Conjugates comprising a gaba- or glycine compound, pharmaceutical compositions and combinations thereof as well as their use in treating cns disorders

Abstract

A novel use of conjugates of psychotropic drugs (e.g., antidepressants or anti-epileptic drugs) and organic acids such as GABA in the treatment of pain is disclosed. A novel GABA conjugate and uses thereof is also disclosed.

1 . A method of treating pain, the method comprising administering to a subject in need thereof a therapeutically effective amount of a chemical conjugate which comprises a first chemical moiety covalently linked to a second chemical moiety, wherein said first chemical moiety is an antidepressant and wherein said second chemical moiety is a GABA agonist. 
     
     
         2 . The method of  claim 1 , wherein said second chemical moiety is covalently linked to said first chemical moiety via a bond selected from the group consisting of a carboxylic ester bond, an alkyloxy carboxylic ester bond, an amide bond, an imine bond and a thioester bond. 
     
     
         3 . The method of  claim 1 , wherein said antidepressant is selected from the group consisting of a tricyclic antidepressant, a selective serotonin reuptake inhibitor, a serotonin and noradrenaline reuptake inhibitor, a reversible monamine oxidase inhibitor and a monoamine oxidase inhibitor. 
     
     
         4 . The method of  claim 1 , wherein said antidepressant is fluoxetine. 
     
     
         5 . The method of  claim 1 , wherein said second chemical moiety is GABA. 
     
     
         6 . The method of  claim 4 , wherein said second chemical moiety is GABA. 
     
     
         7 . The method of  claim 1 , wherein said chemical conjugate is flouxetine-GABA. 
     
     
         8 . The method of  claim 7 , wherein said GABA is covalently linked to said fluoxetine via an amide bond. 
     
     
         9 . The method of  claim 1 , wherein said GABA agonist is selected from the group consisting of (±) baclofen, γ-aminobutyric acid (GABA), γ-hydroxybutyric acid, aminooxyacetic acid, β-(4-chlorophenyl)-γ-aminobutyric acid, isonipecotic acid, piperidine-4-sulfonic acid, 3-aminopropylphosphonous acid, 3-aminopropylphosphinic acid, 3-(aminopropyl)methylphosphinic acid, 1-(aminomethyl)cyclohexaneacetic acid (gabapentin), y-vinyl-γ-aminobutyric acid (4-aminohex-5-enoic acid, y-vinyl GABA, vigabatrin) and 3-(2-imidazolyl)-4-aminobutanoic acid. 
     
     
         10 . The method of  claim 1 , wherein said pain is a chronic pain. 
     
     
         11 . The method of  claim 10 , wherein said chronic pain is a neuropathic pain or a nociceptive pain. 
     
     
         12 . The method of  claim 1 , wherein said pain is an acute pain. 
     
     
         13 . An article-of-manufacture comprising a pharmaceutical composition being packaged in a packaging material and identified in print, in or on said packaging material for use in the treatment of pain, said pharmaceutical composition including a pharmaceutically acceptable carrier and, as an active ingredient, a chemical conjugate which comprises a first chemical moiety covalently linked to a second chemical moiety, wherein said first chemical moiety is an antidepressant and wherein said second chemical moiety is a GABA agonist. 
     
     
         14 . The article-of-manufacture of  claim 13 , wherein said second chemical moiety is covalently linked to said first chemical moiety via a bond selected from the group consisting of a carboxylic ester bond, an alkyloxy carboxylic ester bond, an amide bond, an imine bond and a thioester bond. 
     
     
         15 . The article-of-manufacture of  claim 13 , wherein said antidepressant is selected from the group consisting of a tricyclic antidepressant, a selective serotonin reuptake inhibitor, a serotonin and noradrenaline reuptake inhibitor, a reversible monamine oxidase inhibitor and a monoamine oxidase inhibitor. 
     
     
         16 . The article-of-manufacture of  claim 13 , wherein said antidepressant is fluoxetine. 
     
     
         17 . The article-of-manufacture of  claim 13 , wherein said second chemical moiety is GABA. 
     
     
         18 . The article-of-manufacture of  claim 16 , wherein said second chemical moiety is GABA. 
     
     
         19 . The article-of-manufacture of  claim 13 , wherein said chemical conjugate is flouxetine-GABA. 
     
     
         20 . The article-of-manufacture of  claim 19 , wherein said GABA is covalently linked to said fluoxetine via an amide bond. 
     
     
         21 . The article-of-manufacture of  claim 13 , wherein said GABA agonist is selected from the group consisting of (±) baclofen, γ-aminobutyric acid (GABA), γ-hydroxybutyric acid, aminooxyacetic acid, β-(4-chlorophenyl)-γ-aminobutyric acid, isonipecotic acid, piperidine-4-sulfonic acid, 3-aminopropylphosphonous acid, 3-aminopropylphosphinic acid, 3-(aminopropyl)methylphosphinic acid, 1-(aminomethyl)cyclohexaneacetic acid (gabapentin), y-vinyl-γ-aminobutyric acid (4-aminohex-5-enoic acid, y-vinyl GABA, vigabatrin) and 3-(2-imidazolyl)-4-aminobutanoic acid. 
     
     
         22 . The article-of-manufacture of  claim 13 , wherein said pain is a chronic pain. 
     
     
         23 . The article-of-manufacture of  claim 22 , wherein said chronic pain is a neuropathic pain or a nociceptive pain. 
     
     
         24 . The article-of-manufacture of  claim 13 , wherein said pain is an acute pain. 
     
     
         25 . A method of treating an addictive disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a chemical conjugate which comprises a first chemical moiety covalently linked to a second chemical moiety, wherein said first chemical moiety is an antidepressant and wherein said second chemical moiety is a GABA agonist. 
     
     
         26 . The method of  claim 25 , wherein said second chemical moiety is covalently linked to said first chemical moiety via a bond selected from the group consisting of a carboxylic ester bond, an alkyloxy carboxylic ester bond, an amide bond, an imine bond and a thioester bond. 
     
     
         27 . The method of  claim 25 , wherein said antidepressant is selected from the group consisting of a tricyclic antidepressant, a selective serotonin reuptake inhibitor, a serotonin and noradrenaline reuptake inhibitor, a reversible monamine oxidase inhibitor and a monoamine oxidase inhibitor. 
     
     
         28 . The method of  claim 25 , wherein said antidepressant is fluoxetine. 
     
     
         29 . The method of  claim 25 , wherein said second chemical moiety is GABA. 
     
     
         30 . The method of  claim 28 , wherein said second chemical moiety is GABA. 
     
     
         31 . The method of  claim 25 , wherein said chemical conjugate is flouxetine-GABA. 
     
     
         32 . The method of  claim 31 , wherein said GABA is covalently linked to said fluoxetine via an amide bond. 
     
     
         33 . The method of  claim 25 , wherein said GABA agonist is selected from the group consisting of (±) baclofen, γ-aminobutyric acid (GABA), γ-hydroxybutyric acid, aminooxyacetic acid, β-(4-chlorophenyl)-γ-aminobutyric acid, isonipecotic acid, piperidine-4-sulfonic acid, 3-aminopropylphosphonous acid, 3-aminopropylphosphinic acid, 3-(aminopropyl)methylphosphinic acid, 1-(aminomethyl)cyclohexaneacetic acid (gabapentin), y-vinyl-γ-aminobutyric acid (4-aminohex-5-enoic acid, y-vinyl GABA, vigabatrin) and 3-(2-imidazolyl)-4-aminobutanoic acid. 
     
     
         34 . The method of  claim 25 , wherein said addictive disorder is alcoholism or smoking. 
     
     
         35 . An article-of-manufacture comprising a pharmaceutical composition being packaged in a packaging material and identified in print, in or on said packaging material for use in the treatment of an addictive disorder, said pharmaceutical composition including a pharmaceutically acceptable carrier and, as an active ingredient, a chemical conjugate which comprises a first chemical moiety covalently linked to a second chemical moiety, wherein said first chemical moiety is an antidepressant and wherein said second chemical moiety is a GABA agonist. 
     
     
         36 . The article-of-manufacture of  claim 35 , wherein said second chemical moiety is covalently linked to said first chemical moiety via a bond selected from the group consisting of a carboxylic ester bond, an alkyloxy carboxylic ester bond, an amide bond, an imine bond and a thioester bond. 
     
     
         37 . The article-of-manufacture of  claim 35 , wherein said antidepressant is selected from the group consisting of a tricyclic antidepressant, a selective serotonin reuptake inhibitor, a serotonin and noradrenaline reuptake inhibitor, a reversible monamine oxidase inhibitor and a monoamine oxidase inhibitor. 
     
     
         38 . The article-of-manufacture of  claim 35 , wherein said antidepressant is fluoxetine. 
     
     
         39 . The article-of-manufacture of  claim 35 , wherein said second chemical moiety is GABA. 
     
     
         40 . The article-of-manufacture of  claim 38 , wherein said second chemical moiety is GABA. 
     
     
         41 . The article-of-manufacture of  claim 35 , wherein said chemical conjugate is flouxetine-GABA. 
     
     
         42 . The article-of-manufacture of  claim 41 , wherein said GABA is covalently linked to said fluoxetine via an amide bond. 
     
     
         43 . The article-of-manufacture of  claim 35 , wherein said GABA agonist is selected from the group consisting of (±) baclofen, γ-aminobutyric acid (GABA), γ-hydroxybutyric acid, aminooxyacetic acid, β-(4-chlorophenyl)-γ-aminobutyric acid, isonipecotic acid, piperidine-4-sulfonic acid, 3-aminopropylphosphonous acid, 3-aminopropylphosphinic acid, 3-(aminopropyl)methylphosphinic acid, 1-(aminomethyl)cyclohexaneacetic acid (gabapentin), y-vinyl-γ-aminobutyric acid (4-aminohex-5-enoic acid, y-vinyl GABA, vigabatrin) and 3-(2-imidazolyl)-4-aminobutanoic acid. 
     
     
         44 . The article-of-manufacturing of  claim 35 , wherein said addictive disorder is alcoholism or smoking.