Compounds, Compositions and Methods for the Treatment of Beta-Amyloid Diseases and Synucleinopathies

• US 20090111863A1
• Filed: 10/03/2008
• Published: 04/30/2009
• Est. Priority Date: 10/31/2007
• Status: Active Grant

• Current Assignee: ProtaMed, Inc.
• Original Assignee: Proteotech Inc
• Inventors: Weigele, Manfred, Lake, Thomas, Cummings, Joel, Snow, Alan, Hudson, F. Michael, Esposito, Luke A., Larsen, Lesley
• Granted Patent: US 8,829,198 B2
• Time in Patent Office: Days
• US Class Current: 514/383
• CPC Class Codes: A61K 31/05 Phenols cannabinoids A61K31/658
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 2603/74 Adamantanes
• CPC Class Codes: C07C 311/29 having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 37/16 by condensation involving hydroxy groups of phenols or alcohols or the ether or mineral ester group derived therefrom
• CPC Class Codes: C07C 39/10 Polyhydroxy benzenes; Alkylated derivatives thereof C07C39/08 takes precedence
• CPC Class Codes: C07C 39/17 containing other rings in addition to the six-membered aromatic rings , e.g. cyclohexylphenol
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/54 having two double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Abstract

Dihydroxyaryl compounds and pharmaceutically acceptable esters, their synthesis, pharmaceutical compositions containing them, and their use in the treatment of β-amyloid diseases, such as observed in Alzheimer'"'"'s disease, and synucleinopathies, such as observed in Parkinson'"'"'s disease, and the manufacture of medicaments for such treatment.

Claims

1. A compound selected from the group consisting of:

where R₁, R₂, R₃, and R₄ are independently positioned hydroxyl groups and

R is selected from —

C(O)NR′

, sulfonamide, heteroaryl, tricycloalkyl or pharmaceutically acceptable esters or salts thereof and where R′

is selected from H or CH₃, and

such that when R is —

C(O)NR′ and

one of either the R₁ and R₂ hydroxyl groups or the R₃ and R₄ hydroxyl groups are at the 3,4 position, then the other hydroxyl groups are at one of the positions selected from the group consisting of 2,3;

2,4;

2,5;

2,6;

3,5;

3,6;

4,5;

4,6 and 5,6.

2. The compound of claim 1 where R is —

C(O)NR′ and

R′

is selected from H or CH₃ or pharmaceutically acceptable salts thereof.

3. The compound of claim 1 where R′

is H.

4. The compound of claim 1 selected from the group consisting of:

2,3-dihydroxybenzoic acid 3,4-dihydroxyanilide;

3,4-dihydroxybenzoic acid 2,3-dihydroxyanilide; and

2,3-dihydroxybenzoic acid 2,3-dihydroxyanilide.

5. The compound of claim 1 where R′

is CH₃.

6. The compound of claim 1 where the compound is 3,4 dihydroxybenzoic acid 3,4 dihydroxy N-methyl anilide.

7. The compound of claim 1 where R is sulfonamide.

8. The compound of claim 1 where the compound is 3,4-dihydroxybenzenesulfonic acid 3,4-dihydroxyphenylsulfonamide.

9. The compound of claim 1 where R is heteroaryl.

10. The compound of claim 1 where the compound is selected from the group consisting of imidazole, triazole, and pyrazole.

11. The compound of claim 1 where the compound is selected from the group consisting of:

2,4-bis(3,4-dihydroxyphenyl)imidazole;

3,5-bis(3,4 dihydroxyphenyl) 1,2,4 triazole; and

3,5-bis(3,4 dihydroxyphenyl)pyrazole.

12. The compound of claim 1 where R is tricycloalkyl.

13. The compound of claim 1 where the compound is 1,3 bis-(3,4 dihydroxyphenyl)adamantane.

14. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

15. A method of treating the formation, deposition, accumulation, or persistence of Aβ

amyloid or α

-synuclein fibrils, comprising treating the fibrils with an effective amount of the compound of claim 1.

16. The method of claim 15 where the compound is selected from the group consisting of

(1) the compounds that are:

2,3-dihydroxybenzoic acid 3,4-dihydroxyanilide,

3,4-dihydroxybenzoic acid 2,3-dihydroxyanilide,

2,3-dihydroxybenzoic acid 2,3-dihydroxyanilide,

3,4-dihydroxybenzoic acid 3,4-dihydroxy N-methyl anilide,

3,4-dihydroxybenzenesulfonic acid 3,4-dihydroxyphenylsulfonamide,

2,4-bis(3,4 dihydroxyphenyl)imidazole,

3,5-bis(3,4 dihydroxyphenyl) 1,2,4 triazole,

3,5-bis(3,4 dihydroxyphenyl)pyrazole, and

1,3-bis(3,4 dihydroxyphenyl)adamantane;

(2) the methylenedioxy analogs and pharmaceutically acceptable esters thereof, and

(3) the pharmaceutically acceptable salts of the compounds of (1) and (2).

17. A method of treating a β

-amyloid disease or a synucleinopathy in a mammal suffering therefrom, comprising administration of a therapeutically effective amount of the compound of claim 1.

18. The method of claim 17 where the β

-amyloid disease is selected from the group of diseases consisting of Alzheimer'"'"'s disease, Down'"'"'s syndrome, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, and cerebral β

-amyloid angiopathy.

19. The method of claim 17 where the β

-amyloid disease is Alzheimer'"'"'s disease.

20. The method of claim 17 where the synucleinopathy is selected from the group consisting of Parkinson'"'"'s disease, familial Parkinson'"'"'s disease, Lewy body disease, the Lewy body variant of Alzheimer'"'"'s disease, dementia with Lewy bodies, multiple system atrophy, and the Parkinsonism-dementia complex of Guam.

21. The method of claim 17 where the synucleinopathy is Parkinson'"'"'s disease.

22. The method of claim 17 where the compound is selected from the group consisting of

(1) the compounds that are:

2,3-dihydroxybenzoic acid 3,4-dihydroxyanilide,

3,4-dihydroxybenzoic acid 2,3-dihydroxyanilide,

2,3-dihydroxybenzoic acid 2,3-dihydroxyanilide,

3,4-dihydroxybenzoic acid 3,4-dihydroxy N-methylanilide,

3,4-dihydroxybenzenesulfonic acid 3,4-dihydroxyphenylsulfonamide,

2,4-bis(3,4 dihydroxyphenyl)imidazole,

3,5-bis(3,4 dihydroxyphenyl) 1,2,4 triazole,

3,5-bis(3,4 dihydroxyphenyl)pyrazole, and

1,3-bis(3,4 dihydroxyphenyl)adamantane;

(2) the methylenedioxy analogs and pharmaceutically acceptable esters thereof, and

(3) the pharmaceutically acceptable salts of the compounds of (1) and (2).