RU2486190C2 - Macrocyclic indoles as hepatitis c virus inhibitors - Google Patents

Macrocyclic indoles as hepatitis c virus inhibitors Download PDF

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RU2486190C2
RU2486190C2 RU2010130984A RU2010130984A RU2486190C2 RU 2486190 C2 RU2486190 C2 RU 2486190C2 RU 2010130984 A RU2010130984 A RU 2010130984A RU 2010130984 A RU2010130984 A RU 2010130984A RU 2486190 C2 RU2486190 C2 RU 2486190C2
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compound according
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alkyl
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RU2010130984A
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RU2010130984A (en
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Пьер Жан-Мари Бернар Рабуассон
Лили Ху
Сандрин ВЕНДЕВИЛЛЬ
Орижен НИАНГИЛЬ
Абделлах Тахри
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Тиботек Фармасьютикалз
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Abstract

FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to new compounds of formula I:
Figure 00000187
or pharmaceutically acceptable salts thereof, wherein the values R1, R3, and R4 are specified in cl. one of the patent claim.
EFFECT: compounds inhibit the HCV replication that makes them applicable for preparing a pharmaceutical composition and a drug preparation for HCV infection.
16 cl, 3 tbl, 10 dwg, 30 ex

Description

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The text of the description is given in facsimile form.
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Claims (16)

1. Соединение, имеющее формулу (I)
Figure 00000176

в которой R1 обозначает двухвалентную цепочку, выбранную из
Figure 00000177
или
в которой атом углерода, несущий заместители R5a и R5b, присоединен к остатку молекулы через атом азота амидной группы, и атом углерода ацетамидной группы присоединен к остатку молекулы через азот индольного кольца соединения формулы (I);
или
R1 обозначает двухвалентную цепочку, выбранную из
Figure 00000178

в которой сульфонильная группа присоединена к остатку молекулы через атом азота амидной группы, и атом углерода ацетамидной группы присоединен к остатку молекулы через азот индольного кольца соединения формулы (I);
Х обозначает -CR5aR5b- или -NR5a-;
каждый из а, b, с, d, e, f, q и h независимо означает целое число, выбранное из 0, 1, 2, 3, 4 или 5, при условии, что макроцикл, образованный двухвалентной цепочкой R1, группой C(=O)-NH-, к которой R1 присоединен, и атомами азота и углерода N1, С6, С7 и С7' индольного кольца, имеет от 14 до 17 атомов;
каждая двойная линия (обозначенная как
Figure 00000179
) обозначает возможную двойную связь;
R2 обозначает водород или C1-6алкил;
R3 обозначает С3-7циклоалкил;
R4 обозначает группу, выбранную из
Figure 00000180

R5a и R5b каждый независимо обозначает водород или С1-6алкил;
n=0, 1 или 2;
R6 обозначает водород или галоген;
R6a обозначает водород или галоген;
R7 обозначает фенил или тиазолил, причем каждый фенил может быть замещен одним, двумя или тремя заместителями, причем каждый тиазолил может быть замещен одним или двумя заместителями;
причем заместители как на фениле, так и на тиазолиле, каждый независимо обозначают галоген; C1-6алкил; фенил, в случае необходимости замещенный галогеном; или -OR12;
R8 обозначает водород, фенил, причем каждый фенил может быть замещен одним, двумя или тремя заместителями, причем заместители каждый независимо выбраны из галогена; нитро; С1-6алкила; -OR12; -NR9aR9b; -NR9aC(=O)R13; фенила, в случае необходимости замещенного одним, двумя или тремя галогенами; и Het, возможно замещенного одним или двумя заместителями, выбранными каждый независимо из оксо, C1-6алкилсульфонила и C1-6алкила;
R9a и R9b каждый независимо обозначает водород или С1-6алкил;
R12 обозначает водород или С1-6алкил;
R13 обозначает С1-6алкил;
Het обозначает пирролидинил, морфолинил или пиперазинил;
или его фармацевтически приемлемая соль.1. The compound having the formula (I)
Figure 00000176

in which R 1 denotes a divalent chain selected from
Figure 00000177
or
in which the carbon atom bearing the substituents R 5a and R 5b is attached to the remainder of the molecule through a nitrogen atom of the amide group, and the carbon atom of the acetamide group is attached to the remainder of the molecule through the nitrogen of the indole ring of the compound of formula (I);
or
R 1 denotes a divalent chain selected from
Figure 00000178

in which the sulfonyl group is attached to the remainder of the molecule through a nitrogen atom of the amide group, and the carbon atom of the acetamide group is attached to the remainder of the molecule through the nitrogen of the indole ring of the compound of formula (I);
X is —CR 5a R 5b - or —NR 5a -;
each of a, b, c, d, e, f, q and h independently means an integer selected from 0, 1, 2, 3, 4 or 5, provided that the macrocycle formed by the divalent chain R 1 , group C (= O) —NH— to which R 1 is attached, and with the nitrogen and carbon atoms N1, C6, C7 and C7 ′ of the indole ring, has from 14 to 17 atoms;
each double line (designated as
Figure 00000179
) denotes a possible double bond;
R 2 is hydrogen or C 1-6 alkyl;
R 3 is C 3-7 cycloalkyl;
R 4 denotes a group selected from
Figure 00000180

R 5a and R 5b each independently represents hydrogen or C 1-6 alkyl;
n is 0, 1 or 2;
R 6 is hydrogen or halogen;
R 6a is hydrogen or halogen;
R 7 is phenyl or thiazolyl, wherein each phenyl may be substituted with one, two or three substituents, wherein each thiazolyl may be substituted with one or two substituents;
wherein the substituents on both phenyl and thiazolyl are each independently halogen; C 1-6 alkyl; phenyl optionally substituted with halogen; or -OR 12 ;
R 8 is hydrogen, phenyl, wherein each phenyl may be substituted with one, two or three substituents, the substituents each independently selected from halogen; nitro; C 1-6 alkyl; -OR 12 ; -NR 9a R 9b ; -NR 9a C (= O) R 13 ; phenyl, optionally substituted with one, two or three halogens; and Het, optionally substituted with one or two substituents, each independently selected from oxo, C 1-6 alkylsulfonyl and C 1-6 alkyl;
R 9a and R 9b each independently represents hydrogen or C 1-6 alkyl;
R 12 is hydrogen or C 1-6 alkyl;
R 13 is C 1-6 alkyl;
Het is pyrrolidinyl, morpholinyl or piperazinyl;
or a pharmaceutically acceptable salt thereof. 2. Соединение по п.1, в котором
R1 обозначает двухвалентную цепочку, выбранную из
Figure 00000181

в которой атом углерода, несущий заместители R5a и R5b (левая сторона изображенных цепей R1), присоединен к остатку молекулы через атом азота амидной группы, и атом углерода ацетамидной группы (правая сторона изображенных цепей R1) присоединен к остатку от молекулы через азот индольного кольца соединения формулы (I);
каждая двойная линия (обозначенная как
Figure 00000179
) обозначает возможную двойную связь;
R4 обозначает группу, выбранную из
Figure 00000182
2. The compound according to claim 1, in which
R 1 denotes a divalent chain selected from
Figure 00000181

in which the carbon atom bearing the substituents R 5a and R 5b (the left side of the depicted chains of R 1 ) is attached to the remainder of the molecule through the nitrogen atom of the amide group, and the carbon atom of the acetamide group (the right side of the depicted chains of R 1 ) is attached to the remainder of the molecule through nitrogen of the indole ring of the compound of formula (I);
each double line (designated as
Figure 00000179
) denotes a possible double bond;
R 4 denotes a group selected from
Figure 00000182
 3. Соединение по п.1, имеющее одну из структурных формул
Figure 00000183

в которых двойная линия, a, b, q, h, R3, R6, R7, X, n и R8 имеют то же самое значение, как определено по п.1.3. The compound according to claim 1, having one of the structural formulas
Figure 00000183

in which the double line, a, b, q, h, R 3 , R 6 , R 7 , X, n and R 8 have the same meaning as defined in claim 1. 4. Соединение по п.1, в котором R4 обозначает
Figure 00000184
4. The compound according to claim 1, in which R 4 means
Figure 00000184
 5. Соединение по п.1, в котором R4 обозначает
Figure 00000185
5. The compound according to claim 1, in which R 4 denotes
Figure 00000185
 6. Соединение по п.1, в котором R1 обозначает
Figure 00000186
6. The compound according to claim 1, in which R 1 denotes
Figure 00000186
 7. Соединение по п.1, в котором каждый из а, b, с, d, e, f, q и n независимо означает 0, 1, 2 или 3, при условии, что макроцикл, образованный двухвалентной цепочкой R1, группой C(=O)-NH-, к которой R1 присоединен, и атомами азота и углерода N1, С6, С7 и С7' индольного кольца, имеет от 14 до 16 атомов.7. The compound according to claim 1, in which each of a, b, c, d, e, f, q and n independently means 0, 1, 2 or 3, provided that the macrocycle formed by the divalent chain R 1 group C (= O) —NH— to which R 1 is attached, and the nitrogen and carbon atoms N1, C6, C7 and C7 ′ of the indole ring, have from 14 to 16 atoms. 8. Соединение по п.1, в котором R2 обозначает водород или С1-4алкил.8. The compound according to claim 1, in which R 2 denotes hydrogen or C 1-4 alkyl. 9. Фармацевтическая композиция, ингибирующая репликацию HCV, включающая соединение по любому из пп.1-4 в эффективном количестве и фармацевтически приемлемый носитель.9. A pharmaceutical composition inhibiting HCV replication, comprising a compound according to any one of claims 1 to 4 in an effective amount and a pharmaceutically acceptable carrier. 10. Фармацевтическая композиция по п.9, дополнительно включающая другое соединение анти-HCV.10. The pharmaceutical composition according to claim 9, further comprising another anti-HCV compound. 11. Соединение по любому из пп.1-8 для применения в качестве лекарственного средства, ингибирующего репликацию HCV.11. The compound according to any one of claims 1 to 8 for use as a drug that inhibits HCV replication. 12. Фармацевтическая композиция по любому из пп.9 или 10 для применения в качестве лекарственного средства, ингибирующего репликацию HCV.12. The pharmaceutical composition according to any one of claims 9 or 10 for use as a HCV replication inhibitory drug. 13. Соединение по любому из пп.1-8 для ингибирования репликации HCV.13. The compound according to any one of claims 1 to 8 for inhibiting HCV replication. 14. Фармацевтическая композиция по любому из пп.9 или 10 для ингибирования репликации HCV.14. The pharmaceutical composition according to any one of claims 9 or 10 for inhibiting HCV replication. 15. Применение соединения по любому из пп.1-8 для получения лекарственного средства для ингибирования репликации HCV.15. The use of a compound according to any one of claims 1 to 8 for the manufacture of a medicament for inhibiting HCV replication. 16. Комбинация для лечения инфекции HCV (i) соединения по любому из пп.1-8 и (ii) другого соединения, пригодного для лечения инфекции HCV. 16. A combination for treating HCV infection (i) a compound according to any one of claims 1 to 8 and (ii) another compound suitable for treating HCV infection.
RU2010130984A 2007-12-24 2008-12-23 Macrocyclic indoles as hepatitis c virus inhibitors RU2486190C2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP07150415.3 2007-12-24
EP07150415 2007-12-24

Publications (2)

Publication Number Publication Date
RU2010130984A RU2010130984A (en) 2012-02-10
RU2486190C2 true RU2486190C2 (en) 2013-06-27

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Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Bioorganic & Medicinal Chemistry Letters, 17 (2007), 5143-5149. *

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