Substituted cyclic carbonyls and derivatives thereof useful...

Details Substituted cyclic carbonyls and derivatives thereof useful... Substituted cyclic carbonyls and derivatives thereof useful...

1998-07-10

2003-01-07

Coleman, Brenda (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S063000, C514S110000, C514S111000, C514S218000, C514S219000, C514S220000, C514S221000, C540S487000, C540S489000, C540S492000, C540S542000, C540S545000, C540S553000

Reexamination Certificate

active

06503898

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors, to pharmaceutical compositions comprising such compounds, and to methods of using these compounds for treating viral infection.
BACKGROUND OF THE INVENTION
Current treatments for viral diseases usually involve administration of compounds that inhibit viral DNA synthesis. Current treatments for AIDS (Dagani,
Chem. Eng. News
, Nov. 23, 1987 pp. 41-49) involve administration of compounds such as 2′,3′-dideoxycytidine, trisodium phosphonoformate, ammonium 21-tungsto-9-antimoniate, 1-b-D-ribofuranoxyl-1,2,4-triazole-3-carboxamide, 3′-azido-3′-deoxythymidine (AZT), and adriamycin that inhibit viral DNA synthesis; compounds such as AL-721 and polymannoacetate which may prevent HIV from penetrating the host cell; and compounds which treat the opportunistic infections caused by the immunosuppression resulting from HIV infection. None of the current AIDS treatments have proven to be totally effective in treating and/or reversing the disease. In addition, many of the compounds currently used to treat AIDS cause adverse side effects including low platelet count, renal toxicity, and bone marrow cytopenia.
The genomes of retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products. See Wellink,
Arch. Virol
. 98 1 (1988). Retroviral proteases most commonly process the gag precursor into the core proteins, and also process the pol precursor into reverse transcriptase and retroviral protease.
The correct processing of the precursor polyproteins by the retroviral protease is necessary for the assembly of the infectious virions. It has been shown that in vitro mutagenesis that produces protease-defective virus leads to the production of immature core forms which lack infectivity. See Crawford et al.,
J. Virol
. 53 899 (1985); Katoh et al.,
Virology
145 280 (1985). Therefore, retroviral protease inhibition provides an attractive target for antiviral therapy. See Mitsuya,
Nature
325 775 (1987).
Moore, Biochem.
Biophys. Res. Commun
., 159 420 (1989) discloses peptidyl inhibitors of HIV protease. Erickson, European Patent Application No. WO 89/10752 discloses derivatives of peptides which are inhibitors of HIV protease.
U.S. Pat. No. 4,652,552 discloses methyl ketone derivatives of tetrapeptides as inhibitors of viral proteases. U.S. Pat. No. 4,644,055 discloses halomethyl derivatives of peptides as inhibitors of viral proteases. European Patent Application No. WO 87/07836 discloses L-glutamic acid gamma-monohydroxamate as an antiviral agent.
The ability to inhibit a viral protease provides a method for blocking viral replication and therefore a treatment for viral diseases, such as AIDS, that may have fewer side effects, be more efficacious, and be less prone to drug resistance when compared to current treatments.
The present invention concerns novel substituted cyclic carbonyls and derivatives thereof, which compounds are capable of inhibiting viral protease and which compounds are believed to serve as a means of combating viral diseases, such as AIDS. The substituted cyclic carbonyls and derivatives thereof of this invention provide significant improvements over protease inhibitors that are known in the art. A large number of compounds have been reported to be inhibitors of proteases, such as renin, but these have suffered from lack of adequate bioavailability and are thus not useful as therapeutic agents, particularly if oral administration is desired. This poor activity has been ascribed to the relatively high molecular weight of most protease inhibitors, to inadequate solubility properties, and to the presence of a number of peptide bonds, which are vulnerable to cleavage by mammalian proteases in vivo and which generally cause the molecules to be extensively bound in human serum. The substituted cyclic carbonyls and derivatives described herein have a distinct advantage in this regard, in that they do not contain peptide bonds, are of low molecular weight, and can be hydrophilic yet still inhibit the viral protease enzyme.
Additionally, known inhibitors of other non-HIV proteases do not inhibit HIV protease. The structure-activity requirements of such inhibitors differ from those of HIV protease inhibitors. The substituted cyclic carbonyls and derivatives of the invention are particularly useful as inhibitors of HIV protease and similar retroviral proteases.
The compounds of the invention are of low molecular weight and may, therefore, have good oral absorption properties in mammals.
SUMMARY OF THE INVENTION
This invention provides novel substituted cyclic carbonyl compounds and derivatives thereof, of formula (I) (described below) which are useful as inhibitors of Human Immunodeficiency Virus (HIV). The compounds of the present invention inhibit the HIV protease and thereby inhibit HIV replication. The present invention also includes pharmaceutical compositions containing such compounds of formula I, and methods of using such compounds for the inhibition of HIV in a sample containing HIV, and methods of using such compounds for the treatment of HIV infection in a patient.
The present invention also includes methods of inhibiting HIV or treating HIV infection by administering a compound of formula (I) in combination with one or more second therapeutic agents selected from other inhibitors of HIV and/or therapeutic agents for the treatment of HIV-mediated disease conditions.
Also included in the present invention are pharmaceutical kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of formula I, for the treatment of HIV infection.
DETAILED DESCRIPTION OF THE INVENTION
This invention provides novel substituted cyclic carbonyl compounds and derivatives thereof, of formula (I) (described below) which are useful as inhibitors of Human Immunodeficiency Virus (HIV). The compounds of the present invention inhibit the HIV protease and thereby inhibit HIV replication. The present invention also includes pharmaceutical compositions containing such compounds of formula I, and methods of using such compounds for the inhibition of HIV in a sample containing HIV, and methods of using such compounds for the treatment of HIV infection in a patient.
[1] There is provided by this invention a compound of the formula (I):
or a pharmaceutically acceptable salt or prodrug form thereof wherein:
R
4
and R
7
are independently selected from the following groups:
hydrogen;
C
2
-C
8
alkyl substituted with 0-3 R
11
;
C
2
-C
8
alkenyl substituted with 0-3 R
11
;
C
2
-C
8
alkynyl substituted with 0-3 R
11
;
a C
3
-C
14
carbocyclic ring system substituted with
0-3 R
11
or 0-3 R
12
;
a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R
12
;
—OR
13
; —SR
13
; CO
2
R
13
;
R
4A
and R
7A
are independently selected from the following groups:
hydrogen;
C
1
-C
4
alkyl substituted with 0-6 halogen or 0-3 C
1
-C
2
alkoxy;
benzyl substituted with 0-6 halogen or 0-3 C
1
-C
2
alkoxy;
—OR
13
; —SR
13
; CO
2
R
13
;
R
4
and R
4A
can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R
12
;
R
7
and R
7A
can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R
12
;
n is 0, 1, or 2;
R
5
is selected from H; halogen; C
1
-C
6
alkyl substituted with 0-3 R
11
; —N(R
20
)
2
; —SR
20
; or —OR
20
, —N
3
;
R
6
is independently selected from: hydrogen, halogen, C
1
-C
6
alkyl substituted with 0-3 R
11
, —N(R
20
)
2
, —SR
20
, or —OR
21
, —N
3
;
R
5
and R
6
can alternatively join to form an epoxide or aziridine ring; —OCH
2
SCH
2
O—; —OC(═O)O—; —OCH
2
O—; —OC(═S)O—; —OC(═O)C(═O)O—; —OC(CH
3
)
2
O—; —OC((CH
2
)
3
NH
2
)(CH
3
)O—; —OC(OCH
3
)(CH
2
CH
2
CH
3
)O—; —OS(═O)O—; —NHC(═O)NH—;

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