ISOINDOLINE COMPOUNDS FOR THE TREATMENT OF SPINAL MUSCULAR ATROPHY AND OTHER USES

• US 20100267712A1
• Filed: 09/26/2008
• Published: 10/21/2010
• Est. Priority Date: 09/27/2007
• Status: Abandoned Application

• Current Assignee: Albany Molecular Research Incorporated, United States Department Of Health And Human Services
• Original Assignee: Albany Molecular Research Incorporated, Human Services, Science Applications International Corporation, The United States of America As Represented By The Secretary of Agriculture
• Inventors: Heemskerk, Jill E., Barnes, Keith D., McCall, John M.
• Application Number:
  US12/680,285
• Publication Number:
  US 20100267712A1
• Time in Patent Office: Days
• US Class Current: 514/230.500
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/22 for herpes viruses
• 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 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 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
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/056 with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Abstract

Disclosed is a compound of Formula (I) in which W and R¹-R⁶ are defined herein. Also disclosed is a method of treating spinal muscular atrophy, 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 directly or indirectly by mutation or frameshift.

Claims

1. A compound or pharmaceutically acceptable salt of Formula I:

2. The compound or pharmaceutically acceptable salt of claim 1, wherein R¹ is selected from the group consisting of

a heteroaryl comprising one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom,

a heterocycloalkyl comprising a 5- or 6-membered monocyclic ring that contains one, two, or three heteroatoms selected from nitrogen, oxygen, and/or sulfur, and

a heterocycloalkyl-fused phenyl, wherein the heterocycloalkyl consists of a 5- or 6-membered monocyclic ring that contains one, two, or three heteroatoms selected from nitrogen, oxygen, and/or sulfur,

each of which is optionally substituted with 1 to 3 substituents individually selected from the group consisting of C₁-C₈ alkyl, C₃-C₆ cycloalkyl, C₁-C₈ alkoxy, C₁-C₈ haloalkoxy, C₁-C₈ haloalkyl, halogen, —

CN, —

C(O)OR⁷, —

C(O)NR⁷(R⁸), —

NO₂, —

SO₂NR⁷(R⁸), —

NR⁹(SO₂)R¹⁰, —

NR⁷C(O)NR⁸R⁹, amino, C₁-C₄ alkylamino, C₃-C₆ cycloalkylamino, aryl, heteroaryl, and heterocycloalkyl.

5. The compound or pharmaceutically acceptable salt of claim 1, wherein R¹ is selected from the group consisting of

12. The compound or pharmaceutically acceptable salt of claim 1, wherein W is C(O) or CH₂.

14. The compound or pharmaceutically acceptable salt of claim 1, wherein R² is selected from the group consisting of H, hydroxyl, halogen, C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈ haloalkoxy, nitro, amino, C₁-C₄ alkylamino, aryl, and heterocycloalkyl.

16. The compound or pharmaceutically acceptable salt of claim 1, wherein R³ is selected from the group consisting of H, hydroxyl, halogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₁-C₈ alkoxy, C₃-C₆ cycloalkyloxy, C₁-C₈ haloalkoxy, alkylsulfonyl, nitro, amino, C₁-C₄ alkylamino, —

NR⁷C(O)R⁸, heterocycloalkyl, and heteroaryl.

18. The compound or pharmaceutically acceptable salt of claim 1, wherein R⁴ is selected from the group consisting of H, hydroxyl, halogen, C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈ haloalkoxy, nitro, amino, C₁-C₄ alkylamino, and heterocycloalkyl.

20. The compound or pharmaceutically acceptable salt of claim 1, wherein R⁵ is selected from the group consisting of H, hydroxyl, halogen, C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈ haloalkoxy, amino, C₁-C₄ alkylamino, and —

NR⁷C(O)R⁸.

22. A compound according to claim 1 of Table 1, or pharmaceutically acceptable salt thereof.

23. A composition comprising at least one compound or pharmaceutically acceptable salt of claim 1 and a pharmaceutically acceptable carrier.

24. A method of increasing survival motor neuron protein (SMN) expression in a cell comprising administering a compound or pharmaceutically acceptable salt of claim 1 to a cell comprising a nucleic acid encoding SMN2, wherein the cell optionally is in a host, whereby SMN expression is increased.

26. The method of claim 24, wherein the cell is in a human afflicted with a disease associated with under-expression of SMN.

27. The method of claim 26, wherein the disease is spinal muscular atrophy (SMA).

28. A method of treating spinal muscular atrophy (SMA) in a mammal comprising administering a therapeutically effective amount of at least one compound or pharmaceutically acceptable salt of claim 1 to the mammal, whereupon SMA is treated.

29. A method of increasing in a cell the expression of a nucleic acid that encodes a translational stop codon, the method comprising administering a compound or pharmaceutically acceptable salt of claim 1 to a cell comprising a nucleic acid that encodes a translational stop codon, wherein the cell optionally is in a host, whereby expression of the nucleic acid is increased.

30. The method of claim 29, wherein the stop codon has been introduced directly or indirectly by mutation or frameshift.

32. The method of claim 30, wherein the cell is in a human afflicted with a disease associated with the translational stop codon introduced directly or indirectly by mutation or frameshift.

33. The method of claim 32, wherein the disease is cancer, diabetes, cystic fibrosis, Rett syndrome, ataxia-telangiecstasia, or muscular dystrophy.

34. A method of increasing the expression of excitatory amino acid transporter (EAAT2) in a cell comprising administering to a cell comprising a nucleic acid that encodes EAAT2 a compound or pharmaceutically acceptable salt of claim 1, wherein the cell optionally is in a host, whereby the expression of EAAT2 is increased.

36. The method of claim 34, wherein the cell is in a human that has an elevated level of glutamate in the central nervous system, has suffered stroke or trauma to an area of the central nervous system, or is afflicted with a neurodegenerative disease.

40. A method of treating or preventing a neurological disorder selected from the group consisting of SMA, stroke, Parkinson'"'"'s disease, Alzheimer'"'"'s disease, ALS, MS, Huntington'"'"'s disease, and epilepsy in a mammal comprising administering a therapeutically effective amount of at least one compound or pharmaceutically acceptable salt of claim 1 to the mammal, whereupon the neurological disorder is treated or prevented.

41. A method of treating or preventing an infectious disease in a mammal comprising administering a therapeutically effective amount of at least one compound or pharmaceutically acceptable salt of claim 1 to the mammal, whereupon the infectious disease is treated or prevented.

42. The method of claim 41, wherein the infectious disease is viral.

43. The method of claim 41, wherein the infectious disease is Human Immunodeficiency Virus infection (HIV/AIDS), viral hepatitis, Human Herpes virus (HHV) infection, Human Papilloma Virus (HPV) infection, severe acute respiratory syndrome (SARS), herpes zoster, or Pseduomonas aeruginosa infection.

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