Biphenyl derivatives and their use in treating hepatitis C

• US 8,008,303 B2
• Filed: 09/18/2006
• Issued: 08/30/2011
• Est. Priority Date: 09/16/2005
• Status: Expired due to Fees

• Current Assignee: Arrow Therapeutics Ltd. (Astrazeneca PLC), Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Lumley, James, Wheelhouse, Christopher James, Thomas, Alexander James Floyd, Salter, James Iain, Mathews, Neil, Angell, Richard Martyn, Pilkington, Christopher John, Bushnell, David John, Carter, Malcolm Clive
• Primary Examiner(s): HABTE, KAHSAY
• Application Number:
  US12/066,983
• Publication Number:
  US 20080255105A1
• Time in Patent Office: 1,807 Days
• Field of Search: 544/359, 544/383, 514/252.13, 514/252.12
• US Class Current: 514/252.13
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07D 205/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 237/28 Cinnolines
• CPC Class Codes: C07D 279/12 not condensed with other rings
• CPC Class Codes: C07D 295/135 with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/26 Sulfur atoms
• CPC Class Codes: C07D 307/38 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 333/20 by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

Use of a compound which is a biphenyl derivative of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of Hepatitis C

wherein the variables are described herein.

Claims

1. A compound which is a biphenyl derivative of formula (I), a pharmaceutically acceptable salt, or a mixture thereof

2. A compound according to claim 1, wherein each A₄ moiety is the same or different and is a non-fused 5- to 6- membered heterocyclyl or C₃-C₈ carbocyclyl group, or a phenyl or 5- to 6- membered heteroaryl group which is optionally fused to a phenyl ring or to a 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group.

3. A compound according to claim 1, wherein each A₄ moiety is unsubstituted or substituted by (a) a single unsubstituted substituent selected from —

CO₂R″

′ and

—

CONR′

R″

′ and

/or (b) 1, 2 or 3 unsubstituted substituents selected from halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, —

NR′

R″

′

, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy and cyano, wherein R′

represents hydrogen or C₁-C₄ alkyl and R″

′

represents C₁-C₄ alkyl.

4. A compound according to claim 1, wherein each A₄′

moiety is the same or different and represents a non-fused phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C₃-C₆ carbocyclyl group.

5. A compound according to claim 1, wherein each A₄ ′

moiety is unsubstituted or substituted by (a) an unsubstituted —

SO₂—

(C₁-C₄ alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C₁-C₄ hydroxyalkyl, hydroxy and —

NR′

R″

, wherein each R′ and

R″

are the same or different and are selected from hydrogen and C₁-C₄ alkyl.

6. A compound according to claim 1, wherein L₄ is a C₁-C₃ alkylene group or a C₁-C₃ hydroxyalkylene group.

7. A compound according to claim 1, wherein Y₄ is —

CO—

.

8. A compound according to claim 1, wherein L₄ ′

is a C₁-C₂ alkyl group.

9. A compound according to claim 1, wherein R₂ and R₃ are the same or different and represent C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy or halogen.

10. A compound according to claim 1, wherein R₄ is a C₁-C₅ alkyl group Or a moiety -A₄, -A₄-A₄′

, -L₄-A₄, -A₄-L₄-A₄′

, -A₄-Y₄-A₄′

or -L₄-Het₄-L₄′

.

11. A compound according to claim 1, wherein:

R₂ is C₁-C₄ alkyl;

R₃ is C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy or halogen;

n and m are the same or different and each represent 0 or 1;

R₄ is a C₁-C₅ alkyl group or a moiety -A₄, -A₄-A₄′

, -L₄-A₄,-A₄-L₄-A₄′

, -A₄-CO -A₄′

or -L₄-Het₄-L₄′

;

each A₄ moiety is the same or different and is phenyl, furanyl, imidazolyl, pyrazolyl, pyrrolidinyl, azetidinyl, tetrahydrofuranyl, piperazinyl, piperidinyl, pyrrolidin-2-onyl, thiadiazolyl, isothiazolyl, C₃-C₈ cycloalkyl, morpholinyl, thienyl, pyridyl, pyrrolyl, S,S-dioxo-thiomopholinyl, tetrahydropyranyl, thiazolyl, oxadiazolyl or indazolyl group, each A₄ moiety being unsubstituted or substituted by (a) a single unsubstituted -CONR′

R″

′

substituent and/or (b) 1 or 2 unsubstituted substituents selected from fluorine, chlorine, bromine, —

NR′

R″

′

, C₁-C₄ alkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkyl and cyano, wherein R′

is hydrogen or C₁-C₄ alkyl and R″

′

represents C₁-C₄ alkyl;

each A₄ ′

moiety is the same or different and represents a morpholinyl, piperazinyl, isoxazolyl, pyrrolidinyl, S,S-dioxothiomorpholinyl, 2,6-dioxo-piperidinyl, triazolyl, piperidinyl, cyclopropyl or cyclohexyl group which is unsubstituted or substituted by (a) a single unsubstituted —

SO₂—

(C₁-C₄ alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, C₁-C₂ alkyl and C₁-C₂ haloalkyl;

L₄ is a C₁-C₃ alkylene group or a C₁-C₃ hydroxyalkylene group

L₄′

represents a C₁-C₂ alkyl group; and

Het₄ represents —

O—

or —

NH—

.

12. A compound according to claim 1, wherein:

R₂ is C₁-C₄ alkyl;

R₃ is C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy or halogen;

n and m are the same or different and each represent 0 or 1;

R₄ is a C₁-C₅ alkyl group or a moiety selected from the group consisting of -A₄, -A₄-A₄′

, -L₄-A₄, -A₄-L₄-A₄′

, -A₄-CO-A₄′ and

-L₄-O-L₄′

;

each A₄ moiety is the same or different and is phenyl, furanyl, imidazolyl, pyrazolyl, tetrahydrofuranyl, piperazinyl, piperidinyl, pyrrolidin-2-onyl, thiadiazolyl, isothiazolyl, C₃-C₈ cycloalkyl, morpholinyl, thienyl, pyridyl, pyrrolyl, S,S-dioxo-thiomopholinyl, tetrahydropyranyl, thiazolyl, oxadiazolyl or indazolyl group, each A₄ moiety being unsubstituted or substituted by (a) a single unsubstituted —

CONR′

R″

substituent and/or (b) 1 or 2 unsubstituted substituents selected from fluorine, chlorine, bromine, —

NR′

R″

′

, C₁-C₄ alkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkyl and cyano, wherein R′

is hydrogen or C₁-C₄ alkyl and R″

represents C₁-C₄ alkyl;

each A₄ ′

moiety is the same or different and represents a morpholinyl, isoxazolyl, pyrrolidinyl, S,S-dioxothiomorpholinyl, 2,6-dioxo-piperidinyl, triazolyl, piperidinyl, cyclopropyl or cyclohexyl group which is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, C₁-C₂ alkyl and C₁-C₂ haloalkyl;

L₄ is a C₁-C₃ alkylene group or a C₁-C₃ hydroxyalkylene group; and

L₄′

represents a C₁-C₂ alkyl group.

13. A compound according to claim 1, wherein:

R₂ is C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkyl or halogen;

R₃ is C₁-C₄ alkyl;

n and m are the same or different and each represent 0 or 1;

R₄ is a C₁-C₅ alkyl group or a moiety selected from the group consisting of -A₄, -A₄-A₄′

, -L₄-A₄-A₄-L₄-A₄′

-A₄-CO-A₄ ′ and

-L₄-O-L₄′

;

each A₄ moiety is the same or different and is phenyl, furanyl, imidazolyl, pyrazolyl, tetrahydrofuranyl, piperazinyl, piperidinyl, pyrrolidin-2-onyl, thiadiazolyl, isothiazolyl, C₃-C₈ cycloalkyl, morpholinyl, thienyl, pyridyl, pyrrolyl, S,S-dioxo-thiomopholinyl, tetrahydropyranyl, thiazolyl, oxadiazolyl or indazolyl group, each A₄ moiety being unsubstituted or substituted by (a) a single unsubstituted —

CONR′

R″

′

substituent and/or (b) 1 or 2 unsubstituted substituents selected from fluorine, chlorine, bromine, —

NR′

R″

′

, C₁-C₄ alkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkyl and cyano, wherein R′

is hydrogen or C₁-C₄ alkyl and R′

″

represents C₁-C₄ alkyl;

each A₄ ′

moiety is the same or different and represents a morpholinyl, isoxazolyl, pyrrolidinyl, S,S-dioxothiomorpholinyl, 2,6-dioxo-piperidinyl, triazolyl, piperidinyl, cyclopropyl or cyclohexyl group which is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, C₁-C₂ alkyl and C₁-C₂ haloalkyl;

L₄ is a C₁-C₃ alkylene group or a C₁-C₃ hydroxyalkylene group; and

L₄′

represents a C₁-C₂ alkyl group.

14. A compound according to claim 1, wherein R₄ is -A₄ or -A₄-L₄-A₄′

.

15. A compound according to claim 14, wherein when R₄ is A₄ it is C₃-C₆ cycloalkyl or when R₄ is -A₄-L₄-A₄′

, A₄ is phenyl, L₄ is —

CH₂— and

A₄′

, is a group

16. A pharmaceutical composition comprising a biphenyl derivative of claim 1, a pharmaceutically acceptable salt, or a mixture thereof, and a pharmaceutical acceptable diluent or carrier.

17. A pharmaceutical composition according to claim 16, which further comprises interferon and/or ribavirin.

18. A method of treating an HCV infection in a patient, which method comprises administering to said patient an effective amount of a biphenyl derivative of claim 1, a pharmaceutically acceptable salt, or a mixture thereof

19. The method of claim 18, further comprising administering interferon and/or ribavirin.

20. A compound which is 5′

-(cyclopropanecarbonyl-amino)-2′

-trifluoromethoxy-biphenyl-4-carboxylic acid {4-[4-(propane-1- sulfonyl)-piperazin-1 -ylmethyl]-phenyl}-amide, a pharmaceutically acceptable salt, or a mixture thereof.