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RU2487877C2 - Высокоэффективные конъюгаты и гидрофильные сшивающие агенты (линкеры) - Google Patents

Высокоэффективные конъюгаты и гидрофильные сшивающие агенты (линкеры) Download PDF

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RU2487877C2
RU2487877C2 RU2010148740/04A RU2010148740A RU2487877C2 RU 2487877 C2 RU2487877 C2 RU 2487877C2 RU 2010148740/04 A RU2010148740/04 A RU 2010148740/04A RU 2010148740 A RU2010148740 A RU 2010148740A RU 2487877 C2 RU2487877 C2 RU 2487877C2
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antibody
cells
carbon atoms
chain
cell
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RU2010148740/04A
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RU2010148740A (ru
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Раджиева Сингх
Елена Ковтун
Шарон Д. ВИЛЬХЕЛЬМ
Рави В. Дж. Чари
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Иммьюноджен, Инк.
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Abstract

Изобретение относится к соединению формулы (1) или (1'):
Figure 00000059
Figure 00000060
где: Z представляет собой реактивный карбоксильный эфир, выбранный из группы, состоящей из N-сукцинимидила, N-сульфосукцинимидила, N-фталимидила, N-сульфофталимидила, 2-нитрофенила, 4-нитрофенила, 2,4-динитрофенила, 3-сульфо-4-нитрофенила, 3-карбокси-4-нитрофенила и сложного эфира трифторфенила, или галоацетамида; D представляет собой майтанзиноид; Х представляет собой алифатическую структурную единицу; Y представляет собой алифатическую структурную единицу, присоединенную к майтанзиноиду через тиоэфирную связь; где указанная алифатическая структурная единица, представленная Х или Y, является простой или разветвленной алкильной группой, имеющей 1-20 атомов углерода в цепи, циклической алкильной группой, имеющей 3-10 атомов углерода, простой или разветвленной алкенильной группой, имеющей 2-15 атомов углерода в цепи, или простой или разветвленной алкинильной группой, имеющей 2-15 атома углерода в цепи; 1 представляет собой 0 или 1; p представляет собой 0 или 1; и n представляет собой целое число от 1 до 2000. Изобретение также относится к конъюгату агента, связывающегося с клеткой, и цитотоксического майтанзиноида, где агент, связывающийся с клеткой, и является антителом. Технический результат: получены соединения и конъюгаты, а также фармацевтические композиции на их основе, которые могут найти применение в медицине для лечения опухолей, аутоиммунных заболеваний, отторжений трансплантатов, реакции трансплантата против хозяина, вирусных инфекций и паразитарных инфекций. 6 н. и 14 з.п. ф-лы, 38 ил., 10 пр.

Description

Текст описания приведен в факсимильном виде.
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Claims (20)

1. Соединение формулы (1) или (1'):
Figure 00000045

Figure 00000046

где Z представляет собой реактивный карбоксильный эфир, выбранный из группы, состоящей из N-сукцинимидила, N-сульфосукцинимидила, N-фталимидила, N-сульфофталимидила, 2-нитрофенила, 4-нитрофенила, 2,4-динитрофенила, 3-сульфо-4-нитрофенила, 3-карбокси-4-нитрофенила и сложного эфира трифторфенила или галоацетамида;
D представляет собой майтанзиноид;
Х представляет собой алифатическую структурную единицу;
Y представляет собой алифатическую структурную единицу, присоединенную к майтанзиноиду через тиоэфирную связь;
где указанная алифатическая структурная единица, представленная Х или Y, является простой или разветвленной алкильной группой, имеющей 1-20 атомов углерода в цепи, циклической алкильной группой, имеющей 3-10 атомов углерода, простой или разветвленной алкенильной группой, имеющей 2-15 атомов углерода в цепи или простой или разветвленной алкинильной группой, имеющей 2-15 атома углерода в цепи;
1 представляет собой 0 или 1;
p представляет собой 0 или 1; и
n представляет собой целое число от 1 до 2000.
2. Конъюгат агента, связывающегося с клеткой, и цитотоксического майтанзиноида формулы (2) или (2'):
Figure 00000047

Figure 00000048

где СВ представляет собой агент, связывающийся с клеткой и является антителом;
D представляет собой майтанзиноид;
Х представляет собой алифатическую структурную единицу, присоединенную к агенту, связывающемуся с клеткой через амидную связь;
Y представляет собой алифатическую структурную единицу, присоединенную к майтанзиноиду через тиоэфирную связь;
где указанная алифатическая структурная единица, представленная Х или Y, является простой или разветвленной алкильной группой, имеющей 1-20 атомов углерода в цепи, циклической алкильной группой, имеющей 3-10 атомов углерода, простой или разветвленной алкенильной группой, имеющей 2-15 атомов углерода в цепи или простой или разветвленной алкинильной группой, имеющей 2-15 атома углерода в цепи;
1 представляет собой 0 или 1;
p представляет собой 0 или 1; и
m представляет собой целое число от 2 до 15; и
n представляет собой целое число от 1 до 2000.
3. Конъюгат по п.2, в котором указанный агент, связывающийся с клеткой, представляет собой одноцепочечное антитело, фрагмент антитела, который предпочтительно связывается с клеткой-мишенью, моноклональное антитело, одноцепочечное моноклональное антитело, моноклональное антитело, биспецифическое антитело, фрагмент, который специфически связывается с клеткой-мишенью.
4. Конъюгат по п.2, в котором указанный агент, связывающийся с клеткой, представляет собой моноклональное антитело с измененной поверхностью, одноцепочечное моноклональное антитело с измененной поверхностью или фрагмент моноклонального антитела с измененной поверхностью, который предпочтительно связывается с клеткой-мишенью.
5. Конъюгат по п.2, в котором указанный агент, связывающийся с клеткой, представляет собой гуманизированное моноклональное антитело, гуманизированное одноцепочечное моноклональное антитело, или фрагмент гуманизированного моноклонального антитела, который предпочтительно связывается с клеткой-мишенью.
6. Конъюгат по п.2, в котором указанное антитело представляет собой химерное антитело, фрагмент химерного антитела, домен этого антитела или фрагмент домена этого антитела.
7. Конъюгат по п.2, в котором указанное антитело представляет собой MY9, анти-В4, С242 или антитело, которое связывается с антигеном, выбранным из группы состоящей из ЕрСАМ, CD2, CD3, CD4, CD5, CD6, CD11, CD19, CD20, CD22, CD26. CD30, CD33, CD37, CD38, CD40, CD44, CD56, CD79, CD105, CD138, рецепторы EphA, рецепторы EphB, EGFR, EGFRvIII, HER2, HER3, мезотелин, белок Cripto, интегрин альфаубетаз, альфаубета5 и альфаубета.
8. Конъюгат по п.2, в котором указанное антитело представляет собой гуманизированное, человеческое антитело или антитело с измененной поверхностью, которое выбирают из Му9-б, В4, С242, N901, DS6, рецептора EphA2, CD38, IGF-IR, CNTO 95, В-В4, трастузумаба, пертузумаба, биватузумаба, сибротузумаба или ритуксимаба.
9. Конъюгат по п.2, в котором указанный агент, связывающийся с клеткой, связывается с клеткой-мишенью, которую выбирают из опухолевых клеток; клеток, инфицированных вирусом, клеток, инфицированных микроорганизмами, клеток, инфицированных паразитами, аутоиммунных клеток, активированных клеток, миелоидных клеток, активированных Т-клеток, В-клеток или меланоцитов; клеток, экспрессирующих один или несколько из следующего: IGF-IR, CanAg, EGFR, MUC1, MUC16, VEGF, TF, MY9, анти-В4, ЕрСАМ, CD2, CD3, CD4, CD5, CD6, CD11, CD11a, CD18, CD19, CD20, CD22, CD26, CD30, CD33, CD37, CD38, CD40, CD44, CD56, CD70, CD79, CD105, CD138, рецепторы EphA, рецепторы EphB, EGFRvIII, HER2/neu, HER3, мезотелин, белок Cripto, интегрин альфаvбета3, интегрин альфаубетаз, интегрин альфаvбета6, Аро2 и антигены С242; или клетки, экспрессирующие рецептор инсулиноподобного фактора роста, рецептор эпидермального фактора роста и рецептор фолата.
10. Конъюгат по п.9, в котором опухолевые клетки представляют собой клетки, которые выбирают из клеток рака молочной железы, из клеток рака предстательной железы, из клеток рака яичников, из клеток колоректального рака, из клеток рака желудка, из клеток плоскоклеточного рака, из клеток мелкоклеточного рака легкого и из клеток рака яичек.
11. Соединение, которое представлено формулой, выбранной из следующих:
Figure 00000049

Figure 00000050

Figure 00000051

Figure 00000052
; и
Figure 00000053
,
где n представляет собой целое число от 1 до 2000; R представляет собой Н, q=1 или R представляет собой CH3, а q=2.
12. Конъюгат, представленный формулой, выбранной из:
Figure 00000054
;
Figure 00000055
;
Figure 00000056
;
Figure 00000057
; и
Figure 00000058
,
где n представляет собой целое число от 1 до 2000; m - целое число от 2 до 15; mAb является моноклональным антителом; R представляется собой H, q=1 или R представляет собой СН3, a q=2.
13. Соединение по п.1 или 11, где n является целым числом от 1 до 14.
14. Соединение по п.13, где n является целым числом от 1 до 4.
15. Конъюгат по любому из пп.2-10 и 12, где n является целым числом от 1 до 14.
16. Конъюгат по п.15, где n является целым числом от 1 до 4.
17. Фармацевтическая композиция для лечения опухолей, аутоиммунных заболеваний, отторжений трансплантатов, реакции трансплантата против хозяина, вирусных инфекций и паразитарных инфекций, чувствительных к данной фармацевтической композиции, содержащая эффективное количество конъюгата майтанзиноид-агент, связывающийся с клеткой, по п.2, 12, 15 или 16 или его фармацевтически приемлемой соли, или сольвата, и фармацевтически приемлемый носитель, разбавитель или эксипиент.
18. Способ лечения опухолей, аутоиммунных заболеваний, отторжений трансплантатов, реакции трансплантата против хозяина, вирусных инфекций и паразитарных инфекций, чувствительных к лечению указанным способом, который включает парентеральное введение нуждающемуся в этом пациенту эффективной дозы конъюгата по п.2, 12, 15 или 16.
19. Способ по п.18, в котором указанную опухоль выбирают из одного или нескольких раков легкого, крови, плазмы, молочной железы, толстой кишки, предстательной железы, почек, поджелудочной железы, мозга, костей, яичников, семенников и органов лимфатической системы.
20. Способ по п.18, в котором указанная опухоль экспрессирует одно или несколько из следующего: IGF-IR, FOLR1, CanAg, EGFR, EphA2, MUC1, MUC16, VEGF, TF, MY9, анти-В4, EpCAM, CD2, CDS, CD4, CD5, CD6, CD11, CD11a, CD18, CD19, CD20, CD22, CD26, CD30, CD33, CD37, CD38, CD40, CD44, CD56, CD70, CD79, CD105, CD138, EphA, EphB, EGFRvIII, HER2/neu, HER3, мезотелин, белок Cripto, интегрин альфаубетаз, интегрин альфаvбета5, интегрин альфаvбета6, Аро2 и антигены С242.
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RU2754369C2 (ru) * 2016-03-02 2021-09-01 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Конъюгаты антитело-лекарственное средство на основе эрибулина и способы применения
RU2653443C2 (ru) * 2016-07-15 2018-05-08 Закрытое Акционерное Общество "Биокад" Биспецифичные анти-her2/анти-her3 антитела

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