Benzoxazol-and benzothiazolamine derivatives, useful as anti-anoxic agents

Claim 1

A chemical compound having the formula ##STR56## a pharmaceutically acceptable acid addition salt or a possible stereochemically isomeric form thereof, wherein: --A 1 ═A 2 --A 3 ═A 4 --is a bivalent radical having the formula --C═CH--CH═CH-- (a); --N═CH--CH═CH-- (b); --CH═N--CH═CH-- (c); --CH═C--N═CH-- (d); or --CH═CH--CH═N-- (e); wherein one or two hydrogen atoms in the radical --A 1 ═A 2 --A 3 ═A 4 -- may, each independently from each other, be replaced by halo, C 1-6 alkyl, hydroxy, C 1-6 alkyloxy or trifluoromethyl; Z is O or S; n is 0 or the integer 1; R is a member selected from the group consisting of hydrogen, C 1-6 alkyl, hydroxy and C 1-6 alkyloxy or trifluoromethyl; R 1 or R 2 is hydrogen, C 1-6 alkyl, or Ar C 1-6 alkyl; the dotted line between the nitrogen atom bearing R 1 , the interjacent carbon atom and the nitrogen atom bearing R 2 indicating that a double bond exists between the nitrogen bearing R 1 and said interjacent carbon atom, in which case R 1 is absent, or a double bond exists between the interjacent carbon and the nitrogen bearing R 2 , in which case R 2 is absent; and wherein said interjacent carbon atom is the carbon atom positioned between the nitrogen bearing R 1 and the nitrogen bearing R 2 ; R 3 or R 4 are both hydrogens or R 3 and R 4 combined may form a bivalent radical of formula --CH 2 --CH 2 --; L is a member selected from the group consisting of C 1-12 alkyl, substituted C 1-6 alkyl, Ar C 2-6 alkenyl, C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, a radical of formula ##STR57## and a radical of formula ##STR58## R 5 being hydrogen or C 1-12 alkylcarbonyl; R 6 being hydrogen or C 1-6 alkyl; R 7 being Ar, a radical R 8 -O or a radical R 8 -S; B being a bivalent radical of formula --CH 2 -- or --O--; and said R 8 being hydrogen; Ar; 2,3-dihydro-1H-indenyl; benzodioxolyl; (2,3-dihydro-1,4-benzodioxin-2-yl)methyl; (2H-1-benzopyran-2-yl)methyl; or phenyl substituted with C 2-6 -alkenyloxy, C 1-6 alkylcarbonylamino or C 1-6 alkylphenylcarbonyl; and wherein said substituted C 3-6 cycloalkyl is C 3-6 cycloalkyl being substituted with up to two substitutents each independently selected from the group consisting of aryl, aryloxy and cyano; said substituted C 1-6 alkyl is C 1-6 alkyl being substituted with a member selected from the group consisting of C 3-6 cycloalkyl, pyridinyl, pyridinyloxy, Ar, benzimidazolyl, indolyl, isoxazolyl being optionally substituted with phenyl, 3-oxo-1,2,4-triazolo[4,5-a]-pyridin-2(3H)-yl, a radical of formula ArY--, a radical of formula R 9 O-- and a radical of formula ##STR59## Y being O, S, NH, --CONH--, ##STR60## R 9 being hydrogen, Ar C 1-6 alkyl, C 3-6 cycloalkyl, phenyl substituted with phenyl, or phenyl substituted with C 1-6 alkyloxycarbonyl; R 10 being hydrogen or C 1-6 alkyl; and wherein Ar is phenyl optionally substituted with up to three substituents each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkyloxy, halo, trifluoromethyl, cyano, C 1-6 alkylcarbonyl, nitro, amino and aminocarbonyl.

Claim 15

A method of treating warm-blooded animals suffering from anoxia which method comprises the systemic administration to warm-blooded animals of an anti-anoxic effective amount of a compound having the formula ##STR66## a pharmaceutically acceptable acid addition salt or a possible stereochemically isomeric form thereof, wherein: --A 1 ═A 2 --A 3 ═A 4 -- is a bivalent radical having the formula --CH═CH--CH═CH-- (a); --N═CH--CH═CH-- (b); --CH═N--CH═CH-- (c); --CH═CH--N═CH-- (d); or --CH═CH--CH═N-- (e); wherein one or two hydrogen atoms in the radical --A 1 ═A 2 --A 3 ═A 4 -- may, each independently from each other, be replaced by halo, C 1-6 alkyl, hydroxy, C 1-6 alkyloxy, or trifluoromethyl; Z is O or S; n is 0 or the integer 1; R is a member selected from the group consisting of hydrogen, C 1-6 alkyl, hydroxy and C 1-6 akyloxy; R 1 or R 2 is hydrogen, C 1-6 alkyl, or Ar C 1-6 alkyl; the dotted line between the nitrogen atom bearing R 1 , the interjacent carbon atom and the nitrogen atom bearing R 2 indicating that a double bond exists between the nitrogen bearing R 1 and said interjacent carbon atom, in which case R 1 is absent, or a double bond exists between the interjacent carbon and the nitrogen bearing R 2 , in which case R 2 is absent; and wherein said interjacent carbon atom is the carbon atom positioned between the nitrogen bearing R 1 and the nitrogen bearing R 2 ; R 3 or R 4 are both hydrogens or R 3 and R 4 combined may form a bivalent radical of formula --CH 2 --CH 2 --; L is a member selected from the group consisting of C 1-12 alkyl, substituted C 1-6 alkyl, Ar C 2-6 alkenyl, C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, a radical of formula ##STR67## and a radical of formula ##STR68## R 5 being hydrogen or C 1-12 alkylcarbonyl; R 6 being hydrogen or C 1-6 alkyl; R 7 being Ar, a radical R 8 --O or a radical R 8 --S; B being a bivalent radical of formula --CH 2 -- or --O--; and said R 8 being hydrogen; Ar; 2,3-dihydro-1H-indenyl; benzodioxolyl; (2,3-dihydro-1,4-benzodioxin-2-yl)methyl; (2H-1-benzopyran-2-yl)methyl; or phenyl substituted with C 2-6 alkenyl oxy, C 1-6 alkylcarbonylamino or C 1-6 alkylphenylcarbonyl; and wherein said substituted C 3-6 cycloalkyl is C 3-6 cycloalkyl being substituted with up to two substituents each independently selected from the group consisting of aryl, aryloxy and cyano; said substituted C 1-6 alkyl is C 1-6 alkyl being substituted with a member selected from the group consisting of C 3-6 cycloalkyl, pyridinyl, pyridinyloxy, Ar, benzimidazolyl, indolyl, isoxazolyl being optionally substituted with phenyl, 3-oxo-1,2,4-triazolo[4,5-a]-pyridin-2(3H)-yl, a radical of formula ArY--, a radical of formula R 9 O-- and a radical of formula ##STR69## Y being O, S, NH, --CONH--, ##STR70## R 9 being hydrogen, Ar C 1-6 alkyl, C 3-6 cycloalkyl, phenyl substituted with phenyl, or phenyl substituted with C 1-6 alkyloxycarbonyl; R 10 being hydrogen or C 1-6 alkyl; and wherein Ar is phenyl optionally substituted with up to three substituents each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkyloxy, halo, trifluoromethyl, cyano, C 1-6 alkylcarbonyl, nitro, amino and aminocarbonyl.

Claim 16

A method of treating warm-blooded animals suffering from anoxia which method comprises the systemic administration to warm-blooded animals of an anti-anoxic effective amount of a compound having the formula ##STR66## a pharmaceutically acceptable acid addition salt or a possible stereochemically isomeric form thereof, wherein: --A 1 ═A 2 --A 3 ═A 4 -- is a bivalent radical having the formula --CH═CH--CH═CH-- (a); --N═CH--CH═CH-- (b); --CH═N--CH═CH-- (c); --CH═CH--N═CH-- (d); or --CH═CH--CH═N-- (e); wherein one or two hydrogen atoms in the radical --A 1 ═A 2 --A 3 ═A 4 -- may, each independently from each other, be replaced by halo, C 1-6 alkyl, hydroxy, C 1-6 alkyloxy, or trifluoromethyl; Z is O or S; n is 0 or the integer 1; R is a member selected from the group consisting of hydrogen, C 1-6 alkyl, hydroxy and C 1-6 akyloxy; R 1 or R 2 is hydrogen, C 1-6 alkyl, or Ar C 1-6 alkyl; the dotted line between the nitrogen atom bearing R 1 , the interjacent carbon atom and the nitrogen atom bearing R 2 indicating that a double bond exists between the nitrogen bearing R 1 and said interjacent carbon atom, in which case R 1 is absent, or a double bond exists between the interjacent carbon and the nitrogen bearing R 2 , in which case R 2 is absent; and wherein said interjacent carbon atom is the carbon atom positioned between the nitrogen bearing R 1 and the nitrogen bearing R 2 ; R 3 or R 4 are both hydrogens or R 3 and R 4 combined may form a bivalent radical of formula --CH 2 --CH 2 --; L is a member selected from the group consisting of C 1-12 alkyl, substituted C 1-6 alkyl, Ar C 2-6 alkenyl, C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, a radical of formula ##STR67## and a radical of formula ##STR68## R 5 being hydrogen or C 1-12 alkylcarbonyl; R 6 being hydrogen or C 1-6 alkyl; R 7 being Ar, a radical R 8 --O or a radical R 8 --S; B being a bivalent radical of formula --CH 2 -- or --O--; and said R 8 being hydrogen; Ar; 2,3-dihydro-1H-indenyl; benzodioxolyl; (2,3-dihydro-1,4-benzodioxin-2-yl)methyl; (2H-1-benzopyran-2-yl)methyl; or phenyl substituted with C 2-6 alkenyl oxy, C 1-6 alkylcarbonylamino or C 1-6 alkylphenylcarbonyl; and wherein said substituted C 3-6 cycloalkyl is C 3-6 cycloalkyl being substituted with up to two substituents each independently selected from the group consisting of aryl, aryloxy and cyano; said substituted C 1-6 alkyl is C 1-6 alkyl being substituted with a member selected from the group consisting of C 3-6 cycloalkyl, pyridinyl, pyridinyloxy, Ar, benzimidazolyl, indolyl, isoxazolyl being optionally substituted with phenyl, 3-oxo-1,2,4-triazolo[4,5-a]-pyridin-2(3H)-yl, a radical of formula ArY--, a radical of formula R 9 O-- and a radical of formula ##STR69## Y being O, S, NH, --CONH--, ##STR70## R 9 being hydrogen, Ar C 1-6 alkyl, C 3-6 cycloalkyl, phenyl substituted with phenyl, or phenyl substituted with C 1-6 alkyloxycarbonyl; R 10 being hydrogen or C 1-6 alkyl; and wherein Ar is phenyl optionally substituted with up to three substituents each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkyloxy, halo, trifluoromethyl, cyano, C 1-6 alkylcarbonyl, nitro, amino and aminocarbonyl.