Tetrahydro-3,5-dioxo-1H-pyrrolizine-7a(5H)-carboxylic acids and derivatives as cognition activators

Claim 2

A compound having the following general structural formula wherein n is 0,1,2 or 3; and R is OH; or O-as a salt with a pharmaceutically acceptable metal or amine cation; or O-alkyl of from one to six carbon atoms with the proviso that, when n is 2, R is not O-ethyl; or wherein X is hydrogen, alkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, halo or trifluoromethyl; or NR 1 R 2 wherein R 1 is hydrogen, alkyl of from one to six carbon atoms, alkyl of from two to six carbon atoms substituted by amino, alkylamino or dialkylamino in which alkyl contains one to six carbon atoms, hydroxy, alkoxy of from one to six carbon atoms, mercapto, alkylmercapto of from one to six carbon atoms, 5- or 6-membered cycloalkyl, 5- or 6-membered cycloalkyl substituted by alkyl of from one to four carbon atoms, phenyl, phenyl substituted by alkyl of from one to four carbon atoms, or a 5- or 6-membered heterocyclic group containing up to four heteroatoms selected from nitrogen, oxygen, and sulphur which may be substituted by amino, alkylamino or dialkylamino of from one to four carbon atoms, and R 2 is hydrogen or alkyl of from one to six carbon atoms.

Claim 3

A compound having the following general structural formula wherein R is OH; or O- as a salt with a pharmaceutically acceptable metal or amine cation; or wherein X is hydrogen, alkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, halo, or trifluoromethyl; or O-alkyl having one, three, four, five, or six carbon atoms; or NR 1 R 2 wherein R 2 is hydrogen or alkyl of one to six carbon atoms and R 1 is hydrogen, alkyl of from one to six carbon atoms, alkyl of from two to six carbon atoms substituted by amino, alkylamino or dialkylamino in which alkyl contains one to six carbon atoms, 2,6-dimethylphenyl, 4-amino-3-pyridinyl, 3-amino-4-pyridinyl, 4-pyridinyl, or 5-tetrazol-yl; or where R 1 and R 2 combine with the N to which they are attached to form 2,6-dimethylpiper- idinyl.

Claim 4

A compound having the following general structural formula wherein R is OH; or O- as a salt with a pharmaceutically acceptable metal or amine cation; or wherein X is hydrogen, alkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, halo, or trifluoromethyl; or O-alkyl having one, three, four, five, or six carbon atoms; or NR 1 R 2 wherein R 2 is hydrogen or alkyl of one to six carbon atoms and R 1 is hydrogen, alkyl of from one to six carbon atoms, alkyl of from two to six carbon atoms substituted by amino, alkylamino or dialkylamino in which alkyl contains one to six carbon atoms, 2,6-dimethylphenyl, 4-amino-3-pyridinyl, 3-amino-4-pyridinyl, 4-pyridinyl, or 5-tetrazol-yl; or where R 1 and R 2 combine with the N to which they are attached to form 2,6-dimethylpiper- idinyl.

Claim 5

A compound according to Claim 1 having the structural formula wherein R is OH; or 0- as a salt with a pharmaceutically acceptable metal or amine cation; or wherein X is hydrogen, alkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, halo, or trifluoromethyl; or 0-alkyl having one, three, four, five, or six carbon atoms.

Claim 6

A compound according to Claim 1, which is tetrahydro-3,5-dioxo-1H-pyrrolizine-7a (5H)-propanoic acid, tetrahydro-3,5-dioxo-1H-pyrrolizine-7a(5H)-propanoic acid benzyl ester, or tetrahydro-3,5-dioxo-lH-pyrrolizine-7a(5H)-propanoic acid N-4-pyridinyl amide.

Claim 7

A pharmaceutical composition for the treatment of senility or for reversing amnesia caused by electroconvulsion shock comprising an effective amount of a compound having the structural formula wherein n = 0, 1, 2 or 3; and R 4 is OH; or O- as a salt with a pharmaceutically acceptable metal or amine cation; or wherein X is hydrogen, alkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, halo or trifluoromethyl; or 0-alkyl having from one to six carbon atoms, or NR 1 R 2 wherein R 1 is hydrogen, alkyl of from one to six carbon atoms, alkyl of from two to six carbon atoms substituted by amino, alkylamino or dialkylamino in which alkyl contains one to six carbon atoms, hydroxy, alkoxy of from two to six carbon atoms, mercapto, alkylmercapto of from two to six carbon atoms, 5 or 6-membered cycloalkyl, 5- or 6-membered cycloalkyl substituted by alkyl of from one to four carbon atoms, phenyl, phenyl substituted by alkyl of from one to four carbon atoms, or a 5- or 6-membered heterocyclic group containing up to four heteroatoms selected from nitrogen, oxygen and sulphur which may be substituted by amino, alkylamino or dialkylamino of from one to four carbon atoms, and R 2 is hydrogen or alkyl of from one to six carbon atoms: in combination with a pharmaceutically acceptable carrier.

Claim 8

A pharmaceutical composition for the treatment of senility or for reversing amnesia caused by electroconvulsion shock comprising an effective amount of a compound having the structural formula wherein n = 0, 1, 2 or 3; and R 4 is OH; or O- as a salt with a pharmaceutically acceptable metal or amine cation; or wherein X is hydrogen, alkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, halo or trifluoromethyl; or 0-alkyl having from one to six carbon atoms, or NR 1 R 2 wherein R 1 is hydrogen, alkyl of from one to six carbon atoms, alkyl of from two to six carbon atoms substituted by amino, alkylamino or dialkylamino in which alkyl contains one to six carbon atoms, hydroxy, alkoxy of from two to six carbon atoms, mercapto, alkylmercapto of from two to six carbon atoms, 5 or 6-membered cycloalkyl, 5- or 6-membered cycloalkyl substituted by alkyl of from one to four carbon atoms, phenyl, phenyl substituted by alkyl of from one to four carbon atoms, or a 5- or 6-membered heterocyclic group containing up to four heteroatoms selected from nitrogen, oxygen and sulphur which may be substituted by amino, alkylamino or dialkylamino of from one to four carbon atoms, and R 2 is hydrogen or alkyl of from one to six carbon atoms: in combination with a pharmaceutically acceptable carrier.

Claim 9

As a compound having a first pharmaceutical use, namely for treating senility or for reversing amnesia caused by electroconvulsive shock in humans, the compound tetrahydro-3, 5-dioxo-lH-pyrrolizine-7a(5H)-propanoic acid ethyl ester.

Claim 10

As a compound having a first pharmaceutical use, namely for treating senility or for reversing amnesia caused by electroconvulsive shock in humans, the compound tetrahydro-3, 5-dioxo-lH-pyrrolizine-7a(5H)-propanoic acid ethyl ester.

Claim 11

A process for producing a compound as claimed in Claim 1 or 2, which process comprises reacting a compound of the formula wherein n is 0, 1, 2 or 3, and R is hydrogen or alkyl from one to six carbon atoms with a dehydrating agent derived from a carboxylic acid of the formula R'COOH, wherein R' is alkyl of one to six carbon atoms or aryl, in the presence of an acid acceptor or at an elevated temperature and hydrolyzing the resulting product to form a compound according to Claim 1 or 2 wherein R is OH, and, if desired, converting said product to a salt, an ester, or amide as defined in Claim 1 or 2 by a conventional method.