EP1192144A1 - Derives de la rhodanine et leur utilisation pour l'inhibition et la mise en images d'amyloides - Google Patents

Derives de la rhodanine et leur utilisation pour l'inhibition et la mise en images d'amyloides

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Publication number
EP1192144A1
EP1192144A1 EP00939472A EP00939472A EP1192144A1 EP 1192144 A1 EP1192144 A1 EP 1192144A1 EP 00939472 A EP00939472 A EP 00939472A EP 00939472 A EP00939472 A EP 00939472A EP 1192144 A1 EP1192144 A1 EP 1192144A1
Authority
EP
European Patent Office
Prior art keywords
thioxo
benzylidene
thiazolidin
oxo
methyl
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Withdrawn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
EP00939472A
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German (de)
English (en)
Inventor
Corinne Elizabeth Augelli-Szafran
Shelly Ann Glase
Terri Stoeber Purchase
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Warner Lambert Co LLC
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Warner Lambert Co LLC
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Publication date
Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of EP1192144A1 publication Critical patent/EP1192144A1/fr
Withdrawn legal-status Critical Current

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    • 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
    • C07D417/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • 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
    • C07D417/10—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 aromatic rings

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 amyloid aggregation disorders such as Alzheimer's disease using substituted 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-associated protein, and the presence of amyloid deposits has been shown in various diseases, each with its particular associated protein, such as Mediterranean fever, Muckle-associated protein, and the like.
  • 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 (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
  • the present invention provides compounds having the Formula I: or a pharmaceutically acceptable salts thereof, wherein:
  • Z is hydrogen, Cj-Cg alkyl, C3-C8 cycloalkyl, C ⁇ -Cg perfluoroalkyl, C2-Cg alkenyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, -OH, -OCi-Cg alkyl, -SCi-Cg alkyl,-SO 3 H, -CO 2 H, -CO 2 C ⁇ -Cg alkyl,
  • Ri and R2 are independently C ⁇ -Cgalkyl or -(CH2) n -C3-C6cycloalkyl,
  • R- and R 4 independently are hydrogen, Cj-Cg alkyl, -(CH2) n -phenyl, or
  • R5 is hydrogen, Cj-Cg alkyl, halogen, or -CF3; each m is 2 to 8 inclusive;
  • X is -S-OH, -S-NR 3 R 4 , -SNHC(C ⁇ -C ⁇ perfluoroalkyl), tetrazolyl,
  • Ri is methyl and R2 is pentyl or hexyl. Also preferred are compounds of Formula I wherein X* and X ⁇ both are hydrogen.
  • the / group is located at the para position on the aryl ring, for example
  • Ri and R ⁇ are taken together with the nitrogen to which they are attached to form a cyclic structure.
  • R ⁇ is -(CH2) n -C3-C6 cycloalkyl or -(CH2) n -phenyl when R 1 is Ci-Cg alkyl.
  • Especially preferred compounds are benzylidenes of Formula II wherein n, ⁇ l, X ⁇ , and X are as defined above.
  • the present invention provides the compounds:
  • a pharmaceutical composition comprising a compound of Formula I together with a pharmaceutically acceptable diluent, excipient, or carrier therefor.
  • a method of treating Alzheimer's disease comprising administering to a patient having Alzheimer's disease a therapeutically effective amount of a compound of Formula I.
  • a method of inhibiting the aggregation of amyloid proteins to form amyloid deposits comprising administering to a patient in need of inhibition of the aggregation of amyloid proteins 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 radiolabeled compound.
  • the labeled compound is detected using MRI.
  • 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.
  • alkoxy means an alkyl group 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, -CF 3 , -NO 2 , -NH2, -NH(Cj-C 6 alkyl), -N(C ⁇ -C6alkyl)2, Cj-Cg alkyl, -OCj-C ⁇ alkyl, -CN, -CF 3 , -CO 2 H, and -CO 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.
  • substituents 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, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • esters of the compounds of this invention include Cj-C ⁇ 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. C]-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 C ] -C6 alkyl amines and secondary Cj-Cg 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.
  • the term "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 Delivery Systems. Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • 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.
  • 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 antifiingal 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 as for example, cetyl alcohol and glycerol monostearate
  • a) fillers or extenders as for example, starches, lactose, sucrose, glucose, mannito
  • 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 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, 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, 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.
  • 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.
  • 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.
  • 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 11 C or 1 8 F.
  • a suitable label in a compound of Formula I is an atom such as 13 c, l ⁇ N, or 1"F 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.
  • detection is electron paramagnetic resonance (EPR).
  • EPR probes which are well-known in the art, such as nitroxides, can be used.
  • 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- Wells syndrome, idiopathetic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Alzheimer's disease, Down's syndrome,
  • the radioisotope can be any radioisotope. However ⁇ H, 1 3 ⁇ 125 ⁇ 131 ? 13 and 1 °F a re preferred. Those skilled in the art are familiar with the procedure used to introduce a radioisotope into a compound. For example, compounds of
  • Formula I wherein one carbon atom is ⁇ C are readily prepared by standard method in organic chemistry.
  • 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. For a normal human adult having a body weight of about 70 kg, 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. For example, 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 examples presented below are intended to illustrate particular embodiments of the invention and are not intended to limit the scope of the specification, including the claims, in any manner.
  • the compounds of the present invention can be generally prepared as illustrated in Scheme 1 below.
  • appropriately substituted amino benzaldehydes are commercially available or are prepared by reacting 4-fluorobenzaldehyde with an amine in the presence of a base such as potassium carbonate in a solvent such as dimethylacetamide or dimethylformamide.
  • N-substituted rhodanines that are not commercially available are 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.
  • Other methods of preparing invention compounds will be readily available to those skilled in organic chemistry.
  • Step A Hexylmethyl amine (10 g, 86.8 mmol), 4-fluorobenzaldehyde (8.0 mL,
  • reaction mixture is warmed to room temperature and stirred for 18 hours then concentrated to dryness.
  • This dithiocarbamate is added slowly to a cold (0°C) solution of sodium chloroacetate (8.5 g, 75 mmol) in water (25 mL) made basic with sodium carbonate.
  • the reaction mixture is warmed to room temperature and poured into a warm (70°C) HCl solution (160 mL, 5 M) and heated to 90°C for
  • Ethyl chloroformate (0.23 mL, 2.42 mmol) is dissolved in anh. tetrahydrofuran (10 mL) and cooled to 0°C under N2.
  • a solution of ⁇ 5-[4-(hexyl- methyl-amino)-benzylidene]-4-oxo-2-thioxo-thiazolidin-3-yl ⁇ -acetic acid (0.50 g, 1.27 mmol) and triethylamine (0.32 mL, 2.29 mmol) in anh. tetrahydrofuran (30 mL) is added dropwise. Stirred 2 hours at 0°C, then allowed to warm to room temperature.
  • Example 6 was prepared according to Example 5, except that [5-(4- dipentylamino-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl] -acetic acid is substituted for ⁇ 5-[4-(hexyl-methyl-amino)-benzylidene]-4-oxo-2-thioxo- thiazolidin-3-yl ⁇ -acetic acid, mp 134-138°C. Elemental analysis calculated for C23H33N3O4S3X2.OCH3OH: Calculated: C, 52.15; H, 7.18; N, 7.30. Found: C, 52.36; H, 7.05; N, 6.97.
  • Example 7 was prepared according to Example 5, except that trifluoromethanesuflonamide is substituted for methanesulfonamide, mp 94-97°C. Elemental analysis calculated for C20H24F3N3O4S3XI .OCgH ⁇ N: Calculated: C,
  • Example 8 (Z) N- ⁇ 5-[4-(Dipentylamino-benzylidene)-4-oxo-2-thioxo-thiazoIidin-3-yl]- acetyl ⁇ -C,C,C-trifluoro-methanesulfonamide
  • Example 8 was prepared according to Example 6, except that trifluoromethanesuflonamide is substituted methanesulfonamide, mp 286-288°C. Elemental analysis calculated for C23H30F3N3O4S3: Calculated: C, 48.83; H, 5.35; N, 7.43. Found: C, 47.03; H, 4.90; N, 7.12.
  • Example 9 was prepared according to Example 5, except benzenesulfonamide is substituted for methanesulfonamide, mp 173-177°C. Elemental analysis calculated for C25H29N3O4S3XO.33H2O: Calculated: C, 55.85; H, 5.56; N, 7.82. Found: C, 55.81; H, 5.48; N, 7.59.
  • Triethylamine (0.12 mL, 0.83 mmol) is added to (Z) N-(2- ⁇ 5-[4-(hexyl- methyl-amino)-benzylidene]-4-oxo-2-thioxo-thiazolidin-3-yl ⁇ -ethyl)-amine
  • Example 11 (Z) N-(2- ⁇ 5-[4-(Hexyl-methyl-amino)-benzylidene]-4-oxo-2-thioxo-thiazolidin- 3-yl ⁇ -ethyl)-benzenesulfonamide
  • Example 11 was prepared according to Example 10, except benzenesulfonyl chloride is substituted for methanesulfonyl chloride, mp 152-155°C. Elemental analysis calculated for C25H31N3O3S3: Calculated: C,
  • Example 12 was prepared according to Example 10, except trifluoromethanesulfonyl chloride is substituted for methanesulfonyl chloride, mp 170-173°C. Elemental analysis calculated for C20H26F3N3O3S3: Calculated:
  • Rhodanine-3 -ethyl acetamide was prepared according to Example 1, Step B, except acetyl ethylenediamine is substituted for 2-aminoethane sulfonic acid.
  • Example 14 was prepared according to Example 1, Step C, except rhodanine-3 -ethyl acetamide is substituted for rhodanine-3 -ethyl sulfonic acid, mp 137-140°C. Elemental analysis calculated for C2]H29N ⁇ 2S2 : Calculated: C, 60.11 ; H, 6.97; N, 10.01. Found: C, 60.38; H, 7.06; N, 10.01.
  • Step A Phthalimide (19.5 g, 0.132 mol) is suspended in anhydrous DMF (80 mL) under N2- Potassium t-butoxide (17.8 g, 0.159 mol) is added slowly and the suspension stirred at room temperature for 10 minutes. Chloracetonitrile (10.1 mL, 0.159 mol) is then added and the mixture stirred overnight. Methanol (50 mL) is added and the mixture is concentrated in vacuo. The phthalimide acetonitrile is purified by MPLC ( 100% CH2CI2) to give 16.0 g of white crystalline solid.
  • Step D lH-tetrazol-5-ylmethyl-2-thioxo-thiazolidin-4-one was prepared from the tetrazole methyl amine as previously described in Example 1, Step B.
  • Example 18 (Z) N- ⁇ [5-(4-Dibutylamino-benzy lidene)-4-oxo-2-thioxo-thiazolidin-3-y 1] - acetyl ⁇ -C,C,C-trifluoro-methanesulfonamide. mp 228-230°C. MS 538 (M+).
  • Example 22 (Z) N- ⁇ 2-[5-(4-Dipentylamino-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- acetylj-benzenesulfonamide. mp 121-123°C.
  • Example 26 (Z) 2-[5-(4-Dibutylamino-benzyIidene)-4-oxo-2-thioxo-thiazolidin-3-yI]- ethanesulfonic acid 4-fluoro-benzoylamide. mp 191 - 192°C.
  • Example 28 (Z) 2-[5-(4-Dibutylamino-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- ethanesulfonic acid benzoylamide. mp 183°C.
  • Example 31 (Z) 2-[5-(4-Dipentylamino-benzylidene)-4-oxo-2-thioxo-thiazoIidin-3-yl]- ethanesulfonic acid 4-fluoro-benzoylamide. mp 195-196°C.
  • Triphenylphosphine (3.53 g, 13.45 mmol) is slowly added to the kojic acid azide (1.5 g, 8.97 mmol) in THF (20 mL). The evolution of gas is immediate. Water (0.8 mL) is added and the reaction heated to 55°C for 18 hours. The reaction mixture is cooled and solids are collected and washed with diethyl ether.
  • Example 38 (Z) 4-Fluoro-N-(2- ⁇ 5-[(4aS,8aR)-4-(octahydro-isoquinolin-2-yl)-benzylidene]- 4-oxo-2-thioxo-thiazoIidin-3-yl ⁇ -acetyl)-benzenesuIfonamide. mp 220-221 °C.
  • Example 39 (Z) 4-Fluoro-N-(2- ⁇ 4-oxo-5-[4-(4-propyl-piperidin-l-yI)-benzylidene]-2- thioxo-thiazolidin-3-yl ⁇ -acetyl)-benzenesulfonamide. mp 197°C. MS 562 (M + ).
  • Example 40 (Z) 2-[5-(4-HexyI-methyl-amino-benzylidene)-4-oxo-2-thioxo-thiazolidin-3- yl] -ethanesulfonic acid 4-fluoro-benzoylamide.
  • Example 48 (Z) 2- ⁇ 5-[4-(Octahydro-isoquinolin-2-yl)-benzylidene]-4-oxo-2-thioxo- thiazolidin-3-yl ⁇ S-ethanesulfonic acid methylamide
  • Example 49 (Z) 2- ⁇ 5- [4-(Octahydro-isoquinolin-2-y l)-benzylidene] -4-oxo-2-thioxo- thiazolidin-3-yl ⁇ S-ethanesulfonic acid trifluoroacetylamide
  • Example 56 (Z) N-2- ⁇ 4-Oxo-5-[4-(4-propyl-piperidin-l-yI)-benzylidene]-2-thioxo- thiazolidin-3-yl ⁇ -ethanesulfonic acid 4-fluoro-benzoylamide
  • Example 57 (Z) 2-[5-(4-Hexyl-methyl-benzylidene)-4-oxo-2-thioxo-thiazolidin-3-yl]- ethanesulfonic acid 4-fluoro-benzoylamide
  • Representative compounds of Formula I have been evaluated in the following standard in vitro and in vivo assays which are commonly used to indicate clinical utility in inhibiting amyloid formation and to treat diseases associated with amyloid, such as Alzheimer's disease.
  • BASSR Beta-Amyloid Self-Seeding Radioassav
  • Soluble A ⁇ (l-40) peptide (Bachem, Torrance, CA) - 2.2 mg/mL in deionized H2O
  • 125 ⁇ _ ⁇ a b e ⁇ ec ⁇ A ? (1-40) 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.
  • Final assay conditions 30 ⁇ M soluble A ?(l-40) in deionized water in assay buffer + 20-50K cpm 125 ⁇ _ ⁇ a beled A ? (1-40) per assay.
  • Compound to be tested is dissolved in dimethylsulfoxide (DMSO), typically 5-50 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 ⁇ (1-40) in deionized water in assay buffer.
  • Compound to be tested is dissolved in DMSO, typically 5-50 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 ⁇ (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 A ⁇ (1-40) 675 ⁇ L assay buffer
  • 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.
  • the purpose of this assay is to provide a higher volume method of assaying the amount of beta 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.
  • a ⁇ (l-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
  • 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.
  • Activity of the invention compounds is also evaluated in standard in vivo assays commonly used to evaluate agents to treat diseases related to aggregation of amyloid proteins, especially Alzheimer's disease. Such assays are described by Axelrad et al., Lab. Invest., 1982;47(2):139-146; and by Stenstad et al., J. Biochem., 1994;303(Pt 2):663-670.
  • 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. On Day 12, 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.
  • mice Another in vivo assay in which the invention compounds are evaluated uses transgenic mice.
  • the mice bear a human ⁇ -amyloid precursor protein transgene with a prior promoter and are described by Hsiao et al., "Correlative
  • 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 sterate 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 protein aggregation and treatment of Alzheimer's disease.
  • EXAMPLE 64 EXAMPLE 64
  • Example 26 In a solution of 700 mL of propylene glycol and 200 mL of water for injection is added 20.0 g of Compound No. 26) (from 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 Compound No. 26), and sealed under nitrogen. The solution is administered by injection to a patient suffering from medullary carcinoma of the thyroid and in need of treatment.

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Abstract

L'invention concerne une méthode permettant de traiter la maladie d'Alzheimer au moyen d'un composé représenté par la formule (I). L'invention concerne également une méthode permettant d'inhiber l'agrégation d'amyloïdes au moyen d'un composé représenté par la formule (I) ainsi qu'une méthode permettant de mettre en images des dépôts d'amyloïdes au moyen de dérivés substitués de la rhodanine.
EP00939472A 1999-06-10 2000-05-31 Derives de la rhodanine et leur utilisation pour l'inhibition et la mise en images d'amyloides Withdrawn EP1192144A1 (fr)

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WO2003094916A1 (fr) * 2002-05-10 2003-11-20 Qlt Inc. Procedes d'utilisation de derives de thiazolidine dans le traitement du cancer ou de l'inflammation
US20060281798A1 (en) * 2002-05-17 2006-12-14 Qlt Inc. Methods of using thiazolidinedithione derivatives
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
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US20100041653A1 (en) * 2008-08-15 2010-02-18 Burnham Institute For Medical Research Composition and methods for the design and development of metallo-enzyme inhibitors
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