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US 2007/0191330 A1Published application
Polyhydroxylated aromatic compounds for the treatment of amyloidosis and alpha-synuclein fibril diseases
AssigneeProteotech, Inc.
InventorsGerardo Castillo, Paula Choi, Alan Snow
Life of this patent
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Abstract
Polyhydroxylated aromatic compounds, and compositions containing them, are useful for the treatment of amyloidosis, especially Alzheimer's disease, and for the treatment of diseases characterized by α-synuclein fibril formation, especially Lewy body disease and Parkinson's disease.
Claims11
A drug product for the treatment of amyloidosis in a mammal suffering therefrom, comprising a container labeled or accompanied by a label indicating that the drug product is for the treatment of amyloidosis, the container containing one or more dosage units each comprising at least one pharmaceutically acceptable excipient and, as an active ingredient, an isolated pure compound selected from the group consisting of the compounds of formula A, formula B, formula C, formula D, and formula E:
- where:
- R is selected from the group consisting of hydrogen, 2,3-dihydroxybenzoyl, 3,4-dihydroxybenzoyl, 2,3,4-trihydroxybenzoyl, and 3,4,5-trihydroxybenzoyl;
- R′ is hydrogen or OH;
- R1 and R2 are independently selected from hydrogen and non-interfering substitutents;
- X is selected from hydrogen and the group consisting of
- (a) hydroxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and cycloamino,
- (b) C1-22 alkyl, C1-22 alkoxy, C1-22 alkylthio, and C1-22 alkylcarboxyl, each optionally substituted with 1 to 5 moieties selected from the group consisting of halogen, hydroxy, mercapto, amino, nitro, C1-6 alkoxy, C1-6 alkylthio, and C1-6 alkylcarboxyl,
- (c) aromatic and heteroaromatic groups substituted with 2 or 3 adjacent hydroxy groups, and optionally substituted with 1 to 5 non-interfering substitutents,
- (d) sugars, optionally substituted with one or more anionic groups selected from sulfate, phosphate, phosphonate, carboxylate, and sulfonate groups,
- (e) peptides and peptide derivatives, and
- (f) —C(O)R3 and —C(O)OR3, where R3 is selected from the group consisting of (a) through (e) above;
- and
- Y is hydrogen, hydroxy, C1-6 alkoxy, benzyloxy, where the phenyl group is optionally substituted with 1 to 3 substitutents selected from halo and C1-6 alkyl, or —OSO2R4, where R4 is C1-6 alkyl or phenyl optionally substituted with 1 to 3 substitutents selected from halo and C1-6 alkyl;
- and the group of compounds consisting of acacetin, actinorhodine, alizarin, alizarin blue, alizarin orange, alizarinsulfonic acid, alkannin, anthragallol, anthralin, anthrarobin, antharufin, apigenin, apigetrin, apiose, baicalein, baptigenin, 1,2,4-benzenetriol, bostrycoidin, carbidopa, carminic acid, carubicin, cellobiose, centaurein, chloranilic acid, chondrosine, chromotrope 2B, chromotropic acid, chrysamminic acid, chrysarobin, chrysin, chrysophanic acid, cichoriin, citrazinic acid, citromycetin, collinomycin, curvularin, cyanidin, cyanidin 3-glucoside, cyanidin 3-rhamnoglucoside, cyanidin 3,5-diglucoside, cyanidin 3-sophoroside, daphnetin, datiscetin, daunorubicin, delphinidin, deoxyepinephrine, diosmetin, diosmin, dioxethedrine, dopa, dopamine, doxorubicin, droxidopa, echinochrome A, embelin, emodin, ergoflavin, eriodictyol, esculetin, fenoldopam, fomecin A, fomecin B, fraxetin, fraxin, fredericamycin A, fumigatin, fusarubin, fuscin, fustin, galangin, gallein, gallocyanine, gardenin A, gardenin B, gardenin C, gardenin D, gardenin E, genistein, gentisin, granaticin, guamecycline, hematein, hydroxysophorobioside, hydroxysophoricoside, icariin, isoquercitrin, kaempferol, kermesic acid, laccaic acid A, laccaic acid B, laccaic acid C, laccaic acid D, leucocyanidin, luteolin, maclurin, menogaril, methylenedigallic acid, morin, oosporein, phenicin, phloroglucide, puberulic acid, puberulonic acid, purpurin, purpurogallin, quercetagetin, quercimritrin, quinalizarin, quinic acid, resistomycin, rhamnetin, rhein, rhodizonic acid, rhodomycin A, rhodomycin B, robinin, ruberythric acid, rufigallol, rutin, scutellarein, tannic acid, tetroquinone, tiron, troxerutin, and tunichrome B1,
- but excluding pyrogallol,
- and the pharmaceutically acceptable salts thereof.
13 more elements
A method of treating a mammal suffering from a disease characterized by α-synuclein fibril formation, comprising administration to the mammal of a therapeutically effective amount of an isolated pure compound selected from the group consisting of the compounds of formula A, formula B, formula C, formula D, and formula E:
- where:
- R is selected from the group consisting of hydrogen, 2,3-dihydroxybenzoyl, 3,4-dihydroxybenzoyl, 2,34-trihydroxybenzoyl, and 3,4,5-trihydroxybenzoyl;
- R′ is hydrogen or OH;
- R1 and R2 are independently selected from hydrogen and non-interfering substitutents;
- X is selected from hydrogen and the group consisting of
- (a) hydroxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and cycloamino,
- (b) C1-22 alkyl, C1-22 alkoxy, C1-22 alkylthio, and C1-22 alkylcarboxyl, each optionally substituted with 1 to 5 moieties selected from the group consisting of halogen, hydroxy, mercapto, amino, nitro, C1-6 alkoxy, C1-6 alkylthio, and C1-6 alkylcarboxyl,
- (c) aromatic and heteroaromatic groups substituted with 2 or 3 adjacent hydroxy groups, and optionally substituted with 1 to 5 non-interfering substitutents,
- (d) sugars, optionally substituted with one or more anionic groups selected from sulfate, phosphate, phosphonate, carboxylate, and sulfonate groups,
- (e) peptides and peptide derivatives, and
- (f) —C(O)R3 and —C(O)OR3 (where R3 is selected from the group consisting of (a) through (e) above);
- and
- Y is hydrogen, hydroxy, C1-6 alkoxy, benzyloxy (where the phenyl group is optionally substituted with 1 to 3 substitutents selected from halo and C1-6 alkyl), or —OSO2R4 (where R4 is C1-6 alkyl or phenyl optionally substituted with 1 to 3 substitutents selected from halo and C1-6 alkyl);
- and the group of compounds consisting of acacetin, actinorhodine, alizarin, alizarin blue, alizarin orange, alizarinsulfonic acid, alkannin, anthragallol, anthralin, anthrarobin, antharufin, apigenin, apigetrin, apiose, baicalein, baptigenin, 1,2,4-benzenetriol, bostrycoidin, carbidopa, carminic acid, carubicin, cellobiose, centaurein, chloranilic acid, chondrosine, chromotrope 2B, chromotropic acid, chrysamminic acid, chrysarobin, chrysin, chrysophanic acid, cichoriin, citrazinic acid, citromycetin, collinomycin, curvularin, cyanidin, cyanidin 3-glucoside, cyanidin 3-rhamnoglucoside, cyanidin 3,5-diglucoside, cyanidin 3-sophoroside, daphnetin, datiscetin, daunorubicin, delphinidin, deoxyepinephrine, diosmetin, diosmin, dioxethedrine, dopa, dopamine, doxorubicin, droxidopa, echinochrome A, embelin, emodin, ergoflavin, eriodictyol, esculetin, fenoldopam, fomecin A, fomecin B, fraxetin, fraxin, fredericamycin A, fumigatin, fusarubin, fuscin, fustin, galangin, gallein, gallocyanine, gardenin A, gardenin B, gardenin C, gardenin D, gardenin E, genistein, gentisin, granaticin, guamecycline, hematein, hydroxysophorobioside, hydroxysophoricoside, icariin, isoquercitrin, kaempferol, kermesic acid, laccaic acid A, laccaic acid B, laccaic acid C, laccaic acid D, leucocyanidin, luteolin, maclurin, menogaril, methylenedigallic acid, morin, oosporein, phenicin, phloroglucide, puberulic acid, puberulonic acid, purpurin, purpurogallin, quercetagetin, quercimritrin, quinalizarin, quinic acid, resistomycin, rhamnetin, rhein, rhodizonic acid, rhodomycin A, rhodomycin B, robinin, ruberythric acid, rufigallol, rutin, scutellarein, tannic acid, tetroquinone, tiron, troxerutin, and tunichrome B1,
- but excluding pyrogallol,
- and the pharmaceutically acceptable salts thereof.
13 more elements
A drug product for the treatment of a disease characterized by α-synuclein fibril formation in a mammal suffering therefrom, comprising a container labeled or accompanied by a label indicating that the drug product is for the treatment of a disease characterized by α-synuclein fibril formation, the container containing one or more dosage units each comprising at least one pharmaceutically acceptable excipient and, as an active ingredient, an isolated pure compound selected from the group consisting of the compounds of formula A, formula B, formula C, formula D, and formula E:
- where:
- R is selected from the group consisting of hydrogen, 2,3-dihydroxybenzoyl, 3,4-dihydroxybenzoyl, 2,3,4-trihydroxybenzoyl, and 3,4,5-trihydroxybenzoyl;
- R′ is hydrogen or OH;
- R1 and R2 are independently selected from hydrogen and non-interfering substitutents;
- X is selected from hydrogen and the group consisting of
- (a) hydroxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and cycloamino,
- (b) C1-22 alkyl, C1-22 alkoxy, C1-22 alkylthio, and C1-22 alkylcarboxyl, each optionally substituted with 1 to 5 moieties selected from the group consisting of halogen, hydroxy, mercapto, amino, nitro, C1-6 alkoxy, C1-6 alkylthio, and C1-6 alkylcarboxyl,
- (c) aromatic and heteroaromatic groups substituted with 2 or 3 adjacent hydroxy groups, and optionally substituted with 1 to 5 non-interfering substitutents,
- (d) sugars, optionally substituted with one or more anionic groups selected from sulfate, phosphate, phosphonate, carboxylate, and sulfonate groups,
- (e) peptides and peptide derivatives, and
- (f) —C(O)R3 and —C(O)OR3 (where R3 is selected from the group consisting of (a) through (e) above);
- and
- Y is hydrogen, hydroxy, C1-6 alkoxy, benzyloxy (where the phenyl group is optionally substituted with 1 to 3 substitutents selected from halo and C1-6 alkyl), or —OSO2R4 (where R4 is C1-6 alkyl or phenyl optionally substituted with 1 to 3 substitutents selected from halo and C1-6 alkyl);
- and the group of compounds consisting of acacetin, actinorhodine, alizarin, alizarin blue, alizarin orange, alizarinsulfonic acid, alkannin, anthragallol, anthralin, anthrarobin, antharufin, apigenin, apigetrin, apiose, baicalein, baptigenin, 1,2,4-benzenetriol, bostrycoidin, carbidopa, carminic acid, carubicin, cellobiose, centaurein, chloranilic acid, chondrosine, chromotrope 2B, chromotropic acid, chrysamminic acid, chrysarobin, chrysin, chrysophanic acid, cichoriin, citrazinic acid, citromycetin, collinomycin, curvularin, cyanidin, cyanidin 3-glucoside, cyanidin 3-rhamnoglucoside, cyanidin 3,5-diglucoside, cyanidin 3-sophoroside, daphnetin, datiscetin, daunorubicin, delphinidin, deoxyepinephrine, diosmetin, diosmin, dioxethedrine, dopa, dopamine, doxorubicin, droxidopa, echinochrome A, embelin, emodin, ergoflavin, eriodictyol, esculetin, fenoldopam, fomecin A, fomecin B, fraxetin, fraxin, fredericamycin A, fumigatin, fusarubin, fuscin, fustin, galangin, gallein, gallocyanine, gardenin A, gardenin B, gardenin C, gardenin D, gardenin E, genistein, gentisin, granaticin, guamecycline, hematein, hydroxysophorobioside, hydroxysophoricoside, icariin, isoquercitrin, kaempferol, kermesic acid, laccaic acid A, laccaic acid B, laccaic acid C, laccaic acid D, leucocyanidin, luteolin, maclurin, menogaril, methylenedigallic acid, morin, oosporein, phenicin, phloroglucide, puberulic acid, puberulonic acid, purpurin, purpurogallin, quercetagetin, quercimritrin, quinalizarin, quinic acid, resistomycin, rhamnetin, rhein, rhodizonic acid, rhodomycin A, rhodomycin B, robinin, ruberythric acid, rufigallol, rutin, scutellarein, tannic acid, tetroquinone, tiron, troxerutin, and tunichrome B1,
- but excluding pyrogallol,
- and the pharmaceutically acceptable salts thereof.
13 more elements
Dependencies are inferred from the claim text.