Aliphatic propargylamines as selective MAO-B inhibitors and as neuroprotective agents

A pharmaceutical composition for the in vivo inhibition of MAO-B activity in mammals, said composition comprising an effective amount of a compound having the following formula:

• ##STR25## wherein R.sub.1 is hydrogen or a straight chain or branched lower alkyl;
• and
• R.sub.2 is a straight chain or branched alkyl, alkenyl, alkynyl, alkoxy, alkylthio or alkyl sulphinyl group having from 3 to 11 carbon atoms, said group being unsubstituted or substituted with at least one of the substituents selected from the group consisting of hydroxy, aldehyde, oxo, loweracyloxy, halogen, thio, sulfoxide, sulfone, phenyl, halogen-substituted phenyl, hydroxy-substituted phenyl, cycloalkyl having from 3 to 6 carbon atoms and heterocyclic substituents having between 3 and 6 atoms, of which from 1 to 3 are heteroatoms selected from the group consisting of O, S and N, or R.sub.2 is a straight chain or branched alkyl group having 1, 2, 12, 13 or 14 carbon atoms which is unsubstituted or is substituted by halogen and pharmaceutically acceptable salts thereof, in admixture with a pharmaceutically acceptable carrier, excipient or adjuvant, with the provisos that:
• when R.sub.1 is CH.sub.3, R.sub.2 cannot be an unsubstituted alkyl having from 4 to 7 carbon atoms, and
• when R.sub.2 is substituted with carboxyl or loweracyloxy, the carboxyl or loweracyloxy substituent is not on the last atom of the longest chain of the R.sub.2 group, in admixture with a pharmaceutically acceptable carrier, excipient or adjuvant.

A pharmaceutical composition for the treatment and prevention of neurodegenerative disorders in mammals, said composition comprising an effective amount of a compound having the following formula:

• ##STR26## wherein R.sub.1, R.sub.3 and R.sub.4 are the same or different and represent hydrogen or a straight chain or branched lower alkyl;
• y is an integer ranging from 0 to 5;
• z is an integer ranging from 0 to 5;
• and
• R.sub.2 is a straight chain or branched alkyl, alkenyl, alkynyl, alkoxy, alkylthio or alkyl sulphinyl group having from 3 to 11 carbon atoms, said group being unsubstituted or substituted with at least one of the substituents selected from the group consisting of hydroxy, aldehyde, oxo, loweracyloxy, halogen, thio, sulfoxide, sulfone, phenyl, halogen-substituted phenyl, hydroxy-substituted phenyl, cycloalkyl having from 3 to 6 carbon atoms and heterocyclic substituents having between 3 and 6 atoms, of which from 1 to 3 are heteroatoms selected from the group consisting of O, S and N, or R.sub.2 is a straight chain or branched alkyl group having 1, 2, 12, 13 or 14 carbon atoms which is unsubstituted or is substituted by halogen and pharmaceutically acceptable salts thereof, in admixture with a pharmaceutically acceptable carrier, excipient or adjuvant, with the provisos that:
• when R.sub.1 is CH.sub.3, R.sub.2 cannot be an unsubstituted alkyl having from 4 to 7 carbon atoms, and
• when R.sub.2 is substituted with carboxyl or loweracyloxy, the carboxyl or loweracyloxy substituent is not on the last atom of the longest of the R.sub.2 group.

A method for the in vivo inhibition of MAO-B to alleviate neuropsychiatric disorders in mammalian subjects which comprises administering to a mammalian subject in need thereof a compound having the following formula I:

• ##STR27## wherein R.sub.1 is hydrogen or a straight chain or branched lower alkyl;
• and
• R.sub.2 is a straight chain or branched alkyl, alkenyl, alkynyl, alkoxy, alkylthio or alkyl sulphinyl group having from 3 to 11 carbon atoms, said group being unsubstituted or substituted with at least one of the substituents selected from the group consisting of hydroxy, aldehyde, oxo, loweracyloxy, halogen, thio, sulfoxide, sulfone, phenyl, halogen-substituted phenyl, hydroxy-substituted phenyl, cycloalkyl having from 3 to 6 carbon atoms and heterocyclic substituents having between 3 and 6 atoms, of which from 1 to 3 are heteroatoms selected from the group consisting of O, S and N, or R.sub.2 is a straight chain or branched alkyl group having 1, 2, 12, 13 or 14 carbon atoms which is unsubstituted or is substituted by halogen and pharmaceutically acceptable salts thereof, with the provisos that:
• when R.sub.2 is substituted with carboxyl or loweracyloxy, the carboxyl or loweracyloxy substituent is not on the last carbon atom of the R.sub.2 chain,
• in admixture with a pharmaceutically acceptable carrier, excipient or adjuvant, for the in vivo inhibition of MAO-B to alleviate neuropsychiatric disorders in mammalian subjects.

A method for the in vivo inhibition of MAO-B to alleviate neuropsychiatric disorders in mammalian subjects which comprises administering to a mammalian subject in need thereof a compound having the following formula III:

• ##STR28## wherein R.sub.1, R.sub.3 and R.sub.4 are the same or different and represent hydrogen or a straight chain or branched lower alkyl;
• y is an integer ranging from 0 to 5;
• z is an integer ranging from 0 to 5;
• and
• R.sub.2 is a straight chain or branched alkyl, alkenyl, alkynyl, alkoxy, alkylthio or alkyl sulphinyl group having from 3 to 11 carbon atoms, said group being unsubstituted or substituted with at least one of the substituents selected from the group consisting of hydroxy, aldehyde, oxo, loweracyloxy, halogen, thio, sulfoxide, sulfone, phenyl, halogen-substituted phenyl, hydroxy-substituted phenyl, cycloalkyl having from 3 to 6 carbon atoms and heterocyclic substituents having between 3 and 6 atoms, of which from 1 to 3 are heteroatoms selected from the group consisting of O, S and N, or R.sub.2 is a straight chain or branched alkyl group having 1, 2, 12, 13 or 14 carbon atoms which is unsubstituted or is substituted by halogen and pharmaceutically acceptable salts thereof, in admixture with a pharmaceutically acceptable carrier, excipient or adjuvant in preventing the premature degeneration of neuron cells in mammalian subject.

A method for the in vivo inhibition of MAO-B to alleviate neuropsychiatric disorders in mammalian subjects which comprises administering to a mammalian subject in need thereof a compound having the following formula III:

• ##STR29## wherein R.sub.1, R.sub.3 and R.sub.4 are the same or different and represent hydrogen or a straight chain or branched lower alkyl;
• y is an integer ranging from 0 to 5;
• z is an integer ranging from 0 to 5;
• and
• R.sub.2 is a straight chain or branched alkyl, alkenyl, alkynyl, alkoxy, alkylthio or alkyl sulphinyl group having from 3 to 11 carbon atoms, said group being unsubstituted or substituted with at least one of the substituents selected from the group consisting of hydroxy, aldehyde, oxo, loweracyloxy, halogen, thio, sulfoxide, sulfone, phenyl, halogen-substituted phenyl, hydroxy-substituted phenyl, cycloalkyl having from 3 to 6 carbon atoms and heterocyclic substituents having between 3 and 6 atoms, of which from 1 to 3 are heteroatoms selected from the group consisting of O, S and N, and pharmaceutically acceptable salts thereof, in admixture with a pharmaceutically acceptable carrier, excipient or adjuvant in protecting mammalian neuron cells from the action of neurotoxic agents causing neurodegenerative disorders to mammals.

A method for the in vivo inhibition of MAO-B to alleviate neuropsychiatric disorders in mammalian subjects which comprises administering to a mammalian subject in need thereof a compound having the following formula III:

• ##STR30## wherein R.sub.1, R.sub.3 and R.sub.4 are the same or different and represent hydrogen or a straight chain or branched lower alkyl;
• y is an integer ranging from 0 to 5;
• z is an integer ranging from 0 to 5;
• and
• R.sub.2 is a straight chain or branched alkyl, alkenyl, alkynyl, alkoxy, alkylthio or alkyl sulphinyl group having from 3 to 11 carbon atoms, said group being unsubstituted or substituted with at least one of the substituents selected from the group consisting of hydroxy, aldehyde, oxo, loweracyloxy, halogen, thio, sulfoxide, sulfone, phenyl, halogen-substituted phenyl, hydroxy-substituted phenyl, cycloalkyl having from 3 to 6 carbon atoms and heterocyclic substituents having between 3 and 6 atoms, of which from 1 to 3 are heteroatoms selected from the group consisting of O, S and N, or R.sub.2 is a straight chain or branched alkyl group having 1, 2, 12, 13 or 14 carbon atoms which is unsubstituted or is substituted by halogen and pharmaceutically acceptable salts thereof, in admixture with a pharmaceutically acceptable carrier, excipient or adjuvant, in the treatment of neurodegenerative disorders in mammals.

A commercial package for the in vivo inhibition of MAO-B to alleviate neuropsychiatric disorders in mammalian subjects, said package comprising a pharmaceutical agent therapeutically effective for the in vivo inhibition of MAO-B to alleviate neuropsychiatric disorders in mammals together with instructions to use said pharmaceutical agent in the in vivo inhibition of MAO-B to alleviate neuropsychiatric disorders in mammals, said pharmaceutical agent comprised in said commercial package having the following formula:

• ##STR31## wherein R.sub.1 is hydrogen or a straight chain or branched lower alkyl;
• and
• R.sub.2 is a straight chain or branched alkyl, alkenyl, alkynyl, alkoxy, alkylthio or alkyl sulphinyl group having from 3 to 11 carbon atoms, said group being unsubstituted or substituted with at least one of the substituents the group consisting of hydroxy, aldehyde, oxo, loweracyloxy, halogen, thio, sulfoxide, sulfone, phenyl, halogen-substituted phenyl, hydroxy-substituted phenyl, cycloalkyl having from 3 to 6 carbon atoms and heterocyclic substituents having between 3 and 6 atoms, of which from 1 to 3 are heteroatoms selected from the group consisting of O, S and N, or R.sub.2 is a straight chain or branched alkyl group having 1, 2, 12, 13 or 14 carbon atoms which is unsubstituted or is substituted by halogen and pharmaceutically acceptable salts thereof, with the provisos that:
• when R.sub.2 is substituted with carboxyl or loweracyloxy, the carboxyl or loweracyloxy substituent is not on the last carbon atom of the R.sub.2 chain.

A commercial package for the treatment or prevention of neurodegenerative disorders in mammals, said package comprising a pharmaceutical agent therapeutically effective for the treatment or prevention of neurodegenerative disorders in mammals together with instructions to use said pharmaceutical agent in the treatment or prevention of neurodegenerative disorders in mammals, said pharmaceutical agent comprising in said commercial package having the following formula:

• ##STR32## wherein R.sub.1, R.sub.3 and R.sub.4 are the same or different and represent hydrogen or a straight chain or branched lower alkyl;
• y is an integer ranging from 0 to 5;
• z is an integer ranging from 0 to 5;
• and
• R.sub.2 is a straight chain or branched alkyl, alkenyl, alkynyl, alkoxy, alkylthio or alkyl sulphinyl group having from 3 to 11 carbon atoms, said group being unsubstituted or substituted with at least one of the substituents selected from the group consisting of hydroxy, aldehyde, oxo, loweracyloxy, halogen, thio, sulfoxide, sulfone, phenyl, halogen-substituted phenyl, hydroxy-substituted phenyl, cycloalkyl having from 3 to 6 carbon atoms and heterocyclic substituents having between 3 and 6 atoms, of which from 1 to 3 are heteroatoms selected from the group consisting of O, S and N, or R.sub.2 is a straight chain or branched alkyl group having 1, 2, 12, 13 or 14 carbon atoms which is unsubstituted or is substituted by halogen.