, haloalkoxy, CN, NOz, hydroxyalkylamine, aminoalkyl, alkylamine, aryl or het-eroaryl, sulfone and sulfonamide whereby, R, 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 H
CI
OH
CI
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
I
Z/ 'N"' N~Z
wherein R3 is selected from the group consisting of H, methyl and hydroxyalkyl, and wherein Zs, 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 Rl 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, -CR40, -S02R4, -NR4-CO-R4, alkoxy, alkylthio, -OH, -0-aryl, -0-cycloalkyl, -0-alkyl-aryl, -S-aryl, -S-cycloalkyl, hydroxyalkyl, halogen, haloalkyl, haloalkoxy, -CN, -NOz, hydroxyalkylamine, aminoalkyl, alkylamine, aryl, het-eroaryl 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 Rl and R2 in Za, 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, R, 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 H
N \I /
CI *O'HN
CI
H O 'N+'O
I
CI N,N
COH O. N + I
CI p F F
H CI
V
CI N~N
( I iN
OH CI
CI
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.
I
Z/ 'N"' N~Z
wherein R3 is selected from the group consisting of H, methyl and hydroxyalkyl, and wherein Zs, 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 Rl 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, -CR40, -S02R4, -NR4-CO-R4, alkoxy, alkylthio, -OH, -0-aryl, -0-cycloalkyl, -0-alkyl-aryl, -S-aryl, -S-cycloalkyl, hydroxyalkyl, halogen, haloalkyl, haloalkoxy, -CN, -NOz, hydroxyalkylamine, aminoalkyl, alkylamine, aryl, het-eroaryl 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 Rl and R2 in Za, 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, R, 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 H
N \I /
CI *O'HN
CI
H O 'N+'O
I
CI N,N
COH O. N + I
CI p F F
H CI
V
CI N~N
( I iN
OH CI
CI
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, -0-cycloalkyl, aminoalkyl, alkylamine, aryl and heteroaryl.
In another preferred embodiment, Z, 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 Z. 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 Z1 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 (Z1) is substi-tuted by another phenyl or heteroaryl group which are directly linked to the phenyl group (Z1) or via an ether bond. In a further preferred embodiment, the phenyl group is part of a fused ring sys-tem.
In preferred embodiments, Z1 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 Z1 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, Z, 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 Z. 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 Z1 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 (Z1) is substi-tuted by another phenyl or heteroaryl group which are directly linked to the phenyl group (Z1) or via an ether bond. In a further preferred embodiment, the phenyl group is part of a fused ring sys-tem.
In preferred embodiments, Z1 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 Z1 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.
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 H2Ny NH Oy NH2 N NN N N N
ZN" N I / Z,N, N
H H
The invention further relates to a compound of the formula GI
OH
N\
CI N
H
L5 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 20 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 25 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
30 and most preferred less than 20 pM. The most potent compounds ac-cording to the invention have IC50 values of less than 10 M, more 5 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 10 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.
ZN" N I / Z,N, N
H H
The invention further relates to a compound of the formula GI
OH
N\
CI N
H
L5 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 20 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 25 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
30 and most preferred less than 20 pM. The most potent compounds ac-cording to the invention have IC50 values of less than 10 M, more 5 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 10 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 0.1jig/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 0.1}a.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. 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
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 0.1jig/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 0.1}a.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. 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 Zi, Z2 and R3 are defined as in the foregoing.
H H
+ NZ
Z1 Q ~N Z2 Zi 2 H
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 C1-C6-alkyl, preferably a linear or branched chain of C1-C6 -atoms, a linear or branched C1-C6-alkenyl or a linear or branched C1-C6-alkinyl group, which can optionally be substituted by one or more substituents R3, wherein R3 and R4 are defined as above. C1-C6 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 C1-C4-alkyl, a linear or branched C1-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, t-butyl or the corresponding alkene homologues.
The Cl-C4-alkyl, C1-C4-alkenyl and C1-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 ) =CHZ , -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, -CHz -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 Cl-C4-alkyl and C1-C4-alkenyl residue may include not limited to the following groups -CH3, -C2H5, -CH=CH2, -C3H7, -CH ( CH3 ) Z , -CH2-CH=CH2, -C4H9 , -CH2-CH ( CH3 ) 2 , -CH ( CH3 ) -C2H5 , -CHz-CH ( CH3 ) -CH3 , -C ( CH3 ) 3 =
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, SOz, NR4 and CO; the C4-C7-cycloalkyl residue may be selected from the group comprising -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H11i -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, SOz, NR4 and CO; the C4-C6-cycloalkyl residue may be selected from the group comprising -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H11, 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(R5) 3, -CR5 (R5) 2, -CR5 (R5) R5, -5 C2 (R5) 5, -CHZ-C (R.5) 3, -CH2-CR5 ( RS ) 2, -CH2-CR5 (R5) R5, -C3 (R5) 7 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. 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 10 group is preferably a -C(R5) 3, -CH (R5) a, -CH2-CH (R5) 2, -CH2-C (Rs) 3, -C2H4-CH (R5) Z 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.
H H
+ NZ
Z1 Q ~N Z2 Zi 2 H
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 C1-C6-alkyl, preferably a linear or branched chain of C1-C6 -atoms, a linear or branched C1-C6-alkenyl or a linear or branched C1-C6-alkinyl group, which can optionally be substituted by one or more substituents R3, wherein R3 and R4 are defined as above. C1-C6 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 C1-C4-alkyl, a linear or branched C1-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, t-butyl or the corresponding alkene homologues.
The Cl-C4-alkyl, C1-C4-alkenyl and C1-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 ) =CHZ , -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, -CHz -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 Cl-C4-alkyl and C1-C4-alkenyl residue may include not limited to the following groups -CH3, -C2H5, -CH=CH2, -C3H7, -CH ( CH3 ) Z , -CH2-CH=CH2, -C4H9 , -CH2-CH ( CH3 ) 2 , -CH ( CH3 ) -C2H5 , -CHz-CH ( CH3 ) -CH3 , -C ( CH3 ) 3 =
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, SOz, NR4 and CO; the C4-C7-cycloalkyl residue may be selected from the group comprising -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H11i -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, SOz, NR4 and CO; the C4-C6-cycloalkyl residue may be selected from the group comprising -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H11, 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(R5) 3, -CR5 (R5) 2, -CR5 (R5) R5, -5 C2 (R5) 5, -CHZ-C (R.5) 3, -CH2-CR5 ( RS ) 2, -CH2-CR5 (R5) R5, -C3 (R5) 7 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. 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 10 group is preferably a -C(R5) 3, -CH (R5) a, -CH2-CH (R5) 2, -CH2-C (Rs) 3, -C2H4-CH (R5) Z 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.
15 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 pre f erably a -OC( R5 ) 3, -OCR5 (R5)2, -OCR5 (R5) R5, -OC2 (R5) 5, -OCH2-C (R5) 3, -OCH2-CR5 (R5) 2, -OCH2-CR5 (R5) R5, -OC3 (R5) 7 or -OC2H4-C (R5) 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(R5) 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 (OH-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 R, 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-~ 5 tuted by one or more substituents which are optionally being defined as the residues R1 and/or R2 as mentioned above.
A heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom like 0, N, S. This heterocyc-lic 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, 1,2,4-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, 1H-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 R, 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 R1 and/or R2 as mentioned above.
The invention is further described by way of examples in a merely illustrative manner without limiting the scop.e 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 (4m1) were placed in a G-12 flask. The reaction mixture was heated to reflux for 4 h. A TLC analysis (Hexane/Et0Ac: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 I 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 M. In-Vitro activities were de-termined as described in example 2.
Table 1: List of specific compounds according to general formula I
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 pre f erably a -OC( R5 ) 3, -OCR5 (R5)2, -OCR5 (R5) R5, -OC2 (R5) 5, -OCH2-C (R5) 3, -OCH2-CR5 (R5) 2, -OCH2-CR5 (R5) R5, -OC3 (R5) 7 or -OC2H4-C (R5) 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(R5) 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 (OH-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 R, 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-~ 5 tuted by one or more substituents which are optionally being defined as the residues R1 and/or R2 as mentioned above.
A heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom like 0, N, S. This heterocyc-lic 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, 1,2,4-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, 1H-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 R, 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 R1 and/or R2 as mentioned above.
The invention is further described by way of examples in a merely illustrative manner without limiting the scop.e 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 (4m1) were placed in a G-12 flask. The reaction mixture was heated to reflux for 4 h. A TLC analysis (Hexane/Et0Ac: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 I 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 M. In-Vitro activities were de-termined as described in example 2.
Table 1: List of specific compounds according to general formula I
HPLC/MS
N Structure (ESI) Br ~ I CI 388 Br N, N \ [M+H] +
H
/ CI
2 Cl o 'N\ ~
N [M+H]+
H
CI
&-H-N426 CI H H N Q [M+H]+
v N"-~OH
/
/ O \ I 395 4 a,_ O N' A ~ [M+H] +
i N
H
a-- O / I
N~N ~ O 395 H [M+H]+
H
6 I \ N'N 381 [M+H]+
N
CI
7 O I\ / I 324 / / N~N \ [M+H]+
H
H
N/N )acl 307 8 [M+H]+
N
N Structure (ESI) Br ~ I CI 388 Br N, N \ [M+H] +
H
/ CI
2 Cl o 'N\ ~
N [M+H]+
H
CI
&-H-N426 CI H H N Q [M+H]+
v N"-~OH
/
/ O \ I 395 4 a,_ O N' A ~ [M+H] +
i N
H
a-- O / I
N~N ~ O 395 H [M+H]+
H
6 I \ N'N 381 [M+H]+
N
CI
7 O I\ / I 324 / / N~N \ [M+H]+
H
H
N/N )acl 307 8 [M+H]+
N
CI
I \ ~
9 N H n. d.
O
H
\NN
CI
[M+H]+
CI
/
11 ~ \ ( \ I 289 N"N \ [M+H]+
H
O
12 N I/ \ N~ o 383 N
0 H [M+H]+
H
NN
13 [M+H]+
CI
\ O \ /
14 CI I/ I/ N.N \ [M+H]+
H
H
~
N~N \ [M+H] +
H
N, \ [M+H]
H
S
17 ( 280 N / \ [M+H] +
H
18 JD~! N\ \ I [M+H]+
CI N
H
[M+H]+
. I /
CI
OH o 389 20 I \
[M+H]+
CI / ~NN
H
CI
~ OH /
~ ~ 389 /
I \ ~
9 N H n. d.
O
H
\NN
CI
[M+H]+
CI
/
11 ~ \ ( \ I 289 N"N \ [M+H]+
H
O
12 N I/ \ N~ o 383 N
0 H [M+H]+
H
NN
13 [M+H]+
CI
\ O \ /
14 CI I/ I/ N.N \ [M+H]+
H
H
~
N~N \ [M+H] +
H
N, \ [M+H]
H
S
17 ( 280 N / \ [M+H] +
H
18 JD~! N\ \ I [M+H]+
CI N
H
[M+H]+
. I /
CI
OH o 389 20 I \
[M+H]+
CI / ~NN
H
CI
~ OH /
~ ~ 389 /
21 ci ~ H O
[M+H] +
~ \
/
CI
\. ~cI 299 22 NN [M+H]+
CI
H
OH / CI
~
[M+H] +
~ \
/
CI
\. ~cI 299 22 NN [M+H]+
CI
H
OH / CI
~
23 O N'N [M+H]+
H
CI
CI
H
CI
CI
24 jt cH
\ [M+H]+
CI , N
H
CI
\ OH / ~ CI 315 \ [M+H]+
CI ~ N,N
H
CI
\ [M+H]+
CI , N
H
CI
\ OH / ~ CI 315 \ [M+H]+
CI ~ N,N
H
CI
26 L I \ CI 282 N~N / / [M+H]+
H
OH
CI
H
OH
CI
\ , N\ I / [M+H] +
CI N
H
j:D[ H jo 28 N. O N [M+H]+
H
CI
OH \ 283 CI \ ~ N'N ~ [M+H] +
H
OH \
CI N
H
j:D[ H jo 28 N. O N [M+H]+
H
CI
OH \ 283 CI \ ~ N'N ~ [M+H] +
H
OH \
30 CI \ I N\N /
[M+H]+
H
CI
Ni 'N \
[M+H]+
H
CI
Ni 'N \
H
OJ OH
OH H Br 32 N'N
\ \ \
CI
OJ OH
OH H Br 32 N'N
\ \ \
CI
33 N~ N ~
~1 I
CI NJN~ / CI
H
OH
H
N
+
0:5 la I-O
- HO
35 HN -N~
CI
F
~
- Br 36 F H-N\
-O
CI
CI ~ ~
37 Br H-N~
-O
CI
Br 38 H-N~
-O
F
F
39 Br H_N~
HO
F
F
40 Br H-%
HO Br C(IH OZN 41 N
H
OH /
I OH
N ~H
CI
H
-O OH
CI
- N-N
44 OH O-Cl CI
CI tN-N
45 0=N OH
~-O b CI
CI ~N
I N
46 6cl OH CI CI
H
OH
CI H
~N
OH
O -N"O
H
O
49 OYOHN N+0 I I
H
N~N I \ _ OH N+.O
O~~N+.O
H
51 QO ~ -O
N+0 I I
O
O,Z~, N+.O
H
/ ~N \
I I -OH N+.O
II
O
OH
H
53 N~N
\ \ I /
O
H
O 3r CI
HO
\ N N~ CI
H
56 N 1:?, N H
;10 O ,N,, O
CI
N~N ~
57 N~N ~ I NN~ ~ I CI
H
OH
ci 58 N~ I N
N N ci H OH
Br ci 59 ci N N -N H OH
a i 60 I n. d.
a / /
H
OH
ci [M-H]
H
H I \
ci 386 [M+H]+
I \ I
H
ci N\ [M+H]+
N~ CI
H
F
F
-" 370 [M+H]+
N
H \ / I
H
[M+H]+
a NiN~ \ ( Br [M+H]+
H
OH
a a \ / I
a / N-, [M+H]+
H
OH
CI
I \/ 358 / [M-H] +
OH CI
H
a I I I
\ \ /
[M+H]+
a CI
70 I \ / ( n.d.
H
CI
N~ CI [ M+H ]+
H
OH
N~ [M+H]+
H
OH
N ~ \ I [ M+H ] +
H
OH
74 N)-"N 412 \ I W~ N [ M+H ] +
H
OH
Br / N I N~ I /
H
Br \ I OH
G
76 \ ~ \N 355 CI I [ M+H ] +
H
OH
CI
77 N-)"N / 400 ~~ \ I [M+H]+
H Br OH
cl N--~N [M+H] +
H
a I \ ri~N [ M+H ] +
H
CI
I \ ri \N [M+H]
/ i N
H
CL,a0 81 ~N n. d.
I / /N I
H I
O
82 j N [M+H] +
H
C+1 CI--aO
N ~ \N [M+H]+
H
C
\ I 0 ~ \ I \N [M+H] +
s N
H
F
F
85 N~ I I \
H G-I
a Q
86 \ ~N 352 [M+H]
G
H
O-I
a ~
87 Nl)-,N 367 [M+H]+
H
CH
CI
88 N)'~'N 369 N N ~ \ I CI [ M+H ] +
H
OH
89 N)'~'N 356 I N"N\ \ I [M+H]+
H
OH
~ N I \ [M+H]+
H
OH
C~ a 418 ri,N [M+H] +
a ri'N~ ~ I a H
a-I
a /
N \ I [ M+H ] +
H G
G-I
N Y I a N
93 OH N'NA
[M+H]+
a 94 a 382 'N [M+H]+
a I/ U, l i H
a-I
~ ~
95 c369 I ~ [M+H]+
/ ~
c H
OH
C~
ci I 383 96 ~
OI N N [M+H]+
\
H
OH
/\ ~ F F
97 N/\N 420 I eF [M+H]+
AF
H F
Br 98 Ni 'N 423 N [ M+H ] +
H
OH
99 ~
r~'~nl i I [M+H]+
H
a-I
a 427 N~N / [M+H]+
H N \ \ Br a-I
101 cl 414 ~
\ \ [M+H]+
H Br OH
a 396 N~'N [M+H] +
H
aH
103 ~N 398 N a [M+H]+
H
CH
[M+H]+
N~ CI
H
CH
CI
105 N)~'N 377 , N~N ~ I [M+H]+
H
0-<
a 106 N"~kN 353 ~ N~ N \ \ I [M+H]+
H
~N [M+H]+
H
CH
~ a I [M+H] +
II N a ci /
~ ~
H
CI-I
Ni 'N 343 N [M+H] +
H
& 437 \N [M+H] +
H
OH
a I 411 111 I \ NJi\N +
[M+H]
H
OH
112 ~ N' ~N 399 I ~~
\ ~NiJ\% \ [ M+H ] +
F H
F'- F
~1 I
CI NJN~ / CI
H
OH
H
N
+
0:5 la I-O
- HO
35 HN -N~
CI
F
~
- Br 36 F H-N\
-O
CI
CI ~ ~
37 Br H-N~
-O
CI
Br 38 H-N~
-O
F
F
39 Br H_N~
HO
F
F
40 Br H-%
HO Br C(IH OZN 41 N
H
OH /
I OH
N ~H
CI
H
-O OH
CI
- N-N
44 OH O-Cl CI
CI tN-N
45 0=N OH
~-O b CI
CI ~N
I N
46 6cl OH CI CI
H
OH
CI H
~N
OH
O -N"O
H
O
49 OYOHN N+0 I I
H
N~N I \ _ OH N+.O
O~~N+.O
H
51 QO ~ -O
N+0 I I
O
O,Z~, N+.O
H
/ ~N \
I I -OH N+.O
II
O
OH
H
53 N~N
\ \ I /
O
H
O 3r CI
HO
\ N N~ CI
H
56 N 1:?, N H
;10 O ,N,, O
CI
N~N ~
57 N~N ~ I NN~ ~ I CI
H
OH
ci 58 N~ I N
N N ci H OH
Br ci 59 ci N N -N H OH
a i 60 I n. d.
a / /
H
OH
ci [M-H]
H
H I \
ci 386 [M+H]+
I \ I
H
ci N\ [M+H]+
N~ CI
H
F
F
-" 370 [M+H]+
N
H \ / I
H
[M+H]+
a NiN~ \ ( Br [M+H]+
H
OH
a a \ / I
a / N-, [M+H]+
H
OH
CI
I \/ 358 / [M-H] +
OH CI
H
a I I I
\ \ /
[M+H]+
a CI
70 I \ / ( n.d.
H
CI
N~ CI [ M+H ]+
H
OH
N~ [M+H]+
H
OH
N ~ \ I [ M+H ] +
H
OH
74 N)-"N 412 \ I W~ N [ M+H ] +
H
OH
Br / N I N~ I /
H
Br \ I OH
G
76 \ ~ \N 355 CI I [ M+H ] +
H
OH
CI
77 N-)"N / 400 ~~ \ I [M+H]+
H Br OH
cl N--~N [M+H] +
H
a I \ ri~N [ M+H ] +
H
CI
I \ ri \N [M+H]
/ i N
H
CL,a0 81 ~N n. d.
I / /N I
H I
O
82 j N [M+H] +
H
C+1 CI--aO
N ~ \N [M+H]+
H
C
\ I 0 ~ \ I \N [M+H] +
s N
H
F
F
85 N~ I I \
H G-I
a Q
86 \ ~N 352 [M+H]
G
H
O-I
a ~
87 Nl)-,N 367 [M+H]+
H
CH
CI
88 N)'~'N 369 N N ~ \ I CI [ M+H ] +
H
OH
89 N)'~'N 356 I N"N\ \ I [M+H]+
H
OH
~ N I \ [M+H]+
H
OH
C~ a 418 ri,N [M+H] +
a ri'N~ ~ I a H
a-I
a /
N \ I [ M+H ] +
H G
G-I
N Y I a N
93 OH N'NA
[M+H]+
a 94 a 382 'N [M+H]+
a I/ U, l i H
a-I
~ ~
95 c369 I ~ [M+H]+
/ ~
c H
OH
C~
ci I 383 96 ~
OI N N [M+H]+
\
H
OH
/\ ~ F F
97 N/\N 420 I eF [M+H]+
AF
H F
Br 98 Ni 'N 423 N [ M+H ] +
H
OH
99 ~
r~'~nl i I [M+H]+
H
a-I
a 427 N~N / [M+H]+
H N \ \ Br a-I
101 cl 414 ~
\ \ [M+H]+
H Br OH
a 396 N~'N [M+H] +
H
aH
103 ~N 398 N a [M+H]+
H
CH
[M+H]+
N~ CI
H
CH
CI
105 N)~'N 377 , N~N ~ I [M+H]+
H
0-<
a 106 N"~kN 353 ~ N~ N \ \ I [M+H]+
H
~N [M+H]+
H
CH
~ a I [M+H] +
II N a ci /
~ ~
H
CI-I
Ni 'N 343 N [M+H] +
H
& 437 \N [M+H] +
H
OH
a I 411 111 I \ NJi\N +
[M+H]
H
OH
112 ~ N' ~N 399 I ~~
\ ~NiJ\% \ [ M+H ] +
F H
F'- F
a Ni 'N 397 113 ~ N [M+H]+
H
OH
CI
114 Br / I \ N, N y F n.d.
OH H F F
O, N+-,O
aN---N\ F [M+H]+
Br N
O H F F
F F
F
\ OH 353 [M+H]+
/ N~N
H
OH
O
N [M+H]+
N~N F
H F F
CI
\ N 365 ~ I F
CI / ~ ~N [M+x] +
a I \ I
N-_ / [M+H]+
H
OH
N)--'N N 335 120 ~,NeK N \ \ ~ [ M+H ] +
H
Table 2: List of further specific compounds according to general formula I
Structure HPLC/MS
N (ESI) 1 Br 388 ci [M+H] +
I \ I \
Br N~N
H
2 Ci 254 [M+H]+
I \
CI j ~N /
H
N
+H] +
[M
I I N )ao ~
H N O [M+Hl N
H [M+H]+
N O
N
~
N-\ N [M+H]+
O CI
\ / \ N LM+H]+
N~
CI
N-9 H n. d.
~ ~N
T N
O CI
O
N
\ I /
N [M+Hl +
I \
CI
CI
N [M+Hl +
N~N [M+Hl +
O
N
~ N~N [M+H]+
CI
[M+Hl +
Ci N \ ~ [M+H]+
N
H
N~N Ci [M+Hl N
H
1 [M+Hl N-<\
N I \ I \
N
H
18 Cl 352 0 [M+H]-{ \ \ I
j ~, H
OH
19 ci 352 [M+H]
I / N\ \
N O
H
OH
20 ci 389 Q [M+H]+
I \
CI / ~ ", N
H
OH
[M+H]+
~ ~
OH
22 ci 299 CI [M+H]
, CI N N
H
[M+H]+
CI
N
H
OH
24 ci 328 cl [M+H]+
( \ I \
CI ,,N
H
OH
25 ci 315 CI [M+H]
\ ( \
CI / ~ N
H
OH
26 ci 282 CI [M+Hl -I \ N I
H
OH
27 ci 265 [M+H]+
1 \ I ~
Cl / ~ N.,N
H
0 [M+H}+
j ~N /
c ~ \
H
OH
29 ci 283 [M+H]+
~ \
N., /
Cl ~ H
OH
30 cl 246 [M+H]
( \
N\ /
N
H
OH
H OH
S
N,,N
N ~ \
I /
~.
~~N
S
L N
N
HN
N
OH
H
N\ ~ N
O\
N N NH
N
OH O
O
-N H
~~-N \
HO N N- OH
O
O
H Cf ~~Ny,,,yN"N, N~ N I /
HO
CI
\ \ ~
OH ,IN
HN
Br CI
N N 4 iN ( /
CI H ~ CI
OH
\N~N
O
\ \ N
CI
HO
N
a N
+
p=N
~_ +
N ~ Np N
O
O
NN' N NH ~
O~ ~ N / N /
~
H
OH
H
N
N- H
N J f N'N_ p-O'N N
-~
o HO N{-0 1 ~ ~ H N-N ~ O
- ~ N
0 H/\
N~-,N
O/ N H
N-~
N NH
N
~ O
CI \
130 NH2 Chira!
N IN IN
N N
H
HO,,11 O
I::: OH
HO~~,=.
H / I
N-N O
S~ \
\ \\N CI
I I
F
Br N-N
~
ci j ~
- Br H-N
38 ci 0 Br N-N
~
F
Br HO
F
Br N-N
H 1--o HO Br NH
N ~
O\N N NH CI
N O
N N N, \
~ ~ ~ N
O\N I
N NH O- I
N /
H
NH
N N\1 N) N ~
HO
1 Ir 7 O-N
p N
H H N---N~
F N 1N O~
N / ~N
O' a NH
N ~ N\
N N
1 ~
O-N
~
N N NH O
O / :,, N ~ ~ >
N N N~
H
O ~ ~ S
~ ~_' ~ H
N-~
-'O
HN~ ~
N
S i N
,O
ON
HO -N
H
+
O-N
I
N N NH O
~
'D\ N; , OH
N NH I \
N O CI
O O
F ~ ~ H H-N / \ I OH
- // \\
N N
// \\
N", "IN
142 \
/
x, OH
N
HN
N
N
143 NH2 Chiral N~ 'N N N
~\ ~ \ \
N H
HO,,,,= O
HO OH
~ I OH
N~N ~
H
OH
/ N,N, CI
N\ N
\/ O
CI
O
HN
---' N
S
H OH
S
N,,N Br N-"/ I N
Br N-N
CI
N-N
O-Cl CI
45 c!
H
N~N
OH
+
/ ~
H
- N-N
N _N
-N
S
46 C!
c! Ci C! N\
N
OH H
Cl OH NNH
CI
O OH
I+ H
O%N N,,N
\ l \ I
ci . 148 O -O~N+, HO
CI
4g OH
H
N' N+;O
1_ O
CI
H
N' N+'O
I_ O
51 \ OH
O~
+-O
N N
N' N+,O
O
O1, N+.O
N+ ,O
H
\ \ I I
H
N
0 Br ~ \ \
HN
OH
S N) N-N
N_ N CI
OH
OH
N
-N / +
O-N
N
N
H
N~--N \N-HO CI
CI
58 cI
N
I I \
N N~N CI
H
Br OH
?N\ CI
CI
~ N,~
N OH
N H
O / I
[M+H]+
\
O
H
0 a [M+H]+
~~'p j ~N o \ /
O
[M+H]+
N
H
O
[M+H]+
0 j N
H
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 10 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 15 l/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 l/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, 70~ of 0.1 M Na-Ac pH=4.5 20 and 20 l rhBACE1 (10 g/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)=0 is measured with a Wallac1420 plate reader (excitation 355nm, emission 486nm).
25 The reactions are measured again after incubation for 60 min at 37 C
with gentle shaking. Relative compound inhibition potency is deter-,mined by calculating the concentration of compound that showed a 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 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 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.
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. At the end of the treatment period (24h), conditioned media is analyzed for beta-secretase activity, for example, by analysis of cleavage fragments.
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 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 M:
Nl, N8, N10, 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 C57/b16 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 -80 C. The brain was cut into 200 mg pieces, 800 l 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, õsuch as APP695-SW and the like described herein. Examples of trans-- 5 genic 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.
H
OH
CI
114 Br / I \ N, N y F n.d.
OH H F F
O, N+-,O
aN---N\ F [M+H]+
Br N
O H F F
F F
F
\ OH 353 [M+H]+
/ N~N
H
OH
O
N [M+H]+
N~N F
H F F
CI
\ N 365 ~ I F
CI / ~ ~N [M+x] +
a I \ I
N-_ / [M+H]+
H
OH
N)--'N N 335 120 ~,NeK N \ \ ~ [ M+H ] +
H
Table 2: List of further specific compounds according to general formula I
Structure HPLC/MS
N (ESI) 1 Br 388 ci [M+H] +
I \ I \
Br N~N
H
2 Ci 254 [M+H]+
I \
CI j ~N /
H
N
+H] +
[M
I I N )ao ~
H N O [M+Hl N
H [M+H]+
N O
N
~
N-\ N [M+H]+
O CI
\ / \ N LM+H]+
N~
CI
N-9 H n. d.
~ ~N
T N
O CI
O
N
\ I /
N [M+Hl +
I \
CI
CI
N [M+Hl +
N~N [M+Hl +
O
N
~ N~N [M+H]+
CI
[M+Hl +
Ci N \ ~ [M+H]+
N
H
N~N Ci [M+Hl N
H
1 [M+Hl N-<\
N I \ I \
N
H
18 Cl 352 0 [M+H]-{ \ \ I
j ~, H
OH
19 ci 352 [M+H]
I / N\ \
N O
H
OH
20 ci 389 Q [M+H]+
I \
CI / ~ ", N
H
OH
[M+H]+
~ ~
OH
22 ci 299 CI [M+H]
, CI N N
H
[M+H]+
CI
N
H
OH
24 ci 328 cl [M+H]+
( \ I \
CI ,,N
H
OH
25 ci 315 CI [M+H]
\ ( \
CI / ~ N
H
OH
26 ci 282 CI [M+Hl -I \ N I
H
OH
27 ci 265 [M+H]+
1 \ I ~
Cl / ~ N.,N
H
0 [M+H}+
j ~N /
c ~ \
H
OH
29 ci 283 [M+H]+
~ \
N., /
Cl ~ H
OH
30 cl 246 [M+H]
( \
N\ /
N
H
OH
H OH
S
N,,N
N ~ \
I /
~.
~~N
S
L N
N
HN
N
OH
H
N\ ~ N
O\
N N NH
N
OH O
O
-N H
~~-N \
HO N N- OH
O
O
H Cf ~~Ny,,,yN"N, N~ N I /
HO
CI
\ \ ~
OH ,IN
HN
Br CI
N N 4 iN ( /
CI H ~ CI
OH
\N~N
O
\ \ N
CI
HO
N
a N
+
p=N
~_ +
N ~ Np N
O
O
NN' N NH ~
O~ ~ N / N /
~
H
OH
H
N
N- H
N J f N'N_ p-O'N N
-~
o HO N{-0 1 ~ ~ H N-N ~ O
- ~ N
0 H/\
N~-,N
O/ N H
N-~
N NH
N
~ O
CI \
130 NH2 Chira!
N IN IN
N N
H
HO,,11 O
I::: OH
HO~~,=.
H / I
N-N O
S~ \
\ \\N CI
I I
F
Br N-N
~
ci j ~
- Br H-N
38 ci 0 Br N-N
~
F
Br HO
F
Br N-N
H 1--o HO Br NH
N ~
O\N N NH CI
N O
N N N, \
~ ~ ~ N
O\N I
N NH O- I
N /
H
NH
N N\1 N) N ~
HO
1 Ir 7 O-N
p N
H H N---N~
F N 1N O~
N / ~N
O' a NH
N ~ N\
N N
1 ~
O-N
~
N N NH O
O / :,, N ~ ~ >
N N N~
H
O ~ ~ S
~ ~_' ~ H
N-~
-'O
HN~ ~
N
S i N
,O
ON
HO -N
H
+
O-N
I
N N NH O
~
'D\ N; , OH
N NH I \
N O CI
O O
F ~ ~ H H-N / \ I OH
- // \\
N N
// \\
N", "IN
142 \
/
x, OH
N
HN
N
N
143 NH2 Chiral N~ 'N N N
~\ ~ \ \
N H
HO,,,,= O
HO OH
~ I OH
N~N ~
H
OH
/ N,N, CI
N\ N
\/ O
CI
O
HN
---' N
S
H OH
S
N,,N Br N-"/ I N
Br N-N
CI
N-N
O-Cl CI
45 c!
H
N~N
OH
+
/ ~
H
- N-N
N _N
-N
S
46 C!
c! Ci C! N\
N
OH H
Cl OH NNH
CI
O OH
I+ H
O%N N,,N
\ l \ I
ci . 148 O -O~N+, HO
CI
4g OH
H
N' N+;O
1_ O
CI
H
N' N+'O
I_ O
51 \ OH
O~
+-O
N N
N' N+,O
O
O1, N+.O
N+ ,O
H
\ \ I I
H
N
0 Br ~ \ \
HN
OH
S N) N-N
N_ N CI
OH
OH
N
-N / +
O-N
N
N
H
N~--N \N-HO CI
CI
58 cI
N
I I \
N N~N CI
H
Br OH
?N\ CI
CI
~ N,~
N OH
N H
O / I
[M+H]+
\
O
H
0 a [M+H]+
~~'p j ~N o \ /
O
[M+H]+
N
H
O
[M+H]+
0 j N
H
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 10 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 15 l/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 l/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, 70~ of 0.1 M Na-Ac pH=4.5 20 and 20 l rhBACE1 (10 g/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)=0 is measured with a Wallac1420 plate reader (excitation 355nm, emission 486nm).
25 The reactions are measured again after incubation for 60 min at 37 C
with gentle shaking. Relative compound inhibition potency is deter-,mined by calculating the concentration of compound that showed a 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 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 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.
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. At the end of the treatment period (24h), conditioned media is analyzed for beta-secretase activity, for example, by analysis of cleavage fragments.
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 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 M:
Nl, N8, N10, 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 C57/b16 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 -80 C. The brain was cut into 200 mg pieces, 800 l 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, õsuch as APP695-SW and the like described herein. Examples of trans-- 5 genic 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 (17)
1. Hydrazone derivative of 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 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, -O-aryl, -O-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, -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 hetero-cyclic ring system, or a salt, or a physiologically functional derivative, or a prodrug thereof, whereas the compounds are not comprised within 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 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, -O-aryl, -O-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, -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 hetero-cyclic ring system, or a salt, or a physiologically functional derivative, or a prodrug thereof, whereas the compounds 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 Z, 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.
8. Compound according to one of the claims 1 to 3 and 7, charac-terized in that the compound has one of the following formulas
9. Compound of the formula
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.
Applications Claiming Priority (5)
| 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 | ||
| PCT/EP2005/009902 WO2006029850A1 (en) | 2004-09-14 | 2005-09-14 | Hydrazone derivatives and their use as beta secretase inhibitors |
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| CA2579472A1 true CA2579472A1 (en) | 2006-03-23 |
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| CA002579472A Abandoned CA2579472A1 (en) | 2004-09-14 | 2005-09-14 | Hydrazone derivatives and their use as beta secretase inhibitors |
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| JP (1) | JP2008513364A (en) |
| CA (1) | CA2579472A1 (en) |
| WO (1) | WO2006029850A1 (en) |
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| US7763609B2 (en) | 2003-12-15 | 2010-07-27 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
| CN103936690B (en) | 2005-10-25 | 2016-06-08 | 盐野义制药株式会社 | Aminodihydrothiazinederivative derivative |
| 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 |
| SI2091948T1 (en) | 2006-11-30 | 2012-07-31 | Probiodrug Ag | Novel inhibitors of glutaminyl cyclase |
| EP2481408A3 (en) | 2007-03-01 | 2013-01-09 | Probiodrug AG | New use of glutaminyl cyclase inhibitors |
| DK2142514T3 (en) | 2007-04-18 | 2015-03-23 | Probiodrug Ag | Thiourea derivatives as glutaminyl cyclase inhibitors |
| MX2009011498A (en) | 2007-04-24 | 2009-11-10 | Shionogi & Co | Aminodihydrothiazine derivatives substituted with cyclic groups. |
| EP2151435A4 (en) | 2007-04-24 | 2011-09-14 | Shionogi & Co | Pharmaceutical composition for treatment of alzheimer's disease |
| US7858666B2 (en) * | 2007-06-08 | 2010-12-28 | Mannkind Corporation | IRE-1α inhibitors |
| KR20130018370A (en) | 2008-06-13 | 2013-02-20 | 시오노기세야쿠 가부시키가이샤 | SULFUR-CONTAINING HETEROCYCLIC DERIVATIVE HAVING β-SECRETASE-INHIBITING ACTIVITY |
| EP2330906A4 (en) * | 2008-08-15 | 2014-07-09 | Univ Louisville Res Found | Compounds, their syntheses, and their uses |
| JPWO2010047372A1 (en) | 2008-10-22 | 2012-03-22 | 塩野義製薬株式会社 | 2-Aminopyrimidin-4-one and 2-aminopyridine derivatives having BACE1 inhibitory activity |
| AR077999A1 (en) * | 2009-09-02 | 2011-10-05 | Vifor Int Ag | ANTIGONISTS OF PYRIMIDIN AND TRIAZIN-HEPCIDINE |
| AU2010294214B2 (en) | 2009-09-11 | 2015-05-07 | Vivoryon Therapeutics N.V. | Heterocylcic derivatives as inhibitors of glutaminyl cyclase |
| WO2011041737A2 (en) * | 2009-10-02 | 2011-04-07 | 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 |
| WO2011071135A1 (en) | 2009-12-11 | 2011-06-16 | 塩野義製薬株式会社 | Oxazine derivative |
| JP6026284B2 (en) | 2010-03-03 | 2016-11-16 | プロビオドルグ エージー | Inhibitors of glutaminyl cyclase |
| AU2011226074B2 (en) | 2010-03-10 | 2015-01-22 | Vivoryon Therapeutics N.V. | Heterocyclic inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5) |
| EP2560953B1 (en) | 2010-04-21 | 2016-01-06 | Probiodrug AG | Inhibitors of glutaminyl cyclase |
| EP2634188A4 (en) | 2010-10-29 | 2014-05-07 | Shionogi & Co | Fused aminodihydropyrimidine derivative |
| US8927721B2 (en) | 2010-10-29 | 2015-01-06 | Shionogi & Co., Ltd. | Naphthyridine derivative |
| JP6050264B2 (en) | 2011-03-16 | 2016-12-21 | プロビオドルグ エージー | Benzimidazole derivatives as inhibitors of glutaminyl cyclase |
| WO2012147763A1 (en) | 2011-04-26 | 2012-11-01 | 塩野義製薬株式会社 | Oxazine derivative and bace 1 inhibitor containing same |
| WO2014065434A1 (en) | 2012-10-24 | 2014-05-01 | Shionogi & Co., Ltd. | Dihydrooxazine or oxazepine derivatives having bace1 inhibitory activity |
| US10322125B2 (en) * | 2013-02-22 | 2019-06-18 | Emory University | TGF-beta enhancing compositions for cartilage repair and methods related thereto |
| PL3461819T3 (en) | 2017-09-29 | 2020-11-30 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
| KR102128509B1 (en) * | 2018-12-19 | 2020-07-01 | 한국과학기술연구원 | Novel hydrazone derivatives comprising aryl or heteroaryl group substituted at terminal amine and use thereof |
| BR102020005423A2 (en) | 2020-03-18 | 2021-09-28 | Faculdades Catolicas | N-ACYL HYDRAZONE COMPOUNDS, USE IN THE TREATMENT OF AMYLOID AND NON-AMYLOID DEGENERATIVE AGGREGOPATIES, AND PHARMACEUTICAL COMPOSITION |
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| 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 |
| JP2005516967A (en) * | 2002-01-18 | 2005-06-09 | ザ ジェネティクス カンパニー インコーポレーティッド | β-secretase inhibitor |
| GB0300804D0 (en) * | 2003-01-14 | 2003-02-12 | Novo Pharmaceuticals De Ltd | Compounds and their use |
| EP1612204A4 (en) * | 2003-03-31 | 2007-04-11 | Daiichi Seiyaku Co | Hydrazone derivative |
| US7977366B2 (en) * | 2003-10-14 | 2011-07-12 | Cornell Research Foundation, Inc. | Treating an inflammatory disorder or inhibiting respiratory burst in adherent neutrophils with chemical inhibitors of neutrophil activation |
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- 2005-09-14 CA CA002579472A patent/CA2579472A1/en not_active Abandoned
- 2005-09-14 JP JP2007530679A patent/JP2008513364A/en active Pending
- 2005-09-14 WO PCT/EP2005/009902 patent/WO2006029850A1/en not_active Application Discontinuation
- 2005-09-14 EP EP05787258A patent/EP1791818A1/en not_active Withdrawn
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| Publication number | Publication date |
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| WO2006029850A1 (en) | 2006-03-23 |
| JP2008513364A (en) | 2008-05-01 |
| EP1791818A1 (en) | 2007-06-06 |
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