Compounds for the treatment, alleviation or prevention of disorders associated with Tau aggregates

Patent metadata

Field	Value
Publication number	US-11814378-B2
Application number	US-202016738444-A
Country	US
Kind code	B2
Filing date	Jan 9, 2020
Priority date	Jan 5, 2018
Publication date	Nov 14, 2023
Grant date	Nov 14, 2023

Abstract

The present invention relates to novel compounds that can be employed in the treatment, alleviation or prevention of a group of disorders and abnormalities associated with Tau (Tubulin associated unit) protein aggregates including, but not limited to, Neurofibrillary Tangles (NFTs), such as Alzheimer's disease (AD).

First claim

The invention claimed is:

1. A compound of formula (I):

or all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof;
wherein

A is selected from the group consisting of

can be attached to Q at any available position, wherein

is substituted by one or more substituents R j , wherein if A is

, R j is not —CN, -halogen or —CF 3 ;
wherein if A is

R j is not -halogen; and wherein

can be optionally substituted by one or more substituents R;
B is selected from the group consisting of O and NR a ;
E and V are independently selected from the group consisting of N, NR 5 , O and S;
G is selected from the group consisting of a benzene ring and a pyridine ring;
J is selected from the group consisting of O and N—R 1 ;
Q is selected from the group consisting of N and C—R 1 ;
Y is selected from the group consisting of CZ and N, provided that when Y is N and Y 1 , Y 2 and Y 3 are CZ, B is N—alkyl or O;
Y 1 is selected from the group consisting of CZ and N;
Y 2 is selected from the group consisting of CZ and N;
Y 3 is selected from the group consisting of CZ and N;
alkyl and CN;
Z is independently selected from the group consisting of H, halogen, O-alkyl, alkyl and CN;
R is independently selected from the group consisting of

and —NR 3 R 4 ;
R a is selected from the group consisting of H and alkyl;
R b , R c , R d , R e , R f , and R g are independently selected from the group consisting of H and alkyl, or any two of R b , R c , R d , R e , R f , and R g may be joined to form a 3 to 8-membered ring;
R j independently selected from the group consisting of -halogen, —O-alkyl, —CF 3 , —CN, —NR 3 R 4 ,

wherein a C 1-2 carbon atom-containing bridge can be present between the a carbon atom and the c or d carbon atom or wherein a C 1-2 carbon atom-containing bridge can be present between the b carbon atom and the c or d carbon atom
R 1 is selected from the group consisting of H and alkyl;
R 2 is independently selected from the group consisting of alkyl, F and ═O, wherein the alkyl can be optionally substituted by halogen, —OH or —O-alkyl and wherein if two R 2 are geminal they can be joined to form a 3 to 6-membered ring;
R 3 and R 4 are independently selected from the group consisting of H and alkyl, wherein the alkyl can be optionally substituted by halogen, —OH or —O-alkyl;
R 5 is selected from the group consisting of H and alkyl;
n is 0, 1, 2, 3 or 4;
r and s are independently 0, 1, 2 or 3; and
t and u are independently 1, 2 or 3.

2. The compound according to claim 1 , which is a compound of formula (Ia):

Wherein A, B, R b , R c , R d , R e , R f , R g , Y and Z are as defined in claim 1 .

3. The compound according to claim 1 , which is a compound of formula (Ib):

wherein A, B, R b , R c , R d , R e , R f , R g and Z are as defined in claim 1 .

4. The compound according to claim 1 , wherein A is

wherein

can be attached to Q or to N at any available position, and wherein

can be optionally substituted by one or more substituents R.

5. The compound according to claim 1 , which is a compound of the formula (Ic):

wherein E, R, V and Z are as defined in claim 1 .

6. The compound according to claim 1 , wherein the compound is selected from the group consisting of

7. A pharmaceutical composition comprising a compound as defined in claim 1 and optionally a pharmaceutically acceptable carrier or excipient.

8. The compound as defined in claim 1 for use as a medicament.

9. A method of treating or alleviating a disorder or abnormality associated with Tau protein aggregates, the method comprising administering an effective amount of a compound as defined in claim 1 to a subject in need thereof.

10. The method according to

Assignees

• Ac Immune Sa

Inventors

• Nampally Sreenivasachary
• Gabellieri Emanuele
• Molette Jerome

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/13

  Amines {(A61K31/04 takes precedence)} · CPC title

• A61K31/27

  of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/4375

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title