Substituted diphenyl heterocycles useful for treating HCV...

Details Substituted diphenyl heterocycles useful for treating HCV... Substituted diphenyl heterocycles useful for treating HCV...

2002-11-01

2004-07-06

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S400000, C514S406000, C548S267600, C548S375100, C548S338100

Reexamination Certificate

active

06759538

ABSTRACT:

2. FIELD OF INVENTION
The present invention relates to substituted diphenyl heterocycles and compositions thereof useful for treating or preventing Hepatitis C virus (HCV) infections. In particular, the present invention relates to substituted diphenyl isoxazole, pyrazole and oxadiazole compounds, compositions comprising the compounds and the use of such compounds and compositions to inhibit HCV replication and/or proliferation as a therapeutic approach towards the treatment and/or prevention of HCV infections in humans and animals.
3. BACKGROUND OF THE INVENTION
Hepatitis C virus (HCV) infection is a global human health problem with approximately 150,000 new reported cases each year in the United States alone. HCV is a single stranded RNA virus, which is the etiological agent identified in most cases of non-A, non-B post-transfusion and post-transplant hepatitis and is a common cause of acute sporadic hepatitis (Choo et al.,
Science
244:359, 1989; Kuo et al.,
Science
244:362, 1989; and Alter et al., in
Current Perspective in Hepatology
, p. 83, 1989). It is estimated that more than 50% of patients infected with HCV become chronically infected and 20% of those develop cirrhosis of the liver within 20 years (Davis et al.,
New Engl. J. Med.
321:1501, 1989; Alter et al., in
Current Perspective in Hepatology
, p. 83, 1989; Alter et al.,
New Engl. J. Med.
327:1899, 1992; and Dienstag
Gastroenterology
85:430, 1983). Moreover, the only therapy available for treatment of HCV infection is interferon-&agr; (INTRON® A, PEG-INTRON® A, Schering-Plough; ROFERON-A®, PEGASys®, Roche). Most patients are unresponsive, however, and among the responders, there is a high recurrence rate within 6-12 months after cessation of treatment (Liang et al.,
J. Med. Virol.
40:69, 1993). Ribavirin, a guanosine analog with broad spectrum activity against many RNA and DNA viruses, has been shown in clinical trials to be effective against chronic HCV infection when used in combination with interferon-&agr; (see, e.g., Poynard et al.,
Lancet
352:1426-1432, 1998; Reichard et al.,
Lancet
351:83-87, 1998), and this combination therapy has been recently approved (REBETRON, Schering-Plough; see also Fried et al., 2002, N. Engl. J. Med. 347:975-982). However, the response rate is still at or below 50%. Therefore, additional compounds for treatment and prevention of HCV infection are needed.
4. SUMMARY OF THE INVENTION
In one aspect, the present invention provides substituted diphenyl heterocycles that are potent inhibitors of Hepatitis C virus (“HCV”) replication and/or proliferation. In one embodiment, the compounds are substituted diphenyl isoxazole, pyrazole and/or oxadiazole compounds according to structural formula (I):
where Z is CH (isoxazoles, or pyrazoles) or N (oxadiazoles) and X and Y are each, independently of one another, O and N, provided that: (i) X and Y are not both O and (ii) when X and Y are each N, then Z is CH. The “A” phenyl ring includes at least one, and in many instances two, substituents positioned ortho to the point of attachment (R
2
and/or R
6
) and optionally from 1 to 4 additional substituents, which may be the same or different. Although the “A” ring may include a single ortho (R
2
or R
6
) substituent, compounds which include two ortho substituents (R
2
and R
6
) are particularly active and useful. It is preferable that at least one of the substituent groups at positions R
2
and/or R
6
provide some steric bulk. For example, it is preferable that the R
2
and/or R
6
substituent be larger than a fluoro group.
The nature of the R
2
and/or R
6
substituents, as well as the optional substituents at positions R
3
, R
4
and R
5
, can vary widely. As a consequence, the “A” phenyl ring may be substituted with virtually any substituent groups, provided that at least one of R
2
or R
6
is other than hydrogen. When the “A” phenyl ring includes more than one substituent, the substituents may be the same or different. Typical substituent groups useful for substituting the “A” ring include, but are not limited to, branched, straight-chain or cyclic alkyls, mono- or polycyclic aryls, branched, straight-chain or cyclic heteroalkyls, mono- or polycyclic heteroaryls, halos, branched, straight-chain or cyclic haloalkyls, hydroxyls, oxos, thioxos, branched, straight-chain or cyclic alkoxys, branched, straight-chain or cyclic haloalkoxys, trifluoromethoxys, mono- or polycyclic aryloxys, mono- or polycyclic heteroaryloxys, ethers, alcohols, sulfides, thioethers, sulfanyls (thiols), imines, azos, azides, amines (primary, secondary and tertiary), nitriles (any isomer), cyanates (any isomer), thiocyanates (any isomer), nitrosos, nitros, diazos, sulfoxides, sulfonyls, sulfonic acids, sulfamides, sulfonamides, sulfamic esters, aldehydes, ketones, carboxylic acids, esters, amides, amidines, formadines, amino acids, acetylenes, carbamates, lactones, lactams, glucosides, gluconurides, sulfones, ketals, acetals, thioketals, oximes, oxamic acids, oxamic esters, etc., and combinations of these groups.
These substituent groups may be further substituted at one or more available carbon or heteroatoms with the same or different additional substituents, which may be selected from the substituents described above. Any reactive functionalities in the groups used to substituted the “A” phenyl ring may be masked with a protecting group or a progroup, as is well-known in the art.
The substituent groups may be attached directly to the phenyl ring, or they may be spaced away from the ring by way of a linker. The nature of the linker can vary widely, and can include virtually any combination of atoms or groups useful for spacing one molecular moiety from another. For example, the linker may be an acyclic hydrocarbon bridge (e.g, a saturated or unsaturated alkyleno such as methano, ethano, etheno, propano, prop[1]eno, butano, but[1]eno, but[2]eno, buta[1,3]dieno, and the like), a monocyclic or polycyclic hydrocarbon bridge (e.g., [1,2]benzeno, [2,3]naphthaleno, and the like), a simple acyclic heteroatomic or heteroalkyldiyl bridge (e.g., —O—, —S—, —S—O—, —NH—, —PH—, —C(O)—, —C(O)NH—, —S(O)—, —S(O)
2
—, —S(O)NH—, —S(O)
2
NH—, —O—CH
2
—, —CH
2
—O—CH
2
—, —O—CH═CH—CH
2
—, and the like), a monocyclic or polycyclic heteroaryl bridge (e.g., [3,4]furano, pyridino, thiopheno, piperidino, piperazino, pyrizidino, pyrrolidino, and the like) or combinations of such bridges. In one embodiment, the “A” ring is substituted at both R
2
and R
6
with the same or different halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, methoxy, haloalkyl, trifluoromethyl, 5-6 membered cycloheteroalkyl or substituted 5-6 membered cycloheteroalkyl group.
The “C” ring is substituted at the meta position with a group of the formula —NR
11
C(O)R
12
, where R
11
is hydrogen or lower alkyl and R
12
is monohalomethyl or dihalomethyl. The “C” ring may optionally include from 1 to 4 additional substituents (R
8
, R
9
, R
10
and/or R
13
), which may be the same or different. As for the “A” phenyl ring, the nature of the optional R
8
, R
9
, R
10
and R
13
substituents can vary broadly. Groups useful for substituting the “C” phenyl ring are the same as those described for the “A” phenyl ring, supra. In one embodiment, the “C” ring does not include optional substituents, such that R
8
, R
9
, R
10
and R
13
are each hydrogen.
As will be recognized by skilled artisans, the actual electron distribution or double bonding pattern of the “B” ring will depend upon the identities of substituents X and Y. As illustrated, structural formula (I) is specifically intended to include at least the following six structures:
In another aspect, the invention provides starting and intermediate compounds useful for synthesizing the compounds of the invention. Representative starting and intermediate compounds useful for synthesizing isoxazole and pyrazole compounds of the invention include compounds 201, 203, 205, 207, 209, 223, 225, 227, 229, 231, 245, 247, 248a, 248b, 249,

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