Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-01
2001-04-03
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252120, C514S311000, C514S357000, C514S428000, C514S542000, C514S603000, C514S564000, C514S604000, C544S160000, C544S400000, C546S164000, C546S265000, C548S556000, C548S567000, C560S013000, C562S430000, C564S085000
Reexamination Certificate
active
06211176
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 sulfonyl urea derivatives of 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 2.8Å 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 0 264,795, U.S. SIR H725 and U.S. Pat. No. 4,599,198 disclose urea-containing hydroxyethylamine renin inhibitors. G.B. 2,200,115 also discloses sulfamic acid-containing hydroxyethylamine renin inhibitors, and EP 0264 795 discloses certain sulfamic acid-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.
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 derivatives of hydroxyethylamino sulfonyl urea 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:
R represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, alkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl, heteroaroyl, hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono- and disubstituted aminoalkanoyl radicals wherein the substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkyalkyl radicals, or wherein said aminocarbonyl and aminoalkanoyl radicals are disubstituted, said substituents along with the nitrogen atom to which they are attached form a heterocycloalkyl or heteroaryl radical;
R′ represents hydrogen, radicals as defined for R
3
or R″SO
2
— wherein R″ represents radicals as defined for R
3
;
or R and R′ together with the nitrogen to which they are attached represent heterocycloalkyl and heteroaryl radicals;
R
1
represents hydrogen, —CH
2
SO
2
NH
2
, —CH
2
CO
2
CH
3
, —CO
2
CH
3
, —CONH
2
, —CH
2
C(O)NHCH
3
, —C(CH
3
)
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 methionine and the sulfoxide (SO) and sulfone (SO
2
) derivatives thereof, isoleucine, allo-isoleucine, alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine, norleucine, glutamine, threonine, glycine, allo-threonine, serine, O-alkyl serine, aspartic acid, beta-cyanoalanine and valine side chains;
R
1
′ and R
1
″ independently represent hydrogen and radicals as defined for R
1
or one of R
1
′ and R
1
″, together with R
1
and the carbon atoms to which R
1
, R
1
′ and R
1
″ are attached, represent a cycloalkyl radical;
R
2
represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl radicals, which radicals are optionally substituted with a group selected from alkyl and halogen radials, —NO
2
, —CN, —CF
3
, —OR
9
and —SR
9
, wherein R
9
represents hydrogen and alkyl radicals, and halogen 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, and thioalkyl, alkylthioalkyl and arylthioalkyl radicals or the sulfone or sulfoxide derivatives thereof;
R
4
represents hydrogen and radicals as defined by R
3
;
R
6
represents hydrogen and alkyl radicals;
R
7
and R
7
′ independently represent hydrogen and radicals as defined for R
3
; amino acid side chains selected from the group consisting of valine, isoleucine, glycine, alanine, allo-isoleucine, asparagine, leucine, glutamine, and t-butylglycine; 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
; 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, aralkyll 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
;
whe
DeCrescenzo Gary A.
Getman Daniel P.
Mueller Richard A.
Sun Eric T.
Talley John J.
Banner & Witcoff , Ltd.
G. D. Searle & Co.
Higel Floyd D.
Sackey Ebenezer
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