Cyclic sulfone containing retroviral protease inhibitors

Details Cyclic sulfone containing retroviral protease inhibitors Cyclic sulfone containing retroviral protease inhibitors

1998-10-22

2001-07-24

Seaman, D. Margaret (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C544S003000, C544S053000, C544S055000, C544S056000, C544S059000, C549S009000, C549S013000, C549S028000, C549S059000, C549S072000

Reexamination Certificate

active

06265583

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to retroviral protease inhibitors and, more particularly relates to novel compounds and a composition and method for inhibiting retroviral proteases. This invention, in particular, relates to cyclic sulfone moiety-containing hydroxyethylamine protease inhibitor compounds, a composition and method for inhibiting retroviral proteases such as human immunodeficiency virus infection. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
2. Related Art
During the replication cycle of retroviruses, gag and gag-pol gene products are translated as proteins. These proteins are subsequently processed by a virally encoded protease (or proteinase) to yield viral enzymes and structural proteins of the virus core. Most commonly, the gag precursor proteins are processed into the core proteins and the pol precursor proteins are processed into the viral enzymes, e.g., reverse transcriptase and retroviral protease. It has been shown that correct processing of the precursor proteins by the retroviral protease is necessary for assembly of infectious virons. For example, it has been shown that frameshift mutations in the protease region of the pol gene of HIV prevents processing of the gag precursor protein. It has also been shown through site-directed mutagenesis of an aspartic acid residue in the HIV protease that processing of the gag precursor protein is prevented. Thus, attempts have been made to inhibit viral replication by inhibiting the action of retroviral proteases.
Retroviral protease inhibition typically involves a transition-state mimetic whereby the retroviral protease is exposed to a mimetic compound which binds (typically in a reversible manner) to the enzyme in competition with the gag and gag-pol proteins to thereby inhibit replication of structural proteins and, more importantly, the retroviral protease itself. In this manner, retroviral proteases can be effectively inhibited.
Several classes of mimetic compounds are known to be useful as inhibitors of the proteolytic enzyme renin. See, for example, U.S. Pat. No. 4,599,198; G.B. 2,184,730; G.B. 2,209,752; EPO 264 795; G.B. 2,200,115 and U.S. SIR H725; and U.S. Pat. No. 4,599,198 disclose urea-containing hydroxyethylamine renin inhibitors. However, it is known that, although renin and HIV proteases are both classified as aspartyl proteases, compounds which are effective renin inhibitors generally cannot be predicted to be effective HIV protease inhibitors.
Several classes of mimetic compounds have been proposed, particularly for inhibition of proteases, such as for inhibition of HIV protease. Such mimetics include hydroxyethylamine isoteres and reduced amide isosteres. See, for example, EPO 346 847; EPO 342,541; Roberts et al, “Rational Design of Peptide-Bases Proteinase Inhibitors”, Science, 248, 358 (1990); and Erickson et al, “Design Activity, and 2.8 Å Crystal Structure of a C
2
Symmetric Inhibitor Complexed to HIV-1 Protease”, Science, 249, 527 (1990). EPO 346 847 discloses certain N-heterocyclic moiety-containing hydroxyethylamine protease inhibitor compounds, but does not suggest or disclose those of the present invention.
Dipeptide isosteres as inhibitors of HIV protease are found in EP application numbers 91309292, 91309028.8 and 91309302.7.
BRIEF DESCRIPTION OF THE INVENTION
The present invention is directed to virus inhibiting compounds and compositions. More particularly, the present invention is directed to retroviral protease inhibiting compounds and compositions, to a method of inhibiting retroviral proteases, to processes for preparing the compounds and to intermediates useful in such processes. The subject compounds are characterized as cyclic sulfone- and either urea- or N-heterocyclic moiety-containing hydroxyethylamine inhibitor compounds.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there are provided novel retroviral protease inhibiting compounds or a pharmaceutically acceptable salt, prodrug or ester thereof.
Generally, the present invention is a compound of the formula (I″)
and a pharmaceutically acceptable salt, prodrug or ester thereof; wherein Q, R
2
and R
6
are as defined below and
W represents
wherein Y′ is as defined below; and
t represents 0,1 and 2, preferably 1;
t′ represents 1 and 2, preferably 1;
u represents 0, 1 and 2;
R
40
, R
41
, R
42
, R
43
, R
48
, R
49
, R
50
and R
51
independently represent hydrogen and alkyl;
R
44
, R
45
, R
46
, R
47
and independently represent hydrogen, alkyl and hydroxy; or
one of (a) R
40
together with R
48
, (b) R
43
together with R
45
, (c) R
45
together with R
47
, and (d) R
47
together with R
48
represent a bond; or
one of (a) R
44
together with R
45
, (b) R
46
together with R
47
or (c) R
50
together with R
51
represent a double bond oxygen.
R
40
through R
48
most preferably represent hydrogen, however, both R
46
and R
47
also preferably represent methyl at the same time R
40
through R
45
and R
48
are all hydrogen. Additionally, R
48
is preferably hydrogen and the stereo configuration of the carbon to which R
48
is attached is preferably in the configuration represented by the upper spot in Example 4 set forth hereinafter, and preferably wherein the stereochemistry about the hydroxy group may be designated as (R).
Thus, the present invention compound is preferably of the formula (I′)
or a pharmaceutically acceptable salt, prodrug or ester thereof; and wherein Q is:
and wherein t, Y′, R
6
, R
2
, Y, R
3
, X, R
4
, R
5
, R
4′
and R
5′
are as defined below, q represents 1 or 2;
R
4″
, R
9
and R
9′
independently represent radicals as defined by R
3
;
n represents 0 to 6;
R
7
and R
7′
independently represent radicals as defined for R
3
and amino acid side chains selected from the group consisting of valine, isoleucine, glycine, alanine, alloisoleucine, asparagine, leucine, glutamine, and t-butylglycine or R
7
and R
7′
together with the carbon atom to which they are attached form a cycloalkyl radical;
R
8
represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, aralkyl, heterocycloalkyl and heteroaryl radicals and radicals represented by the formulas C(O)R
16
, CO
2
R
16
, SO
2
R
16
, SR
16
, CONR
16
R
17
, CF
3
and NR
16
R
17
;
wherein R
16
and R
17
independently represent hydrogen and radicals as defined for R
3
, or R
16
and R
17
together with a nitrogen to which they are attached in the formula NR
16
R
17
represent heterocycloalkyl and heteroaryl radicals.
A more preferred class of retroviral inhibitor compounds of the present invention are those represented by the formula (I)
or a pharmaceutically acceptable salt, prodrug or ester thereof, and wherein:
t represents either 0, 1 or 2;
R
2
represents alkyl, aryl, cycloalkyl, cycloalkylalkyl, and aralkyl radicals, which radicals are optionally substituted with a substituent selected from the group consisting of alkyl and halogen radicals, —NO
2
, —CN, —CF
3
, —OR
9
, —SR
9
, wherein R
9
represents hydrogen and alkyl radicals;
R
3
represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkyl radicals, wherein said substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case of a disubstituted aminoalkyl radical, said substituents along with the nitrogen atom to which they are attached, form a heterocycloalkyl or a heteroaryl radical, thioalkyl, alkylthioalkyl, and arylthioalkyl radicals and the sulfone or sulfoxide derivatives thereof;
Y and Y′ independently represent O, S and NR
15
wherein R
15
represents hydrogen and radicals as defined for R
3
;
X represents N, CH or O;
R
4
and R
5
independently represent h

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