ES2396092B1 - AMIDAS OF 2-AMINO-1,3-PROPANODIOLS AND ITS USE AS CERAMIDASAS INHIBITORS. - Google Patents

AMIDAS OF 2-AMINO-1,3-PROPANODIOLS AND ITS USE AS CERAMIDASAS INHIBITORS. Download PDF

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ES2396092B1
ES2396092B1 ES201131119A ES201131119A ES2396092B1 ES 2396092 B1 ES2396092 B1 ES 2396092B1 ES 201131119 A ES201131119 A ES 201131119A ES 201131119 A ES201131119 A ES 201131119A ES 2396092 B1 ES2396092 B1 ES 2396092B1
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compound
formula
alkyl
compounds
dihydroxyoctadecan
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ES2396092A1 (en
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José Luis ABAD SAIZ
Luz del Carmen Camacho Castillo
Josefina Casas Brugulat
Gemma Fabrias Domingo
María GARRIDO MARTÍNEZ
Timothy Thomson Okatsu
Óscar MECA CORTÉS
Antonio Delgado Cirilo
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Consejo Superior de Investigaciones Cientificas CSIC
Universitat Autonoma de Barcelona UAB
Universitat de Barcelona UB
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Universitat Autonoma de Barcelona UAB
Universitat de Barcelona UB
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Priority to PCT/ES2012/070485 priority patent/WO2013004871A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/04—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/05—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to a compound having formula (I) or a stereoisomer, a salt or a solvate, in which: A is -CH(OH)- or -C(=0)-; Z is H or OH; n is 0 or 1; R1 is alkyl(C1-C30), alkenyl(C2-C30) or alkynyl(C2-C30); B is -H, -N3 or -C?CH; R2 is -NHR3 or maleimide; R3 is -COR4, -COCOR4 or -SO2R4; and R4 is alkyl(C1-C16), alkenyl(C2-C16), alkynyl(C2-C16), epoxide or aziridine, on the condition that: a) when A is -CH(OH) and B is H, R3 is different from -COR4, R4 being alkyl(C1-C16); b) when A is -CH(OH), B is H and R3 is -COCOR4,R4 beingalkyl(C6), R1 is different from -CH=CH2-alkyl(C12), -C?CH-alkyl(C12) or alkyl(C13-C15); or c) when A is -C(=O), R1 is alkenyl(C2-C30), B is H and n is 0, R3 is different from -COR4, R4 being alkyl(C1C16). The invention also relates to the use of the compound having formula (I), 2,2-dibromo-N-((2S,3R)-1,3-dihydroxyoctadecan-2-il)acetamide or 2-bromo-N-((2S,3R)-1,3-dihydroxyoctadecan-2-il)acetamide in the treatment or prevention of a disease associated with cellular hyperproliferation, either alone or in combination.

Description

Amidas@de@2-amino-1,3-propanodioles@y@su@uso@como@inhibidores@de@ceramidasas@ Amidas @ de @ 2-amino-1,3-propanedioles @ and @ its @ use @ as @ inhibitors @ of @ ceramidasas @

ESTADO DE LA TÉCNICA STATE OF THE TECHNIQUE

@ @

Las@ceramidasas@son@hidrolasas@que@catalizan@la@hidrolisis@de@las@ceramidas@en@esfingosina@y@acidos@grasos@en@ mamiferos,@bacterias@y@hongos.@Segun@su@pH@optimo,@las@ceramidasas@se@agrupan@en@acidas,@neutras@y@alcalinas.@Hasta@ la@fecha,@se@han@clonado@y@expresado@de@forma@funcional@cinco@ceramidasas@distintas:@la@ceramidasa@acida,@la@neutra@y@ tres@alcalinas.@ The @ ceramidasas @ are @ hydrolasas @ that @ catalyze @ the @ hydrolysis @ of @ the @ ceramides @ in @ sphingosine @ and @ fatty @ acids @ in @ mammals, @ bacteria @ and @ fungi. @ According @ your @ pH @ optimally, @ the @ ceramidasas @ are @ grouped @ in @ acidas, @ neutral @ and @ alkaline. @ Until @ the @ date, @ they have been cloned and @ expressed @ in a @ functional @ way @ five @ ceramidasas @ different: @ la @ ceramidasa @ acida, @ la @ neutra @ and @ tres @ alkalinas. @

@@ @@

Existen@ evidencias@ que@ ponen@ de@ manifiesto@ el@ papel@ importante@ que@ desempefan@ las@ ceramidasas,@ especialmente@la@ceramidasa@acida,@en@el@desarrollo@y@la@progresion@del@cancer,@asi@como@en@la@respuesta@de@los@tumores@ a@la@terapia.@La@ceramidasa@acida@esta@sobreexpresada@en@diversas@lineas@celulares@y@tejidos@cancerosos,@lo@que@parece@ contribuir@a@la@disminucion@de@los@niveles@de@ceramida@y@al@aumento@de@los@de@esfingosina-1-fosfato,@con@el@consiguiente@ aumento@de@la@proliferacion@celular@y@resistencia@a@la@muerte@celular.@En@muchos@casos,@la@inhibicion@de@la@ceramidasa@ acida@conduce@a@apoptosis.@En@numerosos@trabajos@se@confirma@la@relacion@entre@el@aumento@de@la@actividad@ceramidasa@ acida@y@la@resistencia@a@la@radio@y@quimioterapia,@asi@como@el@interes@del@uso@de@inhibidores@de@la@ceramidasa@acida@como@ farmacos@anticancerosos,@tanto@solos@como@en@combinacion@con@otras@terapias.@En@celulas@de@glioblastoma@resistentes@a@ la@radiacion@se@observaron@niveles@elevados@en@la@expresion@de@ceramidasa@acida.@El@tratamiento@de@dichas@celulas@con@ N-oleoiletanolamina@aumento@su@sensibilidad@frente@a@la@radiacion,@con@el@consiguiente@aumento@de@los@niveles@de@ ceramida,@activacion@de@caspasas@y@apoptosis.@@ There are @ evidences @ that @ make @ of @ manifest @ the @ important @ role @ that @ ceramidasas played, @ especially @ the @ ceramidasa @ acida, @ in @ the @ development @ and @ the @ progresion @ del @ cancer, @ as @ as @ in @ the @ response @ of @ the tumors @ a @ the therapy. @ The @ ceramidasa @ acida @ is @ overexpressed @ in @ various @ cell @ lines @ and @ cancerous @ tissues, @ what @ it seems to contribute to the decrease in @ the @ levels @ of @ ceramida @ and @ to the @ increase @ of @ sphingosine-1-phosphate @ with @ the @ consequent @ @ increase in @ cell @ proliferation @ and @ resistance @ to @ cell @ death. @ In @ many @ cases, @ @ inhibition of @ ceramidase @ acida @ leads @ apoptosis. @ numerous @ jobs @ se @ confirms @ the @ relationship between @ the @ increase @ of @ the @ activity @ ceramidasa @ acida @ and @ the @ resistance @ to @ the @ radio @ and @ chemotherapy, @ like @ like @ the @ interest @ of the @ use @ of @ inhibitors @ of @ the @ ceramidasa @ acida @ as @ anti-cancer drugs, @ both @ alone @ and @ in @ combination @ with @ other @ therapies. @ In @ cells @ of @ glioblastoma @ resistant @ a @ la @ radiacion @ se @ observed @ high @ levels @ in @ la @ @ ceramidasa @ acida expression @ The @ treatment @ of @ sayings @ cells @ with @ N-oleoiletanolamine @ increase @ their @ sensitivity @ against @ radiation @, with @ the consequent increase in @ the @ levels @ of @ ceramida, @ activation @ of @ caspasas @ and @ apoptosis. @@

@ @

Respecto@a@la@ceramidasa@neutra,@no@se@ha@examinado@con@tanto@detalle@su@papel@en@el@cancer.@Sin@embargo,@Wu y col@[Biochim Biophys Acta 2009,@1791,@730-739]@comprobaron@que@la@disminucion@de@actividad@ceramidasa@neutra@ inducida@por@gemcitabina@da@lugar@a@una@parada@de@ciclo@celular@en@la@fase@G(0)/G(1)@en@un@tipo@particular@de@celulas@ endoteliales@murinas.@Por@ultimo,@el@aumento@de@la@muerte@celular@inducida@por@el@inhibidor@de@la@ceramidasa@neutra@ DMAPP@es@otro@de@los@ejemplos@que@sustancia@el@papel@de@la@ceramidasa@neutra@en@el@desarrollo@y@progresion@del@cancer.@ Regarding @ la @ ceramidasa @ neutra, @ no @ se @ ha @ examined @ with @ much @ detail @ her @ role @ in @ the @ cancer. @ However, @ Wu et al @ [Biochim Biophys Acta 2009 , @ 1791, @ 730-739] @ checked @ the @ decrease @ of @ activity @ ceramidasa @ neutral @ induced @ by @ gemcitabine @ gives @ place @ a @ a @ stop @ of @ cell @ cycle @ in @ the @ phase @ G (0) / G (1) @ in @ a @ particular @ type @ of @ endothelial @ murine cells. @ Last @, @ the @ increase @ of @ induced @ cell @ death by @ the @ inhibitor @ of @ la @ ceramidasa @ neutra @ DMAPP @ is @ another @ of @ the @ examples @ that @ substance @ the @ paper @ of @ the @ ceramidasa @ neutra @ in @ the @ development @ and @ progression @ of @ cancer. @

@ @

La@busqueda@de@inhibidores@de@la@ceramidasa@acida@ha@recibido@una@mayor@atencion@dado@su@interes@como@ posibles@farmacos@antiproliferativos@y@citostaticos@en@la@quimioterapia@del@cancer.@Uno@de@los@primeros@inhibidores@ descritos@fue@la@N-oleoiletanolamina,@usado@solamente@como@herramienta@farmacologica,@puesto@que@su@escasa@potencia@ hace@inviable@su@uso@terapeutico.@Se@ha@descrito@que@la@N-oleoiletanolamina@inhibe@las@ceramidasas@neutra@y@alcalina@de@ queratinocitos,@asi@como@ la@glucosilacion@de@las@ceramidas@naturales@en@celulas@CHP-100@de@neuroepitelioma@a@ concentraciones@no@toxicas,@proceso@que@va@acompafado@de@un@aumento@de@ceramidas@y@la@induccion@de@la@apoptosis.@ The @ search @ of @ inhibitors @ of @ la @ ceramidasa @ acida @ has @ received @ a @ greater @ attention @ given @ their @ interest @ as @ possible @ anti-proliferative drugs @ and @ cytostatic @ in @ chemotherapy @ of @ cancer. @ One @ of @ the first @ inhibitors @ described @ was @ the @ N-oleoiletanolamine, @ used @ only @ as @ tool @ pharmacological, @ post @ that @ its @ low @ power @ makes @ unfeasible @ its @ therapeutic @ use. @ It has been described that @ the @ N-oleoiletanolamine @ inhibits @ the @ ceramidasas @ neutral @ and @ alkaline @ of @ keratinocytes, @ as well as @ the @ glucosylation @ of @ the @ natural @ ceramides @ in @ cells @ CHP-100 @ of @ neuroepitelioma @ a @ concentrations @ no @ toxic, @ process @ that @ goes @ accompanied by @ a @ increase @ of @ ceramides @ and @ the @ induction @ of @ la @ apoptosis. @

@ @

El@compuesto@ B13@ ((1R,2R)-2-(N-tetradecanoilamino)-1-(4-nitrofenil)-1,3-propanodiol)@es@otro@inhibidor@de@ la@ ceramidasa@acida.@Es@selectivo@de@esta@ceramidasa,@ya@que@no@modifica@la@actividad@de@las@ceramidasas@neutra@y@ alcalinas.@El@B13@induce@la@acumulacion@de@ceramida@y@la@muerte@de@celulas@SW403@(adenocarcinoma@humano),@ melanoma,@y@celulas@LNCaP@de@prostata.@Ademas,@el@B13@previene@el@crecimiento@de@tumores@in vivo@y@sensibiliza@ tumores@de@prostata@frente@a@la@apoptosis@inducida@por@radiacion.@Puesto@que@el@B13@es@una@molecula@neutra@y@lipofila,@no@ es@muy@adecuada@para@alcanzar@y@acumularse@en@el@lisosoma,@el@compartimento@acido@en@el@ que@se@encuentra@la@ ceramidasa@acida.@Por@ello,@se@han@disefado@diversos@analogos@estructurales@con@objeto@de@mejorar@la@capacidad@de@ alcanzar@la@diana@biologica.@De@estos@trabajos@han@surgido@tres@familias@de@analogos@con@diferente@especificidad@respecto@ al@ organulo@ intracelular:@ a)@ alquilaminas@ lisosomotropicas@ (por@ ejemplo,@ LCL204);@ b)@ analogos@ cationicos@ mitocondriotropicos@(como@el@LCL85);@c)@analogos@neutros@sin@selectividad@respecto@al@compartimiento@en@el@que@se@ acumulan@ (LCL15).@ Entre@ los@analogos@ lisosomotropicos,@el@ LCL204@es@capaz@de@ localizarse@selectivamente@en@ lisosomas@y@de@inducir@apoptosis@en@celulas@de@cancer@de@prostata@y@apoptosis@inducida@por@Fas@en@celulas@escamosas@ de@cancer.@Sin@embargo,@el@LCL204@(o@AD2646)@provoca@la@desestabilizacion@lisosomal@y@una@rapida@degradacion,@ dependiente@de@catepsina,@de@la@ceramidasa@acida,@lo@que@sugiere@una@falta@de@especificidad@tumoral.@Un@efecto@similar@ ha@sido@descrito@para@la@desipramina,@que@es@capaz@de@disminuir@la@actividad@de@la@ceramidasa@acida@por@estimulacion@de@ su@degradacion@proteolitica@dependiente@de@catepsina,@asi@como@para@otros@compuestos@anfifilicos@(cloropromazina,@ cloroquina),@aunque@no@para@otros@agentes@lisosomotropicos@(cloruro@amonico,@bafilomicina@A1).@ The @ compound @ B13 @ ((1R, 2R) -2- (N-tetradecanoylamino) -1- (4-nitrophenyl) -1,3-propanediol) @ is @ another @ inhibitor @ of @ ceramidase @ acid. @ It is @ selective @ of @ this @ ceramidasa, @ since @ that @ does not modify @ the @ activity @ of @ the @ ceramidasas @ neutra @ and @ alkalines. @ The @ B13 @ induce @ the @ accumulation of @ ceramida @ and @ the @ death @ of @ cells @ SW403 @ (adenocarcinoma @ human), @ melanoma, @ and @ cells @ LNCaP @ of @ prostata. @ Also, @ the @ B13 @ prevents @ the @ growth @ of @ tumors @in vivo @ and @ sensitize @ tumors @ prostata @ in front of @ the @ apoptosis @ induced @ by @ radiation. @ Since @ the @ B13 @ is @ a @ neutral @ molecule @ and @ lipofila, @ not @ is @ very @ suitable @ to @ reach @ and @ accumulate @ in @ the @ lysosome, @ the @ compartment @ acid @ in @ the @ that @ is @ the @ ceramidasa @ acid. @ For @ it, @ se @ han @ disefado @ diverse @ structural @ analogos @ with @ object @ of @ improve @ the @ ability @ to @ reach @ the @ target @ biologica. @ From @ these @ jobs @ have @ emerged @ three @ families @ of @ analogos @ with @ different @ specificity @ regarding @ the @ intracellular @ organism: @ a) @ alkylamines @ lysosomotropics @ (for @ example, @ LCL2 04); @ b) @ analogs @ cationics @ mitochondriotropics @ (like @ the @ LCL85); @ c) @ analogs @ neutral @ without @ selectivity @ regarding @ the @ compartment @ in @ the @ that @ accumulate @ ( LCL15). @ Enter @ the @ analogos @ lysosomotropics, @ the @ LCL204 @ is @ capable @ of @ selectively @ locating @ in lysosomes @ and @ of @ inducing @ apoptosis @ in @ prostate @ cancer @ cells @ and @ apoptosis @ induced @ by @ Fas @ in @ cells @ squamous @ of @ cancer. @ However, @ the @ LCL204 @ (or @ AD2646) @ causes @ the @ destabilization @ lysosomal @ and @ a @ fast @ degradation, @ dependent @ of cathepsin, @ of @ la @ ceramidasa @ acida, @ what @ suggests @ a @ lack @ of @ tumor @ specificity. @ A @ similar @ effect @ has @ been @ described @ to @ la @ desipramina, @ that @ is @ able @ to @ decrease @ the @ activity @ of @ la @ ceramidasa @ acida @ por @ stimcion @ de @ su @ degradacion @ proteolitica @ dependent @ de @ catepsina, @ asi @ como @ for @ other @ amphiphilic @ compounds (chloropromazine, @ chloroquine), @ although @ not @ for @ other @ lysosomotropic agents @ (ammonic @ chloride, @ bafilomycin @ A1). @

@ @

Se@ha@descrito@una@nueva@generacion@de@inhibidores@lisosomotropicos@de@la@ceramidasa@acida@desprovistos@de@la@ It has been described as a new generation of @ inhibitors @ lisosomotropicos @ de @ la @ ceramidasa @ acida @ desprovistos @ de @ la @

capacidad@desestabilizadora@del@lisosoma@del@LCL204.@Este@tipo@de@inhibidores@muestran@un@grupo@ -aminoacilo@junto@ @ Lysosome @ @ LCL204 destabilizing @ ability. @ This @ type @ of @ inhibitors @ show @ a @ group @ -aminoacilo @ together @

con@la@combinacion@de@elementos@estructurales@del@B13@y@del@LCL204@(AD2646).@Dentro@de@este@grupo@destacan@el@ LCL464,@capaz@de@inhibir@la@ceramidasa@acida@tanto@in vivo@como@in vitro,@pero@sin@capacidad@para@inducir@su@degradacion@ proteolitica.@Ademas,@el@compuesto@LCL464@provoca@un@aumento@de@la@apoptosis@dependiente@de@caspasas@en@diversos@ tipos@de@cancer.@@ with @ the @ combination @ of @ structural @ elements @ of @ B13 @ and @ of @ LCL204 @ (AD2646). @ Within @ this @ group @ stand out @ the @ LCL464, @ able @ to @ inhibit @ the @ ceramidasa @ acida @ both @ in vivo @ and @ in vitro, @ but @ without @ capacity @ to @ induce @ its @ proteolytic degradation. @ Also, @ the @ compound @ LCL464 @ causes @ an @ increase @ of @ the @ apoptosis @ dependent @ of @ caspasas @ in @ various @ types @ of @ cancer. @@

@ @

De@forma@paralela@al@desarrollo@de@analogos@del@B13,@se@introdujeron@modificaciones@estructurales@similares@en@la@ estructura@del@ DMAPP.@ Este@es@un@compuesto@utilizado@frecuentemente@por@sus@ propiedades@inhibidoras@de@las@ ceramidasas@neutra@y@alcalinas,@tal@y@como@se@indica@en@el@trabajo@de@[Bielawska@y@col@Bioorganic and Medicinal Chemistry 2007,@16,@1032-1045].@@ From @ parallel @ form @ to @ B13 @ analog @ @ development, @ similar @ structural @ modifications were @ introduced in @ the @ DMAPP @ structure. @ This @ is @ a @ compound @ used @ frequently @ by @ its @ inhibitory @ properties @ the @ ceramidasas @ neutral @ and @ alkaline, @ as @ and @ as @ indicated @ in @ the @ work @ of [Bielawska @ and @ col @ Bioorganic and Medicinal Chemistry 2007, @ 16, @ 1032-1045]. @@

Se@han@publicado@estructuras@de@analogos@de@ceramidas@diferentes@a@los@compuestos@de@la@presente@invencion@ como@moduladores@de@la@apoptosis@(Chang@et@al.,@J@Am@Chem@Soc.@2002@124,@1856-1857),@inhibidores@de@la@produccion@ de@interleuquina@4@(Park@et@al.@Bioorg@Med@Chem.@2005,@13,@2589-2595.)@e@inhibidores@de@la@activacion@de@la@protein@ quinasa@C@para@el@tratamiento@de@enfermedades@relacionadas@con@el@sistema@nervioso@(US5519007).@La@solicitud@de@ patente@WO200650264@describe@conjugados@de@ceramidas@con@sales@de@piridinio@y@su@uso@en@el@tratamiento@del@cancer.@ Esta@ solicitud@ de@ patente@ tambien@ describe@ el@ compuesto@ I-B2@ (2-bromo-N-((2S,3R)-1,3-dihidroxiheptadecan-2yl)acetamida)@como@un@intermedio@para@la@obtencion@de@los@compuestos@para@el@tratamiento@de@cancer.@Sin@embargo,@ este@documento@del@estado@de@la@tecnica@no@divulga@que@el@compuesto@I-B2@pueda@utilizarse@como@anticancerigeno.@Otras@ patentes@ describen@ otros@ analogos@ de@ ceramidas@ diferentes@ a@ los@ de@ la@ presente@ invencion@ como@ inhibidores@ de@ ceramidasas@ (WO2003005965@ y@ WO2005051891),@ para@ el@ tratamiento@ del@ cancer@ (EP1580187)@ y@ para@ uso@ en@ el@ tratamiento@de@la@inflamacion@(WO2004064823).@ @ @ @ @ Analogos @ structures @ of ceramides @ different @ a @ the @ compounds @ of @ the @ present @ invention @ as @ modulators of @ the @ apoptosis @ (Chang @ et @ al., @ J @ Am @ Chem @ Soc. @ 2002 @ 124, @ 1856-1857), @ inhibitors @ of @ interleukin @ production @ 4 (Park @ et @ al. @ Bioorg @ Med @ Chem. @ 2005, @ 13, @ 2589-2595.) @ E @ inhibitors @ of @ the @ activation @ of the @ protein @ kinase @ C @ for @ the @ treatment @ of @ diseases @ related to @ the @ system @ nervous @ (US5519007). @ The @ application @ of @ patent @ WO200650264 @ describes @ conjugates @ of @ ceramides @ with @ salts @ of @ pyridinium @ and @ its @ use @ in @ the @ cancer @ treatment. @ This @ patent @ application @ also @ describes @ the @ compound @ I-B2 @ (2-bromo-N - ((2S, 3R) -1,3-dihydroxyheptadecan-2yl) acetamide) @ as @ an @ intermediate @ for @ the @ obtaining @ the @ compounds @ for @ the @ cancer @ treatment. @ However, @ this @ document @ of the @ state @ of the @ technique @ does not disclose that the @ @ compound @ I-B2 @ can @ be used @ as @ anti-cancer. @ Other @ patents @ describe @ other @ analogs @ of @ ceramides @ different @ to @ the @ pr @ esente @invention @ as @ ceramidasas @ inhibitors (WO2003005965 @ and @ WO2005051891), @ for @ the @ cancer @ treatment (EP1580187) @ and @ for @ use @ in @ the @ treatment @ of @ inflammation @ (WO2004064823). @

@ @

Se@han@descrito@3-cetoamidas@de@cadena@de@N-acilo@de@corta@longitud@con@capacidad@de@inducir@apoptosis@en@ celulas@de@leucemia@(Azuma@et@al.@Bioorg@Med@Chem.@2007,@15,@2860-2867).@ They have been described @ 3-ketoamides @ of @ chain @ of @ N-acyl @ of @ short @ length @ with @ capacity @ of @ induce @ apoptosis @ in @ cells @ of @ leukemia @ (Azuma @ et @ al . @ Bioorg @ Med @ Chem. @ 2007, @ 15, @ 2860-2867). @

@ @

Tambien@se@han@publicado@diversas@familias@de@inhibidores@de@la@ceramidasa@acida@con@estructura@de@analogos@de@ ceramidas@o@de@aminoetanoles@sustituidos@en@C2@[Bedia@et@al.,@Org.@Biomol.@Chem.@2005@3,@3707-12.@Grijalvo@et@al.,@ Chem.@Phys.@Lipids.@2006@144,@69-84.@Bedia@et@al.,@Chem.@Phys.@Lipids.@2008@@156,@33-40].@Una@de@estas@familias@posee@ estructura@de@tioeter,@aunque@presenta@poca@actividad@citotoxica@frente@a@celulas@tumorales.@ @ Descripción de la invención Also @ have @ been published @ diverse @ families @ of @ inhibitors @ of @ la @ ceramidasa @ acida @ with @ structure @ of @ analogos @ of @ ceramidas @ or @ of @ aminoetanoles @ substituted @ in @ C2 @ [Bedia @ et @ al., @ Org. @ Biomol. @ Chem. @ 2005 @ 3, @ 3707-12. @ Grijalvo @ et @ al., @ Chem. @ Phys. @ Lipids. @ 2006 @ 144, @ 69- 84. @ Bedia @ et @ al., @ Chem. @ Phys. @ Lipids. @ 2008 @@ 156, @ 33-40]. @ One of @ these @ families @ owns @ structure @ of tioeter, @ although @ presents @ little @ activity @ cytotoxic @ versus @ cells @ tumor cells. @ @ Description of the invention

La@presente@invencion@proporciona@nuevos@derivados@de@ceramida@acida.@Asi@mismo,@la@presente@invencion@ tambien@proporciona@una@familia@de@compuestos@con@actividad@antiproliferativa@y@citotoxica@mediante@la@inhibicion@de@la@ actividad@ ceramidasa@ acida.@ En@ particular,@ la@ presente@ invencion@ proporciona@ una@ familia@ de@ compuestos@ para@ el@ tratamiento@del@cancer.@ The @ present @ invention @ provides @ new @ derivatives @ of @ ceramida @ acida. @ Likewise, @ the @ present @ invention @ also @ provides @ a @ family @ of @ compounds @ with @ antiproliferative @ activity @ and @ citotoxica @ by @ la @ inhibicion @ de @ la @ activity @ ceramidasa @ acida. @ In particular, @ the @ present @ invention @ provides @ a @ family @ of @ compounds @ for @ cancer @ treatment. @

@ @

En@un@primer@aspecto,@la@presente@invencion@se@refiere@a@un@compuesto@de@formula@(I):@@ @ In @ a @ first @ aspect, @ the @ present @ invention @ refers to a @ compound @ of @ formula @ (I): @@ @

(I)@ @ o@un@estereoisomero,@una@sal@o@un@solvato@farmaceuticamente@aceptable@de@este;@@ @ (I) @ @ or @ a @ stereoisomer, @ a @ salt @ or @ a pharmaceutically @ acceptable @ solvate @ of @ this; @@ @

donde:@@ A@se@selecciona@entre@-CH(OH)-@y@-C(=O)-,@ Z@se@selecciona@entre@H@y@OH,@ n@es@un@numero@entero@seleccionado@entre@0@y@1,@ R1@se@selecciona@entre@alquilo(C1-C30),@alquenilo(C2-C30),@y@alquinilo(C2-C30),@@ B@se@selecciona@entre@-H,@-N3@y@-C:CH,@ R2@se@selecciona@entre@-NHR3@y@maleimida,@donde@@ R3@se@selecciona@entre@-CO-R4,@-CO-CO-R4@y@-SO2-R4,@donde@@ R4@se@selecciona@entre@alquilo(C1-C16),@alquenilo(C2-C16),@alquinilo(C2-C16),@epoxido@y@aziridina,@ @ donde@los@grupos@alquilo,@alquenilo@o@alquinilo@de@R1@y@R4@pueden@estar,@independientemente,@opcionalmente@ where: @@ A @ se @ is selected @ from @ -CH (OH) - @ and @ -C (= O) -, @ Z @ is @ selected @ between @ H @ and @ OH, @ n @ is @ a @ integer @ number @ selected @ between @ 0 @ and @ 1, @ R1 @ is @ selected @ from @ alkyl (C1-C30), @ alkenyl (C2-C30), @ and @ alkynyl (C2-C30), @ @ B @ se @ is selected @ from @ -H, @ - N3 @ and @ -C: CH, @ R2 @ is @ selected @ between @ -NHR3 @ and @ maleimida, @ where @@ R3 @ is @ selected @ between @ -CO-R4, @ - CO-CO-R4 @ and @ -SO2-R4, @ where @@ R4 @ is @ selected @ from @ alkyl (C1-C16), @ alkenyl (C2-C16), @ alkynyl (C2-C16), @ epoxide @ and @ aziridine, @ @ where @ the @ alkyl @ groups, @ alkenyl @ or @ alkynyl @ of @ R1 @ and @ R4 @ can @ be, @ independently, @ optionally @

sustituidos@por@uno@o@varios@sustituyentes@elegidos@independientemente@entre@halogeno,@OH,@OR,@OCF3,@NH2,@NO2,@ NRR',@NHCOR;@CONRR',@COOH,@COOR,@OCOR@y@CN,@donde@R@y@R'@son@alquilo@o@alquenilo;@ @ con@la@condicion@de@que@ substituted @ by @ one @ or @ several @ substituents @ chosen @ independently @ between @ halogen, @ OH, @ OR, @ OCF3, @ NH2, @ NO2, @ NRR ', @ NHCOR; @CONRR', @ COOH, @ COOR, @ OCOR @ and @ CN, @ where @ R @ and @ R '@ are @ alkyl @ or @ alkenyl; @ @ with the condition of@

a)@cuando@A@es@-CH(OH)@y@B@es@H,@R3@es@diferente@de@-COR4@siendo@R4@alquilo(C1-C16)@@sin@sustituir@o@sustituido@ por@halogeno@o@hidroxilo;@ b)@cuando@A@es@-CH(OH),@B@es@H@y@R3@es@-COCOR4@siendo@R4@alquilo-C6,@R1@es@diferente@de@-CH=CH2-@ a) @ when @ A @ is @ -CH (OH) @ and @ B @ is @ H, @ R3 @ is @ different @ from @ -COR4 @ being @ R4 @ alkyl (C1-C16) @@ without @ replacing @ or @ substituted @ by @ halogen @ or @ hydroxyl; @ b) @ when @ A @ is @ -CH (OH), @ B @ is @ H @ and @ R3 @ is @ -COCOR4 @ being @ R4 @ alkyl -C6, @ R1 @ is @ different @ from @ -CH = CH2- @

alquilo(C12),@-C:CH-alquilo(C12)@@o@@alquilo(C13-C15);@o@ c)@cuando@A@es@-C(=O),@R1@es@alquenilo(C2-C30),@B@es@H@y@n@es@0,@R3@es@diferente@de@-COR4@siendo@R4@ alquilo(C1-C16).@ @ El@termino@"alquilo"@se@refiere,@en@la@presente@invencion,@a@radicales@de@cadenas@hidrocarbonadas@no@ciclicas,@ alkyl (C12), @ - C: CH-alkyl (C12) @@ or @@ alkyl (C13-C15); @ o @ c) @ when @ A @ is @ -C (= O), @ R1 @ is @alquenilo (C2-C30), @ B @ is @ H @ and @ n @ is @ 0, @ R3 @ is @ different @ from @ -COR4 @ being @ R4 @ alkyl (C1-C16). @ @ The @ Term @ "alkyl" @ refers @, @ in @ the @ present @ invention, @ a @ radicals @ of @ hydrocarbon chains @ not @ cyclics, @

lineales@o@ramificadas,@que@se@unen@al@resto@de@la@molecula@mediante@un@enlace@sencillo,@por@ejemplo,@metilo,@etilo,@npropilo,@i-propilo,@n-butilo,@terc-butilo,@sec-butilo,@n-pentilo,@n-hexilo,@decilo@o@dodecilo.@Los@grupos@alquilo@pueden@estar@ linear @ or @ branched, @ that @ join @ the @ rest @ of @ la @ molecula @ via @ a @ simple @ link, @ for example, @ methyl, @ ethyl, @ npropilo, @ i-propyl, @ n-butyl, @ tert-butyl, @ sec-butyl, @ n-pentyl, @ n-hexyl, @ decyl @ or @ dodecyl. @ @ alkyl @ groups can @ be @

opcionalmente@ sustituidos@ por@ uno@ o@ mas@ sustituyentes@ tales@ como@ halogeno,@ hidroxilo,@ azido,@ alcoxilo,@ carboxilo,@ carbonilo,@ciano,@carbaldehido,@alcoxicarbonilo,@amino@o@nitro.@@ @ optionally @ substituted @ by @ one @ or @ more @ substituents @ such as @ halogen, @ hydroxyl, @ azido, @ alkoxy, @ carboxyl, @ carbonyl, @ cyano, @ carbaldehyde, @ alkoxycarbonyl, @ amino @ or @ nitro. @@ @

El@termino@"alquenilo"@se@refiere@a@radicales@de@cadenas@hidrocarbonadas@no@ciclicas,@lineales@o@ramificadas,@que@ contienen@uno@ o@mas@ enlaces@ carbono-carbono@ dobles,@ preferentemente@ contiene@ un@ unico@ doble@enlace@ carbonocarbono,@y@que@estan@unidos@al@resto@de@la@molecula@por@un@enlace@simple,@por@ejemplo,@vinilo,@1-propenilo,@alilo,@ isoprenilo,@2-butenilo@o@1,3-butadienilo.@Los@radicales@alquenilos@pueden@estar@opcionalmente@sustituidos@por@uno@o@mas@ sustituyentes@tales@como@halogeno,@hidroxilo,@azido,@alcoxilo,@carboxilo,@carbonilo,@ciano,@carbaldehido,@alcoxicarbonilo,@ amino@o@nitro.@ @ The @ term "alkenyl" @ refers to @ radicals @ of @ hydrocarbon @ non-cyclic chains, @ linear @ or @ branched chains, @ which @ contain @ one @ or @ more @ carbon-carbon @ links doubles, @ preferably @ contains @ a @ single @ double @ carbon @ carbon link, @ and @ that @ are @ attached @ to the @ rest @ of the @ molecule @ by @ a @ simple @ link, @ by @ example, @ vinyl, @ 1-propenyl, @ allyl, @ isoprenyl, @ 2-butenyl @ or @ 1,3-butadiene. @ @ radicals @ alkenyls @ may @ be @ optionally @ substituted @ by @ one @ or @ more @ substituents @ such @ as @ halogen, @ hydroxyl, @ azido, @ alkoxy, @ carboxyl, @ carbonyl, @ cyano, @ carbaldehyde, @ alkoxycarbonyl, @ amino @ or @ nitro. @ @

El@termino@"alquinilo"@se@refiere@a@radicales@de@cadenas@hidrocarbonadas@no@ciclicas,@lineales@o@ramificadas,@que@ tienen@uno@o@mas@triples@enlaces@carbono-carbono,@preferentemente@contiene@un@unico@triple@enlace@carbono-carbono,@y@ que@estan@unidos@al@resto@de@la@molecula@por@un@enlace@simple@por@ejemplo,@etinilo@o@1-propinilo.@El@grupo@alquinilo@puede@ estar@opcionalmente@sustituido@por@uno@o@mas@sustituyentes@tales@como@halogeno,@hidroxilo,@azido,@alcoxilo,@carboxilo,@ carbonilo,@ciano,@carbaldehido,@alcoxicarbonilo,@amino@o@nitro.@ @ The term "alkynyl" @ refers to @ radicals @ of @ hydrocarbon @ non-cyclic chains, @ linear @ or @ branched, @ that @ have @ one @ or @ more @ triple @ carbon @ links- carbon, @ preferably @ contains @ a @ single @ triple @ link @ carbon-carbon, @ and @ that @ are @ attached @ to the @ rest @ of @ the @ molecule @ by @ a @ simple @ link @ for @ example, @ ethynyl @ or @ 1-propynyl. @ The @ alkynyl @ group may @ be @ optionally @ substituted @ by @ one @ or @ more @ substituents @ such as @ halogen, @ hydroxyl, @ azido, @ alkoxy, @ carboxyl, @ carbonyl, @ cyano, @ carbaldehido, @ alkoxycarbonyl, @ amino @ or @ nitro. @ @

Algunos@ de@ los@ compuestos@ de@ formula@ (I)@ de@ la@ presente@ invencion@ pueden@ tener@ uno@ o@ mas@ centros@ estereogenicos.@La@presente@invencion@abarca@todos@los@posibles@estereoisomeros@no@solo@sus@mezclas@racemicas@sino@ tambien@sus@isomeros@opticamente@activos.@La@obtencion@de@un@unico@enantiomero@puede@conseguirse@mediante@alguno@ de@los@procedimientos@comunmente@empleados,@por@ejemplo,@por@resolucion@de@la@mezcla@racemica@mediante@tecnicas@de@ recristalizacion,@sintesis@quiral,@resolucion@enzimatica,@biotransformacion@o@resolucion@cromatografica.@ @ Some @ of @ the @ compounds @ of @ formula @ (I) @ of @ the @ present @ invention @ may @ have @ one @ or @ more @ stereogenic centers. @ The @ present @ invention @ covers @ all @ the @ possible @ stereoisomers @ not @ only @ their @ racemic mixes @ but @ also @ their @ optically active isomers. @ The @ obtaining @ a @ unique @ enantiomer @ can @ be obtained by @ any @ of @ @ procedures @ commonly @ employees, @ for example, @ by @ resolution @ of @ racemic mix @ by @ recrystallization @ techniques, @ chiral synthesis, @ enzymatic resolution, @ biotransformation @ or @ resolution @ chromatography. @ @

El@ termino@ "sal@ farmaceuticamente@ aceptable"@ significa@ una@ sal@ que@ conserva@ una@ eficacia@ y@ propiedades@ biologicas@similares@a@la@base@libre@o@del@acido@libre@y@que@no@es@molesta@en@sentido@biologico@ni@en@ningun@otro.@ @ The term "pharmaceutically acceptable salt" @ means @ a @ salt @ that @ retains @ an @ efficacy @ and @ biological @ properties @ similar to @ the @ free @ base @ or @ the @ free @ acid @ and @ that @ no @ is @ annoying @ in @ biological @ sense @ or @ in @ no other. @ @

Las@sales@farmaceuticamente@aceptables@pueden@incluir@las@sales@de@adicion@de@acidos,@tales@como@mesilatos,@ fumaratos,@clorhidratos,@citratos,@maleatos@o@tartratos.@Tambien@pueden@formarse@sales@fisiologicamente@aceptables@con@ acidos@inorganicos@como@son@los@acidos@sulfurico@o@fosforico.@Asimismo,@pueden@formarse@sales@de@tipo@basico@de@un@ metal@alcalino,@como@por@ejemplo@el@sodio,@o@de@un@metal@alcalinoterreo,@por@ejemplo@calcio@o@magnesio.@Puede@haber@ mas@de@un@cation@o@anion@dependiendo@del@numero@de@funciones@con@carga@y@de@la@valencia@de@los@cationes@y@aniones.@ The @ pharmaceutically @ acceptable @ salts can @ include @ the @ salts @ of @ additives @ of acids, @ such as @ mesylates, @ smokers, @ hydrochlorides, @ citrates, @ maleates @ or @ tartrates. @ Also @ @ salts @ physiologically @ acceptable @ can be formed with @ inorganic @ acids @ as @ are @ sulfuric @ or @ phosphoric acids. @ Likewise, @ can @ be @ formed @ salts @ of @ basic @ type @ of @ metal @ alkaline, @ as @ by @ example @ sodium @, @ or @ from @ a @ metal @ alkaline earth, @ by @ example @ calcium @ or @ magnesium. @ There may be @ more @ than @ a @ cation @ o @ anion @ depending @ on @ number @ of @ functions @ with @ load @ and @ of @ la @ valencia @ de @ los @ cationes @ and @ aniones. @

@ @

El@termino@"solvato"@en@la@presente@solicitud@de@patente@significa@un@agregado@resultante@de@la@asociacion@ionica@ o@molecular@entre@moleculas@de@uno@o@mas@solventes@y@moleculas@de@uno@de@los@compuestos@objeto@esta@invencion.@El@ solvato@puede@comprender,@por@ejemplo,@moleculas@de@agua,@alcoholes,@cetonas,@acetatos@o@mezclas.@En@particular,@el@ solvato@puede@comprender@moleculas@de@agua,@etanol,@isopropanol,@acetona@o@mezclas.@Los@solvatos@objeto@de@la@ presente@ invencion@ se@ pueden@ obtener@ por@ metodos@ conocidos@ por@ un@ experto@ en@ la@ materia,@ por@ ejemplo,@ por@ cristalizacion@en@condiciones@controladas.@@@ The @ term "solvato" @ in @ the @ present @ application @ of @ patent @ means @ an @ aggregate @ resulting @ of @ the @ ionic @ molecular association between @ molecules @ of @ one @ or @ More @ solvents @ and @ molecules @ of @ one @ of @ the @ compounds @ object @ is @ invention. @ The @ solvate @ can @ understand, @ for example, @ water @ molecules, @ alcohols, @ ketones , @ acetates @ or @ mixtures. @ In particular, @ the @ solvate @ can @ understand @ molecules @ of @ water, @ ethanol, @ isopropanol, @ acetone @ or @ mixtures. @ The @ solvates @ object @ of @ The @ present @ invention @ can @ be obtained @ by @ methods @ known @ by @ an @ expert @ in @ the @ subject, @ by @ example, @ by @ crystallization @ in @ controlled @ conditions. @@@

@ @

De@acuerdo@con@una@realizacion@preferente,@el@compuesto@de@formula@(I)@de@la@presente@invencion@se@caracteriza@ porque@R1@se@selecciona@entre@alquilo(C1-C30)@y@alquenilo(C2-C30),@preferentemente@R1@se@selecciona@entre@alquilo(C1C30)@y@alquenilo(C2-C30)@sin@sustituir,@mas@preferentemente@R1@se@selecciona@entre@alquilo(C8-C16)@y@alquenilo(C8-C16)@sin@ sustituir.@ From @ agreement @ with @ a @ preferred @ realization, @ the @ compound @ of @ formula @ (I) @ of @ the @ present @ invention @ is @ characterized @ because @ R1 @ is @ selected @ from @ alkyl (C1 -C30) @ and @ alkenyl (C2-C30), @ preferably @ R1 @ is @ selected @ from @ alkyl (C1C30) @ and @ alkenyl (C2-C30) @ without @ replacing, @ more preferably @ R1 @ se @ select @ from @ alkyl (C8-C16) @ and @ alkenyl (C8-C16) @ without @ replacing. @

@ @

De@acuerdo@con@una@realizacion@preferente@adicional,@el@compuesto@de@formula@(I)@objeto@de@la@presente@solicitud@ de@patente@se@caracteriza@porque@n@puede@ser@igual@a@cero.@ Of @ agreement @ with @ an @ additional @ preferred realization, @ the @ compound @ of @ formula @ (I) @ object @ of @ the @ present @ application @ of @ patent @ is @ characterized @ because @ n @ can @ be @ equal @ to @ zero. @

@ @

De@acuerdo@con@otra@realizacion@preferente@adicional,@el@compuesto@de@formula@(I)@objeto@de@la@presente@solicitud@ de@patente@se@@caracteriza@porque@R3@es@-CO-R4,@donde@R4@puede@ser@alquilo(C1-C16),@y@B@se@puede@seleccionar@entre@-N3@ y@-C:CH.@@ From @ agreement @ with @ other @ additional @ preferential realization, @ the @ compound @ of @ formula @ (I) @ object @ of @ the @ present @ application @ of @ patent @ is @@ characterized @ because @ R3 @ is @ -CO-R4, @ where @ R4 @ can @ be @ alkyl (C1-C16), @ and @ B @ can @ be selected @ from @ -N3 @ and @ -C: CH. @@

@ @

Preferentemente,@ R4@ puede@ ser@ un@ alquilo(C1-C16)@ sustituido@ con@ al@ menos@ un@ atomo@ de@ halogeno,@ mas@ preferentemente@el@halogeno@puede@ser@un@atomo@de@fluor@o@bromo,@aun@mas@preferentemente@el@halogeno@es@bromo.@@ Preferably, @ R4 @ can @ be @ an @ alkyl (C1-C16) @ substituted @ with @ at least @ an @ halogen @ atom, @ more preferably @ the @ halogen @ can @ be @ an @ atom @ of @ fluor @ or @ bromo, @ even @ more @ preferably @ the @ halogen @ is @ bromo. @@

@ @

De@forma@aun@mas@preferente,@R4@puede@ser@un@alquilo(C1-C5)@sustituido@con@al@menos@un@atomo@bromo.@ @ By @ even @ more @ preferred, @ R4 @ can @ be @ an @ alkyl (C1-C5) @ substituted @ with @ at least @ an @ atom @ bromine. @ @

De@acuerdo@con@otra@realizacion@preferente@adicional,@el@compuesto@de@formula@(I)@objeto@de@la@presente@solicitud@ de@patente@caracterizado@porque@R3@es@-CO-R4,@donde@R4@puede@ser@alquilo(C1-C16),@y@donde@B@se@puede@seleccionar@ entre@-N3@y@-C:CH@tal@como@se@ha@indicado@anteriormente,@tambien@se@caracteriza@porque@A@es@-C(=O).@ From @ agreement @ with @ other @ additional @ preferred realization, @ the @ compound @ of @ formula @ (I) @ object @ of @ the @ present @ application @ of @ patent @ characterized @ because @ R3 @ is @ - CO-R4, @ where @ R4 @ can @ be @ alkyl (C1-C16), @ and @ where @ B @ can @ be selected @ from @ -N3 @ and @ -C: CH @ as @ as @ has @ indicated @ above, @ also @ is @ characterized @ because @ A @ is @ -C (= O). @

@ @

Preferentemente,@ R4@ puede@ ser@ un@ alquilo(C1-C16)@ sustituido@ con@ al@ menos@ un@ atomo@ de@ halogeno,@ mas@ preferentemente@el@halogeno@puede@ser@un@atomo@de@fluor@o@bromo,@aun@mas@preferentemente@el@halogeno@es@bromo.@@ Preferably, @ R4 @ can @ be @ an @ alkyl (C1-C16) @ substituted @ with @ at least @ an @ halogen @ atom, @ more preferably @ the @ halogen @ can @ be @ an @ atom @ of @ fluor @ or @ bromo, @ even @ more @ preferably @ the @ halogen @ is @ bromo. @@

@ @

De@forma@aun@mas@preferente,@R4@puede@ser@un@alquilo(C1-C5)@sustituido@con@al@menos@un@atomo@bromo.@ @ @ De@acuerdo@con@otra@realizacion@preferente@adicional,@el@compuesto@de@formula@(I)@objeto@de@la@presente@solicitud@ By @ even @ more @ preferred, @ R4 @ can @ be @ an @ alkyl (C1-C5) @ substituted @ with @ at least @ an @ atom @ bromine. @ @ @ By @ agreement @ with @ other @ additional @ preferred realization, @ the @ compound @ of @ formula @ (I) @ object @ of @ the @ present @ request @

de@patente@se@caracteriza@porque@R3@es@-CO-R4,@donde@R4@puede@ser@epoxido.@ @ @ Preferentemente,@el@compuesto@de@formula@(I)@objeto@de@la@presente@solicitud@de@patente@donde@R3@es@-CO-R4,@ donde@R4@puede@ser@epoxido,@tambien@se@caracteriza@porque@n@puede@ser@1@y@Z@puede@ser@OH.@ @ of @ patent @ is @ characterized @ because @ R3 @ is @ -CO-R4, @ where @ R4 @ can @ be @ epoxide. @ @ @ Preferably, @ the @ compound @ of @ formula @ (I) @ object @ of @ the @ present @ application @ of @ patent @ where @ R3 @ is @ -CO-R4, @ where @ R4 @ can @ be @ epoxide, @ also @ is @ characterized @ because @ n @ can @ be @ 1 @ and @ Z @ can @ be @ OH. @ @

De@acuerdo@con@otra@realizacion@preferente@adicional,@el@compuesto@de@formula@(I)@objeto@de@la@presente@solicitud@ de@patente@se@caracteriza@porque@R3@es@-CO-R4,@donde@R4@puede@ser@alquenilo(C2-C16)@o@alquinilo(C2-C16).@ @ @ Preferentemente,@R4@puede@ser@un@alquenilo(C2-C16)@sustituido@con@al@menos@un@atomo@de@halogeno,@mas@ preferentemente,@R4@puede@ser@un@alquenilo(C2-C16)@sustituido@con@al@menos@un@atomo@de@fluor@o@bromo,@de@forma@aun@ mas@preferente@R4@puede@ser@un@alquenilo(C2-C16)@sustituido@con@al@menos@un@atomo@de@bromo.@ @ From @ agreement @ with @ other @ additional @ preferential realization, @ the @ compound @ of @ formula @ (I) @ object @ of @ the @ present @ application @ of @ patent @ is @ characterized @ because @ R3 @ is @ -CO-R4, @ where @ R4 @ can @ be @ alkenyl (C2-C16) @ or @ alkynyl (C2-C16). @ @ @ Preferably, @ R4 @ can @ be @ an @ alkenyl (C2-C16 ) @ substituted @ with @ at least @ an @ atom @ of @ halogen, @ more @ preferably, @ R4 @ can @ be @ an @ alkenyl (C2-C16) @ replaced @ with @ at least @ an @ atom @ of @ fluor @ or @ bromo, @ of @ form @ even @ more @ preferred @ R4 @ can @ be @ an @ alkenyl (C2-C16) @ replaced @ with @ at least @ an @ atom of @ bromo . @ @

De@acuerdo@con@otro@modo@de@realizacion@especialmente@preferente,@el@compuesto@de@formula@(I)@objeto@de@la@ presente@solicitud@de@patente@se@caracteriza@porque@R3@es@-CO-R4,@donde@R4@es@alquenilo(C2-C16)@o@alquinilo(C2-C16),@y@ puede@estar@sustituido@por@al@menos@un@grupo@-CHO@o@-@COOH.@ @ From @ agreement @ with @ other @ mode @ of @ realization @ especially @ preferred, @ the @ compound @ of @ formula @ (I) @ object @ of @ the @ present @ request @ of @ patent @ is @ characterized @ because @ R3 @ is @ -CO-R4, @ where @ R4 @ is @ alkenyl (C2-C16) @ or @ alkynyl (C2-C16), @ and @ may @ be @ replaced @ by @ at least @ one @ group @ -CHO @ or @ - @ COOH. @ @

De@acuerdo@con@otra@realizacion@preferente@adicional,@el@compuesto@de@formula@(I)@objeto@de@la@presente@solicitud@ de@patente@se@caracteriza@porque@R3@es@-CO-CO-R4,@donde@R4@puede@ser@alquilo(C1-C16)@y@B@se@puede@seleccionar@entre@-N3@y@-C:CH.@ From @ agreement @ with @ other @ additional @ preferential realization, @ the @ compound @ of @ formula @ (I) @ object @ of @ the @ present @ application @ of @ patent @ is @ characterized @ because @ R3 @ is @ -CO-CO-R4, @ where @ R4 @ can @ be @ alkyl (C1-C16) @ and @ B @ can @ be selected @ from @ -N3 @ and @ -C: CH. @

@ @

De@acuerdo@con@otra@realizacion@preferente@adicional,@el@compuesto@de@formula@(I)@objeto@de@la@presente@solicitud@ de@ patente@ se@ caracteriza@ porque@ R3@ puede@ ser@ -SO2-R4,@ donde@ R4@ se@ puede@ seleccionar@ entre@ alquilo(C1-C16),@ alquenilo(C2-C16),@ alquinilo(C2-C16),@ epoxido@ y@ aziridina@ .@ Preferentemente@ R4@ puede@ ser@ alquilo(C1-C16),@ mas@ preferentemente@alquilo(C1-C8).@ From @ agreement @ with @ other @ additional @ preferential realization, @ the @ compound @ of @ formula @ (I) @ object @ of @ the @ present @ application @ of @ patent @ is @ characterized @ because @ R3 @ can @ be @ -SO2-R4, @ where @ R4 @ can @ be selected @ from @ alkyl (C1-C16), @ alkenyl (C2-C16), @ alkynyl (C2-C16), @ epoxide @ and @ aziridine @. @ Preferably @ R4 @ can @ be @ alkyl (C1-C16), @ more @ preferably @ alkyl (C1-C8). @

@ @ De@acuerdo@con@otra@realizacion@preferente@adicional,@el@compuesto@de@formula@(I)@objeto@de@la@presente@solicitud@ de@ patente@ se@ caracteriza@ porque@ R3@ puede@ ser@ -SO2-R4,@ donde@ R4@ se@ puede@ seleccionar@ entre@ alquilo(C1-C16),@ alquenilo(C2-C16),@alquinilo(C2-C16),@epoxido@y@aziridina,@n@puede@ser@1@y@Z@puede@ser@OH.@Preferentemente@R4@puede@ser@ alquilo(C1-C16),@mas@preferentemente@alquilo(C1-C8).@ @ @ @ From @ agreement @ with @ other @ additional @ preferential realization, @ the @ compound @ of @ formula @ (I) @ object @ of @ the @ present @ application @ of @ patent @ is @ characterized @ because @ R3 @ can @ be @ -SO2-R4, @ where @ R4 @ can @ be selected @ from @ alkyl (C1-C16), @ alkenyl (C2-C16), @ alkynyl (C2-C16), @ epoxide @ and @ aziridine, @ n @ can @ be @ 1 @ and @ Z @ can @ be @ OH. @ Preferably @ R4 @ can @ be @ alkyl (C1-C16), @ more @ preferably @ alkyl (C1-C8). @ @

De@acuerdo@con@otra@realizacion@preferente@adicional,@el@compuesto@de@formula@(I)@objeto@de@la@presente@solicitud@ de@patente@se@caracteriza@porque@R2@puede@ser@maleimida.@ From @ agreement @ with @ other @ additional @ preferential realization, @ the @ compound @ of @ formula @ (I) @ object @ of @ the @ present @ application @ of @ patent @ is @ characterized @ because @ R2 @ can @ be @ maleimida. @

@ @

De@acuerdo@con@otro@modo@de@realizacion@preferente@adicional,@el@compuesto@de@formula@(I)@tal@como@se@ha@ definido@anteriormente@se@selecciona@de@la@lista@que@consiste@en:@@@ 1-[(2S,3R)-1,3-dihidroxioctadecan-2-il]-1H-pirrol-2,5-diona,@ N-[(2S,3R,E)-1,3-dihidroxioctadec-4-en-2-il]etanosulfonamida,@ N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]etanosulfonamida,@ N-[(2S,3R)-1,3-dihidroxioctadec-17-in-2-il]etanosulfonamida,@ N-[(2S,3R)-14-azido-1,3-dihidroxitetradecan-2-il)etanosulfonamida,@ 2-bromo-N-[(2S,3R)-1,3-dihidroxioctadec-17-in-2-il]acetamida,@ N-[(2S,3R)-14-azido-1,3-dihidroxitetradecan-2-il]bromoacetamida,@ N-[(2S,3R,E)-14-azido-1,3-dihidroxitetradec-4-en-2-il]bromoacetamida,@ 2-bromo-N-[(2S,3R,E)-1,3-dihidroxioctadec-4-en-17-in-2-il]acetamida,@ (S)-N-(14-azido-1-hidroxi-3-oxotetradecan-2-il)-2-bromoacetamida,@ (RS)-N-[(2S,3R,E)-1,3-dihidroxioctadec-4-en-2-il]oxirano-2-carboxamida,@ (RS)-N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]oxirano-2-carboxamida,@ @(RS)-N-[(2S,3R,E)-1,3-dihidroxioctadec-4-en-17-in-2-il]oxirano-2-carboxamida,@ (RS)-N-[(2S,3R)-14-azido-1,3-dihidroxitetradecan-2-il]oxirano-2-carboxamida,@ N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]propiolamida,@ N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]but-2-inamida,@ N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]acrilamida,@ (E)-N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]-2-butenamida,@ N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]metacrilamida,@ N-[(2S,3R)-N-1,3-dihidroxyoctadecan-2-il]-3-metil-2-butenamida,@ (2E,4E)-N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]hexa-2,4-dienamida,@ Acido@(E)-4-[(2S,3R)-1,3-dihidroxioctadecan-2-ilamino]-4-oxo-2-butenoico,@ (Z)-2,3-dibromo-N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]-4-oxo-2-butenamida,@ (2S,3R)-2-(bromometil)-N-(1,3-dihidroxioctadecan-2-il)acrilamida,@ (E,2S,3R)-N-(1,3-dihidroxi-2-octadecil)-2-metil-2-butenamida,@ (2S,3R)-N-(1,3-dihidroxi-17-octadecin-2-il)-2-oxooctanamida@y@ (2S,3R)-N-(14-azido-1,3-dihidroxi-2-tetradecil)-2-oxooctanamida,@ o@un@estereoisomero,@una@sal@o@un@solvato@farmaceuticamente@aceptable@de@uno@de@estos@compuestos@.@ @ From @ agreement @ with @ other @ mode @ of @ additional @ preferential realization, @ the @ compound @ of @ formula @ (I) @ as @ as @ has been previously defined @ is @ selected @ from @ the @ list @ which @ consists of: @@@ 1 - [(2S, 3R) -1,3-dihydroxioctadecan-2-il] -1H-pyrrole-2,5-diona, @ N - [(2S, 3R , E) -1,3-dihydroxyoctadec-4-en-2-yl] ethanesulfonamide, @ N - [(2S, 3R) -1,3-dihydroxioctadecan-2-yl] ethanesulfonamide, @ N - [(2S, 3R ) -1,3-dihydroxyoctadec-17-in-2-yl] ethanesulfonamide, @ N - [(2S, 3R) -14-azido-1,3-dihydroxytetradecan-2-yl) ethanesulfonamide, @ 2-bromo-N - [(2S, 3R) -1,3-dihydroxyoctadec-17-in-2-yl] acetamide, @ N - [(2S, 3R) -14-azido-1,3-dihydroxytetradecan-2-yl] bromoacetamide, @ N - [(2S, 3R, E) -14-azido-1,3-dihydroxytetradec-4-en-2-yl] bromoacetamide, @ 2-bromo-N - [(2S, 3R, E) -1, 3-dihydroxyoctadec-4-en-17-in-2-yl] acetamide, @ (S) -N- (14-azido-1-hydroxy-3-oxotetradecan-2-yl) -2-bromoacetamide, @ (RS ) -N - [(2S, 3R, E) -1,3-dihydroxyoctadec-4-en-2-yl] oxirane-2-carboxamide, @ (RS) -N - [(2S, 3R) -1.3 -dihydroxyoctadecan-2-yl] oxirane-2-carboxamide, @ @ (RS) -N - [(2S, 3R, E) -1,3-dihydroxyoc tadec-4-en-17-in-2-yl] oxirane-2-carboxamide, @ (RS) -N - [(2S, 3R) -14-azido-1,3-dihydroxytetradecan-2-yl] oxirane- 2-carboxamide, @ N - [(2S, 3R) -1,3-dihydroxioctadecan-2-yl] propriolamide, @ N - [(2S, 3R) -1,3-dihydroxioctadecan-2-yl] but-2- inamide, @ N - [(2S, 3R) -1,3-dihydroxioctadecan-2-yl] acrylamide, @ (E) -N - [(2S, 3R) -1,3-dihydroxioctadecan-2-il] -2 -butenamide, @ N - [(2S, 3R) -1,3-dihydroxyoctadecan-2-yl] methacrylamide, @ N - [(2S, 3R) -N-1,3-dihydroxyoctadecan-2-yl] -3- methyl-2-butenamide, @ (2E, 4E) -N - [(2S, 3R) -1,3-dihydroxioctadecan-2-yl] hexa-2,4-dienamide, @ Acid @ (E) -4- [ (2S, 3R) -1,3-dihydroxyoctadecan-2-ylamino] -4-oxo-2-butenoic, @ (Z) -2,3-dibromo-N - [(2S, 3R) -1,3-dihydroxioctadecan -2-yl] -4-oxo-2-butenamide, @ (2S, 3R) -2- (bromomethyl) -N- (1,3-dihydroxyoctadecan-2-yl) acrylamide, @ (E, 2S, 3R) -N- (1,3-dihydroxy-2-octadecyl) -2-methyl-2-butenamide, @ (2S, 3R) -N- (1,3-dihydroxy-17-octadecin-2-yl) -2- oxooctanamide @ and @ (2S, 3R) -N- (14-azido-1,3-dihydroxy-2-tetradecyl) -2-oxooctanamide, @ or @ a @ stereoisomer, @ a @ salt @ or @ a @ solvate @ pharmaceutics @ acceptable @ of @ one @ of @ these @ compounds @. @ @

Preferentemente,@el@compuesto@de@formula@(I)@tal@como@se@ha@definido@anteriormente@en@esta@solicitud@de@ Preferably, @ the @ compound @ of @ formula @ (I) @ as @ has @ been @ defined @ previously @ in @ this @ request @ of @

patente@se@selecciona@de@la@lista@que@consiste@en:@ 2-bromo-N-[(2S,3R)-1,3-dihidroxioctadec-17-in-2-il]acetamida,@ N-[(2S,3R)-14-azido-1,3-dihidroxitetradecan-2-il]bromoacetamida,@ N-[(2S,3R,E)-14-azido-1,3-dihidroxitetradec-4-en-2-il]bromoacetamida,@ Patent @ is @ selected @ from @ the @ list @ which @ consists of: @ 2-Bromo-N - [(2S, 3R) -1,3-dihydroxyoctadec-17-in-2-yl] acetamide, @ N - [(2S, 3R) -14-azido-1,3-dihydroxytetradecan-2-yl] bromoacetamide, @ N - [(2S, 3R, E) -14-azido-1,3-dihydroxytetradec-4-en-2-yl] bromoacetamide, @

5 2-bromo-N-[(2S,3R,E)-1,3-dihidroxioctadec-4-en-17-in-2-il]acetamida@y@ (S)-N-(14-azido-1-hidroxi-3-oxotetradecan-2-il)-2-bromoacetamida,@ o@un@estereoisomero,@una@sal@o@un@solvato@farmaceuticamente@aceptable@de@uno@de@estos@compuestos.@ @ 5 2-Bromo-N - [(2S, 3R, E) -1,3-dihydroxioctadec-4-en-17-in-2-yl] acetamide @ y @ (S) -N- (14-azido-1-hydroxy-3-oxotetradecan-2-yl) -2-bromoacetamide, @ o @ a @ stereoisomer, @ a @ salt @ or @ a @ pharmaceutically @ acceptable solvate of one of these compounds. @

De@acuerdo@con@otro@modo@de@realizacion@preferente@adicional,@el@compuesto@de@formula@(I)@cuando@n@es@1@tal@ From @ agreement @ with @ other @ mode @ of @ additional @ preferred realization, @ the @ compound @ of @ formula @ (I) @ when @ n @ is @ 1 @ such @

10 como@se@ha@definido@anteriormente@se@selecciona@de@la@lista@que@consiste@en:@@@ N-[(2S,3S,4R)-1,3,4-trihidroxioctadecan-2-il]etanosulfonamida@y@ (RS)-N-[(2S,3S,4R)-1,3,4-trihidroxioctadecan-2-il]oxirano-2-carboxamida,@ o@un@estereoisomero,@una@sal@o@un@solvato@farmaceuticamente@aceptable@de@uno@de@estos@compuestos.@ @ 10 as @ se @ ha @ defined @ above @ is @ selected @ from @ the @ list @ that @ consists of: @@@ N - [(2S, 3S, 4R) -1,3,4-trihydroxioctadecan-2 -il] ethanesulfonamide @ and @ (RS) -N - [(2S, 3S, 4R) -1,3,4-trihydroxioctadecan-2-yl] oxirane-2-carboxamide, @ or @ a @ stereoisomer, @ una @ sal @ o @ un @ solvato @ pharmaceutically @ acceptable @ of @ one @ of @ these @ compounds. @ @

15 Los@ compuestos@ de@ formula@ (I)@ pueden@ prepararse@ siguiendo@ distintos@ metodos@ conocidos@ para@ cualquier@ persona@experta@en@el@campo@de@la@sintesis@organica,@en@particular@por@los@procedimientos@generales@que@se@describen@a@ continuacion.@Los@materiales@de@partida@estan@disponibles@comercialmente@o@bien@se@pueden@preparar@mediante@metodos@ de@la@literatura.@ @ 15 The @ compounds @ of @ formula @ (I) @ can @ prepare @ following @ different @ known @ methods @ for @ any @ expert @ person @ in @ the @ field @ of @ the @ organic @ synthesis, @ in @ particular @ by @ the @ general @ procedures @ which @ are @ described @ a @ continuation. @ The @ materials @ of @ departure @ are @ commercially @ or @ well @ can @ be prepared by @ methods @ of @Literature.@ @

20 Los@compuestos@de@formula@(I)@pueden@obtenerse@a@partir@de@los@metodos@y@esquemas@descritos@a@continuacion:@ @ Esquema@1.@ 20 The @ compounds @ of @ formula @ (I) @ can @ be obtained @ from @ the @ methods @ and @ schemes @ described @ a @ continuation: @ @ Scheme @ 1. @

25 a:@Cat.@Grubbs@(segunda@generacion);@b:@1)@H2,@Pd/C;@2)@NaN3/DMF;@c:@NaN3/DMF;@d:@NaH/THF;@e:@1)@Li-C:C-TMS;@2)@ Bu4NF;@f:@HCl/MeOH;@g:@1)@cat.@TsOH/MeOH;@2)@NaOH/EtOH;@h:@1)@PCC/CH2Cl2;@2)@cat.@TsOH/MeOH.@ @ 25 a: @ Cat. @ Grubbs @ (second @ generation); @ b: @ 1) @ H2, @ Pd / C; @ 2) @ NaN3 / DMF; @c: @ NaN3 / DMF; @d: @NaH / THF; @e: @ 1) @ Li-C: C-TMS; @ 2) @ Bu4NF; @f: @ HCl / MeOH; @g: @ 1) @ cat. @ TsOH / MeOH; @ 2) @ NaOH / EtOH; @h: @ 1) @ PCC / CH2Cl2; @ 2) @ cat. @ TsOH / MeOH. @ @

En@primer@lugar,@se@hace@reaccionar@el@compuesto@1@(Herold,@Helv. Chim. Acta.@1988,@71,@354-62)@con@una@olefina@ terminal@(como,@por@ejemplo,@2a@o@2b)@en@una@reaccion@de@metatesis@cruzada@en@presencia@del@catalizador@de@Grubbs@de@ 30 segunda@ generacion,@ (Schmidt,@ Angew. Chem. Int. Ed. 2003,@ 42,@ 4996-9)@ obteniendose@ los@ compuestos@ 3.@ Por@ hidrogenacion@del@intermedio@3a@seguida@de@sustitucion@nucleofila@del@atomo@de@bromo@por@azida@sodica@se@llega@a@los@ intermedios@8,@que@por@hidrolisis@de@los@grupos@protectores@conducen@a@los@aminodioles@II-E.@Por@otra@parte,@por@oxidacion@ In @ first @, @ is @ reacted @ the @ compound @ 1 @ (Herold, @ Helv. Chim. Acta. @ 1988, @ 71, @ 354-62) @ with @ an @ olefin @ terminal @ ( like, @ for @ example, @ 2a @ or @ 2b) @ in @ a @ cross @ metathesis @ reaction @ in @ presence @ of @ Grubbs @ @ catalyst @ @ 30 second @ generation, @ (Schmidt, @ Angew. Chem. Int. Ed. 2003, @ 42, @ 4996-9) @ obtaining @ the @ compounds @ 3. @ By @ hydrogenation @ of the intermediate @ 3rd @ followed by @ substitution @ nucleofila @ of the @ atom @ of @ bromo @ by @ azida @ sodica @ se @ arrives @ at @ the @ intermediates @ 8, @ that @ by @ hydrolysis @ of @ the @ protective @ groups @ lead @ the @ aminodioles @ II-E. @ By @ other @ party, @ by @ oxidation @

de@8@y@posterior@hidrolisis@de@los@grupos@protectores@se@obtienen@las@aminas@ II-H.@Para@obtener@las@aminas@II-F,@el@ bromoderivado@3a@se@hace@reaccionar@con@azida@sodica@en@dimetilformamida,@obteniendose@3c,@seguido@de@hidrolisis@ acida@del@anillo@de@oxazolidina@y@del@grupo@Boc.@Mediante@reaccion@de@los@intermedios@ 3b@@con@hidruro@de@sodio@en@ dimetilformamida@ se@ obtienen@ los@ mesilatos@ 4,@ que@ pueden@ hidrogenarse@ a@ 5.@ Mediante@ reaccion@ de@ 4@o@ 5@ con@ trimetilsililacetiluro@de@ litio@ seguida@ de@desproteccion@ del@acetiluro@ con@ fluoruro@de@tetrabutilamonio@ se@ obtienen@ los@ alquinos@terminales@6@y@7,@respectivamente.@Su@transformacion@en@las@correspondientes@aminas@IIG@y@IID@se@consigue@ mediante@hidrolisis@secuencial@de@los@grupos@isopropilideno@y@carbamato.@ from @ 8 @ and @ subsequent @ hydrolysis @ from @ the @ protective @ groups @ are obtained @ the @ amines @ II-H. @ To @ obtain @ the @ amines @ II-F, @ the @ bromoderivado @ 3a @ @ reacts @ with @ azida @ sodica @ in @ dimethylformamide, @ obtaining @ 3c, @ followed by @ hydrolysis @ acid @ of @ ring @ of @ oxazolidine @ and @ of @ group @ Boc. @ Through @ reaction @ de @ los @ intermediaios @ 3b @@ with @ hydride @ of @ sodium @ in @ dimethylformamide @ are @ obtained @ mesilatos @ 4, @ that @ can @ hydrogenate @ a @ 5. @ By @ reaction @ of @ 4 @ or @ 5 @ with @ trimetilsililacetiluro @ of @ lithium @ followed by @ deprotection @ of @ acetyl @ with @ fluoride @ of @ tetrabutylammonium @ are @ obtained @ the @ alkynes @ terminals @ 6 @ and @ 7, @ respectively . @ Your @ transformation @ in @ the corresponding @ amines @ IIG @ and @ IID @ is @ achieved by @ sequential hydrolysis of @ the @ isopropylidene @ and @ carbamate groups.

@ @

Los@anteriores@amino@alcoholes,@asi@como@la@esfingosina@o@la@dihidroesfingosina,@pueden@acilarse@por@reaccion@con@ un@cloruro@de@acido@en@presencia@de@una@base.@Alternativamente,@tambien@puede@emplearse@un@anhidrido@de@acido,@como@ el@anhidrido@maleico,@o@un@acido@carboxilico@en@presencia@de@un@agente@de@acoplamiento@adecuado@como,@por@ejemplo,@la@ 1-etil-3-(3-dimetilaminopropil)carbodiimida@(EDC)@,@la@N,N'-diisopropilcarbodiimida@(DIC),@el@hexafluoro@fosfato@de@O-(7azabenzotriazol-1-il)-N,N,N’N'-tetrametiluronio@ (HATU)@ o@ el@ benzotriazol-1-iloxi-tris@ pirrolidinofosfonio@ (PyBOP)@ y@ un@ activador@como@el@1-hidroxibenzotriazol@(HOBt),@en@presencia@de@una@base@como@trietilamina,@en@un@disolvente@como@ diclorometano@y@bajo@atmosfera@inerte@(E.@Valeur, et al.,Chem Soc Rev@2009,@38,@606-31)@Las@sulfonamidas@pueden@ prepararse@ por@ acoplamiento@ de@ las@ aminas@ correspondientes@ con@ cloruro@ de@ etanosulfonilo@ en@ disolucion@ de@ tetrahidrofurano.@ @ The @ previous @ amino @ alcohols, @ as well as @ the @ sphingosine @ or @ the @ dihydroesfingosine, @ can @ acylate @ by @ reaction @ with @ a @ acid @ chloride @ in @ presence @ of @ a @ base. @ Alternatively, @ also @ can be used @ an @ anhydride @ of @ acid, @ as @ the @ maleic anhydride, @ or @ a @ carboxyl acid @ in @ presence @ of @ an @ agent @ of @ @ suitable coupling @ as, @ for @ example, @ la @ 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide @ (EDC) @, @ la @ N, N'-diisopropylcarbodiimide @ (DIC), @ el @ hexafluoro @ @ O- phosphate (7azabenzotriazol-1-yl) -N, N, N'N'-tetramethyluronium @ (HATU) @ or @ benzotriazol-1-yloxy-tris @ pyrrolidinophosphonium @ (PyBOP) @ y @ an @ activator @ as @ the @ 1-hydroxybenzotriazol @ (HOBt), @ in @ presence @ of @ a @ base @ as @ triethylamine, @ in @ a @ solvent @ as @ dichloromethane @ and @ under @ atmosphere @ inert @ (E. @ Valeur, et al., Chem Soc Rev @ 2009, @ 38, @ 606-31) @ Sulfonamides @ can @ be prepared @ by @ coupling @ of @ the corresponding @ amines @ with @ chloride @ of @ etanosulfonilo @ en @ dissolucion @ de @ tetrahidrofurano. @ @

Otro@ aspecto@ de@ la@ presente@ invencion@ se@ refiere@ a@ una@ composicion@ farmaceutica@ que@ comprende@ un@ compuesto@de@formula@general@(I)@o@uno@de@sus@estereisomeros,@sales@o@solvatos@farmaceuticamente@aceptables@tal@como@ se@define@en@esta@solicitud@de@patente@y@al@menos@un@excipiente@farmaceuticamente@aceptable.@Preferentemente,@la@ composicion@farmaceutica@se@puede@presentar@en@una@forma@adaptada@a@la@administracion@parenteral,@oral,@sublingual,@ nasal,@intratecal,@bronquial,@linfatica,@rectal,@transdermica@o@inhalada.@ @ Another @ aspect @ of @ the @ present @ invention @ is @ refers to a @ pharmaceutical composition @ that @ comprises @ a @ compound @ of @ formula @ general @ (I) @ or @ one @ of @ sus @ stereisomers, @ sales @ or @ pharmaceutically @ acceptable @ solvates @ as @ defined @ in @ this @ patent @ application @ and @ at least @ a @ pharmaceutically @ acceptable excipient. @ Preferably, @ the @ composition @ pharmaceutical @ can be presented in a form adapted to the parenteral administration, oral, sublingual, nasal, intrathecal, bronchial, lymphatic, rectal, transdermal @ or @ inhaled. @ @

De@acuerdo@con@un@aspecto@adicional@de@la@presente@invencion,@tanto@el@compuesto@de@formula@general@(I)@o@un@ estereoisomero,@una@sal@o@un@solvato@farmaceuticamente@aceptable@de@este@tal@como@se@ha@definido@en@la@presente@ solicitud@de@patente,@como@@un@compuesto@elegido@entre@2,2-dibromo-N-((2S,3R)-1,3-dihidroxioctadecan-2-il)acetamida@y@ 2-bromo-N-((2S,3R)-1,3-dihidroxioctadecan-2-il)acetamida@o@un@estereoisomero,@una@sal@o@un@solvato@farmaceuticamente@ aceptable@de@uno@de@estos@compuestos@son@utiles@para@el@tratamiento@de@una@enfermedad@asociada@con@la@inhibicion@de@ la@ceramidasa@acida,@y@por@lo@tanto@son@utiles@en@el@tratamiento@y/o@prevencion@de@una@enfermedad@que@cursa@con@ hiperproliferacion@celular.@ From @ agreement @ with @ an @ additional @ aspect @ of @ the @ present @ invention, @ both @ the @ compound @ of @ formula @ general @ (I) @ or @ a @ stereoisomer, @ a @ salt @ or @ a @ pharmaceutically @ acceptable @ solvate @ of @ this @ as @ has been defined in the present application for a patent, as a@ a composite chosen among @ 2,2- dibromo-N - ((2S, 3R) -1,3-dihydroxioctadecan-2-yl) acetamide @ and @ 2-bromo-N - ((2S, 3R) -1,3-dihydroxioctadecan-2-yl) acetamide @ o @ un @ stereoisomero, @ una @ sal @ o @ un @ solvato @ pharmaceutically @ acceptable @ of @ one @ of @ these @ compounds @ are @ useful @ for @ the @ treatment @ of a @ disease @ associated @ with @ la @ inhibicion @ de @ la @ ceramidasa @ acida, @ and @ por @ lo @ both @ are @ useful @ in @ the @ treatment @ and / or @ prevention @ of @ a @ disease @ that @ courses @ with @ hyperproliferation @ cell. @

@ @

De@acuerdo@con@otro@aspecto@adicional@de@la@presente@invencion,@tanto@las@composiciones@de@un@compuesto@de@ formula@general@(I)@o@un@estereoisomero,@una@sal@o@un@solvato@farmaceuticamente@aceptable@de@este@tal@como@se@ha@ definido@en@la@presente@solicitud@de@patente,@como@las@composiciones@que@comprenden@un@compuesto@que@se@puede@ elegir@entre@2,2-dibromo-N-((2S,3R)-1,3-dihidroxioctadecan-2-il)acetamida@y@2-bromo-N-((2S,3R)-1,3-dihidroxioctadecan2-il)acetamida@o@un@estereoisomero,@una@sal@o@un@solvato@farmaceuticamente@aceptable@de@uno@de@estos@compuestos@y@al@ menos@un@excipiente@farmaceuticamente@aceptable,@son@utiles@para@el@tratamiento@y@prevencion@de@una@enfermedad@que@ cursa@con@hiperproliferacion@celular.@ From @ agreement @ with @ other @ additional @ aspect @ of @ the @ present @ invention, @ both @ the @ compositions @ of @ a @ compound @ of @ formula @ general @ (I) @ or @ a @ stereoisomer, @ a @ sal @ o @ un @ solvato @ pharmaceutically @ acceptable @ from @ this @ as @ has been defined in the present application for a patent, as the compositions that understand @ a @ compound @ that @ can @ be chosen @ from @ 2,2-dibromo-N - ((2S, 3R) -1,3-dihydroxioctadecan-2-il) acetamide @ and @ 2-bromo-N- ((2S, 3R) -1,3-dihydroxioctadecan2-il) acetamide @ or @ a @ stereoisomer, @ a @ salt @ or @ a pharmaceutically @ solvate @ of @ one @ of @ these @ compounds @ and @ at least a pharmaceutically acceptable excipient @, @ are @ useful @ for @ the @ treatment @ and @ prevention @ of @ a disease that @ studies @ with @ cellular hyperproliferation @

@ @

Preferentemente,@el@compuesto@o@composicion@para@utilizar@en@el@tratamiento@o@prevencion@de@una@enfermedad@ que@cursa@con@hiperproliferacion@celular@tal@como@se@han@definido@anteriormente@en@la@presente@solicitud@de@patente,@se@ puede@ utilizar@ para@ el@ tratamiento@ de@ una@ enfermedad@ elegida@ entre@ cancer,@ metastasis,@ inflamacion,@ asma@ y@ arteriosclerosis.@ Preferably, @ the @ compound @ or @ composition @ to @ use @ in @ the @ treatment @ or @ prevention @ of @ a @ disease @ that @ studies @ with @ cellular @ hyperproliferation as @ have been defined @ formerly @ in @ the @ present @ patent @ application, @ can @ be @ used @ for @ the @ treatment @ of a @ disease @ chosen @ among @ cancer, @ metastasis, @ inflammation, @ asthma @ and @ arteriosclerosis. @

@ @

@De@forma@mas@preferente,@el@compuesto@o@composicion@para@utilizar@en@el@tratamiento@o@prevencion@de@una@ enfermedad@que@cursa@con@hiperproliferacion@celular@tal@como@se@han@definido@en@la@presente@solicitud@de@patente,@se@ puede@utilizar@en@el@tratamiento@del@cancer@de@prostata,@pancreas,@cerebro,@colon,@pulmon,@mama,@cabeza@y@cuello,@ ovario,@ laringe,@ vejiga@ urinaria,@ utero,@ piel,@sarcomas,@ linfomas@o@ leucemia.@ Preferentemente,@ cancer@ de@ prostata@o@ pulmon.@ @ @ De @ forma @ mas @ preferente, @ the @ compound @ or @ composition @ to @ use @ in @ the @ treatment @ or @ prevention @ of @ a disease that @ studies @ with @ hyperproliferation @ cell @ such @ as @ se @ han @ defined @ in @ the @ present @ patent @ application, @ can @ be @ used @ in @ the @ cancer @ treatment @ of @ prostata, @ pancreas, @ brain, @ colon, @ lung, @ breast, @ head @ and @ neck, @ ovary, @ larynx, @ urinary bladder, @ uterus, @ skin, @ sarcomas, @ lymphomas @ or @ leukemia. @ Preferably, @ cancer @ of @ prostata @ or @ pulmon. @ @

La@presente@invencion@tambien@se@refiere@a@un@metodo@para@la@prevencion@o@el@tratamiento@de@un@individuo@que@ padece@o@es@susceptible@de@padecer@enfermedad@que@cursa@con@hiperproliferacion@celular,@en@particular@el@tratamiento@del@ cancer@y@mas@preferentemente@el@tratamiento@del@cancer@de@prostata@o@pulmon,@que@comprende@la@administracion@a@dicho@ individuo@de@una@cantidad@terapeuticamente@efectiva@de@un@compuesto@de@formula@(I)@o@de@una@sal@farmaceuticamente@ aceptable@del@mismo@junto@con@cantidades@suficientes@de@excipientes@farmaceuticamente@aceptables.@@ @ The @ present @ invention @ also @ refers to a method for the prevention of an individual who suffers from being susceptible to suffering disease @ that @ attends @ with @ hyperproliferation @ cell phone, @ in particular @ the @ cancer @ treatment @ and @ more @ preferably @ the @ cancer @ treatment @ of prostata @ or @ lung, @ that @ includes @ the @ administration @ said @ individual @ of @ a @ therapeutically @ effective @ amount @ of @ a @ compound @ of @ formula @ (I) @ or @ of a pharmaceutically acceptable salt of the same @ together @ with @ sufficient @ quantities @ of @ pharmaceutically @ acceptable excipients. @@ @

La@ presente@ invencion@ tambien@ se@ refiere@ al@ uso@ tanto@ de@ un@ compuesto@ de@ formula@ general@ (I)@ o@ un@ estereoisomero,@una@sal@o@un@solvato@farmaceuticamente@aceptable@de@este@tal@como@se@ha@definido@en@la@presente@ solicitud@de@patente,@como@ al@uso@de@un@compuesto@elegido@entre@2,2-dibromo-N-((2S,3R)-1,3-dihidroxioctadecan-2il)acetamida@y@2-bromo-N-((2S,3R)-1,3-dihidroxioctadecan-2-il)acetamida@o@un@estereoisomero,@una@sal@o@un@solvato@ farmaceuticamente@aceptable@de@uno@de@estos@compuestos,@para@fabricar@una@composicion@ farmaceutica@util@en@el@ tratamiento@de@una@enfermedad@asociada@con@la@inhibicion@de@la@ceramidasa@acida,@y@por@lo@tanto@util@en@el@tratamiento@y/o@ prevencion@de@una@enfermedad@que@cursa@con@hiperproliferacion@celular.@ @ The @ present @ invention @ also @ refers to the @ use @ both @ of @ a @ compound @ of @ formula @ general @ (I) @ or @ a @ stereoisomer, @ a @ salt @ or @ a @ solvate @ pharmaceutically @ acceptable @ of @ this @ as @ has been defined in @ the @ present @ application @ of @ patent, @ as @ when @ using @ a @ compound @ chosen @ between @ 2, 2-dibromo-N - ((2S, 3R) -1,3-dihydroxyoctadecan-2il) acetamide @ and @ 2-bromo-N - ((2S, 3R) -1,3-dihydroxioctadecan-2-yl) acetamide @ o @ un @ stereoisomero, @ una @ sal @ o @ un @ solvato @ pharmaceutically @ acceptable @ of @ one @ of @ these @ compounds, @ to @ manufacture @ a @ pharmaceutical composition @ useful @ in @ the @ treatment @ of @ una @ illness @ associated @ with @ la @ inhibicion @ de @ la @ ceramidasa @ acida, @ and @ por @ lo @ both @ useful @ in @ the @ treatment @ and / or @ prevention @ of @ a @ disease @ que @ cursa @ con @ hiperproliferacion @ cellular. @ @

Preferentemente,@dicha@composicion@se@puede@utilizar@para@el@tratamiento@de@una@enfermedad@elegida@entre@ cancer,@metastasis,@inflamacion,@asma@y@arteriosclerosis.@ Preferably, @ bliss @ composition @ can be @ used @ for @ the treatment @ of @ a @ disease @ chosen @ among @ cancer, @ metastasis, @ inflammation, @ asthma @ and @ arteriosclerosis.

@ @

De@ forma@mas@ preferente,@ la@ composicion@ tal@ como@ se@ ha@ descrito@ anteriormente@ se@ puede@ utilizar@ en@ el@ tratamiento@del@cancer@de@prostata,@pancreas,@cerebro,@colon,@pulmon,@mama,@cabeza@y@cuello,@ovario,@laringe,@vejiga@ urinaria,@utero,@piel,@sarcomas,@linfomas@o@leucemia.@Preferentemente,@cancer@de@prostata@o@pulmon.@ @ In the most preferred way, @ the @ composition @ as @ has been described previously, can be used in the cancer treatment of prostate, pancreas, brain , @ colon, @ lung, @ breast, @ head @ and @ neck, @ ovary, @ larynx, @ urinary bladder, @ uterus, @ skin, @ sarcomas, @ lymphomas @ or @ leukemia. @ Preferably, @ cancer @ from @ prostata @ or @ pulmon. @ @

Los@compuestos@usados@en@la@presente@invencion@pueden@usarse@solos@o@con@otros@farmacos@para@proporcionar@ una@terapia@de@combinacion.@Los@otros@farmacos@pueden@formar@parte@de@la@misma@composicion,@o@se@pueden@suministrar@ en@forma@de@composicion@separada@para@la@administracion@al@mismo@tiempo@o@en@un@momento@diferente.@Asi,@de@acuerdo@ con@otro@aspecto@adicional@de@la@presente@invencion,@un@compuesto@de@formula@general@(I)@tal@como@se@ha@definido@en@la@ presente@ solicitud@ de@ patente@ o@ un@ compuesto@ elegido@ entre@ 2,2-dibromo-N-((2S,3R)-1,3-dihidroxioctadecan-2il)acetamida@y@2-bromo-N-((2S,3R)-1,3-dihidroxioctadecan-2-il)acetamida@o@un@estereoisomero,@una@sal@o@un@solvato@ farmaceuticamente@aceptable@de@uno@de@estos@compuestos,@se@puede@utilizar@en@combinacion@con@otra@terapia@para@el@ tratamiento@de@una@enfermedad@tal@como@se@ha@definido@anteriormente.@@ @ The @ compounds @ used @ in @ the @ present @ invention @ can @ be used @ alone @ or @ with @ other @ drugs @ to @ provide @ a @ combination @ therapy. @ The @ other @ drugs @ can @ form @ part @ of @ the @ same @ composition, @ or @ can @ be supplied @ in @ form @ of @ separate @ composition @ for @ the @ administration @ at the same time @ or @ in @ a @ moment @ different. @ So, @ of @ agreement @ with @ other @ additional @ aspect @ of @ the @ present @ invention, @ a @ compound @ of @ formula @ general @ (I) @ as @ has been defined @ in @ the @ present @ application @ of @ patent @ or @ a @ compound @ chosen @ between @ 2,2-dibromo-N - ((2S, 3R) -1,3-dihydroxioctadecan-2il) acetamide @ and @ 2-Bromo-N - ((2S, 3R) -1,3-dihydroxioctadecan-2-il) acetamide @ or @ a @ stereoisomer, @ a @ salt @ or @ a pharmaceutically @ solvate @ of @ one @ of @ these @ compounds, @ can @ be used @ in @ combination @ with @ other @ therapy @ for @ the @ treatment @ of @ a @ disease @ as @ was @ defined @ above. @@ @

De@acuerdo@con@otro@aspecto@adicional@de@la@presente@invencion,@la@composicion@de@un@compuesto@de@formula@(I)@ tal@ como@ se@ ha@ definido@ anteriormente@ en@ la@ presente@ solicitud@ de@ patente@ o@ la@ composicion@ que@ comprende@ un@ compuesto@ elegido@ entre@ 2,2-dibromo-N-((2S,3R)-1,3-dihidroxioctadecan-2-il)acetamida@ y@ 2-bromo-N-((2S,3R)-1,3dihidroxioctadecan-2-il)acetamida@o@un@estereoisomero,@una@sal@o@un@solvato@farmaceuticamente@aceptable@de@uno@de@ estos@compuestos@y@al@menos@un@excipiente,@se@puede@utilizar@en@combinacion@con@otra@terapia@para@el@tratamiento@de@ una@enfermedad@tal@como@se@ha@definido@anteriormente.@ @ From @ agreement @ with @ other @ additional @ aspect @ of @ the @ present @ invention, @ the @ composition @ of @ a @ compound @ of @ formula @ (I) @ as @ has been defined previously @ in @ the @ present @ application @ of @ patent @ or @ the @ composition @ that @ comprises @ a @ compound @ chosen @ from @ 2,2-dibromo-N - ((2S, 3R) -1,3- dihydroxioctadecan-2-il) acetamide @ and @ 2-bromo-N - ((2S, 3R) -1,3 dihydroxioctadecan-2-il) acetamide @ or @ a stereoisomer, @ a @ salt @ or @ a @ solvate @ pharmaceutically @ acceptable @ of @ one @ of @ these @ compounds @ and @ at least @ one @ excipient, @ can @ be used @ in @ combination @ with @ another @ therapy @ for @ the @ treatment @ of @ a @ disease @ as @ has been defined previously.

Otros@tipos@de@terapia@pueden@ser@quimioterapia@o@radioterapia.@A@titulo@de@ejemplo,@los@agentes@terapeuticos@ pueden@ ser@ tamoxifen,@ daunorubicina,@ etoposido,@ paclitaxel,@ dacarbacida,@ temozolomida,@ temsirolimus,@ fenretinida,@ resveratrol,@borinostat,@sorafenib,@imatinib,@bortezomib,@gemcitabina@o@cisplatin.@ @ Other @ types @ of @ therapy @ can @ be @ chemotherapy @ or @ radiotherapy. @ A @ title @ of @ example, @ the @ therapeutic @ agents @ can @ be @ tamoxifen, @ daunorubicin, @ etoposide, @ paclitaxel, @ dacarbacida, @ temozolomida, @ temsirolimus, @ fenretinida, @ resveratrol, @ borinostat, @ sorafenib, @ imatinib, @ bortezomib, @ gemcitabine @ or @ cisplatin. @ @

A@lo@largo@de@la@descripcion@y@las@reivindicaciones@la@palabra@"comprende"@y@sus@variantes@no@pretenden@excluir@ otras@caracteristicas@tecnicas,@aditivos,@componentes@o@pasos.@Para@los@expertos@en@la@materia,@otros@objetos,@ventajas@y@ caracteristicas@de@la@invencion@se@desprenderan@en@parte@de@la@descripcion@y@en@parte@de@la@practica@de@la@invencion.@Los@ siguientes@ejemplos@y@dibujos@se@proporcionan@a@modo@de@ilustracion,@y@no@se@pretende@que@sean@limitativos@de@la@ presente@invencion.@ @DESCRIPCIÓN DE LAS FIGURAS @ @ The @ long @ of @ the @ description @ and @ the @ claims @ the @ word @ "comprises" @ and @ its @ variants @ do not intend to exclude @ other @ technical @ features, additives, @ components @ o @ steps. @ For @ the @ experts @ in @ the @ subject, @ other @ objects, @ advantages @ and @ features @ of the @ invention @ will come off @ in @ part of @ the @ description @ and @ in @ part @ of @ the @ practice @ of @ la @ invencion. @ The following @ examples @ and @ drawings @ are @ provided @ mode @ of @ illustracion, @ and @ not @ intended @ that @ be @ limiting @ of @ the @ present @ invention. @ @ DESCRIPTION OF THE FIGURES

Figura 1.@Efecto@de@los@compuestos@sobre@la@actividad@ceramidasa@acida.@Los@ensayos@se@efectuaron@sobre@celulas@de@ Farber@transducidas@para@que@sobreexpresen@la@ceramidasa@acida,@ya@sea@intactas@(barras@blancas)@o@en@lisados@(barras@ grises).@La@incubacion@se@llevo@a@cabo@afadiendo@conjuntamente@el@inhibidor@(16@!M)@con@el@sustrato@fluorogenico@(16@ !M)@durante@3@h.@A@continuacion@se@procedio@tal@como@se@detalla@en@el@ejemplo@1@del@apartado@de@ejemplos@de@ensayos@ biologicos@(Bedia@et@al.@Chembiochem@2007,@8,@642).@@El@eje@y@indica@el@porcentaje@de@actividad@enzimatica@respecto@al@ control.@ @ Figura 2.@Efecto@de@los@compuestos@sobre@la@actividad@ceramidasa@acida.@Los@ensayos@se@efectuaron@sobre@celulas@de@ adenocarcinoma@de@pulmon@humano@A549.@Las@celulas@intactas@se@incubaron@con@el@inhibidor@(16@!M)@durante@24@h@y@ luego@se@afadio@el@sustrato@fluorogenico@(16@!M),@que@se@incubo@durante@3@h.@La@hidrolisis@se@determino@midiendo@la@ fluorescencia@generada@despues@de@proceder@tal@como@se@indica@en@el@ejemplo@1@del@apartado@de@ejemplos@de@ensayos@ biologicos@(Bedia@et@al.@Chembiochem@2007,@8,@642).@@El@eje@y@indica@el@porcentaje@de@actividad@enzimatica@respecto@al@ control.@ @ Figura 3. Efecto@de@los@compuestos@I-B2,@I-B17@e@I-B9@sobre@la@actividad@ceramidasa@acida@de@las@celulas@de@cancer@de@ prostata@PC-3Mc.@Los@ensayos@se@efectuaron@por@incubacion@de@las@celulas@con@el@inhibidor.@Las@celulas@se@sembraron@en@ placas@de@96@pocillos@a@una@densidad@de@10.000@celulas/ml@y@los@compuestos@se@afadieron@24@h@despues@de@la@siembra.@ Se@usaron@tres@dosis@de@cada@inhibidor,@1@ M,@5@ M@y@10@ M,@en@incubaciones@durante@48@h@y@los@ensayos@se@realizaron@ por@triplicado.@Tras@este@periodo@de@incubacion,@se@elimino@el@medio@y@se@afadio@medio@fresco@conteniendo@el@el@sustrato@ fluorogenico@(16@!M)@y@se@incubo@durante@3@h.@La@hidrolisis@se@determina@midiendo@la@fluorescencia@generada@despues@de@ proceder@tal@como@se@indica@en@el@ejemplo@1@del@apartado@de@ejemplos@de@ensayos@biologicos@(Bedia@et@al.@Chembiochem@ 2007,@8,@642).@El@eje@y@indica@el@porcentaje@de@actividad@enzimatica@respecto@al@control.@ Figure 1. @ Effect @ of @ the @ compounds @ on @ the @ activity @ ceramidasa @ acida. @ The @ trials @ were @ carried out on @ cells @ of @ Farber @ transduced @ to @ that @ overexpress @ la @ ceramidasa @ acida, @ ya @ be @ intact @ (white @ bars) @ or @ in @ lysates @ (bars @ gray). @ The @ incubation @ took @ out @ joining @ together @ the @ inhibitor @ (16 @! M) @ with @ the @ fluorogenic substrate @ (16 @ ! M) @ during @ 3 @ h. @ A @ continuation @ se @ procedio @ as @ se @ detailed @ in @ the @ example @ 1 @ of the @ section @ of @ examples @ of @ essays @ Biological @ (Bedia @ et @ al. @ Chembiochem @ 2007, @ 8, @ 642). @@ The @ axis @ and @ indicates @ the @ percentage @ of @ enzymatic @ activity @ respect @ to the @ control.@ @ Figure 2. @ Effect @ of @ the compounds @ on @ the @ activity @ ceramidasa @ acida. @ The @ trials @ were @ carried out on @ cells @ of @ adenocarcinoma @ of @ pulmon @ human @ A549. @ The @ intact cells @ were @ incubated @ with @ the @ inhibitor @ (16 @! M) @ for @ 24 @ h @ y @ then @ se @ afadio @ el @ sustrato @ fluorogenico @ (16 @! M), @ que @ se @ incubo @ during @ 3 @ h. @ The @ hydrolysis @ determined @ measuring @ la @ fluorescence @ generated @ after @ proceed @ as @ is @ indicated @ in @ the @ example @ 1 @ of the @ section @ of @ examples @ of @ tests @ Biological @ (Bedia @ et @ al. @ Chembiochem @ 2007, @ 8, @ 642). @@ The @ axis @ and @ indicates @ the @ percentage @ of @ enzymatic @ activity @ respect @ to the @ control.@ @ Figure 3. Effect of @ the @ compounds @ I-B2, @ I-B17 @ and @ I-B9 @ on @ the @ activity @ ceramidasa @ acida @ of @ the @ cells @ of @ cancer @ of @ prostate @ PC-3Mc. @ The @ trials @ were @ carried out by @ incubation of @ the @ cells @ with @ the @ inhibitor. @ The @ cells @ were @ planted @ in @ @ 96 @ well plates @ a @ a @ density @ of @ 10,000 @ cells / ml @ and @ the @ compounds @ were added @ 24 @ h @ after @ the sowing. @ Three @ doses @ of @ each @ inhibitor, @ 1 @ M, @ 5 @ M @ and @ 10 @ M, @ in @ incubations @ during @ 48 @ h @ and @ the @ trials @ were @ performed @ by @ triplicado. @ After @ this @ period @ of incubation, @ was @ deleted @ the @ middle @ and @ was @ afadio @ half @ fresh @ containing @ the @ the @ substrate @ fluorogenic @ (16 @! M) @ and @ se @ incubo @ during @ 3 @ h. @ Hydrolysis @ is determined by measuring the fluorescence generated after @ proceed @ as @ is @ indicated @ in @ the @ example @ 1 @ of the @ section @ of @ examples @ of @ biological @ trials @ (Bedia @ et @ al. @ Chembiochem @ 2007, @ 8, @ 642). @ The @ axis @ and @ indicates @ the @ percentage @ of @ enzymatic @ activity @ with respect to the @ control.

Figura 4. Efecto@de@los@compuestos@sobre@el@ceramidoma.@Los@ensayos@se@efectuan@sobre@celulas@de@adenocarcinoma@ de@ pulmon@ humano@ A549.@ Las@ celulas@ intactas@ se@ incubaron@ con@ el@ inhibidor@ (16@ !M)@ durante@ 24@ h@ y@ luego@ se@ recolectaron@las@celulas@y@se@procesaron@tal@como@se@detalla@en@el@ejemplo@2@de@ejemplos@de@ensayos@biologicos.@ @ Figura 5. Efecto@de@los@compuestos@I-B2,@I-B17@e@I-B9@sobre@el@esfingolipidoma@de@las@celulas@de@cancer@de@prostata@PC3Mc.@Los@ensayos@se@efectuaron@por@incubacion@de@las@celulas@con@los@compuestos.@Las@celulas@se@sembraron@en@placas@ de@6@pocillos@a@una@densidad@de@250.000@celulas/ml@y@los@compuestos@se@afadieron@24@h@despues@de@la@siembra.@Se@ Figure 4. Effect @ of @ the @ compounds @ on @ the @ ceramidoma. @ The @ trials @ are performed on @ cells @ of @ adenocarcinoma @ @ human @ lung @ A549. @ The @ intact @ cells @ were incubated @ with @ the @ inhibitor @ (16 @! M) @ for @ 24 @ h @ and @ then @ se @ collected @ the @ cells @ and @ were @ processed @ as @ is @ detailed @ in @ the @ example @ 2 @ of @ examples @ of @ biological @ trials. @ @ Figure 5. Effect @ of @ the @ compounds @ I-B2, @ I-B17 @ and @ I-B9 @ on @ the @ sphingolipidoma @ of @ cancer @ cells @ of @ prostata @ PC3Mc. @ Los @ trials @ were @ carried out by @ incubation of @ the @ cells @ with @ the compounds. @ The @ cells @ were seeded @ in @ plates @ from @ 6 @ wells @ to @ a @ density @ of @ 250,000 @ cells / ml @ and @ the @ compounds @ were added @ 24 @ h @ after @ the sowing.

usaron@tres@dosis@de@cada@inhibidor,@1@ M,@5@ M@y@10@ M,@en@incubaciones@durante@48@h@y@los@ensayos@se@realizaron@por@ triplicado.@Se@usaron@tres@dosis@de@cada@compuesto,@1@ M,@5@ M@y@10@ M,@en@incubaciones@durante@48@h.@Tras@este@ periodo@de@incubacion,@se@elimina@el@medio@se@recolectan@las@celulas@y@se@procesan@tal@como@se@detalla@en@el@ejemplo@2@ de@ejemplos@de@ensayos@biologicos.@A,@ceramidas;@B,@dihidroceramidas;@C,@esfingomielinas;@D@dihidroesfingomielinas;@E,@ glucosilceramidas.@ @ Figura 6. Efecto@de@los@compuestos@sobre@la@viabilidad@de@las@celulas@de@A,@adenocarcinoma@de@pulmon@A549@(negro)@y@ de@leucemia@Jurkat@A3@(gris)@y@B,@cancer@de@prostata@PC3/Mc.@Las@celulas@se@sembraron@a@una@densidad@de@200.000@ celulas@por@mililitro@y,@24@h@despues@de@la@siembra,@se@incubaron@con@los@compuestos@durante@24@h@(A)@o@72@h@(B),@tras@las@ cuales@se@determino@el@numero@de@celulas@viables@mediante@el@ensayo@de@reduccion@del@MTT,@tal@como@se@especifica@en@ el@ejemplo@3@de@ejemplos@de@ensayos@biologicos.@El@eje@y@indica@el@porcentaje@del@numero@de@celulas@respecto@al@control. @ Figura 7. Efecto@de@los@compuestos@sobre@el@crecimiento@de@las@celulas@PC-3Mc@sobre@sustrato@plastico.@Se@sembraron@ 500@celulas@en@cada@pocillo@de@placas@de@96@pocillos,@dejandose@adherir@al@plastico@durante@24@h,@seguido@de@tratamiento@ con@los@compuestos@a@una@concentracion@final@de@5@!M.@El@efecto@de@las@incubaciones@con@estos@compuestos@sobre@el@ crecimiento@celular@de@determino@cuantificado@el@numero@de@celulas@presentes@a@las@24@h,@48@h,@72@h,@120@h,@144@h@y@168@h@ despues@del@tratamiento@con@los@compuestos.@El@eje@y@indica@la@proporcion@relativa@del@numero@de@celulas@respecto@al@dia@ 1@y@el@eje@x@se@refiere@al@tiempo@(t)@en@dias.@ @ Figura 8.@Efecto@de@los@inhibidores@sobre@la@formacion@de@colonias@celulares@en@medio@semisolido.@Las@celulas@PC-3Mc,@ sembradas@ en@ medio@ de@ cultivo@ completo@ que@ contiene@ agar@ al@ 3%,@ se@ trataron@ con@ los@ compuestos@ problema@ a@ concentraciones@finales@de@1@ M@o@5@ M,@reafadiendolos@con@una@periodicidad@de@3@dias,@coincidiendo@con@la@adicion@de@ medio@de@cultivo@nuevo.@El@numero@de@colonias@se@conto@3@semanas@despues@del@tratamiento.@El@eje@y@indica@el@numero@ de@colonias@(N°@Col.)@ @ Figura 9.@Efecto@de@los@inhibidores@sobre@la@invasividad@celular.@Las@celulas@PC-3Mc@fueron@tratadas@con@los@compuestos@ problema@a@una@concentracion@final@de@5@ M@durante@las@48@h@previas@al@ensayo@de@invasividad.@Tras@ese@tiempo@de@ tratamiento,@ las@ celulas@ fueron@ recolectadas,@ resuspendidas@ en@ medio@ completo,@ y@ sembradas@ sobre@ las@ camaras@ superiores@de@los@insertos@Transwell@recubiertos@con@Matrigel@(10@mg/mL).@Los@compuestos@problema@se@afadieron@tanto@ a@la@camara@superior@como@a@la@inferior,@a@una@concentracion@de@5@ M,@manteniendose@este@tratamiento@a@lo@largo@de@todo@ el@periodo@de@duracion@del@ensayo.@Cada@condicion@se@realizo@por@triplicado.@El@eje@y@indica@el@numero@de@celulas@(N°)@ @ Figura 10.@Formulas@de@los@compuestos@sintetizados@en@los@ejemplos.@ they used @ three @ doses @ of @ each @ inhibitor, @ 1 @ M, @ 5 @ M @ y @ 10 @ M, @ in @ incubations @ during @ 48 @ h @ and @ the @ trials @ were @ performed @ by @ triplicate. @ Three @ doses @ of @ each @ compound were used, @ 1 @ M, @ 5 @ M @ and @ 10 @ M, @ in @ incubations @ during @ 48 @ h. @ After @ this @ @ incubation period, @ the @ medium @ is removed @ the @ cells @ are collected and @ processed @ as @ detailed @ in @ the @ example @ 2 @ of @ examples @ of @ biological @ assays. @ A, @ ceramides; @ B, @ dihydroceramides; @ C, @ sphingomyelins; @ D @ dihydrosphingomyelins; @ E, @ glucosylceramides. @ @ Figure 6. Effect of @ the @ compounds @ on @ the @ viability @ of @ the @ cells @ of @ A, @ adenocarcinoma @ of @ lung @ A549 @ (black) @ and @ from @ leukemia @ Jurkat @ A3 @ (gray) @ and @ B, @ cancer @ from @ prostata @ PC3 / Mc. @ The @ cells @ were @ planted @ a @ a @ density @ of @ 200,000 @ cells @ by @ milliliter @ and, @ 24 @ h @ after @ the @ planting, @ were @ incubated @ with @ the @ compounds @ during @ 24 @ h @ (A) @ or @ 72 @ h @ (B ), @ after @ las @ which @ was @ determined @ the @ number @ of @ viable @ cells @ by @ the @ test @ of @ MTT reduction, @ as @ as @ specified @ in @ the @ example @ 3 @ of @ examples @ of @ biological @ trials. @ The @ axis @ and @ indicates @ the @ percentage @ of the @ number @ of @ cells @ with respect to the @ control. @ Figure 7. Effect @ of @ the @ compounds @ on @ the @ growth @ of @ the cells @ PC-3Mc @ on @ plastic @ substrate. 500 @ cells @ in @ each @ well @ of @ plates @ of @ 96 @ wells, @ leaving @ adhering @ to the plastic @ for @ 24 @ h, @ followed by @ treatment @ with @ the @ compounds @ a @ a @ final @ concentration @ of @ 5 @! M. @ The @ effect @ of the @ incubations @ with @ these @ compounds @ on @ the @ growth @ cell @ of @ determino @ quantified @ the @ number @ of @ cells @ present @ a @ las @ 24 @ h, @ 48 @ h, @ 72 @ h, @ 120 @ h, @ 144 @ h @ and @ 168 @ h @ after the @ treatment @ with @ the @ compounds. @ The @ axis @ and @ indicates @ the @ relative @ proportion @ of the @ number @ of @ cells @ with respect to the @ day @ 1 @ and @ the @ axis @ x @ refers to @ time @ (t) @ in @ days. @ @ Figure 8. @ Effect @ of @ the @ inhibitors @ on @ the @ formation @ of @ cell colonies @ in @ half @ semi-solid. @ The @ cells @ PC-3Mc, @ seeded @ in @ medium @ of @ full @ crop @ that @ contains @ 3% agar @, @ were @ treated with @ the @ compounds @ problem @ a @ @ final @ concentrations @ 1 @ M @ o @ 5 @ M, @ reafadiendlos @ with @ a @ periodicity @ of @ 3 @ days, @ coinciding with @ the @ addition @ of @ medium @ of @ new @ culture. @ The @ number @ of @ colonies @ was counted @ 3 @ weeks @ after @ the treatment. @ The @ axis @ and @ indicates @ the @ number @ from @ colonias @ (N ° @ Col.) @ @ Figure 9. @ Effect @ of @ inhibitors @ on @ cell @ invasiveness. @ Cells @ PC-3Mc @ were @ treated @ with @ the @ compounds @ problem @ a @ a @ final @ concentration @ of @ 5 @ M @ during @ the @ 48 @ h @ previous @ the @ invasive @ test @ After @ that @ time @ of @ treatment, @ the @ cells @ were @ collected, @ resuspended @ in @ half @ complete, @ and @ seeded @ over @ the @ cameras @ @ of @ the @ inserts @ Transwell @ coated @ with @ Matrigel @ (10 @ mg / mL). @ The @ problem @ compounds @ added @ both @ @ la @ camara @ superior @ como @ a @ la @ inferior, @ a @ una @ concentracion @ de @ 5 @ M, @ staying @ this @ treatment @ a @ lo @ long @ de @ todo @ the @ period @ of @ duration @ of the trial. @ Each @ condition @ was done @ by @ triplicate. @ The @ axis @ and @ indicates @ the @ number @ of @ cells @ (No.) @ @ Figure 10. @ Formulas @ of @ the @ synthesized @ compounds @ in the @ examples.

EJEMPLOS EXAMPLES

@ A@continuacion@se@ilustrara@la@invencion@mediante@unos@ensayos@realizados@por@los@inventores,@que@pone@de@manifiesto@la@ especificidad@y@efectividad@de@los@inhibidores@de@ceramidasas@de@la@presente@invencion.@ @ Ejemplos de síntesis química@ @ Sintesis@de@los@precursores@de@las@bases@esfingoides@II(D-H)@ @ Reaccion@de@metatesis@entre@el@alcohol@1@y@las@olefinas@terminales@2a y2b:@sintesis@de@3a@y@de@3b @ A@una@disolucion@desgasada@del@alcohol@1@(5@mmol)@y@de@la@olefina@terminal@2a@o@2b@(20@mmol)@en@diclorometano@(80@mL)@ se@afadieron@400@mg@(aproximadamente@0.5@mmol)@de@catalizador@de@Grubbs@de@segunda@generacion.@La@mezcla@se@ agito@a@la@temperatura@de@reflujo@bajo@atmosfera@de@Ar@durante@5@h.@Tras@la@evaporacion@del@disolvente,@el@residuo@se@ purifico@por@cromatografia@flash@(hexano@/@EtOAc@1:3).@ @ (S)-4-[(R,E)-12-bromo-1-hidroxidodec-2-enil]-2,2-dimetiloxazolidina-3-carboxilato@de@terc-butilo@(3a)@ @ Rendimiento:@85%@ 1H-RMN@(400@MHz,@CDCl3):@5@5.58@(m,@1H);@5.45@(m,@1H);@4.20-3.70@(m,@4H);@3.35@(t,@2H);@1.95@(m,@2H);@1.78@(m,@2H);@ 1.65-1.35@(m,@12H);@1.45@(s,@9H);@1.18@(s,@6H),@ 13C-RMN@(101@MHz,@CDCl3):@5@154.32,@133.94,@133.40,@129.26,@128.25,@94.51,@81.13,@74.16,@65.03,@62.36,@34.17,@32.90,@ 32.48,@29.46,@29.36,@29.26,@29.19,@28.96,@28.84,@28.79,@28.47,@28.42,@28.24,@26.35,@24.71.@ @ (S)-4-[(R,E)-1-hidroxi-14-(metilsulfoniloxi)tetradec-2-enil]-2,2-dimetiloxazolidina-3-carboxilato@de@terc-butilo@(3b)@ Rendimiento:@89%@ 1H-RMN@(400@MHz,@CDCl3):@5@5.82-5.75@(m,@1H);@5.45-5.30@(m,@1H);@4.22@(t,@2H);@4.30-3.80@(m,@4H);@3.05@(s,@3H);@2.10- 2.05@(m,@2H);@1.75-1.70@(m,@2H);@1.55-1.45@(s@ancho,@15H);@1.70-1.15@(m,@12H)@ @ @ @ @ @ Continuation @ will be illustrated by the invention through @ some @ essays @ carried out by @ the @ inventors, @ who @ puts @ of @ manifest @ the @ specificity @ and @ effectiveness @ of @ the @ inhibitors @ of @ ceramidasas @ of @ the @ present @ invention. @ @ Examples of chemical synthesis @ @ Synthesis @ of @ the @ precursors @ of @ the @ bases @ sphingoids @ II (D-H) @ @ Reaction @ of @ metathesis @ between @ el @ alcohol @ 1 @ and @ las @ olefinas @ terminals @ 2a y2b: @ synthesis @ of @ 3a @ and @ of @ 3b @ A @ a @ worn @ solution @ of @ alcohol @ 1 @ (5 @ mmol) @ and @ of @ la @ olefina @ terminal @ 2a @ o @ 2b @ (20 @ mmol) @ in @ dichloromethane @ (80 @ mL ) @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ Grubbs @ catalyst @ second generation @ @ @ mix @ se @ agito @ a @ la @ temp @ de @ reflujo @ bajo @ atmosfera @ de @ Ar @ during @ 5 @ h. @ After @ the @ evaporation @ of the solvent, @ the @ residue @ se @ purifico @ by @ chromatography @ flash @ (hexane @ / @ EtOAc @ 1: 3). @ @ (S) -4 - [(R, E) -12-Bromo-1-hydroxidedec-2-enyl] -2,2-dimethyloxazolidine-3-carboxylate @ de @ tert-butyl @ (3a) @ @ Yield: @ 85% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 5.58 @ (m, @ 1H); @ 5.45 @ (m, @ 1H); @ 4.20-3.70 @ (m, @ 4H); @ 3.35 @ (t, @ 2H); @ 1.95 @ (m, @ 2H); @ 1.78 @ (m, @ 2H); @ 1.65-1.35 @ (m, @ 12H); @ 1.45 @ (s, @ 9H); @ 1.18 @ (s, @ 6H), @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 154.32, @ 133.94, @ 133.40, @ 129.26, @ 128.25, @ 94.51, @ 81.13, @ 74.16, @ 65.03, @ 62.36, @ 34.17, @ 32.90 , @ 32.48, @ 29.46, @ 29.36, @ 29.26, @ 29.19, @ 28.96, @ 28.84, @ 28.79, @ 28.47, @ 28.42, @ 28.24, @ 26.35, @ 24.71. @ @ (S) -4 - [(R, E) -1-hydroxy-14- (methylsulfonyloxy) tetradec-2-enyl] -2,2-dimethyloxazolidine-3-carboxylate @ de @ tert-butyl @ (3b) @ Yield: @ 89% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 5.82-5.75 @ (m, @ 1H); @ 5.45-5.30 @ (m, @ 1H); @ 4.22 @ (t, @ 2H); @ 4.30-3.80 @ (m, @ 4H); @ 3.05 @ (s, @ 3H); @ 2.10- 2.05 @ (m, @ 2H); @ 1.75-1.70 @ (m, @ 2H); @ 1.55-1.45 @ (s @ width, @ 15H); @ 1.70-1.15 @ (m, @ 12H) @ @ @ @

(S)-4-[(R,E)-12-azido-1-hidroxidodec-2-enil]-2,2-dimetiloxazolidina-3-carboxilato@de@terc-butilo@(3c)@ @ Una@disolucion@de@122@mg@(1.87@mmol)@de@azida@sodica@en@DMF@anhidro@(10@mL)@se@afadio,@gota@a@gota,@sobre@una@ disolucion@del@bromuro@3a@en@5@mL@de@DMF,@bajo@atmosfera@de@Ar@a@temperatura@ambiente.@Finalizada@la@adicion,@la@ mezcla@de@reaccion@se@calento@a@65°@C@y@se@mantuvo@en@agitacion@durante@12h.@A@continuacion,@la@mezcla@se@diluyo@con@ 40@mL@de@agua@y@se@extrajo@con@Et2O@(3@x@15@mL).@Las@fases@organicas@se@lavaron@con@salmuera@(2@x@10@mL),@se@secaron@ sobre@MgSO4@anhidro,@se@filtraron@y@se@evaporaron@para@dar@un@residuo@que@se@purifico@por@cromatografia@flash@(Hexano@/@ EtOAc@7:3).@ Rendimiento:@91%@ 1H-RMN@(400@MHz,@CDCl3):@5@5.82@-@5.66@(m,@1H),@5.48@-@5.36@(m,@1H),@4.22@-@3.75@(m,@4H),@3.25@(t,@J@=@7.0@Hz,@2H),@2.11@ -@1.96@(m,@2H),@1.45@(s,@9H);@1.32@(s,@6H);@1.55-1.35@(m,@18H).@ 13C-RMN@(101@MHz,@CDCl3):@5@133.51,@128.29,@94.58,@81.20,@74.25,@65.08,@62.44,@51.61,@32.53,@29.55,@29.51,@29.45,@ 29.31,@29.28,@29.24,@28.97,@28.51,@26.84,@26.38,@24.74.@ @ Metanosulfonato@de@(E)-13-[(1R,7aS)-5,5-dimetil-3-oxo-tetrahidro-1H-oxazolo[3,4-c]oxazol-1-il]tridec-12-enilo@(4)@ @ Sobre@una@disolucion@de@505@mg@(1@mmol)@de@3b@en@THF@anhidro@(10@mL),@enfriada@en@un@bafo@de@hielo,@se@afadieron@80@ mg@(2@mmol)@de@NaH.@Tras@agitacion@a@temperatura@ambiente@durante@18h,@la@mezcla@de@reaccion@se@enfrio@en@un@bafo@ de@hielo,@se@trato@con@una@disolucion@acuosa@saturada@de@NaHCO3@y@se@extrajo@con@Et2O@(3@x@5@mL).@Los@extractos@ organicos@reunidos@se@lavaron@con@salmuera@y@se@secaron@sobre@MgSO4@anhidro.@Tras@la@evaporacion@del@disolvente@se@ obtuvo@el@compuesto@4,@que@se@sometio@a@la@etapa@posterior@sin@purificacion.@ Rendimiento:@85%@ 1H-RMN@(400@MHz,@CDCl3):@5@5.90-5.85@(m,@1H);@5.80-5.75@(m,@1H);@5.05-4.95@(m,@1H);@4.55@(ancho,@1H);@4.20@(t,@2H);@ 3.90-3.75@(m,@2H);@3.15@(s,@3H);@2.05@(m,@2H);@1.55@(s,@3H);@1.48@(s,@3H);@1.50-1.35@(ancho,@18H).@ @ Metanosulfonato@de@13-[(1R,7aS)-5,5-dimetil-3-oxo-tetrahidro-1H-oxazolo[3,4-c]oxazol-1-il]tridecilo@(5)@ @ Una@ disolucion@ de@430@mg@ (1@ mmol)@ del@compuesto@ 4@en@ etanol@ (10@ mL)@se@ sometio@ a@ hidrogenacion,@ a@presion@ atmosferica,@en@presencia@de@10@mg@de@Pd/C@al@10@%.@Tras@12@h@de@agitacion@a@temperatura@ambiente,@la@mezcla@de@ reaccion@se@filtro@sobre@Celite@y@el@filtrado@obtenido@se@evaporo@a@sequedad@proporcionando@el@compuesto@5.@ Rendimiento:@98%@ 1H-RMN@(400@MHz,@CDCl3):@5@4.62@(m,@1H);@4.30@(m,@1H);@4.20@(t,@2H);@3.75-3.55@(m,@2H);@2.85@(s,@3H);@1.75-1.65@(m,@2H);@ 1.55-1.50@(m,@2H);@1.61@(s,@3H);@1.48@(s,@3H);@1.55-1.25@(ancho,@20H).@ @ Sintesis@de@los@acetilenos@6@y@7 a@partir@de@los@mesilatos 4 y 5 @ Etapa@ 1:@ Sobre@ una@ disolucion@ de@ los@ mesilatos@ 4@o@ 5@ (2@ mmol)@ en@ 8@ mL@ de@ una@ mezcla@ 1:1@ THF/HMPA@ (hexametilfosfotriamida)@ enfriada@ a@ -30@ °C,@ se@ afadieron,@ gota@ a@ gota,@ 4.5@ mL@ de@ una@ disolucion@ 0.5@ M@ de@ trimetilsililacetiluro@de@litio@en@THF@(equivalentes@a@2.25@mmol).@La@mezcla@de@reaccion@se@mantuvo@en@agitacion@mientras@ se@calento@lentamente@hasta@alcanzar@la@temperatura@ambiente.@Tras@el@consumo@del@producto@de@partida@(alrededor@de@ 1h,@por@analisis@por@TLC),@la@reaccion@se@detuvo@por@adicion@de@5@mL@de@disolucion@saturada@de@NH4Cl@y@la@mezcla@se@ extrajo@con@hexano@(3@x@10@mL).@Los@extractos@organicos@reunidos@se@lavaron@con@agua@y@salmuera,@se@secaron@sobre@ MgSO4@ anhidro@ y@ se@ evaporaron@ a@ presion@ reducida@ para@ obtener@ los@ correspondientes@ acetiluros@ de@ trimetilsililo@ intermedios,@que@se@usaron@en@la@etapa@siguiente@sin@purificacion.@ @ Etapa@2:@Una@disolucion@del@acetiluro@de@trimetilsililo@(1.5@mmol)@en@THF@anhidro@(5@mL)@se@ trato@con@2@mL@de@una@ disolucion@1M@de@Bu4NF@en@THF@bajo@atmosfera@de@Ar.@Tras@agitacion@durante@30@min@a@temperatura@ambiente,@la@mezcla@ de@reaccion@se@trato@con@H2O@(0.5@mL),@se@seco@sobre@MgSO4@anhidro@y@se@evaporo@a@presion@reducida,@obteniendose@los@ acetilenos@6@y@7.@ @ (1R,7aS,E)-5,5-dimetil-1-(pentadec-1-en-14-inil)-dihidro-1H-oxazolo[3,4-c]oxazol-3(5H)-ona@(6)@ @ Rendimiento:@75%@ 1H-RMN@(400@MHz,@CDCl3):@5@5.95-5.80@(m,@1H);@5.75-5.70@(m,@1H);@5.15-5.05@(m,@1H);@4.65@(ancho,@1H);@3.85-3.65@(m,@ 2H);@2.15-1.95@(m,@4H);@1.85@(t,@1H);@1.50@(s,@3H);@1.45@(s,@3H);@1.50-1.25@(ancho,@18H).@ @ (1R,7aS)-5,5-dimetil-1-(pentadec-14-inil)-dihidro-1H-oxazolo[3,4-c]oxazol-3(5H)-ona@(7)@ Rendimiento:@79%@ 1H-RMN@(400@MHz,@CDCl3):@5@5.15-5.05@(m,@1H);@4.65@(ancho,@1H);@3.85-3.65@(m,@2H);@2.05-1.95@(ancho,@2H);@1.85@(t,@ 1H);@1.50@(s,@3H);@1.45@(s,@3H);@1.50-1.45@(m,@4H);@1.35-1.25@(ancho,@20H)@ @ (S)-4-[(R)-12-azido-1-hidroxidodecil]-2,2-dimetiloxazolidina-3-carboxilato@de@terc-butilo@(8)@ Etapa@1:@Una@disolucion@de@460@mg@(1@mmol)@del@compuesto@3a@en@etanol@(10@mL)@se@sometio@a@hidrogenacion,@a@presion@ atmosferica,@en@presencia@de@10@mg@de@Pd/C@al@10@%.@Tras@12@h@de@agitacion@a@temperatura@ambiente,@la@mezcla@de@ (S) -4 - [(R, E) -12-azido-1-hydroxidedec-2-enyl] -2,2-dimethyloxazolidine-3-carboxylate @ de @ tert-butyl @ (3c) @ @ A @ dissolution @ of @ 122 @ mg @ (1.87@mmol) @ of @ azida @ sodica @ in @ DMF @ anhydrous @ (10 @ mL) @ se @ afadio, @ drop @ a @ drop, @ over @ a @ @ bromide solution @ 3a @ in @ 5 @ mL @ of @ DMF, @ under @ atmosphere @ of @ Ar @ a @ ambient @ temperature. @ Completed @ the @ addition, @ the @ @ reaction @ se @ calento @ a @ 65 ° @ C @ and @ se @ kept @ in @ agitation @ for @ 12h. @ A @ continuation, @ the @ mix @ se @ diluyo @ con @ 40 @ mL @ of @ water @ and @ was @ extracted @ with @ Et2O @ (3 @ x @ 15 @ mL). @ The @ organic @ phases were @ washed @ with @ brine @ (2 @ x @ 10 @ mL), @ dried @ dried @ about @ MgSO4 @ anhydro, @ se @ leaked @ and @ evaporated @ to @ give @ a @ residue @ that @ was @ purified @ by @ flash @ chromatography (Hexano @ / @ EtOAc @ 7: 3). @ Yield: @ 91% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5@5.82 @ - @ 5.66 @ (m, @ 1H), @ 5.48 @ - @ 5.36 @ (m, @ 1H), @ 4.22 @ - @ 3.75 @ (m, @ 4H), @ 3.25 @ (t, @ J @ = @ 7.0 @ Hz, @ 2H), @ 2.11 @ - @ 1.96 @ (m, @ 2H), @ 1.45 @ (s, @ 9H); @ 1.32 @ (s, @ 6H); @ 1.55-1.35 @ (m, @ 18H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 133.51, @ 128.29, @ 94.58, @ 81.20, @ 74.25, @ 65.08, @ 62.44, @ 51.61, @ 32.53, @ 29.55, @ 29.51, @ 29.45 , @ 29.31, @ 29.28, @ 29.24, @ 28.97, @ 28.51, @ 26.84, @ 26.38, @ 24.74. @ @ Methanesulfonate @ de @ (E) -13 - [(1R, 7aS) -5,5-dimethyl-3-oxo-tetrahydro-1H-oxazolo [3,4-c] oxazol-1-yl] tridec-12-enyl @(4)@ @ About @ a @ dissolution of @ 505 @ mg @ (1 @ mmol) @ of @ 3b @ in @ THF @ anhydrous @ (10 @ mL), @ cooled @ in @ a @ bafo @ of @ ice, @ se @ added @ 80 @ mg @ (2 @ mmol) @ from @ NaH. @ After @ stirring @ at @ room temperature @ during @ 18h, @ the @ reaction @ mix @ cool @ in @ a @ bafo @ of @ ice, @ was @ treated @ with @ a @ aqueous @ saturated @ solution @ NaHCO3 @ and @ was extracted with @ Et2O @ (3 @ x @ 5 @ mL). @ The @ extracts @ Organics @ gathered @ se @ washed @ with @ brine @ and @ dried @ over @ MgSO4 @ anhydrous. @ After @ the @ evaporation @ of the solvent @ se @ obtained @ the @ compound @ 4, @ that @ was @ submitted @ the @ subsequent @ stage @ without @ purification. @ Yield: @ 85% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 5.90-5.85 @ (m, @ 1H); @ 5.80-5.75 @ (m, @ 1H); @ 5.05-4.95 @ (m, @ 1H) ; @ 4.55 @ (width, @ 1H); @ 4.20 @ (t, @ 2H); @ 3.90-3.75 @ (m, @ 2H); @ 3.15 @ (s, @ 3H); @ 2.05 @ (m, @ 2H); @ 1.55 @ (s, @ 3H); @ 1.48 @ (s, @ 3H) ; @ 1.50-1.35 @ (width, @ 18H). @ @ Methanesulfonate @ de @ 13 - [(1R, 7aS) -5,5-dimethyl-3-oxo-tetrahydro-1H-oxazolo [3,4-c] oxazol-1-yl] tridecyl @ (5) @ @ A @ dissolution of @ 430 @ mg @ (1 @ mmol) @ of the compound @ 4 @ in @ ethanol @ (10 @ mL) @ was @ subjected to @ hydrogenation, @ a @ pressure @ atmospheric, @ in @ presence @ of @ 10 @ mg @ of @ Pd / C @ at @ 10 @%. @ After @ 12 @ h @ of @ agitation @ at @ room temperature, @ the @ mix @ of reaction @ se @ filter @ on @ Celite @ and @ the @ filtered @ obtained @ se @ evaporo @ a @ dryness @ providing @ the @ compound @ 5. @ Yield: @ 98% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 4.62 @ (m, @ 1H); @ 4.30 @ (m, @ 1H); @ 4.20 @ (t, @ 2H); @ 3.75-3.55 @ (m, @ 2H); @ 2.85 @ (s, @ 3H); @ 1.75-1.65 @ (m, @ 2H); @ 1.55-1.50 @ (m, @ 2H); @ 1.61 @ (s, @ 3H); @ 1.48 @ (s, @ 3H); @ 1.55-1.25 @ (wide, @ 20H). @ @ Synthesis @ of @ los @ acetilenos @ 6 @ and @ 7 a @ split @ of @ the @ mesilatos 4 and 5 @ Stage @ 1: @ About @ a @ dissolution @ of @ mesilatos @ 4 @ or @ 5 @ (2 @ mmol) @ in @ 8 @ mL @ of @ a @ mix @ 1: 1 @ THF / HMPA @ (hexametilfosfotriamida) @ cooled @ a -30 @ ° C, @ added @, drop @ drop, @ 4.5 @ mL @ of @ a @ dissolution @ 0.5 @ M @ of @ trimetilsililacetiluro @ de @ lithio @ en @ THF @ (equivalent @ a @ 2.25 @ mmol). @ The @ mix @ of @ reaccion @ remained @ in @ agitation @ while @ @ warm @ slowly @ until @ reaching @ ambient @ temperature. @ After @ the @ consumption @ of the @ product @ of @ heading @ (around @ of @ 1h, @ by @ analysis @ by @ TLC), @ the @ reaction @ was @ stopped @ by @ addition of @ 5 @ mL @ of @ saturated @ dissolution @ of NH4Cl @ and @ the @ mix @ se @ extracted @ with @ hexano @ (3 @ x @ 10 @ mL). @ The @ organic extracts @ gathered @ were @ washed @ with @ water @ and @ brine, @ dried @ dried @ on @ MgSO4 @ anhidro @ and @ were @ evaporated @ a @ reduced @ pressure @ to @ obtain @ the corresponding @ acetiluros @ de @ trimetilsililo @ intermediates, @ which @ were @ used @ in @ the @ next @ stage @ without @ purification. @ @ Stage @ 2: @ Una @ dissolucion @ del @ acetiluro @ de @ trimetilsililo @ (1.5@mmol) @ en @ THF @ anhidro @ (5 @ mL) @ se @ deal @ with @ 2 @ mL @ de @ una @ @ 1M @ solution of @ Bu4NF @ in @ THF @ under @ atmosphere @ of @ Ar. @ After @ agitation @ for @ 30 @ min @ at @ room temperature, @ the @ mix @ @ reaccion @ se @ deal @ with @ H2O @ (0.5@mL), @ se @ dry @ over @ MgSO4 @ anhydrous @ and @ se @ evaporo @ a @ reduced @ pressure, @ getting @ the @ acetylenes @ 6 @ and @ 7. @ @ (1R, 7aS, E) -5,5-dimethyl-1- (pentadec-1-en-14-inyl) -dihydro-1H-oxazolo [3,4-c] oxazol-3 (5H) -one @ ( 6) @ @ Yield: @ 75% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 5.95-5.80 @ (m, @ 1H); @ 5.75-5.70 @ (m, @ 1H); @ 5.15-5.05 @ (m, @ 1H) ; @ 4.65 @ (width, @ 1H); @ 3.85-3.65 @ (m, @ 2H); @ 2.15-1.95 @ (m, @ 4H); @ 1.85 @ (t, @ 1H); @ 1.50 @ (s, @ 3H); @ 1.45 @ (s, @ 3H); @ 1.50-1.25 @ (width, @ 18H). @ @ (1R, 7aS) -5,5-dimethyl-1- (pentadec-14-inyl) -dihydro-1H-oxazolo [3,4-c] oxazol-3 (5H) -one @ (7) @ Yield: @ 79% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 5.15-5.05 @ (m, @ 1H); @ 4.65 @ (wide, @ 1H); @ 3.85-3.65 @ (m, @ 2H); @ 2.05-1.95 @ (width, @ 2H); @ 1.85 @ (t, @ 1H); @ 1.50 @ (s, @ 3H); @ 1.45 @ (s, @ 3H); @ 1.50-1.45 @ (m, @ 4H); @ 1.35-1.25 @ (wide, @ 20H) @ @ (S) -4 - [(R) -12-azido-1-hydroxidedecyl] -2,2-dimethyloxazolidine-3-carboxylate @ de @ tert-butyl @ (8) @ Stage @ 1: @ A @ dissolution @ of @ 460 @ mg @ (1 @ mmol) @ of the compound @ 3rd @ in @ ethanol @ (10 @ mL) @ was @ subjected to @ hydrogenation, @ a @ pressure @ atmospheric, @ in @ presence @ of @ 10 @ mg @ of @ Pd / C @ at @ 10 @%. @ After @ 12 @ h @ of @ agitation @ at @ room temperature, @ the @ mix @ of

reaccion@se@filtro@sobre@Celite@y@el@filtrado@obtenido@se@evaporo@a@sequedad@proporcionando@un@crudo@que@se@sometio@a@la@ reaccion@siguiente.@ @ Etapa@2:@Una@disolucion@de@100@mg@(1.54@mmol)@de@azida@sodica@en@DMF@anhidro@(10@mL)@se@afadio,@gota@a@gota,@sobre@ una@disolucion@del@crudo@de@la@reaccion@anterior@en@5@mL@de@DMF,@bajo@atmosfera@de@Ar@a@temperatura@ambiente.@ Finalizada@la@adicion,@la@mezcla@de@reaccion@se@calento@a@65°@C@y@se@mantuvo@en@agitacion@durante@12h.@A@continuacion,@ la@mezcla@se@diluyo@con@40@mL@de@agua@y@se@extrajo@con@Et2O@(3@x@15@mL).@Las@fases@organicas@se@lavaron@con@salmuera@ (2@x@10@mL),@se@secaron@sobre@MgSO4@anhidro,@se@filtraron@y@se@evaporaron@para@dar@un@residuo@que@se@purifico@por@ cromatografia@flash@(Hexano@/@EtOAc@7:3).@ Rendimiento@global@:@72@%@ 1H-RMN@(400@MHz,@CDCl3):@5@4.15-3.95@(m,@2H);@3.90-3.70@(m,@2H);@3.25@(t,@2H);@1.45@(s,@9H);@1.65-1.60@(m,@4H);@1.40- 1.20@(m,@22H)@ 13C-RMN@(101@MHz,@CDCl3):@5@154.1,@94.3,@73.0,@64.8,@62.6,@51.5,@34.5,@33.9,@(29.7-28.4),@26.8,@26.5,@26.1,@24.3.@ @ Sintesis@de@bases@esfingoides@II(D-H)@ @ (2S,3R)-2-amino-14-azidotetradecano-1,3-diol@(II-E)@y@(2S,3R,E)-2-amino-14-azidotetradec-4-eno-1,3-diol@(II-F)@ Una@disolucion@de@(0.5@mmol)@de@8@o@de@3c@en@MeOH@(10@mL)@se@trato@con@cloruro@de@acetilo@(0.6@mL).@La@mezcla@de@ reaccion@se@agito@a@temperatura@ambiente@durante@6@h,@transcurridas@las@cuales@se@evaporo@el@disolvente@a@presion@ reducida.@El@residuo@obtenido@se@disuelve@en@agua,@se@alcalinizo@con@una@disolucion@de@NaOH@1N@y@se@extrajo@con@EtOAc@ (3@x@5@mL).@Las@fases@organicas@reunidas@se@secaron@(MgSO4)@y@se@evaporaron@a@sequedad@y@el@residuo@se@purifico@por@ cromatografia@flash@(hexano@/@EtOAc@7:3)@para@obtener@el@producto@deseado.@ @ (II-E):@Rendimiento@a@partir@de@8@:@82@%@ 1H-RMN@(400@MHz,@CDCl3):@5@3.70@(m,@2H);@3.60@(m,@1H);@3.25@(t,@2H);@2.85@(m,@1H);@1.65-1.55@(m,@2H);@1.53-1.45@(m,@ 3H);@1.40-1.20@(m,@15H).@ 13C-RMN@(101@MHz,@CDCl3):@5@74.61,@63.50,@55.80,@51.57,@33.95,@29.80,@29.71,@29.69,@29.63,@29.60,@29.58,@29.26,@28.93,@ 26.81,@26.23.@ @ (II-F):@Rendimiento@a@partir@de@3c@:@85@%@ 1H-RMN@(400@MHz,@CDCl3):@5@5.80-5.65@(m,@1H);@5.50-5.35@(m.@1H);@4.05@(m,@1H);@3.70-3.55@(m,@2H);@3.25@(t,@2H);@2.85- 2.75@(m,@1H);@2.05@(m,@2H);@1.55@(m,@2H);@1.40-1.20@(m,@13H).@ 13C-RMN@(101@MHz,@CDCl3):@5@134.63,@129.37,@75.20,@63.81,@56.25,@51.57,@32.45,@29.52,@29.46,@29.40,@29.30,@29.24,@ 28.93,@26.80.@ @ (2S,3R)-2-aminooctadec-17-in-1,3-diol@(II-D)@y@(2S,3R,E)-2-aminooctadec-4-en-17-in-1,3-diol@(II-G)@por@hidrolisis@de@6@y@7 Etapa@1.@Una@disolucion@de@0.6@mmol@de@6@o@7@y@TsOH@(12@mg,@0.06@mmol)@en@MeOH@(10@mL)@se@agito@a@25@°C@durante@6@ h.@Transcurrido@este@tiempo,@se@elimino@el@disolvente@a@presion@reducida@y@el@residuo@resultante@se@disolvio@en@EtOAc.@La@ disolucion@ organica@ se@ lavo,@ sucesivamente,@ con@ una@ disolucion@ saturada@ de@ NaHCO3@ y@ salmuera@ y@ se@ seco.@ La@ evaporacion@del@disolvente@proporciona@un@residuo@que@se@uso@directamente@en@la@siguiente@etapa@de@sintesis.@ @ Etapa@2.@Una@disolucion@del@crudo@anterior@en@2N@NaOH@(30@mL)@y@EtOH@(30@mL)@se@calento@a@80@°C@durante@3@h.@La@ mezcla@de@reaccion@se@enfrio@a@continuacion,@se@concentra,@a@presion@reducida,@hasta@una@cuarta@parte@del@volumen@y@se@ extrajo@con@Et2O@(3@x@15@mL).@Las@fases@organicas@reunidas@se@secaron@sobre@MgSO4,@se@filtraron@y@se@evaporaron@para@ dar@el@correspondiente@producto@final.@ @ (II-D):@Rendimiento@global@a@partir@de@7:@70%@ 1H-RMN@(400@MHz,@CDCl3):@5@3.990-3.65@(m,@2H);@3.45@(m,@1H);@2.82@(m,@1H);@2.01@(m,@2H);@1.82@(t,@1H);@1.45@(m,@4H);@ 1.29-1.26@(m,@20H).@ 13C-RMN@(101@MHz,@CDCl3):@5@83.5,@75.1,@62.5,@61.1,@33.1,@(29.9-28.2),@23.5,@21.4.@ @ (II-G):@Rendimiento@global@a@partir@de@6:@73%@ 1H-RMN@(400@MHz,@CDCl3):@5@5.69-5.65@(m,@2H);@4.15@(m,@1H);@3.90-3.65@(m,@2H);@2.85@(m,@1H);@2.05-1.95@(m,@4H);@1.85@ (t,@1H);@1.45-1.30@(m,@18H).@ 13C-RMN@(101@MHz,@CDCl3):@5@131.1,@129.7,@83.5,@75.5,@68.9,@62.3,@56.8,@35.1,@(29.9-28.4),@21.2.@ @ Hidrocloruro@de@(S)-2-amino-14-azido-1-hidroxitetradecan-3-ona@(II-H)@ Etapa@1.@Una@disolucion@de@550@mg@(1.30@mmol)@de@8@en@30@mL@de@CH2Cl2@se@trato@con@clorocromato@de@piridinio@(PCC)@ (420@mg,@1.90@mmol).@La@mezcla@de@reaccion@se@mantuvo@en@agitacion@a@temperatura@ambiente@durante@1@h,@transcurrida@ la@cual@se@afadieron@otros@420@mg@de@PCC@y@se@mantuvo@en@agitacion@durante@12@h@mas.@A@continuacion,@la@mezcla@de@ reaccion@se@filtro@sobre@Celite@y@el@filtrado@se@evaporo@a@presion@reducida@para@dar@un@crudo@que@se@utilizo@directamente@en@ la@siguiente@etapa.@ @ Reaction @ se @ filter @ on @ Celite @ and @ el @ filtered @ obtained @ se @ evaporo @ a @ dryness @ providing @ a @ raw @ that @ was @ submitted @ a @ @ next reaction. @ @ Stage @ 2: @ A @ dissolution @ of @ 100 @ mg @ (1.54@mmol) @ of @ azida @ sodica @ in @ DMF @ anhydrous @ (10 @ mL) @ se @ afadio, @ drop @ a @ drop, @on@ a @ solution @ of @ crude @ of @ the @ previous reaction @ in @ 5 @ mL @ of @ DMF, @ under @ atmosphere @ of @ Ar @ a @ room temperature. Finished @ the @ addiction, @ the @ mix @ of @ reaction @ warmth @ a @ 65 ° @ C @ and @ stayed @ in @ shaking @ for @ 12h. @ A @ continuation, @ the @ mix @ was @ diluted @ with @ 40 @ mL @ of @ water @ and @ was @ extracted @ with @ Et2O @ (3 @ x @ 15 @ mL). @ The @ organic @ phases were @ washed @ with @brine@ (2 @ x @ 10 @ mL), @ dried @ dried @ MgSO4 @ anhydrous, @ filtered @ and @ evaporated @ to @ give @ a @ residue @ that @ was @ purified @ by @ @ flash @ chromatography (Hexano @ / @ EtOAc @ 7: 3). @ Performance @ global @: @ 72 @% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 4.15-3.95 @ (m, @ 2H); @ 3.90-3.70 @ (m, @ 2H); @ 3.25 @ (t, @ 2H); @ 1.45 @ (s, @ 9H); @ 1.65-1.60 @ (m, @ 4H); @ 1.40- 1.20 @ (m, @ 22H) @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 154.1, @ 94.3, @ 73.0, @ 64.8, @ 62.6, @ 51.5, @ 34.5, @ 33.9, @ (29.7-28.4), @ 26.8, @ 26.5, @ 26.1, @ 24.3. @ @ Synthesis @ of @ bases @ sphingoids @ II (D-H) @ @ (2S, 3R) -2-amino-14-azidotetradecane-1,3-diol @ (II-E) @ and @ (2S, 3R, E) -2-amino-14-azidotetradec-4-eno-1, 3-diol @ (II-F) @ A @ dissolution of @ (0.5@mmol) @ of @ 8 @ or @ of @ 3c @ in @ MeOH @ (10 @ mL) @ was @ treated with @ acetyl @ chloride @ (0.6@mL). @The mixture of@ reaccion @ se @ agito @ a @ temperature @ ambient @ during @ 6 @ h, @ elapses @ which @ were @ evaporo @ the @ solvent @ a @ pressure @ reduced. @ The @ residue @ obtained @ dissolves @ in @ water, @ is @ alkaline @ with @ a @ solution @ NaOH @ 1N @ and @ was @ extracted @ with @ EtOAc @ (3 @ x @ 5 @ mL). @ The @ organic @ phases gathered @ dried @ dried (MgSO4) @ and @ evaporated @ a @ dryness @ and @ the @ residue @ was @ purified @ by @ @ flash @ chromatography (hexane @ / @ EtOAc @ 7: 3) @ to @ get @ the @ desired @ product. @ @ (II-E): @ Performance @ to @ from @ 8 @: @ 82 @% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 3.70 @ (m, @ 2H); @ 3.60 @ (m, @ 1H); @ 3.25 @ (t, @ 2H); @ 2.85 @ (m , @ 1H); @ 1.65-1.55 @ (m, @ 2H); @ 1.53-1.45 @ (m, @ 3H); @ 1.40-1.20 @ (m, @ 15H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 74.61, @ 63.50, @ 55.80, @ 51.57, @ 33.95, @ 29.80, @ 29.71, @ 29.69, @ 29.63, @ 29.60, @ 29.58, @ 29.26 , @ 28.93, @ 26.81, @ 26.23. @ @ (II-F): @ Performance @ a @ starting @ from @ 3c @: @ 85 @% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 5.80-5.65 @ (m, @ 1H); @ 5.50-5.35 @ (m. @ 1H); @ 4.05 @ (m, @ 1H); @ 3.70-3.55 @ (m, @ 2H); @ 3.25 @ (t, @ 2H); @ 2.85- 2.75 @ (m, @ 1H); @ 2.05 @ (m, @ 2H); @ 1.55 @ (m, @ 2H); @ 1.40-1.20 @ (m, @ 13H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 134.63, @ 129.37, @ 75.20, @ 63.81, @ 56.25, @ 51.57, @ 32.45, @ 29.52, @ 29.46, @ 29.40, @ 29.30, @ 29.24 , @ 28.93, @ 26.80. @ @ (2S, 3R) -2-aminooctadec-17-in-1,3-diol @ (II-D) @ and @ (2S, 3R, E) -2-aminooctadec-4-en-17-in-1, 3-diol @ (II-G) @ by @ hydrolysis @ of @ 6 @ and @ 7 Stage @ 1. @ A @ dissolution @ of @ 0.6 @ mmol @ of @ 6 @ or @ 7 @ and @ TsOH @ (12 @ mg, @ 0.06 @ mmol) @ in @ MeOH @ (10 @ mL) @ se @ agito @ a @ 25 @ ° C @ for @ 6 @ h. @ After @ this @ time, @ was @ removed @ the @ solvent @ a @ reduced @ pressure @ and @ the resulting @ residue @ was @ dissolved @ in @ EtOAc. @ La @ @ organic @ dissolution @ lavo, @ successively, @ with @ a @ saturated @ solution @ NaHCO3 @ and @ brine @ and @ dry @. @ solvent @ evaporation provides @ a @ residue @ that @ was @ used @ directly @ in @ the @ next @ stage @ of @ synthesis @ @ Stage @ 2. @ A @ dissolution @ of the previous @ crude @ in @ 2N @ NaOH @ (30 @ mL) @ and @ EtOH @ (30 @ mL) @ warmed up @ 80 @ ° C @ during @ 3 @ h. @ La @ mix @ of @ reaction @ se @ cool @ a continuation, @ se @ concentra, @ a @ reduced @ pressure, @ up to a quarter of the volume @ and @ se @ @ extracted with @ Et2O @ (3 @ x @ 15 @ mL). @ The @ organic @ phases @ gathered @ dried @ dried @ MgSO4, @ filtered @ and @ evaporated @ to @ give @ the corresponding @ product @ final @. @ (II-D): @ Global @ Performance @ @ @ @ @ 7: @ 70% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 3,990-3.65 @ (m, @ 2H); @ 3.45 @ (m, @ 1H); @ 2.82 @ (m, @ 1H); @ 2.01 @ (m, @ 2H); @ 1.82 @ (t, @ 1H); @ 1.45 @ (m, @ 4H); @ 1.29-1.26 @ (m, @ 20H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 83.5, @ 75.1, @ 62.5, @ 61.1, @ 33.1, @ (29.9-28.2), @ 23.5, @ 21.4. @ @ (II-G): @ Global @ Performance @ @ @ @ @ 6: @ 73% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 5.69-5.65 @ (m, @ 2H); @ 4.15 @ (m, @ 1H); @ 3.90-3.65 @ (m, @ 2H); @ 2.85 @ (m, @ 1H); @ 2.05-1.95 @ (m, @ 4H); @ 1.85 @ (t, @ 1H); @ 1.45-1.30 @ (m, @ 18H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 131.1, @ 129.7, @ 83.5, @ 75.5, @ 68.9, @ 62.3, @ 56.8, @ 35.1, @ (29.9-28.4), @ 21.2. @ @ Hydrochloride @ de @ (S) -2-amino-14-azido-1-hydroxytetradecan-3-one @ (II-H) @ Stage @ 1. @ Una @ dissolucion @ de @ 550 @ mg @ (1.30@mmol) @ de @ 8 @ en @ 30 @ mL @ de @ CH2Cl2 @ se @ deal @ with @ chlorocromato @ de @ piridinio @ (PCC) @ (420 @ mg, @ 1.90 @ mmol). @ The @ reaction @ mix @ remained @ in @ agitation @ at @ ambient @ temperature @ for @ 1 @ h, @ elapsed @ the @ which @ were @ added @ others @ 420 @ mg @ of @ PCC @ and @ remained @ in @ agitation @ for @ 12 @ h @ more. @ A @ continuation, @ the @ mix @ of @ reaccion @ se @ filter @ on @ Celite @ and @ el @ filtered @ se @ evaporo @ a @ reduced @ pressure @ to @ give @ a @ crude @ that @ was @ used @ directly @ in @ the @ next @ stage. @ @

Etapa@2.@Una@disolucion@del@crudo@anterior@en@20@mL@de@MeOH@se@trato@con@1.2@mL@de@cloruro@de@acetilo@a@25@°C@durante@ 6@h.@Transcurrido@este@tiempo,@se@elimino@el@disolvente@a@presion@reducida@para@dar@el@producto@final@en@forma@del@ correspondiente@hidrocloruro.@ Rendimiento@global@a@partir@de@8:@89@%@ 1H-RMN@(400@MHz,@CD3OD):@5@4.15@(t@ancho,@1H);@4.10@(dd,@1H);@3.95@(dd,@1H),@3.3@(t,@2H);@2.65@(t,@2H);@1.60-1.55@(m,@ 2H);@1.45-1.25@(ancho,@16H).@ 13C-RMN@(101@MHz,@CD3OD):@5@205.19,@62.19,@60.26,@52.44,@39.62,@30.62,@30.60,@30.57,@30.52,@30.27,@30.09,@29.92,@ 27.82,@24.18.@ @ Stage @ 2. @ A @ dissolution @ of @ crude @ previous @ in @ 20 @ mL @ of @ MeOH @ was @ treated @ with @ 1.2 @ mL @ of @ acetyl @ chloride @ @ 25 @ ° C @ during@ 6 @ h. @ After @ this @ time, @ was @ removed @ the @ solvent @ a @ reduced @ pressure @ to @ give @ the @ final @ product @ in @ form @ corresponding @ hydrochloride. @ Performance @ global @ to @ split @ of @ 8: @ 89 @% @ 1H-RMN @ (400 @ MHz, @ CD3OD): @ 5 @ 4.15 @ (t @ wide, @ 1H); @ 4.10 @ (dd, @ 1H); @ 3.95 @ (dd, @ 1H), @ 3.3 @ (t, @ 2H); @ 2.65 @ (t, @ 2H); @ 1.60-1.55 @ (m, @ 2H); @ 1.45-1.25 @ (width, @ 16H). @ 13C-RMN @ (101 @ MHz, @ CD3OD): @ 5 @ 205.19, @ 62.19, @ 60.26, @ 52.44, @ 39.62, @ 30.62, @ 30.60, @ 30.57, @ 30.52, @ 30.27, @ 30.09, @ 29.92 , @ 27.82, @ 24.18. @ @

Obtención de los compuestos de fórmula (I). Obtaining the compounds of formula (I).

@ Ejemplo I-B4.@1-[(2S,3R)-1,3-dihidroxioctadecan-2-il]-1H-pirrol-2,5-diona@@ Una@disolucion@de@esfinganina@(30@mg,@0,10@mmol)@en@CH2Cl2@(1@mL)@se@adiciono,@gota@a@gota,@sobre@1@mL@de@una@ disolucion@de@anhidrido@maleico@0.1@M@en@CH2Cl2,@enfriada@exteriormente@con@un@bafo@de@hielo.@A@continuacion,@se@retiro@ el@bafo@y@la@mezcla@se@mantuvo@en@agitacion@a@temperatura@ambiente@durante@16@h,@transcurridas@las@cuales@se@adiciono@ cloruro@de@oxalilo@(8.5@!L,@0,1@mmol)@y@una@gota@de@DMF,@manteniendo@la@agitacion@durante@otras@8@h.@Al@final@de@este@ periodo,@la@mezcla@de@reaccion@se@trato@con@0,5@mL@de@una@disolucion@0,2@M@de@Et3N@en@de@CH2Cl2@y@se@agito@a@ temperatura@ambiente.@Al@cabo@de@1@h,@la@mezcla@de@reaccion@se@lavo@con@agua@(3@x@2,5@mL)@y@la@fase@organica@se@seco@ sobre@ MgSO4@ anhidro@ y@ se@ evaporo@ a@ presion@ reducida.@ El@ crudo@ resultante@ se@ purifico@ por@ cromatografia@ flash@ (hexano/EtOAc@4:1),@obteniendose@32@mg@(81@%@rendimiento)@del@compuesto@I-B4.@ 1H-RMN@(400@MHz,@CDCl3):@5@6.94@(s,@2H),@3.75@-@3.68@(m,@1H),@3.87@-@3.80@(m,@3H),@1.65@-@1.45@(m,@4H),@1.25@(ancho,@ 24H),@0.85@(t@ancho,@3H).@ 13C-RMN@(101@MHz,@CDCl3):@170.25,@135.84,@69.06,@58.21,@51.53,@33.71,@32.13,@(29.90@-@29.60),@26.04,@22.91,@14.35.@ @ Metodo@general@para@la@preparacion@de@sulfonamidas@por@acoplamiento@con@cloruro@de@etanosulfonilo@ Sobre@una@disolucion@de@la@correspondiente@base@esfingoide@II@(0,10@mmol)@y@Na2CO3@(21@mg,@0,20@mmol)@en@THF@(1@mL)@ y@agua@(2@mL)@se@adicionaron,@gota@a@gota,@14@!L,@(0,15@mmol)@de@cloruro@de@etanosulfonilo.@La@mezcla@de@reaccion@se@ mantuvo@en@agitacion@durante@18h@a@temperatura@ambiente.@A@continuacion,@se@diluyo@con@5@mL@de@disolucion@saturada@ de@NaCl,@se@extrajo@con@CH2Cl2@(3@x@5@mL),@se@seco@sobre@MgSO4@anhidro@y@se@evaporo@a@presion@reducida.@El@residuo@ resultante@se@purifico@por@cromatografia@flash@(hexano/EtOAc@4:1)@para@proporcionar@el@compuesto@deseado.@ @ Example I-B4. @ 1 - [(2S, 3R) -1,3-dihydroxioctadecan-2-yl] -1H-pyrrole-2,5-diona @@ A @ dissolution of @ sphinganine @ (30 @ mg, @ 0.10 @ mmol) @ in @ CH2Cl2 @ (1 @ mL) @ was @ added, @ drop @ to @ drop, @ about @ 1 @ mL @ of @a@ @ anhydride @ maleic @ 0.1 @ M @ solution in @ CH2Cl2, @ cooled @ outside @ with @ an @ ice @ bafo. @ A @ continuation, @ se @ retirement @ el @ bafo @ and @ la @ mix @ se @ remained @ in @ agitacion @ a @ temperature @ atmosphere @ for @ 16 @ h, @ elapses @ the @ which @ were @ added @ @ oxalilo @ chloride (8.5 @! L, @ 0.1 @ mmol) @ and @ a @ drop @ of @ DMF, @ keeping @ the agitation @ for @ other @ 8 @ h. @ At the @ end @ from @ este @ period, @ the @ mix @ of @ reaction @ se @ deal @ with @ 0.5 @ mL @ of @ a @ dissolution @ 0.2 @ M @ of @ Et3N @ in @ of @ CH2Cl2 @ and @ se @ agito @to@ @ ambient temperature. @ After @ 1 @ h, @ the @ mixture @ of reaction @ was @ washed @ with @ water @ (3 @ x @ 2.5 @ mL) @ and @ the @ phase @ organic @ dry @ dry about @ MgSO4 @ anhidro @ and @ se @ evaporo @ a @ reduced @ pressure. @ The resulting @ crude @ was @ purified @ by @ chromatography @ flash @ (hexane / EtOAc @ 4: 1), @ obtaining @ 32 @ mg @ (81 @% @ yield) @ of the @ compound @ I-B4. @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 6.94 @ (s, @ 2H), @ 3.75 @ - @ 3.68 @ (m, @ 1H), @ 3.87 @ - @ 3.80 @ (m, @ 3H), @ 1.65 @ - @ 1.45 @ (m, @ 4H), @ 1.25 @ (width, @ 24H), @ 0.85 @ (t @ width, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 170.25, @ 135.84, @ 69.06, @ 58.21, @ 51.53, @ 33.71, @ 32.13, @ (29.90 @ - @ 29.60), @ 26.04, @ 22.91, @ 14.35. @ @ General @ method for @ the @ sulfonamides @ preparation @ by @ coupling @ with @ ethanesulfonyl chloride @ About @ a @ dissolution @ of the corresponding @ base @ sphingoid @ II @ (0.10 @ mmol) @ and @ Na2CO3 @ (21 @ mg, @ 0.20 @ mmol) @ in @ THF @ (1 @ mL) @ and @ water @ (2 @ mL) @ were added, @ drop @ to @ drop, @ 14 @! L, @ (0.15 @ mmol) @ of @ ethanesulfonyl @ chloride @ @ the @ mix @ of @ reaccion @ se @ kept @ in @ agitation @ for @ 18h @ a @ ambient @ temperature. @ A @ continuation, @ was @ diluted @ with @ 5 @ mL @ of @ dissolution @ saturated @ from @ NaCl, @ was @ extracted @ with @ CH2Cl2 @ (3 @ x @ 5 @ mL), @ was @ dry @ over @ MgSO4 @ anhydrous @ and @ was @ evaporated @ at @ reduced pressure. @ The @ residue @ resulting @ was @ purified @ by @ flash @ chromatography (hexane / EtOAc @ 4: 1) @ to @ provide @ the desired @ compound @

Ejemplo I-A1.@N-[(2S,3R,E)-1,3-dihidroxioctadec-4-en-2-il]etanosulfonamida@ Rendimiento:@75%@ 1H-RMN@(400@MHz,@CDCl3):@5@5.69@(m,@1H);@5.65@(m,@1H);@4.15@(m,@1H);@3.80-3.60@(m,@2H);@3.50@(q,@2H);@2.90@(m,@1H);@ 2.01@(m,@2H);@1.29@(s,@3H);@1.35-1.26@(m,@22H);@0.86@(t,@3H).@ 13C-RMN@(101@MHz,@CDCl3):@5@131.5,@129.9,@72.1,@59.5,@54.3,@48.8,@34.1,@32.2,@(30.0-29.5),@22.7,@14.1,@2.3.@ @ Ejemplo I-B1.@N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]etanosulfonamida@ Rendimiento:@77%@ 1H-RMN@(400@MHz,@CDCl3):@5@3.45@(q@ancho,@2H),@3.97@-@3.70@(m,@3H),@2.78@(m,@1H),@1.68@-@1.41@(m,@4H),@1.28@(t@ancho,@ 3H),@1.23@(ancho,@24H),@0.85@(t@ancho,@3H).@ 13C-RMN@(101@MHz,@CDCl3):@5@75.06,@60.61,@54.83,@47.56,@33.91,@31.93,@(29.95@-@26.04),@22.81,@14.25,@2.35.@ @ Ejemplo I-C1.@N-[(2S,3S,4R)-1,3,4-trihidroxioctadecan-2-il]etanosulfonamida@ Rendimiento:@79%@ 1H-RMN@(400@MHz,@CDCl3):@5@3.90-3.60@(m,@2H);@3.50@(m,@1H);@3.45@(q,@2H);@3.18@(m,@1H);@2.75@(m,@1H);@1.51@(m,@2H);@ 1.30@(s,@3H);@1.30-1.26@(s@ancho,@24H);@0.86@(t,@3H).@ 13C-RMN@(101@MHz,@CDCl3):@5@76.5,@71.3,@59.6,@48.4,@47.2,@31.9,@31.2,@(29.9-29.3),@23.7,@22.6,@14.2,@2.3.@ @ Ejemplo I-D1.@N-[(2S,3R)-1,3-dihidroxioctadec-17-in-2-il]etanosulfonamida@ Rendimiento:@84%@ 1H-RMN@(400@MHz,@CDCl3):@5@3.90-3.70@(m,@3H);@3.45@(q,@2H);@2.80@(m,@1H);@2.03@(m,@2H);@1.85@(t,@J@=@2.5,@1H);@1.28@(s,@ 3H);@1.20-1.40@(s@ancho,@24H).@ 13C-RMN@(101@MHz,@CDCl3):@5@83.5;@72.5;@47.6,@69.1;@60.2;@58.4;@32.9;@(29.5-28.5);@23.4;@21.3,@2.3.@ @ Ejemplo I-E1.@N-[(2S,3R)-14-azido-1,3-dihidroxitetradecan-2-il)etanosulfonamida@ Rendimiento:@71%@ 1H-RMN@(400@MHz,@CDCl3):@5@3.80-3.60@(m,@2H);@3.45@(m,@1H);@3.40@(q,@2H);@2.80@(m,@1H);@1.45@(m,@2H);@1.30-1.25@(m,@ 20H).@ 13C-RMN@(101@MHz,@CDCl3):@5@71.5,@60.1,@55.3,@50.2,@48.7,@33.1,@30.2,@(29.9-29.2);@27.1,@23.2,@2.3.@ @ Metodo@general@para@la@preparacion@de@amidas@por@acoplamiento@con@acidos@carboxilicos@@ Sobre@una@disolucion@de@la@correspondiente@base@esfingoide@II@(0,10@mmol)@y@Et3N@(30@!L,@aproximadamente@0,20@mmol)@ en@CH2Cl2@(1@mL)@bajo@atmosfera@de@argon,@se@afadio,@gota@a@gota,@una@disolucion@del@correspondiente@acido@carboxilico@ (0,10@mmol),@HOBt@(18@mg,@0,13@mmol)@y@EDC@(20@mg,@0,13@mmol)@en@CH2Cl2@(1@mL).@La@mezcla@de@reaccion@se@agito@a@ Example I-A1. @ N - [(2S, 3R, E) -1,3-dihydroxyoctadec-4-en-2-yl] ethanesulfonamide @ Yield: @ 75% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 5.69 @ (m, @ 1H); @ 5.65 @ (m, @ 1H); @ 4.15 @ (m, @ 1H); @ 3.80-3.60 @ (m, @ 2H); @ 3.50 @ (q, @ 2H); @ 2.90 @ (m, @ 1H); @ 2.01 @ (m, @ 2H); @ 1.29 @ (s, @ 3H); @ 1.35-1.26 @ (m, @ 22H); @ 0.86 @ (t, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 131.5, @ 129.9, @ 72.1, @ 59.5, @ 54.3, @ 48.8, @ 34.1, @ 32.2, @ (30.0-29.5), @ 22.7, @ 14.1, @ 2.3. @ @ Example I-B1. @ N - [(2S, 3R) -1,3-dihydroxyoctadecan-2-yl] ethanesulfonamide @ Yield: @ 77% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 3.45 @ (q @ wide, @ 2H), @ 3.97 @ - @ 3.70 @ (m, @ 3H), @ 2.78 @ (m, @ 1H) , @ 1.68 @ - @ 1.41 @ (m, @ 4H), @ 1.28 @ (t @ width, @ 3H), @ 1.23 @ (wide, @ 24H), @ 0.85 @ (t @ wide, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 75.06, @ 60.61, @ 54.83, @ 47.56, @ 33.91, @ 31.93, @ (29.95 @ - @ 26.04), @ 22.81, @ 14.25, @ 2.35 . @ @ Example I-C1. @ N - [(2S, 3S, 4R) -1,3,4-trihydroxyoctadecan-2-yl] ethanesulfonamide @ Yield: @ 79% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 3.90-3.60 @ (m, @ 2H); @ 3.50 @ (m, @ 1H); @ 3.45 @ (q, @ 2H); @ 3.18 @ (m, @ 1H); @ 2.75 @ (m, @ 1H); @ 1.51 @ (m, @ 2H); @ 1.30 @ (s, @ 3H); @ 1.30-1.26 @ (s @ width, @ 24H); @ 0.86 @ (t, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 76.5, @ 71.3, @ 59.6, @ 48.4, @ 47.2, @ 31.9, @ 31.2, @ (29.9-29.3), @ 23.7, @ 22.6, @ 14.2, @ 2.3. @ @ Example I-D1. @ N - [(2S, 3R) -1,3-dihydroxyoctadec-17-in-2-yl] ethanesulfonamide @ Yield: @ 84% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 3.90-3.70 @ (m, @ 3H); @ 3.45 @ (q, @ 2H); @ 2.80 @ (m, @ 1H); @ 2.03 @ (m, @ 2H); @ 1.85 @ (t, @ J @ = @ 2.5, @ 1H); @ 1.28 @ (s, @ 3H); @ 1.20-1.40 @ (s @ width, @ 24H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5@83.5; @ 72.5; @ 47.6, @ 69.1; @ 60.2; @ 58.4; @ 32.9; @ (29.5-28.5); @ 23.4; @ 21.3, @ 2.3. @ @ Example I-E1. @ N - [(2S, 3R) -14-azido-1,3-dihydroxytetradecan-2-yl) ethanesulfonamide @ Yield: @ 71% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 3.80-3.60 @ (m, @ 2H); @ 3.45 @ (m, @ 1H); @ 3.40 @ (q, @ 2H); @ 2.80 @ (m, @ 1H); @ 1.45 @ (m, @ 2H); @ 1.30-1.25 @ (m, @ 20H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 71.5, @ 60.1, @ 55.3, @ 50.2, @ 48.7, @ 33.1, @ 30.2, @ (29.9-29.2); @ 27.1, @ 23.2, @ 2.3. @ @ Method @ general @ for @ the @ preparation @ of @ amidas @ by @ coupling @ with @ acidos @ carboxilicos @@ About @ a @ dissolution @ of the corresponding @ base @ sphingoid @ II @ (0.10 @ mmol) @ and @ Et3N @ (30 @! L, @ about @ 0.20 @ mmol) @ @ CH2Cl2 @ (1 @ mL) @ low @ atmosphere @ of @ argon, @ se @ afadio, @ drop @ a @ drop, @ a @ dissolution @ of the corresponding @ carboxilic acid @ (0.10 @ mmol), @ HOBt @ (18 @ mg, @ 0.13 @ mmol) @ and @ EDC @ (20 @ mg, @ 0.13 @ mmol) @ in @ CH2Cl2 @ (1 @ mL) . @ The @ mix @ of @ reaccion @ se @ agito @ a @

temperatura@ambiente@durante@1@h,@se@lavo@con@agua@(3@x@0,5@mL)@y@se@concentro@a@presion@reducida.@El@crudo@resultante@ se@ purifico@ por@ cromatografia@ flash,@ utilizando@ un@ gradiente@ CH2Cl2/MeOH@ (de@ 0@ a@ 5%),@ obteniendose@ las@ correspondientes@amidas@con@los@rendimientos@que@se@indican@en@cada@ejemplo@ @ Acoplamiento@con@acido@bromoacetico@ Ejemplo I-D2.@2-bromo-N-[(2S,3R)-1,3-dihidroxioctadec-17-in-2-il]acetamida@ Rendimiento:@72%@ 1H-RMN@(400@MHz,@CDCl3):@5@8.05@(d@ancho,@1H);@4.21@(s,@2H);@3.90-3.70@(m,@4H);@2.03@(m,@2H);@1.85@(t,@J@=@2.5,@1H);@ 1.20-1.40@(s@ancho,@24H).@ 13C-RMN@(101@MHz,@CDCl3):@5@177.5;@83.5;@72.5;@69.1;@60.2;@58.4;@33.1;@(29.5-28.5);@23.4;@21.3@ @ Ejemplo I-E2.@N-[(2S,3R)-14-azido-1,3-dihidroxitetradecan-2-il]bromoacetamida@ Rendimiento:@77%@ 1H-RMN@(400@MHz,@CDCl3):@5@7.7@(d@ancho,@1H);@4.10@(s,@2H);@3.90-3.75@(m,@4H);@3.25@(t,@2H);@1.3-1.25@(ancho,@20H).@ 13C-RMN@(101@MHz,@CDCl3):@5@166.3,@74.2,@62.2,@53.9,@51.6,@42.8,@34.6,@29.6,@29.3,@28.9,@26.8,@26.0.@ @ Ejemplo I-F2.@N-[(2S,3R,E)-14-azido-1,3-dihidroxitetradec-4-en-2-il]bromoacetamida@ Rendimiento:@73%@ 1H-RMN@(400@MHz,@CDCl3):@5@7.72@(d@ancho,@1H),@5.81@(m,@1H);@5.53@(m,@1H);@4.35@(m,@1H);@4.10@(s,@2H);@4.01@(dd,@1H);@ 3.90@(m,@1H),@3.73@(dd,@1H);@3.25@(t,@2H);@2.10@(m,@2H);@1.65@(m,@2H);@1.40-1.25@(s@ancho,@14H).@ 13C-RMN@(101@MHz,@CDCl3):@5@166.6,@134.8,@128.6,@77.5,@77.2,@76.8,@74.2,@62.0,@54.8,@51.6,@42.8,@32.4,@29.5,@29.5,@29.2,@ 29.2,@28.9,@26.8.@ @ Ejemplo I-G2.@2-bromo-N-[(2S,3R,E)-1,3-dihidroxioctadec-4-en-17-in-2-il]acetamida@ Rendimiento:@84%@ 1H-RMN@(400@MHz,@CDCl3):@5@8.10@(d@ancho,@1H);@5.71-5.68@(m,@2H);@4.60@(m,@1H);@3.90-3.70@(m,@3H);@2.10-1.95@(m,@4H);@ 1.82@(t,@J@=@2.5,@1H);@1.45-1.30@(m,@18H).@ 13C-RMN@(101@MHz,@CDCl3):@5@177.5;@131.1;@129.7;@83.7;@72.8;@69.1;@60.0;@53.7;@34.1;@(30.0-28.5);@21.4@ @ Ejemplo I-H2.@(S)-N-(14-azido-1-hidroxi-3-oxotetradecan-2-il)-2-bromoacetamida@ Rendimiento:@81%@ 1H-RMN@(400@MHz,@CDCl3):@5@4.20@(s,@2H),@4.16@(d,@J@=@3.8@Hz,@2H),@4.10@(dd,@J@=@12.0,@4.3@Hz,@2H),@3.97@(dd,@J@=@12.0,@ 3.4@Hz,@2H),@2.64@(t,@J@=@7.2@Hz,@4H),@1.60@(dd,@J@=@16.4,@8.9@Hz,@9H),@1.32@(s,@34H).@ 13C-RMN@(101@MHz,@CDCl3):@5@205.2,@178.5,@62.19,@60.26,@52.44,@39.62,@30.62,@30.60,@30.57,@30.52,@30.27,@30.09,@28.7,@ 29.4,@29.92,@27.82,@24.18.@ @ Ejemplo I-B2.@2-bromo-N-((2S,3R)-1,3-dihidroxioctadecan-2-il)acetamida.@ Segun@procedimiento@de@sintesis@descrito@en@la@solicitud@de@patente@WO200650264.@Ejemplo@1.@ @ Acoplamiento@con@acido@dibromoacetico@ Ejemplo I-B17. 2,2-dibromo-N-((2S,3R)-1,3-dihidroxioctadecan-2-il)acetamida.@ Rendimiento:@77%@ 1H-RMN@(400@MHz,@CDCl3):@5@6.23@(s,@1H),@3.80-3.70@(m,@3H),@3.65@(t@ancho,@1H),@1.55@(m.@2H),@1.40-1.20@(s@ancho,@26H),@ 0.91@(t,@3H).@ 13C-RMN@(101@MHz,@CDCl3):@5@166.9,@71.9,@61.7,@57.6,@37.9,@34.9,@33.1,@30.9-30.6,@30.5,@26.6,@23.7,@14.4.@ @@@ Acoplamiento@con@acido@glicidico@ Ejemplo I-A3.@(RS)-N-[(2S,3R,E)-1,3-dihidroxioctadec-4-en-2-il]oxirano-2-carboxamida@ Rendimiento:@77%@ 1H-RMN@(400@MHz,@CDCl3):@5@8.10@(d@ancho,@1H);@5.69-5.67@(m,@2H);@4.62@(m,@1H);@3.80-3.60@(m,@3H);@3.50@(m,@1H);@2.90- 2.60@(m,@2H);@2.01@(m,@2H);@1.33-1.26@(m,@22H);@0.85@(t,@3H).@ 13C-RMN@(101@MHz,@CDCl3):@5@173.5,@131.1,@129.7,@73.1,@60.2,@56.2,@55.4,@48.1,@35.1,@32.2,@(29.9-29.3),@22.8,@14.2.@ @ Ejemplo I-B3.@(RS)-N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]oxirano-2-carboxamida@ Rendimiento:@79%@ 1H-RMN@(400@MHz,@CDCl3):@5@8.10@(d@ancho,@1H);@3.80-3.60@(m,@4H);@3.52@(m,@1H);@2.90-2.60@(m,@2H);@1.50@(m,@2H);@1.30- 1.25@(m,@26H);@0.85@(t,@3H).@ 13C-RMN@(101@MHz,@CDCl3):@5@175.5,@72.4,@(59.9-59.8),@56.2,@48.4,@32.8,@31.7,@(29.6-29.3),@23.4,@22.8,@14.1.@ @ Ejemplo I-C3.@(RS)-N-[(2S,3S,4R)-1,3,4-trihidroxioctadecan-2-il]oxirano-2-carboxamida@ Rendimiento:@72%@ 1H-RMN@(400@MHz,@CDCl3):@5@8.05@(d@ancho,@1H);@3.95-3.60@(m,@4H);@3.51@(m,@1H);@3.20@(m,@1H);@2.90-2.65@(m,@2H);@1.45@ (m,@2H);@1.30-1.25@(m,@24H);@086@(t,@3H).@ 13C-RMN@(101@MHz,@CDCl3):@5@172.5,@77.5,@71.2,@60.3,@56.2,@53.2,@47.6,@(31.8-31.6),@(29.9-29.3),@23.8,@22.6,@14.2.@ @ @ ambient @ temperature for @ 1 @ h, @ se @ washed @ with @ water @ (3 @ x @ 0.5 @ mL) @ and @ concentrated @ reduced @ pressure @ The resulting @ crude @ @ purifico @ by @ flash chromatography, @ using @ a @ gradient @ CH2Cl2 / MeOH @ (from @ 0 @ to @ 5%), @ obtaining @ the @ corresponding @ amidas @ with @ the @ returns @ that @ are @ indicated @ in @ each @ example @ @ Coupling @ with @ acid @ bromoacetic @ Example I-D2. @ 2-Bromo-N - [(2S, 3R) -1,3-dihydroxyoctadec-17-in-2-yl] acetamide @ Yield: @ 72% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 8.05 @ (d @ wide, @ 1H); @ 4.21 @ (s, @ 2H); @ 3.90-3.70 @ (m, @ 4H); @ 2.03 @ (m, @ 2H); @ 1.85 @ (t, @ J @ = @ 2.5, @ 1H); @ 1.20-1.40 @ (s @ width, @ 24H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5@177.5; @ 83.5; @ 72.5; @ 69.1; @ 60.2; @ 58.4; @ 33.1; @ (29.5-28.5); @ 23.4; @ 21.3 @ @ Example I-E2. @ N - [(2S, 3R) -14-azido-1,3-dihydroxytetradecan-2-yl] bromoacetamide @ Yield: @ 77% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 7.7 @ (d @ wide, @ 1H); @ 4.10 @ (s, @ 2H); @ 3.90-3.75 @ (m, @ 4H); @ 3.25 @ (t, @ 2H); @ 1.3-1.25 @ (width, @ 20H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 166.3, @ 74.2, @ 62.2, @ 53.9, @ 51.6, @ 42.8, @ 34.6, @ 29.6, @ 29.3, @ 28.9, @ 26.8, @ 26.0 . @ @ Example I-F2. @ N - [(2S, 3R, E) -14-azido-1,3-dihydroxytetradec-4-en-2-yl] bromoacetamide @ Yield: @ 73% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 7.72 @ (d @ width, @ 1H), @ 5.81 @ (m, @ 1H); @ 5.53 @ (m, @ 1H); @ 4.35 @ (m, @ 1H); @ 4.10 @ (s, @ 2H); @ 4.01 @ (dd, @ 1H); @ 3.90 @ (m, @ 1H), @ 3.73 @ (dd, @ 1H); @ 3.25 @ (t, @ 2H); @ 2.10 @ (m, @ 2H); @ 1.65 @ (m, @ 2H); @ 1.40-1.25 @ (s @ width, @ 14H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 166.6, @ 134.8, @ 128.6, @ 77.5, @ 77.2, @ 76.8, @ 74.2, @ 62.0, @ 54.8, @ 51.6, @ 42.8, @ 32.4 , @ 29.5, @ 29.5, @ 29.2, @ 29.2, @ 28.9, @ 26.8. @ @ Example I-G2. @ 2-Bromo-N - [(2S, 3R, E) -1,3-dihydroxyoctadec-4-en-17-in-2-yl] acetamide @ Yield: @ 84% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 8.10 @ (d @ width, @ 1H); @ 5.71-5.68 @ (m, @ 2H); @ 4.60 @ (m, @ 1H); @ 3.90-3.70 @ (m, @ 3H); @ 2.10-1.95 @ (m, @ 4H); @ 1.82 @ (t, @ J @ = @ 2.5, @ 1H); @ 1.45-1.30 @ (m, @ 18H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5@177.5; @ 131.1; @ 129.7; @ 83.7; @ 72.8; @ 69.1; @ 60.0; @ 53.7; @ 34.1; @ (30.0-28.5); @ 21.4 @ @ Example I-H2. @ (S) -N- (14-azido-1-hydroxy-3-oxotetradecan-2-yl) -2-bromoacetamide @ Yield: @ 81% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 4.20 @ (s, @ 2H), @ 4.16 @ (d, @ J @ = @ 3.8 @ Hz, @ 2H), @ 4.10 @ (dd, @J @ = @ 12.0, @ 4.3 @ Hz, @ 2H), @ 3.97 @ (dd, @ J @ = @ 12.0, @ 3.4 @ Hz, @ 2H), @ 2.64 @ (t, @ J @ = @ 7.2 @ Hz, @ 4H), @ 1.60 @ (dd, @ J @ = @ 16.4, @ 8.9 @ Hz, @ 9H), @ 1.32 @ (s, @ 34H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 205.2, @ 178.5, @ 62.19, @ 60.26, @ 52.44, @ 39.62, @ 30.62, @ 30.60, @ 30.57, @ 30.52, @ 30.27, @ 30.09 , @ 28.7, @ 29.4, @ 29.92, @ 27.82, @ 24.18. @ @ Example I-B2. @ 2-Bromo-N - ((2S, 3R) -1,3-dihydroxyoctadecan-2-yl) acetamide. @ According to @ procedure @ of @ synthesis @ described @ in @ the @ patent application @ WO200650264. @ Example @ 1. @ @ Coupling @ with @ acid @ dibromoacetic @ Example I-B17. 2,2-dibromo-N - ((2S, 3R) -1,3-dihydroxyoctadecan-2-yl) acetamide. @ Yield: @ 77% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 6.23 @ (s, @ 1H), @ 3.80-3.70 @ (m, @ 3H), @ 3.65 @ (t @ wide, @ 1H), @ 1.55 @ (m. @ 2H), @ 1.40-1.20 @ (s @ width, @ 26H), @ 0.91 @ (t, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 166.9, @ 71.9, @ 61.7, @ 57.6, @ 37.9, @ 34.9, @ 33.1, @ 30.9-30.6, @ 30.5, @ 26.6, @ 23.7, @ 14.4. @ @@@ Coupling @ with @ glycidic acid @ Example I-A3. @ (RS) -N - [(2S, 3R, E) -1,3-dihydroxyoctadec-4-en-2-yl] oxirane-2-carboxamide @ Yield: @ 77% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 8.10 @ (d @ wide, @ 1H); @ 5.69-5.67 @ (m, @ 2H); @ 4.62 @ (m, @ 1H); @ 3.80-3.60 @ (m, @ 3H); @ 3.50 @ (m, @ 1H); @ 2.90- 2.60 @ (m, @ 2H); @ 2.01 @ (m, @ 2H); @ 1.33-1.26 @ (m, @ 22H); @ 0.85 @ (t, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 173.5, @ 131.1, @ 129.7, @ 73.1, @ 60.2, @ 56.2, @ 55.4, @ 48.1, @ 35.1, @ 32.2, @ (29.9-29.3 ), @ 22.8, @ 14.2. @ @ Example I-B3. @ (RS) -N - [(2S, 3R) -1,3-dihydroxyoctadecan-2-yl] oxirane-2-carboxamide @ Yield: @ 79% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 8.10 @ (d @ wide, @ 1H); @ 3.80-3.60 @ (m, @ 4H); @ 3.52 @ (m, @ 1H); @ 2.90-2.60 @ (m, @ 2H); @ 1.50 @ (m, @ 2H); @ 1.30- 1.25 @ (m, @ 26H); @ 0.85 @ (t, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 175.5, @ 72.4, @ (59.9-59.8), @ 56.2, @ 48.4, @ 32.8, @ 31.7, @ (29.6-29.3), @ 23.4, @ 22.8, @ 14.1. @ @ Example I-C3. @ (RS) -N - [(2S, 3S, 4R) -1,3,4-trihydroxioctadecan-2-yl] oxirane-2-carboxamide @ Yield: @ 72% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 8.05 @ (d @ wide, @ 1H); @ 3.95-3.60 @ (m, @ 4H); @ 3.51 @ (m, @ 1H); @ 3.20 @ (m, @ 1H); @ 2.90-2.65 @ (m, @ 2H); @ 1.45 @ (m, @ 2H); @ 1.30-1.25 @ (m, @ 24H); @ 086 @ (t, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 172.5, @ 77.5, @ 71.2, @ 60.3, @ 56.2, @ 53.2, @ 47.6, @ (31.8-31.6), @ (29.9-29.3), @ 23.8, @ 22.6, @ 14.2. @ @

Ejemplo I-D3.@(RS)-N-[(2S,3R,E)-1,3-dihidroxioctadec-4-en-17-in-2-il]oxirano-2-carboxamida@ Rendimiento:@73%@ 1H-RMN@(400@MHz,@CDCl3):@5@8.05@(d@ancho,@1H);@3.90-3.70@(m,@4H);@3.51@(m,@1H);@2.90-2.65@(m,@2H);@2.05@(m,@2H);@1.85@ (t,@J@=@2.5,@1H);@1.46-1.42@(m,@4H);@1.29-1.26@(s@ancho,@20H).@ 13C-RMN@(101@MHz,@CDCl3):@5@172.5,@83.5,@72.3,@69.1,@59.9,@59.7,@56.2,@48.2,@32.6,@23.5,@21.4,@(29.9-28.5).@ @ Ejemplo I-E3.@(RS)-N-[(2S,3R)-14-azido-1,3-dihidroxitetradecan-2-il]oxirano-2-carboxamida@ Rendimiento:@79%@ 1H-RMN@(400@MHz,@CDCl3):@5@8.15@(d@ancho,@1H);@3.90-375@(m,@4H);@3.51@(m,@1H);@2.90-2.65@(m,@2H);@1.45-1.30@(s@ancho,@ 22H).@ 13C-RMN@(101@MHz,@CDCl3):@5@173.3,@72.4,@(59.9-59.8),@55.4,@51.2,@47.6,@33.1,@(30.0-29.3),@26.7,@23.3.@ @ Otras@reacciones@de@acoplamiento@ Ejemplo I-B5:@N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]propiolamida@ Rendimiento:@90%@ 1H-RMN@(400@MHz,@CDCl3):@5@7.77@(d@ancho,@1H),@4.23@-@4.03@(m,@1H),@3.97@-@3.70@(m,@3H),@2.72@-@2.49@(m,@2H),@1.68@-@ 1.41@(m,@4H),@1.23@(ancho,@24H),@0.85@(t@ancho,@3H).@ 13C-RMN@(101@MHz,@CDCl3):@5@145.9,@84.5,@77.8,@73.06,@59.98,@57.53,@33.91,@32.75,@(29.90@-@29.58),@26.04,@22.98,@14.42.@ @ Ejemplo I-B6.@N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]but-2-inamida@@ Rendimiento:@91%@ 1H-RMN@(400@MHz,@CDCl3):@5@8.01@(d@ancho,@1H),@4.23@-@4.03@(m,@1H),@3.97@-@3.70@(m,@3H),@2.72@-@2.49@(m,@2H),@1.80@(s,@ 3H),@1.68@-@1.41@(m,@4H),@1.23@(ancho,@24H),@0.85@(t@ancho,@3H).@ 13C-RMN@(101@MHz,@CDCl3):@5@145.2,@91.2,@78.8,@72.0,@59.6,@58.53,@35.1,@32.9,@(29.9-29.5),@26.0,@22.9,@14.3,@2.7.@ @ Ejemplo I-B7.@N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]acrilamida@@ Rendimiento:@89%@ 1H-RMN@(400@MHz,@CDCl3):@5@6.33@(d,@J@=@17.0,@1H),@6.17@(dd,@J@=@10.2,@16.9,@1H),@5.69@(d,@J@=@11.1,@1H),@4.16@-@3.99@(m,@ 1H),@3.96@-@3.71@(m,@3H),@1.68@-@1.46@(m,@4H),@1.25@(s@ancho,@24H),@0.88@(t,@J@=@6.8,@3H).@ 13C-RMN@(101@MHz,@CDCl3):@5@165.7,@131.0,@127.3,@74.5,@62.4,@54.0,@34.7,@32.1,@30.0,@29.7,@29.5,@26.3,@22.8,@14.2.@ @ Ejemplo I-B8.@(E)-N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]but-2-enamida@ Rendimiento:@86%@ 1H-RMN@(400@MHz,@CDCl3):@5@6.88@(dq,@J@=@6.7,@13.3,@1H),@6.40@(d,@J@=@7.6,@1H),@5.87@(d,@J@=@14.3,@1H),@4.04@(d@ancho,@ 1H),@3.92@-@3.74@(m,@3H),@1.87@(d,@J@=@6.6,@3H),@1.70-1.46@(m,@4H),@1.25@(ancho,@24@H),@0.88@(t,@J@=@6.5,@3H).@ 13C-RMN@(101@MHz,@CD3OD):@5@141.0,@126.3,@72.5,@62.3,@56.9,@35.0,@33.1,@30.9,@30.8,@30.5,@26.9,@23.8,@18.0,@14.6.@ @ Ejemplo I-B9.@N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]metacrilamida@ 1H-RMN@(400@MHz,@CDCl3):@5@8.22@(ancho,@1H),@5.89@(s@ancho,@1H),@5.49@(s@ancho,@1H),@3.88-3.63@(m,@2H),@3.83@(m,@1H),@ 3.75@(m,@1H),@1.93@(s@ancho,@1H),@1.75-1.50@(m,@4H),@1.27@(ancho,@24@H),@0.85@(t,@J@=@6.5,@3H)@ 13C-RMN@(101@MHz,@CD3OD):@5@168.6,@141.3,@124.0,@72.3,@59.9,@59.8,@32.7,@31.8,@29.9-29.3,@23.4,@22.7,@14.1@ @ Ejemplo I-B10.@N-[(2S,3R)-N-1,3-dihidroxioctadecan-2-il]-3-metil-2-butenamida@ 1H-RMN@(400@MHz,@CDCl3):@5@6.26@(ancho,@1H),@6.64@(s,@1H),@4.1@(m,@1H),@3.85@(m,@3H);@2.16@(s,@3H),@1.86@(s,@3H),@1.54@ (m,@2H),@1.25@(ancho,@26H),@0.88@(t,@3H).@ 13C-RMN@(101@MHz,@CDCl3):@5@167.4,@151.2,@118.5,@74.3,@62.7,@53.9,@34.7,@32.0,@29.8-29.5,@27.3,@26.1,@22.8,@19.9,@14.2.@ @ Ejemplo I-B11.@(2E,4E)-N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]hexa-2,4-dienamida@ 1H-RMN@(400@MHz,@CDCl3):@5@7.11@(dd,@J=14.8@Hz,@J'=10@Hz,@1H),@6.90@(d@ancho,@1H),@6.05@(m,@2H),@5.78@(d,@J=15.2@Hz,@ 1H),@3.95@(m,@2H),@3.62@(m,@1H),@1.78@(d,@J=6Hz,@3H),@1.45@(ancho,@2H),@1.19@(ancho,@26H),@0.82@(t,@3H).@ 13C-RMN@(101@MHz,@CDCl3,CD3OD):@5@167.3,@141.7,@138.2,@129.7,@121.3,@73.3,@61.9,@54.5,@34.3,@31.9,@29.7-29.3,@26.0,@ 22.7,@18.5,@14.1.@ @ Ejemplo I-B12.@Acido@(E)-4-[(2S,3R)-1,3-dihidroxioctadecan-2-ilamino]-4-oxo-2-butenoico@ 1H-RMN@(400@MHz,@CDCl3):@5@7.8@(ancho,@1H),@6.38@(dd@ancho,@2H),@4.12@(d@ancho,@1H),@3.88@(ancho,@3H),@1.45@(ancho,@ 2H),@1.25@(ancho,@26H),@0.87@(t,@3H).@ 13C-RMN@(101@MHz,@CDCl3):@5166.4,@166.2,@135.5,@132.5,@73.6,@61.2,@54.7,@34.5,@32.1,@29.8-29.5,@26.1,@22.8,@14.2@ @ Ejemplo I-B13.@(Z)-2,3-dibromo-N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]-4-oxo-2-butenamida@ 1H-RMN@(400@MHz,@CDCl3):@5@9.70@(s,@1H),@8.22@(ancho,@1H),@3.85@(m,@2H),@3.75@(m,@1H),@3.63@(m,@1H),@1.45@(m,@2H),@1.28@ (ancho,@26H),@0.85@(t,@3H).@ 13C-RMN@(101@MHz,@CDCl3):@5@192.3,@166.2,@143.2,@134.5,@72.5,@60.2,@58.9,@32.8,@31.8,@29.9-29.3,@23.5,@22.6,@14.1.@ @ Example I-D3. @ (RS) -N - [(2S, 3R, E) -1,3-dihydroxyoctadec-4-en-17-in-2-yl] oxirane-2-carboxamide @ Yield: @ 73% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 8.05 @ (d @ width, @ 1H); @ 3.90-3.70 @ (m, @ 4H); @ 3.51 @ (m, @ 1H); @ 2.90-2.65 @ (m, @ 2H); @ 2.05 @ (m, @ 2H); @ 1.85 @ (t, @ J @ = @ 2.5, @ 1H); @ 1.46-1.42 @ (m, @ 4H); @ 1.29-1.26 @ (s @ width, @ 20H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 172.5, @ 83.5, @ 72.3, @ 69.1, @ 59.9, @ 59.7, @ 56.2, @ 48.2, @ 32.6, @ 23.5, @ 21.4, @ ( 29.9-28.5). @ @ Example I-E3. @ (RS) -N - [(2S, 3R) -14-azido-1,3-dihydroxytetradecan-2-yl] oxirane-2-carboxamide @ Yield: @ 79% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 8.15 @ (d @ width, @ 1H); @ 3.90-375 @ (m, @ 4H); @ 3.51 @ (m, @ 1H); @ 2.90-2.65 @ (m, @ 2H); @ 1.45-1.30 @ (s @ width, @ 22H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 173.3, @ 72.4, @ (59.9-59.8), @ 55.4, @ 51.2, @ 47.6, @ 33.1, @ (30.0-29.3), @ 26.7, @ 23.3. @ @ Other @ reactions @ of @ coupling @ Example I-B5: @N - [(2S, 3R) -1,3-dihydroxioctadecan-2-yl] propiolamide @ Yield: @ 90% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 7.77 @ (d @ width, @ 1H), @ 4.23 @ - @ 4.03 @ (m, @ 1H), @ 3.97 @ - @ 3.70 @ (m , @ 3H), @ 2.72 @ - @ 2.49 @ (m, @ 2H), @ 1.68 @ - @ 1.41 @ (m, @ 4H), @ 1.23 @ (wide, @ 24H), @ 0.85 @ (t @ wide, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 145.9, @ 84.5, @ 77.8, @ 73.06, @ 59.98, @ 57.53, @ 33.91, @ 32.75, @ (29.90 @ - @ 29.58), @ 26.04 , @ 22.98, @ 14.42. @ @ Example I-B6. @ N - [(2S, 3R) -1,3-dihydroxioctadecan-2-yl] but-2-inamida @@ Yield: @ 91% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 8.01 @ (d @ width, @ 1H), @ 4.23 @ - @ 4.03 @ (m, @ 1H), @ 3.97 @ - @ 3.70 @ (m , @ 3H), @ 2.72 @ - @ 2.49 @ (m, @ 2H), @ 1.80 @ (s, @ 3H), @ 1.68 @ - @ 1.41 @ (m, @ 4H), @ 1.23 @ (wide, @ 24H), @ 0.85 @ (t @ wide, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 145.2, @ 91.2, @ 78.8, @ 72.0, @ 59.6, @ 58.53, @ 35.1, @ 32.9, @ (29.9-29.5), @ 26.0, @ 22.9, @ 14.3, @ 2.7. @ @ Example I-B7. @ N - [(2S, 3R) -1,3-dihydroxioctadecan-2-yl] acrylamide @@ Yield: @ 89% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 6.33 @ (d, @ J @ = @ 17.0, @ 1H), @ 6.17 @ (dd, @ J @ = @ 10.2, @ 16.9, @ 1H ), @ 5.69 @ (d, @ J @ = @ 11.1, @ 1H), @ 4.16 @ - @ 3.99 @ (m, @ 1H), @ 3.96 @ - @ 3.71 @ (m, @ 3H), @ 1.68 @ - @ 1.46 @ (m, @ 4H), @ 1.25 @ (s @ width, @ 24H), @ 0.88 @ (t, @ J @ = @ 6.8, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 165.7, @ 131.0, @ 127.3, @ 74.5, @ 62.4, @ 54.0, @ 34.7, @ 32.1, @ 30.0, @ 29.7, @ 29.5, @ 26.3 , @ 22.8, @ 14.2. @ @ Example I-B8. @ (E) -N - [(2S, 3R) -1,3-dihydroxyoctadecan-2-yl] but-2-enamide @ Yield: @ 86% @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 6.88 @ (dq, @ J @ = @ 6.7, @ 13.3, @ 1H), @ 6.40 @ (d, @ J @ = @ 7.6, @ 1H ), @ 5.87 @ (d, @ J @ = @ 14.3, @ 1H), @ 4.04 @ (d @ width, @ 1H), @ 3.92 @ - @ 3.74 @ (m, @ 3H), @ 1.87 @ (d, @ J @ = @ 6.6, @ 3H), @ 1.70-1.46 @ (m, @ 4H), @ 1.25 @ ( wide, @ 24 @ H), @ 0.88 @ (t, @ J @ = @ 6.5, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CD3OD): @ 5 @ 141.0, @ 126.3, @ 72.5, @ 62.3, @ 56.9, @ 35.0, @ 33.1, @ 30.9, @ 30.8, @ 30.5, @ 26.9, @ 23.8 , @ 18.0, @ 14.6. @ @ Example I-B9. @ N - [(2S, 3R) -1,3-dihydroxyoctadecan-2-yl] methacrylamide @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 8.22 @ (width, @ 1H), @ 5.89 @ (s @ width, @ 1H), @ 5.49 @ (s @ width, @ 1H), @ 3.88-3.63 @ (m, @ 2H), @ 3.83 @ (m, @ 1H), @ 3.75 @ (m, @ 1H), @ 1.93 @ (s @ width, @ 1H), @ 1.75-1.50 @ (m, @ 4H), @ 1.27 @ (width, @ 24 @ H), @ 0.85 @ (t , @ J @ = @ 6.5, @ 3H) @ 13C-RMN @ (101 @ MHz, @ CD3OD): @ 5 @ 168.6, @ 141.3, @ 124.0, @ 72.3, @ 59.9, @ 59.8, @ 32.7, @ 31.8, @ 29.9-29.3, @ 23.4, @ 22.7, @ 14.1 @ @ Example I-B10. @ N - [(2S, 3R) -N-1,3-dihydroxyoctadecan-2-yl] -3-methyl-2-butenamide @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 6.26 @ (wide, @ 1H), @ 6.64 @ (s, @ 1H), @ 4.1 @ (m, @ 1H), @ 3.85 @ (m , @ 3H); @ 2.16 @ (s, @ 3H), @ 1.86 @ (s, @ 3H), @ 1.54 @ (m, @ 2H), @ 1.25 @ (wide, @ 26H), @ 0.88 @ (t, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 167.4, @ 151.2, @ 118.5, @ 74.3, @ 62.7, @ 53.9, @ 34.7, @ 32.0, @ 29.8-29.5, @ 27.3, @ 26.1, @ 22.8, @ 19.9, @ 14.2. @ @ Example I-B11. @ (2E, 4E) -N - [(2S, 3R) -1,3-dihydroxioctadecan-2-yl] hexa-2,4-dienamide @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 7.11 @ (dd, @ J = 14.8 @ Hz, @ J '= 10 @ Hz, @ 1H), @ 6.90 @ (d @ width, @ 1H ), @ 6.05 @ (m, @ 2H), @ 5.78 @ (d, @ J = 15.2 @ Hz, @ 1H), @ 3.95 @ (m, @ 2H), @ 3.62 @ (m, @ 1H), @ 1.78 @ (d, @ J = 6Hz, @ 3H), @ 1.45 @ (wide, @ 2H), @ 1.19 @ (wide, @ 26H), @ 0.82 @ (t, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CDCl3, CD3OD): @ 5 @ 167.3, @ 141.7, @ 138.2, @ 129.7, @ 121.3, @ 73.3, @ 61.9, @ 54.5, @ 34.3, @ 31.9, @ 29.7- 29.3, @ 26.0, @ 22.7, @ 18.5, @ 14.1. @ @ Example I-B12. @ Acid @ (E) -4 - [(2S, 3R) -1,3-dihydroxioctadecan-2-ylamino] -4-oxo-2-butenoic @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 7.8 @ (width, @ 1H), @ 6.38 @ (dd @ width, @ 2H), @ 4.12 @ (d @ width, @ 1H), @ 3.88 @ (width, @ 3H), @ 1.45 @ (width, @ 2H), @ 1.25 @ (wide, @ 26H), @ 0.87 @ (t, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5166.4, @ 166.2, @ 135.5, @ 132.5, @ 73.6, @ 61.2, @ 54.7, @ 34.5, @ 32.1, @ 29.8-29.5, @ 26.1, @ 22.8 , @ 14.2 @ @ Example I-B13. @ (Z) -2,3-dibromo-N - [(2S, 3R) -1,3-dihydroxioctadecan-2-yl] -4-oxo-2-butenamide @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 9.70 @ (s, @ 1H), @ 8.22 @ (wide, @ 1H), @ 3.85 @ (m, @ 2H), @ 3.75 @ (m , @ 1H), @ 3.63 @ (m, @ 1H), @ 1.45 @ (m, @ 2H), @ 1.28 @ (width, @ 26H), @ 0.85 @ (t, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 192.3, @ 166.2, @ 143.2, @ 134.5, @ 72.5, @ 60.2, @ 58.9, @ 32.8, @ 31.8, @ 29.9-29.3, @ 23.5, @ 22.6, @ 14.1. @ @

Ejemplo I-B14.@(2S,3R)-2-(bromometil)-N-(1,3-dihidroxioctadecan-2-il)acrilamida@ 1H-RMN@(400@MHz,@CDCl3):@5@8.22@(ancho,@1H),@6.02@(d,@J=2.5@Hz,@1H),@5.81@(d,@J=2.5@Hz,@1H),@4.12@(s,@2H),@3.85-3.53@ (m,@4H),@1.45@(m,@2H),@1.29@(ancho,@26H),@0.85@(t,@3H).@ 13C-RMN@(101@MHz,@CDCl3):@5@169.1,@142.5,@127.2,@71.2,@59.9,@59.7,@36.5,@33.1,@31.5,@29.9-29.1,@23.5,@22.6,@14.1.@ @ Ejemplo I-B15.@(E,2S,3R)-N-(1,3-dihidroxi-2-octadecil)-2-methil-2-butenamida@ 1H-RMN@(400@MHz,@CDCl3):@5@6.62@(ancho,@1H),@6.50@(ancho,@1H),@4.01@(m,@1H),@3.85-3.75@(m,@3H),@1.87@(s@ancho,@3H),@ 1.77@(d,@J=6.8@Hz,@3H),@1.54@(m,@2H),@1.25@(ancho,@26H),@0.87@(t,@3H).@ 13C-RMN@(101@MHz,@CDCl3):@5@169.8,@131.7,@131.6,@74.2,@62.5,@54.1,@34.6,@32.1,29.8-29.5,@26.1,@22.8,@14.3,@14.1,@12.5. @ Ejemplo I-D16.@(2S,3R)-N-(1,3-dihidroxi-17-octadecin-2-il)-2-oxooctanamida@ 1H-RMN@(400@MHz,@CDCl3):@5@8.25@(ancho,@1H),@3.80-3.60@(m,@4H),@2.40@(t@ancho,@2H),@2.03@(m,@2H),@1.85@(t,@J=2.7@Hz,@ 1H),@1.65@(m,@2H),@1.45@(m,@4H),@1.35-1.25@(m,@26H),@0.97@(t,@3H).@ 13C-RMN@(101@MHz,@CDCl3):@5@197.6,@159.9,@83.5,@72.4,@68.1,@59.9,@59.7,@32.8-31.5,@30.1-28.5,@23.5-21.5,@14.2.@ @ Ejemplo I-E16. (2S,3R)-N-(14-azido-1,3-dihidroxi-2-tetradecil)-2-oxooctanamida@ 1H-RMN@(400@MHz,@CDCl3):@5@8.25@(ancho,@1H),@3.85-3.62@(m,@4H),@2.45@(t@ancho,@2H),@1.60-1.45@(m,@4H),@1.35-1.25@ (ancho,@26H),@0.95@(t,@3H).@ 13C-RMN@(101@MHz,@CDCl3):@5@197.5,@160.2,@73.1,@59.9,@59.7,@51.2,@32.6,@32.4,@31.8,@30.0-28.5,@26.8,@23.5,@23.1,@22.9,@ 14.2.@ Example I-B14. @ (2S, 3R) -2- (bromomethyl) -N- (1,3-dihydroxyoctadecan-2-yl) acrylamide @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 8.22 @ (wide, @ 1H), @ 6.02 @ (d, @ J = 2.5 @ Hz, @ 1H), @ 5.81 @ (d, @ J = 2.5 @ Hz, @ 1H), @ 4.12 @ (s, @ 2H), @ 3.85-3.53 @ (m, @ 4H), @ 1.45 @ (m, @ 2H), @ 1.29 @ (wide, @ 26H), @ 0.85 @ (t, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 169.1, @ 142.5, @ 127.2, @ 71.2, @ 59.9, @ 59.7, @ 36.5, @ 33.1, @ 31.5, @ 29.9-29.1, @ 23.5, @ 22.6, @ 14.1. @ @ Example I-B15. @ (E, 2S, 3R) -N- (1,3-dihydroxy-2-octadecyl) -2-methyl-2-butenamide @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 6.62 @ (width, @ 1H), @ 6.50 @ (width, @ 1H), @ 4.01 @ (m, @ 1H), @ 3.85-3.75 @ (m, @ 3H), @ 1.87 @ (s @ width, @ 3H), @ 1.77 @ (d, @ J = 6.8 @ Hz, @ 3H), @ 1.54 @ (m, @ 2H), @ 1.25 @ (wide, @ 26H), @ 0.87 @ (t, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 169.8, @ 131.7, @ 131.6, @ 74.2, @ 62.5, @ 54.1, @ 34.6, @ 32.1,29.8-29.5, @ 26.1, @ 22.8, @ 14.3, @ 14.1, @ 12.5. @ Example I-D16. @ (2S, 3R) -N- (1,3-dihydroxy-17-octadecin-2-yl) -2-oxooctanamide @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 8.25 @ (wide, @ 1H), @ 3.80-3.60 @ (m, @ 4H), @ 2.40 @ (t @ wide, @ 2H), @ 2.03 @ (m, @ 2H), @ 1.85 @ (t, @ J = 2.7 @ Hz, @ 1H), @ 1.65 @ (m, @ 2H), @ 1.45 @ (m, @ 4H), @ 1.35-1.25 @ (m, @ 26H), @ 0.97 @ (t, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 197.6, @ 159.9, @ 83.5, @ 72.4, @ 68.1, @ 59.9, @ 59.7, @ 32.8-31.5, @ 30.1-28.5, @ 23.5-21.5 , @ 14.2. @ @ Example I-E16. (2S, 3R) -N- (14-azido-1,3-dihydroxy-2-tetradecyl) -2-oxooctanamide @ 1H-RMN @ (400 @ MHz, @ CDCl3): @ 5 @ 8.25 @ (wide, @ 1H), @ 3.85-3.62 @ (m, @ 4H), @ 2.45 @ (t @ wide, @ 2H), @ 1.60-1.45 @ (m, @ 4H), @ 1.35-1.25 @ (width, @ 26H), @ 0.95 @ (t, @ 3H). @ 13C-RMN @ (101 @ MHz, @ CDCl3): @ 5 @ 197.5, @ 160.2, @ 73.1, @ 59.9, @ 59.7, @ 51.2, @ 32.6, @ 32.4, @ 31.8, @ 30.0-28.5, @ 26.8, @ 23.5, @ 23.1, @ 22.9, @ 14.2. @

Ejemplos de ensayos biológicos Examples of biological tests

Ejemplo@1.@Actividad@inhibidora@de@las@ceramidasas@ Example @ 1. @ Activity @ inhibitor @ de @ las @ ceramidasas @

La@ actividad@inhibidora@ de@ las@ceramidasas@ por@ los@compuestos@ de@la@ presente@ invencion@se@ ensayo@ sobre@ fibroblastos@de@un@enfermo@de@Farber@transducidos@para@la@sobreexpresion@de@la@ceramidasa@acida@y@sobre@las@lineas@de@ cancer@de@pulmon@A549@(American@Type@Culture@Collection)@y@de@cancer@de@prostata@PC-3/Mc.@La@linea@A549@se@mantuvo@ en@medio@de@HAM@F12@suplementado@con@glutamina@2@mM,@la@linea@de@Farber@se@cultivo@en@medio@DMEM@y@la@linea@PC3/Mc@se@mantuvo@en@medio@RPMI1640.@En@todos@los@casos,@el@medio@se@suplemento@con@un@10%@de@suero@de@feto@ bovino,@100@unidades/mL@de@penicilina@y@10@ g/mL@de@estreptomicina@y@los@cultivos@se@mantuvieron@a@37@°C@en@atmosfera@ de@5%@CO2/95%@aire@y@una@humedad@del@90%.@ The @ inhibitory @ activity of @ the @ ceramidasas @ by @ the @ compounds @ of @ the @ present @ invention @ se @ essay @ on @ fibroblasts @ of @ a @ sick @ of @ Farber @ transduced @ for @ the @ overexpression of @ la @ ceramidasa @ acida @ and @ about @ las @ lines @ de @ cancer @ de @ pulmon @ A549 @ (American @ Type @ Culture @ Collection) @ and @ de @ cancer @ de @ prostata @ PC- 3 / Mc. @ The @ line @ A549 @ remained @ in @ half @ of @ HAM @ F12 @ supplemented @ with @ glutamine @ 2 @ mM, @ the @ line @ of @ Farber @ se @ crop @ in @ @ DMEM @ and @ the @ line @ PC3 / Mc @ was @ kept @ in @ half @ RPMI1640. @ In @ all @ the cases, @ the @ medium @ was @ supplement @ with @ 10% @ of @ serum @ of @ fetus @ bovine, @ 100 @ units / mL @ of @ penicillin @ and @ 10 @ g / mL @ of @ estreptomicina @ and @ the @ crops @ were @ 37 @ ° C @ in @ atmosphere @ of @ 5% @ CO2 / 95% @ air @ and @ a @ humidity @ of @ 90%. @

@ @

Las@celulas@se@sembraron@en@placas@de@96@pocillos@a@una@densidad@de@10.000@celulas@por@mililitro@y@despues@de@ 24-48@h,@el@medio@se@elimino@y@se@sustituyo@por@medio@nuevo@(100@microlitros@por@pocillo)@conteniendo@el@sustrato@ fluorogenico@(Bedia@et@al.@Chembiochem@2007,@8,@642)@y@el@inhibidor@a@una@concentracion@de@16@ M.@Tambien@se@puede@ afadir@el@sustrato@directamente@sin@reemplazar@el@medio@de@cultivo.@En@cualquier@caso,@se@incubo@a@37@°C@durante@3@ horas,@se@procedio@a@la@lisis@de@las@celulas@y@se@determino@la@actividad@enzimatica@siguiendo@el@procedimiento@descrito@ (Bedia@et@al.@Chembiochem@2007,@8,@642).@En@algunos@casos,@el@inhibidor@y@el@sustrato@se@afadieron@conjuntamente@y@se@ incubaron@durante@3@h@antes@de@proceder@a@la@lisis@de@las@celulas.@ The @ cells @ were @ planted @ in @ plates @ of @ 96 @ wells @ a @ a @ density @ of @ 10,000 @ cells @ per @ milliliter @ and @ after @ 24-48 @ h, @ the @ medium @ se @ elimino @ y @ se @ replayo @ by @ medio @ nuevo @ (100 @ microlitros @ by @ well) @ containing @ the @ substrate @ fluorogenico @ (Bedia @ et @ al. @ Chembiochem @ 2007, @ 8, @ 642) @ and @ the @ inhibitor @ a @ a concentration @ of @ 16 @ M. @ Also @ can @ be @ added @ Substrate @ directly @ without @ replace @ the @ culture @ medium. @ In @ any @ case, @ se @ incubo @ a @ 37 @ ° C @ for @ 3 @ hours, @ se @ proceio @ a @ la @ lysis @ of @ the @ cells @ and @ was @ determined @ the @ enzyme @ activity @ following @ the @ procedure @ described (Bedia @ et @ al. @ Chembiochem @ 2007, @ 8, @ 642). some @ cases, @ the @ inhibitor @ and @ the @ substrate @ were added @ together @ and @ were @ incubated @ during @ 3 @ h @ before @ proceed @ to @ the @ lysis of @ the @ cells . @

@ @

En@un@ejemplo@concreto@se@determino@el@efecto@inhibidor@de@los@compuestos@sobre@la@actividad@ceramidasa@acida@ de@las@celulas@de@Farber@transducidas@para@la@sobreexpresion@de@la@ceramidasa@acida.@Es@este@caso,@las@celulas@se@ incubaron@conjuntamente@con@sustrato@y@compuesto@problema@durante@3@h@y@despues@de@este@tiempo,@se@determino@la@ actividad@enzimatica@tal@como@se@describe@mas@arriba.@Tal@como@se@ilustra@en@la@Figura@1,@los@compuestos@I-B2,@I-B8,@I-B9@ y@I-B17,@y@fueron@los@mas@activos@en@celulas@intactas,@aunque@solo@I-B2,@I-B9@y@I-B17@fueron@tambien@activos@in vitro.@ In @ a @ concrete @ example @ was @ determined @ the @ effect @ inhibitor @ of the @ compounds @ on @ the @ activity @ ceramidasa @ acida @ of @ the @ cells @ of @ Farber @ transduced @ for @ the @ overexpression of @ la @ ceramidasa @ acida. @ Is @ this @ case, @ the @ cells @ were @ incubated @ together @ with @ substrate @ and @ compound @ problem @ during @ 3 @ h @ and @ after @ this @ time, @ was @ determined @ the @ enzymatic @ activity @ as @ described @ above @. @ As @ as @ illustrated @ in @ the @ Figure @ 1, @ the @ compounds @ I -B2, @ I-B8, @ I-B9 @ and @ I-B17, @ and @ were @ the @ most @ active @ in @ intact cells, @ although @ only @ I-B2, @ I-B9 @ and @ I-B17 @ were @ also @ active @ in vitro. @

@ @

En@otro@ejemplo@concreto@se@determino@el@efecto@inhibidor@de@los@compuestos@sobre@la@actividad@ceramidasa@acida@ de@las@celulas@de@adenocarcinoma@de@pulmon@A549.@Las@celulas@se@incubaron@con@los@compuestos@problema@durante@24@ h@y@despues@de@este@tiempo@se@afadio@el@sustrato,@se@incubo@durante@3@h@y@se@continuo@tal@como@se@describe@mas@arriba.@ Tal@como@se@muestra@en@la@Figura@2,@los@compuestos@ID2,@IE2@IF2@IG2@y@IH2@fueron@los@mas@activos,@presentando@una@ inhibicion@de@la@ceramidasa@acida@superior@al@95%@respecto@al@control.@ In @ another @ concrete @ example @ was @ determined @ the @ effect @ inhibitor @ of the @ compounds @ on @ the @ activity @ ceramidasa @ acida @ of @ the @ cells @ of @ adenocarcinoma @ of @ lung @ A549. @ The @ cells @ were @ incubated @ with the @ compounds @ problem @ during @ 24 @ h @ and @ after @ this @ time @ was @ afadio @ the @ substrate, @ se @ incubo @ during @ 3 @ h @ y @ se @ continuous @ as @ is @ described @ above @. @ As @ is @ shown @ in @ Figure @ 2, @ the @ compounds @ ID2, @ IE2 @ IF2 @ IG2 @ and @ IH2 @ were @ the @ most @ active, @ presenting @ an @ inhibition @ of @ the @ ceramidasa @ acida @ superior @ at @ 95% @ regarding @ the @ control. @

@ @

En@otro@ejemplo@se@determino@el@efecto@de@los@compuestos@I-B2,@I-9B@y@I-B17@sobre@la@actividad@ceramidasa@ acida@de@las@celulas@de@cancer@de@prostata@PC-3Mc.@Las@celulas@se@sembraron@en@placas@de@96@pocillos@a@una@densidad@ de@10.000@celulas/ml@y@los@compuestos@problema@se@afadieron@24@horas@despues@de@la@siembra.@Se@usaron@tres@dosis@de@ cada@inhibidor,@1@ M,@5@ M@y@10@ M,@en@incubaciones@durante@48@h.@La@Figura@3@representa@graficamente@los@resultados@ obtenidos.@Los@compuestos@I-B17@y@I-B2@causan@una@clara@inhibicion@de@la@actividad@ceramidasa@acida@a@todas@las@dosis@ empleadas,@con@mayor@efecto@inhibidor@a@mayor@dosis.@@ @ Ejemplo@2.@Efecto@de@los@inhibidores@sobre@el@ceramidoma@ In @ another @ example @ se @ determined @ the @ effect @ of @ the @ compounds @ I-B2, @ I-9B @ and @ I-B17 @ on @ the @ activity @ ceramidasa @ acida @ of @ the @ cells @ of @ cancer @ of @ prostata @ PC-3Mc. @ The @ cells @ were @ planted @ in @ plates @ of @ 96 wells @ a @ a density @ of @ 10,000 @ cells / ml @ and @ the @ compounds @ problem @ were added @ 24 @ hours @ after @ planting. @ They were used @ three @ doses @ of @ each @ inhibitor, @ 1 @ M, @ 5 @ M @ and @ 10 @ M, @ in @ incubations @ for @ 48 @ h. @ The @ Figure @ 3 @ represents @ graphically @ the @ results @ obtained. @ compounds @ I-B17 @ and @ I-B2 @ cause @ a clear @ inhibition of @ the @ ceramidase activity @ acida @ a @ all @ the @ doses @ used, @ with @ major @ effect @ inhibitor @ a @ major @ dose. @@ @ Example @ 2. @ Effect @ of @ the @ inhibitors @ on @ the @ ceramidoma @

En@estos@experimentos,@las@celulas@se@sembraron@en@placas@de@6@pocillos@a@una@densidad@de@250.000@celulas/ml.@ Los@compuestos@se@afadieron@24@h@despues@de@la@siembra@y@se@incubaron@durante@distintos@periodos@de@tiempo.@ Despues@de@los@tratamientos,@las@celulas@se@lavaron@con@PBS@y@se@transfirieron@a@viales@de@vidrio,@donde@se@prepararon@ los@extractos@lipidicos@siguiendo@el@procedimiento@descrito@(Merrill@et@al@Methods,@2005,@36,@207).@Los@analisis@se@llevaron@ a@cabo@por@cromatografia@liquida@de@ultrarresolucion@acoplada@a@un@detector@de@masas@de@tiempo@de@vuelo@acelerado,@ que@permite@la@identificacion@de@los@compuestos@en@base@a@su@masa@exacta,@mediante@ionizacion@en@electrospray@en@ modo@positivo.@Las@condiciones@cromatograficas@y@analiticas@son@las@descritas@en@trabajos@anteriores@(Munoz-Olaya@et@al@ In @ these @ experiments, @ the @ cells @ were @ planted @ in @ plates @ of @ 6 @ wells @ a @ a density @ of @ 250,000 @ cells / ml. @ The @ compounds @ were @ added @ 24 @ h @ after @ the @ sowing @ and @ were @ incubated @ during @ different @ periods @ of @ time. @ After @ the @ treatments, @ the @ cells @ were @ washed @ with @ PBS @ and @ @ were @ transferred @ to @ glass vials, @ where @ were @ prepared @ the @ lipid @ extracts @ following the @ procedure @ described (Merrill @ et @ al @ Methods, @ 2005, @ 36, @ 207 ) @ The @ analyzes @ were @ carried out @ by @ liquid @ chromatography @ ultra-resolution @ coupled @ a @ mass @ time @ detector @ of @ accelerated @ flight @ allows @ the @ identification @ of the @ compounds @ in @ base @ to @ its @ exact @ mass, @ by @ ionization @ in @ electrospray @ in @ positive @ mode. @ The @ chromatographic @ and @ analytical conditions @ They are @ the @ described @ in @ previous @ works @ (Munoz-Olaya @ et @ al @

ChemMedChem,@2008,@3,@946@y@Canals@et@al@Bioorg.@Med.@Chem.,@2009,@17,@235).@ ChemMedChem, @ 2008, @ 3, @ 946 @ and @ Canals @ et @ al @ Bioorg. @ Med. @ Chem., @ 2009, @ 17, @ 235). @

@@ @@

En@un@ejemplo@concreto@se@detallan@los@efectos@de@los@compuestos@problema@sobre@la@produccion@de@ceramidas@ totales@en@la@linea@de@cancer@de@pulmon@A549@despues@de@24@h@de@incubacion.@Los@resultados@se@ilustran@en@la@Figura@4.@ Los@compuestos@que@producen@un@mayor@aumento@de@los@niveles@de@ceramidas@son@ID2,@IF2,@IG2@y@IH2,@con@las@cuales@ las@ceramidas@son@6@veces@superiores@a@las@de@las@celulas@tratadas@con@vehiculo.@ In @ a @ concrete @ example @ are @ detailed @ the @ effects @ of the @ compounds @ problem @ on @ the @ production @ of @ ceramides @ total @ in @ the @ line @ of @ cancer @ of @ lung @ A549 @ after @ 24 @ h @ of @ incubation. @ The @ results @ are @ illustrated in @ the @ Figure @ 4. @ The @ compounds @ that @ produce @ a @ greater @ increase @ of @ the @ @ levels of @ ceramides @ are @ ID2, @ IF2, @ IG2 @ and @ IH2, @ with @ the @ which @ the @ ceramides @ are @ 6 times @ higher than @ the @ of @ the @ cells @ treated @ with @ vehicle. @

@ @

En@otro@ejemplo@concreto@se@detallan@los@efectos@de@los@inhibidores@I-B17,@I-B9@y@I-B2@sobre@el@esfingolipidoma@de@ la@linea@celular@de@cancer@de@prostata@PC-3Mc.@El@contenido@en@esfingolipidos@se@determino@tras@48@h@de@incubacion@con@ los@ inhibidores@ a@ dos@ dosis@ diferentes,@ 1@ M@ o@ 5@ M.@ Se@ determinaron@ niveles@ de@ ceramidas,@ dihidroceramidas,@ In @ another @ concrete @ example @ the @ effects @ of @ the @ inhibitors @ I-B17, @ I-B9 @ and @ I-B2 @ on @ the @ sphingolipidoma @ of the @ cell @ line @ are detailed @ de @ cancer @ de @ prostata @ PC-3Mc. @ The @ content @ in @ sphingolipids @ was determined after 48 hours of incubation with @inhibitors @ a @ two @ different @ doses, @ 1 @ M @ or @ 5 @ M. @ Se @ were determined @ levels @ of @ ceramides, @ dihydroceramides, @

esfingomielinas,@dihidroesfingomielinas@y@glucosilceramidas.@La@Figura@5@ilustra@graficamente@los@cambios@en@los@niveles@ de@los@diferentes@esfingolipidos@tras@incubar@las@celulas@PC-3Mc@con@los@inhibidores.@Los@tratamientos@con@I-B2@causaron,@ tanto@a@1@ M@como@a@5@ M,@una@acumulacion@significativa@de@ceramidas@y@dihidroceramidas.@El@tratamiento@con@I-B17@ tambien@causo@una@acumulacion@de@ceramidas@y@dihidroceramidas,@mas@acusada@en@tratamientos@con@una@concentracion@ del@inhibidor@de@5@ M.@@ sphingomyelins, @ dihydroesfingomyelins @ and @ glucosylceramides. @ Figure @ 5 @ illustrates @ graphically @ changes @ in @ levels @ of @ different @ sphingolipids @ after @ incubating @ cells @ PC-3Mc @ with @ the @ inhibitors. @ The @ treatments @ with @ I-B2 @ caused, @ both @ a @ 1 @ M @ and @ a @ 5 @ M, @ a @ significant @ accumulation @ of @ ceramides @ and @ dihydroceramides. @ The @ treatment @ with @ I-B17 @ also @ cause @ a @ accumulation @ de @ ceramidas @ and @ dihidroceramidas, @ mas @ accused @ in @ treatments @ with @ a @ concentration @ of @ inhibitor @ of @ 5 @ M. @@

@ Ejemplo@3.@Efecto@de@los@inhibidores@sobre@la@viabilidad@celular@ @ Example @ 3. @ Effect @ of @ inhibitors @ on @ cell @ viability @

La@citotoxicidad@se@determino@por@medida@de@la@actividad@deshidrogenasa@mitocondrial@con@el@bromuro@de@3-(4,5dimetiltiazol-2-il)-2,5-difeniltetrazolio@ (MTT)@ despues@ de@ 24-72@ h@ de@ incubacion@ de@ las@ celulas@ con@ los@ compuestos@ problema@a@distintas@concentraciones.@La@Figura@6A@ilustra@el@efecto@de@los@compuestos@problema@sobre@la@viabilidad@de@ las@celulas@de@cancer@de@pulmon@A549@y@de@fibroblastos@dermicos@despues@de@24@h@de@incubacion.@La@Figura@6B@ilustra@ graficamente@los@efectos@de@los@inhibidores@I-B17,@I-B9@y@I-B2@sobre@la@viabilidad@de@las@celulas@PC-3Mc@despues@de@72@h@ de@incubacion.@El@analisis@de@la@curva@generada@con@los@datos@representados@proporciona@unos@valores@de@CC 50 @sobre@las@ celulas@PC-3Mc@de@13,7@ M@para@el@compuesto@I-B17,@de@37,2@ M@para@el@compuesto@I-B9@y@de@mas@de@100@ M@para@el@ compuesto@I-B2.@Es@decir,@la@citotoxicidad@relativa@de@los@tres@compuestos@es,@de@mayor@a@menor,@la@causada@por@I-B17,@ I-B9@y@I-B2.@ @ Ejemplo@4.@Efecto@de@los@inhibidores@sobre@el@crecimiento@celular@sobre@sustrato@plastico.@ The @ cytotoxicity @ was @ determined @ by @ measure @ of @ the activity @ dehydrogenase @ mitochondrial @ with @ the @ bromide @ of @ 3- (4,5dimethylthiazol-2-yl) -2,5-diphenyltetrazolium @ (MTT ) @ after @ 24-72 @ h @ of @ incubation of @ the @ cells @ with @ the @ compounds @ problem @ a @ different @ concentrations. @ The @ Figure @ 6A @ illustrates the @ effect @ of @ the @ compounds @ problem @ on @ the @ viability @ of @ the @ cancer @ cells @ of @ lung @ A549 @ and @ of @ dermal fibroblasts @ after @ 24 @ h @ of @ incubbacion. The @ Figure @ 6B @ illustrates @ graphically @ the @ effects @ of the @ inhibitors @ I-B17, @ I-B9 @ and @ I-B2 @ about @ the @ viability of @ the @ cells @ PC-3Mc @ after @ 72 @ h @ of @ incubbacion. @ The @ analysis @ of the @ curve @ generated @ with @ the @ data @ represented @ provides @ some @ values @ of @ CC fifty @ on @ the @ cells @ PC-3Mc @ of @ 13.7 @ M @ for @ the @ compound @ I-B17, @ of @ 37.2 @ M @ for @ the @ compound @ I-B9 @ and @ @ @ @ @ 100 @ M @ for @ the @ compound @ I-B2. @ That is, @ the @ relative @ cytotoxicity of @ the @ three @ compounds @, @ from @ major @ to @ minor , @ the @ caused by @ I-B17, @ I-B9 @ and @ I-B2. @ @ Example @ 4. @ Effect @ of @ inhibitors @ on @ cell @ growth @ on @ substrate @ plastic.@

Las@celulas@PC-3Mc,@cultivadas@en@medio@con@un@10%@de@suero@fetal@bovino,@fueron@expuestas@a@los@compuestos@ problema,@a@una@concentracion@final@de@5@!M.@Para@realizar@este@ejemplo,@se@sembraron@500@celulas@en@cada@pocillo@de@ placas@de@96@pocillos,@dejandose@adherir@al@plastico@durante@24@h,@seguido@de@tratamiento@con@los@compuestos.@Cada@ tratamiento@se@realizo@en@pocillos@triplicados.@La@Figura@7@ilustra@graficamente@el@efecto@de@las@incubaciones@con@estos@ compuestos@sobre@el@crecimiento@celular,@cuantificado@como@numero@de@celulas@presentes@a@las@24@h,@48@h,@72@h,@120@h,@ 144@h@y@168@h@de@tratamiento@con@los@compuestos.@Los@compuestos@I-B17@y@I-B2@causaron@una@casi@total@inhibicion@del@ crecimiento@de@las@celulas@PC-3Mc@durante@los@primeros@6@dias@de@tratamiento.@Por@el@contrario,@el@compuesto@I-B9@no@ causo@diferencias@significativas@sobre@el@numero@de@celulas@presentes@a@lo@largo@de@los@7@dias@del@tratamiento,@en@ comparacion@con@celulas@control,@expuestas@unicamente@al@disolvente@utilizado@para@los@compuestos.@ @ Ejemplo@5.@Efecto@de@los@inhibidores@sobre@la@formacion@de@colonias@celulares@en@medio@semisolido.@ @ Cells @ PC-3Mc, @ cultured @ in @ medium @ with @ 10% @ of @ fetal @ bovine serum, @ were @ exposed @ to @ problem @ compounds, @ to @ concentration @ final @ of @ 5 @! M. @ To @ perform @ this @ example, @ seeded @ 500 @ cells @ in @ every @ well @ of @ plates @ of @ 96 wells, @ leaving @ adhering @ al @ plastic @ for @ 24 @ h, @ followed @ by @ treatment @ with @ the @ compounds. @ Each @ treatment @ was done @ in @ wells @ triplicates. @ The @ Figure @ 7 @ illustrates @ graphically @ the @ effect @ of @ the @ incubations @ with @ these @ compounds @ on @ cell @ growth, @ quantified @ as @ number @ of @ cells @ present @ at @ 24 @ h, @ 48 @ h, @ 72 @ h, @ 120 @ h, @ 144 @ h @ and @ 168 @ h @ of @ treatment @ with @ the @ compounds. @ The @ compounds @ I-B17 @ and @ I-B2 @ caused @ a @ almost @ total @ growth @ inhibition @ of @ cells @ PC-3Mc @ for @ the first @ 6 @ days @ of treatment. @ On the contrary, @ the @ compound @ I-B9 @ no @ causo @ significant @ differences @ over @ the @ number @ of @ cells @ present @ a @ long @ of @ the @ 7 @ days @ of the treatment, @ in @ comparison @ with @ cells @ control, @ exposed @ only @ al @ dissolve @ used @ for @ the @ compounds. @ @ Example @ 5. @ Effect @ of @ the @ inhibitors @ on @ the @ formation @ of @ cell colonies @ in @ half @ semi-solid.

En@ este@ ejemplo,@ se@ determino@ la@ capacidad@ de@ las@ celulas@ PC-3Mc@ para@ crecer@ formando@ colonias@ tridimensionales@en@semisuspension.@En@el@ensayo@utilizado,@las@celulas@se@resuspenden@a@temperaturas@que@preservan@ la@viabilidad@celular@en@medio@de@cultivo@completo@que@contiene@agar@al@0,6%,@dejando@posteriormente@solidificar@a@ temperatura@ambiente,@sobre@un@lecho@de@medio@con@3%@de@agar.@Las@celulas@sembradas@en@esta@disposicion@se@incuban@ durante@2@o@3@semanas@a@37@°C@en@una@atmosfera@del@5%@de@CO2@/@95%@aire@y@humedad@del@90%.@Una@vez@sembradas,@ se@ afadieron@ los@ compuestos@ problemas@ a@ concentraciones@ finales@ de@ 1@ M@ o@ 5@ M,@ reafadiendolos@ con@ una@ periodicidad@de@3@dias,@coincidiendo@con@la@adicion@de@medio@de@cultivo@nuevo.@Despues@de@3@semanas,@las@colonias@se@ fijan@con@glutardehido@al@0.5%,@se@tifen@con@cristal@de@violeta@y@se@visualizan@al@microscopio.@Las@colonias@de@un@diametro@ mayor@o@igual@que@0.2@mm@se@cuentan@con@el@programa@ImageJ@1.43u@(NIH,@USA).@ In @ this @ example, @ was @ determined @ the @ ability @ of @ the cells @ PC-3Mc @ to @ grow @ forming @ three-dimensional @ colonies @ in @ semisuspension. @ In @ the @ test @ used, @ the @ cells @ se @ resuspenden @ a @ temperatures @ that @ preserve @ cell @ viability @ in @ half @ of @ full @ culture @ containing @ agar @ at @ 0.6%, @ leaving @ later @ solidify @ a @ ambient @ temperature, @ over @ a @ bed @ of @ medium @ with @ 3% @ of @ agar. @ The @ cells @ planted @ in @ this @ disposition @ are @ incubated for @ 2 @ or @ 3 @ weeks @ a @ 37 @ ° C @ in @ an @ atmosphere @ 5% @ of @ CO2 @ / @ 95% @ air @ and @ humidity @ @ 90%. @ Once @ sown @ @ the @ compounds @ problems @ a @ concentrations @ end @ of @ 1 @ M @ o @ 5 @ M, @ reafadiendlos @ with @ a @ periodicity @ of @ 3 @ days, @ coinciding with @ la @ Adding @ of @ medium @ of @ new @ culture. @ After @ 3 @ weeks, @ the @ colonies @ are @ fixed @ with @ 0.5% glutardehyde @ @ @ typhen @ with @ glass @ of @ violet @ and @ are @ visualized @ to the microscope. @ The @ colonies @ of @ a @ diameter @ larger @ or @ equal @ than @ 0.2 @ mm @ are @ counted on @ the @ program @ ImageJ @ 1.43u @ (NIH, @ USA). @

@ @

La@Figura@8@ilustra@como,@a@la@concentracion@de@1@ M,@ninguno@de@los@compuestos@afecto@la@capacidad@de@las@ celulas@PC-3Mc@para@formar@colonias,@mientras@que@a@5@ M,@los@compuestos@I-B17@y@I-B2@inhiben@la@formacion@de@ colonias@por@debajo@de@un@25%@respecto@al@control.@@ @ Ejemplo@6.@Efecto@de@los@inhibidores@sobre@la@invasividad@celular.@ The @ Figure @ 8 @ illustrates @ how, @ a @ la @ concentracion @ de @ 1 @ M, @ none @ of @ the @ compounds @ affection @ the @ ability @ of @ the @ cells @ PC-3Mc @ to @ form @ colonies, @ while @ that @ a @ 5 @ M, @ the @ compounds @ I -B17 @ and @ I-B2 @ inhibit @ the @ formation @ of @ colonies @ by @ below @ of @ 25% @ with respect to @ the control. @@ @ Example @ 6. @ Effect @ of @ the @ @ inhibitors on @ cell @ invasiveness @

En@la@realizacion@de@este@ejemplo,@se@utilizo@el@ensayo@conocido@como@de@invasividad@en@camaras@de@Boyden.@La@ version@comercial@que@se@ha@usado@de@estas@camaras@se@llama@Transwell@(de@la@casa@Corning),@y@consiste@en@membranas@ relativamente@inertes@de@poliester,@con@poros@de@8.0@ m,@colocadas@en@un@soporte@plastico@que@se@inserta@en@pocillos@de@ placas@de@96@pocillos.@Estas@membranas@se@recubren@con@componentes@de@la@matriz@extracelular@(Matrigel@Growth@Factor@ Reduced,@de@la@casa@Becton-Dickinson).@Las@celulas@se@depositan@con@medio@carente@de@suero@fetal@bovino@en@la@camara@ superior,@y@en@la@camara@inferior@(el@pocillo@de@la@placa@de@96@pocillos)@se@coloca@el@mismo@medio.@Se@permite@la@invasion@ de@las@celulas@desde@la@camara@superior@hacia@la@camara@inferior@durante@48@h@en@las@condiciones@habituales@de@cultivo@ descritas@en@anteriores@ejemplos.@Al@cabo@de@esa@incubacion,@se@procede@al@recuento@de@las@celulas@que@han@pasado@a@la@ camara@inferior.@ In @ the @ realization @ of @ this @ example, @ was @ used @ the @ essay @ known @ as @ of @ invasivity @ in @ cameras @ of Boyden. @ The @ commercial @ version @ that @ was @ ha @ used @ from @ these @ camaras @ is @ called @ Transwell @ (from @ la @ casa @ Corning), @ and @ consists of @ membranes @ relatively @ inert @ of @ polyester, @ with @ pores @ of @ 8.0 @ m, @ placed @ in @ a @ plastic @ bracket @ that @ is inserted into @ wells of @ plates @ of @ 96 @ wells. @ These @ membranes @ are @ coated with @ components @ of @ the @ extracellular @ matrix (Matrigel @ Growth @ Factor @ Reduced, @ of @ the @ house @ Becton-Dickinson). @ The @ cells @ are @ deposited @ with @ half @ carente @ of @ serum @ fetal @ bovine @ in @ the @ upper @ chamber, @ and @ in @ the @ lower @ chamber @ (the @ well @ of @ the @ plate @ of @ 96 @ wells ) @ is @ placed @ the @ same @ middle. @ It @ is allowed @ the @ invasion @ of @ the @ cells @ from @ the @ upper @ camera @ towards @ the @ lower @ camera @ during @ 48 @ h @ in @ the @ usual @ conditions @ of @ culture @ described @ in @ previous @ examples. @ After @ that @ incubation, @ proceeds @ to @ count @ of @ the @ cells @ that @ have @ passed @ to @ the @ lower @ camera. @

@ @

Para@la@realizacion@de@este@ejemplo,@las@celulas@PC-3Mc@fueron@tratadas@con@los@compuestos@problema@a@una@ concentracion@final@de@5@ M@durante@las@48@h@previas@al@ensayo@de@invasividad.@Tras@ese@tiempo@de@tratamiento,@las@ celulas@fueron@despegadas@de@las@placas@de@cultivo@mediante@incubacion@con@tripisina@(25@unidades@/@mL)@y@EDTA@(0.1@ mM)@durante@5@minutos,@resuspendidas@en@medio@completo,@y@sembradas@sobre@las@camaras@superiores@de@los@insertos@ Transwell@ previamente@ cubiertos@ con@ Matrigel@ a@ una@ concentracion@ de@ 10@ mg/mL.@ Los@ compuestos@ problema@ se@ afadieron@tanto@a@la@camara@superior@como@a@la@inferior,@a@una@concentracion@de@5@mM,@manteniendose@este@tratamiento@ a@lo@largo@de@todo@el@periodo@de@duracion@del@ensayo.@Cada@condicion@se@realizo@por@triplicado.@La@Figura@9@ilustra@como,@ en@estas@condiciones,@tanto@el@I-B17@como@el@I-B2@inhiben@significativamente@la@invasividad@de@las@celulas@PC-3Mc.@@ For @ the @ realization @ of this example, @ the @ cells @ PC-3Mc @ were @ treated @ with @ the @ compounds @ problem @ a @ a @ @ final @ de @ 5 @ M @ concentration during @ the @ 48 @ h @ previous @ the @ trial @ of @ invasiveness. @ After @ that @ time @ of treatment, @ the @ cells @ were @ taken off @ of @ @ culture @ plates @ by @ incubation @ with @ tripisin @ (25 @ units @ / @ mL) @ and @ EDTA @ (0.1 @ mM) @ for @ 5 @ minutes, @ resuspended @ in @ half @ full , @ and @ seeded @ over @ the @ superior cameras @ of @ the @ Transwell @ inserts @ previously @ covered @ with @ Matrigel @ a @ a @ concentration @ of @ 10 @ mg / mL. @ The @ compounds @ problem @ @ @ added @ both @ the @ upper @ camera @ and @ the @ lower @, @ a @ a concentration of @ 5 @ mM, @ staying @ this @ treatment @ the @ long @ of @ all @ the @ period @ of @ duration @ of the essay. @ Each @ condition @ was done @ by @ triplicate. @ Figure @ 9 @ illustrates how, @ in @ these @ conditions, @ both @ the @ I-B17 @ as @ the @ I-B2 @ significantly @ inhibit @ the @ invasiveness @ of @ the @ cells @ PC-3Mc. @@

Claims (3)

REIVINDICACIONES 1.-@Un@compuesto@de@formula@(I)@@ 1 .- @ A @ compound @ of @ formula @ (I) @@ @ @ 5 @ 5 @ Formula@(I)@ @ o@un@estereoisomero,@una@sal@o@un@solvato@farmaceuticamente@aceptable@de@este,@ @@ Formula @ (I) @ @ o @ un @ stereoisomero, @ una @ sal @ o @ un @ solvato @ pharmaceutically @ acceptable @ from @ este, @ @@ 10 donde:@@ A@se@selecciona@entre@-CH(OH)-@y@-C(=O)-,@ Z@se@selecciona@entre@H@y@OH,@ n@es@un@numero@entero@seleccionado@entre@0@y@1,@ R1@se@selecciona@entre@alquilo(C1-C30),@alquenilo(C2-C30)@y@alquinilo(C2-C30),@10 where: @@ A @ se @ is selected @ from @ -CH (OH) - @ and @ -C (= O) -, @ Z @ is @ selected @ between @ H @ and @ OH, @ n @ es @ a @ integer @ number @ selected @ between @ 0 @ and @ 1, @ R1 @ is @ selected @ from @ alkyl (C1-C30), @ alkenyl (C2-C30) @ and @ alkynyl (C2-C30), @ 15 B@se@selecciona@entre@-H,@-N3@y@-C:CH,@ R2@se@selecciona@entre@-NHR3@y@maleimida,@donde@@ R3@se@selecciona@entre@-COR4,@-COCOR4@y@-SO2R4,@donde@@ R4@se@selecciona@entre@alquilo(C1-C16),@alquenilo(C2-C16),@alquinilo(C2-C16),@epoxido@y@aziridina;@ @ 15 B @ se @ is selected @ from @ -H, @ - N3 @ and @ -C: CH, @ R2 @ is @ selected @ between @ -NHR3 @ and @ maleimida, @ where @@ R3 @ is @ selected @ between @ -COR4, @ - COCOR4 @ and @ -SO2R4, @ where @@ R4 @ is @ selected @ from @ alkyl (C1-C16), @ alkenyl (C2-C16), @ alkynyl (C2-C16), @ epoxide @ and @ aziridine; @ @ 20 donde@los@grupos@alquilo,@alquenilo@o@alquinilo@de@R1@y@R4@pueden@estar,@independientemente,@opcionalmente@ sustituidos@por@uno@o@varios@sustituyentes@elegidos@independientemente@entre@halogeno,@OH,@OR,@OCF3,@NH2,@NO2,@ NRR',@NHCOR;@CONRR ',@COOH,@COOR,@OCOR@y@CN,@@donde@R@y@R'@son@alquilo@o@alquenilo@@ @ con@la@condicion@de@que@ 20 where @ the @ alkyl @ groups, @ alkenyl @ or @ alkynyl @ of @ R1 @ and @ R4 @ can @ be, @ independently, @ optionally @ substituted @ by @ one @ or @ several @ substituents @ chosen @ independently @ enter @ halogen, @ OH, @ OR, @ OCF3, @ NH2, @ NO2, @ NRR ', @ NHCOR; @CONRR', @ COOH, @ COOR, @ OCOR @ and @ CN, @@ where @ R @ y @ R '@ are @ alkyl @ or @ alquenilo @@ @ with @ la @ condition @ de @ que @ 25 a)@cuando@A@es@-CH(OH)@y@B@es@H,@R3@es@diferente@de@-COR4@siendo@R4@alquilo(C1-C16)@sin@sustituir@o@sustituido@ por@halogeno@o@hidroxilo;@ b)@cuando@A@es@-CH(OH),@B@es@H,y@R3@es@-COCOR4@siendo@R4@alquilo(C6),@R1@es@diferente@de@-CH=CH2-alquilo(C12),@-C:CH-alquilo(C12)@@o@@alquilo(C13-C15);@o@ c)@cuando@A@es@-C(=O),@R1@es@alquenilo(C2-C30),@B@es@H@y@n@es@0,@R3@es@diferente@de@@-COR4@siendo@R4@ 25 a) @ when @ A @ is @ -CH (OH) @ and @ B @ is @ H, @ R3 @ is @ different @ from @ -COR4 @ being @ R4 @ alkyl (C1-C16) @ without @ replacing @ or @ substituted @ by @ halogen @ or @ hydroxyl; @ b) @ when @ A @ is @ -CH (OH), @ B @ is @ H, and @ R3 @ is @ -COCOR4 @ being @ R4 @ alkyl (C6), @ R1 @ is @ different @ from @ -CH = CH2-alkyl (C12), @ - C: CH-alkyl (C12) @@ or @@ alkyl (C13-C15); @ o @ c) @ when @ A @ is @ -C (= O), @ R1 @ is @ alkenyl (C2-C30), @ B @ is @ H @ and @ n @ is @ 0, @ R3 @ is @ different @ from @ @ -COR4 @ being @ R4 @ 30 alquilo(C1-C16).@ @ 2.-@Un@compuesto@de@formula@(I)@segun@la@reivindicacion@1,@caracterizado@porque@R1@se@selecciona@entre@alquilo(C1-C30)@y@ alquenilo(C2-C30)@ @ 30 alkyl (C1-C16). @ @ 2 .- @ A @ compound @ of @ formula @ (I) @ according to @ claim @ 1, @ characterized @ because @ R1 @ is @ selected @ from @ alkyl (C1 -C30) @ and @ alkenyl (C2-C30) @ @ 35 3.-@Un@compuesto@de@formula@(I)@segun@una@cualquiera@de@las@reivindicaciones@1@o@2,@caracterizado@porque@n@es@0.@ @ 4.-@Un@compuesto@de@formula@(I)@segun@una@cualquiera@de@las@reivindicaciones@@1@a@3,@caracterizado@porque@R3@es@-CO-R4@ siendo@R4@alquilo(C1-C16),@y@B@se@selecciona@entre@-N3@y@-C:CH.@ @ 35 3 .- @ A @ compound @ of @ formula @ (I) @ according to any @ of @ the @ claims @ 1 @ or @ 2, @ characterized @ because @ n @ is @ 0. @ @ 4. - @ A @ compound @ of @ formula @ (I) @ according to any @ of @ the @ claims @@ 1 @ a @ 3, @ characterized @ because @ R3 @ is @ -CO-R4 @ being @ R4 @alkyl (C1-C16), @ and @ B @ is @ selected @ between @ -N3 @ and @ -C: CH. @ @ 40 5.-@Un@compuesto@de@formula@(I)@segun@la@reivindicacion@4,@caracterizado@porque@R4@es@un@alquilo(C1-C16)@sustituido@con@ al@menos@un@atomo@de@halogeno.@ @ 6.-@Un@compuesto@de@formula@(I)@segun@la@reivindicacion@5,@caracterizado@porque@R4@es@un@alquilo(C1-C16)@sustituido@con@ al@menos@un@atomo@de@fluor@o@bromo.@ 40 5 .- @ A @ compound @ of @ formula @ (I) @ according to the @ claim @ 4, @ characterized @ because @ R4 @ is @ an @ alkyl (C1-C16) @ substituted @ with @ at least @ an @ atom @ of @ halogeno. @ @ 6 .- @ A @ compound @ of @ formula @ (I) @ according to the @ claim @ 5, @ characterized @ because @ R4 @ is @ an @ alkyl (C1- C16) @ substituted @ with @ at least @ an @ atom @ of @ fluor @ or @ bromo. @ 45 @ 7.-@Un@compuesto@de@formula@(I)@segun@una@cualquiera@de@las@reivindicaciones@4@a@6,@caracterizado@porque@A@es@-C(=O).@ @ 8.-@Un@compuesto@de@formula@(I)@segun@una@cualquiera@de@las@reivindicaciones@1@a@3@,@caracterizado@porque@R3@es@-CO-R4@ siendo@R4@epoxido.@ 45 @ 7 .- @ A @ compound @ of @ formula @ (I) @ according to any @ of @ the @ claims @ 4 @ a @ 6, @ characterized @ because @ A @ is @ -C (= O ). @ @ 8 .- @ A @ compound @ of @ formula @ (I) @ according to any @ of @ the @ claims @ 1 @ a @ 3 @, @ characterized @ because @ R3 @ is @ -CO -R4 @ being @ R4 @ epoxide. @ 50 @ 9.-@Un@compuesto@de@formula@(I)@segun@una@cualquiera@de@las@reivindicaciones@1@o@2,@caracterizado@porque@R3@es@-CO-R4@ siendo@R4@epoxido,@n@es@1@y@Z@es@OH.@ @ 10.-@Un@compuesto@de@formula@(I)@segun@una@cualquiera@de@las@reivindicaciones@@1@a@3,@caracterizado@porque@R3@es@-CO50 @ 9 .- @ A @ compound @ of @ formula @ (I) @ according to @ any @ of @ the @ claims @ 1 @ or @ 2, @ characterized @ because @ R3 @ is @ -CO-R4 @ being @ R4 @ epoxide, @ n @ is @ 1 @ and @ Z @ is @ OH. @ @ 10 .- @ A @ compound @ of @ formula @ (I) @ according to any one of @ the @ claims @@ 1 @ a @ 3, @ characterized @ because @ R3 @ is @ -CO 55 R4@y@R4@se@selecciona@entre@alquenilo(C2-C16)@y@alquinilo(C2-C16).@ @ 11.-@Un@compuesto@de@formula@(I)@segun@la@reivindicacion@10,@caracterizado@porque@R4@es@un@alquenilo(C2-C16)@sustituido@ con@al@menos@un@atomo@de@halogeno.@ 55 R4 @ and @ R4 @ is @ selected @ from @ alkenyl (C2-C16) @ and @ alkynyl (C2-C16). @ @ 11 .- @ A @ compound @ of @ formula @ (I) @ according to @ claim @ 10, @ characterized @ because @ R4 @ is @ an @ alkenyl (C2-C16) @ substituted @ with @ at least @ an @ halogen @ atom. 12.-@Un@compuesto@de@formula@(I)@segun@la@reivindicacion@11,@caracterizado@porque@R4@es@un@alquenilo(C2-C16)@sustituido@ con@al@menos@un@atomo@de@fluor@o@bromo.@ @ 13.-@Un@compuesto@de@formula@(I)@segun@una@cualquiera@de@las@reivindicaciones@10@a@12,@caracterizado@porque@R4@es@un@ alquenilo(C2-C16)@o@alquinilo(C2-C16)@sustituido@con@al@menos@un@grupo@-CHO@o@-@COOH.@ @ 14.-@Un@compuesto@de@formula@(I)@segun@una@cualquiera@de@las@reivindicaciones@@1@a@3,@caracterizado@porque@R3@es@-CO- CO-R4@siendo@R4@alquilo(C1-C16)@y@B@se@selecciona@entre@-N3@y@-C:CH.@ @ 15.-@Un@compuesto@de@formula@(I)@segun@una@cualquiera@de@las@reivindicaciones@@1@a@3,@caracterizado@porque@R3@es@-SO2R4,@donde@R4@se@selecciona@entre@alquilo(C1-C16),@alquenilo(C2-C16),@alquinilo(C2-C16),@epoxido@y@aziridina.@ @ 16.-@Un@compuesto@de@formula@(I)@segun@la@reivindicacion@15,@caracterizado@porque@R4@es@alquilo(C1-C16).@ @ 17.-@Un@compuesto@de@formula@(I)@segun@una@cualquiera@de@las@reivindicaciones@@1@a@2,@caracterizado@porque@R3@es@-SO2R4,@donde@R4@se@selecciona@entre@alquilo(C1-C16),@alquenilo(C2-C16),@alquinilo(C2-C16),@epoxido@y@aziridina,@n@es@1@y@Z@es@ OH.@ @ 18.-@Un@compuesto@de@formula@(I)@segun@la@reivindicacion@17,@caracterizado@porque@R4@es@alquilo(C1-C16).@ @ 19.-@Un@compuesto@de@formula@(I)@segun@una@cualquiera@de@las@reivindicaciones@@1@a@3,@caracterizado@porque@R2@es@ maleimida.@ @ 20.-@Un@compuesto@de@formula@(I)@segun@una@cualquiera@de@las@reivindicaciones@@1@a@3,@caracterizado@porque@dicho@ compuesto@se@selecciona@de@la@lista@que@consiste@en:@ 1-[(2S,3R)-1,3-dihidroxioctadecan-2-il]-1H-pirrol-2,5-diona,@ N-[(2S,3R,E)-1,3-dihidroxioctadec-4-en-2-il]etanosulfonamida,@ N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]etanosulfonamida,@ N-[(2S,3R)-1,3-dihidroxioctadec-17-in-2-il]etanosulfonamida,@ N-[(2S,3R)-14-azido-1,3-dihidroxitetradecan-2-il)etanosulfonamida,@ 2-bromo-N-[(2S,3R)-1,3-dihidroxioctadec-17-in-2-il]acetamida,@ N-[(2S,3R)-14-azido-1,3-dihidroxitetradecan-2-il]bromoacetamida,@ N-[(2S,3R,E)-14-azido-1,3-dihidroxitetradec-4-en-2-il]bromoacetamida,@ 2-bromo-N-[(2S,3R,E)-1,3-dihidroxioctadec-4-en-17-in-2-il]acetamida,@ (S)-N-(14-azido-1-hidroxi-3-oxotetradecan-2-il)-2-bromoacetamida,@ (RS)-N-[(2S,3R,E)-1,3-dihidroxioctadec-4-en-2-il]oxirano-2-carboxamida,@ (RS)-N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]oxirano-2-carboxamida,@ @(RS)-N-[(2S,3R,E)-1,3-dihidroxioctadec-4-en-17-in-2-il]oxirano-2-carboxamida,@ (RS)-N-[(2S,3R)-14-azido-1,3-dihidroxitetradecan-2-il]oxirano-2-carboxamida,@ N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]propiolamida,@ N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]but-2-inamida,@ N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]acrilamida,@ (E)-N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]-2-butenamida,@ N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]metacrilamida,@ N-[(2S,3R)-N-1,3-dihidroxyoctadecan-2-il]-3-metil-2-butenamida,@ (2E,4E)-N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]hexa-2,4-dienamida,@ Acido@(E)-4-[(2S,3R)-1,3-dihidroxioctadecan-2-ilamino]-4-oxo-2-butenoico,@ (Z)-2,3-dibromo-N-[(2S,3R)-1,3-dihidroxioctadecan-2-il]-4-oxo-2-butenamida,@ (2S,3R)-2-(bromometil)-N-(1,3-dihidroxioctadecan-2-il)acrilamida,@ (E,2S,3R)-N-(1,3-dihidroxi-2-octadecil)-2-metil-2-butenamida,@ (2S,3R)-N-(1,3-dihidroxi-17-octadecin-2-il)-2-oxooctanamida@y@ (2S,3R)-N-(14-azido-1,3-dihidroxi-2-tetradecil)-2-oxooctanamida,@ o@un@estereoisomero,@una@sal@o@un@solvato@farmaceuticamente@aceptable@de@uno@de@estos@compuestos.@ @ 21.-@Un@compuesto@de@formula@(I)@segun@la@reivindicacion@20,@caracterizado@porque@dicho@compuesto@se@selecciona@de@la@ lista@que@consiste@en:@ 2-bromo-N-[(2S,3R)-1,3-dihidroxioctadec-17-in-2-il]acetamida,@ N-[(2S,3R)-14-azido-1,3-dihidroxitetradecan-2-il]bromoacetamida,@ N-[(2S,3R,E)-14-azido-1,3-dihidroxitetradec-4-en-2-il]bromoacetamida,@ 2-bromo-N-[(2S,3R,E)-1,3-dihidroxioctadec-4-en-17-in-2-il]acetamida@y@ (S)-N-(14-azido-1-hidroxi-3-oxotetradecan-2-il)-2-bromoacetamida,@ o@un@estereoisomero,@una@sal@o@un@solvato@farmaceuticamente@aceptable@de@uno@de@estos@compuestos.@ @ 22.-@Un@compuesto@de@formula@(I)@segun@una@cualquiera@de@las@reivindicaciones@@1@a@2,@caracterizado@porque@dicho@ compuesto@se@selecciona@de@la@lista@que@consiste@en:@ 12 .- @ A @ compound @ of @ formula @ (I) @ according to the @ claim @ 11, @ characterized @ because @ R4 @ is @ an @ alkenyl (C2-C16) @ replaced @ with @ at least @ an @ atom @ of @ fluor @ or @ bromo. @ @ 13 .- @ A @ compound @ of @ formula @ (I) @ according to any one of @ the @ claims @ 10 @ to @ 12, @ characterized @ because @ R4 @ is @ a @ alkenyl (C2-C16) @ or @ alkynyl (C2-C16) @ substituted @ with @ at least @ a @ group @ -CHO @ or @ - @ COOH. @ @ 14 .- @ A @ compound @ of @ formula @ (I) @ according to any @ of @ the @ claims @@ 1 @ a @ 3, @ characterized @ because @ R3 @ is @ -CO- CO-R4 @ being @ R4 @ alkyl (C1-C16) @ and @ B @ is @ selected @ between @ -N3 @ and @ -C: CH. @ @ 15 .- @ A @ compound @ of @ formula @ (I) @ according to any @ of @ the @ claims @@ 1 @ a @ 3, @ characterized @ because @ R3 @ is @ -SO2R4, @ where @ R4 @ is @ selected @ from @ alkyl (C1-C16), @ alkenyl (C2-C16), @ alkynyl (C2-C16), @ epoxide @ and @ aziridine. @ @ 16 .- @ A @ compound @ of @ formula @ (I) @ according to @ claim @ 15, @ characterized @ because @ R4 @ is @ alkyl (C1-C16). @ @ 17 .- @ A @ compound @ of @ formula @ (I) @ according to any @ of @ the @ claims @@ 1 @ a @ 2, @ characterized @ because @ R3 @ is @ -SO2R4, @ where @ R4 @ is @ selected @ from @ alkyl (C1-C16), @ alkenyl (C2-C16), @ alkynyl (C2-C16), @ epoxide @ and @ aziridine, @ n @ is @ 1 @ and @ Z @ en @ OH. @ @ 18 .- @ A @ compound @ of @ formula @ (I) @ according to @ claim @ 17, @ characterized @ because @ R4 @ is @ alkyl (C1-C16). @ @ 19 .- @ A @ compound @ of @ formula @ (I) @ according to any one of @ the @ claims @@ 1 @ a @ 3, @ characterized @ because @ R2 @ is @ maleimida. @ @ 20 .- @ A @ compound @ of @ formula @ (I) @ according to any one of @ the @ claims @@ 1 @ a @ 3, @ characterized @ because @ said @ composed @ is @ selected @ from @ the @ list @ that @ consists of: @ 1 - [(2S, 3R) -1,3-dihydroxyoctadecan-2-yl] -1H-pyrrole-2,5-dione, @ N - [(2S, 3R, E) -1,3-dihydroxyoctadec-4-en-2-yl] ethanesulfonamide, @ N - [(2S, 3R) -1,3-dihydroxyoctadecan-2-yl] ethanesulfonamide, @ N - [(2S, 3R) -1,3-dihydroxyoctadec-17-in-2-yl] ethanesulfonamide, @ N - [(2S, 3R) -14-azido-1,3-dihydroxytetradecan-2-yl) ethanesulfonamide, @ 2-Bromo-N - [(2S, 3R) -1,3-dihydroxyoctadec-17-in-2-yl] acetamide, @ N - [(2S, 3R) -14-azido-1,3-dihydroxytetradecan-2-yl] bromoacetamide, @ N - [(2S, 3R, E) -14-azido-1,3-dihydroxytetradec-4-en-2-yl] bromoacetamide, @ 2-Bromo-N - [(2S, 3R, E) -1,3-dihydroxyoctadec-4-en-17-in-2-yl] acetamide, @ (S) -N- (14-azido-1-hydroxy-3-oxotetradecan-2-yl) -2-bromoacetamide, @ (RS) -N - [(2S, 3R, E) -1,3-dihydroxyoctadec-4-en-2-yl] oxirane-2-carboxamide, @ (RS) -N - [(2S, 3R) -1,3-dihydroxyoctadecan-2-yl] oxirane-2-carboxamide, @ @ (RS) -N - [(2S, 3R, E) -1,3-dihydroxyoctadec-4-en-17-in-2-yl] oxirane-2-carboxamide, @ (RS) -N - [(2S, 3R) -14-azido-1,3-dihydroxytetradecan-2-yl] oxirane-2-carboxamide, @ N - [(2S, 3R) -1,3-dihydroxyoctadecan-2-yl] propiolamide, @ N - [(2S, 3R) -1,3-dihydroxyoctadecan-2-yl] but-2-inamide, @ N - [(2S, 3R) -1,3-dihydroxyoctadecan-2-yl] acrylamide, @ (E) -N - [(2S, 3R) -1,3-dihydroxyoctadecan-2-yl] -2-butenamide, @ N - [(2S, 3R) -1,3-dihydroxyoctadecan-2-yl] methacrylamide, @ N - [(2S, 3R) -N-1,3-dihydroxyoctadecan-2-yl] -3-methyl-2-butenamide, @ (2E, 4E) -N - [(2S, 3R) -1,3-dihydroxyoctadecan-2-yl] hexa-2,4-dienamide, @ @ (E) -4 - [(2S, 3R) -1,3-dihydroxyoctadecan-2-ylamino] -4-oxo-2-butenoic acid, @ (Z) -2,3-dibromo-N - [(2S, 3R) -1,3-dihydroxyoctadecan-2-yl] -4-oxo-2-butenamide, @ (2S, 3R) -2- (bromomethyl) -N- (1,3-dihydroxyoctadecan-2-yl) acrylamide, @ (E, 2S, 3R) -N- (1,3-dihydroxy-2-octadecyl) -2-methyl-2-butenamide, @ (2S, 3R) -N- (1,3-dihydroxy-17-octadecin-2-yl) -2-oxooctanamide @ and @ (2S, 3R) -N- (14-azido-1,3-dihydroxy-2-tetradecyl) -2-oxooctanamide, @ o @ a @ stereoisomer, @ a @ salt @ or @ a @ pharmaceutically @ acceptable solvate of one of these compounds. @ 21 .- @ A @ compound @ of @ formula @ (I) @ according to @ claim @ 20, @ characterized @ because @ said @ compound @ is @ selected @ from @ la @ list @ that @ consists of: @ 2-Bromo-N - [(2S, 3R) -1,3-dihydroxyoctadec-17-in-2-yl] acetamide, @ N - [(2S, 3R) -14-azido-1,3-dihydroxytetradecan-2-yl] bromoacetamide, @ N - [(2S, 3R, E) -14-azido-1,3-dihydroxytetradec-4-en-2-yl] bromoacetamide, @ 2-Bromo-N - [(2S, 3R, E) -1,3-dihydroxioctadec-4-en-17-in-2-yl] acetamide @ y @ (S) -N- (14-azido-1-hydroxy-3-oxotetradecan-2-yl) -2-bromoacetamide, @ o @ a @ stereoisomer, @ a @ salt @ or @ a @ pharmaceutically @ acceptable solvate of one of these compounds. @ 22 .- @ A @ compound @ of @ formula @ (I) @ according to any one of @ the @ claims @@ 1 @ a @ 2, @ characterized @ because @ said @ composed @ is @ selected @ from @ the @ list @ that @ consists of: @ N-[(2S,3S,4R)-1,3,4-trihidroxioctadecan-2-il]etanosulfonamida@y@ (RS)-N-[(2S,3S,4R)-1,3,4-trihidroxioctadecan-2-il]oxirano-2-carboxamida,@ o@un@estereoisomero,@una@sal@o@un@solvato@farmaceuticamente@aceptable@de@uno@de@estos@compuestos.@ @ 23.-@Composicion@farmaceutica@que@comprende@un@compuesto@de@formula@general@(I)@o@un@estereoisomero,@una@sal@o@un@ solvato@farmaceuticamente@aceptable@de@este@tal@como@se@ha@definido@en@una@cualquiera@de@las@reivindicaciones@1@a@22,@y@ al@menos@un@excipiente@farmaceuticamente@aceptable.@ @ 24.-@Un@compuesto@de@formula@general@(I)@tal@como@se@ha@definido@en@una@cualquiera@de@las@reivindicaciones@1@a@22@o@un@ compuesto@ elegido@ entre@ 2,2-dibromo-N-((2S,3R)-1,3-dihidroxioctadecan-2-il)acetamida@ y@ 2-bromo-N-((2S,3R)-1,3dihidroxioctadecan-2-il)acetamida@o@un@estereoisomero,@una@sal@o@un@solvato@farmaceuticamente@aceptable@de@uno@de@ estos@compuestos,@para@utilizar@en@el@tratamiento@o@prevencion@de@una@enfermedad@que@cursa@con@hiperproliferacion@ celular.@ @ 25.-@Una@composicion@tal@como@se@define@en@la@reivindicacion@23@o@una@composicion@que@comprende@un@compuesto@ elegido@ entre@ 2,2-dibromo-N-((2S,3R)-1,3-dihidroxioctadecan-2-il)acetamida@ y@ 2-bromo-N-((2S,3R)-1,3dihidroxioctadecan-2-il)acetamida@o@un@estereoisomero,@una@sal@o@un@solvato@farmaceuticamente@aceptable@de@uno@de@ estos@compuestos@y@al@menos@un@excipiente,@para@utilizar@en@el@tratamiento@o@prevencion@de@una@enfermedad@que@cursa@ con@hiperproliferacion@celular.@ @@ 26.-@ Un@ compuesto@ segun@ la@ reivindicacion@ 24@ o@ una@ composicion@ segun@ la@ reivindicacion@ 25,@ para@ utilizar@ en@ el@ tratamiento@o@prevencion@de@una@enfermedad@cursada@con@hiperproliferacion@celular@elegida@entre@cancer,@metastasis,@ inflamacion,@asma@y@arteriosclerosis.@@ @ 27.-@Un@compuesto@o@una@composicion@segun@la@reivindicacion@26,@para@utilizar@en@el@tratamiento@de@un@tipo@de@cancer@ elegido@entre@cancer@de@prostata,@de@pancreas,@de@cerebro,@de@colon,@de@pulmon,@de@mama,@de@cabeza@y@cuello,@de@ ovario,@de@laringe,@de@vejiga@urinaria,@de@utero,@de@piel,@sarcomas,@linfomas@y@leucemia.@ @ 28.-@Un@compuesto@o@una@composicion@segun@la@reivindicacion@27,@para@utilizar@en@el@tratamiento@de@un@tipo@de@cancer@ elegido@entre@cancer@de@prostata@y@cancer@de@pulmon.@ @ 29.-@Un@compuesto@de@formula@general@(I)@tal@como@se@ha@definido@en@una@cualquiera@de@las@reivindicaciones@1@a@22@o@un@ compuesto@ elegido@ entre@ 2,2-dibromo-N-((2S,3R)-1,3-dihidroxioctadecan-2-il)acetamida@ y@ 2-bromo-N-((2S,3R)-1,3dihidroxioctadecan-2-il)acetamida@o@un@estereoisomero,@una@sal@o@un@solvato@farmaceuticamente@aceptable@de@uno@de@ estos@compuestos,@para@utilizar@en@combinacion@con@otra@terapia@para@el@tratamiento@de@una@enfermedad@tal@como@se@ define@en@una@cualquiera@de@las@reivindicaciones@24,@26@a@28.@@ @ 30.-@Una@composicion@tal@como@se@define@en@la@reivindicacion@23@o@una@composicion@que@comprende@un@compuesto@ elegido@ entre@ 2,2-dibromo-N-((2S,3R)-1,3-dihidroxioctadecan-2-il)acetamida@ y@ 2-bromo-N-((2S,3R)-1,3dihidroxioctadecan-2-il)acetamida@o@un@estereoisomero,@una@sal@o@un@solvato@farmaceuticamente@aceptable@de@uno@de@ estos@compuestos@al@menos@un@excipiente,@para@utilizar@en@combinacion@con@otra@terapia@para@el@tratamiento@de@una@ enfermedad@tal@como@se@define@en@una@cualquiera@de@las@reivindicaciones@25,@26@a@28.@ N - [(2S, 3S, 4R) -1,3,4-trihydroxyoctadecan-2-yl] ethanesulfonamide @ and @ (RS) -N - [(2S, 3S, 4R) -1,3,4-trihydroxyoctadecan-2-yl] oxirane-2-carboxamide, @ o @ a @ stereoisomer, @ a @ salt @ or @ a @ pharmaceutically @ acceptable solvate of one of these compounds. @ 23 .- @ Composition @ pharmaceutical @ that @ comprises @ a @ compound @ of @ formula @ general @ (I) @ or @ a @ stereoisomer, @ a @ salt @ or @ a @ solvato @ pharmaceutically @ acceptable @ from @ east @ as @ is @ defined @ in @ any @ of @ the @ claims @ 1 @ a @ 22, @ and @ at least @ a @ pharmaceutically @ acceptable excipient. @ @ 24 .- @ A @ compound @ of @ formula @ general @ (I) @ as @ has @ been @ defined @ in @ any @ of @ the @ claims @ 1 @ a @ 22 @ or @ un @ compound @ chosen @ between @ 2,2-dibromo-N - ((2S, 3R) -1,3-dihydroxioctadecan-2-yl) acetamide @ and @ 2-bromo-N - ((2S, 3R) -1, 3dihydroxioctadecan-2-il) acetamide @ o @ a @ stereoisomer, @ a @ salt @ or @ a pharmaceutically @ acceptable @ solvate @ of @ one @ of @ these @ compounds, @ to @ use @ in @ the @ treatment @ or @ prevention @ of @ a @ disease @ that @ courses @ with @ hyperproliferation @ mobile.@ @ 25 .- @ A @ composition @ as @ is @ defined @ in @ the @ claim @ 23 @ or @ a @ composition @ that @ comprises @ a @ compound @ chosen @ from @ 2,2-dibromo-N - ((2S, 3R) -1,3-dihydroxioctadecan-2-yl) acetamide @ and @ 2-bromo-N - ((2S, 3R) -1,3 dihydroxioctadecan- 2-il) acetamide @ o @ un @ stereoisomero, @ una @ sal @ o @ un @ solvato @ pharmaceutically @ acceptable @ of @ uno @ de @ these @ compounds @ and @ at least @ an @ excipient, @ to @ use @ in @ the @ treatment @ or @ prevention @ of @ a @ disease @ that @ course @ with @ hyperproliferacion @ cell. @ @@ 26 .- @ A @ composite @ according to the @ claim @ 24 @ or @ a @ composition @ according to the @ claim @ 25, @ to @ use @ in @ the @ treatment @ or @ prevention @ of @ a disease @ studied @ with @ hyperproliferation @ cell @ chosen @ among @ cancer, @ metastasis, @ inflammation, @ asthma @ and @ arteriosclerosis. @@ @ 27 .- @ A @ composite @ or @ a @ composition @ according to the @ claim @ 26, @ to @ use @ in @ the @ treatment @ a @ type @ of @ cancer @ chosen @ among @ cancer @ of @ prostate, @ of @ pancreas, @ of @ brain, @ of @ colon, @ of @ lung, @ of @ breast, @ of @ head @ and @ neck, @ of @ ovary, @ of @ larynx, @ of @ urinary bladder, @ of @ utero, @ of @ skin, @ sarcomas, @ lymphomas @ and @ leukemia. @ @ 28 .- @ A @ composite @ or @ a @ composition @ according to the @ claim @ 27, @ to be used in the treatment of a type of cancer chosen @ from @ cancer @ of @ prostata @ and @ cancer @ of @ lung. @ @ 29 .- @ A @ composed @ of @ formula @ general @ (I) @ as @ has @ been @ defined @ in @ any @ of @ the @ claims @ 1 @ a @ 22 @ or @ un @ compound @ chosen @ between @ 2,2-dibromo-N - ((2S, 3R) -1,3-dihydroxioctadecan-2-yl) acetamide @ and @ 2-bromo-N - ((2S, 3R) -1, 3dihydroxioctadecan-2-il) acetamide @ o @ a @ stereoisomer, @ a @ salt @ or @ a pharmaceutically @ acceptable @ solvate @ of @ one @ of @ these @ compounds, @ to @ use @ in @ combination @ with @ other @ therapy @ for @ the @ treatment @ of @ a @ disease @ as @ se @ define @ in @ any @ any @ of @ the @ claims @ 24, @ 26 @ a @ 28. @@ @ 30 .- @ A @ composition @ as @ is @ defined @ in @ the @ claim @ 23 @ or @ a @ composition @ that @ comprises @ a @ compound @ chosen @ from @ 2,2-dibromo-N - ((2S, 3R) -1,3-dihydroxioctadecan-2-yl) acetamide @ and @ 2-bromo-N - ((2S, 3R) -1,3 dihydroxioctadecan- 2-il) acetamide @ o @ un @ stereoisomero, @ una @ sal @ o @ un @ solvato @ pharmaceutically @ acceptable @ of @ uno @ de @ these @ compounds @ at least @ one @ excipient, @ to @ use @ in @ combination @ with @ another @ therapy @ for @ the @ treatment @ of @ a @ disease @ as @ is @ defined @ in @ any @ of @ the @ claims @ 25, @ 26 @ a @ 28. @ OFICINA ESPAÑOLA DE PATENTES Y MARCAS SPANISH OFFICE OF THE PATENTS AND BRAND N.º solicitud: 201131119 Application no .: 201131119 ESPAÑA SPAIN Fecha de presentación de la solicitud: 01.07.2011 Date of submission of the application: 01.07.2011 Fecha de prioridad: Priority Date: INFORME SOBRE EL ESTADO DE LA TECNICA REPORT ON THE STATE OF THE TECHNIQUE 51 Int. Cl. : Ver Hoja Adicional 51 Int. Cl.: See Additional Sheet DOCUMENTOS RELEVANTES RELEVANT DOCUMENTS
Categoría Category
56 Documentos citados Reivindicaciones afectadas 56 Documents cited Claims Affected
A TO
EP 1580187 A1 (DEIGNER, HANS-PETER) 28.09.2005, tablas, páginas 3-5. 1-30 EP 1580187 A1 (DEIGNER, HANS-PETER) 28.09.2005, tables, pages 3-5. 1-30
A TO
WO 200172701 A1 (THE LIPOSOME COMPANY, INC) 04.10.2001, resumen; página 4. 1-30 WO 200172701 A1 (THE LIPOSOME COMPANY, INC) 04.10.2001, summary; page 4. 1-30
A TO
SZULC, Z.M. et al.: "Tailoring structure-function and targeting properties of ceramides by sitespecific cationization". Bioorganic & Medicinal chemistry, 2006, vol. 14, páginas 7083-7104, todo el documento. 1-30 SZULC, Z.M. et al .: "Tailoring structure-function and targeting properties of ceramides by sitespecific cationization". Bioorganic & Medicinal chemistry, 2006, vol. 14, pages 7083-7104, the whole document. 1-30
A TO
PARK, J. et al.: "Divergent syntheses of all stereoisomers of phytosphingosine and their use in the construction of a ceramide library". Bioorganic chemistry, 2008, vol. 36, páginas 220-228, todo el documento. 1-30 PARK, J. et al .: "Divergent syntheses of all stereoisomers of phytosphingosine and their use in the construction of a ceramide library". Bioorganic chemistry, 2008, vol. 36, pages 220-228, the entire document. 1-30
Categoría de los documentos citados X: de particular relevancia Y: de particular relevancia combinado con otro/s de la misma categoría A: refleja el estado de la técnica O: referido a divulgación no escrita P: publicado entre la fecha de prioridad y la de presentación de la solicitud E: documento anterior, pero publicado después de la fecha de presentación de la solicitud Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application
El presente informe ha sido realizado • para todas las reivindicaciones • para las reivindicaciones nº: This report has been prepared • for all claims • for claims no:
Fecha de realización del informe 24.09.2012 Date of realization of the report 24.09.2012
Examinador H. Aylagas Cancio Página 1/4 Examiner H. Aylagas Cancio Page 1/4
INFORME DEL ESTADO DE LA TÉCNICA REPORT OF THE STATE OF THE TECHNIQUE Nº de solicitud: 201131119 Application number: 201131119 CLASIFICACIÓN OBJETO DE LA SOLICITUD C07C233/18 (2006.01) CLASSIFICATION OBJECT OF THE APPLICATION C07C233 / 18 (2006.01) C07C311/04 (2006.01) A61K31/164 (2006.01) Documentación mínima buscada (sistema de clasificación seguido de los símbolos de clasificación) C07C311 / 04 (2006.01) A61K31 / 164 (2006.01) Minimum documentation sought (classification system followed by classification symbols) C07C, A61K C07C, A61K Bases de datos electrónicas consultadas durante la búsqueda (nombre de la base de datos y, si es posible, términos de búsqueda utilizados) INVENES, EPODOC,WPI, NPL, EMBASE, BIOSIS, MEDLINE, REGISTRY, HCAPLUS Electronic databases consulted during the search (name of the database and, if possible, terms of search used) INVENES, EPODOC, WPI, NPL, EMBASE, BIOSIS, MEDLINE, REGISTRY, HCAPLUS Informe del Estado de la Técnica Página 2/4 State of the Art Report Page 2/4 OPINIÓN ESCRITA  WRITTEN OPINION Nº de solicitud: 201131119 Application number: 201131119 Fecha de Realización de la Opinión Escrita: 24.09.2012 Date of Written Opinion: 24.09.2012 Declaración Statement
Novedad (Art. 6.1 LP 11/1986) Novelty (Art. 6.1 LP 11/1986)
Reivindicaciones Reivindicaciones 1-30 SI NO Claims Claims 1-30 IF NOT
Actividad inventiva (Art. 8.1 LP11/1986) Inventive activity (Art. 8.1 LP11 / 1986)
Reivindicaciones Reivindicaciones 1-30 SI NO Claims Claims 1-30 IF NOT
Se considera que la solicitud cumple con el requisito de aplicación industrial. Este requisito fue evaluado durante la fase de examen formal y técnico de la solicitud (Artículo 31.2 Ley 11/1986). The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986). Base de la Opinión.-  Opinion Base.- La presente opinión se ha realizado sobre la base de la solicitud de patente tal y como se publica. This opinion has been made on the basis of the patent application as published. Informe del Estado de la Técnica Página 3/4 State of the Art Report Page 3/4 OPINIÓN ESCRITA  WRITTEN OPINION Nº de solicitud: 201131119 Application number: 201131119 1. Documentos considerados.-  1. Documents considered.- A continuación se relacionan los documentos pertenecientes al estado de la técnica tomados en consideración para la realización de esta opinión. The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.
Documento Document
Número Publicación o Identificación Fecha Publicación Publication or Identification Number publication date
D01 D01
EP 1580187 A1 (DEIGNER, HANS-PETER) 28.09.2005 EP 1580187 A1 (DEIGNER, HANS-PETER) 28.09.2005
D02 D02
WO 200172701 A1 (THE LIPOSOME COMPANY, INC) 04.10.2001 WO 200172701 A1 (THE LIPOSOME COMPANY, INC) 04.10.2001
D03 D03
SZULC, Z.M. et al.: "Tailoring structure-function and targeting properties of ceramides by site-specific cationization". Bioorganic & Medicinal chemistry, 2006, vol. 14, páginas 7083-7104, todo el documento. SZULC, Z.M. et al .: "Tailoring structure-function and targeting properties of ceramides by site-specific cationization". Bioorganic & Medicinal chemistry, 2006, vol. 14, pages 7083-7104, the whole document.
D04 D04
PARK, J. et al.:"Divergent syntheses of all stereoisomers of phytosphingosine and their use in the construction of a ceramide library". Bioorganic chemistry, 2008, vol. 36, páginas 220-228, todo el documento. PARK, J. et al.:"Divergent syntheses of all stereoisomers of phytosphingosine and their use in the construction of a ceramide library ". Bioorganic chemistry, 2008, vol. 36, pages 220-228, the entire document.
2. Declaración motivada según los artículos 29.6 y 29.7 del Reglamento de ejecución de la Ley 11/1986, de 20 de marzo, de Patentes sobre la novedad y la actividad inventiva; citas y explicaciones en apoyo de esta declaración  2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement La presente solicitud se refiere a compuestos de fórmula I que son amidas de 2-amino.1,3 propanodioles, composiciones farmacéuticas que los contienen y su uso como inhibidores de ceramidasas en enfermedades que cursan con hiperproliferación celular tales como cáncer, metástasis, inflamación, asma y arterioesclerosis The present application refers to compounds of formula I which are amides of 2-amino.1,3 propanediols, pharmaceutical compositions containing them and their use as inhibitors of ceramidases in diseases that occur with cellular hyperproliferation such as cancer, metastasis, inflammation, asthma and arteriosclerosis Los documentos D1-D4, se refieren todos ellos a derivados de ceramidas y se cita su actividad antiproliferativa, su utilización en la apoptosis, y en respuestas inflamatorias. Documents D1-D4, all refer to ceramide derivatives and cite its antiproliferative activity, its use in apoptosis, and in inflammatory responses. Ninguno de los documentos citados se refiere específicamente a los compuestos reivindicados en la presente solicitud. None of the documents cited specifically refers to the compounds claimed in the present application. Por lo tanto, la materia correspondiente a las reivindicaciones 1-30 de la presente solicitud presente novedad y actividad inventiva según los artículos 6.1 y 8.1 de la L.P. Therefore, the material corresponding to claims 1-30 of the present application presents novelty and inventive activity according to articles 6.1 and 8.1 of the L.P. Informe del Estado de la Técnica Página 4/4 State of the Art Report Page 4/4
ES201131119A 2011-07-01 2011-07-01 AMIDAS OF 2-AMINO-1,3-PROPANODIOLS AND ITS USE AS CERAMIDASAS INHIBITORS. Expired - Fee Related ES2396092B1 (en)

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PCT/ES2012/070485 WO2013004871A1 (en) 2011-07-01 2012-06-29 Amides of 2-amino-1,3-propanediols and use thereof as ceramidase inhibitors

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