Macrocyclic inhibitors of hepatitis C virus
View Patent ↗Inhibitors of HCV of formula (I). and the N-oxides, salts, and stereoisomers thereof, wherein the dashed line represents an optional double bond between atoms C7 and C8; R 1 is hydrogen or C 1-6 alkyl; R 2 is hydrogen or C 1-6 alkyl; and n is 3, 4, 5, or 6; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I) are provided. Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.
1. A compound having the formula
and the N-oxides, salts, and stereoisomers thereof, wherein
the dashed line represents an optional double bond between atoms C7 and C8;
R 1 is hydrogen or C 1-6 alkyl;
R 2 is hydrogen or C 1-6 alkyl; and
n is 3, 4, 5, or 6.
2. The compound according to claim 1 , wherein the compound has the formula (I-a):
3. The compound of claim 1 , wherein the compound has the formula (I-b):
4. The compound of claim 1 , wherein n is 4 or 5.
5. The compound of claim 1 , wherein R 1 is hydrogen or methyl.
6. The compound of claim 1 , wherein R 2 is hydrogen.
7. The compound of claim 1 , wherein R 2 is methyl.
8. The compound of claim 1 , wherein the compound is selected from
9. The compound of claim 1 other than an N-oxide or salt.
10. A combination comprising
(a) a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof; and
(b) ritonavir, or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising a carrier, and as active ingredient an anti-virally effective amount of the compound of claim 1 .
12. A method of inhibiting HCV replication in a warm-blooded animal, said method comprising administering an effective amount of the compound of claim 1 .
13. A process for preparing a compound of claim 1 , wherein said process comprises:
(a) preparing a compound of formula (I) wherein the bond between C 7 and C 8 is a double bond, which is a compound of formula (I-a), by forming of a double bond between C 7 and C 8 , via an olefin metathesis reaction, with concomitant cyclization to the macrocycle as outlined in the following reaction scheme:
(b) converting a compound of formula (I-a) to a compound of formula (I) wherein the link between C7 and C8 in the macrocycle is a single bond, i.e. a compound of formula (I-b)
wherein R 1 and R 2 are as defined in claim 1 , by a reduction of the C7-C8 double bond in the compound of formula (I-a);
(c) reacting a cyclopropylsulfonamide (IV) with an intermediate (III) via an amide forming reaction as outlined in the following reaction scheme:
(d) etherifying an intermediate (V) with a quinoline of formula (VI) as outlined in the following reaction scheme:
wherein X in (VI) represents hydroxy or a leaving group; which reaction is an O-arylation reaction wherein X represents a leaving group, or a Mitsunobu reaction, wherein X is hydroxy;
(e) preparing a compound of formula (I) wherein R 1 is hydrogen, said compound being represented by (I-d), from a corresponding nitrogen-protected intermediate (VII), wherein PG represents a nitrogen protecting group:
(f) converting compounds of formula (I) into each other by a functional group transformation reaction; or
(g) preparing a salt form by reacting the free form of a compound of formula (I) with an acid or a base.
14. A pharmaceutical composition comprising,
(a) a carrier;
(b) an anti-virally effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof; and
(c) ritonavir, or a pharmaceutically acceptable salt thereof.
15. A method of inhibiting HCV replication in a warm-blooded animal, said method comprising administering:
(a) a compound of claim 1 or a pharmaceutically acceptable salt thereof; and
(b) ritonavir, or a pharmaceutically acceptable salt thereof.