U.S. patent application number 11/480586 was filed with the patent office on 2007-01-18 for cyclic sulfone containing retroviral protease inhibitors.
This patent application is currently assigned to G.D. Searle & Co. (now G.D. Searle, LLC). Invention is credited to Deborah E. Bertenshaw, Robert Alan Chrusciel, Michael Clare, Daniel Getman, Robert M. Heintz, Kathryn L. Reed, John J. Talley.
Application Number | 20070015818 11/480586 |
Document ID | / |
Family ID | 23484633 |
Filed Date | 2007-01-18 |
United States Patent
Application |
20070015818 |
Kind Code |
A1 |
Bertenshaw; Deborah E. ; et
al. |
January 18, 2007 |
Cyclic sulfone containing retroviral protease inhibitors
Abstract
The present invention relates to cyclic sulfone
moiety-containing hydroxyethylamine protease inhibitor compounds
and pharmaceutical or method of use therefor, particularly as an
inhibitor of HIV protease.
Inventors: |
Bertenshaw; Deborah E.;
(Brentwood, MO) ; Getman; Daniel; (Chesterfield,
MO) ; Heintz; Robert M.; (Ballwin, MO) ;
Talley; John J.; (St. Louis, MO) ; Reed; Kathryn
L.; (Raleigh, NC) ; Chrusciel; Robert Alan;
(Portage, MI) ; Clare; Michael; (Skokie,
IL) |
Correspondence
Address: |
BANNER & WITCOFF
1001 G STREET N W
SUITE 1100
WASHINGTON
DC
20001
US
|
Assignee: |
G.D. Searle & Co. (now G.D.
Searle, LLC)
Skokie
IL
Monsanto Company (now Pharmacia Corporation)
St. Louis
MO
|
Family ID: |
23484633 |
Appl. No.: |
11/480586 |
Filed: |
July 5, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10961405 |
Oct 12, 2004 |
7060851 |
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11480586 |
Jul 5, 2006 |
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10325952 |
Dec 23, 2002 |
6849760 |
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10961405 |
Oct 12, 2004 |
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09741087 |
Dec 21, 2000 |
6515162 |
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10325952 |
Dec 23, 2002 |
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09024662 |
Feb 17, 1998 |
6201150 |
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09741087 |
Dec 21, 2000 |
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08376340 |
Jan 20, 1995 |
5831117 |
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09024662 |
Feb 17, 1998 |
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Current U.S.
Class: |
514/432 ;
549/28 |
Current CPC
Class: |
C07C 213/10 20130101;
C07D 207/30 20130101; C07C 215/28 20130101; C07D 211/06 20130101;
C07C 215/18 20130101; C07C 215/26 20130101; C07C 275/24 20130101;
C07D 211/26 20130101; C07C 271/20 20130101 |
Class at
Publication: |
514/432 ;
549/028 |
International
Class: |
A61K 31/382 20070101
A61K031/382; A61K 31/381 20070101 A61K031/381; C07D 335/02 20060101
C07D335/02; C07D 333/20 20070101 C07D333/20 |
Claims
1. A compound having the formula ##STR73## or a pharmaceutically
acceptable salt thereof wherein W represents ##STR74## Y'
represents .dbd.O, .dbd.S or .dbd.NR.sup.15, wherein R.sup.15
represents a hydrogen radical, alkyl, haloalkyl, alkenyl, alkynyl,
hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl,
heteroaralkyl, thioalkyl, alkylthioalkyl, arylthioalkyl, the
sulfone or sulfoxide derivatives of thioalkyl, alkylthioalkyl, or
arylthioalkyl, aminoalkyl, or mono- or di-substituted aminoalkyl
that are mono- or di-substituted with one or two substituents
independently selected from the group consisting of alkyl, aryl,
aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,
heterocycloalkyl, or heterocycloalkylalkyl, or, in the case of
di-substituted aminoalkyl, said two substituents along with the
nitrogen atom to which they are bonded form heterocycloalkyl or
heteroaryl; t represents 0, 1, or 2; t' represents 1 or 2; u
represents 0, 1, or 2; R.sup.40, R.sup.41, R.sup.42, R.sup.43,
R.sup.48, R.sup.49, R.sub.50 and R.sup.51 independently represent a
hydrogen radical or alkyl; R.sup.44, R.sup.45, R.sup.46, and
R.sup.47 independently represent a hydrogen radical, alkyl, or
hydroxy; or one of (a) R.sup.40 together with R.sup.48, (b)
R.sup.43 together with R.sup.45, (c) R.sup.45 together with
R.sup.47 and (d) R.sup.47 together with R.sup.48, represent a bond;
or one of (a) R.sup.44 together with R.sup.45 and the carbon atom
to which they are bonded, (b) R.sup.46 together with R.sup.47 and
the carbon atom to which they are bonded and (c) R.sup.50 together
with R.sup.51 and the carbon atom to which they are bonded,
represent carbonyl; R.sup.6 represents a hydrogen radical or alkyl;
R.sup.2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl, or
aralkyl, each of which may optionally be substituted with a
substituent selected from the group consisting of alkyl,
--NO.sub.2, --CN, --CF.sub.3, --OR.sup.9, --SR.sup.9, and halogen,
wherein R.sup.9 represents a hydrogen radical or alkyl; Q
represents ##STR75## R.sup.3 represents isobutyl, n-propyl,
n-butyl, isoamyl, cyclohexylmethyl, or cyclohexyl; Y represents a
radical as defined for Y'; X represents N, CH, or O; R.sup.4 and
R.sup.5 independently represent a hydrogen radical, alkyl,
haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,
cycloalkylalkyl, heterocycloalkyl, heteroaryl,
heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, thioalkyl,
alkylthioalkyl, arylthioalkyl, the sulfone or sulfoxide derivatives
of thioalkyl, alkylthioalkyl, or arylthioalkyl, aminoalkyl, or
mono- or di-substituted aminoalkyl that are mono- or di-substituted
with one or two substituents independently selected from the group
consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,
heteroaryl, heteroaralkyl, heterocycloalkyl, or
heterocycloalkylalkyl, or, in the case of di-substituted
aminoalkyl, said two substituents along with the nitrogen atom to
which they are bonded form heterocycloalkyl or heteroaryl, or when
X represents N, R.sup.4 and R.sup.5 together with N represent
heterocycloalkyl or heteroaryl, or when X represents CH, R.sup.4
and R.sup.5 together with CH represent cycloalkyl, with the proviso
that R.sup.5 is absent when X is O; R.sup.4' and R.sup.5' together
with the nitrogen atom to which they are bonded form an
N-heterocyclic moiety; R.sup.4'', R.sup.9, and R.sup.9'
independently represent a radical as defined for R.sup.3; q
represents 1 or 2; n represents 0, 1, 2, 3, 4, 5, or 6; R.sup.7 and
R.sup.7' independently represent a hydrogen radical, alkyl,
haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,
cycloalkylalkyl, heterocycloalkyl, heteroaryl,
heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, thioalkyl,
alkylthioalkyl, arylthioalkyl, the sulfone or sulfoxide derivatives
of thioalkyl, alkylthioalkyl, or arylthioalkyl, aminoalkyl, or
mono- or di-substituted aminoalkyl that are mono- or di-substituted
with one or two substituents independently selected from the group
consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,
heteroaryl, heteroaralkyl, heterocycloalkyl, or
heterocycloalkylalkyl, or, in the case of di-substituted
aminoalkyl, said two substituents along with the nitrogen atom to
which they are bonded form heterocycloalkyl or heteroaryl, or
R.sup.7 and R.sup.7' independently represent a side chain of an
amino acid selected from the group consisting of valine,
isoleucine, glycine, alanine, alloisoleucine, asparagine, leucine,
glutamine, and t-butylglycine, or R.sup.7 and R.sup.7' together
with the carbon atom to which they are bonded form cycloalkyl;
R.sup.8 represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl,
aryl, aralkyl, heterocycloalkyl, heteroaryl, --C(O)R.sup.16,
--CO.sub.2R.sup.16, --SO.sub.2R.sup.16, --SR.sup.16,
--CONR.sup.16R.sup.17, --CF.sub.3, or --NR.sup.16R.sup.17; wherein
R.sup.16 and R.sup.17 independently represent a hydrogen radical,
alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl,
cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,
heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, thioalkyl,
alkylthioalkyl, arylthioalkyl, the sulfone or sulfoxide derivatives
of thioalkyl, alkylthioalkyl, or arylthioalkyl, aminoalkyl, or
mono- or di-substituted aminoalkyl that are mono- or di-substituted
with one or two substituents independently selected from the group
consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,
heteroaryl, heteroaralkyl, heterocycloalkyl, or
heterocycloalkylalkyl, or, in the case of di-substituted
aminoalkyl, said two substituents along with the nitrogen atom to
which they are bonded form heterocycloalkyl or heteroaryl, or, in
the case of --NR.sup.16R.sup.17, R.sup.16 and R.sup.17 together
with a nitrogen atom to which they are bonded represent
hetrocycloalkyl or heteroaryl.
2. A compound of claim 1 or a pharmaceutically acceptable salt
thereof wherein W represents (a).
3. A compound of claim 2 having the formula ##STR76## or a
pharmaceutically acceptable salt thereof.
4. A compound of claim 3 or a pharmaceutically acceptable salt
thereof wherein t represents 1, R.sup.6 represents a hydrogen
radical, and R.sup.2 represents aralkyl, alkyl, or
cycloalkylalkyl.
5. A compound of claim 3 having the formula ##STR77## or a
pharmaceutically acceptable salt thereof.
6. A compound of claim 5 or a pharmaceutically acceptable salt
thereof wherein Y and Y' represent .dbd.O, R.sup.6 represents a
hydrogen radical, t represents 1, and X represents N.
7. A compound of claim 5 wherein R.sup.2 represents benzyl,
cyclohexylmethyl, n-butyl, 2-naphthylmethyl, p-fluorobenzyl, or
isobutyl.
8. A compound of claim 5 or a pharmaceutically acceptable salt
thereof wherein R.sup.4 and R.sup.5 independently represent a
hydrogen radical, methyl, ethyl, isopropyl, or t-butyl, or R.sup.4
and R.sup.5 together with the nitrogen atom to which they are
bonded represent heterocycloalkyl having 5 to 8 ring members.
9. A compound of claim 5 wherein R.sup.3 is isobutyl or
isoamyl.
10. A compound of claim 3 having the formula ##STR78## or a
pharmaceutically acceptable salt thereof.
11. A compound of claim 10 or a pharmaceutically acceptable salt
thereof wherein Y' represents .dbd.O, t represents 1, and R.sup.6
represents a hydrogen radical.
12. A compound of claim 10 or a pharmaceutically acceptable salt
thereof wherein R.sup.2 represents benzyl, p-fluorobenzyl,
cyclohexylmethyl, 2-naphthylmethyl, n-butyl, or isobutyl.
13. A compound of claim 10 or a pharmaceutically acceptable salt
thereof wherein ##STR79## represents ##STR80##
14. A compound of claim 3 having the formula ##STR81## or a
pharmaceutically acceptable salt thereof, wherein R.sup.3
represents isobutyl or isoamyl.
15. A compound of claim 14 or a pharmaceutically acceptable salt
thereof wherein Y' represents .dbd.O, t represents 1, R.sup.6
represents a hydrogen radical, and q represents 2.
16. A compound of claim 14 or a pharmaceutically acceptable salt
thereof wherein R.sup.2 represents benzyl, p-fluorobenzyl,
cyclohexylmethyl, 2-naphthylmethyl, n-butyl, or isobutyl.
17. A compound of claim 14 or a pharmaceutically acceptable salt
thereof wherein R.sup.4'' represents aryl or heteroaryl.
18. A compound of claim 3 having the formula ##STR82## or a
pharmaceutically acceptable salt thereof, wherein R.sup.3
represents isobutyl or isoamyl.
19. A compound of claim 3 having the formula ##STR83## or a
pharmaceutically acceptable salt thereof, wherein R.sup.3
represents isobutyl or isoamyl.
20. A compound of claim 3 having the formula ##STR84## or a
pharmaceutically acceptable salt thereof, wherein R.sup.3represents
isobutyl or isoamyl.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/932,331, filed Sep. 2, 2004, now allowed,
which is a continuation of U.S. patent application Ser. No.
10/369,197, filed Feb. 20, 2003, now U.S. Pat. No. 6,875,790, which
is a continuation of U.S. patent application Ser. No. 09/973,991,
filed Oct. 11, 2001, now U.S. Pat. No. 6,552,203, which is a
continuation of U.S. patent application Ser. No. 09/870,748, filed
Jun. 1, 2001, now U.S. Pat. No. 6,329,524, which is a divisional of
U.S. patent application Ser. No. 09/177,100, filed Oct. 22, 1998,
now U.S. Pat. No. 6,265,583, which is a divisional of U.S. patent
application Ser. No. 08/556,883, filed Nov. 2, 1995, now U.S. Pat.
No. 5,849,784, which is a divisional of U.S. patent application
Ser. No. 07/998,187, filed Dec. 29, 1992, now U.S. Pat. No.
5,514,801, each of which applications is hereby incorporated herein
by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to retroviral protease
inhibitors and, more particularly relates to novel compounds and a
composition and method for inhibiting retroviral proteases. This
invention, in particular, relates to cyclic sulfone
moiety-containing hydroxyethylamine protease inhibitor compounds, a
composition and method for inhibiting retroviral proteases such as
human immunodeficiency virus infection. The subject invention also
relates to processes for making such compounds as well as to
intermediates useful in such processes.
[0004] 2. Related Art
[0005] During the replication cycle of retroviruses, gag and
gag-pol gene products are translated as proteins. These proteins
are subsequently processed by a virally encoded protease (or
proteinase) to yield viral enzymes and structural proteins of the
virus core. Most commonly, the gag precursor proteins are processed
into the core proteins and the pol precursor proteins are processed
into the viral enzymes, e.g., reverse transcriptase and retroviral
protease. It has been shown that correct processing of the
precursor proteins by the retroviral protease is necessary for
assembly of infectious virons. For example, it has been shown that
frameshift mutations in the protease region of the pol gene of HIV
prevents processing of the gag precursor protein. It has also been
shown through site-directed mutagenesis of an aspartic acid residue
in the HIV protease that processing of the gag precursor protein is
prevented. Thus, attempts have been made to inhibit viral
replication by inhibiting the action of retroviral proteases.
[0006] Retroviral protease inhibition typically involves a
transition-state mimetic whereby the retroviral protease is exposed
to a mimetic compound which binds (typically in a reversible
manner) to the enzyme in competition with the gag and gag-pol
proteins to thereby inhibit replication of structural proteins and,
more importantly, the retroviral protease itself.
[0007] In this manner, retroviral proteases can be effectively
inhibited.
[0008] Several classes of mimetic compounds are known to be useful
as inhibitors of the. proteolytic enzyme renin. See, for example,
U.S. Pat. No. 4,599,198; G.B. 2,184,730; G.B. 2,209,752; EPO 264
795; G.B. 2,200,115
[0009] and U.S. SIR H725; and U.S. Pat. No. 4,599,198 disclose
urea-containing hydroxyethylamine renin inhibitors. However, it is
known that, although renin and HIV proteases are both classified as
aspartyl proteases, compounds which are effective renin inhibitors
generally cannot be predicted to be effective HIV protease
inhibitors.
[0010] 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, EPO 346 847; EPO
342,541; Roberts et al, "Rational Design of Peptide-Bases
Proteinase Inhibitors", Science, 248, 358 (1990); and
[0011] Erickson et al, "Design Activity, and 2.8 .ANG. Crystal
Structure of a C.sub.2 Symmetric Inhibitor Complexed to HIV-1
Protease", Science, 249, 527 (1990). EPO 346 847 discloses certain
N-heterocyclic moiety-containing hydroxyethylamine protease
inhibitor compounds, but does not suggest or disclose those of the
present invention.
[0012] Dipeptide isosteres as inhibitors of HIV protease are found
in EP application numbers 91309292, 91309028.8 and 91309302.7.
BRIEF DESCRIPTION OF THE INVENTION
[0013] 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 cyclic sulfone- and either urea- or N-heterocyclic
moiety-containing hydroxyethylamine inhibitor compounds.
DETAILED DESCRIPTION OF THE INVENTION
[0014] In accordance with the present invention, there are provided
novel retroviral protease inhibiting compounds or a
pharmaceutically acceptable salt, prodrug or ester thereof.
[0015] Generally, the present invention is a compound of the
formula (I'') ##STR1## and a pharmaceutically acceptable salt,
prodrug or ester thereof; wherein Q, R.sup.2 and R.sup.6 are as
defined below and
[0016] W represents ##STR2## wherein Y'' is as defined below;
and
[0017] t represents 0,1 and 2, preferably 1;
[0018] t' represents 1 and 2, preferably 1;
[0019] u represents 0, 1 and 2;
[0020] R.sup.40, R.sup.41, R.sup.42, R.sup.43, R.sup.48, R.sup.49,
R.sup.50 and R.sup.51 independently represent hydrogen and
alkyl;
[0021] R.sup.44, R.sup.45, R.sup.46, R.sup.47 and independently
represent hydrogen, alkyl and hydroxy; or
[0022] one of (a) R.sup.40 together with R.sup.48, (b) R.sup.43
together with R.sup.45, (c) R.sup.45 together with R.sup.47, and
(d) R.sup.47 together with R.sup.48 represent a bond; or
[0023] one of (a) R.sup.44 together with R.sup.45, (b) R.sup.46
together with R.sup.47 or (c) R.sup.50 together with R.sup.51
represent a double bond oxygen.
[0024] R.sup.40 through R.sup.48 most preferably represent
hydrogen, however, both R.sup.46 and R.sup.47 also preferably
represent methyl at the same time R.sup.40 through R.sup.45 and
R.sup.48 are all hydrogen. Additionally, R.sup.48 is preferably
hydrogen and the stereo configuration of the carbon to which
R.sup.48 is attached is preferably in the configuration represented
by the upper spot in Example 4 set forth hereinafter, and
preferably wherein the stereochemistry about the hydroxy group may
be designated as (R).
[0025] Thus, the present invention compound is preferably of the
formula (I') ##STR3## or a pharmaceutically acceptable salt,
prodrug or ester thereof; and wherein Q is: ##STR4## and wherein t,
Y', R.sup.6, R.sup.2, Y, R.sup.3, X, R.sup.4, R.sup.5, R.sup.4' and
R.sup.5' are as defined below, q represents 1 or 2;
[0026] R.sup.4'', R.sup.9 and R.sup.9' independently represent
radicals as defined by R.sup.3;
[0027] n represents 0 to 6;
[0028] R.sup.7 and R.sup.7' independently represent radicals as
defined for R.sup.3 and amino acid side chains selected from the
group consisting of valine, isoleucine, glycine, alanine,
alloisoleucine, asparagine, leucine, glutanine, and t-butylglycine
or R.sup.7 and R.sup.7' together with the carbon atom to which they
are attached form a cycloalkyl radical;
[0029] R.sup.8 represents cyano, hydroxyl, alkyl, alkoxy,
cycloalkyl, aryl, aralkyl, heterocycloalkyl and heteroaryl radicals
and radicals represented by the formulas C(O)R.sup.16,
CO.sub.2R.sup.16, SO.sub.2R.sup.16, SR.sup.16, CONR.sup.16R.sup.17,
CF.sub.3 and NR.sup.16R.sup.17;
[0030] wherein R.sup.16 and R.sup.17 independently represent
hydrogen and radicals as defined for R.sup.3, or R.sup.16 and
R.sup.17 together with a nitrogen to which they are attached in the
formula NR.sup.16R.sup.17 represent heterocycloalkyl and heteroaryl
radicals.
[0031] A more preferred class of retroviral inhibitor compounds of
the present invention are those represented by the formula (I)
##STR5## or a pharmaceutically acceptable salt, prodrug or ester
thereof, and wherein:
[0032] t represents either 0, 1 or 2;
[0033] R.sup.2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl,
and aralkyl radicals, which radicals are optionally substituted
with a substituent selected from the group consisting of alkyl and
halogen radicals, --NO.sub.2, --CN, --CF.sub.3, --OR.sup.9,
--SR.sup.9, wherein R.sup.9 represents hydrogen and alkyl
radicals;
[0034] R.sup.3 represents alkyl, haloalkyl, alkenyl, alkynyl,
hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl,
heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkyl
radicals, wherein said substituents are selected from alkyl, aryl,
aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl;
heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the
case of a disubstituted aminoalkyl radical, said substituents along
with the nitrogen atom to which they are attached, form a
heterocycloalkyl or a heteroaryl radical, thioalkyl,
alkylthioalkyl, and arylthioalkyl radicals and the sulfone or
sulfoxide derivatives thereof;
[0035] Y and Y' independently represent O, S and NR.sup.15 wherein
R.sup.15 represents hydrogen and radicals as defined for
R.sup.3;
[0036] X represents N, CH or O;
[0037] R.sup.4 and R.sup.5 independently represent hydrogen and
radicals as defined by R.sup.3, or when X represents N, R.sup.4 and
R.sup.5 together with the nitrogen atom to which they are bonded
represent heterocycloalkyl and heteroaryl radicals, or when X
represents CH, R.sup.4 and R.sup.5 together with the carbon atom to
which they are bonded represent a cycloalkyl radical with the
proviso R.sup.5 is nothing when X is O;
[0038] R.sup.6 represents hydrogen and alkyl radicals;
[0039] The compound of the formula I preferably includes a compound
wherein Y and Y' represent O, R.sup.6 represents hydrogen, t
represents 1 and X represents N.
[0040] Another compound of the formula I preferably includes a
compound wherein R.sup.2 represents benzyl, cyclohexylmethyl,
n-butyl, 2-naphthylmethyl, p-fluorobenzyl and isobutyl.
[0041] Another compound of the formula I preferably includes a
compound wherein R.sup.4 and R.sup.5 independently represent
hydrogen, methyl, ethyl, isopropyl and tertiary-butyl.
[0042] Another compound of the formula I preferably includes a
compound wherein R.sup.4 and R.sup.5 together with the nitrogen to
which they are attached represent a 5 to 8 membered
heterocycloalkyl ring.
[0043] And finally, another compound of the formula I preferably
includes a compound wherein R.sup.3 is isobutyl, n-butyl, isoamyl,
benzyl, p-fluorobenzyl and cyclohexylmethyl.
[0044] Another more preferred class of retroviral inhibitor
compounds of the present invention are those represented by the
formula (II) ##STR6## or a pharmaceutically acceptable salt,
prodrug or ester thereof, and wherein:
[0045] t, R.sup.2, Y', and R.sup.6 represent radicals as defined:
above; and
[0046] R.sup.4' and R.sup.5' together with the nitrogen atom to
which they are bonded represent an N-heterocyclic moiety.
[0047] A compound of the formula II preferably includes a compound
wherein Y' represents O, t represents 1 and R.sup.6 represents
hydrogen.
[0048] Another compound of the formula II preferably includes a
compound wherein R.sup.2 represents benzyl, p-fluorobenzyl,
cyclohexylmethyl, 2-naphthylmethyl, n-butyl and isobutyl.
[0049] Another compound of the formula II preferably includes a
compound wherein NR.sup.4'R.sup.5' represents
2-[[(1,1-dimethylethyl)amino]carbonyl]decahydroisoquinolinyl- or
2-[[(1,1-dimethylethyl)amino]carbenyl]piperidinyl.
[0050] Another more preferred class of retroviral inhibitor
compounds of the present invention are those represented by the
formula (III) ##STR7## or a pharmaceutically acceptable salt,
prodrug or ester thereof, and
[0051] wherein t, Y', R.sup.6, R.sup.2 and R.sup.3 represent
radicals as defined above; and
[0052] q represents 1 or 2; and
[0053] R.sup.4'' represents radicals as independently defined by
R.sup.3.
[0054] A compound of the formula III preferably includes a compound
wherein Y' represents O, t represents 1, R.sup.6 represents
hydrogen and q represents 2.
[0055] Another compound of the formula III preferably includes a
compound wherein R.sup.2 represents benzyl, p-fluorobenzyl,
2-naphthylmethyl, cyclohexylmethyl, n-butyl and isobutyl.
[0056] Another compound of the formula III preferably includes a
compound wherein R.sup.3 represents isobutyl, n-propyl, n-butyl,
isoamyl, cyclohexylmethyl and cyclohexyl.
[0057] Another compound of the formula III preferably includes a
compound wherein R.sup.4'' represents an aryl or heteroaryl
radical.
[0058] Another compound of the formula III preferably includes a
compound wherein R.sup.4'' represents a para-substituted phenyl
wherein the substituent is hydrogen, fluoro, chloro, bromo, nitro,
hydroxy, methoxy and amino.
[0059] Other more preferred classes are as follows: ##STR8## or a
pharmaceutically acceptable salt, prodrug or ester thereof; wherein
t, Y', R.sup.6, R.sup.2, R.sup.3, Y, q, R.sup.4, R.sup.5, R.sup.7,
R.sup.7', n and R.sup.8 are as defined above.
[0060] A compound of the formula IV preferably includes a compound
wherein Y' represents O, R.sup.6 represents hydrogen and q
represents 2.
[0061] Another compound of the formula IV preferably includes a
compound wherein R.sup.2 represents benzyl, p-fluorobenzyl,
2-naphthylmethyl, n-butyl, cyclohexylmethyl and isobutyl.
[0062] Another compound of the formula IV preferably includes a
compound wherein R.sup.3 represents isobutyl, n-propyl, n-butyl,
isoamyl, cyclohexylmethyl and cyclohexyl.
[0063] Another compound of the formula IV preferably includes a
compound wherein R.sup.4 and R.sup.5 independently represent
hydrogen, methyl, ethyl, isopropyl, t-butyl, phenyl and cyclohexyl
or wherein R.sup.4 and R.sup.5 and the nitrogen to which they are
attached represent a 5 to 8 membered heterocycloalkyl ring.
[0064] A compound of the formula V preferably includes a compound
wherein Y' represents O, R.sup.6 represents hydrogen, t represents
1, and q represents 2.
[0065] Another compound of the formula V preferably includes a
compound wherein R.sup.2 represents benzyl, p-fluorobenzyl,
2-naphthylmethyl, cyclohexylmethyl, n-butyl, and iso-butyl.
[0066] Another compound of the formula V preferably includes a
compound wherein R.sup.3 represents isobutyl, n-propyl, n-butyl,
isoamyl, cyclohexylmethyl and cyclohexyl.
[0067] A compound of the formula VI preferably includes a compound
wherein Y and Y' both represent O, R.sup.6 represents hydrogen and
t represents 1.
[0068] Another compound of the formula VI preferably includes a
compound wherein R.sup.2 represents benzyl, p-fluorobenzyl,
2-naphthylmethyl, cyclohexylmethyl, n-butyl, and isobutyl.
[0069] Another compound of the formula VI preferably includes a
compound wherein R.sup.3 represents isobutyl, n-propyl, isoamyl,
n-butyl, cyclohexylmethyl, benzyl, p-fleorobenzyl and
p-methoxybenzyl.
[0070] Another compound of the formula VI preferably includes a
compound wherein R.sup.7 and R.sup.7' independentyly represent
hydrogen, methyl and ethyl, or together with the carbon to which
they are attached represent a 3 to 6 membered cycloalkyl ring.
[0071] The most preferred compounds of the present invention are
those of the formula I through VI wherein t is 1, R.sup.6 is
hydrogen, and R.sup.2 is an aralkyl, alkyl or cycloalkylalkyl
radical.
[0072] Each of the compounds of the present invention is
represented by formula having at least three optically active
carbon centers. The present invention is meant to include compounds
having each of the combinations of optical rotation and mixtures
thereof. The present compounds may have additional stereoisomers
and thus is also meant to include each of such isomers.
[0073] In each of the Formula I, II, III, IV, V, and VI a preferred
structure is one where stereo configuration of the group --C(OH)--
shown by the OH on the carbon adjacent the carbon having R.sup.2
attached is represented by the stereochemistry designated as
(R)
[0074] 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,
n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl,
octyl and the like. The term "thioalkyl" means aralkyl radical
having at least one sulfur atom, wherein alkyl has the significance
given above. An example of athioalkyl 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
--C(CH.sub.3).sub.2S(O).sub.2CH.sub.2, respectively. The term
"alkenyl", alone or in combination, means a straight-chain or
branched-chain hydrocarbon radical 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, alyl, 1,4-butadienyl and the like. The term
"alkynyl", alone or in combination, mans a straight-chain
hydrocarbon radical having one or more triple bonds and containing
from 2 to about 10 carbon atoms. Examples of alkynl radicals
include ethynyl, propynyl (propargyl), butynyl and the like. The
term "alkoxy", alone or in combination, means an alkyl ether
radical wherein the. term alkyl is as defined above. Examples of
suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the
like. The term "cycloalkyl", 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, p-tolyl, 4-hydroxyphenyl, 1-naphthyl, 2-naphthyl,
and the like. The term "aralkyl", alone or in combination, means an
alkyl radical as defined above in which one hydrogen atom is
benzyl, 2-phenylethyl and the like. The term "aralkoxy carbonyl",
alone or in combination, means a radical of the formula
--C(O)--O-aralkyl in which the term "aralkyl" has the significance
given above. An example of an aralkoxycarbonyl radical is.
benzyloxycarbonyl. The term "aryloxy", 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 cycloalkanecarboxylic acid which is
optionally substituted by, for example, alkanoylamino, such as
1,2,3,4-tetrahydro-2-naphthoyl,
2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The term "aralkanoyl"
means an acyl radical derived from an aryl-substituted
alkanecarboxylic acid such as phenylacetyl, 3-phenylpropionyl
(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl,
4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl,
4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-phenylbutyryl,
(1-naphthyl)acetyl, derived from a monocylic or bridged
cycloalkanecarboxylic acid such as cyclopropanecarbonyl,
cyclohexanecarbonyl, adamantanecarbonyl, and the like, or from a
benz-fused inonocyclic cycloalkanecarboxylic acid which is
optionally substituted by, for example, alkanoylamino, such as
1,2,3,4-tetrahydro-2-naphthoyl,
2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The term "aralkanoyl"
means an acyl radical derived from an aryl-substituted
alkanecarboxylic acid such as phenylacetyl, 3-phenylpropionyl
(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl,
4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-phenylbutyryl,
(1-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl,
4-methoxyhydrocinnamoyl, and the like. The term "aroyl" means an
acyl radical derived from an aromatic carboxylic acid. Examples of
such radicals include aromatic carboxylic acids, an optionally
substituted benzoic or naphthoic acid such as benzoyl,
4-chlorobenzoyl, 4-carboxybenzoyl, 4-benzyloxycarbonyl)benzoyl,
1-naphthoyl, 2-naphthoyl, 6-carboxy-2-naphthoyl,
6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,
3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the
like. The heterocyclyl or heterocycloalkyl portion of a
heterocyclylcarbonyl, heterocyclyloxycarbonyl,
heterocyclylalkoxycarbonyl, or heterocyclylalkyl group or the like
is a saturated or partially unsaturated monocyclic, bicyclic or-
tricyclic heteroycle which contains one or more hetero atoms
selected from nitrogen, oxygen and sulphur, which is optionally
substituted on one or more carbon atoms by halogen alkyl, alkoxy,
oxo, and the like, and/or on a secondary nitrogen atom (i.e.,
--NH--) by alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl
or on a tertiary nitrogen atom (i.e., +N--) by oxido and which is
attached via a carbon atom. The heteroaryl portion of a
heteroaroyl, heteroaryloxycarbonyl, or heteroaralkoxycarbonyl group
or the like is an aromatic monocyclic, bicyclic, or tricyclic
heterocycle which contains the hetero atoms and is optionally
substituted as defined above with respect to the definition of
heterocyclyl. Examples of such heterocyclyl and heteroaryl groups
are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol-4-yl,
1-benzyloxycarbonylimidazol-4-yl, etc.), pyrazolyl, pyridyl,
pyrazinyl, pyrimidinyl, furyl, thienyl, triazolyl, oxazolyl,
thiazolyl, indolyl (e.g., 2-indolyl, etc.), quinolinyl (e.g.,
2-quinolinyl, 3-quinolinyl, 1-oxido-2-quinolinyl, etc.),
isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, etc.), tetra
hydroquinolinyl (e.g., 1,2,3,4-tetrahydro-1-oxoisoquinolinyl, etc),
quinoxalinyl, beta-carbolinyl, 2-benzofurancarbonyl, 1-,2-,4-, or
5-benzimidazolyl, and the like. The term "cycloalkylalkoxycarbonyl"
means an acyl group derived from a cycloalkylalkoxycarboxylic acid
of the formula cycloalkylalkyl-O--COOH wherein cycloalkylalkyl has
the significance given above. The term "aryloxyalkanoyl", means an
acyl radical of the formula aryl-O-alkanoyl wherein aryl and
alkanoyl have the significance given above. The term
"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--COOH wherein heterocyclyl is as defined above. The
term "heterocyclylalkanoyl" means an acyl radical of the formula
aryl-O-alkanoyl wherein aryl and alkanoyl have the significance
given above. The term "heterocyclylalkoxycarbonyl" means an acyl
radical derived from heterocyclyl-substituted alkane-O--COOH
wherein heterocyclyl has the significance given above. The term
"heteroaryloxycarbonyl" means an acylradical derived from a
carboxylic acid represented by heteroaryl-O--COOH wherein
heteroaryl has the significance given above.
[0075] The term "aminocarbonyl" alone or in combination, means an
amino-substituted carbonyl(carbamoyl) group derived from an
amino-substituted carboxylic acid wherein the amino group can be a
primary, secondary or tertiary amino group continuing 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,
N-dimethylaminoacetyl and N-benzylaminoacetyl. The term "halogen"
means fluorine, chlorine, bromine or iodine. The term "leaving
group" generally refers to groups readily displaceable by a
nucleophile, such as an amine, a thiol or an alcohol nucleophile.
Such leaving groups are well known and include carboxylates,
N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates,
tosylates, --OR and --SR and the like. Preferred leaving groups are
indicated herein where appropriate. The term "N-heterocyclic
moiety" is a heterocyclic radical with a nitrogen 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 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.
[0076] Examples of N-heterocyclic moieties include, but are not
limited to, those represented by the following formulas: ##STR9##
##STR10## wherein:
[0077] R.sup.20 represents hydrogen, alkyl, alkoxycarbonyl,
monoalkylcarbamoyl, monoaralkylcarbamoyl, monoarylcarbamoyl or a
group of the formula:
wherein:
[0078] R.sup.10 and R.sup.11 each represents alkyl;
[0079] R.sup.12 represents hydrogen, hydroxy, alkoxycarbonylamino
or acylamino;
[0080] R.sup.13 represents hydrogen, alkyl, aryl, alkoxycarbonyl or
acyl;
[0081] m is 1, 2, 3, or 4;
[0082] p is 1 or 2; and
[0083] r is independently 0, 1 or 2.
[0084] Procedures for preparing the compounds of Formulas I, II,
III, IV, V and VI are set forth below. It should be noted that the
general procedure is shown as it relates to preparation of
compounds having the specified stereochemistry, for example,
wherein the stereochemistry about the hydroxy 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). 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.
[0085] Likewise, procedures to obtain the preferred stereochemistry
and its opposite configuration for the carbon to which R.sup.48 is
attached, and particularly when R.sup.48 is hydrogen, are generally
applicable from that disclosed in Example 4 below.
Preparation of Compounds of Formula I, III, IV, V and VI
[0086] Preparation of the compounds of Formula I are accomplished
by preparing a cyclic sulfone carboxylic acid according to the
following Scheme 1 and Scheme 1a: ##STR11##
[0087] Exemplary conditions for the preparation of Scheme 1 are
found in Preparation 1 hereinafter. For a cyclic sulfone having a
seven membered ring the corresponding starting material may be
substituted using analogous reaction conditions. On the other hand,
for a cyclic sulfone having a five membered ring, the known
starting material,
3-methoxy-carbonyl-2,5-dihydrothiophene-1,1-dioxide is hydrogenated
and deesterified in a manner analogous to the last two steps shown
in Scheme 1 and exemplified in Preparation 2 hereinafter.
[0088] A urea isostere of the formula A, the formula B, or the
formula C that is prepared according to the methods of PCT Number
WO-PCT/US92/8613 or PCT Application Number PCT/US92/08700, and
PCT/US91/8593, respectively, which are incorporated by reference
therefor, is then coupled with the cyclic sulfone carboxylic acid
prepared above to obtain the compound of the formula I or VI in the
manner set out in Scheme 2 hereinafter: ##STR12##
[0089] Suitable coupling agents are well-known in the art and
include dicyclohexylcarbodiimide or diisopropylcarbodiimide. The
coupling is conducted at a temperature of from 20.degree. C. to
about 50.degree. C., preferably at about 25.degree. C., in a
suitable solvent system such as, for example,
N,N-dimethylformamide, and the like. The amino protecting groups
are those known in the art and include carbobenzoxy, butyryl,
t-butoxycarbonyl, acetyl, benzoyl and the like, preferable
carbobenzoxy and t-butoxycarbonyl.
Preparation of the Compounds of Formula II
[0090] The cyclic sulfone carboxylic acid is again prepared as set
out above in Scheme 1.
[0091] An amino epoxide, which is a mixture of diastereomers of the
corresponding amino-protected epoxides of the formulas: ##STR13##
is prepared by the processes shown in Patent Application Ser.
Number PCT/US91/8617 and is incorporated by reference therefor.
P.sub.1 and P.sup.2independently represent hydrogen and
amino-protection groups well known in the art and include
carbobenzoxy, butyryl, t-butoxycarbonyl, acetyl, benzoyl and the
like, preferably carbobenzoxy and t-butoxycarbonyl, acetyl, benzoyl
and the like, preferably carbobenzoxy and t-butoxycarbonyl; and
R.sup.2 represents a radical as set out above. These diastereomers
can be separated by chromatography or; alternatively, once reacted
in subsequent steps the diastereomeric products can be
separated.
[0092] The amino epoxide is then reacted, in a suitable solvent
system, with an equal amount, of the formula: HNR.sup.4'R.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 C to about 120 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,
dionane and the like, toluene, N,N-dimethylformamide, dimethyl
sulfoxide, and mixtures thereof. A preferred solvent is
isopropanol. Examples of amines corresponding to the formula
HNR.sup.4'R.sup.5' include those having the following formula:
##STR14## ##STR15## wherein R.sup.20, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, m, p and r 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.
[0093] Alternatively, the compounds of the present invention
represented by Formula II above can be prepared utilizing the
following general procedure. An N-protected haloketone derivative
of an amino acid; also prepared by methods in Patent Application
Ser. No. PCT/US91/8617 and incorporated by reference therefor,
having the formula: ##STR17## wherein 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 amount of a
desired amine of the formula: HNR.sup.4'R.sup.5' wherein R.sup.4'
and R.sup.5' are as defined above. The reaction yields a compound
of the general formula (5): ##STR18## wherein P.sup.1, P.sup.2,
R.sup.2, R.sup.4' and R.sup.5' have the significance given
earlier.
[0094] The reaction of the N-protected haloketone derivative of an
amino acid, preferably one in which P.sup.1 and P.sup.2 represent
benzyloxy carbonyl, 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.
[0095] The reduction of the aminoketone compound of Formula 5
results in a compound of the general formula (6): ##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 5 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.).
Conveniently, the reduction is carried out at about room
temperature.
[0096] Then this N-heterocyclic moiety-containing derivative having
an 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.
[0097] Following neutralization of the salt, the amine is then
reacted with a cyclic sulfone carboxylic acid as prepared above to
produce the antiviral compounds of the present invention having the
formula II also as defined above. The reaction of the amine with a
cyclic sulfone carboxylic acid is as shown in the following Scheme
3: ##STR20##
[0098] Conditions of the Scheme 3 are generally as follows. The
cyclic sulfone carboxylic acid can be coupled to any of the desired
isosteres using methods well known to those in the art. For
example, activation of the acid can be accomplished using
dicyclocarbodiimide or
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)
in the presence of N-hydroxybenzotriazole in a suitable solvent,
such as N,N-dimethylformamide, tetrahydrofuran or methylene
chloride. Alternately, the acid can be activated by treatment with
N,N-disuccinimidyl carbonate and pyridine. The resulting active
esters can then be reacted with the desired isostere, optionally
with a base (such as diisopropylethylamine) present, to afford the
desired cyclic sulfone containing retroviral protease
inhibitors.
[0099] The R.sup.6 substituent is then added according to the
analogous procedures also described in PCT/US91/8613and WO9208700,
incorporated by reference therefor.
[0100] Finally, an amino alcohol is prepared by reacting the amino
epoxide described above or a corresponding haloalcohol with
R.sup.3NH.sub.2 also in a manner described in U.S. patent
application Ser. No. PCT/US91/8617 incorporated by reference
therefor to obtain the compound of the formula: ##STR21## wherein
P, R.sup.2 and R.sup.3 are as defined above.
[0101] The amino alcohol defined above is then reacted in a
suitable solvent with a sulfonyl chloride (R.sup.4SO.sub.2Cl) or
sulfonyl anhydride in the presence of an acid scavenger. Suitable
solvents in which the reaction can be conducted include methylene
chloride, tetrahydrofuran and the like. Suitable acid scavengers
include triethylamine, pyridine and the like. Preferred sulfonyl
chlorides are methanesulfonyl chloride and benzenesulfonyl
chloride. The resulting sulfonamide derivative can be represented,
depending on the epoxide utilized by the formulas: ##STR22##
wherein P, P.sub.1, P.sup.2, R.sup.2, R.sup.3 and R.sup.4'' are as
defined above.
[0102] The sulfonyl halides of the formula R.sup.4''SO.sub.2X can
be prepared by the reaction of a suitable Grignard or alkyl lithium
reagent with sulfuryl chloride, or sulfur dioxide followed by
oxidation with a halogen, preferably chlorine. Also, thiols may be
oxidized to sulfonyl chlorides using chlorine in the presence of
water under carefully controlled conditions. Additionally, sulfonic
acids may be converted to sulfonyl halides using reagents such as
PCl.sub.5, and also to anhydrides using suitable dehydrating
reagents. The sulfonic acids may in turn be prepared using
procedures well known in the art. Such sulfonic acids are also
commercially available. In place of the sulfonyl halides, sulfinyl
halides (R.sup.4SOX) or sulfenyl halides (R.sup.4SX) can be
utilized to prepare compounds wherein the --SO.sub.2-- moiety is
replaced by an --SO-- or --S-- moiety, respectively.
[0103] A cyclic sulfone of the formula I' wherein Q is represented
by (4) or (5) above is prepared in a like manner.
[0104] For example, an intermediate, the amino alcohol, is reacted
as shown in the following Scheme 3A. ##STR23##
[0105] In other words, the amino alcohol defined above is then
reacted in a suitable solvent with a sulfamoyl halide, e.g.,
sulfamoyl chloride (R.sup.4R.sup.5NSO.sub.2Cl or
R.sup.4HNSO.sub.2Cl) or corresponding sulfamoyl anhydride in the
presence of an acid scavenger. Suitable solvents in which the
reaction can be conducted include methylene chloride,
tetrahydrofuran. Suitable acid scavengers include triethylamine,
pyridine. The resulting sulfamic acid derivative can be
represented, depending on the epoxide utilized, by the formulas:
##STR24## wherein P, P.sup.1, P.sup.2, R.sup.2, R.sup.3, R.sup.4
and R.sup.5 are as defined above. These intermediates are useful
for preparing inhibitor compounds of the present invention and are
also active inhibitors of retroviral proteases.
[0106] The sulfamoyl halides of the formula R.sup.4NHSO.sub.2X can
be prepared by the reaction of a suitable isocyanate of the formula
R.sup.4NCO with fuming sulfuric acid to produce the corresponding
sulfamate which is then converted to the halide by well known
procedures, such as by treating the sulfamate with PCl.sub.5.
Alternatively, the isocyanate can be treated with chlorosulfonic
acid to produce the corresponding sulfamoyl chloride directly.
[0107] The sulfamoyl halides of the formula
R.sup.4R.sup.5NSO.sub.2Cl can be prepared by reacting an amine of
the formula R.sup.4R.sup.5NH, preferably as a salt such as the
hydrochloride, with sulfuryl chloride in a suitable solvent such as
acetonitrile. The reaction mixture is gradually warmed to reflux
temperature and maintained at the reflux temperature until the
reaction is complete. Alternatively, sulfamoyl halides of the
formula R.sup.4R.sup.5NSO.sub.2Cl can be prepared by reacting an
amine of the formula R.sup.4R.sup.5NH with sulfuryl chloride in
boiling MeCN as disclosed in Matier et al., J. Med. Chem., 15, No.
5, p. 538 (1972).
[0108] In an analogous manner a sulfamoyl halide, preferably Cl, of
the formula: ##STR25## is reacted with the amino alcohol as defined
above.
[0109] Following preparation of the sulfonamide derivative, the
amino protecting group P or P.sup.1 and P.sup.2 is removed under
conditions which will not affect the remaining portion of the
molecule. These methods are well known in the art and include acid
hydrolysis, hydrogenolysis and the like. A preferred method
involves removal of the protecting group, e.g., removal of a
carbobenzoxy group, by hydrogenolysis utilizing palladium on carbon
in a suitable solvent system such as an alcohol, acetic acid, and
the like or mixtures thereof. Where the protecting group is a
t-butoxycarbonyl group, it can be removed utilizing an inorganic or
organic acid, e.g., HCl or trifluoroacetic acid, in a suitable
solvent system, e.g., dioxane or methylene chloride. The resulting
product is the amine salt derivative. Where the protecting group is
a benzyl radical, it an b removed by hydrogenolysis. Following
neutralization of the salt, the amine, D, E or F, is then reacted
with a cyclic sulfone as described below and shown as follows:
##STR26## wherein R.sup.2, R.sup.3, R.sup.4'' and q is as defined
above.
[0110] The conditions of the reaction in Scheme 4 include suitable
solvent systems, such as, generally, recited following Scheme 3
above.
[0111] In order to prepare the tetrahydrothiopyran-4-carboxamide
sulfone and its analogs, one can start from the commercially
available tetrahydrothiopyran-4-one (compound 1 in Scheme 5). The
ketone 1 can be reduced to the alcohol 2 using a variety of methods
including sodium borohydride or lithium aluminum hydride. The
alcohol can then be converted into a leaving group X, such as
chloro, bromo, iodo, O-methanesulfonate, or O-p-toluenesulfonate,
of the like. The leaving group X is then displaced with a cyanide
source, such as sodium cyanide, potassium cyanide, lithium cyanide
or tetra-n-butylammonium cyanide, in a suitable solvent, such as
dimethyl sulfoxide, N,N-dimethylformamide or N-methylpyrrolidinone,
to provide the cyanide 4. The cyano group can then be hydrolyzed
under a variety of conditions well known to those skilled in the
art. The hydrolysis to the acid 6 can either be accomplished
directly in one step or using a two step procedure involving the
amide 5. Thus the cyano compound 4 can be converted to the amide 5
using concentrated sulfuric acid, and the amide converted to the
acid using sodium hydroxide or potassium hydroxide in aqueous
methanol or ethanol. Alternatively, the cyano compound 4 can be
directly hydrolyzed to the acid 6 using concentrated hydrochloric
acid at reflux. The sulfur in acid 6 can then be oxidized to the
sulfone by various methods, such as, meta-chloroperbenzoic acid,
sodium perborate in acetic acid, or hydrogen peroxide in acetic
acid, using greater than two equivalents of oxidizing agent. If one
desires the sulfoxide, rather than the sulfone, one can use one
equivalent of oxidizing agent. The acids 6 and 7can readily be
converted to the compounds of this invention by reaction with
various isosteres using standard coupling techniques. It is
envisioned that through appropriate modifications of the sequence
of reactions in Scheme 5, a variety of analogs can be made with
substituents on the tetrahydrothiopyran ring. ##STR27##
[0112] Further, a compound of the present invention wherein W is a
heterocyclic ring having a substituent other than hydrogen
represented as R.sup.40, R.sup.41, R.sup.42, R.sup.43, R.sup.44,
R.sup.45, R.sup.46, R.sup.47 or R.sup.48 can be prepared by the
method and Scheme showing the method in the following manner.
[0113] In order to prepare the thiomorpholine analog of the cyclic
sulfone, as shown in Scheme 6, one can start with either D-, L-, or
D,L-cysteine. Reaction of cysteine or an ester of cysteine
(compound 8, Scheme 6), where R.sub.1 is hydrogen, methyl, ethyl,
t-butyl, benzyl or other carboxyl protecting groups with a species
X--CKH.sub.2CO.sub.2R.sub.2, where X is a leaving group as defined
above and R.sup.2 is independently hydrogen, methyl, ethyl,
t-butyl, benzyl or other carboxyl protecting groups, in the
presence of a base such as sodium bicarbonate, triethylamine, or
the like provides the cyclic sulfide 9. The sulfide 9 can then be
oxidized to either the sulfoxide or sulfone using the methods
described above. If necessary, the carboxyl protecting group can be
removed from 9 or 10 and the resulting carboxylic acid coupled to
the various isosteres using standard methods. It is also envisioned
that one could use D-, L- or D<L-penicillamine
[HSC(CH.sub.3).sub.2CH(NH.sup.2)CO.sup.2H] in place of cysteine 8.
It is also contemplated that appropriate modifications of the
sequence would provide a variety of analogs. ##STR28##
[0114] For compounds wherein the oxidation state of the cyclic
sulfur in the W substituent is within that of the desired product,
the oxidation of Schemes 1 and 1a can be performed with a suitable
oxidizing agent; such as hydrogen peroxide, sodium perborate or
meta-chloroperbenzoic acid. It is well known to those skilled in
the art that this oxidation can be controlled through the use of
one equivalent of oxidizing agent to provide the sulfoxide or at
least two or more equivalents to provide the the sulfone.
[0115] 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.
[0116] 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 form known starting materials.
[0117] 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.
[0118] 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 VXR-300 or
VXR-400 nuclear magnetic resonance spectrometer using
tetramethylsilane as internal standard. Gas chromatograph was
performed on a Varian 3400 chromatography system. All instruments
were utilized according to the manufacturer's directions.
EXAMPLES
Example 1
[0119] Preparation of the cyclic sulfone carboxylic acid of the
formula: ##STR29## Part A: Preparation of methyl
tetrahydro-2H-thiopyran-4-keto-3-carboxylate. ##STR30##
[0120] To a suspension of 55.1 gm (1.02 mole) of dry, powdered
sodium methoxide in anhydrous ether (200 mL) at 0.degree. C. was
added 56.8 mL (0.33 mole) dimethyl 3,3-thiodipropionate dropwise.
The reaction mixture was stirred under nitrogen, warming to room
temperature over 1 hour, and then refluxed for 4.5 hrs.
Subsequently, the suspension was stirred at room temperature for 17
hrs. upon which was added a solution of acetic acid (100 mL) in
H.sup.2O (300 mL) slowly at 0.degree. C. The aqueous layer was
extracted three times with diethylether. The combined ether layers
were washed three times with saturated sodium bicarbonate and one
time with saturated sodium chloride. The organic layer was dried
with MgSO.sub.4 and concentrated in vacuo to give a pale yellow oil
which was partially purified by vacuum distillation to give 21.11
gm (114-124.degree. fraction/1.5 mm) of oil which was further
purified by flash chromatography on 1 kg silica gel with 4-5% ethyl
acetate in hexane to give 19.48 gm (34%) pure oil which
crystallized upon standing; mass spectrum m/e=174 (EI,M+). Part B:
Preparation of methyl tetrahydro
-2H-thiopyran-4-hydroxy-3-carboxylate. ##STR31##
[0121] To a -78.degree. C. solution of 5.91 gm (0.0339 moles) of
methyl tetrahydro-2H-thiopyran-4-keto-3-carboxylate in anhydrous
methylene chloride (100 mL) and anhydrous methanol (100 mL) was
added 0.644 gm (0.017 mole) soldium borohydride under N.sub.2 over
a period of 6 hrs. The reactor was alloed to warm to 0.degree. C.
over 1 hr upon which was added H.sub.2O (100 mL), slowly at first.
The organnic solvents were removed in vacuo. The aqueous residue
was extracted 4 times with methylene chloride. The combined organic
extracts were dried over magnesium sulfate, filtered, and
concentrated in vacuo to give 4.93 gm (83% crude yield) of a 2:1
mixture of cis;trans methyl
tetrahydro-2H-thriopyran-4-hydroxy-3-carboxylate as an oil; mass
spectrum m/e=176 (EI,M+). Part C: Preparation of methyl
5,6-dihydro-2H-thiopyran-3-carboxylate. ##STR32##
[0122] To a solution of 4.93 gm (0.0279 mole) of methyl
tetrahydro-2H-thiopyran-4-hydroxy-3-carboxylate from part B in
anhydrous methylene chloride (25 mL) was added 6.77 mL (0.0837
mole) anhydrous pyridine. The solution was cooled to 0.degree. C.,
upon which was added 3.25 mL (0.0420 mole) methanesulfonyl
chloride, dropwise via syringe. The solution was allowed to warm to
room temperature and stirred under N.sub.2 for 7.5 hrs. The
reaction was then cooled to 0.degree. C. and an additional 0.648 mL
(0.00837 mole) of methanesulfonyl chloride was added. The solution
was stirred at room temperature an additional 16 hrs. upon which
ethyl acetate (125 mL) was added. The organic layer was washed with
dilute HCl, saturated sodium bicarbonate, and saturated sodium
chloride, dried over magnesium sulfate, filtered, and concentrated
in vacuo to give a mixture of the cis and trans mesylate and
unreacted methanesulfonyl chloride. The crude mesylate mixture was
dissolved in anhydrous methylene chloride (30mL) upon which was
added 12.68 mL (0.09 11 mole) triethyl amine. The reaction was
stirred under N.sub.2 for 7 hrs. upon which was added 8.5 mL (0.061
mole) triethyl amine and the solution stirred 17 more hrs. The
organic layer was washed once with dilute acid and once with
saturated sodium chloride, dried over magnesium sulfate, filtered,
and concentrated in vacuo. The crude material was purified by flash
chromatography on 300 gm silica gel with 4-25% ethyl acetate in
hexane to give 2.76 gm (63%) of methyl
5,6-dihydro-2H-thiopyran-3-carboxylate as a clear oil; mass
spectrum m/z=159 (CI,M+H) Part D: Preparation of methyl
5,6-dihydro-2H-thiopyran-3-carboxylate, 1,1 dioxide. ##STR33##
[0123] To a solution of 0.934 gm (5.75 mmol) of
5,6-dihydro-2H-thiopyran-3-carboxylate from part C in glacial
acetic acid (40 mL) was added 1.98 gm (12.88mmole) sodium
perborate. The reaction mixture was stirred at 55.degree. C. under
N.sub.2 for 19 hrs. whereupon the solution was poured into H.sub.2O
(50 mL) and neutralized with 50% NaOH to pH=7. The solution was
extracted three times with methylene chloride. The combined organic
layers were washed once with saturated sodium bicarbonate and once
with saturated sodium chloride, dried over magnesium sulfate,
filtered and concentrated in vacuo to give 0.832 gm (76%) of methyl
5,6-dihydro-2H-thiopyran-3-carboxylate, 1,1 dioxide as a white
solid; mass spectrum m/e=190 (EI, M+) Part E: Preparation of
methyl-2H-thiopyran-3-carboxylate, 1, 1-dioxide. ##STR34##
[0124] A solution of 832 mg (4.37 mmole) of
5,6-dihydro-2H-thiopyran-3-carboxylate, 1,1 dioxide from part D in
methanol (40 mL) was hydrogenated in the presence of 400 mg (50%
wt) of 10% Pd/charcoal for 4 hrs. at room temperature and 50 psig
of H.sub.2. The catalyst was removed by vacuum filtration through a
short plug of packed celite and the solvent removed in vacuo to
give 802 mg (96%) of methyl 2H-thiopyran-3-carboxylate, 1,1-dioxide
as a white solid; mass spectrum m/z=193 (CI,M+H) Part F:
Preparation of 2H-thiopyran-3-carboxylate, 1,1-dioxide.
##STR35##
[0125] To a solution of 789 mg(4.10 mmole) of methyl
2H-thiopyran-3-carboxylate, 1,1-dioxide from part E in 4N
HCl/dioxane (10 mL) was added H.sub.2O (5 mL) slowly. The reaction
was stirred at room temperature for 116 hrs. whereupon the solvent
was removed in vacuo. The crude material was recrystallized from a
mixture of ethyl acetate and hexane to give 613 mg (84%) of
2H-thiopyran-3-carboxylate,1,1-dioxide as a white solid; mass
spectrum m/z=179 (CI, EI,M+H)
[0126] Alternatively, one can separate the isomers from part B.
Part B2: Preparation of cis methyl
tetrahydro-2H-thiopyran-4-hydroxy-3-carboxylate. ##STR36##
[0127] To a -78.degree. C. solution of 6.01 gm (0.0345 mol) of
methyl tetrahydro-2H-thiopyran-4-keto-3-carboxylate from part A in
anhydrous methylene chloride (100 mL) and anhydrous methanol (100
mL) was added 0.65 gm (0.0172 mol) sodium borohydride under N.sub.2
over a period of 3 hrs. The reaction was allowed to warm to
0.degree. C. over 1 hour upon which was added H.sub.2O (100 mL),
slowly at first. The organic solvents were removed in vacuo. The
aqueous residue was extracted 4 times with methylene chloride. The
combined organic extracts were dried over magnesium sulfate,
filtered, and concentrated in vacuo. The crude material was
purified by flash chromatography on 300 gm silica gel and diluted
with 1 to 1.5% methanol in methylene chloride to give 1.80 gm (30%)
of the cis isomer as a clear oil; mass spectrum m/z=177 (FAB,M+H)
Part C2: Preparation of methyl
5,6-dihydro-2H-thiopyran-3-carboxylate. ##STR37##
[0128] To a solution of 1.79 gm (0.0101 mol) of cis-methyl
tetrahydro-2H-thiopyran-4-hydroxy-3-carboxylate from part B2 in
anhydrous methylene chloride (10 mL) was added 2.45 mL (0.0303 mol)
anhydrous pyridine. The solution was cooled to 0.degree. C., upon
which was added 1.18 mL (0.0152mol) methanesulfonyl chloride,
dropwise via syringe. The solution was allowed to warm to room
temperature and stirred under N.sub.2 for 4 hrs., whereupon the
reaction was cooled to 0.degree. C. and an additional 1.6 mL (0.020
mol) anhydrous pyridine and 1.18 mL (0.0152 mol) methanesulfonyl
chloride were added. The solution was stirred at room temperature
for 48 hrs. upon which ethyl acetate (50 mL) was added. The organic
layer was washed with dilute HCl, saturated sodium bicarbonate, and
saturated sodium chloride, dried over magnesium sulfate, filtered
and concentrated in vacuo. The crude material was purified by flash
chromatography on 200 gm silica with 20-33% ethyl acetate in hexane
to give 2.18 gm (85%) of the cis mesylate which crystallized upon
standing. The pure mesylate (2.15 gm; 8.45 mmol) was dissolved in
anhydrous methylene chloride (8 mL) upon which was added 3.53 mL
(25.3 mmol) of triethyl amine and the solution stirred for 17 hrs.
An additional 2.35 mL (16.9 mmol), of triethyl amine was added and
the reaction stirred for 2 more hrs. The organic layer was washed
with dilute HCl and saturated sodium chloride, dried over magnesium
sulfate, filtered, and concentrated in vacuo to give 1.29 gm (96%)
of methyl 5,6-2H-thiopyran-3-carboxylate as a clear oil; mass
spectrum m/z=159 (CI,M+H), which was identical to the material from
part C of example 1.
Example 2
[0129] Preparation of tetrahydrothiophene-3-carboxylic acid,
1,1-dioxide. ##STR38## Part A: Preparation of methyl
tetrahydrothiophene-3-carboxylic acid, 1,1-dioxide.
[0130] To 3-methoxycarbonyl-2,5-dihydrothiophene-1,1-dioxide (5.0
g, 2.9.times.10.sup.-2 mol) in deoxygenated MeOH (60 ml) was added
10% Pd on carbon (0.5 g) and the resulting suspension hydrogenated
at 50 psi for 48 hours. Subsequently, the catalyst was removed by
filtration through celite, and the filtrate concentrated in vacuo
to give a pale oil (4.23 g, 84%); mass spectrum, m/z 179 (CI,
M+H).
Part B: Preparation of tetrahydrothiophene-3-carboxylic acid,
1,1-dioxide.
[0131] To the ester from part A (4.23g, 2.4.times.10.sup.-2 mol) in
MeOH (75 ml) at 0.degree. C. was added lithium hydroxide (1.01 g,
2.4.times.10.sup.-2 mol) in water (80 ml) and the resulting
solution stirred, warming to ambient temperature over 6.5 hours.
The MeOH was removed in vacuo and the residue neutralized with 2.5N
NaOH and extracted repeatedly with CH.sub.2Cl.sub.2. The combined
organic extracts were dried over MgSO.sub.4, filtered, and
concentrated in vacuo to give an oil which was triturated in
CH.sub.3OH (25 ml). The solids were removed by filtration and the
filtrate concentrated in vacuo to give a pale oil (0.57 g, 15%);
mass spectrum, m/z 165 (CI, M+H).
Example 3
[1S-[1R*(R*), 2S*]]-N.sup.1[3-[[[(1,1-dimethylethyl)
amino]carbonyl](3-methylbutyl)amino]-1-hydroxy
-1-(phenyl-methyl)propyl]-2-amino]butanediamide
[0132] ##STR39##
[0133] Protected [1S-[1R*(R*),
25*]]-N.sup.1[3-[[[(1,1-dimethylethyl)amino]carbonyl](3-methylbutyl)amino-
]-1-hydroxy-1-(phenyl-methyl)propyl]-2-amino]butanediamide is
prepared by methods disclosed or methods analogous therein
PCT/US91/8613 which is incorporated by reference therefor.
Example 4
[0134] Preparation of 2H-thiopyran-3-carboxamide,
N-[3-[[[(1,1-dimethylethyl amino]-carbonyl](3-methylbutyl)
amino]-2-hydroxy-1-(phenylmethyl) propyl]tetrahydro,-1,1-dioxide.
##STR40## Part A
[0135] The following amine is prepared by deprotecting the compound
prepared in Example 3 above by procedures disclosed in
PCT/US91/8613. ##STR41## Part B:
[0136] To a 0.degree. C. solution of 93.5 mg (0.525 mmole) of
2H-thiopyran-3-carboxylate, 1,1-dioxide in anhydrous dimethyl
formamide (1 mL) was added 115 mg (0.75 mmole) of
hydroxybenzotriazole and 105 mg (0.55 mmole) of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC).
The solution was stirred under N.sub.2 for 2 hrs. at 0.degree. C.
upon which was added 175 mg (0.50 mmole) of amine from part A and
stirring continued for 48 hrs. at room temperature. The solvent was
removed in vacuo and redissolved in ethyl acetate whereupon it was
washed with 5% citric acid, saturated sodium bicarbonate, and
saturated sodium chloride. The organic layer was dried with
magnesium sulfate, filtered and concentrated in vacuo to give 214
mg 84% of crude material.
[0137] The 2 diastereomers were purified by flash chromatography on
21 grams of silica gel and eluted with 50-85% ethyl acetate in
hexane to give 30 mg of each diasteromer as a white solid; mass
spectrum [0138] upper spot m/z=516 (FAB,M+Li) [0139] lower spot
m/z=516 (FAB,M+Li)
Example 4a
[0140] In an analogous manner using appropriate corresponding
starting materials a compound of the following formula is prepared.
##STR42##
Example 5
[0141] Preparation of thiophene-3-carboxamide,
N-[3-[[[(1,1-dimethylethyl)amino]-carbonyl](3-methylbutyl)amino]-2-hydrox-
y-1-(phenylmethyl)propyl]tetrahydro,-1,1-dioxide,
[3S-[3R*(1R*,2s*]]-
and
[0142] Preparation of thiophene-3-carboxamide,
N-[3-[[[(1,1-dimethylethyl)amino]-carbonyl](3-methylbutyl)amino]-2-hydrox-
y-1-(phenylmethyl)propyl]tetrahydro,-1,1-dioxide,
[3R-[3R*(1R*,2S*)]]- ##STR43## (and its isomer)
[0143] To the acid from Preparation 2 (0.25 g, 1.5.times.10.sup.-3
mol) in anhydrous DMF (3 ml) was added hydroxy-benzotriazole (0.40
g, 3.0.times.10.sup.-3 mol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (0.41
g, 2.1.times.10.sup.-3 mol) and the resulting solution stirred for
5 minutes. Subsequently was added the amine from Example 4 Part A
(0.44 g, 1.3.times.10.sup.-3 mol) in anhydrous DMF (4 ml) and the
reaction mixture stirred under a nitrogen atmosphere for 23 hours,
upon which it was poured into 60% saturated NaHCO.sub.3 solution
(120 ml), chilled for 3 hours, and the resulting precipitate
isolated via vacuum filtration. The tacky precipitate was taken
into CH.sub.2Cl.sub.2, washed with KHSO.sub.4 (aq), dried over
MgSO.sub.4, recrystallized from EtOAc/hexanes to give a white solid
(0.26 g, 42%); mass spectrum, m/z 502 (FAB, M+Li).
Example 6
[0144] Preparation of
[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.alpha..beta., 8.alpha..beta.]]-
[0145] Preparation of
N-Benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane.
##STR44## Part A
[0146] 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. 1L). 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. 1L) 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-chloro-4-phenyl-2(S-butanol, mp
150-151.degree. C. and M+Li.sup.+=340. formula: ##STR45## Part
B:
[0147] To a solution of 6.52 g (0.116 mol, 1.2 equiv.) of potassium
hydroxide in 969 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: ##STR46##
[0148] 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.alpha..beta., 8.alpha..beta.]]-, also
known as carbamic acid,
[3S-[3-[[(1,1-dimethylethyl)amino]carbonyl]decahydroisoquinolinyl]-2-hydr-
oxy-2-(phenylmethyl)propyl]-, phenylmethyl ester, [3S-[2(1R*,2S*),
3.alpha.,4.alpha..beta.,8.alpha..beta.]]-. ##STR47## Part A:
[0149] 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 (1.5 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, filtered 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: ##STR48## Part B:
[0150] 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
tertbutyl amide which has the following formula: ##STR49## Part
C:
[0151] N-tert-butoxycarbonyl-S-tetrahydroisoquinoline-2-carboxylic
acid tertbutyl amide (10.0 g, 30 mmol) was dissolved in 50 mL of
methanol and placed in a Fischer 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
filtration 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% ethylacetate hexane
gradient elution 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: ##STR50##
Part D:
[0152]
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 structure: ##STR51## Part E:
[0153] The amine from 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]-carbonyl]octahydro-2(1H)-isoquinolinyl]-
-2-hydroxy-1-(phenylmethyl)-propyl]-, phenylmethyl ester,
[3S-[2(1R*,2S*), 3.alpha., 4.alpha..beta., 8.alpha..beta.]].
##STR52##
Example 7
[0154] Synthesis of ##STR53## Part A:
[0155] A solution of carbamic acid,
[3-[3-[[(1,1-dimethylethyl)amino]-carbonyl]octahydro-2(1H)-isoguinolinyl]-
-2-hydroxy-1-(phenylmethyl)-propyl]-phenylmethylester,
[3S-[2(1R*,2S*),3,4.alpha..beta., 8.alpha..beta.]]-(1.01 gm, 1.89
mmole) in N.sub.2 purged THF (20 mL) was hydrogenated in the
presence of 0.50 gm (50% wt) of 10% Pd/charcoal for 17 hrs at 50
psig of H.sub.2. The catalyst was removed by vacuum filtration
through a short plug of packed celite and the solvent was removed
in vacuo to give 759 mg (100%) of a white foam. The amine product
has the following formula: ##STR54## Part B:
[0156] To a solution of 100 mg (0.561 mmole) of
2H-thiopyran-3-carboxylate, 1,1-dioxide in anhydrous methylene
chloride (2.5 mL) was added 143.7 mg (0.561 mmole) of N,N
disuccinimidyl carbonate and 45.4 .mu.l (0.561 mmole) pyridine.
Subsequently, 1 mL acetonitrile was added to form a homogeneous
solution. The resulting solution was stirred under N.sub.2 for 3
hrs. The solvent was removed in vacuo and redissolved in ethyl
acetate, whereupon it was washed with saturated sodium bicarbonate,
5% KHSO.sub.4, and saturated sodium chloride. The organic layer was
dried with magnesium sulfate, filtered, and concentrated in vacuo
to give 63.2 mg (41%) of as a white solid; mass spectrum m/z 282
(FAB,M+Li) having the following structure: ##STR55## Part C:
[0157] To a solution of 57 mg (0.207 mmole) of hydroxysuccinimide
ester from Part B in 1.8 mL methylene chloride and 1.2 mL of THF
was added 83.15 mg (0.207 mmole) of amine from Part A. the reaction
was stirred for 19.5 hrs whereupon the solvent was removed in
vacuo. The crude product was chromatographed on 10 gm silica gel
with 3% methanol in methylene chloride to give 90.2 mg (78% of as a
white powder; mass spectrum m/z=568 (FAB,M+Li) ##STR56##
Example 8
[0158] Part A: ##STR57##
[0159] Preparation of phenylmethyl
[2R-hydroxy-3-[(3-methylbutyl(phenylsulfonyl)amino]-1S-(phenylmethyl)prop-
yl]carbamate
[0160] From the reaction of
N[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]
N-isoamylamine (1.47 gm, 3.8 mmol), triethylamine (528 uL, 3.8
mmol) and benzenesulfonyl chloride (483 uL, 3.8 mmol) one obtains
phenylmethyl (2R-hydroxy-3-[(3-methylbutyl)
(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate. Column
chromotography onsilica gel eluting with chloroform containing 1%
ethanol afforded the pure product. Anal. Calcd. for
C.sub.29H.sub.36N.sub.2O.sub.5S: C, 66.39; H, 6.92; N, 5.34. Found:
C, 66.37; H, 6.93; N, 5.26. Part B: ##STR58##
[0161] A solution of 10.1 gm (19.2 mmole) of phenylmethyl ester of
the carbamic acid from Part A above in N.sub.2 purged MeOH (100 ml)
was hydrogenated in the presence of 2 gm (20% wt) of 10%
Pd/charcoal for 6 hrs. at 50 psig of H.sub.2. The catalyst was
removed by vacuum filtration through a short plug of packed celite
and the solvent was removed in vacuo to give 7.41 gm (99%) of
amine; mass spectrum, m/z=391 (FAB, M+H).
Part C:
[0162] Preparation of: ##STR59##
[0163] To a solution of 190 mg (1.07 mmole) of
2H-thiopyran-3-carboxylate, 1,1-dioxide in anhydrous DMF (3 mL) was
added 240 mg (1.56 mmole) N-hydoxybenzotriazole and 280 mg (1.46
mmole) of 1-(3-dimethyl aminopropyl)-3-ethyl carbodiimide
hydrochloride (EDC). The resulting solution was stirred under
nitrogen for 10 minutes at room temperature upon which was added
290 mg (0.91 mmole) of amine from Part B in DMF (5 ml) and stirring
continued for 18 hrs. Subsequently, the reaction mixture was poured
into 50% saturated sodium bicarbonate (aq) and extracted into ethyl
acetate. The combined organic layers were dried over magnesium
sulfate, filtered and concentrated in vacuo. The crude material was
recrystallized from ethylacetate/diethylether/hexane to give 300 mg
(60%) of a 1:1 mixture of ##STR60## as a white powder; mass
spectrum m/z=557 (FAB, M+Li)
Example 9
[0164] Preparation of ##STR61## Part A
[0165] A 25 mL two-necked RB flask, equipped with a reflux
condenser and dropping funnel and under a nitrogen atmosphere, was
charged with t-butanol. (207 uL, 2.2 mmoles) and 5 mL of hexane.
Chlorosulfonyl isocyanate (192 uL, 2.2 mmoles) in 3 mL of hexane
was added dropwise. Upon warming a homogeneous solution was
obtained. The solution was heated at gentle reflux for 45 min.,
then was cooled to r.t. Solvent was removed under a steady stream
of nitrogen. The crude t-butyl sulfamoyl chloride (a liquid) was
used without further purification.
Part B
[0166] A solution of
N-benzyloxycarbonyl-3(S)-amino-1,2-(S)-epoxy-4-phenyl butane (50.0
g, 0.168 mol) and isobutylamine (246 g, 3.24 mol, 20 equivalents)
in 650 mL of isopropyl alcohol was heated to reflux for 1.25 hours.
The solution was cooled to room temperature, concentrated in vacuo
and then poured into 1 L of stirring hexane whereupon the product
crystallized from solution. The product was isolated by filtration
and air dried to give 57.56 g, 92% of
N[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenyl]N-isobutylamine,
mp 108.0-109.5.degree. C., MH+m/z=371.
Part C
[0167]
N[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]-N-isobut-
ylamine (370 mg, 1.0 mmole) from Part B was mixed with DIEA (139
uL, 1 mmol) in 5 mL of dichloromethane. Chlorotrimethylsilane (126
uL, 1 mmole) was added. After 1 h., additional DIEA (160 uL) was
added, followed by a dichloromethane solution (5 mL) containing 1.1
mmole of t-butyl sulfamoyl chloride from Part A. The reaction
mixture was stirred for 2 days. Solvent was removed under aspirator
pressure. The oily residue was taken p in ethyl acetate and washed
with 5% citric acid, saturated sodium bicarbonate, brine, dried
over sodium sulfate and evaporated to an oily residue (380 mg).
[0168] The crude product was stirred in 4N HCl in dioxane (6 mL)
for 15 min. After the addition of 4 mL of methanol to the reaction
mixture, the solution was stirred for an additional 15 min., then
concentrated to an oily residue. The product, phenylmethyl
[2R-hydroxy-3-[[(1,1-dimethylethyl)amino]sulfonyl](2- an oily
residue. The product, phenylmethyl
[2R-hydroxy-3-[[(1,1-dimethylethyl)amino]sulfonyl](2-methylpropyl)amino]--
1S-(phenylmethyl)propyl] carbamate was obtained after silica gel
chromatography (188 mg, 37%). MS (MH).sup.+=506. The carbobenzoxy
group was then removed via hydrogenolysis in ethanol over 10%
palladium on carbon and under 40 psig hydrogen and the resulting
amine used directly in the next step.
Part D
[0169] To a solution of 42.2 mg (0.24 mmol)(of racemic
2H-thiopyran-3-carboxylic acid, 1,1-dioxide in 1.0 mL of anhydrous
N,N-dimethylformamide (DMF) and 52 mg (0.34 mmol) of
N-hydroxybenzotriazole, was added 47 mg (0.25 mmol) of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at
0.degree. C. After two hours at 0.degree. C., a solution of 84 mg
(0.23 mmol) of free amine from Part C in 0.5 mL of DMF was added
and the reaction stirred for three days at room temperature. The
DMF was removed in vacuo, ethyl acetate added and the solution
washed with 5% aqueous citric acid, saturated brine, dried over
anhydrous magnesium sulfate, filtered and concentrated to afford
109 mg of crude product. This was chromatographed on silica gel
using 2.5% methanol/methylene chloride to afford 64 mg of pure
product as a 1:1 mixture of diasteromers, m/e=532 (M+H).
Example 10
[0170] Preparation of
t-butyl sulfamoylchoride
Part A:
[0171] A 25 mL two-necked RB flask, equipped with a reflux
condenser and dropping funnel and under a nitrogen atmosphere, was
charged with t-butanol (207 uL, 2.2 mmoles) and 5 mL of hexane.
Chlorosulfonyl isocyanate (192 uL, 2.2 mmoles) in 3 mL of hexane is
added dropwise. Upon warming a homogeneous solution is obtained.
The solution is heated at gently reflux for 45 min., then is cooled
to r.t. Solvent is removed under a steady stream of nitrogen. The
crude t-butyl sulfamoyl chloride (a liquid) is used without further
purification.
Example 11
[0172] Preparation of ##STR62## Part A: Preparation of
5-oxo-3-thiomorpholine-1(S)-carboxylic acid. Part A: To a mixture
of 4.0 g (22.8 mmol) of D-cysteine hydrochloride in 42 mL of
methanol and 16 mL of water, was added 9.2 g (45.5 mmol) of
triethylamine, followed by 2.46 g (22.8 mmol) of methyl
chloroacetate. After 72 h at room temperature, the solvents were
removed under reduced pressure and ethyl acetate added as well as
concentrated hydrochloric acid. The layers were separated and the
ethyl acetate, dried and concentrated to afford 203 mg of the
desired product, m/e=162(M+H). Part B: To a solution of 103 mg
(0.64 mmol) of the cyclic sulfide from part A and 147 mg (0.96
mmol) N-hydroxybenzotriazole in 2 mL of anhydrous
N,N-dimethylformamide (DMF) at 0.degree. C., was added 135 mg (0.70
mmol) of EDC. After two hours, a solution of 202 mg (0.58 mmol) of
amine in 2 mL of DMF from Example Part was added and the solution
stirred at room temperature for 17 h. The solvents were removed in
vacuo, ethyl acetate added and washed with saturated aqueous sodium
bicarbonate, 5% aquious citric acid, and saturated sodium chloride,
dried and concentrated to afford 230 mg of crude product.
Chromatography on silica gel using 3-5% methanol/methylene chloride
afforded 196 mg of the desired product, M/e=499 (M+Li), identified
as 3-thiomorpholine-1(S)-carboxamide,
N-[3-[[[(1,1-dimethylethyl)amino]carbonyl](3-methylbutyl)amino]-2(R)-hydr-
oxy-1(S)-(phenylmethyl)propyl]-5-oxo-carbonyl](3-methylbutyl)amino]-2(R)-h-
ydroxy-1(S)-(phenylmethyl)propyl]-5-oxo-. Part C: To a solution of
151 mg (0.31 mmol) of the product of part B in 10 mL of chloroform
was added 200 mg (0.78 mmol) of 67% m-chloroperbenzoic acid. After
16 h at room temperature, methylene chloride was added, the
solution washed with 2 M aquious ammonium hydroxide, dried and
concentrated to afford 150 mg of crude product. Chromatography on
silica gel using 3-5% isopropanol/methylene chloride afforded 70 mg
of the desired product, m/e=521 or 531 (M+Li), identified as
3-thiomorpholine-1(S)-carboxamide,
N-[3-[[[(1,1-dimethylethyl)amino]carbonyl](3-methylbutyl)amino]-2(R)-hydr-
oxy-1(S)-phenylmethylpropyl]-3,3,5-trioxo-.
Example 12
[0173] Preparation of ##STR63## Part A: Preparation of
5-oxo-3-thiomorpholine-1(R)-carboxylic acid.
[0174] To a solution of 2.0 g (16.5 mmol) of L-cysteine in 30 mL of
methanol and 10 mL of water, was added 3.33 g (33mmol) of
triethylamine and then 1.79 g (16.5 mmol) of methyl chloroacetate.
After 21 h at room temperature, the solvents were removed in vacuo,
saturated aqueous sodium bicarbonate was added and the solution
extracted with ethyl acetate. The aquious layer was then acidified
and extracted with ethyl acetate. The organic layer was dried and
concentrated in vacuo. The residue was dried over P.sub.2O.sub.5in
vacuo, ethyl acetate added and the resulting solid collected by
filtration to afford 306 mg of the desired product,
m/e=161(M+).
[0175] Part B: To a solution of 205 mg (1.27 mmol) of the cyclic
sulfide from part A and 292 mg (1.91 mmol) of
N-hydroxybenzotriazole in 5 mL of anhydrous N,N-dimethylformamide
at 0.degree. C. was added 268 mg (1.40 mmol) of EDC. After 2 h, a
solution of 398 mg (1.14 mmol) of amine from Example, Part in 2 mL
of DMF was added. After 17 h at room temperature, the solvent was
removed in vacuo, ethyl acetate added, washed with saturated sodium
becarbonate, 5% aquious citric acid, saturated sodium chloride,
dried and concentrated to afford 448 mg of crude product.
Chromatography on silica gel using 3-5% methanol/methylene chloride
afforded 243 mg of the desired product, m/e=499 (M+Li), identified
as 3-thiomorpholine-(1R)-carboxamide,
N-[3-[[[(1,1-dimethylethyl)amino]carbonyl](3-methylbutyl)amino]-1(R)-hydr-
oxy-1(S)-(phenylmethyl)propyl]-5-oxo-.
[0176] Part C: To a solution of 240 mg (0.49 mmol) of the product
from Part B in 10 mL of chloroform was added 314 mg (1.22 mmol) of
67% m-chloroperbenzoic acid. After 17 h at room temperature,
methylene chloride was added and washed with 2M aqueous ammonia,
water, brine, dried and concentrated to afford 214 mg of crude
material. Chromatography on silica gel using 5%-10%
isopropanol/methylene chloride afforded 100 mg of the desired
sulfone, m/e=531 or 521(M+Li), identified as
3-thiomorpholine-1(R)-carboxamide,
N-[3-[[[1,1-dimethylethyl)amino]carbonyl](3-methylbutyl)amino]-2(R)-hydro-
xy-1(S)-(phenylmethyl)propyl]-3,3,5-trioxo-.
Example 13
[0177] Preparation of 2H-Thiopyran-3-carboxamide,
N-[3-[[[(1,1-dimethylethyl)amino]carbonyl](3-methylbutyl)amino]-2(R)-hydr-
oxy-1(S)-(phenylmethyl)propyl]-5,6-dihydro-, 1,1-dioxide ##STR64##
Part A: Preparation of 5,6-dihydro-2Hthiopyran-3-carboxylic acid,
1,1-dioxide.
[0178] To a solution of 205 mg (1.08 mmol) of methyl
5,6-dihydro-2H-thiopyran-3-carboxylate, 1,1-dioxide from Example 1
part D in 10 mL of 4N HCl/dioxane, was added 5 mL of water, After
stirring at room temperature for 2 weeks, the solvents were removed
in vacuo to provide a 65:35 mixture, respectively, of the desired
acid and unreacted ester, respectively. The mixture was used
directly in the next step.
Step B:
[0179] To a solution of 115 mg of the mixture from Part A, and 136
mg (0.89 mmol) N-hydroxybenzotriazole in 2 mL of anhydrous
N,N-dimethylformamide (DMF) at 0.degree. C., was added 136 mg (0.71
mmol) of EDC. After 2 hours at 0.degree. C., a solution of 206 mg
(0.59 mmol) of amine from Example 4, Part A, above, in 1 mL of DMF
was added. After 16 hours at room temperature, ethyl acetate was
added and washed with aqueous citric acid, water, brine, dried and
concentrated to afford 219 mg of crude material. This was
chromatographed on silica gel using 0.5-2% methanol/methylene
chloride to afford 178 mg (60% yield) of the desired olefinic
cyclic sulfone product, m/e=514 (M+Li).
Example 14
[0180] Preparation of Tetrahydrothiopyran-4-carboxamide,
N-[3-[[[(4-methoxyphenyl)sulfonyl](3-methylbutyl)amino]-2R-hydroxy-15-(ph-
enylmethyl}propyl]]-, 1.1-dioxide. ##STR65## Preparation of
tetrahydrothiopyran-4-carboxylic acid, 1,1-dioxide. Part A:
Preparation of Tetrahydrothiopyran-4-ol
[0181] To a solution of 6.36 g (54.7 mmol) of tetrahydropyran-4-one
in 200 mL of anhydrous methanol at 0.degree. C. under a nitrogen
atmosphere, was added 1.04 g (27.4 mmol) of sodium borohydride.
After 15 Minutes, 30 mL of water was added, the methanol was
removed in vacuo and the resulting residue extracted twice with
methylene chloride, dried and concentrated to afford 6.25 g (97%
yield) of the desired alcohol, m/e=118 (M+).
Part B: Preparation of Tetrahydrothiopyran-4-ol,
O-methanesulfonate.
[0182] To a solution of 6.25 g (53 mmol) of the alcohol from Part A
in 50 mL of anhydrous methylene chloride and 12.9 mL (159 mmol) of
pyridine at 0.degree. C., was added dropwise 7.38 mL (95 mmol) of
methanesulfonyl chloride and the solution allowed to stir at room
temperature for sixteen hours. Ethyl acetate (200 mL) was added and
the reaction mixture washed with 2N hydrochloric acid, saturated
aqueous sodium bicarbonate, brine, dried and concentrated to afford
10.4 g of crude material. Chromatography on silica gel using 0.5%
methanol/methylene chloride afforded 9.88 g (95% yield) of the
desired mesylate, m/e=197 (M+H).
Part C: Preparation of Tetrahydrothiopyran-4-cyano
[0183] To a solution of 7.75 g (39.4 mmol) of the mesylate from
Part B in 100 mL of anhydrous N-methylpyrrolidinone was added 19.3
g (395 mmol) of sodium cyanide. The mixture was heated at
90.degree. C. for twenty hours, cooled, 200 mL of water added and
the solution extracted three times with diethyl ether. The organic
layer was dried and concentrated to afford 15.8 g of material which
still contained N-methylpyrrolidinone. Chromatography on silica gel
using 0.5% methanol/methylene chloride afforded a mixture of the
desired nitrile, contaminated with the olefin resulting from
elimination of the mesylate. Chromatography on silica gel using 10%
ethyl acetate/hexane afforded 1.94 g (39% yield) of the desired
nitrile, m/e=128 (M+H).
Part D: Preparation of Tetrahydrothiopyran-4-carboxamide.
[0184] To 3 mL of concentrated sulfuric acid, was added 813 mg (6.4
mmol) of the nitrile from Part C and the mixture heated at
45.degree. C. for sixteen hours. The solution was cooled and poured
into 50 mL of ice and water, the solids collected, dissolved in
ethyl acetate, dried and concentrated to afford 614 mg (66% yield)
of the desired amide, m/e=145 (M+).
Part E: Preparation of tetrahydrothiopyran-4-carboxylic Acid.
[0185] To a solution of 601 mg (4.1 mmol) of the amide from Part D
in 10 mL of methanol was added 828 mg (21 mmol) of sodium hydroxide
and the mixture heated at reflux for sixteen hours, 5 mL of water
added and heating continued for 72 hours. The methanol was removed
in vacuo, 2N hydrochloric acid added and the solution extracted
with ethyl acetate, dried and concentrated to afford 571 mg (94%
yield) of the desired acid, m/e=147 (CI,M+H).
Part F: Preparation of Tetrahydrothiopyran-4-carboxylic Acid,
1,1-dioxide.
[0186] To a solution of 200 mg (1.3 mmol) of the acid from Part E
in 9 mL of acetic acid was added 620 mg (5.5 mmol) of 30% aqueous
hydrogen peroxide. After heating at reflux for 1.5 hours, the
colution was cooled, sodium sulfite added to quench any excess
oxidizing agent (using potassium iodide/starch paper for
detection), the volatiles removed in vacuo and the residue
extracted with warm ethyl acetate, which was quickly filtered and
concentrated to afford 140 mg (59% yield) of the desired sulfone,
m/e=179 (M+H).
Tetrahydrothiopyran-4-carboxamide,
N-[3-[[[(4-methoxyphenyl)sulfonyl](3-methylbutyl)amino]-2R-hydroxy-1s-(ph-
enylmethyl)propyl]]-, 1,1-dioxide.
[0187] ##STR66##
[0188] To a solution of 53 mg (1.1 mmol) of
tetrahydrothiopyran-4-carboxylic acid, 1,1-dioxide and 62 mg (1.5
mmol) of N-hydroxybenzotriazole in 2 mL of anhydrous
N,N-dimethylformamide (DMF) at 0.degree. C., was added 62 mg (1.2
mmol) of EDC. After 2 hours at 0.degree. C., a solution of
3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-2R-hydroxy-3S-(pheny-
lmethyl)propylamine in 1 mL of DMF was added. After sixteen hours
at room temperature, the volatiles were removed in vacuo, ethyl
acetate acid, washed with 5% aqueous citric acid, saturated sodium
bicarbonate, brine, dried and concentrated to afford 142 mg of
crude product. This was chromatographed on silica gel using 2.5%
methanol/methylene chloride to afford 127 mg (83% yield) of the
desired product, m/e=.
Example 15
Assays
Part A: Enzyme Assay
[0189] The compounds of the present invention are effective HIV
protease inhibitors. Utilizing an enzyme assay as described below,
the compounds set forth in Examples 4, 4a, 7, 8 and 9 inhibited the
HIV enzyme in an amount described as an IC.sub.50 ranging from
about 3 nanomolar to about 140 nanomolar as shown in Table 1. The
calculated IC.sub.50 indicates the concentration providing
inhibition of 50%, i.e., the concentration at which the inhibitor
compound reduces enzyme activity by 50%). The enzyme method is
described below. The substrate is
2-aminobenzoyl-Ile-Nle-Phe(p-NO.sub.2)-Gln-ArgNH.sub.2. The
positive control is MVT-101 [Miller, M. et al, Science, 246, 1149
(1989)]. The assay conditions are as follows: Assay buffer: 20 mM
sodium phosphate, pH 6.4
[0190] 20% glycerol
[0191] 1 mM EDTA
[0192] 1 mM DTT
[0193] 0.1% CHAPS
[0194] The above described substrate is dissolved in DMSO, then
diluted 10 fold in assay buffer. Final substrate concentration in
the assay is 80 IM.
[0195] HIV protease is diluted in the assay buffer to a final
concentration of glycerol is 18%. The test compound is dissolved in
DMSO and diluted in DMSO to 10.times. the test concentration; 10 IL
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 IL 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. TABLE-US-00001 TABLE 1 ##STR67## Examples Q
IC.sub.50 EC.sub.50 TD.sub.50 4 ##STR68## 13 nM 63 NM 308,000 nM 8
##STR69## 4 nM 19 NM 46,000 nM 7 ##STR70## 3 nM 12 nM 48,000 nM 4a
##STR71## 46 nM 295 nM 420,000 nM 9 ##STR72## 140 nM -- --
[0196] Thus, the compounds of the present invention are effective
antiviral compounds and, in particular, are effective retroviral
inhibitors as shown above. Thus, the subject compounds are
effective HIV protease inhibitors. It is contemplated that the
subject compounds will also inhibit other viruses such as human
T-cell leukemia virus, respiratory syncitial virus, hepadnavirus,
cytomegalovirus and picornavirus by the proposed inhibition of post
translational proteolytic processing events. Thus, the subject
compounds are effective in the treatment and/or prophylaxis of
retroviral infections.
[0197] 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-hydroxyethanesulfonate, 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, 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 other. Water or oil-soluble or
dispersible products are thereby obtained.
[0198] 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.
[0199] Total daily dose administered to a host in single or divided
doses may be in amounts, for example, from 0.001 to 10 mg/kg body
weight daily and more usually 0.01 to 1 mg. Dosage unit
compositions may contain such amounts of submultiples thereof to
make up the daily dose.
[0200] 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 made of
administration.
[0201] 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.
[0202] 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 parental as used herein includes
subcutaneous injections, intravenous, intramuscular, intrasternal
injection, or infusion techniques.
[0203] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, and
isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending medium. For
this purpose any bland fixed oil may be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid find use in the preparation of injectables.
[0204] 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.
[0205] Solid dosage forms for oral administration may include
capsules, tablets, pill, 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 A inert diluents, e.g., lubricating agents such as
magnesium stearate. In the case of capsules, tablets, and pills,
the dosage forms may also comprise buffering agents. Tablets and
pills can additionally be prepared with enteric coatings.
[0206] 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.
[0207] Pharmaceutically acceptable carriers encompass all the
foregoing and the like.
[0208] 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 or with
N-butyl-1-deoxynojirimycin for the prophylaxis and/or treatment of
AIDS. When administered as a combination, the therapeutic agents
can be formulated as separate compositions which are given at the
same time or different times, or the therapeutic agents can be
given as a single composition.
[0209] 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.
[0210] 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.
[0211] 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 condition.
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