ES2621257T3 - Ésteres de ciclopropanocarboxilato de análogos de purinas - Google Patents

Ésteres de ciclopropanocarboxilato de análogos de purinas Download PDF

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ES2621257T3
ES2621257T3 ES13778039.1T ES13778039T ES2621257T3 ES 2621257 T3 ES2621257 T3 ES 2621257T3 ES 13778039 T ES13778039 T ES 13778039T ES 2621257 T3 ES2621257 T3 ES 2621257T3
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compound
amino
purine analogue
esters
cyclopropanecarboxylate esters
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Ji-Wang Chern
Shin-Yu LAI
Pei-Teh Chang
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Annji Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/45—Transferases (2)
    • 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
    • A61P31/20—Antivirals for DNA 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
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Un compuesto de Fórmula (T)**Fórmula** o una sal farmacéuticamente aceptable de este, en donde Rx y Rz son cada uno independientemente hidrógeno o (C1-C6)alquilo; y Ry es (C1-C6)alquilo, halo(C1-C6)alquilo, (C6-C18)arilo, halo(C6-C18)arilo, o (C3-C18)heteroarilo.

Description

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imagen11
El Compuesto 11 sesintetizómedianteelusodeunmétodosimilaraldescritoenlosEjemplos2y3.YD:16%. 1HNMR (CD3OD, 400 MHz) 1H NMR (CD3OD, 400 MHz) δ 2,01 (m, 1H), 2,15 (m, 1H), 2,12 (m, 2H), 3,14 (m, 1H), 3,33 (m, 1H), 3,64 (m, 2H), 3,93 (m, 1H), 4,12 (dd, J = 9,4 Hz, J = 4,2 Hz, 1H), 4,25 (dd, J = 9,2 Hz, J = 3,2 Hz, 1H), 5,57 (s, 2H), 7,327,37 (m, 1H), 7,46-7,49 (m, 1H), 7,77-7,83 (m, 1H), 7,86 (s, 1H), 8,60-8,64 (m, 1H). 13C NMR δ 16,7, 17,1, 30,6, 31,48, 39,3, 40,8, 61,7, 62,6, 66,1, 72,8, 78,8, 108,4, 110,9, 128,1, 137,8, 142,3, 148,9, 152,3, 155,6, 160,1, 173,0, 173,2.
Ejemplo 12
Estabilidad hidrolítica del Compuesto 3 y análogos de este
El Compuesto 3 y sus análogos (2-(2-amino-6-oxo-1,6-dihidro-purin-9-il metoxi)-3-hidroxipropil ésteres del ácido 1amino-ciclopropanocarboxílico sustituidos) se sometieron a prueba para determinar la estabilidad hidrolítica en una solución tamponada con fosfato de diversos pH (1, 4, 7,4, 10) a una concentración de 1 mg/ml y 40 °C, mediante el uso de una técnica de HPLC semiautomatizada durante el período de 12 horas. El ácido clorhídrico de 0,1 N se usó para la solución de pH 1.
Las muestras se inyectaron manual y repetidamente en el HPLC a intervalos de tiempo específicos a temperatura ambiente. Las áreas de los picos de los compuestos se controlaron mediante detección de UV. El Compuesto 3 fue estable en una solución ácida (pH 4) con T1/2> 300 horas. En las condiciones fisiológicas (pH = 7,4), su valor de vida media (T1/2) fue de 53 horas (Figura 1). Los valores de vida media (T1/2, a pH 7,4, 40 °C) de sus análogos, de los Compuestos 5, 6, 7, 8, 9, 10, 11 fueron de 85, 75, 68, 58, 33, 29, 43 horas, respectivamente. El "valor de vida media, T1/2" se refiere al tiempo requerido para una mitad de la cantidad total de un compuesto en una solución para ser degradado por los procesos de hidrólisis cuando la velocidad de eliminación es casi exponencial. La vida media se calculó de la siguiente manera: El área del pico de la muestra del compuesto se controló en un período de 12 horas a intervalos de 2 horas, y se graficó contra el tiempo para cada uno de los tampones que se probaron. Un cálculo de primer orden se usó para determinar la velocidad constante para cada tampón sobre la pérdida del área del pico en el tiempo.
Ejemplo 13
Solubilidad acuosa del Compuesto 3 y análogos de este
Se analizó la solubilidad del Compuesto 3 y sus análogos (2-(2-amino-6-oxo-1,6-dihidro-purin-9-il metoxi)-3-hidroxipropil ésteres del ácido 1-amino-ciclopropanocarboxílico sustituidos).
El procedimiento del experimento de solubilidad se modificó debido a las estabilidades químicas. Brevemente, a un exceso de un compuesto de prueba se añadió 0,5 ml de agua en un frasco pequeño de un ml, se llevó al equilibrio previamente, y después se sometió a sonicación a 23 °C durante 3 min. Las alícuotas se filtraron y se analizaron para determinar los contenidos del fármaco. La concentración de cada compuesto se determinó mediante HPCL, a λ = 254 nm, 23° C. La alícuota que contiene el analito se diluyó 100X debido al límite de detección del instrumento. Los resultados mostraron que la solubilidad acuosa del Compuesto 3 fue de 180 mg/ml, lo cual fue superior al ganciclovir (solubilidad 2,6 mg/ml). La solubilidad de los compuestos 4, 5, 6, 7, 9, 10, 11 fue de 227, 155, 170, 213, 261, 260, 253 mg/ml, respectivamente.
Ejemplo 14
Actividad anti-HSV in vitro del 2-(2-amino-6-oxo-1,6-dihidro-purin-9-il metoxi)-3-hidroxipropil éster del ácido 1-aminociclopropanocarboxílico (Compuesto 3)
Se cultivaron células epiteliales humanas (HEp-2) en MEM suplementado con 10 % de suero fetal bovino y 10 % de suero de ternero recién nacido. Las células Vero se cultivaron en RPMI-1640 y 10 % de suero de ternero recién nacido activado por calor. En el medio estaban presentes penicilina (1000 I.U/ml), estreptomicina (100 µg/ml), y tampón de bicarbonato, y las células se mantuvieron a 37°C, 5 % de CO2, atmósfera húmeda, y se subcultivaron 2∼3 veces a la semana.
La actividad antiviral del Compuesto 3 se determinó mediante la evaluación de la atenuación de los efectos citopáticos inducidos por HSV-1 en las células Vero. Las células Vero (10 000 células/pocillo) en una placa de cultivo de 96 pocillos
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Comp. 10
2-(2-Amino-6-oxo-1,6-dihidro-purin9-ilmetoxi)-3-hidroxipropil éster del ácido 1-amino-2-furan-2-ilciclopropanocarboxílico imagen14 Rx = hidrógeno Ry = 2-furilo Rz = hidrógeno
Comp. 11
2-(2-Amino-6-oxo-1,6-dihidro-purin9-ilmetoxi)-3-hidroxipropil éster del ácido 1-amino-2-piridin-2-ilciclopropanocarboxílico imagen15 Rx = hidrógeno Ry = 2-piridilo Rz = hidrógeno
Rx y Rz son cada uno independientemente hidrógeno ometilo; y Ry es hidrógeno, metilo, trifluorometilo, fenilo, 4-bromofenilo, 2-furilo, o 2-piridilo.
15

Claims (1)

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ES13778039.1T 2012-04-20 2013-04-02 Ésteres de ciclopropanocarboxilato de análogos de purinas Active ES2621257T3 (es)

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US201261635931P 2012-04-20 2012-04-20
US201261635931P 2012-04-20
PCT/US2013/035042 WO2013158367A1 (en) 2012-04-20 2013-04-02 Cyclopropanecarboxylate esters of purine analogues

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ES13777764.5T Active ES2600467T3 (es) 2012-04-20 2013-04-03 Derivados de indolin-2-ona como inhibidores de proteína cinasa

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KR101774861B1 (ko) 2017-09-05
WO2013158367A1 (en) 2013-10-24
US8946282B2 (en) 2015-02-03
US8969361B2 (en) 2015-03-03
US20130281451A1 (en) 2013-10-24
WO2013158373A8 (en) 2014-10-30
WO2013158373A1 (en) 2013-10-24
JP6174119B2 (ja) 2017-08-02
KR20150005630A (ko) 2015-01-14
IN2014MN02105A (es) 2015-09-11
TWI458709B (zh) 2014-11-01
ES2600467T3 (es) 2017-02-09
CN104302287B (zh) 2017-12-26
EP2838538A1 (en) 2015-02-25
BR112014026182A2 (pt) 2017-06-27
RU2014145480A (ru) 2016-06-10
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TW201350485A (zh) 2013-12-16
IL235097A (en) 2017-07-31
EP2838531B1 (en) 2016-09-21
RU2642463C2 (ru) 2018-01-25
JP6177879B2 (ja) 2017-08-09
AU2013249714B2 (en) 2016-12-15
IN2014MN02107A (es) 2015-09-11
IL235098A0 (en) 2014-12-31
KR101778095B1 (ko) 2017-09-13
EP2838538B1 (en) 2017-03-15
EP2838531A4 (en) 2015-12-16
CN104394868A (zh) 2015-03-04
EP2838531A1 (en) 2015-02-25
AU2013249708B2 (en) 2017-03-16
EP2838538A4 (en) 2015-09-02
KR20150005600A (ko) 2015-01-14
RU2627706C2 (ru) 2017-08-10
AU2013249708A1 (en) 2014-11-13
AU2013249714A1 (en) 2014-11-13
TW201343627A (zh) 2013-11-01

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