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KR-102963137-B1 - Pharmaceutical salts, polymorphs, and methods for preparing the same of benzothiazole compounds

KR102963137B1KR 102963137 B1KR102963137 B1KR 102963137B1KR-102963137-B1

Abstract

The present disclosure provides polymorphic forms and salts of (1S,2S)-2-fluoro-N-(6-(4-methylpyridine-3-yl)benzo[d]thiazole-2-yl)cyclopropane-1-carboxamide, pharmaceutical compositions comprising such compounds, methods for preparing such compounds, and methods for treating neurodegenerative disorders.

Inventors

  • 이진화
  • 조수연

Assignees

  • 주식회사 퍼스트바이오테라퓨틱스

Dates

Publication Date
20260511
Application Date
20200327
Priority Date
20190328

Claims (13)

  1. Crystalline forms having peaks at diffraction angles (2θ) of 9.8±0.2, 11.6±0.2, 13.2±0.2, 14.0±0.2, 16.7±0.2, 17.6±0.2, 20.6±0.2, 22.9±0.2, 26.2±0.2, 29.3±0.2, 30.7±0.2, and 31.6±0.2; Crystalline form having peaks at diffraction angles (2θ) of 6.0±0.2, 15.9±0.2, 18.1±0.2, 19.7±0.2, 24.6±0.2, 25.4±0.2, and 26.7±0.2; Crystalline form having peaks at diffraction angles (2θ) of 8.7±0.2, 10.9±0.2, 12.9±0.2, 15.4±0.2, 16.4±0.2, 18.9±0.2, 20.3±0.2, 22.1±0.2, 22.7±0.2, and 24.9±0.2; Crystalline forms having peaks at diffraction angles (2θ) of 9.4±0.2, 10.1±0.2, 14.8±0.2, 18.0±0.2, 23.0±0.2, 25.4±0.2, and 29.2±0.2; Crystalline form having peaks at diffraction angles (2θ) of 5.3±0.2, 10.6±0.2, 17.2±0.2, 19.8±0.2, and 26.5±0.2; A crystalline form having peaks at diffraction angles (2θ) of 5.1±0.2, 10.2±0.2, 15.2±0.2, 18.6±0.2, 20.5±0.2, and 21.9±0.2; and Having a crystal form selected from the group consisting of crystal forms having peaks at diffraction angles (2θ) of 6.6±0.2, 13.9±0.2, 15.9±0.2, 22.0±0.2, 23.8±0.2, 24.6±0.2, and 26.8±0.2, (1S,2S)-2-fluoro-N-(6-(4-methylpyridine-3-yl)benzo[d]thiazole-2-yl)cyclopropane-1-carboxamide or crystalline form of a pharmaceutically acceptable salt thereof.
  2. A crystalline form according to claim 1, wherein the crystalline form has peaks at diffraction angles (2θ) of 9.8±0.2, 11.6±0.2, 13.2±0.2, 14.0±0.2, 16.7±0.2, 17.6±0.2, 20.6±0.2, 22.9±0.2, 26.2±0.2, 29.3±0.2, 30.7±0.2, and 31.6±0.2, and the crystalline form has an onset melting point of 267 °C and a peak temperature of 268 °C.
  3. A crystalline form according to claim 1, wherein the crystalline form has peaks at diffraction angles (2θ) of 6.0±0.2, 15.9±0.2, 18.1±0.2, 19.7±0.2, 24.6±0.2, 25.4±0.2, and 26.7±0.2, and the crystalline form has a melting point of 240 °C.
  4. In claim 1, the crystal form has peaks at diffraction angles (2θ) of 8.7±0.2, 10.9±0.2, 12.9±0.2, 15.4±0.2, 16.4±0.2, 18.9±0.2, 20.3±0.2, 22.1±0.2, 22.7±0.2, and 24.9±0.2, and the crystal form has a first melting point of 212 °C and a second melting point of 229 °C.
  5. A crystalline form according to claim 1, wherein the crystalline form has peaks at diffraction angles (2θ) of 9.4±0.2, 10.1±0.2, 14.8±0.2, 18.0±0.2, 23.0±0.2, 25.4±0.2, and 29.2±0.2, and the crystalline form has a melting point of 174 °C.
  6. A crystalline form according to claim 1, wherein the crystalline form has peaks at diffraction angles (2θ) of 5.3±0.2, 10.6±0.2, 17.2±0.2, 19.8±0.2, and 26.5±0.2, and the crystalline form has a melting point of 227 °C.
  7. A crystalline form according to claim 1, wherein the crystalline form has peaks at diffraction angles (2θ) of 5.1±0.2, 10.2±0.2, 15.2±0.2, 18.6±0.2, 20.5±0.2, and 21.9±0.2, and the crystalline form has a melting point of 194 °C.
  8. A crystalline form according to claim 1, wherein the crystalline form has peaks at diffraction angles (2θ) of 6.6±0.2, 13.9±0.2, 15.9±0.2, 22.0±0.2, 23.8±0.2, 24.6±0.2, and 26.8±0.2, and the crystalline form has a melting point of 168 °C.
  9. A composition for treating a neurodegenerative disease selected from the group consisting of α-synucleinopathy, Parkinson's disease, Lewy body dementia, multiple system atrophy (MSA), Alzheimer's disease, and amyotrophic lateral sclerosis (ALS), comprising the crystalline form of claim 1 and at least one pharmaceutically acceptable carrier.
  10. A composition according to claim 9, wherein the crystal form has peaks at diffraction angles (2θ) of 6.0±0.2, 15.9±0.2, 18.1±0.2, 19.7±0.2, 24.6±0.2, 25.4±0.2, and 26.7±0.2, and the crystal form has a melting point of 240 °C.
  11. A pharmaceutical composition for treating a neurodegenerative disease selected from the group consisting of α-synucleinopathy, Parkinson's disease, Lewy body dementia, multiple system atrophy (MSA), Alzheimer's disease, and amyotrophic lateral sclerosis (ALS), comprising a therapeutically effective amount of the crystalline form of claim 1.
  12. A pharmaceutical composition according to claim 11, wherein the crystal form has peaks at diffraction angles (2θ) of 6.0±0.2, 15.9±0.2, 18.1±0.2, 19.7±0.2, 24.6±0.2, 25.4±0.2, and 26.7±0.2, and the crystal form has a melting point of 240 °C.
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Description

Pharmaceutical salts, polymorphs, and methods for preparing the same of benzothiazole compounds Cross-reference regarding related applications This application claims the advantage and priority of U.S. Provisional Application Serial No. 62/825,102 filed on March 28, 2019. The full disclosure of the application referred to in this paragraph is incorporated herein by reference. Technology field The present disclosure generally relates to salts and polymorphs of compounds having enzyme-inhibiting activity, methods for preparing such compounds, and methods for using compounds for treating disorders. α-synuclein is part of a large protein family that includes β- and γ-synuclein and synoretin. α-synuclein is expressed in the synaptic steady state and is believed to play a role in neural plasticity, learning, and memory. Several studies have revealed that α-synuclein plays a central role in the pathogenesis of Parkinson's disease. Molecular changes in the α-synuclein protein that increase protein misfolding and aggregation play a direct role in disease development. The aggregation of α-synuclein contributes to the formation of Lewy bodies and neurites, which are pathological features of Parkinson's disease and α-synucleinopathy. Activation of tyrosine kinase c-abl contributes to α-synuclein-induced neurodegeneration. Tyrosine kinase c-abl is a strictly regulated non-receptor protein tyrosine kinase involved in a wide range of cellular processes, including growth, survival, and stress responses ( Nat Rev Mol Cell Biol , 2004, 5:33-44). c-abl is involved in the regulation of various cellular processes and is associated with the development of the central nervous system by regulating neurogenesis. More recently, there is increasing evidence in various experimental model systems that c-abl is activated in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Nieman-Pick type C disease, and tauopathy ( Human Molecular Genetics , 2014, Vol. 23, No. 11). The stress signaling non-receptor tyrosine kinase c-abl links parkin to the sporadic form of Parkinson's disease through tyrosine phosphorylation. Tyrosine phosphorylation of parkin by c-abl is a major post-translational modification in sporadic Parkinson's disease that leads to the loss of parkin function and disease progression. Inhibition of c-abl offers a new therapeutic opportunity to block the progression of Parkinson's disease. ( The Journal of Neuroscience , 2011, 31(1):157-163) Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive death of motor neurons. Knockdown of c-abl using small interfering RNA (siRNA) also saved motor neuron degeneration in ALS. ( Inamura et al., Sci. Transl. Med. 9, 2017) Multiple System Atrophy (MSA) is a rare, rapidly progressing neurodegenerative disease for which there is currently no cure. In MSA, α-synuclein accumulates in the substantia nigra, striatum, olivopontocerebellar structures, and neurons and oligodendrocytes of the spinal cord. ( J Neural Transm Vienna Austria 1996. 2016;123(6)) Administration of the tyrosine kinase inhibitor nilotinib reduces c-abl activity and improves the autophagic clearance of α-synuclein in transgenic and lentiviral gene transfer models. Activation of c-abl in the mouse forebrain induces neurodegeneration in the hippocampus and striatum. Therefore, increased c-abl activity via phosphorylation may be associated with the α-synuclein pathology detected in Parkinson's disease and other neurodegenerative diseases ( Hum Mol Genet. 2013 Aug 15). U.S. Patent Application No. 16/148,265 describes a benzothiazole compound as a c-abl inhibitor useful for the treatment of diseases or disorders such as α-synucleinopathy, Parkinson's disease, Alzheimer's disease, ALS, Lewy body dementia and MSA. Figure 1 shows an optical microscope image of the crystalline form of chemical formula (I). Figure 2 shows the X-ray powder diffraction (XRPD) pattern of chemical formula (I). Figure 3 shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) results of chemical formula (I). Figure 4 shows the XRPD spectra of pattern A of formula (I) in different solvents: 1-acetone, 2-ethyl acetate, 3-acetonitrile, 4-isopropanol/water (95/5, v/v). Figure 5 shows an overlay of XRPD spectra of salt formation of formula (I) using hydrochloric acid among different solvents: 1-acetone, 2-ethyl acetate, 3-acetonitrile, 4-isopropanol/water (95/5, v/v). Figure 6 shows the overlay of XRPD spectra of the formation of a salt of formula (I) with sulfuric acid among different solvents: 1-acetone, 2-ethyl acetate, 3-acetonitrile, 4-isopropanol/water (95/5, v/v). Figure 7 shows an overlay of XRPD spectra of salt formation of formula (I) using L-aspartic acid among different solvents: 1-acetone, 2-ethyl acetate, 3-acetonitrile, 4-isopropanol/water (95/5, v/v). Figure 8 shows the overlay of XRPD spectra of the formation of a salt of formula (I) with ma