N-(aryl/heteroarylacetyl) amino acid esters, pharmaceutical compositions comprising same, and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use of such compounds

A method for preventing the onset of AD in a patient at risk for developing AD which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I:

• 13
• wherein R1 is selected from the group consisting of
• a) alkyl, alkenyl, alkcycloalkyl, phenyl-(R)m—, naphthyl-(R)m— wherein R is an alkylene group of from 1 to 8 carbon atoms and m is an integer equal to 0 or 1, cycloalkyl, cycloalkenyl, 3-pyridyl, 4-pyridyl and heteroaryl, other than 3- and 4-pyridyl, of 3 to 10 atoms and 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen wherein the heteroaryl group is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, halo, nitro, thioalkoxy, and thioaryloxy with the proviso that for such heteroaryls when there is at least one nitrogen heteroatom, there is also at least one oxygen and/or sulfur heteroatom;
• (b) a substituted phenyl group of formula II:
• 14
• wherein R is alkylene of from 1 to 8 carbon atoms,
• m is an integer equal to 0 or 1,
• Ra and Ra′ are independently selected from the group consisting of hydrogen, hydroxy, fluoro and methyl;
• Rb and Rb′ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, cyano, cycloalkyl, halo, heteroaryl, heterocyclic, nitro, trihalomethyl, thioalkoxy, thioaryloxy, thioheteroaryloxy, and —C(O)R4 where R4 is selected from the group consisting of alkyl, aryl, alkoxy and aryloxy;
• and Rc is selected from the group consisting of hydrogen, alkyl, aryl, cyano, halo, nitro, and where Rb and Rc are fused to form a methylenedioxy ring with the phenyl ring;
• and
• when Rb and/or Rb′ and/or Rc is fluoro, chloro, bromo and/or nitro, then Ra and/or Ra′ can also be chloro;
• and
• (c) 1- or 2-naphthyl-(R)m— substituted at the 5, 6, 7 and/or 8 positions with 1 to 4 substituents selected from the group consisting alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy wherein R is an alkylene group of from 1 to 8 carbon atoms and m is an integer equal to 0 or 1;
• R2 is selected from the group consisting of hydrogen, alkyl, phenyl, alkylalkoxy, alkylthioalkoxy;
• and
• R3 is selected from the group consisting of —(CH2)nCR10R5R6 wherein n is an integer equal to 0, 1 or 2, R5 and R6 are independently selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocyclic, —NR7R8 where R7 and R8 are independently hydrogen or alkyl and —COOR9 where R9 is alkyl, and further wherein R5 and R6 can be joined to form a cycloalkyl group, a cycloalkenyl group, an aryl group, a heteroaryl group, and a heterocyclic group, and when R5 and R6 do not join to form an aryl or heteroaryl group, then R10 is selected from hydrogen and alkyl with the proviso that when n is zero, then R10 is hydrogen and when n is greater than zero and R5 and R6 are joined to form an aryl or heteroaryl group, then R10 becomes a bond within that group;
• X is oxygen or sulfur;
• X′ is hydrogen, hydroxy or fluoro;
• X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form an oxo group, and
• pharmaceutically acceptable salts thereof
• with the provisos that:
• when R1 is phenyl, R2 is —CH(CH3)CH2CH3, X is oxygen, and X′ and X″ are hydrogen, then R3 is not —CH2CH3 or —CH2CH(CH3)2
• when R1 is phenyl, R3 is —CH2CH(CH3)2, X is oxygen, and X′ and X″ are hydrogen, then R2 is not —CH(CH3)2
• when R1 is pyrid-3yl, R2 is ethyl, X is oxygen, and X′ and X″ are hydrogen, then R3 is not —CH2CH(CH3)2,
• when R1 is indoxazin-3-yl, 2,4-dimethylthiazol-5-yl, 4-methyl-1,2,5-thiooxadizol-3-yl or 3,5-di(trifluoromethyl)phenyl, R2 is methyl, X is oxygen, and X′ and X″ are hydrogen, then R3 is not —CH2CH(CH3)2, and
• when R1 is —CH2-phenyl, R3 is —CH2CH3, X is oxygen, and X′ and X″ are hydrogen, then R2 is not —CH2CH(CH3)2.

A method for treating a patient with AD in order to inhibit further deterioration in the condition of that patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I:

• 15
• wherein R1 is selected from the group consisting of
• a) alkyl alkenyl, alkcycloalkyl, phenyl-(R)m—, naphthyl-(R)m— wherein R is an alkylene group of from 1 to 8 carbon atoms and m is an integer equal to 0 or 1, cycloalkyl, cycloalkenyl, 3-pyridyl, 4-pyridyl and heteroaryl, other than 3- and 4-pyridyl, of 3 to 10 atoms and 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen wherein the heteroaryl group is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, halo, nitro, thioalkoxy, and thioaryloxy with the proviso that for such heteroaryls when there is at least one nitrogen heteroatom, there is also at least one oxygen and/or sulfur heteroatom;
• (b) a substituted phenyl group of formula II:
• 16
• wherein R is alkylene of from 1 to 8 carbon atoms,
• m is an integer equal to 0 or 1,
• Ra and Ra′ are independently selected from the group consisting of hydrogen, hydroxy, fluoro and methyl;
• Rb and Rb′ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, cyano, cycloalkyl, halo, heteroaryl, heterocyclic, nitro, trihalomethyl, thioalkoxy, thioaryloxy, thioheteroaryloxy, and —C(O)R4 where R4 is selected from the group consisting of alkyl, aryl, alkoxy and aryloxy;
• and
• Rc is selected from the group consisting of hydrogen, alkyl, aryl, cyano, halo, nitro, and where Rb and Rc are fused to form a methylenedioxy ring with the phenyl ring;
• and
• when Rb and/or Rb′ and/or Rc is fluoro, chloro, bromo and/or nitro, then Ra and/or Ra′ can also be chloro;
• and
• (c) 1- or 2-naphthyl-(R)m— substituted at the 5, 6, 7 and/or 8 positions with 1 to 4 substituents selected from the group consisting alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy wherein R is an alkylene group of from 1 to 8 carbon atoms and m is an integer equal to 0 or 1;
• R2 is selected from the group consisting of hydrogen, alkyl, phenyl, alkylalkoxy, alkylthioalkoxy;
• and
• R3 is selected, from the group consisting of —(CH2)nCR10R5R6 wherein n is an integer equal to 0, 1 or 2, R5 and R6 are independently selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocyclic, —NR7R8 where R7 and R8 are independently hydrogen or alkyl and —COOR9 where R9 is alkyl, and further wherein R5 and R6 can be joined to form a cycloalkyl group, a cycloalkenyl group, an aryl group, a heteroaryl group, and a heterocyclic group, and when R5 and R6 do not join to form an aryl or heteroaryl group, then R10 is selected from hydrogen and alkyl with the proviso that when n is zero, then R10 is hydrogen and when n is greater than zero and R5 and R6 are joined to form an aryl or heteroaryl group, then R10 becomes a bond within that group;
• X is oxygen or sulfur;
• X′ is hydrogen, hydroxy or fluoro;
• X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form an oxo group, and
• pharmaceutically acceptable salts thereof
• with the provisos that:
• when R1 is phenyl, R2 is —CH(CH3)CH2CH3, X is oxygen, and X′ and X″ are hydrogen, then R3 is not —CH2CH3 or —CH2CH(CH3)2
• when R1 is phenyl, R3 is —CH2CH(CH3)2, X is oxygen, and X′ and X″ are hydrogen, then R2 is not —CH(CH)2
• when R1 is pyrid-3-yl, R2 is ethyl, X is oxygen, and X′ and X″ are hydrogen, then R3 is not —CH2CH(CH3)2,
• when R1 is indoxazin-3-yl, 2,4-dimethylthiazol-5-yl, 4-methyl-1,2,5-thiooxadizol-3-yl or 3,5-di(trifluoromethyl)phenyl, R2 is methyl, X is oxygen, and X′ and X″ are hydrogen, then R3 is not —CH2CH(CH3)2, and
• when R1 is —CH2-phenyl, R3 is —CH2CH3, X is oxygen, and X′ and X″ are hydrogen, then R2 is not —CH2CH(CH3)2.

A pharmaceutical composition comprising a pharmaceutically inert carrier and a pharmaceutically effective amount of a compound of formula I:

• 17
• wherein R1 is selected from the group consisting of
• a) alkyl;
• alkenyl, alkcycloalkyl, phenyl-(R)m—, naphthyl-(R)m— wherein R is an alkylene group of from 1 to 8 carbon atoms and m is an integer equal to 0 or 1, cycloalkyl, cycloalkenyl, 3-pyridyl, 4-pyridyl and heteroaryl, other than 3- and 4-pyridyl, of 3 to 10 atoms and 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen wherein the heteroaryl group is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, halo, nitro, thioalkoxy, and thioaryloxy with the proviso that for such heteroaryls when there is at least one nitrogen heteroatom, there is also at least one oxygen and/or sulfur heteroatom;
• (b) a substituted phenyl group of formula II;
• 18
• wherein R is alkylene of from 1 to 8 carbon atoms,
• m is an integer equal to 0 or 1,
• Ra and Ra′ are independently selected from the group consisting of hydrogen, hydroxy, fluoro and methyl;
• Rb and Rb′ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, cyano, cycloalkyl, halo, heteroaryl, heterocyclic, nitro, trihalomethyl, thioalkoxy, thioaryloxy, thioheteroaryloxy, and —C(O)R4 where R4 is selected from the group consisting of alkyl, aryl, alkoxy and aryloxy;
• and
• Rc is selected from the group consisting of hydrogen, alkyl, aryl, cyano, halo, nitro, and where Rb and Rc are fused to form a methylenedioxy ring with the phenyl ring;
• and
• when Rb and/or Rb′ and/or Rc is fluoro, chloro, bromo and/or nitro, then Ra and/or R′″ can also be chloro;
• and
• (c) 1- or 2-naphthyl-(R)m— substituted at the 5, 6, 7 and/or 8 positions with 1 to 4 substituents selected from the group consisting alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy wherein R is an alkylene group of from 1 to 8 carbon atoms and m is an integer equal to 0 or 1;
• R2 is selected from the group consisting of hydrogen, alkyl, phenyl, alkylalkoxy, alkylthioalkoxy;
• and
• R3 is selected from the group consisting of —(CH2)nCR10R5R6 wherein n is an integer equal to 0, 1 or 2, R5 and R6 are independently selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocyclic, —NR7R8 where R7 and R8 are independently hydrogen or alkyl and —COOR9 where R9 is alkyl, and further wherein R5 and R6 can be joined to form a cycloalkyl group, a cycloalkenyl group, an aryl group, a heteroaryl group, and a heterocyclic group, and when R5 and R6 do not join to form an aryl or heteroaryl group, then R10 is selected from hydrogen and alkyl with the proviso that when n is zero, then R10 is hydrogen and when n is greater than zero and R5 and R6 are joined to form an aryl or heteroaryl group, then R10 becomes a bond within that group;
• X is oxygen or sulfur;
• X′ is hydrogen, hydroxy or fluoro;
• X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form an oxo group, and
• pharmaceutically acceptable salts thereof
• with the provisos that:
• when R1 is phenyl, R2 is —CH(CH3)CH2CH3, X is oxygen, and X′ and X″ are hydrogen, then R3 is not —CH2CH3 or CH2CH(CH3)2
• when R1 is phenyl, R3 is —CH2CH(CH3)2, X is oxygen, and X′ and X″ are hydrogen, then R2 is not —CH(CH3)2
• when R1 is pyrid-3-yl, R2 is ethyl, X is oxygen, and X′ and X″ are hydrogen, then R3 is not —CH2CH(CH3)2,
• when R1 is indoxazin-3-yl, 2,4-dimethylthiazol-5-yl, 4-methyl-1,2,5-thiooxadizol-3-yl or 3,5-di(trifluoromethyl)phenyl, R2 is methyl, X is oxygen, and X′ and X″ are hydrogen, then R3 is not —CH2CH(CH3)2, and
• when R1 is —CH2-phenyl, R3 is —CH2CH3, X is oxygen, and X′ and X″ are hydrogen, then R2 is not —CH2CH(CH3)2.

A compound of formula III:

• 19
• wherein R1 is selected from the group consisting of
• a) alkyl, alkenyl, alkcycloalkyl, phenyl-(R)m—, naphthyl-(R)m— wherein R is an alkylene group of from 1 to 8 carbon atoms and m is an integer equal to 0 or 1, cycloalkyl, cycloalkenyl, 3-pyridyl, 4-pyridyl and heteroaryl, other than 3- and 4-pyridyl, of 3 to 10 atoms and 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen wherein the heteroaryl group is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, halo, nitro, thioalkoxy, and thioaryloxy with the proviso that for such heteroaryls when there is at least one nitrogen heteroatom, there is also at least one oxygen and/or sulfur heteroatom;
• (b) a substituted phenyl group of formula II:
• 20
• wherein R is alkylene of from 1 to 8 carbon atoms,
• m is an integer equal to 0 or 1,
• Ra and Ra′ are independently selected from the group consisting of hydrogen, hydroxy, fluoro and methyl;
• Rb and Rb′ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, cyano, cycloalkyl, halo, heteroaryl, heterocyclic, nitro, trihalomethyl, thioalkoxy, thioaryloxy, thioheteroaryloxy, and —C(O)R4 where R4 is selected from the group consisting of alkyl, aryl, alkoxy and aryloxy;
• and
• Rc is selected from the group consisting of hydrogen, alkyl, aryl, cyano, halo, nitro, and where Rb and Rc are fused to form a methylenedioxy ring with the phenyl ring;
• and
• when Rb and/or Rb′ and/or Rc is fluoro, chloro, bromo and/or nitro, then Ra and/or Ra′ can also be chloro;
• and
• (c) 1- or 2-naphthyl-(R)m— wherein R is-an alkylene group of from 1 to 8 carbon atoms and m is an integer equal to 0 or 1 substituted at the 5, 6, 7 and/or 8 positions with 1 to 4 substituents selected from the group consisting alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy;
• R2 is selected from the group consisting of hydrogen, alkyl, phenyl, alkylalkoxy, alkylthioalkoxy;
• and
• R3 is selected from the group consisting of —(CH2)nCR10R5R6 wherein n is an integer equal to 0, 1 or 2, R5 and R6 are independently selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocyclic, —NR7R8 where R7 and R1 are independently hydrogen or alkyl, and —COOR9 where R9 is alkyl, and further wherein R5 and R6 can be joined to form a cycloalkyl group, a cycloalkenyl group, an aryl group, a heteroaryl group, and a heterocyclic group, and when R5 and R6 do not join to form an aryl or heteroaryl group, then R10 is selected from hydrogen and alkyl with the proviso that when n is zero, then R10 is hydrogen and and when n is greater than zero and R5 and R6 are joined to form an aryl or heteroaryl group, then R10 becomes a bond within that group;
• X is oxygen or sulfur;
• X′ is hydrogen, hydroxy or fluoro;
• X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form an oxo group, and
• pharmaceutically acceptable salts thereof
• with the provisos that:
• when R1 is phenyl, R2 is —CH(CH3)CH2CH3, X is oxygen, and X′ and X″ are hydrogen, then R3 is not —CH2CH3 or —CH2CH(CH3)2
• when R1 is phenyl, R3 is —CH2CH(CH3)2, X is oxygen, and X′ and X″ are hydrogen, then R2 is not —CH(CH3)2
• when R1 is pyrid-3-yl, R2 is ethyl, X is oxygen, and X′ and X″ are hydrogen, then R3 is not —CH2CH(CH3)2,
• when R1 is indoxazin-3-yl, 2,4-dimethylthiazol-5-yl, 4-methyl-1,2,5-thiooxadizol-3-yl or 3,5-di(trifluoromethyl)phenyl, R2 is methyl, X is oxygen, and X′ and X″ are hydrogen, then R3 is not —CH2CH(CH3)2, and
• when R1 is —CH2-phenyl, R3 is —CH2CH3, X is oxygen, and X′ and X″ are hydrogen, then R2 is not —CH2CH(CH3)2;
• and still with further proviso excluding the following known compound:
• N-(phenylacetyl)methionine ethyl ester.