Substituted aryl thioureas and related compounds; inhibitors of viral replication

• US 7,094,807 B2
• Filed: 11/18/2003
• Issued: 08/22/2006
• Est. Priority Date: 11/19/2002
• Status: Expired due to Fees

• Current Assignee: Achillion Pharmaceuticals, Inc. (Astrazeneca PLC)
• Original Assignee: Achillion Pharmaceuticals, Inc. (Astrazeneca PLC)
• Inventors: Wang, Xiangzhu, Phadke, Avinash, Deshpande, Milind, Thurkauf, Andrew, Shen, Yiping, Liu, Cuixian, Chen, Dawei, Ohkanda, Junko, Quinn, Jesse, Li, Shouming
• Primary Examiner(s): AULAKH, CHARANJIT
• Application Number:
  US10/716,175
• Publication Number:
  US 20040138205A1
• Time in Patent Office: 1,008 Days
• Field of Search: 514/584, 514/585, 564/23, 564/26, 564/27, 564/28, 564/29
• US Class Current: 514/584
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 335/26 Y being a hydrogen or a carbon atom, e.g. benzoylthioureas
• CPC Class Codes: C07D 207/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 207/34 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 207/416 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/48 with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 211/14 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/62 attached in position 4
• CPC Class Codes: C07D 211/70 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 211/86 Oxygen atoms
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 213/65 attached in position 3 or 5
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 215/06 : having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
• CPC Class Codes: C07D 215/48 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 217/04 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 231/14 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/42 : Sulfur atoms
• CPC Class Codes: C07D 233/90 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 239/26 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 241/24 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 241/44 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 249/06 : with aryl radicals directly attached to ring atoms
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 261/18 : Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• CPC Class Codes: C07D 263/34 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 263/57 : Aryl or substituted aryl radicals
• CPC Class Codes: C07D 271/08 : 1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
• CPC Class Codes: C07D 271/12 : condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 277/56 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 277/66 : with aromatic rings or ring systems directly attached in position 2
• CPC Class Codes: C07D 277/68 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 285/06 : 1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
• 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 295/15 : to an acyclic saturated chain
• CPC Class Codes: C07D 307/52 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 307/85 : attached in position 2
• CPC Class Codes: C07D 311/24 : with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 311/66 : with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 317/66 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 319/20 : with substituents attached to the hetero ring
• CPC Class Codes: C07D 333/20 : by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 333/34 : Sulfur atoms
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/70 : attached in position 2
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems

Abstract

The invention provides compounds and pharmaceutically acceptable salts of Formula I
wherein the variables A₁, A₂, R₁, R₂, V, W, X, Y, and Z are defined herein. Certain compounds of Formula I described herein which possess potent antiviral activity. The invention particularly provides compounds of Formula I that are potent and/or selective inhibitors of Hepatitis C virus replication. The invention also provides pharmaceutical compositions containing one or more compound of Formula I, or a salt, solvate, or acylated prodrug of such compounds, and one or more pharmaceutically acceptable carriers, excipients, or diluents.

The invention further comprises methods of treating patients suffering from certain infectious diseases by administering to such patients an amount of a compound of Formula I effective to reduce signs or symptoms of the disease or disorder. These infectious diseases include viral infections, particularly HCV infections. The invention is particularly includes methods of treating human patients suffering from an infectious disease, but also encompasses methods of treating other animals, including livestock and domesticated companion animals, suffering from an infectious disease.

Methods of treatment include administering a compound of Formula I as a single active agent or administering a compound of Formula I in combination with on or more other therapeutic agent.

Claims

1. A pharmaceutical composition comprising therapeutically effective amount of a compound of Formula 1

or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier or excipient, wherein

A₁ is an optionally substituted aryl group;

A₂ is

R₁ and R₂ are independently hydrogen, or

R₁ and R₂ are independently C₁-C₆alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, C₁-C₄alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy,

R₁₁ and R₁₂ each represent 0 to 3 substituents independently chosen from halogen, hydroxy, cyano, C₁-C₆alkyl, C₁-C₆alkoxy, mono- and di-(C₁-C₆alkyl)amino, C₂-C₆alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, and phenyl; and

R₁₃ and R₁₄ are independently chosen at each occurrence from hydrogen and C₁-C₄alkyl.

2. A pharmaceutical composition according to claim 1 wherein

A₁ is an aryl group which is substituted with 0 to 5 substituents independently chosen from:

(a) halogen, hydroxy, cyano, amino, nitro, oxo, —

COOH, —

CONH₂, —

SO₂NH₂, —

SH, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy,

(b) C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkenyloxy, C₁-C₄alkoxy(C₁-C₄alkyl), amino(C₁-C₆)alkyl, mono- and di-(C₁-C₆alkyl)amino, mono- and di-(C₁-C₄alkyl)aminoC₁-C₄alkyl, C₂-C₆alkanoyl, C₂-C₈alkanoyloxy, C₁-C₈alkoxycarbonyl, -mono- and di-(C₁-C₆alkyl)carboxamide, (C₃-C₇cycloalkyl)carboxamide, mono- and di-(C₁-C₆alkyl)sulfonamide, C₁-C₆alkylthio, aryl(C₀-C₄alkyl)thio, C₁-C₆alkylsulfinyl, and C₁-C₆alkylsulfonyl, and

(c) —

GR_a where

G is chosen from —

(CH₂)_n—

, C₂-C₄alkenyl, C₂-C₄alkynyl, —

(CH₂)_nO(CH₂)_m—

, and —

(CH₂)_nN(CH₂)_m—

, where n and m are independently 0, 1, 2, 3, or 4; and

R_a is chosen from C₃-C₈cycloalkyl, C₂-C₇monocyclic heterocycloalkyl, C₅-C₁₀bicyclicheterocycloalkyl, indanyl, tetrahydronapthyl, aryl, and heteroaryl;

each of which (b) and (c) is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, C₁-C₄alkyl, C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, and phenyl; and

R₁ and R₂ are each independently hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

3. A pharmaceutical composition according to claim 2 in which R₁ and R₂ are independently hydrogen, methyl, or ethyl.

4. A pharmaceutical composition according to claim 3 in which R₁ and R₂ are both hydrogen.

5. A pharmaceutical composition according to any one of claim 2 wherein

A₁ is aryl;

substituted with 0 to 5 substituents independently chosen from;

(a) halogen, hydroxy, cyano, amino, nitro, oxo, —

COOH, —

CONH₂, —

SO₂NH₂, —

SH, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, and

(b) C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkenyloxy, C₁-C₄alkoxy(C₁-C₄alkyl), amino(C₁-C₆)alkyl, mono- and di-(C₁-C₆alkyl)amino, mono- and di-(C₁-C₄alkyl)aminoC₁-C₄alkyl, C₂-C₆alkanoyl, C₂-C₈alkanoyloxy, C₁-C₈alkoxycarbonyl, mono- and di-(C₁-C₆alkyl)carboxamide, (C₃-C₇cycloalkyl)carboxamide, mono- and di-(C₁-C₆alkyl)sulfonamide, C₁-C₆alkylthio, aryl(C₀-C₄alkyl)thio, C₁-C₆alkylsulfinyl, and C₁-C₆alkylsulfonyl, and

(c) —

GR_a where

G is chosen from —

(CH₂)_n—

, C₂-C₄alkenyl, C₂-C₄alkynyl, —

(CH₂)_nO(CH₂)_m—

, and —

(CH₂)_nN(CH₂)_m—

, where n and m are independently 0, 1, 2, 3, or 4; and

R_a is chosen from C₃-C₈cycloalkyl, C₂-C₇monocyclic heterocycloalkyl, C₅-C₁₀bicyclicheterocycloalkyl, indanyl, tetrahydronapthyl, aryl, and heteroaryl;

each of which (b) and (c) is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, C₁-C₄alkyl, C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, and phenyl.

6. A pharmaceutical composition according to claim 5 in which A₁ is substituted with 0 to 5 substituents independently chosen from

(a) halogen, hydroxy, cyano, amino, nitro, oxo, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, and

(b) C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₄alkoxy(C₁-C₄alkyl), amino(C₁-C₄)alkyl, mono- and di-(C₁-C₄alkyl)amino, and mono- and di-(C₁-C₄alkyl)aminoC₁-C₄alkyl;

and

(c) —

GR_a where

G is from —

(CH₂)_n—

, —

(CH₂)_nO(CH₂)_m—

, and —

(CH₂)_nN(CH₂)_m—

, and

R_a is C₃-C₈cycloalkyl, 5 or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently chosen from O, S, and N, 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently chosen from O, S, and N, indanyl, and phenyl,

each of which (b) and (c) is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, C₁-C₄alkyl, C₁-C₄alkoxy, mono- and di-(C₁-C₂alkyl)amino, and C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

7. A pharmaceutical composition according to claim 6 in which

A₁ is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, oxo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₄alkoxy(C₁-C₄alkyl), amino(C₁-C₄)alkyl, mono- and di-(C₁-C₄alkyl)amino, and mono- and di-(C₁-C₄alkyl)aminoC₁-C₄alkyl.

8. A pharmaceutical composition according to claim 2 comprising compound of the formula

wherein

R₁₈ represents 0 to 3 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, C₁-C₄alkyl, C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, and phenyl.

9. The pharmaceutical composition of claim 1 in which the compound is

1-(3,4-Dichlorophenyl-carbonyl)-3-(3-benzoxy-phenyl)thiourea;

1-(3,4-Dichlorophenyl-carbonyl)-3-(3-phenoxy-phenyl)thiourea;

1-(4-Trifluoromethoxy-phenyl-carbonyl)-3-(3-ethoxybenzyloxy)phenyl)-phenyl)thiourea;

1-(4-Trifluoromethyl-phenyl-carbonyl)-3-(3-ethoxybenzyloxy)phenyl)-phenyl)thiourea;

1-(4-Trifluoromethoxyphenyl-carbonyl)-3-(3-phenyloxy)phenyl)-phenyl)thiourea;

1-(4-Trifluoromethylphenyl-carbonyl)-3-(3-phenyloxy)phenyl)-phenyl)thiourea;

1-(3-((R)-1-Phenylethoxy)phenyl)-3-(4-trifluoromethoxy-phenyl-carbonyl)thiourea;

1-(3-((S)-1-Phenylethoxy)phenyl)-3-(4-trifluoromethylphenyl-carbonyl)-thiourea;

1-(3-((S)-1-Phenylethoxy)phenyl)-3-(4-trifluoromethoxyphenyl-carbonyl)-thiourea;

1-(3-(Phenethyloxy)phenyl)-3-(4-trifluoromethylphenyl-carbonyl)-thiourea;

1-(3-(Phenethyloxy)phenyl)-3-(4-trifluoromethoxyphenyl-carbonyl)-thiourea;

1-(4-Cyanophenyl-carbonyl)-3-(3-(benzyloxy)-phenyl)thiourea;

1-(4-Cyanophenyl-carbonyl)-3-(3-phenoxy-phenyl)thiourea;

1-(3-Trifluoromethyl-phenyl-carbonyl)-3-(3-phenoxy-phenyl)thiourea;

1-(3-Difluoromethyl-phenyl-carbonyl)-3-(3-phenoxy-phenyl)thiourea;

1-(3-Trifluoromethyl-4-methoxy-phenyl-carbonyl)-3-(3-phenoxy-phenyl)thiourea;

1-(3-Trifluoromethyl-4-methyl-phenyl-carbonyl)-3-(3-benzyloxy-phenyl)thiourea; and

1-(3-Trifluoromethyl-4-methyl-phenyl-carbonyl)-3-(3-phenoxy-phenyl)thiourea.

10. A method for treating Hepatitis C infection comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition according to claim 1.

11. A pharmaceutical composition comprising therapeutically effective amount of a compound of the formula

or a pharmaceutically acceptable salt thereof, wherein

R₁ and R₂ are independently hydrogen, methyl, or ethyl;

R₁₈ is 1 to 3 substituents independently chosen from hydroxy, cyano, amino, nitro, C₁-C₄alkyl, C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, and phenyl;

A₂ is a group of the formula

wherein

R₁₁ and R₁₂ each represent 0 to 3 substituents chosen from halogen, hydroxy, cyano, C₁-C₆alkyl, C₁-C₆alkoxy, mono- and di-(C₁-C₆alkyl)amino, C₂-C₆alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, and phenyl; and

R₁₃ and R₁₄ are independently chosen at each occurrence from hydrogen and C₁-C₄alkyl.

12. A method for treating Hepatitis C infection comprising administering to a patient in need of such treatment a therapeutically effective amount of pharmaceutical composition according to claim 11.