ES2325851B1 - ANTITUBERCULOSO AGENTS. - Google Patents
ANTITUBERCULOSO AGENTS. Download PDFInfo
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- ES2325851B1 ES2325851B1 ES200800797A ES200800797A ES2325851B1 ES 2325851 B1 ES2325851 B1 ES 2325851B1 ES 200800797 A ES200800797 A ES 200800797A ES 200800797 A ES200800797 A ES 200800797A ES 2325851 B1 ES2325851 B1 ES 2325851B1
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- substituted
- alkyl
- hydrogen
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- compound according
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- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 239000003814 drug Substances 0.000 claims abstract description 32
- 238000011282 treatment Methods 0.000 claims abstract description 14
- 201000008827 tuberculosis Diseases 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims abstract description 3
- -1 alkoxycarbonylazyl Chemical group 0.000 claims description 30
- 229940079593 drug Drugs 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
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- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
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- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 4
- 235000017803 cinnamon Nutrition 0.000 claims description 4
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
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- 239000003795 chemical substances by application Substances 0.000 abstract description 12
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
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- 238000005481 NMR spectroscopy Methods 0.000 description 4
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- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
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- WFHLXOBAUMFTBL-UHFFFAOYSA-N tert-butyl n-(1-aminohexadecan-2-yl)carbamate Chemical compound CCCCCCCCCCCCCCC(CN)NC(=O)OC(C)(C)C WFHLXOBAUMFTBL-UHFFFAOYSA-N 0.000 description 1
- WDUHVGNSRNQNID-UHFFFAOYSA-N tert-butyl n-(1-phenylmethoxyhexadecan-2-yl)carbamate Chemical compound CCCCCCCCCCCCCCC(NC(=O)OC(C)(C)C)COCC1=CC=CC=C1 WDUHVGNSRNQNID-UHFFFAOYSA-N 0.000 description 1
- LFTLIBDLSHDGHR-UHFFFAOYSA-N tert-butyl n-[1-(diethylamino)hexadecan-2-yl]carbamate Chemical compound CCCCCCCCCCCCCCC(CN(CC)CC)NC(=O)OC(C)(C)C LFTLIBDLSHDGHR-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 239000000814 tuberculostatic agent Substances 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K31/13—Amines
- A61K31/132—Amines having two or more amino groups, e.g. spermidine, putrescine
-
- 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
- A61K31/13—Amines
- A61K31/133—Amines having hydroxy groups, e.g. sphingosine
-
- 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
- A61K31/396—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having three-membered rings, e.g. aziridine
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Agentes antituberculosos.TB agents.
Uso del compuesto de fórmula general, para la elaboración de una composición para su empleo como medicamento en el tratamiento de la tuberculosis y/o de la tuberculosis resistente.Use of the compound of general formula, for development of a composition for use as a medicine in the treatment of tuberculosis and / or tuberculosis resistant.
Description
Agentes antituberculosos.TB agents.
La presente invención se refiere a una familia de compuestos de fórmula general I, para su uso como agentes antituberculosos.The present invention relates to a family of compounds of general formula I, for use as agents TB.
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La tuberculosis (TB) es una enfermedad infecciosa latente, provocada principalmente por la micobacteria Mycobacterium tuberculosis (MTB). Se contagia a través del ambiente y causa más de 1,6 millones de muertes cada año (OMS-TDR-2002). Afecta a un tercio de la población mundial, con mayor incidencia en las regiones menos favorecidas del planeta (África: infectado el 35% de la población, América: 18%, Mediterráneo oriental: 29%, Europa: 15%, Sureste asiático: 44%, Pacífico occidental: 35%) y fue declarada emergencia de salud mundial en 1993. Cada año, se infecta el 1% de la población mundial. De ese porcentaje, entre el 5 y el 10% desarrollarán efectivamente la infección; por lo que se asume que, sin un esfuerzo coordinado internacional para combatirla, en el año 2020, se alcanzará la cifra de mil millones de personas infectadas y enfermas y que el numero de muertes en ese año sobrepasaría los 70 millones, debido en gran parte, a la aparición de estirpes de micobacterias resistentes y multirresistentes a los medicamentos disponibles y también al incremento de su oportunismo en los casos de co-infección simultánea SIDA-TB (cf. Página web de la Organización Mundial de la Salud OMS).Tuberculosis (TB) is a latent infectious disease, mainly caused by the mycobacterium Mycobacterium tuberculosis (MTB). It is spread through the environment and causes more than 1.6 million deaths each year (WHO-TDR-2002). It affects a third of the world's population, with the highest incidence in the less favored regions of the planet (Africa: 35% of the population infected, America: 18%, Eastern Mediterranean: 29%, Europe: 15%, Southeast Asia: 44 %, Western Pacific: 35%) and was declared a world health emergency in 1993. Each year, 1% of the world's population is infected. Of that percentage, between 5 and 10% will effectively develop the infection; so it is assumed that, without a coordinated international effort to combat it, in 2020, the figure of one billion infected and sick people will be reached and that the number of deaths in that year would exceed 70 million, due in large part , to the emergence of strains of mycobacteria resistant and multi-resistant to the available medications and also to the increase of their opportunism in the cases of simultaneous AIDS-TB co-infection (see website of the World Health Organization WHO).
La principal característica diferencial de las micobacterias, en comparación con otros tipos de microorganismos patógenos, se relaciona con su especial envoltura celular, de naturaleza poliglicósido-polipeptídica-polilipídica, que protege la célula bacteriana frente a posibles condiciones ambientales extremas y, particularmente, frente al ataque por fármacos y otros agentes fisicoquímicos externos (cf. Brennan PJ et al. 1995. Annu. Rev. Biochem. vol. 64, pp. 29-63).The main differential characteristic of mycobacteria, compared to other types of pathogenic microorganisms, is related to their special cellular envelope, of a polyglycoside-polypeptide-polylipidic nature, which protects the bacterial cell against possible extreme environmental conditions and, particularly, against attack by drugs and other external physicochemical agents (cf. Brennan PJ et al . 1995. Annu. Rev. Biochem . vol. 64, pp. 29-63).
Los agentes terapéuticos utilizados en el tratamiento de la tuberculosis se agrupan en dos categorías que se denominan de primera y segunda línea.The therapeutic agents used in the TB treatment is grouped into two categories that are They call first and second line.
El primer grupo de fármacos, el de los más accesibles, esta constituido por: isoniazida, rifampicina, pirazinamida, etambutol (EMB) y estreptomicina. Dentro de este grupo, el EMB es un agente bacteriostático, poco tóxico, pero no demasiado potente, cuya estructura (i), contiene dos unidades de \beta-aminoalcohol, en una distribución pseudosimétrica y localizada en los extremos de una unidad central de 1,2-etilenodiamina (cf. Myers JP, 2005, Curr. Opin. Infect. Dis, vol. 18, pp. 133–40; Blumberg, HM, et al., 2003, Am. J. Respir. Crit. Care Med. Vol. 167, pp. 603).The first group of drugs, the most accessible, is constituted by: isoniazid, rifampicin, pyrazinamide, ethambutol (EMB) and streptomycin. Within this group, the EMB is a bacteriostatic agent, little toxic, but not too potent, whose structure (i), contains two units of β-aminoalcohol, in a pseudosymmetric distribution and located at the ends of a central unit of 1 , 2-ethylenediamine (cf. Myers JP, 2005, Curr. Opin. Infect. Dis , vol. 18, pp. 133–40; Blumberg, HM, et al ., 2003, Am. J. Respir. Crit. Care Med Vol. 167, pp. 603).
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Desde el punto de vista mecanístico, aunque no esté aún totalmente esclarecido, se acepta que el EMB afecta el metabolismo de los ácidos nucleicos e inhibe específicamente la arabinosil transferasa de la micobacteria, impidiendo o perturbando la formación de arabinogalactosa y del lipoarabinomanano, que son elementos básicos y forman parte de los glicolípidos dominantes en la envoltura de la MTB (cf. Forbes M, et al., 1965, J Bacterial, vol. 89, pp. 1299-1305; Killburn JO, et al., 1981, Antimicrob. Agents Chemother, vol. 19, pp. 346-48; Takayama K. et al.,1989, Antimicrob. Agents Chemother, vol. 33, pp. 1493-99).From the mechanistic point of view, although it is not yet fully clarified, it is accepted that the EMB affects the metabolism of nucleic acids and specifically inhibits the arabinosyl transferase of mycobacteria, preventing or disturbing the formation of arabinogalactose and lipoarabinomannan, which are elements basic and form part of the dominant glycolipids in the MTB envelope (cf. Forbes M, et al ., 1965, J Bacterial , vol. 89, pp. 1299-1305; Killburn JO, et al ., 1981, Antimicrob. Agents Chemother , vol. 19, pp. 346-48; Takayama K. et al ., 1989, Antimicrob. Agents Chemother , vol. 33, pp. 1493-99).
Por otro lado, la esfingosina (SPH, ii), es un componente natural de los fosfolípidos de membrana de los organismos vivos, que se biosintetiza a partir de serina y de ácido palmítico. Contiene una cadena lineal larga, con una instauración olefínica, un grupo amina y dos funciones hidroxilo. Activada por fosforilación se incorpora en la esfingomielina, en las ceramidas y en otra serie de segundos mensajeros, involucrados en diversos procesos quimiofisiológicos de la célula. Las ceramidas, que tienen una función importante en la estabilidad de las membranas, están relacionadas con otro grupo de compuestos lipídicos presentes en la envoltura de la célula de la micobacteria, los ácidos micólicos, un grupo de ácidos grasos con cadenas extraordinariamente largas, entre 60 y 90 átomos de carbono, que contienen algunas funciones hidroxilo, ramificaciones de metilo y anillos de ciclopropano (cf. Barry CE, et al., 1998, Prog. Lipid Res., vol. 37, pp.143-79).On the other hand, sphingosine (SPH, ii), is a natural component of the membrane phospholipids of living organisms, which biosynthesizes from serine and palmitic acid. It contains a long linear chain, with an olefinic installation, an amine group and two hydroxyl functions. Activated by phosphorylation is incorporated into sphingomyelin, ceramides and another series of second messengers, involved in various chemophysiological processes of the cell. Ceramides, which have an important function in the stability of membranes, are related to another group of lipid compounds present in the envelope of the mycobacterial cell, mycolic acids, a group of fatty acids with extraordinarily long chains, between 60 and 90 carbon atoms, which contain some hydroxyl functions, methyl branches and cyclopropane rings (cf. Barry CE, et al ., 1998, Prog. Lipid Res ., vol. 37, pp. 143-79).
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En la actualidad, la TB se considera una enfermedad de la pobreza. Los agentes de primera línea, los más accesibles, desarrollados hace más de 40 años, no son adecuados para tratar con eficacia las infecciones resistentes y la utilización de los agentes de segunda línea, además de ser menos accesibles, no presenta garantías claras de eficacia.Currently, TB is considered a disease of poverty . The first-line agents, the most accessible, developed over 40 years ago, are not suitable for effectively treating resistant infections and the use of second-line agents, in addition to being less accessible, does not present clear guarantees of efficacy.
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En la presente invención, se describen aminoalcoholes y diaminas ciclolipídicos, de tamaño molecular discreto y algunos de sus derivados y análogos, como también compuestos acíclicos, epóxidos, aziridinas y aminoácidos de naturaleza lipídica, intermediarios en las síntesis, que poseen actividad considerable in vitro frente a estirpes de MTB sensibles (S), polirresistentes (PDR) y multirresistentes (MDR) a los fármacos antituberculosos de primera línea. Adicionalmente, algunos elementos seleccionados entre los activos in vitro, en la forma que se describe más adelante, también han demostrado su utilidad terapéutica, mediante ensayos in vivo sobre ratones infectados con cepas S y cepas resistentes a todos los fármacos de primera línea (TDR).In the present invention, amino alcohols and cycloolipid diamines, of discrete molecular size and some of their derivatives and analogs are described, as well as acyclic compounds, epoxides, aziridines and amino acids of a lipid nature, intermediates in the syntheses, which possess considerable activity in vitro against MTB strains sensitive (S), polyresistant (PDR) and multiresistant (MDR) to first-line antituberculosis drugs. Additionally, some elements selected from the in vitro assets, in the manner described below, have also demonstrated their therapeutic utility, by means of in vivo tests on mice infected with S strains and strains resistant to all first-line drugs (TDR) .
Los compuestos de la presente invención son útiles frente a la TB multirresistente, con más eficacia incluso que contra la sensible.The compounds of the present invention are useful against multidrug-resistant TB, more effectively even Than against the sensitive.
De acuerdo con un aspecto de la presente invención se proporciona un compuesto de fórmula general I, para su uso como medicamento, preferiblemente como agente antituberculoso.In accordance with one aspect of the present invention is provided a compound of general formula I, for its use as a medicine, preferably as an agent antituberculous.
El compuesto de fórmula general I es:The compound of general formula I is:
o una sal, isómero, profármaco o solvato farmacéuticamente aceptable del mismo, en la que:or a salt, isomer, prodrug or pharmaceutically acceptable solvate thereof, in the that:
R^{1} es un radical, sustituido o no sustituido, lineal o ramificado, que se selecciona entre el grupo que consiste en alquilo (C_{4}-C_{20}), alquenilo (C_{4}-C_{20}), arilaiquilo (Ar-C_{1} a Ar-C_{12}), o arilalquenilo (Ar-C_{3} a Ar-C_{12}).R1 is a radical, substituted or not substituted, linear or branched, which is selected from the group consisting of (C 4 -C 20) alkyl, (C 4 -C 20) alkenyl, arylalkyl (Ar-C_ {1} to Ar-C_ {12}), or arylalkenyl (Ar-C 3 a Ar-C 12).
R^{2}, R^{3}, R^{4} y R^{5}, son iguales o distintos y se seleccionan cada uno, de forma independiente, del grupo formado por hidrógeno (H); alquilo (C_{1}-C_{10}) sustituido o no sustituido; hidroxialquilo (C_{1}-C_{10}) sustituido o no sustituido; alcoxialquilo (C_{1}-C_{10}) sustituido o no sustituido; alquenilo (C_{1}-C_{10}) sustituido o no sustituido; arilo, sustituido o no sustituido; arilalquilo (Ar-C_{1} a Ar-C_{12}) sustituido o no sustituido, heteroarilo sustituido o no sustituido; heteroarilalquilo (Het-C_{1} a Het-C_{12}) sustituido o no sustituido; un grupo acilo, o alcoxicarbonilacilo, alcoxicarbonilo, hidroxiacilo o hidroxicarbonilacilo y cualquiera de sus posibles sales, ésteres orgánicos e inorgánicos o amidas.R2, R3, R4 and R5, are the same or different and each one is independently selected from the group consisting of hydrogen (H); I rent (C 1 -C 10) substituted or unsubstituted; hydroxyalkyl (C 1 -C 10) substituted or not replaced; (C 1 -C 10) alkoxyalkyl substituted or unsubstituted; alkenyl (C 1 -C 10) substituted or unsubstituted; aryl, substituted or unsubstituted; arylalkyl (Ar-C_ {1} to Ar-C_ {12}) substituted or unsubstituted, substituted or unsubstituted heteroaryl; heteroarylalkyl (Het-C 1 a Het-C12) substituted or unsubstituted; a group acyl, or alkoxycarbonylacil, alkoxycarbonyl, hydroxyacyl or hydroxycarbonylacil and any of its possible salts, esters Organic and inorganic or amides.
X e Y son iguales o distintos y representan cada uno, de forma independiente, un átomo de Nitrógeno (N) o de Oxígeno (O), configurando estructuras de aminoalcohol, diamina o diol y sus derivados.X and Y are the same or different and represent each one, independently, a Nitrogen (N) or Oxygen atom (O), configuring amino alcohol, diamine or diol structures and their derivatives.
Cuando X es Oxígeno R^{3} no existe y cuando Y es Oxígeno R^{5} no existe.When X is Oxygen R3 does not exist and when Y is Oxygen R5 does not exist.
El símbolo
Se incluyen también compuestos en los que uno de los sustituyentes R^{2} (R^{3}, R^{4} o R^{5}) es un espaciador polimetilénico, de tamaño entre 2 y 4 unidades, que une dos restos moleculares simétricos o no simétricos.Compounds are also included in which one of the substituents R 2 (R 3, R 4 or R 5) is a polymethylene spacer, size between 2 and 4 units, which joins two symmetric or non-symmetric molecular residues.
Sobre estas estructuras se han incorporado, en agrupaciones adecuadas diversas, algunas cualidades estructurales parciales del agente terapéutico EMB y otras del aminodiol biosintético natural SPH, para conseguir compuestos activos contra la micobacteria MTB y clínicamente eficaces frente a la tuberculosis resistente.On these structures, some partial structural qualities of the EMB therapeutic agent and others of the natural biosynthetic aminodiol SPH have been incorporated into various suitable groups to achieve compounds active against MTB mycobacteria and clinically effective against resistant tuberculosis.
De forma general, el radical R^{1}, presente en la fórmula general I, es un grupo alquilo o alquenilo, de entre 4 y 20 átomos de carbono, preferiblemente entre 10 y 16 átomos de carbono, más preferiblemente entre 12 y 14 átomos de carbono; o un grupo arilalquilo entre Ar-C_{1} y Ar-C_{12}, preferiblemente de Ar-C_{1} a Ar-C_{6}; o un grupo arilalquenilo entre Ar-C_{3} y Ar-C_{12}, preferiblemente de Ar-C_{3} a Ar-C_{6}.In general, the radical R 1, present in the general formula I, it is an alkyl or alkenyl group, of 4 and 20 carbon atoms, preferably between 10 and 16 atoms of carbon, more preferably between 12 and 14 carbon atoms; or a arylalkyl group between Ar-C 1 and Ar-C 12, preferably of Ar-C 1 to Ar-C 6; or a group arylalkenyl between Ar-C3 and Ar-C 12, preferably of Ar-C 3 to Ar-C 6.
En una realización preferida de la presente invención, la agrupación XR^{2}R^{3} (o la YR^{4}R^{5}), de la fórmula general I, es un grupo carboxilo en forma de ácido libre, sal, éster, amida libre o amida N-sustituida.In a preferred embodiment of the present invention, the XR 2 R 3 (or YR 4 R 5) grouping, of the general formula I is a carboxyl group in the form of acid free, salt, ester, free amide or amide N-substituted
En una realización preferida de la presente invención, los compuestos de fórmula I tiene los siguientes radicales: X es nitrógeno, R^{1} es un alquilo (C_{12}-C_{16}), R^{2} es hidrógeno, alquilo (C_{1}-C_{6}), bencilo, t-butoxicarbonilo, etoxicarbonilmetilo, hidroxicarbonilpropionilo, hidroxicarbonilbutirilo o etoxicarbonilbutirilo, R^{3} es hidrógeno o alquilo (C_{1}-C_{6}), R^{4} es hidrógeno, alquilo (C_{1}-C_{6}), cicloalquilo (C_{5}-C_{6}), etoxicarbonilbutirilo o arilo, y R^{5} es hidrógeno o alquilo (C_{1}-C_{6}) o no existe cuando Y es oxígeno. Más preferiblemente X es nitrógeno, R^{1} es un alquilo (C_{12}-C_{14}), R^{2} es hidrógeno, alquilo (C_{1}-C_{4}) o t-butoxicarbonilo, R^{3} es hidrógeno o alquilo (C_{1}-C_{4}), R_{4} es hidrógeno o arilo y R^{5} es hidrógeno o alquilo (C_{1}-C_{6}) o no existe cuando Y es oxígeno.In a preferred embodiment of the present invention, the compounds of formula I have the following radicals: X is nitrogen, R1 is an alkyl (C 12 -C 16), R 2 is hydrogen, alkyl (C 1 -C 6), benzyl, t-butoxycarbonyl, ethoxycarbonylmethyl, hydroxycarbonylpropionyl, hydroxycarbonylbutyryl or ethoxycarbonylbutyryl, R 3 is hydrogen or alkyl (C 1 -C 6), R 4 is hydrogen, alkyl (C 1 -C 6), cycloalkyl (C 5 -C 6), ethoxycarbonylbutyryl or aryl, and R 5 is hydrogen or (C 1 -C 6) alkyl or It does not exist when Y is oxygen. More preferably X is nitrogen, R 1 is a (C 12 -C 14) alkyl, R 2 is hydrogen, (C 1 -C 4) alkyl or t-butoxycarbonyl, R 3 is hydrogen or alkyl (C 1 -C 4), R 4 is hydrogen or aryl and R 5 is hydrogen or (C 1 -C 6) alkyl or It does not exist when Y is oxygen.
En otra realización preferida, el grupo R^{1} es aquel seleccionado entre los grupos decilo, laurilo, miristilo, palmitilo, estearilo, araquidilo, oleilo, bencilo, fenetilo, fenilpropilo, fenilbutilo, fenilhexilo, feniloctilo, y cinamilo.In another preferred embodiment, the group R1 is the one selected from the decyl, lauryl, myristyl groups, palmityl, stearyl, arachidyl, oleyl, benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylhexyl, phenyloctyl, and cinnamon.
En otra realización preferida de la presente invención, los radicales R^{2}, R^{3}, R^{4} y R^{5} son iguales o distintos y se seleccionan cada uno de forma independiente entre elementos del grupo que comprende: hidrógeno, grupos alquilo, hidroxialquilo, alcoxialquilo, alquenilo, con tamaños de C_{1} a C_{10} y con preferencia de C_{4} a C_{6} para alquilo y alquenilo y de C_{2} a C_{4} para los hidroxialquilos y alcoxialquilos. Comprende así mismo, grupos arilo, preferiblemente fenilo, arilaiquilo y arilalquenilo, preferiblemente de Ar-C_{1} a Ar-C_{12} y heteroarilo y heteroarilalquilo, preferiblemente de Het-C_{1} a Het-C_{12}. Comprende también grupos acilo, hidroxiacilo, alcoxialquilo, alcoxicarbonilo, aminoacilo, hidroxicarbonilacilo y alcoxicarbonilacilo.In another preferred embodiment of the present invention, the radicals R 2, R 3, R 4 and R 5 are same or different and each one is selected independent between elements of the group comprising: hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl groups, with sizes from C 1 to C 10 and preferably from C 4 to C 6 for alkyl and alkenyl and C 2 to C 4 for hydroxyalkyl and alkoxyalkyl. It also includes aryl groups, preferably phenyl, arylalkyl and arylalkenyl, preferably from Ar-C 1 to Ar-C 12 and heteroaryl and heteroarylalkyl, preferably from Het-C 1 to Het-C 12. It also includes acyl groups, hydroxyacyl, alkoxyalkyl, alkoxycarbonyl, aminoacyl, hydroxycarbonylacil and alkoxycarbonylacil.
Más preferidamente, los radicales R^{2},
R^{3}, R^{4} y R^{5} se seleccionan cada uno de forma
independiente del grupo que comprende, etilo, propilo, butilo,
hexilo, decilo, ciclopentilo, ciclohexilo, fenilo, bencilo,
fenetilo, cinamilo, todos ellos pueden estar a su vez sustituidos o
no, furilo, (por ejemplo 2-furilo y
2-furiletilo), tienilo (por ejemplo
2-tienilo y 2-tieniletilo), acetilo,
hidroxiacetilo, glicinilo, metoxicarbonilo,
t-butoxicarbonilo, hemisuccinilo o hemiglu-
tarilo.More preferably, the radicals R 2, R 3, R 4 and R 5 are each independently selected from the group comprising, ethyl, propyl, butyl, hexyl, decyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, cinnamon, all of which may be substituted or not, furyl (for example 2-furyl and 2-furylethyl), thienyl (for example 2-thienyl and 2-thienylethyl), acetyl, hydroxyacetyl, glycinyl, methoxycarbonyl, t-butoxycarbonyl, hemisuccinyl or hemiglu-
tarilo
Todos los compuestos anteriormente descritos pueden existir en formas racémicas o enantiómeras;All the compounds described above they can exist in racemic or enantiomeric forms;
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Dentro de los distintos tipos y variaciones consideradas en este documento, son sustancias aún más preferibles, debido a su mayor potencia antimicobacteriana (ver tabla 1 en los ejemplos), las representadas por las estructuras siguientes:Within the different types and variations considered in this document, they are even more preferable substances, due to its greater antimicobacterial potency (see table 1 in the examples), those represented by the following structures:
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Grupo IGroup I
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Las referencias, en el presente documento, a grupos sustituidos en los compuestos de la presente invención, se refieren al resto especificado que puede sustituirse en una o más posiciones disponibles por uno o más grupos adecuados, por ejemplo, grupos alquilo incluyendo aquellos grupos que tienen de 1 a aproximadamente 14 átomos de carbono o desde 1 hasta aproximadamente 6 átomos de carbono y, más preferiblemente, 1 - 3 átomos de carbono; grupos aiquenilo incluyendo grupos que tienen uno o más enlaces insaturados y desde 2 hasta aproximadamente 14 átomos de carbono o desde 2 hasta aproximadamente 6 átomos de carbono; hidroxilo; acilo (C_{1}-C_{6}) tales como acetilo o similares; alcoxicarbonilacilo; alcoxicarbonilo; hidroxiacilo o hidroxicarbonilacilo.References, in this document, to substituted groups in the compounds of the present invention, are refer to the specified remainder that can be substituted in one or more positions available by one or more suitable groups, for example, alkyl groups including those groups that have 1 to approximately 14 carbon atoms or from 1 to about 6 carbon atoms and, more preferably, 1-3 carbon atoms; alkenyl groups including groups that have one or more unsaturated links and from 2 to about 14 carbon atoms or from 2 to about 6 atoms of carbon; hydroxyl; acyl (C 1 -C 6) such as acetyl or the like; alkoxycarbonylacil; alkoxycarbonyl; hydroxyacyl or hydroxycarbonylacil.
Los autores de la presente invención han preparado compuestos de este tipo con finalidad terapéutica, y presentan ejemplos y resultados de la evaluación antimicobacteriana in vitro, de la evaluación antituberculosa in vivo, y de la preparación sintética de los compuestos que se consideran en la presente invención.The authors of the present invention have prepared compounds of this type for therapeutic purposes, and present examples and results of the in vitro antimicobacterial evaluation, of the in vivo antituberculous evaluation, and of the synthetic preparation of the compounds considered in the present invention. .
Los compuestos de estructura general I, se obtienen con rendimientos variables, mediante procesos químicos controlados y configurados expresamente para sintetizarlos, partiendo de materias primas comunes, mediante transformaciones generalmente conocidas y, en la mayoría de los casos, ya utilizadas anteriormente según el estado de la técnica. La presente invención también comprende los compuestos intermedios de las síntesis, con sus variantes y derivados.The compounds of general structure I, are obtained with variable yields, through chemical processes expressly controlled and configured to synthesize them, starting from common raw materials, through transformations generally known and, in most cases, already used previously according to the state of the art. The present invention it also comprises the intermediate compounds of the syntheses, with its variants and derivatives.
Varios grupos de compuestos de fórmula general I, se prepararon mediante secuencias de reacciones como las que se presentan resumidas en los Esquemas 1, y diversos ejemplos concretos y representativos de los compuestos activos frente a MTB, se describen y caracterizan química y biológicamente en apartados posteriores de este documento:Several groups of compounds of general formula I, were prepared by reaction sequences such as those summarized in Schemes 1, and various concrete and representative examples of the active compounds against MTB , are described and characterized chemically and biologically in subsequent sections. of this document:
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Esquema 1Scheme one
Preparaciones de varios grupos de compuestos del tipo IMulti-group preparations of compounds of the type I
Ejemplos concretos de las preparaciones y evaluaciones de compuestos con la estructura I, que han resultado activos frente a MTB, se describen más detalladamente en apartados posteriores de este documento.Concrete examples of the preparations and evaluations of compounds with structure I, which have been active against MTB , are described in more detail in later sections of this document.
Entre los compuestos de fórmula I, según investigaciones previas que ya hemos publicado, se encuentran algunas sustancias que poseen actividad antiparasitaria (cf. Del Olmo E, et al. 2002, Bioorg Med Chem Lett, vol. 12 pp. 659-62); otras que inhiben la fosfolipasa A2; otras son capaces de provocar apoptosis celular mediante inducción de caspasas (cf. Lucas R et al., 2000, Bioorg. Med. Chem. Lett., vol. 10, pp. 285; Lucas R, et al. 2003, Biochem. Pharmacol, vol. 65, pp.1539-49) y otras resultan eficaces como adyuvantes de vacunación antiparasitaria (cf. Del Olmo E. et al., 2006, Bioorg. Med Chem. Lett. 16, 6091-95).Among the compounds of formula I, according to previous research that we have already published, there are some substances that have antiparasitic activity (cf. Del Olmo E, et al . 2002, Bioorg Med Chem Lett , vol. 12 pp. 659-62); others that inhibit phospholipase A2; others are capable of causing cellular apoptosis by inducing caspases (cf. Lucas R et al ., 2000, Bioorg. Med. Chem. Lett ., vol. 10, pp. 285; Lucas R, et al . 2003, Biochem. Pharmacol , vol. 65, pp. 1539-49) and others are effective as adjuvants for deworming vaccination (cf. Del Olmo E. et al ., 2006, Bioorg. Med Chem. Lett . 16, 6091-95).
Otro aspecto de la presente invención comprende una composición farmacéutica con cualquiera de los agentes antituberculosos descritos anteriormente o cualquiera de sus mezclas, además de un vehículo farmacéuticamente aceptable.Another aspect of the present invention comprises a pharmaceutical composition with any of the agents antituberculosis agents described above or any of their mixtures, in addition to a pharmaceutically acceptable carrier.
A lo largo de la descripción y las reivindicaciones la palabra "comprende" y sus variantes no pretende excluir otras características técnicas, aditivos, componentes o pasos. Para los expertos en la materia, otros objetos, ventajas y características de la invención se desprenderán en parte de la descripción y en parte de la práctica de la invención. Los siguientes ejemplos y dibujos se proporcionan a modo de ilustración, y no se pretende que sean limitativos de la presente invención.Throughout the description and the claims the word "comprises" and its variants not intends to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be partly detached of the description and in part of the practice of the invention. The following examples and drawings are provided by way of illustration, and are not intended to be limiting of the present invention.
Fig. 1.- Determinación de unidades formadoras de colonia (UFC) micobacterianas en ratones Balb/c, después de dos meses de haber sido infectados con M. tuberculosis H37Rv y tratados durante dos meses con los compuestos de esta invención, con fármacos convencionales y con asociaciones de ellos.Fig. 1.- Determination of mycobacterial colony forming units (CFU) in Balb / c mice, after two months of being infected with M. tuberculosis H37Rv and treated for two months with the compounds of this invention, with conventional drugs and with their associations.
Fig. 2.- Cuantificación del porcentaje de área pulmonar afectada por neumonía en ratones tuberculosos Balb/c, después del tratamiento durante dos meses con los diferentes compuestos y asociaciones.Fig. 2.- Quantification of the area percentage pulmonary affected by pneumonia in Balb / c tuberculous mice, after treatment for two months with the different compounds and associations.
A continuación se ilustrará la invención mediante unos ensayos realizados por los inventores, que ponen de manifiesto las particularidades de las preparaciones, la potencia de su acción bactericida sobre micobacterias sensibles y resistentes, cultivadas in vitro, y su eficacia antituberculosa en el tratamiento de animales infectados.The invention will now be illustrated by tests carried out by the inventors, which show the particularities of the preparations, the potency of their bactericidal action on sensitive and resistant mycobacteria, grown in vitro , and their antituberculous efficacy in the treatment of infected animals. .
Ejemplo 1aExample 1st
18,5 g del I-1, se disuelven en 250 mL de THF y se enfría a 10ºC, se añaden sucesivamente 5,5 mL de N-metilmorfolina y lentamente 4,5 mL de CICOOEt, controlando la t de reacción durante 10 min. Se enfría a 0ºC, se añaden 5,60 g de NaBH_{4} y 747 mL de MeOH, goteando, se mantiene a 0ºC durante 15 min, después 10 min a t.a. Se extrae con AcOEt/H_{2}O, se seca con Na_{2}SO_{4} anhidro, se filtra y lleva a sequedad, se cromatografía y se obtienen 12,5 g de 2-(terc-butoxicarbonil)aminohexadecanol, I-2a, sólido blanco de p.f. = 53ºC. IR con máximos a: 3350, 2917, 2850, 1687, 1536, 1366, 1251 y 1173 cm^{-1}. EM (IQ) \nc{m/z}: 380 (M^{+} + Na, 10); 358 (M^{+} + H^{+}, 10); 302 (M^{+} - C_{4}H_{7}, 60); 258 (M^{+} -[Boc + 2H^{+}], 58); 226 (M^{+} - [Boc + H_{2}O], 22).18.5 g of I-1 , dissolved in 250 mL of THF and cooled to 10 ° C, 5.5 mL of N- methylmorpholine and slowly 4.5 mL of CICOOEt were added successively, controlling the reaction t for 10 min . It is cooled to 0 ° C, 5.60 g of NaBH 4 and 747 mL of MeOH are added, dripping, kept at 0 ° C for 15 min, then 10 min at rt. It is extracted with AcOEt / H2O, dried With anhydrous Na 2 SO 4, it is filtered and dried, chromatographed and 12.5 g of 2- ( tert -butoxycarbonyl) aminohexadecanol, I-2a , mp white solid are obtained. = 53 ° C. IR with maximums at: 3350, 2917, 2850, 1687, 1536, 1366, 1251 and 1173 cm -1. MS (CI) m {m / z}: 380 (M + + Na, 10); 358 (M + + H +, 10); 302 (M + - C 4 H 7, 60); 258 (M + - [Boc + 2H +], 58); 226 (M + - [Boc + H 2 O], 22).
5,0 g de I-2a, en 20 mL
de DMF, se enfrían a 0ºC durante 10 min, se añaden 335 mg de HNa y
se deja en agitación a t.a. entre 20 y 25 min. Se añaden 1,6 mL de
CIBn y se mantiene durante 4 a 6 horas, controlando por CCF. Se
lleva a sequedad y se obtienen 5,7 g de crudo de reacción, que por
cromatografía conduce a 2,1 g del benciléter de
2-terc-butoxicarbonilamino-hexadecanol,
1-3, aceite con las características: IR
máx: 3354, 2918, 2849, 1686, 1530, 1370, 1350, 905, 715
cm^{-1}. EM \nc{m/z}: 448 (M^{+}, 2); 348 (M^{+}
-[Boc + H^{+}], 20); 284 (M^{+} - C_{10}H_{14}O, 10); 226
(M^{+} -[Boc +
C_{8}H_{9}O], 10); 154
[C_{11}H_{22}, 10); 91(C_{7}H_{7}, 100).5.0 g of I-2a , in 20 mL of DMF, are cooled at 0 ° C for 10 min, 335 mg of HNa are added and allowed to stir at rt between 20 and 25 min. 1.6 mL of CIBn are added and maintained for 4 to 6 hours, monitored by CCF. It is brought to dryness and 5.7 g of reaction crude are obtained, which by chromatography leads to 2.1 g of the 2- tert -butoxycarbonylamino-hexadecanol benzyl ether, 1-3 , oil with the characteristics: IR max : 3354, 2918, 2849, 1686, 1530, 1370, 1350, 905, 715 cm -1. MS \ mc {m / z: 448 (M +, 2); 348 (M + - [Boc + H +], 20); 284 (M + - C 10 H 14 O, 10); 226 (M + - - Boc +
C 8 H 9 O], 10); 154 [C 11 H 22, 10); 91 (C 7 H 7, 100).
A 3,0 g de I-3, se añaden 70 mL de fenol 4M en CHCl_{3} y 22 mL de Me_{3}SiCl 4M en CHCl_{3} y se mantiene con agitación y a t.a. durante 3 min. Después se añaden 100 mL de fenol 4M en CHCl_{3} y 33 mL de Me_{3}SiCl 4M en CHCl_{3} y se agita durante 17 min. Se evapora a sequedad y se obtienen 2,36 g de crudo de reacción; del cual, por cromatografía, se obtienen 2,1 g (89%) del bencil éter de 2-aminohexadecanol (I-4), sólido blanco de p.f. = 121ºC.To 3.0 g of I-3 , 70 mL of 4M phenol in CHCl3 and 22 mL of 4M Me3 SiCl in CHCl3 are added and kept under stirring at rt for 3 min. Then 100 mL of 4M phenol in CHCl3 and 33 mL of 4M Me3 SiCl in CHCl3 are added and stirred for 17 min. It is evaporated to dryness and 2.36 g of reaction crude are obtained; of which, by chromatography, 2.1 g (89%) of the benzyl ether of 2-aminohexadecanol ( I-4 ), white solid of mp = 121 ° C, are obtained.
Espectro IR (NaCl) con máximos a: 3064,
3029, 2923, 2852, 1650, 1658, 1496, 1402, 1363, 1101, 1028 y
735 cm^{-1}. EM \nc{m/z}: 347 (M^{+}, 2); 226 (M^{+}
- C_{8}H_{9}O, 100); 91 (C_{7}H_{7}, 25). IR spectrum (NaCl) with maximums at: 3064, 3029, 2923, 2852, 1650, 1658, 1496, 1402, 1363, 1101, 1028 and
735 cm -1. MS \ mc {m / z: 347 (M +, 2); 226 (M + - C 8 H 9 O, 100); 91 (C 7 H 7, 25).
A 200 mg de I-4 en 1,1 mL de DMF, se añaden 48 mg de NaHCO_{3}, 0,1 mL de NEt_{3} y 1,45 mL de BrEt, manteniéndose con agitación y a t.a. durante 48 horas. Se extrae con AcOEt/H_{2}O, se seca con Na_{2}SO_{4} anhidro, se filtra y se lleva a sequedad, obteniéndose 158 mg (68%) del bencil éter de 2-dietilaminohexadecanol (I-5b), en forma de aceite amarillento.To 200 mg of I-4 in 1.1 mL of DMF, 48 mg of NaHCO 3, 0.1 mL of NEt 3 and 1.45 mL of BrEt are added, kept stirring at room temperature for 48 hours . It is extracted with AcOEt / H2O, dried with anhydrous Na2SO4, filtered and taken to dryness, obtaining 158 mg (68%) of the benzyl ether of 2-diethylaminohexadecanol ( I-5b ), in the form of yellowish oil.
A 50 mg de I-5b, en 2 mL
de MeOH y 0,5 mL de AcOH glacial, se añaden 10 mg de Pd/C (10%),
manteniéndose en atmósfera de hidrógeno con sobrepresión ligera, a
50ºC durante 2 h y 1 h a t.a ambiente. Se obtuvieron 30 mg de un
crudo de reacción, que por cromatografía condujeron a 20 mg de
2,2-dietilaminohexadecanol,
I-6b, sólido, de p.f. = 90ºC.
EM \nc{m/z}: 312 (M^{+} - H,1); 284
(M^{+}-C_{2}H_{5}, 1); 254 (M^{+} -
[C_{2}H_{5} + H], 100); 88 (M^{+} - C_{16}H_{32}, 25);
58(M^{+}-C_{2}H_{4}NO, 20).At 50 mg of I-5b , in 2 mL of MeOH and 0.5 mL of glacial AcOH, 10 mg of Pd / C (10%) are added, keeping under hydrogen atmosphere with light overpressure, at 50 ° C for 2 h and 1 It has a mood. 30 mg of a reaction crude were obtained, which by chromatography led to 20 mg of solid 2,2-diethylaminohexadecanol, I-6b , of mp = 90 ° C.
MS \ mc {m / z: 312 (M + - H, 1); 284 (M + - C 2 H 5, 1); 254 (M + - [C 2 H 5 + H], 100); 88 (M + - C 16 H 32, 25); 58 (M + - C 2 H 4 NO, 20).
Datos de Resonancia Magnética Nuclear de ^{1}H y ^{13}C de compuestos representativos en Tabla 1.Nuclear Magnetic Resonance Data of 1 H and 13 C of representative compounds in Table 1 .
Ejemplo 1bExample 1 B
Sobre 10,0 g del compuesto I-2a, en 125 mL de CH_{2}Cl_{2}, se añaden en pequeñas fracciones, en frío y con agitación 6 mL de TEA y 3 mL de CIMs. Se mantiene a 0ºC durante 30 min, seguido de 30 min a t.a. El crudo se lava repetidamente con disoluciones acuosas de NaCl saturada y de NaHCO_{3} al 5%. La fase orgánica se seca, filtra y se evapora, obteniéndose 9,6 g del mesilato de 2-terc-butoxicarbonilaminohexadecanol, que se utiliza directamente en la siguiente etapa. Disuelto en DMF y con agitación, se le añaden 4,0 g de NaN_{3} y se calienta a 50 – 60ºC, durante 6 h. Se evapora, se extrae con AcOEt/H_{2}O, se purifica por cromatografía, obteniéndose 4,24 g de 1-azido-2-terc-butoxicarbonilaminohexadecano, de p.f. = 48ºC, que se utilizan en la etapa siguiente. Disuelta la azida en 43 mL de THF, se añaden 850 mg de Pd/C, 1,26 g de NaBH_{4}, y, goteando, 100 mL de MeOH. Se mantiene en agitación durante 30 min, se filtra, se extrae con AcOEt/agua; la fase orgánica se seca con Na_{2}SO_{4} anhidro, se filtra, se lleva a sequedad y se cromatografía, dando lugar a 2,6 g de 2-terc-butoxicarbonilamino-hexadecilamina, I-7a, con p.f. = 56ºC. IR máx: 3349, 2918, 2850, 1687, 1531, 1469, 1365, 1349 y 1174 cm^{-1}. EM \nc{m/z}: 357 (M^{+} + H^{+}, 12); 301 (M^{+} - C_{4}H_{7}, 45); 240 (M^{+} -[Boc + NH], 10).About 10.0 g of compound I-2a , in 125 mL of CH2Cl2, 6 mL of TEA and 3 mL of MICs are added in small fractions, cold and with stirring. It is maintained at 0 ° C for 30 min, followed by 30 min at rt. The crude oil is repeatedly washed with aqueous solutions of saturated NaCl and 5% NaHCO 3. The organic phase is dried, filtered and evaporated, obtaining 9.6 g of the 2- tert -butoxycarbonylaminohexadecanol mesylate, which is used directly in the next stage. Dissolved in DMF and with stirring, 4.0 g of NaN3 are added and heated at 50-60 ° C for 6 h. It is evaporated, extracted with AcOEt / H2O, purified by chromatography, obtaining 4.24 g of 1-azido-2- tert -butoxycarbonylaminohexadecane, mp = 48 ° C, which are used in the next step. Dissolved the azide in 43 mL of THF, 850 mg of Pd / C, 1.26 g of NaBH4 are added, and, dripping, 100 mL of MeOH. It is kept under stirring for 30 min, filtered, extracted with AcOEt / water; The organic phase is dried with anhydrous Na 2 SO 4, filtered, dried and chromatographed, yielding 2.6 g of 2- tert -butoxycarbonylamino-hexadecylamine, I-7a , with mp . = 56 ° C. IR max : 3349, 2918, 2850, 1687, 1531, 1469, 1365, 1349 and 1174 cm -1. MS \ mc / m: 357 (M + + H +, 12); 301 (M + - C 4 H 7, 45); 240 (M + - [Boc + NH], 10).
A 50 mg de I-7a en 2 mL de éter seco, se le añaden 2,6 mL de HCl (IN) en Et_{2}O y se mantiene en agitación, a t.a., hasta la formación de un precipitado, que se filtra y lava con Et_{2}O, obteniendo 36 mg de diclorhidrato de 1,2-hexadeciléndiamina, I-7b, sólido blanco de p.f. = 88ºC. IR máx: 3750, 3620, 2953, 2851, 1653, 1558, 1472 y 720 cm^{-1}. EM \nc{m/z}: 257 (M^{+} +H, 100); 240 (M^{+} - NH_{2}, 31); 226 (M^{+} - CH_{4}N, 35); 154 (C_{11}H_{22}, 70).To 50 mg of I-7a in 2 mL of dry ether, 2.6 mL of HCl (IN) in Et2O is added and kept under stirring, at rt, until a precipitate forms, which is filter and wash with Et2O, obtaining 36 mg of 1,2-hexadecyldiamine dihydrochloride, I-7b , mp white solid. = 88 ° C. IR max : 3750, 3620, 2953, 2851, 1653, 1558, 1472 and 720 cm -1. MS \ mc {m / z: 257 (M + + H, 100); 240 (M + - NH 2, 31); 226 (M + - CH 4 N, 35); 154 (C 11 H 22, 70).
A 307 mg de I-7a disueltos en 1,8 mL de DMF, con agitación y t.a., se añaden 160 mg de NaHCO_{3}, 0,6 mL de TEA y 0,14 mL de BrEt, manteniéndose durante 48 h. Se evapora al vacío, se extrae con CHCl_{3}/H_{2}O y se lava hasta pH neutro. Se seca la fase orgánica, se filtra y se evapora, obteniéndose 360 mg de N,N-dietil-2-terc-butoxicarbonilamino-hexadecilamina, I-8b, en forma aceitosa con IR máx: 3358, 2964, 2853, 1704, 1495, 1389, 1365, 1245, 1174, 1062 y 775 cm^{-1}. EM \nc{m/z}: 413 (M^{+} + H, 3); 357 (M^{+} - C_{4}H_{7}, 9); 298 (M^{+} - C_{5}H_{8}NO_{2}, 1); 267 (M^{+} - [Boc + C_{2}H_{6}N],); 226 (M^{+} - [Boc + C_{5}H_{13}N_{2}],); 86 (C_{5}H_{12}N, 60).To 307 mg of I-7a dissolved in 1.8 mL of DMF, with stirring and rt, 160 mg of NaHCO 3, 0.6 mL of TEA and 0.14 mL of BrEt are added, holding for 48 h. It is evaporated in vacuo, extracted with CHCl3 / H2O and washed until neutral pH. The organic phase is dried, filtered and evaporated, obtaining 360 mg of N, N -diethyl-2- tert -butoxycarbonylamino-hexadecylamine, I-8b , in oily form with IR max : 3358, 2964, 2853, 1704, 1495 , 1389, 1365, 1245, 1174, 1062 and 775 cm -1. MS \ mc {m / z: 413 (M + + H, 3); 357 (M + - C 4 H 7, 9); 298 (M + - C 5 H 8 NO 2, 1); 267 (M + - [Boc + C 2 H 6 N],); 226 (M + - [Boc + C 5 H 13 N 2],); 86 (C 5 H 12 N, 60).
Sobre 360 mg de I-8b se añaden 8,7 mL de fenol 4M en CHCl_{3} y 2,9 mL de Me_{3}SiCl 4M en CHCl_{3} y se mantiene en agitación a t.a. durante 3 min. Después se añaden 13 mL de la mencionada disolución de fenol y 4 mL de la de Me_{3}SiCl M y se deja en agitación durante 17 minutos. Se evapora hasta sequedad y se obtienen 258 mg de crudo de reacción, que por cromatografía, condujo a 190 mg de 1-dietilamino-2-hexadecilamina, I-9b, aceite viscoso amarillo con las características: IR máx: 3410, 2922 2852, 1673, 1560, 1476 y 720 cm^{-1}. EM \nc{m/z}: 313 (M^{+} + H, 1); 296 (M^{+} - NH_{2}, 1); 254 (M^{+} - C_{4}H_{10}, 1); 238 (M^{+} - C_{4}H_{10}N + 2H, 2); 226 (M^{+} - C_{5}H_{13}N, 10); 196 (C_{14}H_{30}, 1); 86 (C_{5}H_{12}N, 100); 72(C_{4}H_{10}N, 80).On 360 mg of I-8b , 8.7 mL of 4M phenol in CHCl3 and 2.9 mL of 4M Me3 SiCl in CHCl3 are added and kept under stirring at rt for 3 min. Then 13 mL of said phenol solution and 4 mL of Me 3 SiCl M are added and left under stirring for 17 minutes. It is evaporated to dryness and 258 mg of reaction crude are obtained, which by chromatography led to 190 mg of 1-diethylamino-2-hexadecylamine, I-9b , yellow viscous oil with the characteristics: IR max : 3410, 2922 2852, 1673, 1560, 1476 and 720 cm -1. MS \ mc {m / z: 313 (M + + H, 1); 296 (M + - NH 2, 1); 254 (M + - C 4 H 10, 1); 238 (M + - C 4 H 10 N + 2H, 2); 226 (M + - C 5 H 13 N, 10); 196 (C 14 H 30, 1); 86 (C 5 H 12 N, 100); 72 (C 4 H 10 N, 80).
411 mg de 1,2-epoxihexadecano y 0,2 mL de ciclohexilamina se mantuvieron a reflujo en 10 mL de MeOH durante 2 h, seguido de 23 h a t.a. Se evaporó el MeOH y se extrajo con AcOEt/ HCl 2N(aq). A la fase acuosa se añadió NaOH acuoso al 10% hasta pH ligeramente básico y se extrajo con AcOEt. El extracto, convenientemente manipulado, condujo a 330 mg de 1-ciclohexilaminohexadecan-2-ol, I-10; sólido amarillo, p.f. = 68ºC. IR máx: 3382, 2918, 2850, 1455, 1215 y 1010 cm^{-1}. EM \nc{m/z}: 338 (M^{+} - H,1); 296 (M^{+} - C_{2}H_{3}O, 1); 266 (M^{+} - C_{7}H_{13}N, 1); 256 (M^{+} - C_{6}H_{11}); 196 (C_{14}H_{28}, 1); 142 (C_{8}H_{16}ON, 5); 112 (M^{+} - C_{16}H_{31}O, 100); 83 (C_{6}H_{4}, 5). RMN ^{1}H: 0,89 t (6,9); 1,28 sa; 4,91 m; 4,91 sa; 3,54 dd (11,6; 6,9),3,76 dd (11,6; 2,8); 3,18 m. RMN ^{13}C: 14,1(CH_{3}); 22,7; 25,8; 25,9; 26,1; 29,4; 29,7; 31,8; 33,6; 34,0; 35,3 (CH_{2}); 69,9 (CH-O); 52,4 (CH_{2}-N); 56,7 (CH-N).411 mg of 1,2-epoxyhexadecane and 0.2 mL of cyclohexylamine were refluxed in 10 mL of MeOH for 2 h, followed by 23 h at MeOH was evaporated and extracted with AcOEt / 2N HCl (aq). To the aqueous phase 10% aqueous NaOH was added until slightly basic pH and extracted with AcOEt. The extract, conveniently manipulated, led to 330 mg of 1-cyclohexylaminohexadecan-2-ol, I-10 ; yellow solid, mp . = 68 ° C. IR max : 3382, 2918, 2850, 1455, 1215 and 1010 cm -1. MS \ mc {m / z}: 338 (M + - H, 1); 296 (M + - C 2 H 3 O, 1); 266 (M + - C 7 H 13 N, 1); 256 (M + - C 6 H 11); 196 (C 14 H 28, 1); 142 (C 8 H 16 ON, 5); 112 (M + - C 16 H 31 O, 100); 83 (C 6 H 4, 5). 1 H NMR : 0.89 t (6.9); 1.28 sa ; 4.91 m ; 4.91 sa ; 3.54 dd (11.6; 6.9), 3.76 dd (11.6; 2.8); 3.18 m . 13 C NMR : 14.1 (CH 3); 22.7; 25.8; 25.9; 26.1; 29.4; 29.7; 31.8; 33.6; 34.0; 35.3 (CH2); 69.9 (CH-O); 52.4 (CH2 -N); 56.7 (CH-N).
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Ejemplo 2aExample 2nd
Diversos compuestos de la fórmula general I, presentan efectos microbicidas considerables sobre Mycobacterium tuberculosis, actuando tanto sobre estirpes sensibles (S) como sobre multifarmacorresistentes (MDR), en comparación con los agentes terapéuticos de primera línea.Various compounds of the general formula I have considerable microbicidal effects on Mycobacterium tuberculosis , acting on both sensitive (S) and multi-drug resistant (MDR) strains, compared to first-line therapeutic agents.
La evaluación in vitro se (levó a cabo por triplicado, según la microtécnica de Alamar Azul, siguiendo el protocolo descrito por Jiménez-Arellanes (Jiménez-Arellanes, A. et al. Phytother. Res. 2003, vol. 17 (8), pp. 903), sobre cepas H37Rv (ATCC), Rockville, MD, USA; y CIBIN/UMF 15:99 (en adelante CIBIN-99), resistente a todos los fármacos antituberculosos de primera línea, que fue obtenida de pacientes ingresados en el Hospital del Seguro Social mexicano, de Monterrey, NL, México.The in vitro evaluation (was carried out in triplicate, according to the Alamar Azul microtechnics, following the protocol described by Jiménez-Arellanes (Jiménez-Arellanes, A. et al. Phytother. Res . 2003 , vol. 17 (8), pp. 903), on strains H37Rv (ATCC), Rockville, MD, USA; and CIBIN / UMF 15:99 (hereinafter CIBIN-99), resistant to all first-line antituberculosis drugs, which was obtained from patients admitted to the Mexican Social Security Hospital, Monterrey, NL, Mexico.
Los resultados de actividad in vitro hallados, según el protocolo citado, para distintos compuestos de esta invención, se ilustran en la Tabla 2, que muestra los valores de Concentración Inhibitoria Mínima (CIM, \muM), en comparación con el agente clínico de referencia etambutol (EMB).The results of in vitro activity found, according to the aforementioned protocol, for different compounds of this invention, are illustrated in Table 2, which shows the values of Minimum Inhibitory Concentration (MIC, µM), in comparison with the clinical reference agent ethambutol (EMB).
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Se aprecia en la tabla, que varios de los compuestos evaluados en esta invención, resultan más potentes (valores de CIM menores que 7,2 \muM) que el agente de uso clínico EMB frente a la micobacteria H37Rv, sensible a los fármacos de primera línea y un mayor número (valores de CIM menores que 58 \muM), lo son frente a la estirpe CIBIN-99, resistente a todos los fármacos de primera línea.It can be seen in the table, that several of the compounds evaluated in this invention, are more potent (CIM values less than 7.2 µM) than the agent of use EMB clinical versus drug-sensitive mycobacteria H37Rv front-line and a greater number (CIM values less than 58 µM), they are in front of the CIBIN-99 lineage, resistant to all first line drugs.
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Ejemplo 2bExample 2b
Complementariamente, se presentan en la Tabla 3, resultados de la evaluación in vitro de algunos compuestos de esta invención, frente a estirpes de micobacterias, aisladas de distintos pacientes refractarios a los tratamientos anti-TB, llevados a cabo con fármacos de primera línea.In addition, Table 3 shows the results of the in vitro evaluation of some compounds of this invention, against mycobacterial strains, isolated from different patients refractory to anti-TB treatments, carried out with first-line drugs.
En la tabla, se puede observar claramente, que los compuestos 1-4 y I-5b son muy eficaces frente a micobacterias con cualquier perfil de resistencia frente a fármacos convencionales; mientras que no lo es tanto, aunque también resulta bastante eficaz, el compuesto I-9b.In the table, it can be clearly seen that compounds 1-4 and I-5b are very effective against mycobacteria with any resistance profile against conventional drugs; while it is not so much, although it is also quite effective, the compound I-9b .
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Ratones Balb/c de 6 a 8 semanas de edad se infectan por inyección intratraqueal con 1 x10^{6} bacterias de la cepa virulenta de M. tuberculosis H37Rv. Este procedimiento experimental genera tuberculosis pulmonar progresiva, que transcurre en dos fases. En la primera, que corresponde al primer mes de infección, se produce inflamación crónica perivascular, peribronquial e intersticial, con la micobacteria controlada por macrófagos activados y linfocitos Th-1. En la segunda fase se produce neumonía progresiva, con incremento logarítmico del número de bacterias vivas en el pulmón, que finalmente provocan la muerte de los animales.Balb / c mice 6 to 8 weeks of age are infected by intratracheal injection with 1 x 10 6 bacteria from the virulent strain of M. tuberculosis H37Rv. This experimental procedure generates progressive pulmonary tuberculosis, which takes place in two phases. In the first, which corresponds to the first month of infection, chronic perivascular, peribronchial and interstitial inflammation occurs, with mycobacterium controlled by activated macrophages and Th-1 lymphocytes. In the second phase, progressive pneumonia occurs, with a logarithmic increase in the number of live bacteria in the lung, which eventually causes the animals to die.
Se infectaron 6 grupos de 5 ratones y se inició el tratamiento a los dos meses post-infección.6 groups of 5 mice were infected and started the treatment at two months post-infection.
- El primer grupo se trato con I-5b;The first group was treated with I-5b ;
- el segundo grupo recibió el compuesto 1-4,the second group received compound 1-4 ,
- al tercer grupo se le administró I-5b, más rifampicina (10 mg/kg), isoniazida (10 mg/kg) y pirazinamida (30 mg/kg);the third group was given I-5b , plus rifampicin (10 mg / kg), isoniazid (10 mg / kg) and pyrazinamide (30 mg / kg);
- el cuarto grupo se trato con el compuesto I-4 más los fármacos mencionados;the fourth group was treated with compound I-4 plus the mentioned drugs;
- el quinto grupo recibió solamente los fármacos mencionados ythe fifth group received only the mentioned drugs and
- el sexto grupo sólo recibió el vehículo (solución salina).The sixth group only received the vehicle (saline solution).
La administraron se efectuó por sonda nasogástrica, diariamente durante dos meses, al final de los cuales se sacrificaron todos los animales y se extrajeron los pulmones. Uno de los pulmones de cada ratón se uso para determinar el número de bacterias vivas, mediante la cuantificación de unidades formadoras de colonia (UFC), el otro pulmón se destino al estudio histológico; específicamente se determinó el porcentaje de superficie pulmonar afectada por neumonía, mediante análisis de imagen computarizada.It was administered by tube nasogastric, daily for two months, at the end of which all animals were sacrificed and the lungs were removed. One of the lungs of each mouse was used to determine the number of live bacteria, by quantifying units colony forming (UFC), the other lung was destined to study histological; specifically the percentage of pulmonary surface affected by pneumonia, by analysis of computerized image
Se muestran en las Figuras 1 y 2.They are shown in Figures 1 and 2.
En la Figura 1 se muestran los valores de unidades formadoras de colonias (UFC) micobacterianas, después del tratamiento con los compuestos I-5b (en las figuras UCI-14), y I-4 (en las figuras UCI-05), con tres fármacos convencionales (3F), con la combinación de I-5b con tres fármacos (14+3F), o la combinación de I-4 con tres fármacos (05+3F). Las barras corresponden a la media de 5 animales por cada grupo. Ctr corresponde al grupo control que no recibió tratamiento.Figure 1 shows the values of mycobacterial colony forming units (CFU), after treatment with compounds I-5b ( in Figures UCI-14 ), and I-4 ( in Figures UCI-05 ), with three conventional drugs (3F), with the combination of I-5b with three drugs (14 + 3F), or the combination of I-4 with three drugs (05 + 3F). The bars correspond to the average of 5 animals per group. Ctr corresponds to the control group that did not receive treatment.
En comparación con el grupo control, no tratado, se observa que:Compared to the untreated control group, It is observed that:
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- Los animales tratados con el compuesto I-5b redujeron 3 veces la carga bacilar pulmonar.Animals treated with compound I-5b reduced pulmonary bacillary load 3 times.
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- Los tratados con el compuesto I-4 disminuyeron 15 veces.Those treated with compound I-4 decreased 15 times.
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- Los ratones que recibieron los tres fármacos convencionales la disminuyeron 30 veces.The mice that received the three conventional drugs the They decreased 30 times.
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- En los animales tratados con I-5b + 3 fármacos casi se igualó la eficiencia del compuesto I-4 solo.In animals treated with I-5b + 3 drugs, the efficiency of compound I-4 alone was almost equalized.
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- La asociación del compuesto I-4 con los 3 fármacos, fue con mucho el tratamiento más eficaz, pues disminuyó 100 veces la cantidad de micobacterias vivas en el pulmón.The association of compound I-4 with the 3 drugs was by far the most effective treatment, since the amount of live mycobacteria in the lung decreased 100 times .
Estos resultados correlacionan adecuadamente con el estudio histológico, realizado después de sacrificar los animales, al término del ensayo, cuyos resultados se muestran en la Fig. 2, observándose:These results correlate adequately with the histological study, performed after sacrificing the animals, at the end of the trial, whose results are shown in the Fig. 2, observing:
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- que los animales tratados con los 3 fármacos convencionales presentan un área neumónica afectada correspondiente al 6% de la superficie pulmonar.that the animals treated with the 3 conventional drugs present an affected pneumonic area corresponding to 6% of the surface pulmonary.
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- que los animales tratados con la asociación I-5b + 3 fármacos presentan un área neumónica menor, correspondiente al 4% de la superficie pulmonar.that animals treated with the I-5b + 3 drug association have a smaller pneumonic area, corresponding to 4% of the lung surface.
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- que los animales tratados con la asociación I-4 + 3 fármacos presentan un área neumónica aún menor, correspondiente solamente al 2% de la superficie pulmonar.that animals treated with the I-4 + 3 drug association have an even smaller pneumonic area, corresponding only to 2% of the lung surface.
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- Los ratones tratados exclusivamente con I-5b mostraron un área neumónica similar a la de los controles no tratados.Mice treated exclusively with I-5b showed a pneumonic area similar to that of untreated controls.
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- Los animales tratados exclusivamente con el compuesto I-4 presentaron una reducción del 20%, en comparación con los controles no tratados.Animals treated exclusively with compound I-4 showed a 20% reduction, compared to untreated controls.
Considerando que el tratamiento actual de la TB se basa en el uso de tres a cinco fármacos, estas observaciones demuestran la utilidad de los compuestos recogidos en esta invención; ya que el compuesto I-4, por si solo y mejor asociado a otros fármacos, y el compuesto I-5b en tratamientos combinados, constituyen nuevas herramientas terapéuticas para combatir con éxito la tuberculosis. La asociación de I-4 con los fármacos convencionales, potencia sustancialmente su efecto convirtiéndose en el mejor tratamiento de los ensayados hasta ahora.Considering that the current treatment of TB is based on the use of three to five drugs, these observations demonstrate the usefulness of the compounds collected in this invention; since compound I-4 , by itself and better associated with other drugs, and compound I-5b in combined treatments, constitute new therapeutic tools to successfully fight tuberculosis. The association of I-4 with conventional drugs substantially enhances its effect, becoming the best treatment of those tested so far.
Claims (10)
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Non-Patent Citations (3)
| Title |
|---|
| DEL OLMO, E. y col. Leishmanicidal activity of some apliphatic diamines and amino-alcohols. Bioorganic & Medicinal Letters. 2002, Vol.12, páginas 659-662. Todo el documento en especial página 660, esquema 1 y página 661, tablas 1 y 2. * |
| HEIFETS, L. y col. Ethambutol MICs and MBCs for Mycobacterium Avium complex and Mycobacterium Tuberculosis. Antimicrobial Agents and Chemotherapy. 1986, Vol. 30, N$^{o}$ 6, páginas 927-932. Página 927, párrafo 1$^{o}$. * |
| LUCAS, R. y col. Synthesis and Enzyme inhibitory activities of a series of lipidic diamine and aminoalcohol derivatives on cytosolic and secretory phospholipases A2. Bioorganic & Medicinal Letters. 2000, Vol.10, páginas 285-288. Todo el documento en especial página 286, esquema 1 y página 287, tablas 1 y 2. * |
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