Anti-viral compounds

Details Anti-viral compounds Anti-viral compounds

2000-12-04

2002-03-19

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S121000

Reexamination Certificate

active

06358971

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to anti-viral compounds and their use in the fields of pharmaceutical and medicinal chemistry.
BACKGROUND OF THE INVENTION
The incidence of viral upper respiratory disease, the common cold, is immense. It has been estimated that nearly a billion cases annually appear in the United States alone. Rhinovirus, a member of the picornaviridae family, is the major cause of the common cold in humans. Since more than 110 strains of rhinovirus have been identified, the development of a comprehensive rhinovirus vaccine is not practical. Accordingly, chemotherapy appears to be a more desirable approach. Another member of the picornavirus family is the enterovirus, which includes approximately eighty human pathogens. Many of these enteroviruses cause cold-like symptoms; others can cause more serious diseases such as polio, conjunctivitis, aseptic meningitis and myocarditis.
Illness related to rhinovirus infection is evidenced by nasal discharge and obstruction. Furthermore, it has been implicated in otitis media, predisposes the development of bronchitis, exacerbates sinusitis, and has been implicated in the precipitation of asthmatic disease. Although it is considered by many to be a mere nuisance, its frequent occurrence in otherwise healthy individuals and the resulting economic importance has made rhinovirus infection the subject of extensive investigation.
The ability of chemical compounds to suppress the growth of viruses in vitro may be readily demonstrated using a virus plaque suppression test or a cytopathic effect test (CPE). Cf Siminoff, Applied Microbiology, 9(1), 66 (1961). Although a number of chemical compounds that inhibit picornaviruses have been identified, many are unacceptable due to 1) limited spectrum of activity, 2) undesirable side effects or 3) inability to prevent infection or illness in animals or humans. See
Textbook of Human Virology
, edited by Robert B. Belshe, chapter 16, “Rhinoviruses,” Roland A. Levandowski, 391-405 (1985). Thus, despite the recognized therapeutic potential associated with a rhinovirus inhibitor and the research efforts expended thus far, a viable therapeutic agent has not yet emerged. For example, antiviral benzimidazole compounds have been disclosed in U.S. Pat. Nos. 4,008,243, 4,018,790, 4,118,573, 4,118,742 and 4,174,454.
Accordingly, the present invention provides novel pyridoimidazole compounds which inhibit the growth of picornaviruses, such as rhinoviruses (bovine and human) and the like; enteroviruses, such as polioviruses and the like; coxsackieviruses of the A and B groups, or echo virus; cardioviruses, such as encephalomyocarditis virus (EMC) and the like; apthoviruses, such as foot and mouth disease virus and the like; and Hepatitis viruses, such as Hepatitis C virus, and the like.
SUMMARY OF THE INVENTION
The present invention provides compounds of Formula (I):
wherein:
A is phenyl, pyridyl, substituted phenyl, substituted pyridyl, or benzyl;
R is hydrogen, COR
4
, or COCF
3
;
X is N—OH, O, or CHR
1
;
R
1
is hydrogen, halo, CN, C
1
-C
4
alkyl, —C≡CH, CO(C
1
-C
4
alkyl), CO
2
(C
1
-C
4
alkyl), or CONR
2
R
3
;
R
2
and R
3
are independently hydrogen or C
1
-C
4
alkyl;
A′ is hydrogen, halo, C
1
-C
6
alkyl, benzyl, naphthyl, thienyl, furyl, pyridyl, pyrrolyl, COR
4
, S(O)
n
R
4
, or a group of the formula
R
4
is C
1
-C
6
alkyl, phenyl, or substituted phenyl;
n is 0, 1, or 2;
R
5
is independently at each occurance hydrogen or halo;
m is 1, 2, 3, or 4; and
R
6
is hydrogen, halo, CF
3
, OH, CO
2
H, NH
2
, NO
2
, CONHOCH
3
, C
1
-C
4
alkyl, or CO
2
(C
1
-C
4
alkyl), C
1
-C
4
alkoxy;
or pharmaceutically acceptable salts thereof.
The present invention also provides pharmaceutical formulations comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, diluent or excipient thereof.
The present invention also provides a method for inhibiting a picornavirus comprising administering to a host in need thereof, an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
The present invention also provides a method for inhibiting a Hepatitis C virus comprising administering to a host in need thereof, an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
The present invention also provides for the use of compounds of Formula (I) for inhibiting a picornavirus, a rhinovirus, or a Hepatitis virus.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds of formula (I), as described above, that are useful as antiviral agents.
All temperatures stated herein are in degrees Celsius (° C.). All units of measurement employed herein are in weight units except for liquids which are in volume units.
The term “C
1
-C
6
alkyl”, as used herein, represents a straight or branched alkyl chain having from one to six carbon atoms. Typical C
1
-C
6
alkyl groups include, but are not intended to be limited to; methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl, and the like. The term “C
1
-C
6
alkyl” includes within its definition the term “C
1
-C
4
alkyl”, and includes within its definition cycloalkyl groups wherein the alkylgroup is formed into a ring.
The term “halo” represents chloro, fluoro, bromo, or iodo.
The term “substituted phenyl”, when used herein, represents a phenyl ring substituted with 1, 2 or 3 substituents independently selected from the group consisting of; halo, C
1
-C
4
alkyl, C
1
-C
6
alkoxy, or trifluoromethyl.
The term “substituted pyridyl”, when used herein, represents a pyridyl ring substituted with 1, 2 or 3 substituents independently selected from the group consisting of; halo, C
1
-C
4
alkyl, C
1
-C
6
alkoxy, or trifluoromethyl.
As mentioned above, the invention includes the pharmaceutically acceptable salts of the compounds defined by Formula (I). Although generally neutral, a compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic bases, and inorganic acids and organic acids, to form a pharmaceutically acceptable salt.
The term “pharmaceutically acceptable salt” as used herein, refers to salts of the compounds of formula I which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base. Such salts are known as acid addition and base addition salts.
Acids commonly employed to form acid addition salts include, but are not intended to be limited to, inorganic acids such as; hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like; and organic acids such as; p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
Examples of such pharmaceutically acceptable salts include, but are not intended to be limited to; sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, &ggr;-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate, and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those forme

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