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    • 专利摘要:
    Modulators of a3 adenosine receptors of formula (I): {image-01} Procedure for preparing said compounds. Other objects of the present invention are pharmaceutical compositions comprising an effective amount of said compounds and the use of the compounds in the preparation of a medicament for treating pathological conditions or diseases that can be improved by modulation of a3 <receptors./sub> adenosine. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2578363A1
    申请号:ES201530085
    申请日:2015-01-22
    公开日:2016-07-26
    发明作者:Julio CASTRO- PALOMINO LÁRIA；Juan CAMACHO GÓMEZ
    申请人:Palobiofarma SL；
    IPC主号:
    专利说明:

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    kB, which is a key actor in the pathogenesis of arthritis patients (Bar-Yehuda, S .; Silverman, MH; Kerns, WD; Ochaion, A .; Cohen, S .; Fishman, P. The anti-inflammatory effect of A3 adenosine receptor agonists: a novel targeted therapy for rheumatoid arthritis. Expert Opin. Invest. Drugs 2007, 16, 1601-1613).
    In a phase II clinical study in patients with RA, oral administration of the A3AR agonist, IB-MECA (1-deoxy-1- [6 - [[(3-iodophenyl) methyl] amino] -9H-purin- 9-yl] -N-methyl-β-Dribofuranuron amide) twice a day for 12 days, proved to be a safe, well tolerated and able to mediate an improvement of the signs and symptoms of the disease, suggesting the use of modulators of adenosine A3 receptors as antirheumatic agents.
    ADENOSINE A3 RECEPTORS IN EYE DISEASES
    Modulation of adenosine A3 receptors has been reported as a possible therapeutic target for the treatment of various eye diseases, such as dry eye syndrome, glaucoma or uveitis (Y. Zhong, et al., Adenosine, adenosine receptors and glaucoma : An updated overview, Biochim. Biophys. Acta, 2013).
    Early studies showed that suppression of adenosine A3 receptors in mice showed a reduction in intraocular pressure, suggesting that A3AR antagonists could represent a new therapy for glaucoma (Yang, H .; Avila, MY; Peterson-Yantorno, K .; Coca-Prados, M .; Stone, RA; Jacobson, KA; Civan, MM The cross-species adenosine-receptor antagonist MRS 1292 inhibits adenosine-triggered human nonpigmented ciliary epithelial cell fluid release and reduces mouse intraocular pressure Curr. Eye Res. 2005, 30, 747-754).
    On the other hand, mRNA and adenosine A3 receptor protein have been found to be increased in the colorless ciliary epithelium of the eye in glaucoma lens pseudoexfoliation syndrome, compared to the normal eye (Schlotzer-Schrehardt, U .; Zenkel, M .; Decking, U .; Haubs, D .; Kruse, FE; Junemann, A .; Coca-Prados, M .; Naumann,
    G. O. Selective upregulation of the A3 adenosine receptor in eyes with pseudoexfoliation syndrome and glaucoma. Invest. Ophthalmol Visual Sci. 2005, 46, 2023-2034).
    A3AR overexpression has also been demonstrated in retinal ganglion cells (Zhang, M .; Hu, HL; Zhang, XL; Lu, WN; Lim, J .; Eysteinsson, T .; Jacobson, KA; Laties, AM ; Mitchell, CH The A3 adenosine receptor attenuates the calcium rise triggered by NMDA receptors in retinal ganglion cells. Neurochem. Int. 2010, 56, 35-41).
    The anti-inflammatory and protective effects mediated by the A3ARs have led us to analyze the effect of IB-MECA in an experimental autoimmune uveitis model that represents human uveitis with an autoimmune etiology. In this model, IB-MECA inhibits the clinical and pathological manifestations of uveitis (Bar-Yehuda, S .; Luger, D .; Ochaion, A .; Cohen, S .; Patokaa, R .; Zozulya, G .; Silver , PB; De Morales, JMGR; Caspi, RR; Fishman, P. Inhibition of experimental auto-immune uveitis by the A3 adenosine agonist receptor CF101. Int. J. Mol. Med. 2011, 28, 727-731).
    ADENOSINE A3 RECEPTORS IN ONCOLOGICAL DISEASES
    A3ARs are present in different types of tumor cells, such as human tumor lines HL60 and K562 of leukemia and lymphoma, glioblastoma and prostate.
    A3ARs are involved in tumor growth and cell cycle regulation (Gessi, S .; Merighi, S .; Varani, K .; Cattabriga, E .; Benini, A .; Mirandola, P .; Leung, E .; Mac Lennan, S .; Feo, C .; Baraldi, S .; Borea, PA Adenosine receptors in colon carcinoma tissues and colon tumor cell lines: focus on the A3 adenosine subtype. J. Cell. Physiol. 2007, 211 , 826-836).
    In particular, it has been published that activation of A3ARs in prostate cancer cells reduces PKA-mediated stimulation of ERK1 / 2 and leads to cancer reduction (Jajoo, S .; Mukherjea, D .; Watabe, K. ; Ramkumar, V. Adenosine A3 receptor suppresses prostate cancer metastasis by inhibiting NADPH oxidase activity. Neoplasia 2009, 11, 1132-1145).
    These data suggest that A3ARs could represent a biological marker and that their modulation could be used for various cancer treatments.
    In the patent literature, the different applications of adenosine A3 receptor modulators are also described. For example, US patent application 200320387 discloses di-substituted 2,4 thiazole derivatives, having inhibitory properties on the production of pro-inflammatory cytokines and inhibition on said adenosine A3 receptor.
    Patent application WO 9921555 discloses compounds derived from 1,3-azoles as antagonists of adenosine A3 receptor and their use as a prophylactic or therapeutic agent for the treatment of asthma, allergies and inflammation, among others.
    In WO 9964418 aryl-pyridinyl-thiazoles are disclosed as adenosine A3 receptor inhibitors and their use also as anti-inflammatory agents.
    US patent application 2012134945 discloses the use of adenosine A3 receptor antagonists in the modulation of melanin production, secretion and / or accumulation, as well as methods of treating conditions such as skin hyperpigmentation.
    US patent application 2011190324 discloses the use of adenosine A3 receptor antagonists for the treatment of atherosclerosis and the combination of said antagonists with other anti-atherosclerotic agents.
    US patent application 2011171130 discloses the use of antagonists and / or partial agonists of the adenosine A3 receptor for the treatment of numerous diseases, including cancer, inflammatory diseases, asthma, glaucoma, among others.
    On the other hand, related to the treatment of glaucoma and with the decrease of intraocular pressure in general, several patent documents have been found that disclose different types of adenosine A3 receptor antagonists, as can be seen in WO 0003741, WO 2008045330 and US 2012053176.
    Other patent documents collected in the state of the art, such as WO2009052310, WO2008006369, EP1180518, ES2360632 and ES2204262 disclose the use of different types of adenosine A3 receptor antagonists for the treatment of other conditions such as neurological and cardiac ischemia, leukopenia , neutropenia, rheumatoid arthritis, multiple sclerosis, gastrointestinal disorders, respiratory conditions such as asthma and diseases of the nervous system, such as Alzheimer's disease, Huntington's disease and Parkinson's disease, among others.
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    a) a hydroxyl group;
    b) a group -N (R5) (R6), where:
    i) R5 and R6 independently represent a C3-C12 cycloalkyl or a group
    linear or branched C1-C4 alkyl, substituted by a carboxyl group (-COOH); or
    ii) R5 and R6 together with the N atom a saturated cycle of 5 or 6 members that
    optionally comprises a heteroatom selected from N and O, which
    it is substituted by a carboxyl group (-COOH).
    Other aspects of the present invention are: a) pharmaceutically acceptable salts of said compounds, b) pharmaceutical compositions comprising an effective amount of said compounds or their pharmaceutically acceptable salts, c) the use of said compounds in the preparation of a medicament for treat a disease that can be improved by modulation of adenosine A3 receptors, such as neurological disorders, including Alzheimer's disease, Huntington's disease and Parkinson's disease, cardiovascular diseases such as atherosclerosis, respiratory diseases such as asthma, oncological diseases such as prostate cancer, kidney diseases such as acute renal failure, autoimmune diseases such as rheumatoid arthritis or diseases of the gastrointestinal system such as Crohn's disease, colitis or irritable bowel syndrome or pathological diseases or conditions such as glaucoma, e l dry eye syndrome or uveitis, d) procedures to treat a disease that can be improved by modulation of adenosine A3 receptors such as neurological disorders such as Alzheimer's disease, Huntington's disease and Parkinson's disease, cardiovascular diseases such as atherosclerosis, respiratory diseases such as asthma, cancer diseases such as prostate cancer, autoimmune diseases such as rheumatoid arthritis or diseases of the gastrointestinal system such as Crohn's disease, colitis or irritable bowel syndrome or pathological diseases or conditions ophthalmologic such as glaucoma, dry eye syndrome or uveitis, said procedures comprising administering the compounds of the invention to a subject in need of treatment and e) combination comprising a compound of formula (I) according to the invention and another agent therapeutic where said agent te It is selected from among agents to treat neurological disorders such as Alzheimer's disease, Huntington's disease and Parkinson's disease, cardiovascular diseases such as atherosclerosis, respiratory diseases such as asthma, cancer diseases such as prostate cancer, kidney diseases such as acute renal failure, autoimmune diseases such as rheumatoid arthritis or diseases of the gastrointestinal system such as Crohn's disease, colitis or irritable bowel syndrome or ophthalmic diseases or pathological conditions such as glaucoma, dry eye syndrome or uveitis.
    As used herein, the term "C1-C6 alkyl group" is used to designate linear or branched, optionally substituted hydrocarbon (CnH2n + 1) radicals having 1 to 6 carbon atoms. In an embodiment of the present invention the alkyl groups preferably contain from 1 to 4 carbon atoms.
    Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl and tertbutyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, 1-ethylpropyl, 1,1-dimethylpropyl radicals, 1,2-dimethylpropyl, n-hexyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methylpentyl, 3- methylpentyl and iso-hexyl.
    As used herein, the term "C1-C6 alkoxy group" is used to designate radicals containing the C1-C6 alkyl group attached to an oxygen atom (C2H2n + 1-O-), linear or branched, optionally substituted, containing 1 to 6 carbon atoms. In one embodiment of the present invention the alkyl groups contain 1 to 4 carbon atoms.
    Preferred alkoxy radicals include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, secbutoxy, t-butoxy, trifluoromethoxy, difluoromethoxy, hydroxymethoxy, 2-hydroxyethoxy or 2-hydroxypropoxy.
    As used herein, the term "alkylthio" includes radicals containing S and C1-C6 alkyl, optionally substituted, linear or branched from 1 to 6 carbon atoms. In a preferred embodiment of the present invention the alkyl groups contain from 1 to 4 carbon atoms.
    Preferred, optionally substituted alkylthio radicals include methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, sec-butylthio, t-butylthio, trifluoromethylthio, difluoromethylthio, hydroxymethylthio, 2-hydroxyethylthio or 2-hydroxypropyl.
    As used herein, the term "C2-C6 alkoxyalkyl group" includes radicals containing an alkyl chain interrupted by at least one oxygen function. The number of carbon atoms indicates the total number of carbon atoms present in the radical. All structural isomers are included.
    As used herein, the term carbonyl means C = O.
    As used herein, the term "C2-C6 alkoxycarbonyl group" includes radicals containing C2-C6 alkoxy group as defined above linked by a carbon atom to a carbonyl group.
    As used herein, the term "C3-C12 cycloalkyl group" is used to designate saturated cyclic (CnH2n-1) or monounsaturated (CnH2n-3) hydrocarbon radicals, optionally substituted, containing from 3 to 12 atoms of carbon. In one embodiment of the present invention the cycloalkyl groups preferably contain from 3 to 8 carbon atoms.
    Preferred, optionally substituted cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. When a cycloalkyl group has two or more substituents, these may be the same or different.
    As used herein, the term "aryl group" is used to designate an optionally substituted C5-C6 aryl radical, such as, for example, phenyl. When an aryl radical carries 2 or more substituents, the substituents may be the same or different.
    As used herein, the term "heteroaryl group" is used to designate a 5- or 6-membered ring with a heteroatom selected from O, S and
    N. The heteroaryl groups in the present invention may be optionally substituted. In an embodiment of the present invention the preferred heteroaryl groups are thienyl and pyridyl. When a heteroaryl group carries 2 or more substituents, the substituents may be the same or different.
    Other preferred, optionally substituted, heteroaryl groups include pyrazinyl, pyrimidinyl, pyridazinyl, furyl, oxadiazolyl, oxazolyl, imidazolyl, -1,3-thiazolyl, thiadiazolyl, and pyrazolyl.
    As used herein, the term "halogen atom" includes chlorine, fluorine, bromine or iodine atoms, typically a fluorine, chlorine or bromine atom, more preferably chlorine or fluorine. The term halo, when used as a prefix has the same meaning.
    As used herein, some of the atoms, groups, radicals, moieties, chains or cycles present in the general structures of the invention are "optionally substituted." This means that these atoms, groups, radicals, moieties, chains or cycles may be unsubstituted or substituted in any position by one or more substituents, for example 1, 2, 3 or 4 substituents, in which the hydrogen atoms attached to atoms, groups, radicals, moieties, chains or unsubstituted cycles are substituted by halogen atoms, C3-C12 cycloalkyl, hydroxy, linear C1-C6 alkoxy
    or branched, C1-C6 alkylthio, amino, mono- or dialkylamino, C1-C6 alkoxyalkyl, hydroxycarbonyl and C2-C6 alkoxycarbonyl. When two or more substituents are present, the substituents may be the same or different.
    As used herein, the term "pharmaceutically acceptable salt" encompasses salts with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include inorganic acids, for example hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, iodine and nitric acids and organic acids, for example citric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, acetic, methanesulfonic acids. , ethanesulfonic, benzenesulfonic or p-toluenesulfonic. Pharmaceutically acceptable bases include alkali metal hydroxides (e.g., sodium
    or potassium and alkaline earth metals (for example, calcium or magnesium) and organic bases, for example alkylamines, arylalkylamines and heterocyclic amines.
    Other preferred salts according to the invention are quaternary ammonium compounds in which an equivalent of an anion (X-) is associated with the positive charge of the N. X- atom can be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulfate, nitrate, phosphate or an anion of an organic acid, such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate,
    image9
    According to another embodiment of the present invention, in the compounds of formula (I) R1 is selected from the group consisting of a phenyl group and a thienyl group optionally substituted by halogen atoms, specifically by 1,2 or 3 halogen atoms and R4 is selected from the group consisting of [-N (R5) (R6)], as defined above. In a more preferred embodiment, in the compounds of formula (I) R1 is selected from the group consisting of a phenyl group and a thienyl group optionally substituted by 1,2 or 3 halogen atoms and R4 is selected from the group consisting of [ -N (R5) (R6)], in which the groups R5 and R6 form, together with the nitrogen atom to which they are attached, a 5 or 6-membered saturated cycle optionally comprising a heteroatom selected from the group consisting of oxygen and nitrogen, and which is substituted by a carboxyl group (-COOH).
    According to a preferred embodiment of the present invention, in the compounds of formula (I), R 4 represents a hydroxyl group, R 3 represents a phenyl group optionally substituted by halogen atoms, specifically by 1.2 or 3 halogen atoms or by a group C1-C6 alkoxy optionally substituted by 1.2 or 3 halogen atoms and R1 represents a phenyl or thienyl group optionally substituted by 1.2 or 3 halogen atoms.
    According to an embodiment of the present invention in the compounds of formula (I), R 3 represents a phenyl group optionally substituted by halogen atoms or by a C 1 -C 6 alkoxy group optionally substituted by 1.2 or 3 halogen atoms. In an even more preferred embodiment R 3 represents a phenyl group optionally substituted by 1,2 or 3 halogen atoms or by a C 1 -C 6 alkoxy group.
    According to an embodiment of the present invention in the compounds of formula (I), R 1 is selected from the group consisting of a phenyl group and a thienyl group optionally substituted by halogen atoms. In an even more preferred embodiment R1 is selected from the group consisting of a phenyl group and a thienyl group optionally substituted by 1,2 or 3 halogen atoms.
    According to an embodiment of the invention in the compounds of formula (I), R4 is selected from the group consisting of [-N (R5) (R6)] as defined above.
    According to an embodiment of the present invention in the compounds of formula (I), R4 is selected from the group consisting of [-N (R5) (R6)], where R5 and R6 form, together with the atom
    of nitrogen to which they are attached, a saturated cycle of 5 or 6 members optionally comprising a heteroatom selected from the group consisting of oxygen and nitrogen, and which is substituted by a carboxyl group (-COOH).
    According to a preferred embodiment of the present invention in the compounds of formula (I), R 1 represents a phenyl group optionally substituted by 1,2 or 3 halogen atoms, R 2 is selected from the group consisting of a cyano group and a halogen atom , R3 represents a phenyl group optionally substituted by 1.2 or 3 halogen atoms or by a C1-C6 alkoxy group optionally substituted by 1.2 or 3 halogen atoms and R4 represents a hydroxyl group; more preferably R3 represents a phenyl group optionally substituted with a methoxy group.
    According to a preferred embodiment of the present invention in the compounds of formula (I), R 1 represents a thienyl group optionally substituted by 1,2 or 3 halogen atoms, R 2 is selected from the group consisting of a cyano group and a halogen atom , R3 represents a phenyl group optionally substituted by 1.2 or 3 halogen atoms or by a C1-C6 alkoxy group optionally substituted by 1.2 or 3 halogen atoms and R4 represents a hydroxyl group; more preferably R3 represents a phenyl group substituted by a methoxy group.
    Individual particular compounds of the invention include:
    3- [5-Cyano-4- (3,4-dimethoxyphenyl) thiazol-2-ylcarbamoyl] benzoic acid, 4- [5-cyano-4- (4-methoxyphenyl) thiazol-2-ylcarbamoyl] benzoic acid, 4 - (5-Cyano-4-phenylthiazol-2-ylcarbamoyl) benzoic acid, 3- (5-cyano-4-phenylthiazol-2-ylcarbamoyl) benzoic acid, 5- (5-cyano-4-phenylthiazol-2-ylcarbamoyl) acid Thiophene-2-carboxylic acid, 6- (5-cyano-4-phenylthiazol-2-ylcarbamoyl) pyridine-2-carboxylic acid, 3- [5-cyano-4- (4-methoxyphenyl) thiazol-2-ylcarbamoyl] benzoic acid , 2- [5-Cyano-4- (4-methoxyphenyl) thiazol-2-ylcarbamoyl] benzoic acid, 5- [5-cyano-4- (4-methoxyphenyl) thiazol-2-ylcarbamoyl] thiophene-2-carboxylic acid , 6- [5-Cyano-4- (4-methoxyphenyl) thiazol-2-ylcarbamoyl] pyridine-2-carboxylic acid, 3- {5-cyano-4- [4- (trifluoromethoxy) phenyl] thiazole-2- ilcarbamoyl} benzoic acid, 5- (5-cyano-4- (4- (trifluoromethoxy) phenyl) thiazol-2-ylcarbamoyl) thiophene-2-carboxylic acid, 3- [5-cyano-4- (4-fluorophenyl) thiazole acid -2-ilcarbamoyl] benzoic,
    5- [5-Cyano-4- (4-fluorophenyl) thiazol-2-ylcarbamoyl] thiophene-2-carboxylic acid, 5- [5-cyano-4- (3-fluorophenyl) thiazol-2-ylcarbamoyl] thiophene- 2-carboxylic acid, 5- [5-cyano-4- (2-fluorophenyl) thiazol-2-ylcarbamoyl] thiophene-2-carboxylic acid, 3- [5-cyano-4- (pyridin-4-yl) thiazole- 2-ilcarbamoyl] benzoic,
    5 3- [5-Cyano-4- (pyridin-2-yl) thiazol-2-ylcarbamoyl] benzoic acid, 3- [5-cyano-4- (6-methylpyridin-2-yl) thiazol-2-ylcarbamoyl acid ] benzoic, 5- (5-cyano-4- (pyridin-3-yl) thiazol-2-ylcarbamoyl) thiophene-2-carboxylic acid, 5- (5-cyano-4- (6-methoxypyridin-3-yl) ) thiazol-2-ylcarbamoyl) thiophene-2-carboxylic acid, 3- (5-cyano-4- (6-methoxypyridin-3-yl) thiazol-2-ylcarbamoyl) benzoic acid,
    10 5- (5-Cyano-4- (4-cyanophenyl) thiazol-2-ylcarbamoyl) thiophene-2-carboxylic acid, 5- (5-cyano-4- (3-cyanophenyl) thiazol-2-ylcarbamoyl) thiophene acid -2-carboxylic acid, 5- (5-fluoro-4-phenylthiazol-2-ylcarbamoyl) thiophene-2-carboxylic acid, 3- (5-fluoro-4-phenylthiazol-2-ylcarbamoyl) benzoic acid, 5- (5 -chloro-4-phenylthiazol-2-ylcarbamoyl) thiophene-2-carboxylic acid,
    15 3- (5-Chloro-4-phenylthiazol-2-ylcarbamoyl) benzoic acid, 5- (5-bromo-4-phenylthiazol-2-ylcarbamoyl) thiophene-2-carboxylic acid, 3- (5-bromo-4 -phenylthiazol-2-ylcarbamoyl) benzoic acid, 5- (4-phenyl-5-iodo-thiazol-2-ylcarbamoyl) thiophene-2-carboxylic acid, 5- (5-chloro-4- (4-methoxyphenyl) thiazole- 2-ylcarbamoyl) thiophene-2-carboxylic acid,
    20 5- [5-Cyano-4- (4-methoxyphenyl) thiazol-2-ylcarbamoyl] -1 H -pyrazol-3-carboxylic acid, 1- (3 - {[5-cyano-4- (4-methoxyphenyl) thiazol-2-yl] carbamoyl} benzoyl) piperidino-4-carboxylic acid, 1- {4 - [(5-cyano-4-phenyl-thiazol-2-yl) carbamoyl] benzoyl} piperidino-4-carboxylic acid, acid 1 - {3 - [(5-cyano-4-phenyl-thiazol-2-yl) carbamoyl] benzoyl} piperidino-4-carboxylic.
    The compounds defined by the formula (I) in the present invention can be synthesized by the procedures described below. Scheme 1
    R3 image10 R3 image11 R2 a)
    b)
    OS +
    image12 N
    image13 S
    image14 NS image15 YR3
    NH2 image16 NH2 NH2 image17 NH2 (II) (III) (IV)
    Reagents and conditions: When R2 = F, Cl, Br or I. a) Y = halogen, ethanol, 40-100 ° C. b) Yes R2
    image18
    = F; Selectfluor®, acetonitrile (ACN), 0 ° C. R2 = Cl or Br; N-chlorosuccinimide or Nbromosuccinimide, dimethylforamide (DMF), room temperature / CuX2 (X = Cl, Br or I), acetonitrile; R2 = l; iodine chloride (ICl), acetic acid (AcOH) / dichloromethane (DCM), 0 ° C.
    When R2 represents a halogen, the 2-amino-5-halo-1,3-thiazoles of formula (IV) are obtained through the halogenation of commercially substituted 4-amino-1,3-thiazole derivatives in position 4 or synthesized as shown in scheme 1.
    10 The fluorination in the thiazole ring of the compound of formula (III) with bis- (tetrafluoroborate) of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane (Selectfluor®), gives rise to compounds of formula (IV) with good yields. The fluorination is carried out in acetonitrile, at temperatures between 0 and 25 ° C, to obtain the monofluorinated product, (Banks,
    15 R. Eric; et al. J. Chem. Soc. Perkin 1: 2069-2076). The introduction of the remaining halogens is carried out using the corresponding N-halosuccinimides in DMF at room temperature or with the corresponding copper (II) salts in acetonitrile (J. Org. Chem. 2009; 74 (6): 2579-2580 ). Iodization instead is performed according to the method described by P. Hebeisen (WO2009 / 068467A1), with iodine chloride in an acid mixture
    20 acetic acid and dichloromethane at temperatures between 0 and 25 ° C.
    In the case where the 2-amino-1,3-thiazole derivatives of formula (III) are not commercial, they can be obtained by the reaction between the commercial aryl or heteroaryl ketones of formula (II), where Y is an atom halogen, with thiourea
    At temperatures between 40 ° to 100 ° C in ethanol or acetonitrile as solvent as shown in scheme 1. Scheme 2
    image19 image20 R3 image21 R2 c) d)
    Or OS R2 +
    image22 N
    S R3 image23 OR image24 R3
    NH2 image25 NH2 image26 NH2
    (V) (VI) (IV)
    image27
    30 Reagents and conditions: When R2 = cyano, c) ACN, NaH, DMSO, room temperature. d) iodine, pyridine, 40-100 ° C.
    image28
    as DCM, THF or ACN at room temperature to give rise to the carboxylic acids of formula (VIII) which are the subject of the present invention and particular cases of the compounds of formula (I). A more effective variant is to use the methyl derivatives (chlorocarbonyl) -R2-carboxylate (XOCR2COMe) instead of the chlorides of
    Dicarbonyl of formula (VII), with subsequent hydrolysis of the corresponding methyl ester, to give rise to the acids of formula (VIII), which are part of the present invention.
    On the other hand, derivatives of formula (IV) can also be acylated using commercial dicarboxylic acid (X = OH) in the presence of N, N, N ′, N′-tetramethyl hexafluorophosphate
    O- (7-Azabenzotriazol-1-yl) uronium (HATU), to also give rise to the amides of formula (VIII), which are particular cases of the compounds of formula (I) according to the invention.
    The acid chlorides of formula (VII) necessary for the synthesis of the amides of formula
    (VIII) can be synthesized simply from the corresponding acids
    15 commercial dicarboxylics using synthetic methods described in the literature (Burdett, K.A., Synthesis, 1991, 441-42).
    The acid derivatives of formula (VIII) can be reacted with corresponding commercial amines or amino esters, such as with ethyl isonipecotate,
    In the presence of HATU to give rise to the amides or amidoesters of formula (IX), these compounds are in turn hydrolyzed with sodium hydroxide resulting in the carboxylic acids of formula (X) as shown in scheme 4, which are particular cases of the compounds of formula (I) according to the invention. 25 Scheme 4
    R3 image29 R2
    R3 image30 R2 N
    R3 image31 R2
    S
    image32 S image33 Og) h), i) N
    image34 image35 SN + HN
    NH image36
    image37
    image38 R1
    NH
    NH O image39 Or R1R1 image40 OR
    OR image41 image42 N
    OR image43 OH OR image44 image45 NOO OR image46
    image47 Or oh
    (VIII) (IX) (X)
    Reagents and conditions: g) HATU, DIPEA, DMF; h) NaOH (1M); i) HCl (4M). 2. 3 Pharmacological Activity
    Competitive radioligand binding assay of adenosine receptor subtypes.
    5 Human membranes for recombinant adenosine receptors were purchased from Receptor Biology, Inc. (USA).
    Competitiveness tests were carried out by incubation of the membranes from human A3 receptors transfected to CHO cells, [3H] -NECA, buffer (10 mM HEPES (pH = 7.4), 100 mM NaCl, MgCl2 10 mM, 2 units / ml adenosine deaminase), and unlabeled ligand in a total volume of 0.2 ml for 60 min at 25 ° C. R-PIA was used to determine non-specific binding. It was filtered on Schleicher & Schuell GF / 52 filters (previously impregnated with 0.5% polyethyleneimine) in a Brandel cell collector. Unbound radioligand was removed with 3 x 250 µl of 20 mM HEPES (pH = 7.4), 100 mM NaCl,
    10 mM MgCl2.
    Table 1 shows the adenosine A3 receptor binding constants obtained for some examples.
    20 Table 1.
    Examples COMPOUNDSA1 adenosine receptor binding (Ki in nM)Adenosine A3 receptor binding (Ki in nM)
    Example 5 5- (5-Cyano-4-phenylthiazol-2-carbobamoyl) thiophene-2-carboxylic acid8766
    Example 7 3- (5-Cyano-4- (4-methoxyphenyl) thiazol-2-carbamoyl) benzoic acid> 100010
    Example 9 5- (5-Cyano-4- (4-methoxyphenyl) thiazol-2-carbamoyl) thiophene-2-carboxylic acid> 10002. 3
    Example 14 5- [5-Cyano-4- (4fluorophenyl) thiazol-2-carbamoyl] thiophene-2-carboxylic acid13166
    Example 16 5- [5-Cyano-4- (2fluorophenyl) thiazol-2-carbamoyl] thiophene-2-carboxylic acid> 50099
    Example 22 3- (5-Cyano-4- (6-methoxypyridin-3-yl) thiazol2-ylcarbamoyl) benzoic acid> 100099
    Example 25 5- (5-Fluoro-4phenylazole-2-carbamoyl) thiophene-2-carboxylic acid6410
    Example 27 5- (5-Chloro-4-phenylthiazol-2-carbamoyl) thiophene-2-carboxylic acid3. 4twenty-one
    Example 32 5- (5-Chloro-4- (4-methoxyphenyl) thiazol-2-carbamoyl) thiophene-2-carboxylic acid> 100024
    Example 38 1- {3 - [(5-Cyano-4-phenyl-thiazol-2-yl) carbamoyl] benzoyl} piperidino-4-carboxylic acid7327
    From the above results it can be concluded that the compounds of formula (I) claimed by the present invention are potent modulators of the adenosine A3 receptor.
    Therefore, another aspect of the present invention is directed to the use of a compound of formula (I) according to the present invention for the manufacture of a medicament for
    treatment of a disease or pathological condition that can be improved by modulation of A3 adenosine receptors.
    The compounds of the present invention are useful in the treatment or prevention of diseases that are known to be improved by treatment with a modulator of adenosine A3 receptors. These diseases are for example diseases or pathological eye conditions such as glaucoma, dry eye syndrome or uveitis, neurological disorders such as Alzheimer's disease, cardiovascular diseases such as atherosclerosis, respiratory diseases such as asthma , kidney diseases such as acute renal failure, oncological diseases such as prostate cancer, autoimmune diseases such as rheumatoid arthritis or diseases of the gastrointestinal system such as irritable bowel syndrome.
    Accordingly, the compounds of the invention, the pharmaceutically acceptable salts thereof, and the pharmaceutical compositions comprising said compounds and / or the salts thereof, can be used in a method of treating disorders of the human body comprising administering to a subject in need of said treatment an effective amount of a 2-amino-1,3-thiazole derivative of formula (I) of the invention or a pharmaceutically acceptable salt thereof.
    The present invention also provides pharmaceutical compositions comprising, as active ingredient, at least one 2-amino-1,3-thiazole derivative of formula (I) according to the present invention or a pharmaceutically acceptable salt thereof, together with a pharmaceutically excipient. acceptable, such as a vehicle or diluent. The active ingredient may comprise from 0.001% to 99% by weight, preferably from 0.01% to 90% by weight of the composition, depending on the nature of the formulation and whether an additional dilution is made before application. Preferably, the compositions are prepared in a form suitable for oral, topical, nasal, rectal, percutaneous or injectable administration.
    Pharmaceutically acceptable excipients that are mixed with the active compound, or salts of said compound, to form the compositions of this invention are well known per se and the actual excipients used depend inter alia on the intended method of administration of the compositions.
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    权利要求:
    Claims (1)
    [1]
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    同族专利:
    公开号 | 公开日
    CA2974596A1|2016-07-28|
    CN107207445A|2017-09-26|
    BR112017015597A2|2018-03-13|
    AU2016210091B2|2019-08-15|
    RS59388B1|2019-11-29|
    AU2016210091A1|2017-08-17|
    EP3248964B1|2019-07-17|
    CN107207445B|2021-03-16|
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    JP2018502881A|2018-02-01|
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    PT3248964T|2019-10-28|
    US20180263963A1|2018-09-20|
    HUE046307T2|2020-02-28|
    JP6637983B2|2020-01-29|
    EP3248964A1|2017-11-29|
    WO2016116652A1|2016-07-28|
    ES2578363B1|2017-01-31|
    ES2750030T3|2020-03-24|
    DK3248964T3|2019-10-07|
    LT3248964T|2019-10-10|
    KR20170104612A|2017-09-15|
    HRP20191779T1|2019-12-27|
    PL3248964T3|2020-02-28|
    EA201791657A1|2017-12-29|
    SI3248964T1|2019-11-29|
    MX2017009514A|2017-11-15|
    US10238637B2|2019-03-26|
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