ES2663869T3 - Procedimiento para la síntesis de análogos de la grelina - Google Patents

Procedimiento para la síntesis de análogos de la grelina Download PDF

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ES2663869T3
ES2663869T3 ES12840868.9T ES12840868T ES2663869T3 ES 2663869 T3 ES2663869 T3 ES 2663869T3 ES 12840868 T ES12840868 T ES 12840868T ES 2663869 T3 ES2663869 T3 ES 2663869T3
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bal
apc
trp
nal
lys
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Fionn Hurley
Katarzyna WEGNER
Patrick Foley
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Ipsen Manufacturing Ireland Ltd
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    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/042—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers characterised by the nature of the carrier
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
    • C07K1/063—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups for alpha-amino functions
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    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/08—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using activating agents
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    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/10—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using coupling agents
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    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/36—Extraction; Separation; Purification by a combination of two or more processes of different types
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    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/60—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

Un procedimiento para la síntesis de un péptido terapéutico mediante el uso de la química de Fmoc en fase sólida por etapas, que comprende las etapas de: (a) hacer hinchar la resina de Fmoc-Sieber (también denominada resina de amida de Sieber o resina de amida de Fmoc-Sieber) en un solvente aprótico dipolar; (b) desproteger el grupo Fmoc con una solución de piperidina en un solvente aprótico dipolar; (c) lavar la resina después de la desprotección del Fmoc con un solvente aprótico dipolar; (d) activar los aminoácidos-Fmoc para la conjugación a la resina desprotegida al disolver el aminoácido-Fmoc y el reactivo o reactivos de conjugación en un solvente aprótico dipolar, y, a continuación, añadir una base y agitar; (e) cargar la solución de aminoácido-Fmoc activado en la resina en el reactor; (f) conjugar el aminoácido-Fmoc activado con el uso de hexafluorofosfato de 2-(6-cloro-1H-benzotriazol-1-il)-1,1,3,3- tetrametilaminio (HCTU) o de tetrafluoroborato de 2-(1H-benzotriazol-1-il)-1,1,3,3-tetrametiluronio (TBTU)/1- hidroxibenzotriazol (HOBt) con una base en un solvente aprótico dipolar como reactivo de conjugación; (g) lavar la resina después de cada conjugación de aminoácido-Fmoc; (h) repetir las etapas (b) a (g) hasta que se forme un péptido; (i) escindir el péptido deseado de la resina mientras que se desprotegen simultáneamente las cadenas laterales de los aminoácidos con un cóctel de escisión; (j) filtrar la mezcla de escisión desde la resina; y (k) hacer que se evaporen los filtrados, y precipitar y purificar parcialmente el producto bruto desde la solución concentrada con un solvente orgánico para producir un péptido parcialmente purificado. en donde dicho péptido es un análogo de la grelina de fórmula (I) R1-A1-A2-A3-A4-A5-R2 (I) en donde A1 es Aib, Apc o Inp; A2 es D-Bal, D-Bip, D-Bpa, D-Dip, D-1-Nal, D-2-Nal, D-Ser(Bzl), o D-Trp; A3 es D-Bal, D-Bip, D-Bpa, D-Dip, D-1-Nal, D-2-Nal, D-Ser(Bzl), o D-Trp; A4 es 2Fua, Orn, 2Pal, 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi, 3Thi, Thr(Bzl); A5 es Apc, Dab, Dap, Lys, Orn, o delecionado; R1 es hidrógeno; y R2 es OH o NH; con tal de que cuando A5 es Dab, Dap, Lys u Orn, entonces: A2 es D-Bip, D-Bpa, D-Dip o D-Bal; o A3 es D-Bip, D-Bpa, D-Dip o D-Bal; o A4 es 2Thi, 3Thi, Taz, 2Fua, 2Pal, 3Pal, 4Pal, Orn, Thr(Bzl), o Pff; cuando A5 está delecionado, entonces: A3 es D-Bip, D-Bpa o D-Dip; o A4 es 2Fua, Pff, Taz, o Thr(Bzl); o A1 es Apc y - A2 es D-Bip, D-Bpa, D-Dip o D-Bal; o A3 es D-Bip, D-Bpa, D-Dip o D-Bal; o A4 es 2Thi, 3Thi, Orn, 2Pal, 3Pal, o 4Pal.

Description

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Figura 2: gráfico en el que se representa la reproducibilidad del rendimiento de la síntesis en una escala de 2 g a 2200 g cuando se utiliza la resina de amida de Sieber para la síntesis de un péptido de 5 aminoácidos. Tal y como está descrito, se consiguió constantemente un rendimiento de síntesis de aproximadamente el 80% para cada escala.
Figura 3: gráfico en el que se representa el coste relativo basado en el material empleado para la síntesis de un péptido de 8 aminoácidos y un péptido de 30 aminoácidos mediante el uso de una resina de amida de Rink frente a una resina de amida de Sieber. El coste relativo basado en los materiales utilizados para esos péptidos sintetizados mediante una resina de amida de Rink para un péptido de 8 aminoácidos y un péptido de 30 aminoácidos está representado por las barras superiores, mientras que el coste relativo para el mismo péptido con el uso de una resina de amida de Sieber está representado por las barras inferiores para cada péptido. Tal y como está descrito, el coste relativo de utilizar una resina de amida de Sieber es menor que el de una resina de amida de Rink.
La mayoría de las etapas de síntesis en fase sólida por etapas necesitan usar una resina de poliestireno para la síntesis de las amidas peptídicas. Las resinas de amida de Rink se utilizan en una síntesis de péptidos en fase sólida para preparar las amidas peptídicas mediante la utilización de aminoácidos protegidos con Fmoc.
La conjugación del primer aminoácido se puede conseguir con los métodos típicos de formación de enlaces amida. La secuencia peptídica se ensambla en condiciones básicas o neutras sobre la resina de amida de Rink, y luego se escinde de la resina el péptido completado en condiciones ácidas. Típicamente, el péptido se escinde desde la resina de amida de Rink con TFA a más del 80% v/v (Stathopoulos, P.; Papas, S.; y Tsikaris, V., J. Pept. Sci., 2006,
12: 227-37). Los ácidos más fuertes o las concentraciones más elevadas de TFA algunas veces escinden parte del conector de Rink desde el soporte de poliestireno e introduce impurezas coloreadas en el producto escindido. Tal cual, para algunos péptidos, el rendimiento de la síntesis con la resina de amida de Rink es tradicionalmente bajo. Ejemplos de resinas de Rink son:
imagen9
La inestabilidad del conector de la resina «supersensible a ácido» o «hipersensible a ácido» a bajas concentraciones de ácido permite que se liberen de la resina los péptidos totalmente protegidos. Típicamente, se necesita del 1 al 5% v/v de TFA para la escisión de los péptidos. Con la excepción de la disminución de la potencia del ácido necesario para la escisión, estas resinas son similares a las resinas de amida de Rink, a saber, son una matriz de poliestireno con un tamaño de perla similar y con una capacidad de carga similar. Como tales, estas resinas son útiles para la síntesis convergente que emplea la misma química de Fmoc con respecto a la carga de primer resto y al acoplamiento de los restos posteriores.
La resina de amida de Sieber, un ejemplo de resinas «supersensibles a ácido» (Sieber, P., Tetrahedron Lett., 1987, 28(19): 2107-10), se utiliza principalmente para la síntesis de amidas peptídicas que conservan los grupos protectores de la cadena lateral, entre ellos, pero sin limitarse a ellos, tert-butiloxicarbonilo (Boc) y éter de tert-butilo (tBu) cuando se utilizan con concentraciones bajas de ácido trifluoroacético (TFA) (1-5% v/v) en el cóctel de escisión.
10
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H-Apc-D-1-Nal-D-Trp-Pff-Apc-NH2 H-Apc-D-1-Nal-D-Trp-Pff-Lys-NH2 H-Apc-D-1-Nal-D-Trp-Pff-NH2 H-Apc-D-2-Nal-D-Trp-2-Fua-Apc-NH2
5 H-Apc-D-2-Nal-D-Trp-2-Fua-Lys-NH2 H-Apc-D-2-Nal-D-Trp-2-Fua-NH2 H-Apc-D-2-Nal-D-Trp-2-Pal-NH2 H-Apc-D-2-Nal-D-Trp-2-Thi-Apc-NH2 H-Apc-D-2-Nal-D-Trp-2-Thi-Lys-NH2
10 H-Apc-D-2-Nal-D-Trp-3-Pal-NH2 H-Apc-D-2-Nal-D-Trp-3-Thi-Apc-NH2 H-Apc-D-2-Nal-D-Trp-3-Thi-Lys-NH2 H-Apc-D-2-Nal-D-Trp-3-Thi-NH2 H-Apc-D-2-Nal-D-Trp-4-Pal-NH2
15 H-Apc-D-2-Nal-D-Trp-Pff-Apc-NH2 H-Apc-D-2-Nal-D-Trp-Pff-Lys-NH2 H-Apc-D-2-Nal-D-Trp-Pff-NH2 H-Apc-D-2-Nal-D-Trp-Taz-Apc-NH2 H-Apc-D-2-Nal-D-Trp-Taz-Lys-NH2
20 H-Apc-D-Bal-D-Bal-2-Fua-Apc-NH2 H-Apc-D-Bal-D-Bal-2-Fua-Lys-NH2 H-Apc-D-Bal-D-Bal-2-Fua-NH2 H-Apc-D-Bal-D-Bal-2-Pal-NH2 H-Apc-D-Bal-D-Bal-2-Thi-Apc-NH2
25 H-Apc-D-Bal-D-Bal-2-Thi-Lys-NH2 H-Apc-D-Bal-D-Bal-2-Thi-NH2 H-Apc-D-Bal-D-Bal-3-Pal-NH2 H-Apc-D-Bal-D-Bal-3-Thi-Apc-NH2 H-Apc-D-Bal-D-Bal-3-Thi-Lys-NH2
30 H-Apc-D-Bal-D-Bal-3-Thi-NH2 H-Apc-D-Bal-D-Bal-4-Pal-NH2 H-Apc-D-Bal-D-Bal-Pff-Apc-NH2 H-Apc-D-Bal-D-Bal-Pff-Lys-NH2 H-Apc-D-Bal-D-Bal-Pff-NH2
35 H-Apc-D-Bal-D-Bal-Phe-Apc-NH2 H-Apc-D-Bal-D-Bal-Phe-Lys-NH2 H-Apc-D-Bal-D-Bal-Phe-NH2
22
H-Apc-D-Bal-D-Bal-Taz-Apc-NH2 H-Apc-D-Bal-D-Bal-Taz-Lys-NH2 H-Apc-D-Bal-D-Bal-Taz-NH2 H-Apc-D-Bal-D-Trp-2-Fua-Apc-NH2
5 H-Apc-D-Bal-D-Trp-2-Fua-Lys-NH2 H-Apc-D-Bal-D-Trp-2-Fua-NH2 H-Apc-D-Bal-D-Trp-2-Pal-NH2 H-Apc-D-Bal-D-Trp-3-Pal-NH2 H-Apc-D-Bal-D-Trp-3-Thi-Apc-NH2
10 H-Apc-D-Bal-D-Trp-3-Thi-Lys-NH2 H-Apc-D-Bal-D-Trp-3-Thi-NH2 H-Apc-D-Bal-D-Trp-4-Pal-NH2 H-Apc-D-Bal-D-Trp-Pff-Apc-NH2 H-Apc-D-Bal-D-Trp-Pff-Lys-NH2
15 H-Apc-D-Bal-D-Trp-Pff-NH2 H-Inp-D-1-Nal-D-Bal-2-Fua-Lys-NH2 H-Inp-D-1-Nal-D-Bal-2-Fua-NH2 H-Inp-D-1-Nal-D-B al-2-Thi-Lys-NH2 H-Inp-D-1-Nal-D-Bal-3-Thi-Lys-NH2
20 H-Inp-D-1-Nal-D-Bal-Pff-Lys-NH2 H-Inp-D-1-Nal-D-Bal-Pff-NH2 H-Inp-D-1-Nal-D-Bal-Phe-Lys-NH2 H-Inp-D-1-Nal-D-Bal-Taz-Lys-NH2 H-Inp-D-1-Nal-D-Bal-Taz-NH2
25 H-Inp-D-1-Nal-D-Trp-2-Fua-Apc-NH2 H-Inp-D-1-Nal-D-Trp-2-Fua-Lys-NH2 H-Inp-D-1-Nal-D-Trp-2-Fua-NH2 H-Inp-D-1-Nal-D-Trp-3-Thi-Apc-NH2 H-Inp-D-1-Nal-D-Trp-3-Thi-Lys-NH2
30 H-Inp-D-1-Nal-D-Trp-Pff-Apc-NH2 H-Inp-D-1-Nal-D-Trp-Pff-Lys-NH2 H-Inp-D-1-Nal-D-Trp-Pff-NH2 H-Inp-D-1-Nal-D-Trp-Taz-NH2 H-Inp-D-2-Nal-D-Trp-2-Fua-Apc-NH2
35 H-Inp-D-2-Nal-D-Trp-2-Fua-NH2 H-Inp-D-2-Nal-D-Trp-2-Thi-Apc-NH2 H-Inp-D-2-Nal-D-Trp-3-Thi-Apc-NH2
23
imagen21
H-Inp-D-Bip-D-Trp-Pff-NH2 H-Inp-D-Bip-D-Trp-Taz-Lys-NH2 H-Inp-D-Bip-D-Trp-Taz-NH2 H-Inp-D-1-Nal-D-Trp-3-Pal-Lys-NH2
5 H-Inp-D-2-Nal-D-Trp-4-Pal-Lys-NH2 H-Inp-D-2-Nal-D-Trp-Orn-Lys-NH2 H-Inp-D-Bip-D-Trp-Phe-Lys-NH2 H-Inp-D-2-Nal-D-Trp-Thr(Bzl)-Lys-NH2 H-Inp-D-2-Nal-D-Trp-Pff-Lys-NH2
10 H-Inp-D-2-Nal-D-Trp-2-Thi-Lys-NH2 H-Inp-D-2-Nal-D-Trp-Taz-Lys-NH2 H-Inp-D-Dip-D-Trp-Phe-Lys-NH2 H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2 H-Inp-D-2-Nal-D-Bpa-Phe-Lys-NH2
15 H-Inp-D-2-Nal-D-Trp-Thr(Bzl)-NH2 H-Inp-D-2-Nal-D-Trp-Pff-NH2 H-Inp-D-2-Nal-D-Trp-Taz-NH2 H-Inp-D-2-Nal-D-Dip-Phe-NH2 H-Inp-D-2-Nal-D-Trp-3-Pal-Lys-NH2
20 H-Inp-D-Bal-D-Trp-2-Thi-Lys-NH2 H-Inp-D-Bal-D-Trp-Phe-Lys-NH2 H-Inp-D-1-Nal-D-Trp-2-Thi-Lys-NH2 H-Inp-D-2-Nal-D-Trp-Phe-Apc-NH2 H-Inp-D-1-Nal-D-Trp-Phe-Apc-NH2
25 H-Inp-D-Bal-D-Trp-Phe-Apc-NH2 H-Apc-D-2-Nal-D-Trp-Phe-Lys-NH2 H-Apc-D-1-Nal-D-Trp-2-Thi-Lys-NH2 H-Inp-D-1-Nal-D-Trp-Taz-Lys-NH2 H-Inp-D-Bal-D-Trp-Taz-Lys-NH2
30 H-Apc-D-1-Nal-D-Trp-Taz-Lys-NH2 H-Apc-D-Bal-D-Trp-Taz-Lys-NH2 H-Apc-D-Bal-D-Trp-2-Thi-Lys-NH2 H-Apc-D-Bal-D-Trp-Phe-Lys-NH2 H-Apc-D-1-Nal-D-Trp-Phe-Apc-NH2
35 H-Apc-D-Bal-D-Trp-Phe-Apc-NH2 H-Apc-D-1-Nal-D-1-Nal-Phe-Apc-NH2 H-Apc-D-1-Nal-D-2-Nal-Phe-Apc-NH2
25
imagen22
H-Apc-D-Bal-D-Bal-Pff-Lys-NH2 H-Inp-D-1-Nal-D-Trp-3-Thi-Lys-NH2 H-Inp-D-1-Nal-D-Trp-2-Fua-Lys-NH2 H-Inp-D-1-Nal-D-Trp-Pff-Lys-NH2
5 H-Inp-D-1-Nal-D-Bal-Phe-Lys-NH2 H-Inp-D-1-Nal-D-Bal-2-Thi-Lys-NH2 H-Inp-D-1-Nal-D-Bal-3-Thi-Lys-NH2 H-Inp-D-1-Nal-D-Bal-Taz-Lys-NH2 H-Inp-D-1-Nal-D-Bal-2-Fua-Lys-NH2
10 H-Inp-D-1-Nal-D-Bal-Pff-Lys-NH2 H-Inp-D-2-Nal-D-Trp-2-Thi-Apc-NH2 H-Inp-D-2-Nal-D-Trp-3-Thi-Apc-NH2 H-Inp-D-2-Nal-D-Trp-Taz-Apc-NH2 H-Inp-D-2-Nal-D-Trp-2-Fua-Apc-NH2
15 H-Inp-D-2-Nal-D-Trp-Pff-Apc-NH2 H-Inp-D-1-Nal-D-Trp-3-Thi-Apc-NH2 H-Inp-D-1-Nal-D-Trp-2-Fua-Apc-NH2 H-Inp-D-1-Nal-D-Trp-Pff-Apc-NH2 H-Apc-D-1-Nal-D-Trp-3-Thi-Lys-NH2
20 H-Apc-D-1-Nal-D-Trp-2-Fua-Lys-NH2 H-Apc-D-1-Nal-D-Trp-Pff-Lys-NH2 H-Apc-D-2-Nal-D-Trp-2-Thi-Lys-NH2 H-Apc-D-2-Nal-D-Trp-3-Thi-Lys-NH2 H-Apc-D-2-Nal-D-Trp-Taz-Lys-NH2
25 H-Apc-D-2-Nal-D-Trp-2-Fua-Lys-NH2 H-Apc-D-2-Nal-D-Trp-Pff-Lys-NH2 H-Inp-D-Bip-D-Trp-2-Thi-Lys-NH2 H-Inp-D-Bip-D-Trp-3-Thi-Lys-NH2 H-Inp-D-Bip-D-Trp-Taz-Lys-NH2
30 H-Inp-D-Bip-D-Trp-2-Fua-Lys-NH2 H-Inp-D-Bip-D-Trp-Pff-Lys-NH2 H-Inp-D-Bip-D-Bal-2-Thi-Lys-NH2 H-Inp-D-Bip-D-Bal-3-Thi-Lys-NH2 H-Inp-D-Bip-D-Bal-Taz-Lys-NH2
35 H-Inp-D-Bip-D-Bal-2-Fua-Lys-NH2 H-Inp-D-Bip-D-Bal-Pff-Lys-NH2 H-Apc-D-Bal-D-Trp-3-Thi-Apc-NH2
27
H-Apc-D-Bal-D-Trp-2-Fua-Apc-NH2 H-Apc-D-Bal-D-Trp-Pff-Apc-NH2 H-Apc-D-Bal-D-Bal-Phe-Apc-NH2 H-Apc-D-Bal-D-Bal-2-Thi-Apc-NH2
5 H-Apc-D-Bal-D-Bal-3-Thi-Apc-NH2 H-Apc-D-Bal-D-Bal-Taz-Apc-NH2 H-Apc-D-Bal-D-Bal-2-Fua-Apc-NH2 H-Apc-D-Bal-D-Bal-Pff-Apc-NH2 H-Apc-D-1-Nal-D-Trp-3-Thi-Apc-NH2
10 H-Apc-D-1-Nal-D-Trp-2-Fua-Apc-NH2 H-Apc-D-1-Nal-D-Trp-Pff-Apc-NH2 H-Apc-D-2-Nal-D-Trp-2-Thi-Apc-NH2 H-Apc-D-2-Nal-D-Trp-3-Thi-Apc-NH2 H-Apc-D-2-Nal-D-Trp-Taz-Apc-NH2
15 H-Apc-D-2-Nal-D-Trp-2-Fua-Apc-NH2 H-Apc-D-2-Nal-D-Trp-Pff-Apc-NH2 H-Inp-D-Bal-D-Trp-Taz-NH2 H-Inp-D-Bal-D-Trp-2-Fua-NH2 H-Inp-D-Bal-D-Trp-Pff-NH2
20 H-Apc-D-Bal-D-Trp-3-Thi-NH2 H-Apc-D-Bal-D-Trp-2-Fua-NH2 H-Apc-D-Bal-D-Trp-Pff-NH2 H-Apc-D-Bal-D-Trp-4-Pal-NH2 H-Apc-D-Bal-D-Trp-3-Pal-NH2
25 H-Apc-D-Bal-D-Trp-2-Pal-NH2 H-Inp-D-Bal-D-Bal-Taz-NH2 H-Inp-D-Bal-D-Bal-2-Fua-NH2 H-Inp-D-Bal-D-Bal-Pff-NH2 H-Apc-D-Bal-D-Bal-Phe-NH2
30 H-Apc-D-Bal-D-Bal-2-Thi-NH2 H-Apc-D-Bal-D-Bal-3-Thi-NH2 H-Apc-D-Bal-D-Bal-Taz-NH2 H-Apc-D-Bal-D-Bal-2-Fua-NH2 H-Apc-D-Bal-D-Bal-Pff-NH2
35 H-Apc-D-Bal-D-Bal-4-Pal-NH2 H-Apc-D-Bal-D-Bal-3-Pal-NH2 H-Apc-D-Bal-D-Bal-2-Pal-NH2
28
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Claims (1)

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