Novobiocin analogues as neuroprotective agents and in the treatment of autoimmune disorders

• US 20070270452A1
• Filed: 05/10/2007
• Published: 11/22/2007
• Est. Priority Date: 11/03/2004
• Status: Active Grant

• Current Assignee: University of Kansas
• Original Assignee: University of Kansas
• Inventors: Michaelis, Mary, McIntosh, Michelle, Blagg, Brian
• Granted Patent: US 7,622,451 B2
• Time in Patent Office: Days
• US Class Current: 514/293
• 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: C07D 311/56 without hydrogen atoms in position 3
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/14 Ortho-condensed systems
• CPC Class Codes: C07D 491/052 the oxygen-containing ring being six-membered
• CPC Class Codes: C07D 493/04 Ortho-condensed systems
• CPC Class Codes: C07H 15/203 Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
• CPC Class Codes: C07H 17/00 Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
• CPC Class Codes: C07H 17/02 Heterocyclic radicals containing only nitrogen as ring hetero atoms
• CPC Class Codes: C07H 17/075 Benzo[b]pyran-2-ones
• CPC Class Codes: C07H 19/00 Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof

Abstract

Novobiocin analogues and pharmaceutical composition containing such compounds useful for the treatment and/or prevention of neurodegenerative disorders and autoimmune disorders.

Claims

1. The method for treating or preventing a neurodegenerative disorder or autoimmune disorder comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds according to Formula I

2. The method of claim 1 wherein the compounds are comarin compounds wherein X₁ is —

O— and

X₂ is —

CO—

.

3. The method of claim 1 wherein the compounds are isocoumarin compounds wherein X₁ is —

CO— and

X₂ is —

O—

.

4. The method of claim 1 wherein R⁴ and R⁵ are both hydrogen.

5. The method of claim 1 wherein R⁴ and R⁵ are independently hydrogen or methyl, and R⁶ is hydrogen.

6. The method of claim 1 wherein X₁ is nitrogen, R¹ together with X₂ and the atom to which R¹ is attached form a heterocyclic ring according to the following Formula I(F):

7. The method of claim 1 wherein X₄, X₅, X₆, and X₈ are all —

CH—

, R^b is oxidized to form a carbonyl, and n is 1 according to the Formula I(F)(i);

8. The method of claim 1 wherein X₉ is —

O—

, and R² and R³ are hydroxyl, R⁴ and R⁵ are methyl, R⁶ is methoxy, and n is 1 according to the Formula I(F)(ii);

9. The method of claim 1 such that X₁ is nitrogen, X₂ is —

CO—

, and R¹ together with X₄ and the atom to which R¹ is attached form a heterocyclic ring according to the following Formula I(G);

10. The method of claim 9 wherein X₄, X₅, X₆, X₈ are all —

CH—

, and n is 1 according to the

11. The method of claim 10, wherein X₉, is —

O— and

R² and R³ are hydroxyl, R⁴ and R⁵ are methyl, R⁶ is methoxy, and n is 1 according to the Formula I(G)(iii);

12. The method of claim 1 wherein that X₅ is nitrogen, X₁ is oxygen, and X² is —

CO—

according to the Formula I(H);

13. The method of according to claim 12 wherein X₄, X₆, X₈ are all —

CH—

, and n is 1 according to the Formula I(H)(i);

14. The method of according to claim 1 wherein R⁵ is hydrogen, and R² and R³ are independently —

OH, or —

OCONH₂.

15. The method of claim 1 wherein X₆, is —

CR²—

, and R²¹ is methoxy, ethoxy, or nitro, and R² and R³ are independently —

OH, or —

OCONH₂.

16. The method of claim 1 such that X₆ is carbon and X₉is nitrogen, and X₆ together with X₉ and the carbon at position 7 form a heterocyclic ring according to the following Formula I(J):

17. The method of claim 16 wherein R^b is oxidized to form a carbonyl according to the Formula I(J)(i):

18. The method of claim 17 wherein X₁ is —

O— and

X₂ is —

CO—

.

19. The method of claim 1 wherein X₁ is —

CO— and

X₂ is —

NR¹⁸—

according to the Formula I(K);

20. The method of claim 19 wherein X₄, X₅, X₆, X₈ are all —

CH—

, and n is 1 according to the Formula I(K)(i);

21. The method of claim 1 wherein X, is —

CR²⁰— and

R²⁰ is hydrogen and wherein X₈ is —

CR³— and

R²³ is hydrogen.

22. The method of claim 1 wherein that X₁ is —

N— and

X₂ is —

CH—

according to the Formula I(L);

23. The method of claim 22 wherein X₄, X₅, X₆, X₈ are all —

CH— and

n is 1 according to the Formula I(L)(i);

24. The method of claim 1:

wherein X₄, X₅, X₆, X₈ are all —

CH—

,

wherein X₁ is —

O—

,

wherein X₂ is —

CO—

,

wherein X₉ is the ether —

O—

, and

R² and R³ are hydroxyl,

such that the compounds are defined according to the formula;

25. The method of claim 1 wherein the compounds are selected from the group consisting of:

N-(7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-2-oxo-2H-chromen-3-yl)acetamide (A1);

(2R,3R,4R,5R)-2-(3-acetamido-2-oxo-2H-chromen-7-yloxy)-4-hydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-3-yl carbamate (A2);

(3R,4S,5R,6R)-6-(3-acetamido-2-oxo-2H-chromen-7-yloxy)-5-hydroxy-3-methoxy-2,2-dimethyl tetrahydro-2H-pyran-4-yl carbamate (A3);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy)-2-oxo-2H-chromen-3-yl)acetamide (A4);

7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-2H-chromen-2-one (B1);

(3R,4S,5R,6R)-5-hydroxy-3-methoxy-2,2-dimethyl-6-(2-oxo-2H-chromen-7-yloxy)-tetrahydro-2H-pyran-4-yl carbamate (B2);

(2R,3R,4R,5R)-4-hydroxy-5-methoxy-6,6-dimethyl-2-(2-oxo-2H-chromen-7-yloxy)-tetrahydro-2H-pyran-3-yl carbamate (B3);

7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy)-2H-chromen-2-one (B4);

7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-4-methyl-3-phenyl-2H-chromen-2-one (C1);

(3R,4S,5R,6R)-5-hydroxy-3-methoxy-2,2-dimethyl-6-(4-methyl-2-oxo-3-phenyl-2H-chromen-7-yloxy)-tetrahydro-2H-pyran-4-yl carbamate (C2);

(2R,3R,4R,5R)-4-hydroxy-5-methoxy-6,6-dimethyl-2-(4-methyl-2-oxo-3-phenyl-2H-chromen-7-yloxy)-tetrahydro-2H-pyran-3-yl carbamate (C3);

7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy)-4-methyl-3-phenyl-2H-chromen-2-one (C4);

8-(7-Methoxy-6,6-dimethyl-2-oxo-tetrahydro-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-chromen-2-one (D1);

Carbamic acid 4-hydroxy-5-methoxy-6,6-dimethyl-2-(2-oxo-2H-chromen-8-yloxy)-tetrahydro-pyran-3-yl ester (D2);

carbamic acid 5-hydroxy-3-methoxy-2,2-dimethyl-6-(2-oxo-2H-chromen-8-yloxy)-tetrahydro-pyran-4-yl ester (D3);

8-(3,4-Dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-pyran-2-yloxy)-chromen-2-one (D4);

6-(7-Methoxy-6,6-dimethyl-2-oxo-tetrahydro-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-chromen-2-one (E1);

Carbamic acid 5-hydroxy-3-methoxy-2,2-dimethyl-6-(2-oxo-2H-chromen-6-yloxy)-tetrahydro-pyran-4-yl ester (E2);

Carbamic acid 4-hydroxy-5-methoxy-6,6-dimethyl-2-(2-oxo-2H-chromen-6-yloxy)-tetrahydro-pyran-3-yl ester (E3); and

6-(3,4-Dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-pyran-2-yloxy)-chromen-2-one

(E4).

26. The method of claim 1 wherein said disorder is a neurodegenerative disorder which is a beta amyloid disorder.

27. The method of claim 1 wherein said disorder is a neurodegenerative disorder which is Alzheimer'"'"'s Disease.

28. The method of claim 1 wherein said disorder is a neurodegenerative disorder selected from the group consisting of diabetic peripheral neuropathy, Alzheimer'"'"'s disease, Pick'"'"'s disease, diffuse Lewy body disease, progressive supranuclear palsy (Steel-Richardson syndrome), multisystem degeneration (Shy-Drager syndrome), motor neuron diseases including amyotrophic lateral sclerosis (“

ALS”

), degenerative ataxias, cortical basal degeneration, ALS-Parkinson'"'"'s-Dementia complex of Guam, subacute sclerosing panencephalitis, Huntington'"'"'s disease, Parkinson'"'"'s disease, multiple sclerosis, synucleinopathies, primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease/spinocerebellar ataxia type 3 and olivopontocerebellar degenerations, Gilles De La Tourette'"'"'s disease, bulbar and pseudobulbar palsy, spinal and spinobulbar muscular atrophy (Kennedy'"'"'s disease), primary lateral sclerosis, familial spastic paraplegia, Weeiicke-Korsakoff s related dementia (alcohol induced dementia), Werdnig-Hoffmann disease, Kugelberg-Welander disease, Tay-Sach'"'"'s disease, Sandhoff disease, familial spastic disease, Wohifart-Kugelberg-Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathy, and prion diseases (including Creutzfeldt-Jakob, Gerstmann-Straussler-Scheinker disease, Kuru and fatal familial insomnia). Other conditions also included within the methods of the present invention include age-related dementia and other dementias, and conditions with memory loss including vascular dementia, diffuse white matter disease (Binswanger'"'"'s disease), dementia of endocrine or metabolic origin, dementia of head trauma and diffuse brain damage, dementia pugilistica, and frontal lobe dementia. Also other neurodegenerative disorders resulting from cerebral ischemia or infarction including embolic occlusion and thrombotic occlusion as well as intracranial hemorrhage of any type (including, but not limited to, epidural, subdural, subarachnoid, and intracerebral), and intracranial and intravertebral lesions (including, but not limited to, contusion, penetration, shear, compression, and laceration). Thus, the term also encompasses acute neurodegenerative disorders such as those involving stroke, traumatic brain injury, schizophrenia, peripheral nerve damage, hypoglycemia, spinal cord injury, epilepsy, and anoxia and hypoxia.

29. The method of claim 1 wherein said disorder is an autoimmune disorder selected from the group consisting of acute disseminated encephalomyelitis, Addison'"'"'s disease, Alopecia universalis, ankylosing spondylitisis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis autoimmune infertility, autoimmune thyroiditis, autoimmune neutropenia, Behget'"'"'s disease, bullous pemphigoid, Chagas'"'"' disease, cirrhosis, Coeliac disease, Crohn'"'"'s disease, Chronic fatigue syndrome, chronic active hepatitis, dense deposit disease, discoid lupus, dermatitis, luten-sensitive enteropathy, dysautonomia, endometriosis, glomerulonephritis, Goodpasture'"'"'s disease, Graves'"'"' disease, Guillain-Barre syndrome, Hashimoto'"'"'s disease, Hidradenitis suppurativa, idiopathic thrombocytopenia purpura, insulin dependent diabetes mellitus, interstitial cystitis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, neuromyotonia, opsoclonus myoclonus syndrome, optic neuritis, Ord'"'"'s thyroiditis, pemphigus vulgaris, pernicious anemia, polyarthritis, polymyositis, primary biliary cirrhosis, psoriasis, Reiter'"'"'s syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren'"'"'s syndrome, systemic lupus erythematosus, Takayasu'"'"'s arteritis, temporal arteritis, ulcerative colitis, vitiligo, vulvodynia, warm autoimmune hemolytic anemia, or Wegener'"'"'s granulomatosis.

30. The method of claim 1 wherein said disorder is multiple sclerosis or experimental autoimmune encephalomyelitis.

31. The method of claim 1 wherein said compound is a heat shock 90 protein (“

Hsp90”

) inhibitor.

32. The method of claim 1 wherein said compound upregulates heat shock 70 protein (“

Hsp70”

) in neuronal cells.

33. The method of claim 1 wherein said compound is not a substrate for P-glycoprotein.