Cyclohexane-1,3-Diones for Use in the Treatment of Amyotrophic Lateral Sclerosis

Patent metadata

Field	Value
Publication number	US-2016039740-A1
Application number	US-201514887550-A
Country	US
Kind code	A1
Filing date	Oct 20, 2015
Priority date	Oct 29, 2009
Publication date	Feb 11, 2016
Grant date	—

Abstract

The present invention relates to the identification of provided cyclohexane-1,3-diones (CHD 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 CHD compounds.

First claim

We claim:

1 . A compound of a formula:

or a pharmaceutically acceptable salt thereof, wherein:
each R is independently hydrogen, halogen, optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted benzyl, or two R on the same carbon are taken together to form a 5-6 membered saturated, partially saturated, or aryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R 1 , R 2 , and R 3 are each independently —R, —OR, —SR, —S(O)R, —SO 2 R, —OSO 2 R, N(R) 2 , —NRC(O)R, —NRC(O)(CO)R, —NRC(O)N(R) 2 , —NRC(O)OR, —N(R)S(O)R, —N(R)SO 2 R, —N(R)SO 2 OR, —C(O)R, —C(O)OR, —OC(O)R, —OC(O)OR, —C(O)N(R) 2 , —OC(O)N(R) 2 , or an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
L is a valence bond or a bivalent saturated or partially unsaturated, branched or unbranched C 1-10 hydrocarbon chain, wherein 1-3 methylene units of L are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —SO 2 —, and wherein L is optionally substituted with 1-4 R groups, wherein two R on the same carbon or on adjacent carbons are optionally taken together to form a 3-6 membered saturated spirocyclic or fused monocyclic ring containing 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring A is a 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring optionally containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
m is 0-5;
each R a is independently —R, —OR, —SR, —S(O)R, —SO 2 R, —OSO 2 R, N(R) 2 , —NRC(O)R, —NRC(O)(CO)R, —NRC(O)N(R) 2 , —NRC(O)OR, —N(R)S(O)R, —N(R)SO 2 R, —N(R)SO 2 OR, —C(O)R, —C(O)OR, —OC(O)R, —OC(O)OR, —C(O)N(R) 2 , —OC(O)N(R) 2 , or:
two R a on adjacent carbons are taken together to form an optionally substituted 3-12 membered saturated, partially unsaturated, or aryl fused ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

at least one R a is independently

wherein Q is a valence bond or a bivalent optionally substituted saturated or partially unsaturated, branched or unbranched C 1-10 hydrocarbon chain, wherein 1-3 methylene units of Q are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —SO 2 —;
Ring B is a 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring optionally containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
n is 0-5;
each R b is independently —R, —OR, —SR, —S(O)R, —SO 2 R, —OSO 2 R, N(R) 2 , —NRC(O)R, —NRC(O)C(O)R, —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —N(R)S(O)R, —N(R)SO 2 R, —N(R)SO 2 OR, —C(O)R, —C(O)OR, —OC(O)R, —OC(O)OR, —C(O)N(R) 2 , —OC(O)N(R) 2 ; and
R 4 and R 4′ are each independently R, or R 4 and R 4′ are taken together to form an alkenylene optionally substituted with one or two R c groups; wherein
each R c is independently —R, —OR, —CN, —NO 2 , —SR, —S(O)R, —SO 2 R, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, —N(R) 2 , or wherein R c is a 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring optionally containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring optionally containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein R c is optionally substituted with p occurrences of R d , wherein:
p is 0 to 5; and
each R d is independently —R, —OR, —CN, —C(R) 3 , —NO 2 , —SR, —S(O)R, —SO 2 R, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 , providing where L is a valence bond, Ring A is phenyl, R a is methyl and m is 2, said Ring A is not 2,6-disubstituted.

2 . The compound according to claim 1 wherein L is a bivalent saturated branched or unbranched C 1-10 hydrocarbon chain.

3 . The compound according to claim 2 , wherein Ring A is a 5-6 membered aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

4 . The compound according to claim 3 , wherein Ring A is of the formula:

wherein m is 0-5.

5 . The compound according to claim 2 , wherein 1 methylene unit of L is replaced by —NR—, —O—, —S—, —C(O)—, or —C(O)O—.

6 . The compound according to claim 5 , wherein L is selected from a bivalent saturated C 2 -C 3 hydrocarbon chain and a bivalent saturated C 2 -C 3 hydrocarbon chain wherein 1 methylene unit of L is replaced by —O—, and wherein L is substituted with 1-2 R groups.

7 . The compound according to claim 6 , wherein Ring A is of the formula:

wherein m is 1-5.

8 . The compound according to claim 7 , wherein each R a is independently fluorine, chlorine, methyl, ethyl, propyl, butyl, methoxy, propoxy, butoxy or trifluoromethyl.

9 . The compound according to claim 8 , wherein m is 1-2.

10 . The compound according to claim 9 , wherein Ring A is of the formula:

11 . The compound according to claim 10 , wherein R 3 is selected from H, methyl and trifluoromethyl.

12 . The compound according to claim 1 , of any of the formulae:

or a stereochemically isomeric form thereof.

13 . A compound of formula I-a or I-b:

or a pharmaceutically acceptable salt thereof, wherein:
each R is independently hydrogen, halogen, or optionally substituted C 1-6 aliphatic;
R 1 , R 2 , and R 3 are each independently —R, or —OR;
L is a bivalent saturated branched or unbranched C 1-10 hydrocarbon chain, wherein 1-3 methylene units of L are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 , —SO 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —SO 2 —, and wherein L is optionally substituted with 1-4 R groups, wherein two R on the same carbon or on adjacent carbons are optionally ta

Assignees

• Kirsch Donald R
• Benmohamed Radhia
• Arvanites Anthony C
• Morimoto Richard J
• Zhang Wei
• Silverman Richard B

Inventors

• Kirsch Donald R
• Benmohamed Radhia
• Arvanites Anthony C
• Morimoto Richard J
• Zhang Wei
• Silverman Richard B

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07C49/577

  containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups · CPC title

• C07C49/563 Primary

  containing six-membered aromatic rings · CPC title

• C07C49/567

  containing halogen · CPC title

• A61P25/28

  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 title