Polyhydroxylated aromatic compounds for the treatment of amyloidosis and alpha-synuclein fibril diseases

• US 20010047032A1
• Filed: 12/26/2000
• Published: 11/29/2001
• Est. Priority Date: 12/30/1999
• Status: Abandoned Application

• Current Assignee: Cognitive Clarity Inc.
• Original Assignee: Cognitive Clarity Inc.
• Inventors: Snow, Alan D., Castillo, Gerardo M., Choi, Paula Y.
• Application Number:
  US09/748,748
• Publication Number:
  US 20010047032A1
• Time in Patent Office: Days
• US Class Current: 514/453
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/05 Phenols cannabinoids A61K31/658
• CPC Class Codes: A61K 31/12 Ketones
• CPC Class Codes: A61K 31/136 having the amino group directly attached to the aromatic ring, e.g. benzeneamine
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/37 Coumarins, e.g. psoralen
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/4353 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 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
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents

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.

Claims

1. A method of treating amyloidosis in a mammal suffering therefrom, comprising a(dministration 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:

2. The method of

claim 1

where only one such compound is administered.

3. The method of

claim 1

where the mammal is a human.

4. The method of

claim 3

where the amyloidosis is selected from the group of diseases consisting of Alzheimer'"'"'s disease, Down'"'"'s syndrome, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, the amyloidosis of chronic inflammation, the amyloidosis of malignancy and familial Mediterranean fever, the amyloidosis of multiple myeloma and B-cell dyscrasias, the amyloidosis of type II diabetes, the amyloidosis of the prion diseases, Creutzfeldt-Jakob disease, Gerstnamnn-Straussler syndrome, kuru, scrapie, the amyloidosis associated with long-term hemodialysis, the amyloidosis associated with carpal tunnel syndrome, senile cardiac amyloidosis, familial amyloidotic polyneuropathy, and the amyloidosis associated with endocrine tumors.

5. The method of

claim 4

where the amyloidosis is Alzheimer'"'"'s disease.

7. The drug product of

claim 5

containing only one such compound.

8. The drug product of

claim 7

indicated for the treatment of Alzheimer'"'"'s disease.

17. The method of

claim 1

where R¹ and R₂ are independently selected from the group consisting of hydrogen;

C_1-6 alkyl, C_1-6 alkoxy, and C_1-6 alkylthio (in each of which the alkyl group is optionally substituted with 1 to 5 halogen atoms); and

halo.

18. The method of

claim 1

where X is selected from hydrogen and the group consisting of

(a) hydroxy, amino, C_1-6 alkylamino, di(C_1-6 alkyl)amino, and cycloamino,

(b) C_1-22 alkyl, C_1-22 alkoxy, C_1-22 alkylthio, and C_1-22 alkylcarboxyl, each optionally substituted with 1 to 5 moieties selected from the group consisting of halogen, hydroxy, mercapto, amino, nitro, C_1-6 alkoxy, C_1-6 alkylthio, and Cl₆ alkylcarboxyl,

(c) aromatic and heteroaromatic groups substituted with 2 or 3 adjacent hydroxy groups, and optionally substituted with 1 to 5 non-interfering substituents, and

(d) —

C(O)R₃ and —

C(O)OR₃ (where R₃ is selected from the group consisting of (a) through (c) above).

19. The method of

claim 1

where X is selected from hydrogen and the group consisting of hydroxy, amino, —

C(O)R₃, and —

C(O)OR₃ (where R₃ is selected from hydroxy, amino, C_{1 6} alkyl optionally substituted with 1 to 5 halogen atoms, and aromatic and heteroaromatic groups substituted with 2 or 3 adjacent hydroxy groups and optionally substituted with 1 to 5 non-interfering substituents selected from halogen atoms and Cl6 alkyl and C_1-6 alkoxy, each optionally substituted with 1 to 5 halogen atoms.

20. The method of

claim 1

where Y is selected from the group consisting of hydrogen, hydroxy, Cl₆ alkoxy, and benzyloxy (where the phenyl group is optionally substituted with 1 to 3 substituents selected from halo and C_1-6 alkyl and C_1-6 alkoxy, each optionally substituted with 1 to 5 halogen atoms).

21. The method of

claim 1

where the compound is a compound of formula A or formula B, or a pharmaceutically acceptable salt thereof.

22. The method of

claim 21

where the compound is selected from the group consisting of dibromogallic acid, digallic acid, ethyl gallate, exifone, fisetin, gallacetophenone, gallami,de, gallic acid, α

-glucogallin, β

-glucogallin, 5-hydroxydopamine, and propyl gallate, and the pharmaceutically acceptable salts thereof.

23. The method of

claim 1

where the compound is a compound of formula C or a pharmaceutically acceptable salt thereof.

24. The method of

claim 22

where the compound is selected from the group consisting of myricetin and quercetin, and the pharmaceutically acceptable salts thereof.

25. The method of

claim 1

where the compound is a compound of formula D or a pharmaceutically acceptable salt thereof.

26. The method of

claim 25

where the compound is ellagic acid or a pharmaceutically acceptable salt thereof.

27. The method of

claim 1

where the compound is a compound of formula E or a pharmaceutically acceptable salt thereof.

28. The method of

claim 27

where the compound is selected from the group consisting of catechin, epicatechin, gallocatechin, epigallocatechin, and their gallate esters, and the pharmaceutically acceptable salts thereof.

29. The method of

claim 1

where the active ingredient is selected from 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, pyrocatechol, 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 B 1, and the pharmaceutically acceptable salts thereof.

30. The method of

claim 1

where the compound is selected from 1,2,4-benzenetriol, ellagic acid, ethyl gallate, exifone, gallamide, gallic acid, 5-hydroxydopamine, myricetin, phloroglucide, propyl gallate, quercetin, quinic acid, and tannic acid, and the pharmaceutically acceptable salts thereof.

6. 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:

9. 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, formida B, formula C, formula D, and formula E;

10. The method of

claim 9

where only one such compound is administered.

11. The method of

claim 10

where the mammal is a human.

12. The method of

claim 11

where the disease is Lewy body disease or Parkinson'"'"'s disease.

13. The method of

claim 12

where the disease is Parkinson'"'"'s disease.

14. 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 o-synuclein fibril formation, the container containing one or more dosage units each comprising at least one pharmaceuticELlly 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;

15. The drug product of

claim 14

containing only one such compound.

16. The drug product of

claim 15

indicated for the treatment of Parkinson'"'"'s disease.