Claims for Patent: 7,935,687

Summary for Patent: 7,935,687

Title:	Methods for treating spinal muscular atrophy using tetracycline compounds
Abstract:	Methods for using tetracycline compounds for the treatment of spinal muscular atrophy are described.
Inventor(s):	Berniac; Joel (Stoneham, MA), Bowser; Todd (Charlton, MA), Draper; Michael (Plaistow, NH), Levy; Stuart B. (Boston, MA), Nelson; Mark L. (Norfolk, MA)
Assignee:	Paratek Pharmaceuticals, Inc. (Boston, MA)
Application Number:	12/102,623
Patent Claims:	1. A method for treating a subject for spinal muscular atrophy, comprising: administering to said subject an effective amount of a tetracycline compound of formula I: ##STR00154## wherein X is CR.sup.6'R.sup.6; R.sup.2 and R.sup.2' are each hydrogen; R.sup.4' and R.sup.4'' are each alkyl; R.sup.3, R.sup.4a, R.sup.11 and R.sup.12 are each hydrogen; R.sup.4 is NR.sup.4'R.sup.4''; R.sup.5 and R.sup.5' are each hydrogen; R.sup.6 and R.sup.6' are each hydrogen; R.sup.7 is acyl, amino, phenyl, pyridinyl, furanyl, pyrrolyl, tetrahydropyridinyl, quinolinyl, or aminoalkyl; R.sup.8 is hydrogen; R.sup.9 is hydrogen or phenyl; and R.sup.10 is hydroxyl; or a pharmaceutically acceptable salt, ester or enantiomer thereof, such that said spinal muscular atrophy in said subject is treated. 2. The method of claim 1, wherein R.sup.7 is amino. 3. The method of claim 2, wherein said amino is dialkylamino. 4. The method of claim 3, wherein said dialkylamino is dimethylamino. 5. The method of claim 1, wherein R.sup.9 is hydrogen. 6. The method of claim 5, wherein R.sup.7 is phenyl or pyridinyl, and further wherein said phenyl or pyridinyl is of formula V: ##STR00155## wherein A.sup.g, A.sup.i, A.sup.j and A.sup.k are each C and A.sup.h is N or C; and when A.sup.h is C, then R.sup.7g, R.sup.7h, R.sup.7i, R.sup.7j and R.sup.7k are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R.sup.7j and R.sup.7i are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring; or R.sup.7h is absent when A.sup.h is N. 7. The method of claim 6, wherein A.sup.h is C. 8. The method of claim 7, wherein R.sup.7g, R.sup.7h, R.sup.7i and R.sup.7k are each hydrogen. 9. The method of claim 6, wherein R.sup.7j is carbonyl, and further wherein said carbonyl is of formula VI: ##STR00156## wherein R.sup.7s and R.sup.7t are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R.sup.7s and R.sup.7t are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring. 10. The method of claim 9, wherein R.sup.7t is hydrogen. 11. The method of claim 9, wherein R.sup.7s is alkyl, and further wherein said alkyl is of formula VII: ##STR00157## wherein D is O, N, NR.sup.7' or CR.sup.7'; n is an integer from 0 to 10; R.sup.7' is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; and when D is N or CR.sup.7', R.sup.71 and R.sup.7m are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R.sup.71 and R.sup.7m are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring; or when D is O, R.sup.71 is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfonyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic and R.sup.7m is absent. 12. The method of claim 11, wherein D is N. 13. The method of claim 11, wherein n is 2. 14. The method of claim 11, wherein R.sup.71 and R.sup.7m are each alkyl. 15. The method of claim 14, wherein said alkyl is methyl. 16. The method of claim 9, wherein R.sup.7s and R.sup.7t are each hydrogen. 17. The method of claim 9, wherein R.sup.7s and R.sup.7t are each alkyl. 18. The method of claim 17, wherein said alkyl is methyl. 19. The method of claim 9, wherein R.sup.7s and R.sup.7t are linked to form a 6-membered heterocyclic ring. 20. The method of claim 11, wherein D is N or O. 21. The method of claim 11, wherein n is 1, 2, 3 or 4. 22. The method of claim 11, wherein R.sup.71 is aryl. 23. The method of claim 21, wherein R.sup.71 and R.sup.7m are each alkyl. 24. The method of claim 21, wherein R.sup.71 and R.sup.7m are each hydrogen. 25. The method of claim 21, wherein R.sup.7m is alkyl or acyl. 26. The method of claim 21, wherein R.sup.71 and R.sup.7m are linked to form a 5- or 6-membered heterocyclic ring. 27. The method of claim 9, wherein R.sup.7s is alkyl and further wherein said alkyl is alkoxycarbonyl substituted alkyl, heterocyclic substituted alkyl, or hydroxyl substituted alkyl. 28. The method of claim 6, wherein R.sup.7i and R.sup.7j are linked to form a 6-membered aryl ring. 29. The method of claim 28, wherein said aryl ring is a benzene ring. 30. The method of claim 6, wherein R.sup.7j is acyl. 31. The method of claim 6, wherein R.sup.7j is carbonyl. 32. The method of claim 31, wherein said carbonyl is alkoxy substituted carbonyl. 33. The method of claim 6, wherein A.sup.h is N. 34. The method of claim 33, wherein R.sup.7g, R.sup.7j and R.sup.7k are each hydrogen. 35. The method of claim 5, wherein R.sup.7 is tetrahydropyridinyl. 36. The method of claim 35, wherein R.sup.7 is ##STR00158## 37. The method of claim 5, wherein R.sup.7 is quinolinyl. 38. The method of claim 5, wherein R.sup.7 is furanyl or pyrrolyl, and further wherein said furanyl or pyrrolyl is of formula X: ##STR00159## wherein G.sup.a is N or O; G.sup.b, G.sup.c, G.sup.d and G.sup.e are each CR.sup.7f*, R.sup.7f* is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl orheterocyclic; R.sup.7a* is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic when G.sup.a is N or R.sup.7a* is absent when G.sup.a is O; R.sup.7b* is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; R.sup.7c* is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; R.sup.7d* is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic orR.sup.7d* is covalently bonded to the 7-position of the tetracycline compound; and R.sup.7e* is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R.sup.7e* is covalently bonded to the 7-position of the tetracycline compound; provided that one of R.sup.7d* or R.sup.7e* are covalently bonded to the 7-position of the tetracycline compound. 39. A method for treating a subject for spinal muscular atrophy, comprising administering to said subject an effective amount of a tetracycline compound selected from: ##STR00160## ##STR00161## ##STR00162## ##STR00163## ##STR00164## ##STR00165## ##STR00166## ##STR00167## ##STR00168## ##STR00169## ##STR00170## ##STR00171## ##STR00172## and pharmaceutically acceptable salts, esters and enantiomers thereof, such that said spinal muscular atrophy in said subject is treated. 40. The method of claim 1, wherein said tetracycline compound is of formula XII: ##STR00173## wherein r is an integer from 1 to 10; M is OR.sup.7o* or NR.sup.7p*R.sup.7q*; Q is hydrogen or alkyl; R.sup.7o* is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; and R.sup.7p* and R.sup.7q* are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R.sup.7p* and R.sup.7q* are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring. 41. The method of claim 1, wherein said tetracycline compound is of formula XIV: ##STR00174## wherein t is an integer from 1 to 10; U is OR.sup.7u* or NR.sup.7v*R.sup.7w*; R.sup.7u* is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; and R.sup.7v* and R.sup.7w* are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R.sup.7v* and R.sup.7w* are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring. 42. The method of claim 1, wherein said tetracycline compound is of formula XV: ##STR00175## wherein u is an integer from 1 to 10; L is OR.sup.7x* or NR.sup.7y*R.sup.7z*; R.sup.7x* is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alloxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; and R.sup.7y* and R.sup.7z* are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R.sup.7y* and R.sup.7z* are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring. 43. The method of claim 1, wherein said tetracycline compound is of formula XVI: ##STR00176## wherein v and v* are each independently an integer from 1 to 10; R.sup.7a** is hydrogen or alkyl; T is OR.sup.7b** or NR.sup.7c**R.sup.7d**; R.sup.7b** is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; and R.sup.7c** and R.sup.7d** are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R.sup.7c** and R.sup.7d** are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring. 44. The method of claim 1, wherein said tetracycline compound is of formula XVII: ##STR00177## wherein x and x* are each independently an integer from 1 to 10; A* is OR.sup.7e** or NR.sup.7f**R.sup.7g** D* is NH, NCH.sub.3, O, or CH.sub.2; R.sup.7e** is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; and R.sup.7f** and R.sup.7g** are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R.sup.7f** and R.sup.7g** are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring. 45. The method of claim 1, wherein said tetracycline is of formula XVIII: ##STR00178## wherein u is an integer from 1 to 10; G* is OR.sup.7h** or NR.sup.7i**R.sup.7j**; E* is NH, NCH.sub.3, O, or CH.sub.2; R.sup.7h** is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; and R.sup.7i** and R.sup.7j** are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R.sup.7i** and R.sup.7j** are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring. 46. The method of claim 1, wherein said tetracycline compound is of formula XIX: ##STR00179## wherein y is an integer from 1 to 10; K* is NR.sup.71**R.sup.7m**; J* is NH or NCH.sub.3; and R.sup.71** and R.sup.7m** are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R.sup.71** and R.sup.7m** are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring. 47. The method of claim 1, wherein said compound is of formula XX: ##STR00180## wherein W'' is O; and R.sup.7a'' and R.sup.7c'' are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R.sup.7a'' and R.sup.7c'' are linked together to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring; or a pharmaceutically acceptable salt thereof. 48. The method of claim 1, wherein said subject is a human. 49. The method of claim 1, further comprising administering said tetracycline compound in combination with a second agent. 50. The method of claim 1, further comprising administering said tetracycline compound in combination with a pharmaceutically acceptable carrier. 51. The method of claim 1, wherein said tetracycline compound increases exon 7 inclusion. 52. The method of claim 1, wherein said tetracycline compound increases intron 6 splicing. 53. The method of claim 1, wherein said tetracycline compound increases cellular SMN protein levels. 54. The method of claim 1, wherein said tetracycline compound increases gems in cells of said subject. 55. The method of claim 1, wherein said tetracycline compound increases FL SMN2 mRNA expression in said subject's liver and/or kidney. 56. The method of claim 1, wherein said compound is: ##STR00181## or a pharmaceutically acceptable salt, ester or enantiomer thereof. 57. The method of claim 1, wherein said compound is: ##STR00182## or a pharmaceutically acceptable salt, ester or enantiomer thereof. 58. The method of claim 1, wherein said compound is: ##STR00183## or a pharmaceutically acceptable salt, ester or enantiomer thereof. 59. The method of claim 1, wherein said compound is: ##STR00184## or a pharmaceutically acceptable salt, ester or enantiomer thereof. 60. The method of claim 1, wherein said compound is: ##STR00185## or a pharmaceutically acceptable salt, ester or enantiomer thereof. 61. The method of claim 1, wherein said compound is: ##STR00186## or a pharmaceutically acceptable salt, ester or enantiomer thereof. 62. The method of claim 1, wherein said compound is: ##STR00187## or a pharmaceutically acceptable salt, ester or enantiomer thereof. 63. The method of claim 1, wherein said compound is: ##STR00188## or a pharmaceutically acceptable salt, ester or enantiomer thereof.

Details for Patent 7,935,687

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132	06/04/1986		2027-04-12
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2027-04-12
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	Injection	103132			2027-04-12