U.S. patent application number 09/828968 was filed with the patent office on 2002-01-31 for novel benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake.
This patent application is currently assigned to G.D. Searle & Co.. Invention is credited to Banerjee, Shyamal C., Huang, Horng-Chih, Lee, Len F., Li, Jinglin J., Miller, Raymond E., Reitz, David B., Tremont, Samuel J..
Application Number | 20020013476 09/828968 |
Document ID | / |
Family ID | 27567498 |
Filed Date | 2002-01-31 |
United States Patent
Application |
20020013476 |
Kind Code |
A1 |
Lee, Len F. ; et
al. |
January 31, 2002 |
Novel benzothiepines having activity as inhibitors of ileal bile
acid transport and taurocholate uptake
Abstract
Provided are novel benzothiepines, derivatives, and analogs
thereof; pharmaceutical compositions containing them; and methods
of using these compounds and compositions in medicine, particularly
in the prophylaxis and treatment of hyperlipidemic conditions such
as those associated with atherosclerosis or hypercholesterolemia,
in mammals.
Inventors: |
Lee, Len F.; (St. Charles,
MO) ; Banerjee, Shyamal C.; (Chesterfield, MO)
; Huang, Horng-Chih; (Chesterfield, MO) ; Li,
Jinglin J.; (Chesterfield, MO) ; Miller, Raymond
E.; (Fairview Heights, IL) ; Reitz, David B.;
(Chesterfield, MO) ; Tremont, Samuel J.; (St.
Louis, MO) |
Correspondence
Address: |
BANNER & WITCOFF
1001 G STREET N W
SUITE 1100
WASHINGTON
DC
20001
US
|
Assignee: |
G.D. Searle & Co.
P. O. Box 5110
Chicago
IL
|
Family ID: |
27567498 |
Appl. No.: |
09/828968 |
Filed: |
April 9, 2001 |
Related U.S. Patent Documents
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Application
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Patent Number |
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09828968 |
Apr 9, 2001 |
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09443403 |
Nov 19, 1999 |
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6262277 |
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09443403 |
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09275463 |
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6107494 |
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09275463 |
Mar 24, 1999 |
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09109551 |
Jul 2, 1998 |
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5994391 |
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09109551 |
Jul 2, 1998 |
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08816065 |
Mar 11, 1997 |
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09828968 |
Apr 9, 2001 |
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08831284 |
Mar 31, 1997 |
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08831284 |
Mar 31, 1997 |
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08517051 |
Aug 21, 1995 |
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08517051 |
Aug 21, 1995 |
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08305526 |
Sep 13, 1994 |
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60013119 |
Mar 11, 1996 |
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60068170 |
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Current U.S.
Class: |
549/5 ;
549/12 |
Current CPC
Class: |
C07D 337/06 20130101;
C07D 409/12 20130101; C07D 487/08 20130101; C07D 495/10 20130101;
B24B 21/12 20130101; C07C 323/18 20130101; C07C 323/12 20130101;
C07D 337/08 20130101; C07C 319/14 20130101; C07D 409/10 20130101;
C07D 495/04 20130101; C08G 65/329 20130101; B24B 5/18 20130101;
A61K 31/38 20130101; C07K 5/06086 20130101; C07F 9/65539 20130101;
C07C 319/14 20130101; C07C 319/14 20130101 |
Class at
Publication: |
549/5 ;
549/12 |
International
Class: |
C07D 337/08; C07F
009/547 |
Claims
What is claimed is:
1. A compound of formula (I): 515wherein: q is an integer from 1 to
4; n is an integer from 0 to 2; R.sup.1 and R.sup.2 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy,
alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and
cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl,
arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,
(polyalkyl)aryl, and cycloalkyl optionally are substituted with one
or more substituents selected from the group consisting of
OR.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.10R.sup.2A.sup.-,
SR.sup.9, S.sup.+R.sup.9R.sup.10A.sup.-.
P.sup.+R.sup.9R.sup.10R.sup.11A.- sup.-, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10, wherein alkyl, alkenyl, alkynyl,
alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl
optionally have one or more carbons replaced by O, NR.sup.9,
N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, P.sup.+R.sup.9R.sup.10A.sup.-, or phenylene,
wherein R.sup.9, R.sup.10, and R.sup.w are independently selected
from the group consisting of H, alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, and
alkylammoniumalkyl; or R.sup.1 and R.sup.2 taken together with the
carbon to which they are attached form C.sub.3-C.sub.10 cycloalkyl;
R.sup.3 and R.sup.4 are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl,
heterocycle, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, and SO.sub.3R.sup.9, wherein R.sup.9 and R.sup.10
are as defined above; or R.sup.3 and R.sup.4 together form .dbd.O,
.dbd.NOR.sup.11, .dbd.S, .dbd.NNR.sup.11R.sup.12, .dbd.NR.sup.9, or
.dbd.CR.sup.11R.sup.12.sub.12, wherein R.sup.11 and R.sup.12 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl,
heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl,
cyanoalkyl, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10 are as
defined above, provided that both R.sup.3 and R.sup.4 cannot be OH,
NH.sub.2, and SH, or R.sup.11 and R.sup.12 together with the
nitrogen or carbon atom to which they are attached form a cyclic
ring; R.sup.5 and R.sup.6 are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycle, quaternary heterocycle, OR.sup.9, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, and SO.sub.3R.sup.9, wherein alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary
heterocycle, and quaternary heteroaryl can be substituted with one
or more substituent groups independently selected from the group
consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary
heterocycle, quaternary heteroaryl, halogen, oxo, OR.sup.13,
NR.sup.13R.sup.14 SR.sup.13 S(O)R.sup.13, SO.sub.2R.sup.13,
SO.sub.3R.sup.13, NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15,
NO.sub.2, CO.sub.2R.sup.13, CN, OM, SO.sub.2OM,
SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14, C(O)OM,
CR.sup.13, P.sup.+R.sup.7R.sup.8A-, or phenylene, and R.sup.13,
R.sup.14, and R.sup.15 are independently selected from the group
consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl,
arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary
heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl,
wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and
polyalkyl optionally have one or more carbons replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-,
P(O)R.sup.9, phenylene, carbohydrate, amino acid, peptide, or
polypeptide, and R.sup.13, R.sup.14, and R.sup.15 are optionally
substituted with one or more groups selected from the
groupconsisting of sulfoalkyl, quaternary heterocycle, quaternary
heteroaryl, OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.10R.sup.11A-,
S.sup.+R.sup.9R.sup.10A-, and C(O)OM, wherein R.sup.16 and R.sup.17
are independently selected from the substituents constituting
R.sup.9 and M; or R.sup.14 and R.sup.15, together with the nitrogen
atom to which they are attached, form a cyclic ring; and R.sup.30
is selected from the group consisting of alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl,
alkylammoniumalkyl, and arylalkyl; and R.sup.7 and R.sup.8 are
independently selected from the group consisting of hydrogen and
alkyl; and one or more R.sub.x are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy,
aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle,
heteroaryl, polyether, quaternary heterocycle, quaternary
heteroaryl, OR.sup.13 NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
S(O).sub.2R.sup.13, SO.sub.3R.sup.13, S.sup.+R.sup.13R.sup.14A-,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14,
NR.sup.14C(O)R.sup.13, C(O)NR.sup.13R.sup.14, NR14C(O)R13, C(O)OM,
COR.sup.13, OR.sup.18, S(O).sub.nNR.sup.18, NR.sup.13R.sup.18,
NR.sup.18OR.sup.14, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.11R.sup.12A.su- p.-, amino acid, peptide,
polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl,
haloalkyl, polyether, quaternary heterocycle, and quaternary
heteroaryl can be further substituted with OR.sup.9,
NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.2A.sup.-, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein R.sup.18 is
selected from the group consisting of acyl, arylalkoxycarbonyl,
arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl,
arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,
quaternary heterocycle, and quaternary heteroaryl optionally are
substituted with one or more substituents selected from the group
consisting of OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.3R.sup.9, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17, and C(O)OM,
wherein in R.sup.x, one or more carbons are optionally replaced by
O, NR.sup.13, N.sup.+R.sup.13R.sup.14A-, S, SO, SO.sub.2,
S.sup.+R.sup.13A.sup.-, PR.sup.13, P(O)R.sup.13,
P.sup.+R.sup.13R.sup.14A-, phenylene, amino acid, peptide,
polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said
polyalkyl, phenylene, amino acid, peptide, polypeptide, and
carbohydrate, one or more carbons are optionally replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-, or
P(O)R.sup.9; wherein quaternary heterocycle and quaternary
heteroaryl are optionally substituted with one or more groups
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, halogen, oxo OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14- ,
C(O)NR.sup.13R.sup.14, C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- , provided that both R.sup.5
and R.sup.6 cannot be hydrogen or SH; provided that when R.sup.5 or
R.sup.6 is phenyl, only one of R.sup.1 or R.sup.2 is H; provided
that when q=1 and R.sup.x is styryl, anilido, or anilinocarbonyl,
only one of R.sup.5 or R.sup.6 is alkyl; or a pharmaceutically
acceptable salt, solvate, or prodrug thereof.
2. A compound of claim 1, wherein R.sup.5 and R.sup.6 are
independently selected from the group consisting of H, aryl,
heterocycle, quaternary heterocycle, and quaternary heteroaryl,
wherein said aryl, heteroaryl, quaternary heterocycle, and
quaternary heteroaryl can be substituted with one or more
substituent groups independently selected from the group consisting
of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,
cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR.sup.13,
NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13,
SO.sub.3R.sup.13, NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15,
NO.sub.2, CO.sub.2R.sup.13, CN, OM, SO.sub.2OM,
SO.sub.2NR.sup.13R.sup.14- , C(O)NR.sup.13R.sup.14, C(O)OM,
COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- , wherein said alkyl,
alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,
cycloalkyl, and heterocycle can optionally have one or more carbons
replaced by O, NR.sup.7, N.sup.+R.sup.7R.sup.8A.sup.-, S, SO,
SO.sub.2, S.sup.+R.sup.7A.sup.-, PR.sup.7, P(O)R.sup.7,
P.sup.+R.sup.7R.sup.8A.sup.-, or phenylene, wherein said alkyl,
alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,
cycloalkyl, and heterocycle can be further substituted with one or
more substituent groups selected from the group consisting of
OR.sup.7, NR.sup.7R.sup.8, SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7,
SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN, oxo, CONR.sup.7R.sup.8,
N.sup.+R.sup.7R.sup.8R.sup.9A-, alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle,
quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8A.sup.-, and P(O)(OR.sup.7)OR.sup.8.
3. A compound of claim 2, wherein R.sup.5 or R.sup.6 has the
formula --Ar--(R.sup.y).sub.twherein: t is an integer from 0 to 5;
Ar is selected from the group consisting of phenyl, thiophenyl,
pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl,
anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl,
pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl,
isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl,
benzothiazolyl, and benzoisothiazolyl; and one or more R.sup.y are
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl,
heterocycle, arylalkyl, halogen, oxo, OR.sup.13, NR.sup.13R.sup.14,
SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14- ,
C(O)NR.sup.13R.sup.14, C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- , wherein said alkyl,
alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,
cycloalkyl, and heterocycle can be further substituted with one or
more substituent groups selected from the group consisting of
OR.sup.7, NR.sup.7R.sup.8, SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7,
SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN, oxo, CONR.sup.7R.sup.8,
N.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle,
quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8A.sup.-, and P(O) (OR.sup.7)OR.sup.8, and
wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
haloalkyl, cycloalkyl, and heterocycle can optionally have one or
more carbons replaced by O, NR.sup.7, N.sup.+R.sup.7R.sup.8A.-
sup.-, S, SO, SO.sub.2, S.sup.+R.sup.7A-, PR.sup.7, P(O)R.sup.7,
P.sup.+R.sup.7R.sup.8A.sup.-, or phenylene.
4. A compound of claim 3, wherein R.sup.5 or R.sup.6 has the
formula (II) 516
5. A compound of claim 4, wherein n is 1 or 2.
6. A compound of claim 5, wherein one of R.sup.7 or R.sup.8 is H
and the other of R.sup.7 or R.sup.8 is alkyl.
7. A compound of claim 5, wherein both R.sup.7 and R.sup.8 are
H.
8. A compound of claim 7, wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting of H and
alkyl.
9. A compound of claim 8, wherein said alkyl is a C.sub.1-C.sub.10
alkyl.
10. A compound of claim 8, wherein R and R.sup.2 are both
alkyl.
11. A compound of claim 10, wherein said alkyl is a
C.sub.1-C.sub.10 alkyl.
12. A compound of claim 11, wherein said alkyl is a C.sub.2-C.sub.7
alkyl.
13. A compound of claim 12, wherein said alkyl is a C.sub.2-C.sub.4
alkyl.
14. A compound of claim 13, wherein said alkyl is independently
selected from the group consisting of ethyl, n-propyl, n-butyl, and
isobutyl.
15. A compound of claim 8, wherein R.sup.1 and R.sup.2 are each
n-butyl.
16. A compound of claim 8, wherein one of R.sup.1 and R.sup.2 is
ethyl and the other of R.sup.1 and R.sup.2 is n-butyl.
17. A compound of claim 15, wherein q is 1, 2, or 3.
18. A compound of claim 16, wherein q is 1, 2, or 3.
19. A compound of claim 17, wherein q is 1 or 2.
20. A compound of claim 19, wherein q is 1.
21. A compound of claim 18, wherein q is 1 or 2.
22. A compound of claim 21, wherein q is 1.
23. A compound of claim 19, wherein R.sup.3 and R.sup.4 are
independently selected from the group consisting of H and
OR.sup.9.
24. A compound of claim 21, wherein R.sup.3 and R.sup.4 are
independently selected from the group consisting of H and
OR.sup.9.
25. A compound of claim 23, wherein R.sup.9 is H.
26. A compound of claim 24, wherein R.sup.9 is H.
27. A compound of claim 25, wherein one or more R.sup.x are in the
7-, 8-, or 9-position of the benzo ring of formula (I).
28. A compound of claim 26, wherein said R.sup.x is in the 7-, 8-,
or 9- position of the benzo ring of formula
29. A compound of claim 27, wherein said R.sup.x are in the 7- and
9- positions of the benzo ring of formula (I).
30. A compound of claim 28, wherein said R.sup.x is in the
7-position of the benzo ring of formula (I).
31. A compound of claim 29, wherein said one or more R.sup.x are
independently selected from the group consisting of alkyl, aryl,
cycloalkyl, heterocycle, polyalkyl, acyloxy, polyether, halogen,
OR.sup.13, NR.sup.13R.sup.14, NR.sup.13NR.sup.14R.sup.15,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.13,
S.sup.+R.sup.13R.sup.14- , CO.sub.2R.sup.13, NR.sup.14C(O)R.sup.13,
and NR.sup.14C(O)R.sup.13, wherein alkyl, aryl, cycloalkyl,
heterocycle, polyalkyl, acyloxy, and polyether, can be further
substituted with OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10 SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16 )OR.sup.17, P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein in R.sup.x,
one or more carbons are optionally replaced by O, NR.sup.13,
N.sup.+R.sup.13R.sup.14A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9R.sup.10A.- sup.-, PR.sup.13, P(O)R.sup.13,
P.sup.+R.sup.9R.sup.10A.sup.-, phenylene, amino acid, peptide,
polypeptide, carbohydrate, polyether, or polyalkyl, and wherein in
said polyalkyl, phenylene, amino acid, peptide, polypeptide, and
carbohydrate, one or more carbons are optionally replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A-, S, SO, SO.sub.2,
S.sup.+R.sup.9A-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-, or
P(O)R.sup.9.
32. A compound of claim 30, wherein said R.sup.x is selected from
the group consisting of alkyl, aryl, cycloalkyl, heterocycle,
polyalkyl, acyloxy, polyether, halogen, OR.sup.13,
NR.sup.13R.sup.14, NR.sup.13NR.sup.14R.sup.15,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.13,
S.sup.+R.sup.13R.sup.14, CO.sub.2R.sup.13, NR.sup.14C(O)R.sup.13,
and NR.sup.14C(O)R.sup.13, wherein alkyl, aryl, cycloalkyl,
heterocycle, polyalkyl, acyloxy, and polyether, can be further
substituted with OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10 SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein in R.sup.x,
one or more carbons are optionally replaced by O, NR.sup.13,
N.sup.+R.sup.13R.sup.14A-, S, SO, SO.sub.2, S.sup.+R.sup.13A-,
PR.sup.13, P(O)R.sup.13, P.sup.+R.sup.13R.sup.14A-, phenylene,
amino acid, peptide, polypeptide, carbohydrate, polyether, or
polyalkyl, and wherein in said polyalkyl, phenylene, amino acid,
peptide, polypeptide, and carbohydrate, one or more carbons are
optionally replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.10A-, S,
SO, SO.sub.2, S.sup.+R.sup.9A-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-,
or P(O)R.sup.9.
33. A compound of claim 31, wherein said one or more R.sup.x are
independently selected from the group consisting of polyether,
OR.sup.13, NR.sup.13R.sup.14, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-.
34. A compound of the claim 32, wherein said R.sup.x is selected
from the group consisting of polyether, OR.sup.13,
NR.sup.13R.sup.14, and N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-.
35. A compound of claim 33, wherein said one or more Rx are
independently selected from the group consisting of OR.sup.13 and
NR.sup.13R.sup.14.
36. A compound of claim 34, wherein said R.sup.x is independently
selected from the group consisting of OR.sup.13 and
NR.sup.13R.sup.14.
37. A compound of claim 35, wherein R.sup.13 and R.sup.14 each
methyl.
38. A compound of the claim 36, wherein R.sup.13 and R.sup.14 each
methyl.
39. A compound of claim 31, wherein one or more R.sup.y are
independently in the 3- or the 4-position of the phenyl ring of
formula (II).
40. A compound of claim 32, wherein one or more Ry are
independently in the 3- or the 4- position of the phenyl ring of
formula (II).
41. A compound of claim 39, wherein t is 1 or 2.
42. A compound of claim 40, wherein t is 1 or 2.
43. A compound of claim 41, wherein said one or more R are
independently selected from the group consisting of alkyl,
polyether, fluoride, chloride, bromide, iodide, NR.sup.13R.sup.14,
NR.sup.14(O)R.sup.13, and OR.sup.13, wherein alkyl and polyether
can be further substituted with SO.sub.3R.sup.9,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, and quaternary
heteroaryl.
44. A compound of claim 42, wherein said R.sup.y is independently
selected from the group consisting of alkyl, polyether, fluoride,
chloride, bromide, iodide, NR.sup.13R.sup.14,
NR.sup.14C(O)R.sup.13, and OR.sup.13, wherein alkyl and polyether
can be further substituted with SO.sub.3R.sup.9,
NR.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, and quaternary
heteroaryl.
45. A compound of claim 43, wherein said one or more R.sup.y are
independently selected from the group consisting of alkyl,
polyether, fluoride, NR.sup.13R.sup.14, NR.sup.14C(O)R.sup.13, and
OR.sup.13, wherein alkyl and polyether can be further substituted
with SO.sub.3R.sup.9, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, and
quaternary heteroaryl.
46. A compound of claim 44 wherein said R.sup.y is independently
selected from the group consisting of alkyl, polyether, fluoride,
NR.sup.13R.sup.14, NR.sup.14C(O)R.sup.13, and OR.sup.13, wherein
alkyl and polyether can be further substituted with
SO.sub.3R.sup.9, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, and
quaternary heteroaryl.
47. A compound of claim 45, wherein said R.sup.13 and R.sup.14 are
alkyl, wherein alkyl can be further substituted with
SO.sup.3R.sup.9, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, and
quaternary heteroaryl.
48. A compound of claim 46, wherein said R.sup.9 and R.sup.10 are
alkyl, wherein alkyl can be further substituted with
SO.sup.3R.sup.9, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, and
quaternary heteroaryl.
49. A compound of claim 47, wherein n is 2.
50. A compound of claim 48, wherein n is 2.
51. A compound of claim 49, wherein said OH group is in a syn
relationship to said structure of formula (II).
52. A compound of claim 50, wherein said OH group is in a syn
relationship to said structure of formula (II).
53. A compound of claim 51, having the formula: 517
54. A compound of claim 51, having the formula: 518
55. A compound of claim 51, having the formula: 519
56. A compound of claim 51, having the formula: 520
57. A compound of claim 51, having the formula: 521
58. A compound of claim 52, having the formula: 522
59. A compound of claim 52, having the formula: 523
60. A compound of claim 52, having the formula: 524
61. A compound of claim 52, having the formula: 525
62. A compound of claim 52, having the formula: 526
63. A compound of claim 31, wherein n is 1.
64. A compound of claim 63, wherein R.sup.y is H.
65. A compound of claim 64, having the formula 527
66. A compound of claim 4, wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting of H and
alkyl.
67. A compound of claim 66, wherein said alkyl is C.sub.1-C.sub.10
alkyl.
68. A compound of claim 67, wherein said alkyl is C.sub.2-C.sub.7
alkyl.
69. A compound of claim 68, wherein said alkyl is C.sub.2-C.sub.4
alkyl.
70. A compound of claim 69, wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting of ethyl,
n-propyl, n-butyl, and isobutyl.
71. A compound of claim 4, wherein R.sup.3 and R.sup.4 are
independently selected from the group consisting of H and
OR.sup.9.
72. A compound of claim 71, wherein R.sup.9 is H.
73. A compound of claim 4, wherein n is 2.
74. A compound of claim 3, wherein R.sup.3 and R.sup.4 are
independently selected from the group consisting of H and
OR.sup.9.
75. A compound of claim 74, wherein R9 is H.
76. A compound of claim 3, wherein one of R.sup.7 or R.sup.8 is
H.
77. A compound of claim 76, wherein both R.sup.7 and R.sup.8 are
H.
78. A compound of claim 3, wherein said one or more R.sup.x are
independently selected from the group consisting of alkyl, aryl,
cycloalkyl, heterocycle, polyalkyl, acyloxy, polyether, halogen,
OR.sup.13, NR.sup.13R.sup.14, NR.sup.13NR.sup.14R.sup.15,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.13,
S.sup.+R.sup.13R.sup.14- , CO.sub.2R.sup.13, NR.sup.14C(O)R.sup.13,
and NR.sup.14C(O)R.sup.13, wherein alkyl, aryl, cycloalkyl,
heterocycle, polyalkyl, acyloxy, and polyether, can be further
substituted with OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(R.sup.16)R.sup.17, P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein in R.sup.x,
one or more carbons are optionally replaced by O, NR.sup.13,
N.sup.+R.sup.13R.sup.14A-, S, SO, SO.sub.2, S.sup.+R.sup.13A-,
PR.sup.13, P(O)R.sup.13, P.sup.+R.sup.13R.sup.14A.sup.-, phenylene,
amino acid, peptide, polypeptide, carbohydrate, polyether, or
polyalkyl, and wherein in said polyalkyl, phenylene, amino acid,
peptide, polypeptide, and carbohydrate, one or more carbons are
optionally replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.11A.sup.-,
S, SO, SO.sub.2, S.sup.+R.sup.9A.sup.-, PR.sup.9,
P.sup.+R.sup.9R.sup.10A.sup.-, or P(O)R.sup.9.
79. A compound of claim 78, wherein said one or more R.sup.x are
independently selected from the group consisting of polyether,
OR.sup.13, NR.sup.13R.sup.14, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-.
80. A compound of claim 79, wherein said one or more R.sup.x are
independently selected from the group consisting of OR.sup.13 and
NR.sup.13R.sup.14.
81. A compound of claim 80, wherein R.sup.13 and R.sup.14 are each
methyl.
82. A compound of claim 3, wherein one or more R.sup.y are
independently in the 3- or the 4-position of the phenyl ring of
formula (II).
83. A compound of claim 82, wherein one or more R.sup.y is selected
from the group consisting of alkyl, polyether, fluoride, chloride,
bromide, iodide, NR.sup.9R.sup.10, and NC(O)R.sup.9, wherein alkyl
and polyether can be substituted with SO.sub.3R.sup.9,
N.sup.+R.sup.9R.sup.11R.sup.12A.- sup.-, and quaternary
heteroaryl.
84. A compound of claim 83, wherein R.sup.9 and R.sup.10 are
alkyl.
85. A compound of claim 84, wherein one or more R.sup.y is selected
from the group consisting of alkyl, polyether, fluoride, chloride,
bromide, iodide, NR.sup.9R.sup.10, and NC(O)R.sup.9.
86. A compound of claim 1, wherein said one or more R.sup.x are
independently selected from the group consisting of alkyl, aryl,
cycloalkyl, heterocycle, polyalkyl, acyloxy, polyether, halogen,
OR.sup.13, NR.sup.13R.sup.14, NR.sup.13NR.sup.14R.sup.15,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.13,
S.sup.+R.sup.13R.sup.14- , CO.sub.2R.sup.13, NR.sup.14C(O)R.sup.13,
and NR.sup.14(O)R.sup.13, wherein alkyl, aryl, cycloalkyl,
heterocycle, polyalkyl, acyloxy, and polyether, can be further
substituted with OR.sup.9, NR.sup.9R.sup.10, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10 SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein in R.sup.x,
one or more carbons are optionally replaced by O, NR.sup.13,
N.sup.+R.sup.13R.sup.14A.sup.-, S, SO, SO.sub.2, S.sup.+R.sup.13A-,
PR.sup.13, P(O)R.sup.13, P.sup.+R.sup.13R.sup.14A-, phenylene,
amino acid, peptide, polypeptide, carbohydrate, polyether, or
polyalkyl, and wherein in said polyalkyl, phenylene, amino acid,
peptide, polypeptide, and carbohydrate, one or more carbons are
optionally replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.10A-, S,
SO, SO.sub.2, S.sup.+R.sup.9A-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-,
or P(O)R.sup.9.
87. A compound of claim 1, wherein n is 1 or 2.
88. A compound of claim 87, wherein n is 2.
89. A compound of claim 1, wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting of H and
alkyl.
90. A compound of claim 89, wherein said alkyl is C.sub.1-C.sub.10
alkyl.
91. A compound of claim 90, wherein said alkyl is C.sub.2-C.sub.7
alkyl.
92. A compound of claim 91, wherein said alkyl is C.sub.2-C.sub.4
alkyl.
93. A compound of claim 92, wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting of ethyl,
n-propyl, n-butyl, and isobutyl.
94. A compound of claim 1, wherein R.sup.3 and R.sup.4 are
independently selected from the group consisting of H and
OR.sup.9.
95. A compound of claim 94, wherein R.sup.9 is H.
96. A compound of claim 1, wherein one of R.sup.7 or R.sup.8 is
H.
97. A compound of claim 96, wherein both R.sup.7 and R.sup.8 are
H.
98. A compound of the formula (III) 528wherein q and r are
independently integers from 0 to 4; d and e are independently
integers from 0 to 2; t and u are independently integers from 0 to
4; R.sup.1, R.sup.1A, R.sup.2, and R.sup.2A are independently
selected from the group consisting of H, alkyl, alkenyl, alkynyl,
haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino,
alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl,
alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,
dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally
are substituted with one or more substituent selected from the
group consisting of OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.10R.s- up.wA.sup.-, SR.sup.9, S.sup.+R.sup.9A-.
P.sup.+R.sup.9R.sup.10R.sup.11A.s- up.-, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10, wherein alkyl, alkenyl, alkynyl,
alkylaryl, alkoxy, alkoxyalkyl, polyalkyl, aryl, and cycloalkyl
optionally have one or more carbons replaced by O, NR.sup.9,
N.sup.+R.sup.9R.sup.10A-, S, SO, SO.sub.2, S.sup.+R.sup.9A-,
P.sup.+R.sup.9R.sup.10A-, or phenylene, wherein R.sup.9,
R.sup.10.sub.10 and R.sup.w are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and
arylalkyl; or R.sup.1 and R.sup.2 taken together with the carbon to
which they are attached form C.sub.3-C.sub.10 cycloalkylidene, or
R.sup.1A and R.sup.2A taken together with the carbon to which they
are attached form C.sub.3-C.sub.10 cycloalkylidene; R.sup.3,
R.sup.3A, R.sup.4, and R.sup.4A are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl,
heterocycle, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, and SO.sub.3R.sup.9, wherein R.sup.9 and R.sup.10
are as defined above; or R.sup.3 and R.sup.4 together form .dbd.O,
.dbd.NOR.sup.11, .dbd.S, .dbd.NNR.sup.11R.sup.12, .dbd.NR.sup.9, or
.dbd.CR.sup.11R.sup.12, or R.sup.3A and R.sup.4A together form
.dbd.O, .dbd.NOR.sup.11, .dbd.S, .dbd.NNR.sup.11R.sup.12,
.dbd.NR.sup.9, or .dbd.CR.sup.11R.sup.12, wherein R.sup.11 and
R.sup.12 are independently selected from the group consisting of H,
alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,
alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl,
cycloalkyl, cyanoalkyl, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN,
halogen, oxo, and CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10
are as defined above, provided that both R.sup.3 and R.sup.4 cannot
be OH, NH2, and SH, or R.sup.11 and R.sup.12 together with the
nitrogen or carbon atom to which they are attached form a cyclic
ring; wherein A.sup.- is a pharmaceutically acceptable anion and M
is a pharmaceutically acceptable cation; R.sup.7, R.sup.7A,
R.sup.8, and R.sup.8A are independently selected from the group
consisting of hydrogen and alkyl; and one or more R.sup.x and
R.sup.xA are independently selected from the group consisting of H,
alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl,
halogen, haloalkyl, cycloalkyl, heterocycle, heterocycle,
polyether, quaternary heterocycle, quaternary heteroaryl,
OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
S(O).sub.2R.sup.13, SO.sub.3R.sup.13, S.sup.+R.sup.13R.sup.14A-,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14,
NR.sup.14C(O)R.sup.13, C(O)NR.sup.13R.sup.14,
NR.sup.14C(O)R.sup.13, C(O)OM, COR.sup.13, OR.sup.18,
S(O).sub.nNR.sup.18, NR.sup.13R.sup.18, N.sup.18OR.sup.14,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, P.sup.+
R.sup.9R.sup.11R.sup.12A.s- up.-, amino acid, peptide, polypeptide,
and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl,
polyether, quaternary heterocycle, and quaternary heteroaryl can be
further substituted with OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein R.sup.18 is
selected from the group consisting of acyl, arylalkoxycarbonyl,
arylalkyl, heterocycle, heterocycle, alkyl, wherein acyl,
arylalkoxycarbonyl, arylalkyl, heterocycle, heterocycle, alkyl
quaternary heterocycle, and quaternary heteroaryl optionally are
substituted with one or more substituent selected from the group
consisting of OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.3R.sup.9, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17, and C(O)OM,
wherein in R.sup.x and R.sup.xA, one or more carbons are optionally
replaced by O, NR.sup.13, N.sup.+R.sup.13R.sup.14A-, S, SO,
SO.sub.2, S.sup.+R.sup.13A-, PR.sup.13, P(O)R13,
P.sup.+R.sup.13R.sup.14A-, phenylene, amino acid, peptide,
polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said
polyalkyl, phenylene, amino acid, peptide, polypeptide, and
carbohydrate, one or more carbons are optionally replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A-, S, SO, SO.sub.2,
S.sup.+R.sup.9A-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-, or
P(O)R.sup.9; wherein quaternary heterocycle and quaternary
heteroaryl are optionally substituted with one or more groups
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, halogen, oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14,
C(O)NR.sup.13R.sup.14, C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R15A-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, R.sup.19 is selected from
the group consisting of alkane diyl, alkene diyl, alkyne diyl,
polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl,
carbohydrate, amino acid, and peptide, polypeptide, wherein alkane
diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl,
polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and
peptide polypeptide, can optionally have one or more carbon
replaced by O, NR.sup.7, N.sup.+R.sup.7R.sup.8, S, SO, SO.sup.2,
S.sup.+R.sup.7R.sup.8, PR.sup.7, P.sup.+R.sup.7R.sup.8, phenylene,
heterocycle, quatarnary heterocycle, quaternary heteroaryl, or
aryl, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane
diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate,
amino acid, peptide, and polypeptide can be substituted with one or
more substituent groups independently selected from the group
consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo,
OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, SO.sub.3R.sup.13, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14,
C(O)OM, COR.sub.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R15A-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- ; wherein one or more
R.sup.y and R.sup.yA are independently selected from from the group
consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycle, quaternary heterocycle, OR.sup.9, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, and SO.sub.3R.sup.9, wherein alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, and heterocycle can be
substituted with one or more substituent groups independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, halogen, oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14- ,
C(O)NR.sup.13R.sup.14, C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R15A-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- , wherein said alkyl,
alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,
cycloalkyl, and heterocycle can be further substituted with one or
more substituent groups selected from the group consisting of
OR.sup.7, NR.sup.7R.sup.8, SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7,
SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN, oxo, CONR.sup.7R.sup.8,
N.sup.+R.sup.7R.sup.8R.sup.9A-, alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle,
quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8A.sup.-, and P(O)(OR.sup.7)OR.sup.8, and
wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
haloalkyl, cycloalkyl, and heterocycle can optionally have one or
more carbons replaced by O, NR.sup.7, N.sup.+R.sup.7R.sup.8A-, S,
SO, SO.sub.2, S.sup.+R.sup.7A-, PR.sup.7, P(O)R.sup.7,
P.sup.+R.sup.7R.sup.8A-, or phenylene.
99. A compound of claim 98, wherein R.sup.1, R.sup.1A, R.sup.2, and
R.sup.2A are independently selected from the group consisting of H
and alkyl.
100. A compound of claim 99, wherein R.sup.1, R.sup.1A, R.sup.2,
and R.sup.2A are independently selected from the group consisting
of H and C.sub.1-C.sub.10 alkyl.
101. A compound of claim 100, wherein said alkyl is a
C.sub.2-C.sub.7 alkyl.
102. A compound of claim 101, wherein R.sup.1, R.sup.1A, R.sup.2,
and R.sup.2A are independently C.sub.2-C.sub.4 alkyl.
103. A compound of claim 102, wherein R.sup.1, R.sup.1A, R.sup.2,
and R.sup.2A are independently selected from the group consisting
of ethyl, n-propyl, n-butyl, and isobutyl.
104. A compound of claim 98, wherein R.sup.3, R.sup.3A, R.sup.4,
and R.sup.4A are independently selected from the group consisting
of H and OR.sup.9.
105. A compound of claim 104, wherein R.sup.9 is H.
106. A compound of claim 98, wherein R.sup.7, R.sup.7A, R.sup.8,
and R.sup.8A are H.
107. A compound of claim 98, wherein d and e are independently 1 or
2.
108. A compound of claim 107, wherein d and e are both 2.
109. A compound of claim 98, wherein one or more R.sup.x and one or
more R.sup.xA are independently selected from the group consisting
of alkyl, aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy,
polyether, halogen, OR.sup.13, NR.sup.13R.sup.14,
NR.sup.13NR.sup.14R.sup.15, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
SR.sup.13, S.sup.+R.sup.13R.sup.14- , CO.sub.2R.sup.13,
NR.sup.14C(O)R.sup.13, and NR.sup.14C(O)R.sup.13, wherein alkyl,
aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, and polyether,
can be further substituted with OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10 SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein in R.sup.x,
one or more carbons are optionally replaced by O, NR.sup.13,
N.sup.+R.sup.13R.sup.14A-, S, SO, SO.sub.2, S.sup.+R.sup.13A-,
PR.sup.13, P(O)R.sub.13, P.sup.+R.sup.13R.sup.14A-, phenylene,
amino acid, peptide, polypeptide, carbohydrate, polyether, or
polyalkyl, and wherein in said polyalkyl, phenylene, amino acid,
peptide, polypeptide, and carbohydrate, one or more carbons are
optionally replaced by O, NR.sup.9, NR.sup.9,
N.sup.+R.sup.9R.sup.10A-, S, SO, SO.sub.2, S.sup.+R.sup.9A-,
PR.sup.9, P.sup.+R.sup.9R.sup.10A-, or P(O)R.sup.9.
110. A compound of claim 98, wherein one or more R.sup.y and one or
more R.sup.yA are independently selected from the group consisting
of alkyl, polyether, fluoride, chloride, bromide, iodide,
NR.sup.13R.sup.14, NR.sup.14C(O)R.sup.13, and OR.sup.13, wherein
alkyl and polyether can be further substituted with
SO.sub.3R.sup.9, N.sup.+R.sup.9R.sup.11R.sup.12A- .sup.-, and
quaternary heteroaryl.
111. A compound of claim 98, wherein R.sup.19 is selected from the
group consisting of alkane diyl, polyalkane diyl, alkoxy diyl, and
polyalkoxy diyl, wherein alkane diyl and polyalkane diyl can
optionally have one or more carbon replaced by O, NR7, N+R7R8, S,
SO, SO2, S+R7R8, PR7, P+R7R8, or phenylene.
112. A compound of claim 111, wherein R.sup.19 is selected from the
group consisting of alkoxy diyl and polyalkoxydiyl wherein one or
more carbons are optionally replaced by O, NR.sup.9,
N.sup.+R.sup.9R.sup.10, S, SO, SO.sub.2, S.sup.+R.sup.9R.sup.10,
PR.sup.9, P.sup.+R.sup.9R.sup.10, phenylene, amino acid, peptide,
polypeptide, carbohydrate, or polyalkyl.
113. A compound of claim 112, wherein R.sup.1, R.sup.1A, R.sup.2,
and R.sup.2A are independently selected from the group consisting
of H and alkyl.
114. A compound of claim 113, wherein R.sup.3, R.sup.3A, R.sup.4,
and R.sup.4A are independently selected from the group consisting
of H and OR.sup.9.
115. A compound of claim 114, wherein R.sup.9 is H.
116. A compound of claim 115, wherein R.sup.7, R.sup.7A, R.sup.8,
and R.sup.8A are each H.
117. A compound of claim 116, wherein d and e are independently 1
or 2.
118. A compound of claim 117, wherein one or more R.sup.x and one
or more R.sup.xA are independently selected from the group
consisting of alkyl, aryl, cycloalkyl, heterocycle, polyalkyl,
acyloxy, polyether, halogen, OR.sup.13, NR.sup.13R.sup.14R.sup.15,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup- .-, SR.sup.13,
S.sup.+R.sup.13R.sup.14, CO.sub.2R.sup.13, NR.sup.14C(O)R.sup.13,
and NR.sup.14C(O)R.sup.13, wherein alkyl, aryl, cycloalkyl,
heterocycle, polyalkyl, acyloxy, and polyether, can be further
substituted with OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10 SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein in R.sup.x,
one or more carbons are optionally replaced by O, NR.sup.13,
N.sup.+R.sup.13R.sup.14A- S, SO, SO.sub.2, S.sup.+R.sup.13A-,
PR.sup.13, P(O)R.sup.13, P.sup.+R.sup.13R.sup.14A-, phenylene,
amino acid, peptide, polypeptide, carbohydrate, polyether, or
polyalkyl, and wherein in said polyalkyl, phenylene, amino acid,
peptide, polypeptide, and carbohydrate, one or more carbons are
optionally replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.10A-, S,
SO, SO.sub.2, S.sup.+R.sup.9A-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-,
or P(O)R.sup.9.
119. A compound of claim 118, wherein one or more R.sup.y and one
or more R.sup.yA are independently selected from the group
consisting of alkyl, polyether, fluoride, chloride, bromide,
iodide, NR.sup.13R.sup.14, NR.sup.14C(O)R.sup.13, and OR.sup.13,
wherein alkyl and polyether can be further substituted with
SO.sub.3R.sup.9, N.sup.+R.sup.9R.sup.11R.sup.12A- .sup.-, and
quaternary heteroaryl.
120. A compound of claim 119, having the formula: 529PEG=3400
molecular weight polyethylene glycol polymer chain
121. A compound of the formula (IV) 530wherein: q and r are
independently integers from 0 to 3; d and e are independently
integers from 0 to 2; t and u are independently integers from 0 to
5; R.sup.1, R.sup.1A, R.sup.2, and R.sup.2A are independently
selected from the group consisting of H, alkyl, alkenyl, alkynyl,
haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino,
alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl,
alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,
dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally
are substituted with one or more substituent selected from the
group consisting of OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.10R.s- up.wA.sup.-, SR.sup.9, S.sup.+R.sup.9A-.
P.sup.+R.sup.9R.sup.10R.sup.11A.s- up.-, S(O) R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10, wherein alkyl, alkenyl, alkynyl,
alkylaryl, alkoxy, alkoxyalkyl, polyalkyl, aryl, and cycloalkyl
optionally have one or more carbons replaced by O, NR.sup.9,
N.sup.+R.sup.9R.sup.10A-, S, SO, SO.sub.2, S.sup.+R.sup.9A-,
P.sup.+R.sup.9R.sup.10A-, or phenylene, wherein R.sup.9, R.sup.10,
and R.sup.w are independently selected from the group consisting of
H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle,
ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; or R.sup.1 and
R.sup.2 taken together with the carbon to which they are attached
form C.sub.3-C.sub.10 cycloalkylidene, or R.sup.1A and R.sup.2A
taken together with the carbon to which they are attached form
C.sub.3-C.sub.10 cycloalkylidene; R.sup.3, R.sup.3A, R.sup.4, and
R.sup.4A are independently selected from the group consisting of H,
alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR.sup.9,
NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, and
SO.sub.3R.sup.9, wherein R.sup.9 and R.sup.10 are as defined above;
or R.sup.3 and R.sup.4 together form .dbd.O, .dbd.NOR.sup.11,
.dbd.S, .dbd.NNR.sup.1R.sup.12, .dbd.NR.sup.9, or
.dbd.CR.sup.11R.sup.12, or R.sup.3A and R.sup.4A together form
.dbd.O, .dbd.NOR.sup.11, .dbd.S, .dbd.NNR.sup.11R.sup.12,
.dbd.NR.sup.9, or .dbd.CR.sup.11R.sup.12, wherein R.sup.11 and
R.sup.12 are independently selected from the group consisting of H,
alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,
alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl,
cycloalkyl, cyanoalkyl, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN,
halogen, oxo, and CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10
are as defined above, provided that both R.sup.3 and R.sup.4 cannot
be OH, NH2, and SH, or R.sup.11 and R.sup.12 together with the
nitrogen or carbon atom to which they are attached form a cyclic
ring; wherein A.sup.- is a pharmaceutically acceptable anion and M
is a pharmaceutically acceptable cation; R.sup.7, R.sup.7A,
R.sup.8, and R.sup.8A are independently selected from the group
consisting of hydrogen and alkyl; and one or more R.sup.x and
R.sup.xA are independently selected from the group consisting of H,
alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl,
halogen, haloalkyl, cycloalkyl, heterocycle, heterocycle,
polyether, quaternary heterocycle, quaternary heteroaryl,
OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
S(O).sub.2R.sup.13, SO.sub.3R.sup.13, S.sup.+R.sup.13R.sup.14A-,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14,
NR.sup.14C(O)R.sup.13, C(O)NR.sup.13R.sup.14,
NR.sup.14C(O)R.sup.13, C(O)OM, COR.sup.13, OR.sup.18,
S(O).sub.nNR.sup.18, NR.sup.13R.sup.18, NR.sup.18OR.sup.14,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, amino acid, peptide,
polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl,
haloalkyl, polyether, quaternary heterocycle, and quaternary
heteroaryl can be further substituted with OR.sup.9,
NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.- 12A.sup.-,
SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.11R- .sup.12A.sup.-,
SR.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein R.sup.18 is
selected from the group consisting of acyl, arylalkoxycarbonyl,
arylalkyl, heterocycle, heterocycle, alkyl, wherein acyl,
arylalkoxycarbonyl, arylalkyl, heterocycle, heterocycle, alkyl
quaternary heterocycle, and quaternary heteroaryl optionally are
substituted with one or more substituent selected from the group
consisting of OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A- .sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.3R.sup.9, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)R.sup.17, and C(O)OM,
wherein in R.sup.x and R.sup.xA, one or more carbons are optionally
replaced by O, NR.sup.13, N.sup.+R.sup.13R.sup.14A-, S, SO,
SO.sub.2, S.sup.+R.sup.13A-, PR.sup.13, P(O)R13,
P.sup.+R.sup.13R.sup.14A-, phenylene, amino acid, peptide,
polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said
polyalkyl, phenylene, amino acid, peptide, polypeptide, and
carbohydrate, one or more carbons are optionally replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A-, S, SO, SO.sub.2,
S.sup.+R.sup.9A-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-, or
P(O)R.sup.9; wherein quaternary heterocycle and quaternary
heteroaryl are optionally substituted with one or more groups
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, halogen, oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14- ,
C(O)NR.sup.13R.sup.14, C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- , R.sup.19 is selected from
the group consisting of alkane diyl, alkene diyl, alkyne diyl,
polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl,
carbohydrate, amino acid, and peptide, polypeptide, wherein alkane
diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl,
polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and
peptide polypeptide, can optionally have one or more carbon
replaced by O, NR.sup.7, N.sup.+R.sup.7R.sup.8, S SO, SO.sup.2,
S.sup.+R.sup.7R.sup.8, PR.sup.7, P.sup.+R.sup.7R.sup.8, phenylene,
heterocycle, quatarnary heterocycle, quaternary heteroaryl, or
aryl, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane
diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate,
amino acid, peptide, and polypeptide can be substituted with one or
more substituent groups independently selected from the group
consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo,
OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, SO.sub.3R.sup.13, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14,
C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R15A-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-; wherein said alkyl, alkenyl,
alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and
heterocycle can be further substituted with one or more substituent
groups selected from the group consisting of OR.sup.7
NR.sup.7R.sup.8, SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7,
SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN, oxo, CONR.sup.7R.sup.8,
N.sup.+R.sup.7R.sup.8R.sup.9A-, alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle,
quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8A.sup.-, and P(O) (OR.sup.7)OR.sup.8, and
wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
haloalkyl, cycloalkyl, and heterocycle can optionally have one or
more carbons replaced by O, NR.sup.7, N.sup.+R.sup.7R.sup.8A-, S,
SO, SO.sub.2, S.sup.+R.sup.7A-, PR.sup.7, P(O)R.sup.7,
P.sup.+R.sup.7R.sup.8A-, or phenylene.
122. A compound of claim 121, wherein R.sup.1, R.sup.1A, R.sup.2,
and R.sup.2A are independently selected from the group consisting
of H and alkyl.
123. A compound of claim 122, wherein R.sup.1, R.sup.1A, R.sup.2,
and R.sup.2A are independently selected from the group consisting
of H and C.sub.1-C.sub.10 alkyl.
124. A compound of claim 123, wherein said alkyl is a
C.sub.2-C.sub.7 alkyl.
125. A compound of claim 124, wherein R.sup.1, R.sup.1A, R.sup.2,
and R.sup.2A are independently C.sub.2-C.sub.4 alkyl.
126. A compound of claim 125, wherein R.sup.1, R.sup.1A, R.sup.2,
and R.sup.2A are independently selected from the group consisting
of ethyl, n-propyl, n-butyl, and isobutyl.
127. A compound of claim 125, wherein R.sup.3, R.sup.3A, R.sup.4,
and R.sup.4A are independently selected from the group consisting
of H and OR.sup.9.
128. A compound of claim 127, wherein R.sup.9 is H.
129. A compound of claim 121, wherein R.sup.7, R.sup.7A, R.sup.8,
and R.sup.8A are H.
130. A compound of claim 121, wherein d and e are independently 1
or 2.
131. A compound of claim 130, wherein d and e are both 2.
132. A compound of claim 121, wherein one or more R.sup.x and one
or more R.sup.xA are independently selected from the group
consisting of alkyl, aryl, cycloalkyl, heterocycle, polyalkyl,
acyloxy, polyether, halogen, OR.sup.13, NR.sup.13R.sup.14,
NR.sup.13NR.sup.14R.sup.15, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
SR.sup.13, S.sup.+R.sup.13R.sup.14- , CO.sub.2R.sup.13,
NR.sup.14C(O)R.sup.13, and NR.sup.14C(O)R.sup.13, wherein alkyl,
aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, and polyether,
can be further substituted with OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein in R.sup.x,
one or more carbons are optionally replaced by O, NR.sup.13,
N.sup.+R.sup.13R.sup.14A-, S, SO, SO.sub.2, S.sup.+R.sup.13A-,
PR.sup.13, P(O)R.sup.13, P.sup.+R.sup.13R.sup.14A-, phenylene,
amino acid, peptide, polypeptide, carbohydrate, polyether, or
polyalkyl, and wherein in said polyalkyl, phenylene, amino acid,
peptide, polypeptide, and carbohydrate, one or more carbons are
optionally replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.10A-, S,
SO, SO.sub.2, S.sup.+R.sup.9A-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-,
or P(O)R.sup.9.
133. A compound of claim 121, wherein one or more R.sub.y and one
or more R.sub.yA are independently selected from the group
consisting of alkyl, polyether, fluoride, chloride, bromide,
iodide, NR.sup.13R.sup.14, NR.sup.14C(O)R.sup.13, and OR.sup.13,
wherein alkyl and polyether can be further substituted with
SO.sub.3R.sup.9, N.sup.+R.sup.9R.sup.11R.sup.12A- .sup.-, and
quaternary heteroaryl.
134. A compound of claim 121, wherein R.sup.19 is selected from the
group consisting of alkane diyl, polyalkane diyl, alkoxy diyl, and
polyalkoxy diyl, wherein alkane diyl and polyalkane diyl can
optionally have one or more carbon replaced by O, NR7, N+R7R8, S,
SO, SO2, S+R7R8, PR7, P+R7R8, or phenylene.
135. A compound of claim 134, wherein R.sup.19 is selected from the
group consisting of alkoxy diyl and polyalkoxydiyl wherein one or
more carbons are optionally replaced by O, NR.sup.9,
N.sup.+R.sup.9R.sup.10, S, SO, SO.sub.2, S.sup.+R.sup.9R.sup.10,
PR.sup.9, P.sup.+R.sup.9R.sup.10, phenylene, amino acid, peptide,
polypeptide, carbohydrate, or polyalkyl.
136. A compound of claim 135, wherein R.sup.1, R.sup.1A, R.sup.2,
and R.sup.2A are independently selected from the group consisting
of H and alkyl.
137. A compound of claim 136, wherein R.sup.3, R.sup.3A, R.sup.4,
and R.sup.4A are independently selected from the group consisting
of H and OR.sup.9.
138. A compound of claim 137, wherein R.sup.9 is H.
139. A compound of claim 138, wherein R.sup.7, R.sup.7A, R.sup.8,
and R.sup.8A are each H.
140. A compound of claim 139, wherein d and e are independently 1
or 2.
141. A compound of claim 140, having the formula: 531PEG 3400
molecular weight polyethylene glycol polymer chain
142. A compound of formula (V) substituted with SO.sub.3R.sup.9,
N.sup.+R.sup.9R R A , and quaternary 532wherein: q is an integer
from 0 to 4; r is an integer from 0 to 3; d and e are independently
integers from 0 to 2; t is an integer from 0 to 4; u is an integer
from 0 to 5; R.sup.1, R.sup.1A, R.sup.2, and R.sup.2A are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy,
alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and
cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl,
arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,
(polyalkyl)aryl, and cycloalkyl optionally are substituted with one
or more substituent selected from the group consisting of OR.sup.9,
NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.10R.sup.wA.sup.-, SR.sup.9,
S.sup.+R.sup.9A-. P.sup.+R.sup.9R.sup.10R.sup.11A.sup.-,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN,
halogen, oxo, and CONR.sup.9R.sup.10, wherein alkyl, alkenyl,
alkynyl, alkylaryl, alkoxy, alkoxyalkyl, polyalkyl, aryl, and
cycloalkyl optionally have one or more carbons replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A-, S, SO, SO.sub.2,
S.sup.+R.sup.9A-, P.sup.+R.sup.9R.sup.10A-, or phenylene, wherein
R.sup.9, R.sup.10, and R.sup.w are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and
arylalkyl; or R.sup.1 and R.sup.2 taken together with the carbon to
which they are attached form C.sub.3-C.sub.1O cycloalkylidene, or
R.sup.1A and R.sup.2A taken together with the carbon to which they
are attached form C.sub.3-C.sub.10 cycloalkylidene; R.sup.3,
R.sup.3A, R.sup.4, and R.sup.4A are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl,
heterocycle, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, and SO.sub.3R.sup.9, wherein R.sup.9 and R.sup.10
are as defined above; or R.sup.3 and R.sup.4 together form .dbd.O,
.dbd.NOR.sup.11, .dbd.S, .dbd.NNR.sup.11R.sup.12, .dbd.NR.sup.9, or
.dbd.CR.sup.11R.sup.12, or R.sup.3A and R.sup.4 together form
.dbd.O, .dbd.NOR.sup.11, .dbd.S, .dbd.NNR.sup.11R.sup.12,
.dbd.NR.sup.9, or .dbd.CR.sup.11R.sup.12, wherein R.sup.11 and
R.sup.12 are independently selected from the group consisting of H,
alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,
alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl,
cycloalkyl, cyanoalkyl, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN,
halogen, oxo, and CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10
are as defined above, provided that both R.sup.3 and R.sup.4 cannot
be OH, NH2, and SH, or R.sup.11 and R.sup.12 together with the
nitrogen or carbon atom to which they are attached form a cyclic
ring; wherein A.sup.- is a pharmaceutically acceptable anion and M
is a pharmaceutically acceptable cation; R.sup.7, R.sup.7A,
R.sup.8, and RBA are independently selected from the group
consisting of hydrogen and alkyl; and one or more R.sup.x and
R.sup.xA are independently selected from the group consisting of H,
alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl,
halogen, haloalkyl, cycloalkyl, heterocycle, heterocycle,
polyether, quaternary heterocycle, quaternary heteroaryl,
OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
S(O).sub.2R.sup.13, SO.sub.3R.sup.13, S.sup.+R.sup.13R.sup.14A-,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15- , NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.1- 4,
NR.sup.14C(O)R.sup.13, C(O)NR.sup.13R.sup.14, NR14C(O)R13, C(O)OM,
COR.sup.13, OR.sup.18, S(O).sub.nNR.sup.18, NR.sup.13R.sup.18,
NR.sup.18OR.sup.14, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, amino acid, peptide,
polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl,
haloalkyl, polyether, quaternary heterocycle, and quaternary
heteroaryl can be further substituted with OR.sup.9,
NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.- 12A.sup.-,
SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.11R- .sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein R.sup.18 is
selected from the group consisting of acyl, arylalkoxycarbonyl,
arylalkyl, heterocycle, heterocycle, alkyl, wherein acyl,
arylalkoxycarbonyl, arylalkyl, heterocycle, heterocycle, alkyl
quaternary heterocycle, and quaternary heteroaryl optionally are
substituted with one or more substituent selected from the group
consisting of OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A- .sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.3R.sup.9, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17, and C(O)OM,
wherein in R.sup.x and R.sup.xA, one or more carbons are optionally
replaced by O, NR.sup.13, N.sup.+R.sup.13R.sup.14A.sup.-, S, SO,
SO.sub.2, S.sup.+R.sup.13A.sup.-, PR.sup.13,
P(O)R.sup.13P.sup.+R.sup.13R- .sup.14A, phenylene, amino acid,
peptide, polypeptide, carbohydrate, polyether, or polyalkyl,
wherein in said polyalkyl, phenylene, amino acid, peptide,
polypeptide, and carbohydrate, one or more carbons are optionally
replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.10A-, SO, SO.sub.2,
S.sup.+R.sup.9A-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-, or P(O)
R.sup.9; wherein quaternary heterocycle and quaternary heteroaryl
are optionally substituted with one or more groups selected from
the group consisting of alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl,
halogen, oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14- ,
C(O)NR.sup.13R.sup.14, C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R15 A-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- , R.sup.19 is selected from
the group consisting of alkane diyl, alkene diyl, alkyne diyl,
polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl,
carbohydrate, amino acid, and peptide, polypeptide, wherein alkane
diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl,
polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and
peptide polypeptide, can optionally have one or more carbon
replaced by O, NR.sup.7, N.sup.+R.sup.7R.sup.8, S, SO, SO.sub.2,
S.sup.+R.sup.7R.sup.8, PR.sup.7, P.sup.+R.sup.7R.sup.8, phenylene,
heterocycle, quatarnary heterocycle, quaternary heteroaryl, or
aryl, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane
diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate,
amino acid, peptide, and polypeptide can be substituted with one or
more substituent groups independently selected from the group
consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo,
OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, SO.sub.3R.sup.13, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14,
C(O)OM, COR.sup.13, P(O)R R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R15A-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-; wherein one or more RI and
R.sub.yA are independently selected from from the group consisting
of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,
quaternary heterocycle, OR.sup.9, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, and SO.sub.3R.sup.9, wherein alkyl, alkenyl,
alkynyl, aryl, cycloalkyl, and heterocycle can be substituted with
one or more substituent groups independently selected from the
group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo,
OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, SO.sub.3R.sup.13, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14,
C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.--- , P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, wherein said alkyl, alkenyl,
alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and
heterocycle can be further substituted with one or more substituent
groups selected from the group consisting of OR.sup.7,
NR.sup.7R.sup.8, SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7,
SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN, oxo, CONR.sup.7R.sup.8,
N.sup.+R.sup.7R.sup.8R.sup.9A-, alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle,
quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8A.sup.-, and P(O) (OR.sup.7)OR.sup.8, and
wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
haloalkyl, cycloalkyl, and heterocycle can optionally have one or
more carbons replaced by O, NR.sup.7, N.sup.+R.sup.7R.sup.8A-, S,
SO, SO.sub.2, S.sup.+R.sup.7A-, PR.sup.7, P(O)R.sup.7,
P.sup.+R.sup.7R.sup.8A-, or phenylene.
143. A compound of claim 142, wherein R.sup.1, R.sup.1A, R.sup.2,
and R.sup.2A are independently selected from the group consisting
of H and alkyl.
144. A compound of claim 143, wherein R.sup.1, R.sup.1A, R.sup.2,
and R.sup.2A are independently selected from the group consisting
of H and C.sub.1-C.sub.10 alkyl.
145. A compound of claim 144, wherein said alkyl is a
C.sub.2-C.sub.7 alkyl.
146. A compound of claim 145, wherein R.sup.1, R.sup.1A, R.sup.2,
and R.sup.2A are independently C.sub.2-C.sub.4 alkyl.
147. A compound of claim 146, wherein R.sup.1, R.sup.1A, R.sup.2,
and R.sup.2A are independently selected from the group consisting
of ethyl, n-propyl, n-butyl, and isobutyl.
148. A compound of claim 142, wherein R.sup.3, R.sup.3A, R.sup.4,
and R.sup.4A are independently selected from the group consisting
of H and OR.sup.9.
149. A compound of claim 148, wherein R.sup.9 is H.
150. A compound of claim 142, wherein R.sup.7, R.sup.7A, R.sup.8,
and R.sup.8A are H.
151. A compound of claim 142, wherein d and e are independently 1
or 2.
152. A compound of claim 151, wherein d and e are both 2.
153. A compound of claim 142, wherein one or more R.sup.x and one
or more R.sup.xA are independently selected from the group
consisting of alkyl, aryl, cycloalkyl, heterocycle, polyalkyl,
acyloxy, polyether, halogen, OR.sup.13, NR.sup.13R.sup.14,
NR.sup.13N.sup.14R.sup.15, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
SR.sup.13, S.sup.+R.sup.13R.sup.14- , CO.sub.2R.sup.13,
NR.sup.14C(O)R.sup.13, and NR.sup.14C(O)R.sup.13, wherein alkyl,
aryl, cycloalkyl, heterocycle, polyalkyl, acyloxy, and polyether,
can be further substituted with OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10 SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein in R.sup.x,
one or more carbons are optionally replaced by O, NR.sup.13,
N.sup.+R.sup.13R.sup.14A-, S, SO, SO.sub.2, S.sup.+R.sup.13A-,
PR.sup.13, P(O)R.sup.13, P.sup.+R.sup.13R.sup.14A-, phenylene,
amino acid, peptide, polypeptide, carbohydrate, polyether, or
polyalkyl, and wherein in said polyalkyl, phenylene, amino acid,
peptide, polypeptide, and carbohydrate, one or more carbons are
optionally replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.10A-, S,
SO, SO.sub.2, S.sup.+R.sup.9A-, PR.sup.9, PR.sup.9R.sup.10A-, or
P(O)R.sup.9.
154. A compound of claim 142, wherein one or more R.sup.y and one
or more R.sub.yA are independently selected from the group
consisting of alkyl, polyether, fluoride, chloride, bromide,
iodide, NR.sup.13R.sup.14, NR.sup.14C(O)R.sup.13, and OR.sup.13,
wherein alkyl and polyether can be further substituted with
SO.sub.3R.sup.9, N.sup.+R.sup.9R.sup.11R.sup.12A- .sup.-, and
quaternary heteroaryl.
155. A compound of claim 142, wherein R.sup.19 is selected from the
group consisting of alkane diyl, polyalkane diyl, alkoxy diyl, and
polyalkoxy diyl, wherein alkane diyl and polyalkane diyl can
optionally have one or more carbon replaced by O, NR7, N+R7R8, S,
SO, SO2, S+R7R8, PR7, P+R7R8, or phenylene.
156. A compound of claim 155, wherein R.sup.19 is selected from the
group consisting of alkoxy diyl and polyalkoxydiyl wherein one or
more carbons are optionally replaced by O, NR.sup.9,
N.sup.+R.sup.9R.sup.10, S, SO, SO.sub.2, S.sup.+R.sup.9R.sup.10,
PR.sup.9, P.sup.+R.sup.9R.sup.10, phenylene, amino acid, peptide,
polypeptide, carbohydrate, or polyalkyl.
157. A compound of claim 156, wherein R.sup.1, R.sup.1A, R.sup.2,
and R.sup.2A are independently selected from the group consisting
of H and alkyl.
158. A compound of claim 157, wherein R.sup.3, R.sup.3A, R.sup.4,
and R.sup.4A are independently selected from the group consisting
of H and OR.sup.9.
159. A compound of claim 158, wherein R.sup.9 is H.
160. A compound of claim 159, wherein R.sup.7, R.sup.7A, R.sup.8,
and R.sup.8A are each H.
161. A compound of claim 160, wherein d and e are independently 1
or 2.
162. A compound of claim 161, having the formula: 533PEG =3400
molecular weight polyethylene glycol polymer chain
163. A pharmaceutical composition comprising an anti-hyperlipidemic
condition effective amount of a compound of formula (I) of claim 1,
and a pharmaceutically acceptable carrier.
164. A pharmaceutical composition comprising an
anti-atherosclerotic effective amount of a compound of formula (I)
of claim 1, and a pharmaceutically acceptable carrier.
165. A pharmaceutical composition comprising an
anti-hypercholesterolemia effective amount of a compound of formula
(I) of claim 1, and a pharmaceutically acceptable carrier.
166. A method for the prophylaxis or treatment of a hyperlipidemic
condition comprising administering to a patient in need thereof a
composition of claim 164 in unit dosage form.
167. A method for the prophylaxis or treatment of an
atherosclerotic condition comprising administering to a patient in
need thereof a composition of claim 165 in unit dosage form.
168. A method for the prophylaxis or treatment of
hypercholesterolemia comprising administering to a patient in need
thereof a composition of claim 166 in unit dosage form.
169. A compound of formula 1: 534wherein: q is an integer from 1 to
4; n is an integer from 0 to 2; R.sup.1 and R.sup.2 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy,
alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and
cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl,
arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,
(polyalkyl)aryl, and cycloalkyl optionally are substituted with one
or more substituents selected from the group consisting of
OR.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.10R.sup.wA.sup.-,
SR.sup.9, S.sup.+R.sup.9R.sup.10R.sup.11A.sup.-, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10, wherein alkyl, alkenyl, alkynyl,
alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl
optionally have one or more carbons replaced by O, NR.sup.9,
N.sup.+R.sup.9R.sup.10A-, S, SO, SO.sub.2, S.sup.+R.sup.9A.sup.-,
P.sup.+R.sup.9R.sup.1A.sup.-, or phenylene, wherein R.sup.9,
R.sup.1 , and R.sup.w are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,
heterocycle, ammoniumalkyl, arylalkyl, and alkylammoniumalkyl; or
R.sup.1 and R.sup.2 taken together with the carbon to which they
are attached form C.sub.3-C.sub.10 cycloalkyl; R.sup.3 and R.sup.4
are independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR.sup.9, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, and SO.sub.3R.sup.9, wherein R.sup.9
and R.sup.10 are as defined above; or R.sup.3 and R.sup.4 together
form .gradient.O, .dbd.NOR.sup.11, .dbd.S, .dbd.NNR.sup.11R.sup.12,
.dbd.NR.sup.9, or .dbd.CR.sup.11R.sup.12, wherein R.sup.11 and
R.sup.12 are independently selected from the group consisting of H,
alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,
alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl,
cycloalkyl, cyanoalkyl, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN,
halogen, oxo, and CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10
are as defined above, provided that both R.sup.3 and R.sup.4 cannot
be OH, NH.sub.2, and SH, or R.sup.11 and R.sup.12 together with the
nitrogen or carbon atom to which they are attached form a cyclic
ring; R.sup.5 is selected from the group consisting of H, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary
heterocycle, OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, and
SO.sub.3R.sup.9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycle, quaternary heterocycle, and quaternary heteroaryl can
be substituted with one or more substituent groups independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen,
oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, SO.sub.3R.sup.13, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14- , C(O)NR.sup.13R.sup.14,
C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- , wherein: A.sup.- is a
pharmaceutically acceptable anion and M is a pharmaceutically
acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be
further substituted with one or more substituent groups selected
from the group consisting of OR.sup.7, NR.sup.7R.sup.8, SR.sup.7,
S(O)R.sup.7, SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN,
oxo, CONR.sup.7R.sup.8, N.sup.+R.sup.7R.sup.8R.sup.9 A-, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl,
quaternary heterocycle, quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, and P(O)(OR.sup.7)OR.sup.8,
and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have
one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A-, S, SO, SO.sub.2, S.sup.+R.sup.7A-,
PR.sup.7, P(O)R.sup.7, P.sup.+R.sup.7R.sup.8A-, or phenylene, and
R.sup.13, R.sup.14, and R.sup.15 are independently selected from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl,
quaternary heterocycle, quaternary heteroaryl, and quaternary
heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl,
heterocycle, and polyalkyl optionally have one or more carbons
replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.10A-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-,
P(O)R.sup.9, phenylene, carbohydrate, amino acid, peptide, or
polypeptide, and R.sup.13, R.sup.14, and R.sup.15 are optionally
substituted with one or more groups selected from the group
consisting of sulfoalkyl, quaternary heterocycle, quaternary
heteroaryl, OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(R.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.10R.sup.11A-,
S.sup.+R.sup.9R.sup.10A-, and C(O)OM, wherein R.sup.16 and R.sup.17
are independently selected from the substituents constituting
R.sup.9 and M; or R.sup.14 and R.sup.15, together with the nitrogen
atom to which they are attached, form a cyclic ring; and R.sup.6 is
hydroxy; and R.sup.7 and R.sup.8 are independently selected from
the group consisting of hydrogen and alkyl; and one or more R.sup.x
are independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen,
haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether,
quaternary heterocycle, quaternary heteroaryl, OR.sup.13,
NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13, S(O).sub.2R.sup.13,
SO.sub.3R.sup.13, S.sup.+R.sup.13R.sup.14A-, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, NR.sup.14C(O)R.sup.13,
C(O)NR.sup.13R.sup.14, NR.sup.14C(O)R.sup.13, C(O)OM, COR.sup.13,
OR.sup.18, S(O).sub.nNR.sup.18, NR.sup.13R.sup.18,
NR.sup.18OR.sup.14, O.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.11R.sup.12A.su- p.-, amino acid, peptide,
polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl,
haloalkyl, polyether, quaternary heterocycle, and quaternary
heteroaryl can be further substituted with OR.sup.9,
NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein R.sup.18 is
selected from the group consisting of acyl, arylalkoxycarbonyl,
arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl,
arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,
quaternary heterocycle, and quaternary heteroaryl optionally are
substituted with one or more substituents selected from the group
consisting of OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.3R.sup.9, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17, and C(O)OM,
wherein in R.sup.x, one or more carbons are optionally replaced by
O, NR.sup.13, N.sup.+R.sup.13R.sup.14A-, S, SO, SO.sub.2,
S.sup.+R.sup.13A.sup.-, PR.sup.13, P(O)R.sup.13,
P.sup.+R.sup.13R.sup.14A-, phenylene, amino acid, peptide,
polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said
polyalkyl, phenylene, amino acid, peptide, polypeptide, and
carbohydrate, one or more carbons are optionally replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-, or
P(O)R.sup.9; wherein quaternary heterocycle and quaternary
heteroaryl are optionally substituted with one or more groups
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, halogen, oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14- ,
C(O)NR.sup.13R.sup.14, C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- , provided that both R.sup.5
and R.sup.6 cannot be hydrogen, OH, or SH; provided that when
R.sup.5 is phenyl, only one of R.sup.1 or R.sup.2 is H; or a
pharmaceutically acceptable salt, solvate, or prodrug thereof.
170. A compound of formula I: 535wherein: q is 1 or 2; n is 2;
R.sup.1 and R.sup.2 are each alkyl; R.sup.3 is hydroxy; R.sup.4 and
R.sup.6 are hydrogen; R.sup.5 has the formula (II) 536wherein t is
an integer from 0 to 5; one or more R.sup.y are OR.sup.13; R.sup.13
is selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle,
heteroaryl, quaternary heterocycle, quaternary heteroaryl, and
quaternary heteroarylalkyl; said R.sup.13 alkyl, alkenyl, alkynyl,
arylalkyl, heterocycle, and polyalkyl groups optionally have one or
more carbons replaced by O, NR.sup.9, NR.sup.9,
N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, PR.sup.9, P.sup.+R.sup.9R.sup.10A.sup.-,
P(O)R.sup.9, phenylene, carbohydrate, amino acid, peptide, or
polypeptide; R.sup.13 is optionally substituted with one or more
groups selected from the group consisting of sulfoalkyl, quaternary
heterocycle, quaternary heteroaryl, OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.10R.sup.11A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, and C(O)OM, wherein A.sup.- is a
pharmaceutically acceptable anion, and M is a pharmaceutically
acceptable cation, R.sup.9 and R.sup.10 are independently selected
from the group consisting of H, alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, and
alkylammoniumalkyl; R.sup.11 and R.sup.12 are independently
selected from the group consisting of H, alkyl, alkenyl, alkynyl,
aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle,
carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR.sup.9,
NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9,
SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen, oxo, and
CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10 are as defined
above, provided that both R.sup.3 and R.sup.4 cannot be OH,
NH.sub.2, and SH; or R.sup.11 and R.sup.12 together with the
nitrogen or carbon atom to which they are attached form a cyclic
ring; and R.sup.16 and R.sup.17 are independently selected from the
substituents constituting R.sup.9 and M; R.sup.7 and R.sup.8 are
hydrogen; and one or more R.sup.x are independently selected from
the group consisting of alkoxy, alkylamino and dialkylamino; or a
pharmaceutically acceptable salt, solvate, or prodrug thereof.
171. A compound of claim 170 wherein R.sup.1 and R.sup.2 are each
n-butyl.
172. A compound of claim 171 wherein t is 1, R.sup.y is OR.sup.13,
and R.sup.13 is as defined in claim 170.
173. A compound of claim 172 wherein one or more R.sup.x are
independently selected from methoxy and dimethylamino.
174. A compound of claim 172 wherein R.sup.x is dimethylamino.
175. A compound of claim 172 wherein: t is 1; R.sup.y is
para-OR.sup.13; and R.sup.13 is as defined in claim 170.
176. A compound of claim 172 wherein: t is 1; Rl is meta-OR.sup.13;
and R.sup.13 is as defined in claim 170.
177. A compound of claim 172 having the 4R,5R configuration.
178. A compound of claim 170 having the structural formula: 537
179. A compound of claim 170 having the structural formula: 538
180. A compound of formula (I): 539wherein: q is an integer from 1
to 4; n is an integer from 0 to 2; R.sup.1 and R.sup.2 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy,
alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and
cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl,
arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,
(polyalkyl)aryl, and cycloalkyl optionally are substituted with one
or more substituents selected from the group consisting of
OR.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.10R.sup.wA.- sup.-,
SR.sup.9, S.sup.+R.sup.9R.sup.10A.sup.-.
P.sup.+R.sup.9R.sup.10R.su- p.11A.sup.-, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10, wherein alkyl, alkenyl, alkynyl,
alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl
optionally have one or more carbons replaced by O, NR.sup.9,
N.sup.+R.sup.9R.sup.10A-, S, SO, SO.sub.2, S.sup.+R.sup.9A.sup.-,
P.sup.+R.sup.9R.sup.10A.sup.-, or phenylene, wherein R.sup.9,
R.sup.10, and R.sup.w are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,
heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl,
carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,
carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and
alkylammoniumalkyl; or R.sup.1 and R.sup.2 taken together with the
carbon to which they are attached form C.sub.3-C.sub.10 cycloalkyl;
R.sup.3 and R.sup.4 are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl,
heterocycle, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9,
SO.sub.2R , and SO.sub.3R 9, wherein R.sup.9 and R.sub.10 are as
defined above; or R.sup.3 and R.sup.4 together form .dbd.O,
.dbd.NOR.sup.11, .dbd.S, .dbd.NNR.sup.11R.sup.12, .dbd.NR.sup.9, or
.dbd.CR.sup.11R.sup.12, wherein R.sup.11 and R.sup.12 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl,
heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl,
cyanoalkyl, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10 are as
defined above, provided that both R.sup.3 and R.sup.4 cannot be OH,
NH.sub.2, and SH, or R.sup.11 and R.sup.12 together with the
nitrogen or carbon atom to which they are attached form a cyclic
ring; R.sup.5 is aryl substituted with one or more OR.sup.13a,
wherein R.sup.13a is selected from the group consisting of
polyether, aryl, alkylarylalkyl, alkylheteroarylalkyl,
alkylheterocyclylalkyl, heterocyclylalkyl, heteroarylalkyl,
quaternary heterocyclylalkyl, alkylammoniumalkyl, and
carboxyalkylaminocarbonylalkyl- , R.sup.13a is optionally
substituted with one or more groups selected from the group
consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl,
heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle,
quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary
heteroarylalkyl, guanidinyl, OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.10A-,
S.sup.+R.sup.9R.sup.10A- -, and C(O)OM, wherein A.sup.- is an
pharmaceutically acceptable anion and M is a pharmaceutically
acceptable cation, wherein R.sup.16 and R.sup.17 are independently
selected from the substituents constituting R.sup.9 and M; and
R.sup.6 is selected from the group consisting of H, alkyl, alkenyl,
alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle,
OR.sup.30, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, and
SO.sub.3R.sup.9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycle, quaternary heterocycle, and quaternary heteroaryl can
be substituted with one or more substituent groups independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen,
oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, SO.sub.3R.sup.13, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14,
C(O)OM, COR.sup.13, NR.sup.13C(O)R.sup.14,
NR.sup.13C(O)NR.sup.14R.sup.15, NR.sup.13CO.sub.2R.sup.14,
OC(O)R.sup.13, OC(O)NR .sup.13R.sup.14, NR.sup.13SOR.sup.14,
NR.sup.13SO.sub.2R.sup.14, NR.sup.13SONR.sup.14R.sup.15,
NR.sup.13SO.sub.2NR.sup.14R.sup.15, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, wherein: A.sup.- is a
pharmaceutically acceptable anion and M is a pharmaceutically
acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be
further substituted with one or more substituent groups selected
from the group consisting of OR.sup.7 NR.sup.7R.sup.8, SR.sup.7,
S(O)R.sup.7, SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN,
oxo, CONR.sup.7R.sup.8, N.sup.+R.sup.7R.sup.8R.sup.9A-, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl,
quaternary heterocycle, quaternary heteroaryl,
P(O)R.sup.7R.sup.P.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, and
P(O)(OR.sup.7)OR.sup.8, and wherein said alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle
can optionally have one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A-, S, SO, SO.sub.2, S.sup.+R.sup.7A-,
PR.sup.7, P(O)R.sup.7, P.sup.+R.sup.7R.sup.8A-, or phenylene, and
R.sup.13, R.sup.14, and R.sup.15 are independently selected from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl,
alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl,
heterocycle, heteroaryl, quaternary heterocycle, quaternary
heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl,
and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl,
alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one
or more carbons replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.10A-,
S, SO, SO.sub.2, S.sup.+R.sup.9A.sup.-, PR.sup.9,
P.sup.+R.sup.9R.sup.10A-, P(O)R.sup.9, phenylene, carbohydrate,
amino acid, peptide, or polypeptide, and R.sup.13, R.sup.14, and
R.sup.15 are optionally substituted with one or more groups
selected from the group consisting of hydroxy, amino, sulfo,
carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl,
quaternary heterocycle, quaternary heteroaryl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl,
OR.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.10R- .sup.11A-, S.sup.+R.sup.9R.sup.10A-, and
C(O)OM, wherein R.sup.16 and R17 are independently selected from
the substituents constituting R.sup.9 and M; or R.sup.13 and
R.sup.14, together with the nitrogen atom to which they are
attached form a mono- or polycyclic heterocycle that is optionally
substituted with one or more radicals selected from the group
consisting of oxo, carboxy and quaternary salts; or R.sup.14 and
R.sup.15, together with the nitrogen atom to which they are
attached, form a cyclic ring; and R.sup.30 is selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl,
carboxyalkyl, carboxyheteroaryl, carboxyheterocycle,
carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl,
heterocyclylalkyl, and alkylammoniumalkyl; and R.sup.7 and R.sup.8
are independently selected from the group consisting of hydrogen
and alkyl; and one or more R.sup.x are independently selected from
the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl,
acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl,
heterocycle, heteroaryl, polyether, quaternary heterocycle,
quaternary heteroaryl, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, S(O).sub.2R.sup.13, SO.sub.3R.sup.13,
S.sup.+R.sup.13R.sup.14A-, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15- , NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.1- 4, NR.sup.14C(O)R.sup.13,
C(O)NR.sup.13R.sup.14, NR14C(O)R13, C(O)OM, COR.sup.13, OR.sup.18,
S(O).sub.nNR.sup.18, NR.sup.13R.sup.18, NR.sup.18OR.sup.14,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, amino acid, peptide,
polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl,
haloalkyl, polyether, quaternary heterocycle, and quaternary
heteroaryl can be further substituted with OR.sup.9,
NR.sup.9R.sup.10, N.sup.+.sup.9R.sup.11R.sup.1- 2A.sup.-, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.11R- .sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein R.sup.18 is
selected from the group consisting of acyl, arylalkoxycarbonyl,
arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl,
arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,
quaternary heterocycle, and quaternary heteroaryl optionally are
substituted with one or more substituents selected from the group
consisting of OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A- .sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.3R.sup.9, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17, and C(O)OM,
wherein in R.sup.x, one or more carbons are optionally replaced by
O, NR.sup.13, N.sup.+R.sup.13R.sup.14A-, S, SO, SO.sub.2,
S.sup.+R.sup.13A.sup.-, PR.sup.13, P(O)R.sup.13,
P.sup.+R.sup.13R.sup.14A- -, phenylene, amino acid, peptide,
polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said
polyalkyl, phenylene, amino acid, peptide, polypeptide, and
carbohydrate, one or more carbons are optionally replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-, or
P(O)R.sup.9; wherein quaternary heterocycle and quaternary
heteroaryl are optionally substituted with one or more groups
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, halogen, oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14- ,
C(O)NR.sup.13R.sup.14, C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- , or a pharmaceutically
acceptable salt, solvate, or prodrug thereof.
181. A compound of claim 180 wherein: R.sup.5 is phenyl substituted
with OR.sup.13a; R.sup.13a is independently selected from the group
consisting of polyether, alkylarylalkyl, alkylheteroarylalkyl,
alkylheterocyclylalkyl, and carboxyalkylaminocarbonylalkyl; and
R.sup.13a is optionally substituted with one or more groups
selected from the group consisting of carboxy, quaternary
heterocycle, quaternary heteroaryl, and NR.sup.9R.sup.10.
182. A compound of claim 180 wherein n is 1 or 2.
183. A compound of claim 180 wherein R.sup.7 and R.sup.8 are
independently selected from the group consisting of hydrogen and
alkyl.
184. A compound of claim 180 wherein R7 and R.sup.8 are
hydrogen.
185. A compound of claim 180 wherein R.sup.3 and R.sup.4 are
independently selected from the group consisting of hydrogen and
OR.sup.9.
186. A compound of claim 180 wherein R.sup.3 is hydrogen and
R.sup.4 is hydroxy.
187. A compound of claim 180 wherein one or more R.sup.x are
independently selected from the group consisting of OR.sup.13 and
NR.sup.13R.sup.14.
188. A compound of claim 180 wherein one or more R.sup.x are
independently selected from methoxy and dimethylamino.
189. A compound of claim 180 wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting of hydrogen and
alkyl.
190. A compound of claim 180 wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting alkyl.
191. A compound of claim 180 wherein R.sup.1 and R.sup.2 are the
same alkyl.
192. A compound of claim 180 wherein R.sup.1 and R.sup.2 are each
n-butyl.
193. A compound of claim 180 wherein n is 1 or 2; R.sup.1 and
R.sup.2 are n-butyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
hydroxy; R.sup.7 and R.sup.8 are hydrogen; and one or more R.sup.x
are independently selected from methoxy and dimethylamino.
194. A compound of claim 180 having the structural formula: 540
195. A compound of claim 180 having the structural formula: 541
196. A compound of claim 180 having the structural formula: 542
197. A compound of claim 180 having the structural formula: 543
198. A compound of claim 180 having the structural formula: 544
199. A compound of claim 180 having the structural formula: 545
200. A compound of claim 180 having the structural formula: 546
201. A compound of formula (I): 547wherein: q is an integer from 1
to 4; n is an integer from 0 to 2; R.sup.1 and R.sup.2 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy,
alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and
cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl,
arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,
(polyalkyl)aryl, and cycloalkyl optionally are substituted with one
or more substituents selected from the group consisting of
OR.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.10R.sup.wA.- sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-.
P.sup.+R.sup.9R.sup.10R.sup.11A.sup.- -, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10, wherein alkyl, alkenyl, alkynyl,
alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl
optionally have one or more carbons replaced by O, NR.sup.9,
N.sup.+R.sup.9R.sup.10A-, S, SO, SO.sub.2, S.sup.+R.sup.9A.sup.-,
P.sup.+R.sup.9R.sup.10A.sup.-, or phenylene, wherein R.sup.9,
R.sup.10, and R.sup.w are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,
heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl,
carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,
carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and
alkylammoniumalkyl; or R.sup.1 and R.sup.2 taken together with the
carbon to which they are attached form C.sub.3-C.sub.10 cycloalkyl;
R.sup.3 and R.sup.4 are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl,
heterocycle, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, and SO.sub.3R.sup.9, wherein R.sup.9 and R.sup.10
are as defined above; or R.sup.3 and R.sup.4 together form .dbd.O,
.dbd.NOR.sup.11, .dbd.S, .dbd.NNR.sup.11R.sup.12, .dbd.NR.sup.9, or
.dbd.CR.sup.11R.sup.12, wherein R.sup.11 and R.sup.12 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl,
heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl,
cyanoalkyl, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO2R.sup.9, CN, halogen, oxo, and
CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10 are as defined
above, provided that both R.sup.3 and R.sup.4 cannot be OH,
NH.sub.2, and SH, or R.sup.11 and R.sup.12 together with the
nitrogen or carbon atom to which they are attached form a cyclic
ring; R.sup.5 is aryl substituted with one or more OR.sup.13b,
wherein R.sup.13b is selected from the group consisting of alkyl,
alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl,
alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl,
cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle,
quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl,
quaternary heterocyclylalkyl, quaternary heteroarylalkyl,
alkylammoniumalkyl, and carboxyalkylaminocarbonylalkyl, R.sup.13b
is substituted with one or more groups selected from the group
consisting of hydroxy, amino, sulfo, carboxy, carboxyalkyl,
heterocycle, heteroaryl, sulfoalkyl, quaternary heterocyclylalkyl,
quaternary heteroarylalkyl, or guanidinyl, and R.sup.6 is selected
from the group consisting of H. alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heterocycle, quaternary heterocycle, OR.sup.30,
SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, and SO.sub.3R.sup.9,
wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,
quaternary heterocycle, and quaternary heteroaryl can be
substituted with one or more substituent groups independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen,
oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, SO.sub.3R.sup.13, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14,
C(O)OM, COR.sup.13, NR.sup.13C(O)R.sup.14,
NR.sup.13C(O)NR.sup.14R.sup.15, NR.sup.13CO.sub.2R.sup.14,
OC(O)R.sup.13, OC(O)NR.sup.13R.sup.14, NR.sup.13SOR.sup.14,
NR.sup.13SO.sub.2R.sup.14, NR.sup.13SONR.sup.14R.sup- .15,
NR.sup.13SO.sub.2NR.sup.14R.sup.15, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- , wherein: A.sup.- is a
pharmaceutically acceptable anian and M is a pharmaceutically
acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be
further substituted with one or more substituent groups selected
from the group consisting of OR.sup.7, NR.sup.7R.sup.8, SR.sup.7,
S(O)R.sup.7, SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN,
oxo, CONR.sup.7R.sup.8, N.sup.+R.sup.7R.sup.8R.sup.9A-, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl,
quaternary heterocycle, quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, and P(O)(OR.sup.7)OR.sup.8,
and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have
one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A-, S, SO, SO.sub.2, S.sup.+R.sup.7A-,
PR.sup.7, P(O)R.sup.7, P.sup.+R.sup.7R.sup.8A-, or phenylene, and
R.sup.13, R.sup.14, and R.sup.15 are independently selected from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl,
alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl,
heterocycle, heteroaryl, quaternary heterocycle, quaternary
heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl,
and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl,
alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one
or more carbons replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.10A-,
S, SO, SO.sub.2, S.sup.+R .sup.9A.sup.-, PR.sup.9,
P.sup.+R.sup.9R.sup.10A-, P(O)R.sup.9, phenylene, carbohydrate,
amino acid, peptide, or polypeptide, and R.sup.13, R.sup.14, and
R.sup.15 are optionally substituted with one or more groups
selected from the group consisting of hydroxy, amino, sulfo,
carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl,
quaternary heterocycle, quaternary heteroaryl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl,
OR.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.10R.sup.11A-, S.sup.+R9R A-, and C(O)OM,
wherein R.sup.16 and R.sup.17 are independently selected from the
substituents constituting R.sup.9 and M; or R.sup.13 and R.sup.14,
together with the nitrogen atom to which they are attached form a
mono- or polycyclic heterocycle that is optionally substituted with
one or more radicals selected from the group consisting of oxo,
carboxy and quaternary salts; or R.sup.14 and R.sup.15, together
with the nitrogen atom to which they are attached, form a cyclic
ring; and R.sup.30 is selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle,
ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl,
carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,
carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and
alkylammoniumalkyl; and R.sup.7 and R.sup.8 are independently
selected from the group consisting of hydrogen and alkyl; and one
or more R.sup.x are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl,
arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl,
polyether, quaternary heterocycle, quaternary heteroaryl,
OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
S(O).sub.2R.sup.13, SO.sub.3R.sup.13, S.sup.+R.sup.13R.sup.14A-,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15- , NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SQ2OM, SO.sub.2NR.sup.13R.sup.14,
NR.sup.14C(O)R.sup.13, C(O)NR.sup.13R.sup.14, NR14C(O)R13, C(O)OM,
COR.sup.13, OR.sup.18, S(O).sub.nNR.sup.18, NR.sup.13R.sup.18,
NR.sup.18O.sup.14, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, amino acid, peptide,
polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl,
haloalkyl, polyether, quaternary heterocycle, and quaternary
heteroaryl can be further substituted with OR.sup.9,
NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.- 12A.sup.-,
SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.11R- .sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein R.sup.18 is
selected from the group consisting of acyl, arylalkoxycarbonyl,
arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl,
arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,
quaternary heterocycle, and quaternary heteroaryl optionally are
substituted with one or more substituents selected from the group
consisting of OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A- .sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.3R.sup.9, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17, and C(O)OM,
wherein in R.sup.x, one or more carbons are optionally replaced by
O, NR.sup.13, N.sup.+R.sup.13R.sup.14A-, S, SO, SO.sub.2,
S.sup.+R.sup.13A.sup.-, PR.sup.13, P(O)R.sup.13,
P.sup.+R.sup.13R.sup.14A- -, phenylene, amino acid, peptide,
polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said
polyalkyl, phenylene, amino acid, peptide, polypeptide, and
carbohydrate, one or more carbons are optionally replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-, or
P(O)R.sup.9; wherein quaternary heterocycle and quaternary
heteroaryl are optionally substituted with one or more groups
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, halogen, oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14- ,
C(O)NR.sup.13R.sup.14, C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- , or a pharmaceutically
acceptable salt, solvate, or prodrug thereof.
202. A compound of claim 201 wherein: R.sup.5 is phenyl substituted
with OR.sup.13b; R.sup.13b is independently selected from the group
consisting of alkyl, quaternary heteroarylalkyl, and quaternary
heterocyclylalkyl; and R.sup.13b is substituted with one or more
groups selected from the group consisting of hydroxy, heterocycle,
heteroaryl, and guanidinyl.
203. A compound of claim 201 wherein n is 1 or 2.
204. A compound of claim 201 wherein R.sup.7 and R.sup.8 are
independently selected from the group consisting of hydrogen and
alkyl.
205. A compound of claim 201 wherein R.sup.7 and R.sup.8 are
hydrogen.
206. A compound of claim 201 wherein R.sup.3 and R.sup.4 are
independently selected from the group consisting of hydrogen and
OR.sup.9.
207. A compound of claim 201 wherein R.sup.3 is hydrogen and
R.sup.4 is hydroxy.
208. A compound of claim 201 wherein one or more R.sup.x are
independently selected from the group consisting of OR.sup.13 and
NR.sup.13R.sup.14.
209. A compound of claim 201 wherein one or more R.sup.x are
independently selected from methoxy and dimethylamino.
210. A compound of claim 201 wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting of hydrogen and
alkyl.
211. A compound of claim 201 wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting alkyl.
212. A compound of claim 201 wherein R.sup.1 and R.sup.2 are the
same alkyl.
213. A compound of claim 201 wherein R.sup.1 and R.sup.2 are each
n-butyl.
214. A compound of claim 201 wherein n is 1 or 2; R.sup.1 and
R.sup.2 are n-butyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
hydroxy; R.sup.7 and R.sup.8 are hydrogen; and one or more R.sup.x
are independently selected from methoxy and dimethylamino.
215. A compound of claim 201 having the structural formula: 548
216. A compound of claim 201 having the structural formula: 549
217. A compound of claim 201 having the structural formula: 550
218. A compound of formula (I): 551wherein: q is an integer from 1
to 4; n is an integer from 0 to 2; R.sup.1 and R.sup.2 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy,
alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and
cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl,
arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,
(polyalkyl)aryl, and cycloalkyl optionally are substituted with one
or more substituents selected from the group consisting of
OR.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.10R.sup.wA.- sup.-,
SR.sup.9, S.sup.+R.sup.9R.sup.10A.sup.-.
P.sup.+R.sup.9R.sup.10R.su- p.11A.sup.-, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10, wherein alkyl, alkenyl, alkynyl,
alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl
optionally have one or more carbons replaced by O, NR.sup.9,
N.sup.+R.sup.9R.sup.10A-, S, SO, SO.sub.2, S.sup.+R.sup.9A.sup.-,
P.sup.+R.sup.9R.sup.10A.sup.-, or phenylene, wherein R.sup.9,
R.sup.10, and R.sup.w are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,
heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl,
carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,
carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and
alkylammoniumalkyl; or R.sup.1 and R.sup.2 taken together with the
carbon to which they are attached form C.sub.3-C.sub.10 cycloalkyl;
R.sup.3 and R.sup.4 are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl,
heterocycle, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, and SO.sub.3R.sup.9, wherein R.sup.9 and R.sup.10
are as defined above; or R.sup.3 and R.sup.4 together form .dbd.O,
.dbd.NOR.sup.11, .dbd.S, .dbd.NNR.sup.11R.sup.12, .dbd.NR.sup.9, or
.dbd.CR.sup.11R.sup.12, wherein R.sup.11 and R.sup.12 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl,
heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl,
cyanoalkyl, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10 are as
defined above, provided that both R.sup.3 and R.sup.4 cannot be OH,
NH.sub.2, and SH, or R.sup.11 and R.sup.12 together with the
nitrogen or carbon atom to which they are attached form a cyclic
ring; R.sup.5 is aryl substituted with one or more ORl.sup.3b,
wherein R.sup.13b is selected from the group consisting ;of alkyl,
alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl,
alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl,
cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle,
quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl,
quaternary heterocyclylalkyl, quaternary heteroarylalkyl,
alkylammoniumalkyl, and carboxyalkylaminocarbonylalkyl, R.sup.13b
is substituted with one or more groups selected from the group
consisting of OR.sup.9a, NR.sup.9aR.sup.10,
N.sup.+R.sup.9aR.sup.11R.sup.12A.sup.-, SR.sup.9a, S(O)R.sup.9a,
S.sub.2R.sup.9a, SO.sub.3R.sup.9a, CO.sub.2.sup.9a,
CONR.sup.9aR.sup.10, SO.sub.2NR.sup.9a, S(O)R.sup.9a,
SO.sub.3R.sup.9a, CO.sub.2R.sup.9a, CONR.sup.9aR.sup.10,
SO.sub.2NR.sup.9aR.sup.10, P.sup.+R.sup.9aR.sup.10R.sup.11A-, and
S.sup.+R.sup.9aR.sup.10A-, wherein A.sup.- is an pharmaceutically
acceptable anion and M is a pharmaceutically acceptable cation, and
wherein R.sup.9a is selected from the group consisting of
carboxyalkyl, carboxyheteroaryl, carboxyheterocycle,
carboalkoxyalkyl, and carboxyalkylamino; R.sup.6 is selected from
the group consisting of H, alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heterocycle, quaternary heterocycle, OR.sup.30,
SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, and SO.sub.3R.sup.9,
wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,
quaternary heterocycle, and quaternary heteroaryl can be
substituted with one or more substituent groups independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen,
oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, SO.sub.3R.sup.13, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14,
C(O)OM, COR.sup.13, NR.sup.13C(O)R.sup.14,
NR.sup.13C(O)NR.sup.14R.sup.15, NR.sup.13CO.sub.2R.sup.14,
OC(O)R.sup.13, OC(O)NR.sup.13R.sup.14, NR.sup.13SOR.sup.14,
NR.sup.13SO.sub.2R.sup.14, NR.sup.13SONR.sup.14R.sup- .15,
NR.sup.13SO.sub.2NR.sup.14R.sup.15, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- , wherein: A.sup.- is a
pharmaceutically acceptable anion and M is a pharmaceutically
acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be
further substituted with one or more substituent groups selected
from the group consisting of OR.sup.7, NR.sup.7R.sup.8, SR.sup.7,
S(O)R.sup.7, SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN,
oxo, CONR.sup.7R.sup.8, N.sup.+R.sup.7R.sup.8R.sup.9A-, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl,
quaternary heterocycle, quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, and P(O)(OR.sup.7)OR.sup.8,
and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have
one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A-, S, SO, SO.sub.2, S.sup.+R.sup.7A-,
PR.sup.7, P(O)R.sup.7, P.sup.+R.sup.7R.sup.8A-, or phenylene, and
R.sup.13, R.sup.14, and R.sup.15 are independently selected from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl,
alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl,
heterocycle, heteroaryl, quaternary heterocycle, quaternary
heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl,
and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl,
alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one
or more carbons replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.10A-,
S, SO, SO.sub.2, S.sup.+R.sup.9A.sup.-, PR.sup.9,
P.sup.+R.sup.9R.sup.10A-, P(O)R.sup.9, phenylene, carbohydrate,
amino acid, peptide, or polypeptide, and R.sup.13, R.sup.14, and
R.sup.15 are optionally substituted with one or more groups
selected from the group consisting of hydroxy, amino, sulfo,
carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl,
quaternary heterocycle, quaternary heteroaryl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl,
OR.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.10R.sup.11A-, S.sup.+R.sup.9R.sup.10 A-, and
C(O)OM, wherein R.sup.16 and R.sup.17 are independently selected
from the substituents constituting R.sup.9 and M; or R.sup.13 and
R.sup.14, together with the nitrogen atom to which they are
attached form a mono- or polycyclic heterocycle that is optionally
substituted with one or more radicals selected from the group
consisting of oxo, carboxy and quaternary salts; or R.sup.14 and
R.sup.15, together with the nitrogen atom to which they are
attached, form a cyclic ring; and R.sup.30 is selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl,
carboxyalkyl, carboxyheteroaryl, carboxyheterocycle,
carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl,
heterocyclylalkyl, and alkylammoniumalkyl; and R.sup.7 and R.sup.8
are independently selected from the group consisting of hydrogen
and alkyl; and one or more R.sup.x are independently selected from
the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl,
acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl,
heterocycle, heteroaryl, polyether, quaternary heterocycle,
quaternary heteroaryl, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, S(O).sub.2R.sup.13, SO.sub.3R.sup.13,
S.sup.+R.sup.13R.sup.14A-, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, NR.sup.14C(O)R.sup.13,
C(O)NR.sup.13R.sup.14, NR14C(O)R13, C(O)OM, COR.sup.13, OR.sup.18,
S(O).sub.nNR.sup.18, NR.sup.13R.sup.18, N.sup.18OR.sup.14,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.11R.sup.12A.su- p.-, amino acid, peptide,
polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl,
haloalkyl, polyether, quaternary heterocycle, and quaternary
heteroaryl can be further substituted with OR.sup.9,
NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P+R.sup.9R.sup.11R.sup.12A.sup.-, S.sup.+R.sup.9R.sup.10A.sup.-, or
C(O)OM, and wherein R.sup.18 is selected from the group consisting
of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl,
alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle,
heteroaryl, alkyl, quaternary heterocycle, and quaternary
heteroaryl optionally are substituted with one or more substituents
selected from the group consisting of OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.3R.sup.9, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, P(OR.sup.16)OR.sup.17, and C(O)OM,
wherein in R.sup.x, one or more carbons are optionally replaced by
O, NR.sup.13, N.sup.+R.sup.13R.sup.14A-, S, SO,
S.sup.+R.sup.13A.sup.-, PR.sup.13, P(O)R.sup.13,
P.sup.+R.sup.13R.sup.14A-, phenylene, amino acid, peptide,
polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said
polyalkyl, phenylene, amino acid, peptide, polypeptide, and
carbohydrate, one or more carbons are optionally replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-, or
P(O)R.sup.9; wherein quaternary heterocycle and quaternary
heteroaryl are optionally substituted with one or more groups
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, halogen, oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14,
C(O)NR.sup.13R.sup.14, C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, or a pharmaceutically
acceptable salt, solvate, or prodrug thereof.
219. A compound of claim 218 wherein: R.sup.5 is phenyl substituted
with OR.sup.13b; R.sup.13b is alkyl; and R.sup.13b is substituted
with one or more groups selected from the group consisting of
OR.sup.9a and NR.sup.9aR.sup.10; and R.sup.9a is selected from the
group consisting of carboxyalkyl, carboxyheteroaryl, and
carboxyheterocycle; and R.sup.10 is carboxyalkyl.
220. A compound of claim 218 wherein n is 1 or 2.
221. A compound of claim 218 wherein R.sup.7 and R.sup.8 are
independently selected from the group consisting of hydrogen and
alkyl.
222. A compound of claim 218 wherein R.sup.7 and R.sup.8 are
hydrogen.
223. A compound of claim 218 wherein R.sup.3 and R.sup.4 are
independently selected from the group consisting of hydrogen and
OR.sup.9.
224. A compound of claim 218 wherein R.sup.3 is hydrogen and
R.sup.4 is hydroxy.
224. A compound of claim 218 wherein one or more R.sup.x are
independently selected from the group consisting of OR.sup.13 and
NR.sup.13R.sup.14.
226. A compound of claim 218 wherein one or more R.sup.x are
independently selected from methoxy and dimethylamino.
227. A compound of claim 218 wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting of hydrogen and
alkyl.
228. A compound of claim 218 wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting alkyl.
229. A compound of claim 218 wherein R.sup.1 and R.sup.2 are the
same alkyl.
230. A compound of claim 218 wherein R.sup.1 and R.sup.2 are each
n-butyl.
231. A compound of claim 218 wherein n is 1 or 2; R.sup.1 and
R.sup.2 are n-butyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
hydroxy; R.sup.7 and R.sup.8 are hydrogen; and one or more R.sup.x
are independently selected from methoxy and dimethylamino.
232. A compound of claim 218 having the structural formula: 552
233. A compound of claim 218 having the structural formula: 553
234. A compound of formula (I): 554wherein: q is an integer from 1
to 4; n is an integer from 0 to 2; R.sup.1 and R.sup.2 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy,
alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and
cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl,
arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,
(polyalkyl)aryl, and cycloalkyl optionally are substituted with one
or more substituents selected from the group consisting of
OR.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.10R.sup.wA.- sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-,
P.sup.+R.sup.9R.sup.10R.sup.11A.sup.- -, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10, wherein alkyl, alkenyl, alkynyl,
alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl
optionally have one or more carbons replaced by O, NR.sup.9,
N.sup.+R.sup.9R.sup.10A-, S, SO, SO.sub.2, S.sup.+R.sup.9A.sup.-,
P.sup.+R.sup.9R.sup.10A.sup.-, or phenylene, wherein R.sup.9,
R.sup.10, and R.sup.w are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,
heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl,
carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,
carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and
alkylammoniumalkyl; or R.sup.1 and R.sup.2 taken together with the
carbon to which they are attached form C.sub.3-C.sub.10 cycloalkyl;
R.sup.3 and R.sup.4 are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl,
heterocycle, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, and SO.sub.3R.sup.9, wherein R.sup.9 and R.sup.10
are as defined above; or R.sup.3 and R.sup.4 together form .dbd.O,
.dbd.NOR.sup.11, .dbd.S, .dbd.NNR.sup.11R.sup.12, .dbd.NR.sup.9, or
.dbd.CR.sup.11R.sup.12, wherein R.sup.11 and R.sup.12 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl,
heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl,
cyanoalkyl, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10 are as
defined above, provided that both R.sup.3 and R.sup.4 cannot be OH,
NH.sub.2, and SH, or R.sup.11 and R.sup.12 together with the
nitrogen or carbon atom to which they are attached form a cyclic
ring; R.sup.5 is aryl substituted with one or more OR.sup.13b,
wherein R.sup.13b is selected from the group consisting of alkyl,
alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl,
alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl,
cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle,
quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl,
quaternary heterocyclylalkyl, quaternary heteroarylalkyl,
alkylammoniumalkyl, and carboxyalkylaminocarbonylalkyl, R.sup.13b
is substituted with one or more groups selected from the group
consisting of NR.sup.9R.sup.10a, CONR.sup.9R.sup.10a,
SO.sub.2NR.sup.9R.sup.10aR.sup.11A-, and S.sup.+R.sup.9R.sup.10aA-,
wherein A.sup.- is an pharmaceutically acceptable anion and M is a
pharmaceutically acceptable cation, wherein R.sup.10a is selected
from the group consisting of carboxyalkyl, carboalkoxyalkyl,
carboxyalkylamino, heteroarylalkyl, and heterocyclylalkyl; or
R.sup.6 is selected from the group consisting of H, alkyl, alkenyl,
alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle,
OR.sup.30, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, and
SO.sub.3R.sup.9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycle, quaternary heterocycle, and quaternary heteroaryl can
be substituted with one or more substituent groups independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen,
oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, SO.sub.3R.sup.13, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14- , C(O)NR.sup.13R.sup.14,
C(O)OM, COR.sup.13, NR.sup.13C(O)R.sup.14,
NR.sup.13C(O)NR.sup.14R.sup.15, NR.sup.13CO.sub.2R.sup.14,
OC(O)R.sup.13, OC(O)NR.sup.13R.sup.14, NR.sup.13SOR.sup.14,
NR.sup.13SO.sub.2R.sup.14, NR.sup.13SONR.sup.14R.sup.15,
NR.sup.13SO.sub.2NR.sup.14R.sup.15, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, wherein: A.sup.- is a
pharmaceutically acceptable anion and M is a pharmaceutically
acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be
further substituted with one or more substituent groups selected
from the group consisting of OR.sup.7, NR.sup.7R.sup.8, SR.sup.7,
S(O)R.sup.7, SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN,
oxo, CONR.sup.7R.sup.8, SR.sup.7, N.sup.+R.sup.7R.sup.8R.sup.9A-,
alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl,
quaternary heterocycle, quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8 R.sup.9A.sup.-, and P(O)(OR.sup.7)OR.sup.8,
and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have
one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A.sup.-, S, SO, SO.sub.2, S.sup.+R.sup.7A-,
PR.sup.7, P(O)R.sup.7, P.sup.+R.sup.7R.sup.8A-, or phenylene, and
R.sup.13, R.sup.14, and R.sup.15 are independently selected from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl,
alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl,
heterocycle, heteroaryl, quaternary heterocycle, quaternary
heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl,
and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl,
alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one
or more carbons replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.10A-,
S, SO, SO.sub.2, S.sup.+R.sup.9A.sup.-, PR.sup.9,
P.sup.+R.sup.9R.sup.10A-, P(O)R.sup.9, phenylene, carbohydrate,
amino acid, peptide, or polypeptide, and R.sup.13, R.sup.14, and
R.sup.15 are optionally substituted with one or more groups
selected from the group consisting of hydroxy, amino, sulfo,
carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl,
quaternary heterocycle, quaternary heteroaryl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl,
OR.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.10R- .sup.11A-, S.sup.+R.sup.9R.sup.10A-, and
C(O)OM, wherein R.sup.16 and R.sup.17 are independently selected
from the substituents constituting R.sup.9 and M; or R.sup.13 and
R.sup.14, together with the nitrogen atom to which they are
attached form a mono- or polycyclic heterocycle that is optionally
substituted with one or more radicals selected from the group
consisting of oxo, carboxy and quaternary salts; or R.sup.14 and
R.sup.15, together with the nitrogen atom to which they are
attached, form a cyclic ring; and R.sup.30 is selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl,
carboxyalkyl, carboxyheteroaryl, carboxyheterocycle,
carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl,
heterocyclylalkyl, and alkylammoniumalkyl; and R.sup.7 and R.sup.8
are independently selected from the group consisting of hydrogen
and alkyl; and one or more R.sup.x are independently selected from
the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl,
acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl,
heterocycle, heteroaryl, polyether, quaternary heterocycle,
quaternary heteroaryl, OR.sup.13, NR.sup.13R.sup.14SR.sup.13- ,
S(O)R.sup.13, S(O).sub.2R.sup.13, SO.sub.3R.sup.13,
S.sup.+R.sup.13R.sup.14A-, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15- , NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2CM, SO.sub.2NR.sup.13R.sup.1- 4, NR.sup.14C(O)R.sup.13,
C(O)NR.sup.13R.sup.14, NR14C(O)R13, C(O)OM, COR.sup.13, OR.sup.18,
S(O).sub.nNR.sup.18, NR.sup.13R.sup.18, NR.sup.18OR.sup.14,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, amino acid, peptide,
polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl,
haloalkyl, polyether, quaternary heterocycle, and quaternary
heteroaryl can be further substituted with OR.sup.9,
NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.- 12A.sup.-,
SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.11R- .sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein R.sup.18 is
selected from the group consisting of acyl, arylalkoxycarbonyl,
arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl,
arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,
quaternary heterocycle, and quaternary heteroaryl optionally are
substituted with one or more substituents selected from the group
consisting of OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A- .sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, 6SO.sub.3R.sup.9, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17, and C(O)OM,
wherein in R.sup.x, one or more carbons are optionally replaced by
O, NR.sup.13, N.sup.+R.sup.13R.sup.14A-, S, SO, SO.sub.2,
S.sup.+R.sup.13A.sup.-, PR.sup.13, P(O)R.sup.13,
P.sup.+R.sup.13R.sup.14A- -, phenylene, amino acid, peptide,
polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said
polyalkyl, phenylene, amino acid, peptide, polypeptide, and
carbohydrate, one or more carbons are optionally replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-, or
P(O)R.sup.9; wherein quaternary heterocycle and quaternary
heteroaryl are optionally substituted with one or more groups
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, halogen, oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14- ,
C(O)NR.sup.13R.sup.14, C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15 A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- , or a pharmaceutically
acceptable salt, solvate, or prodrug thereof.
235. A compound of claim 234 wherein: R.sup.5 is phenyl substituted
with OR.sup.13b; R.sup.13b is alkyl; and R.sup.13b is substituted
with NR.sup.9R.sup.10a; and R.sup.9 is hydrogen; and R.sup.10 is
heteroarylalkyl.
236. A compound of claim 234 wherein n is 1 or 2.
237. A compound of claim 234 wherein R.sup.7 and R.sup.8 are
independently selected from the group consisting of hydrogen and
alkyl.
238. A compound of claim 234 wherein R.sup.7 and R.sup.8 are
hydrogen.
239. A compound of claim 234 wherein R.sup.3 and R.sup.4 are
independently selected from the group consisting of is hydrogen and
OR.sup.9.
240. A compound of claim 234 wherein R.sup.3 is hydrogen and
R.sup.4 is hydroxy.
241. A compound of claim 234 wherein one or more R.sup.x are
independently selected from the group consisting of OR.sup.13 and
NR.sup.13R.sup.14.
242. A compound of claim 234 wherein one or more R.sup.x are
independently selected from methoxy and dimethylamino.
243. A compound of claim 234 wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting of hydrogen and
alkyl.
244. A compound of claim 234 wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting alkyl.
245. A compound of claim 234 wherein R.sup.1 and R.sup.2 are the
same alkyl.
246. A compound of claim 234 wherein R.sup.1 and R.sup.2 are each
n-butyl.
247. A compound of claim 234 wherein n is 1 or 2; R.sup.1 and
R.sup.2 are n-butyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
hydroxy; R.sup.7 and R.sup.8 are hydrogen; and one or more R.sup.x
are independently selected from methoxy and dimethylamino.
248. A compound of claim 234 having the structural formula: 555
249. A compound of formula (I): 556wherein: q is an integer from 1
to 4; n is an integer from 0 to 2; R.sup.1 and R.sup.2 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy,
alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and
cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl,
arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,
(polyalkyl)aryl, and cycloalkyl optionally are substituted with one
or more substituents selected from the group consisting of
OR.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.10R.sub.wA.- sup.-,
SR.sup.9, S.sup.+R.sup.9R.sup.10A.sup.-,
P.sup.+R.sup.9R.sup.10R.su- p.11A.sup.-, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10, wherein alkyl, alkenyl, alkynyl,
alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl
optionally have one or more carbons replaced by O, NR.sup.9,
N.sup.+R.sup.9R.sup.10A-, S, SO, SO.sub.2, S.sup.+R.sup.9A.sup.-,
P.sup.+R.sup.9R.sup.10A.sup.-, or phenylene, wherein R.sup.9,
R.sup.10, and R.sup.w are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,
heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl,
carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,
carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and
alkylammoniumalkyl; or R.sup.1 and R.sup.2 taken together with the
carbon to which they are attached form C.sub.3-C.sub.10 cycloalkyl;
R.sup.3 and R.sup.4 are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl,
heterocycle, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, and SO.sub.3R.sup.9, wherein R.sup.9 and R.sup.10
are as defined above; or R.sup.3 and R.sup.4 together form .dbd.O,
.dbd.NOR.sup.11, .dbd.S, .dbd.NNR.sup.11R.sup.12, .dbd.NR.sup.9, or
.dbd.CR.sup.11R.sup.12, wherein R.sup.11 and R.sup.12 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl,
heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl,
cyanoalkyl, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10 are as
defined above, provided that both R.sup.3 and R.sup.4 cannot be OH,
NH.sub.2, and SH, or R.sup.11 and R.sup.12 together with the
nitrogen or carbon atom to which they are attached form a cyclic
ring; R.sup.5 is aryl substituted with one or more substituent
groups independently selected from the group consisting of
NR.sup.13C(O)R.sup.14, NR.sup.13C(O)NR.sup.14R.sup.15,
NR.sup.13C.sub.2R.sup.14, OC(O)R.sup.13, OC(O)NR.sup.13R.sup.14,
NR.sup.13SOR.sup.14, NR.sup.13SO.sub.2R.sup.14,
NR.sup.13SONR.sup.14R.sup- .15, and
NR.sup.13SO.sub.2NR.sup.14R.sup.15, wherein: R.sup.13, R.sup.14,
and R.sup.15 are independently selected from the group consisting
of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
arylalkyl, alkylarylalkyl, alkylheteroarylalkyl,
alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl,
quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl,
heteroarylalkyl, quaternary heterocyclylalkyl, quaternary
heteroarylalkyl, alkylammoniumalkyl, and
carboxyalkylaminocarbonylalkyl, R.sup.13, R.sup.14, and R.sup.15
are optionally substituted with one or more groups selected from
the group consisting of hydroxy, amino, sulfo, carboxy, alkyl,
carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary
heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl,
quaternary heteroarylalkyl, guanidinyl, OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.s- up.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.2OM, SO.sub.2NR.sup.9R.sub.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.10R- .sup.11A-,
S.sup.+R.sup.9R.sup.10A-, and C(O)OM, wherein A.sup.- is an
pharmaceutically acceptable anion and M is a pharmaceutically
acceptable cation, wherein R.sup.16 and R.sup.17 are independently
selected from the substituents constituting R.sup.9 and M; or
R.sup.13 and R.sup.14, together with the nitrogen atom to which
they are attached form a mono- or polycyclic heterocycle that is
optionally substituted with one or more radicals selected from the
group consisting of oxo, carboxy and quaternary salts; or R.sup.14
and R.sup.15, together with the nitrogen atom to which they are
attached, form a cyclic ring; and R.sup.6 is selected from the
group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycle, quaternary heterocycle, OR.sup.30, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, and SO.sub.3R.sup.9, wherein alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary
heterocycle, and quaternary heteroaryl can be substituted with one
or more substituent groups independently selected from the group
consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary
heterocycle, quaternary heteroaryl, halogen, oxo, OR.sup.13,
NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13,
SO.sub.3R.sup.13, NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15,
NO.sub.2, CO.sub.2R.sup.13, CN, OM, SO.sub.2CM,
SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14, C(O)OM,
COR.sup.13, NR.sup.13C(O)R.sup.14, NR.sup.13C(O)NR.sup.14R.sup.15,
NR.sup.13CO.sub.2R.sup.14, OC(O)R.sup.13, OC(O)NR.sup.13R.sup.14,
NR.sup.13SOR.sup.14, NR.sup.13SO.sub.2R.sup.14,
NR.sup.13SONR.sup.14R.sup- .15, NR.sup.13SO.sub.2NR.sup.14R.sup.15,
P(O)R.sup.13R.sup.14, P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-,
P(OR.sup.13)OR.sup.14, S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sub.12A.sup.-- , wherein: A.sup.- is a
pharmaceutically acceptable anion and M is a pharmaceutically
acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be
further substituted with one or more substituent groups selected
from the group consisting of OR.sup.7, NR.sup.7R.sup.8, SR.sup.7,
S(O)R.sup.7, SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN,
oxo, CONR.sup.7R.sup.8, N.sup.+R.sup.7R.sup.8R.sup.9A-, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl,
quaternary heterocycle, quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, and P(O)(OR.sup.7)OR.sup.8,
and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have
one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A-, S, SO, SO.sub.2, S.sup.+R.sup.7A-,
PR.sup.7, P(O)R.sup.7, P.sup.+R.sup.7R.sup.8A-, or phenylene, and
R.sup.13, R.sup.14, and R.sup.15 are independently selected from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl,
alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl,
heterocycle, heteroaryl, quaternary heterocycle, quaternary
heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl,
and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl,
alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one
or more carbons replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.10A-,
S, SO, SO.sub.2, S.sup.+R.sup.9A.sup.-, PR.sup.9,
P.sup.+R.sup.9R.sup.10A-, P(O)R.sup.9, phenylene, carbohydrate,
amino acid, peptide, or polypeptide, and R.sup.13, R.sup.14, and
R.sup.15 are optionally substituted with one or more groups
selected from the group consisting of hydroxy, amino, sulfo,
carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl,
quaternary heterocycle, quaternary heteroaryl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl,
OR.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16 )OR.sup.17,
P.sup.+R.sup.9R.sup.10R.sup.11A-, S.sup.+R.sup.9R.sup.10A-, and
C(O)OM, wherein R.sup.16 and R.sup.17 are independently selected
from the substituents constituting R.sup.9 and M; or R.sup.13 and
R.sup.14, together with the nitrogen atom to which they are
attached form a mono- or polycyclic heterocycle that is optionally
substituted with one or more radicals selected from the group
consisting of oxo, carboxy and quaternary salts; or R.sup.14 and
R.sup.15, together with the nitrogen atom to which they are
attached, form a cyclic ring; and R.sup.30 is selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl,
carboxyalkyl, carboxyheteroaryl, carboxyheterocycle,
carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl,
heterocyclylalkyl, and alkylammoniumalkyl; and R.sup.7 and R.sup.8
are independently selected from the group consisting of hydrogen
and alkyl; and one or more R.sup.x are independently selected from
the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl,
acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl,
heterocycle, heteroaryl, polyether, quaternary heterocycle,
quaternary heteroaryl, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, S(O).sub.2R.sup.13, SO.sub.3R.sup.13,
S.sup.+R.sup.13R.sup.14A-, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, NR.sup.14C(O).sup.13,
C(O)NR.sup.13R.sup.14, NR14C(O)R13, C(O)OM, COR.sup.13, OR.sup.18,
S(O).sub.nNR.sup.18, NR.sup.13R.sup.18, NR.sup.18OR.sup.14,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.11R.sup.12A.su- p.-, amino acid, peptide,
polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl,
haloalkyl, .polyether, quaternary heterocycle, and quaternary
heteroaryl can be further substituted with OR.sup.9,
NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein R.sup.18 is
selected from the group consisting of acyl, arylalkoxycarbonyl,
arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl,
arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,
quaternary heterocycle, and quaternary heteroaryl optionally are
substituted with one or more substituents selected from the group
consisting of OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.3R.sup.9, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16OR.sup.17, and C(O)OM,
wherein in R.sup.x, one or more carbons are optionally replaced by
O, NR.sup.13, N.sup.+R.sup.13R.sup.14A-, S, SO, SO.sub.2,
S.sup.+R.sup.13A.sup.-, PR.sup.13, P(O)R.sup.13,
P.sup.+R.sup.13R.sup.14A-, phenylene, amino acid, peptide,
polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said
polyalkyl, phenylene, amino acid, peptide, polypeptide, and
carbohydrate, one or more carbons are optionally replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-, or
P(O)R.sup.9; wherein quaternary heterocycle and quaternary
heteroaryl are optionally substituted with one or more groups
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, halogen, oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2CM, SO.sub.2NR.sup.13R.sup.14- ,
C(O)NR.sup.13R.sup.14, C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- , or a pharmaceutically
acceptable salt, solvate, or prodrug thereof.
250. A compound of claim 249 wherein R.sup.5 is aryl substituted
with a radical selected from the group consisting of
NR.sup.13C(O)NR.sup.14R.sup- .15 and NR.sup.13CO.sub.2R.sup.14.
251. A compound of claim 249 wherein R.sup.5 is phenyl substituted
with a radical selected from the group consisting of
NR.sup.13C(O)NR.sup.14R.sup- .15 and NR.sup.13CO.sub.2R.sup.14.
252. A compound of claim 249 wherein n is 1 or 2.
253. A compound of claim 249 wherein R.sup.7 and R.sup.8 are
independently selected from the group consisting of hydrogen and
alkyl.
254. A compound of claim 249 wherein R.sup.7 and R.sup.8 are
hydrogen.
255. A compound of claim 249 wherein R.sup.3 and R.sup.4 are
independently selected from the group consisting of hydrogen and
OR.sup.9.
256. A compound of claim 249 wherein R.sup.3 is hydrogen and
R.sup.4 is hydroxy.
257. A compound of claim 249 wherein one or more R.sup.x are
independently selected from the group consisting of OR.sup.13 and
NR.sup.13R.sup.14.
258. A compound of claim 249 wherein one or more R.sup.x are
independently selected from methoxy and dimethylamino.
259. A compound of claim 249 wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting of hydrogen and
alkyl.
260. A compound of claim 249 wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting alkyl.
261. A compound of claim 249 wherein R.sup.1 and R.sup.2 are the
same alkyl.
262. A compound of claim 249 wherein R.sup.1 and R.sup.2 are each
n-butyl.
263. A compound of claim 249 wherein n is 1 or 2; R.sup.1 and
R.sup.2 are n-butyl; R.sup.3 and R.sup.6 are hydrogen; R.sup.4 is
hydroxy; R.sup.7 and R.sup.8 are hydrogen; and one or more R.sup.x
are independently selected from methoxy and dimethylamino.
264. A compound of claim 98 having the structural formula: 557
265. A pharmaceutical composition comprising an anti-hyperlipidemic
condition effective amount of a compound of formula (I) of claim
170, and a pharmaceutically acceptable carrier.
266. A pharmaceutical composition comprising an
anti-atherosclerotic effective amount of a compound of formula (I)
of claim 170, and a pharmaceutically acceptable carrier.
267. A pharmaceutical composition comprising an
anti-hypercholesterolemia effective amount of a compound of formula
(I) of claim 170, and a pharmaceutically acceptable carrier.
268. A method for the prophylaxis or treatment of a hyperlipidemic
condition comprising administering to a patient in need thereof a
composition of claim 265 in unit dosage form.
269. A method for the prophylaxis or treatment of an
atherosclerotic condition comprising administering to a patient in
need thereof a composition of claim 266 in unit dosage form.
270. A method for the prophylaxis or treatment of
hypercholesterolemia comprising administering to a patient in need
thereof a composition of claim 267 in unit dosage form.
271. A pharmaceutical composition comprising an anti-hyperlipidemic
condition effective amount of a compound of formula (I) of claim
180, and a pharmaceutically acceptable carrier.
272. A pharmaceutical composition comprising an
anti-atherosclerotic effective amount of a compound of formula (I)
of claim 180, and a pharmaceutically acceptable carrier.
273. A pharmaceutical composition comprising an
anti-hypercholesterolemia effective amount of a compound of formula
(I) of claim 180, and a pharmaceutically acceptable carrier.
274. A method for the prophylaxis or treatment of a hyperlipidemic
condition comprising administering to a patient in need thereof a
composition of claim 271 in unit dosage form.
275. A method for the prophylaxis or treatment of an
atherosclerotic condition comprising administering to a patient in
need thereof a composition of claim 272 in unit dosage form.
276. A method for the prophylaxis or treatment of
hypercholesterolemia comprising administering to a patient in need
thereof a composition of claim 273 in unit dosage form.
277. A pharmaceutical composition comprising an anti-hyperlipidemic
condition effective amount of a compound of formula (I) of claim
201, and a pharmaceutically acceptable carrier.
278. A pharmaceutical composition comprising an
anti-atherosclerotic effective amount of a compound of formula (I)
of claim 201, and a pharmaceutically acceptable carrier.
279. A pharmaceutical composition comprising an
anti-hypercholesterolemia effective amount of a compound of formula
(I) of claim 201, and a pharmaceutically acceptable carrier.
280. A method for the prophylaxis or treatment of a hyperlipidemic
condition comprising administering to a patient in need thereof a
composition of claim 277 in unit dosage form.
281. A method for the prophylaxis or treatment of an
atherosclerotic condition comprising administering to a patient in
need thereof a composition of claim 278 in unit dosage form.
282. A method for the prophylaxis or treatment of
hypercholesterolemia comprising administering to a patient in need
thereof a composition of claim 279 in unit dosage form.
283. A pharmaceutical composition comprising an anti-hyperlipidemic
condition effective amount of a compound of formula (I) of claim
218, and a pharmaceutically acceptable carrier.
284. A pharmaceutical composition comprising an
anti-atherosclerotic effective amount of a compound of formula (I)
of claim 218, and a pharmaceutically acceptable carrier.
285. A pharmaceutical composition comprising an
anti-hypercholesterolemia effective amount of a compound of formula
(I) of claim 218, and a pharmaceutically acceptable carrier.
286. A method for the prophylaxis or treatment of a hyperlipidemic
condition comprising administering to a patient in need thereof a
composition of claim 283 in unit dosage form.
287. A method for the prophylaxis or treatment of an
atherosclerotic condition comprising administering to a patient in
need thereof a composition of claim 284 in unit dosage form.
288. A method for the prophylaxis or treatment of
hypercholesterolemia comprising administering to a patient in need
thereof a composition of claim 285 in unit dosage form.
289. A pharmaceutical composition comprising an anti-hyperlipidemic
condition effective amount of a compound of formula (I) of claim
234, and a pharmaceutically acceptable carrier.
290. A pharmaceutical composition comprising an
anti-atherosclerotic effective amount of a compound of formula (I)
of claim 234, and a pharmaceutically acceptable carrier.
291. A pharmaceutical composition comprising an
anti-hypercholesterolemia effective amount of a compound of formula
(I) of claim 234, and a pharmaceutically acceptable carrier.
292. A method for the prophylaxis or treatment of a hyperlipidemic
condition comprising administering to a patient in need thereof a
composition of claim 289 in unit dosage form.
293. A method for the prophylaxis or treatment of an
atherosclerotic condition comprising administering to a patient in
need thereof a composition of claim 290 in unit dosage form.
294. A method for the prophylaxis or treatment of
hypercholesterolemia comprising administering to a patient in need
thereof a composition of claim 291 in unit dosage form.
295. A pharmaceutical composition comprising an anti-hyperlipidemic
condition effective amount of a compound of formula (I) of claim
249, and a pharmaceutically acceptable carrier.
296. A pharmaceutical composition comprising an
anti-atherosclerotic effective amount of a compound of formula (I)
of claim 249, and a pharmaceutically acceptable carrier.
297. A pharmaceutical composition comprising an
anti-hypercholesterolemia effective amount of a compound of formula
(I) of claim 249, and a pharmaceutically acceptable carrier.
298. A method for the prophylaxis or treatment of a hyperlipidemic
condition comprising administering to a patient in need thereof a
composition of claim 295 in unit dosage form.
299. A method for the prophylaxis or treatment of an
atherosclerotic condition comprising administering to a patient in
need thereof a composition of claim 296 in unit dosage form.
300. A method for the prophylaxis or treatment of
hypercholesterolemia comprising administering to a patient in need
thereof a composition of claim 297 in unit dosage form.
301. A process for the preparation of a compound having the
formula: 558comprising: treating a thiophenol with an abstracting
agent; coupling the thiophenyl and a cyclic sulfate to form an
intermediate comprising a sulfate group; and removing the sulfate
group of the intermediate to form the compound of formula XLI;
wherein q is an integer from 1 to 4; R.sup.1 and R.sup.2 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy,
alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and
cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl,
arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,
(polyalkyl)aryl, and cycloalkyl optionally are substituted with one
or more substituents selected from the group consisting of
OR.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.10R.sup.wA.sup.-,
SR.sup.9, S.sup.+R.sup.9R.sup.10A.s- up.-,
P.sup.+R.sup.9R.sup.10R.sup.11A.sup.-, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10, wherein alkyl, alkenyl, alkynyl,
alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl
optionally have one or more carbons replaced by O, NR.sup.9,
N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, P.sup.+R.sup.9R.sup.10A.sup.-, or phenylene,
wherein R.sup.9, R.sup.10, and R.sup.w are independently selected
from the group consisting of H, alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl,
carboxyalkyl, carboxyheteroaryl, carboxyheterocycle,
carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl,
heterocyclylalkyl, and alkylammoniumalkyl; or R.sup.1 and R.sup.2
taken together with the carbon to which they are attached form
C.sub.3-CIO cycloalkyl; R.sup.3 is hydroxy; R.sup.4 is hydrogen;
R.sup.5 and R.sup.6 are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycle, quaternary heterocycle, OR.sup.30, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, and SO.sub.3R.sup.9, wherein alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary
heterocycle, and quaternary heteroaryl can be substituted with one
or more substituent groups independently selected from the group
consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary
heterocycle, quaternary heteroaryl, halogen, oxo, OR.sup.13,
NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13,
SO.sub.3R.sup.13, NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15,
NO.sub.2, CO.sub.2R.sup.13, CN, OM, SO.sub.2OM,
SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14, C(O)OM,
COR.sup.13, NR.sup.13C(O)R.sup.14, NR.sup.13C(O)NR.sup.14R.sup.15,
NR.sup.13CO.sub.2R.sup.14, OC(O)R.sup.13, OC(C)NR.sup.13R.sup.14,
NR.sup.13SOR.sup.14, NR.sup.13SO.sub.2R.sup.14,
NR.sup.13SONR.sup.14R.sup- .15, NR.sup.13SO.sub.2NR.sup.14R.sup.15,
P(O)R.sup.13R.sup.14, P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-,
P(OR.sup.13)OR.sup.14, S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- , wherein: A.sup.- is a
pharmaceutically acceptable anion and M is a pharmaceutically
acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be
further substituted with one or more substituent groups selected
from the group consisting of OR .sup.7, NR.sup.7R.sup.8, SR.sup.7,
S(O)R.sup.7, SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN,
oxo, CONR.sup.7R.sup.8, N.sup.+R.sup.7R.sup.8R.sup.9A-, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl,
quaternary heterocycle, quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, and P(O)(OR.sup.7)OR.sup.8,
and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have
one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A-, S, SO, SO.sub.2, S.sup.+R.sup.7A-,
PR.sup.7, P(O)R.sup.7, P.sup.+R.sup.7R.sup.8A-, or phenylene, and
R.sup.13, R.sup.14, and R.sup.15 are independently selected from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl,
alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl,
heterocycle, heteroaryl, quaternary heterocycle, quaternary
heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl,
and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl,
alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one
or more carbons replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.10A-,
S, SO, SO.sub.2, S.sup.+R.sup.9A.sup.-, PR.sup.9,
P.sup.+R.sup.9R.sup.10A-, P(O)R.sup.9, phenylene, carbohydrate,
amino acid, peptide, or polypeptide, and R.sup.13, R.sup.14, and
R.sup.15 are optionally substituted with one or more groups
selected from the group consisting of hydroxy, amino, sulfo,
carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl,
quaternary heterocycle, quaternary heteroaryl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl,
OR.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.10R.sup.11A-, S.sup.+R.sup.9R.sup.01A-, and
C(O)OM, wherein R.sup.16 and R.sup.17 are independently selected
from the substituents constituting R.sup.9 and M; or R.sup.13 and
R.sup.14, together with the nitrogen atom to which they are
attached form a mono- or polycyclic heterocycle that is optionally
substituted with one or more radicals selected from the group
consisting of oxo, carboxy and quaternary salts; or R.sup.14 and
R.sup.15, together with the nitrogen atom to which they are
attached, form a cyclic ring; and R.sup.30 is selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl,
carboxyalkyl, carboxyheteroaryl, carboxyheterocycle,
carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl,
heterocyclylalkyl, and alkylammoniumalkyl; and R.sup.7 and R.sup.8
are hydrogen; and one or more R.sup.x are independently selected
from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl,
acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl,
heterocycle, heteroaryl, polyether, quaternary heterocycle,
quaternary heteroaryl, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, S(O).sub.2R.sup.13, SO.sub.3R.sup.13,
S.sup.+R.sup.13R.sup.14A.sup.-, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, NR.sup.14C(O)R.sup.13,
C(O)NR.sup.13R.sup.14, NR.sup.14C(O)R.sup.13, C(O)OM, COR.sup.13,
OR.sup.18, S(O).sub.nNR.sup.18, NR.sup.13R.sup.18,
NR.sup.18OR.sup.14, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.11R.sup.12A.su- p.-, amino acid, peptide,
polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl,
haloalkyl, polyether, quaternary heterocycle, and quaternary
heteroaryl can be further substituted with OR.sup.9,
NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9,
S(O)R.sup.9, SO.sub.2R, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein R.sup.18 is
selected from the group consisting of acyl, arylalkoxycarbonyl,
arylalkyl, heterocycle, heteroaryl, and alkyl, wherein acyl,
arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,
quaternary heterocycle, and quaternary heteroaryl optionally are
substituted with one or more substituents selected from the group
consisting of OR.sup.9, NR.sup.9R.sup.10,
NR.sup.9R.sup.11R.sup.12A.sup.-- , SR.sup.9, S(O) R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.3R.sup.9, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17, and C(O)OM,
wherein in R.sup.x, one or more carbons are optionally replaced by
O, NR.sup.13 N.sup.+R.sup.13R.sup.14A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.13A.sup.-, PR.sup.13, P(O)R.sup.13,
P.sup.+R.sup.13R.sup.14A- .sup.-, phenylene, amino acid, peptide,
polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said
polyalkyl, phenylene, amino acid, peptide, polypeptide, and
carbohydrate, one or more carbons are optionally replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, PR.sup.9, P.sup.+R.sup.9R.sup.10A.sup.-, or
P(O)R.sup.9; wherein quaternary heterocycle and quaternary
heteroaryl are optionally substituted with one or more groups
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, halogen, oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, SO.sub.3R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14- ,
C(O)NR.sup.13R.sup.14, C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- .
302. The process of claim 301 wherein the cyclic sulfate has the
formula: 559and the thiophenol has the formula: 560wherein R.sup.1,
R.sup.2, R.sup.5, R.sup.x and q are as defined in claim 301.
303. The process of claim 301 wherein the sulfate group is removed
by treating the intermediate with a hydrolyzing agent.
304. The process of claim 303 wherein the hydrolyzing agent is a
mineral acid.
305. The process of claim 303 wherein the hydrolyzing agent is
selected from the group consisting of hydrochloric acid and
sulfuric acid.
306. The process of claim 302 wherein the abstracting agent is a
base having a pH of at least about 10.
307. The process of claim 302 wherein the abstracting agent is an
alkali metal hydride.
308. The process of claim 302 wherein the abstracting agent is
sodium hydride.
309. The process of claim 302 wherein the R.sup.1 and R.sup.2 are
alkyl.
310. The process of claim 302 wherein the R.sup.1 and R.sup.2 are
selected from the group consisting of ethyl, n-butyl, iso-butyl and
pentyl.
311. The process of claim 302 wherein the R.sup.1 and
312.l A process for the preparation of a compound having the
formula I: 561comprising: reacting a cyclic sulfate with a
thiophenol to form an alcohol; oxidizing said alcohol to form a
sulfone-aldehyde; and cyclizing said sulfone-aldehyde to form the
compound of formula I; wherein: q is an integer from 1 to 4; n is
2; R.sup.1 and R.sup.2 are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl,
arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,
(polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl,
haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino,
alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are
substituted with one or more substituents selected from the group
consisting of OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.10R.sup.wA.- sup.-, SR.sup.9,
S.sup.+R.sup.9R.sup.10A.sup.-, P.sup.+R.sup.9R.sup.10R.su-
p.1A.sup.-, S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9,
CO.sub.2R.sup.9, CN, halogen, oxo, and CONR.sup.9R.sup.10, wherein
alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl,
(polyalkyl)aryl, and cycloalkyl optionally have one or more carbons
replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.10A.sup.-, S, SO,
SO.sub.2, S.sup.+R.sup.9A.sup.-, P.sup.+R.sup.9R.sup.10A.sup.-, or
phenylene, wherein R.sup.9, R.sup.10, and R.sup.w are independently
selected from the group consisting of H, alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl,
carboxyalkyl, carboxyheteroaryl, carboxyheterocycle,
carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl,
heterocyclylalkyl, and alkylammoniumalkyl; or R.sup.1 and R.sup.2
taken together with the carbon to which they are attached form
C.sub.3-C.sub.10 cycloalkyl; R.sup.3 is hydroxy; R.sup.4 is
hydrogen; R.sup.5 and R.sup.6 are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycle, quaternary heterocycle, OR.sup.30, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, and SO.sub.3R.sup.9, wherein alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary
heterocycle, and quaternary heteroaryl can be substituted with one
or more substituent groups independently selected from the group
consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary
heterocycle, quaternary heteroaryl, halogen, oxo, OR.sup.13,
NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13,
SO.sub.3R.sup.13, NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15,
NO.sub.2, CO.sub.2R.sup.13, CN, OM, SO.sub.2OM,
SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14, C(O)OM,
COR.sup.13, NR.sup.13C(O)R.sup.14, NR.sup.13C(O)NR.sup.14R.sup.15,
NR.sup.13CO.sub.2R.sup.14, OC(O)R.sup.13, OC(O)NR.sup.13R.sup.14,
NR.sup.13SOR.sup.14, NR.sup.13SO.sub.2R.sup.14,
NR.sup.13SONR.sup.14R.sup.15, NR.sup.13SO.sub.2NR.sup.14R.sup.15,
P(O)R.sup.13R.sup.14, P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-,
P(OR.sup.13)OR.sup.14, S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, wherein: A.sup.- is a
pharmaceutically acceptable anion and M is a pharmaceutically
acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be
further substituted with one or more substituent groups selected
from the group consisting of OR.sup.7, NR.sup.7R.sup.8, SR.sup.7,
S(O)R.sup.7, SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN,
oxo, CONR.sup.7R.sup.8, N.sup.+R.sup.7R.sup.8R.sup.9A-, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl,
quaternary heterocycle, quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, and P(C)(OR.sup.7)OR.sup.8,
and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have
one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A-, S, SO, SO.sub.2, S.sup.+R.sup.7A-,
PR.sup.7, P(O)R.sup.7, P.sup.+R.sup.7R.sup.8A-, or phenylene, and
R.sup.13, R.sup.14, and R.sup.15 are independently selected from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl,
alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl,
heterocycle, heteroaryl, quaternary heterocycle, quaternary
heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl,
and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl,
alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one
or more carbons replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.10A-,
S, SO, SO.sub.2, S.sup.+R.sup.9A.sup.-, PR.sup.9,
P.sup.+R.sup.9R.sup.10A-, P(O)R.sup.9, phenylene, carbohydrate,
amino acid, peptide, or polypeptide, and R.sup.13, R.sup.14, and
R.sup.15 are optionally substituted with one or more groups
selected from the group consisting of hydroxy, amino, sulfo,
carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl,
quaternary heterocycle, quaternary heteroaryl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR
.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9, R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.10R.sup.11A-, S.sup.+R.sup.9R.sup.10A-, and
C(O)OM, wherein R.sup.16 and R.sup.17 are independently selected
from the substituents constituting R.sup.9 and M; or R.sup.13 and
R.sup.14, together with the nitrogen atom to which they are
attached form a mono-, or polycyclic heterocycle that is optionally
substituted with one or more radicals selected from the group
consisting of oxo, carboxy and quaternary salts; or R.sup.14 and
R.sup.15, together with the nitrogen atom to which they are
attached, form a cyclic ring; and R.sup.30 is selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl,
carboxyalkyl, carboxyheteroaryl, carboxyheterocycle,
carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl,
heterocyclylalkyl, and alkylammoniumalkyl; and R.sup.7 and R.sup.8
are hydrogen; and one or more R.sup.x are independently selected
from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl,
acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl,
heterocycle, heteroaryl, polyether, quaternary heterocycle,
quaternary heteroaryl, OR.sup.3, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, S(O).sub.2R.sup.13, SO.sub.3R.sup.13,
S.sup.+R.sup.13R.sup.14A.sup.-, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13 , CN, OM,,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, NR.sup.14C(O)R.sup.13,
C(O)NR.sup.13R.sup.14, NR.sup.14C(O)R.sup.13, C(C)OM, COR.sup.13,
OR.sup.18, S(O).sub.nNR.sup.18, NR.sup.13R.sup.18,
NR.sup.18OR.sup.14, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.11R.sup.12A.su- p.-, amino acid, peptide,
polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl,
haloalkyl, polyether, quaternary heterocycle, and quaternary
heteroaryl can be further substituted with OR.sup.9,
NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.11R.sup.12A, S.sup.+R.sup.9R.sup.10A.sup.-, or
C(O)OM, and wherein R.sup.18 is selected from the group consisting
of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl,
and alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl,
heterocycle, heteroaryl, alkyl, quaternary heterocycle, and
quaternary heteroaryl optionally are substituted with one or more
substituents selected from the group consisting of OR.sup.9,
NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.3R.sup.9,
SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17, and
C(O)OM, wherein in R.sup.x, one or more carbons are optionally
replaced by O, NR.sup.13, N.sup.+R.sup.13R.sup.14A.sup.-, S, SO,
SO.sub.2, S.sup.+R.sup.13A.sup.-, PR.sup.13, P(O)R.sup.13,
P.sup.+R.sup.13R.sup.14A.sup.-, phenylene, amino acid, peptide,
polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said
polyalkyl, phenylene, amino acid, peptide, polypeptide, and
carbohydrate, one or more carbons are optionally replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, PR.sup.9, P.sup.+R.sup.9R.sup.10A.sup.-, or
P(O)R.sup.9; wherein quaternary heterocycle and quaternary
heteroaryl are optionally substituted with one or more groups
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, halogen, oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14- ,
C(O)NR.sup.13R.sup.14, C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- .
313. The process of claim 312 wherein the cyclic sulfate has the
formula: 562and the thiophenol has the formula: 563wherein R.sup.1,
R.sup.2, R.sup.5, R.sup.x and q are as defined in claim 312.
314. The process of claim 313 wherein the R.sup.1 and R.sup.2 are
alkyl.
315. The process of claim 313 wherein the R.sup.1 and R.sup.2 are
selected from the group consisting of ethyl, n-butyl, iso-butyl and
pentyl.
316. The process of claim 313 wherein the R.sup.1 and R.sup.2 are
n-butyl.
317. The process of claim 313 wherein the alcohol is oxidized with
an oxidizing agent to form an aldehyde.
318. The process of claim 317 wherein the aldehyde is oxidized with
an oxidizing agent to form a sulfone-aldehyde.
319. The process of claim 313 wherein the sulfone-aldehyde is
cyclized with a cyclizing agent that is a base having a pH between
about 8 to about 9.
320. The process of claim 313 wherein the sulfone-aldehyde is
cyclized with a cyclizing agent that is an alkali alkoxide
base.
321. The process of claim 313 wherein the sulfone-aldehyde is
cyclized with potassium tert-butoxide.
322. The process of claim 313 wherein the alcohol is oxidized with
pyridinium chlorochromate to form an aldehyde; the aldehyde is
oxidized with metachloroperbenzoic acid to form a sulfone-aldehyde;
and the sulfone-aldehyde is cyclized with potassium
tert-butoxide.
323. A process for the preparation of a compound having the formula
LI: 564comprising: treating a halobenzene with an abstracting
agent; coupling the halobenzene and a cyclic sulfate to form an
intermediate comprising a sulfate group; and removing the sulfate
group of the intermediate to form the compound of formula LI;
wherein q is an integer from 1 to 4; R.sup.1 and R.sup.2 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy,
alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and
cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl,
arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,
(polyalkyl)aryl, and cycloalkyl optionally are substituted with one
or more substituents selected from the group consisting of
OR.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.10R.sup.wA.sup.-,
SR.sup.9, S.sup.+R.sup.9R.sup.10A.s- up.-,
P.sup.+R.sup.9R.sup.10R.sup.11A.sup.-, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10, wherein alkyl, alkenyl, alkynyl,
alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl
optionally have one or more carbons replaced by O, NR.sup.9,
N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, P.sup.+R.sup.9R.sup.10A.sup.-, or phenylene,
wherein R.sup.9, R10, and R.sup.w are independently selected from
the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl,
carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,
carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and
alkylammoniumalkyl; or R.sup.1 and R.sup.2 taken together with the
carbon to which they are attached form C.sub.3-C.sub.10 cycloalkyl;
R.sup.3 is hydroxy; R.sup.4 is hydrogen; R.sup.5 and R.sup.6 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary
heterocycle, OR.sup.30, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, and
SO.sub.3R.sup.9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycle, quaternary heterocycle, and quaternary heteroaryl can
be substituted with one or more substituent groups independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen,
oxo, OR.sup.13, NR.sup.13R.sup.14, S(O)R.sup.13, SO.sub.2R.sup.13,
SO.sub.3R.sup.13, NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15,
NO.sub.2, CO.sub.2R.sup.13, CN, OM, SO.sub.2OM,
SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14, C(O)OM,
COR.sup.13, NR.sup.13C(O)R.sup.14, NR.sup.13C(O)NR.sup.14R.sup.15,
NR.sup.13CO.sub.2R.sup.14, OC(O)R.sup.13.sub.1,
OC(O)NR.sup.13R.sup.14, NR.sup.13SOR.sup.14,
NR.sup.13SO.sub.2R.sup.14, NR.sup.13SONR.sup.14R.sup- .15,
NR.sup.13SO.sup.2NR.sup.14R.sup.15, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.31)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- , wherein: A.sup.- is a
pharmaceutically acceptable anion and M is a pharmaceutically
acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be
further substituted with one or more substituent groups selected
from the group consisting of OR.sup.7, NR.sup.7R.sup.8, SR.sup.7,
S(O)R.sup.7, SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN,
oxo, CONR.sup.7R.sup.8, N.sup.+R.sup.7R.sup.8R.sup.9A-, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl,
quaternary heterocycle, quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, and P(O)(OR.sup.7)OR.sup.8,
and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have
one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A-, S, SO, SO.sub.2, S.sup.+R.sup.7A-,
PR.sup.7, P(O)R.sup.7, P.sup.+R.sup.7R.sup.8A-, or phenylene, and
R.sup.13, R.sup.14, and R.sup.15 are independently selected from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl,
alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl,
heterocycle, heteroaryl, quaternary heterocycle, quaternary
heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl,
and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl,
alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one
or more carbons replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.10A-,
S, SO, SO.sub.2, S.sup.+R.sup.9A.sup.-, PR.sup.9,
P.sup.+R.sup.9R.sup.10A-, P(O)R.sup.9, phenylene, carbohydrate,
amino acid, peptide, or polypeptide, and R.sup.13, R.sup.14, and
R.sup.15 are optionally substituted with one or more groups
selected from the group consisting of hydroxy, amino, sulfo,
carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl,
quaternary heterocycle, quaternary heteroaryl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR
.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.10R.sup.11A-, S.sup.+R.sup.9R.sup.10A-, and
C(O)OM, wherein R.sup.16 and R.sup.17 are independently selected
from the substituents constituting R9 and M; or R.sup.13 and
R.sup.14, together with the nitrogen atom to which they are
attached form a mono- or polycyclic heterocycle that is optionally
substituted with one or more radicals selected from the group
consisting of oxo, carboxy and quaternary salts; or R.sup.14 and
R.sup.15, together with the nitrogen atom to which they are
attached, form a cyclic ring; and R.sup.30 is selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl,
carboxyalkyl, carboxyheteroaryl, carboxyheterocycle,
carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl,
heterocyclylalkyl, and alkylammoniumalkyl; and R.sup.7 and R.sup.8
are hydrogen; and one or more R.sup.x are independently selected
from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl,
acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl,
heterocycle, heteroaryl, polyether, quaternary heterocycle,
quaternary heteroaryl, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, S(O).sub.2R.sup.13, SO.sub.3R.sup.13,
S.sup.+R.sup.13R.sup.14A.sup.-, NR.sup.13R.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, NR.sup.14C(O)R.sup.13,
C(O)NR.sup.13R.sup.14, NR.sup.14C(O)R.sup.13, C(O)OM, COR.sup.13,
OR.sup.18, S(O).sub.nNR.sup.18, NR.sup.13R.sup.18,
NR.sup.18OR.sup.14, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.11R.sup.12A.su- p.-, amino acid, peptide,
polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl,
haloalkyl, polyether, quaternary heterocycle, and quaternary
heteroaryl can be further substituted with OR.sup.9,
NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9,
S(O)R.sup.9, SO.sub.2R, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CQNR.sup.9R.sup.10R, SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein R.sup.18 is
selected from the group consisting of acyl, arylalkoxycarbonyl,
arylalkyl, heterocycle, heteroaryl, and alkyl, wherein acyl,
arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,
quaternary heterocycle, and quaternary heteroaryl optionally are
substituted with one or more substituents selected from the group
consisting of OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A- .sup.-, SR.sup.9, S(O)R.sup.9,
SC.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SC.sub.3R.sup.9, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17 and C(O)OM,
wherein in R.sup.x, one or more carbons are optionally replaced by
O, NR.sup.13, N.sup.+R.sup.13R.sup.14A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.13A.sup.-, PR.sup.13, P(O)R.sup.13,
P.sup.+R.sup.13R.sup.14A- .sup.-, phenylene, amino acid, peptide,
polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said
polyalkyl, phenylene, amino acid, peptide, polypeptide, and
carbohydrate, one or more carbons are optionally replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, PR.sup.9, P.sup.+R.sup.9R.sup.10A.sup.-, or
P(O)R.sup.9; wherein quaternary heterocycle and quaternary
heteroaryl are optionally substituted with one or more groups
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, halogen, oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14- ,
C(O)NR.sup.13R.sup.14, C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- ; and R.sup.e is an
electron-withdrawing group located at the para or ortho
position.
324. The process of claim 323 wherein the cyclic sulfate has the
formula: 565and the halobenzene has the formula: 566wherein R.sup.h
is halogen, and R.sup.1, R.sup.2, R.sup.3, R.sup.x, R.sup.e and q
are as defined in claim 323.
325. The process of claim 324 wherein the sulfate group is removed
by treating the intermediate with a hydrolyzing agent.
326. The process of claim 325 wherein the hydrolyzing agent is a
mineral acid.
327. The process of claim 325 wherein the hydrolyzing agent is
selected from the group consisting of hydrochloric acid and
sulfuric acid.
328. The process of claim 324 wherein the abstracting agent is a
dialkali metal sulfide.
329. The process of claim 324 wherein the abstracting agent is
dilithium sulfide.
330. The process of claim 324 wherein R.sup.1 and R.sup.2 are
alkyl.
331. The process of claim 324 wherein R.sup.1 and R.sup.2 are
selected from the group consisting of ethyl, n-butyl, iso-butyl and
pentyl.
332. The process of claim 324 wherein R.sup.1 and R.sup.2 are
n-butyl.
333. The process of claim 324 wherein R.sup.h is chloro.
334. The process of claim 324 wherein R.sup.e is p-nitro.
335. A process for the preparation of a compound having the formula
I: 567comprising: reacting a cyclic sulfate with a halobenzene to
form an alcohol; oxidizing said alcohol to form a sulfone-aldehyde;
and cyclizing said sulfone-aldehyde to form the compound of formula
I; wherein q is an integer from 1 to 4; n is 2; R.sup.1 and R.sup.2
are independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy,
alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and
cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl,
arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,
(polyalkyl)aryl, and cycloalkyl optionally are substituted with one
or more substituents selected from the group consisting of
OR.sup.9, NR.sup.9R.sup.10, NR.sup.9R.sup.10R.sup.wA.sup.-,
SR.sup.9, S.sup.+R.sup.9R.sup.10A.sup.-,
P.sup.+R.sup.9R.sup.10R.sup.11A.- sup.-, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10, wherein alkyl, alkenyl, alkynyl,
alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl
optionally have one or more carbons replaced by O, NR.sup.9,
NR.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2, S.sup.+R.sup.9A.sup.-,
P.sup.+R.sup.9R.sup.10A.sup.-, or phenylene, wherein R.sup.9,
R.sup.10, and R.sup.w are independently selected from the group
consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,
heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl,
carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl,
carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and
alkylammoniumalkyl; or R.sup.1 and R.sup.2 taken together with the
carbon to which they are attached form C.sub.3-C.sub.10 cycloalkyl;
R.sub.3 is hydroxy; R.sup.4 is hydrogen; R.sup.5 and R.sup.6 are
independently selected from the group consisting of H, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary
heterocycle, OR.sup.30, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, and
SO.sub.3R.sup.9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycle, quaternary heterocycle, and quaternary heteroaryl can
be substituted with one or more substituent groups independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen,
oxo, OR.sup.9, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, SO.sub.3R.sup.13, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14,
C(O)OM, COR.sup.13, NR.sup.13C(O)R.sup.14,
NR.sup.13C(O)NR.sup.14R.sub.15, NR.sup.13CO.sub.2R.sup.14,
OC(O)R.sup.13, OC(O)NR.sup.13R.sup.14, NR.sup.13SOR.sup.14,
NR.sup.13SO.sub.2R.sup.14, NR.sup.13SONR.sup.14R.sup.15,
NR.sup.13SO.sub.2NR.sup.14R.sup.15, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, wherein: A.sup.- is a
pharmaceutically acceptable anion and M is a pharmaceutically
acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be
further substituted with one or more substituent groups selected
from the group consisting of OR.sup.7, NR.sup.7R.sup.8, SR.sup.7,
S(O)R.sup.7, SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN,
oxo, CONR.sup.7R.sup.8, N.sup.+R.sup.7R.sup.8R.sup.9A-, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl,
quaternary heterocycle, quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, and P(O)(OR.sup.7)OR.sup.8,
and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have
one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A-, S, SO, SO.sub.2, S.sup.+R.sup.7A-,
PR.sup.7, P(O)R.sup.7, P.sup.+R.sup.7R.sup.8A-, or phenylene, and
R.sup.13, R.sup.14, and R.sup.15 are independently selected from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl,
alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl,
heterocycle, heteroaryl, quaternary heterocycle, quaternary
heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl,
and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl,
alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one
or more carbons replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.10A-,
S, SO, SO.sub.2, S.sup.+R.sup.9A.sup.-, PR.sup.9,
P.sup.+R.sup.9R.sup.10A-, P(O)R.sup.9, phenylene, carbohydrate,
amino acid, peptide, or polypeptide, and R.sup.13, R.sup.14, and
R.sup.15 are optionally substituted with one or more groups
selected from the group consisting of hydroxy, amino, sulfo,
carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl,
quaternary heterocycle, quaternary heteroaryl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl,
OR.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.10R- .sup.11A-, S.sup.+R.sup.9R.sup.10A-, and
C(O)OM, wherein R.sup.16 and R.sup.17 are independently selected
from the substituents constituting R.sup.9 and M; or R.sup.13 and
R.sup.14, together with the nitrogen atom to which they are
attached form a mono- or polycyclic heterocycle that is optionally
substituted with one or more radicals selected from the group
consisting of oxo, carboxy and quaternary salts; or R.sup.14 and
R.sup.15, together with the nitrogen atom to which they are
attached, form a cyclic ring; and R.sup.30 is selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl,
carboxyalkyl, carboxyheteroaryl, carboxyheterocycle,
carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl,
heterocyclylalkyl, and alkylammoniumalkyl; and R.sup.7 and R.sup.8
are hydrogen; and one or more R.sup.x are independently selected
from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl,
acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl,
heterocycle, heteroaryl, polyether, quaternary heterocycle,
quaternary heteroaryl, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13,
S(O)R.sup.13, S(O).sub.2R.sup.13, SO.sub.3R.sup.13,
S.sup.+R.sup.13R.sup.14A.sup.-, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, C.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, NR.sup.14C(O)R.sup.13,
C(O)NR.sup.13R.sup.14, NR.sup.14C(O)R.sup.13, C(O)OM, COR.sup.13,
OR.sup.18, S(O).sub.nNR.sup.18, NR.sup.13R.sup.18,
NR.sup.18OR.sup.14, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.11R.sup.12A.su- p.-, amino acid, peptide,
polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl,
haloalkyl, polyether, quaternary heterocycle, and quaternary
heteroaryl can be further substituted with OR.sup.9,
NR.sup.9R.sup.10, NR.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and wherein R.sup.18 is
selected from the group consisting of acyl, arylalkoxycarbonyl,
arylalkyl, heterocycle, heteroaryl, and alkyl, wherein acyl,
arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,
quaternary heterocycle, and quaternary heteroaryl optionally are
substituted with one or more substituents selected from the group
consisting of OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A- .sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.3R.sup.9, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17, and C(O)OM,
wherein in R.sup.x, one or more carbons are optionally replaced by
O, NR.sup.13, N.sup.+R.sup.13R.sup.14A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.13A.sup.-, PR.sup.13, P(O)R.sup.13,
P.sup.+R.sup.13R.sup.14A- .sup.-, phenylene, amino acid, peptide,
polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said
polyalkyl, phenylene, amino acid, peptide, polypeptide, and
carbohydrate, one or more carbons are optionally replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, PR.sup.9, P.sup.+R.sup.9R.sup.10A.sup.-, or
P(O)R.sup.9; wherein quaternary heterocycle and quaternary
heteroaryl are optionally substituted with one or more groups
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, halogen, oxo, OR.sup.13, NR .sup.3R.sup.14, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, SO.sub.3R.sup.13,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14- ,
C(O)NR.sup.13R.sup.14, C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- ; and R.sup.e is an
electron-withdrawing group located at the para or ortho
position.
336. The process of claim 335 wherein the cyclic sulfate has the
formula: 568and the halobenzene has the formula: 569wherein
R.sup.1, R.sup.2, R.sup.5, R.sup.x and R.sup.e are as defined in
claim 335, and R.sup.h is halogen.
337. The process of claim 336 wherein the sulfate group is removed
by treating the intermediate with a hydrolyzing agent.
338. The process of claim 337 wherein the hydrolyzing agent is a
mineral acid.
339. The process of claim 336 wherein the hydrolyzing agent is
selected from the group consisting of hydrochloric acid and
sulfuric acid.
340. The process of claim 336 wherein the abstracting agent is a
dialkali metal sulfide.
341. The process of claim 336 wherein the abstracting agent is
dilithium sulfide.
342. The process of claim 336 wherein R.sup.1 and R.sup.2 are
alkyl.
343. The process of claim 336 wherein R.sup.1 and R.sup.2 are
selected from the group consisting of ethyl, n-butyl, iso-butyl and
pentyl.
344. The process of claim 336 wherein R.sup.1 and R.sup.2 are
n-butyl.
345. The process of claim 336 wherein R.sup.h is chloro.
346. The process of claim 336 wherein R.sup.e is p-nitro.
347. The process of claim 336 wherein the alcohol is oxidized with
an oxidizing agent to form a sulfone.
348. The process of claim 336 wherein the sulfone is oxidized with
an oxidizing agent to form a sulfone-aldehyde.
349. The process of claim 336 wherein the sulfone-aldehyde is
cyclized with a cyclizing agent that is a base having a pH between
about 8 to about 9.
350. The process of claim 336 wherein the sulfone-aldehyde is
cyclized with a cyclizing agent that is an alkali alkoxide
base.
351. The process of claim 336 wherein the sulfone-aldehyde is
cyclized with potassium tert-butoxide.
352. The process of claim 336 wherein the alcohol is oxidized with
metachloroperbenzoic acid to form a sulfone; the aldehyde is
oxidized with pyridinium chlorochromate to form a sulfone-aldehyde;
and the sulfone-aldehyde is cyclized with potassium tert-butoxide.
Description
[0001] This application is a continuation-in-part application of
U.S. application Ser. No. 09/816,065, filed Mar. 11, 1997, which
claims the benefit of priority of U.S. Provisional Application
Serial No. 60/013,119, filed Mar. 11, 1996. This application is
also a continuation-in-part application of U.S. application Ser.
No. 09/831,284, filed Mar. 31, 1997, which is a continuation of
U.S. application Ser. No. 08/517,051, filed Aug. 21, 1995, which is
a continuation-in-part application of U.S. application Ser. No.
08/305,526, filed Sep. 12, 1994. This is application also claims
priority from U.S. Provisional Application Serial No. 60/068,170
filed Dec. 19, 1997.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to novel benzothiepines,
derivatives and analogs thereof, pharmaceutical compositions
containing them, and their use in medicine, particularly in the
prophylaxis and treatment of hyperlipidemic conditions such as is
associated with atherosclerosis or hypercholesterolemia, in
mammals.
[0004] 2. Description of Related Art
[0005] It is well-settled that hyperlipidemic conditions associated
with elevated concentrations of total cholesterol and low-density
lipoprotein cholesterol are major. risk factors for coronary heart
disease and particularly atherosclerosis. Interfering with the
circulation of bile acids within the lumen of the intestinal tract
is found to reduce the levels of serum cholesterol in a causal
relationship. Epidemiological data has accumulated which indicates
such reduction leads to an improvement in the disease state of
atherosclerosis. Stedronsky, in "Interaction of bile acids and
cholesterol with nonsystemic agents having hypocholesterolemic
properties," Biochimica et Biophysica Acta, 1210 (1994) 255-287
discusses the biochemistry, physiology and known active agents
surrounding bile acids and cholesterol.
[0006] Pathophysiologic alterations are shown to be consistent with
interruption of the enterohepatic circulation of bile acids in
humans by Heubi, J. E., et al. See "Primary Bile Acid
Malabsorption: Defective in Vitro Ileal Active Bile Acid
Transport", Gastroenterology, 1982:83:804-11.
[0007] In fact, cholestyramine binds the bile acids in the
intestinal tract, thereby interfering with their normal
enterohepatic circulation (Reihner, E. et al, in "Regulation of
hepatic cholesterol metabolism in humans: stimulatory effects of
cholestyramine on HMG-CoA reductase activity and low density
lipoprotein receptor expression in gallstone patients", Journal of
Lipid Research, Volume 31, 1990, 2219-2226 and Suckling el al,
"Cholesterol Lowering and bile acid excretion in the hamster with
cholestyramine treatment", Atherosclerosis, 89(1991) 183-190). This
results in an increase in liver bile acid synthesis by the liver
using cholesterol as well as an upregulation of the liver LDL
receptors which enhances clearance of cholesterol and decreases
serum LDL cholesterol levels.
[0008] In another approach to the reduction of recirculation of
bile acids, the ileal bile acid transport system is a putative
pharmaceutical target for the treatment of hypercholesterolemia
based on an interruption of the enterohepatic circulation with
specific transport inhibitors (Kramer, et al, "Intestinal Bile Acid
Absorption" The Journal of Biological Chemistry, Vol. 268, No. 24,
Issue of Aug. 25, pp. 18035-18046, 1993).
[0009] In a series of patent applications, eg Canadian Patent
Application Nos. 2,025,294; 2,078,588; 2,085,782; and 2,085,830;
and EP Application Nos. 0 379 161; 0 549 967; 0 559 064; and 0 563
731, Hoechst Aktiengesellschaft discloses polymers of various
naturally occurring constituents of the enterohepatic circulation
system and their derivatives, including bile acid, which inhibit
the physiological bile acid transport with the goal of reducing the
LDL cholesterol level sufficiently to be effective as
pharmaceuticals and, in particular for use as hypocholesterolemic
agents.
[0010] In vitro bile acid transportinhibition is disclosed to show
hypolipidemic activity in The Wellcome Foundation Limited
disclosure of the world patent application number WO 93/16055 for
"Hypolipidemic Benzothiazepine Compounds" Selected benzothiepines
are disclosed in world patent application number WO93/321146 for
numerous uses including fatty acid metabolism and coronary vascular
diseases.
[0011] Other selected benzothiepines are known for use as
hypolipaemic and hypocholesterolaemic agents, especially for the
treatment or prevention of atherosclerosis as disclosed by
application Nos. EP 508425, FR 2661676, and WO 92/18462, each of
which is limited by an amide bonded to the carbon adjacent the
phenyl ring of the fused bicyclo benzothiepine ring.
[0012] The above references show continuing efforts to find safe,
effective agents for the prophylaxis and treatment of
hyperlipidemic diseases and their usefulness as hypocholesterolemic
agents.
[0013] Additionally selected benzothiepines are disclosed for use
in various disease states not within the present invention utility.
These are EP 568 898A as abstracted by Derwent Abstract No.
93-351589; WO 89/1477/A as abstracted in Derwent Abstract No.
89-370688; U.S. Pat. No. 3,520,891 abstracted in Derwent 50701R-B;
U.S. Pat. No. 3,287,370, U.S. Pat. No. 3,389,144; U.S. Pat. No.
3,694,446 abstracted in Derwent Abstr. No. 65860T-B and WO
92/18462.
[0014] The present invention furthers such efforts by providing
novel benzothiepines, pharmaceutical compositions, and methods of
use therefor.
SUMMARY OF THE INVENTION
[0015] Accordingly, among its various apects, the present invention
provides compounds of formula (I): 1
[0016] wherein:
[0017] q is an integer from 1 to 4;
[0018] n is an integer from 0 to 2;
[0019] R.sup.1 and R.sup.2 are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl,
alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,
(polyalkyl)aryl, and cycloalkyl,
[0020] wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl,
arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,
(polyalkyl)aryl, and cycloalkyl optionally are substituted with one
or more substituents selected from the group consisting of
OR.sup.9, NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.10R.sup.2A.sup.-,
SR.sup.9, S.sup.+R.sup.9R.sup.10A.s- up.-.
P.sup.+R.sup.9R.sup.10R.sup.11A.sup.-, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10,
[0021] wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy,
alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or
more carbons replaced by O, NR.sup.9,
N.sup.+R.sup.9R.sup.10A.sup.-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, P.sup.+R.sup.9R.sup.10A.sup.-, or
phenylene,
[0022] wherein R.sup.9, R.sup.10, and R.sup.w are independently
selected from the group consisting of H, alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl,
carboxyalkyl, carboxyheteroaryl, carboxyheterocycle,
carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl,
heterocyclylalkyl, and alkylammoniumalkyl; or
[0023] R.sup.1 and R.sup.2 taken together with the carbon to which
they are attached form C.sub.3-C.sub.10 cycloalkyl;
[0024] R.sup.3 and R.sup.4 are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl,
heterocycle, OR.sup.9, NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, and SO.sub.3R.sup.9, wherein R.sup.9 and R.sup.10
are as defined above; or
[0025] R.sup.3 and R.sup.4 together form .dbd.O, .dbd.NOR.sup.11,
.dbd.S, .dbd.NNR.sup.11R.sup.12, .dbd.NR.sup.9, or
.dbd.CR.sup.11R.sup.12.sub.12,
[0026] wherein R.sup.11 and R.sup.12 are independently selected
from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,
arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl,
carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR.sup.9,
NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9,
SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen, oxo, and
CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10 are as defined
above, provided that both R.sup.3 and R.sup.4 cannot be OH,
NH.sub.2, and SH, or
[0027] R.sup.11 and R.sup.12 together with the nitrogen or carbon
atom to which they are attached form a cyclic ring;
[0028] R.sup.5 and R.sup.6 are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycle, quaternary heterocycle, OR.sup.9, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, and SO.sub.3R.sup.9,
[0029] wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycle, quaternary heterocycle, and quaternary heteroaryl can
be substituted with one or more substituent groups independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen,
oxo, OR.sup.13, NR.sup.13R.sup.14 SR.sup.13 S(O)R.sup.13,
SO.sub.2R.sup.13, SO.sub.3R.sup.13, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14,
C(O)OM, CR.sup.13, NR.sup.13C(O)R.sup.14,
NR.sup.13C(O)NR.sup.14R.sup.15, NR.sup.13CO.sub.2R.sup.14,
OC(O)R.sup.13, OC(O)NR.sup.13R.sup.14, NR.sup.13SOR.sup.14,
NR.sup.13SO.sub.2R.sup.14, NR.sup.13SONR.sup.14R.sup.15,
N.sup.13SO.sub.2NR.sup.14R.sup.15,P(O)R.sup- .13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
[0030] wherein:
[0031] A.sup.- is a pharmaceutically acceptable anion and M is a
pharmaceutically acceptable cation,
[0032] said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
haloalkyl, cycloalkyl, and heterocycle can be further substituted
with one or more substituent groups selected from the group
consisting of OR.sup.7, NR.sup.7R.sup.8, SR.sup.7, S(O)R.sup.7,
SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN, oxo,
CONR.sup.7R.sup.8, N.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl,
quaternary heterocycle, quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8R.sup.9A.sup.- and P(O) (OR.sup.7)OR.sup.8,
and
[0033] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have
one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A.sup.-, S, SO, SO.sub.2, S.sup.+R.sup.7A-,
PR.sup.7, P(O)R.sup.7, P.sup.+R.sup.7R.sup.8A-, or phenylene, and
R.sup.13, R.sup.14, and R.sup.15 are independently selected from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl,
alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl,
heterocycle, heteroaryl, quaternary heterocycle, quaternary
heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl,
and carboxyalkylaminocarbonylalkyl,
[0034] wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and
polyalkyl optionally have one or more carbons replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-,
P(O)R.sup.9, phenylene, carbohydrate, amino acid, peptide, or
polypeptide, and
[0035] R.sup.13, R.sup.14, and R.sup.15 are optionally substituted
with one or more groups selected from the group consisting of
hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle,
heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary
heteroaryl, quaternary heterocyclylalkyl, quaternary
heteroarylalkyl, guanidinyl, OR , NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.10R.sup.11A-,
S.sup.+R.sup.9R.sup.10A-, and C(O)OM,
[0036] wherein R.sup.16 and R.sup.17 are independently selected
from the substituents constituting R.sup.9 and M; or
[0037] R.sup.13 and R.sup.14, together with the nitrogen atom to
which they are attached form a mono- or polycyclic heterocycle that
is optionally substituted with one or more radicals selected from
the group consisting of oxo, carboxy and quaternary salts; or
[0038] R.sup.14 and R.sup.15, together with the nitrogen atom to
which they are attached, form a cyclic ring; and
[0039] R.sup.7 and R.sup.8 are independently selected from the
group consisting of hydrogen and alkyl; and
[0040] one or more R.sup.x are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy,
aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle,
heteroaryl, polyether, quaternary heterocycle, quaternary
heteroaryl, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13 S(O)R.sup.13,
S(O).sup.2R.sup.13, SO.sub.3R.sup.13, S.sup.+R.sup.13R.sup.14 A-,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14,
NR.sup.14C(O)R.sup.13, C(O)NR.sup.13R.sup.14,
NR.sup.14C(O)R.sup.13, C(O)OM, COR.sup.13, OR.sup.18,
S(O).sub.nNR.sup.18, NR.sup.13R.sup.18, NR.sup.18OR.sup.14,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.11R.sup.12A.su- p.-, amino acid, peptide,
polypeptide, and carbohydrate,
[0041] wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether,
quaternary heterocycle, and quaternary heteroaryl can be further
substituted with OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.11R- .sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and
[0042] wherein R.sup.18 is selected from the group consisting of
acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl,
alkyl,
[0043] wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle,
heteroaryl, alkyl, quaternary heterocycle, and quaternary
heteroaryl optionally are substituted is with one or more
substituents selected from the group consisting of OR.sup.9,
NR.sup.9R.sup.10, N.sup.+, R.sup.9R.sup.11R.sup.12A.sup.-,
SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.3R.sup.9,
SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17, and
CO()OM,
[0044] wherein in R.sup.x, one or more carbons are optionally
replaced by O, NR.sup.13, N.sup.+R.sup.13R.sup.14A-, S, SO,
SO.sub.2, S.sup.+R.sup.13A.sup.-, PR.sup.13, P(O)R.sup.13,
P.sup.+R.sup.13R.sup.14A- -, phenylene, amino acid, peptide,
polypeptide, carbohydrate, polyether, or polyalkyl,
[0045] wherein in said polyalkyl, phenylene, amino acid, peptide,
polypeptide, and carbohydrate, one or more carbons are optionally
replaced by 0, NR 9, N R9R10 A, S, SO, SO.sub.2, S.sup.+R.sup.9A-,
PR.sup.9, P.sup.+R.sup.9R.sup.10A-, or P(O)R.sup.9;
[0046] wherein quaternary heterocycle and quaternary heteroaryl are
optionally substituted with one or more groups selected from the
group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo,
OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13, SO.sub.2R,
SO.sub.3R.sup.13, NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15,
NO.sub.2, CO.sub.2R.sup.13, CN, OM, SO.sub.2OM,
SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14, C(O)OM,
COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- ,
[0047] provided that both R.sup.5 and R.sup.6 cannot be hydrogen,
OH, or SH and when R.sup.5 is OH, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.7 and R.sup.8 cannot be all hydrogen;
[0048] provided that when R.sup.5 or R.sup.6 is phenyl, only one of
R.sup.1 or R.sup.2 is H;
[0049] provided that when q=1 and R.sup.x is styryl, anilido, or
anilinocarbonyl, only one of R.sup.5 or R.sup.6 is alkyl;
[0050] provided that when n is 1, R.sup.1, R.sup.3, R.sup.7, and
R.sup.8 are hydrogen, R.sup.2 is hydrogen, alkyl or aryl, R.sup.4
is unsubstituted amino or amino substituted with one or more alkyl
or aryl radicals, and R.sup.5 is hydrogen, alkyl or aryl, then
R.sup.6 is other than hydroxy; or
[0051] a pharmaceutically acceptable salt, solvate, or prodrug
thereof.
[0052] Preferably, R.sup.5 and R.sup.6 can independently be
selected from the group consisting of H, aryl, heterocycle,
quaternary heterocycle, and quaternary heteroaryl,
[0053] wherein said aryl, heteroaryl, quaternary heterocycle, and
quaternary heteroaryl can be substituted with one or more
substituent groups independently selected from the group consisting
of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,
cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR.sup.13,
N.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13,
SO.sub.3R.sup.13, NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15,
NO.sub.2, CO.sub.2R.sup.13, CN, OM, SO.sub.2OM,
SO.sub.2NR.sup.13R.sub.14, C(O)NR.sup.13R.sup.14, C(O)OM,
COR.sup.13, NR.sup.13C(O)R.sup.14, NR.sup.13C(O)NR.sup.14R.sup.15,
NR.sup.13CO.sub.2R.sup.14, OC(O)R.sup.13, OC(O)NR.sup.13R.sup.14,
NR.sup.13SOR.sup.14, NR.sup.13SO.sub.2R.sup.14,
NR.sup.13SONR.sup.14R.sup.15, NR.sup.13SO.sub.2NR.sup.14R.sup.15,
P(O)R.sup.13R.sup.14, P.sup.+R.sup.13R.sup.14R15A-,
P(OR.sup.13O)R.sup.14, S+R.sup.13R.sup.14A-, and
N.sup.+R.sup.9R.sup.11R.- sup.12A.sup.-,
[0054] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have
one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A-, S, SO, SO.sub.2, S.sup.+R.sup.7A-,
PR.sup.7, P(O)R.sup.7, P.sup.+R.sup.7R.sup.8A-, or phenylene,
[0055] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, and heterocycle can be further
substituted with one or more substituent groups selected from the
group consisting of OR.sup.7, NR.sup.7R.sup.8, SR.sup.7,
S(O)R.sup.7, SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN,
oxo, CONR.sup.7R.sup.8, N.sup.+R.sup.7R.sup.8R.sup.9A.sup.-, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl,
quaternary heterocycle, quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8A.sup.-, and P(O)(OR.sup.7)OR.sup.8.
[0056] More preferably, R.sup.5 or R.sup.6 has the formula:
--Ar--(R.sup.y).sub.t
[0057] wherein:
[0058] t is an integer from 0 to 5;
[0059] Ar is selected from the group consisting of phenyl,
thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl,
furanyl, anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl,
imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl,
thiazolyl, triazolyl, isothiazolyl, indolyl, benzoimidazolyl,
benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and
[0060] one or more R.sup.y are independently selected from the
group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo,
OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, SO.sub.3R.sup.13, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14,
C(O)CM, COR.sup.13, NR.sup.13C(O)R.sup.14, NR.sup.13R.sup.14,
C(O)NR.sup.13R.sup.14, NR.sup.13CO.sub.2R.sup.13, OC(O)R.sup.13,
CC(O)NR.sup.13R.sup.14, NR.sup.13SOR.sup.14,
NR.sup.13SO.sub.2R.sup.14, NR.sup.13SONR.sup.14R.sup.15,
NR.sup.13SO.sub.2NR.sup.14R.sup.15, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(R.sup.13).sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- ,
[0061] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, and heterocycle can be further
substituted with one or more substituent groups selected from the
group consisting of OR.sup.7, NR.sup.7R.sup.8, SR.sup.7,
S(O)R.sup.7, SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN,
oxo, CONR.sup.7R.sup.8, N.sup.+R.sup.7R.sup.8R.sup.9A-, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl,
quaternary heterocycle, quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8A.sup.-, and P(O)(OR.sup.7)OR.sup.8, and
[0062] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have
one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A-, S, SO.sub.2, S.sup.+R.sup.7A-, PR.sup.7,
P(O)R.sup.7, P.sup.+R.sup.7R.sup.8A-, or phenylene.
[0063] Most preferably, R.sup.5 or R has the formula (II): 2
[0064] Another embodiment of the invention is further directed to
compounds of Formula I wherein at least one or more of the
following conditions exist:
[0065] (1) R.sup.1 and R .sup.2 are independently selected from the
group consisting of hydrogen and alkyl. Preferably, R.sup.1 and
R.sup.2 are independently selected from the group consisting of
C.sub.1-6 alkyl. More preferably, R.sup.1 and R .sup.2 are the same
C.sub.1-6 alkyl. Still more preferably, R.sup.1 and R .sup.2 are
n-butyl; and/or
[0066] (2) R.sup.3 and R.sup.4 are independently selected from the
group consisting of hydrogen and OR.sup.9 wherein R.sup.9 is
defined as set forth above. Preferably, R.sup.3 is hydrogen and
R.sup.4 is OR.sup.9. Still more preferably, R.sup.3 is hydrogen and
R.sup.4 is hydroxy; and/or
[0067] (3) Rs is substituted aryl. Preferably, R.sup.5 is
substituted phenyl. More preferably, R.sup.5 is phenyl substituted
with a radical selected from the group consisting of OR.sup.13,
NR.sup.13 (O)R.sup.14, NR.sup.13(O)NR.sup.14R.sup.15,
NR.sup.13CO.sub.2R.sup.14, QC(O)R.sup.13, OC(O)NR.sup.13R.sup.14,
NR.sup.13SOR.sup.14, NR.sup.13SO.sub.2R.sup.14,
NR.sup.13SONR.sup.14R.sup.15, and
NR.sup.13SO.sub.2NR.sup.14R.sup.15 wherein R.sup.13, R.sup.14 and
R.sup.15 are as set forth above. Still more preferably, R.sup.5 is
phenyl substituted with OR.sup.13. Still more preferably, R.sup.5
is phenyl substituted at the para or meta position with OR.sup.13
wherein R.sup.13 comprises a quaternary heterocycle, quaternary
heteroaryl or substituted amino; and/or
[0068] (4) R.sup.6 is hydrogen; and/or
[0069] (5) R.sup.7 and R.sup.8 are independently selected from the
group consisting of hydrogen and alkyl. Preferably, R.sup.1 and
R.sup.2 are independently selected from the group C.sub.1-6 alkyl.
Still more preferably, R.sup.1 and R.sup.2 are hydrogen; and/or
[0070] (6) R.sup.x is selected from the group consisting of
OR.sup.13 and NR .sup.3R.sup.14. Preferably, R.sup.x is selected
from the group consisting of alkoxy, amino, alkylamino and
dialkylamino. Still more preferably, R.sup.x is selected from the
group consisting of methoxy and dimethylamino.
[0071] Another embodiment of the invention is further directed to
compounds of formula 1: 3
[0072] wherein:
[0073] q is an integer from 1 to 4;
[0074] n is an integer from 0 to 2;
[0075] R.sup.1 and R.sup.2 are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl,
alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,
(polyalkyl)aryl, and cycloalkyl,
[0076] wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl,
arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,
(polyalkyl)aryl, and cycloalkyl optionally are substituted with one
or more substituents selected from the group consisting of
OR.sup.9, NR.sup.9R.sup.10, NR.sup.+R.sup.9R.sup.wA.sup.-,
SR.sup.9, S.sup.+R.sup.9R.sup.10A.sup.-,
P.sup.+R.sup.9R.sup.10R.sup.11A.sup.-, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen,
oxo, and CONR.sup.9R.sup.10,
[0077] wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy,
alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or
more carbons replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.10A-, S,
SO, SO.sub.2, S.sup.+R.sup.9A.sup.-, P.sup.+R.sup.9R.sup.10A.sup.-,
or phenylene,
[0078] wherein R.sup.9, R.sup.10, and R.sup.w are independently
selected from the group consisting of H, alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl,
carboxyalkyl, carboxyheteroaryl, carboxyheterocycle,
carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl,
heterocyclylalkyl, and alkylammoniumalkyl; or
[0079] R.sup.1 and R.sup.2 taken together with the carbon to which
they are attached form C.sub.3-10 cycloalkyl;
[0080] R.sup.3 and R.sup.4 are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl,
heterocycle, OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, and
SO.sub.3R.sup.9, wherein R.sup.9 and R.sup.10 are as defined above;
or
[0081] R.sup.3 and R.sup.4 together form .dbd.O, .dbd.NOR.sup.11,
.dbd.S, .dbd.NNR.sup.11R.sup.12, .dbd.NR.sup.9, or
.dbd.CR.sup.11R.sup.12,
[0082] wherein R.sup.11 and R.sup.12 are independently selected
from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,
arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl,
carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR.sup.9,
NR.sup.9R.sup.10, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9,
SO.sub.3R.sup.9, CO.sub.2R.sup.9, CN, halogen, oxo, and
CONR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10 are as defined
above, provided that both R.sup.3 and R.sup.4 cannot be OH,
NH.sub.2, and SH, or
[0083] R.sup.11 and R.sup.12 together with the nitrogen or carbon
atom to which they are attached form a cyclic ring;
[0084] R.sup.5 is selected from the group consisting of H, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary
heterocycle, OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, and
SO.sub.3R.sup.9,
[0085] wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycle, quaternary heterocycle, and quaternary heteroaryl can
be substituted with one or more substituent groups independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen,
oxo, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, SO.sub.3R.sup.13, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14,
C(O)OM, CR.sup.13, NR.sup.13C(O)R.sup.14, NR.sup.13R.sub.14,
C(O)NR.sup.14R.sup.15, NR.sup.13CO.sub.2R.sup.14, OC(O)R.sup.13,
OC(O)NR.sup.13R.sup.14, NR.sup.13SOR.sup.14,
NR.sup.13SO.sub.2R.sup.14, NR.sup.13SONR.sup.14R.sup.15,
NR.sup.13SO.sub.2NR.sup.14R.sup.15, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- ,
[0086] wherein:
[0087] A.sup.- is a pharmaceutically acceptable anion and M is a
pharmaceutically acceptable cation,
[0088] said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
haloalkyl, cycloalkyl, and heterocycle can be further substituted
with one or more substituent groups selected from the group
consisting of OR.sup.7, NR.sup.7R.sup.8, SR.sup.7, S(O)R.sup.7,
SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN, oxo,
CONR.sup.7R.sup.8, N.sup.+R.sup.7R.sup.8R.sup.9A-, alkyl, alkenyl,
alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary
heterocycle, quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8R.sup.9A-, and P(O)(OR.sup.7)OR.sup.8, and
[0089] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have
one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A-, S, SO, SO.sub.2, S.sup.+R.sup.7A-,
PR.sup.7, P(O)R.sup.7, P.sup.+R.sup.7R.sup.8A-, or phenylene, and
R.sup.13, R.sup.14, and R.sup.15 are independently selected from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl,
alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl,
heterocycle, heteroaryl, quaternary heterocycle, quaternary
heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary
heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl,
and carboxyalkylaminocarbonylalkyl,
[0090] wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and
polyalkyl optionally have one or more carbons replaced by O,
NR.sup.9, N.sup.+R.sup.9R.sup.10A-, S, SO, SO.sub.2,
S.sup.+R.sup.9A.sup.-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-,
P(O)R.sup.9, phenylene, carbohydrate, amino acid, peptide, or
polypeptide, and
[0091] R.sup.13, R.sup.14, and R.sup.15 are optionally substituted
with one or more groups selected from the group consisting of
hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle,
heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary
heteroaryl, quaternary heterocyclylalkyl, quaternary
heteroarylalkyl, guanidinyl, OR.sup.9, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.2OM, SO.sub.2NR.sup.9R.sup.10,
PO(OR.sup.16)OR.sup.17, P.sup.+R.sup.9R.sup.10R.sup.11A-,
S.sup.+R.sup.9R.sup.10A-, and C(O)OM,
[0092] wherein R.sup.16 and R.sup.17 are independently selected
from the substituents constituting R.sup.9 and M; or
[0093] R.sup.13 and R.sup.14, together with the nitrogen atom to
which they are attached form a mono- or polycyclic heterocycle that
is optionally substituted with one or more radicals selected from
the group consisting of oxo, carboxy and quaternary salts; or
[0094] R.sup.14 and R.sup.15, together with the nitrogen atom to
which they are attached, form a cyclic ring; and
[0095] R.sup.6 is hydroxy; and
[0096] R.sup.7 and R.sup.8 are independently selected from the
group consisting of hydrogen and alkyl; and
[0097] one or more R.sup.x are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy,
aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle,
heteroaryl, polyether, quaternary heterocycle, quaternary
heteroaryl, OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
S(O).sub.2R.sup.13, SO.sub.3R.sup.13, S.sup.+R.sup.13R.sup.14A-,
NR.sup.13OR.sup.14, NR.sup.13NR.sup.14R.sup.15, NO.sub.2,
CO.sub.2R.sup.13, CN, OM, SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14,
NR.sup.14C(O)R.sup.13, C(O)NR.sup.13R.sup.14,
NR.sup.14C(O)R.sup.13, C(O)OM, COR.sup.13, OR.sup.18,
S(O).sub.nNR.sup.18, NR.sup.13R.sup.18, NR.sup.18OR.sup.14,
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
P.sup.+R.sup.9R.sup.11R.sup.12A.su- p.-, amino acid, peptide,
polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl,
haloalkyl, polyether, quaternary heterocycle, and quaternary
heteroaryl can be further substituted with OR.sup.9,
NR.sup.9R.sup.10, N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-, SR.sup.9,
S(O)R.sup.9, SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo,
CO.sub.2R.sup.9, CN, halogen, CONR.sup.9R.sup.10, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17,
P.sup.+R.sup.9R.sup.11R.sup.12A.sup.-,
S.sup.+R.sup.9R.sup.10A.sup.-, or C(O)OM, and
[0098] wherein R18 is selected from the group consisting of acyl,
arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,
[0099] wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle,
heteroaryl, alkyl, quaternary heterocycle, and quaternary
heteroaryl optionally are substituted with one or more substituents
selected from the group consisting of OR, NR.sup.9R.sup.10,
N.sup.+R.sup.9R.sup.11R.sup- .12A.sup.-, SR.sup.9, S(O)R.sup.9,
SO.sub.2R.sup.9, SO.sub.3R.sup.9, oxo, CO.sub.2R.sup.9, CN,
halogen, CONR.sup.9R.sup.10, SO.sub.3R.sup.9, SO.sub.2OM,
SO.sub.2NR.sup.9R.sup.10, PO(OR.sup.16)OR.sup.17, and C(O)OM,
[0100] wherein in R.sup.x, one or more carbons are optionally
replaced by O, NR.sup.13, N.sup.+R.sup.13R.sup.14A-, S, SO,
SO.sub.2, S.sup.+R.sup.13A.sup.-, PR.sup.1, P(O)R.sup.13,
P.sup.+R.sup.9R.sup.10A-, phenylene, amino acid, peptide,
polypeptide, carbohydrate, polyether, or polyalkyl,
[0101] wherein in said polyalkyl, phenylene, amino acid, peptide,
polypeptide, and carbohydrate, one or more carbons are optionally
replaced by O, NR.sup.9, N.sup.+R.sup.9R.sup.10A.sup.-, S, SO,
SO.sub.2, S.sup.+R.sup.9A-, PR.sup.9, P.sup.+R.sup.9R.sup.10A-, or
P(O)R.sup.9;
[0102] wherein quaternary heterocycle and quaternary heteroaryl are
optionally substituted with one or more groups selected from the
group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo,
OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, SO.sub.3R.sup.13, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sub.14- , C(O)NR.sup.3R.sup.14,
C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A.sup.-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- ,
[0103] provided that both R.sup.5 and R.sup.6 cannot be hydrogen,
OH, or SH;
[0104] provided that when R.sup.5 is phenyl, only one of R.sup.1 or
R.sup.2 is H; or
[0105] a pharmaceutically acceptable salt, solvate, or prodrug
thereof.
[0106] The invention is further directed to a compound selected
from among:
R.sup.20-R.sup.19-R.sup.21 (Formula DI)
[0107] 4
[0108] wherein R.sup.19 is selected from the group consisting of
alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy
diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid,
peptide, and polypeptide, wherein alkane diyl, alkene diyl, alkyne
diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy
diyl, carbohydrate, amino acid, peptide, and polypeptide can
optionally have one or more carbon atoms replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8, S, SO, SO.sub.2, S.sup.+R.sup.7R.sup.8,
PR.sup.7, P.sup.+R.sup.7R.sup.8, phenylene, heterocycle, quatarnary
heterocycle, quaternary heteroaryl, or aryl,
[0109] wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane
diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate,
amino acid, peptide, and polypeptide can be substituted with one or
more substituent groups independently selected from the group
consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo,
OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, SO.sub.3R.sup.13, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14,
C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R.sup.15A-, P(OR.sup.13)OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- ,
[0110] wherein R.sup.19 further comprises functional linkages by
which R.sup.19 is bonded to R.sup.20, R.sup.21, or R.sup.22 in the
compounds of Formulae DII and DIII, and R.sup.23 in the compounds
of Formula DIII. Each of R.sup.20, R.sup.21, or R.sup.22 and
R.sup.23 comprises a benzothiepine moiety as described above that
is therapeutically effective in inhibiting ileal bile acid
transport.
[0111] The invention is also directed to a compound selected from
among Formula DI, Formula DII and Formula DIII in which each of
R.sup.20, R.sup.21, R.sup.22 and R.sup.23 comprises a benzothiepine
moiety corresponding to the Formula: 5
[0112] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.x, q, and n are as defined in
Formula I as described above, and R.sup.55 is either a covalent
bond or arylene.
[0113] In compounds of Formula DIV, it is particularly preferred
that each of R.sup.20, R.sup.21, and R.sup.22 in Formulae DII 15
and DIII, and R.sup.23 in Formula DIII, be bonded at its 7- or
8-position to R.sup.19. In compounds of Formula DIVA, it is
particularly preferred that R.sup.55 comprise a phenylene moiety
bonded at a m- or p-carbon thereof to R.sup.19.
[0114] Examples of Formula DI include: 6
[0115] In any of the dimeric or multimeric structures discussed
immediately above, benzothiepine compounds of the present invention
can be used alone or in various combinations.
[0116] In any of the compounds of the present invention, R.sup.1
and R.sup.2 can be ethyl/butyl or butyl/butyl.
[0117] In another aspect, the present invention provides a
pharmaceutical composition for the prophylaxis or treatment of a
disease or condition for which a bile acid transport inhibitor is
indicated, such as a hyperlipidemic condition, for example,
atherosclerosis. Such compositions comprise any of the compounds
disclosed above, alone or in combination, in an amount effective to
reduce bile acid levels in the blood, or to reduce transport
thereof across digestive system membranes, and a pharmaceutically
acceptable carrier, excipient, or diluent.
[0118] In a further aspect, the present invention also provides a
method of treating a disease or condition in mammals, including
humans, for which a bile acid transport inhibitor is indicated,
comprising administering to a patient in need thereof a compound of
the present invention in an effective amount in unit dosage form or
in divided doses.
[0119] In yet a further aspect, the present invention also provides
processes for the preparation of compounds of the present
invention.
[0120] Further scope of the applicability of the present invention
will become apparent from the detailed description provided below.
However, it should be understood that the following detailed
dscription and examples, while indicating preferred embodiments of
the invention, are given by way of illustration only since various
changes and modifications within the spirit and scope of the
invention will beomce apparent to those skilled in the art from
this detailed description.
DETAILED DESCRIPTION OF THE INVENTION
[0121] The following detailed description is provided to aid those
skilled in the art in practicing the present invention. Even so,
this detailed description should not be construed to unduly limit
the present invention as modifications and variations in the
emobodiments discussed herein can be made by those of ordinary
skill in the art without departing from the spirit or scope of the
present inventive discovery.
[0122] The contents of each of the references cited herein,
including the contents of the references cited within these primary
references, are herein incorporated by reference in their
entirety.
[0123] Definitions
[0124] In order to aid the reader in understanding the following
detailed description, the following definitions are provided:
[0125] "Alkyl", "alkenyl," and "alkynyl" unless otherwise noted are
each straight chain or branched chain hydrocarbons of from one to
twenty carbons for alkyl or two to twenty carbons for alkenyl and
alkynyl in the present invention and therefore mean, for example,
methyl, ethyl, propyl, butyl, pentyl or hexyl and ethenyl,
propenyl, butenyl, pentenyl, or hexenyl and ethynyl, propynyl,
butynyl, pentynyl, or hexynyl respectively and isomers thereof.
[0126] "Aryl" means a fully unsaturated mono- or multi-ring
carbocyle, including, but not limited to, substituted or
unsubstituted phenyl, naphthyl, or anthracenyl.
[0127] "Heterocycle" means a saturated or unsaturated mono- or
multi-ring carbocycle wherein one or more carbon atoms can be
replaced by N, S, P, or O. This includes, for example, the
following structures: 7
[0128] wherein Z, Z', Z" or Z'" is C, S, P, O, or N, with the
proviso that one of Z, Z', Z" or Z'" is other than carbon, but is
not O or S when attached to another Z atom by a double bond or when
attached to another O or S atom. Furthermore, the optional
substituents are understood to be attached to Z, Z', Z" or Z'" only
when each is C.
[0129] The term "heteroaryl" means a fully unsaturated
heterocycle.
[0130] In either "heterocycle" or "heteroaryl," the point of
attachment to the molecule of interest can be at the heteroatom or
elsewhere within the ring.
[0131] The term "quaternary heterocycle" means a heterocycle in
which one or more of the heteroatoms, for example, O, N, S, or P,
has such a number of bonds that it is positively charged. The point
of attachment of the quaternary heterocycle to the molecule of
interest can be at a heteroatom or elsewhere.
[0132] The term "quaternary heteroaryl" means a heteroaryl in which
one or more of the heteroatoms, for example, O, N, S, or P, has
such a number of bonds that it is positively charged. The point of
attachment of the quaternary heteryaryl to the molecule of interest
can be at a heteroatom or elsewhere.
[0133] The term "halogen" means a fluoro, chloro, bromo or iodo
group.
[0134] The term "haloalkyl" means alkyl substituted with one or
more halogens.
[0135] The term "cycloalkyl" means a mono- or multi-ringed
carbocycle wherein each ring contains three to ten carbon atoms,
and wherein any ring can contain one or more double or triple
bonds. Examples include radicals such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloalkenyl, and cycloheptyl. The term
"cycloalkyl" additionally encompasses Spiro systems wherein the
cycloalkyl ring has a carbon ring atom in common with the
seven-membered heterocyclic ring of the benzothiepine.
[0136] The term "diyl" means a diradical moiety wherein said moiety
has two points of attachment to molecules of interest.
[0137] The term "oxo" means a doubly bonded oxygen.
[0138] The term "polyalkyl" means a branched or straight
hydrocarbon chain having a molecular weight up to about 20,000,
more preferably up to about 10,000, most preferably up to about
5,000.
[0139] The term "polyether" means a polyalkyl wherein one or more
carbons are replaced by oxygen, wherein the polyether has a
molecular weight up to about 20,000, more preferably up to about
10,000, most preferably up to about 5,000.
[0140] The term "polyalkoxy" means a polymer of alkylene oxides,
wherein the polyalkoxy has a molecular weight up to about 20,000,
more preferably up to about 10,000, most preferably up to about
5,000.
[0141] The term "cycloaklylidene" means a mono- or multi-ringed
carbocycle wherein a carbon within the ring structure is doubly
bonded to an atom which is not within the ring structures.
[0142] The term "carbohydrate" means a mono-, di-, tri-, or
polysaccharide wherein the polysaccharide can have a molecular
weight of up to about 20,000, for example,
hydroxypropyl-methylcellulose or chitosan.
[0143] The term "peptide" means polyamino acid containing up to
about 100 amino acid units.
[0144] The term "polypeptide" means polyamino acid containing from
about 100 amino acid units to about 1000 amino acid units, more
preferably from about 100 amino acid units to about 750 amino acid
untis, most preferably from about 100 amino acid units to about 500
amino acid units.
[0145] The term "alkylammoniumalkyl" means a NH.sub.2 group or a
mono-, di- or tri-substituted amino group, any of which is bonded
to an alkyl wherein said alkyl is bonded to the molecule of
interest.
[0146] The term "triazolyl" includes all positional isomers. In all
other heterocycles and heteroaryls which contain more than one ring
heteroatom and for which isomers are possible, such isomers are
included in the definition of said heterocycles and
heteroaryls.
[0147] The term "sulfo" means a sulfo group, --SO.sub.3H, or its
salts.
[0148] The term "sulfoalkyl" means an alkyl group to which a
sulfonate group is bonded, wherein said alkyl is bonded to the
molecule of interest.
[0149] The term "arylalkyl" means an aryl-substituted alkyl radical
such as benzyl. The term
[0150] "alkylarylalkyl" means an arylalkyl radical that is
substituted on the aryl group with one or more alkyl groups.
[0151] The term "heterocyclylalkyl" means an alkyl radical that is
substituted with one or more heterocycle groups. Preferable
heterocyclylalkyl radicals are "lower heterocyclylalkyl" radicals
having one or more heterocycle groups attached to an alkyl radical
having one to ten carbon atoms.
[0152] The term "heteroarylalkyl" means an alkyl radical that is
substituted with one or more heteroaryl groups. Preferable
heteroarylalkyl radicals are "lower heteroarylalkyl" radicals
having one or more heteroaryl groups attached to an alkyl radical
having one to ten carbon atoms.
[0153] The term "quaternary heterocyclylalkyl" means an alkyl
radical that is substituted with one or more quaternary heterocycle
groups. Preferable quaternary heterocyclylalkyl radicals are "lower
quaternary heterocyclylalkyl" radicals having one or more
quaternary heterocycle groups attached to an alkyl radical having
one to ten carbon atoms.
[0154] The term "quaternary heteroarylalkyl" means an alkyl radical
that is substituted with one or more quaternary heteroaryl groups.
Preferable quaternary heteroarylalkyl radicals are "lower
quaternary heteroarylalkyl" radicals having one or more quaternary
heteroaryl groups attached to an alkyl radical having one to ten
carbon atoms.
[0155] The term "alkylheteroarylalkyl" means a heteroarylalkyl
radical that is substituted with one or more alkyl groups.
Preferable alkylheteroarylalkyl radicals are "lower
alkylheteroarylalkyl" radicals with alkyl portions having one to
ten carbon atoms.
[0156] The term "alkoxy" an alkyl radical which is attached to the
remainder of the molecule by oxygen, such as a methoxy radical.
More preferred alkoxy radicals are "lower alkoxy" radicals having
one to six carbon atoms. Examples of such radicals include methoxy,
ethoxy, propoxy, iso-propoxy, butoxy and tert-butoxy.
[0157] The term "carboxy" means the carboxy group, --CO.sub.2H, or
its salts.
[0158] The term "carboxyalkyl" means an alkyl radical that is
substituted with one or more carboxy groups. Preferable
carboxyalkyl radicals are "lower carboxyalkyl" radicals having one
or more carboxy groups attached to an alkyl radical having one to
six carbon atoms.
[0159] The term "carboxyheterocycle" means a heterocycle radical
that is substituted with one or more carboxy groups.
[0160] The term "carboxyheteroaryl" means a heteroaryl radical that
is substituted with one or more carboxy groups.
[0161] The term "carboalkoxyalkyl" means an alkyl radical that is
substituted with one or more alkoxycarbonyl groups. Preferable
carboalkoxyalkyl radicals are "lower carboalkoxyalkyl" radicals
having one or more alkoxycarbonyl groups attached to an alkyl
radical having one to six carbon atoms.
[0162] The term "carboxyalkylamino" means an amino radical that is
mono- or di-substituted with carboxyalkyl. Preferably, the
carboxyalkyl substituent is a "lower carboxyalkyl" radical wherein
the carboxy group is attached to an alkyl radical having one to six
carbon atoms.
[0163] The term "active compound" means a compound of the present
invention which inhibits transport of bile acids.
[0164] When used in combination, for example "alkylaryl" or
"arylalkyl," the individual terms listed above have the meaning
indicated above.
[0165] The term "a bile acid transport inhibitor" means a compound
capable of inhibiting absorption of bile acids from the intestine
into the circulatory system of a mammal, such as a human. This
includes increasing the fecal excretion of bile acids, as well as
reducing the blood plasma or serum concentrations of cholesterol
and cholesterol ester, and more specifically, reducing LDL and VLDL
cholesterol. Conditions or diseases which benefit from the
prophylaxis or treatment by bile acid transport inhibition include,
for example, a hyperlipidemic condition such as
atherosclerosis.
[0166] Compounds
[0167] The compounds of the present invention can have at least two
asymmetrical carbon atoms, and therefore include racemates and
stereoisomers, such as diastereomers and enantiomers, in both pure
form and in admixture. Such stereoisomers can be prepared using
conventional techniques, either by reacting enantiomeric starting
materials, or by separating isomers of compounds of the present
invention.
[0168] Isomers may include geometric isomers, for example cis
isomers or trans isomers across a double bond. All such isomers are
contemplated among the compounds of the present invention.
[0169] The compounds of the present invention also include
tautomers.
[0170] The compounds of the present invention as discussed below
include their salts, solvates and prodrugs.
[0171] Compound Syntheses
[0172] The starting materials for use in the preparation of the
compounds of the invention are known or can be prepared by
conventional methods known to a skilled person or in an analogous
manner to processes described in the art.
[0173] Generally, the compounds of the present invention can be
prepared by the procedures described below.
[0174] For example, as shown in Scheme I, reaction of aldehyde II
with formaldehyde and sodium hydroxide yields the hydroxyaldehyde
III which is converted to mesylate IV with methansulfonyl chloride
and triethylamine similar to the procedure described in Chem. Ber.
98, 728-734 (1965). Reaction of mesylate IV with thiophenol V,
prepared by the procedure described in WO 93/16055, in the presence
of triethylamine yields keto-aldehyde VI which can be cyclized with
the reagent, prepared from zinc and titanium trichloride in
refluxing ethylene glycol dimethyl ether (DME), to give a mixture
of 2,3-dihydrobenzothiepine VII and two racemic steroisomers of
benzothiepin-(5H)-4-one VIII when R.sup.1 and R.sup.2 are
nonequivalent. Oxidation of VII with 3 equivalents of
m-chloro-perbenzoic acid (MCPBA) gives isomeric sulfone-epoxides IX
which upon hydrogenation with palladium on carbon as the catalyst
yield a mixture of four racemic stereoisomers of
4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxides X and two
racemic stereoisomers of 2,3,4,5-tetrahydrobenzothiepine-1,1-diox-
ides XI when R.sup.1 and R.sup.2 are nonequivalent.
[0175] Optically active compounds of the present invention can be
prepared by using optically active starting material III or by
resolution of compounds X with optical resolution agents well known
in the art as described in J. Org. Chem., 39, 3904 (1974), ibid.,
42, 2781 (1977), and ibid., 44, 4891 (1979). 8
[0176] Alternatively, keto-aldehyde VI where R.sup.2 is H can be
prepared by reaction of thiophenol V with a 2-substituted acrolein.
9
[0177] Benzothiepin-(5H)-4-one VIII can be oxidized with MCPBA to
give the benzothiepin-(5H)-4-one-1,1-dioxide XII which can be
reduced with sodium borohydride to give four racemic stereoisomers
of X. The two stereoisomers of X, Xa and Xb, having the OH group
and R.sup.5 on the opposite sides of the benzothiepine ring can be
converted to the other two isomers of X, Xc and Xd, having the OH
group and R.sup.5 on the same side of the benzothiepine ring by
reaction in methylene chloride with 40-50% sodium hydroxide in the
presence of a phase transfer catalyst (PTC). The transformation can
also be carried out with potassium t-butoxide in THF. 10
[0178] The compounds of the present invention where R.sup.5 is OR,
NRR' and S(O).sub.nR and R.sup.4 is hydroxy can be prepared by
reaction of epoxide IX where R.sup.5 is H with thiol, alcohol, and
amine in the presence of a base. 11
[0179] Another route to Xc and Xd of the present invention is shown
in Scheme 2. Compound VI is oxidized to compound XIII with two
equivalent of m-chloroperbenzoic acid. Hydrogenolysis of compound
XIII with palladium on carbon yields compound XIV which can be
cyclized with either potassium t-butoxide or sodium hydroxide under
phase transfer conditions to a mixture of Xc and Xd. Separation of
Xc and Xd can be accomplished by either HPLC or fractional
crystallization.
[0180] The thiophenols XVIII and V used in the present invention
can also be prepared according to the Scheme 3. Alkylation of
phenol XV with an arylmethyl chloride in a nonpolar solvent
according to the procedure in J. Chem. Soc., 2431-2432 (1958) gives
the ortho substituted phenol XVI. The phenol XVI can be converted
to the thiophenol XVIII via the thiocarbamate XVII by the procedure
described in J. Org. Chem., 31, 3980 (1966). The phenol XVI is
first reacted with dimethyl thiocarbamoyl chloride and
triethylamine to give thiocarbamate XVII which is thermally
rearranged at 200-300 .degree. C., and the rearranged product is
hydrolyzed with sodium hydroxide to yield the thiophenol XVIII.
Similarly, Thiophenol V can also be prepared from 2-acylphenol XIX
via the intermediate thiocarbamate XX. 12 13
[0181] Scheme 4 shows another route to benzothiepine-1,1-dioxides
Xc and Xd starting from the thiophenol XVIII. Compound XVIII can be
reacted with mesylate IV to give the sulfide-aldehyde XXI.
Oxidation of XXI with two equivalents of MCPBA yields the
sulfone-aldehyde XIV which can be cyclized with potassium
t-butoxide to a mixture of Xc and Xd. Cyclyzation of
sulfide-aldehyde with potassium t-butoxide also gives a mixture of
benzothiepine XXIIc and XXIId. 14
[0182] Examples of amine- and hydroxylamine-containing compounds of
the present invention can be prepared as shown in Scheme 5 and
Scheme 6. 2-Chloro-4-nitrobenzophenone is reduced with
triethylsilane and trifluoromethane sulfonic acid to
2-chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium
sulfide followed by reacting the resulting sulfide with mesylate IV
gives sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents
of MCPBA yields sulfone-aldehyde XXIV which can be reduced by
hydrogenation to the hydroxylamine XXV. Protecting the
hydroxylamine XXV with di-t-butyldicarbonate gives the
N,O-di-(t-butoxycarbonyl)hydroxylamino derivative XXVI. Cyclization
of XXVI with potassium t-butoxide and removal of the
t-butoxycarbonyl protecting group gives a mixture of hydroxylamino
derivatives XXVIIc and XXVIId. The primary amine XXXIIIc and
XXXIIId derivatives can also be prepared by further hydrogenation
of XXIV or XXVIIc and XXVIId. 15
[0183] In Scheme 6, reduction of the sulfone-aldehyde XXV with
hydrogen followed by reductive alkylation of the resulting amino
derivative with hydrogen and an aldehyde catalyzed by palladium on
carbon in the same reaction vessel yields the substituted amine
derivative XXVIII. Cyclization of XXVIII with potassium t-butoxide
yields a mixture of substituted amino derivatives of this invention
XXIXc and XXIXd. 16
[0184] Scheme 7 describes one of the methods of introducing a
substituent to the aryl ring at the 5-position of benzothiepine.
Iodination of 5-phenyl derivative XXX with iodine catalyzed by
mercuric triflate gives the iodo derivative XXXI, which upon
palladium-catalyzed carbonylation in an alcohol yields the
carboxylate XXXII. Hydrolysis of the carboxylate and derivatization
of the resulting acid to acid derivatives are well known in the
art. 17
[0185] Abbreviations used in the foregoing description have the
following meanings:
[0186] THF--tetrahydrofuran
[0187] PTC--phase transfer catalyst
[0188] Aliquart 336--methyltricaprylylammonium chloride
[0189] MCPBA--m-chloroperbenzoic acid
[0190] Celite--a brand of diatomaceous earth filtering aid
[0191] DMF--dimethylformamide
[0192] DME--ethylene glycol dimethyl ether
[0193] BOC--t-butoxycarbonyl group
[0194] Me--methyl
[0195] Et--ethyl
[0196] Bu--butyl
[0197] EtOAc--ethyl acetate
[0198] Et.sub.2O--diethyl ether
[0199] CH.sub.2Cl.sub.2--methylene chloride
[0200] MgSO.sub.4--magnesium sulfate
[0201] NaOH--sodium hydroxide
[0202] CH.sub.3OH--methanol
[0203] HCl--hydrochloric acid
[0204] NaCl--sodium chloride
[0205] NaH--sodium hydride
[0206] LAH--lithium aluminum hydride
[0207] LiOH--lithium hydroxide
[0208] Na.sub.2SO.sub.3--sodium sulfite
[0209] NaHCO.sub.3--sodium bicarbonate
[0210] DMSO--dimethylsulfoxide
[0211] KOSiMe.sub.3--potassium trimethylsilanolate
[0212] PEG--polyethylene glycol
[0213] MS--mass spectrometry
[0214] HRMS--high resolution mass spectrometry
[0215] ES--electrospray
[0216] NMR--nuclear magnetic resonance spectroscopy
[0217] GC--gas chromatography
[0218] MPLC--medium pressure liquid chromatography
[0219] HPLC--high pressure liquid chromatography
[0220] RPHPLC--reverse phase high pressure liquid
chromatography
[0221] RT--room temperature
[0222] h or hr--hour(s)
[0223] min--minute(s)
[0224] "Enantiomerically-enriched" (e.e.) means that one enantiomer
or set of diastereomers preponderates over the complementary
enantiomer or set of diastereomers. Enantiomeric enrichment of a
mixture of enantiomers is calculated by dividing the concentration
of the preponderating enantiomer by the concentration of the other
enantiomer, multiplying the dividend by 100, and expressing the
result as a percent. Enantiomeric enrichment can be from about 1%
to about 100%, aid preferably from about 10% to about 100%, and
more preferably from about 20% to 100%.
[0225] R.sup.1 and R.sup.2 can be selected from among substituted
and unsubstituted C.sub.1 to C.sub.10 alkyl wherein the
substituent(s) can be selected from among alkylcarbonyl, alkoxy,
hydroxy, and nitrogen-containing heterocycles joined to the C.sub.1
to C.sub.10 alkyl through an ether linkage. Substituents at the
3-carbon can include ethyl, n-propyl, n-butyl, n-pentyl, isobutyl,
isopropyl, --CH.sub.2C(.dbd.O)C.su- b.2H.sub.5,
--CH.sub.2OC.sub.2H.sub.5, and --CH.sub.2O-- (4-picoline). Ethyl,
n-propyl, n-butyl, and isobutyl are preferred. In certain
particularly preferred compounds of the present invention,
substituents R.sup.1 and R.sup.2are identical, for example
n-butyl/n-butyl, so that the compound is achiral at the 3-carbon.
Eliminating optical isomerism at the 3-carbon simplifies the
selection, synthesis, separation, and quality control of the
compound used as an ileal bile acid transport inhibitor. In both
compounds having a chiral 3-carbon and those having an achiral
3-carbon, substituents (R.sup.x) on the benzo- ring can include
hydrogen, aryl, alkyl, hydroxy, halo, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy,
(N)-hydroxy-carbonylalkyl amine, haloalkylthio, halcalkylsulfinyl,
haloalkylsufonyl, amino, N-alkylamino, N,N-dialkylamino,
(N)-alkoxycarbamoyl, (N)-aryloxycarbamoyl, (N)-aralkyloxycarbamoyl,
trialkylammonium (especially with a halide counterion), (N)-amido,
(N)-alkylamido, -N-alkylamido, -N,N-dialkylamido,
(N)-haloalkylamido, (N)-sulfonamido, (N)-alkylsulfonamido,
(N)-haloalkylsulfonamido, carboxyalkyl-amino, trialkylammonium
salt, (N)-carbamic acid, alkyl or benzyl ester, N-acylamine,
hydroxylamine, haloacylamine, carbohydrate, thiophene a trialkyl
ammonium salt having a carboxylic acid or hydroxy substituent on
one or more of the alkyl substituents, an alkylene bridge having a
quaternary ammonium salt substituted thereon,
--[O(CH.sub.2).sub.w].sub.x-X where x is 2 to 12, w is 2 or 3 and X
is a halo or a quaternary ammonium salt, and (N)-nitrogen
containing heterocycle wherein the nitrogen of said heterocycle is
optionally quaternized. Among the preferred species which may
constitute Rx are methyl, ethyl, isopropyl, t-butyl, hydroxy,
methoxy, ethoxy, isopropoxy, methylthio, iodo, bromo, fluoro,
methylsulfinyl, methylsulfonyl, ethylthio, amino, hydroxylamine,
N-methylamino, N,N-dimethylamino, N,N-diethylamino,
(N)-benzyloxycarbamoyl, trimethylammonium, A.sup.-,
--NHC(.dbd.O)CH.sub.3, --NHC(.dbd.O)C.sub.5H.sub.11,
--NHC(.dbd.O)C.sub.6HI.sub.13, carboxyethylamino, (N) -morpholinyl,
(N) -azetidinyl, (N)-N-methylazetidinium A.sup.-, (N)-pyrrolidinyl,
pyrrolyl, (N)-N-methylpyridinium A.sup.-, (N)-N-methylmorpholinium
A.sup.-, and N-N'-methylpiperazinyl, (N)-bromomethylamido,
(N)-N-hexylamino, thiophene, --N.sup.+ (CH.sub.3).sub.2CO.sub.2H
I.sup.-, --NCH.sub.3CH.sub.2CO.sub.2H,
--(N)-N'-dimethylpiperazinium I.sup.-, (N)-t-butyloxycarbamoyl,
(N)-methylsulfonamido, (N)N'-methylpyrrolidinium- , and
--(OCH.sub.2CH.sub.2).sub.3I, where A.sup.- is a pharmaceutically
acceptable anion. The benzo ring is can be mono-substituted at the
6, 7 or 8 position, or disubstituted at the 7- and -8 positions.
Also included are the 6,7,8-trialkoxy compounds, for example the
6,7,8-trimethoxy compounds. A variety of other substituents can be
advantageously present on the 6, 7, 8, and/or 9- positions of the
benzo ring, including, for example, guanidinyl, cycloalkyl,
carbohydrate (e.g., a 5 or 6 carbon monosaccharide), peptide, and
quaternary ammonium salts linked to the ring via poly(oxyalkylene)
linkages, e.g., --(OCH.sub.2CH.sub.2).sub.x--N-
.sup.+R.sup.13R.sup.14R.sup.15A.sup.- , where x is 2 to 10.
Exemplary compounds are those set forth below in Table 1.
1TABLE 1 Alternative Compounds #3 (Family F101.xxx.yyy) 18 Prefix
(FFF.xxx.yyy) Cpd# R.sup.1.dbd.R.sup.2 R.sup.5 (R.sup.x)q F101.001
01 ethyl Ph-- 7-methyl 02 ethyl Ph-- 7-ethyl 03 ethyl Ph--
7-iso-propyl 04 ethyl Ph-- 7-tert-butyl 05 ethyl Ph-- 7-OH 06 ethyl
Ph-- 7-OCH.sub.3 07 ethyl Ph-- 7-O-(iso-propyl) 08 ethyl Ph--
7-SCH.sub.3 09 ethyl Ph-- 7-SOCH.sub.3 10 ethyl Ph--
7-SO.sub.2CH.sub.3 11 ethyl Ph-- 7-SCH.sub.2CH.sub.3 12 ethyl Ph--
7-NH.sub.2 13 ethyl Ph-- 7-NHOH 14 ethyl Ph-- 7-NHCH.sub.3 15 ethyl
Ph-- 7-N(CH.sub.3).sub.2 16 ethyl Ph-- 7-N.sup.+(CH.sub.3).sub.3,
I.sup.- 17 ethyl Ph-- 7-NHC(.dbd.O)CH.sub.3 18 ethyl Ph--
7-N(CH.sub.2CH.sub.3).sub.2 19 ethyl Ph-- 7-NMeCH.sub.2CO.sub.2H 20
ethyl Ph-- 7-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H, I.sup.- 21 ethyl
Ph-- 7-(N)-morpholine 22 ethyl Ph-- 7-(N)-azetidine 23 ethyl Ph--
7-(N)--N-methylazetidinium, I.sup.- 24 ethyl Ph-- 7-(N)-pyrrolidine
25 ethyl Ph-- 7-(N)--N-methyl-pyrrolidiniu- m, I.sup.- 26 ethyl
Ph-- 7-(N)--N-methyl-morpholinium, I.sup.- 27 ethyl Ph--
7-(N)--N'-methylpiperazine 28 ethyl Ph--
7-(N)--N'-dimethylpiperazinium, I.sup.- 29 ethyl Ph-- 7-NH--CBZ 30
ethyl Ph-- 7-NHC(O)C.sub.5H.sub.11 31 ethyl Ph-- 7-NHC(O)CH.sub.2Br
32 ethyl Ph-- 7-NH--C(NH)NH.sub.2 33 ethyl Ph-- 7-(2)-thiophene 34
ethyl Ph-- 8-methyl 35 ethyl Ph-- 8-ethyl 36 ethyl Ph--
8-iso-propyl 37 ethyl Ph-- 8-tert-butyl 38 ethyl Ph-- 8-OH 39 ethyl
Ph-- 8-OCH.sub.3 40 ethyl Ph-- 8-O(iso-propyl) 41 ethyl Ph--
8-SCH.sub.3 42 ethyl Ph-- 8-SOCH.sub.3 43 ethyl Ph--
8-SO.sub.2CH.sub.3 44 ethyl Ph-- 8-SCH.sub.2CH.sub.3 45 ethyl Ph--
8-NH.sub.2 46 ethyl Ph-- 8-NHOH 47 ethyl Ph-- 8-NHCH.sub.3 48 ethyl
Ph-- 8-N(CH.sub.3).sub.2 49 ethyl Ph-- 8-N.sup.+(CH.sub.3).sub.3,
I.sup.- 50 ethyl Ph-- 8-NHC(.dbd.O)CH.sub.3 51 ethyl Ph--
8-N(CH.sub.2CH.sub.3).sub.2 52 ethyl Ph-- 8-NMeCH.sub.2CO.sub.2H 53
ethyl Ph-- 8-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H, I.sup.- 54 ethyl
Ph-- 8-(N)-morpholine 55 ethyl Ph-- 8-(N)-azetidine 56 ethyl Ph--
8-(N)--N-methylazetidinium, I.sup.- 57 ethyl Ph-- 8-(N)-pyrrolidine
58 ethyl Ph-- 8-(N)--N-methyl-pyrrolidinium, I.sup.- 59 ethyl Ph--
8-(N)--N-methyl-morpholinium, I.sup.- 60 ethyl Ph--
8-(N)--N'-methylpiperazine 61 ethyl Ph--
8-(N)--N'-dimethylpiperazinium, I.sup.- 62 ethyl Ph-- 8-NH--CBZ 63
ethyl Ph-- 8-NHC(O)C.sub.5H.sub.11 64 ethyl Ph-- 8-NHC(O)CH.sub.2Br
65 ethyl Ph-- 8-NH--C(NH)NH.sub.2 66 ethyl Ph-- 8-(2)-thiophene 67
ethyl Ph-- 9-methyl 68 ethyl Ph-- 9-ethyl 69 ethyl Ph--
9-iso-propyl 70 ethyl Ph-- 9-tert-butyl 71 ethyl Ph-- 9-OH 72 ethyl
Ph-- 9-OCH.sub.3 73 ethyl Ph-- 9-O(iso-propyl) 74 ethyl Ph--
9-SCH.sub.3 75 ethyl Ph-- 9-SOCH.sub.3 76 ethyl Ph--
9-SO.sub.2CH.sub.3 77 ethyl Ph-- 9-SCH.sub.2CH.sub.3 78 ethyl Ph--
9-NH.sub.2 79 ethyl Ph-- 9-NHOH 80 ethyl Ph-- 9-NHCH.sub.3 81 ethyl
Ph-- 9-N(CH.sub.3).sub.2 82 ethyl Ph-- 9-N.sup.+(CH.sub.3).sub.3,
I.sup.- 83 ethyl Ph-- 9-NHC(.dbd.O)CH.sub.3 84 ethyl Ph--
9-N(CH.sub.2CH.sub.3).sub.2 85 ethyl Ph-- 9-NMeCH.sub.2CO.sub.2H 86
ethyl Ph-- 9-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H, I.sup.- 87 ethyl
Ph-- 9-(N)-morpholine 88 ethyl Ph-- 9-(N)-azetidine 89 ethyl Ph--
9-(N)--N-methylazetidinium, I.sup.- 90 ethyl Ph-- 9-(N)-pyrrolidine
91 ethyl Ph-- 9-(N)--N-methyl-pyrrolidinium, I.sup.- 92 ethyl Ph--
9-(N)--N-methylmorpholinium, I.sup.- 93 ethyl Ph--
9-(N)--N'-methylpiperazine 93 ethyl Ph--
9-(N)--N'-dimethylpiperazinium, I.sup.- 95 ethyl Ph-- 9-NH--CBZ 96
ethyl Ph-- 9-NHC(O)C.sub.5H.sub.11 97 ethyl Ph-- 9-NHC(O)CH.sub.2Br
98 ethyl Ph-- 9-NH--C(NH)NH.sub.2 99 ethyl Ph-- 9-(2)-thiophene 100
ethyl Ph-- 7-OCH.sub.3, 8-OCH.sub.3 101 ethyl Ph-- 7-SCH.sub.3,
8-OCH.sub.3 102 ethyl Ph-- 7-SCH.sub.3, 8-SCH.sub.3 103 ethyl Ph--
6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3 F101.002 01 n-propyl Ph--
7-methyl 02 n-propyl Ph-- 7-ethyl 03 n-propyl Ph-- 7-iso-propyl 04
n-propyl Ph-- 7-tert-butyl 05 n-propyl Ph-- 7-OH 06 n-propyl Ph--
7-OCH.sub.3 07 n-propyl Ph-- 7-O(iso-propyl) 08 n-propyl Ph--
7-SCH.sub.3 09 n-propyl Ph-- 7-SOCH.sub.3 10 n-propyl Ph--
7-SO.sub.2CH.sub.3 11 n-propyl Ph-- 7-SCH.sub.2CH.sub.3 12 n-propyl
Ph-- 7-NH.sub.2 13 n-propyl Ph-- 7-NHOH 14 n-propyl Ph--
7-NHCH.sub.3 15 n-propyl Ph-- 7-N(CH.sub.3).sub.2 16 n-propyl Ph--
7-N.sup.+(CH.sub.3).sub.3, I.sup.- 17 n-propyl Ph--
7-NHC(.dbd.O)CH.sub.3 18 n-propyl Ph-- 7-N(CH.sub.2CH.sub.3).sub.-
2 19 n-propyl Ph-- 7-NMeCH.sub.2CO.sub.2H 20 n-propyl Ph--
7-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H, I.sup.- 21 n-propyl Ph--
7-(N)-morpholine 22 n-propyl Ph-- 7-(N)-azetidine 23 n-propyl Ph--
7-(N)--N-methylazetidinium, I.sup.- 24 n-propyl Ph--
7-(N)-pyrrolidine 25 n-propyl Ph-- 7-(N)--N-methyl-pyrrolidi- nium,
I.sup.- 26 n-propyl Ph-- 7-(N)--N-methyl-morpholinium, I.sup.- 27
n-propyl Ph-- 7-(N)--N'-methylpiperazine 28 n-propyl Ph--
7-(N)--N'-dimethylpiperazinium, I.sup.- 29 n-propyl Ph-- 7-NH--CBZ
30 n-propyl Ph-- 7-NHC(O)C.sub.5H.sub.11 31 n-propyl Ph--
7-NHC(O)CH.sub.2Br 32 n-propyl Ph-- 7-NH--C(NH)NH.sub.2 33 n-propyl
Ph-- 7-(2)-thiophene 34 n-propyl Ph-- 8-methyl 35 n-propyl Ph--
8-ethyl 36 n-propyl Ph-- 8-iso-propyl 37 n-propyl Ph-- 8-tert-butyl
38 n-propyl Ph-- 8-OH 39 n-propyl Ph-- 8-OCH.sub.3 40 n-propyl Ph--
8-O(iso-propyl) 41 n-propyl Ph-- 8-SCH.sub.3 42 n-propyl Ph--
8-SOCH.sub.3 43 n-propyl Ph-- 8-SO.sub.2CH.sub.3 44 n-propyl Ph--
8-SCH.sub.2CH.sub.3 45 n-propyl Ph-- 8-NH.sub.2 46 n-propyl Ph--
8-NHOH 47 n-propyl Ph-- 8-NHCH.sub.3 48 n-propyl Ph--
8-N(CH.sub.3).sub.2 49 n-propyl Ph-- 8-N.sup.+(CH.sub.3).sub.3,
I.sup.- 50 n-propyl Ph-- 8-NHC(.dbd.O)CH.sub.3 51 n-propyl Ph--
8-N(CH.sub.2CH.sub.3).sub.2 52 n-propyl Ph-- 8-NMeCH.sub.2CO.sub.2H
53 n-propyl Ph-- 8-N.sup.+(Me).sub.2CH.sub- .2CO.sub.2H, I.sup.- 54
n-propyl Ph-- 8-(N)-morpholine 55 n-propyl Ph-- 8-(N)-azetidine 56
n-propyl Ph-- 8-(N)--N-methylazetidinium, I.sup.- 57 n-propyl Ph--
8-(N)-pyrrolidine 58 n-propyl Ph-- 8-(N)--N-methyl-pyrrolidinium,
I.sup.- 59 n-propyl Ph-- 8-(N)--N-methyl-morpholinium, I.sup.- 60
n-propyl Ph-- 8-(N)--N'-methylpiperazine 61 n-propyl Ph--
8-(N)--N'-dimethylpiperazinium, I.sup.- 62 n-propyl Ph-- 8-NH--CBZ
63 n-propyl Ph-- 8-NHC(O)C.sub.5H.sub.11 64 n-propyl Ph--
8-NHC(O)CH.sub.2Br 65 n-propyl Ph-- 8-NH--C(NH)NH.sub.2 66 n-propyl
Ph-- 8-(2)-thiophene 67 n-propyl Ph-- 9-methyl 68 n-propyl Ph--
9-ethyl 69 n-propyl Ph-- 9-iso-propyl 70 n-propyl Ph-- 9-tert-butyl
71 n-propyl Ph-- 9-OH 72 n-propyl Ph-- 9-OCH.sub.3 73 n-propyl Ph--
9-O(iso-propyl) 74 n-propyl Ph-- 9-SCH.sub.3 75 n-propyl Ph--
9-SOCH.sub.3 76 n-propyl Ph-- 9-SO.sub.2CH.sub.3 77 n-propyl Ph--
9-SCH.sub.2CH.sub.3 78 n-propyl Ph-- 9-NH.sub.2 79 n-propyl Ph--
9-NHOH 80 n-propyl Ph-- 9-NHCH.sub.3 81 n-propyl Ph--
9-N(CH.sub.3).sub.2 82 n-propyl Ph-- 9-N.sup.+(CH.sub.3).sub.3,
I.sup.- 83 n-propyl Ph-- 9-NHC(.dbd.O)CH.sub.3 84 n-propyl Ph--
9-N(CH.sub.2CH.sub.3).sub.2 85 n-propyl Ph-- 9-NMeCH.sub.2CO.sub.2H
86 n-propyl Ph-- 9-N.sup.+(Me).sub.2CH.sub- .2CO.sub.2H, I.sup.- 87
n-propyl Ph-- 9-(N)-morpholine 88 n-propyl Ph-- 9-(N)-azetidine 89
n-propyl Ph-- 9-(N)--N-methylazetidinium, I.sup.- 90 n-propyl Ph--
9-(N)-pyrrolidine 91 n-propyl Ph-- 9-(N)--N-methyl-pyrrolidinium,
I.sup.- 92 n-propyl Ph-- 9-(N)--N-methyl-morpholinium, I.sup.- 93
n-propyl Ph-- 9-(N)--N'-methylpiperazine 93 n-propyl Ph--
9-(N)--N'-dimethylpiperazinium, I.sup.- 95 n-propyl Ph-- 9-NH--CBZ
96 n-propyl Ph-- 9-NBC(O)C.sub.5H.sub.11 97 n-propyl Ph--
9-NHC(O)CH.sub.2Br 98 n-propyl Ph-- 9-NH--C(NH)NH.sub.2 99 n-propyl
Ph-- 9-(2)-thiophene 100 n-propyl Ph-- 7-OCH.sub.3, 8-OCH.sub.3 101
n-propyl Ph-- 7-SCH.sub.3, 8-OCH.sub.3 102 n-propyl Ph--
7-SCH.sub.3, 8-SCH.sub.3 103 n-propyl Ph-- 6-OCH.sub.3,
7-OCH.sub.3, 8-OCH.sub.3 F101.003 01 n-butyl Ph-- 7-methyl 02
n-butyl Ph-- 7-ethyl 03 n-butyl Ph-- 7-iso-propyl 04 n-butyl Ph--
7-tert-butyl 05 n-butyl Ph-- 7-OH 06 n-butyl Ph-- 7-OCH.sub.3 07
n-butyl Ph-- 7-O(iso-propyl) 08 n-butyl Ph-- 7-SCH.sub.3 09 n-butyl
Ph-- 7-SOCH.sub.3 10 n-butyl Ph-- 7-SO.sub.2CH.sub.3 11 n-butyl
Ph-- 7-SCH.sub.2CH.sub.3 12 n-butyl Ph-- 7-NH.sub.2 13 n-butyl Ph--
7-NHOH 14 n-butyl Ph-- 7-NHCH.sub.3 15 n-butyl Ph--
7-N(CH.sub.3).sub.2 16 n-butyl Ph-- 7-N.sup.+(CH.sub.3).sub.3,
I.sup.- 17 n-butyl Ph-- 7-NHC(.dbd.O)CH.sub.3 18 n-butyl Ph--
7-N(CH.sub.2CH.sub.3).sub.2 19 n-butyl Ph-- 7-NMeCH.sub.2CO.sub.2H
20 n-butyl Ph-- 7-N.sup.+(Me).sub.2CH.sub.- 2CO.sub.2H, I.sup.- 21
n-butyl Ph-- 7-(N)-morpholine 22 n-butyl Ph-- 7-(N)-azetidine 23
n-butyl Ph-- 7-(N)--N-methylazetidinium, I.sup.- 24 n-butyl Ph--
7-(N)-pyrrolidine 25 n-butyl Ph-- 7-(N)--N-methyl-pyrrolidinium,
I.sup.- 26 n-butyl Ph-- 7-(N)--N-methyl-morpholinium, I.sup.- 27
n-butyl Ph-- 7-(N)--N'-methylpiperazine 28 n-butyl Ph--
7-(N)--N'-dimethylpiperazinium, I.sup.- 29 n-butyl Ph-- 7-NH--CBZ
30 n-butyl Ph-- 7-NHC(O)C.sub.5H.sub.11 31 n-butyl Ph--
7-NHC(O)CH.sub.2Br 32 n-butyl Ph-- 7-NH--C(NH)NH.sub.2 33 n-butyl
Ph-- 7-(2)-thiophene 34 n-butyl Ph-- 8-methyl 35 n-butyl Ph--
8-ethyl 36 n-butyl Ph-- 8-iso-propyl 37 n-butyl Ph-- 8-tert-butyl
38 n-butyl Ph-- 8-OH 39 n-butyl Ph-- 8-OCH.sub.3 40 n-butyl Ph--
8-O(iso-propyl) 41 n-butyl Ph-- 8-SCH.sub.3 42 n-butyl Ph--
8-SOCH.sub.3 43 n-butyl Ph-- 8-SO.sub.2CH.sub.3 44 n-butyl Ph--
8-SCH.sub.2CH.sub.3 45 n-butyl Ph-- 8-NH.sub.2 46 n-butyl Ph--
8-NHOH 47 n-butyl Ph-- 8-NHCH.sub.3 48 n-butyl Ph--
8-N(CH.sub.3).sub.2 49 n-butyl Ph-- 8-N.sup.+(CH.sub.3).sub.3,
I.sup.- 50 n-butyl Ph-- 8-NHC(.dbd.O)CH.sub.3 51 n-butyl Ph--
8-N(CH.sub.2CH.sub.3).sub.2 52 n-butyl Ph-- 8-NMeCH.sub.2CO.sub.2H
53 n-butyl Ph-- 8-N.sup.+(Me).sub.2CH.sub.- 2CO.sub.2H, I.sup.- 54
n-butyl Ph-- 8-(N)-morpholine 55 n-butyl Ph-- 8-(N)-azetidine 56
n-butyl Ph-- 8-(N)--N-methylazetidinium, I.sup.- 57 n-butyl Ph--
8-(N)-pyrrolidine 58 n-butyl Ph-- 8-(N)--N-methyl-pyrrolidinium,
I.sup.- 59 n-butyl Ph-- 8-(N)--N-methyl-morpholinium, I.sup.- 60
n-butyl Ph-- 8-(N)--N'-methylpiperazine 61 n-butyl Ph--
8-(N)--N'-dimethylpiperazinium, I.sup.- 62 n-butyl Ph-- 8-NH--CBZ
63 n-butyl Ph-- 8-NHC(O)C.sub.5H.sub.11 64 n-butyl Ph--
8-NHC(O)CH.sub.2Br 65 n-butyl Ph-- 8-NH-C(NH)NH.sub.2 66 n-butyl
Ph-- 8-(2)-thiophene 67 n-butyl Ph-- 9-methyl 68 n-butyl Ph--
9-ethyl 69 n-butyl Ph-- 9-iso-propyl 70 n-butyl Ph-- 9-tert-butyl
71 n-butyl Ph-- 9-OH 72 n-butyl Ph-- 9-OCH.sub.3 73 n-butyl Ph--
9-O(iso-propyl) 74 n-butyl Ph-- 9-SCH.sub.3 75 n-butyl Ph--
9-SOCH.sub.3 76 n-butyl Ph-- 9-SO.sub.2CH.sub.3 77 n-butyl Ph--
9-SCH.sub.2CH.sub.3 78 n-butyl Ph-- 9-NH.sub.2 79 n-butyl Ph--
9-NHOH 80 n-butyl Ph-- 9-NHCH.sub.3 81 n-butyl Ph--
9-N(CH.sub.3).sub.2 82 n-butyl Ph-- 9-N.sup.+(CH.sub.3).sub.3,
I.sup.- 83 n-butyl Ph-- 9-NHC(.dbd.O)CH.sub.3 84 n-butyl Ph--
9-N(CH.sub.2CH.sub.3).sub.2 85 n-butyl Ph-- 9-NMeCH.sub.2CO.sub.2H
86 n-butyl Ph-- 9-N.sup.+(Me).sub.2CH.sub.- 2CO.sub.2H, I.sup.- 87
n-butyl Ph-- 9-(N)-morpholine 88 n-butyl Ph-- 9-(N)-azetidine 89
n-butyl Ph-- 9-(N)--N-methylazetidinium, I.sup.- 90 n-butyl Ph--
9-(N)-pyrrolidine 91 n-butyl Ph-- 9-(N)--N-methyl-pyrrolidinium,
I.sup.- 92 n-butyl Ph-- 9-(N)--N-methyl-morpholinium, I.sup.- 93
n-butyl Ph-- 9-(N)--N'-methylpiperazine 93 n-butyl Ph--
9-(N)--N'-dimethylpiperazinium, I.sup.- 95 n-butyl Ph-- 9-NH--CBZ
96 n-butyl Ph-- 9-NHC(O)C.sub.5H.sub.11 97 n-butyl Ph--
9-NHC(O)CH.sub.2Br 98 n-butyl Ph-- 9-NH--C(NH)NH.sub.2 99 n-butyl
Ph-- 9-(2)-thiophene 100 n-butyl Ph-- 7-OCH.sub.3, 8-OCH.sub.3 101
n-butyl Ph-- 7-SCH.sub.3, 8-OCH.sub.3 102 n-butyl Ph-- 7-SCH.sub.3,
8-SCH.sub.3 103 n-butyl Ph-- 6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3
F101.004 01 n-pentyl Ph-- 7-methyl 02 n-pentyl Ph-- 7-ethyl 03
n-pentyl Ph-- 7-iso-propyl 04 n-pentyl Ph-- 7-tert-butyl 05
n-pentyl Ph-- 7-OH 06 n-pentyl Ph-- 7-OCH.sub.3 07 n-pentyl Ph--
7-O(iso-propyl) 08 n-pentyl Ph-- 7-SCH.sub.3 09 n-pentyl Ph--
7-SOCH.sub.3 10 n-pentyl Ph-- 7-SO.sub.2CH.sub.3 11 n-pentyl Ph--
7-SCH.sub.2CH.sub.3 12 n-pentyl Ph-- 7-NH.sub.2 13 n-pentyl Ph--
7-NHOH 14 n-pentyl Ph-- 7-NHCH.sub.3 15 n-pentyl Ph--
7-N(CH.sub.3).sub.2 16 n-pentyl Ph-- 7-N.sup.+(CH.sub.3).sub.3,
I.sup.- 17 n-pentyl Ph-- 7-NHC(.dbd.O)CH.sub.3 18 n-pentyl Ph--
7-N(CH.sub.2CH.sub.3).sub.- 2 19 n-pentyl Ph--
7-NMeCH.sub.2CO.sub.2H 20 n-pentyl Ph--
7-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H, I.sup.- 21 n-pentyl Ph--
7-(N)-morpholine 22 n-pentyl Ph-- 7-(N)-azetidine 23 n-pentyl Ph--
7-(N)--N-methylazetidinium, I.sup.- 24 n-pentyl Ph--
7-(N)-pyrrolidine 25 n-pentyl Ph-- 7-(N)--N-methyl-pyrrolidi- nium,
I.sup.- 26 n-pentyl Ph-- 7-(N)--N-methyl-morpholinium, I.sup.- 27
n-pentyl Ph-- 7-(N)--N'-methylpiperazine 28 n-pentyl Ph--
7-(N)--N'-dimethylpiperazinium, I.sup.- 29 n-pentyl Ph-- 7-NH--CBZ
30 n-pentyl Ph-- 7-NHC(O)C.sub.5H.sub.11 31 n-pentyl Ph--
7-NHC(O)CH.sub.2Br 32 n-pentyl Ph-- 7-NH--C(NH)NH.sub.2 33 n-pentyl
Ph-- 7-(2)-thiophene 34 n-pentyl Ph-- 8-methyl 35 n-pentyl Ph--
8-ethyl 36 n-pentyl Ph-- 8-iso-propyl 37 n-pentyl Ph-- 8-tert-butyl
38 n-pentyl Ph-- 8-OH 39 n-pentyl Ph-- 8-OCH.sub.3 40 n-pentyl Ph--
8-O(iso-propyl) 41 n-pentyl Ph-- 8-SCH.sub.3 42 n-pentyl Ph--
8-SOCH.sub.3 43 n-pentyl Ph-- 8-SO.sub.2CH.sub.3 44 n-pentyl Ph--
8-SCH.sub.2CH.sub.3 45 n-pentyl Ph-- 8-NH.sub.2 46 n-pentyl Ph--
8-NHOH 47 n-pentyl Ph-- 8-NHCH.sub.3 48 n-pentyl Ph--
8-N(CH.sub.3).sub.2 49 n-pentyl Ph-- 8-N.sup.+(CH.sub.3).sub.3,
I.sup.- 50 n-pentyl Ph-- 8-NHC(.dbd.O)CH.sub.3 51 n-pentyl Ph--
8-N(CH.sub.2CH.sub.3).sub.2 52 n-pentyl Ph-- 8-NMeCH.sub.2CO.sub.2H
53 n-pentyl Ph-- 8-N.sup.+(Me).sub.2CH.sub- .2CO.sub.2H, I.sup.- 54
n-pentyl Ph-- 8-(N)-morpholine 55 n-pentyl Ph-- 8-(N)-azetidine 56
n-pentyl Ph-- 8-(N)--N-methylazetidinium, I.sup.- 57 n-pentyl Ph--
8-(N)-pyrrolidine 58 n-pentyl Ph-- 8-(N)--N-methyl-pyrrolidinium,
I.sup.- 59 n-pentyl Ph-- 8-(N)--N-methyl-morpholinium, I.sup.- 60
n-pentyl Ph-- 8-(N)--N'-methylpiperazine 61 n-pentyl Ph--
8-(N)--N'-dimethylpiperazinium, I.sup.- 62 n-pentyl Ph-- 8-NH--CBZ
63 n-pentyl Ph-- 8-NHC(O)C.sub.5H.sub.11 64 n-pentyl Ph--
8-NHC(O)CH.sub.2Br 65 n-pentyl Ph-- 8-NH--C(NH)NH.sub.2 66 n-pentyl
Ph-- 8-(2)-thiophene 67 n-pentyl Ph-- 9-methyl 68 n-pentyl Ph--
9-ethyl 69 n-pentyl Ph-- 9-iso-propyl 70 n-pentyl Ph-- 9-tert-butyl
71 n-pentyl Ph-- 9-OH 72 n-pentyl Ph-- 9-OCH.sub.3 73 n-pentyl Ph--
9-O(iso-propyl) 74 n-pentyl Ph-- 9-SCH.sub.3 75 n-pentyl Ph--
9-SOCH.sub.3 76 n-pentyl Ph-- 9-SO.sub.2CH.sub.3 77 n-pentyl Ph--
9-SCH.sub.2CH.sub.3 78 n-pentyl Ph-- 9-NH.sub.2 79 n-pentyl Ph--
9-NHOH 80
n-pentyl Ph-- 9-NHCH.sub.3 81 n-pentyl Ph-- 9-N(CH.sub.3).sub.2 82
n-pentyl Ph-- 9-N.sup.+(CH.sub.3).sub.3, I.sup.- 83 n-pentyl Ph--
9-NHC(.dbd.O)CH.sub.3 84 n-pentyl Ph-- 9-N(CH.sub.2CH.sub.3).sub.2
85 n-pentyl Ph-- 9-NMeCH.sub.2CO.sub.2H 86 n-pentyl Ph--
9-N.sup.+(Me).sub.2CH.sub- .2CO.sub.2H, I.sup.- 87 n-pentyl Ph--
9-(N)-morpholine 88 n-pentyl Ph-- 9-(N)-azetidine 89 n-pentyl Ph--
9-(N)--N-methylazetidinium, I.sup.- 90 n-pentyl Ph--
9-(N)-pyrrolidine 91 n-pentyl Ph-- 9-(N)--N-methyl-pyrrolidinium,
I.sup.- 92 n-pentyl Ph-- 9-(N)--N-methyl-morpholinium, I.sup.- 93
n-pentyl Ph-- 9-(N)--N'-methylpiperazine 93 n-pentyl Ph--
9-(N)--N'-dimethylpiperazinium, I.sup.- 95 n-pentyl Ph-- 9-NH--CBZ
96 n-pentyl Ph-- 9-NHC(O)C.sub.5H.sub.11 97 n-pentyl Ph--
9-NHC(O)CH.sub.2Br 98 n-pentyl Ph-- 9-NH--C(NH)NH.sub.2 99 n-pentyl
Ph-- 9-(2)-thiophene 100 n-pentyl Ph-- 7-OCH.sub.3, 8-OCH.sub.3 101
n-pentyl Ph-- 7-SCH.sub.3, 8-OCH.sub.3 102 n-pentyl Ph--
7-SCH.sub.3, 8-SCH.sub.3 103 n-pentyl Ph-- 6-OCH.sub.3,
7-OCH.sub.3, 8-OCH.sub.3 F101.005 01 n-hexyl Ph-- 7-methyl 02
n-hexyl Ph-- 7-ethyl 03 n-hexyl Ph-- 7-iso-propyl 04 n-hexyl Ph--
7-tert-butyl 05 n-hexyl Ph-- 7-OH 06 n-hexyl Ph-- 7-OCH.sub.3 07
n-hexyl Ph-- 7-O(iso-propyl) 08 n-hexyl Ph-- 7-SCH.sub.3 09 n-hexyl
Ph-- 7-SOCH.sub.3 10 n-hexyl Ph-- 7-SO.sub.2CH.sub.3 11 n-hexyl
Ph-- 7-SCH.sub.2CH.sub.3 12 n-hexyl Ph-- 7-NH.sub.2 13 n-hexyl Ph--
7-NHOH 14 n-hexyl Ph-- 7-NHCH.sub.3 15 n-hexyl Ph--
7-N(CH.sub.3).sub.2 16 n-hexyl Ph-- 7-N.sup.+(CH.sub.3).sub.3,
I.sup.- 17 n-hexyl Ph-- 7-NHC(.dbd.O)CH.sub.3 18 n-hexyl Ph--
7-N(CH.sub.2CH.sub.3).sub.2 19 n-hexyl Ph-- 7-NMeCH.sub.2CO.sub.2H
20 n-hexyl Ph-- 7-N.sup.+(Me).sub.2CH.sub.- 2CO.sub.2H, I.sup.- 21
n-hexyl Ph-- 7-(N)-morpholine 22 n-hexyl Ph-- 7-(N)-azetidine 23
n-hexyl Ph-- 7-(N)--N-methylazetidinium, I.sup.- 24 n-hexyl Ph--
7-(N)-pyrrolidine 25 n-hexyl Ph-- 7-(N)--N-methyl-pyrrolidinium,
I.sup.- 26 n-hexyl Ph-- 7-(N)--N-methyl-morpholinium, I.sup.- 27
n-hexyl Ph-- 7-(N)--N'-methylpiperazine 28 n-hexyl Ph--
7-(N)--N'-dimethylpiperazinium, I.sup.- 29 n-hexyl Ph-- 7-NH--CBZ
30 n-hexyl Ph-- 7-NHC(O)C.sub.5H.sub.11 31 n-hexyl Ph--
7-NHC(O)CH.sub.2Br 32 n-hexyl Ph-- 7-NH--C(NH)NH.sub.2 33 n-hexyl
Ph-- 7-(2)-thiophene 34 n-hexyl Ph-- 8-methyl 35 n-hexyl Ph--
8-ethyl 36 n-hexyl Ph-- 8-iso-propyl 37 n-hexyl Ph-- 8-tert-butyl
38 n-hexyl Ph-- 8-OH 39 n-hexyl Ph-- 8-OCH.sub.3 40 n-hexyl Ph--
8-O(iso-propyl) 41 n-hexyl Ph-- 8-SCH.sub.3 42 n-hexyl Ph--
8-SOCH.sub.3 43 n-hexyl Ph-- 8-SO.sub.2CH.sub.3 44 n-hexyl Ph--
8-SCH.sub.2CH.sub.3 45 n-hexyl Ph-- 8-NH.sub.2 46 n-hexyl Ph--
8-NHOH 47 n-hexyl Ph-- 8-NHCH.sub.3 48 n-hexyl Ph--
8-N(CH.sub.3).sub.2 49 n-hexyl Ph-- 8-N.sup.+(CH.sub.3).sub.3,
I.sup.- 50 n-hexyl Ph-- 8-NHC(.dbd.O)CH.sub.3 51 n-hexyl Ph--
8-N(CH.sub.2CH.sub.3).sub.2 52 n-hexyl Ph-- 8-NMeCH.sub.2CO.sub.2H
53 n-hexyl Ph-- 8-N.sup.+(Me).sub.2CH.sub.- 2CO.sub.2H, I.sup.- 54
n-hexyl Ph-- 8-(N)-morpholine 55 n-hexyl Ph-- 8-(N)-azetidine 56
n-hexyl Ph-- 8-(N)--N-methylazetidinium, I.sup.- 57 n-hexyl Ph--
8-(N)-pyrrolidine 58 n-hexyl Ph-- 8-(N)--N-methyl-pyrrolidinium,
I.sup.- 59 n-hexyl Ph-- 8-(N)--N-methyl-morpholinium, I.sup.- 60
n-hexyl Ph-- 8-(N)--N'-methylpiperazine 61 n-hexyl Ph--
8-(N)--N'-dimethylpiperazinium, I.sup.- 62 n-hexyl Ph-- 8-NH--CBZ
63 n-hexyl Ph-- 8-NHC(O)C.sub.5H.sub.11 64 n-hexyl Ph--
8-NHC(O)CH.sub.2Br 65 n-hexyl Ph-- 8-NH--C(NH)NH.sub.2 66 n-hexyl
Ph-- 8-(2)-thiophene 67 n-hexyl Ph-- 9-methyl 68 n-hexyl Ph--
9-ethyl 69 n-hexyl Ph-- 9-iso-propyl 70 n-hexyl Ph-- 9-tert-butyl
71 n-hexyl Ph-- 9-OH 72 n-hexyl Ph-- 9-OCH.sub.3 73 n-hexyl Ph--
9-O(iso-propyl) 74 n-hexyl Ph-- 9-SCH.sub.3 75 n-hexyl Ph--
9-SOCH.sub.3 76 n-hexyl Ph-- 9-SO.sub.2CH.sub.3 77 n-hexyl Ph--
9-SCH.sub.2CH.sub.3 78 n-hexyl Ph-- 9-NH.sub.2 79 n-hexyl Ph--
9-NHOH 80 n-hexyl Ph-- 9-NHCH.sub.3 81 n-hexyl Ph--
9-N(CH.sub.3).sub.2 82 n-hexyl Ph-- 9-N.sup.+(CH.sub.3).sub.3,
I.sup.- 83 n-hexyl Ph-- 9-NHC(.dbd.O)CH.sub.3 84 n-hexyl Ph--
9-N(CH.sub.2CH.sub.3).sub.2 85 n-hexyl Ph-- 9-NMeCH.sub.2CO.sub.2H
86 n-hexyl Ph-- 9-N.sup.+(Me).sub.2CH.sub.- 2CO.sub.2H, I.sup.- 87
n-hexyl Ph-- 9-(N)-morpholine 88 n-hexyl Ph-- 9-(N)-azetidine 89
n-hexyl Ph-- 9-(N)--N-methylazetidine, I.sup.- 90 n-hexyl Ph--
9-(N)-pyrrolidine 91 n-hexyl Ph-- 9-(N)--N-methyl-pyrrolidinium,
I.sup.- 92 n-hexyl Ph-- 9-(N)--N-methyl-morpholinium, I.sup.- 93
n-hexyl Ph-- 9-(N)--N'-methylpiperazine 93 n-hexyl Ph--
9-(N)--N'-dimethylpiperazinium 95 n-hexyl Ph-- 9-NH--CBZ 96 n-hexyl
Ph-- 9-NHC(O)C.sub.5H.sub.11 97 n-hexyl Ph-- 9-NHC(O)CH.sub.2Br 98
n-hexyl Ph-- 9-NH--C(NH)NH.sub.2 99 n-hexyl Ph-- 9-(2)-thiophene
100 n-hexyl Ph-- 7-OCH.sub.3, 8-OCH.sub.3 101 n-hexyl Ph--
7-SCH.sub.3, 8-OCH.sub.3 102 n-hexyl Ph-- 7-SCH.sub.3, 8-SCH.sub.3
103 n-hexyl Ph-- 6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3 F101.006 01
iso-propyl Ph-- 7-methyl 02 iso-propyl Ph-- 7-ethyl 03 iso-propyl
Ph-- 7-iso-propyl 04 iso-propyl Ph-- 7-tert-butyl 05 iso-propyl
Ph-- 7-OH 06 iso-propyl Ph-- 7-OCH.sub.3 07 iso-propyl Ph--
7-O(iso-propyl) 08 iso-propyl Ph-- 7-SCH.sub.3 09 iso-propyl Ph--
7-SOCH.sub.3 10 iso-propyl Ph-- 7-SO.sub.2CH.sub.3 11 iso-propyl
Ph-- 7-SCH.sub.2CH.sub.3 12 iso-propyl Ph-- 7-NH.sub.2 13
iso-propyl Ph-- 7-NHOH 14 iso-propyl Ph-- 7-NHCH.sub.3 15
iso-propyl Ph-- 7-N(CH.sub.3).sub.2 16 iso-propyl Ph--
7-N.sup.+(CH.sub.3).sub.3, I.sup.- 17 iso-propyl Ph--
7-NHC(.dbd.O)CH.sub.3 18 iso-propyl Ph--
7-N(CH.sub.2CH.sub.3).sub.2 19 iso-propyl Ph--
7-NMeCH.sub.2CO.sub.2H 20 iso-propyl Ph-- 7-N.sup.+(Me).sub.2CH.s-
ub.2CO.sub.2H, I.sup.- 21 iso-propyl Ph-- 7-(N)-morpholine 22
iso-propyl Ph-- 7-(N)-azetidine 23 iso-propyl Ph--
7-(N)--N-methylazetidinium, I.sup.- 24 iso-propyl Ph--
7-(N)-pyrrolidine 25 iso-propyl Ph-- 7-(N)--N-methyl-pyrrolidiniu-
m, I.sup.- 26 iso-propyl Ph-- 7-(N)--N-methyl-morpholinium, I.sup.-
27 iso-propyl Ph-- 7-(N)--N'-methylpiperazine 28 iso-propyl Ph--
7-(N)--N'-dimethylpiperazinium, I.sup.- 29 iso-propyl Ph--
7-NH--CBZ 30 iso-propyl Ph-- 7-NHC(O)C.sub.5H.sub.11 31 iso-propyl
Ph-- 7-NHC(O)CH.sub.2Br 32 iso-propyl Ph-- 7-NH--C(NH)NH.sub.2 33
iso-propyl Ph-- 7-(2)-thiophene 34 iso-propyl Ph-- 8-methyl 35
iso-propyl Ph-- 8-ethyl 36 iso-propyl Ph-- 8-iso-propyl 37
iso-propyl Ph-- 8-tert-butyl 38 iso-propyl Ph-- 8-OH 39 iso-propyl
Ph-- 8-OCH.sub.3 40 iso-propyl Ph-- 8-O(iso-propyl) 41 iso-propyl
Ph-- 8-SCH.sub.3 42 iso-propyl Ph-- 8-SOCH.sub.3 43 iso-propyl Ph--
8-SO.sub.2CH.sub.3 44 iso-propyl Ph-- 8-SCH.sub.2CH.sub.3 45
iso-propyl Ph-- 8-NH.sub.2 46 iso-propyl Ph-- 8-NHOH 47 iso-propyl
Ph-- 8-NHCH.sub.3 48 iso-propyl Ph-- 8-N(CH.sub.3).sub.2 49
iso-propyl Ph-- 8-N.sup.+(CH.sub.3).sub.3, I.sup.- 50 iso-propyl
Ph-- 8-NHC(.dbd.O)CH.sub.3 51 iso-propyl Ph--
8-N(CH.sub.2CH.sub.3).su- b.2 52 iso-propyl Ph--
8-NMeCH.sub.2CO.sub.2H 53 iso-propyl Ph--
8-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H, I.sup.- 54 iso-propyl Ph--
8-(N)-morpholine 55 iso-propyl Ph-- 8-(N)-azetidine 56 iso-propyl
Ph-- 8-(N)--N-methylazetidinium, I.sup.- 57 iso-propyl Ph--
8-(N)-pyrrolidine 58 iso-propyl Ph-- 8-(N)--N-methyl-pyrrolidinium,
I.sup.- 59 iso-propyl Ph-- 8-(N)--N-methyl-morpholinium, I.sup.- 60
iso-propyl Ph-- 8-(N)--N'methylpiperazine 61 iso-propyl Ph--
8-(N)--N'-dimethylpiperazinium, I.sup.- 62 iso-propyl Ph--
8-NH--CBZ 63 iso-propyl Ph-- 8-NHC(O)C.sub.5H.sub.11 64 iso-propyl
Ph-- 8-NHC(O)CH.sub.2Br 65 iso-propyl Ph-- 8-NH--C(NH)NH.sub.2 66
iso-propyl Ph-- 8-(2)-thiophene 67 iso-propyl Ph-- 9-methyl 68
iso-propyl Ph-- 9-ethyl 69 iso-propyl Ph-- 9-iso-propyl 70
iso-propyl Ph-- 9-tert-butyl 71 iso-propyl Ph-- 9-OH 72 iso-propyl
Ph-- 9-OCH.sub.3 73 iso-propyl Ph-- 9-O(iso-propyl) 74 iso-propyl
Ph-- 9-SCH.sub.3 75 iso-propyl Ph-- 9-SOCH.sub.3 76 iso-propyl Ph--
9-SO.sub.2CH.sub.3 77 iso-propyl Ph-- 9-SCH.sub.2CH.sub.3 78
iso-propyl Ph-- 9-NH.sub.2 79 iso-propyl Ph-- 9-NHOH 80 iso-propyl
Ph-- 9-NHCH.sub.3 81 iso-propyl Ph-- 9-N(CH.sub.3).sub.2 82
iso-propyl Ph-- 9-N.sup.+(CH.sub.3).sub.3, I.sup.- 83 iso-propyl
Ph-- 9-NHC(.dbd.O)CH.sub.3 84 iso-propyl Ph--
9-N(CH.sub.2CH.sub.3).sub.2 85 iso-propyl Ph--
9-NMeCH.sub.2CO.sub.2H 86 iso-propyl Ph-- 9-N.sup.+(Me).sub.2CH.s-
ub.2CO.sub.2H, I.sup.- 87 iso-propyl Ph-- 9-(N)-morpholine 88
iso-propyl Ph-- 9-(N)-azetidine 89 iso-propyl Ph--
9-(N)--N-methylazetidinium, I.sup.- 90 iso-propyl Ph--
9-(N)-pyrrolidine 91 iso-propyl Ph-- 9-(N)--N-methyl-pyrrolidiniu-
m, I.sup.- 92 iso-propyl Ph-- 9-(N)--N-methyl-morpholinium, I.sup.-
93 iso-propyl Ph-- 9-(N)--N'-methylpiperazine 93 iso-propyl Ph--
9-(N)--N'-dimethylpiperazinium, I.sup.- 95 iso-propyl Ph--
9-NH--CBZ 96 iso-propyl Ph-- 9-NHC(O)C.sub.5H.sub.11 97 iso-propyl
Ph-- 9-NHC(O)CH.sub.2Br 98 iso-propyl Ph-- 9-NH--C(NH)NH.sub.2 99
iso-propyl Ph-- 9-(2)-thiophene 100 iso-propyl Ph-- 7-OCH.sub.3,
8-OCH.sub.3 101 iso-propyl Ph-- 7-SCH.sub.3, 8-OCH.sub.3 102
iso-propyl Ph-- 7-SCH.sub.3, 8-SCH.sub.3 103 iso-propyl Ph--
6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3 F101.007 01 iso-butyl Ph--
7-methyl 02 iso-butyl Ph-- 7-ethyl 03 iso-butyl Ph-- 7-iso-propyl
04 iso-butyl Ph-- 7-tert-butyl 05 iso-butyl Ph-- 7-OH 06 iso-butyl
Ph-- 7-OCH.sub.3 07 iso-butyl Ph-- 7-O(iso-propyl) 08 iso-butyl
Ph-- 7-SCH.sub.3 09 iso-butyl Ph-- 7-SOCH.sub.3 10 iso-butyl Ph--
7-SO.sub.2CH.sub.3 11 iso-butyl Ph-- 7-SCH.sub.2CH.sub.3 12
iso-butyl Ph-- 7-NH.sub.2 13 iso-butyl Ph-- 7-NHOH 14 iso-butyl
Ph-- 7-NHCH.sub.3 15 iso-butyl Ph-- 7-N(CH.sub.3).sub.2 16
iso-butyl Ph-- 7-N.sup.+(CH.sub.3).sub.3, I.sup.- 17 iso-butyl Ph--
7-NHC(.dbd.O)CH.sub.3 18 iso-butyl Ph-- 7-N(CH.sub.2CH.sub.3).sub-
.2 19 iso-butyl Ph-- 7-NMeCH.sub.2CO.sub.2H 20 iso-butyl Ph--
7-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H, I.sup.- 21 iso-butyl Ph--
7-(N)-morpholine 22 iso-butyl Ph-- 7-(N)-azetidine 23 iso-butyl
Ph-- 7-(N)--N-methylazetidinium, I.sup.- 24 iso-butyl Ph--
7-(N)-pyrrolidine 25 iso-butyl Ph-- 7-(N)--N-methyl-pyrrolidinium,
I.sup.- 26 iso-butyl Ph-- 7-(N)--N-methyl-morpholinium, I.sup.- 27
iso-butyl Ph-- 7-(N)--N'-methylpiperazine 28 iso-butyl Ph--
7-(N)--N'-dimethylpiperazinium, I.sup.- 29 iso-butyl Ph-- 7-NH--CBZ
30 iso-butyl Ph-- 7-NHC(O)C.sub.5H.sub.11 31 iso-butyl Ph--
7-NHC(O)CH.sub.2Br 32 iso-butyl Ph-- 7-NH--C(NH)NH.sub.2 33
iso-butyl Ph-- 7-(2)-thiophene 34 iso-butyl Ph-- 8-methyl 35
iso-butyl Ph-- 8-ethyl 36 iso-butyl Ph-- 8-iso-propyl 37 iso-butyl
Ph-- 8-tert-butyl 38 iso-butyl Ph-- 8-OH 39 iso-butyl Ph--
8-OCH.sub.3 40 iso-butyl Ph-- 8-O(iso-propyl) 41 iso-butyl Ph--
8-SCH.sub.3 42 iso-butyl Ph-- 8-SOCH.sub.3 43 iso-butyl Ph--
8-SO.sub.2CH.sub.3 44 iso-butyl Ph-- 8-SCH.sub.2CH.sub.3 45
iso-butyl Ph-- 8-NH.sub.2 46 iso-butyl Ph-- 8-NHOH 47 iso-butyl
Ph-- 8-NHCH.sub.3 48 iso-butyl Ph-- 8-N(CH.sub.3).sub.2 49
iso-butyl Ph-- 8-N.sup.+(CH.sub.3).sub.3, I.sup.- 50 iso-butyl Ph--
8-NHC(.dbd.O)CH.sub.3 51 iso-butyl Ph-- 8-N(CH.sub.2CH.sub.3).sub.2
52 iso-butyl Ph-- 8-NMeCH.sub.2CO.sub.2H 53 iso-butyl Ph--
8-N.sup.+(Me).sub.2CH.su- b.2CO.sub.2H, I.sup.- 54 iso-butyl Ph--
8-(N)-morpholine 55 iso-butyl Ph-- 8-(N)-azetidine 56 iso-butyl
Ph-- 8-(N)--N-methylazetidinium, I.sup.- 57 iso-butyl Ph--
8-(N)-pyrrolidine 58 iso-butyl Ph-- 8-(N)--N-methyl-pyrrolidinium-
, I.sup.- 59 iso-butyl Ph-- 8-(N)--N-methyl-morpholinium, I.sup.-
60 iso-butyl Ph-- 8-(N)--N'-methylpiperazine 61 iso-butyl Ph--
8-(N)--N'-dimethylpiperazinium, I.sup.- 62 iso-butyl Ph-- 8-NH--CBZ
63 iso-butyl Ph-- 8-NHC(O)C.sub.5H.sub.11 64 iso-butyl Ph--
8-NHC(O)CH.sub.2Br 65 iso-butyl Ph-- 8-NH--C(NH)NH.sub.2 66
iso-butyl Ph-- 8-(2)-thiophene 67 iso-butyl Ph-- 9-methyl 68
iso-butyl Ph-- 9-ethyl 69 iso-butyl Ph-- 9-iso-propyl 70 iso-butyl
Ph-- 9-tert-butyl 71 iso-butyl Ph-- 9-OH 72 iso-butyl Ph--
9-OCH.sub.3 73 iso-butyl Ph-- 9-O(iso-propyl) 74 iso-butyl Ph--
9-SCH.sub.3 75 iso-butyl Ph-- 9-SOCH.sub.3 76 iso-butyl Ph--
9-SO.sub.2CH.sub.3 77 iso-butyl Ph-- 9-SCH.sub.2CH.sub.3 78
iso-butyl Ph-- 9-NH.sub.2 79 iso-butyl Ph-- 9-NHOH 80 iso-butyl
Ph-- 9-NHCH.sub.3 81 iso-butyl Ph-- 9-N(CH.sub.3).sub.2 82
iso-butyl Ph-- 9-N.sup.+(CH.sub.3).sub.3, I.sup.- 83 iso-butyl Ph--
9-NHC(.dbd.O)CH.sub.3 84 iso-butyl Ph-- 9-N(CH.sub.2CH.sub.3).sub.2
85 iso-butyl Ph-- 9-NMeCH.sub.2CO.sub.2H 86 iso-butyl Ph--
9-N.sup.+(Me).sub.2CH.su- b.2CO.sub.2H, I.sup.- 87 iso-butyl Ph--
9-(N)-morpholine 88 iso-butyl Ph-- 9-(N)-azetidine 89 iso-butyl
Ph-- 9-(N)--N-methylazetidinium, I.sup.- 90 iso-butyl Ph--
9-(N)-pyrrolidine 91 iso-butyl Ph-- 9-(N)--N-methyl-pyrrolidinium-
, I.sup.- 92 iso-butyl Ph-- 9-(N)--N-methyl-morpholinium, I.sup.-
93 iso-butyl Ph-- 9-(N)--N'-methylpiperazine 93 iso-butyl Ph--
9-(N)--N'-dimethylpiperazinium, I.sup.- 95 iso-butyl Ph-- 9-NH--CBZ
96 iso-butyl Ph-- 9-NHC(O)C.sub.5H.sub.11 97 iso-butyl Ph--
9-NHC(O)CH.sub.2Br 98 iso-butyl Ph-- 9-NH--C(NH)NH.sub.2 99
iso-butyl Ph-- 9-(2)-thiophene 100 iso-butyl Ph-- 7-OCH.sub.3,
8-OCH.sub.3 101 iso-butyl Ph-- 7-SCH.sub.3, 8-OCH.sub.3 102
iso-butyl Ph-- 7-SCH.sub.3, 8-SCH.sub.3 103 iso-butyl Ph--
6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3 F101.008 01 iso-pentyl Ph--
7-methyl 02 iso-pentyl Ph-- 7-ethyl 03 iso-pentyl Ph-- 7-iso-propyl
04 iso-pentyl Ph-- 7-tert-butyl 05 iso-pentyl Ph-- 7-OH 06
iso-pentyl Ph-- 7-OCH.sub.3 07 iso-pentyl Ph-- 7-O(iso-propyl) 08
iso-pentyl Ph-- 7-SCH.sub.3 09 iso-pentyl Ph-- 7-SOCH.sub.3 10
iso-pentyl Ph-- 7-SO.sub.2CH.sub.3 11 iso-pentyl Ph--
7-SCH.sub.2CH.sub.3 12 iso-pentyl Ph-- 7-NH.sub.2 13 iso-pentyl
Ph-- 7-NHOH 14 iso-pentyl Ph-- 7-NHCH.sub.3 15 iso-pentyl Ph--
7-N(CH.sub.3).sub.2 16 iso-pentyl Ph-- 7-N.sup.+(CH.sub.3).sub.3,
I.sup.- 17 iso-pentyl Ph-- 7-NHC(.dbd.O)CH.sub.3 18 iso-pentyl Ph--
7-N(CH.sub.2CH.sub.3).su- b.2 19 iso-pentyl Ph--
7-NMeCH.sub.2CO.sub.2H 20 iso-pentyl Ph--
7-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H, I.sup.- 21 iso-pentyl Ph--
7-(N)-morpholine 22 iso-pentyl Ph-- 7-(N)-azetidine 23 iso-pentyl
Ph-- 7-(N)--N-methylazetidinium, I.sup.- 24 iso-pentyl Ph--
7-(N)-pyrrolidine 25 iso-pentyl Ph-- 7-(N)--N-methyl-pyrrolidinium,
I.sup.- 26 iso-pentyl Ph-- 7-(N)--N-methyl-morpholinium, I.sup.- 27
iso-pentyl Ph-- 7-(N)--N'-methylpiperazine 28 iso-pentyl Ph--
7-(N)--N'-dimethylpiperazinium, I.sup.- 29 iso-pentyl Ph--
7-NH--CBZ 30 iso-pentyl Ph-- 7-NHC(O)C.sub.5H.sub.11 31 iso-pentyl
Ph-- 7-NHC(O)CH.sub.2Br 32 iso-pentyl Ph-- 7-NH--C(NH)NH.sub.2 33
iso-pentyl Ph-- 7-(2)-thiophene 34 iso-pentyl Ph-- 8-methyl 35
iso-pentyl Ph-- 8-ethyl 36 iso-pentyl Ph-- 8-iso-propyl 37
iso-pentyl Ph-- 8-tert-butyl 38 iso-pentyl Ph-- 8-OH 39 iso-pentyl
Ph-- 8-OCH.sub.3
40 iso-pentyl Ph-- 8-O(iso-propyl) 41 iso-pentyl Ph-- 8-SCH.sub.3
42 iso-pentyl Ph-- 8-SOCH.sub.3 43 iso-pentyl Ph--
8-SO.sub.2CH.sub.3 44 iso-pentyl Ph-- 8-SCH.sub.2CH.sub.3 45
iso-pentyl Ph-- 8-NH.sub.2 46 iso-pentyl Ph-- 8-NHOH 47 iso-pentyl
Ph-- 8-NHCH.sub.3 48 iso-pentyl Ph-- 8-N(CH.sub.3).sub.2 49
iso-pentyl Ph-- 8-N.sup.+(CH.sub.3).sub.3, I.sup.- 50 iso-pentyl
Ph-- 8-NHC(.dbd.O)CH.sub.3 51 iso-pentyl Ph--
8-N(CH.sub.2CH.sub.3).sub.2 52 iso-pentyl Ph--
8-NMeCH.sub.2CO.sub.2H 53 iso-pentyl Ph-- 8-N.sup.+(Me).sub.2CH.s-
ub.2CO.sub.2H, I.sup.- 54 iso-pentyl Ph-- 8-(N)-morpholine 55
iso-pentyl Ph-- 8-(N)-azetidine 56 iso-pentyl Ph--
8-(N)--N-methylazetidinium, I.sup.- 57 iso-pentyl Ph--
8-(N)-pyrrolidine 58 iso-pentyl Ph-- 8-(N)--N-methyl-pyrrolidiniu-
m, I.sup.- 59 iso-pentyl Ph-- 8-(N)--N-methyl-morpholinium, I.sup.-
60 iso-pentyl Ph-- 8-(N)--N'-methylpiperazine 61 iso-pentyl Ph--
8-(N)--N'-dimethylpiperazinium, I.sup.- 62 iso-pentyl Ph--
8-NH--CBZ 63 iso-pentyl Ph-- 8-NHC(O)C.sub.5H.sub.11 64 iso-pentyl
Ph-- 8-NHC(O)CH.sub.2Br 65 iso-pentyl Ph-- 8-NH--C(NH)NH.sub.2 66
iso-pentyl Ph-- 8-(2)-thiophene 67 iso-pentyl Ph-- 9-methyl 68
iso-pentyl Ph-- 9-ethyl 69 iso-pentyl Ph-- 9-iso-propyl 70
iso-pentyl Ph-- 9-tert-butyl 71 iso-pentyl Ph-- 9-OH 72 iso-pentyl
Ph-- 9-OCH.sub.3 73 iso-pentyl Ph-- 9-O(iso-propyl) 74 iso-pentyl
Ph-- 9-SCH.sub.3 75 iso-pentyl Ph-- 9-SOCH.sub.3 76 iso-pentyl Ph--
9-SO.sub.2CH.sub.3 77 iso-pentyl Ph-- 9-SCH.sub.2CH.sub.3 78
iso-pentyl Ph-- 9-NH.sub.2 79 iso-pentyl Ph-- 9-NHOH 80 iso-pentyl
Ph-- 9-NHCH.sub.3 81 iso-pentyl Ph-- 9-N(CH.sub.3).sub.2 82
iso-pentyl Ph-- 9-N.sup.+(CH.sub.3).sub.3, I.sup.- 83 iso-pentyl
Ph-- 9-NHC(.dbd.O)CH.sub.3 84 iso-pentyl Ph--
9-N(CH.sub.2CH.sub.3).su- b.2 85 iso-pentyl Ph--
9-NMeCH.sub.2CO.sub.2H 86 iso-pentyl Ph--
9-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H, I.sup.- 87 iso-pentyl Ph--
9-(N)-morpholine 88 iso-pentyl Ph-- 9-(N)-azetidine 89 iso-pentyl
Ph-- 9-(N)--N-methylazetidinium, I.sup.- 90 iso-pentyl Ph--
9-(N)-pyrrolidine 91 iso-pentyl Ph-- 9-(N)--N-methyl-pyrrolidinium,
I.sup.- 92 iso-pentyl Ph-- 9-(N)--N-methyl-morpholinium, I.sup.- 93
iso-pentyl Ph-- 9-(N)--N'-methylpiperazine 93 iso-pentyl Ph--
9-(N)--N'-dimethylpiperazinium, I.sup.- 95 iso-pentyl Ph--
9-NH--CBZ 96 iso-pentyl Ph-- 9-NHC(O)C.sub.5H.sub.11 97 iso-pentyl
Ph-- 9-NHC(O)CH.sub.2Br 98 iso-pentyl Ph-- 9-NH--C(NH)NH.sub.2 99
iso-pentyl Ph-- 9-(2)-thiophene 100 iso-pentyl Ph-- 7-OCH.sub.3,
8-OCH.sub.3 101 iso-pentyl Ph-- 7-SCH.sub.3, 8-OCH.sub.3 102
iso-pentyl Ph-- 7-SCH.sub.3, 8-SCH.sub.3 103 iso-pentyl Ph--
6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3 F101.009 01
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-methyl 02
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-ethyl 03
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-iso-propyl 04
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-tert-butyl 05
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-OH 06
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-OCH.sub.3 07
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-O(iso-propyl) 08
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-SCH.sub.3 09
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-SOCH.sub.3 10
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-SO.sub.2CH.sub.3 11
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-SCH.sub.2CH.sub.3 12
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-NH.sub.2 13
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-NHOH 14
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-NHCH.sub.3 15
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-N(CH.sub.3).sub.2 16
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-N.sup.+(CH.sub.3).sub.3,
I.sup.- 17 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
7-NHC(.dbd.O)CH.sub.3 18 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
7-N(CH.sub.2CH.sub.3).sub.2 19 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
7-NMeCH.sub.2CO.sub.2H 20 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
7-N.sup.+(Me).sub.2CH.sub.2CO.su- b.2H, I.sup.- 21
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-(N)-morpholine 22
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-(N)-azetidine 23
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-(N)--N-methylazetidinium,
I.sup.- 24 CH.sub.2C(.dbd.O)C.sub.2H.- sub.5 Ph-- 7-(N)-pyrrolidine
25 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
7-(N)--N-methyl-pyrrolidinium, I.sup.- 26
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-(N)--N-methyl-morpholinium,
I.sup.- 27 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
7-(N)--N'-methylpiperazine 28 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
7-(N)--N'-dimethylpiperazinium, I.sup.- 29
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-NH--CBZ 30
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-NHC(O)C.sub.5H.sub.11 31
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-NHC(O)CH.sub.2Br 32
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-NH--C(NH)NH.sub.2 33
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-(2)-thiophene 34
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-methyl 35
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-ethyl 36
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-iso-propyl 37
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-tert-butyl 38
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-OH 39
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-OCH.sub.3 40
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-O(iso-propyl) 41
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-SCH.sub.3 42
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-SOCH.sub.3 43
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-SO.sub.2CH.sub.3 44
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-SCH.sub.2CH.sub.3 45
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-NH.sub.2 46
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-NHOH 47
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-NHCH.sub.3 48
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-N(CH.sub.3).sub.2 49
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-N.sup.+(CH.sub.3).sub.3,
I.sup.- 50 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
8-NHC(.dbd.O)CH.sub.3 51 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
8-N(CH.sub.2CH.sub.3).sub.2 52 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
8-NMeCH.sub.2CO.sub.2H 53 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
8-N.sup.+(Me).sub.2CH.sub.2CO.su- b.2H, I.sup.- 54
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-(N)-morpholine 55
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-(N)-azetidine 56
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-(N)--N-methylazetidinium,
I.sup.- 57 CH.sub.2C(.dbd.O)C.sub.2H.- sub.5 Ph-- 8-(N)-pyrrolidine
58 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
8-(N)--N-methyl-pyrrolidinium, I.sup.- 59
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-(N)--N-methyl-morpholinium,
I.sup.- 60 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
8-(N)--N'-methylpiperazine 61 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
8-(N)--N'-dimethylpiperazinium, I.sup.- 62
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-NH--CBZ 63
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-NHC(O)C.sub.5H.sub.11 64
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-NHC(O)CH.sub.2Br 65
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-NH--C(NH)NH.sub.2 66
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 8-(2)-thiophene 67
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-methyl 68
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-ethyl 69
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-iso-propyl 70
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-tert-butyl 71
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-OH 72
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-OCH.sub.3 73
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-O(iso-propyl) 74
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-SCH.sub.3 75
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-SOCH.sub.3 76
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-SO.sub.2CH.sub.3 77
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-SCH.sub.2CH.sub.3 78
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-NH.sub.2 79
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-NHOH 80
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-NHCH.sub.3 81
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-N(CH.sub.3).sub.2 82
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-N.sup.+(CH.sub.3).sub.3,
I.sup.- 83 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
9-NHC(.dbd.O)CH.sub.3 84 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
9-N(CH.sub.2CH.sub.3).sub.2 85 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
9-NMeCH.sub.2CO.sub.2H 86 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
9-N.sup.+(Me).sub.2CH.sub.2CO.su- b.2H, I.sup.- 87
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-(N)-morpholine 88
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-(N)-azetidine 89
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-(N)--N-methylazetidinium,
I.sup.- 90 CH.sub.2C(.dbd.O)C.sub.2H.- sub.5 Ph-- 9-(N)-pyrrolidine
91 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
9-(N)--N-methyl-pyrrolidinium, I.sup.- 92
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-(N)--N-methyl-morpholinium,
I.sup.- 93 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
9-(N)--N'-methylpiperazine 93 CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph--
9-(N)--N'-dimethylpiperazinium, I.sup.- 95
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-NH--CBZ 96
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-NHC(O)C.sub.5H.sub.11 97
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-NHC(O)CH.sub.2Br 98
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-NH--C(NH)NH.sub.2 99
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 9-(2)-thiophene 100
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-OCH.sub.3, 8-OCH.sub.3 101
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-SCH.sub.3, 8-OCH.sub.3 102
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 7-SCH.sub.3, 8-SCH.sub.3 103
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 Ph-- 6-OCH.sub.3, 7-OCH.sub.3,
8-OCH.sub.3 F101.010 01 CH.sub.2OC.sub.2H.sub.5 Ph-- 7-methyl 02
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-ethyl 03 CH.sub.2OC.sub.2H.sub.5
Ph-- 7-iso-propyl 04 CH.sub.2OC.sub.2H.sub.5 Ph-- 7-tert-butyl 05
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-OH 06 CH.sub.2OC.sub.2H.sub.5 Ph--
7-OCH.sub.3 07 CH.sub.2OC.sub.2H.sub.5 Ph-- 7-O(iso-propyl) 08
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-SCH.sub.3 09 CH.sub.2OC.sub.2H.sub.5
Ph-- 7-SOCH.sub.3 10 CH.sub.2OC.sub.2H.sub.5 Ph--
7-SO.sub.2CH.sub.3 11 CH.sub.2OC.sub.2H.sub.5 Ph--
7-SCH.sub.2CH.sub.3 12 CH.sub.2OC.sub.2H.sub.5 Ph-- 7-NH.sub.2 13
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-NHOH 14 CH.sub.2OC.sub.2H.sub.5 Ph--
7-NHCH.sub.3 15 CH.sub.2OC.sub.2H.sub.5 Ph-- 7-N(CH.sub.3).sub.2 16
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-N.sup.+(CH.sub.3).sub.3, I.sup.- 17
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-NHC(.dbd.O)CH.sub.3 18
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-N(CH.sub.2CH.sub.3).sub.2 19
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-NMeCH.sub.2CO.sub.2H 20
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H
I.sup.- 21 CH.sub.2OC.sub.2H.sub.5 Ph-- 7-(N)-morpholine 22
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-(N)-azetidine 23
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-(N)--N-methylazetidinium, I.sup.- 24
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-(N)-pyrrolidine 25
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-(N)--N-methyl-pyrrolidinium, I.sup.-
26 CH.sub.2OC.sub.2H.sub.5 Ph-- 7-(N)--N-methyl-morpholinium,
I.sup.- 27 CH.sub.2OC.sub.2H.sub.5 Ph-- 7-(N)--N'-methylpiperazine
28 CH.sub.2OC.sub.2H.sub.5 Ph-- 7-(N)--N'-dimethylpiperazinium,
I.sup.- 29 CH.sub.2OC.sub.2H.sub.5 Ph-- 7-NH--CBZ 30
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-NHC(O)C.sub.5H.sub.11 31
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-NHC(O)CH.sub.2Br 32
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-NH--C(NH)NH.sub.2 33
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-(2)-thiophene 34
CH.sub.2OC.sub.2H.sub.5 Ph-- 8-methyl 35 CH.sub.2OC.sub.2H.sub.5
Ph-- 8-ethyl 36 CH.sub.2OC.sub.2H.sub.5 Ph-- 8-iso-propyl 37
CH.sub.2OC.sub.2H.sub.5 Ph-- 8-tert-butyl 38
CH.sub.2OC.sub.2H.sub.5 Ph-- 8-OH 39 CH.sub.2OC.sub.2H.sub.5 Ph--
8-OCH.sub.3 40 CH.sub.2OC.sub.2H.sub.5 Ph-- 8-O(iso-propyl) 41
CH.sub.2OC.sub.2H.sub.5 Ph-- 8-SCH.sub.3 42 CH.sub.2OC.sub.2H.sub.5
Ph-- 8-SOCH.sub.3 43 CH.sub.2OC.sub.2H.sub.5 Ph--
8-SO.sub.2CH.sub.3 44 CH.sub.2OC.sub.2H.sub.5 Ph--
8-SCH.sub.2CH.sub.3 45 CH.sub.2OC.sub.2H.sub.5 Ph-- 8-NH.sub.2 46
CH.sub.2OC.sub.2H.sub.5 Ph-- 8-NHOH 47 CH.sub.2OC.sub.2H.sub.5 Ph--
8-NHOH.sub.3 48 CH.sub.2OC.sub.2H.sub.5 Ph-- 8-N(CH.sub.3).sub.2 49
CH.sub.2OC.sub.2H.sub.5 Ph-- 8-N.sup.+(CH.sub.3).sub.3, I.sup.- 50
CH.sub.2OC.sub.2H.sub.5 Ph-- 8-NHC(.dbd.O)CH.sub.3 51
CH.sub.2OC.sub.2H.sub.5 Ph-- 8-N(CH.sub.2CH.sub.3).sub.2 52
CH.sub.2OC.sub.2H.sub.5 Ph-- 8-NMeCH.sub.2CO.sub.2H 53
CH.sub.2OC.sub.2H.sub.5 Ph-- 8-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H,
I.sup.- 54 CH.sub.2OC.sub.2H.sub.5 Ph-- 8-(N)-morpholine 55
CH.sub.2OC.sub.2H.sub.5 Ph-- 8-(N)-azetidine 56
CH.sub.2OC.sub.2H.sub.5 Ph-- 8-(N)--N-methylazetidinium, I.sup.- 57
CH.sub.2OC.sub.2H.sub.5 Ph-- 8-(N)-pyrrolidine 58
CH.sub.2OC.sub.2H.sub.5 Ph-- 8-(N)--N-methyl-pyrrolidine, I.sup.-
59 CH.sub.2OC.sub.2H.sub.5 Ph-- 8-(N)--N-methyl-morpholinium,
I.sup.- 60 CH.sub.2OC.sub.2H.sub.5 Ph-- 8-(N)--N'-methylpiperazine
61 CH.sub.2OC.sub.2H.sub.5 Ph-- 8-(N)--N'-dimethylpiperazinium,
I.sup.- 62 CH.sub.2OC.sub.2H.sub.5 Ph-- 8-NH--CBZ 63
CH.sub.2OC.sub.2H.sub.5 Ph-- 8-NHC(O)C.sub.5H.sub.11 64
CH.sub.2OC.sub.2H.sub.5 Ph-- 8-NHC(O)CH.sub.2Br 65
CH.sub.2OC.sub.2H.sub.5 Ph-- 8-NH--C(NH)NH.sub.2 66
CH.sub.2OC.sub.2H.sub.5 Ph-- 8-(2)-thiophene 67
CH.sub.2OC.sub.2H.sub.5 Ph-- 9-methyl 68 CH.sub.2OC.sub.2H.sub.5
Ph-- 9-ethyl 69 CH.sub.2OC.sub.2H.sub.5 Ph-- 9-iso-propyl 70
CH.sub.2OC.sub.2H.sub.5 Ph-- 9-tert-butyl 71
CH.sub.2OC.sub.2H.sub.5 Ph-- 9-OH 72 CH.sub.2OC.sub.2H.sub.5 Ph--
9-OCH.sub.3 73 CH.sub.2OC.sub.2H.sub.5 Ph-- 9-O(iso-propyl) 74
CH.sub.2OC.sub.2H.sub.5 Ph-- 9-SCH.sub.3 75 CH.sub.2OC.sub.2H.sub.5
Ph-- 9-SOCH.sub.3 76 CH.sub.2OC.sub.2H.sub.5 Ph--
9-SO.sub.2CH.sub.3 77 CH.sub.2OC.sub.2H.sub.5 Ph--
9-SCH.sub.2CH.sub.3 78 CH.sub.2OC.sub.2H.sub.5 Ph-- 9-NH.sub.2 79
CH.sub.2OC.sub.2H.sub.5 Ph-- 9-NHOH 80 CH.sub.2OC.sub.2H.sub.5 Ph--
9-NHCH.sub.3 81 CH.sub.2OC.sub.2H.sub.5 Ph-- 9-N(CH.sub.3).sub.2 82
CH.sub.2OC.sub.2H.sub.5 Ph-- 9-N.sup.+(CH.sub.3).sub.3, I.sup.- 83
CH.sub.2OC.sub.2H.sub.5 Ph-- 9-NHC(.dbd.O)CH.sub.3 84
CH.sub.2OC.sub.2H.sub.5 Ph-- 9-N(CH.sub.2CH.sub.3).sub.2 85
CH.sub.2OC.sub.2H.sub.5 Ph-- 9-NMeCH.sub.2CO.sub.2H 86
CH.sub.2OC.sub.2H.sub.5 Ph-- 9-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H,
I.sup.- 87 CH.sub.2OC.sub.2H.sub.5 Ph-- 9-(N)-morpholine 88
CH.sub.2OC.sub.2H.sub.5 Ph-- 9-(N)-azetidine 89
CH.sub.2OC.sub.2H.sub.5 Ph-- 9-(N)--N-methylazetidinium, I.sup.- 90
CH.sub.2OC.sub.2H.sub.5 Ph-- 9-(N)-pyrrolidine 91
CH.sub.2OC.sub.2H.sub.5 Ph-- 9-(N)--N-methyl-pyrrolidine, I.sup.-
92 CH.sub.2OC.sub.2H.sub.5 Ph-- 9-(N)--N-methyl-morpholinium,
I.sup.- 93 CH.sub.2OC.sub.2H.sub.5 Ph-- 9-(N)--N'-methylpiperazine
93 CH.sub.2OC.sub.2H.sub.5 Ph-- 9-(N)--N'-dimethylpiperazinium,
I.sup.- 95 CH.sub.2OC.sub.2H.sub.5 Ph-- 9-NH--CBZ 96
CH.sub.2OC.sub.2H.sub.5 Ph-- 9-NHC(O)C.sub.5H.sub.11 97
CH.sub.2OC.sub.2H.sub.5 Ph-- 9-NHC(O)CH.sub.2Br 98
CH.sub.2OC.sub.2H.sub.5 Ph-- 9-NH--C(NH)NH.sub.2 99
CH.sub.2OC.sub.2H.sub.5 Ph-- 9-(2)-thiophene 100
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-OCH.sub.3, 8-OCH.sub.3 101
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-SCH.sub.3, 8-OCH.sub.3 102
CH.sub.2OC.sub.2H.sub.5 Ph-- 7-SCH.sub.3, 8-SCH.sub.3 103
CH.sub.2OC.sub.2H.sub.5 Ph-- 6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3
F101.011 01 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-methyl 02
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-ethyl 03
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-iso-propyl 04
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-tert-butyl 05
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-OH 06 CH.sub.2CH(OH)C.sub.2H.-
sub.5 Ph-- 7-OCH.sub.3 07 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph--
7-O(iso-propyl) 08 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-SCH.sub.3 09
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-SOCH.sub.3 10
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-SO.sub.2CH.sub.3 11
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-SCH.sub.2CH.sub.3 12
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-NH.sub.2 13
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-NHOH 14
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-NHCH.sub.3 15
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-N(CH.sub.3).sub.2 16
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-N.sup.+(CH.sub.3).sub.3,
I.sup.- 17 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-NHC(.dbd.O)CH.sub.3
18 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-N(CH.sub.2CH.sub.3).sub.2 19
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-NMeCH.sub.2CO.sub.2H 20
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph--
7-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H, I.sup.- 21
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-(N)-morpholine 22
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-(N)-azetidine 23
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-(N)--N-methylazetidinium,
I.sup.- 24 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-(N)-pyrrolidine 25
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-(N)--N-methyl-pyrrolidinium,
I.sup.- 26 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph--
7-(N)--N-methyl-morpholinium- , I.sup.- 27
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-(N)--N'-methylpiperazine 28
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-(N)--N'-dimethylpiperazinium,
I.sup.- 29 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-NH--CBZ 30
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-NHC(O)C.sub.5H.sub.11 31
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-NHC(O)CH.sub.2Br 32
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-NH--C(NH)NH.sub.2 33
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-(2)-thiophene 34
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-methyl 35
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-ethyl 36
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-iso-propyl 37
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-tert-butyl 38
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-OH 39 CH.sub.2CH(OH)C.sub.2H.-
sub.5 Ph-- 8-OCH.sub.3 40 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph--
8-O(iso-propyl) 41 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-SCH.sub.3 42
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-SOCH.sub.3 43
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-SO.sub.2CH.sub.3 44
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-SCH.sub.2CH.sub.3 45
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-NH.sub.2 46
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-NHOH 47
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-NHCH.sub.3 48
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-N(CH.sub.3).sub.2 49
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-N.sup.+(CH.sub.3).sub.3,
I.sup.- 50 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-NHC(.dbd.O)CH.sub.3
51 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-N(CH.sub.2CH.sub.3).sub.2 52
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-NMeCH.sub.2CO.sub.2H 53
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph--
8-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H, I.sup.- 54
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-(N)-morpholine 55
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-(N)-azetidine 56
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-(N)--N-methylazetidinium,
I.sup.- 57 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-(N)-pyrrolidine 58
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-(N)--N-methyl-pyrrolidinium,
I.sup.- 59 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph--
8-(N)--N-methyl-morpholinium- , I.sup.- 60
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-(N)--N'-methylpiperazine 61
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-(N)--N'-dimethylpiperazinium,
I.sup.- 62 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-NH--CBZ 63
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-NHC(O)C.sub.5H.sub.11 64
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-NHC(O)CH.sub.2Br 65
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-NH--C(NH)NH.sub.2 66
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 8-(2)-thiophene 67
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-methyl 68
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-ethyl 69
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-iso-propyl 70
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-tert-butyl 71
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-OH 72 CH.sub.2CH(OH)C.sub.2H.-
sub.5 Ph-- 9-OCH.sub.3 73 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph--
9-O(iso-propyl) 74 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-SCH.sub.3 75
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-SOCH.sub.3 76
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-SO.sub.2CH.sub.3 77
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-SCH.sub.2CH.sub.3 78
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-NH.sub.2 79
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-NHOH 80
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-NHCH.sub.3 81
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-N(CH.sub.3).sub.2 82
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-N.sup.+(CH.sub.3).sub.3,
I.sup.- 83 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-NHC(.dbd.O)CH.sub.3
84 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-N(CH.sub.2CH.sub.3).sub.2 85
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-NMeCH.sub.2CO.sub.2H 86
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph--
9-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H, I.sup.- 87
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-(N)-morpholine 88
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-(N)-azetidine 89
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-(N)--N-methylazetidinium,
I.sup.- 90 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-(N)-pyrrolidine 91
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-(N)--N-methyl-pyrrolidinium,
I.sup.- 92 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph--
9-(N)--N-methyl-morpholinium- , I.sup.- 93
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-(N)--N'-methylpiperazine 93
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-(N)--N'-dimethylpiperazinium,
I.sup.- 95 CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-NH--CBZ 96
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-NHC(O)C.sub.5H.sub.11 97
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-NHC(O)CH.sub.2Br 98
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-NH--C(NH)NH.sub.2 99
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 9-(2)-thiophene 100
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-OCH.sub.3, 8-OCH.sub.3 101
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-SCH.sub.3, 8-OCH.sub.3 102
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 7-SCH.sub.3, 8-SCH.sub.3 103
CH.sub.2CH(OH)C.sub.2H.sub.5 Ph-- 6-OCH.sub.3, 7-OCH.sub.3,
8-OCH.sub.3 F101.012 01 CH.sub.2O-(4-picoline) Ph-- 7-methyl 02
CH.sub.2O-(4-picoline) Ph-- 7-ethyl 03 CH.sub.2O-(4-picoline) Ph--
7-iso-propyl 04 CH.sub.2O-(4-picoline) Ph-- 7-tert-butyl 05
CH.sub.2O-(4-picoline) Ph-- 7-OH 06 CH.sub.2O-(4-picoline) Ph--
7-OCH.sub.3 07 CH.sub.2O-(4-picoline) Ph-- 7-O(iso-propyl) 08
CH.sub.2O-(4-picoline) Ph-- 7-SCH.sub.3 09 CH.sub.2O-(4-picoline)
Ph-- 7-SOCH.sub.3 10 CH.sub.2O-(4-picoline) Ph-- 7-SO.sub.2CH.sub.3
11 CH.sub.2O-(4-picoline) Ph-- 7-SCH.sub.2CH.sub.3 12
CH.sub.2O-(4-picoline) Ph-- 7-NH.sub.2 13 CH.sub.2O-(4-picoline)
Ph-- 7-NHOH 14 CH.sub.2O-(4-picoline) Ph-- 7-NHCH.sub.3 15
CH.sub.2O-(4-picoline) Ph-- 7-N(CH.sub.3).sub.2 16
CH.sub.2O-(4-picoline) Ph-- 7-N.sup.+(CH.sub.3).sub.3, I.sup.- 17
CH.sub.2O-(4-picoline) Ph-- 7-NHC(.dbd.O)CH.sub.3 18
CH.sub.2O-(4-picoline) Ph-- 7-N(CH.sub.2CH.sub.3).sub.2 19
CH.sub.2O-(4-picoline) Ph-- 7-NMeCH.sub.2CO.sub.2H 20
CH.sub.2O-(4-picoline) Ph-- 7-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H,
I.sup.- 21 CH.sub.2O-(4-picoline) Ph-- 7-(N)-morpholine 22
CH.sub.2O-(4-picoline) Ph-- 7-(N)-azetidine 23
CH.sub.2O-(4-picoline) Ph-- 7-(N)--N-methylazetidinium, I.sup.- 24
CH.sub.2O-(4-picoline) Ph-- 7-(N)-pyrrolidine 25
CH.sub.2O-(4-picoline) Ph-- 7-(N)--N-methyl-pyrrolidinium, I.sup.-
26 CH.sub.2O-(4-picoline) Ph-- 7-(N)--N-methyl-morpholinium,
I.sup.- 27 CH.sub.2O-(4-picoline) Ph-- 7-(N)--N'-methylpiperazine
28 CH.sub.2O-(4-picoline) Ph-- 7-(N)--N'-dimethylpiperazinium,
I.sup.- 29 CH.sub.2O-(4-picoline) Ph-- 7-NH--CBZ 30
CH.sub.2O-(4-picoline) Ph-- 7-NHC(O)C.sub.5H.sub.11 31
CH.sub.2O-(4-picoline) Ph-- 7-NHC(O)CH.sub.2Br 32
CH.sub.2O-(4-picoline) Ph-- 7-NH--C(NH)NH.sub.2 33
CH.sub.2O-(4-picoline) Ph-- 7-(2)-thiophene 34
CH.sub.2O-(4-picoline) Ph-- 8-methyl 35 CH.sub.2O-(4-picoline) Ph--
8-ethyl 36 CH.sub.2O-(4-picoline) Ph-- 8-iso-propyl 37
CH.sub.2O-(4-picoline) Ph-- 8-tert-butyl 38 CH.sub.2O-(4-picoline)
Ph-- 8-OH 39 CH.sub.2O-(4-picoline) Ph-- 8-OCH.sub.3 40
CH.sub.2O-(4-picoline) Ph-- 8-O(iso-propyl) 41
CH.sub.2O-(4-picoline) Ph-- 8-SCH.sub.3 42 CH.sub.2O-(4-picoline)
Ph-- 8-SOCH.sub.3 43 CH.sub.2O-(4-picoline) Ph-- 8-SO.sub.2CH.sub.3
44 CH.sub.2O-(4-picoline) Ph-- 8-SCH.sub.2CH.sub.3 45
CH.sub.2O-(4-picoline) Ph-- 8-NH.sub.2 46 CH.sub.2O-(4-picoline)
Ph-- 8-NHOH 47 CH.sub.2O-(4-picoline) Ph-- 8-NHCH.sub.3 48
CH.sub.2O-(4-picoline) Ph-- 8-N(CH.sub.3).sub.2 49
CH.sub.2O-(4-picoline) Ph-- 8-N.sup.+(CH.sub.3).sub.3, I.sup.- 50
CH.sub.2O-(4-picoline) Ph-- 8-NHC(.dbd.O)CH.sub.3 51
CH.sub.2O-(4-picoline) Ph-- 8-N(CH.sub.2CH.sub.3).sub.2 52
CH.sub.2O-(4-picoline) Ph-- 8-NMeCH.sub.2CO.sub.2H 53
CH.sub.2O-(4-picoline) Ph-- 8-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H,
I.sup.- 54 CH.sub.2O-(4-picoline) Ph-- 8-(N)-morpholine 55
CH.sub.2O-(4-picoline) Ph-- 8-(N)-azetidine 56
CH.sub.2O-(4-picoline) Ph-- 8-(N)--N-methylazetidinium, I.sup.- 57
CH.sub.2O-(4-picoline) Ph-- 8-(N)-pyrrolidine 58
CH.sub.2O-(4-picoline) Ph-- 8-(N)--N-methyl-pyrrolidinium, I.sup.-
59 CH.sub.2O-(4-picoline) Ph-- 8-(N)--N-methyl-morpholinium,
I.sup.- 60 CH.sub.2O-(4-picoline) Ph-- 8-(N)--N'-methylpiperazine
61 CH.sub.2O-(4-picoline) Ph-- 8-(N)--N'-dimethylpiperazinium,
I.sup.- 62 CH.sub.2O-(4-picoline) Ph-- 8-NH--CBZ 63
CH.sub.2O-(4-picoline) Ph-- 8-NHC(O)C.sub.5H.sub.11 64
CH.sub.2O-(4-picoline) Ph-- 8-NHC(O)CH.sub.2Br 65
CH.sub.2O-(4-picoline) Ph-- 8-NH--C(NH)NH.sub.2 66
CH.sub.2O-(4-picoline) Ph-- 8-(2)-thiophene 67
CH.sub.2O-(4-picoline) Ph-- 9-methyl 68 CH.sub.2O-(4-picoline) Ph--
9-ethyl 69 CH.sub.2O-(4-picoline) Ph-- 9-iso-propyl 70
CH.sub.2O-(4-picoline) Ph-- 9-tert-butyl 71 CH.sub.2O-(4-picoline)
Ph-- 9-OH 72 CH.sub.2O-(4-picoline) Ph-- 9-OCH.sub.3 73
CH.sub.2O-(4-picoline) Ph-- 9-O(iso-propyl) 74
CH.sub.2O-(4-picoline) Ph-- 9-SCH.sub.3 75 CH.sub.2O-(4-picoline)
Ph-- 9-SOCH.sub.3 76 CH.sub.2O-(4-picoline) Ph-- 9-SO.sub.2CH.sub.3
77 CH.sub.2O-(4-picoline) Ph-- 9-SCH.sub.2CH.sub.3 78
CH.sub.2O-(4-picoline) Ph-- 9-NH.sub.2 79 CH.sub.2O-(4-picoline)
Ph-- 9-NHOH 80 CH.sub.2O-(4-picoline) Ph-- 9-NHCH.sub.3 81
CH.sub.2O-(4-picoline) Ph-- 9-N(CH.sub.3).sub.2 82
CH.sub.2O-(4-picoline) Ph-- 9-N.sup.+(CH.sub.3).sub.3, I.sup.- 83
CH.sub.2O-(4-picoline) Ph-- 9-NHC(.dbd.O)CH.sub.3 84
CH.sub.2O-(4-picoline) Ph-- 9-N(CH.sub.2CH.sub.3).sub.2 85
CH.sub.2O-(4-picoline) Ph-- 9-NMeCH.sub.2CO.sub.2H 86
CH.sub.2O-(4-picoline) Ph-- 9-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H,
I.sup.- 87 CH.sub.2O-(4-picoline) Ph-- 9-(N)-morpholine 88
CH.sub.2O-(4-picoline) Ph-- 9-(N)-azetidine 89
CH.sub.2O-(4-picoline) Ph-- 9-(N)--N-methylazetidinium, I.sup.- 90
CH.sub.2O-(4-picoline) Ph-- 9-(N)-pyrrolidine 91
CH.sub.2O-(4-picoline) Ph-- 9-(N)--N-methyl-pyrrolidinium, I.sup.-
92 CH.sub.2O-(4-picoline) Ph-- 9-(N)--N-methylmorpholinium 93
CH.sub.2O-(4-picoline) Ph-- 9-(N)--N'-methylpiperazine 93
CH.sub.2O-(4-picoline) Ph-- 9-(N)--N'-dimethylpiperazinium, I.sup.-
95 CH.sub.2O-(4-picoline) Ph-- 9-NH--CBZ 96 CH.sub.2O-(4-picoline)
Ph-- 9-NHC(O)C.sub.5H.sub.11 97 CH.sub.2O-(4-picoline) Ph--
9-NHC(O)CH.sub.2Br 98 CH.sub.2O-(4-picoline) Ph--
9-NH--C(NH)NH.sub.2 99 CH.sub.2O-(4-picoline) Ph-- 9-(2)-thiophene
100 CH.sub.2O-(4-picoline) Ph-- 7-OCH.sub.3, 8-OCH.sub.3 101
CH.sub.2O-(4-picoline) Ph-- 7-SCH.sub.3, 8-OCH.sub.3 102
CH.sub.2O-(4-picoline) Ph-- 7-SCH.sub.3, 8-SCH.sub.3 103
CH.sub.2O-(4-picoline) Ph-- 6-OCH.sub.3, 7-OCH.sub.3,
8-OCH.sub.3
[0226]
2 19 Compound Number R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 101
ethyl n-butyl OH H phenyl 102 ethyl n-butyl OH H phenyl 103 n-butyl
ethyl OH H phenyl 104 ethyl n-butyl OH H phenyl 105 ethyl n-butyl
OH H phenyl 106 ethyl n-butyl OH H phenyl 107 n-butyl ethyl OH H
4-(decyloxy)phenyl 108 ethyl n-butyl OH H phenyl 109 ethyl n-butyl
OH H 4-(decyloxy)phenyl 110 ethyl n-butyl OH H phenyl 111 n-butyl
ethyl OH H 4-hydroxyphenyl 112 ethyl n-butyl OH H 20 113 ethyl
n-butyl OH H 4-hydroxyphenyl 114 ethyl n-butyl OH H 4-methoxyphenyl
115 n-butyl ethyl OH H 4-methoxyphenyl 116 ethyl n-butyl OH H
4-methoxyphenyl 117 n-butyl ethyl OH H phenyl 118 ethyl n-butyl OH
H phenyl 119 ethyl n-butyl OH H phenyl 120 n-butyl ethyl OH H
phenyl 121 ethyl n-butyl OH H phenyl 122 n-butyl ethyl OH H phenyl
123 ethyl n-butyl OH H phenyl 124 n-butyl ethyl OH H phenyl 125
ethyl n-butyl OH H phenyl 126 n-butyl ethyl OH H 4-fluorophenyl 127
n-butyl ethyl OH H 4-fluorophenyl 128 ethyl n-butyl OH H
4-fluorophenyl 129 ethyl n-butyl OH H 4-fluorophenyl 131 ethyl
n-butyl OH H 4-fluorophenyl 132 ethyl n-butyl OH H phenyl 133 ethyl
n-butyl OH H phenyl 134 ethyl n-butyl OH H phenyl 135 ethyl n-butyl
OH H phenyl 136 ethyl n-butyl OH H phenyl 137 n-butyl ethyl OH H
phenyl 138 n-butyl ethyl OH H phenyl 139 n-butyl ethyl OH H phenyl
140 141 142 ethyl n-butyl H OH H 143 ethyl n-butyl OH H
3-methoxyphenyl 144 ethyl n-butyl OH H 4-fluorophenyl 262 ethyl
n-butyl OH H 3-methoxyphenyl 263 ethyl n-butyl H OH H 264 ethyl
n-butyl OH H 3-trifluoromethylphenyl 265 ethyl n-butyl H OH H 266
ethyl n-butyl OH H 3-hydroxyphenyl 267 ethyl n-butyl OH H
3-hydroxyphenyl 268 ethyl n-butyl OH H 4-fluorophenyl 269 ethyl
n-butyl H OH H 270 ethyl n-butyl OH H 4-fluorophenyl 271 ethyl
n-butyl OH H 3-methoxyphenyl 272 ethyl n-butyl H OH H 273 ethyl
n-butyl H OH H 274 ethyl n-butyl OH H 4-fluorophenyl 275 ethyl
n-butyl H OH H 276 ethyl n-butyl OH H 3-methoxyphenyl 277 ethyl
n-butyl OH H 3-fluorophenyl 278 ethyl n-butyl H OH 2-fluorophenyl
279 ethyl n-butyl H OH 3-fluorophenyl 280 ethyl n-butyl OH H
2-fluorophenyl 281 ethyl n-butyl OH H 4-fluorophenyl 282 ethyl
n-butyl OH H 4-fluorophenyl 283 ethyl n-butyl H OH H 284 ethyl
n-butyl OH H 4-fluorophenyl 286 ethyl ethyl OH H phenyl 287 ethyl
ethyl OH H phenyl 288 methyl methyl OH H phenyl 289 n-butyl n-butyl
OH H phenyl 290 n-butyl n-butyl OH H phenyl 291 n-butyl n-butyl OH
H phenyl 292 n-butyl n-butyl OH H 4-fluorophenyl 293 n-butyl
n-butyl OH H phenyl 294 n-butyl n-butyl OH H phenyl 295 ethyl
n-butyl OH H 21 296 ethyl n-butyl OH H 22 1000 ethyl n-butyl OH H
23 1001 ethyl n-butyl OH H 24 1002 ethyl n-butyl OH H 25 1003 ethyl
n-butyl OH H 26 1004 ethyl n-butyl OH H 27 1005 n-butyl n-butyl OH
H 28 1006 n-butyl n-butyl OH H 29 1007 n-butyl n-butyl OH H 30 1008
n-butyl n-butyl OH H 31 1009 n-butyl n-butyl OH H 32 1010 n-butyl
n-butyl OH H 3-fluoro-4-methoxyphenyl 1011 n-butyl n-butyl OH H
3-fluoro-4-(5-triethylammoniumpentyloxy)phenyl, trifluoroacetate
salt 1012 n-butyl n-butyl OH H 4-hydroxyphenyl 1013 n-butyl n-butyl
OH H 33 1014 n-butyl n-butyl OH H 4-methoxyphenyl 1015 n-butyl
n-butyl OH H 34 1016 n-butyl n-butyl OH H 35 1017 n-butyl n-butyl
OH H 36 1018 n-butyl n-butyl OH H 37 1019 n-butyl n-butyl OH H 38
1020 n-butyl n-butyl OH H 39 1021 n-butyl n-butyl OH H 40 1022
n-butyl n-butyl OH H 41 1023 n-butyl n-butyl OH H 42 1024 n-butyl
n-butyl OH H 43 1025 n-butyl n-butyl OH H 44 1026 n-butyl n-butyl
OH H 45 1027 n-butyl n-butyl OH H 46 1028 n-butyl n-butyl OH H 47
1029 n-butyl n-butyl OH H 48 1030 n-butyl n-butyl OH H 49 1031
n-butyl n-butyl OH H 50 1032 n-butyl n-butyl OH H 51 1033 n-butyl
n-butyl OH H 52 1034 n-butyl n-butyl OH H 53 1035 n-butyl n-butyl
OH H 54 1036 n-butyl n-butyl OH H 55 1037 n-butyl n-butyl OH H
4-hydroxyphenyl 1038 n-butyl n-butyl OH H 56 1039 n-butyl n-butyl
OH H phenyl 1040 n-butyl n-butyl OH H 57 1041 n-butyl n-butyl OH H
58 1042 n-butyl n-butyl OH H 59 1043 n-butyl n-butyl OH H 60 1044
n-butyl n-butyl OH H 61 1045 n-butyl n-butyl OH H 62 1046 n-butyl
n-butyl OH H 3-aminophenyl 1047 n-butyl n-butyl OH H 63 1048
n-butyl n-butyl OH H 64 1049 n-butyl n-butyl OH H 65 1050 n-butyl
n-butyl OH H 66 1051 n-butyl n-butyl OH H 67 1052 n-butyl n-butyl
OH H 68 1053 n-butyl n-butyl OH H 69 1054 n-butyl n-butyl OH H 70
1055 n-butyl n-butyl OH H 71 1056 n-butyl n-butyl OH H 72 1057
n-butyl n-butyl OH H 73 1058 n-butyl n-butyl OH H 74 1059 n-butyl
n-butyl OH H 75 1060 ethyl n-butyl OH H 3-fluoro-4-methoxyphenyl
1061 n-butyl n-butyl OH H 76 1062 n-butyl n-butyl OH H 77 1063
n-butyl n-butyl OH H 78 1064 n-butyl n-butyl OH H 79 1065 n-butyl
n-butyl OH H 80 1066 n-butyl n-butyl OH H 81 1067 n-butyl n-butyl
OH H thiophen-3-yl 1068 n-butyl n-butyl OH H 82 1069 n-butyl
n-butyl OH H phenyl 1070 n-butyl n-butyl OH H 83 1071 n-butyl
n-butyl OH H 84 1072 n-butyl n-butyl OH H 85 1073 n-butyl n-butyl
OH H 86 1074 ethyl n-butyl OH H 3-fluoro-4-methoxyphenyl 1075
n-butyl n-butyl OH H 4-fluorophenyl 1076 n-butyl n-butyl OH H 87
1077 n-butyl n-butyl OH H 3-hydroxymethylphenyl 1078 ethyl n-butyl
OH H 4-hydroxyphenyl 1079 ethyl n-butyl OH H 88 1080 n-butyl
n-butyl OH H 89 1081 n-butyl n-butyl OH H 90 1082 n-butyl n-butyl
OH H 2-pyridyl 1083 n-butyl n-butyl OH H 91 1084 n-butyl n-butyl OH
H 92 1085 n-butyl n-butyl OH H thiophen-3-yl 1086 n-butyl n-butyl
OH H 93 1087 n-butyl n-butyl OH H 94 1088 ethyl n-butyl OH H
3,4-methylenedioxyphenyl 1089 ethyl n-butyl OH H 4-methyoxyphenyl
1090 n-butyl n-butyl OH H 95 1091 n-butyl n-butyl OH H 96 1092
n-butyl n-butyl OH H 97 1093 n-butyl n-butyl OH H 98 1094 n-butyl
n-butyl OH H 99 1095 n-butyl n-butyl OH H 100 1096 n-butyl n-butyl
OH H 101 1097 n-butyl n-butyl OH H 102 1098 n-butyl n-butyl OH H
103 1099 ethyl n-butyl OH H 4-methoxyphenyl 1100 n-butyl n-butyl OH
H 4-methoxyphenyl 1101 n-butyl n-butyl OH H 104 1102 n-butyl
n-butyl OH H 3-carboxymethylphenyl 1103 n-butyl n-butyl OH H 105
1104 n-butyl n-butyl OH H 106 1105 n-butyl n-butyl OH H 5-piperonyl
1106 n-butyl n-butyl OH H 3-hydroxyphenyl 1107 n-butyl n-butyl OH H
107 1108 n-butyl n-butyl OH H 3-pyridyl 1109 n-butyl n-butyl OH H
108 1110 n-butyl n-butyl OH H 109 1111 n-butyl n-butyl OH H 110
1112 n-butyl n-butyl OH H 4-pyridyl 1113 n-butyl n-butyl OH H 111
1114 n-butyl n-butyl OH H 3-methoxyphenyl 1115 n-butyl n-butyl OH H
4-fluorophenyl 1116 ethyl n-butyl OH H 3-tolyl 1117 ethyl n-butyl
OH H 112 1118 ethyl n-butyl OH H 3-fluoro-4-hydroxyphenyl 1119
n-butyl n-butyl OH H 113 1120 n-butyl n-butyl OH H 114 1121 n-butyl
n-butyl OH H 115 1122 n-butyl n-butyl OH H 116 1123 n-butyl n-butyl
OH H phenyl 1124 n-butyl n-butyl OH H 3-methoxyphenyl 1125 n-butyl
n-butyl OH H 3-chloro-4-methoxyphenyl 1126 ethyl n-butyl OH H 117
1127 n-butyl n-butyl OH H 118 1128 n-butyl n-butyl OH H
3-fluoro-4-hydroxyphenyl 1129 n-butyl n-butyl OH H 4-fluorophenyl
1130 n-butyl n-butyl OH H 3-chloro-4-fluorophenyl 1131 ethyl
n-butyl OH H 4-methoxyphenyl 1132 n-butyl n-butyl OH H 119 1133
n-butyl n-butyl OH H 4-cyanomethylphenyl 1134 ethyl n-butyl OH H
120 1135 n-butyl n-butyl OH H 3,4-dimethoxyphenyl 1136 n-butyl
n-butyl OH H 121 1137 n-butyl n-butyl OH H 4-fluorophenyl 1138
n-butyl n-butyl OH H 122 1139 n-butyl n-butyl OH H
3,4-difluorophenyl 1140 n-butyl n-butyl OH H 3-methoxyphenyl 1141
n-butyl n-butyl OH H 4-fluorophenyl 1142 n-butyl n-butyl OH H 123
1143 n-butyl n-butyl H OH H 1144 n-butyl n-butyl OH H 5-piperonyl
1145 n-butyl n-butyl OH H 4-methoxyphenyl 1146 n-butyl n-butyl OH H
124 1147 n-butyl n-butyl OH H 3-methoxyphenyl 1148 n-butyl n-butyl
OH H 4-fluorophenyl 1149 n-butyl n-butyl OH H 4-fluorophenyl 1150
n-butyl n-butyl OH H 3-methoxyphenyl 1151 n-butyl ethyl OH H
3-fluoro-4-methoxyphenyl 1152 n-butyl n-butyl OH H phenyl 1153
n-butyl n-butyl OH H 4-fluorophenyl 1154 n-butyl n-butyl OH H
3-methoxyphenyl 1155 n-butyl n-butyl OH H 4-fluorophenyl 1156
n-butyl n-butyl OH H 4-fluorophenyl 1157 n-butyl n-butyl OH H
4-fluorophenyl 1158 n-butyl n-butyl OH H 4-pyridinyl, hydrochloride
salt 1159 n-butyl ethyl OH H phenyl 1160 n-butyl n-butyl OH H
4-fluorophenyl 1161 n-butyl n-butyl OH H
3,5-dichloro-4-methoxyphenyl 1162 n-butyl n-butyl OH H phenyl 1163
n-butyl n-butyl OH H 3-(dimethylamino)phenyl 1164 n-butyl n-butyl
OH H 4-pyridinyl 1165 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl
1166 n-butyl n-butyl OH H 3-hydroxyphenyl 1167 n-butyl n-butyl OH H
125 1168 n-butyl n-butyl OH H 4-hydroxyphenyl 1169 n-butyl n-butyl
OH H phenyl 1170 n-butyl n-butyl OH H 3-methoxyphenyl 1171 n-butyl
n-butyl OH H 4-(trifluoromethylsulfon- yloxy)phenyl 1172 n-butyl
n-butyl OH H 4-pyridinyl 1173 n-butyl n-butyl OH H 4-fluorophenyl
1174 ethyl n-butyl OH H 3-methoxyphenyl 1175 ethyl n-butyl OH H
3-methoxyphenyl 1176 n-butyl n-butyl OH H 4-fluorophenyl 1177
n-butyl n-butyl OH H 3-methoxyphenyl 1178 n-butyl n-butyl OH H
3-(trifluoromethylsulfon- yloxy)phenyl 1179 n-butyl n-butyl OH H
phenyl 1180 n-butyl n-butyl OH H phenyl 1181 n-butyl n-butyl OH H
4-fluorophenyl 1182 n-butyl n-butyl OH H 4-(dimethylamino)phenyl
1183 n-butyl n-butyl OH H 3-methoxyphenyl 1184 n-butyl n-butyl OH H
4-fluorophenyl 1185 n-butyl n-butyl OH H 4-fluorophenyl 1186
n-butyl n-butyl OH H phenyl 1187 n-butyl n-butyl OH H
3-fluorophenyl 1188 n-butyl n-butyl OH H 4-methoxyphenyl 1189
n-butyl n-butyl OH H 3,4-difluorophenyl 1190 n-butyl n-butyl OH H
2-bromophenyl 1191 n-butyl n-butyl OH H 4-(dimethylamino)phenyl
1192 n-butyl n-butyl OH H 3-(dimethylamino)phenyl 1193 n-butyl
n-butyl OH H 4-(2-(2-methylpropyl))phenyl 1194 n-butyl n-butyl OH H
126 1195 n-butyl n-butyl OH H 4-methoxyphenyl 1196 n-butyl n-butyl
OH H 127 1197 n-butyl ethyl R3 + R3 + phenyl R4 = R4 = oxo oxo 1198
n-butyl n-butyl OH H 4-(pyridinyl-N-oxide) 1199 n-butyl n-butyl OH
H 128 1200 n-butyl n-butyl H OH H 1201 n-butyl n-butyl OH H H 1202
n-butyl n-butyl OH H 129 1203 n-butyl n-butyl OH H 5-piperazinyl
1204 n-butyl n-butyl OH H 4-fluorophenyl 1205 n-butyl n-butyl OH H
130 1206 n-butyl n-butyl OH H 131 1207 n-butyl n-butyl OH H
3,5-dichlorophenyl 1208 n-butyl n-butyl OH H 4-methoxyphenyl 1209
n-butyl n-butyl acetoxy H phenyl 1210 n-butyl n-butyl OH H
2-(dimethylamino)phenyl 1211 ethyl n-butyl OH H 132 1212 n-butyl
n-butyl OH H 4-methoxyphenyl 1213 n-butyl ethyl H OH H 1214 n-butyl
ethyl OH H phenyl 1215 n-butyl n-butyl OH H 4-methoxyphenyl 1216
ethyl n-butyl OH H 5-piperonyl 1217 n-butyl n-butyl OH H
4-carboxyphenyl 1218 n-butyl n-butyl OH H 4-methoxyphenyl 1219
n-butyl n-butyl OH H 133 1220 n-butyl n-butyl OH H 3-methoxyphenyl
1221 n-butyl n-butyl OH H 134 1222 n-butyl n-butyl OH H
3-methoxyphenyl 1223 n-butyl n-butyl OH H phenyl 1224 n-butyl
n-butyl OH H 3-nitrophenyl 1225 n-butyl ethyl OH H 3-methylphenyl
1226 ethyl n-butyl OH H 5-piperonyl 1227 n-butyl n-butyl OH H
4-fluorophenyl 1228 n-butyl n-butyl OH H 2-pyrrolyl 1229 n-butyl
n-butyl OH H 3-chloro-4-hydroxyphenyl 1230 n-butyl n-butyl OH H
phenyl 1231 n-butyl n-butyl OH H 135 1232 n-butyl n-butyl H OH
3-thiophenyl 1233 n-butyl n-butyl OH H 136 1234 n-butyl n-butyl OH
H 137 1235 n-butyl n-butyl OH H 138 1236 n-butyl n-butyl OH H
4-(bromomethyl)phenyl 1237 n-butyl n-butyl OH H 139 1238 n-butyl
n-butyl OH H 140 1239 n-butyl n-butyl OH H 141 1240 n-butyl n-butyl
OH H 4-methoxy-3-methylphenyl 1241 n-butyl n-butyl OH H
3-(dimethylaminomethly)phenyl 1242 n-butyl n-butyl OH H 142 1243
n-butyl n-butyl OH H 143 1244 n-butyl n-butyl OH H 3-methoxyphenyl
1245 n-butyl n-butyl OH H 144 1246 n-butyl n-butyl OH H
3-(bromomethyl)phenyl 1247 n-butyl n-butyl OH H 145 1248 n-butyl
n-butyl OH H 146 1249 n-butyl n-butyl OH H 147 1250 n-butyl n-butyl
OH H 3-(dimethylamino)phenyl 1251 n-butyl n-butyl OH H 1-naphthyl
1252 n-butyl n-butyl OH H 148 1253 n-butyl n-butyl OH H 149 1254
n-butyl n-butyl OH H 150 1255 n-butyl n-butyl OH H 151 1256 n-butyl
n-butyl OH H 3-nitrophenyl 1257 n-butyl n-butyl OH H phenyl 1258
n-butyl n-butyl OH H 4-fluorophenyl 1259 ethyl n-butyl H OH H 1260
ethyl n-butyl OH H 3-hydroxyphenyl 1261 n-butyl n-butyl OH H 152
1262 n-butyl n-butyl OH H 2-thiophenyl 1263 n-butyl n-butyl OH H
5-piperonyl 1264 n-butyl n-butyl OH H 4-fluorophenyl 1265 n-butyl
n-butyl OH H 4-fluorophenyl 1266 n-butyl n-butyl OH H 153 1267
n-butyl ethyl OH H 5-piperonyl 1268 n-butyl n-butyl OH H 154 1269
n-butyl n-butyl OH H 155 1270 n-butyl n-butyl OH H 156 1271 n-butyl
n-butyl OH H 157 1272 n-butyl n-butyl OH H 158 1273 n-butyl n-butyl
OH H 159 1274 n-butyl n-butyl OH H 160 1275 n-butyl n-butyl OH H
161 1276 n-butyl n-butyl OH H 162 1277 n-butyl n-butyl OH H 163
1278 n-butyl n-butyl OH H 164 1279 n-butyl n-butyl OH H 165 1280
n-butyl n-butyl OH H 166 1281 n-butyl n-butyl OH H 167 1282 ethyl
n-butyl OH H 3-fluoro-4-methoxyphenyl 1283 n-butyl n-butyl OH H
4-hydroxymethylphenyl 1284 n-butyl n-butyl OH H 4-fluorophenyl 1285
n-butyl ethyl OH H phenyl 1286 n-butyl n-butyl OH H 168 1287
n-butyl ethyl OH H 4-hydroxyphenyl 1288 n-butyl n-butyl OH H 169
1289 n-butyl n-butyl OH H 170 1290 n-butyl n-butyl OH H 171 1291
n-butyl n-butyl OH H 172 1292 n-butyl n-butyl OH H 173 1293 n-butyl
n-butyl OH H 174 1294 n-butyl n-butyl OH H 175 1295 n-butyl n-butyl
OH H 176 1296 n-butyl n-butyl OH H 177 1297 n-butyl n-butyl OH H
178 1298 n-butyl n-butyl OH H 179 1299 n-butyl n-butyl OH H 180
1300 n-butyl ethyl H OH H 1301 n-butyl
n-butyl OH H 3-methoxyphenyl 1302 n-butyl n-butyl OH H
3-hydroxyphenyl 1303 n-butyl n-butyl OH H 181 1304 n-butyl n-butyl
OH H 3-methoxyphenyl 1305 n-butyl n-butyl OH H 4-fluorophenyl 1306
n-butyl n-butyl OH H 182 1307 n-butyl n-butyl OH H H 1308 ethyl
n-butyl OH H 183 1309 n-butyl n-butyl OH H 4-methoxyphenyl 1310
ethyl n-butyl OH H phenyl 1311 n-butyl ethyl OH H phenyl 1312
n-butyl ethyl OH H phenyl 1313 n-butyl ethyl OH H phenyl 1314 ethyl
n-butyl OH H phenyl 1315 ethyl n-butyl OH H phenyl 1316 n-butyl
ethyl OH H phenyl 1317 n-butyl ethyl OH H phenyl 1318 ethyl n-butyl
OH H phenyl 1319 ethyl n-butyl OH H 3-methoxyphenyl 1320 ethyl
n-butyl OH H phenyl 1321 n-butyl ethyl OH H phenyl 1322 n-butyl
n-butyl OH H 184 1323 n-butyl n-butyl OH H 185 1324 n-butyl n-butyl
OH H 186 1325 n-butyl n-butyl OH H 4-((diethylamino)methyl)phenyl
1326 n-butyl n-butyl OH H 187 1327 n-butyl n-butyl OH H
3-fluoro-4-hydroxy-5-iodophenyl 1328 n-butyl n-butyl OH H 188 1329
n-butyl n-butyl OH H 189 1330 n-butyl n-butyl OH H 190 1331 n-butyl
n-butyl OH H 191 1332 n-butyl n-butyl OH H 192 1333 n-butyl n-butyl
OH H 193 1334 n-butyl n-butyl OH H 194 1335 n-butyl n-butyl OH H
195 1336 n-butyl n-butyl OH H 196 1337 n-butyl n-butyl OH H 197
1338 n-butyl n-butyl OH H 4-methoxyphenyl 1339 n-butyl n-butyl OH H
198 1340 n-butyl ethyl OH H 5-piperonyl 1341 n-butyl n-butyl
acetoxy H 3-methoxyphenyl 1342 n-butyl n-butyl OH H 5-piperonyl
1343 ethyl n-butyl OH H phenyl 1344 n-butyl n-butyl OH H
3-fluoro-4-methoxyphenyl 1345 ethyl n-butyl OH H phenyl 1346 ethyl
n-butyl OH H phenyl 1347 n-butyl n-butyl OH H
3-fluoro-4-methoxyphenyl 1348 isobutyl isobutyl OH H phenyl 1349
ethyl n-butyl OH H phenyl 1350 n-butyl n-butyl OH H
3-fluoro-4-methoxyphenyl 1351 n-butyl n-butyl OH H 199 1352 n-butyl
n-butyl OH H 200 1353 n-butyl n-butyl OH H 201 1354 n-butyl n-butyl
OH H 202 1355 n-butyl n-butyl OH H 203 1356 n-butyl n-butyl OH H
204 1357 n-butyl n-butyl OH H 205 1358 n-butyl n-butyl OH H 206
1359 n-butyl n-butyl OH H 207 1360 n-butyl n-butyl OH H 208 1361
n-butyl n-butyl OH H 209 1362 n-butyl n-butyl OH H 210 1363 n-butyl
n-butyl OH H 211 1364 n-butyl n-butyl OH H 212 1365 n-butyl n-butyl
OH H 213 1366 n-butyl n-butyl OH H 214 1367 n-butyl n-butyl OH H
215 1368 n-butyl n-butyl OH H 216 1369 n-butyl n-butyl OH H 217
1370 n-butyl n-butyl OH H 218 1371 n-butyl n-butyl OH H 219 1372
n-butyl n-butyl OH H 220 1373 n-butyl n-butyl OH H 221 1374 n-butyl
n-butyl OH H 222 1375 n-butyl n-butyl OH H 223 1376 n-butyl n-butyl
OH H 224 1377 n-butyl n-butyl OH H 225 1378 n-butyl n-butyl OH H
226 1379 n-butyl n-butyl OH H 227 1380 n-butyl n-butyl OH H 228
1381 n-butyl n-butyl OH H 229 1382 n-butyl n-butyl OH H 230 1383
n-butyl n-butyl OH H 231 1384 n-butyl n-butyl OH H 232 1385 n-butyl
n-butyl OH H 233 1386 n-butyl n-butyl OH H 234 1387 n-butyl n-butyl
OH H 235 1388 n-butyl n-butyl OH H 236 1389 n-butyl n-butyl OH H
237 1390 n-butyl n-butyl OH H 238 1391 n-butyl n-butyl OH H 239
1392 n-butyl n-butyl OH H 240 1393 n-butyl n-butyl OH H 241 1394
n-butyl n-butyl OH H 242 1395 n-butyl n-butyl OH H 243 1396 n-butyl
n-butyl OH H 244 1397 n-butyl n-butyl OH H 245 1398 n-butyl n-butyl
OH H 246 1399 n-butyl n-butyl OH H 247 1400 n-butyl n-butyl OH H
248 1401 n-butyl n-butyl OH H 249 1402 n-butyl n-butyl OH H 250
1403 n-butyl n-butyl OH H 251 1404 n-butyl n-butyl OH H 252 1405
n-butyl n-butyl OH H 253 1406 n-butyl n-butyl OH H 254 1407 n-butyl
n-butyl OH H 255 1408 n-butyl n-butyl OH H 256 1409 n-butyl n-butyl
OH H 257 1410 n-butyl n-butyl OH H 258 1411 n-butyl n-butyl OH H
259 1412 n-butyl n-butyl OH H 260 1413 n-butyl n-butyl OH H 261
1414 n-butyl n-butyl OH H 262 1415 n-butyl n-butyl OH H 263 1416
n-butyl n-butyl OH H 264 1417 n-butyl n-butyl OH H 265 1418 n-butyl
n-butyl OH H 266 1419 n-butyl n-butyl OH H 267 1420 n-butyl n-butyl
OH H 268 1421 n-butyl n-butyl OH H 269 1422 n-butyl n-butyl OH H
270 1423 n-butyl n-butyl OH H 271 1424 n-butyl n-butyl OH H 272
1425 n-butyl n-butyl OH H 273 1426 n-butyl n-butyl OH H 274 1427
n-butyl n-butyl OH H 275 1428 n-butyl n-butyl OH H 276 1429 n-butyl
n-butyl OH H 277 1430 n-butyl n-butyl OH H 278 1431 n-butyl n-butyl
OH H 279 1432 n-butyl n-butyl OH H 280 1433 n-butyl n-butyl OH H
281 1434 n-butyl n-butyl OH H 282 1435 n-butyl n-butyl OH H 283
1436 n-butyl n-butyl OH H 284 1437 n-butyl n-butyl OH H 285 1438
n-butyl n-butyl OH H 286 1439 n-butyl n-butyl OH H 287 1440 n-butyl
n-butyl OH H 288 1441 n-butyl n-butyl OH H 289 1442 n-butyl n-butyl
OH H 290 1443 n-butyl n-butyl OH H 291 1444 n-butyl n-butyl OH H
292 1445 n-butyl n-butyl OH H 293 1446 n-butyl n-butyl OH H 294
1447 n-butyl n-butyl OH H 295 1448 n-butyl n-butyl OH H 296 1449
n-butyl n-butyl OH H 297 1450 n-butyl n-butyl OH H phenyl 1451
n-butyl n-butyl OH H 298
[0227]
3 Compound Number R.sup.6 (R.sup.x)q 101 H 299 at the 7-position
102 H 7-trimethylammonium iodide 103 H 7-trimethylammonium iodide
104 H 7-dimethylamino 105 H 7-methanesulfonamido 106 H
7-(2'-bromoacetamido) 107 H 7-amino 108 H 7-(hexylamido) 109 H
7-amino 110 H 7-acetamido 111 H 7-amino 112 H 7-amino 113 H 7-amino
114 H 7-amino 115 H 7-(O-benzylcarbamato) 116 H
7-(O-benzylcarbamato) 117 H 7-(O-benzylcarbamato) 118 H
7-(O-benzylcarbamato) 119 H 7-(O-tert-butylcarbamato) 120 H
7-(O-benzylcarbamato) 121 H 7-amino 122 H 7-amino 123 H
7-hexylamino 124 H 7-(hexylamino) 125 H 300 at the 8-position 126 H
7-(O-benzylcarbamato) 127 H 7-amino 128 H 7-(O-benzylcarbamato) 129
H 7-amino 131 H 301 at the 7-position 132 H 302 at the 8-position
133 H 8-(hexyloxy) 134 H 303 at the 8-position 135 H 304 at the
8-position 136 H 8-hydroxy 137 H 305 at the 7-position 138 H
8-acetoxy 139 H 306 at the 7-position 140 141 142 3-methoxy-
7-methylmercapto phenyl 143 H 7-methylmercapto 144 H
7-(N-azetidinyl) 262 H 7-methoxy 263 3-methoxy- 7-methoxy phenyl
264 H 7-methoxy 265 3- 7-methoxy trifluoro- methyl- phenyl 266 H
7-hydroxy 267 H 7-methoxy 268 H 7-methoxy 269 4-fluoro- 7-methoxy
phenyl 270 H 7-hydroxy 271 H 7 -bromo 272 3-methoxy- 7-bromo phenyl
273 4-fluoro- 7-fluoro phenyl 274 H 7-fluoro 275 3-methoxy-
7-fluoro phenyl 276 H 7-fluoro 277 H 7-methoxy 278 H 7-methoxy 279
H 7-methoxy 280 H 7-methoxy 281 H 7-methylmercapto 282 H 7-methyl
283 4-fluoro- 7-methyl phenyl 284 H 7-(4'-morpholino) 286 H
7-(O-benzylcarbamato) 287 H 7-amino 288 H 7-amino 289 H 7-amino 290
H 7-amino 291 H 7-(O-benzylcarbamato) 292 H 7-amino 293 H
7-benzylamino 294 H 7-dimethylamino 295 H 7-amino 296 H 7-amino
1000 H 7-dimethylamino 1001 H 7-dimethylamino 1002 H
7-dimethylamino 1003 H 7-dimethylamino 1004 H 7-dimethylamino 1005
H 7-dimethylamino 1006 H 7-dimethylamino 1007 H 7-dimethylamino
1008 H 7-dimethylamino 1009 H 7-dimethylamino 1010 H
7-dimethylamino 1011 H 7-dimethylamino 1012 H 7-dimethylamino;
9-methoxy 1013 H 7-dimethylamino 1014 H 7-dimethylamino; 9-methoxy
1015 H 7-dimethylamino 1016 H 7-dimethylamino 1017 H
7-dimethylamino 1018 H 7-dimethylamino 1019 H 7-dimethylamino 1020
H 7-dimethylamino 1021 H 7-dimethylamino 1022 H 7-dimethylamino
1023 H 7-dimethylamino 1024 H 7-dimethylamino 1025 H
7-dimethylamino 1026 H 7-dimethylamino 1027 H 7-dimethylamino 1028
H 7-dimethylamino 1029 H 7-dimethylamino 1030 H 7-dimethylamino
1031 H 7-dimethylamino 1032 H 7-dimethylamino 1033 H
7-dimethylamino 1034 H 7-dimethylamino 1035 H 7-dimethylamino 1036
H 7-dimethylamino 1037 H 7-dimethylamino 1038 H 7-dimethylamino
1039 H 7-dimethylamino 1040 H 7-dimethylamino 1041 H
7-dimethylamino 1042 H 7-dimethylamino 1043 H 7-dimethylamino 1044
H 7-dimethylamino 1045 H 7-dimethylamino 1046 H 7-dimethylamino
1047 H 7-dimethylamino 1048 H 7-dimethylamino 1049 H
7-dimethylamino 1050 H 7-dimethylamino 1051 H 7-dimethylamino 1052
H 7-dimethylamino 1053 H 7-dimethylamino 1054 H 7-dimethylamino
1055 H 7-dimethylamino 1056 H 7-dimethylamino 1057 H
7-dimethylamino 1058 H 7-dimethylamino 1059 H 7-dimethylamino 1060
H 7-methylamino 1061 H 7-methylamino 1062 H 7-methylamino 1063 H
7-methylamino 1064 H 7-methylamino 1065 H 7-dimethylamino 1066 H
9-dimethylamino 1067 H 7-dimethylamino 1068 H 7-dimethylamino 1069
H 7-dimethylamino; 9-dimethylamino 1070 H 7-dimethylamino 1071 H
7-dimethylamino 1072 H 7-dimethylamino 1073 H 7-dimethylamino 1074
H 7-dimethylamino 1075 H 7-dimethylamino; 9-dimethylamino 1076 H
7-dimethylamino 1077 H 7-dimethylamino 1078 H 7-dimethylamino 1079
H 7-dimethylamino 1080 H 7-dimethylamino 1081 H 7-dimethylamino
1082 H 7-dimethylamino 1083 H 7-dimethylamino 1084 H
7-dimethylamino 1085 H 7-dimethylamino 1086 H 7-dimethylamino 1087
H 7-dimethylamino 1088 H 7-dimethylamino 1089 H 7-dimethylamino
1090 H 7-dimethylamino 1091 H 7-dimethylamino 1092 H
7-dimethylamino 1093 H 7-dimethylamino 1094 H 7-dimethylamino 1095
H 7-dimethylamino 1096 H 7-dimethylamino 1097 H 7-dimethylamino
1098 H 7-dimethylamino 1099 H 7-dimethylamino 1100 H
7-dimethylamino 1101 H 7-dimethylamino 1102 H 7-dimethylamino 1103
H 7-dimethylamino 1104 H 7-dimethylamino 1105 H 7-dimethylamino
1106 H 7-dimethylamino 1107 H 7-dimethylamino 1108 H
7-dimethylamino 1109 H 7-dimethylamino 1110 H 7-dimethylamino 1111
H 7-dimethylamino 1112 H 7-dimethylamino 1113 H 7-dimethylamino
1114 H 7-methylamino 1115 H 7-dimethylamino 1116 H 7-dimethylamino
1117 H 7-dimethylamino 1118 H 7-dimethylamino 1119 H
7-dimethylamino 1120 H 7-dimethylamino 1121 H 7-dimethylamino 1122
H 7-dimethylamino 1123 H 7-dimethylamino 1124 H 7-dimethylamino
1125 H 7-dimethylamino 1126 H 7-dimethylamino 1127 H
7-dimethylamino 1128 H 7-dimethylamino 1129 H 9-dimethylamino 1130
H 7-dimethylamino 1131 H 7-dimethylamino 1132 H 7-dimethylamino
1133 H 7-dimethylamino 1134 H 7-dimethylamino 1135 H
7-dimethylamino 1136 H 7-dimethylamino 1137 H
9-(2',2'-dimethylhydrazino) 1138 H 7-dimethylamino 1139 H
7-dimethylamino 1140 H 7-(2',2'-dimethylhydrazino) 1141 H
7-ethylmethylamino 1142 H 7-dimethylamino 1143 3-fluoro-
7-dimethylamino 4-methoxy- phenyl 1144 H 7-dimethylamino 1145 H
9-dimethylamino 1146 H 7-dimethylamino 1147 H 7-diethylamino 1148 H
7-dimethylsulfonium, fluoride salt 1149 H 7-ethylamino 1150 H
7-ethylmethylamino 1151 H 7-dimethylamino 1152 H 7-(ethoxymethyl)
methylamino 1153 H 7-methylamino 1154 H 9-methoxy 1155 H 7-methyl
1156 H 7-methylmercapto 1157 H 7-fluoro; 9-dimethylamino 1158 H
7-methoxy 1159 H 7-dimethylamino 1160 H 7-diethylamino 1161 H
7-dimethylamino 1162 H 7-dimethylamino 1163 H 7-methoxy 1164 H
7-methoxy 1165 H 7-trimethylammonium iodide 1166 H
7-trimethylammonium iodide 1167 H 7-dimethylamino 1168 H
7-trimethylammonium iodide 1169 H 8-dimethylamino 1170 H
7-ethylpropylamino 1171 H 7-dimethylamino 1172 H 7-methoxy 1173 H
7-ethylpropylamino 1174 H 7-phenyl 1175 H 7-methylsulfonyl 1176 H
9-fluoro 1177 H 7-butylmethylamino 1178 H 7-dimethylamino 1179 H
8-methoxy 1180 H 7-trimethylammonium iodide 1181 H
7-butylmethylamino 1182 H 7-methoxy 1183 H 7-fluoro 1184 H
7-fluoro; 9-fluoro 1185 H 7-fluoro 1186 H 7-fluoro; 9-fluoro 1187 H
7-methyl 1188 H 7-trimethylammonium iodide 1189 H
7-trimethylammonium iodide 1190 H 7-bromo 1191 H 7-hydroxy 1192 H
7-hydroxy 1193 H 7-dimethylamino 1194 H 7-dimethylamino 1195 H
7-(4'-methylpiperazin-1-yl) 1196 H 7-methoxy 1197 H
7-(N-methylformamido) 1198 H 7-methoxy 1199 H 7-dimethylamino 1200
phenyl 7-dimethylamino 1201 H 7-methyl 1202 H 7-methoxy 1203 H
7-(4'-tert-butylphenyl) 1204 H 7-methoxy 1205 H 7-dimethylamino
1206 H 7-dimethylamino 1207 H 7-dimethylamino 1208 H
7-dimethylamino 1209 H 7-dimethylphenyl 1210 H 7-dimethylamino 1211
H 7-dimethylamino 1212 H 9-(4'-morpholino) 1213 3-fluoro-
7-dimethylamino 4-methoxy- phenyl 1214 H 7-(N-methylformamido) 1215
H 9-methylmercapto 1216 H 7-bromo 1217 H 7-dimethylamino 1218 H
9-methylsulfonyl 1219 H 7-dimethylamino 1220 H 7-isopropylamino
1221 H 7-dimethylamino 1222 H 7-ethylamino 1223 H 8-bromo;
7-methylamino 1224 H 7-fluoro 1225 H 7-dimethylamino 1226 H 7-bromo
1227 H 7-(tert-butylamino 1228 H 8-bromo; 7-dimethylamino 1229 H
7-dimethylamino 1230 H 9-dimethylamino; 7-fluoro 1231 H
7-dimethylamino 1232 H 9-dimethylamino 1233 H 7-dimethylamino 1234
H 7-dimethylamino 1235 H 7-dimethylamino 1236 H 7-dimethylamino
1237 H 7-dimethylamino 1238 H 7-dimethylamino 1239 H
7-dimethylamino 1240 H 7-dimethylamino 1241 H 7-dimethylamino 1242
H 7-dimethylamino 1243 H 7-dimethylamino 1244 H
7-(1'-methylhydrazido) 1245 H 7-dimethylamino 1246 H
7-dimethylamino 1247 H 7-dimethylamino 1248 H 7-dimethylamino 1249
H 7-dimethylamino 1250 H 7-dimethylamino 1251 H 7-dimethylamino
1252 H 7-dimethylamino 1253 H 7-dimethylamino 1254 H
7-dimethylamino 1255 H 7-dimethylamino 1256 H 7-dimethylamino 1257
H 8-bromo; 7-dimethylamino 1258 H 9-(tert-butylamino) 1259 phenyl
7-dimethylamino 1260 H 7-dimethylamino 1261 H 7-dimethylamino 1262
H 7-dimethylamino 1263 H 7-bromo 1264 H 7-isopropylamino 1265 H
9-isopropylamino 1266 H 7-dimethylamino 1267 H 7-carboxy, methyl
ester 1268 H 7-dimethylamino 1269 H 7-dimethylamino 1270 H
7-dimethylamino 1271 H 7-dimethylamino 1272 H 7-dimethylamino 1273
H 7-dimethylamino 1274 H 7-dimethylamino 1275 H 7-dimethylamino
1276 H 7-dimethylamino 1277 H 7-dimethylamino 1278 H
7-dimethylamino 1279 H 7-dimethylamino 1280 H 7-dimethylamino 1281
H 7-dimethylamino 1282 H 7-trimethylammonium iodide 1283 H
7-dimethylamino 1284 H 9-ethylamino 1285 H 7-dimethylamino 1286 H
7-dimethylamino 1287 H 7-dimethylamino 1288 H 7-dimethylamino 1289
H 7-dimethylamino 1290 H 7-dimethylamino 1291 H 7-dimethylamino
1292 H 7-dimethylamino 1293 H 7-dimethylamino 1294 H
7-dimethylamino 1295 H 7-dimethylamino 1296 H 7-dimethylamino 1297
H 7-dimethylamino 1298 H 7-dimethylamino 1299 H 7-dimethylamino
1300 phenyl 7-dimethylamino 1301 H 7-trimethylammonium iodide 1302
H 9-hydroxy 1303 H 7-dimethylamino 1304 H 7-tert-butylamino 1305 H
9-methylamino 1306 H 7-dimethylamino 1307 4-methoxy-
9-(4'-morpholino) phenyl 1308 H 7-dimethylamino 1309 H 9-fluoro
1310 H 7-amino 1311 H 7-(hydroxylamino) 1312 H 8-hexyloxy 1313 H
8-ethoxy 1314 H 7-(hydroxylamino) 1315 H 7-(hexyloxy) 1316 H
8-hydroxy 1317 H 307 at the 8-position 1318 H 7-dimethylamino 1319
H 7-fluoro 1320 H 7-amino 1321 H 308 at the 8-position 1322 H
7-dimethylamino 1323 H 7-dimethylamino 1324 H 7-dimethylamino 1325
H 7-dimethylamino 1326 H 7-dimethylamino 1327 H 7-dimethylamino
1328 H 7-dimethylamino 1329 H 7-dimethylamino 1330 H
7-dimethylamino 1331 H 7-dimethylamino 1332 H 7-dimethylamino 1333
H 7-dimethylamino 1334 H 7-dimethylamino 1335 H 7-dimethylamino
1336 H 7-dimethylamino 1337 H 7-dimethylamino 1338 H
7-(4'-methylpiperazinyl) 1339 H 7-dimethylamino 1340 H 7-methyl
1341 H 7-dimethylamino 1342 H 7-(4'-fluorophenyl) 1343 H 7-amino
1344 H 7-dimethylamino 1345 H 7-trimethylammonium iodide 1346 H 309
at the 8-position 1347 H 7-dimethylamino 1348 H 7-dimethylamino
1349 H 7-dimethylamino 1350 H 7-trimethylammonium iodide 1351 H
7-dimethylamino 1352 H 7-dimethylamino 1353 H 7-dimethylamino 1354
H 7-dimethylamino 1355 H 7-dimethylamino 1356 H 7-dimethylamino
1357 H 7-dimethylamino 1358 H 7-dimethylamino 1359 H
7-dimethylamino 1360 H 7-dimethylamino 1361 H 7-dimethylamino 1362
H 7-dimethylamino 1363 H 7-dimethylamino 1364 H 7-dimethylamino
1365 H 7-dimethylamino 1366 H 7-dimethylamino 1367 H
7-dimethylamino 1368 H 7-dimethylamino 1369 H 7-dimethylamino 1370
H 7-dimethylamino 1371 H 7-dimethylamino 1372 H 7-dimethylamino
1373 H 7-dimethylamino 1374 H 7-dimethylamino 1375 H
7-dimethylamino 1376 H 7-dimethylamino 1377 H 7-dimethylamino 1378
H 7-dimethylamino 1379 H 7-dimethylamino 1380 H 7-dimethylamino
1381 H 7-dimethylamino 1382 H 7-dimethylamino 1383 H
7-dimethylamino 1384 H 7-dimethylamino 1385 H 7-dimethylamino 1386
H 7-dimethylamino 1387 H 7-dimethylamino 1388 H 7-dimethylamino
1389 H 7-dimethylamino 1390 H 7-dimethylamino 1391 H
7-dimethylamino 1392 H 7-dimethylamino 1393 H 7-dimethylamino 1394
H 7-dimethylamino 1395 H 7-dimethylamino 1396 H 7-dimethylamino
1397 H 7-dimethylamino 1398 H 7-dimethylamino 1399 H
7-dimethylamino 1400 H 7-dimethylamino 1401 H 7-dimethylamino 1402
H 7-dimethylamino 1403 H 7-dimethylamino 1404 H 7-dimethylamino
1405 H 7-dimethylamino 1406 H 7-dimethylamino 1407 H
7-dimethylamino 1408 H 7-dimethylamino 1409 H 7-dimethylamino 1410
H 7-dimethylamino 1411 H 7-dimethylamino 1412 H 7-dimethylamino
1413 H 7-dimethylamino 1414 H 7-dimethylamino 1415 H
7-dimethylamino 1416 H 7-dimethylamino 1417 H 7-dimethylamino 1418
H 7-dimethylamino 1419 H 7-dimethylamino 1420 H 7-dimethylamino
1421 H 7-dimethylamino 1422 H 7-dimethylamino 1423 H
7-dimethylamino 1424 H 7-dimethylamino 1425 H 7-dimethylamino 1426
H 7-dimethylamino 1427 H 7-dimethylamino 1428 H 7-dimethylamino
1429 H 7-dimethylamino 1430 H 7-dimethylamino 1431 H
7-dimethylamino 1432 H 7-dimethylamino 1433 H 7-dimethylamino 1434
H 7-dimethylamino 1435 H 7-dimethylamino 1436 H 7-dimethylamino
1437 H 7-dimethylamino 1438 H 7-dimethylamino 1439 H
7-dimethylamino 1440 H 7-dimethylamino 1441 H 7-dimethylamino 1442
H 7-dimethylamino 1443 H 7-dimethylamino 1444 H 7-dimethylamino
1445 H 7-dimethylamino 1446 H 7-methoxy;
8-methoxy 1447 H 7-dimethylamino 1448 H 7-dimethylamino 1449 H
7-dimethylamino 1450 H 7-dimethylamino 1451 H 7-dimethylamino
[0228] 310
[0229] In further compounds of the present invention, R.sup.5 and
R.sup.6 are independently selected from among hydrogen and
ring-carbon substituted or unsubstituted aryl, thiophene, pyridine,
pyrrole, thiazole, imidazole, pyrazole, pyrimidine, morpholine,
N-alkylpyridinium, N-alkylpiperazinium, N-alkylmorpholinium, or
furan in which the substituent(s) are selected from among halo,
hydroxyl, trihaloalkyl, alkoxy, amino, N-alkylamino,
N,N-dialkylamino, quaternary ammonium salts, a C.sub.1 to C.sub.4
alkylene bridge having a quaternary ammonium salt substituted
thereon, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyloxy and
arylcarbonyloxy, (O,O)-dioxyalkylene,
[0230] --[O(CH.sub.2).sub.w].sub.xX where x is 2 to 12, w is 2 or 3
and X comprises halo or a quaternary ammonium salt, thiophene,
pyridine, pyrrole, thiazole, imidazole, pyrazole, or furan. The
aryl group of R.sup.5 or R.sup.6 is preferably phenyl, phenylene,
or benzene triyl, i.e., may be unsubstituted, mono-substituted, or
di-substituted. Among the species which may constitute the
substituents on the aryl ring of R.sup.5 or R.sup.6 are fluoro,
chloro, bromo, methoxy, ethoxy, isopropoxy, trimethylammonium
(preferably with an iodide or chloride counterion),
methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propanoyl,
(N)-hexyldimethylammonium, hexylenetrimethylammonium,
tri(oxyethylene)iodide, and tetra(oxyethylene)trimethyl-ammonium
iodide, each substituted at the p-position, the m-position, or both
of the aryl ring. Other substituents that can be present on a
phenylene, benzene triyl or other aromatic ring include
3,4-dioxymethylene (5-membered ring) and 3,4-dioxyethylene
(6-membered ring). Among compounds which have been or can be
demonstrated to have desirable ileal bile acid transport inhibiting
properties are those in which R.sup.5 or R.sup.6 is selected from
phenyl, p-fluorophenyl, m-fluorophenyl, p-hydroxyphenyl,
m-hydroxyphenyl, p-methoxyphenyl, m-methoxyphenyl,
p-N,N-dimethylaminophenyl, m-N,N-dimethylaminophenyl, I.sup.-
p-(CH.sub.3).sub.3-N.sup.+-phenyl, I.sup.- m-
(CH.sub.3).sub.3-N.sup.+-ph- enyl, I.sup.-
m-(CH.sub.3).sub.3-N.sup.+--CH.sub.2CH.sub.2--(OCH.sub.2CH.s-
ub.2).sub.2-O-phenyl, I.sup.- p-
(CH.sub.3).sub.3-N.sup.+--CH.sub.2CH.sub.-
2--(OCH.sub.2CH.sub.2).sub.2-O-phenyl, I.sup.- m-
(N,N-dimethylpiperaziniu-
m)-(N')--CH.sub.2--(OCH.sub.2CH.sub.2).sub.2-O-phenyl,
3-methoxy-4-fluorophenyl, thienyl-2-yl, 5-cholorothienyl-2-yl,
3,4-difluorophenyl, I.sup.-
p-(N,N-dimethylpiperazinium)-(N')--CH.sub.2---
(OCH.sub.2CH.sub.2).sub.2-O-phenyl, 3-fluoro-4-methoxyphenyl,
-4-pyridinyl, 2-pyridinyl, 3-pyridinyl, N-methyl-4-pyridinium,
I.sup.- N-methyl-3-pyridinium, 3,4-dioxymethylenephenyl,
3,4-dioxyethylenephenyl, and p-methoxycarbonylphenyl. Preferred
compounds include 3-ethyl-3-butyl and 3-butyl-3-butyl compounds
having each of the above preferred R.sup.5 substituents in
combination with the R.sub.x substituents shown in Table 1. It is
particularly preferred that one but not both of R.sup.5 and R.sup.6
is hydrogen.
[0231] It is especially preferred that R.sup.4 and R.sup.6 be
hydrogen, that R.sup.3 and R.sup.5 not be hydrogen, and that
R.sup.3 and R.sup.5 be oriented in the same direction relative to
the plane of the molecule, i.e., both in .alpha.- or both in
.beta.-configuration. It is further preferred that, where R.sup.2
is butyl and R.sup.1 is ethyl, then R.sup.1 has the same
orientation relative to the plane of the molecule as R.sup.3 and
R.sup.5.
[0232] Set forth in Table 1A are lists of species of
R.sup.1/R.sup.2, R.sup.5/R.sup.6 and R.sup.x.
4TABLE 1A Alternative R Groups 311 R.sup.1, R.sup.2 R.sup.3,
R.sup.4 R.sup.5 (R.sup.x)q ethyl HO-- Ph-- 7-methyl n-propyl H--
p-F--Ph-- 7-ethyl n-butyl m-F--Ph-- 7-iso-propyl n-pentyl
p-CH.sub.3O--Ph-- 7-tert-butyl n-hexyl p-CH.sub.3O--Ph-- 7-OH
iso-propyl m-CH.sub.3O--Ph-- 7-OCH.sub.3 iso-butyl
p-(CH.sub.3).sub.2N--Ph-- 7-O(iso-propyl) iso-pentyl
m-(CH.sub.3).sub.2N--Ph-- 7-SCH.sub.3
CH.sub.2C(.dbd.O)C.sub.2H.sub.5 I.sup.-, p-(CH.sub.3).sub.3--N.su-
p.+--Ph-- 7-SOCH.sub.3 CH.sub.2OC.sub.2H.sub.5 I.sup.-,
m-(CH.sub.3).sub.3--N.sup.+--Ph-- 7-SO.sub.2CH.sub.3
CH.sub.2CH(OH)C.sub.2H.sub.5 I.sup.-,
p-(CH.sub.3).sub.3--N.sup.+--CH.su- b.2CH.sub.2--
7-SCH.sub.2CH.sub.3 CH.sub.2O-(4-picoline)
(OCH.sub.2CH.sub.2).sub.2--O--Ph-- 7-NH.sub.2 I.sup.-,
m-(CH.sub.3).sub.3--N.sup.+--CH.sub.2CH.sub.2-- 7-NHOH
(OCH.sub.2CH.sub.2).sub.2--O--Ph-- 7-NHCH.sub.3 I.sup.-, p-(N,N-
7-N(CH.sub.3).sub.2 dimethylpiperazine)- 7-N.sup.+(CH.sub.3).sub-
.3, I.sup.- (N')--CH.sub.2--(OCH.sub.2CH.sub.2).sub.2--O--
7-NHC(.dbd.O)CH.sub.3 Ph-- 7-N(CH.sub.2CH.sub.3).sub.2 I.sup.-,
m-(N,N- 7-NMeCH.sub.2CO.sub.2H dimethylpiperazine)-
7-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H, I.sup.-
(N')--CH.sub.2--(OCH.sub.2CH.sub.2).sub.2--O-- 7-(N)-morpholine
Ph-- 7-(N)-azetidine m-F, p-CH.sub.3O--Ph--
7-(N)--N-methylazetidinium, 3,4, dioxymethylene-Ph I.sup.-
m-CH.sub.3O--, p-F--Ph-- 7-(N)-pyrrolidine 4-pyridine
7-(N)--N-methyl- N-methyl-4-pyridinium, I.sup.- pyrrolidinium,
I.sup.- 3-pyridine 7-(N)--N-methyl- N-methyl-3-pyridinium, I.sup.-
morpholinium, I.sup.- 2-pyridine 7-(N)--N'-methylpiperazine
p-CH.sub.3O.sub.2C--Ph-- 7-(N)--N'- thienyl-2-yl
dimethylpiperazinium, 5-Cl-thienyl-2-yl I.sup.- 7-NH--CBZ
7-NHC(O)C.sub.5H.sub.11 7-NNO(O)CH.sub.2Br 7-NH--C(NH)NH.sub.2
7-(2)-thiophene 8-methyl 8-ethyl 8-iso-propyl 8-tert-butyl 8-OH
8-OCH.sub.3 8-O(iso-propyl) 8-SCH.sub.3 8-SOCH.sub.3
8-SO.sub.2CH.sub.3 8-SCH.sub.2CH.sub.3 8-NH.sub.2 8-NHOH
8-NHCH.sub.3 8-N(CH.sub.3).sub.2 8-N.sup.+(CH.sub.3).sub.3, I.sup.-
8-NHC(.dbd.O)CH.sub.3 8-N(CH.sub.2CH.sub.3).sub.2
8-NMeCH.sub.2CO.sub.2H 8-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H,
I.sup.- 8-(N)-morpholine 8-(N)-azetidine
8-(N)--N-methylazetidinium, I.sup.- 8-(N)-pyrrolidine
8-(N)--N-methyl- pyrrolidinium, I.sup.- 8-(N)--N-methyl-
morpholinium, I.sup.- 8-(N)--N'-methylpiperazine 8-(N)--N'-
dimethylpiperazinium, I.sup.- 8-NH--CBZ 8-NHC(O)C.sub.5H.sub.11
8-NHC(O)CH.sub.2Br 8-NH--C(NH)NH.sub.2 8-(2)-thiophene 9-methyl
9-ethyl 9-iso-propyl 9-tert-butyl 9-OH 9-OCH.sub.3 9-O(iso-propyl)
9-SCH.sub.3 9-SOCH.sub.2 9-SO.sub.2CH.sub.3 9-SCH.sub.2CH.sub.3
9-NH.sub.2 9-NHOH 9-NHCH.sub.3 9-N(CH.sub.3).sub.2
9-N.sup.+(CH.sub.3).sub.3, I.sup.- 9-NHC(.dbd.O)CH.sub.3
9-N(CH.sub.2CH.sub.3).sub.2 9-NMeCH.sub.2CO.sub.2H
9-N.sup.+(Me).sub.2CH.sub.2CO.sub.2H, I.sup.- 9-(N)-morpholine
9-(N)-azetidine 9-(N)--N-methylazetidinium, I.sup.-
9-(N)-pyrrolidine 9-(N)--N-methyl- pyrrolidinium, I.sup.-
9-(N)--N-methyl- morpholinium, I.sup.- 9-(N)--N'-methylpiperazine
9-(N)--N'- dimethylpiperaziniuim, I.sup.- 9-NH--CBZ
9-NHC(O)C.sub.5H.sub.11 9-NHC(O)CH.sub.2Br 9-NH--C(NH)NH.sub.2
9-(2)-thiophene 7-OCH.sub.3, 8-OCH.sub.3 7-SCH.sub.3, 8-OCH.sub.3
7-SCH.sub.3, 8-SCH.sub.3 6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3
[0233] Further preferred compounds of the present invention
comprise a core structure having two or more pharmaceutically
active benzothiepine structures as described above, covalently
bonded to the core moiety via functional linkages. Such active
benzothiepine structures preferably comprise: 312
[0234] where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5R.sup.6,
R.sup.7, R.sup.8, X, q and n are as defined above, and R55 is
either a covalent bond or arylene.
[0235] The core moiety can comprise alkane diyl, alkene diyl,
alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl,
polyalkoxy diyl, carbohydrate, amino acid, and peptide,
polypeptide, wherein alkane diyl, alkene diyl, alkyne diyl,
polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl,
carbohydrate, amino acid, and peptide polypeptide, can optionally
have one or more carbon replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8, S, SO, SO2, S.sup.+R.sup.7R.sup.8, PR7,
P+R7R8, phenylene, heterocycle, quatarnary heterocycle, quaternary
heteroaryl, or aryl,
[0236] wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane
diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate,
amino acid, peptide, and polypeptide can be substituted with one or
more substituent groups independently selected from the group
consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo,
OR.sup.13, NR.sup.13R.sup.14, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, SO.sub.3R.sup.13, NR.sup.13OR.sup.14,
NR.sup.13NR.sup.14R.sup.15, NO.sub.2, CO.sub.2R.sup.13, CN, OM,
SO.sub.2OM, SO.sub.2NR.sup.13R.sup.14, C(O)NR.sup.13R.sup.14,
C(O)OM, COR.sup.13, P(O)R.sup.13R.sup.14,
P.sup.+R.sup.13R.sup.14R15A-, P(OR.sup.13) OR.sup.14,
S.sup.+R.sup.13R.sup.14A.sup.-, and
N.sup.+R.sup.9R.sup.11R.sup.12A.sup.-- ;
[0237] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, and heterocycle can be further
substituted with one or more substituent groups selected from the
group consisting of OR.sup.7, NR.sup.7R.sup.8, SR.sup.7,
S(O)R.sup.7, SO.sub.2R.sup.7, SO.sub.3R.sup.7, CO.sub.2R.sup.7, CN,
oxo, CONR.sup.7R.sup.8, N.sup.+R.sup.7R.sup.8R.sup.9A-, alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl,
quaternary heterocycle, quaternary heteroaryl, P(O)R.sup.7R.sup.8,
P.sup.+R.sup.7R.sup.8A.sup.-, and P(O) (OR.sup.7)OR.sup.8, and
[0238] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,
aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have
one or more carbons replaced by O, NR.sup.7,
N.sup.+R.sup.7R.sup.8A-, S, SO, SO.sub.2, S.sup.+R.sup.7A-,
PR.sup.7, P(O)R.sup.7, P.sup.+R.sup.7R.sup.8A-, or phenylene.
[0239] Exemplary core moieties include: 313
[0240] wherein:
[0241] R.sup.25 is selected from the group consisting of C and N,
and
[0242] R.sup.26 and R.sup.27 are independently selected from the
group consisting of: 314
[0243] wherein R.sup.26, R.sup.27, R.sup.30 and R.sup.31 are
independently selected from alkyl, alkenyl, alkylaryl, aryl,
arylalkyl, cycloalkyl, heterocycle, and heterocycloalkyl,
[0244] A.sup.- is a pharmaceutically acceptable anion, and k=1 to
10.
[0245] In compounds of Formula DIV, R.sup.20 , R.sup.21 , R.sup.22
in Formulae DII and DIII, and R.sup.23 in Formula DIII can be
bonded at any of their 6-, 7-, 8-, or 9- positions to R.sup.19. In
compounds of Formula DIVA, it is preferred that R.sup.55 comprises
a phenylene moiety bonded at a m- or p-position thereof to
R.sup.19.
[0246] In another embodiment, a core moiety backbone, R.sup.19, as
discussed herein in Formulas DII and DIII can be multiply
substituted with more than four pendant active benzothiepine units,
i.e., R.sup.20, R.sup.21, R.sup.22, and R.sup.23 as discussed
above, through multiple functional groups within the core moiety
backbone. The core moiety backbone unit, R.sup.19, can comprise a
single core moiety unit, multimers thereof, and multimeric mixtures
of the different core moiety units discussed herein, i.e., alone or
in combination. The number of individual core moiety backbone units
can range from about one to about 100, preferably about one to
about 80, more preferably about one to about 50, and even more
preferably about one to about 25. The number of points of
attachment of similar or different pendant active benzothiepine
units within a single core moiety backbone unit can be in the range
from about one to about 100, preferably about one to about 80, more
preferably about one to about 50, and even more preferably about
one to about 25. Such points of attachment can include bonds to C,
S, O, N, or P within any of the groups encompassed by the
definition of R.sup.19.
[0247] The more preferred benzothiepine moieties comprising
R.sup.20, R.sup.21, R.sup.22 and/or R.sup.23 conform to the
preferred structures as outlined above for Formula I. The 3-carbon
on each benzothiepine moiety can be achiral, and the substituents
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.x can be
selected from the preferred groups and combinations of substituents
as discussed above. The core structures can comprise, for example,
poly(exyalkylene) or oligo(oxyalkylene), especially poly- or
oligo(exyethylene) or poly- or oligo(oxypropylene).
[0248] Dosages, Formulations, and Routes of Administration
[0249] The iheal bile acid transport inhibitor compounds of the
present invention can be administered for the prophylaxis and
treatment of hyperlipidemic diseases or conditions by any means,
preferably oral, that produce contact of these compounds with their
site of action in the body, for example in the ileum of a mammal,
e.g., a human.
[0250] For the prophylaxis or treatment of the conditions referred
to above, the compounds of the present invention can be used as the
compound per se.
[0251] Pharmaceutically acceptable salts are particularly suitable
for medical applications because of their greater aqueous
solubility relative to the parent compound. Such salts must clearly
have a pharmaceutically acceptable anion or cation. Suitable
pharmaceutically acceptable acid addition salts of the compounds of
the present invention when possible include those derived from
inorganic acids, such as hydrochloric, hydrobromic, phosphoric,
metaphosphoric, nitric, sulfonic, and sulfuric acids, and organic
acids such as acetic, benzenesulfonic, benzoic, citric,
ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic,
lactobionic, maleic, malic, methanesulfonic, succinic,
toluenesulfonic, tartaric, and trifluoroacetic acids. The chloride
salt is particularly preferred for medical purposes. Suitable
pharmaceutically acceptable base salts include ammonium salts,
alkali metal salts such as sodium and potassium salts, and alkaline
earth salts such as magnesium and calcium salts.
[0252] The anions of the definition of A.sup.- in the present
invention are, of course, also required to be pharmaceutically
acceptable and are also selected from the above list.
[0253] The compounds of the present invention can be presented with
an acceptable carrier in the form of a pharmaceutical composition.
The carrier must, of course, be acceptable in the sense of being
compatible with the other ingredients of the composition and must
not be deleterious to the recipient. The carrier can be a solid or
a liquid, or both, and is preferably formulated with the compound
as a unit-dose composition, for example, a tablet, which can
contain from 0.05% to 95% by weight of the active compound. Other
pharmacologically active substances can also be present, including
other compounds of the present invention. The pharmaceutical
compositions of the invention can be prepared by any of the well
known techniques of pharmacy, consisting essentially of admixing
the components.
[0254] These compounds can be administered by any conventional
means available for use in conjunction with pharmaceuticals, either
as individual therapeutic compounds or as a combination of
therapeutic compounds.
[0255] The amount of compound which is required to achieve the
desired biological effect will, of course, depend on a number of
factors such as the specific compound chosen, the use for which it
is intended, the mode of administration, and the clinical condition
of the recipient.
[0256] In general, a daily dose can be in the range of from about
0.3 to about 100 mg/kg bodyweight/day, preferably from about 1 mg
to about 50 mg/kg bodyweight/day, more preferably from about 3 to
about 10 mg/kg bodyweight/day. This total daily dose can be
administered to the patient in a single dose, or in proportionate
multiple subdoses. Subdoses can be administered 2 to 6 times per
day. Doses can be in sustained release form effective to obtain
desired results.
[0257] Orally administrable unit dose formulations, such as tablets
or capsules, can contain, for example, from about 0.1 to about 100
mg of benzothiepine compound, preferably about 1 to about 75 mg of
compound, more preferably from about 10 to about 50 mg of compound.
In the case of pharmaceutically acceptable salts, the weights
indicated above refer to the weight of the benzothiepine ion
derived from the salt.
[0258] Oral delivery of an ileal bile acid transport inhibitor of
the present invention can include formulations, as are well known
in the art, to provide prolonged or sustained delivery of the drug
to the gastrointestinal tract by any number of mechanisms. These
include, but are not limited to, pH sensitive release from the
dosage form based on the changing pH of the small intestine, slow
erosion of a tablet or capsule, retention in the stomach based on
the physical properties of the formulation, bioadhesion of the
dosage form to the mucosal lining of the intestinal tract, or
enzymatic release of the active drug from the dosage form. The
intended effect is to extend the time period over which the active
drug molecule is delivered to the site of action (the ileum) by
manipulation of the dosage form. Thus, enteric-coated and
enteric-coated controlled release formulations are within the scope
of the present invention. Suitable enteric coatings include
cellulose acetate phthalate, polyvinylacetate phthalate,
hydroxypropylmethylcellulose phthalate and anionic polymers of
methacrylic acid and methacrylic acid methyl ester.
[0259] When administered intravenously, the dose can, for example,
be in the range of from about 0.1 mg/kg body weight to about 1.0
mg/kg body weight, preferably from about 0.25 mg/kg body weight to
about 0.75 mg/kg body weight, more preferably from about 0.4 mg/kg
body weight to about 0.6 mg/kg body weight. This dose can be
conveniently administered as an infusion of from about 10 ng/kg
body weight to about 100 ng/kg body weight per minute. Infusion
fluids suitable for this purpose can contain, for example, from
about 0.1 ng to about 10 mg, preferably from about 1 ng to about 10
mg per milliliter. Unit doses can contain, for example, from about
1 mg to about 10 g of the compound of the present invention. Thus,
ampoules for injection can contain, for example, from about 1 mg to
about 100 mg.
[0260] Pharmaceutical compositions according to the present
invention include those suitable for oral, rectal, topical, buccal
(e.g., sublingual), and parenteral (e.g., subcutaneous,
intramuscular, intradermal, or intravenous) administration,
although the most suitable route in any given case will depend on
the nature and severity of the condition being treated and on the
nature of the particular compound which is being used. In most
cases, the preferred route of administration is oral.
[0261] Pharmaceutical compositions suitable for oral administration
can be presented in discrete units, such as capsules, cachets,
lozenges, or tablets, each containing a predetermined amount of at
least one compound of the present invention; as a powder or
granules; as a solution or a suspension in an aqueous or
non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
As indicated, such compositions can be prepared by any suitable
method of pharmacy which includes the step of bringing into
association the active compound(s) and the carrier (which can
constitute one or more accessory ingredients). In general, the
compositions are prepared by uniformly and intimately admixing the
active compound with a liquid or finely divided solid carrier, or
both, and then, if necessary, shaping the product. For example, a
tablet can be prepared by compressing or molding a powder or
granules of the compound, optionally with one or more assessory
ingredients. Compressed tablets can be prepared by compressing, in
a suitable machine, the compound in a free-flowing form, such as a
powder or granules optionally mixed with a binder, lubricant, inert
diluent and/or surface active/dispersing agent(s). Molded tablets
can be made by molding, in a suitable machine, the powdered
compound moistened with an inert liquid diluent.
[0262] Pharmaceutical compositions suitable for buccal
(sub-lingual) administration include lozenges comprising a compound
of the present invention in a flavored base, usually sucrose, and
acacia or tragacanth, and pastilles comprising the compound in an
inert base such as gelatin and glycerin or sucrose and acacia.
[0263] Pharmaceutical compositions suitable for parenteral
administration conveniently comprise sterile aqueous preparations
of a compound of the present invention. These preparations are
preferably administered intravenously, although administration can
also be effected by means of subcutaneous, intramuscular, or
intradermal injection. Such preparations can conveniently be
prepared by admixing the compound with water and rendering the
resulting solution sterile and isotonic with the blood. Injectable
compositions according to the invention will generally contain from
0.1 to 5% w/w of a compound disclosed herein.
[0264] Pharmaceutical compositions suitable for rectal
administration are preferably presented as unit-dose suppositories.
These can be prepared by admixing a compound of the present
invention with one or more conventional solid carriers, for
example, cocoa butter, and then shaping the resulting mixture.
[0265] Pharmaceutical compositions suitable for topical application
to the skin preferably take the form of an ointment, cream, lotion,
paste, gel, spray, aerosol, or oil. Carriers which can be used
include vaseline, lanoline, polyethylene glycols, alcohols, and
combinations of two or more thereof. The active compound is
generally present at a concentration of from 0.1 to 15% w/w of the
composition, for example, from 0.5 to 2%.
[0266] Transdermal administration is also possible. Pharmaceutical
compositions suitable for transdermal administration can be
presented as discrete patches adapted to remain in intimate contact
with the epidermis of the recipient for a prolonged period of time.
Such patches suitably contain a compound of the present invention
in an optionally buffered, aqueous solution, dissolved and/or
dispersed in an adhesive, or dispersed in a polymer. A suitable
concentration of the active compound is about 1% to 35%, preferably
about 3% to 15%. As one particular possibility, the compound can be
delivered from the patch by electrotransport or iontophoresis, for
example, as described in Pharmaceutical Research, 3(6), 318
(1986).
[0267] In any case, the amount of active ingredient that can be
combined with carrier materials to produce a single dosage form to
be administered will vary depending upon the host treated and the
particular mode of administration.
[0268] The solid dosage forms for oral administration including
capsules, tablets, pills, powders, and granules noted above
comprise one or more compounds of the present invention admixed
with at least one inert diluent such as sucrose, lactose, or
starch. Such dosage forms may also comprise, as in normal practice,
additional substances other than inert diluents, e.g., lubricating
agents such as magnesium stearate. In the case of capsules,
tablets, and pills, the dosage forms may also comprise buffering
agents. Tablets and pills can additionally be prepared with enteric
coatings.
[0269] Liquid dosage forms for oral administration can include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs containing inert diluents commonly used in the
art, such as water. Such compositions may also comprise adjuvants,
such as wetting agents, emulsifying and suspending agents, and
sweetening, flavoring, and perfuming agents.
[0270] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or setting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, and
isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending medium. For
this purpose any bland fixed oil may be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid find use in the preparation of injectables.
[0271] Pharmaceutically acceptable carriers encompass all the
foregoing and the like.
[0272] Treatment Regimen
[0273] The dosage regimen to prevent, give relief from, or
ameliorate a disease condition having hyperlipemia as an element of
the disease, e.g., atherosclerosis, or to protect against or treat
further high cholesterol plasma or blood levels with the compounds
and/or compositions of the present invention is selected in
accordance with a variety of factors. These include the type, age,
weight, sex, diet, and medical condition of the patient, the
severity of the disease, the route of administration,
pharmacological considerations such as the activity, efficacy,
pharmacokinetics and toxicology profiles of the particular compound
employed, whether a drug delivery system is utilized, and whether
the compound is administered as part of a drug combination. Thus,
the dosage regimen actually employed may vary widely and therefore
deviate from the preferred dosage regimen set forth above.
[0274] Initial treatment of a patient suffering from a
hyperlipidemic condition can begin with the dosages indicated
above. Treatment should generally be continued as necessary over a
period of several weeks to several months or years until the
hyperlipidemic disease condition has been controlled or eliminated.
Patients undergoing treatment with the compounds or compositions
disclosed herein can be routinely monitored by, for example,
measuring serum cholesterol levels by any of the methods well known
in the art, to determine the effectiveness of therapy. Continuous
analysis of such data permits modification of the treatment regimen
during therapy so that optimal effective amounts of compounds of
the present invention are administered at any point in time, and so
that the duration of treatment can be determined as well. In this
way, the treatment regimen/dosing schedule can be rationally
modified over the course of therapy so that the lowest amount of
ileal bile acid transport inhibitor of the present invention which
exhibits satisfactory effectiveness is administered, and so that
administration is continued only so long as is necessary to
successfully treat the hyperlipidemic condition.
[0275] The following non-limiting examples serve to illustrate
various aspects of the present invention.
EXAMPLES OF SYNTHETIC PROCEDURES
[0276] Preparation 1
[0277] 2-Ethyl-2-(mesyloxymethyl)hexanal (1) 315
[0278] To a cold (10.degree. C.) solution of 12.6 g (0.11 mole) of
methanesulfonyl chloride and 10.3 g (0.13 mole) of triethylamine
was added dropwise 15.8 g of 2-ethyl-2-(hydroxymethyl)hexanal,
prepared according to the procedure described in Chem. Ber. 98,
728-734 (1965), while maintaining the reaction temperature below
30.degree. C. The reaction mixture was stirred at room temperature
for 18 h, quenched with dilute HCl and extracted with methlyene
chloride. The methylene chloride extract was dried over MgSO.sub.4
and concentrated in vacuo to give 24.4 g of brown oil.
[0279] Preparation 2
[0280] 2-((2-Benzoylphenylthio)methyl)-2-ethylhexanal (2) 316
[0281] A mixture of 31 g (0.144 moi) of 2-mercaptobenzophenone,
prepared according to the procedure described in WO 93/16055, 24.4
g (0.1 mole) of 2-ethyl-2-(mesyloxymethyl)-hexanal (1), 14.8 g
(0.146 mole) of triethylamine, and 80 mL of 2-methoxyethyl ether
was held at reflux for 24 h. The reaction mixture was poured into
3N HCl and extracted with 300 mL of methylene chloride. The
methylene chloride layer was washed with 300 mL of 10% NaOH, dried
over MgSO.sub.4 and concentrated in vacuo to remove 2-methoxyethyl
ether. The residue was purified by HPLC (10% EtOAc-hexane) to give
20.5 g (58%) of 2 as an oil.
EXAMPLE 1
[0282] 3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine (3),
cis-3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepin-(5H)4-one (4a)
and
trans-3-Butyl-3-ethyl-5-phenyl-2,3-dihydro-benzothiepin-(5H)4-one
(4b) 317
[0283] A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047
mole) of TiCl.sub.3 and 80 mL of anhydrous ethylene glycol dimethyl
ether (DME) was held at reflux for 2 h. The reaction mixture was
cooled to 5.degree. C. To the reaction mixture was added dropwise a
solution of 3.54 is g (0.01 mole) of 2 in 30 mL of DME in 40 min.
The reaction mixture was stirred at room temperature for 16 h and
then was held at reflux for 2 h and cooled before being poured into
brine. The organic was extract into methylene chloride. The
methylene chloride extract was dried over MgSO.sub.4 and
concentrated in vacuo. The residue was purified by HPLC (hexane) to
give 1.7 g (43%) of 3 as an oil in the first fraction. The second
fraction was discarded and the third fraction was further purified
by HPLC (hexane) to give 0.07 g (2%) of 4a in the earlier fraction
and 0.1 g (3%) of 4b in the later fraction.
Example 2
[0284]
cis-3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepin-(5H)4-one-1,1--
dioxide (5a) and
trans-3-Butyl-3-ethyl-5-phenyl-2,3-dihydro-benzothiepin-(-
5H)4-one-1,1-dioxide (5b) 318
[0285] To a solution of 1.2 g (3.5 mmole) of 50-60% MCPBA in 20 mL
of methylene chloride was added 0.59 g (1.75 mmole) of a mixture of
4a and 4b in 10 mL of methylene chloride. The reaction mixture was
stirred for 20 h. An additional 1.2 g (1.75 mmole) of 50-60% MAPBA
was added and the reaction mixture was stirred for an additional 3
h then was triturated with 50 mL of 10% NaOH. The insoluble solid
was filtered. The methylene chloride layer of the filtrate was
washed with brine, dried over MgSO.sub.4, and concentrated in
vacuo. The residual syrup was purified by HPLC (5% EtOAc-hexane) to
give 0.2 g (30%)of 5a as an oil in the first fraction and 0.17 g
(26%) of 5b as an oil in the second fraction.
Example 3
[0286] (3.alpha.,4.alpha.,5.beta.)
3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,-
4,5-tetrahydrobenzothiepine-1,1-dioxide (6a), (3.alpha.,
4.beta.,5.alpha.)
3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-di-
oxide (6b), (3.alpha.,4.alpha.,5.alpha.)
3-Butyl-3-ethyl-4-hydroxy-5-pheny-
l-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6c), and
(3.beta.,4.beta.,5.beta.)
3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetr-
ahydrobenzothiepine-1,1-dioxide (6d) 319
[0287] A. Reduction of 5a and 5b with Sodium Borohydride
[0288] To a solution of 0.22 g (0.59 mmole) of 5b in 10 mL of
ethanol was added 0.24 g (6.4 mmole) of sodium borohydride. The
reaction mixture was stirred at room temperature for 18 h and
concentrated in vacuo to remove ethanol. The residue was triturated
with water and extracted with methylene chloride. The methylene
chloride extract was dried over MgSO.sub.4 and concentrated in
vacuo to give 0.2 g of syrup. In a separate experiment, 0.45 g of
5a was treated with 0.44 g of sodium borohydride in 10 mL of
ethanol and was worked up as described above to give 0.5 g of syrup
which was identical to the 0.2 g of syrup obtained above. These two
materials were combined and purified by HPLC using 10% EtOAc-hexane
as eluant. The first fraction was 0.18 g (27%) of 6a as a syrup.
The second fraction was 0.2 g (30%) of 6b also as a syrup. The
column was then eluted with 20% EtOAc-hexane to give 0.077 g (11%)
of 6c in the third fraction as a solid. Recrystallization from
hexane gave a solid, mp 179-181.degree. C. Finally, the column was
eluted with 30% EtOAc-hexane to give 0.08 g (12%) of 6d in the
fourth fraction as a solid. Recrystallization from hexane gave a
solid, mp 160-161.degree. C.
[0289] B. Conversion of 6a to 6c and 6d with NaOH and PTC
[0290] To a solution of 0.29 g (0.78 mmole) of 6a in 10 mL
CH.sub.2Cl.sub.2 , was added 9 g of 40% NaOH. The reaction mixture
was stirred for 0.5 h at room temperature and was added one drop of
Aliquat-336 (methyltricaprylylammonium chloride) phase transfer
catalyst (PTC). The mixture was stirred for 0.5 h at room
temperature before being treated with 25 mL of ice-crystals then
was extracted with CH.sub.2Cl.sub.2 (3.times.10 ml), dried over
MgSO4 and concentrated in vacuo to recover 0.17 g of a colorless
film. The components of this mixture were separated using an HPLC
and eluted with EtOAc-hexane to give 12.8 mg (4%) of
2-(2-benzylphenylsulfonylmethyl)-2-ethylhexenal in the first
fraction, 30.9 mg (11%) of 6c in the second fraction and 90.0 mg
(31%) of 6d in the third fraction.
[0291] Oxidation of 6a to 5b
[0292] To a solution of 0.20 g (0.52 mmole) of 6a in 5 mL of
CH.sub.2C1.sub.2 was added 0.23 g (1.0 mmole) of pyridinium
chlorochromate. The reaction mixture was stirred for 2 h then was
treated with additional 0.23 g of pyridinium chlorochromate and
stirred overnight. The dark reaction mixture was poured into a
ceramic filterfrit containing silica gel and was eluted with
CH.sub.2Cl.sub.2. The filtrate was concentrated in vacuo to recover
167 mg (87%) of 5b as a colorless oil.
EXAMPLE 4
[0293]
3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine-1,1-dioxide (7)
320
[0294] To a solution of 5.13 g (15.9 rnmole) of 3 in 50 mL of
CH.sub.2Cl.sub.2 was added 10 g (31.9 mmole) of 50-60% MCPBA
(m-chloroperoxybenzoic acid) portionwise causing a mild reflux and
formation of a white solid. The reaction mixture was allowed to
stir overnight under N.sub.2 and was triturated with 25 mL of water
followed by 50 mL of 10% NaOH solution. The organic was extracted
into CH.sub.2Cl.sub.2 (4.times.20 mL) . The CH.sub.2Cl.sub.2
extract was dried over MgSO.sub.4 and evaporated to dryness to
recover 4.9 g (87%) of an opaque viscous oil.
EXAMPLE 5
[0295] (1a.alpha.,2.beta.,8b.dbd.)
2-Butyl-2-ethyl-8b-phenyl-1.alpha.,2,3,-
8b-tetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide (8a)
(1a.alpha.,2.alpha.,8b.alpha.)
2-Butyl-2-ethyl-8b-phenyl-1a,2,3,8b-tetrah-
ydro-benzothiepino[4,5-b]oxirene-4,4-dioxide (8b) 321
[0296] To 1.3 g (4.03 mole) of 3 in 25 mL of CHCl.sub.3 was added
portionwise 5 g (14.1 mmole) of 50-60% MCPBA causing a mild
exotherm. The reaction mixture was stirred under N.sub.2 overnight
and was then held at reflux for 3 h. The insoluble white slurry was
filtered. The filtrate was extracted with 10% potassium carbonate
(3.times.50 mL), once with brine, dried over MgSO.sub.4, and
concentrated in vacuo to give 1.37 g of a light yellow oil.
Purification by HPLC gave 0.65 g of crystalline product. This
product is a mixture of two isomers. Trituration of this
crystalline product in hexane recovered 141.7 mg (10%) of a white
crystalline product. This isomer was characterized by NMR and mass
spectra to be the (1a.alpha.,2.beta.,8b.alpha.) isomer 8a. The
hexane filtrate was concentrated in vacuo to give 206 mg of white
film which is a mixture of 30% 8a and 70% 8b by .sup.1H NMR.
EXAMPLE 6
[0297]
cis-3-Butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-d-
ioxide (9a),
trans-3-Butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydrobenzothiepin-
e-1,1-dioxide (9b), and
3-Butyl-3-ethyl-4-hydroxy-5-cyclohexylidine-2,3,4,-
5-tetrahydrobenzothiepine-1,1-dioxide (10) 322
[0298] A mixture of 0.15 g (0.4 mmole) of a 3:7 mixture of 8a and
Bb was dissolved in 15 ml MeOH in a 3 oz. Fisher/Porter vessel,
then was added 0.1 g of 10% Pd/C catalyst. This mixture was
hydrogenated at 70 psi H.sub.2 for 5 h and filtered. The filtrate
was evaporated to dryness in vacuo to recover 0.117 g of a
colorless oil. This material was purified by HPLC eluting with
EtOAc-hexane. The first fraction was 4.2 mg (3%) of 9b. The second
fraction, 5.0 mg (4%), was a 50/50 mixture of 9a and 9b. The third
fraction was 8.8 mg (6%) of 6a . The fourth fraction was 25.5 mg
(18%) of 6b. The fifth fraction was 9.6 mg (7%) of a mixture of 6b
and a product believed to be
3-butyl-3-ethyl-4,5-dihydroxy-5-phenyl-2,3,4,5-t-
etrahydrobenzothiepine-1,1-dioxide based on mass spectrum. The
sixth fraction was 7.5 mg (5%) of a mixture of 6d and one of the
isomers of 10, 10a.
EXAMPLE 7
[0299] In another experiment, a product (3.7 g) from epoxidation of
3 with excess MCPBA in refluxing CHCl.sub.3 under air was
hydrogenated in 100 mL of methanol using 1 g of 10% Pd/C catalyst
and 70 psi hydrogen. The product was purified by HPLC to give 0.9 g
(25%) of 9b, 0.45 g (13%) of 9a, 0.27 g (7%) of 6a, 0.51 g (14%) of
6b, 0.02 g (1%) of 6c, 0.06 g (2%) of one isomer of 10, 10a and
0.03 g (1%) of another isomer of 10, 10b.
EXAMPLE 8
[0300] 2-((2-Benzoylphenylthio)methyl)butyraldehyde (11) 323
[0301] To an ice bath cooled solution of 9.76 g (0.116 mole of
2-ethylacrolein in 40 mL of dry THF was added 24.6 g (0.116 mole)
of 2-mercaptobenzophenone in 40 mL of THF followed by 13 g (0.128
mole) of triethylamine. The reaction mixture was stirred at room
temperature for 3 days , diluted with ether, and was washed
successively with dilute HCl, brine, and 1 M potassium carbonate.
The ether layer was dried over MgSO.sub.4 and concentrated in
vacuo. The residue was purified by HPLC (10% EtOAc-hexane) to give
22 g (64%) of 11 in the second fraction. An attempt to further
purifiy this material by kugelrohr distillation at 0.5 torr
(160-190.degree. C.) gave a fraction (12.2 g) which contained
starting material indicating a reversed reaction during
distillation. This material was dissolved in ether (100 mL) and was
washed with 50 mL of 1 M potassium carbonate three times to give
6.0 g of a syrup which was purified by HPLC (10% EtOAc-hexane) to
give 5.6 g of pure 11.
EXAMPLE 9
[0302] 3-Ethyl-5-phenyl-2,3-dihydrobenzothiepine (12) 324
[0303] To a mixture of 2.61 g (0.04 mole) of zinc dust and 60 mL of
DME was added 7.5 g (0.048 mole) of TiCl.sub.3. The reaction
mixture was held at reflux for 2 h. A solution of 2.98 g (0.01
mole) of 11 was added dropwise in 1 h. The reaction mixture was
held at reflux for 18 h, cooled and poured into water. The organic
was extracted into ether. The ether layer was washed with brine and
filtered through Celite. The filtrate was dried over MgSO.sub.4 and
concentrated. The residual oil (2.5 g) was purified by HPLC to give
2.06 g (77%) of 12 as an oil in the second fraction.
EXAMPLE 10
[0304] (1a.alpha.,2.alpha.,8b.alpha.)
2-Ethyl-8b-phenyl-1a,2,3,8b-tetrahyd-
ro-benzothiepino-[4,5-b]oxirene-4,4-dioxide (13) 325
[0305] To a solution of 1.5 g (5.64 mmole) of 12 in 25 ml of
CHCl.sub.3 was added 6.8 g (19.4 mmole) of 50-60% MCPB portionwise
causing an exothem and formation of a white solid. The mixture was
stirred at room temperature overnight diluted with 100 ml methylene
chloride and washed successively with 10% K.sub.2CO.sub.3 (4x50
ml), water (twice with 25 ml) and brine. The organic layer was then
dried over MgSO.sub.4 and evaporated to dryness to recover 1.47 g
of an off white solid. .sup.1H NMR indicated that only one isomer
is present. This solid was slurried in 200 ml of warm Et.sub.2O and
filtered to give 0.82 g (46%) of 13 as a white solid, mp
185-186.5.degree. C.
EXAMPLE 11
[0306] (3.alpha.,4.beta.,5.alpha.)-
3-Ethyl-4-hydroxy-5-phenyl-2,3,4,5-tet-
rahydro-benzothiepine-1,1-dioxide (14a), (3.alpha.,4.beta.,5.beta.)
3-Ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide
(14b), and
cis-3-Ethyl-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-diox- ide
(15) 326
[0307] A mixture of 0.5 g (1.6 mole) of 13, 50 ml of acetic acid
and 0.5 g of 10% Pd/C catalyst was hydrogenated with 70 psi
hydrogen for 4 h. The crude reaction slurry was filtered and the
filtrate was stirred with 150 ml of a saturated NaHCO.sub.3
solution followed by 89 g of NaHCO.sub.3 powder portionwise to
neutralize the rest of acetic acid. The mixture was extracted with
methylene chloride (4.times.25 ml), then the organic layer was
dried over MgSO.sub.4 and concentrated in vacuo to give 0.44 g
(87%) of a voluminous white solid which was purified by HPLC
(EtOAc-Hexane) to give 26.8 mg (6%) of 15 in the first fraction,
272 mg (54%) of 14a as a solid, mp 142-143.5.degree. C., in the
second fraction, and 35 mg (7%) of impure 14b in the third
fraction.
EXAMPLE 12
[0308] 2-Ethyl-2-((2-Hydroxymethylphenyl)thiomethyl)hexenal (16)
327
[0309] A mixture of 5.0 g (0.036 mole) of 2-mercaptobenzyl alcohol,
6.4 g (0.032 mole) of 1, 3.6 g (0.036 mole) of triethylamine and 25
mL of 2-methoxyethyl ether was held at reflux for 7 h. Additional
1.1 g of mercaptobenzyl alcohol and 0.72 g of triethylamine was
added to the reaction mixture and the mixture was held at reflux
for additional 16 h. The reaction mixture was cooled and poured
into 6N HCl and extracted with methylene chloride. The methylene
chloride extract was washed twice with 10% NaOH, dried over
MgSO.sub.4 and concentrated in vacuo to give 9.6 g of residue.
Purification by HPLC (20% EtOAc-hexane) gave 3.7 g (41%)of 16 as an
oil.
EXAMPLE 13
[0310] 2-Ethyl-2-((2-formylphenyl)thiomethyl)hexenal (17) 328
[0311] A mixture of 3.7 g of 16, 5.6 g (0.026 mole) of pyridinium
chlorochromate, 2 g of Celite and 30 mL of methylene chloride was
stirred for 18 h and filtered through a bed of silica gel. The
silica gel was eluted with methylene chloride. The combined
methylene chloride eluant was purified by HPLC (20% ETOAc-hexane)
to give 2.4 g (66%) of an oil.
EXAMPLE 14
[0312] 3-Butyl-3-ethyl-2,3-dihydrobenzothiepine (18) 329
[0313] A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047
mole) of TiCl.sub.3, and 50 mL of DME was held at reflux for 2 h
and cooled to room temperature. To this mixture was added 2.4 g
(8.6 mmole) of 17 in 20 mL of DME in 10 min. The reaction mixture
was stirred at room temperature for 2 h and held at reflux for 1 h
then was let standing at room temperature over weekend. The
reaction mixture was poured into dilute HCl and was stirred with
methylene chloride. The methylene chloride-water mixture was
filtered through Celite. The methylene chloride layer was washed
with brine, dried over MgSO.sub.4, and concentrated in vacuo to
give 3.0 g of a residue. Purification by HPLC gave 0.41 g (20%) of
18 as an oil in the early fraction.
EXAMPLE 15
[0314] (1a.alpha.,2.alpha.,8b.alpha. )
2-Butyl-2-ethyl-1a,2,3,8b-tetrahydr-
o-benzothiepino[4,5-b]oxirene-4,4-dioxide (19a) and
(1a.alpha.,2.beta.,8b.alpha.)
2-Butyl-2-ethyl-8b-phenyl-1a,2,3,8b-tetrahy-
dro-benzothiepino[4,5-b]oxirene-4,4-dioxide (19b) 330
[0315] To a solution of 0.4 g of 0.4 g (1.6 mmole) of 18 in 30 mL
of methylene chloride was added 2.2 g (3.2 mmole) of 50-60% MCPBA.
The reaction mixture was stirred for 2 h and concentrated in vacuo.
The residue was dissolved in 30 mL of CHCl.sub.3 and was held at
reflux for 18 h under N.sub.2. The reaction mixture was stirred
with 100 mL of 10% NaOH and 5 g of sodium sulfite. The methylene
chloride layer was washed with brine, dried over MgSO.sub.4 and
concentrated in vacuo. The residue was purified by HPLC (20%
EtOAc-hexane) to give a third fraction which was further purified
by HPLC (10% EtOAc-hexane) to give 0.12 g of syrup in the first
fraction. Recrystallization from hexane gave 0.08 g (17%) of 19a,
mp 89.5-105.5.degree. C. The mother liquor from the first fraction
was combined with the second fraction and was further purified by
HPLC to give additional 19a in the first fraction and 60 mg of 19b
in the second fraction. Crystallization from hexane gave 56 mg of a
white solid.
EXAMPLE 16
[0316] 3-Butyl-3-ethyl-4,
5-dihydroxy-5-phenyl-2,3,4,5-tetrahydro-benzothi- epine-1,1-dioxide
(20) 331
[0317] This product was isolated along with 6b from hydrogenation
of a mixture of 8a and 8b.
EXAMPLE 17
[0318]
3-Butyl-3-ethyl-4-hydroxy-5-phenylthio-2,3,4,5-tetrahydro-benzothie-
pine-1,1-dioxide (21) 332
[0319] A mixture of 25 mg (0.085 mmole) of 19b, 0.27 g (2.7 mmole)
of thiophenol, 0.37 g (2.7 mmole) of potassium carbonate, and 4 mL
of DMF was stirred at room temperature under N.sub.2 for 19 h. The
reaction mixture was poured into water and extracted with methylene
chloride. The methylene chloride layer was washed successively with
10% NaOH and brine, dried over MgSO.sub.4, and concentrated in
vacuo to give 0.19 g of semisolid which contain substantial amounts
of diphenyl disulfide. This material was purified by HPLC (5%
EtOAc-hexane) to remove diphenyl disulfide in the first fraction.
The column was then eluted with 20% EtOAc-hexane to give 17 mg of a
first fraction, 4 mg of a second fraction and 11 mg of a third
fraction which were three different isomers of 21, i.e. 21a, 21b,
and 21c, respectively, by .sup.1H NMR and mass spectra.
EXAMPLE 18
[0320] Alternative Synthesis of 6c and 6d
[0321] A. Preparation from
2-((2-Benzoylphenylthio)methyl)-2-ethylhexanal (2)
[0322] Step 1. 2-((2-Benzoylphenylsulfonyl)methyl)-2-ethylhexanal
(44) 333
[0323] To a solution of 9.0 g (0.025 mole) of compound 2 in 100 ml
of methylene chloride was added 14.6 g (0.025 mol) of 50-60% MCPBA
portionwise. The reaction mixture was stirred at room temperature
for 64 h then was stirred with 200 ml of 1 M potassium carbonate
and filtered through Celite. The methylene chloride layer was
washed twice with 300 ml of 1 M potassium carbonate, once with 10%
sodium hydroxide and once with brine. The insoluble solid formed
during washing was removed by filtration through Celite. The
methylene chloride solution was dried and concentrated in vacuo to
give 9.2 g (95%)of semisolid. A portion (2.6 g) of this solid was
purified by HPLC(10% ethyl acetate-hexane) to give 1.9 g of
crystals, mp 135-136.degree. C.
[0324] Step 2. 2-((2-Benzylphenylsulfonyl)methyl)-2-ethylhexanal
(45) 334
[0325] A solution of 50 g (0.13 mole) of crude 44 in 250 ml of
methylene chloride was divided in two portions and charged to two
Fisher-Porter bottles. To each bottle was charged 125 ml of
methanol and 5 g of 10% Pd/C. The bottles were pressurized with 70
psi of hydrogen and the reaction mixture was stirred at room
temperature for 7 h before being charged with an additional 5 g of
10% Pd/C. The reaction mixture was again hydrogenated with 70 psi
of hydrogen for 7 h. This procedure was repeated one more time but
only 1 g of Pd/C was charged to the reaction mixture. The combined
reaction mixture was filtered and concentrated in vacuo to give
46.8 g of 45 as brown oil.
[0326] Step 3. (3.alpha.,4.alpha.,5.alpha.)
3-Butyl-3-ethyl-4-hydroxy-5-ph-
enyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6c), and
(3a,4p,5S)
3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-di-
oxide (6d)
[0327] To a solution of 27.3 g (73.4 mmole) of 45 in 300 ml of
anhydrous THF cooled to 2.degree. C. with an ice bath was added 9.7
g (73.4 mmole) of 95% potassium t-butoxide. The reaction mixture
was stirred for 20 min, quenched with 300 ml of 10% HCl and
extracted with methylene chloride. The methylene chloride layer was
dried over magnesium sulfate and concentrated in vacuo to give 24.7
g of yellow oil. Purification by HPLC (ethyl acetate-hexane)
yielded 9.4 g of recovered 45 in the first fraction, 5.5 g (20%) of
6c in the second fraction and 6.5 g (24%) of 6d in the third
fraction.
[0328] B. Preparation from 2-hydroxydiphenylmethane
[0329] Step 1. 2-mercaptodiphenylmethane (46) 335
[0330] To a 500 ml flask was charged 16 g (0.33 mol) of 60% sodium
hydride oil dispersion. The sodium hydride was washed twice with 50
ml of hexane. To the reaction flask was charged 100 ml of DMF. To
this mixture was added a solution of 55.2 g (0.3 mol) of
2-hydroxydiphenylmethane in 200 ml of DMF in 1 h while temperature
was maintained below 30.degree. C. by an ice-water bath. After
complete addition of the reagent, the mixture was stirred at room
temperature for 30 min then cooled with an ice bath. To the
reaction mixture was added 49.4 g (0.4 mole) of dimethyl
thiocarbamoyl chloride at once. The ice bath was removed and the
reaction mixture was stirred at room temperature for 18 h before
being poured into 300 ml of water. The organic was extracted into
500 ml of toluene. The toluene layer was washed successively with
10% sodium hydroxide and brine and was concentrated in vacuo to
give 78.6 g of a yellow oil which was 95% pure dimethyl O
-2-benzylphenyl thiocarbamate. This oil was heated at
280-300.degree. C. in a kugelrohhr pot under house vacuum for 30
min. The residue was kugelrohr distilled at 1 torr (180-280.degree.
C.). The distillate (56.3 g) was crystallized from methanol to give
37.3 g (46%) of the rearranged product dimethyl S-2-benzylphenyl
thiocarbamate as a yellow solid. A mixture of 57 g (0.21 mole) of
this yellow solid, 30 g of potassium hydroxide and 150 ml of
methanol was stirred overnight then was concentrated in vacuo. The
residue was diluted with 200 ml of water and extracted with ether.
The aqueous layer was made acidic with concentrate HCl, The oily
suspension was extracted into ether. The ether extract was dried
over magnesium sulfate and concentrated in vacuo. The residue was
crystallized from hexane to give 37.1 g (88%) of
2-mercaptodiphenylmethan- e as a yellow solid.
[0331] Step 2. 2-((2-Benzylphenylthio)methyl)-2-ethylhexanal (47)
336
[0332] A mixture of 60 g (03 mole) of yellow solid from step 1, 70
g (0.3 mole) of compound 1 from preparation 1, 32.4 g (0.32 mole)
of triethylamine, 120 ml of 2-methoxyethyl ether was held at reflux
for 6 hr and concentrated in vacuo. The residue was triturated with
500 ml of water and 30 ml of concentrate HCl. The organic was
extracted into 400 ml of ether. The ether layer was washed
successively with brine, 10% sodium hydroxide and brine and was
dried over magnesium sulfate and concentrated in vacuo. The residue
(98.3 g) was purified by HPLC with 2-5% ethyl acetate-hexane as
eluent to give 2-((2-benzylphenylthio)methyl)-2-ethylhe- xanal 47
as a yellow syrup.
[0333] Step 3. 2-((2-Benzylphenylsulfonyl)rmethyl)-2-ethylhexanal
(45) 337
[0334] To a solution of 72.8 g (0.21 mole) of yellow syrup from
step 2 in 1 liter of methylene chloride cooled to 10.degree. C. was
added 132 g of 50-60% MCPBA in 40 min. The reaction mixture was
stirred for 2 h. An additional 13 g of 50-60% MCPBA was added to
the reaction mixture. The reaction mixture was stirred for 2 h and
filtered through Celite. The methylene chloride solution was washed
twice with 1 liter of 1 M potassium carbonate then with 1 liter of
brine. The methylene chloride layer was dried over magnesium
sulfate and concentrated to 76 g of
2-((2-benzylphenylsulfonyl)methyl)-2-ethylhexanal 45 as a
syrup.
[0335] Step 4. (3.alpha., 4.alpha., 5.alpha.)
3-Butyl-3-ethyl-4-hydroxy-5--
phenyl-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide (6c), and
(3a,40,5p)
3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-di-
oxide (6d) Reaction of 45 with potassium t-butoxide according to
the procedure in step 3 of procedure A gave pure 6c and 6d after
HPLC.
EXAMPLE 19
[0336] (3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-ph-
enyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (25) and (3a, 4a,
5a)
3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiep-
ine-1,1-dioxide (26)
[0337] Step 1. Preparation of 2-((2-benzoyl-4-methoxy
phenylthio)methyl)-2-ethylhexanal (22) 338
[0338] 2-Hydroxy-4-methoxybenzophenone was converted to the
dimethyl O-2-benzoyphenyl thiocarbamate by methods previously
described in example 18. The product can be isolated by
recrystallization from ethanol. Using this improved isolation
procedure no chromatography was needed. The thermal rearrangement
was performed by reacting the thiocarbamate( 5 g) in diphenyl ether
at 260.degree. C. as previously described. The improved isolation
procedure which avoided a chromatography step was described
below.
[0339] The crude pyrolysis product was then heated at 65.degree. C.
in 100 ml of methanol and 100 ml of THF in the presence of 3.5 g of
KOH for 4 h. After removing THF and methanol by rotary evaporation
the solution was extracted with 5% NaOH and ether. The base layer
was acidified and extracted with ether to obtain a 2.9 g of crude
thiophenol product. The product was further purified by titrating
the desired mercaptan into base with limited KOH. After
acidification and extraction with ether pure
[0340] 2-mercapto-4-methoxybenzophenone (2.3 g) was isolated.
2-mercapto-4-methoxybenzophenone can readily be converted to the
2-((2-benzoyl-4-methoxyphenylthio)methyl)-2-ethylhexanal (22) by
reaction with 2-ethyl-2-(mesyloxymethyl)hexanal (1) as previously
described.
[0341] Step 2.
2-((2-Benzoyl-5-methoxyphenylsulfonyl)methyl)-2-ethylhexana- l (23)
339
[0342] Substrate 22 was readily oxidized to
2-((2-benzoyl-5-methoxyphenyl-- sulfonyl)methyl) -2-ethyihexanal
(23) as described in example 18.
[0343] Step 3. 2- ((2-benzyl-5-methoxyphenylsulfonyl) methyl)
-2-ethyihexanal (24) 340
[0344] Sulfone 23 was then reduced to
2-((2-benzyl-5-methoxyphenyl-sulfony- l)methyl)-2-ethylhexanal (24)
as described in example 18.
[0345] Step 4. (3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-4-hydroxy-8-meth-
oxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (25) and
(3.alpha.,4.alpha.,5.alpha.)
3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-
-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (26) 341
[0346] A 3-neck flask equipped with a powder addition
funnel,thermocouple and nitrogen bubbler was charged with 19.8 g
(0.05 mole) of sulfone 24 in 100 ml dry THF. The reaction was
cooled to -1.6.degree. C. internal temperature by means of ice/salt
bath. Slowly add 5.61 g (0.05 mole) of potassium t-butoxide by
means of the powder addition funnel. The resulting light yellow
solution was maintained at -1.6.degree. C. After 30 min reaction
400 ml of cold ether was added and this solution was extracted with
cold 10% HCl. The acid layer was extracted with 300 ml of methylene
chloride. The organic layers were combined and dried over magnesium
sulfate and after filtration stripped to dryness to obtain 19.9 g
of product. .sup.1H nmr and glpc indicated a 96% conversion to a
50/50 mixture of 25 and 26. The only other observable compound was
4% starting sulfone 24.
[0347] The product was then dissolved in 250 ml of 90/10
hexane/ethyl acetate by warming to 50.degree. C. The solution was
allowed to cool to room temperature and in this way pure 26 can be
isolated. The crystallization can be enhanced by addition of a seed
crystal of 26. After 2 crystallizations the mother liquor which was
now 85.4% 25 and has a dry weight of 8.7 g. This material was
dissolved in 100 ml of 90/10 hexane/ethyl acetate and 10 ml of pure
ethyl acetate at 40 C. Pure 25 can be isolated by seeding this
solution with a seed crystal of 25 after storing it overnight at 0
c.
EXAMPLE 25
[0348] (3.alpha.,4.alpha.,5.alpha.)
3-Butyl-3-ethyl-4,8-dihydroxy-5-phenyl-
-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide (27) 342
[0349] In a 25 ml round bottomed flask, 1 g of 26( 2.5 mmoles) and
10 ml methylene chloride were cooled to -78.degree. C. with
stirring. Next 0.7 ml of boron tribromide(7.5 mmole) was added via
syringe. The reaction was allowed to slowly warm to room
temperature and stirred for 6 h. The reaction was then diluted with
50 ml methylene chloride and washed with saturated NaCl and then
water.The organic layer was dried over magnesium sulfate. The
product (0.88 g) 27 was characterized by NMR and mass spectra.
EXAMPLE 21
[0350] General Alkylation of phenol 27
[0351] A 25 ml flask was charged with 0.15 g of 27(0.38 mmole), 5
ml anhydrous DMF, 54 mg of potassium carbonate(0.38 mmole) and 140
mg ethyl iodide (0.9 mmole). The reaction was stirred at room
temperature overnight.The reaction was diluted with 50 ml ethyl
ether and washed with water (25 ml) then 5% NaOH (20 ml) and then
sat. NaCl. After stripping off the solvent the ethoxylated product
28 was obtained in high yield. The product was characterized by NMR
and mass spectra. This same procedure was used to prepare products
listed in table 1 from the corresponding iodides or bromides. For
higher boiling alkyl iodides and bromides only one equivalent of
the alkyl halide was used.
5TABLE 1 343 Formula for Table 1 Compound No. R 27 H 26 Me 28 Et 29
hexyl 30 Ac 31 (CH2) 6-N-pthalimide
EXAMPLE 22
[0352] (3.alpha.,4.alpha.,5.alpha.)
3-Butyl-3-ethyl-4-hydroxy-7-hydroxyami-
no-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (37) and
(3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phe-
nyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (38)
[0353] Step 1. Preparation of 2-chloro-5-nitrodiphenylmethane (32)
344
[0354] Procedure adapted from reference :Synthesis -Stuttgart 9
770-772 (1986) Olah G. Et al
[0355] Under nitrogen, a 3 neck flask was charged with 45 g (0.172
mole ) of 2-chloro-5-nitrobenzophenone in 345 ml methylene chloride
and the solution was cooled to ice/water temperature. By means of
an additional funnel, 150 g( 0.172 mole) of trifluoromethane
sulfonic acid in 345 ml methylene chloride was added slowly. Next
30 g of triethylsilane (0.172 mole) in 345 ml methylene chloride
was added dropwise to the chilled solution. Both addition steps(
trifluoromethane sulfonic acid and triethylsilane)were repeated.
After the additions were completed the reaction was allowed to
slowly warm up to room temperature and stirred for 12 h under
nitrogen. The reaction mixture was then poured into a chilled
stirred solution of 1600 ml of saturated sodium bicarbonate. Gas
evolution occurred. Poured into a 4 liter separatory funnel and
separated layers. The methylene chloride layer was isolated and
combined with two 500 ml methylene chloride extractions of the
aqueous layer. The methylene chloride solution was dried over
magnesium sulfate and concentrated in vacuo. The residue was
recrystallized from hexane to give 39 g product. Structure 32 was
confirmed by mass spectra and proton and carbon NMR.
[0356] Step 2. Preparation of
2-((2-benzyl-4-nitrophenylthio)methyl)-2-eth- ylhexanal (33)
345
[0357] The 2-chloro-5-nitrodiphenylmethane product 32 (40 g, 0.156
mole) from above was placed in a 2 liter 2 neck flask with water
condenser. Next 150 ml DMSO and 7.18 g (0.156 mole) of lithium
sulfide was added and the solution was stirred at 75.degree. C. for
12 h. The reaction was cooled to room temperature and then 51.7 g
of mesylate IV was added in 90 ml DMSO. The reaction mixture was
heated to 80.degree. C. under nitrogen. After 12 h monitored by TLC
and added more mysylate if necessary.
[0358] Continued the reaction until the reaction was completed.
Next the reaction mixture was slowly poured into a 1900 ml of 5%
acetic aqueous solution with stirring, extracted with 4.times.700
ml of ether, and dried over MgSO.sub.4. After removal of ether,
82.7 g of product was isolated. The material can be further
purified by silica gel chromatography using 95% hexane and 5% ethyl
acetate. If pure mysylate was used in this step there was no need
for further purification. The product 33 was characterized by mass
spectra and NMR.
[0359] Step 3. Oxidation of the nitro product 33 to the sulfone
2-((2-benzyl-4-nitrophenylsulfonyl)methyl)-2-ethylhexanal (34)
346
[0360] The procedure used to oxidize the sulfide 33 to the sulfone
34 has been previously described.
[0361] Step 4. Reduction of 34 to
2-((2-benzyl-4-hydroxyaminophenylsulfony- l)methyl)-2-ethylhexanal
(35) 347
[0362] A 15 g sample of 34 was dissolved in 230 ml of ethanol and
placed in a 500 ml rb flask under nitrogen. Next 1.5 g of 10 wt. %
Pd/C was added and hydrogen gas was bubbled through the solution at
room temperature until the nitro substrate 34 was consumed. The
reaction could be readily monitored by silica gel TLC using 80/20
hexane/EtOAc. Product 35 was isolated by filtering off the Pd/C and
then stripping off the EtOH solvent. The product was characterized
by NMR and mass spectra.
[0363] Step 5. Preparation of the
2-((2-benzyl-4-N,O-di-(t-butoxy-carbonyl-
)hydroxyaminophenylsulfonyl)methyl)-2-ethylhexanal (36). 348
[0364] A 13.35 g sample of 35 (0.0344 mole) in 40 ml of dry THF was
stirred in a 250 ml round bottomed flask. Next added 7.52 g (0.0344
mole) of di-t-butyl dicarbonate in 7 ml THF. Heated at 60.degree.
C. overnight. Striped off THF and redissolved in methylene
chloride. Extracted with 1% HCl; and then 5% sodium
bicarbonate.
[0365] The product was further purified by column chromatography
using 90/10 hexane/ethyl acetate and then 70/30 hexane/ethyl
acetate. The product 36 was obtained (4.12 g) which appeared to be
mainly the di-(t-butoxycarbonyl) derivatives by proton NMR.
[0366] Step 6. (3.alpha.,4.alpha.,5.alpha.)
3-Butyl-3-ethyl-4-hydroxy-7-hy- droxyamino-5-phenyl-2,3,4,
5-tetrahydrobenzothiepine-1,1-dioxide (37) and
(3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phe-
nyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (38) 349
[0367] A 250 ml 3-neck round bottomed flask was charged with 4 g of
36 (6.8 mmoles), and 100 ml of anhydrous THF and cooled to
-78.degree. C. under a nitrogen atmosphere. Slowly add 2.29 g
potassium tert-butoxide(20.4 mmoles) with stirring and maintaining
a -78.degree. C. reaction temperature. After 1 h at -78.degree. C.
the addition of base was completed and the temperature was brought
to -10.degree. C. by means of a ice/salt bath. After 3 h at
-10.degree. C., only trace 36 remained by TLC. Next add 35 ml of
deionized water to the reaction mixture at -10.degree. C. and
stirred for 5 min. Striped off most of the THF and added to
separatory funnel and extracted with ether until all of the organic
was removed from the water phase. The combined ether phases were
washed with saturated NaCl and then dried over sodium sulfate. The
only products by TLC and NMR were the two BOC protected isomers of
37 and 38. The isomers were separated by silica gel chromatography
using 85% hexane and 15% ethyl acetate; BOC-37 (0.71 g) and BOC- 38
(0.78 g).
[0368] Next the BOC protecting group was removed by reacting 0.87 g
of BOC-38 (1.78 mmoles) with 8.7 ml of 4 M HCl (34.8 mmoles)in
dioxane for 30 min. Next added 4.74 g of sodium acetate (34.8
mmoles) to the reaction mixture and 16.5 ml ether and stirred until
clear. After transferring to a separatory funnel extracted with
ether and water and then dried the ether layer with sodium sulfate.
After removing the ether, 0.665 g of 38 was isolated. Isomer 37
could be obtained in a similar procedure.
EXAMPLE 23
[0369] (3.alpha.,4.alpha.,5.alpha.)
3-Butyl-3-ethyl-7-(n-hexylamino)-4-hyd-
roxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (40) and
(3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-p-
henyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (41)
[0370] Step 1.
2-((2-Benzyl-4-(n-hexylamino)phenylsulfonyl)methyl)-2-ethyl-
hexanal (39) 350
[0371] In a Fischer porter bottle weighed out 0.5 g of 34 (1.2
mmoles) and dissolved in 3.8 ml of ethanol under nitrogen. Next
added 0.1 g of Pd/C and 3.8 ml of hexanal. Seal and pressure to 50
psi of hydrogen gas. Stirred for 48 h. After filtering off the
catalyst and removing the solvent by rotary evaporation 39 was
isolated by column chromatography (0.16 g) using 90/10 hexane ethyl
acetate and gradually increasing the mobile phase to 70/30
hexane/ethyl acetate. The product was characterized by NMR and mass
spectra.
[0372] Step 2. (3.alpha.,4.alpha.,5.alpha.)
3-Butyl-3-ethyl-7-(n-hexylamin-
o)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide
(40) and (3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-p-
henyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (41) 351
[0373] A 2-neck, 25 ml round bottomed flask with stir bar was
charged with 0.158 g 39 (0.335 mmole) and 5 ml anhydrous THF under
nitrogen. Cool to -10.degree. C. by means of a salt/water bath.
Slowly add 0.113 g of potassium tert butoxide (0.335 mmole) . After
15 min at -10.degree. C. all of the starting material was consumed
by TLC and only the two isomers 40 and 41 were observed. Next added
5 ml of chilled 10% HCl and stirred at -10.degree. C. for 5 min.
Transferred to a separatory funnel and extract with ether. Dried
over sodium sulfate. Proton NMR of the dried product (0.143 g)
indicated only the presence of the two isomers 40 and 41. The two
isomers were separated by silica gel chromatography using 90/10
hexane ethyl acetate and gradually increasing the mobile phase to
70/30 hexane/ethyl acetate. 40 ( 53.2 mg); 41(58.9 mg).
EXAMPLE 24
[0374] Quaternization of amine substrates 40 and 41
[0375] Amine products such as 40 and 41 can be readily alkylated to
quaternary salts by reaction with alkyl halides. For example 40 in
DMF with 5 equivalents of methyl iodide in the presence of 2,6
dimethyl lutidine produces the dimethylhexylamino quaternary
salt.
EXAMPLE 25
[0376] (3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-4-hydroxy-5-(4-iodopheny-
l)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (42) 352
[0377] In a 25 ml round bottomed flask 0.5 g (1.3 mmole) of 6d ,
0.67 g of mercuric triflate were dissolved in 20 ml of dry
methylene chloride with stirring. Next 0.34 g of Iodine was added
and the solution was stirred at room temperature for 30 h. The
reaction was then diluted with 50 ml methylene chloride and washed
with 10 ml of 1 M sodium thiosulfate; 10 ml of saturated KI ; and
dried over sodium sulfate. See Tetrahedron, Vol.50, No. 17, pp
5139-5146 (1994) Bachki, F. Et al.Mass spectrum indicated a mixture
of 6d , mono iodide 42 and a diiodide adduct. The mixture was
separated by column chromatography and 42 was characterized bt NMR
and mass spectra.
EXAMPLE 26
[0378] (3.alpha.,4.beta.,5.beta.)
3-Butyl-5-(4-carbomethoxyphenyl)-3-ethyl-
-4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (43) 353
[0379] A 0.1 g sample of 42 ( 0.212 mmole), 2.5 ml dry methanol, 38
pl triethylamine (0.275 mmole) , 0.3 ml toluene and 37 mg of
palladium chloride (0.21 mmole) was charged to a glass lined mini
reactor at 300 psi carbon monoxide. The reaction was heated at
100.degree. C. overnight. The catalyst was filtered and a high
yield of product was isolated. The product was characterized by NMR
and mass spectra.
[0380] Note the ester functionalized product 43 can be converted to
the free acid by hydrolysis.
EXAMPLE 27
[0381] (3.alpha.,4.alpha.,5.alpha.)
3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5--
phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (48), and
(3a,4D,50) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,
3,4,5-tetrahydrobenzothie- pine-1,1-dioxide (49)
[0382] Step 1. 2-Mercapto-5-methoxybenzophenone (50) 354
[0383] Reaction of 66.2 g of 4-methoxythiophenol with 360 ml of 2.5
N n-butyllithium, 105 g of tetramethylethylenediamine and 66.7 g of
benzonitrile in 600 ml cyclohexane according to the procedure in WO
93/16055 gave 73.2 g of brown oil which was kugelrohr distilled to
remove 4-methoxythiophenol and gave 43.86 g of crude 50 in the pot
residue.
[0384] Step 2.
2-((2-Benzoyl-4-methoxyphenylthio)methyl)-2-ethylhexanal (51)
355
[0385] Reaction of 10 g (0.04 mole) of crude 50 with 4.8 g (0.02
mole)of mesylate 1 and 3.2 ml (0.23 mole) of triethylamine in 50 ml
of diglyme according to the procedure for the preparation of 2 gave
10.5 g of crude product which was purified by HPLC (5% ethyl
acetate-hexane) to give 1.7 g (22%) of 51.
[0386] Step 3.
2-((2-Benzoyl-4-methoxyphenylsulfonyl)methyl)-2-ethyl-hexan- al
(52) 356
[0387] A solution of 1.2 g (3.1 mmoles) of 51 in 25 ml of methylene
chloride was reacted with 2.0 g (6.2 mmoles) of 50-60% MCPBA
according to the procedure of step 2 of procedure A in example 18
gave 1.16 g (90%) of 52 as a yellow oil.
[0388] Step 4.
2-((2-Benzyl-4-methoxyphenylsulfonyl)methyl)-2-ethylhexanal (53)
357
[0389] Hydrogenation of 1.1 g of 52 according to the procedure of
step 3 of procedure A of example 18 gave 53 as a yellow oil (1.1
g).
[0390] Step 5. (3.alpha.,4.alpha.,5.alpha.)
3-Butyl-3-ethyl-4-hydroxy-7-me-
thoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (48),
and (3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2-
,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (49) 358
[0391] A solution of 1.1 g of 53, 0.36 g of potassium t-butoxide
and 25 ml of anhydrous THF was held at reflux for 2 h and worked up
as in step 4 of procedure A of example 18 to give 1.07 g of a crude
product which was purified by HPLC to give 40 mg (4%) of 48 as
crystals, mp 153-154.degree. C. and 90 mg (8%) of 49 as solid, mp
136-140.degree. C.
EXAMPLE 28
[0392] 5-Phenyl-2,3-dihydrospirobenzothiepine-3,1'-cyclohexane
(57)
[0393] Step 1. 1-(Hydroxymethyl)-cyclohexanecarboxaldehyde (54)
359
[0394] To a cold (0.degree. C.) mixture of 100 g (0.891 mole) of
cyclohexanecarboxaldehyde, 76.5 g of 37% of formaldehyde in 225 ml
of methanol was added dropwise 90 ml of 1 N Sodium hydroxide in 1
h. The reaction mixture was stirred at room temperature over 48
then was evaporated to remove methanol. The reaction mixture was
diluted with water and extracted with methylene chloride. The
organic layer was washed with water, brine, and dried over sodium
sulfate and concentrated under vacuum to give 75 g (59.7%) of thick
oil. Proton NMR and mass spectra were consistent with the
product.
[0395] Step 2. 1-(mesyloxymethyl)cyclohexanecarboxaldehyde (55)
360
[0396] To a cold (0.degree. C.) mixture of alcohol 54 (75 g, 0.54
mole) and 65.29 g (0.57 mole) of methanesulfonyl chloride in 80 ml
of methylene chloride was added a solution of pyridine (47.96 g,
0.57 mole) in 40 ml of methylene chloride. The reaction mixture was
stirred at room temperature for 18 h then quenched with water,
acidified with conc. HCl and extracted with methylene chloride. The
organic layer was washed with water, brine, and dried over sodium
sulfate and concentrated under vacuum to give 91.63 g (77.8%) of
thick oil. Proton NMR and mass spectra were consistent with the
product.
[0397] Step 3.
1-((2-Benzoylphenylthio)methyl)cyclohexanecarboxaldehyde (56)
361
[0398] A mixture of 69 g (0.303 mole) of 2-mercaptobenzophenone, 82
g (0.303 mole) of mesylate 55, 32 g of triethylamine, and 150 ml of
diglyme was stirred and held at reflux for 24 h. The mixture was
cooled, poured into dil. HCl and extracted with methylene chloride.
The organic layer was washed with 10% NaOH, water, brine, and dried
over sodium sulfate and concentrated under vacuum to remove excess
diglyme. This was purified by silica gel flush column (5%
EtOAc:Hexane) and gave 18.6 g (75.9%) of yellow oil. Proton NMR and
mass spectra were consistent with the product.
[0399] Step 4.
5-Phenyl-2,3-dihydrospirobenzothiepine-3,1'-cyclohexane (57)
362
[0400] To a mixture of 6.19 g of zinc dust and 100 ml of dry DME
was added TiCl,(16.8 g, 0.108 mole) . The reaction mixture was
heated to reflux for 2 h. A solution of compound 56 (8.3 g, 0.023
mole) in 50 ml of DME was added dropwise to the reaction mixture in
1 h and the mixture was held at reflux for 18 h. The mixture was
cooled, poured into water and extracted with ether. The organic
layer was washed with water, brine, and dried over sodium sulfate,
filtered through celite and concentrated under vacuum. The residue
was purified by HPLC (10% EtOAc: Hexane) to give 4.6 g (64%) of
white solid, mp 90-91.degree. C. Proton and carbon NMR and mass
spectra were consistent with the product.
EXAMPLE 29
[0401]
8b-Phenyl-1a,2,3,8b-tetrahydrospiro(benzothiepino[4,5-b]oxirene-2,1-
'-cyclohexane)-4,4-dioxide (58) 363
[0402] To a solution of 57 (4.6 g, 15 mmole) in 50 ml chloroform
under nitrogen was added 55% MCPBA (16.5 g, 52.6 mmole) portionwise
with spatula. The reaction was held at reflux for 18 h and washed
with 10% NaOH(3X), water, brine, and dried over sodium sulfate and
concentrated under vacuum to give 5 g of crude product. This was
recrystallized from Hexane/EtOAc to give 4.31 g (81%) of yellow
solid, mp 154-155.degree. C. Proton and carbon NMR and mass spectra
were consistent with the product.
EXAMPLE 30
[0403] trans-4-Hydroxy-5-phenyl-2,3,4,5-tetrahydro
spiro(benzothiepine-3,1- '-cyclohexane)-1,1-dioxide (59) 364
[0404] A mixture of 0.5 g (1.4 mmoles) of 58 , 20 ml of ethanol,10
ml of methylene chloride and 0.4 g of 10% Pd/C catalyst was
hydrogenated with 70 psi hydrogen for 3 h at room temperature. The
crude reaction slurry was filtered through Celite and evaporated to
dryness. The residue was purified by HPLC (10% EtOAc-Hexane, 25%
EtOAc-Hexane). The first fraction was 300 mg (60%) as a white
solid, mp 99-100.degree. C. Proton NMR showed this was a trans
isomer. The second fraction gave 200 mg of solid which was impure
cis isomer.
EXAMPLE 31
[0405] cis-4-Hydroxy-5-phenyl-2,3,4,5-tetrahydro
spiro(benzothiepine-3,1'-- cyclohexane)-1,1-dioxide (60) 365
[0406] To a solution of 0.2 g (0.56 mmole) of 59 in 20 ml of
CH.sub.2Cl.sub.21 was added 8 g of 50% NaOH and one drop of
Aliquat-336 (methyltricaprylylammonium chloride) phase transfer
catalyst. The reaction mixture was stirred for 10 h at room
temperature. Twenty g of ice was added to the mixture and the
mixture was extracted with CH.sub.2Cl.sub.2 (3.times.10 ml) washed
with water, brine and dried over MgSO.sub.4 and concentrated in
vacuo to recover 0.15 g of crude product. This was recrystallized
from Hexane/EtOAc to give 125 mg of white crystal, mp
209-210.degree. C. . Proton and carbon NMR and mass spectra were
consistent with the product.
EXAMPLE 32
[0407] (3.alpha.,4.alpha.,5.alpha.)
3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3- ,
4,5-tetrahydrobenzothiepine (61), and (3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine
(62) 366
[0408] To a solution of 0.5 g (1.47 mmole) of compound 47 in 5 ml
of anhydrous THF was added 0.17 g (1.47 mmole) of 95% potassium
t-butoxide. The reaction mixture was stirred at room temperature
for 18 h and quenched with 10 ml of 10% HCl. The organic was
extracted into methylene chloride. The methylene chloride extract
was dried over magnesium sulfate and concentrated in vacuo. The
residue was purified by HPLC (2% EtOAc-hexane) to give 47 mg of 61
in the second fraction and 38 mg of 62 in the third fraction.
Proton NMR and mass spectra were consistent with the assigned
structures.
EXAMPLE 33
[0409] (3.alpha.,4.alpha.,5.alpha.)
3-Butyl-3ethyl-4-hydroxy-7-amino-5-phe-
nyl-2,3,4,5-tetrahydrobenzothiepine-1,l-dioxide (63) and
(3.alpha.,4.alpha.,5.beta.)
3-Butyl-3-ethyl-4-hydroxy-7-amino-5-phenyl-2,-
3,4,5-tetrahydrobenzothiepine-1,1-dioxide (64) 367
[0410] An autoclave was charged with 200 mg of 37 in 40 cc ethanol
and 0.02 g 10% Pd/C. After purging with nitrogen the clave was
charged with 100 psi hydrogen and heated to 55 C. The reaction was
monitored by TLC and mass spec and allowed to proceed until all of
37 was consumed. After the reaction was complete the catalyst was
filtered and the solvent was removed in vacuo and the only
observable product was amine 63. This same procedure was used to
produce 64 from 38.
EXAMPLE 34
[0411] (3.alpha.,4.alpha.,5.alpha.)
3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5--
(3'-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide
(65), and (3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3'-meth-
oxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (66).
368
[0412] Alkylation of e-methoxyphenol with 3-methoxybenzyl chloride
according to the procedure described in J. Chem. Soc, 2431 (1958)
gave 4-methoxy-2-(3'-methoxybenzyl)phenol in 35% yield. This
material was converted to compound 65, mp 138.5-141.5.degree. C.,
and compound 66, mp 115.5-117.5.degree. C., by the procedure
similar to that in Example 18 method B.
EXAMPLE 35
[0413] (3.alpha.,4.alpha.,5.alpha.)
3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5--
(3'-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzothiepine-1
,1-dioxide (67), and (3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-4-hydroxy-7-methoxy--
5-(3'-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide
(68). 369
[0414] Alkylation of 4-methoxyphenol with 3-(trifluoromethyl)benzyl
chloride according to the procedure described in J. Chem. Soc. 2431
(1958) gave 4-methoxy-2-(3'-(trifluoromethyl)benzyl)phenol. This
material was converted to compound 67, mp 226.5-228.degree. C., and
compound 68, mp 188-190.degree. C., byu the procedure similar to
that in Example 18 method B.
EXAMPLE 36
[0415] (3.alpha.,4.alpha.,5.alpha.)
3-Butyl-3-ethyl-5-(41-fluorophenyl)-4--
hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (69),
and (3a,4p,5S)
3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,-
5-tetrahydrobenzothiepine-1,`-dioxide (70). 370
[0416] Alkylation of 4-methoxyphenol with 4-fluorobenzyl chloride
according to the procedure described in J. Chem. Soc, 2431 (1958)
gave 4-methoxy-2-(4'-fluorobenzyl)phenol. This material was
converted to compound 69 and compound 70 by the procedure similar
to that in Example 18 method B.
EXAMPLE 37
[0417] (3.alpha.,4.alpha.,5.alpha.) 3-Butyl-3-ethyl-5-
(31'-fluorophenyl)
-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide
(71), and (3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-5-(3'-fluorophenyl)-4-hydr-
oxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (72).
371
[0418] Alkylation of 4-methoxyphenol with 3-fluorobenzyl chloride
according to the procedure described in J. Chem. Soc, 2431 (1958)
gave 4-methoxy-2-(3'-fluorobenzyl)phenol. This material was
converted to compound 71 and compound 72 by the procedure similar
to that in Example 18 method B.
EXAMPLE 38
[0419] (3.alpha.,4.alpha.,5.alpha.)
3-Butyl-3-ethyl-5-(2'-fluorophenyl)-4--
hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (73),
and (3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-5-(2'-fluorophenyl)-4-hydroxy--
7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (74). 372
[0420] Alkylation of 4-methoxyphenol with 2-fluorobenzyl chloride
according to the procedure described in J. Chem. Soc, 2431 (1958)
gave 4-methoxy-2-(2'-fluorobenzyl)phenol. This material was
converted to compound 73 and compound 74 by the procedure similar
to that in Example 18 method B.
EXAMPLE 39
[0421] (3.alpha.,4.alpha.,5.alpha.)
3-Butyl-7-bromo-3-ethyl-4-hydroxy-5-(3-
'-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (75),
and (3.alpha.,4.beta.,5.beta.)
3-Butyl-7-bromo-3-ethyl-4-hydroxy-5-(3'-methox-
yphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (76). 373
[0422] Alkylation of 4-bromophenol with 3-methoxybenzyl chloride
according to the procedure described in J. Chem. Soc, 2431 (1958)
gave 4-bromo-2-(3'-methoxybenzyl)phenol. This material was
converted to compound 75, mp 97-101.5.degree. C., and compound 76,
mp 102-106.degree. C., by the procedure similar to that in Example
18 method B.
EXAMPLE 40
[0423] (3.alpha.,4.alpha.,5.alpha.)
3-Butyl-3-ethyl-7-fluoro-5-(4'-fluorop-
henyl)-4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (77),
and (3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-7-fluoro-5-(4'-fluorophenyl)-4-
-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (78). 374
[0424] Alkylation of 4-fluorophenol with 4-fluorobenzyl chloride
according to the procedure described in J. Chem. Soc, 2431 (1958)
gave 4-fluoro-2-(4'-fluorobenzyl)phenol. This material was
converted to compound 77, mp 228-230.degree. C., and compound 78,
mp 134.5-139.degree. C., by the procedure similar to that in
Example 18 method B.
EXAMPLE 41
[0425] (3.alpha.,4.alpha.,5.alpha.)
3-Butyl-3-ethyl-7-fluoro-4-hydroxy-5-(-
3'-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (79),
and (3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-7-fluoro-40hydroxy-5-(3'-metho-
xyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (80). 375
[0426] Alkylation of .sup.4-fluorophenol with 3-methoxybenzyl
chloride according to the procedure described in J. Chem. Soc, 2431
(1958) gave 4-fluoro-2-(3'-methoxybenzyl)phenol. This material was
converted to compound 79, as a solid and compound 80, mp
153-155.degree. C., by the procedure similar to that in Example 18
method B.
EXAMPLE 42
[0427] (3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hy-
droxy-7-methylthio-2,3,4,.sup.5-tetrahydrobenzothiepine-1,1-dioxide
(81). 376
[0428] A mixture of 0.68 (1.66 mmol) of compound 77, 0.2 g (5 mmol)
of sodium methanethiolate and 15 ml of anhydrous DMF was stirred at
room temperature for 16 days. The reaction mixture was dilute with
ether and washed with water and brine and dried over
M.sub.gSO.sub.4 The ether solution was concentrated in vacuo. The
residue was purified by HPLC (20% ethyl acetate in hexanes). The
first fraction was impure (3.alpha.,4.alpha.,5.alpha.)
3-butyl-3-ethyl-4-hydroxy-7-methylthio-5-(4'-
-fluorophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide. The
second fraction was compound 81, mp 185-186.5.degree. C.
EXAMPLE 43
[0429] (3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hy- droxy-7-(1-pyrrolidinyl)
-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (82). 377
[0430] A mixture of 0.53 g (1.30 mmol) of compound 78 and 5 ml of
pyrrolidine was held at reflux for 1 h. The reaction mixture was
diluted with ether and washed with water and brine and dried over
MgSO.sub.4. The ether solution was concentrated in vacuo. The
residue was crystallized from ether-hexanes to give compound 82, mp
174.5-177.degree. C.
EXAMPLE 44
[0431] (3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hy-
droxy-7-(1-morpholinyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide
(83). 378
[0432] A mixture of 0.4 g (0.98 mnmol) of compound 78 and 5.0 g (56
mnmol) of morpholine was held at reflux for 2 h and concentrated in
vacuo. The residue was diluted with ether (30 ml) and washed with
water and brine and dried over M9SO.sub.4 The ether solution was
concentrated in vacuo. The residue was recrystallized from
ether-hexanes to give compound 83, mp 176.5-187.5.degree. C.
EXAMPLE 45
[0433] (3.alpha.,4.alpha.,5.alpha.) 3-Butyl-3-ethyl-5- (4
'-fluorophenyl) -4-hydroxy-7-methyl-2,3,4,
5-tetrahydrobenzothiepine-1,1-dioxiLde (84), and
(3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hydr-
oxy-7-methyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (85).
379
[0434] Alkylation of 4-methylphenol with 4-fluorobenzyl chloride
according to the procedure described in J. Chem. Soc, 2431 (1958)
gave 4-methyl-2-(4'-fluorobenzyl)phenol). This material was
converted to compound 84 and compound 85 by the procedure similar
to that in Example 18 method B.
EXAMPLE 46
[0435] (3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-4-hydroxy-5-(4'-hydroxyp-
henyl)-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (86),
and (3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-4,7-dihydroxy-5-(4'-hydroxyphe-
nyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (87). 380
[0436] To a solution of 0.52 (1.2 mmol) of compound 66 in 20 ml of
methylene chloride was added 1.7 g (6.78 mmol) of born tribromide.
The reaction mixture was cooled to -78.degree. C. and was stirred
for 4 min. An additional 0.3 ml of boron tribromide was added to
the reaction mixture and the reaction mixture was stirred at
-78.degree. C. for 1 h and quenced with 2 N HCl. The organic was
extracted into ether. The ether layer was washed with brine, dried
over MgSO.sub.4, and concentrated in vacuo. The residue (0.48 g)
was purified by HPLC (30% ethyl acetate in hexanes). The first
fraction was 0.11 g of compound 86 as a white solid, mp
171.5-173.degree. C. The second fraction was crystallized from
chloroform to give 0.04 g of compound 87 as a white solid, mp
264.degree. C. (dec).
EXAMPLE 47
[0437] (3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-4,7-dihydroxy-5-(4'-fluo-
rophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (88). 381
[0438] Reaction of compound 70 with excess boron tribromide at room
temperature and worked up as in Example 46 gave compound 88 after
an HPLC purification.
EXAMPLE 48
[0439] (3.alpha.,4.beta.,5.beta.) 3-Butyl-3-ethyl-5-
(4'-fluorophenyl) -4-hydroxy-7- (1-azetidinyl)
-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (89). 382
[0440] A mixture of 0.20 g (0.49 mmol) of compound 78, and 2.0 g
(35 mmol) of aztidine was held at reflux for 3 h and concentrated
in vacuo. The residue was diluted with ether (30 ml) and washed
with water and brine and dried over MgSO4. The ether solution was
concentrated on a steam bath. The separated crystals were filtered
to give 0.136 g of 89 as prisms, mp 196.5-199.5.degree. C.
EXAMPLE 49
[0441] (3.alpha.,4.alpha.,5.alpha.)
3-Butyl-3-ethyl-5-(3'-methoxyphenyl)-4-
-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide
(90). (3.alpha.,4.beta.,5.beta.)
3-Butyl-3-ethyl-5-(3'-methoxyphenyl)-4-hydroxy-
-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (91).
383
[0442] A mixture of 0.4 g (0.95 mmol) of compound 79, 0.08 g (1.14
mmol) of sodium methanethiolate and 15 ml of anhydrous DMF was
stirred at 60.degree. C. for 2 h. An additional 1.4 mmol of sodium
methanethiolate was added to the reaction mixture and the mixture
was stirred at 60.degree. C. for an additional 2 h. The reaction
mixture was triturated with 100 ml of water and extracted methylene
chloride. The methylene chloride water mixture was filtered through
Celite and the methylene chloride layer was dried over MqSO.sub.4
and concentrated in vacuo. The first fraction (0.1 g) was compound
90, mp 117-121.degree. C. The second fraction (0.16 g) was compound
91, mp 68-76.degree. C.
EXAMPLE 50
[0443] Preparation of polyethyleneglycol functionalized
benzothiepine A. 384
[0444] A 50 ml rb flash under a nitrogen atmosphere was charged
with 0.54 g of M-Tres-5000 (Polyethyleneglycol Tresylate
[methoxy-PEG-Tres,MW 5000] purchased from Shearwater Polymers Inc.,
2130 Memorial Parkway, SW, Huntsville, Ala. 35801), 0.055 g
Compound No. 136, 0.326 C.sub.sCO.sub.3 and 2 cc anhydrous
acetonitrile. The reaction was stirred at 30 C for 5 days and then
the solution was filtered to remove salts. Next, the acetonitrile
was removed under vacuum and the product was dissolved in THF and
then precipitated by addition of hexane. The polymer precipitate
was isolate by filtration from the solvent mixture (THF/hexane).
This precipitation procedure was continued until no Compound No.
136 was detected in the precipitated product (by TLC SiO2). Next,
the polymer precipitate was dissolved in water and filtered and the
water soluble polymer was dialyzed for 48 hours through a cellulose
dialysis tube (Spectrum.RTM. 7 ,45 mm.times.0.5 ft, cutoff 1,000
MW). The polymer solution was then removed from the dialysis tube
and lyophilized until dried. The NMR was consistent with the
desired product A and gel permeation chromatography indicated the
presence of a 4500 MW polymer and also verified that no free
Compound No. 136 was present. This material was active in the IBAT
in vitro cell assay.
EXAMPLE 51
[0445] Preparation of Compound 140 385
[0446] A 2-necked 50 ml round bottom Flask was charged with 0.42 g
of Tres-3400 (Polyethyleneglycol Tresylate [Tres-PEG-Tres,MW 3400]
purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW,
Huntsville, Ala. 35801), 0.1 potassium carbonate, 0.100 g of
Compound No. 111 and 5 ml anhydrous DMF. Stir for 6 days at
27.degree. C. TLC indicated the disappearance of the starting
Compound No. 111. The solution was transferred to a separatory
funnel and diluted with 50 cc methylene chloride and then extracted
with water. The organic layer was evaporated to dryness by means of
a rotary evaporator. Dry wgt. 0.4875 g. Next, the polymer was
dissolved in water and then dialyzed for 48 hours at 40.degree. C.
through a cellulose dialysis tube (spectrum.RTM. 7 ,45 mm.times.0.5
ft, cutoff 1,000 MW). The polymer solution was then removed from
the dialysis tube and lyophilized until dried 0.341 g). NMR was
consistent with the desired product B.
EXAMPLE 52
[0447] 386
[0448] A 10 cc vial was charged with 0.21 g of Compound No. 136
(0.5 mmoles), 0.17 g (1.3 mmoles)potassium carbonate, 0.6 g (1.5
mmoles) of 1,2-bis-(2-iodoethoxy)-ethane and 10 cc DMF. The
reaction was stirred for 4 days at room temperature and then worked
up by washing with ether/water. The ether layer was stripped to
dryness and the desired product Compound No. 134 was isolated on a
silica gel column using 80/20 hexane ethyl acetate.
EXAMPLE 53
[0449] 387
[0450] A two necked 25 ml round bottom Flask was charged with 0.5 g
(1.24mmoles) of 69462, 13 mls of anhydrous DMF, 0.055 g of 60% NaH
dispersion and 0.230 g (0.62 mmoles) of 1,2-Bis
[2-iodoethoxylethane] at 10.degree. C. under nitogen. Next, the
reaction was slowly heated to 40.degree. C. After 14 hours all of
the Compound No. 113 was consumed and the reaction was cooled to
room temperature and extracted with ether/water. The ether layer
was evaporated to dryness and then chromatographed on Silicage
(80/20 ethyl acetate/hexane). Isolated Compound No. 112 (0.28 g)
was characterized by NMR and mass spec.
EXAMPLE 55
[0451] 388
[0452] In a 50 ml round bottom Flask, add 0.7 g (1.8 mmoles) of
Compound No. 136, 0.621 g of potassium carbonate, 6 ml DMF, and
0.33 g of 1,2-Bis [2-iodoethoxylethane]. Stir at 40 IC under
nitrogen for 12 hours. The workup and isolation was the same
procedure for Compound No. 112.
EXAMPLES 56 AND 57 (COMPOUND NOS. 131 AND 137)
[0453] The compositions of these compounds are shown in Table 3.
The same procedure as for Example 55 except appropriate
benzothiepine was used.
EXAMPLE 58 (COMPOUND NO. 139)
[0454] The composition of this compound is shown in Table 3. Same
procedure as for Example 55 with appropriate benzothiepine 1,6
diiodohexane was used instead of 1,2-Bis [2-iodoethoxylethane].
EXAMPLE 59 (COMPOUND NO. 101)
[0455] 389
[0456] This compound is prepared by condensing the 7-NH.sub.2
benzothiepine with the 1,12-dodecane dicarboxylic acid or acid
halide.
EXAMPLE 60 (Compound No. 104)
[0457] 390
[0458] 2-Chloro-4-nitrobenzophenone is reduced with triethylsilane
and trifluoromethane sulfonic acid to
2-chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium
sulfide followed by reacting the resulting sulfide with mesylate IV
gives sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents
of MCPBA yields sulfone-aldehyde XXIV (see Scheme 5). Reduction of
the sulfone-aldehyde XXV formaldehyde and 100 psi hydrogen and 55 C
for 12 hours catalyzed by palladium on carbon in the same reaction
vessel yields the substituted dimethylamine derivative XXVIII.
Cyclization of XXVII with potassium t-butoxide yields a mixture of
substituted amino derivatives of this invention Compound No. 104.
391
EXAMPLE 61
[0459] 392
[0460] A 1 oz. Fisher-porter bottle was charged with 0.14 g (0.34
mmoles) of 70112, 0.97 gms (6.8 mmoles) of methyl iodide, and 7 ml
of anhydrous acetonitrile. Heat to 50.degree. C. for 4 days. The
quat. Salt Compound No. 192 was isolated by concentrating to 1 cc
acetonitrile and then precipitating with diethyl ether.
EXAMPLE 62
[0461] 393
[0462] A 0.1 g (0.159 mmoles) sample of Compound No. 134 was
dissolved in 15 ml of anhydrous acetonitrile in a Fischer-porter
bottle and then trimethylamine was bubbled through the solution for
5 minutes at 0.degree. C. and then capped and warmed to room
temperature. The reaction was stirred overnight and the desired
product was isolated by removing solvent by rotary evaporation.
EXAMPLE 63 (COMPOUND NO. 295)
[0463] 394
[0464] Sodium Hydride 60% (11 mg, 0.27 mmnoles) in 1 cc of
acetonitrile at 0.degree. C. was reacted with 0.248 mmoles (0.10 g)
of Compound No. 54 in 2.5cc of acetonitrile at 0.degree. C. Next,
0. (980 g 2.48 mmnoles) of 1,2-Bis [2-iodoethoxylethane]. After
warming to room temperature, stir for 14 hours. The product was
isolated by column chromatography.
EXAMPLE 64 (COMPOUND NO. 286)
[0465] 395
[0466] Following a procedure similar to the one described in
Example 86, infra (see Compound No. 118), the title compound was
prepared and purified as a colorless solid; mp 180-181.degree. C.;
.sup.1H NMR (CHCl.sub.3) .delta. 0.85 (t, J=6 Hz, 3H, 0.92 (t, J=6
Hz, 3H), 1.24-1.42 (m, 2H), 1.46-1.56 (m, 1H), 1.64-1.80 (m, 1H),
2.24-2.38 (m, 1H), 3.15 (AB, J.sub.AB=15 Hz, .DELTA.v=42 Hz, 2H),
4.20 (d, J=8 Hz, 1H), 5.13 (s, 2H), 5.53 (s, 1H), 6.46 (s, 1H),
6.68 (s, 1H), 7.29-7.51 (m, 10H), 7.74 (d, J=8 Hz, 1H), 8.06 (d,
J=8 Hz, 1H). FABMS m/z 494 (M+H), HRMS calcd for (M+H) 494.2001,
found 494.1993. Anal. Calcd. for C.sub.28H.sub.31NO.sub.5S: C,
68.13; H, 6.33; N, 2.84. Found: C, 68.19; H, 6.56; N, 2.74.
EXAMPLE 65 (COMPOUND NO. 287)
[0467] 396
[0468] Following a procedure similar to the one described in
Example 89, infra (see Compound No. 121), the title compound was
prepared and purified as a colorless solid: mp 245-246.degree. C.,
.sup.1H NMR (CDCl.sub.3) .delta. 0.84 (t, J=6 Hz, 3H), 0.92 (t, J=6
Hz, 3H), 1.28, (d, J=8 Hz, 1H), 1.32-1.42 (m, 1H), 1.48-1.60 (m,
1H), 1.64-1.80 (m, 1H), 2.20-2.36 (m, 1H), 3.09 (AB, JA =15 Hz,
.DELTA.v=42 Hz, 2H), 3.97 (bs, 2H), 4.15 (d, J=8 Hz, 1H), 5.49 (s,
1H), 5.95 (s, 1H), 6.54 (d, J=7 Hz, 1H), 7.29-7.53 (m, 5H), 7.88
(d, J=8 Hz, 1H); ESMS 366 (M+Li). Anal. Calcd. for
C.sub.20H.sub.25NO.sub.3S: C, 66.82; H, 7.01; N, 3.90. Found: C,
66.54; H, 7.20; N, 3.69.
EXAMPLE 66 (COMPOUND NO. 288)
[0469] 397
[0470] Following a procedure similar to the one described in
Example 89, infra (see Compound No. 121), the title compound was
prepared and purified by silica gel chromatography to give the
desired product as a colorless solid: mp 185-186.degree. C.;
.sup.1H NMR (CDCl.sub.3) .delta.1.12 (s, 3H), 1.49 (s, 3H), 3.00
(d, J=15 Hz, 1H), 3.28 (d, J=15 Hz, 1H), 4.00 (s, 1H), 5.30 (s,
1H), 5.51 (s, 1H), 5.97 (s, 1H), 6.56 (dd, J=2.1, 8.4 Hz, 1H),
7.31-7.52 (m, 5H), 7.89 (d, J=8.4 Hz, 1H). MS (FAB+) (M+H) m/z
332.
EXAMPLE 67 (COMPOUND NO. 289)
[0471] 398
[0472] Following a procedure similar to the one described in
Example 89 (see Compound No. 121), the title compound was prepared
and purified by silica gel chromatography to give the desired
product as a white solid: mp 205-206.degree. C.; .sup.1H NMR
(CDCl.sub.3) .delta. 0.80-0.95 (m, 6H), 1.10-1.70 (m, 7H), 2.15 (m,
1H), 3.02 (d, J=15.3 Hz, 2H), 3.15 (d, J=15.1 Hz, 2H), 3.96 (s, br,
2H), 4.14 (d, J=7.8 Hz, 1H), 5.51 (s, 1H), 5.94 (d, J=2.2, 1H),
6.54 (dd, J=8.5, 2.2 Hz, 1H), 7.28-7.50 (m, 6H), 7.87 (d, J=8.5 Hz,
1H). MS (FAB): m/z 388 (M+H).
EXAMPLE 68 (COMPOUND NO. 290)
[0473] 399
[0474] Following a procedure similar to the one described in
Example 89, infra (see Compound No. 121), the title compound was
prepared and purified as a colorless solid: mp =96-98.degree. C.,
.sup.1H NMR (CDCl.sub.3) .delta. 0.92 (t, J=7 Hz, 6H), 1.03-1.70
(m, 11H), 2.21 (t, J=8 Hz, 1H), 3.09 (AB, J.sub.AB=-18 Hz,
.DELTA.v=38 Hz, 2H), 3.96 (bs, 2H), 4.14 (d, J=7 Hz, 1H), 5.51 (s,
1H), 5.94 (s, 1H), 6.56 (d, J=9 Hz, 1H), 7.41-7.53 (m, 6H), 7.87
(d, J=8 Hz, 1H); FABMS m/z 416 (M+H).
EXAMPLE 69
[0475] 400
[0476] Following a procedure similar to the one described in
Example 86, infra (see Compound No. 118), the title compound was
prepared and purified as a colorless solid: .sup.1H NMR
(CDCl.sub.3) .delta. 0.91 (t, J=7 Hz, 6H), 1.02-1.52 (m, 11H),
1.60-1.70 (m, 1H), 2.23 (t, J=8 Hz, 1H), 3.12 (AB, JB =18 Hz,
.DELTA.v=36 Hz, 2H), 4.18 (d, J=7 Hz, 1H), 5.13 (s, 2H), 5.53 (s,
1H), 6.43 (s, 1H), 6.65 (s, 1H), 7.29-7.52 (m, 10H), 7.74 (d, J=9
Hz, 1H), 8.03 (d, J=8 Hz, 1H); ESMS m/z 556 (M+Li).
EXAMPLE 70 (COMPOUND NO. 292)
[0477] 401
[0478] Following a procedure similar to the one descried in Example
89, infra (see Compound No. 121), the title compound was prepared
and purified as a colorless solid: mp =111-112.5.degree. C.,
.sup.1H NMR (CDCl.sub.3) .delta. 0.90 (t, J=8 Hz, 6H), 1.03-1.50
(m, 10H), 1.55-1.70 (m, 2H), 2.18 (t, J=12 Hz, 2H), 3.07 (AB,
J.sub.AB=15 Hz, .DELTA.v=45 Hz, 2H), 4.09 (bs, 2H), 5.49 (s, 1H),
5.91 (s, 1H), 6.55 (d, J=9 Hz, 1H), 7.10 (t, J=7 Hz, 2H), 7.46 (t,
J=6 Hz, 2H), 7.87 (d, J=9 Hz, 1H).
EXAMPLE 71 (COMPOUND NO. 293)
[0479] 402
[0480] During the preparation of Compound No. 290 from Compound No.
291 using BBr.sub.3, the title compound was isolated: .sup.1H NMR
(CDCl.sub.3) .delta. 0.85 (t, J=6 Hz, 6H), 0.98-1.60 (m, 10H),
1.50-1.66 (m, 2H), 2.16 (t, J=8 Hz, 1H), 3.04 (AB, JA =15 Hz,
.DELTA.v=41 Hz, 2H), 4.08 (s, 1H), 4.12 (s, 1H), 5.44 (s, 1H), 5.84
(s, lH), 6.42 (d, J=9 Hz, 1H), 7.12 (d, J=8 Hz, 2H), 7.16-7.26 (m,
10H), 7.83 (d, J=8 Hz, 1H); ESMS m/z 512 (M+Li).
EXAMPLE 72 (COMPOUND NO. 294)
[0481] Following a procedure similar to the one described in
Example 60 (Compound No. 104), the title compound was prepared and
purified as a colorless solid: .sup.1H NMR (CDCl.sub.3) .delta.
0.90 (t, J=6 Hz, 6H), 1.05-1.54 (m, 9H), 1.60-1.70 (m, 1H), 2.24
(t, J=8 Hz, 1H), 2.80 (s, 6H), 3.05 (AB, J.sub.AB=15 Hz,
.DELTA.v=42 Hz, 2H), 4.05-4.18 (m, 2H), 5.53 (s, 1H), 5.93 (s, 1H),
6.94 (d, J=9 Hz, 1H), 7.27-7.42 (m, 4H), 7.45 (d, J=8 Hz, 2H), 7.87
(d, J=9 Hz, 1H); ESMS m/z 444 (M+H).
[0482] Structures of the compounds of Examples 33 to 72 are shown
in Tables 3 and 3A.
EXAMPLES 73-79, 87, 88 AND 91-102
[0483] Using in each instance a method generally described in those
of Examples 1 to 72 appropriate to the substituents to be
introduced, compounds were prepared having the structures set forth
in Table 3. The starting materials illustrated in the reaction
schemes shown above were varied in accordance with principles of
organic synthesis well known to the art to introduce the indicated
substituents in the 4- and 5- positions (R.sup.3, R.sup.4, R.sup.5,
R.sup.6) and in the indicated position on the benzo ring
(R.sup.x).
[0484] Structures of the the compounds produced in Examples 73-102
are set forth in Tables 3 and 3A.
EXAMPLES 80-84
[0485] Preparation of 115, 116, 111, 113
[0486] Preparation of
4-chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene.
[0487] In a 500 ml 2-necked rb flask weigh out 68.3 gms phosphorus
pentachloride (0.328 mole 1.1 eq). Add 50 mls chlorobenzene. Slowly
add 60 gms 2-chloro-5-nitrobenzoic acid (0.298 mole). Stir at room
temp overnight under N2 then heat 1 hr at 50C.
[0488] Remove chlorobenzene by high vacuum. Wash residue with
hexane. Dry wt-55.5 gms.
[0489] In the same rb flask, dissolve acid chloride (55.5 g 0.25
mole) from above with 100 mls anisole (about 3.4 eq). Chill
solution with ice bath while purging with N2. Slowly add 40.3 g
aluminum chloride (1.2 eq 0.3 mole). Stir under N.sub.2 for 24
hrs.
[0490] After 24 hrs, the solution was poured into 300 mls iN HCl
soln. (cold). Stir this for 15 min. Extract several times with
diethyl ether. Extract organic layer once with 2% aqueous NaOH then
twice with water. Dry organic layer with MgSO4, dry on vac line.
Solid is washed well with ether and then ethanol before drying.
Wt=34.57 g (mixture of meta, ortho and para).
6 Elemental theory found C 57.65 57.45 H 3.46 5.51 N 4.8 4.8 Cl
12.15 12.16
[0491] With the next step of the reduction of the ketone with
trifluoromethane sulfonic aid and triethyl silane, crystallization
with ethyl acetate/hexane affords pure 4-chloro-3-
[4-methoxy-phenylmethyl] -nitrobenzene.
4-Chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene was then reacted
as specified in the synthesis of 117 and 118 from
2-chloro-4-nitrophenylmethane. From these procedures 115 and 116
can be synthesized. Compounds 111 and 113 can be synthesized from
the procedure used to prepare compound 121.
[0492] Compound 114 can be prepared by reaction of 116 with ethyl
mercaptan and aluminum trichloride.
EXAMPLES 85 AND 86
[0493] Preparation of 117 and 118
[0494] 2-Chloro-4-nitrobenzophenone is reduced with triethylsilane
and trifluoromethane sulfonic acid to
2-chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium
sulfide followed by reacting the resulting sulfide with mesylate IV
gives sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents
of MCPBA yields sulfone-aldehyde XXIII. Oxidation of XXIII with 2
equivalents of MCPBA yields sulfone-aldehyde XXIV (see Scheme
5).
[0495] The sulfone-aldehyde (31.8 g) was dissolved in
ethanol/toluene and placed in a parr reactor with 100 ml toluene
and 100 ml of ethanol and 3.2 g of 10% Pd/C and heated to 55 C and
100 psi of hydrogen gas for 14 hours. The reaction was then
filtered to remove the catalyst. The amine product (0.076 moles,
29.5 g) from this reaction was then reacted with benzyl
chloroformate (27.4 g) in toluene in the presence of 35 g of
potassium carbonate and stirred at room temperature overnight.
After work up by extraction with water, the CBZ protected amine
product was further purified by precipitation from
toluene/hexane.
[0496] The CBZ protected amine product was then reacted with 3
equivalents of potassium t-butoxide in THF at 0 C to yield
compounds 117 and 118 which were separated by silica gel column
chromatography.
EXAMPLES 89 AND 90
[0497] Preparation of 121 or 122
[0498] Compound 118 (.013 moles, 6.79 g) is dissolved in 135 ml of
dry chloroform and cooled to -78 C, next 1.85 ml of boron
tribromide (4.9 g) was added and the reaction is allowed to warm to
room temperature. Reaction is complete after 1.5 hours. The
reaction is quenched by addition of 10% potassium carbonate at 0 C
and extract with ether. Removal of ether yields compound 121. A
similar procedure can be used to produce 122 from 117.
EXAMPLES 93-96
[0499] Compounds 126, 127, 128 and 129 as set forth in Table 3 were
prepared substantially in the manner described above for compounds
115, 116, 111 and 113, respectively, except that fluorobenzene was
used as a starting material in place of anisole.
7TABLE 3 Specific Compounds (#102-111, 113-130, 132-134, 136, 138,
142-144, 262-296) 403 Cp# R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5
R.sup.6 (R.sup.x)q 102 Et- n-Bu- HO-- H-- Ph-- H-- I.sup.-, 7-
(CH.sub.3).sub.3N.sup.+-- 103 n-Bu- Et- HO-- H-- Ph-- H-- I.sup.-,
7- (CH.sub.3).sub.3N.sup.+-- 104 Et- n-Bu- HO-- H-- Ph-- H--
7-(CH.sub.3).sub.2N -- 105 Et- n-Bu- HO-- H-- Ph-- H-- 7-
CH.sub.3SO.sub.2NH-- 106 Et- n-Bu- HO-- H-- Ph-- H--
7-Br--CH.sub.2-- CONH-- 107 n-Bu- Et- HO-- H-- p-n- H--
7-NH.sub.2-- C.sub.10H.sub.21--O-- Ph-- 108 Et- n-Bu- HO-- H-- Ph--
H-- 7- C.sub.5H.sub.11CONH-- 109 Et- n-Bu- HO-- H-- p-n- H--
7-NH.sub.2-- C.sub.10H.sub.21--O-- Ph-- 110 Et- n-Bu- HO-- H-- Ph--
H-- 7-CH.sub.3CONH-- 111 n-Bu- Et- HO-- H-- p-HO--Ph-- H--
7-NH.sub.2-- 113 Et- n-Bu- HO-- H-- p-HO--Ph-- H-- 7-NH.sub.2-- 114
Et- n-Bu- HO-- H-- p-CH.sub.3O--Ph-- H-- 7-NH.sub.2-- 115 n-Bu- Et-
HO-- H-- p-CH.sub.3O--Ph-- H-- 7-NH--CBZ 116 Et- n-Bu- HO-- H--
p-CH.sub.3O--Ph-- H-- 7-NH--CBZ 117 n-Bu- Et- HO-- H-- Ph-- H--
7-NH--CBZ 118 Et- n-Bu- HO-- H-- Ph-- H-- 7-NH--CBZ 119 Et- n-Bu-
HO-- H-- Ph-- H-- 7-NHCO.sub.2-t- Bu 120 n-Bu- Et- HO-- H-- Ph--
H-- 7-NHCO.sub.2-t- Bu 121 Et- n-Bu- HO-- H-- Ph-- H-- 7-NH.sub.2--
122 n-Bu- Et- HO-- H-- Ph-- H-- 7-NH.sub.2-- 123 Et- n-Bu- HO-- H--
Ph-- H-- 7-n-C.sub.6H.sub.13-- NH-- 124 n-Bu- Et- HO-- H-- Ph-- H--
7-n-C.sub.6H.sub.13-- NH-- 125 Et- n-Bu- HO-- H-- Ph-- H-- I.sup.-,
8- (CH.sub.3).sub.3)N.sup.+ (CH.sub.2CH.sub.2O).sub.3-- 126 n-Bu-
Et- HO-- H-- p-F--Ph-- H-- 7-NH--CBZ 127 n-Bu- Et- HO-- H--
p-F--Ph-- H-- 7-NH.sub.2-- 128 Et- n-Bu- HO-- H-- p-F--Ph-- H--
7-NH--CBZ 129 Et- n-Bu- HO-- H-- p-F--Ph-- H-- 7-NH.sub.2-- 130 Et-
n-Bu- HO-- H-- Ph-- H-- I.sup.-, 8- (CH.sub.3).sub.3N.sup.+
C.sub.6H.sub.12O-- 132 Et- n-Bu- HO-- H-- Ph-- H-- 8-phthal-
imidyl- C.sub.6H.sub.12O-- 133 Et- n-Bu- HO-- H-- Ph-- H-- 8-n-
C.sub.10H.sub.21-- 134 Et- n-Bu- HO-- H-- Ph-- H-- 8- I-
(C.sub.2H.sub.4O).sub.3-- 136 Et- n-Bu- HO-- H-- Ph-- H-- 8- HO--
138 n-Bu- Et- HO-- H-- Ph-- H-- 8- CH.sub.3CO.sub.2-- 142 Et- n-Bu-
H-- HO-- H-- m-CH.sub.3O--Ph-- 7-CH.sub.3S-- 143 Et- n-Bu- HO-- H--
m-CH.sub.3O--Ph-- H-- 7-CH.sub.3S-- 144 Et- n-Bu- HO-- H--
p-F--Ph-- H-- 7-(N)- azetidine 262 Et- n-Bu- HO-- H--
m-CH.sub.3O--Ph-- H-- 7-CH.sub.3O-- 263 Et- n-Bu- H-- HO-- H--
m-CH.sub.3O--Ph-- 7-CH.sub.3O-- 264 Et- n-Bu- HO-- H--
m-CF.sub.3--Ph-- H-- 7-CH.sub.3O-- 265 Et- n-Bu- H-- HO-- H--
m-CF.sub.3--Ph-- 7-CH.sub.3O-- 266 Et- n-Bu- HO-- H-- m-HO--Ph--
H-- 7-HO-- 267 Et- n-Bu- HO-- H-- m-HO--Ph-- H-- 7-CH.sub.3O-- 268
Et- n-Bu- HO-- H-- p-F--Ph-- H-- 7-CH.sub.3O-- 269 Et- n-Bu- H--
HO-- H-- p-F--Ph-- 7-CH.sub.3O-- 270 Et- n-Bu- HO-- H-- p-F--Ph--
H-- 7-HO-- 271 Et- n-Bu- HO-- H-- m-CH.sub.3O--Ph-- H-- 7-Br-- 272
Et- n-Bu- H-- HO-- H-- m-CH.sub.3O--Ph-- 7-Br-- 273 Et- n-Bu- H--
HO-- H-- p-F--Ph-- 7-F-- 274 Et- n-Bu- HO-- H-- p-F--Ph-- H-- 7-F--
275 Et- n-Bu- H-- HO-- H-- m-CH.sub.3O--Ph-- 7-F-- 276 Et- n-Bu-
HO-- H-- m-CH.sub.3O--Ph-- H-- 7-F-- 277 Et- n-Bu- HO-- H--
m-F--Ph-- H-- 7-CH.sub.3O-- 278 Et- n-Bu- H-- HO-- H-- o-F--Ph--
7-CH.sub.3O-- 279 Et- n-Bu- H-- HO-- H-- m-F--Ph-- 7-CH.sub.3O--
280 Et- n-Bu- HO-- H-- o-F--Ph-- H-- 7-CH.sub.3O-- 281 Et- n-Bu-
HO-- H-- p-F--Ph-- H-- 7-CH.sub.3S-- 282 Et- n-Bu- HO-- H--
p-F--Ph-- H-- 7-CH.sub.3-- 283 Et- n-Bu- H-- HO-- H-- p-F--Ph--
7-CH.sub.3-- 284 Et- n-Bu- HO-- H-- p-F--Ph-- H 7-(N)- morpholine
285 Et- n-Bu- HO-- H-- p-F--Ph-- H 7-(N)- pyrroli dine 286 Et- Et-
HO-- H-- Ph-- H-- 7-NH--CBZ- 287 Et- Et- HO-- H-- Ph-- H--
7-NH.sub.2-- 288 CH.sub.3-- CH.sub.3-- HO-- H-- Ph-- H--
7-NH.sub.2-- 289 n- n- HO-- H-- Ph-- H-- 7-NH.sub.2--
C.sub.3H.sub.7-- C.sub.3H.sub.7-- 290 n-Bu- n-Bu- HO-- H-- Ph-- H--
7-NH.sub.2-- 291 n-Bu- n-Bu- HO-- H-- Ph-- H-- 7-NH--CBZ- 292 n-Bu-
n-Bu- HO-- H-- p-F--Ph-- H-- 7-NH.sub.2-- 293 n-Bu- n-Bu- HO-- H--
Ph-- H-- 7-PhCH.sub.2N-- 294 n-Bu- n-Bu- HO-- H-- Ph-- H--
7-(CH.sub.3).sub.2N-- 295 Et- n-Bu- HO-- H-- p-I- H-- 7-NH.sub.2--
(C.sub.2H.sub.4O).sub.3-- Ph-- 296 Et- n-Bu- HO-- H-- I.sup.-, p-
H-- 7-NH.sub.2-- (CH.sub.3).sub.3N.sup.+
(C.sub.2H.sub.4O).sub.3--Ph--
[0500] 404
EXAMPLES 104-231
[0501] Using in each instance a method generally described in those
of Examples 1 to 72 appropriate to the substituents to be
introduced, including where necessary other common synthesis
expedients well known to the art, compounds are prepared having the
structures set forth in Table 4. The starting materials illustrated
in the reaction schemes shown above are varied in accordance with
principles of organic synthesis well known to the art in order to
introduce the indicated substituents in the 4- and 5-positions
(R.sup.3, R.sup.4, R.sup.5, R.sup.6) and in the indicated position
on the benzo ring (R.sup.x).
8TABLE 4 Alternative compounds #1 (#302-312, 314-430) 405 Cpd#
R.sup.5 (R.sup.x)q 302 p-F--Ph-- 7-(1-aziridine) 303 p-F--Ph--
7-EtS-- 304 p-F--Ph-- 7-CH.sub.3S(O)-- 305 p-F--Ph--
7-CH.sub.3S(O).sub.2-- 306 p-F--Ph-- 7-PhS-- 307 p-F--Ph--
7-CH.sub.3S-- 9-CH.sub.3S-- 308 p-F--Ph-- 7-CH.sub.3O--
9-CH.sub.3O-- 309 p-F--Ph-- 7-Et- 310 p-F--Ph-- 7-iPr- 311
p-F--Ph-- 7-t-Bu- 312 p-F--Ph-- 7-(1-pyrazole)- 314 m-CH.sub.3O--Ph
7-(1-azetidine) 315 m-CH.sub.3O--Ph-- 7-(1-aziridine) 316
m-CH.sub.3O--Ph-- 7-EtS-- 317 m-CH.sub.3O--Ph-- 7-CH.sub.3S(O)--
318 m-CH.sub.3O--Ph-- 7-CH.sub.3S(O).sub.2-- 319 m-CH.sub.3O--Ph--
7-PhS-- 320 m-CH.sub.3O--Ph 7-CH.sub.3S-- 9-CH.sub.3S-- 321
m-CH.sub.3O--Ph 7-CH.sub.3O-- 9-CH.sub.3O-- 322 m-CH.sub.3O--Ph
7-Et- 323 m-CH.sub.3O--Ph 7-iPr- 324 m-CH.sub.3O--Ph 7-t-Bu-
6-CH.sub.3O-- 325 p-F--Ph-- 7-CH.sub.3O-- 8-CH.sub.3O-- 326
p-F--Ph-- 7-(1-azetidine) 9-CH.sub.3-- 7-EtS-- 327 p-F--Ph--
9-CH.sub.3-- 328 p-F--Ph-- 7-CH.sub.3S(O)-- 9-CH.sub.3-- 329
p-F--Ph-- 7-CH.sub.3S(O).sub.2-- 9-CH.sub.3-- 330 p-F--Ph-- 7-PhS--
9-CH.sub.3-- 7-CH.sub.3S-- 331 p-F--Ph-- 9-CH.sub.3-- 332 p-F--Ph--
7-CH.sub.3O-- 9-CH.sub.3-- 333 p-F--Ph-- 7-CH.sub.3-- 9-CH.sub.3--
334 p-F--Ph-- 7-CH.sub.3O-- 9-CH.sub.3O-- 335 p-F--Ph--
7-(1-pyrrole) 336 p-F--Ph-- 7-(N)N'-methylpiperazine 337 p-F--Ph--
Ph-- 338 p-F--Ph-- 7-CH.sub.3C(.dbd.CH.sub.2)-- 339 p-F--Ph--
7-cyclpropyl 340 p-F--Ph-- 7-(CH.sub.3).sub.2NHN-- 341 p-F--Ph--
7-(N)-azetidine 9-CH.sub.3S-- 342 p-F--Ph-- 7-(N-pyrrolidine)
9-CH.sub.3S-- 343 p-F--Ph-- 7-(CH.sub.3).sub.2N-- 9-CH.sub.3S-- 344
m-CH.sub.3O--Ph-- 7-(1-pyrazole) 345 m-CH.sub.3O--Ph--
7-(N)N'-methylpiperazine 346 m-CH.sub.3O--Ph-- Ph-- 347
m-CH.sub.3O--Ph-- 7-CH.sub.3C(.dbd.CH.sub.2)-- 348
m-CH.sub.3O--Ph-- 7-cyclopropyl 349 m-CH.sub.3O--Ph--
7-(CH.sub.3).sub.2NHN-- 350 m-CH.sub.3O--Ph-- 7-(N)-azetidine
9-CH.sub.3S-- 351 m-CH.sub.3O--Ph-- 7-(N-pyrrolidine)-
9-CH.sub.3S-- 352 m-CH.sub.3O--Ph-- 7-(CH.sub.3).sub.2N--
9-CH.sub.3S-- 353 m-CH.sub.3O--Ph-- 6-CH.sub.3O-- 7-CH.sub.3O--
8-CH.sub.3O-- 354 m-CH.sub.3O--Ph 7-(1-azetidine) 9-CH.sub.3-- 355
m-CH.sub.3O--Ph-- 7-EtS-- 9-CH.sub.3-- 356 m-CH.sub.3O--Ph--
7-CH.sub.3S(O)-- 9-CH.sub.3-- 357 m-CH.sub.3O--Ph--
7-CH.sub.3S(O).sub.2-- 9-CH.sub.3-- 358 m-CH.sub.3O--Ph-- 7-PhS--
9-CH.sub.3-- 359 m-CH.sub.3O--Ph-- 7-CH.sub.3S-- 9-CH.sub.3-- 360
m-CH.sub.3O--Ph-- 7-CH.sub.3O-- 9-CH.sub.3-- 361 m-CH.sub.3O--Ph--
7-CH.sub.3-- 9-CH.sub.3-- 362 m-CH.sub.3O--Ph-- 7-CH.sub.3O--
9-CH.sub.3O-- 363 thien-2-yl 7-(1-aziridine) 364 thien-2-yl 7-EtS--
365 thien-2-yl 7-CH.sub.3S(O)-- 366 thien-2-yl
7-CH.sub.3S(O).sub.2-- 367 thien-2-yl 7-PhS-- 368 thien-2-yl
7-CH.sub.3S-- 9-CH.sub.3S-- 369 thien-2-yl 7-CH.sub.3O--
9-CH.sub.3O-- 370 thien-2-yl 7-Et- 371 thien-2-yl 7-iPr- 372
thien-2-yl 7-t-Bu- 373 thien-2-yl 7-(1-pyrrole)- 374 thien-2-yl
7-CH.sub.3O-- 375 thien-2-yl 7-CH.sub.3S-- 376 thien-2-yl
7-(1-azetidine) 377 thien-2-yl 7-Me- 378 5-Cl-thien-2-yl
7-(1-azetidine) 379 5-Cl-thien-2-yl 7-(1-aziridine) 380
5-Cl-thien-2-yl 7-EtS-- 381 5-Cl-thien-2-yl 7-CH.sub.3S(O)-- 382
5-Cl-thien-2-yl 7-CH.sub.3S(O).sub.2-- 383 5-Cl-thien-2-yl 7-PhS--
384 5-Cl-thien-2-yl 7-CH.sub.3S-- 9-CH.sub.3S-- 385 5-Cl-thien-2-yl
7-CH.sub.3O-- 9-CH.sub.3O-- 386 5-Cl-thien-2-yl 7-Et- 387
5-Cl-thien-2-yl 7-iPr- 388 5-Cl-thien-2-yl 7-t-Bu- 389
5-Cl-thien-2-yl 7-CH.sub.3O-- 390 5-Cl-thien-2-yl 7-CH.sub.3S-- 391
5-Cl-thien-2-yl 7-Me 392 thien-2-yl 7-(1-azetidine) 9-CH.sub.3--
393 thien-2-yl 7-EtS-- 9-CH.sub.3-- 394 thien-2-yl 7-CH.sub.3S(O)--
9-CH.sub.3-- 395 thien-2-yl 7-CH.sub.3S(O).sub.2-- 9-CH.sub.3-- 396
thien-2-yl 7-PhS-- 9-CH.sub.3-- 397 thien-2-yl 7-CH.sub.3S--
9-CH.sub.3-- 398 thien-2-yl 7-CH.sub.3O-- 9-CH.sub.3-- 399
thien-2-yl 7-CH.sub.3-- 9-CH.sub.3-- 400 thien-2-yl 7-CH.sub.3O--
9-CH.sub.3O-- 401 thien-2-yl 7-(1-pyrazrole) 402 thien-2-yl
7-(N)N'-methylpiperazine 403 thien-2-yl Ph-- 404 thien-2-yl
7-CH.sub.3C(.dbd.CH.sub.2)-- 405 thien-2-yl 7-cyclpropyl 406
thien-2-yl 7-(CH.sub.3).sub.2NHN 407 thien-2-yl 7-(N)-azetidine
9-CH.sub.3S-- 408 thien-2-yl 7-(N-pyrrolidine) 9-CH.sub.3S-- 409
thien-2-yl 7-(CH.sub.3).sub.2N-- 9-CH.sub.3S-- 411 5-Cl-thien-2-yl
7-(1-pyrazrole) 412 5-Cl-thien-2-yl 7-(N)N'-methylpiperazine 413
5-Cl-thien-2-yl Ph-- 414 5-Cl-thien-2-yl
7-CH.sub.3C(.dbd.CH.sub.2)-- 415 5-Cl-thien-2-yl 7-cyclopropyl 416
5-Cl-thien-2-yl 7-(CH.sub.3).sub.2NHN-- 417 5-Cl-thien-2-yl
7-(N)-azetidine 9-CH.sub.3S-- 418 5-Cl-thien-2-yl
7-(N-pyrrolidine)- 9-CH.sub.3S-- 419 5-Cl-thien-2-yl
7-(CH.sub.3).sub.2N-- 9-CH.sub.3S-- 420 5-Cl-thien-2-yl
7-(1-azetidine) 9-CH.sub.3-- 421 5-Cl-thien-2-yl 7-EtS--
9-CH.sub.3-- 422 5-Cl-thien-2-yl 7-CH.sub.3S(O)-- 9-CH.sub.3-- 423
5-Cl-thien-2-yl 7-CH.sub.3S(O).sub.2-- 9-CH.sub.3-- 424
5-Cl-thien-2-yl 7-PhS-- 9-CH.sub.3-- 425 5-Cl-thien-2-yl
7-CH.sub.3S-- 9-CH.sub.3-- 426 5-Cl-thien-2-yl 7-CH.sub.3O--
9-CH.sub.3-- 427 5-Cl-thien-2-yl 7-CH.sub.3-- 9-CH.sub.3-- 428
5-Cl-thien-2-yl 7-CH.sub.3O-- 9-CH.sub.3O-- 429 thien-2-yl
6-CH.sub.3O-- 7-CH.sub.3O-- 8-CH.sub.3O-- 430 5-Cl-thien-2-yl
6-CH.sub.3O-- 7-CH.sub.3O-- 8-CH.sub.3O--
EXAMPLES 232-1394
[0502] Using in each instance a method generally described in those
of Examples 1 to 72 appropriate to the substituents to be
introduced, including where necessary other common synthesis
expedients well known to the art, compounds are prepared having the
structures set forth in Table 1. The starting materials illustrated
in the reaction schemes shown above are varied in accordance with
principles of organic synthesis well known to the art in order to
introduce the indicated substituents in the 4- and 5-positions (R3,
R.sup.4, R.sup.5, R.sup.6) and in the indicated position on the
benzo ring (R.sub.x).
EXAMPLE 1395
[0503] Dibutyl 4-fluorobenzene dialdehyde 406
[0504] Step 1: Preparation of dibutyl 4-fluoro benzene
dialdehyde
[0505] To a stirred solution of 17.5 g (123 mmol) of
2,5-difluorobenzaldehyde (Aldrich) in 615 mL of DMSO at ambient
temperature was added 6.2 g (135 mmol) of lithium sulfide
(Aldrich). The dark red solution was stirred at 75 C for 1.5 hours,
or until the starting material was completely consumed, and then 34
g (135 mmol) of dibutyl mesylate aldehyde was added at about 50 C.
The reaction mixture was stirred at 75 C for three hours or until
the reaction was completed. The cooled solution was poured into
water and extracted with ethyl acetate. The combined extracts were
washed with water several times, dried (MgSO.sub.4) and
concentrated in vacuo. Silica gel chromatographic purification of
the crude product gave 23.6 g (59%) of fluorobenzene dialdehyde as
a yellow oil: .sup.1H NMR (CDCl3) d 0.87 (t, J=7.05 Hz, 6H),
1.0-1.4 (m, 8H), 1.5-1.78 (m, 4H), 3.09 (s, 2H), 7.2-7.35 (m, 1H),
7.5-7.6 (m, 2H), 9.43 (s, 1H), 10.50 (d, J=2.62 Hz, 1H).
[0506] Step 2: Preparation of dibutyl 4-fluorobenzyl alcohol
[0507] To a solution of 22.6 g (69.8 mmol) of the dialdehyde
obtained from Step 1 in 650 mL of THF at -60 C was added 69.8 mL
(69.8 mmol) of DIBAL (1M in THF) via a syringe. The reaction
mixture was stirred at -40 C for 20 hours. To the cooled solution
at -40 C was added sufficient amount of ethyl acetae to quench the
excess of DIBAL, followed by 3 N HCl. The mixture was extracted
with ethyl acetate, washed with water, dried (MgSO.sub.4), and
concentrated in vacuo. Silica gel chromatographic purification of
the crude product gave 13.5 g (58%) of recovered starting material,
and 8.1 g (36%) of the desired fluorobenzyl alcohol as a colorless
oil: .sup.1H NMR (CDCl.sub.3) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4
(m, 8H), 1.5-1.72 (m, 4H), 1.94 (br s, 1H), 3.03 (s, 2H), 4.79 (s,
2H), 6.96 (dt, J=8.46, 3.02 Hz, 1H), 7.20 (dd, J=9.47, 2.82 Hz,
1H), 7.42 (dd, J=8.67, 5.64, IH), 9.40 (s, 1H).
[0508] Step 3: Preparation of dibutyl 4-fluorobenzyl bromide
[0509] To a solution of 8.1 g (25 mmol) of benzyl alcohol obtained
from Step 2 in 100 mL of DMF at -40 C was added 47 g (50 mmol) of
bromotriphenyphosphonium bromide (Aldrich). The resulting solution
was stirred cold for 30 min, then was allowed to warm to 0 C. To
the mixture was added 10% solution of sodium sulfite and ethyl
acetate. The extract was washed a few times with water, dried
(MgSO4), and concentrated in vacuo. The mixture was stirred in
small amount of ethyl acetate/hexane mixture (1:4 ratio) and
filtered through a pad of silica gel, eluting with same solvent
mixture. The combined filtrate was concentrated in vacuo to give
9.5 g (98%) of the desired product as a colorless oil: .sup.1H NMR
(CDCl.sub.3) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.55-1.78
(m, 4H), 3.11 (s, 2H), 4.67 (s, 2H), 7.02 (dt, J=8.46, 3.02 Hz,
1H), 7.15 (dd, J=9.47, 2.82 Hz, 1H), 7.46 (dd, J=8.67, 5.64, lH),
9.45 (s, 1H).
[0510] Step 4: Preparation of sulfonyl 4-fluorobenzyl bromide
[0511] To a solution of 8.5 g (25 mmol) of sulfide obtained from
Step 3 in 200 mL of CH.sub.2Cl.sub.2 at 0.degree. C. was added 15.9
g (60 mmol) of mCPBA (64% peracid). The resulting solution was
stirred cold for 10 min, then was allowed to stirred ambient
temperature for 5 hours. To the mixture was added 10% solution of
sodium sulfite and ethyl acetate. The extract was washed several
times with saturated Na.sub.2CO.sub.3, dried (MgSO.sub.4), and
concentrated in vacuo to give 10.2 g (98%) of the desired product
as a colorless oil: .sup.1H NMR (CDCl.sub.3) d 0.91 (t, J=7.05 Hz,
6H), 1.03-1.4 (m, 8H), 1.65-1.82 (m, 2H), 1.90-2.05 (m, 2H), 3.54
(s, 2H), 5.01 (s, 2H), 7.04-7.23 (m, 1H), 7.30 (dd, J=8.87, 2.42
Hz, 1H), 8.03 (dd, J=8.86, 5.64, 1H), 9.49 (s, 1H).
EXAMPLE 1396
[0512] 407 408
[0513] Generic Scheme X: The nucleophilic substitution of an
appropriately substituted 2-fluorobenzaldehyde with lithium sulfide
or other nucleophilic sulfide anion in polar solvent (such as DMF,
DMA, DMSO . . . etc), followed by the addition of dialkyl mesylate
aldehyde (X), provided a dialkyl benzene dialdehyde Y. DIBAL
reduction of the dialdehyde at low temperature yielded benzyl
alcohol monoaldehyde Z. Conversion of benzyl alcohol to benzyl
bromide, followed by oxidation of sulfide to sulfone yielded the
key intermediate W.
[0514] Preparation of N-propylsulfonic acid
[0515] To a solution of 51 mg (111 .mu.m) Compound X in ethanol
(400 .mu.l) was added 1,3 propane sultone (19.5 .mu.l, 222 um). The
reaction was stirred in a sealed vial at 55.degree. C. for 25 hr.
Sample was concentrated under a nitrogen stream and purified by
reversed phase chromatography using acetonitrile/water as eluent
(30-45%) and afforded the desired material as an off-white solid
(28.4 mg, 44%): .sup.1H NMR (CDCL.sub.3) d 0.82-0.96 (m, 6H),
1.11-1.52 (m of m, 10H), 1.58-1.72 (m, 1H), 2.08-2.21 (m, 1H),
2.36-2.50 (m, 2H), 2.93 (s, 6H), 3.02-3.22 (m of m, 5H), 3.58-3.76
(m, 2H), 4.15 (s, 1H), 5.51 (s, 1H), 6.45-6.58 (m, 1H), 6.92-7.02
(m, 1H), 7.35-7.41 (m, 1H), 7.41-7.51 (m, 2H), 8.08 (d, J=8.1 Hz,
1H), 8.12-8.25 (m, 1H); MS ES- M-H m/z 579.
EXAMPLE 1397
[0516] The 7-fluoro, 9-fluoro and 7,9-difluoro analogs of
benzothiepine compounds of this invention can be reacted with
sulfur and nitrogen nucleophiles to give the corresponding sulfur
and nitrogen substituted analogs. The following example
demonstrates the synthesis of these analogs.
[0517]
3,3-Dibutyl-5a-(4'-fluorophenyl)-4a-hydroxy-7-methylthio-2,3,4,5-te-
trahydrobenzothiepine-1,1-dioxide. 409
[0518] A mixture of 0.4 g Of
3,3-dibutyl-7-fluoro-5a-(4'-fluorophenyl)-4a--
hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, prepared by
previously described method, 0.12 g of sodium methanethiolate and
20 ml of DMF was stirred at 50 C for 3 days. An additional 0.1 g of
sodium methanethiolate was added to the reaction mixture and the
mixture was stirred for additional 20 h at 50 C then was
concentrated in vacuo. The residue was triturated with water and
extracte wiith ether. The ether extract was dried over MgSO.sub.4
and concentrated in vacuo to 0.44 g of an oil. Purification by HPLC
(10% EtOAc in hexane) gave 0.26 g of needles, mp 164-165.5 % C.
[0519]
3,3-Dibutyl-9-dimethylamino-7-fluoro-5a-(4'-fluorophenyl)-4a-hydrox-
y-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide and
7,9-Bis(dimethylamino)-3-
,3-dibutyl-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-
-1,1-dioxide. 410
[0520] A solution of 0.105 g of
3,3-dibutyl-7,9-difluoro-5a-(4'-fluorophen- yl)-4a-hydroxy-2,
3,4,5-tetrahydrobenzothiepine-1,1-dioxide, prepared by the method
described previously, in 20 ml of 2 N dimethylamine in THF was
heated at 160 C in a sealed Parr reactor overnight. The reaction
mixture was cooled and concentrated in vacuo. The residue was
triturated with 25 ml of water and extracted with ether. The ether
extract was dried over MgSO.sub.4 and concentrated in vacuo. The
resdue was purified by HPLC (10% EtOAc in hexane) to give 35 mg of
an earlier fraction which was identified as
3,3-dibutyl-9-dimethylamino-7-fluoro-5a-(4'-fluorophenyl)-4-
a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, MS (CI) m/e
480 (M.sup.++1), and 29 mg of a later fraction which was identified
as
7,9-bis(dimethylamino)-3,3-dibutyl-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,-
5-tetrahydrobenzothiepine-1,1-dioxide, MS (CI) m/e 505
(M.sup.++1).
[0521] The compounds of this invention can also be synthesized
using cyclic sulfate (XL, below) as the reagent as shown in the
following schemes XI and XII. The following examples describe a
procedure for using the cyclic sulfate as the reagent. 411
[0522] Scheme XI illustrates yet another route to
benzothiepine-1,1-dioxid- es, particularly 3,3-dialkyl analogs,
starting from the thiophenol XVIIIA. Thiophenol XVIIIA can be
reacted with cyclic sulfate XL to give the alcohol XLI which can be
oxidized to yield the aldehyde XLII. Aldehyde XLII itself can be
further oxidized to give the sulfone XLIII which can be cyclized to
give a stereoisomeric mixture of benzothiepine XLIVa and XLIVb.
[0523] Thiophenol XVIIIA can be prepared according to Scheme 3 as
previously discussed and has the following formula: 412
[0524] wherein R.sup.5, R.sup.x and q are as previously defined for
the compounds of formula I. Cyclic sulfate XL can be prepared
according to synthetic procedures known in the art and has the
following formula: 413
[0525] wherein R.sup.1 and R.sup.2 are as previously defined for
the compounds of formula I. Preferably, R.sup.1 and R.sup.2 are
alkyl; more preferably, they are selected from the group consisting
of methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl,
tert-butyl, and pentyl; and still more preferably, R.sup.1 and
R.sup.2 are n-butyl.
[0526] In the process of Scheme XI, thiophenol XVIIIA is initially
reacted with cyclic sulfate XL. This reaction preferably is
conducted in an aprotic solvent such as methoxyethyl ether. While
the reaction conditions such as temperature and time are not
narrowly critical, the reaction preferably is allowed to proceed at
about room temperature for about two hours. The reaction preferably
employs an approximately stoichiometric ratio of the starting
materials, with a slight excess of cyclic sulfate XL being
preferred. Reaction time and yield can be improved by using about
1.01 to 1.3 equivalents of cyclic sulfate XL for each equivalent of
thiophenol XVIIIA present. More preferably, this ratio is about 1.1
equivalents of cyclic sulfate XL for each equivalent of thiophenol
XVIIIA present.
[0527] In the process of the invention, thiophenol XVIIIA also is
treated with an abstracting agent. The abstracting agent can be
added to the solvent containing thiophenol XVIIIA prior to,
concurrently with, or after the addition of cyclic sulfate XL.
Without being held to a particular theory, it is believed the
abstracting agent removes the hydrogen atom from the mercaptan
group attached to the benzene ring of thiophenol XVIIIA. The
resulting sulfur anion of the thiophenol then reacts with cyclic
sulfate XL to open the sulfate ring. The sulfur anion of the
thiophenol then bonds with a terminal carbon atom of the open ring
sulfate. The terminal group at the unbonded end of the open ring
sulfate is the sulfate group.
[0528] The abstracting agent generally is a base having a pH
greater than about 10. Preferably, the base is an alkali metal
hydride such as sodium hydride, lithium hydride or potassium
hydride; more preferably, the base is sodium hydride. A slight
excess of abstracting agent is preferred relative to thiophenol
XVIIIA. Reaction time and yield is improved by using about 1.0 to
about 1.1 equivalents of abstracting agent for each equivalent of
thiophenol XVIIIA present. More preferably, this ratio is about 1.1
equivalents of abstracting agent for each equivalent of thiophenol
XVIIIA present.
[0529] The sulfate group of the intermediate product of the
reaction of thiophenol XVIIIA with cyclic sulfate XL is then
removed, preferably by hydrolysis, to yield alcohol XLI. Suitable
hydrolyzing agents include mineral acids, particularly hydrochloric
acid and sulfuric acid.
[0530] The several reactions involving thiophenol XVIIIA, cyclic
sulfate XL, the abstracting agent and the hydrolyzing agent can
take place in situ without the need for isolation of any of the
intermediates produced.
[0531] Alcohol XLI is then isolated by conventional methods (for
example, extraction with aqueous methyl salicylate) and oxidized
using standard oxidizing * agents to aldehyde XLII. Preferably, the
oxidizing agent is sulfur trioxide or pyridinium chlorochromate,
and more preferably, it is pyridinium chlorochromate. The reaction
is conducted in a suitable organic solvent such as methylene
chloride or chloroform.
[0532] Aldehyde XLII is then isolated by conventional methods and
further oxidized using standard oxidizing agents to
sulfone-aldehyde XLIII. Preferably, the oxidizing agent is
metachloroperbenzoic acid.
[0533] Sulfone-aldehyde XLIII likewise is isolated by conventional
methods and then cyclized to form the stereoisomeric benzothiepines
XLIVa and XLIVb. The cyclizing agent preferably is a base having a
pH between about 8 and about 9. More preferably, the base is an
alkoxide base, and still more preferably, the base is potassium
tert-butoxide.
[0534] The two oxidation steps of Scheme XI can be reversed without
adversely affecting the overall reaction. Alcohol XLI can be
oxidized first to yield a sulfone-alcohol which is then oxidized to
yield a sulfone-aldehyde. 414
[0535] Scheme XII illustrates still another route to
benzothiepine-1,1-dioxides, particularly 3,3-dialkyl analogs,
starting from the halobenzene L. Halobenzene L can be reacted with
cyclic sulfate XL disclosed above to give the alcohol LI which can
be oxidized to yield the sulfone-alcohol LII. Sulfone-alcohol LII
itself can be further oxidized to give the sulfone-aldehyde LIII
which can be cyclized to give a stereoisomeric mixture of
benzothiepine LIVa and LIVb.
[0536] Halobenzene L (which is commercially available or can be
synthesized from commercially available halobenzenes by one skilled
in the art) has the following formula: 415
[0537] wherein R.sup.5, R.sup.x, and q are as previously defined
for the compounds of formula I; R.sup.h is a halogen such as
chloro, bromo, fluoro or iodo; and R.sup.e is an electron
withdrawing group at the ortho or para position of the halobenzene,
and is preferably a p-nitro or o-nitro group. Cyclic sulfate XL can
be prepared as set forth in Scheme XI and can have the following
formula: 416
[0538] wherein R.sup.1 and R.sup.2 are as previously defined for
the compounds of formula I. Preferably, R.sup.1 and R.sup.2 are
alkyl; more preferably, they are selected from the group consisting
of methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl,
tert-butyl, and pentyl; and still more preferably, R.sup.1 and
R.sup.2 are n-butyl.
[0539] In the process of Scheme XII, halobenzene L is initially
reacted with cyclic sulfate XL. This reaction preferably is
conducted in an aprotic solvent such as dimethyl formamide or
N:N-dimethylacetamide, and more preferably, in dimethyl formamide.
Although the reaction conditions such as temperature and time are
not narrowly critical, the reaction preferably is allowed to
proceed at between about 70.degree. C. and about 90.degree. C. for
about 8 to 12 hours. More preferably, the reaction temperature is
maintained at about 80.degree. C. The reaction preferably employs
an approximately stoichiometric ratio of the starting materials,
with a slight excess of cyclic sulfate XL being preferred. Reaction
time and yield is improved by using about 1.1 to 1.3 equivalents of
cyclic sulfate XL for each equivalent of halobenzene L present.
More preferably, this ratio is about 1.1 equivalents of cyclic
sulfate XL for each equivalent of halobenzene L present.
[0540] In the process of the invention, halobenzene L also is
treated with an abstracting agent. The abstracting agent can be
added to the solvent containing halobenzene L prior to,
concurrently with, or after the addition of cyclic sulfate XL.
Without being held to a particular theory, it is believed the
abstracting agent removes the halogen atom attached to the benzene
ring of halobenzene L and replaces that atom with a divalent sulfur
atom. The resulting sulfur anion reacts with cyclic sulfate XL to
open the sulfate ring. The sulfur anion of the halobenzene then
bonds with a terminal carbon atom of the open ring sulfate. The
terminal group at the unbonded end of the open ring sulfate is the
sulfate group. The abstracting agent generally is a dialkali metal
sulfide, and preferably it is dilithium sulfide. A slight excess of
the abstracting agent is preferred relative to halobenzene L.
Reaction time and yield is improved by using about 1.01 to 1.3
equivalents of abstracting agent for each equivalent of halobenzene
L present. More preferably, this ratio is about 1.05 equivalents of
abstracting agent for each equivalent of halobenzene L present.
[0541] The sulfate group of the product of the reaction of
thiophenol XVIIIA with cyclic sulfate XL is then removed,
preferably by hydrolysis, to yield a mixture of an ester and
alcohol LI. Suitable hydrolyzing agents include mineral acids,
particularly hydrochloric acid and sulfuric acid. The ester is then
converted to alcohol LI by treatment with an alkali metal
hydroxide, preferably sodium hydroxide.
[0542] The several reactions involving halobenzene L, cyclic
sulfate XL, the abstracting agent and the hydrolyzing agent can
take place in situ without the need to isolate any of the
intermediates produced.
[0543] Alcohol LI is then isolated by conventional methods (for
example, extraction with aqueous methyl salicylate) and oxidized
using standard oxidizing agents to sulfone-alcohol LII. Preferably,
the oxidizing agent is metachloroperbenzoic acid. The reaction is
conducted in a suitable organic solvent such as methylene chloride
or chloroform.
[0544] Sulfone-alcohol LII is then isolated by conventional methods
and further oxidized using standard oxidizing agents to
sulfone-aldehyde LIII. Preferably, the oxidizing agent is sulfur
trioxide or pyridinium chlorochromate, and more preferably, it is
pyridinium chlorochromate. The reaction is conducted in a suitable
organic solvent such as methylene chloride or chloroform.
[0545] Sulfone-aldehyde XLIII is then converted to the desired
benzothiepine-1,1-dioxides according to the procedure previously
set forth in Scheme XI.
[0546] The two oxidation steps can be reversed without adversely
affecting the overall reaction. Alcohol XLI can be oxidized first
to yield an aldehyde which is then oxidized to yield a
sulfone-aldehyde.
[0547] Use of the cyclic sulfate reagent instead of a mesylate
reagent in Schemes XI and XII improves the overall yield and avoids
many of the purification difficulties encountered relative to those
reaction schemes proceeding through a mesylate intermediate.
Overall yields are significantlyimproved when a cyclic sulfate is
used instead of a mesylate reagent. In addition, chromatographic
separation of the intermediate product of the cyclic sulfate
coupling step of the reaction is not necessary. For example, in
Schemes XI and XII the intermediate is a water soluble alkali metal
salt and the impurities can be removed by extraction with ether.
The intermediate is then hydrolyzed to the desired alcohol.
EXAMPLE CORRESPONDING TO SCHEME XI:
[0548] Step 1: Preparation of 2,2-dibutyl-1,3-propanediol: 417
[0549] Lithium aluminum hydride (662 ml, 1.2 equivalents, 0.66 mol)
in 662 mL of 1M THF was added dropwise to a stirred solution of
dibutyl-diethylmalonate (150 g, 0.55 mol) (Aldrich) in dry THF
(700ml) while maintaining the temperature of the reaction mixture
at between about -20.degree. C. to about 0.degree. C. using an
acetone/dry ice bath. The reaction mixture was then stirred at room
temperature overnight. The reaction was cooled to -20.degree. C.
and 40 ml of water, 80 ml of 10% NaOH and 80 ml of water were
successively added dropwise. The resulting suspension was filtered.
The filtrate was dried over sodium sulphate and concentrated under
vacuum to give 98.4 g (yield 95%) of the diol as an oil. Proton
NMR, carbon NMR and MS confirmed the product.
[0550] Step 2: Dibutyl-cyclic-sulfite: 418
[0551] A solution of the dibutyl-diol of step 1 (103 g, 0.5478 mol)
in anhydrous methylene chloride (500 ml) and triethylamine (221 g,
4 equivalents, 2.19 mol) was stirred at 0.degree. C. under
nitrogen. Thionyl chloride (97.78 g, 0.82 mol) was added dropwise
to the mixture. Within 5 minutes the solution turned to yellow and
then to black when the addition was completed within about half an
hour. The reaction was completed within 3 hours (gas chromatography
confirmed no starting material was left). The mixture was washed
with ice water twice, and brine twice. The organic phase was dried
over magnesium sulphate and concentrated under vacuum to give 128 g
(yield 100%) of the dibutyl-cyclic-sulfite as a black oil. NMR and
MS were consistent with the product.
[0552] Step 3: Dibutyl-cyclic sulfate: 419
[0553] To a solution of the dibutyl-cyclic-sulfite of step 2 (127.5
g, 0.54 mol) in 600 ml acetonitrile and 500 ml of water cooled in
an ice bath under nitrogen was added ruthenium(III) chloride (1 g)
and sodium periodate (233 g, 1.08 mol). The reaction was stirred
overnight and the color of the solution turned black. Gas
chromatography confirmed there was no starting material left. The
mixture was extracted once with 300 ml of ether and three times
with brine. The organic phase was dried over magnesium sulphate and
passed through celite. The filtrate was concentrated under vacuum
and gave 133 g (yield 97.8%) of the dibutyl-cyclic-sulfate as an
oil. Proton NMR, carbon NMR and MS confirmed the product.
[0554] Step 4: 2-[(2-4'-fluorobenzyl-4-methylphenylthio)
methyl]-2-butylhexanol: 420
[0555] A 60% oil dispersion of sodium hydride (0.27 g, 6.68 mmole)
was washed with hexane. The hexane was decanted and 20 ml of
methoxyethyl ether was added to the washed sodium hydride and
cooled in an ice bath. A mixture of diphenylmethane thiophenol
(1.55 g, 6.68 mmole) in 10 ml of methoxyethyl ether was added
dropwise over a period of 15 minutes. A mixture of the
dibutyl-cyclic-sulfate of step 3 (2.17 g, 8.66 mmole) in 10 ml of
methoxyethyl ether was then added. The resulting mixture was
stirred for 30 minutes at 0.degree. C. and 1 hour at room
temperature under nitrogen. Gas chromatography confirmed there was
no thiol left. The solvent was evaporated and washed with water and
ether two times. The water layer was separated and 20 ml of 10%
NaOH was added. This aqueous mixture was boiled for 30 minutes,
cooled, acidified with 6N HCI, and boiled for 10 minutes. The
mixture was cooled and extracted with ether. The organic layer was
washed successively with water and brine, dried over magnesium
sulphate, and concentrated under vacuum to give 2.47 g (yield
92.5%) of the hexanol as an oil. Proton NMR, C13-NMR and MS
confirmed the product.
[0556] Step 5:
2-[(2-4'-fluorobenzyl-4-methylphenylthio)methyl]-2-butylhex- anal:
421
[0557] To a solution of the hexanol of step 4 (2 g, 4.9 mmole) in
40 ml of methylene chloride cooled in an ice bath under nitrogen
was added pyridinium chlorochromate (2.18 g, 9.9 mmole). The
reaction mixture was stirred for 3 hours and filtered through
silica gel. The filtrate was concentrated under vacuum to give 1.39
g (yield 70%) of the hexanal as an oil. Proton NMR, carbon NMR and
MS confirmed the product.
[0558] Step 6: 2-[(2-4'-fluorobenzyl-4-methylphenylsulfonyl)
methyl]-2-butylhexanal 422
[0559] To a solution of the hexanal of step 5 (0.44 g, 1.1 mmole)
in 20 ml of methylene chloride cooled by an ice bath under nitrogen
was added 70% metachloroperbenzoic acid (0.54 g, 2.2 mmole). The
reaction mixture was stirred for 18 hours and filtered.
[0560] The filtrate was washed successively with 10%
NaOH(3.times.), water, and brine, dried over magnesium sulphate,
and concentrated under vacuum to give 0.42 g (yield 90%) of the
hexanal as an oil. Proton NMR, carbon NMR and MS confirmed the
product.
[0561] Step 7:
Cis-3,3-dibutyl-7-methyl-5-(4'-fluoro-phenyl)-2,3,4,5-tetra-
hydrobenzothiepine-1,1-dioxide: 423
[0562] A mixture of the hexanal of step 6 (0.37 g, 0.85 mmole) in
30 ml of anhydrous THF was stirred in an ice bath at a temperature
of about 0.degree. C. Potassium-tert-butoxide (102 mg, 0.85 mmole)
was then added. After 3 hours thin layer chromatography confirmed
the presence of the product and a small amount of the starting
material. The crude reaction mixture was acidified with 10% HCl,
extracted with ether, washed successively with water and brine,
dried with MgSO.sub.4, and concentrated under vacuum. This
concentrate was purified by HPLC (10% EtOAc-Hexane). The first
fraction came as 0.1 g of the starting material in the form of an
oil. The second fraction yielded 0.27 g (75% yield) of the desired
benzothiepine as a white solid. Proton NMR, carbon NMR and MS
confirmed the product. (M+H=433).
EXAMPLE CORRESPONDING TO SCHEME XII
[0563] Step 1:
2-[(2-4'-methoxybenzyl-4-nitrophenylthio)-methyl]-2-butylhe- xanol:
424
[0564] Chlorodiphenylmethane (10 g) was dissolved in 25 ml of DMF
and lithium sulfide [1.75 g, 1.05 equivalents] was added. The
solution color changed to red. The reaction mixture was heated at
80.degree. C. overnight. The solution was cooled to 0.degree. C.
and dibutyl-cyclic-sulfate (9.9 g; prepared as set forth in Step 3
of the Scheme XI examples) in 10 ml of DMF was added and stirred at
room temperature overnight. The solvent was evaporated and washed
successively with water and ether (three times). The water layer
was separated and 40 ml of concentrated sulfuric acid was added and
the reaction mixture boiled overnight. The mixture was cooled and
extracted with ethyl acetate. The organic layer was washed
successively with water and brine, dried over magnesium sulphate,
and concentrated under vacuum. The product was boiled with 3M of
NaOH for 1 hour. The mixture was cooled and extracted with ethyl
acetate. The organic layer was washed successively with water and
brine, dried over magnesium sulphate, and concentrated under
vacuum. The concentrate was dissolved in methylene chloride,
filtered through silica gel, eluted with 20% ethyl acetate and
hexane, and concentrated under vacuum to give 11.9 g (yield 74%) of
the hexanol as an oil. Proton NMR, C13-NMR and MS confirmed the
product. 425
[0565] To a solution of the hexanol of step 1 (6 g, 13 mmole) in 50
ml methylene chloride cooled in ice bath under nitrogen was added
70% MCPBA (8.261 g, 33 mmole). The reaction was stirred for 18
hours at room temperature and filtered. The filtrate was washed
successively with 10% NaOH (3.times.), water and brine, dried over
magnesium sulphate, and concentrated under vacuum. The concentrate
was dissolved in methylene chloride, filtered through silica gel,
eluted with 20% ethyl acetate and hexane, and concentrated under
vacuum to give 5 g (yield 77.7%) of the hexanal as a white solid,
MP 58-60.degree. C. Proton NMR, C13-NMR and MS confirmed the
product.
EXAMPLE 1398
[0566] 426
[0567] To a solution of 6.0 g of dibutyl 4-fluorobenzene dialdehyde
of Example 1395 (14.3 mmol) in 72 mL of toluene and 54 mL of
ethanol was added 4.7 g 3-nitrobenzeneboronic acid (28.6 mmol), 0.8
g of tetrakis (triphenylphosphine) palladium(0) (0.7 mmol) and 45
mL of a 2 M solution of sodium carbonate in water. This
heterogeneous mixture was refluxed for three hours, then cooled to
ambient temperature and partitioned between ethyl acetate and
water. The organic layer was dried over MgSO.sub.4 and concentrated
in vacuo. Purification by silica gel chromatography (Waters
Prep-2000) using ethyl acetate/hexanes (25/75) gave 4.8 g (73%) of
the title compound as a yellow solid. .sup.1H NMR (CDCl.sub.3) d
0.88 (t, J=7.45 Hz, 6H), 0.99-1.38 (m, 8H), 1.62-1.75 (m, 2H),
1.85-2.00 (m, 2H), 3.20 (s, 2H), 4.59 (s, 2H), 6.93 (dd, J=10.5 and
2.4 Hz, 1H), 7.15 (dt, J=8.4 and 2.85 Hz, lH), 7.46-7.59 (m, 2H),
8.05-8.16 (m, 3H), 9.40 (s, 1H). 427
[0568] A solution of 4.8 g (10.4 mmol) of 2 in 500 mL THF was
cooled to 0.degree. C. in an ice bath. 20 mL of a 1 M solution of
potassium t-butoxide was added slowly, maintaining the temperature
at <5.degree. C. Stirring was continued for 30 minutes, then the
reaction was quenched with 100 mL of saturated ammonium chloride.
The mixture was partitioned between ethyl acetate and water; the
organic layer was washed with brine, then dried (MgSO.sub.4) and
concentrated in vacuo. Purification by silica gel chromatography
through a 100 ml plug using CH.sub.2Cl.sub.2 as eluent yielded 4.3
g (90%) of 3 as a pale yellow foam. .sup.1H NMR (CDCl.sub.3) d 0.93
(t, J=7.25 Hz, 6H), 1.00-1.55 (m, 8H), 1.59-1.74 (m, 3H), 2.15-2.95
(m, 1H), 3.16 (q.sub.AB, J.sub.AB=15.0 Hz, AV =33.2 Hz, 2H), 4.17
(d, J=6.0 Hz, 1H), 5.67 (s, 1H), 6.34 (dd, J=9.6 and 3.0 Hz, 1H),
7.08 (dt, J=8.5 and 2.9 Hz, 1H), 7.64 (t, J=8.1 Hz, 1H), 7.81 (d,
J=8.7 Hz, 1H), 8.13 (dd, J=9.9 and 3.6 Hz, 1H), 8.23-8.30 (m, 1H),
8.44 (s, 1H). MS(FABH.sup.+) m/e (relative intensity) 464.5 (100),
446.6 (65). HRMS calculated for M+H 464.1907. Found 464.1905.
428
[0569] To a cooled (0.degree. C.) solution of 4.3 g (9.3 mmol) of 3
in 30 ml THF contained in a stainless steel reaction vessel was
added 8.2 g dimethyl amine (182 mmol). The vessel was sealed and
heated to 110.degree. C. for 16 hours. The reaction vessel was
cooled to ambient temperature and the contents concentrated in
vacuo. Purification by silica gel chromatography (Waters Prep-2000)
using an ethyl acetate/hexanes gradient (10-40% ethyl acetate) gave
4.0 g (88%) of 4 as a yellow solid. .sup.1H NMR (CDCl.sub.3) d
0.80-0.95 (m, 6H), 0.96-1.53 (m, 8H), 1.60-1.69 (m, 3H), 2.11-2.28
(m, 1H), 2.79 (s, 6H), 3.09 (q.sub.AB, J.sub.AB=15.0 Hz, DV=45.6
Hz, 2H), 4.90 (d, J=9.0 Hz, 1H), 5.65 (s, 1H), 5.75 (d, J=2.1 Hz,
1H), 6.52 (dd, J=9.6 and 2.7 Hz, 1H), 7.59 (t, J=8.4 Hz, 1H), 7.85
(d, J=7.80 Hz, 1H), 7.89 (d, J=9.0 Hz, 1H), 8.20 (dd, J=8.4 and 1.2
Hz, 1H), 8.43 (s, 1H). MS(FABH+) m/e (relative intensity) 489.6
(100), 471.5 (25). HRMS calculated for M+H 489.2423. Found
489.2456. 429
[0570] To a suspension of 1.0 g (2.1 mmol) of 4 in 100 ml ethanol
in a stainless steel Parr reactor was added 1 g 10% palladium on
carbon. The reaction vessel was sealed, purged twice with H.sub.2,
then charged with H.sub.2 (100 psi) and heated to 45.degree. C. for
six hours. The reaction vessel was cooled to ambient temperature
and the contents filtered to remove the catalyst. The filtrate was
concentrated in vacuo to give 0.9 g (96%) of 5. .sup.1H NMR
(CDCl.sub.3) d 0.80-0.98 (m, 6H), 1.00-1.52 (m, 10H), 1.52-1.69 (m,
1H), 2.15-2.29 (m, 1H), 2.83 (s, 6H), 3.07 (q.sub.AB, J.sub.AB=15.1
Hz, DV =44.2 Hz, 2H), 3.70 (s, 2H), 4.14 (s, 1H), 5.43 (s, 1H),
6.09 (d, J=2.4 Hz, 1H), 6.52 (dd, J=12.2 and 2.6 Hz, 1H), 6.65 (dd,
J=7.8 and 1.8 Hz, 1H), 6.83 (s, 1H), 6.93 (d, J=7.50 Hz, 1H), 7.19
(t, J=7.6 Hz, 1H), 7.89 (d, J=8.9 Hz, IH). MS(FABH+) m/e (relative
intensity) 459.7 (100). HRMS calculated for M+H 459.2681. Found
459.2670.
[0571] Step 6. Preparation of 6
[0572] To a solution of 914 mg (2.0 mmol) of 5 in 50 ml THF was
added 800 mg (4.0 mmol) 5-bromovaleroyl chloride. Next was added 4
g (39.6 mmol) TEA. The reaction was stirred 10 minutes, then
partitioned between ethyl acetate and brine. The organic layer was
dried (MgSO.sub.4) and concentrated in vacuo. Purification by
silica gel chromatography through a 70 ml MPLC column using a
gradient of ethyl acetate(20-50%) in hexane as eluent yielded 0.9 g
(73%) of 6 as a pale yellow oil. .sup.1H NMR (CDCl.sub.3) d
0.84-0.95 (m, 6H), 1.02-1.53 (m, 10H), 1.53-1.68 (m, 1H), 1.80-2.00
(m, 4H), 2.12-2.26 (m, 4H), 2.38 (t, J=6.9 Hz, 2H), 2.80 (s, 6H),
3.07 (q.sub.AB, J.sub.AB=15.6 Hz, DV =40.4 Hz, 2H), 3.43 (t, J=6.9
Hz, 2H), 4.10 (s, 1H), 5.51 (s, 1H), 5.95 (d, J=2.4 Hz, 1H), 6.51
(dd, J=9.3 and 2.7 Hz, 1H), 7.28 (s, 1H), 7.32-7.41 (m, 2H), 7.78
(d, J 8.1 Hz, 1H), 7.90 (d, J=9.0 Hz, 1H). 430
[0573] To a solution of 0.9 g (1.45 mmol) of 6 in 25 ml
acetonitrile add 18 g (178 mmol) TEA. Heat at 55.degree. C. for 16
hours. The reaction mixture was cooled to ambient temperature and
concentrated in vacuo. Purification by reverse-phase silica gel
chromatography (Waters Delta Prep 3000) using an acetonitrile
/water gradient containing 0.05% TFA (20-65% acetonitrile) gave 0.8
g (73%) of 7 as a white foam. .sup.1H NMR (CDCl.sub.3) d 0.80-0.96
(m, 6H), 0.99-1.54 (m, 19H), 1.59-1.84 (m, 3H), 2.09-2.24 (m, 1H),
2.45-2.58 (m, 2H), 2.81 (s, 6H), 3.09 (q.sub.AB, J.sub.AB=15.6 Hz,
DV=18.5 Hz, 2H), 3.13-3.31 (m, 8H), 4.16 (s, 1H), 5.44 (s, 1H),
6.08 (d, J=1.8 Hz, 1H), 6.57 (dd, J=9.3 and 2.7 Hz, 1H), 7.24 (t,
J=7.5 Hz, 1H), 7.34 (t, J=8.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.74
(s, 1H), 7.88 (d, J=9.0 Hz, 1H), 9.22 (s, 1H). HRMS calcd 642.4304;
observed 642.4343.
EXAMPLE 1398A
[0574] 431
[0575] In an inert atmosphere, weigh out 68.3 gms phosphorus
pentachloride (0.328mole Aldrich 15,777-5) into a 2-necked 500ml
round bottom flask. Fit flask with a N.sub.2 inlet adapter and suba
seal. Remove from inert atmosphere and begin N.sub.2 purge. Add
50mls anhydrous chlorobenzene (Aldrich 28,451-3) to the PCl.sub.5
via syringe and begin stirring with magnetic stir bar.
[0576] Weigh out 60 gms 2-chloro-5-nitrobenzoic acid (0.298 mole
Aldrich 12,511-3). Slowly add to the chlorobenzene solution while
under N.sub.2 purge. Stir at room temperature overnight. After
stirring at room temperature for .about.20 hrs, place in oil bath
and heat at 50C for 1 hr. Remove chlorobenzene by high vacuum. Wash
residue with anhydrous hexane. Dry acid chloride wt=61.95 gms.
Store in inert and dry atmosphere.
[0577] In inert atmosphere, dissolve acid chloride with 105 mls
anhydrous anisole (0.97 mole Aldrich 29,629-5). Place solution in a
2-necked 500ml round bottom flask.
[0578] Weigh out 45.1 gms aluminum chloride (0.34 moles Aldrich
29,471-3) and place in a solid addition funnel. Fit reaction flask
with addition funnel and a N.sub.2 inlet adapter. Remove from inert
atmosphere. Chill reaction solution with ice bath and begin N.sub.2
purge. Slowly add AlC.sub.3 to chilled solution. After addition is
complete, allow to warm to room temperature. Stir overnight .
[0579] Quench reaction by pouring into a solution of 300 mls 1N HCl
and ice. Stir 15 min. Extract twice with ether. Combine organic
layers and extract twice with 2% NaOH, then twice with deionized
H.sub.2O. Dry with MgSO.sub.4, filter and rotovap to dryness.
Remove anisole by high vacuum. Crystalize product from 90% ethanol
10% ethyl acetate. Dry on vacuum line. Wt=35.2 gms. Yield 41%.
Obtain NMR and mass spec (m/z=292). 432
[0580] Dissolve 38.10 gms (0.131 moles) of the benzophenone from
step 1 in 250 mls anhydrous methylene chloride. Place in a 3 liter
flask fitted with N.sub.2 inlet, addition funnel and stopper. Stir
with magnetic stir bar. Chill solution with ice bath.
[0581] Prepare a solution of 39.32 gms trifluoromethane sulfonic
acid (0.262 mole Aldrich 15,853-4) and 170 mls anhydrous methylene
chloride. Place in addition funnel and add dropwise to chilled
solution under N.sub.2. Stir 5 minutes after addition is
complete.
[0582] Prepare a solution of 22.85 gms triethyl silane (0.197 mole
Aldrich 23,019-7) and 170mls anhydrous methylene chloride. Place in
addition funnel and add dropwise to chilled solution under N.sub.2.
Stir 5 minutes after addition is complete.
[0583] Prepare a second solution of 39.32 gms trifluoromethane
sulfonic acid and 170mls anhydrous methylene chloride. Place in
addition funnel and add dropwise to chilled solution under N.sub.2.
Stir 5 minutes after addition is complete.
[0584] Prepare a second solution of 22.85 gms triethyl silane and
170 mls anhydrous methylene chloride. Place in addition funnel and
add dropwise to chilled solution under N.sub.2. After all additions
are made allow to slowly warm to room temperature overnight. Stir
under N.sub.2 overnight.
[0585] Prepare 1300 mls saturated NaHCO.sub.3 in a 4 liter beaker.
Chill with ice bath. While stirring vigorously, slowly add reaction
mixture. Stir at chilled temperature for 30 min. Pour into a
separatory funnel and allow separation. Remove organic layer and
extract aqueous layer 2 times with methylene chloride. Dry organic
layers with MgSO.sub.4. Crystallize from ethanol. Dry on vacuum
line. Dry wt=28.8 gms. Confirm by NMR and mass spec (m/z=278).
[0586] Step 3 433
[0587] Dissolve 10.12 gms (0.036 moles) of product 2 with 200 mls
anhydrous DMSO. Place in a 500 ml round bottom flask with magnetic
stir bar. Fit flask with water condenser, N.sub.2 inlet, and
stopper. Add 1.84 gms Li.sub.2S (0.040 moles Aldrich 21,324-1).
Place flask in oil bath and heat at 75.degree. C. under N.sub.2
overnight then cool to room temperature.
[0588] Weigh out 10.59 gms dibutyl mesylate (0.040 moles). Dissolve
with anhydrous DMSO and add to reaction solution. Purge well with
N.sub.2, heat overnight at 80.degree. C.
[0589] Cool to room temperature. Prepare 500 mls of 5% acetic acid
in a 2 liter beaker. While stirring, slowly add reaction mixture.
Stir 30 min. Extract with ether 3 times. Combine organic layers and
extract with water and sat'd NaCl. Dry organic layer with
MgSO.sub.4, filter and rotovap to dryness. Dry oil on vacuum line.
Obtain pure product by column chromatography using 95% hexane and
5% ethyl acetate as the mobile phase. Dry wt=7.8 gms. Obtain NMR
and mass spec (m/z=444). 434
[0590] Dissolve 9.33 gms (0.021 moles) of product 3 with 120 mls
anhydrous methylene chloride. Place in a 250 ml round bottom flask
with magnetic stir bar. Fit flask with N.sub.2 inlet and stopper.
Chill solution with ice bath under N.sub.2 purge. Slowly add 11.54
gms 3-chloroperbenzoic acid (0.0435 moles, Fluka 25800,
.about.65%). After addition is complete warm to room temperature
and monitor reaction by TLC. Reaction goes quickly to the
sulphoxide intermediate but takes 8 hrs to convert to the sulphone.
Chill solution over night in freezer. Filter solid from reaction,
extract filtrate with 10% K.sub.2CO.sub.3. Extract aqueous layer
twice with methylene choride. Combine organic layers and dry with
MgSO.sub.4. Filter and rotovap to dryness. Obtain pure product by
crystallizing from ethanol or isolating by column chromatography.
Obtain NMR and mass spec (m/z=476).
[0591] Step 5 435
[0592] Reaction is done in a 300 ml stainless steel Parr stirred
mini reactor. Place 9.68 gms (0.0204 moles) of product 4 in reactor
base. Add 160 mls ethanol. For safety reasons next two compounds
are added in a N.sub.2 atmosphere glove bag. In glove bag, add 15.3
mls formaldehyde (0.204 moles, Aldrich 25,254-9, about 37 wt % in
water) and 1.45 gms 10% Pd/Carbon (Aldrich 20,569-9). Seal reactor
before removing from glove bag. Purge reactor three times with
H.sub.2. Heat to 55.degree. C. under H.sub.2. Run reaction at 200
psig H.sub.2, 55.degree. C., and a stir rate of 250 rpm. Run
overnight under these conditions.
[0593] Cool reactor and vent H.sub.2. Purge with N.sub.2. Check
progress of run by TLC. Reaction is a mixture of desired product
and intermediate. Filter reaction mixture over a bed of celite
washing well with ether. Rotovap and redissolve with ether. Extract
with water. Dry organic layer with MgSO.sub.4, filter and rotovap
to dryness. Dry on vacuum line.
[0594] Charge reactor again with same amounts, seal reactor and run
overnight under same conditions. After second run all of the
material has been converted to the desired product. Cool and vent
H.sub.2 pressure. Purge with N.sub.2. Filter over a bed of celite,
washing well with ether. Rotovap to dryness. Dissolve with ether
and extract with water. Dry organic layer with MgSO.sub.4, filter
and rotovap to dryness. Dry on vacuum line. Obtain NMR and mass
spec (m/z=474).
[0595] Step 6 436
[0596] Dissolve 8.97 gms (0.0189 mole) of product 5 with 135 mls
anhydrous THF. Place in a 250 ml round bottom flask with magnetic
stir bar. Fit flask with N.sub.2 inlet and stopper. Chill solution
with ice/salt bath under N.sub.2 purge. Slowly add 2.55 gms
potassium t-butoxide (0.227 mole Aldrich 15,667-1). After addition
is complete, continue to stir at -10.degree. C. monitoring by TLC.
Once reaction is complete, quench by adding 135 mls 10% HCl
stirring 10 min. Extract three times with ether. Dry organic layer
with MgSO.sub.4, filter and rotovap to dryness. Crystallize from
ether. Obtain NMR and mass spec (m/z=474).
[0597] Step 7 437
[0598] Dissolve 4.67 gms (0.01 moles) of product 6 with 100 mls
anhydrous chloroform. Place in a 250 ml round bottom flask with
magnetic stir bar. Fit flask with N.sub.2 inlet adapter and suba
seal. Chill solution with dry ice /acetone bath under a N2 purge.
Slowly add, via syringe, 2.84 mls boron tribromide (0.03 moles
Aldric h 20,220-7). Stir at cold temperature for 15 min after
addition then allow to warm to room temperature. Monitor reaction
progress by TLC. Reaction is usually complete in 3 hrs.
[0599] Chill solution with ice bath. Quench with 100 mls 10%
K.sub.2CO.sub.3 while stirring rapidly. Stir 10 min. then transfer
to sep funnel and allow separation. Remove aqueous layer. Extract
organic layer once with 10% HCl, once H.sub.2O, and once with
saturated NaCl solution. Dry organic layer with MgSO.sub.4, filter
and rotovap to dryness. Crystallize product from ether. Obtain NMR
and mass spec (m/z=460).
[0600] Step 8 438
[0601] Weigh 0.38 gms NaH (9.57 mmoles Aldrich 19,923-0 60% disp.
in mineral oil) in a 250 ml round bottom flask with magnetic stir
bar. Fit flask with N.sub.2 inlet and stopper. Chill NaH with ice
bath and begin N.sub.2 purge.
[0602] Dissolve 4.0 gms (8.7 mmoles) of product 7 with 60 mls
anhydrous DMF. Add to the cold NaH. Stir at cold temperature for 30
min. Add 1.33 gms K.sub.2CO.sub.3 (9.57 mmoles Fisher P-208).
[0603] Dissolve 16.1 gms 1,2-bis-(2-iodoethoxy)ethane (43.5 mmoles
Aldrich 33,343-3) with 60 mls anhydrous DMF. Add to cold reaction
mixture. Warm to room temperature then heat to 40.degree. C.
overnight under N.sub.2.
[0604] Cleanup by diluting with ether and extracting sequentially
with 5% NaOH, H.sub.2O, and saturated NaCl. Dry organic layer with
MgSO.sub.4, filter and dry. Obtain pure product by column
chromatography using 75% hexane 25% ethyl acetate as the mobile
phase. Obtain NMR and mass spec (m/z=702).
[0605] Step 9 439
[0606] Dissolve 1.0 gms (1.43 mmoles) of product 8 with 10 mls
anhydrous acetonitrile. Place in a 3 ounce Fischer-Porter pressure
reaction vessel with magnetic stir bar. Add 2.9 gms triethyl amine
(28.6 mmoles Aldrich 23,962-3) dissolved in 10 mls anhydrous
acetonitrile. Purge well with N.sub.2 then close system Heat at
45.degree. C. Monitor reaction by TLC. Reaction is usually complete
in 48 hrs.
[0607] Perform cleanup by removing acetonitrile under vacuum.
Redissolve with anhydrous chloroform and precipitate quaternary
ammonium salt with ether. Repeat several times. Dry to obtain
crystalline product. Obtain NMR and mass spec (m/z-675).
EXAMPLE 1399
[0608] Step 1. Preparation of 1 440
[0609] To a solution of 144 g of KOH (2560 mmol) in 1.1 L of DMSO
was added 120 g of 2-bromobenzyl alcohol (641 mmol) slowly via
addition funnel. Then was added 182 g of methyliodide (80 mL, 1282
mmol) via addition funnel. Stirred at ambient temperature for
fifteen minutes. Poured reaction contents into 1.0 L of water and
extracted three times with ethyl acetate. The organic layer was
dried over MgSO.sub.4 and concentrated in vacuo. Purified by
silica-gel chromatography through a 200 mL plug using hexanes
(100%) as elutant yielded 103.2 g (80%) of 1 as a clear colorless
liquid. .sup.1H NMR (CDCl.sub.3) d 3.39 (s, 3H), 4.42 (s, 2H),
7.18-7.27 (m, 2H), 7.12 (d, J=7.45, 1H), 7.50 (s, 1H).
[0610] Step 2. Preparation of 2 441
[0611] To a cooled (-78.degree. C.) solution of 95 g (472 mmol) of
1 in 1.5 L THF was added 240 mL of 2.5 M n-butyl lithium (576
mmol). The mixture was stirred for one hour, and then to it was
added 180 g of zinc iodide (566 mmol) dissolved in 500 ml THF. The
mixture was stirred thirty minutes, allowed to warm to 5 C, cooled
to -10.degree. C. and to it was added 6 g of Pd(PPh.sub.3).sub.4
(5.2 mmol) and 125 g 2,5-difluorobenzoyl chloride (708 mmol). The
mixture was stirred at ambient temperature for 18 hoursand then
cooled to 10.degree. C., quenched with water, partitioned between
ethyl acetate and water, and washed organic layer with 1N HCL and
with 1N NaOH. The organic layer was dried over MgSO.sub.4 and
concentrated in vacuo. Purification by silica gel chromatography
(Waters Prep-500) using 5% ethyl acetate/hexanes as elutant gave
53.6 g (43%) of 2 as an orange oil. .sup.1H NMR (CDCl.sub.3) d 3.40
(s, 3H), 4.51 (s, 2H), 7.12-7.26 (m, 3H), 7.47 (t, J=7.50, 1H),
7.57 (d, J=7.45, 1H), 7.73 (d, J=7.45, 1H), 7.80 (s, 1H).
[0612] Step 3. Preparation of 3 442
[0613] A solution of 53 g (202.3 mmol) of 2 and 11.2 g Li2S (242.8
mmol) in 250 mL DMF was heated to 100.degree. C. for 18 hours. The
reaction was cooled (0.degree. C.) and 60.7 g of X (the cyclic
sulfate compound of example 1397) (242.8 rmmol) in 50 mL DMF was
added. Stirred at ambient temperature for 18 hours then condensed
in vacuo. Added 1 L water to organic residue and extracted twice
with diethyl ether. Aqueous layer acidified (pH 1) and refluxed 2
days. Cooled to ambient temperature and extracted with methylene
chloride, dried organic layer over MgSO.sub.4 and condensed in
vacuo. Purification by silica gel chromatography (Waters Prep-500)
using 10% ethyl acetate / hexanes as elutant gave 42.9 g (48%) of 3
as a yellow oil. .sup.1H NMR (CDCl.sub.3) d 0.86 (t, J=7.25 Hz,
6H), 1.10 - 1.26 (m, 12H), 2.83 (s, 2H), 3.32 (s, 2H), 3.40 (s,
3H), 4.48 (s, 3H), 7.02 (dd, J=8.26 Hz and 2.82 Hz, 1H), 7.16 (dt,
J=8.19 Hz and 2.82 Hz, 1H), 7.45 (t, J=7.65 Hz, 1H), 7.56-7.61 (m,
2H), 7.69 (d, J=7.85 Hz, 1H), 7.74 (s, 1H).
[0614] Step 4. Preparation of 4 443
[0615] To a cooled (-40.degree. C.) solution of 42.9 g (96.2 mmol)
of 3 in 200 mL of methylene chloride was added 21.6 g
trifluoromethane sulfonic acid (12.8 mL, 144 mmol) followed by the
addition of 22.4 g triethyl silane (30.7 mL, 192.4 mmol). Stirred
at -20.degree. C. for two hours, quenched with water and warmed to
ambient temperature. Partitioned between methylene chloride and
water, dried the organic layer over MgSO.sub.4 and condensed in
vacuo. Purification by silica gel chromatography (Waters Prep-500)
using 10% ethyl acetate/ hexanes as elutant gave 24.2 g (60%)of 4
as a oil. .sup.1NMR (CDCl.sub.3) d 0.89 (t, J=7.05 Hz, 6H), 1.17 -
1.40 (m, 12H), 1.46 (t, J=5.84 Hz, 1H), 2.81 (s, 2H), 3.38 (s, 3H),
3.43 (d, J=5.23 Hz, 2H), 4.16 (s, 2H), 4.42 (s, 2H), 6.80 (d,
J=9.67 Hz, 1H), 6.90 (t, J=8.46 Hz, 1H), 7.09 (d, J=7.45 Hz, 1H),
7.15 - 7.21 (m, 2H), 7.25 - 7.32 (m, 2H), 7.42 (m, 1H).
[0616] Step 5. Preparation of 5 444
[0617] To a cooled (15-18.degree. C.) solution of 24.2 g (55.8
inmol) of 4 in 100 mL DMSO was added 31.2 g sulfur trioxide
pyridine complex (195 mmol). Stirred at ambient temperature for
thirty minutes. Poured into cold water and extracted three times
with ethyl acetate. Washed organics with 5% HCl (300 mL) and then
with brine (300 mL), dired organics over MgSO.sub.4 and condensed
in vacuo to give 23.1 g (96%) of 5 as a light brown oil. .sup.1H
NMR (CDCl.sub.3) d 0.87 (t, J=7.05 Hz, 6H), 1.01 - 1.32 (m, 8H),
1.53 - 1.65 (m, 4H), 2.98 (s, 2H), 3.38 (s, 3H), 4.15 (s, 2H), 4.43
(s, 2H), 6.81 (dd, J=9.66 Hz and 2.82 Hz, 1H), 6.91 (t, J=8.62 Hz,
1H), 7.07 (d, J=7.46 Hz, 1H), 7.14 (s, 1H), 7.19 (d, J=7.65 Hz,
1H), 7.26 - 7.32 (m, 1H), 7.42 (dd, J=8.66 Hz and 5.64 Hz, 1H),
9.40 (s, 1H). 445
[0618] To a cooled (0.degree. C.) solution of 23.1 g (53.6 mmol) of
5 in 200 mL methylene chloride was added 28.6 g meta
cholorperoxy-benzoic acid (112.6 mmol). Stirred at ambient
temperature for 24 hours. Quenched with 100 mL 10%
Na.sub.2SO.sub.3, partitioned between water and methylene chloride.
Dried organic layer over MgSO.sub.4 and condensed in vacuo to give
24.5 g (98%) of 6 as a light yellow oil. .sup.1H NMR (CDCl.sub.3) d
0.86 - 1.29 (m, 14H), 1.58 - 1.63 (m, 2H), 1.82 - 1.91 (m, 2H),
3.13 (s, 2H), 3.39 (s, 3H), 4.44 (s, 2H), 4.50 (s, 2H), 6.93 (d,
J=9.07 Hz, 1H), 7.10 - 7.33 (m, 5H), 8.05 (s, 1H), 9.38 (s, 1H).
446
[0619] To a solution of 24.5 g (52.9 mmol) of 6 in 20 mL of THF
contained in a stainless steel reaction vessel was added 100 mL of
a 2.0 M solution of dimethyl amine and 20 mL of neat dimethyl
amine. The vessel was sealed and heated to 110.degree. C. for 16
hours. The reaction vessel was cooled to ambient temperature and
the contents concentrated in vacuo. Purification by silica gel
chromatography (Waters Prep-500) using 15% ethyl acetate/hexanes
gave 21.8 g (84%) of 7 as a clear colorless oil. .sup.1NMR
(CDCl.sub.3) d 0.85 (t, J=7.25 Hz, 6H), 0.93 - 1.29 (m, 8H), 1.49 -
1.59 (m, 2H), 1.70 -1.80 (m, 2H), 2.98 (s, 8H), 3.37 (s, 3H), 4.41
(s, 2H), 4.44 (s, 2H), 6.42 (s, 1H), 6.58 (dd, J=9.0 Hz and 2.61
Hz, 1H), 7.13 (d, J=7.45 Hz, 1H), 7.21 (s, 1H), 7.28 (t, J=7.85 Hz,
1H), 7.82 (d, J=9.06 Hz, 1H), 9.36 (s, 1H). 447
[0620] A solution of 21.8 g (44.8 mmol) of 7 in 600 mL of THF was
cooled to 0.degree. C. 58.2 mL of a 1 M solution of potassium
t-butoxide was added slowly, maintaining the temperature at
<5.degree. C. Stirred for 30 minutes, then quenched with 50 mL
of saturated ammonium chloride. The organic layer was partitioned
between ethyl acetate and water, dried over MgSO4 and concentrated
in vacuo. Purification by recrystalization from .about.10% ethyl
acetate/hexanes gave 15.1 g of 8 as a white solid. The mother
liquor was purified by silica gel chromatography (Waters Prep-500)
using 30% ethyl acetate/hexanes as the elutant to give 3.0 g of 8
as a white solid. MS (FABLi.sup.+) m/e 494.6. HRMS (EI.sup.+)
calculated for M+H 487.2756. Found 487.2746. 448
[0621] A solution of 2.0 g (4.1 mmol) of 8 in 20 mL of methylene
chloride was cooled to -60.degree. C. 4.1 mL of a 1M solution of
boron tribromide was added. Stirred at ambient temperature for
thirty minutes. Cooled reaction to .about.10.degree. C. and
quenched with 50 mL of water. The organic layer was partitioned
between methylene chloride and water, dried over MgSO.sub.4 and
concentrated in vacuo. Purification by recrystalization from 50%
ethyl acetate/methylene chloride gave 1.95 g (89%) of 9 as a white
solid. MS (FABH.sup.+) m/e 537. HRMS (FAB) calculated for M
536.1834. Found 536.1822. 449
[0622] A solution of 1.09 g (2.0 mmol) of 9 and 4.9 g (62 mmol) of
pyridine in 30 mL of acetonitrile was stirred at ambient
temperature for 18 hours. The reaction was concentrated in vacuo.
Purification by recrystallization from methanol/ diethyl ether gave
1.19 g (96%) of 10 as an off white solid. MS (FAB.sup.+) m/e
535.5.
EXAMPLE 1400
[0623] 450
[0624] A 12-liter, 4-neck round-bottom flask was equipped with
reflux condenser, N.sub.2 gas adaptor, mechanical stirrer, and an
addition funnel. The system was purged with N.sub.2. A slurry of
sodium hydride (126.0 g/4.988 mol) in toluene (2.5 L) was added,
and the mixture was cooled to 6 C. A solution of 4-fluorophenol
(560.5 g/5.000 mol) in toluene (2.5 L) was added via addition
funnel over a period of 2.5 h. The reaction mixture was heated to
reflux (100 C) for 1 h. A solution of 3-methoxybenzyl chloride
(783.0 g/5.000 mol) in toluene (750 mL) was added via addition
funnel while maintaining reflux. After 15 h. refluxing, the mixture
was cooled to room temperature and poured into H.sub.20 (2.5 L).
After 20 min. stirring, the layers were separated, and the organic
layer was extracted with a solution of potassium hydroxide (720 g)
in MeOH (2.5 L). The MeOH layer was added to 20% aqueous potassium
hydroxide, and the mixture was stirred for 30 min. The mixture was
then washed 5 times with toluene. The toluene washes were extracted
with 20% aq. KOH. All 20% aq. KOH solutions were combined and
acidified with concentrated HCl. The acidic solution was extracted
three times with ethyl ether, dried (MgSO.sub.4), filtered and
concentrated in vacuo. The crude product was purified by Kugelrohr
distillation to give a clear, colorless oil (449.0 g/39% yield).
b.p.: 120-130 C/50 mtorrHg. .sup.1H NMR and MS [(M+H).sup.+233]
confirmed desired structure. 451
[0625] A 12-liter, 3-neck round-bottom flask was fitted with
mechanical stirrer and N.sub.2 gas adaptor. The system was purged
with N.sub.2. 4-Fluoro-2-(3-methoxybenzyl)-phenol (455.5 g/1.961
mol) and dimethylformamide were added. The solution was cooled to 6
C, and sodium hydride (55.5 g/2.197 mol) was added slowly. After
warming to room temperature, dimethylthiocarbamoyl chloride (242.4
g/1.961 mol) was added. After 15 h, the reaction mixture was poured
into H.sub.2O (4.0 L), and extracted two times with ethyl ether.
The combined organic layers were washed with H.sub.2O and saturated
aqueous NaCl, dried (MgSO.sub.4), filtered, and concentrated in
vacuo to give the product (605.3 g, 97% yield). .sup.1H NMR and MS
[(M+H).sup.+=320] confirm desired structure. 452
[0626] A 12-liter, round-bottom flask was equipped with N.sub.2 gas
adaptor, mechanical stirrer, and reflux condenser. The system was
purged with N.sub.2.
4-Fluoro-2-(3-methoxybenzyl)-phenyldimethylthiocarbamate (605.3
g/1.895 mol) and phenyl ether (2.0 kg) were added, and the solution
was heated to reflux for 2 h. The mixture was stirred for 64 h. at
room temparature and then heated to reflux for 2 h. After cooling
to room temperature, MeOH (2.0 L) and THF (2.0 L) were added, and
the solution was stirred for 15 h. Potassium hydroxide (425.9
g/7.590 mol) was added, and the mixture was heated to reflux for 4
h. After cooling to room temparature, the mixture was concentrated
by rotavap, dissolved in ethyl ether (1.0 L), and extracted with
H.sub.2O. The aqueous extracts were combined, acidified with
concentrated HCl, and extracted with ethyl ether. The ether
extracts were dried (MgSO.sub.4), filtered, and concentrated in
vacuo to give an amber oil (463.0 g, 98% yield). .sup.1H NMR
confirmed desired structure. 453
[0627] A 5-liter, 3-neck, round-bottom flask was equipped with
N.sub.2 gas adaptor and mechanical stirrer. The system was purged
with N.sub.2. 4-Fluoro-2-(3-methoxybenzyl)-thiophenol (100.0
g/403.2mmol) and 2-methoxyethyl ether (1.0 L) were added and the
solution was cooled to 0 C. Sodium hydride (9.68 g/383.2 mmol) was
added slowly, and the mixture was allowed to warm to room
temparature, 2,2-Dibutylpropylene sulfate (110.89 g/443.6 mmol) was
added, and the mixture was stirred for 64 h. The reaction mixture
was concentrated by rotavap and dissolved in H.sub.2O. The aqueous
solution was washed with ethyl ether, and concentrated
H.sub.2SO.sub.4 was added. The aqueous solution was heated to
reflux for 30 min, cooled to room temperature, and extracted with
ethyl ether. The ether solution was dried (MgSO.sub.4), filtered,
and conc'd in vacuo to give an amber oil (143.94 g/85% yield).
.sup.1H NMR and MS [(M +H).sup.+=419] confirm the desired
structure. 454
[0628] A 2-liter, 4-neck, round-bottom flask was equipped with
N.sub.2 gas adaptor, and mechanical stirrer. The system was purged
with N.sub.2. The corresponding alcohol (143.94 g/343.8 mmol) and
CH.sub.2Cl.sub.2 (1.0 L) were added and cooled to 0 C. Pyridinium
chlorochromate (140.53 g/651.6 mmol) was added. After 6 h.,
CH.sub.2Cl.sub.2 was added. After 20 min, the mixture was filtered
through silica gel, washing with CH.sub.2Cl.sub.2. The filtrate was
concentrated in vacuo to give a dark yellow-red oil (110.6 g, 77%
yield). .sup.1H NMR and MS [(M+H).sup.+=417] confirm the desired
structure.
[0629] Step 6 455
[0630] A 2-liter, 4-neck, round-bottom flask was equipped with
N.sub.2 gas adaptor and mechanical stirrer. The system was purged
with N.sub.2. The corresponding sulfide (110.6 g/265.5 mmol) and
CH.sub.2Cl.sub.2 (1.0 L) were added. The solution was cooled to 0
C, and 3-chloroperbenzoic acid (158.21 g/531..sup.7 mmol) was added
portionwise. After 30 min, the reaction mixture was allowed to warm
to room temperature After 3.5 h, the reaction mixture was cooled to
0 C and filtered through a fine fritted funnel. The filtrate was
washed with 10% aqueous K.sub.2CO.sub.3. An emulsion formed which
was extracted with ethyl ether. The organic layers were combined,
dried (MgSO.sub.4), filtered, and concentrated in vacuo to give the
product (93.2 g, 78% yield). .sup.1H NMR confirmed the desired
structure.
[0631] Step 7 456
[0632] A 2-liter, 4-neck, round-bottom flask was equipped with
N.sub.2 gas adaptor, mechanical stirrer, and a powder addition
funnel. The system was purged with N.sub.2. The corresponding
aldehyde (93.2 g/208 mmol) and THF (1.0 L) were added, and the
mixture was cooled to 0 C. Potassium tert-butoxide (23.35 g/208.1
mmol) was added via addition funnel. After 1 h, 10% aq/ HCl (1.0 L)
was added. After 1 h, the mixture was extracted three times with
ethyl ether, dried (MgSO.sub.4), filtered, and concentrated in
vacuo. The crude product was purified by recryst. from 80/20
hexane/ethyl acetate to give a white solid (32.18 g). The mother
liquor was concentrated in vacuo and recrystelized from 95/5
toluene/ethyl acetate to give a white solid (33.60 g/combined
yield: 71%). .sup.1H NMR confirmed the desired product.
[0633] Step 8 457
[0634] A Fisher porter bottle was fitted with N.sub.2 line and
magnetic stirrer. The system was purged with N.sub.2. The
corresponding fluoro-compound (28.lg/62.6 mmol) was added, and the
vessel was sealed and cooled to -78 C. Dimethylamine (17.1 g/379
mmol) was condensed via a CO.sub.2/acetone bath and added to the
reaction vessel. The mixture was allowed to warm to room
temperature and was heated to 60 C. After 20 h, the reaction
mixture was allowed to cool and was dissolved in ethyl ether. The
ether solution was washed with H.sub.2O, saturated aqueous NaCl,
dried (MgSO.sub.4), filtered, and concentrated in vacuo to give a
white solid (28.5 g/96% yield). .sup.1H NMR confirmed the desired
structure.
[0635] Step 9 458
[0636] A 250-mL, 3-neck, round-bottom flask was equipped with
N.sub.2 gas adaptor and magnetic stirrer. The system was purged
with N.sub.2. The corresponding methoxy-compound (6.62 g/14.0 mmol)
and CHCl.sub.3 (150 mL) were added. The reaction mixture was cooled
to -78 C, and boron tribromide (10.50 g/41.9 mmol) was added. The
mixture was allowed to warm to room temperature After 4 h, the
reaction mixture was cooled to 0 C and was quenched with 10%
K.sub.2CO.sub.3 (100 mL). After 10 min, the layers were separated,
and the aqueous layer was extracted two times with ethyl ether. The
CHCl.sub.3 and ether extracts were combined, washed with saturated
aqueous NaCl, dried (MgSO.sub.4), filtered, and concentrated in
vacuo to give the product (6.27 g/98% yield). .sup.1H NMR confirmed
the desired structure.
[0637] Step 10 459
[0638] In a 250 ml single neck round bottom Flask with stir bar
place 2- diethylamineoethyl chloride hydochloride (fw 172.10
g/mole) Aldrich D8, 720-1 (2.4 mmol,4.12 g), 34 ml dry ether and 34
ml of 1N KOH(aqueous). Stir 15 minutes and then separate by ether
extraction and dry over anhydrous potassium carbonate.
[0639] In a separate 2-necked 250 ml round bottom flask with stir
bar add sodium hydride (60% dispersion in mineral oil, 100 mg , 2.6
mmol) and 34 ml of DMF. Cool to ice temperature. Next add phenol
product(previous step) 1.1 g (2.4 rnmilomoles in 5 ml DMF and the
ether solution prepared above. Heat to 40C for 3 days. The product
which contained no starting material by TLC was diluted with ether
and extracted with 1 portion of 5% NaOH, followed by water and then
brine. The ether layer was dried over magnesium sulfate and
isolated by removing ether by rotary evaporation (1.3 gms) .The
product may be further purified by chromatography (SiO2 99% ethyl
acetate/1% NH4OH at 5 ml/min.). Isolated yield: 0.78 g (mass spec ,
and H1 NMR)
[0640] Step 11 460
[0641] The product from step 10 ( 0.57 gms, 1.02 millimole fw
558.83 g/mole) and 1.6 gms iodoethane (10.02 mmol) was placed in 5
ml acetonitrile in a fischer-porter bottle and heated to 45 C for 3
days. The solution was evaporated to dryness and redissolved in 5
mls of chloroform. Next ether was added to the chloroform solution
and the resulting mixture was chilled. The desired product is
isolated as a precipitate 0.7272 gms. Mass spec M-I=587.9 , H
NMR).
EXAMPLE 1401
[0642] Step 1 461
[0643] A 12-liter, 4-neck round-bottom flask was equipped with
reflux condenser, N.sub.2 gas adaptor, mechanical stirrer, and an
addition funnel. The system was purged with N.sub.2. A slurry of
sodium hydride (126.0 g/4.988 mol) in toluene (2.5 L) was added,
and the mixture was cooled to 6 C. A solution of 4-fluorophenol
(560.5 g/5.000 mol) in toluene (2.5 L) was added via addition
funnel over a period of 2.5 h. The reaction mixture was heated to
reflux (100 C) for 1 h. A solution of 3-methoxybenzyl chloride
(783.0 g/5.000 mol) in toluene (750 mL) was added via addition
funnel while maintaining reflux. After 15 h. refluxing, the mixture
was cooled to room temperature and poured into H.sub.2O (2.5 L).
After 20 min. stirring, the layers were separated, and the organic
layer was extracted with a solution of potassium hydroxide (720 g)
in MeOH (2.5 L). The MeOH layer was added to 20% aqueous potassium
hydroxide, and the mixture was stirred for 30 min. The mixture was
then washed 5 times with toluene. The toluene washes were extracted
with 20% aq. KOH. All 20% aqueous KOH solutions were combined and
acidified with concentrated HCl. The acidic solution was extracted
three times with ethyl ether, dried over MgSO.sub.4, filtered and
concentrated in vacuo. The crude product was purified by Kugelrohr
distillation to give a clear, colorless oil (449.0 g/39% yield).
b.p.: 120-130 C/50 mtorrHg. .sup.1H NMR and MS [(M+H).sup.+=233]
confirmed desired structure.
[0644] Step 2 462
[0645] A 12-liter, 3-neck round-bottom flask was fitted with
mechanical stirrer and N.sub.2 gas adaptor. The system was purged
with N.sub.2. 4-Fluoro-2-(3-methoxybenzyl)-phenol (455.5 g/1.961
mol) and dimethylformamide were added. The solution was cooled to 6
C, and sodium hydride (55.5 g/2.197 mol) was added slowly. After
warming to room temperature, dimethylthiocarbamoyl chloride (242.4
g/1.961 mol) was added. After 15 h, the reaction mixture was poured
into H.sub.2O (4.0 L), and extracted two times with ethyl ether.
The combined organic layers were washed with H.sub.2O and saturated
aqueous NaCl, dried over MgSO.sub.4, filtered, and concentrated in
vacuo to give the product (605.3 g, 97% yield). .sup.1H NMR and MS
[(M+H).sup.+=320] confirm desired structure.
[0646] Step 3 463
[0647] A 12-liter, round-bottom flask was equipped with N.sub.2 gas
adaptor, mechanical stirrer, and reflux condenser. The system was
purged with N.sub.2.
4-Fluoro-2-(3-methoxybenzyl)-phenyldimethylthiocarbamate (605.3
g/1.895 mol) and phenyl ether (2.0 kg) were added, and the solution
was heated to reflux for 2 h. The mixture was stirred for 64 h. at
room temperature and then heated to reflux for 2 h. After cooling
to room temperature, MeOH (2.0 L) and THF (2.0 L) were added, and
the solution was stirred for 15 h. Potassium hydroxide (425.9
g/7.590 mol) was added, and the mixture was heated to reflux for 4
h. After cooling to room temperature, the mixture was concentrated
by rotavap, dissolved in ethyl ether (1.0 L), and extracted with
H.sub.2O. The aqueous extracts were combined, acidified with conc.
HCl, and extracted with ethyl ether. The ether extracts were dried
(MgSO.sub.4), filtered, and concentrated in vacuo to give an amber
oil (463.0 g, 98% yield). .sup.1H NMR confirmed desired
structure.
[0648]
[0649] Step 4 464
[0650] A 5-liter, 3-neck, round-bottom flask was equipped with
N.sub.2 gas adaptor and mechanical stirrer. The system was purged
with N.sub.2. 4-Fluoro-2-(3-methoxybenzyl)-thiophenol (100.Og/403.2
mmol) and 2-methoxyethyl ether (1.0 L) were added and the solution
was cooled to 0 C. Sodium hydride (9.68 g/383.2 mmol) was added
slowly, and the mixture was allowed to warm to room temperature
2,2-Dibutylpropylene sulfate (110.89 g/443.6 mmol) was added, and
the mixture was stirred for 64 h. The reaction mixture was
concentrated by rotavap and dissolved in H.sub.2O. The aqueous
solution was washed with ethyl ether, and conc. H.sub.2SO.sub.4 was
added. The aqueous solution was heated to reflux for 30 min, cooled
to room temperature, and extracted with ethyl ether. The ether
solution was dried (MgSO.sub.4), filtered, and concentrated in
vacuo to give an amber oil (143.94 g/85% yield). .sup.1H NMR and MS
[(M+H).sup.+=419] confirm the desired structure.
[0651] Step 5 465
[0652] A 2-liter, 4-neck, round-bottom flask was equipped with
N.sub.2 gas adaptor, and mechanical stirrer. The system was purged
with N.sub.2. The corresponding alcohol (143.94 g/343.8 mmol) and
CH.sub.2Cl.sub.2 (1.0 L) were added and cooled to 0 C. Pyridinium
chlorochromate (140.53 g/651.6 mmol) was added. After 6 h.,
CH.sub.2Cl.sub.2 was added. After 20 min, the mixture was filtered
through silica gel, washing with CH.sub.2Cl.sub.2. The filtrate was
concentrated in vacuo to give a dark yellow-red oil (110.6 g, 77%
yield). .sup.1H NMR and MS [(M+H).sup.+=417] confirm the desired
structure.
[0653] Step 6 466
[0654] A 2-liter, 4-neck, round-bottom flask was equipped with
N.sub.2 gas adaptor and mechanical stirrer. The system was purged
with N.sub.2. The corresponding sulfide (110.6 g/265.5 mmol) and
CH.sub.2Cl.sub.2 (1.0 L) were added. The solution was cooled to 0
C, and 3-chloroperbenzoic acid (158.21 g/531..sup.7 mmol) was added
portionwise. After 30 min, the reaction mixture was allowed to warm
to room temperature After 3.5 h, the reaction mixture was cooled to
0 C and filtered through a fine fritted funnel. The filtrate was
washed with 10% aqueous K.sub.2CO.sub.3. An emulsion formed which
was extracted with ethyl ether. The organic layers were combined,
dried (MgSO.sub.4), filtered, and concentrated in vacuo to give the
product (93.2 g, 78% yield). .sup.1H NMR confirmed the desired
structure.
[0655] Step 7 467
[0656] A 2-liter, 4-neck, round-bottom flask was equipped with
N.sub.2 gas adaptor, mechanical stirrer, and a powder addition
funnel. The system was purged with N.sub.2. The corresponding
aldehyde (93.2 g/208 mmol) and THF (1.0 L) were added, and the
mixture was cooled to 0 C. Potassium tert-butoxide (23.35
g/208.lmmol) was added via addition funnel. After 1 h, 10% aq/ HCl
(1.0 L) was added. After 1 h, the mixture was extracted three times
with ethyl ether, dried (MgSO.sub.4), filtered, and concentrated in
vacuo. The crude product was purified by recrystallized from 80/20
hexane/ethyl acetate to give a white solid (32.18 g). The mother
liquor was concentrated in vacuo and recrystallized from 95/5
toluene/ethyl acetate to give a white solid (33.60 g, combined
yield: 71%). .sup.1H NMR confirmed the desired product.
[0657] Step 8 468
[0658] A Fisher porter bottle was fitted with N.sub.2 line and
magnetic stirrer. The system was purged with N.sub.2. The
corresponding fluoro-compound (28.lg/62.6 mmol) was added, and the
vessel was sealed and cooled to -78 C. Dimethylamine (17.1 g/379
mmol) was condensed via a CO.sub.2/acetone bath and added to the
reaction vessel. The mixture was allowed to warm to room
temperature and was heated to 60 C. After 20 h, the reaction
mixture was allowed to cool and was dissolved in ethyl ether. The
ether solution was washed with H.sub.2O, saturated aqueous NaCl,
dried over MgSO.sub.4, filtered, and concentrated in vacuo to give
a white solid (28.5 g/96% yield). .sup.1H NMR confirmed the desired
structure.
[0659] Step 9 469
[0660] A 250-mL, 3-neck, round-bottom flask was equipped with
N.sub.2 gas adaptor and magnetic stirrer. The system was purged
with N.sub.2. The corresponding methoxy-compound (6.62 g/14.0 mmol)
and CHCl.sub.3 (150 mL) were added. The reaction mixture was cooled
to -78 C, and boron tribromide (10.50 g/41.9 mmol) was added. The
mixture was allowed to warm to room temperature After 4 h, the
reaction mixture was cooled to 0 C and was quenched with 10%
K.sub.2CO.sub.3 (100 mL). After 10 min, the layers were separated,
and the aqueous layer was extracted two times with ethyl ether. The
CHCl.sub.3 and ether extracts were combined, washed with saturated
aqueous NaCl, dried over MgSO.sub.4, filtered, and concentrated in
vacuo to give the product (6.27 g/98% yield). .sup.1H NMR confirmed
the desired structure.
[0661] Step 10 470
[0662] In a 250 ml single neck round bottom flask with stir bar
place 2- diethylamineoethyl chloride hydochioride (fw 172.10
g/mole) Aldrich D8, 720-1 (2.4 millimoles, 4.12 g), 34 ml dry ether
and 34 ml of 1N KOH (aqueous) . Stir 15 minutes and then separate
by ether extraction and dry over anhydrous potassium carbonate.
[0663] In a separate 2-necked 250 ml round bottom flask with stir
bar add sodium hydride (60% dispersion in mineral oil, 100 mg, (2.6
mmol) and 34 ml of DMF. Cool is to ice temperature. Next add phenol
product (previous step) 1.1 g (2.4 mmol in 5 ml DMF and the ether
solution prepared above. Heat to 40C for 3 days. The product which
contained no starting material by TLC was diluted with ether and
extracted with 1 portion of 5% NaOH, followed by water and then
brine. The ether layer was dried over Magnesium sulfate and
isolated by removing ether by rotary evaporation (1.3 gms). The
product may be further purified by chromatography (silica 99% ethyl
acetate/1% NH40H at 5 ml/min.). Isolated yield: 0.78 g (mass spec ,
and Hi NMR)
[0664] Step 11 471
[0665] The product from step 10 (0.57 gms, 1.02 millimole fw 558.83
g/mole) and iodoethane (1.6 gms (10.02 mmilimoles)was place in 5 ml
acetonitrile in a Fischer-Porter bottle and heated to 45 C for 3
days. The solution was evaporated to dryness and redissolved in 5
mls of chloroform. Next ether was added to the chloroform solution
and the resulting mixture was chilled. The desired product is
isolated as a precipitate 0.7272 gms. Mass spec M-I =587.9, .sup.1H
NMR).
EXAMPLE 1402
[0666] 472
[0667]
(4R-cis)-5-[[5-[4-[3,3-Dibutyl-7-(dirmethylamino)-2,3,4,5-tetrahydr-
o-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyl]thio]-1H-tetraz-
ole-1-acetic acid
[0668] Step 1. Preparation of
4-fluoro-2-((4-methoxyphenyl)methyl)-phenol
[0669] To a stirred solution of 23.66 g of 95% sodium hydride (0.94
mol) in 600 mL of dry toluene was added 100.0 g of 4-fluorophenol
(0.89 mol) at 0.degree. C. The mixture was stirred at 90.degree. C.
for 1 hour until gas evolution stopped. The mixture was cooled down
to room temperature and a solution of 139.71 g of 3-methoxybenzyl
chloride (0.89 mol) in 400 mL of dry toluene was added. After
refluxing for 24 hours, the mixture was cooled to room temperature
and quenched with 500 mL of water. The organic layer was separated,
dried over MgSO.sub.4, and concentrated under high vacuum. The
remaining starting materials were removed by distillation. The
crude dark red oil was filtered through a layer of 1 L of silica
gel with neat hexane to yield 53.00 g (25.6%) of the product as a
pink solid: .sup.1H NMR (CDCl.sub.3) .delta. 3.79 (s, 3H), 3.90 (s,
2H), 4.58 (s, 1H), 6.70-6.74 (m, 1H), 6.79-6.88 (m, 4H), 7.11-7.16
(m, 2H).
[0670] Step 2. Preparation of
4-fluoro-2-((4-methoxyphenyl)methyl)-thiophe- nol
[0671] Step 2a. Preparation of thiocarbamate
[0672] To a stirred solution of 50.00 g (215.30 mmol) of
4-fluoro-2-((4-methoxyphenyl)methyl)-phenol in 500 mL of dry DMF
was added 11.20 g of 60% sodium hydride dispersion in mineral oil
(279.90 mmol) at 2.degree. C. The mixture was allowed to warm to
room temperature and 26.61 g of dimethylthiocarbamoyl chloride
(215.30 mmol) was added. The reaction mixture was stirred at room
temperature overnight. The mixture was quenched with 100 mL of
water in an ice bath. The solution was extracted with 500 mL of
diethyl ether. The ether solution was washed with 500 mL of water
and 500 mL of brine. The ether solution was dried over MgSO.sub.4
and stripped to dryness. The crude product was filtered through a
plug of 500 mL silica gel using 5% ethyl acetate/hexane to yield
48.00 g (69.8%) of the product as a pale white solid: .sup.1NMR
(CDCl.sub.3) .delta. 3.21 (s, 3H), 3.46 (s, 3H), 3.80 (s, 3H), 3.82
(s, 2H), 6.78-6.86 (m, 3H), 6.90-7.00 (m, 2H), 7.09 (d, J=8.7 Hz,
2H).
[0673] Step 2b. Rearrangement and hydrolysis of thiocarbamate to
4-fluoro-2-((4-methoxyphenyl)methyl)-thiophenol
[0674] A stirred solution of 48.00 g (150.29 mmol) of thiocarbamate
(obtained from Step 2a) in 200 mL of diphenyl ether was refluxed at
270.degree. C. overnight. The solution was cooled down to room
temperature and filtered through 1 L of silica gel with 2 L of
hexane to remove phenyl ether. The rearrangement product was washed
with 5% ethyl acetate/hexane to give 46.00 g (95.8%) of the product
as a pale yellow solid: .sup.1NMR (CDCl.sub.3) .delta. 3.02 (s,
3H), 3.10 (s, 3H), 3.80 (s, 3H), 4.07 (s, 2H), 6.82-6.86 (m, 3H),
6.93 (dt, J=8.4 Hz, 2.7 Hz, 1H), 7.08 (d, J=8.7 Hz, 2H), 7.49 (dd,
J=6.0 Hz, 8.7 Hz, 1H).
[0675] To a solution of 46.00 g (144.02 mmol) of the rearrangement
product (above) in 200 mL of methanol and 200 mL of THF was added
17.28 g of NaOH (432.06 mmol). The mixture was refluxed under
nitrogen overnight. The solvents were evaporated off and 200 mL of
water was added. The aqueous solution was washed with 200 mL of
diethyl ether twice and placed in an ice bath. The aqueous mixture
was acidified to pH 6 with concentrated HCl solution. The solution
was extracted with 300 mL of diethyl ether twice. The ether layers
were combined, dried over MgSO.sub.4 and stripped to dryness to
afford 27.00 g (75.5%) of the product as a brown oil: .sup.1NMR
(CDCl.sub.3) .delta. 3.24 (s, 1H), 3.80 (s, 3H), 3.99 (s, 2H),
6.81-6.87 (m, 4H), 7.09 (d, J=8.7 Hz, 2H), 7.27-7.33 (m, 1H).
[0676] Step 3. Preparation of dibutyl cyclic sulfate
[0677] Step 3a. Preparation of 2,2-dibutyl-1,3-propanediol.
[0678] To a stirred solution of di-butyl-diethylmalonate (Aldrich)
(150 g, 0.55 mol in dry THF (700 ml) in an acetone/dry ice bath was
added LAH (1 M THF) 662 ml (1.2 eq., 0.66 mol) dropwise maintaining
the temperature between -20 to 0.degree. C. The reaction was
stirred at RT overnight. The reaction was cooled to -20.degree. C.
and 40 ml of water, and 80 mL of 10% NaOH and 80 ml of water were
added dropwise. The resulting suspension was filtered. The filtrate
was dried over sodium sulphate and concentrated in vacuo to give
diol 98.4 g (yield 95%) as an oil. MS spectra and proton and carbon
NMR spectra were consistent with the product.
[0679] Step 3b. Preparation of dibutyl cyclic sulfite
[0680] A solution of 2,2-dibutyl-1,3-propanediol (103 g, 0.548 mol,
obtained from Step 3a) and triethylamine (221 g, 2.19 mol) in
anhydrous methylene chloride (500 ml) was stirred at 0.degree. C.
under nitrogen. To the mixture, thionyl chloride (97.8 g, 0.82 mol)
was added dropwise and within 5 min the solution turned yellow and
then black when the addition was completed within half an hour. The
reaction mixture was stirred for 3 hrs. at 0.degree. C. GC showed
that there was no starting material left. The mixture was washed
with ice water twice then with brine twice. The organic phase was
dried over magnesium sulfate and concentrated under vacuum to give
128 g (100%) of the dibutyl cyclic sulfite as a black oil. Mass
spectrum (MS) was consistent with the product.
[0681] Step 3c. Oxidation of dibutyl cyclic sulfite to dibutyl
cyclic sulfate
[0682] To a solution of the dibutyl cyclic sulfite (127.5 g , 0.54
mol, obtained from Step 3b) in 600 ml acetonitrile and 500 ml of
water cooled in an ice bath under nitrogen was added ruthenium
(III) chloride (1 g) and sodium periodate (233 g, 1.08 mol). The
reaction was stirred overnight and the color of the solution turned
black. GC showed that there was no starting material left. The
mixture was extracted with 300 ml of ether and the ether extract
was washed three times with brine. The organic phase was dried over
magnesium sulfate and passed through celite. The filtrate was
concentrated under vacuum and to give 133 g (97.8%) of the dibutyl
cyclic sulfate as an oil. Proton and carbon NMR and MS were
consistent with the product.
[0683] Step 4. Preparation of aryl-3-hydroxypropylsulfide
[0684] To a stirred solution of 27.00 g (108.73 mmol) of
4-fluoro-2-((4-methoxyphenyl)methyl)thiophenol (obtained from Step
2) in 270 mL of diglyme was added 4.35 g of 60% sodium hydride
dispersion in mineral oil (108.73 mmol) at 0.degree. C. After gas
evolution ceased, 29.94 g (119.60 mmol) of the dibutyl cyclic
sulfate (obtained from Step 3c) was added at 0C and stirred for 10
minutes. The mixture was allowed to warm up to room temperature and
stirred overnight. The solvent was evaporated and 200 mL of water
was added. The solution was washed with 200 mL of diethyl ether and
added 25 mL of concentrated sulfuric acid to make a 2.0 M solution
that was refluxed overnight. The solution was extracted with ethyl
acetate and the organic solution was dried over MgSO.sub.4 and
concentrated in vacuo. The crude aryl-3-hydroxypropylsulfi- de was
purified by silica gel chromatography (Waters Prep 500) using 8%
ethyl acetate/hexane to yield 33.00 g (72.5%) of the product as a
light brown oil: .sup.1NMR (CDCl.sub.3) .delta. 0.90 (t, J=7.1 Hz,
6H), 1.14-1.34 (m, 12H), 2.82 (s, 2H), 3.48 (s, 2H), 3.79 (s, 3H),
4.10 (s, 2H), 6.77-6.92 (m, 4H), 7.09 (d, J 8.7 Hz, 2H), 7.41 (dd,
J=8.7 Hz, 5.7 Hz, H).
[0685] Step 5. Preparation of enantiomerically-enriched
aryl-3-hydroxypropylsulfoxide
[0686] To a stirred solution of 20.00 g (47.78 mmol) of
aryl-3-hydroxypropylsulfide (obtained from Step 4) in 1 L of
methylene chloride was added 31.50 g of 96%
(1R)-(-)-(8,8-dichloro-10-camphor-sulfo- nyl)oxaziridine (100.34
mmol, Aldrich) at 2.degree. C. After all the oxaziridine dissolved
the mixture was placed into a -30.degree. C. freezer for 72 hours.
The solvent was evaporated and the crude solid was washed with 1 L
of hexane. The white solid was filtered off and the hexane solution
was concentrated in vacuo. The crude oil was purified on a silica
gel column (Waters Prep 500) using 15% ethyl acetate/hexane to
afford 19.00 g (95%) of the enantiomerically-enriched
aryl-3-hydroxypropylsulfoxide as a colorless oil: .sup.1H NMR
(CDCl.sub.3) .delta. 0.82-0.98 (m, 6H), 1.16-1.32 (m, 12H), 2.29
(d, J=13.8 Hz, 1H), 2.77 (d, J=13.5 Hz, 1H), 3.45 (d, J=12.3 Hz,
1H), 3.69 (d, J=12.3 Hz, 1H), 3.79 (s, 3H), 4.02 (q, J=15.6 Hz,
1H), 6.83-6.93 (m, 3H), 7.00 (d, J=8.1 Hz, 2H), 7.18-7.23 (m, 1H),
7.99-8.04 (m, 1H). Enantiomeric excess was determined by chiral
HPLC on a (R,R)-Whelk-O column using 5% ethanol/hexane as the
eluent. It showed to be 78% e.e. with the first eluting peak as the
major product.
[0687] Step 6. Preparation of enantiomerically-enriched
aryl-3-propanalsulfoxide
[0688] To a stirred solution of 13.27 g of triethylamine (131.16
mmol, Aldrich) in 200 mL dimethyl sulfoxide were added 19.00 g
(43.72 mmol) of enantiomerically-enriched
aryl-3-hydroxypropylsulfoxide (obtained from Step 5) and 20.96 g of
sulfur trioxide-pyridine (131.16 mmol, Aldrich) at room
temperature. After the mixture was stirred at room temperature for
48 hours, 500 mL of water was added to the mixture and stirred
vigorously. The mixture was then extracted with 500 mL of ethyl
acetate twice. The ethyl acetate layer was separated, dried over
MgSO.sub.4, and concentrated in vacuo. The crude oil was filtered
through 500 mL of silica gel using 15% ethyl acetate/hexane to give
17.30 g (91%) of the enantiomerically-enriched
aryl-3-propanalsulfoxide as a light orange oil: .sup.1H NMR
(CDCl.sub.3) .delta. 0.85-0.95 (m, 6H), 1.11-1.17 (m, 4H),
1.21-1.39 (m, 4H), 1.59-1.76 (m, 4H), 1.89-1.99 (m, 1H), 2.57 (d,
J=14.1 Hz, 1H), 2.91 (d, J=13.8 Hz, 1H), 3.79 (s, 3H), 3.97 (d,
J=15.9 Hz, 1H), 4,12 (d, J=15.9 Hz, 1H), 6.84-6.89 (m, 3H), 7.03
(d, J=8.4 Hz, 2H), 7.19 (dt, J=8.4 Hz, 2.4 Hz, 1H), 8.02 (dd, J=8.7
Hz, 5.7 Hz, 1H), 9.49 (s, 1H).
[0689] Step 7. Preparation of the enantiomerically-enriched
tetrahydrobenzothiepine-l-oxide (4R,5R)
[0690] To a stirred solution of 17.30 g (39.99 mmol) of
enantiomerically-enriched aryl-3-propanalsulfoxide (obtained from
Step 6) in 300 mL of dry THF at -15.degree. C. was added 48 mL of
1.0 M potassium t-butoxide in THF (1.2 equivalents) under nitrogen.
The solution was stirred at -15.degree. C. for 4 hours. The
solution was then quenched with 100 mL of water and neutralized
with 4 mL of concentrated HCl solution at 0.degree. C. The THF
layer was separated, dried over MgSO.sub.4, and concentrated in
vacuo. The enantiomerically-enriched
tetrahydrobenzothiepine-1-oxide (4R,5R) was purified by silica gel
chromatography (Waters Prep 500) using 15% ethyl acetate/hexane to
give 13.44 g (77.7%) of the product as a white solid: .sup.1NMR
(CDCl.sub.3) .delta. 0.87-0.97 (m, 6H), 1.16-1.32 (m, 4H),
1.34-1.48 (m, 4H), 1.50-1.69 (m, 4H), 1.86-1.96 (m, 1H), 2.88 (d,
J=13.0 Hz, 1H), 3.00 (d, J=13.0 Hz, 1H), 3.85 (s, 3H), 4.00 (s,
1H), 4.48 (s, IH), 6.52 (dd, J=9.9 Hz, 2.4 Hz, 1H), 6.94 (d, J=9
Hz, 2H), 7.13 (dt, J=8.4 Hz, 2.4 Hz, 1H), 7.38 (d, J=8.7 Hz, 2H),
7.82 (dd, J=8.7 Hz, 5.7 Hz, 1H).
[0691] Step 8. Preparation of enantiomerically-enriched
tetrahydrobenzothiepine-1,1-dioxide (4R,SR)
[0692] To a stirred solution of 13.44 g (31.07 mmol) of
enantiomerically-enriched tetrahydrobenzothiepine-1-oxide (obtained
from Step 7) in 150 mL of methylene chloride was added 9.46 g of
68% m-chloroperoxybenzoic acid (37.28 mmol, Sigma) at 0.degree. C.
After stirring at 0 .degree. C. for 2 hours, the mixture was
allowed to warm up to room temperature and stirred for 4 hours. 50
mL of saturated Na.sub.2SO.sub.3 was added into the mixture and
stirred for 30 minutes. The solution was then neutralized with 50
mL of saturated NaHCO.sub.3 solution. The methylene chloride layer
was separated, dried over MgSO.sub.4, and concentrated in vacuo to
give 13.00 g (97.5%) of the enantiomerically-enriched
tetrahydrobenzothiepine-1,1-dioxide (4R,5R) as a light yellow
solid: .sup.1NMR (CDCl.sub.3) .delta. 0.89-0.95 (m, 6H), 1.09-1.42
(m, 12H), 2.16-2.26 (m, 1H), 3.14 (q, J=15.6 Hz, 1H), 3.87 (s, 3H),
4.18 (s, 1H), 5.48 (s, 1H), 6.54 (dd, J=10.2 Hz, 2.4 Hz, 1H),
6.96-7.07 (m, 3H), 7.40 (d, J=8.1 Hz, 2H), 8.11 (dd, J=8.6 Hz, 5.9
Hz, 1H).
[0693] Step 9. Preparation of enantiomerically-enriched
7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (4R,5R)
[0694] To a solution of 13.00 g (28.98 mmol) of
enantiomerically-enriched tetrahydrobenzothiepine-1,1-dioxide
(obtained from Step 8) in 73 mL of dimethylamine (2.0 M in THF, 146
mmol) in a Parr Reactor was added about 20 mL of neat
dimethylamine. The mixture was sealed and stirred at 110.degree. C.
overnight, and cooled to ambient temperature. The excess
dimethylamine was evaporated. The crude oil was dissolved in 200 mL
of ethyl acetate and washed with 100 mL of water, dried over
MgSO.sub.4 and concentrated in vacuo. Purification on a silica gel
column (Waters Prep 500) using 20% ethyl acetate/hexane gave 12.43
g (90.5%) of the enantiomerically-enriched
7-(dimethylamino)tetrahydrobenzothiepine-1,1-di- oxide (4R,5R) as a
colorless solid: .sup.1H NMR (CDCl.sub.3) .delta. 0.87-0.93 (m,
6H), 1.10-1.68 (m, 12H), 2.17-2.25 (m, 1H), 2.81 (s, 6H), 2.99 (d,
J=15.3 Hz, 1H), 3.15 (d, J=15.3 Hz, 1H), 3.84 (s, 3H), 4.11 (d,
J=7.5 Hz, 1H), 5.49 (s, 1H), 5.99 (d, J=2.4 Hz, 1H), 6.51 (dd,
J=8.7 Hz, 2.4 Hz, 1H), 6.94 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.4 Hz,
2H), 7.90 (d, J=8.7 Hz, 1H). The product was determined to have 78%
e.e. by chiral HPLC on a Chiralpak AD column using 5%
ethanol/hexane as the eluent. Recrystallization of this solid from
ethyl acetate/hexane gave 1.70 g of the racemic product. The
remaining solution was concentrated and recrystallized to give 9.8
g of colorless solid. Enantiomeric excess of this solid was
determined by chiral HPLC on a Chiralpak AD column using 5%
ethanol/hexane as the eluent. It showed to have 96% e.e with the
first eluting peak as the major product.
[0695] Step 10: Demethylation of
5-(4'-methoxyphenyl)-7-(dimethylamino)tet-
rahydrobenzothiepine-1,1-dioxide (4R,5R)
[0696] To a solution of 47 g (99 mmol) of enantiomeric-enriched
(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from
Step 9) in 500 mL of methylene chloride at -10.degree. C. was added
dropwise a solution of boron tribromide (297 mL, 1M in methylene
chloride, 297 mmol), and the resulting solution was stirred cold
(-5.degree. C. to 0.degree. C.) for 1 hour or until the reaction
was complete. The reaction was cooled in an acetone-dry ice bath at
-10.degree. C., and slowly quenched with 300 mL of water. The
mixture was warmed to 10.degree. C., and further diluted with 300
mL of saturated sodium bicarbonate solution to neutralize the
mixture. The aqueous layer was separated and extracted with 300 mL
of methylene chloride, and the combined extracts were washed with
200 mL of water, brine, dried over MgSO.sub.4 and concentrated in
vacuo. The residue was dissolved in 500 mL of ethyl acetate and
stirred with 50 mL of glacial acetic acid for 30 minutes at ambient
temperature. The mixture was washed twice with 200 mL of water, 200
mL of brine, dried over MgSO.sub.4 and concentrated in vacuo to
give the crude 4-hydroxyphenyl intermediate. The solid residue was
recrystallized from methylene chloride to give 37.5 g (82%) of the
desired
5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide
as a white solid: .sup.1H NMR (CDCl.sub.3) .delta. 0.84-0.97 (m,
6H), 1.1-1.5 (m, 10H), 1.57-1.72 (m, 1H), 2.14-2.28 (m, 1H), 2.83
(s, 6H), 3.00 (d, J=15.3 Hz, 1H), 3.16 (d, J=15.3 Hz, 1H), 4.11 (s,
2H), 5.48 (s, 1H), 6.02 (d, J=2.4 Hz, 1H), 6.55 (dd, J=9, 2.4 Hz,
1H), 6.88 (d, 8,7 Hz, 2H), 7.38 (d, J=8.7 Hz, 2H), 7.91 (d, J=9 Hz,
2H).
[0697] Alternatively, enantiomeric-enriched
5-(4'-hydroxyphenyl)-7-(dimeth-
ylamino)tetrahydrobenzothiepine-1,1-dioxide, the intermediate just
described, can be prepared via non-enantioselective synthesis
followed by chiral chromatography separation. Oxidation of
aryl-3-hydroxypropylsulfid- e (obtained from Step 4) with
m-chloroperbenzoic acid (under the similar conditions as in Step 8,
but with 2.2 equivalent of m-CPBA) gave the racemic sulfone
intermediate. The sulfone was carried through the synthetic
sequences (under the same conditions as in Step 7 and Step 9) to
give the racemic
5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzo-
thiepine-1,1-dioxide. The two enantiomers were further separated
into the desired enantiomeric-enriched
5-(4'-hydroxyphenyl)-7-(dimethylamino)tetra-
hydrobenzothiepine-1,1-dioxide by appropriate chiral
chromatographic purification.
[0698] Step 11: Preparation of ester intermediate
[0699] To a solution of 1.0 g (2.18 mmol) of
5-(4'-hydroxyphenyl)-7-(dimet-
hylamino)tetrahydrobenzo-thiepine-1,1-dioxide (obtained from Step
10) in 10 mL dimethylformamide was added 60 mg (2.38 mmol) of 95%
sodium hydride and stirred for 15 minutes. To the reaction mixture
was added 400 pL (2.52 mmol) of benzyl 2-bromoacetate and stirred
for two hours. Water was added to the reaction mixture, extracted
with ethyl acetate, washed with brine, dried over magnesium
sulfate, filtered and the solvent evaporated to afford 1.30 g (98%)
of the ester intermediate: .sup.1H NMR (CDCl.sub.3) .delta.
0.88-0.94 (m, 6H), 1.13-1.46 (m, 10H), 1.60-1.64 (m, 1H), 2.20-2.24
(m, 1H), 2.81 (s, 6H), 3.00 (d, J=15.1 Hz, 1H), 3.16 (t, J=15.1 Hz,
1H), 4.11 (s, 1H), 5.26 (s, 2H), 5.49 (s, 1H), 6.04 (d, J=2.4 Hz,
1H), 6.63 (dd, J=8.9, 2.4 Hz, 1H), 6.95 (d, J=8.7 Hz, 2H), 7.37 (s,
5H), 7.42 (d, J=8.5 Hz, 2H), 7.93 (d, J=8.9 Hz, 1H).
[0700] Step 12: Preparation of acid
[0701] A solution of 1.30 g (2.14 mmol) of ester intermediate
(obtained from Step 1) in 40 mL ethanol with 10% palladium on
carbon was placed under an atmosphere of hydrogen gas (40 psi) for
three hours. The reaction mixture was filtered through celite and
the solvent was evaporated to afford the desired title compound as
a white solid: mp 119 - 123.degree. C.; .sup.1H NMR (CDCl.sub.3)
.delta. 0.89-0.94 (m, 6H), 1.19-1.43 (m, lOH), 1.61-1.65 (m, 1H),
2.17-2.21 (m, 1H), 2.85 (s, 6H), 3.02 (d, J=15.1 Hz, 1H), 3.17 (t,
J=14.9 Hz, 1H), 4.12 (s, 1H), 4.72 (s, 2H), 5.51 (s, 1H), 6.17 (s,
1H), 6.74 (d, J=9.1 Hz, 1H), 6.99 (d, J=8.3 Hz, 2H), 7.46 (d, J=8.5
Hz, 2H), 7.97 (d, J=8.7 Hz, 1H). HRMS. Calc'd for
C.sub.28H.sub.40NO.sub.6S: 518.2576. Found: 518.2599.
EXAMPLE 1403
[0702] 473
[0703]
(4R-cis)-N-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4--
hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxyacetyl]glycine
[0704] Step 1: Preparation of glycine ester intermediate
[0705] To a solution of 6.4 g (13.9 mmol) of
5-(4'-hydroxyphenyl)-7-(dimet-
hylamino)tetrahydrobenzo-thiepine-1,1-dioxide (obtained from
Example 1402, Step 10) and 2.9 g (21.0 mmol) of potassium carbonate
in 100 ml of acetone was added 3.8 g (21.0 mmol) of
N-(chloroacetyl)glycine ethyl ester and 50 mg (0.14 mmol) of
tetrabutylammonium iodide. The reaction was heated to reflux for 2
days, cooled to ambient temperature and stirred for 20 hours, then
partitioned between ethyl acetate and water. The organic layer was
washed with brine, dried over MgSO.sub.4, and concentrated in
vacuo. Purification by silica gel chromatography (Waters Prep-500)
using 50% ethyl acetate/hexanes afforded 7.5 g (90%) of glycine
ester intermediate as a white foam: .sup.1H NMR (CDCl.sub.3)
.delta. 0.86-0.98 (m, 6H), 1.04-1.56 (m, 13H), 1.58-1.71 (m, 1H),
2.14-2.29 (m, 1H), 2.73 (s, 6H), 3.08 (ABqf JM =15.3 Hz, J=48.9 Hz,
2H), 4.06-4.19 (m, 6H), 4.25 (q, J=7.0 Hz, 2H), 4.57 (s, 2H), 5.50
(s, 1H), 5.98 (s, 1H), 6.56 (d, J=8.6 Hz, 1H), 6.98 (d, J=8.5 Hz,
2H), 7.17 (s, 1H), 7.47 (d, J=8.3 Hz, 2H), 7.91 (d, J=8.7 Hz,
1H)
[0706] Step 2: Preparation of acid
[0707] A solution of 7.3 g (12.1 mmol) of glycine ester
intermediate (obtained from Step 1) and 1.5 g LiOH.H.sub.2O (36.3
mmol) in 60 mL of THF and 60 mL of water was heated to 45.degree.
C. for 2 hours. This was then cooled to ambient temperature,
acidified with 1 N HCl and partitioned between ethyl acetate and
water. The organic layer was washed with brine, dried over
MgSO.sub.4, and concentrated in vacuo. Purification by
recrystallization from ethyl acetate gave 5.45 g (78%) of the
desired title compound as a white crystalline solid: mp
149-150.degree. C.; .sup.1NMR (CD.sub.3OD) .delta. 0.88-0.98 (m,
6H), 1.06-1.56 (m, 10H), 1.70-1.84 (m, 1H), 2.06-2.20 (m, 1H), 2.79
(s, 6H), 3.11 (AB.sub.q, J.sub.Ab=15.3 Hz, J=21.6 Hz, 2H), 4.01 (s,
2H), 4.07 (s, 1H), 4.61 (s, 2H), 5.31 (s, 1H), 6.04 (s, IH), 6.57
(d, J=9.0 Hz, 1H), 7.08 (d, J=7.8 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H),
7.76 (d, J=9.0 Hz, 1H), 8.42 (m, 1H). HRMS(ES+) Calc'd for
C.sub.30H.sub.42N.sub.2O.sub.7S: 575.2712. Found: 575.2790. Anal.
Calc'd for: C.sub.30H.sub.42N.sub.2O.sub- .7S C, 62.69; H, 7.37; N,
4.87. Found: C, 62.87; H, 7.56; N, 4.87.
EXAMPLE 1403
[0708] 474
[0709]
(4R-cis)-N-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4--
hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxyacetyllglycine
[0710] Step 1: Preparation of glycine ester intermediate
[0711] To a solution of 6.4 g (13.9 mmol) of
5-(4'-hydroxyphenyl)-7-(dimet-
hylamino)tetrahydrobenzo-thiepine-1,1-dioxide (obtained from
Example 1402, Step 10) and 2.9 g (21.0 mmol) of potassium carbonate
in 100 ml of acetone was added 3.8 g (21.0 mmol) of
N-(chloroacetyl)glycine ethyl ester and 50 mg (0.14 mmol) of
tetrabutylammonium iodide. The reaction was heated to reflux for 2
days, cooled to ambient temperature and stirred for 20 hours, then
partitioned between ethyl acetate and water. The organic layer was
washed with brine, dried over MgSO.sub.4, and concentrated in
vacuo. Purification by silica gel chromatography (Waters Prep-500)
using 50% ethyl acetate/hexanes afforded 7.5 g =* (90%) of glycine
ester intermediate as a white foam: .sup.1H NMR (CDCl.sub.3)
.delta. 0.86-0.98 (m, 6H), 1.04-1.56 (m, 13H), 1.S8-1.71 (m, 1H),
2.14-2.29 (m, 1H), 2.73 (s, 6H), 3.08 (ABq, J=15.3 Hz, J=48.9 Hz,
2H), 4.06-4.19 (m, 6H), 4.25 (q, J=7.0 Hz, 2H), 4.57 (s, 2H), 5.50
(s, 1H), 5.98 (s, 1H), 6.56 (d, J=8.6 Hz, 1H), 6.98 (d, J=8.5 Hz,
2H), 7.17 (s, 1H), 7.47 (d, J=8.3 Hz, 2H), 7.91 (d, J=8.7 Hz,
1H).
[0712] Step 2: Preparation of acid
[0713] A solution of 7.3 g (12.1 mmol) of glycine ester
intermediate (obtained from Step 1) and 1.5 g LiOH.H.sub.2O (36.3
mmol) in 60 mL of THF and 60 mL of water was heated to 45.degree.
C. for 2 hours. This was then cooled to ambient temperature,
acidified with 1 N HCl and partitioned between ethyl acetate and
water. The organic layer was washed with brine, dried over
MgSO.sub.4, and concentrated in vacuo. Purification by
recrystallization from ethyl acetate gave 5.45 g (78%) of the
desired title compound as a white crystalline solid: mp
149-150.degree. C.; .sup.1H NMR (CD.sub.3OD) .delta. 0.88-0.98 (m,
6H), 1.06-1.56 (m, 10H), 1.70-1.84 (m, 1H), 2.06-2.20 (m, 1H), 2.79
(s, 6H), 3.11 (ABqI JA =15.3 Hz, J=21.6 Hz, 2H), 4.01 (s, 2H), 4.07
(s, 1H), 4.61 (s, 2H), 5.31 (s, 1H), 6.04 (s, 1H), 6.57 (d, J=9.0
Hz, 1H), 7.08 (d, J=7.8 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.76 (d,
J=9.0 Hz, 1H), 8.42 (m, 1H). HRMS(ES+) Calc'd for
C.sub.30H.sub.42N.sub.2O.sub.7S: 575.2712. Found: 575.2790. Anal.
Calc'd for: C.sub.30H.sub.42N.sub.2O.sub.7S C, 62.69; H, 7.37; N,
4.87. Found: C, 62.87; H, 7.56; N, 4.87.
EXAMPLE 1404
[0714] 475
[0715]
(4R-cis)-5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-h-
ydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentanoic acid
[0716] Step 1: Preparation of ester intermediate
[0717] A solution of
5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzo-
thiepine-1,1-dioxide (1.0 g, 2.2 mmol, obtained from Example 1402,
Step 10) in acetone (10 mL) at 25.degree. C. under N.sub.2 was
treated with powdered K.sub.2CO.sub.3 (0.45 g, 3.3 mmol, 1.5 eq.),
benzyl 5-bromovalerate (0.88 g, 3.3 mmol, 1.5 eq.) and a catalytic
amount of tetra-n-butylammonium iodide (2 mg), and the resulting
solution was stirred at 65.degree. C. for 24 hours. The pale amber
slurry was cooled to 25.degree. C. and was concentrated in vacuo to
provide a yellow residue. Purification by flash chromatography
(2.4.times.30 cm silica, 20-40% EtOAc/hexane) afforded the ester
intermediate (1.2 g, 86%) as a colorless oil: .sup.1NMR
(CDCl.sub.3) .delta. 0.91 (m, 6H), 1.11-1.47 (br m, 10H), 1.64 (m,
1H), 1.86 (m, 2H), 2.21 (m, 1H), 2.47 (m, 2H), 2.81 (s, 6H), 3.05
(ABq, J=15.1 Hz, J=47.7 Hz, 2H), 4.10 (d, J=7.9 Hz, 1H), 5.13 (s,
2H), 5.47 (s, 1H), 6.00 (d, J=2.5 Hz, 1H), 6.50 (dd, J=8.9, 2.5 Hz,
1H), 6.91 (d, J=8.7 Hz, 2H), 7.36 (m, 5H), 7.40 (d, J=8.5 Hz, 2H),
7.86 (d, J=8.9 Hz, 1H); HRMS. Calc'd for C.sub.38H.sub.51NO.sub.6S:
650.3515. Found: 650.3473.
[0718] Step 2: Preparation of acid
[0719] A solution of the ester intermediate (0.99 g, 1.5 mmol,
obtained from Step 1) in ethanol (7.5 mL) at 25.degree. C. was
treated with 5% palladium on carbon (0.15 g, 10 wt %) then stirred
under an atmosphere (1 atm) of H.sub.2 via hydrogen balloon. Every
10 min, hydrogen gas was bubbled through the slurry for 1 min, for
a total reaction time of 4 hours. The slurry was placed under an
atmosphere of N.sub.2 and nitrogen was bubbled through the reaction
mixture for 10 min. The mixture was filtered through a plug of
Celiteo (10 g) and concentrated in vacuo to give a white foam.
Purification by flash chromatography (2.6.times.25 cm silica, 1.5%
EtOH/CH.sub.2Cl.sub.2) afforded the desired title compound (0.54 g,
63%) as a white foam: mp: 76-79.degree. C.; .sup.1NMR (CDCl.sub.3)
.delta. 0.90 (m, 6H), 1.10-1.46 (br m, 10H), 1.62 (m, 1H), 1.87 (m,
4H), 2.20 (m, 1H), 2.45 (m, 2H), 2.81 (s, 6H), 3.05 (ABq, J=15.1
Hz, J=49.7 Hz, 2H), 4.00 (s, 2H), 4.09 (s, 1H), 5.45 (s, 1H), 5.99
(d, J=2.4 Hz, 1H), 6.48 (dd, J=8.9, 2.4 Hz, 1H), 6.91 (d, J=8.7 Hz,
2H), 7.39 (m, 5H), 7.39 (d, J=8.3 Hz, 2H), 7.84 (d, J=8.9 Hz, 1H);
HRMS. Calc'd for C.sub.31H.sub.45NO.sub.6S: 560.3046. Found:
560.3043.
EXAMPLE 1405
[0720] 476
[0721] (4R-cis)
-4-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4--
hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy-1-butanesulfonamide
[0722] Step 1: Preparation of sulfonic acid intermediate
[0723] A solution of 7.4 g (16.1 mmol) of
5-(4'-hydroxyphenyl)-7-(dimethyl-
amino)tetrahydrobenzo-thiepine-1,1-dioxide (obtained from Example
1402, Step 10) in acetone (35 mL) at 25.degree. C. under N.sub.2
was treated with powdered potassium carbonate (3.3 g, 24.1 mmol,
1.5 equiv.) and 1,4-butane sultone (2.5 mL, 24.1 mmol, 1.5 equiv.)
and stirred and heated at 65.degree. C. for 64 h. The solution was
allowed to cool to 25.degree. C. and quenched by the addition of
water (50 mL), until a homogeneous mixture was obtained. The clear
and colorless solution was added dropwise to a 4 N HCl solution
cooled to 0.degree. C. over a 30 min period. The mixture was
vigorously stirred for 4 h then allowed to warm to ambient
temperature and stirred for an additional 16 h. The resultant white
precipitate was filtered and washed with water and dried in vacuo
to provide 8.8 g (92%) of the desired sulfonic acid as a white
solid. A portion of the white solid was recrystallized from
CH.sub.3CN/hexane to give the desired sulfonic acid as colorless
needles: mp 229-236.degree. C. (decomposed); .sup.1NMR
(DMSO-d.sub.6) .delta. 0.82 (m, 6H), 1.02-1.33 (br m, 10H), 1.59
(m, 1H), 1.73 (m, 4H), 2.00 (s, 1H), 2.48 (m, 2H), 2.71 (s, 6H),
2.98 (s, 1H), 3.86 (s, 1H), 3.93 (m, 2H), 5.08 (s, 1H), 5.89 (s,
1H), 6.52 (dd, J=8.9, 2.4 Hz, 1H), 6.92 (d, J=8.3 Hz, 2H), 7.29 (d,
J=8.1 Hz, 2H), 7.60 (d, J=8.9 Hz, 1H); Anal. Calc'd for
C.sub.30H.sub.45NO.sub.- 7S.sub.2: C, 60.48; H, 7.61; N, 2.35.
Found: C, 60.53; H, 7.70; N, 2.42.
[0724] Step 2: Preparation of
7-(dimethylamino)-benzothiepin-5-yl]phenoxy-- 1-butanesulfonamide
To a solution of 1.12 g (1.88 mmol) of the sulfonic acid (obtained
from Step 1) in 10 mL CH.sub.2Cl.sub.2 was added 785 mg (3.77 mmol)
PCl.sub.5 and stirred for 1 hour. Water was added and the mixture
was extracted and washed with brine. Dried with MgSO.sub.4,
filtered and solvent evaporated. To the residue was added 30 mL of
0.5M NH.sub.3 in dioxane and stirred 16 hours. The precipitate was
filtered and the solvent evaporated. The residue was purified by
MPLC (33% EtOAc in hexane) to afford the desired title compound as
a beige solid (125 mg, 11%): mp 108-110.degree. C.; .sup.1NMR
(CDCl.sub.3) .delta. 0.85-0.93 (m, 6H), 1.13-1.59 (m, 10H),
1.60-1.67 (m, 1H), 1.94-2.20 (m, 5H), 2.82 (s, 6H), 2.99 (d, J=15.3
Hz, 1H), 3.15 (t, J=15.3 Hz, 1H), 3.23 (t, J=7.7 Hz, 2H), 4.03 (t,
J=5.8 Hz, 2H), 4.08-4.10 (m, 1H), 4.79 (s, 2H), 5.47 (s, 1H), 6.02
(d, J=2.4 Hz, 1H), 6.52 (dd, J=8.9, 2.6 Hz, 1H), 6.91 (d, J=8.9 Hz,
2H), 7.41 (d, J=8.5 Hz, 2H), 7.89 (d, J=8.9 Hz, 1H). HRMS.
[0725] Calc'd for C.sub.30H.sub.47N.sub.2O.sub.6S.sub.2: 595.2876.
Found: 595.2874.
EXAMPLE 1406
[0726] 477
[0727] (4R-cis) -1-[3-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,
5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl] phenoxy)
propyl] -4-aza-1-azoniabicyclo[2.2.2]octane, methanesulfonate
(salt)
[0728] Step 1: Preparation of dimesylate intermediate
[0729] To a cooled (-20.degree. C.) solution of 5.0 g (65.7 mmol)
of 1,3-propanediol in 50 mL of triethylamine and 200 mL of
methylene chloride was added 15.8 g (137.9 mol) of 20
methanesulfonyl chloride. The mixture was stirred for 30 minutes,
then warmed to ambient temperature and partitioned between ethyl
acetate and 1N HCl. The organic layer was washed with brine, dried
over MgSO.sub.41 and concentrated in vacuo to give 13.5 g (89%) of
dimesylate intermediate as a clear yellowish oil: .sup.1H NMR
(CDCl.sub.3) .delta. 2.12 (quintet, J=4.5 Hz, 4H), 3.58 (s, 6H) ,
4.38 (t, J=5.4 Hz)
[0730] Step 2: Preparation of propyl mesylate intermediate
[0731] To a solution of 2.4 g (5.2 mmol) of
5-(4'-hydroxyphenyl)-7-(dimeth-
ylamino)tetrahydrobenz-othiepine-1,1-dioxide (obtained from Example
1402, Step 10) and 6.0 g (26.1 mmol) of dimesylate intermediate
(obtained from Step 1) in 50 mL of acetone was added 3.6 g (26.1
mmol) of K.sub.2CO.sub.3. The reaction was heated to reflux
overnight then cooled to ambient temperature and concentrated in
vacuo. The residue was partitioned between ethyl acetate and water.
The organic layer was washed with brine, dried over MgSO.sub.4, and
concentrated in vacuo. Purification by silica gel chromatography
(Waters-Prep 500) using 36% ethyl acetate/hexanes afforded 2.8 g
(90%) of the propyl mesylate intermediate as a white foam: .sup.1H
NMR (CDCl.sub.3) .delta. 0.86-0.95 (m, 6H), 1.06-1.52 (m, 10H),
1.57-1.70 (m, 1H), 2.14-2.32 (m, 3H), 2.84 (s, 6H), 3.02 (s, 3H),
3.08 (ABq, JA =15.0 Hz, J=46.9 Hz, 4.09-4.18 (m, 3H), 4.48 (t,
J=6.0 Hz, 2H), 5.49 (s, 1H), 6.11 (s, 1H), 6.65 (d, J=8.7 Hz, 1H),
6.94(d, J=8.6 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.94 (d, J=8.9 Hz,
1H).
[0732] Step 3: Preparation of quaternary salt
[0733] To a solution of 1.2 g (2.0 mmol) of propyl mesylate
intermediate (obtained from Step 2) in 20 ml of acetonitrile was
added 0.3 g (2.9 mmol) of 1,4-diazabicyclo[2.2.2]octane (DABCO).
The reaction mixture was stirred at 60.degree. C. for three hours,
then cooled to ambient temperature and concentrated in vacuo.
Purification by trituration with methylene chloride/ethyl ether
gave 1.3 g (91%) of the desired title compound as a white solid:
mp. (dec) 230-235.degree. C.; .sup.1NMR (CDCl.sub.3) .delta.
0.86-0.95 (m, 6H), 1.04-1.52 (m, 10H), 1.57-1.70 (m, 1H), 2.12-2.25
(m, 3H), 2.28-2.39 (m, 2H), 2.83 (s, 6H), 3.04 (s, 3H), 3.09
(AB.sub.q, J.sub.AB=15-6 Hz, J=42.2 Hz, 2H) 3.22-3.32 (m, 6H),
3.56-3.66 (m, 6H), 3.73-3.83 (m, 2H), 4.06-4.17 9m, 3H), 5.47 (s,
1H), 5.97 (s, 1H), 6.51 (d, J=8.6 Hz, 1H), 6.90(d, J=8.6 Hz, 2H),
7.41 (d, J=8.7 Hz, 2H), 7.89 (d, J=8.9 Hz, 1H). MS (ES+) m/e 612.4.
HRMS (ES+) Calc'd for C.sub.3H.sub.54N.sub.3O.sub.4S.sup.+:
612.3835. Found: 612.3840.
EXAMPLE 1407
[0734] 478
[0735]
(4R-cis)-1-[3-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro--
4-hydroxy-1,1-dioxido-1-benzothiepin-5-yllphenoxy]propyl]-4-aza-1-azoniabi-
cyclo[2.2.2]octane,4-methylbenzenesulfonate (salt)
[0736] Step 1: Preparation of propyl tosylate intermediate A
solution of
5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide
(5.0 g, 10.9 mmol, obtained from Example 1402, Step 10) in acetone
(100 mL) at 25.degree. C. under N.sub.2 was treated with powdered
K.sub.2CO.sub.3 (3.8 g, 27.2 mmol, 2.5 eq.) and 1,3-propanediol
di-p-tosylate (13.0 g, 32.6 mmol, 3.0 eq.), and the resulting
mixture was stirred at 65.degree. C. for 21 hours. The
cream-colored slurry was cooled to 25.degree. C. and was filtered
through a sintered glass funnel. The filtrate was concentrated and
the residue was dissolved in EtOAc (150 mL). The organic layer was
washed with saturated aqueous NaHCO.sub.3(2.times.150 mL) and
saturated aqueous NaCl (2.times.150 mL), and was dried (MgSO.sub.4)
and concentrated in vacuo to provide a pale orange oil.
Purification by flash chromatography (4.4.times.35 cm silica,
20-30% EtOAc/hexane) afforded the propyl tosylate intermediate (6.0
g, 80%) as a white foam: .sup.1H NMR (CDCl.sub.3) .delta. 0.91 (m,
6H), 1.11-1.47 (br m, 10H), 1.63 (m, 1H), 2.14 (m, 2H), 2.21 (m,
1H), 2.41 (s, 3H), 2.81 (s, 6H), 3.06 (ABq, J=15.1 Hz, J=49.0 Hz,
2H), 4.01 (t, J=5.3 Hz, 2H), 4.10 (m, IH), 4.26 (t, J=5.9 Hz, 2H),
5.29 (s, 1H), 5.48 (s, 1H), 5.98 (s, 1H), 6.51 (dd, J=8.9, 1.8 Hz,
1H), 6.83 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 7.39 (d, J 8.3
Hz, 2H), 7.78 (d, J=8.3 Hz, 2H), 7.88 (d, J=8.9 Hz, 1H).
[0737] Step 2: Preparation of quaternary salt
[0738] A solution of the propyl tosylate intermediate (1.05 g, 1.56
mmol, obtained from Step 1) in acetonitrile (15 mL) at 25.degree.
C. under N.sub.2 was treated with diazabicyclo[2.2.2]octane (DABCO,
0.26 g, 2.34 mmol, 1.5 eq.) and stirred at 50.degree. C. for 6
hours, then at 25.degree. C. for 14 hours. The pale amber solution
was cooled to 25.degree. C. and concentrated in vacuo to provide an
amber oil. The residue was dissolved in a minimal amount of
CH.sub.2Cl.sub.2 (5 mL) and diluted with Et.sub.2O (100 mL) while
vigorously stirring for 4 hours, during which time a white solid
precipitated. The white solid was collected (Et.sub.2O wash) to
give the desired title compound (1.11 g, 90%) as a white amorphous
solid: mp 136.5-142.degree. C. (decomposed); .sup.1NMR (CDCl.sub.3)
.delta. 0.89 (m, 6H), 1.12-1.43 (br m, 9H), 1.61 (m, 1H), 1.65 (m,
1H), 2.18 (m, 1H), 2.22 (m, 2H), 2.27 (s, 3H), 2.78 (s, 6H), 3.07
(ABq, J=15.1 Hz, J=39.5 Hz, 2H), 3.49 (br s, 6H), 3.68 (m, 1H),
3.74 (br s, 6H), 3.96 (br s, 2H), 4.09 (d, J=7.3 Hz, 1H), 5.46 (s,
1H), 5.96 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.9, 2.4 Hz, 1H), 6.83 (d,
J=8.5 Hz, 2H), 7.11 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 7.74
(d, J=8.1 Hz, 2H), 7.87 (d, J=8.9 Hz, 1H); HRMS. Calc'd for
C.sub.3,H.sub.54N30.sub.4S: 612.3835. Found: 612.3832.
EXAMPLE 1408
[0739] 479
[0740] (4R-cis)-1-[4-[4-[3, 3-Dibutyl-7-(diethylamino)-2,3,4,
5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yllphenoxy]butyl]
-4-aza-1-azoniabicyclo[2.2.2] octanemethanesulfonate (salt)
[0741] Step 1: Preparation of butyl mesylate intermediate
[0742] A mixture of 1.00 g (2.18 mmol) of
5-(4'-hydroxyphenyl)-7-(dimethyl-
amino)tetrahydrobenzo-thiepine-1,1-dioxide (obtained from Example
1402, Step 10), 2.68 g (10.88 mmol) of busulfan, and 1.50 g (10.88
mmol) of potassium carbonate in 20 mL of acetone was stirred at
reflux overnight. The mixture was concentrated in vacuo and the
crude was dissolved in 30 mL of ethyl acetate. The insoluble solid
was filtered off andthe filtrate was concentrated in vacuo. The
resulting white foam was chromatographed through silica gel column,
and eluted with 30% ethyl acetate/hexane to give 1.02 g (77%) of
butyl mesylate intermediate as a white solid: .sup.1NMR
(CDCl.sub.3) .delta. 0.90 (m, 6H), 1.20-1.67 (m, 12H), 1.98 (m,
4H), 2.22 (m, 1H), 2.83 (s, 6H), 3.04 (s, 3H), 3.08 (ABq, 2H), 4.05
(t, J=5.55 Hz, 2H), 4.11 (d, J=6.90 Hz, 1H), 4.35 (t, J=6.0 Hz,
2H), 5.49 (s, 1H), 6.00 (d, J=2.4 Hz, 1H), 6.52 (dd, J=9.0 Hz, 2.7
Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.90 (d,
J=9.0 Hz, 1H).
[0743] Step 2: Preparation of ester intermediate
[0744] A solution of 520 mg (0.85 mmol) of butyl mesylate
intermediate (obtained from Step 1) and 191 mg (1.71 mmol) of DABCO
in 10 mL of acetonitrile was stirred at 80.degree. C. for 4 hours.
The reaction mixture was concentrated in vacuo to yield a white
foam. The foam was crushed and washed with ether. The solid was
filtered off and dried in vacuo to give 540 mg (88%) of the desired
title compound which was recrystallized from methylene chloride and
acetone as a white solid: mp 248-251.degree. C.; .sup.1NMR
(CDCl.sub.3) .delta. 0.91 (m, 6H), 1.14-1.47 (m, 14H), 1.63 (m,
1H), 1.96 (m, 4H), 2.21 (m, 1H), 2.77 (s, 3H), 2.82 (s, 3H), 3.07
(ABq, 2H), 3.26 (t, J=7.1 Hz, 6H), 3.60 (m, 8H), 4.08 (m, 3H), 5.47
(s, 1H), 5.99 (d, J=2.4 Hz, 1H), 6.51 (dd, J=8.9 Hz, 2.6 Hz, 1H),
6.91 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.89 (d, J=9.0 Hz,
1H).
EXAMPLE 1409
[0745] 480
[0746]
(4R-cis)-1-[4-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro--
4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]-4-aza-1-azoniabic-
yclo[2.2.2]octane-4-methylbenzenesulfonate (salt)
[0747] Step 1: Preparation of propyl tosylate intermediate
[0748] A solution of
5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzo-
thiepine-1,1-dioxide (5.0 g, 10.9 mmol, obtained from Example 1402,
Step 10) in acetone (100 mL) at 25.degree. C. under N.sub.2 was
treated with powdered K.sub.2CO.sub.3 (3.8 g, 27. 2 mmol, 2. 5 eq.)
and 1,4-butanediol di-p-tosylate (13.0 g, 32.6 mmol, 3.0 eq.), and
the resulting solution was stirred at 65.degree. C. for 21 hours.
The cream-colored slurry was cooled to 25.degree. C. and filtered
through a sintered glass funnel. The filtrate was concentrated and
the residue was dissolved in EtOAc (150 mL). The organic layer was
washed with saturated aqueous NaHCO.sub.3 (2.times.150 mL) and
saturated aqueous NaCl (2.times.150 mL). The extract was dried
(MgSO.sub.4) and concentrated in vacuo to provide a pale orange
oil. Purification by flash chromatography (4.4.times.35 cm silica,
20-30% EtOAc/hexane) afforded the propyl tosylate intermediate (6.0
g, 80%) as a white foam: .sup.1NMR (CDCl.sub.3) 67 0. 89 (m, 6H),
1.10-1.44 (br m, 10H), 1.61 (m, 1H), 1.84 (m, 4H), 2.19 (m, 1H),
2.43 (s, 3H), 2.80 (s, 6H), 3.03 (ABq, J=15.1 Hz, J=46.3 Hz, 2H),
3.93 (m, 2H), 4.06-4.13 (m, 4H), 5.44 (s, 1H), 5.96 (s, 1H), 6.46
(dd, J=8.9, 1.4 Hz, 1H), 6.85 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz,
2H), 7.38 (d, J=8.1 Hz, 2H), 7.78 (d, J=8.9 Hz, 2H), 7.83 (m,
1H).
[0749] Step 2: Preparation of quaternary salt
[0750] A solution of propyl tosylate intermediate (5.8 g, 8.5 mmol,
obtained from Step 1) in acetonitrile (100 mL) at 25.degree. C.
under N.sub.2 was treated with diazabicyclo[2.2.2]octane (DABCO,
1.1 g, 10.1 mmol, 1.2 eq.) and stirred at 45.degree. C. for 6
hours. The pale yellow solution was cooled to 25.degree. C. and
concentrated in vacuo to provide an off-white solid. The residue
was dissolved in a minimal amount of CH.sub.2Cl.sub.2 (5 mL) and
diluted with Et.sub.2O (100 mL) while vigorously stirring for 3
hours, during which time a white solid precipitated. The white
solid was collected and recrystallized from EtOAc/hexane to give
the desired title compound (5.7 g, 85%) as colorless needles: mp
223-231.degree. C. (decomposed); .sup.1H NMR (CDCl.sub.3) .delta.
0.86 (m, 6H), 1.09-1.43 (br m, 12H), 1.61-1.90 (br m, SH), 2.13 (m,
1H), 2.25 (s, 3H), 2.75 (s, 6H), 3.03 (ABq, J=15.1 Hz, J=30.0 Hz,
2H), 3.05 (br s, 6H), 3.37 (br s, 6H), 3.89 (m, 2H), 4.07 (d, J=7.5
Hz, 1H), 5.39 (s, 2H), 5.97 (d, J=1.6 Hz, 1H), 6.44 (dd, J=8.9, 2.0
Hz, 1H), 6.87 (d, J=8.3 Hz, 2H), 7.08 (d, J=8.1 Hz, 2H), 7.37 (d,
J=8.3 Hz, 2H), 7.71 (d, J=8.1 Hz, 2H), 7.80 (d, J=8.9 Hz, 1H);
HRMS. Calc'd for C.sub.36H.sub.56N.sub.3O.sub.4S: 626.3992. Found:
626.3994. Anal. Calc'd for C.sub.43H.sub.63N.sub.3O.sub.7S.sub.2:
C, 64.71; H, 7.96; N, 5.27. Found: C, 64.36; H, 8.10; N, 5.32.
EXAMPLE 1410
[0751] 481
[0752]
(4R-cis)-4-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-h-
ydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]-N,N,N-triethyl-1-butanamin-
ium
[0753] A solution of 1 g (1.64 mmol) of the butyl mesylate
intermediate (obtained from Example 1408, Step 1) and 15 mL of
triethylamine in 10 mL of acetonitrile was heated at 50.degree. C.
for 2 days. The solvent was evaporated and the residue was
triturated with ether and ethyl acetate to afford 500 mg (43%) of
product as a semi-solid. .sup.1NMR (CDCl.sub.3) .delta. 0.8 (m, 6
H), 1-1.6 (m, 24 H), 2.1 (m, 1 H), 2.6 (s, 3 H), 2.7 (s, 6 H), 2.9
(d, J=15 Hz, 1 H), 3.0 (d, J=15 Hz, 1 H), 3.3 (m, 8 H), 4.0 (m, 4
H), 5.3 (s, 1 H), 5.9 (s, 1 H), 6.4 (m, 1 H), 6.8 (d, J=9 Hz, 2 H),
7.4 (d, J=9 Hz, 2 H), 7.8 (d, J=7 Hz, 1 H). MS m/e 615.
EXAMPLE 1411
[0754] 482
[0755]
(4R-cis)-1-[4-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro--
4-hydroxy-1,l-dioxido-1-benzothiepin-5-yllphenoxylbutyl]-3-hydroxypyridini-
um, methanesulfonate (salt)
[0756] A solution of 1 g (1.64 mmol) of the butyl mesylate
intermediate (obtained from Example 1408, Step 1) and 234 mg (2.46
mmol) of 3-hydroxy pyridine in 1 mL of dimethylformamide was heated
at 70.degree. C. for 20 hours.
[0757] The solvent was evaporated and the residue was triturated
with ether and ethyl acetate to afford 990 mg (86%) of product as a
semi-solid: .sup.1NMR (CDCl.sub.3) .delta. 0.9 (m, 6 H), 1-1.5 (m,
10 H), 1.7 (m, 1 H), 1.9 (m, 2 H), 2-2.4 (m, 3 H), 2.9 (s, 6 H),
3.1 (d, J=15 Hz, 1 H), 3.2 (d, J=15 Hz, 1 H), 4.1 (m, 3 H), 4.7 (m,
2 H), 5.5 (s, 1 H), 6.1 (s, 1 H), 6.6 (m, 1 H), 6.9 (d, J=9 Hz, 2
H), 7.4 (d, J=9 Hz, 2 H), 7.7 (m, 1 H), 8.0 (m, 2 H), 8.2 (m, 1 H),
9.1 (s, 1 H). MS m/e 609.
EXAMPLE 1412
[0758] 483
[0759]
(4R-cis)-1-[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro--
4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyl]quinolinium,
methanesulfonate (salt)
[0760] Step 1: Preparation of pentyl mesylate intermediate
[0761] To a stirred solution of 231 mg (5.79 mmol, 60% disp.) of
NaH in 22 mL of DMF was added 2.05 g (4.45 mmol) of
5-(4'-hydroxyphenyl)-7-(dimethy-
lamino)tetra-hydrobenzothiepine-1,1-dioxide (obtained from Example
1402, Step 10), and the resulting solution was stirred at ambient
temperature for 1 hour. To the mixture was added 18.02 g (55.63
mmol) of 1,5-diiodopentane and the solution was stirred overnight
at ambient temperature. DMF was removed by high vacuum and the
residue was extracted with ethyl acetate and washed with brine. The
extract was dried over MgSO.sub.4, and the concentrated residue was
purified by column chromatography to give the pentyl mesylate
intermediate: .sup.1NMR (CDCl.sub.3) .delta. 0.90(q, 6H), 1.05-2.0
(m, 17H), 2.2 (t, 1H), 2.8 (s, 6h), 3.0 (q, 2H), 3.22 (t, 2H), 3.95
(t, 2H), 4.1 (s, 1H), 5.42 (s, 1H), 6.1 (d, 1H), 6.6 (d, 1H), 6.9
(d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).
[0762] Step 2: Preparation of quaternary salt
[0763] To 1.0 g (1.53 mmol) of the pentyl mesylate intermediate
(obtained from Step 1) was added 3.94 g (30.5 mmol) of quinoline
and 30 mL of acetonitrile.
[0764] The solution was heated at 45.degree. C. under N.sub.2 for
10 days.
[0765] The concentrated residue was purified by reverse phase C18
column chromatography. The obtained material was exchanged to its
mesylate anion by ion exchange chromatography to give the desired
title compound as a solid: mp 136.degree. C.; .sup.1H NMR
(CDCl.sub.3) .delta. 0.95(q, 6H), 1.05-2.25 (m, 18H), 2.8 (s, 9H),
3.0 (q, 2H), 3.95 (t, 2H), 4.1 (s, 1H), 5.28 (t, 2H), 5.42 (s, 1H),
5.95 (s, 1H), 6.45 (d, 1H), 6.82 (d, 2H), 7.4 (d, 2H), 7.82 (d,
1H), 7.9 (t, 1H), 8.2 (t, 2H), 8.3 (q, 2H), 8.98 (d, 1H), 10.2 (d,
1H). HRMS. Calc'd for C.sub.40H.sub.53N.sub.20.sub.4S: 657.3726.
Found: 657.3736. Anal. Calc'd for C.sub.40H.sub.53N.sub.2O.sub.-
4S.CH.sub.30.sub.3S: C, 65.40; H, 7.50; N, 3.72; S, 8.52. Found: C,
62.9; H, 7.42; N, 3.56; S, 8.41.
EXAMPLE 1413
[0766] 484
[0767]
(4S-cis)-[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4--
hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyllpropanedioic
acid
[0768] Step 1: Preparation of pentyl bromide intermediate
[0769] To a stirred solution of 0.63 g (15.72 mmol, 60% disp) of
NaH in 85 mL of DMF was added 6.0 g (13.1 mmol) of
5-(4'-hydroxyphenyl)-7-(dimethyl-
amino)tetra-hydrobenzothiepine-1,1-dioxide (obtained from Example
1402, Step 10), and the resulting solution was stirred at ambient
temperature for 1 hour. To the solution was added 37.7 g (163.75
mmol) of 1,5-dibromopentane, and the mixture was stirred overnight
at ambient temperature. DMF was removed in vacuo and the residue
was extracted with ethyl acetate and washed with brine. The extract
was dried over MgSO.sub.4, and the concentrated residue was
purified by column chromatography to give the pentyl bromide
intermediate: .sup.1NMR (CDCl.sub.3) .delta. 0.90 (q, 6H), 1.05-2.0
(m, 17H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 3.4 (t, 2H), 3.95
(t, 2H), 4.1 (s, 1H), 5.42 (s, 1H), 6.0 (s, 1H), 6.5 (d, 1H), 6.9
(d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).
[0770] Step 2: Preparation of dibenzyl ester intermediate
[0771] To the mixture of 59 mg (1.476 mmol, 60% disp) of NaH in 27
mL of THF and 9 mL of DMF at 0.degree. C. was added 0.84 g (2.952
mmol) of dibenzyl malonate (Aldrich), and the resulting solution
was stirred at ambient temperature for 15 min. To the solution was
added 0.5987 g (0.984 mmol) of the pentyl bromide intermediate, and
the mixture was stirred at 80.degree. C. overnight. Solvent was
removed in vacuo, and the residue was extracted with methylene
chloride and washed with brine. The extract was dried over
MgSO.sub.4, and the concentrated residue was purified by column
chromatography to give the dibenzyl ester intermediate: .sup.1NMR
(CDCl.sub.3) .delta. 0.90 (q, 6H), 1.05-2.0 (m, 19H), 2.2 (t, 1H),
2.8 (s, 6H), 3.0 (q, 2H), 3.4 (t, 1H), 3.9 (t, 2H), 4.1 (d, 1H),
5.18 (s, 4H), 5.42 (s, 1H), 5.95 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H),
7.2-7.4 (m, 12H), 7.85 (d, 1H).
[0772] Step 3: Preparation of diacid
[0773] A suspension of 0.539 g (0.664 mmol) of the dibenzyl ester
intermediate (obtained from Step 2) and 25 mg of 10% Pd/C in 30 mL
of ethanol was agitated at ambient temperature under 20 psi of
hydrogen gas for 2 hours. The catalyst was filtered off, and the
filtrate was concentrated to give the desired title compound as a
solid: mp 118.degree. C.; .sup.1NMR (CDCl.sub.3) .delta. 0.9 (d,
6H), 1.05-2.2 (m, 20H), 2.8 (s, 6H), 3.0 (q, 2H), 3.4 (s, 1H), 3.95
(s, 2H), 4.1 (s, 1H), 5.42 (s, 1H), 5.95 (s, 1H), 6.5 (d, 1H), 6.9
(d, 2H), 7.4 (d, 2H), 7.85 (d, 1H). HRMS. Calc'd for
C.sub.34H.sub.49NO.sub.8S: 632.3257. Found: 632.3264. Anal. Calc'd
for C.sub.34H.sub.49NO.sub.8S: C, 64.63; H, 7.82; N, 2.22; S, 5.08.
Found: C, 63.82; H, 7.89; N, 2.14; S, 4.93.
EXAMPLE 1414
[0774] 485
[0775]
(4R-cis)-3,3-Dibutyl-5-[4-[[5-(diethylamino)pentyl]oxy]phenyl]-7-(d-
imethylamino)-2,3,4,5-tetrahydro-1-benzothiepin-4-ol
1,1-dioxide
[0776] Step 1: Preparation of pentyl iodide intermediate
[0777] To a solution of
5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobe-
nzothiepine-1,1-dioxide (3 g, 6.53 mmol, obtained from Example
1402, Step 10) in 100 mL of dimethylformamide was added 198 mg
(7.83 mmol) of 95% sodium hydride. The mixture was stirred 15
minutes at room temperature and diiodopentane was added. After one
hour at room temperature the mixture was diluted in ethyl acetate
and water. The aqueous layer was extracted with ethyl acetate and
the combined organic layer was washed with brine, dried over
magnesium sulfate and concentrated in vacuo. The residue was
chromatographed over silica gel, eluting with hexane/ethyl acetate
(1/5) to afford 2.92 g (4.46 mmol) of the pentyl iodide
intermediate: .sup.1NMR (CDCl.sub.3) .delta. 0.9 (m, 6 H), 1-1.5
(m, 11 H), 1.6 (m, 3 H), 1.8 (m, 4 H), 2.2 (m, 1 H), 2.8 (s, 6 H),
3.0 (d, J=15 Hz, 1 H), 3.2 (d, J=15 Hz, 1 H), 3.3 (m, 2 H), 4.0 (m,
1 H), 4.1 (s, 1 H), 5.5 (s, 1 H), 6.1 (s, 1 H), 6.6 (m, 1 H), 6.9
(d, J 9 Hz, 2 H), 7.4 (d, J=9 Hz, 2 H), 7.9 (d, J=7 Hz, 1 H).
[0778] Step 2: Preparation of amine
[0779] A solution of 550 mg (0.76 mmol) of the pentyl iodide
intermediate (obtained from Step 1) and 279 mg (3.81 mmol) of
diethylamine in 3 mL of acetonitrile was stirred at 100.degree. C.
overnight. The mixture was concentrated in vacuo to yield a
yellowish brown foam. The foam was dissolved in 10 mL of ethyl
acetate and washed with 50 mL of saturated sodium carbonate
solution twice. The ethyl acetate layer was dried over magnesium
sulfate and concentrated to yield 390 mg (85%) of the desired title
compound as a yellow foamy solid: .sup.1NMR (CDCl.sub.3) .delta.
0.89 (m, 6H), 1.20-1.47 (m, 12H), 1.53-1.67 (m, 4H), 1.76-1.90 (m,
8H), 2.21 (m, 1H), 2.74-2.92 (m, 12H), 3.07 (ABq, 2H), 4.00 (t,
J=6.3 Hz, 2H), 4.10 (d, J=7.8 Hz, 1H), 5.48 (s, 1H), 6.00 (d, J=2.4
Hz, 1H), 6.51 (dd, J=9.2 Hz, 2.6 Hz, 1H), 6.92 (d, J=8.7 Hz, 2H),
7.41 (d, J=8.4 Hz, 2H), 7.90 (d, J=9.0 Hz, 1H).
EXAMPLE 1415
[0780] 486
[0781]
(4R-cis)-N-(Carboxymethyl)-N-[5-[4-[3,3-dibutyl-7-(dimethylamino)-2-
,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yllphenoxylpentyl-
]glycine
[0782] Step 1: Preparation of diester intermediate
[0783] A mixture of 8.6 g (14.1 mmol) of pentyl bromide
intermediate (obtained from Example 1413, Step 1), 65 g (0.35 mol)
of diethylaminodiacetate and 7.5 g (71 mmol) of anhydrous
Na.sub.2CO.sub.3 was stirred at 160.degree. C. for 3 hours. The
reaction mixture was diluted with water and extracted with
methylene chloride. The volatiles was removed in vacuo to give 9.6
g (95%) of the diester intermediate. .sup.1NMR spectrum was
consistent with the structure; MS (M+H) m/e 717.
[0784] Step 2: Preparation of diacid
[0785] The mixture of the diester intermediate (obtained from Step
1) and 2.7 g (64.3 mmol) of LiOH in THF (75 mL) and water (50 mL)
was stirred at 40.degree. C. for 18 hours. The reaction mixture was
acidified with 1% HCl and extracted with dichloromethane. The
residue was triturated with hexane, filtered to give 8.9 g (93%) of
the desired title compound as a solid: mp 148-162.degree. C.;
.sup.1H NMR (CD.sub.3OD) .delta. 0.92 (t, 6H), 1.1-1.9 (m, 31H),
2.15 (t, 1H),2.8(s, 6H), 3.15 (ABq, 2H), 3.75(m, 1H), 4.1 (m, 6H),
5.3(s, 1H), 6.1 (s, 1H), 6.6 (d, 1H), 7.0(d, 2H), 7.4 (d, 2H), 7.8
(d, iH); MS (M+H) m/e 661. Anal. Calc'd for
[C.sub.35H.sub.52N.sub.2O.sub.8S+1.5H.sub.20]: C,61.11; H,8.06;
N,4.07; S,4.66. Found: C,61.00; H,7.72; N,3.89; S,4.47.
EXAMPLE 1416
[0786] 487
[0787] (4R-cis)-5-[4-[[5-[bis[2-(Diethylamino)ethyl]amino]pentyl]
oxy]phenyl]
-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-1-benzothie-
pin-4-ol 1,1-dioxide
[0788] A solution of 1 g of pentyl iodide intermediate (1.53 mmol,
obtained from Example 1414, Step 1) in N,N,N',N'-tetraethyl
diethylenetriamine was heated to 80.degree. C. for 4 hours. The
mixture was dissolved in ethyl acetate and saturated NaHCO.sub.3.
The organic layer was washed with brine, dried over magnesium
sulfate, and concentrated in vacuo. The residue was purified by
reverse phase chromatography. The fractions containing the product
were concentrated in vacuo, dissolved in ethyl acetate and washed
with saturated NaHCO.sub.3. The residue was dried and concentrated
in vacuo to afford 840 mg (74%) of the desired title compound as a
thick oil. .sup.1H NMR (CDCl.sub.3) .delta. 0.8 (m, 6 H), 1-1.6 (m,
28 H), 1.8 (m, 2 H), 2.1 (m, 1 H), 2.5 (m, 18 H), 2.7 (s, 6 H), 2.9
(d, J=15 Hz, 1 H), 3.1 (d, J=15 Hz, 1 H), 3.9 (m, 2 H), 4.0 (m, 1
H), 4.1 (s, 1 H), 5.4 (s, 1 H), 6.0 (s, 1 H), 6.4 (m, 1 H), 6.9 (d,
J=9 Hz, 2 H), 7.4 (d, J=9 Hz, 2 H), 7.8 (d, J=7 Hz, 1 H). MS (M+H)
m/e 743.
EXAMPLE 1417
[0789] 488
[0790] (4R-cis) -3,3-Dibutyl-7-(di,ethylamino)
-2,3,4,5-tetrahydro-5-[4-[[- 5-[[2-
(lH-irnidazol-4-yl)ethyl]amino]pentyl]oxy]phenyl]-1-benzothiepin-4--
ol 1,1-dioxide
[0791] A solution of 1 g of pentyl iodide intermediate (1.53 mmol,
obtained from Example 1414, Step 1) and 3.4 g (30.6 mmol) of
histamine was heated to 50.degree. C. for 17 hours. The mixture was
dissolved in ethyl acetate and saturated NaHCO.sub.3. The organic
layer was washed with brine, dried over magnesium sulfate, and
concentrated in vacuo. The residue was triturated with ether to
afford 588 mg (60%) of the desired title compound as a semi-solid:
.sup.1H NMR (CDCl.sub.3) .delta. 0.9 (m, 6 H), 1-1.7 (m, 14 H), 1.9
(m, 3 H), 2.0 (m, 2 H), 2.2 (m, 1 H), 2.8 (s, 6 H), 3.0 (m, 3 H),
3.2 (m, 2 H), 4.0 (m, 2 H), 4.1 (m, 3 H), 5.5 (s, 1 H), 6.0 (s, 1
H), 6.5 (m, 1 H), 6.8 (s, 1 H), 6.9 (d, J=9 Hz, 2 H), 7.4 (m, 3 H),
7.9 (d, J=8 Hz, 1 H). MS (M+H) m/e 639.
EXAMPLE 1418
[0792] 489
[0793]
(4R-cis)-N-[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro--
4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxylpentyl]-N'-ethyl-N,N,N',-
N'-tetramethyl-1,2-ethanediaminium dichloride
[0794] Step 1: Preparation of pentyl bromide intermediate
[0795] A mixture of
5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzot-
hiepine-1,1-dioxide (1.680 g, 3.66 mmol, obtained from Example
1402, Step 10) and sodium hydride (0.250 g, 6.25 mmol) in 30 mL of
DMF was stirred in a dry 100 mL round-bottom flask under N.sub.2.
To this solution was added 1,5-dibromopentane (6.0 mL/44.0 mmol),
and the resulting mixture was stirred for 18 hours. The reaction
was diluted with brine (100 mL) and H.sub.20 (20 mL), and the
mixture was extracted with EtOAc (3x50 mL). Organic layers were
combined, dried (MgSO.sub.4), filtered and concentrated in vacuo.
Purification by filtration through silica gel eluting with 20%
EtOAc/hexane and evaporation in vacuo gave pentyl bromide
intermediate as a white foamy solid (1.783 g, 80%): .sup.1NMR
(CDCl.sub.3) .delta. 0.84-0.95 (m, 6H), 1.02-1.56 (m, 10H),
1.58-1.70 (m, 3H), 1.78-2.03 (m, 4H), 2.15-2.24 (m, 1H), 2.77 (s,
1H), 2.80 (s, 6H), 3.05 (ABq, 2H), 3.42 (t, 2H), 3.98 (t, 2H), 4.10
(s, iH), 5.47 (s, 1H), 5.99 (d, 1H), 6.50 (dd, 1H), 6.91 (d, 2H),
7.40 (d, 2H), 7.88 (d, 1H).
[0796] Step 2: Preparation of mono-quaternary salt
[0797] The mixture of pentyl bromide intermediate (0.853 g, 1.40
mmol, obtained from Step 1), N,N,N',N'-tetramethylethylenediamine
(1.0 mL/6.62 mmol) in 30 mL of acetonitrile was stirred at
40.degree. C. for 12 hours, and the reaction mixture was
concentrated in vacuo to give an off-white foamy solid (1.052 g).
The crude product was dissolved in acetonitrile (1.5 mL) and
triturated with ethyl ether. The solvent was decanted to yield a
sticky solid. This trituration method was repeated twice, and the
resulting sticky solid was concentrated in vacuo to give the
mono-quaternary salt as an off-white foamy solid (0.951 g, 94%):
.sup.1H NMR (CDCl.sub.3) .delta. 0.81 (t, 6H), 0.96-1.64 (m, 13H),
1.62-1.85 (m, 4H), 2.03-2.18 (m, 1H), 2.20 (s, 6H), 2.67 (t, 2H),
2.74 (s, 6H), 2.98 (ABq, 2H), 3.30-3.42 (m, 1H), 3.38 (s, 6H),
3.60-3.75 (m, 4H), 3.90 (t, 2H), 4.01 (s, 1H), 5.37 (s, 1H), 5.92
(s, 1H), 6.41 (dd, 1H), 6.81 (d, 2H), 7.32 (d, 2H), 7.77 (d,
1H).
[0798] Step 3: Preparation of di-quaternary salt
[0799] The mono-quaternary salt (0.933 g, 1.29 mmol, obtained from
Step 2), iodoethane (0.300 mL/3.75 mmol), and acetonitrile (30.0
mL) were combined in a 4 oz. Fischer Porter bottle. The reaction
vessel was purged with N.sub.2, sealed, equipped with magnetic
stirrer, and heated to 50.degree. C. After 24 hours, the reaction
mixture was cooled to ambient temperature and concentrated in vacuo
to give a yellow foamy solid (1.166 g). The solid was dissolved in
methylene chloride/acetonitrile and precipitated with ethyl ether.
After cooling to 0.degree. C. overnight, the resulting solid was
filtered, washed with ethyl ether and concentrated in vacuo to
yield the di-quaternary salt as an off-white solid (1.046 g, 92%):
.sup.1NMR (CD.sub.3OD) .delta. 0.59 (t, 6H), 0.70-1.10 (m, 9H),
1.16 (t, 3H), 1.22-1.80 (m, 9H), 2.42 (s, 6H), 2.78 (d, 2H), 2.98
(s, 6H), 3.02 (s, 6H), 3.22-3.37 (m, 4H), 3.63-3.78 (m, 4H), 3.80
(s, 4H), 4.93 (s, 1H), 5.71 (s, 1H), 6.22 (dd, 1H), 6.61 (d, 2H),
7.02 (d, 2H), 7.40 (d, 1H).
[0800] Step 4: Preparation of quaternary di-chloride salt
[0801] The iodobromosalt (obtained from Step 3) was converted to
its corresponding dichloride salt using Biorad AG 2X8 resin and
eluting with 70% H.sub.20/acetonitrile to give the desired title
compound as a white foamy solid (0.746 g, 84%): mp
193.0-197.0.degree. C.; .sup.1H NMR (CD.sub.3OD) .delta. 0.59 (t,
J=6.0 Hz, 6H), 0.70-1.12 (m, 9H), 1.16 (t, J=6.6 Hz, 3H), 1.24-1.90
(m, 9H), 2.50 (s, 6H), 2.78 (s, 2H), 3.08 (s, 6H), 3.11 (s, 6H),
3.24-3.50 (m, 4H), 3.68 (s, 2H), 3.81 (s, 2H), 4.16 (s, 4H), 5.02
(s, 1H), 5.72 (s, 1H), 6.19 (d, J=8.4 Hz, 1H), 6.61 (d, J=8.1 Hz,
2H), 7.10 (d, J=7.8 Hz, 2H), 7.46 (d, J-=8.7 Hz, 1H). HRMS. Calc'd
for C.sub.39H.sub.67N.sub.3O.sub.4SCl: 708.4541. Found:
708.4598.
EXAMPLE 1419
[0802] 490
[0803]
[4R-[4a,5a(4R*,5R*)]]-N,N'-bis[5-[4-[3,3-Dibutyl-7-(dimethylamino)--
2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]penty-
ll-N,N,N'N'-tetramethyl-1,6-hexanediaminium dichloride
[0804] The pentyl bromide intermediate (1.002 g, 1.64 mmol,
obtained from Example 1418, Step 1) and
N,N,N',N'-tetramethyl-1,6-hexanediamine (0.100 g, 0.580 mmol) in 5
mL of acetonitrile were placed in a 4 oz. Fischer Porter bottle.
The reaction vessel was purged with N.sub.2, sealed, equipped with
magnetic stirrer and heated to 50.degree. C. After 15 hours, the
reaction mixture was cooled to ambient temperature and concentrated
in vacuo to give an off-white foamy solid (1.141 g). The solid was
dissolved in acetonitrile and precipitated with ethyl ether. After
cooling to 0.degree. C., the solvent was decanted to yield a sticky
off-white solid. This trituration method was repeated, and the
resulting sticky solid was concentrated in vacuo to give the
desired dibromide salt as an off-white foamy solid (0.843 g,
quantitative): .sup.1NMR (CDCl.sub.3) .delta. 0.85 (m, 12H),
1.01-1.70 (m, 30H), 1.76-2.08 (m, 12H), 2.18 (t, J=12.3 Hz, 2H),
2.79 (s, 12H), 3.03 (ABq, 4H), 3.35 (s, 12H), 3.52 (br s, 6H), 3.72
(br s, 4H), 3.97 (br s, 4H), 4.08 (br s, 2H), 5.42 (s, 2H), 6.00
(s, 2H), 6.51 (d, J=9.0 Hz, 2H), 6.86 (d, J=7.8 Hz, 4H), 7.38 (d,
J=7.8 Hz, 4H), 7.83 (d, J=8.7 Hz, 2H). The dibromide salt was
converted to its corresponding dichloride salt using Biorad AG 2X8
resin and eluting with 70% H.sub.2O/CH.sub.3CN to give the desired
title compound as a white foamy solid (0.676 g, 86%): mp
178.0-182.0.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta. 0.80-0.90
(m, 12H), 1.01-1.70 (m, 30H), 1.75-2.06 (m, 12H), 2.16 (t, J=12.9
Hz, 2H), 2.79 (s, 12H), 3.03 (ABq, 4H), 3.33 (s, 12H), 3.49 (br s,
6H), 3.70 (br s, 4H), 3.96 (t, J=5.4 Hz, 4H), 4.08 (s, 2H), 5.42
(s, 2H), 5.986 (s, 1H), 5.993 (s, 1H), 6.49 (d, J=9.0 Hz, 1H), 6.50
(d, J=9.0 Hz, 1H), 6.87 (d, J=8.4 Hz, 4H), 7.38 (d, J=8.1 Hz, 4H),
7.84 (d, J=8.7 Hz, 2 H) . HRMS. Calc'd for
C.sub.36H.sub.5,N.sub.20.sub.4S: 614.4118. Found: 614.4148.
EXAMPLE 1420
[0805] 491
[0806]
(4R-cis)-3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-[4-[[5--
(1H-tetrazol-5-yl)pentyl]oxy]phenyl]-l-benzothiepin-4-ol
1,1-dioxide
[0807] Step 1: Preparation of pentyl bromide intermediate
[0808] To a stirred suspension of 1.01 g (25.4 mmol, 60% oil
dispersion) of sodium hydride in 150 mL of DMF was added 9.0 g
(19.5 mmol) of
5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide
(obtained from Example 1402, Step 10) in portions. After 30 minutes
the reaction was cooled in a water bath (15.degree. C.) and 4.48 g
(195 mmol) of 1,5-dibromopropane was added. The reaction was
stirred at ambient temperature for 1.5 hours and quenched with 50
mL of saturated NH.sub.4Cl. The reaction was diluted with ethyl
acetate, washed with water, brine, dried over MgSO.sub.4, filtered
and concentrated in vacuo. Purification by silica gel
chromatography (Waters-Prep 500) using 25% ethyl acetate/hexanes
afforded 10.17 g (85%) of the pentyl bromide intermediate as a
colorless foam: mp 65-70.degree. C.; .sup.1NMR (CDCl.sub.3) .delta.
0.84-0.98 (M, 6H), 1.04-1.52 (m, lOH), 1.58-1.65 (m, 3H), 1.82 (p,
J=6.8 Hz, 2H), 1.94 (p, J=7.0 Hz, 2H), 2.12-2.26 (m, IH), 2.82 (s,
6H), 3.06 (ABqI JS =15.2, 45.3 Hz, 2H), 3.44 (t, J=6.7 Hz, 2H),
3.99 (t, J=6.3 Hz, 2H), 4.10 (s, 1H), 5.47 (s, 1H), 6.15 (d, J=2.7
Hz, 1H), 6.68 (dd, J=2.5, 8.4 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H), 7.39
(d, J=8.4 Hz, 2H), 7.93 (d, J=8.7 Hz, 1H).
[0809] Step 2: Preparation of pentyl nitrile intermediate
[0810] To a stirred solution of 378 mg (0.621 mmol) of the pentyl
bromide intermediate (obtained from Step 1) in 1 mL of DMSO was
added 37 mg (0.745 mmol) of sodium cyanide. The reaction was
stirred at ambient temperature for 16 hours. The reaction was
concentrated under a nitrogen stream and the residue partitioned
between ethyl acetate and water. The organic layer was washed with
brine, dried over MgSO.sub.4, filtered, and concentrated in vacuo
to afford 278 mg (93% RPHPLC purity, ca. 75%) of the pentyl nitrile
intermediate as a colorless foam: .sup.1H NMR (CDCl.sub.3) .delta.
0.0.86-0.96 (m, 6H), 1.02-1.21(m, 1H), 1.21-1.52 (m, 19H),
1.58-1.92 (m, 7H), 2.16-2.28 (m, 1H), 2.41 (t, J=6.9 Hz, 2H), 2.83
(s, 6H), 3.08 (ABqr 15.0, 47.5 Hz, 2H), 4.01 (t, J=6.2 Hz, 2H), 4.1
(S, 1H), 5.49 (s, 1H), 6.07 (d, J=2.1 Hz, 1H), 6.59 (dd, J=2.4, 8.7
Hz, 1H), 6.92 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.92 (d,
J=8.7 Hz, 1H). MS (ES, M+H) m/e 555.
[0811] Step 3: Preparation of tetrazole
[0812] A solution of 275 mg (0.5 mmol) of the nitrile intermediate
(obtained from Step 2) and 666 mg (3.23 mmol) of azidotrimethyltin
in 5 mL of toluene was stirred with heating at 80.degree. C. for 60
hours. The reaction was concentrated under a nitrogen stream.
[0813] Purification by reversed phase chromatography (Waters-Delta
prep) using 60% water/acetonitrile afforded 226 mg of the desired
title compound (75%) as a colorless foam: mp 80-85.degree. C.;
.sup.1H NMR (CDCl.sub.3) .delta. 0.83-0.95 (m, 6H), 1.30-1.52 (m,
10H), 1.52-1.73 (m, 3H), 1.79-1.99 (m, 4H), 2.14-2.26 (m, 1H), 2.91
(s, 6H), 3.02-3.22 (m, 4H), 3.92-4.06 (m, 2H), 4.16 (s, 1H), 5.47
(s, 1H), 6.28 (d, J=2.4 Hz, 1H), 6.74 (dd, J=2.7, 8.8 Hz, 1H), 6.89
(d, J=8.7 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 7.98 (d, J=8.7 Hz, 1H).
HRMS Calc'd for C.sub.32H.sub.48N.sub.5O- .sub.4S: 598.3427. Found:
598.3443.
EXAMPLE 1421
[0814] 492
[0815]
(4R-cis)-4-[[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-
-4-hydroxy-1,1-dioxido-1-lbenzothiepin-5-yllphenoxylpentyl]oxy]-2,6-pyridi-
necarboxylic acid
[0816] Step 1: Preparation of pentyl bromide intermediate
[0817] To a solution of 0.63 g (15.72 mmol, 60% disp) of NaH in 85
mL of DMF was add 6.0 g (13.1 mmol) of
5-(4'-hydroxyphenyl)-7-(dimethylamino)te-
trahydrobenzo-thiepine-1,1-dioxide (obtained from Example 1402,
Step 10), and the resulting solution was stirred at ambient
temperature for 1 hour. To the solution was added 37.7 g (163.75
mmol) of 1,5-dibromopentane, and stirred overnight at ambient
temperature. DMF was removed in vacuo and the residue was extracted
with ethyl acetate and washed with brine. The extract was dried
over MgSO.sub.4, and the concentrated residue was purified by
column chromatography to give the pentyl bromide intermediate:
.sup.1NMR (CDCl.sub.3) .delta. 0.90 (q, 6H), 1.05-2.0 (m, 17H), 2.2
(t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 3.4 (t, 2H), 3.95 (t, 2H), 4.1
(s, 1H), 5.42 (s, 1H), 6.0 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.4
(d, 2H), 7.9 (d, 1H).
[0818] Step 2: Esterification of chelidamic acid
[0819] A solution of 10 g (54.6 mmol) of chelidamic acid, 23.0 g
(120.12 mmol) of 1-(3-dimethyl amino propyl)-3 ethyl carbodiimide
hydrochloride, 1.33 g (10.8 mmol) of 4-dimethyl amino pyridine, and
12.4 mL (120.12 mmol) of benzyl alcohol in 100 mL of DMF was
stirred at ambient temperature overnight under N.sub.2. DMF was
removed in vacuo and the residue was extracted with methylene
chloride, washed with 5% NaHCO.sub.3, 5% acetic acid, H.sub.2O, and
brine. The extract was dried over MgSO.sub.4, and the concentrated
residue was purified by column chromatography to give dibenzyl
chelidamic ester: .sup.1NMR (CDCl.sub.3) .delta. 5.4 (s, 4H), 7.4
(m, 12H).
[0820] Step 3: Preparation of pyridinyl benzyl ester
intermediate
[0821] A solution of 79 mg (1.972 mmol, 60% disp) of NaH and 0.716
g (1.972 mmol) of dibenzyl chelidamic ester (obtained from Step 2)
in 17.5 mL of DMF was stirred at ambient temperature for 1 hour. To
the solution was added 1.0 g (1.643 mmol) of the pentyl bromide
intermediate and the mixture was stirred under N.sub.2 overnight at
40.degree. C. DMF was removed in vacuo, and the residue was
extracted with ethyl acetate and washed with brine. The extract was
dried over MgSO.sub.4, and the concentrated residue was purified by
column chromatography to give the pyridinyl dibenzyl ester
intermediate: .sup.1NMR (CDCl.sub.3) .delta. 0.90 (q, 6H), 1.05-2.0
(m, 19H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 4.0 (t, 2H), 4.1
(s, 1H), 5.4 (s, 4H), 5.42 (s, 1H), 6.0 (s, 1H), 6.5 (d, 1H), 6.9
(d, 2H), 7.3-7.5 (m, 12H), 7.78 (s, 2H), 7.9 (d, 1H).
[0822] Step 4: Preparation of pyridinyl diacid
[0823] A suspension of 0.8813 g (0.99 mmole) of dibenzyl ester
(obtained from Step 3) and 40 mg of 10% Pd/C in 35 mL of ethanol
and 5 mL of THF was agitated at ambient temperature under 20 psi of
hydrogen gas for 2 hours. The catalyst was filtered off, and the
filtrate was concentrated to give the desired title compound as a
solid: mp 143.degree. C.; 1H NMR (THF-d8) 0.95 (q, 6H), 1.05-1.65
(m, 15H), 1.9 (m, 4H), 2.22 (t, 1H), 2.8 (s, 6H), 3.0 (t, 2H), 4.1
(s, 3H), 4.3 (s, 2H), 5.4 (s, 1H), 6.05 (s, 1H), 6.5 (d, 1H), 6.9
(d, 2H), 7.4 (d, 2H), 7.78 (d, 1H), 7.82 (s, 2H). HRMS. Calc'd for
C.sub.38H.sub.50N.sub.2O.sub.9S: 711.3315. Found: 711.3322. Anal.
Calc'd for C.sub.38H.sub.50N.sub.2O.sub.9S: C, 64.20; H, 7.09; N,
3.94; S, 4.51. Found: C, 62.34; H, 6.97; N, 4.01; S, 4.48.
EXAMPLE 1422
[0824] 493
[0825] (4R-cis)-[5-[4-[3, 3-Dibutyl-7-(dimethylamino)
-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pen-
tyl]guanidine
[0826] Step 1: Preparation of pentyl azide intermediate
[0827] To a stirred solution of 200 mg (0.328 mmol) of the pentyl
bromide intermediate (obtained from Example 1420, Step 1) in 0.75
mL of DMSO was added 32 mg (0.493 mmol) of sodium azide and a
catalytic amount of sodium iodide. The reaction was stirred at
ambient temperature for 64 hours. The reaction was concentrated
under a nitrogen stream and the residue partitioned between ethyl
acetate and water. The organic layer was washed with brine, dried
over MgSO.sub.4, filtered, and concentrated in vacuo to afford 155
mg (92% RPHPLC purity, about 76% yield) of the pentyl azide
intermediate as a colorless foam. Sample was used without further
purification: mp 45-50.degree. C.; .sup.1NMR (CDCl.sub.3) .delta.
0.83-0 93 (m, 6H), 1.03-1.48 (m, 10H), 1.54-1.74 (m, SH), 1.78-1.86
(m, 1H), 2.14-2.26 (m, 1H), 2.81 (s, 6H) , 3.06 (ABq, JA =15.0, 48.
0 Hz, 2H) , 3.31 (t, J=6.3 Hz, 2H), 3.98 (t, J=6.3 Hz, 2H), 4.09
(s, 1H), 5.47 (s, 1H), 6.10 (d, J=1.8 Hz, 1H), 6.63 (dd, J=2.7, 9.0
Hz, 1H), 6.91 (d, J=9.0 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.91 (d,
J=8.7 Hz, 1H) . MS (FAB, M+H) m/e 571.
[0828] Step 2: Preparation of pentyl amine intermediate
[0829] To a solution of 0.67 g (1.17 mmol) of the azide
intermediate (obtained from Step 1) in 75 mL of ethanol was added
0.10 g of 10% palladium on carbon and the mixture shaken under 49
psi of hydrogen at ambient temperature for 3.5 hours. The reaction
was filtered through celite and concentrated in vacuo to give 0.62
g (86% RPHPLC purity, ca. 84%) of pentyl amine intermediate as an
off-white foam. The sample was used without further purification:
mp 70-85.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta. 0.86-0.96 (m,
6H), 1.06-1.75 (m, 15H), 1.79-1.93 (m, 4H), 2.15-2.28 (m, 1H), 2.82
(s, 6H), 2.96-3.20 (m, 4H), 3.99 (t, J=6.0 Hz, 2H), 4.04-4.14 (m,
1H), 5.49 (s, 1H), 6.00 (d, J=1.5 Hz, 1H), 6.51 (d, J=9.0 Hz, 1H),
6.91 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.90 (d, J=8.7 Hz,
1H). MS (ES, M+H) m/e 545.
[0830] Step 3: Preparation of guanidine
[0831] To a stirred solution of 258 mg (0.474 mmol) of pentyl amino
intermediate (obtained from Step 2) and 81 mg (0.551 mmol) of
1H-pyrazole-1-carboxamidine hydrochloride in 1.5 mL of DMF was
added 71 mg (0.551 mmol) of diisopropylethylamine. The reaction was
stirred at ambient temperature for 16 hours.
[0832] Purification by reversed phase chromatography (Waters-Delta
prep) using 60% water/acetonitrile afforded 120 mg (43%) of the
desired title compound as colorless foamy solid: mp
67.0-72.5.degree. C.; 1H NMR (CDCl.sub.3) .delta. 0.89-0.93 (m,
6H), 1.05-1.17 (m, 1H), 1.26-1.90 (m, 16H), 2.07-2.24 (m, IH), 2.81
(s, 6H), 2.99-3.19 (m, 4H), 3.98 (br s, 2H), 4.12 (s, 1H), 5.46 (s,
IH), 6.01 (d, J=2.1 Hz, 1H), 6.51 (dd, J=2.1, 8.0 Hz, 1H), 6.92 (d,
J=8.1 Hz, 2H), 7.41 (d, J=7.8 Hz, 2H), 7.89 (d, J=8.7 Hz, 1H) .
HRMS. Calc'd for C.sub.32H.sub.50N.sub.4O.sub.4S:586.3552- .
Found(M+H): 587.3620.
EXAMPLE 1423
[0833] 494
[0834]
(4R-cis)-N-[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro--
4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxylpentyl]glycine
[0835] Step 1: Preparation of pentyl azide intermediate
[0836] To a solution of pentyl bromide intermediate (400 mg, 0.657
mmol, obtained from Example 1420, Step 1) in dimethyl sulfoxide (20
mL) was added sodium azide (47 mg, 0.723 mmol, 1.1 eq), and the
resulting clear solution was stirred at 23.degree. C. for 16h. The
reaction solution was diluted with 100 mL ethyl acetate, then
washed with water (2.times.100 mL) and brine (lx 100 mL). The
organic layer was dried (MgSO.sub.4) and concentrated in vacuo to
give 390 mg (quantitative) of pentyl azide intermediate as a yellow
oil: .sup.1NMR (CDCl.sub.3) .delta. 0.82-0.90 (m, 7H), 1.05-1.56
(m, 12H), 1.59-1.71 (m, 3H), 1.78-2.01 (m, 4H), 2.20 (t, J=8.3 Hz,
1H), 2.82 (s, 6H), 3.08 (q, 2H), 3.44 (t, J=7.7 Hz, 2H), 3.99 (t,
J=7.7 Hz, 2H), 4.91 (br s, 1H), 5.47 (s, 1H), 6.13 (d, J=7.58 Hz,
1H), 6.68 (d, J=7.7 Hz, 1H), 7.14 (ABq, 4H) , 7.91 (d, U =7.8 Hz,
1H).
[0837] Step 2: Preparation of amino ester intermediate
[0838] A suspension of pentyl azide intermediate (390 mg, 0.684
mmol, obtained from Step 1) and 100 mg of palladium on carbon in
ethanol (15 mL) was agitated under an atmosphere of hydrogen gas
(48 psi) for 4.5 hours. The ethanolic suspension was filtered
through celite and concentrated in vacuo to give a yellow oil. The
oil was immediately diluted with acetonitrile (15 mL), followed by
the addition of triethylamine (0.156 g, 1.54 mmol, 2.25 eq) and
bromo acetic acid benzyl ester (0.212 g, 0.925 mmol, 1.35 eq). The
reaction was stirred at 23.degree. C. for 48 hours. The reaction
was concentrated in vacuo, and the residue was dissolved in ethyl
acetate (20 mL) and washed with water (2.times.20 mL) and brine
(1.times.20 mL). The organic layer was dried (MgSO.sub.4) and dried
in vacuo to give 420 mg (89%) of the amino ester intermediate as a
yellow oil: .sup.1H NMR (CDCl.sub.3) .delta. 0.82-0.90 (m, 6H),
1.05-1.56 (m, 14H), 1.58-1.71 (m, 3H), 1.78-2.01 (m, 4H), 2.20 (t,
J=8.3 Hz, 1H), 2.75 (d, J=7.83 Hz, 1H), 2.795 (s, 6H), 3.08 (q,
2H), 3.68-3.85 (m, 2H), 3.87-4.04 (m, 2H), 4.09 (s, 1H), 5.147 (s,
1H), 5.46 (s, 1H), 5.98 (d, J=7.58, 1H), 6.50 (dd, 1H), 6.85-6.87
(m, 2H), 7.28-7.45 (m, 5H), 7.89 (d, J=8.0 Hz, 1H). MS (ES) m/e
693.
[0839] Step 3: Preparation of acid
[0840] A suspension of benzyl ester intermediate (0.420 g, 0.61
mmol, obtained from Step 2) and 100 mg of palladium on carbon in
ethanol (15 mL) was agitated under an atmosphere of hydrogen gas
(48 psi) for 16 h. The suspension was filtered through celite, and
concentrated in vacuo to give 0.330 g of a yellow semi-solid. The
material was triturated with diethyl ether =and the remaining
semi-solid was dried in vacuo to give 0.19 g (52%) of the desired
title compound as a yellow semi solid: .sup.1NMR (CDCl.sub.3)
.delta. 0.86 (br s, 7H), 1.0-1.72 (m, 18H), 1.79 (br s, 2H), 1.98
(s, 2H), 2.09-2.24 (m, 2H), 2.78 (s, 6H), 2.99 (q, 2H), 3.96 (bs,
2H), 4.08 (s, 1H), 5.46 (s, 1H), 5.97 (s, 1H), 6.40-6.49 (m, 1H),
7.14 (ABq, 4H), 7.85 (t, J=7.93 Hz, 1H). MS (ES) m/e 603.
EXAMPLE 1424
[0841] 495
[0842]
(4R-cis)-4-[[4-[3,3-Dibutyl-7-(dinethylamino)-2,3,4,5-tetrahydro-4--
hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxylmethyllbenzoic
acid
[0843] Step 1: Preparation of benzoate intermediate
[0844] To a solution of 0.53 g (1.15 mmol) of
5-(4'-hydroxyphenyl)-7-(dime-
thylamino)tetrahydrobenzo-thiepine-1,1-dioxide (obtained from
Example 1402, Step 10) in 10 mL dimethylformamide was added 35 mg
(1.39 mmol) of 95% sodium hydride and stirred for 10 minutes. To
the reaction mixture was added 525 mg (2.29 mmol) methyl
4-(bromomethyl)benzoate and stirred for 16 hours. Water was added
to the reaction mixture, extracted with ethyl acetate, washed with
brine, dried over magnesium sulfate, filtered and the solvent
evaporated to afford 0.51 g (73%) of the benzoate intermediate:
.sup.1NMR (CDCl.sub.3) .delta. 0.86-0.96 (m, 6H), 1.14-1.47 (m,
10H), 1.60-1.64 (m, 1H), 2.20-2.23 (m, 1H), 2.80 (s, 6H), 2.99 (d,
J=15.1 Hz, 1H), 3.15 (t, J=15.1 Hz, 1H), 3.92 (s, 3H), 4.09-4.15
(m, 1H), 5.17 (s, 2H), 5.49 (s, 1H), 5.94 (d, J=2.2 Hz, 1H), 6.50
(dd, J=8.9, 2.6 Hz, 1H), 7.00 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.5 Hz,
2H), 7.53 (d, J=8.5 Hz, 2H), 7.93 (d, J=8.9 Hz, 1H), 8.06 (d, J=8.5
Hz, 2H).
[0845] Step 2: Preparation of acid
[0846] A solution of 0.51 g (0.84 mmol) of the benzoate
intermediate (obtained from Step 1) and 325 mg (2.53 mmol) of
KOSi(CH.sub.3).sub.3 (Aldrich) in 16 mL THF was stirred for 3.5
hours. The THF was evaporated, water added, extracted with ethyl
acetate, dried over magnesium sulfate, filtered and the solvent
evaporated to afford 0.30 g (60%) of the desired title compound as
a white solid: mp 156 - 159.degree. C.; .sup.1NMR (CDCl.sub.3)
.delta. 0.89-0.94 (m, 6H), 1.24-1.43 (m, 10H), 1.62-1.66 (m, 1H),
2.20-2.24 (m, 1H), 2.84 (s, 6H), 3.02 (d, J=15.1 Hz, 1H), 3.17 (d,
J=15.1 Hz, 1H), 4.14 (s, 1H), 5.20 (s, 2H), 5.50 (S, 1H), 6.16 (s,
1H), 6.71 (d, J=9.1 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.1
Hz, 2H), 7.57 (d, J=8.3 Hz, 2H), 7.95 (d, J=8.9 Hz, 1H), 8.13 (d,
J=8.1 Hz, 2H) . HRMS. Calc'd for C3.sub.4H.sub.44NO.sub.6S:
594.2889. Found: 594.2913.
EXAMPLE 1425
[0847] 496
[0848]
(4R-cis)-1-[[4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydr-
o-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]--
pyridinium chloride
[0849] Step 1: Preparation of chlorobenzyl intermediate
[0850] A solution of
5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzo-
thiepine-1,1-dioxide (5.0 g, 10.9 mmol, obtained from Example 1402,
Step 10) in acetone (100 mL) at 25.degree. C. under N.sub.2 was
treated with powdered K.sub.2CO.sub.3 (2.3 g, 16.3 mmol, 1.5 eq.)
and .alpha.,.alpha.'-dichloro-p-xylene (6.7 g, 38.1 mmol, 3.5 eq.)
and the resulting solution was stirred at 65.degree. C. for 48
hours. The reaction mixture was cooled to 25.degree. C. and
concentrated to 1/5 of original volume. The residue was dissolved
in EtOAc (150 mL) and washed with water (2.times.150 mL). The
aqueous layer was extracted with EtOAc (2.times.150 mL) and the
combined organic extracts were washed with saturated aqueous NaCl
(2.times.150 mL. The combined extracts were dried (MgSO.sub.4) and
concentrated in vacuo to provide a yellow oil. Purification by
flash chromatography (5.4.times.45 cm silica, 25-40% EtOAc/hexane)
afforded the chlorobenzyl intermediate (4.7 g, 72%) as a white
foam: .sup.1NMR (CDCl.sub.3) .delta. 0.89-0.94 (m, 6H), 1.12-1.48
(br m, 10H), 1.63 (m, 1H), 2.22 (m, 1H), 2.81 (s, 6H), 3.05 (ABq,
J=15.1 Hz, J=50.0 Hz, 2H), 4.11 (d, J=8.1 Hz, 1H), 4.60 (s, 2H),
5.11 (s, 2H), 5.48 (s, 1H), 5.96 (d, J=2.4 Hz, 1H), 6.48 (dd,
J=8.9, 2.6 Hz, 1H), 7.00 (d, J=8.9 Hz, 2H), 7.36-7.47 (m, 5H), 7.85
(d, J=8.9 Hz, 1H).
[0851] Step 2: Preparation of quaternary salt
[0852] A solution of the chlorobenzyl intermediate (1.0 g, 1.7
mmol, obtained from Step 1) in acetonitrile (5 mL) at 25.degree. C.
under N.sub.2 was treated with pyridine (5 mL) and stirred at
35.degree. C. for 36 hours. The pale amber solution was cooled to
25.degree. C. and concentrated in vacuo to give the desired title
compound (1.08 g, 96%) as a yellow solid: mp 154-156.degree. C.;
.sup.1H NMR (CDCl.sub.3) .delta. 0.83 (m, 6H), 1.06-1.44 (br m,
10H), 1.60 (m, IH), 2.13 (m, 1H), 2.71 (s, 6H), 3.02 (ABq, J=15.1
Hz, J=28.4 Hz, 2H), 4.09 (s, 1H), 5.00 (s, 2H), 5.38 (s, 1H), 5.91
(d, J=2.4 Hz, 1H), 6.26 (s, 2H), 6.41 (dd, J=8.9, 2.4 Hz, 1H), 6.91
(d, J=8.7 Hz, 2H), 7.26 (m, 1H), 7.40 (d, J=7.7 Hz, 4H), 7.73 (d,
J=7.9 Hz, 2H), 7.78 (d, J=8.9 Hz, 2H), 7.93 (t, J=6.8 Hz, 1H), 8.34
(t, J=7.7 Hz, 1H), 8.58 (br s, 1H), 9.69 (d, J=5.8 Hz, 2H); HRMS.
Calc'd for C.sub.39H.sub.49N.sub.2O.sub.4S: 641.3413. Found:
641.3425.
EXAMPLE 1426
[0853] 497
[0854] (4R-cis)
-1-[4-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-
-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-4-
-aza-1-azoniabicyclo[2.2.2]octane chloride
[0855] Under N.sub.2, a solution of 8.7 g (14.5 mmol) of the
chlorobenzyl intermediate (obtained from a procedure similar to the
one outlined in Example 1425, Step 1) in 60 mL of acetonitrile was
added dropwise over a 30 min period to a solution of 2.9 g (26.2
mmol) of diazabicyclo[2.2.2]octane (DABCO) in 40 mL of acetonitrile
at 35.degree. C.; during the addition, a colorless precipitate was
formed. The slurry was stirred at 35.degree. C. for an additional 2
h. The product was collected and washed with 1 L of acetonitrile to
give 9.6 g (93%) the title compound as a colorless crystalline
solid: mp 223-230.degree. C. (decomposed); .sup.1H NMR (CDCl.sub.3)
.delta. 0.89 (m, 6H), 1.27-1.52 (br m, 10H), 1.63 (m, 1H), 2.20 (m,
1H), 2.81 (s, 6H), 3.06 (ABq, J 15.1 Hz, J=43.3 Hz, 2H), 3.16 (s,
6H), 3.76 (s, 6H), 4.11 (d, J=7.7 Hz, 1H), 5.09 (s, 2H), 5.14 (s,
2H), 5.48 (s, 1H), 5.96 (s, 1H), 6.49 (d, J 8.9 Hz, 1H), 6.99 (d,
J=8.0 Hz, 2H), 7.26 (m, 1H), 7.44 (d, J 8.0 Hz, 2H), 7.52 (d, J=7.4
Hz, 2H), 7.68 (d, J 7.4 Hz, 2H), 7.87 (d, J=8.9 Hz, 1H); HRMS.
Calc'd for C.sub.40H.sub.56N.sub.3O.sub.4S: 674.3992. Found:
674.4005.
EXAMPLE 1426a
[0856] 498
[0857]
(4R-cis)-1-[[4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydr-
o-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyll--
4-aza-1-azoniabicyclo[2.2.2]octane chloride
[0858] A solution of the chlorobenzyl intermediate (4.6 g, 7.7
mmol, obtained from Example 1425, Step 1) in acetonitrile (100 mL)
at 25.degree. C. under N.sub.2 was treated with
diazabicyclo[2.2.2]-octane (DABCO, 0.95 g, 8.5 mmol, 1.1 eq.) and
stirred at 35.degree. C. for 2 hours, during which time a white
solid precipitated out. The white solid was collected, washed with
CH.sub.3CN and recrystallized from CH.sub.30H/Et.sub.2O to give the
title compound (4.95 g, 91%) as a white solid: mp 223-230.degree.
C. (decomposed); .sup.1NMR (CDCl.sub.3) .delta. 0.89 (m, 6H),
1.27-1.52 (br m, 10H), 1.63 (m, 1H), 2.20 (m, 1H), 2.81 (s, 6H),
3.06 (ABq, J=15.1 Hz, J=43.3 Hz, 2H), 3.16 (s, 6H), 3.76 (s, 6H),
4.11 (d, J=7.7 Hz, 1H), 5.09 (s, 2H), 5.14 (s, 2H), 5.48 (s, 1H),
5.96 (s, 1H), 6.49 (d, J=8.9 Hz, 1H), 6.99 (d, J=8.0 Hz, 2H), 7.26
(m, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.52 (d, J=7.4 Hz, 2H), 7.68 (d,
J=7.4 Hz, 2H), 7.87 (d, J=8.9 Hz, 1H); HRMS. Calc'd for
C.sub.40Hs.sub.6QO.sub.4S: 674.3992. Found: 674.4005.
EXAMPLE 1427
[0859] 499
[0860]
4R-cis)-N-(Carboxymethyl)-N-[[4-[[4-[3,3-dibutyl-7-(dimethylamino)--
2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxylmethy-
llphenyl]methyl]glycine
[0861] Step 1: Preparation of chlorobenzyl intermediate
[0862] To a stirred solution of 144 mg (3.59 mmol, 60% disp) of NaH
in 29 mL of DMF was added 1.5 g (3.26 mmol) of
5-(4'-hydroxyphenyl)-7-(dimethyl-
amino)tetra-hydrobenzothiepine-1,1-dioxide (obtained from Example
1402, Step 10), and the resulting solution was stirred at ambient
temperature for 45 min. To the solution was added 7.13 g (40.75
mmol) of dichloro p-xylene, and the mixture was stirred overnight.
DMF was removed in vacuo, and the residue was extracted with ethyl
acetate and washed with brine. The extract was dried over
MgSO.sub.4, and the concentrated residue was purified by column
chromatography to give the chlorobenzyl intermediate: .sup.1H NMR
(CDCl.sub.3) .delta. 0.90 (q, 6H), 1.05-1.65 (m, 11H), 2.2 (t, 1H),
2.8 (s, 6H), 3.0 (q, 2H), 4.1 (d, 1H), 4.6 (s, 2H), 5.1 (s,2H), 5.5
(s, IH), 6.0 (s, 1H), 6.6 (d,1H), 7.0 (d, 2H), 7.4 (m, 6H), 7.8
(d,1H).
[0863] Step 2: Preparation of amino diester
[0864] A mixture of 1.03 g (1.72 mmol) of chlorobenzyl intermediate
(obtained from Step 1), 1.63 g (8.6 mmol) of diethyl amino
diacetate, and 0.72 g (8.6 mmol) of NaHCO.sub.3 in 30 mL of DMF was
stirred at 100.degree. C. for 6 hours. DMF was removed in vacuo and
the residue was extracted with ether and washed with brine. The
extract was dried over MgSO.sub.4, and the concentrated residue was
purified by column chromatography to give amino diester
intermediate: .sup.1NMR (CDCl.sub.3) .delta. 0.90 (q, 6H),
1.05-1.65 (m, 17H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 3.55 (s,
4H), 3.95 (s, 2H), 4.1-4.2 (m, 5H), 5.05 (s, 2H), 5.42 (s, 1H),
5.95 (s, 1H), 6.5 (d, 1H), 7.0 (d, 2H), 7.4 (s, 6H), 7.8 (d,
1H).
[0865] Step 3: Preparation of amino diacid
[0866] A solution of 0.863 g (1.15 mmol) of dibenzyl ester
(obtained from Step 2) and 0.232 g (5.52 mmol) of LiOH in 30 mL of
THF and 30 mL of water was stirred at 40.degree. C. under N.sub.2
for 4 hours. The reaction mixture was diluted with ether and washed
with 1% HCl. The aqueous layer was extracted twice with ether, and
the combined extracts were washed with brine, dried over
MgSO.sub.4, and concentrated in vacuo to give the desired title
compound as a solid: mp 175.degree. C.; .sup.1NMR (THF-d8) 0.95 (q,
6H), 1.05-1.65 (m, l1H), 2.22 (t, 1H), 2.8 (s, 6H), 3.0 (t, 2H),
3.5 (s, 4H), 3.9 (s, 2H), 4.1 (d, 1H), 5.1 (s, 2H), 5.4 (s, 1H),
6.05 (s, 1H), 6.5 (d, 1H), 7.0 (d, 2H), 7.4 (m, 6H), 7.78 (d, 1H).
HRMS. Calc'd for C.sub.38H.sub.50N.sub.2O.sub.8S: 695.3366. Found:
695.3359. Anal. Calc'd for C.sub.38H.sub.50N.sub.2O.sub.8S: C,
65.68; H, 7.25; N, 4.03; S, 4.61. Found: C, 64.95; H, 7.32; N,
3.94; S, 4.62.
EXAMPLE 1428
[0867] 500
[0868]
(4R-cis)-4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4--
hydroxy-1,1-dioxido-1,1-dioxido-1-benzothiepin-5-yllphenoxy]methyl]-1-meth-
ylpyridinium salt with trifluoroacetic acid (1:1)
[0869] Step 1: Preparation of picolyl intermediate
[0870] To a stirred solution of 12.0 g (26.1 mmol) of
5-(4'-hydroxyphenyl)-7-(dimethylamino)tetra-hydrobenzothiepine-1,1-dioxid-
e (obtained from Example 1402, Step 10) in 200 mL of DMF was added
1.4 g (60% oil dispersion, 35 mmol) of sodium hydride and the
reaction stirred at ambient temperature for one hour. 5.99 g (36.5
mmol) of 4-picolyl chloride hydrochloride was treated with cold
saturated NaHCO, solution and extracted with diethyl ether. The
ethereal extracts were washed with brine, dried over MgSO.sub.4,
and filtered. The reaction was cooled in an ice bath and the
solution of 4-picolyl chloride in diethyl ether was added. The
reaction was stirred at ambient temperature for 17 hours. The
reaction was quenched with 25 mL of saturated NH.sub.4Cl, diluted
with 600 mL ethyl acetate washed with 4X250 mL water, brine, dried
over MgSO.sub.4, filtered and concentrated in vacuo. Purification
by silica gel chromatography (Waters-prep 500) using 60% ethyl
acetate/hexanes afforded 11.05 g (77%) of the picolinyl
intermediate as a colorless solid: mp 95-98.degree. C.; .sup.1NMR
(CDCl.sub.3) .delta. 0.86-0.96 (m, 6H), 1.02-1.52 (m, lOH),
1.58-1.70 (m, 1H), 2.16-2.29 (m, 1H), 2.81 (s, 6H), 3.07 (ABq, Ja
=15.3, 49.6 Hz, 2H), 4.10 (d, J=7.5 Hz, 1H), 5.15 (s, 2H), 5.50 (s,
1H), 5.94 (d, J=2.7 Hz, 1H), 6.51 (dd, J=2.4, 8.7 Hz, 1H), 7.00 (d,
J=9.0 Hz, 2H), 7.39 (d, 6.0 Hz, 2H), 7.44 (s, J=8.7 Hz, 2H), 7.89
(d, J=9.0 Hz, 2H), 8.63 (dd, J=1.6, 4.8 Hz, 2H).
[0871] Step 2: Preparation of quaternary salt
[0872] To a stirred solution of 0.41 g (0.74 mmol) of picolinyl
intermediate (obtained from Step 1) in 10 mL of acetonitrile and 3
mL of dichloromethane was added 137 mg (0.97 mmol) of iodomethane.
The reaction was stirred at ambient temperature for 16 hours, then
concentrated under a nitrogen stream. Purification by reversed
phase chromatography (Waters-Delta prep) using 60-55%
water/acetonitrile afforded 0.304 g (60%) of the desired title
compound as a colorless solid: mp 96-99 .degree. C.; .sup.1H NMR
(CDCl.sub.3) .delta. 0.85-0.95 (m, 6H), 1.03-1.52 (m, 10H),
1.57-1.70 (m, 1H), 2.12-2.27 (m, 1H), 2.84 (s, 6H), 3.09 (ABqf Js
=15.0, 27.9 Hz, 2H), 4.11 (s, 1H), 4.46 (s, 3H), 5.37 (s, 2H), 5.50
(s, 1H), 6.07 (d, J=2.4 Hz, 1H), 6.61 (dd, J=2.5, 8.7 Hz, 1H), 7.02
(d, J=8.7 Hz, 2H), 7.48 (d, J=7.2 Hz, 2H), 7.90 (d, J=8.7 Hz, 1H),
8.14 (d, J=6.3 Hz, 2H), 8.80 (d, J=6.6 Hz, 2H). HRMS Calc'd for
C.sub.33H.sub.4,N.sub.20.sub.4S: 565.3100. Found: 565.3125.
EXAMPLE 1429
[0873] 501
[0874]
(4R-cis)-4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4--
hydroxy-1,1-dioxido-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]-1-meth-
ylpyridinium, methanesulfonate (salt)
[0875] To a stirred solution of 6.5 g (11.8 mmol) of picolyl
intermediate (obtained from Example 1428, Step 1) in 140 mL of
acetonitrile heated at 70.degree. C. was added 1.56 g (14.6 mmol)
methanesulfonic acid methyl ester. Heating was continued at
70.degree. C. for 15 hours. The reaction was cooled and diluted
with 50 mL of ethyl acetate. The solid was collected by vacuum
filtration to give 6.14 g (79%). The filtrate was concentrated in
vacuo and the residue crystallized from hot acetonitrile to give
1.09 g (14%). A total of 7.23 g (93%) of the desired title compound
was obtained as an off-white solid: mp 232-233.5.degree. C.;
.sup.1NMR (CDCl.sub.3) .delta. 0.66-0.76 (m, 6H), 0.85-0.95 (m,
1H), 0.95-1.35 (m, 9H), 1.42- 1.54 (m, 1H), 1.95-2.22 (m, 1H), 2.50
(s, 1H), 2.56 (s, 3H), 2.63 (s, 6H), 2.91 (ABqr J=16.5, 24.0 Hz,
2H), 3.88 (s, 1H), 4.40 (s, 3H), 5.21 (s, 3H), 5.78 (d, J=2.4 Hz,
1H), 6.31 (dd, J=2.5, 8.7 Hz, 1H), 6.84 (d, J=8.7 Hz, 2H), 7.31 (d,
J=8.4 Hz, 2H), 7.64 (d, J=8.7 Hz, 1H), 8.0 (d, J=6.6 Hz, 2H), 9.02
(d, JL=6.6 Hz, 2H). HRMS Calc'd for
C.sub.33H.sub.45N.sub.2O.sub.4S: I565.3100. Found: 656.3087. Anal.
Calc'd for C.sub.34H.sub.48N.sub.2O.sub.7S.sub.2: C, 61.79; H,
7.32; N, 4.24; S, 9.70. Found: C, 61.38, H, 7.47; N, 4.22; S,
9.95.
EXAMPLE 1430
[0876] 502
[0877]
(4R-cis)-6-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4--
hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]-2-pyridinepropanoi-
c acid
[0878] Step 1: Preparation of picolinyl chloride intermediate
[0879] To a solution of
5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobe-
nzothiepine-1,1-dioxide (1 g, 2.1 mmol, obtained from Example 1402,
Step 10) in acetone (50 mL) was added anhydrous K.sub.2CO.sub.3
(0.45 g, 3.2 mmol), tetrabutylammonium iodide (0.1 g, 0.2 mmol) and
2,6-bischloromethylpyridine (1.2 g, 10.8 mmol). The flask was
equipped with nitrogen gas adapter and magnetic stirrer. The
reaction was heated to reflux Ifor overnight. After 18 hours, the
reaction was diluted with ether and washed with water and brine (30
ML). The organic layers were dried over MgSO.sub.4, filtered and
concentrated in vacuo. Chromatographic purification through silica
gel, eluting with 25% EtOAc/Hexane gave 0.75 g (55%) of the picolyl
chloride intermediate as an oil (0.70 g, 55%): .sup.1H NMR
(CDCl.sub.3) .delta. 0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H),
1.56-1.66 (m, 1H), 2.14-2.24 (m, 1H), 2.80 (s, 6H) 3.05 (ABq, 2H),
4.10 (d, 2H), 4.65 (s, 2H), 5.20 (s, 2H), 5.45 (s, 1H), 5.95 (s,
1H), 6.50 (d, 1H), 7.0 (d, 2H),7.35-7.50 (m, 4H), 7.70-7.85 (m,
2H).
[0880] Step 2: Preparation of pyridinyl malonate intermediate
[0881] Dibenzyl malonate (1.42 g, 5.01 mmol) in DMF (20.0 ml) and
sodium hydride (0.13 g, 3.3 mmol) were placed in a dry three-neck
flask. The flask was equipped with nitrogen gas adapter and
magnetic stirrer. The picolyl chloride intermediate (lg, 1.67 mmol)
was added and heated at 90.degree. C. for overnight. The reaction
was cooled and extracted with 5% HC1 with methylene chloride and
washed with water (25 mL), and brine (50 mL). The organic layers
were dried over MgSO.sub.4, filtered and concentrated. The residue
was purified by C-18 reversed phase column eluting with 50%
acetonitrile/water and gave pyridinyl malonate intermediate as a
white foamy solid (lg, 71%): .sup.1NMR (CDCl.sub.3) .delta.
0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H), 1.56-1.66 (m, IH), 2.14-2.24
(m, 1H), 2.80 (s, 6H) 3.05 (ABq, 2H), 3.22 (d, 2H), 4.05 (d, 1H),
4.16 (t, 1H), 5.02(s, 2H), 5.08 (s, 4H), 5.44 (s, 1H), 5.97 (s,
1H), 6.96-7.10 (m, 3H), 7.20-7.32 (m, 12H), 7.5 (t, 1H), 7.9 (d,
1H).
[0882] Step 3: Preparation of pyridinyl acid
[0883] The pyridinyl malonate intermediate (0.6 g, 0.7 mmol,
obtained from Step 2), THF/water (25.0 mL, 1:1) and lithium
hydroxide monohydrate (0.14 g, 3.4 mmol) were placed in a 100 mL
round-bottom flask. The reaction was stirred at ambient temperature
overnight. After 18 hours, the reaction was extracted with 1% HCl
and ether and then washed with water (20 mL) and brine (30 mL). The
organic layers were dried over MgSO.sub.4, filtered and
concentrated in vacuo gave the desired title compound as a white
solid (0.44 g, 90%): mp 105-107.degree. C.; .sup.1NMR (CDCl.sub.3)
.delta. 0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H), 1.56-1.66 (m, 1H),
2.14-2.24 (m, 1H), 2.80 (s, 6H),3.05 (m, 2H), 3.10 (ABq, 2H), 3.22
(m, 2H), 4.05 (s, 1H), 5.30 (s, 2H), 5.50 (s, 1H), 5.97 (s, 1H),
6.50 (d, 1H), 7.02 (d, 2H), 7.3 (d, 1H), 7.42 (d, 2H), 7.58 (d,
1H), 7.8-7.9 (m, 2H). HRMS. Calc'd for
C.sub.35H.sub.46N.sub.2O.sub.6S: 623.3155. Found: 623.3188.
EXAMPLE 1431
[0884] 503
[0885]
(4R-cis)-N-(Carboxymethyl)-N-[[6-[[4-[3,3-dibutyl-7-(dimethylamino)-
-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yllphenoxylmeth-
yl]-2-pyridinyl]methyl]glycine
[0886] Step 1: Preparation of pyridinyl diester intermediate
[0887] A mixture of diethyl aminodiacetate (8 g, 68 mmol) and
sodium carbonate (0.63 g, 5.9 mmol) was treated with picolyl
chloride intermediate (0.72 g, 1.2 mmol, obtained from Example
1430, Step 1), and stirred at 160.degree. C. for three hours. The
reaction was cooled and diluted with ether and washed with 1% HCl,
water (25 mL), and brine (50 mL). The combined extracts were dried
over MgSO.sub.41 filtered and concentrated in vacuo. The residue
was purified by distillation in the Kugelrohr to give pyridinyl
diester intermediate as a yellowish foamy solid (0.72 g, 80%):
.sup.1H NMR (CDCl.sub.3) .delta. 0.84-0.95 (m, 6H), 1.02-1.5 (m,
16H), 1.56-1.66 (m, 1H), 2.14-2.24 (m, 1H), 2.80 (s, 6H) 3.05 (ABq,
2H), 3.70 (s, 4H), 4.2-4.4 (m, 6H), 5.30 (s, 2H), 5.56 (s, 1H),6.02
(s, 1H), 6.60 (d, 1H), 7.10 (d, 2H),7.50 (m, 3H), 7.61 (d, 1H),
7.80 (t, 1H), 7.95 (d, 1H). HRMS. Calc'd for
C.sub.41H.sub.57N.sub.3O.sub- .8S: 752.3945. Found: 752.3948.
[0888] Step 2: Preparation of pyridinyl diacid
[0889] A mixture of pyridine-aminodiacetate intermediate (0.7 g,
0.93 mmol, obtained from Step 1), and lithium hydroxide monohydrate
(0.18 g, 4.5 mmol) in THF/ water (25.0 mL, 1:1) was stirred at
40.degree. C. overnight (18 hours). The reaction mixture was
diluted with ether and washed with 1% HCl, water (20 mL), and brine
(30 mL). The organic layers were dried over MgSO.sub.4, filtered
and concentrated in vacuo to give the desired title compound as a
white solid (0.44 g, 90%): mp 153-155.degree. C.; .sup.1H NMR
(CDCl.sub.3) .delta. 0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H),
1.56-1.66 (m, 1H), 2.14-2.24 (m, 1H), 2.80 (s, 6H), 3.10 (ABq, 2H),
3.90 (m, 3H), 4.05 (s, 1H), 4.40 (s, 2H), 5.20 (s, 2H), 5.50 (s,
1H), 5.97 (s, 1H), 6.50 (d, 1H), 7.02 (d, 2H), 7.3 (d, 1H), 7.42
(d, 2H), 7.58 (d, 1H), 7.8-7.9 (m, 2H). HRMS. Calc'd for
C.sub.37H.sub.49N.sub.3O.sub.8S: 696.3319. Found:696.3331.
EXAMPLE 1432
[0890] 504
[0891]
(4S-cis)-[2-[2-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-
-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxylethoxy]ethyl]propanedio-
ic acid
[0892] Step 1: Preparation of bromoethyl ether intermediate
[0893] To a stirred solution of 0.192 g (4.785 mmol, 60% disp) of
NaH in 28 mL of DMF was added 2.0 g (4.35 mmol) of
5-(4'-hydroxyphenyl)-7-(dimet-
hylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example
1402, Step 10), and the resulting solution was stirred at ambient
temperature for 30 min. To the solution was added 13.2 g (54.38
mmol) of bis(2-bromoethyl)ether, and stirring was continued at
ambient temperature under N.sub.2 overnight. DMF was removed in
vacuo and the residue was extracted with ethyl acetate and washed
with brine. The extract was dried over MgSO.sub.4, and the
concentrated residue was purified by column chromatography to give
bromoethyl ether intermediate: .sup.1NMR (CDCl.sub.3) .delta. 0.90
(q, 6h), 1.05-1.65 (m, 11H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H),
3.5 (t, 2H), 3.9 (m, 4H), 4.1 (d, 1H), 4.2 (d, 2H), 5.42 (s, 1H),
5.95 (s, IH), 6.5 (d, 1H), 6.95 (d, 2H), 7.4 (d, 2H), 7.9 (d,
1H).
[0894] Step 2: Preparation of diester intermediate
[0895] To a mixture of 94 mg (2.34 mmol, 60% disp) of NaH in 45 mL
of THF and 15 mL of DMF at 0.degree. C. was added 1.33 g (4.68
mmol) of dibenzyl malonate (Aldrich), and the resulting solution
was stirred at ambient temperature for 15 min, followed by the
addition of 0.95 g (1.56 mmol) of bromoethyl ether intermediate
(obtained from Step 1). The mixture was stirred under N.sub.2 at
80.degree. C. overnight. Solvent was removed in vacuo and the
residue was extracted with methylene chloride and washed with
brine. The extract was dried over MgSO.sub.4, and the concentrated
residue was purified by column chromatography to give the diester
intermediate: .sup.1NMR (CDCl.sub.3) .delta. 0.90 (q, 6H),
1.05-1.65 (m, 11H), 2.2-2.3 (m, 3H), 2.8 (s, 6H), 3.0 (q, 2H), 3.6
(t, 2H), 3.7 (m, 3H), 4.1 (m, 3H), 5.1 (s, 4H), 5.42 (s, 1H), 5.9
(s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.3 (m, 10H), 7.4 (d, 2H), 7.9
(d, 1H).
[0896] Step 3: Preparation of diacid
[0897] A suspension of 0.761 g (0.935 inmol) of the diester
intermediate (obtained from Step 2) and 35 mg of 10% Pd/C in 25 mL
of ethanol and 5 mL of THF was agitated at ambient temperature
under 20 psi of hydrogen gas for 2 hours. The catalyst was filtered
off, and the filtrate was concentrated to give the desired title
compound as a solid: mp 119.5.degree. C.; .sup.1NMR (THF-d8) 0.95
(q, 6H), 1.05-1.65 (m, l1H), 2.1 (q, 2H), 2.25 (t, 1H), 2.8 (s,
6H), 3.0 (t, 2H), 3.47 (q, 2H), 3.58 (s, 1H), 3.78 (t, 2H), 4.08
(d, 1H), 4.15 (t, 2H), 5.4 (s, 1H), 6.05 (s, 1H), 6.55 (d, 1H),
6.98 (d, 2H), 7.42 (d, 2H), 7.8 (d, 1H). HRMS. Calc'd for
C.sub.33H.sub.47NO.sub.9S: 632.2893. Found: 632.2882. Anal. Calc'd
for C.sub.33H.sub.47NO.sub.9S: C, 62.54; H, 7.47; N, 2.21; S, 5.06.
Found: C, 61.75; H, 7.56; N, 2.13; S, 4.92.
EXAMPLE 1433
[0898] 505
[0899]
(4R-cis)-a-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4--
hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxylmethyl]-w-methoxypoly(oxy--
1,2-ethanediyl)
[0900] Step 1: Preparation of monomethyl PEG mesylate
intermediate
[0901] To a solution of 20 g of monomethyl ether PEG in 100 mL of
methylene chloride was added 2.2 g (22 mmol) of triethyl amine, and
to the resulting solution at 0.degree. C. was added dropwise 2.5 g
(22 mmol) of methanesulfonyl chloride. The resulting solution was
stirred overnight at ambient temperature, and the triethyl amine
hydrochloride was filtered off to give the monomethyl PEG mesylate
intermediate which was used in the next Step without further
purification and characterization.
[0902] Step 2: Preparation of polyethylene-linked benzothiepene
[0903] A mixture of 38 mg (1.52 mmol 95%) of NaH and 0.7 g (1.52
mmol) of
5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide
(obtained from Example 1402, Step 10) in 5.5 mL of DMF was stirred
at ambient temperature under N.sub.2 for 30 min. To the solution
was added 0.55 g (0.51 mmol) of the mesylate PEG intermediate
(obtained from Step 1) in 5.5 mL of DMF, and the resulting solution
was stirred overnight under N.sub.2 at 50.degree. C. DMF was
removed in vacuo and the residue was extracted with methylene
chloride and washed with brine. The extract was dried over
MgSO.sub.4, and the concentrated residue was purified by column
chromatography to give the desired title compound as an oil:
.sup.1NMR (CDCl.sub.3) .delta. 0.9 (q, 6h), 1.05-1.65 (m, l1H), 2.2
(t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 3.4 (s, 4H), 3.5-3.85 (m, 95H),
4.1 (s, 1H), 4.15 (t, 2H), 5.5 (s, 1H), 6.05 (s, 1H), 6.6 (d, 1H),
6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).
EXAMPLE 1434
[0904] Preparation of: 506
[0905] The 3-aminobenzothiepene prepared in Step 5 of Example 1398
(0.380 g, 0.828 mmol), sodium hydroxide (0.35 mL, 0.875 mmol, 10%
in H.sub.2O) and toluene (0.50 mL) were combined in a 10 mL
round-bottom flask. The reaction flask was purged with N.sub.2,
equipped with magnetic stirrer, and cooled to 0.degree. C. A
solution of 3-chloropropyl chloroformate (1.440 g, 1.10 mmol, 12%
in CH.sub.2Cl.sub.2/ THF) was added. After 3.5 hrs, toluene (3.0
mL) was added, and the mixture was washed with H.sub.2O (2.times.4
mL), dried (MgSO.sub.4), filtered and concentrated in vacuo.
[0906] Purification by flash chromatography on silica gel eluting
with 20% EtOAc/hexane and concentrated in vacuo gave a white solid
(0.269 g, 56%). .sup.1H NMR (CDCl.sub.3) .delta. 0.87-0.93 (m, 6H),
1.05-1.70 (m, l1H), 2.14 (t, J=6.3 Hz, 2H), 2.15-2.25 (m, 1H), 2.81
(s, 6H), 3.07 (ABq, 2H), 3.64 (t, J=6.3 Hz, 2H), 4.11 (d, J=7.5 Hz,
1H), 4.33 (t, J=6.0 Hz, 2H), 5.50 (s, 1H), 5.99 (d, J=2.4 Hz, 1H),
6.51 (dd, J=9.0, 2.7 Hz, 1H), 6.65 (s, 1H), 7.23 (d, J=7.8 Hz, 1H),
7.34-7.39 (m, 2H), 7.54 (d, J=7.2 Hz, 1H), 7.89 (d, 8.7 Hz, 1H).
HRMS (M+H). Calc'd for C.sub.30H.sub.44N.sub.2- O.sub.5SCl:
579.2659. Found: 579.2691.
EXAMPLE 1435
[0907] Preparation of: 507
[0908] 1,4-Diazabicyclo(2.2.2)octane (0.0785 g, 0.700 mmol) and
acetonitrile (1.0 mL) were combined in a 10 mL round-bottom flask.
The reaction flask was purged with N.sub.2, equipped with magnetic
stirrer, and heated to 37.degree. C. A solution of the product of
Example 1434 (0.250 g, 0.432 mmol) in acetonitrile (2.50 mL) was
added. After 2.5 hrs, 1,4-diazabicyclo(2.2.2)octane (0.0200 g,
0.178 mmol) was added. After 64 hrs, 1,4-diazabicyclo(2.2.2)octane
(0.0490 g, 0.437 mmol) was added. After 24 hrs, the reaction
mixture was cooled to R.T. and concentrated in vacuo. The crude
product was dissolved in acetonitrile (2.0 mL) and precipitated
with ethyl ether (10.0 mL). The precipitate was filtered to yield a
white solid. This trituration method was repeated, followed by
concentrated in vacuo to give a white solid (0.185 g, 62%). mp
218.0-225.0.degree. C.; .sup.1H NMR (CD.sub.3OD) .delta. 0.90 (m,
6H), 1.05-1.55 (m, 10H), 1.16 (t, J=6.6 Hz, 2H), 1.78 (m, 1H), 2.12
(m, 3H), 2.76 (s, 6H), 3.10 (m, 2H), 3.17 (t, J=7.2 Hz, 6H),
3.30-3.50 (m, 8H), 4.10 (s, 1H), 4.21 (t, J=5.4 Hz, 2H), 5.31 (s,
1H), 6.10 (s, 1H), 6.55 (d, J=7.2 Hz, 1H), 7.25 (d, J=6.9 Hz, 1H),
7.33-7.42 (m, 2H), 7.56 (s, 1H), 7.76 (d, J=9.0 Hz, 1H). HRMS.
Calc'd for C.sub.36H.sub.55N.sub.4O.su- b.5SCl: 655.3893. Found:
655.3880.
EXAMPLE 1436
[0909] Preparation of: 508
[0910] Step 1. Preparation of: 509
[0911] 3-Chloromethylbenzoyl chloride (2.25 mL/15.8 mmol) and
acetone (8.0 mL) were combined in a 25 mL round-bottom flask. The
reaction flask was cooled to 0.degree. C., and an aqueous solution
of sodium azide (1.56 g in 5.50 mL/24.0 mmol) was added. After 1.5
hrs, the reaction mixture was poured into ice water (80.0 mL),
extracted with ethyl ether (2.times.25 mL), dried (MgSO.sub.4), and
concentrated in vacuo to give a colorless oil (2.660 g, 86%).
.sup.1H NMR (CDCl.sub.3) .delta. 4.62 (s, 2H), 7.47 (t, J=7.8 Hz,
1H), 7.66 (d, J=7.8 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 8.05 (s,
1H).
[0912] Step 2.
[0913] 3-Chloromethylbenzoyl azide (0.142 g, 0.726 mmol) and
toluene (2.0 mL) were combined in a 10 mL round-bottom flask. The
reaction flask was purged with N.sub.2, equipped with magnetic
stirrer, and heated to 110.degree. C. After 2 hrs, the reaction
mixture was cooled to R.T, and the 3-aminobenzothiepene prepared in
Step 5 of Example 1398 (0.365 g, 0.796 mmol) was added. After 2.25
hrs, the mixture was heated to 50.degree. C. After 0.75 hrs,
3-chloromethylbenzoyl azide (0.025 g, 0.128 mmol) was added, and
the reaction mixture was heated to reflux. After 0.5 hrs, the
reaction mixture was cooled to R.T. and concentrated in vacuo.
Purification by flash chromatography on silica gel eluting with
20-30% EtOAc/hexane and concentrated in vacuo gave a white foamy
solid (0.309 g, 62%). .sup.1H NMR (CDCl.sub.3) .delta. 0.71 (t,
J=5.4 Hz, 3H), 0.88 (t, J=6.3 Hz, 3H), 1.03-1.60 (m, 11H), 1.85 (d,
6.3 Hz, 1H), 2.27 (m, 1H), 2.76 (s, 6H), 3.15 (t, 2H), 4.17 (d,
J=6.6 Hz, 1H), 4.48 (s, 2H), 5.42 (s, 1H), 6.07 (s, 1H), 6.99 (d,
J=7.5 Hz), 7.18-7.26 (m, 2H), 7.30-7.41 (m, 3H), 7.63 (s, 1H), 7.86
(d, J=9.0 Hz, 2H), 7.96 (s, 1H), 8.17 (s, 1H). HRMS (M+Li).
Calculated for C.sub.34H.sub.44N.sub.3O.sub.4SClLi: 632.2901.
Found: 632.2889.
EXAMPLE 1437
[0914] Preparation of: 510
[0915] 1,4-Diazabicyclo(2.2.2)octane (0.157 g, 1.40 mmol) and
acetonitrile (1.00 mL) were combined in a 10 mL round-bottom flask.
The reaction flask was purged with N.sub.2 and equipped with
magnetic stirrer. A solution of the product of Example 1436 (0.262
g, 0.418 mmol) in acetonitrile (2.70 mL) was added. After 2.5 hrs,
a white precipitate had had formed. Ethyl ether (6.0 mL) was added,
and the precipitate was filtered, washed with ethyl ether, and
dried in vacuo to yield a white solid (0.250 g, 80%). mp
246.0-248.0.degree. C.; .sup.1H NMR (CD.sub.3OD) .delta. 0.88 (m,
6H), 1.03-1.55 (m, 10H), 1.76 (m, 1H), 2.11 (m, 1H), 2.74 (s, 6H),
3.11 (m, 8H), 3.37 (m, 6H), 4.12 (s, 1H), 4.39 (s, 2H), 5.31 (s,
1H), 6.11 (s, 1H), 6.52 (dd, J=8.7, 1.8 Hz, 1H), 7.09 (d, J=7.2 Hz,
1H), 7.23 (d, J=6.9 Hz, 1H), 7.32-7.38 (m, 2H), 7.47 (m, 2H), 7.58
(s, 1H), 7.73 (d, J=8.7 Hz, 2H). HRMS. Calculated for
C.sub.40H.sub.56N.sub.5O.sub.4SCI: 702.4053. Found: 702.4064. Anal.
Calculated for C40H56N504SCl: C, 65.06; H, 7.64; N, 9.48; S, 4.34;
Cl, 4.80. Found: C, 64.90; H, 7.77; N, 9.42; S, 4.16; Cl, 4.89.
EXAMPLES 1438 - 1454
[0916] The compounds of Examples 1438 through 1454 can be prepared
in accordance with one or more of the synthetic schemes previously
disclosed in this application or using methods known to those
skilled in the art. 511
EXAMPLE 1455
[0917] 512
[0918] The 3-aminobenzothiepine of step 5 of Example 1398 (0.0165
g/0.0360 mmol), M-NCO-5000 (0.150 g/0.30 mmol) (Methoxy-PEG-NCO, MW
5000, purchased from Shearwater Polymers Inc., 2130 Memorial
Parkway, SW, Huntsville, Alabama 35801), and CDCl.sub.3 (0.7 mL)
were combined in an 8 mm NMR tube. The tube was purged with
N.sub.2. After 72 hrs, the reaction mixture was heated to
50.degree. C. After 24 hrs, an additional aliquot of the
3-aminobenzothiepine of step 5 of Example 1398 (0.0077 g/0.017
mmol) was added. After 24 hrs, the reaction mixture was transferred
to a 2 mL vial and evaporated to dryness with a N.sub.2 purge. The
resulting white solid was dissolved in hot ethyl ether (2.0 mL) and
ethyl acetate (0.057 mL/4 drops), cooled to precipitate and
filtered. This precipitation procedure was repeated until no
starting material was detected in the precipitate (TLC:
SiO.sub.2/80% EtOAc/hexanes). Concentrated in vacuo to give a white
solid (0.0838 g/51%). .sup.1H NMR (CDCl3) d 0.82-0.90 (m, 6H),
1.05-1.49 (m, 14H), 1.18 (t, J=6.8 Hz, 2H), 1.59 (bt, 1H), 2.18
(bt, 1H), 2.34 (s, 2H), 2.78 (s, 6H), 3.04 (ABq, 2H), 3.35-3.80 (m,
625H), 4.09 (d, J=7.2 Hz, 2H), 5.42 (s, 1H), 5.78 (s, 1H), 6.04 (d,
J=16 Hz, 1H), 6.47 (dd, J=6.4, 3.2 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H),
7.31 (bs, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.66 (s, 1H), 7.85 (d, J=8.8
Hz, 1H). Mass spectroscopy data also verified desired product.
BIOLOGICAL ASSAYS
[0919] The utility of the compounds of the present invention is
shown by the following assays. These assays are performed in vitro
and in animal models essentially using a procedure recognized to
show the utility of the present invention.
[0920] In Vitro Assay of compounds that inhibit IBAT-mediated
uptake of [.sup.14C]-Taurocholate (TC) in H14 Cells
[0921] Baby hamster kidney cells (BHK) transfected with the cDNA of
human IBAT (H14 cells) are seeded at 60,000 cells/well in 96 well
Top-Count tissue culture plates for assays run within in 24 hours
of seeding, 30,000 cells/well for assays run within 48 hours, and
10,000 cells/well for assays run within 72 hours.
[0922] On the day of assay, the cell monolayer is gently washed
once with 100 il assay buffer (Dulbecco's Modified Eagle's medium
with 4.5 g/L glucose+0.2% (w/v) fatty acid free bovine serum
albumin- (FAF)BSA). To each well 50 il of a two-fold concentrate of
test compound in assay buffer is added along with 50 pl of 6 .mu.M
[.sup.14C]-taurocholate in assay buffer (final concentration of 3
.mu.M [L.sup.14C]-taurocholate). The cell culture plates are
incubated 2 hours at 37.degree. C. prior to gently washing each
well twice with 100 .mu.l 4.degree. C. Dulbecco's
phosphate-buffered saline (PBS) containing 0.2% (w/v) (FAF)BSA. The
wells are then gently washed once with 100 .mu.l 4.degree. C. PBS
without (FAF)BSA. To each 200 ol of liquid scintillation counting
fluid is added, the plates are heat sealed and shaken for 30
minutes at room temperature prior to measuring the amount of
radioactivity in each well on a Packard Top-Count instrument.
[0923] In Vitro Assay of compounds that inhibit uptake of
[.sup.14C]-Alanine
[0924] The alanine uptake assay is performed in an identical
fashion to the taurocholate assay, with the exception that labeled
alanine is substituted for the labeled taurocholate.
[0925] In Vivo Assay of compounds that inhibit Rat Ileal uptake of
[.sup.14C]-Taurocholate into Bile
[0926] (See"Metabolism of
3.alpha.,7.beta.-dihydroxy-7.alpha.-methyl-5.bet- a.-cholanoic acid
and 3.alpha.,7.beta.-dihydroxy-7.alpha.-methyl-5.beta.-c- holanoic
acid in hamsters" in Biochimica et Biophysica Acta 833 (1985)
196-202 by Une et al.)
[0927] Male wistar rats (200-300 g) are anesthetized with inactin
@100 mg/kg. Bile ducts are cannulated with a 10" length of PE10
tubing. The small intestine is exposed and laid out on a gauze pad.
A canulae (1/8" luer lock, tapered female adapter) is inserted at
12 cm from the junction of the small intestine and the cecum. A
slit is cut at 4 cm from this same junction (utilizing a 8 cm
length of ileum). 20 ml of warm Dulbeccols phosphate buffered
saline, pH 6.5 (PBS) is used to flush out the intestine segment.
The distal opening is cannulated with a 20 cm length of silicone
tubing (0.02" I.D..times.0.037" O.D.). The proximal cannulae is
hooked up to a peristaltic pump and the intestine is washed for 20
min with warm PBS at 0.25 ml/min. Temperature of the gut segment is
monitored continuously. At the start of the experiment, 2.0 ml of
control sample ([.sup.14C]-taurocholate @ 0.05 mi/ml with 5 mM cold
taurocholate) is loaded into the gut segment with a 3 ml syringe
and bile sample collection is begun. Control sample is infused at a
rate of 0.25 ml/min for 21 min. Bile samples fractions are
collected every 3 minute for the first 27 minutes of the procedure.
After the 21 min of sample infusion, the ileal loop is washed out
with 20 ml of warm PBS (using a 30 ml syringe), and then the loop
is washed out for 21 min with warm PBS at 0.25 ml/min. A second
perfusion is initiated as described above but this with test
compound being administered as well (21 min administration followed
by 21 min of wash out) and bile sampled every 3 min for the first
27 min. If necessary, a third perfusion is performed as above that
typically contains the control sample.
[0928] Measurement of Hepatic Cholesterol Concentration (HEPATIC
CHOL)
[0929] Liver tissue was weighed and homogenized in
chloroform:methanol (2:1). After homogenization and centrifugation
the supernatant was separated and dried under nitrogen. The residue
was dissolved in isopropanol and the cholesterol content was
measured enzymatically, using a combination of cholesterol oxidase
and peroxidase, as described by Allain, C. A., et al. (1974) Clin.
Chem. 20, 470.
[0930] Measurement of Hepatic HMG CoA-Reductase Activity (HMG
COA)
[0931] Hepatic microsomes were prepared by homogenizing liver
samples in a phosphate/sucrose buffer, followed by centrifugal
separation. The final pelleted material was resuspended in buffer
and an aliquot was assayed for HMG CoA reductase activity by
incubating for 60 minutes at 37.degree. C. in the presence of
.sup.14C-HMG-CoA (Dupont-NEN). The reaction was stopped by adding
6N HCl followed by centrifugation. An aliquot of the supernatant
was separated, by thin-layer chromatography, and the spot
corresponding to the enzyme product was scraped off the plate,
extracted and radioactivity was determined by scintillation
counting. (Reference: Akerlund, J. and Bjorkhem, I. (1990) J. Lipid
Res. 31, 2159).
[0932] Determination of Serum Cholesterol (SER.CHOL, HDL-CHOL, TGI
and VLDL+LDL)
[0933] Total serum cholesterol (SER.CHOL) was measured
enzymatically using a commercial kit from Wako Fine Chemicals
(Richmond, Va.); Cholesterol C11, Catalog No. 276-64909. HDL
cholesterol (HDL-CHOL) was assayed using this same kit after
precipitation of VLDL and LDL with Sigma Chemical Co. HDL
Cholesterol reagent, Catalog No. 352-3 (dextran sulfate method).
Total serum triglycerides (blanked) (TGI) were assayed
enzymatically with Sigma Chemical Co. GPO-Trinder, Catalog No.
337-B. VLDL and LDL (VLDL+LDL) cholesterol concentrations were
calculated as the difference between total and HDL cholesterol.
[0934] Measurement of Hepatic Cholesterol 7-.alpha.-Hydroxylase
Activity (7a-OHase)
[0935] Hepatic microsomes were prepared by homogenizing liver
samples in a phosphate/sucrose buffer, followed by centrifugal
separation. The final pelleted material was resuspended in buffer
and an aliquot was assayed for cholesterol 7-.alpha.-hydroxylase
activity by incubating for 5 minutes at 37.degree. C. in the
presence of NADPH. Following extraction into petroleum ether, the
organic solvent was evaporated and the residue was dissolved in
acetonitrile/ methanol. The enzymatic product was separated by
injecting an aliquot of the extract onto a C.sub.18 reversed phase
HPLC column and quantitating the eluted material using UV detection
at 240 nm. (Reference: Horton, J. D., et al. (1994) J. Clin.
Invest. 93, 2084).
[0936] Rat Gavage Assay
[0937] Male Wister rats (275-300 g) are administered IBAT
inhibitors using an oral gavage procedure. Drug or vehicle (0.2%
Tween 80 in water) is administered once a day (9:00-10:0 a.m.) for
4 days at varying dosages in a final volume of 2 mL per kilogram of
body weight. Total fecal samples are collected during the final 48
hours of the treatment period and analyzed for bile acid content
using an enzymatic assay as described below. Compound efficacy is
determined by comparison of the increase in fecal bile acid (FBA)
concentration in treated rats to the mean FBA concentration of rats
in the vehicle group.
[0938] Measurement of Fecal Bile Acid Concentration (PBA)
[0939] Total fecal output from individually housed hamsters was
collected for 24 or 48 hours, dried under a stream of nitrogen,
pulverized and weighed. Approximately 0.1 gram was weighed out and
extracted into an organic solvent (butanol/water). Following
separation and drying, the residue was dissolved in methanol and
the amount of bile acid present was measured enzymatically using
the 3.alpha.-hydroxysteroid steroid dehydrogenase reaction with
bile acids to reduce NAD. (Reference: Mashige, F., et al. (1981)
Clin. Chem. 27, 1352).
[0940] [.sup.3H]taurocholate Uptake in Rabbit Brush Border Membrane
Vesicles (BBMV)
[0941] Rabbit Ileal brush border membranes were prepared from
frozen ileal mucosa by the calcium precipitation method describe by
Malathi et al. (Reference: (1979) Biochimica Biophysica Acta, 554,
259). The method for at measuring taurocholate was essentially as
described by Kramer et al. (Reference: (1992) Biochimica Biophysica
Acta, 1111, 93) except the assay volume was 200 .mu.l instead of
100 .mu.l. Briefly, at room temperature a 190 ul solution
containing 2uM [.sup.3H]-taurocholate(0.75 .mu.Ci), 20 mM tris, 100
mM NaCl, 100 mM mannitol pH 7.4 was incubated for 5 sec with 10
.mu.l of brush border membrane vesicles (60-120 .mu.g protein). The
incubation was initiated by the addition of the BBMV while
vortexing and the reaction was stopped by the addition of 5 ml of
ice cold buffer (20 mM Hepes-tris, 150 mM KCl) followed immediately
by filtration through a nylon filter (0.2 um pore) and an
additional 5 ml wash with stop buffer.
[0942] Acyl-CoA;cholesterol Acyl Transferase (ACAT)
[0943] Hamster liver and rat intestinal microsomes were prepared
from tissue as described previously (Reference: (1980) J. Biol.
Chem. 255, 9098) and used as a source of ACAT enzyme. The assay
consisted of a 2.0 ml incubation containing 24 uM Oleoyl-CoA (0.05
pCi) in a 50 mM sodium phosphate, 2 mM DTT ph 7.4 buffer containing
0.25% BSA and 200 pg of microsomal protein. The assay was initiated
by the addition of oleoyl-CoA. The reaction went for 5 min at
37.degree. C. and was terminated by the addition of 8.0 ml of
chloroform/methanol (2:1). To the extraction was added 125 .mu.g of
cholesterol oleate in chloroform methanol to act as a carrier and
the organic and aqueous phases of the extraction were separated by
centrifugation after thorough vortexing. The chloroform phase was
taken to dryness and then spotted on a silica gel 60 TLC plate and
developed in hexane/ethyl ether (9:1). The amount of cholesterol
ester formed was determined by measuring the amount of
radioactivity incorporated into the cholesterol oleate spot on the
TLC plate with a Packard instaimager.
[0944] Data from each of the noted compounds in the assays
described above is as set forth in TABLES 5, 6, 7, and 8 as
follows:
9TABLE 5 In vitro % % Inhibition Inhibition of TC of Alanine % of
Control IC50 Uptake @ Uptake @ Transport of TC in COMPOUND uM* 100
uM # 100 uM # Rat Ileum @ 0.1 mM # Benzothiaze 2 0 45.4 +/- 0.7
pine= 12 25 3 0 4a 3 5a 34 5b 40 0 72.9 .+-. 5.4 @ 0.5 mM 4b 9 18 6
14b 18 14a 13 13 23 15 60 19a 0 19b 15 8a 41 Mixture of 69 8a and
8b Mixture of 6 9a and 9b 6a 5 6b 85 9a 5 0% @ 25 .mu.M 53.7 +/-
3.9 Mixture of 13 6a and 20 Mixture of 0.8 14% @ 25 .mu.M 6d and
10a 21a 37 21c 52 21b 45 6c 2 58.5 68.8 +/- 5.7 at 0.4 nM 6d 0.6
77.7 16.1 +/- 1.1 @ 0.5 mN 30.2 +/- 0.9 @ 0.15 mM 17 10 7 50 49.3
10a 7 77.6 62.4 =/- 2.5 @ 0.2 mM l0b 15 68.6 25 0.1 4% @ 10 .mu.M
26.0 +/- 3.3 26 2 31% @ 25 .mu.M 87.9 +/-1.5 27 5 7% @ 20 .mu.M 28
8 31% @ 20 .mu.M 29 88 @ 50 .mu.M 30 96 @ 50 .mu.M 31 41 @ 50 .mu.M
37 3 0% @ 5 .mu.M 38 0.3 11% @ 5 .mu.M 20.6 +/- 5.7 40 49 @ 50
.mu.M 41 2 0% @ 20 .mu.M 42 1.5 43 1.5 16% @ 25 .mu.M 48 2 22% @ 20
.mu.M 49 0.15 21% @ 200 .mu.M 21.2 +/- 2.7 57 51 @ 50 .mu.M 58 20 @
50 .mu.M 59 70 60 9 59 61 30 175 62 10 63 90 @ 6 .mu.M 64 l00 @ 6
.mu.M *In vitro Taurocholate Cell Uptake #Unless otherwise noted
=Comparative Example is Example No. 1 in WO 93/16055
[0945]
10TABLE 6 Compound TC-uptake TC-uptake TC-uptake ACAT ACAT (H14
Ileal (BBMV) (liver) intestine cells) Loop IC(50) EC(50) IC(50)
IC(50) IC(50) COMP. 1 .mu.M 74 .mu.M 3 .mu.M 20 .mu.M 20 .mu.M
EXAMPLE* 6d 0.6 .mu.M 31 .mu.M 1.5 .mu.M 25 .mu.M 20 .mu.M *38 0.3
.mu.M 12 .mu.M 2 .mu.M 25 .mu.M N.D. 49 0.1 .mu.M 12 .mu.M N.D. 6
.mu.M N.D. 25 0.1 .mu.M 20 .mu.M 0.8 .mu.M 8 .mu.M 8 .mu.M
Comparative Example is Example No. 1 in WO 93/16055
[0946]
11TABLE 7 EFFICACY OF COMPOUND NO. 25 IN CHOLESTEROL-FED HAMSTERS
4% CHOLES- 0.2% PARAMETER CONTROL TYRAMINE CPD. NO. 25 WEIGHT (G)
(mean .+-. SEM, *p<0.05, A-Student's t, B-Dunnett's) day 1 117
(2) 114 (6) 117 (5) day 14 127 (3) 127 (3) 132 (4) LIVER WEIGHT (G)
5.4( 0.3) 4.9 (0.4) 5.8 (0.2) SER.CHOL(mg%) 143 (7) 119 (4)*A,B 126
(2)*A,B HDL-CHOL(mg%) 89 (4) 76 (3)*A,B 76 (1)*A,B VLDL + LDL 54
(7) 42 (3)*A 50 (3) TGI(mg %) 203 (32) 190 (15) 175 (11) HEPATIC
CHOL(mg/g) 2.5 (0.3) 1.9 (0.1)*A,B 1.9 (0.1)*A,B HMG COA
(pm/mg/min.) 15.8 (7.6) 448.8 (21.6)*A,B 312.9 (37.5)*A,B 7a-OHase
(pm/mg/min.) 235.3 (25.1) 24 HR. FECAL Wt (G) 357.2 (28.3)* 291.0
(6.0)*A FBA (mM/24 H/100 g) 2.3 (0.1) A,B 2.4 (0.04) 6.2 (0.8) 2.7
(0.1)*A,B 11.9 (0.5)*A,B 12.3 (1.5) *A,B
[0947]
12TABLE 8 EFFICACY OF COMPOUND NO. 25 IN RAT ALZET MINIPUMP MODEL
20 MPL/DAY PARAMETER CONTROL CPD. NO. 25 (mean .+-. SEM,
*p<0.05, WEIGHT (G) A-Student's t, B-Dunnett's) day 1 307 (4)
307 (3) day 8 330 (4) 310 (4)*A,B LIVER WEIGHT (G) 15.5 (0.6) 14.6
(0.4) SER.CHOL(mg%) 85 (3) 84 (3) HEPATIC CHOL(mg/g) 21 (0.03) 2.0
(0.03) HMG COA pm/mg/min 75.1 (6.4) 318.0 (40.7)*A,B 7a-OHase
(pm/mg/min) 281.9 (13.9) 535.2 (35.7)*A,B 24 HR. FECAL WT (G) 5.8
(0.1) 5.7 (0.4) FBA (mM/24H/100g) 17.9 (0.9) 39.1 (4.5)*A,B
Additional in vitro taurocholate uptake tests were conducted in the
following compounds listed in Table 9.
[0948]
13TABLE 9 Biological Data for Some Compounds of the Present
Invention Alanine Uptake Human TC Percent Compound IC.sub.50
Inhibition Number (.mu.M) @ .mu.M 101 0 @ 1.0 1U2 0.083 103 13 @
0.25 104 0.0056 105 0.6 106 0.8 107 14.0 @ 0.063 108 0.3 109 2.0 @
0.063 110 0.09 111 2.5 112 3.0 113 0.1 114 0.19 115 8.0 116 0.3 117
12.0 @ 0.625 118 0.4 119 1.3 120 34.0 @ 5.0 121 0.068 122 1.07 123
1.67 124 14.0 @ 6.25 125 18.0 126 18 @ 1.25 127 0.55 128 0.7 129
0.035 131 1.28 132 5.4 @ 0.063 133 16.0 134 0.3 135 22.0 136 0.09
137 2.4 138 3.0 139 >25.0 140 141 142 0.5 143 0.03 144 0.053 262
0.07 263 0.7 264 0.2 265 2.0 266 0.5 267 0.073 268 0.029 269 0.08
270 0.12 271 0.07 272 0.7 273 1.9 274 0.18 275 5.0 @ 0.25 276 0.23
277 0.04 278 3.0 279 0.4 280 0.18 281 0.019 282 0.021 283 0.35 284
0.08 285 286 19.0 287 4.0 288 10.0 @ 6.25 289 0.23 290 0.054 291
0.6 292 0.046 293 1.9 294 0.013 295 1.3 296 1.6 1000 1001 1002 1003
1004 1005 0.0004 1006 0.001 1007 0.001 1008 0.001 1009 0.001 1010
0.001 1011 0.001 1012 0.0015 1013 0.002 1014 0.002 1015 0.002 1016
0.002 1017 0.002 1018 0.002 1019 0.002 1020 0.002 1021 0.002 1022
0.002 1023 0.002 1024 0.002 1025 0.002 1026 0.002 1027 0.002 1028
0.002 1029 0.002 1030 0.002 1031 0.002 1032 0.002 1033 0.002 1034
0.002 1035 0.002 1036 0.002 1037 0.0022 1038 0.0025 1039 0.0026
1040 0.003 1041 0.003 1042 0.003 1043 0.003 1044 0.003 1045 0.003
1046 0.003 1047 0.003 1048 0.003 1049 0.003 1050 0.003 1051 0.003
1052 0.003 1053 0.003 1054 0.003 1055 0.003 1056 0.003 1057 0.003
1058 0.003 1059 0.003 1060 0.0036 1061 0.004 1062 0.004 1063 0.004
1064 0.004 1065 0.004 1066 0.004 1067 0.004 1068 0.004 1069 0.004
1070 0.004 1071 0.004 1072 0.004 1073 0.004 1074 0.004 1075 0.0043
1076 0.0045 1077 0.0045 1078 0.0045 1079 0.005 1080 0.005 1081
0.005 1082 0.005 1083 0.005 1084 0.005 1085 0.005 1086 0.005 1087
0.005 1088 0.0055 1089 0.0057 1090 0.006 1091 0.006 1092 0.006 1093
0.006 1094 0.006 1095 0.006 1096 0.006 1097 0.006 1098 0.006 1099
0.0063 1100 0.0068 1101 0.007 1102 0.007 1103 0.007 1104 0.007 1105
0.007 1106 0.0073 1107 0.0075 1108 0.0075 1109 0.008 1110 0.008
1111 0.008 1112 0.008 1113 0.009 1114 0.009 1115 0.0098 1116 0.0093
1117 0.01 1118 0.01 1119 0.01 1120 0.01 1121 0.01 1122 0.011 1123
0.011 1124 0.011 1125 0.012 1126 0.013 1127 0.013 1128 0.017 1129
0.018 1130 0.018 1131 0.02 1132 0.02 1133 0.02 1134 0.02 1135 0.021
1136 0.021 1137 0.021 1138 0.021 1139 0.021 1140 0.023 1141 0.023
1142 0.024 1143 0.027 1144 0.028 1145 0.029 1146 0.029 1147 0.029
1148 0.03 1149 0.03 1150 0.03 1151 0.031 1152 0.036 1153 0.037 1154
0.037 1155 0.039 1156 0.039 1157 0.04 1158 0.06 1159 0.06 1160
0.062 1161 0.063 1162 0.063 1163 0.09 1164 0.093 1165 0.11 1166
0.11 1167 0.12 1168 0.12 1169 0.12 1170 0.13 1171 0.14 1172 0.14
1173 0.15 1174 0.15 1175 0.17 1176 0.18 1177 0.18 1178 0.19 1179
0.19 1180 0.2 1181 0.22 1182 0.25 1183 0.28 1184 0.28 1185 0.28
1186 0.3 1187 0.32 1188 0.35 1189 0.35 1190 0.55 1191 0.65 1192 1.0
1193 1.6 1194 1.6 1195 1.7 1196 2.0 1197 2.2 1198 2.5 1199 4.0 1200
6.1 1201 8.3 1202 40.0 1203 0 @ 0.063 1204 0.05 1205 0.034 1206
0.035 1207 0.068 1208 0.042 1209 0 @ 0.063 1210 0.14 1211 0.28 1212
0.39 1213 1.7 1214 0.75 1215 0.19 1216 0.39 1217 0.32 1218 0.19
1219 0.34 1220 0.2 1221 0.041 1222 0.065 1223 0.28 1224 0.28 1225
0.12 1226 0.046 1227 0.25 1228 0.038 1229 0.049 1230 0.062 1231
0.075 1232 1.2 1233 0.15 1234 0.067 1235 0.045 1236 0.05 1237 0.07
1238 0.8 1239 0.035 1240 0.016 1241 0.047 1242 0.029 1243 0.63 1244
0.062 1245 0.32 1246 0.018 1247 0.017 1248 0.33 1249 10.2 1250
0.013 1251 0.62 1252 29. 1253 0.3 1254 0.85 1255 0.69 1256 0.011
1257 0.1 1258 0.12 1259 16.5 1260 0.012 1261 0.019 1262 0.03 1263
0.079 1264 0.21 1265 0.24 1266 0.2 1267 0.29 1268 0.035 1269 0.026
1270 0.026 1271 0.011 1272 0.047 1273 0.029 1274 0.028 1275 0.024
1276 0.029 1277 0.018 1278 0.017 1279 0.028 1280 0.76 1281 0.055
1282 0.17 1283 0.17 1284 0.011 1285 0.027 1286 0.068 1287 0.071
1288 0.013 1289 0.026 1290 0.017 1291 0.013 1292 0.025 1293 0.019
1294 0.011 1295 0.014 1296 0.063 1297 0.029 1298 0.018 1299 0.012
1300 1.0 1301 0.15 1302 1.4 1303 0.26 1304 0.25 1305 0.25 1306 1.2
1307 3.1 1308 0.04 1309 0.24 1310 1.16 1311 3.27 1312 5.0 1313 5.0
1314 0.26 1315 1.67 1316 3.9 1317 21.0 1318 1319 11.0 @ 0.25 1320
1321 11.1 @ 5.0 1322 3.0 @ 0.0063 1323 4.0 @ 0.0063 1324 43.0 @
0.0008 1325 1.0 @ 0.0063 1326 36.0 @ 0.0008 1327 3.0 @ 0.0063 1328
68.0 @ 0.0063 1329 2.0 @ 0.0063 1330 9.0 @ 0.0063 1331 57.0 @
0.0008 1332 43.0 @ 0.0008 1333 0 @ 0.0063 1334 50.0 @ 0.0008 1335
38.0 @ 0.0008 1336 45.0 @ 0.0008 1337 0 @ 0.0063 1338 1.0 @ 0.25
1339 0 @ 0.063 1340 9.0 @ 0.063 1341 1.0 @ 0.063 1342 1.0 @ 0.063
1343 1344 1345 13.0 @ 0.25 1346 1347 0.0036 1348 1349 1350 1351
0.44 1352 0.10 1353 0.0015 1354 0.006 1355 0.0015 1356 0.22 1357
0.023 1358 0.008 1359 0.014 1360 0.003 1361 0.004 1362 0.019 1363
0.008 1364 0.006 1365 0.008 1366 0.015 1367 0.002 1368 0.005 1369
0.005 1370 0.002 1371 0.004 1372 0.004 1373 0.008 1374 0.007 1375
0.002 1449 0.052 1450 0.039 1451 0.014
[0949] Additional in vitro taurocholate uptake tests and in vivo
rat gavage tests were conducted on the 5 following compounds listed
in Tables 10 and 11.
14TABLE 10 In Vitro Taurocholate Uptake Assay Data for Some
Additional Compounds of the Present Invention Compound of Example
Human TC IC50 Number (nM) 1402 25 1403 23 1404 10 1405 21 1406 4
1407 3 1408 1 1409 0.9 1410 2 1411 2 1412 3 1413 3 1414 15 1415 2
1416 14 1417 2 1418 <1 1419 3 1420 11 1421 4 1422 3 1423 3 1424
14 1425 2 1426 0.3 1427 2 1428 0.7 1429 1430 3 1431 5 1432 26 1433
67
[0950]
15TABLE 11 Rat Gavage Assay Data for Some Additional Compounds of
the Present Invention Delta (micromoles Compound of Dose fecal bile
Example No. Study No. (mg/kg/day) acid per day) 1402 28 5 58.2 .2
1.3 .04 0.3 1402 30 2 50.3 .4 40.9 .08 48.5 .016 22.9 1403 30 2
41.6 .4 35.2 .08 11.9 .016 3 1404 28 5 93.7 .2 59.1 .04 33.5 1406
32 2 47.8 .4 31.6 .08 12.8 .016 -8.5 1407 32 2 51.9 .4 30.1 .08
27.5 .016 6.4 1407 33 2 35 .4 12.7 .08 -.04 .016 -4.5 1408 29 2
41.2 .4 36.8 .08 16.8 .016 -3.3 1408 37 2 26.2 .4 45.2 .08 26.3
.016 6.6 1409 33 2 19.2 .4 28.7 .08 14.1 .016 -1.7 1409 41 2 44.2
.4 35.9 .08 14.5 .016 11 1410 33 32.4 34.3 27.9 9.3 1410 35 2 26.2
.4 36.5 .08 18.5 .016 20.4 1411 34 2 63.4 .4 54.1 .08 33 .016 22.3
1413 26 5 52.3 .2 42.4 .04 19 1414 27 5 45.2 .2 39.5 .04 14.3 1414
31 2 41.5 .4 33.7 .08 29 .016 3.8 1415 28 5 59.9 .2 48.1 .04 23.9
1415 37 2 48.9 .4 25.7 .08 27.1 .016 12.7 1416 29 .2 46.1 .4 21.9
.08 25 .016 -7.8 1417 31 2 51.4 .4 42 .08 39.6 .016 29.3 1418 29 2
20.3 .4 29.5 .08 -4.6 .016 -10 1419 31 2 28.5 .4 13.9 .08 10.3 .016
5.8 1420 31 2 53.1 .4 45 .08 38.1 .016 29.6 1421 32 2 57.8 .4 27.7
.08 25.3 .016 4.7 1423 34 2 56.5 .4 69.3 .08 35.3 .016 14.4 1425 21
5 91.8 .2 100. .04 66.4 1425 30 2 44.6 .4 62 .08 69.5 .016 31.6
1425 40 2 48.3 .4 45 .08 31.2 .016 30 1426 33 2 52.4 .4 19.5 .08
23.1 .016 24.6 1426 35 2 37.7 .4 41.7 .08 40.5 .016 24.6 1426 39 2
54.3 .4 48.7 .08 51.8 .016 26.8 1426 43 2 40.8 .4 21.7 .08 5.9 .016
4.1 1427 40 2 36.7 .4 35.8 .08 27.3 .016 13.8 1428 34 2 40.4 .4
64.9 .08 24.4 .016 12.2 1428 42 2 46 .4 40.7 .08 26 .016 1.1 1429
41 2 34.5 .4 24.9 .08 18.7 .016 9.2 1429 42 2 47.1 .4 31.1 .08 35.5
.016 4.8 1430 30 2 51.2 .4 50.4 .08 20.7 .016 -5.6 1431 32 28.3
45.8 21.9 1.1 1432 28 5 36.2 .2 9.7 .04 2.4 1433 24 20 66.5 2 47.4
.2 26.5
[0951] The examples herein can be repeated with similar success by
substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0952] Novel compositions of the invention are further illustrated
in attached Exhibits A and B.
[0953] The invention being thus described, it is apparent that the
same can be varied in many ways. Such variations are not to be
regarded as a departure from the spirit and scope of the present
invention, and all such modifications and equivalents as would be
obvious to one skilled in the art are intended to be included
within the scope of the following claims.
Exhibit A
[0954]
16TABLE C2 Alternative Compounds #2 (Families F101-F123) 513 Cpd
Family # R.sup.1.dbd.R.sup.2 R.sup.5 (R.sup.x)q F101 CHOSEN Ph--
CHOSEN FROM FROM TABLE 1 TABLE 1 F102 CHOSEN p-F--Ph-- CHOSEN FROM
FROM TABLE 1 TABLE 1 F103 CHOSEN m-F--Ph-- CHOSEN FROM FROM TABLE 1
TABLE 1 F104 CHOSEN p-CH.sub.3O--Ph-- CHOSEN FROM FROM TABLE 1
TABLE 1 F105 CHOSEN m-CH.sub.3O--Ph-- CHOSEN FROM FROM TABLE 1
TABLE 1 F106 CHOSEN p-(CH.sub.3).sub.2N--Ph-- CHOSEN FROM FROM
TABLE 1 TABLE 1 F107 CHOSEN m-(CH.sub.3).sub.2N--Ph CHOSEN FROM
FROM TABLE 1 TABLE 1 F108 CHOSEN I.sup.-,
p-(CH.sub.3).sub.3--N.sup.+--Ph-- CHOSEN FROM FROM TABLE 1 TABLE 1
F109 CHOSEN I.sup.-, m-(CH.sub.3).sub.3--N.sup.+- --Ph-- CHOSEN
FROM FROM TABLE 1 TABLE 1 F110 CHOSEN I.sup.-,
p-(CH.sub.3).sub.3--N.sup.+--CH.sub.2CH.sub.2-- CHOSEN FROM
(OCH.sub.2CH.sub.2).sub.2--O--Ph-- FROM TABLE 1 TABLE 1 F111 CHOSEN
I.sup.-, m-(CH.sub.3).sub.3--N.sup.+--CH.sub.- 2CH.sub.2-- CHOSEN
FROM (OCH.sub.2CH.sub.2).sub.2--O--Ph-- FROM TABLE 1 TABLE 1 F112
CHOSEN I.sup.-, p-(N,N- CHOSEN FROM dimethylpiperazine)-(N')-- FROM
TABLE 1 CH.sub.2--(OCH.sub.2CH.sub.2).sub.2--O--Ph TABLE 1 F113
CHOSEN I.sup.-, m-(N,N- CHOSEN FROM dimethylpiperazine)-(N')-- FROM
TABLE 1 CH.sub.2--(OCH.sub.2CH.sub.2).sub.2--O--Ph-- TABLE 1 F114
CHOSEN m-F--Ph-- CHOSEN FROM p-CH.sub.3O-- FROM TABLE 1 TABLE 1
F115 CHOSEN 3,4,dioxy-methylene-Ph CHOSEN FROM FROM TABLE 1 TABLE 1
F116 CHOSEN m-F--Ph-- CHOSEN FROM p-F--Ph-- FROM TABLE 1 TABLE 1
F117 CHOSEN m-CH.sub.3O-- CHOSEN FROM p-F--Ph-- FROM TABLE 1 TABLE
1 F118 CHOSEN 4-pyridine CHOSEN FROM FROM TABLE 1 TABLE 1 F119
CHOSEN N-methyl-4-pyridinium CHOSEN FROM FROM TABLE 1 TABLE 1 F120
CHOSEN 3-pyridine CHOSEN FROM FROM TABLE 1 TABLE 1 F121 CHOSEN
N-methyl-3-pyridinium CHOSEN FROM FROM TABLE 1 TABLE 1 F122 CHOSEN
2-pyridine CHOSEN FROM FROM TABLE 1 TABLE 1 F123 CHOSEN
p-CH.sub.3O.sub.2C--Ph-- CHOSEN FROM FROM TABLE 1 TABLE 1 Similar
families can be generated where R.sup.1 is not equal to R.sup.2,
such as R.sup.1 = Et and R.sup.2 = n-Bu, but (R.sup.x)q is chosen
from table C1.
[0955] 514
* * * * *