4-Amino-6-phenyl-5,6-dihydroimidazo[1,5-a]pyrazin-3(2H)-one derivatives as inhibitors of beta-secretase (BACE)

• US 9,834,559 B2
• Filed: 06/12/2014
• Issued: 12/05/2017
• Est. Priority Date: 06/12/2013
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Oehlrich, Daniel, Gijsen, Henricus Jacobus Maria
• Primary Examiner(s): Klinkel, Kortney L
• Assistant Examiner(s): STRONG, TORI
• Application Number:
  US14/897,420
• Publication Number:
  US 20160115171A1
• Time in Patent Office: 1,272 Days
• Field of Search: None
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/28 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 Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 39/02 Antidotes
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/16 for decreasing, blocking or antagonising the activity of the thyroid hormones
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention relates to novel 5,6-dihydroimidazo[1,5-a]pyrazin-3(2H)-one derivatives as inhibitors of beta-secretase, also known as beta-site amyloid cleaving enzyme, BACE, in particular BACE1 and/or BACE2 (wherein BACE1, is also known as Asp2, or memapsin2 and BACE2 is also known as Asp1, Memapsin 1 or DRAP). The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which beta-secretase is involved, such as Alzheimer'"'"'s disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down'"'"'s syndrome, dementia associated with stroke, dementia associated with Parkinson'"'"'s disease, dementia of the Alzheimer'"'"'s type, dementia associated with beta-amyloid, age-related macular degeneration, type 2 diabetes and other metabolic disorders.

Claims

1. A compound of Formula (I)

2. The compound of claim 1, wherein R⁴ is

3. The compound of claim 1, having the configuration shown in Formula (I′

)

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

5. A process for preparing a pharmaceutical composition as defined in claim 4, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound of claim 1.

6. A method of treating or preventing Alzheimer'"'"'s Disease, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of claim 1.

7. A method of treating or preventing a disease or condition selected from neurocognitive disorder due to Alzheimer'"'"'s disease, dementia of the Alzheimer'"'"'s type, and senile dementia of Alzheimer'"'"'s type comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of claim 1.

8. A method of treating or preventing Alzheimer'"'"'s Disease, comprising administering to a subject in need thereof, a therapeutically effective amount of a pharmaceutical composition as defined in claim 4.

9. A method of treating or preventing a disease or condition selected from neurocognitive disorder due to Alzheimer'"'"'s disease, dementia of the Alzheimer'"'"'s type, and senile dementia of the Alzheimer'"'"'s type, comprising administering to a subject in need thereof, a therapeutically effective amount of a pharmaceutical composition according to claim 4.

10. The method of claim 9, wherein the disease or condition is neurocognitive disorder due to Alzheimer'"'"'s disease.