ES2634087T3 - Lípidos biodegradables para la administración de agentes activos - Google Patents

Lípidos biodegradables para la administración de agentes activos Download PDF

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ES2634087T3
ES2634087T3 ES11726579.3T ES11726579T ES2634087T3 ES 2634087 T3 ES2634087 T3 ES 2634087T3 ES 11726579 T ES11726579 T ES 11726579T ES 2634087 T3 ES2634087 T3 ES 2634087T3
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Muthiah Manoharan
Martin Maier
Muthusamy Jayaraman
Shigeo Matsuda
Narayanannair K. Jayaprakash
Kallanthottathil G. Rajeev
Akin Akinc
Thomas A. Baillie
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Alnylam Pharmaceuticals Inc
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Abstract

Un compuesto de fórmula IB **(Ver fórmula)** en la que R1 y R2 son cada uno, independientemente, alquilo opcionalmente sustituido, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo, o heterociclo; o R1 y R2, junto con el átomo de nitrógeno al que están unidos, forman un anillo heterocíclico opcionalmente sustituido; cada aparición de R es, independientemente, -(CR3R4)-; cada aparición de R3 y R4 son, independientemente H, OH, alquilo, alcoxi, -NH2, alquilamino o dialquilamino (en una realización preferida, cada aparición de R3 y R4 son, independientemente, H o alquilo C1-C4); o R3 y R4, junto con el átomo de carbono al que están directamente unidos, forman un grupo cicloalquilo, en la que no más de tres grupos R en cada cadena unida al carbono C* son cicloalquilo (por ejemplo, ciclopropilo); Q está ausente o es -O-, -NH-, -S-, -C(O)O-, -OC(O)-, -C(O)N(R4)-, -N(R5)C(O)-, -S-S-, -OC(O)O-, -ON>= C(R5)-, -C(R5)>=N-O-, -OC(O)N(R5)-, -N(R5)C(O)N(R5)-, -N(R5)C(O)O-, -C(O)S-, -C(S)O- o -C(R5)>=N-OC( O)-; R5 es H o metilo; a es 1, 2, 3, 4, 5 o 6; b es 0, 1, 2 o 3; R' está ausente, es hidrógeno o alquilo (por ejemplo, alquilo C1-C4); M1 y M2 son cada uno, independientemente, un grupo biodegradable; cada uno de R9 y R10 son, independientemente, alquileno, o alquenileno; y cada uno de R11 y R12 son independientemente alquilo o alquenilo, opcionalmente terminado por COOR13 donde cada R13 es independientemente alquilo; con la condición de que: R9, M1, y R11 sean juntos al menos 8 átomos de carbono de longitud; y R11, M2, y R12 sean juntos al menos 8 átomos de carbono de longitud.

Description

imagen1
imagen2
imagen3
imagen4
imagen5
imagen6
imagen7
imagen8
imagen9
(donde n es 0-5)
(donde n es 0-5)
(el carbono con un asterisco es el carbono terciario del lípido catiónico y no es parte del grupo de cabeza) (el carbono con un asterisco es el carbono terciario del lípido catiónico y no es parte del grupo de cabeza)
R = H, alquilo (por ejemplo, metilo) X = halógeno (por ejemplo, Cl)
R = H, alquilo (por ejemplo, metilo) X = halógeno (por ejemplo, Cl)
R = H, alquilo (por ejemplo, metilo) X = halógeno (por ejemplo, Cl)
Algunos grupos de cola hidrófobos adecuados incluyen aquellos representados en la Tabla 2:
imagen10
imagen11
En el presente documento se describe un método de preparación de un compuesto de cualquiera de las fórmulas I-
XXIII. Métodos sintéticos a modo de ejemplo adecuados se ilustran en los Esquemas A-G a continuación. Las variables en los siguientes esquemas son las mismas que aquellas variables en la misma posición en las fórmulas I-XXIII anteriores.
imagen12
Pueden variarse la longitud de cadena del lípido y la longitud del conector en el Esquema A. Adicionalmente, pueden derivatizarse el grupo R en la funcionalidad éster y sustituyentes en el átomo de nitrógeno.
imagen13
10 Como se muestra en el Esquema B, el acoplamiento mediado por cobre proporciona una cadena de lípido que contiene di-ino con grupos funcionales terminales R, que pueden reducirse para generar cadenas de lípido que contiene di-eno. Pueden variarse la longitud del conector y la cadena de lípido, y pueden derivatizarse los grupos sustituyentes funcionales (R, R1, R2).
imagen14
imagen15
imagen16
imagen17
imagen18
imagen19
imagen20
imagen21
imagen22
imagen23
imagen24
imagen25
imagen26
imagen27
imagen28
imagen29
imagen30
imagen31
imagen32
imagen33
imagen34
5
8 5 8 8 5 8
5
6
7 6 7 7 6 7
6
7
6 7 6 6 7 6
7
8
5 8 5 5 8 5
8
9
4 9 4 4 9 4
9
10
3 10 3 3 10 3
10
11
2 11 2 2 11 2
11
12
1 12 1 1 12 1
12
1
12 2 11 12 1 11 2
2
11 3 10 11 2 10 3
3
10 4 9 10 3 9 4
4
9 5 8 9 4 8 5
5
8 6 7 8 5 7 6
6
7 7 6 7 6 6 7
7
6 8 5 6 7 5 8
8
5 9 4 5 8 4 9
9
4 10 3 4 9 3 10
10
3 11 2 3 10 2 11
11
2 12 1 2 11 1 12
12
1 1 12 1 12 12 1
1
12 3 10 12 1 10 3
2
11 4 9 11 2 9 4
3
10 5 8 10 3 8 5
4
9 6 7 9 4 7 6
5
8 7 6 8 5 6 7
6
7 8 5 7 6 5 8
7
6 9 4 6 7 4 9
8
5 10 3 5 8 3 10
9
4 11 2 4 9 2 11
10
3 12 1 3 10 1 12
11
2 2 11 2 11 11 2
12
1 4 9 1 12 10 3
1
12 4 9 12 1 9 4
2
11 5 8 11 2 8 5
3
10 6 7 10 3 7 6
4
9 7 6 9 4 6 7
5
8 8 5 8 5 5 8
6
7 9 4 7 6 4 9
7
6 10 3 6 7 3 10
8
5 11 2 5 8 2 11
9
4 12 1 4 9 1 12
10
3 2 11 3 10 11 2
11
2 3 10 2 11 10 3
12
1 4 9 1 12 11 2
1
12 5 8 12 1 8 5
2
11 6 7 11 2 7 6
3
10 7 6 10 3 6 7
4
9 8 5 9 4 5 8
5
8 9 4 8 5 4 9
6
7 10 3 7 6 3 10
7
6 11 2 6 7 2 11
8
5 12 1 5 8 1 12
9
4 2 11 4 9 11 2
10
3 3 10 3 10 10 3
11
2 4 9 2 11 11 2
12
1 5 8 1 12 12 1
1
12 6 7 12 1 7 6
2
11 7 6 11 2 6 7
3
10 8 5 10 3 5 8
4
9 9 4 9 4 4 9
5
8 10 3 8 5 3 10
6
7 11 2 7 6 2 11
7
6 12 1 6 7 1 12
8
5 2 11 5 8 11 2
9
4 3 10 4 9 10 3
10
3 4 9 3 10 11 2
11
2 5 8 2 11 12 1
12
1 6 7 1 12 1
12
1
12 7 6 12 1 6 7
2
11 8 5 11 2 5 8
3
10 9 4 10 3 4 9
4
9 8 5 9 4 3 10
5
8 9 4 8 5 2 11
6
7 10 3 7 6 1 12
7
6 11 2 6 7 11 2
8
5 12 1 5 8 10 3
9
4 2 11 4 9 11 2
10
3 3 10 3 10 12 1
11
2 4 9 2 11 1 12
12
1 5 8 1 12 2 11
TABLA 6
m
n p q m n p q
1
12 1 12 12 1 12
1
2
11 2 11 11 2 11
2
3
10 3 10 10 3 10
3
4
9 4 9 9 4 9
4
5
8 5 8 8 5 8
5
6
7 6 7 7 6 7
6
7
6 7 6 6 7 6
7
8
5 8 5 5 8 5
8
9
4 9 4 4 9 4
9
10
3 10 3 3 10 3
10
11
2 11 2 2 11 2
11
12
1 12 1 1 12 1
12
1
12 2 11 12 1 11 2
2
11 3 10 11 2 10 3
3
10 4 9 10 3 9 4
4
9 5 8 9 4 8 5
5
8 6 7 8 5 7 6
6
7 7 6 7 6 6 7
7
6 8 5 6 7 5 8
8
5 9 4 5 8 4 9
9
4 10 3 4 9 3 10
10
3 11 2 3 10 2 11
11
2 12 1 2 11 1 12
12
1 1 12 1 12 12 1
1
12 3 10 12 1 10 3
2
11 4 9 11 2 9 4
3
10 5 8 10 3 8 5
4
9 6 7 9 4 7 6
5
8 7 6 8 5 6 7
6
7 8 5 7 6 5 8
7
6 9 4 6 7 4 9
8
5 10 3 5 8 3 10
9
4 11 2 4 9 2 11
10
3 12 1 3 10 1 12
11
2 2 11 2 11 11 2
12
1 4 9 1 12 10 3
1
12 4 9 12 1 9 4
2
11 5 8 11 2 8 5
3
10 6 7 10 3 7 6
4
9 7 6 9 4 6 7
5
8 8 5 8 5 5 8
6
7 9 4 7 6 4 9
7
6 10 3 6 7 3 10
8
5 11 2 5 8 2 11
9
4 12 1 4 9 1 12
10
3 2 11 3 10 11 2
11
2 3 10 2 11 10 3
12
1 4 9 1 12 11 2
1
12 5 8 12 1 8 5
2
11 6 7 11 2 7 6
3
10 7 6 10 3 6 7
4
9 8 5 9 4 5 8
5
8 9 4 8 5 4 9
6
7 10 3 7 6 3 10
7
6 11 2 6 7 2 11
8
5 12 1 5 8 1 12
9
4 2 11 4 9 11 2
10
3 3 10 3 10 10 3
11
2 4 9 2 11 11 2
12
1 5 8 1 12 12 1
1
12 6 7 12 1 7 6
2
11 7 6 11 2 6 7
3
10 8 5 10 3 5 8
4
9 9 4 9 4 4 9
5
8 10 3 8 5 3 10
6
7 11 2 7 6 2 11
7
6 12 1 6 7 1 12
8
5 2 11 5 8 11 2
9
4 3 10 4 9 10 3
10
3 4 9 3 10 11 2
11
2 5 8 2 11 12 1
12
1 6 7 1 12 1
12
1
12 7 6 12 1 6 7
2
11 8 5 11 2 5 8
3
10 9 4 10 3 4 9
4
9 8 5 9 4 3 10
5
8 9 4 8 5 2 11
6
7 10 3 7 6 1 12
7
6 11 2 6 7 11 2
8
5 12 1 5 8 10 3
9
4 2 11 4 9 11 2
10
3 3 10 3 10 12 1
11
2 4 9 2 11 1 12
12
1 5 8 1 12 2 11
TABLA 7
m
n p q m n p q
1
13 1 13 1 13 1 13
2
12 2 12 2 12 2 12
3
11 3 11 3 11 3 11
4
10 4 10 4 10 4 10
5
9 5 9 5 9 5 9
6
8 6 8 6 8 6 8
7
7
7
7
7
7
7
7
8
6 8 6 8 6 8 6
9
5 9 5 9 5 9 5
10
4 10 4 10 4 10 4
11
3 11 3 11 3 11 3
12
2 12 2 12 2 12 2
13
1 13 1 13 1 13 1
1
13 2 12 1 13 2 12
2
12 3 11 2 12 3 11
3
11 4 10 3 11 4 10
4
10 5 9 4 10 5 9
5
9 6 8 5 9 6 8
6
8 7 7 6 8 7 7
7
7
8 6 7 7 8 6
8
6 9 5 8 6 9 5
9
5 10 4 9 5 10 4
10
4 11 3 10 4 11 3
11
3 12 2 11 3 12 2
12
2 13 1 12 2 13 1
13
1 1 13 13 1 1
13
1
13 3 11 1 13 3 11
2
12 4 10 2 12 4 10
3
11 5 9 3 11 5 9
4
10 6 8 4 10 6 8
5
9 7 7 5 9 7 7
6
8 8 6 6 8 8
6
7
7
9 5 7 7 9 5
8
6 10 4 8 6 10 4
9
5 11 3 9 5 11 3
10
4 12 2 10 4 12 2
11
3 13 1 11 3 13 1
12
2 1 13 12 2 1 13
13
1 2 12 13 1 2 14
TABLA 8
m
n p m n p
1
12 18 12 1 18
2
11 18 11 2 18
3
10 18 10 3 18
4
9 18 9 4 18
5
8 18 8 5 18
6
7 18 7 6 18
7
6 18 6 7 18
8
5 18 5 8 18
9
4 18 4 9 18
10
3 18 3 10 18
11
2 18 2 11 18
12
1 18 1 12 18
1
12 17 12 1 17
2
11 17 11 2 17
3
10 17 10 3 17
4
9 17 9 4 17
5
8 17 8 5 17
6
7 17 7 6 17
7
6 17 6 7 17
8
5 17 5 8 17
9
4 17 4 9 17
10
3 17 3 10 17
11
2 17 2 11 17
12
1 17 1 12 17
1
12 16 12 1 16
2
11 16 11 2 16
3
10 16 10 3 16
4
9 16 9 4 16
5
8 16 8 5 16
6
7 16 7 6 16
7
6 16 6 7 16
8
5 16 5 8 16
9
4 16 4 9 16
10
3 16 3 10 16
11
2 16 2 11 16
12
1 16 1 12 16
1
12 15 12 1 15
2
11 15 11 2 15
3
10 15 10 3 15
4
9 15 9 4 15
5
8 15 8 5 15
6
7 15 7 6 15
7
6 15 6 7 15
8
5 15 5 8 15
9
4 15 4 9 15
10
3 15 3 10 15
11
2 15 2 11 15
12
1 15 1 12 15
1
12 14 12 1 14
2
11 14 11 2 14
3
10 14 10 3 14
4
9 14 9 4 14
5
8 14 8 5 14
6
7 14 7 6 14
7
6 14 6 7 14
8
5 14 5 8 14
9
4 14 4 9 14
10
3 14 3 10 14
11
2 14 2 11 14
12
1 14 1 12 14
1
12 13 12 1 13
2
11 13 11 2 13
3
10 13 10 3 13
4
9 13 9 4 13
5
8 13 8 5 13
6
7 13 7 6 13
7
6 13 6 7 13
8
5 13 5 8 13
9
4 13 4 9 13
10
3 13 3 10 13
11
2 13 2 11 13
12
1 13 1 12 13
1
12 12 12 1 12
2
11 12 11 2 12
3
10 12 10 3 12
4
9 12 9 4 12
5
8 12 8 5 12
6
7 12 7 6 12
7
6 12 6 7 12
8
5 12 5 8 12
9
4 12 4 9 12
10
3 12 3 10 12
11
2 12 2 11 12
12
1 12 1
12
12
1
12 11 12 1 11
2
11 11 11 2 11
3
10 11 10 3 11
4
9 11 9 4 11
5
8 11 8 5 11
6
7 11 7 6 11
7
6 11 6 7 11
8
5 11 5 8 11
9
4 11 4 9 11
10
3 11 3 10 11
11
2 11 2
11
11
12
1 11 1 12 11
12
1 10 12 1 10
1
12 10 11 2 10
2
11 10 10 3 10
3
10 10 9 4 10
4
9 10 8 5 10
5
8 10 7 6 10
6
7 10 6 7 10
7
6 10 5 8 10
8
5 10 4 9 10
9
4 10 3 10 10
10
3 10 2 11
10
11
2 10 1 12 10
12
1 10 12 1 10
1
12 9 11 2 9
2
11 9 10 3 9
3
10 9 9 4 9
4
9 9 8 5 9
5
8 9 7 6 9
6
7 9 6 7 9
7
6 9 5 8 9
8
5 9 4 9 9
9
4 9 3 10
9
10
3 9 2 11 9
11
2 9 1 12 9
12
1 9 12 1 9
1
12 8 11 2 8
2
11 8 10 3 8
3
10 8 9 4 8
4
9 8 8 5 8
5
8 8 7 6 8
6
7 8 6 7 8
7
6 8 5 8 8
8
5 8 4 9
8
9
4 8 3 10 8
10
3 8 2 11 8
11
2 8 1 12 8
12
1 8 12 1 8
TABLA 9
m
n p q m n p q
1
12 8 8 12 1 8 8
2
11 8 8 11 2 8 8
3
10 8 8 10 3 8 8
4
9 8 8 9 4 8 8
5
8 8 8 8 5 8 8
6
7 8 8 7 6 8 8
7
6 8 8 6 7 8 8
8
5 8 8 5
8
8
8
9
4 8 8 4 9 8 8
10
3 8 8 3 10 8 8
11
2 8 8 2 11 8 8
12
1 8 8 1 12 8 8
1
12 9 7 12 1 9 7
2
11 9 7 11 2 9 7
3
10 9 7 10 3 9 7
4
9 9 7 9 4 9 7
5
8 9 7 8 5 9 7
6
7 9 7 7 6 9 7
7
6 9 7 6 7 9
7
8
5 9 7 5 8 9 7
9
4 9 7 4 9 9 7
10
3 9 7 3 10 9 7
11
2 9 7 2 11 9 7
12
1 9 7 1 12 9 7
1
12 10 6 12 1 10 6
2
11 10 6 11 2 10 6
3
10 10 6 10 3 10 6
4
9 10 6 9 4 10 6
5
8 10 6 8 5 10 6
6
7 10 6 7 6 10
6
7
6 10 6 6 7 10 6
8
5 10 6 5 8 10 6
9
4 10 6 4 9 10 6
10
3 10 6 3 10 10 6
11
2 10 6 2 11 10 6
12
1 10 6 1 12 10 6
1
12 11 5 12 1 11 5
2
11 11 5 11 2 11 5
3
10 11 5 10 3 11 5
4
9 11 5 9 4 11 5
5
8 11 5 8 5 11
5
6
7 11 5 7 6 11 5
7
6 11 5 6 7 11 5
8
5 11 5 5 8 11 5
9
4 11 5 4 9 11 5
10
3 11 5 3 10 11 5
11
2 11 5 2 11 11 5
12
1 11 5 1 12 11 5
1
12 12 4 12 1 12 4
2
11 12 4 11 2 12 4
3
10 12 4 10 3 12 4
4
9 12 4 9 4 12
4
5
8 12 4 8 5 12 4
6
7 12 4 7 6 12 4
7
6 12 4 6 7 12 4
8
5 12 4 5 8 12 4
9
4 12 4 4 9 12 4
10
3 12 4 3 10 12 4
11
2 12 4 2 11 12 4
12
1 12 4 1 12 12 4
1
12 13 3 12 1 13 3
2
11 13 3 11 2 13 3
3
10 13 3 10 3 13
3
4
9 13 3 9 4 13 3
5
8 13 3 8 5 13 3
6
7 13 3 7 6 13 3
7
6 13 3 6 7 13 3
8
5 13 3 5 8 13 3
9
4 13 3 4 9 13 3
10
3 13 3 3 10 13 3
11
2 13 3 2 11 13 3
12
1 13 3 1 12 13 3
1
12 14 2 12 1 14 2
2
11 14 2 11 2 14
2
3
10 14 2 10 3 14 2
4
9 14 2 9 4 14 2
5
8 14 2 8 5 14 2
6
7 14 2 7 6 14 2
7
6 14 2 6 7 14 2
8
5 14 2 5 8 14 2
9
4 14 2 4 9 14 2
10
3 14 2 3 10 14 2
11
2 14 2 2 11 14 2
12
1 14 2 1 12 14 2
1
12 7 9 12 1 7 9
2
11 7 9 11 2 7 9
3
10 7 9 10 3 7 9
4
9 7 9 9 4 7 9
5
8 7 9 8 5 7 9
6
7 7 9 7 6 7 9
7
6 7 9 6 7 7 9
8
5 7 9 5 8 7 9
9
4 7 9 4 9 7
9
10
3 7 9 3 10 7 9
11
2 7 9 2 11 7 9
12
1 7 9 1 12 7 9
12
1 6 10 12 1 6 10
1
12 6 10 11 2 6 10
2
11 6 10 10 3 6 10
3
10 6 10 9 4 6 10
4
9 6 10 8 5 6 10
5
8 6 10 7 6 6 10
6
7 6 10 6 7 6 10
7
6 6 10 5 8 6 10
8
5 6 10 4 9 6 10
9
4 6 10 3 10 6 10
10
3 6 10 2 11 6
10
11
2 6 10 1 12 6 10
12
1 6 10 12 1 6 10
1
12 5 11 11 2 5 11
2
11 5 11 10 3 5 11
3
10 5 11 9 4 5 11
4
9 5 11 8 5 5 11
5
8 5 11 7 6 5 11
6
7 5 11 6 7 5 11
7
6 5 11 5 8 5 11
8
5 5 11 4 9 5 11
9
4 5 11 3 10 5 11
10
3 5 11 2 11 5 11
11
2 5 11 1 12 5
11
12
1 5 11 12 1 5 11
1
12 4 12 11 2 4 12
2
11 4 12 10 3 4 12
3
10 4 12 9 4 4 12
4
9 4 12 8 5 4 12
5
8 4 12 7 6 4 12
6
7 4 12 6 7 4 12
7
6 4 12 5 8 4 12
8
5 4 12 4 9 4 12
9
4 4 12 3 10 4 12
10
3 4 12 2 11 4 12
11
2 4 12 1 12 4 12
12
1 4 12 12 1 4
12
TABLA 10
m
n p m n p
1
12 18 12 1 18
2
11 18 11 2 18
3
10 18 10 3 18
4
9 18 9 4 18
5
8 18 8 5 18
6
7 18 7 6 18
7
6 18 6 7 18
8
5 18 5 8 18
9
4 18 4 9 18
10
3 18 3 10 18
11
2 18 2 11 18
12
1 18 1 12 18
1
12 17 12 1 17
2
11 17 11 2 17
3
10 17 10 3 17
4
9 17 9 4 17
5
8 17 8 5 17
6
7 17 7 6 17
7
6 17 6 7 17
8
5 17 5 8 17
9
4 17 4 9 17
10
3 17 3 10 17
11
2 17 2 11 17
12
1 17 1 12 17
1
12 16 12 1 16
2
11 16 11 2 16
3
10 16 10 3 16
4
9 16 9 4 16
5
8 16 8 5 16
6
7 16 7 6 16
7
6 16 6 7 16
8
5 16 5 8 16
9
4 16 4 9 16
10
3 16 3 10 16
11
2 16 2 11 16
12
1 16 1 12 16
1
12 15 12 1 15
2
11 15 11 2 15
3
10 15 10 3 15
4
9 15 9 4 15
5
8 15 8 5 15
6
7 15 7 6 15
7
6 15 6 7 15
8
5 15 5 8 15
9
4 15 4 9 15
10
3 15 3 10 15
11
2 15 2 11 15
12
1 15 1 12 15
1
12 14 12 1 14
2
11 14 11 2 14
3
10 14 10 3 14
4
9 14 9 4 14
5
8 14 8 5 14
6
7 14 7 6 14
7
6 14 6 7 14
8
5 14 5 8 14
9
4 14 4 9 14
10
3 14 3 10 14
11
2 14 2 11 14
12
1 14 1 12 14
1
12 13 12 1 13
2
11 13 11 2 13
3
10 13 10 3 13
4
9 13 9 4 13
5
8 13 8 5 13
6
7 13 7 6 13
7
6 13 6 7 13
8
5 13 5 8 13
9
4 13 4 9 13
10
3 13 3 10 13
11
2 13 2 11 13
12
1 13 1 12 13
1
12 12 12 1 12
2
11 12 11 2 12
3
10 12 10 3 12
4
9 12 9 4 12
5
8 12 8 5 12
6
7 12 7 6 12
7
6 12 6 7 12
8
5 12 5 8 12
9
4 12 4 9 12
10
3 12 3 10 12
11
2 12 2 11 12
12
1 12 1
12
12
1
12 11 12 1 11
2
11 11 11 2 11
3
10 11 10 3 11
4
9 11 9 4 11
5
8 11 8 5 11
6
7 11 7 6 11
7
6 11 6 7 11
8
5 11 5 8 11
9
4 11 4 9 11
10
3 11 3 10 11
11
2 11 2
11
11
12
1 11 1 12 11
12
1 10 12 1 10
1
12 10 11 2 10
2
11 10 10 3 10
3
10 10 9 4 10
4
9 10 8 5 10
5
8 10 7 6 10
6
7 10 6 7 10
7
6 10 5 8 10
8
5 10 4 9 10
9
4 10 3 10 10
10
3 10 2 11
10
11
2 10 1 12 10
12
1 10 12 1 10
1
12 9 11 2 9
2
11 9 10 3 9
3
10 9 9 4 9
4
9 9 8 5 9
5
8 9 7 6 9
6
7 9 6 7 9
7
6 9 5 8 9
8
5 9 4 9 9
9
4 9 3 10
9
10
3 9 2 11 9
11
2 9 1 12 9
12
1 9 12 1 9
1
12 8 11 2 8
2
11 8 10 3 8
3
10 8 9 4 8
4
9 8 8 5 8
5
8 8 7 6 8
6
7 8 6 7 8
7
6 8 5 8 8
8
5 8 4 9
8
9
4 8 3 10 8
10
3 8 2 11 8
11
2 8 1 12 8
12
1 8 12 1 8
TABLA 11
m
n p q m n p q
1
12 8 8 12 1 8 8
2
11 8 8 11 2 8 8
3
10 8 8 10 3 8 8
4
9 8 8 9 4 8 8
5
8 8 8 8 5 8 8
6
7 8 8 7 6 8 8
7
6 8 8 6 7 8 8
8
5 8 8 5
8
8
8
9
4 8 8 4 9 8 8
10
3 8 8 3 10 8 8
11
2 8 8 2 11 8 8
12
1 8 8 1 12 8 8
1
12 9 7 12 1 9 7
2
11 9 7 11 2 9 7
3
10 9 7 10 3 9 7
4
9 9 7 9 4 9 7
5
8 9 7 8 5 9 7
6
7 9 7 7 6 9 7
7
6 9 7 6 7 9
7
8
5 9 7 5 8 9 7
9
4 9 7 4 9 9 7
10
3 9 7 3 10 9 7
11
2 9 7 2 11 9 7
12
1 9 7 1 12 9 7
1
12 10 6 12 1 10 6
2
11 10 6 11 2 10 6
3
10 10 6 10 3 10 6
4
9 10 6 9 4 10 6
5
8 10 6 8 5 10 6
6
7 10 6 7 6 10
6
7
6 10 6 6 7 10 6
8
5 10 6 5 8 10 6
9
4 10 6 4 9 10 6
10
3 10 6 3 10 10 6
11
2 10 6 2 11 10 6
12
1 10 6 1 12 10 6
1
12 11 5 12 1 11 5
2
11 11 5 11 2 11 5
3
10 11 5 10 3 11 5
4
9 11 5 9 4 11 5
5
8 11 5 8 5 11
5
6
7 11 5 7 6 11 5
7
6 11 5 6 7 11 5
8
5 11 5 5 8 11 5
9
4 11 5 4 9 11 5
10
3 11 5 3 10 11 5
11
2 11 5 2 11 11 5
12
1 11 5 1 12 11 5
1
12 12 4 12 1 12 4
2
11 12 4 11 2 12 4
3
10 12 4 10 3 12 4
4
9 12 4 9 4 12
4
5
8 12 4 8 5 12 4
6
7 12 4 7 6 12 4
7
6 12 4 6 7 12 4
8
5 12 4 5 8 12 4
9
4 12 4 4 9 12 4
10
3 12 4 3 10 12 4
11
2 12 4 2 11 12 4
12
1 12 4 1 12 12 4
1
12 13 3 12 1 13 3
2
11 13 3 11 2 13 3
3
10 13 3 10 3 13
3
4
9 13 3 9 4 13 3
5
8 13 3 8 5 13 3
6
7 13 3 7 6 13 3
7
6 13 3 6 7 13 3
8
5 13 3 5 8 13 3
9
4 13 3 4 9 13 3
10
3 13 3 3 10 13 3
11
2 13 3 2 11 13 3
12
1 13 3 1 12 13 3
1
12 14 2 12 1 14 2
2
11 14 2 11 2 14
2
3
10 14 2 10 3 14 2
4
9 14 2 9 4 14 2
5
8 14 2 8 5 14 2
6
7 14 2 7 6 14 2
7
6 14 2 6 7 14 2
8
5 14 2 5 8 14 2
9
4 14 2 4 9 14 2
10
3 14 2 3 10 14 2
11
2 14 2 2 11 14 2
12
1 14 2 1 12 14 2
1
12 7 9 12 1 7 9
2
11 7 9 11 2 7 9
3
10 7 9 10 3 7 9
4
9 7 9 9 4 7 9
5
8 7 9 8 5 7 9
6
7 7 9 7 6 7 9
7
6 7 9 6 7 7 9
8
5 7 9 5 8 7 9
9
4 7 9 4 9 7
9
10
3 7 9 3 10 7 9
11
2 7 9 2 11 7 9
12
1 7 9 1 12 7 9
12
1 6 10 12 1 6 10
1
12 6 10 11 2 6 10
2
11 6 10 10 3 6 10
3
10 6 10 9 4 6 10
4
9 6 10 8 5 6 10
5
8 6 10 7 6 6 10
6
7 6 10 6 7 6 10
7
6 6 10 5 8 6 10
8
5 6 10 4 9 6 10
9
4 6 10 3 10 6 10
10
3 6 10 2 11 6
10
11
2 6 10 1 12 6 10
12
1 6 10 12 1 6 10
1
12 5 11 11 2 5 11
2
11 5 11 10 3 5 11
3
10 5 11 9 4 5 11
4
9 5 11 8 5 5 11
5
8 5 11 7 6 5 11
6
7 5 11 6 7 5 11
7
6 5 11 5 8 5 11
8
5 5 11 4 9 5 11
9
4 5 11 3 10 5 11
10
3 5 11 2 11 5 11
11
2 5 11 1 12 5
11
12
1 5 11 12 1 5 11
1
12 4 12 11 2 4 12
2
11 4 12 10 3 4 12
3
10 4 12 9 4 4 12
4
9 4 12 8 5 4 12
5
8 4 12 7 6 4 12
6
7 4 12 6 7 4 12
7
6 4 12 5 8 4 12
8
5 4 12 4 9 4 12
9
4 4 12 3 10 4 12
10
3 4 12 2 11 4 12
11
2 4 12 1 12 4 12
12
1 4 12 12 1 4
12
TABLA 12
m
n m n
1
12 12
1
2
11 11
2
3
10 10
3
4
9 9
4
5
8 8
5
6
7 7
6
7
6 6
7
8
5 5
8
9
4 4
9
10
3 3
10
11
2 2
11
12
1 1
12
1
12 12
1
2
11 11
2
3
10 10
3
4
9 9
4
5
8 8
5
6
7 7
6
7
6 6
7
8
5 5
8
9
4 4
9
10
3 3
10
11
2 2
11
12
1 1
12
TABLA 13
imagen35
imagen36
m
n m n
1
12 12
1
2
11 11
2
3
10 10
3
4
9 9
4
5
8 8
5
6
7 7
6
7
6 6
7
8
5 5
8
9
4 4
9
10
3 3
10
11
2 2
11
12
1 1
12
1
12 12
1
2
11 11
2
3
10 10
3
4
9 9
4
5
8 8
5
6
7 7
6
7
6 6
7
8
5 5
8
9
4 4
9
10
3 3
10
11
2 2
11
imagen37
TABLA 14
Los siguientes compuestos pueden usarse como productos intermedios en la síntesis de los lípidos catiónicos descritos en el presente documento.
imagen38
En una realización, el lípido catiónico de la presente invención está seleccionado de los siguientes compuestos, y sales de los mismos (incluyendo sales farmacéuticamente aceptables de los mismos):
imagen39
Lípidos catiónicos incluyen aquellos que tienen grupos ácido graso alternativos y otros grupos dialquilamino, que incluyen aquellos en los que los sustituyentes alquilo son diferentes (por ejemplo, N-etil-N-metilamino-, N-propil-Netilamino-y similares). Para aquellas realizaciones en las que R1 y R2 son ambos grupos alquilo, alquenilo, alquinilo,
o cicloalquilalquilo de cadena larga, pueden ser iguales o diferentes. En general, lípidos (por ejemplo, un lípido
15 catiónico) que tienen cadenas acilo menos saturadas son más fácilmente dimensionados, particularmente cuando los complejos están dimensionados por debajo de aproximadamente 0,3 micrómetros, para los fines de esterilización por filtración. Son típicos lípidos catiónicos que contienen ácidos grasos insaturados con longitudes de cadena de carbono en el intervalo de C10 a C20. También pueden usarse otros armazones para separar el grupo amino (por ejemplo, el grupo amino del lípido catiónico) y el ácido graso o porción de alquilo graso del lípido catiónico.
20 Armazones adecuados son conocidos para aquellos expertos en la materia.
En ciertas realizaciones, los lípidos catiónicos tienen al menos un grupo protonable o desprotonable, de forma que el lípido esté positivamente cargado a un pH a o por debajo del pH fisiológico (por ejemplo, pH 7,4), y neutro a un
imagen40
imagen41
imagen42
imagen43
imagen44
imagen45
imagen46
imagen47
imagen48
imagen49
imagen50
imagen51
imagen52
imagen53
imagen54
imagen55
imagen56
imagen57
imagen58
imagen59
imagen60
imagen61
imagen62
imagen63
imagen64
imagen65
imagen66
imagen67
imagen68
imagen69
imagen70
imagen71
imagen72
imagen73
imagen74
imagen75

Claims (1)

  1. imagen1
    imagen2
ES11726579.3T 2010-06-03 2011-06-03 Lípidos biodegradables para la administración de agentes activos Active ES2634087T3 (es)

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EP3254672B1 (en) 2025-08-20
AU2020200286B2 (en) 2022-03-17
US10266484B2 (en) 2019-04-23
EP4481047A2 (en) 2024-12-25
EP3254672A1 (en) 2017-12-13
MX341332B (es) 2016-08-16
MX2012014079A (es) 2013-04-05
IL259334A (en) 2018-07-31
AU2024205466A1 (en) 2024-08-22
AU2022204146A1 (en) 2022-06-30
KR20130082141A (ko) 2013-07-18
US20120027803A1 (en) 2012-02-02
JP2013533224A (ja) 2013-08-22
EP2575764B1 (en) 2017-04-19
KR101967411B1 (ko) 2019-04-10
AU2018203382A1 (en) 2018-05-31
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IL259334B2 (en) 2023-07-01

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