Combination treatment comprising administration of 2-amino-3,5,5-trifluoro-3,4,5,6-tetrahydropyridines

Patent metadata

Field	Value
Publication number	US-10004738-B2
Application number	US-201615231182-A
Country	US
Kind code	B2
Filing date	Aug 8, 2016
Priority date	Aug 10, 2015
Publication date	Jun 26, 2018
Grant date	Jun 26, 2018

Abstract

The present invention is directed to the combined use of BACE1 inhibitor of Formula I

and a compound useful in active or passive Tau immunotherapy, a compound useful in active or passive Aβ peptide immunotherapy, an NMDA receptor antagonists, an acetylcholine esterase inhibitor, an antiepileptic, an anti-inflammatory drug, a Tau aggregation inhibitor or an SSRI for the treatment of neurodegenerative or cognitive disorders.

First claim

The invention claimed is:

1. A method for the treatment of a neurodegenerative or cognitive disorder, wherein said method comprises the administration, to a patient in need thereof, of therapeutically effective amounts of:
(A) a BACE1 inhibitor, wherein said inhibitor is a compound of Formula I:

 wherein:
Ar is: (1) selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, thiophenyl, thiazolyl, oxazolyl, isoxazolyl, 1,3,4-thiadiazolyl, isothiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, furazanyl and 1,2,4-thiadiazolyl, and
(2) optionally substituted with one or more halogen, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 fluoroalkyl or C 1 -C 6 alkoxy;

R 1 is C 1 -C 3 alkyl or C 1 -C 3 fluoroalkyl;
R 2 is hydrogen, halogen, C 1 -C 3 fluoroalkyl or C 1 -C 3 alkyl;
R 3 is C 1 -C 3 alkyl;
or a pharmaceutically acceptable salt thereof; and

(B) a compound useful in active or passive Tau immunotherapy, a compound useful in active or passive Aβ peptide immunotherapy, an N-Methyl-D-aspartate (NMDA) receptor antagonist, an acetylcholine esterase inhibitor, an antiepileptic, an anti-inflammatory drug, a Tau protein aggregation inhibitor or a Selective Serotonin Reuptake Inhibitor (SSRI).

2. The method according to claim 1 , wherein said neurodegenerative or cognitive disorder is Alzheimer's disease.

3. The method according to claim 1 , wherein said method comprises said administration of a therapeutically effective amount of a compound useful in passive Aβ peptide immunotherapy.

4. The method according to claim 3 , wherein said compound useful in passive Aβ peptide immunotherapy is an anti-Aβ peptide antibody, an anti-N3-pGlu Aβ antibody, or an antibody to hyperphosphorylated Tau.

5. The method according to claim 4 , wherein said compound useful in passive Aβ peptide immunotherapy is an antibody to hyperphosphorylated Tau, and is selected from the group consisting of:
(1) an antibody to the epitope pSer413 of hyperphosphorylated Tau protein;
(2) an antibody to the epitope pS409 of hyperphosphorylated Tau protein;
(3) an antibody to the epitope pS404 of hyperphosphorylated Tau protein;
(4) an antibody to the epitope pS396 of hyperphosphorylated Tau protein;
(5) an antibody to the conformation epitope pS396/pS404 of hyperphosphorylated Tau protein;
(6) an antibody to the epitope pS422 of hyperphosphorylated Tau protein;
(7) an antibody to the epitope pT212/pS214 of hyperphosphorylated Tau protein; and
(8) an antibody to the epitope pT231/pS235 of hyperphosphorylated Tau protein.

6. The method according to claim 1 , wherein said method comprises said administration of a therapeutically effective amount of a Tau protein aggregation inhibitor.

7. The method according to claim 1 , wherein said method comprises said administration of a therapeutically effective amount of a Selective Serotonin Reuptake Inhibitor (S SRI).

8. The method according to claim 1 , wherein said method comprises said administration of a therapeutically effective amount of an N-Methyl-D-aspartate (NMDA) receptor antagonist.

9. The method according to claim 1 , wherein said method comprises said administration of a therapeutically effective amount of an acetylcholine esterase inhibitor.

10. The method according to claim 1 , wherein said method comprises administration of a non-steroid anti-inflammatory drug (NSAID), a TNFα inhibitor, or a p38 MAP kinase inhibitor.

11. A method for the treatment of a neurodegenerative or cognitive disorder, wherein said method comprises the administration, to a patient in need thereof, of therapeutically effective amounts of: (A) a BACE1 inhibitor selected from the group consisting of:
(1) N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-fluoropicolinamide;
(2) N-(3-((2R,5R)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-fluoropicolinamide;
(3) N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-chloropicolinamide;
(4) N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-cyanopicolinamide;
(5) N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide;
(6) N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-1-(difluoromethyl)-1H-pyrazole-3-carboxamide;
(7) N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-2-methyloxazole-4-carboxamide;
(8) N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)thiazole-2-carboxamide;
(9) N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-4-bromo-1-methyl-1H-imidazole-2-carboxamide;
(10) N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-4-methylthiazole-2-carboxamide,
(11) N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-(trifluoromethyl)picolinamide;
(12) N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-methoxypyrimidine-2-carboxamide;
(13) N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-2-(difluoromethyl)oxazole-4-carboxamide;
(14) N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-4-(fluoromethyl)oxazole-2-carboxamide;
(15) N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-4-(fluoromethyl)thiazole-2-carboxamide;
(16) N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-(difluoromethyl)pyrazine-2-carboxamide;
(17) N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-methoxypicolinamide;
(18) N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide;
(19) N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-3-methyl-1,2,4-oxadiazole-5-carboxamide;
(20) N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-1-methyl-1H-1,2,4-triazole-3-carboxamide;
(21) N-(3-((2R,5R)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-1-(difluoromethyl)-1H-pyrazole-3-carboxamide;
(22) N-(3-((2R,5R)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-(difluoromethyl)pyrazine-2-carboxamide;
(23) N-(3-((2R,5R)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide;
(24) N-(3-((2R,5R)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-methoxypyrimidine-2-carboxamide;
(25) N-(3-((2R,5R)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-4-methylthiazole-2-carboxamide;
(26) N-(3-((2R,5R)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-(trifluoromethyl)picolinamide;
(27) N-(3-((2R,5R)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-2-(difluoromethyl)oxazole-4-carboxamide;
(28) N-(3-((2R,5R)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-4-(f

Assignees

• H Lundbeck As

Inventors

• Juhl Karsten
• Marigo Mauro
• Tagmose Lena
• Jensen Thomas

Classifications

• A61P43/00

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

• A61K31/343

  condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title