β-amyloid protein production/secretion inhibitors

A compound represented by the formula:

• wherein
• Ar′ is an aromatic ring assembly group which may be substituted,
• X′ is [1] a group represented by the formula:
• —(CH2)p1O— wherein p1 is an integer of 1 to 3, [2] —(CH2)p2— wherein p2 is an integer of 1 to 3 or [3] CONH,
• Y′ is [1] a group represented by the formula:
• —(CH2)q1CONR9(CH2)r1— wherein each of q1 and r1 is an integer of 0 to 3 and their sum is an integer of not more than 3, R9 is hydrogen atom or C1-6 alkyl which may be halogenated or C1-6 alkyl-carbonyl which may be halogenated, or [2] a group represented by the formula:
• —CH2)q2 COO(CH2)r2— wherein each of q2 and r2 is an integer of 0 to 3 and their sum is not more than 3,
• each of R1 and R2 is hydrogen atom or C1-6 alkyl which may be substituted, or R1 and R2 may form, together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic ring, and ring A is a phenylene, provided that 4,4′-[[1,1′-biphenyl]-2,5-diylbis(oxy)]bis[benzoic acid] dihydrazide is excluded.

4-(4-biphenylylmethoxy)phenyl-N-(2-piperidino-ethyl)acetamide,

• 4-(4-biphenylylmethoxy)phenyl-N-[2-(N,N-dimethylamino)-ethyl]acetamide,
• 6-(4-biphenylylmethoxy)-N-[2-(pyrrolidine-1-yl)ethyl]-nicotinamide,
• 1-(4-biphenylylmethyl)-1,6-dihydro-6-oxo-N-[2-(pyrrolidine-1-yl)ethyl]-3-pyridinecarboxamido,
• 1-(4-biphenylylmethyl)-1,6-dihydro-6-oxo-N-(2-(piperidinoethyl)-3-pyridinecarboxamido,
• 6-(4-biphenylylmethoxy)-N-(2-piperidinoethyl)nicotinamide,
• 6-(4-biphenylylmethoxy)-N-[2-(N,N-dimethylamino)ethyl]-nicotinamide,
• 4-(4-biphenylylmethoxy)-N-(2-piperidinoethyl)benzamide,
• 4-(4-biphenylylmethoxy)-N-[(2-pyrrolidine-1-yl)ethyl]-benzamide,
• 2-piperidinoethyl=4-(4-biphenylylethoxy)benzoate,
• 2-(pyrrolidin-1-yl)ethyl=4-(4-biphenylylmethoxy)benzoate,
• 4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N,N-dimethylamino)-ethyl]acetamide oxalate,
• 4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N,N-dimethylamino)-ethyl]acetamide maleate,
• 4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N,N-dimethylamino)-ethyl]acetamide fumarate,
• 4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N-methylamino)-ethyl]acetamide hydrochloride,
• 4-[4-(biphenylylmethoxy)phenyl]-N-[2-(N-methylamino)-ethyl]acetamide,
• ethyl 7-[2-[4-[(4-biphenylylmethoxy)phenyl]acetylamino-ethyl](methyl)amino]heptanoate,
• 7-[2-[4-[4-(biphenylylmethoxy)phenyl]acetylaminoethyl]-(methyl)amino]heptanoic acid hydrochloride,
• N-(4-(2-((2-(dimethylamino)ethyl)(methyl)amino)-2-oxoethyl)phenyl)[1,1′-biphenyl]-4-carboxamide,
• N-(2-aminoethyl)-2-(4-([1,1′-biphenyl]-4-ylmethoxy)phenyl)-acetamide hydrochloride,
• 4-([1,1′-biphenyl]-4-ylmethoxy)-N-(2-(1-pyrrolidinyl)-ethyl)benzamide,
• N-(4-(2-((2-dimethylamino)ethyl)(methyl)amino)-2-oxoethyl)phenyl)[1,1′-biphenyl]-4-carboxamide, N-[4-({[2-(diethylamino)ethyl]amino}carbonyl)phenyl](4-biphenylyl)carboxamide,
• 4-(4-biphenylyl)methoxy)-N-[2-(isopropylamino)ethyl]-benzamide,
• 2-(N,N-diethylamino)ethyl-4-[(4-biphenylyl)carbonyl]amino]-benzoate,
• N-[4-({[2-(dimethylamino)ethyl]amino}carbonyl)phenyl](4-biphenylyl)carboxamide,
• N-[4-{[2-(piperidinoethyl)amino]carbonyl}phenyl](4-biphenylyl)carboxamide, or
• N-[4-({[2-(pyrrolidinyl)ethyl]amino}carbonyl)phenyl](4-biphenylyl)carboxamide.

A pharmaceutical composition which comprises a compound represented by the formula:

• wherein Ar′ is aromatic ring assembly group which may be substituted, X′ is [1] a group represented by the formula:
• —(CH2)p1O— wherein p1 is an integer of 1 to 3, [2] —(CH2)p2— wherein
• p2 is an integer of 1 to 3 or [3] CONH,
• Y′ is [1] a group represented by the formula:
• —(CH2)q1CONR9(CH2)r1— wherein each of q1 and r1 is an integer of 0 to 3 and their sum is an integer of not more than 3, R9 is hydrogen atom or C1-6 alkyl which may be halogenated or C1-6 alkyl-carbonyl which may be halogenated, or [2] a group represented by the formula:
• —(CH2)q2COO(CH2)r2— wherein each of q2 and r2 is an integer of 0 to 3 and their sum is not more than 3, each of R1 and R2 is hydrogen atom or C1-6 alkyl which may be substituted, or R1 and R2 may form, together with the adjacent nitrogen atom, a 5- or 6-membered nitrogen-containing heterocyclic ring, and
• ring A is phenylene, provided that 4,4′-[[1,1′-biphenyl]-2,5-diylbis(oxy)]bis[benzoic acid] dihydrazide is excluded, or a salt or a prodrug thereof.

A method for preventing or treating senile dementia, Alzheimer's disease, Down's syndrome, Parkinson's disease, amyloid angiopathy or a disorder due to amyloid-β protein in a cerebrovascular disorder caused by the production and/or secretion of amyloid-β protein, which comprises administering an effective amount of a compound represented by the formula:

• wherein Ar is an aromatic ring assembly group which may be substituted, X is a bivalent group selected from —O—, —S—, —CO—, —SO—, —SO2—, —NR8—, —CONR8—, —SO2NR8— and —COO— wherein R8 is hydrogen atom, a hydrocarbon group which may be substituted or acyl, or a bivalent C1-6 aliphatic hydrocarbon group which may contain one or two of said bivalent groups, Y is [1] a group represented by the formula:
• —(CH2)q1CONR9(CH2)r1— wherein each of q1 and r1 is an integer of 0 to 3 and their sum is an integer of not more than 3, R9 is hydrogen atom or C1-6 alkyl which may be halogenated or C1-6 alkyl-carbonyl which may be halogenated, or [2] a group represented by the formula:
• —(CH2)q2COO(CH2)r2— wherein each of q2 and r2 is an integer of 0 to 3 and their sum is not more than 3, each of R1 and R2 is hydrogen atom or C1-6 alkyl which may be substituted, or R1 and R2 may form, together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic ring, and ring A is phenylene, provided that 4,4′-[[1,1′-biphenyl]-2,5-diylbis(oxy)]bis[benzoic acid] dihydrazide is excluded, or a salt or a prodrug thereof.