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    • 专利摘要:
    TAO allosteric inhibitors as antiparasitic and antifungal agents. The present invention provides a new series of compounds derived from 2,4-dihydroxybenzoic acid. Furthermore, the invention relates to a pharmaceutical composition comprising said compounds and for use in the treatment or prevention of diseases caused by parasites, preferably protozoan parasites or fungi. These diseases can occur in both humans and animals. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2668494A1
    申请号:ES201631335
    申请日:2016-10-17
    公开日:2018-05-18
    发明作者:Christophe DARDONVILLE；Hendrik Pieter DE KONING；Godwin Unekwuojo EBILOMA
    申请人:Consejo Superior de Investigaciones Cientificas CSIC；University of Glasgow；
    IPC主号:
    专利说明:

    The present invention relates to derivatives of 2,4-dihydroxybenzoic acid and its potential for the treatment of infectious (antiparasitic) diseases both human and animal. Therefore, the invention is part of the pharmaceutical and veterinary sector.
    10 STATE OF THE TECHNIQUE
    Human African trypanosomiasis (sleeping sickness) is a parasitosis, transmitted by the tse-tsé fly, caused by two subspecies of Trypanosoma 15 brucei, gambiense and Rhodesian. Other species and subspecies of Trypanosoma (T. congolense, T. brucei subs. Brucel) infect cattle, causing the disease called nagana, with great economic damage in these countries of sub-Saharan Africa. This disease is resurfacing in recent decades and has a huge human and economic cost. There are now four registered drugs 20 to treat this disease: the primary phase is treated with pentamidine or with suramin while in the late phase, (neurological) arsenical melarsoprol is used, whose treatment has a 5-10% mortality. The only alternative to melarsoprol, eflornithine (DFMO), is expensive, active only against T. b. Gambian and complex and uncomfortable administration, so its use is reserved for cases refractory to 25 melarsoprol (Dardonville Expert Opio Ther. Palenls, 2005, 15, 1241-1257). These drugs have many drawbacks due to selective efficacy depending on the trypanosome subspecies or the status of the infection. In addition, both its high toxicity and the mode of parenteral administration and the emerging resistance of current drugs highlight the need to find
    30 new therapeutic weapons for the treatment of HAT. In particular, the discovery of new drugs that penetrate the central nervous system and cure the late stage of the disease, for which there are no satisfactory medications, remains a priority in tropical medicine.
    On the other hand, the phenomenon of resistance to veterinary drugs (diminacene, elidium bromide) used to treat animal trypanosomiasis in cattle is increasing. Therefore, the discovery of new trypanocidal drugs for veterinary use is a highly priority issue.
    Trypanosomes adapt their energy metabolism based on the availability of substrates. Thus, blood trypomastigotes (form of the parasite present in the mammalian host) mainly produce their energy by glycolysis of the glucose present in the host's blood since they do not possess a functional respiratory chain (Grant, al., Biochem. J 1960, 76, 229-237). Clarkson the aJ. have shown that the breathing of blood trypomastigotes of T. b. brucei depends on an enzyme called "trypanosome oxidase alternative" (TAO) (Clarkson et al., J. Biol. ehem. 1989,264,17770-17776.). TAO is the only oxidase available to re-oxidize the NADH that accumulates during the
    15 glycolysis. TAO is a cytochrome independent ubiquinol oxidase that is not inhibited by cyanide. On the contrary, said enzyme is sensitive to specific inhibitors such as salicylic hydroxamic acid (SHAM) or ascofuranone (Minagawa, al., Mol. Biochem. Parasitol. 1997, 84, 271-280).
    20 TAO is an enzyme that mammals do not have and that is essential for the viability of blood trypomastigotes. Therefore, TAO is a good target for chemotherapy since a selective inhibitor should not cause side effects in the host (Chaudhuri, et al., Trends Parasitol. 2006, 22, 464-491). In addition, this enzyme is conserved among the different subspecies of T. brucei so the
    25 TAO inhibitors could be useful for different subspecies of trypanosomes. Previous studies both in vilro and in vivo have shown the potential of TAO inhibitors to inhibit the growth of trypanosomes, and, in certain cases, cure murine models of trypanosomiasis (Yabu, al., Parasitol. Inl. 2003, 52 ,
    155-164). 30
    Other parasites, such as Gryplosporidium parvum, or fungi, such as Gandida albicans, have an alternative oxidase (AOX) that is essential for their growth. It is known that the inhibition of the AOX of the fungus Gandida albicans increases the susceptibility of said fungus to the treatment by drugs of the azole family (Yan, et al. J. Antimicrob. Chemather. 2009, 64, 764-773). Therefore, the TAO inhibitors described in this patent could be useful for the treatment of candidiasis.
    5 To date, three families of TAO inhibitors based on the structure of salicylic hydroxamic acid (SHAM), 3,4-dihydroxybenzoic acid and the naturally occurring antibiotic ascofuranone have been described. Such inhibitors bind to the active site of the enzyme in a manner similar to the endogenous ubiquinone substrate.
    10 However, the inhibitors described to date have several limitations related to their toxicity, their low selectivity or a low inhibitory potency.
    In this the present invention, a strategy is proposed to remedy said problems by preparing new allosteric TAO inhibitors that are
    15 bind at the enzyme interface that interacts with the membrane lipids of the mitochondria. By not competing with the ubiquinone substrate, these inhibitors have low cytoxicity to human cells.
    DESCRIPTION OF THE INVENTION
    The compounds described in the present invention may be useful for treating infections caused by trypanosomatid protozoa (Trypanosoma), apicomplexes (Gryptosporidium), or fungi (Gandida).
    Therefore, a first aspect of the present invention relates to a compound of general formula (1), pharmaceutically acceptable salt, or solvate thereof.
    Or R3
    R1 ~ R) lAO / Z'R2
    (one )
    where: 30 R, is selected from H, OH, NHOH, NH2 and NH-C, -C4 alkyl;
    R, O
    ~ R,
    . /, )the.,
    R2 is selected from halogen, EIGHT, and or ~RJ is selected from OH, halogen, and Cr C4 alkyl;R4 is selected from H and Cr4 alkyl;Z is selected from - (CH2) n where n is an integer comprised
    5 between 6 and 20, Y ~ m where m is an integer between 1 and 3;
    with the proviso that when
    R1 is H, RJ is OH, ~ is H and R2 is Sr, n is different from 6, 8, 9, 10 and 12;
    R, or
    ~ R,
    /, )the.,
    R1 is H, RJ is OH, ~ is H and R2 is o ~, n is different from 6, 8, 10, and 12; 0
    R, or
    ~ R,
    /, )the.,
    R1 is OH, RJ is OH, R4 is H and R2 is o ~, n is different from 6 and 10.
    From now on, the compounds of formula (1) may be referred to as compounds of the invention.
    The term "solvate" is intended to indicate a pharmaceutically acceptable solvate form of a specified compound that maintains the biological efficacy of said compound. Examples of salts include compounds of the invention together with
    20 water, isopropanol, ethanol, methanol, DMSO (dimethylsulfoxide), ethyl acetate, acetic acid or ethanolamine. The term "hydrate" is used when said solvent is water. Solvation methods are of general knowledge in the field.
    The term "pharmaceutically acceptable salt" refers to salts prepared from
    25 non-toxic pharmaceutically acceptable bases including inorganic bases and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganic salts,
    Manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, morphine, pyrazine, pyrazine, pyrazine, pyrazine, pipeline , polyamine, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine resins, and the like. When the compound of the present invention is basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic acid, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,
    Mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, ptoluenesulfonic and the like.
    Preferred examples of pharmaceutically acceptable salts include ammonium, calcium, magnesium, potassium and sodium salts, and those formed from maleic acids,
    20 fumaric, benzoic, ascorbic, pamoic, succinic, hydrochloric, sulfuric, bismethylensalicylic, methanesulfonic, ethanedisulfonic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, bulfamic, bulfonic , phosphoric and nitric.
    The term "alkyl" refers, in the present invention, to saturated, linear or branched hydrocarbon chains having 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, i-propyl, n- butyl, tert-butyl ° sec-butyl. Preferably the alkyl group has between 1 and 2 carbon atoms and more preferably they are a methyl group. The alkyl groups may be optionally substituted by one more
    30 substituents such as alkynyl, alkenyl, halogen, hydroxyl, alkoxy, carboxyl, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro mercapto.
    By "halogen" is meant in the present invention a bromine, chlorine, iodine fluorine atom.
    In a preferred embodiment, R, is selected from H and OH, and more preferably R, is OH.
    In another preferred embodiment, R2 is halogen, and more preferably bromine.
    In another preferred embodiment, R2 is EIGHT.
    R, or
    In another preferred reatization, R, is / 'OR'.
    ~
    In another preferred embodiment, R3 is selected from F, OH and CH 3, and more preferably ~ is OH.
    In another preferred embodiment, R4 is H.
    In another preferred embodiment, Z is - (CH2) n where n is an integer between 8 and 20, and even more preferred n is an integer and even number between 10 Y
    16.
    In another preferred embodiment, the compounds of formula (1) are selected from the list comprising:
    4 - ((1 0-Bromodecyl) oxy) -2-hydroxybenzoic acid (7f),4 - ((1 0- (formyloxy) decyl) oxy) -2-hydroxybenzoic acid (81),4 - ((12-Bromododecyl) oxy) -2-hydroxybenzoic acid (7 g),
    25 4 - ((12- (formyloxy) dodecyl) oxy) -2-hydroxybenzoic acid (8g), 4,4 '- (dodecane-1, 12-diylbis (oxy)) bis (2-hydroxybenzoic) (15g) , 4 - ((14-bromotetradecyl) oxy) -2-hydroxybenzoic acid (7h), 4 - ((14- (formyloxy) tetradecyl) oxy) -2-hydroxybenzoic acid (8h), 4,4 '- (tetradecane acid -l, 14-diylbis (oxy)) bis (2-hydroxybenzoic) (15h),
    30 4 - ((14-Bromotetradecyl) oxy) -2-methylbenzoic acid (9h), 4- "14- (formyloxy) tetradecyl) oxy) -2-methylbenzoic acid (1 Oh),
    4 - ((14-bromotetradecyl) oxy) -2-fluorobenzoic acid (11 h),
    4- ((14-bromotetra decyl) oxy) -2-hydroxybenzaldehyde (12h),14- (4-formyl-3-hydroxyphenoxy) tetradecyl formate (13h),4 - ((14-Bromotetradecyl) oxy) -2-hydroxy-6-methylbenzoic acid (14h),4,4 '- (tetradecane-1, 14-diylbis (oxy »bis (2-methylbenzoic)) acid (16h),
    5 4,4 '- (tetradecane-1, 14-diylbis (oxy »bis (2-hydroxybenzaldehyde) (17h),4,4 '- (tetradecane-1, 14-diylbis (oxy »bis (2-hydroxy-6-methylbenzoic acid) (1Sh),4 - ((16-Bromohexadecyl) oxy) -2-hydroxybenzoic acid (7i),4 - ((16- (formyloxy) hexadecyl) oxy) -2-hydroxybenzoic acid (Si) and4,4 '- (Hexadecane-1, 16-diylbis (oxy »bis (2-hydroxybenzoic)) (15i).
    Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of general formula (1)
    Where: R, is selected from H, OH, NHOH, NH2 and NH-C, -C4 alkyl; R, or (VlR,
    . •
    ~~ o
    R2 is selected from halogen, EIGHT, and or ~RJ is selected from OH, halogen, and CHJ;R4 is selected from H and CHJ;
    20 Z is selected from - (CH2) n where n is an integer comprised
    between 6 and 20, and Hm where m is an integer between 1 and 3;
    together with a pharmaceutically acceptable vehicle.
    The pharmaceutically acceptable carriers that can be used in said compositions are substances known to those skilled in the art and commonly used in the elaboration of therapeutic compositions.
    The compounds and compositions of this invention can be used with other drugs to provide a combination therapy. The other drugs may be part of the same composition, or they may be provided as a
    5 separate composition for administration at the same time or at a different time.
    Therefore, in another preferred embodiment, the composition of the invention is characterized in that it can also comprise at least one other active ingredient, preferably an antiparasitic agent.
    Another aspect of the present invention relates to the use of a compound of the invention, of general formula (1), for the preparation of a medicament.
    Another aspect of the present invention relates to the use of a compound of the
    Invention, of general formula (1), for the preparation of a medicament for the prevention and / or treatment of diseases caused by parasites or fungi, preferably diseases caused by protozoan parasites. These diseases occur in an animal, preferably in a mammal, including humans.
    In a preferred embodiment, the diseases are diseases caused by a parasite of the genus Trypanosoma, Gryptosporidium, or a fungus of the genus Gandida. And even more preferably the parasites are of the species Trypanosoma brucei, Trypanosoma congo / ense, Trypanosoma equinum, Trypanosoma equiperdum,
    Trypanosoma evansi, Trypanosoma vivax, Gryptosporidium parvum, or Gandida albicans.
    In another preferred embodiment, the disease is selected from human African trypanosomiasis (sleeping sickness), animal trypanosomiasis, cryptosporidiosis, or candidiasis.
    Another aspect of the present invention relates to a method of treatment and / or prevention of parasitic or parasitic diseases comprising the administration to an individual in need thereof of a therapeutically effective amount of at least one compound of the invention of formula (1), or of the pharmaceutical composition as described in the present invention. The individual may be an animal, preferably in a mammal, including humans.
    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, for
    The characteristics of the compounds, as well as the age, condition of the patient, the severity of the alteration or disorder, and the route and frequency of administration.
    Said therapeutic composition can be prepared in solid form or in suspension, in a pharmaceutically acceptable diluent. The therapeutic composition provided
    15 by this invention can 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.
    Throughout the description and claims the word "comprises" and its
    20 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.
    DESCRIPTION OF THE FIGURES
    Fig. 1. Synthetic route for the preparation of derivatives of formula (1): (i) Br- (CH2k Br (n = 6.10, 12, 14, and 16; 1 equiv.), NaHCO), DMF or CH) CN, 65 oC.
    Examples
    Next, the invention will be illustrated by tests performed by the 5 inventors, which demonstrates the specificity and effectiveness of the compounds described in the present invention.
    The compounds of formula (1) which are synthesized below are schematized in Figure 1.
    Example 1. Synthesis of the compounds of the invention
    General procedure The reaction is carried out in a Kimax tube under an argon atmosphere. An amount
    Equimolar of 2,4-dihydroxybenzoic acid 1 (142 mg, 0.9 mmol), NaHC03 (78 mg, 0.9 mmol), and dibromoalkane (0.9 mmol) in anhydrous DMF (10 mL) is heated 65 oC for 24 hours The solvent is evaporated in vacuo to obtain a solid crude containing 3 major products 7, 8, and 15. Purification is carried out by chromatography on silica (10 g pre-compacted column) using hexane / EtOAc (10010 -> SO /fifty)
    20 as eluent, obtaining 7 (majority product,> 30%), 8 «10%), and 15«
    30%)
    4- «10-Bromodecyl) oxy) -2-hydroxybenzoic acid (71)
    The general procedure is followed using 1,10-dibromodecane (276 mg, 0.92 mmol). 25 7f is isolated with a mixture of hexane / EtOAc (98/2). Off-white solid (127 mg,
    37%) HPLC (UV)> 91%; P.I = 41 .3 oC. 'H NMR (300 MHz, CDCI,) or 11.06 (s, 1H),
    7.73 (d, J = 8.4 Hz, 1H), 6.43 -6.33 (m, 2H), 6.08 -5.59 (brs, 1H), 4.30 (t, J = 6.6 Hz, 2H), 3.40 (t, J = 6.6 Hz , 2H), 1.92 -1.20 (m, 16H). "c NMR (75 MHz, CDCI,) or 170.19, 163.79, 162.12, 131.98, 107.91, 106.23, 103.26, 65.34, 34.18, 32.95, 29.50, 30 29.46, 29.31, 28.85, 28.73, 28.29, 26.08. LRMS (ES ') miz 375 [M + Hr.
    4- «10- (formyloxy) decyl) oxy) -2-hydroxybenzoic acid (8f)
    81 is isolated with a hexane / EtOAc mixture (96/4). White solid (20 mg, 5.8%). HPLC (UV)> 95%; P.I = 62-68 oC. 'H NMR (300 MHz, CDCI,) or 10.96 (s, 1H), 7.99 (s, 1H), 7.66 (d, J = 8.5 Hz, lH), 6.33 (d, J = 2.4 Hz, 1 H), 6.30 (dd, J = 2.4, 8.5 Hz, lH), 4.23 (1, J = 6.5 Hz, 2H), 4.10 (1, J = 6.6 Hz, 2H), 1.72 -1.09 (m, 16H). 13C NMR (75 MHz, CDCI,) OR 170.18, 163.84, 162.27, 161.63, 131.95, 107.93, 106.18, 103.29, 65.31, 64.43, 29.84, 29.49, 29.28, 29.26, 28.71, 28.64, 26.08, 25.94. LRMS (ES ·) miz 339
    5 [M + Hr.
    4,4 '- (decane-1, 10-diylbis (oxy)) bis (2-hydroxybenzoic acid) (151)
    15t is isolated with a hexane / EtOAc mixture (70/30). White solid (83 mg, 24%).
    HPLC (UV)> 95%; PI. = 118.6-120.1 oC. 'H NMR (300 MHz, DMSO-d,) 010.76 (br,
    10 3H), 7.62 (dd, J = 4.4, 8.8 Hz, 2H), 6.36 (dI, J = 3.6, 7.7 Hz, 2H), 6.28 (dd, J = 2.5, 5.1 Hz, 2H), 4.25 (1, J = 6.4 Hz, 4H), 1.68 (p, J = 6.5 Hz, 4H), 1.30 (m, 12H). .oc NMR (75 MHz, DMSO-d,) OR 169.26, 164.21, 162.79, 131.44, 108.31, 103.97, 102.43, 64.61, 28.76, 28.53, 28.01, 25.36. LRMS (ES ·) miz 447 [M + Hr.
    15 4 - ((12-Bromododecyl) oxy) -2-hydroxybenzoic acid (7g)
    The general procedure is followed using 1,112-dibromododecane (142 mg, 0.92 mmol). 79 is isolated with a hexane / EtOAc mixture (97/3). White solid (176 mg,
    48%) HPLC (UV)> 95%; P.I = 48-51 oC. 'H NMR (300 MHz, CDCI,) OR 11.00 (s, 1H),
    7.67 (d, J = 8.4 Hz, 1 H), 6.33 (d, J = 2.3 Hz, 1 H), 6.30 (dd, J = 2.3, 8.4 Hz, 1 H), 5.68 20 (brs, 1 H), 4.23 (1, J = 6.5 Hz, 2H), 3.33 (1, J = 6.7 Hz, 2H), 1.86 -1.61 (m, 6H), 1.44
    1.12 (m, 14H). .oc NMR (75 MHz, CDCI,) 0170.19, 163.77, 162.04, 131.99, 107.89, 106.26, 103.26, 65.38, 34.23, 32.97, 29.62, 29.55, 29.35, 28.89, 28.73, 28.31, 26.09. LRMS (ES ·) miz 401, 403 [M + Hr.
    25 4 - ((12- (formyloxy) dodecyl) oxy) -2-hydroxybenzoic acid (8g)
    89 is isolated with a hexane / EtOAc mixture (90/10). White amorphous solid (14.6 mg,
    4%). HPLC (U V)> 95%; P.I = 68-70 oC. 'H NMR (300 MHz, CDCI,) OR 10.99 (s, lH), 8.00 (s, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 6.34 (d, J = 2.4 Hz, lH), 6.31 (dd, J = 2.4, 8.4 Hz,
    lH), 6.15 (brs, lH), 4.23 (1, J = 6.6 Hz, 2H), 4.10 (1, J = 6.6 Hz, 2H), 1.73 -1.56 (m, 30 6H), 1.22 (m, 14H) . LRMS (ES ·) miz 367 [M + Hr.
    4,4 '- (dodecane-1, 12-diylbis (oxy ») bis (2-hydroxybenzoic acid) (159)159 is isolated with a hexane / EtOAc mixture (SO / 50). White amorphous solid (90 mg,
    24%) HPLC (UV)> 95%; P.I = 96-97 oC. 'H NMR (300 MHz, CDCI,) OR 10.91 (s, 2H), 9.32 (s, 2H), 7.61 (d, J = 8.6 Hz, 2H), 6.35 (d, J = 2.4 Hz, 2H), 6.32 (dd, J = 2.4, 8.6 Hz, 2H), 4.21 (1, J = 6.5 Hz, 2H), 2.12 (s, 2H), 1.68 (1, J = 7.1 Hz, 4H), 1.35-1.20 (m, 14H). 13C NMR (75 MHz, CDCI,) 0170.26, 164.05, 163.75, 131.53, 108.31, 104.87, 103.05, 64.96, 29.73, 29.52, 29.27, 28.68, 26.02. LRMS (ES ') miz 475 [M + H (
    4- «14-Bromotetradecyl) oxy) -2-hydroxybenzoic acid (7h)
    The general procedure is followed using 1,14-dibromotetradecane (285 mg, 0.8
    mmol). 7h is isolated using hexane / E10Ac (98/2). White solid (123 mg, 36%). HPLC (UV)> 95%; P.I = 72-73.8 oC. 'H NMR (300 MHz, CDCI,) OR 10.99 (s, 1 H), 7.67 (d, J =
    10 8.4 Hz, 1H), 6.34 -6.31 (m, 1H), 6.29 (d, J = 2.6 Hz, 1H), 5.59 (brs, 1H), 4.23 (1, J =
    6.4 Hz, 2H), 3.33 (1, J = 6.6 Hz, 2H), 1.90-1.55 (m, 6H), 1.52-1.01 (m, 18H). 13C NMR (75 MHz, CDCI,) 0170.18, 163.81, 162.01, 132.00, 107.87, 106.31, 103.26, 65.39, 34.23, 32.99, 29.73, 29.68, 29.63, 29.57, 29.37, 28.91, 28.75, 28.36, 28.32, 26.10. LRMS (ES ') mIz 429, 431 [M + Ht.
    4- «14- (formyloxy) tetradecyl) oxy) -2-hydroxybenzoic acid (ah)ah is isolated using hexane / EtOAc (96/4). White solid (3 mg, 0.9%). HPLC (UV)>95%; P.I = 70-71 oC. 'H NMR (300 MHz, CDCI,) OR 10.96 (s, 1 H), 8.00 (s, 1 H), 7.66 (d,
    J = 8.0 Hz, 1 H), 6.38 -6.22 (m, 2H), 5.66 (br, 1 H), 4.24 (d, J = 6.6 Hz, 2H), 4.11 (d, J =
    20 6.8 Hz, 2H), 1.74 -1.52 (m, 6H), 1.33 -1.22 (m, 18H). LRMS (ES ') mIz 395 [M + H (
    4,4 '- (tetradecane-1, 14-diylbis (oxy)) bis (2-hydroxybenzoic acid) (15h)15h is isolated using hexane / E10Ac (70/30). White solid (61 mg, 18%). HPLC (UV)>95%, IP = 132.7-134.8 oC. 'H NMR (300 MHz, CDCI,) OR 10.97 (brs, 2H), 7.62 (dd, J =
    25 2.0, 7.3 Hz, 2H), 6.33 -6.25 (m, 4H), 4.21 (1, J = 6.5 Hz, 4H), 1.67 (p, J = 6.5 Hz, 4H),
    1.40 -1.15 (m, 20H). 13C NMR (75 MHz, CDCI,) OR 170.22, 163.77, 163.27, 131.64, 108.20, 104.89, 102.59, 65.05, 29.56, 29.52, 29.47, 29.21, 28.60, 25.95. LRMS (ES ') miz 503 [M + Ht.
    30 4- "16-Bromohexadecyl) oxy) -2-hydroxybenzoic acid (7i) The general procedure is followed using 1,16-dibromohexadecane (93 mg, 0.24 mmol). 7i is isolated using hexane / EtOAc (98/2). White amorphous solid (35 mg, 32%).
    HPLC (UV)> 95%; P.I = 58-60 oC. 'H NMR (300 MHz, CDCI,) OR 10.98 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 6.33 (d, J = 2.5 Hz, 1 H), 6.30 (dd, J = 2.5 , 8.4 Hz, 1 H), 5.43 (brs, 1 H), 4.23 (t, J = 6.5 Hz, 2H), 3.34 (t, J = 6.7 Hz, 2H), 1.78 (p, J = 6.9 Hz, 4H), 1.67 (p, J =
    6.8 Hz, 4H), 1.46 -1.23 (m, 20H). "c NMR (75 MHz, CDCI,) OR 170.16, 163.85, 161.94, 132.00, 107.83, 106.35, 103.27, 65.37, 34.22, 33.00, 29.79, 29.76, 29.70, 29.69, 29.65, 29.59, 29.39, 28.92, 28.76, 28.33 , 26.12. LRMS (ES ') miz 456, 458
    5 [M + Hr.
    4- «16- (formyloxy) hexadecyl) oxy) -2-hydroxybenzoic acid (8i)8i is isolated using hexane / EtOAc (96/4). White solid (11 mg, 10%). HPLC (UV)>95%; P.I = 7 & -77 oC. 'H NMR (300 MHz, CDCI,) OR 10.96 (s, 1 H), 7.99 (s, 1 H), 7.67 (d,
    10 J = 8.5 Hz, 1H), 6.33 (d, J = 2.4 Hz, 1 H), 6.29 (dd, J = 2.4, 8.5 Hz, 1 H), 5.36 (brs, 1 H),
    4.23 (t, J = 6.5 Hz, 3H), 4.10 (t, J = 6.7 Hz, 2H), 1.89-0.97 (m, 28H). "c NMR (75 MHz, CDCI) 0170.38, 164.16, 162.21, 161.71, 132.23, 108.04, 106.62, 103.54, 65.59, 64.60, 30.11, 30.01 (m, peak overlap), 29.91, 29.87, 29.60, 29.55, 29.01 , 28.91, 26.36, 26.19. LRMS (ES ') miz 423 [M + Hr.
    15 4.4 '- (hexadecane-l, 16- <1iylbis (ox i' bis (2-hydroxybenzoic)) (15i)
    15i is isolated using hexane / EtOAc (70/30). White amorphous solid (3 mg, 2.7%). HPLC
    (UV)> 95%; P.I = 10 & -110 oC. 'H NMR (300 MHz, CDCI,) or 10.99 (s, 2H), 7.70 -7.57 (m, 2H), 6.29 (m, 4H), 4.21 (t, J = 6.5 Hz, 4H), 1.81 -1.56 ( m, 4H), 1.55 -0.99 (m,
    20-20H), 0.77 (m, 4H). "c NMR (75 MHz, CDCI) or 170.25, 163.77, 163.31, 131 .68, 108.25, 104.96, 102.71, 102.64, 65.09.32.60.30.74, 30.08, 29.72, 29.65, 29.58, 29.53, 29.27, 28.65, 26.00 , 25.77. LRMS (ES ') miz 531 [M + Hr.
    4- «14-Bromotetradecyl) oxy) -2-methylbenzoic acid (9h)
    9 9h is isolated using hexane / EtOAc (90/10). White solid (41 mg, 7%); PI = 54.4 -57.3 oC; HPLC (UV)> 95%. 'H NMR (300 MHz, CDCI,) or 7.81 (d, J = 9.2 Hz, 1 H, ArH), 6.66 -6.60 (m, 2H, 2x ArH), 6.17 (s.a., 1H, COOH), 4.18 (s, 2H, CH, O), 3.33 (t, J =
    6.83 Hz, 2H, CH, Br), 2.49 (s, J = 3.23 Hz, 3H, ArCH,) 2.03-0.83 (m, 24H, 12x CH,). "c NMR (75 MHz, CDCI,) OR 167.8, 159.2, 143.4, 133.4, 122.0, 118.5, 112.8, 65.0,
    30 34.2, 33.0, 32.95, 29.8, 29.7, 29.69, 29.65, 29.6, 29.5, 29.4, 28.9, 28.3, 26.3, 22.4. LRMS (ESI ') miz 427, 429 (M + H)'. HRMS (ESI ') miz 426.1790 (C22 H "BrO, requires 426.1770).
    4- ((14- (formyloxy} tetradecyl) oxy} -2-meti Ibenzoi co (10h) acid
    10h is isolated using hexane / EtOAc (80/20). Yellowish solid (31 mg, 6%); Mp = 59.0
    -60.5 oC; HPLC (UV)> 95%. 'H NMR (300 MHz, CDC !,) or 8.00 (s, 1H, EIGHT), 7.86
    -7.75 (m, 1H, ArH), 6.66 -6.60 (m, 2H, 2xArH), 6.36 (s.a., 1H, COOH), 4.18 (1, J =
    6.5 Hz, 2H, CH, EIGHT), 4.10 (1, J = 6.6 Hz, 2H, CH, O), 2.49 (s, 3H, ArCH,), 1.70
    5 1.53 (m, 4H, 2xCH, CH, O), 1.34 -1.15 (m, 20H, 10xCH,). DC NMR (75 MHz, CDC !,) or
    167.8, 161 .7, 159.2, 143.4, 133.4, 122.0, 118.5, 112.8, 65.0, 64.5, 29.8, 29.7, 29.64,
    29.61, 29.5, 29.37, 29.28, 28.9, 28.6, 26.4, 26.3, 25.9, 22.4. LRMS (ESI ') miz 393
    (M + H) '. HRMS (ESI ') miz 392.2548 (C "H" O, requires 392.2563).
    1O 4- «14-Bromolelradecyl) oxy) -2-fluorobenzoic acid (11 h)
    Beige solid (16 mg, 20%); PI = 42-48 oC; HPLC (UV)> 95% 'H NMR (300 MHz,
    CDCI,) or 10.95 (s, 1H, COOH), 7.66 (d, J = 9.5 Hz, 1H, ArH), 6.46 -6.19 (m, 2H, ArH),
    4.24 (1, J = 6.5 Hz, 1 H, CH, O), 3.91 (1, J = 6.4 Hz, 1 H, CH, O), 3.35 (1, J = 6.6 Hz, 2H,
    CH, Br), 1.97-0.57 (m, 24H, 12xCH,). DC NMR (75 MHz, CDCI,) or 170.2, 165.2,
    fifteen 164.0, 131 .3, 108.0, 105.6, 101.3, 68.1, 33.9, 33.8, 32.8, 32.7, 29.0, 28 .01, 27.96, 25.4.
    LRMS (ESI ') miz 431, 433 (M + H (
    4- «14-bromolelradeci I) ox i) -2 -h id roxi be nza I deh gone (12 h)
    12h is isolated using hexane / EIOAc (97/3). White solid (17 mg, 4%); PI = 55.5 -58.6
    twenty oC; HPLC (U V)> 95%; 'H NMR (300 MHz, CDC !,) or 11.41 (s, 1H, CHO), 9.64 (s, 1H,
    OH), 7.35 (d, J = 8.6 Hz, 1H, ArH), 6.46 (dd, J = 2.4, 8.6 Hz, 1H, ArH), 6.34 (d, J = 2.4
    Hz, 1 H, ArH), 3.93 (1, J = 6.6 Hz, 2H, CH, or), 3.34 (1, J = 6.8 Hz, 2H, CH, Br), 1.82 -
    1.69 (m, 4H, CH, CH, O, CH, CH, Br), 1.23 (m, 20H, 10xCH,). DC NMR (75 MHz, CDCI,)
    or 194.4, 166.6, 164.7, 135.3, 115.2, 108 .9, 101.2, 68.8, 34.2, 33.0, 29.9, 29.74, 29.68,
    25 29.6, 29.5, 29.1, 28.9, 28.3, 26.1. LRMS (ESI ') miz 413, 415 (M + H)'. HRMS (ESI ') miz
    412.1621 (C "H" BrO, requires 412.1613).
    14- (4-formi 1-3-hydroxyphenoxy) tetradecyl formate (13h)
    13h is isolated using hexane / EtOAc (97/3). Yellowish solid (40 mg, 9%); Pf = 63.5
    30 68.8 oC; HPLC (UV)> 95%. 'H NMR (300 MHz, CDCI,) or 11.41 (s, 1H, CHO), 9.63 (s,
    1H, OH), 7.99 (s, 1 H, EIGHT), 7.34 (dd, J = 3.3, 8.7 Hz, 1 H, ArH), 6.45 (dd, J = 2.4, 8.7
    Hz, 1 H, ArH), 6.34 (d, J = 2.4 Hz, 1 H, ArH), 4.09 (1, J = 7.2 Hz, 1 H, CH, EIGHT), 4.03 (1,
    J = 7.2 Hz, 1H, CH, EIGHT), 3.93 (1, J = 6.5 Hz, 2H, CH, O-), 1.82 -1.42 (m, 8H,
    2xCH, CH, O, 2xCH, CH, CH, O), 1.42-1.04 (m, 16H, 8xCH,). DC NMR (75 MHz,
    CDCI,) or 194.4, 166.6, 164.7, 161.4, 135.3, 115.1, 108.9, 101.2, 68.7, 64.3, 29.74, 29.69, 29.68.29.63, 29.4,29.3, 29.1, 28.64, 28.57, 26.1, 26.0. LRMS (ESI ') miz 379 (M + H)'. HRMS (ESI ') miz 378.241 7 (C "H" O, requires 378.2406).
    5 4- «14-Bromotetradecyl) oxy) -2-hydroxy-6-methylbenzoic acid (14h)14h is isolated using hexane / EIOAc: 95/5. White solid (155 mg, 26%); PI = 62.5
    64.7 oC; HPLC (UV)> 95%. 'H NMR (300 MHz, CDCI,) or 11.88 (s, 1 H, COOH), 6.28 (d, J = 2.8 Hz, 1H, ArH), 6.22 (d, J = 2.8 Hz, 1H, ArH), 5.38 (s, 1 H, ArOH), 4.33 (1, J = 6.5 Hz, 2H, CH, O), 3.41 (1, J = 6.8 Hz, 2H, CH, Br), 2.50 (s, 3H, ArCH,) , 1.93 -1.67 (m,
    10 4H, CH, CH, O, CH, CH, Br), 1.52-1.14 (m, 20H, 10xCH,). "c NMR (75 MHz, CDCI,) or 172.0, 165.5, 160.3, 144.1, 111 .4, 106.0, 101.4, 65.7, 34.2, 33.0, 29.7, 29.7, 29.67, 29.61, 29.3, 28.9, 28.7, 28.3, 26.3 , 24.6. LRMS (ESI ') miz 443, 445 (M + Hl'. HRMS (ESI ') miz 442.1709 (C "H" BrO, requires 442. 1719).
    15 4,4 '- (lelradecane-1, 14-diylbis (oxy)) bis (2-melylbenzoic acid) (16h)
    16h is isolated using hexane / EtOAc: 90/10. White solid (15 mg, 6.6%); Pf = 42 -46
    oC; HPLC (U V)> 95%. 'H NMR (300 MHz, CD, OD) or 7.82 (d, J = 9.3 Hz, 2H, 2xArH), 6.74 (m, 2H, 2 xArH), 6.64 (d, J = 6.6 Hz, 2H, 2xArH), 4.21 (1, J = 6.5 Hz, 4H, 2x CH, O),
    2.51 (s, 6H, 2xArCH,), 1.73 (1, J = 7.1 Hz, 4H, 2xCH, CH, O), 1.49 -1.03 (m, 20H,
    20 10xCH,). "c NMR (75 MHz, CD, OD) or 168.8, 161.5, 143.8, 133.9, 121.3, 118.9, 113.3, 65.3, 30.3, 30.22, 30.20, 29.9, 29.4, 26.8, 22.6. LRMS (ES n miz 499 (M + H) '. HRMS (ESI') miz 498.2995 (C, oH., O, requires 498.2981).
    4,4 '- (tetradecane-1, 14-dii Ibis (oxy)) bis (2-hydroxybenzaldehyde) (17h) 25 17h is isolated using hexane / EIOAc: 97/3. White solid (12 mg, 3%); PI = 111 .0
    112.8 oC; HPLC (UV)> 95%. 'H NMR (300 MHz, CDCI,) or 11.46 (s, 2H, 2xCHO), 9.69 (s, 2H, 2xOH), 7.40 (d, J = 8.7 Hz, 2H, 2xArH), 6.51 (dd, J = 2.4 , 8.7 Hz, 2H, 2xArH), 6.39 (d, J = 2.4 Hz, 2H, 2xArH), 3.98 (1, J = 6.6 Hz, 4H, 2xCH, O), 1.83 -1.20 (m, 24H,
    12x CH,). "c NMR (75 MHz, CDCI,) or 194.4, 166.6, 164.7, 135.3, 115.2, 108.9, 101.2, 30 68.8.29.8.29.77, 29.71, 29.5,29.1, 26.1. LRMS (ESI ') miz 471 (M + H) '. HRMS (ESI')
    miz 470.2667 (C2sH380 6 requires 470.2668).
    4,4 '- (tetradecane-1,14-diylbis (oxy)) bis (2-hydroxy-6-meti Ibenzoic acid) (18h)
    18h is isolated using hexane / EtOAc: 85/15. White solid (29.6 mg, 5%); HPLC (UV) 89%. 'H NMR (300 MHz, DMSO-d,) OR 10.90 (sa, 2H), 10.02 (sa, 2H), 6.25 -6.06 (m, 4H), 4.22 (1, J = 6.5 Hz, 4H), 2.30 ( s, 6H), 1.73 -1.58 (m, 4H), 1.46 -1.16 (m, 20H). BC NMR (75 MHz, CDCI, + CD, OD) OR 170.2,161.8, 161.3, 141.1,110.5, 107.0,
    5 100.5,64.8,29.05,28.97,28.6,28.1, 25.6, 22.5, 21.3. LRMS (ES l ') miz 531 (M + H)'.
    Example 2. Tests of TAO inhibitory capacity and trypanacidal activity of the compounds of the invention
    The compounds were evaluated as inhibitors of purified recombinant TAO enzyme in the ubiquinol oxidase assay. In this assay, ubiquinoloxidase activity is measured by recording the absorbance change of ubiquinol-1 at 278 nm in the presence of rTAO in Tris-HCI (pH 7.4) at 25 oC. The rTAO enzyme was purified following the protocol of Kido et al (8iochim. 8iophys. Acta, 8ioenerg. 2010, 1797,
    15 4: 443-450).
    In vitro assays of activity on the parasite T. b. brucei (trypomastigotes of the wild and resistant strains Lister 427 and 848, respectively) were performed following the method previously described (Rodenko, et al., Antimicrob. Agents Chemother. 2007,
    20 51, 3796-3802) using the "Alamar blue" test.
    Inhibition of TAO The compounds object of the present patent are potent inhibitors of rTAO with leso values in the nanomolar range (6.9-150 nM). These values are the same
    25 orders that the reference compound ascofuranone and up to 1000 times more potent than the reference drug SHAM (Table 1).
    It is worth noting the potentiating effect of the TAO inhibitory activity of the R2 substituent (formula 1) compared to the unsubstituted compound (eg Comparison of the 30 values of 8t and 1St with 4- (decyloxy) -2-hydroxybenzoic acid) .
    These compounds are particularly interesting when binding to an allosteric site of TAO, near the interface with the inner membrane of the mitochondria.
    Trypanocidal activity in the presence of glycerol
    Co-incubation with glycerol (an anaerobic glycolysis inhibitor) increases by
    significantly the trypanocidal activity of the compounds object of this
    patent, or SHAM, while having no effect on drug activity
    reference pentamidine and diminacene (Table 1). This indicates that TAO is a target
    of said compounds in T. brucei.
    Table 1. ECso values (¡..1M) on T. b. bruceiWT in the presence of glycerol (5 mM) and ICso values (... 1M) for the inhibition of the purified rTAO enzyme.
    Rel CompoundT. b. bruce 'FR 'rTAOc
    TA031 796.2 ± 0.30.420.0174
    TA034 7i11 .1 ± 0.60.240.0124
    TA026 8117.5 ± 0.90.550.15
    TA033 8i5.1 ± 0.50.430.0144
    TA029 15112.2 ± 0.60.250.0069
    TA022 15913.6 ± 1.20.410.007
    TA030 15h15.9 ± 1.50.380.0157
    TA032 15i12.4 ± 0.30.460.0123
    SHAM ' 7.0 ± 0.30.185.9
    4-DHBM9 > 50
    A-4-DHS ' 1.9
    AF ' 0.002
    Pentamidine 0.004 ± 0.00061.32
    Diminacene 0.063 ± 0.0020.97
    ,
    10 aTripomastlgotes of T. b. brucel s427 (n -3). Resistance factor relative to strain s427 without glycerol: FR = ECso (in the presence of glycerol) / ECso (without glycerol). e Recombinant TAO enzyme purified from T. b. brucei (n = 3). d Salicylic hydroxamic acid.
    and 4- (Decyloxy) -2-methyl hydroxybenzoate. f 4- (decyloxy) -2-hydroxybenzoic acid. 9 Ascofuranone.
    Trypacidal activity on T. brucei and T. congolense, and cytotoxicity
    5 The compounds object of this patent show activities on T. brucei in the micromolar range (3.8-49 iJM) being 10h and 13h up to 10 times more potent than SHAM in this test. These compounds are also active on the resistant strain B48 (resistance factor == 1) and therefore do not show cross-resistance with other trypanocidal drugs such as pentamidine and diminacene. It should be noted
    10 the potentiating effect on gut activity born from the presence of a methylene chain of more than 4 carbons. In fact, the compound of structure 7e with a 4-carbon methylene chain (7e: Z = (CH 2k R1 = OH, R2 = Br, R3 = OH, R4 = H) does not show trypanocidal activity at the concentration of 400 iJM (concentration highest tested) while the 6-carbon methylene chain analog (7f: Z = 15 (CH2) 4, R1 = OH, R2 = Br, R3 = OH, R4 = H) has an ECso = 17.7 IJM over T. brucei WT (Table 2).
    Table 2. EC50 values (iJM) on T. b. brucei, T. congoJense and cytotoxicity on human cells.
    T. bruceiT. brucei T.CellsIS '
    Compound WT '84SbFR 'congo / enseHF F "
    EC ", (~ M)EC ", (~ M) CC '"(~ M)
    TA041 7117.7 ± 0.520.5 ± 1.61.20ndnd
    TA031 7914.5 ± 1.014.9 ± 1.01.0259.1 ± 3.7> 400> 28
    TA034 7i45.7 ± 1.549 ± 0.61.07> 100> 400> 9
    TA026 8131.8 ± 0.922.1 ± 4.00.69> 100> 400> 12
    TA033 8i11 .9 ± 1.613.0 ± 3.71.21> 100> 400> 34
    TA038 9h14.4 ± 0.114.4 ± 0.21.0ndnd
    TA039 10h4.1 ± 0.14.44 ± 0.021.1ndnd
    TA051 11 h14.7 ± 0.1417.3 ± 0.21.2ndnd
    TA035 12h17.6 ± 0.515.5 ± 0.60.9ndnd
    TA037 13h3.8 ± 0.13.6 ± 0.21.0ndnd
    TA043 2pm14.6 ± 0.215.6 ± 0.21.1ndnd
    TA029 15149.0 ± 7.641.6 ± 5.50.85> 100> 400> 8
    TA022 15932.9 ± 0.933.6 ± 1.01.02> 100> 400> 12
    TA030 15h42.1 ± 2.836.5 ± 0.90.67> 100> 400> 9
    TA032 15i26.7 ± 5.531.9 ± 8.01.20> 100> 400> 15
    4-DHBM 135 ± 35nd> 400
    A-4-DHB! 1 > 100nd> 400
    SHAM " 49.4 ± 4.2ndnd
    PAO ' ndnd0.036 ± 0.004
    a Tripomastigotes of T. b. brucei s427 (n> 4). b Strain of T. b. Pentamidine and diminacene resistant brucei. e Resistance factor = ECso (B48) / EC50 (s427). d Cytotoxicity on human HFF (Human Foreskin Fibroblast) cells (n = 2); no cytotoxic activity is observed up to 50 IJM. and selectivity index = ECso (T. brucel) / CC50. r 4- (Decyloxy) -2-methyl hydroxybenzoate. g
    5 4- (decyloxy) -2-hydroxybenzoic acid. h Salicylic hydroxamic acid. Phenylarsine oxide.
    Example 3. RTAO binding kinetics determined by Surface Plasmon Resonance (SPR) of the compounds of the invention
    The kinetics of rTAO binding of the compounds was determined in a Biacore T200 instrument by means of "single-cycle kinetics" tests. As a representative example of this series of compounds, the values of association and dissociation constants of 15i (TA032) with rTAO measured by SPR are presented. The fact that the sensograms fit a heterogeneous ligand model better than the
    Model 1: 1 binding (Table 3) suggests that the compounds bind to an allosteric site of TAO, other than the active site of ubiquinol. These results are in agreement with ca-crystallization data of 1St with rTAO that demonstrate that 1St does not bind to the active TAO site but to another enzyme site that interacts with membrane lipids.
    20 Table 3. Association and dissociation constant values of 15i (TA032) with rTAO measured by SPR
    Model K l (l / Ms) •K d l (l / s)Kol (nM)K 2 (l / Ms) •Kl (l / s)Chi (RU ')U-value
    1: 1 union 3,964x l 02.319x l 0584.90.4132
    Flirting 2,804x 109.829x 10 '350.61,579x 1 O3,561xl00.0856N / A
    heterogeneous
    Detection limit: K = 10 -5xl0 (l / Ms); K = 10 -1 (lIs)
    . ,
    Example 4. Efficiency of ligands (LE) and binding efficiency index (BEI) of the compounds of the invention
    5 The efficiency of the ligands (LE) and the binding efficiency index (BEI) at rTAO of the compounds of the invention were calculated to determine whether they were good drug candidates (Table 4). Normally, a compound with LE> 0.3 is considered as a good drug candidate. The higher the EIB, the better. Six of the seven compounds have an LE> 0.3 so they can be considered drug candidates.
    Table 4
    Compound plCsoNHAYOUpKDEIB
    TA031 (7g) 7,759240.4536,05115.1
    TA034 (7i) 7,907280.3956,76414.8
    TA033 (8i) 7,841300.3666,89516.3
    TA029 (15t) 8,161320.3576,39814.3
    TA022 (15g) 8,1553. 40.3366,68014.1
    TA030 (15h) 7,804360.3036,53213.0
    TA032 (15i) 7,910380.2916,45512.2
    AF 9,921290.47910.3224.5
    ""
    .
    plCso - (logICso), NHA. atoms that are not hydrogen (Non hydrogen atoms), LE. Efficiency
    of the ligand rLigand efficiencyH) in kcal / mol / NHA (calculated as 1.4xpICsoINHA); pKo: ;;
    (logKo); EIB: Binding efficiency index [calculated as pKcJMW
    15 (kDa)), AF: Ascofuranone.
    权利要求:
    Claims (16)
    [1]
    1. Compound of general formula (1), pharmaceutically acceptable salt, or solvate thereof
    where: R1 is selected from H, OH, NHOH, NHz and NH-C1-C4 alkyl: R, or
     -Cl'R.
    Rz is selected from halogen, EIGHT, and 1--0 b Ro
    R3 is selected from OH, halogen, and C1-C4 alkyl; R4 is selected from H and C1-C4 alkyl; Z is selected from - (CH2) n where n is an integer from
    6 and 20, Y ~ m where m is an integer between 1 and 3;
    15 on the condition that when
    R1 is H, R3 is OH, Rt is H and R2 is Sr, n is different from 6, 8, 9, 10 and 12; R, or
     -Cl'R,
    R1 is H, R3 is OH, Rt is H and R2 is / '0 b Ro, n is different from 6, 8,10 and 12;
    or
    R, or
    b>
    20 R1 is OH, R3 is OH, Rt is H and R2 is 1- "0 ¿. ~, N is different from 6 and 10.
    [2]
    2. Compound according to claim 1, wherein R1 is selected from H and OH, and preferably R1 is OH.
    [3]
    3. Compound according to any of claims 1-2, wherein R2 is halogen, preferably bromine.
    [4]
    Four. Compound according to any of claims 1-2, wherein R2 is EIGHT.
    [5]
    5. Compound according to any of claims 1-2, wherein R2 is
    [6]
    6. Compound according to any one of claims 1 to 5, wherein RJ is selected from F, OH and CHJ, and preferably RJ is OH.
    [7]
    7. Compound according to any one of claims 1 to 6, wherein R, is H.
    [8]
    8. Compound according to any one of claims 1 to 7, wherein Z is - (CH2k
    15 where n is a number between 8 and 20, and preferably n is an integer and even number between 10 and 16.
    [9]
    9. Compound according to claim 1 selected from the list comprising: 4- «1 O-Bromodeci I) oxy) -2-hydroxybenzoic acid,
    20 4 - ((1 0- (formyloxy) decyl) oxy) -2-hydroxybenzoic acid, 4- "12-bromododecyl) oxy) -2-hydroxybenzoic acid, 4-" 12- (formyloxy) dodecyl) oxy) - 2-hydroxybenzoic acid, 4,4 '- (dodecane-1, 12-diylbis (oxy)) bis (2-hydroxybenzoic acid), 4- "14-bromotetradecyl) oxy) -2-hydroxybenzoic acid,
    25 4- "14- (formyloxy) tetradecyl) oxy) -2-hydroxybenzoic acid, 4,4 '- (tetradecane-1, 14-diylbis (oxy)) bis (2-hydroxybenzoic acid), 4-" 14- bromotetradecyl) oxy) -2-methylbenzoic acid, 4- "14- (formyloxy) tetradecyl) oxy) -2-methylbenzoic acid, 4-" 14-bromotetradecyl) oxy) -2-fluorobenzoic acid,
    30 4- ((14-bromotetradecyl) oxy) -2-hydroxybenzane Idehido, 14- (4-formyl-3-hydroxyphenoxy) tetradecyl formate, Acid or 4- "14-b romotetradeci I) oxy) -2 -hydroxy - 6-methyl benzoi co, 4,4 '- (tetradecane-1, 14-diylbis (oxy)) bis (2-methylbenzoic), 4,4' - (tetradecane-1, 14-diylbis (oxy »bis (2) -hydroxybenzaldehyde), 4,4 '- (tetradecane-1, 14-diylbis (oxy)) bis (2-hydroxy-6-methylbenzoic acid), 4- "16-bromohexadecyl) oxy) -2-h idroxybenzoic acid,
    5 4- "16- (Formyloxy) hexadecyl) oxy) -2-hydroxybenzoic acid and4,4 '- (hexadecane-1, 16-diylbis (oxy)) bis (2-hydroxybenzoic acid).
    [10]
    10. Pharmaceutical composition comprising a compound of general formula (1)
    described according to any one of claims 1 to 9, together with a pharmaceutically acceptable carrier.
    [11]
    11. Composition according to claim 10 which further comprises another antiparasitic active ingredient.
    12. Use of a compound of general formula (1) described according to any of claims 1 to 9 for the preparation of a medicament.
    [13]
    13. Use of a compound of general formula (1) described according to any of the
    claims 1 to 9 for the preparation of a medicament for prevention 20 and / or the treatment of diseases caused by parasites or fungi.
    [14]
    14. Use according to claim 13, wherein the disease is a disease caused by protozoan parasites.
    15. Use according to any of claims 12 to 14, wherein the diseases are diseases caused by a parasite of the genus Trypanosoma or Cryptosporidium.
    [16]
    16. Use according to claim 15, wherein the parasites are of the species
    30 Trypanosoma brucai, Trypanosoma congo / ansa, Trypanosoma aquinum, Trypanosoma equiperdum, Trypanosoma evansi, Trypanosoma vivax, Cryptosporidium parvum.
    [17]
    17. Use according to claim 13, wherein the disease is a disease caused by a fungus of the genus Candida.
    Use according to claim 17, wherein the fungus is Gandida albicans.
    [19]
    19. Use according to any of claims 13 to 18, wherein the diseases occur in animals, preferably in a mammal.
    Use according to any of claims 13 to 19, wherein the disease is selected from human African trypanosomiasis (sleeping sickness), animal trypanosomiasis, cryptosporidiosis, or candidiasis.
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    WO2018073474A1|2018-04-26|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    JP2012097060A|2010-11-01|2012-05-24|Tottori Univ|Novel dihydroxybenzene derivative and antiprotozoal agent comprising the same as active ingredient|
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