TH58467A - Bicyclone (2.2.1) Heptanes and related compounds - Google Patents

Abstract

DC60 (03/06/42) The present invention pertains to a compound of formula I, as described in the specific formulation, a pharmaceutical compound containing such compound, for the use of the compound in the treatment of nervous and psychotic disorders. The present invention pertains to a compound of formula I, as described in the specific formulation, a pharmaceutical compound containing such compound, for the use of the compound in the treatment of nervous and psychotic disorders.

Claims (27)

1. Compounds of the formula (chemical formula) where n is 0-6; X is CH2,CH2,CH2 or oxygen; Z is CHR2 NR2; and R1 and R2 are independently selected from hydrogen, (C1-C6) alkyls, aryls and heteroaryls, where such aryls are selected from phenyls and naphthyls, and such heteroaryls are selected from the 5- and 6-membered thetrocyclic aromatic ring, where 1 to 4 heteroatoms are selected, independently, from nitrogen, oxygen and sulfur, and where such aryls and heteroaryls can be selectively replaced by 1 or more substitutes, requiring 1 or 2 substitutes, which are independently selected, from halogens. (e.g., fluoro, chloro, bromo, or iodo), -S(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, (C1-C6)alkyl selectively substituted with 1 to 7 fluorine atoms, (C1-C6)alkoxy selectively substituted with 1 to 7 fluorine atoms, amino, nitro, cyano, carboxy, -CO2(C-1-C6)alkyl, (C1-C6)alkylamino, di-[(C1-C6)alkyl]amino, pepoxy, amino and phenylthio; provided there is no identical heteroaryl to the preceding compounds, there may be more than one oxygen atom or more than one sulfur atom, or pharmaceutically acceptable salts of such compounds. 2. The compound from claim 1 where Z is CH2. 3. Compounds from claim 1 where R1 is selected from a group containing hydrogen, an unsubstituted phenyl, and a phenyl substituted by one or two agents. 4. Compounds from claim 1 where n is zero, 1, or 2. 5. The compound from claim 1 where X is CH2. 6. Compounds from claim 1 selected from groups containing 2-(endo)-amino-bicyclo[2.2.1]heptane-2(hexo)-6(hexo)-dicarboxylic acid; (+)-(endo)-amino-bicyclo[2.2.1]heptane-2(hexo)-6(hexo)-dicarboxylic acid; (-)-(endo)-amino-bicyclo[2.2.1]heptane-2(hexo)-6(hexo)-dicarboxylic acid; 2-(endo)-benzylamino-bicyclo[2.2.1]heptane-2(hexo)-6(hexo)-dicarboxylic acid; 2-(endo)-phenylethylamino-bicyclo[2.2.1]heptane-2(hexo)-6(hexo)-dicarboxylate acid; 7. Pharmaceutical ingredients for the treatment of disorders or selected conditions resulting from stroke, cerebral ischemia, spinal cord injury, head injury, Alzheimer's disease, Huntington's chorea, lateral stiffness of muscle atrophy, epilepsy, AIDS-related mental degeneration, muscle spasms, migraine headaches, urinary incontinence, psychosis, severe muscle contractions, hypoxia (e.g., conditions resulting from strangulation, surgery, smoke inhalation, hypoxia, drowning, shock, electrocution, or excessive drug or alcohol exposure), cardiac arrest, nervous system damage due to hypoglycemia, addiction to chemicals and drugs (e.g., alcohol, opium, benzodiazepines, nicotine, heroin, or cocaine), eye damage, non-inflammatory retinal disease, and neurodegeneration. Retinal disorders, anxiety, Parkinson's disease of unknown etiology and drug-induced, anxiety disorders (e.g., Post-Traumatic Stress Syndrome, phobia disorders, generalized anxiety disorder, generalized phobias, and social phobias), adolescent mental degeneration, depression, bipolar disorder, obsessive-compulsive disorder, tardive dyskinesia, vomiting, cerebral edema, chronic and acute pain, lethargy, and cerebral deficits due to revascularization and heart transplantation in mammals, containing the potent compounds from patent 1 that are effective in treating the aforementioned disorders or conditions and a pharmacologically accepted vector. 8. Pharmaceutical compounds for the treatment of disorders or conditions, treatments or prevention which can affect or promote by modulating neurotransmission by glutamate in mammals, containing quantities of compounds from the first patent that are effective in treating such disorders or conditions and pharmaceutically accepted carriers. 9. Use of the compounds from Patent 1 in the manufacture of medicines for the treatment of disorders or conditions, selected from: stroke, cerebral ischemia, spinal cord injury, head injury, Alzheimer's disease, Huntington's chorea, lateral sclerosis, epilepsy, AIDS-related mental deterioration, muscle spasms, migraine headaches, urinary incontinence, mental disorders, severe muscle spasms, hypoxia (e.g., conditions resulting from strangulation, surgery, smoke inhalation, hypoxia, drowning, shock, electrocution, or excessive drug or alcohol exposure), cardiac arrest, nervous system damage due to hypoglycemia, addiction to chemicals and drugs (e.g., alcohol, opium, benzodiazepines, nicotine, heroin, or cocaine), eye damage, and other diseases. Non-inflammatory retinalopathy, retinal neurodegeneration, anxiety, Parkinson's disease of unknown etiology and drug-induced, anxiety disorders (e.g., Post-Traumatic Stress Syndrome), fear disorders, depression, bipolar disorder, obsessive-compulsive disorder, tardive dyskinesia, vomiting, cerebral edema, chronic and acute pain, lethargy and cerebral deficits due to transfusion surgery and heart transplantation in mammals. 10. The use of the compounds from Patent 1 in the manufacture of drugs for the treatment of disorders or conditions, which can affect or promote by modulating glutamate-mediated neurotransmission in mammals. 11. Pharmaceutical ingredients for the treatment of disorders or selected conditions resulting from stroke, serological ischemia, spinal cord injury, head injury, Alzheimer's disease, Huntington's chorea, lateral stiffness of muscle atrophy, epilepsy, AIDS-related mental deterioration, muscle spasms, migraine headaches, urinary incontinence, psychosis, severe muscle contractions, hypoxia (e.g., conditions resulting from strangulation, surgery, smoke inhalation, hypoxia in the blood, drowning, shock, electrocution, or excessive drug or alcohol use), cardiac arrest, nervous system damage due to hypoglycemia, and addiction to chemicals and drugs. Examples include: addiction or enslavement to alcohol, opium, benzodiazepines, nicotine, heroin, or cocaine; eye damage; non-inflammatory retinal disease; retinal degeneration; anxiety; idiopathic and drug-induced Tarkinson's disease; anxiety disorders (e.g., Post-Traumatic Stress Syndrome, phobias, generalized anxiety disorder, generalized audacity, and social phobia); adolescent mental degeneration; depression; bipolar disorder; obsessive-compulsive disorder; tardive dyskinesia; vomiting; cerebral edema; chronic and acute pain; lethargy and cerebral deficits due to hemorrhagic rerouting and heart transplantation in mammals; and the presence of metabolite-mediated glutamate-mediated neurotransmission modulation of the compound from patent 1 and a pharmaceutically recognized carrier. 12. Pharmaceutical ingredient for the treatment of a disorder or condition, cure or prevention, which may have an effect or promote it by modulating glutamate-mediated neurotransmission in mammals, containing a quantity that modulates metabolic glutamate-mediated neurotransmission of the compound from Patent 1 and a pharmaceutically accepted carrier. 13. The use of the compounds from Patent 1 in the manufacture of medicines for the treatment of disorders or conditions resulting from stroke, cerebral ischemia, spinal cord injury, head injury, Alzheirner's disease, Huntington's chorea, lateral muscle atrophy, epilepsy, AIDS-related mental deterioration, muscle spasms, migraine headaches, urinary incontinence, psychosis, severe muscle contractions, hypoxia (e.g., conditions resulting from strangulation, surgery, smoke inhalation, hypoxia in the blood, drowning, shock, electrocution, or excessive drug or alcohol exposure), cardiac arrest, nervous system damage due to hypoglycemia, addiction to chemicals and drugs such as alcohol, opium, benzodiazepines, nicotine, heroin, or Cocaine-induced eye damage, non-inflammatory retinopathy, retinal degeneration, anxiety, Parkinson's disease (both idiopathic and drug-induced), anxiety disorders (e.g., Post-Traumatic Stress Syndrome, phobias, generalized anxiety disorder, generalized phobias, and social phobias), adolescent mental degeneration, depression, bipolar disorder, obsessive-compulsive disorder, tardive dyskinesia, vomiting, cerebral edema, chronic and acute pain, lethargy and dyskinesia, and cerebral deficits due to hemorrhagic rerouting and heart transplantation in mammals. 14. The use of the compounds from Patent 1 in the manufacture of medicines for the treatment of disorders or conditions, curative or preventative, which can affect or promote by reducing or inhibiting glutamate-mediated neurotransmission in mammals. 15. Pharmaceutical components for the treatment of disorders or therapeutic conditions which can be acted upon or promoted by glutamate neurotransmission in mammals shall consist of: (a) a compound of formulation I, or its pharmaceutically recognized salts; (b) a serotonin reuptake inhibitor or serotonin-1A(5HT1A) receptor ligand, or its pharmaceutically recognized salts; and (c) a pharmaceutically recognized carrier; where the amount of the compound of formulation I and the serotonin reuptake inhibitor or 5HT1A receptor ligand used in such manner constitutes such a combination of the two active components that have an effect in treating the disorder or condition. 16. Pharmaceutical components from claim 15, where (b) are serotonin reuptake inhibitors selected from sertraline, fluoxatine, fluvosamine, faroxatine, cetalopram, fenfluramine, and femoxitin. 17. The use of (a) a compound of Formula I, or its pharmaceutically recognized salts; and (b) a serotonin reversible inhibitor or serotonin-1A(5HT1A) receptor ligand; or its pharmaceutically recognized salts; in the manufacture of medicines for the treatment of disorders or conditions, therapies which can be exerted or promoted by modulating glutamate-mediated neurotransmission in mammals, where the amount of a compound of Formula I and a serotonin reversible inhibitor or 5HT1A receptor ligand are used as a combination of two active ingredients that have an effect in treating such disorders or conditions. 18. Use under claim 17 where (b) is an inhibitor of serotonin reuptake, selected from sertraline, fluoxatine, fluvosamine, faroxatine, citalopram, fenfluramine, and femoxetin. 19. Pharmaceutical components for the treatment of selected conditions: stroke, serological ischemia, spinal cord injury, head injury, Alzheimer's disease, Huntington's chorea, lateral stiffness of muscle atrophy, epilepsy, AIDS-induced mental deterioration, muscle spasms, migraine headaches, urinary incontinence, psychosis, severe muscle contractions, hypoxia (e.g., conditions resulting from strangulation, surgery, smoke inhalation, hypoxia, drowning, shock, electrocution, or excessive drug or alcohol exposure), cardiac arrest, nervous system damage due to hypoglycemia, addiction to chemicals and drugs (e.g., alcohol, opium, benzodiazepines, nicotine, heroin, or cocaine), eye damage, non-inflammatory tinnitus, and... Retinal degeneration, anxiety, Parkinson's disease of unknown etiology and drug-induced, anxiety disorders (e.g., Post Traumatic Stress Syndrome, phobia disorders, generalized anxiety disorder, generalized phobias and social phobias), adolescent mental degeneration, depression, bipolar disorder, obsessive-compulsive disorder, tardive dyskinesia, vomiting, cerebral edema, chronic and acute pain, lethargy and serotonin deficiency, and serotonin deficits due to revascularization and cardiac transplantation in mammals, consisting of: (a) compounds from patent 1 or their pharmaceutically recognized salts; (b) serotonin reversibility inhibitors or serotonin-1A(5HT1A) receptor ligands, or pharmaceutically recognized salts of their inhibitors or ligands; and (c) pharmaceutically recognized carriers. Where the compound from claim 1 and the 5HT1A receptor ligand or serotonin reversal inhibitor present in the aforementioned components appear in quantities that constitute a mixture of two active components that have an effect on treating the condition. 20. Pharmaceutical components from claim 19, where (b) are serotonin inhibitors selected from sertraline, fluoxetine, fluvosamine, faroxatine, citalopram, fenfluramine, and femoxetin. 21. Use of (a) compounds of formula I, or their pharmaceutically recognized salts; and (b) serotonin reversible inhibitors or serotonin receptor-1A(5HT1A) ligands; or their pharmaceutically recognized salts; in the manufacture of medicines for the treatment of selective conditions of stroke, cerebral ischemia, spinal cord injury, head injury, Alzheimer's disease, Huntington's chorea, lateral stiffness of muscle atrophy, epilepsy, AIDS-induced psychosis, muscle spasms, migraine headaches, urinary incontinence, psychosis, severe muscle contractions, hypoxia in the presence of oxygen (e.g., conditions resulting from strangulation, surgery, smoke inhalation, hypoxia in the blood, drowning, shock, electrocution or exposure). Excessive drug or alcohol use), cardiac arrest, nervous system damage due to hypoglycemia, chemical and drug addiction (e.g., alcohol, opium, benzodiazepines, nicotine, heroin, or cocaine), eye damage, non-inflammatory retinal disease, retinal neurodegeneration, anxiety, Parkinson's disease of unknown etiology and drug-induced, anxiety disorders (e.g., Post-Traumatic Stress Syndrome, phobias, generalized anxiety disorder, generalized phobias, and social phobias), adolescent mental degeneration, depression, bipolar disorder, obsessive-compulsive disorder, tardive dyskinesia, vomiting, cerebral edema, chronic and acute pain, lethargy and dysmorphic movement, and cerebral deficits due to transfusion surgery. Bloodstream and cardiac transplantation in mammals, where the amounts of compound I and a serotonin inhibitor or 5HT1A receptor ligand are used as a combination of two active ingredients, have an effect in treating the aforementioned disorders or conditions. 22. Use from claim 21, where (b) is a serotonin reuptake inhibitor selected from sertraline, fluoxatine, fluvosamine, faroxatine, citalopram, fenfluramine, and femoxetin. 23. Pharmaceutical formulations for the treatment of disorders or conditions, therapies which can be exerted or promoted by modulating glutamate-mediated neurotransmission in mammals, consisting of: (a) a compound modulating glutamate-mediated neurotransmission or its pharmaceutically recognized salts; (b) a serotonin reversible inhibitor or serotonin-1A(5HT1A) receptor ligand, or its pharmaceutically recognized salts; and (c) a pharmaceutically recognized carrier in which the amounts of the glutamate-mediated neurotransmission compound and the serotonin reversible inhibitor or 5HT1A receptor ligand contained in such formulation constitute a combination of the two active compounds potent in the treatment of such disorder or condition. 24. Pharmaceutical compounds from claim 23 where (b) are serotonin reuptake inhibitors selected from sertraline, fluoxatine, fluvosamine, faroxatine, setalopram, fenfluramine, and femoxetin. 25. The use of (a) compounds that modulate glutamate signaling or their pharmaceutically recognized salts; and (b) serotonin reversible inhibitors or serotonin-1A (5HT1A) receptor ligands; or their pharmaceutically recognized salts; in the manufacture of medicines for the treatment of disorders or conditions, therapies which can be exerted or promoted by modulating glutamate signaling in mammals, where the dosage of the glutamate-modifying compound and the serotonin reversible inhibitor or 5HT1A receptor ligand are used as a combination of two active components is effective in treating such disorders or conditions. 26. Use from claim 25, where (b) is a serotonin reuptake inhibitor selected from sertraline, fluoxatine, fluvosamine, faroxatine, citalopram, fenfluramine, and femoxetin. 27. Compounds of the formula (chemical formula) where n is 0-6; X is CH2,CH2,CH2 or oxygen; Z is CHR2NR2; R1 and R2 are independently selected from hydrogen, (C1-C6) alkyls, aryls and heteroaryls, where such aryls are selected from phenyls and naphthyls and such heteroaryls are selected from 5- and 6-member aromatic heterocyclic rings in which 1 to 4 heteroatoms are selected, independently, from nitrogen, oxygen and sulfur, and where such aryls and heteroaryls can be selectively replaced by 1 or more substitutes, requiring 1 or 2 substitutes, which are selected by Free, from halo (e.g., fluoro, chloro, bromo, or iodine), -S(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, (C1-C6)alkyl selectively substituted with 1 to 7 fluorine atoms, (C1-C6)alkoxy selectively substituted with 1 to 7 fluorine atoms, amino, nitro, cyano, carboxy, -CO2(C1-C6)alkyl, (C1-C6)alkylamino, di-[(C1-C6)alkyl]amino, pepoxy, amino and phenylthio, and R7 is hydrogen, (C1-C6)alkyl or benzyl. Under the condition that there is no substance identical to the aforementioned heteroaryl, there is more than one oxygen atom ring or more than one sulfur atom ring (Clause 27, page 11, Figure).