Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-18
2002-10-01
Solola, T. A. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S233800, C514S321000, C514S322000, C514S324000, C544S062000, C544S129000, C546S197000, C546S198000, C546S199000
Reexamination Certificate
active
06458785
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to retroviral protease inhibitors and, more particularly, relates to novel compounds, composition and method for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease. This invention, in particular, relates to amino acid hydroxyethylamine sulfonamide protease inhibitor compounds, composition and method for inhibiting retroviral proteases, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of 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.
During the replication cycle of retroviruses, gag and gag-pol gene transcription 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 poi 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 active site 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 specific processing of structural proteins and the release of 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). U.S. Pat. No. 5,157,041, WO 94/04491, WO 94/04492, WO 94/04493, WO 94/05639, WO 92/08701 and U.S. patent application Ser. No. 08/294,468, filed Aug. 23, 1994, (each of which is incorporated herein by reference in its entirety) for example describe hydroxyethylamine, hydroxyethylurea or hydroxyethyl sulfonamide isostere containing retroviral protease inhibitors.
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. EP 468 641 discloses renin inhibitors and intermediates for the preparation of the inhibitors, which include sulfonamide-containing hydroxyethylamine compounds, such as 3-(t-butoxycarbonyl)amino-cyclohexyl-1-(phenylsulfonyl) amino-2(5)-butanol. G.B. 2,200,115 also discloses sulfamoyl-containing hydroxyethylamine renin inhibitors, and EP 0264 795 discloses certain sulfonamide-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 are not predictive for effective HIV protease inhibition.
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to selected retroviral protease inhibitor compounds, analogs and pharmaceutically acceptable salts, esters and prodrugs thereof. The subject compounds are characterized as amino acid hydroxyethylamine sulfonamide inhibitor compounds. The invention compounds advantageously inhibit retroviral proteases, such as human immunodeficiency virus (HIV) protease. Therefore, this invention also encompasses pharmaceutical compositions, methods for inhibiting retroviral proteases and methods for treatment or prophylaxis of a retroviral infection, such as an HIV infection. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
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 n represents 1 or 2;
R
1
represents alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, imidazolylmethyl, —CH
2
CONH
2
, —CH
2
CH
2
CONH
2
, —CH
2
S(O)
2
NH
2
, —CH
2
SCH
3
, —CH
2
S(O)CH
3
, —CH
2
S(O)
2
CH
3
, —C(CH
3
)
2
SCH
3
, —C(CH
3
)
2
S(O)CH
3
or —C(CH
3
)
2
S(O)
2
CH
3
radicals; preferably, R
1
represents alkyl of 1-5 carbon atoms, alkenyl of 2-5 carbon atoms, alkynyl of 2-5 carbon atoms, hydroxyalkyl of 1-3 carbon atoms, alkoxyalkyl of 1-3 alkyl and 1-3 alkoxy carbon atoms, cyanoalkyl of 1-3 alkyl carbon atoms, imidazolylmethyl, —CH
2
CONH
2
, —CH
2
CH
2
CONH
2
, —CH
2
S(O)
2
NH
2
, —CH
2
SCH
3
, —CH
2
S(O)CH
3
, —CH
2
S(O)
2
CH
3
, —C(CH
3
)
2
SCH
3
, —C(CH
3
)
2
S(O)CH
3
or —C(CH
3
)
2
S(O)
2
CH
3
radicals; more preferably, R
1
represents alkyl of 1-4 carbon atoms, alkenyl of 2-3 carbon atoms, alkynyl of 3-4 carbon atoms, cyanomethyl, imidazolylmethyl, —CH
2
CONH
2
, —CH
2
CH
2
CONH
2
, —CH
2
S(O)
2
NH
2
, —CH
2
SCH
3
, —CH
2
S(O)CH
3
, —CH
2
S(O)
2
CH
3
, —C(CH
3
)
2
SCH
3
, —C(CH
3
)
2
S(O)CH
3
or —C(CH
3
)
2
S(O)
2
CH
3
radicals; and most preferably, R
1
represents sec-butyl, tert-butyl, iso-propyl, 3-propynyl or —C(CH
3
)
2
S(O)
2
CH
3
radicals;
R
2
represents alkyl, aralkyl, alkylthioalkyl, arylthioalkyl or cycloalkylalkyl radicals; preferably, R
2
represents radicals of alkyl of 1-5 carbon atoms, aralkyl of 1-3 alkyl carbon atoms, alkylthioalkyl of 1-3 alkyl carbon atoms, arylthioalkyl of 1-3 alkyl carbon atoms or cycloalkylalkyl of 1-3 alkyl carbon atoms and 3-6 ring member carbon atoms; more preferably, R
2
represents radicals of alkyl of 3-5 carbon atoms, arylmethyl, alkylthioalkyl of 1-3 alkyl carbon atoms, arylthiomethyl or cycloalkylmethyl of 5-6 ring member carbon atoms radicals; even more preferably, R
2
represents isobutyl, n-butyl, CH
3
SCH
2
CH
2
—, benzyl, phenylthiomethyl, (2-naphthylthio)methyl, 4-methoxy phenylmethyl, 4-hydroxyphenylmethyl, 4-fluorophenylmethyl or cyclohexylmethyl radicals; even more preferably, R
2
represents benzyl, 4-fluorophenylmethyl or cyclohexylmethyl radicals; most preferably, R
2
represents benzyl;
R
3
represents alkyl, cycloalkyl or cycloalkylalkyl radicals; preferably, R
3
represents radicals of alkyl radical of 1-5 carbon atoms, cycloalkyl of 5-8 ring members or cycloalkylmethyl radical of 3-6 ring members; more preferably, R
3
represents propyl, isoamyl, isobutyl, butyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexyl or cycloheptyl radicals; more preferably R
3
represents isobutyl or cyclopentylmethyl radicals;
R
4
represents aryl, heteroaryl or heterocyclo radicals; preferably, R
4
represents aryl, benzo fused 5 to 6 ring member heteroaryl or benzo fused 5 to 6 ring member heterocyclo radicals; or
R
4
represents a radical of the formula
wherein A and B each independently represent O, S, SO or SO
2
; preferably, A and B each represent O;
R
6
represents deuterium, alkyl or halogen radicals; preferably, R
6
represents deuterium, alkyl of 1-5 carbon atoms, fluoro or chloro radicals; m
Brown David L.
DeCrescenzo Gary A.
Devadas Balekudru
Freskos John N.
Getman Daniel P
Banner & Witcoff , Ltd.
G. D. Searle
Saeed Kamal
Solola T. A.
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