Heterocyclic Compounds as Monoacylglycerol Lipase (MAGL) Inhibitors

Important Compound Classes

Title

New Heterocyclic Compounds as Monoacylglycerol Lipase Inhibitors

Patent Publication Number

WO 2020/035424 A1

Publication Date

February 20, 2020

Priority Application

EP 18188681.3

Priority Date

August 13, 2018

Inventors

Bell, C.; Benz, J.; Gobbi, L.; Grether, U.; Groebke Zbinden, K.; Hornsperger, B.; Kocer, B.; Kroll, C.; Kuhn, B.; Lutz, M. D. R.; O’Hara, F.; Richter, H.; Ritter, M.; Rombach, D.; Kuratli, M.

Assignee Company

F. Hoffmann-La Roche AG, Switzerland, and Hoffmann-La Roche Inc., USA

Disease Area

Neuroinflammation, neurodegenerative diseases, pain, cancer, mental disorders, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brin injury, stroke, epilepsy, anxiety, migraine, and depression

Biological Target

Monoacylglycerol lipase (MAGL)

Summary

Endocannabinoids (ECs) are signaling lipids that exert their biological actions by interacting with cannabinoid receptors (CBRs), CB1 and CB2. They modulate multiple physiological processes including neuroinflammation, neurodegeneration, and tissue regeneration. In the brain, the main endocannabinoid, 2-arachidonoylglycerol (2-AG), is produced by diacylglycerol lipase (DAGL) and hydrolyzed by the monoacylglycerol lipase (MAGL). MAGL hydrolyzes 85% of 2-AG, with the remaining 15% being hydrolyzed by ABHD6 and ABDH12. MAGL is expressed throughout the brain and in most brain cell types, including neurons, astrocytes, oligodendrocytes, and microglia cells.

Phospholipase A₂ (PLA₂) enzymes have been viewed as the principal source of AA, but cPLA₂-deficient mice have unaltered AA levels in their brain, reinforcing the key role of MAGL in the brain for AA production and regulation of the brain inflammatory process. In addition, genetic and/or pharmacological disruption of MAGL was shown to be protective in several animal models of neurodegeneration and multiple sclerosis.

Both cannabinoids and pharmacological inhibition of MAGL attenuate the vulnerability of oligodendrocytes (OLs) and their precursor (OPCs) to excitotoxic insults and therefore may be neuroprotective. Additionally, pharmacological inhibition of MAGL increases the number of myelinating OLs in the brain of mice, suggesting that MAGL inhibition may promote differentiation of OPCs in the myelinating OLs in vivo. MAGL as an important decomposing enzyme for both lipid metabolism and the endocannabinoids system, additionally as a part of a gene expression signature, contributes to different aspects of tumorigenesis.

The present application describes a series of novel heterocyclic compounds as monoacylglycerol lipase (MAGL) inhibitors for the treatment of neuroinflammation, neurodegenerative diseases, pain, cancer, mental disorders, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy, anxiety, migraine, and depression. Further, the application discloses compounds and their preparation, use, pharmaceutical composition, and treatment.

Definitions

X = CR₃; m = 0 or 1; n = 0, 1 and 2; and L = −(CH₂)_p–, −O–, −OCH₂–, −CH₂OCH₂–, −CF₂CH₂–, −CH₂=CH₂–, −(CR₁₆R₁₇)_q–, CH₂O–, and −CH₂CF₂–; or

X = N; m = 1; n = 1 or 2; and L = −(CH₂)_p–, or −CF₂CH₂–;

p = 1, 2, and 3;

q = 0 or 1;

A = C₆–C₁₄-aryl substituted with R₄, R₅ and R₆;

5- to 14-membered heteroaryl substituted with R₇, R₈ and R₉; and

3- to 14-membered heterocycloalkyl substituted with R₁₀, R₁₁ and R₁₂;

R₁ = H or C_1–6-alkyl;

R₂ = H or C_1–6-alkyl and hydroxy-C_1–6-alkyl;

R₃ = H, halogen, OH, C_1–6-alkoxy, C_1–6-alkyl and halo-C_1–6-alkyl;

R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂ = H, halogen, CN, OH, C_1–6-alkyl, halo-C_1–6-alkyl, hydroxy-C_1–6-alkyl, C_1–6-alkanoyl, halo-C_1–6-alkyl–CH(OH)-, C_1–6-alkoxy, halo-C_1–6-alkoxy, SF₅, CH₃SO₂, C_3–10-cycloalkyl, C_3–10-cycloalkyl substituted with R₁₃, 3- to 14-membered heterocycloalkyl, 3- to 14-membered heterocycloalkyl substituted with R₁₄, and R₁₅, 5- to 14-membered heteroaryl, C₆–C₁₄-aryl, C₆–C₁₄-aryloxy, halo-C₆–C₁₄-aryl, and halo-C₆–C₁₄-aryloxy;

R₁₃, R₁₄ and R₁₅ = C_1–6-alkyl, C_1–6-alkoxy, halo-C_1–6-alkyl, halo-C_1–6-alkoxy, halogen, and OH; and

R₁₆ and R₁₇ taken together with the carbon atom to which they are attached, form a C_3–7-cycloalkyl.

Key Structures

Biological Assay

The MAGL enzymatic assay was performed in a mammal. The compounds described in this application were tested for their ability to inhibit MAGL. The MAGL IC₅₀ (μM) values are shown in the following table.

Biological Data

The table below shows representative compounds were tested for MAGL inhibition. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 56

Compound claims: 47

Pharmaceutical composition claims: 1

Use of compound claims: 4

Method of manufacturing claims: 1

Method of treatment claims: 2

Invention claim: 1

Recent Review Articles

• 1.Gilgenkrantz H.; Mallat A.; Moreau R.; Lotersztajn S.. J. Hepatol. 2021, in press.
• 2.Fowler C. J.J. Int. Med. 2021, in press.
• 3.Maramai S.; Brindisi M.. ChemMedChem 2020, 15, 1985.
• 4.Grimsey N. L.; Savinainen J. R.; Attili B.; Ahamed M.. Drug Discovery Today 2020, 25, 330.
• 5.Liu T.; Liu X.; Chen Q.; Shi Y.. Biomed. Pharmacother. 2020, 128, 110314.
• 6.Deng H.; Li W.. Acta Pharm. Sin. B 2020, 10, 582.

The author declares no competing financial interest.