U.S. patent application number 11/199571 was filed with the patent office on 2006-02-23 for retroviral protease inhibitors.
This patent application is currently assigned to G.D. Searle & Co.. Invention is credited to Daniel P. Getman, Richard A. Mueller.
Application Number | 20060040974 11/199571 |
Document ID | / |
Family ID | 22231476 |
Filed Date | 2006-02-23 |
United States Patent
Application |
20060040974 |
Kind Code |
A1 |
Mueller; Richard A. ; et
al. |
February 23, 2006 |
Retroviral protease inhibitors
Abstract
HIV protease inhibitors are disclosed which are characterized as
having both hydroxyethylamine and N-heterocyclic moieties.
Inventors: |
Mueller; Richard A.;
(Glencoe, IL) ; Getman; Daniel P.; (Chesterfield,
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: |
22231476 |
Appl. No.: |
11/199571 |
Filed: |
August 9, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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09625384 |
Jul 26, 2000 |
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11199571 |
Aug 9, 2005 |
|
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09348711 |
Jul 7, 1999 |
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09625384 |
Jul 26, 2000 |
|
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60092090 |
Jul 8, 1998 |
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Current U.S.
Class: |
514/301 ;
514/310; 546/146 |
Current CPC
Class: |
C07D 217/26 20130101;
C07D 401/12 20130101 |
Class at
Publication: |
514/301 ;
514/310; 546/146 |
International
Class: |
A61K 31/47 20060101
A61K031/47; C07D 217/12 20060101 C07D217/12 |
Claims
1. A compound represented by the formula ##STR128## wherein R'
represents a radical selected from the group consisting of a
hydrogen radical, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,
alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,
heteroaryl, heterocycloalkylalkyl, and heteroaralkyl; t is 0 or 1;
R.sup.1 represents a radical selected from the group consisting of
a hydrogen radical, --CH.sub.2SO.sub.2NH.sub.2, --CO.sub.2CH.sub.3,
--CH.sub.2CO.sub.2CH.sub.3, --C(O)NH.sub.2, --C(O)NHCH.sub.3,
--C(O)N(CH.sub.3).sub.2, --CH.sub.2C(O)NHCH.sub.3,
--CH.sub.2C(O)N(CH.sub.3).sub.2, alkyl, alkylthioalkyl, thioalkyl,
the corresponding sulfoxide and sulfone derivatives of
alkylthioalkyl and thioalkyl, alkenyl, alkynyl, alkoxyalkyl,
haloalkyl, cycloalkyl, and amino acid side chains selected from the
group consisting of asparagine, S-methyl cysteine and the
corresponding sulfoxide and sulfone derivatives of S-methyl
cysteine, glycine, leucine, isoleucine, allo-isoleucine,
tert-leucine, alanine, phenylalanine, ornithine, histidine,
norleucine, glutamine, valine, threonine, allo-threonine, serine,
aspartic acid and beta-cyano alanine; Y' represents O, S, and
NR.sup.3, wherein R.sup.3 represents a radical selected from the
group consisting of a hydrogen radical, alkyl, alkenyl, alkynyl,
haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl,
and heteroaralkyl radicals; R.sup.6 represents a hydrogen radical
or an alkyl radical; and R.sup.20 and R.sup.21 independently
represent radicals as defined for R.sup.1.
2. A compound of claim 1 having the formula ##STR129##
3. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutical carrier.
4. A pharmaceutical composition comprising a compound of claim 1
and pharmaceutical carriers.
5. A method of inhibiting a retroviral protease comprising
administering a protease inhibiting amount of a compound of claim
100.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of application Ser. No.
09/625,384, filed Jul. 26, 2000, now allowed, which is a
continuation of application Ser. No. 09/348,711, filed Jul. 7,
1999, now abandoned, which is a non-provisional application of Ser.
No. 60/092,090 filed Jul. 8, 1998, each of which is hereby
incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of 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 N-heterocyclic moiety
containing hydroxyethylamine protease inhibitor compounds, a
composition and method for inhibiting retroviral proteases such as
human immunodeficiency virus (HIV) protease and for treatment or
prophylaxis of a retroviral infection, e.g., an HIV infection. The
subject invention also relates to processes for making such
compounds as well as to intermediates useful in such processes.
[0004] 2. Related Art
[0005] During the replication cycle of retroviruses, gag and
gag-poll 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 poll 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 poll 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 typically involves a
transition state mimetic whereby the retroviral protease is exposed
to a mimetic compound which binds (typically in a reversible
manner) to the enzyme in competition with the gag and gag-poll
proteins to thereby inhibit replication of structural proteins and,
more importantly, the retroviral protease itself. In this manner,
retroviral proteases can be effectively inhibited.
[0007] 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; G.B. 2,184,730; G.B. 2,209,752; EP 0 264
795; G.B. 2,200,115 and U.S. SIR H.sub.725. Of these, G.B.
2,200,115; G.B. 2,209,752; EP 0 264,795; U.S. SIR H.sub.725; and
U.S. Pat. No. 4,599,198 disclose urea containing hydroxyethylamine
renin inhibitors.
[0008] 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.
[0009] Several classes of mimetic compounds have been proposed,
particularly for inhibition of proteases, such as for inhibition of
HIV protease. Such mimetics include hydroxyethylamine isoteres and
reduced amide isosteres. See, for example, EP 0 346 847; EP 0
342,541; Roberts et al, "Rational Design of Peptide Based
Proteinase Inhibitors, "Science, 248, 358 (1990); and Erickson et
al, "Design, Activity, and 2.8 A Crystal Structure of a C.sub.2
Symmetric Inhibitor Complexed to HIV-1 Protease," Science, 249, 527
(1990). EP 0 346 847 and U.S. Pat. No. 5,648,364 disclose certain
N-heterocyclic moiety-containing hydroxyethylamine protease
inhibitor compounds, but do not suggest or disclose those of the
present invention. WO 95/09843, WO 96/28464, U.S. Pat. No.
5,484,926, U.S. Pat. No. 5,705,500, U.S. Pat. No. 5,756,533, U.S.
Pat. No. 5,776,971 and Kaldor, Stephen W., "A systematic Study of
P.sub.1-P.sub.3 Spanning Sidechains for the Inhibition of HIV-1
Protease", Bioorganic and Medicinal Chemistry Letters, 5, 715-720
(1995) disclose arylthiol containing hydroxyethylamine isosteres
incorporated into HIV-protease inhibitors but do not suggest or
disclose the compounds of the present invention.
[0010] While it has been suggested that no improvement in the in
vitro or ex vivo potency of hydroxyethylamine based inhibitors of
HIV-protease containing a P.sub.2 asparagine can be made (Science,
Roberts et al.), this is not the case. Improvements over P.sub.2
asparagine containing inhibitors are made. The moieties reported
herein are expected to permit certain allowances over the
aforementioned reference including proteolytic stability, duration
of action in vivo and pharmacokinetic profile.
BRIEF DESCRIPTION OF THE INVENTION
[0011] 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 N-heterocyclic moiety containing hydroxyethylamine inhibitor
compounds.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0012] In accordance with the present invention, there are provided
several novel retroviral protease inhibiting compounds or a
pharmaceutically acceptable salt, prodrug or ester thereof.
[0013] A preferred class of retroviral inhibitor compounds of the
present invention are those represented by the formula: ##STR1## or
a pharmaceutically acceptable salt, prodrug or ester thereof,
wherein: [0014] R represents hydrogen, alkoxycarbonyl,
aryloxycarbonylalkyl, aralkoxycarbonyl, alkylcarbonyl,
cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,
alkanoyl, aralkanoyl, aroyl, aryloxycarbanoyl, aryloxyalkanoyl,
heterocyclylcarbonyl, heterocycloxycarbonyl,
heteroaralkoxycarbonyl, heterocyclylalkanoyl,
heterocyclylalkoxycarbonyl, heteroarylcarbonyl,
heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl,
aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl,
aralkylaminoalkylcarbonyl, aminoalkanoyl, aminocarbonyl,
aminocarbonylalkyl, alkylaminoalkylcarbonyl, and mono- and
disubstituted aminocarbonyl and aminoalkanoyl radicals wherein the
substituents are selected from the group consisting of alkyl, aryl,
aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,
heterocycloalkyl, alkoxycarbonyl, arylalkyloxycarbonyl and
heterocycloalkylalkyl radicals, or in the case of disubstituted
aminoalkanoyl, said substituents along with the nitrogen atom to
which they are attached form a heterocyclyl or heteroaryl radical;
[0015] R' represents radicals defined for R.sup.3, or R and R'
together with the nitrogen to which they are attached form a
heterocycloalkyl or heteroaryl radical; [0016] R.sup.1 represents
hydrogen, --CH.sub.2SO.sub.2NH.sub.2, --CO.sub.2CH.sub.3,
--CH.sub.2CO.sub.2CH.sub.3, --C(O)NH.sub.2, --C(O)NHCH.sub.3,
--C(O)N(CH.sub.3).sub.2, --CH.sub.2C(O)NHCH.sub.3,
--CH.sub.2C(O)N(CH.sub.3).sub.2, alkyl, alkylthioalkyl, thiolalkyl
and the corresponding sulfoxide and sulfone derivatives thereof,
alkenyl, alkynyl, haloalkyl, alkoxyalkyl and cycloalkyl radicals
and amino acid side chains selected from the group consisting of
asparagine, S-methyl cysteine and the corresponding sulfoxide and
sulfone derivatives thereof, glycine, leucine, isoleucine,
allo-isoleucine, tert-leucine, alanine, phenylalanine, ornithine,
histidine, norleucine, glutamine, valine, threonine,
allo-threonine, serine, aspartic acid and beta-cyano alanine, side
chains; [0017] R.sup.2 represents alkylthioalkyl,
cycloalkylthioalkyl or arylthioalkyl radicals, which radicals are
optionally substituted with a substituent selected from the group
consisting of --NO.sub.2, --OR.sup.15, --SR.sup.15, and halogen
radicals, wherein R.sup.15 represents hydrogen and alkyl radicals;
[0018] R.sup.3 represents hydrogen, alkyl, alkenyl, alkynyl,
haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl,
and heteroaralkyl radicals; [0019] Y' represents O, S and NR.sup.3;
[0020] R.sup.4 and R.sup.5 together with the nitrogen atom to which
they are bonded represent a N-heterocycle; and R.sup.6 represents
hydrogen and alkyl radicals.
[0021] Another class of preferred inhibitor compounds of the
present invention are those represented by the formula: ##STR2## or
a pharmaceutically acceptable salt, prodrug or ester thereof,
wherein: [0022] R' represents radicals defined for R.sup.3; [0023]
t represents either 0 or 1; [0024] R.sup.1 represents hydrogen,
--CH.sub.2SO.sub.2NH.sub.2, --CO.sub.2CH.sub.3,
--CH.sub.2CO.sub.2CH.sub.3, --C(O)NH.sub.2, --C(O)NHCH.sub.3,
--C(O)N(CH.sub.3).sub.2, --CH.sub.2C(O)NHCH.sub.3,
--CH.sub.2C(O)N(CH.sub.3).sub.2, alkyl, alkylthioalkyl, thioalkyl
and the corresponding sulfoxide and sulfone derivatives thereof,
alkenyl, alkynyl, alkoxyalkyl, haloalkyl and cycloalkyl radicals
and amino acid side chains selected from the group consisting of
asparagine, S-methyl cysteine and the corresponding sulfoxide and
sulfone derivatives thereof, glycine, leucine, isoleucine,
allo-isoleucine, tert-leucine, alanine, phenylalanine, ornithine,
histidine, norleucine, glutamine, valine, threonine,
allo-threonine, serine, aspartic acid and beta-cyano alanine side
chains; [0025] R.sup.2 represents alkylthioalkyl,
cycloalkylthioalkyl or arylthioalkyl radicals, which radicals are
optionally substituted with a substituent selected from the group
consisting of --NO.sub.2, --OR.sup.15, --SR.sup.15, and halogen
radicals, wherein R's represents hydrogen and alkyl radicals;
[0026] R.sup.3 represents hydrogen, alkyl, alkenyl, alkynyl,
haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl,
and heteroaralkyl radicals; [0027] Y' represents O, S and NR.sup.3;
[0028] R.sup.4 and R.sup.5 together with the nitrogen atom to which
they are bonded represent a N-heterocycle; [0029] R.sup.6
represents hydrogen and alkyl radicals; [0030] and R.sup.20 and
R.sup.21 represent radicals as defined for R.sup.1.
[0031] Yet another preferred class of compounds of the present
invention are those represented by the formula: ##STR3## or a
pharmaceutically acceptable salt, prodrug or ester thereof,
wherein: [0032] t represents either 0 or 1; [0033] R.sup.1
represents hydrogen, --CH.sub.2SO.sub.2NH.sub.2,
--CO.sub.2CH.sub.3, --CH.sub.2CO.sub.2CH.sub.3, --C(O)NH.sub.2,
--C(O)NHCH.sub.3, --C(O)N(CH.sub.3).sub.2,
--CH.sub.2C(O)NHCH.sub.3, --CH.sub.2C(O)N(CH.sub.3).sub.2, alkyl,
thioalkyl, thioalkyl and the corresponding sulfoxide and sulfone
derivatives thereof, alkenyl, alkynyl, alkoxyalkyl, haloalkyl and
cycloalkyl radicals and amino acid side chains selected from the
group consisting of asparagine, S-methyl cysteine and the
corresponding sulfoxide and sulfone derivatives thereof, glycine,
leucine, isoleucine, allo-isoleucine, tert-leucine, alanine,
phenylalanine, ornithine, histidine, norleucine, glutamine, valine,
threonine, allo-threonine, serine, aspartic acid and beta-cyano
alanine side chains; [0034] R.sup.2 represents alkylthioalkyl,
cycloalkylthioalkyl, or arylthioalkyl radicals, which radicals are
optionally substituted with a substituent selected from the group
consisting of --NO.sub.2, --OR.sup.15, --SR.sup.15, and halogen
radicals, wherein R.sup.15 represents hydrogen and alkyl radicals;
[0035] R.sup.3 represents hydrogen, alkyl, alkenyl, alkynyl,
haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl,
and heteroaralkyl radicals; [0036] X' represent O, N and
C(R.sup.17) where R.sup.17 represents hydrogen and alkyl radicals;
[0037] Y' and Y'' independently represent O, S and NR.sup.3; [0038]
R.sup.4 and R.sup.5 together with the nitrogen atom to which they
are bonded represent a N-heterocycle; [0039] R.sup.6 represents
hydrogen and alkyl radicals; [0040] R.sup.30, R.sup.31 and R.sup.32
independently represent radicals as defined for R.sup.1, or one of
R.sup.1 and R.sup.30 together with one of R.sup.31 and R.sup.32 and
the carbon atoms to which they are attached form a cycloalkyl
radical; and [0041] R.sup.33 and R.sup.34 independently represent
radicals as defined for R.sup.3, or R.sup.33 and R.sup.34 together
with X' represent cycloalkyl, aryl, heterocyclyl and heteroaryl
radicals, provided that when X' is O, R.sup.14 is absent.
[0042] Still another preferred class of compounds of the present
invention are those represented by the formula: ##STR4## or a
pharmaceutically acceptable salt, prodrug or ester thereof,
wherein: [0043] R represents hydrogen, alkoxycarbonyl,
aryloxycarbonylalkyl, aralkoxycarbonyl, alkylcarbonyl,
cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,
alkanoyl, aralkanoyl, aroyl, aryloxycarbanoyl, aryloxyalkanoyl,
heterocyclylcarbonyl, heterocycloxycarbonyl,
heteroaralkoxycarbonyl, heterocyclylalkanoyl,
heterocyclylalkoxycarbonyl, heteroarylcarbonyl,
heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl,
aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl,
aralkylaminoalkylcarbonyl, aminoalkanoyl, aminocarbonyl,
aminocarbonylalkyl, alkylaminoalkylcarbonyl, and mono- and
disubstituted aminocarbonyl and aminoalkanoyl radicals wherein the
substituents are selected from the group consisting of alkyl, aryl,
aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,
heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the
case of disubstituted aminoalkanoyl, said substituents along with
the nitrogen atom to which they are attached form a heterocyclyl or
heteroaryl radical; [0044] R' represents radicals defined for
R.sup.3, or R and R' together with the nitrogen to which they are
attached form a heterocycloalkyl or heteroaryl radical; n
represents 1 or 2; [0045] R.sup.1 represents hydrogen,
--CH.sub.2SO.sub.2NH.sub.2, --CO.sub.2CH.sub.3,
--CH.sub.2CO.sub.2CH.sub.3, --C(O)NH.sub.2, --C(O)NHCH.sub.3,
--C(O)N(CH.sub.3).sub.2, --CH.sub.2C(O)NHCH.sub.3,
--CH.sub.2C(O)N(CH.sub.3).sub.2, alkyl, alkylthioalkyl, thioalkyl
and the corresponding sulfoxide and sulfone derivatives thereof,
alkenyl, alkynyl, haloalkyl, alkoxyalkyl and cycloalkyl radicals
and amino acid side chains selected from the group consisting of
asparagine, S-methyl cysteine and the corresponding sulfoxide and
sulfone derivatives thereof, glycine, leucine, isoleucine,
allo-isoleucine, tert-leucine, alanine, phenylalanine, ornithine,
histidine, norleucine, glutamine, valine, threonine,
allo-threonine, serine, aspartic acid and beta-cyano alanine side
chains; [0046] R.sup.1' and R.sup.1'' independently represent
hydrogen and radicals as defined for R.sup.3; [0047] R.sup.2
represents alkylthioalkyl, cycloalkylthioalkyl, or arylthioalkyl
radicals, which radicals are optionally substituted with a
substituent selected from the group consisting of --NO.sub.2,
--OR.sup.15, --SR.sup.15, and halogen radicals, wherein R.sup.15
represents hydrogen and alkyl radicals; [0048] R.sup.2 represents
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,
alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,
heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl
radicals; [0049] Y' and Y'' independently represent O, S and
NR.sup.3; [0050] R.sup.4 and R.sup.5 together with the nitrogen
atom to which they are bonded represent a N-heterocycle; [0051]
R.sup.6 and R.sup.6' independently represent hydrogen and alkyl
radicals.
[0052] Another class of preferred inhibitor compounds of the
present invention are those represented by the formula: ##STR5## or
a pharmaceutically acceptable salt, prodrug or ester thereof,
wherein: [0053] R' represents radicals defined for R.sup.3, or R
and R' together with the nitrogen to which they are attached form a
heterocycloalkyl or heteroaryl radical; [0054] t represents either
0 or 1; [0055] R.sup.1 represents hydrogen,
--CH.sub.2SO.sub.2NH.sub.2, --CO.sub.2CH.sub.3,
--CH.sub.2CO.sub.2CH.sub.3, --C(O)NH.sub.2, --C(O)NHCH.sub.3,
--C(O)N(CH.sub.3).sub.2, --CH.sub.2C(O)NHCH.sub.3,
--CH.sub.2C(O)N(CH.sub.3).sub.2, alkyl, alkylthioalkyl, thioalkyl
and the corresponding sulfoxide and sulfone derivatives thereof,
alkenyl, alkynyl and cycloalkyl radicals and amino acid side chains
selected from the group consisting of asparagine, S-methyl cysteine
and the corresponding sulfoxide and sulfone derivatives thereof,
glycine, leucine, isoleucine, allo-isoleucine, tert-leucine,
alanine, phenylalanine, ornithine, histidine, norleucine,
glutamine, valine, threonine, allo-threonine, serine, aspartic acid
and beta-cyano alanine side chains; [0056] R.sup.2 represents
alkylthioalkyl, cycloalkylthioalkyl or arylthioalkyl radicals,
which radicals are optionally substituted with a substituent
selected from the group consisting of --NO.sub.2, --OR.sup.15,
--SR.sup.15, and halogen radicals, wherein R.sup.15 represents
hydrogen and alkyl radicals; [0057] R.sup.3 represents hydrogen,
alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,
cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,
heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl radicals;
[0058] Y' represents O, S and NR.sup.3; [0059] R.sup.4 and R.sup.5
together with the nitrogen atom to which they are bonded represent
a N-heterocycle; [0060] R.sup.6 represents hydrogen and alkyl
radicals; [0061] R.sup.33 and R.sup.34 independently represent
radicals as defined for R.sup.3, or R.sup.33 and R.sup.34 together
with the nitrogen to which they are attached form heterocyclyl and
heteroaryl radicals; [0062] and R.sup.20 and R.sup.21 represent
radicals as defined for R.sup.1.
[0063] 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,
iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
iso-amyl, hexyl, octyl and the like. The term "thioalkyl" means an
alkyl radical having at least one sulfur atom, wherein alkyl has
the significance given above. An example of a thioalkyl is
--C(CH.sub.3).sub.2SCH.sub.3. The corresponding sulfoxide and
sulfone of this thioalkyl are --C(CH.sub.3).sub.2S(O)CH.sub.3 and
(CH.sub.3).sub.2S(O).sub.2CH.sub.3, respectively. The term
"alkenyl", alone or in combination, means a straight-chain or
branched-chain hydrocarbon radial having one or more double bonds
and containing from 2 to about 18 carbon atoms preferably from 2 to
about 8 carbon atoms. Examples of suitable alkenyl radicals include
ethenyl, propenyl, allyl, 1,4-butadienyl and the like. The term
"alkynyl", alone or in combination, means a straight-chain
hydrocarbon radical having one or more triple bonds and containing
from 2 to about 10 carbon atoms. Examples of alkynyl radicals
include ethynyl, propynyl (propargyl), butynyl and the like. The
term "alkoxy", alone or in combination, means an allyl 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 an
alkyl radical which contains from about 3 to about 8 carbon atoms
and is cyclic. Examples of such cycloalkyl radicals include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. 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. 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 and the like,
such as phenyl (CH.sub.5H.sub.5), p-tolyl, 4-methoxyphenyl,
4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl,
4-hydroxyphenyl, 2-hydroxyphenyl, 4-nitrophenyl, 2-nitrophenyl,
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(.dbd.O)--O-- aralkyl in which the term "aralkyl" has the
significance given above. An example of an aralkoxycarbonyl radical
is benzyloxycarbonyl. The term "aryloxy", alone or in combination,
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 cycloalknecarboxylic 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 term "arylthioalkyl" (aryl-5-alkyl) means an aryl radical
as defined above attached to a sulfur atom that is attached to an
alkyl radical as is defined above and with the preferred alkyl
group being 1 to 3 carbon atoms inclusive and the preferred aryl
ring being 6 to 10 carbon atoms inclusive and with the oxidation
states of sulfur including the sulfide (--S--), sulfoxide
(--S(O)--), or sulfone(--S(O).sub.2--), with the preferred
oxidation state of the sulfur being that of the sulfide (--S--).
Most preferred is an aryl ring of 6 carbon atoms. The term
"alkylthioalkyl" means an alkyl group of 1 to 6 carbon atoms
inclusive bonded to a sulfur atom witch is bonded to an alkyl group
of 1 to 3 carbon atoms inclusive. The heterocyclyl or
heterocycloalkyl portion of a heterocyclylcarbonyl,
heterocyclyloxycarbonyl, heterocyclylalkoxycarbonyl, or
heterocyclylalkyl group or the like is a saturated or partially
unsaturated monocyclic, bicyclic or tricyclic heterocycle which
contains one or more hetero atoms selected from nitrogen, oxygen
and sulphur, which is optionally substituted on one or more carbon
atoms by halogen, alkyl, alkoxy, oxo, and the like, and/or on a
secondary nitrogen atom (i.e., --NH--) by alkyl, aralkoxycarbonyl,
alkanoyl, phenyl or phenylalkyl or on a tertiary nitrogen atom
(i.e. .dbd.N--) by oxido and which is attached via a carbon atom.
The heteroaryl portion of a heteroaroyl, heteroaryloxycarbonyl, or
heteroaralkoxycarbonyl group or the like is an aromatic monocyclic,
bicyclic, or tricyclic heterocyle 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, tetrahydrofuryl,
tetrahydrothienyl, 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-quinolinyl, etc.),
1,2,3,4-tetrahydroisoquinolinyl(e.g.,
1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, etc.), quinoxalinyl,
beta-carbolinyl, 2-benzofurancarbonyl, 1-, 2-, 4- or
5-benzimidazolyl, benzofuryl, tetrahydrobenzofuryl and the like.
Heteroaryl or heterocycyl (heterocyclo, heterocycle) groups may be
bonded through a heteroatom or carbon. The term
"cycloalkylalkoxycarbonyl" means an acyl group derived from a
cycloalkylalkoxycarboxylic acid of the formula
cycloalkylalkyl-O--CO--OH 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 "heterocyclylalkanoyl"
is an acyl radical derived from a heterocyclyl-substituted alkane
carboxylic acid wherein heterocyclyl has the significance given
above. The term "heterocyclyloxycarbonyl" means an acyl group
derived from heterocyclyl-O--CO--OH wherein heterocyclyl is as
defined above. The term "heterocyclylalkanoyl" means an acyl
radical of the formula heterocyclyl-alkanoyl wherein heterocyclyl
and alkanoyl have the significance given above. The term
"heterocyclylalkoxycarbonyl" means an acyl radical derived from
heterocyclyl-substituted alkane-O--CO--OH 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 (carbamic acid) N--(C.dbd.O)--
wherein the amino group can be a primary, secondary or tertiary
amino group containing substituents selected from hydrogen, alkyl,
aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.
The term "aminoalkanoyl" means an acyl radical derived from an
amino substituted alkanecarboxylic acid wherein the amino group can
be a primary, secondary or tertiary amino group containing
substituents selected from the group consisting of hydrogen,
cycloalkyl, cycloalkylalkyl radicals and the like, examples of
which include N-methylaminoacetyl, N-cyclopropylaminoacetyl,
N-methoxyethylaminoacetyl, pyrrolidinyacetyl,
N,N-dimethylaminoacetyl and N-benzylaminoacetyl. The term "halogen"
means fluorine, chlorine, bromine or iodine. The term haloalkyl
means an alkyl group substituted with one or more halogen atoms on
one or different carbons such as chloromethyl, chlorobromoethyl,
trifluoromethyl, 2,2,2-trifluoromethylethylene and the like. The
term "leaving group" generally refers to groups readily
displaceable by a nucleophile, such as an amine, a thiol or an
alcohol nucleophile. Such leaving groups are well known and include
carboxylates, N-hydroxysuccinimide, N-hydroxybenzotriazole,
halides, triflates, tosylates, --OR and --SR and the like.
Preferred leaving groups are indicated herein where appropriate.
The term hydroxypropylenediamine means hydroxyethylamine when
applied to this class of protease inhibitors. The term
"N-heterocyclic moiety" or N-heterocycle is a heterocyclic radical
or heterocycle bonded via its nitrogen or with a nitrogen atom
radical bond site which may be a heterocycloalkyl or heteroaryl,
wherein heterocycloalkyl and heteroaryl have the significance given
above, with the addition that polycyclic heteroaryl may be fully
aromatic or partially aromatic, for example, a fused
heterocycloalkylaryl and a fused heteroarylcycloalkyl, and the
heterocycloalkyl and cycloalkyl may also be bridged. Preferably,
the N-heterocyclic moiety has 5, 6 or 7 members when monocyclic; 5,
6 or 7 members in a ring with 1, 2 or 3 members in a bridge when a
bridged monocyclic; 11, 12 or 13 members when bicyclic; and 11 to
16 members when tricyclic. Examples of N-heterocyclic moieties
include, but are not limited to, those represented by the following
formulae: ##STR6## ##STR7## wherein: [0064] R.sup.9 represents
hydrogen, alkyl, alkoxycarbonyl, monoalkylcarbamoyl,
monoaralkylcarbamoyl, monoarylcarbamoyl or a group of the formula:
##STR8## [0065] R.sup.10 and R.sup.11 each represents alkyl; [0066]
R.sup.12 represents hydrogen, hydroxy, alkoxycarbonylamino or
acylamino; [0067] R.sup.13 represents hydrogen, alkyl, aryl,
alkoxycarbonyl or acyl; [0068] m is 1, 2, 3, or 4; [0069] p is 1 or
2; and [0070] q is 0, 1 or 2.
[0071] The term prodrug means esters and amide derivatives of
amines, acids, alcohols, thiols and the like that are able to be
converted in vitro or in vivo by chemical or biochemical or
metabolic processed into an active parent compound. A prodrug may
or may not have intrinsic biological activity.
[0072] Procedures for preparing the compounds of Formulas I-IV are
set forth below. It should be noted that the general procedures are
shown as it relates to preparation of compounds having a specified
stereochemistry, for example, wherein the 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) or
(RS). The terms (R) and (S) configuration are as defined by the
IUPAC 1974 Recommendations for Section E, Fundamental
Stereochemistry, Pure Appl. Chem. (1976) 45, 13-30. The documents
WO 95/09843, U.S. Pat. No. 5,484,926, Kaldor, Stephen W., "A
systematic Study of P.sub.1-P.sub.3 Spanning Sidechains for the
Inhibition of HIV-1 Protease", Bioorganic and Medicinal Chemistry
Letters, 5, 715-720 (1995), WO 96/28463, WO 96/28418, WO 96/28465,
WO 96/22287, EP 0 346 847, U.S. Pat. No. 5,648,364, WO 96/28464,
U.S. Pat. No. 5,521,219, U.S. Pat. No. 5,463,104, U.S. Pat. No.
5,843,946, U.S. Pat. No. 5,756,533, U.S. Pat. No. 5,776,971 and
U.S. Pat. No. 5,705,500 include supplementary or alternative
methods for preparing intermediates or compounds useful or possibly
useful for preparing compounds of this invention as required or
desired by a person of ordinary skill in the art which documents
are incorporated herein by reference.
Preparation of Compounds of Formula I
[0073] The compounds of the present invention represented by
formula I through IV above wherein R.sup.2 is alkylthioalkyl or
arylthioalkyl (ArSCH.sub.2--) can be prepared utilizing the
following general procedures as illustrated in some cases with
compounds wherein R.sup.2 is arylalkyl. An N-protected haloketone
derivative of an amino acid having the formula: ##STR9## wherein P
represents an amino protecting group, R.sup.2 is as defined above
and Z represents a chlorine, bromine or iodine atom, 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. Preferred amino protecting groups are carbobenzoxy
and t-butoxycarbonyl. A preferred N-protected haloketone is a
compound of Formula VIII wherein P is benzyloxycarbonyl (Z or CBZ),
R.sup.2 is phenylthioalkyl and the alkyl group has one carbon atom.
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 haloketones may be commercially available
from Bachem, Inc., Torrance, Calif. Alternatively, the haloketones
can be prepared by the procedure set forth in S. J. Pittkau, J.
Prakt. Chem., 315, 1037 (1973), and subsequently N-protected
utilizing procedures which are well known in the art.
[0074] The resulting alcohol is then reacted, preferably at room
temperature, with a suitable base in a suitable solvent system to
produce an N-protected amino epoxide of the formula: ##STR10##
wherein P and R.sup.2 are as defined above. Suitable solvent
systems for preparing the amino epoxide include methanol, ethanol,
isopropanol, tetrahydrofuran, dioxane, and the like including
mixtures thereof. Suitable bases for producing the epoxide from the
reduced haloketone include potassium hydroxide, sodium hydroxide,
potassium t-butoxide, DBU and the like. A preferred base is
potassium hydroxide.
[0075] Alternatively, a protected amino epoxide can be prepared
starting with an D, L or DL-amino acid (illustrated below with an
L-aminoacid) which is reacted with a suitable amino- and
carboxyl-protecting groups in a suitable solvent to produce an
amino-protected L-amino acid ester of the formula: ##STR11##
wherein P.sup.1 and P.sup.2 independently represent hydrogen and
amino-protecting groups as defined above with respect to P,
provided that P.sup.1 and P.sup.2 are not both hydrogen: P.sup.4
represents hydrogen and a carboxy-protecting group, preferably one
which is also an amino-protecting group as defined above with
respect to P; and R.sup.2 is as defined above.
[0076] The amino protected L-amino acid ester is then reduced, to
the corresponding alcohol. For example, the amino-protected L-amino
acid ester can be reduced with diisobutylaluminum hydride at
-78.degree. C. in a suitable solvent such as toluene. The resulting
alcohol is then converted, by way of a Swern Oxidation, to the
corresponding aldehyde of the formula: ##STR12## wherein P.sup.1,
p.sup.2 and R.sup.3 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.
[0077] The aldehyde resulting from the Swern Oxidation is then
reacted with a halomethyllithium reagent, which reagent is
generated in situ by reacting an alkyl lithium or aryl lithium
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-butyl lithium in hexane is added. The resulting product is a
mixture of diastereomers of the corresponding amino-protected
epoxides of the formulas: ##STR13##
[0078] The diastereomers can be separated by chromatography or,
alternatively, once reacted in subsequent steps the distereomeric
products can be separated.
[0079] The amino epoxide is then reacted, in a suitable solvent
system, with an equivalent or more amount, of a heterocycle of the
formula: HNR.sup.4R.sup.5 wherein R.sup.4 and R.sup.5 are as
defined above. The reaction can be conducted over a wide range of
temperatures, e.g., from about 60.degree. C. to about 120.degree.
C. in an inert organic solvent, but is preferably, but not
necessarily, conducted at a temperature at which the solvent begins
to reflux. Suitable solvent systems include those wherein the
solvent is an alcohol, such as methanol, ethanol, isopropanol, and
the like, ethers such as tetrahydrofuran, dioxane and the like,
toluene, N,N-dimethylformamide, dimethylsulfoxide, and mixtures
thereof. A preferred solvent is isopropanol. Non-limiting examples
of heterocycles corresponding to the formula HNR.sup.4R.sup.5
include those having the following formula: ##STR14## ##STR15##
wherein [0080] R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, m,
p and q have the significance given above, and the like. The
resulting product is a 3-(N-protected
amino)-3-(R.sup.2)-1-(NR.sup.4R.sup.5)-propan-2-ol derivative
(hereinafter referred to as an amino alcohol) is an intermediate
which contains the desired N-heterocyclic moiety or intermediate
thereof and can be represented by the formula: ##STR16## wherein
p.sup.1, p.sup.2, R.sup.2, R.sup.4 and R.sup.5 are as described
above.
[0081] Alternatively, the compounds of the present invention
represented by Formula I above can be prepared utilizing the
following general procedure. An N-protected haloketone derivative
of an amino acid having the formula: ##STR17## wherein P, P.sup.1
and P.sup.2 represent amino protecting groups, R.sup.2 is as
defined above, and Z represents a chlorine, bromine or iodine atom,
is reacted, in a suitable inert organic solvent system, with an
equal or greater equivalent amount, of a desired amine of the
formula: HNR.sup.4R.sup.5 wherein R.sup.4 and R.sup.5 are as
defined above. The reaction yields a compound of the general
formula: ##STR18## wherein p.sup.1, p.sup.2, R.sup.2, R.sup.4 and
R.sup.5 have the significance given earlier.
[0082] The reaction of the N-protected haloketone derivative of an
amino acid, preferably one in which one of P.sup.1 and/or p.sup.2
represent benzyloxy carbonyl and one of P.sup.1 and/or p.sup.2
represent hydrogen, with the desired amine, a heterocyclic compound
of formula HNR.sup.4R.sup.5, can be carried out in any known
manner, for example, in an inert organic solvent such as
halogenated aliphatic hydrocarbon (e.g. dichloromethane,
N,N-dimethylformamide, tetrahydrofuran, isopropanol and ethanol)
and in the presence of a base (e.g. a trialkylamine such as
triethylamine and diisopropylethyl amine, sodium bicarbonate, DBU
and the like), conveniently at about room temperature.
[0083] The reduction of the aminoketone compound of Formula V
results in a compound of the general formula: ##STR19## wherein
p.sup.1, p.sup.2, R.sup.2, R.sup.4 and R.sup.5 have the
significance given earlier. The reduction of the aminoketone
compound of Formula V to the N-heterocyclic moiety-containing
derivative (Formula VI) can be carried out according to known
methods for the reduction of a carbonyl group to a hydroxy group.
Thus, for example, the reduction can be carried out using a complex
metal hydride such as an alkali metal borohydride, especially
sodium borohydride, in an appropriate organic solvent such as
alkanol (e.g. methanol, ethanol, propanol, isopropanol etc.).
[0084] Conveniently, the reduction is carried out at about room
temperature.
[0085] Following preparation of the N-heterocyclic
moiety-containing derivative, the amino protecting group P is, or
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 N,N-dibenzyl, these groups may be removed
by hydrogenolysis utilizing palladium on carbon. 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. Following neutralization of the salt, the amine is then
reacted with an amino acid or corresponding derivative thereof
represented by the formula (RR.sup.1NCH(R.sup.1)COOH) or
(RR.sup.1N[CR.sup.1'R.sup.1'']CH(R.sup.1)COOH) wherein R.sup.1',
R.sup.1'' and R.sup.1 are as defined above and may be P and/or
P.sup.1 and/or P.sup.2 to produce the antiviral compounds of the
present invention having the formula: ##STR20## wherein P, R.sup.1,
R.sup.1', R.sup.1'', R.sup.2, R.sup.4 and R.sup.5 are as defined
above. Preferred protecting groups in this instance are a
benzyloxycarbonyl group or a t-butoxycarbonyl group. Where the
amine is reacted with a derivative of an amino acid and R.sup.1'
and R.sup.1'' are both hydrogen, so that the amino acid is a,
beta-amino acid, such, beta-amino acids can be prepared according
to the procedure set forth in copending applications, U.S. Ser. No.
07/836,163 Method of Preparing Optically Active, beta-Amino Acids;
filed Feb. 14, 1992; Docket No. 07-21(855)A) (a continuation of
U.S. Ser. No. 07/706,508, now abandoned, which is a continuation of
U.S. Ser. No. 07/345,808, now abandoned). Where one of R.sup.1' and
R.sup.1' is hydrogen and R.sup.1 is hydrogen so that the amino acid
is a homo-beta-amino acid, such homo-beta-amino acids can be
prepared according to the procedure set forth in copending
application, U.S. Ser. No. 07/853,561 (Method of Preparing
Optically Active Homo-beta-Amino Acids; filed; Docket No.
07-21(722)A). The process thereof preserves the chirality of the
starting succinates. The method thereof involves Curtis
rearrangement of chiral 3-mono-substituted succinates (succinic
acid half ester) of sufficient purity to exhibit optical activity.
The Curtis rearrangement is preferably effected by treating a
chiral 3-mono-substituted succinate with one equivalent of
diphenoxyphosphoryl azide (PhO).sub.2PON.sub.3 and triethylamine to
form an acyl azide followed by heating in an inert solvent, such as
warm toluene, preferably at about 80.degree. C. for about three
hours to afford an isocyanate derivative which is subsequently
hydrolyzed to give amines. The 3-mono-substituted succinates can be
prepared by a procedure analogous to that described in U.S. Pat.
No. 4,939,288, filed Jan. 23, 1989, which is hereby incorporated by
reference. The alpha-amino acid compounds are prepared using, for
example, methods in U.S. Pat. No. 5,483,946, or variations well
know in the art. It should be noted that compounds of this
invention can be prepared in stepwise as is shown by the example in
Scheme 1 and Scheme 2 herein below or via a convergent synthesis
where parts of the final product are made separately and coupled in
a final step to produce said final product of this invention. The
person skilled in the art will select the appropriate process based
on compound to be made under particular conditions at that
particular time or location. ##STR21## ##STR22##
[0086] Coupling conditions such as mixed anhydride reaction,
activated ester coupling with, for example, hydroxybenzotriazol
(HOBT) and the like are very well know in the art especially the
aminoacid and peptide synthesis and reaction art.
[0087] The N-protecting group can be subsequently removed, if
desired, utilizing the procedures described above, and then reacted
with a carboxylate represented by the formula: ##STR23## wherein R
is as defined above and L is an appropriate leaving group such as a
halide. Examples of such carboxylates include acetylchloride,
phenoxyacetyl chloride, benzoyl chloride, 2-naphthyloxycarbonyl
chloride and 2-benzofurancarbonyl chloride. A solution of the free
amine (or amine acetate salt) and about 1.0 equivalent of the
carboxylate are mixed in an appropriate solvent system and
optionally treated with up to five equivalents of a base such as,
for example, N-methylmorpholine, at about room temperature.
Appropriate solvent systems include tetrahydrofuran, methylene
chloride or N,N-dimethylformamide, and the like, including mixtures
thereof.
[0088] Alternatively, a sulfonyl-containing compound represented by
the formula: ##STR24## wherein R is as defined above and L is an
appropriate leaving group such as halide may be substituted for the
aforementioned carboxylate. Preparation of Compounds of Formula
II
[0089] A mercaptan of the formula R'SH is reacted with a
substituted methacrylate of the formula: ##STR25## 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:
##STR26## 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 alkyl, aryl or aralkyl,
preferably R.sup.22 is methyl, ethyl, t-butyl or benzyl. Suitable
solvents in which the Michael Addition can be conducted include
alcohols such as, for example, methanol, ethanol, butanol and the
like, as well as ethers, e.g., THF, and acetonitrile, DMF, DMSO,
and the like, including mixtures thereof. Suitable bases include
Group I metal alkoxides such as, for example sodium methoxide,
sodium ethoxide, sodium butoxide and the like as well as Group I
metal hydrides, such as sodium hydride, including mixtures
thereof.
[0090] The thiol derivative is converted into the corresponding
sulfone of the formula: ##STR27## 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, potassium peroxy monosulfate,
meta-chloroperoxybenzeic acid, and the like, including mixtures
thereof. Suitable solvents include acetic acid (for sodium
meta-perborate) and, for other peracids, ethers such as THP and
dioxane, and acetonitrile, DME and the like, including mixtures
thereof.
[0091] The sulfone is then converted to the corresponding free acid
of the formula: ##STR28## utilizing a suitable base, e.g., lithium
hydroxide, sodium hydroxide, and the like, including mixtures
thereof, in a suitable solvent, such as, for example, THF,
acetonitrile, DMF, DMSO, methylene chloride and the like, including
mixtures thereof. When R.sup.22 is benzyl, the free acid may be
obtained by hydrogenolysis over palladium on carbon.
[0092] The free acid is then coupled, utilizing, as described
above, procedures well known in the art, to the N-heterocyclic
moiety-containing derivative of an amino alcohol which is described
above for the preparation of compounds of Formula I. The resulting
product is a compound represented by Formula II.
[0093] Alternatively, one can couple the N-heterocyclic
moiety-containing derivative to the commercially available acid,
##STR29## remove the thioacetyl group with a suitable base, such as
hydroxide, or an amine, or 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:
##STR30##
[0094] The sulfur can then be oxidized to the corresponding sulfone
using suitable oxidizing agents, as described above, to afford the
desired compounds of the following structure: ##STR31##
[0095] Alternatively, to prepare compounds of Formula II, a
substituted methacrylate of the formula: ##STR32## wherein L
represents a leaving group as previously defined, R.sup.35 and
R.sup.36 represent hydrogen and radicals as defined for R.sup.1;
and R.sup.37 represents alkyl, aralkyl, cycloalkyl and
cycloalkylalkyl radicals, is reacted with a suitable sulfonating
agent, such as, for example, a sulfinic acid represented by the
formula R'SO.sub.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: ##STR33## 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:
##STR34## 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 such as, for
example, a ruthenium-BINAP complex to produce the reduced product,
substantially enriched in the more active isomer represented by the
formula: ##STR35## 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-stereochemistry, 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
N-heterocyclic moiety-containing derivative, as described above, to
produce compounds of Formula II.
[0096] Alternatively, one can prepare the preferred
2(S)-methyl-3-(methylsulfonyl)propionic acid according to the
scheme outlined below starting from commercially available
D-(-)-S-benzyoyl-beta-mercaptoisobutyric acid tert-butyl ester.
Treatment of D-(-)-S-benzoyl-beta-mercaptoisobutyric acid
tert-butyl ester with a methanolic ammonia solution resulted in the
formation of D-(-)-beta-mercaptoisobutyric acid tert-butyl ester
and benzamide. The free mercaptan thus produced was freed from the
benzamide by filtration and then further purified by
crystallization. Treatment of D-(-)-beta-mercaptoisobutyric acid
tert-butyl ester with methyl iodide in the presence of a suitable
base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) results in
the formation of the corresponding thioether
S-methyl-D-(-)-beta-mercaptoisobutyric acid tert-butylester in
excellent yield. The thioether is then oxidized with a suitable
oxidant such as sodium metaperborate in acetic acid to give the
corresponding sulfone. Specifically,
S-methyl-D-(-)-beta-mercaptoisobutyric acid tert-butyl ester is
treated with sodium perborate in acetic acid to produce
2(S)-methyl-3-(methylsulfonyl)propionic acid tert-butyl ester in
excellent yield. The tert-butyl ester can then selectively removed
by treatment with 4N hydrochloric acid in dioxane to produce
2(S)-methyl-3-(methylsulfonyl)propionic acid as a crystalline acid
in very good yield. It is envisioned that variations of the sulfur
and carboxylate protecting groups would be acceptable for
preparation of 2(S)-methyl-3-(methylsulfonyl)propionic acid and
analogs. ##STR36## Preparation of Compounds of Formula III
[0097] To produce compounds of Formula III, starting with a lactate
of formula: ##STR37## wherein P represents alkyl and aralkyl
radicals, such as, for example, ethyl, methyl, benzyl and the like.
The hydroxyl group of the lactate is protected as its ketal by
reaction in a suitable solvent system with methyl isopropenyl ether
(1,2-methoxypropene) in the presence of a suitable acid. Suitable
solvent systems include methylene chloride, tetrahydrofuran and the
like as well as mixtures thereof. Suitable acids include POCl.sub.3
and the like. It should be noted that well-known groups other than
methyl isopropenyl ether can be utilized to form the ketal. The
ketal is then reduced with diisobutyhluminum hydride (DIBAL) at
-78.degree. C. to produce the corresponding aldehyde which is then
treated with ethylidenetriphenylphosphorane (Wittig reaction) to
produce a compound represented by the formula: ##STR38##
[0098] The ketal protecting group is then removed utilizing
procedures well-known in the art such as by mild acid hydrolysis.
The resulting compound is then esterified with isobutyryl chloride
to produce a compound of the formula: ##STR39##
[0099] This compound is then treated with lithium diisopropyl amide
at -78.degree. C. followed by warming of the reaction mixture to
room temperature to effect a Claisen rearrangement ([3,3]) to
produce the corresponding acid represented by the formula:
##STR40##
[0100] Treatment of the acid with benzyl bromide (BnBr) in the
presence of a tertiary amine base, e.g., DBU, produces the
corresponding ester which is then cleaved oxidatively to give a
trisubstituted succinic acid: ##STR41##
[0101] The trisubstituted succinic acid is then coupled to the
N-heterocyclic moiety-containing derivative as described above. To
produce the free acid, the benzyl ester is removed by
hydrogenolysis to produce the corresponding acid. The acid can then
be converted to the primary amide by methods well-known in the
art.
[0102] An alternative method for preparing trisubstituted succinic
acids involves reacting an ester of acetoacetic acid represented by
the formula: ##STR42## where R is a suitable protecting group, such
as methyl, ethyl, benzyl or t-butyl with sodium hydride and a
hydrocarbyl halide (R.sup.31X or R.sup.32X) in a suitable solvent,
e.g., THF, to produce the corresponding disubstituted derivative
represented by the formula: ##STR43##
[0103] This disubstituted acetoacetic acid derivative is then
treated with lithium diisopropyl amide at about -10.degree. C. and
in the presence of PhN(triflate).sub.2 to produce a vinyl triflate
of the formula: ##STR44##
[0104] The vinyl triflate is then carbonylated utilizing a
palladium catalyst, e.g., Pd(OAc).sub.2(Ph.sub.3)P, in the presence
of an alcohol (R''OH) or water (R''.dbd.H) and a base, e.g.,
triethylamine, in a suitable solvent such as DMF, to produce the
olefinic ester or acid of the formula: ##STR45##
[0105] The olefin can then be subsequently asymmetrically
hydrogenated, as described above, to produce a trisubstituted
succinic acid derivative of the formula: ##STR46##
[0106] If R'' is not H, R'' can be removed by either hydrolysis,
acidolysis, or hydrogenolysis, to afford the corresponding acid,
which is then coupled to the N-heterocyclic moiety-containing
derivative as described above and then, optionally, the R group
removed to produce the corresponding acid, and optionally,
converted to the amide.
[0107] Alternatively, one can react the N-heterocyclic
moiety-containing derivative with either a suitably monoprotected
succinic acid or glutaric acid of the following structures;
##STR47## followed by removal of the protecting group and
conversion of the resulting acid to an amide. One can also react an
anhydride of the following structure: ##STR48## with the
N-heterocyclic moiety-containing derivative and then separate any
isomers or convert the resulting acid to an amide and then separate
any isomers.
[0108] It is contemplated that for preparing compounds of the
Formulas having R.sup.6 being other than hydrogen, the compounds
can be prepared following the procedure set forth above and, prior
to coupling the N-heterocyclic moiety-containing derivative to the
respective acid, the derivative carried through a procedure
referred to in the art as reductive amination. Thus, a sodium
cyanoborohydride and an appropriate aldehyde, such as formaldehyde,
acetaldehyde and the like, can be reacted with the N-heterocyclic
moiety-containing derivative compound at room temperature in order
to reductively aminate any of the compounds of Formulas I-IV.
[0109] Contemplated equivalents of the respective 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.
[0110] Optically active compound isomers as well as mixed or
non-optically active compound isomers are specifically intended to
be included in this discussion and in this invention. Examples of
isomers are RS isomers, enantiomers, diastereomers, racemates, cis
isomers, trans isomers, E isomers, Z isomers, syn-isomers,
anti-isomers, tautomers and the like. Aryl, heterocyclo or
heteroaryl tautomers, heteroatom isomers and ortho, meta or para
substitution isomers are also included as isomers. Solvates or
solvent addition compounds such as hydrates or alcoholates are also
specifically included both as chemicals of this invention and in,
for example, formulations or pharmaceutical compositions for
delivery. In the propylene diamine (hydroxyethylamine) function, a
preferred configuration for the carbon bearing hydroxyl is R when
the configuration at the carbon bearing the phenylthiomethylene
group is R. A preferred set of isomers includes those depicted in
the compounds of Examples 21 through 34 inclusive.
[0111] 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.
[0112] 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.
[0113] In the following examples, melting points were determined on
a Fisher-Johns melting point apparatus and are uncorrected. All
reagents were used as received without purification. All proton and
carbon NMR spectra were obtained on either a Varian VER-300 or
VER-400 nuclear magnetic resonance spectrometer using
tetramethysilane as internal standard. Gas chromatograph was
performed on a Varian 3400 chromatography system. All instruments
were utilized according to the manufacturer's directions.
EXAMPLE 1
Preparation of
N-Benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane
[0114] ##STR49##
Part A
[0115] To a solution of 75.0 g (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., was added 13.17 g (0.348 mol, 1.54 equiv.) of solid
sodium borohydride over one hundred minutes. The solvents were
removed in vacuo at 40.degree. C. and the residue dissolved in
ethyl acetate (approx. 1 L). The solution was washed sequentially
with 1M potassium hydrogen sulfate, saturated sodium bicarbonate
and then saturated sodium chloride solutions. After drying over
anhydrous magnesium sulfate and filtering, the solution was removed
in vacuo. To the resulting oil was added hexane (approx. 1 L) and
the mixture warmed to 60.degree. C. with swirling. After cooling to
room temperature, the solids were collected and washed with 2 L of
hexane. The resulting solid was recrystallized from hot ethyl
acetate and hexane to afford 32.3 g (43% yield) of
N-benzyloxycarbonyl-3(S)-amino-1-chlorophenyl-2(S)-butanol, mp
150-151.degree. C. and M+Li.sup.+=340. formula: ##STR50##
Part B
[0116] To a solution of 6.52 g (0.116 mol, 1.2 equiv.) of potassium
hydroxide in 968 mL of absolute ethanol at room temperature, was
added 32.3 g (0.097 mol) of
N-CBZ-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, wherein CBZ stands
for benzyloxycarbonyl. After stirring for fifteen minutes, the
solvent was removed in vacuo and the solids dissolved in methylene
chloride. After washing with water, drying over magnesium sulfate
(MgSO.sub.4), filtering and stripping, one obtains 27.9 g of a
white solid. Recrystallization from hot ethyl acetate and hexane
afforded 22.3 g (77% yield) of
N-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane, mp
102-103.degree. C. and MH.sup.+ 298; formula: ##STR51##
EXAMPLE 2
[0117] Preparation of carbamic acid,
[3-[3-[[(1,1-dimethylethyl)amino]carbonyl]octahydro-2(1H)-isoquinolinyl]--
2-hydroxy-1-(phenylmethyl)propyl]-phenylmethyl ester,
[3S-[2(1R*,2S*), 3.alpha.,4 a.beta.,8 a.beta.]]-. Also known as
carbamic acid,
[3-[3-[[(1,1-dimethylethyl)amino]carbonyl]decahydro-isoquinolinyl]-2-hydr-
oxy-1-(phenylmethyl)propyl]-, phenylmethyl ester, [3S-[2(1R*,2S*),
3.alpha.,4 a.beta.,8 ##STR52##
Part A
[0118] L-tetrahydroisoquinoline-2-carboxylic acid (24.83 g, 0.140
mol) was suspended in a solution of 80 mL of 2.5 N sodium
hydroxide, 80 mL of water, and 80 mL of tetrahydrofuran. To this
was added with vigorous stirring, 32.0 g (0.147 mol) of
tert-butylpyrocarbonate in 20 mL of tetrahydrofuran. After 1 hour
the pH dropped from 13 to 8.2, at pH 7.8 sodium hydroxide (2.5 N)
was added dropwise to maintain a pH of 8.8. After the pH
stabilized, the contents were extracted with diethylether
(2.times.125 mL). The aqueous phase was acidified (pH.about.2.0)
with more HCl, after cooling the solution in an ice bath. The
precipitate was extracted with ether, which was then dried over
MgSO.sub.4, fltered and concentrated to yield 36.8 grams of crude
product which needed no purification (95% yield). The product was
N-tert-butoxycarbonyl-L-tetrahydroisoquinoline-2-carboxylic acid
which has the following formula: ##STR53##
Part B
[0119] N-tert-butoxycarbonyl-L-tetrahydroisoquinoline-2-carboxylic
acid (27.7 g, 0.10 moles) was dissolved in 50 mL of
dimethylformamide, and to this was added a warmed solution of 21 g
of N-hydroxybenzotriazole in 30 mL of dimethylformamide. The
solution was cooled to 10.degree. C. and to this was added 19.1 g
(0.10 moles) of 1-(3-dimethylaminopropyl)-2-ethylcarbodiimide
hydrochloride (EDC) and the solution stirred for 10-15 minutes, at
which time 7.3 g (0.100 moles) of distilled tert-butylamine was
added. After 14 hours the solution was concentrated and 200 mL of
ethyl acetate was added. The organic layer was washed with 5%
aqueous potassium hydrogen sulfate, saturated sodium bicarbonate
and brine, dried over magnesium sulfate, filtered, and concentrated
to yield a yellow oil, which was crystallized from warm hexane to
yield 15.0 grams of a first crop (45.5% yield). The product was
N-tert-butoxycarbonyl-S-tetrahydroisoquinoline-2-carboxylic acid
tert-butyl amide which has the following formula: ##STR54##
Part C
[0120] N-tert-butoxycarbonyl-5-tetrahydroisoquinoline-2-carboxylic
acid tert-butyl amide (10.0 g, 30 mmol) was dissolved in 50 mL of
methanol and placed in a Fisher Porter bottle with 3.2 g of wet
rhodium (50 wt % H.sub.2O, 10 wt % rhodium on carbon). The bottle
was purged with nitrogen, and charged with 50 psig hydrogen and
heated to 50.degree. C. for 24 hours. The catalyst was removed by
fltration and the methanol evaporated to yield a mixture of (S,S,S)
desired isomer and (S,R,R) undesired isomer in a 2:1 ratio,
respectively. The desired isomer (S,S,S) was separated by column
chromatography on silica gel using a 15-20% ethyl acetate hexane
gradient elusion to yield 6.1 grams of pure isomer (66% yield). The
product was
N-tert-butyloxycarbonyl-(S,S,S)decahydroisoquinoline-2-carboxylic
acid, tert-butylamide which has the following structure:
##STR55##
Part D
[0121]
N-tert-butyloxycarbonyl-(S,S,S)decahydroisoquinoline-2-carboxylic
acid, tert-butylamide (6.3 g, 18.6 mmol) was dissolved in 30 mL of
4N HCl in dioxane and stirred under a nitrogen atmosphere for 1
hour. The solvent was removed and the white solid was suspended in
200 mL of dichloromethane and washed several times with saturated
sodium bicarbonate. The dichloromethane (CH.sub.2Cl.sub.2) layer
was dried over magnesium sulfate, filtered, and concentrated to
yield 3.68 g of freebase (85% yield). The amine product has the
following stucture: ##STR56##
Part E
[0122] The amine from part D (3.68 g, 15.4 mmol) and 4.58 g (15.4
mmol) of epoxide from Example 1 were dissolved in 50 mL of
isopropanol and refluxed under a nitrogen atmosphere for 48 hours.
The isopropanol was removed and the crude solid was chromatographed
on silica gel using methanol methylene chloride eluant to provide
8.0 g of pure product (97% yield) identified as carbamic acid,
[3-[3-[[(1,1-dimethylethyl)amino]carbonyloctahyd-2(1H)-isoquinolinyl]-2-h-
ydroxy-1-(phenylmethyl)-propyl]-, phenylmethyl ester,
[3S-(2(1R*,2S*), 3.alpha.,4 a.beta.,8 a.beta.]]-. ##STR57##
EXAMPLE 3
Alternate General Procedure for the Synthesis of
1,3-Diamino-4-Phenyl-2-ol Derivatives
Step A:
[0123] 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 minutes). 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
layers 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.
Step B:
[0124] 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. C. to -50.degree.
C. (addition time .about.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 minutes, 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 material 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.
Step C:
[0125] 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 hours). The mixture is stirred for 5
minutes, followed by addition of a solution of the alcohol (0.074
mol) in 100 mL of dichloromethane (addition time .about.20 minutes,
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 minutes (temp. -780 to -68.degree. C.) upon
which the ammonium salt precipitated. The cold mixture is stirred
for 30 minutes 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 fltered 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.
[0126] 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.
[0127] 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 .about.15 minutes).
After the first addition, additional chloroidomethane (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 minutes. Each of the reagents, chloroiodomethane
(0.70 mL, 0.010 mol) and n-butyllithium (5 mL, 0.008 mol) are added
4 more times over 45 minutes at -75.degree. C. The cooling bath is
then removed and the solution warmed to 22.degree. C. over 1.5
hours. 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 bane, 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 a
subsequent step. Alternately, the product could be purified by
chromatography.
[0128] The resulting epoxide can be substituted for the epoxide
used in Example 2, Part E.
.beta.-Amino Acid Derivatives
EXAMPLE 4
Preparation of carbamic acid,
[3-[[3-[3-([(1,1-dimethylethyl)-amino]carbonyl]octahydro-2(1H)-isoquinoli-
nyl]-2-hydroxy-1-(phenyl-methyl)propyl]amino]-2-methyl-3-oxopropyl]-,
(4-methoxyphenyl)methyl ester,
[3S-[2[1R*(S*),2S*],3.alpha.,4a.beta.,8a.beta.]]-
[0129] ##STR58##
Part A
[0130] A solution of carbamic acid,
[3-[3-[(1,1-dimethylethyl)amino]-carbonyl]octahydro-2(1H)-isoquinolinyl]--
2-hydroxy-1-(phenylmethyl)-propyl], phenylmethyl ester,
[3S-[2(1R*,2S*),3.alpha.,4a.beta.,8a.beta.]]-(1.00 g, 1.87 mmol) in
methanol (50 mL) was hydrogenated in the presence of 0.50 g (50%
wt) of 10% Pd/charcoal for 191/2 hours at room temperature and 50
psig of H.sub.2 The catalyst was removed by vacuum filtration
through a short plug of celite and the solvent removed in vacuo to
give 0.69 g (92%) of a white foam. Subsequently, the crude material
was triturated with diethylether (Et.sub.2O) to give 0.51 g (68%)
of a white powder. The amine product has the following formula:
##STR59##
Part B
[0131] N-p-methoxybenzyloxycarbonyl-.alpha.-methyl-.beta.-alanine
(430.5 mg, 1.6 mmol) was dissolved in 2.0 mL of dimethyl formamide,
and to this was added 326 mg (1.5 eq) of N-hydroxybenzotriazole and
stirred until the solution was homogeneous. The solution was then
cooled to 5.degree. C. and 308 mg (1.6 mmol) of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide was added the
reaction stirred for 20 minutes. A solution of 547 mg (1.6 mmol) of
the amine from Part A in 5 mL of dimethylformamide (DMF) was added
to the solution and stirred for 16 hours. The dimethylformamide was
removed by rotary evaporation and replaced with ethyl acetate. The
organic layer was washed with water and saturated sodium
bicarbonate, dried over magnesium sulfate, filtered and
concentrated to yield 730 mg of crude product. Flash column
chromatography on silica gel using ethyl
acetate:dichloromethane:ethanol eluant 25:25:1 provided 250 mg of
product (25% yield), M+H=651, identified as carbamic acid,
[3-[[3-[3-[[(1,1-dimethylethyl)-amino]carbonyl]octahydro-2(1H)-isoquinoli-
nyl]-2-hydroxy-1-(phenyl-methyl)propyl]amino]-2-methyl-3-oxopropyl]-,
(4-methoxyphenyl)methyl ester, [3S-[2[1R*(S*),2S*], 3.alpha.,4
a.beta.,8 a.beta.]]-.
EXAMPLE 5
Preparation of
3-(4-methoxybenzyloxycarbonyl)amino-2(R)-methylpropionic acid also
known as N-4-Methoxybenzyloxycarbonyl-.alpha.-methyl-.beta.-alanine
(N-Moz-AMBA) and
N-p-methoxybenzyloxyearbonyl-.alpha.-methyl-.beta.-alanine
[0132] ##STR60##
A. Preparation of 4(4-methoxybenzyl)itaconate
[0133] ##STR61##
[0134] A 5 L three-necked round bottomed flask equipped with
constant pressure addition funnel, reflux condenser, nitrogen
inlet, and mechanical stirrer was charged with itaconic anhydride
(660.8 g, 5.88 mol) and toluene (2300 mL). The solution was warmed
to reflux and treated with 4-methoxybenzyl alcohol (812.4 g, 5.88
mol) dropwise over a 2.6 hour period. The solution was maintained
at reflux for an additional 1.5 hr and then the contents were
poured into three 2 L Erlenmeyer flasks to crystallize. The
solution was allowed to cool to room temperature whereupon the
desired mono-ester crystallized. The product was isolated by
filtration on a Buchner funnel and air dried to give 850.2 g, 58%,
of material with mp 83-85.degree. C., a second crop, 17% was
isolated after cooling of the filtrate in an ice bath. .sup.1H NMR
(CDCl.sub.3) 300 MHz 7.32(d, J=8.7 Hz, 2H), 6.91(d, J=8.7 Hz, 2H),
6.49(s, 1H), 5.85(s, 1H), 5.12(s, 2H), 3.83(s, 3H), 3.40(s,
2H).
B. Preparation of Methyl 4(4-methoxybenzyl! Itaconate
[0135] ##STR62##
[0136] A 5 L three-necked round bottomed flask equipped with reflux
condenser, nitrogen inlet, constant pressure addition funnel and
mechanical stirrer was charged with 4(4-methoxybenzyl) itaconate
(453-4 g, 1.81 mol) and treated with
1,5-diazabicyclo[4.3.0]non-5-ene (275.6 g, 1.81 mol), (DBN),
dropwise so that the temperature did not rise above 15.degree. C.
To this stirring mixture was added a solution of methyl iodide
(256.9 g, 1.81 mol) in 250 mL of toluene from the dropping funnel
over a 45 minute period. The solution was allowed to warm to room
temperature and stirred for an additional 3.25 hours.
[0137] The precipitated DBN hydroiodide was removed by filtration,
washed with toluene and the filtrate poured into a separatory
funnel. The solution was washed with saturated aqueous NaHCO.sub.3
(2.times.500 mL), 0.2N HCl (1.times.500 mL), and brine (2.times.500
ml), dried over anhyd. MgSO.sub.4, fltered, and the solvent removed
in vacuo. This gave a clear colorless oil, 450.2 g, 94% whose NMR
was consistent with the assigned structure. .sup.1H NMR
(CDCl.sub.3) 300 MHz 7.30(d, J=8.7 Hz, 2H), 6.90(d, J=8.7 Hz, 2H),
6.34(s, 1H), 5.71(s, 1H), 5.09(s, 2H), 3.82(s, 3H), 3.73(s, 3H),
3.38(s, 2H). .sup.13C MMR (CDCl.sub.3) 170.46, 166.47, 159.51,
133.55, 129.97, 128.45, 127.72, 113.77, 66.36, 55.12, 51.94,
37.64.
C. Preparation of Methyl 4(4-methoxybenzyl!
2(R)-methylsuccinate
[0138] ##STR63##
[0139] A 500 mL Fisher-Porter bottle was charged with methyl
4(4methoxybenzyl)itaconate (71.1 g, 0.269 mol), rhodium (R,R)
DIPAMP catalyst (204 mg, 0.269 mmol, 0.1 mol %) and degassed
methanol (215 mL). The bottle was flushed 5 times with nitrogen and
5 times with hydrogen to a final pressure of 40 psi. The
hydrogenation commenced immediately and after ca. 1 hour the uptake
began to taper off, after 3 hours the hydrogen uptake ceased and
the bottle was flushed with nitrogen, opened and the contents
concentrated on a rotary evaporator to give a brown oil that was
taken up in boiling iso-octane (ca. 200 mL, this was repeated
twice), filtered through a pad of celite and the filtrate
concentrated in vacuo to give 66.6 g, 93% of a clear colorless-oil,
.sup.1H MMR (CDCl.sub.3 300 MHz 7.30(d, j=8.7 Hz, 2H), 6.91(d,
J=8.7 Hz, 2H), 5.08(s, 2H), 3.82(s, 3H), 3.67(s, 3H), 2.95(ddq,
J=5.7, 7.5, 8.7 Hz, 1H), 2.79(dd, J=8.1, 16.5 Hz, 1H), 2.45(dd,
J=5.7, 16.5 Hz, 1H), 1.23(d, J=7.5 Hz, 3H).
D. Preparation of Methyl 2(R)-methylsuccinate
[0140] A 3 L three-necked round-bottomed flask equipped with a
nitrogen inlet, mechanical stirrer, reflux condenser and constant
pressure addition funnel was charged with methyl 4(4-methoxybenzyl)
2(R)-methylsuccinate (432.6 g, 1.65 mol) and toluene (1200 mL). The
stirrer was started and the solution treated with trifluoroacetic
acid (600 mL) from the dropping funnel over 0.25 hours. The
solution turned a deep purple color and the internal temperature
rose to 45.degree. C. After stirring for 2.25 hours the temperature
was 27.degree. C. and the solution had acquired a pink color. The
solution was concentrated on a rotary evaporator. The residue was
diluted with water (2200 mL) and sat. aq. NaHCO3 (1000 mL).
Additional NaHCO.sub.3 was added until the acid had been
neutralized. The aqueous phase was extracted with ethyl acetate
(2.times.1000 mL) to remove the by-products and the aqueous layer
was acidified to pH=1.8 with conc. HCl. This solution was extracted
with ethyl acetate (4.times.1000 mL), washed with brine, dried over
anhyd. MgSO.sub.4, f.about.iltered and concentrated on a rotary
evaporator to give a colorless liquid 251 g, >100%, that was
vacuum distilled through a short path apparatus cut 1: bath
temperature 120.degree. C. @ 1 mm, bp 25-29.degree. C.; cut 2: bath
temperature 140.degree. C. @ 0.5 mm, bp 95-108.degree. C., 151 g,
[a]D @ 25.degree. C.=+1.38.degree. C. (c=15.475, MeOH),
[a]D=+8.48.degree. C. (neat); cut 3: bath temperature 140.degree.
C., bp 108.degree. C., 36 g, [a]D @ 25.degree. C.=+1.49.degree. C.
(c=15.00, MeOH), [a].sub.D=+8.98.degree. C. (neat). Cuts 2 and 3
were combined to give 189 g, 78% of product, .sup.1H NMR
(CDCl.sub.3) 300 MHz 11.6(brs, 1H), 3.72(s, 3H), 2.92(ddq, J=5.7,
6.9, 8.0 Hz, 1H), 2.81(dd, J=8.0, 16.8 Hz, 1H), 2.47(dd, J=5.7,
16.8 Hz, 1H), 1.26(d, J=6.9 Hz, 3H).
E. Preparation of Methyl Itaconate
[0141] ##STR64##
[0142] A 50 mL round bottomed flask equipped with reflux condenser,
nitrogen inlet and magnetic stir bar was charged with methyl
4(4-methoxybenzyl) itaconate (4.00 g, 16 mmol), 10 mL of toluene
and 10 mL of trifluoroacetic acid. The solution was kept at room
temperature for 18 hours and then the volatiles were removed in
vacuo. The residue was taken up in ethyl acetate and extracted
three times with saturated aqueous sodium bicarbonate solution. The
combined aqueous extract was acidified to pH=1 with aqueous
potassium bisulfate 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 in vacuo. The residue was then
vacuum distilled to give 1.23 g, 75% of pure product, bp 85-87 @
0.1 mm. .sup.1H NMR (CDCl.sub.3) 300 MHz 6.34(s, 1H), 5.73(s, 2H),
3.76(s, 3H), 3.38(s, 2H). .sup.13C NMR (CDCl.sub.3) 177.03, 166.65,
129.220, 132.99, 52.27, 37.46.
F. Curtius Rearrangement of Methyl 2(R)-methylsuccinate:
Preparation of Methyl N-Moz-.alpha.-methyl .beta.-alanine
[0143] ##STR65##
[0144] A 5 L four necked round bottomed flask equipped with a
nitrogen inlet, reflux condenser, mechanical stirrer, constant
pressure addition funnel, and thermometer adapter was charged with
methyl 2(R)-methylsuccinate (184. la, 1.26 mol), triethylamine
(165.6 g, 218 mL, 1.64 mol, 1.3 equivalents), and toluene (1063
mL). The solution was warmed to 85.degree. C. and then treated
dropwise with a solution of diphenylphosphoryl azide (346.8 g, 1.26
mol) over a period of 1.2 hours. The solution was maintained at
that temperature for an additional 1.0 hour and then the mixture
was treated with 4-methoxybenzyl alcohol (174.1 g, 1.26 mol) over a
0.33 hours period from the dropping funnel. The solution was
stirred at 88.degree. C. for an additional 2.25 hours and then
cooled to room temperature. The contents of the flask were poured
into a separatory funnel and washed with saturated aqueous
NaHCO.sub.3 (2.times.500 mL), 0.2N HCl (2.times.500 mL), brine
(1.times.500 mL), dried over anhydrous MgSO.sub.41 fltered, and
concentrated in vacuo to give 302.3 g, 85% of the desired product
as a slightly brown oil. .sup.1H NMR (CDCl.sub.3) 300 MHz 7.32(d,
J=8.4 Hz, 2H), 6.91(d, J=8.4 Hz, 2H), 5.2(brm, 1H), 5.05(s, 2H),
3.83(s, 3H), 3.70(s, 3H), 3.35(m, 2H), 2.70(m, 2H), 1.20(d, J=7.2
Hz, 3H).
G. Hydrolysis of Methyl N-Moz-.alpha.-methyl-.beta.-alanine
Preparation of .alpha.-methyl .beta.-alanine Hydrochloride
[0145] ##STR66##
[0146] A 5 L three-necked round bottomed flask equipped with a
reflux condenser, nitrogen inlet and mechanical stirrer was charged
with methyl N-Moz-.alpha.-methyl-.alpha.-alanine (218.6 g, 0.78
mol), glacial acetic acid (975 mL) and 12N hydrochloric acid (1960
mL). The solution was then heated to reflux for 3 h. After the
solution had cooled to room temperature (ca. 1 hour) the aqueous
phase was decanted from organic residue (polymer) and the aqueous
phase concentrated on a rotary evaporator. Upon addition of acetone
to the concentrated residue a slightly yellow solid formed that was
slurried with acetone and the white solid was isolated by fltration
on a Buchner funnel The last traces of acetone were removed by
evacuation to give 97.7 g, 90% of pure product, mp
128.5-130.5.degree. C. [.alpha.].sub.D 25.degree. C.=9.0.degree. C.
(c=2.535, Methanol). .sup.1H NMR (D2O) 300 MHz 3.29(dd, J=8.6, 13.0
Hz, 1H), 3.16(dd, J=5.0, 13.0 m Hz, 1H), 2.94(ddq, J=7.2, 5.0, 8.6
Hz, 1H), 1.30(d,J=7.2 Hz, 3H); .sup.13C NMR (D2O) 180.84, 44.56,
40.27, 17.49.
H. Preparation of N-Boc .alpha.-Methyl-.beta.-Alanine
[0147] ##STR67##
[0148] A solution of .alpha.-Methyl-.beta.-Alanine hydrochloride
(97.7 g, 0.70 mol) in water (1050 mL) and dioxane (1050 mL) the pH
was adjusted to 8.9 with 2.9N NaOH solution. This stirring solution
was then treated with di-tert-butyl pyrocarbonate (183.3 g, 0.84
mol, 1.2 equivalents) all at once. The pH of the solution was
maintained between 8.7 and 9.0 by the periodic addition of 2.5N
NaOH solution. After 2.5 h the pH had stabilized and the reaction
was judged to be complete. The solution was concentrated on a
rotary evaporator (the temperature was maintained at <40.degree.
C.). The excess di-t-butyl pyrocarbonate was removed by extraction
with dichloromethane and then the aqueous solution was acidified
with cold 1N HCl and immediately extracted with ethyl acetate
(4.times.1000 mL). The combined ethyl acetate extract was washed
with brine, dried over anhydrous MgSO.sub.4, filtered and
concentrated on a rotary evaporator to give a thick oil 127.3 g,
90% crude yield that was stirred with n-hexane whereupon crystals
of pure product formed, 95.65 g, 67%, mp 76-78.degree. C., [a]D @
25.degree. C.=-11.8.degree. C. (c=2.4, EtOH). A second crop was
obtained by concentration of the filtrate and dilution with hexane,
15.4 g, for a combined yield of 111.05 g, 78%. .sup.1H NMR (acetone
D6) 300 MHz 11.7 (brs, 1H), 6.05 (brs 1H), 3.35 (m, 1H), 3.22 (m,
1H), 2.50 (m, 1H), 1.45(s, 9H), 1.19 (d, J=7.3 Hz, 3H); .sup.13C
NMR (acetone D.sub.6) 177.01, 79.28, 44.44, 40.92, 29.08, 15.50.
Elemental analysis calc'd. for C5H,7NO4: C, 53.19, H, 8.42; N,
6.89. Found: C, 53.36; H, 8.46; N, 6.99.
I. Preparation of
N-4-Methoxybenzyloxycarbonyl-.alpha.-Methyl-.beta.-Alanine
[0149] ##STR68##
[0150] A solution of
N-4-methoxybenzyloxycarbonyl-.alpha.-methyl-.beta.-alanine methyl
ester (2.81 g, 10.0 mmol) in 30 mL of 25% aqueous methanol was
treated with lithium hydroxide (1.3 equivalents) at room
temperature for a period of 2 hours. The solution was concentrated
in vacuo and the residue taken up in a mixture of water and ether
and the phases separated and the organic phase discarded. The
aqueous phase was acidified with aqueous potassium hydrogen sulfate
to pH=1.5 and then extracted three times with ether. The combined
ethereal phase was washed with saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, filtered and
concentrated in vacuo to give 2.60 g, 97% of
N-4-methoxybenzyloxycarbonyl-.alpha.-methyl-.beta.-alanine
(N-Moz-AMBA) which was purified by recrystallization from a mixture
of ethyl acetate and hexane to give 2.44 g, 91%, of pure product,
mp 96-97.degree. C., MH.sup.+=268. .sup.1H NMR (D.sub.6-acetone/300
MHz) 1.16 (3H, d, J=7.2 Hz), 2.70 (1H, m), 3.31 (2H, m), 3.31 (3H,
s), 4.99 (2H, s), 6.92 (2H, 4, J=8.7 Hz), 7.13 (2H, d, J=8.7
Hz).
Sulfone Derivatives
EXAMPLE 6
Preparation of 3-Isoquinolinecarboxamide,
N-(1,1-dimethylethyl)decahydro-2-[2-hydroxy-3-[[2-methyl-3-(methylsulfony-
l)-1-oxopropyl]amino]-4-phenylbutyl]-,[3S-[2[2S*,3R*(R*)],3.alpha.,4a.beta-
.,8a.beta.]]-
Part A
[0151] ##STR69##
[0152] A solution of carbamic acid,
[3-[3-[[(1,1-dimethylethyl)amino]-carbonyl]octahydro-2(1H)-isoquinolinyl]-
-2-hydroxy-1-(phenylmethyl)-propyl]-phenylmethyl ester,
[3S-[2(1R*,2S*), 3.alpha.,4a.beta.,8a.beta.]]-(1.00 g, 1.87 mmol)
in methanol (50 mL) was hydrogenated in the presence of 0.50 g (50%
wt) of 10% Pd/charcoal for 191/2 hours at room temperature and 50
psig of H.sub.2. The catalyst was removed by vacuum filtration
through a short plug of celite and the solvent removed in vacuo to
give 0.69 g (92%) of a white foam. Subsequently, the crude material
was triturated with diethylether (Et.sub.2O) to give 0.51 g (68%)
of a white powder. The amine product has the following formula:
Part B
[0153] ##STR70##
[0154] To a solution of 230 mg (1.38 mmol) of
2(S)-methyl-3-(methylsulfonyl)propionic acid in anhydrous DMF (4
mL) was added N-hydroxybenzotriazole (HOBt) (290 mg, 2.15 mmol) as
a powder and EDC (390 mg, 2.03 mmol) as a powder. The resulting
solution was stirred under nitrogen for 10 minutes upon which was
added 500 mg (1.24 mmol) of amine from part A in DME (6 mL) and
stirring continued for 17 hours. Subsequently, the reaction mixture
was poured into 50% saturated NaHCO.sub.3 (aq) and chilled for 1
hour, upon which a pale precipitate formed, which was filtered,
washed with water and dried under reduced pressure to give 430 mg
(63%) of a pale powder. The crude material was chromatographed on
silica, gel eluting with 5% ethanol in ethyl acetate to give 80 mg
(12%) of 3-isoquinolinecarboxamide,
N-(1,1-dimethylethyl)decahydro-2-[(2-hydroxy-3-[[2-methyl-3-(methylsulfon-
yl)-1-oxopropyl]amino]-4-phenylbutyl]-,[3S-[2[2S*,3R*(R*)],3.alpha.,4a.bet-
a.,8a.beta.]]- as a white powder; mass spectrum, m/e 556 (FAB,
M+Li). ##STR71##
[0155] The 2(S)-methyl-3-(methylsulfonyl)propionic acid (see
Example 7 for preparation) may be substituted by sulfonyl alkyl
acids, far example, 2-(R,S)methyl-3-(methylsulfonyl)propionic acid
(see Example 8 for preparation) and
2-(R,S)-methyl-3(.beta.-phenethylsulfonyl)-propionic acid (see
Example 9 for preparation)
EXAMPLE 7
Preparation of 2(S)-methyl-3-(methylsulfonyl)Propionic Acid
[0156] ##STR72##
[0157] To a solution of 10 g of
D-(-)-S-benzoyl-.beta.-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 in vacuo. 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: ##STR73##
[0158] 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[5.4.0]undec-7-ene (DBU) 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:
##STR74##
[0159] 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: ##STR75##
[0160] 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 in vacuo 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:
##STR76##
EXAMPLE 8
Preparation of 2-(R,S)-Methyl-3-(methylsulfonyl)propionic acid by
Asymmetric Hydrogenation
[0161] ##STR77##
Part A
[0162] 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 minutes at room
temperature. The solution was then stirred at room temperature for
a period of 1.25 hours 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 t-butyl ether and allowed to
stand whereupon crystals of pure methyl 2-(methylsulfonylmethyl)
acrylate 18.0 g, 68% formed, mp 65-68.degree. C. Formula:
##STR78##
Part B
[0163] 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 minutes 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.degree. C.;
formula: ##STR79##
Part C
[0164] 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 hours and then the hydrogen was
replaced with nitrogen and the solution filtered through a pad of
celite to remove the catalyst and the filtrate concentrated in
vacuo to give 682 mg, 96%, of 2-(R,S)methyl-3-methylsulfonyl
propionic acid; formula: ##STR80##
EXAMPLE 9
Preparation of Sulfones by Michael Addition to Methyl
Methacrylate
[0165] ##STR81##
Part A
[0166] 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 ma,
1.85 mmol). The solution was stirred under nitrogen for 3 hours 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) Rf=0.41.
Formula: ##STR82##
Part B
[0167] A solution of methyl 2-(R,S)-methyl-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 minutes. The solution was stirred at room
temperature for 16 hours and then filtered and the filtrate 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 minutes and then concentrated in vacuo. The
residue was then acidified with 1N 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, added 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
fltration and air added to give 3.38 g, 79% of
2-(R,S)methyl-3(.about.-phenethylsulfonyl)-propionic acid, mp
91-93.degree. C.; formula: ##STR83## .beta.-Asparagine
Derivatives
EXAMPLE 10
Preparation of butanediamide,
N.sup.4-[3-[3-[[(1,1-dimethylethyl)-amino]carbonyl]octahydro-2(1H)-isoqui-
nolinyl]-2-hydroxy-1-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)amino]-
-,[3S[2[1R*(R*),2S*],3.alpha.,4a .beta.,8a.beta.]]-
[0168] ##STR84##
Part A
[0169] A solution of carbamic acid,
[3-[3-[[(1,1-dimethylethyl)-amino]carbonyl]octahydro-2(1H)-isoquinolinyl]-
-2-hydroxy-1-(phenylmethyl)propyl], phenylmethyl ester,
[3S-[2(1R*,2S*],3.alpha.,4a.beta.,8a.beta.]-(1.2 g, 2.2 mmol) in 50
mL of methanol was charged to a Fisher Porter tube. The contents
were purged with nitrogen and 300 mg, 25 wt % of 10% palladium on
carbon was carefully added. The solution was charged with 50 psig
hydrogen and was vigorously stirred for 2.5 hours. The catalyst was
removed by filtration and the solution was concentrated to yield
849 mg (96% yield) of pure amine which has the following formula:
##STR85##
Part B
[0170] N-(2-quinolinylcarbonyl)-L-isoasparagine (366 mg, 1.2 mmol)
was dissolved in 4.0 mL of dry dimethylformamide, and to this was
added 250 mg (1.8 mmol) of N-hydroxybenzotriazole. After the
solution was homogeneous, 230 mg (1.2 mmol) of
1-(3-dimethyaminopropyl)-3-ethylcarbodiimide was added and the
reaction stirred for 15 minutes. A solution of 510 mg (1.2 mmol) of
amine from part A was added in 4.0 mL of dimethylformamide to the
solution and stirred for 16 hours. The majority of solvent was
removed and replaced with ethyl acetate. The organic phase was
extracted with water, saturated sodium bicarbonate and concentrated
to yield 693 mg of white foam. Flash chromatography on silica gel
using a gradient elution from 5% to 10% methanol/dichloromethane
gave 346 mg of pure product, identified as butanediamide,
N.sup.4-[3-[3-[[(1,1-dimethylethyl)-amino]carbonyl]octahydro-2(1H)-isoqui-
nolinyl]-2-hydroxy-1-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)-amino-
]-,[3S-[2[1R*(R*),2S*],3.alpha.,4a.beta.,8a.beta.]]-. M+Li=677.3.
Formula: ##STR86##
EXAMPLE 11
Preparation of N-(2-Quinolinylcarbonyl)-L-isoasparagine
[0171] ##STR87##
[0172] To a solution of 0.50 g (3.78 mmol) of L-isoasparagine in
5.0 mL H.sub.2O containing .about.45 mg (1.5 eq) of solid
bicarbonate. To this was added a suspension of 1.02 g (3.78 mmol)
quinaldic acid, N-hydroxysuccinamide ester in ethylene glycol
dimethylether, and the suspension was solubilized by the addition
of 10 mL of dimethylformamide. After 3 hours the solution was
acidified by the addition of 5% HCl (aqueous) and the product was
filtered and washed with water, dried under vacuum to yield 750 mg
(70% yield) of N-(2-quinolinylcarbonyl)-L-isoasparagine.
Succinamide Derivatives
EXAMPLE 12
Preparation of Butanamide,
4-[[3-[3-[[(1,1-dimethylethyl)-amino]carbonyl]octahydro-2(1H)-isoquinolin-
yl]-2-hydroxy-1-(phenylmethyl)propyl]amino]-2,2,3-trimethyl-4-oxo-,[3S-[2[-
1R*(S*),2S*],3.alpha.,4 a.beta.,8a.beta.]]-
[0173] ##STR88##
Part A
[0174] A solution of carbamic acid,
[3-[3-1[(1,1-dimethylethyl)amino]carbonyl]octahydro-2(1H)-isoquinolinyl]--
2-hydroxy-1-(phenylmethyl)propyl]-, phenylmethyl ester,
[3S-[2(1R*,2S*),3.alpha.,4 a.beta.,8a.beta.]]-(1.2 g, 2.2 mmol) was
dissolved in 50 mL of methanol and charged to a Fisher Porter tube.
The contents were purged with nitrogen and 300 mg, 25 wt % of 10%
palladium on carbon was carefully added. The solution was charged
with 50 psig hydrogen and was vigorously stirred for 2.5 hours. The
catalyst was removed by filtration and the solution was
concentrated to yield 849 mg (96% yield) of pure amine having the
following formula: ##STR89##
Part B
[0175] To a solution of benzyl 2,2,3(R)-trimethylsuccinate (125 mg,
0.5 mmol) in DMF (1.5 mL) was added HOBt (153 ma, 1.0 mmol). After
all the solid was dissolved, the solution was cooled to 0.degree.
C. and to this was added EDC (143 ma, 0.75 mmol) and stirring was
continued to 2 hours at 0.degree. C. To this cold solution was
added 200 mg (0.5 mmol) of amine from part A and stirred at
0.degree. C. for 2 hours and room temperature for 32 hours. The
solvents were removed in vacuo (less than or equal to 40.degree.
C.) and the residue was dissolved in ethyl acetate (5 mL). This
solution was washed with 60% sat. NaHCO.sub.3 (2 mL.times.2), 5%
citric acid (2 mL) and sat. NaCl (2 mL.times.2). The combined
organic layers were dried (Na.sub.2SO.sub.4) and concentrated to
give a white solid. The purification of the crude product by flash
chromatography (silica gel, 4% MeOH/CH.sub.2Cl.sub.2) gave 188 mg
(59%) of the desired product as a white solid, [M+Li].sup.+=640,
identified as butanoic acid,
4-[[3-[3-[3-[[1,1-dimethylethyl)amino]carbonyl]octahydro-2(1H)-isoquinoli-
nyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]-2,2,3-trimethyl-4-oxo-,
phenylmethyl ester, [3S-[2[1R*(S*),2S*],3.alpha.,4a.beta.,8a
.beta.]]-; formula: ##STR90##
Part C
[0176] A mixture of benzyl ester from part B (180 mg, 0.284 mmol),
10% Pd/C (125 mg) in methanol (MeOH) (2 mL) was hydrogenated
(H.sub.2, 50 psi) at room temperature for 30 minutes. The solid was
filtered and was washed with MeOH (3 mL.times.2). The combined
filtrates were concentrated to give 122 mg (79%) acid as a pale
yellow solid, [M+H].sup.+=544 and [M+Li].sup.+=550, identified as
butanoic acid,
4-[(3-[3-[[(1,1-dimethylethyl)amino]carbonyl]octahydro-2(1H)-isoquinoliny-
l]-2-hydroxy-1-(phenylmethyl)propyl]amino]-2,2,3-trimethyl-4-oxo-,[3S-[2[1-
R*(S*),2S*],3.alpha.,4a.beta.,8.beta.]]-; formula: ##STR91##
Part D
[0177] To a solution of acid from part C (120 ma, 0.22 mmol) in DMF
(0.5 mL) was added HOBt (68 ma, 0.44 mmol), NH.sub.4Cl (11.8 ma,
0.22 mmol) at room temperature. After all the solid was dissolved,
to the solution was added LDC (63 ma, 0.33 mmol) at 0.degree. C.
and stirred at the temperature for 2 hours. To this cold solution
was added 30% NH.sub.4OH (0.124 mL, 1.1 mmol) dropwise and the
resulting mixture was stirred at 0.degree. C. for 6 hours and at
room temperature for 16 hours. The solvents were removed in vacuo
(less than or equal to 40.degree. C.) and the residue was dissolved
in ethyl acetate (5 mL). The solution was washed with 60% sat.
NaHCO.sub.3 (2 mL.times.2), 5% citric acid (2 mL) and sat. NaCl (2
mL.times.2). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated to give a white solid. The
purification of crude product by flash chromatography (silica gel,
5% MeOH/CH.sub.2Cl.sub.2) gave 72 mg (60%) of pure amide,
[M+H]=543, identified as Preparation of Butanamide,
4-[[3-[3-[[(1,1-dimethylethyl)amino]carbonyl]octahydro]2(1H)-isoquinoliny-
l]-2-hydroxy-1-(phenylmethyl)propyl]amino]-2,2,3-trimethyl-4-oxo-,[3S-[2[1-
R*(S*),2S*],3.alpha.,4a.beta.,8a.beta.]]-; formula: ##STR92##
[0178] In Example 12, part B, the benzyl
2,2,3(R)-trimethylsuccinate (see Example 13 for preparation) may be
substituted by the various succinates, succinamides and
itaconamides produced in Examples 513 through 20 infra. in the
appropriate amounts the determination of which is within the skill
of the art.
EXAMPLE 13
Preparation of Benzyl 2,2,3(R)-trimethylsuccinate
[0179] ##STR93##
Part A: Preparation of Methyl (S)-lactate, 2-methoxy-2-propyl
ether
[0180] ##STR94##
[0181] To a mixture of methyl-(S)-(-)-lactate (13.2 g, 100 mmol)
and 2-methoxypropene (21.6 g, 300 mmol) in CH.sub.2Cl.sub.2 (150
mL) was added POCl.sub.3 (about 1.5 mL) at room temperature and the
resulting mixture was stirred at this temperature for 16 hours.
After the addition of triethylamine (NEt.sub.3) (about 2 mL), the
solvents were removed in vacuo to give 20.0 g of (98%) desired
product.
Part B: Preparation of 2(S)-hydroxypropanal, 2-methoxy-2-propyl
ether
[0182] ##STR95##
[0183] To a solution of compound from Part A (20.0 g) in
CH.sub.2Cl.sub.2 (100 mL) was added diisobutyl aluminum hydride
(DIBAL) (65 mL of 1.5M solution in toluene, 97.5 mmol) dropwise at
-78.degree. C. for 45 minutes, then stirring was continued at the
temperature for another 45 minutes. To this cold solution was added
MeOH (20 mL), saturated NaCl solution (10 mL) and allowed the
reaction mixture to warm up to room temperature and diluted with
ether (200 mL), MgSO.sub.4 (lSOg) was added and stirred for another
2 hours. The mixture was filtered and the solid was washed twice
with ether. The combined filtrates were rotavaped to afford 11.2 g
(78%) of the desired aldehyde.
Part C: Preparation of 2(S)-hydroxy-cis-3-butene,
2-methoxy-2-propyl ether
[0184] ##STR96##
[0185] To a suspension of ethyltriphenylphosphonium bromide (28 g,
75.5 mmol) in THF (125 mL) was added potassium
bis(trimethylsilyl)amide (KN(TMS).sub.2) (15.7 g, 95%, 75 mmol) in
portions at 0.degree. C. and stirred for 1 hour at the temperature.
This red reaction mixture was cooled to -78.degree. C. and to this
was added a solution of aldehyde from Part B (11 g, 75 mmol) in THF
(25 mL). After the addition was completed, the resulting reaction
mixture was allowed to warm up to room temperature and stirred for
16 hours. To this mixture was added saturated NH.sub.4Cl (7.5 mL)
and filtered through a pad of celite with a thin layer of silica
gel on the top. The solid was washed twice with ether. The combined
filtrates were concentrated in vacuo to afford 11.5 g of crude
product. The purification of crude product by flash chromatography
(silica gel, 10:1 Hexanes/ethyl acetate) affording 8.2 g (69%) pure
alkene.
Part D: Preparation of 2(S)-hydroxy-cis-3-butene
[0186] ##STR97##
[0187] A mixture of alkene from Part C (8.2 g) and 30% aqueous
acetic acid (25 mL) was stirred at room temperature for 1 hour. To
this mixture was added NaHCO.sub.3 slowly to the pH.about.7, then
extracted with ether (10 mL.times.5). The combined ether solutions
were dried (Na.sub.2SO.sub.4) and filtered. The filtrate was
distilled to remove the ether to give 2.85 g (64%) pure alcohol,
m/e=87(M+H).
Part E: Preparation of 2,2,3-trimethyl-hex-(trans)-4-enoic acid
[0188] ##STR98##
[0189] To a mixture of alcohol from Part D (2.5 g, 29 mmol) and
pyridine (2.5 mL) in CH.sub.2Cl.sub.2 (60 mL) was added isobutyryl
chloride (3.1 g, 29 mmol) slowly at 0.degree. C. The resulting
mixture was stirred at room temperature for 2 hours then washed
with H.sub.2O (30 mL.times.2) and sat. NaCl (25 mL). The combined
organic phases were dried (Na.sub.2SO.sub.4), concentrated to
afford 4.2 g (93%) ester 2(S)-hydroxy-cis-3-butenyl isobutyrate.
This ester was dissolved in THF (10 mL) and was added to a 1.0M
lithium diisopropylamide (LDA) solution (13.5 mL of 2.0M LDA
solution in THF and 13.5 mL of THF) slowly at -78.degree. C. The
resulting mixture was allowed to warm up to room temperature and
stirred for 2 hours and diluted with 5% NaOH (40 mL). The organic
phase was separated, the aqueous phase was washed with Et.sub.2O
(10 mL). The aqueous solution was collected and acidified with 6N
HCl to pH .about.3. The mixture was extracted with ether (30
mL.times.3). The combined ether layers were washed with sat. NaCl
(25 mL), dried (Na.sub.2SO.sub.4) and concentrated to afford 2.5 g
(60%) of desired acid, m/e=157 (M+H)
Part F: Preparation of benzyl
2,2,3(S)-trimethyl-trans-4-hexenoate
[0190] ##STR99##
[0191] A mixture of acid from Part E (2.5 g, 16 mmol),
benzylbromide (BnBr) (2.7 g, 15.8 mmol), K.sub.2CO, (2.2 g, 16
mmol), NaI (2.4 g) in acetone (20 mL) was heated at 75.degree. C.
(oil bath) for 16 hours. The acetone was stripped off and the
residue was dissolved in H.sub.2O (25 mL) and ether (35 mL). The
ether layer was separated, dried (Na.sub.2SO.sub.4) and
concentrated to afford 3.7 g (95%) of benzyl ester,
m/e=247(M+H).
Part G: Preparation of benzyl 2,2,3(R)-trimethylsuccinate
[0192] ##STR100##
[0193] To a well-stirred mixture of KMnO.sub.4 (5.4 g, 34, 2 mmol),
H.sub.2O (34 mL), CH.sub.2Cl.sub.2 (6 mL) and
benzyltriethylammonium chloride (200 mg) was added a solution of
ester from Part F (2.1 g, 8.54 mmol) and acetic acid (6 mL) in
CH.sub.2Cl.sub.2 (28 mL) slowly at 0.degree. C. The resulting
mixture was stirred at the temperature for 2 hours then room
temperature for 16 hours. The mixture was cooled in an ice-water
bath, to this was added 6N HCl (3 mL) and solid NaHSO.sub.3 in
portions until the red color disappeared. The clear solution was
extracted with CH.sub.2Cl.sub.2 (30 mL.times.3). The combined
extracts were washed with sat. NaCl solution, dried
(Na.sub.2SO.sub.4) and concentrated to give an oil. This oil was
dissolved in Et.sub.2O (50 mL) and to this was added sat.
NaHCO.sub.3 (50 mL). The aqueous layer was separated and acidified
with 6N HCl to pH about 3 then extracted with Et.sub.2O (30
mL.times.3). The combined extracts were washed with sat. NaCl
solution (15 mL), dried (Na.sub.2SO.sub.4) and concentrated to
afford 725 mg (34%) of desired acid, benzyl
2,2,3(R)-trimethylsuccinate, m/e=251 (M+H).
EXAMPLE 14
Preparation of methyl 2,2-dimethyl-3-methyl succinate, (R) and (S)
isomers
[0194] ##STR101##
Part A: Preparation of methyl 2,2-dimethyl-3-oxo-butanoate
[0195] ##STR102##
[0196] A 250 mL RB flask equipped with magnetic stir bar and N2
inlet was charged with 100 mL dry THF and 4.57 g (180 mmol) of 95%
NaH. The slurry was cooled to -20.degree. C. and 10 g (87 mmol)
methyl acetoacetate was added dropwise followed by 11.3 mL (181
mmol) CH.sub.3I. The reaction was stirred at 0.degree. C. for 2
hours and let cool to room temperature overnight. The reaction was
filtered to remove NaI and diluted with 125 mL Et.sub.2O. The
organic phase was washed with 1.times.100 L 5% brine, dried and
concentrated in vacuo to a dark golden oil that was filtered
through a 30 g plug of silica gel with hexane. Concentration in
vacuo yielded 10.05 g of desired methyl ester, as a pale yellow
oil, suitable for use without further purification.
Part B: Preparation of methyl
2,2-dimethyl-3-O-(trifluoromethanesulfonate)-but-3-eneoate
[0197] ##STR103##
[0198] A 250 ml RB flask equipped with magnetic stir bar and
N.sub.2 inlet was charged with 80 mL by THP and 5.25 mL (37.5 mmol)
diisopropylamine was added. The solution was cooled to -25.degree.
C. (dry ice/ethylene glycol) and 15 mL (37.5 mmol) of 2.5 M n-butyl
lithium (n-BuLi) in hexanes was added. After 10 minutes a solution
of 5 g (35 mmol) of methyl 2,2-dimethyl-3-oxo-butanoate from Part A
in 8 mL dry THF was added. The deep yellow solution was stirred at
-20.degree. C. for 10 minutes then 12.4 g
N-phenyl-bis(trifluoromethanesulfonimide) (35 mmol) was added. The
reaction was stirred at about -10.degree. C. for 2 hours,
concentrated in vacuo and partitioned between ethyl acetate and
sat. nacho. The combined organic phase was washed with NaHCO.sub.3,
brine and concentrated to an amber oil that was filtered through 60
g silica gel plug with 300 mL 5% ethyl acetate/hexane.
Concentration in vacuo yielded 9.0 g light yellow oil that was
diluted with 65 mL ethyl acetate and washed with 2.times.50 mL 5%
aq. K.sub.2CO.sub.3, 1.times.10 mL brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo to yield 7.5 g (87%)
vinyl triflate, (m/e=277(M+H) suitable for use without further
purification.
Part C: Preparation of methyl
2,2-dimethyl-3-carboxyl-but-3-enoate
[0199] ##STR104##
[0200] A 250 mL Fisher Porter bottle was charged with 7.5 g (27
mmol) of compound prepared in Part B, 50 mL dry DMF, 360 mg (1.37
mmol) triphenyl phosphine and 155 mg (0.69 mmol) palladium (II)
acetate. The reaction mixture was purged twice with N.sub.2 then
charged with 30 psig CO. Meanwhile a solution of 20 mL dry DMF and
7.56 mL (54 mmol) NEt.sub.3 was cooled to 0.degree. C. to this was
added 2.0 g (43 mmol) of 99% formic acid. The mixture was swirled
and added to the vented Fisher Porter tube. The reaction vessel was
recharged to 40 psig of CO and stirred 6 hours @ room temperature.
The reaction mixture was concentrated in vacuo and partitioned
between 100 mL of ethyl acetate and 75 mL 5% aq. K.sub.2CO.sub.3.
The aqueous phase was washed with 1.times.40 mL additional ethyl
acetate and then acidified with concentrated HCl/ice. The aqueous
phase was extracted with 2.times.70 mL of ethyl acetate and the
organics were dried and concentrated to yield 3.5 g (75%) white
crystals, mp 72-75.degree. C., identified as the desired product
(m/e=173(M+H).
Part D: Preparation of methyl 2,2-dimethyl-3-methylsuccinate,
isomer #1
[0201] ##STR105##
[0202] A steel hydrogenation vessel was charged with 510 mg (3.0
mmol) acrylic acid, from Part C, and 6 mg Ru (acac).sub.2 (R-BINAP)
in 10 ml degassed MeOH. The reaction was hydrogenated at 50
psig/room temperature for 12 hours. The reaction was then fltered
through celite and concentrated to 500 mg clear oil which was shown
to be a 93:7 mixture of isomer #1 and #2, respectively as
determined by GC analysis using a 50 M, B-cyclodextrin column
(chiral GC): 150.degree. C.-15 min. then ramp 2.degree. C./min.;
isomer #1, 17.85 minute retention time, isomer #2, 18-20 minute
retention time.
Part E: Preparation of methyl 2,2-dimethyl-3-methylsuccinate,
Isomer #2
[0203] ##STR106##
[0204] A steel hydrogenation vessel was charged with 500 mg (2.9
mmol) acrylic acid, Part C, and 6 mg Ru(OAc) (acac) (S-BINAP) in 10
mL degassed MeOH. The reaction was hydrogenated at 50 psig/room
temperature for 10 hours. The reaction was filtered through celite
and concentrated in vacuo to yield 490 mg of product as a 1:99
mixture of isomers #1 and #2, respectively, as determined by chiral
GC as above.
EXAMPLE 15
Preparation of Chiral Succinamides from Itaconic Anhydride
Part A: Preparation of 4-N-benzyl itaconamide
[0205] ##STR107##
[0206] A 500 mL three necked round bottomed flask equipped with a
dropping funnel, mechanical stirrer, nitrogen inlet and reflux
condenser was charged with itaconic anhydride (33.6 g, 0.3 mol) and
150 mL of toluene. This solution was added a solution of
benzylamine (32. la, 0.3 mol) in 50 mL of toluene dropwise over 30
minutes at room temperature. The solution was stirred at this
temperature an additional 3 hours and then the solid product
isolated by fltration on a Buchner funnel. The crude product, 64.6
g, 98%, was recrystallized from 300 mL of isopropyl alcohol to give
after two crops 52.1 g, 79% of pure product, mp 149150.degree.
C.
Part B: Preparation of 2(R)-Methyl 4-N-benzyl succinamide
[0207] ##STR108##
[0208] A large Fisher-Porter bottle was charged with the acid from
the above reaction (10.9Sg, 0.05 mol), rhodium (R,R)-DiPAMP (220
mg, 0.291 mmol) and 125 mL of degassed methanol. The solution was
then hydrogenated at 40 psig for 16 hours at room temperature.
After the hydrogen uptake ceased, the vessel was opened and the
solution concentrated in vacuo to give a yellow solid, 11.05 g,
100%. The product was then taken up in absolute ethanol and allowed
to stand whereupon crystals of the desired product formed, 7.98 g,
72%, mp 127-129.degree. C., [a]D @ 25.degree. C.=+14.9.degree.
(c=1.332, EtOH), .sup.1H NMR (CDCl+) 300 MHz 7.30(m,5H), 6.80(brs,
1H), 4.41(d, J=5.8 Hz, 2H), 2.94(m, 1H), 2.62(dd, J=8.1, 14.9 Hz,
1H), 2.33(dd, J=5.5, 14.9 Hz, 1H), 1.23(d, J=7.2 Hz, 3H).
Part C: Preparation of 4-N(4-methoxybenzyl)itaconamide
[0209] ##STR109##
[0210] A 500 mL three necked round bottomed flask equipped with a
dropping funnel, mechanical stirrer, nitrogen inlet and reflux
condenser was charged with itaconic anhydride (44.8 g, 0.4 mol) and
150 ml of toluene. This solution was added a solution of
4-methoxybenzylamine (54.8 g, 0.4 mol) in 50 mL of toluene dropwise
over 30 minutes at room temperature. The solution was stirred at
this temperature an additional 2 hours and then the solid product
isolated by filtration on a Buchner funnel. The crude product was
recrystallized from ethyl acetate/ethanol to give after two crops
64.8 g, 65% of pure product, mp 132-134.degree. C., .sup.1H nmr
(CDCl.sub.3) 300 MHz 7.09(d, J=9.1 Hz, 2H), 6.90(brt, J=5.9 Hz,
1H), 6.74(d, J=9.1 Hz, 2H), 6.22(s, 1H), 5.69(s, 1H), 4.24(d, J=5.9
Hz, 2H), 3.69(s,3H), 3.15(s, 2H). .sup.13C nmr (CDCl.sub.3) 170.52,
169.29, 159.24, 135.61, 131.08, 129.37, 128.97, 114.36, 55.72,
43.37, 40.58.
Part D: Preparation of
2(R)-Methyl-4-N(4-methoxybenzyl)succinamide
[0211] ##STR110##
[0212] A large Fisher-Porter bottle was charged with the acid from
the above reaction (5.00 g, 0.02 mol), rhodium (R,R)-DiPAMP (110
mg, 0.146 mmol) and 50 mL of degassed methanol. The starting acid
was not completely soluble initially, but as the reaction
progressed the solution became homogeneous. The solution was then
hydrogenated at 40 psig for 16 hours at room temperature. After the
hydrogen uptake ceased, the vessel was opened and the solution
concentrated in vacuo to give a yellow solid. The crude product was
then taken up in ethyl acetate and washed three times with sat. aq.
NaHCO.sub.3 solution. The combined aqueous extracts were acidified
to pH=1 with 3 N HCl and then extracted three times with ethyl
acetate. The combined ethyl acetate extracts were washed with
brine, dried over anhyd. MgSO.sub.4, filtered and concentrated to
give the expected product as a white solid, 4.81 g, 95%. This
material was recrystallized from a mixture of methyl ethyl
ketone/hexane to give 3.80 g, 75% of pure product, [a].sub.D @
25.degree. C.=+11.6.degree. (c=1.572, MeOH). H nmr (CDCl.sub.3) 300
MHz 11.9(brs,1H), 7.18(d, J=9.2 Hz, 2H), 6.82(d, J=9.2 Hz, 2H),
6.68(brt, J=5.6 Hz, 1H), 4.33(d, J=5.6 Hz, 2H), 3.77(s, 3H),
2.92(ddq, J=7.9, 5.4, 7.3 Hz, 1H), 2.60(dd, J=5.4, 15.0 Hz, 1H),
2.30(dd, J=7.9, 15.0 Hz, 1H),1.22(d, J=7.3 Hz, 3H).
EXAMPLE 16
Preparation of Trans-mono-ethyl 1,2-Cyclopropanedicarboxylate
[0213] To a solution of 4.60 g (24.7 mmol) of
trans-diethyl-1,2-cyclopropanedicarboxylate in 100 mL of 50:50 v:v
tetrahydrofuran/water was added 1.24 g (29.6 mmol) of lithium
hydroxide. After 17 hours, the tetrahydrofuran was removed in
vacuo, the water layer washed with ethyl acetate, acidified with 1N
hydrochloric acid and reextracted with ethyl acetate. The organic
layer was dried and stripped to afford 2.1 g of crude product.
After recrystallization from diethylether/hexane and then methylene
chloride/hexane, one obtains 1.1 g (28%) of
trans-monoethyl-1,2-cyclopropanedicarboxylate, m/e=159 (M+H).
EXAMPLE 17
Preparation of 2(R)-Methyl-4-benzyl Succinate
Part A
[0214] To a suspension of 24.7 g (0.22 mol) of itaconic anhydride
in 100 mL of anhydrous toluene at reflux under a nitrogen
atmosphere was added dropwise over 30 minutes 23.9 g (0.22 mol) of
benzyl alcohol. The insoluble material dissolved to provide a
homogeneous solution which was refluxed for 1.5 hours. The solution
was cooled to room temperature, then in an ice bath and the
resulting white precipitate collected by filtration to afford 24.8
g (51%) of 4-benzyl itaconate.
Part B
[0215] To a solution of 2.13 g (9.5 mmol) of the product from Part
A in 12 mL of methylene chloride at 0.degree. C. was added 4.02 g
(29.1 mmol) of para-methoxybenzyl alcohol, 605 mg (4.95 mmol) of
N,N-dimethyl-4-aminopyridine, 128 mg of
N,N-dimethyl-4-aminopyridine hydrochloride salt and then 2.02 g
(4.7 mmol) dicyclohexylcarbodiimide (DCC). After stirring at
0.degree. C. for 1 hour and then room temperature for 2 hours, the
precipitate was collected and discarded. The filtrate was washed
with 0.5 N HCl, sat. NaHCO.sub.3, dried and stripped to afford 4.76
g of crude product. This was chromatographed on silica gel using
0-50% ethyl acetate/hexane to afford 1.24 g of pure
4'-methoxybenzyl-4-benzylitaconate.
Part C
[0216] A solution of 1.24 g (3.65 mmol) of product from Part B and
20 mg of [(R,R)-DiPAMP)cyclooctadienylrhodium] tetrafluoroborate in
30 mL of methanol was thoroughly degassed, flushed with nitrogen
and then hydrogen and then stirred under 50 psig of hydrogen for 15
hours. The solution was filtered and stripped, dissolved in
methylene chloride and washed with sat. NaHCO.sub.3, dried and
stripped to afford 0.99 g of a brown oil. This was then dissolved
in 40 mL of methylene chloride, 3 mL of trifluoroacetic acid added
and the solution stirred at room temperature for 3.5 hours. Water
was added and separated and the organic layer extracted with sat.
NaHCO.sub.3. The aqueous layer was acidified and reextracted with
ethyl acetate, separated and the organic layer washed with brine,
dried and stripped to afford 320 mg (50%) of
2(R)-methyl-4-benzylsuccinic acid.
EXAMPLE 18
Preparation of 2(S)-Methyl-4-benzyl Succinate
[0217] A solution of 1.41 g (4.1 mmol) of
4'-methoxybenzyl-4-benzylitaconate and 25 mg of
[(S,S-DiPAMP)cyclooctadienyl-rhodium]tetrafluoroborate in 20 mL of
methanol was thoroughly degassed, flushed with nitrogen and then
hydrogen and then stirred under 40 psig hydrogen for 72 hours. The
solution was filtered and concentrated to provide 1.34 g of a brown
oil. This was dissolved in 40 mL of methylene chloride and 3 mL of
trifluoroacetic acid was added. After stirring for 4 hours, water
was added, separated and the organic layer extracted with sat.
NaHCO.sub.3. The aqueous layer was separated, reacidified,
extracted with ethyl acetate which was separated, washed with
brine, dried and stripped to afford 440 mg of
2(S)-methyl-4-benzylsuccinic acid (also known as,
2(S)-Methyl-4-benzyl succinate).
EXAMPLE 19
Preparation of 3(R)-Methyl-4-benzyl Succinate
Part A
[0218] In a similar manner to the procedure used above in Example
17, Part A, p-methoxybenzyl alcohol was reacted with itaconic
anhydride in refluxing toluene to provide
4-(p-methoxybenzyl)itaconate.
Part B
[0219] To a solution of 3.30 g (13.2 mmol) of the product from Part
A in 17 mL of toluene, was added 2.08 g (13.7 mmol) of 1,8
diazabicyclo[5.4.0]undec-7-ene and then 2.35 g (13.7 mmol) of
benzyl bromide. After 2 hours, the solution was fltered and the
filtrate washed with sat. NaHCO.sub.3, 3N HCl, brine, dried and
concentrated to afford 3.12 g of an oil. After chromatography on
silica gel using 0-5% ethyl acetate/hexane one obtains 2.19 g (49%)
of benzyl 4-(4-methoxybenzyl) itaconate.
Part C
[0220] A solution of 1.22 g (3.6 mmol) of product from Part B and
150 mg of [((R,R-DiPAMP)) cyclooctadienylrhodium] tetrafluoroborate
in 15 mL of methanol was thoroughly degassed, flushed with nitrogen
and then hydrogen and hydrogenated under 50 psig for 16 hours. The
solution was filtered and concentrated to afford 1.2 g of a brown
oil. This was dissolved in 5 mL of methylene chloride and 5 mL of
toluene and 3 mL of trifluoroacetic acid was added. After 4 hours,
the solvents were removed in vacuo, the residue dissolved in
methylene chloride, which was then extracted with sat. NaHCO.sub.3.
After separation, the aqueous layer was acidified, reextracted with
methylene chloride which was then dried and concentrated to afford
470 mg (60%) of 3(R)-methyl-4-benzylsuccinic acid (also known as,
3(R)-methyl-4-benzyl succinate).
EXAMPLE 20
Preparation of 3(S)-Methyl-4-benzyl Succinate
[0221] This was prepared in an identical manner to the previous
example (Example 19) except that the asymmetric hydrogenation step
was done in the presence of
[((S,S-DiPAMP)cyclooctadienyl)rhodium]-tetrafluoroborate as
catalyst.
EXAMPLE 21
[0222] ##STR111##
[0223] The compound of this example is prepared using methods
illustrated and referred to hereinabove.
EXAMPLE 22
[0224] ##STR112##
[0225] The compound of this example is prepared using methods
illustrated and referred to hereinabove.
EXAMPLE 23
[0226] ##STR113##
[0227] The compound of this example is prepared using methods
illustrated and referred to hereinabove.
EXAMPLE 24
[0228] ##STR114##
[0229] The compound of this example is prepared using methods
illustrated and referred to hereinabove.
EXAMPLE 25
[0230] ##STR115##
[0231] The compound of this example is prepared using methods
illustrated and referred to hereinabove.
EXAMPLE 26
[0232] ##STR116##
[0233] The compound of this example is prepared using methods
illustrated and referred to hereinabove.
EXAMPLE 27
[0234] ##STR117##
[0235] The compound of this example is prepared using methods
illustrated and referred to hereinabove.
EXAMPLE 28
[0236] ##STR118##
[0237] The compound of this example is prepared using methods
illustrated and referred to hereinabove.
EXAMPLE 29
[0238] ##STR119##
[0239] The compound of this example is prepared using methods
illustrated and referred to hereinabove.
EXAMPLE 30
[0240] ##STR120##
[0241] The compound of this example is prepared using methods
illustrated and referred to hereinabove.
EXAMPLE 31
[0242] ##STR121##
[0243] The compound of this example is prepared using methods
illustrated and referred to hereinabove.
EXAMPLE 32
[0244] ##STR122##
[0245] The compound of this example is prepared using methods
illustrated and referred to hereinabove.
EXAMPLE 33
Assays
Part A: Enzyme Assay
[0246] Utilizing an enzyme assay as described below, the compounds
set forth in Examples 4, 6, 10, 12 and 12C inhibited the HIV enzyme
in an amount ranging from about 3 to about 100% inhibition at a
concentration of 10 microMolar. The calculated IC.sub.50
(inhibiting concentration 50%, i.e., the concentrations at which
the inhibitor compound reduces enzyme activity by 50%) values are
shown in Table 1. The enzyme method is described below. The
substrate is 2-aminobenzoyl-Ile-Nle-phe(p-NO2)-Gln-ArgNH2. The
positive control is MVT-101 (Miller, M. et al, Science, 246, 1149
(1989)] The assay conditions are as follows: [0247] Assay buffer:
20 mM sodium phosphate, pH 6.4 [0248] 20% glycerol [0249] 1 mM EDTA
[0250] 1 mM DTT [0251] 0.1% CHAPS
[0252] 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.
[0253] 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.
[0254] 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.
Part B: CEM Cell Assay
[0255] The effectiveness of the compounds tested in Part A was also
determined in a CEM cell assay. The HIV inhibition assay method of
acutely infected cells is an automated tetrazolium based
calorimetric assay essentially that reported by Pauwles et al, J.
Virol. Methods 20, 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 pg/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: TABLE-US-00001 Cells Drug Virus 1. + - - 2. + + - 3. +
- + 4. + + +
[0256] 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.
[0257] 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 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% CO2 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 pL 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.
[0258] The calculated EC.sub.50 (effective concentration 50%, i.e.,
the concentration at which the inhibitor compound reduces
cytopathicity by 50%) and TD.sub.50 (toxic dose 50%, i.e., the
concentration at which the inhibitor compound reduces cellular
viability by 50%) values for these compounds are also shown in
Table 1. TABLE-US-00002 TABLE 1 Antiviral Activity Enzyme in Cell
Cell Inhibition Culture Toxicity Structure (IC.sub.50) (EC.sub.50)
(TD.sub.50) ##STR123## 7 nM 42 nM 58,000 nM ##STR124## 2 nM 52 nM
2,000 nM ##STR125## 9 nM 37 nM 5,000 nM ##STR126## 9 nM 98 nM
59,000 nM ##STR127## 23 nM 184 nM 50,000 nM
[0259] It is expected that compounds of Formulae I-IV would be
active when tested in the assays described in Example 33 above.
[0260] 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.
[0261] 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.
[0262] 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 ma. Dosage unit
compositions may contain such amounts of submultiples thereof to
make up the daily dose.
[0263] 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.
[0264] The dosage regimen to give relief from or ameliorate a
disease condition (i.e., treatment) or protecting against the
further spreading of the infection (i.e., prophylaxis) 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
deviate from the preferred dosage regimen set forth above.
[0265] 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.
[0266] 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-butanedidol. 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.
[0267] 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.
[0268] 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 additionaUy be prepared with enteric coatings.
[0269] 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.
[0270] Pharmaceutically acceptable carriers encompass all the
foregoing and the like.
[0271] 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, other
nucleoside antivirals, other HIV-protease inhibitors or with
iminosugars such as N-butyl-1-deoxynojirimycin for the prophylaxis
and/or treatment of AIDS or HIV infection. The additional antiviral
agents can be selected, if desired, using phenotyping and/or
genotyping methods to determine sensitivity/resistance parameters
that can be used by the skilled person as an aid in the selection
of the drug or drugs to be used in combination. Included in the
possibilities of for combination therapy are drugs useful for the
treatment of the secondary symptoms of HIV infection, ARC or 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.
[0272] 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.
[0273] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0274] 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.
* * * * *