Myelination stimulator compounds, and methods of treatment

Patent metadata

Field	Value
Publication number	US-2021188792-A1
Application number	US-201917054600-A
Country	US
Kind code	A1
Filing date	May 10, 2019
Priority date	May 11, 2018
Publication date	Jun 24, 2021
Grant date	—

Abstract

The invention is directed towards compounds, methods of stimulating myelination, stimulating proliferation of oligodendrocytes (OLs) or stimulating oligodendrocyte precursor cells and methods of treating diseases, disorders or symptoms thereof.

First claim

What is claimed:

1 . A compound of Formula I:

or pharmaceutically acceptable salts, solvates, or hydrates, thereof, wherein:
each R 1 is independently H, alkyl substituted with 1-3 independent R 4 ;
each R 2 is independently alkyl substituted with 1-3 independent R 4 ; or
R 1 and R 2 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl ring having 1, 2, or 3 heteroatoms selected from N, O, and S, wherein the heterocycloalkyl ring may be optionally substituted with 1-3 independent R 4 ;
each R 3 is independently alkyl, alkoxy, amino, halo, C(O)R 5 , C(O)OR 5 , SR 5 , or NR 5 R 6 ;
each R 4 is independently alkoxy, or aryl optionally substituted with 1-3 independent R 7 ;
each R 5 is independently H, or alkyl;
each R 6 is independently H, or alkyl;
each R 7 is independently alkyl, alkoxy, amino, halo, C(O)R 5 , C(O)OR 5 , SR 5 , S(O) 2 R 5 , S(O) 2 NR 5 R 6 , or NR 5 R 6 ;
n is 0, 1, 2, 3, or 4; and
m is 1,2, 3, or 4.

2 . The compound of claim 1 of Formula I, or pharmaceutically acceptable salts, solvates, or hydrates, thereof, wherein:
each R 1 is independently H;
each R 2 is independently alkyl substituted with 1-3 independent R 4 ;
n is 0, and m is 1.

3 . The compound of claim 1 of Formula I, or pharmaceutically acceptable salts, solvates, or hydrates, thereof, wherein:
each R 1 is independently H;
each R 2 is independently alkyl substituted with 1-3 independent R 4 ;
n is 0, and m is 1; and
each R 4 is independently alkoxy.

4 . The compound of claim 1 of Formula I, or pharmaceutically acceptable salts, solvates, or hydrates, thereof, wherein:
each R 1 is independently H;
each R 2 is independently alkyl substituted with 1-3 independent R 4 ;
n is 0, and m is 2.

5 . The compound of claim 1 of Formula I, or pharmaceutically acceptable salts, solvates, or hydrates, thereof, wherein:
each R 1 is independently H;
each R 2 is independently alkyl substituted with 1-3 independent R 4 ;
n is 0, and m is 2;
each R 4 is independently alkoxy.

6 . The compound of claim 1 of Formula I, or pharmaceutically acceptable salts, solvates, or hydrates, thereof, wherein:
R 1 and R 2 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl ring having 1 or 2 heteroatoms selected from N, O, and S, wherein the heterocycloalkyl ring may be optionally substituted with with 1-3 independent R 4 ;
n is 0, and m is 1.

7 . The compound of claim 1 of Formula I, or pharmaceutically acceptable salts, solvates, or hydrates, thereof, wherein:
R 1 and R 2 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl ring having 1 or 2 heteroatoms selected from N, O, and S, wherein the heterocycloalkyl ring may be optionally substituted with 1-3 independent R 4 ;
n is 0, and m is 1;
each R 4 is independently aryl optionally substituted with 1-3 independent R 7 ;
each R 7 is independently alkyl, alkoxy, amino, halo, C(O)R 5 , C(O)OR 5 , SR 5 , S(O) 2 R 5 , S(O) 2 NR 5 R 6 , or NR 5 R 6 .

8 . The compound of claim 1 of Formula I, or pharmaceutically acceptable salts, solvates, or hydrates, thereof:
wherein n is 0, and m is 1;
wherein n is 0, and m is 2.

9 . The compound of claim 1 , that is:

or a pharmaceutically acceptable salt thereof.

10 . A pharmaceutical composition comprising a compound of any of claims 1 - 9 , or pharmaceutically acceptable salts, solvates, or hydrates, thereof and a pharmaceutically acceptable carrier.

11 . A method of stimulating myelination (e.g., treating hypomyelination), comprising administering to a subject in need thereof, an effective amount of a compound or pharmaceutical composition of any of claims 1 - 10 , or pharmaceutically acceptable salts, solvates, or hydrates, thereof.

12 . A method of stimulating proliferation of oligodendrocytes (OLs) or stimulating oligodendrocyte precursor cells, comprising administering to a subject in need thereof, an effective amount of a compound of Formula I in any of claims 1 - 9 , or pharmaceutically acceptable salts, solvates, or hydrates, thereof, or pharmaceutical composition thereof of claim 10 .

13 . A method of reducing ventriculomegaly, comprising administering to a subject in need thereof, an effective amount of a compound of Formula I in any of claims 1 - 9 , or pharmaceutically acceptable salts, solvates, or hydrates, thereof, or pharmaceutical composition thereof of claim 10 .

14 . A method of treating a subject suffering from or susceptible to a disorder or disease, comprising administering to said subject in need thereof, an effective amount of a compound of any of claims 1 - 9 , or pharmaceutically acceptable salts, solvates, or hydrates, thereof, or pharmaceutical composition thereof of claim 10 , such that said subject is treated for said disorder.

15 . The method of claim 14 , wherein the subject is an animal other than a human.

16 . The method of claim 14 wherein the disease or disorder is periventricular white matter injury (PWMI; also referred to as diffuse white matter injury, or leukoencephalopathy), myelination disorders, abnormal PreOL proliferation, abnormal PreOL differentiation, symptoms associated with PWMI (e.g., attention, behavioral, and socialization deficits, impairment in intellegence, object working memory, various executive functions, impulse control, or some characteristics of autism), or cerebral palsey.

Assignees

• Univ Florida

Inventors

• Rivkees Scott A

Classifications

• C07D285/24 Primary

  with oxygen atoms directly attached to the ring sulfur atom · CPC title

• A61K31/5415 Primary

  ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam · 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

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title