U.S. patent application number 10/600937 was filed with the patent office on 2004-05-20 for sulfonamide inhibitors of aspartyl protease.
Invention is credited to Andrews, Clarence Webster III, Furfine, Eric Steven, Hale, Michael Robin, Lowen, Gregory Thomas, Sherrill, Ronald George, Spaltenstein, Andrew.
Application Number | 20040097594 10/600937 |
Document ID | / |
Family ID | 22221312 |
Filed Date | 2004-05-20 |
United States Patent
Application |
20040097594 |
Kind Code |
A1 |
Hale, Michael Robin ; et
al. |
May 20, 2004 |
Sulfonamide inhibitors of aspartyl protease
Abstract
The present invention relates to a novel class of sulfonamides
which are aspartyl protease inhibitors. In one embodiment, this
invention relates to a novel class of HIV aspartyl protease
inhibitors characterized by specific structural and physicochemical
features. This invention also relates to pharmaceutical
compositions comprising these compounds. The compounds and
pharmaceutical compositions of this invention are particularly well
suited for inhibiting HIV-1 and HIV-2 protease activity and
consequently, may be advantageously used as anti-viral agents
against the HIV-1 and HIV-2 viruses. This invention also relates to
methods for inhibiting the activity of HIV aspartyl protease using
the compounds of this invention and methods for screening compounds
for anti-HIV activity.
Inventors: |
Hale, Michael Robin;
(Bedford, MA) ; Andrews, Clarence Webster III;
(Durham, NC) ; Furfine, Eric Steven; (Durham,
NC) ; Sherrill, Ronald George; (Cary, NC) ;
Spaltenstein, Andrew; (Raleigh, NC) ; Lowen, Gregory
Thomas; (Williamsburg, VA) |
Correspondence
Address: |
FISH & NEAVE
1251 AVENUE OF THE AMERICAS
50TH FLOOR
NEW YORK
NY
10020-1105
US
|
Family ID: |
22221312 |
Appl. No.: |
10/600937 |
Filed: |
June 20, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10600937 |
Jun 20, 2003 |
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09731129 |
Dec 6, 2000 |
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6613743 |
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09731129 |
Dec 6, 2000 |
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PCT/US99/13744 |
Jun 17, 1999 |
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60090094 |
Jun 19, 1998 |
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Current U.S.
Class: |
514/602 |
Current CPC
Class: |
C07D 235/26 20130101;
C07D 215/48 20130101; C07C 311/49 20130101; C07D 319/06 20130101;
A61P 31/18 20180101; C07D 235/32 20130101; C07D 309/22 20130101;
C07D 493/04 20130101; C07D 241/42 20130101; C07D 309/12 20130101;
C07D 235/06 20130101; C07D 265/02 20130101; C07D 417/12 20130101;
C07D 405/12 20130101; C07C 311/48 20130101; C07D 213/30 20130101;
C07D 277/30 20130101; C07D 307/20 20130101; C07D 235/30 20130101;
C07D 309/06 20130101; C07F 9/6561 20130101; C07C 2601/08 20170501;
C07D 413/06 20130101; C07C 2601/14 20170501; C07D 401/12 20130101;
C07D 243/04 20130101; C07D 407/12 20130101 |
Class at
Publication: |
514/602 |
International
Class: |
A61K 031/18 |
Claims
We claim:
1. A compound of formula (I): 824wherein: A is selected from H; Ht;
--R.sup.1-Ht; --R.sup.1--C.sub.1-C.sub.6 alkyl, which is optionally
substituted with one or more groups independently selected from
hydroxy, C.sub.1-C.sub.4 alkoxy, Ht, --O-Ht,
--NR.sup.2--CO--N(R.sup.2).sub.2 or --CO--N(R.sup.2).sub.2;
--R.sup.1--C.sub.2-C.sub.6 alkenyl, which is optionally substituted
with one or more groups independently selected from hydroxy,
C.sub.1-C.sub.4 alkoxy, Ht, --O-Ht, --NR.sup.2--CO--N(R.sup-
.2).sub.2 or --CO--N(R.sup.2).sub.2; or R.sup.7; each R.sup.1 is
independently selected from --C(O)--, --S(O).sub.2--,
--C(O)--C(O)--, --O--C(O)--, --O--S(O).sub.2,
--NR.sup.2--S(O).sub.2--, --NR.sup.2--CO)-- or
--NR.sup.2--C(O)--C(O)--; each Ht is independently selected from
C.sub.3-C.sub.7 cycloalkyl; C.sub.2-C.sub.2 cycloalkenyl;
C.sub.6-C.sub.10 aryl; or a 5-7 membered saturated or unsaturated
heterocycle, containing one or more heteroatoms selected from N,
N(R.sup.2), O, S and S(O).sub.n; wherein said aryl or said
heterocycle is optionally fused to Q; and wherein any member of
said Ht is optionally substituted with one or more substituents
independently selected from oxo, --OR.sup.2, SR.sup.2, --R.sup.2,
--N(R.sup.2)(R.sup.2), --R.sup.2--OH, --CN, --CO.sub.2R.sup.2,
--C(O)--N(R.sup.2).sub.2, --S(O).sub.2--N(R.sup.2).sub.2,
--N(R.sup.2)--C(O)--R.sup.2, --C(O)--R.sup.2,
--S(O).sub.n--R.sup.2, --OCF.sub.3, --S(O).sub.n-Q, methylenedioxy,
--N(R.sup.2)--S(O).sub.2 (R.sup.2) halo, --CF.sub.3, --NO.sub.2, Q,
--OQ, --OR.sup.7, --SR.sup.7, --R.sup.7, --N(R)(R.sup.7) or
--N(R.sup.7).sub.2; each R.sup.2 is independently selected from H,
Ht or C.sub.1-C.sub.6 alkyl optionally substituted with Q or
R.sup.10; B, when present, is
--N(R.sup.2)--C(R.sup.3).sub.2--C(O)--; each x is independently 0
or 1; each R.sup.3 is independently selected from H, Ht,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.6
cycloalkyl or C.sub.5-C.sub.6 cycloalkenyl; wherein any member of
said R.sup.3, except H, is optionally substituted with one or more
substituents selected from --OR.sup.2, --C(O)--NH--R.sup.2,
--S(O).sub.n--N(R.sup.2)(R.sup.2), Ht, --CN, --SR.sup.2,
CO.sub.2R.sup.2, NR.sup.2--C(O)--R.sup.2; each n is independently 1
or 2; G, when present, is selected from H, R.sup.7 or
C.sub.1-C.sub.4 alkyl, or, when G is C.sub.1-C.sub.4 alkyl, G and
R.sup.7 are bound to one another either directly or through a
C.sub.1-C.sub.3 linker to form a heterocyclic ring; or when G Is
not present, the nitrogen to which G is attached is bound directly
to the R.sup.7 group in --OR.sup.7 with the concomitant
displacement of one -ZM group from R.sup.7; D is selected from Q;
C.sub.1-C.sub.6 alkyl or C.sub.2-C.sub.4 alkenyl, which is
optionally substituted with one or more groups selected from
C.sub.3-C.sub.6 cycloalkyl, --OR.sup.2, --S-Ht, --R.sup.3, --O-Q or
Q; C.sub.3-C.sub.6 cycloalkyl or C.sub.5-C.sub.6 cycloalkenyl,
which is optionally substituted with or fused to Q; each Q is
independently selected from a 3-7 membered saturated, partially
saturated or unsaturated carbocyclic ring system; or a 5-7 membered
saturated, partially saturated or unsaturated heterocyclic ring
containing one or more heteroatoms selected from O, N, S,
S(O).sub.n or N(R.sup.2); wherein Q is optionally substituted with
one or more groups selected from oxo, --OR.sup.2, --R.sup.2,
--N(R.sup.2).sub.2, --N(R.sup.2)C(O)--R.sup.2, --R.sup.2--OH, --CN,
--CO.sub.2R.sup.2, --C(O)--N(R.sup.2).sub.2, halo or --CF.sub.3; D'
is selected from --OR.sup.10, --N.dbd.R.sup.10 or
--N(R.sup.10)--R.sup.1-- -R.sup.3; E is selected from Ht; O-Ht;
Ht-Ht; --O--R.sup.3; --N(R.sup.2)(R.sup.3); C.sub.1-C.sub.6 alkyl,
which is optionally substituted with one or more groups selected
from R.sup.4 or Ht; C.sub.2-C.sub.6 alkenyl, which is optionally
substituted with one or more groups selected from R.sup.4 or Ht;
C.sub.3-C.sub.6 saturated carbocycle, which is optionally
substituted with one or more groups selected from R.sup.4 or Ht; or
C.sub.5-C.sub.6 unsaturated carbocycle, which is optionally
substituted with one or more groups selected from R.sup.4 or Ht;
each R.sup.4 is independently selected from --OR.sup.2, --SR.sup.2,
--C(O)--NHR.sup.2, --S(O).sub.2--NHR.sup.2, halo,
--NR.sup.2--C(O)--R.sup- .2, --N(R.sup.2).sub.2 or --CN; each
R.sup.- is independently selected from hydrogen, 825wherein each M
is independently selected from H, Li, Na, K, Mg, Ca, Ba,
--N(R.sup.2).sub.4 C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.2-alkenyl,
or --R.sup.6; wherein 1 to 4 --CH.sub.2 radicals of the alkyl or
alkenyl group, other than the --CH.sub.2 that is bound to Z, is
optionally replaced by a heteroatom group selected from O, S, S(O),
S(O.sub.2), or N(R.sup.2); and wherein any hydrogen in said alkyl,
alkenyl or R.sup.6 is optionally replaced with a substituent
selected from oxo, --OR.sup.2, --R.sup.2, N(R.sup.2).sub.2,
N(R.sup.2).sub.3, R.sup.2OH, --CN, --CO.sub.2R.sup.2,
--C(O)--N(R.sup.2).sub.2, S(O).sub.2--N(R.sup.2).sub.2,
N(R.sup.2)--C(O)--R.sub.2, C(O)R.sup.-, --S(O).sub.n--R.sup.2,
OCF.sub.3, --S(O).sub.n--R.sup.6, N(R.sup.2)--S(O).sub.2(R.sup.2),
halo, --CF.sub.3, or --NO.sub.3; M' is H, C.sub.2-C.sub.2-alkyl,
C.sub.2-C.sub.12-alkenyl, or --R.sup.6; wherein 1 to 4 --CH.sub.2
radicals of the alkyl or alkenyl group is optionally replaced by a
heteroatom group selected from O, S, S(O), S(O.sub.2), or
N(R.sup.2); and wherein any hydrogen in said alkyl, alkenyl or
R.sup.6 is optionally replaced with a substituent selected from
oxo, --OR.sup.2, --R.sup.2, --N(R.sup.2), N(R.sup.2).sub.3,
--R.sup.2OH, --CN, --CO.sub.2R.sup.2, --C(O)--N(R.sup.2).sub.2,
--S(O).sub.2--N(R.sup.2).sub- .2, --N(R.sup.2)--C(O)--R.sub.2,
--C(O)R.sup.2, --S(O).sub.n--R.sup.6, --OCF.sub.3,
--S(O).sub.n--R.sup.6, --N(R.sup.2)--S(O).sub.2(R.sup.2), halo,
--CF.sub.3, or --NO.sub.2; Z is O, S, N(R.sup.2).sub.2, or, when M
is not present, H. Y is P or S; X is Q or S; R.sup.9 is
C(R.sup.2).sub.2, O or N(R.sup.2); and wherein when Y is S, Z is
not S; R.sup.6 is a 5-6 membered saturated, partially saturated or
unsaturated carbocyclic or heterocyclic ring system, or an 8-10
membered saturated, partially saturated or unsaturated bicyclic
ring system; wherein any of said heterocyclic ring systems contains
one or more heteroatoms selected from O, N, S, S(O).sub.n or
N(R.sup.2); and wherein any of said ring systems optionally
contains 1 to 4 substituents independently selected from OH,
C.sub.1-C.sub.4 alkyl, O--C.sub.1-C.sub.4 alkyl or
O--C(O)--C.sub.1-C.sub.4 alkyl; R.sup.8 is selected from
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.7 alkyl or cyano substituted
C.sub.2-C.sub.6 alkenyl; and R.sup.10 is selected from
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.6-C.sub.14
aryl or Ht, wherein R.sup.10 optionally contains up to three
substituents independently selected from --R.sup.3, --CN,
--SR.sup.5, --SOR.sup.5, --SO.sub.2R.sup.5,
--SR--NR.sup.5--C(O)R.sup.6, --NR.sup.5--(SO.sub.2)R.sup.5,
--C(O)N(R.sup.5).sub.2, --C(S)N(R.sup.5).sub.2,
--S(O).sub.2N(R.sup.5).su- b.2, --C(O)R.sup.6, --C(S)R.sup.6,
--N(R.sup.5).sub.2, --NR.sup.5--C(O)R.sup.5,
--NR.sup.5--C(O)OR.sup.5, --NR.sup.5--C(O)N(R.sup.5).sub.2,
--NR.sup.5--C(S)R.sup.5, --NR.sup.5--C(S)OR.sup.5,
--NR.sup.5--C(S)N(R.sup.5).sub.2,
--NR.sup.5--C[.dbd.N(R.sup.5)]-N(R.sup.5).sub.2,
--NH--C[.dbd.N--NO.sub.2- ]--NH.sub.2,
--NH--C[.dbd.N--NO.sub.2]--OR.sup.5, --N(R.sup.8).sub.2--C(O)-
R.sup.8, --NH--C[.dbd.N--NO.sub.2]--NH.sub.2,
--NH--C[.dbd.N--NO.sub.2]--O- R.sup.5,
--N(R.sup.8).sub.2--C(O)R.sup.8, --OC(O)R.sup.6,
--OC(O)N(R.sup.5).sub.2, --OC(S)N(R.sup.5).sub.2, wherein any one
of the --CH.sub.2 groups of said alkyl or alkenyl chains of
R.sup.10 may be optionally replaced by O, S, SO, SO.sub.2, C(O) or
NR.sup.5; wherein each R.sup.5 is independently selected from
hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl or Ht, wherein each R.sup.5, except for
hydrogen, is optionally substituted with --CF3, --PO.sub.3R.sup.3,
azido or halo; or a pharmaceutically acceptable derivative
thereof.
2. The compound according to claim 1, wherein at least one R.sup.7
is selected from: 826827
3. A compound of formula (II): 828wherein A, R.sup.7, D' and E are
as defined in claim 1; or a pharmaceutically acceptable derivative
thereof.
4. A compound of formula (III): 829wherein Ht, x, R.sup.3, R.sup.7,
D' and E are as defined in claim 1; or a pharmaceutically
acceptable derivative thereof.
5. A compound of formula (IV): 830wherein A, R.sup.3, R.sup.7, D'
and E are as defined in claim 1; or a pharmaceutically acceptable
derivative thereof.
6. The compound according to claim 3, wherein: A is --C(O)Ht; D' is
--R.sup.10; E is C.sub.6-C.sub.10 aryl optionally substituted with
one or more substituents selected from oxo, --OR.sup.3, SR.sup.2,
--R.sup.3, --N(R.sup.2).sub.2, --R.sup.2--OH, --CN,
--CO.sub.2R.sup.2, --C(O)--N(R.sup.2).sub.2,
--S(O).sub.2--N(R.sup.2).sub.2, --N(R.sup.2)--C(O)--R.sup.2,
--C(O)--R.sup.2, --S(O).sub.n--R.sup.2, --OCF.sub.3,
--S(O).sub.n-Q, methylenedioxy, --N(R.sup.2)--S(O).sub.2(R.s-
up.2), halo, --CF.sub.3, --NO.sub.2, Q, --OQ, --OR.sup.7,
--SR.sup.7, --R.sup.7, --N(R.sup.2)(R.sup.-) or --N(R.sup.7).sub.2;
or a 5-membered heterocyclic ring containing one S and optionally
containing N as an additional heteroatom, wherein said heterocyclic
ring is optionally substituted with one to two groups independently
selected from --CH.sub.3, R.sup.4, or Ht.
7. The compound according to claim 3, wherein: E is a 5-membered
heterocyclic ring containing one S and optionally containing N as
an additional heteroatom, wherein said heterocyclic ring is
optionally substituted with one to two groups independently
selected from --CH.sub.3, R.sup.4, or Ht.
8. The compound according to claim 3, wherein: R.sup.7 in
--OR.sup.7 group shown in formula II is --PO(OM).sub.2 or
C(O)CH.sub.2OCH.sub.2CH.sub.2OCH- .sub.2CH.sub.2OCH.sub.3 and both
R.sup.-in --N(R.sup.7).sub.7 are H; or R.sup.-in --OR.sup.7 group
shown in formula II is C(O)CH.sub.2OCH.sub.2CH- .sub.2OCH.sub.3,
one R.sup.-in --N(R.sup.7).sub.2 is
C(O)CH.sub.2OCH.sub.2CH.sub.2OCH.sub.3 and the other is H; and
wherein M is H, Li, Na, K or C.sub.1-C.sub.4 alkyl.
9. A compound according to claim 1, having formula (V): 831wherein
A, R.sup.7, R.sup.10 and E are as defined in claim 1; or a
pharmaceutically acceptable derivative thereof.
10. A compound of formula (VI): 832wherein: R.sup.11 and R.sup.7
are as defined in claim 1; E is C.sub.6-C.sub.14 aryl, optionally
substituted with one or more groups selected from the group
consisting of nitro, oxo, alkoxy, amino, hydroxyamino;
heterocyclcyl, optionally substituted with one or more groups
selected from the group consisting of nitro, oxo, alkoxy, amino,
hydroxyamino or --N(CO)OCH.sub.3; or a pharmaceutically acceptable
derivative thereof.
11. A compound of formula (VII): 833wherein A, E, R.sup.7 and
R.sup.10 are as defined in claim 1; or a pharmaceutically
acceptable derivative thereof.
12. A compound of formula (VIII): 834wherein A, R.sup.1, R.sup.3,
R.sup.7 and E are as defined in claim 1; or a pharmaceutically
acceptable salt thereof.
13. A compound selected from: 835836wherein R.sup.10 is selected
from isopropyl or cyclopentyl; R.sup.11 is selected from NHR.sup.7
or OR.sup.7; x, R.sup.7 and G are as defined in claim 1; and
X.sup.- is a pharmaceutically acceptable counterion.
14. A compound selected from: (3R, 3aS,
6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)
[(3-[2-(dimethylamino)ethyl]aminop-
henyl)sulfonyl]amino-2-hydroxypropyl)carbamate; (3S, 3aR,
6aS)hexahydrofuro[2,3-b]furan-3-yl N-((1S,
2R)-1-benzyl-3-(cyclopentyloxy- )
[(3-[2-(dimethylamino)ethyl]aminophenyl)
sulfonyl]amino-2-hydroxypropyl)- carbamate;
(3R,3aS,6aR)Hexahydrofuro[2,3-b]furan-3-yl-N-((1S,2R)-1-benzyl
-3-(cyclopentyloxy)(2-[(methylsulfonyl)amino]benzimidazol-5-ylsulfonyl)am-
ino-2-hydroxypropyl)carbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[[(3-N-methylaminophenyl)sulfonyl](cyclopentyloxy)amino]-1-be-
nzyl -2-hydroxypropylcarbamate; 1,3-Dioxan-5-yl
N-(1S,2R)-1-benzyl-3-[(cyc-
lopentyloxy)(2-{(methoxycarbonyl)amino]-1H-benzimidazol-5-ylsulfonyl)amino-
]-2-hydroxypropylcarbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-(1S,2R)-1-benzyl
-2-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](tetrahydro-2- H
-pyran-4-yloxy)amino]propylcarbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]fu- ran-3-yl N-(1S,
2R)-3-[[(3-aminophenyl)sulfonyl](cyclopentyloxy)amino]-1-b-
enzyl-2-hydroxypropylcarbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-1-benzyl
-3-((cyclopentyloxy)[3-(2-[methoxy(methyl)amino]-2-ox-
oethylamino)phenyl]sulfonylamino)-2-hydroxypropyl]carbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-4-(cyclope-
ntyloxy)-2-hydroxy-4-(6-quinoxalinyl sulfonyl)butyl]carbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclope-
ntyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((cyclop-
entyloxy)[3-(2-[(methylsulfonyl)amino]ethylamino)phenyl]sulfonylamino)-2-h-
ydroxypropyl]carbamate; (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[[(3-N-methylaminophenyl)sulfonyl](cyclopentyloxy)amino]-1-be-
nzyl-2-hydroxypropylcarbamate, phosphate ester;
(3R,3aS,6aR)hexahydrofuro[- 2,3-b]furan-3-yl
N-(1S,2R)-3[[(3-aminophenyl)sulfonyl](cyclopentyloxy)amin-
o]-1-benzyl-2-hydroxypropylcarbamate phosphate ester;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[[(4-aminophenyl)s-
ulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxypropyl carbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl
-3-{(1-ethylpropoxy)[(4-hydroxyphenyl)sulfonyl]amino}2-hydroxypropylcarba-
mate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3[(1,3-benzodioxol-
-5-ylsulfonyl)(1-ethylpropoxy)amino]-1-benzyl
-2-hydroxypropylcarbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-3-[(1,3-benzodioxol-
-5-ylsulfonyl)(cyclopentyloxy)amino]-1-benzyl
-2-(phosphonooxy)propyl]carb- amate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-(1,3-benzodioxo-
l-5-ylsulfonyl)(cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
3-[(1,3-benzodioxol-5-ylsulfon-
yl)(tetrahydro-2H-pyran-4-yloxy)amino]-1-benzyl-2-hydroxypropylcarbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,
2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(cyclopentyloxy)amino]-1-benzyl
-2-(phosphonooxy)propyl]carbamate; or a pharmaceutically acceptable
derivative thereof.
15. The compound according to claim 1 wherein said compound has a
molecular weight less than or equal to about 700 g/mol.
16. The compound according to claim 15 wherein said compound has a
molecular weight less than or equal to about 600 g/mol.
17. A pharmaceutical composition comprising an effective antiviral
amount of a compound according to any one of claims 1-14 or a
pharmaceutically acceptable derivative thereof together with a
pharmaceutically acceptable carrier therefore.
18. The pharmaceutical composition according to claim 17, further
comprising an antiviral agent other than a compound according to
claims 1-14.
19. A pharmaceutical composition according to claim 17 or 18 in the
form of a tablet or capsule.
20. A method of treating a virus infection in a human comprising
administering to said human an effective antiviral treatment amount
of a compound according to any one of claims 1-13 or a
pharmaceutically acceptable derivative thereof.
21. The method according to claim 20 wherein the virus infection is
an HIV infection.
22. The method according to claim 20 or 21 wherein said step of
administering comprises oral administration or administration by
injection.
23. Use of a compound according to any of claims 1-14 for the
manufacture of a medicament for the treatment or prophylaxis of a
viral infection.
24. Use of a compound according to any of claims 1-14 or a
formulation according to claim 17 for use in medical therapy.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a novel class of
sulfonamides which are aspartyl protease inhibitors. In one
embodiment, this invention relates to a novel class of HIV aspartyl
protease inhibitors characterized by specific structural and
physicochemical features. This invention also relates to
pharmaceutical compositions comprising these compounds. The
compounds and pharmaceutical compositions of this invention are
particularly well suited for inhibiting HIV-1 and HIV-2 protease
activity and consequently, may be advantageously used as anti-viral
agents against the HIV-1 and HIV-2 viruses. This invention also
relates to methods for inhibiting the activity of HIV aspartyl
protease using the compounds of this invention and methods for
screening compounds for anti-HIV activity.
BACKGROUND OF THE INVENTION
[0002] The human immunodeficiency virus ("HIV") is the causative
agent for acquired immunodeficiency syndrome ("AIDS")--a disease
characterized by the destruction of the immune system, particularly
of CD4.sup.- T-cells, with attendant susceptibility to
opportunistic infections--and its precursor AIDS-related complex
("ARC")--a syndrome characterized by symptoms such as persistent
generalized lymphadenopathy, fever and weight loss.
[0003] As in the case of several other retroviruses, HIV encodes
the production of a protease which carries out post-translational
cleavage of precursor polypeptides in a process necessary for the
formation of infectious virions (S. Crawford et al., "A Deletion
Mutation in the 5' Part of the pol Gene of Moloney Murine Leukemia
Virus Blocks Proteolytic Processing of the gag and pol
Polyproteins", J. Virol., 53, p. 899 (1985)). These gene products
include pol, which encodes the virion RNA-dependent DNA polymerase
(reverse transcriptase), an endonuclease, HIV protease, and gag,
which encodes the core-proteins of the virion (H. Toh et al.,
"Close Structural Resemblance Between Putative Polymerase of a
Drosophila Transposable Genetic Element 17.6 and pol gene product
of Moloney Murine Leukemia Virus", EMBO J., 4, p. 1267 (1985); L.
H. Pearl et al., "A Structural Model for the Retroviral Proteases",
Nature, pp. 329-351 (1987); M. D. Power et al., "Nucleotide
Sequence of SRV-1, a Type D Simian Acquired Immune Deficiency
Syndrome Retrovirus", Science, 231, p. 1567 (1986)).
[0004] A number of synthetic anti-viral agents have been designed
to target various stages in the replication cycle of HIV. These
agents include compounds which block viral binding to CD4.sup.-
T-lymphocytes (for example, soluble CD4), and compounds which
interfere with viral replication by inhibiting viral reverse
transcriptase (for example, didanosine and zidovudine (AZT)) and
inhibit integration of viral DNA into cellular DNA (M. S. Hirsh and
R. T. D'Aqulia, "Therapy for Human Immunodeficiency Virus
Infection", New Eng. J. Med., 328, p. 1686 (1993)). However, such
agents, which are directed primarily to early stages of viral
replication, do not prevent the production of infectious virions in
chronically infected cells. Furthermore, administration of some of
these agents in effective amounts has led to cell-toxicity and
unwanted side effects, such as anemia and bone marrow
suppression.
[0005] More recently, the focus of anti-viral drug design has been
to create compounds which inhibit the formation of infectious
virions by interfering with the processing of viral polyprotein
precursors. Processing of these precursor proteins requires the
action of virus-encoded proteases which are essential for
replication (Kohl, N. E. et al. "Active HIV Protease is Required
for Viral Infectivity" Proc. Natl. Acad. Sci. USA, 85, p. 4686
(1988)). The anti-viral potential of HIV protease inhibition has
been demonstrated using peptidal inhibitors. Such peptidal
compounds, however, are typically large and complex molecules that
tend to exhibit poor bioavailability and are not generally
consistent with oral administration. Accordingly, the need still
exists for compounds that can effectively inhibit the action of
viral proteases, for use as agents for preventing and treating
chronic and acute viral infections.
SUMMARY OF THE INVENTION
[0006] The present invention provides a novel class of compounds,
and pharmaceutically acceptable derivatives thereof, that are
useful as inhibitors of aspartyl proteases, in particular, HIV
aspartyl protease. These compounds can be used alone or in
combination with other therapeutic or prophylactic agents, such as
anti-virals, antibiotics, immunomodulators or vaccines, for the
treatment or prophylaxis of viral infection.
[0007] According to a preferred embodiment, the compounds of this
invention are capable of inhibiting HIV viral replication in human
CD.sub.4.sup.- T-cells. These compounds are useful as therapeutic
and prophylactic agents to treat or prevent infection by HIV-1 and
related viruses which may result in asymptomatic infection,
AIDS-related complex ("ARC"), acquired immunodeficiency syndrome
("AIDS"), or similar disease of the immune system.
[0008] It is a principal object of this invention to provide a
novel class of sulfonamides which are aspartyl protease inhibitors,
and particularly, HIV aspartyl protease inhibitors. The novel
sulfonamides of this invention are those of formula I: 1
[0009] wherein:
[0010] A is selected from H; Ht; --R.sup.1-Ht;
--R.sup.1-C.sub.1-C.sub.6 alkyl, which is optionally substituted
with one or more groups independently selected from hydroxy,
C.sub.1-C.sub.4 alkoxy, Ht, --O-Ht,
--NR.sup.1--CO--N(R.sup.2).sub.2 or --CO--N(R.sup.2).sub.2;
--R.sup.1--C.sub.2-C.sub.6 alkenyl, which is optionally substituted
with one or more groups independently selected from hydroxy,
C.sub.1-C.sub.4 alkoxy, Ht, --O-Ht,
--NR.sup.1--CO--N(R.sup.2).sub.2 or --CO--N(R.sup.2).sub.2; or
R.sup.7;
[0011] each R.sup.1 is independently selected from --C(O)--,
--S(O).sub.2--, --C(O)--C(O)--, --O--C(O)--, --O--S(O).sub.2,
--NR.sup.2--S(O).sub.2--, --NR.sup.2--C(O)-- or
--NR.sup.2--C(O)--C(O)--;
[0012] each Ht is independently selected from C.sub.3-C.sub.7
cycloalkyl; C.sub.5-C.sub.7 cycloalkenyl; C.sub.6-C.sub.14 aryl; or
a 5-7 membered saturated or unsaturated heterocycle, containing one
or more heteroatoms selected from N, N(R.sup.2), O, S and
S(O).sub.n; wherein said aryl or said heterocycle is optionally
fused to i; and wherein any member of said Ht is optionally
substituted with one or more substituents independently selected
from oxo, --OR.sup.2, SR.sup.2, --R.sup.2, --N(R.sup.2)(R.sup.2),
--R.sup.2--OH, --CN, --CO.sub.2R.sup.2, --C(O)--N(R.sup.2).sub.2,
--S(O).sub.2--N(R.sup.2).sub.2, --N(R.sup.2)--C(O)--R.sup.2,
--C(O)--R.sup.2, --S(O).sub.n--R.sup.2, --OCF.sub.3,
--S(O).sub.n-Q, methylenedioxy, --N(R.sup.2)--S(O).sub.2(R.s- up.2)
halo, --CF.sub.3, --NO.sub.2, Q, --OQ, --OR.sup.-, --SR.sup.-,
--R.sup.-, --N(R.sup.2) (R.sup.-) or --N(R.sup.7).sub.2;
[0013] each R.sup.2 is independently selected from H, or
C.sub.1-C.sub.6 alkyl optionally substituted with Q or
R.sup.10;
[0014] B, when present, is
--N(R.sup.2)--C(R.sup.3).sub.2--C(O)--;
[0015] each x is independently 0 or 1;
[0016] each R.sup.3 is independently selected from H, Ht,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.6
cycloalkyl or C.sub.5-C.sub.6 cycloalkenyl; wherein any member of
said R.sup.3, except H, is optionally substituted with one or more
substituents selected from --OR.sup.2, --C(O)--NH--R.sup.2,
--S(O).sub.n--N(R.sup.2) (R.sup.2), Ht, --CN, --SR.sup.2,
--CO.sub.2R.sup.2, NR.sup.2--C(O)--R.sup.2;
[0017] each n is independently 1 or 2;
[0018] G, when present, is selected from H, R.sup.7 or
C.sub.1-C.sub.4 alkyl, or, when G is C.sub.1-C.sub.4 alkyl, G and
R.sup.7 are bound to one another either directly or through a
C.sub.1-C.sub.3 linker to form a heterocyclic ring; or
[0019] when G is not present (i.e., when x in (G).sub.x is 0), then
the nitrogen to which G is attached is bound directly to the
R.sup.7 group in --OR.sup.7 with the concomitant displacement of
one -ZM group from R.sup.7;
[0020] D is selected from Q; C.sub.1-C.sub.6 alkyl, which is
optionally substituted with one or more groups selected from
C.sub.3-C.sub.6 cycloalkyl, --OR.sup.2, --S-Ht, --R.sup.3, --O-Q or
Q; C.sub.2-C.sub.4 alkenyl, which is optionally substituted with
one or more groups selected from --OR.sup.2, --S-Ht, --R.sup.3,
--O-Q or Q; C.sub.3-C.sub.6 cycloalkyl, which is optionally
substituted with or fused to Q; or C.sub.5-C.sub.6 cycloalkenyl,
which is optionally substituted with or fused to Q;
[0021] each Q is independently selected from a 3-7 membered
saturated, partially saturated or unsaturated carbocyclic ring
system; or a 5-7 membered saturated, partially saturated or
unsaturated heterocyclic ring containing one or more heteroatoms
selected from O, N, S, S(O).sub.n or N(R.sup.2); wherein Q is
optionally substituted with one or more groups selected from oxo,
--OR.sup.2, --R.sup.2, --SO.sub.2R.sup.2,
--SO.sub.2--N(R.sup.2).sub.2, --N(R.sup.2).sub.2,
--N(R.sup.2)--C(O)--R.s- up.2, --R.sup.2--OH, --CN,
--CO.sub.2R.sup.2, --C(O)--N(R.sup.2).sub.2, halo or
--CF.sub.3;
[0022] D' is selected from --OR.sup.10, --N.dbd.R.sup.10 or
--N(R.sup.10)--R.sup.1--R.sup.3;
[0023] E is selected from Ht; O-Ht; Ht-Ht; --O--R.sup.3;
--N(R.sup.2) (R.sup.3); C.sub.1-C.sub.6 alkyl, which is optionally
substituted with one or more groups selected from R.sup.4 or Ht;
C.sub.2-C.sub.6 alkenyl, which is optionally substituted with one
or more groups selected from R.sup.4 or Ht; C.sub.3-C.sub.6
saturated carbocycle, which is optionally substituted with one or
more groups selected from R.sup.4 or Ht; or C.sub.5-C.sub.6
unsaturated carbocycle, which is optionally substituted with one or
more groups selected from R.sup.4 or Ht;
[0024] each R.sup.4 is independently selected from --OR.sup.2,
--SR.sup.2, --SOR.sup.2, --SO.sub.2R.sup.2, --CO.sub.2R.sup.2,
--C(O)--NHR.sup.2, --C(O)--N(R.sup.2).sub.2,
--C(O)--NR.sup.2(OR.sup.2), --S(O).sub.2--NHR.sup.2, halo,
--NR.sup.2--C(O)--R.sup.2, --N(R.sup.2).sub.2 or --CN;
[0025] each R.sup.-is independently selected from hydrogen, 2
[0026] wherein each M is independently selected from H, Li, Na, K,
Mg, Ca, Ba, --N(R.sup.2).sub.4, C.sub.1-C.sub.12-alkyl,
C.sub.2-C.sub.12-alkenyl, or --R.sup.6; wherein 1 to 4 --CH.sub.2
radicals of the alkyl or alkenyl group, other than the --CH.sub.2
that is bound to Z, is optionally replaced by a heteroatom group
selected from O, S, S(O), S(O.sub.2), or N(R.sup.2); and wherein
any hydrogen in said alkyl, alkenyl or R.sup.6 is optionally
replaced with a substituent selected from oxo, --OR.sup.2,
--R.sup.2, N(R.sup.2).sub.2, N(R.sup.2).sub.3, R.sup.2OH, --CN,
--CO.sub.2R.sup.2, --C(O)--N(R.sup.2).sub.2,
S(O).sub.2--N(R.sup.2).sub.2- , N(R.sup.2)--C(O)--R.sub.2,
C(O)R.sup.2, --S(O).sub.n--R.sup.1, OCF.sub.3,
--S(O).sub.n--R.sup.6, N(R.sup.2)--S(O).sub.2(R.sup.2), halo,
--CF.sub.3, or --NO.sub.2;
[0027] M' is H, C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.12-alkenyl,
or --R.sup.6; wherein 1 to 4--CH.sub.2 radicals of the alkyl or
alkenyl group is optionally replaced by a heteroatom group selected
from O, S, S(O), S(O.sub.2), or N(R.sup.2); and wherein any
hydrogen in said alkyl, alkenyl or R.sup.6 is optionally replaced
with a substituent selected from oxo, --OR.sup.2, --R.sup.2,
--N(R.sup.2).sub.2, N(R.sup.2).sub.3, --R.sup.2OH, --CN,
--CO.sub.2R.sup.2, --C(O)--N(R.sup.2).sub.2,
--S(O).sub.2--N(R.sup.2).sub.2, --N(R.sup.2)--C(O)--R.sub.2,
--C(O)R.sup.2, --S(O)--R.sup.2, --OCF.sub.3, --S(O).sub.n--R.sup.6,
--N(R.sup.2)--S(O).sub.2(R.sup.2), halo, --CF.sub.3, or
--NO.sub.2;
[0028] Z is O, S, N(R.sup.2).sub.2, or, when M is not present,
H.
[0029] Y is P or S;
[0030] X is O or S; and
[0031] R.sup.9 is C(R.sup.2).sub.2, O or N(R.sup.2); and wherein
when Y is S, Z is not S; and
[0032] R.sup.6 is a 5-6 membered saturated, partially saturated or
unsaturated carbocyclic or heterocyclic ring system, or an 8-10
membered saturated, partially saturated or unsaturated bicyclic
ring system; wherein any of said heterocyclic ring systems contains
one or more heteroatoms selected from O, N, S, S(O).sub.n or
N(R.sup.2); and wherein any of said ring systems optionally
contains 1 to 4 substituents independently selected from OH,
C.sub.1-C.sub.4 alkyl, --O--C.sub.1-C.sub.4 alkyl or
--O--C(O)--C.sub.1-C.sub.4 alkyl;
[0033] R.sup.10 is selected from C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.6-C.sub.14 aryl or Ht, wherein
R.sup.10 optionally contains up to three substituents independently
selected from --R.sup.3, --CN, --SR.sup.5, --SOR.sup.5,
--SO.sub.2R.sup.5, --SR--NR.sup.5--C(O)R.s- up.6,
--NR.sup.5--(SO.sub.2)R.sup.5, --C(O)N(R.sup.5).sub.2,
--C(S)N(R.sup.5).sub.2, --S(O).sub.2N(R.sup.5).sub.2,
--C(O)R.sup.6, --C(S)R.sup.6, --N(R.sup.5).sub.2,
--NR.sup.5--C(O)R.sup.5, --NR.sup.5--C(O)OR.sup.5,
--NR.sup.5--C(O)N(R.sup.5).sub.2, --NR.sup.5--C(S)R.sup.5,
--NR.sup.5--C(S)OR.sup.5, --NR.sup.5--C(S)N(R.sup.5).sub.2,
--NR.sup.5--C[.dbd.N(R.sup.5)]--N(R.sup- .5).sub.2,
--NH--C[.dbd.N--NO.sub.2]--NH.sub.2, --NH--C[.dbd.N--NO.sub.2]--
-OR.sup.5, --N(R.sup.8).sub.2--C(O)R.sup.8, --OC(O)R.sup.6,
--OC(O)N(R.sup.5).sub.2, --OC(S)N(R.sup.5).sub.2, wherein any one
of the --CH.sub.2 groups of said alkyl or alkenyl chains of
R.sup.10 may be optionally replaced by O, S, SO, SO.sub.2, C(O) or
NR.sup.5;
[0034] wherein each R.sup.5 is independently selected from
hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl or Ht, wherein each R.sup.5, except for
hydrogen, is optionally substituted with --CF3, --PO.sub.3R.sup.3,
azido or halo.
[0035] It is also an object of this invention to provide
pharmaceutical compositions comprising the sulfonamides of formula
(I) and methods for their use as inhibitors of HIV aspartyl
protease.
DETAILED DESCRIPTION OF THE INVENTION
[0036] In order that the invention herein described may be more
fully understood, the following detailed description is set forth.
In the description, the following terms are employed herein:
[0037] Unless expressly stated to the contrary, the terms
"--SO.sub.2--" and "--S(O).sub.2--" as used herein refer to a
sulfone or sulfone derivative (i.e., both appended groups linked to
the S), and not a sulfinate ester.
[0038] For the compounds of formula I, and intermediates thereof,
the stereochemistry of OR.sup.7 is defined relative to D on the
adjacent carbon atom, when the molecule is drawn in an extended
zig-zag representation (such as that drawn for compound of formula
I). If both OR.sup.7 and D reside on the same side of the plane
defined by the extended backbone of the compound, the
stereochemistry of OR.sup.7 will be referred to as "syn". If
OR.sup.7 and D reside on opposite sides of that plane, the
stereochemistry of OR.sup.7 will be referred to as "anti".
[0039] The term "alkyl", alone or in combination with any other
term, refers to a straight-chain or branch-chain saturated
aliphatic hydrocarbon radical containing the specified number of
carbon atoms, or where no number is specified, preferably from 1 to
about 10 and more preferably from 1 to about 8 carbon atoms.
Examples of alkyl radicals include, but are not limited to, methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isoamyl, n-hexyl and the like.
[0040] The term "alkenyl" alone or in combination with any other
term, refers to a straight-chain or branched-chain mono- or
poly-unsaturated aliphatic hydrocarbon radical containing the
specified number of carbon atoms, or where no number is specified,
preferably from 2 to about 18 carbon atoms and more preferably,
from 2 to about 8 carbon atoms. Examples of alkenyl radicals
include, but are not limited to, ethenyl, propenyl, isopropenyl,
1,4-butadienyl, pentenyl and the like.
[0041] The term "alkoxy" refers to an alkyl ether radical, wherein
the term "alkyl" is defined above. Examples of suitable alkyl ether
radicals include, but are not limited to, methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy
and the like.
[0042] The term "aryl" alone or in combination with any other term,
refers to a carbocyclic aromatic radical (such as phenyl or
naphthyl) containing the specified number of carbon atoms,
preferably from 6-14 carbon atoms, and more preferably from 6-10
carbon atoms, optionally substituted with one or more substituents
selected from C1-6 alkoxy, (for example methoxy), nitro, halogen,
(for example chloro), amino, carboxylate and hydroxy. Examples of
aryl radicals include, but are not limited to phenyl, naphthyl,
indenyl, indanyl, azulenyl, fluorenyl, anthracenyl and the
like.
[0043] The term "heterocyclyl" or "heterocycle" refers to a stable
3-7 membered monocyclic heterocyclic ring or 8-11 membered bicyclic
heterocyclcic ring which is either saturated or unsaturated, and
which may be optionally benzofused if monocyclic. Each heterocycle
consists of one or more carbon atoms and from one to four
heteroatoms selected from the group consisting of nitrogen, oxygen
and sulfur. As used herein, the terms "nitrogen and sulfur
heteroatoms" include any oxidized form of nitrogen and sulfur, and
the quaternized form of any basic nitrogen. A heterocyclyl radical
may be attached at any endocyclic carbon or heteroatom which
results in the creation of a stable structure. Preferred
heterocycles include 5-7 membered monocyclic heterocycles and 8-10
membered bicyclic heterocycles. Examples of such groups include
imidazolyl, imidazolinoyl, imidazolidinyl, quinolyl, isoqinolyl,
indolyl, indazolyl, indazolinolyl, perhydropyridazyl, pyridazyl,
pyridyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazinyl,
quinoxolyl, piperidinyl, pyranyl, pyrazolinyl, piperazinyl,
pyrimidinyl, pyridazinyl, morpholinyl, thiamorpholinyl, furyl,
thienyl, triazolyl, thiazolyl, carbolinyl, tetrazolyl,
thiazolidinyl, benzofuranoyl, thiamorpholinyl sulfone, oxazolyl,
benzoxazolyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl,
azepinyl, isoxozolyl, isothiazolyl, furazanyl, tetrahydropyranyl,
tetrahydrofuranyl, thiazolyl, thiadiazoyl, dioxolyl, dioxinyl,
oxathiolyl, benzodioxolyl, dithiolyl, thiophenyl,
tetrahydrothiophenyl, sulfolanyl, dioxanyl, dioxolanyl,
tetahydrofurodihydrofuranyl, tetrahydropyranodihydrofuranyl,
dihydropyranyl, tetradyrofurofuranyl and
tetrahydropyranofuranyl.
[0044] The term "pharmaceutically effective amount" refers to an
amount effective in treating a virus infection, for example an HIV
infection, in a patient either as monotherapy or in combination
with other agents. The term "treating" as used herein refers to the
alleviation of symptoms of a particular disorder in a patient or
the improvement of an ascertainable measurement associated with a
particular disorder. The term "prophylactically effective amount"
refers to an amount effective in preventing a virus infection, for
example an HIV infection, in a patient. As used herein, the term
"patient" refers to a mammal, including a human.
[0045] The terms "HIV protease" and "HIV aspartyl protease" are
used interchangeably and refer to the aspartyl protease encoded by
the human immunodeficiency virus type 1 or 2. In a preferred
embodiment of this invention, these terms refer to the human
immunodeficiency virus type 1 aspartyl protease.
[0046] The term "thiocarbamates" refers to compounds containing the
functional group N--SO.sub.2--O.
[0047] Combinations of substituents and variables envisioned by
this invention are only those that result in the formation of
stable compounds. The term "stable", as used herein, refers to
compounds which possess stability sufficient to allow manufacture
and administration to a mammal by methods known in the art.
Typically, such compounds are stable at a temperature of 40.degree.
C. or less, in the absence of moisture or other chemically reactive
conditions, for at least a week.
[0048] This invention also envisions the quaternization of any
basic nitrogen-containing groups of the compounds disclosed herein.
The basic nitrogen can be quaternized with any agents known to
those of ordinary skill in the art including, for example, lower
alkyl halides, such as methyl, ethyl, propyl and butyl chloride,
bromides and iodides; dialkyl sulfates including dimethyl, diethyl,
dibutyl and diamyl sulfates; long chain halides such as decyl,
lauryl, myristyl and stearyl chlorides, bromides and iodides; and
aralkyl halides including benzyl and phenethyl bromides. Water or
oil-soluble or dispersible products may be obtained by such
quaternization.
[0049] The novel sulfonamides of this invention are those of
formula I: 3
[0050] wherein:
[0051] A is selected from H; Ht; --R.sup.2-Ht;
--R.sup.1--C.sub.1-C.sub.6 alkyl, which is optionally substituted
with one or more groups independently selected from hydroxy,
C.sub.1-C.sub.4 alkoxy, Ht, --O-Ht,
--NR.sup.2--CO--N(R.sup.2).sub.2 or --CO--N(R.sup.2).sub.2;
--R.sup.2--C.sub.2-C.sub.6 alkenyl, which is optionally substituted
with one or more groups independently selected from hydroxy,
C.sub.1-C.sub.4 alkoxy, Ht, --O-Ht,
--NR.sup.2--CO--N(R.sup.-).sub.1 or --CO--N(R.sup.2).sub.2; or
R.sup.7;
[0052] each R.sup.1 is independently selected from --C(O)--,
--S(O).sub.2--, --C(O)--C(O)--, --O--C(O)--, --O--S(O).sub.2,
--NR.sup.2--S(O).sub.2--, --NR.sup.2--C(O)-- or
--NR.sup.2--C(O)--C(O)--;
[0053] each Ht is independently selected from C.sub.3-C.sub.7
cycloalkyl; C.sub.3-C.sub.7 cycloalkenyl; C.sub.6-C.sub.14 aryl; or
a 5-7 membered saturated or unsaturated heterocycle, containing one
or more heteroatoms selected from N, N(R.sup.2), O, S and
S(O).sub.n; wherein said aryl or said heterocycle is optionally
fused to Q; and wherein any member of said Ht is optionally
substituted with one or more substituents independently selected
from oxo, --OR.sup.2, SR.sup.2, --R.sup.2, --N(R.sup.2)(R.sup.2),
--R.sup.2--OH, --CN, --CO.sub.2R.sup.1, --C(O)--N(R.sup.2).sub.2,
--S(O).sub.1--N(R.sup.2).sub.2, --N(R.sup.2)--C(O)--R.sup.2,
--C(O)--R.sup.2, --S(O).sub.nR.sup.2, --OCF.sub.3, --S(O).sub.n-Q,
methylenedioxy, --N(R.sup.2)--S(O).sub.2(R.s- up.2), halo,
--CF.sub.3, --NO.sub.2, Q, --OQ, --OR.sup.7, --SR.sup.7, --R.sup.7,
--N(R.sup.2)(R.sup.7) or --N(R.sup.7).sub.2;
[0054] each R.sup.2 is independently selected from H, or
C.sub.1-C.sub.6 alkyl optionally substituted with Q or
R.sup.10,
[0055] B, when present, is
--N(R.sup.2)--C(R.sup.3).sub.2--C(O)--;
[0056] each x is independently 0 or 1;
[0057] each R.sup.3 is independently selected from H, Ht,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.6
cycloalkyl or C.sub.5-C.sub.6 cycloalkenyl; wherein any member of
said R.sup.3, except H, is optionally substituted with one or more
substituents selected from --OR.sup.2, --C(O)--NH--R.sup.2,
--S(O).sub.n--N(R.sup.2)(R.sup.2), Ht, --CN, --SR.sup.2,
--CO.sub.2R.sup.2, NR.sup.2--C(O)--R.sup.2;
[0058] each n is independently 1 or 2;
[0059] G, when present, is selected from H, R.sup.7 or
C.sub.1-C.sub.4 alkyl, or, when G is C.sub.1-C.sub.4 alkyl, G and
R.sup.7 are bound to one another either directly or through a
C.sub.1-C.sub.3 linker to form a heterocyclic ring; or
[0060] when G is not present (i.e., when x in (G).sub.x is 0), then
the nitrogen to which G is attached is bound directly to the
R.sup.7 group in --OR.sup.7 with the concomitant displacement of
one -ZM group from R.sup.7;
[0061] D is selected from Q; C.sub.1-C.sub.6 alkyl, which is
optionally substituted with one or more groups selected from
C.sub.3-C.sub.6 cycloalkyl, --OR.sup.2, --S-Ht, --R.sup.3, --O-Q or
Q; C.sub.2-C.sub.4 alkenyl, which is optionally substituted with
one or more groups selected from --OR.sup.2, --S-Ht, --R.sup.3,
--O-Q or Q, C.sub.3-C.sub.6 cycloalkyl, which is optionally
substituted with or fused to Q; or C.sub.5-C.sub.6 cycloalkenyl,
which is optionally substituted with or fused to Q;
[0062] each Q is independently selected from a 3-7 membered
saturated, partially saturated or unsaturated carbocyclic ring
system; or a 5-7 membered saturated, partially saturated or
unsaturated heterocyclic ring containing one or more heteroatoms
selected from O, N, S, S(O).sub.n or N(R.sup.2); wherein Q is
optionally substituted with one or more groups selected from oxo,
--OR.sup.2, --R.sup.2, --SO.sub.2R.sup.2,
--SO.sub.2--N(R.sup.2).sub.2, --N(R.sup.2).sub.2,
--N(R.sup.2)--C(O)--R.s- up.1, --R.sup.1--OH, --CN,
--CO.sub.2R.sup.1, --C(O)--N(R.sup.2).sub.2, halo or
--CF.sub.3;
[0063] D' is selected from --OR.sup.10, --N.dbd.R.sup.10 or
--N(R.sup.10)--R.sup.1--R.sup.3;
[0064] E is selected from Ht; O-Ht; Ht-Ht; --O--R.sup.3;
--N(R.sup.2)(R.sup.3); C.sub.1-C.sub.6 alkyl, which is optionally
substituted with one or more groups selected from R.sup.4 or Ht;
C.sub.2-C.sub.6 alkenyl, which is optionally substituted with one
or more groups selected from R.sup.4 or Ht; C.sub.3-C.sub.6
saturated carbocycle, which is optionally substituted with one or
more groups selected from R.sup.4 or Ht; or C.sub.5-C.sub.6
unsaturated carbocycle, which is optionally substituted with one or
more groups selected from R.sup.4 or Ht;
[0065] each R.sup.4 is independently selected from --OR.sup.2,
--SR.sup.2, --SOR.sup.2, --SO.sub.2R.sup.2, --CO.sub.2R.sup.2,
--C(O)--NHR.sup.2, --C(O)--N(R.sup.2).sub.2,
--C(O)--NR.sup.2(OR.sup.2), --S(O).sub.2--NHR.sup.2, halo,
--NR.sup.2--C(O)--R.sup.2, --N(R.sup.2).sub.2 or --CN;
[0066] each R.sup.- is independently selected from hydrogen, 4
[0067] wherein each M is independently selected from H, Li, Na, K,
Mg, Ca, Ba, --N(R.sup.2).sub.4, C.sub.1-C.sub.12-alkyl,
C.sub.2-C.sub.12-alkenyl, or --R.sup.6; wherein 1 to 4 --CH.sub.2
radicals of the alkyl or alkenyl group, other than the --CH.sub.2
that is bound to Z, is optionally replaced by a heteroatom group
selected from O, S, S(O), S(O.sub.2), or N(R.sup.2); and wherein
any hydrogen in said alkyl, alkenyl or R.sup.6 is optionally
replaced with a substituent selected from oxo, --OR.sup.2,
--R.sup.2, N(R.sup.2).sub.2, N(R.sup.2).sub.3, R.sup.2OH, --CN,
--CO.sub.2R.sup.2, --C(O)--N(R.sup.2).sub.2,
S(O).sub.2--N(R.sup.2).sub.2- , N(R.sup.2)--C(O)--R.sub.2,
C(O)R.sup.2, S(O).sub.n--R.sup.2, OCF.sub.3, --S(O).sub.n--R.sup.6,
N(R.sup.2)--S(O).sub.2(R.sup.2), halo, --CF.sub.3, or
--NO.sub.2;
[0068] M' is H, C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.12-alkenyl,
or --R.sup.6; wherein 1 to 4 --CH.sub.2 radicals of the alkyl or
alkenyl group is optionally replaced by a heteroatom group selected
from O, S, S(O)S(O.sub.2), or N(R.sup.2); and wherein any hydrogen
in said alkyl, alkenyl or R.sup.6 is optionally replaced with a
substituent selected from oxo, --OR.sup.2, --R.sup.2,
--N(R.sup.2).sub.2, N(R.sup.2).sub.3, --R.sup.2OH, --CN,
--CO.sub.2R.sup.2--C(O)--N(R.sup.2).sub.2,
--S(O).sub.2--N(R.sup.2).sub.2, --N(R.sup.2)--C(O)--R.sub.2,
--C(O)R.sup.2, S(O).sub.n--R.sup.2, --OCF.sub.3,
S(O).sub.n--R.sup.6, --N(R.sup.2)--S(O).sub.2(R.sup.2), halo,
--CF.sub.3, or --NO.sub.2;
[0069] Z is O, S, N(R.sup.2).sub.2, or, when M is not present,
H.
[0070] Y is P or S;
[0071] X is O or S; and
[0072] R.sup.9 is C(R.sup.2).sub.2, O or N(R.sup.2); and wherein
when Y is S, Z is not S; and
[0073] R.sup.6 is a 5-6 membered saturated, partially saturated or
unsaturated carbocyclic or heterocyclic ring system, or an 8-10
membered saturated, partially saturated or unsaturated bicyclic
ring system; wherein any of said heterocyclic ring systems contains
one or more heteroatoms selected from O, N, S, S(O).sub.n or
N(R.sup.2); and wherein any of said ring systems optionally
contains 1 to 4 substituents independently selected from OH,
C.sub.1-C.sub.4 alkyl, --O--C.sub.1-C.sub.4 alkyl or
--O--C(O)--C.sub.1-C.sub.4 alkyl;
[0074] R.sup.10 is selected from C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.6-C.sub.14 aryl or Ht, wherein
R.sup.10 optionally contains up to three substituents independently
selected from --R.sup.3--CN, --SR.sup.5, --SOR.sup.5,
--SO.sub.2R.sup.5, --SR--NR.sup.5--C(O)R.sup.6,
--NR.sup.5--(SO.sub.2)R.sup.5, --C(O)N(R.sup.5).sub.2,
--C(S)N(R.sup.5).sub.2, --S(O).sub.2N(R.sup.5).su- b.2,
--C(O)R.sup.6, --C(S)R.sup.6, --N(R.sup.5).sub.2,
--NR.sup.5--C(O)R.sup.5, --NR.sup.5--C(O)OR.sup.5,
--NR.sup.5--C(O)N(R.sup.5).sub.2--NR--C(S)R.sup.5,
--NR.sup.5--C(S)OR.sup.5, --NR.sup.5--C(S)N(R.sup.5).sub.2,
--NR--C[.dbd.N(R.sup.5)]--N(R.sup.5).sub.2,
--NH--C[.dbd.N--NO.sub.2]--NH- .sub.2,
--NH--C[.dbd.N--NO.sub.2]--OR.sup.5, --N(R.sup.8).sub.2--C(O)R.sup-
.8, --OC(O)R.sup.6, --OC(O)N(R.sup.5).sub.2,
--OC(S)N(R.sup.5).sub.2, wherein any one of the --CH.sub.2 groups
of said alkyl or alkenyl chains of R.sup.10 may be optionally
replaced by O, S, SO, SO.sub.2, C(O) or NR.sup.5;
[0075] wherein each R.sup.5 is independently selected from
hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl or Ht, wherein each R.sup.5, except for
hydrogen, is optionally substituted with --CF3, --PO.sub.3R.sup.3,
azido or halo;
[0076] Preferably, at least one R.sup.- is selected from: 56
[0077] It will be understood by those of skill in the art that
component M or M' in the formulae set forth herein will have either
a covalent, a covalent/zwitterionic, or an ionic association with
either Z or R.sup.9 depending upon the actual choice for M or M'.
When M or M' is hydrogen, alkyl, alkenyl, or R.sup.6, M or M' is
covalently bound to R.sup.9 or Z. If M is a mono- or bivalent metal
or other charged species (i.e., NH.sub.4.sup.-), there is an ionic
interaction between M and Z and the resulting compound is a
salt.
[0078] When x is 0 in (M).sub.x, Z may be a charged species. When
that occurs, the other M may be oppositely charged to produce a 0
net charge on the molecule. Alternatively, the counter ion may
located elsewhere in the molecule.
[0079] Except where expressly provided to the contrary, as used
herein, the definitions of variables A, R.sup.1-R.sup.4,
R.sup.6-R.sup.9, Ht, B, x, n, D, D', M, Q, X, Y, Z and E are to be
taken as they are defined above for the compounds of formula I.
[0080] According to a preferred embodiment, the compounds of this
invention are those represented by formula II, formula III or
formula IV: 7
[0081] wherein A, R.sup.3, R.sup.7, Ht, D, D', x, E are as defined
above for compounds of formula I. For ease of reference, the two
R.sup.3 moieties present in formula IV have been labeled R.sup.3
and R.sup.3'.
[0082] For compounds of formula II, more preferred compounds are
those wherein:
[0083] A is --C(O)Ht;
[0084] D' is --O--R.sup.10;
[0085] E is C.sub.6-C.sub.10 aryl optionally substituted with one
or more substituents selected from oxo, --OR.sup.2, SR.sup.2,
--R.sup.2, --N(R.sup.2).sub.2, --R.sup.2--OH, --CN,
--CO.sub.2R.sup.2, --C(O)--N(R.sup.2).sub.2,
--S(O).sub.2--N(R.sup.2).sub.2, --N(R.sup.2)--C(O)--R.sup.2,
--C(O)--R.sup.2, --S(O).sub.n--R.sup.2, --OCF.sub.3,
--S(O).sub.n-Q, methylenedioxy, --N(R.sup.2)--S(O).sub.2(R.s-
up.2), halo, --CF.sub.3, --NO.sub.2, Q, --OQ, --OR.sup.7,
--SR.sup.7, --R.sup.7, --N(R.sup.2) (R.sup.7) or
--N(R.sup.7).sub.2; or a 5-membered heterocyclic ring containing
one S and optionally containing N as an additional heteroatom,
wherein said heterocyclic ring is optionally substituted with one
to two groups independently selected from --CH.sub.3, R.sup.4, or
Ht.
[0086] all other variables are as defined for formula I.
[0087] Another preferred embodiment for the formula II compounds
are those wherein:
[0088] E is a 5-membered heterocyclic ring containing one S and
optionally containing N as an additional heteroatom, wherein said
heterocyclic ring is optionally substituted with one to two groups
independently selected from --CH.sub.3, R.sup.4, or Ht; and
[0089] all other variables are as defined for formula I.
[0090] More preferred are any of the formula II compounds set forth
above, wherein R.sup.7 in --OR.sup.7 is --PO(OM).sub.2 or
C(O)CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.3 and both
R.sup.7 in --N(R.sup.7).sub.2 are H, wherein M is H, Li, Na, K or
C.sub.1-C.sub.4 alkyl; or wherein R.sup.7 in --OR.sup.7 is
C(O)CH.sub.2OCH.sub.2CH.sub.2O- CH.sub.3, one R.sup.7 in
--N(R.sup.7).sub.2 is C(O)CH.sub.2OCH.sub.2CH.sub- .2OCH.sub.3 and
the other is H.
[0091] According to another preferred embodiment of the present
invention, there is provided compounds of formula (V): 8
[0092] wherein:
[0093] A is C.sub.6-C.sub.14 aryl optionally substituted with one
or more groups independently selected from the group consisting of
C.sub.1-C.sub.8 alkyl or hydroxy, or OR.sup.4, wherein R.sup.4 is
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.8
alkyl substituted with C.sub.6-C.sub.14, C.sub.6-C.sub.14 aryl
optionally substituted with C.sub.1-C.sub.8 alkyl, heterocyclyl or
heterocyclylalkyl;
[0094] E is C.sub.6-C.sub.14 aryl, optionally substituted with one
or more groups selected from nitro, oxo, alkoxy, amino,
hydroxyamino; heterocyclcyl, optionally substituted with one or
more groups selected from the group consisting of nitro, oxo,
alkoxy, amino, hydroxyamino or N(CO)OCH.sub.3;
[0095] R.sup.10 and R.sup.7 are as defined above;
[0096] or a pharmaceutically acceptable derivative thereof.
[0097] According to yet another preferred embodiment, there is
provided compounds of Formula (VI): 9
[0098] wherein:
[0099] R.sup.7 and R.sup.10 are as defined above for formula I;
[0100] E is C.sub.6-C.sub.14 aryl, optionally substituted with one
or more groups selected from the group consisting of nitro, oxo,
alkoxy, amino, hydroxyamino; heterocyclcyl, optionally substituted
with one or more groups selected from the group consisting of
nitro, oxo, alkoxy, amino, hydroxyamino or N(CO)OCH.sub.3;
[0101] or a pharmaceutically acceptable derivative thereof.
[0102] According to yet another preferred embodiment, there is
provided a compound of Formula (VII): 10
[0103] wherein:
[0104] A, E, R.sup.7 and R.sup.10 are as defined in formula
(I);
[0105] or a pharmaceutically acceptable derivative thereof.
[0106] According to yet another preferred embodiment, there is
provided a compound of formula (VIII): 11
[0107] wherein A, R.sup.1, R.sup.3, R.sup.-and E are as defined in
formula (I).
[0108] According to yet another embodiment of the present
invention, there are provided compounds of the formula: 12
[0109] wherein X.sup.- is a pharmaceutically suitable counterion;
1314
[0110] wherein R.sup.10 is selected from isopropyl or cyclopentyl;
R.sup.11 is selected from NHR.sup.7 or OR.sup.7; x, R.sup.7 and G
are as defined above; and X.sup.- is a pharmaceutically acceptable
counterion.
[0111] The compounds according to the invention contain one or more
asymmetric carbon atoms and thus occur as racemates and racemic
mixtures, single enantiomers, diastereomeric mixtures and
individual diastereomers. All such isomeric forms of these
compounds are expressly included in the present invention. Each
stereogenic carbon may be of the R or S configuration. Although the
specific compounds exemplified in this application may be depicted
in a particular stereochemical configuration, compounds having
either the opposite stereochemistry at any given chiral center or
mixtures thereof are also envisioned.
[0112] More preferred compounds of formula (I) of the present
invention are set forth below in Table 1.
1TABLE 1 15 Compound A R.sup.10 E 1 16 17 18 2 19 20 21 3 22 23 24
4 25 26 27 5 28 29 30 6 31 32 33 7 34 35 36 8 37 38 39 9 40 41 42
10 43 44 45 11 46 47 48 12 49 50 51 13 52 53 54 14 55 56 57 15 58
59 60 16 61 62 63 17 64 65 66 18 67 68 69 19 70 71 72 20 73 74 75
21 76 77 78 22 79 80 81 23 82 83 84 24 85 86 87 25 88 89 90 26 91
92 93 27 94 95 96 28 97 98 99 100 29 101 102 103 104 30 105 106 107
108 31 109 110 111 112 32 113 114 115 116 33 117 118 119 120 34 121
122 123 124 35 125 126 127 128 36 129 130 131 132 37 133 134 135
136 38 137 138 139 39 140 141 142 40 143 144 145 41 146 147 148 42
149 150 151 43 152 153 154 44 155 156 157 45 158 159 160 46 161 162
163 47 164 165 166 48 167 168 169 49 170 171 172 50 173 174 175 51
176 177 178 52 179 180 181 53 182 183 184 54 185 186 187 55 188 189
190 56 191 192 193 57 194 195 196 58 197 198 199 59 200 201 202 60
203 204 205 61 206 207 208 62 209 210 211 63 212 213 214 64 215 216
217 65 218 219 220 66 221 222 223 67 224 225 226 68 227 228 229 69
230 231 232 70 233 234 235 71 236 237 238 72 239 240 241 73 242 243
244 74 245 246 247 75 248 249 250 76 251 252 253 77 254 255 256 78
257 258 259 79 260 261 262 263 82 264 265 266 83 267 268 269 270 84
271 272 273 274 85 275 276 277 278 86 279 280 281 282 87 283 284
285 286 88 287 288 289 290 89 291 292 293 294 90 295 296 297 91 298
299 300 301 92 302 303 304 93 305 306 307 94 308 309 310 95 311 312
313 96 314 315 316 97 317 318 319 98 320 321 322 99 323 324 325 102
326 327 328 103 329 330 331 104 332 333 334 105 335 336 337 106 338
339 340 107 341 342 343 108 344 345 346 109 347 348 349 110 350 351
352 111 353 354 355 112 356 357 358 113 359 360 361 362 114 363 364
365 115 366 367 368 116 369 370 371 117 372 373 374 118 375 376 377
120 378 379 380 121 381 382 383 384 122 385 386 387 388 123 389 390
391 124 392 393 394 395 125 396 397 398 126 399 400 401 127 402 403
404 128 405 406 407 129 408 409 410 130 411 412 413 131 414 415 416
132 417 418 419 133 420 421 422 423 134 424 425 426 135 427 428 429
136 430 431 432 137 433 434 435 138 436 437 438 139 439 440 441 140
442 443 444 141 445 446 447 142 448 449 450 145 451 452 453 146 454
455 456 147 457 458 459 148 460 461 462 149 463 464 465 150 466 467
468 151 469 470 471 152 472 473 474 153 475 476 477 154 478 479 480
155 481 482 483 156 484 485 486 157 487 488 489 158 490 491 492 159
493 494 495 160 496 497 498 161 499 500 501 162 502 503 504 163 505
506 507 164 508 509 510 165 511 512 513 166 514 515 516 167 517 518
519 520 168 521 522 523 524 169 525 526 527 528 170 529 530 531 532
171 533 534 535 172 536 537 538 173 539 540 541
[0113]
2 542 Com- pound A R.sup.8 E 80 543 544 545 81 546 547 548
[0114]
3 549 Compound A R.sup.10 E 100 550 551 552 101 553 554 555 119 556
557 558 143 559 560 561 144 562 563 564
[0115] Most preferred compounds of the present invention include
the following:
[0116] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-((1S,
2R)-1-benzyl-3-(cyclopentyloxy)[(3-[2-(dimethylamino)ethyl]aminophenyl)su-
lfonyl]amino-2-hydroxypropyl)carbamate;
[0117] (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)[(3-[2-(dimethylamino)ethyl]aminophenyl)sulfonyl]amino-2-hyd-
roxypropyl)carbamate;
[0118]
(3R,3aS,6aR)Hexahydrofuro[2,3-b]furan-3-yl-N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)(2-[(methylsulfonyl)amino]benzimidazol-5-ylsulfonyl)amino-2--
hydroxypropyl)carbamate;
[0119] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-(1S,
2R)-3-[[(3-N-methylaminophenyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-
-hydroxypropylcarbamate;
[0120] 1,3-Dioxan-5-yl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-{(methoxyc-
arbonyl)amino]-1H-benzimidazol-5-ylsulfonyl)amino]-2-hydroxypropylcarbamat-
e;
[0121] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-2-hyd-
roxy-3-[[(4-methoxyphenyl)sulfonyl](tetrahydro
2H-pyran-4-yloxy)amino]prop- ylcarbamate;
[0122] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-(1S,
2R)-3-[[(3-aminophenyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxy-
propylcarbamate;
[0123] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[((1S,2R)-1-benzyl-3-(-
(cyclopentyloxy)[3-(2-[methoxy(methyl)amino]-2-oxoethylamino)phenyl]sulfon-
ylamino)-2-hydroxypropyl]carbamate;
[0124] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(13
S2R)-1-benzyl-4-(cyclopentyloxy)-2-hydroxy-4-(6-quinoxalinyl
sulfonyl)butyl]carbamate;
[0125] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate;
[0126] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,
2R)-1-benzyl-3-((cyclopentyloxy)
[3-(2-[(methylsulfonyl)amino]ethylamino)-
phenyl]sulfonylamino)-2-hydroxypropyl]carbamate;
[0127] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-(1S,
2R)-3[[(3-N-methylaminophenyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2--
hydroxypropylcarbamate phosphate ester;
[0128] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-(1S,
2R)-3-[[(3-aminophenyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxy-
propylcarbamate phosphate ester;
[0129] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[[(4-aminoph-
enyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxypropyl
carbamate;
[0130]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-{(1-et-
hylpropoxy)[(4-hydroxyphenyl)sulfonyl]amino}-2-hydroxypropylcarbamate;
[0131]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[(1,3-benzodiox-
ol-5-ylsulfonyl)(1-ethylpropoxy)amino]-1-benzyl-2-hydroxypropylcarbamate;
[0132] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,
2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(cyclopentyloxy)amino]-1-benzyl-2-(p-
hosphonooxy)propyl]carbamate;
[0133]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3[(1,3-benzodioxo-
l-5-ylsulfonyl)(cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate;
[0134] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
3-[(1,3-benzodioxol-5-yl-
sulfonyl)(tetrahydro-2H-pyran-4-yloxy)amino]-1-benzyl-2-hydroxypropylcarba-
mate;
[0135] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-3-[(1,3-benzo-
dioxol-5-ylsulfonyl)(cyclopentyloxy)amino]-1-benzyl-2-(phosphonooxy)propyl-
]carbamate;
[0136] or a pharmaceutically acceptable derivative thereof.
[0137] The compounds of the present invention can be readily
prepared by techniques known in the art. Scheme I illustrates a
general synthetic route to compounds of formula (V), a preferred
sub-genus of formula (I).
[0138] According to Scheme I, commercially available
N-hydroxyphthalimide is reacted with R.sup.10--Br or R.sup.10--OH
under displacement or Mitsonobu-type conditions respectively,
followed by hydrazinolysis in ethanol to produce the amine of
formula (I). Amine of formula (I) is further utilized in two
synthetic routes, Path 1 and Path 2.
[0139] Path 1
[0140] Step 1: Amine of formula (I) is reacted with a sulfonyl
chloride of formula (A) to produce sulfonamide of formula
(II').
[0141] Step 2: Sulfonamide of formula (II') is reacted with
intermediate of formula (B), which bears an amine protecting group
P, such as t-butoxycarbonyl, to produce compound of formula (III').
Suitable amine protecting groups are described in numerous
references, including T. W. Greene and P. G. M. Wuts, Protective
Groups in Organic Synthesis, 2d Ed., John Wiley and Sons (1991); L.
Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic
Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.
Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons
(1995). Examples of such amino protecting groups include, but are
not limited to, Cbz or Alloc.
[0142] Step 3: Compound of formula (III') is then reacted with A-L,
wherein L is a leaving group, to produce compound of formula (IV).
A leaving group is an atom or group which is displaceable upon
reaction with an appropriate amine or sulfonamide. Suitable leaving
groups would be obvious to one of skill in the art and include but
are not limited to hydroxyls, carboxylates and halides. 565
[0143] Step 4: Compound of formula (IV) is then converted to
compound of formula (V) by functional transformation of the hydroxy
group.
[0144] Path 2 differs from Path 1 only in the sequence of reagents
employed to convert compound of formula (I) to compound of formula
(IV).
[0145] The synthetic approach illustrated in Scheme I can be
readily extended to produce other compounds of the present
invention. The above synthetic scheme is not intended to comprise a
comprehensive list of all means by which compounds described and
claimed in this application may be synthesized. Further methods
will be evident to those of ordinary skill in the art.
[0146] As discussed above, the novel compounds of the present
invention are excellent ligands for aspartyl proteases,
particularly HIV-1 and HIV-2 proteases. Accordingly, these
compounds are capable of targeting and inhibiting late stage events
in HIV replication, i.e., the processing of the viral polyproteins
by HIV encoded proteases. Such compounds inhibit the proteolytic
processing of viral polyprotein precursors by inhibiting aspartyl
protease. Because aspartyl protease is essential for the production
of mature virions, inhibition of that processing effectively blocks
the spread of virus by inhibiting the production of infectious
virions, particularly from chronically infected cells. Compounds
according to this invention advantageously inhibit the ability of
the HIV-1 virus to infect immortalized human T cells over a period
of days, as determined by an assay of extracellular p24 antigen--a
specific marker of viral replication. Other anti-viral assays have
confirmed the potency of these compounds.
[0147] The compounds of this invention may be employed In a
conventional manner for the treatment of viruses, such as HIV and
HTLV, which depend on aspartyl proteases for obligatory events in
their life cycle. Such methods of treatment, their dosage levels
and requirements may be selected by those of ordinary skill in the
art from available methods and techniques. For example, a compound
of this invention may be combined with a pharmaceutically
acceptable adjuvant for administration to a virally-infected
patient in a pharmaceutically acceptable manner and in an amount
effective to lessen the severity of the viral infection.
[0148] Alternatively, the compounds of this invention may be used
in vaccines and methods for protecting individuals against viral
infection over an extended period of time. The compounds may be
employed in such vaccines either alone or together with other
compounds of this invention in a manner consistent with the
conventional utilization of protease inhibitors in vaccines. For
example, a compound of this invention may be combined with
pharmaceutically acceptable adjuvants conventionally employed in
vaccines and administered in prophylactically effective amounts to
protect individuals over an extended period time against HIV
infection. As such, the novel protease inhibitors of this invention
can be administered as agents for treating or preventing HIV
infection in a mammal.
[0149] The compounds of formula I, especially those having a
molecular weight of less than about 700 g/mole, may be readily
absorbed by the bloodstream of mammals upon oral administration.
Compounds of formula I having a molecular weight of less than about
600 g/mole are most likely to demonstrate oral availability. This
surprisingly impressive oral availability makes such compounds
excellent agents for orally-administered treatment and prevention
regimens against HIV infection.
[0150] The compounds of this invention may be administered to a
healthy or HIV-infected patient either as a single agent or in
combination with other anti-viral agents which interfere with the
replication cycle of HIV. By administering the compounds of this
invention with other anti-viral agents which target different
events in the viral life cycle, the therapeutic effect of these
compounds is potentiated. For instance, the co-administered
anti-viral agent can be one which targets early events in the life
cycle of the virus, such as cell entry, reverse transcription and
viral DNA integration into cellular DNA. Anti-HIV agents targeting
such early life cycle events include, didanosine (ddI), alcitabine
(ddC), d4T, zidovudine (AZT), polysulfated polysaccharides, sT4
(soluble CD4), 3TC, 935U83, 1592U89, 524W91, ganciclovir,
dideoxycytidine, trisodium phosphonoformate, eflornithine,
ribavirin, acyclovir, alpha interferon and trimenotrexate.
Ribonucleotide reductase inhibitors such as hydroxyurea may also be
used. Additionally, non-nucleoside inhibitors of reverse
transcriptase, such as TIBO, delavirine (U90) or nevirapine, may be
used to potentiate the effect of the compounds of this invention,
as may viral uncoating inhibitors, inhibitors of trans-activating
proteins such as tat or rev, or inhibitors of the viral
integrase.
[0151] Combination therapies according to this invention exert a
synergistic effect in inhibiting HIV replication because each
component agent of the combination acts on a different site of HIV
replication. The use of such combinations also advantageously
reduces the dosage of a given conventional anti-retroviral agent
which would be required for a desired therapeutic or prophylactic
effect as compared to when that agent is administered as a
monotherapy. These combinations may reduce or eliminate the side
effects of conventional single anti-retroviral agent therapies
while not interfering with the anti-retroviral activity of those
agents. These combinations reduce potential of resistance to single
agent therapies, whale minimizing any associated toxicity. These
combinations may also increase the efficacy of the conventional
agent without increasing the associated toxicity. In particular, we
have discovered that these compounds act synergistically in
preventing the replication of HIV in human T cells. Preferred
combination therapies include the administration of a compound of
this invention with AZT, ddI, ddC or d4T.
[0152] Alternatively, the compounds of this invention may also be
co-administered with other HIV protease inhibitors such as
Agenerase (VX-478, Vertex), saquinavir, Ro 31-8959 (Roche),
L-735,524 (Merck), XM 323 (Du-Pont Merck) A-80,987 Abbott), MK 639
(Merck), ABT 538 (A-80538, Abbott), AG 1343(Agouron), XM 412
(Du-Pont Merck), XM 450 (Du-Pont Merck), BMS 186318 (Bristol-Meyers
Squibb), ABT 378 (Abbott) and CPG 53,437 (Ciba Geigy) to increase
the effect of therapy or prophylaxis against various viral mutants
or members of other HIV quasi species.
[0153] We prefer administering the compounds of this invention as
single agents or in combination with retroviral reverse
transcriptase inhibitors, such as derivatives of AZT, or other HIV
aspartyl protease inhibitors. We believe that the co-administration
of the compounds of this invention with retroviral reverse
transcriptase inhibitors or HIV aspartyl protease inhibitors may
exert a substantial synergistic effect, thereby preventing,
substantially reducing, or completely eliminating viral infectivity
and its associated symptoms.
[0154] The compounds of this invention can also be administered in
combination with immunomodulators (e.g., bropirimine, anti-human
alpha interferon antibody, IL-2, GM-CSF, methionine enkephalin,
interferon alpha, diethyldithiocarbamate, tumor necrosis factor,
naltrexone, tuscarasol and rEPO); and antibiotics (e.g.,
pentamicine isethiorate) to prevent or combat infection and disease
associated with HIV infections, such as AIDS and ARC.
[0155] When the compounds of this invention are administered in
combination therapies with other agents, they may be administered
sequentially or concurrently to the patient. Alternatively,
pharmaceutical or prophylactic compositions according to this
invention may be comprised of a combination of an aspartyl protease
inhibitor of this invention and another therapeutic or prophylactic
agent.
[0156] Although this invention focuses on the use of the compounds
disclosed herein for preventing and treating HIV infection, the
compounds of this invention can also be used as inhibitory agents
for other viruses which depend on similar aspartyl proteases for
obligatory events in their life cycle. These viruses include, as
well as other AIDS-like diseases caused by retroviruses, such as
simian immunodeficiency viruses, but are not limited to, HTLV-I and
HTLV-II. In addition, the compounds of this invention may also be
used to inhibit other aspartyl proteases, and in particular, other
human aspartyl proteases, including renin and aspartyl proteases
that process endothelin precursors. Pharmaceutical compositions of
this invention comprise any of the compounds of the present
invention, and pharmaceutically acceptable salts thereof, with any
pharmaceutically acceptable carrier, adjuvant or vehicle.
Pharmaceutically acceptable carriers, adjuvants and vehicles that
may be used in the pharmaceutical compositions of this invention
include, but are not limited to, ion exchangers, alumina, aluminum
stearate, lecithin, serum proteins, such as human serum albumin,
buffer substances such as phosphates, glycine, sorbic acid,
potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, salts or electrolytes, such as
protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
waxes, polyethylene-polyoxypropylene-block polymers, polyethylene
glycol and wool fat.
[0157] The pharmaceutical compositions of this invention may be
administered orally, parenterally, by inhalation spray, topically,
rectally, nasally, buccally, vaginally or via an implanted
reservoir. We prefer oral administration or administration by
injection. The pharmaceutical compositions of this invention may
contain any conventional non-toxic pharmaceutically-acceptable
carriers, adjuvants or vehicles. The term parenteral as used herein
includes subcutaneous, intracutaneous, intravenous, intramuscular,
intra-articular, intrasynovial, intrasternal, intrathecal,
intralesional and intracranial injection or infusion
techniques.
[0158] The pharmaceutical compositions may be in the form of a
sterile injectable preparation, for example, as a sterile
injectable aqueous or oleaginous suspension. This suspension may be
formulated according to techniques known in the art using suitable
dispersing or wetting agents (such as, for example, Tween 80) and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a non-toxic
parenterally-acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are mannitol, 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. Fatty acids,
such as oleic acid and its glyceride derivatives are useful in the
preparation of injectables, as are natural
pharmaceutically-acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil solutions
or suspensions may also contain a long-chain alcohol diluent or
dispersant such as Ph. Helv or a similar alcohol.
[0159] The pharmaceutical compositions of this invention may be
orally administered in any orally acceptable dosage form including,
but not limited to, capsules, tablets, and aqueous suspensions and
solutions. In the case of tablets for oral use, carriers which are
commonly used include lactose and corn starch. Lubricating agents,
such as magnesium stearate, are also typically added. For oral
administration in a capsule form, useful diluents include lactose
and dried corn starch. When aqueous suspensions are administered
orally, the active ingredient is combined with emulsifying and
suspending agents. If desired, certain sweetening and/or flavoring
and/or coloring agents may be added.
[0160] The pharmaceutical compositions of this invention may also
be administered in the form of suppositories for rectal
administration. These compositions can be prepared by mixing a
compound of this invention with a suitable nonirritating excipient
which is solid at room temperature but liquid at the rectal
temperature and therefore will melt in the rectum to release the
active components. Such materials include, but are not limited to,
cocoa butter, beeswax and polyethylene glycols.
[0161] Topical administration of the pharmaceutical compositions of
this invention is especially useful when the desired treatment
involves areas or organs readily accessible by topical application.
For application topically to the skin, the pharmaceutical
composition should be formulated with a suitable ointment
containing the active components suspended or dissolved in a
carrier. Carriers for topical administration of the compounds of
this invention include, but are not limited to, mineral oil, liquid
petroleum, white petroleum, propylene glycol, polyoxyethylene
polyoxypropylene compound, emulsifying wax and water.
Alternatively, the pharmaceutical composition can be formulated
with a suitable lotion or cream containing the active compound
suspended or dissolved in a carrier. Suitable carriers include, but
are not limited to, mineral oil, sorbitan monostearate, polysorbate
60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl
alcohol and water. The pharmaceutical compositions of this
invention may also be topically applied to the lower intestinal
tract by rectal suppository formulation or in a suitable enema
formulation. Topically-transdermal patches are also included in
this invention.
[0162] The pharmaceutical compositions of this invention may be
administered by nasal aerosol or inhalation. Such compositions are
prepared according to techniques well-known in the art of
pharmaceutical formulation and may be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluorocarbons,
and/or other solubilizing or dispersing agents known in the
art.
[0163] Dosage levels of between about 0.01 and about 100 mg/kg body
weight per day, preferably between about 0.5 and about 50 mg/kg
body weight per day of the active ingredient compound are useful in
the prevention and treatment of viral infection, including HIV
infection. Typically, the pharmaceutical compositions of this
invention will be administered from about 1 to about 5 times per
day or alternatively, as a continuous infusion. Such administration
can be used as a chronic or acute therapy. 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. A typical
preparation will contain from about 5% to about 95% active compound
(w/w). Preferably, such preparations contain from about 20% to
about 80% active compound.
[0164] Upon improvement of a patient's condition, a maintenance
dose of a compound, composition or combination of this invention
may be administered, if necessary. Subsequently, the dosage or
frequency of administration, or both, may be reduced, as a function
of the symptoms, to a level at which the improved condition is
retained when the symptoms have been alleviated to the desired
level, treatment should cease. Patients may, however, require
intermittent treatment on a long-term basis upon any recurrence of
disease symptoms.
[0165] As the skilled artisan will appreciate, lower or higher
doses than those recited above may be required. Specific dosage and
treatment regimens 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 status, sex, diet,
time of administration, rate of excretion, drug combination, the
severity and course of the infection, the patient's disposition to
the infection and the judgment of the treating physician.
[0166] The compounds of this invention are also useful as
commercial reagents which effectively bind to aspartyl proteases,
particularly HIV aspartyl protease. As commercial reagents, the
compounds of this invention, and their derivatives, may be used to
block proteolysis of a target peptide or may be derivatized to bind
to a stable resin as a tethered substrate for affinity
chromatography applications. These and other uses which
characterize commercial aspartyl protease inhibitors will be
evident to those of ordinary skill in the art.
[0167] As used herein, the compounds according to the invention are
defined to include pharmaceutically acceptable derivatives or
prodrugs thereof. A "pharmaceutically acceptable derivative" or
"pharmaceutically acceptable prodrug" means any pharmaceutically
acceptable salt, ester, salt of an ester, or other derivative of a
compound of this invention which, upon administration to a
recipient, is capable of providing (directly or indirectly) a
compound of this invention or an inhibitorily active metabolite or
residue thereof. Particularly favored derivatives and prodrugs are
those that increase the bioavailability of the compounds of this
invention when such compounds are administered to a mammal (e.g.,
by allowing an orally administered compound to be more readily
absorbed into the blood) or which enhance delivery of the parent
compound to a biological compartment (e.g., the brain or lymphatic
system) relative to the parent species.
[0168] The compounds according to the invention may be used in the
form of salts derived from inorganic or organic acids. Included
among such acid salts, for example, are the following: acetate,
adipate, alginate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, citrate, camphorate, camphorsulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate,
pamoate, pectianate, persulfate, phenylproprionate, picrate,
pivalate, propionate, succinate, tartrate, thiocyanate, tosylate
and undecanoate. Other acids, such as oxalic, while not in
themselves pharmaceutically acceptable, may be employed in the
preparation of salts useful as intermediates in obtaining the
compounds of the invention and their pharmaceutically acceptable
acid addition salts.
[0169] Salts derived from appropriate bases include alkali metal
(e.g. sodium), alkaline earth metal (e.g., magnesium), ammonium and
.sup.-NW4 (wherein W is C.sub.1-4 alkyl). Physiologically
acceptable salts of a hydrogen atom or an amino group include salts
or organic carboxylic acids such as acetic, lactic, tartaric,
malic, isethionic, lactobionic and succinic acids; organic sulfonic
acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and
p-toluenesulfonic acids and inorganic acids such as hydrochloric,
sulfuric, phosphoric and sulfamic acids. Physiologically acceptable
salts of a compound with a hydroxy group include the anion of said
compound in combination with a suitable cation such as Na.sup.+,
NH.sub.4.sup.+, and NW.sub.4.sup.+ (wherein W is a C.sub.1-4 alkyl
group).
[0170] Pharmaceutically acceptable salts include salts of organic
carboxylic acids such as ascorbic, acetic, citric, lactic,
tartaric, malic, maleic, isothionic, lactobionic, p-aminobenzoic
and succinic acids; organic sulphonic acids such as
methanesulphonic, ethanesulphonic, benzenesulphonic and
p-toluenesulphonic acids and inorganic acids such as hydrochloric,
sulphuric, phosphoric, sulphamic and pyrophosphoric acids.
[0171] For therapeutic use, salts of the compounds according to the
invention will be pharmaceutically acceptable. However, salts of
acids and bases which are non-pharmaceutically acceptable may also
find use, for example, in the preparation or purification of a
pharmaceutically acceptable compound.
[0172] Preferred salts include salts formed from hydrochloric,
sulfuric, acetic, succinic, citric and ascorbic acids.
[0173] Preferred esters of the compounds according to the invention
are independently selected from the following groups: (1)
carboxylic acid esters obtained by esterification of the hydroxy
groups, in which the non-carbonyl moiety of the carboxylic acid
portion of the ester grouping is selected from straight or branched
chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl),
alkoxyalkyl (for example, methoxymethyl), aralkyl (for example,
benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for
example, phenyl optionally substituted by, for example, halogen,
C.sub.1-4alkyl, or C.sub.1-4alkoxy or amino); (2) sulfonate esters,
such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl);
(3) amino acid esters (for example, L-valyl or L-isoleucyl); (4)
phosphonate esters and (5) mono-, di- or triphosphate esters. The
phosphate esters may be further esterified by, for example, a
C.sub.2 alcohol or reactive derivative thereof, or by a 2,3-di
(C.sub.2)acyl glycerol.
[0174] In such esters, unless otherwise specified, any alkyl moiety
present advantageously contains from 1 to 18 carbon atoms,
particularly from 1 to 6 carbon atoms, more particularly from 1 to
4 carbon atoms, Any cycloalkyl moiety present in such esters
advantageously contains from 3 to 6 carbon atoms. Any aryl moiety
present in such esters advantageously comprises a phenyl group.
[0175] Any reference to any of the above compounds also includes a
reference to a pharmaceutically acceptable salts thereof.
[0176] The compounds according to the invention are especially
useful for the treatment of AIDS and related clinical conditions
such as AIDS related complex (ARC) progressive generalized
lymphadenopathy (PGL), Kaposi's sarcoma, thrombocytopenic purpura,
AIDS-related neurological conditions such as AIDS dementia complex,
multiple sclerosis or tropical paraperesis, and also anti-HIV
antibody-positive and HIV-positive conditions, including such
conditions in asymplomatic patients.
[0177] In a further aspect of the invention there are provided the
compounds according to the invention for use in medical therapy
particularly for the treatment or prophylaxis of viral infections
such as HIV infections.
[0178] According to another aspect, the present invention provides
a method for the treatment or prevention of the symptoms or effects
of a viral infection in an infected animal, for example, a mammal
including a human, which comprises treating said animal with a
therapeutically effective amount of a compound according to the
invention. According to a particular embodiment of this aspect of
the invention, the viral infection is an HIV infection. A further
aspect of the invention includes a method for the treatment or
prevention of the symptoms or effects of an HBV infection.
[0179] The compounds according to the invention may also be used in
adjuvant therapy in the treatment of HIV infections or
HIV-associated symptoms or effects, for example Kaposi's
sarcoma.
[0180] The present invention further provides a method for the
treatment of a clinical condition in an animal, for example, a
mammal including a human which clinical condition includes those
which have been discussed in the introduction hereinbefore, which
comprises treating said animal with a therapeutically effective
amount of a compound according to the invention. The present
invention also includes a method for the treatment or prophylaxis
of any of the aforementioned infections or conditions.
[0181] In yet a further aspect, the present invention provides the
use of a compound according to the invention the manufacture of a
medicament for the treatment or prophylaxis of any of the above
mentioned viral infections or conditions. It will be appreciated
that of compounds of Formlula (I), (II), (III), (IV), and (V) and
one or more other HIV protease inhibitors, reverse transcriptase
inhibitors, or non-nucleoside reverse transcriptase inhibitors may
be used in the manufacture of the above medicament.
[0182] Reference herein to treatment extends to prophylaxis as well
as the treatment of established infections or symptoms.
[0183] The above compounds according to the invention and their
pharmaceutically acceptable derivatives may be employed in
combination with other therapeutic agents for the treatment of the
above infections or conditions. Combination therapies according to
the present invention comprise the administration of at least one
compound of the formula (I) or a pharmaceutically acceptable
derivative thereof and at least one other pharmaceutically active
ingredient. The active ingredient(s) and pharmaceutically active
agents may be administered simultaneously in either the same or
different pharmaceutical formulations or sequentially in any order.
The amounts of the active ingredient(s) and pharmacuetically active
agent(s) and the relative timings of administration will be
selected in order to achieve the desired combined therapeutic
effect. Preferably the combination therapy involves the
administration of one compound according to the invention and one
of the agents mentioned herein below.
[0184] Examples of such further therapeutic agents include agents
that are effective for the treatment of viral infections or
associated conditions such as (1 alpha, 2 beta, 3
alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl]gu- anine [(-)BHCG,
SQ-34514], oxetanocin-G (3,4-bis-(hydroxymethyl)-2-oxetano-
syl]guanine), acyclic nucleosides (e.g. acyclovir, valaciclovir,
famciclovir, ganciclovir, penciclovir), acyclic nucleoside
phosphonates (e.g.
(S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC),
ribonucleotide reductase inhibitors such as 2-acetylpyridine
5-[(2-chloroanilino)thiocarbonyl)thiocarbonohydrazone,
3'azido-3'-deoxythymidine, hydroxyurea, other
2',3'-dideoxynucleosides such as 2',3'-dideoxycytidine,
2',3'-dideoxyadenosine, 2',3'-dideoxyinosine,
2',3'-didehydrothymidine, protease inhibitors such as agenerase,
indinavir, ritonavir, nelfinavir, [3S-[3R*(1R*,2S*)]]-[3[[(-
4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)pr-
opyl]-tetrahydro-3-furanyl ester (141W94), oxathiolane nucleoside
analogues such as (-)-cis-1-(2-hydroxymethyl)-1,3-oxathiolane
5-yl)-cytosine flamivudine) or
cis-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-- yl-5-fluorocytosine
(FTC), 3'-deoxy-3'-fluorothymidine,
5-chloro-2',3'-dideoxy-3'-fluorouridine,
(-)-cis-4-[2-amino-6-(cyclopropy-
lamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol, ribavirin,
9-[4-hydroxy-2-(hydroxymethyl)but-1-yl]-guanine (H2G), tat
inhibitors such as
7-chloro-5-(2-pyrryl)-3H-1,4-benzodiazepin-2-(H)one (Ro5-3335),
7-chloro-1,3-dihydro-5-H-pyrrol-2yl)-3H-1,4-benzodiazepin-2-amine
(Ro24-7429), interferons such as .alpha.-interferon, renal
excretion inhibitors such as probenecid, nucleoside transport
inhibitors such as dipyridamole; pentoxifylline, N-acetylcysteine
(NAC), Procysteine, .alpha.-trichosanthin, phosphonoformic acid, as
well as immunomodulators such as interleukin II or thymosin,
granulocyte macrophage colony stimulating factors, erythropoetin,
soluble CD.sub.4 and genetically engineered derivatives thereof, or
non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as
neviradine (BI-RG-587), loviride (.alpha.-APA) and delavuridine
(BHAP), and phosphonoformic acid,
and-1,4-dihydro-2H-3,1-benzoxazin-2-ones NNRTIs such as
(-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-be-
nzoxazin-2-one (L-743,726 or DMP-266), and quinoxaline NNRTIs such
as
isopropyl(2S)-7-fluoro-3,4-dihydro-2-ethyl-3-oxo-[(2H)-quinoxalinecarboxy-
late (HBY1293).
[0185] More preferably the combination therapy involves the
administration of one of the above mentioned agents and a compound
within one of the preferred or particularly preferred sub-groups
within formula (I) as described above. Most preferably the
combination therapy involves the joint use of one of the above
named agents together with one of the compounds of formula (I)
specifically named herein.
[0186] The present invention further includes the use of a compound
according to the invention in the manufacture of a medicament for
simultaneous or sequential administration with at least one other
therapeutic agent, such as those defined hereinbefore.
[0187] In order that this invention may be more fully understood,
the following examples are set forth. These examples are for the
purpose of illustration only and are not to be construed as
limiting the scope of the invention in any way.
EXAMPLES
[0188] General Methods and Conditions
[0189] All temperatures are recorded in decrees Celsius. Thin layer
chromatography (TLC) was carried out using 0.25 mm thick E. Merck
silica gel 60 F.sub.254 plates and elution with the indicated
solvent system. Detection of the compounds was carried out by
treating the plate with an appropriate visualizing agent, such as
10% solution of phosphomolybdic acid in ethanol or a 0.1% solution
of ninhydrin ethanol, followed by healing, and/or by exposure to UV
light or iodine vapors when appropriate. Thick layer silica gel
chromatography was also carried out using E. Merck 60 F.sub.254
planes ("prep plates") of 0.5, 1.0, or 2.0 mm thickness. Following
development of the plate, the band of silica containing the desired
compound was isolated and eluted with an appropriate solvent.
Analytical HPLC was carried out using a Water's Delta Pak, 5 .mu.M
silica, C18 reversed-phase column, 3.9 mm ID.times.15 cm L with a
flow rate of 1.5 mL/min using the following table:
4 Mobile phase: A = 0.1% CF.sub.3CO.sub.2H in H.sub.2O B = 0.1%
CF.sub.3CO.sub.2H in CH.sub.3CN Gradient: T = 0 min., A (95%), B
(5%) T = 20 min., A (0%), B (100%) T = 22.5 min., A (0%), B
(100%)
[0190] Preparative HPLC was also carried out using C.sub.18
reversed-phase media. HPLC retention times were recorded in
minutes. NMR spectral data was recorded using a Bruker AMX500,
equipped with either a reverse or QNP probe, at 500 MHz, and was
taken in the indicated solvent.
[0191] We have measured the inhibition constants of each compound
against HIV-1 protease using the method described essentially by M.
W. Pennington et al., Peptides 1990, Gimet, E. and D. Andrew, Eds.,
Escom, Leiden, Netherlands (1990); and the method described
essentially by Partaledis et al., J. Virol., 69, pp. 5228-35
(1995).
[0192] Compounds of invention were tested for their antiviral
potency in several virological assays.
[0193] Insofar as the compounds of this invention are able to
inhibit the replication of the HIV virus in CD4.sup.+ cells of
human lineage, they are of evident clinical utility for the
treatment of HIV infection. These tests are predictive of the
compounds ability to inhibit HIV protease in vivo.
Example 1
[0194] 566
[0195] N.sup.1-isopropoxy-3-nitro-1-benzenesulfonamide.
[0196] To a cooled solution (0.degree. C.) of O-isopropyl
hydroxyphthalimide (4.10 g, 0.02 mol) in anhydrous THF (45 mL) was
added anhydrous hydrazine (0.69 mL, 0.022 mmol) with stirring. The
solution was allowed to warm to RT and stir for 20.0 h, filtered
and the ppt. was washed with anhydrous THF (20 mL). To the filtrate
was added 3-nitro-benzenesulfonylchloride (4.86 g, 0.022 mol) and
diiosopropylethylamine (4.17 mL, 0.024 mol) at RT and the mixture
was stirred at RT for 20 h. The solution was evaporated and the
reside was partioned between ethyl acetate (200 mL) and Aq. 1.0N
HCl (30 mL). The organic layer was washed with 1.0N HCl (2.times.50
mL), 5% Aq. NaHCOC.sub.3 (2.times.50 mL), brine (2.times.25 mL),
dried (MgSO.sub.4), filtered, and evaporated to give a yellow oil.
The oil was purified by column chromatography: hexane/ethyl ace ate
(80/20) to give 3.58 g (69%) of the product as a white solid.
.sup.1H NMR (CDCl.sub.3): 1.20 (d, 6H); 4.27 (m, 1H); 7.05 (s, 1H);
7.75 (1, 1H); 8.22 (d, 1H); 8.48 (dd, 1H); 8.74 (t, 1H). 567
[0197] 3-amino-N.sup.1-isopropoxy-1-benzenesulfonamide.
[0198] To a Parr H.sub.2 vessel containing 5% Pd/BaSO.sub.4 (0.350
g) was added a methanolic solution (125 mL) of
N.sup.1-isopropoxy-3-nitro-1-benz- enesulfonamide (3.50 g, 0.0135
mol) at rt under Ar atm. The solution was hydrogenated at 45 psi
for approx. 1.0 h. The reaction mixtire was filtered (1/2" celite
pad) and evaporated to give the product as yellow crystalline solid
2.90 g (96%). .sup.1H NMR (CDCl.sub.3) 1.20 (d, 25H); 4.27 (m, 1H);
7.05 (s, 1H); 7.75(1, 1H); 8.22 (d, 1H); 8.48 (dd, 1H); 8.74 (t,
1H). 568
[0199]
tert-butyl-N-(1S,2R)-3-{[(3-aminophenyl)sulfonyl](isopropoxy)amino]-
-1-benzyl-2-hydroxypropylcarbamate.
[0200] To a solution of
3-amino-N.sup.1-isopropoxy-1-benzenesulfonamide (2.20 g, 9.56 mmol)
and tert-butyl N-(1S)-1-[(2S)oxiran-2-yl]-2-phenyleth- ylcarbamate
(2.01 g, 7.65 mmol) in anhydrous THF (10.0 mL) was added
phosphazene base P4 t-butyl solution (1.0 M in hexanes, 1.53 m,
1.53 mmol) with stirring at rt. After 8.0 h at rt, the THF was
evaporated to give a dark yellow residue that was dissloved in
ethyl acetate (200 mL). This solution was washed with 0.50M HCl
(3.times.20.0 mL), sat. NaHCO.sub.3 (3.times.20 mL), brine
(2.times.25 mL), dried (MgSO.sub.4), filtered, and evaporated to
give a yellow foam. The crude product was purified by column
chromatography: methylene chloride/ethyl acetate (95/5) to give the
product as a light yellow foam (3.61 g, 95%). MS: product: M+Na=516
.sup.1H NMR (CD.sub.3OD) 0.90 (m, 15H); 2.50-3.10 (m, 4H);
3.60-3.85 (m, 2H); 4.70 (m, 1H); 6.90 (d, 1H); 7.05 (d, 1H);
7.10-7.30 (m, 6H).
Example 2
[0201] 569
[0202] 4-amino-N.sup.1-isopropoxy-3-nitro-1-benzenesulfonamide.
[0203] Prepared using the procedure outlined in Example 1. The
crude product was purified by column chromatography: 60/40
hexane/ethyl acetate to give the product as a yellow solid (63%).
.sup.1H NMR (DMSO) 1.05 (d, 6H); 4.00 (m, 1H); 7.10 (d, 1H); 7.65
(d, 1H); 8.10 (s, 2H); 8.40 (s, 1H). 570
[0204] 3,4-diamino-N.sup.1-isopropoxy-1-benzenesulfonamide.
[0205] Prepared using the procedure outlined in Step 2, Example 1.
.sup.1H NMR (DMSO) 1.05 (d, 6H); 3.95 (m, 1H); 4.80 (s, 2H); 5.30
(s, 2H); 6.50 (d, 1H); 6.92 (d, 1H); 7.97 (s, 1H); 9.50 (s, 1H).
571
[0206]
tert-butyl-N-(1S,2R)-1-benzyl-3-[[(3,4-diaminophenyl)sulfonyl](isop-
ropoxy)amino]-2-hydroxypropylcarbamate.
[0207] Prepared using the procedure outlined in Step 3, Example 1.
The product was purified by column chromatography: to 40/60
hexane/ethyl acetate give the product as a dark orange solid (91%).
MS: M+Na=531 .sup.1H NMR (CD.sub.3OD) 0.90 (m, 15H); 2.50-3.10 (m,
4H); 3.60-3.85 (m, 2H); 4.45 (m, 1H); 6.40 (d, 1H); 6.70 (d, 1H);
7.00-7.30 (m, 6H).
Example 3
[0208] 572
[0209]
tert-butyl-N-(1S,2R)-3-[(1H-1,3-benzimidazol-5-ylsulfonyl)(isopropo-
xy)amino]-1-benzyl-2-hydroxypropylcarbamate.
[0210] To a solution of tert-butyl
N-(1S,2R)-1-benzyl-3-[[(3,4-diaminophen-
yl)sulfonyl](isopropoxy)amino]-2-hydroxy propylcarbamate (0.70 g,
1.38 mmol) in ethanol (10 mL) was added triethylorthoformate (0.64
mL, 3.86 mmol) and TFA (5.0 .mu.l) with stirring at rt. After 1.0
h., the reaction was neutralized with Aq. sat. NaHCO.sub.3 (50
.mu.l) and evaporated to give an orange residue. The residue was
dissolved in ethyl acetate (100 mL) and washed with aq. sat.
NaHCO.sub.3 (1.times.20 mL), water (2.times.20 mL), brine
(1.times.20 mL), dried (MgSO.sub.4), filtered, and evaporated to
give the crude product as a orange foam. The crude product was
purified by column chromatography: 30/70 hexane/ethyl acetate give
the product as a white solid (0.60 g, 85%). MS: M+H=519 .sup.1H NMR
(CD.sub.3OD) 1.00-1.40 (m, 15H); 2.50-3.10 (m, 4H); 3.60-3.85 (m,
2H); 4.60 (m, 1H); 7.20 (m, 5H); 7.80 (s, 2H) 8.20 (s, 1H); 8.40
(s, 1H).
Example 4
[0211] 573
[0212]
tert-butyl-N-((1S,2R)-1-benzyl-2-hydroxy-3-isopropoxy[(2-oxo-2,3-di-
hydro-1H-1,3-benzimidazol-5-yl)sulfonyl]aminopropyl)carbamate.
[0213] To a solution of tert-butyl
N-(1S,2R)-1-benzyl-3-[[(3,4-diaminophen-
yl)sulfonyl](isopropoxy)amino]-2-hydroxypropyl carbamate (0.70 g,
1.38 mmol) and DIEA (0.24 mL, 1.38 mmol) in anhydrous THF (10 mL)
was added triphosgene (0.136 g, 0.46 mmol) with stirring at rt.
After 0.5 h., the THF was removed in vacuo and the residue was
dissolved in ethyl acetate (100 mL). This solution was washed with
0.5M HCl (2.times.25 mL), aq. sat. NaHCO.sub.3 (2.times.25 mL),
brine (1.times.25 mL), dried (MgSO.sub.4), filtered and evaporated
to give the crude product. The crude product was purified by column
chromatography: 30/70 hexane/ethyl acetate give the product as a
yellow solid (0.63 g, 86%) MS: M+Na=557 .sup.1H NMR (CD.sub.3OD)
1.00-1.40 (m, 15H); 2.5-3.10 (m, 4H); 3.60-3.85 (m, 2H); 4.55 (m,
1H); 7.20 (m, 6H); 7.50 (m, 2H).
Example 5
[0214] 574
[0215] N-methanesulfonyl-2-aminobenzimidazole.
[0216] 2-amino-benzimidazole (1.0 g, 7.5 mmol) was dissolved in 15
mL of anhydrous CH.sub.2Cl.sub.2 and 3 mL anhydrous DMF and cooled
to .about.0.degree. C. Trethylamine (1.6 mL, 1.5 eq.) was added
followed by an addition of methanesulfonylchloride (580 .mu.L, 7.5
mmol) over .about.1 minute. After 1 minute at 0.degree. C., the
reaction was warmed to RT. After 1 hour the reaction was quenched
with water, and partitioned between a saturated sodium bicarbonate
solution and CH.sub.2Cl.sub.2. The aqueous layer was extracted with
CH.sub.2Cl.sub.2 and the combined organic layers were washed with
water (2 times), brine then dried over NaSO.sub.4, filtered and the
solvent was removed in vacuo to give 455 mg of
N-methanesulfonyl-2-aminobenzimidazole. HPLC shows the material to
be 91% pure, (ret. time=3.70). LCMS: obs. M+H@ 212.1 amu. The
material was carried on without purification. 575
[0217] N-methanesulfonyl-5-chlorosulfonyl-2-aminobenzimidazole.
[0218] To 9.5 mL (20 eq., 142 mmol) of well stirred chlorosulfonic
acid at .about.25.degree. C. was added
N-methanesulfonyl-2-aminobenzimidazole (1.5 g, 7.1 mmol) in small
portions over 10 minutes with slight exotherming. The solution was
stirred at .about.25.degree. C. for 3.5 hours, then was added
dropwise to a well stirred mixture of ice and water. The aqueous
solution was slowly basified to pH .about.7.5 with solid sodium
bicarbonate and extracted with EtOAc. A precipitate formed in the
organic phase which was filtered off and was washed with H.sub.2O
and dried on the filter to yield 1.23 g of
N-methanesulfonyl-5-chlorosulf- onyl-2-aminobenzimidazole. HPLC,
single peak, ret. time=7.61 min. MS: Obs. M+H @ 310.0 amu. 576
[0219] tert-Butyl-N-((1S,2R)-1-benzyl-3-(isopropyloxy)
(2-[(methylsulfonyl)amino]benzimidazol-5-ylsulfonyl)amino-2-hydroxypropyl-
)carbamate.
[0220]
tert-Butyl-N-((1S,2R)-1-benzyl-3-(isopropyloxy)amino-2-hydroxypropy-
l)carbamate (86 mg, 0.25 mmol) was combined with
2-[(methylsulfonyl)amino]- benzimidazol-5-ylsulfonyl chloride (77
mg, 0.25 mmol) in anhydrous pyridine (1 ml) with a catalytic amount
of N,N-dimethylaminopyridine. The reaction was stirred at room
temperature overnight. The solvent was evaporated under vacuum. The
crude mixture was diluted in EtOAc and washed with water and brine.
Organic phase was dried with MgSO.sub.4 and solvent was removed in
vacuo. Purification by TLC prep (2% MeOH/CH.sub.2Cl.sub.2).
Recovered 56 mg (37%) of product as a white solid. HPLC showed the
material to be 98% pure; Ret. time=9.87 min. .sup.1H NMR
(CDCl.sub.3): 7.12-8.04 (m, 8H), 6.5 (m, 1H), 4.47-4.51 (m, 2H),
3.68 (m, 2H), 3.22 (s, 3H), 2.81-2.88 (m, 3H), 1.75 (m, 2H), 1.22
(s, 9H), 1.16 (d, 6H). MS (ES+): obs. M+H @ 612.1 amu.
Example 6
[0221] 577
[0222] N.sup.1-(isopropoxy)-4-methoxy-1-benzenesulfonamide.
[0223] A vigorously stirred solution of
2-isopropoxy-1H-isoindole-1,3 (2H)-dione [2.50 g, 12.2 mmol, Synth.
Comm., 22(10), 1427-1432 (1992)] in 35 mL of tetrahydrofuran under
an Argon atmosphere at ambient temperature was treated with
anhydrous hydrazine (0.421 mL, 13.41 mmol). After 1.5 hours,
4-methoxybenzenesulphonyl chloride (3.024 g, 14.63 mmol),
dichloromethane (20 mL) and N,N-diisopropylethylamine (6.38 mL,
36.6 mmol) was added with continued stirring. After an additional 2
hours at ambient temperature, the reaction mixture was evaporated
in vacuo to a residue and partitioned between ethyl acetate and 1N
hydrochloric acid. The layers were separated and the aqueous layer
was extracted again with ethyl acetate. The combined organic layers
were washed with 5% w/v potassium carbonate and brine, dried over
anhydrous magnesium sulfate, filtered and evaporated in vacuo to a
residue. The crude material was purified on flash grade silica gel
eluting with 30% ethyl acetate in hexane. Fractions containing the
product were combined, evaporated in vacuo, and dried under high
vacuum to provide N-(isopropoxy)-4-methoxy-1-- benzenesulfonamide
(2.061 g, 69%) as a white solid. H1-NMR (chloroform-D3): 1.22 (d,
6H), 3.92 (s, 3H), 4.27 (m, 1H), 6.70 (s, 1H), 7.05 (d, 2H), 7.90
(d, 2H). MS (ESI): 268 (M+Na). 578
[0224] tert-butyl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)-
sulfonyl)amino-2-hydroxypropyl)carbamate.
[0225] A solution of N-(isopropoxy)-4-methoxy-1-benzenesulfonamide
(0.147 g, 0.599 mmol) and tert-butyl
N-(1S)-1-[(2S)oxiran-2-yl]-2-phenylethylcar- bamate (75 mg, 0.285
mmol) in anhydrous tetrahydrofuran (1 mL) under an Argon atmosphere
was treated with phosphazene base P<t/4>t-Bu (0.285 mL, 0.285
mmol, 1.0 M in hexane). After stirring for 30 minutes at ambient
temperature, the reaction mixture was quenched with several drops
of glacial acetic acid and evaporated in vacuo to a residue. The
crude product was purified on a preparative TLC plate (20.times.20,
500 .mu.M) eluting with 35:65 ethyl acetate hexane. The product
band was removed, eluted with ethyl acetate, and evaporated in
vacuo to a residue. The crude product was purified again on a
preparative TLC plate (25.times.20, 1000 .mu.M) eluting with 4:1
dichloromethane: ethyl acetate. The product band was removed,
eluted with ethyl acetate, and evaporated in vacuo. The residue was
triturated with water and the resulting slurry was stirred
overnight, filtered, and dried under high vacuum to provide
tert-butyl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2--
hydroxypropyl)carbamate (87 mg, 60%) as a white solid. H1-NMR
(methanol-D4): 1.22 (s, 9H), 1.24 (d, 6H), 2.52 (m, 2H), 3.07 (m,
2H), 3.68 (m, 2H), 3.87 (s, 3H), 4.50 (m, 1H), 7.08 (m, 2H), 7.19
(m, 5H), 7.75 (m, 2H). MS (ESI): 531 (M+Na)
Example 7
[0226] 579
[0227] 2-(cyclopentyloxy)-1H-isoindole-1,3 (2H)-dione.
[0228] A mixture of N-hydroxypthalimide (10.00 g, 61.3 mmol),
cyclopentylbromide (8.21 mL, 76.63 mmol), and
1,8-diazabicyclo[5.4.0]unde- c-7-ene (13.75 mL, 76.6 mmol) were
combined under an Argon atmosphere in dimethylformamide (50 mL).
The mixture was heated to 55.degree. C. and stirred vigorously for
1.5 hours. After cooling to ambient temperature, the solvent was
removed in vacuo and the residue was partitioned between ethyl
acetate and 1N hydrochloric acid. After separating the phases, the
aqueous layer was extracted again with ethyl acetate. The combined
organic layers were washed with 5% w/v potassium carbonate,
saturated aqueous brine, dried over anhydrous magnesium sulfate,
filtered and evaporated in vacuo. The residue was triturated with
hexane, filtered, and dried under high vacuum to provide
2-(cyclopentyloxy)-1H-isoindole-1,- 3 (2H)-dione (11.37 g, 80%).
H1-NMR (chloroform-D3): 1.61 (m, 2H), 1.77 (m, 2H), 1.97 (m, 4H),
4.91 (m, !H), 7.73 (m, 2H), 7.82 (m, 2H). MS (ESI): 254 (M+Na).
580
[0229] N.sup.1-(cyclopentyloxy)-4-methoxy-1-benzenesulfonamide.
[0230] A mixture of 2-(cyclopentyloxy)-1H-isoindole-1,3(2H)-dione
(3.00 g, 12.99 mmol) in anhydrous tetrahydrofuran (15 mL) at
ambient temperature under an Argon atmosphere was treated with
anhydrous hydrazine (0.448 mL, 14.29 mmol). After stirring
vigorously for 1.5 hours, the resulting slurry was filtered and
washed with approximately 15 mL of anhydrous tetrahydrofuran. The
filtrate was combined with 4-methoxybenzenesulphonyl chloride (2.95
g, 14.29 mmol) and N,N-diisopropylethylamine (2.72 mL, 15.6 mmol).
After stirring at ambient temperature for approximately 18 hours,
the reaction mixture was evaporated in vacuo to a residue and
partitioned between ethyl acetate and 1N hydrochloric acid. The
layers were separated and the organic phase was extracted again
with ethyl acetate. The combined organic layers were washed with 5%
w/v potassium carbonate and ovine, dried over anhydrous magnesium
sulfate, filtered and evaporated in vacuo to a residue. The crude
material was purified on flash grade silica gel eluting with 15:85
ethyl acetate:hexane. Fractions containing the product were
combined, evaporated in vacuo, and dried under high vacuum to
provide N-(cyclopentyloxy)-4-methoxy-1-benzenesulfon- amide (2.771
g, 79%) as an oil. H1-NMR chloroform-D3): 1.61 (m, 8H), 3.87 (s,
3H), 4.57 (m, 1H), 6.67 (s, 1H), 6.99 (m, 2H), 7.83 (m, 2H). MS
(ESI): 294 (M+Na). 581
[0231] tert-butyl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)-
sulfonyl)amino-2-hydroxypropyl)carbamate.
[0232] A solution of
N-(cyclopentyloxy)-4-methoxy-1-benzenesulfonamide (1.005 g, 3.71
mmol) and tert-butyl N-(1S)-1-[(2S)oxiran-2-yl]-2-phenylet-
hylcarbamate (0.780 g, 2.97 mmol) in anhydrous tetrahydrofuran (5
mL) under an Argon atmosphere was treated with phosphazene base
P<t/4>t-Bu (0.593 mL, 0.593 mmol, 1.0 M in hexane). The
mixture was stirred at ambient temperature for 2.5 hours and then
quenched with several drops of glacial acetic acid. The solution
was evaporated in vacuo to a residue and partitioned between ethyl
acetate and 1N hydrochloric acid. After separating the phases, the
aqueous layer was extracted with ethyl acetate. The combined ethyl
acetate layers were washed with brine, dried over anhydrous
magnesium sulfate, filtered and evaporated in vacuo. The residue
was purified or flash grade silica gel eluting with 9:1 hexane
ethyl acetate (0.5 L), 85:15 hexane ethyl acetate (0.5 L), and
finally 4:1 hexane ethyl acetate (1.5 L). Fractions containing the
product were combined, evaporated In vacuo and dried under high
vacuum to provide tert-butyl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[-
(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate (1.418 g,
89%) as a foam. H1-NMR (chloroform-D3): 1.38 (s, 9H), 1.70 (m, 8H),
2.98 (m, 4H), 3.85 (bm, 2H), 3.92 (s, 3H), 4.61 (bs, 1H), 4.85 (m,
1H), 7.02 (m, 2H), 7.29 (m, 5H), 7.76 (m, 2H) MS (ESI): 535
(MH.sup.+)
Example 8
[0233] 582
[0234] Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2[(methoxycarbony-
l)amino]-1H-benzimidazol-5-ylsulfonyl)amino]-2-hydroxypropylcarbamate.
[0235] Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)amino]-2-hydroxypr-
opylcarbamate (Step 1, Example 54) (1.73 g, 4.75 mmol), methyl
N-5-(chlorosulfonyl)-1H-benzimidazol-2-yl]carbamate (1.37 g, 4.75
mmol), anhydrous diisopropylethylamine (0.83 mL, 4.75 mmol), and
N,N-dimethylaminopyridine (170 mg, 1.42 mmol) were combined in
anhydrous tetrahydrofuran (15 mL) and anhydrous
N,N-dimethylformamide (8 mL) in a 50 mL round bottomed flask under
nitrogen. The reaction was stirred for 24 hours and concentrated in
vacuo. After the workup described in Step 3, Example 54, the
product was isolated as a white foam (2.56 g, 4.14 mmol) and used
directly without further purification. .sup.1H NMR (d.sub.6-DMSO)
.delta.: .delta. 7.60-6.64 (m, 9H), 5.11 (d, J=6.1 Hz, 1H), 4.83
(bs, 1H), 3.81 (s, 3H), 3.54-1.42 (m, 14H), 1.15 (s, 9H). MS (ES):
618 (M+1), 616 (M-1). 583
[0236] Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-amino-1H-benzim-
idazol-5-ylsulfonyl)amino]-2-hydroxypropylcarbamate.
[0237] Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-[(methoxycarbon-
yl)amino]-1H-benzimidazol-5-ylsulfonyl)amino]-2-hydroxypropylcarbamate
(Step 1, above) (2.52 g, 4.08 mmol) and lithium iodide hydrate
(2.60 g, 19.4 mmol) were dissolved in pyridine (15 mL) in a 50 mL
round bottomed flask and heated at 100.degree. C. for 8 hours. The
reaction was allowed to cool and then concentrated in vacuo. After
the workup described in Step 3, Example 54, the product was
purified by silica gel flash chromatography using a gradient
elution of chloroform: methanol: water (90:10:0 to 10:3:0.5) to
yield a beige powder (1.75 g, 3.13 mmol, 77%). .sup.1H NMR
(d.sub.6-DMSO) .delta.: 7.50-6.64 (m, 9H), 5.07 (d, J=6.0 Hz, 1H),
4.80 (bs, 1H), 3.56-1.40 (m, 16H), 1.18 (s, 9H). MS (ES): 560
(M+1), 558 (M-1). 584
[0238] Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-[(N-morpholinoc-
arbonyl)-amino]-1H-benzimidazol-5-ylsulfonyl)amino]-2-hydroxypropylcarbama-
te.
[0239] Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-amino-1H-benzim-
idazol-5-ylsulfonyl)amino]-2-hydroxypropylcarbamate (Step 2, above)
(300 mg, 0.536 mmol), 4-morpholine carbonyl chloride (0.08 mL,
0.643 mmol), and anhydrous diisopropylethylamine (0.11 mL, 0.643
mmol), were combined in anhydrous tetrahydrofuran (8 mL) in a 25 mL
round bottomed flask under nitrogen. The reaction was refluxed for
18 hours, allowed to cool, and concentrated in vacuo. After the
workup described in Step 3, Example 54, the residue was purified by
preparative silica gel TLC using 90:10 chloroform methanol as an
eluent to give the product as a beige solid (70 mg, 0.104 mmol,
20%). .sup.1H NMR (d.sub.6-DMSO) .delta.: 7.54-6.65 (m, 8H), 5.11
(d, J=6.0 Hz, 1H), 4.81 (bs, 1H), 3.82-1.40 (m, 23H), 1.17 (s, 9H).
MS (ES): 673 (M+1), 671 (M-1).
Example 9
[0240] 585
[0241] Prepartion of tert-butyl
N-[(1S,2R)-1-benzyl-4-(cyclopentyloxy)-2-h-
ydroxy-4-(6-quinoxalinylsulfonyl)butyl]carbamate.
[0242] A mixture of tert-butyl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(3,4-
-diaminophenyl)sulfonyl]amino-2-hydroxypropyl)carbamate (Example
10), (750 mg, 1.41 mmol) and 1,5-dioxane-2,3-diol (219 mg, 1.83
mmol) were combined under Argon in absolute ethanol (3 mL) at
ambient temperature. After stirring for approximately 11 days, the
reaction was evaporated in vacuo and the residue was purified on
flash grade silica gel eluting with ethyl acetate:hexane (1:1).
Fractions containing the product were combined, evaporated in vacuo
and dried under high vacuum to provide tert-butyl
N-[(1S,2R)-1-benzyl-4-(cyclopentyloxy)-2-hydroxy-4-(6-quinoxalinylsulfony-
l)butyl]carbamate as a yellow foam (696 mg, 89%). An analytical
sample was prepared by purification of 75 mg on a preparative TLC
plate (20.times.20 cm, 1000 .mu.M) eluting with 95:5
dichloromethane: methanol. The product band was removed, eluted
with 4:1 methylene chloride:methanol, filtered, and evaporated in
vacuo. The residue was triturated with water and filtered to
provide tert-butyl N-[(1S,2R)-1-benzyl-4-(cyclopentyloxy)-2-h-
ydroxy-4-(6-quinoxalinylsulfonyl)butyl]carbamate as a white solid.
H1-NMR (dimethylsulfoxide-D6): 1.05 (s, 9H), 1.74 (m, 8H), 2.47 (m,
1H), 2.73 (m, 1H), 3.07 (m, 2H), 3.55 (m, 2H), 4.90 (m, 1H), 5.24
(m, b, 1H), 6.68 (d, 1H), 7.19 (m, 5H), 8.15 (m, 1H), 8.39 (m, 1H),
8.49 (s, 1H), 9.18 (m, 2H). MS (ESI): 579 (M+Na).
Example 10
[0243] 586
[0244] o-nitroaniline-p-sulfonyl chloride.
[0245] A mixure of o-nitroaniline-p-sulfonic acid sodium salt
(25.00 g, 104 mmol) and phosphoryl chloride (75 mL, 804 mmol) under
Argon was heated to reflux and vigorously stirred for 4 hours.
After cooling to ambient temperature, the reaction mixture was
carefully added to a large excess of ice. The resulting slurry was
stirred for 15 min., filtered and dried under vacuum to provide
o-nitroaniline-p-sulfonyl chloride (21.43 g, 87%) as a yellow
solid. H1-NMR (dimethylsulfoxide-D6) 5.8 (b, 2H), 6.97 (d, 1H,
J=8.8), 7.57 (m, 1H), 8.18 (d, 1H, J=2.0). 587
[0246] 4-amino-N-(cyclopentyloxy)-3-nitrobenzenesulfonamide.
[0247] A solution of 2-(cyclopentyloxy)-1H-isoindole-1,3(2H)-dione
(10.00 g, 43.30 mmol) in anhydrous tetrahydrofuran (100 mL) at
ambient temperature under an Argon atmosphere was treated with
anhydrous hydrazine (1.49 mL, 47.63 mmol). After stirring
vigorously for 2.5 hours, the resulting slurry was filtered and
washed with approximately 20 mL of anhydrous tetrahydrofuran. The
filtrate was combined with o-nitroaniline-p-sulfonyl chloride
(11.26 g, 47.63 mmol) and N,N-diisopropylethylamine (9.05 mL, 51.96
mmol) and stirred under an Argon atmosphere for 16 hrs. at ambient
temperature. The reaction mixture was diluted with 1N NaHSO.sub.4
and dichloromethane and transferred to a separatory funnel. The
organic phase was separated and the aqueous layer was extracted
twice with dichloromethane. The combined organic layers were washed
with 5% aqueous potassium carbonate, dried over anhydrous magnesium
sulfate, filtered through a pad of diatomaceous earth and
evaporated in vacuo. The residue was purified on flash grade silica
gel eluting with 1:1 ethyl acetate:hexane. Fractions containing the
product were combined, evaporated in vacuo to a residue and
triturated with hexane. The slurry was filtered and the product was
dried under high vacuum to provide
4-amino-N-(cyclopentyloxy)-3-nitrobenzenesulfonamide (8.89 g, 68%)
as a yellow solid. H1-NMR (chloroform-D3): 1.57 (m, 4H), 1.74 (m,
4H), 4.61 (m, 1H), 6.52 (b, 2H), 6.73 (s 1H), 6.90 (d, 1H), 7.79
(m, 1H), 8.70 (d, 1H). MS (ESI): 324 (M+Na). 588
[0248] 3,4-diamino-N-(cyclopentyloxy)benzenesulfonamide.
[0249] A solution of
4-amino-N-(cyclopentyloxy)-3-nitrobenzenesulfonamide (4.50 g, 14.95
mmol) in 1:1 ethyl acetate:ethanol (150 mL) was combined with 5% Pd
on barium sulfate and reduced under a hydrogen atmosphere over 72
hours. The reaction mixture was filtered through a pad of
diatomaceous earth and evaporated in vacuo to a residue which
crystallized on standing. The solid was slurried in hexane,
filtered and dried under high vacuum to provide
3,4-diamino-N-(cyclopentyloxy)benzenesulfonamide (4.086 g, 100%) as
a light brown solid H1-NMR (dimethylsulfoxide-D6): 1.61 (m, 8H),
4.37 (m, 1H), 4.90 (b, 2H), 5.38 (b, 2H), 6.57 (d, 1H), 6.88 (m,
1H), 6.96 (d, 1H), 9.64 (s, 1H). MS (ESI): 272 (M+H). 589
[0250] tert-butyl N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)
[(3,4-diaminophenyl)sulfonyl)amino-2-hydroxypropyl)carbamate.
[0251] A solution of
3,4-diamino-N-(cyclopentyloxy)benzenesulfonamide (2.00 g, 7.38
mmol) and tert-butyl N-(1S)-1-[(2S)oxiran-2-yl]-2-phenyleth-
ylcarbamate (1.553 g, 5.90 mmol) in anhydrous tetrahydrofuran (10
mL) under an Argon atmosphere was treated with phosphazene base
P<t/4>t-Bu (1.2 mL, 1.2 mmol, 1.0 M in hexane). After
stirring at ambient temperature for approximately 18 hours, the
reaction mixture was quenched with several drops of glacial acetic
acid and evaporated in vacuo. The residue was partitioned between
ethyl acetate and 1N aqueous sodium hydrogen sulfate. After
separating the layers, the organic phase was washed with 5% w/v
aqueous potassium carbonate, brine, dried over anhydrous sodium
sulfate and evaporated in vacuo to a residue. The crude product was
purified on flash grade silica gel eluting with 3:2 ethyl
acetate:hexane. Fractions containing the product were combined,
evaporated in vacuo and dried under high vacuum to provide
tert-butyl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(3,4-diaminophenyl)sulfonyl]amino--
2-hydroxypropyl)carbamate (2.553 g, 65%) as a foam. H1-NMR
(chloroform-D3): 1.33 (s, 9H), 1.53 (m, 4H), 1.74 (m, 4H), 2.91 (m,
3H), 3.04 (m, 1H), 3.61 (b, 4H), 3.79 (m, 2H), 4.58 (m, 1H), 4.77
(m, 1H), 6.69 (d, 1H), 7.09 (s, 1H), 7.22 (m, 7H). MS (ESI): 535
(M+H).
Example 11
[0252] 590
[0253] N.sup.1-(cyclopentyloxy)-3-nitro-1-benzenesulfonamide.
[0254] A mixture of 2-(cyclopentyloxy)-1H-isoindole-1,3(2H)-dione
(3.00 g, 12.99 mmol) in anhydrous tetrahydrofuran (25 mL) under an
Argon atmosphere was treated with anhydrous hydrazine (0.448 mL,
14.29 mmol). After stirring vigorously for 2.5 hours, the resulting
slurry was filtered and washed with approximately 15 mL of
anhydrous tetrahydrofuran. The filtrate was combined with
3-nitro-1-benzenesulphony- l chloride (3.17 g, 14.29 mmol) and
N,N-diisopropylethylamine (2.72 mL, 15.6 mmol). After stirring at
ambient temperature for approximately 18 hours, the reaction
mixture was evaporated in vacuo to a residue and partitioned
between ethyl acetate and 1N hydrochloric acid. The phases were
separated and the aqueous layer was extracted twice with ethyl
acetate. The combined organic layers were washed with 5% w/v
potassium carbonate and brine, dried over anhydrous magnesium
sulfate, filtered and evaporated in vacuo to a residue. The crude
material was purified on flash grade silica gel eluting with 15:85
ethyl acetate:hexane. Fractions containing the product were
combined, evaporated in vacuo, and dried under high vacuum to
provide N-(cyclopentyloxy)-3-nitro-1-benzenesulfonam- ide (3.224 g,
87%) as a solid. H1-NMR (chloroform-D3): 1.71 (m, 8H), 4.71 (m,
1H), 6.93 (bs, 1H), 7.83 (m, 1H), 8.28 (m, 1H), 8.55 (m, 1H), 8.81
(m, 1H). 591
[0255] 3-amino-N.sup.1-(cyclopentyloxy)-1-benzenesulfonamide.
[0256] A solution of
N.sup.1-(cyclopentyloxy)-3-nitro-1-benzenesulfonamide (2.98 g,
10.41 mmol) in 50 mL of absolute ethanol was combined with 5 wt %
Palladium on barium sulfate (300 mg) and reduced under a balloon of
hydrogen gas with vigorous agitation for 18 hours. The mixture was
filtered, washed with ethanol, and evaporated in vacuo to a
residue. The crude product was purified on flash grade silica gel
eluting with 4:1 hexane:ethyl acetate. Fractions containing the
product were combined, evaporated in vacuo and dried under vacuum
to provide 3-amino-N.sup.1-(cyclopentyloxy)-1-benzenesulfonamide
(2.67 g, 100%) as an oil. H1-NMR (chloroform-D3): 1.62 (m, 8H),
3.92 (bs, 2H), 4.58 (m, 1H), 6.74 (bs, 1H), 6.88 (m, 1H), 7.16 (m,
1H), 7.27 (m, 2H). MS (ESI): 257(MH+). 592
[0257]
N-(1S,2R)-3-[[(3-aminophenyl)sulfonyl](cyclopentyloxy)amino]-1-benz-
yl-2-hydroxypropylcarbamate.
[0258] A solution of
3-amino-N.sup.1-(cyclopentyloxy)-1-benzenesulfonamide (2.654 g,
10.36 mmol) and tert-butyl N-(1S)-1-[(2S)oxiran-2-yl]-2-phenyle-
thylcarbamate (2.181 g, 8.29 mmol) in anhydrous tetrahydrofuran (10
mL) under an Argon atmosphere was treated with phosphazene base
P<t/4>tBu (1.60 mL, 1.60 mmol, 1.0 M in hexane). After
stirring at ambient temperature for approximately 18 hours, the
reaction mixture was quenched with several drops of glacial acetic
acid and evaporated in vacuo. The residue was partitioned between
ethyl acetate and 1N NaHSO.sub.4. After separating the phases, the
aqueous layer was extracted three times with ethyl acetate. The
combined organic layers were washed with saturated aqueous brine,
dried over anhydrous magnesium sulfate, filtered and evaporated in
vacuo to a residue. The crude product was purified on flash grade
silica gel eluting with 95:5 methylene chloride:ethyl acetate (2L);
9:1 methylene chloride:ethyl acetate (2L); and finally 1:1
methylene chloride:ethyl acetate. Fractions containing the product
were combined, evaporated in vacuo, and dried under high vacuum to
provide tert-butyl N-(1S,2R)-3-[[(3-aminophenyl)sulfonyl](cyclo-
pentyl oxy)amino]-1-benzyl-2-hydroxypropylcarbamate (3.328 g, 77%)
as a foam. An analytical sample was obtained by purifying 100 mg on
two preparative TLC plate (20.times.20 cm, 1000 .mu.M, silica gel)
eluting with 9:1 methylene chloride:methanol. The product bands
were removed, eluted with 4:1 methylene chloride:methanol,
filtered, and evaporated in vacuo. The residue purified again on a
preparative TLC plate (20.times.20 cm, 1000 .mu.M, silica gel)
eluting with 1:1 ethyl acetate:hexane. The product band was
removed, eluted with ethyl acetate, filtered, and evaporated in
vacuo. The residue was dissolved in diethylether, evaporated in
vacuo and dried under high vacuum to provide tert-butyl
N-(1S,2R)-3-[[(3-aminophenyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-h-
ydroxypropylcarbamate (54 mg) as a foam. H1-NMR (methanol-D4): 1.24
(s, 9H), 1.71 (m, 8H), 2.55 (m, 1H), 2.90 (bm, 1H), 3.04 (m, 2H),
3.73 (m, 2H), 4.81 (m, 1H), 6.44 (d, 1H), 6.93 (m, 1H), 7.02 (m,
1H), 7.17 (m, 7H). MS (ESI): 520 (MH+).
Example 12
[0259] 593
[0260] Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-[(3,4,5-trimeth-
oxyphenyl-carbonyl)amino]-1H-benzimidazol-5-ylsulfonyl)amino]-2-hydroxypro-
pylcarbamate. Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-amino-1H-
-benzimidazol-5-ylsulfonyl)amino]-2-hydroxypropylcarbamate (Step 2,
Example 8) (130 mg, 0.232 mmol), 3,4,5-trimethoxybenzoyl chloride
(70 mg, 0.302 mmol), and anhydrous pyridine (5 mL) were combined in
a 25 mL round bottomed flask under nitrogen. The reaction was
stirred for 18 hours and then concentrated in vacuo. After the
workup described in Step 3, Example 54, the residue was purified by
preparative silica gel TLC using 90:10 chloroform:methanol as an
eluent to give the product as a white film (3 mg, 0.004 mmol).
.sup.1HNMR (d.sub.6-DMSO) .delta.: 7.56-6.63 (m, 7H), 5.21 (bs,
1H), 4.64 (bs, 1H), 3.86 (s, 6H), 3.76 (s, 3H), 3.40-1.30 (m, 18H),
1.23 (s, 9H). MS (ES): 754 (M+1), 752 (M-1).
Example 13
[0261] 594
[0262] Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-[(methyl3-oxopr-
opionate)amino]-1H-benzimidazol-5-ylsulfonyl)amino]-2-hydroxypropylcarbama-
te.
[0263] Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-amino-1H-benzim-
idazol-5-ylsulfonyl)amino]-2-hydroxypropylcarbamate (Step 2,
Example 8) (130 mg, 0.232 mmol), methyl malonyl chloride (0.04 mL,
0.348 mmol), and anhydrous pyridine (5 mL) were combined in a 25 mL
round bottomed flask under nitrogen. The reaction was stirred for
18 hours and then concentrated in vacuo. After the workup described
in Step 3, Example 54, the residue was purified by preparative
silica gel TLC using 90:10 chloroform:methanol as an eluent to give
the product as a pale yellow solid (6 mg, 0.009 mmol). .sup.1H NMR
(d.sub.6-DMSO) .delta.: 8.62 (d, J=8.5 Hz, 1H), 7.89-6.67 (m, 9H),
5.17 (d, J=6.0 Hz, 1H), 4.85 (bs, 1H), 3.65 (s, 3H), 3.77-1.40 (m,
16H), 1.14 (s, 9H). MS (ES): 660 (M+1), 658 (M-1).
Example 14
[0264] 595
[0265] Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-[(dimethylamino-
-carbonyl)amino]-1H-benzimidazol-5-ylsulfonyl)amino]-2-hydroxypropylcarbam-
ate.
[0266] Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-amino-1H-benzim-
idazol-5-ylsulfonyl)amino]-2-hydroxypropylcarbamate (Step 2,
Example 8) (100 mg, 0.179 mmol), dimethyl carbamyl chloride (0.03
mL, 0.286 mmol), and anhydrous pyridine (5 mL) were combined in a
25 mL round bottomed flask under nitrogen. The reaction was stirred
for 18 hours and then concentrated in vacuo. After the workup
described in Step 3, Example 54, the residue was purified by
preparative silica gel TLC using 90:10 chloroform:methanol as an
eluent to give the product as a white film (35 mg, 0.056 mmol,
31%). .sup.1H NMR (d.sub.6-DMSO) .delta.: 7.53-6.66 (m, 8H), 5.10
(bs, 1H), 4.80 (bs, 1H), 3.56 (bs, 2H), 3.20 (s, 3H), 3.18 (s, 3H),
3.10-1.40 (m, 13H), 1.18 (s, 9H). MS (ES): 631 (M+1), 629
(M-1).
Example 15
[0267] 596
[0268] 2-(sec-butoxy)-1H-isoindole-1,3(2)-dione.
[0269] N-hydroxylphthalimide (18.4 mmol, 3.0 g) was dissolved in
anhydrous DMF (20 mL) under nitrogen. To the stirring solution, DBU
(1,8-diazabicyclo[5.4.0]undec-7-ene) (27.6 mmol, 4.13 mL) was
injected followed by 2-bromobutane (22.1 mmol, 2.41 mL) and the
reaction was warmed to 55.degree. C. After stirring for 18 hour,
the reaction was cooled to room temperature and concentrated to a
red oil. The reaction was partitioned between ethyl acetate and 1N
HCl. The organic layer was washed with saturated aqueous sodium
bicarbonate solution, distilled water, brine and dried over
magnesium sulfate. The solvent was removed under vacuum providing
3.57 g (89%) of a yellow solid. R.sub.f: 0.8 (2:1 hexanes/ethyl
acetate); H1-NMR (CDCl.sub.3): .delta. 7.80 (2H, m), 7.73 (2H, m),
4.31 (1H, m), 1.81 (1H, m), 1.64 (1H, m), 1.32 (3H, d), 1.03 (3H,
t). 597
[0270] N.sup.1-(sec-butoxy)-4-methoxy-1-benzenesulfonamide.
[0271] O-sec-butoxy-N-hydroxylphthalimide (16.3 mmol, 3.57 g) was
combined with hydrazine (17.9=mol, 0.56 mL) in anhydrous THF (30
mL) under nitrogen. The reaction immediately formed a white
suspension and was allowed to stir at room temperature for 5 hours.
The suspension was filtered directly into a flask containing
4-methoxybenzenesulfonyl chloride (14.6 mmol, 3.03 g) and
diisopropylethylamine (17.6 mmol, 3.1 mL) was added. After stirring
at room temperature for 15 hours, the reaction was concentrated to
a yellow solid and partitioned between ethyl acetate and 1N HCl.
The organic layer was separated and washed with a saturated aqueous
solution of sodium bicarbonate and brine, and dried over magnesium
sulfate. The product was concentrated to a white solid and purified
by silica gel chromatography (5:1 hexanes/ethyl acetate), providing
3.13 g (66%) of a white solid. H1-NMR (CDCl.sub.3): .delta. 7.84
(2H, d), 6.98 (2H, d), 6.64 (1H, s), 4.02 (1H, m), 3.86 (3H, s),
1.62-1.55 (1H, m), 1.45-1.38 (1H, m), 1.15 (3H, d), 0.87 (3H, t).
598
[0272] tert-butyl
N-((1S,2R)-1-benzyl-3-sec-butoxy[(4-methoxyphenyl)sulfon-
yl]amino-2-hydroxypropyl)carbamate.
[0273] N-(sec-butoxy)-4-methoxy-1-benzenesulfonamide (12.1 mmol,
3.13 g) was combined with tert-butyl
N-(1S)-1-[(2S)oxiran-2-yl]-2-phenylethylcarb- amate (13.3 mmol, 3.5
g) and THF (25 mL) under nitrogen. Phosphazine base
P<t/4>t-Bu (2.4 mmol, 2.4 mL, 1M in hexanes) was injected
into the stirring solution. The reaction was allowed to stir for 48
hours at room temperature and was quenched by the addition of a few
drops of glacial acetic acid. The reaction product was concentrated
to an oil and partitioned between ethyl acetate and 1N HCl. The
organic layer was separated and washed with saturated aqueous
sodium bicarbonate and brine, dried over magnesium sulfate and
concentrated under vacuum to a clear oil. The crude product was
purified by silica gel chromatography (2:1 hexanes/ethyl acetate)
providing 3.03 g (48%) of a white solid. H1-NMR (CDCl.sub.3):
.delta. 7.12 (2H, d), 7.30-7.19 (6H, m), 6.97 (2H, d), 4.55 (1H,
bs), 4.31 (1H, m), 3.86 (3H, s), 3.78 (2H, m), 3.5-2.5 (1H, m),
2.90 (2H, m), 1.80-1.60 (1H, m), 1.5-1.3 (1H, m), 1.32 (9H, s),
1.21-1.18 (3H, m), 0.93-0.85 (3H, m); MS (ESI): M+Na=545.
Example 16
[0274] 599
[0275] 2-(cyclohexylmethoxy)-1H-isoindole-1,3 (2H)-dione.
N-hydroxylphthalimide (18.4 mmol, 3.0 g) was dissolved in anhydrous
DMF (20 mL) under nitrogen. To the stirring solution, DBU (27.6
mmol, 4.13 mL) was injected followed by cyclohexylmethyl bromide
(23.0 mmol, 3.21 mL) and the reaction was warmed to 55.degree. C.
After stirring for 15 hours, the reaction was cooled to room
temperature and concentrated to a red oil. The reaction was
partitioned between ethyl acetate and 1N HCl. The organic layer was
washed with saturated aqueous sodium bicarbonate solution, brine
and dried over magnesium sulfate. The solvent was removed under
vacuum, and the crude product was triturated with hexanes providing
3.05 g (64%) of an off-white colored solid. H1-NMR (CDCl.sub.3):
.delta. 7.80 (2H, m), 7.73 (2H, m), 3.98 (2H, d), 2.03-1.65 (5H,
m), 1.31-1.03 (6H, m). 600
[0276] N.sup.1-(cyclohexylmethoxy)-4-methoxy-1-benzenesulfonamide.
2-(cyclohexylmethoxy)-1H-isoindole-1,3(2H)-dione (11.8 mmol, 3.05
g) was combined with hydrazine (12.9 mmol, 0.41 mL) in anhydrous
THF (25 mL) under nitrogen. The reaction immediately formed a white
suspension and was allowed to stir at room temperature for 48
hours. The suspension was filtered directly into a flask containing
4-methoxybenzenesulfonyl chloride (9.5 mmol, 1.97 g) and
diisopropylethylamine (11.6 mmol, 2.03 mL) was added. After
stirring at room temperature for 18 hours, the reaction was
concentrated to a solid residue and partitioned between ethyl
acetate and 1N HCl. The organic layer was separated and washed with
a saturated aqueous solution of sodium bicarbonate, and brine, and
dried over magnesium sulfate. The product was concentrated to a
solid and purified by silica gel chromatography (2:1 hexanes/ethyl
acetate) providing 2.55 g (80%) of a yellow solid. H1-NMR
(CDCl.sub.3): .delta. 7.81 (2H, d), 6.97 (2H, d), 6.78 (1H, s),
3.85 (3H, s), 3.75 (2H, d), 1.65-1.55 (6H, m), 1.25-1.07 (3H, m),
0.93-0.85 (2H, m). 601
[0277] tert-butyl
N-((1S,2R)-1-benzyl-3-(cyclohexylmethoxy)[(4-methoxyphen-
yl)sulfonyl]amino-2-hydroxypropyl)carbamate.
[0278] N.sup.1-(cyclohexylmethoxy)-4-methoxy-1-benzenesulfonamide
(8.52 mmol, 2.55 g) was combined with tert-butyl
N-(1S)-1-[(2S)oxiran-2-yl]-2-p- henylethylcarbamate (9.37 mmol,
2.47 g) and THF (16 mL) under nitrogen. Phosphazine base
P<t/4>t-Bu (1.7 mmol, 1.7 mL, 1M in hexanes) was injected
into the stirring solution. The reaction was allowed to stir for 15
hours at room temperature and was quenched by the addition of a few
drops of glacial acetic acid. The reaction product was concentrated
to an oil and partitioned between ethyl acetate and 1N HCl. The
organic layer was separated and washed with saturated aqueous
sodium bicarbonate and brine, dried over magnesium sulfate and
concentrated under vacuum to a clear oil. The crude product was
purified by silica gel chromatography (2:1 hexanes/ethyl acetate)
providing a white solid. HL-NMR (CDCl.sub.3): .delta. 7.70 (2H, d),
7.28-7.19 (6H, m), 6.97 (2H, d), 4.6 (1H, m), 3.96 (1H, m), 3.87
(3H, s), 3.82 (2H, m), 3.21 (1H, m), 2.99 (1H, m), 2.90 (2H, m),
2.80 (1H, m), 1.65 (6H, m), 1.33 (9H, m), 1.2-1.0 (3H, m),
1.00-0.80 (2H, m); MS (ESI): M+Na=585.
Example 17
[0279] 602
[0280] 4-methoxy-N.sup.1-phenoxy-1-benzenesulfonamide.
O-phenylhydroxylamine hydrochloride (6.9 mmol, 1.0 g),
4-methoxybenzenesulfonyl chloride (6.2 mmol, 1.29 g),
diisopropylethylamine (13.1 mmol, 2.28 mL) and andhydrous THF (15
mL) were combined under nitrogen. After stirring for 2 hours at
room temperature, a few crystals of 4-dimethylaminopyridine were
added and the flask was re-sealed. After another 2 hours, 4 mL of
N,N-dimethylformamide was injected and the reaction stirred for an
additional 15 hours. The resulting red solution was concentrated to
an oil and partitioned between ethyl acetate and 1N HCl. The
organic layer was separated and washed with saturated aqueous
sodium bicarbonate and brine, dried over magnesium sulfate and
concentrated under vacuum. The resulting dark brown residue was
purified by silica gel chromatography (3:1 hexanes/ethyl acetate)
providing 360 ma (21%) of a redish solid. H1-NMR (CDCl.sub.3):
.delta. 7.89 (2H, d), 7.30-7.20 (3H, m), 7.11 (2H, d), 7.02 (1H,
s), 7.00 (2H, d), 3.88 (3H, s). 603
[0281] tert-butyl
N-(1S,2R)-1-benzyl-2-hydroxy-3-[[(4-methoxyphenyl)sulfon-
yl](phenoxy)amino]propylcarbamate.
[0282] 4-methoxy-N.sup.1-phenoxy-1-benzenesulfonamide (1.3 mmol,
360 mg) was combined with tert-butyl
N-(1S)-1-[(2S)oxiran-2-yl]-2-phenylethylcarb- amate (1.4 mmol, 373
mg) and THF (3 mL) under nitrogen. Phosphazine base
P<t/4>t-Bu (0.26 mmol, 0.26 mL, 1M in hexanes) was injected
into the stirring solution. The reaction was allowed to stir for 48
hours at room temperature and was quenched by the addition of a few
drops of glacial acetic acid. The reaction product was concentrated
to a red oil and partitioned between ethyl acetate and 1N HCl. The
organic layer was separated and washed with saturated aqueous
sodium bicarbonate and brine, dried over magnesium sulfate and
concentrated under vacuum to a red oil. The crude product was
purified by silica gel chromatography (2:1 hexanes/ethyl acetate)
and crystallization (hexanes/ethyl acetate) providing 300 mg (43%)
of red crystals. H1-NMR (CDCl.sub.3): .delta. 7.74 (2H, d),
7.37-7.10 (10H, m), 7.04 (1H, m), 6.98 (2H, d), 4.56 (1H, bs), 3.88
(3H, s), 3.76 (2H, bs), 3.35-3.25 (1H, m), 3.20-2.95 (1H, m),
2.95-2.75 (2H, m), 1.30 (9H, s); MS (ESI): M+Na=565.
Example 18
[0283] 604
[0284]
2-(tetrahydro-2H-pyran-4-yloxy)-1H-isoindole-1,3(2H)-dione.
[0285] A light suspension containing N-hydroxylphthalimide (18.4
mmol, 3.0 g), triphenylphosphine (18.4 mmol, 4.82 g),
tetrahydro-4H-pyran-4-ol (18.4 mmol, 1.75 mL) and anhydrous THF (50
mL), were transferred to a flask containing di-tert-butyl
azodicarboxylate (20.2 mmol, 4.66 g) under nitrogen. Over 2 hours
the reaction stirred at room temperature and changed from a dark
orange to yellow in appearance. The solvent was removed under
vacuum and replaced with trifluoroacetic acetic acid (10 mL). The
reaction was stirred for 30 minutes and the TFA was removed under
vacuum. The crude residue was then dissolved in ethyl acetate,
washed with a saturated aqueous solution of sodium bicarbonate, 5%
aqueous solution of potassium carbonate, brine and dried over
magnesium sulfate. The solvent was removed under vacuum and the
residual triphenylphosphine oxide was crystallized and filtered
using hexanes and ether. The solvent was again removed and the
crude solid was purified by silica gel chromatography (2:1
hexanes/ethyl acetate) and recrystallization using methylene
chloride and hexanes providing 1.69 g (37%) of a white crystal.
R.sub.f=0.3 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl.sub.3):
.delta. 7.84-7.82 (2H, m), 7.75-7.73 (2H, m), 4.46-4.40 (1H, m),
4.08-4.02 (2H, m), 3.50-3.44 (2H, m), 2.04-1.98 (2H, m), 1.92-1.84
(2H, m). 605
[0286]
N-(tetrahydro-2H-pyran-4-yloxy)-4-methoxy-1-benzenesulfonamide.
[0287] 2-(tetrahydro-2H-pyran-4-yloxy)-1H-isoindole-1,3(2H)-dione
(6.8 mmol, 1.69 g) was combined with hydrazine (6.8 mmol, 0.22 mL)
in anhydrous THF (20 mL) under nitrogen. The reaction immediately
formed a white suspension and was allowed to stir at room
temperature for 1 hour. The suspension was filtered directly into a
flask containing 4-methoxybenzenesulfonyl chloride (6.5 mmol, 1.34
go and diisopropylethylamine (20.5 mmol, 3.6 mL) was added. After
stirring at room temperature for 15 hours, the reaction was
refluxed for 4 hours, then stirred at room temperature for 12 days
and concentrated to a yellow solid. The resulting solid was
partitioned between ethyl acetate and 1N HCl, and the organic layer
was separated and washed with a saturated aqueous solution of
sodium bicarbonate and brine, and dried over magnesium sulfate. The
crude product was concentrated to a white solid and purified by
silica gel chromatography (1:1 hexanes/ethyl acetate) and
crystallization (hexanes/ethyl acetate) providing 0.554 g (30%) of
a white solid. R.sub.f=0.4 (1:1 hexanes/ethyl acetate); H1-NMR
(CDCl.sub.3): .delta. 7.83 (2H, d), 7.00 (2H, d), 6.72 (1H, s),
4.23-4.11 (1H, m), 3.91-3.81 (2H, m), 3.87 (3H, s), 3.46-3.38 (2H,
m), 2.03-1.94 (2H, m), 1.63-1.51 (2H, m). 606
[0288] tert-butyl
N-(1S,2R)-1-benzyl-2-hydroxy-3-[[(4-methoxyphenyl)sulfon-
yl](tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamate.
[0289]
N-(tetrahydro-2H-pyran-4-yloxy)-4-methoxy-1-benzenesulfonamide
(1.93 mmol, 554 mg) was combined with tert-butyl
N-(1S)-1-[(2S)oxiran-2-y- l]-2-phenylethylcarbamate (1.54 mmol, 406
mg) and THF (5 mL) under nitrogen. Phosphazine base
P<t/4>t-Bu (0.31 mmol, 0.31 mL, 1M in hexanes) was injected
into the stirring solution. The reaction was allowed to stir for 15
hours at room temperature, quenched by the addition of a few drops
of glacial acetic acid and concentrated. The organic layer was
separated and washed with 1N NaOH, dried over magnesium sulfate and
concentrated under vacuum. The crude product was purified by silica
gel chromatography (2:1 hexanes/ethyl acetate) and crystallization
(hexanes/ethyl acetate) providing 367 mg (43%) of a white crystal.
R.sub.f=0.2 (8:1 CH.sub.2Cl.sub.2/ethyl acetate); H1-NMR
(CDCl.sub.3): .delta. 7.70 (2H, d), 7.307.18 (6H, m), 6.97 (2H, d),
4.60-4.51 (1H, m), 4.44-4.33 (2H, m), 3.97-3.88 (2H, m), 3.86 (3H,
s), 3.83-3.71 (2H, m), 3.48-3.34 (2H, m), 3.40-2.60 (1H, bs),
2.95-2.85 (2H, m), 2.07-1.95 (2H, m), 1.56-1.49 (2H, m), 1.32 (9H,
s); MS (ESI): M+Na=573.
Example 19
[0290] 607
[0291]
2-(tetrahydro-2H-pyran-2-ylmethoxy)-1H-isoindole-1,3(2H)-dione.
[0292] This reaction was conducted according to the procedure
reported in Grochowski, E; Jurczak, J. Synthesis 1976, 682.
R.sub.f=0.3 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl.sub.3):
.delta. 7.83-7.79 (2H, m), 7.75-7.70 (2H, m), 4.24-4.18 (1H, m),
4.07-4.03 (1H, m), 3.94-3.89 (1H, m), 3.81-3.75 (1H, m), 3.46-3.37
(1H, m), 1.87-1.85 (1H, m), 1.63-1.33 (5H, m). 608
[0293]
N-(tetrahydro-2H-pyran-2-ylmethoxy)-4-methoxy-1-benzenesulfonamide.
2-(tetrahydro-2H-pyran-2-ylmethoxy)-1H-isoindole-1,3 (2H)-dione
(6.8 mmol, 1.77 g) was combined with hydrazine (6.8 mmol, 0.21 mL)
in anhydrous THF (15 mL) under nitrogen. The reaction immediately
formed a white suspension and was allowed to stir at room
temperature for 2 hours. The suspension was filtered directly into
a flask containing 4-methoxybenzenesulfonyl chloride (6.8 mmol,
1.40 g) and diisopropylethylamine (8.1 mmol, 1.42 mL) was added.
After stirring at room temperature for 24 hours, the reaction was
concentrated to a yellow solid. The resulting solid was partitioned
between ethyl acetate and 1N HCl, and the organic layer was
separated and washed with a saturated aqueous solution of sodium
bicarbonate and brine, and dried over magnesium sulfate. The crude
product was concentrated to a yellow solid and purified by silica
gel chromatography (2:1 hexanes/ethyl acetate). The purified
product was combined with ether and filtered to remove the residual
phthalimide-hydrazine biproduct. The final product was crystallized
using hexanes and ethyl acetate to provide 141 mg (7%) of white
crystals. R.sub.f=0.3 (2:1 hexanes/ethyl acetate); H1-NMR
(CDCl.sub.3): .delta. 7.83 (2H, d), 7.05 (1H, s), 6.97 (2H, d),
4.01-3.86 (3H, m), 3.86 (3H, s), 3.63-3.57 (1H, m), 3.42-3.36 (1H,
m), 1.88-1.78 (1H, m), 1.59-1.43 (4H, m), 1.3-1.15 (1H, m). 609
[0294] tert-butyl
N-(1S,2R)-1-benzyl-2-hydroxy-3-[[(4-methoxyphenyl)sulfon-
yl](tetrahydro-2H-pyran-2-ylmethoxy)amino]propylcarbamate.
[0295]
N-(tetrahydro-2H-pyran-2-ylmethoxy)-4-methoxy-1-benzenesulfonamide
(0.47 mmol, 141 mg) was combined with tert-butyl
N-(1S)-1-[(2S)oxiran-2-y- l]2-phenylethylcarbamate (0.37 mmol, 99
mg) and THF (1 mL) under nitrogen. Phosphazine base
P<t/4>t-Bu (0.08 mmol, 0.08 mL, 1M in hexanes) was injected
into the stirring solution. The reaction was allowed to stir for 15
hours at room temperature, quenched by the addition of a few drops
of glacial acetic acid and concentrated. The crude residue was
partitioned between ethyl acetate and 1N HCl, and the organic layer
was separated and washed with saturated aqueous sodium bicarbonate
solution and brine, and dried over magnesium sulfate. The crude
product was purified by silica gel chromatography (2:1
hexanes/ethyl acetate). The purified product was then washed with
1N NaOH to remove remaining sulfonamide starting material that
coeluted, brine, and was again dried over magnesium sulfate. The
silica gel chromatography was repeated and yielded 130 mg (62%) of
a white solid. R.sub.f=0.2 (2:1 hexanes/ethyl acetate); H1-NMR
(CDCl.sub.3): .delta. 7.68-7.64 (2H, m), 7.28-7.18 (6H, m), 6.96
(2H, d), 4.74-4.60 (1H, m), 4.37-4.18 (1H, m), 4.14-4.06 (1H, m),
4.01-3.93 (2H, m), 3.90-3.75 (2H, m), 3.87 (3H, s), 3.66-3.46 (1H,
m), 3.46-3.35 (1H, m), 2.92-2.74 (2H, m), 3.50-2.50 (1H, bs),
1.90-1.81 (1H, m), 1.63-1.42 (4H, m), 1.34 (9H, s), 1.29-1.20 (1H,
m); MS (ESI): M=565.
Example 20
[0296] 610
[0297] 2-(tetrahydro-3-furanyloxy)-1H-isoindole-1,3 (2H)-dione.
[0298] To a light suspension containing N-hydroxylphthalimide (5.7
mmol, 926 mg), triphenylphosphine (5.7 mmol, 1.49 g),
tetrahydro-4H-furan-3-ol (5.7 mmol, 0.459 mL) and anhydrous THF (10
mL), diisopropylazodicarboxyla- te (6.2 mmol, 1.23 mL) was injected
under nitrogen atmosphere. The reaction stirred at room temperature
for 5 hours and changed from a dark orange to yellow in appearance.
The solvent was removed under vacuum, and the resulting residue was
purified by silica gel chromatography (2:1 hexanes/ethyl acetate)
and crystallization (hexanes/ethyl acetate) providing 373 mg (28%)
of white crystals. R.sub.f=0.5 (1:1 hexanes/ethyl acetate); HL-NMR
(CDCl.sub.3): .delta. 7.85-7.82 (2H, m), 7.77-7.74 (2H, m), 5.05
(1H, m), 4.16-4.09 (2H, m), 3.92-3.87 (2H, m), 2.34-2.28 (1H, m),
2.11-2.03 (1H, m). 611
[0299]
N-(tetrahydro-3-furanyloxy)-4-methoxy-1-benzenesulfonamide.
[0300] 2-(tetrahydro-3-furanyloxy)-1H-isoindole-1,3 (2H)-dione (1.5
mmol, 357 mg) was combined with hydrazine (1.7 mmol, 0.053 mL) in
anhydrous THF (3 mL) under nitrogen. The reaction immediately
formed a white suspension and was allowed to stir at room
temperature for 1 hour. The suspension was filtered directly into a
flask containing 4-methoxybenzenesulfonyl chloride (1.5 mmol, 316
mg) and diisopropylethylamine (1.8 mmol, 0.320 mL) was added. After
stirring at room temperature for 18 hours, the reaction was
concentrated to a solid. The resulting solid was partitioned
between ethyl acetate and 1N HCl, and the organic layer was
separated and washed with a saturated aqueous solution of sodium
bicarbonate and brine, and dried over magnesium sulfate. The crude
product was concentrated to a white solid and purified by silica
gel chromatography (1:1 hexanes/ethyl acetate). The purified
product was then combined with ether and filtered to remove the
residual phthalimide-hydrazine biproduct. The filtrate was then
crystallized by adding hexanes providing 203 mg (48%) white
crystals. R.sub.f=0.2 (1:1 hexanes/ethyl acetate); H1-NMR
(CDCl.sub.3): .delta. 7.82 (2H, d), 6.99 (2H, d), 6.85 (1H, s),
4.82-4.79 (1H, m), 3.97-3.87 (2H, m), 3.87 (3H, s), 3.83-3.70 (2H,
m), 2.12-1.99 (2H, m). 612
[0301] tert-butyl
N-(1S,2R)-1-benzyl-2-hydroxy-3-[[(4-methoxyphenyl)sulfon-
yl](tetrahydro-3-furanyloxy)amino]propylcarbamate.
[0302] N-(tetrahydro-3furanyloxy)-4-methoxy-1-benzenesulfonamide
(1.03 mmol, 283 mg) was combined with tert-butyl
N-(1S)-1-[(2S)oxiran-2-yl]-2-p- henylethylcarbamate (1.35 mmol, 300
mg) and THF (1 mL) under nitrogen. Phosphazine base
P<t/4>t-Bu (0.21 mmol, 0.21 mL, 1M in hexanes) was injected
into the stirring solution. The reaction was allowed to stir for 15
hours at room temperature, quenched by the addition of a few drops
of glacial acetic acid and concentrated. The crude residue was
partitioned between ethyl acetate and 1N HCl, and the organic layer
was separated and washed with saturated aqueous sodium bicarbonate
solution and brine, and dried over magnesium sulfate. The crude
product was purified by silica gel chromatography (2:1
hexanes/ethyl acetate) and reverse phase HPLC (water/acetonitrile)
yielding 60 mg (11%) of a white solid. H1-NMR (CDCl.sub.3): .delta.
7.68 (2H, d), 7.32-7.13 (6H, m), 7.01-6.93 (2H, m), 5.17-5.00 (1H,
m), 4.66-4.51 (1H, m), 4.34-4.16 (1H, m), 3.87 (3H, s), 3.83-3.68
(5H, m), 3.67-3.57 (1H, m), 2.95-2.78 (2H, m), 2.70 (1H, bs),
2.18-1.97 (2H, m), 1.34 (9H, m); MS (ESI): M+Na=559.
Example 21
[0303] 613
[0304] N.sup.1-(benzyloxy)-4-methoxy-1-benzenesulfonamide.
[0305] O-Benzyihydroxylamine hydrochloride (31.3 mmol, 5.0 g),
4-methoxybenzenesulfonyl chloride (34.5 mmol, 7.12 g) and anhydrous
THF (50 mL) were combined under nitrogen. The reaction was cooled
to 0.degree. C. and diisopropylethylamine (69.0 mmol, 12.0 mL) was
injected. The reaction was allowed to warm to room temperature and
continued to stir for 18 hours. An additional 0.25 equivalents of
O-Benzylhydroxylamine hydrogen chloride (7.8 mmol, 1.25 g) and 0.75
equivalents of diisopropylethylamine (23.5 mmol, 4.1 mL) were added
to encourage complete conversion of the remaining sulfonyl
chloride. The reaction stirred for 4 additional hours at room
temperature. The reaction solution was concentrated to a solid and
partitioned between ethyl acetate and 1N HCl. The organic layer was
dried over magnesium sulfate and concentrated under vacuum to yield
9.83 g (76%) of an off-white colored solid. R.sub.f: 0.2 (2:1
hexanes/ethyl acetate); H1-NMR (CDCl.sub.3): .delta. 7.84 (2H, d),
7.34 (5H, s) 7.08 (2H, d), 4.92 (2H, s), 3.88 (3H, s) 614
[0306] tert-butyl
N-((1S,2R)-1-benzyl-3-(benzyloxy)[(4-methoxyphenyl)sulfo-
nyl)amino-2-hydroxypropyl)carbamate.
[0307] Lithium hexamethyldisilazide (0.6 mmol, 0.6 mL, 1M in THF)
was injected into a stirring solution of
N.sup.1-(benzyloxy)-4-methoxy-1-benz- enesulfonamide (3.0 mmol, 1.0
g), tert-butyl N-(1S)-1-[(2S)oxiran-2-yl]-2-- phenylethylcarbamate
(2.4 mmol, 0.64 g), and anhydrous THF (8 mL). The reaction was
allowed to stir for 15 hours at room temperature under nitrogen.
The reaction was quenched with a few drops of glacial acetic acid
and concentrated to a thick oil. The crude was partitioned between
ethyl acetate and 1N HCl, washed with saturated sodium bicarbonate
solution and brine, dried over magnesium sulfate and concentrated.
The crude product was purified by silica gel chromatography (2:1
hexanes/ethyl acetate) and crystallized from ethyl acetate with
hexanes, providing 400 mg (22%) of a white crystal. R.sub.f: 0.4
(2:1 hexanes/ethyl acetate); H1-NMR (CDCl.sub.3): .delta. 7.72 (2H,
d), 7.47.3 (5H, m), 7.3-7.2 (5H, m), 7.19 (1H, d), 6.93 (2H, d),
5.08 (2H, s), 4.40 (1H, m), 3.82 (3H, s), 3.69 (1H, m), 3.53 (1H,
bs), 2.98 (1H, bs), 2.83 (2H, m), 2.71 (1H, bs), 1.33 (9H, s); MS
(ESI): M+Na=579.
Example 22
[0308] 615
[0309] N.sup.1-isobutoxy-4-methoxy-1-benzenesulfonamide.
[0310] Isobutoxyamine hydrochloride (7.96 mmol, 1.0 g),
4-methoxybenzenesulfonyl chloride (7.24 mmol, 1.5 g),
diisopropylethylamine (18.09 mmol, 3.15 mL) and anhydrous THF (15
mL) were combined under nitrogen. The reaction stirred at room
temperature for 15 hours. The reaction solution was concentrated to
a white solid and partitioned between ethyl acetate and 1N HCl. The
organic layer was separated and washed with saturated aqueous
sodium bicarbonate and brine, dried over magnesium sulfate and
concentrated under vacuum to yield an off-white colored solid.
R.sub.f: 0.5 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl.sub.3):
.delta. 7.84 (2H, d), 6.99 (2H, d), 6.81 (1H, s), 3.87 (3H, s),
3.74 (2H, d), 1.90 (1H, septet), 0.86 (6H, d). 616
[0311] tert-butyl
N-((1S,2R)-1-benzyl-2-hydroxy-3-isobutoxy[(4-methoxyphen-
yl)sulfonyl]aminopropyl)carbamate.
[0312] Synthesized under the same conditions as outlined for
tert-butyl
N-((1S,2R)-1-benzyl-3-(benzyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydro-
xypropyl)carbamate 21. HL-NMR (CDCl.sub.3): .delta. 7.70 (2H, d),
7.30-7.10 (6H, m), 6.96 (2H, d), 4.60 (1H, m), 3.93 (1H, m), 3.86
(3H, s), 3.81 (2H, m), 3.24 (1H, m), 3.01 (1H, m), 2.90 (2H, m),
2.82 (1H, m), 1.82 (1H, septet), 1.32 (9H, s), 0.93-0.81 (6H, m);
MS (ESI): M+Na=545.
Example 23
[0313] 617
[0314] 2-(cyclohexyloxy)-1H-isoindole-1,3 (2H)-dione.
[0315] N-hydroxylphthalimide (61.3 mmol, 10.0 g) was dissolved in
anhydrous DMF (60 mL) under nitrogen. To the stirring solution, DBU
(92.0 mmol, 13.75 mL) was injected followed by cyclohexyl bromide
(76.6 mmol, 9.43 mL) and the reaction was warmed to 55.degree. C.
After stirring for 15 hours, the reaction was warmed to 80.degree.
C. for 5 hours, then cooled to room temperature and concentrated to
a red oil. The reaction was partitioned between ethyl acetate and
1N HCl. The organic layer was washed with 1N NaOH, brine and dried
over magnesium sulfate. The solvent was removed under vacuum and
the crude product was triturated with hexanes providing 2.89 g
(19%) of a yellow solid. R.sub.f: 0.7 (2:1 hexanes/ethyl acetate);
H1-NMR (CDCl.sub.3): .delta. 7.80 (2H, m), 7.73 (2H, m), 4.21 (1H,
m), 2.02-1.98 (2H, m), 1.87-1.82 (2H, m), 1.59-1.53 (4H, m),
1.30-1.24 (2H, m). 618
[0316] N.sup.1-(cyclohexyloxy)-4-methoxy-1-benzenesulfonamide.
[0317] 2-(cyclohexyloxy)-1H-isoindole-1,3 (2H)-dione (11.8 mmol,
2.89 g) was combined with hydrazine (13.0 mmol, 0.41 mL) in
anhydrous THF (20 mL) under nitrogen. The reaction immediately
formed a white suspension and was allowed to stir at room
temperature for 18 hours. The suspension was filtered directly into
a flask containing 4-methoxybenzenesulfonyl chloride (10.6 mmol,
2.20 g) and diisopropylethylamine (14.2 mmol, 2.47 mL) was added.
After stirring at room temperature for 24 hours, the reaction was
concentrated to a yellow solid and partitioned between ethyl
acetate and 1N HCl. The organic layer was separated and washed with
a saturated aqueous solution of sodium bicarbonate, and brine, and
dried over magnesium sulfate. The product was concentrated to a
yellow solid and purified by silica gel chromatography (1:1
hexanes/ethyl acetate) providing 2.53 g (83%) of a white solid.
R.sub.f: 0.2 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl.sub.3):
.delta. 7.86 (2H, d), 7.00 (2H, d), 6.67 (1H, s), 3.98-3.95 (1H,
m), 3.88 (3H, s), 2.00-1.94 (2H, m), 1.75-1.55 (2H, m), 1.35-1.17
(6H, m). 619
[0318] tert-butyl
N-((1S,2R)-1-benzyl-3-(cyclohexyloxy)[(4-methoxyphenyl)s-
ulfonyl]amino-2-hydroxypropyl)carbamate.
[0319] Synthesized under the same conditions as outlined for
tert-butyl N-((1S,2R)-1-benzyl-3-(benzyloxy)
[(4-methoxyphenyl)sulfonyl]amino-2-hydr- oxypropyl)carbamate.
H1-NMR (CDCl.sub.3): .delta. 7.77 (2H, d), 7.33-7.25 (6H, m), 7.02
(2H, d), 4.60 (1H, m), 4.24 (1H, m), 3.87 (3H, s), 3.84 (3H, m),
3.5-2.5 (1H, m), 2.96 (2H, m), 2.09 (2H, m), 1.77 (2H, m), 1.38
(9H, s), 1.2-1.0 (6H, m); MS (APCI) M+Na=571.
Example 24
[0320] 620
[0321] Phenylmethyl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxypheny-
l)sulfonyl]amino-2-hydroxypropyl)carbamate. To a solution of
N.sup.1-[(2R,
3S)-3-amino-2-hydroxy-4-phenylbutyl]-N.sup.1-(cyclopentyloxy)-4-methoxy-1-
-benzenesulfonamide.times.trifluoracetic acid (Step 1, Example 48),
(50 mg, 0.091 mmol) in approximately 1.5 mL of dichloromethane
under Argon was added benzylchloroformate (15.6 .mu.L, 0.109 mmol)
followed by N,N-diisopropylethylamine (47.9 .mu.L, 0.273 mmol).
After stirring 18 hours, the reaction mixture was evaporated in
vacuo to a residue and purified on a preparative silica gel TLC
plate (20.times.20 cm, 1000 .mu.M) eluting with 95:5 methylene
chloride:methanol. The product band was removed, eluted with 4:1
methylene chloride:methanol, filtered, and evaporated in vacuo. The
residue was partitioned between dichloromethane and water. The
organic layer was separated, dried over anhydrous magnesium
sulfate, filtered, and evaporated in vacuo. The residue was
lyophilized from acetonitrile and water to provide phenylmethyl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2--
hydroxypropyl)carbamate (37 mg, 71%). HL-NMR (methanol-D4) 1.71 (m,
8H), 2.59 (m, 1H), 2.93 (m, 2H), 3.10 (m, 3), 3.81 (m, 2H), 3.83
(s, 3H), 4.86 (m, 3H), 7.06 (m, 2H), 7.21 m, 10H), 7.73 (m, 2H). MS
(ESI): 591(M+Na).
[0322] An isomer of Compound 24, with inverted stereochemistry a,
C-2 was prepared as follows: 621
[0323] Phenylmethyl
N-((1S,2S)-1-benzyl-3-(cyclopentyloxy)[(4-methoxypheny-
l)sulfonyl]amino-2-hydroxypropyl)carbamate.
[0324] A mixture of phenylmethyl
N-(1S)-1-[(2S)oxiran-2-yl]-2-phenylethylc- arbamate [250 mg, 0.842
mmol, Tetrahedron (1994), 50(21), 6333-46] and
N.sup.1-(cyclopentyloxy)-4-methoxy-1-benzenesulfonamide (285 mg,
1.05 mmol) in anhydrous tetrahydrofuran (3 mL) under an Argon
atmosphere was treated with phosphazene base P<t/4>t-Bu
(0.168 mL, 0.168 mmol., 1.0 M in hexane). The mixture was stirred
at ambient temperature for approximately 18 hours, quenched with
several drops of glacial acetic acid and evaporated in vacuo. The
residue was purified on flash grade silica gel eluting with 4:1
hexane:ethyl acetate. Fractions containing the product were
combined and evaporated in vacuo. The residue was triturated with
hexane and then evaporated in vacuo and dried under high vacuum to
provide phenylmethyl N-((1S,2S)-1-benzyl-3-(cyclopentyloxy)[(4--
methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate (439 mg,
92%) as a foam. H1-NMR (methanol-D4) 1.66 (m, 8H), 2.94 (m, 4H),
3.83 (m, 2H), 3.92 (s, 3H), 4.59 (m, 1H), 5.10 (m, 2H), 7.10 (m,
2H), 7.29 (m, 10H), 7.69 (m, 2H). MS (ESI): 591 (M+Na).
Example 25
[0325] 622
[0326] 3-pyridylmethyl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyph-
enyl)sulfonyl]amino-2-hydroxypropyl)carbamate.
[0327] Carbonyldiimidazole (13.0 mg, 0.080 mmol) and
3-hydroxymethylpyridine (7.8 .mu.L, 0.080 mmol) were combined under
an Argon atmosphere in 2.5 mL of anhydrous ethyl acetate. After
stirring for 1.5 hours at ambient temperature,
N.sup.1-[(2R,3S)-3-amino-2-hydroxy-4-ph-
enylbutyl]-N.sup.1-(cyclopentyloxy)-4-methoxy-1-benzenesulfonamide.times.t-
rifluoracetic acid (Step 1, Example 48), (40 mg, 0.073 mmol) was
added and the mixture was heated at reflux for 5 hours. Heating was
discontinued and the solvent was removed under vacuum. The crude
product was purified on a preparative TLC plate (20.times.20 cm,
1000 .mu.M) eluting with 93:7 methylene chloride:methanol. The
product band was removed, eluted with 3:1 methylene
chloride:methanol, filtered, and evaporated in vacuo. The residue
was dissolved in diethylether, evaporated in vacuo and dried under
high vacuum to provide 3-pyridylmethyl
N-((1S,2R)-1-benzyl-3-(cyclo-
pentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
(18.9 mg, 41%) as a foam. H1-NMR (chloroform-D3): 1.66 (m, 8H),
2.95 (m, 5H), 3.86 (s, 3H), 3.87 (m, 2H), 4.77 (m, 1H), 4.98 (m,
3H), 6.97 (d, 2.times.), 7.20 (m, 6H), 7.54 (m, 1H), 7.68 (d, 2H),
8.54 (bm, 2H). MS (ESI): 570(MH.sup.+).
Example 26
[0328] 623
[0329]
N.sup.1-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)
sulfonyl]amino-2-hydroxypropyl)-2-methylbenzamide.
[0330] o-Toluoyl chloride (7.8 uL, 0.0602 mmol) was added to a
solution of
N.sup.1-[(2R,3)-3-amino-2-hydroxy-4-phenylbutyl]-N.sup.1-(cyclopentyloxy)-
-4-methoxy-1-benzenesulfonamide.times.trifluoracetic acid (Step 1,
Example 48), (30 mg, 0.055 mmol) and N,N-diisopropylethylamine
(23.8 .mu.L, 0.137 mmol) in approximately 1.5 mL of dichloromethane
under Argon. After stirring for 18 hours at ambient temperature,
the reaction solvent was removed in vacuo and the residue was
purified on a preparative TLC plate (20.times.20 cm, 500 .mu.M)
eluting with 96:4 methylene chloride:methanol. The product band was
removed, eluted with 4:1 methylene chloride:methanol, filtered, and
evaporated in vacuo. The residue was triturated from diethylether
and hexane and the solvents were evaporated in vacuo to provide
N.sup.1-((1S,2R)-1-benzyl-3-(cyclopentylox-
y)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)-2-methylbenzamide
(27 mg, 89%) as a solid. H1-NMR (dimethylsulfoxide-D6): -0.75 (m,
8H), 1.87 (s, 3H), 2.63 (m, 1H), 2.79 (bm, 1H), 3.05 (bm, 1H), 3.21
(bm, 1H), 3.69 (bm, 1H), 3.86 (s, 3H), 4.13 (bm, 1H), 4.86 (bm,
1H), 5.28 (bs, 1H), 6.79 (m, 1H), 7.21 (m, 10H), 7.72 (d, 2H), 8.06
(d, 1H). MS (ESI): 575 (M+Na).
Example 27
[0331] 624
[0332]
3-amino-N.sup.1-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N.sup.1-(-
cyclopentyloxy)-1-benzenesulfonamide.
[0333] A mixture of
N-(1S,2R)-3-[[(3-aminophenyl)sulfonyl](cyclopentyloxy)-
amino]-1-benzyl-2-hydroxypropylcarbamate (Step 3, Example 11),
1.500 g, 2.89 mmol) and trifluoroacetic acid (5 mL) was stirred
under an Argon atmosphere at ambient temperature for 30 minutes.
Trifluoroacetic acid was removed in vacuo and the residue was
partitioned between dichloromethane and 1N NaOH. After separating
the phases, the aqueous layer was extracted twice with
dichloromethane. The combined organic layers were dried over
anhydrous sodium sulfate, filtered, evaporated in vacuo and dried
under high vacuum to provide 3-amino-N.sup.1-[(2R,
3S)-3-amino-2-hydroxy-4-phenylbutyl]-N.sup.1-(cyclopentyloxy)-1-benzenesu-
lfonamide (1.157 g, 96%) as a foam. H1-NMR (methanol-D4): 1.68 (m,
8H), 2.55 (m, 1H), 2.79 (m, 1H), 2.94 (bm, 1H), 3.12 (m, 2H), 3.77
(m, 1H), 4.76 (m, 1H), 6.96 (m, 1H), 7.05 (m, 1H), 7.16 (m, 4H),
7.27 (m, 3H). MS (ESI): 420(MH+). 625
[0334] (3S)tetrahydro-3-furanyl
N-(1S,2R)-3-[[(3-aminophenyl)sulfonyl](cyc-
lopentyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate.
[0335] A mixture of 3-amino-N.sup.1- [(2R,
3S)-3-amino-2-hydroxy-4-phenylb-
utyl]-N.sup.1-(cyclopentyloxy)-1-benzenesulfonamide (100 mg, 0.239
mmol), 2,5-dioxo-1-pyrrolidinyl [(3S)tetrahydro-3-furanyl]carbonate
(55 mg, 0.239 mmol, WO94/05639) and N,N-diisopropylethylamine (41.6
.mu.L, 0.239 mmol) were combined under Argon at ambient temperature
in approximately 1.5 mL of acetonitrile. After stirring for
approximately 18 hours, the reaction mixture was evaporated in
vacuo and purified on two preparative silica gel TLC plates
(20.times.20 cm, 1000 .mu.M) eluting with 95:5 methylene chloride
methanol. The product band was removed, eluted with 3:1 methylene
chloride:methanol, filtered, evaporated in vacuo and dried under
high vacuum to provide (3S)tetrahydro-3-furanyl
N-(1S,2R)-3-[[(3-aminophenyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-h-
ydroxypropylcarbamate (111 mg, 87%) as a foam. H1-NMR
(methanol-D4): 1.80 (m, 9H), 2.61 (m, 1H), 3.02 (m, 2H), 3.14 (m,
1H), 3.50 (m, 1H), 3.64 (m, 1H), 3.73 (m, 1H), 3.81 (m, 3H), 4.87
(m, 1H), 5.00 (m, 1H), 6.98 (m, 1H), 7.08 (m, 1H), 7.15 (m, 1H),
7.26 (m, 6H). MS (ESI): 534 (MH+)
Example 28
[0336] 626
[0337] (3S,3aR,7aS)hexahydro-4H-furo[2,3-b]pyran-3-yl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2--
hydroxypropyl)carbamate and
3R,3aS,7aR)hexahydro-4H-furo[2,3-b]pyran-3-yl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2--
hydroxypropyl)carbamate.
[0338] A mixture of
(3R,3aS,7aR)+(3S,3aR,7aS)hexahydro-4H-furo[2,3-b]pyran-
-3-yl(4-nitrophenyl)carbonate (68 mg, 0.219 mmol),
N.sup.1-[(2R,3S)-3-amin-
o-2-hydroxy-4-phenylbutyl]-N-(cyclopentyloxy)-4-methoxy-1-benzenesulfonami-
de.times.trifluoracetic acid (Step 1, Example 48), (60 mg, 0.109
mmol) and N,N-diisopropylethylamine (66.8 .mu.L, 0.385 mmol) were
combined in approximately 1.5 mL of acetonitrile and stirred at
ambient temperature under an Argon atmosphere for 18 hours. An
additional quantity of carbonate (20 mg, 0.065 mmol) and
N,N-diisopropylethylamine (40 .mu.L, 0.224 mmol) was added and the
reaction mixture was heated at 60.degree. C. for 1.5 hours. The
reaction was cooled and evaporated in vacuo. The residue was
dissolved in ethyl acetate and washed three times with 5% w/v
potassium carbonate, saturated aqueous brine, dried over anhydrous
magnesium sulfate, filtered and evaporated in vacuo to a residue.
The crude product was purified on a preparative TLC plate
(20.times.20 cm, 500 .mu.M) eluting with 95:5/methylene
chloride:methanol. The product band was removed, eluted with 4:1
methylene chloride:methanol, filtered, and evaporated in vacuo. The
residue was dissolved in diethylether, evaporated in vacuo and
dried under high vacuum to provide a 1:1 mixture of
(3S,3aR,7aS)hexahydro-4H-furo[2,3-b]pyran-3-yl
N-((1S,2R)-1-benzyl-3-(-
cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
and 3R,3aS,7aR)hexahydro-4H-furo[2,3-b]pyran-3-yl
N-((1S,2R)-1-benzyl-3-(-
cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
as a foam (55 mg, 83%). HL-NMR (chloroform-D3): 1.80 (m, 12H), 2.19
(m, 1H), 3.00 (m, 5H), 3.48 (m, 1H), 3.89 (m, 7H), 4.21 (m, 1H),
4.92 (m, 2H), 5.08 (m, 1H), 5.27 (bm, 1H), 7.04 (m, 2H), 7.28 (m,
5H), 7.76 (m, 2H). MS (ESI): 627 (M+Na).
Example 29
[0339] 627
[0340] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyc-
lopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate.
A mixture of
(3R,3aS,6aR)+(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl(4-nitr-
ophenyl)carbonate (96.5 mg, 0.327 mmol, WO 9721683),
N.sup.1-[(2R,35)-3-amino-2-hydroxy-4-phenylbutyl]-N.sup.1-(cyclopentyloxy-
)-4-methoxy-1-benzenesulfonamide.times.trifluoracetic acid (Step 1,
Example 48), (60 mg, 0.109 mmol) and N,N-diisopropylethylamine
(85.6 .mu.L, 0.491 mmol) were combined in approximately 1.5 mL of
acetonitrile and stirred at ambient temperature under an Argon
atmosphere for 18 hours. The reaction mixture was evaporated In
vacuo and the residue was purified on a preparative TLC plate
(20.times.20 cm, 500 .mu.M) eluting with 1:1/ethyl acetate:hexane.
The product band was removed, eluted with 3:1/methylene
chloride:methanol, filtered, and evaporated in vacuo. The residue
was dissolved in diethylether, evaporated in vacuo and dried under
high vacuum to provide a 1:1 mixture of
(3R,3aS,6aR)hexahydrofuro[2- ,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)su-
lfonyl]amino-2-hydroxypropyl)carbamate and
(3S,3aR,6aS)hexahydrofuro[2,3-b- ]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfon-
yl]amino-2-hydroxypropyl)carbamate (50 mg, 26%) as a foam. H1-NMR
(chloroform-D3): 1.68 (m, 10H), 2.95 (m, 6H), 3.64 (m, 2H), 3.88
(s, 3H), 3.93 (m, 4H), 4.82 (m, 2H), 5.01 (bm, 1H), 5.65 (m, 1H),
6.98 (m, 2H), 7.23 (m, 5H), 7.71 (m, 2H). MS (ESI): 613 (M+Na).
Example 30
[0341] 628
[0342] t rt-butyl
2-(3-[[(2R,3S)-3-([(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-
-3-yloxy)carbonylamino)-2-hydroxy-4-phenylbutyl](cyclopentyloxy)amino]sulf-
onylanilino)acetate and tert-butyl
2-(3-[[(2R,3S)-3-([(3S,3aR,6aS)hexahydr-
ofuro[2,3-b]furan-3-yloxy]carbonylamino)-2-hydroxy-4-phenylbutyl](cyclopen-
tyloxy)amino]sulfonylanilino)acetate
[0343] A solution of 0.250 g (0.434 mmol) of a 1:1 mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclope-
ntyloxy)[(3-aminophenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclope-
ntyloxy)[(3-aminophenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
(see example 31), 0.13 mL (0.87 mmol) of tert-butyl bromoacetate,
and 0.15 mL (0.87 mmol) of N,N-diisopropylethylamine in 5 mL of
anyhydrous DMF was stirred at 80.degree. C. for 18 hours. The
solution was cooled to RT and concentrated in vacuo. The residue
was dissolved in dichloromethane. The solution was washed with
saturated aqueous brine (3.times.), dried over anhydrous
MgSO.sub.4, and concentrated in vacuo. The crude product was
purified by flash chromatography (silica gel, 4:6 hexane/EtOAc) to
afford 0.28 g (94%) of the desired product as a light yellow foam.
H1-NMR (DMSO-d.sub.6): 7.31-7.07 (7H), 6.93-6.80 (3H), 6.61 (1H),
5.47 (1H), 5.19 (1H), 4.83-4.64 (2H), 3.81-3.40 (7H), 3.06-2.60
(5H), 2.53-2.27 (1H), 1.95-1.16 (19H). LCMS (ESI): 690 (M+H).
Example 31
[0344] 629
[0345] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[[(3-aminoph-
enyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate
(1) and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[[(3-aminophen-
yl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate
(2) as a white lyophile.
[0346] A mixture of
(3R,3aS,6aR)+(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-y-
l(4-nitrophenyl)carbonate (211 mg, 0.716 mmol),
3-amino-N.sup.1-[(2R,3S)-3-
-amino-2-hydroxy-4-phenylbutyl]-N.sup.1-(cyclopentyloxy)-1-benzenesulfonam-
ide (Step 1, Example 27), (100 mg, 0.239 mmol), and
N,N-diisopropylethylamine (166.4 .mu.L, 0.955 mmol) were combined
in approximately 3 mL of acetonitrile and stirred at ambient
temperature under an Argon atmosphere for approximately 18 hours.
The reaction mixture was evaporated in vacuo and purified on two
preparative silica TLC plates (20.times.20 cm, 1000 .mu.M) eluting
with 93:7/methylene chloride:methanol. The product band was
removed, eluted with 4:1/methylene chloride:methanol, filtered, and
evaporated in vacuo. The residue was partitioned between 1N NaOH
and dichloromethane. The layers were separated and the aqueous
layer was extracted with dichloromethane. The combined organic
layers were dried over anhydrous magnesium sulfate, filtered and
evaporated in vacuo to a foam. The mixture of diastereomers were
separated by supercritical fluid chromatography [Chiralpak AD (2
cm, Chiral Technologies), 21 Mpa; 11.3 mL/min methanol+0.1%
triethylamine; 45 g/min CO.sub.2; 40.degree. C.]. The fraction
containing the diastereomer possessing a shorter retention time was
evaporated in vacuo to a residue and then purified again by
preparative TLC as above. The product was lyophilized from
acetonitrile and water to provide
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[[(3-aminophenyl)s-
ulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate
(1) as a white lyophile (18 mg, 13%). The fraction containing the
diastereomer possessing a longer retention time was evaporated in
vacuo to a residue and then purified again by preparative TLC as
above. The product was lyophilized from acetonitrile and water to
provide (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl N-(1S,
2R)-3-[[[(3-aminophenyl-
)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate
(2) as a white lyophile (18 mg, 13%). 1 H1-NMR (methanol-D4) 1.62
(m, 10H), 2.52 (m, 1H), 2.88 (m, 2H), 3.10 (m, 2H), 3.62 (m, 2H),
3.76 (m, 3H), 3.87 (m, 1H), 4.81 (m, 1H), 4.90 (m, 1H), 5.55 (d,
1H), 6.93 (m, 1H), 7.02 (m, 1H), 7.08 (m, 1H), 7.14 (m, 1H), 7.21
(m, 5H). MS (ESI): 598(M+Na).
[0347] 2 H1-NMR (methanol-D4): 1.73 (m, 10H), 2.57 (m, 1H), 2.93
(m, 2H), 1 3.09 (m, 2H), 3.46 (m, 1H), 3.79 (m, 5H), 4.84 (m, 2H),
5.57 (d, 1H), 6.92 (m, 1H), 7.02 (m, 1H), 7.09 (m, 1H), 7.20 (m,
6H). MS (ESI): 598(M+Na).
Example 32
[0348] 630
[0349] methyl
2-(3-[[(2R,3S)-3-([(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-y-
loxy]carbonylamino)-2-hydroxy-4-phenylbutyl](cyclopentyloxy)amino]sulfonyl-
anilino)acetate and methyl
2-(3-[[(2R,3S)-3-([(3S,3aR,6aS)hexahydrofuro[2,-
3-b]furan-3-yloxy]carbonylamino)-2-hydroxy-4-phenylbutyl](cyclopentyloxy)a-
mino]sulfonylanilino)acetate.
[0350] A solution of 0.500 g (0.869 mmol) of a 1:1 mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclope-
ntyloxy)[(3-aminophenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclope-
ntyloxy)[(3-aminophenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
(see example 31), 0.250 mL (2.61 mmol) of methyl bromoacetate, and
0.450 mL (2.61 mmol) of N,N-diisopropylethylamine in 5 mL of
anyhydrous DMF was stirred at 80.degree. C. for 18 hours. The
solution was cooled to RT and concentrated in vacuo. The residue
was dissolved in ethyl acetate. The solution was washed with
saturated aqueous brine (3.times.), dried over anhydrous
MgSO.sub.4, and concentrated in vacuo. The crude product was
purified by flash chromatography (silica gel, 97:3
CH.sub.2Cl.sub.2/MeOH) to afford 0.50 g (89%) of the desired
product as a light yellow foam. H1-NMR (DMSO-d.sub.6): 7.38-7.08
(7H), 7.01-6.85 (3H), 6.71 (1H), 5.52 (1H), 5.21 (1H), 4.88-4.70
(2H), 3.99 (2H), 3.88-3.46 (8H), 3.13-2.64 (5H), 2.57-2.35 (1H),
2.01-1.17 (10H). LCMS (ESI): 648 (M+H). 631
[0351] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)[(3-[2-(methylamino)-2-oxoethyl]aminophenyl)sulfonyl]amino-2-
-hydroxypropyl)carbamate and
(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)
[(3-[2-(methylamino)-2-oxoethyl]am-
inophenyl)sulfonyl]amino-2-hydroxypropyl)carbamate.
[0352] A solution of 50.0 mg (0.0770 mmol) of a 1:1 mixture of
methyl
2-(3-[[(2R,3S)-3-([(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl-
amino)-2-hydroxy-4-phenylbutyl](cyclopentyloxy)amino]sulfonylanilino)aceta-
te and methyl
2-(3-[[(2R,3S)-3-([(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-y-
loxy]carbonyl
amino)-2-hydroxy-4-phenylbutyl](cyclopentyloxy)amino]sulfony-
lanilino)acetate in 5 mL of 2M methylamine in MeOH was stirred at
RT in a sealed tube. After 4 hours the solution was concentrated in
vacuo and the residue subjected to flash chromatography (silica
gel, 97:3 EtOAc/MeOH) to afford 38 mg (76%) of the desired product
as a white foam. H1-NMR (CDCl.sub.3): 7.53-7.00 (11H), 6.80-6.59
(1H), 6.68 (1H), 5.50-5.18 (1H), 5.06 (1H), 4.85 (1H), 4.09-3.60
(7H), 3.28-2.78 (8H), 2.00-1.47 (10H). MS (ESI): 647 (M+H), 669
(M+Na).
Example 33
[0353] 632
[0354] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)[(3-[2-(dimethylamino)ethyl]aminophenyl)sulfonyl]amino-2-hyd-
roxypropyl)carbamate and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(3-[2-(dimethylamino)ethyl]aminoph-
enyl)sulfonyl]amino-2-hydroxypropyl)carbamate.
[0355] A solution of 65.0 mg (0.110 mmol) of a 1:1 mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(3-[(2-aminoethyl-
)amino]phenylsulfonyl)(cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarba-
mate and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(3-[(2-aminoethyl)amino]phenylsulfonyl)(cyclopentyloxy)amino-
]-1-benzyl-2-hydroxypropylcarbamate (see example 83), 0.050 mL
(0.55 mmol) of 37% aqueous formaldehyde, and 0.117 g (0.550 mmol)
of NaBH(OAc).sub.3 was treated with 0.150 g of powdered 4A
molecular sieves and the mixture was stirred at RT. After stirring
at RT for 18 hours, tic (silica gel, 9:1 CH.sub.2Cl.sub.2/MeOH)
indicated complete loss of starting material at R.sub.f=0.05 and
two new components at R.sub.f=0.31 and 0.63. The reaction mixture
was filtered and the filtrate concentrated to dryness. The residue
was dissolved in CH.sub.2Cl.sub.2. The solution was washed with
saturated aqueous NaHCO.sub.3 (3.times.), dried over MgSO.sub.4,
and concentrated in vacuo. The crude product was subjected to flash
chromatography (silica gel, 95:5 to 90:10 CH.sub.2Cl.sub.2/MeOH) to
afford 14 mg (20%) of the R.sub.f=0.31 product as a white foam.
H1-NMR (CDCl.sub.3): 7.37-7.11 (8H), 7.10-6.90 (2H), 6.85 (1H),
5.62 (1H), 5.18-4.89 (2H), 4.79 (1H), 4.00-3.49 (5H), 3.32-2.60
(10H), 2.38 (6H), 1.94-1.40 (10H). LCMS (ESI): 647 (M+H).
Example 34
[0356] 633
[0357] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((-
cyclopentyloxy)[3-(3-methyl-1-imidazolidinyl)phenyl)sulfonylamino)-2-hydro-
xypropyl]carbamate and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((cyclopentyloxy)[3-(3-methyl-1-imidazolidinyl)phen-
yl)sulfonylamino)-2-hydroxypropyl]carbamate
[0358] A solution of 65.0 mg (0.110 mmol) of a 1:1 mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(3[(2-aminoethyl)-
amino)phenylsulfonyl)(cyclopentyloxy)amino]1-benzyl-2-hydroxypropylcarbama-
te and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(3-[(2-amin-
oethyl)amino]phenylsulfonyl)(cyclopentyloxy)amino]-1-benzyl-2-hydroxypropy-
lcarbamate (see example 83), 0.050 mL (0.55 mmol) of 37% aqueous
formaldehyde, and 0.117 g (0.550 mmol) of NaBH(OAc).sub.3 was
treated with 0.150 g of powdered 4A molecular sieves and the
mixture stirred at RT. After stirring at RT for 18 hours, tlc
(silica gel, 9:1 CH.sub.2Cl.sub.2/MeOH) indicated complete loss of
starting material at R.sub.f=0.05 and two new components at
R.sub.f=0.31 and 0.63. The reaction mixture was filtered and the
filtrate concentrated to dryness. The residue was dissolved in
CH.sub.2Cl.sub.2. The solution was washed with saturated aqueous
NaHCO.sub.3 (3.times.), dried over MgSO.sub.4, and concentrated in
vacuo. The crude product was subjected to flash chromatography
(silica gel, 95:5 to 90:10 CH.sub.2Cl.sub.2/MeOH) to afford 20 mg
(28%) of the R.sub.f=0.63 product as a white foam. H1-NMR
(CDCl.sub.3): 7.40-7.01 (8H), 6.88 (1H), 6.70 (1H), 5.62 (1H),
5.06-4.73 (3H), 4.21-3.39 (7H), 3.23-2.62 (10H), 2.52 (3H),
1.93-1.20 (10H). LCMS (ESI): 645 (M+H).
Example 35
[0359] 634
[0360]
2-2-(3-[[(2R,3S)-3-([(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]-
carbonylamino)-hydroxy-4-phenylbutyl](cyclopentyloxy)amino]sulfonylanilino-
)acetic acid and
2-2-(3-[[(2R,3S)-3-([(3S,3aR,6aS)hexahydrofuro[2,3-b]fura-
n-3-yloxy]carbonylamino)-hydroxy-4-phenylbutyl](cyclopentyloxy)amino]sulfo-
nylanilino)acetic acid.
[0361] A solution of 0.218 g (0.316 mmol) of a 1:1 mixture of
tert-butyl
2-(3-[[(2R,3S)-3-([(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl-
amino)-2-hydroxy-4-phenylbutyl](cyclopentyloxy)amino]sulfonylanilino)aceta-
te and tert-butyl
2-(3-[[(2R,3S)-3-([(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-
-3-yloxy]carbonylamino)-2-hydroxy-4-phenylbutyl](cyclopentyloxy)amino]sulf-
onylanilino)acetate (see example 30) in 5 mL of CH.sub.2Cl.sub.2
was treated with 6 mL of trifluoroacetic acid. After stirring at RT
for 2 hours tlc (silica gel, hexane/EtOAc) indicated complete loss
of starting material and the formation of a new more polar product.
The solution was concentrated in vacuo. The residue was dissolved
in a minimum volume of CH.sub.2Cl.sub.2 and the solution added
dropwise to rapidly stirred 4:1 hexane/ether. An off-white solid
precipitated which was collected by filtration and dried in vacuo.
yield=0.183 g (92%). H1-NMR (DMSO-d.sub.6): 7.25-7.05 (7H), 6.87
(3H), 6.53 (1H), 5.46 (1H), 5.16 (1H), 4.82-4.65 (2H), 3.83-3.23
(7H), 3.08-2.60 (5H), 2.38 (1H), 1.91-1.04 (10H). MS (ESI): 634
(M+H), 656 (M+Na).
Example 36
[0362] 635
[0363] methyl
2-(3-[[(2R,3S)-3-([(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-y-
loxy]carbonylamino)-2-hydroxy-4-phenylbutyl](cyclopentyloxy)amino]sulfonyl-
anilino)acetate and methyl
2-(3-[[(2R,3S)-3-([(3S,3aR,6aS)hexahydrofuro[2,-
3-b]furan-3-yloxy]carbonylamino)-2-hydroxy-4-phenylbutyl](cyclopentyloxy)a-
mino]sulfonylanilino)acetate
[0364] A solution of 0.500 g (0.869 mmol) of a 1:1 mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclope-
ntyloxy)[(3-aminophenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclope-
ntyloxy)[(3-aminophenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
(see example 31), 0.250 mL (2.61 mmol) of methyl bromoacetate, and
0.450 mL (2.61 mmol) of N,N-diisopropylethylamine in 5 mL of
anyhydrous DMF was stirred at 80.degree. C. for 18 hours. The
solution was cooled to RT and concentrated in vacuo. The residue
was dissolved in ethyl acetate. The solution was washed with
saturated aqueous brine (3.times.), dried over anhydrous
MgSO.sub.4, and concentrated in vacuo. The crude product was
purified by flash chromatography (silica gel, 97:3
CH.sub.2Cl.sub.2/MeOH) to afford 0.50 g (89%) of the desired
product as a light yellow foam. H1-NMR (DMSO-d.sub.6): 7.38-7.08
(7H), 7.01-6.85 (3H), 6.71 (1H), 5.52 (1H), 5.21 (1H), 4.88-4.70
(2H), 3.99 (2H), 3.88-3.46 (8H), 3.13-2.64 (5H), 2.57-2.35 (1H),
2.01-1.17 (10H). LCMS (ESI): 648 (M+H). 636
[0365] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(c-
yclopentyloxy)(3-[(2-hydroxyethyl)amino]phenylsulfonyl)amino]-2-hydroxypro-
pylcarbamate and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)
(3-[(2-hydroxyethyl)amino]phenylsu-
lfonyl)amino]-2-hydroxypropylcarbamate.
[0366] A solution of 0.100 g (0.154 mmol) of a 1:1 mixture of
methyl
2-(3-[[(2R,3S)-3-([(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl-
amino)-2-hydroxy-4-phenylbutyl](cyclopentyloxy)amino]sulfonylanilino)aceta-
te and methyl
2-(3-[[(2R,3S)-3-([(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-y-
loxy]carbonyl
amino)-2-hydroxy-4-phenylbutyl](cyclopentyloxy)amino]sulfony-
lanilino)acetate in 10 mL of anhydrous THF at -78.degree. C. was
treated with 0.23 mL (0.34 mmol) of 1.5 M diisobutylaluminum
hydride in toluene by dropwise addition. The solution was allowed
to warm to RT. The reaction progress was monitored by tlc (silica
gel, hexane/EtOAc). Two additional 0.30 mL aliquots of DIBAL
solution were added at 1 hour intervals (cooling the reaction
vessel to -78.degree. C. each time) to induce complete loss of
starting material. After 2 additional hours the reaction mixture
was mixed with 25 mL of saturated potassium sodium tartrate and
stirred vigorously for 30 minutes. The mixture was diluted with
water and extracted with CH.sub.2Cl.sub.2 (3.times.). The combined
extracts were washed with water (3.times.), dried over anhydrous
MgSO.sub.4, and concentrated in vacuo. The residue was purified by
flash chromatography (silica gel, 99:1 EtOAc/MeOH) to afford 25 mg
(26%) of the desired product as a white foam. H1-NMR (CDCl.sub.3):
7.40-7.03 (10H), 6.92 (1H), 5.62 (1H), 5.13-4.88 (2H), 4.81 (1H),
3.96-3.44 (8H), 3.32 (2H), 3.22-2.59 (6H), 1.90-1.20 (10H). LCMS
(ESI): 620 (M+H).
Example 37
[0367] 637
[0368] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(c-
yclopentyloxy)(3-[2-[(2-hydroxyethyl)amino]-2-oxoethyl(isobutoxycarbonyl)a-
mino)phenylsulfonyl)amino]-2-hydroxypropylcarbamate and
(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(cyclope-
ntyloxy)(3-[2-[(2-hydroxyethyl)amino]-2-oxoethyl(isobutoxycarbonyl)amino]p-
henylsulfonyl)amino]-2-hydroxypropylcarbamate.
[0369] A solution of 60.0 mg (0.0947 mmol) of a 1:1 mixture of
2-2-(3-[[(2R,3S)-3-([(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbon-
ylamino)-hydroxy-4-phenylbutyl](cyclopentyloxy)amino]sulfonylanilino)aceti-
c acid and
2-2-(3-[[(2R,3S)-3-([(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl-
oxy]carbonyl
amino)-hydroxy-4-phenylbutyl](cyclopentyloxy)amino]sulfonylan-
ilino)acetic acid (see example 35) in 3 mL of anhydrous DMF at
0.degree. C. was treated with 0.033 mL (0.19 mmol) of
N,N-diisopropylethylamine followed by 0.025 mL (0.19 mmol) of
isobutyl chloroformate. After stirring at 0.degree. C. for 15
minutes the reaction was treated with 3 drops (excess) of
ethanolamine. After warming to RT and stirring for 18 hours the
solution was concentrated to dryness. The residue was purified by
flash chromatography (silica gel, 93:7 CH.sub.2Cl.sub.2/MeOH) to
afford 66 mg (90%) of the desired compound as a white foam. H1-NMR
(DMSO-d.sub.6): 8.05 (1H), 7.80 (1H), 7.69 (1H), 7.63-7.50 (2H),
7.24-7.02 (5H), 6.96 (1H), 5.47 (1H), 5.21 (1H), 4.80-4.67 (2H),
4.63 (1H), 4.56 (1H), 4.20 (2H), 3.82-3.20 (8H), 3.10 (2H),
3.05-2.35 (8H), 1.88-1.10 (11H), 0.90-0.72 (6H). LCMS (ESI): 777
(M+H).
Example 38
[0370] 638
[0371] (1S,2R)-1-benzyl-3-(isopropyloxy)
[(3-nitrophenyl)sulfonyl)amino-2--
hydroxypropylamine.cndot.trifluoroacetic salt.
[0372]
tert-Butyl-N-((1S,2R)-1-benzyl-3-(isopropyloxy)[(3-nitrophenyl)
sulfonyl]amino-2-hydroxypropyl)carbamate (1.37 g, 2.62 mmol) was
dissolved in CH.sub.2Cl.sub.2 (50 ml). Trifluoroacetic acid (10 mL)
was added at 0.degree. C. with stirring and the reaction was
stirred 2 h at room temperature. The solvent was removed by
evaporation and was keeped under vacuum. The product was used
without purification. 639
[0373]
(3R,3aS,6aR)Hexahydrofuro[2,3b]furan-3-yl-N-(1S,2R)-1-benzyl-3-[(is-
opropyloxy)[(3-nitrophenyl)sulfonyl]amino-2-hydroxypropylcarbamate.
[0374]
(1S,2R)-1-benzyl-3-(isopropyloxy)[(3-nitrophenyl)sulfonyl]amino-2-h-
ydroxypropylamine.cndot.trifluoroacetic salt (305 mg, 0.57 mmol)
was combined with (3R,3aS,
6aR)Hexahydrofuro[2,3b]furan-3-yl(4-nitrophenyl)ca- rbonate (184
mg, 0.62 mmol) in anhydrous CH.sub.3CN (8 ml) under a N.sub.2
atmosphere. Triethylamine (400 .mu.L, 2.8 mmol) was added and the
reaction was stirred at 50.degree. C. for 16 hours. Reaction
mixture was diluted in EtOAc and washed with water and brine. The
organic phase was dried with MgSO.sub.4 and solvent was removed in
vacuo. Purification by flash chromatography (30% EtOAc/Hex).
Recovered 204 mg (62%) of the product as a white foam. HPLC showed
the material to be 98% pure; Ret. time=10.10 min. .sup.1H NMR
(CDCl.sub.3): 8.60 (s, 1H), 8.46 (m, 1H), 8.02 (m, 1H), 7.72 (m,
1H), 7.10-7.23 (m, 5H), 5.58 (m, 1H), 4.97 (m, 1H), 4.80 (m, 1H),
4.94 (m, 1H), 4.50-4.55 (m, 1H), 3.77-3.96 (m, 4H), 3.59-3.64 (m,
2H), 2.70-2.97 (m, 5H), 1.60 (m, 1H), 1.45 (m, 1H), 1.21 (m, 6H).
MS (ES+): Obs M+H @ 580.1 amu. 640
[0375]
(3R,3aS,6aR)Hexahydrofuro[2,3b]furan-3-yl-N-(1S,2R)-1-benzyl-3-[(is-
opropyloxy)[(3-aminophenyl)sulfonyl)amino-2-hydroxypropylcarbamate.
[0376]
(3R,3aS,6aR)Hexahydrofuro[2,3b]furan-3-yl-N-(1S,2R)-1-benzyl-3-[(is-
opropyloxy)[(3-nitrophenyl)sulfonyl]amino-2-hydroxypropylcarbamate
(100 mg, 0.17 mmol) was added in 10 mL of NH.sub.3 (2N) in MeOH. To
this solution was added 100 mg of 10% Pd/C. The hydrogenation was
performed under 30 psi of hydrogen over 30 minutes. The catalyst
was removed by filtration throught a pad of celite. The solvant was
removed in vacuo. Recovered 91 mg (96%) of the product as a white
foam. HPLC showed the material to be 98% pure; Ret. time=9.12 min.
.sup.1H NMR (CDCl.sub.3): 7.09-7.24 (m, 9H), 7.00 (s, 1H), 6.84 (m,
1H), 5.58 (d, 1H), 4.97 (m, 1H), 4.78 (m, 1H), 4.44-4.48 (m, 1H),
3.77-3.91 (m, 5H), 3.64 (m, 2H), 2.713.10 (m, 6H), 1.44-1.62
(2.times.m, 2H), 1.17 (d, 6H). MS (ES+): Obs M+H @ 550.2 amu.
Example 39
[0377] 641
[0378]
(3S,3aR,6aS)Hexahydrofuro[2,3-b]furan-3-yl-N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)(2-[(methylsulfonyl)amino]benzimidazol-5-ylsulfonyl)amino-2--
hydroxypropyl)carbamate.
[0379]
(3S,3aR,6aS)Hexahydrofuro[2,3-b]furan-3-yl-N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)amino-2-hydroxypropyl)carbamate (0.050 g, 0.1 mmol)
was combined with
2-[(methylsulfonyl)amino]benzimidazol-5-ylsulfonyl chloride (0.055
g, 0.2 mmol) in anhydrous DMF (1 ml) under a N.sub.2 atmosphere.
The resulting solution was chilled to 0.degree. C. and
diisopropylethylethyl amine (0.062 ml, 0.4 mmol) was added. The
reaction was allowed to warm to room temperature and stirred for 24
hours. Reaction mixture was diluted in EtOAc and washed with sat.
NaHCO.sub.3, 0.5N KHSO.sub.4 and brine. Organic phase was dried
with MgSO.sub.4 and solvent was removed in vacuo. Purification by
preparative TLC (5% MeOH/EtOAc). Recovered 0.051 g (62%) of the
product as a white foam. Rf=0.42 (5% MeOH/EtOAc). .sup.1H NMR
(CDCl.sub.3) 8.09 (1H, s), 7.76 (1H, d), 7.39 (1H, d), 7.32-7.12
(5H, m), 6.54-6.40 (2H, m), 5.67 (1H, d), 5.10-4.92 (2H, m), 4.85
(1H, m), 4.00-3.83 (3H, m), 3.82-3.70 (2H, m), 3.62-3.51 (1H, m),
3.38 (1H, m), 3.31 (3H, s), 3.10 (1H, m), 3.04-2.80 (4H, m),
1.92-1.70 (6H, m), 1.69-1.44 (4H, m). LRMS (M+H).sup.+ 694.1.
Example 40
[0380] 642
[0381]
(3R,3aS,6aR)Hexahydrofuro[2,3-b]furan-3-yl-N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)(2-[(methylsulfonyl)amino]benzimidazol-5-ylsulfonyl)amino-2--
hydroxypropyl)carbamate.
[0382]
(3R,3aS,6aR)Hexahydrofuro[2,3-b]furan-3-yl-N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)amino-2-hydroxypropyl)carbamate (Step 2, Example 54),
(0.065 g, 0.2 mmol) was combined with
2-[(methylsulfonyl)amino]benzimidazol-5-yl- sulfonyl chloride
(0.071 g, 0.2 mmol) in anhydrous DMF (2 ml) under a N.sub.2
atmosphere. The resulting solution was chilled to 0.degree. C. and
diisopropylethylethyl amine (0.080 ml, 0.5 mmol) was added. The
reaction was allowed to warm to room temperature and stirred for 24
hours. Reaction mixture was diluted in EtOAc and washed with sat.
NaHCO.sub.3, 0.5N KHSO.sub.4 and brine. Organic phase was dried
with MgSO.sub.4 and solvent was removed in vacuo. Purification by
preparative TLC (5% MeOH/EtOAc). Recovered 0.051 g (62%) of the
product as a white foam. Rf=0.53 (5% MeOH/EtOAc). .sup.1H NMR
(CDCl.sub.3) 8.09 (1H, s), 7.69 (1H, d), 7.43 (1H, d), 7.32-7.08
(5H, m), 6.31-6.18 (2H, m), 5.71-5.59 (2H, m), 5.10-4.92 (2H, m),
4.85 (1H, m), 4.00-3.83 (3H, m), 3.82-3.70 (2H, m), 3.62-3.51 (1H,
m), 3.38 (1H, m), 3.31 (3H, s), 3.10 (1H, m), 3.04-2.80 (4H, m),
1.92-1.70 (6H, m), 1.69-1.44 (4H, m). LRMS (M+H).sup.+ 694.0.
Example 41
[0383] 643
[0384] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)[(4-hydroxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate.
[0385]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ylN-(1S,2R)-1-benzyl-3-[[4--
(benzyloxy)phenyl]sulfonyl(cyclopentyloxy)amino]-2-hydroxypropylcarbamate
(Example 95), (1.4 mmol, 903 mg) was stirred vigorously with 10%
palladium on carbon (200 mg), glacial acetic acid (2.8 mmol, 0.156
mL) and ethyl acetate (1 mL) under hydrogen for 20 hours at room
temperature. The reaction was filtered and the filtrate
concentrated to produce 781 mg (>99%) of a white solid.
R.sub.f=0.2 (1:1 hexanes/ethyl acetate); H1-NMR (CDCl.sub.3):
.delta. 7.66 (2H, d), 7.30-7.12 (6H, m), 6.93 (2H, d), 5.78 (1H,
bs), 5.66 (1H, s), 4.98 (1H, m), 4.81-4.70 (2H, m), 3.98-3.80 (4H,
m), 3.80-3.54 (3H, m), 3.15-2.53 (6H, m), 1.85-1.65 (4H, m),
1.65-1.35 (4H, m); M.S. (ESI) M+H=577.
Example 42
[0386] 644
[0387] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((-
cyclopentyloxy)[4-(2-hydroxyethoxy)phenyl]sulfonylamino)-2-hydroxypropyl]c-
arbamate.
[0388] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)[(4-hydroxyphenyl)sulfonylamino-2-hydroxypropyl)carbamate
(Example 41), (0.13 mmol, 75 mg),
(2-bromoethoxy)(tert-butyl)dimethylsila- ne (0.16 mmol, 37 mg),
potassium carbonate (0.40 mmol, 54 mg), and anhydrous DMF (0.5 mL)
were stirred at room temperature for 20 hours under nitrogen. The
reaction was warmed to 50.degree. C. for 2 additional hours. The
reaction was concentrated under vacuum, dissolved in ethyl acetate,
washed with distilled water and brine, and dried over magnesium
sulfate. The crude material was concentrated under vacuum and the
resulting clear oil was purified by silica gel flash chromatography
(2:1 hexanes/ethyl acetate) to yield 60 mg (63%) of a clear oil.
The resulting silyl ether was then stirred in a 3:1 (CH.sub.3CN/HF
(49%)) solution for 1 hour and quenched with a saturated aqueous
solution of sodium bicarbonate. The reaction was concentrated under
vacuum, dissolved in ethyl acetate, washed with distilled water and
brine, and dried over magnesium sulfate. The desired alcohol was
crystallized from an ether/hexanes solution yielding 20 mg (39%) of
white powdery crystals. R.sub.f=0.1 (1:1 hexanes/ethyl acetate);
H1-NMR (CDCl.sub.3): .delta. 7.72 (2H, d), 7.30-7.12 (6H, m), 7.01
(2H, d), 5.64 (1H, s), 4.98 (1H, m), 4.85-4.70 (2H, m), 4.18-4.11
(2H, m), 4.04-3.76 (7H, m), 3.73-3.55 (2H, m), 3.10 (1H, bs),
3.04-2.55 (5H, m), 2.10 (1H, m), 1.86-1.68 (4H, m), 1.68-1.44 (4H,
m); MS (ESI): M+H=621.
Example 43
[0389] 645
[0390] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[[(3-N,N-dim-
ethylaminophenyl)sulfonyl)(cyclopentyloxy)amino)-1-benzyl-2-hydroxypropylc-
arbamate. A mixture of 58 mg (0.1 mMol) of
(3R,3aS,6aR)hexahydrofuro[2,3-b- ]furan-3-yl
N-(1S,2R)-3-[[(3-aminophenyl)sulfonyl](cyclopentyloxy)amino]-1-
-benzyl-2-hydroxypropylcarbamate (Example 77) and 0.25 mL of 37%
formaldehyde in 25 mL ethanol was treated with ca.10 mg of 5%
palladium on carbon and hydrogenated at 50 PSI for 20 minutes. The
mixture was filtered, evaporated and purified on a 2 inch plug of
silica gel (5% methanol-dichloromethane) to give the desired
product as a white foam (30 mg). 1H-NMR (CDCl.sub.3): 1.5-1.9
(13H), 2.8 (4H), 2.97 (6H), 3.18 (1H), 3.64 (2H), 3.9 (4H),
4.75-4.95 (4H), 4.99 (1H), 5.62 (1H), 6.95 (1H), 7.0-7.4 (8H). MS:
(LC-MS): 604 (MH+).
Example 44
[0391] 646
[0392] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)[(3-hydroxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate.
This compound was formed (from Example 96) under the same
conditions used for (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyc-
lopentyloxy)[(4-hydroxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
(Example 41). R.sub.f=0.2 (1:1 hexanes/ethyl acetate); H1-NMR
(CDCl.sub.3): .delta. 7.43-7.35 (2H, m), 7.30-7.10 (8H, m), 6.63
(1H, bs), 5.70 (1H, s), 5.11-4.95 (2H, m), 4.79 (1H, m), 4.03-3.64
(7H, m), 3.16-2.79 (6H, m), 1.88-1.69 (4H, m), 1.69-1.43 (4H, m);
MS (ESI): M+Na=599.
Example 45
[0393] 647
[0394] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[[(3-N-methy-
laminophenyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarba-
mate. A mixture of 40 mg (0.069 mMol) of
(3R,3aS,6aR)hexahydrofuro[2,3-b]f- uran-3-yl
N-(1S,2R)-3-[[(3-aminophenyl)sulfonyl)(cyclopentyloxy)amino-]1-b-
enzyl-2-hydroxypropylcarbamate (Example Example 77), 0.0048 mL
(0.077 mMol) of iodomethane and 0.014 mL (0.1 mMol) of
triethylamine in 1 mL of dimethyl formamide was heated to
80.degree. C. for 12 h. The volatiles were removed in vacuo and the
residue was purified by semi-prep C-18 HPLC to give the desired
mono-amine as a white soild (8 mg). .sup.1H-NMR (CDCl.sub.3):
1.5-1.9 (13H), 2.75 (1H), 2.8-3.0 (3H), 2.99 (3H), 3.15 (1H), 3.7
(1H), 3.9 (5H), 4.8 (1H), 5.0 (1H), 5.5 (1H), 7.0-7.4 (7H), 7.5
(2H). MS (LC-MS): 590 (MH+).
[0395] Alternatively this material can also be obtained according
to the following method:
[0396] In a dried flask was introduced 1 eq. of
(3R,3aS,6aR)Hexahydrofuro[-
2,3b]furan-3-yl-N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)[(3-(N-(methyl-tert--
Butoxycarbonyl))phenyl)sulfonyl]amino-2-hydroxy propylcarbamate
(21.5 mg, 0.031 mmol) in 2 mL dichloromethane. To this solution was
added 1 mL of trifluoroacetic acid. The reaction was continued at
room temperature for 45 min. The solvant was evaporated in vacuo to
an oil. The crude material was purified on flash grade silica gel
eluting with 50% ethyl acetate in hexane. Fractions containing the
product were combined, evaporated in vacuo and dried under high
vacuum to provide (3R,3aS,6aR)Hexahydrofuro[2,-
3b]furan-3-yl-N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)[(3-N-methylphenyl)sul-
fonyl]amino-2-hydroxypropyl carbamate (17.1 mg, 93%). HPLC showed
the material to be 98% pure; Ret. time=11.0 min. H.sup.1-NMR
(CDCl.sub.3): 7.12-7.35 (m, 9H), 5.60 (m, 1H), 4.75-5.10 (m, 3H),
3.70-3.91 (m, 6H), 3.54 (m, 2H), 3.29 (m, 1H), 2.84-3.09 (m, 7H),
1.18-1.98 (m, 9H) and LCMS (ES+), M+H=590.2.
Example 46
[0397] 648
[0398]
N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(cyclopentyloxy)-1H-b-
enzimidazole-6-sulfonamide. A mixture of tert-butyl
N-(1S,2R)-3-[(1H-benzimidazol-6-ylsulfonyl)(cyclopentyloxy)amino]-1-benzy-
l-2-hydroxypropylcarbamate (Example 82), (0.500 g, 0.919 mmol) and
trifluoroacetic acid (5 mL) was stirred under an Argon atmosphere
at ambient temperature for approximately one hour. The reaction was
evaporated in vacuo and the residue was partitioned between 1N
aqueous sodium hydroxide and dichloromethane. After separating the
layers, the aqueous phase was diluted with saturated aqueous brine
and extracted three times with dichloromethane followed by two
extractions with ethyl acetate. The organic layers were combined,
dried over anhydrous sodium sulfate, filtered, evaporated in vacuo
and dried under high vacuum to provide
N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(cyclopentyloxy)-1H-
-benzimidazole-6-sulfonamide (0.423 g, 104%). H1-NMR
(chloroform-D3): 1.60 (m, 4H), 1.84 (m, 4H), 2.52 (m, 4H), 2.90 (m,
1H), 3.03 (m, 1H), 3.27 (m, 2H), 3.86 (m, 1H), 4.90 (m, 1H), 7.25
(m, 6H), 7.81 (m, 2H), 8027 (m, 2H). MS (ESI): 445(M+H). 649
[0399] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(1H-benzimi-
dazol-6-ylsulfonyl)(cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarbamat-
e. A mixture of (2R,3aS,6aR)hexahydrofuro[2,3-b]furan-2-yl
4-nitrophenyl carbonate (38.3 mg, 0.124 mmol) and imidazole (15 mg,
0.222 mmol) were heated under Argon in approximately 2 mL of
acetonitrile for 1.5 hrs. To this mixture was then added (N-[(2R,
3S)-3-amino-2-hydroxy-4-phenylbutyl]-
-N-(cyclopentyloxy)-1H-benzimidazole-6-sulfonamide (50 mg, 0.113
mmol) and N,N-diisopropylethylamine (58.9 .mu.L, 0.338 mmol). After
heating at reflux for an additional 6 hrs., the reaction was cooled
and evaporated in vacuo. The residue was dissolved in ethyl
acetate, washed three times with 5% aqueous potassium carbonate,
washed with brine, dried over anhydrous sodium sulfated, filtered
and evaporated in vacuo. The residue was purified on a preparative
TLC plate (20.times.20 cm, 1000 .mu.M) eluting with 95:5 methylene
chloride:methanol. The plate was allowed to dry through evaporation
and then eluted again with 93:7 chloroform:methanol. The product
band was removed, eluted with 4:1 methylene chloride:methanol,
filtered, and evaporated in vacuo. The residue was lyophilized from
acetonitrile: water to provide
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-(1S,
2R)-3-[(1H-benzimidazol-
-6-ylsulfonyl)(cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate
(25 mg, 37%). H1-NMR (dimethylsulfoxide-D6): 1.05 (m, 1H), 1.27 (m,
1H), 1.58 (m, 8H), 2.33 (m, 1H), 2.64 (m, 2H), 2.96 (m, 2H), 3.45
(m, 4H), 3.62 (m, 2H), 4.72 (m, 2H), 5.16 (m, 1H), 5.42 (d, 1H),
7.10 (m, 6H), 7.51 (m, 1H), 7.72 (m, 1H), 7.93 (m, 1H); 8.44 (s,
1H), 13.0 (b, 1H). MS (ESI): 601 (M+H).
Example 47
[0400] 650
[0401] 3S)tetrahydro-3-furanyl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-m-
ethoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate. A mixture of
2,5-dioxo-1-pyrrolidinyl[(3S)tetrahydro-3-furanyl]carbonate (13.8
mg, 0.0602 mmol, WO94/05639),
N.sup.1-[(2R,3S)-3-amino-2-hydroxy-4-phenylbuty-
l]-NT-(cyclopentyloxy)-4-methoxy-1-benzenesulfonamide.times.trifluoracetic
acid (Step 1, Example 48), (30 mg, 0.0547 mmol), and
N,N-diisopropylethylamine (23.8 .mu.L, 0.137 mmol) were combined at
ambient temperature under an Argon atmosphere. After stirring for
18 hours, the reaction mixture was evaporated in vacuo to a residue
and purified on a preparative silica gel TLC plate (20.times.20 cm,
500 .mu.M) eluting with 96:4 chloroform:methanol. The product band
was removed, eluted with 3:1 methylene chloride methanol, filtered,
evaporated in vacuo and dried under high vacuum to provide
(3S)tetrahydro-3-furanyl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methox-
yphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate (26 mg, 87%) as a
foam. H1-NMR (chloroform-D3): 1.73 (m, 9H), 2.14 (m, 1H), 2.92 (m,
5H), 3.77 (m, 6H), 3.87 (s, 3H), 4.79 (bm, 2H), 5.10 (bs, 1H), 6.97
(d, 2H), 7.23 (m, 5H), 7.70 (d, 2H). MS (ESI): 571 (M+Na).
Example 48
[0402] 651
[0403]
N.sup.1-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N.sup.1-(cyclopen-
tyloxy)-4-methoxy-1-benzenesulfonamide. trifluoracetic acid.
Tert-butyl N-((1S,
2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-
-hydroxypropyl)carbamate (0.693 g, 1.29 mmol) was combined with
trifluoroacetic acid (5 mL) under an Argon atmosphere at ambient
temperature. After stirring for 20 minutes, the reaction mixture
was evaporated in vacuo. The residue was dissolved several times in
dichloromethane and evaporated to remove excess trifluoroacetic
acid. The crude product was triturated with hexane and then
evaporated and dried under high vacuum to provide the
trifluoracetic acid salt of
N.sup.1-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]N.sup.1-(cyclopentyloxy)-
-4-methoxy-1-benzenesulfonamide (0.769 g, 108%). H1-NMR
(chloroform-D3+NaOD): 1.58 (m, 4H), 1.78 (m, 4H), 2.45 (m, 1H),
2.85 (m, 1H), 2.96 (m, 1H), 3.15 (m, 1H), 3.22 (m, 1H), 3.77 (m,
1H), 3.88 (s, 3H), 4.78 (m, 1H), 7.00 (m, 2H), 7.23 (m, 5H), 7.78
(m, 2H). MS (ESI): 435 (MH+). 652
[0404] 1,3-dioxan-5-yl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyph-
enyl)sulfonyl]amino-2-hydroxypropyl)carbamate. A mixture of
1,3-dioxan-5-yl(4-nitrophenyl)carbonate [16.2 mg, 0.0602 mmol,
Application: WO 96-US5473),
N.sup.1-[(2R,3S)-3-amino-2-hydroxy-4-phenylbu-
tyl]-N.sup.1-(cyclopentyloxy)-4-methoxy-1-benzenesulfonamide.trifluoraceti-
c acid (30 mg, 0.0547 mmol], and N,N-diisopropylethylamine (23.8
.mu.L, 0.137 mmol) were combined in approximately 1.5 mL
acetonitrile at ambient temperature under an Argon atmosphere.
After stirring for 18 hours, the reaction mixture was evaporated in
vacuo to a residue and purified on a preparative silica gel TLC
plate (20.times.20 cm, 500 .mu.M) eluting with 96:4
chloroform:methanol. The product band was removed, eluted with 3:1
methylene chloride:methanol, filtered, and evaporated in vacuo. The
residue was dissolved in diethylether, evaporated in vacuo and
dried under high vacuum to provide 1,3-dioxan-5-yl
N-((1S,2R)-1-benzyl-3-(cyclo-
pentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
(20.6 mg, 67%) as a foam. H1-NMR (chloroform-D3): 1.66 (m, 8H),
2.94 (m, 5H), 3.87 (m, 8H), 4.48 (bs, 1H), 4.76 (m, 2H), 4.94 (m,
2H), 6.97 (m, 2H), 7.24 (m, 5H), 7.69 (m, 2H). MS (ESI): 587
(M+Na).
Example 49
[0405] 653
[0406]
(2S)-N.sup.1-(1S,2R)-3-[[(3-aminophenyl)sulfonyl](cyclopentyl
oxy)amino]-1-benzyl-2-hydroxypropyl-2-[(2-quinolinyl
carbonyl)amino]butanediamide. A mixture of
3-amino-N.sup.1-[(2R,3S)-3-ami-
no-2-hydroxy-4-phenylbutyl]-N.sup.1-(cyclopentyloxy)-1-benzenesulfonamide
(Step 1, Example 27), (60 mg, 0.143),
1-(3-dimethylaminopropyl)-3-ethylca- rbodiimide hydrochloride (29
mg, 0.15 mmol), N-hydroxybenzotriazole (20 mg, 5 mmol), and
(2S)-4-amino-4-oxo-2-[(2-quinolinylcarbonyl, amino]butanoic
acid.cndot.hydrochloride (49 mg, 0.15 mmol, Eur. Pat. Appl. EP
432694) was combined under an Argon atmosphere at ambient
temperature in anhydrous dimethylformamide (2 mL). After addition
of N,N-diisopropylethylamine (76 .mu.L, 0.437 mmol), the mixture
was stirred for 16 hours. The reaction solvent was removed in vacuo
and the residue was dissolved in ethyl acetate. The solution was
transferred to a separatory funnel and washed twice with 1N sodium
hydrogen sulfate. The combined aqueous layers were extracted with
ethyl acetate. The combined organic layers were washed with 5%
aqueous potassium carbonate and brine, dried over anhydrous sodium
sulfate, filtered and evaporated in vacuo. The residue was purified
on a preparative TLC plate (20.times.20 cm, 1000 .mu.M) eluting
with 95:5 methylene chloride:methanol. The product band was
removed, eluted with 3:1 methylene chloride:methanol, filtered, and
evaporated in vacuo. The residue was purified again on a
preparative TLC plate (20.times.20 cm, 500 .mu.M) eluting with 95:5
methylene chloride:methanol. The product band was removed, eluted
with 3:1 methylene chloride:methanol, filtered, and evaporated in
vacuo. The residue was lyophilized from acetonitrile: water to
provide
(2S)-N.sup.1-(1S,2R)-3-[[(3-aminophenyl)sulfonyl](cyclopentyloxy)amino]-1-
-benzyl-2-hydroxypropyl-2-[(2-quinolinylcarbonyl)amino]butanediamide
(32 mg, 33%) as a white lyophile. H1-NMR (chloroform-D3): 1.57 (m,
8H), 2.57 (m, 1H), 2.82 (m, 4H), 3.09 (m, 1H), 3.35 (b, 1H), 3.73
(b, 1H), 4.18 (m, 3H), 4.74 (m, 1H), 4.87 (m, 1H), 5.47 (b, 1H),
5.86 (b, 1H), 7.00 (m, 10H), 7.56 (m, 1H), 7.73 (m, 1H), 7.81 (d,
1H), 8.11 (m, 2H), 8.24 (d, 1H), 9.15 (d, 1H). MS (ESI): 689
(M+H).
Example 50
[0407] 654
[0408] (2S)-N.sup.1-((1S, 2R)-1-benzyl-3-(cyclopentyloxy)
(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)-2-[(2-quinolinylcarbonyl-
)amino]butanediamide. A mixture of
N.sup.1-[(2R,3S)-3-amino-2-hydroxy-4-ph-
enylbutyl]-N.sup.1-(cyclopentyloxy)-4-methoxy-1-benzenesulfonamide
(Step 1, Example 48), (73 mg, 0.168),
1-(3-dimethylaminopropyl)-3-ethylcarbodii- mide hydrochloride (34
mg, 0.18 mmol), N-hydroxybenzotriazole (24 mg, 0.18 mmol), and
(2S)-4-amino-4-oxo-2-[(2-quinolinylcarbonyl)amino]butanoic acid
hydrochloride (57 mg, 0.18 mmol, Eur. Pat. Appl. EP 432694) was
combined under an Argon atmosphere at ambient temperature in
anhydrous dimethylformamide (2 mL). After addition of
N,N-diisopropylethylamine (896 .mu.L, 0.513 mmol), the mixture was
stirred for 16 hours. The reaction solvent was removed in vacuo and
the residue was dissolved in ethyl acetate. The solution was
transferred to a separatory funnel and washed twice with 1N sodium
hydrogen sulfate. The combined aqueous layers were extracted with
ethyl acetate. The combined organic layers were washed with 5%
aqueous potassium carbonate and brine, dried over anhydrous
magnesium sulfate, filtered and evaporated in vacuo. The, residue
was purified on a preparative TLC plate (20.times.20 cm, 1000
.mu.M) eluting with 97:3 chloroform:methanol. The product band was
removed, eluted with 3:1 methylene chloride:methanol, filtered, and
evaporated in vacuo. The residue was triturated with hexane and
diethyl ether. The slurry was evaporated in vacuo to a residue and
dried under high vacuum to provide
(2S)-N.sup.1-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[-
(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)-2-[(2-quinolinylcarbonyl)-
amino]butanediamide (49 mg, 41%) as a white solid. H1-NMR
(chloroform-D3): 1.52 (m, 4H), 1.75 (m, 4H), 2.82 (m, 5H), 3.10 (m,
1H), 3.82.degree. (b, 1H), 3.84 (s, 3H), 3.91 m, 1H), 4.29 (m, 1H),
4.78 (m, 1H), 4.95 (m, 1H), 5.76 (b, 1H), 6.22 (b, 1H), 7.00 (m,
5H), 7.12 (d, 2H), 7.22 (d, 1H), 7.60 (m, 1H). 7.75 (m, 3H), 7.83
(d, 1H), 8.14 (m, 2H), 8.25 (d, 1H), 9.15 (d, 1H). MS (ESI): 704
(M+H).
Example 51
[0409] 655
[0410] (2S)-4-Amino-4-oxo-2-[(2-quinolinylcarbonyl)amino]butanamido
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)amino]-2-hydroxypropylcarbamate.
Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)amino]-2-hydroxypropylca-
rbamate (412 mg, 1.13 mmol) was dissolved in dichloromethane (8 mL)
in a 25 mL round bottomed flask under nitrogen and trifluoroacetic
acid (4 mL) was added slowly. After the solution was stirred for 4
hours, TLC indicated loss of starting material. After the workup
described in Step 2, Example 54, the residue was dissolved in
anhydrous DMF (5 mL) followed by
(2S)-4-amino-4-oxo-2-[(2-quinolinylcarbonyl)amino]butanoic acid
hydrochloride (320 mg, 1.13 mmol), anhydrous diisopropylethylamine
(0.4 mL, 2.26 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide
hydrochloride (220 mg, 1.13 mmol), and 1-hydroxy-benzotriazole (150
mg, 1.13 mmol). The reaction was stirred for 18 h and concentrated
in vacuo. Ethyl acetate (15 mL) and 1N HCl (15 mL) were added and
the layers were separated. The aqueous layer was adjusted with
solid sodium carbonate to pH 9 and then extracted with ethyl
acetate (25 mL). The organic layer was dried over sodium sulfate,
filtered, and concentrated in vacuo. Preparative silica gel TLC of
the residue using 90:10 chloroform:methanol as eluent yielded the
product as a white solid (91 mg, 0.171 mmol, 15%). MS (ES): 534
(M+1), 532 (M-1). 656
[0411] (2S)-4-Amino-4-oxo-2-[(2-quinolinylcarbonyl)amino]butanamido
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-{(methoxycarbonyl)amino]-1H-benz-
imidazol-5-ylsulfonyl)amino]-2-hydroxypropylcarbamate.
[0412] (2S)-4-Amino-4-oxo-2-[(2-quinolinylcarbonyl)amino]butanamido
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)-amino]-2-hydroxypropylcarbamate
(Step 1, above), (44 mg, 0.0825 mmol), methyl
N-[5(chlorosulfonyl)-1H-ben- zimidazol-2-yl]carbamate (24 mg,
0.0825 mmol), and anhydrous diisopropylethylamine (0.05 mL, 0.280
mmol) were combined in anhydrous tetrahydrofuran (3 mL) in a 25 mL
round bottomed flask under nitrogen. The reaction was stirred for
24 hours and concentrated in vacuo. Ethyl acetate (30 mL) and water
(10 mL) were added and the layers were separated. The organic layer
was washed with brine (10 mL), dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo. The residue was purified by
preparative silica gel TLC using 90:10 chloroform:methanol as an
eluent to provide the desired product as a white solid (11 mg,
0.014 mmol, 17%). .sup.1HNMR (d.sub.6-DMSO) .delta.: 8.86 (d, J=8.4
Hz, 1H), 8.62 (d, J=8.4 Hz, 1H), 8.22-6.94 (m, 12H)--, 5.19 (d,
J=6.2 Hz, 1H), 4.77-4.72 (m, 2H), 4.02-1.35 (m, 17H), 3.80 (s, 3H).
MS (ES): 787 (M+1), 785 (M-1)
Example 52
[0413] 657
[0414] (2S)-4-Amino-4-oxo-2-[(2-quinolinylcarbonyl)amino]butanamido
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(1H-indazol-6-ylsulfonyl)amino]-2-h-
ydroxypropylcarbamate.
[0415]
(2S)-4-Amino-4-oxo-2-[(2-quinolinylcarbonyl)-amino]butanamido
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)-amino]-2-hydroxypropylcarbamate
(Step 1, Example 51), (44 mg, 0.0825 mmol),
1-trityl-1H-indazole-6-sulfon- yl chloride (38 mg, 0.0825 mmol),
and anhydrous diisopropylethylamine (0.05 mL, 0.280 mmol) were
combined in anhydrous tetrahydrofuran (3 mL) in a 25 mL round
bottomed flask under nitrogen. The reaction was stirred for 24
hours and concentrated in vacuo. Ethyl acetate (30 mL) and water
(10 mL) were added and the layers were separated. The organic layer
was washed with brine (10 mL), dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo. The compound was deprotected
as described in Example 57 and purified by preparative silica gel
TLC using 90:10 chloroform:methanol as an eluent to provide the
desired product as a white film (9 mg, 0.013 mmol, 15%). .sup.1HNMR
(d.sub.6-DMSO) .delta.: 8.84 (d, J=8.5 Hz, 1H), 8.61 (d, J=8.5 Hz,
1H), 8.31-6.95 (m, 13H), 5.24 (d, J=6.6 Hz, 1H), 4.81-4.72 (m, 2H),
3.97 (bs, 1H), 3.68 (bs, 1H), 3.401.20 (m, 15H). MS (ES): 714
(M+1), 712 (M-1).
Example 53
[0416] 658
[0417] (3S)Tetrahydro-3-furanyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)amin-
o]-2-hydroxypropylcarbamate. Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyl-
oxy)amino]-2-hydroxypropylcarbamate [Example 54] (1.05 g, 2.88
mmol) was dissolved in dichloromethane (12 mL) in a 50 mL round
bottomed flask under nitrogen and trifluoroacetic acid (8 mL) was
added slowly. After the solution was stirred for 4 hours, TLC
indicated loss of starting material. After the workup described in
Step 2, Example 54, the residue was dissolved in anhydrous
acetonitrile (15 mL), followed by
1-([(3S)tetrahydro-3-furanyloxy]-carbonyloxy)dihydro-1H-pyrrole-2,5-dione
(660 mg, 2.88 mmol), anhydrous diisopropylethylamine (0.50 mL, 2.88
mmol), and N,N-dimethylaminopyridine (105 mg, 0.86 mmol). The
reaction was heated at 50.degree. C. for 2 hours, allowed to cool,
and concentrated in vacuo. After the workup described in Step 2,
Example 54, the residue was purified by flush chromatography over a
bed of silica gel using a gradient elution of hexane:ethyl acetate
(1:2 to 1:5) to give the desired product as a white foam (440 mg,
1.16 mmol, 40%). MS (ES): 379 (M+1). 659
[0418] (3S)Tetrahydro-3-furanyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-[-
(methoxycarbonyl)amino]-1H-benzimidazol-5-ylsulfonyl)amino]-2-hydroxypropy-
lcarbamate.
[0419] (3S)Tetrahydro-3-furanyl
N-(1S,2R)-1-benzyl-3[(cyclopentyloxy)amino-
]-2-hydroxypropylcarbamate (120 mg, 0.317 mmol), methyl
N-[5-(chlorosulfonyl)-1H-benzimidazol-2-yl]carbamate (100 mg, 0.345
mmol), anhydrous diisopropylethylamine (0.06 mL, 0.345 mmol), and
N,N-dimethylaminopyridine (12 mg, 0.09 mmol) were combined in
anhydrous tetrahydrofuran (6 mL) and anhydrous
N,N-dimethylformamide (3 mL) in a 25 mL round bottomed flask under
nitrogen. The reaction was stirred for 24 hours and concentrated in
vacuo. After the workup described in Step 3, Example 54, the
residue was purified by preparative silica gel TLC using 90:10
chloroform:methanol as an eluent to provide the desired product as
a colorless glass (43 mg, 0.068 mmol, 21%). .sup.1HNMR
(d.sub.6-DMSO) .delta.: 7.96-7.08 (m, 10H), 5.19 (d, J=6.7 Hz, 1H),
4.96-4.82 (m, 3H), 3.81 (s, 3H), 3.75-3.40 (m, 6H), 3.09-2.40 (m,
4H), 2.09-1.35 (m, 8H). MS (ES): 632 (M+1), 630 (M-1).
Example 54
[0420] 660
[0421] Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)amino]-2-hydroxypr-
opylcarbamate.
[0422] To a solution of 2-(cyclopentyloxy)-1H-isoindole-1,3
(2H)-dione (11.3 g, 48.9 mmol) in anhydrous tetrahydrofuran (60 mL)
in a 200 mL round bottomed flask under nitrogen was added anhydrous
hydrazine (1.6 g, 48.9 mmol) dropwise via syringe. The resulting
thick white slurry was vigorously stirred for 2.5 hours and then
filtered through a fritted funnel. The cake was washed with
tetrahydrofuran (2.times.20 mL) and the combined filtrates is were
placed in a 300 mL round bottomed flask under nitrogen and equipped
with a condenser. Tert-butyl
N-(1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate (7.50 g, 28.5 mmol)
was added along with anhydrous lithium triflate (6.20 g, 39.7 mmol)
and the reaction was heated at reflux for 24 hours. The reaction
was allowed to cool and was concentrated in vacuo to a viscous oil.
Diethyl ether (150 mL) and water (50 mL) were added and the layers
were separated. The ethereal layer was dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo. Flush chromatography
over a bed of silica gel using a gradient elution of hexane:ethyl
acetate (4:1 to 2:1) gave the desired product as a white solid
(8.90 g, 24.4 mmol, 86% based upon starting epoxide). .sup.1HNMR
(CDCl.sub.3) .delta.: 7.32-7.19 (m, 5H), 5.90 (bs, 1H), 4.59 (d,
J=8.1 Hz, 1H), 4.24-4.20 (m, 1H), 3.90-3.58 (m, 3H), 3.16-2.83 (m,
4H), 1.69-1.35 (m, 16H) MS (ES): 365 (M+1), 265 (M-BOC). 661
[0423] (3aS,6aR)Hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(cycl-
opentyloxy)amino]-2-hydroxypropylcarbamate.
[0424] Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)amino]-2-hydroxy-p-
ropylcarbamate (step 1 above), (1.50 g, 4.12 mmol) was dissolved in
dichloromethane (15 mL) in a 50 mL round bottomed flask under
nitrogen and trifluoroacetic acid (10 mL) was added slowly. After
the solution was stirred for 3 hours, TLC indicated loss of
starting material. The reaction was concentrated in vacuo and ethyl
acetate (30 mL) was added. A 10% solution of aqueous sodium
carbonate was added portionwise until the pH was adjusted to 9. The
layers were separated and the organic layer was extracted with 1 N
HCl (20 mL). The aqueous layer was then neutralized with solid
sodium carbonate until the pH was 9. The resulting white
precipitate was dissolved by the addition of ethyl acetate (100 mL)
and the layers were separated. The aqueous layer was extracted with
ethyl acetate (25 mL) and the combined organic layers were dried
over anhydrous sodium sulfate, filtered, and concentrated in vacuo
to a sticky white solid. Anhydrous acetonitrile (20 mL) was added,
followed by racemic (3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
4-nitrophenyl carbonate (1.21 g, 4.12 mmol), anhydrous
diisopropylethylamine (0.72 mL, 4.12 mmol), and
N,N-dimethylaminopyridine (150 mg, 1.23 mmol). The reaction was
heated at 50.degree. C. for 2 hours, allowed to cool, and
concentrated in vacuo. Diethyl ether (50 mL) and 5% sodium
carbonate (20 mL) were added and the layers were separated. The
organic layer was washed with water (20 mL), brine (15 mL), dried
over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
Flush chromatography over a bed of silica gel using a gradient
elution of hexane:ethyl acetate (1:1 to 1:4) gave the desired
product as a pale yellow foam (1.41 g, 33.5 mol, 81%). .sup.1HNMR
(d.sub.6-DMSO): .delta. 7.29-7.13 (m, 5H), 6.18 (bs, 1H), 5.58-5.52
(m, 1H), 4.96-4.82 (m, 2H), 4.14 (bs, 1H), 3.88-3.34 (m, 6H),
3.04-2.53 (m, 6H), 1.92-1.30 (m, 9H). MS (ES): 421 (M+1), 419
(M-1). 662
[0425] (3aS,6aR)Hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(cycl-
opentyloxy)(2-[(methoxycarbonyl)amino]-1H
benzimidazol-5-ylsulfonyl)amino]- -2-hydroxypropylcarbamate.
[0426] (3aS,6aR)Hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(cycl-
opentyloxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.238 mmol),
methyl N-[5-(chlorosulfonyl)-1H-benzimidazol-2-yl]carbamate (70 mg,
0.238 mmol), anhydrous diisopropylethylamine (0.04 mL, 0.238 mmol),
and N,N-dimethylamino-pyridine (9 mg, 0.07 mmol) were combined in
anhydrous tetrahydrofuran (5 mL) and anhydrous
N,N-dimethylformamide (3 mL) in a 25 mL round bottomed flask under
nitrogen. The reaction was stirred for 24 hours and concentrated in
vacuo. Ethyl acetate (30 mL) and 0.5 N HCl (10 mL) were added and
the layers were separated. The organic layer was washed with brine
(10 mL), dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. Preparative silica gel TLC using 90:10
chloroform:methanol as an eluent provided the product as a white
foam (83 mg, 0.123 mmol, 52%). .sup.1HNMR (d.sub.6-DMSO) .delta.:
7.60-7.15 (m, 10H), 5.51-5.46 (m, 1H), 5.21 (bd, J=5.9 Hz, 1H),
4.82-4.69 (m, 2H), 3.81 (s, 3H), 3.78-3.57 (m, 8H), 3.19-2.42 (m,
4H), 2.02-1.30 (m, 8H). MS (ES): 674 (M+1), 672 (M-1).
Example 55
[0427] 663
[0428] 1,3-Dioxan-5-yl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)amino]-2-hydr-
oxypropylcarbamate. Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)amino-
]-2-hydroxypropylcarbamate (1.38 g, 3.79 mmol) was dissolved in
dichloromethane (15 mL) in a 50 mL round bottomed flask under
nitrogen and trifluoroacetic acid (8 mL) was added slowly. After
the solution was stirred for 4 hours, TLC Indicated loss of
starting material. After the workup described in Step 2, Example
54, the residue was dissolved in anhydrous acetonitrile (20 mL),
followed by 1,3-dioxan-5-yl 4-nitrophenyl carbonate (1.02 g, 3.79
mmol), anhydrous diisopropylethylamine (0.65 mL, 3.8 mmol), and
N,N-dimethylaminopyridine (140 mg, 1.14 mmol). The reaction was
heated at 50.degree. C. for 2 hours, allowed to cool, and
concentrated in vacuo. After the workup described in Step 2,
Example 54, the residue was purified by flush chromatography over a
bed of silica gel using a gradient elution of hexane:ethyl acetate
(1:2 to 1:4) to give the desired product as a white foam (600 mg,
1.52 mmol, 40%). .sup.1HNMR (d.sub.6-DMSO) .delta.: 7.30-7.17 (m,
5H), 6.15 (bs, 1H), 4.914.67 (m, 3H), 4.35-3.50 (m, 4H), 3.11-2.52
(m, 8H), 1.68-1.36 (m, 8H). MS (ES): 395 (M+1). 664
[0429] 1,3-Dioxan-5-yl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-{(methoxyc-
arbonyl)amino]-1H-benzimidazol-5-ylsulfonyl)amino]-2-hydroxypropylcarbamat-
e.
[0430] 1,3-Dioxan-5-yl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)-amino]-2-hyd-
roxypropylcarbamate (Step 1, above), (100 mg, 0.254 mmol), methyl
N-[5-(chlorosulfonyl)-1H-benzimidazol-2-yl]carbamate (73 mg, 0.254
mmol), anhydrous diisopropylethyl-amine (0.05 mL, 0.254 mmol), and
N,N-dimethylaminopyridine (9 mg, 0.08 mmol) were combined in
anhydrous tetrahydrofuran (5 mL) and anhydrous
N,N-dimethylformamide (2 mL) in a 25 mL round bottomed flask under
nitrogen. The reaction was stirred for 24 hours and concentrated in
vacuo. After the workup described in Step 3, Example 54, the
residue was purified by preparative silica gel TLC using 93:7
chloroform:methanol as an eluent to provide the desired product as
a colorless glass (40 mg, 0.0618 mmol, 24%). .sup.1HNMR
(d.sub.6-DMSO) .delta.: 7.96-7.16 (m, 10H), 5.17 (d, J=6.4 Hz, 1H),
4.82-4.65 (m, 3H), 4.26 (bs, 1H), 3.81 (s, 3H), 3.78-3.49 (m, 5H),
3.05-2.40 (m, 4H), 2.05-1.40 (m, 8H). MS (ES): 648 (M+1), 646
(M-1).
Example 56
[0431] 665
[0432] (3S)Tetrahydro-3-furanyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(1H--
indazol-5-ylsulfonyl)amino]-2-hydroxypropylcarbamate.
[0433] (3S)Tetrahydro-3-furanyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)amin-
o]-2-hydroxypropylcarbamate (Step 1, Example 53), (90 mg, 0.238
mmol), 1-trityl-1H-indazole-5-sulfonyl chloride (110 mg, 0.238
mmol), anhydrous diisopropylethylamine (0.04 mL, 0.238 mmol), and
N,N-dimethylaminopyridin- e (9 mg, 0.07 mmol) were combined in
anhydrous tetrahydrofuran (4 mL) in a 25 mL round bottomed flask
under nitrogen. The reaction was stirred for 24 hours and
concentrated in vacuo. After the workup described in Step 3,
Example 54, the residue was purified by preparative silica gel TLC
using 1:1 hexane:ethyl acetate as an eluent to give the tritylated
product as a colorless film. The compound was deprotected as
described in Example 57 and purified by preparative silica gel TLC
using 3:1 ethyl acetate:hexane as an eluent to provide the desired
product as a colorless film (6 mg, 0.01 mmol, 5%). (no HNMR data
available). MS (ES): 559 (M+1), 557 (M-1).
Example 57
[0434] 666
[0435] (3aS,6aR)Hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(cycl-
opentyloxy)(1H-indazol-5-ylsulfonyl)amino]-2-hydroxypropylcarbamate.
[0436] (3aS,6aR)Hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(cycl- opentyloxy)-amino]-2-hydroxy
propylcarbamate (100 mg, 0.238 mmol) (Step 2, Example 54),
1-trityl-1H-indazole-5-sulfonyl chloride (110 mg, 0.238 mmol),
anhydrous diisopropylethylamine (0.04 mL, 0.238 mmol), and
N,N-dimethylaminopyridine (9 mg, 0.07 mmol) were combined in
anhydrous tetrahydrofuran (5 mL) in a 25 mL round bottomed flask
under nitrogen. The reaction was stirred for 24 hours and
concentrated in vacuo. After the workup described in Step 3,
Example 54, the residue was purified by preparative silica gel TLC
using 1:1 hexane:ethyl acetate as an eluent to give the tritylated
product as a colorless film (80 mg, 0.095 mmol, 40%). The trityl
protecting group was removed by dissolving the compound in
dichloromethane (3 mL) and adding trifluoroacetic acid (1 mL).
After 2.5 hours of stirring, the reaction was concentrated in
vacuo. Ethyl acetate (15 mL) and 10% aqueous sodium carbonate (5
mL) were added and the layers separated. The organic layer was
dried over anhydrous sodium sulfate, filtered, and concentrated in
vacuo. The residue was purified by preparative silica gel TLC using
3:1 ethyl acetate:hexane as an eluent to provide the desired
product as a white solid (30 mg, 0.05 mmol, 53%). .sup.1HNMR
(d.sub.6-DMSO) .delta.: 8.39-8.30 (m, 2H), 7.81-7.67 (m, 2H),
7.25-7.17 (m, 5H), 5.51-5.46 (m, 1H), 5.25 (d, J=6.3 Hz, 1H),
4.83-4.62 (m, 2H), 4.14-4.12 (m, 4H), 3.72-1.26 (m, 18H). MS (ES):
601 (M+1), 599 (M-1).
Example 58
[0437] 667
[0438] (3S)Tetrahydro-3-furanyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(1H--
indazol-6-ylsulfonyl)amino]-2-hydroxypropylcarbamate.
[0439] (3S)Tetrahydro-3-furanyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)amin-
o]-2-hydroxypropylcarbamate (Step 1, Example 53), (120 mg, 0.317
mmol), 1-trityl-1H-indazole-6-sulfonyl chloride (146 mg, 0.317
mmol), anhydrous diisopropylethylamine (0.06 mL, 0.317 mmol), and
N,N-dimethylaminopyridin- e (12 mg, 0.1 mmol) were combined in
anhydrous tetrahydrofuran (5 mL) in a 25 mL round bottomed flask
under nitrogen. The reaction was stirred for 24 hours and
concentrated in vacuo. After the workup described in Step 3,
Example 54, the residue was purified by preparative silica gel TLC
using 1:1 hexane:ethyl acetate as an eluent to give the tritylated
product as a colorless film (100 mg, 0.125 mmol). The compound was
deprotected as described in Example 57 and purified by preparative
silica gel TLC using 3:1 ethyl acetate:hexane as an eluent to
provide the desired product as a colorless glass (30 mg, 0.0537
mmol, 43%). .sup.1HNMR (d.sub.6-DMSO) .delta.: 8.33 (bs, 1H),
8.07-8.00 (m, 2H), 7.49-7.41 (m, 1H), 7.26-7.08 (m, 5H), 5.32-4.78
(m, 4H), 3.81-1.25 (m, 20H). MS (ES): 559 (M+1), 557 (M-1).
Example 59
[0440] 668
[0441] (3aS,6aR)Hexahydro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(cyclopen-
tyloxy)(1H-indazol-6-ylsulfonyl)amino]-2-hydroxypropylcarbamate.
[0442] (3aS,6aR)Hexahydrofuro[2,3-b)-furan-3-yl
N-(1S,2R)-1-benzyl-3-[(cyc-
lopentyloxy)-amino]-2-hydroxypropylcarbamate (Step 2, Example 54),
(100 mg, 0.238 mmol), 1-trityl-1H-indazole-6-sulfonyl chloride (110
mg, 0.238 mmol), anhydrous diisopropylethylamine (0.04 mL, 0.238
mmol), and N,N-dimethylamino-pyridine (9 mg, 0.07 mmol) were
combined in anhydrous tetrahydrofuran (5 mL) in a 25 mL round
bottomed flask under nitrogen. The reaction was stirred for 24
hours and concentrated in vacuo. After the workup described in Step
3, Example 54, the residue was purified by preparative silica gel
TLC using 1:1 hexane:ethyl acetate as an eluent to give the
tritylated product as a colorless film (117 mg, 0.139 mmol, 58%).
The compound was deprotected as described in Example 57 and
purified by preparative silica gel TLC using 3:1 ethyl
acetate:hexane as an eluent to provide the desired product as a
colorless film (60 mg, 0.100 mmol, 72%). .sup.1HNMR (d.sub.6-DMSO)
.delta.: 8.33 (bs, 1H), 8.08-7.99 (m, 2H), 7.50-7.45 (m, 1H),
7.23-7.15 (m, 5H), 5.51-5.45 (m, 1H), 5.26 (bd, J=5.9 Hz, 1H),
4.85-4.66 (m, 2H), 3.77-1.14 (m, 22H). MS (ES): 601 (M+1), 599
(M-1).
Example 60
[0443] 669
[0444] 1,3-Dioxan-5-yl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(1H-indazol-6-
-ylsulfonyl)amino]-2-hydroxypropylcarbamate. 1,3-Dioxan-5-yl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)amino)-2-hydroxypropylcarbamate
(Step 1, Example 55), (100 mg, 0.254 mmol),
1-trityl-1H-indazole-6-sulfon- yl chloride (117 mg, 0.254 mmol),
anhydrous diisopropylethylamine (0.05 mL, 0.254 mmol), and
N,N-dimethylaminopyridine (9 mg, 0.08 mmol) were combined in
anhydrous tetrahydrofuran (5 mL) in a 25 mL round bottomed flask
under nitrogen. The reaction was stirred for 24 hours and
concentrated in vacuo. After the workup described in Step 3,
Example 54, the residue was purified by preparative silica gel TLC
using 1:1 hexane:ethyl acetate as an eluent to give the tritylated
product as a beige foam. The compound was deprotected as described
in Example 57 and purified by preparative silica gel TLC using 3:1
ethyl acetate:hexane as an eluent to provide the desired product as
a colorless glass (53 mg, 0.0922 mmol, 36%). .sup.1HNMR
(d.sub.6-DMSO) .delta.: 8.32 (bs, 1H), 8.06-8.00 (m, 2H), 7.49-7.46
(m, 1H), 7.33-7.16 (m, 5H), 5.22 (d, J=6.5 Hz, 1H), 4.85-4.66 (m,
3H), 4.23-3.00 (m, 12H), 2.01-1.43 (m, 8H). MS (ES): 575 (M+1), 573
(M-1).
Example 61
[0445] 670
[0446] (3S)tetrahydro-3-furanyl
N-(1S,2R)-3-[[(3-aminophenyl)sulfonyl](iso-
propoxy)amino]-1-benzyl-2-hydroxypropylcarbamate.
[0447] tert-Butyl
N-(1S,2R)-3-[[(3-aminophenyl)sulfonyl](isopropoxy)amino]-
-1-benzyl-2-hydroxypropylcarbamate (0.50 g, 1.01 mmol) was
dissolved in TFA/CH.sub.2Cl.sub.2(50/50, 5.0 mL) at rt. After 0.5
h., the TFA/CH.sub.2Cl.sub.2 was removed in vacuo and the reside
was partitioned between CH.sub.2Cl.sub.2 (100 mL) and 1.0N NaOH (50
mL). The organic layer was washed with water (1.times.25 mL), brine
(1.times.25 mL), dried (MgSO.sub.4), filtered, and evaporated to
give the free base. To a solution of the free base in CH.sub.3CN
(10 mL) was added DIEA (0.175 mL, 1.01 mmol) and
2,5-dioxo-1-pyrrolidinyl[(3S)tetrahydro-3-furanyl]carbonat- e
(0.213 g, 0.93 mmol) respectively with stirring at rt. After 1.0
h., the reaction mixture was evaporated and the crude residue
purified by column chromatography: 40/60 hexane/ethyl acetate to
give the product as a white solid (0.320 g, 63%). MS: M+NA=530.
.sup.1H NMR (CD.sub.3OD) 1.25 (m, 6H); 1.80 (m, 1H); 2.05 (m, 1H);
2.403.10 (m, 4H); 3.45 (d, 1H); 3.75 (m, 1H); 3.70-3.90 (m, 5H);
4.50 (m, 1H); 4.95 (m, 1H); 6.90 (d, 1H); 7.05 (d, 1H); 7.10-7.35
(m, 7H).
Example 62
[0448] 671
[0449] (3S)tetrahydro-3-furanyl
N-((1S,2R)-1-benzyl-2-hydroxy-3-isopropoxy-
[(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-5-yl)sulfonyl]aminopropyl)carbamat-
e. Prepared using the procedure outlined in Example 61. The product
was purified by column chromatography: 97/3 CH.sub.2Cl.sub.2/MeOH
and isolated as a white solid (40%). MS: M+H=549 .sup.1H NMR
(CD.sub.3OD) 1.25 (m, 6H); 1.60 (m, 1H); 1.95 (m, 1H); 2.40-3.10
(m, 4H); 3.40 (d, 1H); 3.70-3.90 (m, 5H); 4.55 (m, 1H); 4.90 (m,
1H); 7.20 (m, 5H); 7.80 (m, 2H) 8.20 (s, 1H); 8.40 (s, 1H) 7.20 (m,
6H); 7.50 (m, 2H).
Example 63
[0450] 672
[0451] (3S)tetrahydro-3-furanyl
N-(1S,2R)-3-[(1H-1,3-benzimidazol-5-ylsulf-
onyl)(isopropoxy)amino]-1-benzyl-2-hydroxypropylcarbamate. Prepared
using the procedure outlined in Example 6. The product was purified
by column chromatography: 97/3 CH.sub.2Cl.sub.2/MeOH and isolated
as white solid (31%). MS: M+H=533 .sup.1H NMR (CD.sub.3OD) 1.25 (m,
6H); 1.60 (m, 1H); 1.95 (m, 1H); 2.40-3.10 (m, 4H); 3.40 (d, 1H);
3.70-3.90 (m, 5H); 4.55 (m, 1H); 4.90 (m, 1H); 7.20 (m, 5H); 7.80
(m, 2H) 8.20 (s, 1H); 8.40 (s, 1H).
Example 64
[0452] 673
[0453] (3S)tetrahydro-3-furanyl
N-((1S,2R)-1-benzyl-3-(cyclohexyloxy)[(4-m-
ethoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate.
[0454] tert-butyl
N-((1S,2R)-1-benzyl-3-(cyclohexyloxy)[(4-methoxyphenyl)s-
ulfonyl]amino-2-hydroxypropyl)carbamate (0.09 mmol, 50 mg) was
dissolved in a 1:1 solution of CH.sub.2Cl.sub.2/TFA (1 mL) and
allowed to stir at room temperature for 1 hour. The solution was
then extracted into ethyl acetate, washed with saturated sodium
bicarbonate solution and brine, dried over magnesium sulfate, and
concentrated to a clear oil. The resulting oil was then dissolved
in THF (1 mL) and combined with
2,5-dioxo-1-pyrrolidinyl[(3S)tetrahydro-3-furanyl]carbonate (0.05
mmol, 13 mg) DIEA (0.08 mmol, 14 .mu.L) and allowed to stir for 15
hours. The reaction was neutralized by the addition of acetic acid
and partitioned between water and ethyl acetate. The organic layer
was washed with saturated sodium bicarbonate and brine, and dried
over magnesium sulfate. The crude product was concentrated to a
white solid and purified by silica gel chromatography (1:1
hexanes/ethyl acetate), providing 19 mg (37%) of a white solid.
H1-NMR (CDCl.sub.3): .delta. 7.70 (2H, d), 7.29-7.17 (6H, m), 6.97
(2H, d), 5.1 (1H, s), 4.76 (1H, d), 4.17 (1H, m), 3.86 (3H, s),
3.87-3.70 (6H, m), 3.68-3.60 (1H, m), 3.06 (1H, bs), 2.89 (2H, m),
2.02 (3H, m), 1.89 (1H, m), 1.71 (2H, m),1.28-1.08 (6H, m); MS
(ESI): M+Na=585.
Example 65
[0455] 674
[0456] 1,3-dioxan-5-yl
N-((1S,2R)-1-benzyl-3-(cyclohexyloxy)[(4-methoxyphe-
nyl)sulfonyl]amino-2-hydroxypropyl)carbamate.
[0457] tert-butyl
N-((1S,2R)-1-benzyl-3-(cyclohexyloxy)[(4-methoxyphenyl)s-
ulfonyl)amino-2-hydroxypropyl)carbamate (0.09 mmol, 50 mg) was
stirred in 1 mL trifluoroacetic acid (TFA) at room temperature for
5 hours. The TFA was removed under vacuum, and the resulting
residue was dissolved in ethyl acetate, washed with 5% aq.
potassium carbonate solution, brine, dried over magnesium sulfate,
and concentrated to a residue. The resulting free amine,
1,3-dioxan-5-yl 4-nitrophenyl carbonate (0.09 mmol, 25 mg),
diisopropylethylamine (0.14 mmol, 0.024 mL), a crystal of
N,N-dimethylaminopyridine, 4 .ANG. molecular sieves and
acetonitrile (0.5 mL) were combined and stirred at room temperature
for 20 hours. The reaction solution was concentrated to a residue,
dissolved in ethyl acetate, washed with 1N HCl, 5% aq. potassium
carbonate solution, brine, dried over magnesium sulfate, and
concentrated under vacuum. The crude residue was purified by silica
gel chromatography (2:1 hexanes/ethyl acetate) and crystallization
from ether and hexanes to yield 10 mg (19%) of white solid. R. =0.2
(2:1 hexanes/ethyl acetate); H1-NMR (CDCl.sub.3): .delta. 7.69 (2H,
d), 7.29-7.18 (6H, m), 6.96 (2H, d), 5.01-4.93 (1H, m), 4.93-4.85
(1H, m), 4.74-4.70 (1H, m), 4.51-4.45 (1H, m), 4.22-4.11 (1H, m),
3.95-3.72 (7H, m), 3.86 (3H, s), 3.00-2.80 (3H, m), 2.10-1.97 (2H,
m), 1.79-1.67 (2H, m), 1.61-1.53 (2H, m), 1.38-1.02 (6H, m); MS
(ESI): M+H=580.
Example 66
[0458] 675
[0459] (2S)-N.sup.1-((S, 2R)-1-benzyl-3-(cyclohexyloxy)
(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)-2-[(2-quinolinylcarbonyl-
)amino]butanediamide.
[0460] tert-butyl
N-((1S,2R)-1-benzyl-3-(cyclohexyloxy)[(4-methoxyphenyl)s-
ulfonyl]amino-2-hydroxypropyl)carbamate (0.18 mmol, 100 mg) was
stirred in 1 mL trifluoroacetic acid (TFA) at room temperature for
1 hour. The TFA was removed under vacuum, and the resulting residue
was dissolved in ethyl acetate, washed with 5% aq. potassium
carbonate solution, brine, dried over magnesium sulfate, and
concentrated to a residue. The resulting free amine,
(2S)-4-amino-4-oxo-2-[(2-quinolinylcarbonyl)amino]b- utanoic acid
hydrochloride (0.18 mmol, 56 mg), 1-hydroxybenzotriazole hydrate
(0.18 mmol, 25 mg), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimid-
e hydrochloride (0.20 mmol, 38 mg), diisopropylethylamine (0.91
mmol, 0.157 mL) and anhydrous N,N-dimethylformamide (0.5 mL) were
combined at room temperature and stirred for 15 hours. The crude
reaction mixture was concentrated to a residue, dissolved in ethyl
acetate, washed with 1N HCl, 5% aq. potassium carbonate solution,
brine and dried over magnesium sulfate. The solution was
concentrated to a residue, purified by silica gel chromatography
(ethyl acetate), and lyophylized providing a fluffy white solid.
H-1-NMR (CDCl.sub.3): .delta. 9.19-9.17 (1H, m), 8.32-8.30 (1H, m),
8.23-8.16 (2H, m), 7.89-7.87 (1H, m), 7.79-7.76 (3H, m), 7.65-7.61
(1H, m), 7.13-7.11 (2H, m), 7.05-6.94 (6H, m), 5.73-5.64 (1H, m),
5.41-5.33 (1H, m), 4.96-4.85 (1H, m), 4.28-4.08 (2H, m), 3.89-3.74
(1H, m), 3.86 (3H, s), 3.25 (1H, bs), 2.95-2.79 (5H, m), 2.65-2.60
(1H, m), 2.04 (2H, bs), 1.70 (2H, bs), 1.57-1.41 (1H, m), 1.30-1.10
(5H, m); MS (ESI): M+H=719.
Example 67
[0461] 676
[0462]
N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(sec-butoxy)-4-methox-
ybenzene-sulfonamide.
[0463] tert-butyl
N-((1S,2R)-1-benzyl-3-sec-butoxy[(4-methoxyphenyl)sulfon-
yl)amino-2-hydroxy-propyl)carbamate (1.9 mmol, 1 g) was stirred in
neat trifluoroacetic acid (TFA) at room temperature for 1 hour. The
TFA was removed under vacuum, and the resulting residue was
dissolved in ethyl acetate, washed with 5% aq. potassium carbonate
solution, brine and dried over magnesium sulfate. The dried
solution was concentrated under vacuum and stored as a sticky white
solid. H1-NMR (CDCl.sub.3): .delta. 7.81 (2H, d), 7.28-7.16 (5H,
m), 7.01 (2H, d), 4.31 (2H, bs), 4.01-3.90 (1H, bs), 3.88 (3H, s),
3.5-2.5 (1H, bs), 3.33 (2H, bs), 2.89 (2H, bs), 2.63 (2H, bs), 1.71
(1H, bs), 1.43-1.40 (1H, m), 1.27-1.19 (3H, m), 0.98-0.85 (3H, m);
MS (ESI): M+H=423. 677
[0464] (3S)tetrahydro-3-furanyl
N-((1S,2R)-1-benzyl-3-sec-butoxy[(4-methox-
yphenyl)sulf-onyl]amino-2-hydroxypropyl)carbamate.
[0465]
N-[(2R,35)-3-amino-2-hydroxy-4-phenylbutyl]-N-(sec-butoxy)-4-methox-
ybenzenesulfon-amide (0.12 mmol, 50 mg),
1-([(3S)tetrahydro-3-furanyloxy]c-
arbonyloxy)dihydro-1H-pyrrole-2,5-dione (0.12 mmol, 29 mg),
diisopropylethylamine (0.18 mmol, 0.031 mL) and anhydrous THF (1
mL) were combined and stirred at room temperature for 20 hours. The
reaction product was concentrated to a residue, purified directly
by silica gel chromatography (2:1 hexanes/ethyl acetate) and
crystallized from diethyl ether providing 40 mg (63%) of a white
crystal. H1-NMR (CDCl.sub.3): .delta. 7.74-7.70 (2H, m), 7.30-7.17
(6H, m), 7.00-6.96 (2H, m), 5.11 (1H, bs), 4.75 (1H, bs), 4.31-4.30
(1H, m), 3.87 (3H, s), 3.87-3.75 (6H, m), 3.65-3.60 (1H, m),
3.21-2.64 (1H, bs), 2.89 (2H, bs), 2.15-2.01 (1H, m), 1.95-1.78
(1H, m), 1.78-1.58 (1H, m), 1.47-1.32 (1H, m), 1.24-1.13 (3H, m),
0.94-0.84 (3H, m); MS (ESI): M+Na=560.
Example 68
[0466] 678
[0467] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-se-
c-butoxy[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate.
[0468]
N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(sec-butoxy)-4-methox-
ybenzenesulfon-amide (step 1, Example 67) (0.12 mmol, 50 mg) was
combined with (2R,3aS,6aR)hexahydrofuro[2,3-b]furan-2-yl
4-nitrophenyl carbonate (0.12 mmol, 35 mg), diisopropylethylamine
(0.18 mmol, 0.031 mL) and acetonitrile (1 mL). The reaction was
allowed to stir at room temperature for 15 hours, then heated to
reflux for a minute and cooled to room temperature. The reaction
was concentrated to a yellow oil, dissolved in ethyl acetate,
washed with 1N HCl, saturated aq. sodium bicarbonate solution,
brine and dried over magnesium sulfate. The crude product was
purified by silica gel chromatgraphy (1:1 hexanes/ethyl acetate)
and crystallization from an ether/hexanes solution to yield 30 mg
(43%) of white crystals. R.sub.f=0.2 (1:1 hexanes/ethyl acetate);
H1-NMR (CDCl.sub.3): .delta. 7.74-7.71 (2H, m), 7.28-7.14 (6H, m),
7.00-6.97 (2H, m), 5.63-5.62 (1H, m), 5.05-4.93 (1H, m), 4.87-4.75
(1H, m), 4.36-4.23 (1H, m), 3.98-3.76 (4H, m), 3.87 (3H, s), 3.68
(2H, m), 3.10 (1H, bs), 3.08-2.70 (6H, m),1.77-1.57 (1H, m),
1.50-1.32 (1H, m), 1.23-1.18 (3H, m), 0.93-0.86 (3H, m); MS (ESI):
M+Na=601.
Example 69
[0469] 679
[0470] 1,3-dioxan-5-yl
N-((1S,2R)-1-benzyl-3-sec-butoxy[(4-methoxyphenyl)s-
ulfonyl]amino-2-hydroxypropyl)carbamate.
[0471]
N[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(sec-butoxy)-4-methoxy-
benzenesulfon-amide (Step 1, Example 67) (0.09 mmol, 38 mg),
1,3-dioxan-5-yl 4-nitrophenyl carbonate (0.09 mmol, 24 mg),
diisopropylethylamine (0.13 mmol, 0.024 mL), 4 .ANG. molecular
sieves, a crystal of N,N-dimethylaminopyridine and acetonitrile (1
mL) were combined and allowed to stir for 20 hours at room
temperature. The reaction was then concentrated to a residue,
dissolved in ethyl acetate, washed with 1N HCl, 5% aq. potassium
carbonate solution, brine, and dried over magnesium sulfate. The
reaction was purified directly by crystallization from a solution
of diethyl ether and hexanes to yield 30 mg (60%) of white
crystals. R.sub.f=0.7 (1:1 hexanes/ethyl acetate); H1-NMR
(CDCl.sub.3) .delta. 7.72-7.69 (2H, m), 7.29-7.18 (6H, m),
6.98-6.95 (2H, m), 5.03-4.93 (1H, m), 4.93-4.87 (1H, m), 4.76-4.69
(1H, m), 4.53-4.44 (1H, m), 4.38-4.25 (1H, m), 3.95-3.72 (7H, m),
3.86 (3H, s), 3.24-2.62 (3H, m), 1.76-1.60 (1H, m), 1.47-1.29 (1H,
m), 1.22-1.16 (3H, m), 0.94-0.83 (3H, m); MS (ESI): M+H=553.
Example 70
[0472] 680
[0473] N-(sec-butoxy)-N-[(2R,
3S)-2-hydroxy-3-(3-hydroxy-2-methylanilino)--
4-phenylbutyl]-4-methoxybenzenesulfonamide.
N-[(2R,3S)-3-amino-2-hydroxy-4-
-phenylbutyl]-N-(sec-butoxy)-4-methoxybenzenesulfon-amide (Step 1,
Example 67)(0.12 mmol, 50 mg), 3-hydroxy-2-methylbenzoic acid (0.12
mmol, 18 mg), 1-hydroxybenzotriazole hydrate (0.12 mmol, 16 mg),
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.13
mmol, 25 mg), diisopropylethylamine (0.14 mmol, 0.025 mL) and
anhydrous N,N-dimethylformamide (0.5 mL) were combined at room
temperature and stirred for 18 hours. The crude reaction mixture
was concentrated to a residue, dissolved in ethyl acetate, washed
with 1N HCl, 5% aq. potassium carbonate solution, brine and dried
over magnesium sulfate. The solution was concentrated to a residue,
purified by RPHPLC (water/acetonitrile) and lyophylized providing
20 mg (30%) of a white solid. HL-NMR (CDCl.sub.3): .delta.
7.76-7.73 (2H, m), 7.32-7.23 (5H, m), 7.00-6.97 (3H, m), 6.78-6.76
(1H, m), 6.56-6.53 (1H, m), 5.90 (1H, bs), 4.42-4.27 (2H, m),
4.09-3.95 (1H, m), 3.87 (3H, s), 3.25-2.27 (5H, m), 2.05-1.95 (3H,
m), 1.77-1-0.58 (1H, m), 1.55-1.22 (1H, m), 1.24-1.20 (3H, m),
0.93-0.86 (3H, m); MS (ESI): M+H=557.
Example 71
[0474] 681
[0475]
(2S)-N-((1S,2R)-1-benzyl-3-sec-butoxy[(4-methoxyphenyl)sulfonyl]ami-
no-2-hydroxypropyl)-2-[(2-quinolinylcarbonyl)amino]butanediamide.
[0476]
N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(sec-butoxy)-4-methox-
ybenzenesulfon-amide (Step 1, Example 67) (0.114 mmol, 48 mg),
(25)-4-amino-4-oxo-2-[(2-quinolinylcarbonyl)amino]butanoic acid
hydrochloride (0.136 mmol, 42 mg), 1-hydroxybenzotriazole hydrate
(0.136 mmol, 19 mg), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (0.148 mmol, 28 mg), diisopropylethylamine (5.68
mmol, 0.990 mL) and anhydrous N,N-dimethylformamide (0.5 mL) were
combined at room temperature and stirred for 15 hours. The crude
reaction mixture was concentrated to a residue, dissolved in ethyl
acetate, washed with 1N HCl, 5% aq. potassium carbonate solution,
brine and dried over magnesium sulfate. The solution was
concentrated to a residue, purified by silica gel chromatography
(1:1 hexanes/ethyl acetate) and crystallization from ether and
hexanes, providing 20 mg (25%) of a pink solid. H1-NMR
(CDCl.sub.3): .delta. 9.20-9.18 (1H, m), 8.32-8.30 (1H, m),
8.22-8.16 (2H, m), 7.89-7.87 (1H, m), 7.80-7.76 (3H, m), 7.65-7.61
(1H, m), 7.14-7.11 (2H, m), 7.05-6.97 (6H, m), 5.76-5.64 (1H, bs),
5.49-5.26 (1H, m), 4.94-4.86 (1H, m), 4.36-4.14 (2H, m), 3.99-3.80
(1H, m), 3.86 (3H, s), 3.14 (1H, bs), 2.98-2.71 (5H, m), 2.71-2.59
(1H, m), 1.80-1.52 (1H, m), 1.48-1.30 (1H, m), 1.22-1.14 (3H, m),
0.94-0.80 (3H, m); MS (ESI): M+H=692.
Example 72
[0477] 682
[0478] (3S)tetrahydro-3-furanyl
N-(1S,2R)-1-benzyl-2-hydroxy-3-[[(4-methox-
yphenyl)sulfonyl](tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamate.
[0479] tert-butyl
N-(1S,2R)-1-benzyl-2-hydroxy-3-[[(4-methoxyphenyl)sulfon-
yl](tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamate, (Example
18), (0.09 mmol, 50 mg) was stirred in 1 mL trifluoroacetic acid
(TFA) at room temperature for 1 hour. The TFA was removed under
vacuum, and the resulting residue was dissolved in ethyl acetate,
washed with 1N HCl, 5% aq. potassium carbonate solution, brine, and
dried over magnesium sulfate. The resulting free amine,
1-([(3S)tetrahydro-3-furanyloxy]carbon-
yloxy)dihydro-1H-pyrrole-2,5-dione (0.09 mmol, 22 mg),
diisopropylethylamine (0.14 mmol, 0.024 mL) and acetonitrile (0.5
mL) were combined and stirred at room temperature for 30 minutes.
The reaction product was concentrated to a residue, dissolved in
ethyl acetate, washed with 1N HCl, 5% aq. potassium carbonate
solution, brine, and dried over magnesium sulfate. The crude
solution was concentrated, and the purified reaction product
crystallized out of diethyl ether providing 28 mg (55%) of a white
crystal. R.sub.f=0.1 (1:1 hexanes/ethyl acetate); H1-NMR
(CDCl.sub.3): .delta. 7.70 (2H, d), 7.32-7.15 (6H, m), 6.98 (2H,
d), 5.11 (1H, bs), 4.81-4.71 (1H, m), 4.44-4.35 (1H, m), 3.97-3.70
(8H, m), 3.87 (3H, s), 3.65 (1H, m), 3.52-3.33 (2H, m), 3.25-2.5
(1H, bs), 2.93-2.88 (2H, m), 2.12-1.95 (3H, m), 1.93-1.80 (1H, m),
1.57-1.41 (2H, m); MS (ESI): M+H=565.
Example 73
[0480] 683
[0481] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-2-hyd-
roxy-3-[[(4-methoxyphenyl)sulfonyl](tetrahydro-2H
-pyran-4-yloxy)amino]pro- pylcarbamate
[0482] tert-butyl
N-(1S,2R)-1-benzyl-2-hydroxy-3-[[(4-methoxyphenyl)sulfon-
yl](tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamate (Example 18),
(0.09 mmol, 50 mg) was stirred in 1 mL trifluoroacetic acid (TFA)
at room temperature for 1 hour. The TFA was removed under vacuum,
and the resulting residue was dissolved in ethyl acetate, washed
with 5% aq. potassium carbonate solution, brine, dried over
magnesium sulfate, and concentrated to a residue. The resulting
free amine, (2R,3aS,6aR)hexahydrofuro[2,3-b]furan-2-yl
4-nitrophenyl carbonate (0.09 mmol, 27 mg), diisopropylethylamine
(0.14 mmol, 0.024 mL), a crystal of N,N-dimethylaminopyridine, 4
.ANG. molecular sieves and acetonitrile (0.5 mL) were combined and
stirred at room temperature for 15 hours. The reaction solution was
concentrated to a residue, dissolved in ethyl acetate, washed with
1N HCl, 5% aq. potassium carbonate solution, brine, dried over
magnesium sulfate, and concentrated under vacuum. The crude residue
was purified by silica gel chromatography (1:1 hexanes/ethyl
acetate) and crystallization from ether and hexanes to yield 20 mg
36%) of white crystals. R.sub.f=0.2 (1:1 hexanes/ethyl acetate);
H1-NMR (CDCl.sub.3): .delta. 7.71 (2H, d), 7.31-7.12 (6H, m), 6.99
(2H, d), 5.65-5.61 (1H, m), 5.05-4.95 (1H, m), 4.90-4.72 (1H, m),
4.49-4.34 (1H, m), 4.00-3.76 (7H, m), 3.88 (3H, s), 3.71-3.60 (2H,
m), 3.48-3.35 (2H, m), 3.40-2.40 (1H, bs), 3.28-2.61 (5H, m),
3.04-2.71 (2H, m), 2.09-1.97 (2H, m); MS (ESI): M+H=607.
Example 74
[0483] 684
[0484] 1,3-dioxan-5-yl
N-(1S,2R)-1-benzyl-2-hydroxy-3-[[(4-methoxyphenyl)s-
ulfonyl](tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamate.
[0485] tert-butyl N-(1S,
2R)-1-benzyl-2-hydroxy-3-[[(4-methoxyphenyl)sulfo-
nyl](tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamate (Example
18), (0.09 mmol, 50 mg) was stirred in 1 mL trifluoroacetic acid
(TFA) at room temperature for 5 hours. The TFA was removed under
vacuum, and the resulting residue was dissolved in ethyl acetate,
washed with 5% aq. potassium carbonate solution, brine, dried over
magnesium sulfate, and concentrated to a residue. The resulting
free amine, 1,3-dioxan-5-yl 4-nitrophenyl carbonate (0.08 mmol, 22
mg), diisopropylethylamine (0.14 mmol, 0.024 mL), a crystal of
N,N-dimethylaminopyridine, 4 .ANG. molecular sieves and
acetonitrile (0.5 mL) were combined and stirred at room temperature
for 20 hours. The reaction solution was concentrated to a residue,
dissolved in ethyl acetate, washed with 1N HCl, 5% aq. potassium
carbonate solution, brine, dried over magnesium sulfate, and
concentrated under vacuum. The crude residue was purified by silica
gel chromatography (1:1 hexanes/ethyl acetate) and crystallization
from ether and hexanes to yield 3 mg (6%) of white crystals.
R.sub.f=0.2 (1:1 hexanes/ethyl acetate); H1-NMR (CDCl.sub.3):
.delta. 7.69 (2H, d), 7.32-7.17 (6H, m), 6.98 (2H, d), 5.02-4.94
(1H, m), 4.94-4.87 (1H, m), 4.76-4.69 (1H, m), 4.53-4.45 (1H, m),
4.45-4.34 (1H, m), 4.00-3.70 (9H, m), 3.87 (3H, s), 3.49-3.30 (2H,
m), 3.10 (1H, bs), 3.47-3.35 (2H, m), 2.99-2.78 (2H, m), 2.07-1.95
(2H, m); MS (ESI): M+H=581.
Example 75
[0486] 685
[0487]
N-(1S,2R)-1-benzyl-2-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](tetrahy-
dro-2H-pyran-4-yloxy)amino]propyl-3-hydroxy-2-methylbenzamide.
[0488] tert-butyl
N-(1S,2R)-1-benzyl-2-hydroxy-3-[[(4-methoxyphenyl)sulfon-
yl](tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamate (Example 18),
(0.10 mmol, 54 mg) was stirred in 1 mL trifluoroacetic acid (TFA)
at room temperature for 5 hours. The TFA was removed under vacuum,
and the resulting residue was dissolved in ethyl acetate, washed
with 5% aq. potassium carbonate solution, brine, dried over
magnesium sulfate, and concentrated to a residue. The resulting
free amine, 3-hydroxy-2-methylbenzoic aced (0.10 mmol, 15 mg),
1-hydroxybenzotriazole hydrate (0.10 mmol, 14 mg),
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimid- e hydrochloride
(0.11 mmol, 21 mg), diisopropylethylamine (0.15 mmol, 0.026 mL) and
anhydrous N,N-dimethylformamide (0.5 mL) were combined at room
temperature and stirred for 20 hours. The crude reaction mixture
was concentrated to a residue, dissolved in ethyl acetate, washed
with 1N HCl, 5% aq. potassium carbonate solution, brine and dried
over magnesium sulfate. The solution was concentrated to a residue,
and purified by crystallization from ether and hexanes providing 21
mg (37%) of a white solid. R.sub.f=0.2 (1:1 hexanes/ethyl acetate);
H1-NMR (CDCl.sub.3): .delta. 7.73 (2H, d), 7.33-7.17 (5H, m),
7.02-6.94 (3H, m), 6.77 (1H, d), 6.53 (1H, d), 5.84-5.76 (1H, m),
4.49-4.28 (2H, m), 3.99-3.89 (3H, m), 3.87 (3H, s), 3.47-3.35 (2H,
m), 3.50-2.50 (1H, bs), 3.14-3.04 (2H, m), 3.00-2.88 (2H, m),
2.08-1.88 (2H, m), 2.01 (3H, s), 1.7-1.3 (2H, m); MS (ESI):
M+H=585.
Example 76
[0489] 686
[0490]
(2S)-N-(1S,2R)-1-benzyl-2-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](te-
trahydro-2H-pyran-4-yloxy)amino]propyl-2-[(2-quinolinyl
carbonyl)amino]butanediamide.
[0491] tert-butyl
N-(1S,2R)-1-benzyl-2-hydroxy-3-[[(4-methoxyphenyl)sulfon-
yl](tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamate (Example 18),
(0.09 mmol, 50 mg) was stirred in 1 mL trifluoroacetic acid (TFA)
at room temperature for 5 hours. The TFA was removed under vacuum,
and the resulting residue was dissolved in ethyl acetate, washed
with 5% aq. potassium carbonate solution, brine, dried over
magnesium sulfate, and concentrated to a residue. The resulting
free amine,
(2S)-4-amino-4-oxo-2-[(2-quinolinylcarbonyl)amino]butanoic acid
hydrochloride (0.09 mmol, 28 mg), 1-hydroxybenzotriazole hydrate
(0.09 mmol, 13 mg), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (0.10 mmol, 19 mg), diisopropylethylamine (0.27 mmol,
0.047 mL) and anhydrous N,N-dimethylformamide (0.5 mL) were
combined at room temperature and stirred for 20 hours. The crude
reaction mixture was concentrated to a residue, dissolved in ethyl
acetate, washed with 1N HCl, 5% aq. potassium carbonate solution,
brine and dried over magnesium sulfate. The solution was
concentrated to a residue, purified by silica gel chromatography
(20:1 ethyl acetate/methanol) and crystallization from ether and
hexanes, providing 6 mg (8%) of a pink solid. H1-NMR (CDCl.sub.3):
.delta. 9.18 (1H, d), 8.31 (1H, d), 8.24-8.13 (2H, m), 7.88 (1H,
d), 7.80-7.74 (3H, m), 7.66-7.60 (1H, m), 7.15-7.08 (2H, m),
7.08-6.93 (6H, m), 5.74 (1H, bs), 5.46 (1H, bs), 4.94-4.85 (1H, m),
4.44-4.35 (1H, m), 4.27-4.18 (1H, m), 3.96-3.80 (3H, m), 3.88 (3H,
s), 3.47-3.34 (2H, m), 3.14 (1H, bs), 2.98-2.76 (5H, m), 2.72-2.60
(1H, m), 2.09-1.95 (2H, bs), 1.65-1.39 (2H, m); MS (ESI):
M+H=720.
Example 77
[0492] 687
[0493] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[[(3-aminoph-
enyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate.
This material was obtained from the corresponding m-nitro precursor
(Example 100, Step 1) via hydrogenation. The material was identical
to isomer 1 of Example 31.
Example 78
[0494] 688
[0495] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(c-
yclohexyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate.
tert-butyl N-((1S,
2R)-1-benzyl-3-(cyclohexyloxy)[(4-methoxyphenyl)sulfon-
yl]amino-2-hydroxypropyl)carbamate (0.09 mmol, 50 mg) was stirred
in 1 mL trifluoroacetic acid (TFA) at room temperature for 5 hours.
The TFA was removed under vacuum, and the resulting residue was
dissolved in ethyl acetate, washed with 5% aq. potassium carbonate
solution, brine, dried over magnesium sulfate, and concentrated to
a residue. The resulting free amine,
(2R,3aS,6aR)hexahydrofuro[2,3-b]furan-2-yl 4-nitrophenyl carbonate
(0.09 mmol, 27 mg), diisopropylethylamine (0.13 mmol, 0.018 mL), a
crystal of N,N-dimethylaminopyridine, 4 .ANG. molecular sieves and
acetonitrile (0.5 mL) were combined and stirred at room temperature
for 3 days. The reaction solution was concentrated to a residue,
dissolved in ethyl acetate, washed with 1N HCl, 5% aq. potassium
carbonate solution, brine, dried over magnesium sulfate, and
concentrated under vacuum. The crude residue was purified by
crystallization from ether to yield 15 mg (27%) of white crystals.
H1-NMR (CDCl.sub.3): .delta. 7.71 (2H, d), 7.28-7.16 (6H, m), 6.97
(2H, d), 5.63-5.61 (1H, m), 5.00-4.98 (1H, m), 4.87-4.77 (1H, m),
4.24-4.11 (1H, m), 3.98-3.79 (4H, m), 3.87 (3H, s), 3.72-3.61 (2H,
m), 3.05 (1H, bs), 3.05-2.72 (6H, m), 2.10-1.98 (2H, m), 1.78-1.68
(2H, m), 1.37-1.04 (6H, m); MS (ESI): M+H=605.
Example 79
[0496] 689
[0497] (3S,3aR,7aS)hexahydro-4H-furo[2,3-b]pyran-3-yl
N-(1S,2R)-3-[[(3-aminophenyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-h-
ydroxypropylcarbamate+(3R,3aS,7aR)hexahydro-4H-furo[2,3-b]pyran-3-yl
N-(1S,
2R)-3-[[(3-aminophenyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2--
hydroxypropylcarbamate.
[0498] A mixture of
(3R,3aS,7aR)+(3S,3aR,7aS)hexahydro-4H-furo[2,3-b]pyran-
-3-yl(4-nitrophenyl)carbonate (332 mg, 1.074 mmol, WC 9633187),
3-amino-N.sup.1-[(2R,
3S)-3-amino-2-hydroxy-4-phenylbutyl]-N.sup.1-(cyclo- pentyloxy)
-1-benzenesulfonamide (Step 1, Example 27), (150 mg, 0.358 mmol)
and N,N-diisopropylethylamine (249 .mu.L, 1.432 mmol) were combined
in approximately 3 mL of acetonitrile and stirred at ambient
temperature under an Argon atmosphere for 18 hours. The reaction
solvent was removed in vacuo and the residue was partitioned
between dichloromethane and 1N NaOH. After separating the layers,
the aqueous phase was extracted with dichloromethane. The combined
organic layers were combined, dried over anhydrous magnesium
sulfated, filtered and evaporated in vacuo. The residue was
purified on three preparative silica gel TLC plates (20.times.20
cm, 1000 .mu.M) eluting with 65:35 ethyl acetate:hexane. The
product band was removed, eluted with 4:1 methylene
chloride:methanol, filtered, and evaporated in vacuo. The residue
was dissolved in dichloromethane, dried over anhydrous magnesium
sulfate, filtered, evaporated in vacuo, and dried under high vacuum
to provide a 1:1 mixture of
(3S,3aR,7aS)hexahydro-4H-furo[2,3-b]pyran-3-yl
N-(1S,2R)-3-[[(3-aminop-
henyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate
and (3R,3aS,7aR)hexahydro-4H-furo[2,3-b]pyran-3-yl
N-(1S,2R)-3-[[(3-aminophenyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-h-
ydroxypropylcarbamate (146 mg, 69%) as a foam. HL-NMR (methanol-D4)
1.14 (m, 1H), 1.78 (m, 11H), 2.56 (m, 1H), 3.05 (m, 3H), 3.41 (m,
1H), 3.76 (m, 5H), 4.06 (m, 1H), 4.84 (m, 1H), 4.96 (m, 1H), 5.06
(m, 1H), 6.93 (m, 1H), 7.02 (m, 1H), 7.09 (m, 1H), 7.14 (m, 1H),
7.22 (m, 5H). MS (ESI): 612 (M+Na).
Example 80
[0499] 690
[0500] tert-butyl
N-[(1S,2R)-1-benzyl-3-hydrazino-2-hydroxypropyl]carbamat- e.
[0501] A mixture of tert-butyl
N-(1S)-1-[(2S)oxiran-2-yl]-2-phenylethylcar- bamate (2.50 g, 9.51
mmol) and anhydrous hydrazine (3.00 mL, 95.0 mmol) in 15 mL of
isopropanol was heated at reflux under an Argon atmosphere for 18
hours. The reaction solvent was removed in vacuo and the residue
was triturated with diethylether, filtered and dried under high
vacuum to provide tert-butyl
N-[(1S,2R)-1-benzyl-3-hydrazino-2-hydroxypropyl]carbam- ate (1.766
g, 63%) as a white solid. H1-NMR (chloroform-D3) 1.35 (d, 9H), 1.67
(b, 4H), 2.89 (m, 4H), 3.91 (m, 3H), 4.63 (m, 1H), 7.25 (m, 5H). MS
(ESI): 318 (M+Na). 691
[0502] tert-butyl
N--C(1S,2R)-1-benzyl-3-(2-cyclopentylidenhydrazino)-2-hy-
droxypropyl]carbamate.
[0503] A solution of tert-butyl
N-[(1S,2R)-1-benzyl-3-hydrazino-2-hydroxyp- ropyl]carbamate (500
mg, 1.695 mmol) in 5 mL of isopropanol under Argon was treated with
cyclopentanone (180 .mu.L, 2.034 mmol). After stirring for
approximately 18 hours, the reaction solvent was removed in vacuo
and the residue was triturated with diethylether. The slurry was
filtered and the solid was dried under high vacuum to provide
tert-butyl
N-[(1S,2R)-1-benzyl-3-(2-cyclopentylidenhydrazino)-2-hydroxypropyl]carbam-
ate (85 mg, 14%) as a white solid. H1-NMR (chloroform-D3) 1.34 (s,
9H), 1.54 (b, 2H), 1.73 (m, 2H), 1.83 (m, 2H), 2.22 (m, 2H), 2.35
(m, 2H), 2.90 (m, 1H), 3.02 (m, 1H), 3.14 (m, 1H), 3.38 (m, 1H),
3.64 (bm, 1H), 3.84 (bm, 1H), 4.52 (m, 1H), 7.25 (m, 5H). MS
(APCI): 361(M+Na). 692
[0504] tert-butyl
N-((1S,2R)-1-benzyl-3-2-cyclopentyliden-1-[(4-methoxyphe-
nyl)sulfonyl]hydrazino-2-hydroxypropyl)carbamate.
[0505] A solution of tert-butyl
N-[(1S,2R)-1-benzyl-3-(2-cyclopentylidenhy- drazino)
-2-hydroxypropyl]carbamate (76 mg, 0.210 mmol) in 2 mL of
dichloromethane at ambient temperature under Argon was treated with
4-methoxyphenylsulphonylchloride (46 mg, 0.221 mmol) and
N,N-diisopropylethylamine (38.5 .mu.L, 0.221 mmol) and allowed to
stir at ambient temperature over approximately 18 hours. The
reaction solvent was removed in vacuo and the residue was purified
on flash grade silica gel eluting with 2:3 ethyl acetate:hexane.
Fractions containing the product were combined, evaporated in vacuo
to a residue and triturated with hexane and diethyl ether. The
solvents were removed in vacuo and the residual solid was dried
under high vacuum to provide tert-butyl
N-((1S,2R)-1-benzyl-3-2-cyclopentyliden-1-[(4-methoxyphenyl)sulfonyl]hydr-
azino-2-hydroxypropyl) carbamate (26 mg, 23%) as a solid. H1-NMR
(chloroform-D3): 1.34 (m, 9H), 1.62 (m, 4H), 1.83 (m, 2H), 2.42 (m,
H), 2.87 (m, 3H), 3.12 (m, 1H), 3.58 (m, 1H), 3.83 (m, 5H), 4.32
(m, 1H), 4.57 (b, 1H), 6.97 (m, 2H), 7.20 (m, 5H), 7.69 (m, 2H). MS
(APCI): 554(M+Na).
Example 81
[0506] 693
[0507] tert-butyl
N-((1S,2R)-1-benzyl-2-hydroxy-3-1-[(4-methoxyphenyl)sulf-
onyl]-2-[(Z)-2-methylpropylidene]hydrazinopropyl)carbamate.
[0508] A solution of tert-butyl
N-[(1S,2R)-1-benzyl-3-hydrazino-2-hydroxyp- ropyl]carbamate (Step
1, Example 80), (100 mg, 0.339 mmol) in approximately 2 mL of
dichloromethane under Argon was treated with isobutyraldehyde (46.2
.mu.L, 0.508 mmol). After stirring at ambient temperature for 20
minutes, 4-methoxyphenylsulphonylchloride (77 mg, 0.372 mmol) and
N,N-diisopropylethylamine (88.6 .mu.L, 0.508 mmol) were added and
the reaction was maintained for an additional 18 hours. The
reaction mixture was evaporated in vacuo and purified on flash
grade silica gel eluting with 3:7 ethyl acetate hexane. Fractions
containing the product were combined, evaporated in vacuo, and
crystallized from ethyl acetate and hexane. The slurry was
filtered, washed with hexane, and dried under high vacuum to
provide tert-butyl N-((1S,2R)-1-benzyl-2-h-
ydroxy-3-1-[(4-methoxyphenyl)sulfonyl]-2-[(Z)-2-methylpropylidene]hydrazin-
opropyl)carbamate (34 mg, 19%) as a solid. H1-NMR (chloroform-D3):
1.00 (m, 6H), 1.44 (s, 9H), 1.77 (m, 1H), 2.57 (m, 1H), 2.94 (m,
3H), 3.54 (m, 1H), 3.93 (s, 3H), 3.94 (m, 2H), 4.35 (m, 1H), 7.02
(m, 2H), 7.17 (m, 2H), 7.31 (m, 4H), 7.81 (m, 2H). MS (ESI): 542
(M+Na).
Example 82
[0509] 694
[0510] tert-butyl
N-(1S,2R)-3-[(1H-benzimidazol-6-ylsulfonyl)(cyclopentylo-
xy)amino]1-benzyl-2-hydroxypropylcarbamate.
[0511] A solution of tert-butyl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(3,-
4-diaminophenyl)sulfonyl]amino-2-hydroxypropyl)carbamate (Step 4,
Example 10), (0.600 g, 1.12 mmol) in absolute ethanol (15 mL) was
treated with triethylorthoformate (280 .mu.L, 1.69 mmol) followed
by trifluoroacetic acid (15 .mu.L, 0.19 mmol). After stirring at
ambient temperature under an Argon atmosphere for 1.5 hrs., the
reaction mixture was quenched with several drops of 5% w/v aqueous
potassium carbonate and evaporated in vacuo. The residue was
purified on flash grade silica gel sequentially eluting with 4:1
ethyl acetate:hexane (0.5 L); ethyl acetate (0.5 L); and 95:5 ethyl
acetate: methanol (0.5 L). Fractions containing the product were
combined, evaporated in vacuo to a residue and dried under high
vacuum to provide tert-butyl
N-(1S,2R)-3-[(1H-benzimidazol-6-ylsulfonyl)(-
cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate (0.570 g,
93%). H1-NMR (dimethylsulfoxide-D6): 1.14 (s, 9H), 1.72 (m, 8H),
2.47 (m, 1H), 2.70 (m, 1H), 2.99 (m, 2H), 3.55 (m, 2H), 4.85 (m,
1H), 5.14 (m, 1H), 6.67 (d, 1H), 7.20 (m, 6H), 7.61 (d, 1H), 7.81
(d, 1H), 8.04 (s, 1H), 8.52 (s, 1H). MS (ESI): 545 (M+H).
Example 83
[0512] 695
[0513] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(3[(2-amino-
ethyl)amino]phenylsulfonyl)(cyclopentyloxy)amino]-1-benzyl-2-hydroxypropyl-
carbamate and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(3[(2-aminoethyl)amino]phenylsulfonyl)(cyclopentyloxy)amino]-
-1-benzyl-2-hydroxypropylcarbamate.
[0514] A solution of 25 mg (0.041 mmol) of a 1:1 mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(3-[(cya-
nomethyl)amino]phenylsulfonyl)(cyclopentyloxy)amino]-2-hydroxypropylcarbam-
ate and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N,-(1S,2R)-1-benzyl-3-[-
(3-[(cyanomethyl)amino]phenylsulfonyl)(cyclopentyloxy)amino]-2-hydroxyprop-
ylcarbamate (see example 86) in 8 mL of 2M NH.sub.3/MeOH in a Parr
bottle was treated with approximately 20 mg of Raney nickel. The
resulting mixture was subjected to hydrogenation at 30 psi for 1
hour. The vessel was purged, catalyst removed by filtration through
celite and the filtrate concentrated in vacuo. The residue was
dissolved in a minimum volume of CH.sub.2Cl.sub.2 and the solution
added dropwise to rapidly stirred 1:1 ether/hexane. A white solid
precipitated which was collected by filtration and dried in vacuo.
yield=16 mg (64%). .sup.1H-NMR (DMSO-d.sub.6): 7.32-7.03 (7H),
6.95-6.78 (3H), 6.20 (1H), 5.45 (1H), 5.19 (1H), 4.82-4.65 (2H),
3.81-3.40 (7H), 3.18-2.60 (9H), 2.39 (1H), 1.93-1.04 (10H). MS
(ESI): 619 (M+H).
Example 84
[0515] 696
[0516] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[[(3-[2-(ace-
tylamino)ethyl]aminophenyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydr-
oxypropylcarbamate and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[[(3-[2-(acetylamino)ethyl]aminophenyl)sulfonyl](cyclopentylo-
xy)amino]-1-benzyl-2-hydroxypropylcarbamate.
[0517] A solution of 33 mg (0.053 mmol) of a 1:1 mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-(1S,
2R)-3-[(3-[(2-aminoethy-
l)amino]phenylsulfonyl)(cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarb-
amate and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(3-[(2-aminoethyl)amino]phenylsulfonyl)(cyclopentyloxy)amino-
]-1-benzyl-2-hydroxypropylcarbamate in 3 mL of anhydrous THF at
0.degree. C. was treated with 0.010 mL (0.058 mmol) of
N,N-diisopropylethylamine followed by 0.004 mL (0.06 mmol) of
acetyl chloride. The resulting solution was allowed to warm to RT
with stirring. After 18 hours the solution was concentrated in
vacuo and the residue subjected to flash chromatography (silica
gel, 95:5 CH.sub.2Cl.sub.2/2M NH.sub.3 in MeOH) to afford 30 mg
(86%) of the desired product as a white foam. .sup.1H-NMR
(CDCl.sub.3): 7.71-7.00 (10H), 6.90 (1H), 6.40-6.02 (1H), 5.62
(1H), 5.32 (1H), 4.99 (1H), 4.80 (1H), 4.02-3.40 (7H), 3.38-2.60
(8H), 2.20-1.40 (13H). LCMS (ESI): 661 (M+H).
Example 85
[0518] 697
[0519] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(3-[(2-amin-
o-2-oxoethyl)amino]phenylsulfonyl)(cyclopentyloxy)amino]-1-benzyl-2-hydrox-
ypropylcarbamate and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(3[(2-amino-2-oxoethyl)amino]phenylsulfonyl)
(cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate.
[0520] A solution of 0.100 g (0.163 mmol) of a 1:1 mixture of
(3R,3aS, 6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(3-[(cyanomethyl-
)amino]phenylsulfonyl)(cyclopentyloxy)amino]-2-hydroxypropylcarbamate
and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl N-(1S,
2R)-1-benzyl-3-[(3-[(cy-
anomethyl)amino]phenylsulfonyl)(cyclopentyloxy)amino]-2-hydroxypropylcarba-
mate (see example 86) and 5.0 mg (0.033 mmol) of K.sub.2CO.sub.3 in
2 mL of 3:1 acetone/water was treated with 0.150 g (1.63 mmol) of
urea-hydrogen peroxide addition compound and stirred at RT. After
18 hours tic (silica gel, 95:5 CH.sub.2Cl.sub.2/MeOH) indicated no
remaining starting material at R.sub.f=0.43, a major new component
at R,=0.21, and a lesser component at R,=0.61. The solution was
diluted with CH.sub.2Cl.sub.2, washed with water (3.times.), dried
over anhydrous MgSO.sub.4, and concentrated. The residue was
subjected to flash chromatography (silica gel, 95:5
CH.sub.2Cl.sub.2/MeOH) to afford 49 mg (46%) of the R.sub.f=0.21
product as a white foam. .sup.1H-NMR (CDCl.sub.3): 7.46-6.92 (11H),
6.60-5.80 (2H), 5.60 (2H), 5.06-4.77 (2H), 4.03-3.40 (7H),
3.24-2.43 (6H), 1.91-1.32 (10H). LCMS (ESI): 633 (M+H).
Example 86
[0521] 698
[0522] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(3-
-[(cyanomethyl)amino]phenylsulfonyl)(cyclopentyloxy)amino]-2-hydroxypropyl-
carbamate and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(3-[(cyanomethyl)amino]phenylsulfonyl)(cyclo
pentyloxy)amino]-2-hydroxypropylcarbamate
[0523] A solution of 0.200 g (0.347 mmol) of a 1:1 mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclope-
ntyloxy)[(3-aminophenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclope-
ntyloxy)[(3-aminophenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
(see example 31), 0.050 mL (0.70 mmol) of bromoacetonitrile, and
0.12 mL (0.70 mmol) of N,N-diisopropylethylamine in 5 mL of
anhydrous DMF was heated to 80.degree. C. with stirring in a sealed
tube. After 21 hours the solution was cooled to RT and concentrated
in vacuo. The residue was dissolve in CH.sub.2Cl.sub.2. The
resulting solution was washed with aqueous brine (3.times.), dried
over anhydrous MgSO.sub.4, and concentrated to dryness. The crude
product was purified by flash chromatography (silica gel, 95:5
CHCl.sub.2/MeOH) to afford 145 mg (67%) of the desired product as a
tan solid. .sup.1H-NMR (DMSO-d.sub.6): 7.41 (1H), 7.28-6.99 (9H),
6.83 (1H), 5.46 (1H), 5.20 (1H), 4.82-4.63 (2H), 4.30 (2H),
3.80-3.40 (5H), 3.04-2.60 (5H), 2.40 (1H), 1.98-1.10 (10H). MS
(ESI): 615(M+H).
Example 87
[0524] 699
[0525] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(c-
yclopentyloxy)(3-[(2-morpholino-2-oxoethyl)amino]phenylsulfonyl)amino]-2-h-
ydroxypropylcarbamate and
(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(3-[(2-morpholino
-2-oxoethyl)amino]phenylsulfonyl)amino]-2-hydroxypropylcarbamate.
[0526] A solution of 0.100 g (0.174 mmol) of a 1:1 mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclope-
ntyloxy)[(3-aminophenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclope-
ntyloxy)[(3-aminophenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
(see example 31), 54.0 mg (0.261 mmol) of
N-(bromoacetyl)morpholine, and 0.050 mL (0.26 mmol) of
N,N-diisopropylethylamine in 4 mL of anhydrous DMF was heated to
80.degree. C. with stirring in a sealed tube. After 4.5 hours the
solution was cooled to RT and was treated with an additional 54.0
mg of N-(bromoacetyl)morpholine, and 0.050 mL (0.26 mmol) of
N,N-diisopropylethylamine. The solution was heated at 80.degree. C.
for an additional 18 hours, cooled to RT, and concentrated in
vacuo. The crude product was purified b by flash chromatography
(silica gel, EtOAc) to give a viscous yellow oil. This material was
dissolved in a minimum volume of CH.sub.2Cl.sub.2 and the solution
was added to rapidly stirred 1:1 ether/hexane. A white solid
precipitated which was collected by filtration and dried in vacuo.
yield=54 mg (44%). .sup.1H-NMR (DMSO-d.sub.6): 7.31-7.06 (7H),
7.03-6.83 (3H), 6.26 (1H), 5.45 (1H), 5.18 (1H), 4.71 (2H), 3.92
(2H), 3.79-3.22 (13H), 3.08-2.60 (5H), 2.39 (1H), 1.95-1.04 (10H).
LCMS (ESI): 703 (M+H).
Example 88
[0527] 700
[0528] N-methoxy-N-methylbromoacetamide
[0529] A solution of 4.5 mL (51.3 mmol) of bromoacetylbromide and
5.00 g (51.3 mmol) of N,O-dimethylhydroxylamine hydrochloride in 80
mL of anhydrous CH.sub.2Cl.sub.2 at 0.degree. C. was treated with a
solution of 18.7 mL (108 mmol) of N,N-diisopropylethylamine in 40
mL of CH.sub.2Cl.sub.2 via addition funnel over 10 minutes. A dark
brown solution resulted which was allowed to warm to RT. After 18
hours the solution was washed with 5% aqueous citric acid
(3.times.), saturated aqueous NaHCO.sub.3 (3.times.), dried over
MgSO.sub.4, and concentrated to give a dark brown oil. This
material was subjected to flash chromatography (8:2 to 6:4
hexane/EtOAc) to afford 2.97 g (32%) of the desired product as a
yellow-brown liquid. 1H-NMR (CDCl.sub.3): 4.22 (2H), 3.72 (3H),
3.20 (3H). 701
[0530] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((-
cyclopentyloxy)[3-(2-[methoxy(methyl)amino]-2-oxoethylamino)phenyl]sulfony-
lamino)-2-hydroxypropyl]carbamate and
(3S,3aR,6aS)hexahydrofuro[2,3-b]fura- n-3-yl
N-[(1S,2R)-1-benzyl-3-((cyclopentyloxy)[3-(2[methoxy(methyl)amino]--
2-oxoethylamino)phenyl]sulfonylamino)-2-hydroxypropyl]carbamate. A
solution of 0.100 g (0.174 mmol) of a 1:1 mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclope-
ntyloxy)[(3-aminophenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclope-
ntyloxy)[(3-aminophenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
(see example 31), 40.0 mg (0.210 mmol) of
N-methoxy-N-methylbromoacetamide, and 0.040 mL (0.21 mmol) of
N,N-diisopropylethylamine in 3 mL of anhydrous DMF was heated to
80.degree. C. with stirring in a sealed tube. After 24 hours the
solution was cooled to RT and was treated with an additional 20.0
mg of N-methoxy-N-methylbromoacetamide and 0.020 mL of
N,N-diisopropylethylamine. The solution was again warmed to
80.degree. C. After an additional 18 hours the solution was cooled
to RT and was concentrated in vacuo. The residue was dissolved in
CH.sub.2Cl.sub.21. The solution was washed with saturated aqueous
brine (3.times.), dried over MgSO.sub.4, and concentrated to
dryness. The crude product was purified by flash chromatography
(silica gel, 85:15 hexane/EtOAc) to afford 40 mg (34%) of the
desired product as a white foam. .sup.1H-NMR (CDCl.sub.3):
7.40-6.84 (11H), 5.62 (1H), 5.18-4.87 (2H), 4.81 (1H), 4.05 (2H),
3.99-3.53 (8H), 3.26-2.70 (9H), 1.92-1.41 (10H). LCMS (ESI): 677
(M+H)
Example 89
[0531] 702
[0532] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)[(3-nitrophenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclope-
ntyloxy)[(3-nitrophenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
[0533] A solution of 0.100 g (0.163 mmol) of a 1:1 mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]-furan-3-yl
N-(1S,2R)-1-benzyl-3-[(3-[(cy-
anomethyl)amino]phenylsulfonyl)(cyclo
pentyloxy)amino]-2-hydroxypropylcarb- amate and (3S,3aR,
6aS)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(3-[(cyanomethyl)amino]phenylsulfonyl)(cyclopentylo-
xy)amino]-2-hydroxypropylcarbamate (see example 86) and 5.0 mg
(0.033 mmol) of K.sub.2CO.sub.3 in 2 mL of 3:1 acetone/water was
treated with 0.150 g (1.63 mmol) of urea-hydrogen peroxide addition
compound and was stirred at RT. After 18 hours tic (silica gel,
95:5 CH.sub.2Cl.sub.2/MeOH) indicated no remaining starting
material at R.sub.f=0.43, a major new component at R.sub.f=0.21,
and a lesser component at R.sub.f=0.61. The solution was diluted
with CH.sub.2CL.sub.2, washed with water (3.times.), dried over
anhydrous MgSO.sub.4, and concentrated. The residue was subjected
to flash chromatography (silica gel, 95:5 CH.sub.2Cl.sub.2/MeOH) to
afford 15 mg (15%) of the R.sub.f=0.61 product as a white foam.
.sup.1H-NMR (CDCl.sub.3): 8.62 (1H), 8.51 (1H), 8.06 (1H), 7.75
(1H), 7.31-7.14 (6H), 5.65 (1H), 5.08-4.78 (3H), 3.98-3.57 (5H),
3.22-2.60 (6H), 1.95-1.40 (10H). LCMS (ESI): 606 (M+H)
Example 90
[0534] 703
[0535]
(3R,4S)-4-amino-1-(cyclopentyloxy)-5-phenyl-1-(6-quinoxalinyl
sulfonyl)-3-pentanol.
[0536] A mixture of tert-butyl
N-[(1S,2R)-1-benzyl-4-(cyclopentyloxy)-2-hy-
droxy-4-(6-quinoxalinylsulfonyl)butyl]carbamate (563 mg, 1.01 mmol)
and trifluoroacetic acid (5 mL) was stirred under an Argon
atmosphere for 0.5 hrs. The acid was removed in vacuo and the
residue was partitioned between dichloromethane and 1N sodium
hydroxide. The organic layer was separated and the aqueous layer
was extracted again with dichloromethane. The combined organic
layers were dried over anhydrous sodium sulfate, filtered and
evaporated in vacuo. The crude product was purified on flash grade
silica gel eluting with dichloromethane:methanol (98:2). Fractions
containing the product were combined and evaporated in vacuo and
dried under high vacuum to provide
(3R,4S)-4-amino-1-(cyclopentyloxy)-5-phenyl--
1-(6-quinoxalinylsulfonyl)-3-pentanol as a foam (379 mg, 82%).
H1-NMR (chloroform-D3): 1.66 (m, 11H), 2.51 (m, 1H), 2.86 (m, 1H),
3.07 (m, 1H), 3.23 (m, 1H), 3.32 (m, 1H), 3.84 (m, 1H), 4.90 (m,
1H), 7.20 (m, 5H), 8.16 (m, 1H), 8.28 (d, 1H), 8.70 (m, 1H), 8.99
(m, 2H), MS (ESI): 457 (M+H) 704
[0537] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-4-(c-
yclopentyloxy)-2-hydroxy-4-(6-quinoxalinylsulfonyl)butyl]carbamate.
A mixture of
(3R,4S)-4-amino-1-(cyclopentyloxy)-5-phenyl-1-(6-quinoxalinyls-
ulfonyl)-3-pentanol (50 mg, 0.110 mmoL),
(2R,3aS,6aR)hexahydrofuro[2,3-b]f- uran-2-yl 4-nitrophenyl
carbonate (37.3 mg, 0.121 mmol), and N,N-diisopropylethylamine
(47.8 .mu.L, 0.274 mmol) were combined under an Argon atmosphere in
approximately 1.5 mL of acetonitrile. After stirring at ambient
temperature for 16 hours, the solvent was removed in vacuo and the
residue was dissolved in ethyl acetate and washed three times with
5% w/v aqueous potassium carbonate. The combined aqueous layers
were back-extracted with ethyl acetate. The combined organic layers
were washed with brine, dried over anhydrous magnesium sulfate,
filtered and evaporated in vacuo. The crude product was purified on
a preparative TLC plate (20.times.20 cm, 1000 .mu.M) eluting with
95:5 dichloromethane: methanol. The product band was removed,
eluted with 3:1 methylene chloride:methanol, filtered, and
evaporated in vacuo. The residual solid was dried under high vacuum
to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]fu- ran-3-yl
N-[(1S,2R)-1-benzyl-4-(cyclopentyloxy)-2-hydroxy-4-(6-quinoxaliny-
lsulfonyl)butyl]carbamate (53 mg, 79%). H1-NMR (chloroform-D3):
1.58 (m, 6H), 1.81 (m, 4H), 2.80 (m, 1H), 2.95 (m, 4H), 3.17 (m,
1H), 3.65 (m, 2H), 3.88 (m, 4H), 4.85 (m, 2H), 4.98 (m, 1H), 5.62
(d, 1H), 7.21 (m, 5H), 8.08 (m, 1H), 8.26 (d, 1H), 8.63 (m, 1H),
9.00 (m, 1H). MS (ESI): 613 (M+H).
Example 91
[0538] 705
[0539] (3aS,6aR)Hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(cycl-
opentyloxy)(benzotriazole-5-ylsulfonyl)amino]-2-hydroxypropylcarbamate.
(3aS,6aR)Hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(cyclopenty-
loxy)-amino]-2-hydroxypropylcarbamate (280 mg, 0.666 mmol) (Step 2,
Example 54), benzotrizole-5-sulfonyl chloride (140 mg, 0.666 mmol),
and anhydrous diisopropylethylamine (0.04 mL, 0.238 mmol) were
combined in anhydrous tetrahydrofuran (5 mL) in a 25 mL round
bottomed flask under nitrogen. The reaction was stirred for 24
hours and concentrated in vacuo. After the workup described in Step
3, Example 54, the residue was purified by preparative silica gel
TLC using 90:10 chloroform:methanol as an eluent to give the
product as a white foam (70 mg, 0.116 mmol, 17%). .sup.1HNMR
(d.sub.6-DMSO) .delta.: 8.42 (bs, 1H), 8.16 (bs, 1H), 7.84 (bs,
1H), 7.26-7.15 (m, 5H), 5.51-5.47 (m, 1H), 5.31-5.28 (m, 1H),
4.85-4.70 (m, 2H), 4.12 (m, 1H), 3.79-1.15 (m, 21H). MS (ES): 602
(M+1), 600 (M-1).
Example 92
[0540] 706
[0541] 1,3-Dioxan-5-yl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(benzotriazol-
e-5-ylsulfonyl)amino]-2-hydroxypropylcarbamate. 1,3-Dioxan-5-yl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)amino]-2-hydroxypropylcarbamate
(Step 1, Example 55), (130 mg, 0.330 mmol),
benzotriazole-5-sulfonyl chloride (72 mg, 0.330 mmol), and
anhydrous diisopropylethylamine (0.06 mL, 0.330 mmol), were
combined in anhydrous tetrahydrofuran (5 mL) in a 25 mL round
bottomed flask under nitrogen. The reaction was stirred for 24
hours and concentrated in vacuo. After the workup described in Step
3, Example 54, the residue was purified by preparative silica gel
TLC using 90:10 chloroform:methanol as an eluent to give the
product as a white film (56 mg, 0.0973 mmol, 30%). .sup.1HNMR
(d.sub.6-DMSO) .delta.: 8.43 (bs, 1H), 8.14 (m, 1H), 7.83 (m, 1H),
7.27-7.15 (m, 5H), 4.86-4.66 (m, 3H), 4.23-3.02 (m, 13H), 1.93-1.40
(m, 8H). MS (ES): 576 (M+1), 574 (M-1).
Example 93
[0542] 707
[0543] tert-butyl
N-(1S,2R)-1-benzyl-3-[[4-(benzyloxy)phenyl]sulfonyl(cycl-
opentyloxy)amino]-2-hydroxypropylcarbamate. tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)amino]-2-hydroxypropylcarbamate
(3.5 mmol, 807 mg), 3-phenoxybenzenesulfonyl chloride (3.5 mmol,
1.0 g), and diisopropylethylamine (5.3 mmol, 0.924 mL) were
dissolved in anhydrous THF (10 mL), and the solution was stirred at
room temperature under nitrogen for 72 hours. The reaction was
concentrated to a white solid under vacuum, dissolved in ethyl
acetate, washed with 1N HCl, 1N NaOH, brine, dried over magnesium
sulfate and concentrated. The crude product was purified by silica
gel chromatography (2:1 hexanes/ethyl acetate) and yielded 1.08 g
(50%) of a white solid. Note: The 3-phenoxybenzenesulfonyl chloride
was prepared from 4-bromophenylbenzylether (Corrie, J.;
Papageorgiou, G. J. Chem. Soc., Perkin Trans. 1 1996, 1583).
R.sub.f=0.3 (5:1 hexanes/ethyl acetate); H1-NMR (CDCl.sub.3):
.delta. 7.69 (2H, d), 7.41-7.28 (5H, m), 7.27-7.19 (6H, m), 7.03
(2H, d), 5.11 (2H, s), 4.79 (1H, m), 4.56 (1H, m), 3.79 (2H, bs),
3.31 (1H, bs), 3.02 (1H, m), 2.91 (2H, m), 2.79 (1H, m), 1.85-1.67
(4H, m), 1.67-1.43 (4H, m), 1.32 (9H, s).
Example 94
[0544] 708
[0545] tert-butyl
N-(1S,2R)-1-benzyl-3-[[3-(benzyloxy)phenyl]sulfonyl(cycl-
opentyloxy)amino]-2-hydroxypropylcarbamate.
[0546] This compound was prepared under the same conditions
described for the tert-butyl
AN-(1S,2R)-1-benzyl-3-[[4-(benzyloxy)phenyl]sulfonyl(cyclo-
pentyloxy)amino]-2-hydroxypropylcarbamate. R.sub.f=0.3 (5:1
hexanes/ethyl acetate); H1-NMR (CDCl.sub.3): .delta. 7.44-7.30 (8H,
m), 7.29-7.16 (7H, m), 5.08 (2H, s), 4.79 (1H, m), 4.53 (1H, m),
3.78 (2H, bs), 3.34 (1H, bs), 3.06 (1H, m), 2.91 (2H, m), 1.85-1.66
(4H, m), 1.66-1.43 (4H, m), 1.32 (9H, s).
Example 95
[0547] 709
[0548] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[[4-
-(benzyloxy)phenyl]sulfonyl(cyclopentyloxy)amino]-2-hydroxypropylcarbamate-
. This compound was prepared (from Example 93) under the conditions
described for (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclohexyloxy)-[(4-methoxyphenyl)sulfonyl]amino-2--
hydroxypropyl)carbamate. R.sub.f=0.2 (2:1 hexanes/ethyl acetate);
H1-NMR (CDCl.sub.3): .delta. 7.70 (2H, d), 7.44-7.31 (5H, m),
7.29-7.11 (6H, m), 7.05 (2H, d), 5.63 (1H, s), 5.11 (2H, s), 5.00
(1H, m), 4.88-4.74 (2H, m), 3.96-3.78 (4H, m), 3.67 (2H, m), 3.08
(1H, bs), 3.05-2.94 (2H, m), 2.90 (2H, m), 2.81 (2H, m), 1.87-1.68
(4H, m), 1.68-1.44 (4H, m).
Example 96
[0549] 710
[0550] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[[3-
-(benzyloxy)phenyl]sulfonyl(cyclopentyloxy)amino]-2-hydroxypropylcarbamate-
.
[0551] This compound was prepared under the conditions (from
Example 94) described for
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclohexyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-h-
ydroxypropyl)carbamate. R.sub.f=0.2 (2:1 hexanes/ethyl acetate);
H1-NMR (CDCl.sub.3): .delta. 7.48-7.30 (8H, m), 7.30-7.11 (7H, m),
5.59 (1H, s), 5.09 (2H, s), 4.97 (1H, m), 4.78 (2H, m), 3.95-3.77
(4H, m), 3.71-3.57 (2H, m), 3.12 (1H, bs), 3.05-2.90 (3H, m),
2.90-2.72 (3H, m), 1.88-1.67 (4H, m), 1.67-1.42 (4H, m).
Example 97
[0552] 711
[0553] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((- cyclopentyloxy)
[3-(2-hydroxyethoxy)phenyl]sulfonylamino)-2-hydroxypropyl]-
carbamate.
[0554] This compound was synthesized (from Example 44) under the
same conditions as Example 42
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((cyclopentyloxy)[4-(2-hydroxyethoxy)phenyl]sulfony-
lamino)-2-hydroxypropyl]carbamate. R.sub.f=0.1 (1:1 hexanes/ethyl
acetate); H1-NMR (CDCl.sub.3): .delta. 7.47-7.14 (10H, m), 5.63
(1H, s), 5.00 (1H, m) 4.88-4.70 (2H, m), 4.12 (2H, m), 3.98 (2H,
m), 3.94-3.72 (5H, m), 3.72-3.51 (2H, m), 3.14 (1H, bs), 3.07-2.69
(5H, m), 2.20 (1H, bs), 1.89-1.69 (4H, m), 1.69-1.42 (4H, m); MS
(ESI): M+H=621.
Example 98
[0555] 712
[0556] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((-
cyclopentyloxy)[4-(2-morpholinoethoxy)phenyl]sulfonylamino)-2-hydroxypropy-
l]carbamate. To a solution of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-hydroxyphenyl)sulfonyl]amino-2--
hydroxypropyl)carbamate (Example 41), (0.13 mmol, 75 mg),
triphenylphosphine (0.16 mmol, 43 mg), 4-(2-hydroxyethyl)morpholine
(0.16 mmol, 0.020 mL), and anhydrous THF (0.5 mL) stirring under
nitrogen, diethylazodicarboxylate (0.17 mmol, 0.027 mL) was
injected. T-he reaction stirred for 3 hours at room temperature and
was then concentrated to a viscous oil under vacuum. The crude was
purified directly by silica gel flash chromatography (1:1
hexanes/ethyl acetate) resulting in 50 mg (56%) of a white solid.
R.sub.f=0.15 (ethyl acetate); H1-NMR (CDCl.sub.3): .delta. 7.70
(2H, d), 7.30-7.10 (6H, m), 6.99 (2H, d), 5.63 (1H, s), 5.00 (1H,
m), 4.86-4.73 (2H, m), 4.16 (2H, m), 3.97-3.79 (4H, m), 3.78-3.58
(6H, m), 3.15-2.69 (9H, m), 2.57 (4H, m), 1.88-1.66 (4H, m),
1.66-1.43 (4H, m); MS (ESI): M+H=690.
Example 99
[0557] 713
[0558] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,
2R)-1-benzyl-3-((cyclopentyloxy)[3-(2-morpholinoethoxy)phenyl]sulfonylami-
no)-2-hydroxypropyl]carbamate.
[0559] This compound was prepared from Example 44 under the same
conditions used for the preparation of Example 98
(3R,3aS,6aR)hexahydrofu- ro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((cyclopentyloxy)[4-(2-morpholin-
oethoxy)phenyl]sulfonylamino)-2-hydroxypropyl]carbamate.
R.sub.f=0.15 (ethyl acetate); H1-NMR (CDCl.sub.3): .delta.
7.44-7.14 (10H, m), 5.62 (1H, s), 5.00 (1H, m), 4.79 (2H, m), 4.16
(2H, m), 3.98-3.60 (10H, m), 3.12 (1H, bs), 3.02-2.71 (8H, m), 2.58
(4H, m), 1.90-1.72 (4H, m), 1.72-1.42 (4H, m); MS (ESI):
M+H=690.
Example 100
[0560] Phosphate ester of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[[(3-aminophenyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-h-
ydroxypropylcarbamate. 714
[0561] A solution of 0.792 g (2.18 mMol) of tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)amino]-2-hydroxypropylcarbamate
(Example 54), 0.445 g (2.4 mMol) of m-nitrobenzenesulfonyl chloride
and 0.35 mL (2.5 mMol) of triethylamine in 10 mL of tetrahydrofuran
was stirred at rt for 12 h, diluted with ethyl acetate and exracted
with 1N HCl and saturated sodium bicarbonate. Purification on
silica gel afforded the desired sulfonamide which was treated with
50 mL of 1:1 trifluoroacetic acid/dichloromethane for 1 h at rt.
Evaporation of the volatiles and partitioning between ethyl acetate
and 1N sodium hydroxide, afforded the free base which was treated
with 0.885 g (3 mmol) of
(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(4-nitrophenyl)carbonate,
10 mg of dimethylamino pyridine, and 0.7 mL of triethylamine in 20
mL of tetrahydrofuran for 12 h at rt. The resulting mixture was
loaded onto a bed of silica gel and eluted with 50% to 100%
ethylacetate-hexanes) to give the desired compound (750 mg) as a
white foam. 715
[0562] A solution of 60.5 mg (0.1 mmol) of the material obtained in
Step 1 above, 0.042 mL (0.125 mmol) of
diisopropylamino-dibenzylphosphite and 9 mg (0.13 mmol) of
tetrazole in 2 mL of dichloromethane was stirred for 3 h at rt and
then loaded onto a bed of silica gel and eluted with 30%
ethylacetate-hexane to give the intermediate phosphite which was
redissolved in 3 mL of acetonitrile and treated with 48.3 mg (0.15
mmol) of iodosobenzene diacetate. The mixture was stirred at rt for
1 h and then loaded on a plug of silica gel and eluted with 80%
ethylacetate-hexane. The resulting phosphate ester was obtained as
a white foam (48 mg), which was re-dissolved in 50 ml methanol and
treated with ca. 50 mg of 5% palladium on carbon. The mixture was
hydrogenated at 55 PSI for 8 h, filtered and evaporated.
Purification on C-18 semi-preparative HPLC gave the desired
phosphate (6 mg) as a white fluffy solid. .sup.1H-NMR
(methanol-d4): 1.4-2.0 (14H), 2.65 (1H), 2.9 (1H), 3.2 (2H), 3.55
(1H), 3.6-4.0 (4H), 4.4 (1H), 4.65 (1H), 4.8 (2H), 5.6 (1H),
7.2-7.6 (9H). 31P-NMR: 1.1 ppm. MS (LC-MS): 656 (MH+).
Example 101
[0563] 716
[0564] Phosphate ester of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2--
hydroxypropyl)carbamate.
[0565] A solution of 0.6 g (1 mmol) of
(3R,3aS,6aR)hexahydrofuro[2,3-b]fur- an-3-yl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]a-
mino-2-hydroxypropyl)carbamate (Example 102), 0.42 mL (1.25 mmol)
of diisopropylamino-dibenzylphosphite and 0.09 g (1.25 mmol) of
tetrazole in 10 mL of dichloromethane was stirred at rt for 12 h.
The mixture was loaded onto a plug of silica gel and eluted with
40% ethylacetate-hexane to give the desired phosphite. 250 mg of
the material so obtained were dissolved in 15 mL of acetonitrile
and treated with 0.19 g (0.6 mmol) of iodosobenzene diacetate.
After 2 h at rt, the mixture was diluted with ethyl acetate and
extracted with 1N HCl and 1N NaOH. The volatiles were removed and
the residue was chromatographed on silica gel to give 220 mg of the
protected phosphate as a white foam. 100 mg of the so obtained
material was dissolved in 20 mL of methanol and trated with ca. 20
mg of 5% palladium on carbon. Hydrogenation at 50 PSI for 1 h and
filtration gave the desired acid which was dissolved in 2M
methanolic ammonia and re-evaporated. The ammoinum salt was
isolated as a white solid (65 mg).
[0566] .sup.1H-NMR (methanol-D4): 1.5-2.2 (14H), 2.7 (1H), 2.9
(3H), 3.15 (1H), 3.4-4 (5H), 3.97 (3H), 4.2-4.7 (2H), 4.9 (2H), 5.6
(1H), 7.2 (3H), 7.3 (4H), 7.85 (2H). 31P-NMR: 0.08 ppm MS (LC-MS):
671 (MH+).
Example 102
[0567] 717
[0568] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate.
[0569] This compound was obtained in analogous manner to Example
29, using the appropriate optically pure activated carbonate.
.sup.1H-NMR (CDCl.sub.3): 1.4-1.9 (12H), 2.75 (2H), 2.9 (1H), 3.1
(2H), 3.65 (2H), 3.9 (6H), 4.75 (2H), 5.00 (1H), 5.62 (1H), 7.0
(2H), 7.15 (5H), 7.75 (2H).
Example 103
[0570] Prepared as outlined for Example 86, using chiral starting
materials.
Example 104
[0571] 718
[0572]
1,3-Dioxan-5-yl-N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(3-(carbometh-
oxyamino)-indazole-5-ylsulfonyl)amino]-2-hydroxypropylcarbamate.
[0573] 1,3-Dioxan-5-yl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(1-carbometho-
xy-3-(carbomethoxyamino)indazole-5-ylsulfonyl)amino]-2-hydroxypropylcarbam-
ate (Example 120), (40 mg, 0.057 mmol) and lithium iodide. (23 mg,
0.17 mmol) were dissolved In pyridine (3 mL) in a 10 mL round
bottomed flask and heated at 95.degree. C. for 2 hours. The
reaction was allowed to cool and then concentrated in vacuo. The
product was purified by preparative silica gel TLC using 90:10
chloroform:methanol as an eluent to yield a beige solid (35 mg,
0.054 mmol, 95%). .sup.1HNMR (d.sub.6-DMSO) .delta.: 13.12 (s, 1H),
10.26 (s, 1H), 8.42 (s, 1H), 7.62 (m, 2H), 7.25-7.09 (m, 6H), 5.12
(d, J=6.2 Hz, 1H), 4.76-4.18 (m, 5H), 3.76-2.91 (m, 9H), 3.66 (s,
3H), 1.90-1.40 (m, 8H). MS (ES): 648 (M+1), 646 (M-1).
Example 105
[0574] 719
[0575] Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-[(3-chloropropi-
onyl)amino]-1H-benzimidazol-5-ylsulfonyl)amino]-2-hydroxypropylcarbamate.
[0576] Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-amino-1H-benzim-
idazol-5-ylsulfonyl)amino]-2-hydroxypropylcarbamate (Step 2,
Example 8) (65 mg, 0.116 mmol), 3-chloropropionyl chloride (0.01
mL, 0.116 mmol), and 4,4-dimethylaminopyridine were combined in
anhydrous THF (5 mL) in a 25 mL round bottomed flask under
nitrogen. The reaction was stirred for 18 hours and then
concentrated in vacuo. After the workup described in Step 3,
Example 54, the residue was purified by preparative silica gel TLC
using 10:3:0.5 chloroform:methanol: water as an eluent to give the
product as a white solid (17 mg, 0.026 mmol, 22%). .sup.1HNMR
(d.sub.6-DMSO) .delta.: 7.55-6.62 (m, 8H), 5.08 (bs, 1H), 4.62 (bs,
1H), 4.15 (bs, 1H), 3.57 (m, 2H), 3.10-1.40 (m, 16H), 1.18 (s, 9H).
MS (ES): 650, 652 (M+1).
Example 106
[0577] Prepared as outlined in Example 8, Step 2.
Example 107
[0578] 720
[0579] Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-amino-1-methyl--
1H-benzimidazol-5-ylsulfonyl)amino]-2-hydroxypropylcarbamate and
Tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-amino-3-methyl-1H-ben-
zimidazol-5-ylsulfonyl)amino]-2-hydroxypropylcarbamate.
[0580] Tert-butyl N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)
(2-amino-1H-benzimidazol-5-ylsulfonyl)amino]-2-hydroxypropyl-carbamate
(Step 2, Example 8) (120 mg, 0.214 mmol), methyl iodide (0.03 mL,
0.429 mmol), and anhydrous diisopropylethylamine (0.07 mL, 0.429
mmol) were combined in anhydrous THF (5 mL) in a 25 mL round
bottomed flask under nitrogen. The reaction was heated at reflux
for 18 hours and then concentrated in vacuo. After the workup
described in Step 3, Example 54, the residue was purified by
preparative silica gel TLC using 90:10 chloroform:methanol as an
eluent to give the product as mixture of two compounds methylated
at the 1- and 3-positions of the imidazole ring (76 mg, 0.133 mmol,
62%). LC-MS: 574 (M+1), 572 (M-1).
Example 108
[0581] 721
[0582] (3R,3aS,6aR)Hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(c- yclopentyloxy)
(3-aminoindazole-5-ylsulfonyl)amino]-2-hydroxypropylcarbama-
te.
[0583] (3R,3aS,6aR)Hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(c- yclopentyloxy)
(1-carbomethoxy-3-aminoindazole-5-ylsulfonyl)amino]-2-hydro-
xypropylcarbamate (100 mg, 0.148 mmol) and lithium iodide hydrate
(50 mg, 0.37 mmol) were dissolved in pyridine (3 mL) in a 10 mL
round bottomed flask and heated at 75 C for 5 hours. The reaction
was allowed to cool and then concentrated in vacuo. The product was
purified by preparative silica gel TLC using 90:10
chloroform:methanol as an eluent to yield a class (76 mg, 0.124
mmol, 84%). .sup.1HNMR (d.sub.6-DMSO): 12.05 (s, 1H), 8.35 (m, 1H),
7.56-7.14 (m, 7H), 5.86 (bs, 2H), 5.50 (d, J=5.2 Hz, 1H) 5.22 (d,
J=6.5 Hz, 1H), 4.85-4.79 (m, 2H), 3.781.14 (m, 22H). MS (ES): 616
(M+1), 614 (M-1).
Example 109
[0584] 722
[0585]
N.sup.1-(cyclopentyloxy)-4-(methoxymethoxy)-1-benzenesulfonamide
[0586] The 4-methoxymethoxybenzenesulfonyl chloride (2.4 mmol, 568
mg) was prepared from methylmethoxy-protected 4-bromophenol
(Corrie, J.; Papageorgiou, G. J. Chem. Soc., Perkin Trans. 1 1996,
1583) and was combined with cyclopentyl hydroxylamine (2.4 mmol,
243 mg) in the presence of diisopropylethylamine (3.6 mmol, 0.628
mL), and anhydrous THF. The reaction stirred under nitrogen for 36
hours at room temperature and was concentrated under vacuum. The
resulting oil was diluted in ethyl acetate, washed with 1N HCl, 5%
potassium carbonate, brine and was dried over magnesium sulfate.
The crude product was concentrated under vacuum and purified by
silica gel chromatography (5:1 hex/ethyl acetate) followed by
crystallization from ether/hexanes. The reaction produced 173 mg
(24%) of white crystals. R.sub.f=0.15 (1:1 hexanes/ethyl acetate);
H1-NMR (CDCl.sub.3): 7.82 (2H, d), 7.12 (2H, d), 6.67 (1H, s), 5.23
(2H, s), 4.58 (1H, m), 3.47 (3H, s), 1.84-1.64 (4H, m), 1.64-1.43
(4H, m). 723
[0587] tert-butyl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxymethoxy-
phenyl)sulfonyl]amino-2-hydroxypropyl)carbamate.
[0588]
N.sup.1-(cyclopentyloxy)-4-methoxymethoxy-1-benzenesulfonamide
(0.57 mmol, 173 mg) was combined with tert-butyl
N-(1S)-1-[(2S)oxiran-2-y- l]-2-phenylethylcarbamate (0.46 mmol, 121
mg) and anhydrous THF (1 mL) under nitrogen. Phosphazine base
P<t/4>t-Bu (0.09 mmol, 0.092 mL, 1M in hexanes) was injected
into the stirring solution. The reaction was allowed to stir for 4
hours at room temperature and was quenched by the addition of a few
drops of glacial acetic acid. The reaction product was concentrated
to an oil and partitioned between ethyl acetate and 1N HCl. The
organic layer was separated and washed with 1 N NaOH and brine,
dried over magnesium sulfate and concentrated under vacuum to a
clear oil. The crude product was purified by silica gel
chromatography (5:1 hexanes/ethyl acetate) and crystallization from
ether/hexanes providing 110 mg (43%) of a white crystal.
R.sub.f=0.5 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl.sub.3): 7.69
(2H, d), 7.31-7.16 (6H, m), 7.11 (2H, d), 5.21 (2H, s), 4.83-4.75
(1H, m), 4.61-4.51 (1H, m), 3.85-3.70 (2H, m), 3.47 (3H, s),
3.12-2.95 (1H, m), 2.95-2.87 (2H, m), 2.87-2.68 (1H, m), 1.86-1.66
(4H, m), 1.66-1.43 (4H, m), 1.33 (9H, s); MS (ESI): M+H=565.
Example 110
[0589] 724
[0590] (3S)tetrahydro-3-furanyl
N-[(1S,2R)-1-benzyl-4-(cyclopentyloxy)-2-h-
ydroxy-4-(6-quinoxalinylsulfonyl)butyl]carbamate.
[0591] A mixture of
(3R,4S)-4-amino-1-(cyclopentyloxy)-5-phenyl-1-(6-quino-
xalinylsulfonyl)-3-pentanol (50 mg, 0.110 mmoL),
2,5-dioxo-1-pyrrolidinyl[- (35)tetrahydro-3-furanyl]carbonate (28
mg, 0.121 mmol, WO 94/05639) and N,N-diisopropylethylamine (47.8
uL, 0.274 mmol) were combined under Argon at ambient temperature in
approximately 1.5 mL of acetonitrile. After stirring for
approximately 16 hours at ambient temperature, the reaction mixture
was evaporated in vacuo and partitioned between ethyl acetate and
aqueous potassium carbonate (5% w/v). The layers were separated and
the aqueous layer was back extracted with ethyl acetate. The
combined organic layers were washed twice with 1N sodium hydrogen
sulfate. The acid layers were combined and back extracted with
ethyl acetate. The combined organic layers were washed with brine,
dried over anhydrous magnesium sulfate, filtered and evaporated in
vacuo. The residue was purified on a preparative TLC plate
(20.times.20 cm, 1000 .mu.M) eluting with 93:7
dichloromethane:methanol. The product band was removed, eluted with
3:1 methylene chloride:methanol, filtered, and evaporated in vacuo.
The residue was crystallized with several drops of methanol. The
residual solid was dried under high vacuum to provide
(3S)tetrahydro-3-furanyl
N-[(1S,2R)-1-benzyl-4-(cyclopentyloxy)-2-hydroxy-4-(6-quinoxalinyl
sulfonyl)butyl]carbamate (54 mg, 86%) as a white solid. H1-NMR
(chloroform-D3): 1.61 (m, 5H), 1.86 (m, 4H), 2.09 (m, 1H), 2.97 (m,
3H), 3.20 (m, 2H), 3.80 (m, 6H), 4.83 (m, 1H), 4.93 (m, 1H), 5.14
(m, 1H), 7.28 (m, 5H), 8.13 (m, 1H), 8.31 (d, 1H), 8.69 (d, 1H),
9.05 (s, 2H). MS (ESI): 571 (M+H).
Example 111
[0592] 725
[0593] (1S,2R)-1-benzyl-3-(tert-butyloxy)
[(phenyl)sulfonyl]amino-2-hydrox- ypropylamine hydrochloride.
[0594]
tert-Butyl-N-((1S,2R)-1-benzyl-3-(tert-butyloxy)[(phenyl)sulfonyl]a-
mino-2-hydroxypropyl)carbamate (Example 112, Step 2), (0.060 g,
0.12 mmol) was dissolved in EtOAc (50 ml). Dry hydrochloric acid
gas was bubbled through the stirred solution 15 minutes at
-10.degree. C. The reaction was warmed to ambient temperature,
solvent removed in vacuo and the resulting crude residue used
directly in the next reaction. 726
[0595] (3S) Tetrahydro-3-furanyl-N-(1S,2R)-1-benzyl-3-(tert
butyloxy)[(phenyl)sulfonyl]amino-2-hydroxypropylcarbamate.
[0596] (1S,2R)-1-benzyl-3-(tert-butyloxy)[(phenyl)
sulfonyl]amino-2-hydrox- ypropylamine hydrochloride (0.12 mmol) was
combined with diisopropylethylamine (0.064 ml, 0.37 mmol) in
CH.sub.2Cl.sub.2 (10 ml). To the reaction was added
2,5-dioxo-1-pyrrolidinyl[(3S)tetrahydro-3-furan- yl]carbonate
(0.042 g, 0.18 mmol) with stirring. After 3 h at ambient
temperature, the reaction mixture was concentrated in vacuo, taken
up in EtOAc, washed with sat. aq. NaHCO.sub.3, and brine. The
organic phase was dried over MgSO.sub.4, filtered and solvent
removed in vacuo. Purification by preparative TLC (1:1 EtOAc/Hex).
Recovered 0.044 g (67%) of the product as a white foam. Rf=0.38
(1:1 EtOAc/Hex), LRMS (M+H).sup.+ 507.3.
Example 112
[0597] 727
[0598]
tert-Butyl-N-((1S,2R)-1-benzyl-3-(tert-butyloxy)amino-2-hydroxyprop-
yl)carbamate.
[0599] tert-Butyl-N-((1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate
(0.155 g, 0.59 mmol) and O-(tert-butyl)hydroxylamine hydrochloride
(0.089 g, 0.71 mmol) were heated with diisopropylethylamine (0.154
ml, 0.88 mmol) in isopropanol (2 ml) in a sealed tube at 60.degree.
C. for 5 days. The reaction mixture was concentrated in vacuo,
taken up in EtOAc, washed with sat. aq. NaHCO.sub.3, and brine. The
organic chase was dried over MgSO.sub.4, filtered and solvent
removed in vacuo. Purication by column chromatography (1% MeOH in
CH.sub.2Cl.sub.2) gave 100 mg of a white solid which was used
directly in the next reaction. 728
[0600]
tert-Butyl-N-((1S,2R)-1-benzyl-3-(tert-butyloxy)[(phenyl)sulfonyl]a-
mino-2-hydroxypropyl)carbamate.
tert-Butyl-N-((1S,2R)-1-benzyl-3-(tert-but-
yloxy)amino-2-hydroxypropyl)carbamate (0.100 g, 0.28 mmol) was
combined with diisopropylethylamine (0.075 ml, 0.43 mmol) in
CH.sub.2Cl.sub.2 (10 ml). Benzenesulfonyl chloride (0.060 g, 0.34
mmol) was added and the reaction was stirred at room temperature
overnight. Reaction mixture was concentrated in vacuo, taken up in
EtOAc, washed with sat. aq. NaHCO.sub.3, and brine. The organic
phase was dried over MgSO.sub.4, filtered and solvent removed in
vacuo. Purication by preparative TLC (1:1/EtOAc/Hex). Recovered
0.064 g (46%) of the product as a white foam. Rf=0.78
(1:1/EtOAc/Hex), LRMS (M+H).sup.+ 493.4.
Example 113
[0601] 729
[0602] Ethyl
2-[([2-(3-[[(2R,3S)-3-([(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-
-3-yloxy]carbonylamino)-2-hydroxy-4-phenylbutyl](cyclopentyloxy)amino]sulf-
onylanilino)ethyl]aminocarbonyl)amino]acetate and ethyl
2-[([2-(3-[[(2R,3S)-3-([(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yloxy]car-
bonylamino)-2-hydroxy-4
phenylbutyl](cyclopentyloxy)amino]sulfonylanilino)-
ethyl]aminocarbonyl)amino]acetate. A solution of 50 mg (0.081 mmol)
of a 1:1 mixture of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(3-[(2-aminoethyl)amino]phenylsulfonyl)(cyclopentyloxy)amino-
]-1-benzyl-2-hydroxypropylcarbamate and
(3S,3aR,6aS)hexahydrofuro[2,3-b]fu- ran-3-yl
T-(1S,2R)-3-[(3-[(2-aminoethyl)amino]phenylsulfonyl)(cyclopentylo-
xy)amino]-1-benzyl-2-hydroxypropylcarbamate (Example 83) in 1.5 mL
of anhydrous THF was treated with 0.010 mL (0.085 mmol) of ethyl
isocyanatoacetate. The resulting solution was stirred at RT. After
18 hours the solution was concentrated in vacuo and the residue
subjected to flash chromatography (silica gel,
95:5/CH.sub.2Cl.sub.2/2M NH.sub.3 in MeOH) to afford 56 mg (92%) of
the desired product as a white foam. .sup.1H-NMR (CDCl.sub.3):
7.60-7.06 (13H), 6.00-4.80 (4H), 4.34-2.62 (19H), 2.10-1.43 (10H),
1.32 (3H). LCMS (ESI): 748 (M+H).
Example 114
[0603] 730
[0604] 1,3-Dioxane-5-yl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-acetamido-
)]-benzothiazol-6-ylsulfonyl)amino]-2-hydroxypropylcarbamate. To 21
mg (0.034 mmol) of 1,3-Dioxane-5-yl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2-
-amino)]-benzothiazol-6-ylsulfonyl)amino]-2-hydroxypropylcarbamate,
(Example 125, Step 3), dissolved in 1 mL of dichloromethane and
cooled to approximately-0.degree. C., was added 5.3 .mu.L (1.2 eq.)
of chlorotrimethylsilane. The reaction was warmed to 25.degree. C.
and stirred for 45 minutes. Triethylamine (12 .mu.L, 2.5 eq.) was
added followed by 100 .mu.l (1.2 eq.) of a dilute solution of (24
.mu.l acetyl chloride in 1 mL CH.sub.2Cl.sub.2). The reaction was
stirred at 25.degree. C. for 3 hours. 105 .mu.L (3.0 eq.) of 1.0 M
tetrabutylammonium fluoride was added and the reaction stirred for
1 hour. The solvent was removed in vacuo and the residue was
purified by preparative chromatography to give 8 mg of carbamate,
114. HPLC showed the material to be over 80% pure. Ret. time=10.48
min. LC/MS, M+H=649.1.
Example 115
[0605] 731
[0606]
1N-(3-Methylsulfonylisobutyryl)-(1S,2R)-1-benzyl-3-(cyclopentyloxy)-
[4-methoxyphenylsulfonyl]amino-2-hydroxypropylamine.
(1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hyd-
roxypropylamine trifluoroacetic acid salt (0.012 g, 0.03 mmol) was
combined with 3-methylsulfonylisobutyric acid (0.005 g, 0.03 mmol)
and 1-hydroxybenzotriazole hydrate (0.004 g, 0.03 mmol) in
anhydrous DMF (1 ml). Triethylamine (0.010 ml, 0.05 mmol) was added
followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (0.009 g, 0.03 mmol). Reaction was stirred at room
temperature for 2 hours. Reactiom mixture was diluted in EtOAc and
washed with sat. NaHCO.sub.3, 0.5N KHSO.sub.4 and brine. Organic
phase was dried with MgSO.sub.4 and the solvent was removed in
vacuo. Purification by preparative TLC (3:1/EtOAc/Hex). Recovered
0.010 g (70%) of the product as a colorless residue. Rf=0.44 (3:1
EtOAc/Hex). .sup.1H NMR (CDCl.sub.3) 8.78 (1H, d), 7.38-7.17 (5H,
m), 7.05-6.98 (2H, m), 6.09 (0.5H, d), 5.96 (0.5H, d), 5.80 (1H,
m), 4.32 (0.5H, m), 4.20 (0.5H, m), 4.02 (0.5H, m), 3.90 (3H, s),
3.60 (0.5H, m), 3.49 (1H, m), 3.12-2.96 (2H, m), 2.95-2.70 (4H, m),
1.90-1.70 (4H, m), 1.69-1.50 (4H, m), 1.20 (1.5H, d), 1.00 (1.5H,
d). LRMS (M+H).sup.+ 583.0.
Example 116
[0607] Step 1:
[0608] (3S,3aS,6aR)hexahydrofuro[2,3b]furan-3-p-nitrobenzoyl ester
(A) and (3R,3aR,6aS)hexahydrofuro[2,3b]furan-3-p-nitrobenzoyl ester
(B) 732
[0609] In a dried flask was introduced 1 eq. of
(3S,3aS,6aR)-3-Hydroxyhexa- hydrofuro[2,3b]furan (200 mg, 1.54
mmol) in 10 mL of dried THF. To this solution was introduced 1.1
eq. of PPh.sub.3 (443 mg, 1.69 mmol) and 1.1 eq. of p-nitrobenzoic
acid (282 mg, 1.69 mmol). The solution was cooled to 0.degree. C.
and then 1.2 eq of diethyl azodicarboxylate (290 .mu.L, 1.84 mmol)
was added dropwise. The reaction was continued at room temperature
for 24 h. The solvent was evaporated in vacuo to an oil which was
solubilized in dichloromethane washed with 1N hydrochloric acid,
saturated sodium bicarbonate and brine. The organic layer was dried
over anhydrous magnesium sulfate, filtered and evaporated in vacuo
to a residue. The crude material was purified on flash grade silica
gel eluting with 20-50% ethyl acetate in hexane. Fractions
containing the product were combined, evaporated in vacuo and dried
under high vacuum to provide
(3S,3aS,6aR)Hexahydrofuro[2,3b]furan-3-p-nitrobenzoyl ester (914
mg, 98%). HPLC showed the material to be 98% pure;
[0610] Ret. time=9.88 min. .sup.1H NMR (CDCl.sub.3): 8.14-8.24 (dd,
4H), 5.88 (d, 1H), 5.29 (s, 1H), 4.07-4.17 (m, 2H), 3.83-3.93 (m,
2H), 2.97 (m, 1H), 2.19-2.28 (m, 1H), 1.86-1.98 (m, 1H).
[0611] Step 2:
[0612] (3S,3aS, 6aR)-3-Hydroxyhexahydrofuro[2,3b]furan (C) and
(3R,3aR, 6aS)-3-Hydroxyhexahydrofuro[2,3b]furan (D) 733
[0613] In a flask was introduced 1 eq. of
(3R3aR,6aS)Hexahydrofuro[2,3b]fu- ran-3-p-nitrobenzoyl ester (1.34
g, 4.82 mmol) in 20 mL of methanol. To this solution was introduced
at room temperature 1 eq. of lithium hydroxide (202 mg, 4.82 mmol).
After 45 min the solvant was evaporated in vacuo to an oil who was
purified on flash grade silica gel eluting with 50-100% ethyl
acetate in hexane. Fractions containing the product were combined,
evaporated in vacuo and dried under high vacuum to provide
(3R,3aR,6aS)-3-Hydroxyhexahydrofuro[2,3b]furan (401 mg, 80%).
.sup.1H NMR (CDCl.sub.3): 5.82 (s 1H), 4.15 (s, 1H), 3.74-3.94 (m,
4H), 2.72-2.76 (m, 1H), 2.06-2.14 (m, 1H), 1.99 (s, 1H), 1.60-1.66
(m, 1H).
[0614] Step 3:
[0615]
(3S,3aS,6aR)Hexahydrofuro[2,3b]furan-3-yl(4-nitrophenyl)carbonate
(E) and
(3R,3aR,6aS)hexahydrofuro[2,3b]furan-3-yl(4-nitrophenyl)carbonate
(F) 734
[0616] In a dried flask was introduced 1 eq. of
(3S,3aS,6aR)-3-Hydroxy hexahydrofuro[2,3b]furan (210 mg, 1.61 mmol)
in 5 mL of dried dichloromethane. To this solution was introduced 1
eq. of p-nitrobenzylchloroformate (325 mg, 1.61 mmol) and 1 eq. of
N-methylmorpholine (177 .mu.L, 1.61 mmol). The reaction was
continued at room temperature for 24 h. The precipitate was
filtered off and the solvant was evaporated in vacuo to an oil. The
crude material was purified on flash grade silica gel eluting with
50% ethyl acetate in hexane. Fractions containing the product were
combined, evaporated in vacuo and dried under high vacuum to
provide (3S,3aS,6aR)Hexahydrofuro[2,-
3b]furan-3-yl(4-nitrophenyl)carbonate (350 mg, 99%). HPLC showed
the material to be 99% pure; Ret. time=8.8 min. .sup.1H NMR
(CDCl.sub.3): 7.28-8.25 (dd, 4H), 5.88 (d, 1H), 5.05 (s, 1H),
4.04-4.15 (m, 2H), 3.80-3.91 (m, 2H), 2.97-3.01 (m, 1H), 2.18-2.26
(m, 1H), 1.77-1.83 (m, 1H). 735
[0617]
(3R,3aR,6aS)hexahydrofuro[2,3b]furan-3-yl-N-(1S,2R)-1-benzyl-3-[(cy-
clopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropylcarbamate.
In a dried flask was introduced 1 eq. of
N.sup.1-[(2R,3S)-3-amino-2-hydroxy--
4-phenylbutyl]-N.sup.1-(cyclopentyloxy)-4-methoxy-1-benzenesulfonamide
trifluoroacetic acid (40.9 mg, 0.083 mmol) in 1 mL of
N,N-dimethylformamide. To this solution was added 1.1 eq. of
(3R,3aR,6aS)hexahydrofuro[2,3b]furan-3-yl-(4-nitrophenyl)carbonate
(27 mg, 0.091 mmol) and 5 eq. of triethylamine (58 .mu.L, 0.4
mmol). The reaction was continued at room temperature for 4 days.
The reaction mixture was solubilized in ethyl acetate washed with
water and brine. The organic layer was dried over anhydrous
magnesium sulfate, filtered and evaporated in vacuo to a residue.
The crude material was purified on a preparative TLC plate
(20.times.20 cm, 1 mm) eluting with 50% ethyl acetate in hexane.
The product band was removed, eluted
(4:1/dichloromethane:methanol), filtered and evaporated in vacuo
and dried under high vacuum to provide
(3S,3aS,6aR)Hexahydrofuro[2,3b]furan-3- -yl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-
-2-hydroxypropyl)carbamate (19.5 mg, 40%). HPLC showed the material
to be 96% pure; Ret. time=11.88 min. .sup.1H NMR (CDCl.sub.3): 7.65
(d, 2H), 7.13-7.24 (m, 5H), 6.92 (d, 2H), 5.71 (m, 1H), 4.73-4.82
(m, 3H), 3.71-3.91 (m, 7H), 2.68-3.03 (m, 7H), 2.12 (m, 1H),
1.48-1.74 (m, 10H) and MS (ES+), M+H=591.0.
Example 117
[0618] (3S,3aS,
6aR)hexahydrofuro[2,3b]furan-3-yl-N-(1S,2R)-1-benzyl-3-[(c-
yclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropylcarbamate
736
[0619] In a dried flask was introduced 1 eq. of N.sup.1--
[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N.sup.1-(cyclopentyloxy)-4-meth-
oxy-1-benzenesulfonamide.cndot.trifluoroacetic acid (40.2 mg, 0.081
mmol) in 1 mL of N,N-dimehylformamide. To this solution was added
1.1 eq. of
(3S,3aS,6aR)hexahydrofuro[2,3b]furan-3-yl(4-nitrophenyl)carbonate
(26 mg, 0.089 mmol) and 5 eq. of triethylamine (56 .mu.L, 0.4
mmol). The reaction was continued at room temperature for 4 days.
The reaction mixture was solubilized in ethyl acetate washed with
water and brine. The organic layer was dried over anhydrous
magnesium sulfate, filtered and evaporated in vacuo to a residue.
The crude material was purified on a preparative TLC plate
(20.times.20 cm, 1 mm) eluting with 50% ethyl acetate in hexane.
The product band was removed, eluted (4:1/dichloromethane:methano-
l), filtered and evaporated in vacuo and dried under high vacuum to
provide (3S, 3aS, 6aR)Hexahydrofuro[2,3b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2--
hydroxypropyl)carbamate (18.4 mg, 38%). HPLC showed the material to
be 96% pure; Ret. time=11.8 min. .sup.1H NMR (CDCl.sub.3): 7.65 (d,
2H), 7.13-7.24 (m, 5H), 6.92 (d, 2H), 5.71 (m, 1H), 4.73-4.82 (m,
3H), 3.71-3.91 (m, 7H), 2.68-3.03 (m, 7H), 2.12 (m, 1H), 1.48-1.74
(m, 10H) and MS (ES+), M+4=591.0.
Example 119
[0620] 737
[0621] Phosphate ester of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[[(3-N-methylaminophenyl)sulfonyl](cyclopentyloxy)amino]-1-be-
nzyl-2-hydroxypropylcarbamate. A solution of 0.145 g (0.25 mMol) of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-(1S,
2R)-3-[[(3-N-aminopheny-
l)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate
(Example 77), 0.042 mL (0.3 mMol) of triethylamine and 0.081 g (0.3
mMol) of 2,4-dinitrobenzenesulfonyl chloride in 2 mL of
tetrahydrofuran was treated with 0.2 mL of pyridine and 0.03 g of
4-N,N-dimethylamino pyridine and stirred at rt overnight. The
mixture was diluted with ethylacetate and extracted with 1N HCl and
saturated sodium bicarbonate. Chromatography on silica gel (1:1
ethyl acetate-hexanes) gave 75 mg of a yellow foam which was
dissolved in 1 mL of dimethylformamide and treated with 0.03 mL of
iodomethane and 0.06 mL of triethylamine. The resulting mixture was
heated to 70.degree. C. for 10 h and then evaporated.
Chromatography on silicagel (40% ethylacetate-hexanes) gave a white
foam which was dissolved in 1 mL of acetonitrile and 1 mL of
dichloromethane. This solution was treated with 0.06 mL of
dibenzyldiisopropyl phosphoramidite and 0.02 g of tetrazole. The
resulting solution was stirred at rt for 0.5 h and evaporated.
Chromatography on silicagel (40% ethylacetate-hexanes) gave a
colorless oil which was dissolved in 1 mL of acetonitrlle and 1 mL
of dichloromethane and treated with 0.2 g of iodosobenzene
diacetate. After two hours at rt, the volatiles were removed and
the the residue was re-dissolved in dichloromethane. The solution
was treated with 1.5 mL of n-propylamine for 15 minutes and then
evaporated. Chromatography on silicagel (60% ethylacetate-hexanes)
gave a yellow oil which was dissolved in 20 mL of 2M ammonia in
methanol and treated with 5 mg of 5% palladium on carbon. The
mixture was hydrogenated for 1 h at 50 PSI, filtered and
evaportated to give 15 mg of a white powdery solid. .sup.1H NMR
(CD.sub.3CN): 1.5-1.9 (13H), 2.75 (1H), 2.8-3.0 (3H), 2.90 (3H),
3.15 (1H), 3.7 (1H), 3.9 (5H), 4.8 (1H), 5.0 (1H), 5.5 (1H),
7.0-7.4 (7H), 7.5 (2H). .sup.31P NMR (CD.sub.3CN): 2.1 ppm). LC-MS:
671 (MH+).
Example 120
[0622] 738
[0623] 1,3-Dioxan-5-yl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(1-carbometho-
xy-3-(carbomethoxyamino)indazole-5-ylsulfonyl)amino]-2-hydroxypropylcarbam-
ate. 1,3-Dioxan-5-yl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)amino]-2-hydrox-
ypropylcarbamate (Step 1, Example 55), (130 mg, 0.330 mmol),
1-carbomethoxy-3-(carbomethoxyamino)indazole-5-sulfonyl chloride
(110 mg, 0.330 mmol), and anhydrous diisopropylethylamine (0.06 mL,
0.330 mmol), were combined in anhydrous tetrahydrofuran (5 mL) in a
25 mL round bottomed flask under nitrogen. The reaction was stirred
for 24 hours and concentrated in vacuo. After the workup described
in Step 3, Example 54, the residue was purified by preparative
silica gel TLC using 3:1/ethyl acetate:hexane as an eluent to give
the product as a oil (91 mg, 0.129 mmol, 39%). .sup.1HNMR
(d.sub.6-DMSO): 10.99 (s, 1H), 8.73 (s, 1H), 8.35 (d, J=8.9 Hz,
1H), 7.95 (d, J=8.9 Hz, 1H), 7.27-7.16 (m, 5H), 5.24 (d, J=6.5 Hz,
1H), 4.85-4.63 (m, 3H), 4.06 (s, 3H), 3.80-3.00 (m, 11H), 3.76 (s,
3H), 1.97-1.40 (m, 8H). MS (ES): 706 (M+1), 704 (M-1).
Example 121
[0624] 739
[0625] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(c-
yclopentyloxy)(3-[(2-[(methylamino)carbonyl]aminoethyl)amino]phenylsulfony-
l)amino]-2-hydroxypropylcarbamate and
(3S,3aR,6aS)hexahydrofuro[2,3-b]fura- n-3-yl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(3-[(2-[(methylamino)carbonyl-
]amino ethyl)amino]phenylsulfonyl)amino]-2-hydroxypropylcarbamate.
A solution of 33 mg (0.053 mmol) of a 1:1 mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(3-[(2-aminoethyl-
)amino]phenylsulfonyl)(cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarba-
mate and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(3-[(2-aminoethyl)amino]phenylsulfonyl)(cyclopentyloxy)amino-
]-1-benzyl-2-hydroxypropylcarbamate (Example 83) in 1 mL of
anhydrous 1,4-dioxane was treated with 0.003 mL (0.05 mmol) of
methyl isocyanate. The resulting solution was stirred at RT. After
2 hours the solution was concentrated in vacuo to afford 35 mg
(97%) of the desired product as a white foam. 1H-NMR (CDCl.sub.3):
7.43-7.01 (13H), 5.76-4.80 (4H), 4.08-2.70 (18H), 1.90-1.30 (10H).
LCMS (ESI): 676 (M+H).
Example 122
[0626] 740
[0627] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((-
cyclopentyloxy)[3-(2-[(methylsulfonyl)amino]ethylamino)phenyl]sulfonylamin-
o)-2-hydroxypropyl]carbamate and
(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-y- l
N-[(1S,2R)-1-benzyl-3-((cyclopentyloxy)[3-(2-[(methylsulfonyl)amino]ethy-
lamino)phenyl]sulfonylamino)-2-hydroxypropyl]carbamate. A solution
of 33 mg (0.053 mmol) of a 1:1 mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan- -3-yl
N-(1S,2R)-3-[(3-[(2-aminoethyl)amino]phenylsulfonyl)(cyclopentyloxy)-
amino]-1-benzyl-2-hydroxypropylcarbamate and
(3S,3aR,6aS)hexahydrofuro[2,3- -b]furan-3-yl
N-(1S,2R)-3-[(3-[(2-aminoethyl)amino]phenylsulfonyl)(cyclope-
ntyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate (Example 83) in 2
mL of anhydrous THF at 0.degree. C. was treated with 0.010 mL
(0.059 mmol) of N,N-diisopropylethylamine followed by 0.005 mL
(0.06 mmol) of methanesulfonyl chloride. The resulting solution was
allowed to warm to RT with stirring. After 3 hours the solution was
concentrated in vacuo and the residue subjected to flash
chromatography (silica gel, 95:5 CH.sub.2Cl.sub.2/2M NH.sub.3 in
MeOH) to afford 31 mg (86%) of the desired product as a white foam.
1H-NMR (CDCl.sub.3): 7.40-6.81 (12H), 5.62 (1H), 5.43-5.04 (1H),
4.99 (1H), 4.81 (1H), 3.97-2.60 (18H), 1.90-1.30 (10H). LCMS (ESI):
697 (M+H).
Example 123
[0628] 741
[0629] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((-
cyclopentyloxy)[(3-methoxyphenyl)sulfonyl]amino)-2-hydroxypropyl]carbamate
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclope-
ntyloxy)[(3-hydroxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
was combined with potassium carbonate (0.86 mmol, 120 mg),
iodomethane (0.86 mmol, 0.054 mL), and anhydrous DMF (0.5 mL) under
nitrogen. The reaction stirred for 3 hours at 50.degree. C. and was
concentrated to an oil under vacuum, diluted in ethyl acetate,
washed with distilled water and brine, and dried over magnesium
sulfate. The crude reaction product was concentrated and purified
by silica gel chromatography (1:1/hexanes/ethyl acetate) and
yielded 51 mg (>99%) of a fine white powder R.sub.f=0.15 (1:1
hexanes/ethyl acetate); .sup.1H NMR (CDCl.sub.3): .delta. 7.46-7.39
(1H, m), 7.38-7.32 (1H, m), 7.32-7.13 (8H, m), 5.65-5.60 (1H, m),
5.03-4.94 (1H, m), 4.84-4.71 (2H, m), 3.95-3.84 (5H, m), 3.84 (3H,
s), 3.70-3.61 (2H, m), 3.13 (1H, bs), 3.06-2.72 (5H, m), 1.87-1.69
(4H, m), 1.70-1.54 (4H, m); MS (ESI): M+H=591.
Example 124
[0630] 742
[0631] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((-
cyclopentyloxy)[3-(2-[(methoxycarbonyl)amino]ethylamino)phenyl]sulfonylami-
no)-2-hydroxypropyl]carbamate and
(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-- yl
N-[(1S,2R)-1-benzyl-3-((cyclopentyloxy)[3-(2-[(methoxycarbonyl)amino]et-
hylamino)phenyl]sulfonylamino)-2-hydroxypropyl)carbamate. A
solution of 33 mg (0.053 mmol) of a 1:1 mixture of (3R,3aS,
6aR)hexahydrofuro[2,3-b]fura- n-3-yl
N-(1S,2R)-3-[(3-[(2-aminoethyl)amino]phenylsulfonyl)(cyclopentyloxy-
)amino]-1-benzyl-2-hydroxypropylcarbamate and
(3S,3aR,6aS)hexahydrofuro[2,- 3-b]furan-3-yl
N-(1S,2R)-3-[(3-[(2-aminoethyl)amino]phenylsulfonyl)(cyclop-
entyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate (Example 83) in 2
mL of anhydrous THF at 0.degree. C. was treated with 0.010 mL
(0.059 mmol) of N,N-diisopropylethylamine followed by 0.005 mL
(0.06 mmol) of methyl chloroformate. The resulting solution was
allowed to warm to RT with stirring. After 3 hours the solution was
concentrated in vacuo and the residue subjected to flash
chromatography (silica gel, 95:5 CH.sub.2Cl.sub.2/2M NH.sub.3 in
MeOH) to afford 32 mg (89%) of the desired product as a white foam.
1H-NMR (CDCl.sub.3): 7.40-6.81 (12H), 5.61 (1H), 5.40-4.87 (2H),
4.80 (1H), 3.97-2.63 (18H), 1.90-1.30 (10H). LCMS (ESI): 677
(M+H).
Example 125
[0632] 743
[0633] Preparation of 1,3-Dioxane-5-yl
N-(1S,2R)-1-benzyl-3-[(cyclopentylo-
xy)(2-amino)]-benzothiazol-6-ylsulfonyl)amino]-2-hydroxypropylcarbamate
[0634] Step 1:
[0635] To a suspension of 2-aminobenzothiazole (4 g, 26.6 mmol) in
20 ml of dichloromethane under nitrogen was added 4 mL of anhydrous
DMF. The solution was cooled to -5.degree. C. and triethylamine
(7.4 mL, 53.2 mmol, 2.0 eq.) was added. Methanesulfonyl chloride
(2.3 mL, 29.3 mmol, 1.1 eq.) was added over 5 minutes followed by
an additional 4 mL of dichloromethane. The reaction was warmed to
25.degree. C. After approximately 24 hours at 25.degree. C., the
reaction was quenched with saturated bicarbonate solution and
partitioned between water and ethyl acetate. The aqueous layer was
extracted with ethyl acetate and the combined organic layers were
washed with water (4.times.), saturated brine solution, dried over
sodium sulfate, filtered and the solvent removed in vacuo to give
930 mg of a residue that was shown by LCMS to contain almost no
product. The combined aqueous layers were extracted with excess
ethyl acetate. These organic layers were washed with saturated
brine solution, dried over sodium sulfate, filtered and the solvent
removed in vacuo to give 1.2 g of product that was shown by HPLC
and LCMS to be over 97% pure desired product which was used without
further purification. LCMS: 229.0 (M+H).
[0636] Step 2:
[0637] To 2.4 mL (35 mmol, 20 eq.) of chlorosulfonic acid, stirred
under nitrogen at -40.degree. C., was added
2-methane-sulfonamidobenzothiazole (Step 1) (400 mg, 1.75 mmol) in
small portions over 10 minutes. The suspension was stirred at
-40.degree. C. for 5 minutes, then was warmed to 0.degree. C. for
2.5 hours, then warmed to 25.degree. C. After approximately 4 days
at 25.degree. C., the reaction was quenched by adding dropwise to
well stirred ice water. A small amount of solid was filtered off
and shown by HPLC to contain only a small amount of the desired
product. The aqueous layer was extracted with ethyl acetate
(2.times.) and the combined organic layers were washed with
saturated brine solution, dried over sodium sulfate, filtered and
the solvent removed in vacuo to give 146 mg of the desired
material. HPLC showed the material to be .about.80% pure, Ret.
time=9.42 min. The material was used without further
purification.
[0638] Step 3:
[0639] To 64 mg (0.26 mmol) of 2-aminobenzothiazole-6-sulfonyl
chloride, (2), was added 102 mg (0.26 mmol, 1.0 eq.) of
1,3-Dioxane-5-yl
N-(1S,2R)-1-benzyl-3-(cyclopentyloxyamino)2-hydroxypropylcarbamate
(Example 55, Step 1) and 7 mg of 4-dimethylaminopyridine. The
mixture was dissolved in 3 mL of anhydrous pyridine to give a
yellow solution. Solid formed within 5 minutes and the suspension
stirred at 25.degree. C., under nitrogen, for approximately 21
hours. The reaction was quenched with saturated sodium bicarbonate
solution and ethyl acetate. The solvent removed in vacuo to remove
excess pyridine, and the residue was extracted with ethyl acetate
(2.times.). The combined organic layers were washed with saturated
brine solution, dried over sodium sulfate, filtered and the solvent
was removed in vacuo to give 100 mg of
2-aminobenzothiazole-6-sulfonyl chloride, (2). HPLC showed the
material to be 94% pure, Ret. time=8.343 min. The material was used
without further purification.
[0640] .sup.1H NMR (chloroform-D3) 5.71 (s, 2H), 8.62 (d, 1H), 7.95
(d, 1H), 8.29 (s, 1H) and LC/MS, M+H=248.9 confirms no
methanesulfonyl group present.
Example 126
[0641] 744
[0642] 3-Bromo-N-tert-butoxycarbonylaniline.
[0643] 3-Bromoaniline (0.50 ml, 4.6 mmol) di-tert-butyldicarbonate
(1.20 g, 5.5 mmol) and 4-dimethylaminopyridine (0.003 g) were
combined in anhydrous CH.sub.2Cl.sub.2 (10 ml). Solution chilled to
0.degree. C. and triethylamine (1.28 ml, 9.2 mmol) was added.
Reaction was allowed to warm to room temperature then was heated to
reflux for 1 hour. Reactiom mixture was diluted in EtOAc and washed
with sat. NaHCO.sub.3, 0.5N KHSO.sub.4 and brine. Organic phase was
dried with MgSO.sub.4 and the solvent was removed in vacuo.
Purification by flash chromatography (1:4/EtOAc/Hex to 1:3 to 1:2).
Recovered 1.01 g (81%) of the product as a light yellow solid.
Rf=0.62 (1:4 EtOAc/Hex). .sup.1H NMR (CDCl.sub.3) 7.68 (1H, s),
7.22-7.10 (3H, m), 6.48 (1H, b), 1.51 (9H, s). 745
[0644] 3-Bromo-N-tert-butoxycarbonyl-N-methylaniline.
[0645] 3-Bromo-N-tert-butoxycarbonylaniline (0.50 g, 1.8 mmol) was
dissolved in anhydrous DMF (5 ml). Sodium hydride (0.088 g, 2.2
mmol) was added to the solution and the deprotonation was stirred
10 minutes at room temperature. Methyl iodide (0.137 ml, 2.2 mmol)
was added slowly and the reaction was stirred overnight at room
temperature. Reaction mixture was diluted in EtOAc and washed with
H.sub.2O and brine. The organic phase was dried with MgSO.sub.4 and
and the solvent was removed in vacuo to give 0.51 g (96%) of the
product cleanly as a light yellow oil. Rf=0.63 (1:4 EtOAc/Hex).
.sup.1H NMR (CDCl.sub.3) 7.41 (1H, s), 7.30 (1H, m), 7.20 (2H, m),
3.23 (3H, s), 1.49 (9H, s). 746
[0646] N-tert-Butoxycarbonyl-3-chlorosulfonyl-N-methylaniline.
[0647] 3-Bromo-N-tert-butoxycarbonyl-N-methylaniline (0.358 g, 1.2
mmol) was dissolved in freshly distilled THF (5 ml) under a N.sub.2
atmosphere. The solution was chilled to -78.degree. C. and n-butyl
lithium (0.750 ml, 2.0 M solution in cyclohexane, 1.5 mmol) was
added. After 15 minutes, sulfuryl chloride (0.121 ml, 1.5 mmol) was
added and the reaction was allowed to warm to room temperature and
stirring was continued overnight. THF was removed by evaporation
and the resulting residue was diluted in EtOAc. Organic phase was
washed with H.sub.2O and brine before being dried with MgSO.sub.4.
The solvent was removed in vacuo. Purification by flash
chromatography (1.19/EtOAc/Hex gradient to 1:9 and then to 1:4).
Recovered 0.089 g (23%) of the product as a colorless oil. Rf=0.14
(1:9 EtOAc/Hex). .sup.1H NMR (CDCl.sub.3) 7.96 (1H, s), 7.80 (1H,
d), 7.68 (1H, d), 7.57 (1H, t), 3.33 (3H, s), 1.50 (9H, s).
[0648] Step 4:
[0649]
(3R,3aS,6aR)Hexahydrofuro[2,3b]furan-3-yl-N-(1S,2R)-1-benzyl-3-[(is-
opropyloxy)[(3-(N-(methyl-tert-Butoxycarbonyl))phenyl)sulfonyl]amino-2-hyd-
roxypropylcarbamate 747
[0650] In a dried flask was introduced 1 eq. of
(3R,3aS,6aR)Hexahydrofuro[-
2,3b]furan-3-yl-N-(1S,2R)-1-benzyl-3-[(isopropyloxy)amino]-2-hydroxypropyl-
carbamate (53.6 mg, 0.14 mmol) in 2 mL of dried pyridine. To this
solution was added 1.2 eq. of
N-tert-Butoxycarbonyl-3-chlorosulfonyl-N-methylanili- ne (50 mg,
0.16 mmol) and catalytic amount of N,N-dimethyl aminopyridine. The
reaction was continued at room temperature for 24 h. The solvent
was evaporated in vacuo to an oil who was solubilized in ethyl
acetate washed with 1N hydrochloric acid, and brine. The organic
layer was dried over anhydrous magnesium sulfate, filtered and
evaporated in vacuo to a residue. The crude material was purified
on flash grade silica gel eluting with 50% ethyl acetate in hexane.
Fractions containing the product were combined, evaporated in vacuo
and dried under high vacuum to provide
(3R,3aS,6aR)Hexahydrofuro[2,3b]furan-3-yl-N-(1S,2R)-1-benzyl-3-[(-
isopropyloxy)[(3-(N-(methyl-tert-Butoxycarbonyl))phenyl)sulfonyl]amino-2-h-
ydroxy propylcarbamate (29.2 mg, 31%). HPLC showed the material to
be 98% pure; Ret. time=12.1 min. .sup.1H NMR (CDCl.sub.3):
7.09-7.78 (m, 9H), 5.56 (d, 1H), 5.15 (bs, 1H), 4.91 (q, 1H), 4.49
(q, 1H), 3.57-3.88 (m, 5H), 3.24 (s, 3H), 2.96 (m, 2H), 2.72 (m,
1H), 2.56 (m, 1H), 1.42-1.50 (m+s, 13H), 1.19 (d, 6H) and LCMS
(ES+), M+H=664.3.
Example 127
[0651]
(3R,3aS,6aR)Hexahydrofuro[2,3b]furan-3-yl-N-(1S,2R)-1-benzyl-3-[(is-
opropyloxy)[(3-N-methylphenyl)sulfonyl]amino-2-hydroxypropylcarbamate
748
[0652] In a dried flask was introduced 1 eq. of
(3R,3aS,6aR)Hexahydrofuro[-
2,3b]furan-3-yl-N-(1S,2R)-1-benzyl-3-[(isopropyloxy)[(3-(N-(methyl-tert-Bu-
toxycarbonyl))phenyl)sulfonyl]amino-2-hydroxy propylcarbamate (10.8
mg, 0.016 mmol) in 1 mL dichloromethane. To this solution was added
600 .mu.L of trifluoroacetic acid. The reaction was continued at
room temperature for 45 min. The solvent was evaporated in vacuo to
an oil. The crude material was purified on flash grade silica gel
eluting with 50% ethyl acetate in hexane. Fractions containing the
product were combined, evaporated in vacuo and dried under high
vacuum to provide
(3R,3aS,6aR)Hexahydrofuro[2,3b]furan-3-yl-N-(1S,2R)-1-benzyl-3-[(isopropy-
loxy)[(3-N-methylphenyl)sulfonyl]amino-2-hydroxypropyl carbamate
(7.2 mg, 78%). HPLC showed the material to be 98% pure; Ret.
time=10.1 min. H.sup.1-NMR (CDCl.sub.3): 7.09-7.35 (m, 9H), 6.86
(m, 1H), 5.58 (d, 1H), 4.92-4.96 (m, 2H), 4.46-4.50 (m, 2H),
3.56-3.85 (m, 5H), 2.71-2.97 (m+s, 7H), 1.45-1.80 (m, 3H), 1.17 (d,
6H) and LCMS (ES+), M+H=564.3.
Example 128
[0653]
(3R,3aS,6aR)hexahydrofuro[2,3b]furan-3-yl-N-(1S,2R)-1-benzyl-3-[(cy-
clopentyloxy)[(3-(N-(methyl-tert-Butoxycarbonyl))phenyl)sulfonyl]amino-2-h-
ydroxypropylcarbamate 749
[0654] In a dried flask was introduced 1 eq. of
(3R,3aS,6aR)Hexahydrofuro[-
2,3b]furan-3-yl-N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)amino]-2-hydroxyprop-
ylcarbamate (60 mg, 0.14 mmol) in 2 mL of dried pyridine. To this
solution was added 1.3 eq. of
N-tert-Butoxycarbonyl-3-chlorosulfonyl-N-methylanili- ne (57 mg,
0.19 mmol) and catalytic amount of N,N-dimethylaminopyridine. The
reaction was continued at room temperature for 24 h. The solvent
was evaporated in vacuo to an oil who was solubilized in ethyl
acetate washed with 1N hydrochloric acid, and brine. The organic
layer was dried over anhydrous magnesium sulfate, filtered and
evaporated in vacuo to a residue. The crude material was purified
on flash grade silica gel eluting with 50% ethyl acetate in hexane.
Fractions containing the product were combined, evaporated in vacuo
and dried under high vacuum to provide
(3R,3aS,6aR)hexahydrofuro[2,3b]furan-3-yl-N-(1S,2R)-1-benzyl-3-[(-
cyclopentyloxy)[(3-(N-(methyl-tert-Butoxycarbonyl))phenyl)sulfonyl]amino-2-
-hydroxypropylcarbamate (26.8 mg, 28%). HPLC showed the material to
be 99% pure; Ret. time=12.88 min. H.sup.1-NMR (CDCl.sub.3): 7.74
(m, 1H), 7.09-7.51 (m, 9H), 5.60 (m, 1H), 5.25 (bs, 1H), 4.94 (q,
1H), 4.77 (q, 1H), 3.71-3.86 (m, 6H), 3.52 (m, 1H), 3.24 (m, 3H),
3.08 (m, 1H), 2.85-2.93 (m, 4H), 2.68 (m, 1H), 1.73-1.83 (m, 5H),
1.42-1.59 (m+s, 12H) and LCMS (ES+), M+H=690.2.
Example 129
[0655] 750
[0656]
tert-Butyl-N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(3-nitrophenyl)su-
lfonyl]amino-2-hydroxypropyl)carbamate.
[0657]
tert-Butyl-N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)amino-2-hydroxypro-
pyl)carbamate (0.52 g, 1.4 mmol) was combined with
3-nitrobenzenesulfonyl chloride (0.47 g, 2.1 mmol) in freshly
distilled THF (5 ml). Diisopropylethylamine (0.74 ml, 4.3 mmol) was
added and the reaction was stirred at room temperature overnight.
Reaction mixture was diluted in EtOAc and washed with 0.5 N
KHSO.sub.4, and brine. Organic phase was dried with MgSO.sub.4 and
solvent was removed in vacuo. Purication by flash chromatography
(1:4/EtOAc/Hex gradient to 1:3, to 1:2, to 1:1 and then to 2:1).
Recovered 0.44 g (56%) of the product as a white foam. Rf=0.45 (2:1
EtOAc/Hex), .sup.1H NMR (CDCl.sub.3) 8.67 (1H, s), 8.49 (1H, d),
8.08 (1H, d), 7.77 (1H, t), 7.36-7.17 (5H, m), 4.88 (1H, m), 4.62
(1H, b), 3.88-3.71 (2H, m), 3.41 (1H, b), 3.07 (1H, b), 2.98-2.79
(3H, m), 1.92-1.75 (4H, m), 1.73-1.52 (4H, m), 1.45 (9H, s).
751
[0658]
(1S,2R)-1-benzyl-3-(cyclopentyloxy)[(3-nitrophenyl)sulfonyl]amino-2-
-hydroxypropylamine.
[0659]
tert-Butyl-N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(3-nitrophenyl)su-
lfonyl]amino-2-hydroxypropyl)carbamate (0.34 g, 0.6 mmol) was
dissolved in CH.sub.2Cl.sub.2 (3 ml). Trifluoroacetic acid was
added with stirring and the reaction was stirred 15 minutes at room
temperature. The solvent was removed by evaporation and the
resulting residue was partitioned between EtOAc and sat.
NaHCO.sub.3. Organic phase was washed with sat. NaHCO.sub.3 and
brine then dried with MgSO.sub.4. Solvent was removed in vacuo to
give 0.27 g (100%) of the product as a white foam. Rf=0.11 (2:1
EtOAc/Hex). .sup.1H NMR (CDCl.sub.3) 8.75 (1H, s), 8.52 (1H, d),
8.19 (1H, d), 7.80 (1H, t), 7.40-7.08 (5H, m), 4.90 (1H, m), 3.80
(1H, m), 3.36-3.14 (2H, m), 3.05 (1H, b), 2.88 (1H, d), 2.48 (1H,
m), 1.96-1.75 (4H, m), 1.74-1.50 (4H, m). 752
[0660]
1,3-Dioxan-5-yl-N-(1S,2R)-benzyl-3-(cyclopentyloxy)[(3-nitrophenyl)-
sulfonyl)amino-2-hydroxypropylcarbamate.
[0661]
(1S,2R)-1-benzyl-3-(cyclopentyloxy)[(3-nitrophenyl)sulfonyl]amino-2-
-hydroxypropylamine (0.070 g, 0.2 mmol) was combined with
1,3-dioxan-5-yl-(4-nitrophenyl)carbonate (0.066 g, 0.2 mmol) in
anhydrous DMF (4 ml) under a N.sub.2 atmosphere. Triethyl amine
(0.045 ml, 0.3 mmol) was added and the reaction was stirred at room
temperature for 2 hours. Reaction mixture was diluted in EtOAc and
washed with sat. NaHCO.sub.3, 0.5N KHSO.sub.4 and brine. The
organic phase was dried with MgSO.sub.4 and solvent was removed in
vacuo. Purification by flash chromatography (1:2 EtOAc/Hex to 1:1
to 2:1). Recovered 0.073 g (78%) of the product as a white foam.
Rf=0.26 (1:1 EtOAc/Hex). .sup.1H NMR (CDCl.sub.3) 8.66 (1H, s),
8.50 (1H, d), 8.08 (1H, d), 7.77 (1H, t), 7.36-7.13 (5H, m), 5.01
(1H, d), 4.92 (1H, d), 4.88 (1H, m), 4.73 (1H, d), 4.50 (1H, s),
4.00-3.79 (6H, m), 3.13 (1H, m), 3.08-2.88 (2H, m), 2.77 (1H, m),
1.96-1.73 (4H, m), 1.72-1.52 (4H, m). 753
[0662]
1,3-Dioxan-5-yl-N-(1S,2R)-benzyl-3-(cyclopentyloxy)[(3-aminophenyl)-
sulfonyl)amino-2-hydroxypropylcarbamate.
1,3-Dioxan-5-yl-N-(1S,2R)-benzyl--
3-(cyclopentyloxy)[(3-nitrophenyl)sulfonyl]amino-2-hydroxypropylcarbamate
(0.070 g, 0.1 mmol) was combined with tin chloride dihydrate (0.109
g, 0.5 mmol) is absolute ethanol (10 ml). Reation was heated to
reflux and stired for 2.5 hours. Ethanol was removed in vacuo and
the material was purified by preparative TLC (2:1/EtOAc/Hex).
Recovered 0.045 g (68%) of the product as a colorless residue.
Rf=0.36 (2:1 EtOAc/Hex). .sup.1H NMR (CDCl.sub.3) 7.38-7.18 (6H,
m), 7.15 (1H, d), 7.07 (1H, s), 6.85 (1H, d), 5.00 (1H, d), 4.92
(1H, d), 4.83 (1H, m), 4.76 (1H, d), 4.53 (1H, s), 4.05-3.80 (5H,
m), 3.73 (1H, m), 3.19 (1H, m), 3.10 (1H, m), 3.00-2.82 (2H, m),
1.91-1.70 (4H, m), 1.69-1.50 (4H, m). LRMS (M+H).sup.+ 550.3.
Example 130
[0663] 754
[0664]
tert-Butyl-N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)(2-[(methoxycarbon-
yl)amino]benzimidazol-5-ylsulfonyl)amino-2-hydroxypropyl)carbamate.
[0665]
tert-Butyl-N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)amino-2-hydroxypro-
pyl)carbamate (step 1, Example 54), (0.75 g, 2.1 mmol) was combined
with 2-(methoxycarbonyl)amino benzimidazol-5-ylsulfonyl chloride
(0.89 g, 3.1 mmol) in anhydrous DMF (15 ml) under a N.sub.2
atmosphere. Diisopropylethylethyl amine (1.08 ml, 6.2 mmol) was
added and the reaction was stirred at room temperature for 24
hours. The reaction mixture was diluted in EtOAc and washed with
sat. NaHCO.sub.3, 0.5N KHSO.sub.4 and brine. Organic phase was
dried with MgSO.sub.4 and solvent was removed in vacuo.
Purification by flash chromatography (CH.sub.2Cl.sub.2 to 1% MeOH
in CH.sub.2Cl.sub.2 to 2% to 3% to 4%). Recovered 0.79 g (62%) of
product as a white foam. Rf=0.08 (3% MeOH/CH.sub.2Cl.sub.2). HPLC
t.sub.R=10.47 min (C18 column). LRMS (M+H).sup.+ 618.2.
Example 131
[0666] 755
[0667]
tert-Butyl-N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)(2-oxybenzimidazol-
-5-ylsulfonyl)amino-2-hydroxypropyl)carbamate.
[0668]
tert-Butyl-N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)amino-2-hydroxypro-
pyl)carbamate (Step 1, Example 54), (0.100 g, 0.3 mmol) was
combined with 2-oxobenzimidazol-5-ylsulfonyl chloride (0.070 g, 0.3
mmol) in anhydrous DMF (2 ml) under a N.sub.2 atmosphere.
Diisopropylethylethyl amine (1.08 ml, 6.2 mmol) was added and the
reaction was stirred at room temperature overnight. The reaction
mixture was diluted in EtOAc and washed with sat. NaHCO.sub.3, 0.5N
KHSO.sub.4 and brine. Organic phase was dried with MgSO.sub.4 and
solvent was removed in vacuo. Purification by flash chromatography
(1:1/EtOAc/Hex to 2:1 to 3:1 to EtOAc). Recovered 0.052 g (54%) of
product as a white foam. Rf=0.10 (2:1 EtOAc/Hex). HPLC
t.sub.R=10.08 min (C18 column). LRMS (M+H).sup.+ 561.2.
Example 132
[0669] 756
[0670]
1,3-Dioxan-5-yl-N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)(2-[(methylsu-
lfonyl)amino)benzimidazol-5-ylsulfonyl)amino-2-hydroxypropyl)carbamate.
[0671]
1,3-Dioxan-5-yl-N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)amino-2-hydro-
xypropyl)carbamate (Step 1, Example 55), (0.148 g, 0.4 mmol) was
combined with 2-[(methylsulfonyl)amino]benzimidazol-5-ylsulfonyl
chloride (0.162 g, 0.5 mmol) in anhydrous DMF (4 ml) under a
N.sub.2 atmosphere. The resulting solution was chilled to 0.degree.
C. and diisopropylethylethyl amine (0.196 ml, 1.1 mmol) was added.
The reaction was allowed to warm to room temperature and stirred
for 24 hours. Reaction mixture was diluted in EtOAc and washed with
sat. NaHCO.sub.3, 0.5N KHSO.sub.4 and brine. Organic phase was
dried with MgSO.sub.4 and solvent was removed in vacuo.
Purification by flash chromatography (EtOAc to 2% MeOH/EtOAc to
4%). Recovered 0.159 g (64%) of the product as a white foam.
Rf=0.48 (5% MeOH/EtOAc). .sup.1H NMR (CDCl.sub.3) 8.10 (1H, s),
7.67 (1H, d), 7.41 (1H, d), 7.30-7.15 (5H, m), 6.35 (2H, s), 5.14
(1H, d), 4.90 (1H, d), 4.85 (1H, m), 4.72 (1H, d), 4.48 (1H, m),
3.93-3.73 (5H, m), 3.29 (3H, s), 1.89-1.70 (4H, m), 1.69-1.47 (4H,
m). LRMS (M+H).sup.+ 668.0.
Example 133
[0672] 757
[0673]
N-[2-(3-[[(2R,3S)-3-([(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy-
]carbonylamino)-2-hydroxy-4-phenylbutyl](cyclopentyloxy)amino]sulfonylanil-
ino)ethyl]-O-methyl-N'-(nitro)isourea and
N-[2-(3-[[(2R,3S)-3-([(3S,3aR,6a-
S)hexahydrofuro[2,3-b]furan-3-yloxy]carbonylamino)-2-hydroxy-4-phenylbutyl-
](cyclopentyloxy)amino]sulfonylanilino)ethyl]-O-methyl-N'-(nitro)isourea.
[0674] A solution of 25 mg (0.040 mmol) of a 1:1 mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(3-[(2-aminoethyl-
)amino]phenylsulfonyl)(cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarba-
mate and (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(3-[(2-aminoethyl)amino]phenyl
sulfonyl)(cyclopentyloxy)amin- o]-1-benzyl-2-hydroxypropylcarbamate
(Example 83) and 0.008 mL (0.048 mmol) of N,N-diisopropyl
ethylamine in 1.5 mL of anhydrous DMF was treated with 6 mg (0.05
mmol) of O-methyl-N-nitroisourea (Heyboer et al. Rec. Chim Trav.
Pay-Bas (1962), 81, 69-72). The resulting solution was stirred at
RT. After 20 hours the solution was concentrated in vacuo and the
residue subjected to flash chromatography (silica gel, 85:15
CH.sub.2Cl.sub.2/2M NH.sub.3 in MeOH) to afford 21 mg (72%) of the
desired product as a white foam. .sup.1H-NMR (CDCl.sub.3):
7.60-7.06 (12H), 5.63-4.65 (4H), 4.10-2.50 (18H), 1.90-1.31 (10H).
LCMS (ESI): 721 (M+H).
Example 134
[0675] 758
[0676] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(c-
yclohexyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate.
[0677] tert-butyl
N-((1S,2R)-1-benzyl-3-(cyclohexyloxy)[(4-methoxyphenyl)s-
ulfonyl]amino-2-hydroxypropyl)carbamate (0.09 mmol, 50 mg) was
stirred in 1 mL trifluoroacetic acid (TFA) at room temperature for
5 hours. The TFA was removed under vacuum, and the resulting
residue was dissolved in ethyl acetate, washed with 5% aq.
potassium carbonate solution, brine, dried over magnesium sulfate,
and concentrated to a residue. The resulting free amine, (2R, 3aS,
6aR)hexahydrofuro[2,3-b]furan-2-yl 4-nitrophenyl carbonate (0.09
mmol, 27 mg), diisopropylethylamine (0.13 mmol, 0.018 mL), a
crystal of N,N-dimethylaminopyridine, 4 .ANG. molecular sieves and
acetonitrile (0.5 mL) were combined and stirred at room temperature
for 3 days. The reaction solution was concentrated to a residue,
dissolved in ethyl acetate, washed with 1N HCl, 5% aq. potassium
carbonate solution, brine, dried over magnesium sulfate, and
concentrated under vacuum. The crude residue was purified by
crystallization from ether to yield 15 mg (27%) of white crystals.
H1-NMR (CDCl.sub.3): .delta. 7.71 (2H, d), 7.28-7.16 (6H, m), 6.97
(2H, d), 5.63-5.61 (1H, m), 5.00-4.98 (1H, m), 4.87-4.77 (1H, m),
4.24-4.11 (1H, m), 3.98-3.79 (4H, m), 3.87 (3H, s), 3.72-3.61 (2H,
m), 3.05 (1H, bs), 3.05-2.72 (6H, m), 2.10-1.98 (2H, m), 1.78-1.68
(2H, m), 1.37-1.04 (6H, m); MS (ESI): M+H=605.
Example 135
[0678] 759
[0679] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((-
cyclopentyloxy)[3-(2-morpholino-2-oxoethoxy)phenyl]sulfonylamino)-2-hydrox-
ypropyl]carbamate.
[0680] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)[(3-hydroxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
(0.09 mmol, 50 mg) was combined with
2-bromo-1-morpholino-1-ethanone (0.09 mmol, 18 mg) and potassium
carbonate (0.26 mmol, 36 mg), and stirred in anhydrous DMF (1 mL)
under nitrogen for 15 hours at room temperature. The reaction was
concentrated to a residue, dissolved in ethyl acetate, washed in
distilled water and brine, and dried over magnesium sulfate. The
dried solution was then concentrated and purified by silica gel
flash chromatography (1:1 hexanes/ethyl acetate) to provide 41 mg
(67%) of a white solid. R.sub.f=0.1 (1:1 hexanes/ethyl acetate);
H1-NMR (CDCl.sub.3) .delta. 7.47 (2H, m), 7.38 (1H, m), 7.327.14
(7H, m), 5.64 (1H, s), 5.03 (2H, m), 4.91-4.76 (1H, m), 4.78 (2H,
s), 3.98-3.89 (2H, m), 3.89-3.77 (2H, m), 3.74-3.63 (8H, m),
3.63-3.52 (2H, m), 3.15 (1H, br.s), 3.08-2.98 (2H, m), 2.98-2.84
(3H, m), 2.84-2.74 (1H, m), 1.89-1.71 (4H, m), 1.71-1.49 (4H, m).
MS (ESI): M+H=704.
Example 136
[0681] 760
[0682] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[[3-(2-amino-
-2-oxoethoxy)phenyl]sulfonyl(cyclopentyloxy)amino]-1-benzyl-2-hydroxypropy-
lcarbamate.
[0683] This reaction was set-up, run and purified under the same
conditions as for (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((cyclopentyloxy)
[3-(2-morpholino-2-oxoethoxy)phen-
yl]sulfonylamino)-2-hydroxypropyl]carbamate and generated 44 mg
(80%) of a white solid. R.sub.f=0.1 (1:1 hexanes/ethyl acetate);
H1-NMR (CDCl.sub.3): .delta. 7.58-7.42 (2H, m), 7.33-7.06 (8H, m),
6.39 (1H, s), 5.79 (1H, s), 5.63 (1H, s), 5.20-5.12 (1H, m),
5.09-4.99 (1H, m), 4.85 (1H, m), 4.60 (2H, s), 4.0-3.78 (4H, m),
3.71 (2H, m), 3.14 (1H, br.s), 3.09-2.70 (6H, m), 1.93-1.70 (4H,
m), 1.70-1.51 (4H, m). MS (ESI): M+H=634.
Example 137
[0684] 761
[0685] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)[(3-2-[methoxy(methyl)amino]-2-oxoethoxyphenyl)sulfonyl]amin-
o-2-hydroxypropyl)carbamate.
[0686] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)[(3-hydroxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
(0.17 mmol, 100 mg), 2-bromo-N-methoxy-N-methylacetamide (0.26
mmol, 43 mg) and excess potassium carbonate were stirred in
anhydrous DMF (1 mL) under nitrogen for 20 hours at room
temperature. The DMF was removed under vacuum and the residue was
dissolved in ethyl acetate. The crude solution was washed with 1N
HCl, saturated aqueous sodium bicarbonate and brine, and dried over
magnesium sulfate. The dried solution was concentrated to an oil
and purified by silica gel flash chromatography (1:1 hexanes/ethyl
acetate) to yield 65 mg (55%) of a white solid. R.sub.f=0.1 (1:1
hexanes/ethyl acetate); H1-NMR (CDCl.sub.3): .delta. 7.45 (2H, m),
7.26 (5H, m), 7.20 (3H, m), 5.64 (1H, s), 5.09-4.97 (2H, m), 4.91
(2H, s), 4.83 (1H, m), 3.92 (2H, m), 3.78 (3H, s), 3.85-3.74 (2H,
m), 3.73-3.59 (2H, m), 3.23 (3H, s), 3.28-3.11 (1H, br.s),
3.06-2.84 (5H, m), 2.75 (1H, m), 1.89-1.72 (4H, m), 1.71-1.48 (4H,
m). MS (ESI): M+H=678.
Example 138
[0687] 762
[0688] tert-butyl
N-(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(cyclopentylo-
xy)amino]-1-benzyl-2-hydroxypropylcarbamate.
[0689] tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)amino]-2-hydroxypr-
opylcarbamate (0.19 mmol, 69 mg) was combined with
1,3-benzodioxole-5-sulf- onyl chloride (0.23 mmol, 50 mg) and
diisopropylethylamine (0.57 mmol, 73 mg) in anhydrous THF (2 mL).
The reaction stirred under nitrogen for 72 hours at room
temperature. The reaction was diluted with diethyl ether, washed
with 1 N HCl, saturated aqueous sodium bicarbonate, brine, and was
dried over magnesium sulfate. The crude product was concentrated to
an oil and purified by silica gel flash chromatography (5:1
hexanes/ethyl acetate) to provide 82 mg (79%) of a white solid. The
1,3-benzodioxole-5-sulfonyl chloride was synthesized as described
in Eur. Pat. Appl. 583960, Feb. 23, 1994. R.sub.f=0.40 (2:1
hexanes/ethyl acetate); H1-NMR (CDCl.sub.3): .delta. 7.37-7.15 (8H,
m), 6.89 (1H, d), 6.10 (2H, s), 4.82 (1H, m), 4.60 (1H, m), 3.82
(2H, m), 3.06 (1H, br.s), 2.94 (2H, m), 2.86 (1H, m), 1.90-1.70
(4H, m), 1.65-1.48 (4H, m), 1.35 (9H, s). MS (ESI): M+H=549.
763
[0690] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(1,3-benzod-
ioxol-5-ylsulfonyl)(cyclopentyloxy)amino)-1-benzyl-2-hydroxypropylcarbamat-
e. tert-butyl N-(1S,
2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(cyclopentyloxy)-
amino]-1-benzyl-2-hydroxypropylcarbamate (0.15 mmol, 80 mg) was
dissolved in neat trifluoroacetic acid (TFA) and stirred for 2
hours at room temperature. The TFA was removed under vacuum, and
the reaction residue was dissolved in ethyl acetate. The reaction
solution was washed with 5% aqueous potassium carbonate, brine and
dried over magnesium sulfate. The crude solution was concentrated
and re-dissolved in 1:1 hexanes/methylene chloride to exchange out
the ethyl acetate. The resulting oil was combined with
(2R,3aS,6aR)hexahydrofuro[2,3-b]furan-2-yl 4-nitrophenyl carbonate
(0.22 mmol, 65 mg), diisopropylethylamine (0.44 mmol, 0.076 mL), 4
.ANG. molecular sieves and stirred in anhydrous THF (2 mL) under
nitrogen for 15 hours at room temperature. The reaction was diluted
with ethyl acetate, washed with 1N HCl, saturated aqueous sodium
bicarbonate, brine and was dried over magnesium sulfate. The crude
product was purified by silica gel flash chromatography (2:1
hexanes/ethyl acetate) to provide 41 mg (47%) of a white solid.
R.sub.f=0.20 (1:1 hexanes/ethyl acetate); H1-NMR (CDCl.sub.3):
.delta. 7.41-7.14 (8H, m), 6.91 (1H, d), 6.12 (2H, s), 5.66 (1H,
s), 5.03 (2H, m), 4.84 (2H, m), 3.91 (4H, m), 3.70 (2H, m), 3.12
(1H, s), 3.01 (2H, m), 2.93 (1H, m), 2.84 (2H, m), 1.91-1.71 (4H,
m), 1.71-1.49 (4H, m). MS (ESI): M+H=606.
Example 139
[0691] 764
[0692] tert-butyl
N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)(2,3-dihydro-1,4-b-
enzodioxin-6-ylsulfonyl)amino]-2-hydroxypropylcarbamate. This
reaction was set-up, run and purified using the same protocol
described for tert-butyl
N-(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(cyclopentyloxy)amino]-1-benzy-
l-2-hydroxypropylcarbamate. The 1,4-benzodioxan-6-sulfonyl chloride
was synthesized according to the procedure described in Eur. Pat.
Appl. 583960, Feb. 23, 1994. R.sub.f=0.40 (2:1 hexanes/ethyl
acetate); H1-NMR (CDCl.sub.3): .delta. 7.36-7.18 (8H, m), 6.95 (1H,
d), 4.82 (1H, m), 4.60 (1H, m), 4.32 (4H, m), 3.82 (2H, m), 3.05
(1H, br.s), 2.93 (2H, m), 2.87 (1H, m), 1.88-1.69 (4H, m),
1.69-1.47 (4H, m), 1.35 (9H, s). MS (ESI): M+H=563. 765
[0693] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-1-benzyl-3-[(c-
yclopentyloxy)(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)amino]-2-hydroxypr-
opylcarbamate. This reaction was set-up, run and purified using the
same protocol described for
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(cyclopentyloxy)amino]-1-benzy-
l-2-hydroxypropylcarbamate. R.sub.f=0.20 (1:1 hexanes/ethyl
acetate); H1-NMR (CDCl.sub.3): .delta. 7.37-7.12 (8H, m), 6.97 (1H,
d), 5.65 (1H, s), 5.03 (2H, m), 5.06-4.77 (2H, m), 4.81 (1H, m),
4.33 (4H, d), 3.91 (4H, m), 3.70 (2H, m), 3.12 (1H, s), 3.07-2.97
(2H, m), 2.93 (2H, m), 2.85 (2H, m), 1.90-1.70 (4H, m), 1.7-1.46
(4H, m). MS (ESI): M+H=619.
Example 140
[0694] 766
[0695] 3,4-dimethoxybenzenesulfonyl chloride.
3,4-dimethoxybenzenesulfonyl chloride was synthesized as described
in Eur. Pat. Appl. 583960, Feb. 23, 1994. R.sub.f=0.4 (2:1
hexanes/ethyl acetate). H1-NMR: .delta. 7.69 (1H, d), 7.45 (1H, m),
7.00 (1H, d), 4.00 (3H, s), 3.98 (3H, s). 767
[0696] tert-butyl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(3,4-dimethoxyphe-
nyl)sulfonyl]amino-2-hydroxypropyl)carbamate. tert-butyl
N-(1S,2R)-1-benzyl-3-((cyclopentyloxy)amino]-2-hydroxypropylcarbamate
(0.41 mmol, 150 mg) was combined with 3,4-dimethoxybenzenesulfonyl
chloride (0.82 mmol, 142 mg) and diisopropyl-ethylamine (2.05 mmol,
0.358 mL) in anhydrous THF (1 mL). The reaction was allowed to
reflux for 72 hours. The reaction was worked-up by diluting with an
equal volume of ethyl acetate, washing with 1N HCl, saturated aq.
sodium bicarbonate and brine, and dried over magnesium sulfate. The
crude solution was concentrated to an oil and purified by silica
gel chromatography (2:1 hexanes/ethyl acetate) yielding 100 mg
(43%) of a white solid. R.sub.f=0.1 (1:1 hexanes/ethyl acetate);
H1-NMR (CDCl.sub.3): .delta. 7.41 (1H, d), 7.33-7.17 (7H, m), 6.95
(1H, d), 4.82 (1H, m), 4.52 (1H, m), 3.96 (3H, s), 3.93 (3H, s),
3.80 (2H, m), 3.08 (1H, br.s), 3.00-2.79 (3H, m), 1.90-1.45 (8H,
m), 1.32 (9H, s). 768
[0697] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-((1S,
2R)-1-benzyl-3-(cyclopentyloxy)[(3,4-dimethoxyphenyl)sulfonyl]amino-2-hyd-
roxypropyl)carbamate. This reaction was set-up, run and purified
using the same protocol described for
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(cyclopentyloxy)amino]-1-benzy-
l-2-hydroxypropylcarbamate. R.sub.f=0.20 (2:1 hexanes/ethyl
acetate); H1-NMR (CDCl.sub.3): .delta. 7.42 (1H, d), 7.35-7.14 (8H,
m), 6.97 (1H, d), 5.64 (1H, s), 5.00 (1H, m), 4.80 (2H, m), 3.9-6
(3H, s), 3.93 (3H, s), 3.99-3.80 (4H, m), 3.67 (2H, m), 3.15 (1H,
br.s), 3.08-2.98 (2H, m), 2.95-2.75 (3H, m), 1.90-1.71 (4H, m),
1.70-1.43 (4H, m). MS (ESI): M+H=621.
Example 141
[0698] 769
[0699] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)[(4-isopropoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamat-
e. (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclo-
pentyloxy)[(4-hydroxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
(0.13 mmol, 75 mg) was combined with .degree. C. 2-bromopropane
(0.26 mmol, 0.025 mL), potassium carbonate (0.65 mmol, 90 mg),
tetrabutylammonium iodide (5 mg) and anhydrous DMF (1 mL). The
reaction stirred under a nitrogen atmosphere at room temperature
for 15 hours, then was heated to 50.degree. C. for 3 hours. The
reaction mixture was concentrated under vacuum to a residue and
diluted with ethyl acetate (2 mL). The reaction was washed in
distilled water and brine, and was dried over magnesium sulfate.
The dried solution was then concentrated to an oil and purified by
silica gel chromatography (2:1 hexanes/ethyl acetate) to yield 61
mg (76%) of a white solid. R.sub.f=0.50 (2:1 hexanes/ethyl
acetate); H1-NMR (CDCl.sub.3): .delta. 7.69 (2H, d), 7.33-7.13 (6H,
m), 6.96 (2H, d), 5.65 (1H, s), 5.02 (1H, m), 4.86 (1H, m), 4.80
(1H, m), 4.65 (1H, m), 3.99-3.80 (5H, m), 3.69 (2H, m), 3.11 (1H,
br.s), 3.09-2.98 (3H, m), 2.91 (1H, m), 2.83 (1H, m), 1.89-1.72
(4H, m), 1.7-1.46 (4H, m), 1.38 (6H, d). MS (ESI): M+H=619.
Example 142
[0700] 770
[0701] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(c-
yclopentyloxy)[(3-isopropoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamat-
e. (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclo-
pentyloxy)[(3-hydroxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate
(0.13 mmol, 75 mg) was combined with 2-bromopropane (0.26 mmol,
0.025 mL), potassium carbonate (0.65 mmol, 90 mg),
tetrabutylammonium iodide (5 mg) and anhydrous DMF (1 mL). The
reaction was stirred under a nitrogen atmosphere at room
temperature for 72 hours. The reaction mixture was concentrated
under vacuum to a residue and diluted with ethyl acetate (2 mL).
The reaction was washed in distilled water and brine, and was dried
over magnesium sulfate. The dried solution was then concentrated to
an oil and purified by silica gel chromatography (2:1 hexanes/ethyl
acetate) to yield 38 mg (48%) of a white solid. R.sub.f=0.40 (2:1
hexanes/ethyl acetate); H1-NMR (CDCl.sub.3): .delta. 7.40 (1H, m),
7.33-7.10 (9H, m), 5.63 (1H, s), 5.00 (1H, m), 4.80 (2H, m), 4.58
(1H, m), 3.88 (4H, m), 3.67 (2H, m), 3.13 (1H, br.s), 3.00 (2H, m),
2.94-2.74 (2H, m), 1.88-1.71 (5H, m), 1.69-1.43 (5H, m), 1.35 (6H,
d).
Example 143
[0702] 771
[0703] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-3-[(1,3-benzo-
dioxol-5-ylsulfonyl)(cyclopentyloxy)amino]-1-benzyl-2-(phosphonooxy)propyl-
]carbamate.
[0704] Step 1:
[0705] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(1,3-benzod-
ioxol-5-ylsulfonyl)(cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarbamat-
e (0.38 mmol, 231 mg) was combined with dibenzyl
diisopropylphosphoramidit- e (0.57 mmol, 0.192 mL), imidazole (0.38
mmol, 27 mg) and methylene chloride (5 mL), and stirred for 15
hours at room temperature. The reaction was concentrated to a
residue and purified by silica gel chromatography (2:1
hexanes/ethyl acetate) which produced 325 mg of a clear oil.
[0706] Step 2:
[0707] The oil from the previous step was oxidized by combining
with iodobenzene diacetate (0.57 mmol, 185 mg) and acetonitrile (10
mL). The reaction was instantaneous and was concentrated to a crude
white solid. The product was purified by silica gel chromatography
(1:1 hexanes/ethyl acetate) and produced 170 mg of a sticky white
residue.
[0708] Step 3:
[0709] The phosphate ester from the previous step was stirred
vigorously with 10% Pd/Carbon (34 mg) and methanolic ammonia (2 M
in methanol, 2 mL) under a hydrogen atmosphere for 3 hours at room
temperature. The reaction was filtered, and the filtrate was
concentrated to a residue and crystallized from methylene
chloride/diethyl ether. The reaction produced 80 mg (31%-3 steps)
of white crystals. R.sub.f=0.20 (1:1 hexanes/ethyl acetate); H1-NMR
(D.sub.2O): .delta. 7.38 (1H, m), 7.26-7.05 (6H, m), 6.95 (1H, m),
6.00 (2H, d), 5.51-5.42 (1H, m), 4.78 (1H, m), 4.30 (1H, m),
4.16-3.99 (1H, m), 3.86-3.62 (3H, m), 3.57-3.42 (1H, m), 3.41-3.27
(1H, m), 3.07-2.90 (2H, m), 2.89-2.72 (1H, m), 2.55-2.43 (1H, m),
1.82-1.57 (5H, m), 1.57-1.30 (5H, m), 1.00-0.90 (1H, m). MS (ESI):
M+H=685.
Example 144
[0710] 772
[0711] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-[(-
cyclopentyloxy)(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)amino]-2-(phospho-
nooxy)propyl]carbamate
[0712] Step 1:
[0713] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-(1S,
2R)-1-benzyl-3-[(cyclopentyloxy)(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl-
)amino]-2-hydroxypropylcarbamate (0.14 mmol, 86 mg) was combined
with dibenzyl diisopropylphosphoramidite (0.21 mmol, 0.070 mL),
imidazole (0.18 mmol, 13 mg) and methylene chloride (3 mL), and
stirred for 20 hours at room temperature. The reaction was
concentrated to a residue and purified by silica gel chromatography
(2:1 hexanes/ethyl acetate) which produced 100 mg of a clear
oil.
[0714] Step 2:
[0715] The oil from the previous step was oxidized by combining
with iodobenzene diacetate (0.18 mmol, 56 mg) and acetonitrile (3
mL). The reaction was instantaneous and was concentrated to a crude
white solid. The product was purified by silica gel chromatography
(1:1 hexanes/ethyl acetate) and produced 65 mg of a white foam.
[0716] Step 3:
[0717] The phosphate ester from the previous step was stirred
vigorously with 10% Pd/Carbon (12 mg) and methanolic ammonia (2 M
in methanol, 2 mL) under a hydrogen atmosphere for 2 hours at room
temperature. The reaction was filtered, and the filtrate was
concentrated to a residue and crystallized from methylene
chloride/diethyl ether. The crystals were purified by RP HPLC
(acetonitrile/water) and produced 20 mg (20%-3 steps) of a white
solid after lyophylization. R.sub.f=0.20 (1:1 hexanes/ethyl
acetate); H1-NMR (D.sub.2O): .delta. 7.31 (1H, m), 7.26-7.07 (6H,
m), 7.03-6.97 (1H, m), 5.52-5.43 (1H, m), 4.78 (1H, m), 4.34-4.15
(5H, m), 4.15-4.00 (1H, m), 3.79-3.65 (3H, m), 3.53-3.41 (1H, m),
3.38-3.23 (1H, m), 3.08-2.92 (2H, m), 2.89-2.71 (1H, m), 2.52-2.43
(1H, m), 1.80-1.57 (5H, m), 1.56-1.33 (5H, m), 0.98-0.88 (1H, m).
MS (ESI): M+H=699.
Example 145
[0718] 773
[0719] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-2-hy-
droxy-3-isobutoxy[(4-methoxyphenyl)sulfonyl]aminopropyl)carbamate.
This reaction was set-up, run and purified using the same protocol
described for (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(1,3-benzodio-
xol-5-ylsulfonyl)(cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate.
R.sub.f=0.20 (1:1 hexanes/ethyl acetate); H1-NMR (CDCl.sub.3):
.delta. 7.74 (2H, d), 7.35-7.12 (6H, m), 7.01 (2H, d), 5.65 (1H,
s), 5.03 (1H, m), 4.89 (1H, m), 3.90 (3H, s), 4.03-3.79 (7H, m),
3.70 (2H, m), 3.11 (1H, br.s), 3.04-2.69 (5H, m), 1.86 (1H, m),
0.92 (6H, m). MS (ESI): M+Na=601.
Example 146
[0720] 774
[0721] 4-nitro-N-(tetrahydro-2H-pyran-4-yloxy)benzenesulfonamide
4-tetrahydropyranoxyhydroxylamine (33.2 mmol, 3.77 g) and
4-nitrobenzenesulfonylchloride (38.6 mmol, 8.56 g) were combined in
anhydrous THF (100 mL) with diisopropylethylamine (69.3 mmol, 11.2
mL). The reaction was stirred at room temperature for 48 hours.
Hydrazine (2 mL) was injected to the stirring solution to break-up
the bisarylsulfonamide dimer biproduct. The reaction was stirred
for an additional 24 hours. The reaction was diluted in ethyl
acetate, washed in brine, filtered to remove insoluble solids and
concentrated. The crude was purified by crystallization from hot
ethyl acetate to provide 3.5 g (36%) of white crystals. R.sub.f=0.3
(2:1 hexanes/ethyl acetate); H1-NMR (CDCl.sub.3): .delta. 8.42 (2H,
d), 8.13 (2H, d), 6.93 (1H, s), 4.27 (1H, m), 3.91 (2H, m), 3.45
(2H, m), 2.02 (2H, m), 1.61 (2H, m). 775
[0722]
tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[[(4-nitrophenyl)sulfonyl](t-
etrahydro-2H-pyran-4-yloxy)amino]propylcarbamate.
4-nitro-N-(tetrahydro-2H- -pyran-4-yloxy)benzenesulfonamide (8.6
mmol, 2.61 g) was combined with tert-butyl
N-(1S)-1-[(2S)oxiran-2-yl]-2-phenylethylcarbamate (7.2 mmol, 1.89
g), lithium bis(trimethylsllyl)amide (1.0 M in THF)(1.4 mmol, 1.4
mL) and anhydrous THF (80 mL). The reaction was stirred under
nitrogen at room temperature for 96 hours. The reaction was diluted
in ethyl acetate (200 mL) and washed with a 5% aqueous solution of
potassium carbonate, brine, and was dried over magnesium sulfate.
The crude solution was concentrated to a foam and purified by
crystallization from diethylether to provide 3.5 g (86%) of light
yellow crystals. R.sub.f=0.3 (2:1 hexanes/ethyl acetate); H1-NMR
(CDCl.sub.3): .delta. 8.36 (2H, d), 7.96 (2H, d), 7.33-7.15 (6H,
m), 4.55 (1H, m), 4.42 (1H, m), 3.95 (2H, m), 3.77 (2H, m), 3.43
(2H, m), 3.07 (1H, br.s), 2.90 (2H, m), 2.03 (2H, m), 1.65-1.42
(3H, m), 1.32 (9H, s). 776
[0723]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-2-hydrox-
y-3-[[(4-nitrophenyl)sulfonyl](tetrahydro-2H-pyran-4-yloxy)amino]propylcar-
bamate. This reaction was set-up, run and purified using the same
protocol described for (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(cyclopentyloxy)amino]-1-benzy-
l-2-hydroxypropylcarbamate. R.sub.f=0.1 (1:1 hexanes/ethyl
acetate); H1-NMR (CDCl.sub.3): .delta. 8.38 (2H, d), 7.95 (2H, d),
7.337.20 (4H, m), 7.17 (2H, m), 5.64 (1H, s), 5.02 (1H, m), 4.87
(1H, m), 4.45 (1H, m), 4.00-3.77 (6H, m), 3.68 (2H, m), 3.43 (2H,
m), 3.31-2.30 (4H, m), 2.05 (2H, m), 1.86 (1H, m), 1.76-1.42 (4H,
m). 777
[0724] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
3-[[(4-aminophenyl)sulfo-
nyl](tetrahydro-2H-pyran-4-yloxy)amino]-1-benzyl-2-hydroxypropylcarbamate.
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-2-hydroxy-3-[[-
(4-nitrophenyl)sulfonyl](tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamate
(0.16 mmol, 100 mg) was combined with 10% palladium on carbon (20
mg) and ethyl acetate (2 mL), and the reaction was stirred
vigorously under a hydrogen atmosphere for 15 hours. The reaction
was filtered and the filtrate was concentrated to an oil. The crude
product was purified by crystallization from hexanes/ethyl acetate
to provide 30 mg (32%) of fine white crystals. R.sub.f=0.5 (ethyl
acetate); H1-NMR (CDCl.sub.3): .delta. 7.56 (2H, d), 7.33-7.11 (6H,
m), 6.72 (2H, d), 5.64 (1H, s), 5.0 (1H, m), 4.83 (1H, m), 4.39
(1H, septet), 4.01-3.78 (6H, m), 3.73-3.59 (2H, m), 3.48-3.33 (2H,
m), 3.31-2.28 (2H, br.s), 3.16-2.72 (6H, m), 1.74-1.45 (5H, m). MS
(ESI): M+H=592.
Example 147
[0725] 778
[0726] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
(1S,2R)-1-benzyl-2-hydro-
xy-3-[(tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamate.
[0727]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-2-hydrox-
y-3-[[(4-nitrophenyl)sulfonyl](tetrahydro-2H-pyran-4-yloxy)amino]propylcar-
bamate (3.62 mmol, 2.25 g) was combined with mercaptoacetic acid
(7.24 mmol, 0.501 mL), lithium hydroxide (14.5 mmol, 607 mg) and
anhydrous DMF (10 mL) and stirred for 2 hours at room temperature
under nitrogen. The reaction was concentrated to a red suspension
under vacuum and disolved in 700 mL ethyl acetate. The crude
solution was washed with distilled water, saturated aqueous sodium
bicarbonate, brine and dried over magnesium sulfate. The crude
product was concentrated to a yellow solid and purified by silca
gel chromatography (10:1 ethyl acetate/methanol) followed by
crystallization from methylene chloride/hexanes to provide 650 mg
(41%) of white crystals. R.sub.f=0.15 (ethyl acetate); H1-NMR
(CDCl.sub.3): .delta. 7.39-7.18 (6H, m), 5.69 (1H, s), 5.08 (2H,
m), 4.25 (1H, m), 4.10-3.58 (8H, m), 3.52-3.27 (3H, m), 3.19 (1H,
m), 3.03 (1H, br.s), 2.90 (1H, m), 2.71 (1H, m), 2.13-1.80 (3H, m),
1.74-1.29 (4H, m). 779
[0728] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
3-[[(3-aminophenyl)sulfo-
nyl](tetrahydro-2H-pyran-4-yloxy)amino]-1-benzyl-2-hydroxypropylcarbamate.
[0729] Step 1:
[0730]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-2-hydrox-
y-3-[(tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamate (0.17 mmol,
75 mg) was combined with 3-nitrobenzenesulfonyl chloride (0.26
mmol, 57 mg), diisopropylethylamine (0.69 mmol, 0.120 mL),
N,N-dimethylaminopyridine (5 mg), and anhydrous THF (5 mL). The
reaction was stirred at 50.degree. C. for 15 hours under nitrogen.
The reaction product was diluted in ethyl acetate (10 mL), washed
with 1N HCl, saturated aqueous sodium bicarbonate, brine, and was
dried over magnesium sulfate. The crude solution was concentrated
under vacuum and purified by silica gel chromatography (1:1
methylene chloride/ethyl acetate) to provide 100 mg (93%) of a
white solid.
[0731] Step 2:
[0732] The product of the previous step was combined with 10%
palladium on carbon (20 mg) and stirred vigorously in ethyl acetate
(2 mL) under hydrogen for 20 hours. The reaction was filtered and
concentrated under vacuum. The crude product was purified by
crystallization (diethylether/ethyl acetate/hexanes) to yield 40 mg
(42%) of white crystals. R.sub.f=0.45 (ethyl acetate); H1-NMR
(CDCl.sub.3): .delta. 7.41-7.02 (10H, m), 6.96 (1H, br.s), 5.62
(1H, s), 5.02 (1H, m), 4.85 (1H, br.s), 4.42 (1H, m), 4.02-3.77
(6H, m), 3.69 (2H, m), 3.48-3.33 (3H, m), 3.22-2.52 (6H, m),
1.87-1.30 (5H, m). MS (ESI): M+H=592.
Example 148
[0733] 780
[0734] 3-benzyloxybenzenesulfonyl chloride
[0735] The aryl bromide (12 g, 45.6 mmol) was dissolved in THF (100
mL) and cooled to -78.degree. C. n-Butyl lithium 1.6 M in hexanes
(28.5 mL, 45.6 mmol) was injected and the reaction stirred for 1
hr. before being warmed to 0.degree. C. The resulting solution was
then transferred to a -78.degree. C. solution of SO.sub.2 (41 mL,
913 mmol), Et.sub.2O (100 mL) and THF (100 mL). The solution became
a yellow suspension immediately upon addition of the aryl lithium.
The suspension was warmed to room temperature and stirred for 3
days. The yellow mixture was sparged with nitrogen for 2 hr. The
suspension was concentrated and the resulting solid triturated with
Et.sub.2O to provide 7.23 g of the sulfinate intermediate. The
lithium sulfinate was stirred in a bi-phasic mixture of pH 6
aqueous dibasic sodium phosphate buffer (27 g in 200 mL distilled
water--adjusted to pH 6 with conc. phosphoric acid) and ethyl
acetate (200 mL) and cooled to 0.degree. C. While stirring
vigorously, N-chlorosuccinimide (3.80 g, 28.4 mmol) was added. The
reaction was immediately warmed to room temperature and the aqueous
layer was drained. The organic layer was washed with distilled
water, brine and dried over magnesium sulfate. The crude was
concentrated to a yellow solid under reduced pressure and washed
with Et.sub.2O. The product was purified by eluting through a
silica gel column with Et.sub.2O and resulted in 4.81 g (37%) of
the desired product. R.sub.f=0.2 (5:1 hexanes/ethyl acetate).
H1-NMR: 7.67-7.27 (9H, m), 5.13 (2H, s). 781
[0736] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
1-benzyl-2-hydroxy-3-[[(-
3-hydroxyphenyl)sulfonyl](tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamat-
e.
[0737] Step 1:
[0738]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-2-hydrox-
y-3-[(tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamate (0.17 mmol,
75 mg) was combined with 3-benzyloxybenzenesulfonyl chloride (0.26
mmol, 73 mg), diisopropylethylamine (0.69 mmol, 0.12 mL) in
methylene chloride (2 mL) and allowed to stir for 15 hours at room
temperature under nitrogen. The reaction was diluted with ethyl
acetate and washed with 1N HCl, 5% aqueous potassium bicarbonate
solution, brine and was dried over magnesium sulfate. The solution
was concentrated under vacuum and the crude product was purified by
silica gel chromatography (1:1 hexanes/ethyl acetate) to provide 60
mg (51%) of a clear
[0739] Step 2:
[0740] The product of the previous step was stirred vigorously with
10% palladium on carbon (20 mg), acetic acid (0.5 mL), and ethyl
acetate (2 mL) under hydrogen for 6 hours. The reaction was
filtered and concentrated to an oil. The crude product was purified
by silica gel chromatography (1:1 hexanes/ethyl acetate), and
crystallized from diethylether/hexanes to provide 31 mg (36%) of
white crystals. R.sub.f=0.2 (1:1 methylene chloride/ethyl acetate);
H1-NMR (CDCl.sub.3) .delta. 7.40 (2H, m), 7.32-7.21 (5H, m), 7.17
(3H, m), 6.81 (1H, br.s), 5.69 (1H, s), 5.00 (2H, m), 4.40 (1H, m),
4.02-3.70 (8H, m), 3.48-3.35 (2H, m), 3.23-2.71 (6H, m), 2.04 (2H,
m), 1.79-1.67 (1H, m), 1.65-1.42 (3H, m). MS (ESI): M+H=593.
Example 149
[0741] 782
[0742] 4-benzyloxybenzenesulfonyl chloride.
[0743] The aryl bromide (12 g, 45.6 mmol) was dissolved in THF (100
mL) and cooled to -78.degree. C. n-Butyl lithium 1.6 M in hexanes
(28.5 mL, 45.6 mmol) was injected and the reaction stirred for 1
hr. before being warmed to 0.degree. C. The resulting solution was
then transferred to a -78.degree. C. solution of SO.sub.2 (41 mL,
913 mmol), Et.sub.2O (100 mL) and THF (100 mL). The solution became
a yellow suspension immediately upon addition of the aryl lithium.
The suspension was warmed to room temperature and sparged with
nitrogen for 1 hr. The suspension was concentrated to a yellow
solid and triturated with Et.sub.2O to provide 6.27 g of the
sulfinate intermediate. The lithium sulfinate was stirred in a
bi-phasic mixture of pH 6 aqueous dibasic sodium phosphate buffer
(27 g in 200 mL distilled water--adjusted to pH 6 with conc.
phosphoric acid) and ethyl acetate (200 mL) and cooled to 0.degree.
C. While stirring vigorously, N-chlorosuccinimide (3.27 g, 24.7
mmol) was added. The reaction was immediately warmed to room
temperature and the aqueous layer was drained. The organic layer
was concentrated to a yellow solid under reduced pressure. The
crude sulfonyl chloride was purified by silica gel chromatography
(5:1 hexanes/ethyl acetate) to provide 3.35 g (26%) of an off-white
solid. R.sub.f=0.2 (5:1 hexanes/ethyl acetate). H1-NMR: .delta.
7.97 (2H, d), 7.45-7.30 (5H, m), 7.10 (2H, d), 5.16 (2H, s).
783
[0744] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
1-benzyl-2-hydroxy-3-[[(-
4-hydroxyphenyl)sulfonyl](tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamat-
e.
[0745] Step 1:
[0746]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-2-hydrox-
y-3-[(tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamate (0.17 mmol,
75 mg) was combined with 4-benzyloxybenzenesulfonyl chloride (0.26
mmol, 73 mg), diisopropylethylamine (0.69 mmol, 0.12 mL), and a few
crystals of N,N-dimethylaminopyridine in a 1:1 solution of
anhydrous THF/methylene chloride (2 mL) and allowed to stir for 15
hours at room temperature under nitrogen. The reaction was diluted
with ethyl acetate and washed with 1N HCl, 5% aqueous potassium
carbonate solution, brine and was dried over magnesium sulfate. The
solution was concentrated under vacuum and the crude product was
purified by silica gel chromatography (1:1 hexanes/ethyl acetate)
to provide 50 mg (43%) of a clear oil.
[0747] Step 2:
[0748] The product of the previous step was stirred vigorously with
10% palladium on carbon (10 mg), acetic acid (0.5 mL), and ethyl
acetate (2 mL) under hydrogen for 15 hours. The reaction was
filtered and concentrated to an oil. The crude product was
crystallized from diethylether/hexanes to provide 8 mg (19%) of
white crystals. R.sub.f=0.2 (1:1 methylene chloride/ethyl acetate);
H1-NMR (CDCl.sub.3): .delta. 7.66 (2H, d), 7.32-7.12 (6H, m), 6.94
(2H, d), 6.25 (1H, br.s), 5.66 (1H, s), 4.98 (1H, m), 4.76 (1H, m),
4.41 (1H, m), 4.00-3.78 (6H, m), 3.68 (2H, m), 3.51-3.36 (2H, m),
3.29-2.51 (6H, m), 2.12-1.95 (2H, m), 1.69 (1H, m), 1.63-1.45 (2H,
m). MS (ESI): M+H=593.
Example 150
[0749] 784
[0750] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
1-benzyl-3-[(2,3-dihydro-
-1,4-benzodioxin-6-ylsulfonyl)(tetrahydro-2H-pyran-4-yloxy)amino]-2-hydrox-
ypropylcarbamate.
[0751] (3R, 3aS,
6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-2-hydr-
oxy-3-[(tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamate (0.17
mmol, 75 mg) was combined with 1,4-benzodioxan-6-sulfonyl chloride
(0.21 mmol, 48 mg), diisopropylethylamine (0.69 mmol, 0.12 mL) in
anhydrous THF (2 mL) and allowed to stir for 20 hours at room
temperature under nitrogen. The reaction was diluted with
diethylether and washed with 1N HCl, 5% aqueous potassium carbonate
solution, brine and was dried over magnesium sulfate. The solution
was concentrated under vacuum and the crude product was purified by
silica gel chromatography (1:1 hexanes/ethyl acetate). The purified
oil was lyophylized to provide 13 mg (12%) of a white powder.
R.sub.f=0.6 (ethyl acetate); H1-NMR (CDCl.sub.3) .delta. 7.37-7.14
(8H, m), 6.98 (1H, d), 5.66 (1H, s), 5.03 (1H, m), 4.83 (1H, m),
4.43 (1H, m), 4.33 (4H, d), 4.03-3.79 (6H, m), 3.70 (2H, m), 3.45
(2H, m), 3.29-2.68 (6H, m), 2.06 (2H, m), 1.74-1.46 (3H, m). MS
(ESI): M+H=635.
Example 151
[0752] 785
[0753] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
3-[(1,3-benzodioxol-5-yl-
sulfonyl)(tetrahydro-2H-pyran-4-yloxy)amino]-1-benzyl-2-hydroxypropylcarba-
mate.
[0754] (3R, 3aS,
6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-2-hydr-
oxy-3-[(tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamate (0.23
mmol, 100 mg) was combined 1,3-benzodioxole-5-sulfonyl chloride
(0.28 mmol, 61 mg), diisopropylethylamine (0.69 mmol, 0.12 mL) in
anhydrous THF (2 mL) and allowed to stir 72 hours at room
temperature under nitrogen. The reaction was diluted with ethyl
acetate and washed with 1N HCl, saturated sodium bicarbonate
solution, brine and was dried over magnesium sulfate. The solution
was concentrated under vacuum and the crude product was purified by
silica gel chromatography (1:5 hexanes/ethyl acetate). The purified
oil was crystallized to provide 55 mg (39%) of white crystals.
R.sub.f=0.2 (1:5 hexanes/ethyl acetate); H1-NMR (CDCl.sub.3):
.delta. 7.38-7.13 (9H, m), 6.90 (1H, d), 6.10 (2H, s), 5.64 (1H,
s), 5.02 (1H, m), 4.82 (1H, m), 4.41 (1H, m), 3.99-3.79 (6H, m),
3.72-3.59 (2H, m), 3.49-3.33 (2H, m), 3.25-2.51 (6H, m), 2.09-1.98
(2H, m), 1.69-1.43 (2H, m). MS (ESI): M+H=621.
Example 152
[0755] 786
[0756] 4-oxobutanenitrile. 4-butenenitrile (43.9 mmol, 3.56 grams)
was dissolved in 150 mL of a 3:1 methylene chloride/methanol
solution, cooled to -78.degree. C., and ozonated until the solution
turned blue (15 minutes). The excess ozone was sparged by bubbling
nitrogen through the solution while warming to room temperature.
Excess dimethylsulfoxide was added and the reaction stirred for 15
hours at room temperature. The reaction was concentrated to a clear
liquid, dissolved in ethyl acetate, washed in distilled water,
brine and dried over magnesium sulfate. The concentrated crude
product was purified by silica gel flash chromatography (2:1
hexanes/ethyl acetate) to provide a brown liquid which was
distilled at reduced pressure (150.degree. C./15 mbar) to provide
2.11 grams (58%) of the purified clear liquid. R.sub.f=0.2 (2:1
hexanes/ethyl acetate); H1-NMR (CDCl.sub.3): .delta. 9.78 (1H, s),
2.90 (2H, m), 2.61 (2H, m). 787
[0757] 4-hydroxypentanenitrile. The 4-oxobutanenitrile (17.9 mmol,
1.49 grams) was dissolved in anhydrous THF (50 mL) and cooled to
-78.degree. C. Methylmagnesium bromide (17.9 mmol, 5.98 mL, 3M in
diethyl ether) solution was injected slowly by syringe. The
reaction stirred at -78.degree. C. for 15 min. and was warmed to
room temperature. The reaction was diluted in methylene chloride
(50 mL) and dried over magnesium sulfate. The concentrated crude
product was purified by silica gel flash chromatography (4:1
methylene chloride/ethyl acetate) and provided 1.2 grams (67%) of
the desire alcohol as a yellow liquid. R.sub.f=0.2 (4:1 methylene
chloride/ethyl acetate); HL-NMR (CDCl.sub.3): .delta. 3.91 (1H, m),
2.47 (2H, m), 1.86-1.60 (3H, m), 1.23 (3H, m). 788
[0758] 4-(aminooxy)pentanenitrile. A solution of
ditertbutylazodicarboxyla- te (DTBAD) (13.9 mmol, 3.21 grams) in
anhydrous THF (20 mL) was canulated dropwise into a stirring slurry
of 4-hydroxypentanenitrile (11.6 mmol, 1.15 grams),
N-hydroxyphthalimide (11.6 mmol, 1.89 grams), triphenylphosphine
(13.9 mmol, 3.65 grams) and anhydrous THF (30 mL). The slurry
dissolved on addition and changed color first to orange, then to
yellow. The yellow solution stirred at room temperature for 3
hours. The solvent was removed under vacuum and the residue was
dissolved in TFA. The reaction stirred in TFA for 2 hours to
decompose the DTBAD biproduct. The TFA was removed under vacuum and
the crude product was dissolved in ethy acetate, washed in
distilled water, 5% aqueous potassium carbonate solution, brine and
dried over magnesium sulfate. The crude yellow solid was purified
by silica gel flash chromatography (2:1 hexanes/ethyl acetate) and
provided 850 mg (32%) of a white crystalline solid. R.sub.f=0.3
(2:1 hexanes/ethyl acetate); H-1-NMR (CDCl.sub.3): .delta. 7.83
(2H, m), 7.76 (2H, m), 4.39 (1H, m), 2.78 (2H, m), 2.03 (2H, m),
1.41 (3H, d). 789
[0759] 4-{[(4-methoxybenzyl)amino]oxy}pentanenitrile
[0760] 4-(aminooxy)pentanenitrile (1.3 mmol, 150 mg) and
4-methoxybenzenesulfonylchloride (1.3 mmol, 272 mg) were combined
in anhydrous THF with diisopropylethylamine (1.4 mmol, 0.69 mL) and
a few crystals of DMAP. The reaction was stirred at 50.degree. C.
for 15 hours. The reaction was diluted in diethyl ether, washed
with 1N HCl, 1N NaOH and brine and dried over mangesium sulfate.
NMR analysis revealed that the isolated crude was the double
sulfonyl chloride addition product. The aqueous NaOH fraction was
acidified to neutral pH, extracted into ethyl acetate and dried
over magnesium sulfate. The solvent was removed under vacuum
leaving a very clean 195 mg (52%) crude product. R.sub.f=0.4 (1:1
hexanes/ethyl acetate); H1-NMR (CDCl.sub.3): .delta. 7.82 (2H, d),
7.01 (2H, d), 6.84 (1H, s), 4.17 (1H, m), 3.88 (3H, s), 2.42 (2H,
m), 1.88 (2H, m), 1.23 (3H, d). 790
[0761] tert-butyl
1-benzyl-3-{(3-cyano-1-methylpropoxy)[(4-methoxyphenyl)s-
ulfonyl]amino}-2-hydroxypropylcarbamate.
4{[(4-methoxybenzyl)amino]oxy}pen- tanenitrile (0.69 mmol, 195 mg)
was combined with tert-butyl
N-(1S)-1-[(2S)oxiran-2-yl]-2-phenylethylcarbamate (0.57 mmol, 151
mg), lithium bis(trimethylsilyl)amide (0.11 mmol, 0.114 mL, 1.0 M
in THF) and anhydrous THF (2 mL). The reaction was stirred under
nitrogen at room temperature for 20 hours. The reaction was diluted
in ethyl acetate (2 mL) and washed with 1N HCl, saturated aqueous
sodium bicarbonate, brine, and was dried over magnesium sulfate.
The crude solution was concentrated and purified by silica gel
flash chromatography (1:1 hexanes/ethyl acetate) and RP HPLC
followed by lyophylization to yield 78 mg (25%) of a white solid.
R.sub.f=0.2 (1:1 hexanes/ethyl acetate); H1-NMR (CDCl.sub.3):
.delta. 7.76-7.61 (2H, m), 7.34-7.11 (6H, m), 7.04-6.92 (2H, m),
4.72-4.53 (1H, m), 4.42 (1H, m), 3.89 (3H, s), 3.78 (2H, m),
3.25-2.51 (6H, m), 2.42 (2H, m), 2.02-1.79 (2H, m), 1.43-1.15 (10H,
m). MS (ESI): M+H=548.
Example 153
[0762] 791
[0763] 2-(cyclohexyloxy)-1H-isoindole-1,3(2H)-dione. A solution of
triphenylphosine (15.53 g, 59.2 mmol), cyclohexanol (6.25 mL, 59.2
mmol), and N-hydroxypthalimide (9.66 g, 59.2 mmol) in anhydrous
tetrahydrofuran (500 mL) under Argon was treated dropwise over
approximately 20 minutes with a solution of di-tert-butyl
azodicarboxylate (15.00 g, 65.14 mmol) in tetrahydrofuran (100 mL)
with a water bath to control the exotherm. After the reddish color
had dissipated, a mixture of di-tert-butyl azodicarboxylate (3.00
g, 13.0 mmol) and triphenylphosine (3.11 g, 11.8 mmol) in anhydrous
tetrahydrofuran (50 mL) was added to the reaction mixture and
allowed to stir overnight at ambient temperature. After evaporation
in vacuo, the residue was treated with trifluoroacetic acid (100
mL) and stirred for 20 minutes. The reaction was evaporated in
vacuo and the residue was partitioned between water and
dichloromethane. The layers were separated and the aqueous phase
was extracted with dichloromethane. The combined organic layers
were dried over anhydrous magnesium sulfate, filtered and
evaporated in vacuo to a residue. The crude material was purified
twice by flash silica gel chromatography eluting with hexane:ethyl
acetate (4:1 and 9:1). Pure fractions were concentrated in vacuo to
a solid and dried under high vacuum to provide
2-(cyclohexyloxy)-1H-isoindole-1,3(2H)-dione as a solid (10.90 g,
75%). 792
[0764]
tert-butyl(1S,2R)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropyl-
carbamate.
[0765] A solution 2-(cyclohexyloxy)-1H-isoindole-1,3(2H)-dione
(10.00 g, 40.82 mmol) in anhydrous tetrahydrofuran (100 mL) under
Argon was treated with anhydrous hydrazine (1.28 mL, 40.82 mmol).
After stirring for approximately two hours, the slurry was treated
with additional anhydrous hydrazine (0.13 mL, 4.1 mmol). After
stirring an additional hour, the reaction mixture was filtered and
washed with a minimum quantity of anhydrous tetrahydrofuran. The
filtrate was combined with lithium triflate (5.09 g, 32.7 mmol) and
tert-butyl N-(1S)-1-[(2S)oxiran-2-yl]-2-- phenylethylcarbamate
(8.58 g, 32.6 mmol) and brought to reflux. After heating for 16
hours, additional lithium triflate (5.00 g, 32.1 mmol) was added.
The reaction was stirred at reflux for an additional 24 hours and
then evaporated in vacuo. The residue was partitioned between ethyl
acetate and water. After separating the layers, the organic phase
was washed again with water. The aqueous phases were combined and
extracted with ethyl acetate. The combined organic phases were
washed with brine, dried over anhydrous sodium sulfate, filtered,
and evaporated in vacuo. The residue was triturated with diethyl
ether and then filtered. The mother liquor was evaporated in vacuo
and the residue was triturated again with diethyl ether. The second
crop was collected by filtration and the mother liquor was
evaporated in vacuo. The residue was dissolved in diethyl ether and
placed in the freezer overnight. A third crop was collected by
filtration. All three crops were dried under high vacuum to provide
tert-butyl(1S,2R)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxyprop-
ylcarbamate (4.48 g, 36%) as a solid. H1-NMR (chloroform-D3): 1.34
(m, 14H), 1.52 (m, 1H), 1.72 (m, 2H), 1.95 (m, 2H), 2.97 (m, 4H),
3.25 (m, 1H), 3.67 (m, 1H), 3.83 (m, 1H), 3.92 (m, 1H), 4.32 (b,
1H), 4.61 (d, 1H), 7.26 (m, 5H). MS (ESI): 379 (M+H). 793
[0766]
(2R,3S)-3-amino-1-[(cyclohexyloxy)amino]-4-phenyl-2-butanol.
[0767] A combination of trifluoroacetic acid (20 mL) and tert-butyl
(1S,2R)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropylcarbamate
(2.00 g, 5.29 mmol) was stirred under Argon at ambient temperature
for approximately 30 minutes. The reaction was evaporated in vacuo
and the residue was partitioned between dichloromethane and aqueous
sodium hydroxide (1N). After separating the layers, the aqueous
phase was extracted with dichloromethane. The combined organic
phases were dried over anhydrous sodium sulfate, filtered and
evaporated in vacuo to a solid which was dried under high vacuum to
provide (2R,3S)-3-amino-1-[(cyclohexyloxy)amino]-4-phenyl-2-butanol
(1.426 g, 97%). H1-NMR (chloroform-D3): 1.24 (m, 5H), 1.58 (m, 4H),
1.73 (m, 2H), 1.95 (m, 2H), 2.51 (m, 1H), 2.97 (m, 2H), 3.16 (m,
2H), 3.33 (m, 1H), 3.57 (m, 1H), 3.77 (m, 1H), 7.26 (m, 5H) MS
(ESI): 279 (M+H). 794
[0768]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-[(cycl-
ohexyloxy)amino]-2-hydroxypropylcarbamate.
[0769] A mixture of (2R,3aS,6aR)hexahydrofuro[2,3-b]furan-2-yl
4-nitrophenyl carbonate (1.49 g, 4.82 mmol),
(2R,3S)-3-amino-1-[(cyclohex- yloxy)amino]-4-phenyl-2-butanol
(1.341 g, 4.82 mmol) and diisoproylethylamine (0.841 mL, 4.82 mmol)
in acetonitrile (15 mL) under Argon was stirred at ambient
temperature for 16 hours. The resulting slurry was filtered and
washed with cold acetonitrile to provide the first crop of product.
The mother liquor was evaporated in vacuo dissolved in ethyl
acetate and washed twice with aqueous sodium hydroxide (1N). The
combined aqueous phases were extracted with ethyl acetate. The
combined organic phases were washed with brine, dried over
anhydrous sodium sulfate, filtered and evaporated in vacuo. The
residue was triturated with diethyl ether and filtered to provide a
second crop of product. The mother liquor was evaporated in vacuo
and a third crop was crystallized from the residue dissolved in a
minimum quantity of diethyl ether. The three crops were dried under
high vacuum to provide
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-[(cyclohexyl-
oxy)amino]-2-hydroxypropylcarbamate (1.555 g, 74%). H1-NMR
(chloroform-D3): 1.31 (m, 7H), 1.56 (m, 2H), 1.73 (m, 2H), 1.99 (m,
2H), 2.74 (m, 1H), 2.89 (m, 1H), 3.10 (m, 2H), 3.30 (m, 1H), 3.83
(m, 8H), 5.01 (m, 2H), 5.63 (d, 1H), 7.21 (m, 5H).) MS (ESI): 456
(M+Na). 795
[0770]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-{(cycl-
ohexyloxy)[(4-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate.
A mixture
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-[(cy-
clohexyloxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.23 mmol),
4-nitrobenzenesuphonyl chloride (61 mg, 0.276 mmol),
diisoproylethylamine (0.048 mL, 0.276 mmol) and
4-dimethylaminopyridine (.about.1 mg, cat.) was combined in
anhydrous tetrahydrofuran (3 mL) and stirred at ambient temperature
under an Argon atmosphere for approximately 16 hours. The reaction
mixture was evaporated in vacuo and the residue was partitioned
between ethyl acetate and aqueous hydrochloric acid (1N). The
organic phase was dried over anhydrous magnesium sulfate, filtered
and evaporated in vacuo. The residue was purified on flash silica
gel eluting with 3:2 hexane:ethyl acetate followed by 1:1
hexane:ethyl acetate. Fractions containing the product were
combined, evaporated in vacuo, and triturated with diethyl ether.
The solvent was removed and the residual solid was dried under high
vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan--
3-yl(1S,2R)-1-benzyl-3-{(cyclohexyloxy)[(4-nitrophenyl)sulfonyl]amino}-2-h-
ydroxypropylcarbamate (129 mg, 91%). %). H1-NMR (chloroform-D3):
1.22 (m, 7H), 1.64 (m, 2H), 1.78 (m, 2H), 2.08 (m, 2H), 2.90 (m,
5H), 3.69 (m, 2H), 3.88 (m, 4H), 4.23 (m, 1H), 4.87 (m, 1H), 5.04
(m, 1H), 5.64 (d, 1H), 7.18 (m, 2H), 7.25 (m, 3H), 7.96 (d, 2H),
8.36 (d, 2H). MS (ESI) 642 (M+Na) 796
[0771]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-aminopheny-
l)sulfonyl](cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate.
To a solution of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3--
{(cyclohexyloxy)[(4-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate
(115 mg, 0.186 mmol) in a 1:1 mixture of ethanol: ethyl acetate (6
mL) was added Palladium on charcoal (10 wt %, 30 mg). The starting
material was reduced under an atmosphere of Hydrogen gas over 16
hrs. The reaction mixture was filtered and evaporated in vacuo. The
residue was purified on a preparative TLC plate (20.times.20 cm,
500 uM) eluting with 3:1 ethyl acetate:hexane. The product band was
removed, eluted with 3:1 methylene chloride:methanol, filtered, and
evaporated in vacuo. The residue was triturated with water,
filtered and dried under high vacuum to provide
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-aminophenyl)sulf-
onyl](cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate (89
mg, 81%). H1-NMR (chloroform-D3): 1.26 (m, 6H), 1.58 (m, 5H), 2.05
(m, 2H), 2.90 (m, 4H), 3.09 (b, 2H), 3.68 (m, 2H), 3.88 (m, 4H),
4.16 (m, 1H), 4.24 (b, 1H), 4.81 (d, 1H), 5.00 (m, 1H), 5.63 (d,
1H), 6.66 (d, 2H), 7.23 (m, 5H), 7.56 (d, 2H). MS (ESI): 612
(M+Na).
Example 154
[0772] 797
[0773] (3R,3aS,
6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-{(cyc-
lohexyloxy)[(3-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate.
A mixture
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-[(cy-
clohexyloxy)amino]-2-hydroxypropylcarbamate (342 mg, 0.788 mmol),
3-nitrobenzenesuphonyl chloride (175 mg, 0.788 mmol) and
diisoproylethylamine (0.137 mL, 0.867 mmol) was combined in
anhydrous tetrahydrofuran (10 mL) and stirred at ambient
temperature under an Argon atmosphere for approximately 40 hours.
The reaction mixture was partitioned between ethyl acetate and
aqueous hydrochloric acid (1N). After separating the phases, the
aqueous layer was extracted with ethyl acetate. The combined
organic phases were washed with brine, dried over anhydrous
magnesium sulfate, and evaporate in vacuo. The residue was purified
on flash grade silica gel eluting with 1:1 ethyl acetate:hexane.
The fractions containing the product were combined, evaporated in
vacuo and dried under high vacuum to provide (3R,3aS,
6aR)hexahydrofuro[2,3-b]f-
uran-3-yl(1S,2R)-1-benzyl-3-{(cyclohexyloxy)[(3-nitrophenyl)sulfonyl]amino-
}-2-hydroxypropylcarbamate (428 mg, 88%) as a foam. H1-NMR
(chloroform-D3): 1.29 (m, 6H), 1.57 (m, 3H), 1.76 (m, 2H), 2.08 (m,
2H), 2.91 (m, 4H), 3.10 (b, 1H), 3.68 (m, 2H), 3.88 (m, 4H), 4.25
(m, 1H), 4.83 (d, 1H), 5.00 (m, 1H), 5.64 (d, 1H), 7.22 (m, 5H),
7.76 (m, 1H), 8.07 (d, 1H), 8.50 (d, 1H), 8.66 (s, 1H). MS (ESI):
642 (M+Na). 798
[0774]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(3-aminopheny-
l)sulfonyl](cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate.
A solution of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3--
{(cyclohexyloxy)[(3-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate
(403 mg, 0.651 mmol) in absolute ethanol (12 mL) was combined with
Palladium on carbon (10 wt %, 80 mg) and reduced under a Hydrogen
atmosphere for 16 hours. The reaction mixture was filtered and
evaporated in vacuo to provide
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[-
[(3-aminophenyl)sulfonyl](cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcar-
bamate (356 mg, 93%) as a foam. A sample of the product (30 mg) was
purified on a preparative TLC plate (20.times.20 cm, 500 uM)
eluting with 95:5 dichloromethane:methanol. The product band was
removed, eluted with 3:1 methylene chloride:methanol, filtered, and
evaporated in vacuo. The residue was triturated with water,
filtered and dried under high vacuum to provide
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(3-amino-
phenyl)sulfonyl](cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate
(18 mg) as a solid. H1-NMR (chloroform-D3): 1.26 (m, 6H), 1.64 (m,
5H), 2.07 (m, 2H), 2.93 (m, 4H), 3.14 (b, 1H), 3.69 (m, 2H), 3.87
(m, 4H), 3.94 (b, 2H), 4.19 (m, 1H), 4.83 (b, 1H), 5.03 (m, 1H),
5.64 (d, 1H), 6.89 (d, 1H), 7.06 (s, 1H), 7.21 (m, 7H). MS (ESI)
612 (M+Na)
Example 155
[0775] 799
[0776]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[(1,3-benzodiox-
ol-5-ylsulfonyl)(cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate.
A mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-[-
(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.230),
1,3-benzodioxole-5-sulfonyl chloride (Eur. Pat. Appl. 583960, Feb.
23, 1994, 56 mg, 0.253 mmol) and diisoproylethylamine (0.042 mL,
0.242 mmol) in anhydrous tetrahydrofuran (3 mL) was stirred at
ambient temperature under an Argon atmosphere for 16 hours. A
catalytic quantity of dimethylaminopyridine (.about.1 mg) was added
and the reaction was heated at reflux for approximately 2 hours. An
additional quantity of 1,3-benzodioxole-5-sulfonyl chloride (11 mg,
0.050 mmol) was added and the reaction was heated for an additional
hour. After cooling to ambient temperature, the reaction mixture
was partitioned between ethyl acetate and aqueous hydrochloric
acid. After separating the phases, the organic layer was washed
with brine, dried over anhydrous magnesium sulfate, filtered and
evaporated in vacuo. The residue was purified on a preparative TLC
plate (20.times.20 cm, 500 .mu.M) eluting with 1:1 ethyl
acetate:hexane. The product band was removed, eluted with 3:1
methylene chloride:methanol, filtered, and evaporated in vacuo. The
residue was triturated with water, filtered and dried under high
vacuum to provide
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[(1,3-benzodioxol-5-y-
lsulfonyl)(cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate
(123 mg, 87%) as a white solid. H1-NMR (chloroform-D3): 1.32 (m,
6H), 1.70 (m, 5H), 2.14 (m, 2H), 3.00 (m, 4H), 3.18 (b, 1H), 3.74
(m, 2H), 3.97 (m, 4H), 4.27 (m, 1H), 4.90 (m, 1H), 5.07 (m, 1H),
5.70 (d, 1H), 6.15 (s, 2H), 6.95 (d, 1H), 7.30 (m, 7H). MS (ESI):
641(M+Na).
Example 156
[0777] 800
[0778]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-[(cycl-
ohexyloxy)(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)amino]-2-hydroxypropyl-
carbamate. A mixture of 1,4-benzodioxan-6-sulfonyl chloride (Eur.
Pat. Appl. 583960, Feb. 23, 1994; 60 mg; 0.253 mmol),
(3R,3aS,6aR)hexahydrofur-
o[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropy-
lcarbamate (100 mg, 0.230 mmol), and diisoproylethylamine (0.042
mL, 0.242 mmol) in anhydrous tetrahydrofuran (3 mL) was stirred at
ambient temperature under an Argon atmosphere for 16 hours. A
catalytic quantity of dimethylaminopyridine (-1 mg) was added and
the reaction was heated at reflux for approximately 2 hours. An
additional quantity of 1,4-benzodioxan-6-sulfonyl chloride (12 mg,
0.051 mmol) was added and the reaction was heated for an additional
30 minutes. After cooling to ambient temperature, the reaction
mixture was partitioned between ethyl acetate and aqueous
hydrochloric acid. After separating the phases, the organic layer
was washed with brine, dried over anhydrous magnesium sulfate,
filtered and evaporated in vacuo. The residue was purified on a
preparative TLC plate (20.times.20 cm, 500 .mu.M) eluting with 1:1
ethyl acetate:hexane. The product band was removed, eluted with 3:1
methylene chloride:methanol, filtered, and evaporated in vacuo. The
residue was triturated with water, filtered and dried under high
vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,
2R)-1-benzyl-3-[(cyclohexy-
loxy)(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)amino]-2-hydroxypropylcarba-
mate (125 mg, 86%) as a white solid. H1-NMR (chloroform-D3): 1.20
(m, 6H), 1.60 (m, 5H), 2.07 (m, 2H), 2.90 (m, 4H), 3.09 (b, 1H),
3.67 (m, 2H), 3.90 (m, 4H), 4.23 (m, 1H), 4.31 (m, 4H), 4.82 (d,
1H), 5.01 (m, 1H), 5.64 (d, 1H), 6.95 (d, 1H) 7.25 (m, 7H). MS
(ESI): 655 (M+Na).
Example 157
[0779] 801
[0780]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-[{[4-(-
benzyloxy)phenyl]sulfonyl}(cyclohexyloxy)amino]-2-hydroxypropylcarbamate.
[0781] A mixture of 4-benzyloxybenzenesulfonyl chloride (65 mg;
0.230 mmol), (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
(1S,2R)-1-benzyl-3-[(cy-
clohexyloxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.230 mmol),
diisoproylethylamine (0.042 mL, 0.242 mmol) and
4-dimethylaminopyridine (.about.1 mg) in anhydrous tetrahydrofuran
(3 mL) was stirred at ambient temperature under an Argon atmosphere
for 16 hours. An additional quantity of 4-benzyloxybenzenesulfonyl
chloride (13 mg, 0.046 mmol) and 45 dimethylaminopyridine (.about.1
mg) was added and the reaction was heated at reflux for
approximately 2 hours. After cooling to ambient temperature, the
reaction mixture was partitioned between ethyl acetate and aqueous
hydrochloric acid. The phases were separated and the organic layer
was then washed with brine, dried over anhydrous magnesium sulfate,
filtered and evaporated in vacuo. The crude product was purified on
flash grade silica gel eluting with 1:1 ethyl acetate:hexane.
Fractions containing the product were combined and evaporated in
vacuo and dried under high vacuum to provide
[0782]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-[{[4-(-
benzyloxy)phenyl]sulfonyl}(cyclohexyloxy)amino]-2-hydroxypropylcarbamate
(143 mg, 91%). H1-NMR (chloroform-D3): 1.27 (m, 6H), 1.61 (m, 5H),
2.07 (m, 2H), 2.91 (m, 4H), 3.10 (b, 1H), 3.68 (m, 2H), 3.89 (m,
4H), 4.19 (m, 1H), 4.84 (m, 1H), 5.01 (m, 1H), 5.12 (s, 2H), 5.64
(d, 1H), 7.05 (d, 2H), 7.28 (m, 10H), 7.71 (d, 2H). MS (ESI): 703
(M+Na).
Example 158
[0783] 802
[0784]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-[{[3-(-
benzyloxy)phenyl]sulfonyl}(cyclohexyloxy)amino]-2-hydroxypropylcarbamate.
[0785] A mixture of 3-benzyloxybenzenesulfonyl chloride (65 mg;
0.230 mmol),
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-[(cyc-
lohexyloxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.230 mmol) and
diisoproylethylamine (0.042 mL, 0.242 mmol) in anhydrous
tetrahydrofuran (3 mL) was stirred at ambient temperature under an
Argon atmosphere for 16 hours. A catalytic quantity of
dimethylaminopyridine (.about.1 mg) was added and the reaction was
heated at reflux for approximately one hour. An additional quantity
of 3-benzyloxybenzenesulfonyl chloride (13 mg, 0.046 mmol) was
added and the reaction was heated at reflux for approximately 1
hour. After cooling to ambient temperature, the reaction mixture
was partitioned between ethyl acetate and aqueous hydrochloric
acid. The phases were separated and the organic layer was then
washed with brine, dried over anhydrous magnesium sulfate, filtered
and evaporated in vacuo. The residue was dried under high vacuum to
provide
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-[{[3-(benzyl-
oxy)phenyl]sulfonyl}(cyclohexyloxy)amino]-2-hydroxypropylcarbamate
(140 mg, 89%). H1-NMR (chloroform-D3): 1.22 (m, 6H), 1.62 (m, 5H),
2.05 (m, 2H), 2.90 (m, 4H), 3.11 (b, 1H), 3.66 (m, 2H), 3.87 (m,
4H), 4.18 (m, 1H), 4.77 (m, 1H), 4.95 (m, 1H), 5.10 (m, 2H), 5.60
(d, 1H), 7.29 (m, 14H). MS (ESI): 703 (M+Na).
Example 159
[0786] 803
[0787]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-{(cycl-
ohexyloxy)[(3-hydroxyphenyl)sulfonyl]amino}-2-hydroxypropylcarbamate.
[0788] A solution of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-b-
enzyl-3-[{[3-(benzyloxy)phenyl]sulfonyl}(cyclohexyloxy)amino]-2-hydroxypro-
pylcarbamate (131 mg, 0.193 mmol) in ethyl acetate (.about.5 mL)
was combined with Palladium on carbon (10 wt %, 25 mg) and reduced
under an atmosphere of Hydrogen gas. After stirring for 16 hours,
the reaction mixture was filtered and evaporated in vacuo to a
residue. The residue was purified on a preparative TLC plate
(20.times.20 cm, 500 .mu.M) eluting with 3:2 ethyl acetate:hexane.
The product band was removed, eluted with 3:1 methylene
chloride:methanol, filtered, and evaporated in vacuo. The residue
was triturated with water, filtered and dried under high vacuum to
provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)--
1-benzyl-3-{(cyclohexyloxy)[(3-hydroxyphenyl)sulfonyl]amino}-2-hydroxyprop-
ylcarbamate (93 mg, 82%) as a white solid. H1-NMR (chloroform-D3):
1.28 (m, 6H), 1.67 (m, 5H), 2.06 (m, 2H), 2.96 (m, 4H), 3.09 (b,
1H), 3.87 (m, 6H), 4.19 (m, 1H), 5.01 (m, 2H), 5.69 (d, 1H), 6.60
(b, 1H), 7.23 (m, 9H). MS (ESI): 613 (M+Na).
Example 160
[0789] 804
[0790]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-{(cycl-
ohexyloxy)[(4-hydroxyphenyl)sulfonyl]amino}-2-hydroxypropylcarbamate.
[0791] A solution of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-b-
enzyl-3-[{[4-(benzyloxy)phenyl]sulfonyl}(cyclohexyloxy)amino]-2-hydroxypro-
pylcarbamate (140 mg, 0.206 mmol) in ethyl acetate (5 mL) was
combined with Palladium on carbon (10 wt %, 28 mg) and reduced
under an atmosphere of Hydrogen gas. After stirring for 16 hours,
the reaction mixture was filtered and evaporated in vacuo to a
residue. The residue was purified on a preparative TLC plate
(20.times.20 cm, 500 .mu.M) eluting with 3:2 ethyl acetate:hexane.
The product band was removed, eluted with 4:1 methylene
chloride:methanol, filtered, and evaporated in vacuo. The residue
was triturated with water, filtered and dried under high vacuum to
provide
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-{-
(cyclohexyloxy)[(4-hydroxyphenyl)sulfonyl]amino}-2-hydroxypropylcarbamate
(106 mg, 87%) as a white solid. H1-NMR (chloroform-D3): 1.27 (m,
6H), 1.67 (m, 5H), 2.05 (m, 2H), 2.93 (m, 4H), 3.11 (b, 1H), 3.68
(m, 2H), 3.90 (m, 4H), 4.19 (m, 1H), 4.81 (d, 1H), 4.99 (m, 1H),
5.65 (d, 1H), 6.24 (b, 1H), 6.92 (d, 2H), 7.22 (m, 5H), 7.67 (d,
2H). MS (ESI): 613 (M+Na).
Example 161
[0792] 805
[0793]
tert-butyl(1S,2R)-1-benzyl-3-[(1-ethylpropoxy)amino]-2-hydroxypropy-
lcarbamate.
[0794] A solution of 2-(1-ethylpropoxy)-1H-isoindole-1,3 (2H)-dione
[Synth. Comm., 22(10), 1427-1432 (1992), 10.00 g, 42.9 mmol] in
anhydrous tetrahydrofuran (100 mL) under Argon was treated with
anhydrous hydrazine (1.48 mL, 47.2 mmol) over approximately 5
minutes. The reaction was stirred for 45 minutes and diluted with
anhydrous tetrahydrofuran (50 mL). An additional quantity of
anhydrous hydrazine (0.888 mL, 28.3=mol) was added in six
increments over 90 minutes. The mixture was filtered washing with
tetrahydrofuran (50 mL). The mother liquor was combined with
tert-butyl N-(1S)-1-[(2S)oxiran-2-yl]-2-phenylethylcarbamate (9.03
g, 34.3 mmol) and lithium triflate (5.36 g, 34.3 mmol) and heated
to reflux. After stirring for 3.5 days, the reaction was evaporated
in vacuo and the residue was partitioned between aqueous potassium
carbonate (5% w/v) and ethyl acetate. The aqueous phase was
separated and extracted with ethyl acetate. The combined organic
layers were washed with saturated brine, dried over magnesium
sulfate, filtered and evaporated in vacuo. The residue was purified
on flash grade silica gel eluting with 3:1 hexane:ethyl acetate.
Fractions containing the product were evaporated in vacuo and dried
under high vacuum to tert-butyl(1S,2R)-1-benzyl-3-[(1-eth-
ylpropoxy)amino]-2-hydroxypropylcarbamate (6.425 g, 51%) as a
solid. H1-NMR (chloroform-D3): 0.88 (m, 6H), 1.34 (s, 9H), 1.51 (m,
4H), 2.91 (m, 4H), 3.15 (d, 1H), 3.47 (m, 1H), 3.69 (m, 2H), 3.89
(m, 1H), 4.57 (m, 1H), 7.24 (m, 5H). MS (ESI): 389 (M+Na). 806
[0795]
(2R,3S)-3-amino-1-[(1-ethylpropoxy)amino]-4-phenyl-2-butanol.
[0796] A mixture of
tert-butyl(1S,2R)-1-benzyl-3-[(1-ethylpropoxy)amino]-2-
-hydroxypropylcarbamate (3.285 g, 8.98 mmol) and trifluoroacetic
acid (25 mL) was stirred at ambient temperature under Argon for
approximately 30 minutes. The reaction was evaporated in vacuo and
the residue was partitioned between dichloromethane and aqueous
sodium hydroxide (1N). The phases were separated and the aqueous
phase was extracted with dichloromethane. The combined organic
phases were dried over anhydrous sodium sulfate, filter, evaporated
in vacuo and dried under high vacuum to provide
(2R,3S)-3-amino-1-[(1-ethylpropoxy)amino]-4-phenyl-2-butanol (2.455
g, 100%) as a solid. H1-NMR (chloroform-D3): 0.94 (m, 6H), 1.56 (m,
4H), 2.55 (m, 1H), 3.01 (m, 2H), 3.22 (m, 2H), 3.51 (m, 1H), 3.81
(m, 1H), 7.30 (m, 5H). MS (ESI): 267 (M+H). 807
[0797]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-[(1-et-
hylpropoxy)amino]-2-hydroxypropylcarbamate.
[0798] A mixture of (2R,3aS,6aR)hexahydrofuro[2,3-b]furan-2-yl
4-nitrophenyl carbonate (2.764 g, 8.94 mmol),
(2R,3S)-3-amino-1-[(1-ethyl- propoxy)amino]-4-phenyl-2-butanol
(2.379 g, 8.94 mmol), and diisoproylethylamine (1.56 mL, 8.94 mmol)
in acetonitrile (25 mL) under Argon was stirred at ambient
temperature for 16 hours. The reaction mixture was evaporated in
vacuo and the residue was partitioned between ethyl acetate and
aqueous potassium carbonate (5% w/v). The phases were separated and
the organic layer was washed again with aqueous potassium carbonate
(5% w/v). The aqueous phases were combined and extracted with ethyl
acetate. The combined organic layers were washed with brine, dried
over anhydrous magnesium sulfate and evaporated in vacuo. The
residue was triturated with diethyl ether and filtered. The mother
liquor was evaporated in vacuo and the residue was purified on
flash grade silica gel eluting with 1:1 ethyl acetate:hexane.
Fractions containing the product were combined and evaporated in
vacuo to a solid. Both crops of product were dried under high
vacuum to provide (3R,3aS,6aR)hexahydrofuro-
[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-[(1-ethylpropoxy)amino]-2-hydroxypropy-
lcarbamate (2.554 g, 68%). H1-NMR (chloroform-D3): 0.88 (m, 6H),
1.52 (m, 7H), 2.77 (m, 1H), 2.91 (m, 2H), 3.07 (m, 1H), 3.16 (m,
1H), 3.37 (b, 1H), 3.46 (m, 1H), 3.75 (m, 4H), 3.94 (m, 2H), 4.87
(d, 1H), 5.03 (m, 1H), 5.63 (d, 1H), 7.23 (m, 5H). MS (ESI): 445
(M+Na). 808
[0799]
tert-butyl(1S,2R)-1-benzyl-3-{(1-ethylpropoxy)[(4-methoxyphenyl)sul-
fonyl]amino}-2-hydroxypropylcarbamate.
[0800] A mixture of
tert-butyl(1S,2R)-1-benzyl-3-[1-(ethylpropoxy)amino]-2-
-hydroxypropylcarbamate (100 mg, 0.273 mmol),
4-methoxyphenylsulphonyl chloride (57 mg, 0.273 mmol), and
diisoproylethylamine (0.0476 mL, 0.273 mmol) in anhydrous
tetrahydrofuran (2 mL) was stirred under Argon for 16 hours at
ambient temperature. A catalytic quantity of
4-dimethylaminopyridine (.about.1 mg) was added and the reaction
was heated at reflux for approximately two hours. After cooling,
the reaction was evaporated in vacuo and the residue was dissolved
in ethyl acetate. The solution was washed with aqueous potassium
carbonate (5% w/v), aqueous hydrochloric acid (1N) and brine. The
organic layer was then dried over anhydrous magnesium sulfate,
filtered and evaporated in vacuo. The residue was purified on a
preparative TLC plate (20.times.20 cm, 500 .mu.M) eluting with 95:5
methylene chloride:methanol. The product band was removed, eluted
with 4:1 methylene chloride:methanol, filtered, and evaporated in
vacuo. The residue was purified again on a preparative TLC plate
(20.times.20 cm, 500 .mu.M) eluting with 95:5 methylene
chloride:ethyl acetate. The product band was removed, eluted with
4:1 methylene chloride:methanol, filtered, and evaporated in vacuo
to provide tert-butyl
(1S,2R)-1-benzyl-3-{(1-ethylpropoxy)[(4-methoxyphenyl)sulfonyl-
]amino}-2-hydroxypropylcarbamate (103 mg, 70%) as a foam. H1-NMR
(chloroform-D3): 0.95 (m, 6H), 1.38 (s, 9H), 1.64 (m, 4H), 3.01 (m,
5H), 3.83 (m, 2H), 3.93 (s, 3H), 4.20 (m, 1H), 4.61 (m, 1H), 7.03
(d, 2H), 7.29 (m, 5H), 7.80 (d, 2H). MS (ESI): 559 (M+Na).
Example 162
[0801] 809
[0802]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[(1,3-benzodiox-
ol-5-ylsulfonyl)(1-ethylpropoxy)amino]-1-benzyl-2-hydroxypropylcarbamate.
[0803] A mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-be-
nzyl-3-[(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (0.100 g,
0.237 mmol), 1,3-benzodioxole-5-sulfonyl chloride (52 mg, 0.237
mmol), diisoproylethylamine (0.042 mL, 0.237 mmol) and
dimethylaminopyridine (.about.1 mg) in anhydrous tetrahydrofuran (3
mL) was stirred at ambient temperature over 16 hours under an Argon
atmosphere. The reaction was evaporated in vacuo and the residue
was partitioned between dichloromethane and aqueous hydrochloric
acid (1N). The organic phase was separated and dried over anhydrous
magnesium sulfate, filtered and evaporated in vacuo. The residue
was purified on a preparative TLC plate (20.times.20 cm, 500 uM)
eluting with 97:3 dichloromethane: methanol. The product band was
removed, eluted with 4:1 methylene chloride:methanol, filtered, and
evaporated in vacuo. The residue was triturated with water,
filtered and dried under high vacuum to provide
(3R,3aS,6aR)hexahydrofuro-
[2,3-b]furan-3-yl(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(1-ethylpropoxy)-
amino]-1-benzyl-2-hydroxypropylcarbamate (114 mg, 80%) as a white
solid. H1-NMR (chloroform-D3): 0.89 (m, 6H), 1.57 (m, 7H), 2.95 (m,
5H), 3.69 (m, 2H), 3.89 (m, 4H), 4.15 (m, 1H), 4.82 (d, 1H), 5.01
(m, 1H), 5.64 (d, 1H), 6.10 (s, 2H), 6.90 (d, 1H), 7.23 (m, 6H),
7.39 (m, 1H). MS (ESI): 629 (M+Na).
Example 163
[0804] 810
[0805]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-{(1-et-
hylpropoxy)[(4-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate.
[0806] A mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-be-
nzyl-3-[(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (200 mg,
0.474 mmol), 4-nitrophenylsulphonyl chloride (105 mg, 0.474 mmol),
diisoproylethylamine (0.084 mL, 0.474 mmol) and
dimethylaminopyridine (.about.1 mg) in anhydrous tetrahydrofuran (3
mL) was stirred at ambient temperature over 16 hours under an Argon
atmosphere. The reaction was evaporated in vacuo and the residue
was partitioned between dichloromethane and aqueous sodium hydrogen
sulfate (1N). The phases were separated and the aqueous layer was
extracted with dichloromethane. The combined organic phases were
dried over anhydrous magnesium sulfate, filtered and evaporated in
vacuo. The residue was purified on flash grade silica gel eluting
with 1:1 ethyl acetate:hexane. Fractions containing the product
were combined, evaporated in vacuo and dried under high vacuum to
provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-ben-
zyl-3-{(1-ethylpropoxy)[(4-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarb-
amate (254 mg, 88%) as a foam. H1-NMR (chloroform-D3): 0.90 (m,
6H), 1.60 (m, 7H), 2.90 (m, 5H), 3.68 (m, 2H), 3.87 (m, 4H), 4.17
(m, 1H), 4.83 (d, 1H), 5.02 (m, 1H), 5.64 (d, 1H), 7.23 (m, 5H),
7.99 (d, 2H), 8.38 (d, 2H). MS (ESI): 630 (M+Na). 811
[0807]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-aminopheny-
l)sulfonyl](1-ethylpropoxy)amino]-1-benzyl-2-hydroxypropylcarbamate.
A solution of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3--
{(1-ethylpropoxy)[(4-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate
(237 mg, 0.390 mmol) in absolute methanol (5 mL) was combined with
Palladium on carbon (10 wt %, 50 mg) and reduced under a Hydrogen
atmosphere over 16 hours. The reaction was filtered and evaporated
in vacuo. The residue was purified on silica gel eluting with
50-60% ethyl acetate in hexane. Fractions containing the product
were combined and evaporated in vacuo. The residue was triturated
with water, filtered and dried under high vacuum to provide
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan--
3-yl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](1-ethylpropoxy)amino]-1-benzyl-2--
hydroxypropylcarbamate (160 mg, 71%) as a white solid. H1-NMR
(chloroform-D3): 0.90 (m, 6H), 1.58 (m, 7H), 2.95 (m, 5H), 3.69 (m,
2H), 3.91 (m, 4H), 4.13 (m, 1H), 4.26 (b, 2H), 4.80 (d, 1H), 5.00
(m, 1H), 5.63 (d, 1H), 6.67 (d, 2H), 7.22 (m, 5H), 7.58 (d, 2H).).
MS (ESI): 600 (M+Na).
Example 164
[0808] 812
[0809] Preparation of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1--
benzyl-3-{(1-ethylpropoxy)[(3-nitrophenyl)sulfonyl]amino}-2-hydroxypropylc-
arbamate. A mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-
-benzyl-3-[(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (200 mg,
0.474 mmol), 3-nitrophenylsulphonyl chloride (105 mg, 0.474 mmol),
diisoproylethylamine (0.084 mL, 0.474 mmol) and
dimethylaminopyridine (-1 mg) in anhydrous tetrahydrofuran (3 mL)
was stirred at ambient temperature over 16 hours under an Argon
atmosphere. The reaction was evaporated in vacuo and the residue
was partitioned between dichloromethane and aqueous hydrochloric
acid (1N). After separating the phases, the aqueous layer was
extracted with dichloromethane. The combined organic phases were
dried over anhydrous magnesium sulfate, filtered and evaporated in
vacuo. The residue was purified on flash grade silica gel eluting
with 1:1 ethyl acetate:hexane. Fractions containing the product
were combined, evaporated in vacuo and dried under high vacuum to
provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-ben-
zyl-3-{(1-ethylpropoxy)[(3-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarb-
amate (246 mg, 86%). H1-NMR (chloroform-D3): 0.98 (m, 6H), 1.68 (m,
7H), 2.99 (m, 5H), 3.73 (m, 2H), 3.96 (m, 4H), 4.27 (m, 1H), 4.86
(d, 1H), 5.07 (m, 1H), 5.69 (d, 1H), 7.27 (m, 5H), 7.84 (m, 1H),
8.16 (d, 1H), 8.57 (d, 1H), 8.76 (s, 1H). MS (ESI): 630 (M+Na).
813
[0810]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(3-aminopheny-
l)sulfonyl](1-ethylpropoxy)amino]-1-benzyl-2-hydroxypropylcarbamate.
A solution of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3--
{(1-ethylpropoxy)[(3-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate
(239 mg, 0.394 mmol) in absolute ethanol (3 mL) was combined with
Palladium on carbon (10 wt %, 25 mg) and reduced under a Hydrogen
atmosphere over 16 hours. The reaction was filtered and evaporated
in vacuo. The residue was purified on flash grade silica gel
eluting with 3:2 ethyl acetate:hexane. Fractions containing the
product were combined and evaporated in vacuo. The residue was
triturated with water, filtered and dried under high vacuum to
provide (3R,3aS,6aR)hexahydrofuro[2,3-b]fu-
ran-3-yl(1S,2R)-3-[[(3-aminophenyl)sulfonyl](1-ethylpropoxy)amino]-1-benzy-
l-2-hydroxypropylcarbamate (153 mg, 67%) as a white solid. H1-NMR
(chloroform-D3): 0.96 (m, 6H), 1.62 (m, 7H), 3.05 (m, 5H), 3.76 (m,
2H), 3.96 (m, 6H), 4.19 (m, 1H), 4.88 (m, 1H), 5.07 (m, 1H), 5.69
(d, 1H), 6.95 (d, 1H), 7.14 (s, 1H), 7.28 (m, 7H). MS (ESI): 600
(M+Na).
Example 165
[0811] 814
[0812]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-[{[4-(-
benzyloxy)phenyl]sulfonyl}(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate.
A mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-
-[(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (200 mg, 0.474
mmol), 4-benzyloxybenzenesulphonyl chloride (134 mg, 0.474 mmol),
diisoproylethylamine (0.083 mL, 0.474 mmol) and
dimethylaminopyridine (1 mg) in anhydrous tetrahydrofuran (3 mL)
was stirred at ambient temperature over 16 hours under an Argon
atmosphere. The reaction mixture was warmed to 55.degree. C. and an
additional quantity of dimethylaminopyridine (.about.2 mg) was
added. After stirring for 2 hours, the reaction was evaporated in
vacuo and the residue was partitioned between dichloromethane and
aqueous sodium hydrogen sulfate (1N). After separating the phases,
the aqueous layer was extracted with dichloromethane. The combined
organic phases were dried over anhydrous magnesium sulfate,
filtered and evaporated in vacuo. The residue was purified on flash
grade silica gel eluting with 3:2 ethyl acetate:hexane. Fractions
containing the product were combined, evaporated in vacuo, and
dried under high vacuum to provide
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan--
3-yl(1S,2R)-1-benzyl-3-[{[4-(benzyloxy)phenyl]sulfonyl}(1-ethylpropoxy)ami-
no]-2-hydroxypropylcarbamate (235 mg, 74%) as a foam. H1-NMR
(chloroform-D3): 0.94 (m, 6H), 1.62 (m, 7H), 3.05 (m, 5H), 3.74 (m,
2H), 3.98 (m, 4H), 4.18 (m, 1H), 4.88 (d, 1H), 5.08 (m, 1H), 5.19
(s, 2H), 5.70 (d, 1H), 7.13 (d, 2H), 7.34 (m, 10H), 7.80 (d, 2H).
MS (ESI): 691 (M+Na).
Example 166
[0813] 815
[0814]
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-{(1-et-
hylpropoxy)[(4-hydroxyphenyl)sulfonyl]amino}-2-hydroxypropylcarbamate.
A solution of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3--
[{[4-(benzyloxy)phenyl]sulfonyl}(1-ethylpropoxy)amino]-2-hydroxypropylcarb-
amate (222 mg, 0.384 mmol) in 3:1 absolute ethanol: ethyl acetate
was combined with Palladium on carbon (10 wt %, 44 mg) and reduced
under an atmosphere of Hydrogen gas over 16 hours. The reaction was
filtered and evaporated in vacuo. The residue was purified on flash
grade silica gel eluting with 3:2 ethyl acetate:hexane. Fractions
containing the product were combined and evaporated in vacuo. The
residue was triturated with water, filtered and dried under high
vacuum to provide
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-1-benzyl-3-{(1-ethylpro-
poxy)[(4-hydroxyphenyl)sulfonyl]amino}-2-hydroxypropylcarbamate
(103 mg, 46%) as a white solid. H1-NMR (chloroform-D3): 0.91 (m,
6H), 1.61 (m, 7H), 2.93 (m, 5H), 3.70 (m, 2H), 3.92 (m, 4H), 4.17
(m, 1H), 4.79 (d, 1H), 5.01 (m, 1H), 5.66 (d, 1H), 6.12 (s, 1H),
6.94 (d, 2H), 7.26 (m, 5H), 7.72 (d, 2H). MS (ESI): 601(M+Na).
Example 167
[0815] 816
[0816] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((-
cyclopentyloxy)[3-([(2-[methylamino]-2-oxoethylamino)carbonylamino]ethylam-
ino)phenyl]sulfonylamino)-2-hydroxypropyl]carbamate and
(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((cyclop-
entyloxy)[3-([2-[methylamino)-2-oxoethylamino)carbonylamino]ethylamino)phe-
nyl]sulfonylamino)-2-hydroxypropyl]carbamate. A solution of 30 mg
(0.048 mmol) of a 1:1 mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[(3-[(2-aminoethyl)amino]phenylsulfonyl)(cyclopentyloxy)amino-
]-1-benzyl-2-hydroxypropylcarbamate and
(3S,3aR,6aS)hexahydrofuro[2,3-b]fu- ran-3-yl N-(1S,
2R)-3-[(3-[(2-aminoethyl)amino]phenylsulfonyl)(cyclopentyl-
oxy)amino]-1-benzyl-2-hydroxypropylcarbamate in 2 mL of anhydrous
THF was treated with 6.0 .mu.L (0.05 mmol) of ethyl
isocyanatoacetate. After stirring at RT for 2.5 hours the solution
was concentrated in vacuo. The residue was dissolved in 3 mL of 2M
NH.sub.3/MeOH and the solution stirred at RT. After 18 hours the
solution was concentrated to dryness and the residue subjected to
flash chromatography (silica gel, 9:1 CH.sub.2Cl.sub.2/2M NH.sub.3
in MeOH) to afford 23 mg (66%) of the desired product as a white
foam. .sup.1H-NMR (CDCl.sub.3): 7.38-7.07 (10H), 6.88 (2H), 6.39
(1H), 6.16-5.88 (2H), 5.68 (1H), 5.09 (1H), 4.84 (1H), 4.17-2.59
(20H), 2.10-1.25 (10H). MS (ESI): 733 (M+H).
Example 168
[0817] 817
[0818] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((-
cyclopentyloxy)[3-(2-[methoxyamino]-2-oxoethylamino)phenyl]sulfonylamino)--
2-hydroxypropyl]carbamate and
(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((cyclopentyloxy)[3-(2-[methoxyamino]-2-oxoethylami-
no)phenyl]sulfonylamino)-2-hydroxypropyl]carbamate. A solution of
0.100 g (0.174 mmol) of a 1:1 mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-- yl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(3and
-aminophenyl)sulfonyl]amin- o-2-hydroxypropyl)carbamate and
(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(3-aminophenyl)sulfonyl]amino-2-hy-
droxypropyl)carbamate (see example 31), 44 mg (0.26 mmol) of
N-methoxybromoacetamide (prepared in a manner analogous to
N-methoxy-N-methylbromoacetamide, example 88), and 0.045 mL (0.26
mmol) of N,N-diisopropylethylamine in 5 mL of anhydrous DMF was
heated to 80.degree. C. with stirring in a sealed tube. The
reaction progress was monitored by HPLC (C18, H.sub.2O/MeCN/0.1%
TFA). In order to push the reaction further toward completion,
additional 1.5 equivalent portions of N-methoxybromoacetamide and
N,N-diisopropylethylamine were added after 4 hours and 3 days.
After a total reaction time of 4 days the solution was cooled to RT
and concentrated in vacuo. The residue was subjected to flash
chromatography (SiO.sub.2, 93:7 CH.sub.2Cl.sub.2/2M NH.sub.3 in
MeOH) to afford 16 mg (14%) of the desired product as a white foam.
.sup.1H-NMR (CDCl.sub.3): 7.367.00 (9H), 6.85 (2H), 5.60 (1H),
5.20-4.82 (2H), 4.75 (2H), 4.10-3.43 (10H), 3.21-2.45 (6H),
1.90-1.39 (10H). MS (ESI): 663 (M+H).
Example 169
[0819] 818
[0820] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((-
cyclopentyloxy)[3-(2-[dimethylamino]-2-oxoethylamino)phenyl)sulfonylamino)-
-2-hydroxypropyl]carbamate and
(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((cyclopentyloxy)[3-(2-[dimethylamino]-2-oxoethylam-
ino)phenyl]sulfonylamino)-2-hydroxypropyl]carbamate. A solution of
0.100 g (0.174 mmol) of a 1:1 mixture of
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-- yl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(3-aminophenyl)sulfonyl]amino-2--
hydroxypropyl)carbamate and
(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(3-aminophenyl)sulfonyl]amino-2-hy-
droxypropyl)carbamate (see example 31), 32 mg (0.19 mmol) of
N,N-dimethylbromoacetamide (prepared in a manner analogous to
N-methoxy-N-methylbromoacetamide, example 88), and 0.033 mL (0.19
mmol) of N,N-diisopropylethylamine in 3 mL of anhydrous DMF was
heated to 80.degree. C. with stirring in a sealed tube. The
reaction progress was monitored by HPLC (C18, H.sub.2O/MeCN/0.1%
TFA). In order to push the reaction further toward completion,
additional 1.1 equivalent portions of N,N-dimethylbromoacetamide
and N,N-diisopropylethylamine were added after 18 hours and 42
hours. After a total reaction time of 3 days the solution was
cooled to RT and concentrated in vacuo. The residue was dissolved
in EtOAc and the solution washed with aqueous brine (3.times.),
dried over MgSO.sub.4, and concentrated. The crude product was
purified by flash chromatography (SiO.sub.2, EtOAc) to afford 53 mg
(46%) of the desired product as a light yellow foam. .sup.1H-NMR
(CDCl.sub.3): 7.32-7.14 (8H), 7.10 (1H), 6.93 (1H), 6.86 (1H), 5.61
(1H), 4.96 (1H), 4.91-4.77 (2H), 3.92-3.55 (7H), 3.23-2.77 (12H),
1.86-1.38 (10H). MS (ESI): 661 (M+H).
Example 170
[0821] 819
[0822] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-[(1S,2R)-1-benzyl-3-((-
cyclopentyloxy)[3-(2-[ethyl(methyl)amino]-2-oxoethylamino)phenyl]sulfonyla-
mino)-2-hydroxypropyl)carbamate and
(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-- 3-yl
N-[(1S,2R)-1-benzyl-3-((cyclopentyloxy)[3-(2-[ethyl(methyl)amino]-2-o-
xoethylamino)phenyl]sulfonylamino)-2-hydroxypropyl]carbamate. A
solution of 0.100 g (0.174 mmol) of a 1:1 mixture of
(3R,3aS,6aR)hexahydrofuro[2,3- -b]]furan-3-yl N-((1S,
2R)-1-benzyl-3-(cyclopentyloxy)[(3-aminophenyl)sulf-
onyl]amino-2-hydroxypropyl)carbamate and
(3S,3aR,6aS)hexahydrofuro[2,3-b]f- uran-3-yl
N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(3-aminophenyl)sulfonyl]a-
mino-2-hydroxypropyl)carbamate (see example 31), 34 mg (0.19 mmol)
of N-ethyl-N-methylacetamide (prepared in a manner analogous to
N-methoxy-N-methylbromoacetamide, example 88), and 0.033 mL (0.19
mmol) of N,N-diisopropylethylamine in 3 mL of anhydrous DMF was
heated to 80.degree. C. with stirring in a sealed tube. The
reaction progress was monitored by HPLC (C18, H.sub.2O/MeCN/0.1%
TFA). In order to push the reaction further toward completion,
additional 1.1 equivalent portions of N-ethyl-N-methylacetamide and
N,N-diisopropylethylamine were added after 18 hours and 42 hours.
After a total reaction time of 3 days the solution was cooled to RT
and concentrated in vacuo. The residue was dissolved in EtOAc and
the solution washed with aqueous brine (3.times.), dried over
MgSO.sub.4, and concentrated. The crude product was purified by
flash chromatography (SiO.sub.2, EtOAc) to afford 61 mg (52%) of
the desired product as a light yellow foam. 1-NMR (CDCl.sub.3):
7.32-7.14 (8H), 7.09 (1H), 6.91 (1H), 6.85 (1H), 5.62 (1H),
5.01-4.77 (3H), 3.95-3.53 (7H), 3.48 (1H), 3.34 (1H), 3.23-2.75
(9H), 1.88-1.41 (10H), 1.27-1.08 (3H). MS (ESI): 675 (M+H).
Example 171
[0823] 820
[0824] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[[(4-aminoph-
enyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxypropyl
carbamate. This material was obtained in an analogous manner to
Example 77, but p-nitrobenzenesulfonyl chloride was used instead of
meta nitrobenzenesulfonyl chloride.
[0825] MS: 598 (M+Na), NMR (chloroform-d): 1.2-2.0 (m), 2.75-3.2
(m), 3.6 (dd), 3.7-4.0 (m), 4.2 (s), 4.75 (m), 4.85 (m), 5.0 (m),
5.62 (d), 6.65 (d), 7.2-7.3 (m), 7.55 (d).
Example 172
[0826] 821
[0827] (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[[(4-aminoph-
enyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxypropyl
carbamate. This material was obtained in an analogous manner to
Example 77, but p-nitrobenzenesulfonyl chloride was used instead of
meta nitrobenzenesulfonyl chloride and the starting scaffold was
that used in Example 39 (oposite stereochemistry at the
furanylfuran ring system).
[0828] MS: 598 (M+Na).), NMR (chloroform-d): 1.2-2.0 (m), 2.75-3.2
(m, 3.6 (dd), 3.7-4.0 (m), 4.2 (s), 4.75 (m), 4.95 (m), 5.1 (m),
5.8 (d), 6.65 (d), 7.2-7.3 (m), 7.55 (d).
Example 173
[0829] 822
[0830] Step 1:
[0831] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3-[[(3-cyanoph-
enyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxypropyl
carbamate.
[0832] In a dried flask was introduced 1 eq. of
(3R,3aS,6aR)Hexahydrofuro[-
2,3b]furan-3-yl-N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)amino]-2-hydroxyprop-
ylcarbamate (53.6 mg, 0.127 mmol) in 2 mL of dried pyridine. To
this solution was added 1.2 eq. of the m-cyanophenyl sulfonyl
chloride (31 mg, 0.153 mmol). This was followed by the addition of
catalytic DMAP (1 mg). The reaction was continued at room
temperature for 24 h. The solvent was evaporated in vacuo to an oil
who was solubilized in ethyl acetate and then washed with 1N
hydrochloric acid, and brine. The organic layer was dried over
anhydrous magnesium sulfate, filtered and evaporated in vacuo to a
residue. The crude material was purified on flash grade silica gel
eluting with 50% ethyl acetate in hexane. Fractions containing the
product were combined, evaporated in vacuo and dried under high
vacuum to provide
(3R,3aS,6aR)Hexahydrofuro[2,3b]furan-3-yl-N-(1S,2R)-1-benzyl-3-[(-
cyclopentyloxy)[(m-cyanophenyl)sulfonyl]amino-2-hydroxypropyl
carbamate (31 mg, 42%). HPLC showed the material to be 98% pure;
Ret. time=12.1 min, tic in 50% ethyl acetate/Hexanes indicated an
Rf of 0.3 and LCMS (ES+), M+H=586.3 (M+H). 823
[0833] Step 2:
[0834] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl
N-(1S,2R)-3[[(3-carbamoy-
lphenyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxypropyl
carbamate.
[0835] In a flask was introduced 1 eq.
(3R,3aS,6aR)Hexahydrofuro[2,3b]fura-
n-3-yl-N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)[(m-cyanophenyl)sulfonyl]amin-
o-2-hydroxypropyl carbamate (28 mg, 0.048 mmol) in 1 mL acetone. To
this solution was added: 1 urea hydroperoxide (4 EQ., 18 mg, 0.19
mmol), K.sub.2CO.sub.3 (0.1 EQ., 0.7 mg), and the 1 mL H.sub.2O.
The reaction was continued at room temperature for 5 h. The solvent
was evaporated in vacuo to an oil who was solubilized in ethyl
acetate and then washed with and brine. The organic layer was dried
over anhydrous magnesium sulfate, filtered and evaporated in vacuo
to a residue. The crude material was purified on flash grade silica
gel eluting with ethyl acetate. Fractions containing the product
were combined, evaporated in vacuo and dried under high vacuum to
provide (3R,3aS,6aR)Hexahydrofuro[2,3b]furan-3-yl-N-(1S,2R-
)-1-benzyl-3-[(cyclopentyloxy)[(m-phenyl-carboxamide)sulfonyl]amino-2-hydr-
oxypropyl carbamate (20.2 mg). HPLC showed the material to be 98%
pure; Ret. time=10.68 min, tlc in ethyl acetate indicated an Rf of
0.5 and LCMS (ES+), M+H=604.3 (M+H).
Example 173
[0836] Tablet Formulation
[0837] The following formulations A, B and C are prepared by wet
granulation of the ingredients with a solution of povidone,
followed by addition of magnesium stearate and compression.
5 Formulation A mg/tablet Active Ingredient 250 Lactose B.P. 210
Povidone B.P. 15 Sodium Starch Glycollate 20 Magnesium Stearate 5
500
[0838]
6 Formulation B mg/tablet Active Ingredient 250 Lactose B.P. 150
Avicel PH 101 60 Povidone B.P. 15 Sodium Starch Glycollate 20
Magnesium Stearate 5 500
[0839]
7 Formulation C mg/tablet Active Ingredient 250 Lactose B.P. 200
Starch 50 Povidone 5 Magnesium Stearate 4 359
[0840] The following formulations, D and E, are prepared by direct
compression of the admixed ingredients. The lactose in formulation
E is of the direct compression type (Dairy Crest-"Zeparox").
8 Formulation D mg/tablet Active Ingredient 250 Pregelatinized
Starch NF15 150 400
[0841]
9 Formulation E mg/tablet Active Ingredient 250 Lactose B.P. 150
Avicel 100 500
[0842] Formulation F (Controlled Release Formulation)
[0843] The formulation is prepared by wet granulation of the
ingredients with a solution of povidone followed by the addition of
magnesium stearate and compression.
10 mg/tablet Active Ingredient 500 Hydroxypropylmethylcellulose 112
(Methocel K4M Premium) Lactose B.P. 53 Povidone B.P. 28 Magnesium
Stearate 7 700
[0844] Drug release takes place over a period of about 6-8 hours
and is complete after 12 hours.
Example 174
[0845] Capsule Formulations
[0846] Formulation A
[0847] A capsule formulation is prepared by admixing the
ingredients of formulation D in Example 134 above and filling into
a two-part hard gelatin capsule. Formulation B (infra) is prepared
in a similar manner.
11 Formulation B mg/capsule Active Ingredient 250 Lactose B.P. 143
Sodium Starch Glycollate 25 Magnesium Stearate 2 420
[0848]
12 Formulation C mg/capsule Active Ingredient 250 Macrogel 4000
B.P. 350 600
[0849] Capsules of formulation C are prepared by melting the
Macrogel 4000 B.P., dispersing the active ingredient in the melt
and filling the melt into a two-part hard gelatin capsule.
13 Formulation D mg/capsule Active Ingredient 250 Lecithin 100
Arachis Oil 100 450
[0850] Capsules of formulation D are prepared by dispersing the
active ingredient in the lecithin and arachis oil and filling the
dispersion into soft, elastic gelatin capsules.
14 Formulation E mg/capsule Active Ingredient 150.0 Vitamin E TPGS
400.0 Polyethylene Glycol 400 NF 200.5 Propylene Glycol USP
39.5
[0851] Four (4) kilograms (kg) of Vitamin E TPGS (obtained from
Eastman Chemical Co.) was heated at 50.degree. C. until liquefied.
To the liquified Vitamin E TPGS, 2.005 kg of polyethylene glycol
400 (PEG400) (low aldehyde, <10 ppm, obtained from Union Carbide
or Dow Chemical Co.) heated to 50.degree. C. was added and mixed
until a homogeneous solution was formed. The resultant solution was
heated to 65.degree. C. 1.5 kg of active ingredient was dissolved
in the liquefied solution of Vitamin E TPGS and PEG 400. 0.395 kg
of propylene glycol at room temperature was added and mixed until a
homogenous solution was formed. The solution was cooled to
28-35.degree. C. The solution was then de-gassed. The mixture was
preferably encapsulated at 28-35.degree. C. at a fill weight
equivalent to 150 mg of volatiles-free compound, into Size 12
oblong, white opaque soft gelatin capsules using a capsule filling
machine. The capsule shells were dried to a constant fill moisture
of 3-6% water and a shell hardness of 7-10 newtons, and placed in a
suitable container.
[0852] Formulation F (Controlled Release Capsule)
[0853] The following controlled release capsule formulation is
prepared by extruding ingredients a,b, and c using an extruder,
followed by spheronization of the extrudate and drying. The dried
pellets are then coated with release-controlling membrane (d) and
filled into a two-piece, hard gelatin capsule.
15 mg/capsule (a) Active Ingredient 250 (b) Microcrystalline
Cellulose 125 (c) Lactose B.P. 125 (d) Ethyl Cellulose 13 513
Example 175
[0854] Injectable Formulation
16 Formulation A Active Ingredient 200 mg Hydro chloric Acid
Solution 0.1 M or 4.0 to 7.0 Sodium Hydroxide Solution 0.1 M q.s.
to pH Sterile water q.s. to 10 ml
[0855] The active ingredient is dissolved in most of the water
(350-40.degree. C.) and the pH adjusted to between 4.0 and 7.0 with
the hydrochloric acid or the sodium hydroxide as appropriate. The
batch is then made up to volume with water and filtered through a
sterile micropore filter into a sterile 10 ml amber glass vial
(type 1) and sealed with sterile closures and overseals.
17 Formulation B Active Ingredient 125 mg Sterile, Pyrogen-free, pH
7 Phosphate Buffer, q.s. to 25 ml
Example 176
[0856]
18 Intramuscular Injection Active Ingredient 200 mg Benzyl Alcohol
0.10 g Glycofurol 75 1.45 g Water for injection q.s. to 3.00 ml
[0857] The active ingredient is dissolved in the glycofurol. The
benzyl alcohol is then added and dissolved, and water added to 3
ml. The mixture is then filtered through a sterile micropore filter
and sealed in sterile 3 ml amber glass vials (type 1).
Example 177
[0858]
19 Syrup Formulation Active Ingredient 250 mg Sorbitol Solution
1.50 g Glycerol 2.00 g Sodium Benzoate 0.005 g Flavor, Peach
17.42.3169 0.0125 ml Purified Water q.s. to 5.00 ml
[0859] The active ingredient is dissolved in a mixture of the
glycerol and most of the purified water. An aqueous solution of the
sodium benzoate is then added to the solution, followed by addition
of the sorbital solution and finally the flavor. The volume is made
up with purified water and mixed well.
Example 178
[0860]
20 Suppository Formulation mg/capsule suppository Active Ingredient
250 Hard Fat, B.P. (Witepsol H15-Dynamit Nobel) 1770 2020
[0861] One-fifth of the Witepsol H15 is melted in a steam-jacketed
pan at 45.degree. C. maximum. The active ingredient is sifted
through a 200 .mu.m sieve and added to the molten base with mixing,
using a Silverson fitted with a cutting head, until a smooth
dispersion is achieved. Maintaining the mixture at 45.degree. C.,
the remaining Witepsol H15 is added to the suspension and stirred
to ensure a homogenous mix. The entire suspension is passed through
a 250 .mu.m stainless steel screen and, with continuous stirring,
is allowed to cool to 45.degree. C. At a temperature of 38.degree.
C. to 40.degree. C., 2.02 g of the mixture is filled into suitable,
2 ml plastic molds. The suppositories are allowed to cool to room
temperature.
Example 179
[0862]
21 Pessary Formulation mg/pessary Active Ingredient 250 Anhydrate
Dextrose 380 Potato Starch 363 Magnesium Stearate 7 1000
[0863] The above ingredients are mixed directly to form a
pessary.
Example 180
[0864] Anti-Viral Activity
[0865] We measured the enzyme inhibition constants of the compounds
listed in Table I against HIV-1 protease using the methods of:
[0866] Maschera, B., Darby, G., Pal, G., Wright, L. L., Tisdale,
M., Myers, R., Blair, E. D. and Furfine, E. S., Human
Immunodefficiency Virus: Mutations in the Viral Protease that
Confer Resistance to Saquinavir Increase the Dissociation Rate
Constant for the Protease-Saquinavir Complex, J. Biol. Chem., 271:
33231-33235 (1996); and
[0867] Toth, M. V. and Marshall, G. R. (1990) Int. J. Peptide
Protein Res. 36, 544-550.
[0868] Antiviral Activity Assay in MT4 Cells
[0869] Antiviral HIV activity and compound-induced cytotoxicity
were measured in parallel by means of a propidium iodide based
procedure in the human T-cell lymphotropic virus transformed cell
line MT4. Aliquots of the test compounds were serially diluted in
medium (RPMI 1640, 10% fetal calf serum (FCS), and gentamycin) in
96-well plates (Costar 3598) using a Cetus Pro/Pette. Exponentially
growing MT4 cells were harvested and centrifuged at 1000 rpm for 10
min in a Jouan centrifuge (model CR 4 12). Cell pellets were
resuspended in fresh medium (RPMI 1640, 20% FCS, 20% IL-2, and
gentamycin) to a density of 5.times.10.sup.5 cells/ml. Cell
aliquots were infected by the addition of HIV-1 (strain IIIB)
diluted to give a viral multiplicity of infection of
100.times.TCID.sub.50. A similar cell aliquot was diluted with
medium to provide a mock-infected control. Cell infection was
allowed to proceed for 1 hr at 37.degree. C. in a tissue culture
incubator with humidified 5% CO.sub.2 atmosphere. After the 1 hr
incubation the virus/cell suspensions were diluted 6-fold with
fresh medium, and 125 .mu.l of the cell suspension was added to
each well of the plate containing prediluted compound. Plates were
then placed in a tissue culture incubator with humidified 5%
CO.sub.2 for 5 days. At the end of the incubation period, 27 .mu.l
of 5% Nonidet-40 was added to each well of the incubation plate.
After thorough mixing with a Costar multitip pipetter, 60 .mu.l of
the mixture was transferred to filter-bottomed 96-well plates. The
plates were analyzed in an automated assay instrument (Screen
Machine, Idexx Laboratories). The assay makes use of a propidium
iodide dye to estimate the DNA content of each well.
REFERENCES
[0870] 1. Averett, D. R. 1989. Anti-HIV compound assessment by two
novel high capacity assays. J. Virol. Methods 23: 263-276.
[0871] 2. Schwartz, O., et al. 1988. A rapid and simple
calorimetric test for the study of anti-HIV agents. AIDS Res. and
Human Retroviruses, 4(6): 441-447.
[0872] 3. Daluge, S. M., et al. 1994.
5-chloro-2'3'-deoxy-3'fluorouridine (935U83), a selective
anti-human immunodeficiency virus agent with an improved metabolic
and toxicological profile. Antimicro. Agents and Chemother., 38
(7):1590-1603.
[0873] The anti-viral potency of the compounds of Table 1 in MT-4
cells was determined using the above technique. The results are
shown in Table 2 as IC.sub.50 values expressed in .mu.M.
[0874] In Table 2, the following classifications have been
employed:
[0875] "A": K.sub.i of less than 1 nM;
[0876] "B": K.sub.i between 1 and 10 nM;
[0877] "C": K.sub.i between 10 and 100 nM;
[0878] "D": K.sub.i greater than 100 nM;
[0879] "E": IC50 of 0.1 .mu.M or less;
[0880] "IF": IC50 between 0.1 and 0.5 .mu.M;
[0881] "G": IC50 between 0.5 and 1.0 .mu.M;
[0882] "H": IC50 greater than 1.0 .mu.M.
[0883] The designation "NA" is used where a given compound was not
tested.
[0884] The designation ">" is used where a given K1 or IC50 for
a compound is greater than the range given for the designated
letters.
22TABLE 2 Ki (enzyme) [nM] IC50 Compound (MT-4 cells) [.mu.M] 1 C H
2 C H 3 C H 4 C H 5 B G 6 C H 7 B H 8 A G 9 B >E 11 B H 12 >B
NA 13 C NA 14 A F 15 B H 16 C H 17 C H 18 B >G 19 C H 20 B H 21
C H 22 B H 23 B H 24 A H 25 A G 26 B H 27 A G 28 A F 29 A E 30 A F
31 A E 32 A E 33 A E 34 A F 35 A >G 36 A E 37 A E 38 A E 39 A F
40 A E 41 A E 42 A NA 43 A NA 44 A E 45 A E 46 A E 47 A G 48 A F 49
A E 50 A E 51 A F 52 A E 52 A E 53 A E 54 A E 55 A E 56 A F 57 A E
58 A F 59 A E 60 A F 61 B G 62 B H 63 B NA 64 A H 65 A F 66 A E 67
A F 68 A E 69 A F 70 A >F 71 A E 72 B G 73 A E 74 A E 75 A >F
76 A F 77 A E 78 A E 79 A F 83 A F 84 A NA 85 A NA 86 A E 87 A E 88
A E 89 A NA 90 A E 91 A NA 92 A NA 97 A E 98 A NA 99 A NA 100 C F
103 A E 104 A E 105 A E 106 A F 107 A NA 108 C >F 109 C >E
110 A F 111 B H 112 B H 113 A E 114 A E 115 D G 116 D G 117 D G 118
D G 119 D H 120 NA NA 121 A F 122 A E 123 A E 124 A E 125 A E 126 D
H 127 A E 128 D H 129 NA NA 130 A E 131 A E 132 A E 133 A F 134 A E
135 B E 136 A E 137 A E 138 A E 139 A E 140 A E 141 A H 142 A F 143
A E 144 A E 145 A E 146 A E 147 A E 148 A E 149 A E 150 A E 151 A E
152 C G 153 A E 154 A E 155 A E 156 A E 157 NA NA 158 NA NA 159 A E
160 A E 161 B H 162 A E 163 A E 164 A E 165 NA NA 166 A E 167 A F
168 A E 169 A E 170 A E 171 A E 172 A E 173 A E
[0885] As demonstrated above, all of the compounds tested displayed
inhibitory and anti-viral activity. Moreover, several of these
compounds exhibited activity levels far greater than those of known
HIV protease inhibitors. While we have described a number of
embodiments of this invention, it is apparent that our basic
constructions may be altered to provide other embodiments which
utilize the products, processes and methods of this invention.
Therefore, it will be appreciated that the scope of this invention
is to be defined by the appended claims, rather than by the
specific embodiments which have been presented by way of
example.
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