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RU2017124136A - Трициклическое спиро-соединение - Google Patents

Трициклическое спиро-соединение Download PDF

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Publication number
RU2017124136A
RU2017124136A RU2017124136A RU2017124136A RU2017124136A RU 2017124136 A RU2017124136 A RU 2017124136A RU 2017124136 A RU2017124136 A RU 2017124136A RU 2017124136 A RU2017124136 A RU 2017124136A RU 2017124136 A RU2017124136 A RU 2017124136A
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RU
Russia
Prior art keywords
carbonyl
phenyl
amino
cyano
dihydrospiro
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RU2017124136A
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English (en)
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RU2707073C2 (ru
RU2017124136A3 (ru
Inventor
Масаки АСАДА
Коусуке ТАНИ
Масая ХИРОБЕ
Сатонори ХИГУТИ
Кадзухиро ФУТИБЕ
Рё ОИКАВА
Тохру КОТАНИ
Хироцугу ТАКАНО
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Оно Фармасьютикал Ко., Лтд.
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Publication of RU2017124136A3 publication Critical patent/RU2017124136A3/ru
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    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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Claims (106)

1. Соединение, представленное следующей общей формулой (I), или его соль, N-оксид или сольват или их пролекарство,
Figure 00000001
,
в которой:
R1 обозначает COOR8, тетразол, SO3H, SO2NH2, SO2NHR8-1, CONHSO2R8-1, SO2NHCOR8-1 или гидроксамовую кислоту, причем R8 обозначает атом водорода, C1-4 алкил или бензил, R8-1 обозначает C1-4 алкил, C1-4 галогеналкил, C3-10 углеродное кольцо или трех-десяти-членное гетероциклическое кольцо, причем C3-10 углеродное кольцо и трех-десяти-членное гетероциклическое кольцо могут быть замещены C1-4 алкилом, C1-4 галогеналкилом, C1-4 алкокси, -O(C1-4 галогеналкилом), C1-4 алкилтио, -S(C1-4 галогеналкилом), галогеном или нитрилом (здесь и ниже «-CN»),
L1 обозначает C1-5 алкилен, C2-5 алкенилен или C2-5 алкинилен,
R2 обозначает галоген, C1-4 алкил, C1-4 алкокси, C1-4 алкилтио, C2-4 алкенил, C2-4 алкинил, -O(C1-4 галогеналкил), -S(C1-4 галогеналкил), -C(O)(C1-4 алкил), -SO2(C1-4 алкил), -CONH (C1-4 алкил), -CON(C1-4 алкил)2, -NHC(O)(C1-4 алкил), -N(C1-4 алкил)C(O)(C1-4 алкил), -NHSO2(C1-4 алкил), -N(C1-4 алкил)SO2(C1-4 алкил), -SO2NH(C1-4 алкил), -SO2N(C1-4 алкил)2, -NR17R17, нитро, нитрил, гидроксильную группу, альдегид или карбоксил, причем C1-4 алкил может быть замещен галогеном, и причем (C1-4 алкил)2, представленный R2, представляет собой две независимые C1-4 алкильные группы, которые могут быть одинаковыми или разными,
X1 обозначает CR6 или атом азота, причем R6 обозначает атом водорода или R2,
X2 обозначает CR7 или атом азота, причем R7 обозначает атом водорода, R2 или -L3-R9, причем L3 обозначает метилен, атом кислорода или атом серы, который может быть окислен, и R9 обозначает четырех-десяти-членное гетероциклическое кольцо, которое может быть замещено заместителем, выбранным из группы, состоящей из галогена, C1-4 алкила и C1-4 галогеналкила,
L2 обозначает -CH2CH2-, -CH=CH-, -CH2O-, -OCH2-, -CH2S-, -SCH2-, -CH2S(O)-S(O)CH2-, -CH2SO2-, -SO2CH2-, -CH2NH-, -NHCH2-, -NHCO-, -CONH-, -NHSO2- или -SO2NH-,
R3 обозначает C1-4 алкил или галоген,
R4 обозначает галоген, C1-4 алкил или C1-4 галогеналкил,
X3 обозначает метилен, атом кислорода, атом серы, который может быть окислен, или NR10, причем R10 обозначает C1-4 алкил, -C(O)(C1-4 алкил), -C(O)O(C1-4 алкил) или -SO2(C1-4 алкил), причем C1-4 алкил может быть замещен галогеном,
кольцо обозначает бензольное кольцо или пяти-шести-членное моноциклическое ароматическое гетероциклическое кольцо,
Figure 00000002
обозначает одинарную связь или двойную связь,
R5 обозначает (1) галоген, (2) C1-4 алкил, (3) карбоксил, (4) нитрил, (5) -CONHR11, (6) -C(O)R12, (7) -OR14, (8) -S(O)tR15, (9) -CH2R16, (10) -NR17R17, (11) -NHCOR11, (12) C4-10 углеродное кольцо или (13) четырех-десяти-членное гетероциклическое кольцо, причем C4-10 углеродное кольцо или четырех-десяти-членное гетероциклическое кольцо может быть замещено одним - тремя R18, причем, когда существует множество R18, множество R18 независимо могут быть одинаковыми или разными, R11 обозначает C1-6 алкил, C3-6 циклоалкил, фенил или четырех-шести-членное гетероциклическое кольцо и может быть замещен одним - тремя R13, причем, когда существует множество R13, множество R13 независимо могут быть одинаковыми или разными, R13 обозначает галоген, C1-6 алкил, C3-6 циклоалкил, C1-4 алкокси, гидроксильную группу, -NR20R21, бензол или четырех-шести-членное гетероциклическое кольцо, причем R20 и R21, каждый независимо, обозначают атом водорода или C1-4 алкил, R12 обозначает C1-6 алкил, C3-6 циклоалкил, бензол или четырех-шести-членное гетероциклическое кольцо, причем C3-6 циклоалкил, бензол и четырех-шести-членное гетероциклическое кольцо, каждый независимо, может быть замещен галогеном, C1-4 алкилом или C1-4 алкокси, R14 обозначает атом водорода, C1-6 алкил, C3-6 циклоалкил, бензол или бензил, причем C1-6 алкил может быть замещен одним - тремя R19, причем, когда существует множество R19, множество R19 независимо могут быть одинаковыми или разными, R19 обозначает C1-4 алкокси, -CONH(C1-4 алкил), -CON(C1-4 алкил)2 или пяти-шести-членное моноциклическое ароматическое гетероциклическое кольцо, которое может быть замещено заместителем, выбранным из группы, состоящей из C1-4 алкила и C1-4 галогеналкила, причем (C1-4 алкил)2, представленный R19, представляет собой две независимых C1-4 алкильных группы, которые могут быть одинаковыми или разными, R15 обозначает C1-6 алкил, C3-6 циклоалкил, бензол или бензил, R16 обозначает гидроксильную группу или C1-4 алкокси, R17, каждый независимо, обозначает атом водорода, C1-6 алкил или C3-6 циклоалкил, R18 обозначает галоген, C1-6 алкил, C3-6 циклоалкил, C1-4 алкокси, оксо, нитрил, гидроксильную группу, гидроксиметил, 1-метил-1-гидроксиэтил, (C1-4 алкил)SO2-, четырех-шести-членное гетероциклическое кольцо, (C1-4 алкил)NH- или (C1-4 алкил)2N-, причем (C1-4 алкил)2, представленный R18, представляет собой две независимые C1-4 алкильные группы, которые могут быть одинаковыми или разными,
m обозначает целое число от 1 до 4,
n обозначает целое число от 0 до 4,
p обозначает целое число от 0 до 2,
q обозначает целое число от 0 до 6,
r обозначает целое число от 0 до 6,
s обозначает целое число от 0 до 4,
t обозначает целое число от 0 до 2, и
R2, R3, R4 и R5, каждый независимо, могут быть одинаковыми или разными, когда p, q, r и s обозначают, каждый, целое число 2 или больше.
2. Соединение по п.1, представленное следующей общей формулой (I-1),
Figure 00000003
,
в которой na обозначает целое число от 0 до 1, qa обозначает целое число от 0 до 3, ra обозначает целое число от 0 до 4, X3a обозначает метилен или атом кислорода, и другие символы имеют значения, определенные в п.1.
3. Соединение по п.1 или 2, в котором по меньшей мере один R5 обозначает -CONHR11.
4. Соединение по любому из пп. 1-3, в котором L2 обозначает -NHCO- или -CONH-.
5. Соединение по любому из пп. 1-4, представленное следующей общей формулой (I-2),
Figure 00000004
в которой R2a обозначает галоген, R6a обозначает атом водорода или галоген, и другие символы имеют значения, определенные в пп. 1 и 2.
6. Соединение по п.1, которое является любым из следующих соединений:
(1) 4-[4-циано-2-({[(2ʹR,4S)-6-(метилкарбамоил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(2) 4-{4-циано-2-[({(2ʹR,4S)-6-[(циклопропилметил)карбамоил]-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил}карбонил)амино]фенил}бутеновая кислота,
(3) 4-{4-циано-2-[({(2ʹR,4S)-6-[(2-метоксиэтил)карбамоил]-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил}карбонил)амино]фенил}бутеновая кислота,
(4) 4-{4-циано-2-[({(2ʹR,4S)-6-[(2-метил-2-пропанил)карбамоил]-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил}карбонил)амино]фенил}бутеновая кислота,
(5) 4-[4-циано-2-({[(2ʹR,4S)-6-{[(2S)-1-метокси-2-пропанил]карбамоил}-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(6) 4-{4-циано-2-[({(2ʹR,4S)-6-[(1-метил-1H-пиразол-3-ил)карбамоил]-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил}карбонил)амино]фенил}бутеновая кислота,
(7) 4-[4-циано-2-({[(2ʹR,4S)-6-(циклопропилкарбамоил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(8) 4-[4-циано-2-({[(2ʹR,4S)-6-(изопропилкарбамоил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(9) 4-[4-циано-2-({[(2ʹR,4S)-6-(циклопентилкарбамоил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(10) 4-{2-[({(2ʹR,4S)-6-[(2S)-2-бутанилкарбамоил]-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил}карбонил)амино]-4-цианофенил}бутеновая кислота,
(11) 4-{4-циано-2-[({(2ʹR,4S)-6-[(транс-4-гидроксициклогексил)карбамоил]-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил}карбонил)амино]фенил}бутеновая кислота,
(12) 4-{4-циано-2-[({(2ʹR,4S)-6-[(цис-4-гидроксициклогексил)карбамоил]-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил}карбонил)амино]фенил}бутеновая кислота,
(13) 4-[4-циано-2-({[(2ʹR,4S)-6-(2-пиридинилкарбамоил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(14) 4-[4-циано-2-({[(2ʹR,4S)-6-(3-пиридазинилкарбамоил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(15) 4-[4-циано-2-({[(2ʹR,4S)-6-(циклобутилкарбамоил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(16) 4-[4-циано-2-({[(2ʹR,4S)-6-{[1-(2-метил-2-пропанил)-1H-пиразол-4-ил]карбамоил}-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(17) 4-[4-циано-2-({[(2ʹR,4S)-6-(тетрагидро-2H-пиран-4-илкарбамоил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(18) 4-[4-циано-2-({[(2ʹR,4S)-6-(пропилкарбамоил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(19) 4-{4-циано-2-[({(2ʹR,4S)-6-[карбамоил(2-этоксиэтил)]-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил}карбонил)амино]фенил}бутеновая кислота,
(20) 4-[4-циано-2-({[(2ʹR,4S)-6-(этилкарбамоил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(21) 4-[4-циано-2-({[(1R,2R)-6ʹ-(метилкарбамоил)-2ʹ,3ʹ-дигидроспиро[циклопропан-1,1ʹ-инден]-2-ил]карбонил}амино)фенил]бутеновая кислота,
(22) 4-{4-циано-2-[({(1R,2R)-6ʹ-[(2-метоксиэтил)карбамоил]-2ʹ,3ʹ-дигидроспиро[циклопропан-1,1ʹ-инден]-2-ил}карбонил)амино]фенил}бутеновая кислота,
(23) 4-{4-циано-2-[({(1R,2R)-6ʹ-[(1-метил-1H-пиразол-4-ил)карбамоил]-2ʹ,3ʹ-дигидроспиро[циклопропан-1,1ʹ-инден]-2-ил}карбонил)амино]фенил}бутеновая кислота,
(24) 4-[4-циано-2-({[(2ʹR,4S)-7-фтор-6-(метилкарбамоил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(25) 4-{4-циано-2-[({(2ʹR,4S)-7-фтор-6-[(2-метоксиэтил)карбамоил]-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил}карбонил)амино]фенил}бутеновая кислота,
(26) 4-[4-циано-2-({[(2ʹR,4S)-7-фтор-6-(изопропилкарбамоил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(27) 4-[4-циано-2-({[(2ʹR,4S)-7-(метилкарбамоил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(28) 4-{4-циано-2-[({(2ʹR,4S)-7-[(2-метоксиэтил)карбамоил]-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил}карбонил)амино]фенил}бутеновая кислота,
(29) 4-[4-циано-2-({[(2ʹR,4S)-7-метокси-6-(метилкарбамоил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(30) 4-{4-циано-2-[({(2ʹR,4S)-7-метокси-6-[(2-метоксиэтил)карбамоил]-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил}карбонил)амино]фенил}бутеновая кислота,
(31) 4-[4-циано-2-({[(2ʹR,3S)-5-(метилкарбамоил)спиро[1-бензофуран-3,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(32) 4-{4-циано-2-[({(2ʹR,3S)-5-[(2-метоксиэтил)карбамоил]спиро[1-бензофуран-3,1ʹ-циклопропан]-2ʹ-ил}карбонил)амино]фенил}бутеновая кислота,
(33) 4-[4-циано-2-({[(1S,2R)-6ʹ-[(2-метоксиэтил)карбамоил]-3ʹ,3ʹ-диметил-2ʹ,3ʹ-дигидроспиро[циклопропан-1,1ʹ-инден]-2-ил]карбонил}амино)фенил]бутеновая кислота, и
(34) 4-[4-циано-2-({[(1S,2R)-3ʹ,3ʹ-диметил-6ʹ-(метилкарбамоил)-2ʹ,3ʹ-дигидроспиро[циклопропан-1,1ʹ-инден]-2-ил]карбонил}амино)фенил]бутеновая кислота.
7. Соединение по п.1 или 2, в котором по меньшей мере один R5 обозначает C4-10 углеродное кольцо, которое может быть замещено одним - тремя R18, или четырех-десяти-членное гетероциклическое кольцо, которое может быть замещено одним - тремя R18, причем, когда существует множество R18, множество R18, каждый независимо, могут быть одинаковыми или разными.
8. Соединение по п.7, в котором L2 обозначает -NHCO- или -CONH-.
9. Соединение по любому из пп. 1, 2, 7 и 8, которое представлено следующей общей формулой (I-3),
Figure 00000005
,
в которой R5a обозначает C4-10 углеродное кольцо, которое может быть замещено одним - тремя R18, или четырех-десяти-членное гетероциклическое кольцо, которое может быть замещено одним - тремя R18, причем, когда существует множество R18, множество R18, каждый независимо, могут быть одинаковыми или разными, и другие символы имеют значения, определенные в пп. 1, 2 и 5.
10. Соединение по п.1, представляющее собой одно из следующих соединений:
(1) 4-[4-циано-2-({[(2ʹR,4S)-6-(5-метил-1,3,4-оксадиазол-2-ил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(2) 4-[4-циано-2-({[(2ʹR,4S)-6-(5-циклопропил-1,3,4-оксадиазол-2-ил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(3) 4-[4-циано-2-({[(2ʹR,4S)-6-(3-метил-1,2,4-оксадиазол-5-ил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(4) 4-[4-циано-2-({[(2ʹR,4S)-6-(3-пиридинил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(5) 4-[4-циано-2-({[(2ʹR,4S)-6-(1H-пиразол-1-ил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(6) 4-[4-циано-2-({[(2ʹR,4S)-6-(1H-пиразол-5-ил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(7) 4-[4-циано-2-({[(2ʹR,4S)-6-(4-пиридазинил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(8) 4-[4-циано-2-({[(2ʹR,4S)-6-(2-оксо-1-пирролидинил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(9) 4-[4-циано-2-({[(2ʹR,4S)-6-(6-метокси-3-пиридинил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(10) 4-{4-циано-2-[({(2ʹR,4S)-6-[6-(1H-пиразол-1-ил)-3-пиридинил]-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил}карбонил)амино]фенил}бутеновая кислота,
(11) 4-{4-циано-2-[({(2ʹR,4S)-6-[6-(диметиламино)-3-пиридинил]-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил}карбонил)амино]фенил}бутеновая кислота,
(12) 4-[4-циано-2-({[(2ʹR,4S)-6-(6-метил-3-пиридинил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(13) 4-{4-циано-2-[({(2ʹR,4S)-6-[6-(метиламино)-3-пиридинил]-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил}карбонил)амино]фенил}бутеновая кислота,
(14) 4-[4-циано-2-({[(2ʹR,4S)-6-(2-пиридинил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(15) 4-[4-циано-2-({[(2ʹR,4S)-6-(1,3-тиазол-2-ил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(16) 4-[4-циано-2-({[(2ʹR,4S)-6-(1,3-оксазол-2-ил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(17) 4-[4-циано-2-({[(2ʹR,4S)-6-(1-метил-1H-1,2,3-триазол-4-ил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(18) 4-[4-циано-2-({[(2ʹR,4S)-6-(3-пиридазинил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота,
(19) 4-[4-циано-2-({[(2ʹR,3S)-5-(3-пиридинил)спиро[1-бензофуран-3,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновая кислота, и
(20) 4-[4-циано-2-({[(1S,2R)-3ʹ,3ʹ-диметил-6ʹ-(3-пиридинил)-2ʹ,3ʹ-дигидроспиро[циклопропан-1,1ʹ-инден]-2-ил]карбонил}амино)фенил]бутеновая кислота.
11. Фармацевтическая композиция, включающая соединение общей формулы (I) по п.1, его соль, N-оксид или сольват или их пролекарство в качестве активного ингредиента.
12. Композиция по п.11, которая является антагонистом рецептора EP4.
13. Композиция по п.11, которая является профилактическим и/или терапевтическим агентом против заболевания, вызванного активацией рецептора EP4.
14. Композиция по п.13, где заболевание, вызванное активацией рецептора EP4, является заболеванием костей, раком, системным гранулематозным заболеванием, иммунопатологическим заболеванием, альвеолярной пиореей, гингивитом, периодонтитом, болезнью Кавасаки, полиорганной недостаточностью, хронической головной болью, болью, васкулитом, венозной недостаточностью, варикозом вен, аневризмой, аневризмой аорты, анальным свищем, несахарным диабетом, незаращением артериального протока у новорожденных или холелитиазом.
15. Композиция по п.14, где рак является раком молочной железы, раком яичника, раком ободочной и прямой кишки, раком легких, раком предстательной железы, раком головы и шеи, лимфомой, увеальной меланомой, тимомой, мезотелиомой, раком пищевода, раком желудка, раком двенадцатиперстной кишки, гепатоцеллюлярным раком, холангиокарциномой, раком желчного пузыря, раком поджелудочной железы, почечно-клеточным раком, раком почечной лоханки и мочеточника, раком мочевого пузыря, раком полового члена, тестикулярным раком, раком матки, раком влагалища, раком вульвы, раком кожи, злокачественной опухолью кости, саркомой мягких тканей, хондросаркомой, лейкозом, миелодиспластическим синдромом или множественной миеломой.
16. Лекарственное средство, включающее соединение общей формулы (I) по п.1, его соль, N-оксид или сольват или их пролекарство с по меньшей мере одним средством, выбранным из алкилирующего агента, антиметаболита, противоракового антибиотика, препарата на растительной основе, гормонального агента, соединения платины, ингибитора топоизомеразы, ингибитора киназы, антитела анти-CD20, антитела анти-HER2, антитела анти-EGFR, антитела анти-VEGF, ингибитора протеасомы, ингибитора HDAC и иммуномодулятора.
17. Лекарственное средство, включающее соединение общей формулы (I) по п.1, его соль, N-оксид или сольват или их пролекарство с по меньшей мере одним средством, выбранным из ингибитора HMG-CoA редуктазы, гипотензивного средства и антибиотика тетрациклинового ряда.
18. Лекарственное средство, включающее соединение общей формулы (I) по п.1, его соль, N-оксид или сольват или их пролекарство с по меньшей мере одним средством, выбранным из ингибитора кальциевого канала N-типа, ингибитора синтетазы оксида азота (NOS) и реагента, стимулирующего каннабиноидный рецептор-2.
19. Способ профилактики и/или лечения заболевания, вызванного активацией рецептора EP4, включающий введение эффективного количества соединения общей формулы (I) по п.1, его соли, N-оксида или сольвату или их пролекарства пациенту, нуждающемуся в профилактике и/или лечении заболевания, вызываемого активацией рецептора EP4.
20. Соединение общей формулы (I) по п.1, его соль, N-оксид или сольват или их пролекарство для профилактики и/или лечения заболевания, вызываемого активацией рецептора EP4.
21. Применение соединения общей формулы (I) по п.1, его соли, N-оксида или сольвата для получения профилактического и/или терапевтического агента для лечения заболевания, вызываемого активацией рецептора EP4.
22. Соединение, представляющее собой 4-{4-циано-2-[({(2ʹR,4S)-6-[(2-метоксиэтил)карбамоил]-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил}карбонил)амино]фенил}бутеновую кислоту.
23. Соединение, представляющее собой 4-[4-циано-2-({[(2ʹR,4S)-6-(изопропилкарбамоил)-2,3-дигидроспиро[хромен-4,1ʹ-циклопропан]-2ʹ-ил]карбонил}амино)фенил]бутеновую кислоту.
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