Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-21
2003-11-04
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S362000, C544S376000, C544S364000, C544S295000, C514S253040, C514S253110, C514S253010, C514S252010
Reexamination Certificate
active
06642237
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to &ggr;-hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamide compounds, their pharmaceutically acceptable salts, their synthesis, and their use as inhibitors of HIV protease. The compounds of the present invention are useful for preventing or treating infection by HIV and for treating AIDS.
References are made throughout this application to various publications in order to more fully describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference in their entireties for all purposes.
BACKGROUND OF THE INVENTION
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl et al.,
Proc. Nat'l Acad. Sci.
1988, 85: 4686, demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicated that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner et al.,
Nature
1985, 313: 277]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh et al.,
EMBO J.
1985, 4: 1267; Power et al.,
Science
1986, 231: 1567; Pearl et al.,
Nature
1987, 329: 351].
Several HIV protease inhibitors are presently in clinical use for the treatment of AIDS and HIV infection, including indinavir (see U.S. Pat. No. 5,413,999), nelfinavir (U.S. Pat. No 5,484,926), saquinavir (U.S. Pat. No. 5,196,438), and ritonavir (U.S. Pat. No. 5,484,801). Each of these protease inhibitors is a peptidomimetic, competitive inhibitor of the viral protease which prevents cleavage of the HIV gag-pol polyprotein precursor. Indinavir, for example, has been found to be highly effective in reducing HIV viral loads and increasing CD4 cell counts in HIV-infected patients, when used in combination with nucleoside reverse transcriptase inhibitors. See, for example, Hammer et al.,
New England J. Med.
1997, 337: 725-733 and Gulick et al.,
New England J. Med.
1997, 337: 734-739.
A substantial and persistent problem in the treatment of AIDS has been the ability of the HIV virus to develop resistance to the therapeutic agents employed to treat the disease. Resistance to HIV-1 protease inhibitors has been associated with 25 or more amino acid substitutions in both the protease and the cleavage sites. Many of these viral variants are resistant to all of the HIV protease inhibitors currently in clinical use. See Condra et al.,
Drug Resistance Updates
1998, 1: 1-7; Condra et al.,
Nature
1995, 374: 569-571; Condra et al.,
J. Virol.
1996, 70: 8270-8276; Patrick et al.,
Antiviral Ther.
1996, Suppl. 1: 17-18; and Tisdale et al.,
Antimicrob. Agents Chemother.
1995, 39: 1704-1710.
Attempts to address the resistance issue with “salvage therapy” consisting of high doses of multiple protease inhibitors have only been moderately successful due to the high level of cross resistance and toxicities associated with these protease inhibitors. Accordingly, there remains a need for new protease inhibitors having improved effectiveness against the viral variants.
The present invention is directed to novel protease inhibitors which are much more potent against HIV viral mutants than the known protease inhibitors.
SUMMARY OF THE INVENTION
The present invention provides a novel group of &ggr;-hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamide compounds which are potent inhibitors of HIV protease including mutant forms thereof that are resistant to known protease inhibitors. These compounds are useful in the inhibition of HIV protease, the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS and/or ARC, when employed as compounds or pharmaceutically acceptable salts or hydrates (when appropriate) thereof, optionally as pharmaceutical composition ingredients, and optionally in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. More particularly, the present invention includes a compound of Formula (I):
wherein
R
1
is C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
3
-C
6
cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; wherein
(i) each of the substituents on substituted aryl is independently
(a) halogen,
(b) cyano,
(c) hydroxy,
(d) C
1
-C
6
alkyl,
(e) C
2
-C
6
alkenyl,
(f) C
2
-C
6
alkynyl,
(g) fluorinated C
1
-C
6
alkyl,
(h) C
1
-C
6
alkoxy,
(i) fluorinated C
1
-C
6
alkoxy,
(j) S—(C
1
-C
6
alkyl),
(k) heterocycle, or
(l) heterocycle substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, fluorinated C
1
-C
6
alkyl, C
1
-C
6
alkoxy, fluorinated C
1
-C
6
alkoxy, S—(C
1
-C
6
alkyl), and NR
a
R
b
;
(ii) each of the substituents on substituted heteroaryl is independently
(a) halogen,
(b) cyano,
(c) hydroxy,
(d) NR
a
R
b
,
(e) C
1
-C
6
alkyl,
(f) C
2
-C
6
alkenyl,
(g) C
2
-C
6
alkynyl,
(h) fluorinated C
1
-C
6
alkyl,
(i) C
1
-C
6
alkoxy,
(j) fluorinated C
1
-C
6
alkoxy,
(k) S—(C
1
-C
6
alkyl),
(l) phenyl,
(m) phenyl substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, fluorinated C
1
-C
6
alkyl, C
1
-C
6
alkoxy, fluorinated C
1
-C
6
alkoxy, and S—(C
1
-C
6
alkyl),
(l) heterocycle, or
(m) heterocycle substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, fluorinated C
1
-C
6
alkyl, C
1
-C
6
alkoxy, fluorinated C
1
-C
6
alkoxy, S—(C
1
-C
6
alkyl), NR
a
R
b
, and a 5AAAAAAA- or 6-membered heteroaromatic ring consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, O and S;
R
2
and R
3
are each independently hydrogen or C
1
-C
4
alkyl; or R
2
and R
3
together with the carbon to which they are attached form C
3
-C
6
cycloalkyl;
R
4
is C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; wherein each of the substituents on substituted aryl is independently halogen, hydroxy, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, fluorinated C
1
-C
6
alkyl, C
1
-C
6
alkoxy, or heteroaryl; and each of the substituents on substituted heteroaryl is independently halogen, hydroxy, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, fluorinated C
1
-C
6
alkyl, C
1
-C
6
alkoxy, or aryl;
R
5
is carbocyclic, substituted carbocyclic, heterocyclic or substituted heterocyclic, wherein each of the substituents on substituted carbocyclic or substituted heterocyclic is independently halogen, hydroxy, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, fluorinated C
1
-C
6
alkyl, or C
1
-C
6
alkoxy;
R
6
is fluorinated C
1
-C
6
alkyl; and
R
a
and R
b
are each independently hydrogen or C
1
-C
4
alkyl; or R
a
and R
b
together with the nitrogen to which they are attached form C
3
-C
6
azacycloalkyl;
or a pharmaceutically acceptable salt thereof.
The present invention also includes pharmaceutical compositions containing a compound of the present invention and methods of preparing such pharmaceutical compositions. The present invention further includes methods
Armstrong, III Joseph D.
Askin David
Chapman Kevin T.
Cheng Yuan
Duffy Joseph Leslie
Camara Valerie J.
Liu Hong
Merck & Co. , Inc.
Raymond Richard L.
Walton Kenneth R.
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