GB2309167A - The use of azaspiranes in the treatment of Alzheimer's disease - Google Patents
The use of azaspiranes in the treatment of Alzheimer's disease Download PDFInfo
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- GB2309167A GB2309167A GB9709416A GB9709416A GB2309167A GB 2309167 A GB2309167 A GB 2309167A GB 9709416 A GB9709416 A GB 9709416A GB 9709416 A GB9709416 A GB 9709416A GB 2309167 A GB2309167 A GB 2309167A
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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Description
METHODS FOR TREATMENT OF ALZHEIMER'S DISEASE USING
AZASPIRANES
This invention relates to a method of treatment of Alzheimer's disease in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a substituted azaspirane.
Background of the Invention
Alzheimer's disease is the most common cause of dementia in old age. It afflicts approximately 5% of the population over the age of 65 years in developed parts of the world such as the U.S. and Europe (Cross, A.J., Eur. J. Pharmacol.
(1982) 82: 77-80; Terry, R.D., et al., Ann. Neurol. (1983) 14: 497-506) where it is estimated be the fourth most common cause of death after heart disease, cancer and stroke. There are currently around 20 million patients worldwide with this disease (Schenk, D.B., et al., J. Med. Chem. (1995) 38: 4141-4154), the consequences of which are devastating to the individuals and families involved. In the final stages of Alzheimer's disease, the patients are severely demented, and often completely unable to speak, or to take care of themselves. There are presently no treatments available that are directed at the underlying causes of
Alzheimer's disease.
The characteristic neuropathological changes in the brains of patients with
Alzheimer's disease include tangles of paired helical filaments inside neurons, together with extracellular 'senile' or 'neuritic' plaques. There is also an extensive degeneration and loss of neurons. The paired helical filaments are composed mainly of the cystoskeletal component, tau. In contrast, the senile plaques consist of a central deposit (or core) of a fibrillar protein termed amyloid, surrounded by a rim of abnormal, dystrophic neurites and synapses. The senile plaque amyloid cores were first isolated from freshly frozen Alzheimer brain tissue by Allsop, D., et al., (Brain. Res. (1983) 259: 348-352) and were subsequently shown to be composed mainly of a peptide, commonly 3943 amino acids in length, referred to by a variety of names including ss-amyloid, A4, Ass, or ssA4 (Glenner, G.G. and
Wong, C.W. Biochem. Biophys. Res. Commun. (1984) 120: 855-890; Masters,
C.L., et al., Proc. Natl. Acad. Sci. USA (1985) 82: 42454249). Deposits of this same ssA4 peptide can be found in the cerebrovasculature where they can lead to cerebral haemmorhage. The first report of the partial amino acid sequence of the ssA4 peptide was obtained from amyloid isolated from meningeal blood vessels (Glenner, G.G. and Wong, C.W. Biochem. Biophys. Res. Commun. (1984) 120: 855-890). Antibodies raised to synthetic peptide subsequences of ssA4 were shown subsequently to react by immunohistochemical methods with both senile plaque and cerebrovascular amyloid, confirming that both types of amyloid deposit contain the ssA4 peptide (Wong, C.W., et al. Proc. Natl. Acad. Sci. USA (1985) 82:8729-8732; Allsop, D., et al., Neurosci. Lett. (1986) 68:252-256).
The amino acid sequence of the ssA4 peptide was used by Kang, J., et al., (Nature (1987) 325:733-736) to construct oligonucleotide probes that allowed the first identification (from a brain foetal cDNA library) of a full-length clone that encoded ssA4 as part of a 695 amino acid precursor protein. This precursor (termed APP) contained a single membrane-spanning domain towards its carboxyl-terminal end, with the sequence of the ssA4 peptide commencing at amino acid residue 597 and terminating part way through the membrane-spanning region. Subsequently, a number of slightly longer cDNA clones were isolated by other workers. The 751 amino acid APP sequence described by Ponte, P., et al., (Nature (1988) 331: 525-527) contained an additional 57-amino acid insert encoding a Kunitz-type serine proteinase inhibitor (KPI). Kitaguchi, N., et al., (Nature (1988) 331:530-532) identified another precursor with both the KPI sequence and an additional 19 amino acid insert. These isoforms of APP arise as a result of alternative splicing of exons 7 and 8 during transcription of the APP gene.
Additional isoforms generated by alternative splicing of exon 15 have also been detected (Sandbrink, R., et al., J. Biol. Chem. (1994) 269: 1510-1517).
The ssA4 peptide is considered to be a product of the normal metabolism of
APP, since it is present in the conditioned culture medium of a variety of celllines, and is also present in normal human cerebrospinal fluid (Haass, C., et al.,
Nature (1992) 359: 322-325; Shoji, et al., Science (1992) 258: 126-129; Seubert et al., Nature (1992) 359:325-327). However, in individuals with Alzheimer's disease the peptide is present in a highly aggregated and insoluble state in the form of amyloid fibrils at the centre of senile plaques, and in the walls of cerebral blood vessels. The reason for the increased aggregation of ssA4 in the brain in
Alzheimer's disease is unknown.
Evidence indicates that aggregation and deposition of ssA4 in the brain is a crucial, early event in the pathogenesis of Alzheimer's disease (Hardy, J. and
Allsop, D., Trends Pharmacol. Sci. (1991) 12: 383-388). Therapy aimed at blocking or reducing the formation of ssA4 in the brain would provide a novel method for treating Alzheimer's disease. Such therapy would be directed at the actual pathogenic disease process rather than being merely palliative.
Badger, et al., U.S. Patent No. 4,963,557 (Badger I) discloses compounds of the formula
wherein: n is 3-7; m is 1 or 2; R1 and R2 are the same or different and are selected from hydrogen or straight or branched chain alkyl, provided that the total number of carbon atoms contained by R1 and R2 when taken together is 5-10; or R1 and
R2 together form a cyclic alkyl group having 3-7 carbon atoms; R3 and R4 are the same or different and are selected from hydrogen or straight chain alkyl having 1-3 carbon atoms; or R3 and R4 are joined together with the nitrogen atom to form a heterocyclic group having 5-8 atoms; or a pharmaceutically acceptable salt or hydrate or solvate thereof.
Badger I discloses compounds of Formula I as a class of novel compounds which induce an immunomodulatory effect which is characterized by the stimulation of suppressor cell activity.
Badger I does not disclose the compounds of Formula I as agents for treating
Alzheimer's disease in mammals, including humans.
Summary of the Invention
This invention relates to a method of treating Alzheimer's disease in mammals, including humans, which comprises administering to such mammal an effective amount of a compound of the formula
wherein:
n is 3-7;
m is 1 or 2;
R1 and R2 are the same or different and are selected from hydrogen or straight or branched chain alkyl, provided that the total number of carbon atoms contained by R1 and R2 when taken together is 5-10; or R1 and R2 together form a cyclic alkyl group having 3-7 carbon atoms;
R3 and R4 are the same or different and are selected from hydrogen or
straight chain alkyl having 1-3 carbon atoms; or R3 and R4 are joined together with the nitrogen atom to form a heterocyclic group having 5-8 atoms; or a pharmaceutically acceptable salt or hydrate or solvate thereof.
Detailed Description of the Invention
The preparation of all compounds of Formula (I) and pharmaceutically acceptable salts, hydrates and solvates and formulations thereof is disclosed in
U.S. Patent No. 4,963,557, the entire disclosure of which is hereby incorporated by reference.
By the term "treating" and derivatives thereof, as used herein, is meant prophylactic as well as therapeutic therapy.
A preferred compound used in the novel method is the dihydrochloride salt of a compound of Formula (I) where R1 and R2 are propyl, R3 and R4 are methyl, m is 1 and n is 3 which is N,N-dimethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2- propanamine dihydrochloride [Compound A].
A particularly preferred compound used in the novel method is the dihydrochloride salt of a compound of Formula (I) where R1 and R2 are propyl,
R3 and R4 are ethyl, m is 1 and n is 3 which is N,N-diethyl-8,8-dipropyl-2 azaspiro[4.5]decane-2-propanamine dihydrochloride [Compound B].
A particularly preferred compound used in the novel method is the dihydrochloride salt of a compound of Formula (I) where R1 and R2 are propyl,
R3 and R4 are joined together with the nitrogen to form a piperidine ring, m is 1 and n is 3 which is 8,8-dipropyl-2-azaspiro[4.5]decane-2-piperidinopropyl dihydrochloride.
A preferred form of the above compounds are prepared by replacing the dihydrochloride salt with a dimaleate salt.
This invention discloses compounds of Formula (I) and pharmaceutically acceptable salts or hydrates or solvates thereof as being useful for treating
Alzheimer's disease in mammals, including humans.
The compounds of Formula I are tested for their ability to block the release of ssA4 according to the following procedure.
Adherent IMR-32 human neuroblastoma cells (which have been transfected with an SV40 episomal vector containing the coding sequence for the 751 amino acid isoform of human APP-described in Ponte, P., et al., Nature (1988) 331: 525 to 527) are grown in microtitre plates. Cells are grown to 80% confluency in a complex growth medium (pH 7.4) consisting of 43.3% (v/v) DMEM14500mg/1 glucose, 43.3% (v/v) 361 medium (3 volumes DMEM, 6 volumes Hams F12, 1 volume alpha-MEM, 2.7gel sodium bicarbonate), 15mM sodium bicarbonate, l5mM HEPES, 12mM sodium hydroxide, 3.3gel glucose, 2mM L-glutamine, 1% (v/v) foetal calf serum, 4% (v/v) newborn calf serum, 50microg/ml penicillin/streptomycin and 260microg/ml hygromycin. Test compounds are dissolved in dimethyl sulphoxide at a stock concentration of 2mM, then diluted 1 in 200 with MEM/25mM Hepes containing 2mM glutamine, 50microg/ml penicillin/streptomycin, 2% (v/v) foetal calf serum and 260microglmi hygromycin.
After removal of the growth medium, 200microlitres of the diluted compounds are added to the adherent cells in triplicate wells. Appropriate control cultures containing diluted solvent are set up in triplicate. The plates are incubated for 24 hours at 370C, 95% air/5% CO2 in a humidified incubator, then centrifuged at 200xg for 3 minutes.
The release of ssA4 into the medium of the cells is measured according to the immunoassay outlined below.
The conditioned media are assayed in a 96-well immunoassay format which utilizes two ssA4-specific mouse monoclonal antibodies configured in a sandwich assay. One ssA4 antibody (termed 1E8) serves as the capture reagent for the ssA4 present in the media, and the second ssA4-specific antibody (2F12) serves as a component of the complex used for detection. The 1 E8 antibody is raised (using standard methods for mouse monoclonal antibodies) to a synthetic peptide corresponding to residues 12-26 of the human ssA4 sequence, whereas 2F12 is raised to another peptide corresponding to residues 1-16. Thus the two antibodies recognise different epitopes on the ssA4 peptide. The second antibody is used in the form of a Fab fragment which has been conjugated with dextran and biotinylated. This is detected by time-resolved fluorescence following further incubations with a streptavidin-europium complex (DELFIA; EG & G Berthold and
Wallac) followed by enhancer solution. A positive result is one in which there is little or no fluorescence, indicating the absence of the ssA4 protein in the medium as a result of inhibition by the test compound. The results are expressed as the percentage inhibition of the signal obtained in wells conditioned with medium which contained solvent alone. A synthetic peptide corresponding to residues 1-40 of ssA4 is used to obtain a standard curve for calibration of the assay.
Compound A was tested according to the above procedure and found to have an IC50 of 649 nM.
Compound B was tested according to the above procedure and found to have an IC50 of 459 nM.
This invention relates to a method of treating Alzheimer's disease in a mammal, including a human, in need thereof which comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof. A compound of Formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof can be administered to such human in a conventional dosage form prepared by combining a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof, with a conventional pharmaceutically acceptable carrier or diluent according to known techniques, such as those described in
Badger (I), U.S. Patent No. 4,963,557.
It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. A compound of Formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof is administered to a mammal, including a human, in need of treatment for Alzheimer's disease in an amount sufficient to lower the release of ssA4 to desired levels.
The route of administration of the Formula (I) ("Active Ingredient") compound is not critical but is usually oral or parenteral, preferably oral.
The term parenteral as used herein includes intravenous, intramuscular, subcutaneous, intranasal, intrarectal, transdermal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. The daily parenteral dosage regimen will preferably be from about 0.01 mg/kg to about 10 mg/kg of total body weight, most preferably from about 0.1 mg/kg to about 1 mg/kg. Preferably, each parenteral dosage unit will contain the active ingredient in an amount of from about 0.1 mg to about 100 mg.
The compounds of Formula (I) which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or coloring agent.
A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
The daily oral dosage regimen will preferably be from about 0.01 mg/kg to about 10 mg/kg of total body weight. Preferably each oral dosage unit will contain the active ingredient in an amount of from about 0.1 mg to about 100 mg.
While it is possible for an active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation.
It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof given per day and duration of therapy, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
The method of this invention of treating Alzheimer's disease in mammals, including humans, comprises administering to a subject in need of such treatment an effective amount of a pharmaceutically active compound of the present invention.
The invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in treating Alzheimer's disease in mammals, including humans.
The invention also provides for a pharmaceutical composition for use in the treatment of Alzheimer's disease which comprises a compound of Formula I and a pharmaceutically acceptable carrier.
The invention also provides for a process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and a compound of Formula I which comprises bringing the compound of Formula I into association with the pharmaceutically acceptable carrier or diluent.
No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.
In addition, the compounds of the present invention can be co-administered with further active ingredients, such as compounds known to treat Alzheimer's disease.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent.
The following examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.
EXAMPLE 1 - CAPSULE COMPOSITION
An oral dosage form for administering Formula (I) compounds is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table I, below.
Table I
INGREDIENTS AMOUNTS N,N-diethyl-8,8-dipropyl-2-azaspiro[4,5 ]decane-2- 25 mg
propanamine dimaleate
Lactose 55 mg
Talc 16 mg
Magnesium Stearate 4 mg
EXAMPLE 2 - INJECTABLE PARENTERAL COMPOSITION An injectable form for administering Formula (I) compounds is produced by stirring 1.5% by weight of N,N-diethyl-8,8-dipropyl-2-azaspiro[4,Sjdecane-2- propanamine dimaleate in 10% by volume propylene glycol in water.
Example 3 - Tablet Composition
The sucrose, calcium sulfate dihydrate and Formula (I) compound shown in
Table II below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.
Table II
Ingredients Amounts N,N-diethyl-8,8-dipropyl-2-azaspiro[4,5]decane- 20 mg
2-propanamine dimaleate
calcium sulfate dihydrate 30 mg
sucrose 4 mg
starch 2 mg
talc 1 mg
stearic acid 0.5 mg
While the above descriptions and examples fully describe the invention and the preferred embodiments thereof, it is understood that the invention is not limited to the particular disclosed embodiments coming within the scope of the following claims.
Claims (6)
1. A method for treating Alzheimer's disease in mammals, including humans, which comprises administering to such mammal an effective amount of a compound of the formula
wherein:
n is 3-7;
m is 1 or 2; R1 and R2 are the same or different and are selected from hydrogen or straight or branched chain alkyl, provided that the total number of carbon atoms contained by R1 and R2 when taken together is 5-10; or R1 and R2 together form a cyclic alkyl group having 3-7 carbon atoms;
R3 and R4 are the same or different and are selected from hydrogen or straight chain alkyl having 1-3 carbon atoms; or R3 and R4 are joined together with the nitrogen to form a heterocyclic group having 5-8 atoms; or a pharmaceutically acceptable salt or hydrate or solvate thereof.
2. The method of claim 1 wherein the compound is N,N-diethyl-8,8 dipropyl-2-azaspiro[4.5]decane-2-propanamine; or a pharmaceutically acceptable salt, hydrate or solvate thereof.
3. The method of claim 1 wherein the compound is administered orally.
4. The method of claim 3 wherein from about 0.01 mglkg to about 10 mg/kg of compound is administered per day.
5. The method of claim 1 wherein the compound is administered parenterally.
6. The method of claim 5 wherein from about 0.01 mg/kg to about 10 mg/kg of compound is administered per day.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9709416A GB2309167A (en) | 1997-05-10 | 1997-05-10 | The use of azaspiranes in the treatment of Alzheimer's disease |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9709416A GB2309167A (en) | 1997-05-10 | 1997-05-10 | The use of azaspiranes in the treatment of Alzheimer's disease |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB9709416D0 GB9709416D0 (en) | 1997-07-02 |
| GB2309167A true GB2309167A (en) | 1997-07-23 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9709416A Withdrawn GB2309167A (en) | 1997-05-10 | 1997-05-10 | The use of azaspiranes in the treatment of Alzheimer's disease |
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| Country | Link |
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| GB (1) | GB2309167A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2021004A2 (en) * | 2006-05-08 | 2009-02-11 | Neurogen Corporation | Substituted azaspiro derivatives |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992014462A1 (en) * | 1991-02-19 | 1992-09-03 | Smithkline Beecham Corporation | Cytokine inhibitors |
| WO1993007869A1 (en) * | 1991-10-25 | 1993-04-29 | Smithkline Beecham Corporation | Methods for treatment of hyperlipidemia using azaspiranes |
-
1997
- 1997-05-10 GB GB9709416A patent/GB2309167A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992014462A1 (en) * | 1991-02-19 | 1992-09-03 | Smithkline Beecham Corporation | Cytokine inhibitors |
| WO1993007869A1 (en) * | 1991-10-25 | 1993-04-29 | Smithkline Beecham Corporation | Methods for treatment of hyperlipidemia using azaspiranes |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2021004A2 (en) * | 2006-05-08 | 2009-02-11 | Neurogen Corporation | Substituted azaspiro derivatives |
| EP2021004A4 (en) * | 2006-05-08 | 2011-06-22 | Neurogen Corp | Substituted azaspiro derivatives |
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| Publication number | Publication date |
|---|---|
| GB9709416D0 (en) | 1997-07-02 |
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