U.S. patent application number 11/476330 was filed with the patent office on 2006-10-26 for heterocyclic amide derivatives for the treatment of diabetes and other diseases.
Invention is credited to Hussien A. Al-Shamma, Mohamed Boudjelal, Andrea Fanjul Giachino, Jianhua Guo, Karine Jakubowicz-Jaillardon, Magnus Pfahl, Catherine Tachdjian, James W. Zapf.
Application Number | 20060241138 11/476330 |
Document ID | / |
Family ID | 27805215 |
Filed Date | 2006-10-26 |
United States Patent
Application |
20060241138 |
Kind Code |
A1 |
Pfahl; Magnus ; et
al. |
October 26, 2006 |
Heterocyclic amide derivatives for the treatment of diabetes and
other diseases
Abstract
The present invention relates to methods of treating breast
cancer, diabetes, and/or related metabolic disorders with certain
substituted heterocycles of Formula (200), ##STR1## wherein B, H,
I, J and K together with the Ar.sub.5 form a ring containing at
least one amide residue, and W, X, Y and Z together form a
2,4-thiazolidinedione, 2-thioxo-thiazolidine-4-one,
2,4-imidazolidinedione or 2-thioxo-imidazolidine-4-one residue; or
a pharmaceutically acceptable salt thereof.
Inventors: |
Pfahl; Magnus; (Solana
Beach, CA) ; Tachdjian; Catherine; (San Diego,
CA) ; Al-Shamma; Hussien A.; (Encinitas, CA) ;
Giachino; Andrea Fanjul; (San Diego, CA) ;
Jakubowicz-Jaillardon; Karine; (Villebon sur Yvette, FR)
; Guo; Jianhua; (San Diego, CA) ; Boudjelal;
Mohamed; (San Diego, CA) ; Zapf; James W.;
(San Diego, CA) |
Correspondence
Address: |
NEEDLE & ROSENBERG, P.C.
SUITE 1000
999 PEACHTREE STREET
ATLANTA
GA
30309-3915
US
|
Family ID: |
27805215 |
Appl. No.: |
11/476330 |
Filed: |
June 28, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10384352 |
Mar 6, 2003 |
7102000 |
|
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11476330 |
Jun 28, 2006 |
|
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60362702 |
Mar 8, 2002 |
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Current U.S.
Class: |
514/312 ;
514/365; 514/369; 514/389 |
Current CPC
Class: |
A61P 9/10 20180101; C07D
417/06 20130101; C07D 417/10 20130101; C07D 277/20 20130101; A61P
3/06 20180101; A61P 35/00 20180101; A61P 3/10 20180101 |
Class at
Publication: |
514/312 ;
514/365; 514/369; 514/389 |
International
Class: |
A61K 31/4709 20060101
A61K031/4709; A61K 31/427 20060101 A61K031/427; A61K 31/4178
20060101 A61K031/4178 |
Claims
1. A method of treating type 2 Diabetes comprising administering to
a mammal diagnosed as needing such treatment one or more compounds
a compound of Formula (200): ##STR83## wherein: a) the B, H, I, J
and K residues are independently selected from --C(O)--, --C(S)--,
--O--, --S--, --N(R.sub.101)--, --N(R.sub.102)--,
--C(R.sub.103)(R.sub.104)--, --C(R.sub.105)(R.sub.106), or
--C(R.sub.107)(R.sub.108)-- residues, and from zero to two of the
B, H, I, J or K residues can be absent; wherein: i) R.sub.101,
R.sub.102, R.sub.103, R.sub.104, R.sub.105, R.sub.106, R.sub.107
and R.sub.108 are independently selected from hydrogen, hydroxyl, a
halogen, amino, or an organic residue comprising 1 to 12 carbon
atoms; or two of the R.sub.101, R.sub.102, R.sub.103, R.sub.104,
R.sub.105, R.sub.106, R.sub.107 and R.sub.108 residues can be
connected together to form an exocyclic substituent residue
comprising 1 to 6 ring carbon atoms and from 0 to 3 optional ring
heteroatoms selected from O, S, or N; and ii) B, H, I, J and K
together with the Ar.sub.5 form a ring containing at least one
amide residue having the formula ##STR84## wherein R.sub.x is a
R.sub.101 or R.sub.102 residue; b) Ar.sub.5 is an aryl, substituted
aryl, heteroaryl, or substituted heteroaryl residue comprising from
3 to 6 ring carbon atoms and from 0 to 3 optional ring heteroatoms
selected from O, S, or N; c) Ar.sub.6 is an aryl, substituted aryl,
heteroaryl, or substituted heteroaryl residue comprising from 2 to
6 ring carbon atoms and from 0 to 3 optional ring heteroatoms
selected from O, S, or N; d) R.sub.109 is hydrogen, hydroxy, or an
organic residue comprising 1 to 10 carbon atoms; e) ----- is either
present or absent; f) W, X, Y and Z form a 2,4-thiazolidinedione,
2-thioxo-thiazolidine-4-one, 2,4-imidazolidinedione or
2-thioxo-imidazolidine-4-one residue; or a pharmaceutically
acceptable salt thereof, in an amount effective to treat type 2
diabetes.
2. The method of claim 1 wherein the radical: ##STR85## has the
structure: ##STR86## wherein R.sub.101 is selected from hydrogen or
an organic radical comprising 1 to 12 carbon atoms, and wherein
R.sub.103, R.sub.104, R.sub.105, R.sub.106, and R.sub.110 are
independently selected from hydrogen or alkyls comprising 1 to 4
carbon atoms.
3. The method of claim 1 wherein the radical: ##STR87## has the
structure: ##STR88## wherein R.sub.101, R.sub.103, R.sub.104,
R.sub.105, R.sub.106, and R.sub.110 are independently selected from
hydrogen or alkyls comprising 1 to 4 carbon atoms.
4. The method of claim 1 wherein the radical: ##STR89## has the
structure: ##STR90## wherein R.sub.101 and R.sub.110 are an alkyl
comprising 1 to 4 carbon atoms.
5. The method of claim 1 wherein Ar.sub.6 comprises a phenyl
ring.
6. The method of claim 5 wherein the Ar.sub.6 ring is substituted
with one, two or three substituents independently selected from
halogens or a radical comprising 1 to 4 carbon atoms selected from
an alkyl, a haloalkyl, an amino, a mono-substituted amino, a
di-substituted amino, an alkoxy, or a haloalkoxy.
7. The method of claim 1 wherein Ar.sub.6 comprises a pyridyl
ring.
8. The method of claim 7 wherein the Ar.sub.6 ring is substituted
with one, two or three substituents independently selected from
halogens or a radical comprising 1 to 4 carbon atoms selected from
an alkyl, a haloalkyl, an amino, a mono-substituted amino, a
di-substituted amino, an alkoxy, or a haloalkoxy.
9. The method of claim 1 wherein Ar.sub.6 has the structure:
##STR91## wherein R.sub.125, R.sub.126, R.sub.127 and R.sub.128 are
substituents independently selected from hydrogen, halogen, nitro,
hydroxyl, amino, or an organic radical comprising 1 to 4 carbon
atoms.
10. The method of claim 9 wherein R.sub.125 is not hydrogen.
11. The method of claim 10 wherein R.sub.125 is an alkyl,
substituted alkyl, haloalkyl, alkoxy, substituted alkoxy,
haloalkoxy, halogen, amino, mono-substituted amino, or
disubstituted amino radical comprising 1 to four carbons.
12. The method of claim 1 wherein Ar.sub.6 has the structure:
##STR92## wherein R.sub.126, R.sub.127 and R.sub.128 are
independently or together hydrogen or halogen.
13. The method of claim 1 wherein ----- is present.
14. The method of claim 1 wherein R.sub.109 is hydrogen.
15. The method of claim 1 wherein the heterocycle comprising W, X,
Y and Z has the structure ##STR93##
16. The method of claim 1 in the form of a salt wherein the
heterocycle comprising W, X, Y and Z forms an anion having the
structure: ##STR94##
17. A method of treating breast cancer comprising administering to
a mammal diagnosed as needing such treatment a compound having the
formula
5-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-t-
rifluoromethoxy-benzylidene]-thiazolidine-2,4-dione, or a
pharmaceutically acceptable salt thereof, in an amount effective to
treat breast cancer.
18. A method of treating Type 2 Diabetes comprising administering
to a human diagnosed as needing such treatment, a compound having
the formula
5-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-t-
rifluoromethoxy-benzylidene]-thiazolidine-2,4-dione or a
pharmaceutically acceptable salt thereof, in an amount effective to
decrease serum glucose levels by at least about 5% and also
decrease serum triglyeride levels by at least about 5%.
19. A method of treating hypercholesterolemia comprising
administering to a mammal diagnosed as needing such treatment one
or more compounds having the structure: ##STR95## wherein a)
Ar.sub.5 is an aryl, substituted aryl, heteroaryl, or substituted
heteroaryl; b) B, H, I, J and K are independently selected from
--C(O)--, --C(S), --O--, --S--, --N(R.sub.101)--, --N(R.sub.102)--,
--C(R.sub.103)(R.sub.104)--, --C(R.sub.105)(R.sub.106)--, or
--C(R.sub.107)(R.sub.108)--, wherein one, or two of B, H, I, J or K
can optionally be absent; and i) R.sub.101, R.sub.102, R.sub.103,
R.sub.104, R.sub.105, R.sub.106, R.sub.107 and R.sub.108 are
independently selected from hydrogen, hydroxyl, a halogen, amino,
or an organic radical comprising 1 to 12 carbon atoms; ii) two of
B, H, I, J and K form at least one radical having the structure:
##STR96## wherein R.sub.x is a R.sub.101 or R.sub.102 radical; iii)
Ar.sub.5 together with B, H, I, J and K comprise from 2 to 24
carbon atoms; c) Ar.sub.6 is an aryl, substituted aryl, heteroaryl,
or substituted heteroaryl comprising from 2 to 18 carbon atoms; d)
R.sub.109 is hydrogen, hydroxy, or an organic radical comprising 1
to 10 carbon atoms; e) ----- is either present or absent; f) HAr is
a heterocycle having the structure: ##STR97## or a pharmaceutically
acceptable salt thereof.
20. The method of claim 19 wherein the one or more compounds or
salts are applied in an amount effective to decrease serum
cholesterol levels by at least about 5%.
21. A method of treating dyslipidemia comprising administering to a
mammal diagnosed as needing such treatment one or more compounds
having the structure: ##STR98## wherein a) Ar.sub.5 is an aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; b) B, H,
I, J and K are independently selected from --C(O)--, --C(S), --O--,
--S--, --N(R.sub.101)--, --N(R.sub.102)--,
--C(R.sub.103)(R.sub.104)--, --C(R.sub.105)(R.sub.106)--, or
--C(R.sub.107)(R.sub.108)--, wherein one, or two of B, H, I, J or K
can optionally be absent; and i) R.sub.101, R.sub.102, R.sub.103,
R.sub.104, R.sub.105, R.sub.106, R.sub.107 and R.sub.108 are
independently selected from hydrogen, hydroxyl, a halogen, amino,
or an organic radical comprising 1 to 12 carbon atoms; ii) two of
B, H, I, J and K form at least one radical having the structure:
##STR99## wherein R.sub.x is a R.sub.101 or R.sub.102 radical; iii)
Ar.sub.5 together with B, H, I, J and K comprise from 2 to 24
carbon atoms; c) Ar.sub.6 is an aryl, substituted aryl, heteroaryl,
or substituted heteroaryl comprising from 2 to 18 carbon atoms; d)
R.sub.109 is hydrogen, hydroxy, or an organic radical comprising 1
to 10 carbon atoms; e) ----- is either present or absent; f) HAr is
a heterocycle having the structure: ##STR100## or a
pharmaceutically acceptable salt thereof, in an amount effective to
decrease serum triglyceride levels in the animal.
22. The method of claim 21, wherein the one or more compounds or
salts are applied in an amount effective to decrease triglyceride
levels by at least about 5%.
23. A method of treating type 2 Diabetes comprising administering
to a mammal diagnosed as needing such treatment one or more
compounds having the structure: ##STR101## wherein a) Ar.sub.5 is
an aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
b) B, H, I, J and K are independently selected from --C(O)--,
--C(S), --O--, --S--, --N(R.sub.101)--, --N(R.sub.102)--,
--C(R.sub.103)(R.sub.104)--, --C(R.sub.105)(R.sub.106)--, or
--C(R.sub.107)(R.sub.108)--, wherein one, or two of B, H, I, J or K
can optionally be absent; and i) R.sub.101, R.sub.102, R.sub.103,
R.sub.104, R.sub.105, R.sub.106, R.sub.107 and R.sub.108 are
independently selected from hydrogen, hydroxyl, a halogen, amino,
or an organic radical comprising 1 to 12 carbon atoms; ii) two of
B, H, I, J and K form at least one radical having the structure
##STR102## wherein R.sub.x is a R.sub.101 or R.sub.102 radical;
iii) Ar.sub.5 together with B, H, I, J and K comprise from 2 to 24
carbon atoms; c) Ar.sub.6 is an aryl, substituted aryl, heteroaryl,
or substituted heteroaryl comprising from 2 to 18 carbon atoms; d)
R.sub.109 is hydrogen, hydroxy, or an organic radical comprising 1
to 10 carbon atoms; e) ----- is either present or absent; f) HAr is
a heterocycle having the structure: ##STR103## or a
pharmaceutically acceptable salt thereof, in an amount effective to
treat type 2 diabetes.
24. The method of claim 23, wherein the one or more compounds or
salts are applied in an amount effective to decrease blood glucose
levels by at least about 5%.
25. A method of treating Type 2 Diabetes comprising administering
to a human diagnosed as needing such treatment one or more
compounds having the structure: ##STR104## wherein a) Ar.sub.5 is
an aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
b) B, H, I, J and K are independently selected from --C(O)--,
--C(S)--, --O--, --S--, --N(R.sub.101)--, --N(R.sub.102)--,
--C(R.sub.103)(R.sub.104)--, --C(R.sub.105)(R.sub.106)--, or
--C(R.sub.107)(R.sub.108)--, wherein one, or two of B, H, I, J or K
can optionally be absent; and i) R.sub.101, R.sub.102, R.sub.103,
R.sub.104, R.sub.105, R.sub.106, R.sub.107 and R.sub.108 are
independently selected from hydrogen, hydroxyl, a halogen, amino,
or an organic radical comprising 1 to 12 carbon atoms; ii) two of
B, H, I, J and K form at least one radical having the structure:
##STR105## wherein R.sub.x is a R.sub.101 or R.sub.102 radical;
iii) Ar.sub.5 together with B, H, I, J and K comprise from 2 to 24
carbon atoms; c) Ar.sub.6 is an aryl, substituted aryl, heteroaryl,
or substituted heteroaryl comprising from 2 to 18 carbon atoms; d)
R.sub.109 is hydrogen, hydroxy, or an organic radical comprising 1
to 10 carbon atoms; e) ----- is either present or absent; f) HAr is
a heterocycle having the structure: ##STR106## or a
pharmaceutically acceptable salt thereof, in an amount effective to
decrease serum glucose levels by at least about 5% and also
decrease serum triglyeride levels by at least about 5%.
26. A method of treating breast cancer comprising administering to
a mammal diagnosed as needing such treatment one or more compounds
having the structure: ##STR107## wherein a) Ar.sub.5 is an aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; b) B, H,
I, J and K are independently selected from --C(O)--, --C(S)--,
--O--, --S--, --N(R.sub.101)--, --N(R.sub.102)--,
--C(R.sub.103)(R.sub.104)--, --C(R.sub.105)(R.sub.106)--, or
--C(R.sub.107)(R.sub.108)--, wherein one, or two of B, H, I, J or K
can optionally be absent; and i) R.sub.101, R.sub.102, R.sub.103,
R.sub.104, R.sub.105, R.sub.106, R.sub.107 and R.sub.108 are
independently selected from hydrogen, hydroxyl, a halogen, amino,
or an organic radical comprising 1 to 12 carbon atoms; ii) two of
B, H, I, J and K form at least one radical having the structure:
##STR108## wherein R.sub.x is a R.sub.101 or R.sub.102 radical;
iii) Ar.sub.5 together with B, H, I, J and K comprise from 2 to 24
carbon atoms; c) Ar.sub.6 is an aryl, substituted aryl, heteroaryl,
or substituted heteroaryl comprising from 2 to 18 carbon atoms; d)
R.sub.109 is hydrogen, hydroxy, or an organic radical comprising, 1
to 10 carbon atoms; e) ----- is either present or absent; f) HAr is
a heterocycle having the structure: ##STR109## or a
pharmaceutically acceptable salt thereof, in an amount effective to
treat the breast cancer.
Description
RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 10/384,352, filed Mar. 6, 2003, now allowed, which claimed
priority to the U.S. Provisional Application Ser. No. 60/362,702,
filed Mar. 8, 2002. The disclosure of all the above-recited parent
applications is hereby incorporated herein in their entirety by
this reference.
BACKGROUND OF THE INVENTION
[0002] Type 2 diabetes also referred to as non-insulin dependent
diabetes mellitus (NIDDM), afflicts between 80 and 90% of all
diabetic patients in developed countries. In the United States
alone, approximately 15 million people, and more than 100 million
worldwide, are affected. Because this disorder is a late onset
disease and occurs often in overweight persons, it can be expected
that the number of patients suffering from this disease will
increase further. Patients suffering from type 2 diabetes usually
still produce insulin but become increasingly resistant to their
own insulin and to insulin therapy.
[0003] A new class of drugs has been recently introduced that
resensitizes patients to their own insulin (insulin sensitizers),
thereby reducing blood glucose and triglyceride levels, and thus
abolishing, or at least reducing, the requirement for exogenous
insulin. Troglitazone (Resulin.TM.) and rosiglitazone (Avandia.TM.)
were among the first representatives of this class of drugs
approved for the treatment of type 2 diabetes in the United States
and several other countries. The currently approved compounds can
however have side effects including rare but severe liver
toxicities and they can increase body weight in humans. Such side
effects are of major concern for diabetes patients who can require
treatment for a decade or longer. Therefore, new and better drugs
for the treatment of type 2 diabetes and related disorders are
needed. In particular, drugs that can control blood sugar levels
and simultaneously control hyperlipidemia and hypercholesterolemia
are desirable. Elevated levels of cholesterol lead to
atherosclerosis and heart disease which in many type 2 diabetes
patients is the cause of death.
[0004] There is also a need for the more effective drugs to treat
diseases of uncontrolled cellular proliferation, such as cancers.
Certain molecules that have strong cellular differentiation
activity can inhibit the uncontrolled cellular proliferation of
cancer cells, in particular breast cancer.
[0005] Small molecules that can be effective for the treatment of
diabetes and/or disorders of carbohydrate metabolism were disclosed
in U.S. Pat. No. 6,515,003, issued Feb. 4, 2003, based on U.S.
patent application Ser. No. 09/652,810, filed Aug. 31, 2000, which
claimed priority to U.S. Provisional Patent Application 60/151,670,
filed Aug. 31, 1999. Related small molecules that can be useful in
the treatment of certain cancers were disclosed in PCT Patent
Application WO 01/16122, published Mar. 8, 2001, which claimed
priority to the same U.S. Provisional Patent Application 60/151,670
cited above. The disclosures of all the above-described patent
documents are hereby incorporated herein by this reference, for
both their chemical structural disclosures, their teachings of the
biological activities of those compounds, and methods for their use
as pharmaceutical compositions.
[0006] There is however a continuing need for effective drugs for
the treatment of cancers, and for the treatment of type 2 diabetes
and associated disorders of carbohydrate and/or lipid metabolism,
including hyperlipidemia and hypercholesterolemia. In particular,
there is a continuing need new drugs that can control the blood
sugar levels of diabetics, and simultaneously control
hyperlipidemia and hypercholesterolemia so as to lessen or prevent
atherosclerosis.
SUMMARY OF THE INVENTION
[0007] Some embodiments of the invention relate to heterocyclic
compounds having the structure: ##STR2##
[0008] wherein [0009] a) Ar.sub.5 is an aryl, substituted aryl,
heteroaryl, or substituted heteroaryl; [0010] b) B, H, I, J and K
are independently selected from --C(O)--, --C(S)--, --O--, --S--,
--N(R.sub.101)--, --N(R.sub.102)--, --C(R.sub.103)(R.sub.104)--,
--C(R.sub.105)(R.sub.106)--, or --C(R.sub.107)(R.sub.108)--,
wherein one, or two of B, H, I, J or K can optionally be absent;
and [0011] i) R.sub.101, R.sub.102, R.sub.103, R.sub.104,
R.sub.105, R.sub.106, R.sub.107 and R.sub.108 are independently
selected from hydrogen, hydroxyl, a halogen, amino, or an organic
radical; [0012] ii) two of B, H, I, J and K form at least one
radical having the structure: ##STR3## [0013] wherein R.sub.x is a
R.sub.101 or R.sub.102 radical; [0014] iii) Ar.sub.5 together with
B, H, I, J and K comprise from 2 to 24 carbon atoms; [0015] c)
Ar.sub.6 is an aryl, substituted aryl, heteroaryl, or substituted
heteroaryl; [0016] d) R.sub.109 is hydrogen, hydroxy, or an organic
radical; [0017] e) ----- is either present or absent; [0018] f) HAr
is a heterocycle having the structure: ##STR4##
[0019] or a pharmaceutically acceptable salt thereof.
[0020] As can be seen from the above description, the compounds of
the invention have a heterocyclic ring comprising B, H, I, J and K
residues, wherein the heterocyclic ring comprises an amide residue
having the structure: ##STR5##
[0021] The heterocyclic amide compounds comprising an amide residue
have been found to be unexpectedly active for advantageously
regulating carbohydrate metabolism, including serum glucose levels.
The heterocyclic amide compounds have also been found to be
unexpectedly effective modulators of lipid metabolism, and are
therefore useful for the treatment of hyperlipidemia and/or
hypercholesterdemia. Therefore, the heterocyclic amide compounds of
the invention can simultaneously and beneficially regulate
carbohydrate and lipid metabolism so as to simultaneously decrease
levels of serum glucose, serum triglycerides, and serum
cholesterol. As a result, it has been found that the heterocyclic
amide compounds are unexpectedly useful for the treatment of type 2
diabetes and the simultaneous treatment of the hyperlipidemia,
hypercholesterdemia, and/or atherosclerosis which is often
associated with diabetes. The heterocyclic amide compounds of the
invention have also been found to have unexpectedly superior
pharmaceutical properties, including unexpectedly superior oral
bioavailability as compared to prior art compounds.
[0022] The heterocyclic compounds of the present invention also
show activity for inducing adipocyte differentiation in certain
well known cell lines of pre-adipocytes. The ability of a compound
to induce differentiation of these cell lines is also known to
correlate with anticancer activity. As a result, the heterocyclic
compounds of the invention have been tested for utility in the
treatment of diseases of uncontrolled proliferation. The
heterocyclic compound described herein have shown unexpectedly
effective results for the treatment of breast cancer in an in vivo
rat model of breast cancer.
[0023] Further embodiments of the amide compounds of the invention,
and pharmaceutical compositions comprising one or more of the
compounds of the invention will be described in more detail in the
specification and written description hereinbelow. Other
embodiments of the invention relate to methods of synthesizing the
amide compounds disclosed herein.
[0024] The invention also provides methods for the treatment of
diabetes and associated diseases, as well as methods for the
treatment of diseases of uncontrolled cellular proliferation
comprising administering to a mammal diagnosed as having a disease
of uncontrolled cellular proliferation one or more compounds of the
invention, or a pharmaceutical composition thereof.
[0025] Additional advantages of the invention will be set forth in
part in the description which follows, and in part will be obvious
from the description, or can be learned by practice of the
invention. The advantages of the invention will be realized and
attained by means of the elements and combinations particularly
pointed out in the appended claims. It is to be understood that
both the foregoing general description and the following detailed
description are exemplary and explanatory only and are not
restrictive of the invention, as claimed.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] FIG. 1 shows the results of in-vitro screening assays for
the ability of some of the compounds of the invention to induce
differentiation of 3T3-L1 pre-adipocytes to adipocytes.
[0027] FIGS. 2a-d show the ability of certain compounds 1, 2, 11,
13, and 25, when orally administered, to simultaneously decrease
the serum glucose and triglyceride levels of KKA.sup.y mice, as
compared to control KKA.sup.y mice that do not receive the
compounds.
[0028] FIG. 2e shows the ability of compound 25, when orally
administered, to simultaneously decrease the serum glucose, serum
triglyceride, and serum cholesterol levels of KKA.sup.y mice at
various dosage levels, as compared to control KKA.sup.y mice that
do not receive the compound.
[0029] FIG. 3 shows the glucose and triglyceride lowering activity
of compound 25 in the type 2 diabetic db/db Mouse Model.
[0030] FIG. 4 shows the ability of compound 2 to increase
cholesterol efflux from macrophage cells.
[0031] FIG. 5 a-c show the ability of compounds 2, 6, and 25 to
decrease total cholesterol and LDL (bad cholesterol) while
increasing HDL (good cholesterol) in Sprague Dawley rats.
[0032] FIG. 6 shows the ability of the compounds to decrease the
number of progressing carcinogen induced mammary tumors in Sprague
Dawley rats, and increase the number of static and regressing
tumors.
[0033] FIG. 7 shows the unexpectedly improved oral bioavailability
of compound 25 compared to comparative compound 24.
[0034] FIG. 8 shows examples of methods for synthesizing precancers
of the compounds disclosed herein.
[0035] FIG. 9 shows examples of methods for synthesizing the
compounds disclosed herein.
DETAILED DESCRIPTION
[0036] The present invention can be understood more readily by
reference to the following detailed description of various
embodiments of the invention and the Examples included therein and
to the Figures and their previous and following description. Before
the present compounds, compositions, and/or methods are disclosed
and described, it is to be understood that this invention is not
limited to specific synthetic methods, specific pharmaceutical
carriers or formulations, or to particular modes of administering
the compounds of the invention, as such can, of course, vary. It is
also to be understood that the terminology used herein is for the
purpose of describing particular embodiments only and is not
intended to be limiting.
[0037] The present invention provides heterocyclic amide compounds
that are useful, for example, to modulate lipid and/or carbohydrate
metabolism, and especially for the treatment of diabetes, such as
type 2 diabetes, and other diseases. In addition, compounds of the
invention have demonstrated unexpectedly superior oral
bioavailability, as exhibited by their high blood levels after oral
dosing in animals. Oral bioavailability allows oral dosing for use
in chronic diseases, with the advantage of self-administration and
decreased cost over other means of administration. The compounds
described herein can be used effectively to prevent, alleviate or
otherwise treat type 2 diabetes and/or other disease states in
mammals and/or humans, such as atherosclerosis and diseases related
to inflammation and/or uncontrolled proliferation, including
cancers such as breast cancer.
Definitions
[0038] In the specification and Formulae described herein the
following terms are hereby defined.
[0039] "Optional" or "optionally" means that the subsequently
described event or circumstance may or may not occur, and that the
description includes instances where said event or circumstance
occurs and instances where it does not. For example, the phrase
"optionally substituted lower alkyl" means that the lower alkyl
group may or may not be substituted and that the description
includes both unsubstituted lower alkyl and lower alkyls where
there is substitution.
[0040] It must be noted that, as used in the specification and the
appended claims, the singular forms "a," "an" and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "an aromatic compound" includes
mixtures of aromatic compounds.
[0041] Often, ranges are expressed herein as from "about" one
particular value, and/or to "about" another particular value. When
such a range is expressed, another embodiment includes from the one
particular value and/or to the other particular value. Similarly,
when values are expressed as approximations, by use of the
antecedent "about," it will be understood that the particular value
forms another embodiment. It will be further understood that the
endpoints of each of the ranges are significant both in relation to
the other endpoint, and independently of the other endpoint.
[0042] By "pharmaceutically acceptable" is meant a material that is
not biologically or otherwise undesirable, i.e., the material can
be administered to an individual along with the relevant active
compound without causing clinically unacceptable biological effects
or interacting in a deleterious manner with any of the other
components of the pharmaceutical composition in which it is
contained.
[0043] I By the term "effective amount" of a compound as provided
herein is meant a sufficient amount of the compound to provide the
desired regulation of a desired function, such as gene expression,
protein function, or a disease condition. As will be pointed out
below, the exact amount required will vary from subject to subject,
depending on the species, age, and general condition of the
subject, the severity of the disease that is being treated, the
particular compound used, its mode of administration, and the like.
Thus, it is not possible to specify an exact "effective amount."
However, an appropriate effective amount can be determined by one
of ordinary skill in the art using only routine
experimentation.
[0044] The term "alkyl" denotes a hydrocarbon group or residue
which is structurally similar to a non-cyclic alkane compound
modified by the removal of one hydrogen from the non-cyclic alkane
and the substitution therefore of a non-hydrogen group or residue.
Alkyls comprise a noncyclic, saturated, straight or branched chain
hydrocarbon residue having from 1 to 12 carbons, or 1 to 8 carbons,
or 1 to 6 carbons. Examples of such alkyl radicals include methyl,
ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, amyl,
t-amyl, n-pentyl and the like. Lower alkyls comprise a noncyclic,
saturated, straight or branched chain hydrocarbon residue having
from 1 to 4 carbon atoms.
[0045] The term "substituted alkyl" denotes an alkyl radical
analogous to the above definition that is further substituted with
one, two, or more additional organic or inorganic substituent
groups. Suitable substituent groups include but are not limited to
hydroxyl, cycloalkyl, amino, mono-substituted amino, di-substituted
amino, acyloxy, nitro, cyano, carboxy, carboalkoxy,
alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide,
substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl,
thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkoxy,
heteroaryl, substituted heteroaryl, aryl or substituted aryl. When
more than one substituent group is present then they can be the
same or different. The organic substituent groups can comprise from
1 to 12 carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 4
carbon atoms.
[0046] The term "alkenyl" denotes an alkyl residue as defined above
that comprises at least one carbon-carbon double bond. Examples
include but are not limited to vinyl, allyl, 2-butenyl, 3-butenyl,
2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl,
4-hexenyl, 5-hexanyl, 2-heptenyl, 3-heptenyl, 4-heptenyl,
5-heptenyl, 6-heptenyl and the like. The term "alkenyl" includes
dienes and trienes of straight and branch chains.
[0047] The term "substituted alkenyl" denotes an alkenyl residue as
defined above definitions that is substituted with one or more
groups, but preferably one, two or three groups, selected from
halogen, hydroxyl, cycloalkyl, amino, mono-substituted amino,
di-substituted amino, acyloxy, nitro, cyano, carboxy, carboalkoxy,
alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide,
substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl,
thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy or haloalkoxy.
When more than one group is present then they can be the same or
different. The organic substituent groups can comprise from 1 to 12
carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon
atoms.
[0048] The term "alkynyl" denotes a residue as defined above that
comprises at least one carbon-carbon double bond. Examples include
but are not limited ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,
2-butynyl-3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,
4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl
and the like. The term "alkynyl" includes di- and tri-ynes.
[0049] The term "substituted alkynyl" denotes an alkylnyl residue
of the above definition that is substituted with one or more
groups, but preferably one or two groups, selected from halogen,
hydroxyl, cycloalkyl, amino, mono-substituted amino, di-substituted
amino, acyloxy, nitro, cyano, carboxy, carboalkoxy,
alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide,
substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl,
thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy or haloalkoxy.
When more than one group is present then they can be the same or
different. The organic substituent groups can comprise from 1 to 12
carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon
atoms.
[0050] The term "cycloalkyl" denotes a hydrocarbon group or residue
which is structurally similar to a cyclic alkane compound modified
by the removal of one hydrogen from the cyclic alkane and
substitution therefore of a non-hydrogen group or residue.
Cycloalkyl groups, or residues radical contain 3 to 18 carbons, or
preferably 4 to 12 carbons, or 5 to 8 carbons. Examples include as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
decahydronapthyl, adamantyl, and like residues.
[0051] The term "substituted cycloalkyl" denotes a cycloalkyl
residue as defined above that is further substituted with one, two,
or more additional organic or inorganic groups that can include but
are not limited to halogen, alkyl, substituted alkyl, hydroxyl,
alkoxy, substituted alkoxy, carboxy, carboalkoxy, alkylcarboxamide,
substituted alkylcarboxamide, dialkylcarboxamide, substituted
dialkylcarboxamide, amino, mono-substituted amino or di-substituted
amino. When the cycloalkyl is substituted with more than one
substituent group, they can be the same or different. The organic
substituent groups can comprise from 1 to 12 carbon atoms, or from
1 to 6 carbon atoms, or from 1 to 4 carbon atoms.
[0052] The term "cycloalkenyl" denotes a cycloalkyl radical as
defined above that comprises at least one carbon-carbon double
bond. Examples include but are not limited to cyclopropenyl,
1-cyclobutenyl, 2-cyclobutenyl, 1-cyclopentenyl, 2-cyclopentenyl,
3-cyclopentenyl, 1-cyclohexyl, 2-cyclohexyl, 3-cyclohexyl and the
like. The term "substituted cycloalkenyl" denotes a cycloalkyl as
defined above further substituted with one or more groups selected
from halogen, alkyl, hydroxyl, alkoxy, substituted alkoxy,
haloalkoxy, carboxy, carboalkoxy, alkylcarboxamide, substituted
alkylcarboxamide, dialkylcarboxamide, substituted
dialkylcarboxamide, amino, mono-substituted amino or di-substituted
amino. When the cycloalkenyl is substituted with more than one
group, they can be the same or different. The organic substituent
groups can comprise from 1 to 12 carbon atoms, or from 1 to 6
carbon atoms, or from 1 to 4 carbon atoms.
[0053] The term "alkoxy" as used herein denotes an alkyl residue,
defined above, attached directly to a oxygen to form an ether
residue. Examples include methoxy, ethoxy, n-propoxy, iso-propoxy,
n-butoxy, t-butoxy, iso-butoxy and the like.
[0054] The term "substituted alkoxy" denotes an alkoxy residue of
the above definition that is substituted with one or more
substituent groups, but preferably one or two groups, which include
but are not limited to hydroxyl, cycloalkyl, amino,
mono-substituted amino, di-substituted amino, acyloxy, nitro,
cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted
alkylcarboxamide, dialkylcarboxamide, substituted
dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl,
thiohaloalkyl, alkoxy, substituted alkoxy or haloalkoxy. When more
than one group is present then they can be the same or different.
The organic substituent groups can comprise from 1 to 12 carbon
atoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon
atoms.
[0055] The term "mono-substituted amino" denotes an amino
substituted with one organic substituent groups, which include but
are not limited to alkyl, substituted alkyl or arylalkyl wherein
the terms have the same definitions found hereinabove.
[0056] The term "di-substituted amino" denotes an amino residue
substituted with two radicals that can be same or different
selected from aryl, substituted aryl, alkyl, substituted alkyl or
arylalkyl wherein the terms have the same definitions found
throughout. Some examples include dimethylamino, methylethylamino,
diethylamino and the like.
[0057] The term "haloalkyl" denotes a alkyl residue as defined
above, substituted with one or more halogens, preferably fluorine,
such as a trifluoromethyl, pentafluoroethyl and the like.
[0058] The term "haloalkoxy" denotes a haloalkyl residue as defined
above, that is directly attached to an oxygen to form
trifluoromethoxy, pentafluoroethoxy and the like.
[0059] The term "acyl" denotes a R--C(O)-- residue containing 1 to
8 carbons. Examples include but are not limited to formyl, acetyl,
propionyl, butanoyl, iso-butanoyl, pentanoyl, hexanoyl, heptanoyl,
benzoyl and the like.
[0060] The term "acyloxy" denotes a an acyl radical as defined
above directly attached to an oxygen to form an R--C(O)O-- residue.
Examples include but are not limited to acetyloxy, propionyloxy,
butanoyloxy, iso-butanoyloxy, benzoyloxy and the like.
[0061] The term "aryl" denotes a ring radical containing 6 to 18
carbons, or preferably 6 to 12 carbons, having at least one
six-membered aromatic "benzene" residue therein. Examples of such
aryl radicals include phenyl and naphthyl. The term "substituted
aryl" denotes an aryl ring radical as defined above that is
substituted with one or more, or preferably 1, 2, or 3 organic or
inorganic substituent groups, which include but are not limited to
a halogen, alkyl, substituted alkyl, hydroxyl, cycloalkyl, amino,
mono-substituted amino, di-substituted amino, acyloxy, nitro,
cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted
alkylcarboxamide, dialkylcarboxamide, substituted
dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl,
thiohaloalkyl, alkoxy, substituted alkoxy or haloalkoxy, aryl,
substituted aryl, heteroaryl, heterocyclic ring, substituted
heterocyclic ring wherein the terms are defined herein. The organic
substituent groups can comprise from 1 to 12 carbon atoms, or from
1 to 6 carbon atoms, or from 1 to 4 carbon atoms.
[0062] The term "heteroaryl" denotes an aryl ring radical as
defined above, wherein at least one of the carbons, or preferably
1, 2, or 3 carbons of the aryl aromatic ring has been replaced with
a heteroatom, which include but are not limited to nitrogen,
oxygen, and sulfur atoms. Examples of heteroaryl residues include
pyridyl, bipyridyl, furanyl, and thiofuranyl residues. Substituted
"heteroaryl" residues can have one or more organic or inorganic
substituent groups, or preferably 1, 2, or 3 such groups, as
referred to herein-above for aryl groups, bound to the carbon atoms
of the heteroaromatic rings. The organic substituent groups can
comprise from 1 to 12 carbon atoms, or from 1 to 6 carbon atoms, or
from 1 to 4 carbon atoms.
[0063] The term "halo" or "halogen" refers to a fluoro, chloro,
bromo or iodo group.
[0064] The term "thioalkyl" denotes a sulfide radical containing 1
to 8 carbons, linear or branched. Examples include methylsulfide,
ethyl sulfide, isopropylsulfide and the like.
[0065] The term "thiohaloalkyl" denotes a thioalkyl radical
substituted with one or more halogens. Examples include
trifluoromethylthio, 1,1-difluoroethylthio,
2,2,2-trifluoroethylthio and the like.
[0066] The term "carboalkoxy" refers to an alkyl ester of a
carboxylic acid, wherein alkyl has the same definition as found
above. Examples include carbomethoxy, carboethoxy, carboisopropoxy
and the like.
[0067] The term "alkylcarboxamide" denotes a single alkyl-group
attached to the amine of an amide, wherein alkyl has the same
definition as found above. Examples include N-methylcarboxamide,
N-ethylcarboxamide, N-(iso-propyl)carboxamide and the like. The
term "substituted alkylcarboxamide" denotes a single "substituted
alkyl" group, as defined above, attached to the amine of an
amide.
[0068] The term "dialkylcarboxamide" denotes two alkyl or arylalkyl
groups that are the same or different attached to the amine of an
amide, wherein alkyl has the same definition as found above.
Examples of a dialkylcarboxamide include N,N-dimethylcarboxamide,
N-methyl-N-ethylcarboxamide and the like. The term "substituted
dialkylcarboxamide" denotes two alkyl groups attached to the amine
of an amide, where one or both groups is a "substituted alkyl", as
defined above. It is understood that these groups can be the same
or different. Examples include N,N-dibenzylcarboxamide,
N-benzyl-N-methylcarboxamide and the like.
[0069] The term "arylalkyl" defines an alkylene, such as
--CH.sub.2-- for example, which is substituted with an aryl group
that can be substituted or unsubstituted as defined above. Examples
of an "arylalkyl" include benzyl, phenethylene and the like.
[0070] A residue of a chemical species, as used in the
specification and concluding claims, refers to a structural
fragment, or a moiety that is the resulting product of the chemical
species in a particular reaction scheme or subsequent formulation
or chemical product, regardless of whether the structural fragment
or moiety is actually obtained from the chemical species. Thus, an
ethylene glycol residue in a polyester refers to one or more
--OCH.sub.2CH.sub.2O-- repeat units in the polyester, regardless of
whether ethylene glycol is used to prepare the polyester.
Similarly, a 2,4-thiazolidinedione residue in a chemical compound
refers to one or more -2,4-thiazolidinedione moieties of the
compound, regardless of whether the residue was obtained by
reacting 2,4-thiazolidinedione to obtain the compound.
[0071] The term "organic residue" defines a carbon containing
residue, i.e. a residue comprising at least one carbon atom, and
includes but is not limited to the carbon-containing groups,
residues, or radicals defined hereinabove. Organic residues can
contain various heteroatoms, or be bonded to another molecule
through a heteroatom, including oxygen, nitrogen, sulfur,
phosphorus, or the like. Examples of organic residues include but
are not limited alkyl or substituted alkyls, alkoxy or substituted
alkoxy, mono or di-substituted amino, amide groups, etc. Organic
resides can preferably comprise 1 to 18 carbon atoms, 1 to 15,
carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, or 1 to 4
carbon atoms.
[0072] A very close synonym of the term "residue" is the term
"radical," which as used in the specification and concluding
claims, refers to a fragment, group, or substructure of a molecule
described herein, regardless of how the molecule is prepared. For
example, a 2,4-thiazolidinedione radical in a particular compound
has the structure ##STR6## regardless of whether thiazolidinedione
is used to prepare the compound. In some embodiments the radical
(for example an alkyl) can be further modified (i.e., substituted
alkyl) by having bonded thereto one or more "substituent radicals."
The number of atoms in a given radical is not critical to the
present invention unless it is indicated to the contrary elsewhere
herein.
[0073] "Inorganic radicals," as the term is defined and used herein
contain no carbon atoms and therefore comprise only atoms other
than carbon. Inorganic radicals comprise bonded combinations of
atoms selected from hydrogen, nitrogen, oxygen, silicon,
phosphorus, sulfur, selenium, and halogens such as fluorine,
chlorine, bromine, and iodine, which can be present individually or
bonded together in their chemically stable combinations. Inorganic
radicals have 10 or fewer, or preferably one to six or one to four
inorganic atoms as listed above bonded together. Examples of
inorganic radicals include, but not limited to, amino, hydroxy,
halogens, nitro, thiol, sulfate, phosphate, and like commonly known
inorganic radicals. The inorganic radicals do not have bonded
therein the metallic elements of the periodic table (such as the
alkali metals, alkaline earth metals, transition metals, lanthanide
metals, or actinide metals), although such metal ions can sometimes
serve as a pharmaceutically acceptable cation for anionic inorganic
radicals such as a sulfate, phosphate, or like anionic inorganic
radical. Inorganic radicals do not comprise metalloids elements
such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or
tellurium, or the noble gas elements, unless otherwise specifically
indicated elsewhere herein.
[0074] "Organic radicals" as the term is defined and used herein
contain one or more carbon atoms. An organic radical can have, for
example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms,
1-8 carbon atoms, or 1-4 carbon atoms. Organic radicals often have
hydrogen bound to at least some of the carbon atoms of the organic
radical. One example, of an organic radical that comprises no
inorganic atoms is a 5,6,7,8-tetrahydro-2-naphthyl radical. In some
embodiments, an organic radical can contain 1-10 inorganic
heteroatoms bound thereto or therein, including halogens, oxygen,
sulfur, nitrogen, phosphorus, and the like. Examples of organic
radicals include but are not limited to an alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino,
di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy,
alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide,
substituted dialkylcarboxaamide, alkylsulfonyl, alkylsulfinyl,
thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl,
haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or
substituted heterocyclic radicals, wherein the terms are defined
elsewhere herein. A few non-limiting examples of organic radicals
that include heteroatoms include alkoxy radicals, trifluoromethoxy
radicals, acetoxy radicals, dimethylamino radicals and the
like.
[0075] The term "amide" as defined hereby and used in the instant
specification refers to a functional group or residue that contains
a carbonyl (CO) group bound to a nitrogen atom, i.e. a residue
having the formula: ##STR7##
[0076] It is to be understood that for the purposes, of this
disclosure and the accompanying claims, any molecule or compound
that comprises the above functional group or reside can be termed
an amide, regardless of the identity of the three unspecified
substituent groups. For example, if the carbonyl carbon and one of
the unspecified nitrogen substituents are bound to carbon atoms,
the resulting compound would be described herein as an "amide."
Nevertheless, if the substituent of the carbonyl group were a
2.sup.nd nitrogen atom, as shown below, the resulting compound
would still be termed an "amide" herein, even though many of
ordinary skill in the art might often use a more specific term,
such as "urea." Similarly, if the substituent of the carbonyl group
were an oxygen atom, the compound would still be termed an amide
herein, even though the more specific term "urethane" might
alternatively be employed. ##STR8##
COMPOUNDS OF THE INVENTION
[0077] Some disclosed embodiments of the invention relate to a
genus of compounds of Formula (200): ##STR9##
[0078] wherein: [0079] a) the B, H, I, J and K residues are
independently selected from --C(O)--, --C(S)--, --O--, --S--,
--N(R.sub.101)--, --N(R.sub.102)--, --C(R.sub.103)(R.sub.104)--,
--C(R.sub.105)(R.sub.106)--, or --C(R.sub.107)(R.sub.108)--
residues, and from zero to two of the B, H, I, J or K residues can
be absent; wherein: [0080] i) R.sub.101, R.sub.102, R.sub.103,
R.sub.104, R.sub.105, R.sub.106, R.sub.107 and R.sub.108 are
independently selected from hydrogen, hydroxyl, a halogen, amino,
or an organic residue comprising 1 to 12 carbon atoms; or two of
the R.sub.101, R.sub.102, R.sub.103, R.sub.104, R.sub.105,
R.sub.106, R.sub.107 and R.sub.108 residues can be connected
together to form an exocyclic substituent residue comprising 1 to 6
ring carbon atoms and from 0 to 3 optional ring heteroatoms
selected from O, S, or N; and [0081] ii) B, H, I, J and K together
with the Ar.sub.5 form a ring containing at least one amide residue
having the formula ##STR10## [0082] wherein R.sub.x is a R.sub.101
or R.sub.102 residue; [0083] b) Ar.sub.5 is an aryl, substituted
aryl, heteroaryl, or substituted heteroaryl residue comprising from
3 to 6 ring carbon atoms and from 0 to 3 optional ring heteroatoms
selected from O, S, or N; [0084] c) Ar.sub.6 is an aryl,
substituted aryl, heteroaryl, or substituted heteroaryl residue
comprising from 2 to 6 ring carbon atoms and from 0 to 3 optional
ring heteroatoms selected from O, S, or N; [0085] d) R.sub.109 is
hydrogen, hydroxy, or an organic residue comprising 1 to 10 carbon
atoms; [0086] e) ----- is either present or absent; [0087] f) W, X,
Y and Z are independently or together --C(O)--, --C(S)--, --S--,
--O-- or --NH--, to form a 2,4-thiazolidinedione,
2-thioxo-thiazolidine-4-one, 2,4-imidazolidinedione or
2-thioxo-imidazolidine-4-one residue; or
[0088] a pharmaceutically acceptable salt thereof.
[0089] In the embodiments described immediately above, the W, X, Y
and Z radicals, together with a carbon atom, form one of four
separate five membered heterocycles, selected from a
2,4-thiazolidinedione, 2-thioxo-thiazolidine-4-one,
2,4-imidazolidinedione or 2-thioxo-imidazolidine-4-one residue, as
shown in the drawing below: ##STR11##
[0090] For purposes of ease of reference and brevity, the
2,4-thiazolidinedione, 2-thioxothiazolidine-4-one,
2,4-imidazolidinedione or 2-thioxo-imidazolidine-4-one heterocyclic
residues can be generically termed an "HAr" heterocyclic residue or
radical. When the "HAr" terminology is employed, an alternative
description embodying the invention, which is closely related to
the genus of compounds of formula 200 described above can be
recited. This alternative description relates to a genus of
compounds having the structure ##STR12##
[0091] wherein [0092] a) Ar.sub.5 is an aryl, substituted aryl,
heteroaryl, or substituted heteroaryl; [0093] b) B, H, I, J and K
are independently selected from --C(O)--, --C(S)--, --O--, --S--,
--N(R.sub.101)--, --N(R.sub.102)--, --C(R.sub.103)(R.sub.104)--,
--C(R.sub.105)(R.sub.106)--, or --C(R.sub.107)(R.sub.108)--,
wherein one, or two of B, H, I, J or K can optionally be absent;
and [0094] i) R.sub.101, R.sub.102, R.sub.103, R.sub.104,
R.sub.105, R.sub.106, R.sub.107 and R.sub.108 are independently
selected from hydrogen, hydroxyl, a halogen, amino, or an organic
radical comprising 1 to 12 carbon atoms; [0095] ii) two of B, H, I,
J and K form at least one radical having the structure ##STR13##
[0096] wherein R.sub.x is a R.sub.101 or R.sub.102 radical; [0097]
iii) Ar.sub.5 together with B, H, I, J and K comprise from 2 to 24
carbon atoms; [0098] c) Ar.sub.6 is an aryl, substituted aryl,
heteroaryl, or substituted heteroaryl comprising from 2 to 18
carbon atoms; [0099] d) R.sub.109 is hydrogen, hydroxy, or an
organic radical comprising 1 to 10 carbon atoms; [0100] e) ----- is
either present or absent; [0101] f) HAr is a heterocycle having the
structure ##STR14##
[0102] or a pharmaceutically acceptable salt thereof.
[0103] The detailed description of the preferred embodiments
recited below is intended to be applicable, to the extent
reasonably possible, to either of the two alternative descriptions
of the compounds of the invention cited immediately above.
[0104] Ar.sub.5 is an aryl, substituted aryl, heteroaryl, or
substituted heteroaryl residue or radical. As noted in the
accompanying definitions, aryl radicals have at least one
six-membered aromatic "benzene" residue therein, although
additional aromatic rings might be attached thereto, so as to form,
for example, a naphthalene or biphenyl radical. The aryl ring
residues are bonded to the Ar.sub.6 radical, and have bonded
thereto a non-aromatic ring residue comprising one or more of the
B, H, I, J and K residues. In many embodiments, Ar.sub.5 is a
benzene radical, which can be optionally additionally substituted
with one or more additional organic or inorganic radicals or
residues.
[0105] Ar.sub.5 can also comprise a heteroaryl radical or residue,
wherein the term is defined elsewhere herein. The heteroaryl ring
residue is bonded to the Ar.sub.6 radical and a non-aromatic
heterocyclic ring residue comprising one or more of the B, H, I, J
and K residues. In many embodiments, Ar.sub.5 comprises a pyridine,
pyrimidine, or pyrazine ring.
[0106] The aryl or heteroaryl ring residues can optionally and
additionally have one, two, or more additional substituent residues
or radicals bonded to the aryl or heteroaryl rings, so as to
comprise a "substituted aryl" or "substituted heteroaryl" residue
or radical, as the terms are defined elsewhere herein. The
additional substituents can be selected from organic residues,
inorganic radicals, or organic radicals as those terms are defined
elsewhere herein. In some embodiments, the Ar.sub.5 aryl or
heteroaryl ring is substituted with one or two additional
substituents independently selected from a halogen, an amino, or a
radical comprising 1 to 4 carbon atoms selected from an alkyl, a
monosubstituted amino, a disubstituted amino, an alkoxy, or a
haloalkoxy.
[0107] In some embodiments, Ar.sub.5 is a benzene ring, optionally
substituted with one additional substituent selected from a
halogen, an amino, or a radical comprising 1 to 4 carbon atoms
selected from an alkyl, a monosubstituted amino, a disubstituted
amino, an alkoxy, or a haloalkoxy. An example of a substituted
Ar.sub.5 radical comprising a benzene ring and one additional
substituent would be a radical having the structure shown below,
wherein R.sub.a is the additional substituent residue or radical.
##STR15##
[0108] As is also shown in the drawing immediately above, and
elsewhere herein, the Ar.sub.5 radical is also bonded to a
non-aromatic heterocyclic ring residue comprising one or more of
the B, H, I, J and K residues, wherein the non-aromatic
heterocyclic ring residue is bound to adjacent carbon atoms on the
Ar.sub.5 aryl or heteroaryl ring. One or two of the B, H, I, J and
K residues can optionally be absent. Therefore, the non-aromatic
heterocyclic ring residue can form five, six, or seven membered
rings, wherein the carbons that are part of the Ar.sub.5 aryl or
heteroaryl ring are also considered to be part of the non-aromatic
heterocyclic ring residue.
[0109] The B, H, I, J and K residues are independently selected
from --C(O)--, --C(S)--, --O--, --S--, --N(R.sub.101)--,
--N(R.sub.102)--, --C(R.sub.103)(R.sub.104)--,
--C(R.sub.105)(R.sub.106)--, or --C(R.sub.107)(R.sub.108)--
residues, with the proviso that two of B, H, I, J and K must form
an amide residue, as will be further discussed below. R.sub.101,
R.sub.102, R.sub.103, R.sub.104, R.sub.105, R.sub.106, R.sub.107
and R.sub.108 can be independently selected from hydrogen,
hydroxyl, a halogen, amino, or an organic radicals. In many
embodiments, suitable organic radicals for R.sub.101, R.sub.102,
R.sub.103, R.sub.104, R.sub.105, R.sub.106, R.sub.107 and R.sub.108
comprise 1 to 12 carbon atoms, 1 to 6 carbon atoms, or 1 to 4
carbon atoms. In some embodiments, lower alkyl radicals such as
methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl
are particularly suitable R.sub.101, R.sub.102, R.sub.103,
R.sub.104, R.sub.105, R.sub.106, R.sub.107 or R.sub.108
substituents.
[0110] Although not wishing to be bound by theory, the heterocyclic
amide compounds of the invention, including the Ar.sub.5 radical
together with the non-aromatic heterocyclic ring residue and any
additional substituent radicals for Ar.sub.5 are selected so that
the Ar.sub.5 radical has a geometry, size, and polarity that is
suitable to allow the compounds of the invention to interact with
and substantially fill, yet fit within the binding regions of the
target biological molecules, so as to contribute to the effective
binding of the compounds to the binding sites in the biological
target molecules. Therefore, in some embodiments, the Ar.sub.5
radical, together with the non-aromatic heterocyclic ring residue
and any additional substituent radicals for Ar.sub.5 comprises from
2 to 24 carbon atoms, or from 3 to 20 carbon atoms, or from 4 to 18
carbon atoms, or from 5 to 16 carbon atoms.
[0111] It must be noted that for all the compounds of the
invention, the B, H, I, J and K residues together with the Ar.sub.5
form a non-aromatic heterocyclic ring containing at least one amide
residue. The amide residues as defined elsewhere herein for the
purposes of this disclosure have the structure indicated below,
wherein Rx is a R.sub.101 or R.sub.102 residue. ##STR16##
[0112] The amide residue is contained within the non-aromatic
heterocyclic ring comprising B, H, I, J and K. Therefore, in one
embodiment of the invention, ring radical comprising the Ar.sub.5
ring and the non-aromatic heterocyclic ring comprising B, H, I, J
and K would have the structure shown immediately below: ##STR17##
wherein R.sub.x is a R.sub.101 or R.sub.102 residue. In such
embodiments, the J atom or residue could be one of several
alternatives. If the J atom or residue was a
--C(R.sub.103)(R.sub.104)-- residue, the resulting structure would
be: ##STR18##
[0113] Such cyclic compounds comprising an amide group whose
carbonyl carbon is bound to another carbon are often termed
"lactams."
[0114] Alternatively, if J is an oxygen atom, the resulting
compounds are termed "cyclic carbamates", and would have the
structure: ##STR19##
[0115] If the J atom or residue is an --N(R.sub.102)-- residue, the
resulting compounds are termed a "cyclic urea," and would have the
structure: ##STR20##
[0116] It is to be understood that in the various embodiments
described above, 0, 1, or 2, of the B, H, I, J or K residues could
be absent. Typically the B and K residues are bound to two adjacent
carbon atoms on the Ar.sub.5 aryl or heteroaryl ring. Therefore the
ring comprising the B, H, I, J and K residues often comprise 5, 6,
or 7 ring atoms and the B, H, I, J and K residues form at least one
amide residue.
[0117] In some embodiments B, H, I, J and K together with Ar.sub.5
form a ring containing at least one amide residue having one of the
Formulas (205a-k) wherein Ar.sub.5 is benzene or a substituted
benzene radical. Similar structures can also be formed where
Ar.sub.5 is a heteroaryl, such as pyridine, pyrimidene, pyrazine,
and the like: ##STR21## ##STR22##
[0118] In the drawing above, R.sub.101, R.sub.102, R.sub.103,
R.sub.104, R.sub.105, R.sub.106, R.sub.107, R.sub.108, R.sub.110,
R.sub.111 or R.sub.112 can be independently selected from inorganic
substituents, which include but are not limited to inorganic
substituents such as hydrogen, halogen, cyano, nitro, hydroxyl, or
amino. R.sub.101, R.sub.102, R.sub.103, R.sub.104, R.sub.105,
R.sub.106, R.sub.107, R.sub.108, R.sub.110, R.sub.111 or R.sub.112
can also be independently selected from organic residues or organic
radicals, as those terms are defined elsewhere herein. Examples of
suitable organic residues or radicals include but are not limited
to an alkyl, substituted alkyl, haloalkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, acyloxy, amino,
mono-substituted amino, di-substituted amino, alkylsulfonamide,
arylsulfonamide, alkylurea, arylurea, alkylcarbamate,
arylcarbamate, aryl, heteroaryl, alkoxy, substituted alkoxy,
haloalkoxy, thioalkyl, thiohaloalkyl, carboxy, carboalkoxy,
alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide
or substituted dialkylcarboxamide residue. In some embodiments,
preferred R.sub.101, R.sub.102, R.sub.103, R.sub.104, R.sub.105,
R.sub.106, R.sub.107, R.sub.108, R.sub.110, R.sub.111 or R.sub.112
groups are an alkyl, substituted alkyl, haloalkyl, alkoxy,
substituted alkoxy, or haloalkoxy residues, particularly those
comprising from 1 to 12 carbons, 1 to 6 carbons, or I to four
carbons.
[0119] In some embodiments, the residue bonded to the nitrogen atom
of the amide groups (i.e. R.sub.101 or R.sub.102) can hydrogen or
an organic radical comprising 1 to 12 carbon atoms, 1 to 8 carbon
atoms, or 1 to 4 carbon atoms. In some embodiments, R.sub.101 or
R.sub.102 is a lower alkyl group, such as methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, or t-butyl. In some embodiments,
methyl, ethyl, or i-propyl radicals are preferred R.sub.101 or
R.sub.102 residues.
[0120] Some embodiments of the invention relate to lactam compounds
of Formula (206): ##STR23##
[0121] Some embodiments of the invention relate to lactam compounds
of Formula (207): ##STR24##
[0122] Some embodiments of the invention relate to compounds of
Formula (208): ##STR25##
[0123] In some embodiments R.sub.101 is hydrogen, alkyl or
substituted alkyl. Some examples R.sub.101 is a straight or
branched alkyl of C.sub.1-C.sub.12. In other examples R.sub.101 is
a straight or branched alkyl of C.sub.1-C.sub.8. In still other
examples R.sub.101 is a straight or branched alkyl of
C.sub.1-C.sub.6. In yet other examples R.sub.101 is a straight or
branched alkyl of C.sub.1-C.sub.4.
[0124] Some embodiments of the invention relate to compounds of
Formula (200) wherein the two R substituents of
--C(R.sub.103)(R.sub.104)--, --C(R.sub.105)(R.sub.106)--, or
--C(R.sub.107)(R.sub.108)--, together form an exocyclic cycloalkyl
ring, which can optionally contain O, S or N-alkyl atom groups
within the ring. In many embodiments, the exocyclic cycloalkyl ring
comprises from 3 to 6 ring carbon atoms. Representative examples
include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl
exocyclic rings. Representative examples of compounds comprising, a
five membered lactam ring wherein --C(R.sub.103)(R.sub.104)--
together form an exocyclic cycloalkyl, include those of Formulae
(209a-c). ##STR26##
[0125] One or two of the carbons of the exocyclic rings could
optionally be replaced with an O, S or N-alkyl residue, to form
tetrahydrofuranyl, tetrahydropyrrolidinyl, and
tetrahydrothiofuranyl and like exocyclic ring radicals.
[0126] Some embodiments of the invention relate to compounds
wherein --C(R.sub.105)(R.sub.106)-- form an exocyclic cycloalkyl
optionally substituted with O, S or N-alkyl. Representative
examples of compounds for (205b) wherein
--C(R.sub.103)(R.sub.104)-- together form a cycloalkyl optionally
substituted with O, S or N-alkyl include those of Formulae
(209d-f). ##STR27##
[0127] Some embodiments of the invention relate to compounds of
Formula (200) wherein --C(R.sub.107)(R.sub.108)-- form a cycloalkyl
optionally substituted with O, S or N-alkyl.
[0128] Some embodiments of the invention relate to compounds of
Formula (200) where --C(R.sub.103)(R.sub.104)--,
--C(R.sub.105)(R.sub.106)-- and --C(R.sub.107)(R.sub.108)--
independently form a cycloalkyl optionally substituted with O, S or
N-alkyl.
[0129] In some embodiments R.sub.101 is a substituted alkyl that
include aryl alkyl, substituted-aryl alkyl and heteroaryl alkyl.
Some representative examples are of the Formulae-(210a-b):
##STR28##
[0130] wherein R.sub.115, R.sub.116, R.sub.117, R.sub.118 and
R.sub.119 are independently or together hydrogen, alkyl,
substituted alkyl, haloalkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, halogen, cyano, nitro, hydroxyl,
acyloxy, amino, mono-substituted amino, di-substituted amino,
alkylsulfonamide, arylsulfonamide, alkylurea, arylurea,
alkylcarbamate, arylcarbamate, heteroaryl, alkoxy, substituted
alkoxy, haloalkoxy, thioalkyl, thiohaloalkyl, carboxy, carboalkoxy,
alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide
or substituted dialkylcarboxamide; and N, represent the number of
nitrogen in the ring wherein x is 1, 2 or 3 thus forming a
substituted or unsubstituted pyridyl, pyrimidinyl or triazinyl
respectively.
[0131] In some embodiments R.sub.101 is a substituted alkyl that
include heteroaryl alkyl. Some interesting heteroaryl residues are
five membered rings, some examples include, but are not limited to
those of the Formulae (212a-x): ##STR29## ##STR30## ##STR31##
[0132] wherein R.sub.115, R.sub.116, R.sub.117, R.sub.118 and
R.sub.119 are independently or together hydrogen, alkyl,
substituted alkyl, haloalkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, halogen, cyano, nitro, hydroxyl,
acyloxy, amino, mono-substituted amino, di-substituted amino,
alkylsulfonamide, substituted alkylsulfonamide, arylsulfonamide,
heteroarylsulfonamide, alkylurea, alkylthiourea, arylurea, acyl,
substituted acyl, alkylcarbamate, arylcarbamate,
alkylthiocarbamate, substituted alkylthiocarbamate,
arylthiocarbamate, heteroaryl, substituted heteroaryl, alkoxy,
substituted alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide,
alkylsulfonyl, thiohaloalkyl, carboxy, carboalkoxy,
alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide
or substituted dialkylcarboxamide.
[0133] It is understood that compounds of Formula (200) possessing
heteroaryl residues wherein N--R.sub.222 is a hydrogen, that
tautomers are possible and are within the scope of the invention.
For example, triazole (212e) can exist in several tautomeric forms
when R.sub.117 is hydrogen. These forms can be represented as
shown: ##STR32##
[0134] Other represented structures that can exist as various
tautomeric forms include, for example, (212i), (212m), (212t) and
(212u).
[0135] The compounds of the invention comprise an Ar.sub.6 ring
radical which is an aryl, substituted aryl, heteroaryl, or
substituted heteroaryl residue, as those terms are defined
elsewhere herein. Ar.sub.6 is bonded to the aromatic ring of
Ar.sub.5, and to a carbon atom that bridges and is bonded to the
HAr heterocycle.
[0136] The atoms comprising the aromatic ring of Ar.sub.6 can
optionally be bonded to one, two, three, or four ring substituents,
so as to form a substituted aryl or substituted heteroaryl ring, as
those terms are defined elsewhere herein.
[0137] The optional substituent residues or radicals bonded to
Ar.sub.6 can be selected from inorganic or organic radicals, as
those terms are defined elsewhere herein. Although not wishing to
be bound by theory, the heterocyclic amide compounds of the
invention, including the Ar.sub.6 radical together with any
additional substituent radicals are selected so that the Ar.sub.6
radical has a geometry, size, and polarity that is suitable to
allow the compounds of the invention to interact with and
substantially fill, yet fit within, the binding regions of the
target biological molecules, so as to contribute to the effective
binding of the compounds to the binding sites in the biological
target molecules. Therefore, in some embodiments, the Ar.sub.6 aryl
or heteroaryl radical, together any additional substituent radicals
for comprises from 2 to 18 carbon atoms, or from 3 to 12 carbon
atoms, or from 4 to 10 carbon atoms, or from 5 to 8 carbon
atoms.
[0138] In many embodiments, Ar.sub.6 is a substituted or
unsubstituted six membered aromatic or heteroaromatic radical, such
as a benzene, pyridine, pyrimidine, or pyrazine ring radical. In
such embodiments, any relative orientation of the bonds to Ar.sub.5
and to the carbon atom that bridges to the HAr heterocycles (i.e.
ortho, meta, or para) can be employed. Nevertheless, in some
embodiments, a "meta" orientation of the bonds to Ar.sub.5 and to
the carbon atom that bridges to the HAr heterocycles can provide
superior biological activity. Such "meta" Ar.sub.6 rings can have
additional substituents, as discussed above. In some such
embodiments Ar.sub.6 has the Formula (215a), (215b), (215c) or
(215d): ##STR33##
[0139] wherein R.sub.125, R.sub.126, R.sub.127 and R.sub.128 can be
independently selected from inorganic substituents which include
but are not limited to hydrogen, halogen, nitro, hydroxyl, or
amino, or organic residues or radicals, examples of which include
but are not limited to an alkyl, substituted alkyl, haloalkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cyano,
acyloxy, mono-substituted amino, di-substituted amino,
alkylsulfonamide, arylsulfonamide, alkylurea, arylurea,
alkylcarbamate, arylcarbamate, heteroaryl, alkoxy, haloalkoxy,
substituted alkoxy, haloalkoxy, thioalkyl, thiohaloalkyl, carboxy,
carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide,
dialkylcarboxamide or substituted dialkylcarboxamide residue.
[0140] In some compounds of the invention comprising Ar.sub.6 rings
of formulas (215a-d), R.sub.125 is not hydrogen. Although the
biochemical basis for the effect may not necessarily be well
understood, it believed that the presence of a non-hydrogen
R.sub.125 substituent can significantly and unexpectedly improve
the activity of the compounds as agents, for modulating lipid or
carbohydrate metabolism, and/or producing anti-diabetic and/or
anti-cholesteric activity. In some embodiments, preferred
R.sub.125, residues are an alkyl, substituted alkyl, haloalkyl,
alkoxy, substituted alkoxy, haloalkoxy, halogen, amino,
mono-substituted amino, or disubstituted amino residue,
particularly those comprising from 1 to 6 carbons, or 1 to four
carbons. Unexpectedly good biological activity can often be
obtained if R.sub.125 is a small organic radical such as a methoxy,
triflouromethoxy, dimethylamino, or chloride radical, so as to
yield an Ar.sub.6 radical comprising Formulas (217a), (217b),
(217c) or (217d): ##STR34##
[0141] wherein R.sub.126, R.sub.127 and R.sub.128 are independently
or together hydrogen or halogen.
[0142] The compounds of the invention have a carbon atom bonded to
both the Ar.sub.6 radical and the HAr heterocyclic radical, so as
to bridge or link the Ar.sub.6 radical and the HAr heterocyclic
radical. The bridging carbon atom bears an R.sub.109 substituent
that can be selected from hydrogen, hydroxy, or an organic residue
comprising 1 to 10 carbon atoms. In some embodiments R.sub.109 is
selected from hydrogen, an alkyl, a substituted alkyl, hydroxy, an
alkoxy or a haloalkoxy radical. In many embodiments, R.sub.109 is
hydrogen.
[0143] In some embodiments ----- represents a bond present and the
compound is a benzylidene compound having Formula (220):
##STR35##
[0144] When ----- is present both E and Z configurations of the
carbon-carbon bond between the benzylidene carbon and the HAr
heterocycle are within the scope of the invention. Either isomer
can predominate or be present in pure form, or in a mixture, which
may or may not have equal proportions of the E and Z isomers. For
example, 2,4-thiazolidinedione and 2-thioxo-4-thiazolidinedione of
Formula (200) can have the following structures respectively:
##STR36##
[0145] When only one of the two isomer is shown in this
specification or in the claims, it should be presumed that both
isomers and mixtures thereof are intended unless the context makes
it plain that only a single isomer is intended.
[0146] In some embodiments ----- represents a bond absent and the
compound is a benzyl compound with a single carbon-carbon bond
between a benzylic carbon and the HAr ring, the compounds having
the Formula (222): ##STR37##
[0147] As already noted above, the 5 membered heterocyclic ring
radical comprising the W, X, Y, and Z groups form one of four
heterocycles, selected from a 2,4-thiazolidinedione,
2-thioxo-thiazolidine-4-one, 2,4-imidazolidinedione or
2-thioxo-imidazolidine-4-one residue, which can be collectively
termed "HAr" heterocycles. The four possible HAr heterocyclic
residues are shown in the drawing below: ##STR38##
[0148] All four of the HAr heterocycles shown above comprise at
least one ring nitrogen atom bonded to a hydrogen atom. The
nitrogen-bound hydrogen atoms of all four of the HAr heterocycles
are known to be sufficiently acidic so as to react with common
laboratory bases such as organic amine compounds, hydroxide salts,
and the like.
[0149] The acidity of the four HAr heterocycles provides a ready
method for preparing salts of the compounds of the invention, by
reaction with an appropriate base, so as to generate an anion from
the compound of the invention and a cation derived from the base
employed. The salts formed by such reactions have the structure:
##STR39##
[0150] A wide variety of bases could be employed to produce such
salts, including monovalent alkali metal hydroxides, divalent
alkaline earth metal hydroxides, or bases comprising trivalent
metal salts such as aluminum. Alternatively, organic bases such as
primary, secondary, or tertiary amines can react with the acidic
hydrogens of the compounds of the invention to form ammonium salts.
The base and/or its associated cation are chosen so as to provide
desirable solubility, toxicity, and/or bioavailability
characteristics in the salt after formation of the desired salts.
The identity of the base and/or the resulting cation will of course
vary somewhat with the identity of the compound of the invention,
and the nature of the pharmaceutical composition to be employed and
its physical form as a solid or liquid, and the nature of any
solvents and/or carriers employed.
[0151] Nevertheless, the United States Food and Drug Administration
has published a list of pharmaceutically acceptable cations for
pharmaceutically acceptable salts that includes aluminum, calcium,
lithium, magnesium, potassium, sodium, and zinc cations, ammonium
cations formed by the reactions of acidic compounds with
benzathine, chloroprocaine, choline, diethanolamine,
ethylenediamine, meglumine, procaine, t-butylamine, and
tris(hydroxymethyl)aminomethane ("Tris"). Such "pharmaceutically
acceptable" salts are often employed and/or evaluated for use in
the invention simply because of the likelihood of decreased FDA
regulatory scrutiny. Example 25 provides an example of the
synthesis of a particularly useful "Tris" salt of one of the
compounds of the invention.
[0152] Also, one or more compounds disclosed herein can include
zwitterionic salts formed by reaction of a nitrogen contained
internally within the compound, such as an amine, aniline,
substituted aniline, pyridyl and like residues with the acidic
hydrogen of the HAr group. Alternatively, a basic nitrogen
contained internally within the compound can be reacted with an
external acid, such as HCl, sulfuric acid, a carboxylic acid or the
like.
[0153] Compounds disclosed herein can exist in various tautomeric
forms. For example, 2,4-thiazolidinedione-containing compounds
disclosed herein can exist in the form of tautomers (224a), (224b)
and (224c). ##STR40##
[0154] It is understood by those of skill in the art that tautomers
can also exist with compounds of the invention that contain the
heterocycle 2-thioxo-thiazolidine-4-one, 2,4-imidazolidinedione or
2-thioxo-imidazolidine-4-one. For convenience, all of the tautomers
can be presented herein by a single formula, but it is understood
that all tautomers are within the scope of the invention.
[0155] Selected compounds of the invention can also be described
more narrowly than the broadest embodiments described above. Two
examples of such narrower descriptions are set forth below, but the
meanings of the various relevant terms and symbols are intended the
same as those same terms and symbols in the description above.
[0156] In one narrower description of the invention, the invention
relates to a compound having the structure: ##STR41##
[0157] wherein [0158] a) the residue ##STR42## [0159] has the
structure: ##STR43## [0160] wherein R.sub.101, R.sub.102,
R.sub.103, R.sub.104, R.sub.105, or R.sub.106, R.sub.110, R.sub.111
and R.sub.112 are independently selected from hydrogen, hydroxyl, a
halogen, amino, or an organic residue comprising 1 to 6 carbon
atoms; [0161] b) Ar.sub.6 has the structure: ##STR44## [0162]
wherein R.sub.125 is halogen, or an organic substituent residue
comprising 1 to 4 carbon atoms selected from alkyl, haloalkyl;
cyano, amino, mono-substituted amino, di-substituted amino, alkoxy,
or haloalkoxy; and R.sub.126, R.sub.127, and R.sub.128 are
independently selected from hydrogen, halogen, amino, and/or
organic substituents comprising 1 to 4 carbon atoms selected from
alkyl, halo alkyl, cyano, acyloxy, mono-substituted amino,
di-substituted amino, alkoxy, or haloalkoxy; [0163] c) ----- is
either present or absent; and [0164] d) W, X, Y and Z together form
a heterocyclic radical having the structure: ##STR45##
[0165] or a pharmaceutically acceptable salt thereof.
[0166] In another yet narrower description of the invention, the
invention relates to a compound having the structure: ##STR46##
[0167] wherein [0168] a) the residue ##STR47## [0169] has the
structure: ##STR48## [0170] wherein R.sub.101, R.sub.103,
R.sub.104, R.sub.105, R.sub.106 and R.sub.110 are independently
selected from hydrogen, or an alkyl comprising 1 to 4 carbon atoms.
[0171] b) Ar.sub.6 has the structure: ##STR49## [0172] wherein
R.sub.126, R.sub.127 and R.sub.128 are independently selected from
hydrogen or a halogen; and [0173] c) W, X, Y and Z together form a
heterocyclic radical having the structure: ##STR50##
[0174] or a pharmaceutically acceptable salt thereof.
[0175] The present invention also provides, but is not limited to,
the specific species compounds set forth in the Examples, or a
pharmaceutically acceptable salt thereof:
Making Compounds of the Invention
[0176] Various synthetic methods can be employed in the making of
the compounds disclosed herein. A representative set of synthetic
pathways is shown in FIG. 8 for the synthesis of precursors of the
Ar.sub.5 radical and the attached non-aromatic heterocyclic ring
comprising an amide group. The synthetic precursors whose synthesis
is shown in FIG. 8 that can be coupled with Ar.sub.6 and
subsequently elaborated to provide the compounds of the invention
by the methods illustrated in FIG. 9.
[0177] One method of synthesizing precursors of the Ar.sub.5
radical is shown in FIG. 8, and begins with anilines of structure
(230), many of which are commercially available from suppliers such
as Aldrich Chemical Company of Milwaukee Wis. Compounds of
structure (230) can be coupled with an appropriately substituted
acid chloride derivative of acrylic acid to give amide (232). The
groups R.sub.103, R.sub.105, and R.sub.106 can be introduced into
compounds of the invention by the selection of the appropriately
substituted acrylic acid chloride. Such acrylic acid chlorides are
available by a variety of known methods, including as products of
Wittig reactions of appropriate aldehydes and ketones with
phosphorus ylids of haloacetic acid derivatives. Amide (232) can
also be prepared by methods known in the art utilizing a carboxylic
acid and a coupling agent such as, for example, a carbodiimide. The
amide (232) is converted to 2-oxo-1,2,3,4-tetrahydroquinoline (234)
through a Lewis Acid cyclization. One Lewis acid that can be
utilized in the process is, for example, AlCl.sub.3. Mineral acids
my effect the same cyclization. At this stage R.sub.101 can be
introduced to give 2-oxo-1,2,3,4-tetrahydro-quinoline (236) by
allowing R.sub.101-LG, wherein LG is a leaving group, such as, for
example, Cl, Br, I, OTf, and the like, to react with the nitrogen
anion of 2-oxo-1,2,3,4-tetrahydro-quinoline (234). The anion of
2-oxo-1,2,3,4-tetrahydro-quinoline (234) can be generated using a
base such as, for example, KOH/DMSO, NaH and the like.
[0178] Another method, for example, includes the use of aniline
(237) that can be coupled with an acid chloride to give amide
(238). The groups R.sub.103 and R.sub.104 can be introduced into
compounds of the invention by the selection of the appropriate acid
chloride. Amide (238) can also be prepared by methods known in the
art utilizing a carboxylic acid and a coupling agent such as, for
example, a carbodiimide. At this stage R.sub.101 can be introduced
to give amide (240) by allowing R.sub.101-LG to react with the
nitrogen anion of amide (238), wherein LG is a leaving group, such
as, for example, Cl, Br, I, OTf, and the like.
2-oxo-2,3-dihydro-1H-indole (242) can be prepared from amide (240)
through a Pd-assisted cyclization. Various ligands with Pd can be
employed, such as, for example, tricyclohexyl-phosphine. The
methoxy group of amide (242) can be converted to phenol (244) using
a variety of methods known in the art, such as, for example,
BBr.sub.3. The resulting phenol (244) can be converted into
triflate (246), or the like, using triflic anhydride or similar
reagent that is suitable for coupling with Ar.sub.6.
[0179] Another method, for example, includes the use of readily
available phenylene diamines of structure (248), that can be
condensed with oxylyl chloride to give quinoxaline-2,3-dione (250).
R.sub.101 can be introduced by allowing R.sub.101-LG to react with
the nitrogen anion of quinoxaline-2,3-dione (250), wherein LG is a
leaving group, such as, for example, Cl, Br, I, OTf, and the like.
R.sub.102 can be introduced by allowing R.sub.102-LG to react with
the nitrogen anion of quinoxaline-2,3-dione (250), wherein LG is a
leaving group, such as, for example, Cl, Br, I, OTf, and the like.
R.sub.101 and R.sub.102 can be the same or different.
Quinoxaline-2,3-dione (252) can be brominated to give
quinoxaline-2,3-dione (254) using methods known in the art, such
as, for example, Br.sub.2 or equivalent, in an appropriate solvent,
such as acetic acid. Bromination might also be carried out prior to
the introduction of R.sub.101 and R.sub.102.
[0180] Various synthetic methods can be employed in coupling
Ar.sub.5 and Ar.sub.6. A representative set of synthetic pathways
is shown in FIG. 9. One method, for example, includes coupling a
boronic acid of Formula (262), R.sub.140=H, with a suitable
carbonyl-containing aryl of Formula (264), such as R.sub.150=Br, I,
Cl, triflate or the like, to give biaryl (266) that is substituted
with a carbonyl group, such as a formyl group (i.e., R.sub.109=H).
Alternatively, boronic acid (262) can be coupled with aryl (268),
such as when R.sub.150=Br, I, Cl, triflate or the like, to give
biaryl (270) that is subsequently formylated using techniques known
in the art, such as the Vilsmeier or the Vilsmeier-Haack reaction,
the Gatterman reaction, the Duff reaction, the Reimer-Tiemann
reaction or a like reaction. Coupling reactions such as that
described for the formation of Biary) (266) and (270) can also be
conducted using boronic esters, such as where R.sub.140 together
with the boron from a pinacol borate ester (formation of pinacol
esters: Ishiyama, T., et al., J. Org. Chem. 1995, 60, 7508-7510,
Ishiyama, T., et al., Tetrahedron Letters 1997, 38, 3447-3450;
coupling pinacol esters: Firooznia, F. et al., Tetrahedron Letters
1999, 40, 213-216, Manickam, G. et al., Synthesis 2000, 442-446;
all four citations incorporated herein by reference). In the
example for aryl (268) when R.sub.150 is a triflate, it can easily
be obtained by known methods from the corresponding phenol.
[0181] Biaryl (270) can also be acylated, for example by the
Friedel-Crafts Acylation reaction (using an acid chloride) or the
like to give biaryl (266) where R.sub.109 is not hydrogen.
Alternatively, in a two step manner, biaryl (270) is formylated by
first performing a halogenation step to give biaryl (272), such as
a bromination, followed by a halogen-metal exchange reaction using
an alkyl lithium or lithium tributylmagnesate complex as described
by lida, et. al. in Tetrahedron Letters 2001, 42, 4841-4844 and
reaction with DMF or equivalent known in the art to give biaryl
(266) where R.sub.109 is H. The carbonyl group of biaryl (266) can
subsequently be condensed with a heterocycle possessing an active
methylene moiety, such as 2,4-thiazolidinedione,
2-thioxo-thiazohdine-4-one, 2,4-imidazolidinedione or
2-thioxo-imidazolidine-4-one to give benzylidene (274). The
carbonyl group of biaryl (266) can also be reduced, such as with
sodium borohydride, diisobutyl aluminum hydride, or the like, to
give benzyl alcohol (276, R.sub.160=OH) and converted to benzyl
bromide (278, R.sub.160=Br) with HBr or some other method known in
the art, such as PPh.sub.3/CBr.sub.4 or converted to another
leaving group, such as, for example, mesylate or iodide. Benzyl
bromide (278, R.sub.160=Br) or like compound is allowed to react
with the anion(s) of 2,4-thiazolidinedione to give biaryl [(280),
where: W=--C(O)--, X=--NH--, Y=--C(O)-- and Z=--S--]. Similarly,
anions of other heterocycles disclosed herein can be used.
Alternative, biaryl [(280), where: W=--C(O)--, X=--NH--, Y=--C(O)--
and Z=--S--] can be prepared by a reduction of benzylidene [(274),
where: W=--C(O)--, X=--NH--, Y=--C(O)-- and Z=--S--] using methods
known in the art, such as hydrogenation in the presence of Pd/C,
Mg/MeOH, LiBH.sub.4 in THF/pyridine and the like. A number of
methods suitable for reducing benzylidene compounds to benzyl
compounds (including hydrogenation, reaction with metal hydride
reagents, or dissolving metal reductions) are known to those of
skill in the art, and those methods can be applied in the methods
of the instant invention.
[0182] In an alternative manner, the coupling can take place
between aryl (282), such as where R.sub.150=Br, I, Cl, triflate or
the like, and boronic acid (284, R.sub.140=H or alkyl) to give the
above mention biaryl (266). Also aryl (282) can be coupled with
boronic acid (286) to give biaryl (270). Employing the same
strategy as described above biaryl (270) can be converted to biaryl
(266).
[0183] Coupling of two aryl rings can be conducted using an aryl
boronic acid or esters with an aryl halide (such as, iodo, bromo,
or chloro), triflate or diazonium tetrafluoroborate; as described
respectively in Suzuki, Pure & Applied Chem., 66:213-222
(1994), Miyaura and Suzuki, Chem. Rev. 95:2457-2483 (1995),
Watanabe, Miyaura and Suzuki, Synlett. 207-210 (1992), Littke and
Fu, Angew. Chem. Int. Ed., 37:3387-3388 (1998), Indolese,
Tetrahedron Letters, 38:3513-3516 (1997), Firooznia, et. al.,
Tetrahedron Letters 40:213-216 (1999), and Darses, et. al., Bull.
Soc. Chim. Fr. 133:1095-1102 (1996); all incorporated herein by
reference. According to this coupling reaction, precursors such as
(262) and (264) can be employed: ##STR51## where R.sub.140 is
either alkyl, cycloalkyl (i.e., pinacol) or hydrogen and R.sub.150
is a halide (such as, iodo, bromo, or chloro), triflate or
diazonium tetrafluoroborate. Alternately, it is understood that the
coupling groups can be reversed, such as the use of (282) and
(284), to achieve the same coupling product: ##STR52## where
R.sub.140 and R.sub.150 have the same meaning as described above.
The preparation of the above mentioned precursors can be prepared
by methods readily available to those skilled in the art. For
example, the boronic ester can be prepared from aryl (282, where
R.sub.150=halide) by conversion of the halide to the corresponding
aryl lithium, followed by treatment with a trialkyl borate. Methods
are know in the art to prepare pinacol boronic esters from
triflates such as aryl (282, where R.sub.150=triflate). The
coupling reaction can also be conducted between an arylzinc halide
and an aryl halide or triflate. Alternately, the coupling reaction
can also be executed using an aryl trialkyltin derivative and an
aryl halide or triflate. These coupling methods are reviewed by
Stanforth, Tetrahedron 54:263-303 (1998) and incorporated herein by
reference. In general, the utilization of a specific coupling
procedure is selected with respect to available precursors,
chemoselectivity, regioselectivity and steric considerations.
[0184] Condensation of the biaryl carbonyl containing derivatives
(e.g., FIG. 9, compound (266)) with a suitable active methylene
compound, such as, 2,4-thiazolidinedione, can be accomplished by
the use of methods known in the art. For example, the biaryl
carbonyl product from the coupling reaction can be condensed with
an active methylene compound to give a benzylidene compound of
Formula (200) (i.e., ----- is a bond) as described by Tietze and
Beifuss, Comprehensive Organic Synthesis (Pergamon Press),
2:341-394, (1991), incorporated herein by reference. It is
understood by those skilled in the art that intermediates having
hydroxyl groups bonded thereto can be formed during condensation of
a biaryl carbonyl containing derivative and an active methylene
compound, as shown below. ##STR53##
[0185] The hydroxyl groups of intermediates (267) are often
eliminated (as water) during the condensation reaction, to form the
desired benzylidene compound. Nevertheless, the conditions of the
reaction can be modified for the isolation or further use of
hydroxyl containing intermediates, and such embodiments are within
the scope of the invention. Effective catalysts for the
condensation can be selected from ammonia, primary, secondary and
tertiary amines, either as the free base or the amine salt with an
organic acid, such as acetic acid. Examples of catalysts include
pyrrolidine, piperidine, pyridine, diethylamine and the acetate
salts thereof. Inorganic catalysts can also be used for the
condensation. Inorganic catalysts include, but are not limited to,
titanium tetrachloride and a tertiary base, such as pyridine; and
magnesium oxide or zinc oxide in an inert solvent system. This type
of condensation can be strongly solvent-dependent and it is
understood that routine experimentation may be necessary to
identify the optimal solvent with a particular catalyst, preferable
solvents include ethanol, tetrahydrofuran, dioxane or toluene; or
mixtures thereof.
[0186] In view of the teachings and disclosure above, in some
aspects, the invention relates to methods for preparing the
compounds of the invention, wherein the method comprises [0187] a)
coupling [0188] i) an Ar.sub.5 precursor compound having the
structure: ##STR54## [0189] ii) with an Ar.sub.6 precursor compound
having the structure: ##STR55## [0190] iii) to form a carbonyl
containing precursor compound having the structure: ##STR56##
[0191] b) further reacting the carbonyl containing precursor
compound so as to connect to the carbonyl of the carbonyl
containing precursor an HAr heterocycle.
[0192] The methods of making the compounds of the invention further
comprise steps wherein the further reacting comprises condensing
the carbonyl containing precursor compound with a compound having
the structure ##STR57##
[0193] As is understood by those of ordinary skill in the art of
synthetic organic chemistry, the various synthetic strategies,
organic reactions, and/or functional group transformations utilized
herein can be performed by a number of strategies, reactions, or
procedures other than those explicitly described above. References
for other synthetic procedures that can be utilized for the
synthetic steps leading to the compounds disclosed herein can be
found in, for example, March, J., Advanced Organic Chemistry,
4.sup.th Edition, Weiley-Interscience (1992); or Larock, R. C.,
Comprehensive Organic Transformations, A Guide to Functional Group
Preparations, VCH Publishers, Inc. (1989), both incorporated herein
by reference.
Pharmaceutical Compositions
[0194] Although the compounds described herein can be administered
as pure chemicals, it is preferable to present the active
ingredient as a pharmaceutical composition. Thus another embodiment
is the use of a pharmaceutical composition comprising one or more
compounds and/or a pharmaceutically acceptable salt thereof,
together with one or more pharmaceutically acceptable carriers
thereof and, optionally, other therapeutic and/or prophylactic
ingredients. The carrier(s) must be `acceptable` in the sense of
being compatible with the other ingredients of the composition and
not overly deleterious to the recipient thereof.
[0195] Pharmaceutical compositions include those suitable for oral,
enteral, parental (including intramuscular, subcutaneous and
intravenous), topical, nasal, vaginal, ophthalinical, sublingually
or by inhalation administration. The compositions can, where
appropriate, be conveniently presented in discrete unit dosage
forms and can be prepared by any of the methods well known in the
art of pharmacy. Such methods include the step of bringing into
association the active compound with liquid carriers, solid
matrices, semi-solid carriers, finely divided solid carriers or
combination thereof, and then, if necessary, shaping the product
into the desired delivery system.
[0196] Pharmaceutical compositions suitable for oral administration
can be presented as discrete unit dosage forms such as hard or soft
gelatin capsules, cachets or tablets each containing a
predetermined amount of the active ingredient; as a powder or as
granules; as a solution, a suspension or as an emulsion. The active
ingredient can also be presented as a bolus, electuary or paste.
Tablets and capsules for oral administration can contain
conventional excipients such as binding agents, fillers,
lubricants, disintegrants, or wetting agents. The tablets can be
coated according to methods well known in the art., e.g., with
enteric coatings.
[0197] Oral liquid preparations can be in the form of, for example,
aqueous or oily suspensions, solutions, emulsions, syrups or
elixirs, or can be presented as a dry product for constitution with
water or other suitable vehicle before use. Such liquid
preparations can contain conventional additives such as suspending
agents, emulsifying agents, non-aqueous vehicles (which can include
edible oils), or one or more preservative.
[0198] The compounds can also be formulated for parenteral
administration (e.g., by injection, for example, bolus injection or
continuous infusion) and can be presented in unit dose form in
ampules, pre-filled syringes, small bolus infusion containers or in
multi-does containers with an added preservative. The compositions
can take such forms as suspensions, solutions, or emulsions in oily
or aqueous vehicles, and can contain formulatory agents such as
suspending, stabilizing and/or dispersing agents. Alternatively,
the active ingredient can be in powder form, obtained by aseptic
isolation of sterile solid or by lyophilization from solution, for
constitution with a suitable vehicle, e.g., sterile, pyrogen-free
water, before use.
[0199] For topical administration to the epidermis, the compounds
can be formulated as ointments, creams or lotions, or as the active
ingredient of a transdermal patch. Suitable transdermal delivery
systems are disclosed, for example, in Fisher et al. (U.S. Pat. No.
4,788,603, incorporated herein by reference) or Bawas et al. (U.S.
Pat. Nos. 4,931,279, 4,668,504, and 4,713,224; all incorporated
herein by reference). Ointments and creams can, for example, be
formulated with an aqueous or oily base with the addition of
suitable thickening and/or gelling agents. Lotions can be
formulated with an aqueous or oily base and will in general also
contain one or more emulsifying agents, stabilizing agents,
dispersing agents, suspending agents, thickening agents, or
coloring agents. The active ingredient can also be delivered via
iontophoresis, e.g., as disclosed in U.S. Pat. Nos. 4,140,122,
4,383,529, or 4,051,842; incorporated herein by reference.
[0200] Compositions suitable for topical administration in the
mouth include unit dosage forms such as lozenges comprising active
ingredient in a flavored base, usually sucrose and acacia or
tragacanth; pastilles comprising the active ingredient in an inert
base such as gelatin and glycerin or sucrose and acacia;
mucoadherent gels, and mouthwashes comprising the active ingredient
in a suitable liquid carrier.
[0201] When desired, the above-described compositions can be
adapted to provide sustained release of the active ingredient
employed, e.g., by combination thereof with certain hydrophilic
polymer matrices, e.g., comprising natural gels, synthetic polymer
gels or mixtures thereof. The pharmaceutical compositions according
to the invention can also contain other adjuvants such as
flavorings, coloring, antimicrobial agents, or preservatives.
[0202] Therefore, in some embodiments the invention relates to a
pharmaceutical composition comprising one or more pharmaceutically
acceptable carriers and one or more compounds of the invention, or
a pharmaceutically acceptable salt thereof, in an amount that can
be used to effectively treat diabetes, cancer, or atherosclerosis,
or modulate lipid metabolism, carbohydrate metabolism, lipid and
carbohydrate metabolism, or adipocyte differentiation, in a
mammal.
Biological Activity Testing for Compounds of the Invention
[0203] The compounds of the present invention have been found to be
potent compounds in a number of biological assays, both in vitro
and in vivo, that correlate to, or are representative of, human
diseases.
[0204] For instance, many of the compounds of the invention can
induce the differentiation of preadipocytes into adipocytes. This
biological activity (Harris and Kletzien, Mol. Pharmacol.,
45:439-445 (1994); Wilson et al., J. Med. Chem. 39:665-668 (1996))
has been observed for certain compounds that have antidiabetic
activity in humans (Teboul et al., J. Biol. Chem. 270:28183-28187
(1995)) and has been used by many in the art to screen new
compounds for anti-diabetic activity. The ability of the compounds
to induce cells of the adipocyte lineage to differentiate can also
correlate to the ability of the compounds to treat or prevent other
diseases including proliferative diseases such as breast, prostate
and other cancers.
[0205] The compounds of the invention have been screened in an
in-vitro adipocyte differentiation assay, as described in Example
26. Mouse pre-adipocyte 3T3-L1 cells were treated with compounds at
concentrations less than or equal to 10.sup.-6 M for 7 days.
Pre-adipocyte cells that become differentiated into adipocytes
begin to accumulate lipids, and accordingly can exhibit an increase
in lipid content. Results from the testing are shown in FIG. 1,
wherein the lipid content of the cells after treatment with the
compounds of the invention is displayed as a function of the
identity of the compound and the concentration at which it was
applied. The relative lipid content of the cells is plotted in FIG.
1 relative to the results obtained by the application of compound
24, which has been shown to be a potent inducer of adipocyte
differentiation, and also a compound that is useful for the
treatment of diabetes.
[0206] As can be seen from FIG. 1 and/or Example 26, several of the
compounds whose preparation is documented in the examples induced
differentiation of the pre-adipocytes at concentrations ranging as
low as 1.times.10.sup.-10 Molar, and hence showed a positive
indication of biological activity sufficient to justify further
in-vivo testing.
[0207] In order to demonstrate the activity of the various
compounds of the invention for effectiveness and/or activity for
adipocyte differentiation, the compound can be applied at a
concentration of about 1.times.10.sup.-6 M for a period of about 7
days, to mouse preadipocyte 3T3-L1 cells, and measure the increase
the lipid content of the cells. The compounds can be considered
active for adipocyte differentiation if the lipid accumulation
induced is at least about 20%, or at least about 40% of the lipid
accumulation induced by
5-[3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-trifluo-
romethoxy-benzylidene]-thiazolidine-2,4-dione when it is applied to
control cultures of mouse preadipocyte 3T3-L1 cells at a
concentration of about 1.times.10.sup.-7 M.
[0208] The ability of the compounds to function as antidiabetic
agents can be demonstrated in-vivo in certain known animal models
for type 2 diabetes [Coleman, D. L, Diabetes, vol. 31, suppl 1, pp
1-6, (1982); Chang A. Y. et al, diabetes, pp 466-470, (1986)].
These known animal models include among others, db/db mice, ob/ob
mice, and KKA.sup.y mice.
[0209] Diabetes and Lipid Metabolism Efficacy Testing in KKA.sup.y
Mice (See Results in FIGS. 2a-e and Example 27.)
[0210] Of the three mouse models, the KKA.sup.y mice exhibit the
most severe symptoms of type 2 diabetes, including hyperglycemia,
hypertriglyceridemia and hypercholesterolemia, and therefore are
often the most difficult to treat.
[0211] As can be readily seen from FIGS. 2a-2e, the compounds of
the invention were found to be very effective for simultaneously
and beneficially decreasing serum glucose, serum triglyceride,
and/or serum cholesterol in KKA.sup.y Mice.
[0212] Diabetes and Lipid Metabolism Efficacy Testing in db/db
Mutant Mice
[0213] (See Results in FIG. 3 and Example 28).
[0214] While both db/db mice, ob/ob mice are considered model of
type 2 diabetes, the severity of the disease in these models is
less pronounced than in KKA.sup.y mice. They are however still used
as tools to demonstrate the efficacy of the compounds in treating
type 2 diabetes. As can be readily seen from FIG. 3, Compound 25
was found to be effective very for simultaneously and beneficially
decreasing serum glucose and serum triglycerides in db/db Mice.
[0215] Activity for Inducing Cholesterol Efflux from Macrophage
Foam Cells
[0216] (See Results in FIG. 4 and Example 29)
[0217] Elevated levels of cholesterol lead to atherosclerosis and
heart disease, which in many type 2 diabetes patients is the cause
of death. Atherosclerotic lesions results from Cholesterol-loaded
macrophage foam cells [Gown et al. (1986) Am. J. Phathol. 125,
191-207]. In vitro, macrophages that are cholesterol-loaded in cell
culture can unload excess cholesterol, which can be measured in a
"Cholesterol Efflux Assay" (see example 29). The cholesterol
released from the Macrophage Foam Cells can be metabolized by the
liver and eliminated from the body. Therefore, novel therapeutic
agents that increase cholesterol efflux from macrophages in
arteriosclerotic lesions can improve the outcome for patients with
coronary artery disease such as in obese and diabetes patients.
[0218] As can be readily seen from FIG. 4, Compound 2 was found to
be very effective for inducing cholesterol efflux from Macrophage
Foam Cells, this indicating its use for the control and/or
treatment of atherosclerosis.
[0219] Activity for Modulation of HDL and LDL Cholesterol Levels in
Diet Induced Hypercholesterolemic Sprague Dawley Rats
[0220] (See Results in FIG. 5 and Example 30.)
[0221] The ability of a compound to reduce certain lipids such as
cholesterol or to change the ratio of good versus bad cholesterol,
i.e. HDL versus LDL, can be measured in animal models. One animal
model commonly used for such testing is the diet-induced
hypercholesterolemic wild type Sprague Dawley rat (see example
30).
[0222] As can be readily seen from FIG. 5a-c, Compounds 2, 6, and
25 were found to provide unexpectedly beneficial modulation of HDL
and LDL cholesterol levels in diet-induced hypercholeterolemic
Sprague Dawley Rats, thus indicating significant potential for the
control and/or treatment of atherosclerosis in diabetes
patients.
[0223] Effect on Breast Cancer Tumor Progression Caucinogen Induced
Mammary Tumors in Wild Type Sprague Dawley Rats
[0224] (See Results in FIG. 6 and Example 31.)
[0225] The ability of the compounds to function as anti-breast
cancer agents can be demonstrated in vivo in carcinogen induced
mammary tumors in wild type Sprague Dawley Rats [Thompson H. J et
al, Carcinogenesis, 13(9), 1535-1539 (1992)].
[0226] As can be readily seen from FIG. 6, Compounds 6, 11, 13, and
25 were unexpectedly found to slow or cause regression in the
growth of breast cancer tumors in Sprague Dawley Rats, thus
indicating significant potential for the control and/or treatment
of breast cancer in humans.
[0227] Comparison of Oral Bioavailability of Comparative Compound
24 and Compound 25.
[0228] (See Results in FIG. 7 and Example 32.)
[0229] Oral bioavailability is an important pharmaceutical
characteristic for a compound to advance through drug development.
A basic assessment of the oral bioavailability of a compound can be
done in a single dose pharmacokinetic study in wild type rats.
[0230] As can be readily seen from FIG. 7, Compounds 25 exhibit
unexpectedly superior bioavailability as compared to Compound
24.
Methods of Treating Diseases
[0231] Compounds disclosed herein are useful, for example, to
modulate metabolism (such as, for example, lipid metabolism and
carbohydrate metabolism) or adipocyte differentiation. Changes in
carbohydrate metabolism can directly or indirectly also result in
changes of lipid metabolism and, similarly, changes in lipid
metabolism can lead to changes in carbohydrate metabolism. An
example is type 2 diabetes where an increase in free fatty acids in
the patients leads to decreased cellular uptake and metabolism of
glucose.
[0232] Carbohydrate metabolism can be up-regulated or
down-regulated to either approach the level of carbohydrate
metabolism in a control or to deviate from the level of
carbohydrate metabolism in a control. For example, the compounds of
the invention can be effective to lower serum glucose levels of
KKA.sup.y or db/db mice maintained on a high fat diet by at least
about 5%, or at least about 10%, when orally administered to the
mice at a concentration of about 0.3 mg/kg for 7 days, as compared
to control mice that do not receive the compounds.
[0233] As a result of their activity for regulating carbohydrate
metabolism, the compounds of the invention can be effective for
treating type 2 diabetes. Therefore, in some embodiments, the
invention relates to methods of treating type 2 diabetes comprising
administering to a mammal diagnosed as needing such treatment,
including humans, one or more compounds of the invention, or a
pharmaceutically acceptable salt thereof, in an amount effective to
treat type 2 diabetes. In some embodiments, the one or more
compounds or salts are applied in an amount effective to decrease
blood glucose levels in the mammal by at least about 5%, or at
least about 10%.
[0234] Modulation of lipid metabolism, for example, can include an
increase of lipid content intracellularly or extracellularly.
Modulation, for example, could involve increase in lipid
metabolism, such that lipid metabolism is greater than that of a
control. Modulation, also includes, for example, an increase in
lipid metabolism, such that the lipid metabolism approaches that of
a control. For example, the compounds of the invention and their
pharmaceutically acceptable salts can be employed to induce
cholesterol efflux from Macrophage Foam Cells as described in
Example 29, in order to treat atherosclerosis.
[0235] Modulation of lipid metabolism could also include a decrease
of lipid content intracellularly or extracellularly. Modulation of
metabolism can occur directly for example, through binding of the
compound of the invention with its cognate receptor, which directly
affects an increase or decrease in lipid content by up-regulation
or down-regulation of a gene involved in lipid metabolism.
Modulation of metabolism can also occur indirectly, for example,
through binding of the compound of the invention with its cognate
receptor, which up-regulates or down-regulates cellular
differentiation or growth of cells that produce lipids, thereby
indirectly causing lipid metabolism to be modulated. As shown in
Examples 28 and 29, the compounds of the invention can be effective
to lower serum triglyceride levels of KKA.sup.y or db/db mice
maintained on a high fat diet by at least about 5%, or at least
about 10%, when orally administered to the mice at a concentration
of about 0.3 mg/kg for 7 days, as compared to control mice that do
not receive the compounds.
[0236] Therefore, in some embodiments, the invention relates to
methods of treating dyslipidemia comprising administering to a
mammal diagnosed as needing such treatment one or more compounds of
the invention, or a pharmaceutically acceptable salt thereof, in an
amount effective to decrease triglyceride levels in the animal. In
some such embodiments, the invention relates to such methods
wherein the one or more compounds or salts are applied in an amount
effective to decrease triglyeride levels by at least about 5%, or
at least about 10%.
[0237] As is well known, cholesterol is a lipid that is closely
linked with many biochemical functions, but also with diseases such
as atherosclerosis. As is illustrated in Examples 29 and 30, the
compounds of the invention can benefit modulate the level of
cholesterol, including its manifestations in the HDL and LDL forms.
Therefore, in some embodiments, the invention relates to a method
of treating hypercholesterolemia comprising administering to a
mammal diagnosed as needing such treatment one or more compounds
the invention, or a pharmaceutically acceptable salt thereof. In
some embodiments, the methods apply the one or more compounds or
salts in an amount effective to decrease serum cholesterol levels
by at least about 5%, or at least about 10%., or to increase the
concentration of HDL cholesterol, or decrease the concentration of
LDL cholesterol, or increase the HDL/LDL ratio by at least about
5%, or at least about 10%.
[0238] It is understood that a variety of lipid molecules can be
modulated. The compounds disclosed herein can modulate a single
type of lipid molecule, such as a triglyceride, or the compounds
disclosed herein can modulate multiple types of lipid molecules.
The compounds disclosed herein can also modulate a single or
variety of carbohydrate molecules. Unexpectedly, the compounds of
the invention can simultaneously and beneficially regulate
carbohydrate and lipid metabolism so as to simultaneously decrease
levels of serum glucose, serum triglycerides, and serum
cholesterol. Drugs having such a combination of beneficial
properties are of very high value for simultaneous treatment of
type 2 diabetes and/or its associated diseases, such as
atherosclerosis.
[0239] The amide compounds of the invention are also useful for
inducing adipocyte differentiation, which can produce a modulation
of the metabolism of lipids, including triglycerides and
cholesterol. As is shown in Example 26, the compounds of the
invention can be effective, when applied at a concentration of
about 1 uM for a period of about 7 days, to induce differentiation
of mouse preadipocyte 3T3-L1 cells so as to increase their lipid
content by at least about 20%, or at least about 40%, or at least
about 50%. Such activity for adipocyte differentiation is well
known to those of skill in the art to be associated with activity
for the treatment of diabetes, cancer, and/or inflammatory
diseases. Inflammatory responses of macrophage foam cells are known
to be involved in the formation atherosclerotic lesions. Without
wishing to be bound by theory, the compounds of the invention are
believed to be involved in lessening such inflammatory responses,
and/or inducing the macrophages to increase their release of
cholesterol, so as to lessen the buildup of cholesterol in blood
vessel walls. Therefore, the compounds of the invention are
unexpectedly useful in treating diabetes and simultaneously
treating the atherosclerosis, which often occurs in diabetic
patients.
[0240] The compounds of the invention are also useful for treating
diseases of uncontrolled cellular proliferation, for which chronic
inflammatory responses are known to be a factor, including various
cancers. The composition can be useful in the treatment of
polycystic kidney disease and cancers such as, carcinomas,
lymphomas, leukemias, and sarcomas. A representative but
non-limiting list of cancers is lymphoma, Hodgkin's disease,
myeloid leukemia, bladder cancer, brain cancer, head and neck
cancer, kidney cancer, lung cancers such as small cell lung cancer
and non-small cell lung cancer, myeloma,
neuroblastoma/glioblastoma, ovarian cancer, pancreatic cancer,
prostate cancer, skin cancer, liver cancer, melanoma, colon cancer,
cervical carcinoma, breast cancer, and epithelial cancer. Compounds
disclosed herein can also be used for the treatment of inflammatory
diseases such as osteoarthritis, rheumatoid arthritis, Crohn's
Disease, pulmonary fibrosis, and Inflammatory Bowel Disease.
[0241] Therefore, in some embodiments, the invention relates to
method of treating cancer comprising administering to a mammal
diagnosed as needing such treatment one or more compounds of the
invention, or a pharmaceutically acceptable salt thereof, in an
amount effective to treat the cancer. In some embodiments the
cancer treated is breast cancer.
[0242] The compounds of the invention have suitably low molecular
weights and good physiological stability. The compounds of the
invention also have excellent oral bio-availability, as illustrated
in Examples 27, 28, 30, 31, and 32, and therefore, represent a
class that have superior pharmacological and physical properties
that can be readily implemented to prevent, alleviate, and/or
otherwise, treat disorders of lipid and carbohydrate metabolism,
such as obesity, dyslipidemia, type 2 diabetes and other diseases
related to type 2 diabetes.
[0243] A preferred embodiment of the invention relates to the use
of the compounds disclosed herein. The compounds disclosed herein
can be either used singularly or plurally, and in pharmaceutical
compositions thereof for the treatment of mammalian diseases,
particularly those related to humans. Compounds disclosed herein
and compositions thereof can be administered by various methods
including, for example, orally, enterally, parentally, topically,
nasally, vaginally, ophthalinically, sublingually or by inhalation
for the treatment of diseases related to lipid metabolism,
carbohydrate metabolism, lipid and carbohydrate metabolism such as
polycystic ovary syndrome, syndrome X, type 2 diabetes, including
disorders related to type 2 diabetes such as, diabetic retinopathy,
neuropathy, macrovascular disease or differentiation of adipocytes.
Routes of administration and dose ages known in the art can be
found in Comprehensive Medicinal Chemistry, Volume 5, Hansch, C.
Pergamon Press, 1990; incorporated herein by reference.
[0244] It will be further appreciated that the amount of the
compound, or an active salt or derivative thereof, required for use
in treatment will vary not only with the particular salt selected
but also with the route of administration, the nature of the
condition being treated and the age and condition of the patient
and will be ultimately at the discretion of the attendant physician
or clinician.
[0245] In general, one of skill in the art understands how to
extrapolate in vivo data obtained in a model organism, such as an
ob/ob or db/db mouse, to another mammal, such as a human. These
extrapolations are not simply based on the weights of the two
organisms, but rather incorporate differences in metabolism,
differences in pharmacological delivery, and administrative routes.
Based on these types of considerations, a suitable dose will, in
alternative embodiments, typically be in the range of from about
0.5 to about 100 mg/kg/day, from about 1 to about 75 mg/kg of body
weight per day, from about 3 to about 50 mg per kilogram body
weight of the recipient per day.
[0246] The compound is conveniently administered in unit dosage
form; for example, in alternative embodiments, containing 0.5 to
1000 mg, 5 to 750 mg, most conveniently, or 10 to 500 mg of active
ingredient per unit dosage form.
[0247] One skilled in the art will recognize that dosage and dosage
forms outside these typical ranges can be tested and, where
appropriate, be used in the methods of this invention.
[0248] In separate embodiments, the active ingredient can be
administered to achieve peak plasma concentrations of the active
compound of from about 0.5 to about 75 .mu.M, about 1 to 50 .mu.M,
or about 2 to about 30 .mu.M. This can be achieved, for example, by
the intravenous injection of a 0.05 to 5% solution of the active
ingredient, optionally in saline, or orally administered as a bolus
containing about 0.5-500 mg of the active ingredient. Desirable
blood levels can be maintained by continuous infusion to provide
about 0.01-5.0 mg/kg/hr or by intermittent infusions containing
about 0.4-15 mg/kg of the active ingredients.
[0249] The desired dose can conveniently be presented in a single
dose or as divided doses administered at appropriate intervals, for
example, as two, three, four or more sub-doses per day. The
sub-dose itself can be further divided, e.g., into a number of
discrete loosely spaced administrations; such as multiple
inhalations from an insufflator or by application of a plurality of
drops into the eye.
[0250] While the invention has been described in connection with
specific embodiments thereof, it will be understood that it is
capable of further modifications and this application is intended
to cover any variations, uses, or adaptations of the invention
following, in general, the principles of the invention and
including such departures from the present disclosure as come
within known or customary practice within the art to which the
invention pertains and as can be applied to the essential features
hereinbefore set forth, and as follows in the scope of the appended
claims.
[0251] The following examples are given to illustrate the invention
and are not intended to be inclusive in any manner:
EXAMPLES
Example 1
5-[3-(1,4,4,6-Tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-triflu-
oromethoxy-benzylidene]-thiazolidine-2,4-dione, which can be
referred to as "Compound 1"
[0252] ##STR58##
[0253] A mixture of toluene (80 mL), piperidine (380 .mu.L), acetic
acid (380 .mu.L),
3-(1,4,4,6-Tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluor-
omethoxy-benzaldehyde (7.5 g, 19.16 mmol) and 2,4-thiazolidinedione
(2.25 g, 19.16 mmol) was heated at reflux overnight. The reaction
mixture was cooled to room temperature, diluted with ethyl acetate
and washed with water and brine, dried over MgSO.sub.4. The residue
was recrystallized successively from ethanol,
dichloromethane/hexane and ethanol to afford 4.3 g (46%) of
5-[3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifl-
uoromethoxy-benzylidene]-thiazolidine-2,4 dione. mp 182-184.degree.
C. .sup.1H-NMR (300 MHz, DMSO-d-6): 1.27 (s, 6H), 2.08 (s, 3H),
2.49 (s, 2H), 3.25 (s, 3H), 6.93 (s, 1H), 7.31 (s, 1H), 7.66 (s,
1H), 7.67 (d, J=7.6 Hz, 1H), 7.75 (dd, J=7.6 and 1.7 Hz, 1H), 7.84
(s, 1H), 12.71 (br s, 1H).
[0254] The intermediate
3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluor-
omethoxy-benzaldehyde was prepared as follows:
[0255] a.
3-(1,4,4,6-Tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)--
4-trifluoromethoxy-benzaldehyde.
[0256] A mixture of 3-formyl-6-trifluoromethoxy-1-phenyl boronic
acid (3.14 g, 13.42 mmol),
7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one (3.15 g,
11.19 mmol) and potassium carbonate (3.1 g, 22.38 mmol) in toluene
(35 mL), ethanol (11.8 mL) and water (7.3 mL) was degassed with
argon for 15 minutes. Tetrakis(triphenylphosphine)palladium(0)
(0.259 g, 0.02 mmol) was added and the mixture heated at reflux
under argon overnight. The solution was cooled to room temperature,
diluted with ethyl acetate and washed successively with water and
brine, dried over anhydrous magnesium sulfate, filtered and
evaporated. The residue was purified on silica gel (20 to 30% ethyl
acetate in hexane) to give 2.34 g of
3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluor-
omethoxy-benzaldehyde (54%). .sup.1H NMR (300 MHz; CDCl.sub.3):
1.35 (s, 6H), 2.11 (s, 3H), 2.55 (s, 2H), 3.35 (s, 3H), 6.79 (s,
1H), 7.20 (s, 1H), 7.54 (dd, J=3 and 8.4 Hz, 1H), 7.85 (d, J=2.7
Hz, 1H), 7.90 (dd, J=2.1 and 8.7 Hz, 1H), 10.04 (s, 1H).
[0257] b. 3-formyl-6-trifluoromethoxy-1-phenyl boronic acid.
[0258] To a mixture of
2-(3-bromo-4-trifluoromethoxy-1-phenyl)-1,3-dioxolane (7.20 g, 22.9
mmol) in THF (70 mL) cooled to -78.degree. C. under an atmosphere
of argon was added n-BuLi (13.8 mL, 2.5 M, 34.4 mmol) dropwise. The
resulting suspension was stirred for 5 minutes and
triisopropylborate (15.9 mL, 68.7 mmol) was added dropwise via
syringe. The mixture was stirred at -50.degree. C. for 2 hours then
warmed up to room temperature and stirred overnight at room
temperature. 1.0 N HCl (50 mL) was slowly added to the reaction
mixture. After 3 hours the mixture was diluted with ethyl acetate
and the layers separated, the aqueous layer was extracted once with
ethyl acetate and the two organic layers combined. The resulting
organic layer was washed with water, brine and dried (MgSO.sub.4).
The mixture was filtered, evaporated and the residue stirred in
hexane. The resulting white suspension was filtered and the white
solid dried under high vacuum to afford 3.00 g of
3-formyl-6-trifluoromethoxy-1-phenyl boronic acid (56%). .sup.1H
NMR (300 MHz; CDCl.sub.3): .delta. 7.42 (d, J=7.0 Hz, 1H), 8.07
(dd, J.sub.1=2.1 Hz, J.sub.2=8.7 Hz, 1H), 8.47 (d, J=1.8 Hz, 1H),
10.05 (s, 1H).
[0259] c.
2-(3-bromo-4-trifluoromethoxy-1-phenyl)-1,3-dioxolane.
[0260] To a solution of 3-bromo-4-trifluoromethoxybenzaldehyde (20
g, 74.0 mmol) in toluene (200 mL) was added ethylene glycol (82.6
mL, 1.48 mol) and p-toluenesulfonic acid monohydrate (0.84 g, 4.44
mmol). The reaction mixture was heated at reflux overnight and the
water was removed using a Dean Stark apparatus. The solution was
cooled to room temperature, poured into aqueous potassium carbonate
(10%) and extracted with ethyl acetate. The organic layer was
washed with water, brine and dried (MgSO.sub.4). The residue was
purified on silica gel (eluent: 10% ethyl acetate in hexane) to
give 15.4 g of 2-(3-bromo-4-trifluoromethoxy)-1,3-dioxolane (66%).
.sup.1H NMR (500 MHz; CDCl.sub.3): .delta.4.05 (m, 2H), 4.11 (m,
2H), 5.79 (s, 1H), 7.32 (d, 1H), 7.43 (d, 1H), 7.77 (d, J=1.1 Hz,
1H).
[0261] d.
7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one.
[0262] A mixture of powdered KOH (14.06 g, 0.250 mol) in DMSO (150
mL) was stirred at 0.degree. C. for 10 min.
7-Bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (33.59 g,
0.125 mol) was added cautiously, followed immediately by the
addition of methyl iodide (39 mL, 0.625 mol). The reaction mixture
was kept at 0.degree. C. for 30 min then slowly warmed up to room
temperature and stirred overnight at room temperature. The reaction
mixture was poured into water and extracted with dichloromethane
washed with water and brine, dried (MgSO.sub.4), filtered and
evaporated to give 35.74 g of
7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one (99%)
and used without further purification in the Suzuki coupling (step
a). .sup.1H NMR (300 MHz; CDCl.sub.3): 1.27 (s, 6H), 2.37 (s, 3H),
2.48 (s, 2H), 3.35 (s, 3H), 7.12 (s, 1H), 7.16 (s, 1H).
[0263] e.
7-bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one.
[0264] To a solution of 3-methyl-but-2-enoic acid
(3-bromo-4-methyl-phenyl)-amide (70.0 g, 261 mmol) at 90.degree. C.
was added portion wise, under argon, with vigorous stirring
aluminum chloride (52.3 g, 391 mmol) over 1.5 hr. The reaction
mixture was stirred for 2 hours at 110-120.degree. C. The reaction
mixture was cooled to room temperature and ice-water was carefully
added. The solution was extracted with dichloromethane and the
organic washed with 2N HCl, water, saturated aqueous NaHCO.sub.3,
water and brine, dried (MgSO.sub.4), filtered and evaporated. The
residue was crystallized from dichloromethane/hexane to give 46 g
of 7-bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one. The
mother liquor was further chromatographed on silica gel (20% ethyl
acetate in hexane) to give 6.2 g more of product. (75%). .sup.1H
NMR (300 MHz; CDCl.sub.3): 1.30 (s, 6H), 2.33 (s, 3H), 2.46 (s,
2H), 7.07 (s, 1H), 7.10 (s, 1H), 9.87 (br s, 1H).
[0265] f. 3-Methyl-but-2-enoic acid
(3-bromo-4-methyl-phenyl)-amide.
[0266] To a biphasic mixture of 3-bromo-4-methylaniline (50 g,
0.269 mol), 10% NaOH (270 mL) and dichloromethane (160 mL) was
added dropwise over a period of 2 hours 3,3-dimethylacryloyl
chloride (36 mL, 0.322 mol) in dichloromethane (95 mL). The
solution was stirred at room temperature for 48 hours then diluted
with water (100 mL). The aqueous layer was further extracted with
dichloromethane. The organic layers were combined and washed with
water and brine, dried (MgSO.sub.4), filtered and evaporated. The
white solid was triturated with hexane and collected to give 70 g
(97%) of 3-Methyl-but-2-enoic acid (3-bromo-4-methyl-phenyl)-amide.
.sup.1H NMR (300 MHz; CDCl.sub.3): 1.89 (s, 3H), 2.21 (s, 3H), 2.33
(s, 3H), 5.68 (s, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.17 (br s, 1H),
7.33 (d, J=8.0 Hz, 1H), 7.79 (s, 1H).
[0267] g. 3-bromo-4-methylaniline.
[0268] To a solution of 2-bromo-4-nitrotoluene (50 g, 0.231 mol in
ethylacetate (330 mL) and Ethanol (150 mL) was added
Tin(II)chloride dihydrate (208 g, 0.924 mol) portionwise. The
reaction mixture was stirred at room temperature overnight. The
solution was then treated with potassium carbonate until pH=7 and
filtered over celite. The filtrate was washed with water, aqueous
NaHCO.sub.3, water and brine, dried (MgSO.sub.4), filtered and
evaporated to give 42.71 g (100%) of 3-bromo-4-methylaniline.
.sup.1H NMR (300 MHz; CDCl.sub.3): 2.27 (s, 3H), 3.57 (br s, 2H),
6.54 (dd, J=2.7 Hz and 8.1 Hz, 1H), 6.90 (d, J=2.1 Hz, 1H), 6.98
(d, J=8.1 Hz, 1H).
Example 2
5-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-tr-
ifluoromethoxy-benzylidene]-thiazolidine-2,4-dione, which can be
referred to as "Compound 2"
[0269] ##STR59##
[0270] Prepared in a similar manner to example 1 using
3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trif-
luoromethoxy-benzaldehyde. 56% yield after column chromatography on
silica gel (40% ethyl acetate in hexane). mp 156-154.degree. C.
.sup.1H-NMR (300 MHz, DMSO-d-6): 1.06 (t, J=7.5 Hz, 3H); 1.26 (s,
6H>, 2.08 (s, 3H), 2.46 (s, 2H), 3.95 (br d, 2H), 6.97 (s, 1H),
7.31 (s, 1H), 7.65 (s, 1H), 7.66 (dd, J=1.5 Hz and 9 Hz, 1H), 7.75
(dd, J=2.4 Hz and 8.7 Hz, 1H), 7.87 (s, 1H), 12.71 (br s, 1H).
[0271] The intermediate
3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trif-
luoromethoxy-benzaldehyde was prepared as follows:
[0272] a.
3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7--
yl)-4-trifluoromethoxy-benzaldehyde.
[0273] A mixture of 3-formyl-6-trifluoromethoxy-1-phenyl boronic
acid (Example 1b) (8.2 g, 34.84 mmol),
7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (8.6
g, 29.03 mmol) and potassium carbonate (8 g, 58.06 mmol) in toluene
(80 mL), ethanol (16 mL) and water (12 mL) was degassed with argon
for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (1.34 g,
0.04 mmol) was added and the mixture heated at reflux under argon
for 48 hrs. The solution was cooled to room temperature, diluted
with ethyl acetate and washed successively with water and brine,
dried over anhydrous magnesium sulfate, filtered and evaporated.
The residue was purified on silica gel (30% ethyl acetate in
hexane) to give 6.66 g of
3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trif-
luoromethoxy-benzaldehyde (57%). .sup.1H NMR (300 MHz; CDCl.sub.3):
1.20 (t, J=7.2 Hz, 3H), 1.33 (s, 6H), 1.62 (s, 3H), 2.10 (s, 3H),
2.53 (s, 2H), 4.00 (br d, 2H), 6.81 (s, 1H), 7.19 (s, 1H), 7.55
(dd, J=1.8 and 8.4 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.97 (dd, J=2.1
and 8.4 Hz, 1H), 10.05 (s, 1H).
[0274] b.
7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one.
[0275] A mixture of powdered potassium hydroxide (3.35 g, 59.67
mmol) in DMSO (40 mL) was stirred at 0.degree. C. for 10 min.
7-bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (Example 1e)
(8.0 g, 29.83 mmol) was added cautiously, followed immediately by
the addition of ethyl iodide (12 mL, 149.17 mmol). The reaction
mixture was kept at 0.degree. C. for 30 min then slowly warmed up
to room temperature and stirred overnight at room temperature. The
reaction mixture was poured into water and extracted with
dichloromethane washed with water and brine, dried (MgSO.sub.4),
filtered and evaporated to give 8.8 g of
7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one and used
without further purification in the Suzuki coupling (step a).
.sup.1H NMR (300 MHz; CDCl.sub.3): 1.24 (t, J=7.2 Hz, 1H), 1.25 (s,
6H), 2.37 (s, 3H), 2.45 (s, 2H), 3.98 (q, 2H), 7.13 (s, 1H), 7.18
(s, 1H).
Example 3
5-[4-Dimethylamino-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydroquinolin-
-7-yl)-benzylidene]-thiazolidine-2,4-dione, which can be referred
to as "Compound 3"
[0276] ##STR60##
[0277] Prepared in a similar manner to example 1 using
4-Dimethylamino-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin--
7-yl)-benzaldehyde. 73% yield after recrystallisation from ethanol.
mp 258-260.degree. C. .sup.1H NMR (300 MHz; DMSO) 1.25 (s, 3H);
1.27 (s, 3H), 2.07 (s, 3H), 2.47 (s, 2H), 2.59 (s, 6H), 3.26 (s,
3H), 6.96 (s, 1H), 7.10 (d, J=9 Hz, 1H), 7.24 (s, 1H), 7.28 (d,
J=2.1 Hz, 1H), 7.49 (dd, J.sub.1=2.1 Hz, J.sub.2=8.7 Hz, 1H), 7.73
(s, 1H), 12.44 (s, 1H).
[0278] The intermediate
4-Dimethylamino-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-
-yl)-benzaldehyde was prepared as followed:
[0279] a.
4-Dimethylamino-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-
-quinolin-7-yl)-benzaldehyde.
[0280] A mixture of 6-dimethylamino-3-formyl-1-phenyl boronic acid
(11.5 g, 59.5 mmol),
7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one (Example
1d) (14.0 g, 49.6 mmol) and potassium carbonate (13.7 g, 99.2 mmol)
in toluene (140 mL), ethanol (28 mL) and water (21 mL) was degassed
with argon for 40 minutes. Tetrakis(triphenylphosphine)palladium(0)
(3.5 g, 0.06 mmol) was added and the mixture heated at reflux under
argon for 24 hrs. The solution was cooled to room temperature,
diluted with ethyl acetate and washed successively with water and
brine, dried over anhydrous magnesium sulfate, filtered and
evaporated. The residue was purified on silica gel (30% ethyl
acetate in hexane) to give 14.66 g of
4-Dimethylamino-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin--
7-yl)-benzaldehyde (84%). .sup.1H NMR (300 MHz; CDCl.sub.3): 1.31
(s, 3H), 1.33 (s, 3H), 2.10 (s, 3H), 2.53 (s, 2H), 2.69 (s, 6H),
3.36 (s, 3H), 6.89 (s, 1H), 6.99 (d, J=8.7 Hz, 1H), 7.14 (s, 1H),
7.58 (d, J=2.4 Hz, 1H), 7.77 (dd, J=2.4 Hz and 8.4 Hz, 1H), 9.82
(s, 1H).
[0281] b. 6-dimethylamino-3-formyl-1-phenyl boronic acid.
[0282] To a mixture of
2-(3-bromo-4-dimethylamino-1-phenyl)-1,3-dioxolane (8.8 g, 32.34
mmol) in THF (80 mL) cooled to -78.degree. C. under an atmosphere
of argon was added n-BuLi (19.4 mL, 2.5 M, 48.50 mmol) dropwise.
The resulting suspension was stirred for 5 minutes and
triisopropylborate (22.4 mL, 97.0 mmol) was added dropwise via
syringe. The mixture was stirred at -50.degree. C. for 2 hours then
warmed up to room temperature and stirred overnight at room
temperature. 1.0 N HCl (50 mL) was slowly added to the reaction
mixture. After 4 hours 10% aqueous potassium carbonate was added to
the reaction mixture until pH=6-7. The solution was diluted with
ethyl acetate and the layers separated. The organic layer was
further washed with water, brine and dried (MgSO.sub.4). The
mixture was filtered and evaporated to afford 6.4 g of crude
6-dimethylamino-3-formyl-1-phenyl boronic acid used without further
purification in the Suzuki coupling (step a).
[0283] c. 2-(3-bromo-4-dimethylamino-1-phenyl)-1,3-dioxolane.
[0284] To a solution of 3-bromo-4-dimethylamino-benzaldehyde (10 g,
43.84 mmol) in toluene (80 mL) was added ethylene glycol (48.9 mL,
877 mmol) and p-toluenesulfonic acid monohydrate (0.5 g, 2.63
mmol). The reaction mixture was heated at reflux overnight and the
water was removed using a Dean Stark apparatus. The solution was
cooled to room temperature, aqueous potassium carbonate (10%) was
added and the solution extracted with ethyl acetate. The organic
layer was washed with water, brine and dried (MgSO.sub.4). The
residue was purified on silica gel (eluent: 10% ethyl acetate in
hexane) to give 10.84 g of
2-(3-bromo-4-dimethylamino-1-phenyl)-1,3-dioxolane. (90%). .sup.1H
NMR (300 MHz; CDCl.sub.3): .delta. 2.81 (s, 6H), 4.02 (m, 2H), 4.13
(m, 2H), 5.74 (s, 1H), 7.06 (d, J=8.1 Hz, 1H), 7.43 (dd, J=1.1 Hz
and 8.4 Hz, 1H), 7.69 (d, J=1.5 Hz, 1H).
[0285] d. 3-bromo-4-dimethylamino-benzaldehyde.
[0286] To a solution of 4-dimethylamino-benzaldehyde (10 g, 67.03
mmol) in dichloromethane (250 mL) was added pyridinium tribromide
(21.4 g, 67.03 mmol) and the reaction mixture stirred at room
temperature overnight. The solution was washed with water and
brine, dried (MgSO.sub.4), filtered and evaporated. The residue was
purified on silica gel (eluent: 15% ethyl acetate in hexane) to
give 14.06 g of 3-bromo-4-dimethylamino-benzaldehyde (92%). .sup.1H
NMR (300 MHz; CDCl.sub.3): .delta. 2.59 (s, 6H), 7.06 (d, J=8.1 Hz,
1H), 7.75 (dd, J=7.8 Hz and 1.5 Hz, 1H), 5.74 (s, 1H), 7.06 (d,
J=8.1 Hz, 1H), 7.43 (dd, J=2.1 Hz and 8.4 Hz, 1H), 8.04 (d, J=1.8
Hz, 1H), 9.81 (s, 1H).
Example 4
5-[4-Dimethylamino-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-qui-
nolin-7-yl)-benzylidene]-thiazolidine-2,4-dione, which can be
referred to as "Compound 4"
[0287] ##STR61##
[0288] Prepared in a similar manner to example 1 using
4-Dimethylamino-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quino-
lin-7-yl)-benzaldehyde. 61% yield after recrystallisation from
ethanol. mp 266-268.degree. C. .sup.1H-NMR (300 MHz, DMSO-d-6):
1.09 (t, J=6.6 Hz, 3H), 1.27 (2 s, 6H), 2.08 (s, 3H), 2.49 (d, 2H),
2.59 (s, 6H), 3.98 (m, 2H), 7.01 (s, 1H), 7.10 (d, J=8.7 Hz, 1H),
7.25 (s, 1H), 7.28 (d, J=2.4 Hz, 1H), 7.50 (dd, J.sub.1=7.7 Hz,
J.sub.2=2.1 Hz, 1H), 7.74 (s, 1H), 7.84 (s, 1H), 12.44 (br s,
1H).
[0289] The intermediate
4-Dimethylamino-3-(1-ethyl-4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-qui-
nolin-7-yl)-benzaldehyde was prepared in a similar manner to
example 3a using 6-dimethylamino-3-formyl-1-phenyl boronic acid
(example 3b) and
7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one
(example 2b). 59% yield. .sup.1H NMR (300 MHz; CDCl.sub.3): 1.21
(t, J=6.9 Hz, 3H), 1.32 (s, 6H), 2.12 (s, 3H), 2.52 (s, 2H), 2.70
(s, 6H), 4.09 (m, 2H), 6.93 (s, 1H), 6.98 (d, J=8.7 Hz, 1H), 7.16
(s, 1H), 7.59 (d, J=2.1 Hz, 1H), 7.77 (dd, J=2.1 Hz and 8.4 Hz,
1H), 9.84 (s, 1H).
Example 5
5-[3-(1,4,4,6-Tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-chloro-
-benzylidene]-thiazolidine-2,4-dione, which can be referred to as
"Compound 5"
[0290] ##STR62##
[0291] Prepared in a similar manner to example 1 using
4-chloro-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-b-
enzaldehyde. 50% yield after recrystallisation from ethanol. mp
176-178.degree. C. .sup.1H-NMR (300 MHz, DMSO-d-6): 1.25 (s, 3H),
1.28 (s, 3H), 2.07 (s, 3H), 2.50 (s, 2H), 3.24 (s, 3H), 7.90 (s,
1H), 7.29 (s, 1H), 7.56 (s, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.73 (d,
J=8.1 Hz, 1H), 7.83 (s, 1H), 12.68 (br s, 1H).
[0292] The intermediate
4-chloro-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-b-
enzaldehyde. was prepared as follows:
[0293] a.
4-chloro-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinol-
in-7-yl)-benzaldehyde.
[0294] A mixture of 6-chloro-3-formyl-1-phenyl boronic acid (1.18
g, 6.38 mmol),
7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one (Example
1d) (1.5 g, 5.32 mmol) and potassium carbonate (1.47 g, 10.64 mmol)
in toluene (15 mL), ethanol (3 mL) and water (2 mL) was degassed
with argon for 30 minutes. Pd (Ph.sub.3).sub.4 (0.123 g, 0.02 mmol)
was added and the mixture heated at reflux under argon overnight.
The solution was cooled to room temperature, diluted with ethyl
acetate and washed successively with water and brine, dried over
anhydrous magnesium sulfate, filtered and evaporated. The residue
was purified on silica gel (0 to 20% ethyl acetate in hexane) to
give 0.514 g of
4-chloro-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-b-
enzaldehyde (28%). .sup.1H NMR (300 MHz; CDCl.sub.3): 1.33 (s, 3H),
1.36 (s, 3H), 2.09 (s, 3H), 2.55 (2 s, 2H), 3.35 (s, 3H), 6.76 (s,
1H), 7.19 (s, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.77 (d, J=2.1 Hz, 1H),
7.97 (dd, J=2.1 and 8.4 Hz, 1H), 10.02 (s, 1H).
[0295] b. 6-chloro-3-formyl-1-phenyl boronic acid.
[0296] Prepared in a similar manner to example 1b using
2-(3-bromo-4-chloro-1-phenyl)-1,3-dioxolane e (70%). .sup.1H NMR
(300 MHz; DMSO-d.sub.6+1 drop of D.sub.2O): .delta. 7.61 (d, J=8.4
Hz, 1H), 7.84 (dd, J.sub.1=2.1 Hz, J.sub.2=8.4 Hz, 1H), 7.95 (d,
J=2.4 Hz, 1H), 10.0 (s, 1H).
[0297] c. 2-(3-bromo-4-chloro-1-phenyl)-1,3-dioxolane.
[0298] Prepared in a similar manner to example 1c using
3-bromo-4-chlorobenzaldehyde (90%). .sup.1H NMR (500 MHz;
CDCl.sub.3): .delta. 4.03 (m, 2H), 4.09 (m, 2H), 5.79 (s, 1H), 7.35
(dd, J=2.1 Hz and 8.4 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.74 (d,
J=2.1 Hz, 1H).
[0299] d. 3-bromo-4-chlorobenzaldehyde.
[0300] To a solution of 4-chlorobenzaldehyde (20.5 g, 0.142 mol) in
trifluoroacetic acid (83 mL) and sulfuric acid (16.6 mL) was added
N-bromosuccinimide (51.6 g, 0.288 mol) in portion over 6 hrs. The
reaction mixture was stirred at room temperature for 4 days. The
solution was poured on ice-water and extracted with
dichloromethane. The organic layer was washed with water, saturated
aqueous NaHCO.sub.3, water and brine, dried (MgSO.sub.4), filtered
and evaporated. The residue was taken up in hexane, filtered and
evaporated to give 20.4 g of crude 3-bromo-4-chlobenzaldehyde that
was used without purification in the next step (5c). .sup.1H NMR
(300 MHz; CDCl.sub.3): 7.62 (d, J=8.1 Hz, 1H), 7.80 (dd, J=2.1 and
8.4 Hz, 1H), 8.12 (d, J=1.5 Hz, 1H), 9.94 (s, 1H).
Example 6
5-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-ch-
loro-benzylidene]-thiazolidine-2,4-dione, which can be referred to
as "Compound 6"
[0301] ##STR63##
[0302] Prepared in a similar manner to example 1 using
4-chloro-3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-y-
l)-benzaldehyde. 41% yield after recrystallisation from ethanol. mp
221-223.degree. C. .sup.1H-NMR (300 MHz, DMSO-d-6): 1.07 (t, J=7.5
Hz, 3H), 1.26 (2 s, 6H), 2.05 (s, 3H), 2.46 (s, 2H), 2.50 (m, 2H),
3.95 (br d, 2H), 6.94 (s, 1H), 7.03 (s, 1H), 7.56 (d, J=2.1 Hz,
1H), 7.61 (dd, J=2.1 and 8.1 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.84
(s, 1H), 12.68 (br s, 1H).
[0303] The intermediate
4-chloro-3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl-
)-benzaldehyde was prepared in a similar manner as example 5a using
7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one
(example 2b) and 6-chloro-3-formyl-1-phenyl boronic acid (example
5b). Yield: 46%. .sup.1H NMR (300 MHz, CDCl.sub.3): 1.21 (t, J=6.9
Hz), 1.32 (s, 3H), 1.34 (s, 3H), 2.09 (s, 3H), 2.53 (2 s, 2H), 4.01
(m, 2H), 6.76 (s, 1H), 7.20 (s, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.77
(d, J=2.1 Hz, 1H), 7.84 (dd, J=2.1 and 8.4 Hz, 1H), 10.02 (s,
1H).
Example 7
5-[2-Fluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quin-
olin-7-yl)-benzylidene]-thiazolidine-2,4-dione, which can be
referred to as "Compound 7"
[0304] ##STR64##
[0305] Prepared in a similar manner to example 1 using
2-Fluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinol-
in-7-yl)-benzaldehyde. 64% yield. mp 271-276.degree. C. .sup.1H-NMR
(300 MHz, DMSO-d-6): 1.27 (s, 6H), 2.01 (s, 3H), 2.48 (s, 2H), 3.22
(s, 3H), 3.82 (s, 3H), 6.90 (s, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.28
(s, 1H), 7.58 (t, J=8.8 Hz, 1H), 7.76 (s, 1H), 12.66 (br s,
1H).
[0306] The intermediate
2-Fluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinol-
in-7-yl)-benzaldehyde was prepared as follows:
[0307] a.
2-Fluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahy-
droquinolin-7-yl)-benzaldehyde.
[0308] To a solution of
7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one (example
1d) (0.96 g, 3.40 mmol) in dioxane (2 mL) were added under argon,
triethylamine 1.9 mL, 13.61 mmol), palladium acetate (38 mg, 0.17
mmol), 2-(dicyclohexylphosphino) biphenyl (238 mg, 0.68 mmol) and
pinacolborane (1M in THF, 10.2 mL, 10.2 mmol). The mixture was
stirred at 80.degree. C. for 1 hr 45 min, then cooled to room
temperature. Water (1.5 mL), barium hydroxide octahydrate (3.22 g,
10.20 mmol) and 2-Fluoro-3-iodo-4-methoxy benzaldehyde dissolved in
dioxane (7 mL) were successively added and the mixture heated at
100.degree. C. for 13 hrs. The mixture was cooled to room
temperature and filtered over celite. Brine was added and the
aqueous layer was extracted with dichloromethane. The organic
extract was washed successively with water and brine, dried over
anhydrous magnesium sulfate, filtered and evaporated. The residue
was purified on silica gel (20% to 30% ethyl acetate in hexane) to
give 0.63 g of
2-Fluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinol-
in-7-yl)-benzaldehyde (52%). .sup.1H NMR (300 MHz; CDCl.sub.3):
1.33 (s, 3H), 1.35 (s, 3H), 2.09 (s, 3H), 2.54 (s, 2H), 3.35 (s,
3H), 3.87 (s, 3H), 6.79 (s, 1H), 6.92 (d, J=8.7 Hz, 1H), 7.21 (s,
1H), 7.94 (t, J=8.7 Hz, 1H), 10.25 (s, 1H).
[0309] b. 2-Fluoro-3-iodo-4-methoxy benzaldehyde.
[0310] To a solution of 3-fluoroanisole (24 g, 190 mmol) in
dichloromethane (350 mL) was added at room temperature pyridium
tribromide (61 g, 190 mmol). The reaction mixture was stirred at
room temperature for 24 hrs, then washed successively with water
and brine, dried (MgSO.sub.4), filtered and evaporated. The residue
was chromatographed on silica gel (10% ethyl acetate in hexane) to
give 34.5 g of 4-bromo-3-fluoro anisole (88%) use as this in the
next step. .sup.1H NMR (300 MHz; CDCl.sub.3): 3.79 (s, 3H), 6.62
(d, J=10 Hz, 1H), 6.71 (d, J=10 Hz, 1H), 7.40 (t, J=9 Hz, 1H),
10.25 (s, 1H).
[0311] To a solution of 4-bromo-3-fluoro anisole (34.4 g, 168 mmol)
in anhydrous THF (300 mL) was added dropwise, at -78.degree. C.
under argon, n-BuLi (2.5 M in THF, 101 mL, 252 mol). After 5 min
DMF (40 mL, 503 mmol) was added and the reaction micture was kept
at -78.degree. C. for 2 hrs. Aqueous NH.sub.4Cl (250 mL) was
carefully added and the layers separated. The aqueous phase was
further extracted with ethyl acetate. The organic phases were
combined and washed successively with water, brine and dried
(MgSO.sub.4). The residue was purified on silica get (eluent: 10%
ethyl acetate in hexane) to give 13.99 g of
2-fluoro-4-methoxy-benzaldehyde (54%). .sup.1H NMR (300 MHz;
CDCl.sub.3): 3.88 (s, 3H), 6.65 (d, J=12.3 Hz, 1H), 6.80 (d, J=8.7
Hz, 1H), 7.82 (t, J=8.7 Hz, 1H), 10.21 (s, 1H).
[0312] To a solution of 2-fluoro-4-methoxy-benzaldehyde (13.98 g,
90.7 mmol) in toluene (100 mL) was added ethylene glycol (101 mL,
1.81 mol) and p-toluenesulfonic acid monohydrate (1.04 g, 5.44
mmol). The reaction mixture was heated at reflux for 16 hrs. The
water was removed using a Dean Starck apparatus. After cooling,
aqueous potassium carbonate (10%, 200 mL) was added and the mixture
stirred for 30 minutes. The solution was extracted with ethyl
acetate. The organic phase was washed successively with 10% aqueous
potassium carbonate, brine and dried (MgSO.sub.4). The residue was
purified on silica gel (eluent: 10% ethyl acetate in hexane) to
give 9.187 g of 2-(2-fluoro-4-methoxy-phenyl)-[1,3] dioxolane
(51%). .sup.1H NMR (300 MHz; CDCl.sub.3): 3.81 (s, 3H), 4.06 (m,
2H), 4.15 (m, 2H), 6.03 (s, 1H), 6.60 (dd, J=12.3 and 2.7 Hz, 1H),
6.72 (d, J=8.4 Hz, 1H), 7.44 (t, J=8.4 Hz, 1H).
[0313] To a solution of 2-(2-fluoro-4-methoxy-phenyl)-[1,3]
dioxolane (4.27 g, 21.54 mmol) in anhydrous THF (30 mL) was added,
at -78.degree. C. under argon, n-BuLi (1.6 M in hexane, 13.5, 21.54
mmol). The resulting orange solution was stirred at -78.degree. C.
for 2 hours then iodine (6.015 g, 23.70 mmol) in THF (30 mL) was
added. At the end of the addition the reaction mixture was warmed
to room temperature and stirred for 1 hr. The solution was
extracted with ethyl acetate. The organic phase was washed
successively with 10% aqueous sodium thiosulfate (2.times.50 mL),
water, brine and dried (MgSO.sub.4), filtered and evaporated to
give 5.794 g of crude
2-(2-fluoro-3-iodo-4-methoxy-phenyl)-[1,3]dioxolane use as this in
the next step.
[0314] To a solution of 2-(2-fluoro-3-iodo-4-methoxy-phenyl)-[1,3]
dioxolane (5.284 g, 16.30 mmol) in acetone (170 mL) was added HCl
(1N, 170 mL) and the solution stirred at room temperature for 48
hrs. The solution was extracted with ethyl acetate and washed
successively with water, brine, dried (MgSO.sub.4), filtered and
evaporated. The residue was purified on silica gel (eluent: 10%
ethyl acetate in hexane) to give 2.22 g of
2-Fluoro-3-iodo-4-methoxy benzaldehyde (38% for 2 steps). .sup.1H
NMR (300 MHz; CDCl.sub.3): 4.00 (s, 3H), 6.74 (d, J=8.4 Hz, 1H),
7.88 (t, J=8.1 Hz, 1H), 10.21 (s, 1H).
Example 8
5-[3-(1-Propyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-t-
rifluoromethoxy-benzylidene]-thiazolidine-2,4-dione, which can be
referred to as "Compound 8"
[0315] ##STR65##
[0316] Prepared in a similar manner to example 1 using
3-(1-Porpyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-tri-
fluoromethoxy-benzaldehyde. 45% yield after crystallization from
ethyl acetate and hexane. mp 219-2230C. .sup.1H-NMR (300 MHz,
DMSO-d-6): 0.84 (t, J=7.2 Hz, 3H), 1.26 (s, 6H), 1.49 (m, 2H), 2.07
(s, 3H), 2.46 (s, 2H), 3.95 (br d, 2H), 6.97 (s, 1H), 7.31 (s, 1H),
7.63 (d, J=1.8 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.75 (dd,
J.sub.1=2.4 Hz, J.sub.2=8.7 Hz, 1H), 7.87 (s, 1H), 12.71 (br s,
1H). The intermediate
3-(1-propyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-tri-
fluoromethoxy-benzaldehyde was prepared as follows:
[0317] a.
3-(1-Propyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-
-yl)-4-trifluoromethoxy-benzaldehyde.
[0318] A mixture of 3-formyl-6-trifluoromethoxy-1-phenyl boronic
acid (Example 1b) (0.905 g, 3.87 mmol),
7-bromo-1-propyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one
(1.0 g, 3.22 mmol) and potassium carbonate (0.89 g, 6.44 mmol) in
toluene (10 mL), ethanol (2 mL) and water (1.5 mL) was degassed
with argon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0)
(0.186 g, 0.161 mmol) was added and the mixture heated at reflux
under argon for 24 hrs. The solution was cooled to room
temperature, diluted with ethyl acetate and washed successively
with water and brine, dried over anhydrous magnesium sulfate,
filtered and evaporated. The residue was purified on silica gel
(0-15% ethyl acetate in hexane) to give 0.70 g of
3-(1-propyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-tri-
fluoromethoxy-benzaldehyde (52%). .sup.1H NMR (300 MHz;
CDCl.sub.3): 0.92 (t, J=7.2 Hz, 3H), 1.33 (s, 6H), 1.61 (m, 5H),
2.09 (s, 3H), 2.53 (s, 2H), 3.95 (br d, 2H), 6.78 (s, 1H), 7.19 (s,
1H), 7.55 (d, J=8.1 Hz, 1H), 7.83 (d, J=2.1 Hz, 1H), 7.98 (dd,
J=2.1 and 8.74 Hz, 1H), 10.05 (s, 1H).
[0319] b.
7-bromo-1-propyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one-
.
[0320] A mixture of powdered potassium hydroxide (1.26 g, 22.38
mmol) in DMSO (40 mL) was stirred at 0.degree. C. for 10 min.
7-bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (Example 1e)
(3.0 g, 11.19 mmol) was added cautiously, followed immediately by
the addition of 1-iodopropane (5.5 mL, 55.95 mmol). The reaction
mixture was warmed up to room temperature and stirred overnight at
room temperature. The reaction mixture was poured into water and
extracted with dichloromethane washed with water and brine, dried
(MgSO.sub.4), filtered and evaporated to give 4.0 g of
7-bromo-1-propyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one and
used without further purification in the Suzuki coupling (step a).
.sup.1H NMR (300 MHz; CDCl.sub.3): 0.98 (t, J=7.5 Hz, 1H), 1.26 (s,
6H), 1.65 (t, J=7.5 Hz, 1H), 2.37 (s, 3H), 2.46 (s, 2H), 3.88 (t,
J=7.8 Hz, 2H), 7.13 (s, 1H), 7.15 (s, 1H).
Example 9
5-[4-Dimethylamino-3-(1-propyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-qu-
inolin-7-yl)-benzylidene]-thiazolidine-2,4-dione, which can be
referred to as "Compound 9"
[0321] ##STR66##
[0322] Prepared in a similar manner to example 1 using
4-Dimethylamino-3-(1-propyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quin-
olin-7-yl)-benzaldehyde. 67% yield after recrystallisation from
ethanol. mp 258-260.degree. C. .sup.1H-NMR (300 MHz, DMSO-d-6):
0.86 (t, J=7.5 Hz, 3H), 1.24 (s, 3H), 1.26 (s, 3H), 1.53 (m, 2H),
2.07 (s, 3H), 2.46 (2 s, 2H), 2.58 (s, 6H), 3.90 (br m, 2H), 7.02
(s, 1H), 7.10 (d, J=9.0 Hz, 1H), 7.25 (s+d, 2H), 7.50 (dd,
J.sub.1=2.1 Hz, J.sub.2=8.4 Hz, 1H), 7.74 (s, 1H), 12.44 (brs,
1H).
[0323] The intermediate
4-Dimethylamino-3-(1-propyl-4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-qu-
inolin-7-yl)-benzaldehyde was prepared in a similar manner to
example 3a using 6-dimethylamino-3-formyl-1-phenyl boronic acid
(example 3b) and
7-bromo-1-propyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one
(example 8b). 57% yield. .sup.1H NMR (300 MHz; CDCl.sub.3): 0.93
(t, J=7.2 Hz, 3H), 1.32 (2 s, 6H), 1.64 (m, 5H), 2.12 (s, 3H), 2.68
(s, 6H), 3.91 (m, 2H), 6.89 (s, 1H), 6.98 (d, J=8.1 Hz, 1H), 7.15
(s, 1H), 7.59 (d, J=2.1 Hz, 1H), 7.78 (dd, J=2.1 Hz and 8.4 Hz,
1H), 9.83 (s, 1H).
Example 10
5-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-2-fl-
uoro-4-methoxy-benzylidene]-thiazolidine-2,4-dione, which can be
referred to as "Compound 10"
[0324] ##STR67##
[0325] Prepared in a similar manner to example 1 using
2-Fluoro-4-methoxy-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-qu-
inolin-7-yl)-benzaldehyde. 81% yield after recrystallisation from
ethanol. mp 279-281.degree. C. .sup.1H-NMR (300 MHz, DMSO-d-6):
1.05 (t, J=6.7 Hz, 3H), 1.25 (s, 6H), 2.01 (s, 3H), 2.46 (s, 2H),
3.83 (s, 3H), 3.93 (q, J=6.7 Hz, 2H), 6.94 (s, 1H), 7.20 (d, J=8.8
Hz, 1H), 7.28 (s, 1H), 7.58 (t, J=8.8 Hz, 1H), 7.77 (s, 1H), 12.65
(br s, 1H).
[0326] The intermediate
2-Fluoro-4-methoxy-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-qu-
inolin-7-yl)-benzaldehyde was prepared in a similar manner to
example 7a using
7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one
(example 2b) and 2-Fluoro-3-iodo-4-methoxy benzaldehyde (example
7b). 59% yield. .sup.1H NMR (300 MHz; CDCl.sub.3): 1.21 (t, J=6.9
Hz, 3H), 1.31 (s, 3H), 1.34 (s, 3H), 1.60 (s, 2H), 2.10 (s, 3H),
2.52 (s, 2H), 3.88 (s, 3H), 4.02 (q, J=7.2 Hz, 1H), 6.82 (s, 1H),
6.93 (d, J=9.0 Hz, 1H), 7.22 (s, 1H), 7.95 (t, J=8.1 Hz, 1H), 10.26
(s, 1H).
Example 11
5-[3-(1-Isopropyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)--
4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione, which can
be referred to as, "Compound 11"
[0327] ##STR68##
[0328] Prepared in a similar manner to example 1 using
3-(1-isopropyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4--
trifluoromethoxy-benzaldehyde. 48% yield after crystallization from
ethanol/water. mp 233-235.degree. C. .sup.1H-NMR (300 MHz,
DMSO-d-6): 1.26 (s, 6H), 1.38 (s, 3H), 1.40 (s, 3H), 2.07 (s, 3H),
2.38 (s, 2H), 4.62 (m, 1H), 6.98 (s, 1H), 7.28 (s, 1H), 7.66 (m,
2H), 7.76 (dd, J.sub.1=1.8 Hz, J.sub.2=8.7 Hz, 1H), 7.87 (s, 1H),
12.71 (br s, 1H).
[0329] The intermediate
3-(1-isopropyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4--
trifluoromethoxy-benzaldehyde was prepared as follows:
[0330] a.
3-(1-Isoropyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-
-7-yl)-4-trifluoromethoxy-benzaldehyde.
[0331] A mixture of 3-formyl-6-trifluoromethoxy-1-phenyl boronic
acid (Example 1b) (1.09 g, 4.64 mmol),
7-bromo-1-isopropyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one
(1.2 g, 3.87 mmol) and potassium carbonate (1.07 g, 7.74 mmol) in
toluene (10 mL), ethanol (2 mL) and water (1.5 mL) was degassed
with argon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0)
(0.224 g, 0.194 mmol) was added and the mixture heated at reflux
under argon for 24 hrs. The solution was cooled to room
temperature, diluted with ethyl acetate and washed successively
with water and brine, dried over anhydrous magnesium sulfate,
filtered and evaporated. The residue was purified on silica gel
(0-15% ethyl acetate in hexane) to give 0.54 g of
3-(1-isopropyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4--
trifluoromethoxy-benzaldehyde (33%). .sup.1H NMR (300 MHz;
CDCl.sub.3): 1.32 (s, 6H), 1.48 (s, 3H), 1.50 (s, 3H), 2.09 (s,
3H), 2.45 (s, 2H), 4.7 (m, 1H), 6.91 (s, 1H), 7.16 (s, 1H), 7.55
(d, J=8.4 Hz, 1H), 7.84 (d, J=1.8 Hz, 1H), 7.98 (dd, J=1.8 and 8.4
Hz, 1H), 10.05 (s, 1H).
[0332] b.
7-bromo-1-isopropyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2--
one.
[0333] Prepared in a similar manner to example 1d using
7-bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-7-yl)-2-one
(example 1e) and 2-iodopropane. 72% yield. .sup.1H NMR (300 MHz;
CDCl.sub.3): 1.25 (s, 1H), 1.51 (s, 3H), 1.53 (s, 3H), 2.36 (s,
3H), 2.38 (s, 2H), 4.62 (m, 1H), 7.10 (s, 1H), 7.27 (s, 1H).
Example 12
5-[4-Dimethylamino-3-(1-isopropyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-
-quinolin-7-yl)-benzylidene]-thiazolidine-2,4-dione, which can be
referred to as "Compound 12"
[0334] ##STR69##
[0335] Prepared in a similar manner to example 1 using
4-Dimethylamino-3-(1-isopropyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-q-
uinolin-7-yl)-benzaldehyde. 72% yield. mp 274-276.degree. C.
.sup.1H-NMR (300 MHz, DMSO-d-6): 1.24 (s, 3H), 1.26 (s, 3H), 1.40
(m, 6H), 2.08 (s, 3H), 2.38 (d, 2H), 2.58 (s, 6H), 4.71 (m, 1H),
7.02 (s, 1H), 7.12 (d, J=9 Hz, 1H), 7.22 (s, 1H), 7.28 (d, J=2.1
Hz, 1H), 7.50 (dd, J.sub.1=1.8 Hz, J.sub.2=8.7 Hz, 1H), 7.75 (s,
1H), 12.45 (br s, 1H).
[0336] The intermediate
4-Dimethylamino-3-(1-isopropyl-4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-
-quinolin-7-yl)-benzaldehyde was prepared in a similar manner to
example 3a using 6-dimethylamino-3-formyl-1-phenyl boronic acid
(example 3b) and
7-bromo-1-isoprpyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one
(example 11b). 48% yield. .sup.1H NMR (300 MHz; CDCl.sub.3): 1.31
(s, 6H), 1.48 (s, 6H), 2.10 (s, 3H), 2.44 (s, 2H), 2.69 (s, 6H),
4.76 (m, 2H), 6.98 (d, 1H), 7.02 (s, 1H), 7.12 (s, 1H), 7.59 (d,
J=1.5 Hz, 1H), 7.77 (dd, J=1.5 Hz and 8.7 Hz, 1H), 9.83 (s,
1H).
Example 13
5-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-2,5--
difluoro-4-methoxy-benzylidene]-thiazolidine-2,4-dione, which can
be referred to as "Compound 13"
[0337] ##STR70##
[0338] Prepared in a similar manner to example 1 using
3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-2,5-di-
fluoro-4-methoxy-benzaldehyde. 22% yield after recrystallisation
from dichloromethane and hexane. mp 203-207.degree. C. .sup.1H NMR
(300 MHz; DMSO) 1.05 (t, J=6.9 Hz, 3H), 1.25 (s, 6H), 2.05 (s, 3H),
2.47 (s, 2H), 3.80 (s, 3H), 3.94 (m, 1H), 7.04 (s, 1H), 7.31 (s,
1H), 7.47 (dd, J.sub.1=6.9 Hz, J.sub.2=12.3 Hz, 1H), 12.77 (s,
1H).
[0339] The intermediate
3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-2,5-di-
fluoro-4-methoxy-benzaldehyde was prepared in a similar manner to
example 7a using
7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one
(example 2b) and 3-bromo-2,5-difluoro-4-methoxy benzaldehyde. 14%
yield. .sup.1H NMR (300 MHz; CDCl.sub.3): 1.21 (t, J=6.9 Hz, 3H),
1.32 (s, 3H), 1.33 (s, 3H), 2.13 (s, 3H), 2.53 (s, 2H), 3.81 (2 s,
3H), 4.02 (q, J=6.9 Hz, 1H), 6.81 (s, 1H), 7.23 (s, 1H), 7.68 (dd,
J.sub.1=6.3 Hz, J.sub.2=11.7 Hz, 1H), 10.25 (2 s, 1H).
[0340] a. 3-bromo-2,5-difluoro-4-methoxy benzaldehyde
[0341] Hexamethyltetramine (53.88 g, 0.384 mmol) was added
carefully to TFA-(140 mL) and the solution warmed to 80.degree. C.
A solution of 2,5-dinitrophenol (25 g, 0.192 mmol) in THF (60 mL)
was added dropwise to the reaction mixture and the reaction stirred
for 3 hrs at 80.degree. C. The solution was diluted with toluene
and the TFA removed under reduced pressure. The solution was then
poured into ice-water and extracted with ethylacetate, washed
successively with water, saturated aqueous NaHCO.sub.3 (to pH=6),
water and brine, dried (MgSO.sub.4), filtered and evaporated to
give 17 g of crude 2,5-difluoro-4-hydroxybenzaldehyde use as this
in the next step.
[0342] To a solution of 2,5-difluoro-4-hydroxybenzaldehyde (37.5 g,
0.237 mmol) in dichloromethane (1.5 L) was added pyridinium
tribromide (75.9 g, 0.237 mmol). The reaction mixture was stirred
at 400C for 7 hrs then at room temperature overnight. The reaction
was washed with water and brine, dried over magnesium sulfate,
filtered and evaporated to give 48.4 g of crude
3-bromo-2,5-difluoro-4-hydroxybenzaldehyde use as this in the next
step.
[0343] To a solution of 3-bromo-2,5-difluoro-4-hydroxybenzaldehyde
(48.4 g, 0.193 mmol) in DMF (200 mL) was added potassium carbonate
(40.0 g) and dimethylsulfate (27.4 mL). The reaction mixture was
stirred at room temperature overnight. The reaction was diluted wit
ethylacetate and washed successively with water and brine, dried
over magnesium sulfate, filtered and evaporated. The residue was
triturated with hexane to afford 26 g of
3-bromo-2,5-difluoro-4-methoxy benzaldehyde. The mother liquor was
evaporated and chromatographed on silica gel (0-10% ethyl acetate
in hexane) to give 10.86 g of more product. (38% overall yield from
2,5-dinitrophenol).
Example 14
5-[4-Ethylamino-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydroquinoli-
n-7-yl)-benzylidene]-thiazolidine-2,4-dione, which can be referred
to as "Compound 14"
[0344] ##STR71##
[0345] Prepared in a similar manner to example 1 using
4-ethylamino-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-
-7-yl)-benzaldehyde. 86% yield after crystallisation from
dichloromethane and hexane. mp 283-2850C. .sup.1H-NMR (300 MHz,
DMSO-d-6): 1.08 (t, J=7.0 Hz, 3H), 1.09 (t, J=7.0 Hz, 3H), 1.25 (s,
3H), 1.28 (s, 3H), 2.06 (s, 3H), 2.45 (d, J=3.5 Hz, 2H), 3.22 (m,
2H), 3.95 (m, 2H), 5.19 (t, J=5.9 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H),
6.89 (s, 1H), 7.14 (d, J=2.3 Hz, 1H), 7.30 (s, 1H), 7.46 (dd,
J.sub.1=8.8 Hz J.sub.2=2.3 Hz, 1H), 7.69 (s, 1H).
[0346] a.
4-ethylamino-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydr-
o-quinolin-7-yl)-benzaldehyde.
[0347] The intermediate
4-ethylamino-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydroquinolin--
7-yl)-benzaldehyde was prepared in a similar manner to example 7a
using
7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one
(example 2b) and 3-bromo-4-ethylamino benzaldehyde. 53% yield.
.sup.1H NMR (300 MHz; CDCl.sub.3): 1.21 (t, J=6.9 Hz, 3H), 1.31 (s,
3H), 1.35 (s, 3H), 2.08 (s, 3H), 2.53 (s, 2H), 3.27 (m, 2H), 4.02
(q, J=7.5 Hz, 1H), 6.75 (d, J=8.7 Hz, 1H), 6.83 (s, 1H), 7.21 (s,
1H), 7.52 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 9.76 (s, 1H).
[0348] b. 3-bromo-4-ethylamino benzaldehyde.
[0349] To a solution of 4-diethylamino-benzaldehyde (10 g, 56.4
mmol) in dichloromethane (300 mL) was added at room temperature
pyridium tribromide (54 g, 169.2 mmol). The reaction mixture was
stirred at room temperature for 48 hrs, then it was washed
successively with water and brine, dried (MgSO.sub.4), filtered and
evaporated. The residue was chromatographed on silica gel (10%
ethyl acetate in hexane) to give 10.3 g of 3-bromo-4-ethylamino
benzaldehyde (80%). .sup.1H NMR (300 MHz; CDCl.sub.3): 1.38 (t,
J=6.9 Hz, 3H), 3.31 (m, 2H), 4.92 (br s, 1H), 6.67 (d, J=9 Hz, 1H),
7.69 (dd, J.sub.1=1.5 Hz, J.sub.2=8.1 Hz, 1H), 7.95 (d, J=1.5 Hz,
1H), 9.68 (s, 1H).
Example 15
6-[2-Dimethylamino-5-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenyl]-1,4,7-
-trimethyl-1,4-dihydro-quinoxaline-2,3-dione, which can be referred
to as "Compound 15"
[0350] ##STR72##
[0351] Prepared in a similar manner to example 1 using
4-Dimethylamino-3-(1,4,7-trimethyl-2,3-dioxo-1,2,3,4-tetrahydro-quinoxali-
n-6-yl)-benzaldehyde (8%). mp 247-251.degree. C. .sup.1H-NMR (300
MHz, DMSO-d-6): 2.15 (s, 3H), 2.58 (s, 6H), 3.51 (s, 3H), 3.57 (s,
3H), 7.12 (d, J=8.8 Hz, 1H), 7.26 (s, 1H), 7.28 (d, 1H, J=2.3 Hz),
7.36 (s, 1H), 7.50 (dd, J.sub.1=2.3 Hz, J.sub.2=8.8 Hz, 1H), 7.72
(s, 1H), 12.4 (br s, 1H).
[0352] The intermediate
4-Dimethylamino-3-(1,4,7-trimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-
-6-yl)-benzaldehyde was prepared in a similar manner to example 3a
using 6-dimethylamino-3-formyl-1-phenyl boronic acid (example 3b)
and 6-bromo-1,4,7-trimethyl-1,4-dihydro-quinoxaline-2,3-dione
(18%). .sup.1H NMR (300 MHz; CDCl.sub.3): 2.12 (s, 3H), 2.69 (s,
6H), 3.65 (s, 6H), 7.1-7.6 (m, 5H), 9.84 (s, 1H).
[0353] a.
6-bromo-1,4,7-trimethyl-1,4-dihydro-quinoxaline-2,3-dione.
[0354] To a solution of
1,4,6-trimethyl-1,4-dihydro-quinoxaline-2,3-dione (0.66 g, 3.2
mmol) in acetic acid (40 mL) was added bromine (0.52 g, 3.2 mmol)
and the solution stirred at 50.degree. C. overnight. The reaction
mixture was cooled to room temperature and poured into water. The
solution was neutralized with aqueous NaOH to Ph=7, extracted with
dichloromethane and washed with brine, dried (MgSO.sub.4), filtered
and evaporated to give 0.9 g of
6-bromo-1,4,7-trimethyl-1,4-dihydro-quinoxaline-2,3-dione used
without further purification in the Suzuki coupling (step a).
.sup.1H NMR (300 MHz; CDCl.sub.3): 2.47 (s, 3H), 3.64 (s, 6H), 7.09
(s, 1H), 7.40 (s, 1H).
[0355] b. 1,4,6-trimethyl-1,4-dihydro-quinoxaline-2,3-dione.
[0356] To a solution of 6-methyl-1,4-dihydro-quinoxaline-2,3-dione
(5.3 g, 30 mmol) in THF (150 mL) was added, at 0.degree. C. under
argon, sodium hydride (3.68 g, 80% in mineral oil, 120 mmol)
followed by methyl iodide (7.5 mL, 120 mmol). The solution was
stirred at 0.degree. C. for 3 hrs and at room temperature
overnight. The reaction mixture was cooled to 0.degree. C. and
acidified with 1N HCl. The solution was extracted with
dichloromethane washed with brine, dried (MgSO.sub.4), filtered and
evaporated. The residue was chromatographed on silica gel (10 to
25% acetonitrile in dichloromethane) to give 1.1 g of
1,4,6-trimethyl-1,4-dihydroquinoxaline-2,3-dione (18%). .sup.1H NMR
(300 MHz; CDCl.sub.3): 2.44 (s, 3H), 3.66 (s, 6H), 7.06-7.15 (m,
3H).
[0357] c. 6-methyl-1,4-dihydro-quinoxaline-2,3-dione.
[0358] 3,4-Diaminotoluene (24.4 g, 0.2 mmol) was dissolved in 2N
HCl (300 mL), oxalic acide dihydrate (27.7 g, 0.22 mmol) was added
and the mixture was heated at reflux for 3.5 hrs. The reaction
mixture was cooled to room temperature, filtered, washed with
water, dried (MgSO.sub.4), filtered and evaporated to give 34 g of
6-methyl-1,4-dihydro-quinoxaline-2,3-dione (96%). .sup.1H NMR (300
MHz; CDCl.sub.3): 2.25 (s, 3H), 6.87-6.99 (m, 3H), 11.87 (br s,
2H).
Example 16
5-[3-(1-Benzyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-4-trifluor-
omethoxy-benzylidene]-thiazolidine-2,4-dione, which can be referred
to as "Compound 16"
[0359] ##STR73##
[0360] Prepared in a similar manner to example 1 using
3-(1-Benzyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-4-trifluorom-
ethoxy-benzaldehyde. 72% yield. .sup.1H-NMR (300 MHz, DMSO-d-6):
1.37 (s, 6H), 2.03 (s, 3H), 4.89 (s, 2H), 6.77 (s, 1H), 7.28 (m,
5H), 7.37 (s, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.61 (dd, J=1.6 Hz and
8.8 Hz, 1H), 7.74 (dd, J=2.3 Hz and 8.8 Hz, 1H), 7.82 (s, 1H),
12.71 (br s, 1H).
[0361] a.
3-(1-Benzyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-4--
trifluoromethoxy-benzaldehyde.
[0362] The intermediate
3-(1-Benzyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-4-trifluorom-
ethoxy-benzaldehyde was prepared in a similar manner to example 1a
using 3-formyl-6-trifluoromethoxy-1-phenyl boronic acid (Example
1b) and trifluoro-methanesulfonic acid
1-benzyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl ester. 27%
yield. .sup.1H NMR (300 MHz; CDCl.sub.3): 1.48 (s, 6H), 2.07 (s,
3H), 4.89 (s, 2H), 6.50 (s, 1H), 1.74 (t, J=6.0 Hz, 2H), 2.01 (s,
3H), 2.69 (s, 6H), 2.91 (dd, J=7.2 and 14.7 Hz, 1H), 7.13 (s, 1H),
7.27 (m, 5H), 7.47 (d, J=8.4 Hz, 1H), 7.71 (s, 1H), 7.93 (d, J=8.4
Hz, 1H)), 9.99 (s, 1H).
[0363] b. Trifluoro-methanesulfonic acid
1-benzyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl ester.
[0364] To a solution of
1-benzyl-6-hydroxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one (1.85 g,
6.60 mmol) in anhydrous dichloromethane (30 mL) was added slowly,
under argon at 0.degree. C., pyridine (0.64 mL, 7.92 mmol) followed
by triflic anhydride (1.33 mL, 7.92 mmol). The reaction was warmed
up to room temperature and stirred overnight. The mixyure was
washed successively with water, 1N HCl, water, saturated aqueous
NaHCO.sub.3, water and brine. The organic extract was dried over
MgSO.sub.4, filtered and evaporated to give 2.6 g of
trifluoro-methanesulfonic acid
1-benzyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl ester (95%
yield). .sup.1H NMR (300 MHz; CDCl.sub.3): 1.42 (s, 6H), 2.31 (s,
3H), 4.87 (s, 2H), 6.55 (s, 1H), 7.09 (s, 1H), 7.29 (m, 5H).
[0365] c.
1-benzyl-6-hydroxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one.
[0366] To a solution of
1-benzyl-6-methoxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one (1.52 g,
5.15 mmol) in anhydrous dichloromethane (50 mL) was added slowly,
under argon at -78.degree. C., BBr.sub.3 (0.87 mL, 9.27 mmol). The
reaction was warmed up to -20.degree. C. and stirred overnight at
room temperature. Water and the layer separated. The aqueous layer
was neutralized with NaHCO.sub.3 and extracted with
dichloromethane. The organic combined extract was washed with
aqueous NaHCO.sub.3, water and brine, dried over MgSO.sub.4,
filtered and evaporated to give
1-benzyl-6-hydroxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one (93%
yield). .sup.1H NMR (300 MHz; CDCl.sub.3): 1.38 (s, 6H), 2.19 (s,
3H), 4.82 (s, 2H), 5.47 (br s, 1H), 6.26 (s, 1H), 6.93 (s, 1H),
7.26 (m, 5H).
[0367] d.
1-benzyl-6-methoxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one.
[0368] To a solution of
N-benzyl-N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (4.35
g, 11.56 mmol) in 1,4-dioxane (115 mL) was added sodium
tert-butoxide (1.66 g, 17.34 mmol). The mixture was degassed under
argon for 30 minutes, then palladium (II) acetate (130 mg, 0.58
mmol) and tricyclohexylphosphine (162 mg, 0.58 mmol) were added and
the mixture refluxed overnight. A solution of saturated aqueous
ammonium chloride was added and the solution extracted with ethyl
acetate. The organic extract was washed successively with water and
brine, dried over MgSO.sub.4, filtered and evaporated. The residue
was chromatographed on silica gel (20% ethyl acetate in hexane) to
give 1.94 g of
1-benzyl-6-methoxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one (57%
yield). .sup.1H NMR (300 MHz; CDCl.sub.3): 1.40 (s, 6H), 2.16 (s,
3H), 3.67 (s, 3H), 4.90 (s, 2H), 6.26 (s, 1H), 6.96 (s, 1H), 7.27
(m, 5H).
[0369] e.
N-benzyl-N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide.
[0370] A mixture of powdered KOH (1.3 g, 23.13 mmol) in DMSO (25
mL) was stirred at 0.degree. C. for 5 minutes.
N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (3.30 g, 11.56
mmol) was added cautiously followed immediately by the addition of
benzylbromide (2.75 mL, 23.13 mmol) and the reaction stirred at
room temperature for 48 hrs. Water was added and the mixture
extracted with ethyl acetate. The organic extract was washed
successively with water and brine, dried over MgSO.sub.4, filtered
and evaporated. The residue was chromatographed on silica gel (20%
ethyl acetate in hexane) to give 4.3 g of
N-benzyl-N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (99%
yield). .sup.1H NMR (300 MHz; CDCl.sub.3): 1.02 (d, J=6.6 Hz, 3H),
1.15 (d, J=6.6 Hz, 3H), 2.16 (s, 3H), 2.29 (m, 1H), 3.43 (s, 3H),
3.85 (d, J=14.1 Hz, 1H), 5.75 (d, J=14.1 Hz, 1H), 6.02 (s, 1H),
7.18-7.27 (m, 5H), 7.38 (s, 1H).
[0371] f. N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide.
[0372] To a biphasic mixture of 2-bromo-5-methoxy-4-methyl-aniline
(5.6 g, 25.96 mmol), 10% KOH (27 mL) and dichloromethane (30 mL),
was added dropwise isobutyryl chloride (3 mL, 28.55 mmol) in
dichloromethane (10 mL). The reaction mixture was stirred at room
temperature for 48 hrs. The layers were separated. The aqueous
layer was further extracted with dichloromethane and the combined
organics washed successively with water and brine, dried over
MgSO.sub.4, filtered and evaporated to give 7.38 g of
N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (99% yield).
.sup.1H NMR (300 MHz; CDCl.sub.3): 1.29 (d, J=6.9 Hz, 6H), 2.14 (s,
3H), 2.59 (m, 1H), 3.84 (s, 3H), 7.24 (s, 1H), 7.66 (br s, 1H),
8.07 (s, 1H).
[0373] g. 2-bromo-5-methoxy-4-methyl-aniline.
[0374] To a solution of 3-methoxy-4-methyl-aniline (8.19 g, 59.71
mmol) in dichloromethane (200 mL), was added tetrabutylammonium
tribromide (28.79 g, 59.71 mmol) and the reaction mixture was
stirred at room temperature for 2.5 hrs. Aqueous NaHCO.sub.3 was
added and the layers separated. The aqueous layer was further
extracted with dichloromethane and the combined organics washed
successively with water and brine, dried over MgSO.sub.4, filtered
and evaporated. The residue was chromatographed on silica gel (20%
ethyl acetate in hexane) to give 11.05 g of
2-bromo-5-methoxy-4-methyl-aniline (85% yield). .sup.1H NMR (300
MHz; CDCl.sub.3): 2.09 (s, 3H), 3.75 (s, 3H), 3.95 (br s, 1H), 6.27
(s, 1H), 7.13 (s, 1H).
[0375] h. 3-methoxy-4-methyl-aniline.
[0376] To a solution of 2-methyl-5-nitroanisole (11.56 g, 69.2
mmol) in a mixture of ethyl acetate (200 mL) and ethanol (70 mL)
was added portionwise tin (II) chloride dihydrate (109 g, 0.483
mol) and the mixture was stirred at room temperature overnight. The
reaction mixture was basified with aq. K.sub.2CO.sub.3 and filtered
over celite. The layers were separated.
[0377] The aqueous layer was further extracted with ethyl acetate
and the combined organics washed successively with water and brine,
dried over MgSO.sub.4, filtered and evaporated to give 8.02 g of
3-methoxy-4-methyl-aniline (86% yield). .sup.1H NMR (300 MHz;
CDCl.sub.3): 2.09 (s, 3H), 3.76(s, 3H), 4.01 (br s, 1H), 6.20 (m,
2H), 6.90 (d, J=8.4 Hz, 1H).
Example 17
5-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-5-fl-
uoro-4-methoxy-benzylidene]-thiazolidine-2,4-dione, which can be
referred to as "Compound 17"
[0378] ##STR74##
[0379] Prepared in a similar manner to example 1 using
3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-5-fluo-
ro-4-methoxy-benzaldehyde. 36% yield, mp 260-262.degree. C.
.sup.1H-NMR (300 MHz, DMSO-d-6): 1.08 (t, J=6.7 Hz, 3H), 1.25 (s,
6H), 2.09 (s, 3H), 2.46 (s, 2H), 3.83 (s, 3H), 3.96 (q, J=6.7 Hz,
2H), 6.98 (s, 1H), 7.25 (br s, 1H), 7.28 (s, 1H), 7.56 (dd,
J.sub.1=12.6 Hz, J.sub.2=2.0 Hz, 1H), 7.80 (s, 1H), 12.67 (br s,
1H).
[0380] The intermediate
3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-5-fluo-
ro-4-methoxy-benzaldehyde was prepared in a similar manner to
example 7a using
7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one
(example 2b) and 3-bromo-5-fluoro-4-methoxy-benzaldehyde. 12%
yield. .sup.1H-NMR (300 MHz, CDCl.sub.3): 1.23 (t, J=7.0 Hz, 3H),
1.33 (s, 6H), 2.13 (s, 3H), 2.53 (s, 2H), 3.91 (s, 3H), 4.01 (q,
J=7.0 Hz, 2H), 6.83 (s, 1H), 7.19 (s, 1H), 7.50 (d, J=1.8 Hz, 1H),
7.66 (dd, J.sub.1=11.7 Hz, J.sub.2=2.1 Hz, 1H), 9.91 (s, 1H).
[0381] The intermediate 3-bromo-5-fluoro-4-methoxy-benzaldehyde was
prepared in a similar manner to example 5d using
3-fluoro-4-methoxy-benzaldehyde. It was used without purification
in the next step. .sup.1H-NMR (300 MHz, CDCl.sub.3): 4.11 (s, 3H),
7.60 (d, J=11.1 Hz, 1H), 7.87 (s, 1H), 9.87 (s, 1H).
Example 18
5-(1'-Ethyl-4',4',6'-trimethyl-2'-oxo-1',2',3',4'-tetrahydro-[4,7']biquino-
linyl-2-ylmethylene)-thiazolidine-2,4 which can be referred to as
"Compound 18"
[0382] ##STR75##
[0383] Prepared in a similar manner to example I using
1'-Ethyl-4',4',6'-trimethyl-2'-oxo-1',2',3',4'-tetrahydro-[4,7']biquinoli-
nyl-2-carbaldehyde. mp 299-301.degree. C. .sup.1H-NMR (300 MHz,
DMSO-d-6): 1.05 (t, J=7.2 Hz, 3H); 1.28 (s, 3H); 1.33 (s, 3H); 1.97
(s, 3H); 3.94 (q, J=6.0 Hz, 2H); 7.06 (s, 1H); 7.40 (s, 1H); 7.49
(d, J=8.4 Hz, 1H); 7.64 (t, J=7.2 Hz, 1H); 7.86 (t, J=7.5 Hz, 1H);
7.90 (s, 1H); 8.01 (s, 1H); 8.22 (d, J=8.1, 1H); 12.54 (br s,
1H).
[0384] a.
1'-Ethyl-4',4',6'-trimethyl-2'-oxo-1',2',3',4'-tetrahydro-[4,7'-
]biquinolinyl-2-carbaldehyde.
[0385] A mixture of
1-Ethyl-4,4,'-trimethyl-2-oxo-1,2,3,'-tetrahydro-quinoline-7-boronic
acid (0.25 g, 0.96 mmol),
4-trifluoromethanesulfonyloxy-quinoline-2-carbaldehyde (example 18
d) (0.17 g, 0.80 mmol) and potassium carbonate (0.21 g, 1.6 mmol)
in toluene (5 mL), ethanol (1 mL) and water (0.75 mL) was degassed
with argon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0)
(20 mg, 0.016 mmol) was added and the mixture heated at reflux
under argon for 20 hrs. The solution was cooled to room
temperature, diluted with ethyl acetate and washed successively
with water and brine, dried over anhydrous magnesium sulfate,
filtered and evaporated. The residue was purified on silica gel
(0%-20% ethyl acetate in hexane) to give 0.18 g of
1'-Ethyl-4',4',6'-trimethyl-2'-oxo-1',2',3',4'-tetrahydro-[4,7']biquinoli-
nyl-2-carbaldehyde (52%). .sup.1H NMR (300 MHz; CDCl.sub.3): 1.20
(t, J=7.2 Hz, 3H), 1.35 (s, 3H), 1.39 (s, 3H), 1.99 (s, 3H), 2.56
(s, 2H), 4.00 (br d, 2H), 6.86 (s, 1H), 7.26 (d, J=2.7 Hz, 1H),
7.62 (d, J=3.6 Hz, 1H), 7.83 (m, J=1H), 7.92 (s, 1H), 8.33 (d,
J=8.4 Hz, 1H), 10.29 (s, 1H).
[0386] b.
1-Ethyl-4,4,'-trimethyl-2-oxo-1,2,3,'-tetrahydro-quinoline-7-bo-
ronic acid.
[0387] To a solution of
1-Ethyl-4,4,6-trimethyl-7-(4,45,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-
,4-dihydro-1H-quinolin-2-one (13.8 g, 40.20 mmol) in
dichloromethane (150 mL), was added dropwise under argon at
-78.degree. C. boron tribromide (19 mL, 201 mmol) and the solution
slowly warmed up to room temperature and left overnight at room
temperature. The solution was poored on ice-water slowly and
extracted with ethylacetate, washed successively with water and
brine, dried over anhydrous magnesium sulfate, filtered and
evaporated. The residue was recrystalised from ethylacetate and
hexane to give
1-ethyl-4,4,'-trimethyl-2-oxo-1,2,3,'-tetrahydro-quinoline-7-boronic
acid (9 g, 86% yield). .sup.1H NMR (300 MHz; CDCl.sub.3): 1.06 (t,
J=7.5 Hz, 3H), 1.12 (s, 6H), 2.30 (s, 3H), 3.84 (br d, 2H), 7.05
(s, 1H), 7.11 (s, 1H).
[0388] c.
1-Ethyl-4,4,6-trimethyl-7-(4,45,5-tetramethyl-[1,3,2]dioxaborol-
an-2-yl)-3,4-dihydro-1H-quinolin-2-one.
[0389] To a solution of
7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one
(example 2b) (6.5 g, 91.95 mmol) in dioxane (65 mL), were added
dropwise under argon triethylamine (12.3 mL, 87.78 mmol),
palladium(II)acetate (0,246 g, 1.098 mmol),
2-(dicyclohexylphosphino)biphenyl (1.54 g, 4.39 mmol) and
pinacolborane (9,6 mL, 65.85 mmol). The reaction mixture was heated
at 85.degree. C. for 3 hours then cooled to room temperature. Water
(7 mL) was added slowly to the mixture followed by a saturated
aqueous solution of ammonium chloride (100 mL). The mixture was
extrated with ethylacetate and washed successively with water and
brine, dried over anhydrous magnesium sulfate, filtered and
evaporated. The crude was purified on silica gel (0-20%
ethylacetate in hexane) to give
1-Ethyl-4,4,6-trimethyl-7-(4,45,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-
,4-dihydro-1H-quinolin-2-one (5.1 g, 67% yield). .sup.1H NMR (300
MHz; CDCl.sub.3): 1.24 (m, 9H), 1.31 (s, 12H), 2.45 (s, 2H), 2.51
(s, 3H), 4.09 (m, 2H), 7.09 (s, 1H), 7.42 (s, 1H).
[0390] d.
4-trifluoromethanesulfonyloxy-quinoline-2-carbaldehyde.
[0391] To a solution of
4-trifluoromethanesulfonyloxy-quinoline-2-carboxylic acid ethyl
ester (4.5 g, 12.88 g) in toluene (80 mL) was added slowly under
argon at -78.degree. C. diisobuthylaluminum hydride (1.5M in
toluene, 12.88 mL, 19.33 mmol). The reaction mixture was stirred at
-78.degree. C. for 1 hour. Methanol (13 mL) was added slowly
followed by water (26 mL). The reaction mixture was slowly warmed
up to room temperature extracted with ethylacetate and washed with
brine, dried over magnesium sulfate, filtered and evaporated. The
residue was purified on silica gel (5-10% ethylacetate in hexane)
to give 2.9 g of
4-trifluoromethanesulfonyloxy-quinoline-2-carbaldehyde (74%).
.sup.1H NMR (300 MHz; DMSO-d.sub.6): 8-8.2 (m, 4H), 8.43 (m, 1H),
10.05 (s, 1H).
[0392] e. 4-trifluoromethanesulfonyl-quinoline-2-carboxylic acid
ethyl ester.
[0393] To a solution of 4-hydroxy-quinoline-2-carboxylic acid ethyl
ester (3.7 g, 17.03 g) in dichloromethane (100 mL) was added slowly
under argon pyridine (1.65 mL, 20.44 mmol). The reaction mixture
was cooled to 0.degree. C. then trific anhydride (3.44 mL, 20.44
mmol) was added dropwise. The reaction mixture was slowly warmed up
to room temperature and stirred at room temperature overnight. The
solution was successively washed with water, 1N HCl, water, sat.
NaHCO.sub.3, water and brine, dried over magnesium sulfate,
filtered and evaporated. The residue was purified on silica gel
(5-15% ethylacetate in hexane) to give 4.5 g of
4-trifluoromethanesulfonyl-quinoline-2-carboxylic acid erthyl ester
(76%).
Example 19
5-[2,5-Difluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro--
quinolin-7-yl)-benzylidene]-thiazolidine-2,4-dione which can be
referred to as "Compound 19"
[0394] ##STR76##
[0395] Prepared in a similar manner to example 1 using
2,5-Difluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-qu-
inolin-7-yl)-benzaldehyde. mp 165-167.degree. C. .sup.1H-NMR (300
MHz, DMSO-d-6): .delta. 1.27 (s, 6H); 2.06 (s, 3H); 2.49 (s, 2H);
3.24 (s, 3H); 3.81(d, J=1.8 Hz, 3H); 6.98 (s, 1H); 7.31 (s, 1H);
7.46 (dd, J.sub.1=7.2 Hz, J.sub.2=12.3 Hz, 1H); 7.70(s, 1H); 12.77
(s, 1H).
[0396] a.
2,5-Difluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tet-
rahydroquinolin-7-yl)-benzaldehyde.
[0397] A mixture of
1,4,4,6-tetramethyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4--
dihydro-1H-quinoline-2-one (0.36 g, 1.1 mmol),
3-bromo-2,5-difluoro-4-methoxybenzaldehyde (example 13 a) (0.25 g,
0.1 mmol) and potassium carbonate (0.275 g, 1.99 mmol) in toluene
(5 mL), ethanol (1 mL) and water (0.75 mL) was degassed with argon
for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (58 mg,
0.05 mmol) was added and the mixture heated at reflux under argon
for 20 hrs. The solution was cooled to room temperature, diluted
with ethyl acetate and washed successively with water and brine,
dried over anhydrous magnesium sulfate, filtered and evaporated.
The residue was purified on silica gel (0%-20% ethyl acetate in
hexane) to give 97 mg of
2,5-Difluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-qu-
inolin-7-yl)-benzaldehyde.
[0398] b.
1,4,4,6-tetramethyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan--
2-yl)-3,4-dihydro-1H-quinoline-2-one.
[0399] To a solution of
7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one (example
1d) (1 g, 3.54 mmol) in dioxane (10 mL), were added dropwise under
argon triethylamine (1.98 mL, 14.175 mmol), palladium(II)acetate
(39.8 mg, 1.772 mmol), 2-(dicyclohexylphosphino)biphenyl (248 mg,
0.709 mmol) and pinacolborane (1.54 mL, 10.632 mmol). The reaction
mixture was heated at 85.degree. C. for 1.5 hours then cooled to
room temperature. Water (1 mL) was added slowly to the mixture
followed by a saturated aqueous solution of ammonium chloride. The
mixture was extrated with ethylacetate and washed successively with
water and brine, dried over anhydrous magnesium sulfate, filtered
and evaporated. The crude was purified on silica gel (25%
ethylacetate in hexane) to give
1,4,4,6-tetramethyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4--
dihydro-1H-quinoline-2-one (0.91 g, 78% yield).
Example 20
5-[4-Trifluoromethoxy-3-(4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydroquinolin--
7-yl)-benzylidene]-thiazolidine-2,4-dione, which can be referred to
as "Compound 20"
[0400] ##STR77##
[0401] Prepared in a similar manner to example 1 using
4-Trifluoromethoxy-3-(4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-
-yl)-benzaldehyde. 76% yield. mp 306-308.degree. C. .sup.1H-NMR
(300 MHz, DMSO-d-6): .sup.1H NMR (300 MHz: DMSO): 1.26 (s, 3H);
1.29 (s, 3H); 2.04 (s, 3H); 2.38 (m, 2H); 6.69 (s, 1H); 7.26 (s,
1H); 7.58 (d, J=1.8 Hz, 1H); 7.64 (dd, J.sub.1=1.2 Hz, J.sub.2=8.7
Hz, 1H); 7.74 (dd, J.sub.1=2.4 Hz, J.sub.2=8.7 Hz., 1H); 7.86 (s,
1H); 10.16 (s, 1H); 12.71 (br. s, 1H)
[0402] The intermediate
4-Trifluoromethoxy-3-(4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7--
yl)-benzaldehyde was prepared in a similar manner to example 1a
using 7-bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one
(Example 1e) and 3-formyl-6-trifluoromethoxy-1-phenyl boronic acid
(example 1b).
Example 21
5-[3-(1-Ethyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-4-trifluoro-
methoxy-benzylidene]-thiazolidine-2,4-dione, which can be referred
to as "Compound 21"
[0403] ##STR78##
[0404] Prepared in a similar manner to example 1 using
3-(1-Ethyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-4-trifluorome-
thoxy-benzaldehyde. 51% yield. .sup.1H-NMR (300 MHz, DMSO-d-6): 1.1
(t, J=7.03 Hz, 3H), 1.30 (s, 6H), 2.07 (s, 3H), 3.70 (q, J=7.33 Hz,
2H), 6.91 (s, 1H), 7.34 (s, 1H), 7.65-7.68 (m, 2H), 7.75 (dd,
J.sub.1=2.35, J.sub.2=8.79 Hz, 1H), 7.88 (s, 1H), 12.7 (bs,
1H).
[0405] a.
3-(1-Ethyl-3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-4-t-
rifluoromethoxy-benzaldehyde.
[0406] To a solution of
4-trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-be-
nzaldehyde (210 mg, 0.58 mmol) in DMSO (5 mL) was added KOH
(powder, 65 mg, 1.16 mmol) and iodoethane (180 mg, 1.16 mmol) under
argon. The mixture was stirred at room temperature for about 2
hours. 5 mL of water was added, the product was extracted with
EtOAc, washed with brine, dried over MgSO.sub.4, filtered and
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel (hexane:EtOAc/4:1). 120 mg of
pale colorles solid was obtained (yield: 53%). .sup.1H NMR (300
MHz, CDCl.sub.3, ppm): .delta.: 1.24 (t, J=7.03 Hz, 3H), 2.10 (s,
3H), 3.74 (m, 2H), 6.65 (s, 1H), 7.12 (s, 1H), 7.53 (dd,
J.sub.1=1.76 Hz, J.sub.2=8.50 Hz, 1H), 7.85 (d, J=2.34 Hz, 1H),
7.96 (dd, J.sub.1=2.34 Hz, J.sub.2=8.50 Hz, 1H), 10.05 (s, 1H).
[0407] b.
-Trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-
-6-yl)-benzaldehyde
[0408] A mixture of trifluoro-methanesulfonic acid
3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl ester (243 mg, 0.75
mmol), 3-formyl-6-trifluoromethoxy-1-phenyl boronic acid (Example
1b) (194 mg, 0.83 mmol) in toluene (10 mL), EtOH (1.5 mL) and water
(1 mL) was deassed with argon for 20 minutes.
Tetrakis(triphenylphosphine)palladium(0) (398 mg, 0.34 mmol),
sodium carbonate (159 mg, 1.50 mmol) and lithium chloride (98 mg,
2.25 mmol) were added and the reaction mixture was heated to reflux
under argon for 22 hours. The reaction was cooled to room
temperature, diluted with ethylacetate and washed successively with
water and brine, dried over MgSO.sub.4, filtered and evaporated
under reduced pressure. The residue was purified by column
chromatography on silica gel (hexane:EtOAc/3:1) to give 166 mg of
4-trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-be-
nzaldehyde (61%). .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): .delta.:
1.44 (s, 6H), 2.09 (s, 3H), 6.72 (s, 1H), 7.10 (s, 1H), 7.50-7.53
(m, 1H), 7.82 (d, J=2.34 Hz, 1H), 7.94-7.97 (m, 2H), 10.03 (s,
1H).
[0409] c. Trifluoro-methanesulfonic acid
3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl ester
[0410] To a solution of
6-Hydroxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one (640 mg, 3.17
mmol) in dichloromethane (15 mL) was added at 0.degree. C.
triethylamine (642 mg, 884 uL, 6.34 mmol) followed by slow addition
of trifluomethanesulfonic anhydride (984 mg, 586 uL, 3.49 mmol).
The mixture was slowy warmed to room temperature and stirred at
room temperature overnight. The solution was washed with water and
brine, dried over MgSO.sub.4, filtered and evaporated under reduced
pressure. The residue was purified by column chromatography on
silica gel (hexane:EtOAc/2:1) to give 750 mg of
trifluoromethanesulfonic acid
3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl ester (73%).
.sup.1H NMR (300 MHz, CDCl.sub.3, ppm): .delta.: 1.40 (s, 6H), 2.35
(s, 3H), 6.82 (s, 1H), 7.09 (s, 1H), 8.10 (bs, 1H).
[0411] d. 6-Hydroxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one
[0412]
6-Methoxy-1-(4-methoxy-benzyl-3,3,5-trimethyl-1,3-dihydro-indol-2--
one (640 mg, 1.97 mmol) was mixed with acetic acid (0.7 mL) and 48%
hydrobromic acid (7 mL) and heated to reflux 12 hours. The solution
was cooled to 0.degree. C. and aqueous Na.sub.2CO.sub.3 was added
to adjust to pH=7 then extracted with EtOAc, washed with brine,
dried over MgSO.sub.4, filtered and evaporated under reduced
pressure. The residue was purified by column chromatography on
silica gel (hexane:EtOAc/4:1 to 1:1) to give 280 mg of
6-Hydroxy-3,3,5-trimethyl-1,3-dihydro-indol-2-one (74%). .sup.1H
NMR (300 MHz, DMSO-d.sub.6, ppm): .delta.: 1.15 (s, 6H), 2.026.34
(s, 1H), 6.89 (s, 1H), 9.21 (s, 1H), 10.01(s, 1H).
[0413] e.
6-Methoxy-1-(4-methoxy-benzyl-3,3,5-trimethyl-1,3-dihydro-indol-
-2-one
[0414] To a solution of
N-(2-bromo-5-methoxy-4-methyl-phenyl)-N-(4-methoxy-benzyl)-isobutyramide
(8.72 g, 21.4 mmol) in dry 1,4-dioxane (80 mL) was added sodium
tert-butoxide (3.09 g, 32.1 mmol). Argon was bubbled through for
about 15 minutes before adding palladium(II) acetate (241 mg, 1.07
mmol) and tricyclohexylphosphine (300 mg, 1.07 mmol). The mixture
was heated to reflux for 16 hours. The mixture was cooled to room
temperature, diluted with water and extracted with EtOAc, washed
with brine, dried over MgSO.sub.4, filtered and evaporated. The
residue was purified by column chromatography on silica gel
(hexane:EtOAc/5:1 to 3:1) to give 5.4 g of
6-Methoxy-1-(4-methoxy-benzyl-3,3,5-trimethyl-1,3-dihydro-indol-2-one
(77%). .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): .delta.: 1.38 (s,
6H), 2.16(s, 3H), 3.71(s, 3H), 3.77 (s, 3H), 4.84 (s, 2H), 6.28 (s,
1H), 6.82-6.85(m, 2H), 6.95(s, 1H), 7.19-7.22 (m, 2H).
[0415] f.
N-(2-bromo-5-methoxy-4-methyl-phenyl)-N-(4-methoxy-benzyl)-isob-
utyramide
[0416] To a solution of
N-(2-bromo-5-methoxy-4-methyl-phenyl)isobutyramide (6.83 g) in DMSO
(40 mL) was added powder KOH (2.68 g, 47.7 mmol) and
4-methoxybenzyl chloride (7.5 g, 47.7 mmol) under argon. The
mixture was stirred at room temperature for 17 hours. Water (30 mL)
was added and the mixture extracted with EtOAc, washed with brine,
dried over MgSO.sub.4, filtered and evaporated under reduced
pressure. The residue was purified by column chromatography on
silica gel (hexane:EtOAc/10:1 to 3:1) to give 8.72 g of
N-(2-bromo-5-methoxy-4-methyl-phenyl)-N-(4-methoxy-benzyl)-isobutyramide
(90%). .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): .delta.: 1.00 (d,
J=7.03 Hz, 3H), 1.13 (d, J=6.45 Hz, 3H), 2.17 (s, 3H), 2.28 (m,
1H), 3.48 (s, 3H), 3.78(s, 3H), 3.84 (d, J=14.07 Hz, I H), 5.62 (d,
J=14.07 Hz, 1H), 6.06 (s, 1H), 6.78-6.81 (m, 2H), 7.10-7.13 (m,
2H), 7.38 (s, 1H).
[0417] g. N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide
[0418] To a solution of N-(3-methoxy-4-methyl-phenyl)-isobutyramide
(5.0 g, 24.1 mmol) in dichloromethane (200 mL) was added
tetrabutylammonium tribromide (12.2 g, 25.3 mmol) at 0.degree. C.
The mixture was then stirred at room temperature for 20 hours. The
solution was washed with water, brine, aqueous sodium bicarbonate
solution, brine, dried over MgSO.sub.4, filtered and evaporated
under reduced pressure to give 6.83 g of
N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (99%). .sup.1H
NMR (300 MHz, CDCl.sub.3, ppm): .delta.: 1.29 (d, J=7.03 Hz, 6H),
2.15 (s, 3H), 2.59 (m, 1H), 3.84 (s, 1H), 7.24 (s, 1H), 7.65 (bs,
1H), 8.08 (s, 1H).
[0419] h. N-(3-methoxy-4-methyl-phenyl)-isobutyramide
[0420] N-(3-hydroxy-4-methyl-phenyl)-isobutyramide (6.48 g, 33.5
mmol) was dissolved in 40 mL of acetone, potassium carbonate (13.9
g, 100.5 mmol) was added followed by methyl iodide (14.3 g, 100.5
mmol). The mixture was stirred at room temperature for about 3
days. The solution was filtered and evaporated under reduced
pressure to give 6.6 g of
N-(3-methoxy-4-methyl-phenyl)-isobutyramide (95%). .sup.1H NMR (300
MHz, CDCl.sub.3, ppm): .delta.: 1.26 (d, J=7.03 Hz, 6H), 2.17 (s,
3H), 2.49 (m, 1H), 3.83 (s, 3H), 6.71 (dd, J=2.05 Hz, 8.21 Hz, 1H),
7.02 (d, J=7.91 Hz, 1H), 7.11 (bs, 1H), 7.47 (d, J=1.76 Hz,
1H).
[0421] i. N-(3-hydroxy-4-methyl-phenyl)-isobutyramide
[0422] To a mixture of 5-amino-2-methylphenol (30 g, 244 mmol), 10%
NaOH (210 mL) and dichloromethane (120 mL) was added at 0.degree.
C. slowly isobuyryl chloride (25.5 mL, 244 mmol) in dichloromethane
(50 mL). The mixture was stirred at room temperature overnight. The
aqueous layer was separated and extracted with EtOAc, washed with
brine, dried over MgSO.sub.4, filtered and evaporated under reduced
pressure to give 37.2 g of
N-(3-hydroxy-4-methyl-phenyl)-isobutyramide (78%). .sup.1H NMR (300
MHz, CDCl.sub.3 ppm): .delta.: 1.21(d, J=7.03 Hz, 6H), 2.17(s, 3H),
2.53 (m, 1H), 2.58 (s, 3H), 6.81(dd, J=2.05 Hz, 7.91 Hz, 1H), 6.97
(d, J=7.91 Hz, 1H), 7.38 (d, J=2.05 Hz, 1H), 8.14 (bs, 1H), 8.58
(s, 1H).
Example 22
5-[4-Trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)--
benzylidene]-thiazolidine-2,4-dione, which can be referred to as
"Compound 22"
[0423] ##STR79##
[0424] Prepared in a similar manner to example 1 using
4-trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-be-
nzaldehyde (example 21b; 58% yield. .sup.1H-NMR (300 MHz,
DMSO-d-6): 1.29 (s, 6H), 2.03 (s, 3H), 6.64 (s, 1H), 7.28 (s, 1H),
7.61-7.66 (m, 2H), 7.74 (dd, J=2.34, 8.79 Hz, 1H), 7.86(s, 1H),
10.33 (s, 1H), 12.71 (bs, 1H).
Example 23
5-[4-Trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-1-propyl-2,3-dihydro-1H-ind-
ol-6-yl)-benzylidene]-thiazolidine-2,4-dione, which can be referred
to as "Compound 23"
[0425] ##STR80##
[0426] Prepared in a similar manner to example 1 using
4-trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-1-propyl-2,3-dihydro-1H-indol-
-6-yl)-benzaldehyde. 58% yield. .sup.1H-NMR (300 MHz, DMSO-d.sub.6,
ppm): 0.82 (t, J=7.33 Hz, 3H), 1.31 (s, 6H), 1.58 (m, 2H), 2.06 (s,
3H), 3.62 (t, J=7.62 Hz, 2H), 6.91 (s, 1H), 7.34 (s, 1H), 7.65 (d,
J=2.35 Hz, 1H), 7.6 (m, 1H), 7.75 (dd, J=2.34, 8.79 Hz, 1H), 7.87
(s, 1H), 12.7 (bs, 1H).
[0427] The intermediate
4-trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-1-propyl-2,3-dihydro-1H-indol-
-6-yl)-benzaldehyde was prepared in a similar manner to example 21a
using
4-trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-be-
nzaldehyde (example 21b) and propyl iodide. .sup.1H NMR (300 MHz,
CDCl.sub.3, ppm): .delta.: 0.93(t, J=7.3 Hz, 3H), 1.45(s, 6H),
1.70(m, 2H), 2.10(s, 3H), 3.66 (m, 2H), 6.63 (s, 1H), 7.11 (s, 1H),
7.52-7.55 (m, 1H), 7.85 (m, 1H), 7.98 (m, 1H), 10.05 (s, 1H).
Example 24
5-[3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-trifluor-
omethoxy-benzylidene]-thiazolidine-2,4-dione, which can be referred
to as "Compound 24"
[0428] ##STR81##
[0429] The synthesis and utility of Compound 24 was disclosed in
U.S. Pat. No. 6,515,003, issued Feb. 4, 2003, which is incorporated
herein in its entirety by this reference.
Example 25
5-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-tr-
ifluoromethoxy-benzylidene]-thiazolidine-2,4-dione, TRIS salt,
which can be referred to as "Compound 25"
[0430] ##STR82##
[0431] Compound 2 (14.85 g, 29.37 mmol) was dissolved in dry THF
(100 mL) and a solution of tris(hydroxymethyl)aminomethane ("Tris,"
3.56 g, 29.37 mmol) in dry methanol (20 mL0 was added dropwise at
room temperature. The reaction mixture was stirred 48 hrs at room
temperature, filtered and evaporated. The residue was redissolved
in ethanol, evaporated and dried under high vacuum to afford 16.6 g
of:
5-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-t-
rifluoromethoxy-benzylidene]-thiazolidine-2,4-dione. TRIS.
.sup.1H-NMR (300 MHz, DMSO-d-6): 1.06 (t, J=7.2 Hz, 3H); 1.26 (s,
6H), 2.08 (s, 3H), 2.46 (s, 2H), 3.47 (s, 6H), 3.96 (br d, 2H),
5.16 (s, 3H), 6.97 (s, 1H), 7.30 (s, 1H), 7.36(s, 1H), 7.52 (d,
J=2.4 Hz, 1H), 7.55 (dd, J=1.5 Hz and 8.4 Hz, 1H), 7.68 (dd, J=2.1
Hz and 8.7 Hz, 1H).
Example 26
Differentiation of 3T3-L1 Pre-Adipocytes in an In Vitro Assay. (See
Results in FIG. 1)
[0432] The following protocol was used to determine adipocyte
differentiation activity of the compounds of the invention:
[0433] Mouse pre-adipocyte 3T3-L1 cells obtained from ATCC
(American Tissue Culture Collection, Md.) were initially grown in
DME Dulbecco's modified Eagle's medium containing 4500 mg/L
glucose; 4 mM L-glutamine; 10 U/ml Pen-G; 10 mcg/ml Streptomycin
and 10% Bovine Calf Serum (CS) at 37.degree. C. and 10% CO.sub.2.
Cells were plated in 96 well plates at a density of approximately
3,000 cells/well and grown to confluence (when cells use 100% of
the available space on the well) in the same medium.
Differentiation experiments were conducted two days after
confluence in a differentiation medium (DM) consisting of DME
Dulbecco's modified Eagle's medium containing 4500 mg/L glucose; 4
mM L-glutamine; 10 U/ml Pen-G; 10 mcg/ml Streptomycin and 10% Fetal
Calf Serum (FCS) and 1 .mu.g/mL of insulin. Cells were then treated
with the test compound at a concentration of 10.sup.-10 to
10.sup.-6M, or with a control for fully-differentiated adipocytes,
such as Dexamethasone/Insulin (2.5 .mu.M; 10 .mu.g/ml,
respectively). Differentiation medium containing the compounds,
with no further addition of insulin, was replaced every 2-3 days
for a total of 7 days. Compound 24 was used as a standard for
differention activity, and its ability to differentiate 3T3-L1
cells at 0.1 .mu.M was taken as reference for 100% differentiation.
Upon termination of the experiments the treated cells were washed
once with PBS (Phosphate Buffer Saline, Irvine Scientific, Irvine,
Calif.) and lysed in situ with 50 .mu.L 10% Hecameg (Detergent,
Calbiochem, San Diego). The cellular lysates were analyzed for
their lipid content using the Triglyceride-GPO Trinder reagent from
Sigma.
[0434] As shown in FIG. 1, many of compounds of the invention
induce differenciation of 3T3-L1 cells.
Example 27
Oral Administration of Selected Compounds in the Treatment of Type
2 Diabetes in KKA.sup.y Mice (FIG. 2a-e)
[0435] The procedure for this in-vivo assay for anti-diabetes
activity was described in detail by Iwatsuka, et al. (1970 General
Survey of Diabetic Features of Yellow KK Mice. Endocrinol. Japon.
17: 23-35, incorporated herein in its entirety by reference).
[0436] Experimental Procedures: Six to eight week-old male
KKA.sup.y mice (obtained from Jackson Labs of Bar Harbord, Me.)
were housed in a fixed 12-12-hr artificial light-dark cycle, and
maintained on a standard rodent diet provided ad libitum. Animals
were allowed two days to acclimate in this experimental environment
prior to the initiation of the study.
[0437] Prior to initiation of treatment with the compounds of the
invention, the animals were bled from the tail vein (100-200 .mu.L
of whole blood) and serum levels of glucose and triglycerides were
measured in duplicate (Trinder kits; Sigma, St. Louis, Mo.). Based
on these initial measures, animals were sorted into groups with
approximately the same average serum glucose levels. Once sorted,
the animals were housed one per cage and provided rodent diet ad
libitum. Unless otherwise indicated, compounds were suspended in
sesame oil, and administered by oral gavage once daily to animals
in a volume of 3 ml/kg/dose.
[0438] Treatment Group A (n=5/group): (See Results in FIG. 2a)
[0439] 1) KKA.sup.y vehicle control (sesame oil) [0440] 2) Compound
1 (3 mg/kg) [0441] 3) Compound 1 (10 mg/kg) [0442] 4) Compound 2 (3
mg/kg) [0443] 5) Compound 2 (10 mg/kg)
[0444] Treatment Group B (n=6/group): (See Results in FIG. 2b)
[0445] 1) KKA.sup.y vehicle control (sesame oil) [0446] 2) Compound
11 (15 mg/kg)
[0447] Treatment Group C (n=6/group): (See Results in FIG. 2c)
[0448] 1) KKA.sup.y vehicle control (sesame oil) [0449] 2) Compound
13 (15 mg/kg)
[0450] Treatment Group D (n=6/group): (See Results in FIG. 2d)
[0451] 1) KKA.sup.y vehicle control (CMC) [0452] 2) Compound 25 (3
mg/kg, CMC) Compound 25 was suspended in a solution of
carboxymethyl cellulose (CMC; 1% carboxy methyl cellulose in
H.sub.2O, with 10% polyethelene glycol 400), and administered to
animals in a volume of 5 ml/kg/dose.
[0453] Treatment Group E (n=5/group): (See Results in FIG. 2e)
[0454] 1) KKA.sup.y vehicle control (10% HPPCD) [0455] 2) Compound
25 (1 mg/kg) [0456] 3) Compound 25 (3 mg/kg) [0457] 4) Compound 25
(10 mg/kg) Compound 25 was dissolved in a 10% hydroxy propyl beta
cyclodextrin solution, and administered to animals in a volume of
10 ml/kg/dose.
[0458] To monitor the effect of the tested compounds, animals were
bled at the end of the dark cycle on days 7, 14, and/or 21 of the
treatment period. Serum glucose, triglyceride and/or cholesterol
levels were measured in duplicate. The blood is kept at room
temperature to allow coagulation, after which the serum is
separated and assayed for glucose, triglyceride and/or cholesterol
levels. As shown in FIGS. 2a-2d all of the compounds tested reduced
serum glucose and triglyceride levels, some with doses as low as 3
mg/kg when administered once a day. Also, as shown in FIG. 2e
compound 25 causes an unexpectedly strong and simultaneous
reduction in serum glucose, triglyceride and total cholesterol
levels of type 2 diabetic KKAy mice following 4 weeks of
treatment.
Example 28
Oral Administration of Selected Compounds in the Treatment of Type
2 Diabetes in db/db Mutant Mice (See Results in FIG. 3)
[0459] Experimental Procedure: Seven week-old female db/db mutant
mice (C57BL/KsJ-db+/+m; Jackson Labs, Bar Harbour, Me.) were housed
in a fixed 12-12-hr artificial light-dark cycle, and maintained on
a standard high fat diet (containing at least 11% crude fat)
provided ad libitum (Teklad S-2335). Animals were allowed two days
to acclimate in this experimental environment prior to the
initiation of the study. Prior to initiation of treatment, the
animals were bled from the tail vein (100-200 .mu.L of whole blood)
and serum levels of glucose and triglycerides were measured in
duplicate (Trinder kits; Sigma, St. Louis, Mo.). Based on these
initial measures, animals were sorted into treatment groups with
approximately the same average serum glucose levels. Once sorted,
the animals were housed five per cage and provided high fat rodent
diet ad libitum.
[0460] Treatment groups (n=5/group): [0461] 1) db/db control (CMC)
[0462] 2) Compound 25 (0.1 mg/kg, in CMC) [0463] 3) Compound 25
(0.3 mg/kg, in CMC) [0464] 4) Compound 25 (1 mg/kg, in CMC)
[0465] Compound 25 was suspended in a solution of carboxymethyl
cellulose (CMC; 1% carboxy methyl cellulose in H.sub.2O, with 10%
polyethelene glycol 400), and administered to animals in a volume
of 5 ml/kg/dose. The drug is administered by oral gavage once daily
at the beginning of the artificial light cycle.
[0466] To monitor the effect of the tested compounds, animals were
bled following a three-hour fast at the end of the dark cycle on
days 0, 7, 14 of the treatment period. Fasting serum glucose and
triglyceride levels were measured in duplicate. The blood is kept
at room temperature to allow coagulation, after which the serum is
separated and assayed for glucose and triglyceride levels. As shown
in FIG. 3, compound 25 ameliorate the symptoms of diabetes in with
doses as low as, 0.3 mg/kg when administered once daily. Both serum
glucose and triglyceride were reduced compared to control animals,
which showed the typical hyperglycemia and hypertriglyceridemia
associated with type 2 diabetes.
Example 29
Cholesterol Efflux Assay from Macrophage Foam Cells as Induced by
Compound 2. (See Results in FIG. 4)
[0467] Cholesterol efflux from macrophage foam cells was assayed as
described by Sparrow. et al, J. Biol. Chem., 2002, 277,
10021-10027, which is encorporated herein in its entirety by this
reference. THP-1 cells obtained from ATCC (Manassas, VI), were
cultured in RPMI medium (Sigma, St-Louis, Mo.), containing 10%
fetal calf serum (Sigma, St-Louis, Mo.), 0.05 .mu.M
2-mercaptoethanol, 1 mM sodium pyruvate, 2 mM L-glutamine, 100
units/ml penicillin, 0.1 .mu.g/ml streptomycin and 0.25 .mu.g/ml
amphotericin B obtained from Sigma (St-Louis, Mo.). The THP-1 cells
were differentiated into macrophages in 24 well tissue culture
dishes at a density of 0.5 million cells/well by incubation in the
same medium plus 100 nM tetradecanoyl phorbol acetate (Sigma,
St-Louis, Mo.), for 3 days.
[0468] After differentiation into macrophages, the cells were
tested for cholesterol efflux as induced by compound 2 of the
invention. Cells were labeled by incubation for 24 hr in fresh
growth medium containing [3H]-cholesterol (10 .mu.Ci/ml)
(PerkinElmer, Boston, Mass.), and 50 .mu.g/ml acetylated-LDL
(Frederick, Md.) and 1% Fetal bovine serum (Sigma, St-Louis, Mo.).
Following labeling with [3H]-cholesterol, cells were washed, and
incubated for an additional 24 hr in serum-free media containing 1
mg/ml bovine serum albumin (Sigma, St-Louis, Mo.), to allow for
equilibration of [3H]-cholesterol with intracellular cholesterol.
Cholesterol efflux was initiated by adding the 10 .mu.g/ml ApoA-I
(CalBiochem, La Jolla, Calif.), with or without Compound 2 (1 .mu.M
final concentration) in serum free media. Compound 2 was added to
cultured cells from stock solution, and control cells received an
equivalent amount of vehicle. After 24 hr, media were harvested and
cells were dissolved in 1 mM HEPES, pH 7.5 containing 0.5% of a
detergent Triton X-100 (Sigma, St-Louis, Mo.). Media were briefly
centrifuged to remove non-adherent cells, and then aliquots of both
the supernatant and the dissolved cells were counted by liquid
scintillation spectrometry to determine radioactivity.
[0469] Cholesterol efflux is expressed as a percentage, calculated
as ([3H]Cholesterol in medium)/([3H]Cholesterol in
medium+[3H]cholesterol in cells).times.100
[0470] As shown in FIG. 4, compound 2 increases cholesterol efflux
from THP-1 cells as compared to non treated cells.
Example 30
Oral Administration of Selected Compounds in the Treatment of
Diet-Induced Hypercholesterolemia in Wild Type Sprague Dawley Rats
(See Results in FIGS. 5a-c)
[0471] Experimental Procedure: Six week-old male Sprague Dawley
rats (obtained from Harlan of San Diego, Calif.) were housed in a
fixed 12-12-hr artificial light-dark cycle, and maintained on a
high cholesterol atherogenic diet (Paigen's Diet, obtained from
Research Diet Inc. of New Brounswick, N.J.) was provided ad
libitum. Animals were allowed six days to acclimate in this
experimental environment prior to the initiation of the study.
[0472] Prior to initiation of treatment, the animals were bled from
the tail vein (100-200mL of whole blood) and serum levels of
cholesterol were measured in duplicate (Cholesterol Infinity kits;
Sigma, St. Louis, Mo.). Based on these initial measures, animals
were sorted into groups with approximately the same average total
cholesterol levels. Once sorted, the animals were housed three per
cage and maintained on Paigen's diet ad libitum. All compounds to
be tested were suspended in sesame oil and administered in a final
volume of 3 ml/kg. Drug is administered by oral gavage once daily
at the beginning of the artificial light cycle. To obtain a base
line for lipid measurement, a control group maintained on standart
rodent diet is included (lean control).
[0473] Treatment Group A (n=6/group): (See Results in FIG. 5a)
[0474] 1) Lean control (Sesame Oil) [0475] 2) Control [0476] 3)
Compound 2 (0.3 mg/kg) [0477] 4) Compound 2 (1 mg/kg) [0478] 5)
Compound 2 (3 mg/kg)
[0479] Treatment Group B (n=6/group): (See Results in FIG. 5b)
[0480] 1) Lean control (Sesame Oil) [0481] 2) Control [0482] 3)
Compound 6 (3 mg/kg)
[0483] Treatment Group C (n=6/group): (See Results in FIG. 5c)
[0484] 1) Lean control (10% HPPCD) [0485] 2) Control [0486] 3)
Compound 25 (1 mg/kg) [0487] 4) Compound 25 (3 mg/kg) [0488] 5)
Compound 25 (10 mg/kg) [0489] 6) Compound 25 (15 mg/kg) [0490] The
compounds were dissolved in a 10% hydroxy propyl beta cyclodextrin
solution, and administered to animals in a volume of 10
ml/kg/dose.
[0491] To monitor the effect of the tested compounds, animals were
bled from the tail vein at the end of the dark cycle on days 0 (for
sorting) and day 5 of the treatment period. Fed serum cholesterol
levels were measured in duplicate. The blood is kept at room
temperature to allow coagulation, after which the serum is
separated and assayed for total cholesterol (Infinity reagent,
Sigma), HDL cholesterol (using HDL precipitating reagent and
infinity reagent, Sigma) and LDL cholesterol (EzLDL kit, Sigma). As
shown in FIGS. 5a-c, all compounds tested show significant
reduction in total and LDL cholesterol levels and a significant
increase in HDL cholesterol levels compared to high fat fed control
animals.
Example 31
Oral Administration of Selected Compounds Slows the Progression of
Mammary Tumors in Sprague Dawley Rats (See Results in FIG. 6)
[0492] Procedure: Five week-old female Sprague Dawley rats (Harlan)
were housed in a fixed 12-12-hr artificial light-dark cycle, and
maintained on a standard rodent diet provided ad libitum. Animals
were allowed two days to acclimate in this experimental environment
prior to the initiation of the study. To induce mammary tumors, the
female mice were injected intraperitoneally with the carcinogen
n-nitroso-n-methylurea, in a single dose of 50 mg/kg in acidified
normal saline (pH4 w/acetic acid) at a final volume of 10 mg/ml (5
ml/kg). After eight weeks, mammary tumors are detected, and the
tumor bearing females are sorted into treatment groups. Once
sorted, the animals were housed four per cage and provided rodent
diet ad libitum. All animals are treated with compound 1 or a
vehicle for four weeks, during which time changes in tumor size are
monitored. Tumors were classified as regressing, static or
progressing.
[0493] Treatment groups (n=8/group): [0494] 1) Control (sesame oil)
[0495] 2) Compound 6 (20 mg/kg) [0496] 3) Compound 11 (100 mg/kg)
[0497] 4) Compound 13 (50 mg/kg) [0498] 5) Compound 24 (50 mg/kg)
[0499] 6) Compound 25 (20 mg/kg) [0500] 7) Compound 25 (100
mg/kg)
[0501] All of the compounds tested were suspended in sesame oil,
and administered to animals in a volume of 3 ml/kg/dose, except
compound 25 which was dissolved in a 10% hydroxy propyl beta
cyclodextrin solution, and administered to animals in a volume of
10 m/kg/dose. All treatments were administered by oral gavage once
daily for four weeks.
[0502] To monitor the effect of the tested compound, animals were
examined for mammary tumors once every week. Tumors were classified
into one of three categories, progressing, static or regressing.
All of the compounds tested slowed the progression of mammary
tumors compared to vehicle treated controls as shown in FIG. 6.
Nevertheless, some of the compounds showed greater efficacy in this
model. For example, Compound 25 caused the regression of tumors at
doses as low as 20 mg/kg, whereas, compounds 11 and 13 only
increase the number of static tumors (tumors that do not change in
volume over the course of the study) compared to control animals
without causing any regressions.
Example 32
A Comparison of Oral Bioavailability between Compound 24 and
Compound 25 (See Results in FIG. 7)
[0503] Six to eight week-old male Sprague Dawley rats (Harlan) were
housed in a fixed 12-12-hr artificial light-dark cycle, and
maintained on a standard rodent diet provided ad libitum. Animals
were allowed two days to acclimate in this experimental environment
prior to the initiation of the study. Compounds 24 and 25 were
dissolved in a 10% hydroxypropyl beta cyclodextrin solution and
administered by oral gavage in a final dose of 10 mg/kg in a volume
of 5 ml/kg. Treatment groups were divided as follows:
[0504] Treatment groups (n=3/group): [0505] 1) Compound 24 (10
mg/kg) [0506] 2) Compound 25 (10 mg/kg)
[0507] Each animal received a single treatment, after which, the
animal was bled from the tail vein at the following time points:
0.5, 1, 2, 4, 6, 9, 12, and 26 hours after treatment. To measure
the concentration of each compound in plasma, blood samples were
collected in heparin-coated tubes, and the plasma was isolated and
analyzed by HPLC. Compound 25 was present at a significantly higher
concentration as compared to compound 24, which was only detected
as being present at near the limit of detection in the plasma
samples (FIG. 7). This highlights the improved bioavailability and
pharmaceutical properties of Compound 25 over Compound 24.
[0508] It will be apparent to those skilled in the art that various
modifications and variations can be made in the present invention
without departing from the scope or spirit of the invention. Other
embodiments of the invention will be apparent to those skilled in
the art from consideration of the specification and practice of the
invention disclosed herein. It is intended that the specification
and examples be considered as exemplary only, with a true scope and
spirit of the invention being indicated by the following
claims.
* * * * *