Compounds for the treatment of spinal muscular atrophy and other uses

• US 8,110,681 B2
• Filed: 03/13/2007
• Issued: 02/07/2012
• Est. Priority Date: 03/17/2006
• Status: Expired due to Fees

• Current Assignee: Albany Molecular Research Incorporated, Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services, United States Department Of Health And Human Services
• Original Assignee: Albany Molecular Research Incorporated, Science Applications International Corporation, United States Department Of Health And Human Services
• Inventors: Heemskerk, Jill, Barnes, Keith D., McCall, John M., Johnson, Graham, Fairfax, David, Johnson, Matthew Robert
• Primary Examiner(s): Saeed, Kamal
• Assistant Examiner(s): Grazier, Nyeemah A
• Application Number:
  US12/293,268
• Publication Number:
  US 20090312323A1
• Time in Patent Office: 1,792 Days
• Field of Search: None
• US Class Current: 544/144
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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: C07D 209/46 with an oxygen atom in position 1
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond

Abstract

Compounds of Formula (I) or (II) useful for the treatment of spinal muscular atrophy or other uses, as well as methods of using such compounds to increase SMN expression, increase EAAT2 expression, or increase the expression of a nucleic acid that encodes a translational stop codon introduced by mutation or frameshift.

Claims

1. A compound of Formula I:

2. The compound of claim 1, wherein:

B is CH₂;

R₄, R₅, R₆ and R₇ are independently selected from the group consisting of H, halogen, CN, NO₂, sulfonamide, C₁-C₈ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl, amino, C₁-C₄ dialkyl amino, C₁-C₄ alkylamino, C₃-C₆ cycloalkyl amino, morpholinyl, heteroaryl, and phenyl, wherein the C₁-C₈ alkyl is optionally substituted with one or more members selected from the group consisting of C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₆ dialkyl amino, C₁-C₆ alkylamino, cycloalkylamino, and morpholinyl, and the phenyl is optionally substituted with one or more members selected from the group consisting of halogen, NO₂, CN, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxy;

wherein at least R₅, R₆, or both are further selected from the group consisting of halogen, C₁-C₈ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ dialkyl amino, C₁ C₄ alkylamino, C₃-C₆ cycloalkyl amino, and morpholinyl, wherein the C₁-C₈ alkyl is optionally substituted with one or more members selected from the group consisting of C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₆ dialkyl amino, C₁-C₆ alkylamino, cycloalkylamino, and morpholinyl;

X is selected from the group consisting of

CN;

C(O)NR₉R₁₀ or CH₂NR₉R₁₀, wherein R₉ and R₁₀ are independently selected from the group consisting of H and C₁-C₆ alkyl, or R₉ and R₁₀ together with the nitrogen to which they are attached form a C₅-C₆ cycloalkyl ring or a heteroring such as morphline;

CH₂OR₁₁, wherein R₁₁ is H, C₁-C₈ alkyl, or C₃-C₆ cycloalkyl, wherein the C₁-C₈ alkyl optionally is substituted with one or members selected from the group consisting of C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₆ dialkyl amino, C₁-C₆ alkylamino, cycloalkylamino, and morpholinyl;

CH₂Z, wherein Z is halogen;

C(O)NHOH;

C(O)NHCN;

C(O)N(R₁)SO₂R₁₃, wherein R₁₃ is C₁-C₄ alkyl, phenyl, or substituted phenyl;

C₁-C₈ alkyl, optionally substituted with one or more members selected from the group consisting of C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₆ dialkylamino, and C₁-C₆ alkylamino; and

C₂-C₈ alkenyl optionally substituted with one or more members selected from the group consisting of C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₆ dialkylamino, and C₁-C₆ alkylamino.

3. The compound of claim 1, wherein X is selected from the group consisting of

CN;

CH₂OR₁₁, wherein R₁₁ is H, C₁-C₈ alkyl, or C₃-C₆ cycloalkyl, wherein the C₁-C₈ alkyl optionally is substituted with one or members selected from the group consisting of C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₆ dialkyl amino, C₁-C₆ alkylamino, cycloalkylamino, and morpholinyl;

C₁-C₈ alkyl, optionally substituted with one or more members selected from the group consisting of C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₆ dialkylamino, and C₁-C₆ alkylamino.

4. The compound of claim 1, wherein R₁ and R₂ are independently selected from the group consisting of H and C₁-C₃ alkyl.

5. The compound of claim 1, wherein R₅ and R₆ are independently selected from the group consisting of halogen, C₁-C₈ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl, amino, C₁-C₄ dialkyl amino, C₁-C₄ alkylamino, C₃-C₆ cycloalkyl amino, and morpholinyl, wherein the C₁-C₈ alkyl is optionally substituted with one or more members selected from the group consisting of C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₆ dialkyl amino, C₁-C₆ alkylamino, cycloalkylamino, and morpholinyl.

6. The compound of claim 1, wherein R₇ is selected from the group consisting of halogen, C₁-C₈ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl, amino, C₁-C₄ dialkyl amino, C₁-C₄ alkylamino, C₃-C₆ cycloalkyl amino, and morpholinyl, wherein the C₁-C₈ alkyl is optionally substituted with one or more members selected from the group consisting of C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₆ dialkyl amino, C₁-C₆ alkylamino, cycloalkylamino, and morpholinyl.

7. The compound of claim 1, wherein X is selected from the group consisting of

CN;

C(O)NR₉R₁₀, wherein R₉ and R₁₀ are independently selected from the group consisting of H and C₁-C₆ alkyl, or R₉ and R₁₀ together with the nitrogen to which they are attached form a C₅-C₆ cycloalkyl ring or a heteroring such as morphline;

CH₂OR₁₁, wherein R₁₁ is H, C₁-C₈ alkyl, or C₃-C₆ cycloalkyl, wherein the C₁-C₈ alkyl optionally is substituted with one or members selected from the group consisting of C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₆ dialkyl amino, C₁-C₆ alkylamino, cycloalkylamino, and morpholinyl;

CH₂NR₉R₁₀, wherein R₉ and R₁₀ are as defined above,

CH₂Z, wherein Z is halogen;

C(O)NHOH;

C(O)NHCN; and

C(O)N(R₁)SO₂R₁₃, wherein R₁₃ is C₁-C₄ alkyl, phenyl, or substituted phenyl.

8. The compound of claim 7, wherein X is selected from the group consisting of

CN;

CH₂OR₁₁, wherein R₁₁ is H, C₁-C₈ alkyl, or C₃-C₆ cycloalkyl, wherein the C₁-C₈ alkyl is optionally substituted one or more members selected from the group consisting of C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₆ dialkyl amino, C₁-C₆ alkylamino, cycloalkylamino, and morpholinyl;

CH₂NR₉R₁₀, wherein R₉ and R₁₀ are independently selected from the group consisting of H and C₁-C₆ alkyl, or R₉ and R₁₀ together with the nitrogen to which they are attached form a C₅-C₆ cycloalkyl ring or a heteroring such as morphline; and

CH₂Z, wherein Z is halogen.

9. The compound of claim 1, wherein X is selected from the group consisting of

C₁-C₈ alkyl, optionally substituted with one or more members selected from the group consisting of C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₆ dialkylamino, and C₁-C₆ alkylamino;

and

C₁-C₈ alkenyl, optionally substituted with one or more members selected from the group consisting of C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₆ dialkylamino, and C₁-C₆ alkylamino.

10. A compound according to claim 1, wherein the compound is:

11. A composition comprising a compound of claim 1, and a carrier.

12. A compound of Formula I:

13. A compound of claim 12, wherein the compound is:

14. A compound of Formula I:

15. A compound of claim 14, wherein the compound is: