Patent EA-001713-B1 (EA)
Title: Compositions useful as neuro-protective agents
Inventor: HEINZ LAWRENCE J
IPC: A61P25/00
Filed: 1997-10-06
Abstract: 1. A compound of the formula (III)   wherein: Ar is phenyl, pyridyl, tetrahydronaphthyl, benzofuranyl or chromanyl substituted with zero to two substituents selected from the group consisting of -(C1-C6)alkyl, hydroxy and halo; and substituted with either: (i) one or two substituents selected from the group consisting of -O(CH2)tR<6>,  , and -(C1-C6-alkyl)R<6>; or (ii) two substituents which when taken together with the carbon atoms to which they are attached form a pyridyl or tetrahydropyridyln ring; provided that when substituent pattern (i) is present, the phenyl or pyridyl group of Ar may additionally be substituted with two substituents which when taken together with the carbon atoms to which they are attached form a phenyl ring; where R<6> is -NR<7>R<8>, morpholin-l-yl, imidazol-l-yl, 4,5-dihydro-1H-imidazol-2-yl, thiomorpholin-l-yl, piperazin-l-yl or piperazin-l-yl substituted with -(C1-C4)alkyl or   and R<7> and R<8> are each individually hydrogen, -(C1-C6)alkyl, -(CH2)pOH,   -(CH2)p-piperidyl, -(CH2)pS(C1-C6)alkyl, -(CH2)pO(C1-C6)alkyl,   where R<9> is (C1-C6)alkyl; ---- represents a double or single bond; X is -O- or -S-; Y is -CR<5'>R<5>-, -O- or -S-, where R<5>' is H and R<5> is -H or -OH or R<5> and R<5>' taken together are =O; Z is -CH2- or -N-; R is H or -(C1-C6)alkyl; R<1> and R<2> are each individually -(C1-C6)alkyl, -(C1-C6)alkoxy or phenyl; R<3> is H or -(C1-C6)alkyl or R<3> and R<4> taken together form a phenyl group with the ring to which they are attached; R<4> is hydrogen or -OH, or when Y is -CHR<5>, R<4> and R<5> are each individually H or when taken together form a bond; m is an integer from 0 to 2, both inclusive; q is 0 or 1; n is an integer from 0 to 4 both inclusive; p is an integer from 1 to 6 both inclusive; and t is an integer from 1 to 4 both inclusive; or a pharmaceutically acceptable salt, hydrate or optical isomer thereof. 2. A compound of the formula (II)   wherein: Ar is phenyl, pyridyl, or tetrahydronaphthyl substituted with zero to two substituents selected from the group consisting of -(C1-C6)alkyl, hydroxy and halo; and substituted with either: (i) one or two substituents selected from the group consisting of -O(CH2)tR<6>,   and -(C1-C6 alkyl)R<6>; or (ii) two substituents which when taken together with the carbon atoms to which they are attached form a pyridyl or tetrahydropyridyl ring; provided that when substituent pattern (i) is present, the phenyl or pyridyl group of Ar may additionally be substituted with two substituents which when taken together with the carbon atoms to which they are attached form a phenyl ring; where R<6> is -NR<7>R<8>, morpholin-l-yl, imidazol-l-yl, 4,5-dihydro-1H-imidazol-2-yl, thiomorpholin-l-yl, piperazin-l-yl or piperazin-l-yl substituted with -(C1-C4)alkyl,   and R<7> and R<8> are each individually hydrogen, -(C1-C6)alkyl, -(CH2)pOH, -(CH2)p-piperidyl, -(CH2)pS(C1-C6)alkyl or   ---- represents a double or single bond; X is -O- or -S-; Y is -CHR<5>-, -O- or -S-; Z is -CH- or -N-; R is H or -(C1-C6)alkyl; R<1> and R<2> are each individually -(C1-C6)alkyl or -(C1-C6) alkoxy; R<3> is H or -(C1-C6)alkyl, or R<3> and R<4> taken together form a phenyl group with the ring to which they are attached; R<4> is hydrogen, or when Y is -CHR<5>, R<4> and R<5> are each individually H or when taken together form a bond; m is an integer from 0 to 2, both inclusive; q is 0 or 1; n is an integer from 0 to 4 both inclusive; p is an integer from 1 to 6 both inclusive; and t is an integer from 1 to 4 both inclusive; or a pharmaceutically acceptable salt, hydrate or optical isomer thereof. 3. A compound of the formula (I)   wherein Ar is phenyl or pyridyl substituted with zero to two substituents selected from the group consisting of -(C1-C6)alkyl, hydroxy and halo; and substituted with either: (i) one or two substituents selected from the group consisting of  and -(C1-C6-alkyl)R<6>; or (ii) two substituents which when taken together with the carbon atoms to which they are attached form a pyridyl or tetrahydropyridyl ring; provided that when substituent pattern (i) is present, the phenyl or pyridyl group of Ar may additionally be substituted with two substituents which when taken together with the carbon atoms to which they are attached form a phenyl ring; where R<6> is -NR<7>R<8>, morpholin-l-yl, imidazol-l-yl, 4,5-dihydro-1H-imidazol-2-yl, thiomorpholin-l-yl, piperazin-l-yl or piperazin-l-yl substituted with -(C1-C4)alkyl or   and R<7> and R<8> are each individually hydrogen, -(C1-C6)alkyl, -(CH2)pOH or -(CH2)p-piperidyl; X is -O- or -S-; Y is -CHR<5>-, -O- or -S-; R is -H or -(C1-C6)alkyl; R<1> and R<2> are each individually -(C1-C6)alkyl; R<3> is H or -(C1-C6)alkyl; R<4> is hydrogen, or when Y is -CHR<5>, R<4> and R<5> are each individually H or when taken together form a bond; m is 0 or 1; n is an integer from 0 to 4 both inclusive; and p is an integer from 1 to 6 both inclusive; or a pharmaceutically acceptable salt, hydrate or optical isomer thereof. 4. The compound of Claim 3 wherein Ar is phenol substituted with one or two substituents selected from -(CH2)nR<6>,   -(C1-C6-alkyl)R<6>; where R<6> is -NR<7>R<8> and R<7> and R<8> are H or -(C1-C6)alkyl; and one or two substituents selected from hydrogen, -(C1-C6)alkyl, hydroxy; or two substituents which when taken together form a phenyl group. R<1> and R<2> are -(C1-C6)alkyl; R, R<3>, R<4> and R are H; X is -O-; Y is -O- or -S-; 5. The compound of Claim 4 where R<1> and R<2> are 1,1-dimethylethyl. 6. The compound of Claim 5 where Ar is phenyl substituted with one or two substituents selected from -(CH2)nR<6> or -(C1-C6-alkyl)R<6> and one or two substituents selected from hydrogen or -(C1-C6)alkyl. 7. The compound of Claim 6 where Ar is phenyl substituted with -(CH2)nR<6>-. 8. The compound of Claim 4 which is 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-(2-(4-methylethylaminomethyl-phenyloxy)ethyl)oxazole; 2-(3,5-di-tert-butyl-4-hydroxyphenyl))-4-((4-N-methyl-N-ethylaminomethyl)phenoxymethyl)-oxazole hydrochloride; 2-(3,5- di-tert-butyl-4-hydroxyphenyl)-4-((4-N-ethyl-N-propylaminoethylphenoxy)methyl)oxazole hydrochloride or 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-(2-(4-ethylpropylaminoethylphenoxy)ethyl)oxazole. 9. A method for treating a disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, amytrophic lateral sclerosis or cerebral trauma in a mammal in need of such treatment which comprises administering to said mammal a therapeutically effective amount of a compound of any of Claims 1, 2, 3 or 8. 10. A method for inhibiting lipid peroxidation in a mammal in need of such treatment which comprises administering to said mammal a therapeutically effective amount of a compound of any of Claims 1, 2, 3 or 8. 11. A method for preventing ischemia-induced cell damage in mammals by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of any of Claims 1, 2, 3 or 8. 12. A pharmaceutical composition comprising a compound of Claim 1 together with one or more pharmaceutically acceptable diluents, carriers or excipients thereof.