U.S. patent application number 10/750213 was filed with the patent office on 2004-12-30 for sulfonylalkanoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors.
This patent application is currently assigned to G. D. Searle & Co.. Invention is credited to DeCrescenzo, Gary A., Freskos, John N., Getman, Daniel, Mueller, Richard A., Talley, John J., Vazquez, Michael L..
Application Number | 20040267022 10/750213 |
Document ID | / |
Family ID | 32330190 |
Filed Date | 2004-12-30 |
United States Patent
Application |
20040267022 |
Kind Code |
A1 |
Vazquez, Michael L. ; et
al. |
December 30, 2004 |
Sulfonylalkanoylamino hydroxyethylamino sulfonamides useful as
retroviral protease inhibitors
Abstract
Sulfonamide-containing hydroxyethylamine compounds are effective
as retroviral protease inhibitors, and in particular as inhibitors
of HIV protease.
Inventors: |
Vazquez, Michael L.;
(Gurnee, IL) ; Mueller, Richard A.; (Glencoe,
IL) ; Talley, John J.; (St. Louis, MO) ;
Getman, Daniel; (Chesterfield, MO) ; DeCrescenzo,
Gary A.; (St. Peters, MO) ; Freskos, John N.;
(Clayton, MO) |
Correspondence
Address: |
BANNER & WITCOFF
1001 G STREET N W
SUITE 1100
WASHINGTON
DC
20001
US
|
Assignee: |
G. D. Searle & Co.
Chicago
IL
|
Family ID: |
32330190 |
Appl. No.: |
10/750213 |
Filed: |
January 2, 2004 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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10750213 |
Jan 2, 2004 |
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09655844 |
Sep 6, 2000 |
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6743929 |
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09655844 |
Sep 6, 2000 |
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09352215 |
Jul 13, 1999 |
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6147117 |
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09352215 |
Jul 13, 1999 |
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09048034 |
Mar 26, 1998 |
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5965588 |
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09048034 |
Mar 26, 1998 |
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08867430 |
Jun 6, 1997 |
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5760064 |
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08867430 |
Jun 6, 1997 |
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08587688 |
Jan 17, 1996 |
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5639769 |
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08587688 |
Jan 17, 1996 |
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08110913 |
Aug 24, 1993 |
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5521219 |
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08110913 |
Aug 24, 1993 |
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07935071 |
Aug 25, 1992 |
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Current U.S.
Class: |
546/329 ;
548/571; 562/430; 564/86 |
Current CPC
Class: |
A61K 31/18 20130101;
C07C 317/44 20130101; A61K 31/63 20130101 |
Class at
Publication: |
546/329 ;
548/571; 562/430; 564/086 |
International
Class: |
C07D 213/53; C07C
311/35 |
Claims
1-123. (canceled)
124. An amino alcohol of the following formula: 96where P.sup.1 is
hydrogen; P.sup.2 is selected from benzyl and an amino-protecting
group; R.sup.2 is selected from alkyl, aryl, cycloalkyl,
cycloalkylalkyl and aralkyl, which are optionally substituted with
a group selected from alkyl, halogen, nitro, cyano,
trifluoromethyl, --OR.sup.9 and --SR.sup.9, where R.sup.9 is
selected from hydrogen, alkyl and halogen and R.sup.3 is selected
from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,
alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,
heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl,
aminoalkyl and mono- and disubstituted aminoalkyl, wherein said
substituents are selected from alkyl, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and
heterocycloalkylalkyl, or in the case of a disubstituted
aminoalkyl, said substituents along with the nitrogen atom to which
they are attached, from a heterocycloalkyl or a heteroaryl.
125. The amino alcohol of claim 124 wherein R.sup.2 is selected
from alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl,
substituted with a group selected from alkyl, halogen, nitro,
cyano, trifluoromethyl, --OR.sup.9 and --SR.sup.9, where R.sup.9 is
selected from hydrogen, alkyl and halogen.
126. The amino alcohol of claim 125 wherein R.sup.2 is an aralkyl
substituted with a group selected from alkyl, halogen, nitro,
cyano, trifluoromethyl, --OR.sup.9 and --SR.sup.9, where R.sup.9 is
selected from hydrogen, alkyl and halogen.
127. The amino alcohol of claim 126 wherein R.sup.2 is an aralkyl
substituted with one or more halogens.
128. The amino alcohol of claim 127 wherein R.sup.3 is selected
from alkyl, haloalkyl, alkenyl, hydroxyalkyl, alkoxyalkyl,
cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,
heterocycloalkylalkyl, aryl, aralkyl and heteroaralkyl.
129. The amino alcohol of claim 127 wherein the one or more
halogens is fluorine.
Description
RELATED APPLICATION
[0001] This application is a continuation in part in U.S.
application Ser. No. 07/935,071 filed Aug. 25, 1992.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] 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.
[0004] 2- Related Art
[0005] 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.
[0006] 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.
[0007] 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 0 346 847; EP 0
342,541; Roberts et al, "Rational Design of Peptide-Based
Proteinase Inhibitors," Science, 24, 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).
[0008] 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. 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 sulfamoyl-containing hydroxyethylamine
renin inhibitors and EP 0264795 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 cannot be predicted to be effective HIV
protease inhibitors.
BRIEF DESCRIPTION OF THE INVENTION
[0009] 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 sulfonylalkanoylamino hydroxyethylamino sulfonamide inhibitor
compounds.
DETAILED DESCRIPTION OF THE INVENTION
[0010] In accordance with the present invention, there is provided
a retroviral protease inhibiting compound of the formula: 1
[0011] or a pharmaceutically acceptable salt, prodrug or ester
thereof wherein:
[0012] R represents hydrogen, alkyl, alkenyl, alkynyl,
hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl,
heteroaralkyl, aminocarbonylalkyl, aminoalkylcarbonylalkyl,
aminoalkyl, alkylcarbonylalkyl, aryloxyalkylcarbonylalkyl,
aralkoxycarbonylalkyl radicals and mono- and disubstituted
aminocarbonylalkyl, aminoalkylcarbonylalkyl and 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 radical, said substituents along with the
nitrogen atom to which they are attached, form a heterocycloalkyl
or a heteroaryl radical;
[0013] each x independently represents 0, 1 or 2;
[0014] t represents either 0 or 1;
[0015] R.sup.1, R.sup.20 and R.sup.21 independently represent
hydrogen, --CH2SO.sub.2NH.sub.2, --CH.sub.2CO.sub.2CH.sub.3,
--CO.sub.2CH.sub.3, --CONH.sub.2, --CH.sub.2C(O)NHCH.sub.3,
--C(CH.sub.3).sub.2(SH), --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.2CH.sub.3), alkyl, haloalkyl, alkenyl,
alkynyl and cycloalkyl radicals, and amino acid side chains
selected from asparagine, S-methyl cysteine and the sulfoxide (SO)
and sulfone (SO.sub.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-cyano
alanine and valine side chains; R.sup.2 represents alkyl, aryl,
cycloalkyl, cycloalkylalkyl and aralkyl radicals, which radicals
are optionally substituted with a group selected from --NO.sub.2,
CN, .sup.--C.ident.N,CF.sup..sub.3, OR.sup.9, SR.sup.9, haloalkyl
and halogen and alkyl radicals, wherein R.sup.9 represents hydrogen
and alkyl radicals;
[0016] R.sup.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;
[0017] R.sup.4 represents radicals as defined by R.sup.3, excluding
hydrogen;
[0018] Y represents O,S and NR.sup.15 wherein R.sup.15 represents
hydrogen and radicals as defined for R.sup.3; and
[0019] R.sup.6 represents hydrogen, and alkyl radicals.
[0020] A preferred class of retroviral inhibitor compounds of the
present invention are those represented by the formula: 2
[0021] or a pharmaceutically acceptable salt, prodrug or ester
thereof, preferably wherein the absolute stereochemistry about the
hydroxy group is designated as (R);
[0022] R represents alkyl, alkenyl, alkynyl, cycloalkyl,
hydroxyalkyl, cycloalkylalkyl, heterocycloalkyl,
heterocycloalkylalkyl, alkoxyalkyl, aryl, heteroaryl, aralkyl,
heteroalkyl, heteroaralkyl, aminocarbonylalkyl,
aminoalkylcarbonylalkyl, alkylcarbonylalkyl, aryloxyalkylcarbonyl,
and aralkoxycarbonylalkyl radicals;
[0023] R.sup.1, R.sup.20and R.sup.21 independently represent
hydrogen, --CH.sub.2SO.sub.2NH.sub.2, --CH.sub.2CO.sub.2CH.sub.3,
--CO.sub.2CH.sub.3, --CONH.sub.2, --CH.sub.2C(O)NHCH.sub.3,
--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.2CH.sub.3), alkyl, haloalkyl, alkenyl,
alkynyl and cycloalkyl radicals, and amino acid side chains
selected from asparagine, S-methyl cysteine and the sulfoxide (SO)
and sulfone (SO.sub.2) derivatives thereof, isoleucine,
allo-isoleucine, alanine, leucine, tert-leucine, phenylalanine,
ornithine, histidine, norleucine, glutamine, threonine, glycine,
allo-threonine, serine, O-methyl serine, aspartic acid, beta-cyano
alanine and valine side chains;
[0024] R.sup.2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl,
and aralkyl radicals, which radicals are optionally substituted
with a group selected from alkyl and halogen radicals, NO.sub.2,
CN, .sup.--C.ident.N,CF.sup..sub.3, OR.sup.9 and SR.sup.9 wherein
R.sup.9 represents hydrogen and alkyl radicals, and halogen
radicals;
[0025] R.sup.3 represents alkyl, haloalkyl, alkenyl, hydroxyalkyl,
alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,
heterocycloalkylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl
radicals; and
[0026] R.sup.4 represents radicals as defined by R.sup.3 except for
hydrogen;
[0027] t represents 0 or 1;
[0028] Y represents O, S, and NR.sup.15 wherein R.sup.15 represents
hydrogen and radicals as defined for R.sup.3. Preferably, Y
represents O.
[0029] A preferred class of compounds within Formula I are those
represented by the formula: 3
[0030] or a pharmaceutically acceptable salt, prodrug or ester
thereof wherein R, R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as
defined above, with respect to Formula (II).
[0031] 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, 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 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", alone or in
combination, means a saturated or partially saturated monocyclic,
bicyclic or tricyclic alkyl radical wherein each cyclic moiety
contains from about 3 to about 8 carbon atoms. 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, nitro, cyano, haloalkyl 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
heterocyclyalkyl 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-isoquinol- inyl, etc.), quinoxalinyl,
.beta.-carbolinyl, 2-benzofurancarbonyl, 1-,2-,4- or
5-benzimidazolyl, 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 "heterocyclylalkanoyl" 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 "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 in the art. Examples of such leaving groups
include, but are not limited to, N-hydroxysuccinimide,
N-hydroxybenzotriazole, halides, triflates, tosylates and the like.
Preferred leaving groups are indicated herein where
appropriate.
[0032] 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 absolute stereochemistry
about the hydroxyl group is designated as (R). However, such
procedures are generally applicable to those compounds of opposite
configuration, e.g., where the stereochemistry about the hydroxyl
group is (S). In addition, the compounds having the (R)
stereochemistry can be utilized to produce those having the (S)
stereochemistry, and vice versa. For example, a compound having the
(R) stereochemistry can be inverted to the (S) stereochemistry
using well-known methods.
[0033] Preparation of Compounds of Formula I
[0034] 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: 4
[0035] 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, e.g., such as 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), band subsequently N-protected utilizing procedures which
are well known in the art.
[0036] The halo alcohol can be used directly, as described below,
or, preferably, 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: 5
[0037] 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.
[0038] 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: 6
[0039] wherein P.sup.1 and p.sup.2 independently represent
hydrogen, benzyl and amino-protecting groups (as defined above with
respect to P), provided that P.sup.1 and p.sup.2 are not both
hydrogen; P3 is a carboxyl protecting group (such as methyl, ethyl,
tertiary-butyl, benzyl and the like); and R.sup.2 is as defined
above.
[0040] 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, for example, by way of a Swern
oxidation, to the corresponding aldehyde of the formula: 7
[0041] 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 to -68.degree. C.) solution of oxalyl chloride in
dichloromethane and DMSO in dichloromethane and stirred for 35
minutes.
[0042] 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.1CH.sub.2X.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: 8
[0043] The diastereomers can be separated e.g., by chromatography,
or, alternatively, once reacted in subsequent steps the
diastereomeric products can be separated. For compounds having the
(S) stereochemistry, a D-amino acid can be utilized in place of the
L-amino acid.
[0044] 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:
R.sup.3NH.sub.2
[0045] 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 protic, non-protic and dipolar aprotic organic solvents
such as, for example, 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.3NH.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)
represented by the formulas: 9
[0046] wherein P, P1, P2, R.sup.2 and R.sup.3 are as described
above. Alternatively, a haloalcohol can be utilized in place of the
amino epoxide.
[0047] The amino alcohol defined above is then reacted in a
suitable solvent with a sulfonyl chloride (R.sup.4SO.sub.2Cl) or
sulfonyl anhydride in the presence of an acid scavenger. Suitable
solvents in which the reaction can be conducted include methylene
chloride, tetrahydrofuran and the like. Suitable acid scavangers
include triethylamino, pyridine and the like. Preferred sulfonyl
chlorides are methane sulfonyl chloride and benzenesulfonyl
chloride. The resulting sulfonamide derivative can be represented,
depending on the epoxide utilized, by the formulas 10
[0048] wherein P, P.sup.1, P.sup.2, R.sup.2, R.sup.3 and R.sup.4
are as defined above. These intermediates are useful for preparing
inhibitor compounds of the present invention and are also active
inhibitors of retroviral proteases.
[0049] The sulfonyl halides of the formula R.sup.4SO.sub.2X can be
prepared by the reaction of a suitable Grignard or alkyl lithium
reagent with sulfuryl chloride, or sulfur dioxide followed by
oxidation with a halogen, preferably chlorine. Also, thiols may be
oxidized to sulfonyl chlorides using chlorine in the presence of
water under carefully controlled conditions. Additionally, sulfonic
acids may be converted to sulfonyl halides using reagents such as
PCl.sub.5, and also to anhydrides using suitable dehydrating
reagents. The sulfonic acids may in turn be prepared using
procedures well known in the art. Such sulfonic acids are also
commercially available.
[0050] In place of the sulfonyl halides, sulfinyl halides
(R.sup.4SOCl) and sulfenyl halides (R.sup.4SCl) can be utilized to
produce compounds wherein the --SO.sub.2-- moiety is replaced by
--SO-- and --S--, respectively.
[0051] Following preparation of the sulfonamide derivative, the
amino protecting group P is removed, or the groups P.sup.1 and
P.sup.2 are 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 can 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 product is the amine salt
derivative. Where the protecting group is a benzyl radical, it can
be removed by hydrogenolysis. Following neutralization of the salt,
the amine is then reacted with a sulfone of the formula: 11
[0052] Wherein R, R.sup.1, R.sup.26, R.sup.21 and t are as defined
above. The sulfone is prepared according to the following
procedure.
[0053] A mercaptan of the formula RSH is reacted with a substituted
methacrylate of the formula: 12
[0054] 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: 13
[0055] 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 a carboxyl protecting group
such as methyl, ethyl, benzyl, t-butyl or the like. Suitable
solvents in which the Michael Addition can be conducted include
protic, non-protic and dipolar aprotic organic solvents, e.g.,
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.
[0056] The thiol derivative is converted into the corresponding
sulfone or sulfoxide of the formula: 14
[0057] 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, periodic 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.
[0058] The sulfone is then converted to the corresponding free acid
of the formula: 15
[0059] One method involves 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, water,
acetonitrile, DMF, DMSO, methylene chloride and the like, including
mixtures thereof. Other methods which can be used for deprotection
depend on the nature of R.sup.22 . For example, when R.sup.22 is a
tertiary-butyl group, one can use a strong acid such as
hydrochloric acid or trifluoroacetic acid. When R.sup.22 is a
benzyl group, it can be removed via hydrogenolysis.
[0060] The free acid is then coupled, utilizing procedures well
known in the art, to the sulfonamide derivative, or analog thereof,
of an amino alcohol which is described above. The resulting product
is a compound represented by Formula I.
[0061] Alternatively, one can couple the sulfonamide isostere to
the commercially available acid, 16
[0062] 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: 17
[0063] The sulfur can then be oxidized to the corresponding sulfone
or sulfoxide using suitable oxidizing agents, as described above,
to afford the desired compounds of the following structure: 18
[0064] Alternatively, to prepare compounds of Formula I, a
substituted methacrylate of the formula: 19
[0065] 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 RSO.sub.2M, 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: 20
[0066] 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: 21
[0067] 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: 22
[0068] 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
sulfonamide isostere, as described above, to produce compounds of
Formula II.
[0069] Alternatively, an acid or a derivative of an acid properly
substituted with a leaving group (discussed above) can be treated
with a Mercaptan and a base (see above) to provide an organic
sulfide. Acid derivatives are defined above. The resulting sulfide
can be oxidized to the corresponding sulfoxide or sulfone by
methods previously discussed.
[0070] A preferred method to prepare
2(S)-methyl-3-(methylsulfonyl)propion- ic acid is as follows.
Beginning with the commercially available compounds of the
following structure; 23
[0071] Where P.sup.3 is a protecting group for sulfur; preferably a
benzoyl or acetyl, and P.sup.4 is either hydrogen or a carboxylic
acid protecting group such as methyl, ethyl, tertiary-butyl, benzyl
and the like. Preferably, P.sup.4 is tertiary-butyl. The sulfur
protecting group P.sup.3 can be selectively removed using methods
known to those skilled in the art. For example, where P3 is either
benzoyl or acetyl, it can be removed by treatment with an inorganic
base or an amine, preferably ammonia, in an appropriate solvent
such as methanol, ethanol, isopropanol, toluene or tetrahydrofuran.
The preferred solvent is methanol. This provides a compound of the
following structure; 24
[0072] which can be alkylated on the sulfur with a compound of the
structure
RX
[0073] Where R is as defined above, and X is an appropriate leaving
group, such as a halide (chloride, bromide, iodide), mesylate,
tosylate or triflate. The reaction is performed in the presence of
a suitable base, such as triethylamine, diisopropylethylamine,
1,8-diazabicyclo(5.4.0] undec-7-ene (DBu) and the like, in a
suitable solvent such as toluene, tetrahydrofuran, or methylene
chloride. The preferred base is DBU and the preferred solvent is
toluene. Where R is a methyl group, RX can be methyl chloride,
methyl. bromide, methyl iodide, or dimethyl sulfate. Preferably RX
is methyl iodide. The product of the reaction is a compound of the
structure; 25
[0074] The sulfur can then be oxidized to either the sulfoxide or
sulfone using methods known to those skilled in the art. Suitable
oxidizing agents are meta-chloroperbenzoic acid, hydrogen peroxide,
sodium perborate and the like. Appropriate solvents are methylene
chloride, toluene, acetic acid, propionic acid and the like. The
preferred method is using hydrogen peroxide or sodium perborate in
acetic acid. The sulfone product has the structure; 26
[0075] The carboxylic acid protecting group P.sup.4can-then be
removed using methods well known to those in the art. For example,
when P.sup.4 is a tertiary-butyl group, it can be removed by
treatment with an acid, such as hydrochloric acid or trifluoracetic
acid. The preferred method is using 4N hydrochloric acid in
dioxane. This provides the desired final compound of the structure;
27
[0076] It is envisioned that one skilled in the art could utilize
variations on the synthetic sequence such as the use of different
protecting groups for the sulfur (P.sup.3) or for the carboxylic
acid (P.sup.4), and different reagents to carry out the same
transformations.
[0077] 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
sulfonamide derivative or analog thereof to the sulfone carried
through a procedure referred to in the art as reductive amination.
Thus, a sodium cyanoborohydride and an appropriate aldehyde or
ketone can be reacted with the sulfonamide derivative compound or
appropriate analog at room temperature in order to reductively
aminate any of the compounds of Formulas I-III. It is also
contemplated that where R.sup.3 of the amino alcohol intermediate
is hydrogen, the inhibitor compounds 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.
[0078] 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 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.
[0079] 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.
[0080] 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.
[0081] 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.
EXAMPLE 1A
[0082] Preparation of
N[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylb-
utyl]-N-isoamylamine. 28
[0083] Part A
[0084] To a solution of N-benzyloxycarbonyl-L-phenylalanine
chloromethyl ketone (75 g, 0.2 mol) in a mixture of 800 mL of
methanol and 800 mL of tetrahydrofuran was added sodium borohydride
(13.17 g, 0.348 mol, 1.54 equiv.) over 100 min. The solution was
stirred at room temperature for 2 h and then concentrated in vacuo.
The residue was dissolved in 1000 mL of ethyl acetate and washed
with 1N KHSO.sub.4, saturated aqueous NaHCO.sub.3, saturated
aqueous NaCl, dried over anhyd MgSO.sub.4, filtered and
concentrated in vacuo to give an oil. The crude product was
dissolved in 1000 mL of hexanes at 60.degree. C. and allowed to
cool to room temperature whereupon crystals formed that were
isolated by filtration and washed with copious amounts of hexanes.
This solid was then recrystallized from hot ethyl acetate and
hexanes to provide 32.3 g 43% of
N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp
150-151.degree. C., FAB MS: MLi.sup.+=340.
[0085] Part B
[0086] A solution of potassium hydroxide (6.52 g, 0.116 mol, 1.2
equiv.) in 970 mL of absolute ethanol was treated with
N-benzyloxycarbonyl-3(S)-a- mino-1-chloro-4-phenyl-2(s)-butanol
(32.3 g, 0.097 mol). This solution was stirred at room temperature
for 15 min and then concentrated in vacuo to give a white solid.
The solid was dissolved in dichloromethane and washed with water,
dried over anhyd MgSO.sub.4, filtered and concentrated in vacuo to
give a white solid. The solid was crystallized from hexanes and
ethyl acetate to give 22.3 g, 77% of
N-benzyloxycarbonyl-3(S)-amino-1,2(S- )epoxy-4-phenylbutane, mp
102-103.degree. C., FAB MS: MH.sup.+=298.
[0087] Part C
[0088] A solution of
N-benzyloxycarbonyl-3(S)-amino-1,2(S)epoxy-4-phenylbu- tane (11.54
g, 38.81 mmol) and isoamylamine (66.90 g, 0.767 mol, 19.9
equivalents) in 90 mL of isopropyl alcohol was heated to reflux for
3.1 h. The solution was cooled to room temperature and partially
concentrated in vacuo and the remaining solution poured into 200 mL
of stirring hexanes whereupon the product crystallized from
solution. The product was isolated by filtration and air dried to
give 11.76 g, 79% of
N[[3(S)-phenylmethylcarbamoyl)amino-2(R)-hydroxy-4-phenylbutyl]N-[(3-meth-
ylbutyl)]amine, mp 118-122.degree. C., FAB MS: MH.sup.+=385.
EXAMPLE 1B
Preparation of
N-[(3S-(phenylmethylcarbamoyl)amino]-2R-hydroxy-4-phenyl]-1-
-[(2-methylpropyl)amino-2-(1,1-dimethylethoxyl)carbonyl]butane
[0089] 29
[0090] To a solution of 7.51g (20.3 mmol) of
N-[(3S-(phenylmethylcarbamoyl-
)amino]-2R-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)]amine in 67 mL
of anhydrous tetrahydrofuran was added 2.25 g (22.3 mmol) of
triethylamine. After cooling to O C, 4.4 g (20.3 mmol) of
di-tert-butyldicarbonate was added and stirring continued at room
temperature for 21 hours. The volatiles were removed in vacuo,
ethyl acetate added, then washed with 5% citric acid, saturated
sodium bicarbonate, brine, dried over magnesium sulfate, filtered
and concentrated to afford 9.6 g of crude product. Chromatography
on silica gel using 30% ethyl acetate/hexane afforded 8.2 g of pure
N-([3S-(phenylmethylcarbamoyl)amino]-2R-hydroxy-4-phenyl]-1-((2-
-methylpropyl)amino-2-(1,1-dimethylethoxyl)carbonyl]butane, mass
spectrum m/e=477 (M+Li).
EXAMPLE 2
[0091] 30
Preparation of Propanamide,
N-[2-hydroxy-3[(3-methylbutyl)(4-methoxyphenyl-
sulfonyl)amino]-1-(phenylmethyl)propyl]-2-methyl-3-(methylsulfonyl)-[1S-[1-
R*(R*),2S*]]-
[0092] Part A
[0093] A solution of the amino alcohol from Example 1, Part C
(1.1515 g, 2.99 mmol), and triethylamine (313.5 mg, 3.10 mmol) in
15 mL of dichloromethane was treated with 4-methoxybenzenesulfonyl
chloride (630.6 mg, 3.05 mmol) via syringe. The solution was
stirred at room temperature for 40 min and then concentrated in
vacuo. The residue was dissolved in ethyl acetate and washed with
1N KHSO.sub.4, saturated aqueous NaHCO.sub.3, brine, dried over
anhyd MgSO.sub.4, filtered and concentrated to give 1.5622 g, of a
white foam. The crude product was purified by recrystallization
from a mixture of hexanes and ethyl acetate to give 1.1047 g, 67%
of pure product mp 95-98.degree. C. High resolution FAB Mass
spectrum calc'd. for C.sub.30H.sub.38N.sub.2O.sub.6S: 555.2529.
Found: 555.2559.
[0094] Part B
[0095] A solution of the product from Part A (970 mg, 1.68 mmol) in
30 mL of methanol was treated with 70 mg of 10% palladium on carbon
catalyst and hydrogenated at 41 psig for 16 h at room temperature.
The catalyst was removed by filtration and the filtrate
concentrated in vacuo to give a clear oil that solidified upon
standing, mp 81-85.degree. C., FAB MS; MH.sup.+=421, 764.1 mg that
was used directly in the next step.
[0096] Part C
[0097] A mixture of 2(S)-methyl-3-methylsulfonyl propionic acid
(194 mg, 1.17 mmol), N-hydroxybenzotriazole (276 mg, 1.34 mmol),
and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDC) (256 mg, 1.34 mmol) was dissolved in 3.5 mL of
dimethylformamide (DMF) and allowed to react for 30 min at
0.degree. C. The amine from Part B (451.1 mg, 1.07 mmol) dissolved
in 1.5 mL of DMF was added to the above mixture and stirred at room
temperature for 16 h. The solution was then poured into 20 mL of
saturated aqueous NaHCO.sub.3 and extracted 4 times with ethyl
acetate. The combined ethyl acetate extracts were washed with 5%
aqueous citric acid, saturated aqueous NaHCO.sub.3, brine, dried
over anhyd MgSO.sub.4, filtered and concentrated to give a clear
oil that crystallized upon standing. The material was
recrystallized from hexanes and ethyl acetate to give 517.6 mg, 35%
of pure product with mp 125-129.degree. C. HRFAB MS: calc'd. for
C.sub.27H.sub.40N.sub.2O.sub.7S.- sub.2: 569.2355. Found:
569.2397.
EXAMPLE 3
[0098] 31
Preparation of Propanamide,
N-[2-hydroxy-3-[(2-methylpropyl)(phenylsulfony-
l)amino]-1-(phenylmethyl)propyl]-2-methyl-3-(methylsulfonyl)-,
[1S-[1R*(R*),2S*]]-
[0099] Part A
[0100] A solution of
N-benzyloxycarbonyl-3(S)-amino-1,2-(S)-epoxy-4-phenyl butane (50.0
g, 0.168 mol) and isobutylamine (246 g, 3.24 mol, 20 equivalents)
in 650 mL of isopropyl alcohol was heated to reflux for 1.25 hours.
The solution was cooled to room temperature, concentrated in vacuo
and then poured into 1 L of stirring hexane whereupon the product
crystallized from solution. The product was isolated by filtration
and air dried to give 57.56 g, 92% of
N[3(S)-benzyloxycarbonylamino-2(R)-hydr-
oxy-4-phenyl]N-isobutylamine, mp 108.0-109.5.degree. C.,
MH+m/z=371.
[0101] Part B
[0102] The amine from Part A (936.5 mg, 2.53 mmol) and
triethylamine (288.5 mg, 2.85 mmol) was dissolved in 20 mL of
dichloromethane and treated with benzenesulfonyl chloride (461 mg,
2.61 mmol). The solution was stirred at room temperature for 16 h
and then concentrated in vacuo. The residue was dissolved in ethyl
acetate and this solution was washed with 1N KHSO.sub.4, saturated
aqueous NaHCO.sub.3, brine, dried over anhyd MgSO.sub.4, filtered,
and concentrated to give a clear oil 1.234 g. The oil was
crystallized from a mixture of ether and hexanes, 729.3 mg, 56.5%,
mp 95-99.degree. C., FAB MS; MH.sup.+=511.
[0103] Part C
[0104] A solution of phenylmethyl
[2(R)-hydroxy-3-[2-methylpropyl](benzene-
sulfonyl)amino]1-S-(phenylmethyl) propyl carbamate (671.1 mg, 1.31
mmol) from Part B in 10 mL of methanol was hydrogenated over 50 mg
of 10% palladium on carbon at 40 psig at room temperature for 15 h.
The catalyst was removed by filtration through diatomaceous earth
and the filtrate concentrated to give a white foam, 474.5 mg, 96%,
FAB Ms; MH.sup.+=377, which was used directly in the next step
without further purification.
[0105] Part D
[0106] A mixture of 2(S)methyl-3(methylsulfonyl)propionic acid
(210.6 mg, 1.27 mmol), N-hydroxybenzotriazole (260.4 mg, 1.70 mmol)
and EDC (259 mg, 1.35 mmol) in 3.5 mL of DMF was stirred at
0.degree. C. for 0.5 h. The amine from Part C (474 mg, 1.15 mmol)
dissolved in 2 mL of DMF was added to the above solution and
stirred at room temperature for 16 h and then poured into 100 mL of
50% saturated aqueous NaHCO.sub.3. The aqueous solution was
extracted with ethyl acetate. The ethyl acetate solution was washed
with 5% aqueous citric acid, saturated aqueous NaHCO.sub.3, brine,
dried over anhyd MgSO.sub.4, filtered and concentrated to give a
white foam, 560.5 mg which was crystallized from ethyl acetate and
hexanes to provide 440.3 mg of pure product, mp 112-116.5.degree.
C., HR FAB MS; Calc'd for C.sub.25H.sub.36N.sub.2O.sub.6S.sub.2:
525.2093. Found: 525.2077
EXAMPLE 4
[0107] 32
Preparation of Propanamide,
N-[2-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl-
)amino]-1-(phenylmethyl)propyl]-2-methyl-3-(methylsulfonyl)-,
[1S-[1R*(R*),2S*]]-
[0108] Part A
[0109] A mixture of
N[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbut-
yl]N-((3-methylbutyl)]amine (Example 1, Part C) (3.89 g, 10.1 mmol)
and triethylamine (1.02 g, 10.1 mmol) were dissolved in 25 mL of
tetrahydrofuran (THF) and treated with a solution of
di-tert-butylpyrocarbonate (2.21 g, 10.1 mmol) dissolved in 10 mL
of THF. The solution was stirred at room temperature for 1.5 h and
then concentrated in vacuo. The residue was dissolved in ethyl
acetate and washed with IN KHSO.sub.4, saturated aqueous
NaHCO.sub.3, brine, dried over anhyd MgSO.sub.4, filtered and
concentrated to give a thick clear oil, 4.66 g, 98.5%, R.sub.f=0.23
on silica gel eluting with 5:1 hexanes:ethyl acetate. This material
was used directly in the next step without further
purification.
[0110] Part B
[0111] The product from Part A (4.66 g, 10.1 mmol) was dissolved in
40 mL of anhyd ethanol and treated with 30 mg of 15% palladium on
carbon catalyst. This mixture 30 was then hydrogenated for 18 h at
room temperature and 40 psig. The catalyst was removed by
filtration through diatomaceous earth and the filtrate concentrated
to give an oil that was used directly in the next step without
purification.
[0112] Part C
[0113] A mixture of 2(S)-methyl-3-methylsulfonyl propionic acid
(1.39 g, 8.3 mmol), N-hydroxybenzotriazole (1.84 g, 12.0 mmol), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)
(1.77 g, 9.2 mmol) was dissolved in 10 mL of dimethylformamide
(DMF) and allowed to react for 30 min at 0.degree. C. The amine
from Part B (2.80 g, 8.0 mmol) dissolved in 10 mL of DMF was added
to the above mixture and stirred at room temperature for 24 h. The
solution was concentrated in vacuo and the residue taken up in
ethyl acetate. The ethyl acetate solution was washed with 5%
aqueous citric acid, saturated aqueous NaHCO.sub.3, brine, dried
over anhyd MgSO.sub.4, filtered and concentrated to give a clear
oil, that was purified by flash chromatography to give 3.00 g, 75%,
this material was used directly in the next step.
[0114] Part D
[0115] The product from Part C (3.00 g, 6.02 mmol) was treated with
30 mL of 4N HCl in dioxane at room temperature for 24 h. The
solution was concentrated in vacuo and the semi-solid residue was
triturated with ether and dried under vacuum to give a white
amorphous solid, mp>250.degree. C., turns yellow at 221.degree.
C., FAB MS, MH.sup.+=436.
[0116] Part E
[0117] The product from Part D was dissolved in dichloromethane and
treated with saturated aqueous NaHCO.sub.3 to provide a solution of
the free amine. The organic phase was dried over anhyd MgSO.sub.4,
filtered and concentrated in vacuo to give (610 mg, 1.75 mmol).
This amine was suspended in 50 mL of THF and treated sequentially
with triethylamine (1.01 g, 10 mmol) and benzenesulfonyl chloride
(283 mg, 1.75 mmol). The solution was stirred at room temperature
for 19.5 h. The solids were removed by filtration and the filtrate
concentrated and dissolved in dichloromethane. The dichloromethane
solution was washed with 1N KHSO.sub.4, saturated aqueous
NaHCO.sub.3, brine, dried over anhyd MgSO.sub.4, filtered and
concentrated to give an oil that was triturated with methanol to
give a white solid that was isolated by filtration. The crude solid
was then crystallized from ethyl acetate and hexanes to give 200
mg, 21% of material with mp 112-115.degree. C., HRFAB MS, calc'd.
for C.sub.26H.sub.38N.sub.2O.sub.6S.sub.2: 538.2171. Found:
533.2180.
EXAMPLE 5
[0118] 33
Preparation of Propanamide,
N-[2-hydroxy-3-(propyl)(phenylsulfonyl)amino]--
1-(phenylmethyl)propyl]-2-methyl-3-(methylsulfonyl)-,
[1S-[1R*(R*),2S*]]-
[0119] Part A
[0120] A solution of N-benzyloxycarbonyl
3(S)-amino-1,2-(S)-epoxy-4-phenyl- butane (6.06 g, 20.4 mmol) and
n-propylamine (20.9 g, 0.35 mmol) in 100 mL of isopropyl alcohol
was heated to reflux for 3 h. The solution was then concentrated,in
vacuo to give a solid that was crystallized from hexanes and ethyl
acetate to give 6.53 g, 90%, of the desired product, mp
120-123.degree. C., FAB MS: MH.sup.+=357.
[0121] Part B
[0122] The amine from Part A was reacted with benzenesulfonyl
chloride in a manner similar to Example 3, Part B. The resulting
compound (1.426 g, 2.87 mmol) dissolved in 25 mL of methanol was
hydrogenated over 40 mg of 10% palladium on carbon at 40 psig for
16 h at room temperature. The solution was then filtered through
diatomaceous earth and the filtrate concentrated to give 1.04 g,
100%, of a clear oil that was used directly in the next step
without further purification, HRFAB MS Calc'd for
C.sub.19H.sub.24N.sub.2O.sub.3S: 363.1742. Found: 363.1763.
[0123] Part C
[0124] A mixture of 2(S)methyl-3(methylsulfonyl)propionic acid
(243.7 mg, 1.47 mmol), N-hydroxybenzotriazole (332.0 mg, 2.16
mmol), and EDC (304.8 mg, 1.59 mmol) in 2.5 mL of DMF was stirred
at 0.degree. C. for 0.5 h and then treated with a solution of the
free amine from Part B (513.3 mg, 1.42 mmol) in 1.5 mL of DMF. The
solution was stirred at room temperature for 16 h and then poured
into 80 mL of 50% saturated aqueous NaHCO.sub.3. The solution was
extracted with ethyl acetate and the ethyl acetate solution was
washed with 5% aqueous citric acid, saturated aqueous NaHCO.sub.3,
brine, dried over anhyd MgSO.sub.4, filtered and concentrated to
give a white foam, 576.8 mg, that was purified by crystallized
ethyl acetate/hexanes to give 441.1 mg, 61% of product with mp
134-136.5.degree. C., HRFAB MS, Calc'd for
C.sub.24H.sub.34N.sub.2O.su- b.6S.sub.2+Li: 517.2019. Found:
517.1973.
EXAMPLE 6
[0125] 34
Preparation of Propranamide,
N-[2-hydroxy-3-(butyl)(phenylsulfonyl)amino]--
1-(phenylmethyl)propyl]-2-methyl-3-(methylsulfonyl)-,[1S-[1R*(R*),2S*]]-
[0126] Part A
[0127] From the reaction of (1.48 g, 5.0 mmol) of
N-benzyloxycarbonyl 3(S)-amino-1,2-(S)-epoxy-4-phenylbutane and
(7.314 g, 100.0 mmol) of n-butylamine, one obtains 1.50 g (80%) of
N-(3(S)-benzyloxycarbonylamino--
2(R)-hydroxy-4-phenylbutyl]-N-butylamine, mp 125-128.degree. C.,
FAB MS, Spectrum: MH.sup.+=371.
[0128] Part B
[0129] The amine from Part A (1.67 g, 4.5 mmol) and triethylamine
(859.4 mg), was dissolved in 60 mL of dichloromethane and treated
with benzene sulfonyl chloride (822.3 mg, 4.66 mmol) at room
temperature. After stirring for 15 min. the solution was
concentrated in vacuo and the residue dissolved in ethyl acetate.
The ethyl acetate solution was washed with 1N KHSO.sub.4, saturated
aqueous NaHCO.sub.3, brine, dried over anhyd MgSO.sub.4, filtered
and concentrated to give an oil. The oil was crystallized from
hexanes and ether to give 2.04 g 89% of pure product, mp
68-77.degree. C., FAB MS: MH.sup.+=511.
[0130] Part C
[0131] A solution of phenylmethyl
[2(R)-hydroxy-3-[n-butyl](benzenesulfony-
l)amino]-1S-(phenylmethyl)-propyl carbamate from Part B (1.86 g,
3.64 mmol) in 40 mL of methanol was hydrogenated over 110 mg of 10%
palladium on carbon at 40 psig for 4 h. The solution was filtered
through diamtomaceous earth and concentrated in vacuo to give a
solid, mp 68-88.degree. C., FAB MS: MH.sup.+=377, that was used in
the next step without further purification.
[0132] Part D
[0133] A mixture of 2(S)methyl-3(methylsulfonyl)propionic
acid(288.4 mg, 1.74 mmol), EDC (369.6 mg, 1.93 mmol), and
N-hydroxybenzotriazole (368.1 mg, 2.41 mmol) was dissolved in 3.5
mL of DMF and stirred at ).degree. C. for 30 min. This solution was
then treated with the amine from Part C (621.9 mg, 1.65 mmol)
dissolved in 2 mL of DMF. The mixture was allowed to stir at room
temperature for 48 h and then was concentrated in vacuo. The
residue was dissolved in ethyl acetate, washed with 1N KHSO.sub.4,
saturated aqueous NaHCO.sub.3, brine, dried over anhyd MgSO.sub.4,
filtered and concentrated in vacuo to give an oil. The crude
product was purified by flash chromatography on silica get eluting
with hexanes/ethyl acetate mixtures to give the desired product as
a white solid, 353 mg, 41%, mp 99-103.degree. C., HRFAB MS: Calc'd
for C.sub.25H.sub.36N.sub.2O.- sub.6S.sub.2: 531.2175. Found:
513.2176
EXAMPLE 7
[0134] 35
Preparation of Propanamide,
N-[2-hydroxy-3-[(2-methylpropyl)(4-methoxyphen-
ylsulfonyl)amino]-1-(phenylmethyl)propyl]-2-methyl-3-(methylsulfonyl)-,
[1S-[1R*(R*),2S*]]-
[0135] Part A
[0136] The amine from Example 3, Part A,
N(3(S)-benzyloxy-carbonylamino-2(- R)-hydroxy-4-phenyl]N-isobutyl
amine (1.1131 g, 3.00 mmol) and triethylamine (324.0 mg, 3.20 mmol)
in 20 mL of dichloromethane was treated with
4-methoxy-benzenesulfonyl chloride (715.4 mg, 3.46 mmol). The
solution was stirred at room temperature for 6 h and then was
concentrated in vacuo. The residue was dissolved in ethyl acetate
and washed with 1N KHSO.sub.4, saturated aqueous NaHCO.sub.3,
brine, dried over anhyd MgSO.sub.4, filtered, and concentrated to
give a clear oil. The oil was crystallized from ether to give a
white solid 1.273 g, 78%, mp 97-101.degree. C., of pure product,
FAB MS; MH.sup.+=541.
[0137] Part B
[0138] The product from Part A (930 mg, 1.68 mmol) was dissolved in
30 mL of methanol and hydrogenated at 40 psig over 70 mg of 10%
palladium on carbon at room temperature for 17 h. The catalyst was
removed by filtration through diatomaceous earth and the filtrate
was concentrated in vacuo to give 704 mg of a clear oil, that
solidified upon standing, mp 105-110.degree. C., FAB MS,
MH.sup.+=407, and was used directly in the next step without
further purification.
[0139] Part C
[0140] A mixture of 2-methyl-3(methylsulfonyl)propionic acid (174.9
mg, 1.05 mmol), N-hydroxybenzotriazole (230 mg, 1.50 mmol) and EDC
(220.5 mg, 1.15 mmol) in 2 mL of DMF was stirred at 0.degree. C.
for 0.5 mL and then treated with the amine from Part B (401.2 mg,
0.99 mmol) in 1 mL of DMF. The solution was stirred at room
temperature for 16 h and then poured into 20 mL of saturated
aqueous NaHCO.sub.3. The aqueous solution was extracted with ethyl
acetate and then the ethyl acetate solution was washed with 5%
aqueous citric acid, saturated aqueous NaHCO.sub.3, brine, dried
over anhyd MgSO.sub.4, filtered and concentrated in vacuo to give a
clear oil, 260 mg, which was purified by flash chromatography on
Silica gel eluting with hexanes and ethyl acetate to provide 52.7
mg, 9.6%, mp 87-92.degree. C., HRFAB MS; Calc'd for
C.sub.26H.sub.38N.sub.2O.sub.7S.su- b.2: 555.2199. Found:
555.2234
EXAMPLE 8
[0141] 36
Preparation of Propanamide,
N-[2-hydroxy-3-[(butyl)(4-methoxyphenylsulfony-
l)amino]-1-(phenylmethyl)propyl]-2-methyl-3-(methylsulfonyl)-,
[1S-[1R*(R*),2S*]]-
[0142] Part A
[0143] The amine from Example 6, Part A (1.52 mg, 4.10 mmol) and
triethylamine (488 mg, 4.82 mmol) in 30 mL of dichloromethane was
treated with 4-methoxybenzenesulfonyl chloride (869 mg, 4.20 mmol)
at room temperature for 3 h. The solution was removed in vacuo and
the residue was taken up in ethyl acetate. The ethyl acetate
solution was washed with 1N KHSO.sub.4, saturated aqueous
NaHCO.sub.3, brine, dried over anhyd MgSO.sub.4, filtered and
concentrated to give a white solid that was washed with ether and
air dried to provide 1.71 g, 77%, mp 118-120.degree. C., FAB MS;
M+Li=547, of pure product.
[0144] Part B
[0145] The product from Part A (1.514 g, 2.80 mmol) in 30 mL of
methanol was hydrogenated at 40 psig over 110 mg of 10% palladium
on carbon for 16 h at room temperature. The catalyst was removed by
filtration through diatomaceous earth and the filtrate concentrated
to give a white solid, 1.20 g, 100%., mp 103-108.degree. C., HRFAB
MS; Calc'd for C.sub.21H.sub.30N.sub.2O.sub.4S: 413.2086. Found:
413.2121, which was used directly in the next step without further
purification.
[0146] Part C
[0147] A mixture of 2(S)-methyl-3(methylsulfonyl)propionic acid
(354.4 mg, 2.13 mmol), N-hydroxybenzotriazole (473.4 mg, 3.09 mmol)
and EDC (445.3 mg, 2.33 mmol) in 1.5 mL of DMF was stirred at
0.degree. C. for 25 min. and then treated with the amine from Part
B (815 mg, 2.00 mmol) in 2 mL of DMF. The mixture was stirred at
room temperature for 16 h and then poured into 50 mL of saturated
aqueous NaHCO.sub.3 and then extracted with ethyl acetate. The
ethyl acetate solution was washed with 5% aqueous citric acid,
saturated aqueous NaHCO.sub.3, brine, dried over anhyd MgSO.sub.4,
filtered and concentrated in vacuo to give 905 mg of a white foam.
The product was purified by flash chromatography on Silica gel
eluting with ethyl acetate/hexanes to provide 711.6 mg, 65%, of
pure product, mp 87-92.degree. C., HRFAB MS, M+Li; Calc'd for
C.sub.26H.sub.38N.sub.2O.sub.7S.sub.2Li: 561.2281 Found:
561.2346
EXAMPLE 9
[0148] 37
Preparation of Propanamide.
N-[2-hydroxy-3-[(propyl)(4-methoxyphenylsulfon-
yl)amino]-1-(phenylmethyl)propyl]-2-methyl-3-(methylsulfonyl)-,
[1S-[1R*(R*),2S*]]-
[0149] Part A
[0150] A solution of the product from Example 5, Part A (620 mg,
1.74 mmol) and triethylamine (250 mg, 2.47 mmol) in 15 mL of
dichloromethane was treated with 4-methoxybenzenesulfonyl chloride
(371 mg, 1.79 mmol) at room temperature for 2.33 h. The solvent was
removed in vacuo and the residue taken up in ethyl acetate and then
washed with 1N KHSO.sub.4, saturated aqueous NaHCO, brine, dried
over anhyd MgSO.sub.4, filtered and concentrated to give 1.0622 g,
of a white foam. The crude product was purified by flash
chromatography over silica gel eluting with hexanes and ethyl
acetate to give 615 mg, 67%, of pure product with mp 88-92.degree.
C., HRFAB MS; calc'd. for C.sub.28H.sub.34N.sub.2O.sub.6S:
533.2298. Found: 533.2329.
[0151] Part B
[0152] A solution of carbamic acid, product from Part A (519 mg,
0.98 mmol) in 30 mL of methanol was treated with 70 mg of 10%
palladium on carbon catalyst and hydrogenated at 46 psig for 22 h
at room temperature. The catalyst was removed by filtration through
diatomaceous earth and the filtrate concentrated in vacuo to give a
clear oil that solidified upon standing, mp 124-127.degree. C., FAB
MS; M+Li.sup.+=399, 387 mg, 100%, that was used directly in the
next step.
[0153] Part C
[0154] A mixture of 2(S)-methyl-3-methylsulfonyl propionic acid
(138.5 mg, 0.83 mmol), N-hydroxybenzotriazole (174.6 mg, 1.14
mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC) (171.8 mg, 0.90 mmol) was dissolved in 2.5 mL
of dimethylformamide (DMF) and allowed to react for 30 min at
0.degree. C. The amine from Part B (304.9 mg, 0.78 mmol) dissolved
in 1.5 mL of DMF was added to the above mixture and stirred at room
temperature for 14.5 h. The solution was then poured into 20 mL of
saturated aqueous NaHCO.sub.3 and extracted with ethyl acetate. The
ethyl acetate extracts were washed with 5% aqueous citric acid,
saturated aqueous NaHCO.sub.3, brine, dried over anhyd MgSO.sub.4,
filtered and concentrated to give a white solid. The material was
recrystallized from hexanes and ethyl acetate to give 228 mg, 54%
of pure product with mp 115-118.degree. C. HRFAB MS; calc'd. for
C.sub.27H.sub.40N.sub.2O.sub.7S.sub.2: 541.2042. Found:
541.2064.
EXAMPLE 10
[0155] 38
Preparation of Propanamide,
N-[2-hydroxy-3-[(2-methylpropyl)(4-acetamido)p-
henylsulfonyl)amino]-1-(phenylmethyl)propyl]-2-methyl-3-(methylsulfonyl)-[-
1S-[1R*(R*)2S*]]-
[0156] Part A
[0157] A solution of the product from Example 3, Part A (1.1082 g,
2.99 mmol) and triethylamine (713 mg, 3.05 mmol) in 20 mL of
dichloromethane was treated with N-acetylsulfanilyl chloride (713.2
mg, 3.05 mmol) at room temperature for 3.67 h. The solvent was
removed in vacuo and the residue taken up in ethyl-acetate and then
washed with 1N KHSO.sub.4, saturated aqueous NaHCO.sub.3, brine,
dried over anhyd MgSO.sub.4, filtered and concentrated to give
1.398 g, of a white solid, mp 155-158.degree. C., FAB MS;
M+Li=574.
[0158] Part B
[0159] A solution of product from Part A (900 mg, 1.58 mmol) in 30
mL of methanol was treated with 90 mg of 10% palladium on carbon
catalyst and hydrogenated at 32 psig for 15 h at room temperature.
The catalyst was removed by filtration through diatomaceous earth
and the filtrate concentrated in vacuo to give a white foam, FAB
MS; M+H.sup.+=334, 680 mg, 99%, that was used directly in the next
step without further purification.
[0160] Part C
[0161] A mixture of 2(S)-methyl-3-methylsulfonyl propionic acid
(159.7 mg, 0.96 mmol), N-hydroxybenzotriazole (210.8 mg, 1.38
mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC) (203.9 mg, 1.06 mmol) was dissolved in 1.5 mL
of dimethylformamide (DMF) and allowed to react for 30 min at
0.degree. C. The amine from Part B (401.9 mg, 1.06 mmol) dissolved
in 0.5 mL of DMF was added to the above mixture and stirred at room
temperature for 16.5 h. The solution was then poured into 75 mL of
saturated aqueous NaHCO.sub.3 and extracted with ethyl acetate. The
ethyl acetate extracts were washed with 5% aqueous citric acid,
saturated aqueous NaHCO.sub.3, brine, dried over anhyd MgSO.sub.4,
filtered and concentrated to give a white foam, 490 mg. The
material was crystallized from hexanes and ethyl acetate to give
428 mg, 80% of pure product with mp 123-127.degree. C. HRFAB MS;
calc'd. for C.sub.27H.sub.39N.sub.3O.sub.7S.sub.2: 588.2398. Found:
588.2395.
EXAMPLE 11
[0162] 39
Preparation of Propanamide,
N-[2-hydroxy-3-[(3-methylbutyl)(4-aminophenyls-
ulfonyl)amino]-1-(phenylmethyl)propyl]-2-methyl-3-(methylsulfonyl)-,
[1S-[1R*(R*),2S*]]-
[0163] Part A
[0164] A solution of product from Example 1, Part C (1.1812 g, 3.07
mmol) and triethylamine (325.7 mg, 3.22 mmol) in 20 mL of
dichloromethane was treated with 4-nitrobenzensulfonyl chloride
(767 mg, 90% purity 3.11 mmol) at room temperature for 10 min. The
solvent was removed in vacuo and the residue taken up in ethyl
acetate and then washed with 1N KHSO.sub.4, saturated aqueous
NaHCO.sub.3, brine, dried over anhyd MgSO.sub.4, filtered and
concentrated to give 2.3230 g, of a tan solid, that was
crystallized from ethyl acetate and petroleum ether to provide 870
mg, 50%, mp 130-132.degree. C. of pure product, HRFAB MS; M+Li,
calc'd. for C.sub.29H.sub.35N.sub.3O.sub.7SLi: 576.2316. Found:
576.2350.
[0165] Part B
[0166] A solution of product from Part A (574 mg, 1.01 mmol) in 40
mL of methanol, (the solution was not completely homogeneous), was
treated with 70 mg of 10% palladium on carbon catalyst and
hydrogenated at 42 psig for 15 h at room temperature. The catalyst
was removed by filtration through diatomaceous earth and the
filtrate concentrated in vacuo to give a white solid that was
crystallized from chloroform, mp 123-127.degree. C., FAB MS;
M+Li.sup.+=412, 400 mg, 91%, that was used directly in the next
step without further purification.
[0167] Part C
[0168] A mixture of 2(S)-methyl-3-methylsulfonyl propionic acid
(112.3 mg, 0.675 mmol), N-hydroxybenzotriazole (159.1 mg, 1.04
mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC) (147.8 mg, 0.77 mmol) was dissolved in1.0 mL of
dimethylformamide (DMF) and allowed to react for 30 min at
0.degree. C. The amine from Part B (261.9 mg, 0.646 mmol) dissolved
in 0.5 mL of DMF was added to the above mixture and stirred at room
temperature for 16.5 h. The solution was then poured into 75 mL of
saturated aqueous NaHCO.sub.3 and extracted with ethyl acetate. The
ethyl acetate extracts were washed with 5% aqueous citric acid,
saturated aqueous NaHCO.sub.3, brine, dried over anhyd MgSO.sub.4,
filtered and concentrated to give a white foam, 326.3 mg. The
material was purified by flash chromatography over silica gel
eluting with ethyl acetate to provide 213.6 mg, 64% of pure product
as a white foam, FAB MS; MH.sup.+=554.
EXAMPLE 12
[0169] 40
Preparation of Propanamide,
N-[2-hydroxy-3-[(2-methylpropyl)(3,4-dimethoxy-
phenylsulfonyl)amino]-1-(phenylmethyl)propyl]-2-methyl-3-(methylsulfonyl)--
, [1S-[1R*(R*),2S*]]-
[0170] Part A
[0171] A solution of the product from Example 3, Part A (1.5356 g,
4.14 mmol) and triethylamine (522 mg, 5.17 mmol) in 15 mL of
dichloromethane was treated with 3,4-dimethoxybenzenesulfonyl
chloride (1.0087 g, 4.26 mmol) at room temperature for 14 h. The
solvent was removed in vacuo and the residue taken up in ethyl
acetate and then washed with 1N KHSO.sub.4, saturated aqueous
NaHCO.sub.3, brine, dried over anhyd MgSO.sub.4, filtered and
concentrated to give 2.147 g, 90.5%, of a white solid, mp
124-127.degree. C., HRFAB MS; M+Li; calc'd. for
C.sub.30H.sub.38N.sub.2O.- sub.7S+Li: 577.2560. Found:
577.2604.
[0172] Part B
[0173] A solution of carbamic acid, product from Part A (513 mg,
0.90 mmol) in 30 mL of methanol was stirred with 20 mg of palladium
black catalyst and 10 mL of formic acid for 15 h at room
temperature. The catalyst was removed by filtration through
diatomaceous earth and the filtrate concentrated in vacuo and the
residue taken up in ethyl acetate. The ethyl acetate solution was
washed with saturated aqueous NaHCO.sub.3, brine and dried over
anhyd MgSO.sub.4, filtered and concentrated in vacuo to give a
white solid, 386 mg, 98%, mp 123-130.degree. C., FAB MS;
M+Li.sup.+=443, that was used directly in the next step without
further purification.
[0174] Part C
[0175] A mixture of 2(S)-methyl-3-methylsulfonyl propionic acid
(128 mg, 0.77 mmol), N-hydroxybenzotriazole (179.9 mg, 1.17 mmol),
and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDC) (177.3 mg, 0.92 mmol) was dissolved in 1.5 mL of
dimethylformamide (DMF) and allowed to react for 30 min at
0.degree. C. The amine from Part B (359 mg, 0.82 mmol) dissolved in
1 mL of DMF was added to the above mixture and stirred at room
temperature for 48 h. The solution was then poured into 75 mL of
saturated aqueous NaHCO.sub.3 and extracted with ethyl acetate. The
ethyl acetate extracts were washed with 5% aqueous citric acid,
saturated aqueous NaHCO.sub.3, brine, dried over anhyd MgSO.sub.4,
filtered and concentrated to give a clear oil, 220 mg. The material
was crystallized from hexanes and ethyl acetate to give 178 mg, 40%
of pure product with mp 130-133.degree. C. HRFAB MS;M+Li.sup.+;
calc'd. for C.sub.27H.sub.40N.sub.2O.sub.8S.sub.2Li: 591.2386.
Found: 591.2396.
EXAMPLE 13
Preparation of Propanamide,
N-[(2-hydroxy-3-[(2-methylpropyl)(4-hydroxyphe-
nylsulfonyl)amino]-1-(phenylmethyl)propyl]-2-methyl-3-(methylsulfonyl)-,
[1S-(1R*(R*),2S*]]-
[0176] 41
[0177] Part A: A solution of 0.98 g (1.85 mmol) of carbamic acid,
[2R-hydroxy-3-[[(4-fluorophenyl)sulfonyl](2-methylpropyl)amino]-1S-(pheny-
lmethyl)propyl]-phenylmethyl ester in 3.8 mL of anhydrous DMF was
added to 22 mg (7.4 mmol) of 80% sodium hydride in 2 mL of DMF. To
this mixture was added 0.40 g (3.7 mmol) of benzyl alcohol. After 2
hours, the solution was cooled to O C, water added, and then ethyl
acetate. The organic layer was washed with 5% cirtic acid,
saturated sodium bicarbonate and brine, dried over magnesium
sulfate, filtered and concentrated to afford 0.90 g of crude
material. This was chromatographed on basic alumina using 3%
methanol/methylene chloride to afford 0.70 g of.
2R-hydroxy-3-[(2-methylpropyl)(4-benzyloxyphenyl)sulfonyl]amino-1S-(p-
henylmethyl)propylamine, cyclic carbamate; mass spectrum
m/e=509(M+H).
[0178] Part B: To a solution of 0.65 g (1.28 mmol) of the cyclic
carbamate from part A in 15 mL of ethanol, was added 2.6 mL (6.4
mmol) of 2.5N sodium hydroxide solution. After 1 hour at reflux, 4
mL of water was added and the solution refluxed for an additional
eight hours. The volatiles were removed, ethyl acetate added, and
washed with water, brine, dried over magnesium sulfate, filtered
and concentrated to afford 550 mg of crude
2R-hydroxy-3-[(2-methylpropyl)(4-benzyloxyphenyl)sulfonyl-
]amino-1S-(phenylmethyl)propylamine.
[0179] Part C: A solution of crude
2R-hydroxy-3-[(2-methylpropyl)(4-benzyl-
oxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine in 10 mL of
ethanol was hydrogenated in the presence of 500 mg of a 10%
palldium on carbon catalyst under 50 psig of hydrogen for 2 hours.
The catalyst was removed by filtration and the solvent removed in
vacuo to afford 330 mg of 2R-hydroxy-3-[(2-methylpropyl)(4-
hydroxyphenyl)sulfonyl]amino-1S-(phenyl- methyl)propylamine, mass
spectrum m/e=393 (M+H).
[0180] Part D: To a solution of 337 mg (2.03 mmol) of
2(S)-methyl-3-(methylsulfonyl)propionic acid and 423 mg (2.21 mmol)
of N-hydroxybenzotriazole in 4 mL of anhydrous DMF at 0 C, was
added 423 mg (2.76 mmol) of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. After
stirring for 2 hours, 725 mg (1.84 mmol) of amine from part C above
was added and the solution stirred at room temperature for 17
hours. The solvent was removed in vacuo, ethyl acetate added, and
then washed with saturated aqueous sodium bicarbonate, brine, dried
over magnesium sulfate, filtered and concentrated to afford 939 mg
of crude product. Chromatography on silica gel using 2-5%
methanol/methylene chloride afforded 533 mg of propanamide,
N-[2-hydroxy-3-[(2-methylpropyl)-
(4-hydroxyphenylsulfonyl)amino]-1-(phenylmethyl)propyl]-2-methyl-3-(methyl-
sulfonyl)-, (1S-(1R*(R*),2S*]]-, mass spectrum m/e=547 (M+Li).
EXAMPLE 14
[0181] The following general procedures can be utilized to prepare
additional compounds within the scope of the present invention.
General Procedure for the Synthesis of Amino Epoxides
[0182] To a solution of 0.226 mol of
N-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a
mixture of 807 mL of methanol and 807 mL of tetrahydrofuran at
-2.degree. C., is added 1.54 equiv. of solid sodium borohydride
over one hundred minutes. The solvents are then removed under
reduced pressure at 40.degree. C. and the residue is dissolved in
ethyl acetate (approx. 1 L). The solution is washed sequentially
with 1M potassium hydrogen sulfate, saturated sodium bicarbonate
and is then saturated sodium chloride solutions. After drying over
anhydrous magnesium sulfate and filtering, the solution is removed
under reduced pressure. To the resulting oil is added hexane
(approx. 1 L) and the mixture is warmed to 60.degree. C. with
swirling. After cooling to room temperature, the solids are
collected and washed with 2 L of hexane. The resulting solid is
recrystallized from hot ethyl acetate and hexane to afford 32.3 g
(43% yield) of N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-ph-
enyl-2(s)-butanol, mp 150-151.degree. C. and M+Li.sup.+=340.
[0183] Part B
[0184] To a solution of 1.2 equiv. of potassium hydroxide in 968 mL
of absolute ethanol at room temperature, is added 0.097 mol of
N--CBZ-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol. After stirring
for fifteen minutes, the solvent is removed under reduced pressure
and the solids are dissolved in methylene chloride. After washing
with water, drying over magnesium sulfate, filtering and stripping,
one obtains a white solid. Recrystallization from hot ethyl acetate
and hexane will afford
N-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane.
Alternate Procedure for the Synthesis of Amino Epoxides
[0185] Step A:
[0186] A solution of L-phenylalanine (50.0 g, 0.302 mol), sodium
hydroxide (24.2 g, 0.605 mol) and potassium carbonate (83.6 g.
0.605 mol) in water (500 ml) is heated to 97.degree. C. Benzyl
bromide (108.5 ml, 0.912 mol) is then slowly added (addition time
.about.25 min). The mixture is then stirred at 97.degree. C. for 30
minutes. The solution is cooled to room temperature and extracted
with toluene (2.times.250 ml). The combined organic alyers are then
washed with water, brine, dried over magnesium sulfate, filtered
and concentrated to give an oil product. The crude product is then
used in the next step without purification.
[0187] Step B:
[0188] The crude benzylated product of the above step is dissolved
in toluene (750 ml) and cooled to -55.degree. C. A 1.5 M solution
of DIBAL-H in toluene (443.9 ml, 0.666 mol) is then added at a rate
to maintain the temperature between -55.degree. to -50.degree. C.
(addition time--1 hour). The mixture is stirred for 20 minutes at
-55.degree. C. The reaction is quenched at -55.degree. C. by the
slow addition of methanol (37 ml). The cold solution is then poured
into cold (5.degree. C.) 1.5 N HCl solution (1.8 L). The
precipitated solid (approx. 138 g) is filtered off and washed with
toluene. The solid material is suspended in a mixture of toluene
(400 ml) and water (100 ml). The mixture is cooled to 5.degree. C.,
treated with 2.5 N NaOH (186 ml) and then stirred at room
temperature until the solid is dissolved. The toluene layer is
separated from the aqueous phase and washed with water and brine,
dried over magnesium sulfate, filtered and concentrated to a volume
of 75 ml (89 g). Ethyl acetate (25 ml) and hexane (25 ml) are then
added to the residue upon which the alcohol product begins to
crystallize. After 30 min., an additional 50 ml hexane is added to
promote further crystallization. The solid is filtered off and
washed with 50 ml hexane to give approximately 35 g of material. A
second crop of matrial can be isolated by refiltering the mother
liquor. The solids are combined and recrystallized from ethyl
acetate (20 ml) and hexane (30 ml) to give, in 2 crops,
approximately 40 g (40% from L-phenylalanine) of analytically pure
alcohol product. The mother liquors are combined and concentrated
(34 g). The residue is treated with ethyl acetate and hexane which
provides an additional 7 g (.about.7% yield) of slightly impure
solid product. Further optimization in the recovery from the mother
liquor is probable.
[0189] Step C
[0190] A solution of oxalyl chloride (8.4 ml, 0.096 mol) in
dichloromethane (240 ml) is cooled to -74.degree. C. A solution of
DMSO (12.0 ml. 0.155 mol) in dichloromethane (50 ml) is then slowly
added at a rate to maintain the temperature at -74.degree. C.
(addition time .about.1.25 hr). The mixture is stirred for 5 min.
followed by addition of a solution of the alcohol (0.074 mol) in
100 ml of dichloromethane (addition time--20 min., temp.
-75.degree. C. to -68.degree. C.). The solution is stirred at
-78.degree. C. for 35 minutes. Triethylamine (41.2 ml, 0.295 mol)
is then added over 10 min. (temp. -78.degree. to -68.degree. C.)
upon which the ammonium salt precipitated. The cold mixture is
stirred for 30 min. and then water (225 ml) is added. The
dichloromethane layer is separated from the aqueous phase and
washed with water, brine, dried over magnesium sulfate, filtered
and concentrated. The residue is diluted with ethyl acetate and
hexane and then filtered to further remove the ammonium salt. The
filtrate is concentrated to give the desired aldehyde product. The
aldehyde was carried on to the next step without purification.
[0191] Temperatures higher than -70.degree. C. have been reported
in the literature for the Swern oxidation. Other Swern
modifications and alternatives to the Swern oxidations are also
possible.
[0192] A solution of the crude aldehyde 0.074 mol and
chloroiodomethane (7.0 ml, 0.096 mol) in tetrahydrofuran (285 ml)
is cooled to -78.degree. C. A 1.6 M solution of n-butyllithium in
hexane (25 ml, 0.040 mol) is then added at a rate to maintain the
temperature at -75.degree. C. (addition time--15 min.). After the
first addition, additional chloroiodomethane (1.6 ml, 0.022 mol) is
added again, followed by n-butyllithium (23 ml, 0.037 mol), keeping
the temperature at -75.degree. C. The mixture is stirred for 15
min. Each of the reagents, chloroiodomethane (0.70 ml, 0.010 mol)
and n-butyllithium (5 ml, 0.008 mol) are added 4more times over 45
min. at -75.degree. C. The cooling bath is then removed and the
solution warmed to 22.degree. C. over 1.5 hr. The mixture is poured
into 300 ml of saturated aq. ammonium chloride solution. The
tetrahydrofuran layer is separated. The aqueous phase is extracted
with ethyl acetate (1.times.300 ml). The combined organic layers
are washed with brine, dried over magnesium sulfate, filtered and
concentrated to give a brown oil (27.4 g). The product could be
used in the next step without purification. The desired
diastereomer can be purified by recrystallization at the subsequent
sulfonamide formation step. Alternately, the product could be
purified by chromatography.
General Procedure for the Synthesis of 1,3-Diamino4-phenyl
Butan-2-ol Derivatives (Amino Alcohols)
[0193] A mixture of the amine R.sup.3NH.sub.2 (20 equiv.) in dry
isopropyl alcohol (20 mL/mmol of epoxide to be converted) is heated
to reflux and then is treated with an N--Cbz amino epoxide of the
formula: 42
[0194] from a solids addition funnel over a 10-15 minute period.
After the addition is complete the solution is maintained at reflux
for an additional 15 minutes and the progress of the reaction
monitored by TLC. The reaction mixture is then concentrated in
vacuo to give an oil and is then treated with n-hexane with rapid
stirring whereupon the ring opened-material precipitates from
solution. Precipitation is generally complete within 1 hr and the
product is then isolated by filtration on a Buchner funnel and is
then air dried. The product is further dried in vacuo. This method
affords amino alcohols of sufficient purity for most purposes.
[0195] Table 1 shows representative amino alcohols prepared
according to the above general procedures.
1TABLE 1 43 Entry R.sup.3 1 i-Butyl 2 CH.sub.3 3 i-Propyl 4
--CH.sub.2CH(CH.sub.3).sub.2 5 i-Propyl 6 Phenyl 7 Benzyl 8
Cyclohexylmethyl 9 Cyclohexyl 10 2-Naphthylmethyl 11 n-Butyl 12
n-Pentyl 13 n-Hexyl 14 p-Methyoxybenzyl 15 3-Pyridylmethyl 16
4-Pyridylmethyl 17 n-Butoxy 18 p-Fluorobenzyl
General Procedure for the Reaction of Amino Alcohols with Sulfonyl
Halides or Sulfonyl Anhydrides: Preparation of Sulfonamides
[0196] To a solution of
N[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-pheny-
lbutyl]N-isoamylamine (2.0 gm, 5.2 mmol) and triethylamine (723 uL,
5.5 mmol) in dichloromethane (20 mL) is added dropwise
methanesulfonyl chloride (400 uL, 5.2 mmol). The reaction mixture
is stirred for 2 hours at room temperature, then the
dichloromethane solution is concentrated to ca. 5 mL and applied to
a silica gel column (100 gm). The column is eluted with chloroform
containing 1% ethanol and 1% methanol.
[0197] Alternatively, from the reaction of
N[3(S)-benzyloxycarbonylamino-2-
(R)-hydroxy-4-phenylbutyl]N-isoamylamine (1.47 gm, 3.8 mmol),
triethylamine (528 uL, 3.8 mmol) and benzenesulfonyl chloride (483
uL, 3.8 mmol) one can obtain the appropriate (phenylsulfonyl)amino
derivative.
[0198] The following Table 2 shows representative sulfonamides
prepared according to the above procedure.
2TABLE 2 44 Entry R.sup.3 R.sup.4 1 isoamyl p-fluorophenyl 2
isoamyl p-nitrophenyl 3 isoamyl o-nitrophenyl 4 isoamyl
.beta.-naphthyl 5 isoamyl 2-thienyl 6 isoamyl benzyl 7 isobutyl
p-fluorophenyl B p-fluorobenzyl phenyl 9 4-methylpyridyl phenyl 10
cyclohexylmethyl phenyl 11 allyl phenyl 12 propyl phenyl 13
cyclopropylmethyl phenyl 14 methyl phenyl 15 propargyl phenyl 16
isoamyl p-chlorophenyl 17 isoamyl p-methoxyphenyl 18 isoamyl
m-nitrophenyl 19 isoamyl m-trifluoromethylphenyl 20 isoamyl
o-methoxycarbonylphenyi 21 isoamyl p-acetamidophenyl 22 isobutyl
phenyl 23 --CH.sub.2Ph -Ph 24 45 -Ph 25 46 -Ph 26 47 -Ph 27 48 -Ph
28 49 -Ph 29 --CH.sub.2CH.dbd.CH.sub.2 -Ph 30 50 -Ph 31 51 -Ph 32
--CH.sub.2CH.sub.2Ph -Ph 33 --CH.sub.2CH.sub.2CH.sub.2CH.sub.2O- H
-Ph 34 --CH.sub.2CH.sub.2N(CH.sub.3).sub.2 -Ph 35 52 -Ph 36
--CH.sub.3 -Ph 37 --CH.sub.2CH.sub.2CH.sub.2SCH.sub.3 -Ph 38
--CH.sub.2CH.sub.2CH.su- b.2S(O).sub.2CH.sub.3 -Ph 39
--CH.sub.2CH.sub.2CH(CH.sub.3- ).sub.2 53 40
--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2 --CH.sub.2CH.sub.2CH.sub.3 41
--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2 --CH.sub.3 42
--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2 54 43
--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2 55 44
--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2 56 45
--CH.sub.2CH(CH.sub.3).sub.2 57 46 --CH.sub.2CH(CH.sub.3).sub.2 58
47 --CH.sub.2CH(CH.sub.3).sub.2 59 48 --CH.sub.2CH.sub.2CH.sub.3 60
49 --CH.sub.2CH.sub.2CH.sub- .2CH.sub.3 61
General Procedure for the Removal of the Protecting Groups by
Hydrogenolysis with Palladium on Carbon
[0199] A. Alcohol Solvent
[0200] The Cbz-protected peptide derivative is dissolved in
methanol (ca.20 mL/mmol) and 10% palladiumon carbon catalyst is
added under a nitrogen atmosphere. The reaction vessel is sealed
and flushed 5 times with nitrogen and then 5 times with hydrogen.
The pressure is maintained at 50 psig for 1-16 hours and then the
hydrogen is replaced with nitrogen and the solution is filtered
through a pad of celite to remove the catalyst. The solvent is
removed in vacuo to give the free amino derivative of suitable
purity to be taken directly on to the next step.
[0201] B. Acetic Acid Solvent
[0202] The Cbz-protected peptide derivative is dissolved in glacial
acetic acid (20 mL/mmol) and 10% palladium on carbon catalyst is
added under a nitrogen atmosphere. The reaction vessel is flushed 5
times with nitrogen and 5 times with hydrogen and then maintained
at 40 psig for about 2 h. The hydrogen is then replaced with
nitrogen and the reaction mixture filtered through a pad of celite
to remove the catalyst. The filtrate is concentrated and the
resulting product is taken up in anhydrous ether and is evaporated
to dryness 3 times. The final product, the acetate salt, is dried
in vacuo and is of suitable purity for subsequent conversion.
General Procedure for Removal of Boc-protecting Group with 4N
Hydrochloric Acid in Dioxane
[0203] The Boc-protected amino acid or peptide derivative is
treated with a solution of 4N HCl in dioxane with stirring at room
temperature. Generally the deprotection reaction is complete within
15 minutes, the progress of the reaction is monitored by thin layer
chromatography (TLC). Upon completion, the excess dioxane and HCl
are removed by evaporation in vacuo. The last traces of dioxane and
HCl are best removed by evaporation again from anhydrous ether or
acetone. The hydrochloride salt thus obtained is thoroughly dried
in vacuo and is suitable for further reaction.
Procedures for Preparation of Sulfonyl Compounds
[0204] The procedures described below in Examples 13A, 13B and 13C
illustrate procedures for preparing sulfonyl alkanoyl compounds
which can be coupled to the sulfonamides as prepared above.
EXAMPLE 14A
[0205] 62
Preparation of 2(S)-methyl-3-( methylsulfonyl)propionic Acid
[0206] To a solution of 10 g of
D-(-)-S-benzoyl-b-mercaptioisobutyric acid t-butyl ester in 20 mL
of methanol was bubbled in gaseous ammonia at 0.degree. C. The
reaction was allowed to then warm to room temperature, stirred
overnight and concentrated under reduced pressure. The resulting
mixture of a solid (benzamide) and liquid was filtered to provide
5.21 g of a pale oil which then solidified. This was identified as
2(S)-methyl-3-mercaptopropionic acid t-butyl ester.
[0207] To a solution of 5.21 g of 2(S)-methyl-3-mercaptopropionic
acid t-butyl ester in 75 mL of toluene at 0.degree. C. was added
4.50 g of 1,8-diazabicyclo[5.40]undec-7-ene and 1.94 mL of methyl
iodide. After stirring at room temperature for 2.5 hours, the
volatiles were removed, ethyl acetate added, washed with dilute
hydrochloric acid, water, brine, dried and concentrated to afford
2.82 g of a pale oil, identified as
2(S)-methyl-3-(thiomethyl)propionic acid t-butyl ester.
[0208] To a solution of 2.82 g of
2(S)-methyl-3-(thiomethyl)propionic acid t-butyl ester in 50 mL of
acetic acid was added 5.58 g of sodium perborate and the mixture
heated to 55.degree. C. for 17 hours. The reaction was poured into
water, extracted with methylene chloride, washed with aqueous
sodium bicarbonate, dried and concentrated to afford 2.68 g of
2(S)-methyl-3-(methylsulfonyl)propionic acid t-butyl ester as a
white solid.
[0209] To 2.68 g of 2(S)-methyl-3-(methylsulfonyl)-propionic acid
t-butyl ester was added 20 mL of 4N hydrochloric acid/dioxane and
the mixture stirred at room temperature for 19 hours. The solvent
was removed under reduced pressure to afford 2.18 g of crude
product, which was recrystallized from ethyl acetate/hexane to
yield 1.44 g of 2(S)-methyl-3-(methylsulfonyl)propionic acid as
white crystals.
EXAMPLE 14B
[0210] Part A
[0211] A solution of methyl methacrylate (7.25 g, 72.5 mmol) and
phenethyl mercaptan (10.0 g, 72.5 mmol) in 100 mL of methanol was
cooled in an ice bath and treated with sodium methoxide (100 mg,
1.85 mmol). The solution was stirred under nitrogen for 3 h and
then concentrated in vacuo to give an oil that was taken up in
ether and washed with 1 N aqueous potassium hydrogen sulfate,
saturated aqueous sodium chloride, dried over anhydrous magnesium
sulfate, filtered and concentrated to give 16.83 g, 97.5% of methyl
2-(R,S)-methyl-4-thia-6-phenyl hexanoate as an oil. TLC on
SiO.sub.2 eluting with 20:1 hexane:ethyl acetate (v:v)
R.sub.f=0.41. Alternatively, one can use methyl 3-bromo-2-methyl
propionate in place of methyl methacrylate.
[0212] Part B
[0213] A solution of methyl 2-(R,S)-methyl-4-thia-6-phenyl
hexanoate (4.00 g, 16.8 mmol) in 100 mL of dichloromethane was
stirred at room temperature and treated portion wise with
meta-chloroperoxybenzoic acid (7.38 g, 39.2 mmol) over
approximately 40 m. The solution was stirred at room temperature
for 16 h and then filtered and the filterate washed with saturated
aqueous sodium bicarbonate, 1N sodium hydroxide, saturated aqueous
sodium chloride, dried over anhydrous magnesium sulfate, filtered,
and concentrated to give 4.50 g, 99% of desired sulfone. The
unpurified sulfone was dissolved in 100 mL of tetrahydrofuran and
treated with a solution of lithium hydroxide (1.04 g, 24.5 mmol) in
40 mL of water. The solution was stirred at room temperature for 2
m and then concentrated in vacuo. The residue was then acidified
with IN aqueous potassium hydrogen sulfate to pH=1 and then
extracted three times with ethyl acetate. The combined ethyl
acetate solution was washed with saturated aqueous sodium chloride,
dried over anhydrous magnesium sulfate, filtered and concentrated
to give a white solid. The solid was taken up in boiling ethyl
acetate/hexane and allowed to stand undisturbed whereupon white
needles formed that were isolated by filtration and air dried to
give 3.38 g, 79% of 2-(R,S)-methyl-3(9-phenethylsulfonyl)-propio-
nic acid, mp 91-93.degree. C.
[0214] Part C
[0215] A-solution of 2-(R,S) -methyl-3
(.beta.-phenethylsulfonyl)-propioni- c acid (166.1 mg, 0.65 mmol),
N-hydroxybenzotriazole (HOBT) (146.9 mg, 0.97 mmol), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)
(145.8 mg, 0.75 mmol) in 4 mL of anhydrous dimethylformamide (DMF)
cooled to 0.degree. C. and stirred under nitrogen for 0.5 h. This
solution is then treated with a desired sulfonamide isostere and
stirred at room temperature for 16 h. The solution is poured into
30 mL of 60% saturated aqueous sodium bicarbonate solution. The
aqueous solution is then decanted from the organic residue. The
organic residue is taken up in dichloromethane and washed with 10%
aqueous citric acid, brine, dried over anhydrous magnesium sulfate,
filtered and concentrated. Flash chromatography of the mixture on
silica gel eluting with 1:1 hexane:ethyl acetate can be utilized
and will afford the separated diastereomers.
EXAMPLE 14C
[0216] Part A
[0217] A solution of methyl 2-(bromomethyl)-acrylate (26.4 g, 0.148
mol) in 100 mL of methanol was treated with sodium methanesulfinate
(15.1 g, 0.148 mol) portion wise over 10 m at room temperature. The
solution was then stirred at room temperature for a period of 1.25
h and the solution concentrated in vacuo. The residue was then
taken up in water and extracted four times with ethyl acetate. The
combined ethyl acetate solution was washed with saturated sodium
chloride, dried over anhydrous magnesium sulfate, filtered and
concentrated to give a white solid, 20.7 g which was taken up in
boiling acetone/methyl tert-butyl ether and allowed to stand
whereupon crystals of pure methyl 2-(methylsulfonylmethyl) acrylate
18.0 g, 68% formed, mp 65-68 0.degree. C.
[0218] Part B
[0219] A solution of methyl 2-(methylsulfonylmethyl) acrylate (970
mg, 5.44 mmol) in 15 mL of tetrahydrofuran was treated with a
solution of lithium hydroxide (270 mg, 6.4 mmol) in 7 mL of water.
The solution was stirred at room temperature for 5 m and then
acidified to pH=1 with 1 N aqueous potassium hydrogen sulfate and
the solution extracted three times with ethyl acetate. The combined
ethyl acetate solution was dried over anhydrous magnesium sulfate,
filtered, and concentrated to give 793 mg, 89% of
2-(methylsulfonylmethyl)acrylic acid, mp 147-149 0.degree. C.
[0220] Part C
[0221] A solution of 2-(methylsulfonylmethyl)acrylic acid (700 mg,
4.26 mmol) in 20 mL of methanol was charged into a Fisher-Porter
bottle along with 10% palladium on carbon catalyst under a nitrogen
atmosphere. The reaction vessel was sealed and flushed five times
with nitrogen and then five times with hydrogen. The pressure was
maintained at 50 psig for 16 h and then the hydrogen was replaced
with nitrogen and the solution filtered through a pad of celite to
remove the catalyst and the filterate concentrated in vacuo to give
682 mg 96% of 2-(R,S)-methyl-3-methylsulfon- yl propionic acid.
[0222] Part D
[0223] A solution of 2-(R,S)-methyl-3(methylsulfonyl) propionic
acid (263.5 mg, 1.585 mmol), N-hydroxybenzotriazole (HOBT) (322.2
mg, 2.13 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC) (339.1 mg, 1.74 mmol) in 4 mL of anhydrous
dimethylformamide (DMF) is cooled to 0.degree. C. and stirred under
nitrogen for 0.5 h. This solution is then treated with a desired
sulfonamide and stirred at room temperature for 16 h. The solution
is poured into 60 mL of 60% saturated aqueous sodium bicarbonate
solution. The aqueous solution is then decanted from the organic
residue. The organic residue is taken up in dichloromethane and
washed with 10% aqueous citric acid, brine, dried over anhydrous
magnesium sulfate, filtered and concentrated to give the desired
product.
EXAMPLE 14D
Preparation of Sulfone Inhibitors from
L-(+)-S-acetyl-.beta.-mercaptoisobu- tyric Acid
[0224] Part A
[0225] A round-bottomed flask is charged with the desired
sulfonamide isostere (2.575 mmol), for example, the amine from
Example 3, Part C, can be coupled to L-(+)-S-acetyl-.beta.-mercapto
butyric acid in the presence of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)
(339.1 mg, 1.74 mmol), in 10 mL of CH.sub.2Cl.sub.2 and is allowed
to stir at room temperature for 16 h. The solution is concentrated
in vacuo and the residue taken up in ethyl acetate, washed with 1N
KHSO.sub.4, sat. aq. NaHCO.sub.3, brine, dried over anhydrous
MgSO.sub.4, filtered and concentrated to give an oil which can be
purified by radial chromatography on SiO.sub.2 eluting with ethyl
acetate to give the pure product.
[0226] Part B
[0227] A solution of the product of Part A (0.85 mmol) in 10 mL of
methanol is treated with anhydrous ammonia for ca. 1 m at 0.degree.
C. The solution is stirred at that temperature for 16 h and then
concentrated i vacuo to give the desired product that can be used
directly in the next step without further purification.
[0228] Part C
[0229] A solution of the product of Part B (0.841 mmol) in 10 mL of
dry toluene under nitrogen is treated in rapid succession with
1,8-diazabicyclo[5.4.0]undec-7-ene, (DBU), (128.1 mg. 0.841 mmol)
and iodomethane (119.0 mg, 0.841 mmol). After 0.5 h at room
temperature the reaction is diluted with ethyl acetate washed with
1N KHSO.sub.4, sat. aq. NaHCO.sub.3, brine. After the solution is
dried over anhydrous MgSO4, filtered and concentrated in vacuo the
desired product is obtained and can be used directly in the next
step.
[0230] Part D
[0231] A solution of the product of Part C (0.73 mmol) and sodium
perborate (500 mg, 3.25 mmol) in 30 mL of glacial acetic acid is
warmed to 55.degree. C. for 16 h. The solution is conentrated in
vacuo and then the residue is taken up in ethyl acetate, washed
with water, sat. aq. NaHCO.sub.3, brine, dried over anhydrous
MgSO.sub.4, filtered and concentrated to give the desired
product.
[0232] Representative sulfones prepared according to the above
general procedures are shown in Table 3.
3TABLE 3 63 Entry R 1 CH.sub.3-- 2 PhCH.sub.2CH.sub.2-- 3 Ph-
General Procedure for Coupling Sulfonyl Compounds to
Sulfonamides
[0233] A mixture of the sulfonyl alkanoyl compound (approximately 1
mmol), N-hydroxybenzotriazole (1.5 mmol), and
1-(3-dimethylaminopropyl)-3-ethylc- arbodiimide hydrochloride (EDC)
(1.2 mmol) is dissolved in a suitable solvent such as DMF and
allowed to react for about 30 min. at 0.degree. C. The sulfonamide
(1.05 mmol) is dissolved in DMF, added to the above mixture and
stirred at room temperature for a period of time sufficient for the
reaction to take place. The solution is then poured into saturated
aqueous NaHCO.sub.3 and extracted with, for example, ethyl acetate.
The extracts are washed, dried, filtered and concentrated. The
resulting material is then crystallized from a suitable solvent or
solvent mixture such as hexanes and ethyl acetate to produce the
product.
[0234] Representative compounds prepared according to these general
procedures are shown in the following Table.
4 64 Entry R.sup.1 1 --CH.sub.3 2 --CH.sub.2CH.sub.3 3
--CH(CH.sub.3).sub.2 4 --C(CH.sub.3).sub.3
EXAMPLE 15
[0235] Utilizing the general and specific procedures shown in
Examples 1-14, the compounds shown in Tables 4-8 could be
prepared.
5TABLE 4 65 Entry R.sup.3 R.sup.4 1 CH.sub.3 n-Butyl 2 i-Butyl
CH.sub.3 3 i-Butyl n-Butyl 4 i-Butyl sec-butyl 5 i-Propyl n-Butyl 6
i-Propyl n-Butyl 7 C.sub.6H.sub.5-- n-Butyl 8 66 n-Butyl 9 67
CF.sub.3 10 68 Phenyl 11 69 CH.sub.3 12 i-Butyl n-Propyl 13 i-Butyl
--CH.sub.2CH(CH.sub.3).sub.2 14 70 CH.sub.3 15 71 i-Propyl 16 72
--CH.sub.2CH.sub.2CH(CH- .sub.3).sub.2 17 i-Butyl
--CH.sub.2CH.sub.3 18 i-Butyl --CH(CH.sub.3).sub.2 19 i-Butyl 73 20
i-Butyl 74 21 75 --(CH.sub.2).sub.2CH(CH.sub.3).sub.2 22
(CH.sub.2).sub.2CH(CH.sub.3).sub.2 --CH(CH.sub.3).sub.2 23 i-Butyl
--CH(CH.sub.3).sub.2 24 i-Butyl --C(CH.sub.3).sub.3 25 n-Butyl
--C(CH.sub.3).sub.3 26 76 --CH.sub.3 27 77 --C.sub.6H.sub.5 28
--(CH.sub.2).sub.2CH(CH.sub.3).sub.2 --C(CH.sub.3).sub.3 29
--(CH.sub.2).sub.2CH(CH.sub.3).sub.2 sec-butyl 30
--CH.sub.2C.sub.6H.sub.5 Ethyl 31 --CH.sub.2C.sub.6H.sub.5 Phenyl
32 --(CH.sub.2).sub.2C.sub.6H.sub.5 --CH.sub.3 33
--(CH.sub.2).sub.2C.sub.6H.sub.5 Phenyl 34 n-Butyl Ethyl 35
n-Pentyl Ethyl 36 n-Hexyl Ethyl 37 78 Ethyl 38
--CH.sub.2C(CH.sub.3).sub.3 --CH.sub.3 39
--CH.sub.2C(CH.sub.3).sub.3 79 40 80 --CH.sub.3 41
--CH.sub.2C.sub.6H.sub.5OCH.sub.3(para) --CH.sub.3 42 81 --CH.sub.3
43 82 --CH.sub.3 44 --(CH.sub.2).sub.2C(CH.sub.3).sub.3 Ethyl 45
--(CH.sub.2).sub.2C(CH.sub.3).sub.3 n-Propyl 46
--(CH.sub.2).sub.4OH --CH.sub.3 47 --(CH.sub.2).sub.4OH Phenyl 48
83 --CH.sub.3 49 84 Phenyl 50 --CH.sub.2CH(CH.sub.3).sub.2
Ethyl
[0236]
6TABLE 5 85 Entry R.sup.1 1 CH.sub.2SO.sub.2CH.sub.3 2 (R)
--CH(OH)CH.sub.3 3 (R,S)CH.sub.2SOCH.sub.3 4
CH.sub.2SO.sub.2NH.sub.2 5 CH.sub.2SCH.sub.3 6
CH.sub.2CH(CH.sub.3).sub.2 7 CH.sub.2CH.sub.2C(O)NH.sub.2 8 (S)
--CH(OH)CH.sub.3 9 --CH.sub.2C.ident.CH
[0237]
7TABLE 6 86 Entry R R.sup.2 1 --OCH.sub.3 n-Bu 2 --OCH.sub.3
cyclohexylmethyl 3 --NHA.sub.C n-Bu 4 --NH.sub.2 n-Bu 5 --OCH.sub.3
C.sub.6H.sub.5CH.sub.2 6 --NHA.sub.C C.sub.6H.sub.5CH.sub.2 7
--NH.sub.2 C.sub.6H.sub.5CH.sub.2 8 --NHA.sub.C cyclohexylmethyl 9
--C(CH.sub.3).sub.3 n-Bu 10 --NH.sub.2 cyclohexylmethyl 11
--C(CH.sub.3).sub.3 C.sub.6H.sub.5CH.sub.2 12 --OCH.sub.3
2-naphthylmethyl 13 --NHA.sub.C 2-naphthylmethyl 14 --NH.sub.2
2-naphthylmethyl 15 --C(CH.sub.3.sub.).sub.3 2-naphthylmethyl 16
--OCH.sub.3 p-F(C.sub.6H.sub.4)CH.sub.2 17 --NH.sub.2
p-F(C.sub.6H.sub.4)CH.sub.2 18 --NHA.sub.C
p-F(C.sub.6H.sub.4)CH.sub.2 19 --C(CH.sub.3).sub.3
p-F(C.sub.6H.sub.4)CH.sub.2 20 --CF.sub.3 C.sub.6H.sub.5CH.sub.2 21
--CO.sub.2CH.sub.3 C.sub.6H.sub.5CH.sub.2 22 --F
C.sub.6H.sub.5CH.sub.2 23 Cl C.sub.6H.sub.5CH.sub.2
[0238]
8TABLE 7 87 Entry R.sup.3 R.sup.4 1 --CH.sub.2CH(CH.sub.3).sub.2
--C(CH.sub.3).sub.2 2 --CH.sub.2CH.sub.2CH(CH.sub.3).sub.- 2 88 3
--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2 89 4
--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2 90 5
--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2 91
[0239]
9TABLE 8 92 Entry R 1 CH.sub.3-- 2 CH.sub.3CH.sub.2-- 3
CH.sub.3CH.sub.2CH.sub.2-- 4 PhCH.sub.2CH.sub.2-- 5 PhCH.sub.2-- 6
Ph- 7 (CH.sub.3).sub.2CH-- 8 HOCH.sub.2CH.sub.2-- 9 93 10 94 11 95
12 CH.sub.2.dbd.CH--CH.sub.2--
EXAMPLE 16
[0240] The compounds of the present invention are effective HIV
protease inhibitors. Utilizing an enzyme assay as described below,
the compounds set forth in the examples herein disclosed inhibited
the HIV enzyme. The preferred compounds of the present invention
and their calculated IC.sub.50 (inhibiting concentration 50%, i.e.,
the concentration at which the inhibitor compound reduces enzyme
activity by 50%) values are shown in Table 16. The enzyme method is
described below. The substrate is
2-aminobenzoyl-Ile-Nle-Phe(p-NO.sub.2)-Gln-ArgNH.sub.2. The
positive control is MVT-101 (Miller, M. et al, Science, 246, 1149
(1989)] The assay conditions are as follows:
[0241] Assay buffer: 20. mM sodium phosphate, pH 6.4
[0242] 20% glycerol
[0243] 1 mM EDTA
[0244] 1 mM DTT
[0245] 0.1% CHAPS
[0246] The above described substrate is dissolved in DMSO, then
diluted 10 fold in assay buffer. Final substrate concentration in
the assay is 80 .mu.M.
[0247] HIV protease is diluted in the assay buffer to a final
enzyme concentration of 12.3 nanomolar, based on a molecular weight
of 10,780.
[0248] The final concentration of DMSO is 14% and the final
concentration of glycerol is 18%. The test compound is dissolved in
DMSO and diluted in DMSO to 10.times. the test concentration; 10
.mu.l of the enzyme preparation is added, the materials mixed and
then the mixture is incubated at ambient temperature for 15
minutes. The enzyme reaction is initiated by the addition of 40
.mu.l of substrate. The increase in fluorescence is monitored at 4
time points (0, 8, 16 and 24 minutes) at ambient temperature. Each
assay is carried out in duplicate wells.
10 TABLE 9 Example No. IC.sub.50 (nanomolar) 2 3.2 3 3.2 4 3 5 13 6
8.8 7 1.9 8 3.1 9 4.1 10 2.2 11 7.8 12 38
EXAMPLE 17
[0249] The effectiveness of compounds of the present invention were
determined in a CEM cell assay.
[0250] The HIV inhibition assay method of acutely infected cells is
an automated tetrazolium based colorimetric assay essentially that
reported by Pauwles et al. J. Virol. Methods, 309-321 (1988).
Assays were performed in 96-well tissue culture plates. CEM cells,
a CD4.sup.+ cell line, were grown in RPMI-1640 medium (Gibco)
supplemented with a 10% fetal calf serum and were then treated with
polybrene (2 .mu.g/ml). An 80 .mu.l volume of medium containing
1.times.10.sup.4 cells was dispensed into each well of the tissue
culture plate. To each well was added a 100 .mu.l volume of test
compound dissolved in tissue culture medium (or medium without test
compound as a control) to achieve the desired final concentration
and the cells were incubated at 37.degree. C. for 1 hour. A frozen
culture of HIV-1 was diluted in culture medium to a concentration
of 5.times.10.sup.4 TCID.sub.50 per ml (TCID.sub.50= the dose of
virus that infects 50% of cells in tissue culture), and a 20 .mu.L
volume of the virus sample (containing 1000 TCID.sub.50 of virus)
was added to wells containing test compound and to wells containing
only medium (infected control cells). Several wells received
culture medium without virus (uninfected control cells). Likewise,
the intrinsic toxicity of the test compound was determined by
adding medium without virus to several wells containing test
compound. In summary, the tissue culture plates contained the
following experiments:
11 Cells Drug Virus 1. + - - 2. + + - 3. + - + 4. + + +
[0251] In experiments 2 and 4 the final concentrations of test
compounds were 1, 10, 100 and 500 .mu.g/ml. Either azidothymidine
(AZT) or dideoxyinosine (ddI) was included as a positive drug
control. Test compounds were dissolved in DMSO and diluted into
tissue culture medium so that the final DMSO concentration did not
exceed 1.5% in any case. DMSO was added to all control wells at an
appropriate concentration.
[0252] Following the addition of virus, cells were incubated at
37.degree. C. in a humidified, 5% CO.sub.2 atmosphere for 7 days.
Test compounds could be added on days 0, 2 and 5 if desired. On day
7, post-infection, the cells in each well were resuspended and a
100 .mu.l sample of each cell suspension was removed for assay. A
20 .mu.L volume of a 5 mg/ml solution of
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
was added to each 100 .mu.L cell suspension, and the cells were
incubated for 4 hours at 27.degree. C. in a 5% CO.sub.2
environment. During this incubation, MTT is metabolically reduced
by living cells resulting in the production in the cell of a
colored formazan product. To each sample was added 100 .mu.l of 10%
sodium dodecylsulfate in 0.01 N HCl to lyse the cells, and samples
were incubated overnight. The absorbance at 590 nm was determined
for each sample using a Molecular Devices microplate reader.
Absorbance values for each set of wells is compared to assess viral
control infection, uninfected control cell response as well as test
compound by cytotoxicity and antiviral efficacy.
12TABLE 10 Example No. IC.sub.50 (nM) EC.sub.50 (nM) TD.sub.50 (nM)
2 3.2 12 90,000 3 3.2 10 213,000 4 3 12 >1,000,000 5 13 25
438,000 6 8.8 29 133,000 7 1.9 2 >1,000,000 8 3.1 9
>1,000,000 9 4.1 16 >1,000,000 10 22 223 860,000 11 7.8 45
170,000 12 38 87 77,000
[0253] Utilizing the procedures set forth above in the examples
along with the general description, it is contemplated that the
compounds listed below could be prepared and that such compounds
would have activities as HIV protease inhibitors substantially
similar to the activities of the compounds set forth in the
examples.
[0254] The compounds of the present invention are effective
antiviral compounds and, in particular, are effective retroviral
inhibitors as shown above. Thus, the subject compounds are
effective HIV protease inhibitors. It is contemplated that the
subject compounds will also inhibit other retroviruses such as
other lentiviruses in particular other strains of HIV, e.g. HIV-2,
human T-cell leukemia virus, respiratory syncitial virus, simian
immunodeficiency virus, feline leukemia virus, feline
immuno-deficiency virus, hepadnavirus, cytomegalovirus and
picornavirus. Thus, the subject compounds are effective in the
treatment and/or proplylaxis of retroviral infections.
[0255] Compounds of the present can possess one or more asymmetric
carbon atoms and are thus capable of existing in the form of
optical isomers as well as in the form of racemic or nonracemic
mixtures thereof. The optical isomers can be obtained by resolution
of the racemic mixtures according to conventional processes, for
example by formation of diastereoisomeric salts by treatment with
an optically active acid or base. Examples of appropriate acids are
tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric
and camphorsulfonic acid and then separation of the mixture of
diastereoisomers by crystallization followed by liberation of the
optically active bases from these salts. A different process for
separation of optical isomers involves the use of a chiral
chromatography column optimally chosen to maximize the separation
of the enantiomers. Still another available method involves
synthesis of covalent diastereoisomeric molecules by reacting
compounds of Formula I with an optically pure acid in an activated
form or an optically pure isocyanate. The synthesized
diastereoisomers can be separated by conventional means such as
chromatography, distillation, crystallization or sublimation, and
then hydrolyzed to deliver the enantiomericaly pure compound. The
optically active compounds of Formula I can likewise be obtained by
utilizing optically active starting materials. These isomers may be
in the form of a free acid, a free base, an ester or a salt.
[0256] The compounds of the present invention can be used in the
form of salts derived from inorganic or organic acids. These salts
include but are not limited to the following: acetate, adipate,
alginate, citrate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,
cyclopentanepropionate, dodecylsulfate, ethanesulfonate,
glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,
hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate,
nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate,
persulfate, 3-phenylpropionate, picrate, pivalate, propionate,
succinate, tartrate, thiocyanate, tosylate, mesylate and
undecanoate. Also, the basic nitrogen-containing groups can be
quaternized with such agents as lower alkyl halides, such as
methyl, ethyl, propyl, and butyl chloride, bromides, and iodides;
dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl
sulfates, long chain halides such as decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides, aralkyl halides like
benzyl and phenethyl bromides, and others. Water or oil-soluble or
dispersible products are thereby obtained.
[0257] Examples of acids which may be employed to form
pharmaceutically acceptable acid addition salts include such
inorganic acids as hydrochloric acid, sulphuric acid and phosphoric
acid and such organic acids as oxalic acid, maleic acid, succinic
acid and citric acid. Other examples include salts with alkali
metals or alkaline earth metals, such as sodium, potassium, calcium
or magnesium or with organic bases.
[0258] Total daily dose administered to a host in single or divided
doses may be in amounts, for example, from 0.001 to 10 mg/kg body
weight daily and more usually 0.01 to 1 mg. Dosage unit
compositions may contain such amounts of submultiples thereof to
make up the daily dose.
[0259] The amount of active ingredient that may be combined with
the carrier materials to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration.
[0260] The dosage regimen for treating a disease condition with the
compounds and/or compositions of this invention is selected in
accordance with a variety of factors, including the type, age,
weight, sex, diet and medical condition of the patient, the
severity of the disease, the route of administration,
pharmacological considerations such as the activity, efficacy,
pharmacokinetic and toxicology profiles of the particular compound
employed, whether a drug delivery system is utilized and whether
the compound is administered as part of a drug combination. Thus,
the dosage regimen actually employed may vary widely and therefore
may deviate from the preferred dosage regimen set forth above.
[0261] The compounds of the present invention may be administered
orally, parenterally, by inhalation spray, rectally, or topically
in dosage unit formulations containing conventional nontoxic
pharmaceutically acceptable carriers, adjuvants, and vehicles as
desired. Topical administration may also involve the use of
transdermal administration such as transdermal patches or
iontophoresis devices. The term parenteral as used herein includes
subcutaneous injections, intravenous, intramuscular, intrasternal
injection, or infusion techniques.
[0262] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, and
isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending medium. For
this purpose any bland fixed oil may be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid find use in the preparation of injectables.
[0263] Suppositories for rectal administration of the drug can be
prepared by mixing the drug with a suitable nonirritating excipient
such as cocoa butter and polyethylene glycols which are solid at
ordinary temperatures but liquid at the rectal temperature and will
therefore melt in the rectum and release the drug.
[0264] Solid dosage forms for oral administration may include
capsules, tablets, pills, powders, and granules. In such solid
dosage forms, the active compound may be admixed with at least one
inert diluent such as sucrose lactose or starch. Such dosage forms
may also comprise, as in normal practice, additional substances
other than inert diluents, e.g., lubricating agents such as
magnesium stearate. In the case of capsules, tablets, and pills,
the dosage forms may also comprise buffering agents. Tablets and
pills can additionally be prepared with enteric coatings.
[0265] Liquid dosage forms for oral administration may include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs containing inert diluents commonly used in the
art, such as water. Such compositions may also comprise adjuvants,
such as wetting agents, emulsifying and suspending agents, and
sweetening, flavoring, and perfuming agents.
[0266] While the compounds of the invention can be administered as
the sole active pharmaceutical agent, they can also be used in
combination with one or more immunomodulators, antiviral agents or
other antiinfective agents. For example, the compounds of the
invention can be administered in combination with AZT, DDI, DDC or
with N-butyl-1-deoxynojirimycin for the prophylaxis and/or
treatment of AIDS. When administered as a combination, the
therapeutic agents can be formulated as separate compositions which
are given at the same time or different times, or the therapeutic
agents can be given as a single composition.
[0267] The foregoing is merely illustrative of the invention and is
not intended to limit the invention to the disclosed compounds.
Variations and changes which are obvious to one skilled in the art
are intended to be within the scope and nature of the invention
which are defined in the appended claims.
[0268] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention,
and without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *