# US 8,148,399 B2 · Macrocyclic inhibitors of hepatitis C virus

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- Number: US 8,148,399 B2
- Document ID: US8148399B2
- Status: Granted
- Kind: B2
- Application number: 11/632,102
- Filed: 2006-07-28
- Published: 2009-11-12
- Granted: 2012-04-03
- Earliest claimed: 2005-07-29
- Assignees: Tibotec Pharmaceuticals Ltd.; Medivar AB
- Inventors: Kenneth Alan Simmen; Herman Augustinus De Kock; Pierre Jean-Marie Bernard Raboisson; Karl Magnus Nilsson; Bengt Bertil Samuelsson; Åsa Annica Kristina Rosenquist
- Web page: https://patentgrep.com/patent/US8148399B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/7056: containing five-membered rings with nitrogen as a ring hetero atom
- A61K 38/05: Dipeptides
- A61K 38/212: {IFN-alpha}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 245/04: condensed with carbocyclic rings or ring systems
- C07D 277/56: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 401/14: containing three or more hetero rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/14: containing three or more hetero rings
- C07K 5/06139: {with the first amino acid being heterocyclic}
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Inhibitors of HCV replication of formula (I) and the N-oxides, salts, and stereoisomers, wherein each dashed line represents an optional double bond; X is N, CH and where X bears a double bond it is C; R1 is —OR7, —NH—SO2R8; R2 is hydrogen, and where X is C or CH, R2 may also be C1-6alkyl; R3 is hydrogen, C1-6alkyl, C3-7cycloalkyl; R4 is aryl or Het; n is 3, 4, 5, or 6; R5 is halo, C1-6alkyl, hydroxy, C1-6alkoxy, phenyl, or Het; R6 is C1-6alkoxy, or dimethylamino; R7 is hydrogen; aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; R8 is aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; aryl is phenyl optionally substituted with one, two or three substituents; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.

## Claims

### Claim 1

A compound of the formula:
or a pharmaceutically acceptable salt thereof or a stereochemically isomeric form thereof or a pharmaceutically acceptable salt of the stereochemically isomeric form.

### Claim 2

A compound of the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

The compound according to claim 2 in its pharmaceutically acceptable salt form.

### Claim 4 (depends on 3)

The compound according to claim 3 wherein the pharmaceutically acceptable salt is an acid addition salt.

### Claim 5 (depends on 3)

The compound according to claim 3 wherein the pharmaceutically acceptable salt is a base addition salt.

### Claim 6 (depends on 3)

The compound according to claim 3 wherein the pharmaceutically acceptable salt is a hydrochloride acid addition salt.

### Claim 7 (depends on 3)

The compound according to claim 3 wherein the pharmaceutically acceptable salt is a sodium addition salt.

### Claim 8 (depends on 2)

The compound according to claim 2, which is stereochemically pure.

### Claim 9 (depends on 1)

The compound according to claim 1 wherein the compound is a powder.

### Claim 10 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier therefore.

### Claim 11 (depends on 1)

A method of inhibiting HCV replication in a warm-blooded animal comprising administering to said animal in need thereof a therapeutically effective amount of a compound according to claim 1.

### Claim 12 (depends on 11)

The method according to claim 11 wherein the warm-blooded animal is human.

### Claim 13 (depends on 11)

The method according to claim 11 wherein the compound has the formula
or a pharmaceutically acceptable salt thereof.

### Claim 14

A process of preparing a compound of the formula
which comprises reacting under effective conditions a compound of formula 46
and cyclopropylsulfonamide.

### Claim 15 (depends on 14)

The process according to claim 14 wherein the process comprises
(a) stirring at reflux under nitrogen for 2 hours, a solution of 560 mg (0.867 mmol) of compound no. 46 and 308 mg (1.90 mmol) of carbonyldiimidazole in 10 mL of dry tetrahydrofuran;
(b) cooling the reaction mixture obtainable from step a) to room temperature and adding 400 mg (3.301 mmol) of cyclopropylsulfonamide and 286 mg of DBU (1.881 mmol);
(c) heating the solution obtainable from step b) at 50° C. for 15 hours;
(d) cooling down the reaction mixture obtainable from step c) at room temperature and concentrating it under reduced pressure;
(e) partitioning the residue obtainable from step d) between CH2Cl2 and HCl 1 N, washing the organic layer with brine, drying said organic layer with MgSO4, and evaporating said organic layer;
(f) purifying the organic layer obtainable from step e) by flash chromatography (gradient of EtOAc (0 to 25%) in CH2Cl2) affording 314 mg of an off-white solid; and
(g) washing the off-white solid obtainable from step f) with water and then with isopropyl ether, and drying said off-white solid in a vacuum oven.