U.S. patent number RE43,833 [Application Number 13/205,768] was granted by the patent office on 2012-11-27 for thiazolidin-4-one derivatives.
This patent grant is currently assigned to Actelion Pharmaceuticals Ltd.. Invention is credited to Christoph Binkert, Martin Bolli, Boris Mathys, Claus Mueller, Oliver Nayler, Michael Scherz.
United States Patent |
RE43,833 |
Binkert , et al. |
November 27, 2012 |
Thiazolidin-4-one derivatives
Abstract
The invention relates to pharmaceutical compositions containing
at least one thiazolidin-4-one derivative to prevent or treat
disorders associated with an activated immune system. Furthermore,
the invention relates to novel thiazolidin-4-one derivatives
notably for use as pharmaceutically active compounds. Said
compounds particularly act also as immunosuppressive agents.
Inventors: |
Binkert; Christoph (Basel,
CH), Bolli; Martin (Allschwil, CH), Mathys;
Boris (Egerkingen, CH), Mueller; Claus (Weil am
Rhein, DE), Scherz; Michael (Ettingen, CH),
Nayler; Oliver (Arlesheim, CH) |
Assignee: |
Actelion Pharmaceuticals Ltd.
(Allschwil, CH)
|
Family
ID: |
47192291 |
Appl.
No.: |
13/205,768 |
Filed: |
August 9, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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10580169 |
Dec 1, 2006 |
7435828 |
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PCT/EP2004/012953 |
Nov 16, 2004 |
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Reissue of: |
12026277 |
Feb 5, 2008 |
7626037 |
Dec 1, 2009 |
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Foreign Application Priority Data
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Nov 21, 2003 [WO] |
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PCT/EP03/13072 |
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Current U.S.
Class: |
548/184 |
Current CPC
Class: |
C07D
277/42 (20130101); C07D 277/20 (20130101); A61K
31/426 (20130101); C07D 417/06 (20130101) |
Current International
Class: |
A61K
31/426 (20060101); C07D 277/54 (20060101) |
Field of
Search: |
;548/184 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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1 219 612 |
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Jul 2002 |
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EP |
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1 219 612 |
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Jul 2009 |
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EP |
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999796 |
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Jul 1965 |
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GB |
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WO 91/17151 |
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Nov 1991 |
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WO |
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WO-96/20936 |
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Jul 1996 |
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WO |
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WO 96/20936 |
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Jul 1996 |
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WO |
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WO 96/20936 |
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Jul 1996 |
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WO |
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WO 2004/007491 |
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Jan 2004 |
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WO |
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WO-2004/007491 |
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Jan 2004 |
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WO |
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WO 2004/007491 |
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Jan 2004 |
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WO |
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WO 2004/010987 |
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Feb 2004 |
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WO |
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WO 2005/054215 |
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Jun 2005 |
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WO |
|
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|
Primary Examiner: Stockton; Laura L.
Attorney, Agent or Firm: Hoxie & Associates, LLC
Parent Case Text
This application is a .Iadd.reissue application of U.S. application
Ser. No. 12/026,277 filed Feb. 5, 2008, now U.S. Pat. No.
7,626,037, issued on Dec. 1, 2009, which patent is a
.Iaddend.continuation .[.application.]. of .Iadd.U.S.
.Iaddend.application Ser. No. 10/580,169, filed Dec. 1, 2006
.Iadd.(now U.S. Pat. No. 7,435,828).Iaddend., which .Iadd.patent
.Iaddend.is a .[.U.S. National Stage Application of International
Application No..]. .Iadd.continuation-in-part of PCT Application
No. .Iaddend.PCT/EP04/12953, filed .Iadd.on .Iaddend.Nov. 16, 2004,
which claims .[.priority to International.]. .Iadd.the benefit of
PCT .Iaddend.Application No. PCT/EP03/13072, filed .Iadd.on
.Iaddend.Nov. 21, 2003, all of which are incorporated by reference
in their entireties.
Claims
The invention claimed is:
1. A pharmaceutical composition containing at least one
thiazolidin-4-one derivative of the Formula (I) ##STR00236##
wherein: R.sup.1 represents lower alkyl, lower alkenyl; cycloalkyl;
5,6,7,8-tetrahydronaphth-1-yl; 5,6,7,8-tetrahydronaphth-2-yl; or an
unsubstituted phenyl group; R.sup.2 represents lower alkyl; allyl;
cyclopropyl; cyclobutyl; cyclopentyl; or mono- or di-lower
alkylamino; R.sup.3 represents
--O--CR.sup.7R.sup.8--CR.sup.9R.sup.10--(CR.sup.11R.sup.12).sub.n--O--R.s-
up.13; R.sup.4 represents hydrogen; hydroxy; lower alkoxy; lower
alkyl; or halogen; R.sup.5 and R.sup.6 each represents
independently lower alkyl; R.sup.7 represents hydrogen, lower
alkyl, or hydroxymethyl; R.sup.8, R.sup.9, R.sup.11 and R.sup.12
each represents independently hydrogen or methyl; R.sup.10
represents hydrogen or lower alkyl; in case n represents the
integer 1, R.sup.10 in addition represents lower alkoxy, hydroxy,
--NH.sub.2, --NHR.sup.5 or --NR.sup.5R.sup.6; R.sup.13 represents
hydrogen; lower alkyl; hydroxycarbonyl-lower alkyl; 1-glyceryl or
2-glyceryl; n represents the integer 0 or 1; in a configurational
isomeric, an optically pure enantiomeric, a mixture of
enantiomeric, an enantiomeric racemate, a diastereomeric, a mixture
of diastereomeric, a diastereomeric racemate, a mixture of
diastereomeric racemates, a meso-form, free or pharmaceutically
acceptable salt form, and an inert carrier material.
2. The pharmaceutical composition according to claim 1, in which
said thiazolidin-4-one derivatives is a (Z,Z)-isomer.
3. The pharmaceutical composition of claim 1, further comprising
one or more immunosuppressant compounds.
4. The pharmaceutical composition according to claim 3, wherein
said immunosuppressant compound is selected from the group
consisting of cyclosporin, daclizumab, basiliximab, everolimus,
tacrolimus (FK506), azathiopirene, leflunomide, and
15-deoxyspergualin.
5. A thiazolidin-4-one derivative of Formula (II) ##STR00237##
wherein: R.sup.14 represents lower alkyl, lower alkenyl;
cycloalkyl; 5,6,7,8-tetrahydronaphth-1-yl;
5,6,7,8-tetrahydronaphth-2-yl; or an unsubstituted phenyl group;
R.sup.15 represents lower alkyl; allyl; cyclopropyl; cyclobutyl;
cyclopentyl; or mono- or di-lower alkylamino; R.sup.16 represents
hydrogen; hydroxy; lower alkoxy; lower alkyl or halogen; R.sup.17
represents hydrogen, lower alkyl, or hydroxymethyl; R.sup.18,
R.sup.19, R.sup.21 and R.sup.22 each represents independently
hydrogen or methyl; R.sup.20 represents hydrogen or lower alkyl;
and in case m represents the integer 1, R.sup.20 in addition
represents lower alkoxy, hydroxy, --NH.sub.2, --NHR.sup.5 or
--NR.sup.5R.sup.6; R.sup.23 represents hydrogen; lower alkyl;
hydroxycarbonyl-lower alkyl; 1-glyceryl or 2-glyceryl; R.sup.5 and
R.sup.6 each represents independently lower alkyl; m represents the
integer 0 or 1; in a configurational isomeric, an optically pure
enantiomeric, a mixture of enantiomeric, an enantiomeric racemate,
a diastereomeric, a mixture of diastereomeric, a diastereomeric
racemate, a mixture of diastereomeric racemates, a meso-form, a
free or a pharmaceutically acceptable salt form.
6. The thiazolidin-4-one derivative according to claim 5 in which
said thiazolidin-4-one derivative according to formula (II) is a
(Z,Z) isomer.
7. The thiazolidin-4-one derivative according to claim 5 or 6,
wherein R.sup.14 represents an unsubstituted phenyl group.
8. The thiazolidin-4-one derivative according to claim 5 or 6,
wherein R.sup.15 represents lower alkyl.
9. The thiazolidin-4-one derivative according to claim 5 or 6,
wherein R.sup.16 represents halogen or methyl.
10. The thiazolidin-4-one derivative according to claim 5 or 6,
wherein m represents the integer 0, and R.sup.17, R.sup.18,
R.sup.19 and R.sup.20 represent hydrogen.
11. The thiazolidin-4-one derivative according to claim 5 or 6,
wherein m represents the integer 1, R.sup.17, R.sup.18, R.sup.19,
R.sup.21 and R.sup.22 represent hydrogen, and R.sup.20 represents
hydroxy.
12. The thiazolidin-4-one derivative according to claim 5 or 6,
wherein R.sup.23 represents hydrogen.
13. The thiazolidin-4-one derivative according to claim 5 or 6,
wherein m represents the integer 0, and R.sup.17, R.sup.18,
R.sup.19, R.sup.20 and R.sup.23 represent hydrogen.
14. The thiazolidin-4-one derivative according to claim 5 or 6,
wherein m represents the integer 1, R.sup.17, R.sup.18, R.sup.19,
R.sup.21, R.sup.22 and R.sup.23 represent hydrogen, and R.sup.20
represents hydroxy.
15. The thiazolidin-4-one derivative according to claim 5 or 6,
wherein R.sup.14 represents an unsubstituted phenyl group, and
R.sup.15 represents lower alkyl.
16. The thiazolidin-4-one derivative according to claim 5 or 6,
wherein R.sup.14 represents an unsubstituted phenyl group, m
represents the integer 0, and R.sup.17, R.sup.18, R.sup.19,
R.sup.20 and R.sup.23 represent hydrogen.
17. The thiazolidin-4-one derivative according to claim 5 or 6,
wherein R.sup.14 represents an unsubstituted phenyl group, m
represents the integer 1, R.sup.17, R.sup.18, R.sup.19, R.sup.21,
R.sup.22 and R.sup.23 represent hydrogen, and R.sup.20 represents
hydroxy.
18. The thiazolidin-4-one derivative according to claim 5 or 6,
wherein R.sup.14 represents an unsubstituted phenyl group, R.sup.15
represents lower alkyl, R.sup.16 represents methyl or halogen, m
represents the integer 0, and R.sup.17, R.sup.18, R.sup.19,
R.sup.20 and R.sup.23 each represent hydrogen.
19. The thiazolidin-4-one derivative according to claim 5 or 6,
wherein R.sup.14 represents an unsubstituted phenyl group, R.sup.15
represents lower alkyl, R.sup.16 represents methyl or halogen, m
represents the integer 1, R.sup.17, R.sup.18, R.sup.19, R.sup.21,
R.sup.22 and R.sup.23 represent hydrogen, and R.sup.20 represents
hydroxy.
20. The thiazolidin-4-one derivative according to claim 5 selected
from the group consisting of:
5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-phenyl-t-
hiazolidin-4-one,
{2-[4-(2-([Z]-isopropylimino)-4-oxo-3-phenyl-thiazolidin-5-[Z]-ylidenemet-
hyl)-phenoxy]-ethoxy}-acetic acid,
5-{4-[2-(2,3-dihydroxy-propoxy)-ethoxy]-benz[Z]ylidene}-2-([Z]-isopropyli-
mino)-3-phenyl-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-
-phenyl-thiazolidin-4-one,
5-[3-fluoro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-
-phenyl-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-3-methyl-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-
-phenyl-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-3-methoxy-benz[Z]ylidene]-2-([Z]-isopropylimino)--
3-phenyl-thiazolidin-4-one,
5-[4-(3-hydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-phenyl--
thiazolidin-4-one,
5-[4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-phe-
nyl-thiazolidin-4-one,
5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-isopropylimi-
no)-3-phenyl-thiazolidin-4-one,
3-allyl-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-th-
iazolidin-4-one,
3-allyl-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropyl-
imino)-thiazolidin-4-one,
3-allyl-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-isop-
ropylimino)-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-2-([Z]-propylimino)-thia-
zolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-2-([Z]-propylim-
ino)-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-3-methyl-benz[Z]ylidene]-3-phenyl-2-([Z]-propylim-
ino)-thiazolidin-4-one,
5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-phenyl-2-([Z]-pro-
pylimino)-thiazolidin-4-one,
2-([Z]-tert-butylimino)-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]--
3-phenyl-thiazolidin-4-one,
2-(dimethyl-hydrazono)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-t-
hiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-(dimethyl-hydrazono)-3-
-phenyl-thiazolidin-4-one,
2-([Z]-ethylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-thiaz-
olidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-ethylimino)-3-phe-
nyl-thiazolidin-4-one,
2-([Z]-butylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-thiaz-
olidin-4-one,
2-([Z]-butylimino)-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phe-
nyl-thiazolidin-4-one,
2-([Z]-sec-butylimino)-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-
-phenyl-thiazolidin-4-one,
2-([Z]-cyclopropylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-
-thiazolidin-4-one,
3-cyclohexyl-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimin-
o)-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-cyclohexyl-2-([Z]-isop-
ropylimino)-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-isopropyl-2-([Z]-isopropylimino-
)-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-isopropyl-2-([Z]-isopr-
opylimino)-thiazolidin-4-one,
5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-isopropyl-2-([Z]--
isopropylimino)-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-
-phenyl-thiazolidin-4-one,
2-([Z]-allylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-thiaz-
olidin-4-one,
2-([Z]-allylimino)-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phe-
nyl-thiazolidin-4-one,
3-allyl-2-([Z]-allylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-thiazo-
lidin-4-one,
3-allyl-2-([Z]-allylimino)-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]yliden-
e]-thiazolidin-4-one, and
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-methylimino)-3-ph-
enyl-thiazolidin-4-one.
21. The thiazolidin-4-one derivative according to claim 5 selected
from the group consisting of:
5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-phenyl-t-
hiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-
-phenyl-thiazolidin -4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-2-([Z]-propylim-
ino)-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-3-methyl-benz[Z]ylidene]-3-phenyl-2-([Z]-propylim-
ino)-thiazolidin-4-one,
5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-phenyl-2-([Z]-pro-
pylimino)-thiazolidin-4-one,
2-(dimethyl-hydrazono)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-t-
hiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-ethylimino)-3-phe-
nyl-thiazolidin -4-one, and
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-isopropyl-2-([Z]-isopr-
opylimino)-thiazolidin-4-one.
22. A pharmaceutical composition comprising at least one
thiazolidin-4-one derivative of claim 5 and inert carrier
material.
23. A process for the preparation of a pharmaceutical composition
comprising mixing one or more thiazolidin-4-one derivatives of any
one of claim 5, 20 or 21 with an inert excipient.
24. A process for the preparation of the pharmaceutical composition
of claim 1, comprising mixing one or more thiazolidin-4-one
derivatives according to claim 1 with an inert excipient.
Description
FIELD OF THE INVENTION
The present invention relates to novel thiazolidin-4-one
derivatives of the General Formula (I) and their use as active
ingredients in the preparation of pharmaceutical compositions. The
invention also concerns related aspects including processes for the
preparation of the compounds, pharmaceutical compositions
containing one or more compounds of the General Formula (I), and
their use as immunosuppressant agents, either alone or in
combination with other immunosuppressant therapies.
BACKGROUND OF THE INVENTION
The immune system attempts to fight a transplanted organ in the
same way it fights an infection or a cancer. Without
immunosuppressive medication to inhibit the immune system's action,
a transplanted organ is quickly rejected and stops functioning.
Organ transplant recipients can experience some organ rejection
even when they are taking immunosuppressive drugs. Rejection occurs
most frequently in the first few weeks after transplantation, but
rejection episodes can also happen months or even years after
transplantation. Combinations of up to three or four medications
are commonly used to give maximum protection against rejection
while minimizing side effects. Current standard drugs used to treat
the rejection of transplanted organs interfere with discrete
intracellular pathways in the activation of T-type or B-type white
blood cells. Examples of such drugs are cyclosporin, daclizumab,
basiliximab, everolimus, or FK506, which interfere with cytokine
release or signaling; azathiopirene or leflunomide, which inhibit
nucleotide synthesis; or 15-deoxyspergualin, an inhibitor of
leukocyte differentiation. The beneficial effects of these
therapies relate to their broad immunosuppressive effects; however,
the generalized immunosuppression which these drugs produce also
diminishes the immune system's defence against infection and
malignancies. Furthermore, standard immunosuppressive drugs are
often used at high dosages and can themselves cause or accelerate
organ damage in either the transplanted organ itself, or in other
target organs of the transplant recipient.
DESCRIPTION OF THE INVENTION
The present invention provides compounds having a powerful and
long-lasting immunosuppressive effect which is achieved by reducing
the number of circulating and infiltrating T- and B-lymphocytes,
without affecting their maturation, memory, or expansion. In
consequence, the compounds of the present invention can be utilized
alone or in combination with standard T-cell activation inhibiting
drugs, to provide a new immunosuppressive therapy with a reduced
propensity for infections or malignancies when compared to standard
immunosuppressive therapy. Furthermore, the compounds of the
present invention can be used in combination with reduced dosages
of traditional immunosuppressant therapies, to provide on the one
hand effective immunosuppressive activity, while on the other hand
reducing end organ damage associated with higher doses of standard
immunosuppressive drugs.
Biological Assay
The immunosuppressive activity of the compounds of the invention
can be demonstrated by measuring the number of circulating
lymphocytes in whole blood of rats as follows.
Normotensive male Wistar rats are housed in climate-controlled
conditions with a 12-hour light/dark cycle, and have free access to
normal rat chow and drinking water. Blood (0.5 mL) is collected by
retro-orbital sampling before drug administration, and 3 and 6 h
thereafter. Blood cell count is measured in whole blood using a
Beckman-Coulter Synchron CX5 Pro cytometer. Statistical analysis of
lymphocyte counts are performed by analysis of variance (ANOVA)
using Statistica (StatSoft) and the Student-Newman-Keuls procedure
for multiple comparisons.
Thus, compounds of the invention decrease the number of circulating
lymphocytes in whole blood when compared to pre-drug values.
Table 1 shows the effect on lymphocyte counts 6 h after oral
administration of 10 mg/kg of a compound of the present invention
to normotensive male Wistar rats as compared to a group of animals
treated with vehicle only.
TABLE-US-00001 TABLE 1 Compound of Example Lymphocyte counts [%] 4
-32 7 -67 24 -54 42 -23 46 -37 75 -47 76 -58 77 -55 84 -68 85 -63
86 -30* 91 -35 95 -53 100 -53 103 -47 110 -30 130 -26 *at 3 mg/kg
p.o.
The following paragraphs provide definitions of the various
chemical moieties that make up the compounds according to the
invention and are intended to apply uniformly throughout the
specification and claims unless an otherwise expressly set out
definition provides a broader definition.
The term lower alkyl, alone or in combination with other groups,
means saturated, straight or branched chain groups with one to
seven carbon atoms, preferably one to four carbon atoms. Examples
of lower alkyl groups are methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl or
n-heptyl.
The term lower alkoxy means a R--O group, wherein R is a lower
alkyl. Preferred examples of lower alkoxy groups are methoxy,
ethoxy, propoxy, iso-propoxy, iso-butoxy, sec-butoxy or
tert-butoxy.
The term mono- or di-lower alkylamino means a R'--NH-- or a
R'--NR''-- group, wherein R' and R'' are each independently a lower
alkyl. Preferred examples of mono- or di-lower alkylamino groups
are methylamino, ethylamino, N,N-dimethylamino, or
N-methyl-N-ethyl-amino.
The term lower alkenyl, alone or in combination with other groups,
means straight or branched chain groups comprising an olefinic bond
and three to seven carbon atoms, preferably three to five carbon
atoms. Examples of lower alkenyl are allyl, (E)-but-2-enyl,
(Z)-but-2-enyl, or but-3-enyl.
The term halogen means fluoro, chloro, bromo or iodo.
The term cycloalkyl alone or in combination, means a saturated
cyclic hydrocarbon ring system with 3 to 7 carbon atoms, preferably
three to six carbon atoms. Examples of cycloalkyl are cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
The expression pharmaceutically acceptable salts encompasses either
salts with inorganic acids or organic acids like hydrochloric or
hydrobromic acid, sulfuric acid, phosphoric acid, citric acid,
formic acid, acetic acid, maleic acid, tartaric acid, benzoic acid,
methanesulfonic acid, and the like that are non-toxic to living
organisms. In case the compound of General Formula (I) or General
Formula (II) is acidic in nature the expression encompasses salts
with an inorganic base like an alkali or earth alkali base, e.g.
sodium hydroxide, potassium hydroxide, calcium hydroxide, or with
an organic base such as benzathine, choline, meglumine, and the
like which are also non-toxic to living organisms (S. M. Berge, L.
D. Bighley and D. C. Monkhouse, Pharmaceutical salts, J. Pharm.
Sci., 66 (1977), 1-19; P. L. Gould, Salt selection of basic drugs,
Int. J. Pharmaceutics 33 (1986), 201-217).
The compounds of the General Formula (I) and General Formula (II)
can contain one or more asymmetric carbon atoms and may be prepared
in form of optically pure enantiomers, mixtures of enantiomers such
as racemates, diastereomers, mixtures of diastereomers,
diastereomeric racemates, mixtures of diastereomeric racemates, and
meso-forms. The present invention encompasses all these forms.
A first aspect of the invention consists of a novel pharmaceutical
composition comprising at least one thiazolidin-4-one derivative of
the General Formula (I):
##STR00001## wherein: R.sup.1 represents lower alkyl, lower
alkenyl; cycloalkyl; 5,6,7,8-tetrahydronaphth-1-yl;
5,6,7,8-tetrahydronaphth-2-yl; a phenyl group; a phenyl group
independently mono-, di- or trisubstituted with lower alkyl,
halogen, lower alkoxy, or --CF.sub.3; R.sup.2 represents lower
alkyl; allyl; cyclopropyl; cyclobutyl; cyclopentyl; mono- or
di-lower alkylamino; R.sup.3 represents --NR.sup.5R.sup.6;
--O--CR.sup.7R.sup.8--CR.sup.9R.sup.10--(CR.sup.11R.sup.12).sub.n--O--R.s-
up.13; R.sup.4 represents hydrogen; hydroxy; lower alkoxy; lower
alkyl; halogen; or R.sup.3 and R.sup.4 together may form a
methylenedioxy or ethylenedioxy ring optionally further substituted
with a hydroxy methyl group; R.sup.5 and R.sup.6 each represents
independently lower alkyl; R.sup.7 represents hydrogen, lower
alkyl, or hydroxymethyl; R.sup.8, R.sup.9, R.sup.11 and R.sup.12
each represents independently hydrogen or methyl; R.sup.10
represents hydrogen or lower alkyl; in case n represents the
integer 1, R.sup.10 in addition represents lower alkoxy, hydroxy,
--NH.sub.2, --NHR.sup.5 or --NR.sup.5R.sup.6; R.sup.13 represents
hydrogen; lower alkyl; hydroxycarbonyl-lower alkyl; 1-glyceryl or
2-glyceryl; n represents the integer 0 or 1; and configurational
isomers, optically pure enantiomers, mixtures of enantiomers such
as racemates, diastereomers, mixtures of diastereomers,
diastereomeric racemates, mixtures of diastereomeric racemates and
the meso-form, as well as pharmaceutically acceptable salts,
solvent complexes, and morphological forms, and inert carrier
material.
The compounds of General Formula (I) and their pharmaceutically
acceptable salts can be used as medicaments, e.g. in the form of
pharmaceutical preparations for enteral, parental or topical
administration. They can be administered, for example, perorally,
e.g. in the form of tablets, coated tablets, dragees, hard and soft
gelatine capsules, solutions, emulsions or suspensions, rectally,
e.g. in the form of suppositories, parenterally, e.g. in the form
of injection solutions or infusion solutions, or topically, e.g. in
the form of ointments, cream or oils.
The production of the pharmaceutical preparations can be effected
in a manner which will be familiar to any person skilled in the art
(see for example Mark Gibson, Editor, Pharmaceutical Preformulation
and Formulation, IHS Health Group, Englewood, Colo., USA, 2001;
Remington, The Science and Practice of Pharmacy, 20th Edition,
Philadelphia College of Pharmacy and Science) by bringing the
described compounds of General Formula (I) and their
pharmaceutically acceptable salts, optionally in combination with
other therapeutically valuable substances, into a galenical
administration form together with suitable, non-toxic, inert,
therapeutically compatible solid or liquid carrier materials and,
if desired, usual pharmaceutical adjuvants.
Suitable inert carrier materials are not only inorganic carrier
materials, but also organic carrier materials. Thus, for example,
lactose, corn starch or derivatives thereof, talc, stearic acid or
its salts can be used as carrier materials for tablets, coated
tablets, dragees and hard gelatine capsules. Suitable carrier
materials for soft gelatine capsules are, for example, vegetable
oils, waxes, fats and semi-solid and liquid polyols (depending on
the nature of the active ingredient no carriers are, however,
required in the case of soft gelatine capsules). Suitable carrier
materials for the production of solutions and syrups are, for
example, water, polyols, sucrose, invert sugar and the like.
Suitable carrier materials for injection solutions are, for
example, water, alcohols, polyols, glycerol and vegetable oils.
Suitable carrier materials for suppositories are, for example,
natural or hardened oils, waxes, fats and semi-liquid or liquid
polyols. Suitable carrier materials for topical preparations are
glycerides, semi-synthetic and synthetic glycerides, hydrogenated
oils, liquid waxes, liquid paraffins, liquid fatty alcohols,
sterols, polyethylene glycols and cellulose derivatives.
Usual stabilizers, preservatives, wetting and emulsifying agents,
consistency-improving agents, flavour-improving agents, salts for
varying the osmotic pressure, buffer substances, solubilizers,
colorants and masking agents and antioxidants come into
consideration as pharmaceutical adjuvants.
The dosage of the compounds of General Formula (I) can vary within
wide limits depending on the disease to be controlled, the age and
the individual condition of the patient and the mode of
administration, and will, of course, be fitted to the individual
requirements in each particular case. For adult patients a daily
dosage of about 0.5 mg to about 1000 mg, especially about 1 mg to
about 500 mg, comes into consideration for the treatment of
disorders associated with an activated immune system for adult
patients. Depending on the dosage it may be convenient to
administer the daily dosage in several dosage units.
The pharmaceutical preparations conveniently contain about 0.5 to
500 mg, preferably 1 to 250 mg, of a compound of General Formula
(I).
In a preferred embodiment according to the invention, the
above-mentioned pharmaceutical composition comprises the (Z,
Z)-isomers of the thiazolidin-4-one derivatives of the General
Formula (I).
The above-mentioned pharmaceutical composition is useful for the
prevention and treatment of disorders associated with an activated
immune system.
Such diseases or disorders are selected from the group consisting
of rejection of transplanted organs or tissue; graft-versus-host
diseases brought about by transplantation; autoimmune syndromes
including rheumatoid arthritis; systemic lupus erythematosus;
Hashimoto's thyroiditis; lymphocytic thyroiditis; multiple
sclerosis; myasthenia gravis; type I diabetes; uveitis; posterior
uveitis; uveitis associated with Behcet's disease; uveomeningitis
syndrome; allergic encephalomyelitis; chronic allograft
vasculopathy; post-infectious autoimmune diseases including
rheumatic fever and post-infectious glomerulonephritis;
inflammatory and hyperproliferative skin diseases; psoriasis;
atopic dermatitis; osteomyelitis; contact dermatitis; eczematous
dermatitis; seborrhoeic dermatitis; lichen planus; pemphigus;
bullous pemphigoid; epidermolysis bullosa; urticaria; angioedema;
vasculitis; erythema; cutaneous eosinophilia; acne; alopecia
greata; keratoconjunctivitis; vernal conjunctivitis; keratitis;
herpetic keratitis; dystrophia epithelialis corneae; corneal
leukoma; ocular pemphigus; Mooren's ulcer; ulcerative keratitis;
scleritis; Graves' opthalmopathy; Vogt-Koyanagi-Harada syndrome;
sarcoidosis; pollen allergies; reversible obstructive airway
disease; bronchial asthma; allergic asthma; intrinsic asthma;
extrinsic asthma; dust asthma; chronic or inveterate asthma; late
asthma and airway hyper-responsiveness; bronchitis; gastric ulcers;
ischemic bowel diseases; inflammatory bowel diseases; necrotizing
enterocolitis; intestinal lesions associated with thermal burns;
coeliac diseases; proctitis; eosinophilic gastroenteritis;
mastocytosis; Crohn's disease; ulcerative colitis; vascular damage
caused by ischemic diseases and thrombosis; atherosclerosis; fatty
heart; myocarditis; cardiac infarction; arteriosclerosis; aortitis
syndrome; cachexia due to viral disease; vascular thrombosis;
migraine; rhinitis; eczema; interstitial nephritis; IgA-induced
nephropathy; Goodpasture's syndrome; hemolytic-uremic syndrome;
diabetic nephropathy; glomerulosclerosis; glomerulonephritis;
multiple myositis; Guillain-Barre syndrome; Meniere's disease;
polyneuritis; multiple neuritis; mononeuritis; radiculopathy;
hyperthyroidism; Basedow's disease; thyrotoxicosis; pure red cell
aplasia; aplastic anemia; hypoplastic anemia; idiopathic
thrombocytopenic purpura; autoimmune hemolytic anemia;
agranulocytosis; pernicious anemia; megaloblastic anemia;
anerythroplasia; osteoporosis; sarcoidosis; fibroid lung;
idiopathic interstitial pneumonia; dermatomyositis; leukoderma
vulgaris; ichthyosis vulgaris; photoallergic sensitivity; cutaneous
T cell lymphoma; polyarteritis nodosa; Huntington's chorea;
Sydenham's chorea; myocardosis; scleroderma; Wegener's granuloma;
Sjogren's syndrome; adiposis; eosinophilic fascitis; lesions of
gingiva, periodontium, alveolar bone, substantia ossea dentis; male
pattern alopecia or alopecia senilis; muscular dystrophy; pyoderma;
Sezary's syndrome; chronic adrenal insufficiency; Addison's
disease; ischemia-reperfusion injury of organs which occurs upon
preservation; endotoxin shock; pseudomembranous colitis; colitis
caused by drug or radiation; ischemic acute renal insufficiency;
chronic renal insufficiency; lung cancer; malignancy of lymphoid
origin; acute or chronic lymphocytic leukemias; lymphoma;
psoriasis; pulmonary emphysema; cataracta; siderosis; retinitis
pigmentosa; senile macular degeneration; vitreal scarring; corneal
alkali burn; dermatitis erythema; ballous dermatitis; cement
dermatitis; gingivitis; periodontitis; sepsis; pancreatitis;
carcinogenesis; metastasis of carcinoma; hypobaropathy; autoimmune
hepatitis; primary biliary cirrhosis; sclerosing cholangitis;
partial liver resection; acute liver necrosis; cirrhosis; alcoholic
cirrhosis; hepatic failure; fulminant hepatic failure; late-onset
hepatic failure; "acute-on-chronic" liver failure.
Particularly preferred diseases comprise the group consisting of
rejection of transplanted organs or tissue; graft-versus-host
diseases brought about by transplantation; autoimmune syndromes
including rheumatoid arthritis, multiple sclerosis, myasthenia
gravis; pollen allergies; type I diabetes; prevention of psoriasis;
Crohn's disease; post-infectious autoimmune diseases including
rheumatic fever and post-infectious glomerulonephritis; and
metastasis of carcinoma.
Furthermore, compounds of the General Formula (I) are also useful,
in combination with one or several immunosuppressant agents, for
the treatment of disorders associated with an activated immune
system and selected from the list as above-mentioned. According to
a preferred embodiment of the invention, said immunosuppressant
agent is selected from the group comprising or consisting of
cyclosporin, daclizumab, basiliximab, everolimus, tacrolimus
(FK506), azathiopirene, leflunomide, 15-deoxyspergualin, or other
immunosuppressant drugs.
Another aspect of the invention concerns a method for the
prevention or treatment of disorders associated with an activated
immune system comprising the administration to the patient of a
pharmaceutical composition containing a compound of the General
Formula (I). A suitable dose of the compound of General Formula (I)
in the pharmaceutical composition is between 0.5 mg and 1000 mg per
day. In a preferred embodiment of the invention, said dose is
comprised between 1 mg and 500 mg per day and more particularly
between 5 mg and 200 mg per day.
A further aspect of the invention are novel thiazolidin-4-one
derivatives of the following General Formula (II):
##STR00002## wherein: R.sup.14 represents lower alkyl, lower
alkenyl; cycloalkyl; 5,6,7,8-tetrahydronaphth-1-yl;
5,6,7,8-tetrahydronaphth-2-yl; a phenyl group; a phenyl group
mono-, di- or trisubstituted independently with lower alkyl,
halogen, lower alkoxy, or --CF.sub.3; R.sup.15 represents lower
alkyl; allyl; cyclopropyl; cyclobutyl; cyclopentyl; mono- or
di-lower alkylamino; R.sup.16 represents hydrogen; hydroxy; lower
alkoxy; lower alkyl or halogen; R.sup.17 represents hydrogen, lower
alkyl, or hydroxymethyl; R.sup.18, R.sup.19, R.sup.21 and R.sup.22
each represents independently hydrogen or methyl; R.sup.20
represents hydrogen or lower alkyl; and in case m represents the
integer 1, R.sup.20 in addition represents lower alkoxy, hydroxy,
--NH.sub.2, --NHR.sup.5 or --NR.sup.5R.sup.6; R.sup.23 represents
hydrogen; lower alkyl; hydroxycarbonyl-lower alkyl; 1-glyceryl or
2-glyceryl; m represents the integer 0 or 1; and configurational
isomers, optically pure enantiomers, mixtures of enantiomers such
as racemates, diastereomers, mixtures of diastereomers,
diastereomeric racemates, mixtures of diastereomeric racemates and
the meso-form, as well as pharmaceutically acceptable salts.
Preferred thiazolidin-4-one derivatives according to General
Formula (II) are (Z,Z) isomers of General Formula (II).
In a preferred embodiment, R.sup.14 represents an unsubstituted, a
mono- or disubstituted phenyl group.
In another preferred embodiment, R.sup.14 represents an
unsubstituted, a mono- or disubstituted phenyl group, substituted
with methyl or halogen.
In a further preferred embodiment, R.sup.15 represents lower
alkyl.
In another preferred embodiment, R.sup.16 represents halogen or
methyl.
In another preferred embodiment, m represents the integer 0; and
R.sup.17, R.sup.18, R.sup.19 and R.sup.20 represent hydrogen.
In yet another preferred embodiment, m represents the integer 1,
R.sup.17, R.sup.18, R.sup.19, R.sup.21, R.sup.22 represent
hydrogen, and R.sup.20 represents hydroxy.
In a particularly preferred embodiment, R.sup.23 represents
hydrogen.
In another particularly preferred embodiment, m represents the
integer 0; R.sup.17, R.sup.18, R.sup.19, R.sup.20, and R.sup.23
represents hydrogen.
In another particularly preferred embodiment, m represents the
integer 1, R.sup.17, R.sup.18, R.sup.19, R.sup.21, R.sup.22, and
R.sup.23 represent hydrogen, and R.sup.20 represents hydroxy.
In a further preferred embodiment, R.sup.14 represents an
unsubstituted, a mono- or disubstituted phenyl group, substituted
with methyl or halogen, and R.sup.15 represents lower alkyl.
In another further preferred embodiment, R.sup.14 represents an
unsubstituted, a mono- or disubstituted phenyl group, substituted
with methyl or halogen, m represents the integer 0; R.sup.17,
R.sup.18, R.sup.19, R.sup.20, and R.sup.23 represents hydrogen.
In another further preferred embodiment, R.sup.14 represents an
unsubstituted, a mono- or disubstituted phenyl group, substituted
with methyl or halogen, m represents the integer 1, R.sup.17,
R.sup.18, R.sup.19, R.sup.21, R.sup.22, and R.sup.23 represent
hydrogen, and R.sup.20 represents hydroxy.
In particularly preferred embodiment, R.sup.14 represents an
unsubstituted, a mono- or disubstituted phenyl group, substituted
with methyl or halogen, R.sup.15 represents lower alkyl; R.sup.16
represents halogen or methyl, m represents the integer 0, and
R.sup.17, R.sup.18, R.sup.19, R.sup.20 and R.sup.23 each represent
hydrogen.
In another particularly preferred embodiment, R.sup.14 represents
an unsubstituted, a mono- or disubstituted phenyl group,
substituted with methyl or halogen, R.sup.15 represents lower
alkyl; R.sup.16 represents halogen or methyl, m represents the
integer 1, R.sup.17, R.sup.18, R.sup.19, R.sup.21, R.sup.22, and
R.sup.23 represent hydrogen, and R.sup.20 represents hydroxy.
Specific thiazolidin-4-one derivatives according to formula (II)
are:
5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-phenyl-t-
hiazolidin-4-one,
{2-[4-(2-([Z]-isopropylimino)-4-oxo-3-phenyl-thiazolidin-5-[Z]-ylidenemet-
hyl)-phenoxy]-ethoxy}-acetic acid,
rac-5-{4-[2-(2,3-dihydroxy-propoxy)-ethoxy]-benz[Z]ylidene}-2-([Z]-isopro-
pylimino)-3-phenyl-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-
-phenyl-thiazolidin-4-one,
5-[3-fluoro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-
-phenyl-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-3-methyl-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-
-phenyl-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-3-methoxy-benz[Z]ylidene]-2-([Z]-isopropylimino)--
3-phenyl-thiazolidin-4-one,
5-[4-(3-hydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-phenyl--
thiazolidin-4-one,
rac-5-[4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-
-phenyl-thiazolidin-4-one,
rac-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-isopropy-
limino)-3-phenyl-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-o-tolyl--
thiazolidin-4-one,
rac-5-{4-[2-(2,3-dihydroxy-propoxy)-ethoxy]-benz[Z]ylidene}-2-([Z]-isopro-
pylimino)-3-o-tolyl-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-
-o-tolyl-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-
-o-tolyl-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-3-methoxy-benz[Z]ylidene]-2-([Z]-isopropylimino)--
3-o-tolyl-thiazolidin-4-one,
5-[4-(3-hydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-o-tolyl-
-thiazolidin-4-one,
rac-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-isopropy-
limino)-3-o-tolyl-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-m-tolyl--
thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-
-m-tolyl-thiazolidin-4-one,
rac-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-isopropy-
limino)-3-m-tolyl-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-p-tolyl--
thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-
-p-tolyl-thiazolidin-4-one,
rac-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-isopropy-
limino)-3-p-tolyl-thiazolidin-4-one,
3-(2,3-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-is-
opropylimino)-thiazolidin-4-one,
rac-5-{4-[2-(2,3-dihydroxy-propoxy)-ethoxy]-benz[Z]ylidene}-3-(2,3-dimeth-
yl-phenyl)-2-([Z]-isopropylimino)-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)--
2-([Z]-isopropylimino)-thiazolidin-4-one,
3-(2,3-dimethyl-phenyl)-5-[3-fluoro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]--
2-([Z]-isopropylimino)-thiazolidin-4-one,
3-(2,3-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-3-methyl-benz[Z]ylidene]--
2-([Z]-isopropylimino)-thiazolidin-4-one,
3-(2,3-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-3-methoxy-benz[Z]ylidene]-
-2-([Z]-isopropylimino)-thiazolidin-4-one,
rac-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-
-phenyl)-2-([Z]-isopropylimino)-thiazolidin-4-one,
3-(2,4-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-is-
opropylimino)-thiazolidin-4-one,
5-(2,3-dihydro-benzo[1,4]dioxin-6-[Z]-ylmethylene)-3-(2,6-dimethyl-phenyl-
)-2-([Z]-isopropylimino)-thiazolidin-4-one,
3-(2,6-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-is-
opropylimino)-thiazolidin-4-one,
3-(2-chloro-phenyl)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopro-
pylimino)-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-(2-chloro-phenyl)-2-([-
Z]-isopropylimino)-thiazolidin-4-one,
5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-(2-chloro-phenyl)-
-2-([Z]-isopropylimino)-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-(2-metho-
xy-phenyl)-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-
-(2-methoxy-phenyl)-thiazolidin-4-one,
5-(2,3-dihydro-benzo[1,4]dioxin-6-[Z]-ylmethylene)-2-([Z]-isopropylimino)-
-3-methoxy-phenyl)-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-(4-metho-
xy-phenyl)-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-
-(4-methoxy-phenyl)-thiazolidin-4-one,
3-allyl-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-th-
iazolidin-4-one,
3-allyl-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropyl-
imino)-thiazolidin-4-one,
rac-3-allyl-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]--
isopropylimino)-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-2-([Z]-propylimino)-thia-
zolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-2-([Z]-propylim-
ino)-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-3-methyl-benz[Z]ylidene]-3-phenyl-2-([Z]-propylim-
ino)-thiazolidin-4-one,
rac-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-phenyl-2-([Z]-
-propylimino)-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thi-
azolidin-4-one,
5-[4-(3-hydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-th-
iazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o--
tolyl-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-3-methyl-benz[Z]ylidene]-2-([Z]-propylimino)-3-o--
tolyl-thiazolidin-4-one,
rac-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylim-
ino)-3-o-tolyl-thiazolidin-4-one,
(R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylim-
ino)-3-o-tolyl-thiazolidin-4-one,
(S)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylim-
ino)-3-o-tolyl-thiazolidin-4-one,
3-(2,3-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-pr-
opylimino)-thiazolidin-4-one,
rac-5-{4-[2-(2,3-dihydroxy-propoxy)-ethoxy]-benz[Z]ylidene}-3-(2,3-dimeth-
yl-phenyl)-2-([Z]-propylimino)-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)--
2-([Z]-propylimino)-thiazolidin-4-one,
3-(2,3-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-3-methyl-benz[Z]ylidene]--
2-([Z]-propylimino)-thiazolidin-4-one,
3-(2,3-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-3-methoxy-benz[Z]ylidene]-
-2-([Z]-propylimino)-thiazolidin-4-one,
rac-5-[4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)--
2-([Z]-propylimino)-thiazolidin-4-one,
rac-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-
-phenyl)-2-([Z]-propylimino)-thiazolidin-4-one,
2-([Z]-tert-butylimino)-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]--
3-phenyl-thiazolidin-4-one,
2-(dimethyl-hydrazono)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-t-
hiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-(dimethyl-hydrazono)-3-
-phenyl-thiazolidin-4-one,
2-([Z]-ethylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-thiaz-
olidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-Ethylimino)-3-phe-
nyl-thiazolidin-4-one,
2-([Z]-ethylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-o-tolyl-thia-
zolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-ethylimino)-3-o-t-
olyl-thiazolidin-4-one,
3-(2,3-dimethyl-phenyl)-2-([Z]-ethylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z-
]ylidene]-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)--
2-([Z]-ethylimino)-thiazolidin-4-one,
2-([Z]-butylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-thiaz-
olidin-4-one,
2-([Z]-butylimino)-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phe-
nyl-thiazolidin-4-one,
2-([Z]-butylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-o-tolyl-thia-
zolidin-4-one,
2-([Z]-butylimino)-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-o-t-
olyl-thiazolidin-4-one,
2-([Z]-butylimino)-3-(2,3-dimethyl-phenyl)-5-[4-(2-hydroxy-ethoxy)-benz[Z-
]ylidene]-thiazolidin-4-one,
2-([Z]-butylimino)-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-(2,-
3-dimethyl-phenyl)-thiazolidin-4-one,
2-([Z]-sec-butylimino)-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-
-phenyl-thiazolidin-4-one,
2-([Z]-cyclopropylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-
-thiazolidin-4-one,
3-cyclohexyl-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimin-
o)-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-cyclohexyl-2-([Z]-isop-
ropylimino)-thiazolidin-4-one,
5-[4-(2-Hydroxy-ethoxy)-benz[Z]ylidene]-3-isopropyl-2-([Z]-isopropylimino-
)-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-isopropyl-2-([Z]-isopr-
opylimino)-thiazolidin-4-one,
rac-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-isopropyl-2-(-
[Z]-isopropylimino)-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-
-phenyl-thiazolidin-4-one,
2-([Z]-allylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-thiaz-
olidin-4-one,
2-([Z]-allylimino)-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phe-
nyl-thiazolidin-4-one,
3-allyl-2-([Z]-allylimino)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-thiazo-
lidin-4-one,
3-allyl-2-([Z]-allylimino)-5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]yliden-
e]-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-methylimino)-3-ph-
enyl-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)--
2-([Z]-methylimino)-thiazolidin-4-one,
More specific thiazolidin-4-one derivatives according to formula
(II) are:
5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-phe-
nyl-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-isopropylimino)-3-
-phenyl-thiazolidin-4-one,
rac-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-isopropy-
limino)-3-o-tolyl-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)--
2-([Z]-isopropylimino)-thiazolidin-4-one,
rac-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-
-phenyl)-2-([Z]-isopropylimino)-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-2-([Z]-propylim-
ino)-thiazolidin-4-one,
5-[4-(2-hydroxy-ethoxy)-3-methyl-benz[Z]ylidene]-3-phenyl-2-([Z]-propylim-
ino)-thiazolidin-4-one,
rac-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-phenyl-2-([Z]-
-propylimino)-thiazolidin-4-one,
rac-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylim-
ino)-3-o-tolyl-thiazolidin-4-one,
(R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylim-
ino)-3-o-tolyl-thiazolidin-4-one,
(S)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylim-
ino)-3-o-tolyl-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)--
2-([Z]-propylimino)-thiazolidin-4-one,
rac-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-
-phenyl)-2-([Z]-propylimino)-thiazolidin-4-one,
2-(dimethyl-hydrazono)-5-[4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-phenyl-t-
hiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-2-([Z]-Ethylimino)-3-phe-
nyl-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-(2,3-dimethyl-phenyl)--
2-([Z]-ethylimino)-thiazolidin-4-one,
5-[3-chloro-4-(2-hydroxy-ethoxy)-benz[Z]ylidene]-3-isopropyl-2-([Z]-isopr-
opylimino)-thiazolidin-4-one,
Compounds of General Formula (I) and General Formula (II) are
suitable for the use as medicament.
Still a further object of the present invention is a process to
prepare a pharmaceutical composition comprising a compound of the
General Formula (I) or a compound of the General Formula (II) by
mixing one or more active ingredients with inert excipients in a
manner known per se.
The compounds of General Formulae (I) and (II) can be manufactured
by the methods given below, by the methods given in the Examples or
by analogous methods. Optimum reaction conditions may vary with the
particular reactants or solvents used, but such conditions can be
determined by a person skilled in the art by routine optimisation
procedures.
Compounds of the General Formula (I) and General Formula (II) of
the present invention can be prepared according to the general
sequence of reactions outlined below. Only a few of the synthetic
possibilities leading to compounds of General Formula (I) and
General Formula (II) are described as summarized in Scheme 1.
##STR00003##
According to Scheme 1, compounds of the General Formula (I) can be
prepared by reacting a compound of Structure I with a compound of
Structure II, for instance, in acetic acid at elevated temperatures
and in the presence of a base such as sodium acetate. The reaction
can also be carried out in a non-polar solvent such as toluene or
benzene in the presence of an amine such as pyrrolidine or
piperidine.
Likewise, compounds of the General Formula (II) can be prepared by
reacting a compound of Structure III with a compound of Structure
IV (Scheme 2).
##STR00004##
Depending on the nature of R.sup.23, it may be beneficial to
prepare the compounds of General Formula (II) by first reacting a
compound of Structure III with the compound of Structure V to form
a compound of Structure VI (Scheme 3). The compound of Structure VI
is then treated with a compound of Structure VII wherein X
represents a leaving group such a chlorine, a bromine or an iodine
atom, or a sulfonic acid ester group in the presence of a base such
as K.sub.2CO.sub.3, NaH, or triethylamine in a solvent such as THF,
DMF, acetone, or DMSO.
##STR00005##
As outlined in Scheme 1, the compounds of Structure I can be
prepared by reacting a compound of Structure VIII with a compound
of Structure IX to form the intermediate of Structure X which is
then cyclised to the compound of Structure I with a bromo- or
chloroacetic acid ester of Structure XI. This reaction is ideally
performed in a two step-one pot procedure at room temperature using
an alcohol such as methanol or ethanol as solvent. The second step
can be catalysed by the addition of pyridine.
Alternatively, the compounds of Structure I can also be prepared by
reacting a compound of Structure Xil with a compound of Structure
XIII in the presence of a base such as NaH in a solvent such as THF
or DMF. Compounds of the Structure XII are prepared by treating a
compound of Structure XIV with chloroacetic acid chloride or
bromoacetic acid bromide in a solvent such as THF, DMF or DCM in
the presence of a base such as triethylamine, ethyldiisopropylamine
at temperatures between -60 and +50.degree. C. (Scheme 4).
##STR00006##
The preparation of compounds of Structure III is in analogy to the
preparation of compounds of Structure I.
EXAMPLES
The following examples illustrate the invention but do not at all
limit the scope thereof.
All temperatures are stated in .degree. C. Compounds are
characterized by .sup.1H-NMR (300 MHz) or .sup.13C-NMR (75 MHz)
(Varian Oxford; chemical shifts are given in ppm relative to the
solvent used; multiplicities: s=singlet, d=doublet, t=triplet;
p=pentuplet, hex=hexet, hept=heptet, m=multiplet, br=broad,
coupling constants are given in Hz); by LC-MS (Finnigan Navigator
with HP 1100 Binary Pump and DAD, column: 4.6.times.50 mm, Zorbax
SB-AQ, 5 m, 120A, gradient: 5-95% acetonitrile in water, 1 min,
with 0.04% trifluoroacetic acid, flow: 4.5 ml/min), t.sub.R is
given in min; by TLC (TLC-plates from Merck, Silica gel 60
F.sub.254); or by melting point. Compounds are purified by
preparative HPLC (column: Grom Saphir Rp-C.sub.18, 110A, 5 m,
30.times.30 mm, gradient: 10-95% acetonitrile in water containing
0.5% of formic acid, in 2 min, flow: 75 mL/min) or by MPLC
(Labomatic MD-80-100 pump, Linear UVIS-201 detector, column:
350.times.18 mm, Labogel-RP-18-5s-100, gradient: 10% methanol in
water to 100% methanol).
ABBREVIATIONS
aq. aqueous atm atmosphere DCM dichloromethane DMF
dimethylformamide DMSO dimethylsulfoxide EA ethyl acetate h hour
Hex hexane HV high vacuum conditions min minutes THF
tetrahydrofuran rt room temperature sat. saturated t.sub.R
retention time tlc thin layer chromatography Typical Procedure for
the Preparation of the 2-imino-thiazolidin-4-one Scaffold (Method
A)
To a solution of isopropylamine (1.31 g, 22.19 mmol) in methanol
(25 mL) is added portionwise phenylisothiocyanate (3.0 g, 22.19
mmol). The solution which becomes slightly warm during the addition
is stirred at rt for 4 h before pyridine (2.63 g, 33.29 mmol) and
methyl bromoacetate (3.39 g, 22.19 mmol) is added. The mixture is
stirred for another 16 h at rt before it is poured onto 1 N aq. HCl
(100 mL) and extracted with diethyl ether (150 mL). The aq. layer
is neutralised by adding sat. aq. NaHCO.sub.3 and extracted with
diethyl ether (4.times.150 mL). The organic extracts are dried over
MgSO.sub.4 and evaporated. The remaining solid is suspended in
diethyl ether/heptane, filtered off, washed with additional diethyl
ether/heptane and dried to give
3-phenyl-2-[(Z)-isopropylimino]-thiazolidin-4-one.
Typical Procedure for the Preparation of the
2-imino-thiazolidin-4-one Scaffold (Method B)
a) A solution of aniline (9.31 g, 100 mmol) and triethylamine (15.2
g, 150 mmol) in THF (150 mL) is cooled to -40.degree. C. before
chloroacetic acid chloride (11.3 g, 100 mmol) is slowly added in
portions such that the temperature does not rise above 0.degree. C.
After completion of the addition, the brown suspension is stirred
at rt for 1 h. The dark purple mixture is poured onto water (300
mL) and extracted twice with EA (300 mL). The organic extracts are
washed with sat. aq. NaHCO.sub.3, 0.5 N aq. HCl, followed by water,
and evaporated. The brown residue is suspended in diethyl ether,
filtered off, washed with additional diethyl ether and dried under
high vacuum to give 2-chloro-N-phenyl-acetamide. LC-MS:
t.sub.R=0.75 min, [M+1].sup.+=170, .sup.1H NMR (CDCl.sub.3):
.delta. 8.22 (s br, 1H), 7.56-7.51 (m, 2H), 7.40-7.24 (m, 2H),
7.20-7.14 (m, 1H), 4.20 (s, 2H).
b) At rt, NaH (154 mg of 55% dispersion in mineral oil, 3.54 mmol)
is added in portions to a solution of n-propylisothiocyanate (596
mg, 5.90 mmol) and the above 2-chloro-N-phenyl-acetamide (1000 mg,
5.90 mmol) in DMF (30 mL). Stirring is continued for 2 h after
completion of the addition. The mixture is poured onto EA (150 mL)
and is extracted twice with 1 N aq. HCl (200 mL). The aq. layer is
neutralised by adding 3 N NaOH followed by sat. aq. NaHCO.sub.3,
and extracted twice with EA (200 mL). The organic extracts are
washed with water (200 mL) and evaporated to give a pale yellow,
crystalline solid. This material is suspended in a small amount of
diethyl ether/hexane 1:1, filtered, washed with additional diethyl
ether/hexane and dried under high vacuum to give
3-phenyl-2-[(Z)-propylimino]-thiazolidin-4-one.
Typical Procedure for the Introduction of the Benzylidene
Substituent (Method C)
A solution of 3-phenyl-2-[(Z)-isopropylimino]-thiazolidin-4-one
(150 mg, 0.64 mmol), piperonal (192 mg, 1.28 mmol) and sodium
acetate (105 mg, 1.28 mmol) in acetic acid (3 mL) is stirred at
110.degree. C. for 4 h. The dark yellow to brown solution is cooled
to rt, diluted with EA (75 mL), washed with sat. aq. NaHCO.sub.3,
followed by water, and evaporated. The crude product is purified by
crystallisation from a small amount of methanol (approx. 5 mL) to
give
5-benzo[1,3]dioxol-5-ylmeth-(Z)-ylidene-2-[(Z)-isopropylimino]-3-phenyl-t-
hiazolidin-4-one.
Typical Procedure for the Introduction of the benz-(Z)-ylidene
Substituent (Method D)
A solution of 3-phenyl-2-[(Z)-isopropylimino]-thiazolidin-4-one
(150 mg, 0.64 mmol), 4-(2-hydroxyethoxy)benzaldehyde (213 mg, 1.28
mmol) and sodium acetate (105 mg, 1.28 mmol) in acetic acid (3 mL)
is stirred at 110.degree. C. for 3 h. The brown solution is cooled
to rt, diluted with EA (75 mL), washed with sat. aq. NaHCO.sub.3,
followed by water, and evaporated. The residue is dissolved in
methanol (20 mL) and sodium methylate is added (150 mg). The
resulting solution is allowed to stand for 40 min at rt before it
is diluted with EA, washed with 10% aq. citric acid, and twice with
water. The organic extracts are evaporated and the residue is
crystallised from methanol to give
(2Z,5Z)-3-phenyl-5-[4-(2-hydroxy-ethoxy)-benz-(Z)-yl
idene]-2-[(Z)-isopropylimino]-thiazolidin-4-one.
Typical Procedure for the Introduction of the benz-(Z)-ylidene
Substituent (Method E)
A solution of 3-(2-methyl
phenyl)-2-[(Z)-isopropylimino]-thiazolidin-4-one (50 mg, 0.200
mmol), 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (49 mg, 0.300
mmol) and sodium acetate (33 mg, 0.400 mmol) in acetic acid (1 mL)
is stirred at 110.degree. C. for 5 h. The reaction mixture is
cooled to rt and subjected to prep. HPLC purification. The product
containing fractions are evaporated and dried to give
5-(2,3-dihydro-benzo[1,4]dioxin-6-ylmeth-(Z)-yl
idene)-2-[(Z)-isopropylimino]-3-o-tolyl-thiazolidin-4-one.
Typical Procedure for the Introduction of the benz-(Z)-ylidene
Substituent (Method F)
A solution of
3-(2-methylphenyl)-2-[(Z)-propylimino]-thiazolidin-4-one (87 mg,
0.351 mmol),
3-chloro-4-((4R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-benzaldehyde
(190 mg, 0.702 mmol) and sodium acetate (58 mg, 0.702 mmol) in
acetic acid (4 mL) is stirred at 110.degree. C. for 4 h. Water is
added (50 .mu.L) and stirring is continued at 110.degree. C. for 1
h. The reaction mixture is cooled to rt, diluted with EA (75 mL),
washed with sat. aq. NaHCO.sub.3, followed by water, and
evaporated. The residue is dissolved in methanol (20 mL) and sodium
methylate is added (150 mg). The resulting solution is allowed to
stand for 40 min at rt before it is diluted with EA, washed with
10% aq. citric acid, and twice with water. The organic extracts are
evaporated and the residue is purified on prep. TLC plates using
toluene/EA 1:3 to give
5-[3-chloro-4-((2R)-2,3-dihydroxy-propoxy)-benz-(Z)-ylidene]-2-[(Z)-propy-
limino]-3-o-tolyl-thiazolidin-4-one (98 mg) as a pale yellow
foam.
Preparation of
rac-4-[2-(2,3-dihydroxy-propoxy)-ethoxy]-benzaldehyde
To a solution of 4-82-hydroxyethoxy)-benzaldehyde (2.50 g, 15.0
mmol) in THF (100 mL) is added NaH (722 mg of 55% dispersion in
mineral oil, 16.5 mmol) in two portions. The mixture is stirred at
rt for 30 min and allylbromide (2.18 g, 18.0 mmol) is added. After
stirring for 1 h at rt the thick mixture is diluted with DMF (20
mL) and stirring is continued for another 2 h. The mixture is
diluted with EA (300 mL), washed with sat. aq. NaHCO.sub.3 (150
mL), and water (2.times.150 mL) and concentrated. The residue is
chromatographed on silica gel eluting with heptane/EA 3:2 to afford
4-(2-allyloxy-ethoxy)-benzaldehyde (2.11 g) as an almost colourless
oil. LC-MS: t.sub.R=0.88 min, [M+1].sup.+=207.
The above material (1.5 g, 7.27 mmol) is dissolved in acetone (40
mL) and treated with a 2.5% solution of OsO.sub.4 in tert.-butanol
(1.48 mL, 0.146 mmol). N-Methylmorpholine-N-oxide (1.03 g, 8.73
mmol) followed by water (1 mL) is added and the resulting yellow to
green solution is stirred at rt for 4.5 h before it is diluted with
EA (250 mL) and washed with 10% aq. citric acid solution (100 mL)
and water (2.times.200 mL). The washings are extracted back once
with EA (200 mL). The combined organic extracts are concentrated to
leave rac-4-[2-(2,3-dihydroxy-propoxy)-ethoxy]-benzaldehyde (1.26
g) as a brownish oil. This material which reversibly polymerizes
upon standing is used without further purification in the next
step. LC-MS: t.sub.R=0.62 min, [M+1].sup.+=241.
Preparation of 3-chloro-4-(2-acetoxy-ethoxy)-benzaldehyde
A mixture of 3-chloro-4-hydroxybenzaldehyde (10 g, 63.9 mmol),
K.sub.2CO.sub.3 (26.5 g, 191.6 mmol) and 2-bromoethyl acetate (26.7
g, 159.7 mmol) in acetone (250 mL) is refluxed for 18 h before it
is diluted with diethyl ether (200 mL) and washed with water
(3.times.200 mL). The washings are extracted with diethyl ether
(200 mL). The combined organic extracts are dried over MgSO.sub.4
and concentrated. The remaining residue is purified by column
chromatography on silica gel eluting with heptane/EA 1:1 to afford
the title compound (6.44 g) as colourless solid. .sup.1H NMR
(CDCl.sub.3): .delta. 9.85 (s, 1H9, 7.91 (d, J=1.8 Hz, 1H), 7.75
(dd, J=1.8, 8.2 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 4.53-4.49 (m, 2H),
4.35-4.31 (m, 2H), 2.12 (s, 3H).
Preparation of 4-(2-acetoxy-ethoxy)-3-fluoro-benzaldehyde
A mixture of 3-fluoro-4-hydroxybenzaldehyde (2.0 g, 14.3 mmol),
K.sub.2CO.sub.3 (5.92 g, 42.8 mmol) and 2-bromoethyl acetate (4.77
g, 28.5 mmol) in acetone (30 mL) is stirred at 55.degree. C. for 24
h before it is diluted with diethyl ether (150 mL) and washed with
water (3.times.50 mL). The organic extract is dried over MgSO.sub.4
and concentrated. The remaining residue is chromatographed on
silica gel to give the title aldehyde (1.65 g) as a colourless oil.
.sup.1H NMR (CDCl.sub.3): .delta. 9.85 (s, 1H), 7.64-7.58 (m, 2H),
7.07 (t, J=8.2 Hz, 1H), 4.49-4.45 (m, 2H), 4.35-4.30 (m, 2H), 2.10
(s, 3H).
Preparation of 4-(2-acetoxy-ethoxy)-3-methylbenzaldehyde
A mixture of 4-hydroxy-3-methyl-benzaldehyde (7.0 g, 51.4 mmol),
K.sub.2CO.sub.3 (21.32 g, 154.2 mmol) and 2-bromoethyl acetate
(25.8 g, 154.2 mmol) in acetone (250 mL) is refluxed for 18 h
before it is diluted with diethyl ether (300 mL) and washed with
water (3.times.250 mL). The washings are extracted with diethyl
ether (200 mL). The combined organic extracts are dried over
MgSO.sub.4 and concentrated. The remaining residue is purified by
column chromatography on silica gel eluting with heptane/EA 1:1 to
afford the title compound (11.14 g) as colourless solid. .sup.1H
NMR (CDCl.sub.3): .delta. 9.85 (s, 1H), 7.72-7.67 (m, 2H),
6.92-6.88 (m, 1H), 4.51-4.46 (m, 2H), 4.29-4.25 (m, 2H), 2.27 (s,
3H), 2.11 (s, 3H).
Preparation of 4-(2-acetoxy-ethoxy)-3-methoxy-benzaldehyde
A mixture of 4-hydroxy-3-methoxy-benzaldehyde (2.5 g, 16.4 mmol),
K.sub.2CO.sub.3 (6.81 g, 49.3 mmol) and 2-bromoethyl acetate (5.49
g, 32.9 mmol) in acetone (50 mL) is refluxed for 48 h before it is
diluted with diethyl ether (250 mL) and washed with water
(2.times.200 mL). The washings are extracted with diethyl ether
(200 mL). The combined organic extracts are dried over MgSO.sub.4
and concentrated. The remaining residue is purified by column
chromatography on silica gel eluting with heptane/EA 1:1 to afford
the title compound (2.94 g) as colourless solid. .sup.1H NMR
(CDCl.sub.3): .delta. 9.85 (s, 1H), 7.45-7.41 (m, 2H), 6.99 (d,
J=7.6 Hz, 1H), 4.51-4.47 (m, 2H), 4.34-4.30 (m, 2H), 3.94 (s, 3H),
2.11 (s, 3H).
Preparation of 4-(3-hydroxy-propoxy)-benzaldehyde
To a solution of 3-(4-hydroxymethylphenoxy)propionic acid (4.00 g,
20.40 mmol) in THF (20 mL) is added a solution of LiAlH.sub.4 (10
mL, 1 M in THF). The mixture becomes warm and is diluted with THF
(20 mL) before it is refluxed. After 1 and 2 h two further portions
of LiAlH.sub.4 (2.times.10 mL, 1 M in THF) are added. The mixture
is refluxed overnight, cooled to rt and carefully quenched by the
addition of water (1.2 g), 15% aq. NaOH (1.2 g) and water (3.2 g).
The white precipitate is filtered off, and the filtrate is
evaporated and dried to give
3-(4-hydroxymethyl-phenoxy)-propan-1-ol. .sup.1H NMR
(D.sub.6-DMSO): .delta. 7.21-7.15 (m, 2H), 6.86-6.81 (m, 2H), 5.00
(t, J=5.9 Hz, 1H), 4.51 (t, J=5.3 Hz, 1H), 4.39 (d, J=5.3 Hz, 2H),
3.99 (t, J=6.4 Hz, 2H), 3.57-3.50 (m, 2H), 1.83 (p, J 06.4 Hz,
2H).
To a suspension of the above
3-(4-hydroxymethyl-phenoxy)-propan-1-ol (1.50 g, 8.23 mmol) in
acetonitrile (25 mL) is added N-methylmorpholine-N-oxide (1.50 g,
12.38 mmol) followed by tetrapropylammonium perruthenate (140 mg,
0.43 mmol). The dark solution is stirred at rt for 2 h before the
solvent is removed in vacuo. The crude product is purified by
column chromatography on silica gel (heptane/EA) to give
4-(3-hydroxy-propoxy)-benzaldehyde. .sup.1H NMR (D.sub.6-DMSO):
.delta. 9.83 (s, 1H), 7.85-7.81 (m, 2H), 7.12-7.07 (m, 2H9, 4.56
(t, J=5.3 Hz, 1H), 4.14 (t, J=6.4 Hz, 2H), 3.57-3.51 (m, 2H), 1.88
(p, J=6.4 Hz, 2H).
Preparation of rac-4-(2,3-dihydroxy-propoxy)-benzaldehyde
To a solution of 4-allyloxybenzaldehyde (1.0 g, 6.17 mmol) in
acetone (40 mL) and water (5 mL) is added a 2.5% solution of
OsO.sub.4 in tert. butanol (1.25 mL) followed by N-methyl
morpholine-N-oxide (867 mg, 7.4 mmol). The pale yellow solution is
stirred at rt for 6 h, diluted with EA (250 mL) and washed with 10%
aq. citric acid solution (100 mL) and water (2.times.100 mL). The
washings are extracted with EA (150 mL). The combined organic
extracts are concentrated and purified by column chromatography on
silica gel to give the title compound (731 mg) as a turbid oil. The
title compound reversibly polymerizes upon standing. LC-MS:
t.sub.R=0.58 min, [M+1+CH.sub.3CN].sup.+=238.
Preparation of
rac-4-(2,3-dihydroxy-propoxy)-3-chloro-benzaldehyde
To a solution of 3-chloro-4-hydroxybenzaldehyde (5.0 g, 31.9 mmol)
in DMF/THF 1:3 (120 mL) is added NaH (1.67 g of a 55% dispersion in
mineral oil, 38.3 mmol) in four portions. The mixture is stirred at
rt for 1 h before allylbromide (9.66 g, 79.8 mmol) is added. The
reaction mixture is heated to 65.degree. C. for 18 h, diluted with
water (250 mL) and extracted with diethyl ether (3.times.250 mL).
The organic extracts are washed with water (250 mL), combined and
concentrated. The remaining oil is chromatographed on silic gel
with heptane/EA 4:1 to afford 4-allyloxy-3-chlorobenzaldehyde (5.37
g) as an almost colourless oil. LC: t.sub.R=0.95 min. The above
4-allyloxy-3-chloro-benzaldehyde (5.37 g, 27.3 mmol) is dissolved
in acetone (100 mL) and water (10 mL) and treated with a 2.5%
solution of OsO.sub.4 in tert.-butanol (1.71 mL, 0.137 mmol
OsO.sub.4). N-methyl morpholine-N-oxide (3.87 g, 32.8 mmol) is
added and the reaction mixture is stirred at rt for 20 h before it
is diluted with EA (300 mL) and washed with 10% aq. citric acid
solution (200 mL) and water (2.times.150 mL). The washings are
extracted with EA (300 mL) and the combined organic extracts are
dried over MgSO.sub.4, filtered and concentrated to furnish the
title compound (6.02 g) as beige foam which was used in the
following steps without further purification. LC: t.sub.R=0.67
min.
Preparation of
3-chloro-4-((4R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-benzaldehyde
To a solution of 3-chloro-4-hydroxybenzaldehyde (4.21 g, 27 mmol)
in degassed toluene (100 mL) is added
((4R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (5.35 g, 40.5
mmol), 1,1'-(azodicarbonyl)dipiperidide (13.63 g, 54 mmol) followed
by tributylphosphine (10.93 g, 54 mmol). The mixture becomes
slightly warm and a precipitate forms. The reaction mixture is
diluted with degassed toluene (500 mL) and is stirred at rt for 2
h, then at 60.degree. C. for further 18 h before it is washed with
1 N aq. NaOH (3.times.150 mL) and water (150 mL). The organic phase
is dried over MgSO.sub.4, filtered and concentrated to leave a dark
brown oil which is chromatographed on silica gel eluting with
hexane/EA 4:1 to give the title compound (4.30 g) as yellow oil.
.sup.1H NMR (CDC.sub.3): .delta. 9.82 (s, 1H), 7.89 (d, J=1.8 Hz,
1H), 7.74 (dd, J=1.8, 8.2 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H),
4.56-4.43 (m, 1H), 4.23-4.17 (m, 2H), 4.14-4.08 (m, 1H), 4.06-4.00
(m, 1H), 1.47 (s, 3H), 1.41 (s, 3H).
Preparation of
3-chloro-4-((4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-benzaldehyde
The title compound (174 mg) is obtained as a pale yellow oil
starting from 3-chloro-4-hydroxybenzaldehyde (500 mg, 3.20 mmol),
((4S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (633 mg, 4.79
mmol), 1,1'-(azodicarbonyl)dipiperidide (1.61 g, 6.39 mmol), and
tributylphosphine (1.29 g, 6.39 mmol) following the procedure given
for the (R)-enantiomer above using THF as solvent, however.
Preparation of
rac-2-hydroxymethyl-2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde
To a cold (5.degree. C.) solution of 3,4-dihydroxybenzaldehyde
(3.20 g, 23.2 mmol) in DMF (70 mL) is carefully added NaH (1.96 g
55% in mineral oil, 48.5 mmol) in portions. The temperature rises
to 12.degree. C. Upon completion of the addition, the cooling is
removed and a solution of 2-chloromethyl-oxirane (2.57 g, 27.7
mmol) in DMF (3 mL) is added. The reaction mixture is stirred at rt
overnight. The mixture is diluted with 1N aq. NaOH (150 mL) and
extracted with EA (2.times.200 mL). The organic extracts are washed
with 1 M aq. NaOH (2.times.200 mL) and water (200 mL), combined,
dried over MgSO.sub.4, filtered and concentrated. The remaining
residue is purified by column chromatography on silica gel eluting
with heptene/EA 5:1 to 1:1 to afford the title aldehyde (0.53 g) as
a solid. LC: t.sub.R=0.69 min. .sup.1H NMR (D.sub.6-DMSO): .delta.
9.77 (s, 1H), 7.41 (dd, J=2.3, 8.2 Hz, 1H), 7.36 (d, J=2.3 Hz, 1H),
7.04 (d, J=8.2 Hz, 1H), 5.10 (t, J=5.9 Hz, 1H, D.sub.2O
exchangeable), 4.37 (dd, J=2.3, 11.1 Hz, 1H), 4.30-4.23 (m, 1H),
4.05 (dd, J=7.6, 11.1 Hz, 1H), 3.67-3.60 (m, 2H).
##STR00007##
2-[(Z)-Isopropylimino]-3-phenyl-thiazolidin-4-one is prepared as
described in Method A. LC-MS: t.sub.R=0.58 min, [M+1].sup.+=235.
.sup.1H NMR (CDCl.sub.3): .delta. 7.50-7.36 (m, 3H), 7.29-7.24 (m,
2H), 3.98 (s, 2H), 3.51 (hept, J=6.4 Hz, 1H), 1.14 (d, J=5.9 Hz,
6H).
##STR00008##
2-[(Z)-Isopropylimino]-3-o-tolyl-thiazolidin-4-one is obtained
following Method A and starting from o-tolylisothiocyanate (3.0 g,
20.10 mmol), isopropylamine (1.19 g, 20.10 mmol), and methyl
bromoacetate (3.08 g, 20.1 mmol). LC-MS: t.sub.R=0.67 min,
[M+1].sup.+=249; .sup.1H NMR (CDCl.sub.3): .delta. 7.34-7.26 (m,
3H), 7.14-7.08 (m, 1H), 4.00 (s, 2H), 3.50 (hept, J=6.4 Hz, 1H),
2.16 (s, 3H), 1.12 (d, J=6.4 Hz, 3H), 1.11 (d, J=6.4 Hz, 3H).
##STR00009##
2-[(Z)-Isopropylimino]-3-m-tolyl-thiazolidin-4-one is obtained
following Method A and starting from m-tolylisothiocyanate (3.0 g,
20.10 mmol), isopropylamine (1.19 g, 20.10 mmol), and methyl
bromoacetate (3.08 g, 20.1 mmol). LC-MS: t.sub.R=0.65 min,
[M+1].sup.+=249; .sup.1H NMR (CDCl.sub.3): .delta. 7.37-7.30 (m,
1H), 7.21-7.17 (m, 1H), 7.08-7.03 (m, 2H), 3.96 (s, 2H), 3.50
(hept, J=6.4 Hz, 1H), 2.40 (s, 3H), 1.14 (d, J=6.4 Hz, 6H).
##STR00010##
2-[(Z)-Isopropylimino]-3-p-tolyl-thiazolidin-4-one is obtained
following Method A and starting from p-tolylisothiocyanate (3.0 g,
20.10 mmol), isopropylamine (1.19 g, 20.10 mmol), and methyl
bromoacetate (3.08 g, 20.1 mmol). LC-MS: t.sub.R=0.64 min,
[M+1].sup.+=249; .sup.1H NMR (CDCl.sub.3): .delta. 7.28-7.24 (m,
2H), 7.16-7.12 (m, 2H), 3.96 (s, 2H), 3.50 (hept, J=6.4 Hz, 1H),
2.39 (s, 3H), 1.14 (d, J=6.4 Hz, 6H).
##STR00011##
2-[(Z)-Isopropylimino]-3-(2,3-dimethylphenyl)-thiazolidin-4-one is
obtained following Method A and starting from
2,3-dimethylphenylisothiocyanate (3.0 g, 18.38 mmol),
isopropylamine (1.09 g, 18.38 mmol), and methyl bromoacetate (2.81
g, 18.38 mmol). LC-MS: t.sub.R=0.74 min, [M+1].sup.+=263; .sup.1H
NMR (CDCl.sub.3): .delta. 7.22-7.14 (m, 2H), 6.98-6.93 (m, 1H),
3.98 (s, 2H), 3.48 (hep, J=6.4 Hz, 1H), 2.32 (s, 3H), 2.02 (s, 3H),
1.10 (d, J=6.4 Hz, 6H).
##STR00012##
2-[(Z)-Isopropylimino]-3-(2,4-dimethylphenyl)-thiazolidin-4-one is
obtained following Method A and starting from
2,4-dimethylphenylisothiocyanate (3.0 g, 18.38 mmol),
isopropylamine (1.64 g, 27.57 mmol), and methyl bromoacetate (2.81
g, 18.38 mmol). LC-MS: t.sub.R=0.75 min, [M+1].sup.+=263; .sup.1H
NMR (CDCl.sub.3): .delta. 7.12-7.06 (m, 2H), 6.98 (d, J=8.2 Hz,
1H), 3.98 (s, 2H), 3.49 (hept, J=6.0 Hz, 1H), 2.35 (s, 3H), 2.12
(s, 3H), 1.12 (d, J=5.9 Hz, 3H), 1.11 (d, J=6.4 Hz, 3H).
##STR00013##
2-[(Z)-Isopropylimino]-3-(2,6-dimethylphenyl)-thiazolidin-4-one is
obtained following Method A and starting from
2,6-dimethylphenylisothiocyanate (3.0 g, 18.38 mmol),
isopropylamine (1.09 g, 18.38 mmol), and methyl bromoacetate (2.81
g, 18.38 mmol). LC-MS: t.sub.R=0.80 min, [M+1].sup.+=263; .sup.1H
NMR (CDCl.sub.3): .delta. 7.24-7.10 (m, 3H), 4.00 (s, 2H), 3.48
(hept, J=6.4 Hz, 1H), 2.14 (s, 6H), 1.10 (d, J=6.4 Hz, 6H).
##STR00014##
2-[(Z)-Isopropylimino]-3-(2-chlorophenyl)-thiazolidin-4-one is
obtained following Method A and starting from
2-chlorophenylisothiocyanate (3.0 g, 17.68 mmol), isopropylamine
(1.04 g, 17.68 mmol), and methyl bromoacetate (2.70 g, 17.68 mmol).
LC-MS: t.sub.R=0.81 min, [M+1].sup.+=269; .sup.1H NMR (CDCl.sub.3):
.delta. 7.53-7.48 (m, 1H), 7.40-7.34 (m, 2H), 7.30-7.24 (m, 1H),
4.07-3.93 (m, 2H), 3.48 (hept, J=6.4 Hz, 1H), 1.11 (d, J=6.4 Hz,
3H), 1.10 (d, J=6.4 Hz, 3H).
##STR00015##
2-[(Z)-Isopropylimino]-3-(2-methoxyphenyl)-thiazolidin-4-one is
obtained following Method A and starting from
2-methoxyphenylisothiocyanate (3.0 g, 18.16 mmol), isopropylamine
(1.08 g, 18.16 mmol), and methyl bromoacetate (2.78 g, 18.16 mmol).
LC-MS: t.sub.R=0.62 min, [M+1].sup.+=265; .sup.1H NMR (CDCl.sub.3):
.delta.7.42-7.35 (m, 1H), 7.19-7.14 (m, 1H), 7.06-6.98 (m, 2H),
3.80 (s, 3H), 3.55-3.42 (m, 1H), 1.11 (t, 5.9 Hz, 6H).
##STR00016##
2-[(Z)-Isopropylimino]-3-(3-methoxyphenyl)-thiazolidin-4-one is
obtained following Method A and starting from
3-methoxyphenylisothiocyanate (3.0 g, 18.16 mmol), isopropylamine
(1.08 g, 18.16 mmol), and methyl bromoacetate (2.78 g, 18.16 mmol).
LC-MS: t.sub.R=0.65 min, [M+1].sup.+=265; .sup.1H NMR (CDCl.sub.3):
.delta. 7.35 (t, J=7.8 Hz, 1H), 6.95-6.90 (m, 1H), 6.87-6.83 (m,
1H), 6.82-6.80 (m, 1H), 3.96 (s, 2H), 3.82 (s, 3H), 3.54-3.45 (m,
1H), 1.13 (d, J=5.9 Hz, 6H).
##STR00017##
2-[(Z)-Isopropylimino]-3-(4-methoxyphenyl)-thiazolidin-4-one is
obtained following Method A and starting from
4-methoxyphenylisothiocyanate (3.0 g, 18.16 mmol), isopropylamine
(1.08 g, 18.16 mmol), and methyl bromoacetate (2.78 g, 18.16 mmol).
LC-MS: t.sub.R=0.62 min, [M+1].sup.+=265; .sup.1H NMR (CDCl.sub.3):
.delta. 7.20-7.14 (m, 2H), 7.00-6.94 (m, 2H), 3.96 (s, 2H), 3.84
(s, 3H), 3.51 (hept, J=6.4 Hz, 1H), 1.14 (d, J=6.4 Hz, 6H).
##STR00018##
2-[(Z)-Isopropylimino]-3-allyl-thiazolidin-4-one is obtained
following Method A and starting from allylisothiocyanate (5.95 g,
60 mmol), isopropylamine (3.55 g, 60 mmol), and methyl bromoacetate
(9.18 g, 60 mmol). LC-MS: t.sub.R=0.55 min, [M+1].sup.+=199;
.sup.1H NMR (CDCl.sub.3): .delta. 5.82-5.69 (m, 1H), 5.10-5.02 (m,
2H), 4.17-4.13 (m, 2H), 4.01 (s, 2H), 3.39 (hept, J=6.1 Hz, 1H),
1.10 (d, J=5.9 Hz, 6H).
##STR00019##
3-Phenyl-2-[(Z)-propylimino]-thiazolidin-4-one is prepared as
described in Method B. LC-MS: t.sub.R=0.60 min, [M+1].sup.+=235,
.sup.1H NMR (CDCl.sub.3): .delta. 7.51-7.36 (m, 3H), 7.28-7.24 (m,
2H), 3.99 (s, 2H), 3.27 (t, J=7.0 Hz, 2H), 1.60 (hex, J=7.0 Hz,
2H), 0.91 (t, J=7.6 Hz, 3H).
##STR00020##
2-[(Z)-Propylimino]-3-o-tolyl-thiazolidin-4-one is obtained
following Method B and starting from toluidine (2.21 g, 20.6 mmol),
chloroacetyl chloride (2.32 g, 20.6 mmol) and
n-propylisothiocyanate (1.62 g, 16.0 mmol). LC-MS: t.sub.R=0.68
min, [M+1].sup.+=249. .sup.1H NMR (CDCl.sub.3): .delta. 7.34-7.26
(m, 3H), 7.14-7.09 (m, 1H), 4.01 (s, 2H), 3.34-3.18 (m, 2H), 2.18
(s, 3H), 1.58 (hept, J=7.0 Hz, 2H), 0.88 (t, J=7.0 Hz, 3H).
##STR00021##
2-[(Z)-Propylimino]-3-(2,3-dimethylphenyl)-thiazolidin-4-one is
obtained following Method B and starting from 2,3-dimethylaniline
(3.36 g, 27.8 mmol), chloroacetyl chloride (3.14 g, 27.7 mmol) and
n-propylisothiocyanate (2.05 g, 20.2 mmol). LC-MS: t.sub.R=0.71
min, [M+1].sup.+=263. .sup.1H NMR (CDCl.sub.3): .delta. 7.22-7.16
(m, 2H), 6.98-6.94 (m, 1H), 4.00 (s, 2H), 3.34-3.18 (m, 2H), 2.32
(s, 3H), 2.05 (s, 3H), 1.57 (hex, J=7.3 Hz, 2H), 0.88 (t, J=7.6 Hz,
3H).
##STR00022##
2-[(Z)-tert.-Butylimino]-3-o-tolyl-thiazolidin-4-one (6.79 g) is
obtained as an off-white crystalline powder following Method A and
starting from phenylisothiocyanate (5.0 g, 37.0 mmol), tert.
butylamine (2.71 g, 37.0 mmol), and methyl bromoacetate (5.66 g,
37.0 mmol). LC-MS: t.sub.R=0.69 min, [M+1].sup.+=249, .sup.1H NMR
(CDCl.sub.3): .delta. 7.46-7.31 (m, 3H), 7.24-7.19 (m, 2H), 3.98
(s, 2H), 1.26 (s, 9H).
##STR00023##
2-[(Z)-(Dimethyl-hydrazono)]-3-phenyl-thiazolidin-4-one is obtained
following Method A and starting from phenylisothiocyanate (4.05 g,
30.0 mmol), dimethylhydrazine (asym.) (1.80 g, 30.0 mmol), and
methyl bromoacetate (4.59 g, 30.0 mmol). LC-MS: t.sub.R=0.69 min,
[M+1].sup.+=236, .sup.1H NMR (CDCl.sub.3): .delta. 7.50-7.36 (m,
3H), 7.32-7.28 (m, 2H), 3.82 (s, 2H), 2.48 (s, 6H).
##STR00024##
2-[(Z)-Ethylimino]-3-phenyl-thiazolidin-4-one (1.02 g) is obtained
as an off-white powder following Method B and starting from
2-chloro-N-phenyl-acetamide (7.50 g, 44.2 mmol) and
ethylisothiocyanate (3.85 g, 44.2 mmol). LC-MS: t.sub.R=0.48 min,
[M+1].sup.+=221. .sup.1H NMR (CDCl.sub.3): .delta. 7.52-7.37 (m,
3H), 7.29-7.27 (m, 2H), 4.01 (s, 2H), 3.37 (q, J=7.6 Hz, 2H), 1.20
(t, J=7.6 Hz, 3H).
##STR00025##
2-[(Z)-Ethylimino]-3-(2-methylphenyl)-thiazolidin-4-one is prepared
following Method B and starting from o-tolylamine, chloroacetyl
chloride and ethylisothiocyanate. LC-MS: t.sub.R=0.59 min,
[M+1].sup.+=235, .sup.1H NMR (CDCl.sub.3): .delta. 7.36-7.28 (m,
3H), 7.15-7.10 (m, 1H), 4.01 (s, 2H), 3.41-3.30 (m, 2H), 2.19 (s,
3H), 1.20-1.13 (m, 3H).
##STR00026##
2-[(Z)-Ethylimino]-3-(2,3-dimethylphenyl)-thiazolidin-4-one is
prepared following Method B and starting from 2,3-dimethylaniline,
chloroacetyl chloride and ethylisothiocyanate. LC-MS: t.sub.R=0.66
min, [M+1].sup.+=249, .sup.1H NMR (CDCl.sub.3): .delta. 7.24-7.19
(m, 2H), 7.00-6.96 (m, 1H), 4.01 (s, 2H), 3.45-3.27 (m, 2H), 2.34
(s, 3H), 2.05 (s, 3H), 1.16 (t, J=7.0 Hz, 3H).
##STR00027##
2-[(Z)-n-butylimino]-3-phenyl-thiazolidin-4-one (1.80 g) is
obtained as a pale beige powder following Method B and starting
from 2-chloro-N-phenyl-acetamide (7.50 g, 44.2 mmol) and
n-butylisothiocyanate (5.09 g, 44.2 mmol). LC-MS: t.sub.R=0.69 min,
[M+1].sup.+=249. .sup.1H NMR (CDCl.sub.3): .delta. 7.51-7.37 (m,
3H), 7.29-7.25 (m, 2H), 4.00 (s, 2H), 3.31 (t, J=7.0 Hz, 2H),
1.62-1.52 (m, 2H), 1.41-1.28 (m, 2H), 0.92 (t, J=7.0 Hz, 3H).
##STR00028##
2-[(Z)-n-butylimino]-3-(2-methylphenyl)-thiazolidin-4-one is
prepared following Method B and starting from o-tolylamine,
chloroacetyl chloride and n-butylisothiocyanate. LC-MS:
t.sub.R=0.77 min, [M+1].sup.+=263, .sup.1H NMR (CDCl.sub.3):
.delta. 7.35-7.28 (m, 3H), 7.14-7.10 (m, 1H), 4.01 (s, 2H),
3.38-3.22 (, 2H), 2.18 (s, 3H), 1.59-1.47 (m, 2H), 1.38-1.25 (m,
2H), 0.90 (t, J=7.0 Hz, 3H).
##STR00029##
2-[(Z)-n-butylimino]-3-(2,3-dimethylphenyl)-thiazolidin-4-one is
prepared following Method B and starting from 2,3-dimethylaniline,
chloroacetyl chloride and n-butylisothiocyanate. LC-MS:
t.sub.R=0.80 min, [M+1].sup.+=277, .sup.1H NMR (CDCl.sub.3):
.delta. 7.23-7.16 (m, 2H), 6.99-6.94 (m, 1H), 4.01 (s, 2H),
3.38-3.23 (m, 2H), 2.33 (s, 3H), 2.05 (s, 3H), 1.59-1.49 (m, 2H),
1.38-1.25 (m, 2H), 0.91 (t, J=7.0 Hz, 3H).
##STR00030##
rac-2-[(Z)-sec-Butylimino]-3-phenyl-thiazolidin-4-one (6.98 g) is
obtained as a white powder following Method A and starting from
sec-butylamine (2.70 g, 36.98 mmol), phenylisothiocyanate (5.00 g,
36.98 mmol) and methyl bromoacetate (5.66 g, 36.98 mmol). LC-MS:
t.sub.R=0.68 min, [M+1].sup.+=249, .sup.1H NMR (CDCl.sub.3):
.delta. 7.48-7.33 (m, 3H), 7.28-7.23 (m, 2H), 3.96 (s, 2H), 3.21
(hex, J=6.4 Hz, 1H), 1.52-1.39 (m, 2H), 1.09 (d, J=6.4 Hz, 3H),
0.82 (t, J=7.3 Hz, 3H).
##STR00031##
2-[(Z)-Cyclopropylimino]-3-phenyl-thiazolidin-4-one (1.62 g) is
obtained as a white powder following Method A and starting from
cyclopropylamine (0.84 g, 14.8 mmol), phenylisothiocyanate (2.00 g,
14.8 mmol) and methyl bromoacetate (2.26 g, 14.8 mmol). LC-MS:
t.sub.R=0.64 min, [M+1].sup.+=233, .sup.1H NMR (CDCl.sub.3):
.delta. 7.47-7.33 (m, 3H), 7.24-7.20 (m, 2H), 4.00 (s, 2H), 2.67
(hept, J=3.5 Hz, 1H), 0.82-0.75 (m, 2H), 0.64-0.59 (m, 2H).
##STR00032##
3-Cyclohexyl-2-[(Z)-isopropylimino]-thiazolidin-4-one is prepared
starting from cyclohexylamine, chloroacetyl chloride and
isopropylisothiocyanate following Method B. LC-MS: t.sub.R=0.83
min, [M+1].sup.+=241, .sup.1H NMR (CDCl.sub.3): .delta. 4.30 (tt,
J=3.6, 12.0 Hz, 1H), 3.69 (s, 2H), 3.37 (hep, J=6.4 Hz, 1H),
2.40-2.25 (m, 2H), 1.84-1.75 (m, 2H), 1.64-1.50 (m, 2H), 1.40-1.20
(m, 4H), 1.14 (d, J=6.4 Hz, 6H).
##STR00033##
2-[(Z)-Isopropylimino]-3-isopropyl-thiazolidin-4-one (2.68 g) is
obtained as a colourless oil following Method A and starting from
isopropylamine (1.17 g, 19.8 mmol), isopropylisothiocyanate (2.00
g, 19.8 mmol) and methyl bromoacetate (3.02 g, 19.8 mmol). LC-MS:
t.sub.R=0.61 min, [M+1].sup.+=201, .sup.1H NMR (CDCl.sub.3):
.delta. 4.73 (hept, J=7.0 Hz, 1H), 3.71 (s, 2H), 3.40 (hept, J=6.0
Hz, 1H), 1.42 (d, J=7.0 Hz, 6H), 1.17 (d, J=6.0 Hz, 6H).
##STR00034##
2-[(Z)-Isopropylimino]-3-(2-ethylphenyl)-thiazolidin-4-one (5.07 g)
is obtained as an off-white powder following Method A and starting
from isopropylamine (1.98 g, 33.5 mmol),
2-ethylphenylisothiocyanate (5.0 g, 30.8 mmol) and methyl
bromoacetate (5.12 g, 33.5 mmol). LC-MS: t.sub.R=0.90 min,
[M+1].sup.+=223, .sup.1H NMR (CDCl.sub.3): .delta. 7.41-7.26 (m,
3H), 7.08 (d, J=7.6 Hz, 1H), 3.99 (s, 2H), 3.48 (hept, J=6.4 Hz,
1H), 2.49 (q, J=7.6 Hz, 2H), 1.19 (t, J=7.6 Hz, 3H), 1.09 (d, J=6.4
Hz, 6H).
##STR00035##
2-[(Z)-Isopropylimino]-3-(5,6,7,8-tetrahydro-naphthalen-1-yl)-thiazolidin-
-4-one is obtained as a yellow solid following Method B and
starting from 5,6,7,8-tetrahydro-naphthalen-1-ylamine, chloroacetyl
chloride and isopropylisothiocyanate. LC-MS: t.sub.R=0.81 min,
[M+1].sup.+=289, .sup.1H NMR (CDCl.sub.3): .delta. 7.23-7.13 (m,
2H), 6.96-6.91 (m, 1H), 3.99 (s, 2H), 3.50 (hept, J=6.4 Hz, 1H),
2.86-2.80 (m, 2H), 2.52-2.45 (m, 2H), 1.84-1.74 (m, 4H), 1.13 (d,
J=6.4 Hz, 6H).
##STR00036##
2-[(Z)-Isopropylimino]-3-(3-chloro-2-methylphenyl)-thiazolidin-4-one
(2.7 g) is obtained as an oil following Method A and starting from
isopropylamine (1.29 g, 21.8 mmol),
3-chloro-2-methylphenylisothiocyanate (4.0 g, 21.8 mmol) and methyl
bromoacetate (3.33 g, 21.8 mmol). LC-MS: t.sub.R=086 min,
[M+1].sup.+=283, .sup.1H NMR (CDCl.sub.3): .delta. 7.48-7.44 (m,
1H), 7.30-7.23 (m, 1H), 7.10-7.06 (m, 1H), 3.51 (hept, J=6.2 Hz,
1H), 2.21 (s, 3H), 1.15 (d, J=6.2 Hz, 3H), 1.13 (d, J=6.2 Hz,
3H).
##STR00037##
2-[(Z)-Isopropylimino]-3-(3-chloro-4-methylphenyl)-thiazolidin-4-one
(4.0 g) is obtained as pale yellow solid following Method A and
starting from isopropylamine (1.72 g, 29.0 mmol),
3-chloro-4-methylphenylisothiocyanate (5.33 g, 29.0 mmol) and
methyl bromoacetate (4.44 g, 29.0 mmol). LC-MS: t.sub.R=0.80 min,
[M+1].sup.+=283, .sup.1H NMR (CDCl.sub.3): .delta. 7.33 (s, 1H),
7.30-7.27 (m, 2H), 3.96 (s, 2H), 3.49 (hept, J=6.4 Hz, 1H), 2.40
(s, 3H), 1.14 (d, J=6.4 Hz, 6H).
##STR00038##
2-[(Z)-Isopropylimino]-3-(3-trifluoromethylphenyl)-thiazolidin-4-one
(2.77 g) is obtained as an oil following Method A and starting from
isopropylamine (1.50 g, 25.4 mmol),
3-trifluoromethylphenylisothiocyanate (5.17 g, 25.4 mmol) and
methyl bromoacetate (3.89 g, 25.4 mmol). LC-MS: t.sub.R=0.88 min,
[M+1].sup.+=303, .sup.1H NMR (CDCl.sub.3): .delta. 7.65-7.46 (m,
4H), 3.98 (s, 2H), 3.50 (hept, J=6.4 Hz, 1H), 1.13 (d, J=6.4 Hz,
6H).
##STR00039##
2-[(Z)-Isopropylimino]-3-(3-chlorophenyl)-thiazolidin-4-one (1.0 g)
is obtained as an oil following Method A and starting from
isopropylamine (1.67 g, 28.3 mmol), 3-chlorophenylisothiocyanate
(4.80 g, 28.3 mmol) and methyl bromoacetate (4.33 g, 28.3 mmol).
LC-MS: t.sub.R=0.77 min, [M+1].sup.+=269, .sup.1H NMR (CDCl.sub.3):
.delta. 7.41-7.28 (m, 3H), 7.20-7.15 (m, 1H), 3.96 (s, 2H),
3.53-3.44 (m, 1H), 1.13 (d, 5.9 Hz, 6H).
##STR00040##
2-[(Z)-allyl]-3-phenyl-thiazolidin-4-one is obtained as a yellow
powder following Method B and starting from aniline, chloroacetyl
chloride and allylisothiocyanate. LC-MS: t.sub.R=0.63 min,
[M+1].sup.+=233, .sup.1H NMR (CDCl.sub.3): .delta. 7.52-7.38 (m,
3H), 7.31-7.25 (m, 2H), 5.96-5.82 (m, 1H), 5.20-5.06 (m, 2H), 4.01
(s, 2H), 3.99-3.95 (m, 2H).
##STR00041##
2-[(Z)-allylimino]-3-allyl-thiazolidin-4-one (3.12 g) is obtained
as a pale yellow oil following Method A and starting from
allylamine (1.15 g, 20.2 mmol), allylisothiocyanate (2.0 g, 20.2
mmol) and methyl bromoacetate (3.08 g, 20.2 mmol). LC-MS:
t.sub.R=0.66 min, [M+1].sup.+=197; .sup.1H NMR (CDCl.sub.3):
.delta. 6.02-5.79 (m, 2H), 5.29-5.25 (m, 1H), 5.22-5.18 (m, 1H),
5.17-5.09 (m, 2H), 4.38-4.35 (m, 2H), 3.95 (dt, J.sub.d=5.3 Hz,
J.sub.t=1.7 Hz, 2H), 3.83 (s, 2H).
##STR00042##
2-[(Z)-Methylimino]-3-phenyl-thiazolidin-4-one is obtained as a
beige solid following Method B and starting from aniline,
chloroacetyl chloride and methylisothiocyanate. LC-MS: t.sub.R=0.37
min, [M+1].sup.+=207, .sup.1H NMR (CDCl.sub.3): .delta. 7.52-7.38
(m, 3H), 7.28-7.24 (m, 2H), 4.01 (s, 2H), 3.13 (s, 3H).
##STR00043##
2-[(Z)-Methylimino]-3-(2,3-dimethylphenyl)-thiazolidin-4-one is
obtained as a pale orange solid following Method B and starting
from 2,3-dimethylaniline, chloroacetyl chloride and
methylisothiocyanate. LC-MS: t.sub.R=0.59 min, [M+1].sup.+=235,
.sup.1H NMR (CDCl.sub.3): .delta. 7.24-7.19 (m, 2H), 7.00-6.95 (m,
1H), 4.04 (s, 2H), 3.12 (s, 3H), 2.33 (s, 3H), 2.06 (s, 3H).
Example 1
##STR00044##
5-Benzo[1,3]dioxol-5-ylmeth-(Z)-ylidene-2-[(Z)-isopropylimino]-3-phenyl-t-
hia-zolidin-4-one is prepared as described in Method C.
LC-MS: t.sub.R=1.06 min, [M+1].sup.+=367. .sup.1H NMR (CDCl.sub.3):
.delta. 7.70 (s, 1H), 7.52-7.32 (m, 5H), 7.12-7.07 (m, 2H), 6.92
(d, J=7.6 Hz, 1H), 6.06 (s, 2H), 3.61 (hept, J=6.1 Hz, 1H), 1.21
(d, J=6.4 Hz, 6H).
Example 2
##STR00045##
5-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmeth-(Z)-ylidene)-2-[(Z)-isopropylimi-
no]-3-phenyl-thiazolidin-4-one is obtained starting from Scaffold 1
(19 mg, 0.08 mmol) and 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde
(26 mg, 0.16 mmol) following Method E.
LC-MS: t.sub.R=1.05 min, [M+1].sup.+=381.
Example 3
##STR00046##
5-(4-Dimethylamino-benz-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-phenyl-thia-
zolidin-4-one is obtained starting from Scaffold 1 (19 mg, 0.08
mmol) and 4-dimethylamino-benzaldehyde (24 mg, 0.16 mmol) following
Method E. LC-MS: t.sub.R=1.09 min, [M+1].sup.+=379.
Example 4
##STR00047##
5-[4-(2-Hydroxy-ethoxy)-benz-(Z)-ylidene]-2-[(Z)-isopropylimino]-3-phenyl-
-thia-zolidin-4-one is prepared as described in Method D
LC-MS: t.sub.R=0.94 min, [M+1].sup.+=383.
.sup.1H NMR (CDCl.sub.3): .delta. 7.74 (s, 1H), 7.56-7.44 (m, 4H),
7.42-7.32 (m, 3H), 7.04-6.99 (m, 2H), 4.17-4.13 (m, 2H), 4.03-3.97
(m, 2H), 3.60 (hept, J=6.4 Hz, 1H), 2.01 (s br, 1H), 1.19 (d, J=6.4
Hz, 6H).
Example 5
##STR00048##
A mixture of
5-[4-(2-Hydroxy-ethoxy)-benz-(Z)-ylidene]-2-[(Z)-isopropylimino]-3-phenyl-
-thiazolidin-4-one (75 mg, 0.196 mmol, Example 4), K.sub.2CO.sub.3
(81 mg, 0.588 mmol), and methyl chloroacetate (250 L) in DMF (2 mL)
is stirred at 60.degree. C. for 96 h before it is diluted with EA
(75 mL) and washed with 10% aq. citric acid (50 mL) and water
(2.times.50 mL). The organic layer is evaporated and the resulting
residue is purified by prep. TLC (heptane/EA 1:1) followed by
crystallisation from a small amount of methanol to give
{2-[4-(2-[(Z)-isopropylimino]-4-oxo-3-phenyl-thiazolidin-5-ylidene-methyl-
)-phenoxy]-ethoxy}-acetic acid. LC-MS: t.sub.R=1.06 min,
[M+1].sup.+=441. .sup.1H NMR (CDCl.sub.3): .delta. 7.73 (s, 1H),
7.55-7.44 (m, 4H), 7.42-7.32 (m, 3H), 7.03-6.98 (m, 2H), 4.55-4.50
(m, 2H), 4.29-4.25 (m, 2H), 3.83 (s, 2H), 3.60 (hept, J=6.4 Hz,
1H), 1.19 (d, J=6.4 Hz, 6H).
Example 6
##STR00049##
After purification on prep. TLC plates,
rac-5-{4-[2-(2,3-dihydroxy-propoxy)-ethoxy]-benz-(Z)-ylidene}-2-[(Z)-isop-
ropylimino]-3-phenyl-thiazolidin-4-one is obtained as a pale beige
foam starting from Scaffold 1 (150 mg, 0.604 mmol) and
rac-4-[2-(2,3-dihydroxy-propoxy)-ethoxy]-benzaldehyde (290 mg,
1.208 mmol) following Method D. LC-MS: t.sub.R=0.99 min,
[M+1].sup.+=471; .sup.1H NMR (CDCl.sub.3): .delta. 7.73 (s, 1H),
7.55-7.51 (m, 2H), 7.35-7.28 (m, 3H), 7.20-7.15 (m, 1H), 7.04-6.98
(m, 2H), 4.20 (t, J=4.7 Hz, 2H), 3.94-3.88 (m, 3H), 3.77-3.55 (m,
5H), 2.65 (s br, 1H), 2.19 (s, 3H), 2.08 (s br, 1H), 1.17 (d, J=6.4
Hz, 3H), 1.16 (d, J=6.4 Hz, 3H).
Example 7
##STR00050##
5-[3-Chloro-4-(2-hydroxy-ethoxy)-benz-(Z)-ylidene]-2-[(Z)-isopropylimino]-
-3-phenyl-thiazolidin-4-one is obtained as pale yellow powder
starting from 3-chloro-4-(2-acetoxy-ethoxy)-benzaldehyde (311 mg,
1.28 mmol) and Scaffold 1 (150 mg, 0.64 mmol) following Method D.
LC-MS: t.sub.R=1.01 min, [M+1].sup.+=417; .sup.1H NMR (CDCl.sub.3):
.delta. 7.654 (s, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.51-7.32 (m, 6H),
7.03 (d, J=8.8 Hz, 1H), 4.24-4.20 (m, 2H), 4.06-4.01 (m, 2H), 3.60
(hept, J=6.4 Hz, 1H), 2.15 (s br, 1H), 1.19 (d, J=6.4 Hz, 6H).
Example 8
##STR00051##
5-[3-Fluoro-4-(2-hydroxy-ethoxy)-benz-(Z)-ylidene]-2-[(Z)-isopropylimino]-
-3-phenyl-thiazolidin-4-one is prepared following Method D and
starting from 4-(2-acetoxy-ethoxy)-3-fluoro-benzaldehyde (390 mg,
1.7 mmol) and Scaffold 1 (200 mg, 0.85 mmol). LC-MS: t.sub.R=0.98
min, [M+1].sup.+=401; .sup.1H NMR (CDCl.sub.3): .delta. 7.66 (s,
1H), 7.51-7.28 (m, 7H), 7.06 (t, J=8.2 Hz, 1H), 4.24-4.20 (m, 2H),
4.06-4.00 (m, 2H), 3.60 (hept, J=6.4 Hz, 1H), 2.11 (t br, 1H), 1.19
(d, J=6.4 Hz, 6H).
Example 9
##STR00052##
5-[4-(2-Hydroxy-ethoxy)-3-methyl-benz-(Z)-ylidene]-2-[(Z)-isopropylimino]-
-3-phenyl-thiazolidin-4-one is obtained as an off-white powder
starting from 4-(2-acetoxy-ethoxy)-3-methylbenzaldehyde (284 mg,
1.28 mmol) and Scaffold 1 (150 mg, 0.64 mmol) following Method D.
LC-MS: t.sub.R=0.98 min, [M+1].sup.+=397; .sup.1H NMR (CDCl.sub.3):
.delta. 7.69 (s, 1H), 7.49-7.30 (m, 7H), 6.90 (d, J=8.2 Hz, 1H),
4.17-4.12 (m, 2H), 4.03-3.98 (m, 2H), 3.59 (hept, J=6.4 Hz, 1H),
2.30 (s, 3H), 1.95 (s br, 1H), 1.17 (d, J=6.4 Hz, 6H).
Example 10
##STR00053##
5-[4-(2-Hydroxy-ethoxy)-3-methoxy-benz-(Z)-ylidene]-2-[(Z)-isopropylimino-
]-3-phenyl-thiazolidin-4-one is obtained as a pale yellow powder
starting from 4-(2-acetoxy-ethoxy)-3-methoxy-benzaldehyde (305 mg,
1.28 mmol) and Scaffold 1 (150 mg, 0.64 mmol) following Method D.
LC-MS: t.sub.R=0.95 min, [M+1].sup.+=413; .sup.1H NMR (CDCl.sub.3):
.delta. 7.72 (s, 1H), 7.51-7.45 (m, 2H), 7.42-7.39 (m, 1H),
7.37-7.32 (m, 2H), 7.18 (dd, J=2.3, 8.2 Hz, 1H), 7.08 (d, J=2.3 Hz,
1H), 7.00 (d, J=8.2 Hz, 1H), 4.22-4.17 (m, 2H), 4.06-3.98 (m, 3H),
3.95 (s, 3H), 3.60 (hept, J=6.4 Hz, 1H), 1.22 (d, J=6.4 Hz, 3H),
1.19 (d, J=6.4 Hz, 3H).
Example 11
##STR00054##
5-[4-(3-Hydroxy-propoxy)-benz-(Z)-ylidene]-2-[(Z)-isopropylimino]-3-pheny-
l-thiazolidin-4-one is obtained starting from Scaffold 1 (150 mg,
0.640 mmol) and 4-(3-hydroxy-propoxy)-benzaldehyde (173 mg, 0.960
mmol) following Method D. LC-MS: t.sub.R=0.97 min, [M+1].sup.+=397.
.sup.1H NMR (CDCl.sub.3): .delta. 7.73 (s, 1H), 7.55-7.33 (m, 7H),
7.02-6.97 (m, 2H), 4.19 (t, J=5.9 Hz, 2H), 3.89 (t, J=5.9 Hz, 2H),
3.60 (hept, J=6.4 Hz, 1H), 2.09 (p, J=5.9 Hz, 2H), 1.19 (d, J=6.4
Hz, 6H).
Example 12
##STR00055##
rac-5-[4-(2,3-Dihydroxy-propoxy)-benz-(Z)-ylidene]-2-[(Z)-isopropylimino]-
-3-o-tolyl-thiazolidin-4-one is obtained as an off-white powder
starting from rac-4-(2,3-dihydroxy-propoxy)-benzaldehyde (335 mg,
1.70 mmol) and Scaffold 1 (200 mg, 0.85 mmol) following Method D.
LC-MS: t.sub.R=0.86 min, [M+1].sup.+=413. .sup.1H NMR (CDCl.sub.3):
.delta. 7.73 (s, 1H), 7.55-7.45 (m, 4H), 7.43-7.32 (m, 3H),
7.03-6.99 (m, 2H), 4.16-4.10 (m, 3H), 3.91-3.84 (m, 1H), 3.81-3.74
(m, 1H), 3.60 (hept, J=6.4 Hz, 1H), 2.56 (s br, 1H), 1.95 (s br,
1H); 1.19 (d, J=6.4 Hz, 6H).
Example 13
##STR00056##
rac-5-[3-Chloro-4-(2,3-dihydroxy-propoxy)-benz-(Z)-yl
idene]-2-[(Z)-isopropylimino]-3-phenyl-thiazolidin-4-one is
obtained as pale olive powder starting from
rac-4-(2,3-dihydroxy-propoxy)-3-chloro-benzaldehyde (295 mg, 1.28
mmol) and Scaffold 1 (150 mg, 0.64 mmol) following Method D. LC-MS:
t.sub.R=0.94 min, [M+1].sup.+=447.
.sup.1H NMR (CDCl.sub.3): .delta. 7.64 (s, 1H), 7.59 (d, J=2.3 Hz,
1H), 7.50-7.30 (m, 6H), 7.01 (d, J=8.2 Hz, 1H), 4.25-4.13 (m, 3H),
3.92-3.80 (m, 2H), 3.59 (hept, J=6.4 Hz, 1H), 2.70 (s br, 1H), 2.05
(s br, 1H), 1.18 (d, J=6.4 Hz, 6H).
Example 14
##STR00057##
rac-5-(3-Hydroxymethyl-2,3-dihydro-benzo[1,4]dioxin-6-yl
meth-(Z)-ylene)-2-[(Z)-isopropylimino-3-phenyl-thiazolidin-4-one is
obtained as almost colourless crystals (EA/methanol) starting from
rac-2-hydroxymethyl-2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde
(210 mg, 1.08 mmol) and Scaffold 1 (150 mg, 0.64 mmol) following
Method D. LC-MS: t.sub.R=0.97 min, [M+1].sup.+=411. .sup.1H NMR
(CDCl.sub.3): .delta. 7.58 (s, 1H), 7.42-7.35 (m, 2H), 7.33-7.24
(m, 3H), 7.06-7.01 (m, 2H), 6.92-6.89 (m, 1H), 4.42-4.35 (m, 1H),
4.30-4.23 (m, 3H), 4.03 (dd, J=7.0, 11.1, 1H), 3.51 (hept, J=6.4
Hz, 1H), 1.10 (d, J=6.4 Hz, 6H).
Examples 15 to 25
Starting from Scaffold 2, the following examples are prepared:
TABLE-US-00002 ##STR00058## Scale LC-MS Example R Method (mmol)
t.sub.R [M + 1].sup.+ 15 ##STR00059## C 0.604 1.10 381 16
##STR00060## E 0.200 1.09 395 17 ##STR00061## C 0.604 1.03 380 18
##STR00062## D 0.400 0.98 397 19 ##STR00063## D 0.604 0.91 471 20
##STR00064## D 0.604 1.04 431 21 ##STR00065## D 0.604 1.02 411 22
##STR00066## D 0.604 0.98 427 23 ##STR00067## D 0.604 1.01 411 24
##STR00068## D 0.604 0.96 461 25 ##STR00069## D 0.650 1.01 425
Example 15
.sup.1H NMR (CDCl.sub.3): .delta. 7.69 (s, 1H), 7.34-7.27 (m, 3H),
7.20-7.14 (m, 1H), 7.12-7.07 (m, 2H), 6.91 (d, J=7.6 Hz, 1H), 6.06
(s, 2H), 3.58 (hept, J=6.4 Hz, 1H), 2.19 (s, 3H), 1.18 (d, J=5.9
Hz, 3H), 1.17 (d, J=5.9 Hz, 3H).
Example 20
.sup.1H NMR (CDCl.sub.3): .delta. 7.65 (s, 1H), 7.62 (d, J=2.3 Hz,
1H), 7.45 (dd, J=2.3, 8.2 Hz, 1H), 7.36-7.29 (m, 3H), 7.20-7.15 (m,
1H), 7.03 (d, J=8.8 Hz, 1H), 4.24-4.20 (m, 2H), 4.07-4.01 (m, 2H),
3.59 (hept, J=5.9 Hz, 1H), 2.18 (s, 3H), 2.14 (s br, 1H), 1.18 (d,
J=5.9 Hz, 3H), 1.16 (d, J=5.9 Hz, 3H).
Example 23
.sup.1H NMR (CDCl.sub.3): .delta. 7.73 (s, 1H), 7.55-7.50 (m, 2H),
7.35-7.27 (m, 3H), 7.20-7.15 (m, 1H), 7.02-6.98 (m, 2H), 4.20 (t,
J=5.9 Hz, 2H), 3.88 (t, J=5.9 Hz, 2H), 3.58 (hept, J=6.4 Hz, 1H),
2.18 (s, 3H), 2.09 (p, J=5.9 Hz, 2H), 1.17 (d, J=6.4 Hz, 3H), 1.16
(d, J=6.4 Hz, 3H).
Example 24
.sup.1H NMR (CDCl.sub.3): .delta. 7.63 8s, 1H), 7.59 8d, J=2.3 Hz,
1H), 7.43 (dd, J=2.3, 8.8 Hz, 1H), 7.35-7.26 (m, 3H), 7.17-7.13 (m,
1H), 7.01 (d, J=8.8 Hz, 1H), 4.24-4.13 (m, 3H), 3.91-3.79 (m, 2H),
3.57 (hept, J=5.9 Hz, 1H), 2.74 (s br, 1H), 2.16 (s, 3H), 1.17 (d,
J=5.9 Hz, 3H), 2.15 (d, J=5.9 Hz, 3H).
Examples 26 to 31
Starting from Scaffold 3, the following examples are prepared:
TABLE-US-00003 ##STR00070## LC-MS Example R Method Scale (mmol)
t.sub.R [M + 1].sup.+ 26 ##STR00071## E 0.200 1.08 381 27
##STR00072## E 0.200 1.08 395 28 ##STR00073## E 0.200 1.01 380 29
##STR00074## D 0.400 0.97 397 30 ##STR00075## D 0.604 1.04 431 31
##STR00076## D 0.604 0.97 461
Example 31
.sup.1H NMR (CDCl.sub.3) .delta. 7.64 (s, 1H), 7.60 (d, J=2.3 Hz,
1H), 7.44 (dd, J=2.3, 8.8 Hz, 1H), 7.39-7.33 (m, 1H), 7.23-7.19 (m,
1H), 7.15-7.10 (m, 2H), 7.02 (d, J=8.8 Hz, 1H), 4.25-4.15 (m, 3H),
3.93-3.80 (m, 2H), 3.60 (hept, J=6.4 Hz, 1H), 2.75 (s br, 1H), 2.41
(s, 3H), 1.85 (s br, 1H), 1.21 (d, J=6.4 Hz, 6H).
Examples 32 to 36
Starting from Scaffold 4, the following examples have been
prepared:
TABLE-US-00004 ##STR00077## Scale LC-MS Example R Method (mmol)
t.sub.R [M + 1].sup.+ 32 ##STR00078## E 0.200 1.09 381 33
##STR00079## E 0.200 1.09 395 34 ##STR00080## D 0.400 0.97 397 35
##STR00081## D 0.604 1.05 431 36 ##STR00082## D 0.604 0.98 461
Example 35
.sup.1H NMR (CDCl.sub.3): .delta. 7.64 (s, 1H), 7.60 (d, J=2.3 Hz,
1H), 7.44 (dd, J=2.3, 8.2 Hz, 1H), 7.30-7.19 (m, 4H), 7.02 (d,
J=8.2 Hz, 1H), 4.23-4.19 (m, 2H), 4.07-4.00 (m, 2H), 3.59 (hept,
J=6.4 Hz, 1H), 2.40 (s, 3H), 2.14 (s br, 1H), 1.19 (d, J=6.4 Hz,
6H).
Examples 37 to 47
Starting from Scaffold 5, the following examples have been
prepared:
TABLE-US-00005 ##STR00083## Scale LC-MS Example R Method (mmol)
t.sub.R [M + 1].sup.+ 37 ##STR00084## E 0.200 1.11 395 38
##STR00085## 0 0.200 1.11 409 39 ##STR00086## E 0.200 1.05 394 40
##STR00087## D 0.763 0.99 411 41 ##STR00088## D 0.572 0.93 485 42
##STR00089## D 0.572 1.06 445 43 ##STR00090## D 0.572 1.03 429 44
##STR00091## D 0.572 1.03 425 45 ##STR00092## D 0.572 1.00 441 46
##STR00093## D 0.572 0.98 475 47 ##STR00094## D 0.650 1.00 439
Example 40
.sup.1H NMR (CDCl.sub.3): .delta. 7.73 (s, 1H), 7.56-7.51 (m, 2H),
7.24-7.18 (m, 2H), 7.06-7.00 (m, 3H), 4.18-4.14 (m, 2H), 4.04-3.98
(m, 2H), 3.50 (hep, J=6.4 Hz, 1H), 2.35 (s, 3H), 2.05 (s, 3H), 2.00
(s br, 1H), 1.18 (d, J=6.4 Hz, 3H), 1.17 (d, J=6.4 Hz, 3H).
Example 47
.sup.1H NMR (CDCl.sub.3): .delta. 7.57 (s, 1H), 7.17-7.00 (m, 4H),
6.97-6.85 (m, 2H), 4.30-4.18 (m, 2H), 4.11-4.03 (m, 1H), 3.86-3.70
(m, 2H), 3.49 (hept, J=6.4 Hz, 1H), 2.26 (s, 3H), 1.95 (s, 3H),
1.07 (d, J=6.4 Hz, 6H).
Examples 48 and 49
Starting from Scaffold 6, the following examples are prepared:
TABLE-US-00006 ##STR00095## Scale LC-MS Example R Method (mmol)
t.sub.R [M + 1].sup.+ 48 ##STR00096## E 0.200 1.12 409 49
##STR00097## D 0.762 1.00 411
Example 48
.sup.1H NMR (CDCl.sub.3): .delta. 7.72 (s, 1H), 7.56-7.50 (m, 2H),
7.14-6.98 (m, 5H), 4.17-4.12 (m, 2H), 4.02-3.96 (m, 2H), 3.58
(hept, J=6.2 Hz, 1H), 2.37 (s, 3H), 2.14 (s, 3H), 2.04 (s br, 1H),
1.17 (d, J=6.2 Hz, 3H), 1.16 (d, J=6.2 Hz, 3H).
Examples 50 to 51
Starting from Scaffold 7, the following examples are prepared:
TABLE-US-00007 ##STR00098## Scale LC-MS Example R Method (mmol)
t.sub.R [M + 1].sup.+ 50 ##STR00099## E 0.200 1.13 409 51
##STR00100## D 0.762 1.02 411
Example 51
.sup.1H NMR (CDCl.sub.3): .delta. 7.73 (s, 1H), 7.57-7.52 (m, 2H),
7.27-7.21 (m, 1H), 7.17-7.12 (m, 2H), 7.04-6.99 (m, 2H), 4.18-4.13
(m, 2H), 4.03-3.98 (m, 2H), 3.57 (hept, J=6.1 Hz, 1H), 2.15 (s,
6H), 2.01 (s br, 1H), 1.16 (d, J=6.4 Hz, 6H).
Examples 52 to 57
Starting from Scaffold 8, the following examples are prepared:
TABLE-US-00008 ##STR00101## Ex- LC-MS am- Scale [M + ple R Method
(mmol) t.sub.R 1].sup.+ 52 ##STR00102## E 0.200 1.11 401 53
##STR00103## E 0.200 1.11 415 54 ##STR00104## E 0.200 1.09 400 55
##STR00105## D 0.744 0.99 417 56 ##STR00106## D 0.558 1.05 451 57
##STR00107## D 0.558 0.98 481
Example 55
.sup.1H NMR (CDCl.sub.3): .delta. 7.74 (s, 1H), 7.56-7.50 (m, 3H),
7.41-7.32 (m, 3H), 7.04-7.00 (m, 2H), 4.18-4.13 (m, 2H), 4.04-3.98
(m, 2H), 3.58 (hept, J=6.1 Hz, 1H), 2.01 (s br, 1H), 1.17 (d, J=5.9
Hz, 3H), 1.16 (d, J=6.4 Hz, 3H).
Example 58
##STR00108##
5-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmeth-(Z)-ylidene)-2-[(Z)-isopropylimi-
no]-3-(2-methoxyphenyl)-thiazolidin-4-one is obtained starting from
Scaffold 9 (53 mg, 0.200 mmol) and
2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (49 mg, 0.300 mmol)
following Method C. LC-MS: t.sub.R=1.03 min, [M+1].sup.+=411.
Examples 58 to 60
Starting from Scaffold 9, the following examples are prepared:
TABLE-US-00009 ##STR00109## Ex- am- Scale LC-MS ple R Method (mmol)
t.sub.R [M + 1].sup.+ 58 ##STR00110## C 0.200 1.03 411 59
##STR00111## D 0.378 0.92 413 60 ##STR00112## D 0.567 0.99 447
Example 60
.sup.1H NMR (CDCl.sub.3): .delta. 7.55 (s, 1H), 7.52 (d, J=2.3 Hz,
1H), 7.38-7.29 (m, 2H), 7.15 (dd, J=1.8, 7.6 Hz, 1H), 7.00-6.92 (m,
3H), 4.15-4.11 (m, 2H), 3.98-3.93 (m, 2H), 3.72 (s, 3H), 3.50
(hept, J=6.4 Hz, 1H), 2.08 (s br, 1H), 1.09 (d, J=6.4 Hz, 3H), 1.08
(d, J=6.4 Hz, 3H).
Examples 61 and 62
Starting from Scaffold 10, the following examples are prepared:
TABLE-US-00010 ##STR00113## Scale LC-MS Example R Method (mmol)
t.sub.R [M + 1].sup.+ 61 ##STR00114## E 0.200 1.06 411 62
##STR00115## D 0.380 0.95 413
Example 63 to 65
Starting from Scaffold 11, the following examples are prepared:
TABLE-US-00011 ##STR00116## Ex- am- Scale LC-MS ple R Method (mmol)
t.sub.R [M + 1].sup.+ 63 ##STR00117## E 0.200 1.05 411 64
##STR00118## D 0.380 0.93 413 65 ##STR00119## D 0.567 0.99 447
Example 66 to 71
Starting from Scaffold 12, the following examples are prepared:
TABLE-US-00012 ##STR00120## Ex- LC-MS am- Scale [M + ple R Method
(mmol) t.sub.R 1].sup.+ 66 ##STR00121## E 0.200 1.07 331 67
##STR00122## E 0.080 1.05 345 68 ##STR00123## C 20.0 0.99 330.2 69
##STR00124## D 0.757 0.94 347 70 ##STR00125## D 0.756 1.02 381 71
##STR00126## D 0.756 0.94 411
Example 68
.sup.1H NMR (D.sub.6-DMSO): .delta. 7.55 (s, 1H), 7.46-7.42 (m,
2H), 6.82-6.76 (m, 2H), 5.90-5.76 (m, 1H), 5.13-5.02 (m, 2H),
4.36-4.27 (m, 2H), 3.50 (hept, J=6.0 Hz, 1H), 2.99 (s, 6H), 1.16
(d, J=5.9 Hz, 6H).
Example 69
.sup.1H NMR (CDCl.sub.3): .delta. 7.66 (s, 1H), 7.51-7.46 (m, 2H),
7.01-6.96 (m, 2H), 5.96-5.83 (m, 1H), 5.28-5.14 (m, 2H), 4.49-4.44
(m, 2H), 4.16-4.12 (m, 2H), 4.03-3.96 (m, 2H), 3.55 (hept, J=6.1
Hz, 1H), 2.01 (t br, J=5 Hz, 1H), 1.24 (d, J=5.9 Hz, 6H).
Examples 72 to 77
Starting from Scaffold 13, the following examples are prepared:
TABLE-US-00013 ##STR00127## Ex- LC-MS am- Scale [M + ple R Method
(mmol) t.sub.R 1].sup.+ 72 ##STR00128## C 0.640 1.06 367 73
##STR00129## C 0.333 1.05 381 74 ##STR00130## D 0.854 0.95 383 75
##STR00131## D 1.067 1.01 417 76 ##STR00132## D 1.067 0.97 397 77
##STR00133## D 0.640 0.94 447
Example 74
.sup.1H NMR (CDCl.sub.3): .delta. 7.74 (s, 1H), 7.56-7.44 (m, 4H),
7.43-7.32 (m, 3H), 7.03-6.98 (m, 2H), 4.18-4.13 (m, 2H), 4.04-3.96
(m, 2H), 3.38 (t, J=6.6 Hz, 2H), 2.01 (s br, 1H), 1.72-1.59 (m,
2H), 0.95 (t, J=7.6 Hz, 3H).
Example 76
.sup.1H NMR (CDCl.sub.3): .delta. 7.72 (s, 1H), 7.53-7.33 (m, 7H),
6.93 (d, J=8.8 Hz, 1H), 4.19-4.15 (m, 2H), 4.06-4.00 (m, 2H), 3.40
(t, J=7.0 Hz, 2H), 2.33 (s, 3H), 1.98 (t br, J=6 Hz, 1H), 1.67
(hex, J=7.0 Hz, 2H), 0.96 (t, J=7.0 Hz, 3H).
Example 78 to 86
Starting from Scaffold 14, the following examples are prepared:
TABLE-US-00014 ##STR00134## Ex- LC-MS am- Scale [M + ple R Method
(mmol) t.sub.R 1].sup.+ 78 ##STR00135## C 0.805 1.08 381 79
##STR00136## C 0.805 1.08 395 80 ##STR00137## D 0.805 0.96 397 81
##STR00138## D 0.427 0.99 411 82 ##STR00139## D 0.805 1.03 431 83
##STR00140## D 0.604 1.01 411 84 ##STR00141## D 0.604 0.96 461 85
##STR00142## F 0.351 0.96 461 86 ##STR00143## F 0.314 0.96 461
Example 80
.sup.1H-NMR (CDCl.sub.3): .delta. 7.74 (s, 1H), 7.57-7.52 (m, 2H),
7.36-7.28 (m, 3H), 7.20-7.16 (m, 1H), 7.05-7.00 (m, 2H), 4.18-4.14
(m, 2H), 4.04-3.98 (m, 2H), 3.46-3.30 (m, 2H), 2.20 (s, 3H), 2.00
(s br, 1H), 1.68-1.56 (m, 2H), 0.93 (t, J=7.0 Hz, 3H).
Example 81
.sup.1H NMR (CDCl.sub.3): .delta. 7.74 (s, 1H), 7.56-7.51 (m, 2H),
7.35-7.28 (m, 3H), 7.20-7.15 (m, 1H), 7.03-6.98 (m, 2H), 4.20 (t,
J=5.9 Hz, 2H), 3.89 (t, J=5.9 Hz, 2H), 3.49-3.30 (m, 2H), 2.20 (s,
3H), 2.15-2.03 (m, 2H), 1.68-1.55 (m, 2H), 0.92 (t, J=7.6 HZ,
3H).
Example 86
.sup.1H NMR (CDCl.sub.3): .delta. 7.66 (s, 1H), 7.62 (d, J=2.3 Hz,
1H), 7.47 (dd, J=2.3, 8.8 Hz, 1H), 7.36-7.28 (m, 3H), 7.21-7.16 (m,
1H), 7.05 (d, J=8.8 Hz, 1H), 4.25-4.16 (m, 3H), 3.94-3.82 (m, 2H),
3.45-3.30 (m, 2H), 2.72 (d, J=4.1 Hz, 1H), 2.20 (s, 3H), 2.07 (t,
J=6.2 Hz, 1H), 1.63 (hex, J=7.0 Hz, 2H), 0.93 (t, J=7.0 Hz,
3H).
Example 87 to 95
Starting from Scaffold 15, the following examples are prepared:
TABLE-US-00015 ##STR00144## Scale LC-MS Example R Method (mmol)
t.sub.R [M + 1].sup.+ 87 ##STR00145## C 0.762 1.09 395 88
##STR00146## C 0.762 1.10 409 89 ##STR00147## D 0.762 0.98 411 90
##STR00148## D 0.762 0.92 485 91 ##STR00149## D 1.906 1.05 445 92
##STR00150## D 0.572 1.02 425 93 ##STR00151## D 0.762 0.99 441 94
##STR00152## D 0.762 0.90 441 95 ##STR00153## D 0.572 0.98 475
Example 87
.sup.1H NMR (CDCl.sub.3): .delta. 7.69 (s, 1H), 7.23-7.18 (m, 2H),
7.13-7.08 (m, 2H), 7.04-7.00 (m, 1H), 6.93-6.90 (m, 1H), 6.06 (s,
2H), 3.46-3.30 (m, 2H), 2.34 (s, 3H), 2.07 (s, 3H), 1.70-1.55 (m,
2H), 0.92 8t, J=7.6 Hz, 3H).
Example 89
.sup.1H NMR (CDCl.sub.3): .delta. 7.74 (s, 1H), 7.57-7.52 (m, 2H),
7.23-7.20 (m, 2H), 7.05-7.00 (m, 3H), 4.18-4.14 (m, 2H), 4.03-3.98
(m, 2H), 3.48-3.30 (m, 2H), 2.35 (s, 3H), 2.07 (s, 3H), 1.67-1.57
(m, 2H), 0.93 (t, J=7.6 Hz, 3H).
Examples 96 and 97
Starting from Scaffold 16 the following examples are prepared:
TABLE-US-00016 ##STR00154## Ex- am- Scale LC-MS ple R Method (mmol)
t.sub.R [M + 1].sup.+ 96 ##STR00155## C 0.08 1.11 395 97
##STR00156## D 0.604 1.08 431
Example 98 to 101
Starting from Scaffold 17, the following examples are prepared:
TABLE-US-00017 ##STR00157## Ex- am- Scale LC-MS ple R Method (mmol)
t.sub.R [M + 1].sup.++ 98 ##STR00158## C 0.850 1.06 368 99
##STR00159## E 0.08 1.04 382 100 ##STR00160## D 0.850 0.95 384 101
##STR00161## D 0.638 1.01 418
Example 98
.sup.1H NMR (CDCl.sub.3): .delta. 7.68 (s, 1H), 7.53-7.35 (m, 5H),
7.14-7.10 (m, 2H), 6.92-6.88 (m, 1H), 6.05 (s, 2H), 2.60 (s,
6H).
Example 99
.sup.1H NMR (CDCl.sub.3): .delta. 7.65 (s, 1H), 7.54-7.35 (m, 5H),
7.15-7.09 (m, 2H), 6.94 (d, J=8.2 Hz, 1H), 4.35-4.29 (m, 4H), 2.58
(s, 6H).
Example 100
.sup.1H NMR (CDCl.sub.3): .delta. 7.74 (s, 1H), 7.58-7.35 (m, 7H),
7.04-6.99 (m, 2H), 4.17-4.13 (m, 2H), 4.03-3.98 (m, 2H), 2.62 (s,
6H), 2.00 (s br, 1H).
Example 102 and 103
Starting from Scaffold 18, the following examples are prepared:
TABLE-US-00018 ##STR00162## Ex- am- Scale LC-MS ple R Method (mmol)
t.sub.R [M + 1].sup.++ 102 ##STR00163## D 0.681 0.89 369 103
##STR00164## D 1.815 0.96 403
Example 103
.sup.1H NMR (CDCl.sub.3): .delta. 7.67 (s, 1H), 7.62 (d, J=2.3 Hz,
1H), 7.54-7.33 (m, 6H), 7.04 (d, J=8.8 Hz, 1H), 4.25-4.20 (m, 2H),
4.09-4.02 (m, 2H), 3.49 (q, J=7.0 Hz, 2H), 2.16 (s br, 1H), 1.25
(t, J=7.0 Hz, 3H).
Example 104 to 108
Starting from Scaffold 19, the following examples are prepared:
TABLE-US-00019 ##STR00165## Ex- am- Scale LC-MS ple R Method (mmol)
t.sub.R [M + 1].sup.++ 104 ##STR00166## E 0.200 1.05 367 105
##STR00167## E 0.200 1.05 381 106 ##STR00168## E 0.200 0.98 366 107
##STR00169## D 0.200 0.92 383 108 ##STR00170## D 0.640 1.00 417
Example 109 and 110
Starting from Scaffold 20, the following examples are prepared:
TABLE-US-00020 ##STR00171## Ex- am- Scale LC-MS ple R Method (mmol)
t.sub.R [M + 1].sup.++ 109 ##STR00172## D 0.604 0.94 397 110
##STR00173## D 0.604 1.02 431
Example 110
.sup.1H NMR (CDCl.sub.3): .delta. 7.67 (s, 1H), 7.63 (d, J=2.3 Hz,
1H), 7.46 (dd, J=2.3, 8.8 Hz, 1H), 7.25-7.19 (m, 2H), 7.07-7.01 (m,
2H), 4.25-4.20 (m, 2H), 4.08-4.02 (m, 2H), 3.55-3.43 (m, 2H), 2.35
(s, 3H), 2.15 (s br, 1H), 2.07 (s, 3H), 1.25-1.19 (m, 3H).
Example 111 and 112
Starting from Scaffold 21, the following examples are prepared:
TABLE-US-00021 ##STR00174## Exam- Meth- Scale LC-MS ple R od (mmol)
t.sub.R [M + 1].sup.++ 111 ##STR00175## D 0.604 0.98 397 112
##STR00176## D 0.604 1.05 431
Example 113 and 114
Starting from Scaffold 22, the following examples are prepared:
TABLE-US-00022 ##STR00177## Exam- Meth- Scale LC-MS ple R od (mmol)
t.sub.R [M + 1].sup.++ 113 ##STR00178## D 0.572 1.01 411 114
##STR00179## D 0.572 1.07 445
Example 114
.sup.1H NMR (CDCl.sub.3): .delta. 7.67 (s, 1H), 7.62 (d, J=2.3 Hz,
1H), 7.46 (dd, J=2.3, 8.2 Hz, 1H), 7.39-7.29 (m, 3H), 7.20-7.16 (m,
1H), 7.05 (d, J=8.8 Hz, 1H), 4.25-4.20 (m, 2H), 4.07-7.02 (m, 2H),
3.51-3.35 (m, 2H), 2.20 (s, 3H), 2.14 (s br, 1H), 1.65-1.55 (m,
2H), 1.43-4.30 (m, 2H), 0.93 (t, J=7.3 Hz, 3H).
Example 115 and 116
Starting from Scaffold 23, the following examples are prepared:
TABLE-US-00023 ##STR00180## Exam- Meth- Scale LC-MS ple R od (mmol)
t.sub.R [M + 1].sup.++ 115 ##STR00181## D 0.543 1.03 425 116
##STR00182## D 0.543 1.09 459
Examples 117 to 120
Starting from Scaffold 24, the following examples are prepared:
TABLE-US-00024 ##STR00183## Exam- Meth- Scale LC-MS ple R od (mmol)
t.sub.R [M + 1].sup.++ 117 ##STR00184## E 0.200 1.12 381 118
##STR00185## E 0.200 1.10 395 119 ##STR00186## E 0.200 1.02 380 120
##STR00187## D 0.604 1.04 431
Example 120
.sup.1H NMR (CDCl.sub.3): .delta. 7.65 (s, 1H), 7.61 (d, J=2.3 Hz,
1H), 7.51-7.32 (m, 6H), 7.03 (d, J=8.2 Hz, 1H), 4.24-4.20 (m, 2H),
4.06-4.01 (m, 2H), 3.32 (hex, J=6.4 Hz, 1H), 2.15 (s br, 1H),
1.60-1.49 (m, 2H), 1.17 (d, J=6.4 Hz, 3H), 0.87 (t, J=7.3 Hz,
3H).
Examples 121 to 123
Starting from Scaffold 25, the following examples are prepared:
TABLE-US-00025 ##STR00188## Scale LC-MS Example R Method (mmol)
t.sub.R [M + 1].sup.++ 121 ##STR00189## E 0.200 1.08 365 122
##STR00190## E 0.200 1.08 379 123 ##STR00191## D 0.200 0.96 381
Examples 124 and 125
Starting from Scaffold 26, the following examples are prepared:
TABLE-US-00026 ##STR00192## Exam- Meth- Scale LC-MS ple R od (mmol)
t.sub.R [M + 1].sup.++ 124 ##STR00193## D 0.283 1.08 389 125
##STR00194## D 0.283 1.14 423
Example 124
.sup.1H NMR (CDCl.sub.3): .delta. 7.60 (s, 1H), 7.51-7.46 (m, 2H),
7.01-6.96 (m, 2H), 4.49 (tt, J=3.5, 11.8 Hz, 1H), 4.16-4.11 (m,
2H), 4.02-3.96 (m, 2H), 3.51 (hept, J=6.4 Hz, 1H), 2.50-2.35 (m,
2H), 1.99 (s br, 1H), 1.90-1.80 (m, 2H), 1.70-1.35 (m, 6H), 1.25
(d, J=6.4 Hz, 6H).
Example 126 to 131
Starting from Scaffold 27, the following examples are prepared:
TABLE-US-00027 ##STR00195## Ex- LC-MS am- Meth- Scale [M + ple R od
(mmol) t.sub.R 1].sup.++ 126 ##STR00196## E 0.200 1.12 333 127
##STR00197## E 0.200 1.12 347 128 ##STR00198## E 0.200 1.07 332 129
##STR00199## D 0.200 0.95 345 130 ##STR00200## D 0.499 1.07 383 131
##STR00201## D 0.750 0.99 413
Example 131
.sup.1H NMR (CDCl.sub.3): .delta. 7.55 (d, J=2.3 Hz, 1H), 7.52 (s,
1H), 7.40 (dd, J=2.3, 8.2 Hz, 1H), 7.00 (d, J=8.2 Hz, 1H), 4.91
(hept, J=7.0 Hz, 1H), 4.25-4.14 (m, 3H), 3.94-3.81 (m, 2H), 3.53
(hept, J=6.4 Hz, 1H), 2.72 (s br, 1H), 2.09 (s br, 1H), 1.50 (d,
J=7.0 Hz, 6H), 1.26 (d, J=6.4 Hz, 6H).
Example 132 to 134
Starting from Scaffold 28, the following examples are prepared:
TABLE-US-00028 ##STR00202## Exam- Meth- Scale LC-MS ple R od (mmol)
t.sub.R [M + 1].sup.++ 132 ##STR00203## E 0.200 1.11 409 133
##STR00204## E 0.200 1.06 394 134 ##STR00205## D 0.572 1.07 445
Examples 135 and 136
Starting from Scaffold 29, the following examples are prepared:
TABLE-US-00029 ##STR00206## Scale LC-MS Example R Method (mmol)
t.sub.R [M + 1].sup.++ 135 ##STR00207## E 0.160 1.14 421 136
##STR00208## E 0.160 1.14 435
Examples 137 and 139
Starting from Scaffold 30, the following examples are prepared:
TABLE-US-00030 ##STR00209## Scale LC-MS Example R Method (mmol)
t.sub.R [M + 1].sup.++ 137 ##STR00210## E 0.200 1.14 415 138
##STR00211## E 0.200 1.15 429 139 ##STR00212## E 0.200 1.12 414
Example 140 to 142
Starting from Scaffold 31, the following examples are prepared:
TABLE-US-00031 ##STR00213## Scale LC-MS Example R Method (mmol)
t.sub.R [M + 1].sup.++ 140 ##STR00214## E 0.200 1.14 415 141
##STR00215## E 0.200 1.15 429 142 ##STR00216## E 0.200 1.10 414
Example 143 to 145
Starting from Scaffold 32, the following examples are prepared:
TABLE-US-00032 ##STR00217## Scale LC-MS Example R Method (mmol)
t.sub.R [M + 1].sup.++ 143 ##STR00218## E 0.200 1.14 435 144
##STR00219## E 0.200 1.15 449 145 ##STR00220## E 0.200 1.13 434
Examples 146 to 148
Starting from Scaffold 33, the following examples are prepared:
TABLE-US-00033 ##STR00221## Scale LC-MS Example R Method (mmol)
t.sub.R [M + 1].sup.++ 146 ##STR00222## E 0.200 1.12 401 147
##STR00223## E 0.200 1.12 415 148 ##STR00224## E 0.200 1.09 400
Examples 149 and 150
Starting from Scaffold 34, the following examples are prepared:
TABLE-US-00034 ##STR00225## Exam- Meth- Scale LC-MS ple R od (mmol)
t.sub.R [M + 1].sup.++ 149 ##STR00226## D 0.650 0.95 381 150
##STR00227## D 0.650 1.01 415
Example 150
.sup.1H NMR (CDCl.sub.3): .delta. 7.69 (s, 1H), 7.62 (d, J=2.3 Hz,
1H), 7.55-7.34 (m, 4H), 7.05 (d, J=8.2 Hz, 1H), 6.01-5.88 (m, 1H),
5.25-5.10 (m, 2H), 4.26-4.20 (m, 2H), 4.12-4.08 (m, 2H), 4.07-4.02
(m, 2H).
Examples 151 to 155
Starting from Scaffold 35, the following examples are prepared:
TABLE-US-00035 ##STR00228## Exam- Meth- Scale LC-MS ple R od (mmol)
t.sub.R [M + 1].sup.++ 151 ##STR00229## E 0.200 1.06 329 152
##STR00230## E 0.200 1.07 343 153 ##STR00231## E 0.200 1.05 328 154
##STR00232## D 0.200 0.95 345 155 ##STR00233## D 0.764 1.01 379
Example 155
.sup.1H NMR (CDCl.sub.3): .delta. 7.62 (s, 1H), 7.57 (d, J=2.3 Hz,
1H), 7.41 (dd, J=2.3, 8.2 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H),
6.06-5.85 (m, 2H), 5.33-5.15 (m, 4H), 4.55-4.50 (m, 2H), 4.24-4.19
(m, 2H), 4.10-4.08 (m, 2H), 4.07-4.01 (m, 2H), 2.13 (s br, 1H).
Example 156
##STR00234##
5-[3-Chloro-4-(2-hydroxy-ethoxy)-benz-(Z)-ylidene]-2-[(Z)-methylimino]-3--
phenyl-thiazolidin-4-one is obtained as an off-white powder
starting from Scaffold 36 (150 mg, 0.727 mmol) and
3-chloro-4-(2-acetoxy-ethoxy)-benzaldehyde (353 mg, 1.45 mmol)
following Method D. LC-MS: t.sub.R=0.91 min, [M+1].sup.+=389.
.sup.1H NMR (CDCl.sub.3): .delta. 7.69 (s, 1H), 7.63 (d, J=2.3 Hz,
1H), 7.55-7.40 (m, 4H), 7.35-7.30 (m, 2H), 7.05 (d, J=8.2 Hz, 1H),
4.25-4.20 (m, 2H), 4.08-4.00 (m, 2H), 3.27 (s, 3H).
Example 157
##STR00235##
5-[3-Chloro-4-(2-hydroxy-ethoxy)-benz-(Z)-ylidene]-2-[(Z)-methylimino]-3--
(2,3-diemthylphenyl)-thiazolidin-4-one is obtained as a pale yellow
powder starting from Scaffold 37 (150 mg, 0.640 mmol) and
3-chloro-4-(2-acetoxy-ethoxy)-benzaldehyde (311 mg, 1.28 mmol)
following Method D. LC-MS: t.sub.R=0.97 min, [M+1].sup.+=417.
.sup.1H NMR (CDCl.sub.3): .delta. 7.69 (s, 1H), 7.64 (d, J=2.3 Hz,
1H), 7.47 (dd, J=2.3, 8.8 Hz, 1H), 7.25-7.20 (m, 2H), 7.06-7.01 (m,
2H), 4.25-4.20 (m, 2H), 4.07-4.02 (m, 2H), 3.25 (s, 3H), 2.35 (s,
3H), 2.07 (s, 3H).
* * * * *
References