Glycosidase inhibitors

Patent metadata

Field	Value
Publication number	US-9469657-B2
Application number	US-201414502213-A
Country	US
Kind code	B2
Filing date	Sep 30, 2014
Priority date	Aug 25, 2011
Publication date	Oct 18, 2016
Grant date	Oct 18, 2016

Abstract

Novel compounds of formula (I)

wherein R 1 to R 4 and X have the meaning according to the claims, are glucosidase inhibitors, and can be employed, inter alia, for the treatment of Alzheimer's disease.

First claim

The invention claimed is:

1. A method for treating a condition selected from the group of tauopathy, Parkinson's disease and amyotrophic lateral sclerosis, said method comprising administering an effective amount of at least one compound of formula (I)

wherein
R 1 denotes Y, COA, COOA, COO—(CH 2 ) n —Ar or COO—(CH 2 ) n -Cyc;
R 2 , R 3 denote independently from one another Y or SO 2 Y;
R 4 denotes Cl, Br, I, COOY, SO 2 Y, CN, CAr 3 , (CH 2 ) m —Ar,

R 5 denotes (CH 2 ) n —Ar, (CH 2 ) n -Cyc, (CH 2 ) n -Het, (CH 2 ) n —O—Ar, (CH 2 ) n —CY(OH)—Ar, (CH 2 ) n —CO—Ar or (CH 2 ) n —NY—Ar;
X denotes CH 2 , CO or CH(OH);
Y denotes H or A;
A denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atoms can be replaced independently from one another by Hal or in which one CH 2 group can be replaced by a —CH═CH— group;
Cyc denotes cycloalkyl having 3-7 C atoms, in which 1-4 H atoms can be replaced independently from one another by Hal or which can be substituted by Ar;
Ar denotes an unsaturated or aromatic mono- or bicyclic carbocycle having 3-12 C atoms, which can be substituted by at least one substituent selected from the group of Hal, A, (CY 2 ) n —OY, (CY 2 ) n —NYY, COOY, CONYY, NHCOY, SO 2 Y, CN and phenoxy;
Het denotes an unsaturated or aromatic mono-, bi- or tricyclic heterocycle having 1-12 C atoms and 1-4 N atoms, which can be substituted by at least one substituent selected from the group of Hal, A, (CY 2 ) n —OY, (CY 2 ) n —NYY, COOY, CONYY, NHCOY, SO 2 Y, SO 2 Ar, CN and thiophenyl;
Hal denotes F, Cl, Br or I;
m denotes 1, 2 or 3; and
n denotes 0, 1, 2, 3, 4, 5 or 6;

or a physiologically acceptable salt thereof to a mammal in need of such treatment.

2. The method according to claim 1 , wherein the condition is selected from the group of Progressive supranuclear palsy (PSP), Frontotcmporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Corticobasal degeneration (CBP), Pick's disease (PiD), Niemann Pick Disease (type c), Parkinson-dementia complex of Guam and Alzheimer's disease.

3. The method according to claim 1 , wherein
R 1 , R 2 , R 3 denote independently from one another H or A.

4. The method according to claim 3 , wherein
R 1 , R 2 , R 3 denote H.

5. The method according to claim 1 , wherein
R 5 denotes (CH 2 ) n —Ar, (CH 2 ) n -Cyc, (CH 2 ) n -Het, (CH 2 ) n —O—Ar or CY(OH)—Ar.

6. The method according to claim 1 , administering sub-formula (IA), (IB) or (IC)

wherein
R 6 denotes Cl, Br, I, COOY, CAr 3 or

R 7 denotes (CH 2 ) m —Ar or

R 8 denotes (CH 2 ) m —Ar; and
R 1 , R 2 , R 3 , R 5 , Y, Ar, Het, m and n have the meaning as defined in claim 1 ;
or a physiologically acceptable salt thereof.

7. The method according to claim 6 , administering sub-formula (IA-1) or (IA-2)

wherein
Hal denotes Cl, Br or I; and
R 5 and Y have the meaning as defined in claim 6 ;

or a physiologically acceptable salt thereof.

8. The method according to claim 1 , wherein
A denotes unbranched or branched alkyl having 1-6 C atoms,
in which 1-4 H atoms can be replaced independently from one another by Hal;

Ar denotes an aromatic mono- or bicyclic carbocycle having 3-12 C atoms,
which can be substituted by at least one substituent selected from the group of Hal, A, (CY 2 ) n —OY, (CY 2 ) n —NYY, SO 2 Y, CN and phenoxy;

Het denotes an unsaturated or aromatic mono-, bi- or tricyclic heterocycle having 2-12 C atoms and 1-3 N atoms,
which can be mono-, di- or trisubstituted by at least one substituent selected from the group of Hal, A, (CH 2 ) n —OY, (CY 2 ) n —NYY, SO 2 Y, SO 2 Ar, CN and thiophenyl; or
n denotes 0, 1, 2, 3 or 4.

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

or a physiologically acceptable salt thereof.

Assignees

• Merck Patent Gmbh

Inventors

• Donnelly Marianne
• Qiu Hui
• Yu Henry
• Liu-Bujalski Lesley
• Goutopoulos Andreas

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

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

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title