Treatment of amyotrophic lateral sclerosis

Patent metadata

Field	Value
Publication number	US-10167263-B2
Application number	US-200913129854-A
Country	US
Kind code	B2
Filing date	Nov 20, 2009
Priority date	Nov 20, 2008
Publication date	Jan 1, 2019
Grant date	Jan 1, 2019

Abstract

The present invention relates to the identification of compounds and pharmaceutical compositions thereof for treating subjects with amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. The invention also provides methods of preparing the provided compounds.

First claim

What is claimed is:

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H;
R 2 is H and
R 3 is —R 10 , —OR 10 , —SR 10 , —S(O)R 10 , —SO 2 R 10 , —OSO 2 R 10 , —C(O)R 10 , —C(O)OR 10 , —OC(O)R 10 , —OC(O)OR 10 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , a suitable amino protecting group, or an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, or sulfur;
wherein R 10 is hydrogen, halogen, optionally substituted C 1-20 alkyl, optionally substituted phenyl, optionally substituted arylalkyl or monocyclic aryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein R 10 optionally is substituted with substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, nitro, hydroxy, amino, C 1-6 alkylamino, cyano, isocyano, isocyanato, and isothiocyanato substituents,
providing that R 3 is not benzimidazolyl and
providing that R 3 is not benzothiazolyl;

m is 0-5;
each R 4 is independently —R 11 , —SR 11 , —CN, —S(O)R 11 , —SO 2 R 11 , —OSO 2 R 11 , —N(R 11 ) 2 , —NR 11 C(O)R 11 , —NR 11 C(O)(CO)R 11 , —NR 11 C(O)N(R 11 ) 2 , —NR 11 C(O)OR 11 , —N(R 11 )S(O)R 11 , —N(R 11 )SO 2 R 11 , —N(R 11 )SO 2 OR 11 , —C(O)R 11 , —C(O)OR 11 , —OC(O)R 11 , —OC(O)OR 11 , —C(O)N(R 11 ) 2 , —OC(O)N(R 11 ) 2 , or a 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring optionally containing 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,
wherein R 11 is halogen, optionally substituted C 1-20 alkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted arylalkyl or aryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein R H optionally is substituted with substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, nitro, hydroxy, amino, C 1-6 alkylamino, cyano, isocyano, isocyanato, and isothiocyanato substituents; and,

providing where R 3 is H and m=1 or 2, R 4 is —R 12 , —OR 12 , —SR 12 , CN, —S(O)R 12 , —SO 2 R 12 , —OSO 2 R 12 , N(R 12 ) 2 , —NR 12 C(O)R 12 , —NR 12 C(O)(CO)R 12 , —NR 12 C(O)N(R 12 ) 2 , —NR 12 C(O)OR 12 , —N(R 12 )S(O)R 12 , —N(R 12 )SO 2 R 12 , —N(R 12 )SO 2 OR 12 , —C(O)R 12 , —C(O)OR 12 , —OC(O)R 12 , —OC(O)OR 12 , —C(O)N(R 12 ) 2 , —OC(O)N(R 12 ) 2 , or a 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring optionally containing 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
wherein R 12 is halogen, optionally substituted C 5-20 alkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted arylalkyl or aryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein R 12 optionally is substituted with substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, nitro, hydroxy, amino, C 1-6 alkylamino, cyano, isocyano, isocyanato, and isothiocyanato substituents,

providing where R 3 is H, m=2 and at least one R 4 is halogen, the at least one R 4 that is halogen is mew or ortho to the C—O bond; and
providing where R 3 is H, m=1, and R 4 is bromine, R 4 is meta to the C—O bond.

2. The compound of claim 1 , wherein m is 2 and said di-substituted phenyl moiety is

3. The compound of claim 2 , wherein said phenyl moiety is

4. The compound of claim 1 , wherein R 3 is selected from the group consisting of hydrogen and substituted or unsubstituted C 1-6 alkyl.

5. The compound of claim 1 of any one of the formulae:

6. A pharmaceutical composition for treating ALS comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.

7. A method of treating amyotrophic lateral sclerosis (ALS) comprising administering a therapeutically effective amount of a compound of claim 1 to a subject with ALS.

8. The compound of claim 1 wherein R 3 is selected from

9. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
R 2 is H and
R 3 is R 10 , —OR 10 , —SR 10 , —S(O)R 10 , —SO 2 R 10 , —OSO 2 R 10 , —C(O)R 10 , —C(O)OR 10 , —OC(O)R 10 , —OC(O)OR 10 , —C(O)N(R 10 ) 2 , —OC(O)N(R 10 ) 2 , a suitable amino protecting group, or an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-4 heteroatoms independently selected from nitrogen or sulfur,
wherein R 10 is halogen, optionally substituted C 1-20 alkyl, optionally substituted phenyl, optionally substituted arylalkyl or aryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein R 10 optionally is substituted with substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, nitro, hydroxy, amino, C 1-6 alkylamino, cyano, isocyano, isocyanato, and isothiocyanato substituents,
providing that R 3 is not benzimidazolyl and
providing that R 3 is not benzothiazolyl;

m is 0-5; and
each R 4 is independently R 11 , —OR 11 , —SR 11 , —CN, —S(O)R 11 , —SO 2 R 11 , —OSO 2 R 11 , —N(R 11 ) 2 , —NO 2 , —NR 11 C(O)R 11 , —NR 11 C(O)(CO)R 11 , —NR 11 C(O)N(R 11 ) 2 , —NR 11 C(O)OR 11 , —N(R 11 )S(O)R 11 , —N(R 11 )SO 2 R 11 , —N(R 11 )SO 2 OR 11 , —C(O)R 11 , —C(O)OR 11 , —OC(O)R 11 , —OC(O)OR 11 , —C(O)N(R 11 ) 2 , —OC(O)N(R 11 ) 2 , or a 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring optionally containing 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,
wherein R 11 is halogen, optionally substituted C 1-20 alkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted arylalkyl or aryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein R 11 optionally is substituted by substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, nitro, hydroxy, amino, C 1-6 alkylamino, cyano, isocyano, isocyanato, and isothiocyanato substituents.

10. The compound of claim 9 , wherein m is 2 and said di-substituted phenyl moiety is

11. The compound of claim 10 , wherein said phenyl moiety is

Assignees

• Kirsch Donald R
• Benmohamed Radhia
• Arvanites Anthony C
• Morimoto Richard I
• Chen Tian
• Silverman Richard B
• Univ Northwestern
• Cambria Pharmaceuticals Inc

Inventors

• Kirsch Donald R
• Benmohamed Radhia
• Arvanites Anthony C
• Morimoto Richard I
• Chen Tian
• Silverman Richard B

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D231/22 Primary

  with aryl radicals attached to ring nitrogen atoms · CPC title

• A61B5/412

  Detecting or monitoring sepsis · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title