What is claimed is:
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 diseasespinocerebellar 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, Wohlfart-Kugelberg-Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathy, and prion diseases (including Creutzfeldt-Jakob, Gerstmann-Strussler-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 A1-42.
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 A1-42 with the human alpha-7 nicotinic acetylcholine receptor by binding to A1-42.
7. The method of claim 3, wherein the compound inhibits the binding of A1-42 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 A1-42 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
9
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.
10. A method of treating andor 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 A1-42 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
10
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 andor 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 A1-42 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
11
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.
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 125I-A1-40, A1-40 and A1-42 with nicotine acetylcholine receptors.
17. The method of claim 16, wherein the nicotine acetycholine receptors are human alpha-7, human alpha-8, andor 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 125I-A1-40.
20. A compound of the formula I:
12
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.
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-C46 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
13
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-trans-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 Alzheimer’s disease andor 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 andor 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.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A method for permitting a client to access a database system on a server via an Internet connection, comprising:
providing middleware communicating with the client and server;
the middleware including at least one file;
the file having at least one parameterized database system query language (SQL) statement;
in response to a client request for data including values and specific methods but not an SQL query, accessing the file; and
using the parameterized statement to return data satisfying the request to the client.
2. The method of claim 1, wherein the data satisfying the request is sent via Hypertext Transfer Protocol (HTTP) in Extensible Markup Language (XML).
3. The method of claim 1, wherein the parameterized statement facilitates a query for data.
4. The method of claim 1, wherein the parameterized statement facilitates an update to the database system.
5. The method of claim 1, wherein the parameterized statement facilitates an SQL stored procedure call.
6. The method of claim 1, wherein the client request is one of the following: a SOAP request, an HTTP GET request, or an HTTP POST request.
7. The method of claim 1, wherein the middleware further comprises:
at least one router receiving the client request; and
the router including at least one servlet.
8. The method of claim 7, wherein the servlet replaces at least some parameters in the parameterized statement with corresponding values from the client request to establish a fully qualified SQL statement.
9. The method of claim 8, wherein the servlet sends the SQL statement to the database system for execution thereof.
10. The method of claim 9, wherein the database system generates a response to the SQL statement and the method further comprises:
sending the response to the client.
11. The method of claim 10, further comprising the act of:
converting the response to XML.
12. The method of claim 7, wherein the servlet generates documentation and a test page in HTML at least partially based on the client request.
13. The method of claim 7, wherein the servlet generates a service description (WSDL file) at least partially based on the client request.
14. The method of claim 7, wherein the servlet incorporates a document access definition (DAD) at least partially based on the client request.
15. The method of claim 7, wherein the servlet generates Extensible Markup Language Schema data (XSD) at least partially based on the client request.
16. A computer system, comprising:
at least one client transmitting a client request including values but not a fully qualified SQL statement;
at least one middleware accessible to the client;
at least one file accessible to the middleware and containing at least one parameterized statement; and
at least one database system accessible to the middleware, wherein the middleware replaces at least some parameters in the parameterized statement corresponding values from the client to establish a fully qualified SQL statement for execution thereof by the database system.
17. The system of claim 16, wherein:
the middleware sends the SQL statement to the database system for execution thereof.
18. The system of claim 17, wherein:
the database system generates a response to the SQL statement and the response is returned to the client.
19. The system of claim 16, wherein the client request is one of the following: a SOAP request, an HTTP GET request, or an HTTP POST request.
20. The system of claim 16, wherein:
the middleware generates documentation and a test page in HTML at least partially based on the client request.
21. The system of claim 16, wherein:
the middleware generates a service description (WSDL file) at least partially based on the client request.
22. The system of claim 16, wherein:
the middleware servlet incorporates a document access definition (DAD) at least partially based on the client request.
23. The system of claim 16, wherein:
the middleware generates Extensible Markup Language Schema data (XSD) at least partially based on the client request.
24. A method for permitting a client to access a database system on a server via a wide area network, comprising:
providing a file between the client and database system, the file having at least one parameterized SQL statement;
replacing at least some parameters in the parameterized statement with corresponding values from the client request to establish a fully qualified SQL statement;
sending the SQL statement to the database system for execution thereof;
at the database system, generating a response to the SQL statement;
converting the response to XML if necessary; and
sending the response to the client.
25. A computer program device, comprising:
a computer readable means having logic means for facilitating data communication between a client and a database at a server, comprising:
logic means for receiving at least one client request for data from the client, the client request including desired values but not constituting a fully qualified SQL statement;
logic means for accessing a file having at least one parameterized SQL statement at least partially based on the client request;
means for replacing at least one parameter in the parameterized SQL statement with at least one value from the client to establish a fully qualified SQL statement; and
logic means for returning a response to the client at least partially based on the parameterized SQL statement.
26. The computer program device of claim 25, wherein the client request is one of the following: a SOAP request, an HTTP GET request, or an HTTP POST request.
27. The computer program device of claim 26, wherein the computer readable means further comprises:
logic means for generating documentation or a test page in HTML at least partially based on the client request.
28. The computer program device of claim 26, wherein the computer readable means further comprises:
logic means for generating a service description (WSDL file) at least partially based on the parameterized SQL statement.
29. The computer program device of claim 26, wherein the computer readable means further comprises:
logic means for incorporating a DAD file at least partially based on the client request.