EP1225886A2 - Procede d'inhibition de l'agregation de proteines amyloides et de formation d'images de depots amyloides - Google Patents

Procede d'inhibition de l'agregation de proteines amyloides et de formation d'images de depots amyloides

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Publication number
EP1225886A2
EP1225886A2 EP00939471A EP00939471A EP1225886A2 EP 1225886 A2 EP1225886 A2 EP 1225886A2 EP 00939471 A EP00939471 A EP 00939471A EP 00939471 A EP00939471 A EP 00939471A EP 1225886 A2 EP1225886 A2 EP 1225886A2
Authority
EP
European Patent Office
Prior art keywords
phenylamino
phenyl
benzoic acid
ethyl
dichloro
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Withdrawn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
EP00939471A
Other languages
German (de)
English (en)
Inventor
Corinne Elizabeth Augelli-Szafran
Mark Robert Barvian
Christopher Franklin Bigge
Shelly Ann Glase
Shunichiro Hachiya
John Steven Keily
Takenori Kimura
Yingjie Lai
Annette Theresa Sakkab
Mark James Suto
Lary Craswell Walker
Tomoyuki Yasunaga
Nian Zhuang
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 EP1225886A2 publication Critical patent/EP1225886A2/fr
Withdrawn legal-status Critical Current

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/64—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring the carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
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Definitions

  • This invention relates to a method of inhibiting amyloid protein aggregation and imaging amyloid deposits. More particularly, this invention relates to a method of inhibiting amyloid protein aggregation in order to treat Alzheimer's disease.
  • 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
  • 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 (i.e., density and water content) as normal tissues. Attempts to image amyloid deposits directly using magnetic resonance imaging (MRI) and computer-assisted tomography (CAT) have been disappointing and have detected amyloid deposits only under certain favorable conditions. In addition, efforts to label amyloid deposits with antibodies, serum amyloid P protein, or other probe molecules has provided some selectivity on the periphery of tissues, but has provided for poor imaging of tissue interiors. 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.
  • MRI magnetic resonance imaging
  • CAT computer-assisted tomography
  • the present invention provides a method of treating Alzheimer's disease, the method comprising administering to a patient having Alzheimer's disease a therapeutically effective amount of a compound of Formula I wherein
  • R a is hydrogen, C ⁇ -Cg alkyl, or -CC ⁇ -C ⁇ alkyl; n is 0 to 5 inclusive;
  • Rl, R ⁇ , R3, R4 5 R5 5 R6 ? and R7 r e independently hydrogen, halogen
  • -CH CH-phenyl, -O(CH 2 ) p NR b R c , -CNR b R c , -NHCR b , -NH(CH 2 ) p NR b RC, -N(C 1 -C 6 alkyi ⁇ CH 2 ) p NR b RC,
  • R 8 is COOH, tetrazolyl, -SO 2 R d , or -CONHSO 2 R d ;
  • R b and R c are independently hydrogen, -C ⁇ -C alkyl, -(CH2) m -phenyl, or
  • R D and R c taken together with the nitrogen atom to which they are attached form a cyclic ring selected from piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-Cj-C6 alkylpiperazinyl, morpholino, thiomo holino, decahydroisoquinoline, or pyrazolyl;
  • R d is hydrogen, -C ⁇ -C alkyl, -CF3, or phenyl; m is 0 to 5 inclusive; p is 1 to 5 inclusive; A is CH orN; R! and R2, when adjacent to one another, can be methylene-dioxy; or the pharmaceutically acceptable salts thereof.
  • the n group is attached at the 4-position of the phenyl ring.
  • R a is hydrogen; n is 2;
  • R3 and R 4 are hydrogen.
  • R a is hydrogen
  • R! is halo
  • R2 is hydrogen or halo
  • R3, R 4 , R5. and R ⁇ are hydrogen
  • n is 2 to 5 inclusive.
  • R a is hydrogen; n is 2 or 3;
  • R 1 is -NR b R c ;
  • R 2 , R 3 , R 4 , R5, and R 7 all are hydrogen.
  • R 2 , R 3 , R 4 , R5, and R 7 all are hydrogen.
  • R a is hydrogen; n is 2;
  • R3 and R4 are hydrogen
  • R a is hydrogen; n is 3, 4, or 5;
  • R3 and R 4 are hydrogen
  • Rl, R 2 , and R 7 are independently chlorine or hydrogen.
  • R a is hydrogen; n is 2;
  • R3 and R 4 are hydrogen
  • R 5 , R 6 , and R 8 are independently hydrogen, -CO2H, -NO2, -OCH3, O
  • R a is hydrogen; n is 2;
  • R and R 4 are hydrogen; and R 5 is -CO 2 H. Also preferred is a method of treating Alzheimer's disease, the method comprising administering to a patient having Alzheimer's disease a therapeutically effective amount of a compound of Formula I
  • R a is hydrogen; n is 1 to 5 inclusive;
  • R3 and R4 are hydrogen
  • R 1 , R 7 , and R 2 are independently chlorine, -N(CH2CH3) 2 , -OH, CH3-, fluorine, -CF3, phenyl, hydrogen, -OCH 2 phenyl,
  • R 5 and R 6 are independently hydrogen, -CO2H, -NO 2 , -OCH3, imidazolyl, -CN, fluorine, -CH3, -CF3, or pyrrolyl; or the pharmaceutically acceptable salts thereof.
  • compounds of Formula I are 2- ⁇ 4-[2-(3 ,4-Dichlorophenyl)ethyl]phenylamino ⁇ -benzoic acid; 2- ⁇ 4-[2-(3,4-Dichloro-phenyl)-ethyl]phenylamino ⁇ -5-nitrobenzoic acid;
  • the invention also provides the foregoing compounds wherein the benzoic acid portion is replaced with a pyridyl carboxylic acid, for example, 4-[4-(3,4- dichlorophenyl)phenylamino]-3-hydroxycarbonylpyridine.
  • a pyridyl carboxylic acid for example, 4-[4-(3,4- dichlorophenyl)phenylamino]-3-hydroxycarbonylpyridine.
  • R a is hydrogen, Cj-Cg alkyl, or -CCj-C alkyl; n is 0 to 5 inclusive;
  • Rl, R 2 , R3, R4, R5 5 R6 5 and R? are independently hydrogen, halogen,
  • -CH CH-phenyl, -O(CH 2 ) p NR R c , -CNR b R c , -NHCR b , -NH(CH 2 ) p NR b R C , -N(C j -C 6 alkyl)(CH 2 ) p NR b R c ,
  • R8 is COOH, tetrazolyl, -SO R d or -CONHSO 2 R d ;
  • R and R c are independently hydrogen, -Cj-Cg alkyl, -(CH 2 ) m -phenyl, or
  • R b and R c taken together with the nitrogen atom to which they are attached form a cyclic ring selected from piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-Cj-C6 alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline, or pyrazolyl;
  • R d is hydrogen, -Cj-Cg alkyl, -CF3, or phenyl; m is 0 to 5 inclusive; p is 1 to 5 inclusive;
  • A is CH orN
  • R! and R 2 when adjacent to one another, can be methylene-dioxy; or the pharmaceutically acceptable salts thereof.
  • R a is hydrogen; n is 2; and
  • R3 and R4 are hydrogen.
  • R a is hydrogen; R3 and R are hydrogen; and n is 2 to 5 inclusive.
  • R a is hydrogen; n is 3, 4, or 5; R3 and R 4 are hydrogen; and
  • Rl, R 2 , and R 7 are independently chlorine or hydrogen.
  • R a is hydrogen; n is 2; R3 and R 4 are hydrogen; and
  • R 5 and R 6 are independently hydrogen, -CO 2 H, -NO 2 , -OCH3, imidazolyl, -CN, fluorine, -CH3, -CF3, halogen,
  • R a is hydrogen; n is 2;
  • R3 and R 4 are hydrogen
  • R 5 is -CO2H.
  • R a is hydrogen; n is 1 to 5 inclusive;
  • R3 and R 4 are hydrogen
  • R 5 and R 6 are independently hydrogen, -CO2H, -NO 2 , -OCH3, imidazolyl, -CN, fluorine, -CH3, -CF3, or pyrrolyl; R 8 is COOH or tetrazolyl; or the pharmaceutically acceptable salts thereof.
  • R! is halo
  • R 2 is H or halo; and n and R ⁇ are as defined above in Formula I.
  • R! is halo
  • R 2 is H or halo; and n and R" are as defined above in Formula I.
  • R! is halo
  • R 2 is H or halo; and n and R ⁇ are as defined above in Formula I.
  • the present invention also provides the compounds:
  • Typical 2- and 3-substituted compounds are:
  • compositions of the novel compounds admixed with a pharmaceutically acceptable diluent, carrier, or excipient are also provided.
  • Also provided is a method of imaging amyloid deposits comprising: introducing into a patient a detectable quantity of a labeled compound having the Formula I or a pharmaceutically acceptable salt thereof:
  • R a is hydrogen, C ⁇ -C6 alkyl, or -CCi-Cg alkyl; n is 0 to 5 inclusive;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, -OH, -NH 2 , NR b R C , -CO 2 H, -CO 2 C!-C 6 alkyl, -
  • -CH CH-phenyl, -O(CH 2 ) p NR b R c , -CNR b R c , -NHCR b , -NH(CH 2 ) p NR b R C , -N(C ] -C 6 alkyl)(CH 2 ) p NR b R c ,
  • R 8 is COOH, tetrazolyl, -SO 2 R d , or -CONHSO 2 R d ;
  • R and R c are independently hydrogen, -Cj-Cg alkyl, -(CH 2 ) m - phenyl, or R b and R c taken together with the nitrogen atom to which they are attached form a cyclic ring selected from piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C ⁇ -Cg alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline, or pyrazolyl;
  • R d is hydrogen, -Ci-Cg alkyl, -CF3, or phenyl; m is 0 to 5 inclusive; p is 1 to 5 inclusive;
  • A is CH or N
  • R! and R 2 when adjacent to one another, can be methylene-dioxy; or the pharmaceutically acceptable salts thereof; 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 radio labeled compound.
  • the labeled compound is detected using MRI.
  • the present invention also provides the preferred compounds: 2- ⁇ 4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino ⁇ -benzoic acid;
  • alkyl means a straight or branched chain hydrocarbon having from 1 to 12 carbon atoms.
  • Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, hexyl, octyl, decyl, and 1,1-dimethyloctyl.
  • Preferred alkyl groups are Cj-Cg alkyl, and especially C1-C6 alkyl.
  • alkoxy means an alkyl group attached to an oxygen atom.
  • Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy.
  • Preferred alkoxy groups are Cj-C ⁇ alkoxy, and especially C ⁇ -C alkoxy.
  • 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, especially chloro, -OH, -CF3, -NO2, -NH 2 , -NH(C!-C 6 alkyl), -N(C!-C 6 alkyl) 2 , C ⁇ Cg alkyl, -OC!-C 6 alkyl, -CN, -CF3,
  • 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.
  • Typical "substituted phenyl” groups include 4-chlorophenyl, 3,4-dibromophenyl, 3-fluoro-4-methylphenyl,
  • Substituent groups represented by R , R 3 , and R ⁇ include amino(NR b R c ) and acylamino (-NHCOR b ).
  • R b and R c can be hydrogen, alkyl and phenylalkyl and substituted phenylalkyl, and typical NR b R c groups include methylamino, diethylamino, isobutyl-propylamino, benzylamino, and 3,4- dimethoxybenzylamino.
  • Examples of acylamino groups include formamido, acetamido, 2-phenylacetamido, and 2-(3-nitrophenyl)acetamido.
  • R ⁇ , R 3 , and R5 can also be aminoalkoxy (-O(CH2) p NR b R c ) such as N-methylaminomethoxy and 2-(N-benzylamino)ethoxy, as well as aminoalkylamino (-NH(CH2) p NR b R c ) such as 3-(dimethylamino)propylamino and 2-(N-ethyl-N-benzylamino)ethylamino.
  • Substituent groups such as Rl, R 3 , and R ⁇ additionally can be cyclic structures, for instance when NR b R c is part of the substituent group, and R b and R c are taken together with the nitrogen to which they are attached to form a cyclic ring selected from imidazole, pyrrole, piperidine, piperazine, 4-Cj-C6 alkylpiperazine, morpholine, thiomorpholine, pyrazole, and decahydroisoquinoline.
  • benzyl such as 2-trifluoromethylbenzyloxy and 4-aminobenzyloxy.
  • pharmaceutically acceptable salt, ester, amide, and prodrug refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • salts refers to the relatively nontoxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laureate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate 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.
  • ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like See, for example, Berge S.M., et al., Pharmaceutical Salts, J. Pharm. Sci., 66:1-19 (1977) which is incorporated herein by reference.
  • esters of the compounds of this invention examples include Cj-C6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C 7 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, for example by reacting a carboxylic acid of Formula I with an alcohol such as ethanol or benzyl alcohol.
  • Examples of pharmaceutically acceptable, nontoxic amides of the compounds of this invention include amides derived from ammonia, primary C ⁇ -C alkyl amines and secondary C ⁇ -C 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
  • 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. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • the compounds of the present invention can exist in different stereoisometric forms by virtue of the presence of asymmetric centers in the compounds. It is contemplated that all stereoisometric forms of the compounds, as well as mixture thereof, including racemic mixtures, form part of this invention.
  • a labeled compound of Formula I is introduced into a tissue or a patient in a detectable quantity.
  • the compound is typically part of a pharmaceutical composition and is administered to the tissue or the patient by methods well-known to those skilled in the art.
  • a compound in the methods of the present invention, can be administered either orally, rectally, parenterally (intravenous, by intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments or drops), or as a buccal or nasal spray.
  • Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • a coating such as lecithin
  • surfactants for example, water, alcohol, alcohol, and the like.
  • compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • isotonic agents for example sugars, sodium chloride, and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid;
  • binders as for example, carboxymethylcellulose, alginates, 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
  • lubricants as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof.
  • the dosage forms may also comprise buffering agents.
  • 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, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3 -butyl eneglycol, 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, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, eth
  • the 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.
  • 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.
  • 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.
  • association 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 1 3 C, l ⁇ N, 0 r l" which can be detected using magnetic resonance imaging (MRI) which is also sometimes called nuclear magnetic resonance
  • MRI magnetic resonance imaging
  • the labeled compounds of Formula I may also be detected by MRI using paramagnetic contrast agents.
  • Another example of detection is electron paramagnetic resonance (EPR).
  • EPR electron paramagnetic resonance
  • 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, 3 H, 123 L 125 ⁇ 131 T ; 11 and l 8 F are preferred. Those skilled in the art are familiar with the procedure used to introduce a radioisotope into a compound. For example, a compound of Formula I wherein one carbon atom is ⁇ C or ⁇ C is 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. 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, however, 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 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.
  • Schemes 6 through 9 show synthetic routes that can be used to obtain the desired starting amines (IV), (VIII), (XV), and (XXI).
  • Scheme 2 depicts the synthesis of amine (NIII) which contains a three methylene tether. Condensation of aldehyde (I) and nitro-ketone (N) in the presence of sodium hydroxide gives the desired alpha, beta-unsaturated ketone, which upon standard hydrogenation conditions (Raney nickel) gives (Nil) and then Wolff-Kishner conditions yields the desired amine (VIII).
  • Scheme 3 is very similar to Scheme 2, except that the aldehyde (I) is condensed with a substituted aniline (IX).
  • Scheme 4 illustrates standard Wittig conditions in which the starting materials (XII) and (XIII) are obtained via aldol condensation and ylide chemistry, respectively.
  • Standard reduction conditions e.g., Raney nickel
  • (XIN) yields the desired amine (XV).
  • Scheme 5 illustrates the synthesis of amine (XXI) which contains a 5-methylene tether. Wittig reaction of the bromophosporane (XVII), which is formed from the corresponding substituted bromide (XVI), and nitro aldehyde
  • Scheme 6 illustrates one route to obtain compounds of Formula I. Either by Buchwald coupling (Method A) followed by saponification or utilizing the
  • Protecting groups will also be used when reactive functional groups such as amino and carboxylic acids are present, so as to avoid unwanted side reactions.
  • Carboxy groups typically are converted to esters (e.g., tert-butyl, benzyl), and amino groups generally are acylated (e.g., acetyl or trimethylsilyl).
  • esters e.g., tert-butyl, benzyl
  • amino groups generally are acylated (e.g., acetyl or trimethylsilyl).
  • Scheme 7 illustrates the synthesis of compounds of Formula I by reacting amines such as (IN), (NIII), and (XXI) with fluoro-nitro intermediate (XXIN), in the presence of a base (e.g., LHMDS or Et3 ⁇ ) to give ester (XXV).
  • a base e.g., LHMDS or Et3 ⁇
  • ester can then be saponified using standard conditions, such as sodium hydroxide.
  • amine (XV) can be coupled with readily available fluoro- substituted carboxylic acids [e.g., (XXVI) or (XXNII)] in the presence of various bases (such as DBU or triethylamine) to yield compounds of Formula I.
  • fluoro- substituted carboxylic acids e.g., (XXVI) or (XXNII)
  • bases such as DBU or triethylamine
  • Scheme 9 depicts coupling of amine (VIII) with readily available methyl ester (XXVIII) in the presence of a base, such as imidazole, to give ester (XXIX). This ester can then be saponified as usual to give compounds of Formula I.
  • Scheme 10 illustrates the synthesis of fluoro-intermediate (XXIV) which is obtained by nitration of readily available methyl ester (XXX) to give (XXVIII). Treatment of (XXVIII) with potassium cyanide gives (XXIV).
  • Scheme 11 the synthesis of compounds related to Example 18 is illustrated. Reaction of the potassium salts of ortho-substituted benzoic acids (XXVI) with substituted anilines (XXVII) in the presence of potassium carbonate and cupric acetate yields various iodo-substituted aminobenzoic acids (XXVIII). Reaction of (XXVIII) with substituted boronic acids and palladium chloride gives the desired substituted aminobenzoic acids (XXX).
  • the benzoic acids are readily converted to esters and amides, as well as salts and other prodrugs by routine processes.
  • the benzoic acid can be reacted with oxalylchloride to form the acid chloride, which then readily reacts with a sulfonamide such as methanesulfonamide to produce the corresponding invention compound where R 8 is -CONHSO 2 CH3.
  • a sulfonamide such as methanesulfonamide
  • R is an ester forming group such as alkyl or benzyl.
  • Step A (Scheme 1): Preparation of l,2-Dichloro-4-[2-(4-nitrophenyl)ethenyl]- benzene A mixture ofp-nitrophenylacetic acid (51.23 g, 0.28 mol) and
  • Step B (Scheme 1): Preparation of 4-[2-(3,4-Dichlorophenyl)ethyl]benzenamine A sample of l,2-dichloro-4-[2-(4-nitrophenyl)ethenyl]benzene (98.0 g,
  • Step C (Scheme 6): Preparation of 2- ⁇ 4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino ⁇ -benzoic acid
  • Example 1 An orange solid (31.95 g, 0.083 mol, 77.6%). mp 175.0-177.0°C.
  • Example 1 An orange solid (2.3 g, 0.006 mol, 17.5%). mp 165.0-173.0°C. Analysis for C2iH 17 N 1 O 2 Cl2: Calcd: C, 65.30; H, 4.44; N, 3.63.
  • Step C (Scheme 6): Preparation of 2- ⁇ 4-[2-(3,4-Dichloro-phenyl)- ethyl]phenylamino ⁇ -5-nitrobenzoic acid methyl ester
  • Step A (Scheme 1): Preparation of l,2-Dimethoxy-4-[2-(4-nitrophenyl)ethenyl]- benzene The title compound was prepared from /.-nitrophenylacetic acid (25.0 g,
  • Step B (Scheme 1): Preparation of 4-[2-(3,4-Dimethoxy-phenyl)ethyl]- phenylamine l,2-Dimethoxy-4-[2-(4-nitrophenyl)ethenyl]benzene (12.1 g, 0.042 mol) was reduced in the presence of 10% Pd-C (2.0 g) in dimethylformamide (DMF) (120 mL) at 25°C under a hydrogen atmosphere. The reaction mixture was concentrated in vacuo to give a solid. The solid was recrystallized from MeOH (400 mL) to yield a white crystalline product, 6.8 g (0.026 mol, 63%) of the desired product, mp 115-116°C.
  • DMF dimethylformamide
  • Step C (Scheme 6): Preparation of 2- ⁇ 4-[2-(3,4-Dimethoxy-phenyl)ethyl]- phenylamino ⁇ benzoic acid
  • the title compound was prepared from 4-[2-(3,4-dimethoxy-phenyl)- ethyl]phenylamine (9.25 g, 0.036 mol), 2-chlorobenzoic acid (5.2 g, 0.036 mol), anhydrous potassium carbonate (15.0 g, 0.11 mol), copper powder (0.45 g,
  • Step D Preparation of 2- ⁇ 4-[2-(3,4-Dihydroxy-phenyl)-ethyl]-phenylamino ⁇ - benzoic acid
  • Step A (Scheme 1): Preparation of l,l-Dibutylamino-4-[2-(4- nitrophenyl)ethenyl]benzene
  • Step B (Scheme 1): Preparation of 4-[2-(4,4-Dibutylaminophenyl)ethyl]- phenylamine
  • Step C (Scheme 6): Preparation of 2- ⁇ 4-[2-(4-Dibutylamino-phenyl)- ethyljphenylamino ⁇ -benzoic acid
  • Step A (Scheme 1): Preparation of l,2,3-Trimethoxy-5-[2-(4- nitrophenyl)ethenyl]benzene
  • the title compound was prepared from .-nitrophenylacetic acid (18.6 g,
  • Step B (Scheme 1): Preparation of 4-[2-(3,4,5-Trimethoxy-phenyl)ethyl]- phenylamine
  • Step C (Scheme 6): Preparation of 2- ⁇ 4-[2-(3,4,5-Trimethoxy-phenyl)- ethyl]phenylamino ⁇ -benzoic acid methyl ester
  • Step D Preparation of 2- ⁇ 4-[2-(3,4,5-Trihydroxyphenyl)ethyl]phenylamino ⁇ - benzoic acid
  • the title compound was prepared from 2- ⁇ 4-[2-(3,4,5-trimethoxy-phenyl)- ethyljphenylamino ⁇ benzoic acid (0.50 g, 1.23 mmol) in CH2C-2 (40 mL) and
  • Step A (Scheme 1): Preparation of trans - 1 -Chloro-2-trifluoromethyl-4-[2-(4- nitrophenyl)ethenyl]benzene
  • Step B (Scheme 1): Preparation of 4-[2-(4-Chloro-3-trifluoromethylphenyl)ethyl]- benzenamine
  • This procedure yielded a white solid, 20.0 g (66.73 mmol, 97%) of the desired product, mp 62-64°C.
  • EXAMPLE 28 2- ⁇ 4-[3-(3 -Dimethylaminophenyl)propyl]phenylamino ⁇ benzoic acid. mp l l5-117°C.
  • EXAMPLE 38 2- ⁇ 4-[2-(3-Dibutylaminophenyl)ethyl]phenylamino ⁇ benzoic acid monohydrochloride. mp 175- 180°C.
  • EXAMPLE 54 2- ⁇ 4-[3-(3 -Piperidin- 1 yl-phenyl)-propyl] -phenylamino ⁇ -benzoic acid, mp 59-61°C.
  • EXAMPLE 58 4- ⁇ 5- [( 1 -Butyl- 1 ,2,3 ,4-tetrahydroquinolin-6-yl)methylidene]-4-oxo-2-thioxo- thiazolidin-3-yl ⁇ butanoic acid, mp 152-154°C. MS: 417 (M"l+), 418 (M+), 419 (M+1+).
  • EXAMPLE 64 5-Amino-2- ⁇ 4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino ⁇ -benzoic acid was prepared by reacting the product from Example 2 with hydrogen gas in the presence of Raney nickel, mp 137-142°C.
  • EXAMPLE 68 ⁇ 4- [2-(3 ,4-Dichloro-phenyl)-ethyl] -phenyl ⁇ - [2-( 1 H-tetrazol-5 -yl)-phenyl] -amine was prepared as described in Example 1 , using a tetrazole fluoro intermediate that was synthesized from commercially available 2-fluorobenzonitrile and sodium azide under standard reaction conditions, mp 129 shrink, 152-157°C.
  • a Distriman pipet is used to add 1 mL (0.15 mmol, 1 eq) of each halo benzoate solution to the appropriate vials containing 1 mL (0.18 mmol, 1.2 eq) of the aniline reactants.
  • a catalyst solution is prepared by dissolving 0.025 M of
  • Typical compounds prepared by this method are as follows. The structure of the compounds are generally confirmed by mass spectral analysis.
  • EXAMPLE 84 2-(3',5'-Dibromo-3-methyl-biphenyl-4-ylamino)-benzoic acid MS: 459; MW: 461.1515.
  • EXAMPLE 85 -(4- 1 ,3-Benzodioxol-5-yl-2-methyl-phenylamino)-benzoic acid S: 347; MW: 347.3683.
  • EXAMPLE 105 4- ⁇ 4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino ⁇ -nicotinic acid
  • EXAMPLE 106 2-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-2,3-dihydro-lH-isoindol-5-ylamino]- benzoic acid
  • EXAMPLE 120 2- ⁇ 4- [2-(3 ,4-Dichloro-phenyl)-ethyl] -phenylamino ⁇ -benzoate-2 -hydroxy- 1 , 1 -bis- hydroxymethyl-ethyl-ammonium; mp 185-187°C.
  • EXAMPLE 124 2- ⁇ 3-[2-(3,4-Dimethyl-phenyl)-ethyl]-phenylamino ⁇ -benzoic acid; mp 182- EXAMPLE 125 - ⁇ 4-[2-(2,4-Dimethoxy-phenyl)-ethyl]-phenylamino ⁇ -benzoic acid; mp 180- 181°C.
  • EXAMPLE 130 2- ⁇ 4-[2-(2,4-Dichloro-phenyl)-ethyl]-phenylamino ⁇ -benzoic acid; mp 181-183°C.
  • EXAMPLE 132 4- ⁇ 4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino ⁇ -benzoic acid; mp 214-215°C.
  • EXAMPLE 134 2- ⁇ 4-[2-(4-Phenoxy-phenyl)-ethyl]-phenylamino ⁇ -benzoic acid; mp 153-154°C.
  • EXAMPLE 135 2- ⁇ 4-[5-(3,4-Dichloro-phenyl)-pentyl]-phenyl--mino ⁇ -benzoic acid; mp 106- 108°C.
  • EXAMPLE 138 4- ⁇ 4-[3 -(3 ,4-Dichloro-phenyl)-propyl] -phenylamino ⁇ -2-methoxy-5-nitro-benzoic acid; mp 74-78°C.
  • EXAMPLE 142 N-(2- ⁇ 4-[3-(3,4-Dichloro-phenyl)-propyl]-phenylamino ⁇ -benzoyl)- benzenesulfonamide; MS 539.
  • EXAMPLE 143 2- ⁇ 4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino ⁇ -5-trifluoromethyl-benzoic acid; mp 190-192°C. MS 453 (M" 1 ).
  • EXAMPLE 150 5-Dibutylamino-2- ⁇ 4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino ⁇ -benzoic acid;
  • Examples 158-163 illustrate the use of invention compounds as starting materials and intermediates in the synthesis of other invention compounds and derivatives.
  • the examples illustrate reduction of nitro groups to amino groups, alkylation of amino group, and esterification of carboxylic acid groups. These reactions are depicted in the following generalized
  • R D and R c are as defined above, and E is an ester forming group such as Cj-C6 alkyl (e.g., methyl, 2,2,2-trichloroethyl), benzyl, diphenylmethyl, or the like.
  • Cj-C6 alkyl e.g., methyl, 2,2,2-trichloroethyl
  • benzyl e.g., benzyl, diphenylmethyl, or the like.
  • EXAMPLE 162 2- ⁇ 4- [3 -(4-Diethylaminophenyl)propyl]phenylamino ⁇ benzoic acid methyl ester (1.68 g, 4.03 mmol) in EtOH (50 mL) was added aqueous 3 M-KOH solution (4.0 mL, 12.0 mmol) at room temperature, then the mixture was allowed to heat under reflux for 40 minutes. The reaction mixture was cooled to room temperature and neutralized with aqueous 1.0 M-HCl solution to pH 9.0. The mixture was concentrated under reduced pressure to remove EtOH, and the resulting aqueous solution was extracted with CHCI3 (50 mL, 3 times).
  • Representative compounds of Formula I have been evaluated in several in vitro and in vivo assays which are well-established as indicative of clinical usefulness in treating Alzheimer's disease.
  • Soluble A ⁇ (l -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.
  • 125i-i a beled A/? (1-40) can be made in accordance with the procedure set forth by H. LeNine, III in Neurobiol. Aging, 16, 755, (1995), which is hereby incorporated by reference, or this reagent may be purchased from Amersham, Arlington
  • reaction mixture 1) Prepare reaction mixture above by mixing components and storing on ice. 2) Pipet 14.5 ⁇ L of reaction mixture into each of 50 wells on a polypropylene
  • RESULTS Materials: Stock Solutions: Assay Buffer - 50 mM sodium phosphate, pH 7.5, 100 mM NaCl, 0.02% NaN3,
  • 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 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 ⁇ (l-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.
  • 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) (pH 7.4).
  • 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 ⁇ 1-42; final concentration 100 ⁇ M).
  • Inhibition (%) ⁇ (F(A ⁇ )-F(A ⁇ +compound) ⁇ / ⁇ F(A ⁇ )-F(solvent + compound) ⁇ x 100
  • the IC50S were calculated by a curve fitting program using the following equation. The data were obtained from two different experiments in triplicate.
  • Representative compounds of Formula I have exhibited inhibitory activities (IC50) ranging from 0.1 ⁇ M to greater than 100 ⁇ M in the foregoing assays.

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Abstract

La présente invention se rapporte à un procédé de traitement de la maladie d'Alzheimer à l'aide d'un composé représenté par la formule (I). Elle se rapporte également à un procédé d'inhibition de l'agrégation de protéines amyloïdes à l'aide d'un composé représenté par la formule (I) et à un procédé de formation d'images de dépôts amyloïdes, ainsi qu'à de nouveaux composés représentés par la formule (I).
EP00939471A 1999-06-10 2000-05-31 Procede d'inhibition de l'agregation de proteines amyloides et de formation d'images de depots amyloides Withdrawn EP1225886A2 (fr)

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WO2001070667A1 (fr) * 2000-03-22 2001-09-27 Bf Research Institute, Inc. Sonde de diagnostic par image, a base d'azobenzene substitue ou d'un analogue de celui-ci, pour les maladies imputables a l'accumulation d'amyloide et composition pour le diagnostic par image le contenant
CA2357450A1 (fr) * 2000-09-29 2002-03-29 Warner-Lambert Company Analogues de phenoxazine pouvant etre utilises comme inhibiteurs d'agregation de substances amyloides et traitement de la maladie d'alzheimer et des troubles relatifs a l'amyloidose
GB0225548D0 (en) 2002-11-01 2002-12-11 Glaxo Group Ltd Compounds
ES2327372B1 (es) * 2007-04-23 2010-08-24 Laboratorios Almirall S.A. Nuevos derivados de los acidos amino-nicotinico y amino-isonicotinico.
ES2319596B1 (es) 2006-12-22 2010-02-08 Laboratorios Almirall S.A. Nuevos derivados de los acidos amino-nicotinico y amino-isonicotinico.
US20100204230A1 (en) 2007-02-12 2010-08-12 Peter Blurton Piperazine derivatives for treatment of ad and related conditions
US20080253967A1 (en) * 2007-04-13 2008-10-16 Kung Hank F Halo-Stilbene Derivatives And Their Use For Binding And Imaging Of Amyloid Plaques
UY31272A1 (es) 2007-08-10 2009-01-30 Almirall Lab Nuevos derivados de ácido azabifenilaminobenzoico
EP2135610A1 (fr) 2008-06-20 2009-12-23 Laboratorios Almirall, S.A. Combinaison comportant des inhibiteurs DHODH et de la méthotrexate
JP2012501344A (ja) * 2008-08-29 2012-01-19 トレヴェンティス コーポレイション アミロイド症を治療する組成物及び方法
EP2239256A1 (fr) 2009-03-13 2010-10-13 Almirall, S.A. Sel de sodium de l'acide 5-cyclopropyl-2-{[2-(2,6-difluorophényl)pyrimidin-5-yl]amino}benzoïque en tant qu'inhibiteurs de la DHOD
EP2228367A1 (fr) * 2009-03-13 2010-09-15 Almirall, S.A. Sels adjuvants d'amines contenant des groupes hydroxyle et/ou carbonyle avec des dérivés d'acides aminonicotiques en tant qu'inhibiteurs de la DHODH
EP2314577A1 (fr) 2009-10-16 2011-04-27 Almirall, S.A. Procédé de fabrication de l'acide 2-[(3,5-difluoro-3'-méthoxy-1,1'-biphényl-4-yl)amino]nicotinique
WO2011101787A1 (fr) * 2010-02-16 2011-08-25 Università Degli Studi Di Siena Inhibiteurs non peptidiques des protéines 14-3-3 et leur utilisation
EP2643303A1 (fr) * 2010-11-24 2013-10-02 Allergan, Inc. Modulateurs de récepteurs de la s1p
CN108524482B (zh) * 2017-03-02 2022-11-25 中国科学院上海药物研究所 2-(取代苯氨基)苯甲酸类fto抑制剂治疗白血病的用途
WO2019031472A1 (fr) * 2017-08-07 2019-02-14 国立大学法人広島大学 NOUVEAU COMPOSÉ À BASE D'ACIDE ANTHRANILIQUE, ET INHIBITEUR DE Pin1, AGENT THÉRAPEUTIQUE CONTRE LES MALADIES INFLAMMATOIRES AINSI QU'AGENT THÉRAPEUTIQUE CONTRE LE CANCER METTANT EN ŒUVRE CELUI-CI

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US5196444A (en) * 1990-04-27 1993-03-23 Takeda Chemical Industries, Ltd. 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof
US5739169A (en) * 1996-05-31 1998-04-14 Procept, Incorporated Aromatic compounds for inhibiting immune response
SK17622001A3 (sk) * 1999-06-10 2003-06-03 Warner-Lambert Company Izoindolínové deriváty, ich použitie a farmaceutické kompozície na ich báze

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AU775157B2 (en) 2004-07-22
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BG106293A (en) 2002-06-28
GEP20053423B (en) 2005-01-25
CN1378446A (zh) 2002-11-06
HUP0202508A2 (hu) 2002-12-28
HRP20020026A2 (en) 2003-08-31
EA200101135A1 (ru) 2002-06-27
ZA200109794B (en) 2003-07-01
NZ515621A (en) 2004-05-28
BR0011728A (pt) 2002-02-26
WO2000076489A3 (fr) 2002-05-30
CR6528A (es) 2004-02-23
SK17632001A3 (sk) 2003-03-04
DZ3252A1 (fr) 2000-12-21
IS6193A (is) 2001-12-07
OA11963A (en) 2006-04-17
HK1048258A1 (zh) 2003-03-28
PL352430A1 (en) 2003-08-25
EE200100673A (et) 2003-02-17
YU86701A (sh) 2004-09-03
AU5455300A (en) 2001-01-02
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AP2002002387A0 (en) 2002-03-31
MA26805A1 (fr) 2004-12-20
NO20015995L (no) 2002-02-04
TR200103551T2 (tr) 2002-12-23
EA004632B1 (ru) 2004-06-24
WO2000076489A2 (fr) 2000-12-21

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