Succinoylamino hydroxyethylamino sulfonamides useful as...

Details Succinoylamino hydroxyethylamino sulfonamides useful as... Succinoylamino hydroxyethylamino sulfonamides useful as...

2001-06-20

2002-10-22

Gerstl, Robert (Department: 1626)

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

Organic compounds

Amino nitrogen containing

C544S159000, C546S336000, C549S065000, C560S013000, C562S430000, C564S090000

Reexamination Certificate

active

06469207

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 sulfonamide-containing hydroxyethylamine protease inhibitor compounds, a composition and method for inhibiting retroviral proteases such as human immunodeficiency virus (HIV) protease and for treating a retroviral infection, e.g., an HIV 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 may involve a transition-state mimetic whereby the retroviral protease is exposed to a mimetic compound which binds 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 replication proteases can be effectively inhibited.
Several classes of compounds have been proposed, particularly for inhibition of proteases, such as for inhibition of HIV protease. Such compounds include hydroxyethylamine isosteres and reduced amide isosteres. See, for example, EP O 346 847; EP O 342,541; Roberts et al, “Rational Design of Peptide-Based 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).
Several classes of compounds are known to be useful as inhibitors of the proteolytic enzyme renin. See, for example, U.S. Pat. No. 4,599,198; U.K. 2,184,730; G.B. 2,209,752; EP O 264 795; G.B. 2,200,115 and U.S. SIR H725. Of these, G.B. 2,200;115, GB 2,209,752, EP O 264,795, U.S. SIR H725 and U.S. Pat. No. 4,599,198 disclose urea-containing hydroxyethylamine renin inhibitors. G.B. 2,200,115 also disclose certain sulfamoyl-containing hydroxyethylamine renin inhibitors. EP O 264 795 also discloses certain sulfonamide-containing renin inhibitor compounds. 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.
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 succinoylamino hydroxyethylamino sulfonamide inhibitor compounds.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there is provided a retroviral protease inhibiting compound of the formula:
or a pharmaceutically acceptable salt, prodrug or ester thereof wherein:
x represents 0, 1 or 2;
t represents either 0 or 1;
R
1
represents hydrogen, —CH
2
SO
2
NH
2
, —CO
2
CH
3
, —CONHCH
3
, —CON(CH
3
)
2
, —CH
2
C(O)NHCH
3
, —CH
2
C(O)N(CH
3
)
2
, —CONH
2
, —C(CH3)
2
(SH)—C(CH
3
)
2
(SCH
3
), —C(CH
3
)
2
(S[O]CH
3
), —C(CH
3
)
2
(S[O]
2
CH
3
), alkyl, haloalkyl, alkenyl, alkynyl and cycloalkyl radicals and amino acid side chains selected from asparagine, S-methyl cysteine and the corresponding sulfoxide and sulfone derivatives thereof, glycine, leucine, isoleucine, allo-isoleucine, tert-leucine, phenylalanine, ornithine, alanine, histidine, norleucine, glutamine, valine, threonine, serine, o-alkyl serine, aspartic acid, beta-cyano alanine, and allothreonine side chains;
R
2
represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl radicals, which radicals are optionally substituted with a group selected from alkyl and halogen radicals, and —NO
2
, —C≡N, CF
3
, —OR
9
, —SR
9
wherein R
9
represents hydrogen and alkyl radicals;
R
3
represents hydrogen, 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;
X′ represents N, O and C(R
17
) where R
17
represents hydrogen and alkyl radicals;
Y and Y′ independently represent O,S and NR
15
wherein R
15
represents hydrogen and radicals as defined for R
3
;
R
4
represents radicals as defined by R
3
except for hydrogen;
R
6
represents hydrogen and alkyl radicals as defined for R
3
;
R
30
, R
31
and R
32
represent radicals as defined for R
1
, or one of R
1
and R
30
together with one of R
31
and R
32
and the carbon atoms to which they are attached form a cycloalkyl radical; and
R
33
and R
34
independently represent hydrogen, radicals as defined for R
3
or R
33
and R
34
together with X′ represent cycloalkyl, aryl, heterocyclyl and heteroaryl radicals, provided that when X′ is O; R
34
is absent.
A preferred class of retroviral inhibitor compounds of the present invention are those represented by the formula:
or a pharmaceutically acceptable salt, prodrug or ester thereof, preferably wherein the absolute stereochemistry about the hydroxy group is designated as (R);
R
1
represents hydrogen, —CH
2
SO
2
NH
2
, —CO
2
CH
3
, —CONHCH
3
, —CON(CH
3
)
2
, —CH
2
C(O)NHCH
3
, —CH
2
C(O)N(CH
3
)
2
, —CONH
2
, —C(CH
3
)
2
(SCH
3
), —C(CH
3
)
2
(S[O]CH
3
), —C(CH
3
)
2
(S[O]
2
CH
3
), alkyl, haloalkyl, alkenyl, alkynyl and cycloalkyl radicals and amino acid side chains selected from asparagine, S-methyl cysteine and the corresponding sulfoxide and sulfone derivatives thereof, glycine, leucine, isoleucine, allo-isoleucine, tert-leucine, phenylalanine, ornithine, alanine, histidine, norleucine, glutamine, valine, threonine, serine, aspartic acid, beta-cyano alanine, and allothreonine side chains;
R
2
represents alkyl, aryl, cycloalkyl, cycloalkylalkyl, and aralkyl radicals, which radicals are optionally substituted with a group selected from alkyl and halogen radicals, NO
2
, —C≡N, CF
3
, OR
9
and SR
9
wherein R
9
represents hydrogen and alkyl radicals;
R
3
represents hydrogen, 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 r

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