Retroviral protease inhibitors

Hydroxyethylamine compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.

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 
hydroxyethylamine protease inhibitor compounds, a composition and method 
for inhibiting retroviral proteases such as human immunodeficiency virus 
(HIV) protease and for treatment, such as prophylactic treatment or 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. 
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 replication proteases can be 
effectively inhibited. 
Several classes of mimetic compounds have been proposed, particularly for 
inhibition of proteases, such as for inhibition of HIV protease. Such 
mimetics include hydroxyethylamine isosteres and reduced amide isosteres. 
See, for example, EP 0 346 847; EP 0 342,541; Roberts et al, "Rational 
Design of Peptide-Based Proteinase Inhibitors, "Science, 248, 358 (1990); 
and Erickson et al, "Design Activity, and 2.8 .ANG. Crystal Structure of a 
C.sub.2 Symmetric Inhibitor Complexed to HIV-1 Protease," Science, 249, 
527 (1990). 
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; U.K. 2,184,730; G.B. 2,209,752; EP 0 264 795; G.B. 2,200,115 
and U.S. SIR H725. 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. 
DETAILED DESCRIPTION OF THE INVENTION 
In accordance with the present invention, there is provided a retroviral 
protease inhibiting compound of the formula: 
##STR1## 
or a pharmaceutically acceptable salt, prodrug or ester thereof wherein: 
A represents radicals represented by the formulas: 
##STR2## 
wherein R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, 
aryloxycarbonylalkyl, alkylcarbonyl, cycloalkylcarbonyl, 
cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, 
aryloxycarbonyl, aryloxyalkanoyl, heterocyclylcarbonyl, 
heterocyclyloxycarbonyl, heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, 
heteroaralkanoyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl, 
heteroaroyl, alkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, 
hydroxyalkyl, aminoalkanoyl, aminocarbonyl, and mono- and disubstituted 
aminoalkanoyl and mono- and disubstituted aminocarbonyl radicals wherein 
the substituents are selected from alkyl, aryl, arolkyl, cycloalkyl, 
cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and 
heterocycloalkyalkyl radicals, or in the case of a disubstituted 
aminoalkanoyl, said substitutents along with the nitrogen atom to which 
they are attched form a heterocyclyl or heteroaryl radical; 
R' represents hydrogen and radicals as defined for R.sup.3 or R and 
R' together with the nitrogen to which they are attached form a 
heterocycloalkyl or heteroaryl radical or when A is A1, R' represents 
hydrogen and aminocarbonyl radicals as defined for R.sup.3 and 
aralkoxycarbonylalkyl and aminocarbonylalkyl and aminocarbonyl radicals 
wherein said amino group may be mono- or disubstituted with substitutents 
selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylclkyl, 
heteroaryl, heteroaralkyl, hetercycloalkyl and heterocycloalkylalkyl 
radicals; 
t represents either 0 or 1; 
R.sup.1 represents hydrogen, --CH.sub.2 SO.sub.2 NH.sub.2, --CO.sub.2 
CH.sub.3, --CH.sub.2 CO.sub.2 CH.sub.3, --CONH.sub.2, --CONHCH.sub.3, 
--CON(CH.sub.3).sub.2, --CH.sub.2 CONHCH.sub.3, --CH.sub.2 
CON(CH.sub.3).sub.2, --(CH.sub.3).sub.2 (SCH.sub.3), --C(CH.sub.3).sub.2 
(S O!CH.sub.3), --C(CH.sub.3).sub.2 (S O!.sub.2 CH.sub.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 allo-threonine side chains; 
R.sup.1' and R.sup.1" independently represent hydrogen and radicals as 
defined for R.sup.1, or one of R.sup.1' and R.sup.1", together with 
R.sup.1 and the carbon atoms to which they are attached, represent a 
cycloalkyl radical; 
R.sup.2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl 
radicals, which radicals are optionally substituted with a group selected 
from --OR.sup.9, --SR.sup.9, --NO.sub.2 and halogen radicals, wherein 
R.sup.9 represents hydrogen and alkyl radicals; 
R.sup.3 represents alkyl, 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 O and C(R.sup.17) where R.sup.17 represents hydrogen and and 
alkyl radicals; 
X' represents O, N and C(R.sup.17); provided that when X and/or X' is 
absent, R.sup.5 and/or R.sup.34 are absent; 
Y, Y', and Y" independently represent O, S and NR.sup.15 wherein R.sup.15 
represents radicals as defined for R.sup.3 ; 
R.sup.4 and R.sup.5 independently represent hydrogen and radicals as 
defined by R.sup.3, or R.sup.4 and R.sup.5 together with the carbon atom 
to which they are bonded represent cycloalkyl, heterocycloalkyl, 
heteroaryl and aryl radicals; 
R.sup.6 represents hydrogen and alkyl radicals; 
R.sup.20, R.sup.21, R.sup.30, R.sup.31 and R.sup.32 represent radicals as 
defined for R.sup.1, or one of R.sup.1 and R.sup.30 together with one of 
R.sup.31 and R.sup.32 and the carbon atoms to which they are attached form 
a cycloalkyl radical; and 
R.sup.33 and R.sup.34 independently represent hydrogen and radicals as 
defined for R.sup.3, or R.sup.33 and R.sup.34 together with X' represent 
cycloalkyl, aryl, heterocyclyl and heteroaryl radicals. 
A preferred class of retroviral inhibitor compounds of the present 
invention are those represented by the formula: 
##STR3## 
or a pharmaceutically acceptable salt, prodrug or ester thereof, 
preferably wherein the stereochemistry about the hydroxy group is 
designated as (R); wherein 
R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, 
aryloxycarbonylalkyl, alkylcarbonyl, cycloalkylcarbonyl, 
cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, 
aryloxycarbonyl, aryloxyalkanoyl, heterocyclylcarbonyl, 
heterocyclyloxycarbonyl, heteroaralkanoyl, heterocyclylalkanoyl, 
heterocyclylalkoxycarbonyl, heteroaralkoxycarbonyl, hetroaryloxycarbonyl, 
heteroaroyl, alkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, 
hydroxyalkyl, aminoalkanoyl, aminocarbonyl and mono- and disubstituted 
aminoalkanoyl and mono- and disubstituted aminocarbonyl radicals wherein 
the substituents are selected from alkyl, aryl, arolkyl, cycloalkyl, 
cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and 
heterocycloalkyalkyl radicals, or in the case of a disubstituted 
aminoalkanoyl, said substitutents along with the nitrogen atom to which 
they are attched form a heterocyclyl or heteroaryl radical; 
R' represents hydrogen and radicals as defined for R.sup.3 or R and R' 
together with the nitrogen to which they are attached form a 
heterocycloalkyl or heteroaryl radical, or when A is A1, R' represents 
hydrogen and radicals as defined for R.sup.3 and aralkoxycarbonylalkyl and 
aminocarbonylalkyl radicals wherein said amino group may be mono- or 
disubstituted with substitutents selected from alkyl, aryl, atalkyl, 
cycloalkyl, cycloalkylclkyl, heteraryl, heteroaralkyl, hetercycloalkyl and 
heterocycloalkylalkyl radicals; 
R.sup.1 represents hydrogen, --CH.sub.2 SO.sub.2 NH.sub.2, --CO.sub.2 
CH.sub.3, --CH.sub.2 CO.sub.2 CH.sub.3, --CONH.sub.2, --CONHCH.sub.3, 
CON(CH.sub.3).sub.2, --CH.sub.2 CONHCH.sub.3, --CH.sub.2 
CON(CH.sub.3).sub.2, C(CH.sub.3).sub.2 (SCH.sub.3), C(CH.sub.3).sub.2 
(S O!CH.sub.3), C(CH.sub.3).sub.2 (S O!.sub.2 CH.sub.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 allo-threonine side chains; 
R.sup.1' and R.sup.1" independently represent hydrogen and radicals as 
defined for R.sup.1, or one of R.sup.1' and R.sup.1", together with 
R.sup.1 and the carbon atoms to which they are attached, represent a 
cycloalkyl radical; 
R.sup.2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl, and aralkyl 
radicals, which radicals are optionally substituted with a group selected 
from alkyl radicals, --NO.sub.2, OR.sup.9 and SR.sup.9 wherein R.sup.9 
represents hydrogen and alkyl radicals, and halogen radicals; 
R.sup.3 represents alkyl, 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; 
R.sup.4 and R.sup.5 independently represent hydrogen and radicals as 
defined by R.sup.3, or together with a carbon atom to which they are 
bonded represent cycloalkyl, heterocycloalkyl, heteroaryl and aryl 
radicals; 
t represents 0 or 1; 
X represents O and C (R.sup.17) wherein R.sup.17 represents hydrogen and 
alkyl radicals; provided that when X is O, R.sup.5 is absent; and 
Y and Y' independently represent O, S, and NR.sup.15 wherein R.sup.15 
represents radicals as defined for R.sup.3. Preferably, Y and Y' represent 
O. 
Preferably, R.sup.3 represents radicals as defined above which contain no 
.alpha.-branching, e.g., as in an isopropyl radical or a t-butyl radical. 
The preferred radicals are those which contain a --CH.sub.2 -- moiety 
between the nitrogen and the remaining portion of the radical. Such 
preferred groups include, but are not limited to, benzyl, isobutyl, 
n-butyl, isoamyl, cyclohexylmethyl and the like. 
Another preferred class of compounds are those represented by the formula: 
##STR4## 
or a pharmaceutically acceptable salt, prodrug or ester thereof wherein t, 
X, Y, Y', R', R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.20 and 
R.sup.21 are as defined above. 
Yet another preferred class of compounds are those represented by the 
formula: 
##STR5## 
or a pharmaceutically acceptable salt, prodrug or ester thereof wherein t, 
X, X', Y, Y', Y", R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.30, 
R.sup.31, R.sup.32, R.sup.33 and R.sup.34 are as defined above. 
As utilized herein, the term "alkyl", alone or in combination, means a 
straight-chain or branched-chain alkyl radical containing from 1 to about 
10, preferably from 1 to about 8, carbon atoms. Examples of such radicals 
include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 
tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. The term 
"alkenyl", alone or in combination, means a straight-chain or 
branched-chain hydrocarbon radial having one or more double bonds and 
containing from 2 to about 18 carbon atoms preferably from 2 to about 8 
carbon atoms. Examples of suitable alkenyl radicals include ethenyl, 
propenyl, allyl, 1,4-butadienyl and the like. The term alkynyl, alone or 
in combination, means a straight-chain hydrocarbon radical having one or 
more triple bonds and containing from 2 to about 10 carbon atoms. Examples 
of alkynyl radicals include ethynyl, propynyl (propargyl), butynyl and the 
like. The term "alkoxy", alone or in combination, means an alkyl ether 
radical wherein the term alkyl is as defined above. Examples of suitable 
alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, 
n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like. The term 
"cycloalkyl" means an alkyl radical which contains from about 3 to about 8 
carbon atoms and is cyclic. The term "cycloalkylalkyl" means an alkyl 
radical as defined above which is substituted by a cycloalkyl radical 
containing from about 3 to about 8, preferably from about 3 to about 6, 
carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, 
cyclobutyl, cyclopentyl, cyclohexyl and the like. The term "aryl", alone 
or in combination, means a phenyl or naphthyl radical which optionally 
carries one or more substituents selected from alkyl, alkoxy, halogen, 
hydroxy, amino and the like, such as phenyl, p-tolyl, 4-methoxyphenyl, 
4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 
1-naphthyl, 2-naphthyl, and the like. The term "aralkyl", alone or in 
combination, means an alkyl radical as defined above in which one hydrogen 
atom is replaced by an aryl radical as defined above, such as benzyl, 
2-phenylethyl and the like. The term "aralkoxy carbonyl", alone or in 
combination, means a radical of the formula --C(O)--O-aralkyl in which the 
term "aralkyl" has the significance given above. An example of an 
aralkoxycarbonyl radical is benzyloxycarbonyl. The term "aryloxy" means a 
radical of the formula aryl-O in which the term aryl has the significance 
given above. The term "alkanoyl", alone or in combination, means an acyl 
radical derived from an alkanecarboxylic acid, examples of which include 
acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like. The 
term "cycloalkylcarbonyl" means an acyl group derived from a monocyclic or 
bridged cycloalkanecarboxylic acid such as cyclopropanecarbonyl, 
cyclohexanecarbonyl, adamantanecarbonyl, and the like, or from a 
benz-fused monocyclic cycloalkanecarboxylic acid which is optionally 
substituted by, for example, alkanoylamino, such as 
1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. 
The term "aralkanoyl" means an acyl radical derived from an 
aryl-substituted alkanecarboxylic acid such as phenylacetyl, 
3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 
4-chlorohydrocinnamoyl, 4 -aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl, 
and the like. The term "aroyl" means an acyl radical derived from an 
aromatic carboxylic acid. Examples of such radicals include aromatic 
carboxylic acids, an optionally substituted benzoic or naphthoic acid such 
as benzoyl, 4-chlorobenzoyl, 4-=carboxybenzoyl, 
4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2 
naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 
3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like. 
The heterocyclyl or heterocycloalkyl portion of a heterocyclylcarbonyl, 
heterocyclyloxycarbonyl, heterocyclylalkoxycarbonyl, or heterocyclylalkyl 
group or the like is a saturated or partially unsaturated monocyclic, 
bicyclic or tricyclic heterocycle which contains one or more hetero atoms 
selected from nitrogen, oxygen and sulphur, which is optionally 
substituted on one or more carbon atoms by halogen, alkyl, alkoxy, oxo, 
and the like, and/or on a secondary nitrogen atom (i.e., --NH--) by alkyl, 
aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiary 
nitrogen atom (i.e. =N-) by oxido and which is attached via a carbon atom. 
The heteroaryl portion of a heteroaroyl, heteroaryloxycarbonyl, or a 
heteroaralkoxy carbonyl group or the like is an aromatic monocyclic, 
bicyclic, or tricyclic heterocycle which contains the hetero atoms and is 
optionally substituted as defined above with respect to the definition of 
heterocyclyl. Examples of such heterocyclyl and heteroaryl groups are 
pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 
pyrrolyl, imidazolyl (e.g., imidazol 4-yl, 
1-benzyloxycarbonylimidazol-4-yl, etc.), pyrazolyl, pyridyl, pyrazinyl, 
pyrimidinyl, furyl, thienyl, triazolyl, oxazolyl, thiazolyl, indolyl 
(e.g., 2-indolyl, etc.), quinolinyl, (e.g., 2-quinolinyl, 3-quinolinyl, 
1-oxido-2-quinolinyl, etc.), isoquinolinyl (e.g., 1-isoquinolinyl, 
3-isoquinolinyl, etc.), tetrahydroquinolinyl (e.g., 
1,2,3,4-tetrahydro-2-quinolyl, etc.), 1,2,3,4-tetrahydroisoquinolinyl 
(e.g., 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, etc.), quinoxalinyl, 
.beta.-carbolinyl, benzofurancarbonyl, benzimidazolyl radicals and the 
like. The term "cycloalkylalkoxycarbonyl" means an acyl group derived from 
a cycloalkylalkoxycarboxylic acid of the formula cycloalkylalkyl-O--COOH 
wherein cycloalkylalkyl has the significance given above. The term 
"aryloxyalkanoyl" means an acyl radical of the formula aryl-O-alkanoyl 
wherein aryl and alkanoyl have the significance given above. The term 
"heterocyclyloxycarbonyl" means an acyl group derived from 
heterocyclyl-O--COOH wherein heterocyclyl is as defined above. The term 
"heterocyclyl alkanoyl" is an acyl radical derived from a 
heterocyclyl-substituted alkane carboxylic acid wherein heterocyclyl has 
the significance given above. The term "heterocyclylalkoxycarbonyl" means 
an acyl radical derived from a heterocyclyl-substituted alkane-O--COOH 
wherein heterocyclyl has the significance given above. The term 
"heteroaryloxycarbonyl" means an acyl radical derived from a carboxylic 
acid represented by heteroaryl-O--COOH wherein heteroaryl has the 
significance given above. The term "aminocarbonyl" alone or in 
combination, means an amino-substituted carbonyl (carbamoyl) group derived 
from an amino-substituted carboxylic acid wherein the amino group can be a 
primary, secondary or tertiary amino group containing substituents 
selected from hydrogen, and alkyl, aryl, aralkyl, cycloalkyl, 
cycloalkylalkyl radicals and the like. The term "aminoalkanoyl" means an 
acyl group derived from an amino-substituted alkanecarboxylic acid wherein 
the amino group can be a primary, secondary or tertiary amino group 
containing substituents selected from hydrogen, and alkyl, aryl, aralkyl, 
cycloalkyl, cycloalkylalkyl radicals and the like. The term "haloalkyl" 
means an alkyl radical having the significance as defined above wherein 
one or more hydrogens are replaced with a halogen. Examples of such 
haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, 
difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like. The 
term "halogen" means fluorine, chlorine, bromine or iodine. The term 
"leaving group" generally refers to groups readily displaceable by a 
nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such 
leaving groups are well known and include carboxylates, 
N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, 
tosylates --OR and --SR and the like. Preferred leaving groups are 
indicated herein where appropriate. 
Procedures for preparing the compounds of Formula I are set forth below. It 
should be noted that the general procedure is shown as it relates to 
preparation of compounds having the specified stereochemistry, for 
example, wherein the stereochemistry about the hydroxyl group is 
designated as (R). However, such procedures are generally applicable, as 
illustrated, to those compounds of opposite configuration, e.g., where the 
stereochemistry about the hydroxyl group is (S). 
Preparation of Compounds of Formula II 
The compounds of the present invention represented by Formula II above can 
be prepared utilizing the following general procedure. An N-protected 
chloroketone derivative of an amino acid having the formula: 
##STR6## 
wherein P represents an amino protecting group, and R.sup.2 is as defined 
above, is reduced to the corresponding alcohol utilizing an appropriate 
reducing agent. Suitable amino protecting groups are well known in the art 
and include carbobenzoxy, butyryl, t-butoxycarbonyl, acetyl, benzoyl and 
the like. A preferred amino protecting group is carbobenzoxy. A preferred 
N-protected chloroketone is N-benzyloxycarbonyl-L-phenylalanine 
chloromethyl ketone. A preferred reducing agent is sodium borohydride. The 
reduction reaction is conducted at a temperature of from -10.degree. C. to 
about 25.degree. C., preferably at about 0.degree. C., in a suitable 
solvent system such as, for example, tetrahydrofuran, and the like. The 
N-protected chloroketones are commercially available from Bachem, Inc., 
Torrance, Calif. Alternatively, the chloroketones can be prepared by the 
procedure set forth in S. J. Fittkau, J. Prakt. Chem., 315, 1037 (1973), 
and subsequently N-protected utilizing procedures which are well known in 
the art. 
The resulting alcohol is then reacted, preferably at room temperature, with 
a suitable base in a suitable solvent system to produce an N-protected 
amino epoxide of the formula: 
##STR7## 
wherein P and R.sup.2 are as defined above. Suitable solvent systems for 
preparing the amino epoxide include ethanol, methanol, isopropanol, 
tetrahydrofuran, dioxane, and the like including mixtures thereof. 
Suitable bases for producing the epoxide from the reduced chloroketone 
include potassium hydroxide, sodium hydroxide, potassium t-butoxide, DBU 
and the like. A preferred base is potassium hydroxide. 
Alternatively, a protected amino epoxide can be prepared starting with an 
L-amino acid which is reacted with a suitable amino-protecting group in a 
suitable solvent to produce an amino-protected L-amino acid ester of the 
formula: 
##STR8## 
wherein P, p.sup.1 and p.sup.2 independently represent hydrogen and 
amino-protecting groups as defined above with respect to P, provided that 
p.sup.1 and p.sup.2 are not both hydrogen; and R.sup.2 is as defined 
above. 
The amino-protected L-amino acid ester is then reduced, to the 
corresponding alcohol. For example, the amino-protected L-amino acid ester 
can be reduced with diisobutylaluminum hydride at -78.degree. C. in a 
suitable solvent such as toluene. The resulting alcohol is then converted, 
by way of a Swern Oxidation, to the corresponding aldehyde of the formula: 
##STR9## 
wherein p.sup.1, p.sup.2 and R.sup.2 are as defined above Thus, a 
dichloromethane solution of the alcohol is added to a cooled (-75.degree. 
to -68.degree. C.) solution of oxalyl chloride in dichloromethane and DMSO 
in dichloromethane and stirred for 35 minutes. 
The aldehyde resulting from the Swern Oxidation is then reacted with a 
halomethyllithium reagent, which reagent is generated in situ by reacting 
an alkyllithium or arylithium compound with a dihalomethane represented by 
the formula X.sup.1 CH.sub.2 X.sup.2 wherein X.sup.1 and X.sup.2 
independently represent I, Br or Cl. For example, a solution of the 
aldehyde and chloroiodomethane in THF is cooled to -78.degree. C. and a 
solution of n-butyllithium in hexane is added. The resulting product is a 
mixture of diastereomers of the corresponding amino-protected epoxides of 
the formulas: 
##STR10## 
The diastereomers can be separated by chromatography or, alternatively, 
once reacted in subsequent steps the diastereomeric products can be 
separated. 
The amino epoxide is then reacted, in a suitable solvent system, with an 
equal amount, or preferably an excess of, a desired amine of the formula: 
EQU R.sup.3 NH.sub.2 
wherein R.sup.3 is hydrogen or is as defined above. The reaction can be 
conducted over a wide range of temperatures, e.g., from about 10.degree. 
C. to about 100.degree. C., but is preferably, but not necessarily, 
conducted at a temperature at which the solvent begins to reflux. Suitable 
solvent systems include those wherein the solvent is an alcohol, such as 
methanol, ethanol, isopropanol, and the like, ethers such as 
tetrahydrofuran, dioxane and the like, and toluene, N,N-dimethylformamide, 
dimethyl sulfoxide, and mixtures thereof. A preferred solvent is 
isopropanol. Exemplary amines corresponding to the formula R.sup.3 
NH.sub.2 include benzyl amine, isobutylamine, n-butyl amine, isopentyl 
amine, isoamylamine, cyclohexanemethyl amine, naphthylene methyl amine and 
the like. The resulting product is a 3-(N-protected 
amino)-3-(R.sup.2)-1-(NHR.sup.3)-propan-2-ol derivative (hereinafter 
referred to as an amino alcohol) can be represented by the formula: 
##STR11## 
wherein P, R.sup.2 and R.sup.3 are as described above. 
Where X is either O or C, the appropriate analogs can be prepared by 
reacting the above described amino alcohol with an acid chloride or 
anhydride to form the analog wherein X is C, or with a chloroformate or 
pyrocarbonate where X is O. Procedures for reacting these compounds with 
an amine are well known in the art. Examples of such compounds include 
t-butylacetyl chloride, acetic anhydride, t-butyl pyrocarbonate, and 
N-butyl chloroformate. These analogs can be represented by the formulas: 
##STR12## 
The derivative of the amino alcohol and the corresponding sulfur analog can 
be represented by the formula: 
##STR13## 
Following preparation of such derivatives, the amino protecting group P is 
removed under conditions which will not affect the remaining portion of 
the molecule. These methods are well known in the art and include acid 
hydrolysis, hydrogenolysis and the like. A preferred method involves 
removal of the protecting group, e.g., removal of a carbobenzoxy group, by 
hydrogenolysis utilizing palladium on carbon in a suitable solvent system 
such as an alcohol, acetic acid, and the like or mixtures thereof. Where 
the protecting group is a t-butoxycarbonyl group, it cab be removed 
utilizing an inorganic or organic acid, e.g., HCl or trifluoroacetic acid, 
in a suitable solvent system, e.g., dioxane or methylene chloride. The 
resulting produce is the amine salt derivative. Following neutralization 
of the salt, the amine is then reacted with an amino acid or corresponding 
derivative thereof represented by the formula (PN CR.sup.1 'R.sup. 
"!.sub.t CH(R.sup.1)COOH) wherein t, R.sup.1, R.sup.1' and R.sup.1" are as 
defined above, to produce the antiviral compounds of the present invention 
having the formula: 
##STR14## 
wherein t, X, P, R.sup.1, R.sup.1', R.sup.1", R.sup.2, R.sup.3, R.sup.4, 
R.sup.5 and Y are as defined above. Preferred protecting groups in this 
instance are a benzyloxycarbonyl group or a t-butoxycarbonyl group. Where 
the amine is reacted with a derivative of an amino acid, e.g., when t=1 
and R.sup.1' and R.sup.1" are both H, so that the amino acid is a 
.beta.-amino acid, such .beta.-amino acids can be prepared according to 
the procedure set forth in a copending application, U.S. Ser. No. 
07/345,808. Where t is 1, one of R.sup.1' and R.sup.1" is H and R.sup.1 is 
hydrogen so that the amino acid is a homo-.beta.-amino acid, such 
homo-.beta.-amino acids can be prepared by the procedure set forth in a 
copending application, U.S. Ser. No. 07/853,561. Where t is O and R.sup.1 
is alkyl, cycloalkyl, --CH.sub.2 SO.sub.2 NH.sub.2 or an amino acid side 
chain, such materials are well known and many are commercially available 
from Sigma-Aldrich. 
The N-protecting group can be subsequently removed, if desired, utilizing 
the procedures described above, and then reacted with a carboxylate 
represented by the formula: 
##STR15## 
wherein R is as defined above and L is an appropriate leaving group such 
as a halide. Preferably, where R.sup.1 is a side chain of a naturally 
occurring .alpha.-amino acid, R is a 2-quinoline group derived from 
N-hydroxysuccinimide-2-quinoline carboxylate, i.e., L is hydroxy 
succinimide. A solution of the free amine (or amine acetate salt) and 
about 1.0 equivalent of the carboxylate are mixed in an appropriate 
solvent system and optionally treated with up to five equivalents of a 
base such as, for example, N-methylmorpholine, at about room temperature. 
Appropriate solvent systems include tetrahydrofuran, methylene chloride or 
N,N-dimethylformamide, and the like, including mixtures thereof. 
Preparation of Compounds of Formula III 
A mercaptan of the formula R'SH is reacted with a substituted methacrylate 
of the formula: 
##STR16## 
by way of a Michael Addition. The Michael Addition is conducted in a 
suitable solvent and in the presence of a suitable base, to produce the 
corresponding thiol derivative represented by the formula: 
##STR17## 
wherein R' and R.sup.1 represent radicals defined above; R.sup.20 and 
R.sup.21 represent hydrogen and radicals as defined for R.sup.1 ; and 
R.sup.22 represents radicals as defined by R.sup.3. Suitable solvents in 
which the Michael Addition can be conducted include alcohols such as, for 
example, methanol, ethanol, butanol and the like, as well as ethers, e.g., 
THF, and acetonitrile, DMF, DMSO, and the like, including mixtures 
thereof. Suitable bases include Group I metal alkoxides such as, for 
example sodium methoxide, sodium ethoxide, sodium butoxide and the like as 
well as Group I metal hydrides, such as sodium hydride, including mixtures 
thereof. 
The thiol derivative is converted into the corresponding sulfone of the 
formula: 
##STR18## 
by oxidizing the thiol derivative with a suitable oxidation agent in a 
suitable solvent. Suitable oxidation agents include, for example, hydrogen 
peroxide, sodium meta-perborate, oxone (potassium peroxy monosulfate), 
meta-chloroperoxybenzoic acid, and the like, including mixtures thereof. 
Suitable solvents include acetic acid (for sodium meta-perborate) and, for 
other peracids, ethers such as THF and dioxane, and acetonitrile, DMF and 
the like, including mixtures thereof. 
The sulfone is then converted to the corresponding free acid of the 
formula: 
##STR19## 
utilizing a suitable base, e.g., lithium hydroxide, sodium hydroxide and 
the like, including mixtures thereof, in a suitable solvent, such as, for 
example, THF, acetonitrile, DMF, DMSO, methylene chloride and the like, 
including mixtures thereof. 
The free acid is then coupled, utilizing, as described above, procedures 
well known in the art, to the urea derivative, or analog thereof, of an 
amino alcohol which is described above for the preparation of compounds of 
Formula II. The resulting product is a compound represented Formula III. 
Alternatively, one can couple the urea isostere to the commercially 
available acid, 
##STR20## 
remove the thioacetyl group with a suitable base, such as hydroxide, or an 
amine, such as ammonia, and then react the resulting thiol with an 
alkylating agent, such as an alkyl halide, tosylate or mesylate to afford 
compounds at the following structure: 
##STR21## 
The sulfur can then be oxidized to the corresponding sulfone using suitable 
oxidizing agents, as described above, to afford the desired compounds of 
the following structure: 
##STR22## 
Alternatively, to prepare compounds of Formula III, a substituted 
methacrylate of the formula: 
##STR23## 
wherein L represents a leaving group as previously defined, R.sup.35 and 
R.sup.36 represent hydrogen and radicals as defined for R.sup.1 ; and 
R.sup.37 represents alkyl, aralkyl, cycloalkyl and cycloalkylalkyl 
radicals, is reacted with a suitable sulfonating agent, such as, for 
example, a sulfinic acid represented by the formula R'SO.sub.2 M, wherein 
R' represents radicals as defined above and M represents a metal adapted 
to form a salt of the acid, e.g., sodium, to produce the corresponding 
sulfone represented by the formula: 
##STR24## 
wherein R', R.sup.35, R.sup.36 and R.sup.37 are as defined above. The 
sulfone is then hydrolyzed in the presence of a suitable base, such as 
lithium hydroxide, sodium hydroxide and the like, to the compound 
represented by the formula: 
##STR25## 
wherein R', R.sup.35 and R.sup.36 represent radicals as defined above. The 
resulting compound is then asymmetrically hydrogenated utilizing an 
asymmetric hydrogenation catalyst such as, for example, a ruthenium-BINAP 
complex, to produce the reduced product, substantially enriched in the 
more active isomer, represented by the formula: 
##STR26## 
wherein R', R.sup.35 and R.sup.36 represent radicals as defined above. 
Where the more active isomer has the R-stereochemistry, a Ru(R-BINAP) 
asymmetric hydrogenation catalyst can be utilized. Conversely, where the 
more active isomer has the S-sterochemistry, a Ru(S-BINAP) catalyst can be 
utilized. Where both isomers are active, or where it is desired to have a 
mixture of the two diastereomers, a hydrogenation catalyst such as 
platinum, or palladium, on carbon can be utilized to reduce the above 
compound. The reduced compound is then coupled to the amino alcohol 
derivatives, as described above, to produce compounds of Formula III. 
Preparation of Compounds of Formula IV 
To produce compounds of Formula IV, starting with a lactate of the formula: 
##STR27## 
wherein P" represents alkyl radicals, such as, for example, ethyl, methyl, 
benzyl and the like. The hydroxyl group of the lactate is protected as its 
ketal by reaction in a suitable solvent system with methyl isopropenyl 
ether (1,2-methoxypropene) in the presence of a suitable acid. Suitable 
solvent systems include methylene chloride, tetrahydrofuran and the like 
as well as mixtures thereof. Suitable acids include POCl.sub.3 and the 
like. It should be noted that well-known groups other than methyl 
isopropenyl ether can be utilized to form the ketal. The ketal is then 
reduced with diisobutylaluminum hydride (DIBAL) at -78.degree. C. to 
produce the corresponding aldehyde which is then treated with ethylidene 
triphenylphosphorane (Wittig reaction) to produce a compound represented 
by the formula: 
##STR28## 
The ketal protecting group is then removed utilizing procedures well-known 
in the art such as by mild acid hydrolysis. The resulting compound is then 
esterified with isobutyryl chloride to produce a compound of the formula: 
##STR29## 
This compound is then treated with lithium diisopropyl amide at -78.degree. 
C. followed by warming of the reaction mixture to room temperature to 
effect a Claisen rearrangement ( 3,3!) to produce the corresponding acid 
represented by the formula: 
##STR30## 
Treatment of the acid with benzyl bromide in the presence of a tertiary 
amine base, e.g., DBU, produces the corresponding ester which is then 
cleaved oxidatively to give a trisubstituted succinic acid: 
##STR31## 
The trisubstituted succinic acid is then coupled to the urea isostere as 
described above. To produce the free acid, the benzyl ester is removed by 
hydrogenolysis to produce the corresponding acid. The acid can then be 
converted to the primary amide by methods well-known in the art. 
An alternative method for preparing trisubstituted succinic acids involves 
reacting an ester of acetoacetic acid represented by the formula: 
##STR32## 
where R is a suitable protecting group, such as methyl, ethyl, benzyl or 
t-butyl with sodium hydride and a hydrocarbyl halide (R.sup.31 X or 
R.sup.32 X) in a suitable solvent, e.g., THF, to produce the corresponding 
disubstituted derivative represented by the formula: 
##STR33## 
This disubstituted acetoacetic acid derivative is then treated with lithium 
diisopropyl amide at about -10.degree. C. and in the presence of 
PhN(triflate).sub.2 to produce a vinyl triflate of the formula: 
##STR34## 
The vinyl triflate is then carbonylated utilizing a palladium catalyst, 
e.g. , Pd.sub.2 (OAc)(Ph.sub.3)P, in the presence of an alcohol (R"OH) or 
water (R"=H) and a base, e.g., triethylamine, in a suitable solvent such 
as DMF, to produce the olefinic ester or acid of the formula: 
##STR35## 
The olefin can then be subsequently asymmetrically hydrogenated, as 
described above, to produce a trisubstituted succinic acid derivative of 
the formula: 
##STR36## 
If R" is not H, the ester group can be removed either by hydrolysis, 
acidolysis, or hydrogenolysis, and the corresponding acid is then coupled 
to the amino alcohol derivatives as described above and then, optionally, 
the R group removed to produce the corresponding acid, and optionally, 
converted to the amide. 
Alternatively, one can react the amino alcohol derivatives with either a 
suitably monoprotected succinic acid or glutaric acid of the following 
structure; 
##STR37## 
followed by removal of the protecting group and conversion of the 
resulting acid to an amide. One can also react an anhydride of the 
following structure; 
##STR38## 
with the amino alcohol derivatives and then separate any isomers or 
convert the resulting acid to an amide and then separate any isomers. 
it is contemplated that for preparing compounds of the Formulas having 
R.sup.6, the compounds can be prepared following the procedure set forth 
above and, prior to coupling the urea derivative or analog thereof, e.g. 
coupling, to the amino acid PNH(CH.sub.2).sub.t CH(R.sup.1)COOH, carried 
through a procedure referred to in the art as reductive amination. Thus, a 
sodium cyanoborohydride and an appropriate aldehyde R.sup.6 C(O)H or 
ketone R.sup.6 C(O)R.sup.6 can be reacted with the urea derivative 
compound or appropriate analog at room temperature in order to reductively 
aminate any of the compounds of Formulas I-VI. It is also contemplated 
that where R.sup.3 of the amino alcohol intermediate is hydrogen, the 
inhibitor compounds of the present invention wherein R.sup.3 is an alkyl 
radical, or other substituent wherein the .alpha.-C contains at least one 
hydrogen, can be prepared through reductive amination of the final product 
of the reaction between the amino alcohol and the amine or at any other 
stage of the synthesis for preparing the inhibitor compounds. 
Contemplated equivalents of the general formulas set forth above for the 
antiviral compounds and derivatives as well as the intermediates are 
compounds otherwise corresponding thereto and having the same general 
properties such as tautomers thereof and compounds wherein one or more of 
the various R groups are simple variations of the substituents as defined 
therein, e.g., wherein R is a higher alkyl group than that indicated. In 
addition, where a substituent is designated as, or can be, a hydrogen, the 
exact chemical nature of a substituent which is other than hydrogen at 
that position, e.g., a hydrocarbyl radical or a halogen, hydroxy, amino 
and the like functional group, is not critical so long as it does not 
adversely affect the overall activity and/or synthesis procedure. 
The chemical reactions described above are generally disclosed in terms of 
their broadest application to the preparation of the compounds of this 
invention. Occasionally, the reactions may not be applicable as described 
to each compound included within the disclosed scope. The compounds for 
which this occurs will be readily recognized by those skilled in the art. 
In all such cases, either the reactions can be successfully performed by 
conventional modifications known to those skilled in the art, e.g., by 
appropriate protection of interfering groups, by changing to alternative 
conventional reagents, by routine modification of reaction conditions, and 
the like, or other reactions disclosed herein or otherwise conventional, 
will be applicable to the preparation of the corresponding compounds of 
this invention. In all preparative methods, all starting materials are 
known or readily preparable from known starting materials. 
Without further elaboration, it is believed that one skilled in the art 
can, using the preceding description, utilize the present invention to its 
fullest extent. The following preferred specific embodiments are, 
therefore, to be construed as merely illustrative, and not limitative of 
the remainder of the disclosure in any way whatsoever. 
Examples 1-45 illustrate compounds wherein X is N rather than O or 
C(R.sup.17). However, as shown in Examples 46 and 47, the nitrogen can be 
replaced as shown in such Examples 46 and 47 by replacing the isocyanate 
R.sup.4 NCO with an acid chloride or anhydride where X is C, or with a 
chloroformate or pyrocarbonate where X is O, to produce the compounds of 
the present invention. Furthermore, as shown in Examples 48 and 49, such 
compounds are effective retroviral protease inhibitors. Thus, utilizing 
the procedures set forth herein, the compounds shown in Tables 20-46 could 
be prepared. 
All reagents were used as received without purification. All proton and 
carbon NMR spectra were obtained on either a Varian VXR-300 or VXR-400 
nuclear magnetic resonance spectrometer.