WO2001083425A1 - Method of inhibiting amyloid protein aggregation and imaging amyloid deposits using aminoindane derivatives - Google Patents
Method of inhibiting amyloid protein aggregation and imaging amyloid deposits using aminoindane derivatives Download PDFInfo
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- WO2001083425A1 WO2001083425A1 PCT/US2001/013254 US0113254W WO0183425A1 WO 2001083425 A1 WO2001083425 A1 WO 2001083425A1 US 0113254 W US0113254 W US 0113254W WO 0183425 A1 WO0183425 A1 WO 0183425A1
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- WIPO (PCT)
- Prior art keywords
- compound
- amyloid
- patient
- indan
- nitro
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 60
- 208000037259 Amyloid Plaque Diseases 0.000 title claims abstract description 49
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- 238000003384 imaging method Methods 0.000 title claims abstract description 14
- 230000004845 protein aggregation Effects 0.000 title claims description 11
- XJEVHMGJSYVQBQ-UHFFFAOYSA-N 2,3-dihydro-1h-inden-1-amine Chemical class C1=CC=C2C(N)CCC2=C1 XJEVHMGJSYVQBQ-UHFFFAOYSA-N 0.000 title description 6
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- JLWCPMSWUQZPGP-UHFFFAOYSA-N methyl 2-[[2-[(3,4-dichlorophenyl)methylamino]-2,3-dihydro-1h-inden-5-yl]amino]benzoate Chemical compound COC(=O)C1=CC=CC=C1NC1=CC=C(CC(C2)NCC=3C=C(Cl)C(Cl)=CC=3)C2=C1 JLWCPMSWUQZPGP-UHFFFAOYSA-N 0.000 claims description 4
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- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- 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
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/56—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/56—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position
- C07C229/58—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position having the nitrogen atom of at least one of the amino groups further bound to a carbon atom of a six-membered aromatic ring, e.g. N-phenyl-anthranilic acids
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- 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
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
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- 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
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/64—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring the carbon skeleton being further substituted by singly-bound oxygen atoms
-
- 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
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Definitions
- This invention relates to a method of inhibiting amyloid protein aggregation and imaging amyloid deposits. More particularly, this invention relates to a method of inhibiting amyloid protein aggregation in order to treat Alzheimer's disease using aminoindane derivatives.
- Amyloidosis is a condition characterized by the accumulation of various insoluble, fibrillar proteins in the tissues of a patient.
- the fibrillar proteins that comprise the accumulations or deposits are called amyloid proteins. While the particular proteins or peptides found in the deposits vary, the presence of fibrillar morphology and a large amount of ⁇ -sheet secondary structure is common to many types of amyloids.
- An amyloid deposit is formed by the aggregation of amyloid proteins, followed by the further combination of aggregates and/or amyloid proteins.
- amyloid deposits has been shown in various diseases, each with its particular associated protein, such as Mediterranean fever, Muckle- Wells syndrome, idiopathetic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Alzheimer's disease, Down syndrome, Scrapie, Creutzfeldt- Jacob disease, Kuru, Gerstmann-Straussler-Scheinker syndrome, medullary carcinoma of the thyroid, Isolated atrial amyloid, ⁇ 2-microglobulin amyloid in dialysis patients, inclusion body myositis, ⁇ 2-amyloid deposits in muscle wasting disease, Sickle Cell Anemia, Parkinson's disease, and Islets of Langerhans diabetes type 2 insulinoma.
- a simple, noninvasive method for detecting and quantitating amyloid deposits in a patient has been eagerly sought.
- detection of amyloid deposits involves histological analysis of biopsy or autopsy materials. Both methods have major drawbacks.
- an autopsy can only be used for a postmortem diagnosis.
- amyloid deposits in vivo are difficult, as the deposits have many of the same physical properties (i.e., density and water content) as normal tissues. Attempts to image amyloid deposits directly using magnetic resonance imaging (MRI) and computer-assisted tomography (CAT) have been disappointing and have detected amyloid deposits only under certain favorable conditions. In addition, efforts to label amyloid deposits with antibodies, serum amyloid P protein, or other probe molecules has provided some selectivity on the periphery of tissues, but has provided for poor imaging of tissue interiors.
- MRI magnetic resonance imaging
- CAT computer-assisted tomography
- Alzheimer's disease is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgement, and emotional stability that gradually leads to mental deterioration and ultimately death. Because Alzheimer's disease and related degenerative brain disorders are a major medical issue for an increasingly aging population, the need for new treatments and methods for diagnosing the disorders are needed.
- Several classes of compounds have been shown to have activity against
- Alzheimer's disease The only two agents currently approved for clinical treatment of Alzheimer's disease are the acetylcholinesterase inhibitors tacrine and donepezil (see US Patent No. 4,816,456).
- US Patent Nos. 5,716,975 and 5,523,314 relate to rhodanine derivatives useful as hypoglycemic agents and for treating Alzheimer's disease.
- the present invention provides a group of aminoindanyl analogs that are inhibitors of amyloid aggregation and are thus useful for treating Alzheimer's disease.
- the compounds are also useful as imaging agents because of their ability to selectively bind to amyloid proteins.
- the present invention provides compounds of the Formula I
- Ri and R ⁇ independently are hydrogen, Ci -Cg alkyl, C2 ⁇ Cg alkenyl, C2-Cg alkynyl, (CH2) n phenyl or (CH2) n substituted phenyl, provided that one of Ri and R ⁇ is other than hydrogen; R4 and R ⁇ independently are hydrogen, halo, Cj-Cg alkyl, C2-Cg alkenyl,
- R ⁇ is hydrogen or Cj-Cg alkyl
- R is hydrogen, Cj-Cg alkyl, or (CH2)nPhenyl or (CH2) n substituted phenyl; n is an integer from 0 to 4 inclusive; or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
- Preferred compounds have Formula I wherein one of Ri and R ⁇ is (CH2)nphenyl or (CH2) n substituted phenyl, and R 5 is CO2R 6 , tetrazolyl, or SO2 R 6 , and R 6 is hydrogen.
- a preferred group of compounds have Formula II where Rl, R ⁇ , R4, and R ⁇ are as defined above.
- R ⁇ , R , and R" are as defined above, and R ⁇ is hydrogen, halo,
- a further embodiment of this invention is a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula I together with a carrier, excipient, or diluent therefor.
- Another embodiment of this invention is a method for inhibiting amyloid aggregation in a mammal comprising administering an effective amount of a compound of Formula I.
- a further method provided is a method of treating Alzheimer's disease and central and/or peripheral amyloidosis syndromes in mammals comprising administering an effective amount of a compound of
- Also provided is a method of imaging amyloid deposits comprising the steps of: a. introducing into a patient a detectable quantity of a labeled compound of Formula I; b. allowing sufficient time for the labeled compound to become associated with amyloid deposits; and c. detecting the labeled compound associated with the amyloid deposits.
- the patient has or is suspected to have Alzheimer's disease.
- the labeled compound is a radiolabeled compound. In another preferred embodiment, the labeled compound is detected using
- composition comprising a compound of Formula I.
- alkyl means a straight or branched chain hydrocarbon.
- alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, and hexyl.
- Preferred alkyl groups are Cj-Cg alkyl.
- Alkenyl means a carbon chain having one or two points of unsaturation in the form of double bonds. Examples include ethenyl, prop-2-enyl, and hex-
- Alkynyl means a carbon chain having one or two triple bonds, for example, 2-butynyl, octa-3,5-diynyl, and the like.
- alkoxy means an alkyl group such as Ci -Cg alkyl attached to an oxygen atom.
- Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy.
- halogen includes chlorine, fluorine, bromine, and iodine.
- alkyl, alkenyl, alkynyl, and alkoxy groups can be substituted.
- substituted means that one or more hydrogen atoms in a molecule has been replaced with another atom or group of atoms.
- substituents include halogen, -OH, -CF3, -NO2, -NH2, -NH(C ⁇ -Cgalkyl),
- substituted phenyl means a phenyl ring in which from 1 to 4 hydrogen atoms have been independently replaced with a substituent, preferably one selected from the list above.
- substituted phenyl include 2,6-dichlorophenyl, 2-methoxycarbonylphenyl, 3-cyanophenyl, 2,3,4,5-tetrafluorophenyl, 3-aminophenyl, 2-hydroxyphenyl, and the like.
- pharmaceutically acceptable salt, ester, amide, and prodrug refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
- salts refers to the relatively nontoxic, inorganic and organic acid addition salts of compounds of the present invention.
- salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
- Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laureate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts, and the like.
- alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like
- nontoxic ammonium, quaternary ammonium and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
- esters of the compounds of this invention include C ⁇ -Cg alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
- Examples of pharmaceutically acceptable, nontoxic amides of the compounds of this invention include amides derived from ammonia, primary
- C1 -Cg alkyl amines and secondary Cj-Cg dialkyl amines wherein the alkyl groups are straight or branched chain.
- the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom.
- Amides derived from ammonia, C ⁇ -C3 alkyl primary amides, and j-C2 dialkyl secondary amides are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
- prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulas, for example, by hydrolysis in blood.
- the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
- the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
- the compounds of the present invention can exist in different stereoisometric forms by virtue of the presence of asymmetric centers in the compounds. It is contemplated that all stereoisometric forms of the compounds, as well as mixture thereof, including racemic mixtures, form part of this invention.
- a labeled compound of Formula I is introduced into a tissue or a patient in a detectable quantity.
- the compound is typically part of a pharmaceutical composition and is administered to the tissue or the patient by methods well-known to those skilled in the art.
- a compound in the methods of the present invention, can be administered either orally, rectally, parenterally (intravenous, by intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments or drops), or as a buccal or nasal spray.
- Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
- aqueous and nonaqueous carriers examples include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
- a coating such as lecithin
- surfactants for example, water, alcohol, alcohol, and the like.
- compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
- adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
- Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
- isotonic agents for example sugars, sodium chloride, and the like.
- Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
- fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid;
- binders as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia;
- humectants as for example, glycerol;
- disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate;
- solution retarders as for example paraffin;
- absorption accelerators as for example, quaternary ammonium compounds;
- wetting agents such as sodium citrate or dicalcium phosphate or
- compositions of a similar type may also be employed as fillers in soft- and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethyleneglycols, and the like.
- Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubihzing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil,, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan or mixtures of these substances, and the like.
- inert diluents commonly used in the art, such as water or other solvents, solubi
- composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
- suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
- compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable nonirritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
- suitable nonirritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
- Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants.
- the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
- the labeled compound is introduced into a patient in a detectable quantity and after sufficient time has passed for the compound to become associated with amyloid deposits, the labeled compound is detected noninvasively inside the patient.
- a labeled compound of Formula I is introduced into a patient, sufficient time is allowed for the compound to become associated with amyloid deposits, and then a sample of tissue from the patient is removed and the labeled compound in the tissue is detected apart from the patient.
- a tissue sample is removed from a patient and a labeled compound of Formula I is introduced into the tissue sample. After a sufficient amount of time for the compound to become bound to amyloid deposits, the compound is detected.
- the administration of the labeled compound to a patient can be by a general or local administration route.
- the labeled compound may be administered to the patient such that it is delivered throughout the body.
- the labeled compound can be administered to a specific organ or tissue of interest. For example, it is desirable to locate and quantitate amyloid deposits in the brain in order to diagnose or track the progress of Alzheimer's disease in a patient.
- tissue means a part of a patient's body. Examples of tissues include the brain, heart, liver, blood vessels, and arteries.
- a detectable quantity is a quantity of labeled compound necessary to be detected by the detection method chosen. The amount of a labeled compound to be introduced into a patient in order to provide for detection can readily be determined by those skilled in the art. For example, increasing amounts of the labeled compound can be given to a patient until the compound is detected by the detection method of choice. A label is introduced into the compounds to provide for detection of the compounds.
- the term "patient” means humans and other animals. Those skilled in the art are also familiar with determining the amount of time sufficient for a compound to become associated with amyloid deposits. The amount of time necessary can easily be determined by introducing a detectable amount of a labeled compound of Formula I into a patient and then detecting the labeled compound at various times after administration.
- the term "associated” means a chemical interaction between the labeled compound and the amyloid deposit. Examples of associations include covalent bonds, ionic bonds, hydrophilic-hydrophilic interactions, hydrophobic- hydrophobic interactions, and complexes.
- MRI positron emission tomography
- SPECT single photon emission computed tomography
- the label that is introduced into the compound will depend on the detection method desired. For example, if PET is selected as a detection method, the compound must possess a positron-emitting atom, such as HC or ⁇ F.
- a suitable label in a compound of Formula I is an atom such as 13Q 15] ⁇ or 19p hich can be detected using MRI which is also sometimes called nuclear magnetic resonance (NMR).
- NMR nuclear magnetic resonance
- the labeled compounds of Formula I may also be detected by MRI using paramagnetic contrast agents.
- EPR electron paramagnetic resonance
- the imaging of amyloid deposits can also be carried out quantitatively so that the amount of amyloid deposits can be determined.
- the present invention also provides a method of inhibiting the aggregation of amyloid proteins to form amyloid deposits, by administering to a patient in need of inhibition of the aggregation of amyloid protein an amyloid protein inhibiting amount of a compound of Formula I.
- an amyloid inhibiting amount by simply administering a compound of Formula I to a patient in increasing amounts until the growth of amyloid deposits is decreased or stopped. The rate of growth can be assessed using imaging or by taking a tissue sample from a patient and observing the amyloid deposits therein.
- a patient in need of inhibition of the aggregation of amyloid proteins is a patient having a central or peripheral disease or condition in which amyloid proteins aggregate.
- diseases and conditions include:
- Mediterranean fever Muckle-Wells syndrome, idiopathetic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Alzheimer's disease, Down syndrome, Scrapie, Creutzfeldt- Jacob disease, Kuru, Gerstmann- Straussler-Scheinker syndrome, medullary carcinoma of the thyroid, Isolated atrial amyloid, ⁇ 2- icroglobulin amyloid in dialysis patients, inclusion body myositis, ⁇ 2-amyloid deposits in muscle wasting disease, Sickle Cell Anemia, Parkinson's disease, and Islets of Langerhans diabetes type 2 insulinoma.
- Also provided by the present invention are compounds of Formula I wherein one or more atom in the compound has been replaced with a radioisotope.
- the radioisotope can be any radioisotope. However,-1H, 123 s li 5 13 Ij ⁇ 11 and
- compounds of Formula I are made where a ⁇ C atom is replaced by a ⁇ C atom.
- the compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day, which are "effective amounts" for inhibiting amyloid formation and treating the above mentioned diseases, especially Alzheimer's disease.
- dosage levels in the range of about 0.1 to about 1,000 mg per day, which are "effective amounts" for inhibiting amyloid formation and treating the above mentioned diseases, especially Alzheimer's disease.
- a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is sufficient.
- the specific dosage used can vary.
- the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used.
- the determination of optimum dosages for a particular patient is well-known to those skilled in the art.
- the compounds of Formula I can be prepared by any of several processes, utilizing readily available starting materials and methods well-known in organic chemistry.
- Scheme 1 illustrates a typical method for making starting materials and the final products of Formula I.
- the invention compounds are generally prepared by reacting an amino indane with a phenyl halide such as a phenyl iodide or phenyl bromide.
- Scheme 1 starts with a 2-amino-5-nitro-indane, which can be prepared by reacting 2-amino-indane with nitric acid and sulfuric acid, generally in a solvent such as trifluoroacetic acid.
- the 2-amino-5-nitro-indane is readily reduced to the corresponding 2,5- diaminoindane, for instance by hydrogenation in the presence of a catalyst such as Raney nickel.
- the 5-amino group is then readily phenylated by reaction with a
- phenyl compound bearing a good leaving group L for example where L is halo such as iodo.
- the reaction is carried out under standard palladium-mediated coupling conditions, such as in an organic solvent (e.g., toluene) and in the presence of a mild base (e.g., cesium carbonate).
- a 2-amino-5-phenylaminoindane is further alkylated or phenylated at the 2-amino position, again utilizing standard alkylation methods.
- Schemes 2, 3, and 4 illustrate the initial alkylation or phenylation of the 2-amino group of a 2-amino-5-nitro-indane, followed by reduction of the nitro group and phenylation of the 5-amino group. All of these reactions are carried out under standard conditions, for example in an unreactive organic solvent, in the presence of a mild base, and generally at an elevated temperature of about 60°C to about 150°C. The products are readily isolated by simply removing the reaction solvent, for example by evaporation under reduced pressure, and they can be purified if desired by standard methods such as chromatography, crystallization, distillation, and the like.
- Trifluoroacetic acid 60 mL was charged into a flask, cooled in an ice/water bath, and 2-aminoindane hydrochloride (10.08 g) was added cautiously, followed by H2SO4 (6.0 mL) and HNO3 (3.0 mL). The ice bath was removed, and the mixture was allowed to warm to room temperature and stir for 2 hours. The mixture was then placed in an ice' water bath for the slow addition of diethyl ether (300 mL) over 35 minutes. The mixture was stirred at room temperature overnight, then the solids were filtered and dried in vacuo to give 15.43 g of 2-amino-5-nitro-indane sulfate.
- the desired mono-alkylated aminoindane was obtained in 35% yield (1.10 g), and the bis-dialkylated aminoindane was also isolated (1.38 g, 32% yield).
- the nitro substituted indanes from Preparation 2 were reacted with hydrogen in the presence of Raney nickel to give the corresponding 2-alkyl and 2-dialkylamino-5-aminoindanes.
- the 2-amino-5-nitro-indane sulfate from Preparation 1 can be similarly hydrogenated to provide 2,5-diamino-indane.
- the residual black oil was dissolved in THF (25 mL), cooled to 0°C for the addition of NaH (0.4 g, 60% dispersion in mineral oil). After 5 minutes, dichloro benzyl bromide (3.0 g) was added, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with 20 mL water and 40 mL Et2 ⁇ , the layers were separated, and the organics were washed with 20 mL water. The aqueous layers were combined and washed with 30 mL Et2 ⁇ , and the organic layers were combined, dried over MgSO4/Na2SO4, filtered through celite, and concentrated. The black oil was purified by column chromatography
- the methyl benzoate (0.65 g) was dissolved in 10 mL 1:1 THF/MeOH, and this solution was treated with 2 mL 50% NaOH and 1 mL water and stirred at room temperature for 18 hours.
- the mixture was concentrated, the solids were dissolved in ethyl acetate/water 1:1.
- the layers were separated, and the aqueous layer was extracted with 2 x 20 mL ethyl acetate.
- the organic layers were combined and washed with 10 mL 50% saturated NaCl, dried over MgSO4/ a2SO4, filtered, and concentrated.
- the methyl benzoate (0.130 g) was taken up in 20 mL 1 : 1 THF/MeOH and was treated with 1 M LiOH (3 mL). The mixture was stirred at room temperature for 48 hours. The mixture was then concentrated, and the residual oil was purified by chromatography (MPLC, silica, gradient 95:5 to 75:25 (C ⁇ C ⁇ /MeOH).
- 2-(2-Dipentylamino)-5-amino-indane (0.5 g) was taken up in THF (8.7 mL) and cooled to -78°C for the addition of LiHMDS (4.0 mL, 1 M in THF).
- 2-Fluoro-5-methyl benzoic acid (0.27 g) was added after 5 minutes, and the cold bath was removed. The mixture was allowed to warm to room temperature and stir for 16 hours. The mixture was diluted with diethyl ether and water. The layers were separated, and the aqueous layer was extracted with 2 x 20 mL diethyl ether. The organic layers were combined, dried over MgSO4/Na2SO4, filtered, and concentrated.
- Invention compounds of Formula I can be evaluated in several standard in vitro and in vivo assays which are well-established as indicative of clinical usefulness in treating Alzheimer's disease and other conditions associated with amyloid formation.
- AMYLOID ASSAYS BASSR Beta-Amyloid Self-Seeding Radioassay
- Assay Buffer 50 mM sodium phosphate, pH 7.5, 100 mM NaCl, 0.02% NaN3,
- Soluble A ⁇ ( 1-40) peptide (Bachem, Torrance, California) — 2.2 mg/mL in deionized H2O (stored in aliquots at -20°C, keep on ice when thawed) will self-seed after 1 week storage. Typically, the solution should be stored until no lag phase is seen in the assay.
- 125i-i a beled A ⁇ (l-A ⁇ ) can be made in accordance with the procedure set forth by H. Levine, III in Neurobiol. Aging, 16:755 (1995), which is hereby incorporated by reference, or this reagent may be purchased from Amersham, Arlington Heights, Illinois.
- Reaction mixture for 50 assays (on ice) is comprised of 0.1 to 0.2 ⁇ L of 125 I-labeled A 125 I-labeledA ⁇ (l-A0) + 1 ⁇ L of soluble A ⁇ ( 1-40) + 13.5 ⁇ L assay buffer per assay.
- the following are the amounts of the components of the reaction mixture sufficient for 50 assay wells. 5 to 10 ⁇ L 125 I-labeled ⁇ /?(l-40) dried down 675 ⁇ L assay buffer 50 ⁇ L soluble A ⁇ (l-A0)
- Assay Method 1 Prepare reaction mixture above by mixing components and storing on ice.
- Assay Buffer 50 mM sodium phosphate, pH 7.5, 100 mM NaCl, 0.02% NaN3, 1 M urea (filter and store at 4°C)
- Final assay conditions 30 ⁇ M soluble A ⁇ (1-40) in deionized water in assay buffer.
- Compound to be tested is dissolved in DMSO, typically 5 to 50 mM stock, such that the final concentration of DMSO is ⁇ 1% v/v in the assay.
- Reaction mixture for 50 assays comprised of 1 ⁇ L of soluble -4 7(1-40) + 13.5 ⁇ L assay buffer per assay. The following are the amounts of the components of the reaction mixture that result in each of the 50 assay wells. 50 ⁇ L soluble ⁇ /?(l-40)
- BAPA Beta-Amyloid Peptide Aggregation
- this assay is to provide a higher volume method of assaying the amount of ⁇ -amyloid aggregation using an endpoint assay based on filtration.
- hexafluoroisopropanol HFIP is used to break down the initial amyloid peptide to a monomer state and use a concentration of 33 ⁇ M which is high enough so that aggregation will occur at pH 6.0 in several hours.
- Beta-Amyloid Peptide Aggregation pH 6.0 (BAPA)
- a ⁇ (1-42) (California Peptide) was dried from its HFIP stock solution.
- the A ⁇ (1-42) was dissolved in DMSO and then mixed with phosphate buffered saline (PBS) (pH 7.4).
- PBS phosphate buffered saline
- the mixed A ⁇ (1-42) solution was filtered with a Omnipore membrane 0.2- ⁇ m syringe filter (Millipore, Bedford, Massachusetts).
- the compound to be tested in DMSO 50 x concentrate
- the A ⁇ (1-42) solution was added into each well (24.5 ⁇ L/well).
- the plate was centrifuged at 1,000 g for 5 minutes and incubated at 37°C for 1 day (A ⁇ l-42; final concentration 100 ⁇ M).
- the inhibitory activity was calculated as the reduction of fluorescence with the following formula:
- Inhibition (%) ⁇ (F(A ⁇ )-F(A ⁇ + compound) ⁇ / ⁇ F(A ⁇ )-F(solvent + compound) ⁇ x 100.
- the IC50S were calculated by a curve fitting program using the following equation. The data were obtained from two different experiments in triplicate.
- Representative compounds of Formula I have exhibited inhibitory activities (IC50) ranging from about 0.1 to > 100 ⁇ M in the foregoing assays.
- IC50 inhibitory activities
- the invention compounds can also be evaluated in standard in vivo assays commonly used to evaluate agents to treat conditions associated with amyloid aggregation such as Alzheimer's disease.
- amyloid protein is induced into the spleen of mice by subcutaneous injections of silver nitrate, Freund's complete adjuvant, and an intravenous injection of amyloid enhancing factor.
- Silver nitrate is administered each day through Day 1 1.
- Test compounds are administered to the mice daily starting on Day 1 through Day 11.
- the animals are sacrificed, and the spleens are removed, histologically prepared, stained with Congo red, and the percent area of the spleen occupied by birefringent, Congo red-stained amyloid is quantitated microscopically.
- Invention compounds will inhibit splenic amyloid deposition.
- mice Another in vivo assay in which the invention compounds can be evaluated uses transgenic mice.
- the mice bear a human ⁇ -amyloid precursor protein transgene with a prion promoter, as descried by Hsiao et al., "Correlative memory deficits, A ⁇ elevation, and amyloid plaques in transgenic mice," Science
- mice develop ⁇ -amyloid deposits at about 9 months of age. By 15 months, diffuse and compact senile plaques are abundant, primarily in the neocortex, olfactory bulb, and hippocampus. Invention compounds are administered orally to the mice beginning at the age of 8 months (just prior to the onset of amyloid deposits) and continuing for several months (up to about age 14-18 months). The animals are then sacrificed, and the brains are removed. The amount of amyloid in the brain is quantitated both histologically and biochemically. Invention compounds will inhibit amyloid accumulation in the cortex and hippocampus of the test animals.
- invention compounds of Formula I are potent inhibitors of protein aggregation, and are thus useful in treating diseases associated with amyloid deposits and to image amyloid deposits for diagnostic use.
- the compounds typically will be used in the form of pharmaceutical formulations for therapeutic use, and the following examples further illustrate typical compositions.
- Example 1 The compound of Example 1 is mixed with the lactose and cornstarch (for mix) and blended to uniformity to a powder.
- the cornstarch (for paste) is suspended in 6 mL of water and heated with stirring to form a paste.
- the paste is added to the mixed powder, and the mixture is granulated.
- the wet granules are passed through a No. 8 hard screen and dried at 50°C.
- the mixture is lubricated with 1% magnesium stearate and compressed into a tablet.
- the tablets are administered to a patient at the rate of 1 to 4 each day for prevention of amyloid and treatment of Alzheimer's disease.
- EXAMPLE 14 Parenteral Solution
- the solution is sterilized, filled into 5.0 mL ampoules, each containing 2.0 mL (40 mg of compound of Example 9), and sealed under nitrogen.
- the 10 solution is administered by injection to a patient suffering from medullary carcinoma of the thyroid and in need of treatment.
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Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
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DE60113407T DE60113407T2 (en) | 2000-05-04 | 2001-04-25 | PROCESS FOR THE INHIBITION OF AMYLOID PROTEIN AGGREGATION AND FOR THE DIAGNOSTIC DETECTION OF AMYLOID DEPOSITION USING AMINO INDIGENOUS DERIVATIVES |
AT01928832T ATE304522T1 (en) | 2000-05-04 | 2001-04-25 | METHOD FOR INHIBITING AMYLOID PROTEIN AGGREGATION AND FOR DIAGNOSTIC DETECTION OF AMYLOID DEPOSIT USING AMINOINDANDERIVATES |
BR0110519-1A BR0110519A (en) | 2000-05-04 | 2001-04-25 | Method for inhibiting amyloid protein aggregation and imaging of amyloid deposits using aminoindan derivatives |
CA002405611A CA2405611A1 (en) | 2000-05-04 | 2001-04-25 | Method of inhibiting amyloid protein aggregation and imaging amyloid deposits using aminoindane derivatives |
AU2001255646A AU2001255646A1 (en) | 2000-05-04 | 2001-04-25 | Method of inhibiting amyloid protein aggregation and imaging amyloid deposits using aminoindane derivatives |
EP01928832A EP1284958B1 (en) | 2000-05-04 | 2001-04-25 | Method of inhibiting amyloid protein aggregation and imaging amyloid deposits using aminoidane derivatives |
MXPA02009948A MXPA02009948A (en) | 2000-05-04 | 2001-04-25 | Method of inhibiting amyloid protein aggregation and imaging amyloid deposits using aminoindane derivatives. |
JP2001580856A JP2003531883A (en) | 2000-05-04 | 2001-04-25 | Method for suppressing amyloid protein aggregation using aminoindan derivative and method for imaging amyloid deposits |
US10/275,351 US6949575B2 (en) | 2000-05-04 | 2001-04-25 | Method of inhibiting amyloid protein aggregation and imaging amyloid deposits using aminoindane derivatives |
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US20199600P | 2000-05-04 | 2000-05-04 | |
US60/201,996 | 2000-05-04 |
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PCT/US2001/013254 WO2001083425A1 (en) | 2000-05-04 | 2001-04-25 | Method of inhibiting amyloid protein aggregation and imaging amyloid deposits using aminoindane derivatives |
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US (1) | US6949575B2 (en) |
EP (1) | EP1284958B1 (en) |
JP (1) | JP2003531883A (en) |
AT (1) | ATE304522T1 (en) |
AU (1) | AU2001255646A1 (en) |
BR (1) | BR0110519A (en) |
CA (1) | CA2405611A1 (en) |
DE (1) | DE60113407T2 (en) |
ES (1) | ES2248315T3 (en) |
MX (1) | MXPA02009948A (en) |
WO (1) | WO2001083425A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007522077A (en) * | 2003-08-21 | 2007-08-09 | アクセス ファーマシューティカルズ, インコーポレイテッド | Liquid formulations for prevention and treatment of mucosal diseases and disorders |
WO2008099210A2 (en) | 2007-02-12 | 2008-08-21 | Merck & Co., Inc. | Piperazine derivatives for treatment of ad and related conditions |
CN104870422A (en) * | 2012-10-31 | 2015-08-26 | 富山化学工业株式会社 | Novel amine derivative or salt thereof |
Families Citing this family (11)
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JP2009084254A (en) * | 2007-10-03 | 2009-04-23 | Sumitomo Chemical Co Ltd | PHARMACEUTICAL COMPOSITION FOR INHIBITING ACCUMULATION OF AMYLOID beta PROTEIN |
CA2707309A1 (en) | 2007-12-18 | 2009-06-25 | Acumen Pharmaceuticals, Inc. | Novel addl receptor polypeptides, polynucleotides and host cells for recombinant production |
US9464319B2 (en) | 2009-03-24 | 2016-10-11 | California Institute Of Technology | Multivolume devices, kits and related methods for quantification of nucleic acids and other analytes |
US9447461B2 (en) | 2009-03-24 | 2016-09-20 | California Institute Of Technology | Analysis devices, kits, and related methods for digital quantification of nucleic acids and other analytes |
WO2010111265A1 (en) | 2009-03-24 | 2010-09-30 | University Of Chicago | Slip chip device and methods |
US10196700B2 (en) | 2009-03-24 | 2019-02-05 | University Of Chicago | Multivolume devices, kits and related methods for quantification and detection of nucleic acids and other analytes |
EP2839260B1 (en) | 2012-04-20 | 2018-07-18 | Talis Biomedical Corporation | Fluidic devices and systems for sample preparation or autonomous analysis |
WO2013159116A1 (en) | 2012-04-20 | 2013-10-24 | University Of Chicago | Fluidic devices for biospecimen preservation |
US9803237B2 (en) | 2012-04-24 | 2017-10-31 | California Institute Of Technology | Slip-induced compartmentalization |
US10478513B2 (en) * | 2015-08-18 | 2019-11-19 | The Regents Of The University Of Califonia | Nitroxide containing amyloid binding agents for imaging and therapeutic uses |
WO2018111805A1 (en) | 2016-12-13 | 2018-06-21 | St. Jude Children's Research Hospital | Tetrahydroquinoline-based bromodomain inhibitors |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0535496A1 (en) * | 1991-09-25 | 1993-04-07 | Hoechst-Roussel Pharmaceuticals Incorporated | (1-Indanon-2yl)methylpiperidines, intermediates and a process for their preparation and their use as medicaments |
EP0538134A2 (en) * | 1991-10-16 | 1993-04-21 | Teva Pharmaceutical Industries, Ltd. | Mono-fluorinated derivatives of N-propargyl-1-aminoindan and their use as inhibitors of monoamine oxidase |
US5658904A (en) * | 1989-02-14 | 1997-08-19 | Toyama Chemical Co., Ltd. | 1,2-ethanediol derivative and salt thereof and cerebral function-improving agent comprising the same |
US6001331A (en) * | 1996-01-24 | 1999-12-14 | Warner-Lambert Company | Method of imaging amyloid deposits |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4816456A (en) * | 1986-10-01 | 1989-03-28 | Summers William K | Administration of monoamine acridines in cholinergic neuronal deficit states |
GB8707123D0 (en) * | 1987-03-25 | 1987-04-29 | Pfizer Ltd | Antiarrhythmic agents |
ZA936492B (en) * | 1992-09-10 | 1995-03-02 | Lilly Co Eli | Compounds useful as hypoglycemic agents and for treating Alzheimer's disease. |
SE9802360D0 (en) * | 1998-07-01 | 1998-07-01 | Wikstroem Hakan Vilhelm | New 2-aminothiazole-fused 2-amino indans and 2-aminotetralins ((basic) -N-substituted and (basic) -N, N-disubstituted derivatives of 2,6-diamino-thiazolo (4,5-f) indan and 2 , 7-di-amino-thiazolo (4,5-g) tetralin |
-
2001
- 2001-04-25 WO PCT/US2001/013254 patent/WO2001083425A1/en active IP Right Grant
- 2001-04-25 ES ES01928832T patent/ES2248315T3/en not_active Expired - Lifetime
- 2001-04-25 BR BR0110519-1A patent/BR0110519A/en not_active IP Right Cessation
- 2001-04-25 AT AT01928832T patent/ATE304522T1/en not_active IP Right Cessation
- 2001-04-25 MX MXPA02009948A patent/MXPA02009948A/en unknown
- 2001-04-25 CA CA002405611A patent/CA2405611A1/en not_active Abandoned
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- 2001-04-25 US US10/275,351 patent/US6949575B2/en not_active Expired - Fee Related
- 2001-04-25 EP EP01928832A patent/EP1284958B1/en not_active Expired - Lifetime
- 2001-04-25 AU AU2001255646A patent/AU2001255646A1/en not_active Abandoned
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5658904A (en) * | 1989-02-14 | 1997-08-19 | Toyama Chemical Co., Ltd. | 1,2-ethanediol derivative and salt thereof and cerebral function-improving agent comprising the same |
EP0535496A1 (en) * | 1991-09-25 | 1993-04-07 | Hoechst-Roussel Pharmaceuticals Incorporated | (1-Indanon-2yl)methylpiperidines, intermediates and a process for their preparation and their use as medicaments |
EP0538134A2 (en) * | 1991-10-16 | 1993-04-21 | Teva Pharmaceutical Industries, Ltd. | Mono-fluorinated derivatives of N-propargyl-1-aminoindan and their use as inhibitors of monoamine oxidase |
US6001331A (en) * | 1996-01-24 | 1999-12-14 | Warner-Lambert Company | Method of imaging amyloid deposits |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007522077A (en) * | 2003-08-21 | 2007-08-09 | アクセス ファーマシューティカルズ, インコーポレイテッド | Liquid formulations for prevention and treatment of mucosal diseases and disorders |
WO2008099210A2 (en) | 2007-02-12 | 2008-08-21 | Merck & Co., Inc. | Piperazine derivatives for treatment of ad and related conditions |
CN104870422A (en) * | 2012-10-31 | 2015-08-26 | 富山化学工业株式会社 | Novel amine derivative or salt thereof |
EP2915804A4 (en) * | 2012-10-31 | 2016-06-08 | Toyama Chemical Co Ltd | Novel amine derivative or salt thereof |
US9624215B2 (en) | 2012-10-31 | 2017-04-18 | Toyama Chemical Co., Ltd. | Amine derivative or salt thereof |
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EP1284958A1 (en) | 2003-02-26 |
ES2248315T3 (en) | 2006-03-16 |
MXPA02009948A (en) | 2003-02-12 |
CA2405611A1 (en) | 2001-11-08 |
ATE304522T1 (en) | 2005-09-15 |
BR0110519A (en) | 2003-04-08 |
JP2003531883A (en) | 2003-10-28 |
AU2001255646A1 (en) | 2001-11-12 |
US6949575B2 (en) | 2005-09-27 |
DE60113407D1 (en) | 2005-10-20 |
DE60113407T2 (en) | 2006-06-29 |
EP1284958B1 (en) | 2005-09-14 |
US20030220382A1 (en) | 2003-11-27 |
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