ES2637547T3 - (+)-2-[1-(3-Etoxi-4-metoxifenil)-2-metilsulfoniletil]-4-acetilaminoisoindolin-1,3-diona: métodos de uso y composiciones del mismo - Google Patents
(+)-2-[1-(3-Etoxi-4-metoxifenil)-2-metilsulfoniletil]-4-acetilaminoisoindolin-1,3-diona: métodos de uso y composiciones del mismo Download PDFInfo
- Publication number
- ES2637547T3 ES2637547T3 ES10186076.5T ES10186076T ES2637547T3 ES 2637547 T3 ES2637547 T3 ES 2637547T3 ES 10186076 T ES10186076 T ES 10186076T ES 2637547 T3 ES2637547 T3 ES 2637547T3
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- Prior art keywords
- compound
- hydrochloride
- methoxyphenyl
- ethoxy
- inhibitors
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 229960005212 vindesine sulfate Drugs 0.000 description 1
- BCXOZISMDZTYHW-IFQBWSDRSA-N vinepidine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@H](C2)CC)N2CCC2=C1NC1=CC=CC=C21 BCXOZISMDZTYHW-IFQBWSDRSA-N 0.000 description 1
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- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002166 vinorelbine tartrate Drugs 0.000 description 1
- GBABOYUKABKIAF-IWWDSPBFSA-N vinorelbinetartrate Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC(C23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IWWDSPBFSA-N 0.000 description 1
- 206010047470 viral myocarditis Diseases 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- DVPVGSLIUJPOCJ-XXRQFBABSA-N x1j761618a Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(=O)CN(C)C)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(=O)CN(C)C)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 DVPVGSLIUJPOCJ-XXRQFBABSA-N 0.000 description 1
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Abstract
(+)-2-[1-(3-Etoxi-4-metoxifenil)-2-metilsulfoniletil]-4-acetilaminoisoindolin-1,3-diona, o un polimorfo, sal, solvato o hidrato del mismo farmacéuticamente aceptable, para usar en un método para tratar o prevenir la espondilitis reumatoide u osteoartritis.
Description
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Un aspecto distinto de la descripción incluye métodos de tratamiento o prevención de una enfermedad mieloproliferativa (MPD), que comprende administrar a un paciente que requiere dicho tratamiento o prevención, una cantidad terapéutica o profilácticamente eficaz de Compuesto A estereoméricamente puro o una sal, solvato o hidrato del mismo farmacéuticamente aceptable. Una enfermedad mieloproliferativa (MPD) se refiere a un grupo de trastornos caracterizados por anomalías clónicas de la célula madre hematopoyética. Véase, p. ej., Current Medical Diagnosis & Treatment, págs. 499 (37ª ed., Tierney et al. compilador, Appleton & Lange, 1998).
La descripción también incluye un método de tratamiento, prevención o control del síndrome de dolor regional complejo, que comprende administrar a un paciente que requiere tal tratamiento, prevención o control, una cantidad terapéutica o profilácticamente eficaz de Compuesto A estereoméricamente puro o una sal, solvato o hidrato del mismo farmacéuticamente aceptable. En una realización específica, la administración es antes, durante o después de una cirugía o fisioterapia dirigida a reducir o evitar un síntoma del síndrome de dolor regional complejo en el paciente.
En los métodos particulares descritos en esta memoria, el Compuesto A estereoméricamente puro, o un polimorfo, sal, solvato o hidrato del mismo farmacéuticamente aceptable, se administra conjuntamente con al menos un agente terapéutico adicional. Ejemplos de agentes terapéuticos adicionales incluyen, pero no se limitan a, fármacos contra el cáncer, antiinflamatorios, antihistamínicos y descongestionantes.
4.1 SÍNTESIS Y PREPARACIÓN
La 2-[1-(3-etoxi-4-metoxifenil)-2-metilsulfonil-etil]-4-acetilaminoisoindolin-1,3-diona racémica se prepara fácilmente usando los métodos del documento de patente de Estados Unidos nº 6.020.358.
El Compuesto A se puede aislar del compuesto racémico por métodos conocidos en la técnica. Ejemplos incluyen, pero no se limitan a, la formación de sales quirales y el uso de cromatografía quiral o líquida de alta resolución “HPLC” y la formación y cristalización de sales quirales. Véanse, por ejemplo, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, Nueva York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962) y Wilen S. H., Tables of Resolving Agents and Optical Resolutions, p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).
En un método específico, el Compuesto A se sintetiza a partir de anhídrido 3-acetamidoftálico y una sal de aminoácido quiral de (S)-2-(3-etoxi-4-metoxifenil)-1-(metilsulfonil)-et-2-ilamina. Las sales de aminoácido quiral de (S)-2-(3-etoxi-4-metoxifenil)-1-(metilsulfonil)-et-2-ilamina incluyen, pero no se limitan a, sales formadas con los isómeros L de alanina, arginina, asparagina, ácido aspártico, cisteína, glutamina, ácido glutámico, glicina, histidina, isoleucina, leucina, lisina, metionina, fenilalanina, prolina, serina, treonina, triptófano, tirosina, valina, ornitina, ácido 4-aminobutírico, ácido 2-aminoisobutírico, ácido 3-aminopropiónico, norleucina, norvalina, hidroxiprolina, sarcosina, citrulina, ácido cistéico, t-butilglicina, t-butilalanina, fenilglicina, ciclohexilalanina y N-acetil-leucina. Una sal de aminoácido quiral específica es la sal (S)-2-(3-etoxi-4-metoxifenil)-1-(metilsulfonil)-et-2-ilamina N-acetil-L-leucina, mediante la resolución de 2-(3-etoxi-4-metoxifenil)-1-(metilsulfonil)-et-2-ilamina y N-acetil-L-leucina en metanol.
4.2 MÉTODOS DE TRATAMIENTO
La descripción incluye métodos de tratamiento y prevención de enfermedades o trastornos que mejoran con la reducción de los niveles de TNF-α en un paciente, que comprenden administrar a un paciente que requiera dicho tratamiento o prevención una cantidad terapéuticamente eficaz de Compuesto A estereoméricamente puro o un profármaco, metabolito, polimorfo, sal, solvato, hidrato o clatrato del mismo farmacéuticamente aceptable.
Los trastornos que mejoran con la inhibición de TNF-α incluyen, pero no se limitan a: enfermedad cardiaca, tal como insuficiencia cardíaca congestiva, cardiomiopatía, edema pulmonar, choque séptico mediado por endotoxinas, miocarditis viral aguda, rechazo de alotrasplante de corazón e infarto de miocardio; tumores sólidos, que incluyen pero no se limitan a, sarcoma, carcinomas, fibrosarcoma, mixosarcoma, liposarcoma, condrosarcoma, sarcoma osteogénico, cordoma, angiosarcoma, endoteliosarcoma, linfangiosarcoma, linfangioendoteliosarcoma, sinovioma, mesotelioma, tumor de Ewing, leiomiosarcoma, rabdomiosarcoma, carcinoma de colon, cáncer de páncreas, cáncer de mama, cáncer de ovario, cáncer de próstata, carcinoma de células escamosas, carcinoma de células basales, adenocarcinoma, carcinoma de glándulas sudoríparas, carcinoma de glándula sebácea, carcinoma papilar, adenocarcinomas papilares, cistoadenocarcinoma, carcinoma medular, carcinoma broncogénico, carcinoma de células renales, hepatoma, carcinoma de conducto biliar, coriocarcinoma, seminoma, carcinoma embrionario, tumor de Wilms, cáncer de cuello uterino, tumor testicular, carcinoma de pulmón, carcinoma de células pequeñas de pulmón, carcinoma de vejiga, carcinoma epitelial, glioma, astrocitoma, meduloblastoma, craneofaringioma, ependimoma, sarcoma de Kaposi, pinealoma, hemangioblastoma, neuroma acústico, oligodendroglioma, menangioma, melanoma, neuroblastoma y retinoblastoma; y tumores nacidos en la sangre que incluyen pero no se limitan a, leucemia linfoblástica aguda "LLA", leucemia linfoblástica aguda de linfocitos B, leucemia linfoblástica aguda de linfocitos T, leucemia mieloblástica aguda "LMA", leucemia promielocítica aguda "LPA", leucemia monoblástica aguda, eritroleucemia aguda, leucemia megacarioblásticac aguda, leucemia mielomonocítica aguda, leucemia no linfocítica aguda, leucemia indiferenciada aguda, leucemia mielocítica crónica "LMC", leucemia linfocítica crónica "LLC", leucemia de células pilosas, mieloma múltiple y leucemias agudas y crónicas, por ejemplo,
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leucemia linfoblástica, mielógena, linfocítica y mielocítica.
Los métodos específicos descritos en esta memoria comprenden además la administración de un agente terapéutico adicional (es decir, un agente terapéutico que no sea el Compuesto A). Ejemplos de agentes terapéuticos adicionales incluyen, pero no están limitados a fármacos contra el cáncer tales como, pero limitados a: agentes alquilantes, mostazas de nitrógeno, etileniminas, metilmelaminas, alquil sulfonatos, nitrosoureas, triazenos, análogos de ácido fólico, análogos de pirimidina, análogos de purina, alcaloides de la vinca, epipodofilotoxinas, antibióticos, inhibidores de la topoisomerasa y vacunas contra el cáncer.
Agentes terapéuticos adicionales específicos incluyen, pero no se limitan a: acivicina; aclarrubicina; clorhidrato de acodazol; acronina; adozelesina; aldesleuquina; altretamina; ambomicina; acetato de ametantrona; aminoglutetimida; amsacrina; anastrozol; antramicina; asparaginasa; asperlina; azacitidina; azetepa; azotomicina; batimastat; benzodepa; bicalutamida; clorhidrato de bisantreno; dimesilato de bisnafida; bizelesina; sulfato de bleomicina; brequinar sódico; bropirimina; busulfán; cactinomicina; calusterona; caracemida; carbetimer; carboplatino; carmustina; clorhidrato de carubicina; carzelesina; cedefingol; clorambucilo; cirolemicina; cisplatino; cladribina; mesilato de crisnatol; ciclofosfamida; citarabina; dacarbazina; dactinomicina; clorhidrato de daunorrubicina; decitabina; dexormaplatino; dezaguanina; mesilato de dezaguanina; diazicuona; docetaxel; doxorrubicina; clorhidrato de doxorrubicina; droloxifeno; citrato de droloxifeno; propionato de dromostanolona; duazomicina; edatrexato; clorhidrato de eflornitina; elsamitrucina; enloplatino; enpromato; epipropidina; clorhidrato de epirrubicina; erbulozol; clorhidrato de esorrubicina; estramustina; sodio fosfato de estramustina; etanidazol; etopósido; fosfato de etopósido; etoprina; clorhidrato de fadrozol; fazarabina; fenretinida; floxuridina; fosfato de fludarabina; fluorouracilo; flurocitabina; fosquidona; fostriecina sódica; gemcitabina; clorhidrato de gemcitabina; hidroxiurea; clorhidrato de idarrubicina; ifosfamida; ilmofosina; interleucina II (incluyendo interleucina II recombinante
o rlL2), interferón alfa-2a; interferón alfa-2b; interferón alfa-n1; interferón alfa-n3; interferón beta-I a; interferón gamma-I b; iproplatina; clorhidrato de irinotecán; acetato de lanreotida; letrozol; acetato de leuprolida; clorhidrato de liarozol; lometrexol sódico; lomustina; clorhidrato de losoxantrona; masoprocol; maytansina; clorhidrato de meclormetina; acetato de megestrol; acetato de melengestrol; melfalán; menogaril; mercaptopurina; metotrexato; metotrexato sódico; metoprina; meturedepa; mitindomida; mitocarcina; mitocromina; mitogillina; mitomalcina; mitomicina; mitosper; mitotano; clorhidrato de mitoxantrona; ácido micofenólico; nocodazol; nogalamicina; ormaplatina; oxisurán; paclitaxel; pegaspargasa; peliomicina; pentamustina; sulfato de peplomicina; perfosfamida; pipobromán; piposulfán; clorhidrato de piroxantrona; plicamicina; plomestano; porfímero sódico; porfiromicina; prednimustina; clorhidrato de procarbazina; puromicina; clorhidrato de puromicina; pirazofurina; riboprina; rogletimida; safingol; clorhidrato de safingol; semustina; simtrazeno; esparfosato sódico; esparsomicina; clorhidrato de espirogermanio; espiromustina; espiroplatina; estreptonigrina; estreptozocina; sulofenur; talisomicina; tecogalán sodico; tegafur; clorhidrato de teloxantrona; temoporfina; tenipósido; teroxirona; testolactona; tiamiprina; tioguanina; tiotepa; tiazofurina; tirapazamina; citrato de toremifeno; acetato de trestolona; fosfato de triciribina; trimetrexato; glucuronato de trimetrexato; triptorelina; clorhidrato de tubulozol; mostaza de uracilo; uredepa; vapreotida; verteporfina; sulfato de vinblastina; sulfato de vincristina; vindesina; sulfato de vindesina; sulfato de vinepidina; sulfato de vinglicinato; sulfato de vinleurosina; tartrato de vinorelbina; sulfato de vinrosidina; sulfato de vinzolidina; vorozol; zeniplatino; zinostatino; clorhidrato de zorrubicina. Otros fármacos contra el cáncer incluyen pero no se limitan a: 20-epi-1,25 dihidroxivitamina D3; 5-etiniluracilo; abiraterona; aclarrubicina; acilfulveno; adecipenol; adozelesina; aldesleucina; antagonistas de LLA-TK; altretamina; ambamustina; amidox; amifostina; ácido aminonolevulínico; amrrubicina; amsacrina; anagrelida; anastrozol; andrografolida; inhibidores de la angiogénesis; antagonista de D; antagonista de G; antarelix; proteína 1 morfogenéticas anti-dorsalización; antiandrógeno, carcinoma prostático; antiestrógeno; antineoplastón; oligonucleótidos antisentido; glicinato de afidicolina; moduladores de genes de la apoptosis; reguladores de la apoptosis; ácido apurínico; ara-CDP-DL-PTBA; desaminasa de arginina; asulacrina; atamestano; atrimustina; axinastatina 1; axinastatina 2; axinastatina 3; azasetrón; azatoxina; azatirosina; derivados de bacatina III; balanol; batimastat; antagonistas de BCR/ABL; benzoclorinas; benzoilestaurosporina; derivados betalactámicos; beta-aletina; betaclamicina B; ácido betulínico; inhibidor de bFGF; bicalutamida; bisantreno; bisaziridinilespermina; bisnafida; bistrateno A; bizelesina; breflato; bropirimina; budotitano; butionina sulfoximina; calcipotriol; calfostina C; derivados de camptotecina; IL-2 de la viruela del canario; capecitabina; carboxamida-amino-triazol; carboxiamidotriazol; CaRest M3; CARN 700; inhibidor derivado de cartílago; carzelesina; inhibidores de la cinasa de caseína (ICOS); castanoespermina; cecropina B; cetrorelix; clorinas; sulfamida de cloroquinoxalina; cicaprost; cis-porfirina; cladribina; análogos de clomifeno; clotrimazol; colismicina A; colismicina B; combretastatina A4; análogo de combretastatina; conagenina; crambescidina 816; crisnatol; criptoficina 8; derivados de criptoficina A; curacina A; ciclopentantraquinonas; cicloplatam; cipemicina; ocfosfato de citarabina; factor citolítico; citostatina; dacliximab; decitabina; dehidrodidemnina B; deslorelina; dexametasona; dexifosfamida; dexrazoxano; dexverapamil; diazicuona; didemnina B; didox; dietilnorespermina; dihidro-5-azacitidina; dihidrotaxol, 9-; dioxamicina; difenil espiromustina; docetaxel; docosanol; dolasetrón; doxifluridina; droloxifeno; dronabinol; duocarmicina SA; ebseleno; ecomustina; edelfosina; edrecolomab; eflornitina; elemeno; emitefur; epirrubicina; epristerida; análogo de estramustina; agonistas de estrógenos; antagonistas de estrógenos; etanidazol; fosfato de etopósido; exemestano; fadrozol; fazarabina; fenretinida; filgrastim; finasterida; flavopiridol; flezelastina; fluasterona; fludarabina; clorhidrato de fluorodaunorunicina; forfenimex; formestano; fostriecina; fotemustina; texafirina de gadolinio; nitrato de galio; galocitabina; ganirelix; inhibidores de la gelatinasa; gemcitabina; inhibidores de glutatión; hepsulfam; heregulina; hexametilen bisacetamida; hipericina; ácido ibandrónico; idarrubicina; idoxifeno; idramantona; ilmofosina; ilomastat; imidazoacridonas; imiquimod; péptidos
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inmunoestimulantes; inhibidor del receptor del factor de crecimiento 1 similar a insulina; agonistas de interferón; interferones; interleucinas; iobenguano; iododoxorrubicina; ipomeanol, 4-; iroplact; irsogladina; isobengazol; isohomohalicondrina B; itasetrón; jasplakinolida; kahalalida F; triacetato de lamelarina-N; lanreotida; leinamicina; lenograstim; sulfato de lentinano; leptolestatina; letrozol; factor inhibidor de leucemia; interferón alfa leucocitario; leuprolida + estrógeno + progesterona; leuprorelina; levamisol; liarozol; análogo lineal de poliamina; péptido disacárido lipofílico; compuestos lipofílicos de platino; lisoclinamida 7; lobaplatino; lombricina; lometrexol; lonidamina; losoxantrona; lovastatina; loxoribina; lurtotecán; texafirina de lutecio; lisofillna; péptidos líticos; maitansina; manostatina A; marimastat; masoprocol; maspina; inhibidores de matrilisina; inhibidores de metaloproteinasa matricial; menogaril; merbarona; meterelina; metioninasa; metoclopramida; Inhibidor de MIF; mifepristona; miltefosina; mirimostim; ARN bicatenario desemparejado; mitoguazona; mitolactol; análogos de mitomicina; mitonafida; factor de crecimiento de fibroblastos de mitotoxina saporina; mitoxantrona; mofaroteno; molgramostim; anticuerpo monoclonal, gonadotropina coriónica humana; monofosforil lípido A + pared celular de miobacteria sk; mopidamol; inhibidor del gene de resistencia a multifármacos; terapia basada en el supresor 1 de tumores múltiples; agente anticancerígeno de mostaza; micaperóxido B; extracto de la pared celular de micobacterias; miriaporona; Nacetildinalina; benzamidas N-sustituidas; nafarelina; nagrestip; naloxona + pentazocina; napavina; nafterpina; nartograstim; nedaplatina; nemorrubicina; ácido neridrónico; endopeptidasa neutra; nilutamida; nisamicina; moduladores de óxido nítrico; nitróxido antioxidante; nitrulina; O6-benzilguanina; octreotida; okicenona; oligonucleótidos; onapristona; ondansetrón; ondansetrón; oracina; inductor de citocinas oral; ormaplatina; osaterona; oxaliplatino; oxaunomicina; paclitaxel; análogos de paclitaxel; derivados de paclitaxel; palauamina; palmitoilrizoxina; ácido pamidrónico; panaxitriol; panomifeno; parabactina; pazeliptina; pegaspargasa; peldesina; polisulfato de pentosán sódico; pentostatina; pentrozol; perflubron; perfosfamida; alcohol perílico; fenazinomicina; fenilacetato; inhibidores de fosfatasa; picibanil; clorhidrato de pilocarpina; pirarrubicina; piritrexim; placetina A; placetina B; inhibidor del activador del plasminógeno; complejo de platino; compuestos de platino, complejo de platino-triamina; porfímero sódico; porfiromicina; prednisona; propil bis-acridona; prostaglandina J2; inhibidores de proteasoma; inmunomodulador basado en proteína A; inhibidor de proteína cinasa C; inhibidores de proteína cinasa C, microalgal; inhibidores de proteína tirosina fosfatasa; inhibidores de fosforilasa de nucleósido de purina; purpurinas; pirazoloacridina; conjugado de polioxietileno hemoglobina piridoxilada; antagonistas de raf; raltitrexed; ramosetrón; inhibidores de la farnesil proteína transferasa ras; inhibidores de ras; inhibidor de ras-GAP; reteliptina desmetilada; etidronato de renio Re 186; rizoxina; ribozimas; retinamida RII; rogletimida; rohitukina; romurtida; roquinimex; rubiginona B1; ruboxil; safingol; saintopin; SarCNU; sarcofitol A; sargramostim; miméticos de Sdi 1; semustina; inhibidor 1 derivado de senescencia; oligonucleótidos de sentido; inhibidores de la transducción de señales; moduladores de la transducción de señales; proteína que se une a antígeno de cadena sencilla; sizofirán; sobuzoxano; borocaptato sódico; fenilacetato sódico; solverol; proteína que se une a somatomedina; sonermina; ácido esparfósico; espicamicina D; espiromustina; esplenopentina; espongistatina 1; escualamina; inhibidor de células madre; inhibidores de la división celular de células madre; estipiamida; inhibidores de estromelisina; sulfinosina; antagonista superactivo del péptido intestinal vasoactivo; suradista; suramina; swainsonina; glicosaminoglicanos sintéticos; talimustina; metiodida tamoxifeno; tauromustina; tazaroteno; tecogalán sódico; tegafur; telurapirilio; inhibidores de la telomerasa; temoporfina; temozolomida; tenipósido; tetraclorodecaóxido; tetrazomina; taliblastina; tiocoralina; trombopoyetina; mimético de trombopoyetina; timalfasina; agonista del receptor de timopoietina; timotrinan; hormona estimulante de la tiroides; etil etiopurpurina de estaño; tirapazamina; bicloruro titanoceno; topsentina; toremifeno; factor totipotente de células madre; inhibidores de la traducción; tretinoina; triacetiluridina; triciribina; trimetrexato; triptorelina; tropisetrón; turosterida; inhibidores de cinasa de tirosina; tirfostinas; inhibidores de UBC; ubenimex; factor inhibidor del crecimiento derivado del seno urogenital; antagonistas del receptor de urocinasa; vapreotida; variolina B; sistema de vectores, terapia génica de eritrocitos; velaresol; veramina; verdinas; verteporfina; vinorelbina; vinxaltina; vitaxin; vorozol; zanoterona; zeniplatino; zilascorb; y estimalámero de zinostatina.
La descripción incluye además un método de tratamiento o prevención de enfermedades o trastornos que mejoran con la inhibición de PDE4 en un paciente que comprende administrar a un paciente que requiera dicho tratamiento o prevención, una cantidad terapéuticamente eficaz de Compuesto A estereoméricamente puro o un polimorfo, sal, solvato o hidrato del mismo farmacéuticamente aceptable. Los trastornos mejorados por la inhibición de PDE4 incluyen, pero no se limitan a, asma, inflamación, enfermedad pulmonar obstructiva crónica o aguda, enfermedad inflamatoria pulmonar crónica o aguda, enfermedad inflamatoria intestinal, enfermedad de Crohn, enfermedad de Behcet, colitis, colitis ulcerosa y artritis o inflamación debida a reperfusión. En una realización preferida, la enfermedad o el trastorno que se va a tratar o prevenir es la enfermedad pulmonar obstructiva crónica.
Métodos específicos descritos en esta memoria pueden implicar la administración de un agente terapéutico adicional tal como: pero no limitado a, fármacos antiinflamatorios, antihistamínicos y descongestivos. Ejemplos de estos agentes terapéuticos adicionales incluyen, pero no se limitan a: antihistamínicos que incluyen pero no se limitan a, etanolaminas, etilenediaminas, piperazinas y fenotiazinas; fármacos antiinflamatorios; AINES, que incluyen pero no se limitan a, aspirina, salicilatos, paracetamol, indometacina, sulindac, etodolac, fenamatos, tolmetina, ketorolaco, diclofenaco, ibuprofeno, naproxeno, fenoprofeno, ketoprofeno, flurbiprofeno, oxaprozin, piroxicam, meloxicam, derivados de pirazolón; y esteroides que incluyen pero no se limitan a, esteroides corticales y esteroides adrenocorticales.
Los métodos específicos descritos en este documento evitan o reducen las interacciones entre fármacos y otros
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efectos adversos asociados con agentes utilizados en el tratamiento de tales trastornos, incluyendo feniletilsulfonas sustituidas racémicas. Sin estar limitado por ninguna teoría, el Compuesto A estereoméricamente puro puede proporcionar una eficacia terapéutica mejorada globalmente, o un índice terapéutico, frente a la 2-[1-(3-etoxi-4metoxifenil)-2-metilsulfoniletil]-4-acetilaminoisoindolin-1,3-diona racémica. Por ejemplo, una cantidad más pequeña del fármaco se puede administrar en algunas circunstancias para alcanzar el mismo nivel de eficacia.
Tal como se ha indicado anteriormente, el compuesto activo para usar en la invención (es decir, el Compuesto A) se puede utilizar en el tratamiento o la prevención de una amplia gama de enfermedades y afecciones. Sin embargo, la magnitud de una dosis profiláctica o terapéutica de un determinado ingrediente activo para usar en la invención, para el tratamiento agudo o crónico de una enfermedad o afección puede variar con la naturaleza y la gravedad de la enfermedad o afección y la ruta por la que se administra el ingrediente activo. La dosis y tal vez la frecuencia de la dosis, también varían según la edad, el peso corporal y la respuesta de cada paciente. Los regímenes de dosificación apropiados pueden ser fácilmente seleccionados por los expertos en la técnica, teniendo en consideración tales factores. En general, el intervalo de dosis diaria recomendada para las afecciones descritas en esta memoria, se encuentra dentro del intervalo desde aproximadamente 1 mg a aproximadamente 1000 mg al día, proporcionados como una dosis única una vez al día, preferentemente como dosis divididas a lo largo de un día. Más específicamente, la dosis diaria se administra dos veces al día en dosis igualmente divididas. En concreto, un intervalo de dosis diaria debe ser desde aproximadamente 5 mg a aproximadamente 500 mg por día, más concretamente, entre aproximadamente 10 mg y aproximadamente 200 mg por día. En concreto, la dosis diaria puede administrarse en formas de dosificación de 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg o 100 mg. En el tratamiento del paciente, la terapia debe iniciarse a una dosis inferior, tal vez desde aproximadamente 1 mg a aproximadamente 25 mg y aumentarla si es necesario hasta desde aproximadamente 200 mg a aproximadamente 1000 mg por día en una dosis única o dosis divididas, dependiendo de la respuesta general del paciente. Alternativamente, la dosis diaria es de 0,01 mg/kg a 100 mg/kg.
Puede ser necesario utilizar dosificaciones del ingrediente activo fuera de los intervalos descritos en esta memoria en algunos casos, como será evidente para los expertos con habilidad ordinaria en la técnica. Además, se observa que el médico clínico o de cabecera sabrá cómo y cuándo interrumpir, ajustar o terminar la terapia junto con la respuesta del paciente.
Las expresiones "cantidad terapéuticamente eficaz", "cantidad profilácticamente eficaz" y "cantidad terapéutica o profilácticamente eficaz", tal y como se emplean en esta memoria, incluyen las cantidades de dosificación descritas anteriormente y las pautas de frecuencia de la dosis. Diferentes cantidades terapéuticamente eficaces pueden ser aplicables para diferentes enfermedades y afecciones, como es conocido por los expertos ordinarios en la técnica. Asimismo, cantidades suficientes para tratar o evitar tales trastornos pero insuficientes para causar, o suficientes para reducir efectos adversos asociados con 2-[1-(3-etoxi-4-metoxifenil)-2-metilsulfoniletil]-4-acetilaminoisoindolin1,3-diona racémica, también se incluyen en las cantidades de dosificación descritas anteriormente y las pautas de frecuencia de la dosis.
4.3 COMPOSICIONES FARMACÉUTICAS
Las composiciones farmacéuticas y las formas de dosificación unitaria que comprenden el Compuesto A, o un polimorfo, sal, solvato o hidrato del mismo farmacéuticamente aceptable para usar en el tratamiento o prevención de espondilitis reumatoide u osteoartritis, se encuentran abarcadas por la invención. Las formas de dosificación individuales de la invención pueden adecuadas para administración oral, a través de la mucosa (incluyendo rectal, nasal o vaginal), parenteral (incluyendo subcutánea, intramuscular, inyección de bolo, intraarterial o intravenosa), sublingual, transdérmica, bucal o tópica.
Las composiciones farmacéuticas y las formas de dosificación de la invención comprenden Compuesto A estereoméricamente puro o un polimorfo, sal, solvato o hidrato del mismo farmacéuticamente aceptable para usar en el tratamiento o prevención de espondilitis reumatoide u osteoartritis. Las composiciones farmacéuticas y las formas de dosificación de la invención también comprenden típicamente uno o más excipientes farmacéuticamente aceptables.
Una composición farmacéutica particular abarcada por esta realización comprende un Compuesto A estereoméricamente puro, o un polimorfo, sal, solvato o hidrato del mismo farmacéuticamente aceptable y al menos un agente terapéutico adicional. Ejemplos de agentes terapéuticos adicionales incluyen, pero no se limitan a: fármacos contra el cáncer y terapias anti-inflamación que incluyen, pero no se limitan a los mencionados en la sección 4.2.
Las formas de dosificación unitarias de la invención son adecuados para administración oral, a través de la mucosa (incluyendo nasal, sublingual, vaginal, bucal o rectal), parenteral (p. ej., subcutánea, intravenosa, inyección de bolo, intramuscular o intraarterial) o transdérmica a un paciente. Ejemplos de formas de dosificación incluyen pero no se limitan a: comprimidos; comprimidos oblongos; cápsulas, tales como cápsulas de gelatina elástica suave; píldoras; trociscos; pastillas; dispersiones; supositorios; ungüentos; cataplasmas (emplastos); pastas; polvos; apósitos; cremas; tiritas; soluciones; parches; aerosoles (por ejemplo, aerosoles nasales o inhaladores); geles; formas de dosificación líquida adecuadas para administración oral o mucosa a un paciente, que incluyen suspensiones (por
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aceite de semilla de algodón, aceite de cacahuete, aceite de sésamo, oleato de etilo, miristato de isopropilo y benzoato bencílico.
5. EJEMPLOS
5.1. EJEMPLO DE REFERENCIA 1: SÍNTESIS DE 2-[1-(3-ETOXI-4-METOXIFENIL)-2-METILSULFONILETIL]-4-ACETILAMINOISOINDOLIN-1,3-DIONA
Se calentó a reflujo durante 15 h una solución agitada de 1-(3-etoxi-4-metoxifenil)-2-metilsulfoniletilamina (1,0 g, 3,7 mmol) y anhídrido 3-acetamidoftálico (751 mg, 3,66 mmol) en ácido acético (20 ml). El disolvente se eliminó a vacío para proporcionar un aceite. La cromatografía del aceite resultante proporcionó el producto como un sólido amarillo (1,0 g, 59% de rendimiento): pf 144°C; 1H NMR (CDCl3) δ 1,47 (t, J=7,0 Hz, 3H, CH3), 2,26 (s, 3H, CH3), 2,88 (s, 3H, CH3), 3,75 (dd, J=4,4, 14,3 Hz, 1H, CHH), 3,85 (s, 3H, CH3), 4,11 (q, J=7 Hz, 2H, CH2), 5,87 (dd, J=4,3, 10,5 Hz, 1H, NCH), 6,82-6,86 (m, 1H, Ar) 7,09-7,11 (m, 2H, Ar), 7,47 (d, J=7 Hz, 1H, Ar), 7,64 (t, J=8 Hz, 1H, Ar), 8,74 (d, J=8 Hz, 1H, Ar), 9,49 (br s, 1H, NH); 13C NMR (CDCl3) δ 14,61, 24,85, 41,54, 48,44, 54,34, 55,85, 64,43, 111,37, 112,34, 115,04, 118,11, 120,21, 124,85, 129,17, 130,96, 136,01, 137,52, 148,54, 149,65, 167,38, 169,09, 169,40. Análisis calculado para C22H24NO7S: C, 57,38, H, 5,25, N, 6,08. Encontrado: C, 57,31; H, 5,34; N, 5,83.
5.2. EJEMPLO 2: SÍNTESIS DE (+)2-[1-(3-ETOXI-4-METOXIFENIL)-2-METILSULFONILETIL]-4-ACETILAMINOISOINDOLIN-1,3-DIONA
Preparación de ácido 3-aminoftálico
Se cargaron Pd al 10%/C (2,5 g), ácido 3-nitroftálico (75,0 g, 355 mmol) y etanol (1,5 l) en un hidrogenador Parr de 2,5 l, bajo atmósfera de nitrógeno. Se cargó hidrógeno al recipiente de reacción hasta 379,23 kPa (55 psi). La mezcla se agitó durante 13 horas, manteniendo la presión de hidrógeno entre 344,75 y 379,23 kPa (50 y 55 psi). Se liberó el hidrógeno y la mezcla se purgó con nitrógeno 3 veces. La suspensión se filtró a través de un lecho de celite y se enjuagó con metanol. El filtrado se concentró in vacuo. El sólido resultante se volvió a suspender en éter y se aisló por filtración a vacío. El sólido se secó in vacuo hasta un peso constante, dando 54 g (84% de rendimiento) de ácido 3-aminoftálico como un producto amarillo. 1H NMR (DMSO-d6) δ: 3,17 (s, 2H), 6,67 (d, 1H), 6,82 (d, 1H), 7,17 (t, 1H), 8-10 (br s, 2H). 13C NMR (DMSO-d6) δ:112,00, 115,32, 118,20, 131,28, 135,86, 148,82, 169,15, 170,09.
Preparación de anhídrido 3-acetamidoftálico
Se equipó un matraz de 1 l, de 3 bocas, de fondo redondo, con un agitador mecánico, termómetro y condensador y se cargó con ácido 3-aminoftálico (108 g, 596 mmol) y anhídrido acético (550 ml). La mezcla de reacción se calentó hasta reflujo durante 3 horas, se enfrió hasta temperatura ambiente y adicionalmente hasta 0-5°C durante otra hora. El sólido cristalino se recogió por filtración a vacío y se lavó con éter. El producto sólido se secó in vacuo a temperatura ambiente hasta un peso constante, dando 75 g (61% de rendimiento) de anhídrido 3-acetamidoftálico como un producto blanco. 1H NMR (CDCl3) δ: 2,21 (s, 3H), 7,76 (d, 1H), 7,94 (t, 1H), 8,42 (d, 1H), 9,84 (s, 1H).
Resolución de 2-(3-etoxi-4-metoxifenil)-1-(metilsulfonil)-et-2-ilamina
Se equipó un matraz de 3 l, de 3 bocas, de fondo redondo, con un agitador mecánico, termómetro y condensador y se cargó con 2-(3-etoxi-4-metoxifenil)-1-(metilsulfonil)-et-2-ilamina (137,0 g, 500 mmol), N-acetil-L-leucina (52 g, 300 mmol) y metanol (1,0 l). La suspensión agitada se calentó hasta reflujo durante 1 hora. La mezcla agitada se dejó enfriar hasta temperatura ambiente y se continuó la agitación durante otras 3 horas a temperatura ambiente. La suspensión se filtró y se lavó con metanol (250 ml). El sólido se secó al aire y después se secó in vacuo a temperatura ambiente hasta un peso constante, dando 109,5 g (98% de rendimiento) del producto crudo (85,8% de ee). El sólido crudo (55,0 g) y metanol (440 ml) se llevaron hasta reflujo durante 1 hora, se enfriaron hasta temperatura ambiente y se agitaron durante 3 horas adicionales a temperatura ambiente. La suspensión se filtró y la torta del filtro se lavó con metanol (200 ml). El sólido se secó al aire y después se secó in vacuo a 30°C hasta un peso constante, dando 49,6% (90% de recuperación) de sal (S)-2-(3-etoxi-4-metoxifenil)-1-(metilsulfonil)-et-2ilamina-N-acetil-L-leucina (98,4% de ee). HPLC quiral (1/99 EtOH/KH2PO4 20 mM a pH 7,0, Ultron Chiral ES-OVS de Agilent Technologies, 150 mm x 4,6 mm, 0,5 ml/min, a 240 nm): 18,4 min (isómero S, 99,2%), 25,5 min (isómero R, 0,8%).
Preparación de Compuesto A
Se equipó un matraz de 500 ml, de 3 bocas, de fondo redondo, con un agitador mecánico, termómetro y condensador. El recipiente de reacción se cargó con sal (S)-2-(3-etoxi-4-metoxifenil)-1-(metilsulfonil)-et-2-ilamina N-acetil-L-leucina (25 g, 56 mmol, 98% de ee), anhídrido 3-acetamidoftálico (12,1 g, 58,8 mmol) y ácido acético glacial (250 ml). La mezcla se puso a reflujo por la noche y después se enfrió hasta <50°C. El disolvente se eliminó in vacuo, y el residuo se disolvió en acetato de etilo. La solución resultante se lavó con agua (250 ml x 2), NaHCO3 acuoso saturado (250 ml x 2), salmuera (250 ml x 2) y se secó sobre sulfato sódico. El disolvente se evaporó in vacuo y el residuo se recristalizó en un disolvente binario que contenía etanol (150 ml) y acetona (75 ml). El sólido se aisló por filtración a vacío y se lavó con etanol (100 ml x 2). El producto se secó in vacuo a 60°C hasta un peso
Biophys. Acta 429:485, y Nicholsen et al., 1991 Trends Pharmaco. Sci. 12:19), y PDE6 de segmentos externos de bastoncillos de retina bovina (Baehr et al. 1979, J. Biol. Chem. 254:11669, y Gillespie et al. 1989, Mol. Pharm. 36:773). Los resultados se enumeran en la Tabla 1.
Ensayo con enzima PDE7
5 La PDE7 es una PDE selectiva de AMPc expresada principalmente en linfocitos T y en músculo esquelético. Las citocinas obtenidas a partir de linfocitos T tales como IL-2 e IFN-γ son potencialmente regulables por medio de la inhibición de PDE7. Se purificó PDE7 a partir de linfocitos T humanos Hut78 mediante cromatografía de intercambio aniónico como se ha descrito anteriormente (Bloom y Beavo 1996, Proc. Natl. Acad. Sci. USA 93:14188-14192). Se sometieron a ensayo compuestos frente a la preparación de PDE7 en presencia de AMPc 10
10 nM como se describe para PDE4 en la Tabla 1 siguiente.
Tabla 1
- Compuesto Racémico
- Compuesto A Compuesto B*
- Inhibición de PDE
- CI50 de PDE4 (de células U937) (nM)
- 81,8 73,5 611
- PDE1 (% inhib a 10 µM)
- 9% 23% 27%
- PDE2 (% inhib a 10 µM)
- 19% 6% 10%
- PDE3 (% inhib a 10 µM)
- 21% 20% 31%
- PDE5 (% inhib a 10 µM)
- 3% 3% -9%
- PDE6 (% inhib a 10 µM)
- ND -6% 10%
- CI50 de PDE7 (nM)
- 22110 20500 ND
- Relaciones específicas de PDE de los datos anteriores (*veces)
- PDE4/PDE1
- > 2700 > 500 > 50
- PDE4/PDE2
- > 800 > 10000 > 260
- PDE4/PDE3
- > 670 > 1200 > 45
- PDE4/PDE5
- > 12000 > 30000 > 39000
- PDE4/PDE6
- ND > 40000 > 250
- CI50 de PDE7/CI50 de PDE4
- 270 279 ND
* El Compuesto B es el enantiómero opuesto del Compuesto A
5.5. EJEMPLO 5: INHIBICIÓN DE PDE4
Ensayo enzimático con PDE4 (obtenida a partir de células U937)
15 Se purificó la enzima PDE4 de células monocíticas humanas U937 mediante cromatografía de filtración en gel como se ha descrito anteriormente (Muller et al., 1998, Bioorg. & Med. Chem. Lett. 8:2669-2674). Las reacciones con fosfodiesterasa se llevaron a cabo en Tris HCl 50 mM pH 7,5, MgCl2 5 mM, AMPc 1 µM, [3H]-AMPc 10 nM durante 30 min a 30°C, terminaron por ebullición, se trataron con veneno de serpiente a 1 mg/ml, y se separaron usando resina de intercambio iónico AG-IXS (BioRad) como se describe (Muller et al., 1998, Bioorg. & Med. Chem.
20 Lett. 8:2669-2674). Las reacciones consumieron menos del 15% del sustrato disponible. Los resultados se enumeran en la Tabla 1.
5.6. EJEMPLO 6: ENSAYOS CON LINFOCITOS T HUMANOS
Producción de IL-2 e IFN-γ inducida por EEB
La enterotoxina estafilocócica B (EEB) es un superantígeno derivado de la bacteria gram-positiva Staphylococcus
25 aureus. La EEB proporciona el estímulo fisiológico específico apropiado para los linfocitos T que expresan cadenas Vβ del receptor de linfocitos T particular. Se aislaron CMSP humanas (que consisten aproximadamente en 50% de
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linfocitos T) de unidades de leucocitos fuentes como se ha descrito anteriormente y se colocaron en placa en placas de cultivo de tejidos de 96 pocillos a 3 x 105 células/pocillo en medio completo, se pretrataron con compuestos a 10, 2, 0,4, 0,08, 0,016, 0,0032, 0,00064 y 0 µM, por duplicado, a una concentración final de DMSO de 0,1% a 37°C, en una incubadora humidificada a 5% de CO2 durante 1 hora, después se estimularon con 100 ng/ml de EEB (Sigma Chemical Co., St. Louis, MO, EE UU) durante 18 horas. Se midieron los niveles de IL-2 e IFN-γ mediante ELISA (R&D Systems, Minneapolis, MN, EE UU). CI50 de IL-2 = 291 nM; CI50 de IFN-γ = 46 nM.
5.7. EJEMPLO 6: ENSAYOS DE ELEVACIÓN DE AMPc
Elevación de AMPc inducida por PGE2
La prostaglandina E2 (PGE2) se une a los receptores de prostanoides en los monocitos, linfocitos T y otros leucocitos y, en consecuencia, eleva los niveles intracelulares de AMPc, dando como resultado la inhibición de las respuestas celulares. La combinación de PGE2 y un inhibidor de la PDE4 eleva sinérgicamente los niveles de AMPc en estos tipos de células, y la elevación de AMPc en CMSP producida por los inhibidores de la PDE4 en presencia de PGE2 es proporcional a la actividad inhibitoria de ese inhibidor de la PDE4. El AMPc intracelular se midió en CMSP humanas del modo siguiente. Se aislaron CMSP como se ha descrito anteriormente y se colocaron en placa en placas de 96 pocillos a 1 x 106 células por pocillo en RPMI-1640. Las células se pretrataron con compuestos a 100, 10, 1, 0,1, 0,01 y 0 µM en una concentración final de 2% de DMSO, por duplicado, a 37°C, en una incubadora humidificada a 5% de CO2 durante una hora. Las células se estimularon después con PGE2 (10 µM) (Sigma) durante 1 h. Las células se lisaron con HCl, concentración final 0,1 N, para inhibir la actividad de la fosfodiesterasa y las placas se congelaron a -20°C. El AMPc producido se midió usando el kit de Inmunoensayo (R&D Systems) de AMPc (pH bajo). La CE50 de AMPc de CMSP para el racemato es 3,09 µM. La CE50 de AMPc de CMSP para el Compuesto A es 1,58 µM
La elevación del AMPc en neutrófilos humanos se midió del modo siguiente. Se separaron CMSP de leucocitos fuente (Sera-Tec Biologicals) por centrifugación sobre Ficoll-Paque Plus (Amersham Pharmacia). El sedimento de eritrocito/célula polimorfonuclear (PMN) resultante se volvió a suspender en Hank’s Balanced Salt Solution (Bio Whittaker) y se mezcló con un volumen igual de Dextrano T-500 al 3% (Amersham Pharmacia) en solución salina al 0,9%. Los eritrocitos se dejaron sedimentar durante 20 minutos y las PMN se separaron y centrifugaron a 120 rpm durante 8 minutos a 4°C. Los eritrocitos restantes se lisaron en solución salina al 0,2% fría durante 30 segundos, y las células se restauraron hasta isotonicidad mediante la adición de un volumen igual de solución salina al 1,6%. Las PMN se centrifugaron a 1200 rpm durante 8 minutos a 4°C, después se volvieron a suspender en RPMI-1640 y se sometieron a ensayo para determinar la elevación de AMPc como se ha descrito para las CMSP anteriormente. Se encontró que las PMN eran aproximadamente neutrófilos con 74% de CD18/CD11b+, 71% de CD16+CD9+ por citometría de flujo en un FACSCalibur (Becton Dickinson, San José, CA, EE UU). Los resultados se muestran en la Tabla 2.
Producción de LTB4 inducida por fMLF
La N-formil-metionina-leucina-fenilalanina (fMLF) es un péptido obtenido a partir de bacterias que activa los neutrófilos para desgranularse, migrar y adherirse rápidamente a células endoteliales y liberar leucotrieno LTB4, un producto del metabolismo del ácido araquidónico y él mismo un quimioatrayente de neutrófilos. Los compuestos se sometieron a ensayo para determinar la capacidad para bloquear la producción de LTB4 de neutrófilo inducida por fMLF como se ha descrito anteriormente (Hatzelmann y Schudt 2001, J. Pharm. Exp. Ther. 297:267-279), con las siguientes modificaciones. Los neutrófilos se aislaron como se ha descrito anteriormente y se volvieron a suspender en solución salina tamponada con fosfato sin calcio o magnesio (Bio Whittaker) que contenía HEPES pH 7,2 10 mM, y se colocaron en placa en placas de cultivo de tejidos de 96 pocillos a una concentración de 1,7 x 106 células/pocillo. Las muestras se trataron con timerosal 50 µM (Sigmna)/CaCl2 1 mM/MgCl2 1 mM durante 15 minutos a 37°C, 5% de CO2, después se trataron con compuestos a 1000, 200, 40, 8, 1,6, 0,32, 0,064 y 0 µM en una concentración final de DMSO de 0,01%, por duplicado, durante 10 minutos. Los neutrófilos se estimularon con fLMF 1µM durante 30 minutos, después se lisaron mediante la adición de metanol (20% de concentración final) y se congelaron en un baño de hielo seco/isopropanol durante 10 minutos. Los lisados se almacenaron a -70°C hasta que se midió el contenido en LTB4 por ELISA de LTB4 competitivo (R&D Systems). Los resultados se muestran en la Tabla 2.
Producción de IL-8 inducida por Zimosano
El Zimosano A, o la levadura Saccharomyces cerevisiae destruida térmicamente, se une a la molécula de adhesión Mac-1 sobre la superficie del neutrófilo y pone en funcionamiento la fagocitosis, activación de la célula y producción de IL-8. La producción de IL-8 inducida por Zimosano se midió como se ha descrito anteriormente (Au et al., 1998, Brit. J. Pharm. 123:1260-1266) con las siguientes modificaciones. Se purificaron neutrófilos humanos como se ha descrito anteriormente, se colocaron en placa en placas de cultivo de tejidos de 96 pocillos a 3 x 105 células/pocillo en medio completo, se trataron con compuestos a 10, 2, 0,4, 0,08, 0,016, 0,0032, 0,00064 y 0 µM, por duplicado, en una concentración final de DMSO de 0,1%, durante 1 hora a 37°C, 5% de CO2. Los neutrófilos se estimularon después con Zimosano A (Sigma) hervido, no opsonizado, a 2,5 x 105 partículas/pocillo durante 18 horas. Se recolectaron los líquidos sobrenadantes y se sometieron a ensayo para determinar IL-8 por ELISA (R&D Systems).
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Los resultados se muestran en la Tabla 2.
Expresión de CD18/CD11b inducida por fMLF
Se midió la expresión de CD18/CD11b (Mac-1) sobre neutrófilos como se ha descrito anteriormente (Derian et al., 1995, J. Immunol.: 154:308-317) con las siguientes modificaciones. Se aislaron neutrófilos como se ha descrito anteriormente, después se volvieron a suspender en medio completo a 1 x 106 células/ml, se pretrataron con compuestos a 10, 1, 0,1, 0,01 y 0 µM, por duplicado, a una concentración final de DMSO de 0,1%, durante 10 minutos a 37°C, 5% de CO2. Las células se estimularon después con fMLF 30 nM durante 30 minutos y después se enfriaron hasta 4°C. Las células se trataron con IgG de conejo (Jackson ImmunoResearch Labs, West Grove, PA, EE UU) (10 µg/1 x 106 células) para bloquear los receptores de Fe, se tiñeron con CD18-FITC y CD11b-PE (Becton Dickinson) y se analizaron mediante citometría de flujo en un FACSCalibur. La expresión de CD18/CD11b (fluorescencia media) en ausencia de estimulación se restó de todas las muestras para obtener las curvas de inhibición y calcular los CI50. Los resultados se muestran en la Tabla 2.
Adhesión a CEVUH inducida por fMLF
Se usaron células endoteliales de vena umbilical humana (CEVUH) como sustrato para la adhesión de neutrófilos como se ha descrito anteriormente (Derian et al., 1995, J. Immunol.: 154:308-317) con las siguientes modificaciones. Las células CEVUH se obtuvieron de Anthrogenesis (Cedar Knolls, NJ, EE UU), y los neutrófilos no se trataron con citocalasina B. Las células se trataron con compuestos a 10, 1, 0,1, 0,01, 0,001 y 0 µM, en una concentración final de DMSO de 0,1%, por duplicado, durante 10 minutos, se estimularon con fMLF 500 nM durante 30 minutos, y se lavaron dos veces con PBS antes de medir la fluorescencia en un lector de placas FLX800 (Bio-Tek Instruments, Winooski, VT, EE UU). Los resultados se muestran en la Tabla 2.
Tabla 2
- Ensayos con neutrófilos humanos (todos los valores en nM)
- Compuesto Racémico Compuesto A
- CE50 de AMPc inducido por PGE2
- 12589 4570
- CI50 de LTB4 inducido por fMLF
- 20,1 2,48
- CI50 de IL-8 inducido por Zimosano
- ND 94
- CI50 de la expresión de CD18 inducida por fMLF
- ND 390
- CI50 de la expresión de CD11b inducida por fMLF
- ND 74
- CI50 de la adhesión a CEVUH inducida por fMLF
- ND 150
5.8. EJEMPLO 8: SOLUBILIDAD ACUOSA
Se midieron solubilidades en equilibrio en tampón acuoso a pH 7,4. El tampón a pH 7,4 se preparó ajustando el pH de una solución de NaH2PO4 0,07 M hasta 7,4 con NaOH 10 N. La fuerza iónica de la solución era 0,15. Al menos 1 mg de polvo se combinó con 1 ml de tampón para hacer una mezcla >1 mg/kg. Estas muestras se sacudieron durante >2 horas y se dejaron reposar por la noche a temperatura ambiente. Las muestras se filtraron después a través de un filtro de jeringa de nailon de 0,45 µm que se saturó primero con la muestra. El filtrado se muestreó dos veces, consecutivamente. El filtrado se sometió a ensayo por HPLC frente a patrones preparados en metanol al 50%. El Compuesto A tenía una solubilidad acuosa 3,5 veces mayor que la mezcla racémica. Solubilidad del Compuesto A medida = 0,012 mg/ml; mezcla racémica = 0,0034 mg/ml.
5.9. EJEMPLO 8: MODELO EN HURÓN DE NEUTROFILIA DE PULMÓN INDUCIDA POR LPS
Se ha usado el modelo de hurón consciente para investigar los efectos antiinflamatorios, eméticos y de comportamiento de los inhibidores de la PDE4 cuando se administran por la ruta oral (p.o.). De estos experimentos se puede determinar un índice terapéutico (IT) para cada inhibidor de la PDE4. El índice terapéutico ha sido calculado dividiendo la dosis umbral para producir episodios eméticos y cambios de comportamiento por la dosis antiinflamatoria (dosis que produce el 50% de inhibición de la neutrofilia inducida por LPS).
Manejo de animales
Hurones macho (Mustela Pulorius Euro, que pesaban 1-2 kg). Los hurones fueron suministrados tanto por Bury Green Farm como por Misay Consultanci. Después del transporte, los animales se dejaron aclimatar en las cámaras de estancia durante un periodo no menor que 7 días. La dieta comprendía comida peletizada C de dieta
(7/22), se vieron cambios de comportamiento leves (lamido de labios y marcha hacia atrás).
El Compuesto A (0,1-3 mg/kg, p.o.) no produjo episodios eméticos (náuseas y vómitos). Se observaron algunos cambios de comportamiento (postura aplastada, lamido de labios y marcha hacia atrás) y se clasificaron como leves. A 10 mg/kg en 2/6 hurones, se observaron algunas náuseas pero no emesis marcada junto con salivación y cambios de comportamiento (valorados como leves o moderados). A la dosis más alta sometida a ensayo (30 mg/kg) se observó emesis de moderada a marcada en 3/4 animales junto con cambios de comportamiento pronunciados. Estos datos se resumen en la Tabla III.
Tabla III. Hurón consciente: Episodios eméticos y cambios de comportamiento después de la administración oral de Compuesto A.
- Tratamiento/ Dosis (mg/kg)
- Vómitos Náuseas Salivación Jadeo Arañado de la boca Postura aplastada Ataxia Lamido de los labios Marcha hacia atrás
- Vehículo (acetona/ cremofor/ H2O destil.)
- Ninguno Ninguno Ninguno Ninguno Ninguno Ninguno Ninguno Leve (6/22) Leve (7/22)
- Compuesto A (0,1 mg/kg)
- Ninguno Ninguno Ninguno Ninguno Ninguno Leve (2/5) Ninguno Leve (4/5) Leve (3/5)
- Compuesto A (0,3 mg/kg)
- Ninguno Ninguno Ninguno Ninguno Ninguno Leve (2/6) Ninguno Leve (3/6) Leve (4/6)
- Compuesto A (1,0 mg/kg)
- Ninguno Ninguno Ninguno Ninguno Ninguno Leve (2/6) Ninguno Leve (6/6) Leve (4/6)
- Compuesto A (3,0 mg/kg)
- Ninguno Ninguno Ninguno Ninguno Leve (1/8) Marcado (7/8) Ninguno Leve (2/8) Moderado (5/8)
- Compuesto A (10 mg/kg)
- Ninguno Leve (2/6) Leve (1/6) Ninguno Leve (1/6) Marcado (6/6) Ninguno Moderado (5/6) Marcado (6/6)
- Compuesto A (30 mg/kg)
- Moderad o (3/4) Marcado (3/4) Moderado (3/4) Leve (1/4) Marcado (4/4) Marcado (4/4) Leve (3/4) Moderado (4/4) Leve (2/4)
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Se observaron los animales hasta 3 horas después de la dosificación. Los números entre paréntesis se refieren al número de animales que respondieron. Los números de animales en cada grupo varían de 4-22.
Cálculo del Índice Terapéutico
A partir de estos experimentos, se determinó un índice terapéutico (IT) para cada compuesto dividiendo la dosis
15 umbral para inducir episodios eméticos por el valor de ED50 para inhibir la neutrofilia pulmonar. El cálculo del IT se resume en la Tabla IV. El Compuesto A tenía un IT de 12, no produciendo episodios eméticos a una dosis antiinflamatoria de 1 mg/kg.
Tabla IV. Resumen de las dosis eficaces (DE50) para la inhibición de la neutrofilia pulmonar inducida por LPS y la inducción de emesis y el índice terapéutico derivado de estos valores.
- Compuesto
- Inhibición de neutrofilia inducida por LPS(DE50, mg/kg) Dosis emética umbral (mg/kg) Índice terapéutico
- Compuesto A
- 0,8 10 12
5.10. EJEMPLO 9: CÁPSULA DE DOSIFICACIÓN DE 200 MG
La Tabla V ilustra una formulación de carga y una formulación de dosificación única para una unidad de dosis única de Compuesto A de 200 mg, es decir, aproximadamente 40 por ciento en peso, en una cápsula de tamaño nº 0.
Tabla V. Formulación para una cápsula de 200 mg
- Material
- Porcentaje en peso Cantidad (mg/cápsula) Cantidad (kg/carga)
- Compuesto A
- 40,0% 200 mg 16,80 kg
- Almidón de maíz pregelatinizado, NF5
- 9,5% 297,5 mg 24,99 kg
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- Material
- Porcentaje en peso Cantidad (mg/cápsula) Cantidad (kg/carga)
- Estearato magnésico
- 0,5% 2,5 mg 0,21 kg
- Total
- 100,0% 500 mg 42,00 kg
Los componentes de almidón de maíz pregelatinizado (SPRESS B-820) y Compuesto A se pasan a través de un tamiz de 710 µm y después se cargan en un Diffusion Mixer con una inserción deflectora y se mezclan durante 15 minutos. El estearato magnésico se pasa a través de un tamiz de 210 µm y se añade al Diffusion Mixer. La mezcla se encapsula después en una cápsula de tamaño nº 0, 500 mg por cápsula (tamaño de la carga 8400 cápsulas) usando una máquina de llenado de cápsulas tipo Dosator.
5.11. EJEMPLO 10: FORMA DE DOSIFICACIÓN ORAL DE 100 MG
La Tabla VI ilustra una formulación de carga y una formulación de unidad de dosis única que contiene 100 mg de Compuesto A.
Tabla VI. Formulación para un comprimido de 100 mg
- Material
- Porcentaje en peso Cantidad (mg/comprimido) Cantidad (kg/carga)
- Compuesto A
- 40% 100,00 20,00
- Celulosa microcristalina, NF
- 53,5% 133,75 26,75
- Tensioactivo Pluronic F-68
- 4,0% 10,00 2,00
- Croscarmelosa sódica Tipo A, NF
- 2,0% 5,00 1,00
- Estearato magnésico, NF
- 0,5% 1,25 0,25
- Total
- 100,0% 250,00 mg 50,00 kg
Los componentes celulosa microcristalina, croscarmelosa sódica y Compuesto A se pasan a través de un tamiz de tamaño de malla nº 30 (aproximadamente 430 µm hasta aproximadamente 655 µm). El tensioactivo Pluronic F-68® (fabricado por JRH Biosciences, Inc. de Lenexa, KS) se pasa a través de un tamiz de tamaño de malla nº 20 (aproximadamente 457 µm hasta aproximadamente 1041 µm). El tensioactivo Pluronic F-68® y 0,5 kg de croscarmelosa sódica se cargan en un mezclador de volteo de cámaras gemelas de 15,1 l (16 qt) y se mezclan durante aproximadamente 5 minutos. La mezcla se transfiere después a un mezclador de volteo de cámaras gemelas de 84,96 litros (3 pies cúbicos) donde se añade y mezcla la celulosa microcristalina durante aproximadamente 5 minutos. La talidomida se añade y mezcla durante 25 minutos adicionales. Esta mezcla previa se pasa a través de un compactador de rodillo con un molino de martillos unido a la descarga del compactador de rodillo y se lleva de vuelta al mezclador de volteo. La croscarmelosa sólida y el estearato magnésico residuales se añaden al mezclador de volteo y se mezclan durante aproximadamente 3 minutos. La mezcla final se comprime en una prensa de comprimidos rotatoria con 250 mg por comprimido (tamaño de la carga 200.000 comprimidos).
5.12. EJEMPLO 11: FORMA DE DOSIFICACIÓN EN AEROSOL
Se prepara un concentrado combinando el Compuesto A y una porción de 12,6 kg de tricloromonofluorometano en un recipiente de acero inoxidable sellado equipado con un mezclador de alto cizallamiento. La mezcla se lleva a cabo durante aproximadamente 20 minutos. La suspensión a granel se prepara después en un recipiente sellado combinando el concentrado con el resto de los propulsores en un depósito de producto a granel que está a temperatura controlada de 21 hasta 27°C y presión controlada a 2,8 hasta 4,0 bar. Se preparan recipientes de aerosol de 17 ml que tienen una válvula dosificadora que está diseñada para proporcionar 100 inhalaciones de la composición de la invención. Cada recipiente está provisto con lo siguiente:
- Compuesto A
- 0,0120 g
- tricloromonofluormetano
- 1,6939 g
- diclorodifluormetano
- 3,7175 g
- diclorotetrafluoretano
- 1,5766 g
- total
- 7,0000 g
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