CA2333951A1 - Method for treating neurodegenerative disorders - Google Patents

Method for treating neurodegenerative disorders Download PDF

Info

Publication number
CA2333951A1
CA2333951A1 CA002333951A CA2333951A CA2333951A1 CA 2333951 A1 CA2333951 A1 CA 2333951A1 CA 002333951 A CA002333951 A CA 002333951A CA 2333951 A CA2333951 A CA 2333951A CA 2333951 A1 CA2333951 A1 CA 2333951A1
Authority
CA
Canada
Prior art keywords
alkyl
disease
hydrogen
aralkyl
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CA002333951A
Other languages
French (fr)
Other versions
CA2333951C (en
Inventor
Allen B. Reitz
David A. Demeter
Daniel H. S. Lee
Hoau-Yan Wang
Robert H. Chen
Tina Morgan Ross
Malcolm K. Scott
Carlos R. Plata-Salaman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceuticals Inc
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CA2333951A1 publication Critical patent/CA2333951A1/en
Application granted granted Critical
Publication of CA2333951C publication Critical patent/CA2333951C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/14—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of carbon skeletons containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
    • C07F9/32—Esters thereof
    • C07F9/3258—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/3282—Esters with hydroxyaryl compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Abstract

The invention is directed to a method of treating a neurodegenerative disord er in a subject in need thereof which comprises administering to the subject an amount of a compound effective to inhibit the interaction of amyloid-beta wi th alpha-7 nicotinic acetylcholine receptors.

Claims (27)

1.A method of treating a neurodegenerative disorder in a subject in need thereof which comprises administering to the subject an amount of a compound effective to inhibit the binding of an amyloid beta peptide with alpha-7 nicotinic acetylcholine receptors.
2. The method of Claim 1, wherein the alpha-7 nicotinic acetylcholine receptors are human alpha-7 nicotinic acetylcholine receptors.
3. The method of Claim 2, wherein the neurodegenerative disorder is selected from Alzheimer's disease, Pick's disease, diffuse Lewy body disease, progressive supranuclear palsy (Steel-Richardson syndrome), multisystem degeneration (Shy-Drager syndrome), motor neuron diseases including amyotrophic lateral sclerosis, degenerative ataxias, cortical basal degeneration, ALS-Parkinson's-Dementia complex of Guam, subacute sclerosing panencephalitis, Huntington's disease, Parkinson's disease, synucleinopathies, primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease/spinocerebellar ataxia type 3 and olivopontocerebellar degenerations, Gilles De La Tourette's disease, bulbar and pseudobulbar palsy, spinal and spinobulbar muscular atrophy (Kennedy's disease), primary lateral sclerosis, familial spastic paraplegia, Werdnig-Hoffmann disease, Kugelberg-Welander disease, Tay-Sach's disease, Sandhoff disease, familial spastic disease, Wohtfart-Kugelberg-Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathy, and prion diseases (including Creutzfeldt-Jakob, Gerstmann-Straussler-Scheinker disease, Kuru and fatal familial insomnia, age-related dementia, vascular dementia, diffuse white matter disease (Binswanger's disease), dementia of endocrine or metabolic origin, dementia of head trauma and diffuse brain damage, dementia pugilistica or frontal lobe dementia, neurodegenerative disorders resulting from cerebral ischemia or infaction including embolic occlusion and thrombotic occlusion as well as intracranial hemorrhage of any type, intracranial and intravertebral lesions, hereditary cerebral angiopathy, nonneuropathic hereditary amyloid, Down's syndrome, macroglobulinemia, secondary familial Mediterranean fever, Muckle-Wells syndrome, multiple myeloma, pancreatic and cardiac-related amyloidosis, chronic hemodialysis arthropathy, or Finnish and Iowa amyloidosis.
4. The method of Claim 3, wherein the amyloid beta peptide is A.beta.1-42..
5. The method of Claim 3, wherein the neurodegenerative disorder is Alzheimer's disease.
6. The method of Claim 5, wherein the compound inhibits the binding of A.beta.1-42 with the human alpha-7 nicotinic acetylcholine receptor by binding to A.beta.1-42.
7. The method of Claim 3, wherein the compound inhibits the binding of A.beta.1-42 with the human alpha-7 nicotinic acetylcholine receptor by binding to human alpha-7 nicotinic acetylcholine receptors.
8. The method of Claim 3, wherein the compound inhibits the binding of A.beta.1-42 with the human alpha-7 nicotinic acetylcholine receptor by inhibiting aggregation of amyloid beta peptides.
9. The method of Claim 5, wherein the compound is of the formula I
wherein R1 is hydrogen or C1-C4 alkyl;
R2 is selected from hydrogen, C1-C6 alkyl, aryl or C7-C10 aralkyl;
R3 is selected from hydrogen, C1-C8 alkyl, C3-C10 alkenyl, C3-C8 cycloalkylC1-6alkyl, C1-C6 alkoxycarbonylC1-C8 alkyl, C1-C6 alkylthio, heteroarylC1-C4 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted C7-C10 aralkyl wherein the substituent on the aryl or aralkyl are one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl and unsubstituted or substituted C1-C6 alkoxy wherein the substituents on the alkoxy are one or more substituents independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, pyrrolidinyl, piperidinyl, azepinyl or morpholinyl; or R2 and R3, together with the nitrogen to which they are attached, form a five or six-membered heterocyclic ring selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl;
R4 is C1-C6 alkyl, aryl, or C7-C10 aralkyl; and R5 and R6 are each independently selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C1-C8 alkylcarbonyl, or diphenylphosphinyl;
and pharmaceutically acceptable salts and prodrugs thereof.
10. A method of treating and/or preventing dementia in an Alzheimer's disease patient which comprises administering to the subject a therapeutically effective amount of a compound which inhibits the binding of an amyloid beta peptide with alpha-7 nicotinic acetylcholine receptors.
11. The method of Claim 10, wherein the amyloid beta peptide is A.beta.l-42 and the alpha-7 nicotinic acetylcholine receptors are human alpha-7 nicotinic acetylcholine receptors.
12. The method of Claim 11, wherein the compound is of the formula I
wherein R1 is hydrogen or C1-C4 alkyl;

R2 is selected from hydrogen, C1-C6 alkyl, aryl or C7-C10 aralkyl;
R3 is selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C3-C8 cycloalkylC1-C6 alkyl, C1-C6 alkoxycarbonylC1-C6 alkyl, C1-C6 alkylthio, heteroarylC1-C4 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted C7-C10 aralkyl wherein the substituent on the aryl or aralkyl are one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl and unsubstituted or substituted C1-C6 alkoxy wherein the substituents on the alkoxy are one or more substituents independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, pyrrolidinyl, piperidinyl, azepinyl or morpholinyl; or R2 and R3, together with the nitrogen to which they are attached, form a five or six-membered heterocyclic ring selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl;
R4 is C1-C6 alkyl, aryl, or C7-C10 aralkyl; and R5 and R6 are each independently selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C1-C8 alkylcarbonyl, or diphenylphosphinyl;
and pharmaceutically acceptable salts and prodrugs thereof.
13. A method of improving memory and/or of halting the progression of mental deterioration in an Alzheimer's disease patient which comprises administering to the subject a therapeutically effective amount of a compound to inhibit the binding of an amyloid beta peptide with alpha-7 nicotinic acetylcholine receptors.
14. The method of Claim 13, wherein the amyloid beta peptide is A.beta.1-42 and the alpha-7 nicotinic acetylcholine receptors are human alpha-7 nicotinic acetylcholine receptors.
15. The method of Claim 14, wherein the compound is of the formula I

wherein R1 is hydrogen or C1-C4 alkyl;
R2 is selected from hydrogen, C1-C6 alkyl, aryl or C7-C10 aralkyl;
R3 is selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C3-C8 cycloalkylC1-C6 alkyl, C1-C6 alkoxycarbonylC1-C6 alkyl, C1-C6 alkylthio, heteroarylC1-C4 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted C7-C10 aralkyl wherein the substituent on the aryl or aralkyl are one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl and unsubstituted or substituted C1-C6 alkoxy wherein the substituents on the alkoxy are one or more substituents independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, pyrrolidinyl, piperidinyl, azepinyl or morpholinyl; or R2 and R3, together with the nitrogen to which they are attached, form a five or six-membered heterocyclic ring selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl;
R4 is C1-C6 alkyl, aryl, or C7-C10 aralkyl; and R5 and R6s are each independently selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C1-C8 alkylcarbonyl, or diphenylphosphinyl;
and pharmaceutically acceptable salts and prodrugs thereof.
16. A method for identifying compounds which are useful for the treatment of neurodegenerative disorders involving screening test compounds for their ability to block the interaction of a peptide selected from the group consisting of 125¦-A.beta.1-40 A.beta.1-40 and A.beta.1-42 with nicotine acetylcholine receptors.
17. The method of Claim 16, wherein the nicotine acetycholine receptors are human alpha-7, human alpha-8, and/or human alpha-9 nicotinic acetylcholine receptors.
18. The method of Claim 17, wherein the nicotine acetylcholine receptors are human alpha-7 nicotine acetylcholine receptors.
19. The method of Claim 18, wherein the peptide is 124¦-A.beta.1-40.
20. A compound of the formula I:
wherein R1 is hydrogen or C1-C4 alkyl;
R2 is selected from hydrogen, C1-C6 alkyl, aryl or C1-C10 aralkyl;
R3 is selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C3-C8 cycloalkylC1-C6 alkyl, C1-C6 alkoxycarbonylC1-C6 alkyl, C1-C6 alkylthio, heteroarylC1-C4 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted C71-C10 aralkyl wherein the substituent on the aryl or aralkyl are one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl and unsubstituted or substituted C1-C6 alkoxy wherein the substituents on the alkoxy are one or more substituents independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, pyrrolidinyl, piperidinyl, azepinyl or morpholinyl; or R2 and R3, together with the nitrogen to which they are attached, form a five or six-membered heterocyclic ring selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl;
R4 is C1-C6 alkyl, aryl, or C7-C10 aralkyl; and R5 and R6s are each independently selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C1-C8 alkylcarbonyl, or diphenylphosphinyl;
and pharmaceutically acceptable salts and prodrugs thereof.
21. The compound of Claim 20, wherein R1, is hydrogen;
R2 is selected from hydrogen or C1-C4 alkyl;
R3 is selected from C1-C4 alkyl, C3-C10 alkenyl, C5-C6 cycloalkylC1-C4 6 alkyl, C1-C6 alkoxycarbonylC1-C4 alkyl, C1-C6 alkylthio, heteroarylC1-C4 alkyl, or unsubstituted or substituted C7-C10 aralkyl wherein the substituent on the aralkyl are one or two substituents independently selected from the group consisting of halogen, hydroxy, C1-C4 alkyl and unsubstituted or substituted C1-C4 alkoxy wherein the substituents on the alkoxy are one or two substituents independently selected from amino, C1-C4 alkylamino, C1-C4 dialkylamino, pyrrolidinyl, or piperidinyl; or R2 and R3, together with the nitrogen to which they are attached, form a morpholinyl ring;
R4 is C1-C4 alkyl; and R5 and R6 are each independently selected from hydrogen, C1-C4 alkyl, C3-C6 alkenyl, C1-C6 alkylcarbonyl, or diphenylphosphinyl;
and pharmaceutically acceptable salts and prodrugs thereof.
22. The compound of Claim 20 of the formula wherein R1 is hydrogen or C1-C4 alkyl;

R2 and R3 are each independently selected from hydrogen, C1-C6 alkyl, aryl or C7-C10 aralkyl; and R4 is C1-C6 alkyl, aryl, or C7-C10 aralkyl;
and pharmaceutically acceptable salts and prodrugs thereof.
23. A compound of Claim 22 which is 5,8-dihydroxy-traps-2-di(N
propylamino)-3-methyl-1,2,3,4-tetrahydronaphthalene and pharmaceutically acceptable salts and prodrugs thereof.
24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Claim 20.
25. A pharmaceutical composition made by mixing a compound of Claim 20 and a pharmaceutically acceptable carrier.
26. A process for making a pharmaceutical composition comprising mixing a compound of Claim 20 and a pharmaceutically acceptable carrier.
27. A method for diagnosing Alzheimer's disease, monitoring the progression and prognosis of Alzheimers disease and/or monitoring the therapeutic efficacy of any intervention or treatment of Alzheimer's disease comprising:
(a) obtaining a test sample from a subject wherein the test sample comprises circulating blood cells and/or olfactory neuroepithelial neuronal cell bodies or their neuronal processes; and (b) analyzing the test sample for interaction of an amyloid beta peptide with alpha-7 nicotinic acetylcholine receptors.
CA2333951A 1998-06-01 1999-05-27 Method for treating neurodegenerative disorders Expired - Lifetime CA2333951C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US8757798P 1998-06-01 1998-06-01
US60/087,577 1998-06-01
PCT/US1999/011702 WO1999062505A2 (en) 1998-06-01 1999-05-27 Method for treating neurodegenerative disorders

Publications (2)

Publication Number Publication Date
CA2333951A1 true CA2333951A1 (en) 1999-12-09
CA2333951C CA2333951C (en) 2012-02-28

Family

ID=22206004

Family Applications (1)

Application Number Title Priority Date Filing Date
CA2333951A Expired - Lifetime CA2333951C (en) 1998-06-01 1999-05-27 Method for treating neurodegenerative disorders

Country Status (12)

Country Link
US (2) US6441049B2 (en)
EP (1) EP1083889B1 (en)
JP (1) JP4637351B2 (en)
AR (1) AR018431A1 (en)
AT (1) ATE255888T1 (en)
AU (1) AU765142B2 (en)
CA (1) CA2333951C (en)
DE (1) DE69913520T2 (en)
DK (1) DK1083889T3 (en)
ES (1) ES2212570T3 (en)
PT (1) PT1083889E (en)
WO (1) WO1999062505A2 (en)

Families Citing this family (71)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7214686B2 (en) 1997-06-30 2007-05-08 Targacept, Inc. Pharmaceutical compositions and methods for effecting dopamine release
GB9923078D0 (en) * 1999-09-29 1999-12-01 Phytopharm Plc Sapogenin derivatives and their use
US8188043B2 (en) 1999-07-28 2012-05-29 The Board Of Trustees Of The Leland Stanford Jr. University Nicotine in therapeutic angiogenesis and vasculogenesis
ES2250170T3 (en) * 1999-07-28 2006-04-16 Ortho-Mcneil Pharmaceutical, Inc. DERIVATIVES OF AMINAS AND AMIDAS USED AS BINDING FOR THE Y5 RECEPTOR OF THE NEUROPEPTIDE AND, USEFUL IN THE TREATMENT OF OBESITY AND OTHER DISORDERS.
IL150374A0 (en) * 1999-12-23 2002-12-01 Neurochem Inc Compounds and methods for modulating cerebral amyloid angiopathy
JP2001261652A (en) 2000-03-21 2001-09-26 Suntory Ltd Disubstituted iminoheterocyclic compound
GB2364385B (en) * 2000-03-29 2002-08-14 Synaptica Ltd Alpha 7 nicotinic receptor screening assays
WO2001089453A2 (en) * 2000-05-19 2001-11-29 Wayne State University Derivatives of 2-aminotetralins and pharmaceutical analogs thereof exhibiting differential cns receptor activity and behavior
US20030092613A1 (en) * 2000-08-14 2003-05-15 Lee Daniel H. S. Alpha7 nicotinic receptor peptides as ligands for beta amyloid peptides
CA2462453C (en) 2001-10-02 2009-07-28 Pharmacia & Upjohn Company Azabicyclic-substituted fused-heteroaryl compounds for the treatment of disease
EP1442037A1 (en) 2001-11-09 2004-08-04 PHARMACIA & UPJOHN COMPANY Azabicyclic-phenyl-fused-heterocyclic compounds and their use as alpha7 nachr ligands
JP2005538683A (en) 2001-12-14 2005-12-22 ターガセプト，インコーポレイテッド Methods and compositions for treatment of central nervous system disorders
DE10164139A1 (en) 2001-12-27 2003-07-10 Bayer Ag 2-heteroaryl carboxamides
US7045534B2 (en) * 2002-02-12 2006-05-16 The Board Of Trustees Of The Leland Stanford Junior University Methods of reducing angiogenesis
BR0307782A (en) * 2002-02-19 2005-01-04 Upjohn Co Azabicycle compounds for the treatment of disease
WO2003070732A1 (en) * 2002-02-19 2003-08-28 Pharmacia & Upjohn Company Fused bicyclic-n-bridged-heteroaromatic carboxamides for the treatment of disease
WO2004019943A1 (en) 2002-08-30 2004-03-11 Memory Pharmaceuticals Corporation Anabaseine derivatives useful in the treatment of neurodegenerative diseases
ES2405594T3 (en) 2002-09-25 2013-05-31 Memory Pharmaceuticals Corporation Idazoles, benzothiazoles and benzisothiazoles, and preparation and uses thereof
EP1562959A2 (en) * 2002-11-01 2005-08-17 Pharmacia & Upjohn Company LLC Compounds having both alpha7 nachr agonist and 5ht antagonist activity for treatment of cns diseases
US7238715B2 (en) * 2002-12-06 2007-07-03 The Feinstein Institute For Medical Research Treatment of pancreatitis using alpha 7 receptor-binding cholinergic agonists
CN102657651A (en) * 2002-12-06 2012-09-12 范因斯坦医学研究院 Inhibition of inflammation using alpha 7 receptor-binding cholinergic agonists
DE10303974A1 (en) 2003-01-31 2004-08-05 Abbott Gmbh & Co. Kg Amyloid β (1-42) oligomers, process for their preparation and their use
WO2004074973A2 (en) * 2003-02-19 2004-09-02 Balin Advertising Ltd. A system for providing private offers to customers of web sites
MXPA05012350A (en) * 2003-05-20 2006-05-25 Transtech Pharma Inc Rage antagonists as agents to reverse amyloidosis and diseases associated therewith.
WO2005013910A2 (en) * 2003-08-07 2005-02-17 University Of South Florida Cholinergic modulation of microglial activation via alpha-7 nicotinic receptors
ATE451368T1 (en) 2003-10-15 2009-12-15 Targacept Inc AZABICYCLIC COMPOUNDS FOR RELIEVING PAIN AND TREATING CENTRAL NERVOUS SYSTEM DISEASES
EP1541547A1 (en) * 2003-12-11 2005-06-15 Newron Pharmaceuticals S.p.A. Hydroxylamine derivatives
US20050170360A1 (en) * 2004-01-30 2005-08-04 Papke Roger L. Variant neuronal nicotinic alpha-7 receptor and methods of use
DE102004014841B4 (en) * 2004-03-24 2006-07-06 Schwarz Pharma Ag Use of rotigotine for the treatment and prevention of Parkinson-Plus syndrome
CN103724343A (en) 2004-03-25 2014-04-16 记忆药物公司 Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, and preparation and uses thereof
US7678823B2 (en) 2004-10-04 2010-03-16 Myriad Pharmaceticals, Inc. Compounds for alzheimer's disease
US9216966B2 (en) 2004-10-04 2015-12-22 John Manfredi Compounds for Alzheimer's disease
WO2007024814A1 (en) 2005-08-22 2007-03-01 Targacept, Inc. HETEROARYL-SUBSTiTUTED DIAZATRICYCLOALKANES, METHODS FOR ITS PREPARATION AND USE THEREOF
EP1928827B1 (en) * 2005-09-27 2012-08-22 Myriad Genetics, Inc. Pyrrole derivatives as therapeutic compounds
US8316104B2 (en) 2005-11-15 2012-11-20 California Institute Of Technology Method and apparatus for collaborative system
EP1954718B1 (en) 2005-11-30 2014-09-03 AbbVie Inc. Anti-a globulomer antibodies, antigen-binding moieties thereof, corresponding hybridomas, nucleic acids, vectors, host cells, methods of producing said antibodies, compositions comprising said antibodies, uses of said antibodies and methods of using said antibodies
PT1976877E (en) 2005-11-30 2014-04-29 Abbvie Inc Monoclonal antibodies against amyloid beta protein and uses thereof
KR20080081175A (en) * 2005-12-19 2008-09-08 코멘티스, 인코포레이티드 Topical mecamylamine formulations for ocular administration and uses thereof
US8846937B2 (en) 2006-06-16 2014-09-30 University Of Kentucky Research Foundation Mono quaternary ammonium salts and methods for modulating neuronal nicotinic acetylcholine receptors
FR2905009A1 (en) * 2006-08-18 2008-02-22 Servier Lab METHOD OF SCREENING COMPOUNDS WITH ANTI-AMYLOID PROPERTIES
CA2662870A1 (en) * 2006-09-07 2008-03-13 Myriad Genetics, Inc. Therapeutic compounds for diseases and disorders
US8314119B2 (en) 2006-11-06 2012-11-20 Abbvie Inc. Azaadamantane derivatives and methods of use
US8455626B2 (en) 2006-11-30 2013-06-04 Abbott Laboratories Aβ conformer selective anti-aβ globulomer monoclonal antibodies
TW200901974A (en) 2007-01-16 2009-01-16 Wyeth Corp Compounds, compositions, and methods of making and using them
US20100311767A1 (en) 2007-02-27 2010-12-09 Abbott Gmbh & Co. Kg Method for the treatment of amyloidoses
SA08290475B1 (en) 2007-08-02 2013-06-22 Targacept Inc (2S,3R)-N-(2-((3-Pyridinyl)Methyl)-1-Azabicyclo[2.2.2]Oct-3-yl)Benzofuran-2-Carboxamide, Novel Salt forms, and Methods of Use Thereof
WO2009046025A1 (en) 2007-10-01 2009-04-09 Comentis, Inc. Quinuclidin-4-ylmethyl 1h-indole-3-carboxylate derivatives as alpha 7 nicotinic acetylcholine receptor ligands for the treatment of alzheimer's disease
SG188144A1 (en) 2008-02-13 2013-03-28 Targacept Inc Alpha 7 nicotinic agonists and antipsychotics
TW201031664A (en) 2009-01-26 2010-09-01 Targacept Inc Preparation and therapeutic applications of (2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide
TWI517850B (en) 2009-09-30 2016-01-21 Ｖｔｖ治療有限責任公司 Substituted imidazole derivatives and methods of use thereof
JP2013523182A (en) 2010-04-15 2013-06-17 アボット・ラボラトリーズ Amyloid beta-binding protein
DE102010020553A1 (en) 2010-05-14 2011-11-17 Bayer Schering Pharma Aktiengesellschaft Substituted 8-alkoxy-2-aminotetralin derivatives and their use
CN103221411B (en) 2010-05-17 2016-05-11 富瑞姆制药公司 (R) crystal formation of the chloro-N-of-7-(quinuclidine-3-yl) benzo [b] thiophene-2-carboxamide derivatives hydrochloride monohydrate
EP2603524A1 (en) 2010-08-14 2013-06-19 AbbVie Inc. Amyloid-beta binding proteins
CN106074548A (en) 2010-09-23 2016-11-09 艾伯维巴哈马有限公司 The monohydrate of azaadamantane derivatives
FR2966827B1 (en) 2010-10-27 2014-08-22 Kimonella Ventures Ltd PEPTIDE COMPOUND USEFUL FOR INHIBITING AMYLOID PLATE FORMATION
EP2808679A4 (en) * 2012-01-27 2015-01-14 Panasonic Healthcare Co Ltd Diagnosis method and diagnosis system for alzheimer's disease
CA2872005A1 (en) 2012-05-08 2013-11-14 Forum Pharmaceuticals, Inc. Methods of maintaining, treating or improving cognitive function
US10017736B2 (en) * 2012-07-13 2018-07-10 Pain Therapeutics, Inc. Method of inhibiting tau phosphorylation
JP6566867B2 (en) 2012-07-13 2019-08-28 ペイン セラピューティクス インコーポレイテッド Alzheimer's disease assay in living patients
PE20150350A1 (en) 2012-07-20 2015-02-28 Bayer Pharma AG NOVEL 5-AMINOTETRAHYDROQUINOLIN-2-CARBOXYL ACIDS AND THEIR USE
WO2014012935A1 (en) 2012-07-20 2014-01-23 Bayer Pharma Aktiengesellschaft Substituted aminoindane- and aminotetralincarboxylic acids and use thereof
US9717710B2 (en) 2012-10-05 2017-08-01 Vtv Therapeutics Llc Treatment of mild and moderate Alzheimer's disease
GB201303507D0 (en) * 2013-02-27 2013-04-10 Hollfelder Florian Assays
WO2016007630A1 (en) 2014-07-11 2016-01-14 Alpharmagen, Llc Quinuclidine compounds for modulating alpha7 -nicotinic acetylcholine receptor activity
US9724340B2 (en) 2015-07-31 2017-08-08 Attenua, Inc. Antitussive compositions and methods
WO2018067662A1 (en) * 2016-10-04 2018-04-12 University Of Miami Protein amyloidogenesis and related methods
WO2019190823A1 (en) 2018-03-28 2019-10-03 Vtv Therapeutics Llc Pharmaceutically acceptable salts of [3-(4- {2-butyl-1-[4-(4-chlorophenoxy)-phenyl]-1h-imidazol-4-yl} -phenoxy)-propyl]-diethyl-amine
WO2019190822A1 (en) 2018-03-28 2019-10-03 Vtv Therapeutics Llc Crystalline forms of [3-(4- {2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1h-imidazol-4-yl} -phenoxy)-propyl]-diethyl-amine
EP3864008A1 (en) 2018-10-10 2021-08-18 vTv Therapeutics LLC Metabolites of [3-(4-{2-butyl-l-[4-(4-chloro-phenoxy)-phenyl]-lh-imidazol-4-yl } -phen ox y)-prop yl] -diethyl-amine
CU24626B1 (en) 2019-12-26 2022-11-07 Centro Nac De Biopreparados PHARMACEUTICAL COMPOSITION BASED ON PROTEINS WITH NEUROPROTECTIVE, IMMUNOMODULATORY, ANTI-INFLAMMATORY AND ANTIMICROBIAL ACTIVITIES

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH637363A5 (en) * 1977-11-24 1983-07-29 Sandoz Ag Process for preparing novel 2-aminotetralins
DE3831888A1 (en) * 1988-09-20 1990-03-29 Troponwerke Gmbh & Co Kg MEDICINES FOR TREATING APOPLEXIA CEREBRI
US5554601A (en) 1993-11-05 1996-09-10 University Of Florida Methods for neuroprotection
US6689574B1 (en) * 1997-10-07 2004-02-10 Merck & Co., Inc. Assays for nuclear receptor agonists and antagonists using fluorescence resonance energy transfer
US6329159B1 (en) * 1999-03-11 2001-12-11 Millennium Pharmaceuticals, Inc. Anti-GPR-9-6 antibodies and methods of identifying agents which modulate GPR-9-6 function
US6689578B2 (en) * 2001-12-06 2004-02-10 Paradigm Genetics, Inc. Methods for the identification of inhibitors of 5-aminolevulinate synthase as antibiotics

Also Published As

Publication number Publication date
WO1999062505A3 (en) 2000-04-06
EP1083889A2 (en) 2001-03-21
AR018431A1 (en) 2001-11-14
DE69913520T2 (en) 2004-11-25
JP4637351B2 (en) 2011-02-23
CA2333951C (en) 2012-02-28
DK1083889T3 (en) 2004-04-13
AU4543399A (en) 1999-12-20
US20030130165A1 (en) 2003-07-10
US6441049B2 (en) 2002-08-27
JP2002516853A (en) 2002-06-11
ES2212570T3 (en) 2004-07-16
WO1999062505A2 (en) 1999-12-09
US7018797B2 (en) 2006-03-28
PT1083889E (en) 2004-04-30
US20020013374A1 (en) 2002-01-31
DE69913520D1 (en) 2004-01-22
EP1083889B1 (en) 2003-12-10
AU765142B2 (en) 2003-09-11
ATE255888T1 (en) 2003-12-15

Similar Documents

Publication Publication Date Title
CA2333951A1 (en) Method for treating neurodegenerative disorders
JP2002516853A5 (en)
CN109071528B (en) Bicyclic compounds for diagnosis and therapy
US11058781B2 (en) Diazacarbazole derivatives as tau-PET-ligands
AU2007231126B2 (en) Inhibitors of protein aggregation
Bonuccelli Essential tremor is a neurodegenerative disease
BRPI0619748B8 (en) monoclonal antibody, polynucleotide, composition, mixture, use of a monoclonal antibody or a functional part thereof, method for preparing a pharmaceutical composition, isolated hybridoma cell line, method of diagnosing a disease or condition associated with amyloid in a patient, method to diagnose a predisposition to a disease or condition, method to monitor minimal residual disease, method to predict a patient's responsiveness, and test kits
WO2014187762A1 (en) 2-phenylimidazo[1,2-a]pyrimidines as imaging agents
Shill et al. Pathology in essential tremor
EP3049411B1 (en) Imidazo[1,2-a]pyridin-7-amines as imaging tools
IL157591A (en) Carbamate compounds for use in preventing or treating neurodegenerative disorders
Brilliant et al. The distribution of amyloid β protein deposition in the corpus striatum of patients with Alzheimer's disease
CN112533928A (en) Novel compounds for use in diagnostics
Molina et al. Tau protein concentrations in cerebrospinal fluid of non-demented Parkinson's disease patients
WO2023285661A1 (en) Novel compounds for the diagnosis of tdp-43 proteinopathies
Abarbanel et al. Motor neuron disease in textile factory workers
Rauch Neuroimaging in OCD: clinical implications
JPWO2019234243A5 (en)
Eberhardt et al. The preclinical stage of movement disorders
CN117940435A (en) Novel compounds for diagnosing TDP-43 proteinopathies
Zéphir et al. Severe and rapidly evolving peripheral neuropathy revealing sporadic Creutzfeldt-Jakob disease
Nowaczyk et al. Impairment of cognitive functions in patients with the most frequent autoimmune disorders of the central nervous system
Anthony et al. Could aberrant neurotrophic activity cause schizophrenia?
ANCES PET-CT scans are an established clinical tool in neurodegenerative dementias and epilepsy. The most clinically used PET tracer is [18F] FDG.[18F] FDG allows visualisation of brain metabolism in vivo and is a proxy for neuronal activity.
Altamura et al. Plasma and platelets glutamate levels in major psychoses

Legal Events

Date Code Title Description
EEER Examination request
MKEX Expiry

Effective date: 20190527