Novobiocin analogues

• US 8,212,011 B2
• Filed: 02/20/2009
• Issued: 07/03/2012
• Est. Priority Date: 11/03/2004
• Status: Active Grant

• Current Assignee: University of Kansas
• Original Assignee: University of Kansas
• Inventors: Blagg, Brian
• Primary Examiner(s): Lewis, Patrick
• Application Number:
  US12/390,011
• Publication Number:
  US 20090187014A1
• Time in Patent Office: 1,229 Days
• Field of Search: None
• US Class Current: 536/13
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 487/14 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/14 Ortho-condensed systems
• CPC Class Codes: C07D 493/04 Ortho-condensed systems
• 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, as well as cancer.

Claims

1. Compounds according to the formula:

2. The compounds according to claim 1 according to:

3. The compounds according to claim 1 wherein R¹ is an amido which is NR′

COR″

, and R′

is hydrogen and R″

is aryl according to;

4. The compounds according to claim 1 wherein R¹ is an amido which is NR′

COR″

, and R′

is hydrogen and R″

is aryl according to;

5. The compounds according to claim 1 wherein R¹ is an amido which is NR′

COR″

, and wherein R′

is hydrogen and R″

is aryl according to;

6. The compounds according to claim 1 wherein R¹ is an amido which is NR′

COR″

, and wherein R′

is hydrogen and R″

is aryl selected from the group consisting of

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-6-methoxybiphenyl-3-carboxamide (28);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-6-methoxy-2′

-methylbiphenyl-3-carboxamide (29);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-6-methoxy-3′

-methylbiphenyl-3-carboxamide (30);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-6-methoxy-4′

-methylbiphenyl-3-carboxamide (31);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-2′

,6-dimethoxybiphenyl-3′

-carboxamide (32);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-3′

,6-dimethoxybiphenyl-3-carboxamide (33);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-4′

,6-dimethoxybiphenyl-3′

-carboxamide (34);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-2′

-hydroxy-6-methoxybiphenyl-3-carboxamide (35);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-3¹-hydroxy-6-methoxybiphenyl-3-carboxamide (36); and

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-4′

-hydroxy-6-methoxybiphenyl-3-carboxamide (37).

7. The compounds according to claim 1 wherein R¹ is an amido which is NR′

COR″

, and wherein R′

is hydrogen and R″

is aryl according to;

8. The compounds according to claim 1 wherein R¹ is an amido which is NR′

COR″

, and wherein R′

is hydrogen and R″

is a an indole according to;

9. The compounds according to claim 1 which are selected from the group consisting of:

N-(7-((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-6-methoxy-8-methyl-2-oxo-2H-chromen-3-yl)-3′

,6-dimethoxybiphenyl-3-carboxamide (26a);

N-(7-((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-6-propoxy-2H-chromen-3-yl)-3′

,6-dimethoxybiphenyl-3-carboxamide (26b);

N-(7-((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-6-isopropoxy-8-methyl-2-oxo-2H-chromen-3-yl)-3′

,6-dimeth-oxybiphenyl-3-carboxamide (26c);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-5-methoxy-8-methyl-2-oxo-2H-chromen-3-yl)-3′

,6-dimethoxybiphenyl-3-carboxamide (26d);

N-(8-benzyl-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-2-oxo-2H-chromen-3-yl)-3′

,6-dimethoxybiphenyl-3-carboxamide (26e);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-2-oxo-8-phenyl-2H-chromen-3-yl)-3′

,6-dimethoxybiphenyl-3-carboxamide (260;

N-(7-((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methoxy-2-oxo-2H-chromen-3-yl)-3′

,6-dimethoxybiphenyl-3-carboxamide (26g);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-ethyl-2-oxo-2H-chromen-3-yl)-3′

,6-dimethoxybiphenyl-3-carboxamide (26h).

10. The compounds according to claim 1 which are selected from the group consisting of:

N-(7-((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-6-methoxy-8-methyl-2-oxo-2H-chromen-3-yl)-1H-indole-2-carboxamide (26i);

N-(7-((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-6-propoxy-2H-chromen-3-yl)-1H-indole-2-carboxamide (26j);

N-(7-((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-6-isopropoxy-8-methyl-2-oxo-2H-chromen-3-yl)-1H-indole-2-carboxamide (26k);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-5-methoxy-8-methyl-2-oxo-2H-chromen-3-yl)-1H-indole-2-carboxamide (26l);

N-(8-benzyl-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-2-oxo-2H-chromen-3-yl)-1H-indole-2-carboxamide (26m);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-2-oxo-8-phenyl-2H-chromen-3-yl)-1H-indole-2-carboxamide (26n);

N-(7-((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methoxy-2-oxo-2H-chromen-3-yl)-1H-indole-2-carboxamide (26o); and

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-ethyl-2-oxo-2H-chromen-3-yl)-1H-indole-2-carboxamide (26p).

11. The compounds according to claim 1 wherein R¹ is an amido which is NR′

COR″

, and R′

is hydrogen and R″

is a heterocycle selected from the group consisting of pyridine, benzofuran, indole, and oxazole.

12. The compounds according to claim 1:

wherein R¹ is an amido which is NR′

COR″

, and R′

is hydrogen and R″

is a heterocycle selected from the group consisting of pyridine, benzofuran, and indole; and

wherein R² is hydroxy;

or R² together with R³ and the atoms to which they are attached form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;

wherein R³ is hydroxy, or R³ together with R² and the atoms to which they are attached form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;

wherein R⁴ is methyl;

wherein R⁵ is methyl;

wherein R⁶ is methoxy;

wherein X₁ is —

O—

;

wherein X₂ is —

CO—

;

wherein X₄ is —

CR²⁰—

, wherein R²⁰ is hydrogen, alkyl, alkenyl, or alkynyl;

wherein X₅, is —

CR²¹, wherein R²¹ is hydrogen, alkyl, alkenyl, alkynyl;

wherein X₆, is —

CR²², wherein R²² is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, halogen, or nitro;

wherein X₈, is —

CR²³, wherein R²³ is hydrogen, alkyl, alkenyl, alkynyl;

wherein X₉ is ether which is —

O—

;

wherein n is 1.

13. The compounds according to claim 1:

wherein R¹ is an amido which is NR′

COR″

, and R′

is hydrogen and R″

is a heterocycle selected from the group consisting of pyridine, benzofuran, and indole;

wherein R² is hydroxy;

wherein R³ is hydroxy;

wherein R⁴ is methyl;

wherein R⁵ is methyl;

wherein R⁶ is methoxy;

wherein X₁ is —

O—

or —

N—

;

wherein X₂ is —

CR¹⁹—

or —

CO—

, wherein R¹⁹ is hydrogen or alkyl;

wherein X₄ is —

CR²⁰—

, wherein R²⁰ is hydrogen;

wherein X₅, is —

CR²¹, wherein R²¹ is hydrogen;

wherein X₆, is —

CR²², wherein R²² is hydrogen;

wherein X₈, is —

CR²³, wherein R²³ is hydrogen or alkyl;

wherein X₉ is ether which is —

O—

; and

wherein n is 1.

14. The compounds according to claim 1 wherein R¹ is an amido which is NR′

COR″

, and R′

is hydrogen and R″

is aryl or heterocycle according to;

15. The compounds according to claim 1 wherein R¹ is an amido which is NR′

COR″

, and R′

is hydrogen and R″

is aryl or heterocycle according to;

16. The compounds according to claim 1 wherein R¹ is an amido which is NR′

COR″

, and R′

is hydrogen and R″

is a heterocycle according to;

17. The compounds according to claim 1 wherein R¹ is an amido which is NR′

COR″

, and R′

is hydrogen and R″

is a heterocyle according to;

18. The compounds according to claim 1 wherein R¹ is an amido which is NR′

COR″

, and R′

is hydrogen and R″

is aryl according to one of the following;

19. The compounds according to claim 1 wherein R¹ is an amido which is NR′

COR″

, and R′

is hydrogen and R″

is aryl selected from the group consisting of;

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-2-phenylacetamide (22);

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-3-phenylpropanamide (23);

Benzyl 7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-ylcarbamate (24); and

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)cinnamamide (25).

20. The compounds according to claim 1 wherein R¹ is an amido which is NR′

COR″

, and R′

is hydrogen and R″

is a heterocycle according to one of the following;

21. The compounds according to claim 1 wherein R¹ is an amido which is NR′

COR″

, and R′

is hydrogen and R″

is heterocycle and selected from the group consisting of;

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)picolinamide (40);

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)nicotinamide (41);

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)isonicotinamide (42);

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)benzofuran-2-carboxamide (43);

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-1H-indole-2-carboxamide (46); and

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-1H-indole-3-carboxamide (47).

22. The compound according to claim 1 which is:

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-1H-indole-2-carboxamide (46).

23. The compounds of claim 1 wherein X₁ is —

O— and

X₂ is —

CO—

.

24. The compounds of claim 1 wherein X₁ is —

CO— and

X₂ is —

O—

.

25. The compounds of claim 1 wherein R⁴ and R⁵ are both hydrogen.

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

27. The compound of claim 1 which is N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy)quinolin-3-yl)-4-methoxy-3-(3-methoxyphenyl)-benzamide (42b).

28. Compounds according to formula:

29. The compounds of claim 28, wherein R² is hydroxy;

wherein R³ is hydroxy,

wherein R⁴ is alkyl;

wherein R⁵ is alkyl;

wherein R⁶ is alkoxy;

wherein X₁ is —

N—

, or CR, wherein CR is hydrogen, hydroxy, alkyl, or alkoxy;

wherein R²⁰ is hydrogen;

wherein R²¹ is hydrogen;

wherein R²² is hydrogen; and

wherein R²³ is hydrogen.

30. Compounds of claim 28 which are selected from the group consisting of:

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)benzamide (8);

-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)biphenyl-2-carboxamide (12);

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)biphenyl-3-carboxamide (13);

2-Amino-N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)benzamide (18);

3-Amino-N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)benzamide (19); and

4-Amino-N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)benzamide (20).

31. Compounds of claim 28 which are selected from the group consisting of:

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-2-methoxybenzamide (9);

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-3-methoxybenzamide (10); and

N-(7-((2R,3,R4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-4-methoxybenzamide (11).