Anti-viral compound

• US 5,891,874 A
• Filed: 06/04/1997
• Issued: 04/06/1999
• Est. Priority Date: 06/05/1996
• Status: Expired due to Fees

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Victor, Frantz, Miller, Shawn Christopher, Spitzer, Wayne Alfred, Tang, Joseph Chiou-chung, Heinz, Beverly Ann, Jungheim, Louis Nickolaus, Tebbe, Mark Joseph, Colacino, Joseph Matthew
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Kifle, Bruck
• Application Number:
  US08/868,760
• Time in Patent Office: 671 Days
• Field of Search: 548/306.1, 548/307.4, 548/310.1, 548/181, 546/199, 544/139, 544/55, 514/394, 514/322, 514/234.5, 514/226.8, 514/369, 514/370
• US Class Current: 514/234.5
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07D 235/30 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links

Abstract

A series of benzimidazole compounds having the following general structure are provided which inhibit the growth of picornaviruses (e.g., rhinoviruses, enteroviruses, polioviruses, coxsackieviruses of the A and B groups, echo virus and Mengo virus) and flaviviruses (e.g., hepatitis C and bovine diarrheal virus). ##STR1## A method for inhibiting picornaviruses and flaviviruses is also provided which includes administering to a host an effective amount of the inventive benzimidazole compounds.

Claims

1. A compound of the formula I ##STR35## wherein:

a is 1, 2 or 3;

each R is independently halo, cyano, amino, halo(C₁ -C₄)alkyl, di(C₁ -C₄)alkylamino, azido, C₁ -C₆ alkyl, carbamoyl, carbamoyloxy, carbamoylamino, C₁ -C₄ alkoxy, C₁ -C₄ alkylthio, C₁ -C₄ alkylsulfinyl, C₁ -C₄ alkylsulfonyl, pyrrolidino, piperidino or morpholino;

R⁰ is hydrogen, halo, C₁ -C₄ alkyl or C₁ -C₄ alkoxy;

R¹ is halo, cyano, hydroxy, methyl, ethyl, methoxy, ethoxy, methylthio, methylsulfinyl or methylsulfonyl;

R² is hydrogen, amino or --NHC(O) (C₁ -C₆ alkyl);

R³ is dimethylamino, C₁ -C₁₀ alkyl, halo(C₁ -C₆)alkyl, C₃ -C₇ cycloalkyl, substituted C₃ -C₇ cycloalkyl, phenyl, substituted phenyl, naphthyl, thienyl, thiazolidinyl, furyl, pyrrolidino, piperidino, morpholino or a group of the formula;

##STR36## R⁴ and R⁵ are independently hydrogen or C₁ -C₄ alkyl;

with the proviso that when R is in the 2- or 6-position, then R cannot be halo, cyano, methyl, ethyl, methoxy, ethoxy, methylthio, methylsulfinyl or methylsulfonyl;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 where:

##STR37## where;

a is 1 or 2;

each R is independently halo, C₁ -C₄ alkyl, C₁ -C₄ alkoxy or di(C₁ -C₄)alkylamino;

R⁰ is hydrogen;

R² is amino;

R³ is dimethylamino, C₁ -C₆ alkyl, halo(C₁ -C₆)alkyl, C₃ -C₇ cycloalkyl, substituted C₃ -C₇ cycloalkyl, thienyl, thiazolidinyl, pyrrolidino, piperidino or morpholino;

R⁴ is hydrogen, methyl or ethyl;

R⁵ is hydrogen, methyl or ethyl;

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 2 where:

a is or 1;

each R is independently fluoro, methyl, ethyl, methoxy, ethoxy, dimethylamino;

R⁰ is hydrogen;

R³ is dimethylamino, C₁ -C₄ alkyl, C₃ -C₇ cycloalkyl or pyrrolidino;

or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 3 which is:

##STR38## or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical formulations comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, diluent or excipient therefor.

6. A pharmaceutical formulation according to claim 5 where the compound is one where:

##STR39## where;

a is 1 or 2;

each R is independently halo, C₁ -C₄ alkyl, C₁ -C₄ alkoxy or di(C₁ -C₄)alkylamino;

R⁰ is hydrogen;

R² is amino;

R³ is dimethylamino, C₁ -C₆ alkyl, halo(C₁ -C₆)alkyl, C₃ -C₇ cycloalkyl, substituted C₃ -C₇ cycloalkyl, thienyl, thiazolidinyl, pyrrolidino, piperidino or morpholino;

R⁴ is hydrogen, methyl or ethyl;

R⁵ is hydrogen, methyl or ethyl;

or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical formulation according to claim 6 where the compound is one where:

a is or 1;

each R is independently fluoro, methyl, ethyl, methoxy, ethoxy, dimethylamino;

R⁰ is hydrogen;

R³ is dimethylamino, C₁ -C₄ alkyl, C₃ -C₇ cycloalkyl or pyrrolidino;

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical formulation according to claim 7 where the compound is:

##STR40## or a pharmaceutically acceptable salt thereof.

9. A method for inhibiting a rhinovirus or enterovirus comprising administering to a host in need thereof, an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

10. A method according to claim 9 where the compound is one where:

##STR41## where;

a is 1 or 2;

each R is independently halo, C₁ -C₄ alkyl, C₁ -C₄ alkoxy or di(C₁ -C₄)alkylamino;

R⁰ is hydrogen;

R² is amino;

R³ is dimethylamino, C₁ -C₆ alkyl, halo(C₁ -C₆)alkyl, C₃ -C₇ cycloalkyl, substituted C₃ -C₇ cycloalkyl, thienyl, thiazolidinyl, pyrrolidino, piperidino or morpholino;

R⁴ is hydrogen, methyl or ethyl;

R⁵ is hydrogen, methyl or ethyl;

or a pharmaceutically acceptable salt thereof.

11. A method according to claim 10 where the compound is one where:

a is or 1;

each R is independently fluoro, methyl, ethyl, methoxy, ethoxy, dimethylamino;

R⁰ is hydrogen;

R³ is dimethylamino, C₁ -C₄ alkyl, C₃ -C₇ cycloalkyl or pyrrolidino;

or a pharmaceutically acceptable salt thereof.

12. A method according to claim 11 where the compound is:

##STR42## or a pharmaceutically acceptable salt thereof.