Site News  |   Monitor Keywords  |   Monitor Archive  |   Organizer  |   Account Info  |

Protease inhibitors

Protease inhibitors description/claims

This application is a divisional application of U.S. Utility Application Ser. No. 11/024,929, filed on Dec. 29, 2004, which in turn claims priority to U.S. Provisional Application Ser. No. 60/533,779, filed Dec. 31, 2003. The contents of both applications are hereby incorporated by reference.

Coronavirus is a family of viruses that have the appearance of a corona when viewed under a microscope. Members of the coronavirus family can cause hepatitis in mice, gastroenteritis in pigs, and respiratory infections in birds and humans. Coronavirus was first isolated from chickens in 1937 by Beaudette and Hudson. In 1965, Tyrrell and Bynoe used cultures of human ciliated embryonic trachea to propagate the first human coronavirus in vitro.

Among the more than 30 strains of coronavirus isolated so far, three or four infect humans. For example, the severe acute respiratory syndrome, a newly emerged infectious disease, is associated with a novel coronavirus (Ksiazek et al. New England Journal Medicine, 2003, 348(20): 1953-1966). This life-threatening respiratory disease caused worldwide outbreaks in 2003. Vaccines and drugs against severe acute respiratory syndrome virus are being vigorously sought. Nevertheless, the progress is rather slow due to safety concerns. Thus, there exists a need to develop drags that are effective in treating infections with corona viruses, as well as infections with other viruses.

This invention is based on the unexpected discovery that certain peptide-like compounds are effective in treating viral infections by inhibiting viral proteases (e.g., corona viral 3CL proteases, picornaviral proteases, or hepatitis C viral proteases).

In one aspect, this invention features a method for treating an infection with a virus. The method includes administering to a subject in need thereof an effective amount of a compound of formula (I):

In this formula, X is N(Ra1), O, or CH2; or X and one of R2 and R3, together with the atom or atoms to which they are bonded, are C3-C20 heterocycloalkyl; in which Ra1 is H or C1-C15 alkyl; R1 is H, C1-C15 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, heteroaryl, aryl, C(O)Rb1, CO2Rb1, C(O)NRb1Rb2, C(O)—N(Rb1)—ORb2, C(S)Rb1, C(S)NRb1Rb2, S(O)Rb1, SO2Rb1, S(O)NRb1Rb2, S(O)—N(Rb1)—ORb2, SO2NRb1Rb2, or SO3Rb1; in which each of Rb1 and Rb2, independently, is H, C1-C15 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, heteroaryl, or aryl; each of R2 and R3, independently, is H, C1-C15 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, heteroaryl, aryl, ORc1, SRc1, or NRc1Rc2; or X and one of R2 and R3, together with the atom or atoms to which they are bonded, are C3-C20 heterocycloalkyl; in which each of Rc1 and Rc2, independently, is H, C1-C15 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, heteroaryl, or aryl; each of R4 and R5, independently, is H, halogen, C1-C15 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, heteroaryl, or aryl; one of R6 and R7 is C1-C15 alkyl substituted with C3-C20 heterocycloalkyl, heteroaryl, or aryl; and the other of R6 and R7 is H, C1-C15 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, heteroaryl, or aryl; R8 is H, halogen, C1-C15 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, heteroaryl, aryl, ORd1, or SRd1; in which Rd1 is H and C1-C15 alkyl; and each of R9 and R10, independently, is H, halogen, C1-C15 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, heteroaryl, aryl, C(O)Re1, CO2Re1, C(O)NRe1Re2, C(O)—N(Re1)—ORe2, C(S)Re1, C(S)NRe1Re2, CN, NO2, S(O)Re1, SO2Re1, S(O)NRe1Re2, S(O)—N(Re1)—ORe2, SO2NRe1Re2, SO3Re1, PO(ORe1)(ORe2), PO(Re1)(Re2), PO(NRe1Re2)(ORe3), PO(NRe1Re2)(NRe3Re4), C(O)—N(Re1)—NRe2Re3 or C(S)—N(Re1)—NRe2Re3; or R8 and R10, taken together, is C3-C20 cycloalkyl or C3-C20 heterocycloalkyl; or R9 and R10, taken together, is C3-C20 cycloalkyl or C3-C20 heterocycloalkyl; in which each of Re1, Re2, Re3, and Re4, independently, is H, C1-C15 alkyl, C3-C20 cycloalkyl C3-C20 heterocycloalkyl, heteroaryl, or aryl; or any two of Re1, Re2, Re3, and Re4, together with the atom or atoms to which they are bonded, is C3-C20 heterocycloalkyl; and the virus is a coronavirus or a hepatitis C virus.

In particular, this invention features a method for treating an infection with a severe acute respiratory syndrome virus, a human coronavirus 229E, or a hepatitis C virus, by administering to a subject in need thereof an effective amount of a compound of formula (I) shown above.

For example, one can administer to a subject infected with a virus (e.g., a severe acute respiratory syndrome virus) a compound of formula (I), in which X is N(Ra1) or O; or X and one of R2 and R3, together with the atom or atoms to which they are bonded, are C3-C20 heterocycloalkyl; R1 is H, C(O)Rb1, CO2Rb1, C(O)NRb1Rb2, C(S)NRb1Rb2, or SO2Rb1; each of R2 and R3, independently, is H or C1-C15 alkyl; or X and one of R2 and R3, together with the atom or atoms to which they are bonded, are C3-C20 heterocycloalkyl; each of R4 and R5, independently, is H or C1-C15 alkyl; one of R6 and R7 is C1-C15 alkyl substituted with C3-C20 heterocycloalkyl, and the other of R6 and R7 is H; R8 is H; and each of R9 and R10, independently, is H or CO2Re1. In this compound, one of R6 and R7 can be

one of R2 and R3 can be H or C1-C15 alkyl optionally substituted with halogen, heteroaryl, aryl, ORc1, SRc1, OC(O)Rc1, CO2Rc1, C(O)NRc1Rc2, NRc1Rc2, N(Rc1)—CO2Rc2, N(Rc1)—C(O)Rc2, N(Rc1)—C(O)—NRc2Rc3, N(Rc1)—SO2Rc2, SO2Rc1, or O—SO2—Rc1; or X and one of R2 and R3, together with the atom or atoms to which they are bonded, are C3-C20 heterocycloalkyl; in which Rc3 is H, C1-C15 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, heteroaryl, or aryl; and one of R4 and R5 can be H or C1-C15 alkyl optionally substituted with halogen, aryl, ORf1, SRf1, CO2Rf1, C(O)NRf1Rf2, SO2Rf1, SO3Rf1, or NRf1Rf2; in which each of Rf1 and Rf2, independently, is H, C1-C15 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, heteroaryl, or aryl.

The term “treating” refers to administering one or more compounds of the invention to a subject, who has an infection with a virus, a symptom of such an infection, or a predisposition toward such an infection, with the purpose to confer a therapeutic effect, e.g., to cure, relieve, alter, affect, ameliorate, or prevent the infection with a virus, the symptom of it, or die predisposition toward it. The term “an effective amount” refers to the amount of one or more active compounds of the invention that is required to confer a therapeutic effect on a treated subject.

• Provisional Patent
• Utility Patent

• What Is a Patent?
• What Is a Trademark or Servicemark?
• What Is a Copyright?
• Patent Laws