U.S. patent application number 09/777282 was filed with the patent office on 2001-07-19 for retroviral protease inhibiting compounds.
Invention is credited to Chen, Xiaoqi, Kempf, Dale J., Mohammadi, Fariborz, Norbeck, Daniel W..
Application Number | 20010008892 09/777282 |
Document ID | / |
Family ID | 26773005 |
Filed Date | 2001-07-19 |
United States Patent
Application |
20010008892 |
Kind Code |
A1 |
Chen, Xiaoqi ; et
al. |
July 19, 2001 |
Retroviral protease inhibiting compounds
Abstract
The present invention discloses novel compounds, compositions,
and methods for inhibiting retroviral proteases and in particular
for inhibiting human immunodeficiency virus (HIV) protease. The
present invention also relates to compositions and methods for
treating a retroviral infection and in particular an HIV infection,
and to processes for making such compounds and synthetic
intermediates employed in these processes.
Inventors: |
Chen, Xiaoqi; (San Mateo,
CA) ; Kempf, Dale J.; (Libertyville, IL) ;
Norbeck, Daniel W.; (Grayslake, IL) ; Mohammadi,
Fariborz; (Lake Forest, IL) |
Correspondence
Address: |
Steven F. Weinstock
Abbott Laboratories
Department 377 / AP6D-2
100 Abbott Park Road
Abbott Park
IL
60064-6050
US
|
Family ID: |
26773005 |
Appl. No.: |
09/777282 |
Filed: |
February 6, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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09777282 |
Feb 6, 2001 |
|
|
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09309141 |
May 10, 1999 |
|
|
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60085709 |
May 15, 1998 |
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Current U.S.
Class: |
514/252.13 ;
514/326; 544/363; 544/369; 546/139; 546/209 |
Current CPC
Class: |
C07D 417/14 20130101;
C07D 417/12 20130101; C07D 277/24 20130101 |
Class at
Publication: |
514/252.13 ;
514/326; 544/363; 544/369; 546/139; 546/209 |
International
Class: |
A61K 031/497; A61K
031/445; C07D 401/00; C07D 417/00 |
Claims
1. A compound having formula I: 21wherein R.sup.1 is a thiazolyl
group having the formula 22and R.sup.2 is a group having the
formula: 23wherein R.sup.3 is selected from the group consisting of
hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl;
and Y is CH or N; R.sup.4 is --W--R.sup.5; W is --O--, --S--, or
--(CH.sub.2).sub.n--; and R.sup.5 is selected from the group
consisting of alkyl, and aryl; n is from 0 to 6; or R.sup.4 and the
ring taken together can form a bicyclic group having the formula:
24with the proviso that when W is O, or S then Y is CH; R.sup.6 is
hydrogen, alkyl, cycloalkyl, aryl, (aryl)alkyl, heterocyclic,
(heterocyclic)alkyl, heteroaryl,or (heteroaryl)alkyl; and Z is
--O--, --S--, --CH.sub.2-- or --N(R.sup.7)--; and R.sup.7 is
hydrogen, alkyl, aryl, (aryl)alkyl, heterocyclic,
(heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl; wherein the
alkyl, aryl, heterocyclic, and heteroaryl groups can be optionally
substituted with 1 to 5 substituents selected from the group
consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino and
halogen; or a pharmaceutically acceptable salt, ester or prodrug
thereof.
2. The compound according to claim 1, wherein R.sup.3 is alkyl or
cycloalkyl and Z is --O--, or --N(R.sup.7)--.
3. The compound according to claim 2, wherein R.sup.3 is alkyl.
4. The compound according to claim 2, wherein R.sup.3 is cycloalkyl
selected from the group consisting of cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl.
5. The compound according to claim 3, wherein R.sup.3 is selected
from the group consisting of hydrogen, methyl, ethyl, propyl and
isopropyl.
6. The compound according to claim 5, wherein R.sup.3 is
isopropyl.
7. The compound according to claim 1, wherein Z is --O--.
8. The compound according to claim 1, wherein Z is --N(R.sup.7)--
and R.sup.7 is methyl.
9. The compound according to claim 1, wherein Y is nitrogen, W is
--CH.sub.2-- and R.sup.5 is aryl selected from the group consisting
of phenyl, methylenedioxyphenyl, and heteroaryl.
10. The compound according to claim 9, wherein R.sup.5 is
substituted with fluorine.
11. The compound according to claim 9, wherein R.sup.5 is
substituted with 1 to 3 hydroxy groups.
12. The compound according to claim 9, wherein R.sup.5 is
substituted with 1 to 3 alkoxy or alkylthio groups.
13. The compound according to claim 9, wherein R.sup.5 is
substituted with two alkoxy groups.
14. The compound according to claim 9, wherein R.sup.5 is
substituted with at least one hydroxy group and at least one
methoxy group.
15. The compound according to claim 1, wherein Y is CH, and R.sup.5
is alkyl, or aryl selected from the group consisting of phenyl,
methylenedioxyphenyl, and heteroaryl.
16. The compound according to claim 15, wherein R.sup.5 is
substituted with 1 to 3 alkoxy or alkylthio groups.
17. The compound according to claim 15, wherein R.sup.5 is
substituted with a hydroxy group.
18. The compound according to claim 15, wherein R.sup.5 is
substituted with a methoxy group.
19. The compound according to claim 15, wherein W is --O--.
20. The compound according to claim 19, wherein R.sup.5 is methyl
substituted with a thiazolyl group.
21. The compound according to claim 1, wherein R.sup.6 is selected
from the group consisting of alkyl, hydroxyalkyl, and
cycloalkyl.
22. The compound according to claim 21, wherein R.sup.6 is lower
alkyl selected from the group consisting of methyl, ethyl, propyl,
or butyl.
23. The compound according to claim 22, wherein R.sup.6 is
tert-butyl or hydroxybutyl.
24. A compound having formula II: 25wherein R.sup.1 is a thiazolyl
group having the formula 26and R.sup.2 is a group having the
formula: 27wherein R.sup.3 is selected from the group consisting of
hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl;
and X is --C(O)-- or --S(O).sub.2--; R.sup.8 is alkyl, aryl,
(aryl)alkyl, alkylamino, dialkylamino, heterocyclic,
(heterocyclic)alkyl, heteroaryl,or (heteroaryl)alkyl; R.sup.9 is
alkyl, cycloalkyl, aryl, (aryl)alkyl, heterocyclic,
(heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl; and Z is
--O--, --S--, --CH.sub.2-- or --N(R.sup.7)-- wherein R.sup.7 is
hydrogen, alkyl, aryl, (aryl)alkyl, heterocyclic, heteroaryl, or
(heteroaryl)alkyl; wherein the alkyl, aryl, heterocyclic, and
heteroaryl groups can be optionally substituted with 1 to 5
substituents selected from the group consisting of hydroxy, alkoxy,
alkylthio, amino, alkylamino, dialkylamino and halogen; or a
pharmaceutically acceptable salt, ester or prodrug thereof.
25. The compound according to claim 24, wherein R.sup.3 is alkyl or
cycloalkyl and Z is --O--, or --N(R.sup.7)--.
26. The compound according to claim 25, wherein R.sup.3 is
alkyl.
27. The compound according to claim 25, wherein R.sup.3 is
cycloalkyl selected from the group consisting of cyclopropyl,
cyclobutyl, cyclopentyl, and cyclohexyl.
28. The compound according to claim 26, wherein R.sup.3 is selected
from the group consisting of hydrogen, methyl, ethyl, or
propyl.
29. The compound according to claim 27, wherein R.sup.3 is
isopropyl.
30. The compound according to claim 25, wherein Z is --O--.
31. The compound according to claim 25, wherein Z is --N(R.sup.7)--
and R.sup.7 is methyl.
32. The compound according to claim 24, wherein R.sup.8 is selected
from the group consisting of alkyl, aryl, (aryl)alkyl, alkylamino,
dialkylamino, or heteroaryl.
33. The compound according to claim 24, wherein X is
--S(O).sub.2--; R.sup.8 is aryl selected from the group consisting
of phenyl, and heteroaryl; and R.sup.9 is lower alkyl.
34. The compound according to claim 24, wherein R.sup.9 is selected
from the group consisting of isopropyl, isobutyl, or
3-methyl-1-butyl.
35. The compound according to claim 34, wherein R.sup.9 is
iso-butyl.
36. The compound according to claim 32, wherein R.sup.8 is
substituted with 1 to 3 amino groups.
37. The compound selected from the group consisting of
2-(1-methylethyl)-4-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-4-(1,3-ben-
zodioxol-5-ylmethyl)-2-(((1,1-dimethylethyl)amino)carbonyl)-1-piperazinyl)-
-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate-
;
2-(1-methylethyl)-4-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-2-(((1,1--
dimethylethyl)amino)carbonyl)-4-(phenylmethyl)-1-piperazinyl)-2-hydroxy-1--
(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;
2-(1-methylethyl)-4-thiazolylmethyl-(1S)-1-((((1S,2R)-3-((2S)-2-(((1,1-di-
methylethyl)amino)carbonyl)-4-((4-fluorophenyl)methyl)-1-piperazinyl)-2-hy-
droxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;
2-(1-methylethyl)-4-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-2-(((1,1-d-
imethylethyl)amino)carbonyl)-4-(5-thienylmethyl)-1-piperazinyl)-2-hydroxy--
1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;
2-(1-methylethyl)-4-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-2-(((1,1-d-
imethylethyl)amino)carbonyl)-4-(4-(3-hydroxyphenyl)methyl)-1-piperazinyl)--
2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;
2-(1-methylethyl)-4-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-2-(((1,1-d-
imethylethyl)amino)carbonyl)-4-(3-pyridinylmethyl)-1-piperazinyl)-2-hydrox-
y-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;
2-(1-methylethyl)-4-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-2-(((1,1-d-
imethylethyl)amino)carbonyl)-4-(4-pyridinylmethyl)-1-piperazinyl)-2-hydrox-
y-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;
2-(1-methylethyl)-4-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-2-(((1,1-d-
imethylethyl)amino)carbonyl)-4-((4-hydroxyphenyl)methyl)-1-piperazinyl)-2--
hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;
2-(1-methylethyl)-4-thiazolylmethyl-(1S)-1-((((1S,2R)-3-((2S)-4-(1H-benzi-
midiazol-2-ylmethyl)-2-(((1,1-dimethylethyl)amino)carbonyl)-1-piperazinyl)-
-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate-
;
2-(1-methylethyl)-4-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-2-(((1,1--
dimethylethyl)amino)carbonyl)-4-(2-quinolinylmethyl)-1-piperazinyl)-2-hydr-
oxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;
2-(1-methylethyl)-4-thiazolylmethyl
((1S)-1-((((1S,2R)-3-((2S)-4-((3,4-di-
methoxylphenyl)methyl)-2-(((1,1-dimethylethyl)amino)carbonyl)-1-piperaziny-
l)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbama-
te;
N'-((1S)-1-((((1S,2R)-3-((2S)-2-(((1,1-dimethylethyl)amino)carbonyl)-4-
-(5-thiazolylmethyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino-
)carbonyl)-2-methylpropyl)-N-methyl-N-(2-(1-methylethyl)-4-thiazolylmethyl-
)urea;
N'-((1S)-1-((((1S,2R)-3-((2S)-2-(((1,1-dimethylethyl)amino)carbonyl-
)-4-(phenylmethyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)c-
arbonyl)-2-methylpropyl)-N-methyl-N-(2-(1-methylethyl)-4-thiazolylmethyl)u-
rea;
N'-((1S)-1-((((1S,2R)-3-((2S)-2-(((1,1-dimethylethyl)amino)carbonyl)--
4-((4-hydroxy-3-methoxyphenyl)methyl)-1-piperazinyl)-2-hydroxy-1-(phenylme-
thyl)propyl)amino)carbonyl)-2-methylpropyl)-N-methyl-N-(2-(1-methylethyl)--
4-thiazolylmethyl)urea;
2-methyl-4-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((-
2S)-4-(1,3-benzodioxol-5-ylmethyl)-2-(((1,1-dimethylethyl)amino)carbonyl)--
1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpr-
opyl)carbamate;
2-methyl-4-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-4-((-
3,4-dimethoxylphenyl)methyl)-2-(((1,1-dimethylethyl)amino)carbonyl)-1-pipe-
razinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)c-
arbamate;
2-methyl-4-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-2-(((1,1-d-
imethylethyl)amino)carbonyl)-4-((4-fluorophenyl)methyl)-1-piperazinyl)-2-h-
ydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;
2-ethyl-4-thiazolylmethyl-(1S)-1-((((1S,2R)-3-((2S)-4-((3,4-dimethoxylphe-
nyl)methyl)-2-(((1,1-dimethylethyl)amino)carbonyl)-1-piperazinyl)-2-hydrox-
y-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;
2-(1-methylethyl)-5-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-4-((3,4-di-
methoxylphenyl)methyl)-2-(((1,1-dimethylethyl)amino)carbonyl)-1-piperaziny-
l)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbama-
te;
2-ethyl-5-thiazolylmethyl-(1S)-1-((((1S,2R)-3-((2S)-4-((3,4-dimethoxyl-
phenyl)methyl)-2-(((1,1-dimethylethyl)amino)carbonyl)-1-piperazinyl)-2-hyd-
roxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;
2-methyl-5-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-4-((3,4-dimethoxylp-
henyl)methyl)-2-(((1,1-dimethylethyl)amino)carbonyl)-1-piperazinyl)-2-hydr-
oxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;
N'-((1R)-1-((((1S,2R)-3-((2S)-2-(((1,1-dimethylethyl)amino)carbonyl)-4-(5-
-thiazolylmethyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)ca-
rbonyl)-2-methylpropyl)-N-methyl-N-(5-thiazolylmethyl)urea;
N'-((1S)-1-((((1S,2R)-3-((2S)-2-(((1,1-dimethylethyl)amino)carbonyl)-4-(5-
-thiazolylmethyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)ca-
rbonyl)-2-methylpropyl)-N-methyl-N-(5-thiazolylmethyl)urea;
5-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-2-(((1,1-dimethylethyl)amino-
)carbonyl)-4-(phenylmethyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propy-
l)amino)carbonyl)-2-methylpropyl)carbamate;
5-thiazolylmethyl-(1S)-1-((((1-
S,2R)-3-((2S)-2-(((1,1-dimethylethyl)amino)carbonyl)-4-(5-thiazolylmethyl)-
-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylp-
ropyl)carbamate;
N'-((1S)-1-((((1S,2R)-3-((((1,1-dimethylethyl)amino)carbo-
nyl)(2-methylethyl)propylamino)-2-hydroxy-1-(phenylmethyl)propyl)amino)car-
bonyl)-2-methylpropyl)-N-methyl-N-(2-(1-methylethyl)-4-thiazolylmethyl)ure-
a;
2-(1-methylethyl)-4-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((((1,1-dimeth-
ylethyl)amino)carbonyl)(2-methylethyl)propylamino)-2-hydroxy-1-(phenylmeth-
yl)propyl)amino)carbonyl)-2-methylpropyl)carbamate;
2-(1-methylethyl)-4-thiazolylmethyl-(1S)-1-((((1S,2R)-3-(((4-aminophenyl)-
sulfonyl)(1-methylethyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)amino)carb-
onyl)-2-methylpropyl)carbamate;
N'-((1S)-1-((((1S,2R)-3-(((4-aminophenyl)s-
ulfonyl)(1-methylethyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbo-
nyl)-2-methylpropyl)-N-methyl-N-(2-(1-methylethyl)-4-thiazolylmethyl)urea;
2-(1-methylethyl)-5-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((3S)-3-(((1,1-d-
imethylethyl)amino)carbonyl)(4a.alpha.,8a.alpha.)octahydro-2-isoquinolinyl-
)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamat-
e;
N'-((1S)-1-((((1S,2R)-3-((3S)-3-(((1,1-dimethylethyl)amino)carbonyl)(4a-
.alpha.,8a.alpha.)octahydro-2-isoquinolinyl)-2-hydroxy-1-(phenylmethyl)pro-
pyl)amino)carbonyl)-2-methylpropyl)-N-methyl-N-(2-(1-methylethyl)-5-thiazo-
lylmethyl)urea,
N'-((1S)-1-((((1S,2R)-3-((2S,4R)-2-(((1,1-dimethylethyl)am-
ino)carbonyl)-4-(5-thiazolylmethoxy)-1-piperidinyl)-2-hydroxy-1-(phenylmet-
hyl)propyl)amino)carbonyl)-2-methylpropyl)-N-methyl-N-(2-(1-methylethyl)-4-
-thiazolylmethyl)urea; 2-(1-methylethyl)-4-thiazolylmethyl
((1S)-1-((((1S,2R)-3-((2S,4R)-2-(((1,1-dimethylethyl)amino)carbonyl)-4-(5-
-thiazolylmethoxy)-1-piperidinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)c-
arbonyl)-2-methylpropyl)carbamate;
S-(2-(1-methylethyl)-4-thiazolylmethyl)
((1S)-1-((((1S,2R)-3-((2S)-4-(1,3-benzodioxol-5-ylmethyl)-2-(((1,1-dimeth-
ylethyl)amino)carbonyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)am-
ino)carbonyl)-2-methylpropyl)carbamothioate; and
4-(1,3-benzodioxol-5-ylme-
thyl)-N-(1,1-dimethylethyl)-1-((2R,3S)-3-(((2S)-2-((3-(2-(1-methylethyl)-4-
-thiazolyl)-1-oxopropyl)amino)-3-methyl-1-oxobutyl)amino)-2-hydroxy-4-phen-
ylbutyl)-2-piperazinecarboxamide; or a pharmaceutically acceptable
salt, ester or prodrug thereof.
38. The compound according to claim 37, selected from the group
consisting of:
2-(1-Methylethyl)-4-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((2S)-4-(1,3-
-benzodioxol-5-ylmethyl)-2-(((1,1-dimethylethyl)amino)carbonyl)-1-piperazi-
nyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carba-
mate;
2-(1-Methylethyl)-4-thiazolylmethyl-(1S)-1-((((1S,2R)-3-(((4-aminoph-
enyl)sulfonyl)(1-methylethyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)amino-
)carbonyl)-2-methylpropyl)carbamate;
2-(1-Methylethyl)-4-thiazolylmethyl-(-
(1S)-1-((((1S,2R)-3-((2S)-2-(((1,1-dimethylethyl)amino)carbonyl)-4-(5-thie-
nylmethyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-
-2-methylpropyl)carbamate; 2-(1-Methylethyl)-4-thiazolylmethyl
((1S)-1-((((1S,2R)-3-((2S)-4-((3,4-dimethoxylphenyl)methyl)-2-(((1,1-dime-
thylethyl)amino)carbonyl)-1-piperazinyl)-2-hydroxy-1-(phenylmethyl)propyl)-
amino)carbonyl)-2-methylpropyl)carbamate;
N'-((1S)-1-((((1S,2R)-3-((2S,4R)-
-2-(((1,1-Dimethylethyl)amino)carbonyl)-4-(5-thiazolylmethoxy)-1-piperidin-
yl)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)-N-met-
hyl-N-(2-(1-methylethyl)-4-thiazolylmethyl)urea; and
2-(1-Methylethyl)-5-thiazolylmethyl-((1S)-1-((((1S,2R)-3-((3S)-3-(((1,1-d-
imethylethyl)amino)carbonyl)(4a.alpha.,8a.alpha.)octahydro-2-isoquinolinyl-
)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-2-methylpropyl)carbamat-
e; or a pharmaceutically acceptable salt, ester or prodrug
thereof.
39. A pharmaceutical composition for treating an HIV infection
comprising a pharmaceutical carrier and a therapeutically effective
amount of a compound of claim 1.
40. A pharmaceutical composition for treating an HIV infection
comprising a pharmaceutical carrier and a therapeutically effective
amount of a compound of claim 24.
41. A method for inhibiting HIV protease comprising administering
to a mammal in need of such treatment a therapeutically effective
amount of a compound of claim 1.
42. A method for treating an HIV infection comprising administering
to a mammal in need of such treatment a therapeutically effective
amount of a compound of claim 24.
43. A pharmaceutical composition for treating an HIV infection
comprising a pharmaceutical carrier and a therapeutically effective
amount of a compound of claim 9.
44. A pharmaceutical composition for treating an HIV infection
comprising a pharmaceutical carrier and a therapeutically effective
amount of a compound of claim 20.
45. A pharmaceutical composition for treating an HIV infection
comprising a pharmaceutical carrier and a therapeutically effective
amount of a compound of claim 36.
46. A process for the preparation of a compound of the formula I:
28wherein R.sup.1 is a thiazolyl group having the formula 29and
R.sup.2 is a group having the formula: 30wherein R.sup.3 is
selected from the group consisting of hydrogen, alkyl, amino,
alkylamino, dialkylamino and cycloalkyl; and Y is CH or N; R.sup.4
is --W--R.sup.5; W is --O--, --S--, or --(CH.sub.2).sub.n--; and
R.sup.5 is selected from the group consisting of alkyl, and aryl; n
is from 0 to 6; or R.sup.4 and the ring taken together can form a
bicyclic group having the formula: 31with the proviso that when W
is O, or S then Y is CH; R.sup.6 is hydrogen, alkyl, cycloalkyl,
aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl,
(heterocyclic)alkyl, heteroaryl,or (heteroaryl)alkyl; and Z is
--O--, --S--, --CH.sub.2-- or --N(R.sup.7)--; and R.sup.7 is
hydrogen, alkyl, aryl, (aryl)alkyl, heterocyclic, heteroaryl, or
(heteroaryl)alkyl; wherein the alkyl, aryl, heterocyclic, and
heteroaryl groups can be optionally substituted with 1 to 5
substituents selected from the group consisting of hydroxy, alkoxy,
alkylthio, amino, alkylamino, dialkylamino and halogen.
47. A process for the preparation of a compound of the formula II:
32wherein R.sup.1 is a thiazolyl group having the formula 33and
R.sup.2 is a group having the formula: 34wherein R.sup.3 is
selected from the group consisting of hydrogen, alkyl, amino,
alkylamino, dialkylamino and cycloalkyl; and X is --C(O)-- or
--S(O).sub.2--; R.sup.8 is alkyl, aryl, (aryl)alkyl, alkylamino,
dialkylamino, heterocyclic, (heterocyclic)alkyl, heteroaryl,or
(heteroaryl)alkyl; R.sup.9 is alkyl, cycloalkyl, aryl, (aryl)alkyl,
heterocyclic, (heterocyclic)alkyl, heteroaryl, or
(heteroaryl)alkyl; and Z is --O--, --S--, --CH.sub.2-- or
--N(R.sup.7)-- wherein R.sup.7 is hydrogen, alkyl, aryl,
(aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl, or
(heteroaryl)alkyl; wherein the alkyl, aryl, heterocyclic, and
heteroaryl groups can be optionally substituted with 1 to 5
substituents selected from the group consisting of hydroxy, alkoxy,
alkylthio, amino, alkylamino, dialkylamino and halogen.
Description
[0001] This application claims the benefit of U.S Provisional
Application for Patent No. 60/085,709, filed May 15, 1998.
TECHNICAL FIELD
[0002] The present invention relates to novel compounds
compositions and methods for inhibiting retroviral proteases and in
particular for inhibiting human immunodeficiency virus (HIV)
protease. The present invention also relates to compositions and
methods for treating a retroviral infection and in particular an
HIV infection, and to processes for making such compounds and
synthetic intermediates employed in these processes.
BACKGROUND OF THE INVENTION
[0003] Retroviruses are those viruses which utilize a ribonucleic
acid (RNA) intermediate and a RNA-dependent deoxyribonucleic acid
(DNA) polymerase, reverse transcriptase, during their life cycle.
Retroviruses include, but are not limited to, the RNA viruses of
the Retroviridae family, and also the DNA viruses of the
Hepadnavirus and Caulimovirus families. Retroviruses cause a
variety of disease states in man, animals and plants. Some of the
more important retroviruses from a pathological standpoint include
human immunodeficiency viruses (HIV-1 and HIV-2), which cause
acquired immune deficiency syndrome (AIDS) in man, hepatitis B
virus, which causes hepatitis and hepatic carcinomas in man, human
T-cell lymphotrophic viruses I, II, IV and V, which cause human
acute cell leukemia, and bovine and feline leukemia viruses which
cause leukemia in domestic animals.
[0004] Proteases are enzymes which cleave proteins at specific
peptide bonds. Many biological functions are controlled or mediated
by proteases and their complementary protease inhibitors. For
example, the protease renin cleaves the peptide angiotensinogen to
produce the peptide angiotensin I. Angiotensin I is further cleaved
by the protease angiotensin converting enzyme (ACE) to form the
hypotensive peptide angiotensin II. Inhibitors of renin and ACE are
known to reduce high blood pressure in vivo. An inhibitor of a
retroviral protease will provide a therapeutic agent for diseases
caused by the retrovirus.
[0005] The genomes of retroviruses encode a protease that is
responsible for the proteolytic processing of one or more
polyprotein precursors such as the pol and gag gene products. See
Wellink, Arch. Virol. 98 1 (1988). Retroviral proteases most
commonly process the gag precursor into core proteins, and also
process the pol precursor into reverse transciptase and retroviral
protease. In addition, retroviral proteases are sequence specific.
See Pearl, Nature 328 482 (1987).
[0006] The correct processing of the precursor polyproteins by the
retroviral protease is necessary for the assembly of infectious
virions. It has been shown that in vitro mutagenesis that produces
protease-defective virus leads to the production of immature core
forms which lack infectivity. See Crawford, J. Virol. 53 899
(1985); Katoh, et al., Virology 145 280 (1985). Therefore,
retroviral protease inhibition provides an attractive target for
antiviral therapy. See Mitsuya, Nature 325 775 (1987).
[0007] Current treatments for viral diseases usually involve
administration of compounds that inhibit viral DNA synthesis.
Current treatments for AIDS involve administration of compounds
such as 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxycytidine
(DDC) and 2',3'-dideoxyinosine (DDI) and compounds which treat the
opportunistic infections caused by the immunosuppression resulting
from HIV infection. None of the current AIDS treatments have proven
to be totally effective in treating and/or reversing the disease.
In addition, many of the compounds currently used to treat AIDS
cause adverse side effects including low platelet count, renal
toxicity and bone marrow cytopenia.
[0008] Recently the HIV protease inhibitors ritonavir, saquinavir,
nelfinavir, and indinavir have been approved in the U.S. for
treatment of HIV infections. However, there is a continuing need
for improved HIV protease inhibitors.
SUMMARY OF THE INVENTION
[0009] The present invention comprises retroviral protease
inhibiting compounds having formula I: 1
[0010] wherein R.sup.1 is a thiazolyl group having the formula
2
[0011] and R.sup.2 is a group having the formula: 3
[0012] wherein R.sup.4 group is --WR.sup.5.
[0013] The R.sup.3 group is selected from the group consisting of
hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl,
and Y is CH or N. W is selected from the group consisting of --O--,
--S--, or --(CH.sub.2).sub.n--, where n is from 0 to 6, with the
proviso that when W is O, or S then Y is CH. R.sup.5 is selected
from the group consisting of alkyl, and aryl. Optionally, R.sup.4
and the ring to which it is attached, taken together can form a
bicyclic group having the formula: 4
[0014] The R.sup.6 group is hydrogen, alkyl, cycloalkyl, aryl,
(aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl, or
(heteroaryl)alkyl, Z is --O--, --S--, --CH.sub.2-- or
--N(R.sup.7)--; and R.sup.7 is hydrogen, alkyl, aryl, (aryl)alkyl,
heterocyclic, (heterocyclic)alkyl, heteroaryl, or
(heteroaryl)alkyl.
[0015] The present invention also comprises retroviral protease
inhibiting compounds having formula II: 5
[0016] wherein R.sup.1 is a thiazolyl group having the formula
6
[0017] and R.sup.2 is a group having the formula: 7
[0018] wherein X is --C(O)-- or --S(O).sub.2-- and R.sup.8 is
alkyl, aryl, (aryl)alkyl, alkylamino, dialkylamino, heterocyclic,
(heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl.
[0019] R.sup.3 is selected from the group consisting of hydrogen,
alkyl, amino, alkylamino, dialkylamino and cycloalkyl and R.sup.9
is alkyl, cycloalkyl, aryl, (aryl)alkyl, heterocyclic,
(heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl. The Z group
is --O--, --S--, --CH.sub.2-- or --N(R.sup.7)--, and R.sup.7 is
hydrogen, alkyl, aryl, (aryl)alkyl, heterocyclic,
(heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl.
[0020] The alkyl, aryl, heterocyclic, and heteroaryl groups in the
compounds of the invention can be optionally substituted with from
1 to 5 substituents and preferrably from 1 to 3 substituents. The
substituents are selected from the group consisting of hydroxy,
alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen. The
invention also includes pharmaceutically acceptable salts, esters
or prodrugs of compounds I and II.
DETAILED DESCRIPTION OF THE INVENTION
[0021] All patents, patent applications, and literature references
cited in the specification are hereby incorporated by reference in
their entirety. In the case of inconsistencies, the present
disclosure, including definitions, will prevail.
[0022] The present invention comprises retroviral protease
inhibiting compounds having formula I: 8
[0023] wherein R.sup.1 is a thiazolyl group having the formula
9
[0024] and R.sup.2 is a group having the formula: 10
[0025] wherein R.sup.4 group is --WR.sup.5.
[0026] The R.sup.3 group is selected from the group consisting of
hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl,
and Y is CH or N. W is selected from the group consisting of --O--,
--S--, or --(CH.sub.2).sub.n--, where n is from 0 to 6, with the
proviso that when W is O, or S then Y is CH. R.sup.5 is selected
from the group consisting of alkyl, and aryl. Optionally, R.sup.4
and the ring to which it is attached, taken together can form a
bicyclic group having the formula: 11
[0027] with the proviso that when W is O, or S then Y is CH. The
R.sup.6 group is hydrogen, alkyl, cycloalkyl, aryl, (aryl)alkyl,
heterocyclic, (heterocyclic)alkyl, heteroaryl, or
(heteroaryl)alkyl, Z is --O--, --S--, --CH.sub.2-- or
--N(R.sup.7)--; and R.sup.7 is hydrogen, alkyl, aryl, (aryl)alkyl,
heterocyclic, (heterocyclic)alkyl, heteroaryl, or
(heteroaryl)alkyl.
[0028] The present invention also comprises retroviral protease
inhibiting compounds having formula II: 12
[0029] wherein R.sup.1 is a thiazolyl group having the formula:
13
[0030] and R.sup.2 is a group having the formula: 14
[0031] wherein X is --C(O)-- or --S(O).sub.2-- and R.sup.8 is
alkyl, aryl, (aryl)alkyl, alkylamino, dialkylamino, heterocyclic,
(heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl.
[0032] R.sup.3 is selected from the group consisting of hydrogen,
alkyl, amino, alkylamino, dialkylamino and cycloalkyl and R.sup.9
is alkyl, cycloalkyl, aryl, (aryl)alkyl, heterocyclic, heteroaryl,
or (heteroaryl)alkyl. The Z group is --O--, --S--, --CH.sub.2-- or
--N(R.sup.7)--, and R.sup.7 is hydrogen, alkyl, aryl, (aryl)alkyl,
heterocyclic, (heterocyclic)alkyl, heteroaryl, or
(heteroaryl)alkyl.
[0033] The alkyl, aryl, heteroaryl, and heterocyclic groups of the
compounds of the invention, having formula I or II, can optionally
be substituted with from 1 to 5 substituents and preferrably from 1
to 3 substituents. The substituents are selected from the group
consisting of hydroxy, alkoxy, alkylthio, amino, alkylamino,
dialkylamino and halogen. The invention also includes
pharmaceutically acceptable salts, esters or prodrugs of compounds
I and II.
[0034] In the compounds of the invention, a preferred R.sup.3 group
is alkyl or cycloalkyl. More preferred are compounds where R.sup.3
is alkyl selected from the group consisting of methyl, ethyl, or
propyl or cycloalkyl selected from the group consisting of
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The most
preferred R.sup.3 group is isopropyl.
[0035] The preferred Z groups are --O--, or --N(R.sup.7)--. When Z
is --N(R.sup.7)-- a preferred R.sup.7 is methyl.
[0036] In compounds having formula I, and R.sup.2 is a group having
the formula: 15
[0037] wherein Y is CH or N and R.sup.4 is --W--R.sup.5, the
preferred R.sup.5 group is aryl selected from the group consisting
of phenyl, methylenedioxyphenyl, and heteroaryl. In compounds where
Y is nitrogen, W is --(CH.sub.2).sub.n--, R.sup.5 is alkyl or aryl
and n is from 0 to 6.
[0038] In compounds where Y is CH, a preferred W is --O--, and
preferably, R.sup.5 is alkyl, or aryl selected from the group
consisting of phenyl, methylenedioxyphenyl, and heteroaryl.
[0039] The alkyl, aryl, heterocyclic, and heteroaryl groups can be
substituted with from 1 to 5 substituents and preferrably from 1 to
3 substituents.
[0040] Examples of substituents, for the alkyl, aryl, heterocyclic,
and heteroaryl groups, are selected from the group consisting of
hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and
halogen. Preferred substituents are fluorine, hydroxy, alkoxy, or
alkylthio groups. The preferred alkoxy is methoxy. The preferred
halogen is fluorine
[0041] In a preferred embodiment the alkyl or aryl groups can be
substituted with one to three groups. The preferred substituents
are hydroxy, methoxy or fluorine. The preferred aryl groups include
phenyl, such as, for example, methylenedioxyphenyl, and heteroaryl
such as, for example, furanyl, thienyl, benzothienyl, thiazolyl and
the like. A preferred heteroaryl group is thiazolyl. In a preferred
compound n is zero, and R.sup.5 is methyl substituted with a
thiazolyl group.
[0042] The R.sup.6 group is selected from the group consisting of
alkyl, hydroxyalkyl, and cycloalkyl. Preferably R.sup.6 is lower
alkyl group such as, for example, methyl, ethyl, propyl, butyl and
the like. A preferred R.sup.6 group is tert-butyl or
hydroxy-butyl.
[0043] The R.sup.8 group is selected from the group consisting of
alkyl, aryl, (aryl)alkyl, alkylamino, dialkylamino, heterocyclic,
(heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl. A preferred
R.sup.8 group is (alkyl)amino, such as, for example,
(tertbutyl)amino.
[0044] The preferred R.sup.9 group is a lower alkyl group such as,
for example propyl, butyl, pentyl and the like. More preferred
R.sup.9 groups are isopropyl, tert-butyl, isobutyl,
3-methyl-1-butyl, and the like. Most preferred is the iso-butyl
group.
[0045] In a preferred compound of the invention X is
--S(O).sub.2--, R.sup.8 is aryl selected from the group consisting
of phenyl, and heteroaryl and R.sup.9 is iso-butyl.
[0046] In the compounds of the invention, combinations of
substituents and/or variables are permissible only if such
combinations result in stable compounds. As used herein, the term
"stable compound" refers to a compound that is sufficiently stable
to survive isolation to a useful degree of purity from a reaction
mixture and formulation into a therapeutic dosage form suitable for
administration.
[0047] Preferred compounds of the invention are selected from the
group consisting of:
[0048] 2-(1-methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R
)-3-[(2S)-4-(1,3-benzodioxol-5-ylmethyl)-2-[[(1,1-dimethylethyl)amino]car-
bonyl]-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-m-
ethylpropyl]carbamate;
[0049]
2-(1-methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[-
-(1,1-dimethylethyl)amino]carbonyl]-4-(phenylmethyl)-1-piperazinyl]-2-hydr-
oxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate;
[0050]
2-(1-methylethyl)-4-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(-
1,1-dimethylethyl)amino]carbonyl]-4-[(4-fluorophenyl)methyl]-1-piperazinyl-
]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamat-
e;
[0051]
2-(1-methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[-
(1,1-dimethylethyl)amino]carbonyl]-4-(5-thienylmethyl)-1-piperazinyl]-2-hy-
droxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate;
[0052]
2-(1-methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[-
(1,1-dimethylethyl)amino]carbonyl]-4-[4-(3-hydroxyphenyl)methyl]-1-piperaz-
inyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carb-
amate;
[0053]
2-(1-methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[-
(1,1-dimethylethyl)amino]carbonyl]-4-(3-pyridinylmethyl)-1-piperazinyl]-2--
hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate;
[0054]
2-(1-methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[-
(1,1-dimethylethyl)amino]carbonyl]-4-(4-pyridinylmethyl)-1-piperazinyl]-2--
hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate;
[0055]
2-(1-methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[-
(1,1-dimethylethyl)amino]carbonyl]-4-[(4-hydroxyphenyl)methyl]-1-piperazin-
yl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbam-
ate;
[0056]
2-(1-methylethyl)-4-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[(2S)-4-(1H-
-benzimidiazol-2-ylmethyl)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-pipera-
zinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]car-
bamate;
[0057]
2-(1-methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[-
(1,1-dimethylethyl)amino]carbonyl]-4-(2-quinolinylmethyl)-1-piperazinyl]-2-
-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate;
[0058] 2-(1-methylethyl)-4-thiazolylmethyl
[(1S)-1-[[[(1S,2R)-3-[(2S)-4-[(-
3,4-dimethoxylphenyl)methyl]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-pipe-
razinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]c-
arbamate;
[0059]
N'-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-dimethylethyl)amino]carbonyl-
]-4-(5-thiazolylmethyl)-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)propyl]am-
ino]carbonyl]-2-methylpropyl]-N-methyl-N-[2-(1-methylethyl)-4-thiazolylmet-
hyl]urea;
[0060]
N'-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-dimethylethyl)amino]carbonyl-
]-4-(phenylmethyl)-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]c-
arbonyl]-2-methylpropyl]-N-methyl-N-[2-(1-methylethyl)-4-thiazolylmethyl]u-
rea;
[0061]
N'-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-dimethylethyl)amino]carbonyl-
]-4-[4-hydroxy-3-methoxyphenyl)methyl]-1-piperazinyl]-2-hydroxy-1-(phenylm-
ethyl)propyl]amino]carbonyl]-2-methylpropyl]-N-methyl-N-[2-(1-methylethyl)-
-4-thiazolylmethyl]-urea;
[0062]
2-methyl-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-4-(1,3-benzod-
ioxol-5-ylmethyl)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-2--
hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate;
[0063]
2-methyl-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-4-[(3,4-dimet-
hoxylphenyl)methyl]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]--
2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate;
[0064]
2-methyl-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-dime-
thylethyl)amino]carbonyl]-4-[(4-fluorophenyl)methyl]-1-piperazinyl]-2-hydr-
oxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate;
[0065]
2-ethyl-4-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[(2S)-4-[(3,4-dimetho-
xylphenyl)methyl]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-2--
hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate;
[0066]
2-(1-methylethyl)-5-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-4-[(-
3,4-dimethoxylphenyl)methyl]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-pipe-
razinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]c-
arbamate;
[0067]
2-ethyl-5-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[(2S)-4-[(3,4-(dimeth-
oxylphenyl)methyl]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-2-
-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate;
[0068]
2-methyl-5-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-4-[(3,4-dimet-
hoxylphenyl)methyl]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]--
2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate;
[0069]
N'-[(1R)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-dimethylethyl)amino]carbonyl-
]-4-(5-thiazolylmethyl)-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)propyl]am-
ino]carbonyl]-2-methylpropyl-9
-N-methyl-N-(5-thiazolylmethyl)urea;
[0070]
N'-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-dimethylethyl)amino]carbonyl-
]-4-(5-thiazolylmethyl)-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)propyl]am-
ino]carbonyl]-2-methylpropyl]-N-methyl-N-(5-thiazolylmethyl)urea;
[0071]
5-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-dimethylethyl-
)amino]carbonyl]-4-(phenylmethyl)-1-piperazinyl]-2-hydroxy-1-(phenylmethyl-
)propyl]amino]carbonyl]-2-methylpropyl]carbamate;
[0072]
5-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-dimethylethyl)-
amino]carbonyl]-4-(5-thiazolylmethyl)-1-piperazinyl]-2-hydroxy-1-(phenylme-
thyl)propyl]amino]carbonyl]-2-methylpropyl]-carbamate;
[0073]
N'-[(1S)-1-[[[(1S,2R)-3-[[[(1,1-dimethylethyl)amino]carbonyl](2-met-
hylethyl)propylamino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-m-
ethylpropyl]-N-methyl-N-[2-(1-methylethyl)-4-thiazolylmethyl]urea;
[0074]
2-(1-methylethyl)-4-thiazolylmnethyl-[(1S)-1-[[[(1S,2R)-3-[[[(1,1-d-
imethylethyl)amino]carbonyl](2-methylethyl)propylamino]-2-hydroxy-1-(pheny-
lmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate;
[0075]
2-(1-methylethyl)-4-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[[(4-aminop-
henyl)sulfonyl](1-methylethyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]amin-
o]carbonyl]-2-methylpropyl]carbamate;
[0076]
N'-[(1S)-1-[[[(1S,2R)-3-[[(4-aminophenyl)sulfonyl](1-methylethyl)am-
ino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]-N-me-
thyl-N-[2-(1-methylethyl)-4-thiazolylmethyl]urea;
[0077]
2-(1-methylethyl)-5-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(3S)-3-[[-
(1,1-dimethylethyl)amino]carbonyl](4a.alpha.,8a.alpha.)octahydro-2-isoquin-
olinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]ca-
rbamate;
[0078]
N'-[(1S)-1-[[[(1S,2R)-3-[(3S)-3-[[(1,1-dimethylethyl)amino]carbonyl-
](4a.alpha.,8a.alpha.)octahydro-2-isoquinolinyl]-2-hydroxy-1-(phenylmethyl-
)propyl]amino]carbonyl]-2-methylpropyl]-N-methyl-N-[2-(1-methylethyl)-5-th-
iazolylmethyl]urea,
[0079]
N'-[(1S)-1-[[[(1S,2R)-3-[(2S,4R)-2-[[(1,1-dimethylethyl)amino]carbo-
nyl]-4-(5-thiazolylmethoxy)-1-piperidinyl]-2-hydroxy-1-(phenylmethyl)propy-
l]amino]carbonyl]-2-methylpropyl]-N-methyl-N-[2-(1-methylethyl)-4-thiazoly-
lmethyl]urea;
[0080] 2-(1-methylethyl)-4-thiazolylmethyl
[(1S)-1-[[[(1S,2R)-3-[(2S,4R)-2-
-[[(1,1-dimethylethyl)amino]carbonyl]-4-(5-thiazolylmethoxy)-1-piperidinyl-
]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamat-
e;
[0081] S-[2-(1-methylethyl)-4-thiazolylmethyl]
[(1S)-1-[[[(1S,2R)-3-[(2S)--
4-(1,3-benzodioxol-5-ylmethyl)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-pi-
perazinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl-
]-carbamothioate; and
[0082]
4-(1,3-benzodioxol-5-ylmethyl)-N-(1,1-dimethylethyl)-1-[(2R,3S)-3-[-
[(2S)-2-[[3-[2-(1-methylethyl)-4-thiazolyl]-1-oxopropyl]amino]-3-methyl-1--
oxobutyl]amino]-2-hydroxy-4-phenylbutyl]-2-piperazinecarboxamide;
[0083] or a pharmaceutically acceptable salt, ester or prodrug
thereof.
[0084] Most preferred compounds of the invention are selected from
the group consisting of:
[0085]
2-(1-Methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-4-(1-
,3-benzodioxol-5-ylmethyl)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-pipera-
zinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]car-
bamate;
[0086]
2-(1-Methylethyl)-4-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[[(4-aminop-
henyl)sulfonyl](1-methylethyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]amin-
o]carbonyl]-2-methylpropyl]carbamate;
[0087]
2-(1-Methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[-
(1,1-dimethylethyl)amino]carbonyl]-4-(5-thienylmethyl)-1-piperazinyl]-2-hy-
droxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate;
[0088] 2-(1-Methylethyl)-4-thiazolylmethyl
[(1S)-1-[[[(1S,2R)-3-[(2S)-4-[(-
3,4-dimethoxylphenyl)methyl]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-pipe-
razinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]c-
arbamate;
[0089]
N'-[(1S)-1[[[(1S,2R)-3-[(2S,4R)-2-[[(1,1-Dimethylethyl)amino]carbon-
yl]-4-(5-thiazolylmethoxy)-1-piperidinyl]-2-hydroxy-1-(phenylmethyl)propyl-
]amino]carbonyl]-2-methylpropyl]-N-methyl-N-[2-(1-methylethyl)-4-thiazolyl-
methyl]urea; and
[0090]
2-(1-Methylethyl)-5-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(3S)-3-[[-
(1,1-dimethylethyl)amino]carbonyl](4a.alpha.,8a.alpha.)octahydro-2-isoquin-
olinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]ca-
rbamate;
[0091] or a pharmaceutically acceptable salt, ester or prodrug
thereof.
[0092] The term "alkyl" as used herein refers to straight or
branched chain alkyl radicals containing from 1 to 12 carbon atoms.
The term "lower alkyl" refers to straight or branched chain alkyl
radicals containing from 1 to 6 carbon atoms including, but not
limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, sec-butyl, t-butyl n-pentyl, 1-methylbutyl,
2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, and
the like. The alkyl groups can be unsubstituted or substituted with
from one to five substituents independently selected from hydroxy,
alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen. The
alkyl groups can be optionally interrupted by one or more
heteroatoms selected from the group consisting of oxygen, nitrogen,
sulfur, and phosphorous.
[0093] The term "cycloalkyl" as used herein refers to an aliphatic
ring system having 3 to 8 carbon atoms including, but not limited
to, cyclopropyl, cyclopentyl, cyclohexyl, and the like.
[0094] The term "alkoxy" as used herein refers to groups having the
formula --OR.sup.10 wherein R.sup.10 is a lower alkyl group.
[0095] The term "thioalkyl" as used herein refers to groups having
the formula --SR.sup.11 wherein R.sup.11 is a lower alkyl
group.
[0096] The term "alkylamino" as used herein refers to groups having
the formula --NHR.sup.12 wherein R.sup.12 is a lower alkyl
group.
[0097] The term "dialkylamino" as used herein refers to groups
having the formula --N(R.sup.13).sub.2 wherein each R.sup.13 is
independently a lower alkyl group.
[0098] The term "halo or halogen" as used herein refers to F, Cl,
Br or I.
[0099] The term "(halo)alkyl" as used herein refers to a lower
alkyl group in which one or more hydrogen atoms has been replaced
with a halogen including, but not limited to, trifluoromethyl,
trichloromethyl, difuoromethyl, dichloromethyl, fluoromethyl,
chloromethyl, chloroethyl, 2,2-dichloroethyl and the like.
[0100] The term "aryl" as used herein refers to a mono- or bicyclic
carbocyclic ring system comprising 6 to 12 carbon atoms and having
one or two aromatic rings including, but not limited to, phenyl,
naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Aryl
groups can be unsubstituted or substituted with from one to five
substituents independently selected from hydroxy, alkoxy,
alkylthio, amino, alkylamino, dialkylamino and halogen.
[0101] The term "(aryl)alkyl" as used herein refers to an aryl
group as previously defined, appended to a lower alkyl radical, for
example, benzyl and the like.
[0102] The term "heterocyclic ring" or "heterocyclic" or
"heterocycle" as used herein refers lo any 3- or 4-membered ring
containing a heteroatom selected from oxygen, nitrogen and sulfur;
or a 5-, 6- or 7-membered ring containing one, two or three
heteroatoms independently selected from the group consisting of
nitrogen, oxygen and sulfur or a 5-membered ring containing 4
nitrogen atoms; and includes a 5-, 6- or 7-membered ring containing
one, two or three nitrogen atoms; one oxygen atom; one sulfur atom;
one nitrogen and one sulfur atom; one nitrogen and one oxygen atom;
two oxygen atoms in non-adjacent positions; one oxygen and one
sulfur atom in non-adjacent positions; two sulfur atoms in
non-adjacent positions; two sulfur atoms in adjacent positions and
one nitrogen atom; two adjacent nitrogen atoms and one sulfur atom;
two non-adjacent nitrogen atoms and one sulfur atom; two
non-adjacent nitrogen atoms and one oxygen atom. The 5-membered
ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3
double bonds. The nitrogen heteroatoms can be optionally
quaternized. The term "heterocyclic" also includes bicyclic groups
in which any of the above heterocyclic rings is fused to a benzene
ring or a cyclohexane ring or another heterocyclic ring (for
example, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl,
benzofuryl, bistetrahydrofuranyl or benzothienyl and the like).
Heterocyclics include: azetidinyl, pyrrolyl, pyrrolinyl,
pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl,
imidazolinyl, imidazolidinyl, pyridyl, piperidinyl,
homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl,
oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl,
thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl,
quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl,
benzoxazolyl, furyl, thienyl, tetrahydrofuranyl, tetrahydrothienyl,
thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl,
oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl.
Heterocyclics also include compounds of the formula: 16
[0103] wherein X* is --CH.sub.2--, --NH-- or --O--, Y* is --C(O)--
or [--C(R").sub.2--].sub.v wherein R" is hydrogen or
C.sub.1-C.sub.4-alkyl and v is 1, 2 or 3 and Z* is --O-- or --NH--;
such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like.
[0104] The term "methylenedioxyphenyl" refers to a substituent
having the formula: 17
[0105] Heterocyclic groups can be unsubstituted or substituted with
from one to five substituents independently selected from hydroxy,
alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen. In
addition, nitrogen containing heterocycles can be N-protected.
[0106] The term "(heterocyclic)alkyl" as used herein refers to a
heterocyclic group appended to a lower alkyl radical including, but
not limited to, pyrrolidinylmethyl, morpholinylmethyl and the
like.
[0107] The term "heteroaryl" as used herein refers to an
heterocyclic group containing at least one aromatic ring. Examples
include groups such as, for example, furanyl, thienyl,
benzothienyl, thiazolyl and the like.
[0108] The term "(heteroaryl)alkyl" as used herein refers to a
heteroaryl group appended to a lower alkyl radical including, but
not limited to, thienylmethyl, thienylethyl, furanylmethyl, and the
like.
[0109] The term "N-protecting group" or "N-protected" as used
herein refers to those groups intended to protect the N-terminus of
an amino acid or peptide or to protect an amino group against
undesirable reactions during synthetic procedures. Commonly used
N-protecting groups are disclosed in T. H. Greene and P. G. M.
Wuts, Protective Groups in Organic Synthesis. 2nd edition, John
Wiley & Sons, New York (1991). N-protecting groups comprise
acyl groups such as formyl, acetyl, propionyl, pivaloyl,
t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl,
trichloroacetyl, phthalyl, o-nitrophenoxyacetyl,
.alpha.-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl,
4-nitrobenzoyl, and the like; sulfonyl groups such as
benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming
groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,
p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,
2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,
3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,
2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
2-nitro-4,5-dimethoxybenzyloxycarbonyl,
3,4,5-trimethoxybenzyloxycarbonyl,
1-(p-biphenylyl)-1-methylethoxycarbony- l,
.alpha.,.alpha.-dimethyl-3,5-dimethoxybenzyloxycarbonyl,
benzhydryloxycarbonyl, t-butyloxycarbonyl,
diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl,
methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl,
phenoxycarbcnyl, 4-nitro-phenoxycarbonyl,
fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,
adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and
the like; alkyl groups such as benzyl, triphenylmethyl,
benzyloxymethyl and the like; and silyl groups such as
trimethylsilyl and the like. Preferred N-protecting groups are
formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl,
benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
[0110] The term "activated carboxylic acid derivative" as used
herein refers to acid halides such as acid chlorides, and activated
esters including, but not limited to, formic and acetic acid
derived anhydrides, anhydrides derived from alkoxycarbonyl halides
such as isobutyloxycarbonylchloride and the like,
N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived
esters, N-hydroxybenzotriazole derived esters,
N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters,
2,4,5-trichlorophenol derived esters, thiophenol derived esters,
propylphosphonic acid derived anhydrides and the like.
[0111] The term "leaving group" as used herein refers to a group
which is easily displaced from the compound, such as, for example,
a halide (for example, Cl, Br or I) or a sulfonate (for example,
mesylate, tosylate, triflate and the like).
[0112] As used herein, the terms "S" and "R" configuration are as
defined by the IUPAC 1974 Recommendations for Section E,
Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-
30.
[0113] The compounds of the invention can comprise asymmetrically
substituted carbon atoms. As a result, all stereoisomers of the
compounds of the invention are meant to be included in the
invention, including racemic mixtures, mixtures of diastereomers,
as well as single diastereomers of the compounds of the
invention.
[0114] This invention is intended to encompass compounds having
Formula I or Formula II when prepared by synthetic processes or by
metabolic processes. Preparation of the compounds of the invention
by metabolic processes include those occurring in the human or
animal body (in vivo) or processes occurring in vitro.
[0115] The reagents required for the synthesis of the compounds of
the invention are readily available from a number of commercial
sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA); Sigma
Chemical Co. (St. Louis, Mo., USA); and Fluka Chemical Corp.
(Ronkonkoma, N.Y., USA); Alfa Aesar (Ward Hill, Mass. 01835-9953);
Eastman Chemical Company (Rochester, N.Y. 14652-3512); Lancaster
Synthesis Inc. (Windham, N.H. 03087-9977); Spectrum Chemical
Manufacturing Corp. (Janssen Chemical) (New Brunswick, N.J. 08901);
Pfaltz and Bauer (Waterbury, Conn. 06708). Compounds which are not
commercially available can be prepared by employing known methods
from the chemical literature.
[0116] The compounds of the invention can be prepared as shown in
Schemes I-III. As outlined in Scheme I, an N-protected (for
example, with a benzyloxycarbonyl group) phenylalanylepoxide 2 is
coupled with an N-protected (for example, N-Boc) piperazine
compound, 1 (using, for example,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
(EDAC),1-hydroxybenzotriazole (HOBT), and an amine, such as,
triethyl amine, and the like, in an inert solvent, for example,
tetrahydrofuran, methylene chloride, and the like). The protected
carboxamide product, 3, is deprotected (for example, by treatment
with hydrogen gas, and an hydrogenation catalyst). The amine
carboxamide 3a, is then coupled with a carboxylic acid, 4, or an
activated derivative thereof, using, for example,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
(EDAC),1-hydroxybenzotriazole (HOBT), and triethyl amine in an
inert solvent, for example, tetrahydrofuran, methylene chloride,
and the like, to provide the N-protected piperazine, 5. The
piperazine is N-deprotected, (with for example, trifluoroacetic
acid (TFA), and the like) and alkylated (where X.sup.1 is a leaving
group) to provide the final product, 6. 18
[0117] For piperidyl compounds, where Y is --CH--, the synthesis is
outlined in Scheme II, shown below. A mono-protected piperidine
carbamate, 7, is alkylated to provide compound 8. The alkylated
carbamate is N-deprotected, (with, for example, trifluoroacetic
acid, and the like), followed by coupling with the epoxide, 9, to
provide carboxamide, 10. The carboxamide is N-deprotected to
provide compound 10a. Compound 10a is coupled with a carboxylic
acid, 4, or an activated derivative thereof, to provide the
product, 11. 19
[0118] The synthesis of compounds of the invention having the
--N(R.sup.9)--X--R.sup.8 group, is outlined in Scheme III., Urea,
12, prepared according to the description in J. Med. Chem., 1993,
36, 288-291, is coupled with a carboxylic acid, 4, or an activated
derivative thereof, using, for example,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimid- e
(EDAC),1-hydroxybenzotriazole (HOBT), and triethyl amine in an
inert solvent, for example, tetrahydrofuran, methylene chloride,
and the like, to provide the product 13. 20
[0119] The following examples will serve to further illustrate the
preparation of the novel compounds of the invention.
EXAMPLE 1
2-(1-Methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-4-(1,3-benz-
odioxol-5-ylmethyl)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]--
2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0120] 1A.
Benzyl-1-[(1S,2R)-3-[(2S)-4-(1,1-dimethylethyloxy(carbonyl))-2--
[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-2-hydroxy-1-(phenylmet-
hyl)propyl]carbamate.
[0121] The title compound was prepared according to the method
described in J. Med. Chem,1993, 36, 288-291, starting with 3.6 g
(12 mmol) of N-benzyloxycarbonyl-phenylalanylepoxide and 3.4 g (12
mmol) of N-tert-butyl-4-(tert-butyloxycarbonyl)-piperazine
-2(S)-carboxamide, prepared according to the method described in J.
Med. Chem., 1994 37, 3443-3451.
[0122] 1B.
1-[(1S,2R)-3-[(2S)-4-(1,1-Dimethylethyloxy(carbonyl))-2-[[(1,1--
dimethylethyl)amino]carbonyl]-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)pro-
pyl]amine.
[0123] A solution of 2.1 g (3.6 mmol) of
benzyl-1-[(1S,2R)-3-[(2S)-4-(1,1--
dimethylethyloxy(carbonyl))-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piper-
azinyl]-2-hydroxy-1-(phenylmethyl)propyl]carbamate in 20 ml of
methanol was treated with hydrogen, at greater than 1 atmosphere,
in the presence of Pd/C (50 mg; 10%), and stirred for 2 hours. The
catalyst was removed via filtration over a celite pad and the
solvent was evaporated at reduced pressure to provide the title
compound as a yellow oil (yield: 1.6 g; 99%).
[0124] 1C.
2-(1-Methylethyl)-4-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[(2S)-4-
-(1,1-dimethylethyloxy(carbonyl))-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-
-piperazinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpro-
pyl]carbamate.
[0125] A solution of 1.5 g (3.3 mmol) of
1-[(1S,2R)-3-[(2S)-4-(1,1-dimethy-
lethyloxy(carbonyl))-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-
-2-hydroxy-1-(phenylmethyl)propyl]amine. in 7 ml of tetrahydrofuran
(THF) and 7 ml of methylene chloride was prepared and treated with
1.0 g (3.3 mmol) of
[(2-isopropyl-4-thiazolyl)methyloxycarbonyl]-L-valine, 642 mg (3.3
mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDAC), 45
mg (0.33 mmol) of 1-hydroxybenzotriazole (HOBT), and 466 .mu.l (3.3
mmol) of triethyl amine. The solution was stirred at room
temperature for 6 hours, and concentrated in vacuo. The residue was
taken up with ethyl acetate, washed with equal portions of 3 N HCl
solution, 10% aqueous NaHCO.sub.3 (20 mL), saturated brine, and
dried over MgSO.sub.4. The product was concentrated in vacuo and
purified by chromatography on silica gel, using 5%
methanol:methylene chloride, to provide the title compound (yield:
2.4 g, 98%).
[0126] MS: 731 (M+H).sup.+.
[0127] .sup.1H NMR (DMSO-d.sub.6) .delta. 1.08 (d, J=7 Hz, 6H),
2.78 (heptet, J=7 Hz, 1H), 9.06 (br s, 1H), 9.30 (br s, 1H).
[0128] 1D.
2-(1-Methylethyl)-4-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[(2S)-2-
-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-2-hydroxy-1-(phenylme-
thyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate.
[0129] A solution of 2.4 g (3.2 mmol) of
2-(1-methylethyl)-4-thiazolylmeth-
yl-(1S)-1-[[[(1S,2R)-3-[(2S)-4-(1,1-dimethylethyloxy(carbonyl))-2-[[(1,1-d-
imethylethyl)amino]carbonyl]-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)prop-
yl]amino]carbonyl]-2-methylpropyl]carbamate in 20 ml of
dichloromethane was prepared and treated with 2 ml of
trifluoroacetic acid. The reaction was monitored by TLC. After the
reaction was completed, the solvent was removed at reduced
pressure. The residue was dissolved in methylene chloride, washed
with saturated aqueous NaHCO.sub.3 and saturated brine. The organic
layer was dried over Na.sub.2SO.sub.4 and concentrated in vacuo to
provide the title compound as a light yellow oil (yield: 2.0 g;
90%).
[0130] 1E.
2-(1-Methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)--
4-(1,3-benzodioxol-5-ylmethyl)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-pi-
perazinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl-
]carbamate.
[0131] A solution of 514 mg (0.82 mmol) of
2-(1-methylethyl)-4-thiazolylme-
thyl-(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-pi-
perazinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl-
]carbamate in 5 ml of dimethylformamide (DMF) was prepared and
treated with 140 mg (0.8 mmol) of 3,4-dioxomethylenebenzyl chloride
followed by 284 .mu.l (1.6 mmol) of N,N-diisopropyl ethyl amine,
stirred at room temperature over night, and partitioned between
ethyl acetate and saturated sodium bicarbonate solution. The
organic layer was washed with brine, dried over sodium sulfate, and
concentrated in vacuo. The residue was purified by chromatography
on silica gel, using 5% methanol:methylene chloride, to provide the
title compound (yield: 502 mg; 81%).
[0132] MS: 765 (M+H).sup.+.
[0133] .sup.1H NMR (CDCl.sub.3) .delta. 0.67 (d, J=6.3 Hz, 3H),
0.83 (d, J=6.3 Hz, 3H), 1.37 (s, 9H), 1.41 (t, J=7.5, 6H), 2.05
(hexlet, J=6.0 Hz, 1H), 2.26 (m, 1H), 2.41 (m, 1H), 2.58 (m, 2H),
2.73 (m, 3H), 2.83 (m, 2H), 2.90 (m, 1H), 3.33 (AB, J=15.0 Hz, 2H),
3.46 (s, 2H), 3.80 (m, 1H), 3.93 (m, 1H), 4.22 (septet, J=4.5 Hz,
1H), 5.08 (m, 1H), 5.17 (d, J=4.5 Hz, 2H), 5.97 (s, 2H), 6.13 (d,
J=9.0 Hz, 1H), 6.71 (s, 1H), 6.75 (s, 2H), 7.12-7.22 (m, 7H), 8.19
(br s, 1H).
EXAMPLE 2
2-(1-Methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-di-
methylethyl)amino]carbonyl]-4-(phenylmethyl)-1-piperazinyl]-2-hydroxy-1-(p-
henylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0134] The title compound was prepared according to the method
described in Example 1E, substituting benzyl bromide in place of
3,4-dioxomethylenebenzyl chloride.
[0135] MS: 721 (M+H).sup.+.
[0136] .sup.1H NMR (CDCl.sub.3) .delta. 0.68 (d, J=6.3 Hz, 3H),
0.84 (d, J=6.3 Hz, 3H), 1.36 (s, 9H), 1.40 (d, J=6.3, 6H), 2.04
(hextet, J=6.0 Hz, 1H), 2.28 (dt, J=9.3, 3.3 Hz, 1H), 2.45 (dt,
J=12.0, 3.0 Hz, 1H), 2.58 (m, 2H), 2.75 (m, 2H), 2.88 (m, 2H), 3.33
(heptet, J=6.3 Hz, 1H), 3.37 (m, 1H), 3.46 (s, 2H), 3.79 (m, 1H),
3.85 (dd, J=8.4, 6.0 Hz, 1H), 4.22 (septet, J=4.5 Hz, 1H), 5.11
(dd, J=10.8, 7.5 Hz, 1H), 5.17 (d, J=3.3 Hz, 2H), 6.13 (d, J=9.0
Hz, 2H), 7.12-7.33 (m, 11 H), 8.02 (s, 1H), 8.26 (br s, 1H).
EXAMPLE 3
2-(1-Methylethyl)-4-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-dim-
ethylethyl)amino]carbonyl]-4-[(4-fluorophenyl)methyl]-1-piperazinyl]-2-hyd-
roxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0137] The title compound was prepared according to the method
described in Example 1E, substituting 4-fluorobenzyl chloride in
place of 3,4-dioxomethylenebenzyl chloride.
[0138] MS: 739 (M+H).sup.+.
[0139] .sup.1H NMR (CDCl.sub.3) .delta. 0.67 (d, J=6.3 Hz, 3H),
0.84 (d, J=6.3 Hz, 3H), 1.35 (s, 9H), 1.41 (d, J=7.5, 6H), 2.06
(hextet, J=6.0 Hz, 1H), 2.30 (m, 1H), 2.48 (m, 1H), 2.59 (m, 1H),
2.73 (m, 2H), 2.83 (m, 2H), 2.92 (m, 2H), 3.33 (AB, J=15.0 Hz, 2H),
3.37 (m, 1H), 3.44 (s, 2H), 3.83 (m, 2H), 4.22 (m, 1H), 5.09 (m,
1H), 5.17 (d, J=4.8 Hz, 2H), 6.19 (d, J=9.0 Hz, 1H), 7.03 (d, J=8.4
Hz, 1H), 7.12-7.22 (m, 9H), 8.09 (br s, 1H).
EXAMPLE 4
2-(1-Methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-di-
methylethyl)amino]carbonyl]-4-(5-thienylmethyl)-1-piperazinyl]-2-hydroxy-1-
-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0140] The title compound was prepared according to the method
described in Example 1E, substituting 5-(chloromethyl)thiazole in
place of 3,4-dioxomethylenebenzyl chloride.
[0141] MS: 728 (M+H).sup.+.
[0142] .sup.1H NMR (CDCl.sub.3) .delta. 0.68 (d, J=6.3 Hz, 3H),
0.83 (d, J=6.3 Hz, 3H), 1.38 (s, 9H), 1.41 (d, J=7.5, 6H), 2.06
(hextet, J=6.0 Hz, 1H), 2.33 (m, 1H), 2.58 (m, 2H), 2.73 (m, 2H),
2.83 (m, 2H), 2.90 (m, 1H), 3.33 (heptet, J=4.5 Hz, 1H), 3.36 (m,
1H), 3.73 (d, J=3.0 Hz, 2H), 3.80 (m, 1H), 3.83 (dd, J=7.5, 6.0 Hz,
1H), 4.22 (septet, J=4.5 Hz, 1H), 5.07 (d, J=7.5 Hz, 1H), 5.17 (d,
J=4.5 Hz, 2H), 6.15 (d, J=7.5 Hz, 1H), 7.12-7.22 (m, 8H), 7.40 (m,
1H), 7.73 (s, 1H), 7.79 (s, 1H), 8.80 (s, 1H).
EXAMPLE 5
2-(1-Methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-di-
methylethyl)amino]carbonyl]-4-[4-(3-hydroxyphenyl)methyl]-1-piperazinyl]-2-
-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0143] The title compound was prepared according to the method
described in Example 1E, substituting 3-hydroxybenzyl chloride in
place of 3,4-dioxomethylenebenzyl chloride.
[0144] MS: 7:37 (M+H).sup.+.
[0145] .sup.1H NMR (CDCl.sub.3) .delta. 0.67 (d, J=6.3 Hz, 3H),
0.83 (d, J=6.3 Hz, 3H), 0.96 (m, 1H), 1.37 (s, 9H), 1.40 (d, J=7.5,
6H), 2.03 (hextet, J=6.0 Hz, 1H), 2.32 (m, 1H), 2.45 (m, 1H), 2.61
(m, 2H), 2.76 (m, 2H), 2.85 (m, 2H,), 2.89 (m, 2H), 3.32 (m, 1H),
3.37 (s, 1H), 3.42 (m, 1H), 3.61 (t, J=8.4 Hz, 1H), 3.87 (m, 2H),
4.22 (m, 1H), 4.63 (s, 1H), 5.16 (s, 2H), 6.36 (m, 1H), 6.78 (d,
J=7.5 Hz, 2H), 7.12-7.22 (m, 9H), 8.19 (br s, 1H).
EXAMPLE 6
2-(1-Methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-di-
methylethyl)amino]carbonyl]-4-(3-pyridinylmethyl)-1-piperazinyl]-2-hydroxy-
-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0146] The title compound was prepared according to the method
described in Example 1E, substituting 3-picolyl chloride
hydrochloride in place of 3,4-dioxomethylenebenzyl chloride.
[0147] MS: 722 (M+H).sup.+.
[0148] .sup.1H NMR (CDCl) .delta. 0.68 (d, J=6.3 Hz, 3H), 0.83 (d,
J=6.3 Hz, 3H), 1.36 (s, 9H), 1.41 (d, J=7.5 Hz, 6H), 2.06 (Hextet,
J=4.5 Hz, 1H), 2.47 (m, 1H), 2.60 (m, 2H), 2.71 (m, 2H), 2.81 (m,
1H), 2.83 (m, 2H), 2.92 (m, 1H), 3.34 (heptet, J=4.5 Hz, 1H), 3.35
(m, 1H), 3.51 (s, 2H), 3.81 (m, 1H), 3.85 (m, 1H), 4.22 (m, 1H),
4.75 (m, 1H), 5.07 (d, J=9.0 Hz, 1H), 5.17 (d, J=7.8 Hz, 2H), 6.15
(d, J=7.8 Hz, 1H), 7.12-7.22 (m, 8H), 7.61 (d, J=7.8 Hz, 1H), 7.89
(br s, 1H), 8.55 (d, J=3 Hz, 1H), 8.56 (d, J=6.0 Hz, 1H).
EXAMPLE 7
2-(1-Methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-di-
methylethyl)amino]carbonyl]-4-(4-pyridinylmethyl)-1-piperazinyl]-2-hydroxy-
-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0149] The title compound was prepared according to the method
described in Example 1E substituting 4-picolyl chloride
hydrochloride in place of 3,4-dioxomethylenebenzyl chloride.
[0150] MS: 722 (M+H).sup.+.
[0151] .sup.1H NMR (CDCl.sub.3) .delta. 0.65 (d, J=6.3 Hz, 3H),
0.94 (d, J=6.3 Hz, 3H), 1.37 (s, 9H), 1.41 (d, J=7.5, 6H), 2.07
(hex let, J=6.0 Hz, 1H), 2.37 (m, 1H), 2.57 (m, 1H), 2.62 (m, 2H),
2.69 (m, 2H), 2.81 (m, 2H), 2.91 (m, 1H), 3.32 (m, 1H), 3.34 (m,
1H), 3.49 (AB, J=15.0 Hz, 2H), 3.80 (m, 1H), 3.85 (m, 1H), 4.21 (m,
1H), 4.62 (m, 1H), 5.06 (d, J=7.5 Hz, 1H), 5.14 (m, 1H), 5.17 (d,
J=4.5 Hz, 2H), 6.14 (d, J=8.4 Hz, 1H), 7.12-7.22 (m, 8H), 7.77 (br
s, 1H), 8.08 (d, J=6.0 Hz, 2H).
EXAMPLE 8
2-(1-Methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-di-
methylethyl)amino]carbonyl]-4-[(4-hydroxyphenyl)methyl]-1-piperazinyl]-2-h-
ydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0152] The title compound was prepared according to the method
described in Example 1E, substituting 4-hydroxybenzyl chloride
hydrochloride in place of 3,4-dioxomethylenebenzyl chloride.
[0153] MS: 737 (M+H).sup.+.
[0154] .sup.1H NMR (CDCl.sub.3) .delta. 0.68 (d, J=6.3 Hz, 3H),
0.83 (d, J=6.3 Hz, 3H), 1.35 (s, 9H), 1.41 (ed, J=7.5, 6H), 2.03
(hextet, J=4.5 Hz, 1H), 2.27 (dt, J=7.5, 3.0 Hz, 1H), 2.36 (dd,
J=12.0, 3.0 Hz, 1H), 2.59 (m, 2H), 2.74 (m, 2H), 2.87 (m, 2H), 2.79
(m, 1H), 2.92 (m, 1H), 3.32 (m, 1H), 3.33 (AB, J=15.0 Hz, 2H), 3.40
(m, 2H), 3.72 (m, 1H), 3.78 (dd, J=8.4, 6.0 Hz, 1H), 4.22 (septet,
J=4.5 Hz, 1H), 5.22 (d, J=4.5 Hz, 2H), 5.23 (m, 1H), 6.17 (m, 1H),
6.40 (d, J=9.0 Hz, 1H), 6.80 (d, J=8.7 Hz, 2H), 7.09-7.21 (m, 8H),
8.31 (br s, 1H).
EXAMPLE 9
2-(1-Methylethyl)-4-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[(2S)-4-(1H-benzim-
idiazol-2-ylmethyl)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]--
2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0155] The title compound was prepared according to the method
described in Example 1E, substituting 2-(chloromethyl)benzimidazole
in place of 3,4-dioxomethylenebenzyl chloride.
[0156] MS: 761 (M+H).sup.+.
[0157] .sup.1H NMR (CDCl.sub.3) .delta. 0.62 (d, J=6.3 Hz, 3H),
0.83 (d, J=6.3 Hz, 3H), 1.41 (d, J=7.5, 6H), 1.43 (s, 9H), 2.11
(hextet, J=4.5 Hz, 1H), 2.52 (m, 1H), 2.57 (dd, J=12.0, 3.0 Hz,
1H), 2.72 (m, 2H), 2.79 (m, 3H), 3.02 (dd, J=15.0, 4.5 Hz, 1H),
3.17 (m, 3H), 3.34 (heptet, J=4.5 Hz, 1H), 3.85 (m, 2H), 3.95 (d,
J=9.0 Hz, 1H), 4.25 (m, 1H), 4.98 (m, 1H), 5.13 (s, 2H), 5.17 (m,
1H), 6.17 (m, 1H), 7.12-7.28 (m, 11 H), 7.63 (m, 2H).
EXAMPLE 10
2-(1-Methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-di-
methylethyl)amino]carbonyl]-4-(2-quinolinylmethyl)-1-piperazinyl]-2-hydrox-
y-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0158] The title compound was prepared according to the method
described in Example 1E, substituting 2-(chloromethyl)quinoline
monohydrochloride in place of 3,4-dioxomethylenebenzyl
chloride.
[0159] MS: 772 (M+H).sup.+.
[0160] .sup.1H NMR (CDCl.sub.3) .delta. 0.67 (d, J=6.3 Hz, 3H),
0.83 (d, J=6.3 Hz, 3H), 1.37 (s, 9H), 1.40 (d, J=7.5, 6H), 2.05
(hextet, J=6.0 Hz, 1H), 2.50 (m, 1H), 2.61 (m, 2H), 2.70 (m, 1H),
2.71 (m, 2H), 2.85 (m, 2H), 2.92 (m, 1H), 3.32 (m, 1H), 3.47 (m,
1H), 3.82 (m, 2H), 3.85 (m, 1H), 4.22 (septet, J=4.5 Hz, 1H), 4.79
(s, 1H), 5.10 (m, 1H), 5.17 (d, J=8.4 Hz, 2H), 6.11 (s, 1H),
7.12-7.22 (m, 9H), 7.47 (d, J=6.6 Hz, 1H), 7.56 (t, J=7.5 Hz, 1H),
7.73 (t, J=8.4 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 8.07 (d, J=7.5 Hz,
1H), 8.17 (d, J=8.4 Hz, 1H).
EXAMPLE 11
2-(1-Methylethyl)-4-thiazolylmethyl[(1S)-1-[[[(1S,2R)-3-[(2S)-4-[(3,4-dime-
thoxylphenyl)methyl]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-
-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0161] The title compound was prepared according to the method
described in Example 1E, substituting 3,4-dimethoxy benzyl chloride
in place of 3,4-dioxomethylenebenzyl chloride.
[0162] MS: 781 (M+H).sup.+.
[0163] .sup.1H NMR (CDCl.sub.3) .delta. 0.68 (d, J=6.3 Hz, 3H),
0.84 (d, J=6.3 Hz, 3H), 1.35 (s, 9H), 1.41 (d, J=6.3, 6H), 2.05
(hextet, J=6.0 Hz, 1H), 2.25 (m, 1H), 2.45 (m, 1H), 2.58 (m, 2H),
2.74 (m, 3H), 2.84 (m, 2H), 2.90 (m, 1H), 3.35 (heptet, J=6.3 Hz,
1H), 3.40 (AB, J=15.0 Hz, 2H), 3.81 (m, 1H), 3.87 (s, 3H), 3.88 (s,
3H), 4.21 (m, 1H), 5.08 (m, 1H), 5.17 (d, J=3.3 Hz, 2H), 6.12 (m,
1H), 6.26 (s, 1H), 6.82 (s, 2H), 7.10-7.22 (m, 8H), 8.21 (br s,
1H).
EXAMPLE 12
N'-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-Dimethylethyl)amino]carbonyl]-4-(5--
thiazolylmethyl)-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]car-
bonyl]-2-methylpropyl]-N-methyl-N-[2-(1-methylethyl)-4-thiazolylmethyl]ure-
a
[0164] 12A.
N'-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-Dimethylethyl)amino]car-
bonyl]-4-(1,1-dimethylethyloxy(carbonyl))-1-piperazinyl]-2-hydroxy-1-(phen-
ylmethyl)propyl]amino]carbonyl]-2-methylpropyl]-N-methyl-N-[2-(1-methyleth-
yl)-4-thiazolylmethyl]urea.
[0165] A solution of 1.5 g (3.3 mmol) of
1-[(1S,2R)-3-[(2S)-4-(1,1-dimethy-
lethyloxy(carbonyl))-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-
-2-hydroxy-1-(phenylmethyl)propyl]amine in 7 ml of THF and 7 ml of
methylene chloride was prepared and treated with 1.0 g (3.3 mmol)
of
N-methyl-N-[(((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl]-L-valine,
642 mg (3.3 mmol) of EDAC, 45 mg (0.33 mmol) of HOBT, and 466 .mu.l
(3.3 mmol) of triethyl amine. The solution was stirred at room
temperature for 6 hours, and concentrated in vacuo. The residue was
taken up with ethyl acetate, washed with equal portions (15 ml) of
3 N HCl solution, 10% aqueous NaHCO.sub.3, and saturated brine. The
organic layer was dried over MgSO.sub.4 and concentrated in vacuo.
The mixture was purified by chromatography on silica gel using 5%
methanol:methylene chloride to provide the title compound (yield:
2.4 g; 98%).
[0166] 12B.
N'-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-Dimethylethyl)amino]car-
bonyl]-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-m-
ethylpropyl]-N-methyl-N-[2-(1-methylethyl)-4-thiazolylmethyl]urea.
[0167] A solution of 2.4 g (3.2 mmol) of
N'-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[-
[(1,1-dimethylethyl)amino]carbonyl]-4-(1,1-dimethylethyloxy(carbonyl))-1-p-
iperazinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropy-
l]-N-methyl-N-[2-(1-methylethyl)-4-thiazolylmethyl]urea in 20 ml of
dichloromethane, was prepared and treated with 2 ml of
trifluoroacetic acid. The reaction was monitored by TLC. After the
reaction was completed, the solvent was removed at reduced
pressure. The residue was dissolved in methylene chloride, washed
with saturated aqueous NaHCO.sub.3, and saturated brine. The
organic layer was dried over Na.sub.2SO.sub.4 and concentrated in
vacuo to provide the title compound as a light oil (yield: 2.0 g;
90%). The product was used in Example 12C without further
purification.
[0168] 12C.
N'-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-Dimethylethyl)amino]car-
bonyl]-4-(5-thiazolylmethyl)-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)prop-
yl]amino]carbonyl]-2-methylpropyl]-N-methyl-N-[2-(1-methylethyl)-4-thiazol-
ylmethyl]urea.
[0169] The title compound was prepared according to the method
described in Example 1E, starting with the product, prepared in
Example 12B, and substituting 5-thiazolylmethyl chloride in place
of 3,4-dioxomethylenebenzyl chloride.
[0170] MS: 741 (M+H).sup.+.
[0171] .sup.1H NMR (CDCl.sub.3) .delta. 0.75 (d, J=6.3 Hz, 3H),
0.89 (d, J=6.3 Hz, 3H), 1.33 (d, J=3.0 Hz, 3H), 1.45 (d, J=3.0 Hz,
3H), 1.47 (s, 9H), 2.18 (m, 1H), 2.40 (dt, J=7.5, 3.0 Hz, 1H), 2.55
(m, 1H), 2.62 (m, 4H), 2.73 (dd, J=15.0, 4.5 Hz, 2H), 2.89 (m, 1H),
2.95 (s, 3H), 3.22 (heptet, J=6.0 Hz, 1H), 3.27 (d, J=3.0 Hz, 2H),
3.73 (d, J=3.0 Hz, 2H), 3.87 (m, 1H), 3.99 (dd, J=6.3, 6.0 Hz, 1H),
4.16 (septet, J=4.5 Hz, 1H), 4.37 (s, 2H), 4.61 (br s, 1H), 6.00
(br s, 1H), 6.39 (d, J=9.0 Hz, 1H), 6.97 (s, 1H), 7.08-7.17 (m,
5H), 7.54 (s, 1H), 7.72 (s, 1H), 8.79 (s, 1H).
EXAMPLE 13
N'-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-Dimethylethyl)amino]carbonyl]-4-(ph-
enylmethyl)-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl-
]-2-methylpropyl]-N-methyl-N-[2-(1-methylethyl)-4-thiazolylmethyl]urea
[0172] The title compound was prepared according to the method
described in Example 12C, substituting benzyl bromide in place of
5-thiazolylmethyl chloride.
[0173] MS: 734 (M+H).sup.+.
[0174] .sup.1H NMR (CDCl.sub.3) .delta. 0.75 (d, J=6.3 Hz, 3H),
0.88 (d, J=6.3 Hz, 3H), 1.45 (d, J=7.5 Hz, 6H), 1.46 (s, 9H), 2.15
(hextet, J=6.3 Hz, 1H), 2.32 (dt, J=9.0, 3.0 Hz, 1H), 2.51 (dd,
J=8.4, 3.0 Hz, 1H), 2.59 (dd, J=8.4, 3.0 Hz, 1H), 2.70 (m, 2H),
2.78 (m, 2H), 2.95 (s, 3H), 3.24 (heptet, J=7.5 Hz, 1H), 3.32 (t,
J=3.0 Hz, 1H), 3.45 (s, 2H), 3.81 (m, 1H), 4.01 (dd, J=7.5, 6.0 Hz,
1H), 4.17 (septet, J=4.5 Hz, 1H), 4.48 (s, 2H), 4.84 (br s, 1H),
5.89 (m, 1H), 6.48 (d, J=9.0 Hz, 1H), 6.95 (s, 1H), 7.07-7.18 (m,
5H), 7.25-7.34 (m, 5H), 8.04 (br s, 1H).
EXAMPLE 14
N'-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-Dimethylethyl)amino]carbonyl]-4-[(4-
-hydroxy-3-methoxyphenyl)methyl]-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)-
propyl]amino]carbonyl]-2-methylpropyl]-N-methyl-N-[2-(1-methylethyl)-4-thi-
azolylmethyl]urea
[0175] The title compound was prepared according to the method
described in Example 12C substituting 3-methoxy-4-hydroxybenzyl
chloride in place of 5-thiazolylmethyl chloride.
[0176] MS: 780 (M+H).sup.+.
[0177] .sup.1H NMR (CDCl.sub.3) .delta. 0.76 (d, J=6.3 Hz, 3H),
0.88 (d, J=6.3 Hz, 3H), 1.35 (s, 9H), 1.36 (d, J=7.5, 6H), 2.17
(hextet, J=6.0 Hz, 1H), 2.31 (dt, J=7.5, 3.0 Hz, 1H), 2.53 (m, 2H),
2.63 (m, 2H), 2.78 (m, 2H), 2.91 (m, 1H), 2.96 (s, 3H), 3.26 (q,
J=7.5 Hz, 2H), 3.29 (m, 1H), 3.38 (AB, J=15.0 Hz, 2H), 3.83 (m,
1H), 3.89 (s, 3H), 4.01 (dd, J=7.5, 6.0 Hz, 1H), 4.17 (septet,
J=4.5 Hz, 1H), 4.38 (s, 2H), 4.77 (m, 1H), 5.58 (s, 1H), 5.92 (m,
1H), 6.38 (d, J=9.0 Hz, 1H), 6.77 (m, 2H), 6.87 (d, J=8.4 Hz, 1H),
6.96 (s, 1H), 7.12-7.22 (m, 6H), 7.96 (br s, 1H).
EXAMPLE 15
2-Methyl-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-4-(1,3-benzodioxol-5-
-ylmethyl)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-2-hydroxy-
-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0178] 15A.
2-Methyl-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-4-(1,1-d-
imethylethyloxy(carbonyl))-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-pipera-
zinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]car-
bamate.
[0179] The title compound was prepared according to the method of
Example 1C substituting
[(2-methyl-4-thiazolyl)methyloxycarbonyl]-L-valine in place of
[(2-isopropyl-4-thiazolyl)methyloxycarbonyl]-L-valine. This was
followed by treatment of the product with trifluoroacetic acid
according to the method of Example 1D
[0180] 15B.
2-Methyl-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-4-(1,3-b-
enzodioxol-5-ylmethyl)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperaziny-
l]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbama-
te.
[0181] A solution of 98 mg (0.16 mmol) of
2-methyl-4-thiazolylmethyl-[(1S)-
-1-[[[(1S,2R)-3-[(2S)-4-(1,1-dimethylethyloxy(carbonyl))-2-[[(1,1-dimethyl-
ethyl)amino]carbonyl]-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)propyl]amin-
o]carbonyl]-2-methylpropyl]carbamate in 1 ml of DMF was treated
with 30 mg (0.18 mmol)l of 3,4-dioxomethylenebenzyl chloride
followed by 43 .mu.l (0.24 mmol) of N,N-diisopropyl ethyl amine.
The solution was stirred at room temperature over night. After
stirring, the solution was partitioned between ethyl acetate and
saturated sodium bicarbonate solution. The organic solution was
washed with brine, dried over sodium sulfate, and concentrated in
vacuo. The mixture was purified by chromatography on silica gel,
using 5% methanol:methylene chloride, to provide the title compound
(yield: 31 mg; 26%).
[0182] MS: 737 (M+H).sup.+.
[0183] .sup.1H NMR (CDCl.sub.3) .delta. 0.67 (d, J=6.3 Hz, 3H),
0.84 (d, J=6.3 Hz, 3H), 1.37 (s, 9H), 2.05 (hextet, J=4.5 Hz, 1H),
2.26 (m, 1H), 2.41 (dd, J=12.0, 3.0 Hz, 1H), 2.55 (m, 1H), 2.59
(dd, J=9.3, 3.0 Hz, 2H), 2.72 (m, 2H), 2.73 (s, 3H), 2.76 (m, 1H),
2.83 (m, 2H), 2.91 (m, 1H), 3.35 (m, 1H), 3.47 (s, 2H), 3.79 (m,
1H), 3.86 (dd, J=7.5, 6.0 Hz, 1H), 4.22 (m, 1H), 4.93 (m, 1H), 5.62
(m, 2H), 5.65 (d, J=3.0 Hz, 2H), 5.96 (s, 2H), 6.18 (d, J=9.0 Hz,
1H), 6.70 (d, J=7.5 Hz, 1H), 6.75 (s, 1H), 6.78 (d, J=7.5 Hz, 1H),
7.12-7.22 (m, 6H), 8.19 (br s, 1H).
EXAMPLE 16
2-Methyl-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-4-[(3,4-dimethoxylph-
enyl)methyl]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-2-hydro-
xy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0184] The title compound was prepared according to the method
described in Example 15B, substituting 3,4-dimethoxybenzyl chloride
in place of 3,4-dioxomethylenebenzyl chloride.
[0185] MS: 753 (M+H).sup.+.
[0186] .sup.1H NMR (DMSO-d.sub.6) .delta. 0.67 (d, J=6.3 Hz, 3H),
0.69 (d, J=6.3 Hz, 3H), 1.23 (s, 9H), 1.78 (hextet, J=4.5 Hz, 1H),
2.22 (m, 2H), 2.27 (m, 1H), 2.32 (m, 1H), 2.53 (m, 3H), 2.63 (s,
3H), 2.67 (m, 1H), 2.87 (m, 2H), 2.98 (m, 1H), 3.33 (m, 3H), 3.63
(m, 1H), 3.72 (s, 3H), 3.73 (s, 3H), 4.05 (m, 1H), 4.86 (d, J=9.0
Hz, 1H), 5.00 (s, 2H), 6.79 (d, J=7.5 Hz, 1H), 6.87 (s, 1H), 6.89
(d, J=7.5 Hz, 1H), 7.10 (d, J=6.0 Hz, 2H), 7.18 (d, J=6.3 Hz, 2H),
7.26 (d, J=7.5 Hz, 2H), 7.41 (s, 1H), 7.53 (s, 1H), 7.67 (d, J=9.0
Hz, 1H).
EXAMPLE 17
2-Methyl-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-dimethyleth-
yl)amino]carbonyl]-4-[(4-fluorophenyl)methyl]-1-piperazinyl]-2-hydroxy-1-(-
phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0187] The title compound was prepared according to the method
described in Example 15B, substituting 4-fluorobenzyl chloride in
place of 3,4-dioxomethylenebenzyl chloride.
[0188] MS: 711 (M+H).sup.+.
[0189] .sup.1H NMR (CDCl.sub.3) .delta. 0.68 (d, J=6.3 Hz, 3H),
0.84 (d, J=6.3 Hz, 3H), 1.35 (s, 9H), 2.06 (hextet, J=6.0 Hz, 1H),
2.28 (m, 1H), 2.47 (m, 1H), 2.55 (m, 1H), 2.59 (m, 2H), 2.71 (m,
2H), 2.73 (s, 3H), 2.76 (m, 1H), 2.83 (m, 2H), 2.90 (m, 1H), 3.35
(m, 1H), 3.43 (s, 2H), 3.80 (m, 1H), 3.86 (dd, J=7.5, 6.0 Hz, 1H),
4.22 (septet, J=4.5 Hz, 1H), 5.10 (m, 1H), 5.14 (s, 2H), 6.15 (d,
J=7.5 Hz, 1H), 7.03 (t, J=8.4 Hz, 2H), 7.12-7.22 (m, 8H), 8.21 (br
s, 1H).
EXAMPLE 18
2-Ethyl-4-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[(2S)-4-[(3,4-dimethoxylphen-
yl)methyl]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-2-hydroxy-
1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0190] 18A.
2-Ethyl-4-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[(2S)-4-[1,1-dim-
ethylethyloxy(carbonyl)]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazi-
nyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carba-
mate.
[0191] The title compound was prepared according to the method of
Example 1C, substituting
[(2-ethyl-4-thiazolyl)methyloxycarbonyl]-L-valine in place of
[(2-isopropyl-4-thiazolyl)methyloxycarbonyl]-L-valine. This was
followed by treatment of the product with trifluoroacetic acid
according to the method of Example 1D.
[0192] 18B.
2-Ethyl-4-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[(2S)-4-[(3,4-di-
methoxylphenyl)methyl]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperaziny-
l]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbama-
te.
[0193] The title compound was prepared by reacting
2-ethyl-4-thiazolylmeth-
yl(1S)-1-[[[(1S,2R)-3-[(2S)-4-[1,1-dimethylethyl-oxy(carbonyl)]-2-[[(1,1-d-
imethylethyl)amino]carbonyl]-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)prop-
yl]amino]carbonyl]-2-methylpropyl]carbamate, 98 mg (0.16 mmol),
with 3,4-dimethoxybenzyl chloride, 30 mg (0.18 mmol), according to
the method described in Example 15(B).
[0194] MS: 767 (M+H).sup.+.
[0195] .sup.1H NMR (CDCl.sub.3) .delta. 0.67 (d, J=6.3 Hz, 3H),
0.84 (d, J=6.3 Hz, 3H), 1.36 (s, 9H), 1.40 (d, J=7.5, 6H), 2.05
(hextet, J=6.0 Hz, 1H), 2.23 (m, 1H), 2.48 (m, 1H), 2.58 (dd,
J=12.0, 3.0 Hz, 2H), 2.71 (m, 2H), 2.83 (m, 1H), 2.90 (m, 1H), 3.05
(q, J=7.5 Hz, 2H), 3.31 (m, 1H), 3.35 (m, 1H), 3.40 (AB, J=15.0 Hz,
2H), 3.88 (s, 3H), 3.89 (s, 3H), 4.22 (m, 1H), 4.88 (m, 1H), 5.08
(m, 1H), 5.16 (s, 2H), 6.11 (d, J=7.5 Hz, 1H), 6.77 (s, 1H), 6.82
(s, 2H), 7.12-7.22 (m, 8H), 8.21 (br s, 1H).
EXAMPLE 19
2-(1-Methylethyl)-5-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-4-[(3,4-dim-
ethoxylphenyl)methyl]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl-
]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamat-
e
[0196] 19A.
2-(1-Methylethyl)-5-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-
-4-[1,1-dimethylethyloxy(carbonyl)]-2-[[(1,1-dimethylethyl)amino]carbonyl]-
-1-piperazinyl[-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylp-
ropyl]carbamate.
[0197] A solution of 1.5 g (3.3 mmol) of
1-[(1S,2R)-3-[(2S)-4-(1,1-dimethy-
lethyloxy(carbonyl))-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-
-2-hydroxy-1-(phenylmethyl)propyl]amine in 7 ml of THF and 7 ml of
methylene chloride was prepared and treated with 1.0 g (3.3 mmol)
of [(2-isopropyl-5-thiazolyl)methyloxycarbonyl]-L-valine, 642 mg
(3.3 mmol) of EDAC, 45 mg (0.33 mmol) of HOBT, and 466 .mu.l (3.3
mmol) of triethyl amine. The solution was stirred at room
temperature for 6 hours, and concentrated in vacuo. The residue was
taken up with ethyl acetate, washed with equal portions (15 mL) of
3 N HCl solution, 10% aqueous NaHCO.sub.3, and saturated brine,
dried over MgSO.sub.4, and concentrated in vacuo. The resulting
mixture was purified by chromatography on silica gel, using 5%
methanol:methylene chloride, to provide the title compound yield:
2.1 g, 88%).
[0198] MS: 731 (M+H).sup.+.
[0199] .sup.1H NMR (DMSO-d.sub.6) .delta. 1.08 (d, J=7 Hz, 6H),
2.78 (heptet, J=7 Hz, 1H), 9.06 (br s, 1H), 9.30 (br s, 1H).
[0200] 19B.
2-(1-Methylethyl)-5-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-
-4-[(3,4-dimethoxylphenyl)methyl]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-
-piperazinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpro-
pyl]carbamate.
[0201] The title compound was prepared in two steps. First,
2-(1-methylethyl)-5-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-4-[1,1-dim-
ethylethyloxy(carbonyl)]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazi-
nyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carba-
mate was treated with trifluoroacetic acid according to the method
described in Example 1D. This was followed by akylation of the
product according to the method of Example 1E, substituting
3,4-dimethylbenzyl chloride in place of 3,4-dioxomethylenebenzyl
chloride.
[0202] MS: 781 (M+H).sup.+.
[0203] .sup.1H NMR (CDCl.sub.3) .delta. 0.72 (d, J=6.3 Hz, 3H),
0.86 (d, J=6.3 Hz, 3H), 1.37 (s, 9H), 1.40 (d, J=6.3, 6H), 2.01
(hextet, J=6.0 Hz, 1H), 2.22 (dt, J=7.5, 3.0 Hz, 1H), 2.43 (m, 1H),
2.55 (m, 2H), 2.73 (m, 3H), 2.88 (m, 2H), 2.93 (m, 1H), 3.30
(heptet, J=6.3 Hz, 1H), 3.38 (m, 1H), 3.41 (AB, J=15.0 Hz, 2H),
3.80 (m, 1H), 3.87 (s, 3H), 3.88 (s, 3H), 4.22 (septet, J=4.5 Hz,
1H), 5.07 (d, J=8.4 Hz, 1H), 5.20 (d, J=3.0 Hz, 2H), 6.06 (d, J=9.0
Hz, 1H), 6.76 (s, 1H), 6.82 (s, 2H), 7.12-7.22 (m, 7H), 7.61 (s,
1H), 8.28 (br s, 1H).
EXAMPLE 20
2-Ethyl-5-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[(2S)-4-[(3,4-dimethoxylphen-
yl)methyl]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-2-hydroxy-
-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0204] 20A.
2-Ethyl-5-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[(2S)-4-[1,1-dim-
ethylethyloxy(carbonyl)]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazi-
nyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carba-
mate.
[0205] The title compound was prepared according to the method
described in Example 19A, substituting
[(2-ethyl-5-thiazolyl)methyloxycarbonyl]-L-v- aline in place of
[(2-isopropyl-5-thiazolyl)methyloxycarbonyl]-L-valine.
[0206] 20B.
2-Ethyl-5-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[(2S)-4-[(3,4-di-
methoxylphenyl)methyl]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperaziny-
l]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbama-
te.
[0207] The title compound was prepared in two steps. First,
2-ethyl-5-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[(2S)-4-[1,1-dimethylethylo-
xy(carbonyl)]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-2-hydr-
oxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
was treated with trifluoroacetic acid according to the method
described in Example 1D. This was followed by akylation of the
product according to the method of Example 1E, substituting
3,4-dimethylbenzyl chloride in place of 3,4-dioxomethylenebenzyl
chloride.
[0208] MS: 767 (M+H).sup.+.
[0209] .sup.1H NMR (CDCl.sub.3) .delta. 0.73 (d, J 6.3 Hz, 3H),
0.86 (d, J=6.3 Hz, 3H), 1.37 (s, 9H), 1.38 (t, J=7.5, 3H), 2.02 (m,
1H), 2.23 (dt, J=7.5, 3.0 Hz, 1H), 2.45 (m, 1H), 2.56 (m, 2H), 2.72
(m, 2H), 2.77 (m, 1H), 2.89 (m, 2H), 3.02 (q, J=7.5 Hz, 2H), 3.39
(t, J=3.3 Hz, 1H), 3.41 (AB, J=15.0 Hz, 2H), 3.81 (m, 2H), 3.88 (s,
3H), 3.89 (s, 3H), 4.21 (m, 1H), 5.06 (d, J=9.0 Hz, 1H), 5.20 (d,
J=5.4 Hz, 2H), 6.06 (d, J=9.0 Hz, 1H), 6.76 (s, 1H), 6.82 (s, 2H),
7.13-7.23 (m, 7H), 7.61 (s, 1H), 8.27 (br s, 1H).
EXAMPLE 21
2-Methyl-5-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-4-[(3,4-dimethoxylph-
enyl)methyl]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-2-hydro-
xy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0210] 21 A.
2-Methyl-5-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-4-[1,1--
dimethylethyloxy(carbonyl)]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piper-
azinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]ca-
rbamate.
[0211] The title compound was prepared according to the method
described in Example 19A, substituting
[(2-methyl-5-thiazolyl)methyloxycarbonyl]-L-- valine in place of
[(2-isopropyl-5-thiazolyl)methyloxycarbonyl]-L-valine.
[0212] 21B.
2-Methyl-5-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-4-[(3,4--
dimethoxylphenyl)methyl]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazi-
nyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carba-
mate.
[0213] The title compound was prepared in two steps. First,
2-methyl-5-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-4-[1,1-dimethylethy-
loxy(carbonyl)]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-2-hy-
droxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
was treated with trifluoroacetic acid according to the method
described in Example 1D. This was followed by akylation of the
product according to the method of Example 1E, substituting
3,4-dimethylbenzyl chloride in place of 3,4-dioxomethylenebenzyl
chloride.
[0214] MS: 753 (M+H).sup.+.
[0215] .sup.1H NMR (CDCl.sub.3) .delta. 0.72 (d, J=6.3 Hz, 3H),
0.86 (d, J=6.3 Hz, 3H), 1.46 (s, 9H), 2.01 (hextet, J=6.0 Hz, 1H),
2.22 (dt, J=7.5, 3.0 Hz, 1H), 2.43 (dd, J=12.0, 3.0 Hz, 1H), 2.56
(m, 2H), 2.69 (s, 3H), 2.72 (m, 1H), 2.77 (m, 1H), 2.86 (m, 2H),
2.92 (m, 1H), 3.39 (t, J=3.0 Hz, 1H), 3.41 (AB, J=15.0 Hz, 2H),
3.80 (m, 2H), 3.87 (s, 3H), 3.88 (s, 3H), 4.21 (septet, J=4.5 Hz,
1H), 5.06 (d, J=9.0 Hz, 1H), 5.19 (AB, J=9.6 Hz, 2H), 6.07 (d,
J=9.0 Hz, 1H), 6.75 (s, 1H), 6.82 (s, 2H), 7.12-7.22 (m, 7H), 7.58
(s, 1H), 8.27 (br s, 1H).
EXAMPLE 22
N'-[(1R)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-Dimethylethyl)amino]carbonyl]-4-(5--
thiazolylmethyl)-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]car-
bonyl]-2-methylpropyl]-N-methyl-N-(5-thiazolylmethyl)urea
[0216] 22A.
N'-[(1R)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-Dimethylethyl)amino]car-
bonyl]-4-[1,1-dimethylethyloxy(carbonyl)]-1-piperazinyl]-2-hydroxy-1-(phen-
ylmethyl)propyl]amino]carbonyl]-2-methylpropyl]-N-methyl-N-(5-thiazolylmet-
hyl)urea.
[0217] The title compound was prepared according to the method
described in Example 19A, substituting
[N-methyl-(5-thiazolyl)methylaminocarbonyl]-- D-valine in place of
[(2-isopropyl-5-thiazolyl)methyloxycarbonyl]-L-valine- .
[0218] 22B.
N'-[(1R)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-Dimethylethyl)amino]car-
bonyl]-4-(5-thiazolylmethyl)-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)prop-
yl]amino]carbonyl]-2-methylpropyl]-N-methyl-N-(5-thiazolylmethyl)urea.
[0219] The title compound was prepared in two steps.
N'-[(1R)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-dimethylethyl)amino]carbonyl]-4-[1-
,1-dimethylethyloxy(carbonyl)]-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)pr-
opyl]amino]carbonyl]-2-methylpropyl]-N-methyl-N-(5-thiazolylmethyl)urea
was treated with trifluoroacetic acid according to the method
described in Example 1D. This was followed by akylation of the
product according to the method of Example 1E, substituting
5-thiazolyl chloride in place of 3,4-dioxomethylenebenzyl
chloride.
[0220] MS: 699 (M+H).sup.+.
[0221] .sup.1H NMR CDCl.sub.3) .delta. 0.58 (d, J=6.3 Hz, 3H), 0.66
(d, J=6.3 Hz, 3H), 1.38 (s, 9H), 1.75 (m, 1H), 2.35 (m, 1H), 2.60
(m, 2H), 2.70 (m, 2H), 2.85 (m, 2H), 2.86 (s, 3H), 2.92 (m, 3H),
3.30 (t, J=3.3 Hz, 1H), 3.74 (s, 2H), 3.88 (m, 1H), 3.97 (dd,
J=8.4, 6.0 Hz, 1H), 4.28 (m, 2H), 4.53 (br s, 1H), 4.65 (d, J=3.3
Hz, 2H), 5.03 (d, J=7.5, 1 H), 6.09 (d, J=9.0 Hz, 1H), 7.17-7.27
(m, 5H), 7.73 (s, 2H), 8.73 (s, 1H), 8.80 (s, 1H).
EXAMPLE 23
N'-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-Dimethylethyl)amino]carbonyl]-4-(5--
thiazolylmethyl)-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]car-
bonyl]-2-methylpropyl]-N-methyl-N-(5-thiazolylmethyl)urea
[0222] 23A.
N'-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-Dimethylethyl)amino]car-
bonyl]-4-[1,1-dimethylethyloxy(carbonyl)]-1-piperazinyl]-2-hydroxy-1-(phen-
ylmethyl)propyl]amino]carbonyl]-2-methylpropyl]-N-methyl-N-(5-thiazolylmet-
hyl)urea.
[0223] The title compound was prepared according to the method
described in Example 19A, substituting
[N-methyl-(5-thiazolyl)methylaminocarbonyl]-- L-valine in place of
[(2-isopropyl-5-thiazolyl)methyloxycarbonyl]-L-valine- .
[0224] 23B.
N'-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-Dimethylethyl)amino]car-
bonyl]-4-(5-thiazolylmethyl)-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)prop-
yl]amino]carbonyl]-2-methylpropyl]-N-methyl-N-(5-thiazolylmethyl)urea.
[0225] The title compound was prepared in two steps. First,
N'-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-dimethylethyl)amino]carbonyl]-4-[1-
,1-dimethylethyloxy(carbonyl)]-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)pr-
opyl]amino]carbonyl]-2-methylpropyl]-N-methyl-N-(5-thiazolylmethyl)urea
was treated with trifluoroacetic acid according to the method
described in Example 1D. This was followed by akylation of the
product according to the method of Example 1E, substituting
5-thiazolyl chloride in place of 3,4-dioxomethylenebenzyl
chloride.
[0226] MS: 699 (M+H).sup.+.
[0227] .sup.1H NMR (CDCl.sub.3) .delta. 0.78 (d, J=6.3 Hz, 3H),
0.87 (d, J=6.3 Hz, 3H), 1.49 (s, 9H), 2.02 (m, 1H), 2.33 (m, 2H),
2.57 (m, 2H), 2.75 (m, 2H), 2.82 (s, 3H), 2.89 (m, 3H), 3.38 (t,
J=3.0 Hz, 1H), 3.73 (d, J=3.3 Hz, 2H), 3.79 (m, 1H), 4.03 (dd,
J=8.4, 6.3 Hz, 1H), 4.20 (m, 1H), 4.66 (AB, J=15 Hz, 2H), 4.78 (m,
1H), 4.81 (d, J=8.4 Hz, 2H), 6.11 (d, J=9.0 Hz, 1H), 7.11-7.23 (m,
5H), 7.73 (s, 1H), 7.76 (s, 1H), 7.82 (br s, 1H), 8.75 (s, 1H),
8.80 (s, 1H).
EXAMPLE 24
5-Thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-dimethylethyl)amino]-
carbonyl]-4-(phenylmethyl)-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)propyl-
]amino]carbonyl]-2-methylpropyl]carbamate
[0228] 24A.
5-Thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-dimethyl-
ethyl)amino]carbonyl]-4-[1,1-dimethylethyloxy(carbonyl)]-1-piperazinyl]-2--
hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate.
[0229] The title compound was prepared according to the method
described in Example 19A, substituting
[(5-thiazolyl)methyloxycarbonyl]-L-valine, in place of
[(2-isopropyl-5-thiazolyl)methyloxycarbonyl]-L-valine.
[0230] 24B.
5-Thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-dimethyl-
ethyl)amino]carbonyl]-4-(phenylmethyl)-1-piperazinyl]-2-hydroxy-1-(phenylm-
ethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate.
[0231] The title compound was prepared in two steps. First,
5-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-dimethylethyl)amino-
]carbonyl]-4-[1,1-dimethylethyloxy(carbonyl)]-1-piperazinyl]-2-hydroxy-1-(-
phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate was
treated with trifluoroacetic acid according to the method described
in Example 1D. This was followed by akylation of the product
according to the method of Example 1E, substituting benzyl bromide
in place of 3,4-dioxomethylenebenzyl chloride.
[0232] MS: 699 (M+H).sup.+.
[0233] .sup.1H NMR CDCl.sub.3) .delta. 0.78 (d, J=6.3 Hz, 3H), 0.87
(d, J=6.3 Hz, 3H), 1.49 (s, 9H), 2.02 (m, 1H), 2.33 (m, 2H), 2.57
(m, 2H), 2.75 (m, 2H), 2.82 (s, 3H), 2.89 (m, 3H), 3.38 (t, J=3.0
Hz, 1H), 3.73 (d, J=3.3 Hz, 2H), 3.79 (m, 1H), 4.03 (dd, J=8.4, 6.3
Hz, 1H), 4.20 (m, 1H), 4.66 (AB, J=15 Hz, 2H), 4.78 (m, 1H), 4.81
(d, J=8.4 Hz, 2H), 6.11 (d, J=9.0 Hz, 1H), 7.11-7.23 (m, 5H), 7.73
(s, 1H), 7.76 (s, 1H), 7.82 (br s, 1H), 8.75 (s, 1H), 8.80 (s,
1H).
EXAMPLE 25
5-Thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-dimethylethyl)amino]c-
arbonyl]-4-(5-thiazolylmethyl)-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)pr-
opyl]amino]carbonyl]-2-methylpropyl]carbamate
[0234] The title compound was prepared according to the method
described in Example 24B, by akylation of
5-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(-
2S)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-2-hydroxy-1-(phe-
nylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate with
5-thiazolyl methyl chloride in place of benzyl bromide.
[0235] MS: 686 (M+H).sup.+.
[0236] .sup.1H NMR (CDCl.sub.3) .delta. 0.62 (d, J=6.3 Hz, 3H),
0.86 (d, J=6.3 Hz, 3H), 1.39 (s, 9H), 2.01 (m, 1H), 2.30 (m, 1H),
2.52 (m, 1H), 2.67 (m, 2H), 2.71 (m, 1H), 2.75 (m, 2H), 2.87 (m,
2H), 2.92 (m, 1H), 3.29 (t, J=3.0 Hz, 1H), 3.74 (d, J=4.5 Hz, 2H),
4.80 (m, 2H), 4.85 (m, 1H), 4.21 (m, 1H), 5.08 (t, J=9.0 Hz, 1H),
5.18 (d, J=4.5 Hz, 1H), 6.07 (d, J=9.6 Hz, 2H), 7.11-7.24 (m, 5H),
7.74 (s, 1H), 7.88 (s, 1H), 8.80 (s, 1H), 8.81 (s, 1H).
EXAMPLE 26
N'-[(1S)-1-[[[(1S,2R)-3-[[[(1,1-Dimethylethyl)amino]carbonyl](2-methylethy-
l)propylamino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpr-
opyl]-N-methyl-N-[2-(1-methylethyl)-4-thiazolylmethyl]urea
[0237] The title compound was prepared according to the method
described in Example 12A, by coupling
N-methyl-N-[(((2-isopropyl-4-thiazolyl)methyl-
)amino)-carbonyl]-L-valine with
N-(3S-amino-2R-hydroxy-4-phenylbutyl)-N-(2-
-methylpropyl)-N'-(1,1-dimethylethyl)urea, prepared according to
the method described in J. Med. Chem., 1993, 36, 288-291.
[0238] Elemental analysis: Theory: C: 62.34, H: 8.44, N: 13.64
Found: C: 59.60, H: 7.37, N: 12.86
Example 27
2-(1-Methylethyl)-4-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[[[(1,1-dimethyle-
thyl)amino]carbonyl](2-methylethyl)propylamino]-2-hydroxy-1-(phenylmethyl)-
propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0239] The title compound was prepared according to the method
described in Example 26, by coupling
N-[(2-isopropyl-4-thiazolyl)methyloxycarbonyl]- -L-valine with
N-(3S-amino-2R-hydroxy-4-phenylbutyl)-N-(2-methylpropyl)-N'-
-(1,1-dimethylethyl)urea, prepared according to the method
described in J. Med. Chem., 1993, 36, 288-291.
[0240] Elemental analysis: Theory: C: 61.69, H: 8.13, N: 11.61
Found: C: 60.80, H: 8.21, N: 11.18
EXAMPLE 28
2-(1-Methylethyl)-4-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[[(4-aminophenyl)s-
ulfonyl](1-methylethyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbo-
nyl]-2-methylpropyl]carbamate
[0241] The title compound was prepared in two steps. First,
N-isobutyl-2(R)-hydroxy-3(S)-amino-4-phenyl-(4'-nitrophenyl)sulfonamide,
prepared according to the method described in J. Am. Chem. Soc.,
1995, 117, 1181-1182, was coupled with
[(2-isopropyl-4-thiazolyl)methyloxycarbo- nyl]-L-valine according
to the method described in Example 1C. This was followed by
hydrogenation of the product over Pd/C under 1 atmosphere of
hydrogen. The catalyst was removed via filtration over a celite pad
and the solvent was evaporated at reduced pressure to provide the
title compound as a white foam.
[0242] MS: 674 (M+H).sup.+.
[0243] .sup.1H NMR (DMSO-d.sub.6) .delta. 0.65 (d, J=6.3 Hz, 3H),
0.67 (d, J=6.3 Hz, 3H), 0.77 (d, J=6.0 HZ, 3H), 0.81 (t, J=6.0 HZ,
3H), 1.32 (d, J=6.3 Hz, 6H), 1.77 (m, 1H), 1.90 (m, 1H), 2.60 (m,
2H), 2.65 (m, 1H), 2.72 (m, 1H), 2.83 (d, J=7.5 Hz, 1H), 2.89 (d,
J=9.0 Hz, 1H), 3.00 (m, 2H), 3.25 (m, 1H), 3.61 (m, 1H), 3.75 (dd,
J=9.0, 6.3 Hz, 1H), 3.94 (m, 1H), 4.96 (d, J=6.3 Hz, 1H), 5.02 (s,
2H), 5.98 (s, 2H), 6.60 (t, J=9.0 Hz, 2H), 7.10 (m, 2H), 7.15-7.22
(m, 3H), 7.39 (d, J=8.4 Hz, 2H), 7.43 (s, 1H), 7.72 (d, J=9.0 Hz,
1H).
EXAMPLE 29
N'-[(1S)-1-[[[(1S,2R)-3-[[(4-Aminophenyl)sulfonyl](1-methylethyl)amino]-2--
hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]-N-methyl-N--
[2-(1-methylethyl)-4-thiazolylmethyl]urea
[0244] The title compound was prepared in two steps. First,
N-isopropyl-2(R)-hydroxy-3(S)-amino-4-phenyl-(4'-nitrophenyl)sulfonamide
was coupled with
N-methyl-N-[(((2-isopropyl-4-thiazolyl)methyl)amino)carb-
onyl]-L-valine according to the method described in Example 12A.
This was followed by hydrogenation of the product over Pd/C under 1
atmosphere of hydrogen. The catalyst was removed via filtration
over a celite pad and the solvent was evaporated at reduced
pressure to provide the title compound as a white foam.
[0245] MS: 674 (M+H).sup.+.
[0246] Elemental analysis: Theory: C: 58.93, H: 7.14, N: 12.50
Found: C: 58.30, H: 7.28, N: 12.11
EXAMPLE 30
2-(1-Methylethyl)-5-thiazolylmethyl-[(1S)-1-[[[(1S,2R)-3-[(3S)-3-[[(1,1-di-
methylethyl)amino]carbonyl](4a.alpha.,8a.alpha.)octahydro-2-isoquinolinyl]-
-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0247] The title compound was prepared according to the method
described in Example 1C, by coupling
2-(3(S)-amino-2(R)-hydroxy-4-phenylbutyl)-N-te-
rt-butyldecahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide with
[(2-isopropyl-4-thiazolyl)methyloxycarbonyl]-L-valine, prepared
according to the method described in J. Org Chem., 1994, 59,
3656-3664.
[0248] Elemental analysis: Theory: C: 65.01, H: 8.35, N: 10.25
Found: C: 63.70, H: 8.19, N: 10.05
EXAMPLE 31
N'-[(1S)-1-[[[(1S,2
R)-3-[(3S)-3-[[(1,1-Dimethylethyl)amino]carbonyl](4a.a-
lpha.,8a.alpha.)-octahydro-2-isoquinolinyl]-2-hydroxy-1-(phenylmethyl)prop-
yl]amino]carbonyl]-2-methylpropyl]-N-methyl-N-[2-(1-methylethyl)-5-thiazol-
ylmethyl]urea
[0249] The title compound was synthesized according to the method
described in Example 12A by coupling of
2-(3(S)-amino-2(R)-hydroxy-4-phen-
ylbutyl)-N-tert-butyldecahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide
with
N-methyl-N-[(((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl]-L-vali-
ne which was prepared according to the method described in J. Org
Chem., 1994, 59, 3656-3664.
[0250] Elemental analysis: Theory: C: 65.52, H: 8.62, N: 12.07
Found: C: 64.50, H: 8.72, N: 12.09
EXAMPLE 32
N'-[(1S)-1-[[[(1S,2R)-3-[(2S,4R)-2-[[(1,1-Dimethylethyl)amino]carbonyl]-4--
(5-thiazolylmethoxy)-1-piperidinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino-
]carbonyl]-2-methylpropyl]-N-methyl-N-[2-(1-methylethyl)-4-thiazolylmethyl-
]urea
[0251] 32A.
1-cis-N-(1,1-Dimethylethyl)-1-(1,1-dimethylethyloxycarbonyl)-4-
-(5-thiazolylmethyloxy)piperidine-2-carboxamide.
[0252]
1-cis-N-(1,1-Dimethylethyl)-1-(1,1-dimethylethyloxycarbonyl)-4-hydr-
oxy-piperidine-2-carboxamide was prepared according to the methods
described in EP 560 268 A1. The hydroxy-carboxamide compound was
treated with sodium hydride and 5-thiazolyl methyl chloride in DMF
at 0.degree. C. to provide the title compound.
[0253] 32B. 1-cis
N-(1,1-Dimethylethyl)-4-(5-thioazoylmethyloxy)piperidine-
-2-carboxamide.
[0254] A solution of 1.24 g of
1-cis-N-(1,1-dimethylethyl)-1-(1,1-dimethyl-
ethyloxycarbonyl)-4-(5-thiazolylmethyloxy)piperidine-2-carboxamide
in 10 ml of THF was prepared. The mixture was treated with 3 N HCl,
and stirred at room temperature for 1 hour. After stirring, the
reaction was it was partitioned between methylene chloride and
saturated sodium bicarbonate. The organic layer was washed with
brine, dried with Na.sub.2SO.sub.4 and evaporated to dryness to
provide 836 mg of desired product.
[0255] 32C.
N'-[(1S)-1-[[[(1S,2R)-3-[(2S,4R)-2-[[(1,1-Dimethylethyl)amino]-
carbonyl]-4-(5-thiazolylmethoxy)-1-piperidinyl]-2-hydroxy-1-(phenylmethyl)-
propyl]amine.
[0256] The title compound was synthesized in two steps.
N'-[(1S)-1-[[[(1S,2R)-3-[(2S,4R)-2-[[(1,1-Dimethylethyl)amino]carbonyl]-4-
-(5-thiazolylmethoxy)-1-piperidinyl]-2-hydroxy-1-(phenylmethyl)propyl]amin-
e was prepared according to the method described in Example 1A by
using t-butyloxycarbonyl phenylalanylepoxide replacing
N-benzyloxycarbonyl phenylalanylepoxide followed by column
purification. The resulting product was treated with
trifluoroacetic acid (TFA) in methylene chloride at room
temperature.
[0257] 32D.
N'-[(1S)-1-[[[(1S,2R)-3-[(2S,4R)-2-[[(1,1-Dimethylethyl)amino]-
carbonyl]-4-(5-thiazolylmethoxy)-1-piperidinyl]-2-hydroxy-1-(phenylmethyl)-
propyl]amino]carbonyl]-2-methylpropyl]-N-methyl-N-[2-(1-methylethyl)-4-thi-
azolylmethyl]urea.
[0258] The title compound was synthesized by the method described
in Example 12A using
N'-[(1S)-1-[[[(1S,2R)-3-[(2S,4R)-2-[[(1,1-dimethylethyl-
)amino]carbonyl]-4-(5-thiazolylmethoxy)-1-piperidinyl]-2-hydroxy-1-(phenyl-
methyl)propyl]amine and
N-methyl-N-[(((2-isopropyl-4-thiazolyl)methyl)amin-
o)carbonyl]-L-valine.
[0259] MS: 756 (M+H).sup.+.
[0260] .sup.1H NMR (CDCl.sub.3) d 0.65 (d, J=6.3 Hz, 3H), 0.92 (d,
J=6.3 Hz, 3H), 1.32 (d, J=3.0 HZ, 3H), 1.34 (d, J=3.0 Hz, 2H), 1.35
(s, 9H), 1.53 (m, 1H), 1.58 (m, 1H), 1.91 (m, 1H), 2.20 - 2.37 (m,
4H), 2.67 (m, 1H), 2.69 (m, 1H), 2.80 (dd, J=11.4, 3.0 Hz, 1H),
2.87 (dd, J=15.0, 3.3 Hz, 1H), 2.97 (s, 3H), 3.21 (heptet, J=6.3
Hz, 1H), 3.40 (t, J=4.5 Hz, 1H), 3.44 (m, 1H), 3.91 (t, J=5.7 Hz,
1H), 4.03 (m, 2H), 4.12 (m, 1H), 4.35 (AB, J=15.0 Hz, 2H), 4.78
(AB, J=12.0 Hz, 2H), 6.48 (d, J=8.1 Hz, 1H), 6.61 (s, 1H), 7.00 (s,
1H), 7.09-7.18 (m, 6H), 7.78 (s, 1H), 8.79 (s, 1H).
EXAMPLE 33
2-(1-Methylethyl)-4-thiazolylmethyl
[(1S)-1-[[[(1S,2R)-3-[(2S,4R)-2-[[(1,1-
-dimethylethyl)amino]carbonyl]-4-(5-thiazolylmethoxy)-1-piperidinyl]-2-hyd-
roxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate
[0261] The title compound is prepared according to the procedure
described in example 32C using
N-[(2-isopropyl-4-thiazolyl)methyloxycarbonyl]-L-val- ine in place
of N-methyl-N-[(((2-isopropyl-4-thiazolyl)methyl)amino)carbon-
yl]-L-valine as a coupling reagent.
EXAMPLE 34
S-[2-(1-Methylethyl)-4-thiazolylmethyl]
[(1S)-1-[[[(1S,2R)-3-[(2S)-4-(1,3--
benzodioxol-5-ylmethyl)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazin-
yl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbam-
othioate
[0262] 34A. 2-Isopropyl-4-(methanesulfonyloxymethyl)thiazole.
[0263] A solution of 1.2 mmol of
4-(hydroxymethyl)-2-isopropylthiazole and 1.3 mmol of
diisopropylethylamine in 20 ml of dichloromethane is cooled to
-20.degree. C. and treated dropwise with 1.3 mmol of
methanesulfonyl chloride. The resulting mixture is stirred for 1
hour, quenched with aqueous citric acid, separated, dried over
Na.sub.2SO.sub.4, and concentrated in vacuo to provide the title
compound.
[0264] 34B. 2-Isopropyl-4-(mercaptomethyl)thiazole.
[0265] A mixture of 0.8 mmol of the product prepared in Example 34A
and 1.0 mmol of sodium hydrosulfide hydrate in 20 ml of THF is
heated at reflux until analysis by thin layer chromatography
indicates consumption of the starting material. The resulting
mixture is allowed to cool, concentrated in vacuo, partitioned
between dichloromethane and water, dried over Na.sub.2SO.sub.4, and
concentrated to provide the crude compound.
[0266] 34C. N-((2-Isopropyl-4-thiazolyl)thiomethoxycarbonyl)valine
methyl ester.
[0267] A solution of 2.18 g (15 mmol) of
2-Isopropyl-4-(mercaptomethyl)thi- azole, 15.8 mmol of
.alpha.-isocyanato-valine methyl ester and 1.5 mmol of
4-dimethylaminopyridine in 75 ml of dichloromethane is heated at
reflux for about 5 hours. The resulting solution is washed
successively with 10% citric acid, aqueous NaHCO.sub.3 and brine,
dried over Na.sub.2SO.sub.4, and concentrated ion vacuo. Silica gel
chromatography of the residue using 5% ethyl acetate in chloroform
will provide the title compound.
[0268] 34D.
N-((2-Isopropyl-4-thiazolyl)thiomethoxycarbonyl)valine.
[0269] A solution of product, prepared in Example 34C in dioxane is
treated with 0.50 M aqueous LiOH. The resulting solution is stirred
at ambient temperature for about 30 minutes, treated with 1 M HCl,
and concentrated in vacuo. The residue is taken up in
dichloromethane, washed with water, dried over Na.sub.2SO.sub.4,
and concentrated in vacuo to provide the title compound.
[0270] 34E. S-[2-(1-Methylethyl)-4-thiazolylmethyl
[(1S)-1-[[[(1S,2R)-3-[(-
2S)-2-[[(1,1-dimethylethyl)amino]carbonyl-4-[[(1,1-dimethylethyl)carbonyl]-
oxy]-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-met-
hylpropyl]carbamothioate.
[0271] The title compound is prepared according to the method
described in Example 10, substituting
N-((2-Isopropyl-4-thiazolyl)thiomethoxycarbonyl)- valine in place
of [(2-isopropyl-4-thiazolyl)methyloxycarbonyl]-L-valine.
[0272] 34F.
S-[2-(1-Methylethyl)-4-thiazolylmethyl[(1S)-1-[[[(1S,2R)-3-[(2-
S)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-2-hydroxy-1-(phen-
ylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamothioate.
[0273] The title compound is prepared according to the method
described in Example 1D, substituting
S-[2-(1-methylethyl)-4-thiazolylmethyl]
[(1S)-1-[[[(1S,2R)-3-[(2S)-4-(1,1-dimethylethyloxy(carbonyl))-2-[[(1,1-di-
methylethyl)amino]carbonyl]-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)propy-
l]amino]carbonyl]-2-methylpropyl]carbamothioate in place of
2-(1-methylethyl)-4-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[(2S)-4-(1,1-dime-
thylethyloxy(carbonyl))-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazin-
yl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbam-
ate.
[0274] 34G.
S-[2-(1-Methylethyl)-4-thiazolylmethyl][(1S)-1-[[[(1S,2R)-3-[(-
2S)-4-(1,3-benzodioxol-5-ylmethyl)-2-[[(1,1-dimethylethyl)amino]carbonyl]--
1-piperazinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpr-
opyl]carbamothioate
[0275] The title compound is prepared according to the method
described in Example 1E, substituting
S-[2-(1-methylethyl)-4-thiazolylmethyl]
[(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piper-
azinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]ca-
rbamothioate in place of
2-(1-methylethyl)-4-thiazolylmethyl-(1S)-1-[[[(1S-
,2R)-3-[(2S)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinyl]-2-hydro-
xy-1-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate.
EXAMPLE 35
4-(1,3-Benzodioxol-5-ylmethyl)-N-(1,1-dimethylethyl)-1-[(2R,3S)-3-[[(2S)-2-
-[[3-[2-(1-methylethyl)-4-thiazolyl]-1-oxopropyl]amino]-3-methyl-1-oxobuty-
l]amino]-2-hydroxy-4-phenylbutyl]-2-piperazinecarboxamide
[0276] 35A. 2-Isopropylthiazole-4-carboxaldehyde.
[0277] A solution of 3.1 g (15.6 mmol) of ethyl
2-isopropylthiazole-4-carb- oxylate in 50 ml of dichloromethane was
cooled under N.sub.2 atmosphere to -78.degree. C. and treated
dropwise with 15.6 ml (23.4 mmol) of a 1.5 M solution of
diisobutylaluminum hydride in toluene over a period of 1.5 h. After
being stirred for an additional 0.5 h, the solution was quenched
with 5 ml of methanol followed by 15 ml of aqueous Rochelle's salt.
The resulting mixture was partitioned between chloroform and
aqueous Rochelle's salt, dried over Na.sub.2SO.sub.4, and
concentrated to provide 1.37 g (56%) of the crude desired compound,
R.sub.f 0.47 (20% ethyl acetate in hexane).
[0278] .sup.1H NMR (CDCl.sub.3) d 1.45 (d, J=7 Hz, 6 H), 3.39
(heptet, J=7 Hz, 1H), 8.07 (s, 1H), 10.00 (s, 1H).
[0279] Mass spectrum: (M+H).sup.+=156.
[0280] 35B. (E)-Ethyl 3-(2-Isopropyl-4-thiazolyl)propenoate.
[0281] A slurry of 60% NaH (18 mmol) in mineral oil was washed with
hexane, decanted under N.sub.2 atmosphere, and diluted with 25 ml
of THF. The resulting mixture was cooled to 0.degree. C., treated
portionwise with 3.24 ml (16.4 mmol) of triethylphosphonoacetate.
After addition, the solution was stirred for 10 minutes, treated
with 1.37 g (8.84 mmol) of 2-isopropylthiazole-4-carboxaldehyde in
25 ml of THF, allowed to warm to ambient temperature for 25
minutes, and quenched with 100 ml of saturated aqueous NH.sub.4Cl.
The mixture was extracted with three 100 ml portions of ethyl
acetate, dried over Na.sub.2SO.sub.4, and concentrated in vacuo,
Silica gel chromatography of the residue using 5-10% ethyl acetate
in hexane provided 1.61 g (81%) of the desired compound, R.sub.f
0.64 (20% ethyl acetate in hexane).
[0282] .sup.1H NMR (CDCl.sub.3) d 1.33 (t, J=7 Hz, 3 H), 1.42 (d,
J=7 Hz, 6 H), 3.32 (heptet, J=7 Hz, 1H), 4.26 (q, J=7 Hz, 2 H),
6.75 (d, J=15 Hz, 1H), 7.29 (s, 1H), 7.57 (d, J=15 Hz, 1H).
[0283] 35C. Methyl 3-(2-Isopropyl-4-thiazolyl)propanoate.
[0284] A solution of 225 mg (1 mmol) of (E)-ethyl
3-(2-isopropyl-4-thiazol- yl)propenoate in 10 ml of freshly
distilled (from calcium hydride) methanol and 1 ml of dry THF is
treated with 49 mg (2 mmol) of magnesium turnings. The mixture is
stirred for 20 minutes, and the magnesium is consumed. The
resulting solution is poured over cold aqueous HCl, basified to pH
8 with NaHCO.sub.3, extracted with ethyl acetate, dried over
Na.sub.2SO.sub.4, and concentrated. Silica gel chromatography using
10% ethyl acetate in hexane provides a mixture of the desired
compound and methyl 3-(2-isopropyl-4-thiazolinyl)propanoate.
[0285] 35D. 3-(2-Isopropyl-4-thiazolyl)propanoic Acid.
[0286] A solution of product, prepared in Example 35C in dioxane is
treated with 0.50 M aqueous LiOH. The resulting solution is stirred
at ambient temperature for about 30 minutes, treated with 8.7 ml of
1 M HCl, and concentrated in vacuo. The residue is taken up in
dichloromethane, washed with water, dried over Na.sub.2SO.sub.4,
and concentrated in vacuo to provide the title compound.
[0287] 35E.
N-(1,1-Dimethylethyl)-4-[[(1,1-dimethylethyl)carbonyl]oxy]-1-[-
(2R,3S)-3-[[(2S)-2-[[3-[2-(1-methylethyl)-4-thiazolyl]-1-oxopropyl]amino]--
3-methyl-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]-2-piperazinecarboxamid-
e.
[0288] A solution of 3-(2-isopropyl-4-thiazolyl)propanoic acid, 1,1
equivalents of .alpha.-isocyanato-valine methyl ester and
4-dimethylaminopyridine (catalytic) in of dichloromethane is heated
at reflux for about 5 hours. The resulting solution is washed
successively with 10% citric acid, aqueous NaHCO.sub.3 and brine,
dried over Na.sub.2SO.sub.4, and concentrated in vacuo. Silica gel
chromatography of the residue using 5% ethyl acetate in chloroform
to provide the title compound.
[0289] 35F.
N-(1,1-Dimethylethyl)-1-[(2R,3S)-3-[[(2S)-2-[[3-[2-(1-methylet-
hyl)-4-thiazolyl]-1-oxopropyl]amino]-3-methyl-1-oxobutyl]amino]-2-hydroxy--
4-phenylbutyl]-2-piperazinecarboxamide.
[0290] The title compound is prepared according to the method
described in Example 1C, substituting
N-((2-Isopropyl-4-thiazolyl)propionyl)valine in place of
[(2-isopropyl-4-thiazolyl)methyloxycarbonyl]-L-valine.
[0291] 35G.
N-(1,1-Dimethylethyl)-1-[(2R,3S)-3-[[(2S)-2-[[3-[2-(1-methylet-
hyl)-4-thiazolyl]-1-oxopropyl]amino]-3-methyl-1-oxobutyl]amino]-2-hydroxy--
4-phenylbutyl]-2-piperazinecarboxamide.
[0292] The title compound is prepared according to the method
described in Example 1D, substituting
4-(1,1-dimethylethyloxy(carbonyl))-N-(1,1-dimeth- ylethyl)-1-[(2R
,3S)-3-[[(2S)-2-[[3-[2-(1-methylethyl)-4-thiazolyl]-1-oxop-
ropyl]amino]-3-methyl-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]-2-piperaz-
inecarboxamide in place of
2-(1-methylethyl)-4-thiazolylmethyl-(1S)-1-[[[(-
1S,2R)-3-[(2S)-4-(1,1-dimethylethyloxy(carbonyl))-2-[[(1,1-dimethylethyl)a-
mino]carbonyl]-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbo-
nyl]-2-methylpropyl]carbamate.
[0293] 35H.
4-(1,3-Benzodioxol-5-ylmethyl)-N-(1,1-dimethylethyl)-1-[(2R,3S-
)-3-[[(2S)-2-[[3-[2-(1-methylethyl)-4-thiazolyl-1-oxopropyl]amino]-3-methy-
l-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]-2-piperazinecarboxamide.
[0294] The title compound is prepared according to the method
described in Example 1E, substituting
N-(1,1-dimethylethyl)-1-[(2R,3S)-3-[[(2S)-2-[[3--
[2-(1-methylethyl)-4-thiazolyl]-1-oxopropyl]amino]-3-methyl-1-oxobutyl]ami-
no]-2-hydroxy-4-phenylbutyl]-2-piperazinecarboxamide in place of
2-(1-methylethyl)-4-thiazolylmethyl-(1S)-1-[[[(1S,2R)-3-[(2S)-2-[[(1,1-di-
methylethyl)amino]carbonyl]-1-piperazinyl]-2-hydroxy-1-(phenylmethyl)propy-
l]amino]carbonyl]-2-methylpropyl]carbamate.
Fluorogenic Assay for Screening Inhibitors of HIV Protease
[0295] The inhibitory potency of the compounds of the invention can
be determined by the following method:
[0296] A compound of the invention is dissolved in DMSO. A small
aliquot is diluted with DMSO to 100 times the final concentration
desired for testing. The test is carried out in a 6.times.50 mm
tube in a total volume of 300 microliters. The final concentrations
of the components in the reaction buffer are: 125 mM sodium
acetate, 1 M sodium chloride, 5 mM dithiothreitol, 0.5 mg/ml bovine
serum albumin, 1.3 .mu.M fluorogenic substrate, 2% (v/v)
dimethylsulfoxide, pH 4.5. After addition of inhibitor, the
reaction mixture is placed in the fluorometer cell holder and
incubated at 30.degree. C. for several minutes. The reaction is
initiated by the addition of a small aliquot of cold HIV protease.
The fluorescence intensity (excitation 340 nM, emmision 490 nM) is
recorded as a function of time. The reaction rate is determined for
the first six to eight minutes. The observed rate is directly
proportional to the moles of substrate cleaved per unit time. The
percent inhibition is 100.times.(1- (rate in presence of
inhibitor)/(rate in absence of inhibitor)).
[0297] Fluorogenic substrate:
Dabcyl-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-EDANS wherein
DABCYL=4-(4-dimethylaminophenyl)azobenzoic acid and
EDANS=5-((2-aminoethyl)amino)naphthalene-1-sulfonic acid. All
compounds tested at 1.0 nM were found to have an IC.sub.50 of 100%.
The test compounds were then tested at a concentration of 0.5 nM.
The results are reported as percent inhibition, in Table 1,
below.
1 TABLE 1 Example No. % Inhib. (0.5 nM) Example 1 60% Example 2 66%
Example 3 64% Example 4 67% Example 5 69% Example 6 60% Example 7
73% Example 8 54% Example 9 65% Example 10 70% Example 11 62%
Example 12 61% Example 13 66% Example 14 63% Example 15 45% Example
16 49% Example 17 50% Example 18 82% Example 19 51% Example 20 37%
Example 21 44% Example 23 51% Example 24 40% Example 25 45% Example
26 42% Example 27 50% Example 28 77% Example 29 64% Example 30 55%
Example 31 48% Example 32 66%
[0298] Table 1 shows the inhibitory potencies of compounds of the
invention against HIV-1 protease.
Antiviral Activity
[0299] The anti-HIV activity of the compounds of the invention can
be determined in MT4 cells according to the procedure of Kempf, et.
al. (Antimicrob. Agents Chemother. 1991, 35, 2209). The IC.sub.50
is the concentration of compound that gives 50% inhibition of the
cytopathic effect of HIV. The LC.sub.50 is the concentration of
compound at which 50% of the cells remain viable.
2TABLE 2 Example No. EC.sub.50(nM) LC.sub.50(.mu.M) Example 1 3
12.76 Example 2 22 47.11 Example 3 21 15.73 Example 4 12 68.95
Example 5 40 16.70 Example 6 12 58.61 Example 7 17 55.20 Example 8
47 18.90 Example 9 46 18.45 Example 10 14 18.18 Example 11 17 18.33
Example 12 13 70.34 Example 13 48 60.35 Example 14 41 22.74 Example
15 11 53.09 Example 16 10 61.73 Example 17 11 39.17 Example 18 19
44.64 Example 19 17 20.69 Example 20 16 49.74 Example 21 11 53.05
Example 23 259 >100 Example 24 17 55.42 Example 25 57 >100
Example 26 817 17.35 Example 27 374 20.60 Example 28 11 49.52
Example 29 175 31.15 Example 30 20 17.87 Example 31 58 17.22
Example 32 15 64.14
[0300] 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 (isethionate), lactate, maleate,
methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,
pamoate, pectinate, persulfate, 3-phenylpropionate, picrate,
pivalate, propionate, succinate, tartrate, thiocyanate,
p-toluenesulfonate and undecanoate. Also, the basic
nitrogen-containing groups can be quaternized with such agents as
lower alkyl halides, such as methyl, ethyl, propyl, and butyl
chloride, bromides, and iodides; dialkyl sulfates like dimethyl,
diethyl, dibutyl, and diamyl sulfates, long chain halides such as
decyl, lauryl, myristyl and stearyl chlorides, bromides and
iodides, aralkyl halides like benzyl and phenethyl bromides, and
others. Water or oil-soluble or dispersible products are thereby
obtained.
[0301] Examples of acids which may be employed to form
pharmaceutically acceptable acid addition salts include such
inorganic acids as hydrochloric acid, sulfuric acid and phosphoric
acid and such organic acids as oxalic acid, maleic acid, succinic
acid and citric acid. Other salts include salts with alkali metals
or alkaline earth metals, such as sodium, potassium, calcium or
magnesium or with organic bases.
[0302] Preferred salts of the compounds of the invention include
hydrochloride, methanesulfonate, sulfonate, phosphonate and
isethionate.
[0303] The compounds of the present invention can also be used in
the form of esters. Examples of such esters include a
hydroxyl-substituted compound of formula I or II which has been
acylated with a blocked or unblocked amino acid residue, a
phosphate function, a hemisuccinate residue, an acyl residue of the
formula R.sup.14C(O)-- or R.sup.14C(S)-- wherein R.sup.14 is
hydrogen, lower alkyl, haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl,
thioalkoxyalkyl or haloalkoxy, or an acyl residue of the formula
R.sup.a--C(R.sup.b)(R.sup.d)--C(O)-- or R.sup.a--C(R.sup.b)(R.sup-
.d)--C(S)-- wherein R.sup.b and R.sup.d are independently selected
from hydrogen or lower alkyl and R.sup.a is --N(R.sup.e)(R.sup.f),
OR.sup.e or --SR.sup.e wherein R.sup.e and R.sup.f are
independently selected from hydrogen, lower alkyl and haloalkyl, or
an amino-acyl residue having the formula
R.sup.15NH(CH.sub.2).sub.2NHCH.sub.2C(O)-- or
R.sup.15NH(CH.sub.2).sub.2OCH.sub.2C(O)-- wherein R.sup.15 is
hydrogen, lower alkyl, arylalkyl, cycloalkylalkyl, alkanoyl,
benzoyl or an .alpha.-amino acyl group. The amino acid esters of
particular interest are glycine and lysine; however, other amino
acid residues can also be used, including those wherein the amino
acyl group is --C(O)CH.sub.2NR.sup.16R.sup.17 wherein R.sup.16 and
R.sup.17 are independently selected from hydrogen and lower alkyl,
or the group --NR.sup.16R.sup.17, where R.sup.16R.sup.17, taken
together, forms a nitrogen containing heterocyclic ring. These
esters serve as pro-drugs of the compounds of the present invention
and serve to increase the solubility of these substances in the
gastrointestinal tract. These esters also serve to increase
solubility for intravenous administration of the compounds. Other
prodrugs include a hydroxyl-substituted compound of formula I or II
wherein the hydroxyl group is functionalized with a substituent of
the formula --CH(R.sup.18)OC(O)R.sup.19 or
--CH(R.sup.18)OC(S)R.sup.19 wherein R.sup.19 is lower alkyl,
haloalkyl, alkoxy, thioalkoxy or haloalkoxy and R.sup.18 is
hydrogen, lower alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl,
alkylaminocarbonyl or dialkylaminocarbonyl. Such prodrugs can be
prepared according to the procedure of Schreiber (Tetrahedron Lett.
1983, 24, 2363) by ozonolysis of the corresponding methallyl ether
in methanol followed by treatment with acetic anhydride.
[0304] The prodrugs of this invention are metabolized in vivo to
provide the hydroxyl-substituted compound of formula I or II. The
preparation of the prodrug esters is carried out by reacting a
hydroxyl-substituted compound of formula I or II with an activated
amino acyl, phosphoryl, hemisuccinyl or acyl derivative as defined
above. The resulting product is then deprotected to provide the
desired pro-drug ester. Prodrugs of the invention can also be
prepared by alkylation of the hydroxyl group with (halo)alkyl
esters, transacetalization with bis-(alkanoyl)acetals or
condensation of the hydroxyl group with an activated aldehyde
followed by acylation of the intermediate hemiacetal.
[0305] The compounds of the invention are useful for inhibiting
retroviral protease, in particular HIV protease, in vitro or in
vivo (especially in mammals and in particular in humans). The
compounds of the present invention are also useful for the
inhibition of retroviruses in vivo, especially human
immunodeficiency virus (HIV). The compounds of the present
invention are also useful for the treatment or prophylaxis of
diseases caused by retroviruses, especially acquired immune
deficiency syndrome or an HIV infection in a human or other
mammal.
[0306] Total daily dose administered to a human or other mammal
host in single or divided doses may be in amounts, for example,
from 0.001 to 300 mg/kg body weight daily and more usually 0.1 to
10 mg. Dosage unit compositions may contain such amounts of
submultiples thereof to make up the daily dose.
[0307] The amount of active ingredient that may be combined with
the carrier materials to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration.
[0308] It will be understood, however, that the specific dose level
for any particular patient will depend upon a variety of factors
including the activity of the specific compound employed, the age,
body weight, general health, sex, diet, time of administration,
route of administration, rate of excretion, drug combination, and
the severity of the particular disease undergoing therapy.
[0309] The compounds of the present invention may be administered
orally, parenterally, sublingually, by inhalation spray, rectally,
or topically in dosage unit formulations containing conventional
nontoxic pharmaceutically acceptable carriers, adjuvants, and
vehicles as desired. Topical administration may also involve the
use of transdermal administration such as transdermal patches or
iontophoresis devices. The term parenteral as used herein includes
subcutaneous injections, intravenous, intramuscular, intrasternal
injection, or infusion techniques.
[0310] Injectable preparations, for example, sterile injectable
aqueous or oleagenous 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-propanediol. 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.
[0311] 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.
[0312] Solid dosage forms for oral administration may include
capsules, tablets, pills, powders, and granules. In such solid
dosage forms, the active compound may be admixed with at least one
inert diluent such as sucrose lactose or starch. Such dosage forms
may also comprise, as is normal practice, additional substances
other than inert diluents, e.g., lubricating agents such as
magnesium stearate. In the case of capsules, tablets, and pills,
the dosage forms may also comprise buffering agents. Tablets and
pills can additionally be prepared with enteric coatings.
[0313] 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.
[0314] The compounds of the present invention can also be
administered in the form of liposomes. As is known in the art,
liposomes are generally derived from phospholipids or other lipid
substances. Liposomes are formed by mono- or multi-lamellar
hydrated liquid crystals that are dispersed in an aqueous medium.
Any non-toxic, physiologically acceptable and metabolizable lipid
capable of forming liposomes can be used. The present compositions
in liposome form can contain, in addition to a compound of the
present invention, stabilizers, preservatives, excipients, and the
like. The preferred lipids are the phospholipids and phosphatidyl
cholines (lecithins), both natural and synthetic.
[0315] Methods to form liposomes are known in the art. See, for
example, Prescott, Ed., Methods in Cell Biology, Volume XIV,
Academic Press, New York, N.Y. (1976), p. 33 et seq.
[0316] 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,
other antiinfective agents or vaccines. Other antiviral agents to
be administered in combination with a compound of the present
invention include AL-721, beta interferon, polymannoacetate,
reverse transcriptase inhibitors (for example, dideoxycytidine
(DDC), dideoxyinosine (DDI), BCH-189, AzdU, carbovir, DDA, D4C,
D4T, DP-AZT, FLT (fluorothymidine), BCH-189,
5-halo-3'-thiadideoxycytidine, PMEA, zidovudine (AZT) and the
like), non-nucleoside reverse transcriptase inhibitors (for
example, R82193, L-697,661, BI-RG-587 (nevirapine), DMP-266, and
the like) retroviral protease inhibitors (for example, HIV protease
inhibitors such as ritonavir, ABT-378, saquinavir, nelfinavir,
indinavir, VX-478 (amprenavir), SC-52151, KNI-227, KNI-272,
U-140690, DMP-450, and the like), HEPT compounds, L,697,639,
R82150, U-87201 E and the like), TAT inhibitors (for example,
RO-24-7429 and the like), trisodium phosphonoformate, HPA-23,
eflonithine, Peptide T, Reticulose (nucleophosphoprotein),
ansamycin LM 427, trimetrexate, UA001, ribavirin, alpha interferon,
oxetanocin, oxetanocin-G, cylobut-G, cyclobut-A, ara-M, BW882C87,
foscarnet, BW256U87, BW348U87, L-693,989, BV ara-U, CMV triclonal
antibodies, FIAC, HOE-602, HPMPC, MSL-109, TI-23, trifluridine,
vidarabine, famciclovir, penciclovir, acyclovir, ganciclovir,
castanospermine, rCD4/CD4-IgG, CD4-PE40, butyl-DNJ, hypericin,
oxamyristic acid, dextran sulfate and pentosan polysulfate.
Immunomodulators that can be administered in combination with a
compound of the present invention include bropirimine, Ampligen,
anti-human alpha interferon antibody, colony stimulting factor,
CL246,738, Imreg-1, Imreg-2, diethydithiocarbamate, interleukin-2,
alpha-interferon, inosine pranobex, methionine enkephalin,
muramyl-tripeptide, TP-5, erythropoietin, naltrexone, tumor
necrosis facator, beta interferon, gamma interferon, interleukin-3,
interleukin-4, autologous CD8+infusion, alpha interferon
immunoglobulin, IGF-1, anti-Leu-3A, autovaccination,
biostimulation, extracorporeal photophoresis, FK-565, FK-506,
G-CSF, GM-CSF, hyperthermia, isopinosine, IVIG, HIVIG, passive
immunotherapy and polio vaccine hyperimmunization. Other
antiinfective agents that can be administered in combination with a
compound of the present invention include pentamidine isethionate.
Any of a variety of HIV or AIDS vaccines (for example, gp120
(recombinant), Env 2-3 (gp120), HIVAC-1e (gp120), gp160
(recombinant), VaxSyn HIV-1 (gp160), Immuno-Ag (gp160), HGP-30,
HIV-Immunogen, p24 (recombinant), VaxSyn HIV-1 (p24) can be used in
combination with a compound of the present invention.
[0317] Other agents that can be used in combination with the
compounds of this invention are ansamycin LM 427, apurinic acid,
ABPP, Al-721, carrisyn, AS-101, avarol, azimexon, colchicine,
compound Q, CS-85, N-acetyl cysteine,
(2-oxothiazolidine-4-carboxylate), D-penicillamine,
diphenylhydantoin, EL-10, erythropoieten, fusidic acid, glucan,
HPA-23, human growth hormone, hydroxchloroquine, iscador,
L-ofloxacin or other quinolone antibiotics, lentinan, lithium
carbonate, MM-1, monolaurin, MTP-PE, naltrexone, neurotropin,
ozone, PAI, panax ginseng, pentofylline, pentoxifylline, Peptide T,
pine cone extract, polymannoacetate, reticulose, retrogen,
ribavirin, ribozymes, RS-47, Sdc-28, silicotungstate, THA, thymic
humoral factor, thymopentin, thymosin fraction 5, thymosin alpha
one, thymostimulin, UA001, uridine, vitamin B12 and wobemugos.
[0318] Other agents that can be used in combination with the
compounds of this invention are antifungals such as amphotericin B,
clotrimazole, flucytosine, fluconazole, itraconazole, ketoconazole
and nystatin and the like.
[0319] Other agents that can be used in combination with the
compounds of this invention are antibacterials such as amikacin
sulfate, azithromycin, ciprofloxacin, tosufloxacin, clarithromycin,
clofazimine, ethambutol, isoniazid, pyrazinamide, rifabutin,
rifampin, streptomycin and TLC G-65 and the like.
[0320] Other agents that can be used in combination with the
compounds of this invention are anti-neoplastics such as alpha
interferon, COMP (cyclophosphamide, vincristine, methotrexate and
prednisone), etoposide, mBACOD (methotrexate, bleomycin,
doxorubicin, cyclophosphamide, vincristine and dexamethasone),
PRO-MACE/MOPP(prednisone, methotrexate (w/leucovin rescue),
doxorubicin, cyclophosphamide, etoposide/mechlorethamine,
vincristine, prednisone and procarbazine), vincristine,
vinblastine, angioinhibins, pentosan polysulfate, platelet factor 4
and SP-PG and the like.
[0321] Other agents that can be used in combination with the
compounds of this invention are drugs for treating neurological
disease such as peptide T, ritalin, lithium, elavil, phenytoin,
carbamazipine, mexitetine, heparin and cytosine arabinoside and the
like.
[0322] Other agents that can be used in combination with the
compounds of this invention are anti-protozoals such as
albendazole, azithromycin, clarithromycin, clindamycin,
corticosteroids, dapsone, DIMP, eflornithine, 566C80, fansidar,
furazolidone, L,671,329, letrazuril, metronidazole, paromycin,
pefloxacin, pentamidine, piritrexim, primaquine, pyrimethamine,
somatostatin, spiramycin, sulfadiazine, trimethoprim, TMP/SMX,
trimetrexate and WR 6026 and the like.
[0323] Among the preferred agents for treatment of HIV or AIDS in
combination with the compounds of this invention are reverse
transcriptase inhibitors and other HIV protease inhibitors.
[0324] It will be understood that agents which can be combined with
the compounds of the present invention for the treatment or
prophylaxis of AIDS or an HIV infection are not limited to those
listed above, but include in principle any agents useful for the
treatment or prophylaxis of AIDS or an HIV infection.
[0325] 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.
[0326] 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.
* * * * *