[go: up one dir, main page]

EP1192143A1 - Rhodanine derivatives for use in a method of inhibiting amyloid protein aggregation and imaging amyloid deposits - Google Patents

Rhodanine derivatives for use in a method of inhibiting amyloid protein aggregation and imaging amyloid deposits

Info

Publication number
EP1192143A1
EP1192143A1 EP00938021A EP00938021A EP1192143A1 EP 1192143 A1 EP1192143 A1 EP 1192143A1 EP 00938021 A EP00938021 A EP 00938021A EP 00938021 A EP00938021 A EP 00938021A EP 1192143 A1 EP1192143 A1 EP 1192143A1
Authority
EP
European Patent Office
Prior art keywords
oxo
thioxo
thiazolidin
benzylidene
acetic acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00938021A
Other languages
German (de)
English (en)
French (fr)
Inventor
Corinne Elizabeth Augelli-Szafran
Shelly Ann Glase
Lary Craswell Walker
Tomoyuki Yasunaga
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Lambert Co LLC
Original Assignee
Yamanouchi Pharmaceutical Co Ltd
Warner Lambert Co LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yamanouchi Pharmaceutical Co Ltd, Warner Lambert Co LLC filed Critical Yamanouchi Pharmaceutical Co Ltd
Publication of EP1192143A1 publication Critical patent/EP1192143A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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, for example to treat Alzheimer's disease using rhodanine 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's 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.
  • 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.
  • 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 (ie, density and water content) as normal tissues. Attempts to image amyloid deposits directly using magnetic resonance imaging (MRJ) 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. Thus, it would be useful to have a noninvasive technique for imaging and quantitating amyloid deposits in a patient. In addition, it would be useful to have compounds that inhibit the aggregation of amyloid proteins to form amyloid deposits.
  • US Patent Number 5,523,314 relates to rhodanine compounds useful as hypoglycemic agents and for treating Alzheimer's disease.
  • the presently claimed compounds can be distinguished from the compounds disclosed in the patent because the patent does not provide for R.2 to be -(CH2) n -C3-C6 cycloalkyl, -(CH2) m -phenyl, or for Rl and R ⁇ together with the nitrogen atom of Formula I to be a cyclic structure.
  • the specific compounds disclosed in the present application show unexpectedly superior activity when compared with the specific compounds disclosed in the 5,523,314 patent. Representative examples in the 5,523,314 patent were tested in the BASST and BASSR assay set forth below with the following results.
  • Compounds of the present invention comprise both a nitrogen atom substituted with Rl and R ⁇ attached to a cyclic or bicyclic group and a -CO2H group attached to a rhodanine group. None of the compounds exemplified in the 5,523,314 patent contain both functional groups. Additionally, the invention compounds are potent inhibitors of amyloid formation in the above assays.
  • the present invention provides compounds of the Formula I
  • Z is hydrogen, Cj-Cg alkyl, C3-C8 cycloalkyl, Cj-Cg perfluoroalkyl, C2-Cg alkenyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, -OH, -OC1 -Cg alkyl, -SCi-Cg alkyl,-SO 3 H, -CO 2 H, -CO 2 C ⁇ -Cg alkyl,
  • Rl and R ⁇ are independently Cj-Cgalkyl or -(CH2) n -C3-C6cycloalkyl,
  • R ⁇ and R ⁇ independently are hydrogen, Cj-Cg alkyl, -(CH2) n -phenyl, or
  • R ⁇ is hydrogen, Cj-Cg alkyl, halogen or -CF3; and each m is 2 to 8 inclusive.
  • a preferred group of compounds are benzylidene derivatives of Formula II
  • R ⁇ , R ⁇ , ⁇ l, ⁇ 2, and n are as defined above.
  • Another preferred group of compounds are naphthalenylmethylene derivatives of Formula III
  • Rl, RX, ⁇ X ⁇ , X- and n are as defined above.
  • Still another preferred group of compounds are quinolinylmethylene derivatives of Formula IV
  • the group -NR1R2 is located at the para position of the aromatic ring portion of X, for example 4-aminophenyl.
  • compounds of Formula I where X has the Z geometry on the double bond. Also preferred are compounds of Formula I wherein R ⁇ is (CH2) n -C3-C6 cycloalkyl or -(CH2) n phenyl when Rl is Cj-Cg alkyl.
  • the compounds of Formula I are:
  • the invention also provides pharmaceutical formulations comprising a compound of Formula I admixed with a pharmaceutically acceptable diluent, excipient, or carrier therefor.
  • Also provided is a method of inhibiting the aggregation of amyloid proteins to form amyloid deposits comprising administering to a patient in need of inhibition of amyloid protein aggregation an amyloid protein aggregation inhibiting amount of a compound of Formula I.
  • 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 radiolabled compound.
  • the labeled compound is detected using MRI.
  • composition comprising a compound of Formula I.
  • alkyl means a straight or branched chain hydrocarbon.
  • Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyi, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, and hexyl.
  • Preferred alkyl groups are Cj-Cg alkyl.
  • alkoxy means an alkyl group such as C ⁇ -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.
  • substituted means that one or more hydrogen atom in a molecule has been replaced with another atom or group of atoms.
  • substituents include halogen, -OH, -CF3, -NO2, -NH2, -NH(C ⁇ -C6alkyl), -N(C 1 -C 6 alkyl) 2 , C1-C6 alkyl, -OC!-C 6 alkyl, -CN, -CF3, -CO 2 H, and -CO 2 C!-C6 alkyl.
  • 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.
  • salts 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, laurate, 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, tetramethylammomum, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • esters of the compounds of this invention examples include Cj-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 Cj-Cg alkyl amines and secondary C1-C6 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amides and C1-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.
  • a thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Deliverv Systems, Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche,
  • 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 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.
  • suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles 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.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • 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
  • Solid 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 poly ethylenegly cols, 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, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyi 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, and 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, solub
  • 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 magnetic resonance imaging
  • PET 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 ! ! C or 1 8 F.
  • a suitable label in a compound of Formula I is an atom such as 13c, I ⁇ N, or 19p which can be detected using magnetic resonance imaging (MRI) which is also sometimes called nuclear magnetic resonance (NMR).
  • MRI magnetic resonance imaging
  • 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 disease or condition in which amyloid proteins aggregate.
  • diseases and conditions include Mediterranean fever, Muckle-
  • idiopathetic myeloma amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Alzheimer's disease, Down's 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.
  • 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 ⁇ H, 123 ; lj 5 131 s 1 I an( ⁇
  • a radioisotope into a compound.
  • compounds of Formula I wherein the COOH group is replaced by 11 COOH are readily prepared.
  • 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.
  • 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.
  • 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 I below illustrates a typical method for making starting materials and the final products of Formula I.
  • the invention compounds are generally prepared by reacting a substituted rhodanine with an aldehyde such as benzaldehyde.
  • Appropriately substituted amino benzaldehydes are prepared by reacting 4-fluorobenzaldehyde with an amine (HNR1R2) in the presence of a base such as potassium carbonate or sodium hydroxide. The reaction generally is carried out in a solvent such as dimethylacetamide or dimethylformamide. Many of the aryl aldehydes are commercially available.
  • N-substituted rhodanines also are commercially available, or they can be prepared by condensing carbon disulfide and chloroacetic acid with the appropriate amine.
  • the compounds of the present invention can be prepared by condensation of an appropriately N-substituted rhodanine with an appropriately substituted aromatic aldehyde in refluxing glacial acetic acid in the presence of sodium acetate.
  • W is COOH or an ester group such as CO2CH2PI .
  • Example 2 was prepared according to Example 1, except that dibutylaminobenzaldehyde is substituted for diethylaminobenzaldehyde; mp 268-269°C. Elemental analysis calculated for C2()H26N2 ⁇ 3S2-0.25 H2O: Calculated: C, 58.44; H, 6.50; N, 6.82. Found: C, 58.04; H, 6.40; N, 6.44.
  • Example 3 was prepared according to Example 1, except that dipropylaminobenzaldehyde is substituted for diethylaminobenzaldehyde; mp 233°C. Elemental analysis calculated for Ci 8H22 2O3S2: Calculated: C, 57.12;
  • Example 4 [5-(4-Diisobutylamino-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- acetic acid
  • Example 4 was prepared according to Example 3, except that diisobutylamine is substituted for dipropylamine in Step A; mp 234°C. Elemental analysis calculated for C2 ⁇ H26N2 ⁇ 3S -0.1 H 2 0: Calculated: C, 58.82; H, 6.75; N, 6.86. Found: C, 58.43; H, 6.25; N, 6.57.
  • Example 5 [5-(4-Dipentylamino-benzyIidene)-4-oxo-2-thioxo-thiazoIidin-3-yl]-acetic acid
  • Example 5 was prepared according to Example 3, except that dipentylamine is substituted for dipropylamine in Step A; mp 195-196°C.
  • Example 6 was prepared according to Example 3, except that diisoamylamine is substituted for dipropylamine in Step A; mp 257°C. Elemental analysis calculated for C22H3()N2 ⁇ 3S2-0.15 H2O: Calculated: C, 60.42; H, 6.98; N, 6.41. Found: C, 60.06; H, 6.83; N, 6.23.
  • Example 7 was prepared according to Example 3, except that hexamethyleneimine is substituted for dipropylamine in Step A; mp 275°C. Elemental analysis calculated for C ⁇ H2()N2 ⁇ 3S2: Calculated: C, 57.42; H, 5.35;
  • Example 8 [5-(4-Dihexylamino-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]-acetic acid
  • Example 8 was prepared according to Example 3, except that dihexylamine is substituted for dipropylamine in Step A; mp 152-153°C. Elemental analysis calculated for C24H34N2O3S2: Calculated: C, 62.30; H, 7.41; N, 6.05. Found: C, 62.05; H, 7.31; N, 5.87.
  • Example 9 (Z) ⁇ 5-[4-(MethyI-octyl-amino)-benzylidene]-4-oxo-2-thioxo-thiazolidin-3-yl ⁇ - acetic acid
  • Example 9 was prepared according to Example 3, except that N-methyl-N- octylamine is substituted for dipropylamine in Step A; mp 203-204°C. Elemental analysis calculated for C21H28N2O3S2: Calculated: C, 59.97; H, 6.71; N, 6.66. Found: C, 59.90; H, 6.62; N, 6.50.
  • Example 10 was prepared according to Example 3, except that perhydroisoquinoline is substituted for dipropylamine in Step A; mp 234°C. Elemental analysis calculated for C21H24N2O3S2: Calculated: C, 60.55; H, 5.81; N, 6.72. Found: C, 60.40; H, 5.82; N, 6.60.
  • Example 11 was prepared according to Example 3, except that N-propylcyclopropanemethylamine is substituted for dipropylamine in Step A; mp 289°C. Elemental analysis calculated for C19H22N2O3S2: Calculated: C, 58.44;
  • Example 12 (Z) ⁇ 5- [4-(Hexyl-methyl-amino)-benzylidene] -4-oxo-2-thioxo-thiazolidin- 3-yl ⁇ -acetic acid
  • Example 12 was prepared according to Example 3, except that
  • Example 13 was prepared according to Example 3, except that N-methylphenethylamine is substituted for dipropylamine in Step A; mp
  • Example 14 was prepared according to Example 3, except that 3-azaspiro(5.5)undecane is substituted for dipropylamine in Step A; mp 265°C. Elemental analysis calculated for C22H26 N 2°3 S 2 : Calculated: C, 61.37; H, 6.09; N, 6.51. Found: C, 61.37; H, 6.13; N, 6.42.
  • Example 15 was prepared according to Example 2, except that N-carboxyethylrhodanine is substituted for rhodanine-3 -acetic acid; mp 164-165°C. Elemental analysis calculated for C21H28N2O3S2: Calculated: C,
  • Example 16 (Z) ⁇ 5-[4-(ButyI-methyI-amino)-benzylidene]-4-oxo-2-thioxo-thiazolidin-3-yI ⁇ - acetic acid
  • Example 16 was prepared according to Example 3, except that
  • N-methylbutylamine is substituted for dipropylamine in Step A; mp 223 °C. Elemental analysis calculated for C17H20 2O3S2: Calculated: C, 56.02; H, 5.53; N, 7.69. Found: C, 56.33; H, 5.56; N, 7.66. WO 00/76987 PCT/USOO/l 5069
  • Example 17 was prepared according to Example 3, except that N-ethylbutylamine is substituted for dipropylamine in Step A; mp 206°C.
  • Example 18 was prepared according to Example 3, except that N-benzylbutylamine is substituted for dipropylamine in Step A; mp 205°C. Elemental analysis calculated for C23H24N2O3S2: Calculated: C, 62.70; H, 5.49; N, 6.36. Found: C, 63.10; H, 5.51; N, 6.28.
  • Example 19 was prepared according to Example 3, except that dioctylamine is substituted for dipropylamine in Step A; mp 140-145°C. Elemental analysis calculated for C28H42N2O3S2: Calculated: C, 64.83; H, 8.16;
  • Example 20 was prepared according to Example 12, except that rhodanine- 3-butyric acid is substituted for rhodanine-3 -acetic acid; mp 147-150°C.
  • Example 21 was prepared according to Example 1 except that 4-( «- hexylmethylamino)benzaldehyde and N-carboxyethylrhodanine are used; mp 169-173°C. Elemental analysis calculated for C2()H26N2 ⁇ 3S2-0.21 H2O:
  • Example 22 was prepared according to Example 1 except 4-(dipentylamino)benzaldehyde and N-carboxyethylrhodanine are used; mp 127-130°C. Elemental analysis calculated for C23H32N2O3S2-0.27 H2O:
  • Example 23 was prepared according to Example 20 except 4-(dibutylamino)benzaldehyde is substituted for 4-( «-hexylmethylamino)- benzaldehyde; mp 145-148°C. Elemental analysis calculated for C22H30N2O3S2: Calculated: C, 60.80; H, 6.96; N, 6.45. Found: C, 60.59; H, 6.88; N, 6.33.
  • Example 24 was prepared according to Example 20 except 4-(dipentylamino)benzaldehyde is substituted for 4-( «-hexylmethylamino)- benzaldehyde; mp 132-133°C. Elemental analysis calculated for C24H34N2O3S2: Calculated: C, 62.30; H, 7.41; N, 6.05. Found: C, 62.10; H, 7.28; N, 5.85.
  • Example 25 was prepared according to Example 20 except dl-alanine is substituted for ethyl-4-aminobutyrate in Step A and 4-(dibutylamino)- benzaldehyde is substituted for 4-( «-hexylmethylamino)benzaldehyde in Step B; mp 168-169°C. Elemental analysis calculated for C21H28N2O3S2: Calculated: C, 59.97; H, 6.71; N, 6.66. Found: C, 60.11; H, 6.93; N, 6.76.
  • Example 26 was prepared according to Example 20 except dl-phenylalanine is substituted for ethy-4-aminobutyrate in Step A and 4-(dibutylamino)benzaldehyde is substituted for 4-( «-hexylmethylamino)- benzaldehyde in Step B; mp 205°C. Elemental analysis calculated for C27H32N2O3S2T.OC2H4O2: Calculated: C, 62.56; H, 6.52; N, 5.03. Found: C, 62.72; H, 6.69; N, 5.11.
  • Example 27 was prepared according to Example 20 except dl-histidine is substituted for ethyl-4-aminobutyrate in Step A and 4-(dibutylamino)- benzaldehyde is substituted for 4-( «-hexylmethylamino)benzaldehyde in Step B; mp 280-281°C. Elemental analysis calculated for C24H30N4O3S2: Calculated: C, 59.23; H, 6.21; N, 11.51. Found: C, 59.02; H, 6.09; N, 11.30.
  • Step A N-Methylhexylamine (6.5 mL, 43.0 mmol), 4-fluoro-l-naphthaldehyde
  • the resulting oil is purified by medium pressure liquid chromatography (MPLC) on silica gel eluting with 5% ethyl acetate/hexane to give 5.94 g of 4-( «-hexylmethylamino)- 1-naphthaldehyde as a yellow oil.
  • MPLC medium pressure liquid chromatography
  • Step B Example 28 was prepared according to Example 1 except that 4-( «- hexylmethylamino)-l-naphthaldehyde is substituted for diethylaminobenzaldehyde; mp 132°C. Elemental analysis calculated for C23H26 2O3S2: Calculated: C, 62.42; H, 5.92; N, 6.33. Found: C, 62.65; H, 5.99; N, 6.12. WO 00/76987 PCT/USOO/l 5069
  • Example 38 (Z) ⁇ 4-Oxo-5-[4-(4-propyl-piperidin-l-yl)-benzyIidene]-4-oxo-2-thioxo- thiazolidin-3-yl ⁇ -butyric acid, mp 181°C, MS 433 (M+).
  • Phosphorus oxychloride (1.57 mL, 16.8 mmol) is added dropwise to DMF (2.0 mL), and the mixture is stirred at room temperature for 15 minutes. To this mixture is added dropwise 1 -butyl- 1,2,3, 4-tetrahydro-quinoline (2.65 g, 14 mmol) in DMF (2.3 mL) over a period of 10 minutes. After the initial exothermic reaction ceases, the mixture is heated to 60°C for 20 minutes then poured onto ice (50 g). To the mixture is added IN NaOH (120 mL), and the resulting heterogeneous mixture is stirred vigorously for 10 minutes and extracted with EtOAc.
  • Step D 1 -Butyl- 1 ,2,3 ,4-tetrahydro-quinoline-6-carboxaldehyde is reacted with rhodanine-3 -acetic acid as previously described to obtain Example 39 as a purple solid; mp 222-224°C, MS 391 (M + ).
  • Example 41 (Z) 4- ⁇ 5- [(4aS,8aR)-4-(Octahy dro-isoquinolin-2-y l)-benzylidene] -4-oxo-2- thioxo-thiazolidin-3-yl ⁇ -butyric acid, mp 186°C, MS 445 (M + ).
  • Example 44 4-[4-Oxo-5-(4-perhydro-azepin-l-yl-benzylidene)-2-thioxo-thiazolidin-3- yl]-butyric acid, mp 185°C, MS 405 (M + ).
  • Example 45 (Z) 4- ⁇ 5-[(4aS,8aS)-4-(Octahydro-isoquinoIin-2-yl)-benzylidene]-4-oxo-2- thioxo-thiazolidin-3-yl ⁇ -butyric acid, mp 173°C, MS 445 (M + ).
  • Phosphorus oxychloride (0.69 mL, 7.14 mmol) is added dropwise to DMF (1.09 mL), and the mixture is stirred at room temperature for 15 minutes. To this mixture is added dropwise 1-butylindoline (1.18 g, 6.74 mmol) in DMF (1.0 mL) over a period of 10 minutes. After the initial exothermic reaction ceases, the mixture is heated to 60°C for 20 minutes then poured onto ice. To the mixture is added IN NaOH (80 mL), and the resulting heterogeneous mixture is stirred vigorously for 10 minutes and extracted with EtOAc. The organic layer is washed with water and brine, dried (MgSO4), and concentrated in vacuo.
  • the resulting oil is purified by medium pressure liquid chromatography (MPLC) on silica gel eluting with 5% ethyl acetate/hexane to give 0.792 g of 1 -butylindoline- 5-carboxaldehyde as a yellow oil.
  • MPLC medium pressure liquid chromatography
  • Step B l-Butylindoline-5-carboxaldehyde is reacted with rhodanine-3-acetic acid as previously described to obtain Example 52 as a solid; mp >250°C, MS 377
  • Example 60 (Z) 3-[4-Oxo-5-(4-azocan-l-yl-benzylidene)-2-thioxo-thiazolidin-3- yl]propionic acid, mp 224°C, MS 405 (M + ).
  • Example 65 (Z) 4- ⁇ 5-[4-(4-HexyI-piperidin-l-yl)-benzylidene]-4-oxo-2-thioxo-thiazoIidin- 3-yl ⁇ -butyric acid, mp 192-193°C, MS 475 (M + ).
  • BIOLOGICAL EXAMPLES Invention compounds of Formula I have been 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.
  • Soluble A ⁇ ( 1-40) peptide (Bachem, Torrance, CA) - 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.
  • 125j_ ⁇ a b e ⁇ e( i A ?(l-40) 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.
  • -37- Final assay conditions 30 ⁇ M soluble A/? (1-40) in deionized water in assay buffer + 20K to 50K cpm 125 I-labeled A ⁇ (1-40) per assay.
  • Compound to be tested is dissolved in dimethylsulfoxide (DMSO), typically 5 to 50 mM stock, such that the final concentration of DMSO is ⁇ 1% v/v in the assay.
  • DMSO dimethylsulfoxide
  • Reaction mixture for 50 assays (on ice) is comprised of 0.1-0.2 ⁇ L of
  • reaction mixture 1) Prepare reaction mixture above by mixing components and storing on ice.
  • Soluble A ⁇ (1-40) - 2.2 mg/mL in deionized H2O (store 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.
  • Final assay conditions 30 ⁇ M soluble A ⁇ X-4i)) 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 A ⁇ X-4J) + 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.
  • Assay Method 1 Prepare the reaction mix above by mixing the components and storing on ice.
  • This assay is used to provide a measure of inhibition by a compound against the aggregation behavior of the beta amyloid peptide.
  • HFIP hexafluoroisopropanol
  • a ⁇ (1-42) (California Peptide) was dried from its hexafluoroisopropanol (HFIP) stock solution.
  • the A ⁇ (1-42) was dissolved in dimethylsulfoxide (DMSO) and then mixed with phosphate buffered saline (PBS)
  • the mixed A ⁇ (1-42) solution was filtered with a 0.2 ⁇ m Omnipore membrane syringe filter (Millipore, Bedford, MA).
  • the compound to be tested in DMSO 50 times concentrate was put into each well (0.5 ⁇ L/well) of a 96-well plate.
  • 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).
  • Thioflavin T (ThT) (30 ⁇ M) solution in glycine-NaOH buffer (pH 8.5, 50 mM) was added into each well (250 ⁇ L/well), fluorescence was measured (ex. 440/20 nm, em; 485/20 nm) using a fluorescence plate reader.
  • 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 IC5o's were calculated by a curve fitting program using the following equation. The data were obtained from two different experiments in triplicate.
  • Inhibition(x) 100-100/ ⁇ l+(x/IC 50 ) n ⁇ .
  • x concentration of tested compound (M).
  • IC 50 (M).
  • n Hill coefficient.
  • Representative compounds of Formula I have exhibited inhibitory activities (IC50) ranging from about 0.1 ⁇ M to greater than 100 ⁇ M in the foregoing assays.
  • IC50 inhibitory activities
  • the results of these assays for specific representative compounds of the present invention are shown in the table below.
  • the invention compounds have also shown good activity in standard in vivo mouse assays commonly used to evaluate agents to treat diseases related to aggregation of amyloid proteins, especially Alzheimer's disease.
  • assays are WO 00/76987 PCT/USOO/l 5069
  • 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 11. Test compounds are administered to the mice daily starting on Day 1 through Day 11.
  • mice Another in vivo assay in which the invention compounds have been 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,"
  • 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 evaluated in this model have shown good inhibition of amyloid accumulation in the cortex and hippocampus relative to untreated controls.
  • 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 26 In a solution of 700 mL of propylene glycol and 200 mL of water for injection is added 20.0 g of the compound of Example 26. The mixture is stirred and the pH is adjusted to 5.5 with hydrochloric acid. The volume is adjusted to 1000 mL with water for injection. The solution is sterilized, filled into 5.0 mL ampoules, each containing 2.0 mL (40 mg of Example 26), 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.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Hospice & Palliative Care (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Psychiatry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
EP00938021A 1999-06-10 2000-05-31 Rhodanine derivatives for use in a method of inhibiting amyloid protein aggregation and imaging amyloid deposits Withdrawn EP1192143A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US13854499P 1999-06-10 1999-06-10
US138544P 1999-06-10
PCT/US2000/015069 WO2000076987A1 (en) 1999-06-10 2000-05-31 Rhodanine derivatives for use in a method of inhibiting amyloid protein aggregation and imaging amyloid deposits

Publications (1)

Publication Number Publication Date
EP1192143A1 true EP1192143A1 (en) 2002-04-03

Family

ID=22482512

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00938021A Withdrawn EP1192143A1 (en) 1999-06-10 2000-05-31 Rhodanine derivatives for use in a method of inhibiting amyloid protein aggregation and imaging amyloid deposits

Country Status (8)

Country Link
EP (1) EP1192143A1 (pt)
JP (1) JP2003502320A (pt)
AU (1) AU5311800A (pt)
BR (1) BR0011441A (pt)
CA (1) CA2374616A1 (pt)
MX (1) MXPA01010490A (pt)
TR (1) TR200103562T2 (pt)
WO (1) WO2000076987A1 (pt)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PE20020394A1 (es) 2000-08-18 2002-06-21 Agouron Pharma Compuestos de pirazol y composiciones farmaceuticas que los contienen, que modulan y/o inhiben la actividad de erab/hadh2
JP2006510661A (ja) 2002-12-06 2006-03-30 ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー Ｐｉ３ｋの阻害剤としてのベンズオキサジン−３−オン類及びその誘導体
WO2005007123A2 (en) * 2003-07-18 2005-01-27 Pintex Pharmaceuticals, Inc. Pin1-modulating compounds and methods of use thereof
WO2008099210A2 (en) 2007-02-12 2008-08-21 Merck & Co., Inc. Piperazine derivatives for treatment of ad and related conditions
CN103402516B (zh) 2010-06-17 2018-01-30 富津世生物技术有限公司 用作抗病毒药物的化合物、组合物及使用方法
CN106045986B (zh) * 2016-05-31 2019-12-06 广东工业大学 一种新型吩噻嗪衍生物及其制备方法与应用
CN106045987B (zh) * 2016-06-21 2019-04-23 广东工业大学 一种具有多功能近红外荧光磁性纳米微粒及其制备和应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000010573A1 (en) * 1998-08-21 2000-03-02 Viropharma Incorporated Compounds, compositions and methods for treating or preventing viral infections and associated diseases

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5740478A (en) * 1980-08-22 1982-03-06 Ono Pharmaceut Co Ltd Rhodanine derivative, its preparation and aldose reductase inhibitor containing rhodanine derivative
JPH01147462A (ja) * 1987-12-03 1989-06-09 Mita Ind Co Ltd 電荷発生材料およびその製法
JPH01147476A (ja) * 1987-12-03 1989-06-09 Mita Ind Co Ltd 光導電性トナー
US5143929A (en) * 1991-05-09 1992-09-01 Warner-Lambert Company 2-substituted thiazolidinone, oxazolidinone, and imidazolidinone derivatives of fenamates as antiinflammatory agents
IL106877A (en) * 1992-09-10 1998-03-10 Lilly Co Eli Rodinin derivatives for use as drugs for the treatment of Alzheimer's disease
DE4318550A1 (de) * 1993-06-04 1994-12-08 Boehringer Mannheim Gmbh Aryliden-4-oxo-2-thioxo-3- thiazolidincarbonsäuren, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel
US6251928B1 (en) * 1994-03-16 2001-06-26 Eli Lilly And Company Treatment of alzheimer's disease employing inhibitors of cathepsin D
AU1529297A (en) * 1996-01-24 1997-08-20 Warner-Lambert Company Method of imaging amyloid deposits
WO2000018747A1 (en) * 1998-09-30 2000-04-06 Roche Diagnostics Gmbh Rhodanine carboxylic acid derivatives for the treatment and prevention of metabolic bone disorders

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000010573A1 (en) * 1998-08-21 2000-03-02 Viropharma Incorporated Compounds, compositions and methods for treating or preventing viral infections and associated diseases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO0076987A1 *

Also Published As

Publication number Publication date
WO2000076987A1 (en) 2000-12-21
TR200103562T2 (tr) 2002-04-22
MXPA01010490A (es) 2005-05-27
JP2003502320A (ja) 2003-01-21
AU5311800A (en) 2001-01-02
CA2374616A1 (en) 2000-12-21
BR0011441A (pt) 2002-07-16

Similar Documents

Publication Publication Date Title
EP1192131B1 (en) Method of inhibiting amyloid protein aggregation and imaging amyloid deposits using isoindoline derivatives
US6001331A (en) Method of imaging amyloid deposits
WO2007110629A1 (en) Inhibitors of protein aggregation
US6949575B2 (en) Method of inhibiting amyloid protein aggregation and imaging amyloid deposits using aminoindane derivatives
WO2005016888A1 (ja) アミロイド蓄積性疾患のプローブ、アミロイド染色剤、アミロイド蓄積性疾患の治療および予防薬、ならびに神経原線維変化の診断プローブおよび染色剤
WO2000076987A1 (en) Rhodanine derivatives for use in a method of inhibiting amyloid protein aggregation and imaging amyloid deposits
WO2000076988A1 (en) Rhodanine derivatives and their use in inhibiting and imaging amyloids
US6972287B1 (en) Method of inhibiting amyloid protein aggregation and imaging amyloid deposits
US20040180943A1 (en) Oxazolone analogs as amyloid aggregation inhibitors and for the treatment of alzheimer's disease and disorders related to amyloidosis
EP1193260B1 (en) Phenoxazine analogs for the treatment of amyloidosis
US20040197268A1 (en) Method of imaging amyloid deposits using substituted rhodanine derivatives

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20020110

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

17Q First examination report despatched

Effective date: 20030115

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: WARNER-LAMBERT COMPANY LLC

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20060208