CRYSTALLINE COMPOUND OF MUSCARINIC ACETYLCHOLINE M1 RECEPTOR ANTAGONISTS
Disclosed herein, inter alia, are a crystalline compound of mAChR M 1 antagonist, its pharmaceutical composition and methods of treatment.
1 . A crystalline compound having the formula:
characterized by an x-ray powder diffraction pattern with peaks at 13.4±0.15° 2θ, 14.0±0.15° 2θ, 15.2±0.15° 2θ, 19.3±0.15° 2θ, 20.0±0.15° 20 and 21.2±0.15° 2θ.
2 . The crystalline compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern with peaks at 6.7±0.15° 2θ, at 13.4±0.15° 2θ, 14.0±0.15° 20, 15.2±0.15° 2θ, 17.7±0.15° 2θ, 18.1±0.15° 2θ, 18.8±0.15° 2θ, 19.3±0.15° 2θ, 19.8±0.15° 2θ, 20.0±0.15° 2θ, 21.0±0.15° 2θ, 21.2±0.15° 2θ, and 24.1±0.15° 2θ.
3 . The crystalline compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern with peaks at 6.7±0.15° 2θ, 10.7±0.15° 2θ, 13.4±0.15° 2θ, 14.0±0.15° 2θ, 15.2±0.15° 2θ, 17.7±0.15° 2θ, 18.1±0.15° 2θ, 18.8±0.15° 2θ, 19.3±0.15° 2θ, 19.8±0.15° 2θ, 20.0±0.15° 2θ, 20.7±0.15° 2θ, 21.0±0.15° 2θ, 21.2±0.15° 2θ, 24.1±0.15° 2θ, 25.9±0.15° 2θ, 27.8±0.15° 2θ, and 30.6±0.15° 2θ.
4 . The crystalline compound of claim 1 , wherein the compound is characterized by an x-ray powder diffraction pattern with peaks at 6.7±0.15° 2θ, 10.7±0.15° 2θ, 13.4±0.15° 2θ, 14.0±0.15° 2θ, 15.2±0.15° 2θ, 16.6±0.15° 2θ, 17.7±0.15° 2θ, 18.1±0.15° 2θ, 18.4±0.15° 2θ, 18.8±0.15° 2θ, 19.3±0.15° 2θ, 19.8±0.15° 2θ, 20.0±0.15° 2θ, 20.7±0.15° 2θ, 21.0±0.15° 2θ, 21.2±0.15° 2θ, 24.1±0.15° 2θ, 25.9±0.15° 2θ, 26.3±0.15° 2θ, 26.6±0.15° 2θ, 27.0±0.15° 2θ, 27.8±0.15° 2θ, and 30.6±0.15° 2θ.
5 . The crystalline compound of claim 1 , wherein the compound is further characterized as having a differential scanning calorimetry endotherm onset at about 117° C.
6 . A pharmaceutical composition comprising a crystalline compound of claim 1 and at least one pharmaceutically acceptable excipient.
7 . A method of treating a neurodegenerative disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline compound of claim 1 .
8 . The method of claim 7 , further comprising the administration of one or more immunomodulatory agents.
9 . The method of claim 8 , wherein the one or more immunomodulatory agents are selected from: an IFN-β 1 molecule; a corticosteroid; a polymer of glutamic acid, lysine, alanine and tyrosine or glatiramer; an antibody or fragment thereof against alpha-4 integrin or natalizumab; an anthracenedione molecule or mitoxantrone; a fingolimod or FTY720 or other S1P1 functional modulator; a dimethyl fumarate or other NRF2 functional modulator; an antibody to the alpha subunit of the IL-2 receptor of T cells (CD25) or daclizumab; an antibody against CD52 or alemtuzumab; an antibody against CD20 or ocrelizumab; and an inhibitor of a dihydroorotate dehydrogenase or teriflunomide.
10 . A method of treating a demyelinating disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline compound of claim 1 .
11 . The method of claim 10 , wherein the demyelinating disease is a demyelinating disease of the central nervous system.
12 . The method of claim 11 , wherein the demyelinating disease is multiple sclerosis.
13 . The method of claim 10 , wherein the demyelinating disease is a demyelinating disease of the peripheral nervous system.
14 . The method of claim 10 , further comprising the administration of one or more immunomodulatory agents.
15 . The method of claim 14 , wherein the one or more immunomodulatory agents are selected from: an IFN-β 1 molecule; a corticosteroid; a polymer of glutamic acid, lysine, alanine and tyrosine or glatiramer; an antibody or fragment thereof against alpha-4 integrin or natalizumab; an anthracenedione molecule or mitoxantrone; a fingolimod or FTY720 or other S1P1 functional modulator; a dimethyl fumarate or other NRF2 functional modulator; an antibody to the alpha subunit of the IL-2 receptor of T cells (CD25) or daclizumab; an antibody against CD52 or alemtuzumab; an antibody against CD20 or ocrelizumab; and an inhibitor of a dihydroorotate dehydrogenase or teriflunomide.
16 . A method of treating a neuropathic disease, optionally a peripheral neuropathy, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline compound of claim 1 .
17 . The method of claim 16 , wherein the neuropathic disease is diabetic neuropathy.
18 . The method of claim 16 , further comprising the administration of one or more immunomodulatory agents.
19 . The method of claim 18 , wherein the one or more immunomodulatory agents are selected from: an IFN-β 1 molecule; a corticosteroid; a polymer of glutamic acid, lysine, alanine and tyrosine or glatiramer; an antibody or fragment thereof against alpha-4 integrin or natalizumab; an anthracenedione molecule or mitoxantrone; a fingolimod or FTY720 or other S1P1 functional modulator; a dimethyl fumarate or other NRF2 functional modulator; an antibody to the alpha subunit of the IL-2 receptor of T cells (CD25) or daclizumab; an antibody against CD52 or alemtuzumab; an antibody against CD20 or ocrelizumab; and an inhibitor of a dihydroorotate dehydrogenase or teriflunomide.
20 . A method of modulating muscarinic acetylcholine receptor M 1 activity in a subject comprising administering to the subject a crystalline compound of claim 1 .
21 . The method of claim 20 , wherein the compound acts as a selective M 1 antagonist.