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ES2586668T3 - Análogos de nucleósidos fluorados modificados - Google Patents

Análogos de nucleósidos fluorados modificados Download PDF

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Publication number
ES2586668T3
ES2586668T3 ES13152340.9T ES13152340T ES2586668T3 ES 2586668 T3 ES2586668 T3 ES 2586668T3 ES 13152340 T ES13152340 T ES 13152340T ES 2586668 T3 ES2586668 T3 ES 2586668T3
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compound
pharmaceutically acceptable
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nucleoside analogs
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ES2586668T5 (es
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Jeremy Clark
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Gilead Pharmasset LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/048—Pyridine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/14—Pyrrolo-pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals

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Abstract

Un nucleosido (ß-D o ß-L) de (2'R)-2'-desoxi-2'-fluoro-2'-C-metilo o una sal farmaceuticamente aceptable del mismo de la estructura:**Fórmula** en la que la Base es una base pirimidinica representada por la siguiente formula**Fórmula** X es O; R1 y R7 son independientemente H, un monofosfato, un difosfato o un trifosfato; R3 es H y R4 es NH2 u OH.

Description

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En las diversas realizaciones, se prefieren los derivados fluorados. Flúor es considerado como “isostérico” del hidrógeno debido a su tamaño (los radios de Van der Waals son para el H 1,20 A y para el F 1,35 A). Sin embargo, el peso atómico (18,998) y la electronegatividad del flúor (4,0 [escala de Pauling], 4,000 [escala de Sanderson]) son más similares al oxígeno (3,5 [Pauling], 3,654 [Sanderson]) que al hidrógeno (2,1 [Pauling], 2,592 [Sanderson]) (March, J., "Advances in Organic Chemistry: Reactions, Mechanisms, and Structure" Third edition, 1985, p. 14., Wiley Interscience, New York). El flúor es conocido por ser capaz de formar un enlace de hidrógeno, pero a diferencia del grupo hidroxilo (que puede actuar tanto como aceptor de protones como donador de protones), el flúor actúa solamente como aceptor de protones. Por otro lado, los 2'-fluoro-ribonucleósidos pueden ser considerados como análogos tanto de ribonucleósidos como de desoxinucleósidos. Pueden ser reconocidos mejor por la ARN polimerasa viral a nivel del trifosfato que por la ARN polimerasa del hospedador inhibiendo selectivamente así la enzima viral.
II. Sales farmacéuticamente aceptables
En los casos donde los compuestos son suficientemente básicos o ácidos para formar sales de ácido o base no tóxicas, estables, puede ser apropiada la administración del compuesto como una sal farmacéuticamente aceptable. Las sales farmacéuticamente aceptables incluyen aquellas derivadas de bases y ácidos inorgánicos u orgánicos farmacéuticamente aceptables. Las sales adecuadas incluyen aquellas derivadas de metales alcalinos tales como potasio y sodio, metales alcalinotérreos tales como calcio y magnesio, entre numerosos ácidos distintos bien conocidos en la técnica farmacéutica. En particular, ejemplos de sales farmacéuticamente aceptables son sales de adición de ácido orgánico formadas con ácidos, que forman un anión fisiológicamente aceptable, por ejemplo, tosilato, metanosulfonato, acetato, citrato, malonato, tartrato, succinato, benzoato, ascorbato, α-cetoglutarato y αglicerofosfato. También pueden formarse sales inorgánicas adecuadas, incluyendo, sales de sulfato, nitrato, bicarbonato y carbonato.
Pueden obtenerse sales farmacéuticamente aceptables utilizando procedimientos estándar bien conocidos en la técnica, por ejemplo, haciendo reaccionar un compuesto suficientemente básico tal como una amina con un ácido adecuado que produce un anión fisiológicamente aceptable. También pueden obtenerse sales de metal alcalino (por ejemplo, sodio, potasio o litio) o de metal alcalinotérreo (por ejemplo calcio) de ácidos carboxílicos.
III. Composiciones farmacéuticas
Las composiciones farmacéuticas basadas en un compuesto β -D o β -L divulgadas en la presente memoria o su sal farmacéuticamente aceptable pueden prepararse en una cantidad terapéuticamente efectiva para tratar una infección por Flaviviridae, incluyendo el virus de la hepatitis C, el virus del Nilo Occidental, el virus de la fiebre amarilla y una infección por rinovirus, opcionalmente en combinación con un aditivo, vehículo o excipiente farmacéuticamente aceptable. La cantidad farmacéuticamente efectiva puede variar con la infección o afección a ser tratada, su gravedad, el régimen de tratamiento a ser empleado, la farmacocinética del agente empleado, así como el paciente tratado.
En un aspecto de acuerdo con la presente invención, el compuesto de acuerdo con la presente invención es formulado preferiblemente en una mezcla con un vehículo farmacéuticamente aceptable. En general, es preferible administrar la composición farmacéutica en forma de administración oral, pero las formulaciones pueden administrarse por vía parenteral, intravenosa, intramuscular, transdérmica, bucal, subcutánea, por supositorio o por otra vía. Las formulaciones intravenosas o intramusculares se administran preferiblemente en solución salina estéril. Un experto con habilidades ordinarias en la técnica puede modificar la formulación dentro de las enseñanzas de la memoria para proporcionar diversas formulaciones para una vía particular de administración sin que las composiciones de la presente invención se conviertan en inestables o se vea comprometida su actividad terapéutica. En particular, una modificación de un compuesto deseado para hacerlo más soluble en agua o en otro vehículo, por ejemplo, puede realizarse fácilmente mediante una modificación de rutina (formulación salina, esterificación, etc.).
La cantidad del compuesto incluido dentro de las formulaciones terapéuticamente activas, de acuerdo con la presente invención, es una cantidad efectiva para tratar la infección o afección, en las realizaciones preferidas, una infección por Flaviviridae, incluyendo el virus de la hepatitis C, el virus del Nilo Occidental, el virus de la fiebre amarilla y una infección por rinovirus. En general, una cantidad terapéuticamente efectiva del compuesto presente en forma de dosificación farmacéutica normalmente varía de aproximadamente 50 mg a aproximadamente 2.000 mg
o más, dependiendo del compuesto empleado, la afección o infección tratada y la vía de administración. Para los propósitos de la presente invención, una cantidad profiláctica o preventivamente efectiva de las composiciones, de acuerdo con la presente invención, está dentro del mismo intervalo de concentración que el establecido anteriormente para una cantidad terapéuticamente efectiva y es normalmente la misma que una cantidad terapéuticamente efectiva.
La administración del compuesto activo puede variar de la administración continua (goteo intravenoso) a varias orales por día (por ejemplo, Q.I.D., B.I.D., etc.) y puede incluir la administración oral, tópica, parenteral, intramuscular, intravenosa, subcutánea, transdérmica (que puede incluir un agente adyuvante de la penetración), bucal y por supositorio, entre otras vías de administración. También pueden utilizarse comprimidos orales con
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tópica, en forma líquida o sólida.
Una dosis preferida del compuesto para una infección por Flaviviridae, incluyendo el virus de la hepatitis C, el virus del Nilo Occidental, el virus de la fiebre amarilla y una infección por rinovirus estará en el intervalo de aproximadamente 50 a aproximadamente 2000 mg una a cuatro veces por día. Pueden ser útiles dosis inferiores, y de esta forma los intervalos pueden incluir de 50 – 1.000 mg una a cuatro veces por día. El intervalo de dosis efectiva de las sales farmacéuticamente aceptables y profármacos pueden calcularse basándose en el peso del nucleósido original a ser administrado. Si la propia sal o profármaco presenta actividad, la dosificación efectiva puede estimarse como antes utilizando el peso de la sal o profármaco, o por otros medios conocidos para aquellos expertos en la técnica.
El compuesto se administra convenientemente en cualquier forma farmacéutica unitaria adecuada, incluyendo pero sin limitarse a una que contiene de 25 a 3.000 mg, preferiblemente de 50 a 2.000 mg de principio activo por forma farmacéutica unitaria. Una dosis oral de 50-1.000 mg es normalmente conveniente, incluyendo en una o múltiples formas farmacéuticas de 50, 100, 200, 250, 300, 400, 500, 600, 700, 800, 900 o 1.000 mg. También son contempladas dosis de 0,1-50 mg o de 0,1-20 mg o de 0,1-10 mg. Además, pueden utilizarse dosis inferiores en el caso de administración por una vía no oral, como, por ejemplo, por inyección o inhalación.
Idealmente el principio activo debe administrarse para lograr concentraciones plasmáticas máximas (Cmáx) del compuesto activo desde aproximadamente 5,0 a 70 µM, preferiblemente de aproximadamente 5,0 a 15 µM. Esto puede lograrse, por ejemplo, mediante la inyección intravenosa de una solución de 0,1 a 5 % del principio activo, opcionalmente en solución salina, o administrada como un bolo del principio activo.
La concentración del compuesto activo en la composición del fármaco dependerá de las tasas de absorción, inactivación y excreción del fármaco, así como de otros factores conocidos para aquellos expertos en la técnica. Hay que señalar que los valores de la dosis también variarán con la gravedad de la afección a ser aliviada. Se entiende además que para cualquier sujeto particular, los regímenes posológicos específicos deben ajustarse durante un tiempo de acuerdo con la necesidad del individuo y el criterio profesional de la persona que administra o supervisa la administración de las composiciones y que los intervalos de concentración establecidos en la presente memoria son solamente ilustrativos y no están destinados a limitar el alcance o práctica de la composición reivindicada. El principio activo puede administrarse una vez o puede dividirse en varias dosis más pequeñas para ser administradas en intervalos de tiempo variables.
Un modo preferido de administración del compuesto activo es oral. Las composiciones orales incluirán en general un diluyente inerte o un vehículo comestible. Pueden estar incluidas en cápsulas de gelatina o comprimidos en comprimidos. Para el propósito de la administración terapéutica oral, el compuesto activo puede incorporarse con excipientes y utilizarse en la forma de comprimidos, trociscos o cápsulas. Pueden incluirse como parte de la composición agentes aglutinantes farmacéuticamente compatibles, y/o materiales adyuvantes.
Los comprimidos, píldoras, cápsulas, trociscos y similares pueden contener cualquiera de los ingredientes siguientes, o compuestos de una naturaleza similar: un aglutinante tal como celulosa microcristalina, goma tragacanto o gelatina; un excipiente tal como almidón o lactosa, un agente disgregante tal como ácido algínico, Primogel o almidón de maíz; un lubricante tal como estearato de magnesio o Sterotes; un deslizante tal como dióxido de silicio coloidal; un agente edulcorante tal como sacarosa o sacarina; o un agente saborizante tal como menta, salicilato de metilo o saborizante de naranja. Cuando la forma farmacéutica unitaria es una cápsula, puede contener, además del material del tipo anterior, un vehículo líquido tal como aceite graso. Además, las formas farmacéuticas unitarias pueden contener varios materiales distintos que modifican la forma física de la unidad de dosificación, por ejemplo, recubrimientos de azúcar, goma laca u otros agentes entéricos.
El compuesto puede administrarse como un componente de un elíxir, suspensión, jarabe, oblea, goma de mascar o similares. Un jarabe puede contener, además de los compuestos activos, sacarosa como un agente edulcorante y ciertos conservantes, tintes y colorantes y sabores.
El compuesto o una sal farmacéuticamente aceptable del mismo puede mezclarse también con otros materiales activos que no afectan a la acción deseada, o con materiales que complementan la acción deseada, tal como antibióticos, antifúngicos, anti-inflamatorios u otros antivirales, incluyendo otros compuestos nucleósidos. Las soluciones o suspensiones utilizadas para la aplicación parenteral, intradérmica, subcutánea o tópica pueden incluir los siguientes componentes: un diluyente estéril tal como agua para inyección, solución salina, aceites fijos, polietilenglicoles, glicerina, propilenglicol u otros disolventes sintéticos; agentes antibacterianos tales como alcohol bencílico o metilparabenos; antioxidantes tales como ácido ascórbico o bisulfito de sodio; agentes quelantes tales como ácido etilendiaminotetraacético; tampones tales como acetatos, citratos o fosfatos y agentes para el ajuste de la tonicidad tales como cloruro de sodio o dextrosa. La preparación parenteral puede incluirse en ampollas, jeringas desechables o viales de dosis múltiples de vidrio o plástico.
Si se administra por intravenosa, los vehículos preferidos son solución salina o solución salina tamponada con fosfato (PBS).
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Claims (1)

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ES13152340T 2003-05-30 2004-04-21 Análogos de nucleósidos fluorados modificados Expired - Lifetime ES2586668T5 (es)

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TW202014413A (zh) 2014-06-11 2020-04-16 美商基利法瑪席特有限責任公司 製備抗病毒化合物之方法
TWI721947B (zh) 2014-06-11 2021-03-21 美商基利法瑪席特有限責任公司 抗病毒化合物的固態形式

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