ES2549260T3 - Profármacos de cianoguanidina - Google Patents

Profármacos de cianoguanidina Download PDF

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ES2549260T3
ES2549260T3 ES01983436.5T ES01983436T ES2549260T3 ES 2549260 T3 ES2549260 T3 ES 2549260T3 ES 01983436 T ES01983436 T ES 01983436T ES 2549260 T3 ES2549260 T3 ES 2549260T3
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ethoxy
cyano
methoxyethoxy
pyridinium
chlorophenoxy
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Ernst Torndal Binderup
Pernill-Julia Vig Hjarnaa
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Leo Pharma AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring

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  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyridine Compounds (AREA)
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Abstract

Un compuesto elegido entre el grupo que consiste en: cloruro de 1-[2-(2-(2-metoxietoxi)-etoxi)-etoxi-carboniloximetil]-4-[N'-ciano-N''-(6-(4-clorofenoxi)-hexil)-N-guanidino]- piridinio; cloruro de 1-[2-(2-metoxietoxi)-etoxi-carboniloximetil]-4-[N' 5 -ciano-N''-(6-(4-clorofenoxi)-hexil)-N-guanidino]-piridinio; cloruro de 1-[(2-metoxietoxi)-carboniloximetil]-4-[N'-ciano-N''-(6-(4-clorofenoxi)-hexil)-N-guanidino]-piridinio; yoduro de 1-[2-(2-(2-metoxietoxi)-etoxi)-etoxi-carboniloximetil]-4-[N'-ciano-N''-(6-(4-clorofenoxi)-hexil)-N-guanidino]- piridinio; N-[1-(2-(2-(2-metoxietoxi)-etoxi)-etoxicarboniloximetil)-1,4-dihidropiridin-4-ilideno]-N'-ciano-N''-(6-(4-clorofenoxi)- hexil)-guanidina; cloruro de 1-[2-(2-(2-metoxietoxi)-etoxi)-etoxi-carboniloximetil]-4-[N'-ciano-N''-(6-(4-clorofenoxi)-hexil)-N-guanidino]- piridinio; cloruro de 1-[1-(2-(2-metoxietoxi)-etoxi-carboniloxi)-etil]-4-[N'-ciano-N''-(6-(4-clorofenoxi)-hexil)-N-guanidino]-piridinio; cloruro de 1-[2-(2-(2-metoxietoxi)-etoxi)-etoxi-acetoximetil]-4-[N'-ciano-N''-(6-(4-clorofenoxi)-hexil)-N-guanidino]- piridinio; cloruro de 1-[2-(2-(2-(2-metoxietoxi)-etoxi)-etoxi)-etoxi-carboniloximetil]-4-[N'-ciano-N''-(6-(4-clorofenoxi)-hexil)-Nguanidino]- piridinio; cloruro de 1-[2-(2-(2-(2-(2-metoxietoxi)-etoxi)-etoxi)-etoxi)-etoxi-carboniloximetil]-4-[N'-ciano-N''-(6-(4-clorofenoxi)- hexil)-N-guanidino]-piridinio; cloruro de 1-[2-(2-(2-(2-(2-(2-metoxietoxi)-etoxi)-etoxi)-etoxi)-etoxi)-etoxi-carboniloximetil]-4-[N'-ciano-N''-(6-(4- clorofenoxi)-hexil)-N-guanidino]-piridinio; cloruro de 1-[2-(2-(2-metoxietoxi)-etoxi)-etoxi-carboniloximetil]-4-[N'-ciano-N''-(9-(dietoxifosfinoiloxi)-nonil)-Nguanidino]- piridinio; yoduro de 1-[2-(2-(2-metoxietoxi)-etoxi)-etoxi)-carboniloximetil]-4-[N'-ciano-N''-(12-(terc-butiloxicarbonilamino)- dodecil)-N-guanidino]-piridinio; cloruro de 1-[2-(2-(2-metoxietoxi)-etoxi)-etoxi)-carboniloximetil]-4-[N'-ciano-N''-(12-(terc-butiloxicarbonilamino)- dodecil)-N-guanidino]-piridinio; cloruro de 1-[2-(2-(2-(2-metoxietoxi)-etoxi)-etoxi)-etoxi-carboniloximetil]-4-[N'-ciano-N''-(12-(tercbutiloxicarbonilamino)- dodecil)-N-guanidino]-piridinio; yoduro de 1-[1-terc-butoxicarbonil)-4-piperidiloxi-carboniloximetil]-4-[N'-ciano-N''-(6-(4-clorofenoxi)-hexil)-Nguanidino]- piridinio; cloruro de 1-[4-piperidiloxi-carboniloximetil]-4-[N'-ciano-N''-(6-(4-clorofenoxi)-hexil)-N-guanidino]-piridinio, hidrocloruro; y N-[1-(α-(2-(2-(2-metoxietoxi)-etoxi)-etoxicarboniloxi)-bencil]-1,4-dihidropiridin-4-iliden]-N'-ciano-N''-(6-(4-clorofenoxi)- hexil)-guanidino.

Description

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Preparación 18
Carbonato de 3-(N-terc-butoxicarbonilamino)-propilo y yodometilo
Preparado como se describe en la preparación 5 pero sustituyendo por carbonato de 3-(N-terc-butoxicarbonilamino)propilo y clorometilo el carbonato de 2-(2-(2-metoxietoxi)-etoxi)-etilo y clorometilo. El aceite amarillo resultante se purificó por cromatografía sobre gel de sílice con éter de petróleo/acetato de etilo (2:1) como eluyente. Aceite amarillo pálido.
RMN de 1H (CDCl3)  = 5,95 (s, 2H), 4,68 (br, 1H), 4,29 (t, 2H), 3,21 (q, 2H), 1,89 (m, 2H), 1,44 (s, 9H).
Preparación 19 N-(3-(N-terc-butoxicarbonilamino)-propil)-carbamato de clorometilo
Una disolución de cloroformato de clorometilo (2,84 g) en diclorometano (10 ml) se añadió gota a gota con agitación a una disolución enfriada en hielo de 3-(N-terc-butoxicarbonilamino)-propilamina (3,49 g) y diisopropiletilamina (3,10 g) en diclorometano (30 ml). Después de agitar durante 3 horas adicionales a temperatura ambiente, la mezcla se extrajo con ácido clorhídrico 0,5M enfriado en hielo seguido por agua y bicarbonato de sodio acuoso. Por secado sobre sulfato de magnesio y evaporación a vacío se obtuvo el compuesto del título como cristales incoloros.
RMN de 1H (CDCl3)  = 5,75 (s, 2H), 5,74 (br, 1H), 4,77 (br, 1H), 3,27 (q, 2H), 3,19 (q, 2H),1,65 (m, 2H), 1,44 (s, 9H).
Preparación 20 N-(3-(N-terc-butoxicarbonilamino)-propil)-carbamato de yodometilo
Una disolución de N-(3-(N-terc-butoxicarbonilamino)-propil)-carbamato de clorometilo (2 g) y yoduro de sodio (4,5 g) en acetonitrilo (15 ml) se agitó durante 1 hora a temperatura ambiente, se evaporó a vacío, se redisolvió en diclorometano y se filtró. El filtrado se evaporó a vacío y el residuo se purificó por cromatografía sobre gel de sílice con acetato de etilo/hexano (1:2) como eluyente para obtener el compuesto del título como cristales incoloros.
RMN de 1H (CDCl3)  = 5,97 (s, 2H), 5,65 (br, 1H), 4,77 (br, 1H), 3,26 (q, 2H), 3,19 (q, 2H),1,66 (m, 2H), 1,44 (s, 9H).
Preparación 21
5-(N-terc-butoxicarbonilamino)-pentanoato de clorometilo
Este compuesto se preparó como se describe en la preparación 7 pero sustituyendo por ácido 5-(N-tercbutoxicarbonilamino)-pentanoico el ácido 2-(2-(2-metoxietoxi)-etoxi)-etoxi-acético. El material bruto se repartió entre dietil éter y agua. La fase orgánica se separó y se secó sobre sulfato de magnesio. Por evaporación a vacío se obtuvo un aceite incoloro que se usó en la siguiente etapa sin purificación adicional.
RMN de 1H (CDCl3)  = 5,70 (s, 2H), 4,6 (br, 1H), 3,13 (q, 2H), 2,42 (t, 2H),1,69 (m, 2H), 1,53 (m, 2H), 1,44 (s, 9H).
Preparación 22 5-(N-terc-butoxicarbonilamino)-pentanoato de yodometilo Se preparó como se describe en la preparación 5 pero sustituyendo con 5-(N-terc-butoxicarbonilamino)-pentanoato
de clorometilo el carbonato de 2-(2-(2-metoxietoxi)-etoxi)-etilo y clorometilo. Aceite incoloro que cristalizó en el refrigerador. RMN de 1H (CDCl3)  = 5,90 (s, 2H), 4,55 (q, 1H), 3,12 (q, 2H), 2,36 (t, 2H),1,66 (m, 2H), 1,52 (m, 2H), 1,44 (s, 9H).
Preparación 23 terc-Butil-succinato de clorometilo Preparado como se describe en la preparación 7 pero sustituyendo con succinato de mono-terc-butilo el ácido 2-(2
(2-metoxietoxi)-etoxi)-etoxi-acético. El producto bruto se purificó por cromatografía sobre gel de sílice con éter de petróleo/acetato de etilo (9:1) como eluyente. RMN de 1H (CDCl3)  = 5,71 (s, 2H), 2,7-2-5 (m, 4H), 1,45 (s, 9H).
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Preparación 24 N-(terc-butoxicarbonilmetil)-carbamato de clorometilo
Una disolución de cloroformato de clorometilo (1,69 g) en diclorometano (5 ml) se añadió gota a gota con agitación a una disolución enfriada en hielo de glicinato de terc-butilo, hidrocloruro (2,0 g) y diisopropiletilamina (3,7 g) en diclorometano (20 ml). Después de agitar durante 2 horas adicionales a temperatura ambiente, la mezcla se extrajo con ácido clorhídrico 0,5M enfriado en hielo seguido por agua y bicarbonato de sodio acuoso. Por secado sobre sulfato de magnesio y evaporación a vacío se obtuvo el compuesto del título como un polvo incoloro.
RMN de 1H (CDCl3)  = 5,75 (s, 2H), 5,42 (br, 1H), 3,91 (d, 2H), 1,48 (s, 9H).
Preparación 25 N-(terc-butoxicarbonilmetil)-carbamato de yodometilo Preparado como se describe en la preparación 20, pero sustituyendo con N-(terc-butoxicarbonilmetil)-carbamato de
clorometilo el N-(3-(N-terc-butoxicarbonilamino)-propil)-carbamato de clorometilo. Polvo amarillo pálido. RMN de 1H (CDCl3)  = 5,97 (s, 2H), 5,34 (br, 1H), 3,88 (d, 2H), 1,47 (s, 9H).
Preparación 26 Carbonato de 1-(terc-butoxicarbonil)-4-piperidilo y clorometilo Preparado como se describe en la preparación 1 pero sustituyendo con 1-(terc-butoxicarbonil)-4-hidroxi-piperidina el
monometil éter de trietilenglicol. Aceite rojo pálido. RMN de 1H (CDCl3)  = 5,73 (s, 2H), 4,88 (m, 1H), 3,71 (m, 2H), 3,26 (m, 2H),1,93 (m, 2H), 1,72 (m, 2H), 1,46 (s, 9H).
Preparación 27
Carbonato de 1-(terc-butoxicarbonil)-4-piperidilo y yodometilo
Preparado como se describe en la preparación 5 pero sustituyendo con carbonato de 1-(terc-butoxicarbonil)-4piperidilo y clorometilo el carbonato de 2-(2-(2-metoxietoxi)-etoxi)-etilo y clorometilo. El aceite resultante se purificó por cromatografía sobre gel de sílice con hexano/acetato de etilo (3:1) como eluyente. Aceite amarillo.
RMN de 1H (CDCl3)  = 5,95 (s, 2H), 4,87 (m, 1H), 3,71 (m, 2H), 3,26 (m, 2H),1,93 (m, 2H), 1,71 (m, 2H), 1,46 (s, 9H).
Preparación 28 Carbonato de terc-butoxicarbonilmetilo y clorometilo Preparado como se describe en la preparación 1 pero sustituyendo con glicolato de terc-butilo el monometil éter de
trietilenglicol. Aceite incoloro. RMN de 1H (CDCl3)  = 5,76 (s, 2H), 4,58 (s, 1H), 1,49 (s, 9H).
Preparación 29
Carbonato de terc-butoxicarbonilmetilo y yodometilo
Se añadió carbonato de terc-butoxicarbonilmetilo y clorometilo (6,45 g) a una disolución de yoduro de sodio (1,65 g) en acetonitrilo (65 ml). Después de agitar a 40ºC durante 4 horas, la mezcla de reacción se enfrió en hielo, se filtró y se evaporó a vacío. El residuo se absorbió con diclorometano, se lavó con bicarbonato de sodio acuoso y tiosulfato de sodio, se secó sobre sulfato de magnesio, se filtró y se evaporó a vacío. Por purificación sobre gel de sílice con hexano/acetato de etilo (3:1) como eluyente se obtuvo el compuesto del título como un aceite incoloro.
RMN de 1H (CDCl3)  = 5,98 (s, 2H), 4,56 (s, 2H), 1,49 (s, 9H).
Preparación 30
Carbonato de 2-(2-(2-metoxietoxi)-etoxi)-etilo y -clorobencilo
Se añadió cloroformato de -clorobencilo (1 g) a una disolución enfriada en hielo de monometil éter de trietilenglicol (0,7 ml) en diclorometano (5 ml) seguido por piridina (0,43 ml) con un caudal tal que la temperatura se mantuvo por debajo de 10ºC. Después de agitar durante la noche a temperatura ambiente, la mezcla de reacción se lavó dos
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Ejemplo 17
Cloruro de 1-[4-piperidiloxi-carboniloximetil]-4-[N’-ciano-N’’-(6-(4-clorofenoxil)-hexil)-N-guanidino]-piridinio, hidrocloruro
Una suspensión de yoduro de 1-[1-(terc-butoxicarbonil)-4-piperidiloxi-carboniloximetil]-4-[N’-ciano-N’’-(6-(4clorofenoxi)-hexil)-N-guanidino]-piridinio (1,0 g) en diclorometano (30 ml) se agitó con un exceso de bicarbonato de sodio. La fase orgánica se secó sobre sulfato de magnesio y se filtró. El filtrado claro se enfrió en hielo con agitación y se trató con un exceso de cloruro de hidrógeno en éter. Se retiró el baño de hielo después de agitar durante 4 horas y se eliminó el disolvente a vacío. El residuo se cristalizó en etanol para obtener el compuesto del título analíticamente puro.
RMN de 1H (DMSO)  = 11,9 (br, 1H), 9,22 (br, 3H), 8,73 (d, 2H), 7,58 (br, 2H), 7,30 (d, 2H), 6,95 (d, 2H), 6,22 (s, 2H), 4,88 (m, 1H), 3,96 (t, 2H), 3,44 (br, 2H), 3,09 (m, 4H), 2,07 (m, 2H), 1,89 (m, 2H), 1,71 (m, 2H), 1,58 (m, 2H), 1,41 (m, 4H).
Ejemplo 18
N-[1-(-(2-(2-(2-metoxietoxi)-etoxi)-etoxicarboniloxi)-bencil]-1,4-dihidropiridin-4-iliden]-N’-ciano-N’’-(6-(4-clorofenoxi)hexil)-guanidino
Una mezcla de N-(6-(4-clorofenoxi)-hexil)-N’-ciano-N’’-(4-piridil)-guanidina (67 mg) y carbonato de 2-(2-(2metoxietoxi)-etoxi)-etilo y -clorobencilo (150 mg) se colocó en un baño de aceite precalentado a 90ºC. Después de 10 minutos se formó un fundido amarillo claro y después de 20 minutos adicionales la mezcla se enfrió a temperatura ambiente y se añadió EtOAc (4 ml). Por decantación y evaporación a vacío se obtuvo un residuo que se trató con éter. Después de decantación del éter, el residuo se absorbió en diclorometano y se lavó con un exceso de bicarbonato de sodio. Por cromatografía sobre gel de sílice con diclorometano/etanol (98:2) como eluyente se obtuvo el compuesto del título como un aceite incoloro.
RMN de 1H (DMSO)  = 7,70 (d, 2H), 7,48 (m, 5H), 7,42 (s, 1H), 7,30 (d, 2H), 6,92 (d, 2H), 6,13 (d, 2H), 4,32 (m, 2H), 3,95 (t, 2H), 3,65 (t, 2H), 3,52 (m, 6H), 3,42 (m, 2H), 3,22 (w, 3H), 3,10 (m, 2H), 1,2-1,8 (m, 8H).
Ejemplo 19
Solubilidad en agua de los compuestos de la invención
La solubilidad en agua de los compuestos de la presente invención se determinó agitando los compuestos en agua durante una hora a temperatura ambiente seguido por filtración y determinación de la concentración del compuesto en el filtrado por HPLC. La solubilidad de los compuestos preparados en los ejemplos 8 y 9 se comparó con la solubilidad del compuesto precursor, N-(6-(4-clorofenoxi)-hexil)-N’-ciano-N’’-(4-piridil)-guanidina. Los resultados aparecen en la tabla 1 siguiente.
Tabla 1
Compuesto
Solubilidad en agua (mg/ml)
N-(6-(4-clorofenoxi)-hexil)-N’-ciano-N’’-(4-piridil)-guanidina
0,0002
Compuesto del ejemplo 8
> 50
Compuesto del ejemplo 9
> 50
Los datos de la tabla 1 muestran claramente que se obtiene un aumento significativo de la solubilidad usando los profármacos de la presente invención. El compuesto activo es insoluble para todos los propósitos prácticos, mientras que el profármaco es soluble a más de 50 mg/g lo que permite la preparación de medicamentos.
16

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