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    • 专利摘要:
    Inhibitory compounds of CDC-7 and its use for the treatment of neurological pathologies. The present invention relates to a series of substituted purine derivatives which are capable of inhibiting the activity of the CDC7 kinase, so they are useful for the treatment of neurological diseases such as Alzheimer's disease, amyotrophic lateral sclerosis or dementia. frontotemporal, among others, where hyperphosphorylation of TDP-43 and subsequent formation of agglomerates induced by CDC7 occurs. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2686909A1
    申请号:ES201730399
    申请日:2017-03-22
    公开日:2018-10-22
    发明作者:Ana Martinez Gil；Daniel I. PEREZ；Carmen GIL AYUSO-GONTÁN；Angeles MARTIN-REQUERO；Elisa ROJAS PRATS；Loreto MARTINEZ-GONZALEZ；Concepción PEREZ
    申请人:Consejo Superior de Investigaciones Cientificas CSIC；
    IPC主号:
    专利说明:

    CDC-7 inhibitor compounds and their use for the treatment of neurological pathologies
    DESCRIPTION
      5
    The present invention relates to a series of substituted purine derivatives that are capable of inhibiting the activity of the CDC7 kinase, so they are useful for the treatment and / or prevention of neurological diseases such as amyotrophic lateral sclerosis, the disease of Alzheimer's disease or frontotemporal dementia, where there is hyperphosphorylation of TDP-43 and subsequent formation of agglomerates 10 induced by CDC7.
    STATE OF THE TECHNIQUE

    The kinase hyperactivity occurs in many types of diseases and particularly in neurodegenerative diseases and cancer. Hyperphosphorylation of the TDP-43 protein induces the formation of aggregates that have been detected in patients with amyotrophic lateral sclerosis or with frontotemporal lobular degeneration. It has been detected that CDC7 kinase is responsible for the dual hyperphosphorylation of TDP-43 in serines 409/410 in certain models, so the inhibition of this CDC7 would be an interesting strategy to develop drugs for neurodegerative diseases, such as example amyotrophic lateral sclerosis (ALS) or with frontotemporal lobular degeneration (Lianchko, NF et al., Ann Neurol. 2013 74 (1): 39-52). There are other neurological diseases also mediated by TDP-43, such as chronic traumatic encephalopathy and cognitive impairment associated with age 25 (Iverson GL, et al., Neurosci Biobehav Rev. 2015 Sep; 56: 276-293; Nag S, et al., Neurology. 2017 Feb 14; 88 (7): 653-660; Wilson RS, et al., JAMA Neurol. 2013 Nov; 70 (11): 1418-1424).

    US2013 / 0072506A1 describes derivatives of 6,8-disubstituted purines that are useful for a number of therapeutic and cosmetic uses. Among the possible therapeutic uses, the treatment of multiple sclerosis or as antineurodegenerative drugs is mentioned.

    WO2007 / 124288A1 describes a series of compounds with a structural core of indazole that have the ability to inhibit CDC-7 and that are useful for
    the treatment of a disease in which this kinase is involved, such as cancer.

    In ACS Med. Chem. Lett. 2013, 4, 211-215, Penning et al. describe a study on the interaction of azaindole-derived compounds with the CDC-7 and the possibility of using these compounds in cancer therapy.

    US2011 / 015172A1 describes a family of pyrrolpyrazines that are kinase inhibitors such as CDC-7 and its use for the treatment of diseases associated with this kinase such as cancer. 10
    DESCRIPTION OF THE INVENTION

    The present invention provides a series of purine-derived compounds that are CDC-7 inhibitors and useful as potential drugs for diseases mediated by TDP-43 proteinopathies, such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and dementia. frontotemporal.

    Therefore, in a first aspect, the present invention relates to the use of a compound of formula (I)



    where:
    G represents a group selected from aryl, heteroaryl or C1-C10 alkyl, any of them optionally substituted by at least one substituent selected from CF3, C1-C6 alkyl, S-C1-C6 alkyl, halogen, CN, O-C1-C6 alkyl, NO2, COO-C1-C6 alkyl, NHCO-C1-C6 alkyl, NH2 and NH-C1-C6 alkyl, or
    optionally substituted by two substituents formed a condensed cycle to the group G when it is an aryl or a heteroaryl and
    Z is selected from O or S;

    or any of its pharmaceutically acceptable salts, solvates or isomers for the manufacture of a medicament for the treatment of pathologies related to the TDP-43 protein, in particular with post-translational modifications of TDP-43. These compounds are CDC7 inhibitors in the phosphorylation of TDP-43.

    In a preferred embodiment G is an aryl group, more preferably the aryl group is a phenyl that may be optionally substituted and the compound of formula (I) would be the compound of formula (II):

    (II)
    where: 15
    R1 to R5 are each independently selected from H, CF3, S-C1-C6 alkyl, halogen, C1-C6 alkyl, CN, O-C1-C6 alkyl, NO2, COO-C1-C6 alkyl, NHCO-C1 alkyl -C6, NH2 and NH-C1-C6 alkyl or two of the radicals R1 to R5 form a condensed cycle to the phenyl; Y
    Z is selected from O or S. 20

    The term "aryl" refers, in the present invention, to aromatic rings, single or multiple, having between 5 and 18 carbon atoms in the part of the ring, such as but not limited to, phenyl, naphthyl, diphenyl, indenyl, phenanthryl, fluorenyl or anthracil. Preferably the aryl group has 5 to 7 carbon atoms and more preferably 25
    The aryl group is a phenyl. The aryl groups may be optionally substituted in any of their positions by one or more substituents or by two substituents forming a fused cycle to the aryl and are independently selected from among such as CF3, C1-C6 alkyl, S-C1-C6 alkyl, halogen, CN, O-C1-C6 alkyl, NO2, COO-C1-C6 alkyl, NHCO-C1-C6 alkyl, NH2 and NH-C1-C6 alkyl, and more preferably between CF3, C1-C6 alkyl, halogen, CN and NO2.

    The term "heteroaryl" refers to an aryl, as defined above, which contains at least one atom other than carbon, such as S, N, or O, forming part of the aromatic ring. The heteroaryl groups may be optionally substituted in any of their positions by one or more substituents or by two substituents forming a heteroaryl fused cycle and are independently selected from among such as CF3, C1-C6 alkyl, S-C1-C6 alkyl, halogen , CN, O-C1-C6 alkyl, NO2, COO-C1-C6 alkyl, NHCO-C1-C6 alkyl, NH2 and NH-C1-C6 alkyl, and more preferably between CF3, C1-C6 alkyl, halogen, CN and NO2. fifteen

    The term "alkyl" refers, in the present invention, to saturated, linear or branched hydrocarbon chains having 1 to 10 carbon atoms, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl , tert-butyl, sec-butyl, n-pentyl, n-hexyl, etc. Preferably the alkyl group has between 1 and 6 carbon atoms and more than 20 the alkyl group has between 1 and 3 carbon atoms. The alkyl groups may be optionally substituted by one or more substituents such as CF3, C1-C6 alkyl, S-C1-C6 alkyl, halogen, CN, O-C1-C6 alkyl, NO2, COO-C1-C6 alkyl, NHCO- C1-C6 alkyl, NH2 and NH-C1-C6 alkyl, and more preferably between CF3, halogen, CN and NO2. 25

    By "halogen" is meant in the present invention a bromine, chlorine, iodine or fluorine atom, preferably bromine, chlorine or iodine.

    In a preferred embodiment of the compounds of formula (II), R1 to R5 are independently selected from H, CF3, halogen, C1-C6 alkyl, CN, NO2 or two of the radicals R1 to R5 form a phenyl fused cycle .

    More preferably R5 is H and even more preferably at least one of R1, R2, R3 or R4 is Cl, Br, I, methyl, CF3, CN or NO2, more preferably at least one of R1, R2, R3 or R4 is Cl, Br, I, CF3, CN or NO2.

    More preferably R5 is H and even more preferably two of the radicals R1 to R4 form a condensed cycle to the phenyl, more preferably R1 and R2 form a condensed cycle to the phenyl, even more preferably forming a naphthyl.
     5
    In another preferred embodiment, R1, R2, R3, R4 and R5 are H.

    In a more preferred embodiment the compound of formula (I) or (II) is selected from:
    - 6- (benzylthio) -9H-purine (1) 10
    - 6 - ((Naphthalen-1-ylmethyl) thio) -9H-purine (2)
    - 6 - ((3- (cyanobenzyl) uncle) -9H-purine (3)
    - 6 - ((2- (trifluoromethyl) benzyl) thio) -9H-purine (4)
    - 6 - ((4-chlorobenzyl) thio) -9H-purine (5)
    - 6 - ((3-chlorobenzyl) oxy) -9H-purine (6) 15
    - 6 - ((3- (trifluoromethyl) benzyl) thio) -9H-purine (7)
    - 6 - ((3-chlorobenzyl) thio) -9H-purine (8)
    - 6 - ((3-iodobenzyl) thio) -9H-purine (9)
    - 6 - ((3-nitrobenzyl) thio) -9H-purine (10)
    - 6 - ((3-bromobenzyl) thio) -9H-purine (11) 20
    - 6 - ((4-bromobenzyl) thio) -9H-purine (12) and
    - 6 - ((2-bromobenzyl) thio) -9H-purine (13).

    Preferably the disease related to the TDP-43 protein is a neurological or neurodegenerative disease and 25 can be selected primarily from amyotrophic lateral sclerosis, frontotemporal dementia and Alzheimer's disease, it can also be selected between chronic traumatic encephalopathy and cognitive impairment associated with age. Preferably the disease is selected from amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's disease and age-related cognitive impairment, 30 even more preferably the disease is amyotrophic lateral sclerosis.

    Another aspect of the invention relates to a compound, henceforth composed of the second aspect of the invention, which is selected from:
    - 6 - ((Naphthalen-1-ylmethyl) thio) -9H-purine (2) 35
    - 6 - ((3- (cyanobenzyl) uncle) -9H-purine (3)
    - 6 - ((4-chlorobenzyl) thio) -9H-purine (5)
    - 6 - ((3-chlorobenzyl) oxy) -9H-purine (6)
    - 6 - ((3- (trifluoromethyl) benzyl) thio) -9H-purine (7)
    - 6 - ((3-chlorobenzyl) thio) -9H-purine (8)
    - 6 - ((3-iodobenzyl) thio) -9H-purine (9) 5
    - 6 - ((3-nitrobenzyl) thio) -9H-purine (10) and
    - 6 - ((2-bromobenzyl) thio) -9H-purine (13).

    Another aspect of the present invention relates to a pharmaceutical composition comprising at least one compound of the second aspect of the invention together with a pharmaceutically acceptable carrier and may optionally comprise another active ingredient.

    A further aspect of the present invention relates to the use of a compound of the second aspect of the invention for the manufacture of a medicament. fifteen

    The compounds of the present invention represented by the formula (I), (II) or by the compounds of the second aspect of the invention, may include isomers, depending on the presence of multiple bonds (eg, Z, E), including isomers optical or enantiomers, depending on the presence of chiral centers. The individual isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention, that is, the term isomer also refers to any mixture of isomers, such as diastereomers, racemic, etc., even their isomers. optically active or mixtures in different proportions thereof. The individual enantiomers or diastereoisomers, as well as their mixtures, can be separated by conventional techniques.

    All compounds described in the invention may be in crystalline form as free compounds or as solvates. In this sense, the term "solvate", as used herein, includes both pharmaceutically acceptable solvates, that is, solvates 30 of the compound of formula (I) that can be used in the manufacture of a medicament, as pharmaceutically acceptable solvates , which may be useful in the preparation of pharmaceutically acceptable solvates or 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 known to those skilled in the art.

    For their application in therapy, the compounds of formula (I), (II) or the compounds of the second aspect of the present invention, their salts, solvates or isomers, will preferably be found in a pharmaceutically acceptable or substantially pure form, that is, it has a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and not including material considered toxic at normal dosage levels. The purity levels for the active ingredient are preferably greater than 50%, more preferably greater than 70%, and still more preferably greater than 90%. In a preferred embodiment, they are greater than 95% of the compound of formula (I), (II) or the compounds of the second aspect of the present invention, or of their salts, solvates or isomers.
     fifteen
    In another aspect, the present invention relates to pharmaceutical compositions comprising at least one compound of the invention, or an isomer, a pharmaceutically acceptable salt or a derivative thereof, together with a pharmaceutically acceptable carrier or carrier, an excipient. or a vehicle, for administration to a patient. twenty

    In a preferred embodiment, the pharmaceutical composition further comprises another active ingredient.

    The pharmaceutically acceptable adjuvants and vehicles that can be used in said compositions are the adjuvants and vehicles known to those skilled in the art and commonly used in the elaboration of therapeutic compositions.

    Another aspect of the invention is a method of treating a neurodegenerative disease, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), preferably of formula (II), or of a pharmaceutical composition which This includes, where neurological or neurodegenerative disease is a disease related to the TDP-43 protein that can be selected primarily from amyotrophic lateral sclerosis, 35
    Frontotemporal dementia, Alzheimer's disease, age-related cognitive impairment and chronic traumatic encephalopathy.

    In the sense used in this description, the term "therapeutically effective amount" refers to the amount of the agent or compound capable of developing the therapeutic action determined by its pharmacological properties, calculated to produce the desired effect and, in general, will be determined , among other causes, due to the characteristics of the compounds, including the age, condition of the patient, the severity of the alteration or disorder, and the route and frequency of administration. 10

    The compounds described in the present invention, their salts or solvates, as well as the pharmaceutical compositions containing them can be used together with other drugs, or active ingredients, additional 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), preferably a compound of formula (II), or a salt or solvate thereof.
     twenty
    In another particular embodiment, said therapeutic composition is prepared in the form of a solid form or aqueous suspension, in a pharmaceutically acceptable diluent. The therapeutic composition provided by this invention may be administered by any appropriate route of administration, for which said composition will be formulated in the pharmaceutical form appropriate to the route of administration chosen. In a particular embodiment, administration of the therapeutic composition provided by this invention is performed orally, topically, rectally or parenterally (including subcutaneously, intraperitoneally, intradermally, intramuscularly, intravenously, etc.).
     30
    In a preferred embodiment of the present invention, the pharmaceutical compositions are suitable for oral administration, in solid or liquid form. Possible forms for oral administration are tablets, capsules, syrups or solutions and may contain conventional excipients known in the pharmaceutical field, such as additives (eg syrup, acacia, gelatin, sorbitol, tragacanth or polyvinyl pyrrolidone), fillers (eg lactose , sugar, corn starch,
    calcium phosphate, sorbitol or glycine), disintegrants (e.g. starch, polyvinyl pyrrolidone or microcrystalline cellulose) or a pharmaceutically acceptable surfactant such as sodium lauryl sulfate.

    Compositions for oral administration can be prepared by conventional methods of Galenic Pharmacy, as a mixture and dispersion. The tablets can be coated following methods known in the pharmaceutical industry.

    The pharmaceutical compositions can be adapted for parenteral administration, such as sterile solutions, suspensions, or lyophilized products of the invention, using the appropriate dose. Suitable excipients, such as pH buffering agents or surfactants, can be used.

    The aforementioned formulations can be prepared using conventional methods, such as those described in the Pharmacopoeias of different countries 15 and in other reference texts.

    The administration of the compounds or compositions of the present invention can be performed by any suitable method, such as intravenous infusion and oral, intraperitoneal or intravenous routes. Oral administration is preferred for the convenience of patients and for the chronic nature of the diseases to be treated.

    The amount administered of a compound of the present invention will depend on the relative efficacy of the compound chosen, the severity of the disease to be treated and the weight of the patient. However, the compounds of this invention will be administered one or more times a day, for example 1, 2, 3 or 4 times daily, with a total dose between 0.1 and 1000 mg / kg / day. It is important to keep in mind that it may be necessary to introduce variations in the dose, depending on the age and condition of the patient, as well as modifications in the route of administration.
     30
    The compounds and compositions of the present invention can be used together with other medicaments in combination therapies. The other drugs may be part of the same composition or of a different composition, for administration at the same time or at different times.
     35
    The use of the compounds of the invention is compatible with their use in protocols in which the compounds of the formula (I), or mixtures thereof are used by themselves or in combinations with other treatments or any medical procedure.

    Throughout the description and the claims the word "comprises" and its 5 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. 10
    BRIEF DESCRIPTION OF THE FIGURES

    FIG. 1. Shows the linear correlation between the described and experimental permeability of 10 commercial compounds using the PAMPA methodology. fifteen

    FIG. 2. It shows the neuroprotective effect of CDC7 inhibitors (compounds 1 and 8) on SH-SY5Y human neuroblastoma cells previously treated with ethacrynic acid (20 μM) for 12 hours in the presence or absence of inhibitors at 10 μM. Data represent the average of 4 different experiments ± SEM (* p <0.05) 20

    FIG. 3. Sample of the effect of CDC7 inhibitors (compounds 1 and 8) on phosphorylation of TDP-43. Quantification and representation of phosphorylated TDP-43 levels by western blot.
     25 EXAMPLES

    The invention will now be illustrated by tests carried out by the inventors, which show the effectiveness of the product of the invention.
     30
    Example 1: synthesis of the new compounds of the invention.

    Compound 1: 6- (benzylthio) -9H-purine
    This compound is described in Pathak A.K. et al, Journal of Medical Chemistry, 2004, 47 (1): 273-276. 35
    Compound 2: 6 - ((Naphthalen-1-ylmethyl) thio) -9H-purine
    6-Mercaptopurine monohydrate (300.0 mg, 1.76 mmol) and K2CO3 (243.7 mg, 1.76 mmol) are dissolved in DMF (25 mL). The reaction mixture is kept under stirring for 1 h at room temperature. 1- (Chloromethyl) naphthalene (311.4 mg, 5.76 mmol) is added and kept under stirring overnight at room temperature. The solvent is evaporated under reduced pressure and AcOEt (100 mL) is added. The organic phase is washed with distilled water (3 x 100 mL) by adding a little NaCl. Dry over anhydrous Mg2SO4, filter and concentrate to dryness. The crude is purified by chromatographic column using CH2Cl2 / MeOH (10: 1) as eluent. In this way, product 2 is obtained as a white solid (218.0 mg, 42%). 1H-NMR (500 MHz, DMSO-d6): δ 13.55 (s, 1H), 8.81 (s, 1H), 8.42 (s, 1H), 8.19 (dd, J = 8, 3, 1.4 Hz, 1H), 7.96 (dd, J = 7.9, 1.5 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.72 ( dd, J = 7.1, 1.3 Hz, 1H), 7.63-7.52 (m, 2H), 7.45 (dd, J = 8.2, 7.0 Hz, 1H), 5.16 (s, 2H). 13C-NMR (125 MHz, DMSO-d6): δ 158.2 (1C), 151.2 (1C), 149.4 (1C), 143.0 (1C), 15 133.5 (1C), 133 , 0 (1C), 131.1 (1C), 130.1 (1C), 128.7 (1C), 128.2 (1C), 127.7 (1C), 126.4 (1C), 126, 0 (1C), 125.5 (1C), 123.7 (1C), 29.5 (1C). HPLC: Purity> 99%, t.r. = 4.33 min. MS (ES): m / z 293 [M + 1]. P.f. 221 - 222 ° C. Elemental analysis (C16H12N4S) Calculated: C 65.73%, H 4.14%, N 19.16%, S 10.97%. Found: C 65.41%, H 4.07%, N 19.11%, S 10.99%. twenty

    Compound 3: 6 - ((3- (cyanobenzyl) uncle) -9H-purine
    6-Mercaptopurine monohydrate (300.0 mg, 1.76 mmol) and K2CO3 (243.7 mg, 1.76 mmol) are dissolved in DMF (25 mL). The reaction mixture is kept under stirring for 1 h at room temperature. 3- (Bromomethyl) benzonitrile (345.6 25 mg, 1.76 mmol) is added and kept under stirring overnight at room temperature. The solvent is evaporated under reduced pressure and AcOEt (100 mL) is added. The organic phase is washed with distilled water (3 x 100 mL) by adding a little NaCl. Dry over anhydrous Mg2SO4, filter and concentrate to dryness. It is not necessary to purify by chromatographic column. In this way, product 3 is obtained in the form of a white solid (438.7 mg, 93%). 1H-NMR (300 MHz, DMSO-d6): δ 13.57 (s, 1H), 8.74 (s, 1H), 8.46 (s, 1H), 7.93 (t, J = 1, 7 Hz, 1H), 7.85 - 7.79 (m, 1H), 7.71 (dt, J = 7.8, 1.4 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 4.70 (s, 2H). 13C-NMR (75 MHz, DMSO-d6): δ 156.9 (1C), 151.4 (1C), 150.2 (1C), 143.5 (1C), 140.1 (1C), 134, 0 (1C), 132.4 (1C), 130.9 (1C), 129.7 (2C), 118.6 (1C), 111.3 (1C), 30.7 (1C). MS (ES): m / z 268 [M + 1]. 35
    P.f. 189-191 ° C. Elemental analysis (C13H9N5S) Calculated: C 58.41%, H 3.39%, N 26.20%, S 12.00%. Found: C 58.46%, H 3.47%, N 26.03%, S 11.84%.

    Compound 4: 6 - ((2- (trifluoromethyl) benzyl) thio) -9H-purine
    This compound is described in Kamper C. et al., Mol Diversity, 2012, 16 (3): 541-551. 5

    Compound 5: 6 - ((4-chlorobenzyl) thio) -9H-purine
    6-Mercaptopurine monohydrate (300.0 mg, 1.76 mmol) and K2CO3 (243.7 mg, 1.76 mmol) are dissolved in DMF (25 mL). The reaction mixture is kept under stirring for 1 h at room temperature. 4-Chlorobenzene bromide (362.3 10 mg, 1.76 mmol) is added and kept under stirring overnight at room temperature. The solvent is evaporated under reduced pressure and AcOEt (100 mL) is added. The organic phase is washed with distilled water (3 x 100 mL) by adding a little NaCl. Dry over anhydrous Mg2SO4, filter and concentrate to dryness. The crude is purified by chromatographic column using CH2Cl2 / MeOH (10: 1) as eluent. In this way, product 5 is obtained as a white solid (387.2 mg, 79%). 1H-NMR (300 MHz, DMSO-d6): δ 13.55 (s, 1H), 8.73 (s, 1H), 8.45 (s, 1H), 7.55 - 7.43 (m, 2H), 7.42-7.29 (m, 2H), 4.65 (s, 2H). 13C-NMR (75 MHz, DMSO-d6): δ 157.8 (1C), 151.4 (1C), 149.4 (1C), 143.2 (1C), 137.2 (1C), 131, 7 (1C), 130.8 (2C), 130.0 (1C), 128.4 (2C), 30.8 (1C). MS (ES): m / z 279 [M + 3], 277 [M + 1]. P.f. 198 - 200 20 ° C. Elemental analysis (C12H9ClN4S) Calculated: C 52.08%, H 3.28%, N 20.24%, S 11.59%. Found: C 52.19%, H 3.28%, N 20.27%, S 11.59%.

    Compound 6: 6 - ((3-chlorobenzyl) oxy) -9H-purine
    3-Chlorobenzyl alcohol (2766.2 mg, 19.40 mmol) is dissolved in NaOH (155.2 mg, 3.88 mmol) and heated until NaOH dissolves. The solution is cooled, 6-chloro-9H-purine (300.0 mg, 1.94 mmol) is added and heated at reflux (100 ° C) for 1 day. Et2O (120 mL) is added and extracted twice with a 1% aqueous NaOH solution (70 mL). The aqueous phases are combined, washed with toluene and, after removing toluene, neutralized with 37% HCl until pH 6-8. The solution is cooled in an ice bath and the precipitate obtained is collected by filtration. The crude is purified by chromatographic column using CH2Cl2 / MeOH (10: 1) as eluent. In this way, product 6 is obtained as a white solid (153.7 mg, 30%). 1H-NMR (300 MHz, DMSO-d6): δ 13.48 (s, 1H), 8.52 (s, 1H), 8.41 (s, 1H), 7.60 (s, 1H), 7 , 53-7.45 (m, 1H), 7.45-7.38 (m, 2H), 5.62 (s, 2H). 13C-NMR (75 MHz, DMSO-d6): 35 δ 158.4 (1C), 155.4 (1C), 151.2 (1C), 143.0 (1C), 139.0 (1C), 133 , 1 (1C), 130.4 (1C),
    128.0 (1C), 127.9 (1C), 126.7 (1C), 118.0 (1C), 66.7 (1C). P.f. 197-199 ° C. Elemental analysis (C12H9ClN4O) Calculated: C 55.29%, H 3.48%, N 21.49%. Found: C 55.12%, H 3.51%, N 21.34%.

    Compound 7: 6 - ((3- (trifluoromethyl) benzyl) thio) -9H-purine
    6-Mercaptopurine monohydrate (300.0 mg, 1.76 mmol) and K2CO3 (243.7 mg, 1.76 mmol) are dissolved in DMF (25 mL). The reaction mixture is kept under stirring for 1 h at room temperature. 3- (Trifluoromethyl) benzyl bromide (421.4 mg, 1.76 mmol) is added and kept under stirring overnight at room temperature. The solvent is evaporated under reduced pressure and AcOEt (100 mL) is added. The organic phase is washed with distilled water (3 x 100 mL) by adding a little NaCl. Dry over anhydrous Mg2SO4, filter and concentrate to dryness. The crude is purified by chromatographic column using CH2Cl2 / MeOH (10: 1) as eluent. In this way, product 7 is obtained as a white solid (283.3 mg, 52%). 1H-NMR (300 MHz, DMSO-d6): δ 13.57 (s, 1H), 8.74 (s, 1H), 8.46 (s, 1H), 7.86 15 (s, 1H), 7.79 (d, J = 7.3 Hz, 1H), 7.65-7.49 (m, 2H), 4.74 (s, 2H). 13C-NMR (75 MHz, DMSO-d6): δ 157.2 (1C), 151.4 (1C), 150.2 (1C), 143.5 (1C), 139.8 (1C), 133, 1 (1C), 129.5 (2C), 129.1 (c, J = 31.4 Hz, 1C), 125.5 (c, J = 3.9 Hz, 1C), 124.1 (m, 1C), 123.8 (c, J = 3.9 Hz, 1C), 30.9 (1C). MS (ES): m / z 311 [M + 1]. P.f. 180-182 ° C. Elemental analysis (C13H9F3N4S) Calculated: C 50.32%, H 2.92%, N 18.06%, S 10.33%. 20 Found: C 50.49%, H 3.03%, N 18.03%, S 10.32%.

    Compound 8: 6 - ((3-Chlorobenzyl) thio) -9H-purine
    6-Mercaptopurine monohydrate (300.0 mg, 1.76 mmol) and K2CO3 (243.7 mg, 1.76 mmol) are dissolved in DMF (25 mL). The reaction mixture is kept under stirring 25 for 1 h at room temperature. 3-Chlorobenzyl bromide (362.3 mg, 1.76 mmol) is added and kept under stirring overnight at room temperature. The solvent is evaporated under reduced pressure and AcOEt (100 mL) is added. The organic phase is washed with distilled water (3 x 100 mL) by adding a little NaCl. Dry over anhydrous Mg2SO4, filter and concentrate to dryness. The crude is purified by chromatographic column using CH2Cl2 / MeOH (10: 1) as eluent. In this way, product 8 is obtained as a white solid (233.1 mg, 48%). 1H-NMR (300 MHz, DMSO-d6): δ 13.56 (s, 1H), 8.74 (s, 1H), 8.46 (s, 1H), 7.54 (t, J = 2, 0 Hz, 1H), 7.47-7.40 (m, 1H), 7.39-7.27 (m, 2H), 4.66 (s, 2H). 13C-NMR (75 MHz, DMSO-d6): δ 157.3 (1C), 151.4 (1C), 149.5 (1C), 143.4 (1C), 140.8 (1C), 132, 9 35 (1C), 130.3 (2C), 128.8 (1C), 127.7 (1C), 127.1 (1C), 30.9 (1C). MS (ES): m / z 279
    [M + 3], 277 [M + 1]. P.f. 167-169 ° C. Elemental analysis (C12H9ClN4S) Calculated: C 52.08%, H 3.28%, N 20.24%, S 11.59%. Found: C 51.98%, H 3.28%, N 20.21%, S 11.58%.

    Compound 9: 6 - ((3-Iodobenzyl) uncle) -9H-purine 5
    6-Mercaptopurine monohydrate (300.0 mg, 1.76 mmol) and K2CO3 (243.7 mg, 1.76 mmol) are dissolved in DMF (25 mL). The reaction mixture is kept under stirring for 1 h at room temperature. 3-iodobenzyl bromide (523.5 mg, 1.76 mmol) is added and kept under stirring for 4 h at room temperature. The solvent is evaporated under reduced pressure and AcOEt (100 mL) is added. The organic phase 10 is washed with distilled water (3 x 100 mL) by adding a little NaCl. Dry over anhydrous Mg2SO4, filter and concentrate to dryness. It is not necessary to purify by chromatographic column. In this way, product 9 is obtained as a pale yellow solid (379.6 mg, 58%). 1H-NMR (300 MHz, DMSO-d6): δ 13.56 (s, 1H), 8.74 (s, 1H), 8.46 (s, 1H), 7.85 (t, J = 1, 8 Hz, 1H), 7.60 (dt, J = 7.6, 1.4 15 Hz, 1H), 7.48 (dt, J = 7.6, 1.4 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 4.61 (s, 2H). 13C-NMR (75 MHz, DMSO-d6): δ 157.3 (1C), 151.4 (1C), 149.8 (1C), 143.4 (1C), 140.8 (1C), 137, 4 (1C), 135.8 (1C), 130.6 (1C), 129.8 (1C), 128.4 (1C), 94.7 (1C), 30.7 (1C). P.f. 185-187 ° C. Elemental analysis (C12H9IN4S) Calculated: C 39.14%, H 2.46%, N 15.22%, S 8.71%. Found: C 39.26%, H 2.53%, N 15.05%, S 8.58%. twenty

    Compound 10: 6 - ((3-nitrobenzyl) thio) -9H-purine
    6-Mercaptopurine monohydrate (300.0 mg, 1.76 mmol) and K2CO3 (243.7 mg, 1.76 mmol) are dissolved in DMF (25 mL). The reaction mixture is kept under stirring for 1 h at room temperature. 3-Nitrobenzyl bromide (380.9 mg, 25 1.76 mmol) is added and kept stirring for 3 hours at room temperature. The solvent is evaporated under reduced pressure and AcOEt (100 mL) is added. The organic phase is washed with distilled water (3 x 100 mL) by adding a little NaCl. Dry over anhydrous Mg2SO4, filter and concentrate to dryness. It is not necessary to purify by chromatographic column. In this way, the product 10 is obtained in the form of a pale yellow solid (460.6 mg, 91%). 1H-NMR (300 MHz, DMSO-d6): δ 13.58 (s, 1H), 8.74 (s, 1H), 8.47 (s, 1H), 8.36 (t, J = 2.0 Hz , 1H), 8.09 (ddd, J = 8.4, 2.3, 1.1 Hz, 1H), 7.94 (dt, J = 7.8, 1.2 Hz, 1H), 7, 60 (t, J = 8.0 Hz, 1H), 4.79 (s, 2H). 13C-NMR (75 MHz, DMSO-d6): δ 156.8 (1C), 151.4 (1C), 150.2 (1C), 147.7 (1C), 143.6 (1C), 140, 9 (1C), 135.7 (1C), 129.9 (2C), 123.6 (1C), 122.0 (1C), 30.6 (1C). P.f. 193-195 ° C. Analysis 35
    elemental (C12H9N5O2S) Calculated: C 50.17%, H 3.16%, N 24.38%, S 11.16%. Found: C 50.05%, H 2.76%, N 24.15%, S 11.05%.

    Compound 11: 6 - ((3-bromobenzyl) thio) -9H-purine
    This compound is described in Kamper C. et al., Mol Diversity, 2012, 16 (3): 541-551. 5

    Compound 12: 6 - ((4-bromobenzyl) thio) -9H-purine
    This compound is described in Kamper C. et al., Mol Diversity, 2012, 16 (3): 541-551.

    Compound 13: 6 - ((2-bromobenzyl) thio) -9H-purine
    6-Mercaptopurine monohydrate (300.0 mg, 1.76 mmol) and K2CO3 (243.7 mg, 1.76 mmol) are dissolved in DMF (25 mL). The reaction mixture is kept under stirring for 1 h at room temperature. 2-Bromobenzyl bromide (440.6 mg, 1.76 mmol) is added and kept under stirring for 4 h at room temperature. The solvent is evaporated under reduced pressure and AcOEt (100 mL) is added. The organic phase is washed with distilled water (3 x 100 mL) by adding a little NaCl. Dry over anhydrous Mg2SO4, filter and concentrate to dryness. It is not necessary to purify by chromatographic column. In this way, product 13 is obtained as a white solid (438.7 mg, 93%). 1H-NMR (300 MHz, DMSO-d6): δ 13.58 (s, 1H), 8.76 (s, 1H), 8.45 (s, 1H), 7.66 (dt, J = 7, 9, 1.8 Hz, 2H), 7.33 (td, J = 7.5, 1.4 20 Hz, 1H), 7.22 (td, J = 7.6, 1.8 Hz, 1H) , 4.74 (s, 2H). 13C-NMR (75 MHz, DMSO-d6): δ 157.7 (1C), 151.5 (1C), 149.4 (1C), 143.2 (1C), 136.8 (1C), 132, 8 (1C), 131.5 (1C), 130.1 (1C), 129.6 (1C), 128.0 (1C), 124.2 (1C), 32.4 (1C).
    P.f. 209 - 211 ° C. Elemental analysis (C12H9BrN4S) Calculated: C 44.87%, H 2.82%, N 17.44%, S 9.98%. Found: C 44.96%, H 2.83%, N 17.43%, S 9.97%. 25

    Example 2: Measurement of CDC7 inhibition

    The method used is a non-radioactive enzyme inhibition assay using recombinant human CDC7. This is based on the luminometric quantification of the inhibition using the ADP-GloTM Kinase Kit. In this test, the luminescent signal correlates positively with the amount of adenosine diphosphate (ADP) and the kinase activity. All compounds were evaluated at a fixed concentration of 10 µM. For those compounds with a percentage of inhibition greater than 50%, a dose-response study is carried out determining 35
    its IC50 value (concentration of compound capable of 50% inhibition of CDC7 function).

    Enzymatic inhibition studies of CDC7 were carried out using the promega kit: ADP-GloTM Kinase Assay + CDC7 / DBF4 Kinase Enzyme System (No. 5 catalog V5089). ATP and other reagents were purchased from Sigma-Aldrich (St. Louis, MO). The tests were performed in a buffer solution using 96-well plates. The compound to be tested (5 µL, 40 µM dissolved in 4% DMSO) was added to each well followed by the enzyme (5 µL, 25 ng / well), ATP (5 µL, final concentration in the 10 µM well) and PDKtidE (5 µL, 4 µg / well). Then, 10 was allowed to incubate for 60 min at room temperature and ADP-GloTM reagent (20 µL) was added and allowed to incubate again for 40 min at room temperature. After incubation, the kinase detection agent (40 µL) was added and allowed to incubate for 30 min at room temperature. Finally, the luminescence (integration time of 0.5-1 sec) was measured using a POLARstar Optima multimode 15 reader polarimeter. Inhibition activities were calculated based on maximum activity, measured in the absence of inhibitor. The inhibition values determined for the prepared compounds are shown in table 1.

    Table 1. Inhibition values in CDC7 of the compounds of formula (II):

    (II)

     Comp.  R1 to R5 Z CDC7 IC50 (µM)
     one  H S 6.74 ± 0.35
     2  2.3 - [(CH) 4] S 11.22 ± 0.84
     3  3-CN S 8.38 ± 0.27
     4  2-CF3 S 9.73 ± 1.03
     5  4-Cl S 8.46 ± 1.05
     6  3-Cl O 8.98 ± 0.21
     7  3-CF3 S 6.90 ± 0.83
     8  3-Cl S 5.21 ± 0.38
     9  3-I S 3.34 ± 0.27
     10  3-NO2 S 6.54 ± 0.32
     eleven  3-Br S 5.29 ± 0.71
     12  4-Br S 9.14 ± 0.79
     13  2-Br S 6.24 ± 0.99




     5




     10




     fifteen




     twenty


    Example 3: Blood brain barrier passage prediction

    An essential requirement that drugs destined to the treatment of neurodegenerative diseases 25 must meet is the ability to cross the blood brain barrier (BHE) since, otherwise, they could not act on the target of interest. Therefore, for compounds that are not permeable or located in the area of uncertainty, it may be necessary that their pharmaceutical formulation be suitably vehiculized by methods known to a person skilled in the art 30, such as encapsulation. This capacity can be predicted in vitro using a method known by the acronym PAMPA (Parallel Artificial Membrane Permeability Assay) described by Di et al. (Di, L .; Kerns, EH; Fan, K .; McConnell, OJ; Carter, GT Eur. J. Med. Chem., 2003, 38 (3), 223-232) and which has subsequently been developed in our research group. Said 35
    The method allows predicting effective permeability through artificial membranes through a passive diffusion process.

    First, it is necessary to validate the method, for which 10 commercial compounds are used whose penetration capacity in the central nervous system (CNS) is known to be specified below, obtaining in this case a good linear correlation between the values of experimental permeability (Pe) and those described (FIG. 1). This correlation line obtained following the pattern described in the literature allows us to establish the limits to predict whether or not a compound can cross the blood brain barrier. Thus, a compound is considered to be permeable to BHE (SNC +) if it has a permeability> 4.48 x 10-6 cm · s-1.

    For the procedure, 3-5 mg of caffeine, desipramine, enoxacin, hydrocortisone, ofloxacin, piroxicam and testosterone, 12 mg of promazine and 25 mg of atenolol and verapamil were taken and dissolved in EtOH (1000 µL). 100 µL of these solutions were taken and EtOH (1400 µL) and phosphate buffer (PBS) pH = 7.4 (3500 µL) were added in order to reach a final EtOH concentration of 30% v / v in solution. Finally, the solutions were filtered.

    On the other hand, a solution of PBS / EtOH (70:30) was added to each well of the acceptor plate (180 µL). The donor plate was impregnated with a solution of porcine brain lipid (4 µL) dissolved in dodecane (20 mg · mL-1). After 5 min, each compound solution was added on this plate (180 µL).
     25
    Of the compounds 1 to 10 evaluated, they were taken between 1-2 mg and dissolved in EtOH (1500 µL) and phosphate buffer (PBS) pH = 7.4 (3500 µL), filtered and added to the donor plate. With these solutions, the wavelengths at which the compounds absorb are determined and the initial absorbance levels at these wavelengths are measured using a UV absorbance reader. Each sample 30 was analyzed from two to five wavelengths, in three wells and in two independent experiments.

    Then, the donor plate was deposited on the acceptor forming a kind of "sandwich" and allowed to incubate for 2 h and 30 min at 25 ° C. In this way, the compounds will pass from the donor plate to the acceptor plate through
    of porcine brain lipid by passive diffusion. After that time, the donor plate is carefully removed and the final concentration and absorbance of both commercial and synthesized compounds are determined. The results obtained are expressed as the average of the measurements [standard deviation (SD)] of the different experiments performed and are shown in table 2. 5
    .

    Table 2. Permeability values (Pe 10-6 cm s-1) in the PAMPA-BHE experiment and prediction of central nervous system (CNS) penetration of the compounds of formula (II) as also described in the table. 1: 10


     Comp.  R1 to R5 Z Pe (10-6 cm S-1) PAMPA prediction
     one  H S 6.2  1.1 SNC +
     2  2.3 - [(CH) 4] S 13.2  2.0 SNC +
     3  3-CN S 2.3  0.2 SNC +/-
     4  2-CF3 S 17.5  0.9 SNC +
     5  4-Cl S 12.2  1.2 SNC +
     6  3-Cl O 7.2  0.6 SNC +
     7  3-CF3 S 16.3  0.6 SNC +
     8  3-Cl S 15.1  0.6 SNC +
     9  3-I S 13.8  2.5 SNC +
     10  3-NO2 S 3.9  0.4 SNC +/-


     fifteen




     twenty




     25




    Example 4: Neuroprotective effect of CDC 7 inhibitors against ethacrynic acid
    The human neuroblastoma cell line SH-SY5Y was grown at 37 ° C with 5% CO2 in DMEN medium (Dulbecco's Modified Eagle Medium) enriched with L-glutamine (2mM), 1% non-essential amino acids, 1% Penicillin / Streptomycin and 10% fetal bovine serum. In the semi-confluence state, the cells were treated with CDC7 inhibitors (compounds 1 and 8) at different concentrations.
    for 1.30 hours post-addition of the causative agent of phosphorylation of TPD-43; Ethacrynic acid (20 µM) (Sigma). At 24 hours the cell viability was evaluated with MTT ([3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium Bromide) following a procedure described (Denizot F, Lang R. J Immunol Methods. 1987 ; 89: 271-7) and phosphorylated TDP-43 levels by western blot (FIG. 2). 5

    Example 5: Effect of CDC 7 inhibitors on phosphorylation of TDP-43
    To evaluate phosphorylated TDP-43 levels in the presence of CDC7 inhibitors (compounds 1 and 8), the cells after 24 h of incubation with ethacrynic acid, were washed with PBS and subsequently cold lysed with lysis buffer (50mM 10 Tris pH 7.4, 150 mM NaCl, 50 mM NaF, 1% Nonidet P-40 and Protease and phosphatase inhibitors (Roche). The collected cell extracts were centrifuged for 10 minutes at 4,000 rpm. Protein quantification was performed with the Pierce BCA protein assay kit (Thermo Scientific). 10 µg of protein was loaded on the polyacrylamide gel with SDS and subsequently transferred to a polyvinylidene fluoride (PVDF) membrane (Millipore). The membrane was blocked with 5% bovine serum albumin (Sigma), and incubated for 12 hours with the following concentrations of primary antibodies (anti-phospho (S409 / 410) -TDP-43 human (1: 500) (22309- 1AP, Proteintech); α-tubulin (1: 1,000) (sc-23948, Santa Cruz Biotechnologies). Signal amplification was carried out with secondary antibodies conjugated to horseradish peroxidase, corresponding to the species used in the antibody Primary (Bio-Rad) Band density was quantified with the Image J program (National Institutes of Health, Bethesda, Maryland, USA) Figure 3 shows that the treatment of cells with CDC7 inhibitors (compounds of the invention 1 and 8) allowed to reduce the phosphorylation of TDP-43.

    权利要求:
    Claims (17)
    [1]

    1. Use of a compound of formula (I)
     5
    where:
    G represents a group selected from aryl, heteroaryl or C1-C10 alkyl, any of them optionally substituted by at least one substituent selected from CF3, C1-C6 alkyl, S-C1-C6 alkyl, halogen, CN, O -C1-C6 alkyl, NO2, COO-C1-C6 alkyl, NHCO-C1-C6 alkyl, NH2 and NH-C1-C6 alkyl, or optionally substituted by two substituents forming a fused cycle to the group G when it is an aryl or heteroaryl, and
    Z is selected from O or S;
    or any of its pharmaceutically acceptable salts, solvates or isomers for the manufacture of a medicament for the treatment and / or prevention of 15 pathologies related to the TDP-43 protein.

    [2]
    2. Use according to claim 1, wherein G is an aryl group, optionally substituted by at least one substituent selected from CF3, C1-C6 alkyl, S-C1-C6 alkyl, halogen, CN, O-C1-C6 alkyl, NO2, COO-C1-C6 alkyl, NHCO-C1-20 C6 alkyl, NH2 and NH-C1-C6 alkyl, or optionally substituted by two substituents forming an aryl fused cycle.

    [3]
    3. Use according to any one of claims 1 or 2, wherein G is a phenyl group and the compound is of formula (II):
    (II)
    where R1 to R5 are independently selected from H, CF3, S-C1-C6 alkyl, halogen, C1-C6 alkyl, CN, O-C1-C6 alkyl, NO2, COO-C1-C6 alkyl, NHCO-C1-alkyl C6, NH2 and NH-C1-C6 alkyl, or two of the radicals R1 to R5 form a condensed cycle to the phenyl; Y
    Z is described in claim 1.

    [4]
    4. Use according to claim 3, wherein R1 to R5 are independently selected from H, CF3, halogen, C1-C6 alkyl, CN and NO2 or two of the radicals R1 to R5 form a phenyl fused cycle.

    [5]
    5. Use according to any of claims 3 or 4, wherein R5 is H.

    [6]
    6. Use according to claim 4, wherein at least one of R1, R2, R3 or R4 is Cl, Br or I 15 and R5 is H.

    [7]
    7. Use according to claim 4, wherein at least one of R1, R2, R3 or R4 is methyl, CF3, CN or NO2 and R5 is H.
     twenty
    [8]
    8. Use according to claim 4, wherein two of the radicals R1 to R4 form a condensed cycle to the phenyl and R5 is H.

    [9]
    9. Use according to claim 8, wherein R1 and R2 form a condensed cycle to phenyl.
     25
    [10]
    10. Use according to claim 4, wherein R1, R2, R3, R4 and R5 are H.

    [11]
    11. Use according to claim 1, wherein the compound is selected from:
    - 6- (benzylthio) -9H-purine
    - 6 - ((naphthalen-1-ylmethyl) thio) -9H-purine
    - 6 - ((3- (cyanobenzyl) uncle) -9H-purine
     - 6 - ((2- (trifluoromethyl) benzyl) thio) -9H-purine
    - 6 - ((4-chlorobenzyl) thio) -9H-purine 5
    - 6 - ((3-chlorobenzyl) oxy) -9H-purine
    - 6 - ((3- (trifluoromethyl) benzyl) thio) -9H-purine
    - 6 - ((3-chlorobenzyl) thio) -9H-purine
    - 6 - ((3-iodobenzyl) uncle) -9H-purine
    - 6 - ((3-nitrobenzyl) thio) -9H-purine 10
    - 6 - ((3-bromobenzyl) thio) -9H-purine
    - 6 - ((4-bromobenzyl) thio) -9H-purine and
    - 6 - ((2-bromobenzyl) thio) -9H-purine.

    [12]
    12. Use according to any of claims 1 to 11, wherein the disease related to the TDP-43 protein is a neurological disease.

    [13]
    13. Use according to any of claims 1 to 12, wherein the TDP-43 protein-related disease is a neurological disease that is selected from amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's disease, age-related cognitive impairment and chronic traumatic encephalopathy.

    [14]
    14. Use according to claim 13, wherein the disease is selected from amyotrophic lateral sclerosis, frontotemporal dementia and Alzheimer's disease.

    [15]
    15. Compound selected from:
    - 6 - ((Naphthalen-1-ylmethyl) thio) -9H-purine
    - 6 - ((3- (cyanobenzyl) uncle) -9H-purine 30
    - 6 - ((4-chlorobenzyl) thio) -9H-purine
    - 6 - ((3-chlorobenzyl) oxy) -9H-purine
    - 6 - ((3- (trifluoromethyl) benzyl) thio) -9H-purine
    - 6 - ((3-chlorobenzyl) thio) -9H-purine
    - 6 - ((3-iodobenzyl) uncle) -9H-purine 35
    - 6 - ((3-nitrobenzyl) thio) -9H-purine and
    - 6 - ((2-bromobenzyl) thio) -9H-purine.

    [16]
    16. Pharmaceutical composition comprising a compound as described in claim 15 together with a pharmaceutically acceptable carrier.
     5
    [17]
    17. Use of a compound as described in claim 15 for the manufacture of a medicament.

     10
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    同族专利:
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    ES2686909B1|2019-08-16|
    US20200093828A1|2020-03-26|
    WO2018172587A1|2018-09-27|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    ES2749743A1|2018-09-21|2020-03-23|Consejo Superior Investigacion|PURINE DERIVATIVES CDC7 INHIBITORS AND THEIR USE FOR THE TREATMENT OF NEUROLOGICAL PATHOLOGIES |US3232937A|1962-08-02|1966-02-01|Burroughs Wellcome Co|6-benzylmercaptopurines|
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    JP2004161716A|2002-11-15|2004-06-10|Takeda Chem Ind Ltd|Jnk inhibitor|
    EP1444982A1|2003-02-06|2004-08-11|Merckle Gmbh|The use of purine derivatives as selective kinase inhibitors|
    WO2007124288A1|2006-04-19|2007-11-01|Novartis Ag|Indazole compounds and methods for inhibition of cdc7|
    EP2365810A2|2008-12-04|2011-09-21|The U.S.A. As Represented By The Secretary, Department Of Health And Human Services|Phosphatidylinositol-3-kinase p110 delta-targeted drugs in the treatment of cns disorders|
    ES2483594T3|2009-07-15|2014-08-06|Abbott Laboratories|Kinase inhibitor pyrrolopyrazines|
    US20130072506A1|2011-09-16|2013-03-21|Lenka ZAHAJSKA|6,8-disubstituted purine compositions|
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