Tetrahydroprotoberbine compounds and uses thereof in the treatment of neurological, psychiatric and neurodegenerative diseases
OwnerJames Jackson MILLER, Anthony George PHILLIPS +2inventors
InventorsJames Jackson MILLER, Anthony George PHILLIPS, Christopher Court LAPISH, Glenn Martin SAMMIS
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Abstract
Tetrahydroprotoberbine (THPB) compounds and their use in the treatment of neurological, psychiatric and neurodegenerative diseases is provided. The compounds include d-govadine, l-govadine and racemic govadine, as well as d-THPBs of general formula (I). Enantioselective processes for preparing compounds of formula (I), and d- and l-govadine are also provided.(I)
Claims38
A method of treating a neurological, psychiatric of neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound of formula (I):
- or a pharmaceutically acceptable salt, solvate or prodrug thereof,
- wherein:
- R1 and R2 are independently H, alkyl, benzyl or —COR9;
- or R1 and R2 together form (CH2)m;
- R4 is H, alkyl, benzyl, or —COR9;
- R3 is H or OR10, wherein R10 is H, alkyl, benzyl or —COR9, or R10 taken together with R4 forms (CH2)m;
- R5 is H or OR11, wherein R11 is H, alkyl, benzyl or —COR9, or R11 taken together with R4 forms (CH2)m;
- R6 is H or halogen;
- R9 is H or alkyl;
- m is 1 or 2, and
- wherein when R10 taken together with R4 forms (CH2)m, then R5 is H or OR11, wherein R11 is H, alkyl, benzyl or —COR9, and
- wherein when R11 taken together with R4 forms (CH2)m, then R3 is H or OR11, wherein R11 is H, alkyl, benzyl or —COR9, and
- wherein at least one of R3 and R5 is other than H.
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A method of increasing dopamine release in the prefrontal cortex comprising administering to a subject in need thereof an effective amount of a compound of formula (I):
- or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
- R1 and R2 are independently H, alkyl, benzyl or —COR9;
- or R1 and R2 together form (CH2)m;
- R4 is H, alkyl, benzyl or —COR9;
- R3 is H or OR10, wherein R10 is H, alkyl, benzyl or —COR9, or R10 taken together with R4 forms (CH2)m;
- R5 is H or OR11, wherein R11 is H, alkyl, benzyl or —COR9, or R11 taken together with R4 forms (CH2)m;
- R6 is H or halogen;
- R9 is H or alkyl;
- m is 1 or 2, and
- wherein when R10 taken together with R4 forms (CH2)m, then R5 is H or OR11, wherein R11 is H, alkyl, benzyl or —COR9, and
- wherein when R11 taken together with R4 forms (CH2)m, then R3 is H or OR11, wherein R11 is H, alkyl, benzyl or —COR9, and
- wherein at least one of R3 and R5 is other than H.
A method of treating a cognitive disorder comprising administering to a subject in need thereof an effective amount of a compound of formula (I):
- or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
- R1 and R2 are independently H, alkyl, benzyl or —COR9;
- or R1 and R2 together form (CH2)m;
- R4 is H, alkyl, benzyl or —COR9;
- R3 is H or OR10, wherein R10 is H, alkyl, benzyl or —COR9, or R10 taken together with R4 forms (CH2)m;
- R5 is H or OR11, wherein R11 is H, alkyl, benzyl or —COR9 or R11 taken together with R4 forms (CH2)m;
- R6 is H or halogen;
- R9 is H or alkyl;
- m is 1 or 2, and
- wherein when R10 taken together with R4 forms (CH2)m, then R5 is H or OR11, wherein R11 is H, alkyl, benzyl or —COR9, and
- wherein when R11 taken together with R4 forms (CH2)m, then R3 is H or OR11, wherein R11 is H, alkyl, benzyl or —COR9, and
- wherein at least one of R3 and R5 is other than H.
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A compound having the structure:
- or a prodrug, derivative, salt, ester or solvate thereof.
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A method of treating a neurological, psychiatric or neurodegenerative disease in a subject in need thereof comprising administering to the subject an effective amount of a compound having the structure
- or a pharmaceutically acceptable salt, solvate or prodrug thereof.
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A method of cognitive enhancement comprising administering to a subject an effective amount of a compound having the structure
- or a pharmaceutically acceptable salt, solvate or prodrug thereof.
A process for preparing enantiomerically pure d- or l-govadine comprising the steps:
- (a) performing a coupling reaction between compounds (XVI) and (XVII) to provide amide (XVIII);
- (b) performing a Bischler-Napieralski reaction on the amide (XVIII) to provide dihydroisoquinoline intermediate (XIX);
- (c) reducing the dihydroisoquinoline intermediate (XIX) with a chiral catalyst to provide compound (XIV) or (XV);
- (d) performing a Mannich-type cyclization on compound (XIV) or (XV) to obtain d- or l-govadine,
- wherein the synthesis route is as follows:
- and wherein X is Cl or OH, and R12 is a protecting group.
Dependencies are inferred from the claim text.