JP2008513364A - Hydrazone derivatives and their use as beta-secretase inhibitors - Google Patents

Abstract

ただし、Ｒ_３は、Ｈ、メチル、及びヒドロキシアルキルからなる群より選択され、さらに、Ｚ_１およびＺ_２は、それぞれ独立して、置換基としてｎ個のＲ_１及びｍ個のＲ_２を有する置換されたまたは非置換のフェニル、ナフチル、ピリジニル、ピラゾリル、ピリミジニル、ピラジジニル、キノリニル、イソ−キノリニル、クマリニル、インドリル、チアゾリル及びチオフェニル基からなる群より選択され、Ｒ_１およびＲ_２は、同じであってもあるいは互いに異なるものであってもよく、Ｈ、アルキル、シクロアルキル、−ＣＯ_２Ｒ_４、−ＣＯＮＨＲ_４、−ＣＲ_４Ｏ、−ＳＯ_２Ｒ_４、−ＮＲ_４−ＣＯ−Ｒ_４、アルコキシ、アルキルチオ、−ＯＨ、−Ｏ−アリール、−Ｏ−シクロアルキル、−Ｓ−アリール、−Ｓ−シクロアルキル、ヒドロキシアルキル、ハロゲン、ハロアルキル、ハロアルコキシ、−ＣＮ、−ＮＯ_２、ヒドロキシアルキルアミン、アミノアルキル、アルキルアミン、アリール、ヘテロアリールおよびスルホンアミドからなる群より選択され、この際、Ｒ_４は、Ｈ、Ｃ_１からＣ_６の分岐鎖のまたは分岐しないアルキル、アリール、シクロアルキル、アルコキシ、ヘテロシクロアルキル、−ＯＨ、−Ｏ−アリール、−Ｏ−アルキル、−Ｏ−シクロアルキル、アミノアルキル、アルキルアミン、アリール及びヘテロアリールからなる群より選択され、さらに、ｎおよびｍは、それぞれ、Ｚ_１およびＺ_２中の置換基Ｒ_１及びＲ_２の数であり、０〜５であり、この際、ｎおよびｍが２以上の整数である場合には、Ｒ_１および／またはＲ_２は、縮合芳香族環系または炭素環系または複素環系を形成してもよい、
を有する化合物、またはこの塩、または生理学的に機能を有する誘導体、またはプロドラッグに関する。The present invention relates to general formula (I)

Wherein R ₃ is selected from the group consisting of H, methyl, and hydroxyalkyl, and Z ₁ and Z ₂ each independently have n R ₁ and m R ₂ as substituents. Selected from the group consisting of substituted or unsubstituted phenyl, naphthyl, pyridinyl, pyrazolyl, pyrimidinyl, pyrazidinyl, quinolinyl, iso-quinolinyl, coumarinyl, indolyl, thiazolyl and thiophenyl groups, and R ₁ and R ₂ are the same Or may be different from each other, H, alkyl, cycloalkyl, —CO ₂ R ₄ , —CONHR ₄ , —CR ₄ O, —SO ₂ R ₄ , —NR ₄ —CO—R ₄ , alkoxy , Alkylthio, -OH, -O-aryl, -O-cycloalkyl, -S-aryl, -S-cycloalkyl , Hydroxyalkyl, halogen, haloalkyl, haloalkoxy, -CN, -NO _2, hydroxyalkylamines, aminoalkyl, alkylamine, aryl, heteroaryl and sulfonamide, this time, _{R 4} is, H , C ₁ to C ₆ branched or unbranched alkyl, aryl, cycloalkyl, alkoxy, heterocycloalkyl, —OH, —O-aryl, —O-alkyl, —O-cycloalkyl, aminoalkyl, alkylamine , Aryl and heteroaryl, and n and m are the number of substituents R ₁ and R ₂ in Z ₁ and Z ₂ , respectively, 0 to 5, where n and when m is an integer of 2 or more, R ₁ and / or R ₂ are fused aromatic ring Or it may form a carbocyclic or heterocyclic ring system,
Or a salt thereof, or a physiologically functional derivative or prodrug.

Description

  The present invention relates to novel hydrazone derivatives and the use of such hydrazone derivatives as β-secretase inhibitors.

  Alzheimer's disease (AD) is a very common form of human dementia, particularly affecting the parts of the brain that control memory and language.

  The onset of AD is associated with brain protein clusters, also called “amyloid plaques” and “neurofibrillary tangles”. These protein clusters include β-amyloid precursor protein (β-APP). β-APP is degraded by β-Amyloid Converting Enzyme (BACE, also known as β-secretase) and β-amyloid peptide is the main component of these clusters of amyloid plaques To produce. BACE activity has been shown to be an early step in the pathogenesis of AD.

  Accordingly, it is an object of the present invention to provide novel compounds that function as inhibitors of BACE and are therefore useful for therapeutic purposes in the treatment of AD.

  The purpose of this is to formula I

Where R ₃ is selected from the group consisting of H, methyl, and hydroxyalkyl;
In addition, Z ₁ and Z ₂ are each independently substituted or unsubstituted phenyl, naphthyl, pyridinyl, pyrazolyl, pyrimidinyl, pyrazidinyl, quinolinyl having n R ₁ and m R ₂ as substituents. , Selected from the group consisting of iso-quinolinyl, coumarinyl, indolyl, thiazolyl and thiophenyl groups;
R ₁ and R ₂ may be the same or different from each other, and H, alkyl, cycloalkyl, —CO ₂ R ₄ , —CONHR ₄ , —CR ₄ O, —SO ₂ R ₄ , —NR ₄ —CO—R ₄ , alkoxy, alkylthio, —OH, —O-aryl, —O-cycloalkyl, —S-aryl, —S-cycloalkyl, hydroxyalkyl, halogen, haloalkyl, haloalkoxy, —CN , —NO ₂ , hydroxyalkylamine, aminoalkyl, alkylamine, aryl, heteroaryl and sulfonamide,
In this case, R ₄ is H, C ₁ to C ₆ branched or unbranched alkyl, aryl, cycloalkyl, alkoxy, heterocycloalkyl, —OH, —O-aryl, —O-alkyl, —O—. Selected from the group consisting of cycloalkyl, aminoalkyl, alkylamine, aryl and heteroaryl;
N and m are the numbers of substituents R ₁ and R ₂ in Z ₁ and Z ₂ , respectively, and are 0 to 5,
In this case, when n and m are integers of 2 or more, R ₁ and / or R ₂ may form a condensed aromatic ring system, a carbocyclic system or a heterocyclic ring system,
A hydrazone derivative that acts as a β-secretase inhibitor, or a salt thereof, or a physiologically functional derivative or prodrug,
However, the following compounds

Not included in Formula I,
It is solved by providing a hydrazone derivative, or a salt thereof, or a physiologically functional derivative, or prodrug.

  The above objects are further solved by providing a hydrazone derivative that acts as a β-secretase inhibitor having the general formula I, or a salt thereof, or a physiologically functional derivative, or prodrug.

Provided that Z ₁ and Z ₂ are each independently substituted or unsubstituted cyclic and acyclic alkyl having the substituents (R ₁ ) _n and (R ₂ ) _m , phenyl, naphthyl, pyridinyl, Selected from the group consisting of pyrrolinyl, pyrazolyl, pyrimidinyl, pyrazidinyl, quinolinyl, isoquinolinyl, coumarinyl, indolyl, triazinyl (including 1,2,4 and 1,3,5-triazinyl), imidazolyl, thiazolyl, thiophenyl and oxazolyl groups;
The number of the substituents (R ₁ ) _n and (R ₂ ) _m in Z ₁ and Z ₂ is 0 to 5, and R ₁ and R ₂ are H, alkyl, cycloalkyl, —CO _{2. R 4, -CONHR 4, -CR 4} O, -SO 2 R 4, -NR 4 -CO-R 4, alkoxy, alkylthio, -OH, -SH, -O- aryl, -O- cycloalkyl, -S - aryl, -S- cycloalkyl, hydroxyalkyl, halogen, haloalkyl, haloalkoxy, CN, NO _2, hydroxyalkylamine, aminoalkyl, alkylamine, aryl or heteroaryl, selected from the group consisting of sulfones and sulfonamides,
Here, R ₁ and R ₂ may be the same or different from each other,
Furthermore, when n and m are integers greater than or equal to 2, R ₁ and / or R ₂ may form a fused aromatic or carbocyclic or heterocyclic ring system,
R ₃ is selected from the group consisting of H, C ₁ to C ₆ branched or unbranched alkyl, aryl, heteroaryl; haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocycloalkyl;
R ₄ is H, C ₁ to C ₆ branched or unbranched alkyl, aryl, cycloalkyl, alkoxy, heterocycloalkyl, —OH, —O-aryl, —O-alkyl, —O-cycloalkyl, Selected from the group consisting of aminoalkyl, alkylamine, aryl or heteroaryl;
In this case, the following compound

Not included in Formula I.

  The above objects are further solved by providing a hydrazone derivative that acts as a β-secretase inhibitor having the general formula I, or a salt thereof, or a physiologically functional derivative, or prodrug.

Where R ₃ is selected from the group consisting of H, methyl and hydroxyalkyl;
In addition, Z ₁ and Z ₂ are each independently substituted or unsubstituted phenyl, naphthyl, pyridinyl, pyrazolyl, pyrimidinyl, pyrazidinyl, quinolinyl having n R ₁ and m R ₂ as substituents. Selected from the group consisting of isoquinolinyl, coumarinyl, indolyl, thiazolyl and thiophenyl groups;
In this case, R ₁ and R ₂ may be the same or different from each other, but H, alkyl, cycloalkyl, —CO ₂ R ₄ , —CONHR ₄ , —CR ₄ O, — _{SO 2 R 4, -NR 4 -CO} -R 4, alkoxy, alkylthio, -OH, -O- aryl, -O- cycloalkyl, -O- alkyl - aryl, -S- aryl, -S- cycloalkyl, Selected from the group consisting of hydroxyalkyl, halogen, haloalkyl, haloalkoxy, —CN, —NO ₂ , hydroxyalkylamine, aminoalkyl, alkylamine, aryl, heteroaryl and sulfonamide;
In this case, R ₄ is H, C ₁ to C ₆ branched or unbranched alkyl, aryl, cycloalkyl, alkoxy, heterocycloalkyl, —OH, —O-aryl, —O-alkyl, —O—. Selected from the group consisting of cycloalkyl, aminoalkyl, alkylamine, aryl and heteroaryl;
In this case, n and m are the numbers of substituents R ₁ and R ₂ in Z ₁ and Z ₂ , respectively, and are in the range of 0 to 5,
When n and m are integers greater than or equal to 2, R ₁ and / or R ₂ may form a fused aromatic or carbocyclic or heterocyclic ring system,
However, the following compounds

Not included in Formula I.

  It is understood that general formula I includes the corresponding isomers, ie the E and Z forms.

  Examples of such salts include, but are not limited to, alkali metal salts, particularly sodium and potassium salts, or ammonium salts.

  The compounds according to the invention may contain one or more asymmetric carbons in the R or S configuration, so that the compounds may exist as racemates or racemic mixtures, pure enantiomers, diastereomeric mixtures, etc. It is understood.

In preferred embodiments, R ₄ is H, C ₁ to C ₄ branched or unbranched alkyl, aryl, cycloalkyl, alkoxy, heterocycloalkyl, —OH, —O-aryl, —O-alkyl, Selected from the group consisting of -O-cycloalkyl, aminoalkyl, alkylamine, aryl and heteroaryl.

In other preferred embodiments, Z ₁ is a substituted phenyl group, wherein in an even more preferred embodiment, the substituted phenyl is exemplified by the numbers 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, Substituted with at least one halogen atom or at least one hydroxyl group, such as 113, 114, 118 and 119.

In a further preferred embodiment of the invention, Z ₁ is a substituted phenyl substituted with at least two halogen atoms and one hydroxyl group, and in another preferred embodiment of the invention the hydroxyl group is O-position relative to the binding position of the hydrazone motif.

Furthermore, in a preferred embodiment of the invention, Z ₁ is a substituted phenyl group having at least one substituted or unsubstituted aryl or heteroaryl ring or one or two tert-butyl groups. is there.

  In another preferred embodiment, the phenyl group (Z1) is substituted with another phenyl or heteroaryl group linked to the phenyl group (Z1) directly or via an ether bond. In a more preferred embodiment, the phenyl group is part of a fused ring system.

In preferred embodiments, Z ₁ is a substituted phenyl group, where in an even more preferred embodiment, the substituted phenyl group is at least one halogen atom or at least one hydroxy group. Replaced.

Furthermore, in another preferred embodiment of the invention, Z ₁ has 2 or 3 substituents which may be the same or different from each other, preferentially 1 In the o-position relative to the binding position of the hydrazone motif.

In other preferred embodiments, Z ₂ is selected from the group consisting of substituted or unsubstituted phenyl, pyridinyl and pyrimidinyl groups.

In further preferred embodiments, Z ₂ is a phenyl group that is preferably substituted with a benzyl group attached to the phenyl group via an ether linkage, such as Exemplification numbers 4-6, 18-21, and 65.

  Furthermore, in a preferred embodiment of the present invention, the benzyl group linked to the phenyl group via an ether bond is a substituted or unsubstituted benzyloxy group.

In further preferred embodiments, Z ₂ is a substituted or unsubstituted cycloalkyl group or disubstituted, such as Exemplified Numbers 3, 31, 74, 76-84, 86-102, 105-110 and 112. It is a pyrimidyl ring having an amino group.

In a further preferred embodiment, Z ₂ is a pyridyl ring having a trifluoromethyl group, such as exemplary numbers 114-118.

In still other preferred embodiments, Z ₂ is an unsubstituted phenyl group.

In another preferred embodiment, Z ₂ is a phenyl group having at least one halogen substituent.

In a further preferred embodiment of the invention, Z ₂ is a phenyl group having at least two halogen substituents which may be the same or different from each other.

In another preferred embodiment of the invention, Z ₂ is a phenyl group having at least one substituent selected from the group consisting of methyl, trifluoromethyl, hydroxy, carboxyl or ether groups, and even more preferred In embodiments, it is a substituted or unsubstituted benzyloxy group.

In another preferred embodiment, one substituent in Z ₂ are in the o- respect to the binding position of the hydrazone motif.

  In yet a further preferred embodiment, the compound has one of the following formulas:

  The invention further relates to compounds of the formula

  Other preferred compounds are those listed in Table 1.

  Other preferred compounds are those listed in Table 2.

  The invention further relates to the use of the compounds according to the invention as a medicament.

  The invention further relates to the use of the compounds according to the invention for the preparation of a pharmaceutical composition for the treatment or prevention of conditions or diseases mediated by β-secretase. The compounds according to the present invention are useful as drugs, in particular as β-secretase inhibitors. β-secretase is very effectively inhibited and the compounds according to the invention have an IC50 value of less than 120 μM, more preferably less than 100 μM, even more preferably less than 50 μM and most preferably less than 20 μM. The most potent compounds according to the invention have IC50 values of less than 10 [mu] M, more preferably less than 8 [mu] M and most preferably less than 6 [mu] M, such as for example compound numbers 60, 61, 74-81.

  The invention further relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition which inhibits the formation of β-amyloid peptide of the amyloid precursor protein APP. The compounds according to the invention are well suited for inhibiting the formation of β-amyloid peptide of the amyloid precursor protein APP. Thus, the compounds according to the invention are due to the formation of β-amyloid peptides such as Alzheimer's disease, Down's syndrome, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with Dutch amyloidosis (HCHWA-D) and other degenerative dementias Suitable for the manufacture of a pharmaceutical composition for the treatment or prevention of symptoms or diseases.

  The present invention further provides a pharmaceutical composition for the treatment or prevention of Alzheimer's disease, neurodegeneration, memory and attention deficits, cell proliferation dysfunction, or other diseases associated with or responsive to inhibition of β-amyloid peptide The use of the compounds according to the invention for the preparation of

  The present invention is further selected from the group consisting of Alzheimer's disease, Down's syndrome, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with Dutch amyloidosis (HCHWA-D) and other degenerative dementia characterized by β-amyloid deposition The use of the compounds according to the invention for the preparation of a pharmaceutical composition for the treatment or prevention of certain symptoms or diseases.

  The present invention further relates to a pharmaceutical composition comprising a compound according to the present invention or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the pharmaceutical 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 their pharmaceutically acceptable salts. A pharmaceutical composition comprising a compound according to the invention or a pharmaceutically active salt thereof may further comprise at least one pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, it is also understood that more active compounds are included in the composition.

  The compounds according to the invention are administered, for example, in the form of tablets, gels, capsules, patches, ointments, creams, topically, orally, transdermally, parenterally, sublingually, intranasally, intrathecally, rectally, inhaled or intravenously May be formulated for use. Parenteral delivery may be carried by a depot, syringe, ampoule or vial.

  Thus, the compounds of the present invention may be incorporated into pharmaceutical compositions and unit dosage forms thereof with known adjuvants, carriers, or diluents, and in such forms, as solid, liquid or sterile injections It may be used in the form of a possible solution. When using a solid carrier, the formulation may be tableted and placed in a hard gelatin capsule in the form of a powder or pellets, or in the form of a troche or lozenge. The solid carrier may contain known excipients such as binders, tableting lubricants, fillers, disintegrants, wetting agents and the like. The tablets may be film coated by known techniques. When using a liquid carrier, the formulation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile vehicle for injection, aqueous or non-aqueous liquid suspension, or water prior to use. Alternatively, it may be a dry product that is reconstituted with another suitable vehicle. Liquid formulations may contain known additives such as suspending agents, emulsifying agents, wetting agents, non-aqueous vehicles (including edible oils), preservatives, and even fragrances and / or coloring agents. For parenteral administration, the vehicle will usually contain sterile water, at least in large part, although saline, glucose solutions, and the like may be used. Injectable suspensions may be used, in which case known suspending agents may be used. Known preservatives, buffers and the like may also be added to the parenteral dosage form. However, administration can also be effected rectally, for example in the form of suppositories, or vaginally in the form of, for example, pessaries, tampons, creams or, for example, ointments, creams or tinctures. It may be carried out transdermally in the form of an agent.

  A suitable dose of a compound or pharmaceutical composition according to the present invention to a mammal, particularly a human, suffering from or likely to suffer from any of the symptoms described herein is about 0.1 μg / kg ( NB: There are several examples of compounds delivered at lower doses, such as certain hormones, for example) active ingredient in an amount of 500 mg / kg body weight. For parenteral administration, the dosage can range from 0.1 μg / kg to 100 mg / kg body weight by intravenous administration. It may be preferable to administer the active ingredient in an equal amount 1 to 4 times daily. The compound of formula (I) may also be used in the form of a precursor (prodrug) or in a form suitably modified to release the active compound in vivo. Usually, the dosage will increase gradually until the optimum effective dosage in the treatment host is determined. The optimal dosage may vary depending on the condition being treated, the choice of compound to be administered, the route of administration, the individual's gender, age, weight and specific response regarding the severity of the individual's symptoms, depending on the attending physician or other It will be determined by one skilled in the art.

  The pharmaceutical compositions are prepared by known techniques appropriate to the desired formulation containing the appropriate amount of the active ingredient, ie the compound of the invention. Such pharmaceutical compositions and unit dosage forms thereof may contain known ingredients in known proportions, with or without the addition of active compounds or ingredients, such unit dosage forms being used An appropriate effective amount of the active ingredient commensurate with the prescribed daily dosage range to be administered.

The compounds of the present invention are prepared by methods known in the art for the synthesis of hydrazones. Reaction of an aldehyde or ketone of formula II with a compound of formula III yields a general I hydrazone derivative according to the invention, wherein the substituents Z ₁ , Z ₂ and R ₃ are as defined above. Is particularly preferred.

  The hydrazine of the general formula III is not limited to the following, but preferably is reacted at room temperature with an aldehyde or ketone of the general formula II under an appropriate condition under an ion exchange resin catalyst to obtain a compound I.

In compounds I and III of the reaction scheme, Z ₂ is preferably selected from the group consisting of substituted or unsubstituted phenyl, pyridinyl and pyrimidinyl groups.

The terms used herein for chemical substances are defined as follows.
Unless otherwise specified, alkyl groups are straight or branched C ₁ -C ₆ alkyl, preferably straight or branched C ₁ -C ₆ -atoms, straight or branched C ₁ -C ₆ -alkenyl. Or a linear or branched C ₁ -C ₆ -alkynyl group, which may be optionally substituted with one or more substituents R ₃ , wherein R ₃ and R ₄ are The definition is the same as described above. C ₁ -C ₆ alkyl, especially methyl, ethyl, propyl, butyl, pentyl, hexyl or the corresponding alkene and alkyne analogues. Preferably, an alkyl group means a linear or branched C ₁ -C ₄ -alkyl, linear or branched C ₁ -C ₄ -alkenyl group, which, if necessary, contains one or more It may be substituted with a substituent, and the substituent has the same definition as the above-described residue R ₃ or R ₄ . C ₁ -C ₄ alkyl, especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl or corresponding alkene analog.

C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkenyl and C ₁ -C ₄ -alkynyl residues include, but are not limited to, the following groups:

_{-CH 3, -C 2 H 5,} -CH = CH 2, -C≡CH, -C 3 H 7, -CH (CH 3) 2, -CH 2 -CH = CH 2, -C (CH 3) ═CH ₂ , —CH═CH—CH ₃ , —C≡C—CH ₃ , —CH ₂ —C≡CH, —C ₄ H ₉ , —CH ₂ —CH (CH ₃ ) ₂ , —CH (CH _{3 ) -C 2 H 5, -CH 2} -CH (CH 3) -CH 3, -C (CH 3) 3, -C 2 H 4 -CH = CH 2, -CH = CH-C 2 H 5, - _{CH = C (CH 3) 2} , -CH 2 -CH = CH-CH 3, -CH 2 -C (CH 3) = CH 2, -C (CH 3) = CH-CH 3, -C (CH 3 _{) -CH = CH 2, -CH =} CH-CH = CH 2, -C 2 H 4 -C≡CH, -C≡C-C 2 H 5, -CH 2 -C≡C-CH _{, -C≡C-CH = CH 2,} -CH = CH-C≡CH, -C≡C-C≡CH.

Preferentially, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkenyl residues may include, but are not limited to:

_{-CH 3, -C 2 H 5,} -CH = CH 2, -C 3 H 7, -CH (CH 3) 2, -CH 2 -CH = CH 2, -C 4 H 9, -CH 2 -CH _{(CH 3) 2, -CH (} CH 3) -C 2 H 5, -CH 2 -CH (CH 3) -CH 3, -C (CH 3) 3.

A cycloalkyl group means a non-aromatic ring system containing 3 to 8 carbon atoms, preferably 4 to 7 carbon atoms, wherein one or more carbon atoms in the ring may be substituted with the group X, here, X is, N, S, O, _SO, is selected from the group consisting of SO 2, NR ₄ and _CO; C 4 -C ₇ - cycloalkyl residues are - cyclo _-C 3 _H 5, - cyclo _-C 4 _{H 7,} - cyclo _-C 5 _{H 9,} - cyclo _-C 6 _{H 11,} - may be selected from the group consisting of cyclo _-C 7 _{H 13,} cycloalkyl groups, if necessary, It may be substituted with one or more substituents R ₃ , wherein R ₃ and R ₄ are as defined above. Preferentially, a cycloalkyl group means a non-aromatic ring system containing 3 to 6 carbon atoms, wherein one or more carbon atoms in the ring may be substituted with the group X, where X Is selected from the group consisting of N, S, O, SO, SO ₂ , NR ₄ and CO; the C ₄ -C ₇ -cycloalkyl residue is —cyclo-C ₃ H ₅ , —cyclo-C _4. Selected from the group consisting of H ₇ , -cyclo-C ₅ H ₉ , -cyclo-C ₆ H ₁₁ , the cycloalkyl group may be optionally substituted with one or more substituents, , Are the same definition as the above-mentioned residues R ₃ and / or R ₄ .

  An alkoxy group means an O-alkyl group, and the alkyl group has the same definition as described above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy group or pentoxy group.

The haloalkyl group means an alkyl group substituted with 1 to 5 halogen atoms, and the alkyl group has the same definition as described above; the haloalkyl group is preferably —C (R ₅ ) ₃ , — _{CR 5 (R 5) 2,} -CR 5 (R 5) R 5, -C 2 (R 5) 5, -CH 2 -C (R 5) 3, -CH 2 -CR 5 (R 5) 2, _{-CH 2 -CR 5 (R 5)} R 5, -C 3 (R 5) 7 or _{-C 2 H 4 -C (R 5} ) _3, wherein, _{R 5} is, F, Cl, Br or Represents I, preferably F or Cl, and R ₅ may be the same or different. Preferentially, a haloalkyl group means an alkyl group substituted with 1 to 3 halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably —C (R ₅ ). ₃ , —CH (R ₅ ) ₂ , —CH ₂ —CH (R ₅ ) ₂ , —CH ₂ —C (R ₅ ) ₃ , —C ₂ H ₄ —CH (R ₅ ) ₂ or —C ₂ H ₄ -C _{(R 5) 3,} wherein, _{R 5} represents F, Cl, Br or I, preferably F or Cl, also, _{R 5} is different even or mutually the same It may be a thing.

  A hydroxyalkyl group means a HO-alkyl group, and the alkyl group has the same definition as described above.

A haloalkyloxy group means an alkoxy group substituted with 1 to 5 halogen atoms, the alkyl group having the same definition as above; the haloalkyloxy group is preferably —OC (R ₅ ) _{3. , -OCR 5 (R 5) 2} , -OCR 5 (R 5) R 5, -OC 2 (R 5) 5, -OCH 2 -C (R 5) 3, -OCH 2 -CR 5 (R 5) ₂ , —OCH ₂ —CR ₅ (R ₅ ) R ₅ , —OC ₃ (R ₅ ) ₇ or —OC ₂ H ₄ —C (R ₅ ) ₃ , wherein R ₅ is F, Cl, Represents Br or I, preferably F or Cl, and R ₅ may be the same or different. Preferentially, a haloalkoxy group means an alkoxy group substituted with 1 to 3 halogen atoms, an alkyl group is as defined above; a haloalkyloxy group is preferably —OC ( R ₅ ) ₃ , —OCH ₂ —C (R ₅ ) ₃ , —OC ₂ H ₄ —C (R ₅ ) ₃ , wherein R ₅ represents F, Cl, Br or I, and R ₅ may be the same or different from each other.

The hydroxyalkylamino group means a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, and the alkyl group has the same definition as described above. Preferentially, a hydroxyalkylamino group means an (OH-alkyl) ₂ -N- group, a HO-alkyl-NH- group or a HO-alkyl-NR ₄ -group, where the alkyl group and the R ₄ group are as described above. It is the same definition as.

  A halogen group means chlorine, bromine, fluorine or iodine.

An aryl group preferably means an aromatic group having 5 to 10 carbon atoms and / or heteroatoms, which may be optionally substituted with one or more substituents, wherein R ₁ And R ₂ has the same definition as above. Preferentially, an aryl group means an aromatic group having 5 to 6 carbon atoms and / or heteroatoms, which may be optionally substituted with one or more substituents, , Are the same definitions as the above-mentioned residues R ₁ and / or R ₂ .

A heteroaryl group is a 5- or 6-membered heterocyclic group containing at least one heteroatom such as O, N, S. This heterocyclic group may be fused to another ring. For example, the group may be oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, iso Thiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazole-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- Limidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, indolyl, indolinyl, benzo- [b] -furanyl, benzo [b] Thiophenyl, benzimidazolyl, benzothiazolyl, quinazolinyl, quinoxazolinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolidinyl, isoxazol-3-yl, isoxazol-4-yl, isoxazole-5 -Yl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, phthalazinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, pheno Azinyl, phenoxazinyl, indenyl, coumarinyl, Nafutariniru, fluorenyl may be selected from Antaseniru group. This heterocyclic group may be substituted with one or more substituents R ₁ or R ₂ if necessary, and the substituent has the same definition as described above.

Preferentially, a heteroaryl group is a 5- or 6-membered heterocyclic group containing at least one heteroatom such as O, N, S and is thiazol-2-yl, thiazol-4-yl, thiazole -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, indolyl, benzimidazolyl, benzothiazolyl, quinazolinyl, isoindolyl, 3H-indolyl Quinolinyl, isoquinolinyl, phthalazinyl, 1,8 naphthyridinyl, is selected from the group consisting of coumarinyl and Nafutariniru group. If necessary, this heterocyclic group may be substituted with one or more substituents, and the substituents have the same definition as the above-described residues R ₁ and / or R ₂ .

  The invention will be further illustrated by the following examples, which are merely illustrative and do not limit the scope of the invention.

Examples Example 1: General synthetic method for the preparation of compounds of formula I Hydrazine compounds of formula III (~ 100 mg), aldehydes of formula II (1 eq) in tetrahydrofuran (4 ml), about 100 mg Amberlyst 15 The ion exchange resin and molecular sieve were placed in a G-12 flask. The reaction mixture was heated at reflux for 4 hours. TLC analysis (Hexane / EtOAc: 1/1) indicated that all hydrazine had reacted. The reaction mixture was filtered and the solution was concentrated to a small volume (ca. 0.5 mL). The resulting residue was suspended in methanol (about 1.5 mL), sonicated, centrifuged, and decanted. This process was repeated twice. The white-yellowish solid that formed was dried in vacuo.

  This method is applicable to all compounds of general formula I according to the invention. However, other synthetic paths are not excluded. Included in the knowledge of those skilled in the art.

  Specific compounds are shown in Table 1 below.

  Additional specific compounds are shown in Table 2 below.

  Mass was measured by mass spectrometry. The compounds in Tables 1 and 2 exhibit in vitro activity of less than 50 μM. In vitro activity was measured as described in Example 2.

Example 2: Inhibition of β-secretase activity-FRET assay Assays to determine APP cleavage at the β-secretase cleavage site are known in the art. Specific assay methods are described, for example, in US Pat. Nos. 5,744,346 and 5,942,400.

One assay useful for testing the inhibitory activity of β-secretase is based on the fluorescence resonance energy transfer (FRET) technique that monitors peptide substrate cleavage. Pipette 5 μl / well of substrate (0.2 mM in 0.1 M Na-Ac pH = 4.5; Bachem No. M-2470) into a black 96 well plate and store in the dark. DMSO containing 5 μl / well inhibitor compound (final concentration of compound: 1 nanomolar to 500 micromolar) was pipetted into a 96-well clear V-shaped plate and 70 μl 0.1 M Na-Ac pH = 4. Add 5 and 20 μl rhBACE1 (10 μg / ml in 0.1 M Na-Ac pH = 4.5; R & D Systems No 931-AS) and incubate at room temperature for 10 minutes. Next, 94 ml of each well is transferred to the black plate substrate to initiate the reaction. Immediately after mixing, time (T) = 0 is measured with a Wallac 1420 plate reader (excitation 355 nm, emission 486 nm). After incubation for 60 minutes at 37 ° C. with gentle shaking, the reaction is measured again. Relative compound inhibitory potency is determined by calculating the concentration of compound that showed a 50% reduction in detection signal (IC ₅₀ ) when compared to the enzyme reaction signal in a control without compound addition.

Example 3: Inhibition of β-secretase activity-cellular assay Specific assays aimed at analyzing inhibition of β-secretase activity include those described in US Pat. No. 5,604,102 It is referred to as a Swedish mutation and is shown to overproduce Abeta (Citron et al., 1992, Nature 360: 672-674), and the naturally occurring two mutations Lys651Met652 to Asn651Met652 ( Some use the human embryonic kidney cell line HEK293 (ATCC Deposit No. CRL-1573) transfected with APP751, including the numbering for APP751). However, other transformed cell lines such as CHO or SH-SY5Y may be used in a similar manner.

Cells are incubated at the desired concentration, usually 100 μM or less, in the presence / absence of inhibitory compound (diluted with DMSO; final concentration of DMSO: 0.05%). At the end of the treatment period (24 hours), the conditioned medium is analyzed for β-secretase activity, for example by analyzing the cleaved fragments. Abeta can be analyzed by immunoassay using a specific detection antibody (HS40 ABeta kit from The Genetics Company). Enzyme activity is measured in the presence and absence of compound inhibitors that show specific inhibition of β-secretase mediated cleavage of the APP substrate. Relative compound inhibitory potency is determined by calculating the concentration of compound that showed a 50% reduction in detection signal (IC ₅₀ ) when compared to the Abeta40 signal in controls without compound addition.

  The following compounds exhibited IC50 values of less than 50 μM.

  N1, N8, N10, N13, N15 to N21, N23 to N30, N40, N43, N58 to N66, N69 to N70, N76 to N81, N83 to N88, N90 to N94, N96, N98 to N100, N102, N108 to N109, N114, N119.

Example 4: Measurement of compounds in the brain C57 / bl6 mice, referred to as “wt” mice, were obtained. These mice were treated with phenylhydrazone number 29. Dosing was administered either intraperitoneally or orally. Oral dosing was administered by gavage. Intraperitoneally treated animals received a single injection or dosed once or twice daily for up to 8 days. In addition, a group of wt mice matched in age was treated with carrier vehicle only.

  Animals were necropsied between 0.5-24 hours after the last dose. The brain was removed and stored at -80 ° C. The brain was cut into 200 mg pieces, 800 μl acetonitrile: water solution (80:20; v: v) was added, and the brain samples were sonicated for 2 minutes. The sample was vortexed for 2 minutes and insoluble particles were removed by centrifugation. Compounds in the samples were detected by high performance liquid chromatography at 254 or 360 nm. The concentration was measured by adding an internal standard to the brain sample.

  After a single intraperitoneal administration at a dose of 55 mg / kg, compound levels become detectable in the brain within 30 minutes and remain at this level for at least 5 hours after administration and 2.5 hours after injection. Indicates the peak level. When mice were treated once a day with similar doses for 3 consecutive days, the amount of compound detected in the brain 24 hours after the last injection was at the peak level measured after one dose. It was twice. Similar levels of compound could be detected after treatment twice daily for 8 consecutive days, indicating a saturating effect on the accumulation of the compound in the brain.

  After a single oral dose (100 mg / kg), the compound could be detected in the brain of “wt” mice, indicating that the compound is absorbed orally.

Example 5: Inhibition of β-secretase in animal models of AD Various animal models can be used to screen for inhibition of β-secretase activity. Examples of animal models that can be used in the present invention include, but are not limited to, mice, guinea pigs, dogs and the like. The animal used may be a wild type, transformation, or knockout model. In addition, the mammalian model may be one that expresses a mutation in APP, such as APP695-SW described herein. Examples of transformed non-human mammal models are described in Hsiao et al., 1996, Science 274, 99-102 and Kawarabayshi et al., 2001, J Neuroscie 21, 372-381.

  For example, Tg2576 mice, prepared as described in Hsiao et al., 1996, Science 274, 99-102, analyze in vivo suppression of Abeta release in the presence of putative inhibitory compounds. Can be used to

  For example, as described in Chang et al., 2004, J. Neurochem. 89, 1409-1416, a certain amount of BACE inhibitor formulated in a carrier suitable for a given administration trait is administered to the transformed animal. . Control animals are untreated, treated with vehicle, or treated with an inactive compound. Administration may be acute, ie once or multiple times daily, or chronic, ie, daily dosing may be repeated for a predetermined number of days. Beginning at time 0, brain tissue, cerebrospinal fluid or blood is obtained from a given animal and analyzed for the presence of an APP-cleaved peptide, such as Abeta, for example by immunoassay using an antibody specific for Abeta detection. . At the end of the test period, the animals are necropsied and analyzed for the presence of Abeta and / or β-amyloid plaques in brain tissue, cerebrospinal fluid or blood. Alternatively, treated transgenic animals (eg, Tg2576 mice) are monitored for APP-induced phenotypic changes as described, for example, in Hsiao et al., 1996, Science 274, 99-102. May be.

Claims (17)

The following general formula I

Where R ₃ is selected from the group consisting of H, methyl, and hydroxyalkyl;
In addition, Z ₁ and Z ₂ are each independently substituted or unsubstituted phenyl, naphthyl, pyridinyl, pyrazolyl, pyrimidinyl, pyrazidinyl, quinolinyl having n R ₁ and m R ₂ as substituents. , Selected from the group consisting of iso-quinolinyl, coumarinyl, indolyl, thiazolyl and thiophenyl groups;
R ₁ and R ₂ may be the same or different from each other, and H, alkyl, cycloalkyl, —CO ₂ R ₄ , —CONHR ₄ , —CR ₄ O, —SO ₂ R ₄ , —NR ₄ —CO—R ₄ , alkoxy, alkylthio, —OH, —O-aryl, —O-cycloalkyl, —S-aryl, —S-cycloalkyl, hydroxyalkyl, halogen, haloalkyl, haloalkoxy, —CN , —NO ₂ , hydroxyalkylamine, aminoalkyl, alkylamine, aryl, heteroaryl and sulfonamide,
In this case, R ₄ is H, C ₁ to C ₆ branched or unbranched alkyl, aryl, cycloalkyl, alkoxy, heterocycloalkyl, —OH, —O-aryl, —O-alkyl, —O—. Selected from the group consisting of cycloalkyl, aminoalkyl, alkylamine, aryl and heteroaryl;
N and m are the numbers of substituents R ₁ and R ₂ in Z ₁ and Z ₂ , respectively, and are 0 to 5,
In this case, when n and m are integers of 2 or more, R ₁ and / or R ₂ may form a condensed aromatic ring system, a carbocyclic system or a heterocyclic ring system,
A hydrazone derivative of or a salt thereof, or a physiologically functional derivative or prodrug,
In this case, the following compound

Hydrazone derivatives, or salts thereof, or physiologically functional derivatives or prodrugs not included in Formula I. A compound according to claim 1, characterized in that Z ₁ is a substituted phenyl group substituted by at least two halogen atoms and one hydroxyl group. Z ₁ is a substituted phenyl group having at least one substituted or unsubstituted aryl or heteroaryl ring or one or two tert-butyl groups, or 2. The compound according to 2. Z ₂ is preferably characterized in that it is a phenyl group substituted with a benzyl group attached to the phenyl group via an ether bond, a compound according to any one of claims 1 to 3. The compound according to claim 1, wherein Z ₂ is a pyrimidyl ring having a substituted or unsubstituted cycloalkyl group or a disubstituted amino group.   The compound according to claim 4, wherein the benzyl group bonded to the phenyl group via an ether bond is a substituted or unsubstituted benzyloxy group.   3. A compound according to claim 2, characterized in that the hydroxyl group is in the o-position relative to the binding position of the hydrazone motif. The compound has the following formula:

8. A compound according to any one of claims 1 to 3 and 7, characterized in that it has one of the following: Following formula:

Compound. Z ₂ is a substituted or unsubstituted phenyl, characterized in that it is selected from the group consisting of pyridinyl and pyrimidinyl group, a compound according to any one of claims 1, 2, 3 and 7.   Use of a compound according to any one of claims 1 to 10 as a medicament.   Use of a compound according to any one of claims 1 to 10 for the manufacture of a pharmaceutical composition for the treatment or prevention of symptoms or diseases mediated by β-secretase.   Use of the compound according to any one of claims 1 to 10 for the manufacture of a pharmaceutical composition that inhibits the formation of β-amyloid peptide of the amyloid precursor protein APP.   Aimed at the manufacture of a pharmaceutical composition for the treatment or prevention of Alzheimer's disease, neurodegeneration, memory and attention deficits, cell proliferation dysfunction, or other diseases associated with or responding to inhibition of β-amyloid peptide Use of a compound according to any one of claims 1-10.   Of a symptom or disease selected from the group consisting of Alzheimer's disease, Down's syndrome, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with Dutch amyloidosis (HCHWA-D) and other degenerative dementia characterized by β-amyloid deposition Use of a compound according to any one of claims 1 to 10 for the manufacture of a pharmaceutical composition for treatment or prevention.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.   17. A pharmaceutical composition according to claim 16, further comprising at least one pharmaceutically acceptable carrier, diluent or excipient.