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    • 专利摘要:
    LRRK2 inhibitor compounds and their use for the treatment of neurodegenerative diseases. The present invention relates to a series of compounds with a structural core of benzothiazol-benzamide that have the ability to inhibit the LRRK2 enzyme, whereby the invention also relates to the use of these compounds for the treatment of neurodegenerative diseases in which this Enzyme is involved, such as Parkinson's disease or Alzheimer's disease. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2744304A1
    申请号:ES201830841
    申请日:2018-08-24
    公开日:2020-02-24
    发明作者:Gil Ana Martinez；Ayuso-Gontan Carmen Gil；Diaz De Bonilla Josefa Zaldivar；Fernandez Rocio Benitez
    申请人:Consejo Superior de Investigaciones Cientificas CSIC；
    IPC主号:
    专利说明:

    [0001]
    [0002] LRRK2 inhibitor compounds and their use for the treatment of neurodegenerative diseases
    [0003]
    [0004] The present invention relates to a series of compounds with a structural core of benzothiazol-benzamide that have the capacity to inhibit the LRRK2 enzyme and are therefore useful for the treatment of neurodegenerative diseases in which this enzyme is involved, such as the disease of Parkinson's or Alzheimer's disease.
    [0005]
    [0006] BACKGROUND OF THE INVENTION
    [0007]
    [0008] The increase in the incidence of neurodegenerative diseases due to the increase in life expectancy in today's society has made the search for treatments of these diseases a priority. A common characteristic in people affected by any of these pathologies is the progressive loss of neurons in specific regions of the nervous system and the consequent deterioration of cognitive and motor functions. Considering the etiology still unknown and the absence of effective treatments, the discovery of therapeutically effective targets is necessary.
    [0009]
    [0010] It is widely known that in certain CNS pathologies the hyperphosphorylated tau protein is added and forms neurofibrillary tangles in the neurons, thus causing the microtubule to be disrupted. However, the mechanism that leads to this situation is not yet fully known. The possible kinases involved in this process are common targets in some proposed treatments, such as Dyrk1A, for which inhibitors have been described that are potential drugs for the treatment of so-called tauopathies (WO2015 / 118026).
    [0011]
    [0012] LRRK2 is an especially large protein that has been classified as a member of the ROCO ( Ras-like GTPase) superfamily. The physiological role of LRRK2 is not yet well determined and many of its substrates are unknown, but it has become an interesting target for neurodegenerative diseases, especially Parkinson's disease. Additionally, it is considered that LRRK2 may be related to other pathologies in which the tau protein is affected, as well as with the inflammatory response, oxidative stress, synaptic and mitochondrial dysfunctions and neurogenesis in adults through the Wnt signaling pathway.
    [0013]
    [0014] LRRK2 is abundantly expressed in microglia in addition to neurons, having been shown to be a positive modulator of inflammation in murine microglia and that mutations in LRRK2 can alter the brain microenvironment favoring neuroinflammation. Therefore, it can be related to various neurodegenerative diseases that occur with neuroinflammation, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis, and their inhibitors play a neuroprotective role by decreasing the inflammatory response. In addition, LRRK2 increases the activity of the GSK-3 enzyme and therefore, hyperphosphorylation of the TAU protein and other pathological proteins such as TDP-43 is promoted. This known relationship allows us to establish which compounds that inhibit the activity of LRRK2 will indirectly decrease the phosphorylation of tau and TDP-43, so that LRRK2 inhibitors may be useful for the treatment of tautopathies such as Alzheimer's disease, supranuclear paralysis progressive, frontotemporal dementia, Pick's disease, etc., and diseases associated with TDP-43 such as amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's disease, among others.
    [0015]
    [0016] Taking into account the interest of LRRK2 as a therapeutic target for neurodegenerative diseases, various inhibitors of this enzyme have been described that would be potential treatments (such as in WO2013 / 139882 and WO2011 / 141756). However, most of these compounds have the difficulty of not crossing the blood-brain barrier or being less selective against other protein kinases, which is a problem in drug candidate molecules for the treatment of diseases of the central nervous system (CNS) .
    [0017]
    [0018] Thus, since there is a need for advantageous therapeutic agents, the design and synthesis of molecules that are selective for the LRRK2 protein is vital, with the ability to penetrate into the CNS for the treatment of neurodegenerative diseases.
    [0019] DESCRIPTION OF THE INVENTION
    [0020]
    [0021] The present invention is based on a series of compounds with a benzothiazole-benzamide structural core that typically has a morpholino substituent, hereinafter compounds of the invention. These structural factors make them selective inhibitors of the LRRK2 protein, involved in signaling pathways that are impaired in neurodegenerative diseases. In addition, the compounds of the present invention have the ability to cross the blood-brain barrier (BBB) as will be demonstrated below in the examples provided.
    [0022]
    [0023] Therefore, in a first aspect, the present invention relates to a compound of formula (I):
    [0024]
    [0025]
    [0026]
    [0027] where R 1 is selected from H, C 1 -C 6 alkyl, halogen, CF 3 , -O-C 1 -C 6 alkyl.
    [0028]
    [0029] In a preferred embodiment of compound (I), R 1 is H.
    [0030]
    [0031] In another preferred embodiment of compound (I), R 1 is a C 1 -C 4 alkyl. In a more preferred embodiment of compound (I), R 1 is selected from methyl or isopropyl.
    [0032]
    [0033] In another preferred embodiment of compound (I), R 1 is selected from F, Cl or Br.
    [0034]
    [0035] In another preferred embodiment of compound (I), R 1 is a -O-C 1 -C 4 alkyl. In a more preferred embodiment of compound (I), R 1 is selected from -O-methyl, -O ethyl, -O-propyl.
    [0036]
    [0037] In another preferred embodiment of compound (I), R 1 is CF 3 .
    [0038] In another preferred embodiment, the compound of formula (I) is selected from the following list:
    [0039] • N- (benzothiazol-2-yl) -4-morpholinobenzamide,
    [0040] • N- (6-methoxybenzothiazol-2-yl) -4-morpholinobenzamide,
    [0041] • N- (6-trifluoromethylbenzothiazol-2-yl) -4-morpholinobenzamide,
    [0042] • N- (6-methylbenzothiazol-2-yl) -4-morpholinobenzamide,
    [0043] • N- (6-Chlorobenzothiazol-2-yl) -4-morpholinobenzamide,
    [0044] • N- (6-flurobenzothiazol-2-yl) -4-morpholinobenzamide,
    [0045] • N- (6-ethoxybenzothiazol-2-yl) -4-morpholinobenzamide,
    [0046] • N- (6-Bromobenzothiazol-2-yl) -4-morpholinobenzamide,
    [0047] • N- (6-propoxybenzothiazol-2-yl) -4-morpholinobenzamide,
    [0048] • N- (6-isopropylbenzothiazol-2-yl) -4-morpholinobenzamide.
    [0049]
    [0050] In the present invention, the term "C 1 -C 6 alkyl" refers to an aliphatic, linear or branched chain radical having 1 to 6 carbon atoms, preferably between 1 and 4 carbon atoms, such as , but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl The alkyl group may be optionally substituted by one or more substituents such as halogen, hydroxyl, -O-C 1 -C 6 alkyl, -CO-C 1 -C 6 alkyl, -CN, -COOH, -COO-C 1 -C 6 alkyl, -CONH-C 1 -C alkyl 6 or -SO 2 -C 1 -C 6 alkyl.
    [0051]
    [0052] The term "halogen" refers, in the present invention, to fluorine, bromine, chlorine or iodine.
    [0053]
    [0054] The present invention also relates to isomers of the compounds of formula (I). The term isomers is understood as chemical compounds with the same number and type of atoms as another chemical species, but with different arrangement or orientation, and refers to functional isomers, structural isomers, tautomers, valence isomers or stereoisomers.
    [0055]
    [0056] Another aspect of the invention is the compound of formula (I) as described above for use as a medicament.
    [0057]
    [0058] Another aspect of the invention relates to the compound of formula (I) described above for use in the treatment of a neurodegenerative disease that may be a synucleinopathy or a tauopathy.
    [0059] Synuclein is a presynaptic protein whose physiological role is undetermined and is thought to be involved in synaptic plasticity processes. It abounds in brain tissue and the conformational and biochemical changes that this protein undergo determine cytoplasmic inclusions that characterize various neurodegenerative disorders, including Parkinson's disease, Lewis body dementia or multisystemic atrophy, grouping under the term synucleinopathies.
    [0060]
    [0061] The set of diseases known as tauopathies derives from the neuropathological study of different neurodegenerative diseases that present intraneuronal accumulations of tau protein. Among the tauopathies, Alzheimer's disease, progressive supranuclear paralysis or the frontal-temporal lobar degeneration complex stand out.
    [0062]
    [0063] In a preferred embodiment of the use of the compound of formula (I), neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia, chromosome 17-linked parkinsonism, dementia Argyrophilic, post-encephalitic parkinsonism, primary tauopathy associated with age.
    [0064]
    [0065] In a more preferred embodiment of the use of the compound of formula (I), the neurodegenerative disease is Parkinson's disease.
    [0066]
    [0067] In another more preferred embodiment of the use of the compound of formula (I), the neurodegenerative disease is Alzheimer's disease.
    [0068]
    [0069] Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula (I) as described above, and optionally a pharmaceutically acceptable carrier or excipient.
    [0070]
    [0071] In a preferred embodiment, said pharmaceutical composition further comprises another active ingredient.
    [0072]
    [0073] The compounds of the invention, in their therapeutic use or as part of a pharmaceutical composition, may be in crystalline form as free compounds or as solvates and both forms are intended to be within the scope of the present invention. In this sense, the term "solvate", as used herein, includes both pharmaceutically acceptable solvates, that is, solvates of the compound of formula (I) that may be used in the manufacture of a medicament, such as pharmaceutically acceptable solvates, which may be useful in the preparation of solvates or pharmaceutically acceptable salts. The nature of the pharmaceutically acceptable solvate is not critical as long as it is pharmaceutically acceptable. In a particular embodiment, the solvate is a hydrate. Solvates can be obtained by conventional solvation methods well known to those skilled in the art.
    [0074]
    [0075] The compounds of formula (I) for therapeutic use or as part of a pharmaceutical composition are prepared in solid form or aqueous suspension, in a pharmaceutically acceptable diluent. These preparations may be administered by any appropriate route of administration, for which said preparation will be formulated in the pharmaceutical form appropriate to the route of administration chosen. In a particular embodiment, the administration of the compound of formula (I) provided by this invention is carried out orally, topically, rectally or parenterally (including subcutaneously, intraperitoneally, intradermally, intramuscularly, intravenously, etc.). A review of the different pharmaceutical forms of drug administration and of the excipients necessary to obtain them can be found, for example, in the "Galician Pharmacy Treaty", C. Faulí i Trillo, 1993, Luzán 5, SA Ediciones , Madrid, or in other or similar ones of the Spanish Pharmacopoeias and in the United States.
    [0076]
    [0077] The compounds described in the present invention, their pharmaceutically acceptable salts, solvates as well as the pharmaceutical compositions containing them can be used together with other additional drugs to provide a combination therapy. Said additional drugs may be part of the same pharmaceutical composition or, alternatively, they may be provided in the form of a separate composition for simultaneous or non-simultaneous administration to the pharmaceutical composition comprising a compound of formula (I), or a salt, pharmaceutically acceptable stereoisomer or solvate thereof.
    [0078]
    [0079] Unless otherwise indicated, the compounds of the invention also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having said structure, except for the Replacement of a hydrogen with a deuterium or tritium, or the replacement of a carbon with a carbon enriched in 13C or 14C or a nitrogen enriched in 15N, are within the scope of this invention.
    [0080]
    [0081] Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples and figures are provided by way of illustration, and are not intended to be limiting of the present invention.
    [0082]
    [0083] BRIEF DESCRIPTION OF THE FIGURES
    [0084]
    [0085] FIGs. 1. They show neuroprotection against tau hyperphosphorylation of the compounds of the invention 1-10 LRRK2 inhibitors.
    [0086]
    [0087] FIG. 2. It shows the linear correlation between the described and experimental permeability of ten commercial compounds using the PAMPA-Blood-brain barrier methodology.
    [0088]
    [0089] EXAMPLES
    [0090]
    [0091] Next, the invention will be illustrated by tests carried out by the inventors, which demonstrates the effectiveness of the product of the invention.
    [0092]
    [0093] Example 1. Synthesis and characterization of the compounds of the invention.
    [0094]
    [0095] M- (benzothiazol-2-yl) -4-morpholmobenzamide (1) : 276.0 mg of 4-morpholinobenzoic acid (1.3 mmol), 331.00 mg of EDCI (1.4 mmol), 24.4 mg of DMAP (0.3 mmol) and 335 pL ( 2.4 mmol) of triethylamine were dissolved in dichloromethane. After one hour of stirring at room temperature 200 mg of 2-aminobenzothiazole (1.3 mmol) were added. The reaction is allowed to stir at room temperature overnight. After that time the crude was washed with saturated solutions of NaHCO 3 and NaCl respectively. The organic phase is then dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, and purified by flash column chromatography using a mixture of CH 2 Ch / MeOH eluents (20: 1) to obtain a yellow solid (72 mg, 16%). HPLC purity> 95%. MS: m / z 340 [M 1] +. 1 H NMR (300 MHz, CDCh) 510.21 (s, 1 H, NH), 7.90 (d, J = 9.0 Hz, 2 H), 7.84 (dd, J = 8.5, 1.5 Hz, 1 H), 7.62 (dd, J = 8.3, 1.2 Hz, 1 H), 7.44 - 7.35 (m, 1 H), 7.35 - 7.27 (m, 1 H), 4.01 - 3.71 (m, 4 H), 3.49 - 3.16 (m, 4 H) . 13C NMR (75 MHz, DMSO) 5164.6, 159.1, 154.3, 148.2, 132.2, 129.4, 126.0, 123.7, 121.3, 121.1, 120.7, 113.8, 66.5, 47.4.
    [0096]
    [0097] M- (6-methoxybenzothiazol-2-yl) -4-morpholinobenzamide (2) : 230.0 mg of 4-morpholinobenzoic acid (1.1 mmol), 276.6 mg of EDCI (1.4 mmol), 24.43 mg of DMAP (0.2 mmol) and 248 pL (1.7 mmol) of triethylamine were dissolved in dichloromethane. After one hour of stirring at room temperature 200 mg of 2-amino-6-methoxybenzothiazole (1.1 mmol) were added. The reaction is allowed to stir at room temperature overnight. After that time the crude was washed with saturated solutions of NaHCÜ 3 and NaCl respectively. The organic phase is then dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, and purified by flash column chromatography using a mixture of CH 2 Cl 2 / MeOH eluents (50: 1) to obtain a yellow solid. (36 mg, 9%). Mp: 237.6-240.0 ° C. HPLC purity: 95%. MS: m / z 370 [M + H] +. 1H NMR (300 MHz, CDCh) 59.47 (s, 1H), 7.88 (d, J = 9.0 Hz, 2H), 7.64 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 2.6 Hz, 1H) , 7.04 (dd, J = 8.8, 2.6 Hz, 1H), 6.94 (d, J = 9.0 Hz, 2H), 3.93-3.83 (m, 7H), 3.36-3.31 (m, 4H). 13C NMR (75 MHz, DMSO) 5 164.8, 156.9, 156.0, 153.8, 142.7, 132.8, 129.8, 120.8, 120.5, 114.80, 113.1, 104.6, 65.8, 55.6, 46.8.
    [0098]
    [0099] M- (6-Trifluoromethylbenzothiazol-2-yl) -4-morpholinobenzamide (3) : 189.9 mg of 4-morpholinobenzoic acid (0.9 mmol), 228.53 mg of EDCI (1.2 mmol), 22.41 mg of DMAP (0.2 mmol) and 223 pL (1.5 mmol) of triethylamine were dissolved in dichloromethane. After stirring for one hour at room temperature, 200 mg of 2-amino-6-trifluorobenzothiazole (0.9 mmol) was added. The reaction is allowed to stir at room temperature overnight. After that time the crude was washed with saturated solutions of NaHCO 3 and NaCl respectively. The organic phase is then dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, and purified by automatic column chromatography (Biotage®Isolera One) using a mixture of hexane / AcOEt eluents to obtain a yellow solid (79 mg, 26%). Mp: 218.5-218.5 ° C. HPLC purity: 95%. MS: m / z 408 [M + H] +. 1H NMR (300 MHz, CDCh) 5 10.85 (s, 1H), 8.13 (s, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.57-7.53 (m, 2H), 6.84 (d, J = 9.0 Hz, 2H), 3.87-3.83 (m, 4H), 3.31-3.26 (m, 4H). 13C NMR (125 MHz, CDCh) 5 163.8, 160.8, 153.4, 149.4, 131.2, 128.5, 124.9 (d, J = 32.5 Hz), 124.3, 122.1 (d, J = 3.4 Hz), 119.6 (d, J = 32.2 Hz), 118.0 (d, J = 4.2 Hz), 112.7, 65.4, 46.3, 28.6. C 19 H 16 F 3 N 3 O 2 S: Theoretical (%) C, 56.01; H, 3.96; N, 10.31; S, 7.87. Found C, 56.13; H, 3.98; N, 10.38; S, 7.59.
    [0100]
    [0101] M- (6-methylbenzothiazol-2-yl) -4-morpholinobenzamide (4) : 252.4 mg of 4-morpholinobenzoic acid (1.2 mmol), 303.5 mg of EDCI (1.58 mmol), 20.06 mg of DMAP (0.2 mmol) and 272 ^ L (1.9 mmol) of triethylamine were dissolved in dichloromethane. After stirring for one hour at room temperature, 200 mg of 2-amino-6-methylbenzothiazole (1.2 mmol) was added. The reaction is allowed to stir at room temperature overnight. After that time the crude was washed with solutions of HCl (0.1M), saturated NaHCO 3 and saturated NaCl respectively. The organic phase is then dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, and purified by automatic column chromatography (Biotage®Isolera One) using a mixture of hexane / AcOEt eluents to obtain a yellow solid (43 mg, 10%). P. f .: 287.7-288.8 ° C. MS (ESI +): m / z 354 [M + H] +. 1H NMR (300 MHz, CDCh) 510.56 (s, 1H), 7.89 (d, J = 8.9 Hz, 2H), 7.63 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.16 (dd, J = 8.3, 1.7 Hz, 1H), 6.85 (d, J = 8.9 Hz, 1H), 3.87-3.83 (m, 4H), 3.29-3.26 (m, 4H), 2.46 (s, 3H). 13C NMR (75 MHz, CDCh) 5 164.7, 158.5, 154.2, 146.1, 133.7, 132.3, 129.4, 127.5, 121.3, 121.1, 120.3, 113.8, 66.5, 47.5, 21.4. C 19 H 19 N 3 O 2 S: Theoretical (%) C, 64.57; H, 5.42; N, 11.89; S, 9.07. Found C, 64.33; H, 5.38; N, 11.85; S, 8.96.
    [0102]
    [0103] M- (6-Chlorobenzothiazol-2-yl) -4-morpholinobenzamide (5) : 224.4 mg of 4-morpholinobenzoic acid (1.1 mmol), 269.89 mg of EDCI (1.4 mmol), 26.4 mg of DMAP (0.2 mmol) and 242 ^ L (1.7 mmol) of triethylamine were dissolved in dichloromethane. After one hour of stirring at room temperature 200 mg of 2-amino-6-chlorobenzothiazole (1.1 mmol) were added. The reaction is allowed to stir at room temperature overnight. After that time the crude was washed with solutions of HCl (0.1M), saturated NaHCO 3 and saturated NaCl respectively. The organic phase is then dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, and purified by automatic column chromatography (Biotage® Isolera One) using a mixture of hexane / AcOEt eluents to obtain a white solid (96 mg, 24%). Mp: 245.4-246.4 ° C. HPLC purity: 97%. MS: m / z 374 [M + H] +. 1H NMR (300 MHz, CDCh) 510.25 (s, 1H), 7.89 (d, J = 8.9 Hz, 2H), 7.81 (d, J = 2.1 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H) , 7.33 (dd, J = 8.7, 2.1 Hz, 1H), 6.89 (d, J = 9.0 Hz, 2H), 3.92-3.82 (m, 4H), 3.33 3.30 (m, 4H). 13C NMR (75 MHz, CDCh) 5 164.5, 159.3, 154.4, 146.8, 139.7, 133.5, 129.4, 126.7, 121.5, 121.0, 120.8, 113.7, 66.5, 47.4. C 18 H 16 CIN 3 O 2 S: Theoretical (%) C, 57.83; H, 4.31; N, 11.24; S, 8.58. Found C, 57.56; H, 4.09; N, 11.43; S, 8.40.
    [0104]
    [0105] M- (6-flurobenzothiazol-2-yl) -4-morpholinobenzamide (6) : 168.20 mg of 4-morpholinobenzoic acid (1.2 mmol), 296.3 mg of EDCI (1.5 mmol), 29.05 mg of DMAP (0.2 mmol) and 265 qL (1.9 mmol) of triethylamine were dissolved in dichloromethane. After stirring for one hour at room temperature, 200 mg of 2-amino-6-flurobenzothiazole (1.2 mmol) was added. The reaction is allowed to stir at room temperature overnight. After that time the crude was washed with solutions of HCl (0.1M), saturated NaHCO 3 and saturated NaCl respectively. The organic phase is then dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, and purified by automatic column chromatography (Biotage®Isolera One) using a mixture of hexane / AcOEt eluents to obtain a white solid (79 mg, 19%). Mp: 228.3-229.3 ° C. HPLC purity: 98% MS: m / z 358 [M + H] +. 1H NMR (300 MHz, CDCh) 59.96 (s, 1H), 7.81 (d, J = 8.9 Hz, 2H), 7.74 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H) , 7.28 (dd, J = 8.7, 2.1 Hz, 1H), 6.84 (d, J = 8.7 Hz, 2H), 3.87-3.85 (m, 4H), 3.34 3.30 (m, 4H). 13C NMR (75 MHz, CDCh) 5 164.4, 159.2, 154.4, 147.0, 138.7, 133.6, 129.3, 126.8, 121.6, 121.0, 120.8, 113.8, 66.5, 47.4. C 18 H 16 FN 3 O 2 S: Theoretical (%) C, 60.49; H, 4.51; N, 11.76; S, 8.97. Found C, 60.68; H, 4.50; N, 11.55; S, 8.72.
    [0106]
    [0107] M- (6-ethoxybenzothiazol-2-yl) -4-morpholinobenzamide (7) : 213.1 mg of 4-morpholinobenzoic acid (1.0 mmol), 256.2 mg of EDCI (1.3 mmol), 25.12 mg of DMAP (0.2 mmol) were dissolved in dichloromethane. After 6 hours of stirring at room temperature 200 mg of 2-amino-6-ethoxybenzothiazole (1.0 mmol) and 229 qL of triethylamine (1.9 mmol) were added. The reaction is allowed to stir at room temperature overnight. After that time the crude was washed with solutions of HCl (0.1M), saturated NaHCO 3 and saturated NaCl respectively. The organic phase is then dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, and purified by automatic column chromatography (Biotage®Isolera One) using a mixture of hexane / AcOEt eluents to obtain a yellow solid (20mg , 5%). Mp: 222.8-223.8 ° C. HPLC purity: 95%. MS: m / z 384 [M + H] +. 1H NMR (300 MHz, CDCh) 5 8.07 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.9 Hz, 1H), 7.35-7.18 (m, 1H), 7.04 (dd, J = 8, 9, 2.4 Hz, 1H), 6.89 (d, J = 8.6 Hz, 2H), 4.07 (q, J = 6.9 Hz, 2H), 3.89-3.69 (m, 4H), 3.38 3.25 (m, 4H), 1.43 (t, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCh) 5164.4, 157.1, 156.0, 154.2, 142.3, 133.3, 129.3, 121.3, 121.2, 119.7, 115.5, 114.2, 113.8, 106.0, 104.9, 99.5, 66.5, 64.1, 64.1, 47.5, 14.8.
    [0108]
    [0109] M- (6-Bromobenzothiazol-2-yl) -4-morpholinobenzamide (8) : 180.9 mg of 4-morpholinobenzoic acid (0.9 mmol), 217.6 mg of EDCI (1.1 mmol), 21.33 mg of DMAP (0.2 mmol) were dissolved in dichloromethane. After 6 hours of stirring at room temperature 200 mg of 2-amino-6-bromobenzothiazole (0.9 mmol) and 195 pL of triethylamine (1.4 mmol) were added. The reaction is allowed to stir at room temperature overnight. After that time the crude was washed with solutions of HCl (0.1M), saturated NaHCO 3 and saturated NaCl respectively. The organic phase is then dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, and purified by automatic column chromatography (Biotage®Isolera One) using a mixture of hexane / AcOEt eluents to obtain a yellow solid (41 mg, 11%). Mp: 237.5-238.5 ° C. HPLC purity: 98% MS: m / z 418 [M + H]. 1H NMR (300 MHz, CDCh) 5 10.51 (s, 1H), 7.96 (s, 1H), 7.87 (d, J = 9.0 Hz, 3H), 7.44 (dd, J = 8.6, 1.9 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 9.0 Hz, 3H), 3.89-3.83 (m, 11H), 3.33-3.26 (m, 11H).
    [0110] 13C NMR (125 MHz, CDCh) 5 165.2, 160.4, 154.8, 147.1, 134.1, 130.0, 129.9, 124.3, 122.1, 121.1, 117.2, 114.1, 66.9, 47.8.
    [0111]
    [0112] M- (6-propoxybenzothiazol-2-yl) -4-morpholinobenzamide (9) : 248.8 mg of 4-morpholinobenzoic acid (1.2 mmol), 299.00 mg of EDCI (1.6 mmol), 29.3 mg of DMAP (0.2 mmol) were dissolved in dichloromethane. After six hours of stirring at room temperature 250 mg of 2-amino-6-propoxybenzothiazole (1.2 mmol) and 267.6 pL (1.9 mmol) of triethylamine were added. The reaction is allowed to stir at room temperature overnight. After that time the crude was washed with a solution of HCl (0.1M). The organic phase is then dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, and purified by flash column chromatography using a mixture of CH 2 Ch / MeOH eluents (50: 1) to obtain a yellow solid ( 127 mg, 27%). HPLC purity> 95% MS: m / z 398 [M + H] +. 1H NMR (300 MHz, CDCh) 5 7.88 (d, J = 9.0 Hz, 2H), 7.46 (d, J = 8.9 Hz, 1H), 7.31 (d, J = 2.5 Hz, 1H), 6.96 (dd, J = 8.9, 2.5 Hz, 1H), 6.88 (d, J = 9.0 Hz, 2H), 3.98 (t, J = 6.6 Hz, 2H), 3.89 - 3.83 (m, 4H), 3.32 - 3.27 (m, 4H) , 1.85 (h, J = 7.3 Hz, 2H), 1.06 (t, J = 7.4 Hz, 2H). 13C NMR (75 MHz, CDCh) 5 163.6, 156.3, 155.2, 153.3, 141.27, 132.2, 128.4, 120.4, 120.3, 114.5, 112.8, 103.9, 69.2, 65.5, 46.5, 21.6, 9.5. C 21 H 23 N 3 O 3 S: Theoretical (%) C, 63.46; H, 5.83; N, 10.57; S, 8.07. Found C, 63.73; H, 5.74, N, 10.09; S, 7.71.
    [0113] N - (6-Isopropylbenzothiazol-2-yl) -4-morpholinobenzamide (10) : 269.4 mg of 4-morpholinobenzoic acid (1.3 mmol), 324.00 mg of EDCI (1.7 mmol), 32.00 mg of DMAP (0.3 mmol) were dissolved in dichloromethane. After six hours of stirring at room temperature 250 mg of 2-amino-6-isopropylbenzothiazole (1.3 mmol) and 290.0pL (2.1 mmol) of triethylamine were added. The reaction is allowed to stir at room temperature overnight. After that time the crude was washed with a solution of HCl (0.1M). The organic phase is then dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, and purified by flash column chromatography using a mixture of CH 2 Cl 2 / MeOH eluents (50: 1) to obtain a yellow solid. (218.4mg, 44%). HPLC purity> 95% MS: m / z 382 [M + H] + . 1 H NMR (300 MHz, CDCh) 5 10.35 (s, 1H), 7.89 (d, J = 9.0 Hz, 2H), 7.68 (d, J = 1.7 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.26 - 7.22 (m, 1H), 6.88 (d, J = 9.0 Hz, 2H), 3.89 - 3.81 (m, 4H), 3.33 - 3.25 (m, 4H), 3.03 (p, J = 6.9 Hz , 1H), 1.31 (d, J = 6.9 Hz, 6H). 13 C NMR (75 MHz, CDCh) 5 163.7, 157.7, 153.2, 145.3, 143.9, 131.3, 128.4, 124.0, 120.4, 119.4, 119.1, 117.5, 112.8, 65.5, 46.5, 33.2, 23.3. C 21 H 23 N 3 O 2 S: Theoretical (%) C, 66.12; H, 6.08; N, 11.00; S, 8.40. Found C, 66.09; H, 6.13; N, 10.69; S, 8.54.
    [0114]
    [0115] Example 2. Inhibition of LRRK2 and LRRK2 G2019S
    [0116]
    [0117] The compounds were evaluated in LRRK2 and in the mutated form LRRK2 G2019S. This mutation is the most frequent in the familiar forms of Parkinson's disease and presents a significant increase in kinase activity. The experimental determination of the inhibition of both enzymes was carried out using the Adapta® method which is a method of evaluation of fluorescent kinase activity that determines ADP in a very sensitive manner. The methodology can be divided into two stages: kinase reaction and ADP determination. In the first stage, all components of the kinase reaction are added in the well and incubated for 60 min. After the reaction, the ADP detection solution containing a Europium-labeled anti-ADP antibody (Alexa Fluor® 647 labeled ADP tracer) and EDTA, to stop the kinase reaction, are added to the reaction well. The ADP formed in the kinase reaction in the absence of an inhibitor will displace the Alexa Fluor® 647 labeled ADP tracer from the antibody by decreasing the TR-FRET signal. In the presence of the inhibitor, the amount of ADP formed is smaller, which does not change the antibody- tracer interaction and therefore has a higher TR-FRET signal.
    [0118] The test is performed on 384 well plates. 100 nL of the solution with the compound to be evaluated in 1% DMSO, 2.4 pL of HEPES solution, 2.5 pL of ATP solution, 4.5 pL of substrate solution are added. The 10 pL of the kinase reaction has: 75 - 70 ng LRRK2 and 200 pM ERM (LRRKtide) in 25 mM Tris / 7.5 mM HEPES pH 8.2, 0.005% BRIJ-35, 5 mM MgCb, 0.5 mM EGTA, 0.01% NaN or 3 - 12 ng LRRK2 G2019S and 200 pM ERM (LRRKtide) in 25 mM Tris / 7.5 mM HEPES pH 8.2, 0.005% BRIJ-35, 5 mM MgCh, 0.5 mM EGTA, 0.01% NaN 3 . The plate is stirred for 30 s on a stir plate, and centrifuged for 1 min in a centrifuge at 1000 x g. The reaction is incubated at room temperature for 60 min. After this time, 5 pL of the detection mixture is added, the plate is stirred for 30 s in a stirring plate, and centrifuged for 1 min in a centrifuge at 1000 x g. Fluorescence is determined in a plate reader and the data analyzed.
    [0119]
    [0120] Table 1 Inhibition of LRRK2 and LRRK2 G2019S of heterocyclic compounds
    [0121]
    [0122]
    [0123]
    [0124] n.d. undetermined
    [0125] Example 3. Neuroprotection against hyperphosphorylation of tau.
    [0126]
    [0127] The neuroprotective potential of the compounds was evaluated in a cellular model of neurodegeneration induced by okadaic acid (OA). OA is a phosphatase 1 and 2 inhibitor and is commonly used to induce tau hyperphosphorylation in different cell lines. In this case, the human neural line SH-SY5Y is used. The cells are grown in a DMEM medium supplemented with 10% FBS and 1% penicillin / streptomycin at 37 ° C and in an incubator with 5% CO 2 . SH-SY5Y cells are seeded in a 96-well plate at a density of 60,000 cells per well for 48 hours. After this time, the cells are pre-incubated with the compounds to be studied at the concentration of 1, 5 and 10 pM for 1 hour. After this time, the OA is added at a concentration of 30nM, allowing the plate to incubate for an additional 24 hours. Next, the cells were incubated with a MTT solution at 0.5 mg.mL -1 for at least 4 hours at 37 ° C and 5% CO 2. Subsequently, the culture medium is removed and the formazan crystals attached to the base of the plate are dissolved with 200 pL of DMSO. Finally, the UV absorbance was measured at 595nM in a plate reader (Varioskan Flash Microplate reader, Thermo Scientific). The neuroprotection results shown by the studied compounds (1, 2, 3, 4, 5, 6, 7, 8, 9 and 10) are shown in Figure 1. In all cases, the treatment of the compounds prevents damage produced by okadaic acid and consequent hyperphosphorylation of the tau protein. These data indicate that the compounds used are likely to decrease this phosphorylation and increase neuronal viability, that is, they protect the neurons in culture.
    [0128]
    [0129] Example 4. Physical chemical properties compatible with the passage of the blood brain barrier
    [0130] The physicochemical properties of the synthesized compounds were determined using the LigPrep module and the QikProp tool both of the Maestro® program (Maestro version 11.0.015 release 2016-4, Maestro, Schrodinger, LLC, New York, NY, 2016). With these chemoinformatic tools, the structures were prepared in a medium similar to the first physiological one; and once obtained, the physical-chemical properties were calculated. The physicochemical properties of a compound are important to achieve therapeutic efficacy since they condition many of the ADME series processes (absorption, distribution, metabolism and excretion. Therefore, a prediction of the following characteristics was made: the prediction of passage in blood-brain barrier (QPlogBB), polar surface area (PSA) and octanol / water partition coefficient (QPlogP o / w) (table 2) According to these data, all the compounds are within the appropriate ranges; Therefore, they all have good lipophilic characteristics, the ability to form hydrogen bonds and cross the blood brain barrier.
    [0131] Table 2. Calculated physical chemical properties: QPlogBB (brain / blood distribution coefficient, interval (-3.0 to 1.2)); PSA (polar surface area, range (7.0 to 200.0)); QPlogP o / w (octanol / water partition coefficient, interval (-2.0 to 6.5)).
    [0132]
    [0133]
    [0134]
    [0135]
    [0136] Example 5. Permeability in the central nervous system (CNS) using parallel artificial membranes (PAMPA).
    [0137]
    [0138] The prediction of the permeability of the various compounds on the central nervous system (CNS), passage of the blood brain barrier, was determined using the parallel artificial membrane methodology (PAMPA) [Di, L .; kerns, EH; Fan, K .; McConnell, OJ; Carter, GT "High throughput artificial membrane permeability assay for blood-brain barrier” Eur. J. Med. Chem., 2003, 38 (3), 223-232]. Commercial reference compounds, phosphate buffer at pH = 7.4 (PBS), Ethanol and dodecane were obtained from the Sigma, Acros organics, Merck, Aldrich and Fluka commercial houses, respectively, the porcine brain lipid (reference catalog 141101) was purchased from Avanti Polar Lipids, both the 96-well donor plate (Multiscreen® IP Sterile Plate PDVF membrane, pore size 0.45 pM, catalog reference MAIPS4510) as the acceptor 96-well plate (Multiscreen®, catalog reference MAMCS9610) were purchased in Millipore. Filters were used to filter the samples. of PDVF membrane (30 mm diameter, pore size 0.45 pm) from the Symta commercial house The equipment used to perform ultraviolet absorbance measurements in 96-well plates was a Thermoscientific Multiskan spectrum.
    [0139] Ten reference compounds were selected, whose blood brain barrier passage is known, in order to validate the experiment. Different amounts of these were taken [(3-5 mg of caffeine, enoxacin, hydrocortisone, desipramine, ofloxacin, piroxicam, testosterone), (12 mg of promazine) and 25 mg of verapamil and atenolol] which were dissolved in ethanol ( 1000 pL). 100 microliters of these solutions were taken and 1400 pL of EtOH and 3500 pL of phosphate buffer PBS (pH = 7.4) buffer were added, in order to reach a final EtOH concentration of 30% in the solution. The solutions were filtered. Subsequently, 180 pL of a solution of PBS / EtOH (70/30) was added to each well of the acceptor plate. The donor plate was impregnated with 4 pL of a solution of the porcine brain lipid dissolved in dodecane (20 mg mL-1). After 5 minutes, 180 pL of solution of each compound was added on this plate. Of the compounds to evaluate their penetration into the central nervous system, they were taken between 1-2 mg and dissolved in 1500 pL of EtOH and 3500 pL of phosphate buffer PBS (pH = 7.4) buffer, filtered and added to the plate 96 well donor. Then, the donor plate was placed on the acceptor forming a kind of "sandwich" and left to incubate for 2h and 30 min at 25 ° C. The compounds by passive transport pass from the donor plate through the porcine brain lipid to the acceptor plate After 2 h and 30 min, the donor plate is carefully removed The concentration and absorbance of both commercial compounds and synthesized derivatives that were evaluated in the acceptor and donor plates were determined using a UV absorbance reader. Each sample was analyzed from 2 to 5 wavelengths, in 3 wells and in at least 2 independent experiments.The results are the average of the [standard deviation (SD)] measurements of the different experiments performed.Two commercial compounds of reference whose penetration into the central nervous system is known, in each experiment in order to validate the method. relationship between experimental (Pe) permeability values and those described, Pe (exptl) = 1.3711 (bibl) - 1.4509 (R2 = 0.972) (Figure 2). From this equation and following the pattern described in the literature [Crivori, P .; Cruciani, G .; Testa, B. "Predicting Blood-Brain Barrier Permeation from Three-Dimensional Molecular Structure." J. Med. Chem., 2000, 43, 2204-2216] for the prediction of blood brain barrier permeability, the compounds can be classified as permeable to the central nervous system (CNS) when they have a permeability> 4.03 x 10-6 cm s-1. The results are shown in Table 3, where it can be seen how some of the compounds evaluated (1, 4, 6) are able to cross the barrier Hematoencephalic by passive diffusion.
    [0140]
    [0141] Table 3.- Permeability ( Pe 10-6 cm s-1) in the PAMPA-Blood-brain Barrier experiment for ten commercial compounds, used for the validation of the experiment, and different derivatives synthesized with their corresponding prediction of penetration into the central nervous system ( SNC).
    [0142]
    [0143] Compound Bibl.a Pe (10-6 cm s-1) b Prediction
    [0144] Atenolol 0.8 1.0 ± 0.6
    [0145] Caffeine 1.3 1.0 ± 0.8
    [0146] Desipramine 12 12.9 ± 0.4
    [0147] Enoxacin 0.9 0.2 ± 0.2
    [0148] Hydrocortisone 1.9 0.4 ± 0.1
    [0149] Ofloxacino 0.8 0.3 ± 0.3
    [0150] Piroxicam 2.5 0.6 ± 0.2
    [0151] Promazine 8.8 9.8 ± 0.5
    [0152] Testosterone 17 25.0 ± 0.2
    [0153] Verapamil 16 19.3 ± 0.7
    [0154]
    [0155]
    [0156]
    [0157]
    [0158]
    [0159]
    [0160] aReference Di et al Eur. J. Med. Chem., 2003, 38 (3), 223-232. bMedia data ± standard deviation (SD) of at least 2 independent experiments.
    权利要求:
    Claims (15)
    [1]
    1. Compound of formula (I):

    [2]
    2. Compound according to claim 1, wherein R 1 is H.
    [3]
    3. Compound according to claim 1, wherein R 1 is a C 1 -C 4 alkyl.
    [4]
    4. Compound according to claim 3, wherein R 1 is selected from methyl or isopropyl.
    [5]
    5. Compound according to claim 1, wherein R 1 is selected from F, Cl or Br.
    [6]
    6. Compound according to claim 1, wherein R 1 is a -O-C 1 -C 4 alkyl.
    [7]
    7. Compound according to claim 6, wherein R 1 is selected from -O-methyl, -O-ethyl, -O-propyl.
    [8]
    8. Compound according to claim 1, wherein R 1 is CF 3 .
    [9]
    9. Compound according to claim 1 which is selected from the following list:
    • N- (benzothiazol-2-yl) -4-morpholinobenzamide,
    • N- (6-methoxybenzothiazol-2-yl) -4-morpholinobenzamide,
    • N- (6-trifluoromethylbenzothiazol-2-yl) -4-morpholinobenzamide,
    • N- (6-methylbenzothiazol-2-yl) -4-morpholinobenzamide,
    • N- (6-Chlorobenzothiazol-2-yl) -4-morpholinobenzamide,
    • N- (6-flurobenzothiazol-2-yl) -4-morpholinobenzamide,
    • N- (6-ethoxybenzothiazol-2-yl) -4-morpholinobenzamide,
    • N- (6-Bromobenzothiazol-2-yl) -4-morpholinobenzamide,
    • N- (6-propoxybenzothiazol-2-yl) -4-morpholinobenzamide,
    • N- (6-isopropylbenzothiazol-2-yl) -4-morpholinobenzamide.
    [10]
    10. Compound of formula (I) according to any of claims 1 to 9 for use as a medicament.
    [11]
    11. Compound of formula (I) according to any of claims 1 to 9 for use in the treatment of a neurodegenerative disease selected from Alzheimer's disease, Parkinson's disease, Pick's disease, progressive supranuclear paralysis, corticobasal degeneration, Frontotemporal dementia, parkinsonism attached to chromosome 17, argyrophilic dementia, post-encephalitic parkinsonism and age-related primary tauopathy.
    [12]
    12. Compound for use according to claim 11, wherein the neurodegenerative disease is Parkinson's disease.
    [13]
    13. Compound for use according to claim 11, wherein the neurodegenerative disease is Alzheimer's disease.
    [14]
    14. Pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 9.
    [15]
    15. Pharmaceutical composition according to claim 14 further comprising another active ingredient.
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    同族专利:
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    WO2020039110A1|2020-02-27|
    EP3842422A1|2021-06-30|
    ES2744304B2|2020-06-22|
    US20210323936A1|2021-10-21|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2006038039A1|2004-10-01|2006-04-13|Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa|Modulators of hcv replication|
    WO2010077068A2|2008-12-29|2010-07-08|Korea Institute Of Science And Technology|Benzoarylureido compounds, and composition for prevention or treatment of neurodegenerative brain disease containing the same|
    WO2015118026A1|2014-02-04|2015-08-13|Lytix Biopharma As|Neurodegenerative therapies|
    GB201008134D0|2010-05-14|2010-06-30|Medical Res Council Technology|Compounds|
    GB201204985D0|2012-03-21|2012-05-02|Genentech Inc|Compounds|
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