Compositions and methods for the prevention and/or treatment of mitochondrial disease, including Friedreich's ataxia

Patent metadata

Field	Value
Publication number	US-12049455-B2
Application number	US-202218087890-A
Country	US
Kind code	B2
Filing date	Dec 23, 2022
Priority date	Oct 4, 2019
Publication date	Jul 30, 2024
Grant date	Jul 30, 2024

Abstract

The disclosure provides therapeutic compositions (i.e., therapeutic agents) and methods of preventing or treating Friedreich's ataxia in a mammalian subject, reducing risk factors, signs and/or symptoms associated with Friedreich's ataxia (e.g., Complex I deficiency), and/or reducing the likelihood or severity of Friedreich's ataxia. The disclosure further provides novel intermediates for the production of said therapeutic compositions and related reduced versions of said therapeutic compositions, which reduce forms may also be used as therapeutic agents (or prodrugs of the therapeutic agent(s)).

First claim

What is claimed is:

1. A compound of formula E-G, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and/or solvates thereof, wherein E is 21 or 22:

and G is 23 or 24:

wherein,
J is O, S or N—R 11 ;
K is absent or —(CR 12 R 13 )—;
L is —(CR 12 R 13 )—;
each W is independently C (carbon) or N (nitrogen) and wherein for each use of W W, the bond between each W can be a single bond or double bond and further provided that if a single bond, each C (carbon) atom will have a hydrogen atom linked hereto in addition to one of R 4 , R 5 , R 6 or R 7 and in either case each of R 4 , R 5 , R 6 and R 7 attached thereto is independently selected from H, D, F, Cl, Br, I, C 1 -C 6 alkyl and C 1 -C 6 alkoxy, and if W is N (nitrogen), each of R 4 , R 5 , R 6 and R 7 attached thereto is independently absent (if W W is a double bond) or selected from H, D and C 1 -C 6 alkyl (if W W is a single bond);
each Q is independently a group of formula —(CR 12 R 13 )-, O or Si provided that each O and each Si is not directly bonded to O or Si;
each of R 1 , R 2 and R 3 is independently H, D, F, Cl, Br, I, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
or R 1 and R 2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic or heteroaromatic ring, or a 6-membered heterocyclic ring;
each R 8 ′, R 9 ′ and R 10 ′ is independently a C 1 -C 4 alkyl; or taken together R 8 ′ and R 9 ′ form a 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring;
R 11 is H, D or C 1 -C 6 alkyl;
each of R 12 and R 13 is independently H, D, F, Cl, Br, I, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
R 20 is H, D, F or C 1 -C 12 alkyl;
p is an integer from 0 to 20, inclusive; and
*** indicates the point of attachment of E to G and ** indicates the point of attachment of G to E.

2. The compound of claim 1 , wherein E is 21.

3. The compound of claim 2 , wherein the compound is of formula Compound M-0:

wherein each of R 1 , R 2 and R 3 is independently H, F, —CH 3 , —OCH 3 , —CH 2 CH 3 , —OCH 2 CH 3 , or —OCF 3 , p′ is an integer from 1 to 9, inclusive and p″ is an integer from 1 to 9, inclusive.

4. The compound of claim 2 , wherein the compound is

or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers, a tautomer, a hydrate, and/or a solvate thereof.

5. A composition or medicament comprising a compound of claim 1 .

Assignees

• Stealth Biotherapeutics Inc

Inventors

• Keefe Dennis
• Zheng Guozhu
• Arsenjans Pavels

Classifications

• C07C49/835

  having unsaturation outside an aromatic ring · CPC title

• C07C2601/08

  the ring being saturated · CPC title

• C07C2601/04

  with a four-membered ring · CPC title

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• A61K31/122

  having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin · CPC title