Patent EA-002164-B1 (EA)
Title: High purity (1r,2r,4r)-(-)-2-[n,n-(dimethyllaminoethoxy)]-2-phenyl-1,7,7-trimethyl-bicyclo[2.2.1]heptane, pharmaceutical acceptable salts thereof, process for preparing the same and medicaments containg one or more of said compounds
Inventor: LUKACS GYULA
IPC: A61K31/13
Filed: 2000-05-10
Abstract: 1. (1R,2S,4R)-(-)-2-[N,N-(dimethylamino-ethoxy)]-2-phenyl-l,1,7-trimethyl-bicyclo[2.2.1]-heptane of Formula I   and pharmaceutically acceptable acid addition salts thereof, characterized in that they contain not more than 0.2 % of (1R,33,4R)-(-)-3-[2-N,N-(dimethylaminoethyl)]-1,7,7-trimethyl-bicyclo-[2.2.1]heptane-2-one of Formula V   or a pharmaceutically acid addition salt thereof. 2. (1R,2S,4R)-(-)-2-[N,N-(dimethylamino-ethoxy)]-2-phenyl-1,7,7-trimethyl-bicyclo[2.2.1]-heptane fumarate (1:1) according to Claim 1, characterized in that it contains not more than 0,2% of (lR,3S,4R)-3-[2-N,N-(dimethylamino-ethoxy)]-2-phenyl-1,7,7-trimethyl-bicyclo[2.2.1]-heptane-2-one fumarate (1:1). 3. (1R,2S,4R)-(-)-2-[N,N-(dimethylamino-ethoxy)]-2-phenyl-1,1,7-trimethyl-bicyclo[2.2.1]-heptane of Formula I according to claims 1 or 2, characterized in that it contains not more than 0,05% of (lR,3S,4R)-3-[2-N,N-(dimethylamino-ethoxy)]-2-phenyl-1,7,7-trimethyl-bicyclo[2.2.1]-heptane-2-one of Formula V or a pharmaceutically acid addition salt thereof. 4. (1R,2S,4R)-(-)-2-[N,N-(dimethylamino-ethoxy)]-2-phenyl-1,7,7-trimethyl-bicyclo[2.2.1]-heptane fumarate (1:1) according to any of Claims 1 to 3, characterized in that it contains not more than 0,05% of (lR,3S,4R)-3-[2-N,N-(dimethylamino-ethoxy)]-2-phenyl-1,7,7-trimethyl-bicyclo[2.2.1]-heptane-2-one fumarate (1:1). 5. (1R,2S,4R)-(-)-2-[N,N-(dimethylamino-ethoxy)]-2-phenyl-1,7,7-trimethyl-bicyclo[2.2.1]-heptane of Formula I and pharmaceutically acid addition salts thereof according to any of Claims 1 to 4 by converting (+)-1,7,7-trimethyl-bicycio[2.2.1]heptane-2-one {(+)-camphor} of Formula II   into 1R,2S,4R)-(-)-2-phenyl- phenyl-1,7,7-trimethyl-bicyclo[2.2.1]-heptane-2-ol of Formula III   by reacting (+)-1,7,7-trimethyl-bicycio[2.2.1]heptane-2-one {(+)-camphor} of Formula II with a metallo-organic compound, if necessary carrying outa decomposition of the reaction product, and reacting the 1R,2S,4R)-(-)-2-phenyl- phenyl-1,7,7-trimethyl-bicyclo[2.2.1]-heptane-2-ol of Formula III thus obtained with a (2-halogenoethyl)dimethylamine) in the presence of a basic salt-forming agent in an organic solvent and if desired, converting the base (1R,2S,4R)-(-)-2-[N,N-(dimethylamino-ethoxy)]-2-phenyl-1,7,7-trimethyl-bicyclo[2.2.1]-heptane of Formula I thus obtained into a salt characterized by carrying out the reaction of (1R,2S,4R)-(-)-2-phenyl--1,7,7-trimethyl-bicyclo[2.2.1]heptane-2-ol of the Formula III and 2-(halogenoethyl)dimethylamine in a medium containing dioxane as solvent. 6. A process according to claim 5, characterized in that a phenyl magnesium halide is used as a metallo-organic compound. 7. The process according to claim 5 or 6, characterized in that a phenyl magnesium bromide is used as a metallo-organic compound. 8. The process according to claim 5 or 6, characterized in that a phenyl magnesium chloride is used as a metallo-organic compound. 9. The process according to any of claims 5 to 8, characterized in that as a (2-halogenethyl)dimethylamine (2-chloroethyl) dimethylamine is used. 10. The process according to any of Claims 5 to 9 characterized by using sodium amide as basic salt-forming agent. 11. The process according to any of Claims 5 to 10 characterized by carrying out the alkylation (1R,2S,4R)-(-)-2-phenyl-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2-ol of the Formula III and 2-(halogenoethyl)dimethylamine under heating, preferably at the boiling point of the reaction mixture. 12. The process according to any of Claims 5 to 11 characterized by converting (1R,2S,4R)-(-)-2-[N,N- -(dimethylaminoethoxy)]-2-phenyl-1,1,7-trimethyl--bicycio[2.2.1]heptane of the Formula I into fumarate (1:1) without isolation a compound of Formula I. 13. Medicaments, characterized in that they contain as (an) active component(s) one or more according to any of claims 1 to 4, preferably together with one or more in pharmaceutical preparations usual excipient(s). 14. The medicaments according to claim 13, characterized in that they contain (lR,3S,4R)-3-[2-N,N-(dimethylamino-ethoxy)]-2-phenyl-1,7,7-trimethyl-bicyclo[2.2.1]-heptane-2-one fumarate (1:1) according to claim 2 or 4 as an active component. 15. A use of the compound according to any of claims 1 to 4 for preparing anxiolytic medicaments. 16. The use according to claim 15, characterized in that (1R,2S,4R)-(-)-2-[N,N- -(dimethylaminoethoxy)]-2-phenyl-1,1,7-trimethyl--bicycio[2.2.1]heptane of the Formula I into fumarate (1:1) of claim 2 or 4 is used as a compound  according to clams 1 to 4.