WO2019102054A1 - Non-glycosidic analogues of alpha-galactosylceramide as nkt cell activators - Google Patents

Non-glycosidic analogues of alpha-galactosylceramide as nkt cell activators Download PDF

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WO2019102054A1
WO2019102054A1 PCT/ES2018/070753 ES2018070753W WO2019102054A1 WO 2019102054 A1 WO2019102054 A1 WO 2019102054A1 ES 2018070753 W ES2018070753 W ES 2018070753W WO 2019102054 A1 WO2019102054 A1 WO 2019102054A1
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dihydroxy
octadecan
tetracos
hydroxymethyl
dihydroxyoctadecyl
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PCT/ES2018/070753
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Spanish (es)
French (fr)
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Amadeu Llebaria Soldevila
Roser BORRAS TUDURÍ
Carme Serra Comas
Anna ALCAIDE LÓPEZ
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Consejo Superior De Investigaciones Científicas (Csic)
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Definitions

  • the present invention relates to non-glycosidic derivatives of alpha-galactosylceramide (alpha-GalCer) as well as their pharmaceutical compositions and their use in therapy, particularly as a single therapy or as adjuvants for vaccines, antibodies or cellular immunotherapies in cancer, as well as in infections or in autoimmune diseases.
  • alpha-GalCer alpha-galactosylceramide
  • Natural killer T cells are a class of lymphocytes that regulate a wide range of immune responses. NKT cells recognize glycolipid-like antigens presented by MHC CD1d proteins and participate in various immune responses by promoting cytokine secretion. The role of these cells has been described in the regulation of autoimmunity, the response to tumors, microbial infections and the pathogenesis of inflammatory processes such as asthma.
  • NKT invariant NKT cells
  • NKT cells possess a TCR-a chain (Val4 / Jal8 in mice and Va24 / Jal8 in humans)
  • NKT cells secrete different Th1 type cytokines (such as, IFN-gamma, IL-2) and Th2 (for example, IL-4, IL-6) in response to the glycolipid stimulation presented by the CD1d protein present in cells antigen presenting agents (Arase, H. et al Eur. J.
  • cytokines can subsequently transactivate other cells of the immune system such as dendritic cells, CD4 + and CD8 + T lymphocytes, natural killer cells or B cells, maintaining characteristics of innate and adaptive immunity (Eberl, G et al J. Immunol. 2000, 165, 4305).
  • alpha-GalCer The synthetic glycolipid alpha-galactosylceramide (alpha-GalCer) was the first known antigen presented by CD1d that stimulates the invariant T-cell receptor (TCR), expressed by NKT cells.
  • alpha-GalCer is an optimized structural analog of antitumour compounds isolated from marine sponges that contains a galactose attached to the primary hydroxyl of phytoceramide in alpha configuration, and which is acylated in nitrogen with long-chain fatty acids. Since its discovery, alpha-GalCer has been the antigen prototype for the stimulation of NKT cells, although other glycolipids that act as antigens presented by CD1 proteins have also been identified (Kawano, T.
  • alpha-GalCer in the stimulation of NKT cells originates a series of biological responses, derived from the simultaneous release of Th1 and Th2 cytokines, which exert opposite cellular effects and determine an anergy phase before recovering the homeostatic balance , limiting the efficacy of alpha-GalCer as an immunomodulator.
  • Th1 / Th2 balance of the cytokines induced by NKT cells stimulated by alpha-GalCer may limit the clinical applications of this molecule (Tahir, SM et al J. Immunol., 2001, 167, 4046; Dhodapkar, MVet al. J. Exp. Med. 2003, 197, 1667; Giaccone, G. et al Clin Cancer Res. 2002, 8, 3702; Bricard, G. et al J. Immunol., 2009, 182, 5140).
  • the extraordinary power of stimulation of NKT cells by alpha-GalCer is not without problems, a fact that has driven the design and synthesis of similar compounds in order to improve their biological properties, even at the expense of obtaining less potent compounds , and directed mainly to the modulation of the Th1 / Th2 ratio in the production of induced cytokines.
  • glycolipids with substituted acyl groups can preferentially induce Th1 cytokines and have potent antitumor activity in mice (Chang, YJet al Proc. Nati, Acad Sci USA USA, 104, 10299; Wu, et al Proc. Nati. Acad. Sci. USA 2011, 108, 17275).
  • Some alpha-GalCer analogues with non-glycosidic linear groups are capable of activating NKT cells and induce immunological responses, demonstrating that modulation of glycolipid effects is possible after the introduction of structural modifications in the alpha-galactose ring.
  • GalCer JD Silk et al., J Immunol 2008, 180, 6452; RW Franck, Acc Chem Res 2006, 39, 692, Harrak et al J Am Chem Soc. 2011, 133, 12079, Kerzerho et al J Immunol. 2012, 188, 2254).
  • glycolipids and their analogs are the difference in activity of these compounds in the stimulation of NKT cells from different species (Birkholz et al. J Biol Chem. 2015, 290, 17206).
  • WO2015035337 claims that glucose-derived glycosphingolipids possess greater potency in the stimulation of human NKT cells with respect to mouse NKT cells, contrary to what happens with the corresponding galactose derivatives.
  • Another example of different activity between human and mouse NKT cells occurs with the alpha-C-GalCer derivative (Franck, RW C R Chim 2012, 15, 46, Li X et al J Immunol., 2009, 183).
  • the present invention relates to non-glycosidic analogues of alpha-GalCer of formula (I), in which the glycosidic group has been replaced by an aromatic ring.
  • These non-glycosidic derivatives have shown strong in vitro activity to stimulate NKT cells by inducing the release of cytokines.
  • the compounds have also shown activity in the stimulation of human NKT cells.
  • NKT cells Due to the role of NKT cells, these compounds may have application in cancer immunotherapy for cooperative stimulation of the patient's immune system and as vaccine adjuvants, as well as in autoimmune diseases or infections.
  • the modulation of the Th1 or Th2 response compared to alpha-GalCer depends on the structure of the compound
  • NKT cells are unconventional regulators of innate and adaptive immunity.
  • the activation of NKT initiates a cascade of adjuvants that reinforces innate immunity and promotes the subsequent adaptive immune response.
  • the present invention relates to a compound of formula (I):
  • A represents aryl or heteroaryl, optionally substituted by one, two or three R c groups independently selected and which may be optionally linked together to form a 3- to 8-membered ring;
  • Z represents S, O or NR ⁇
  • R a represents C 9 -C 30 alkyl, C 9 -C 30 alkenyl or C 9 -C 30 alkynyl, where R a is optionally substituted by one or more R 2 groups;
  • R b represents C 10 -C 16 alkyl, C 10 -C 16 alkenyl or C 10 -C 16 alkynyl, where R b is optionally substituted by one or more R n groups; each R c independently represents Y, halogen, -CN, -N0 2 , -N 3 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, where the groups C r C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl independently are optionally substituted by one or more R 7 substituents, and the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups independently are optionally substituted by one or more R 8 groups;
  • Y represents -OR 9 , -COR 9 , -NR I R 9 , -C0 2 R 9 , -OCOR 9 , -CONR ⁇ Rg, -NR I COR 9 , -S0 2 R 9 , -NR I S0 2 R 9 , -S0 2 NR I R 9 , -NR I CONR I R 9 , -OCONR ⁇ Rg or -NRiC0 2 R 9 ; each Ri independently represents H or C r C 4 alkyl; each R 2 independently represents halogen, -N 3 , -NR 1 COR 4 , -OR 4 , -CONR 1 R 4 , -NR 1 S0 2 R 4 , -NR 1 CONR 1 R 4 , -OCONR 1 R 4 , - NR 1 C0 2 R 4 , aryl, heteroaryl or cycloalkyl, wherein the aryl, heteroaryl and cycloalkyl groups independently
  • the invention relates to the compound of formula (I), wherein A represents phenyl, thiophenyl or pyridyl, and is optionally substituted by one, two or three R c groups. In another embodiment the invention relates to the compound of formula (I), wherein A represents phenyl, thiophenyl or pyridyl.
  • the invention relates to the compound of formula (I), wherein R a represents C 9 -C 30 alkyl or C 9 -C 30 alkenyl, wherein R a is optionally substituted by one or more R 2 groups.
  • the invention relates to the compound of formula (I), wherein R a represents C 9 -C 30 alkyl or C 9 -C 30 alkenyl.
  • the invention relates to the compound of formula (I) wherein R a is C 9 - C 30 alkyl and preferably C 9 -C 30 alkyl represents C 9 alkyl, C ⁇ or alkyl, C 15 Cu alkyl or C 25 alkyl.
  • the invention relates to the compound of formula (I), wherein R a is C 9 -C 30 alkenyl and preferably C 9 -C 30 alkenyl is C 23 alkenyl.
  • the invention relates to the compound of formula (I), wherein R b is C 10 -C 16 alkyl, and preferably C 10 -C 16 alkyl is C 14 alkyl.
  • the invention relates to the compound of formula (I), wherein R c represents Y, halogen, -CN, C r C 4 alkyl or aryl.
  • the invention relates to the compound of formula (I), wherein Y represents -OR 9 , -C0 2 R 9 , -CONR ⁇ g, -NR ⁇ ORg, -S0 2 Rg or S0 2 NR 1 R 9 .
  • the invention relates to the compound of formula (I), wherein:
  • R c represents Y, halogen, -CN, C r C 4 alkyl or aryl
  • Y represents -ORg, -C0 2 R 9 , -CONR ⁇ g, -NR ⁇ ORg, -S0 2 R 9 or S0 2 NR 1 R 9 .
  • the invention relates to the compound of formula (I), wherein:
  • R c represents Y, halogen, -CN, C r C 4 alkyl or aryl
  • Y represents -OR 9 , -C0 2 R 9 , -CONR ⁇ g, -NR ⁇ ORg, -S0 2 R 9 or S0 2 NR 1 R 9 ;
  • Ri is H; Y
  • R 9 represents H or Ci alkyl.
  • the invention relates to the compound of formula (I), wherein:
  • R c represents Y, halogen, -CN, C r C 4 alkyl or aryl
  • Ci alkyl Ci alkyl
  • halogen is chlorine
  • Aryl is phenyl
  • the invention relates to the compound of formula (I), wherein R 2 represents -NR ⁇ COR ⁇ -NR ⁇ SO ⁇ O aryl.
  • the invention relates to the compound of formula (I), wherein R 3 represents -OR 4 or halogen, and preferably wherein R 3 represents -OR 4 or fluorine.
  • the invention relates to the compound of formula (I) wherein R 4 represents C ⁇ or alkyl, Ci 2 alkyl, C ⁇ or alkenyl, C ⁇ or alkynyl or aryl.
  • the invention relates to the compound of formula (I), wherein R 6 represents Ci alkyl or halogen, and preferably wherein R 6 represents Ci alkyl or fluorine.
  • the invention relates to the compound of formula (I), wherein: R 7 is Y; and
  • the invention relates to the compound of formula (I), wherein R 8 is halogen, and preferably wherein R 8 is fluorine or chlorine, and even more preferably wherein R 8 is fluorine.
  • the invention relates to the compound of formula (I), wherein R g represents H or Ci alkyl.
  • the invention relates to a compound of formula (I) selected from the list of compounds 1-1 to I-60.
  • the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof selected from:
  • alkyl refers to saturated straight and branched chain hydrocarbon chains containing the number of carbon atoms indicated in each case throughout of the invention and linked to the rest of the molecules through a single bond.
  • alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tere-butyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl , decyl, dodecyl and their various branched chain isomers.
  • the alkyl groups may be optionally substituted by one or more substituents as indicated in each case throughout the invention.
  • alkenyl refers to both straight and branched chain hydrocarbon chains containing one or more carbon-carbon double bonds, containing the number of carbon atoms indicated in each case throughout the invention and linked to the rest of the molecules through a single bond.
  • alkenyl groups are vinyl, 1-propenyl, allyl, isoprenyl, 2-butenyl, 1,3-butadienyl and their various branched chain isomers.
  • the alkenyl groups may be optionally substituted by one or more substituents as indicated in each case throughout the invention.
  • alkynyl refers to both straight chain and branched hydrocarbon chains containing one or more triple carbon-carbon bonds, containing the number of carbon atoms indicated in each case throughout the invention and linked to the rest of the molecules through a single bond.
  • alkynyl groups are ethynyl and 1-propynyl.
  • the alkynyl groups may be optionally substituted by one or more substituents as indicated in each case throughout the invention.
  • cycloalkyl refers to saturated or partially saturated monocyclic or bicyclic hydrocarbon groups, containing a total of 3 to 10 carbon atoms forming part of the cycle system.
  • Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and adamantyl.
  • the cycloalkyl groups may be optionally substituted by one or more substituents as indicated in each case throughout the invention.
  • heterocycloalkyl refers to monocyclic or bicyclic, saturated or partially saturated groups, containing a total of 3 to 10 members that are part of the system of cycles, consisting of carbon atoms and between 1 and 3 heteroatoms selected from N, O and S.
  • heterocycloalkyl groups are furanyl, piperidinyl, piperazinyl, tetrahydrofuranyl and morpholinyl.
  • the heterocycloalkyl groups may be optionally substituted by one or more substituents as indicated in each case throughout the invention.
  • aryl refers to monocyclic, bicyclic or tricyclic aromatic hydrocarbon groups containing from 6 to 14 carbons that are part of the cycle system.
  • aryl groups are phenyl, naphthyl (including 1-naphthyl and 2-naphthyl), indenyl, phenanthryl and anthracyl.
  • the aryl groups may be optionally substituted by one or more substituents as indicated in each case throughout the invention.
  • heteroaryl refers to monocyclic, bicyclic or condensed tricyclic aromatic hydrocarbon groups containing from 5 to 14 members that are part of the cycle system, which consists of carbon atoms and between 1 and 4 heteroatoms selected from N, O and S.
  • heteroaryl groups are thiazolyl, benzimidazolyl, benzothiazolyl, isothiazolyl, indolyl, pyridyl, pyrimidyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiophenyl .
  • heteroaryl groups may be optionally substituted by one or more substituents as indicated in each case throughout the invention.
  • halogen as used in the present invention, alone or as part of another group, refers to chlorine, bromine, fluorine and iodine.
  • Another aspect of the present invention relates to the use of a compound of formula
  • A, Z, R a , R b and R c have the meaning described in the first aspect of the invention, for the manufacture of a medicament.
  • Another aspect of the present invention relates to the use of a compound of formula
  • A, Z, R a , R b and R c have the meaning described in the first aspect of the invention, for the manufacture of a medicament for the treatment and / or prevention of diseases through the stimulation of NKT cells, preferably for the manufacture of a medicament for the treatment and / or prevention of autoimmune diseases, inflammatory diseases, cancer and infections caused by pathogenic microorganisms.
  • the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament wherein the medicament is a vaccine or a vaccination adjuvant.
  • the invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof where the autoimmune or inflammatory diseases are selected from the list comprising asthma, chronic obstructive pulmonary disease (COPD), chronic colitis, allergies, systemic lupus erythematosus, diabetes mellitus type 1, multiple sclerosis, Sjögren's syndrome and rheumatoid arthritis.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic colitis
  • allergies systemic lupus erythematosus
  • diabetes mellitus type 1 multiple sclerosis
  • Sjögren's syndrome and rheumatoid arthritis.
  • the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the infectious diseases caused by pathogenic microorganisms are selected from the list comprising viral infections such as influenza, AIDS and hepatitis; bacterial infections such as chlamydiosis, tuberculosis, streptococcosis and pseudomoniasis; and parasitic infections such as leishmaniasis, malaria and trypanosomiasis.
  • viral infections such as influenza, AIDS and hepatitis
  • bacterial infections such as chlamydiosis, tuberculosis, streptococcosis and pseudomoniasis
  • parasitic infections such as leishmaniasis, malaria and trypanosomiasis.
  • the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the list comprising breast cancer, gynecological cancers, colon cancer, prostate cancer, cancer. of skin, hepatocellular cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, bladder cancer, liver cancer, urinary tract cancer, thyroid cancer, kidney cancer, melanoma, brain cancer, sarcoma, lymphoma and leukemia.
  • the cancer is selected from the list comprising breast cancer, gynecological cancers, colon cancer, prostate cancer, cancer. of skin, hepatocellular cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, bladder cancer, liver cancer, urinary tract cancer, thyroid cancer, kidney cancer, melanoma, brain cancer, sarcoma, lymphoma and leukemia.
  • the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, selected from:
  • the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, selected from:
  • a medicament for the treatment and / or prevention of diseases through the stimulation of NKT cells preferably for the manufacture of a medicament for the treatment and / or prevention of autoimmune diseases, inflammatory diseases, cancer and infections caused by pathogenic microorganisms, preferably for the manufacture of a medicament wherein the medicament is a vaccine or a vaccination adjuvant, more preferably where:
  • - autoimmune or inflammatory diseases are selected from the list that includes asthma, chronic obstructive pulmonary disease (COPD), chronic colitis, allergies, systemic lupus erythematosus, diabetes mellitus type 1, multiple sclerosis, Sjögren's syndrome and rheumatoid arthritis,
  • Infectious diseases caused by pathogenic microorganisms are selected from the list that includes viral infections such as influenza, AIDS and hepatitis; bacterial infections such as chlamydiosis, tuberculosis, streptococcosis and pseudomoniasis; and parasitic infections such as leishmaniasis, malaria and trypanosomiasis, and
  • the cancer is selected from the list comprising breast cancer, gynecological cancers, colon cancer, prostate cancer, skin cancer, hepatocellular cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, bladder cancer, liver cancer, cancer of the urinary tract, thyroid cancer, kidney cancer, melanoma, brain cancer, sarcoma, lymphoma and leukemia.
  • Another aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament wherein the medicament is a vaccine or a vaccination adjuvant.
  • Another aspect of the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of diseases through the stimulation of NKT cells, preferably for treatment and / or prevention of autoimmune diseases, inflammatory diseases, cancer and infections caused by pathogenic microorganisms.
  • the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of autoimmune or inflammatory diseases selected from the list comprising asthma, chronic obstructive pulmonary disease ( COPD), chronic colitis, allergies, systemic lupus erythematosus, diabetes mellitus type 1, multiple sclerosis, Sjögren's syndrome and rheumatoid arthritis.
  • autoimmune or inflammatory diseases selected from the list comprising asthma, chronic obstructive pulmonary disease ( COPD), chronic colitis, allergies, systemic lupus erythematosus, diabetes mellitus type 1, multiple sclerosis, Sjögren's syndrome and rheumatoid arthritis.
  • the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of infectious diseases caused by pathogenic microorganisms selected from the list comprising viral infections such as influenza, AIDS or hepatitis; bacterial infections such as chlamydiosis, tuberculosis, streptococcosis or pseudomoniasis; and parasitic infections such as leishmaniasis, malaria or trypanosomiasis.
  • infectious diseases caused by pathogenic microorganisms selected from the list comprising viral infections such as influenza, AIDS or hepatitis; bacterial infections such as chlamydiosis, tuberculosis, streptococcosis or pseudomoniasis; and parasitic infections such as leishmaniasis, malaria or trypanosomiasis.
  • the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the cancer is selected from the list comprising breast cancer, gynecological cancers, cancer colon, prostate cancer, skin cancer, hepatocellular cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, bladder cancer, liver cancer, urinary tract cancer, thyroid cancer, kidney cancer, melanoma, cancer of brain, sarcoma, lymphoma and leukemia.
  • the cancer is selected from the list comprising breast cancer, gynecological cancers, cancer colon, prostate cancer, skin cancer, hepatocellular cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, bladder cancer, liver cancer, urinary tract cancer, thyroid cancer, kidney cancer, melanoma, cancer of brain, sarcoma, lymphoma and leukemia.
  • Another aspect of the present invention relates to a method of treatment and / or prevention of diseases in an individual through the stimulation of NKT cells or through the preparation of vaccination vaccines or adjuvants or other methods of activating the response of the system.
  • immunitary wherein these diseases may be autoimmune diseases, inflammatory diseases, cancer or infections caused by pathogenic microorganisms, which comprises administering to said individual a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention relates to the method of treatment and / or prevention of diseases defined above where the autoimmune or inflammatory diseases are selected from the list comprising asthma, chronic obstructive pulmonary disease (COPD), chronic colitis, allergies, systemic lupus erythematosus. , diabetes mellitus type 1, multiple sclerosis, Sjögren's syndrome and rheumatoid arthritis.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic colitis
  • allergies systemic lupus erythematosus.
  • diabetes mellitus type 1 multiple sclerosis
  • Sjögren's syndrome and rheumatoid arthritis.
  • the invention relates to the method of treatment and / or prevention of diseases defined above wherein the infectious diseases caused by pathogenic microorganisms are selected from the list comprising viral infections such as influenza, AIDS or hepatitis; bacterial infections such as chlamydiosis, tuberculosis, streptococcosis or pseudomoniasis; and parasitic infections like leishmaniosis, malaria or trypanosomiasis.
  • viral infections such as influenza, AIDS or hepatitis
  • bacterial infections such as chlamydiosis, tuberculosis, streptococcosis or pseudomoniasis
  • parasitic infections like leishmaniosis, malaria or trypanosomiasis.
  • the invention relates to the method of treatment and / or prevention of diseases defined above wherein the cancer is selected from the list comprising breast cancer, gynecological cancers, colon cancer, prostate cancer, skin cancer, hepatocellular cancer , lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, bladder cancer, liver cancer, urinary tract cancer, thyroid cancer, kidney cancer, melanoma, brain cancer, sarcoma, lymphoma and leukemia.
  • the cancer is selected from the list comprising breast cancer, gynecological cancers, colon cancer, prostate cancer, skin cancer, hepatocellular cancer , lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, bladder cancer, liver cancer, urinary tract cancer, thyroid cancer, kidney cancer, melanoma, brain cancer, sarcoma, lymphoma and leukemia.
  • the compounds of the present invention contain one or more basic nitrogens and could therefore form salts with acids, both organic and inorganic.
  • salts include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and salts with organic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid , glycolic acid, succinic acid and propionic acid, among others.
  • Some compounds of the present invention may contain one or more acidic protons and therefore may also form salts with bases.
  • salts include: salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminum, zinc, etc .; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, / V-methylglucamine, procaine and the like.
  • salts there is no limitation on the type of salt that can be used, with the proviso that when they are used for therapeutic purposes they are pharmaceutically acceptable.
  • pharmaceutically acceptable salts are meant those salts which, under medical criteria, are suitable for use in contact with the tissues of humans or other mammals without causing undue toxicity, irritation, allergic response or the like.
  • the pharmaceutically acceptable salts are well known to any person skilled in the art.
  • the salts of a compound of formula (I) can be obtained during the final isolation and purification of the compounds of the invention or they can be prepared by treatment of a compound of formula (I) with a sufficient amount of the desired acid or base to give the salt in a conventional manner.
  • the salts of the compounds of formula (I) can in turn be converted into other salts of compounds of formula (I) by exchange of ions by an ion exchange resin.
  • the compounds of formula (I) and their salts may differ in certain physical properties, but are equivalent for purposes of the invention. All salts of the compounds of formula (I) are included within the scope of the invention.
  • the compounds of the present invention can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as solvates.
  • solvate refers to a complex of variable stoichiometry formed by a solute (a compound of formula (I) or a salt thereof) and a solvent.
  • solvents include pharmaceutically acceptable solvents such as water, ethanol and the like.
  • a complex with water is known as a hydrate.
  • the solvates of the compounds of the invention (or their salts), including hydrates, are included within the scope of the invention.
  • the compounds of formula (I) can exist in different physical forms, i.e. in amorphous form and crystalline forms. Likewise, the compounds of the present invention may have the ability to crystallize in more than one way, a feature known as a polymorphism.
  • the polymorphs can be differentiated by several physical properties well known to those skilled in the art such as, for example, X-ray diffractograms, melting points or solubility. All physical forms of the compounds of formula (I), including all their polymorphic forms (“polymorphs”), are included within the scope of the present invention.
  • Some compounds of the present invention could exist in the form of several diastereoisomers and / or several optical isomers.
  • the diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization.
  • the optical isomers can be solved by the use of conventional optical resolution techniques, to give the optically pure isomers. This resolution can be made on the synthesis intermediates that are chiral or on the products of formula (I).
  • the optically pure isomers can also be obtained individually using enantiospecific syntheses.
  • the present invention covers both the individual isomers and their mixtures (for example racemic mixtures or mixtures of diastereomers), whether obtained by synthesis or by physically mixing them.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • the excipients must be "acceptable” in the sense of being compatible with the other ingredients of the composition and of not being harmful to whoever takes said composition.
  • the pharmaceutical composition further comprises another active ingredient.
  • the compounds of the present invention can be administered in the form of any pharmaceutical formulation, the nature of which, as is well known, will depend on the nature of the active ingredient and its route of administration.
  • any route of administration for example oral, parenteral, nasal, ocular, rectal, and topical can be used.
  • Solid compositions for oral administration include tablets, granules and capsules.
  • the manufacturing method is based on a simple mixture, dry granulation or wet granulation of the active principle with excipients.
  • excipients may be, for example, diluents such as lactose, microcrystalline cellulose, mannitol or calcium hydrogen phosphate; binding agents such as, for example, starch, gelatin or polyvinylpyrrolidone; disintegrants such as sodium carboxymethylstarch or croscarmellose sodium; and lubricating agents such as, for example, magnesium stearate, stearic acid or talc.
  • the tablets can also be coated with suitable excipients and by known techniques in order to delay their disintegration and absorption in the gastrointestinal tract and thus achieve a sustained action for a longer period of time, or simply to improve their organoleptic properties or their stability.
  • the active principle can also be incorporated by coating on inert pellets by the use of natural or synthetic film-forming polymers. It is also possible to carry out soft gelatine capsules, in which the active ingredient is mixed with water or with an oily medium, for example coconut oil, liquid paraffin or olive oil.
  • Powders and granules can be obtained for the preparation of oral suspensions by the addition of water, mixing the active principle with dispersing or wetting agents; suspensants and preservatives.
  • Other excipients may also be added, for example sweeteners, flavorings and colorants.
  • Liquid forms for oral administration may include emulsions, solutions, suspensions, syrups and elixirs containing commonly used inert diluents, such as distilled water, ethanol, sorbitol, glycerol, polyethylene glycols (macrogols) and propylene glycol.
  • Said compositions may also contain adjuvants such as wetting agents, suspending agents, sweeteners, flavorings, preservatives and pH regulators.
  • Injectable preparations for parenteral administration, comprise sterile solutions, suspensions or emulsions, in an aqueous or non-aqueous solvent such as propylene glycol, polyethylene glycol or vegetable oils. These compositions may also contain adjuvants, such as humectants, emulsifiers, dispersants and preservatives. They could be sterilized by any of the known methods or prepared as sterile solid compositions which will be dissolved in water or any other sterile injectable medium immediately before use. It is also possible to start from sterile raw materials and keep them in these conditions throughout the manufacturing process.
  • the active principle can be formulated preferably as a suppository in an oily base, such as for example vegetable oils or solid semi-synthetic glycerides, or in a hydrophilic base such as polyethylene glycols (macrogol).
  • an oily base such as for example vegetable oils or solid semi-synthetic glycerides
  • a hydrophilic base such as polyethylene glycols (macrogol).
  • the compounds of the invention can also be formulated for topical application for the treatment of pathologies in areas or organs accessible by this route, such as eyes, skin and intestinal tract.
  • Formulations include creams, lotions, gels, powders, solutions and patches in which the compound is dispersed or dissolved in suitable excipients.
  • the compound can be formulated in an aerosol form from where it is conveniently released with the use of suitable propellants.
  • Dosage and frequency of doses will vary depending on the nature and severity of the disease to be treated, the age, general condition and weight of the patient, as well as the particular compound administered and the route of administration, among other factors .
  • Protective group may be any known to one skilled in the art, such as, for example, without limitation, acetal, benzyl, trityl, tert-butyldiphenylsilyl (TBDPS) and other suitable protecting groups in each case (see Green, Protective Groups in Organic Chemistry, 1999, Ed. John Wiley &Sons);
  • Activating Group may be any known to one skilled in the art, such as, without limitation, chloride, bromide, nitrobenzensulfonyl (Ns), toluenesulfonyl (Ts), methylsulfonyl (Ms) or, naphthalenesulfonyl.
  • a first way (scheme 1) consists of the formation of type II intermediates by reaction of an activated acid (type 2 compounds) with the corresponding aziridines (type 1 compounds) in the presence, if necessary, of a tertiary organic base such as for example Et 3 N.
  • a tertiary organic base such as for example Et 3 N.
  • the acyl aziridine formed II reacts with compounds of type 3 in the presence of a base (DBU, K 2 C03, CsC0 3 ) giving rise to intermediate III.
  • DBU, K 2 C03, CsC0 3 a base
  • a second way (scheme 1) consists in obtaining the type IV intermediates by opening activated type 4 aziridines with type 3 compounds in the presence of inorganic bases, if necessary (Na 2 C0 3 , NaHCO 3 , Cs 2 C0 3 ).
  • the deprotection of the activating group of the amine leads to the type V intermediates.
  • the reaction of the intermediates V with the activated acids 2) leads to the same type III intermediates.
  • n alkyl, alkenyl, C9-C30 alkynyl
  • ACN Acetonitrile
  • AcOEt Ethyl Acetate
  • Anh. Anhydrous
  • CSA Camphorsulfonic Acid
  • DCM Dichloromethane
  • DMAP Dimethylaminopyridine
  • DMF Dimethylformamide
  • EDC 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide
  • Et 3 N Triethylamine
  • HPLC high resolution liquid chromatography; MeOH, Methanol; MS, Mass spectrometer; m / z, Mass / load ratio
  • ND Not determined
  • NHS N-hydroxysuccinimide
  • tBuOLi tert- Lithium butoxide
  • THF Tetrahydrofuran
  • the MS detector has operated in positive and negative electrospray ionization mode and has performed a m / z sweep of 50 to 1500 Da. 8 microliters of each sample were injected with a flow rate of 0.07 ml / min using the following solvents: A: Acetonitrile and B: Water in proportion 70% to 30% respectively during 2 min.
  • the MS detector has operated in positive and negative electrospray ionization mode and has performed a m / z sweep of 50 to 2000Da. 5 microliters of each sample was injected at 0.5mg / ml with a flow rate of 0.7 ml / min using the following solvents: A: Acetonitrile + 0.05% formic acid and B: Water + 0.05% formic acid in proportion 60% to 40% respectively for 2 min.
  • METHOD A Being the solvent A: Water + 0.05% formic acid and B: Acetonitrile + 0.05% formic acid, the mobile phase flow rate of 0.6ml / ml and a gradient of 5-100% B, 0-3min; 100% B, 3-6min; 100-5% B, 6-7min; 5% B, 7-10min.
  • METHOD B Being the solvent A: Water + 0.1% ammonium hydroxide and B: Acetonitrile + 0.1% ammonium hydroxide, the mobile phase flow rate of 0.6ml / ml and a gradient of 5-100% B, 0-3min; 100% B, 3-6min; 100-5% B, 6-7min; 5% B, 7- 10min.
  • the m / z values of the compounds correspond to (M + H) in positive mode unless otherwise indicated, where (M + 18) corresponds to (M + NH 4 ) and (M + 23) corresponds to (M) + Na), both in positive mode, and (M-1) corresponds to (MH) and (M + 45) corresponds to (M + HCOO), both in negative mode.
  • the compound of type 1 (1eq) was dissolved in DCM anh. and 2eq Et3N at -10 ° C was added. To the previous solution was added another solution of 1.2eq of the corresponding acyl chloride (compound of type 2) in DCM anh. - Final concentration of compound 1 at 0.05M. The mixture was left at room temperature and stirred overnight. The solvent was removed under reduced pressure and purified by silica gel column chromatography.
  • the type II intermediate (1eq) was placed in a tube suitable for microwave reactors together with the corresponding type 3 reagent (1, 2eq). ACN anh was added. at 0.1M concentration. Finally, an organic base (1, 2eq) was added. The mixture reacted in a microwave reactor at 150W and 100ps for variable times between 5 and 90 min. until total consumption of intermediate II. The solvent was removed under reduced pressure and the reaction crude was purified by silica gel column chromatography to obtain the corresponding intermediate III.
  • the type 2 compound was dissolved in ACM at 0.1M.
  • Compound type 4 (1, 2eq) and NaHCO 3 (1, 2eq) were added and the resulting mixture was stirred at 50 ° C until total consumption of the starting product. Then the resulting mixture was treated following the method described in treatment 1 or 2 as appropriate to obtain the final type IV compound.
  • Treatment 1 The reaction crude that showed a single product was used directly in the next reaction without being able to isolate.
  • Treatment 2 The reaction crude was dissolved in AcOEt and H 2 0, the phases were separated and the organic phase was washed with a saturated NaCl solution. The organic phase was dried with drying agents such as MgSO 4 , filtered and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography.
  • the compounds of Formula I listed in Table 6 were synthesized following the general method described below: The corresponding type III compound was dissolved in a DCM / MeOH 1: 1 to 0.015M mixture. CSA (2-4eq as appropriate) was added and the mixture was stirred at 30 ° C until total consumption of the starting product. Then the resulting mixture was treated following the method described in treatment 3 or 4 as appropriate to obtain the corresponding compound I.
  • Treatment 3 Filtration. Those products that precipitate in the reaction medium are isolated by filtration.
  • Treatment 4 Neutralization.
  • the aforementioned crude was neutralized with acidic resin IRA-400, filtered and the solvent was removed under reduced pressure.
  • purification was required by silica gel column chromatography.
  • Splenocytes were obtained from Balb / c mice by known standard protocols. Splenocytes were incubated at 5x10 5 cells / well in 96-well plates together with 1 microgram / ml of the compound to be tested, dissolved in a mixture of 99% v: v PBS (phosphate buffer at pH7.2 with 1% v: v of DMSO The culture was incubated for 96 hours and the supernatant was collected. The levels of IFN-gamma and IL-4 were measured by ELISAs (from the Enzyme-Linked ImmunoSorbent Assay, enzyme-linked immunosorbent assay) sandwich type (BioLegend) following the protocols provided by the manufacturer. Determination of the activating capacity of human NKT cells
  • C1 R cells transfected with CD1d protein (C1 r-CD1d + ) were used as host cells, PBMCs (peripheral blood mononuclear cells) as cell complement and NKT cells extracted from blood of healthy donors.
  • PBMCs peripheral blood mononuclear cells
  • NKT cells extracted from blood of healthy donors.
  • C1 R-CD1d + cells were incubated with 10 micrograms / ml of the analogues. During 1 hour at 37 ° C, they were subsequently irradiated at 45Gy to slow their growth. Similarly, PBMC cells were irradiated at 30 Gy.
  • the C1 R-CD1d + cells incubated with the analogs were placed in a 96-well plate so that 30,000 cells were pooled together with 40,000 PBMC cells, to this mixture 10,000 cells / well of purified NKT cells were added. . At 48 hours the supernatants were collected. The levels of IFN-gamma and IL-4 were measured by sandwich ELISAs (InvitroGen) following the protocols provided by the manufacturer.
  • alpha-GalCer 1 ⁇ 4 pg / ml of cytokine than the reference (alpha-GalCer); 0: pg / ml cytokines of the order of the target.

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Abstract

Non-glycosidic analogues of alpha-galactosylceramide of formula (I), wherein A, Z, Ra, Rb and Rc have the meaning indicated in the description, as NKT cell activators.

Description

ANÁLOGOS NO GLICOSÍDICOS DE ALFA-GALACTOSILCERAM IDA COMO ACTIVADORES DE CÉLULAS NKT  NON-GLYCOSIDIC ANALOGUES OF ALPHA-GALACTOSILCERAM IDA AS ACTIVATORS OF CELLS NKT
DESCRIPCIÓN DESCRIPTION
La presente invención se refiere a derivados no glicosídicos de alfa-galactosilceramida (alfa-GalCer) así como sus composiciones farmacéuticas y su uso en terapia, particularmente como terapia única o como adyuvantes para vacunas, anticuerpos o inmunoterapias celulares en cáncer, así como en infecciones o en enfermedades autoinmunes. The present invention relates to non-glycosidic derivatives of alpha-galactosylceramide (alpha-GalCer) as well as their pharmaceutical compositions and their use in therapy, particularly as a single therapy or as adjuvants for vaccines, antibodies or cellular immunotherapies in cancer, as well as in infections or in autoimmune diseases.
ANTECEDENTES DE LA INVENCIÓN BACKGROUND OF THE INVENTION
Las células T asesinas naturales NKT (del inglés natural killer T cells) son una clase de linfocitos que regula una amplia gama de respuestas inmunes. Las células NKT reconocen antígenos de tipo glicolipídico presentados por proteínas MHC CD1d y que participan en diversas respuestas inmunes mediante la promoción de la secreción de citoquinas. El papel de estas células ha sido descrito en la regulación de la autoinmunidad, la respuesta a los tumores, las infecciones microbianas y la patogenia de procesos inflamatorios como el asma. Natural killer T cells (NKT) are a class of lymphocytes that regulate a wide range of immune responses. NKT cells recognize glycolipid-like antigens presented by MHC CD1d proteins and participate in various immune responses by promoting cytokine secretion. The role of these cells has been described in the regulation of autoimmunity, the response to tumors, microbial infections and the pathogenesis of inflammatory processes such as asthma.
Una subclase de células NKT, las células NKT invariantes (¡NKT) poseen una cadena TCR-a (Val4/Jal8 en ratones y Va24/Jal8 en humanos) (Lantz, O. et al. J. Exp. Med. 1994, 180, 1097; (2) Dellabona, P. et al. J. Exp. Med. 1994, 180, 1171). Las células NKT secretan diferentes citoquinas de tipo Th1 (tales como, IFN-gamma, IL-2) y Th2 (por ejemplo, IL-4, IL-6) en respuesta a la estimulación por glicolípidos presentados por la proteína CD1d presente en células presentadoras de antígenos (Arase, H.et al Eur. J. Immunol. 2003, 33, 3322; Nieuwenhuis, E. E. et al. Nat. Med. 2002, 8, 588). Estas citoquinas pueden posteriormente transactivar otras células del sistema inmunitario tales como las células dendríticas, linfocitos T CD4+ y CD8+, células natural killer o las células B, manteniendo características de la inmunidad innata y adaptativa (Eberl, G et al J. Immunol. 2000, 165, 4305). A subclass of NKT cells, invariant NKT cells (NKT) possess a TCR-a chain (Val4 / Jal8 in mice and Va24 / Jal8 in humans) (Lantz, O. et al., J. Exp. Med. 1994, 180 , 1097; (2) Dellabona, P. et al., J. Exp. Med. 1994, 180, 1171). NKT cells secrete different Th1 type cytokines (such as, IFN-gamma, IL-2) and Th2 (for example, IL-4, IL-6) in response to the glycolipid stimulation presented by the CD1d protein present in cells antigen presenting agents (Arase, H. et al Eur. J. Immunol., 2003, 33, 3322; Nieuwenhuis, EE et al., Nat. Med. 2002, 8, 588). These cytokines can subsequently transactivate other cells of the immune system such as dendritic cells, CD4 + and CD8 + T lymphocytes, natural killer cells or B cells, maintaining characteristics of innate and adaptive immunity (Eberl, G et al J. Immunol. 2000, 165, 4305).
El glicolípido sintético alfa-galactosilceramida (alfa-GalCer) fue el primer antígeno conocido presentado por CD1d que estimula el receptor de células T invariantes (TCR), expresadas por las células NKT. alfa-GalCer es un análogo estructural optimizado de compuestos antitumorales aislados a partir de esponjas marinas que contiene una galactosa unida al hidroxilo primario de fitoceramida en configuración alfa, y que se encuentra acilada en el nitrógeno con ácidos grasos de cadena larga. Desde su descubrimiento, alfa-GalCer ha sido el prototipo de antígeno para la estimulación de células NKT, aunque otros glicolípidos que actúan como antígenos presentados por proteínas CD1 han sido también identificados (Kawano, T. et al Science 1997, 278, 1626; Yoshimoto, T et al J. Exp. Med. 1994, 179, 1285). La excepcional potencia de alfa-GalCer en la estimulación de células NKT origina una serie de respuestas biológicas, derivadas de la liberación simultánea de citoquinas de tipo Th1 y Th2, que ejercen efectos celulares opuestos y determinan una fase de anergia antes de recuperar el equilibrio homeostático, limitando la eficacia de alfa- GalCer como inmunomodulador. The synthetic glycolipid alpha-galactosylceramide (alpha-GalCer) was the first known antigen presented by CD1d that stimulates the invariant T-cell receptor (TCR), expressed by NKT cells. alpha-GalCer is an optimized structural analog of antitumour compounds isolated from marine sponges that contains a galactose attached to the primary hydroxyl of phytoceramide in alpha configuration, and which is acylated in nitrogen with long-chain fatty acids. Since its discovery, alpha-GalCer has been the antigen prototype for the stimulation of NKT cells, although other glycolipids that act as antigens presented by CD1 proteins have also been identified (Kawano, T. et al Science 1997, 278, 1626; Yoshimoto , T et al J. Exp. Med. 1994, 179, 1285). The exceptional potency of alpha-GalCer in the stimulation of NKT cells originates a series of biological responses, derived from the simultaneous release of Th1 and Th2 cytokines, which exert opposite cellular effects and determine an anergy phase before recovering the homeostatic balance , limiting the efficacy of alpha-GalCer as an immunomodulator.
Por otra parte, los determinantes estructurales de la interacción del glicolípido con la proteína presentadora CD1d son conocidos, y también la estructura cristalina del complejo de la alfa-GalCer unida a las proteínas CD1d y TCR. Estos estudios estructurales muestran que la ceramida se une a CD1d en dos bolsillos hidrófobos donde se insertan las cadenas de los lípidos, mientras que una red de enlaces de hidrógeno bloquea la posición de la galactosa, que sobresale del sitio de unión y se presenta al TCR para su reconocimiento, donde los grupos hidroxilo del glicolípido desempeñan un papel fundamental. On the other hand, the structural determinants of the interaction of the glycolipid with the CD1d presenter protein are known, and also the crystal structure of the alpha-GalCer complex bound to the CD1d and TCR proteins. These structural studies show that ceramide binds to CD1d in two hydrophobic pockets where the lipid chains are inserted, while a network of hydrogen bonds blocks the position of the galactose, which protrudes from the binding site and presents to the TCR for its recognition, where the glycolipid hydroxyl groups play a fundamental role.
Sin embargo, el balance Th1/Th2 de las citoquinas inducidas por las células NKT estimuladas por alfa-GalCer puede limitar las aplicaciones clínicas de esta molécula (Tahir, S. M. et al J. Immunol. 2001 , 167, 4046; Dhodapkar, M. V.et al J. Exp. Med. 2003, 197, 1667; Giaccone, G. et al Clin. Cáncer Res. 2002, 8, 3702; Bricard, G. et al J. Immunol. 2009, 182, 5140). La extraordinaria potencia de la estimulación de las células NKT por alfa-GalCer no está exenta de problemas, hecho que ha impulsado el diseño y síntesis de compuestos similares con el fin de mejorar sus propiedades biológicas, incluso a expensas de la obtención de compuestos menos potentes, y dirigido principalmente a la modulación de la proporción Th1/Th2 en la producción de citoquinas inducidas. However, the Th1 / Th2 balance of the cytokines induced by NKT cells stimulated by alpha-GalCer may limit the clinical applications of this molecule (Tahir, SM et al J. Immunol., 2001, 167, 4046; Dhodapkar, MVet al. J. Exp. Med. 2003, 197, 1667; Giaccone, G. et al Clin Cancer Res. 2002, 8, 3702; Bricard, G. et al J. Immunol., 2009, 182, 5140). The extraordinary power of stimulation of NKT cells by alpha-GalCer is not without problems, a fact that has driven the design and synthesis of similar compounds in order to improve their biological properties, even at the expense of obtaining less potent compounds , and directed mainly to the modulation of the Th1 / Th2 ratio in the production of induced cytokines.
Se han descrito varios enfoques para el diseño de compuestos análogos de alfa- GalCer, principalmente en relación con las variaciones en la longitud y naturaleza de los lípidos (cfr. C. McCarthy, et al., J Exp Med 2007, 204, 1131 ; M. Trappeniers, et al., ChemMedChem 2008, 3, 1061 ; K. Fuhshuku, et al., Bioorg Med Chem 2008, 16, 950; T. Tashiro, et al., Bioorg Med Chem 2008, 16, 8896) o la sustitución de la galactosa por otros mono o polisacáridos (cfr. T. Kawano et al., Science 1997, 278, 1626) y otras diversas sustituciones relacionadas (cfr. US2007238871A1). Por otra parte, glicolípidos con grupos acilos sustituidos pueden inducir preferentemente citoquinas Th1 y tienen actividad antitumoral potente en ratones (Chang, Y. J.et al Proc. Nati. Acad. Sci. U. S. A. 2007, 104, 10299; Wu, et al Proc. Nati. Acad. Sci. U. S. A. 2011 , 108, 17275). Algunos análogos de alfa-GalCer con grupos lineales no glicosídicos son capaces de activar células NKT e inducen respuestas inmunológicas, lo que demuestra que es posible la modulación de los efectos del glicolípido después de la introducción de modificaciones estructurales en el anillo de galactosa de alfa-GalCer (cfr. J. D. Silk et al., J Immunol 2008, 180, 6452; R. W. Franck, Acc Chem Res 2006, 39, 692, Harrak et al J Am Chem Soc. 2011 ,133, 12079, Kerzerho et al J Immunol. 2012 ,188, 2254). Several approaches have been described for the design of analogue alpha- GalCer, mainly in relation to variations in the length and nature of lipids (cf C. McCarthy, et al., J Exp Med 2007, 204, 1131; M. Trappeniers, et al., ChemMedChem 2008, 3, 1061 K. Fuhshuku, et al., Bioorg Med Chem 2008, 16, 950, T. Tashiro, et al., Bioorg Med Chem 2008, 16, 8896) or the replacement of galactose with other mono or polysaccharides (cf. Kawano et al., Science 1997, 278, 1626) and various other related substitutions (cf US2007238871A1). On the other hand, glycolipids with substituted acyl groups can preferentially induce Th1 cytokines and have potent antitumor activity in mice (Chang, YJet al Proc. Nati, Acad Sci USA USA, 104, 10299; Wu, et al Proc. Nati. Acad. Sci. USA 2011, 108, 17275). Some alpha-GalCer analogues with non-glycosidic linear groups are capable of activating NKT cells and induce immunological responses, demonstrating that modulation of glycolipid effects is possible after the introduction of structural modifications in the alpha-galactose ring. GalCer (JD Silk et al., J Immunol 2008, 180, 6452; RW Franck, Acc Chem Res 2006, 39, 692, Harrak et al J Am Chem Soc. 2011, 133, 12079, Kerzerho et al J Immunol. 2012, 188, 2254).
Otro de los aspectos relevantes de los glicolípidos y sus análogos es la diferencia de actividad que presentan estos compuestos en la estimulación de células NKT de especies diferentes (Birkholz et al J Biol Chem. 2015, 290, 17206). Por ejemplo en la patente WO2015035337 se reivindica que glucoesfingolípidos derivados de glucosa poseen mayor potencia en la estimulación de células NKT humanas respecto a células NKT de ratón, contrariamente a lo que ocurre con los correspondientes derivados de galactosa. Otro ejemplo de diferente actividad entre células NKT humanas y de ratón ocurre con el derivado alfa-C-GalCer (Franck, RW C R Chim 2012, 15, 46; Li X et al J Immunol. 2009, 183). Another relevant aspect of glycolipids and their analogs is the difference in activity of these compounds in the stimulation of NKT cells from different species (Birkholz et al. J Biol Chem. 2015, 290, 17206). For example, WO2015035337 claims that glucose-derived glycosphingolipids possess greater potency in the stimulation of human NKT cells with respect to mouse NKT cells, contrary to what happens with the corresponding galactose derivatives. Another example of different activity between human and mouse NKT cells occurs with the alpha-C-GalCer derivative (Franck, RW C R Chim 2012, 15, 46, Li X et al J Immunol., 2009, 183).
A la vista de lo anteriormente expuesto, sería conveniente disponer de nuevos compuestos para la estimulación de células NKT o bien análogos de glicolípidos conocidos, tales como la alfa-GalCer, que permitan la modulación de la respuesta inmune mediada por células y que sean de utilidad para el desarrollo de medicamentos, adyuvantes, vacunas y para cualquier inmunoterapia diseñada para estimular las células NKT. DESCRIPCIÓN DE LA INVENCIÓN In view of the foregoing, it would be convenient to have available new compounds for the stimulation of NKT cells or analogs of known glycolipids, such as alpha-GalCer, which allow the modulation of the cell-mediated immune response and which are useful. for the development of medicines, adjuvants, vaccines and for any immunotherapy designed to stimulate NKT cells. DESCRIPTION OF THE INVENTION
La presente invención se refiere a análogos no glicosídicos de alfa-GalCer de fórmula (I), en los que se ha sustituido el grupo glicosídico por un anillo aromático. Estos derivados no glicosídicos han mostrado una fuerte actividad in vitro para estimular las células NKT mediante la inducción de la liberación de citoquinas. Los compuestos también han mostrado actividad en la estimulación de células NKT humanas. The present invention relates to non-glycosidic analogues of alpha-GalCer of formula (I), in which the glycosidic group has been replaced by an aromatic ring. These non-glycosidic derivatives have shown strong in vitro activity to stimulate NKT cells by inducing the release of cytokines. The compounds have also shown activity in the stimulation of human NKT cells.
Debido al papel de las células NKT, estos compuestos pueden tener aplicación en la inmunoterapia del cáncer para la estimulación cooperativa del sistema inmune del paciente y como adyuvantes de vacuna, así como en enfermedades autoinmunes o infecciones. Due to the role of NKT cells, these compounds may have application in cancer immunotherapy for cooperative stimulation of the patient's immune system and as vaccine adjuvants, as well as in autoimmune diseases or infections.
En los compuestos de fórmula (I) se ha observado que: In the compounds of formula (I) it has been observed that:
- el reemplazo del grupo galactosa por un grupo no glicosídico evita la degradación por parte de las glicosidasas celulares, confiriendo una vida media más larga y, por tanto, efectos sostenidos; - the replacement of the galactose group by a non-glycosidic group prevents degradation by cellular glycosidases, conferring a longer half-life and, therefore, sustained effects;
- la modulación de la respuesta Th1 o Th2 en comparación con alfa-GalCer depende de la estructura del compuesto;  - the modulation of the Th1 or Th2 response compared to alpha-GalCer depends on the structure of the compound;
- un mecanismo de acción definido, que implica la presentación de CD1d por las células presentadoras de antígeno y la estimulación de la proliferación de células NKT; y - a defined mechanism of action, which involves the presentation of CD1d by the antigen-presenting cells and the stimulation of NKT cell proliferation; Y
- las células NKT son reguladores no convencionales de la inmunidad innata y adaptativa. La activación de NKT inicia una cascada de adyuvantes que refuerza la inmunidad innata y promueve la respuesta inmune adaptativa subsiguiente.  - NKT cells are unconventional regulators of innate and adaptive immunity. The activation of NKT initiates a cascade of adjuvants that reinforces innate immunity and promotes the subsequent adaptive immune response.
Así pues, en un primer aspecto, la presente invención se refiere a un compuesto de fórmula (I):
Figure imgf000006_0001
Thus, in a first aspect, the present invention relates to a compound of formula (I):
Figure imgf000006_0001
o un sal farmacéuticamente aceptable del mismo, donde: A representa arilo o heteroarilo, opcionalmente sustituido por uno, dos o tres grupos Rc independientemente seleccionados y que pueden estar opcionalmente unidos entre ellos formando un anillo de 3 a 8 miembros; or a pharmaceutically acceptable salt thereof, wherein: A represents aryl or heteroaryl, optionally substituted by one, two or three R c groups independently selected and which may be optionally linked together to form a 3- to 8-membered ring;
Z representa S, O o NR^ Z represents S, O or NR ^
Ra representa C9-C30 alquilo, C9-C30 alquenilo o C9-C30 alquinilo, donde Ra está opcionalmente sustituido por uno o más grupos R2; R a represents C 9 -C 30 alkyl, C 9 -C 30 alkenyl or C 9 -C 30 alkynyl, where R a is optionally substituted by one or more R 2 groups;
Rb representa C10-C16 alquilo, C10-C16 alquenilo o C10-C16 alquinilo, donde Rb está opcionalmente sustituido por uno o más grupos Rn; cada Rc independientemente representa Y, halógeno, -CN, -N02, -N3, C1-C4 alquilo, C2-C4 alquenilo, C2-C4 alquinilo, arilo, heteroarilo, cicloalquilo o heterocicloalquilo, donde los grupos CrC4 alquilo, C2-C4 alquenilo, C2-C4 alquinilo independientemente están opcionalmente sustituidos por uno o más sustituyentes R7, y los grupos arilo, heteroarilo, cicloalquilo y heterocicloalquilo independientemente están opcionalmente sustituidos por uno o más grupos R8; R b represents C 10 -C 16 alkyl, C 10 -C 16 alkenyl or C 10 -C 16 alkynyl, where R b is optionally substituted by one or more R n groups; each R c independently represents Y, halogen, -CN, -N0 2 , -N 3 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, where the groups C r C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl independently are optionally substituted by one or more R 7 substituents, and the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups independently are optionally substituted by one or more R 8 groups;
Y representa -OR9, -COR9, -NRI R9, -C02R9, -OCOR9, -CONR^Rg, -NRICOR9, -S02R9, -NRIS02R9, -S02NRI R9, -NRICONRI R9, -OCONR^Rg o -NRiC02R9; cada Ri independientemente representa H o CrC4 alquilo; cada R2 independientemente representa halógeno, -N3, -NR1COR4, -OR4, -CONR1R4, - NR1S02R4, -NR1CONR1R4, -OCONR1R4, -NR1C02R4, arilo, heteroarilo o cicloalquilo, donde los grupos arilo, heteroarilo y cicloalquilo independientemente están opcionalmente sustituidos por uno o más grupos R3; cada R3 independientemente representa CrCi4 alquilo, C2-CM alquenilo, C2-CM alquinilo, halógeno, -NR^, -NR1COR4, -OR4 o -CN; cada R4 independientemente representa H, CrCi4 alquilo, C2-CM alquenilo, C2-CM alquinilo, arilo o cicloalquilo, donde los grupos CrCi4 alquilo, C2-CM alquenilo y C2-CM alquinilo independientemente están opcionalmente sustituidos por uno o más grupos R5, y los grupos arilo y cicloalquilo independientemente están opcionalmente sustituidos por uno o más grupos R6; cada R5 independientemente representa halógeno, -ORi o NR^ORi; cada R6 independientemente representa halógeno, CrCi4 alquilo o -0(CrCi4 alquilo); cada R7 independientemente representa Y, halógeno, -CN, -N02, -N3, arilo, heteroarilo, cicloalquilo o heterocicloalquilo, donde los grupos arilo, heteroarilo, cicloalquilo y heterocicloalquilo independientemente están opcionalmente sustituidos por uno o más grupos Rn; cada R8 independientemente representa Y, CrC4 alquilo-Y, halógeno, -CN, -N02 o -N3; cada Rg independientemente representa H, CrC4 alquilo, arilo, heteroarilo, cicloalquilo o heterocicloalquilo, donde el grupo CrC4 alquilo está opcionalmente sustituido por uno o más grupos R10, y donde los grupos arilo, heteroarilo, cicloalquilo y heterocicloalquilo independientemente están opcionalmente sustituidos por uno o más grupos Rn; cada R10 independientemente representa halógeno, -ORi, -NR1R1, -N3, arilo, heteroarilo, cicloalquilo o heterocicloalquilo, donde los grupos arilo, heteroarilo, cicloalquilo y heterocicloalquilo independientemente están opcionalmente sustituidos por uno o más grupos Rn; y cada Rn independientemente representa halógeno, CrC4 alquilo, -ORi, -NR^ o -N3, con la condición de que el compuesto de fórmula (I) no es: Y represents -OR 9 , -COR 9 , -NR I R 9 , -C0 2 R 9 , -OCOR 9 , -CONR ^ Rg, -NR I COR 9 , -S0 2 R 9 , -NR I S0 2 R 9 , -S0 2 NR I R 9 , -NR I CONR I R 9 , -OCONR ^ Rg or -NRiC0 2 R 9 ; each Ri independently represents H or C r C 4 alkyl; each R 2 independently represents halogen, -N 3 , -NR 1 COR 4 , -OR 4 , -CONR 1 R 4 , -NR 1 S0 2 R 4 , -NR 1 CONR 1 R 4 , -OCONR 1 R 4 , - NR 1 C0 2 R 4 , aryl, heteroaryl or cycloalkyl, wherein the aryl, heteroaryl and cycloalkyl groups independently are optionally substituted by one or more R 3 groups; each R 3 independently represents CrCi 4 alkyl, C 2 -C M alkenyl, C 2 -C M alkynyl, halogen, -NR ^, -NR 1 COR 4 , -OR 4 or -CN; each R 4 independently represents H, CrCi 4 alkyl, C 2 -C M alkenyl, C 2 -C M alkynyl, aryl or cycloalkyl, where the groups C r Ci 4 alkyl, C 2 -C M alkenyl and C 2 -C M alkynyl independently are optionally substituted by one or more R 5 groups, and the aryl and cycloalkyl groups independently are optionally substituted by one or more R 6 groups; each R 5 independently represents halogen, -ORi or NR ^ ORi; each R 6 independently represents halogen, C r C 4 alkyl or -0 (C r C 4 alkyl); each R 7 independently represents Y, halogen, -CN, -N0 2 , -N 3 , aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups independently are optionally substituted by one or more R n groups; each R 8 independently represents Y, C r C 4 alkyl-Y, halogen, -CN, -N0 2 or -N 3 ; each R g independently represents H, C r C 4 alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein the group C r C 4 alkyl is optionally substituted by one or more R 10 groups, and where the aryl, heteroaryl, cycloalkyl and heterocycloalkyl independently are optionally substituted by one or more Rn groups; each R 10 independently represents halogen, -ORi, -NR 1 R 1 , -N 3 , aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups independently are optionally substituted by one or more R n groups; Y each Rn independently represents halogen, C r C 4 alkyl, -ORi, -NR ^ or -N 3 , with the proviso that the compound of formula (I) is not:
(Z)-N-((2R,3S,4R)-3,4-dihidroxi-1-(feniltio)octadecan-2-il)tetracos-15-enamida, (Z)-N-((2R,3S,4R)-1-((4-(4-bromofenil)tiazol-2-il)tio)-3,4-dihidroxi-octadecan-2-il) tetracos-15-enamida, o (Z) -N - ((2R, 3S, 4R) -3,4-dihydroxy-1- (phenylthio) octadecan-2-yl) tetracos-15-enamide, (Z) -N - ((2R, 3S, 4R) -1 - ((4- (4-bromophenyl) thiazol-2-yl) thio) -3,4-dihydroxy-octadecan-2-yl) tetracos-15-enamide, or
(Z)-N-((2R,3S,4R)-3,4-dihidroxi-1-(piridin-2-iltio)-octadecan-2-il)tetracos-15-enamida.  (Z) -N - ((2R, 3S, 4R) -3,4-dihydroxy-1- (pyridin-2-ylthio) -octadecan-2-yl) tetracos-15-enamide.
En una realización la invención se refiere al compuesto de fórmula (I), donde A representa fenilo, tiofenilo o piridilo, y está opcionalmente sustituido por uno, dos o tres grupos Rc. En otra realización la invención se refiere al compuesto de fórmula (I), donde A representa fenilo, tiofenilo o piridilo. In one embodiment the invention relates to the compound of formula (I), wherein A represents phenyl, thiophenyl or pyridyl, and is optionally substituted by one, two or three R c groups. In another embodiment the invention relates to the compound of formula (I), wherein A represents phenyl, thiophenyl or pyridyl.
En otra realización la invención se refiere al compuesto de fórmula (I), donde Ra representa C9-C30 alquilo o C9-C30 alquenilo, donde Ra está opcionalmente sustituido por uno o más grupos R2. In another embodiment the invention relates to the compound of formula (I), wherein R a represents C 9 -C 30 alkyl or C 9 -C 30 alkenyl, wherein R a is optionally substituted by one or more R 2 groups.
En otra realización la invención se refiere al compuesto de fórmula (I), donde Ra representa C9-C30 alquilo o C9-C30 alquenilo. En otra realización la invención se refiere al compuesto de fórmula (I), donde Ra es C9- C30 alquilo y preferiblemente C9-C30 alquilo representa C9 alquilo, Cío alquilo, Cu alquilo, C15 alquilo o C25 alquilo. In another embodiment, the invention relates to the compound of formula (I), wherein R a represents C 9 -C 30 alkyl or C 9 -C 30 alkenyl. In another embodiment the invention relates to the compound of formula (I) wherein R a is C 9 - C 30 alkyl and preferably C 9 -C 30 alkyl represents C 9 alkyl, C í or alkyl, C 15 Cu alkyl or C 25 alkyl.
En otra realización la invención se refiere al compuesto de fórmula (I), donde Ra es C9- C30 alquenilo y preferiblemente C9-C30 alquenilo es C23 alquenilo. In another embodiment the invention relates to the compound of formula (I), wherein R a is C 9 -C 30 alkenyl and preferably C 9 -C 30 alkenyl is C 23 alkenyl.
En otra realización la invención se refiere al compuesto de fórmula (I), donde Rb es C10-C16 alquilo, y preferiblemente C10-C16 alquilo es C14 alquilo. En otra realización la invención se refiere al compuesto de fórmula (I), donde Rc representa Y, halógeno, -CN, CrC4 alquilo o arilo. In another embodiment the invention relates to the compound of formula (I), wherein R b is C 10 -C 16 alkyl, and preferably C 10 -C 16 alkyl is C 14 alkyl. In another embodiment the invention relates to the compound of formula (I), wherein R c represents Y, halogen, -CN, C r C 4 alkyl or aryl.
En otra realización la invención se refiere al compuesto de fórmula (I), donde Y representa -OR9, -C02R9, -CONR^g, -NR^ORg, -S02Rg o S02NR1R9. In another embodiment the invention relates to the compound of formula (I), wherein Y represents -OR 9 , -C0 2 R 9 , -CONR ^ g, -NR ^ ORg, -S0 2 Rg or S0 2 NR 1 R 9 .
En otra realización la invención se refiere al compuesto de fórmula (I), donde: In another embodiment, the invention relates to the compound of formula (I), wherein:
Rc representa Y, halógeno, -CN, CrC4 alquilo o arilo; e R c represents Y, halogen, -CN, C r C 4 alkyl or aryl; and
Y representa -ORg, -C02R9, -CONR^g, -NR^ORg, -S02R9 o S02NR1R9. Y represents -ORg, -C0 2 R 9 , -CONR ^ g, -NR ^ ORg, -S0 2 R 9 or S0 2 NR 1 R 9 .
En otra realización la invención se refiere al compuesto de fórmula (I), donde: In another embodiment, the invention relates to the compound of formula (I), wherein:
Rc representa Y, halógeno, -CN, CrC4 alquilo o arilo; R c represents Y, halogen, -CN, C r C 4 alkyl or aryl;
Y representa -OR9, -C02R9, -CONR^g, -NR^ORg, -S02R9 o S02NR1R9; Y represents -OR 9 , -C0 2 R 9 , -CONR ^ g, -NR ^ ORg, -S0 2 R 9 or S0 2 NR 1 R 9 ;
Ri es H; y  Ri is H; Y
R9 representa H o Ci alquilo. R 9 represents H or Ci alkyl.
En otra realización la invención se refiere al compuesto de fórmula (I), donde: In another embodiment, the invention relates to the compound of formula (I), wherein:
Rc representa Y, halógeno, -CN, CrC4 alquilo o arilo; R c represents Y, halogen, -CN, C r C 4 alkyl or aryl;
CrC4 alquilo es Ci alquilo; C r C 4 alkyl is Ci alkyl;
halógeno es cloro; y halogen is chlorine; Y
arilo es fenilo. Aryl is phenyl.
En otra realización la invención se refiere al compuesto de fórmula (I), donde R2 representa -NRÍCOR^ -NRÍSO^ O arilo. In another embodiment, the invention relates to the compound of formula (I), wherein R 2 represents -NR ÍCOR ^-NR ÍSO ^O aryl.
En otra realización la invención se refiere al compuesto de fórmula (I), donde R3 representa -OR4 o halógeno, y preferiblemente donde R3 representa -OR4 o flúor. In another embodiment the invention relates to the compound of formula (I), wherein R 3 represents -OR 4 or halogen, and preferably wherein R 3 represents -OR 4 or fluorine.
En otra realización la invención se refiere al compuesto de fórmula (I), donde R4 representa Cío alquilo, Ci2 alquilo, Cío alquenilo, Cío alquinilo o arilo. In another embodiment the invention relates to the compound of formula (I) wherein R 4 represents C í or alkyl, Ci 2 alkyl, C í or alkenyl, C í or alkynyl or aryl.
En otra realización la invención se refiere al compuesto de fórmula (I), donde R6 representa Ci alquilo o halógeno, y preferiblemente donde R6 representa Ci alquilo o flúor. In another embodiment the invention relates to the compound of formula (I), wherein R 6 represents Ci alkyl or halogen, and preferably wherein R 6 represents Ci alkyl or fluorine.
En otra realización la invención se refiere al compuesto de fórmula (I), donde: R7 es Y; e In another embodiment, the invention relates to the compound of formula (I), wherein: R 7 is Y; and
Y es -ORg And it's -ORg
En otra realización la invención se refiere al compuesto de fórmula (I), donde R8 es halógeno, y preferiblemente donde R8 es flúor o cloro, y aún más preferiblemente donde R8 es flúor. In another embodiment the invention relates to the compound of formula (I), wherein R 8 is halogen, and preferably wherein R 8 is fluorine or chlorine, and even more preferably wherein R 8 is fluorine.
En otra realización la invención se refiere al compuesto de fórmula (I), donde Rg representa H o Ci alquilo. In another embodiment the invention relates to the compound of formula (I), wherein R g represents H or Ci alkyl.
En otra realización, la invención se refiere a un compuesto de fórmula (I) seleccionado de entre la lista de compuestos 1-1 a I-60. In another embodiment, the invention relates to a compound of formula (I) selected from the list of compounds 1-1 to I-60.
En otra realización la invención se refiere a un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo seleccionado de: In another embodiment, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof selected from:
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)palmitamida;- N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) palmitamide;
- (Z)-N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)tetracos- 15-enamida; - (Z) -N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) tetracos-15-enamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)decanamida; - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) decanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-11-(4-(4- fluorofenoxi)fenil)undecanamida; - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -11- (4- (4-fluorophenoxy) phenyl) undecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-11-(4- fluorofenil)undecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -11- (4-fluorophenyl) undecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-(feniltio)octadecan-2-il)hexacosanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1- (phenylthio) octadecan-2-yl) hexacosanamide;
- N-((2R,3S,4R)-1-((3,4-dimetoxifenil)tio)-3,4-dihidroxioctadecan-2- il)hexacosanamida;  - N - ((2R, 3S, 4R) -1 - ((3,4-dimethoxyphenyl) thio) -3,4-dihydroxyoctadecan-2-yl) hexacosanamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-(2-metoxifenoxi)octadecan-2-il)hexacosanamida; - N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2-methoxyphenoxy) octadecan-2-yl) hexacosanamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-fenoxioctadecan-2-il)hexacosanamida; - N - ((2S, 3S, 4R) -3,4-dihydroxy-1-phenoxyoctadecan-2-yl) hexacosanamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-((2-metoxifenil)amino)octadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((2-methoxyphenyl) amino) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(fenilamino)octadecan-2-il)tetracos-15-enamida; - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (phenylamino) octadecan-2-yl) tetracos-15-enamide;
- 2-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)tereftalato de dimetilo; - (((2S, 3S, 4R) -3,4-Dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) -dimethyl terephthalate;
- 3-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)ftalato de dimetilo; - 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)tereftalato de dimetilo;- 3 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) dimethyl phthalate; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) dimethyl terephthalate;
- 3-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)amino)ftalato de dimetilo; - 3 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) amino) dimethyl phthalate;
- 2-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)amino)tiofen-3- carboxilato de metilo;  - 2 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) amino) thiophene-3-carboxylic acid methyl ester;
- 5-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)amino)isoftalato de dimetilo;  - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) amino) dimethyl isophthalate;
- 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-ennamido)octadecil)amino)isoftalato de dimetilo;  - 4 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-ennamido) octadecyl) amino) dimethyl isophthalate;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-((3-(hidroximetil)fenil)amino)octadecan-2- il)tetracos-15-enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((3- (hydroxymethyl) phenyl) amino) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-((4-(hidroximetil-2-metoximetil)fenil)amino)-3,4- dihidroxioctadecan-2-il)tetracos-15-enamida;  - (Z) -N - ((2S, 3S, 4R) -1 - ((4- (hydroxymethyl-2-methoxymethyl) phenyl) amino) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enamide;
- 3-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzamida;  - 3 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzamide;
- 4-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzamida;  - 4 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzamide;
- 4-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)isoftalamida;  - 4 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) isophthalamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-((2-metoxifenil)amino)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((2-methoxyphenyl) amino) octadecan-2-yl) hexacosanamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-(fenilamino)octadecan-2-il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (phenylamino) octadecan-2-yl) hexacosanamide;
- 3-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)benzamida; - 3 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) benzamide;
- 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)benzamida;- 4 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) benzamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(4-(hidroximetil)fenoxi)octadecan-2-il)tetracos-15- enamida; - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (4- (hydroxymethyl) phenoxy) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(3-(hidroximetil)fenoxi)octadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (3- (hydroxymethyl) phenoxy) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-([1,1'-bifenil]-4-iloxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -1 - ([1,1'-biphenyl] -4-yloxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enamide;
- 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)-[1 ,T-bifenil]- 3-carboxilato de metilo;  - 4 - (((2S, 3S, 4R) -3,4-Dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) - [1, T-biphenyl] -3-carboxylic acid methyl ;
- (Z)-N-((2S,3S,4R)-1-([1 ,1'-bifenil]-3-iloxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -1 - ([1,1'-biphenyl] -3-yloxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(o-toliloxi)octadecan-2-il)tetracos-15-enamida; - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (o-tolyloxy) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-(2-clorofenoxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- enamida; - (Z)-N-((2S,3S,4R)-1-(2-cianofenoxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- enamida; - (Z) -N - ((2S, 3S, 4R) -1- (2-chlorophenoxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enamide; - (Z) -N - ((2S, 3S, 4R) -1- (2-cyanophenoxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-(2-acetamidofenoxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -1- (2-acetamidophenoxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(2-(metilsulfonil)fenoxi)octadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2- (methylsulfonyl) phenoxy) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(2-sulfamoilfenoxi)octadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2-sulfamoylphenoxy) octadecan-2-yl) tetracos-15-enamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12- undecanamidododecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- undecanamidododecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12-(4- metilfenilsulfonamido)dodecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- (4-methylphenylsulfonamido) dodecanamide;
- N-(12-(((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)amino)- 12-oxododecil)tridecanamida;  - N- (12 - (((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) amino) -12-oxododecyl) tridecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12-(undec- 10-enamido)dodecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- (unde-10-enamido) dodecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12-(undec- 10-inamido)dodecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- (undec-10-inamido) dodecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2- il)hexacosanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) hexacosanamide;
- 2-(((2R,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)tio)benzoato de metilo; - 2 - (((2R, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) thio) methyl benzoate;
- ácido 2-(((2R,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)tio)benzoico; - 2 - (((2R, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) thio) benzoic acid;
- 2-(((2R,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)tio)benzamida;  - 2 - (((2R, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) thio) benzamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-(2-(hidroximetil)fenoxi)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2- (hydroxymethyl) phenoxy) octadecan-2-yl) hexacosanamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)benzoato de metilo; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) benzoate methyl;
- ácido 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)benzoico; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) benzoic acid;
- N-((2S,3S,4R)-3,4-dihidroxi-1-((2-(metiloximetil)fenil)amino)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((2- (methyloxymethyl) phenyl) amino) octadecan-2-yl) hexacosanamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzoato de metilo; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) methyl benzoate;
- ácido 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzoico;- 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzoic acid;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzamida; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-((3-(hidroximetil)piridin-2-il)oxi)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((3- (hydroxymethyl) pyridin-2-yl) oxy) octadecan-2-yl) hexacosanamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)nicotinato de metilo; - 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)nicotinamida; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) methyl nicotinate; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) nicotinamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)benzamida;  - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) benzamide;
- 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)-2',4'-difluoro- [1 ,1'-bifenil]-3-carboxilato de metilo; y  - 4 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) -2 ', 4'-difluoro- [1, 1' methyl-biphenyl] -3-carboxylate; Y
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-((4-(hidroximetil)-[1 ,1'-bifenil]-3-il)oxi)octadecan-2- 1 l)tetracos-15-enamida  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((4- (hydroxymethyl) - [1, 1'-biphenyl] -3-yl) oxy) octadecan-2 - 1 l) tetracos-15-enamide
El término "alquilo", tal como se utiliza en la presente invención, solo o como parte de otro grupo, se refiere a cadenas hidrocarbonadas saturadas tanto de cadena lineal como ramificada que contienen el número de átomos de carbono indicado en cada caso a lo largo de la invención y unidos al resto de las moléculas a través de un enlace sencillo. Ejemplos de grupos alquilo son metilo, etilo, n-propilo, isopropilo, n-butilo, isobutilo, tere-butilo, pentilo, hexilo, isohexilo, heptilo, 4,4-dimetilpentilo, octilo, 2,2,4- trimetilpentilo, nonilo , decilo, dodecilo y sus diversos isómeros de cadena ramificada. Los grupos alquilo pueden estar opcionalmente sustituidos por uno o más sustituyentes tal como se indica en cada caso a lo largo de la invención. The term "alkyl", as used in the present invention, alone or as part of another group, refers to saturated straight and branched chain hydrocarbon chains containing the number of carbon atoms indicated in each case throughout of the invention and linked to the rest of the molecules through a single bond. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tere-butyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl , decyl, dodecyl and their various branched chain isomers. The alkyl groups may be optionally substituted by one or more substituents as indicated in each case throughout the invention.
El término "alquenilo", tal como se utiliza en la presente invención, solo o como parte de otro grupo, se refiere a cadenas hidrocarbonadas tanto de cadena lineal como ramificada que contienen uno o más dobles enlaces carbono-carbono, que contienen el número de átomos de carbono indicado en cada caso a lo largo de la invención y unidos al resto de las moléculas a través de un enlace sencillo. Ejemplos de grupos alquenilo son vinilo, 1-propenilo, alilo, isoprenilo, 2-butenilo, 1 ,3-butadienilo y sus diversos isómeros de cadena ramificada. Los grupos alquenilo pueden estar opcionalmente sustituidos por uno o más sustituyentes tal como se indica en cada caso a lo largo de la invención. The term "alkenyl", as used in the present invention, alone or as part of another group, refers to both straight and branched chain hydrocarbon chains containing one or more carbon-carbon double bonds, containing the number of carbon atoms indicated in each case throughout the invention and linked to the rest of the molecules through a single bond. Examples of alkenyl groups are vinyl, 1-propenyl, allyl, isoprenyl, 2-butenyl, 1,3-butadienyl and their various branched chain isomers. The alkenyl groups may be optionally substituted by one or more substituents as indicated in each case throughout the invention.
El término "alquinilo", tal como se utiliza en la presente invención, solo o como parte de otro grupo, se refiere a cadenas hidrocarbonadas tanto de cadena lineal como ramificada que contienen uno o más triples enlaces carbono-carbono, que contienen el número de átomos de carbono indicado en cada caso a lo largo de la invención y unidos al resto de las moléculas a través de un enlace sencillo. Ejemplos de grupos alquinilo son etinilo y 1-propinilo. Los grupos alquinilo pueden estar opcionalmente sustituidos por uno o más sustituyentes tal como se indica en cada caso a lo largo de la invención. El término "cicloalquilo", tal como se utiliza en la presente invención, solo o como parte de otro grupo, se refiere a grupos hidrocarbonados monocíclicos o bicíclicos, saturados o parcialmente saturados, que contienen un total de 3 a 10 átomos de carbono que forman parte del sistema de ciclos. Ejemplos de grupos cicloalquilo son ciclopropilo, ciclobutilo, ciclopentilo, ciclohexilo, cicloheptilo, ciclooctilo, ciclodecilo y adamantilo. Los grupos cicloalquilo pueden estar opcionalmente sustituidos por uno o más sustituyentes tal como se indica en cada caso a lo largo de la invención. El término "heterocicloalquilo", tal como se utiliza en la presente invención, solo o como parte de otro grupo, se refiere a grupos monocíclicos o bicíclicos, saturados o parcialmente saturados, que contienen un total de 3 a 10 miembros que forman parte del sistema de ciclos, que consiste en átomos de carbono y entre 1 y 3 heteroátomos seleccionados entre N, O y S. Ejemplos de grupos heterocicloalquilo son furanilo, piperidinilo, piperazinilo, tetrahidrofuranilo y morfolinilo. Los grupos heterocicloalquilo pueden estar opcionalmente sustituidos por uno o más sustituyentes tal como se indica en cada caso a lo largo de la invención. The term "alkynyl", as used in the present invention, alone or as part of another group, refers to both straight chain and branched hydrocarbon chains containing one or more triple carbon-carbon bonds, containing the number of carbon atoms indicated in each case throughout the invention and linked to the rest of the molecules through a single bond. Examples of alkynyl groups are ethynyl and 1-propynyl. The alkynyl groups may be optionally substituted by one or more substituents as indicated in each case throughout the invention. The term "cycloalkyl", as used in the present invention, alone or as part of another group, refers to saturated or partially saturated monocyclic or bicyclic hydrocarbon groups, containing a total of 3 to 10 carbon atoms forming part of the cycle system. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and adamantyl. The cycloalkyl groups may be optionally substituted by one or more substituents as indicated in each case throughout the invention. The term "heterocycloalkyl", as used in the present invention, alone or as part of another group, refers to monocyclic or bicyclic, saturated or partially saturated groups, containing a total of 3 to 10 members that are part of the system of cycles, consisting of carbon atoms and between 1 and 3 heteroatoms selected from N, O and S. Examples of heterocycloalkyl groups are furanyl, piperidinyl, piperazinyl, tetrahydrofuranyl and morpholinyl. The heterocycloalkyl groups may be optionally substituted by one or more substituents as indicated in each case throughout the invention.
El término "arilo", tal como se utiliza en la presente invención, solo o como parte de otro grupo, se refiere a grupos hidrocarburo aromáticos monocíclicos, bicíclicos o tricíclicos que contienen de 6 a 14 carbonos que forman parte del sistema de ciclos. Ejemplos de grupos arilo son fenilo, naftilo (incluyendo 1-naftilo y 2-naftilo), indenilo, fenantrilo y antracilo. Los grupos arilo pueden estar opcionalmente sustituidos por uno o más sustituyentes tal como se indica en cada caso a lo largo de la invención. The term "aryl", as used in the present invention, alone or as part of another group, refers to monocyclic, bicyclic or tricyclic aromatic hydrocarbon groups containing from 6 to 14 carbons that are part of the cycle system. Examples of aryl groups are phenyl, naphthyl (including 1-naphthyl and 2-naphthyl), indenyl, phenanthryl and anthracyl. The aryl groups may be optionally substituted by one or more substituents as indicated in each case throughout the invention.
El término "heteroarilo", tal como se utiliza en la presente invención, solo o como parte de otro grupo, se refiere a grupos hidrocarburo aromáticos monocíclicos, bicíclicos o tricíclicos condensados que contienen de 5 a 14 miembros que forman parte del sistema de ciclos, que consiste en átomos de carbono y entre 1 y 4 heteroátomos seleccionados entre N, O y S. Ejemplos de grupos heteroarilo son tiazolilo, bencimidazolilo, benzotiazolilo, isotiazolilo, indolilo, piridilo, pirimidilo, tiadiazolilo, pirrolilo, pirazolilo, imidazolilo, furanilo, tiofenilo. Los grupos heteroarilo pueden estar opcionalmente sustituidos por uno o más sustituyentes tal como se indica en cada caso a lo largo de la invención. El término "halógeno", tal como se utiliza en la presente invención, solo o como parte de otro grupo, se refiere a cloro, bromo, flúor y yodo. The term "heteroaryl", as used in the present invention, alone or as part of another group, refers to monocyclic, bicyclic or condensed tricyclic aromatic hydrocarbon groups containing from 5 to 14 members that are part of the cycle system, which consists of carbon atoms and between 1 and 4 heteroatoms selected from N, O and S. Examples of heteroaryl groups are thiazolyl, benzimidazolyl, benzothiazolyl, isothiazolyl, indolyl, pyridyl, pyrimidyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiophenyl . The heteroaryl groups may be optionally substituted by one or more substituents as indicated in each case throughout the invention. The term "halogen", as used in the present invention, alone or as part of another group, refers to chlorine, bromine, fluorine and iodine.
Otro aspecto de la presente invención se refiere al uso de un compuesto de fórmulaAnother aspect of the present invention relates to the use of a compound of formula
(I): (I):
Figure imgf000015_0001
Figure imgf000015_0001
o de una sal farmacéuticamente aceptable del mismo, donde or a pharmaceutically acceptable salt thereof, where
A, Z, Ra, Rb y Rc tienen el significado descrito en el primer aspecto de la invención, para la fabricación de un medicamento. A, Z, R a , R b and R c have the meaning described in the first aspect of the invention, for the manufacture of a medicament.
Otro aspecto de la presente invención se refiere al uso de un compuesto de fórmulaAnother aspect of the present invention relates to the use of a compound of formula
(I): (I):
Figure imgf000015_0002
Figure imgf000015_0002
o de una sal farmacéuticamente aceptable del mismo, donde or a pharmaceutically acceptable salt thereof, where
A, Z, Ra, Rb y Rc tienen el significado descrito en el primer aspecto de la invención, para la fabricación de un medicamento para el tratamiento y/o prevención de enfermedades a través de la estimulación de células NKT, preferiblemente para la fabricación de un medicamento para el tratamiento y/o prevención de enfermedades autoinmunes, enfermedades inflamatorias, cáncer e infecciones causadas por microorganismos patógenos. A, Z, R a , R b and R c have the meaning described in the first aspect of the invention, for the manufacture of a medicament for the treatment and / or prevention of diseases through the stimulation of NKT cells, preferably for the manufacture of a medicament for the treatment and / or prevention of autoimmune diseases, inflammatory diseases, cancer and infections caused by pathogenic microorganisms.
En una realización la invención se refiere al uso de un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo para la fabricación de un medicamento donde el medicamento es una vacuna o un adyuvante de vacunación. In one embodiment the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament wherein the medicament is a vaccine or a vaccination adjuvant.
En una realización la invención se refiere uso del compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo donde las enfermedades autoinmunes o inflamatorias se seleccionan de la lista que comprende asma, enfermedad pulmonar obstructiva crónica (EPOC), colitis crónica, alergias, lupus eritematoso sistémico, diabetes mellitus de tipo 1 , esclerosis múltiple, síndrome de Sjógren y artritis reumatoide. In one embodiment the invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof where the autoimmune or inflammatory diseases are selected from the list comprising asthma, chronic obstructive pulmonary disease (COPD), chronic colitis, allergies, systemic lupus erythematosus, diabetes mellitus type 1, multiple sclerosis, Sjögren's syndrome and rheumatoid arthritis.
En otra realización la invención se refiere uso de un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo, donde las enfermedades infecciosas causadas por microorganismos patógenos se seleccionan de la lista que comprende infecciones víricas como gripe, SIDA y hepatitis; infecciones bacterianas como clamidiosis, tuberculosis, estreptococosis y pseudomoniasis; e infecciones parasitarias como leishmaniosis, malaria y tripanosomiasis. In another embodiment the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the infectious diseases caused by pathogenic microorganisms are selected from the list comprising viral infections such as influenza, AIDS and hepatitis; bacterial infections such as chlamydiosis, tuberculosis, streptococcosis and pseudomoniasis; and parasitic infections such as leishmaniasis, malaria and trypanosomiasis.
En otra realización la invención se refiere uso de un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo, donde el cáncer se selecciona de la lista que comprende cáncer de mama, cánceres ginecológicos, cáncer de colon, cáncer de próstata, cáncer de piel, cáncer hepatocelular, cáncer de pulmón, cáncer de esófago, cáncer gástrico, cáncer de páncreas, cáncer de vejiga, cáncer de hígado, cáncer del tracto urinario, cáncer tiroideo, cáncer renal, melanoma, cáncer de cerebro, sarcoma, linfoma y leucemia. In another embodiment, the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the list comprising breast cancer, gynecological cancers, colon cancer, prostate cancer, cancer. of skin, hepatocellular cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, bladder cancer, liver cancer, urinary tract cancer, thyroid cancer, kidney cancer, melanoma, brain cancer, sarcoma, lymphoma and leukemia.
En otra realización la invención se refiere al uso de un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo, seleccionado de: In another embodiment the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, selected from:
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)palmitamida;- N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) palmitamide;
- (Z)-N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)tetracos- 15-enamida; - (Z) -N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) tetracos-15-enamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)decanamida; - N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-11-(4-(4- fluorofenoxi)fenil)undecanamida; - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) decanamide; - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -11- (4- (4-fluorophenoxy) phenyl) undecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-11-(4- fluorofenil)undecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -11- (4-fluorophenyl) undecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-(feniltio)octadecan-2-il)hexacosanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1- (phenylthio) octadecan-2-yl) hexacosanamide;
- N-((2R,3S,4R)-1-((3,4-dimetoxifenil)tio)-3,4-dihidroxioctadecan-2- il)hexacosanamida;  - N - ((2R, 3S, 4R) -1 - ((3,4-dimethoxyphenyl) thio) -3,4-dihydroxyoctadecan-2-yl) hexacosanamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-(2-metoxifenoxi)octadecan-2-il)hexacosanamida; - N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2-methoxyphenoxy) octadecan-2-yl) hexacosanamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-fenoxioctadecan-2-il)hexacosanamida; - N - ((2S, 3S, 4R) -3,4-dihydroxy-1-phenoxyoctadecan-2-yl) hexacosanamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-((2-metoxifenil)amino)octadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((2-methoxyphenyl) amino) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(fenilamino)octadecan-2-il)tetracos-15-enamida; - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (phenylamino) octadecan-2-yl) tetracos-15-enamide;
- 2-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)tereftalato de dimetilo; - (((2S, 3S, 4R) -3,4-Dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) -dimethyl terephthalate;
- 3-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)ftalato de dimetilo; - 3 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) dimethyl phthalate;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)tereftalato de dimetilo;- 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) dimethyl terephthalate;
- 3-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)amino)ftalato de dimetilo; - 3 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) amino) dimethyl phthalate;
- 2-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)amino)tiofen-3- carboxilato de metilo;  - 2 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) amino) thiophene-3-carboxylic acid methyl ester;
- 5-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)amino)isoftalato de dimetilo;  - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) amino) dimethyl isophthalate;
- 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-ennamido)octadecil)amino)isoftalato de dimetilo;  - 4 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-ennamido) octadecyl) amino) dimethyl isophthalate;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-((3-(hidroximetil)fenil)amino)octadecan-2- il)tetracos-15-enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((3- (hydroxymethyl) phenyl) amino) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-((4-(hidroximetil-2-metoximetil)fenil)amino)-3,4- dihidroxioctadecan-2-il)tetracos-15-enamida;  - (Z) -N - ((2S, 3S, 4R) -1 - ((4- (hydroxymethyl-2-methoxymethyl) phenyl) amino) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enamide;
- 3-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzamida;  - 3 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzamide;
- 4-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzamida;  - 4 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzamide;
- 4-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)isoftalamida;  - 4 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) isophthalamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-((2-metoxifenil)amino)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((2-methoxyphenyl) amino) octadecan-2-yl) hexacosanamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-(fenilamino)octadecan-2-il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (phenylamino) octadecan-2-yl) hexacosanamide;
- 3-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)benzamida; - 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)benzamida;- 3 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) benzamide; - 4 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) benzamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(4-(hidroximetil)fenoxi)octadecan-2-il)tetracos-15- enamida; - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (4- (hydroxymethyl) phenoxy) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(3-(hidroximetil)fenoxi)octadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (3- (hydroxymethyl) phenoxy) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-([1,1'-bifenil]-4-iloxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -1 - ([1,1'-biphenyl] -4-yloxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enamide;
- 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)-[1 ,1'-bifenil]- 3-carboxilato de metilo;  - 4 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) - [1,1'-biphenyl] -3-carboxylate of methyl;
- (Z)-N-((2S,3S,4R)-1-([1 ,1'-bifenil]-3-iloxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- ena ida;  - (Z) -N - ((2S, 3S, 4R) -1 - ([1,1'-biphenyl] -3-yloxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enylaken;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(o-toliloxi)octadecan-2-il)tetracos-15-enamida; - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (o-tolyloxy) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-(2-clorofenoxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- ena ida; - (Z) -N - ((2S, 3S, 4R) -1- (2-chlorophenoxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enylaken;
- (Z)-N-((2S,3S,4R)-1-(2-cianofenoxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -1- (2-cyanophenoxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-(2-acetamidofenoxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- ena ida;  - (Z) -N - ((2S, 3S, 4R) -1- (2-acetamidophenoxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enylaken;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(2-(metilsulfonil)fenoxi)octadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2- (methylsulfonyl) phenoxy) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(2-sulfamoilfenoxi)octadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2-sulfamoylphenoxy) octadecan-2-yl) tetracos-15-enamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12- undecanamidododecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- undecanamidododecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12-(4- metilfenilsulfonamido)dodecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- (4-methylphenylsulfonamido) dodecanamide;
- N-(12-(((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)amino)- 12-oxododecil)tridecanamida;  - N- (12 - (((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) amino) -12-oxododecyl) tridecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12-(undec- 10-enamido)dodecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- (unde-10-enamido) dodecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12-(undec- 10-inamido)dodecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- (undec-10-inamido) dodecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2- il)hexacosanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) hexacosanamide;
- 2-(((2R,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)tio)benzoato de metilo; - ácido 2-(((2R,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)tio)benzoico; - 2 - (((2R, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) thio) methyl benzoate; - 2 - (((2R, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) thio) benzoic acid;
- 2-(((2R,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)tio)benzamida;  - 2 - (((2R, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) thio) benzamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-(2-(hidroximetil)fenoxi)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2- (hydroxymethyl) phenoxy) octadecan-2-yl) hexacosanamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)benzoato de metilo; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) benzoate methyl;
- ácido 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)benzoico; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) benzoic acid;
- N-((2S,3S,4R)-3,4-dihidroxi-1-((2-(metiloximetil)fenil)amino)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((2- (methyloxymethyl) phenyl) amino) octadecan-2-yl) hexacosanamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzoato de metilo; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) methyl benzoate;
- ácido 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzoico;- 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzoic acid;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzamida; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-((3-(hidroximetil)piridin-2-il)oxi)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((3- (hydroxymethyl) pyridin-2-yl) oxy) octadecan-2-yl) hexacosanamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)nicotinato de metilo; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) methyl nicotinate;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)nicotinamida; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) nicotinamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)benzamida;  - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) benzamide;
- 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)-2',4'-difluoro- [1 ,1'-bifenil]-3-carboxilato de metilo;  - 4 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) -2 ', 4'-difluoro- [1, 1' methyl-biphenyl] -3-carboxylate;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-((4-(hidroximetil)-[1 ,1'-bifenil]-3-il)oxi)octadecan-2- 1 l)tetracos-15-enamida  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((4- (hydroxymethyl) - [1, 1'-biphenyl] -3-yl) oxy) octadecan-2 - 1 l) tetracos-15-enamide
- (Z)-N-((2R,3S,4R)-3,4-dihidroxi-1-(feniltio)octadecan-2-il)tetracos-15-enamida; - (Z) -N - ((2R, 3S, 4R) -3,4-dihydroxy-1- (phenylthio) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2R,3S,4R)-1-((4-(4-bromofenil)tiazol-2-il)tio)-3,4-dihidroxi-octadecan-2-il) tetracos-15-enamida; y - (Z) -N - ((2R, 3S, 4R) -1 - ((4- (4-bromophenyl) thiazol-2-yl) thio) -3,4-dihydroxy-octadecan-2-yl) tetracos- 15-enamide; Y
- (Z)-N-((2R,3S,4R)-3,4-dihidroxi-1-(piridin-2-iltio)-octadecan-2-il)tetracos-15- enamida. para la fabricación de un medicamento.  - (Z) -N - ((2R, 3S, 4R) -3,4-dihydroxy-1- (pyridin-2-ylthio) -octadecan-2-yl) tetracos-15-enamide. for the manufacture of a medicine.
En otra realización la invención se refiere al uso de un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo, seleccionado de: In another embodiment the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, selected from:
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)palmitamida;- N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) palmitamide;
- (Z)-N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)tetracos- 15-enamida; - (Z) -N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) tetracos-15-enamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)decanamida; - N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-11-(4-(4- fluorofenoxi)fenil)undecanamida; - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) decanamide; - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -11- (4- (4-fluorophenoxy) phenyl) undecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-11-(4- fluorofenil)undecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -11- (4-fluorophenyl) undecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-(feniltio)octadecan-2-il)hexacosanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1- (phenylthio) octadecan-2-yl) hexacosanamide;
- N-((2R,3S,4R)-1-((3,4-dimetoxifenil)tio)-3,4-dihidroxioctadecan-2- il)hexacosanamida;  - N - ((2R, 3S, 4R) -1 - ((3,4-dimethoxyphenyl) thio) -3,4-dihydroxyoctadecan-2-yl) hexacosanamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-(2-metoxifenoxi)octadecan-2-il)hexacosanamida; - N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2-methoxyphenoxy) octadecan-2-yl) hexacosanamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-fenoxioctadecan-2-il)hexacosanamida; - N - ((2S, 3S, 4R) -3,4-dihydroxy-1-phenoxyoctadecan-2-yl) hexacosanamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-((2-metoxifenil)amino)octadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((2-methoxyphenyl) amino) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(fenilamino)octadecan-2-il)tetracos-15-enamida; - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (phenylamino) octadecan-2-yl) tetracos-15-enamide;
- 2-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)tereftalato de dimetilo; - (((2S, 3S, 4R) -3,4-Dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) -dimethyl terephthalate;
- 3-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)ftalato de dimetilo; - 3 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) dimethyl phthalate;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)tereftalato de dimetilo;- 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) dimethyl terephthalate;
- 3-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)amino)ftalato de dimetilo; - 3 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) amino) dimethyl phthalate;
- 2-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)amino)tiofen-3- carboxilato de metilo;  - 2 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) amino) thiophene-3-carboxylic acid methyl ester;
- 5-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)amino)isoftalato de dimetilo;  - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) amino) dimethyl isophthalate;
- 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-ennamido)octadecil)amino)isoftalato de dimetilo;  - 4 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-ennamido) octadecyl) amino) dimethyl isophthalate;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-((3-(hidroximetil)fenil)amino)octadecan-2- il)tetracos-15-enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((3- (hydroxymethyl) phenyl) amino) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-((4-(hidroximetil-2-metoximetil)fenil)amino)-3,4- dihidroxioctadecan-2-il)tetracos-15-enamida;  - (Z) -N - ((2S, 3S, 4R) -1 - ((4- (hydroxymethyl-2-methoxymethyl) phenyl) amino) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enamide;
- 3-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzamida;  - 3 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzamide;
- 4-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzamida;  - 4 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzamide;
- 4-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)isoftalamida;  - 4 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) isophthalamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-((2-metoxifenil)amino)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((2-methoxyphenyl) amino) octadecan-2-yl) hexacosanamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-(fenilamino)octadecan-2-il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (phenylamino) octadecan-2-yl) hexacosanamide;
- 3-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)benzamida; - 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)benzamida;- 3 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) benzamide; - 4 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) benzamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(4-(hidroximetil)fenoxi)octadecan-2-il)tetracos-15- enamida; - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (4- (hydroxymethyl) phenoxy) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(3-(hidroximetil)fenoxi)octadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (3- (hydroxymethyl) phenoxy) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-([1,1'-bifenil]-4-iloxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -1 - ([1,1'-biphenyl] -4-yloxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enamide;
- 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)-[1 ,1'-bifenil]- 3-carboxilato de metilo;  - 4 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) - [1,1'-biphenyl] -3-carboxylate of methyl;
- (Z)-N-((2S,3S,4R)-1-([1 ,1'-bifenil]-3-iloxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- ena ida;  - (Z) -N - ((2S, 3S, 4R) -1 - ([1,1'-biphenyl] -3-yloxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enylaken;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(o-toliloxi)octadecan-2-il)tetracos-15-enamida; - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (o-tolyloxy) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-(2-clorofenoxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- ena ida; - (Z) -N - ((2S, 3S, 4R) -1- (2-chlorophenoxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enylaken;
- (Z)-N-((2S,3S,4R)-1-(2-cianofenoxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -1- (2-cyanophenoxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-(2-acetamidofenoxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- ena ida;  - (Z) -N - ((2S, 3S, 4R) -1- (2-acetamidophenoxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enylaken;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(2-(metilsulfonil)fenoxi)octadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2- (methylsulfonyl) phenoxy) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(2-sulfamoilfenoxi)octadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2-sulfamoylphenoxy) octadecan-2-yl) tetracos-15-enamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12- undecanamidododecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- undecanamidododecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12-(4- metilfenilsulfonamido)dodecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- (4-methylphenylsulfonamido) dodecanamide;
- N-(12-(((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)amino)- 12-oxododecil)tridecanamida;  - N- (12 - (((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) amino) -12-oxododecyl) tridecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12-(undec- 10-enamido)dodecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- (unde-10-enamido) dodecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12-(undec- 10-inamido)dodecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- (undec-10-inamido) dodecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2- il)hexacosanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) hexacosanamide;
- 2-(((2R,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)tio)benzoato de metilo; - ácido 2-(((2R,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)tio)benzoico; - 2 - (((2R, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) thio) methyl benzoate; - 2 - (((2R, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) thio) benzoic acid;
- 2-(((2R,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)tio)benzamida;  - 2 - (((2R, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) thio) benzamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-(2-(hidroximetil)fenoxi)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2- (hydroxymethyl) phenoxy) octadecan-2-yl) hexacosanamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)benzoato de metilo; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) benzoate methyl;
- ácido 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)benzoico; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) benzoic acid;
- N-((2S,3S,4R)-3,4-dihidroxi-1-((2-(metiloximetil)fenil)amino)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((2- (methyloxymethyl) phenyl) amino) octadecan-2-yl) hexacosanamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzoato de metilo; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) methyl benzoate;
- ácido 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzoico;- 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzoic acid;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzamida; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-((3-(hidroximetil)piridin-2-il)oxi)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((3- (hydroxymethyl) pyridin-2-yl) oxy) octadecan-2-yl) hexacosanamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)nicotinato de metilo; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) methyl nicotinate;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)nicotinamida; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) nicotinamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)benzamida;  - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) benzamide;
- 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)-2',4'-difluoro- [1 ,1'-bifenil]-3-carboxilato de metilo;  - 4 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) -2 ', 4'-difluoro- [1, 1' methyl-biphenyl] -3-carboxylate;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-((4-(hidroximetil)-[1 ,1'-bifenil]-3-il)oxi)octadecan-2- 1 l)tetracos-15-enamida  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((4- (hydroxymethyl) - [1, 1'-biphenyl] -3-yl) oxy) octadecan-2 - 1 l) tetracos-15-enamide
- (Z)-N-((2R,3S,4R)-3,4-dihidroxi-1-(feniltio)octadecan-2-il)tetracos-15-enamida;  - (Z) -N - ((2R, 3S, 4R) -3,4-dihydroxy-1- (phenylthio) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2R,3S,4R)-1-((4-(4-bromofenil)tiazol-2-il)tio)-3,4-dihidroxi-octadecan-2-il) tetracos-15-enamida; y  - (Z) -N - ((2R, 3S, 4R) -1 - ((4- (4-bromophenyl) thiazol-2-yl) thio) -3,4-dihydroxy-octadecan-2-yl) tetracos- 15-enamide; Y
- (Z)-N-((2R,3S,4R)-3,4-dihidroxi-1-(piridin-2-iltio)-octadecan-2-il)tetracos-15- enamida. para la fabricación de un medicamento para el tratamiento y/o prevención de enfermedades a través de la estimulación de células NKT, preferiblemente para la fabricación de un medicamento para el tratamiento y/o prevención de enfermedades autoinmunes, enfermedades inflamatorias, cáncer e infecciones causadas por microorganismos patógenos, preferiblemente para la fabricación de un medicamento donde el medicamento es una vacuna o un adyuvante de vacunación, más preferiblemente donde:  - (Z) -N - ((2R, 3S, 4R) -3,4-dihydroxy-1- (pyridin-2-ylthio) -octadecan-2-yl) tetracos-15-enamide. for the manufacture of a medicament for the treatment and / or prevention of diseases through the stimulation of NKT cells, preferably for the manufacture of a medicament for the treatment and / or prevention of autoimmune diseases, inflammatory diseases, cancer and infections caused by pathogenic microorganisms, preferably for the manufacture of a medicament wherein the medicament is a vaccine or a vaccination adjuvant, more preferably where:
- las enfermedades autoinmunes o inflamatorias se seleccionan de la lista que comprende asma, enfermedad pulmonar obstructiva crónica (EPOC), colitis crónica, alergias, lupus eritematoso sistémico, diabetes mellitus de tipo 1 , esclerosis múltiple, síndrome de Sjógren y artritis reumatoide, - autoimmune or inflammatory diseases are selected from the list that includes asthma, chronic obstructive pulmonary disease (COPD), chronic colitis, allergies, systemic lupus erythematosus, diabetes mellitus type 1, multiple sclerosis, Sjögren's syndrome and rheumatoid arthritis,
- las enfermedades infecciosas causadas por microorganismos patógenos se seleccionan de la lista que comprende infecciones víricas como gripe, SIDA y hepatitis; infecciones bacterianas como clamidiosis, tuberculosis, estreptococosis y pseudomoniasis; e infecciones parasitarias como leishmaniosis, malaria y tripanosomiasis, y  - Infectious diseases caused by pathogenic microorganisms are selected from the list that includes viral infections such as influenza, AIDS and hepatitis; bacterial infections such as chlamydiosis, tuberculosis, streptococcosis and pseudomoniasis; and parasitic infections such as leishmaniasis, malaria and trypanosomiasis, and
el cáncer se selecciona de la lista que comprende cáncer de mama, cánceres ginecológicos, cáncer de colon, cáncer de próstata, cáncer de piel, cáncer hepatocelular, cáncer de pulmón, cáncer de esófago, cáncer gástrico, cáncer de páncreas, cáncer de vejiga, cáncer de hígado, cáncer del tracto urinario, cáncer tiroideo, cáncer renal, melanoma, cáncer de cerebro, sarcoma, linfoma y leucemia. the cancer is selected from the list comprising breast cancer, gynecological cancers, colon cancer, prostate cancer, skin cancer, hepatocellular cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, bladder cancer, liver cancer, cancer of the urinary tract, thyroid cancer, kidney cancer, melanoma, brain cancer, sarcoma, lymphoma and leukemia.
Otro aspecto de la presente invención se refiere a un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo para su uso como medicamento. Another aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.
En una realización la invención se refiere a un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo para su uso como medicamento donde el medicamento es una vacuna o un adyuvante de vacunación. In one embodiment the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament wherein the medicament is a vaccine or a vaccination adjuvant.
Otro aspecto de la invención se refiere a un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo para su uso en el tratamiento y/o prevención de enfermedades a través de la estimulación de células NKT, preferiblemente para el tratamiento y/o prevención de enfermedades autoinmunes, enfermedades inflamatorias, cáncer e infecciones causadas por microorganismos patógenos. Another aspect of the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of diseases through the stimulation of NKT cells, preferably for treatment and / or prevention of autoimmune diseases, inflammatory diseases, cancer and infections caused by pathogenic microorganisms.
En una realización la invención se refiere a un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo para su uso en el tratamiento y/o prevención de enfermedades autoinmunes o inflamatorias seleccionadas de la lista que comprende asma, enfermedad pulmonar obstructiva crónica (EPOC), colitis crónica, alergias, lupus eritematoso sistémico, diabetes mellitus de tipo 1 , esclerosis múltiple, síndrome de Sjógren y artritis reumatoide. In one embodiment the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of autoimmune or inflammatory diseases selected from the list comprising asthma, chronic obstructive pulmonary disease ( COPD), chronic colitis, allergies, systemic lupus erythematosus, diabetes mellitus type 1, multiple sclerosis, Sjögren's syndrome and rheumatoid arthritis.
En otra realización la invención se refiere a un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo para su uso en el tratamiento y/o prevención de enfermedades infecciosas causadas por microorganismos patógenos seleccionadas de la lista que comprende infecciones víricas como gripe, SIDA o hepatitis; infecciones bacterianas como clamidiosis, tuberculosis, estreptococosis o pseudomoniasis; e infecciones parasitarias como leishmaniosis, malaria o tripanosomiasis. In another embodiment the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of infectious diseases caused by pathogenic microorganisms selected from the list comprising viral infections such as influenza, AIDS or hepatitis; bacterial infections such as chlamydiosis, tuberculosis, streptococcosis or pseudomoniasis; and parasitic infections such as leishmaniasis, malaria or trypanosomiasis.
En otra realización la invención se refiere a un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo para su uso en el tratamiento del cáncer, donde el cáncer se selecciona de la lista que comprende cáncer de mama, cánceres ginecológicos, cáncer de colon, cáncer de próstata, cáncer de piel, cáncer hepatocelular, cáncer de pulmón, cáncer de esófago, cáncer gástrico, cáncer de páncreas, cáncer de vejiga, cáncer de hígado, cáncer del tracto urinario, cáncer tiroideo, cáncer renal, melanoma, cáncer de cerebro, sarcoma, linfoma y leucemia. In another embodiment the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the cancer is selected from the list comprising breast cancer, gynecological cancers, cancer colon, prostate cancer, skin cancer, hepatocellular cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, bladder cancer, liver cancer, urinary tract cancer, thyroid cancer, kidney cancer, melanoma, cancer of brain, sarcoma, lymphoma and leukemia.
Otro aspecto de la presente invención se refiere a un método de tratamiento y/o prevención de enfermedades en un individuo a través de la estimulación de células NKT o mediante la elaboración de vacunas o adyuvantes de vacunación u otros métodos de activación de la respuesta del sistema inmunitario, donde estas enfermedades pueden ser enfermedades autoinmunes, enfermedades inflamatorias, cáncer o infecciones causadas por microorganismos patógenos, que comprende la administración a dicho individuo de una cantidad terapéuticamente efectiva del compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo. Another aspect of the present invention relates to a method of treatment and / or prevention of diseases in an individual through the stimulation of NKT cells or through the preparation of vaccination vaccines or adjuvants or other methods of activating the response of the system. immunitary, wherein these diseases may be autoimmune diseases, inflammatory diseases, cancer or infections caused by pathogenic microorganisms, which comprises administering to said individual a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
En una realización la invención se refiere al método de tratamiento y/o prevención de enfermedades definido anteriormente donde las enfermedades autoinmunes o inflamatorias se seleccionan de la lista que comprende asma, enfermedad pulmonar obstructiva crónica (EPOC), colitis crónica, alergias, lupus eritematoso sistémico, diabetes mellitus de tipo 1 , esclerosis múltiple, síndrome de Sjógren y artritis reumatoide. In one embodiment the invention relates to the method of treatment and / or prevention of diseases defined above where the autoimmune or inflammatory diseases are selected from the list comprising asthma, chronic obstructive pulmonary disease (COPD), chronic colitis, allergies, systemic lupus erythematosus. , diabetes mellitus type 1, multiple sclerosis, Sjögren's syndrome and rheumatoid arthritis.
En otra realización la invención se refiere al método de tratamiento y/o prevención de enfermedades definido anteriormente donde las enfermedades infecciosas causadas por microorganismos patógenos se seleccionan de la lista que comprende infecciones víricas como gripe, SIDA o hepatitis; infecciones bacterianas como clamidiosis, tuberculosis, estreptococosis o pseudomoniasis; e infecciones parasitarias como leishmaniosis, malaria o tripanosomiasis. In another embodiment the invention relates to the method of treatment and / or prevention of diseases defined above wherein the infectious diseases caused by pathogenic microorganisms are selected from the list comprising viral infections such as influenza, AIDS or hepatitis; bacterial infections such as chlamydiosis, tuberculosis, streptococcosis or pseudomoniasis; and parasitic infections like leishmaniosis, malaria or trypanosomiasis.
En otra realización la invención se refiere al método de tratamiento y/o prevención de enfermedades definido anteriormente donde el cáncer se selecciona de la lista que comprende cáncer de mama, cánceres ginecológicos, cáncer de colon, cáncer de próstata, cáncer de piel, cáncer hepatocelular, cáncer de pulmón, cáncer de esófago, cáncer gástrico, cáncer de páncreas, cáncer de vejiga, cáncer de hígado, cáncer del tracto urinario, cáncer tiroideo, cáncer renal, melanoma, cáncer de cerebro, sarcoma, linfoma y leucemia. In another embodiment the invention relates to the method of treatment and / or prevention of diseases defined above wherein the cancer is selected from the list comprising breast cancer, gynecological cancers, colon cancer, prostate cancer, skin cancer, hepatocellular cancer , lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, bladder cancer, liver cancer, urinary tract cancer, thyroid cancer, kidney cancer, melanoma, brain cancer, sarcoma, lymphoma and leukemia.
Los compuestos de la presente invención contienen uno o más nitrógenos básicos y podrían por tanto formar sales con ácidos, tanto orgánicos como inorgánicos. Ejemplos de dichas sales incluyen: sales con ácidos inorgánicos como ácido clorhídrico, ácido bromhídrico, ácido yodhídrico, ácido nítrico, ácido perclórico, ácido sulfúrico o ácido fosfórico; y sales con ácidos orgánicos, como ácido metanosulfónico, ácido trifluorometanosulfónico, ácido etanosulfónico, ácido bencenosulfónico, ácido p- toluenosulfónico, ácido fumárico, ácido oxálico, ácido acético, ácido maleico, ácido ascórbico, ácido cítrico, ácido láctico, ácido tartárico, ácido malónico, ácido glicólico, ácido succínico y ácido propiónico, entre otros. Algunos compuestos de la presente invención podrían contener uno o más protones ácidos y por tanto podrían formar también sales con bases. Ejemplos de dichas sales incluyen: sales con cationes inorgánicos como sodio, potasio, calcio, magnesio, litio, aluminio, zinc, etc.; y sales formadas con aminas farmacéuticamente aceptables como amoníaco, alquilaminas, hidroxialquilaminas, lisina, arginina, /V-metilglucamina, procaína y similares. The compounds of the present invention contain one or more basic nitrogens and could therefore form salts with acids, both organic and inorganic. Examples of such salts include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and salts with organic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid , glycolic acid, succinic acid and propionic acid, among others. Some compounds of the present invention may contain one or more acidic protons and therefore may also form salts with bases. Examples of such salts include: salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminum, zinc, etc .; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, / V-methylglucamine, procaine and the like.
No hay limitación en el tipo de sal que se puede utilizar, con la condición de que cuando se usen con fines terapéuticos sean farmacéuticamente aceptables. Se entiende por sales farmacéuticamente aceptables aquellas sales que, a criterio médico, son adecuadas para el uso en contacto con los tejidos de seres humanos u otros mamíferos sin provocar una toxicidad indebida, irritación, respuesta alérgica o similar. Las sales farmacéuticamente aceptables son ampliamente conocidas por cualquier experto en la materia. There is no limitation on the type of salt that can be used, with the proviso that when they are used for therapeutic purposes they are pharmaceutically acceptable. By pharmaceutically acceptable salts is meant those salts which, under medical criteria, are suitable for use in contact with the tissues of humans or other mammals without causing undue toxicity, irritation, allergic response or the like. The pharmaceutically acceptable salts are well known to any person skilled in the art.
Las sales de un compuesto de fórmula (I) pueden obtenerse durante el aislamiento final y purificación de los compuestos de la invención o bien pueden prepararse por tratamiento de un compuesto de fórmula (I) con una cantidad suficiente del ácido o la base deseados para dar la sal de una forma convencional. Las sales de los compuestos de fórmula (I) se pueden transformar a su vez en otras sales de compuestos de fórmula (I) por intercambio de iones mediante una resina de intercambio iónico. The salts of a compound of formula (I) can be obtained during the final isolation and purification of the compounds of the invention or they can be prepared by treatment of a compound of formula (I) with a sufficient amount of the desired acid or base to give the salt in a conventional manner. The salts of the compounds of formula (I) can in turn be converted into other salts of compounds of formula (I) by exchange of ions by an ion exchange resin.
Los compuestos de fórmula (I) y sus sales pueden diferir en ciertas propiedades físicas, pero son equivalentes a efectos de la invención. Todas las sales de los compuestos de fórmula (I) quedan incluidas dentro del ámbito de la invención. The compounds of formula (I) and their salts may differ in certain physical properties, but are equivalent for purposes of the invention. All salts of the compounds of formula (I) are included within the scope of the invention.
Los compuestos de la presente invención pueden formar complejos con disolventes en los que se hacen reaccionar o desde los que se hacen precipitar o cristalizar. Estos complejos se conocen como solvatos. Tal como se utiliza aquí, el término solvato se refiere a un complejo de estequiometría variable formado por un soluto (un compuesto de fórmula (I) o una sal del mismo) y un disolvente. Ejemplos de disolventes incluyen los disolventes farmacéuticamente aceptables como agua, etanol y similares. Un complejo con agua se conoce como hidrato. Los solvatos de los compuestos de la invención (o sus sales), incluyendo hidratos, quedan incluidos dentro del ámbito de la invención. The compounds of the present invention can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as solvates. As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (a compound of formula (I) or a salt thereof) and a solvent. Examples of solvents include pharmaceutically acceptable solvents such as water, ethanol and the like. A complex with water is known as a hydrate. The solvates of the compounds of the invention (or their salts), including hydrates, are included within the scope of the invention.
Los compuestos de fórmula (I) pueden existir en diferentes formas físicas, es decir en forma amorfa y formas cristalinas. Asimismo, los compuestos de la presente invención pueden tener la capacidad de cristalizar de más de una forma, una característica que se conoce como polimorfismo. Los polimorfos se pueden diferenciar por varias propiedades físicas bien conocidas por los entendidos en la materia como por ejemplo sus difractogramas de rayos X, puntos de fusión o solubilidad. Todas las formas físicas de los compuestos de fórmula (I), incluyendo todas sus formas polimórficas (“polimorfos”), quedan incluidas dentro del ámbito de la presente invención. The compounds of formula (I) can exist in different physical forms, i.e. in amorphous form and crystalline forms. Likewise, the compounds of the present invention may have the ability to crystallize in more than one way, a feature known as a polymorphism. The polymorphs can be differentiated by several physical properties well known to those skilled in the art such as, for example, X-ray diffractograms, melting points or solubility. All physical forms of the compounds of formula (I), including all their polymorphic forms ("polymorphs"), are included within the scope of the present invention.
Algunos compuestos de la presente invención podrían existir en forma de varios diastereoisómeros y/o varios isómeros ópticos. Los diastereoisómeros pueden separarse mediante técnicas convencionales como la cromatografía o la cristalización fraccionada. Los isómeros ópticos pueden ser resueltos mediante el uso de técnicas convencionales de resolución óptica, para dar los isómeros ópticamente puros. Esta resolución puede realizarse sobre los intermedios de síntesis que sean quirales o bien sobre los productos de fórmula (I). Los isómeros ópticamente puros también pueden ser obtenidos individualmente empleando síntesis enantioespecíficas. La presente invención cubre tanto los isómeros individuales como sus mezclas (por ejemplo mezclas racémicas o mezclas de diastereoisómeros), tanto si se obtienen por síntesis como mezclándolos físicamente. Some compounds of the present invention could exist in the form of several diastereoisomers and / or several optical isomers. The diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization. The optical isomers can be solved by the use of conventional optical resolution techniques, to give the optically pure isomers. This resolution can be made on the synthesis intermediates that are chiral or on the products of formula (I). The optically pure isomers can also be obtained individually using enantiospecific syntheses. The present invention covers both the individual isomers and their mixtures (for example racemic mixtures or mixtures of diastereomers), whether obtained by synthesis or by physically mixing them.
Otro aspecto de la presente invención se refiere a una composición farmacéutica que comprende un compuesto de fórmula I o una sal farmacéuticamente aceptable del mismo y uno o más excipientes farmacéuticamente aceptables. Los excipientes deben ser“aceptables” en el sentido de ser compatibles con los demás ingredientes de la composición y de no ser perjudiciales para quién tome dicha composición. Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The excipients must be "acceptable" in the sense of being compatible with the other ingredients of the composition and of not being harmful to whoever takes said composition.
En una realización de la invención la composición farmacéutica comprende además otro principio activo. In an embodiment of the invention the pharmaceutical composition further comprises another active ingredient.
Los compuestos de la presente invención pueden ser administrados en forma de cualquier formulación farmacéutica, la naturaleza de la cual, como es bien sabido, dependerá de la naturaleza del principio activo y de su vía de administración. En principio se puede utilizar cualquier vía de administración, por ejemplo oral, parenteral, nasal, ocular, rectal, y tópica. The compounds of the present invention can be administered in the form of any pharmaceutical formulation, the nature of which, as is well known, will depend on the nature of the active ingredient and its route of administration. In principle, any route of administration, for example oral, parenteral, nasal, ocular, rectal, and topical can be used.
Las composiciones sólidas para la administración oral incluyen comprimidos, granulados y cápsulas. En cualquier caso el método de fabricación está basado en una mezcla simple, granulación seca o granulación húmeda del principio activo con excipientes. Estos excipientes pueden ser, por ejemplo, diluyentes tales como lactosa, celulosa microcristalina, manitol o hidrogenofosfato cálcico; agentes aglutinantes como por ejemplo almidón, gelatina o polivinilpirrolidona; disgregantes como carboximetilalmidón sódico o croscarmelosa sódica; y agentes lubricantes como por ejemplo estearato magnésico, ácido esteárico o talco. Los comprimidos pueden ser además recubiertos con excipientes adecuados y mediante técnicas conocidas con el objeto de retrasar su disgregación y absorción en el tracto gastrointestinal y así conseguir una acción sostenida durante un mayor período de tiempo, o simplemente para mejorar sus propiedades organolépticas o su estabilidad. El principio activo puede también ser incorporado por recubrimiento sobre pellets inertes mediante el uso de polímeros filmógenos naturales o sintéticos. También es posible la realización de cápsulas de gelatina blanda, en las que el principio activo se mezcla con agua o con medio oleoso, por ejemplo aceite de coco, parafina líquida o aceite de oliva. Solid compositions for oral administration include tablets, granules and capsules. In any case, the manufacturing method is based on a simple mixture, dry granulation or wet granulation of the active principle with excipients. These excipients may be, for example, diluents such as lactose, microcrystalline cellulose, mannitol or calcium hydrogen phosphate; binding agents such as, for example, starch, gelatin or polyvinylpyrrolidone; disintegrants such as sodium carboxymethylstarch or croscarmellose sodium; and lubricating agents such as, for example, magnesium stearate, stearic acid or talc. The tablets can also be coated with suitable excipients and by known techniques in order to delay their disintegration and absorption in the gastrointestinal tract and thus achieve a sustained action for a longer period of time, or simply to improve their organoleptic properties or their stability. The active principle can also be incorporated by coating on inert pellets by the use of natural or synthetic film-forming polymers. It is also possible to carry out soft gelatine capsules, in which the active ingredient is mixed with water or with an oily medium, for example coconut oil, liquid paraffin or olive oil.
Se pueden obtener polvos y granulados para la preparación de suspensiones orales mediante la adición de agua, mezclando el principio activo con agentes dispersantes o humectantes; suspensantes y conservantes. También pueden añadirse otros excipientes, por ejemplo edulcorantes, aromatizantes y colorantes. Powders and granules can be obtained for the preparation of oral suspensions by the addition of water, mixing the active principle with dispersing or wetting agents; suspensants and preservatives. Other excipients may also be added, for example sweeteners, flavorings and colorants.
Como formas líquidas para la administración oral se pueden incluir emulsiones, soluciones, suspensiones, jarabes y elixires que contienen diluyentes inertes comúnmente utilizados, tales como agua destilada, etanol, sorbitol, glicerol, polietilenglicoles (macrogoles) y propilénglicol. Dichas composiciones pueden también contener coadyuvantes como agentes humectantes, suspensantes, edulcorantes, aromatizantes, conservantes y reguladores de pH. Liquid forms for oral administration may include emulsions, solutions, suspensions, syrups and elixirs containing commonly used inert diluents, such as distilled water, ethanol, sorbitol, glycerol, polyethylene glycols (macrogols) and propylene glycol. Said compositions may also contain adjuvants such as wetting agents, suspending agents, sweeteners, flavorings, preservatives and pH regulators.
Preparaciones inyectables, de acuerdo con la presente invención, para la administración parenteral, comprenden soluciones, suspensiones o emulsiones estériles, en un solvente acuoso o no acuoso como propilénglicol, polietilénglicol o aceites vegetales. Estas composiciones pueden también contener coadyuvantes, como humectantes, emulsionantes, dispersantes y conservantes. Podrían ser esterilizadas por cualquiera de los métodos conocidos o preparadas como composiciones sólidas estériles que serán disueltas en agua o cualquier otro medio inyectable estéril inmediatamente antes de uso. También es posible partir de materias primas estériles y mantenerlas en estas condiciones durante todo el proceso de fabricación. Injectable preparations, according to the present invention, for parenteral administration, comprise sterile solutions, suspensions or emulsions, in an aqueous or non-aqueous solvent such as propylene glycol, polyethylene glycol or vegetable oils. These compositions may also contain adjuvants, such as humectants, emulsifiers, dispersants and preservatives. They could be sterilized by any of the known methods or prepared as sterile solid compositions which will be dissolved in water or any other sterile injectable medium immediately before use. It is also possible to start from sterile raw materials and keep them in these conditions throughout the manufacturing process.
Para la administración rectal, el principio activo puede ser formulado preferentemente como supositorio en una base oleosa, como por ejemplo aceites vegetales o glicéridos semisintéticos sólidos, o en una base hidrófila como polietilénglicoles (macrogol). For rectal administration, the active principle can be formulated preferably as a suppository in an oily base, such as for example vegetable oils or solid semi-synthetic glycerides, or in a hydrophilic base such as polyethylene glycols (macrogol).
Los compuestos de la invención pueden también ser formulados para su aplicación tópica para el tratamiento de patologías en zonas o órganos accesibles por esta vía, como ojos, piel y tracto intestinal. Formulaciones incluyen cremas, lociones, geles, polvos, soluciones y parches en las que el compuesto se encuentra dispersado o disuelto en excipientes adecuados. Para la administración nasal o por inhalación, el compuesto puede presentarse formulado en forma de aerosol de dónde es convenientemente liberado con el empleo de propelentes adecuados. The compounds of the invention can also be formulated for topical application for the treatment of pathologies in areas or organs accessible by this route, such as eyes, skin and intestinal tract. Formulations include creams, lotions, gels, powders, solutions and patches in which the compound is dispersed or dissolved in suitable excipients. For nasal administration or by inhalation, the compound can be formulated in an aerosol form from where it is conveniently released with the use of suitable propellants.
La dosificación y la frecuencia de las dosis variarán en función de la naturaleza y gravedad de la enfermedad a tratar, la edad, la condición general y el peso del paciente, así como también del compuesto particular administrado y la vía de administración, entre otros factores. Dosage and frequency of doses will vary depending on the nature and severity of the disease to be treated, the age, general condition and weight of the patient, as well as the particular compound administered and the route of administration, among other factors .
A lo largo de la descripción y las reivindicaciones la palabra "comprende" y sus variantes no pretenden excluir otras características técnicas, aditivos, componentes o pasos. Para los expertos en la materia, otros objetos, ventajas y características de la invención se desprenderán en parte de la descripción y en parte de la práctica de la invención. Los siguientes ejemplos y figuras se proporcionan a modo de ilustración, y no se pretende que sean limitativos de la presente invención. Throughout the description and the claims the word "comprises" and its variants do not intend to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and characteristics of the invention will emerge 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.
Los compuestos de fórmula (I) pueden ser preparados siguiendo distintos métodos conocidos para cualquier persona experta en el campo de la síntesis orgánica, en particular por los procedimientos generales que se presentan en los esquemas 1 y 2. The compounds of formula (I) can be prepared following different methods known to any person skilled in the field of organic synthesis, in particular by the general procedures presented in schemes 1 and 2.
Esquema 1 Scheme 1
Figure imgf000030_0001
Figure imgf000030_0001
GA: Grupo activador  GA: Activator group
GP: Grupo protector  GP: Protective group
“Grupo protector” o GP, puede ser cualquiera conocido por un experto en la materia, como como por ejemplo, sin limitarse, acetal, bencilo, tritilo, tert-butildifenilsililo (TBDPS) y otros grupos protectores adecuados en cada caso (ver Green, Protective Groups in Organic Chemistry. 1999, Ed. John Wiley & Sons); "Protective group" or GP, may be any known to one skilled in the art, such as, for example, without limitation, acetal, benzyl, trityl, tert-butyldiphenylsilyl (TBDPS) and other suitable protecting groups in each case (see Green, Protective Groups in Organic Chemistry, 1999, Ed. John Wiley &Sons);
“Grupo Activador” o GA, puede ser cualquiera conocido por un experto en la materia, como por ejemplo, sin limitarse, cloruro, bromuro, nitrobenzensulfonilo (Ns), toluensulfonilo (Ts), metilsulfonilo (Ms) o, naftalensulfonilo. "Activating Group" or GA, may be any known to one skilled in the art, such as, without limitation, chloride, bromide, nitrobenzensulfonyl (Ns), toluenesulfonyl (Ts), methylsulfonyl (Ms) or, naphthalenesulfonyl.
Una primera vía (esquema 1) consiste en la formación de los intermedios de tipo II por reacción de un ácido activado (compuestos de tipo 2) con las correspondientes aziridinas (compuestos de tipo 1) en presencia, en caso de ser necesaria, de una base orgánica terciaria como por ejemplo la Et3N. Seguidamente, la acil-aziridina formada II reacciona con compuestos de tipo 3 en presencia de una base (DBU, K2C03, CsC03) dando lugar al intermedio III. La desprotección final de los grupos hidroxilo presentes en la molécula conduce a los compuestos de fórmula (I). A first way (scheme 1) consists of the formation of type II intermediates by reaction of an activated acid (type 2 compounds) with the corresponding aziridines (type 1 compounds) in the presence, if necessary, of a tertiary organic base such as for example Et 3 N. Next, the acyl aziridine formed II reacts with compounds of type 3 in the presence of a base (DBU, K 2 C03, CsC0 3 ) giving rise to intermediate III. The final deprotection of the hydroxyl groups present in the molecule leads to the compounds of formula (I).
Una segunda vía (esquema 1) consiste en la obtención de los intermedios de tipo IV por apertura de las aziridinas activadas de tipo 4 con compuestos de tipo 3 en presencia de bases inorgánicas en caso de ser necesario (Na2C03,NaHC03, Cs2C03). La desprotección del grupo activador de la amina conduce a los intermedios de tipo V. La reacción de los intermedios V con los ácidos activados 2) conduce a los mismos intermedios de tipo III. A second way (scheme 1) consists in obtaining the type IV intermediates by opening activated type 4 aziridines with type 3 compounds in the presence of inorganic bases, if necessary (Na 2 C0 3 , NaHCO 3 , Cs 2 C0 3 ). The deprotection of the activating group of the amine leads to the type V intermediates. The reaction of the intermediates V with the activated acids 2) leads to the same type III intermediates.
Por último, se puede utilizar una tercera vía (esquema 1) en la cual los compuestos de tipo 5 se someten a una sustitución nucleófila aromática por parte de los compuestos de tipo 6 dando lugar a los intermedios de tipo VI. En este caso, la reducción de grupo azida por métodos descritos en la literatura conduce a los intermedios de tipo V antes comentados. Finally, a third way (scheme 1) can be used in which the compounds of type 5 are subjected to an aromatic nucleophilic substitution by the compounds of type 6 giving rise to the intermediates of type VI. In this case, the reduction of the azide group by methods described in the literature leads to the type V intermediates discussed above.
Esquema 2 Scheme 2
Figure imgf000032_0001
Figure imgf000032_0001
Alternativamente, en casos concretos donde Re contenga grupos funcionales susceptibles a diferentes modificaciones, éstas pueden ser llevadas a cabo sobre los intermedios de tipo III, VI o incluso sobre compuestos de fórmula (I) siguiendo metodologías conocidas por expertos en el campo. En el esquema 2 se ilustran dichas modificaciones en el caso particular en el cual Re es igual a Y. Así, en el caso de tener una amina como sustituyente directo del anillo A, esta se puede transformar en amida, urea, carbamato o sulfonamida y también se puede poli-alquilar utilizando métodos ampliamente descritos en la literatura. De igual forma, si el anillo de tipo A presenta un grupo alcohol directamente unido, éste se puede transformar en un éter, un carbamato o un éster utilizando los reactivos adecuados en cada caso. Si unido directamente al anillo A encontramos un ácido sulfónico éste se puede transformar en una sulfonamida. Y, por último, si unido al anillo A se encuentra un grupo ácido o éster, se puede transformar en amida, ácido, éster o alcohol siguiendo métodos descritos en la literatura. Alternatively, in specific cases where Re contains functional groups susceptible to different modifications, these can be carried out on the intermediates of type III, VI or even on compounds of formula (I) following methodologies known to experts in the field. In scheme 2 such modifications are illustrated in the particular case in which Re is equal to Y. Thus, in the case of having an amine as a direct substituent of ring A, it can be transformed into amide, urea, carbamate or sulfonamide and It can also be poly-alkylated using methods widely described in the literature. Similarly, if the ring type A presents a directly linked alcohol group, it can be transformed into an ether, a carbamate or an ester using the appropriate reagents in each case. If attached directly to ring A we find a sulphonic acid that can be transformed into a sulfonamide. And finally, if an acid or ester group is attached to ring A, it can be converted to amide, acid, ester or alcohol following methods described in the literature.
Los materiales de partida para los métodos preparativos (compuestos de tipo 1-6) están disponibles comercialmente o bien se pueden preparar mediante métodos descritos en la literatura. En los esquemas 3, 4 y 5 se ilustran algunos de ellos. En el caso de los compuestos de tipo 1 , 4 y 5 en los cuales el grupo Rb corresponde a un grupo alquílico de Ci4H2g, la ruta sintética utilizada fue descrita por Harrak et al Eur. J. Org. Chem. 2008, 4647 y se ilustra en el esquema 3. The starting materials for the preparative methods (compounds of type 1-6) are commercially available or can be prepared by methods described in the literature. In schemes 3, 4 and 5 some of them are illustrated. In the case of compounds of type 1, 4 and 5 in which the group Rb corresponds to an alkyl group of Ci 4 H 2g , the synthetic route used was described by Harrak et al Eur. J. Org. Chem. 2008, 4647 and illustrated in scheme 3.
Esquema 3: síntesis de compuestos de tipo 1, 4 y 5 donde Rb es C14H29 alquilo Scheme 3: synthesis of compounds of type 1, 4 and 5 where Rb is C 14 H 29 alkyl
Figure imgf000033_0001
Figure imgf000033_0001
i) Tf20, NaN3, CuS04, K2C03 en MeOH/DCM/H20; ii)TBDPSCI, Imidazol, DMAP en DMF; i) Tf 2 0, NaN 3 , CuSO 4 , K 2 CO 3 in MeOH / DCM / H 2 0; ii) TBDPSCI, Imidazole, DMAP in DMF;
iii) DMP, pTSA en DCM; iv) TBAF en THF; v) MsCI, TEA en THF anh.; vi) PPh3, DI PEA en iii) DMP, pTSA in DCM; iv) TBAF in THF; v) MsCl, TEA in THF anh .; vi) PPh 3 , DI PEA in
THF:H20 9:1 ; vii) NsCI, TEA en DCM anh. THF: H 2 0 9: 1; vii) NsCI, TEA in DCM anh.
En el caso de los compuestos de tipo 2 en los cuales el grupo Ra presenta un grupo amida, carbamato, urea, sulfonamida, éster o éter unido a R4, éstos se pueden sintetizar siguiendo la ruta sintética descrita en el esquema 4 y ampliamente conocida por expertos en la materia. In the case of type 2 compounds in which the Ra group has an amide, carbamate, urea, sulfonamide, ester or ether group bound to R 4 , these can be synthesized following the synthetic route described in scheme 4 and widely known by experts in the field.
Esquema 4: síntesis de compuestos de tipo 2. Scheme 4: synthesis of type 2 compounds.
1) Desprotección 1) Deprotection
Acilación O 2) Activación de
Figure imgf000034_0001
O Acylation O 2) Activation of
Figure imgf000034_0001
OR
1) Desprotección  1) Deprotection
2) Activación de  2) Activation of
Figure imgf000034_0006
Figure imgf000034_0006
1) Desprotección 1) Deprotection
2) Activación de  2) Activation of
Alquilación acilo  Acyl Alkylation
O
Figure imgf000034_0002
Formación de 1) Desprotección OR
Figure imgf000034_0002
Training of 1) Deprotection
carbamato 2) Activación de carbamate 2) Activation of
Figure imgf000034_0004
acilo
Figure imgf000034_0004
acilo
Figure imgf000034_0003
Figure imgf000034_0003
1) Desprotección  1) Deprotection
0 0 0 0  0 0 0 0
2) Activación de  2) Activation of
acilo acilo
Figure imgf000034_0005
Figure imgf000034_0005
Figure imgf000034_0007
Figure imgf000034_0007
n = alquilo, alquenilo, alquinilo C9-C30  n = alkyl, alkenyl, C9-C30 alkynyl
En el caso de los compuestos de tipo 3 y 6 en los cuales el grupo Re contenga grupos funcionales susceptibles a diferentes modificaciones, éstas pueden ser realizadas antes de incorporarse a los intermedios III, IV y VI siguiendo metodologías conocidas por expertos en el campo. En el esquema 5 se ilustran algunas de ellas. Así, en el caso de tener una amina como sustituyente directo del anillo A, ésta se puede transformar en amida, urea, carbamato o sulfonamida y también se puede poli-alquilar utilizando métodos ampliamente descritos en la literatura. De igual forma, si el anillo de tipo A presenta un grupo alcohol directamente unido, éste se puede transformar en un éter, un carbamato o un éster utilizando los reactivos adecuados en cada caso. Si unido directamente al anillo A encontramos un ácido sulfónico éste se puede transformar en una sulfonamida. Y, por último, si unido al anillo A se encuentra un grupo ácido o éster, se puede transformar en amida, ácido, éster o alcohol siguiendo métodos descritos en la literatura. Esquema 5: síntesis de compuestos de tipo 3 y 6.
Figure imgf000035_0002
In the case of compounds of type 3 and 6 in which the group Re contains functional groups susceptible to different modifications, these can be carried out before joining the intermediates III, IV and VI following methodologies known to experts in the field. In scheme 5 some of them are illustrated. Thus, in the case of having an amine as a direct substituent of ring A, it can be transform into amide, urea, carbamate or sulfonamide and can also be poly-alkylated using methods widely described in the literature. Similarly, if the ring type A has a directly linked alcohol group, it can be transformed into an ether, a carbamate or an ester using the appropriate reagents in each case. If attached directly to ring A we find a sulphonic acid that can be transformed into a sulfonamide. And finally, if an acid or ester group is attached to ring A, it can be converted to amide, acid, ester or alcohol following methods described in the literature. Scheme 5: synthesis of type 3 and 6 compounds.
Figure imgf000035_0002
Figure imgf000035_0001
EJEMPLOS
Figure imgf000035_0001
EXAMPLES
Los siguientes ejemplos sirven para una mejor ilustración de la invención, pero no deben ser considerados como limitantes de ella. The following examples serve for a better illustration of the invention, but should not be considered as limiting thereof.
Abreviaturas: Abbreviations:
ACN, Acetonitrilo; AcOEt, Acetato de etilo; Anh., Anhidro; CSA, Ácido canforsulfónico; DCM, Diclorometano; DMAP, Dimetilaminopiridina; DMF, Dimetilformamida; EDC, 1- (3-Dimetilaminopropil)-3-etilcarbodiimida; Et3N, Trietilamina; HPLC, Cromatografía líquida de alta resolución; MeOH, Metanol; MS, Espectrómetro de masas; m/z, Relación masa/carga; ND, No determinada; NHS, N-hidroxisuccinimida; tBuOLi, terc- Butóxido de litio; THF, Tetrahidrofurano ACN, Acetonitrile; AcOEt, Ethyl Acetate; Anh., Anhydrous; CSA, Camphorsulfonic Acid; DCM, Dichloromethane; DMAP, Dimethylaminopyridine; DMF, Dimethylformamide; EDC, 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide; Et 3 N, Triethylamine; HPLC, high resolution liquid chromatography; MeOH, Methanol; MS, Mass spectrometer; m / z, Mass / load ratio; ND, Not determined; NHS, N-hydroxysuccinimide; tBuOLi, tert- Lithium butoxide; THF, Tetrahydrofuran
Datos generales: General data:
Los productos fueron analizados por FIA (Flow injection analysis - Análisis por inyección de flujo) empleando uno de los siguientes equipos: The products were analyzed by FIA (Flow injection analysis) using one of the following equipment:
Un equipo UPLC-TOF de Waters, provisto de un espectrómetro de masas modelo LCT Premier Orthogonal Accelerated Time of Flight (TOF). El detector de MS ha operado en modo de ionización electropulverización positiva y negativa y ha realizado un barrido de m/z de 50 a 1500 Da. Se inyectaron 8 microlitros de cada muestra con un caudal de 0.07 ml/min utilizando los siguientes disolventes: A: Acetonitrilo y B: Agua en proporción 70% a 30% respectivamente durante 2 min. A UPLC-TOF team from Waters, equipped with an LCT Premier Orthogonal Accelerated Time of Flight (TOF) mass spectrometer. The MS detector has operated in positive and negative electrospray ionization mode and has performed a m / z sweep of 50 to 1500 Da. 8 microliters of each sample were injected with a flow rate of 0.07 ml / min using the following solvents: A: Acetonitrile and B: Water in proportion 70% to 30% respectively during 2 min.
Un equipo HPLC-PDA-MS de Thermo Scientific Dionex (Thermo Ultímate 3000SD) provisto de un detector de diodos en serie y un espectrómetro de masas LTQ XL ESI- ion trap de Thermo Scientific. El detector de MS ha operado en modo de ionización electropulverización positiva y negativa y ha realizado un barrido de m/z de 50 a 2000Da. Se inyectaron 5 microlitros de cada muestra a 0.5mg/ml con un caudal de 0.7 ml/min utilizando los siguientes disolventes: A: Acetonitrilo+0.05% acido fórmico y B: Agua+0.05% acido fórmico en proporción 60% a 40% respectivamente durante 2 min. Alternativamente, el análisis se realizó mediante el mismo equipo de HPLC-PDA-MS utilizando para la separación cromatográfica una columna ZORBAX Extend-C18 3.5 micrómetros 2.1x50mm. Para la elución se siguió uno de los dos gradientes de solventes que se describen a continuación: An HPLC-PDA-MS from Thermo Scientific Dionex (Thermo Ultimate 3000SD) equipped with a diode detector in series and an LTQ XL ESI-ion trap mass spectrometer from Thermo Scientific. The MS detector has operated in positive and negative electrospray ionization mode and has performed a m / z sweep of 50 to 2000Da. 5 microliters of each sample was injected at 0.5mg / ml with a flow rate of 0.7 ml / min using the following solvents: A: Acetonitrile + 0.05% formic acid and B: Water + 0.05% formic acid in proportion 60% to 40% respectively for 2 min. Alternatively, the analysis was carried out using the same HPLC-PDA-MS equipment, using a ZORBAX Extend-C18 column for the chromatographic separation. 3.5 micrometers 2.1x50mm. For the elution, one of the two solvent gradients described below was followed:
MÉTODO A: Siendo el solvente A: Agua+0.05% acido fórmico y B: Acetonitrilo+0.05% acido fórmico, el caudal de fase móvil de 0.6ml/ml y un gradiente de 5-100% de B, 0- 3min; 100% B, 3-6min; 100-5% B, 6-7min; 5% B, 7-10min. METHOD A: Being the solvent A: Water + 0.05% formic acid and B: Acetonitrile + 0.05% formic acid, the mobile phase flow rate of 0.6ml / ml and a gradient of 5-100% B, 0-3min; 100% B, 3-6min; 100-5% B, 6-7min; 5% B, 7-10min.
MÉTODO B: Siendo el solvente A: Agua+0.1% hidróxido amónico y B: Acetonitrilo+0.1% hidróxido amónico, el caudal de fase móvil de 0.6ml/ml y un gradiente de 5-100% de B, 0-3min; 100% B, 3-6min; 100-5% B, 6-7min; 5% B, 7- 10min. METHOD B: Being the solvent A: Water + 0.1% ammonium hydroxide and B: Acetonitrile + 0.1% ammonium hydroxide, the mobile phase flow rate of 0.6ml / ml and a gradient of 5-100% B, 0-3min; 100% B, 3-6min; 100-5% B, 6-7min; 5% B, 7- 10min.
Los valores m/z de los compuestos corresponden a (M+H) en modo positivo a menos que se indique lo contrario, donde (M+18) corresponde a (M+NH4) y (M+23) corresponde a (M+Na), ambos en modo positivo, y (M-1) corresponde a (M-H) y (M+45) corresponde a (M+HCOO ), ambos en modo negativo. The m / z values of the compounds correspond to (M + H) in positive mode unless otherwise indicated, where (M + 18) corresponds to (M + NH 4 ) and (M + 23) corresponds to (M) + Na), both in positive mode, and (M-1) corresponds to (MH) and (M + 45) corresponds to (M + HCOO), both in negative mode.
SINTESIS INTERMEDIOS INTERMEDIATE SYNTHESIS
Intermedios tipo II. Intermediates type II.
Los intermedios de tipo II que se listan en la Tabla 1 se sintetizaron siguiendo el método general siguiente: The type II intermediates listed in Table 1 were synthesized following the following general method:
El compuesto de tipo 1 (1eq), se disolvió en DCM anh. y se añadieron 2eq Et3N a - 10°C. A la disolución anterior se le añadió otra solución de 1 ,2eq del cloruro de acilo correspondiente (compuesto de tipo 2) en DCM anh. - Concentración final del compuesto 1 a 0.05M. La mezcla se dejó a temperatura ambiente y se agitó toda la noche. Se eliminó el disolvente a presión reducida y se purificó por cromatografía en columna de Sílica-Gel. The compound of type 1 (1eq) was dissolved in DCM anh. and 2eq Et3N at -10 ° C was added. To the previous solution was added another solution of 1.2eq of the corresponding acyl chloride (compound of type 2) in DCM anh. - Final concentration of compound 1 at 0.05M. The mixture was left at room temperature and stirred overnight. The solvent was removed under reduced pressure and purified by silica gel column chromatography.
Tabla 1
Figure imgf000038_0001
Table 1
Figure imgf000038_0001
Intermedios tipo III Intermediates type III
Los intermedios de tipo III que se listan en la Tabla 2 se sintetizaron siguiendo uno de los métodos generales A, B.1 , B.2 o B.3 que se describen a continuación: The type III intermediates listed in Table 2 were synthesized following one of the general methods A, B.1, B.2 or B.3 described below:
Método A: Apertura Acil-Aziridina II Method A: Acyl-Aziridine II Opening
Se dispuso el intermedio tipo II (1eq) en un tubo apto para reactores de microondas junto con el correspondiente reactivo tipo 3 (1 ,2eq). Se añadió ACN anh. a concentración 0.1M. Finalmente, se adicionó una base orgánica (1 ,2eq). La mezcla reaccionó en un reactor de microondas a 150W y 100ps durante tiempos variables entre 5 y 90 min. hasta consumición total del intermedio II. Se eliminó el disolvente a presión reducida y se purificó el crudo de reacción por cromatografía en columna de Sílica-Gel para obtener el intermedio III correspondiente. The type II intermediate (1eq) was placed in a tube suitable for microwave reactors together with the corresponding type 3 reagent (1, 2eq). ACN anh was added. at 0.1M concentration. Finally, an organic base (1, 2eq) was added. The mixture reacted in a microwave reactor at 150W and 100ps for variable times between 5 and 90 min. until total consumption of intermediate II. The solvent was removed under reduced pressure and the reaction crude was purified by silica gel column chromatography to obtain the corresponding intermediate III.
Método B.1 : Acilación Intermedios V Method B.1: Intermediate Acylation V
Se dispuso el intermedio V (1eq) en THF anh. a 0.05M junto con el cloruro de acilo (1 ,2eq) correspondiente (reactivo tipo 2) y Et3N (1 ,5eq). La mezcla se agitó a 50°C toda la noche. El disolvente se eliminó a presión reducida y el crudo resultante se purificó por cromatografía en columna de Sílica-Gel para obtener el intermedio III correspondiente. Intermediate V (1eq) was placed in THF anh. at 0.05M together with the corresponding acyl chloride (1, 2eq) (type 2 reagent) and Et3N (1.5eq). The mixture was stirred at 50 ° C overnight. The solvent was removed under reduced pressure and the resulting crude was purified by silica gel column chromatography to obtain the corresponding intermediate III.
Método B.2: Acilación Intermedios V Method B.2: Intermediate Acylation V
Se disolvió el intermedio V (1eq) junto con el derivado NHS-acilo correspondiente (1 ,2eq) (reactivo tipo 2) en THF anh. Se añadieron 3eq de Et3N y la mezcla se agitó a 50°C toda la noche. El disolvente se evaporó a presión reducida y el crudo resultante se purificó por cromatografía en columna de Sílica-Gel para obtener el intermedio III correspondiente. Método B.3: Acilación Intermedio V Intermediate V (1eq) was dissolved together with the corresponding NHS-acyl derivative (1, 2eq) (reagent type 2) in THF anh. 3eq of Et 3 N was added and the mixture was stirred at 50 ° C all night. The solvent was evaporated under reduced pressure and the resulting crude was purified by silica gel column chromatography to obtain the corresponding intermediate III. Method B.3: Intermediate Acilation V
Sobre el intermedio de tipo V (1eq) se adicionó una disolución 0,1 M formada por EDC (2eq), DMAP (0,2eq) y el ácido correspondiente (1eq, compuesto tipo 2) en DCM. La mezcla resultante se mantuvo en agitación a temperatura ambiente de 18 a 24h según el caso hasta la desaparición total del compuesto de partida. Seguidamente, se adicionó una mezcla de H20/DCM o H20/AcOEt, se separó la fase orgánica y se lavó con una disolución de NaCI saturada. Se secó con Na2S04 anh, se filtró y se eliminó el disolvente a presión reducida. El crudo resultante se purificó por cromatografía en columna de Sílica-Gel columna de Sílica-Gel para obtener el intermedio III correspondiente. A 0.1 M solution formed by EDC (2eq), DMAP (0.2eq) and the corresponding acid (1eq, compound type 2) in DCM was added to the intermediate of type V (1eq). The resulting mixture was kept stirring at room temperature from 18 to 24 h depending on the case until the total disappearance of the starting compound. Subsequently, a mixture of H 2 O / DCM or H 2 O / AcOEt was added, the organic phase was separated and washed with a saturated NaCl solution. It was dried with Na 2 SO 4 anh, filtered and the solvent was removed under reduced pressure. The resulting crude was purified by column chromatography of Silica-Gel column of Silica-Gel to obtain the corresponding intermediate III.
Tabla 2 Table 2
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
ND: No determinado  ND: Not determined
Intermedio tipo IV Los intermedios de tipo IV que se listan en la Tabla 3 se sintetizaron siguiendo uno de los métodos generales C.1 , C.2 o C.3 que se describen a continuación: Intermediate type IV The type IV intermediates listed in Table 3 were synthesized following one of the general methods C.1, C.2 or C.3 described below:
Método C.1 : Cuando Z=Q, GA = grupo Nosilo El compuesto tipo 4 se disolvió en ACN a 0.1 M. Se añadió el correspondiente reactivo tipo 3 (1 ,1 eq) y Cs2C03 (1 ,1 eq) y la mezcla resultante se agitó a 85°C hasta consumición total del producto de partida. Seguidamente la mezcla resultante se trató siguiendo la metódica descrita en el tratamiento 1 o 2 según proceda para obtener el compuesto tipo IV final. Method C.1: When Z = Q, GA = Nosilo group Compound type 4 was dissolved in ACN at 0.1 M. The corresponding type 3 reagent (1.1 eq) and Cs 2 C0 3 (1.1 eq) were added. and the resulting mixture was stirred at 85 ° C until total consumption of the starting product. Then the resulting mixture was treated following the method described in treatment 1 or 2 as appropriate to obtain the final type IV compound.
Método C.2: Cuando Z=S, GA = grupo Nosilo Method C.2: When Z = S, GA = Nosilo group
El compuesto tipo 2 se disolvió en ACN a 0.1M. Se añadió el compuesto tipo 4 (1 ,2eq) y NaHC03 (1 ,2eq) y la mezcla resultante se agitó a 50°C hasta consumición total del producto de partida. Seguidamente la mezcla resultante se trató siguiendo la metódica descrita en el tratamiento 1 o 2 según proceda para obtener el compuesto tipo IV final. The type 2 compound was dissolved in ACM at 0.1M. Compound type 4 (1, 2eq) and NaHCO 3 (1, 2eq) were added and the resulting mixture was stirred at 50 ° C until total consumption of the starting product. Then the resulting mixture was treated following the method described in treatment 1 or 2 as appropriate to obtain the final type IV compound.
Método C.3: Cuando Z=NH, GA = grupo Nosilo El compuesto tipo 2 se disolvió en ACN a 0.1M. Se añadió el compuesto tipo 4 (1 , 1 eq) y la mezcla resultante se agitó a 85°C hasta consumición total del producto de partida. Seguidamente la mezcla resultante se trató siguiendo la metódica descrita en el tratamiento 1 o 2 según proceda para obtener el compuesto tipo IV final. Method C.3: When Z = NH, GA = Nosilo group The type 2 compound was dissolved in ACM at 0.1M. Compound type 4 (1.1 eq) was added and the resulting mixture was stirred at 85 ° C until complete consumption of the starting product. Then the resulting mixture was treated following the method described in treatment 1 or 2 as appropriate to obtain the final type IV compound.
Tratamiento 1: Los crudos de reacción que mostraron un solo producto se utilizaron directamente en la siguiente reacción sin llegarse a aislar. Tratamiento 2: Se disolvió el crudo de reacción en AcOEt y H20, se separaron las fases y se lavó la fase orgánica con una disolución de NaCI saturada. Se secó la fase orgánica con agentes desecantes tales como MgS04, se filtró y se eliminó el disolvente a presión reducida. El residuo resultante se purificó por cromatografía en columna de Sílica-Gel. Treatment 1: The reaction crude that showed a single product was used directly in the next reaction without being able to isolate. Treatment 2: The reaction crude was dissolved in AcOEt and H 2 0, the phases were separated and the organic phase was washed with a saturated NaCl solution. The organic phase was dried with drying agents such as MgSO 4 , filtered and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography.
Tabla 3 Table 3
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Intermedio tipo V Los intermedios de tipo V que se listan en la Tabla 4 se sintetizaron siguiendo uno de los métodos D o E descritos a continuación: Intermediate type V The intermediates of type V that are listed in Table 4 were synthesized following one of the methods D or E described below:
Método D: Desprotección de GA (GA = grupo Nosilo) Intermedios IV El intermedio tipo IV (1eq) se disolvió en ACN a 0.1 M y se le añadió tiofenol (3eq) y Cs2C03 (4eq). La mezcla resultante se agitó a temperatura ambiente toda la noche. Se diluyó el crudo de reacción en AcOEt y H20, se separaron las fases y se lavó la fase orgánica con una disolución de NaCI saturada. La fase orgánica se secó con un agente desecante tipo MgS04, se filtró y se eliminó el disolvente a presión reducida. El crudo obtenido se purificó por cromatografía en columna de Sílica-Gel. Method D: Deprotection of GA (GA = Nosilo group) Intermediate IV Intermediate type IV (1eq) was dissolved in 0.1 M ACN and thiophenol (3eq) and Cs2C03 (4eq) were added. The resulting mixture was stirred at room temperature overnight. The reaction crude was diluted in AcOEt and H 2 0, the phases were separated and the organic phase was washed with a saturated NaCl solution. The organic phase was dried with a desiccant agent type MgSO 4 , filtered and the solvent was removed under reduced pressure. The crude obtained was purified by chromatography on a silica-gel column.
Método E: Reducción del grupo azida Intermedios VI Method E: Reduction of azide group Intermediates VI
El intermedio tipo VI (1eq) se disolvió en AcOEt a 0.02M, se le añadió Pd/C y se agitó bajo presión de Hidrogeno a 1 atmosfera durante tiempo necesario para la consumición total del producto de partida. Se filtró el crudo de reacción y se eliminó el disolvente a presión reducida. Tabla 4 The intermediate type VI (1eq) was dissolved in AcOEt at 0.02M, Pd / C was added and it was stirred under pressure of Hydrogen to 1 atmosphere for time necessary for the total consumption of the starting product. The reaction crude was filtered and the solvent was removed under reduced pressure. Table 4
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Intermedio tipo VI Los intermedios de tipo VI que se listan en la Tabla 5 se sintetizaron siguiendo el método general que se describe a continuación: Se disolvió el compuesto de tipo 5 en DMF anh. a 0.1M y se agitó 15 min bajo atmosfera inerte. Posteriormente se añadió 1 ,5eq de NaH o 1 ,2eq de tBuOLi, el reactivo tipo 6 y se calentó la mezcla a 50°C hasta consumición total del compuesto 5 de partida. Se diluyó el crudo con AcOEt y H20, se separó la fase orgánica y se lavó con una disolución saturada de NaCI. La fase orgánica se secó con un agente desecante tipo MgS04, se filtró y se evaporó el disolvente a presión reducida. Se purificó el residuo resultante por cromatografía en columna de Sílica-Gel para obtener el correspondiente intermedio tipo VI. Tabla 5 Intermediate type VI The intermediates of type VI that are listed in Table 5 were synthesized following the general method described below: The compound of type 5 was dissolved in DMF anh. at 0.1M and stirred 15 min under inert atmosphere. Subsequently, 1.5eq of NaH or 1.2eq of tBuOLi, type 6 reagent was added and the mixture was heated at 50 ° C until total consumption of the starting compound 5 was used. The crude was diluted with AcOEt and H 2 0, the organic phase was separated and washed with a saturated solution of NaCl. The organic phase was dried with a desiccant agent type MgSO 4 , filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the corresponding type VI intermediate. Table 5
Figure imgf000052_0001
Figure imgf000052_0001
Compuestos de Formula I Formula I compounds
Los compuestos de Fórmula I que se listan en la Tabla 6 se sintetizron siguiendo el método general que se describe a continuación: Se disolvió el correspondiente compuesto tipo III en una mezcla DCM/MeOH 1 :1 a 0.015M. Se añadió CSA (2-4eq según proceda) y la mezcla se agitó a 30°C hasta consumición total del producto de partida. Seguidamente la mezcla resultante se trató siguiendo la metódica descrita en el tratamiento 3 o 4 según proceda para obterer el correspondiente compuesto I. The compounds of Formula I listed in Table 6 were synthesized following the general method described below: The corresponding type III compound was dissolved in a DCM / MeOH 1: 1 to 0.015M mixture. CSA (2-4eq as appropriate) was added and the mixture was stirred at 30 ° C until total consumption of the starting product. Then the resulting mixture was treated following the method described in treatment 3 or 4 as appropriate to obtain the corresponding compound I.
Tratamiento 3: Filtración. Aquellos productos que precipitan en el medio de reacción se aislaron por filtración. Treatment 3: Filtration. Those products that precipitate in the reaction medium are isolated by filtration.
Tratamiento 4: Neutralización. En el caso de productos solubles, se neutralizó el crudo antes mencionado con Resina ácida IRA-400, se filtró y se eliminó el disolvente a presión reducida. En algunos casos, se requirió purificación por cromatografía en columna de Sílica-Gel. Treatment 4: Neutralization. In the case of soluble products, the aforementioned crude was neutralized with acidic resin IRA-400, filtered and the solvent was removed under reduced pressure. In some cases, purification was required by silica gel column chromatography.
Tabla 6 Table 6
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Ensayos de actividad farmacológica Determinación de la capacidad activadora de células NKT de ratón Pharmacological activity assays Determination of the activating capacity of mouse NKT cells
Los esplenocitos se obtuvieron de ratones Balb/c mediante protocolos estándar conocidos. Los esplenocitos se incubaron a 5x105 células/pocillo en placas de 96 pocilios junto con 1 microgramo/ml del compuesto a ensayar, disueltos en una mezcla de 99% v:v de PBS (tampón fosfato a pH7,2 con 1% v:v de DMSO. El cultivo se incubó durante 96 horas y se recogió el sobrenadante. Se midieron los niveles de IFN-gamma e IL-4 mediante ensayos ELISAs (del inglés Enzyme-Linked ImmunoSorbent Assay; ensayo por inmunoabsorción ligado a enzimas) tipo sándwich (BioLegend) siguiendo los protocolos facilitados por el fabricante. Determinación de la capacidad activadora de células NKT humanas Splenocytes were obtained from Balb / c mice by known standard protocols. Splenocytes were incubated at 5x10 5 cells / well in 96-well plates together with 1 microgram / ml of the compound to be tested, dissolved in a mixture of 99% v: v PBS (phosphate buffer at pH7.2 with 1% v: v of DMSO The culture was incubated for 96 hours and the supernatant was collected.The levels of IFN-gamma and IL-4 were measured by ELISAs (from the Enzyme-Linked ImmunoSorbent Assay, enzyme-linked immunosorbent assay) sandwich type (BioLegend) following the protocols provided by the manufacturer. Determination of the activating capacity of human NKT cells
Para los estudios con células humanas, se utilizaron células C1 R transfectadas con proteína CD1d (C1 r-CD1d+) como células presentadoras, PBMCs (células mononucleares de sangre periférica) como complemento celular y células NKT extraídas de sangre de donantes sanos. 90.000 células C1 R-CD1d+ se incubaron con 10 microgramos/ml de los análogos. Durante 1 hora a 37°C, posteriormente se irradiaron a 45Gy para frenar su crecimiento. Del mismo modo, las células PBMCs se irradiaron a 30Gy. Posteriormente, las células C1 R-CD1d+ incubadas con los análogos, se dispusieron en una placa de 96 pocilios de manera que se juntaron 30.000 células por pocilio junto con 40.000 células PBMCs, a esta mezcla se añadieron 10.000 células/pocillo de células NKT purificadas. A las 48 horas se recogieron los sobrenadantes. Los niveles de IFN-gamma e IL-4 se midieron mediante ELISAs tipos sandwich (InvitroGen) siguiendo los protocolos facilitados por el fabricante. For studies with human cells, C1 R cells transfected with CD1d protein (C1 r-CD1d + ) were used as host cells, PBMCs (peripheral blood mononuclear cells) as cell complement and NKT cells extracted from blood of healthy donors. 90,000 C1 R-CD1d + cells were incubated with 10 micrograms / ml of the analogues. During 1 hour at 37 ° C, they were subsequently irradiated at 45Gy to slow their growth. Similarly, PBMC cells were irradiated at 30 Gy. Subsequently, the C1 R-CD1d + cells incubated with the analogs were placed in a 96-well plate so that 30,000 cells were pooled together with 40,000 PBMC cells, to this mixture 10,000 cells / well of purified NKT cells were added. . At 48 hours the supernatants were collected. The levels of IFN-gamma and IL-4 were measured by sandwich ELISAs (InvitroGen) following the protocols provided by the manufacturer.
En la tabla siguiente (Tabla 7) se resumen los resultados obtenidos de algunos de los compuestos descritos en los ejemplos. Tabla 7 The results obtained from some of the compounds described in the examples are summarized in the following table (Table 7). Table 7
Figure imgf000058_0001
Figure imgf000058_0001
+: pg/ml de ci :oquina del mismo orden que la referencia (alfa-GalCer). ¾ pg/ml de citoquina que la referencia (alfa-GalCer); - ½ pg/ml de citoquina que la referencia+: pg / ml of ci: oquina of the same order as the reference (alpha-GalCer). ¾ pg / ml of cytokine than the reference (alpha-GalCer); - ½ pg / ml of cytokine as reference
(alfa-GalCer); - : ¼ pg/ml de citoquina que la referencia (alfa-GalCer); 0: pg/ml citoquinas del orden del blanco. (alpha-GalCer); -: ¼ pg / ml of cytokine than the reference (alpha-GalCer); 0: pg / ml cytokines of the order of the target.

Claims

REIVINDICACIONES
1.- Compuesto de fórmula (I): 1.- Compound of formula (I):
Figure imgf000060_0001
o un sal farmacéuticamente aceptable del mismo, donde:
Figure imgf000060_0001
or a pharmaceutically acceptable salt thereof, wherein:
A representa arilo o heteroarilo, opcionalmente sustituido por uno, dos o tres grupos Rc independientemente seleccionados y que pueden estar opcionalmente unidos entre ellos formando un anillo de 3 a 8 miembros; A represents aryl or heteroaryl, optionally substituted by one, two or three R c groups independently selected and which may be optionally linked together to form a 3- to 8-membered ring;
Z representa S, O o -NR^ Ra representa C9-C30 alquilo, C9-C30 alquenilo o C9-C30 alquinilo, donde Ra está opcionalmente sustituido por uno o más grupos R2; Z represents S, O or -NR ^ R a represents C 9 -C 30 alkyl, C 9 -C 30 alkenyl or C 9 -C 30 alkynyl, where R a is optionally substituted by one or more R 2 groups;
Rb representa C10-C16 alquilo, C10-C16 alquenilo o C10-C16 alquinilo, donde Rb está opcionalmente sustituido por uno o más grupos Rn; cada Rc independientemente representa Y, halógeno, -CN, -N02, -N3, C1-C4 alquilo, C2-C4 alquenilo, C2-C4 alquinilo, arilo, heteroarilo, cicloalquilo o heterocicloalquilo, donde los grupos CrC4 alquilo, C2-C4 alquenilo, C2-C4 alquinilo independientemente están opcionalmente sustituidos por uno o más sustituyentes R7, y los grupos arilo, heteroarilo, cicloalquilo y heterocicloalquilo independientemente están opcionalmente sustituidos por uno o más grupos R8; R b represents C 10 -C 16 alkyl, C 10 -C 16 alkenyl or C 10 -C 16 alkynyl, where R b is optionally substituted by one or more R n groups; each R c independently represents Y, halogen, -CN, -N0 2 , -N 3 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, where the groups C r C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl independently are optionally substituted by one or more R 7 substituents, and the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups independently are optionally substituted by one or more R 8 groups;
Y representa -OR9, -COR9, -NR^Rg, -CO2R9, -OCOR9, -CONR^Rg, -NR1COR9, -SO2R9, -NR1SO2R9, -SO2NR1 R9, -NR1CONR1 R9, -OCONR^ Rg O -NR1CO2R9] cada Ri independientemente representa H o CrC4 alquilo; cada R2 independientemente representa halógeno, -N3, -NR1COR4, -OR4, - CONR^, -NR1S02R4, -NR1CONR1R4, -OCONR1R4, -NR1C02R4, arilo, heteroarilo o cicloalquilo, donde los grupos arilo, heteroarilo y cicloalquilo independientemente están opcionalmente sustituidos por uno o más grupos R3; cada R3 independientemente representa CrCi4 alquilo, C2-CM alquenilo, C2-CM alquinilo, halógeno, -NR^, -NR1COR4, -OR4 o -CN; cada R4 independientemente respresenta H, CrCi4 alquilo, C2-CM alquenilo, C2-CM alquinilo, arilo o cicloalquilo, donde los grupos CrCi4 alquilo, C2-CM alquenilo y C2-CM alquinilo independientemente están opcionalmente sustituidos por uno o más grupos R5, y los grupos arilo y cicloalquilo independientemente están opcionalmente sustituidos por uno o más grupos R6; cada R5 independientemente representa halógeno, -OR1 o -NR^ORi; cada R6 independientemente representa halógeno, CrCi4 alquilo o -0(CrCi4 alquilo); cada R7 independientemente representa Y, halógeno, -CN, -N02, -N3, arilo, heteroarilo, cicloalquilo o heterocicloalquilo, donde los grupos arilo, heteroarilo, cicloalquilo y heterocicloalquilo independientemente están opcionalmente sustituidos por uno o más grupos Rn; cada R8 independientemente representa Y, CrC4 alquilo-Y, halógeno, -CN, -N02 o -N3; cada Rg independientemente representa H, CrC4 alquilo, arilo, heteroarilo, cicloalquilo o heterocicloalquilo, donde el grupo CrC4 alquilo está opcionalmente sustituido por uno o más grupos R10, y donde los grupos arilo, heteroarilo, cicloalquilo y heterocicloalquilo independientemente están opcionalmente sustituidos por uno o más grupos Rn; cada R10 independientemente representa halógeno, -ORi, -NR1R1, -N3, arilo, heteroarilo, cicloalquilo o heterocicloalquilo, donde los grupos arilo, heteroarilo, cicloalquilo y heterocicloalquilo independientemente están opcionalmente sustituidos por uno o más grupos Rn; y cada Rn independientemente representa halógeno, CrC4 alquilo, -ORi, -NR^ o -N3, con la condición de que el compuesto de fórmula (I) no es: Y represents -OR 9 , -COR 9 , -NR ^ Rg, -CO 2 R 9 , -OCOR 9 , -CONR ^ Rg, -NR 1 COR 9 , -SO 2 R 9 , -NR 1 SO 2 R 9 , -SO 2 NR 1 R 9 , -NR 1 CONR 1 R 9 , -OCONR → Rg OR -NR 1 CO 2 R 9 ] each Ri independently represents H or C r C 4 alkyl; each R 2 independently represents halogen, -N 3 , -NR 1 COR 4 , -OR 4 , - CONR ^, -NR 1 S0 2 R 4 , -NR 1 CONR 1 R 4 , -OCONR 1 R 4 , -NR 1 C0 2 R 4 , aryl, heteroaryl or cycloalkyl, wherein the aryl, heteroaryl and cycloalkyl groups independently are optionally substituted by one or more R 3 groups; each R 3 independently represents CrCi 4 alkyl, C 2 -C M alkenyl, C 2 -C M alkynyl, halogen, -NR ^, -NR 1 COR 4 , -OR 4 or -CN; each R 4 independently represents H, C r Ci 4 alkyl, C 2 -C M alkenyl, C 2 -C M alkynyl, aryl or cycloalkyl, where the groups C r Ci 4 alkyl, C 2 -C M alkenyl and C 2 - C M alkynyl independently are optionally substituted by one or more R 5 groups, and the aryl and cycloalkyl groups independently are optionally substituted by one or more R 6 groups; each R 5 independently represents halogen, -OR 1 or -NR ^ ORi; each R 6 independently represents halogen, C r C 4 alkyl or -0 (C r C 4 alkyl); each R 7 independently represents Y, halogen, -CN, -N0 2 , -N 3 , aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups independently are optionally substituted by one or more R n groups; each R 8 independently represents Y, C r C 4 alkyl-Y, halogen, -CN, -N0 2 or -N 3 ; each R g independently represents H, C r C 4 alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein the group C r C 4 alkyl is optionally substituted by one or more R 10 groups, and where the aryl, heteroaryl, cycloalkyl and heterocycloalkyl independently are optionally substituted by one or more Rn groups; each R 10 independently represents halogen, -ORi, -NR 1 R 1 , -N 3 , aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups independently are optionally substituted by one or more R n groups; and each Rn independently represents halogen, C r C 4 alkyl, -ORi, -NR ^ or -N 3 , with the proviso that the compound of formula (I) is not:
(Z)-N-((2R,3S,4R)-3,4-dihidroxi-1-(feniltio)octadecan-2-il)tetracos-15-enamida, (Z) -N - ((2R, 3S, 4R) -3,4-dihydroxy-1- (phenylthio) octadecan-2-yl) tetracos-15-enamide,
(Z)-N-((2R,3S,4R)-1-((4-(4-bromofenil)tiazol-2-il)tio)-3,4-dihidroxi-octadecan-2-il) tetracos-15-enamida, o (Z) -N - ((2R, 3S, 4R) -1 - ((4- (4-bromophenyl) thiazol-2-yl) thio) -3,4-dihydroxy-octadecan-2-yl) tetracos-15 -enamide, or
(Z)-N-((2R,3S,4R)-3,4-dihidroxi-1-(piridin-2-iltio)-octadecan-2-il)tetracos-15-enamida.  (Z) -N - ((2R, 3S, 4R) -3,4-dihydroxy-1- (pyridin-2-ylthio) -octadecan-2-yl) tetracos-15-enamide.
2.- El compuesto de fórmula (I) según la reivindicación 1 , donde A representa fenilo, tiofenilo o piridilo y está opcionalmente sustituido por uno, dos o tres grupos Rc. 2. The compound of formula (I) according to claim 1, wherein A represents phenyl, thiophenyl or pyridyl and is optionally substituted by one, two or three groups R c .
3.- El compuesto de fórmula (I) según cualquiera de las reivindicaciones 1 o 2, donde Ra representa C9-C30 alquilo o C9-C30 alquenilo, donde Ra está opcionalmente sustituido por uno o más grupos R2. 3. The compound of formula (I) according to any of claims 1 or 2, wherein R a represents C 9 -C 30 alkyl or C 9 -C 30 alkenyl, wherein R a is optionally substituted by one or more R 2 groups .
4 - Compuesto de fórmula (I) según la reivindicación 3, donde C9-C30 alquilo representa C9 alquilo, Cío alquilo, Cu alquilo, C15 alquilo o C25 alquilo. 4 - Compound of formula (I) according to claim 3, where C 9 -C 30 alkyl represents C 9 alkyl, C í or alkyl, Cu alkyl, C 15 alkyl or C 25 alkyl.
5.- Compuesto de fórmula (I) según la reivindicación 3, donde C9-C30 alquenilo es C23 alquenilo. 5. Compound of formula (I) according to claim 3, wherein C 9 -C 30 alkenyl is C 23 alkenyl.
6.- Compuesto de fórmula (I) según cualquiera de las reivindicaciones 1 a 5, donde Rb es C10-C16 alquilo. 6. Compound of formula (I) according to any of claims 1 to 5, wherein R b is C 10 -C 16 alkyl.
7.- Compuesto de fórmula (I) según la reivindicación 6, donde C10-C16 alquilo es C14 alquilo. 7. Compound of formula (I) according to claim 6, wherein C 10 -C 16 alkyl is C 14 alkyl.
8.- Compuesto de fórmula (I) según cualquiera de las reivindicaciones 1 a 7, donde Rc representa Y, halógeno, -CN, CrC4 alquilo o arilo. 8. Compound of formula (I) according to any of claims 1 to 7, wherein R c represents Y, halogen, -CN, C r C 4 alkyl or aryl.
9.- Compuesto de fórmula (I) según la reivindicación 8, donde Y representa -OR9, -CO2R9, -CONR1R9, -NR1COR9, -SO2R9 O -SO2NR1R9. 9. Compound of formula (I) according to claim 8, wherein Y represents -OR 9 , -CO 2 R 9 , -CONR 1 R 9 , -NR 1 COR 9 , -SO 2 R 9 O -SO 2 NR 1 R 9
10.- Compuesto de fórmula (I) según la reivindicación 9, donde R1 es H y Rg representa H 0 C1 alquilo. 10. Compound of formula (I) according to claim 9, wherein R 1 is H and R g represents H 0 C 1 alkyl.
11.- Compuesto de fórmula (I) según la reivindicación 8, donde CrC4 alquilo es C1 alquilo. 11. Compound of formula (I) according to claim 8, wherein C r C 4 alkyl is C 1 alkyl.
12.- Compuesto de fórmula (I) según la reivindicación 8, donde el halógeno es cloro. 12. Compound of formula (I) according to claim 8, wherein the halogen is chloro.
13.- Compuesto de fórmula (I) según la reivindicación 8, donde el arilo es fenilo. 13. Compound of formula (I) according to claim 8, wherein the aryl is phenyl.
14.- Compuesto de fórmula (I) según cualquiera de las reivindicaciones 1 a 13, donde R2 representa -NR1COR4, -NR1S02R4 o arilo. 14. Compound of formula (I) according to any of claims 1 to 13, wherein R 2 represents -NR 1 COR 4 , -NR 1 S 0 2 R 4 or aryl.
15.- Compuesto de fórmula (I) según cualquiera de las reivindicaciones 1 a 14, donde R3 representa -OR4 o halógeno. 15. Compound of formula (I) according to any of claims 1 to 14, wherein R 3 represents -OR 4 or halogen.
16.- Compuesto de fórmula (I) según cualquiera de las reivindicaciones 1 a 15, donde R4 representa C10 alquilo, C12 alquilo, C10 alquenilo, C10 alquinilo o arilo. 16. Compound of formula (I) according to any of claims 1 to 15, wherein R 4 represents C 10 alkyl, C 12 alkyl, C 10 alkenyl, C 10 alkynyl or aryl.
17.- Compuesto de fórmula (I) según cualquiera de las reivindicaciones 1 a 16, donde R6 representa C1 alquilo o halógeno. 17. Compound of formula (I) according to any of claims 1 to 16, wherein R 6 represents C 1 alkyl or halogen.
18.- Compuesto de fórmula (I) según cualquiera de las reivindicaciones 1 a 17, donde: R7 es Y; e 18. Compound of formula (I) according to any of claims 1 to 17, wherein: R 7 is Y; and
Y es -ORg.  And it's -ORg.
19- Compuesto de fórmula (I) según cualquiera de las reivindicaciones 1 a 18, donde R8 es halógeno. 19- Compound of formula (I) according to any of claims 1 to 18, wherein R 8 is halogen.
20.- Compuesto de fórmula (I) según cualquiera de las reivindicaciones 1 a 19, donde Rg representa H 0 C1 alquilo. 20. Compound of formula (I) according to any of claims 1 to 19, wherein R g represents H 0 C 1 alkyl.
21.- Compuesto de fórmula (I) según la reivindicación 1 seleccionado de: 21. Compound of formula (I) according to claim 1 selected from:
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)palmitamida; - (Z)-N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)tetracos-- N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) palmitamide; - (Z) -N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) tetracos-
15-enamida; 15-enamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)decanamida; - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) decanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-11-(4-(4- fluorofenoxi)fenil)undecanamida; - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -11- (4- (4-fluorophenoxy) phenyl) undecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-11-(4- fluorofenil)undecanamida; - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -11- (4-fluorophenyl) undecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-(feniltio)octadecan-2-il)hexacosanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1- (phenylthio) octadecan-2-yl) hexacosanamide;
- N-((2R,3S,4R)-1-((3,4-dimetoxifenil)tio)-3,4-dihidroxioctadecan-2- il)hexacosanamida;  - N - ((2R, 3S, 4R) -1 - ((3,4-dimethoxyphenyl) thio) -3,4-dihydroxyoctadecan-2-yl) hexacosanamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-(2-metoxifenoxi)octadecan-2-il)hexacosanamida;- N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2-methoxyphenoxy) octadecan-2-yl) hexacosanamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-fenoxioctadecan-2-il)hexacosanamida; - N - ((2S, 3S, 4R) -3,4-dihydroxy-1-phenoxyoctadecan-2-yl) hexacosanamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-((2-metoxifenil)amino)octadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((2-methoxyphenyl) amino) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(fenilamino)octadecan-2-il)tetracos-15-enamida; - 2-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)tereftalato de dimetilo;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (phenylamino) octadecan-2-yl) tetracos-15-enamide; - (((2S, 3S, 4R) -3,4-Dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) -dimethyl terephthalate;
- 3-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)ftalato de dimetilo; - 3 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) dimethyl phthalate;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)tereftalato de dimetilo;- 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) dimethyl terephthalate;
- 3-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)amino)ftalato de dimetilo; - 3 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) amino) dimethyl phthalate;
- 2-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)amino)tiofen-3- carboxilato de metilo;  - 2 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) amino) thiophene-3-carboxylic acid methyl ester;
- 5-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)amino)isoftalato de dimetilo;  - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) amino) dimethyl isophthalate;
- 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-ennamido)octadecil)amino)isoftalato de dimetilo; - 4 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-ennamido) octadecyl) amino) dimethyl isophthalate;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-((3-(hidroximetil)fenil)amino)octadecan-2- il)tetracos-15-enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((3- (hydroxymethyl) phenyl) amino) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-((4-(hidroximetil-2-metoximetil)fenil)amino)-3,4- dihidroxioctadecan-2-il)tetracos-15-enamida; - 3-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzamida; - (Z) -N - ((2S, 3S, 4R) -1 - ((4- (hydroxymethyl-2-methoxymethyl) phenyl) amino) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enamide; - 3 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzamide;
- 4-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzamida;  - 4 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzamide;
- 4-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)isoftalamida;  - 4 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) isophthalamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-((2-metoxifenil)amino)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((2-methoxyphenyl) amino) octadecan-2-yl) hexacosanamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-(fenilamino)octadecan-2-il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (phenylamino) octadecan-2-yl) hexacosanamide;
- 3-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)benzamida; - 3 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) benzamide;
- 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)benzamida;- 4 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) benzamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(4-(hidroximetil)fenoxi)octadecan-2-il)tetracos-15- enamida; - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (4- (hydroxymethyl) phenoxy) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(3-(hidroximetil)fenoxi)octadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (3- (hydroxymethyl) phenoxy) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-([1,1'-bifenil]-4-iloxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -1 - ([1,1'-biphenyl] -4-yloxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enamide;
- 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)-[1 ,1'-bifenil]- 3-carboxilato de metilo;  - 4 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) - [1,1'-biphenyl] -3-carboxylate of methyl;
- (Z)-N-((2S,3S,4R)-1-([1 ,1'-bifenil]-3-iloxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- ena ida;  - (Z) -N - ((2S, 3S, 4R) -1 - ([1,1'-biphenyl] -3-yloxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enylaken;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(o-toliloxi)octadecan-2-il)tetracos-15-enamida; - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (o-tolyloxy) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-(2-clorofenoxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- enamida; - (Z) -N - ((2S, 3S, 4R) -1- (2-chlorophenoxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-(2-cianofenoxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- ena ida;  - (Z) -N - ((2S, 3S, 4R) -1- (2-cyanophenoxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enylaken;
- (Z)-N-((2S,3S,4R)-1-(2-acetamidofenoxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- ena ida;  - (Z) -N - ((2S, 3S, 4R) -1- (2-acetamidophenoxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enylaken;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(2-(metilsulfonil)fenoxi)octadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2- (methylsulfonyl) phenoxy) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(2-sulfamoilfenoxi)octadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2-sulfamoylphenoxy) octadecan-2-yl) tetracos-15-enamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12- undecanamidododecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- undecanamidododecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12-(4- metilfenilsulfonamido)dodecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- (4-methylphenylsulfonamido) dodecanamide;
- N-(12-(((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)amino)- 12-oxododecil)tridecanamida; - N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12-(undec- 10-enamido)dodecanamida; - N- (12 - (((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) amino) -12-oxododecyl) tridecanamide; - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- (unde-10-enamido) dodecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12-(undec- 10-¡namido)dodecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- (undec-10-amido) dodecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2- il)hexacosanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) hexacosanamide;
- 2-(((2R,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)tio)benzoato de metilo; - 2 - (((2R, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) thio) methyl benzoate;
- ácido 2-(((2R,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)tio)benzoico; - 2 - (((2R, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) thio) benzoic acid;
- 2-(((2R,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)tio)benzamida;  - 2 - (((2R, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) thio) benzamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-(2-(hidroximetil)fenoxi)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2- (hydroxymethyl) phenoxy) octadecan-2-yl) hexacosanamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)benzoato de metilo; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) benzoate methyl;
- ácido 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)benzoico; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) benzoic acid;
- N-((2S,3S,4R)-3,4-dihidroxi-1-((2-(metiloximetil)fenil)amino)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((2- (methyloxymethyl) phenyl) amino) octadecan-2-yl) hexacosanamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzoato de metilo; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) methyl benzoate;
- ácido 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzoico;- 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzoic acid;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzamida; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-((3-(hidroximetil)piridin-2-il)oxi)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((3- (hydroxymethyl) pyridin-2-yl) oxy) octadecan-2-yl) hexacosanamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)nicotinato de metilo; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) methyl nicotinate;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)nicotinamida; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) nicotinamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)benzamida;  - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) benzamide;
- 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)-2',4'-difluoro- [1 ,1'-bifenil]-3-carboxilato de metilo; y  - 4 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) -2 ', 4'-difluoro- [1, 1' methyl-biphenyl] -3-carboxylate; Y
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-((4-(hidroximetil)-[1 ,1'-bifenil]-3-il)oxi)octadecan-2- 1 l)tetracos-15-enamida o una sal farmacéuticamente aceptable del mismo.  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((4- (hydroxymethyl) - [1, 1'-biphenyl] -3-yl) oxy) octadecan-2 - 1 l) tetracos-15-enamide or a pharmaceutically acceptable salt thereof.
22.- Uso de un compuesto de fórmula (I):
Figure imgf000067_0001
22. Use of a compound of formula (I):
Figure imgf000067_0001
o de una sal farmacéuticamente aceptable del mismo, donde: or a pharmaceutically acceptable salt thereof, wherein:
A, Z, Ra, Rb y Rc tienen el significado descrito en cualquiera de las reivindicaciones 1 a 20; A, Z, R a , R b and R c have the meaning described in any of claims 1 to 20;
para la fabricación de un medicamento. for the manufacture of a medicine.
23.- Uso de un compuesto de fórmula (I): 23.- Use of a compound of formula (I):
Figure imgf000067_0002
Figure imgf000067_0002
o de una sal farmacéuticamente aceptable del mismo, donde: or a pharmaceutically acceptable salt thereof, wherein:
A, Z, Ra, Rb y Rc tienen el significado descrito en cualquiera de las reivindicaciones 1 a 20, A, Z, R a , R b and R c have the meaning described in any of claims 1 to 20,
para la fabricación de un medicamento para el tratamiento y/o prevención de enfermedades autoinmunes, enfermedades inflamatorias, cáncer e infecciones causadas por microorganismos patógenos. for the manufacture of a medicament for the treatment and / or prevention of autoimmune diseases, inflammatory diseases, cancer and infections caused by pathogenic microorganisms.
24.- Uso según la reivindicación 23 de un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo donde las enfermedades autoinmunes o inflamatorias se seleccionan de la lista que comprende asma, enfermedad pulmonar obstructiva crónica (EPOC), colitis crónica, alergias, lupus eritematoso sistémico, diabetes mellitus de tipo 1 , esclerosis múltiple, síndrome de Sjógren y artritis reumatoide. 24. Use according to claim 23 of a compound of formula (I) or a pharmaceutically acceptable salt thereof where the autoimmune or inflammatory diseases are selected from the list comprising asthma, chronic obstructive pulmonary disease (COPD), chronic colitis, allergies , systemic lupus erythematosus, type 1 diabetes mellitus, multiple sclerosis, Sjögren's syndrome and rheumatoid arthritis.
25.- Uso según la reivindicación 23 de un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo, donde las enfermedades infecciosas causadas por microorganismos patógenos se seleccionan de la lista que comprende infecciones víricas como gripe, SIDA y hepatitis; infecciones bacterianas como clamidiosis, tuberculosis, estreptococosis y pseudomoniasis; e infecciones parasitarias como leishmaniosis, malaria y tripanosomiasis. 25. Use according to claim 23 of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the infectious diseases caused by pathogenic microorganisms are selected from the list comprising viral infections such as influenza, AIDS and hepatitis; bacterial infections such as chlamydiosis, tuberculosis, streptococcosis and pseudomoniasis; and parasitic infections such as leishmaniasis, malaria and trypanosomiasis.
26.- Uso según la reivindicación 23 de un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo, donde el cáncer se selecciona de la lista que comprende cáncer de mama, cánceres ginecológicos, cáncer de colon, cáncer de próstata, cáncer de piel, cáncer hepatocelular, cáncer de pulmón, cáncer de esófago, cáncer gástrico, cáncer de páncreas, cáncer de vejiga, cáncer de hígado, cáncer del tracto urinario, cáncer tiroideo, cáncer renal, melanoma, cáncer de cerebro, sarcoma, linfoma y leucemia. 26. Use according to claim 23 of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the list comprising breast cancer, gynecological cancers, colon cancer, prostate cancer, cancer of skin, hepatocellular cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, bladder cancer, liver cancer, urinary tract cancer, thyroid cancer, kidney cancer, melanoma, brain cancer, sarcoma, lymphoma and leukemia.
27.- Uso según cualquiera de las reivindicaciones 22 a 26 de un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo, donde el medicamento es una vacuna o un adjuvante de vacunación. 27. Use according to any of claims 22 to 26 of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the medicament is a vaccine or a vaccination adjuvant.
28.- El uso de un compuesto de fórmula (I) según cualquiera de las reivindicaciones 22 a 27, seleccionado de: 28. The use of a compound of formula (I) according to any of claims 22 to 27, selected from:
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)palmitamida;- N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) palmitamide;
- (Z)-N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)tetracos- 15-enamida; - (Z) -N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) tetracos-15-enamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)decanamida; - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) decanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-11-(4-(4- fluorofenoxi)fenil)undecanamida; - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -11- (4- (4-fluorophenoxy) phenyl) undecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-11-(4- fluorofenil)undecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -11- (4-fluorophenyl) undecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-(feniltio)octadecan-2-il)hexacosanamida; - N-((2R,3S,4R)-1-((3,4-dimetoxifenil)tio)-3,4-dihidroxioctadecan-2- il)hexacosanamida; - N - ((2R, 3S, 4R) -3,4-dihydroxy-1- (phenylthio) octadecan-2-yl) hexacosanamide; - N - ((2R, 3S, 4R) -1 - ((3,4-dimethoxyphenyl) thio) -3,4-dihydroxyoctadecan-2-yl) hexacosanamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-(2-metoxifenoxi)octadecan-2-il)hexacosanamida; - N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2-methoxyphenoxy) octadecan-2-yl) hexacosanamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-fenoxioctadecan-2-il)hexacosanamida; - N - ((2S, 3S, 4R) -3,4-dihydroxy-1-phenoxyoctadecan-2-yl) hexacosanamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-((2-metoxifenil)amino)octadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((2-methoxyphenyl) amino) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(fenilamino)octadecan-2-il)tetracos-15-enamida; - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (phenylamino) octadecan-2-yl) tetracos-15-enamide;
- 2-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)tereftalato de dimetilo; - (((2S, 3S, 4R) -3,4-Dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) -dimethyl terephthalate;
- 3-(((2S,3S,4R)-2-hexacosana ido-3,4-dihidroxioctadecil)oxi)ftalato de dimetilo; - 3 - (((2S, 3S, 4R) -2-hexacosana ido-3,4-dihydroxyoctadecyl) oxy) dimethyl phthalate;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)tereftalato de dimetilo;- 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) dimethyl terephthalate;
- 3-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)amino)ftalato de dimetilo; - 3 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) amino) dimethyl phthalate;
- 2-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)amino)tiofen-3- carboxilato de metilo;  - 2 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) amino) thiophene-3-carboxylic acid methyl ester;
- 5-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)amino)isoftalato de dimetilo;  - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) amino) dimethyl isophthalate;
- 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-ennamido)octadecil)amino)isoftalato de dimetilo;  - 4 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-ennamido) octadecyl) amino) dimethyl isophthalate;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-((3-(hidroximetil)fenil)amino)octadecan-2- il)tetracos-15-enamida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((3- (hydroxymethyl) phenyl) amino) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-((4-(hidroximetil-2-metoximetil)fenil)amino)-3,4- dihidroxioctadecan-2-il)tetracos-15-enamida;  - (Z) -N - ((2S, 3S, 4R) -1 - ((4- (hydroxymethyl-2-methoxymethyl) phenyl) amino) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enamide;
- 3-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzamida;  - 3 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzamide;
- 4-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzamida;  - 4 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzamide;
- 4-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)isoftalamida;  - 4 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) isophthalamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-((2-metoxifenil)amino)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((2-methoxyphenyl) amino) octadecan-2-yl) hexacosanamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-(fenilamino)octadecan-2-il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (phenylamino) octadecan-2-yl) hexacosanamide;
- 3-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)benzamida; - 3 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) benzamide;
- 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)benzamida;- 4 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) benzamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(4-(hidroximetil)fenoxi)octadecan-2-il)tetracos-15- enamida; - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (4- (hydroxymethyl) phenoxy) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(3-(hidroximetil)fenoxi)octadecan-2-il)tetracos-15- enamida; - (Z)-N-((2S,3S,4R)-1-([1 ,1'-bifenil]-4-iloxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- enamida; - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (3- (hydroxymethyl) phenoxy) octadecan-2-yl) tetracos-15-enamide; - (Z) -N - ((2S, 3S, 4R) -1 - ([1,1'-biphenyl] -4-yloxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enamide;
- 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)-[1 ,1'-bifenil]- 3-carboxilato de metilo;  - 4 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) - [1,1'-biphenyl] -3-carboxylate of methyl;
- (Z)-N-((2S,3S,4R)-1-([1 ,1'-bifenil]-3-iloxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- ena ida;  - (Z) -N - ((2S, 3S, 4R) -1 - ([1,1'-biphenyl] -3-yloxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enylaken;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(o-toliloxi)octadecan-2-il)tetracos-15-enamida; - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (o-tolyloxy) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-(2-clorofenoxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- enamida; - (Z) -N - ((2S, 3S, 4R) -1- (2-chlorophenoxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-(2-cianofenoxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- enamida;  - (Z) -N - ((2S, 3S, 4R) -1- (2-cyanophenoxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2S,3S,4R)-1-(2-acetamidofenoxi)-3,4-dihidroxioctadecan-2-il)tetracos-15- ena ida;  - (Z) -N - ((2S, 3S, 4R) -1- (2-acetamidophenoxy) -3,4-dihydroxyoctadecan-2-yl) tetracos-15-enylaken;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(2-(metilsulfonil)fenoxi)octadecan-2-il)tetracos-15- ena ida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2- (methylsulfonyl) phenoxy) octadecan-2-yl) tetracos-15-enylaken;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-(2-sulfamoilfenoxi)octadecan-2-il)tetracos-15- ena ida;  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2-sulfamoylphenoxy) octadecan-2-yl) tetracos-15-ena ida;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12- undecana idododecana ida;  N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- undecanediododocan ida;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12-(4- metilfenilsulfonamido)dodecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- (4-methylphenylsulfonamido) dodecanamide;
- N-(12-(((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)amino)- 12-oxododecil)tridecanamida;  - N- (12 - (((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) amino) -12-oxododecyl) tridecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12-(undec- 10-ena ido)dodecana ida;  - N - ((2R, 3S, 4R) -3,4-Dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- (unde-10-ena) dodecane ida ;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2-il)-12-(undec- 10-inamido)dodecanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) -12- (undec-10-inamido) dodecanamide;
- N-((2R,3S,4R)-3,4-dihidroxi-1-((2-(hidroximetil)fenil)tio)octadecan-2- il)hexacosanamida;  - N - ((2R, 3S, 4R) -3,4-dihydroxy-1 - ((2- (hydroxymethyl) phenyl) thio) octadecan-2-yl) hexacosanamide;
- 2-(((2R,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)tio)benzoato de metilo; - 2 - (((2R, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) thio) methyl benzoate;
- ácido 2-(((2R,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)tio)benzoico; - 2 - (((2R, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) thio) benzoic acid;
- 2-(((2R,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)tio)benzamida;  - 2 - (((2R, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) thio) benzamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-(2-(hidroximetil)fenoxi)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1- (2- (hydroxymethyl) phenoxy) octadecan-2-yl) hexacosanamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)benzoato de metilo; - ácido 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)benzoico; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) benzoate methyl; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) benzoic acid;
- N-((2S,3S,4R)-3,4-dihidroxi-1-((2-(metiloximetil)fenil)amino)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((2- (methyloxymethyl) phenyl) amino) octadecan-2-yl) hexacosanamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzoato de metilo; - ácido 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzoico; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) methyl benzoate; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzoic acid;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)amino)benzamida; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) amino) benzamide;
- N-((2S,3S,4R)-3,4-dihidroxi-1-((3-(hidroximetil)piridin-2-il)oxi)octadecan-2- il)hexacosanamida;  - N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((3- (hydroxymethyl) pyridin-2-yl) oxy) octadecan-2-yl) hexacosanamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)nicotinato de metilo; - 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)nicotinamida;  - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) methyl nicotinate; - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) nicotinamide;
- 2-(((2S,3S,4R)-2-hexacosanamido-3,4-dihidroxioctadecil)oxi)benzamida;  - 2 - (((2S, 3S, 4R) -2-hexacosanamido-3,4-dihydroxyoctadecyl) oxy) benzamide;
- 4-(((2S,3S,4R)-3,4-dihidroxi-2-((Z)-tetracos-15-enamido)octadecil)oxi)-2',4'-difluoro- [1 ,1'-bifenil]-3-carboxilato de metilo;  - 4 - (((2S, 3S, 4R) -3,4-dihydroxy-2 - ((Z) -tetracos-15-enamido) octadecyl) oxy) -2 ', 4'-difluoro- [1, 1' methyl-biphenyl] -3-carboxylate;
- (Z)-N-((2S,3S,4R)-3,4-dihidroxi-1-((4-(hidroximetil)-[1 ,1'-bifenil]-3-il)oxi)octadecan-2- 1 l)tetracos-15-enamida  - (Z) -N - ((2S, 3S, 4R) -3,4-dihydroxy-1 - ((4- (hydroxymethyl) - [1, 1'-biphenyl] -3-yl) oxy) octadecan-2 - 1 l) tetracos-15-enamide
- (Z)-N-((2R,3S,4R)-3,4-dihidroxi-1-(feniltio)octadecan-2-il)tetracos-15-enamida;  - (Z) -N - ((2R, 3S, 4R) -3,4-dihydroxy-1- (phenylthio) octadecan-2-yl) tetracos-15-enamide;
- (Z)-N-((2R,3S,4R)-1-((4-(4-bromofenil)tiazol-2-il)tio)-3,4-dihidroxi-octadecan-2-il) tetracos-15-enamida; y  - (Z) -N - ((2R, 3S, 4R) -1 - ((4- (4-bromophenyl) thiazol-2-yl) thio) -3,4-dihydroxy-octadecan-2-yl) tetracos- 15-enamide; Y
- (Z)-N-((2R,3S,4R)-3,4-dihidroxi-1-(piridin-2-iltio)-octadecan-2-il)tetracos-15- enamida.  - (Z) -N - ((2R, 3S, 4R) -3,4-dihydroxy-1- (pyridin-2-ylthio) -octadecan-2-yl) tetracos-15-enamide.
29.- Composición farmacéutica que comprende un compuesto de fórmula (I) o una sal farmacéuticamente aceptable del mismo y uno o más excipientes farmacéuticamente aceptables. 29. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
30.- Composición farmacéutica según la reivindicación 29, que además comprende otro agente terapéutico. 30. A pharmaceutical composition according to claim 29, further comprising another therapeutic agent.
PCT/ES2018/070753 2017-11-22 2018-11-22 Non-glycosidic analogues of alpha-galactosylceramide as nkt cell activators WO2019102054A1 (en)

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