CN112225703B - Medicine for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity - Google Patents

Medicine for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity Download PDF

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CN112225703B
CN112225703B CN202011046968.XA CN202011046968A CN112225703B CN 112225703 B CN112225703 B CN 112225703B CN 202011046968 A CN202011046968 A CN 202011046968A CN 112225703 B CN112225703 B CN 112225703B
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lrrk2
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谢伟东
程星
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Guangzhou Zhirui Medical Technology Co ltd
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Abstract

The invention provides a medicine for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity, and belongs to the field of medicines. The medicine comprises at least one of a compound shown in chemical formula 1, an optical isomer thereof, a prodrug thereof, a salt thereof, a hydrate thereof, a solvate thereof, an N-oxide thereof and a deuterated analog thereof, has a good inhibiting effect on LRRK2 kinase or abnormal LRRK2 mutant kinase, and can be used for treating or preventing diseases related to the activity of LRRK2 kinase or abnormal LRRK2 mutant kinase, such as Alzheimer's disease, L-dopa induced dyskinesia, Parkinson's disease, dementia, kidney cancer, breast cancer, prostate cancer, leukemia, papilloma, lung cancer, acute myelogenous leukemia, multiple myeloma, leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis or ankylosing spondylitis.

Description

Medicine for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity
Technical Field
The invention belongs to the field of medicines, and particularly relates to a medicine for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity.
Background
The protein encoded by the LRRK2 gene includes a leucine-rich repeat (LRR) domain, a kinase domain, a DFG-like motif, a RAS domain, a GTPase domain, an MLK-domain, and a WD40 domain. There is a lot of genetic and biochemical evidence that LRRK2 kinase activity is associated with susceptibility to parkinson's Disease PD, pathogenic mutations in the LRRK2 gene (especially the most common Gly2019Ser mutation) increase LRRK2 kinase activity and decrease the rate of GTP hydrolysis in cells and tissues, and that blocking these activities by small molecule LRRK2 kinase inhibitors may also provide neuroprotection in certain PD models, which discovery has made LRRK2 the most promising target for treating Parkinson's Disease (PD) (Tolosa et al, Nature Reviews in Neurology, vol.16, 2020, pp.97-10; Paisan-Ruiz et al, j.kinson's Disease, vol.3, 2013, pp.85-103; Guo et al, Experimental Research, vol.313(16), 2007, 3658-3670; Andrew b.west, Experimental, pp.298, 2017.245, pp.236). LRRK2 was identified as a gene potentially associated with increased susceptibility to Crohn's disease and susceptibility to leprosy (Zhang et al, New England J.Med., Vol.361, 2009, pp.2609-2618; Barrett et al, Nature Genetics, Vol.40, 2008, pp.955-962); it is also associated with spinal rigidity (ankyissing spondifications) (Danoy et al, PLoS Genetics, Vol 6(12), 2010, pp.1-5) and Amyotrophic lateral Sclerosis (Shtilans et al, Amyotrophic lateral Sclerosis, 2011, pp.1-7).
LRRK2 is also associated with Alzheimer's disease conversion from mild cognitive impairment (WO 2007149798); l-dopa-induced dyskinesia (Hurley et al, Eur. J, Neurosci, Vol.26, 2007, pp.171-177); CNS disorders associated with proliferation and migration of neuroblasts, and modulation of LRRK2 can be used to improve neurological outcome after ischemic injury and stimulate CNS functional recovery after neuronal injury, such as ischemic stroke, traumatic brain injury, or spinal cord injury (Milosevic et al, neuroregen, vol.4, 2009, 25; Zhang et al, j.neurosci.res, vol.88, 2010, pp.3275-3281). Other diseases: including diabetes, obesity, motor neuron disease, epilepsy, and some cancers (Rubinsztein et al, nat. rev. drug Discovery, vol.11, 2012, 709-. Cancers such as renal, breast, prostate (e.g. solid tumors), blood and lung cancers and Acute Myeloid Leukemia (AML) (WO 2011038572); lymphomas and leukemias (Ray et al, j.immunolo., vol.230, 2011, 109); papillary renal and thyroid carcinomas (Bredan D Looyenga et al, Proc Natl Acad Sci U S A, Vol.108(4), 2011, pp.1439-44); multiple myeloma (Chapman et al, Nature, Vol.471, 2011, pp.467-472). Diseases of the immune system: including rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure erythrodysgenesis, Idiopathic Thrombocytopenic Purpura (ITP), Evans syndrome, vasculitis, bullous skin Disease, type I diabetes, Huggen's syndrome (Sjogren's syndrome), Devickers ' Disease, and inflammatory diseases (Nakamura et al, DNA Res., Vol.13(4), 2006, pp.169-183; Engel et al, Pharmacol. Rev., Vol.63, 2011, 127. minus 156; Homam et al, J.Clin. Neurocusu Disease, Vol.12, 2010, 91-102.) pulmonary diseases such as chronic obstructive pulmonary Disease and idiopathic pulmonary fibrosis (Araya et al, Intern.52, Internally. 2013, as inhibitors of bacterial infection by bacteria such as LR kinase, intracellular kinase (RK et al, RK. 19. 2, RK 3, and RK kinase) for increasing the host cell infection, nat.rev., 2012, 709-; araya et al, lntern.med., vol.52, 2013, 95-2303; gutierrez, Biochemical Society Conference, Leucine rich repeat kinase 2. ten year eyes from the road to the therapeutic intervention, Henley Business School, UK 12July 2016), HIV, West Nile virus, and Cherokee virus (Shoji-Kawata et al, Nature, Vol.494, 2013, pp.201-206). Also for other a-synucleinopathies (Orenstein et al, Nature Neurosci., Vol.16, 2013, 394-406), Tau proteinopathies (Li et al, neuroodegen.Dis., Vol.7, 2010, pp.265-271), Alzheimer's disease and other neurodegenerative diseases (Nixon, Nat.Med., Vol.19, 2013, pp.983-97) and gaucher's disease (Westbrook et al, trends.mol.Med., Vol.17, 2011, 485-493); tauopathies characterized by hyperphosphorylation of Tau, such as granule disease of argentism, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, and hereditary frontotemporal dementia and parkinson's disease associated with chromosome 17 (Jakes R et al, biochemica Acta, vol.1739,2005, pp. 240-250); microglial proinflammatory responses (Moehle et al, J.Neuroscience, Vol.32, 2012, pp.1602-1611).
Thus, compounds that effectively modulate LRRK2 activity may provide treatment for diseases or conditions mediated by LRRK2 that are neurodegenerative diseases, cancer, inflammatory diseases, bacterial, viral infections, and other diseases.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a medicament for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity.
To achieve the above objects, the present invention provides a medicament for treating or preventing diseases associated with LRRK2 kinase or abnormal LRRK2 mutant kinase activity, comprising an LRRK2 inhibitor, wherein the LRRK2 inhibitor comprises at least one of a compound represented by chemical formula 1, an optical isomer thereof, a prodrug thereof, a salt thereof, a hydrate thereof, a solvate thereof, an N-oxide thereof, and a deuterated analog thereof;
[ chemical formula 1]
Figure BDA0002706277720000031
In chemical formula 1, L1、L2、L3Are each independently C or N; l is4C, N, O or S;
R1independently is an unsubstituted or an amide group,
R2independently is unsubstituted, -H, -NHAr, -CH ═ CHPh,
Figure BDA0002706277720000032
Or a 5-to 8-membered cyclic heterocyclic group containing at least one heteroatom at N, O, which is unsubstituted or substituted with a first substituent,
or L3Is N, L1、L2、R1And R2Co-form
Figure BDA0002706277720000033
or-ArRbRdWherein, X is halogen;
R3is unsubstituted, -H, halogen, C1-10Hydrocarbyl, or-NHRa；
R4independently-H, -NHAr, -CH ═ CHPh, -NHRaA substituted or unsubstituted 5-to 8-membered heterocyclylvinyl group containing N, O, S at least one heteroatom, C1-5Straight-chain or branched alkylaminosulfonyl C6-10Arylamino, di (C)1-5Straight-chain or branched alkyl) phosphoric acid group C6-10An arylamino group,
Figure BDA0002706277720000041
A 5-to 8-membered ring heterocyclyl group containing at least one heteroatom at N, O, or a 5-to 8-membered ring heterocyclylamino group, unsubstituted or substituted with a second substituent,
R5independently is
Figure BDA0002706277720000042
Or L1Is N, R4And R5Co-form
Figure BDA0002706277720000043
Wherein L is5is-O-, -S-, or-NH-,
Y1is C unsubstituted or substituted by a third substituent1-10A linear or branched alkyl group,
ring Y is a benzene ring, or a 4-to 8-membered cycloheterocycloalkyl or heteroaryl group containing at least one heteroatom of N, O, unsubstituted or substituted with a fourth substituent;
R6is unsubstituted or-H;
R7is-H, C1-10Hydrocarbyl, - (CH)2)nOH、-ORc、-O(CH2)nRaHalogen, or a 4 to 8 membered ring heterocycloalkyl or heteroaryl group containing at least one heteroatom of N, O, unsubstituted or substituted with a third substituent;
R8、R9、R10、R11are all independently-H, C1-10Hydrocarbyl, - (CH)2)nOH、-O(CH2)nRa、-C(O)ORaHalogen, -CF3or-OCF3；
Each RaAre all independently-H, C1-10Hydrocarbyl radical, C1-10Cycloalkyl, aryl, or N, O-containing radical unsubstituted or substituted by a fifth substituentA 5 to 8 membered ring heterocycloalkyl or heteroaryl of a heteroatom;
each RbAre all independently-H, C1-10Hydrocarbyl, -O (CH)2)nRa、-NRaRcOr a 3-to 8-membered ring heterocyclic group containing at least one heteroatom at N, O, unsubstituted or substituted with a sixth substituent;
each RcAre all independently-H, C1-10Hydrocarbyl, - (CH)2)nOH, aryl, or a 4 to 8 membered ring heterocycloalkyl or heteroaryl group containing at least one heteroatom of N, O, unsubstituted or substituted with a third substituent;
each RdAre all independently-H or-O (CH)2)nRa；
The first substituent, the second substituent, the fourth substituent, the fifth substituent and the sixth substituent are respectively and independently-OH, halogen, -CN, nitro-NH2、C1-10Hydrocarbyl, substituted or unsubstituted C3-10At least one of cycloalkyl, substituted or unsubstituted 3 to 8 membered ring heterocycloalkyl containing at least one heteroatom of N, O;
each n is independently selected from any integer from 0 to 4.
Preferably, the structural formula of the compound represented by chemical formula 1 is as follows:
Figure BDA0002706277720000051
the R is3Is halogen or C1-10A hydrocarbyl group; the R is4Is C1-5Straight-chain or branched alkylaminosulfonyl C6-10Arylamino, di (C)1-5Straight-chain or branched alkyl) phosphoric acid group C6-10An arylamino group,
Figure BDA0002706277720000052
Or a 5-to 8-membered ring heterocyclic group containing at least one heteroatom of N, O, unsubstituted or substituted with a second substituent; the R is7Is composed of
Figure BDA0002706277720000053
RbIs C1-10Hydrocarbyl radicals, -NRaRcOr by C1-10A 3-to 8-membered, hydrocarbyl-substituted heterocyclic group containing at least one heteroatom from N, O, RaIs C1-10Hydrocarbyl radical, RcIs- (CH)2)nOH; the R is10、R11Are all independently-H, -O (CH2)nRa、C1-10Hydrocarbyl or halogen.
Further preferably, said R3is-F, -Cl or-CH3(ii) a The R is4Is composed of
Figure BDA0002706277720000054
Figure BDA0002706277720000061
The R is7Is composed of
Figure BDA0002706277720000062
Figure BDA0002706277720000063
The R is10、R11Are all independently-H, -OCH3、-CH3or-F.
Preferably, the structural formula of the compound represented by chemical formula 1 is as follows:
Figure BDA0002706277720000064
said L4N, S or O; the R is5Is composed of
Figure BDA0002706277720000065
Or by-O (CH)2)nRaAt least one substituted phenyl group of halogen; rbis-O (CH)2)nRa；Rais-H, or unsubstituted or substituted by a fifth substituent, a 5-to 8-membered cyclic heterocycloalkyl or hetero atom containing at least one heteroatom of N, OA cyclic aryl group; rdis-H or-O (CH)2)nRa。
Further preferably, said L4N, S or O; the R is5Is composed of
Figure BDA0002706277720000066
Figure BDA0002706277720000067
The R isbIs composed of
Figure BDA0002706277720000068
Rdis-H or-OCH3。
Preferably, the structural formula of the compound represented by chemical formula 1 is as follows:
Figure BDA0002706277720000071
the R is4Is a quilt C1-10A 5 to 8 membered ring heterocyclylamino substituted with a hydrocarbon group; said L4N, S or O; the R is7Is O (CH)2)nRa，RaIs aryl or a 5 to 8 membered ring heterocycloalkyl or heterocycloaryl containing at least one heteroatom of N, O, unsubstituted or substituted with a fifth substituent.
Preferably, the structural formula of the compound represented by chemical formula 1 is as follows:
Figure BDA0002706277720000072
the R is2Is a 5-to 8-membered ring heterocyclic group containing at least one heteroatom of N, O, unsubstituted or substituted with a first substituent; said L4Is N; the R is4is-CH ═ CHPh, or a substituted or unsubstituted 4 to 8 membered ring heterocyclylvinyl group containing at least one heteroatom from N, O, S; the R is5Is composed of
Figure BDA0002706277720000073
Preferably, the structural formula of the compound represented by chemical formula 1 is as follows:
Figure BDA0002706277720000074
the R is1Is an amide group; the R is3Is C1-10A hydrocarbyl group; the R is4Is a 5 to 8 membered ring heterocyclylamino group; the R is7Is composed of
Figure BDA0002706277720000081
The R isbIs a 3-to 8-membered ring heterocyclic group containing at least one heteroatom of N, O, unsubstituted or substituted with a sixth substituent; the R is9is-O (CH)2)nRa。
Preferably, the structural formula of the compound represented by chemical formula 1 is as follows:
Figure BDA0002706277720000082
preferably, the compound represented by chemical formula 1 is any one of the following compounds:
(1) (1S, 2S, 3R, 4R) -3- [ [ 5-fluoro-2- [ 3-methyl-4- (4-methylpiperazin-1-yl) anilino ] pyrimidin-4-yl ] amino ] bicyclo [2.2.1] hept-5-ene-2-carboxamide;
(2) n-tert-butyl-3- [ [ 5-methyl-2- [4- (4-methylpiperazin-1-yl) anilino ] pyrimidin-4-yl ] amino ] benzenesulfonamide;
(3)2- [ [1- [ 2-fluoro-4- [ [ 5-methyl-4- (1-prop-2-ylpyrazol-4-yl) pyrimidin-2-yl ] amino ] phenyl ] piperidin-4-yl ] -methylamino ] ethanol;
(4) 5-chloro-4-N- (2-dimethylphosphorylphenyl) -2-N- [ 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl ] pyrimidine-2, 4-diamine;
(5)1- (4-methylphenyl) -3- [5- [7- (3-morpholin-4-ylpropoxy) quinazolin-4-yl ] sulfonyl-1, 3, 4-thiadiazol-2-yl ] urea;
(6) n- (2-chloro-5-methoxyphenyl) -6-methoxy-7- [ (1-methylpiperidin-4-yl) methoxy ] quinazolin-4-amine;
(7) 8-bromo-2- [ (1-methylpiperidin-4-yl) amino ] -4- (4-phenoxyaniline) -6H-pyridin [4,3-d ] pyrimidin-5-one;
(8)6- (4-methylpiperazin-1-yl) -N- (5-methyl-1H-pyrazol-3-yl) -2- [ ((E) -2-phenylethenyl ] pyrimidin-4-amine;
(9) 6-ethyl-3- [ 3-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] anilino ] -5- (oxa-4-ylamino) pyrazine-2-carboxamide;
(10) (16E) -11- (2-pyrrolidin-1-ethoxy) -14, 19-dioxin-5, 7, 27-triazacyclo [19.3.1.12,6.18,12] hepta-1 (24), 2(27), 3,5,8(26), 9,11,16,21(25), 22-decene.
Preferably, the disease includes at least one of neurodegenerative diseases, pre-cancerous conditions and cancers, autoimmune diseases, inflammation.
Preferably, the disease comprises at least one of alzheimer's disease, L-dopa induced dyskinesia, parkinson's disease, enhanced cognitive memory, central nervous system disorders, dementia, amyotrophic lateral sclerosis, kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myelogenous leukemia, multiple myeloma, leprosy, crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.
It is to be noted that the above hydrocarbon groups each include an alkyl group as well as an unsaturated hydrocarbon group such as an alkenyl group; the above halogens include F, Cl, Br, etc.; ar represents an aryl group such as phenyl, naphthyl, etc.; ph represents a phenyl group; the 5-to 8-membered heterocyclic group containing at least one heteroatom of N, O which is unsubstituted or substituted by a first substituent means that the atoms constituting the 5-to 8-membered ring contain at least one heteroatom of N, O in addition to carbon atoms, and the 5-to 8-membered ring is unsubstituted or substituted by the first substituent, and the other meanings are as similarly expressed; two (C)1-5Straight-chain or branched alkyl) phosphoric acid group C6-10In the arylamino group, the substituent alkyl groups on the phosphate group may be the same or differentSuch as
Figure BDA0002706277720000091
Etc.; quilt C1-10The 5-to 8-membered ring heterocyclylamino substituted with a hydrocarbon group means that a 5-to 8-membered ring heterocyclyl group in the 5-to 8-membered ring heterocyclylamino is substituted with C1-10Hydrocarbyl substitution; r2Independently is unsubstituted, -H, -NHAr, -CH ═ CHPh,
Figure BDA0002706277720000092
Or a 5-to 8-membered ring heterocyclic group containing at least one heteroatom at N, O, unsubstituted or substituted with a first substituent, refers to R2Independently is unsubstituted, -H, -NHAr, -CH ═ CHPh,
Figure BDA0002706277720000101
A 5-to 8-membered ring heterocyclic group containing N, O at least one hetero atom without substituent, or a 5-to 8-membered ring heterocyclic group containing N, O at least one hetero atom substituted with a first substituent, and the like.
Compared with the prior art, the invention has the beneficial effects that: the medicaments of the invention comprise specific inhibitors of LRRK2, are effective in the treatment or prevention of diseases associated with the activity of LRRK2 kinase or any mutant thereof (e.g. LRRK2 mutant G2019S), e.g. are useful in the prevention and treatment of neurodegenerative diseases such as parkinson's disease and other lewy body type diseases, including diffuse lewy body disease, the lewy body variant of alzheimer's disease, combined parkinson's disease and alzheimer's disease, multiple system atrophy and dementia with lewy bodies, etc.; can also be used for preventing and treating cancer such as renal cancer, breast cancer, prostate cancer, blood cancer, papilloma, lung cancer, acute myelogenous leukemia, multiple myeloma, melanoma, etc.; it can also be used for preventing and treating autoimmune diseases and inflammations, such as leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.
Drawings
FIG. 1 is the kinase bioactivity Kd curves of LRRK2 WT and LRRK2G2019S determined by experimental example 11 for the compound of example 1;
FIG. 2 is the kinase bioactivity Kd curves of LRRK2 WT and LRRK2G2019S determined by experimental example 11 for the compound of example 2;
FIG. 3 is the kinase bioactivity Kd curves of LRRK2 WT and LRRK2G2019S determined by experimental example 11 for the compound of example 4;
FIG. 4 is the kinase bioactivity Kd curves of LRRK2 WT and LRRK2G2019S determined by experimental example 11 for the compound of example 7;
FIG. 5 is the kinase bioactivity Kd curves of LRRK2 WT and LRRK2G2019S determined by experimental example 11 for the compound of example 9.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
The present invention relates to a drug for treating or preventing diseases associated with LRRK2 kinase or abnormal LRRK2 mutant kinase activity, comprising LRRK2 inhibitor, wherein the LRRK2 inhibitor comprises at least one of compound represented by chemical formula 1, optical isomer thereof, prodrug thereof, pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, N-oxide thereof, deuterated analog thereof.
According to the present invention, the compound represented by chemical formula 1 can be used for preventing and treating related disorders caused by mutation of LRRK2 or abnormal LRRK2, such as alzheimer's disease, L-dopa induced dyskinesia, parkinson's disease, dementia, amyotrophic lateral sclerosis, kidney cancer, breast cancer, prostate cancer, blood cancer, papilloma, lung cancer, acute myelogenous leukemia, multiple myeloma, leprosy, crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, ankylosing spondylitis, and the like.
According to the present invention, the compound represented by chemical formula 1 may be used for preventing and treating diseases or conditions mediated at least in part by LRRK2 or abnormal LRRK2 mutation, which are neurodegenerative diseases, for example, Central Nervous System (CNS) disorders such as Parkinson's Disease (PD), Alzheimer's Disease (AD), dementia including lewy body dementia and vascular dementia, Amyotrophic Lateral Sclerosis (ALS), age-related memory dysfunction, mild cognitive impairment (e.g., including transition from mild cognitive impairment to alzheimer's disease), silvery particle disease, lyhehal disease (e.g., niemann-pick C, gaucher's disease), corticobasal degeneration, progressive supranuclear palsy, hereditary frontopal dementia and parkinson's disease associated with chromosome 17 (FTDP-17), withdrawal symptoms/relapse associated with drug addiction, L-dopa-induced dyskinesia, Huntington's Disease (HD), and HIV-associated dementia (HAD). Disorders are ischemic diseases of organs including, but not limited to, the brain, heart, kidney, and liver.
In some embodiments, the compound of formula 1 is used for treating a disease or condition mediated at least in part by LRRK2 or an aberrant LRRK2 mutation is cancer, such as thyroid cancer, renal cancer (including papillary renal cancer), breast cancer, lung cancer, blood cancer, and prostate cancer (e.g., solid tumors), leukemia (including Acute Myeloid Leukemia (AML), or lymphoma.
In other embodiments, the compound of formula 1 is used to treat a disease or condition mediated at least in part by LRRK2 or an aberrant LRRK2 mutation is an inflammatory disorder. The inflammatory disorder is an inflammatory bowel disease, such as crohn's disease or ulcerative colitis (the two together generally being referred to as inflammatory bowel disease). The inflammatory disease is leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.
In other embodiments, the compounds of formula 1 are useful for treating other diseases mediated at least in part by LRRK2 or aberrant LRRK2 mutations: multiple sclerosis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure red cell aplasia, Idiopathic Thrombocytopenic Purpura (ITP), Evan's syndrome, vasculitis, bullous skin disease, type 1 diabetes, Hugger's syndrome, Devkker's disease, and inflammatory myopathy.
According to the present invention, the compound represented by chemical formula 1 may be used in the form of a pharmaceutically acceptable salt thereof. Here, the pharmaceutically acceptable salt may be an acid addition salt formed from a pharmaceutically acceptable free acid. Acid addition salts can be obtained from inorganic acids (e.g., hydrochloric, nitric, phosphoric, sulfuric, bromic, hydroiodic, nitrous, phosphorous, and the like), nontoxic organic acids (e.g., aliphatic mono-and di-carboxylic acid esters, phenyl-substituted alkanoates, hydroxyalkanoates and alkanoates, aromatic acids, aliphatic and aromatic sulfonic acids, and the like), or organic acids (e.g., acetic, benzoic, citric, lactic, maleic, gluconic, methanesulfonic, 4-toluenesulfonic, tartaric, fumaric, and the like). The acid addition salts may be obtained from pharmaceutically non-toxic salts including sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate (decanoate), octanoate, acrylate, formate, isobutyrate, decanoate (caprate), heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioleate, hexane-1, 6-oleate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxykorate, tolylbenzoate phthalate, terephthalate, benzenesulfonate, tosylate, Chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, bane-2-sulfonate, mandelate and the like.
According to the present invention, the acid addition salt may be prepared by a conventional method, for example, by dissolving the compound represented by chemical formula 1 or a derivative thereof in an organic solvent such as methanol, ethanol, acetone, dichloromethane or acetonitrile, and adding an organic acid or an inorganic acid thereto to obtain a precipitate, and then filtering and drying the precipitate, or subjecting the solvent and an excess of the acid to vacuum distillation, drying and then crystallizing in the presence of the organic solvent.
In addition, according to the present invention, the compound represented by chemical formula 1 may be prepared and used in the form of a pharmaceutically acceptable metal salt thereof. Specifically, the alkali metal or alkaline earth metal salt can be obtained by the following method: for example, the compound is dissolved in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, the undissolved compound salt is filtered off, and the filtrate is evaporated to dryness. Here, sodium, potassium or calcium salts are pharmaceutically suitable as metal salts. Furthermore, the corresponding salts can be obtained by reacting alkali metal or alkaline earth metal salts with suitable silver salts (e.g. silver nitrate).
According to the present invention, the compound represented by chemical formula 1 may be prepared and used in the form of at least one of its pharmaceutically acceptable deuterated analog, prodrug, stereoisomer, salt thereof, hydrate thereof, solvate thereof, and N-oxide thereof.
In the pharmaceutical according to the present invention, the compound represented by chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be administered in a single dose or multiple dose form at the time of clinical administration. The agents of the invention may be administered using a variety of methods including, for example, rectal, pulmonary, oral, buccal, intranasal, and transdermal routes. In certain embodiments, the medicament may be administered by intraarterial injection, intravenously, intraperitoneally, enterally, parenterally, intramuscularly, subcutaneously, orally, topically, or in the form of an inhalant.
The pharmaceutical preparation of the present invention may be prepared using commonly used diluents or excipients, such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and the like.
Examples of the pharmaceutical of the present invention used as a preparation for oral administration include tablets, pills, hard/soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, lozenges and the like. In addition to the active ingredient, these preparations may contain diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine) or lubricants (e.g., silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methyl cellulose, sodium carboxymethyl cellulose, and polyethylene rebuke pyrrolidine, and the like, and may optionally contain disintegrating agents (e.g., starch, agar, alginic acid or a sodium salt thereof, or boiling mixtures), absorbing agents, coloring agents, flavoring agents, sweetening agents, and the like.
One mode of administration of the agents of the invention is parenteral, e.g., by injection, and may be formulated as an aqueous or oily suspension or emulsion containing one of sesame oil, corn oil, cottonseed oil, peanut oil, and elixirs, mannitol and dextrose, or as a sterile aqueous solution and similar pharmaceutical vehicles.
When the medicament of the present invention is used by inhalation or insufflation, it may include pharmaceutically acceptable aqueous or organic solvents of solutions and suspensions, or mixtures thereof, and powders. The liquid or solid medicament may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the medicament is administered by the oral or nasal respiratory route for local or systemic effects. In other embodiments, the drug in a pharmaceutically acceptable solvent may be nebulized by using an inert gas. The nebulized solution may be inhaled directly from the nebulizing device or the nebulizing device may be connected to a face mask support or intermittent positive pressure ventilator. May be a solution, suspension or powder composition suitable for administration by a delivery device, preferably orally or nasally.
Furthermore, the present invention relates to a pharmaceutical kit for preventing or treating a disorder associated with LRRK2 or aberrant LRRK2 mutations, the kit comprising a compound represented by chemical formula 1 or a pharmaceutically acceptable salt, deuterated analog, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analog thereof, and a label and/or instructions for using the compound for treating an indication, including a disease or condition described herein. Including a compound described herein or a pharmaceutically acceptable salt, deuterated analog, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof in a suitable container. The containers may be vials, jars, ampoules, preloaded syringes and intravenous bags.
Further, in another aspect of the present disclosure, the compound represented by chemical formula 1 may be administered in combination with other agents including (but not limited to): compounds that are inhibitors of apoptosis, PARP poly (ADP-ribose) polymerase inhibitors, Src inhibitors, agents for the treatment of vascular disease, hypertension, hypercholesterolemia, and type II diabetes, anti-inflammatory agents, anti-embolic agents, fibrinolytic agents, anti-platelet agents, lipid lowering agents, direct thrombin inhibitors, glycoprotein IIb/IIla receptor inhibitors, calcium channel blockers, B adrenergic receptor blockers, cyclooxygenase (e.g., COX-1 and COX-2) inhibitors, angiotensin system inhibitors (e.g., Angiotensin Converting Enzyme (ACE) inhibitors), renin inhibitors, and/or agents that bind to cell adhesion molecules and inhibit the ability of white blood cells to attach to such molecules (e.g., polypeptide antibodies, polyclonal antibodies, and monoclonal antibodies). In addition, the compounds of the present disclosure may be administered in combination with additional agents having activity in the treatment of neurodegenerative diseases. For example, in some embodiments, the compound may be administered in combination with one or more additional therapeutic agents useful in the treatment of parkinson's disease. In some embodiments, the additional therapeutic agent is L-dopa (e.g., sinemet CR), a dopamine agonist (e.g., robininol or Pramipexole), a catechol-0-methyltransferase (COMT) inhibitor (e.g., Entacapone (Entacapone)), an L-monoamine oxidase (MAO) inhibitor (e.g., selegiline or rasagiline), or an agent that increases dopamine release (e.g., Zonisamide (Zonisamide)).
Example 1
Reference is made to patent WO2006055561A3 for the preparation of (1S, 2S, 3R, 4R) -3- [ [ 5-fluoro-2- [ 3-methyl-4- (4-methylpiperazin-1-yl) anilino ] pyrimidin-4-yl ] amino ] bicyclo [2.2.1] hept-5-ene-2-carboxamide, which has the following structural formula:
Figure BDA0002706277720000151
example 2
Reference is made to WO2016022460A1 for the preparation of N-tert-butyl-3- [ [ 5-methyl-2- [4- (4-methylpiperazin-1-yl) anilino ] pyrimidin-4-yl ] amino ] benzenesulfonamide of the formula:
Figure BDA0002706277720000152
example 3
Reference to the Journal of Medicinal Chemistry (Journal of Medicinal Chemistry, (2019),62(22),10305-10320) for the preparation of 2- [ [1- [ 2-fluoro-4- [ [ 5-methyl-4- (1-prop-2-ylpyrazol-4-yl) pyrimidin-2-yl ] amino ] phenyl ] piperidin-4-yl ] -methylamino ] ethanol of the formula:
Figure BDA0002706277720000161
example 4
Reference patent WO2009143389 for the preparation of 5-chloro-4-N- (2-dimethylphosphorylphenyl) -2-N- [ 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl ] pyrimidine-2, 4-diamine, the formula of which is as follows:
Figure BDA0002706277720000162
example 5
Reference to Journal of Medicinal Chemistry (Journal of Medicinal Chemistry, (2012),55(8), 3852-:
Figure BDA0002706277720000163
example 6
Reference is made to WO02092577A1 for the preparation of N- (2-chloro-5-methoxyphenyl) -6-methoxy-7- [ (1-methylpiperidin-4-yl) methoxy ] quinazolin-4-amine of the formula:
Figure BDA0002706277720000171
example 7
Reference is made to WO 2013142382A 1 for the preparation of 8-bromo-2- [ (1-methylpiperidin-4-yl) amino ] -4- (4-phenoxyaniline) -6H-pyridine [4,3-d ] pyrimidin-5-one of the following formula:
Figure BDA0002706277720000172
example 8
Reference is made to WO2007041358A2 for the preparation of 6- (4-methylpiperazin-1-yl) -N- (5-methyl-1H-pyrazol-3-yl) -2- [ ((E) -2-phenylvinyl ] pyrimidin-4-amine, the formula of which is as follows:
Figure BDA0002706277720000173
example 9
Reference is made to patent WO2010128659 a1 for the preparation of 6-ethyl-3- [ 3-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] anilino ] -5- (oxan-4-ylamino) pyrazine-2-carboxamide, of the formula:
Figure BDA0002706277720000181
example 10
Reference is made to patent WO2007058627 a1 for the preparation of (16E) -11- (2-pyrrolidine-1-ethoxy) -14, 19-dioxine-5, 7, 27-triazatetracyclo [19.3.1.12,6.18,12] hept-1 (24), 2(27), 3,5,8(26), 9,11,16,21(25), 22-decene, of the formula:
Figure BDA0002706277720000182
comparative example
Reference is made to WO2011151360 for the preparation of [4- [ [ 5-chloro-4- (methylamino) pyrimidin-2-yl ] amino ] -3-methoxyphenyl ] morpholin-4-yl methanone, of the formula:
Figure BDA0002706277720000183
the structures of the compounds prepared in examples 1 to 10 are shown in table 1.
TABLE 1
Figure BDA0002706277720000191
Example 11: determination of biological Activity of Compounds
(1) Material
LRRK2G2019S enzyme, substrate (LRRK peptide), ATP, TR-FRET diluent buffer, pLRRK peptide antibody, 384-well assay plates, and DMSO.
(2) Enzyme reaction conditions: 50mM Tris pH7.5, 10mM MgCl21mM EGTA, 0.01% Brij-35, 2mM DTT, 5nM LRRK2, 134. mu.M ATP, 60 min reaction time, 23 ℃ reaction temperature, 10. mu.L total reaction volume.
Detecting the reaction conditions: 1 XDilute buffer, 10mM EDTA, 2nM antibody, reaction temperature 23 ℃ 10 u L total reaction volume.
(3) Experimental procedure
Dilution of test compounds with 100% DMSO to give stock stocks of 10mM or 100 μ M), in proportions: dilutions of buffer at 1:3.16(20 μ L +43.2 μ L) gave the highest assay concentration 100 μ M or 1 μ M. mu.L of the test solution was transferred to the assay plate and untreated blank control wells containing 5. mu.L of DMSO and 5. mu.L of a DMSO solution of a control of a known inhibitor comparative example were added sequentially to the source culture dish (384 well assay dish, Labcyte). The plates were centrifuged at 2500rpm for 1 minute and sealed with foil. A 3-fold serial dilution was performed using reaction buffer to obtain 11 test spots, and blanks of 100nL of test compound solution, known inhibitor comparative compound solution, DMSO solution after dilution were transferred to assay plates, 2 duplicate wells per concentration. The assay plates were centrifuged at 2500rpm for 1 minute and sealed with foil.
For the enzyme reaction, 5. mu.L of 50mM Tris pH7.5, 10mM MgCl2, 1mM EGTA, 0.01% Brij-35, 2mM DTT buffer containing 5nM LRRK2 enzyme was added to all wells of the assay plate. The culture dish was centrifuged to concentrate the mixture at the bottom of the well. The assay plates were incubated at 23 ℃ for 20 minutes. After incubation, 5 μ L of 1X kinase reaction buffer 2X LRRKtide succinate and ATP were added to each well and the culture dish was centrifuged to concentrate the mixture at the bottom of the well. The plates were incubated at 23 ℃ for 60 minutes.
For detection of the reaction, 10 μ L of TR-FRET dilution buffer detection reagent containing antibody reagent and 10mM EDTA was added to all wells of each well of the assay plate, and the plate was centrifuged to concentrate the mixture at the bottom of the well. Subsequently, the plates were incubated at 23 ℃ for 60 minutes. The plates were read on a Perkin elmer envision 2104 instrument in TR-FRET mode using a 340m excitation filter, a 520nm fluorescence emission filter and a 490 or 495nm terbium emission filter. The inhibitory effect of variant G2019S LRRK2 was measured in exactly the same way. All final concentrations of substrate ATP and enzyme were the same.
Data analysis was performed using Graphpad software and Kd activity was calculated.
Several compounds disclosed herein were tested according to the methods above, each concentration tested being a duplicate well, averaged, and the corresponding Kd activity values of LRRK2 and LRRK2G2019S are provided in table 2.
TABLE 2
Figure BDA0002706277720000211
All patents and other publications identified in this specification and examples are expressly incorporated herein by reference for all purposes. These publications are provided solely for their disclosure prior to the filing date of the present application. In this regard, no admission should be made that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.

Claims (1)

1. Use of a compound for the manufacture of a medicament for the treatment of a disease caused by increased activity of LRRK2 kinase or LRRK2 mutant kinase, wherein the compound is any one of the following compounds:
(1) (1S, 2S, 3R, 4R) -3- [ [ 5-fluoro-2- [ 3-methyl-4- (4-methylpiperazin-1-yl) anilino ] pyrimidin-4-yl ] amino ] bicyclo [2.2.1] hept-5-ene-2-carboxamide;
(2) 2- [ [1- [ 2-fluoro-4- [ [ 5-methyl-4- (1-prop-2-ylpyrazol-4-yl) pyrimidin-2-yl ] amino ] phenyl ] piperidin-4-yl ] -methylamino ] ethanol;
(3) 5-chloro-4-N- (2-dimethylphosphorylphenyl) -2-N- [ 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl ] pyrimidine-2, 4-diamine;
(4) 6-ethyl-3- [ 3-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] anilino ] -5- (oxa-4-ylamino) pyrazine-2-carboxamide;
the disease is Crohn's disease.
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US10106507B2 (en) * 2014-08-03 2018-10-23 H. Lee Moffitt Cancer Center and Research Insitute, Inc. Potent dual BRD4-kinase inhibitors as cancer therapeutics
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US20190275040A1 (en) * 2016-09-26 2019-09-12 Yale University Compounds and methods for treating or preventing alzheimer's disease
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