U.S. patent number RE39,266 [Application Number 10/697,926] was granted by the patent office on 2006-09-05 for heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases.
This patent grant is currently assigned to Dr. Reddy's Laboratories, Limited. Invention is credited to Ranjan Chakrabarti, Ranga Madhavan Gurram, Braj Bhushan Lohray, Vidya Bhushan Lohray, Sarma K. S. Pakala, Rao Bheema Paraselli, Rajagopalan Ramanujam.
United States Patent |
RE39,266 |
Lohray , et al. |
September 5, 2006 |
Heterocyclic compounds, process for their preparation and
pharmaceutical compositions containing them and their use in the
treatment of diabetes and related diseases
Abstract
The present invention relates to novel antidiabetic compounds,
their tautomeric forms, their derivatives, their stereoisomers,
their polymorphs, their pharmaceutically acceptable salts, their
pharmaceutically acceptable solvates and pharmaceutically
acceptable compositions containing them. This invention
particularly relates to novel azolidinedione derivatives of the
general formula (I), and their pharmaceutically acceptable salts,
pharmaceutically acceptable solvates and pharmaceutical
compositions containing them. ##STR00001##
Inventors: |
Lohray; Vidya Bhushan
(Hyderabad, IN), Lohray; Braj Bhushan (Hyderabad,
IN), Paraselli; Rao Bheema (Hyderabad, IN),
Gurram; Ranga Madhavan (Hyderabad, IN), Ramanujam;
Rajagopalan (Hyderabad, IN), Chakrabarti; Ranjan
(Hyderabad, IN), Pakala; Sarma K. S. (Hyderabad,
IN) |
Assignee: |
Dr. Reddy's Laboratories,
Limited (Hyderabad, IN)
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Family
ID: |
27272452 |
Appl.
No.: |
10/697,926 |
Filed: |
October 30, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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09353286 |
Jul 14, 1999 |
6114526 |
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08884816 |
Jun 30, 1997 |
5985884 |
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08777627 |
Dec 31, 1996 |
5885997 |
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Reissue of: |
09535387 |
Mar 24, 2000 |
06310069 |
Oct 30, 2001 |
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Foreign Application Priority Data
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Jul 1, 1996 [IN] |
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1150/MAS/96 |
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Current U.S.
Class: |
514/256;
514/264.11; 514/266.2; 544/242; 544/253; 544/298; 544/299;
544/301 |
Current CPC
Class: |
C07D
239/36 (20130101); C07D 239/47 (20130101); C07D
239/88 (20130101); C07D 277/34 (20130101); C07D
413/12 (20130101); C07D 417/12 (20130101); C07D
471/04 (20130101); C07D 495/04 (20130101) |
Current International
Class: |
A61K
31/505 (20060101); C07D 239/02 (20060101); C07D
239/70 (20060101) |
Field of
Search: |
;514/256,266.2,264.11
;544/242,253,298,299,301 |
References Cited
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|
Primary Examiner: Qazi; Sabiha N.
Attorney, Agent or Firm: Ladas & Parry
Parent Case Text
This application is a DIV of 09/353,286, filed on Jul. 14, 1999,
now U.S. Pat. No. 6,114,526, which is a DIV of 08/884,816, filed
Jun. 30, 1997, now U.S. Pat. No. 5,985,884 and a CIP of 08/772,627,
filed Dec. 31, 1996, now U.S. Pat. No. 5,885,997.
Claims
What is claimed is:
1. An intermediate of formula (III) ##STR00126## where G represents
--CHO, --NH.sub.2, --CH.dbd.NOH, --CH.sub.2NHOH,
--CH.sub.2N(OH)CONH.sub.2 or --CH.sub.2CH(J)-COOR, wherein J
represents hydroxy or halogen atom and R represents hydrogen, or
lower alkyl group; and of X, Y and Z represents C.dbd.O or C.dbd.S
and one of the remaining of X, Y and Z represents a group C.dbd.
and the other of the remaining of X, Y or Z represents C.dbd.C;
with a proviso that when cyclic structure represented by X, Y and N
form a pyrimidinone group, G does not represent CHO, R.sup.1,
R.sup.2 and R.sup.3 are the substituents either on X, Y or Z or on
a nitrogen atom and are the same or different and represent
hydrogen atom, halogen, hydroxy or nitro, or optionally substituted
groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl,
aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl selected
from acetyl, propionyl or benzoyl; acyloxy selected from acetyloxy,
propionyloxy, or benzoyloxy; hydroxyalkyl, amino, arylamino,
arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino,
alkoxyalkyl, thioalkyl, alkylthio or carboxylic acid or its amides
or sulfonic acid or its amides with the provision that when
R.sup.1, R.sup.2 or R.sup.3 is on a nitrogen atom it does not
represent hydrogen, halogen, hydroxy, nitro; or substituted or
unsubstituted aryloxy, alkoxy, cycloalkoxy, acyloxy selected from
acetyloxy, propionyloxy, or benzoyloxy; alkylthio, carboxy or
sulfonic acid groups; or any two of R.sup.1, R.sup.2 and R.sup.3
along with the adjacent atoms to which they are attached may form a
substituted or unsubstituted cyclic structure of 4 to 7 atoms, with
one or more double bonds, which are carboxylic or optionally
contain one or more heteroatoms selected from oxygen, nitrogen and
sulfur; the linking group represented by --(CH.sub.2).sub.n--O-- is
attached either through nitrogen atom or through X, Y or Z, where n
is an integer ranging from 1-4; and Ar represents an optionally
substituted divalent aromatic or heterocyclic group.
2. A pharmaceutical composition which comprises, a compound
according to claim 1 as an effective ingredient and a
pharmaceutically acceptable carrier, diluent or excipient.
.Iadd.3. A compound selected from the group consisting of:
4-[2-[4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde,
4-[2-[2-Methyl-4-oxo-3,4,-dihydro-3-quinazolinyl]ethoxy]benzaldehyde,
4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde,
4-[2-[8-Aza-2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde-
,
4-[[3-Methyl-5-oxo-3,4,-dihydro-2-quinazolinyl]methoxy]benzaldehyde,
4-[[3-Ethyl-4-oxo-3,4,-dihydro-2-quinazolinyl]methoxy]benzaldehyde,
4-[[methyl-4-oxo-1,4,-dihydro-2-quinazolinyl]methoxy]benzaldehyde,
3-Methoxy-4-[[3-Methyl-4-oxo-3,4,-dihydro-2-quinazolinyl]methoxy]benzalde-
hyde,
4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benza-
ldehyde oxime,
N-[4-[2[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzyl]N--
hydroxyurea,
4-[2-[2-Ethyl-4-methyly-6-oxo-1,6,-dihydro-1-pyrimidinyl]ethoxy]analine
4-[2-[2-Ethyl-4-oxo-3,4,-dihydro-3-quinazolinyl]ethoxy]aniline,
Ethyl
2-bromo-3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]-
phenyl]propanoate, Ethyl
2-bromo-3-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl]p-
ropionate,
3-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6,-dihydro-1-pyrimidinyl]ethoxy]phenyl]-
-2-hydroxypropanoic acid, Ethyl
3-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6,-dihydro-1-pyrimidinyl]ethoxy]phenyl]-
-2-hydroxypropanoate,
4-[2-[2,5,6-Trimethyl-4-oxo-3,4-dihydro-thieno-[2,3-d]pyrimidin-3-yl]etho-
xy]benzaldehyde,
4-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]aniline, and
Ethyl
2-bromo-3-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]p-
henyl]propanoate..Iaddend.
Description
FIELD OF THE INVENTION
The present invention relates to novel antidiabetic compounds,
their tautomeric forms, their derivatives, their stereoisomers,
their polymorphs, their pharmaceutically acceptable salts, their
pharmaceutically acceptable solvates and pharmaceutically
acceptable compositions containing them. This invention
particularly relates to novel azolidinedione derivatives of the
general formula (I), and their pharmaceutically acceptable salts,
pharmaceutically acceptable solvates and pharmaceutical
compositions containing them. ##STR00002##
The present invention also relates to a process for the preparation
of the above said novel, azolidinedione derivatives, their
tautomeric forms, their stereoisomers, their polymorphs, their
pharmaceutically acceptable salts, pharmaceutically acceptable
solvates, novel intermediates and pharmaceutical compositions
containing them.
The azolidinedione derivatives of the general formula (I) defined
above of the present invention are useful for the treatment and/or
prophylaxis of diseases or conditions in which insulin resistance
is the underlying pathophysiological mechanism. Examples of these
diseases and conditions are type II diabetes, impaired glucose
tolerance, dyslipidsemia, hypertension, coronary heart disease and
other cardiovascular disorders including atherosclerosis. The
azolidinedione derivatives of the formula (I) are useful for the
treatment of insulin resistance associated with obesity and
psoriasis. The azolidinedione derivatives of the formula (I) can
also be used to treat diabetic complications and can be used for
treatment and/or prophylaxis of other diseases and conditions such
as polycystic ovarian syndrome (PCOS), certain renal diseases
including diabetic nephropathy, glomerulonephritis, glomerular
sclerosis, nephrotic syndrome, hypertensive nephrosclerosis,
end-stage renal diseases and microalbuminaria as well as certain
eating disorders, as aldose reductase inhibitors and for improving
cognitive functions in dementia.
BACKGROUND OF THE INVENTION
Insulin resistance is the diminished ability of insulin to exert
its biological action across a broad range of concentrations. In
insulin resistance, the body secretes abnormally high amounts of
insulin to compensate for this defect; failing which, the plasma
glucose concentration inevitably rises and develops into diabetes.
Among the developed countries, diabetes mellitus is a common
problem and is associated with a variety of abnormalities including
obesity, hypertension, hyperlipidemia (J. Clin. Invest. (1985)
75:809-817; N. Engl. J. Med.; (1987) 317:350-357; J. Clin.
Endocrinol. Metab., (1988) 66:580-583; J. Clin. Invest., (1975)
68:957-969) and other renal complications. (See patent application
No. WO 95/21608). It is now increasingly being recognized that
insulin resistance and relative hyperinsulinemia have a
contributory role in obesity, hypertension, artherosclerosis and
type 2 diabetes mellitus. The association of insulin resistance
with obesity, hypertension and angina has been described as a
syndrome having insulin resistance as the central pathogenic
link-Syndrome-X. In addition, polycystic ovarian syndrome (patent
application No. WO 95/07697), psoriasis (patent application No. WO
95/35108), dementia (Behavioral Brain Research (1996) 75:1-11) etc.
may also have insulin resistance as a central pathogenic
feature.
A number of molecular defects have been associated with insulin
resistance. These include reduced expression of insulin receptors
on the plasma membrane of insulin responsive cells and alterations
in the signal transduction pathways that become activated after
insulin binds to its receptor including glucose transport and
glycogen synthesis.
Since defective insulin action is thought to be more important than
failure of insulin secretion in the development of non-insulin
dependent diabetes mellitus and other related complications, this
raises doubts about the intrinsic suitability of antidiabetic
treatment that is based entirely upon stimulation of insulin
release. Recently, Takeda has developed a new class of compounds
which are the derivatives of
5-(4-alkoxybenzyl)-2,4-thiazolidinediones of the formula (II) (Ref.
Chem. Pharm. Bull. 1982, 30, 3580-3600). In the formula (II), V
represents substituted or unsubstituted divalent aromatic group and
U represents various groups which have been reported in various
patent documents. ##STR00003##
By way of examples, U may represent the following groups:
(i) a group of the formula (IIa) where R.sup.1 is hydrogen or
hydrocarbon residue or heterocyclic residue which may each be
substituted, R.sup.2 is hydrogen or a lower alkyl which may be
substituted by hydroxy group, X is an oxygen or sulphur atom, Z is
a hydroxylated methylene or a carbonyl, m is 0 or 1, n is an
integer of 1-3. These compounds have been disclosed in the European
Patent Application No. 0 177 353. ##STR00004##
An example of these compounds is shown in formula (IIb)
##STR00005##
(ii) a group of the formula (IIc) wherein R.sup.1 and R.sup.2 are
the same or different and each represents hydrogen or
C.sub.1-C.sub.5 alkyl, R.sup.3 represents hydrogen, acyl group, a
(C.sub.1-C.sub.6) alkoxycarbonyl group or aralkyloxycarbonyl group,
R.sup.4-R.sup.5 are same or different and each represent hydrogen,
C.sub.1-C.sub.5 alkyl or C.sub.1-C.sub.5 alkoxy or R.sup.4, R.sup.5
together represent C.sub.1-C.sub.4 alkenedioxy group, n is 1, 2, or
3, W represents CH.sub.2, CO, CHOR.sup.6 group in which R.sup.6
group in which R.sup.6 represents any one of the items or groups
defined for R.sup.3 and may be the same or different from R.sup.3.
These compounds are disclosed in the European Patent Application
No. 0 139 421. ##STR00006##
An example of these compounds is shown in (IId) ##STR00007##
iii) A group of formula (IIe) where A.sup.1 represents substituted
or unsubstituted aromatic heterocyclic group, R.sup.1 represents a
hydrogen atom, alkyl group, acyl group, an aralkyl group wherein
the aryl moiety may be substituted or unsubstituted, or a
substituted or unsubstituted aryl group, n represents an integer in
the range from 2 to 6. These compounds are disclosed in European
Patent No. 0 306 228. ##STR00008##
An example of this compound is shown in formula (IIf)
##STR00009##
iv) A group of formula (IIg) where Y represents N or CR.sup.5,
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 represents hydrogen,
halogen, alkyl and the like and R.sup.6 represents hydrogen, alkyl,
aryl and the like, n represents an integer of 0 to 3. These
compounds are disclosed in European Patent Application No. 0 604
983. ##STR00010##
An example of this compound is shown in formula (IIh)
##STR00011##
Still another class of antihyperglycemic agents are 5-substituted
oxazolidine-2,4-diones and
2-substituted-1,2,4-oxadiazolidine-3,5-diones which can be
represented in the formula (IIi). ##STR00012## where V represents
substituted or unsubstituted divalent aryl or hetero aryl group. W
represents various groups which have been reported in various
patent documents, A represents nitrogen atom or a CH group and B is
an oxygen atom.
By way of examples, W may represent the following groups:
v) a group of formula (IIj), where R is (C.sub.1-C.sub.6) alkyl
groups, cycloalkyl group, furyl, thienyl, substituted or
unsubstituted phenyl group, X is hydrogen, methyl, methoxy, chloro
or fluoro. These compounds have been disclosed in the U.S. Pat. No.
5,037,842. ##STR00013##
An example of these compounds is shown in formula (IIk).
##STR00014##
(vi) A group of formula (III) wherein A.sup.1 represents a
substituted or unsubstituted aromatic heterocyclyl group; R.sup.1
represents a hydrogen atom, an alkyl group, an acyl group, an
aralkyl group, wherein the aryl moiety may be substituted or
unsubstituted or a substituted or unsubstituted aryl group, n
represents an integer in the range of from 2 to 6. These compounds
have been disclosed in the patent application No. WO 92/02520.
##STR00015##
An example of these compounds is shown in formula (IIm).
##STR00016##
(vii) A group of formulae (IIn) and (IIo), where R.sup.1 is
hydrogen, (C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)alkoxy,
trifuoroalkoxy, halogen or trifluoromethyl group, R.sup.2is
hydrogen or methyl and X is oxygen or sulfur. These compounds have
been described in U.S. Pat. No. 5,480,486. ##STR00017##
An example of these compounds is shown in formula (IIp)
##STR00018##
Some of the above referenced hitherto known antidiabetic compounds
seem to possess bone marrow depression, liver and cardiac
toxicities and modest potency and consequently, their regular use
for the treatment and control of diabetes is becoming limited and
restricted.
SUMMARY OF THE INVENTION
With an objective of developing new compounds for the treatment of
type II diabetes [non-insulin-dependent-diabetes mellitus (NIDDM)]
which could be more potent at relatively lower doses and having
better efficacy with lower toxicity, we focused our research
efforts in a direction of incorporating safety and to have better
efficacy, which has resulted in the development of novel
azolidinedione derivatives having the general formula (I) as
defined above.
The main objective of the present invention is therefore, to
provide novel azolidinedione derivatives, their tautomeric forms,
their stereoisomers, their polymorphs, their pharmaceutically
acceptable salts, their pharmaceutically acceptable solvates and
pharmaceutical compositions containing them, or their mixtures.
Another objective of the present invention is to provide novel
azolidinedione derivatives, their tautomeric forms, their
stereoisomers, their polymorphs, their pharmaceutically acceptable
salts, their pharmaceutically acceptable solvates and
pharmaceutical compositions containing them or their mixtures
having enhanced activities, no toxic effect or reduced toxic
effect.
Yet another objective of the present invention is to produce a
process for the preparation of novel azolidinediones of the formula
(I) as defined above, their tautomeric forms, their stereoisomers,
their polymorphs, their pharmaceutically acceptable salts and their
pharmaceutically acceptable solvates.
Still another objective of the present invention is to provide
pharmaceutical compositions containing compounds of the general
formula (I), their tautomers, their stereoisomers, their
polymorphs, their salts, solvates or their mixtures in combination
with suitable carriers, solvents, diluents and other media normally
employed in preparing such compositions.
Yet another objective of the present invention is to provide a
process for the preparation of the novel intermediate of the
formula (III) ##STR00019## where G represents --CHO, --NO.sub.2,
--NH.sub.2, --CH.dbd.NHOH, --CH.sub.2NHOH,
--CH.sub.2N(OH)CONH.sub.2 or --CH.sub.2CH(J)--COOR, where J
represents hydroxy group, halogen atom such as chlorine, bromine or
iodine and R represents H or lower alkyl group such as methyl,
ethyl, or propyl, X, Y, Z, R.sup.1, R.sup.2, R.sup.3, n, and Ar are
defined as in formula (I).
DETAILED DESCRIPTION OF THE INVENTION
Azolidinedione derivatives of the present invention have the
general formula (I) ##STR00020##
In the above formula (I), one of X, Y or Z represents C.dbd.O or
C.dbd.S and the remaining of X, Y and Z represent a group C.dbd. or
C.dbd.C; R.sup.1, R.sup.2 and R.sup.3 are groups either on X, Y or
Z or on a nitrogen atom. R.sup.1, R.sup.2 and R.sup.3 may be same
or different and represent hydrogen, halogen, hydroxy, or nitro, or
optionally substituted groups selected from alkyl, cycloalkyl,
alkoxy, cycloalkoxy, aryl, aralkyl, hetereocyclyl, heteroaryl,
heteroaralkyl, acyl, aryloxy, hydroxyalkyl, amino, acylamino,
arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino,
alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its
derivatives, or sulfonic acid or its derivatives with the provision
that when R.sup.1, R.sup.2 or R.sup.3 is on a nitrogen atom it does
not represent hydrogen, halogen, nitro, carboxylic acid or sulfonic
acid groups; or any two of R.sup.1, R.sup.2and R.sup.3 along with
the adjacent atoms to which they are attached may also form a
substituted or unsubstituted cyclic structure of from 4 to 7 atoms
with one or more double bonds, the cyclic structure may be
carbocyclic or may contain one or more heteroatoms selected from
oxygen, nitrogen and sulfur. When the groups representing R.sup.1,
R.sup.2 or R.sup.3 are substituted, the substituents are selected
from the same groups that may represent R.sup.1, R.sup.2, and
R.sup.3 such as hydroxy, halogen, or nitro, or optionally
substituted groups selected from alkyl, cycloalkyl, alkoxy,
cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl,
heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino,
arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino,
alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its
derivatives, or sulfonic acid or its derivatives. The linking group
represented by --(CH.sub.2).sub.n--O-- in formula (I) may be
attached either through nitrogen atom or through X, Y or Z where n
is an integer ranging from 1-4. Ar represents an optionally
substituted divalent aromatic or heterocyclic group, R.sup.4
represents hydrogen atom, halogen or lower alkyl group or forms a
bond together with the adjacent group A. A represents a nitrogen
atom or a group CR.sup.5 where R.sup.5 represents hydrogen, halogen
or lower alkyl group such as methyl, ethyl, propyl or the like or
R.sup.5 forms a bond together with R.sup.4; B represents an oxygen
atom or a sulfur atom when A is CR.sup.5 and B represents an oxygen
atom when A is a nitrogen atom.
Suitable combinations of X, Y and Z that form the ring structure
containing X, Y and Z in the formula (I) are represented in the
following Table:
TABLE-US-00001 S.No. X Y Z 1. C.dbd.O or C.dbd.S .dbd.C C.dbd.C 2.
C.dbd.O or C.dbd.S C.dbd.C .dbd.C 3. .dbd.C C.dbd.O or C.dbd.S
C.dbd.C 4. .dbd.C C.dbd.C C.dbd.O or C.dbd.S 5. C.dbd.C C.dbd.O or
C.dbd.S .dbd.C 6. C.dbd.C .dbd.C C.dbd.O or C.dbd.S
It is preferred that at least one of X, Y or Z be C.dbd.C.
It is preferred that one of X or Y be C.dbd.O. Suitable ring
structures containing X, Y and Z include ##STR00021## A preferred
ring structure is ##STR00022##
When R.sup.1, R.sup.2 and R.sup.3 groups are attached to X, Y, and
Z it is preferred that R.sup.1, R.sup.2, and R.sup.3 are selected
from hydrogen, halogen atom such as fluorine, chlorine, bromine, or
iodine; hydroxy, nitro; substituted or unsubstituted
(C.sub.1-C.sub.12)alkyl group, especially, linear or branched
(C.sub.1-C.sub.6) alkyl group, such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, iso-butyl, t-butyl and the like; cycloalkyl
group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
the like; cycloalkyloxy group such as cyclopropyloxy,
cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like; aryl
group such as phenyl or naphthyl, the aryl group may be
substituted; aralkyl such as benzyl or phenethyl, the aralkyl group
may be substituted; heteroaryl group such as pyridyl, thienyl,
furyl, pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl tetrazolyl,
benzopyranyl, benzofuranyl and the like, the heteroaryl group may
be substituted; heterocyclyl groups such as aziridinyl,
pyrrolidinyl, morpholinyl, piperidinyl and the like, the
heterocyclyl group may be substituted; aryloxy such as phenoxy,
naphthyloxy, the aryloxy group may be substituted; alkoxycarbonyl
such as methoxycarbonyl or ethoxycarbonyl; aryloxycarbonyl group
such as optionally substituted phenoxycarbonyl; arylamino group
such as HNC.sub.6H.sub.5; amino group; amino(C.sub.1-C.sub.6)alkyl;
hydroxy (C.sub.1-C.sub.6)alkyl; (C.sub.1-C.sub.6)alkoxy;
thio(C.sub.1-C.sub.6)alkyl; (C.sub.1-C.sub.6)alkylthio; acyl group
such as acetyl, propionyl or benzoyl, the acyl group may be
substituted; acylamino groups such as NHCOCH.sub.3,
NHCOC.sub.2H.sub.5, NHCOC.sub.3H.sub.7, NHCOC.sub.6H.sub.5;
aralkoxycarbonylamino group such as NHCOOCH.sub.2C.sub.6H.sub.5;
alkoxycarbonylamino group such as NHCOOC.sub.2H.sub.5,
NHCOOCH.sub.3 and the like; carboxylic acid or its derivatives such
as amides, like CONH.sub.2, CONHMe, CONMe.sub.2, CONHEt,
CONEt.sub.2, CONHPh and the like, the carboxylic acid derivatives
may be substituted; acyloxy group such as OCOMe, OCOEt, OCOPh and
the like; which may optionally be substituted; sulfonic acid or its
derivatives such as SO.sub.2NH.sub.2, SO.sub.2NHMe,
SO.sub.2NMe.sub.2, SO.sub.2NHCF.sub.3 and the like; the sulfonic
acid derivatives may be substituted.
All of the preferred groups that may represent R.sup.1, R.sup.2 and
R.sup.3 may be substituted or unsubstituted.
When R.sup.1, R.sup.2 or R.sup.3 are attached to nitrogen atom, it
is preferred that R.sup.1, R.sup.2 and R.sup.3 are selected from
(C.sub.1-C.sub.12)alkyl group, especially linear or branched
(C.sub.1-C.sub.6)alkyl group, such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, t-butyl groups and the like;
cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and the like; aryl group such as phenyl or naphtyl;
aralkyl such as benzyl a phenethyl; heteroaryl group such as
pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl,
oxadiazolyl, tetrazolyl and the like; heterocyclyl groups such as
aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl and the like;
alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl;
aryloxycarbonyl group such as phenoxycarbonyl;
amino(C.sub.1-C.sub.6)alkyl; hydroxy(C.sub.1-C.sub.6)alkyl;
thio(C.sub.1-C.sub.6) alkyl; or acyl group such as acetyl,
propionyl, benzoyl, and the like.
All of the preferred groups that may represent R.sup.1, R.sup.2 and
R.sup.3 may be substituted or unsubstituted.
When the groups represented by R.sup.1, R.sup.2 and R.sup.3 are
substituted, the substituents selected are from the same groups as
those groups that represent R.sup.1, R.sup.2 and R.sup.1 and may be
selected from halogen, hydroxy, or nitro, or optionally substituted
groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl,
aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy,
hydroxyalkyl, amino, acylamino, arylamino, aminoalky, aryloxy,
alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl
groups, carboxylic acid or its derivatives, or sulfonic acid or its
derivatives.
Suitable ring structure formed by any two of R.sup.1, R.sup.2 and
R.sup.3 along with the adjacent atoms to which they are attached,
include substituted or unsubstituted 4-7 membered cyclic structure
which may contain one or more double bonds, the cyclic structure
may be carbocyclic or optionally contains one or more hetero atoms
selected from nitrogen, oxygen and sulfur. Examples of the cyclic
structures are phenyl, naphthyl, thienyl, furyl, pyrrolyl,
oxazolyl, oxadiazolyl, thiazolyl, imidazolyl, azacyclobutenyl,
isoxazolyl, azepinyl, pyridyl, pyridazyl, pyrimidinyl,
dihydrofuryl, dihydrothienyl, tetrahydropyridyl, tetrahydrophenyl,
tetrahydronaphthyl and the like. The substituents on the cyclic
structure may be selected from the same groups as that of R.sup.1,
R.sup.2 and R.sup.3. Examples of possible substituents are halogen,
alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl,
heterocyclyl, heteroaralkyl, hydroxy, acyl, acyloxy, hydroxyalkyl,
amino, arylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl,
alkylamino, alkoxyalkyl, carboxylic acid or its derivatives, or
sulfonic acid or its derivatives.
It is more preferred that R.sup.1, R.sup.2 and R.sup.3 groups
represent hydrogen; halogen atom such as fluorine, chlorine,
bromine, or iodine; alkyl group such as methyl, ethyl, n-propyl or
n-butyl; cycloalkyl group such as cyclopropyl; aryl group such as
phenyl; or aralkyl group such as benzyl.
When the groups represented by R.sup.1, R.sup.2 and R.sup.3 are
substituted, it is preferred that the substituents are selected
from halogen, haloalkyl, haloalkoxy, and halocycloalkoxy wherein
the halogen atom is preferably a flourine atom.
The ring structure formed by any two of R.sup.1, R.sup.2 and
R.sup.3 along with the adjacent atoms to which they are attached,
may be substituted a unsubstituted. Preferred ring structures are
phenyl, thienyl, furyl or pyridyl groups. When these ring
structures are substituted, it is preferred that the substituents
are selected from halogen, lower alkyl group such as methyl or
ethyl; trifluoromethyl; fluoromethyl; difuoromethyl, and alkoxy
groups such as methoxy; trifluoromethoxy, fluoromethoxy and
difluoromethoxy.
The linking group --(CH.sub.2).sub.n--O-- may be linked either
through a nitrogen atom or through X, Y or Z. The integer n may
range from 1 to 4, preferably n is 1 to 2. It is preferred that the
linking group be linked either through nitrogen or through Z when Z
represents .dbd.C.
It is preferred that the group represented by Ar be substituted or
unsubstituted divalent phenylene, naphthylene, pyridyl, quinolinyl,
benzofuryl, dihydrobenzofuryl, benzopyranyl, indolyl, indolinyl,
azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl
and the like. The substituents on the group represented by Ar may
be selected from linear or branched (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.3)alkoxy, halogen, acyl, amino, acylamino, thio, or
carboxylic or sulfonic acids or their derivatives.
It is more preferred that Ar represents substituted or
unsubstituted divalent phenylene, naphthylene, benzofuryl,
indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or
benzoxazolyl.
It is still more preferred that Ar is represented by divalent
phenylene or naphthylene, which may be optionally substituted by
methyl, halomethyl, methoxy or halomethoxy groups.
Suitable R.sup.4 includes hydrogen; lower alkyl group such as
methyl, ethyl or propyl; halogen atom such as fluorine, chlorine,
bromine or iodine, or R.sup.4 together with A represents a
bond.
Suitable A group may be nitrogen or CR.sup.5 where R.sup.5 may be a
hydrogen atom, halogen, lower alkyl group or together with R.sup.4
forms a bond.
Suitable B group includes a hetero atom selected from O or S, with
the provision that when A is CR.sup.5, B is selected from sulfur or
oxygen, and when A is nitrogen, B represents oxygen.
Suitable ring structure comprising A and B include
2,4-dioxooxazolidin-5-yl, 2,4-dioxothiazolidin-5-yl, 3,5-dioxol,
2,4-oxodiazolidin-2-yl groups. Preferred ring structures
comprising, A and B include 2,4-dioxooxazolidine-5-yl and
2,4-dioxothiazolidin-5-yl groups.
It is more preferred that the ring structure comprising A and B is
a 2,4l-dioxothiazolidin-5-yl group.
Pharmaceutically acceptable salts forming part of this invention
include salts of the azolidinedione moiety such as alkali metal
salts like Li, Na, and K salts, alkaline earth metal salts like Ca
and Mg salts, salts of organic bases such as lysine, arginine,
guanidine, diethanolamine, choline and the like, ammonium or
substituted ammonium salts, salts of carboxy group wherever
appropriate, such as aluminum, alkali metal salts; alkaline earth
metal salts, ammonium or substituted ammonium salts. Salts may
include acid addition salts which are, sulphates, nitrates,
phosphates, perchlorates, borates, hydrohalides, acetates,
tartrates, maleates, citrates, succinates, palmoates,
methanesulfonates, benzoates, salicylates, hydroxynaphthoates,
benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates
and the like. Pharmaceutically acceptable solvates may be hydrates
or comprising other solvents of crystallization such as
alcohols.
Particularly useful compounds according to the present invention
includes:
5-[4-[2-[2,4-dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]ph-
enyl methyl]thiazolidine-2,4-dione and its salts.
5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidiny]ethoxy]phenyl
methyl]thiazolidine-2,4-dione and its salts,
5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione and its salts,
5-[4-[2-[2-butyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione and its salts,
5-[4-[2-[2-ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione and its salts;
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methyl]thiazolidine-2,4-dione and its salts and its polymorphs.
5-[4-[[3-ethyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methyl]thiazolidine-2,4-dione and its salts,
5-[4-[2[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methyl]thiazolidine-2,4diode and its salts,
5-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione and its salts.
5-[4-[2-[6,7-dimethoxy-2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]ph-
enyl methyl]thiazolidine-2,4-dione and its salts,
5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]oxazolidine-2,4-dione and its salts,
5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]oxazolidine-2,4-dione and its salts,
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methyl]oxazolidine-2,4-dione and its salts,
2-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-primidinyl]ethoxy]phenyl
methyl]-1,2,4-oxadiazolidine-3,5-dione and its salts,
2-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-primidinyl]ethoxy]phenyl
methyl]-1,2,4-oxadiazolidine-3,5-dione and its salts,
2-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methyl]-1,2,4-oxadiazolidine-3,5-dione and its salts,
5-[4-[2-[2,4-dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione and its salts,
5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione and its salts,
5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione and its salts,
5-[4-[2-[2-ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione and its salts,
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methylene]thiazolidine-2,4-dione and its salts,
5-[4-[[3-ethyl-4-oxo-3,4-dihydro-2-qunazolinyl]methoxy]phenyl
methylene]thiazolidine-2,4-dione and its salts,
5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione and its salts,
5-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione and its salts.
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quanzolinyl]methoxy]-3-methoxyphenyl
methylene]thiazolidine-2,4-dione and its salts,
More preferred compounds according to the present invention include
5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione.
5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione,
5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione, sodium salt.
5-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione, sodium salt.
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methyl]thiazolidine-2,4-dione and its polymorphs.
5[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methyl]thiazolidine-2,4-dione sodium salt and its polymorphs,
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methyl]thiazolidine-2,4-dione, potassium salt.
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methylene]thiazolidine-2,4-dione, sodium salt.
According to a feature of the present invention, there is provided
a process for the preparation of novel intermediate of the general
formula (III) ##STR00023## where X, Y, Z, R.sup.1, R.sup.2, R.sup.3
and u are as defined earlier, -(CH.sub.2).sub.n-O-- linker is
attached to nitrogen atom, G represents --CHO or --NO.sub.2 group
which comprises, reacting a compound of the general formula (IV)
##STR00024## where X, Y, Z, R.sup.1, R.sup.2 and R.sup.3 are as
defined earlier and H atom is attached to one of the nitrogen atoms
of the ring, with a compound of general formula (V)
L.sup.1--(CH.sub.2).sub.n--O--Ar--G (V) where Ar and n are as
defined earlier and L.sup.1 may be a halogen atom such as Cl, Br, I
or a leaving group such as methanesulfonate,
trifluoromethanesulfonate, p-toluenesulfonate etc, and G represent
CHO, or NO.sub.2 group.
The reaction of a compound of general formula (IV) with a compound
of general formula (V) to produce a compound of general formula
(III) may be carried out in the presence of solvents such as DMSO,
DMF, DME, THF, dioxane, ether and the like or a combination
thereof. The reaction may be carried out in an inert atmosphere
which may be maintained by using inert gases such as N.sub.2, Ar,
He. The reaction may be effected in the presence of a base such as
alkalis like sodium hydroxide, potassium hydroxide, alkali metal
carbonates like sodium carbonate, potassium carbonate; alkali metal
hydrides such as sodium hydride or potassium hydride;
organometallic bases like n-butyl lithium, alkali metal amides like
sodamide or mixtures thereof. The amount of base may range from 1
to 5 equivalents, based on the amount of the compound of formula
(IV), preferably the amount of base ranges from 1 to 3 equivalents.
1 to 3 equivalents of alkali metal halides based on the amount of
compound of formula (IV) such as lithium bromide may be added as an
additive. The reaction may be carried out at a temperature in the
range of 0.degree. C. to 150.degree. C., preferably at a
temperature in the range of 15.degree. C. to 100.degree. C. The
duration of the reaction may range from 0.25 to 24 hours,
preferably from 0.25 to 6 hours.
In another embodiment of the invention, the novel intermediate of
the general formula (III) defined and obtained above where G is CHO
or NO.sub.2 group, can be prepared by reacting the compound of the
general formula (VI), ##STR00025## wherein, X, Y, Z, R.sup.1,
R.sup.2, R.sup.3 and n are as defined earlier, with a compound of
general formula (VII) L.sup.2--Ar--G (VII) where L.sup.2 is a
halogen atom, G is a CHO or a NO.sub.2 group and Ar is as defined
earlier.
The reaction of compound of formula (VI) with the compound of
formula (VII) to produce a compound of formula (III) may be carried
out in the presence of solvents such as THF, DMF, DMSO, DME and the
like. The inert atmosphere may be maintained by using inert gases
such as N.sub.2, Ar or He. The reaction may be effected in the
presence of a base such as K.sub.2CO.sub.3, Na.sub.2CO.sub.3, NaH.
The reaction temperature may range from 20.degree. C. to
150.degree. C., preferably at a temperature in the range of
30.degree. C. to 100.degree. C. The duration of the reaction may
range from 1 to 24 hours, preferably from 2 to 6 hours.
In another embodiment of the present invention, the novel
intermediate of general formula (III), where G is a CHO or NO.sub.2
group, can also be prepared by the reaction of compound of general
formula (VIII) ##STR00026## where X, Y, Z, R.sup.1, R.sup.2,
R.sup.3, n and L.sup.1 are as defined earlier with a compound of
general formula (IX) HO--Ar--G (IX) where G is a CHO or NO.sub.2
group and Ar is as defined earlier.
The reaction of compound of formula (VIII) with compound of formula
(IX) to produce a compound of the formula (III) may be carried out
in the presence of solvents such as THF, DMF, DMSO, DME and the
like or mixtures thereof. The reaction may be carried out in an
inert atmosphere which may be maintained by using inert gases such
as N.sub.2, Ar, or He. The reaction may be effected in the presence
of a base such as K.sub.2CO.sub.3, Na.sub.2CO.sub.3 or NaH or
mixtures thereof. The reaction temperature may range from
20.degree. C.-120.degree. C., preferably at a temperature in the
range of 30.degree. C.-100.degree. C. The duration of the reaction
may range from 1 to 12 hours, preferably from 2 to 6 hours.
The present invention provides a process for the preparation of
novel azolidinedione derivatives of general formula (I), their
tautomeric forms, their stereoisomers, their polymorphs, their
pharmaceutically acceptable salts and their pharmaceutically
acceptable solvents wherein R.sup.1, R.sup.2, R.sup.3, X, Y, Z, n
and Ar are ad defined earlier and A represents CR.sup.5 where
R.sup.5 together with R.sup.4 represent a bond and B represents a
sulfur or a oxygen atom, and further to a compound of formula (I)
wherein R.sup.4 and R.sup.5 represent hydrogen and all symbols are
as defined above, which comprises: reacting the novel intermediate
of the general formula (III) obtained above where G represents CHO
group with 2,4-thiazolidinedione or 2,4-oxazolidinedione and
removing the water formed during the reaction by conventional
methods to yield a compound of general formula (X) ##STR00027##
where R.sup.1, R.sup.2, R.sup.3, X, Y, Z, n and Ar are as defined
earlier and B represents sulfur or oxygen.
The reaction between the compound of the general formula (III)
where G is a CHO group with 2,4-thiazolidinedione or
2,4-oxazolidinedione, to yield compound of general formula (X)
wherein B represents a sulfur or an oxygen atom respectively, may
be carried out neat in the presence of sodium acetate or in the
presence of a solvent such as benzene, toluene, methoxyethanol or
mixtures thereof. The reaction temperature may range from
80.degree. C. to 140.degree. C. depending upon the solvents
employed and in the range from 80.degree. C. to 180.degree. C. when
the reaction is carried out neat in the presence of sodium acetate.
Suitable catalyst such as piperidinium acetate or benzoate, sodium
acetate or mixtures of catalysts may also be employed. Sodium
acetate can be used in the presence of solvent, but it is preferred
that sodium acetate is used neat. The water produced in the
reaction may be removed, for example, by using Dean Star water
separator or by using water absorbing agents like molecular seives.
Oxazolidine-2-oxo-4-thione may be used instead of
2,4-oxazolidinedione. However, the thio group needs to be converted
to oxo group by oxidation using agents such as hydrogen peroxide or
peroxyacids like mCPBA.
The compound of the general formula (X) obtained in the manner
described above is reduced by known method to obtain the compound
of general formula (XI) ##STR00028## wherein R.sup.1, R.sup.2,
R.sup.3, X, Y, Z, n and Ar are as defined earlier and B represents
a sulfur atom or an oxygen atom. The compound of general formula
(XI) represents the compound of general formula (I), wherein
R.sup.4 is hydrogen, A is CR.sup.5 where R.sup.5 is hydrogen and
other symbols are as defined earlier.
The reduction of compound of the formula (X) to yield a compound of
the general formula (XI) may be carried out in the presence of
gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, and the
like. Mixtures of catalysts may be used. The reaction may also be
conducted in the presence of solvents such as dioxane, acetic acid,
ethyl acetate and the like. A pressure between atmospheric pressure
and 80 psi may be employed. The catalyst may be 5-10% Pd/C and the
amount of catalyst used may range from 50-300% w/w. The reaction
may also be carried out by employing metal solvent reduction such
as magnesium in methanol or sodium amalgam in methanol.
The compound of the general formula (XI) obtained above is
converted into its pharmaceutically acceptable salts, or its
pharmaceutically acceptable solvates by conventional methods.
In another embodiment of the present invention, the compound of the
general formula (I) can also be prepared by reacting a compound of
the general formula (VIII) defined above with a compound of general
formula (XII) ##STR00029## where R.sup.4, A, B and Ar are as
defined earlier and R.sup.6 is hydrogen or a nitrogen protecting
group which is removed after the reaction.
The reaction of compound of formula (VIII) with compound of formula
(XII) to produce a compound of the formula (I) may be carried out
in the presence of solvents such as THF, DMF, DMSO, DME and the
like or mixtures thereof. The reaction may be carried out in an
inert atmosphere which is maintained by using inert gases such as
N.sub.2, Ar or He. The reaction may be effected in the presence of
a base such as K.sub.2CO.sub.3, Na.sub.2CO.sub.3 or NaH or mixtures
thereof. The reaction temperature may range from 20.degree.
C.-120.degree. C. preferably at a temperature in the range of
30.degree. C.-80.degree. C. The duration of the reaction may range
from 1 to 12 hours, preferably from 2 to 6 hours.
In still another embodiment of the invention, the compound of the
general formula (I), where -(CH.sub.2).sub.n-O-- linker is attached
to nitrogen atom can be prepared by reacting the compound of the
general formula (IV) defined above with a compound of general
formula (XIII) ##STR00030## where L.sup.1, n, Ar, A, B, R.sup.4 and
R.sup.6 are as defined earlier and removal of the protecting group
when R.sup.6 is a nitrogen protecting group.
The reaction of compound of general formula (IV) with a compound of
general formula (XIII) to produce a compound of general formula (I)
may be carried out in the presence of solvents such as THF, DMF,
DMSO, DME and the like or mixtures thereof. The reaction may be
carried out in an inert atmosphere which is maintained by using
inert gases such as N.sub.2, Ar or He. The reaction may be effected
in the presence of a base such as alkalis like sodium hydroxide, or
potassium hydroxide; alkali metal carbonates like sodium carbonate,
or potassium carbonate; alkali metal hydrides such as sodium
hydride; organometallic bases like n-butyl lithium; alkali metal
amides like sodamide, or mixtures thereof. Multiple solvents and
bases can be used. The amount of base may range from 1 to 5
equivalents, preferably 1 to 3 equivalents. 1 to 3 equivalents of
alkali metal halides such as lithium bromide may be added as an
additive. The reaction temperature may be in the range of 0.degree.
C. to 120.degree. C. preferably at a temperature in the range of
20.degree. C. to 100.degree. C. The duration of the reaction may
range from 0.5 to 24 hours, preferably from 0.5 to 6 hours
In yet another embodiment of the present invention, the compound of
general formula (I), where R.sup.1, R.sup.2, R.sup.3, X, Y, Z, n
and Ar are as defined earlier, R.sup.4 represents hydrogen and A is
CH and B represents S or O can be prepared by the reaction of
compound of general formula (XIV) ##STR00031## where R.sup.1,
R.sup.2, R.sup.3, X, Y, Z, n and Ar are as defined earlier. J is a
halogen atom like chlorine, bromine or iodine or a hydroxy group
and R is a lower alkyl group, with urea when J is a OH group and
with thiourea when J is a halogen atom, followed by treatment with
an acid.
The reaction of compound of general formula (XIV) with urea or
thiourea is normally carried out in the presence of alcoholic
solvent such as methanol, ethanol, propanol, isobutanol,
2-methoxybutanol, etc or DMSO or sulfolane. The reaction may be
conducted at a temperature in the range between 20.degree. C. and
the reflux temperature of the solvent used. Bases such as NaOAc,
KOAc, NaOMe, NaOEt etc. can be used. The reaction is normally
followed by treatment with a mineral acid such as hydrochloric acid
at 20.degree. C. to 100.degree. C.
The compound of general formula (XIV) where J is hydroxy group is
prepared by the hydrolysis of compound of general formula (XIV)
where J is a halogen atom using aqueous alkali at a temperature
ranging from 20.degree. C. to 100.degree. C. followed by
reesterification of the hydrolysed acid group by conventional
methods.
The compound of general formula (XIV) where J is a OH group may
also be prepared from compound of formula (XIV) where J is a
halogen atom by reacting with formamide in the presence of water.
The amount of formamide used in the reaction ranges from 0.5 to 15
mL and water used ranges from 20 .mu.L to 0.1 mL for one mmol of
the halo compound (XIV). The reaction is conducted at a temperature
ranging from 80.degree. C. to 180.degree. C. preferably from
120.degree. C. to 150.degree. C. over a period ranging from 1 to 8
hours.
The compound of general formula (XIV) where J is a halogen atom an
be prepared by the diazotization of the amino compound of the
general formula (XV) ##STR00032## where all symbols are as defined
earlier, using alkali metal nitrites followed by treatment with
acrylic acid esters in the presence of hydrohalo acids and
catalytic amount of copper oxide or copper halide.
The compound of general formula (XV) can in turn be prepared by the
conventional reduction of the novel intermediate (III) where G is
NO.sub.2 group and other symbols are as defined earlier.
In another embodiment of the present invention, the compound of
general formula (I), where R.sup.1, R.sup.2, R.sup.3, X, Y, Z, n
and Ar are as defined earlier and A is nitrogen atom and B is
oxygen atom can be prepared by a process which comprises: reaction
of novel intermediate of formula (III) where all symbols are as
defined above, and G represents a CHO group with NH.sub.2OH. HCl to
yield a compound of general formula (III) where G represents
CH.dbd.NOH group and all symbols are as defined earlier, followed
by metal borohydride reduction to yield a compound of general
formula (XVI) ##STR00033## where all symbols are as defined
earlier.
The reaction of compound of general formula (III), where G is CHO
group and other symbols are as defined earlier, with hydroxylamine
hydrochloride is carried out in solvents such as ethanol, methanol,
THF, dioxane and the like following the conventional method to make
oximes. 1 to 10 equivalents of NH.sub.2OH.HCl may be used,
preferably, 2 to 5 equivalents. Bases such as alkali metal acetates
or ammonium acetate may be used. Reaction may be carried out in the
presence of water. Temperature in the range of 0.degree. C. to
reflux temperature of the solvent may be used. The oxime obtained
in the manner described above is reduced using reducing agents such
as alkali metal borohydrides like sodium borohydride a sodium
cyanoborohydride or borane reagents using conventional conditions
to yield the compound of general formula (XVI).
The compound of general formula (XVI) in turn is reacted with
halocarbonyl isocyanate or alkoxycarbonyl isocyanate to yield a
compound of general formula (I) or with KOCN to yield a compound of
general formula (III) where G is CH.sub.2N(OH)CONH.sub.2, followed
by treatment with carbonylating agents such as alkyl haloformate to
produce the compound of general formula (I) where R.sup.1, R.sup.2,
R.sup.3, X, Y, Z, n, Ar are as defined earlier, A represents
nitrogen atom and B is oxygen atom.
The reaction of compound of general formula (XVI) with halocarbonyl
isocyanate such as chlorocarbonyl isocyanate or alkoxycarbonyl
isocyanate such as ethoxycarbonyl isocyanate may be carried out in
inert solvents such as THF, dioxane, etc at a temperature in the
range -15.degree. C. to 50.degree. C. The reaction may be carried
out for 0.5 to 12 hours depending on the substrates used for the
reaction.
Alternatively, the compound of general formula (XVI) may be treated
with excess of KOCN is organic acids such as acetic acid. Water may
be used in the reaction. The reaction may be carried out at a
temperature in the range of 20.degree. C. to 120.degree. C. The
product isolated in the reaction is further treated with alkyl
haloformate such as ethyl chloroformate in the presence of 1 to 10
equivalents of alkali such as sodium hydroxide, potassium hydroxide
and the like to obtain compound of general formula (I) where all
the symbols are as defined earlier and A represents nitogen atom
and B represents oxygen atom.
In yet another embodiment of the invention, the compound of general
formula (I), where the linker -(CH.sub.2).sub.n-O-- is attached
through Z, where Z represents .dbd.C, and all other symbols are as
defined earlier can be prepared by reacting the compound of general
formula (XVII) ##STR00034## where R.sup.1, R.sup.2, and R.sup.3 are
as defined earlier, X represents C.dbd.O or C.dbd.S and Y
represents C.dbd.C; or when R.sup.2 and R.sup.3 together with Y
form a cyclic structure as defined earlier, X represents C.dbd.O or
C.dbd.S, Y represents C.dbd.C and R.sup.1 is as defined earlier,
with a compound of general formula (XVIII) ##STR00035## where Ar,
R.sup.4, A, B and n are as defined earlier, D may be --CN;
--C(OR.sup.7).sub.3 where R.sup.7 is (C.sub.1-C.sub.4)alkyl;
--C(.dbd.O)-R.sup.8 where R.sup.8 may be selected from --OH, Cl,
Br, I, --NH.sub.2, --NHR, OR where R is a lower alkyl group such as
methyl, ethyl, propyl and the like, or R.sup.8 may be
O-(C.dbd.O)-R.sup.9, where R.sup.9 may be a linear or branched
(C.sub.1-C.sub.5)alkyl group such as methyl, ethyl, propyl,
isopropyl, butyl, t-butyl and the like, 2,4-dichlorophenyl,
2,4,6-trichlorophenyl groups. The reaction proceeds through the
intermediate formation of compound of general formula (XIX).
##STR00036## where all symbols R.sup.1, R.sup.2, R.sup.3, R.sup.4,
X, Y, A, B, Ar and n are as defined earlier.
The group X--NHR.sup.1 in formula (XIX) can also be generated by
conventional methods such amidation of an ester group (XOR) or
partial hydrolysis of a CN (in a compound where CN group is present
in the place of X--NHR.sup.1) group.
The reaction of compound of general formula (XVII) with a compound
of general formula (XVII) to produce a compound of general formula
(I) may be carried out in neat or in the presence of solvents such
as xylene, toluene, THF, dioxane, acetic acid, DMF, DMSO and the
like or mixtures thereof. The reaction may be carried out in an
inert atmosphere which may be maintained by using inert gases such
as N.sub.2, Ar or He. The reaction may be carried out at a
temperature in the range of 50.degree. C. to 200.degree. C.,
preferably at a temperature in the range of 60.degree. C. to
180.degree. C. The reaction may be effected in the presence or in
absence of a base or an acid. The nature of the base or the acid is
not critical. Example of such bases include organic bases such as
pyridine, lutidine, triethyl amine, diisopropylethyl amine and the
like, metal carbonates such as K.sub.2CO.sub.3, Na.sub.2CO.sub.3.
Examples of acids include organic acids such as AcOH,
C.sub.2H.sub.5COOH, butyric acid, p-toluenesulfonic acid,
benzenesulfonic acid and the like, mineral acids such as HCl, HBr
etc. The duration of the reaction may range from 0.25 to 48 hours,
preferably from 0.50 to 18 hours.
Alternatively, the novel intermediate of formula (XIX) may be
isolated and then cyclised to yield a compound of formula (I).
The reaction of compound of the formula (XVII) with a compound of
formula (XVIII) to yield a compound of the formula (XIX) may be
carried out neat or in presence of solvent such as xylene, toluene,
dioxane, DMF, DMSO, halogenated hydrocarbons such as
CH.sub.2Cl.sub.2, CHCl.sub.3, ClCH.sub.2CH.sub.2Cl and the like or
mixtures thereof. The reaction may be effected in the presence or
absence of a base or an acid. The nature of the base or acid is not
critical. Example of such bases include organic bases such as
pyridine, lutidine, triethyl amine, diisopropylethyl amine and the
like. Examples of acids used for this reaction includes
CH.sub.3COOH, C.sub.2H.sub.5COOH, butyric acid, benzenesulfonic
acid, p-toluenesulfonic acid and the like. The reaction may be
carried out in an inert atmosphere which may be maintained by using
inert gases such as N.sub.2, Ar or He. The reaction may be carried
out at a temperature in the range of 25.degree. C. to 180.degree.
C., preferably in the range of 25.degree. C. to 100.degree. C. The
reaction is generally instantaneous and the duration of the
reaction may range from 0.25 to 24 h, preferably 0.25 to 2 h.
The cyclisation of the compound of formula (XIX) to yield a
compound of the formula (I) may be carried out neat or in the
presence of solvents such as THF, toluene, xylene, 1,4-dioxane and
the like or mixtures thereof. The reaction temperature may range
from 60.degree. C. to 150.degree. C. depending upon the solvent
employed and in the range from 100.degree. C. to 200.degree. C.
when the reaction is carried out neat. The reaction may be effected
in presence or absence of acids. The acids normally used include
acetic acid, propionic acid, butyric acid, pTsOH and the like. The
amount of acid used may range from 0.1 to 100 equivalents,
preferably 0.1 to 10 equivalents. The reaction can also be carried
out in neat acid. The reaction is preferably carried out in
solvents such as THF, toluene, xylene, 1,4-dioxane or mixtures
thereof in the presence of an acid such as acetic acid, propionic
acid, p-TsOH and the like. The duration of the reaction may range
from 3 to 48 h preferably from 4 to 18 h.
The process described in the above embodiment is novel and unique
since the heterocycle has been built in the final step of the
process. In the present process no side products are observed. The
yields are high and no purification is required for any
intermediate involved. The process described in the above
embodiment does not involve any stringent conditions. This process
works well for both small scale and large scale reactions. The
process described in the above embodiment is preferably used for
compounds of formula (I) wherein R.sup.2 and R.sup.3 together form
a cyclic structure as defined earlier with Y, where Y represents
C.dbd.C.
The compound of general formula (XVIII) where D represents --COOH
and all other symbols are as defined earlier is prepared from the
compound of general formula (XVIII) where D represents --COOR where
R is a lower alkyl group such as CH.sub.3, C.sub.2H.sub.5,
C.sub.3H.sub.7 and all other symbols are as defined earlier by
conventional hydrolysis procedures.
The hydrolysis of the compound of formula (XVIII) where D
represents COOR group to yield a compound of the formula (XVIII)
where D represents COOH group, may be carried out in the presence
of solvents such as methanol, ethanol, dioxane, ether, THF, water
and the like or mixtures thereof. The reaction may be effected in
the presence of a base such as an alkali like NaOH, KOH or alkali
metal carbonates like sodium carbonate, potassium carbonate and the
like. The amount of base may range from 1 to 5 equivalents. The
reaction may be carried out at a temperature in the range of
0.degree. C. to 120.degree. C. preferably at a temperature in the
range of 15.degree. C. to 100.degree. C. The duration of the
reaction may range from 0.25 to 24 h, preferably from 0.5 to 5
h.
The compound of general formula (XVIII) where D represents COCl or
COBr and other symbols are as defined earlier may be prepared by
the reaction of compound of general formula (XVIII) where D
represents COOH and other symbols are as defined earlier with
reagents such as SOCl.sub.2, PCl.sub.3, PCl.sub.5, PBr.sub.3 and
the like. The reaction may be carried out neat or in the presence
of solvents such as benzene, xylene etc. The reaction may be
carried out in the range of 0.degree. C. to 140.degree. C.
preferably in the range of 25.degree. C. to 100.degree. C. The
duration of the reaction may range from 0.25 to 24 h, preferably
0.5 to 5 h.
The compound of general formula (XVIII) where all symbols are as
defined earlier and D represents --C(.dbd.O)-O-(C.dbd.O)-R.sup.9,
where R.sup.9 represents a linear or branched (C.sub.1-C.sub.5)
alkyl group, dichlorophenyl, trichlorophenyl group and the like,
may be prepared by the reaction of compound of general formula
(XVIII) where D represents COOH may all other symbols are as
defined earlier, with organic acid halides such as acetyl chloride,
acetyl bromide, propanoyl chloride, butanoyl chloride, pivaloyl
chloride, trichlorobenzoylchloride and the like in the presence of
a base such as pyridine, N,N-dimethylaminopyridine, triethyl amine,
diisopropylethyl, lutidine and the like or a mixture thereof. The
reaction may be carried out in solvents such as CH.sub.2Cl.sub.2,
CHCl.sub.3, ClCH.sub.2CH.sub.2Cl, 1,4-dioxane, xylene and the like.
The reaction may be carried out at a temperature in the range of
0.degree. C. to 120.degree. C., preferably in the range of
0.degree. C. to 50.degree. C. The duration of the reaction may
range from 0.25 to 12 h, preferably 0.5 to 5 h.
Particularly useful compound of general formula (I) where X
represents C.dbd.O, Y represents C.dbd.C, Z represents .dbd.C, n
represents an integer 1, R.sup.1 represents methyl group, B
represents sulfur atom, R.sup.2 and R.sup.3 together with Y form a
phenyl ring represented by formula (XX) can be prepared according
to the process described in the above embodiment comprising:
##STR00037##
a) Reducing a compound of formula (XXI) which is disclosed in JP
2558473 ##STR00038## where R.sup.10 is a lower alkyl group such as
methyl, ethyl and the like using conventional reduction conditions
to yield a compound of formula (XXII) ##STR00039## where R.sup.10
is as defined above.
The reduction of compound of the formula (XXI) to yield a compound
of the formula (XXII) may be carried out in the presence of gaseous
hydrogen and a catalyst such as Pd/C or Raney nickel. Mixtures of
catalysts may be used. Solvents such as dioxane, acetic acid, ethyl
acetate and the like may be used. A pressure between atmospheric
pressure and 80 psi may be employed. The catalyst may be 5-10% Pd/C
and the amount of catalyst used may range from 50-300% w/w. The
reaction may also be carried out by employing metal solvent
reduction such as magnesium in methanol or sodium amalgam in
methanol. b) Hydrolysis of compound of formula (XXII) using
conventional conditions to yield a compound of formula (XXIII)
##STR00040##
The hydrolysis of the compound of formula (XXII) to yield a
compound of the formula (XXIII) maybe carried out in the presence
of solvents such as methanol, ethanol, dioxane, ether, THF, water
and the like or mixtures thereof. The reaction may be effected in
the presence of a base such as alkali like NaOH, KOH, alkali metal
carbonates like sodium carbonate potassium carbonate. The amount of
base may range from 1 to 5 equivalents, based on the amount of the
compound of formula (XXII). The reaction may be carried out at a
temperature in the range of 0.degree. C. to 120.degree. C.,
preferably at a temperature in the range of 15.degree. C. to
100.degree. C. The duration of the reaction may range from 0.25 to
24 h, preferably from 0.5 to 5 h. c) Reacting a compound of formula
(XXIII) which acid halide or halogenating agent to obtain a
compound of formula (XXIV), ##STR00041## where D represents COCl or
COBr or --C(.dbd.O)--O--(C.dbd.O)--R.sup.9, where R.sup.9
represents methyl or t-butyl group.
The reaction of compound of formula (XXIII) with halogenating agent
such as SOCl.sub.2, PCl.sub.5, PBr.sub.3 may be carried out neat or
in presence of solvent such as benzene, xylene etc. The reaction
may be carried out at 0.degree. C. to 140.degree. C., preferably at
25.degree. C. to 100.degree. C. The duration of the reaction may
range from 0.25 to 24 h, preferably 0.5 to 5 h. The reaction of
compound of formula (XXIII) with acid halide to yield mixed
anhydride, may be carried out with acid halides such as acetyl
chloride or pivaloyl chloride in the presence of a base such as
pyridine, triethyl amine, N,N-dimethylamino pyridine or mixtures
thereof. The amount of base may range from 1 to 5 equivalents,
based on the compound of formula (XXIII). The reaction may be
carried out in solvents like dichloromethane, chloroform,
dichloroethane, 1,4-dioxane, xylene and the like. The reaction may
be carried out at a temperature in the range of 0.degree. C. to
120.degree. C., preferably at a temperature in the range of
15.degree. C. to 50.degree. C. The duration of the reaction may
range from 0.25 to 12 h preferably from 0.5 to 5 h. d) Reaction of
compound of formula (XXIV) with a compound of formula (XXV)
##STR00042## to yield a compound of formula (XX) defined above. The
reaction proceeds through the intermediate formation of compound of
formula (XXVI). ##STR00043##
The reaction of compound of formula (XXIV) with a compound of
formula (XXV) to produce a compound of general formula (XX) may be
carried out in neat or in the presence of solvents such as xylene,
toluene, THF, dioxane, acetic acid, DMF, DMSO, and the like or
mixtures thereof. The reaction may be carried out in an inert
atmosphere which may be maintained by using inert gases such as
N.sub.2, Ar or He. The reaction may be carried out at a temperature
in the range of 50.degree. C. to 200.degree. C., preferably at a
temperature in the range of 80.degree. C. to 180.degree. C. The
reaction may be effected in the presence of an acid. The nature of
the acid is not critical. Examples of acids include organic acids
such as AcOH, C.sub.2H.sub.5COOH, p-toluenesulfonic acid and the
like, mineral acids such as HCl, HBr etc. The duration of the
reaction may range from 0.25 to 48 hours, preferably from 0.50 to
18 hours, based on solvent, temperature and acid used.
Alternatively, the novel intermediate of formula (XXVI) may be
isolated and then cyclised to yield a compound of formula (XX).
The reaction of compound of the formula (XXIV) with a compound of
formula (XXV) to yield a compound of the formula (XXVI) may be
carried out neat or in presence of solvent such as xylene, toluene,
dioxane, DMF, DMSO, halogenated hydrocarbons such as
CH.sub.2Cl.sub.2, CHCl.sub.3, ClCH.sub.2CH.sub.2Cl and the like or
mixtures thereof. The reaction may be effected in the presence of
an acid. The nature of the acid is not critical. Examples of acids
used for this reaction includes CH.sub.3COOH, C.sub.2H.sub.5COOH,
butyric acid, benzenesulfonic acid, p-toluenesulfonic acid and the
like. The reaction may be carried out in an inert atmosphere which
may be maintained by using inert gases such as N.sub.2, Ar or He.
The reaction may be carried out at a temperature in the range of
25.degree. C. to 180.degree. C., preferably in the range of
25.degree. C. to 60.degree. C. The reaction is generally
instantaneous and the duration of the reaction may range from 0.25
to 12 h, preferably 0.25 to 2 h.
The cyclisation of the compound of formula (XXVI) to yield a
compound of the formula (XX) may be carried out neat or in the
presence of solvents such as THF, toluene, xylene, 1,4-dioxane and
the like or mixtures thereof. The reaction temperature may range
from 60.degree. C. to 150.degree. C. depending upon the solvent
employed and in the range from 100.degree. C. to 200.degree. C.
when the reaction is carried out neat. The reaction may be effected
in the presence of acids. The acids normally used include acetic
acid, propionic acid, and pTsOH. The amount of acid used may range
from 0.1 to 100 equivalents, preferably 0.1 to 10 equivalents. The
reaction can also be carried out in neat acid. The reaction is
preferably carried out in solvents such as THF, toluene, xylene,
1,4-dioxane or mixtures thereof in the presence of an acid such as
acetic acid, propionic acid, p-TsOH and the like. The duration of
the reaction may range from 3 to 48 h preferably from 4 to 18 h,
based on solvent, temperature and acid used.
The term neat as used herein means the reaction carried out without
the use of solvent.
The pharmaceutically acceptable salts are prepared by reacting the
compound of the formula (I) with 1 to 4 equivalents of a base such
a sodium hydroxide, sodium methoxide, sodium hydride, potassium
t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in
solvents like ether, THF, methanol, t-butanol, dioxane,
isopropanol, ethanol etc. Mixture of solvents may be used. Organic
bases like lysine, arginine, diethanolamine, choline, guanidine and
their derivatives etc. may also be used. Alternatively, acid
addition salts are prepared by treatment with acids such as
hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,
phosphoric acid, p-toluenesulphonic acid, methane-sulfonic acid,
acetic acid, citric acid, maleic acid, salicyclic acid,
hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid,
benzoic acid, benzenesulfonic acid, tartaric acid and the like in
solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane
etc. Mixture of solvents may also be used.
The stereoisomers of the compounds forming part of this invention
may be prepared by using reactants in their single enantiomeric
form in the process wherever possible or by conducting the reaction
in the presence of reagents or catalysts in their single enantiomer
form or by resolving the mixture of stereoisomers by conventional
methods. Some of the preferred methods include use of microbial
resolution, resolving the diastereomeric salts formed with chiral
acids such as mandelic acid camphorsulfonic acid, tartaric acid
lactic acid and the like or chiral bases such as rucine, cinchona
alkaloids and their derivatives and the like.
Various polymorphs of compound of general formula (I) forming part
of this invention may be prepared by crystallization of compound of
formula (I) under different conditions. For example, using
different solvents commonly used or their mixtures for
recrystallization; crystallizations ions at different temperatures;
various modes of cooling, ranging from very fast to very slow
cooling during crystallizations. Polymorphs may also be obtained by
heating or melting the compound followed by gradual or fast
cooling. The presence of polymorphs may be determined by solid
probe nmr spectroscopy, it spectroscopy, differential scanning
calorimetry, powder X-ray diffractogram or such other
techniques.
The present invention also provides a pharmaceutical composition,
containing the compounds of the general formula (I), as defined
above, their tautomeric forms, their stereoisomers, their
polymorphs, their pharmaceutically acceptable salts, their
pharmaceutically acceptable solvates in combination with the usual
pharmaceutically employed carriers, diluents and the like, useful
for the treatment and/or prophylaxis of diseases in which insulin
resistance is the underlying pathophysioligcal mechanism such as
type II diabetes, impaired glucose tolerance, dyslipidaemia,
hypertension, coronary heart disease and other cardiovascular
disorders including atherosclerosis; insulin resistance associated
with obesity and psoriasis, for treating diabetic complications and
other diseases such as polycystic ovarian syndrome (PCOS), certain
renal diseases including diabetic nephropathy, glomerulonephritis,
glomerular sclerosis, nephrotic syndrome, hypertensive
nephrosclerosis, end-stage renal diseases and microalbuminuria as
well as certain eating disorders, as aldose reductase inhibitors
and for improving cognitive functions in dementia.
The pharmaceutical composition may be in the forms normally
employed, such as tablets, capsules, powders, syrups, solutions,
suspensions and the like, may contain flavourants, sweeteners etc.
in suitable solid or liquid carriers or diluents, or in suitable
sterile media to form injectable solutions or suspensions. Such
compositions typically contain from 1 to 20%, preferably 1 to 10%
by weight of active compound, the remainder of the compositions
being pharmaceutically acceptable carriers, diluents or
solvents.
A typical tablet production method is exemplified below:
TABLET PRODUCTION EXAMPLE
TABLE-US-00002 a) 1) Active ingredient 10 g 2) Lacrose 110 g 3)
Corn starch 35 g 4) Carboxymethyl cellulose 44 g 5) Magnesium
stearate 1 g 200 g for 1000 tablets
The ingredients 1 to 3 are uniformly blended with water and
granulated after drying under reduced pressure. The ingredient 4
and 5 are mixed well with the granules and compressed by tabletting
machine to prepare 1000 tablets each containing 10 mg of active
ingredient.
TABLE-US-00003 b) 1) Active ingredient 10 g 2) Calcium phosphate 90
g 3) Lacrose 50 g 4) Corn starch 45 g 5) Polyvinyl pyrrolidase 3.5
g 6) Magnesium stearate 1.5 g 200 g for 1000 tablets
The ingredients 1 to 4 are uniformly moistened with an aqueous
solution of ingredients 5 and granulated after drying under reduced
pressure. Ingredient 6 is added and granules are compresses by a
tabletting machine to prepare 1000 tablets containing 10 mg of
active ingredient 1.
The compound of the formula (I) as defined above are clinically
administered to mammals, including man, via either oral or
parenteral routes. Administration by the oral route is preferred,
being more convenient and avoiding the possible pain and irritation
of injection. However, in circumstances where the patient cannot
swallow the medication, or absorption following oral administration
is impaired, as by disease or other abnormality, it is essential
that the drug be administered parenterally. By either route, the
dosage is in the range of about 0.10 to about 200 mg/kg body weight
of the subject per day or preferably about 0.10 to about 30 mg/kg
body weight per day administered singly or as a divided dose.
However, the optimum dosage for the individual subject being
treated will be determined by the person responsible for treatment,
generally smaller doses being administered initially and thereafter
increments made to determine the most suitable dosage.
Suitable pharmaceutically acceptable carriers include solid fillers
or diluents and sterile aqueous or organic solutions. The active
compound will be present in such pharmaceutical compositions in the
amounts sufficient to provide the desired dosage in the range as
described above. Thus, for oral administration the compounds can be
combined with a suitable solid or liquid carrier or diluent to form
capsules, tablets, powders, syrups, solutions, suspensions and the
like. The pharmaceutical compositions, may, if desired, contain
additional components such as flavourants, sweeteners, excipients
and the like. For parenteral administration, the compounds can be
combined with sterile aqueous or organic media to form injectable
solutions or suspensions. For example, solutions in sesame or
peanut oil, aqueous propylene glycol and the like can be used, as
well as aqeuous solutions of water-soluble
pharmaceutically-acceptable acid addition salts or salts with base
of the compounds. The injectable solutions prepared in this manner
can then be administered intravenously, intraperitoneally,
subcutaneously, or intramuscularly, with intramuscular
administration being preferred in humans.
The invention is explained in detail in examples given below which
are provided by way of illustration only and therefore should not
be construed to limit the scope of the invention.
Preparation 1
4-[2-[4-Methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyd-
e
##STR00044##
To a stirred suspension of NaH (570 mg, 22.57 mmol, 95%) in dry DMF
(35 ml) at 25.degree. C. was added a solution of
4-methyl-2-propyl-1,6-dihydro-6-pyrimidione (2.64 g, 17.36 mmol) in
dry DMF. After the effervescence has ceased, anhydrous LiBr (3.51
g, 40.0 mmol) was added followed by 4-[2-bromoethoxy]benzaldehyde
(4.37 g, 19.08 mmol) in dry DMF at the same temperature. The
reaction mixture was immersed in a preheated oil bath at 70.degree.
C. and stirred for 2 h. The reaction mixture was cooled to room
temperature, poured into water and extracted with EtOAc. The
combined EtOAc layers were washed with brine, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The crude compound was
chromatographed over silica gel using 3:7 EtOAc-pet. ether as
eluent to obtain the title compound (1.61 g, 31%).
.sup.1H NMR (CDCl.sub.3): .delta. 9.80 (s, 1H), 7.82 (d, J=8.72 Hz,
2H), 6.95 (d, J=8.72 Hz, 2H), 6.20 (s, 1H), 4.45 (t, J=5.30 Hz,
2H), 4.35 (t, J=5.30 Hz, 2H), 2.92 (t, J=7.50 Hz, 2H), 2.25 (s,
3H), 1.92-1.70 (m, 2H), 1.20 (t, J=7.50 Hz, 3H).
Preparation 2
4-[2-[2,4-Dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde
##STR00045##
The title compound (0.8 g, 30%) was prepared from
2,4-dimethyl-1,6-dihydro-6-pyrimidione (1,3 g, 10.48 mmol) and
4-[2-bromoethoxy]benzaldehyde (2.4 g, 10.48 mmol) in the presence
of a base K.sub.2 CO.sub.3 (2.89 g, 20.96 mmol) by a similar
procedure as described in preparation 1.
.sup.1H NMR (CDCl.sub.3): .delta. 9.90 (s, 1H), 7.80 (d, J=8.70 Hz,
2H), 7.02 (d, J=8.70 Hz, 2H), 6.20 (s, 1H), 4.50-4.30 (m, 4H), 2.70
(s,3H), 2.20 (s, 3H).
Preparation 3
4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde
##STR00046##
The title compound (1.7 g, 42%) was prepared from
2-ethyl-4-methyl-1,6-dihydro-6-pyrimidone (2.0 g, 14.49 mmol),
4-[2-bromoethoxy]benzaldehyde (332 g, 14.19 mmol). LIBr (2.9 g,
33.33 mmol) and NaH (0.45 g, 18.84 mmol) as base, by a similar
procedure to that described in preparation 1.
.sup.1H NMR (CDCl.sub.3): .delta. 9.90 (s, 1H), 7.80 (d, J=8.70 Hz,
2H), 6.98 (d, J=8.70 Hz, 2H), 6.20 (s, 1H), 4.52-4.25 (m, 4H), 3.02
(q, J=7.40 Hz, 2H), 2.30 (s, 3H), 1.40 (t, J=7.40 Hz, 3H).
Preparation 4
4-[2-[2-Butyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde
##STR00047##
The title compound (1.1 g, 25%) was prepared from
2-butyl-4-methyl-1,6-dihydro-6-pyrimidione (2.3 g, 13.85 mmol),
4-[2-bromoethoxy]benzaldehyde (3.17 g, 13.85 mmol) in the presence
of K.sub.2CO.sub.3 (3.82 g, 27.7 mmol) as base by a similar
procedure that described in preparation 1.
.sup.1H NMR (CDCl.sub.3): .delta. 9.90 (s, 1H), 7.84 (d, J=8.72 Hz,
2H), 6.98 (d, J=8.72 Hz, 2H), 6.20 (s, 1H), 4.52-4.30 (m, 4H), 2.96
(t, J=7.47 Hz, 2H), 2.26 (s, 3H), 1.90-1.70 (m, 2H), 1.70-1.50 (m,
2H), 1.01 (t, J=7.47 Hz, 3H).
Preparation 5
4-[2-[2-Benzyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyd-
e
##STR00048##
The title compound (2.0 g, 20.6%) was prepared from
2-benzyl-4-methyl-1,6-dihydro-6-pyrimidione (5.6 g, 28.0 mmol),
4-[2-bromoethoxy]benzaldehyde (17.05 g, 30.1 mmol) in the presence
of 95% NaH (873 mg, 35.0 mmol) as base by a similar procedure to
that described in preparation 1.
.sup.1H NMR (CDCl.sub.3): .delta. 9.89 (s, 1H), 7.83 (d, J=8.72 Hz,
2H), 7.45-7.15 (m, 5H), 6.98 (d, J=8.72 Hz, 2H), 6.44 (s, 1H), 4.70
(t, J=4.71 Hz, 2H), 4.30 (t, J=4.71 Hz, 2H), 4.14 (s, 2H), 2.42 (s,
3H).
Preparation 6
4-[2-[2,5-Diethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzalde-
hyde
##STR00049##
The title compound (1.42 g, 28%) was prepared from
2,5-diethyl-4-methyl-1,6-dihydro-6-pyrimidone (2.70 g, 16.26 mmol)
and 4-[2-bromoethoxy]benzaldehyde (4.09 g, 17.86 mmol) in the
presence of 95% NaH (508 mg, 20 mmol) as base by a similar
procedure to that described in preparation 1.
.sup.1H NMR (CDCl.sub.3): .delta. 9.88 (s, 1H), 7.82 (d, J=8.62 Hz,
2H), 6.97 (d, J=8.62 Hz, 2H), 4.50-4.20 (m, 4H), 2.95 (q, J=7.47
Hz, 2H), 2.52 (q, J=7.47 Hz, 2H), 2.28 (s, 3H), 1.34 (t, J=7.47 Hz,
3H), 1.09 (t, J=7.47 Hz, 3H).
Preparation 7
4-[2-[2-Ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde
##STR00050##
The title compound (2.0 g, 44%) was prepared from
2-ethyl-4-phenyl-1,6-dihydro-6-pyrimidone (2.6 g, 13.0 mmol),
4-[2-bromoethoxy]benzaldehyde (2.97 g, 13.0 mmol) and LiBr (2.59 g,
29.9 mmol) in the presence of NaH as base (0.4 g, 16.9 mmol) by a
similar procedure to that described in preparation 1.
.sup.1H NMR (CDCl.sub.3): .delta. 9.89 (s, 1H), 8.10-7.95 (m, 2H),
7.83 (d, J=8.72 Hz, 2H), 7.55-7.45 (m, 3H), 6.98 (d, J=8.72 Hz,
2H), 6.78 (s, 1H), 4.60-4.40 (m, 4H), 3.08 (q, J=7.30 Hz, 2H) 1.48
(t, J=7.30 Hz, 3H).
Preparation 8
4-[2-[4-N-Acetylamino-2-oxo-1,2-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde
##STR00051##
The title compound (1.8 g, 66%) was prepared from
4-acetylamino-1,2-dihydro-2-pyrimidione (1.8 g, 11.9 mmol) and
4-[2-bromoethoxy]benzaldehyde (2.72 g, 11.9 mmol) in the presence
of K.sub.2CO.sub.3 (3.28 g, 23.8 mmol) as base by a similar
procedure to that described in preparation 1.
.sup.1H NMR (CDCl.sub.3): .delta. 9.90 (s, 1H), 8.70 (bs, 1H,
D.sub.2O exchangeable), 7.85 (d, J=8.70 Hz, 2H), 7.75 (d, J=7.80
Hz, 1H), 7.42 (d, J=7.80 Hz, 1H), 6.95 (d, J=8.70 Hz, 2H),
4.40-4.20 (m, 4H), 2.30 (s, 3H).
Preparation 9
4-[2-[4-Oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde
##STR00052##
The title compound (1.5 g 73%) was prepared from
4-oxo-3,4-dihydroquinazoline (1.03 g, 7.05 mmol) and
4-[2-bromoethoxy]benzaldehyde (1.77 g, 7.7 mmol) in the presence of
K.sub.2CO.sub.3 (2.0 g, 14.5 mmol) as base, by a similar procedure
to that described in preparation 1.
.sup.1H NMR (CDCl.sub.3): .delta. 9.88 (s, 1H), 8.32 (d, J=7.88 Hz,
1H), 8.21 (s, 1H), 7.88-7.70 (m, 2H), 7.82 (d, J=8.72 Hz, 2H),
7.60-7.42 (m, 1H), 7.00 (d, J=8.72 Hz, 2H), 455-4.25 (m, 4H).
Preparation 10
4-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde
##STR00053##
The title compound (0.6 g, 39%) was prepared from
2-methyl-4-oxo-3,4-dihydroquinazoline (0.8 g, 5 mmol) and
4-[2-bromoethoxy]benzaldehyde (1.37 g, 6 mmol) in the presence of
K.sub.2CO.sub.3 (1.38 g, 10.0 mmol) as base, by a similar procedure
to that described is preparation 1.
.sup.1H NMR (CDCl.sub.3): .delta. 9.85 (s, 1H), 8.13 (d, J=8.0 Hz,
1H), 7.84-7.72 (m, 3H), 7.59-7.41 (m, 2H), 7.10 (d, J=7.0 Hz, 2H),
4.50-4.40 (m, 2H), 4.40-4.30 (m, 2H), 2.76 (s, 1H).
Preparation 11
4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde
##STR00054##
The title compound (5.0 g, 27%) was prepared from
2-ethyl-4-oxo-3,4-dihydroquinazoline (9.2 g, 57.5 mmol) and
4-(2-bromoethoxy)benzaldehyde (14.5 g, 69.0 mmol) in the presence
of K.sub.2CO.sub.3 (14.6 g, 115.0 mmol) as base, by a similar
procedure to that described in preparation 1.
.sup.1H NMR (CDCl.sub.3): .delta. 9.86 (s,1H), 8.14 (d, J=8.0 Hz,
1H), 7.87-7.76 (m, 3H), 7.65-4.45 (m, 2H), 7.13 (d, J=8.0 Hz, 2H),
4.60-4.50 (m, 2H), 4.50-4.40 (m, 2H), 3.07 (q, J=7.0 Hz, 2H), 1.35
(t, J=7.0 Hz, 3H).
Preparation 12
4-[2-[8-Aza-2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde
##STR00055##
The title compound (0.26 g, 41%) was prepared from
8-aza-2-methyl-4-oxo-3,4-dihydro quinazoline (0.33 g, 2.0 mmol),
4-[2-bromoethoxy]benzaldehyde (0.52 g, 2.25 mmol) in the presence
of K.sub.2CO.sub.3 (0.57 g, 4.1 mmol) as base by a similar
procedure to that described in preparation 1.
.sup.1H NMR (CDCl.sub.3): .delta. 9.87 (s, 1H), 9.02-8.90 (m, 1H),
8.58 (d, J=7.30 Hz, 1H), 7.82 (d, J=8.72 Hz, 2H), 7.48-7.35 (m,
1H), 6.97 (d, J=8.72 Hz, 2H), 4.58 (t, J=4.72 Hz, 2H), 4.43 (t,
J=4.72 Hz, 2H), 2.91 (s, 3H).
Preparation 13
4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]benzaldehyde
##STR00056##
A mixture of 4-hydroxybenzaldehyde (3.21 g, 26.3 mmol and
K.sub.2CO.sub.3 (3.64 g, 26.3 mmol) in dry DMF (50 ml) was stirred
for 15 min at 30.degree. C. To the above stirred mixture a solution
of 2-chloromethyl-3-methyl-4-oxo-3,4-dihydroquinazoline (5.0 g,
24.0 mmol) was added and stirred further for 90 minutes at the same
temperature. The reaction mixture was diluted with EtOAc (200 ml),
washed with aqueous Na.sub.2CO.sub.3 solution (3.times.50 ml) and
then with brine, dried over anhydrous Na.sub.2SO.sub.4 and
concentrated to yield the title compound (5.08 g, 72%).
.sup.1H NMR (CDCl.sub.3): .delta. 9.89 (s, 1H), 8.29 (d, J=7.89 Hz,
1H), 7.85 (d, J=8.71 Hz, 2H), 7.80-7.62 (m, 2H), 7.52 (t, J=7.81
Hz, 1H), 7.19 (d, J=8.71 Hz, 2H), 5.27 (s, 2H), 3.74 (s, 3H).
Preparation 14
4-[[3-Ethyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]benzaldehyde
##STR00057##
The title compound (4.24 g, 88%) was prepared from
2-chloromethyl-3-ethyl-4-oxo-3,4-dihydroquinazoline (3.5 g, 15.7
mmol) and 4-hydroxybenzaldehyde (2.10 g, 17.21 mmol) in the
presence of K.sub.2CO.sub.3 (2.38 g, 17.26 mmol) as base by a
similar procedure to that described in preparation 13.
.sup.1H NMR (CDCl.sub.3): .delta. 9.91 (s, 1H), 8.31 (d, J=7.89 Hz,
1H), 7.88 (d, J=8.72 Hz, 2H), 7.82-7.68 (m, 2H), 7.65-7.45 (m, 1H),
7.22 (d, J=8.72 Hz, 2H), 5.28 (s, 2H), 4.28 (q, J=7.06 Hz, 2H),
1.41 (t, J=7.06 Hz, 3H).
Preparation 15
4-[[1-methyl-4-oxo-1,4-dihydro-2-quinazolinyl]methoxy]benzaldehyde
##STR00058##
The title compound (3.64 mg, 65%) was prepared from
2-chloromethyl-1-methyl-4-oxo-1,4-dihydroquinazoline (416 mg, 2.0
mmol) and 4hydroxybenzaldehyde (244 mg, 2.0 mmol) in the presence
of K.sub.2CO.sub.3 (276 mg, 2.0 mmol) as base by a similar
procedure to that described in preparation 13.
.sup.1H NMR (CDCl.sub.3): .delta. 9.88 (s, 1H), 8.34 (d, J=7.89 Hz,
1H), 7.83 (d, J=8.71 Hz, 2H), 7.80-7.70 (m, 1H), 7.60-7.40 (m, 2H),
7.22 (d, J=8.71 Hz, 2H), 5.34 (s, 2H), 3.91 (s, 3H).
Preparation 16
3-Methoxy-4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]benzaldehy-
de
##STR00059##
The title compound (250 mg, 77%) was obtained from
2-chloromethyl-3-methyl-4-oxo-3,4-dihydroquinazoline (209 mg, 1.0
mmol) and vanillin (167 mg, 1.1 mmol) in the presence of
K.sub.2CO.sub.3 (276 mg, 2.0 mmol) as base by a similar procedure
to that described in preparation 13.
.sup.1H NMR (CDCl.sub.3): .delta. 9.88 (s, 1H), 8.29 (d, J=8.30 Hz,
1H), 7.80-7.62 (m, 2H), 7.58-7.39 (m, 2H), 7.26 (d, J=8.30 Hz, 2H),
5.30 (s, 2H), 3.90 (s, 3H), 3.78 (s, 3H).
Preparation 17
4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde
oxime:
##STR00060##
To a stirred solution of hydroxylamine hydrochloride (10.0 g, 143.0
mmol) and sodium acetate trihydrate (20.0 g, 146.9 mmol) in water
(100 ml) at 30.degree. C. was added a hot solution of
4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyd-
e (5.72 g, 20.0 mmol) (obtained from preparation 3) in ethanol (100
ml). The reaction mixture was immersed in a preheated oil bath
(95.degree. C.) and refluxed for 3 h. The reaction mixture was then
cooled to room temperature and concentrated to a volume where
crystals of oxime started separating out and the mixture was kept
aside for 30 min. to 1 h at 25.degree. C. The resultant crystals
were filtered and washed with water and dried to obtain the title
compound (5.42 g, 90%).
.sup.1H NMR (CDCl.sub.3+DMSO-d.sub.6): .delta. 10.56 (s, 1H, OH,
D.sub.2O exchangeable), 8.08 (s, 1H), 7.55 (d, J=8.56 Hz, 2H), 6.88
(d, J=8.56 Hz, 2H), 6.20 (s, 1H), 4.51-4.40 (m, 2H), 4.40-4.28 (m,
2H), 3.05 (q, J=7.06 Hz, 2H), 2.30 (s, 3H), 1.40 (t, J=7.06 Hz,
3H).
Preparation 18
4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzylhydrox-
ylamine:
##STR00061##
To a stirred solution of
4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimudubtk]ethoxy]benzaldehyd-
e oxime (301 mg, 1.0 mmol) obtained from preparation 17) in a
mixture of methanol (7 ml) and THF (3 ml) was added 4 N HCl (2 ml)
in dioxane at 30.degree. C. and stirred for 10 min. at the same
temperature. The reaction mixture was basified to pH 9 with 1 N
NaOH and extracted with EtOAc (3.times.10 ml). The combined organic
layers were washed with brine and dried over anhydrous
Na.sub.2SO.sub.4 and concentrated to yield the of title compound
(272 mg, 90%).
.sup.1H NMR (CDCl.sub.3): .delta. 7.23 (d, J=8.72 Hz, 2H), 6.80 (d,
J=8.72 Hz, 2H), 6.18 (s, 1H), 4.45-4.35 (m, 2H), 4.35-4.20 (m, 2H),
3.98 (s, 2H), 3.01 (q, J=7.56 Hz, 2H), 2.22 (s, 3H), 1.32 (t,
J=7.56 Hz, 3H).
Preparation 19
N-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzyl]N--
hydroxyurea:
##STR00062##
To a stirred solution of
4-[2-[2-ethyl-4-methyl-6-oxo-1,6dihydro-1-pyrimidinyl]ethoxy]benzyl
hydroxylamine (303 mg, 1.0 mmol) (obtained from preparation 18) in
a mixture of water (2 ml) and acetic acid (0.5 ml) was added a
solution of KOCN (343 mg, 3.0 mmol) in water (1 ml) and stirred for
1 h at 30.degree. C. The reaction mixture was diluted with water
and extracted with ethyl acetate (3.times.10 ml). The combined
organic layers were washed with brine, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated to yield the compound (295 mg,
85%).
.sup.1H NMR (CDCl.sub.3): .delta. 7.18 (d, J=8.65 Hz, 2H), 6.90 (d,
J=8.65 Hz, 2H), 6.60 (bs, 1H, D.sub.2O exchangeable), 6.15 (s, 1H),
5.85 (bs, 1H, D.sub.2O exchangeable), 4.70 (s, 2H), 4.50 (bs, 1H,
D.sub.2O exchangeable), 4.40-4.30 (m, 2H), 4.22-4.10 (m, 2H), 2.92
(q, J=7.56 Hz, 2H), 2.20 (s, 3H), 1.20 (t, J=7.56 Hz, 3H).
Preparation 20
4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]nitrobenzene-
:
##STR00063##
The title compound (5.2 g, 25%) was prepared from
2-ethyl-4-methyl-1,6-dihydro-6-pyrimidone (7.65 g, 55.43 mmol),
4-[2-bromoethoxy]nitrobenzene (15.0 g, 60.97 mmol), LiBr (11.09 g,
127.49 mmol) and 60% NaH (2.76 g, 72.06 mmol) as base by a similar
procedure to that described in preparation 1.
.sup.1H NMR (CDCl.sub.3): .delta. 8.20 (d, J=8.81 Hz, 2H), 6.94 (d,
J=8.81 Hz, 2H), 6.22 (s, 1H), 4.55-4.42 (m, 2H), 4.42-4.34 (m, 2H),
2.99 (q, J=7.4 Hz, 2H), 2.27 (s, 3H, 1.38 (t, J=7.4 Hz, 3H).
Preparation 21
4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]nitrobenzene:
##STR00064##
The title compound (1.246 g, 64%) was prepared from
2-ethyl-4-oxo-3,4-dihydroquinazoline (1.0 g, 5.7 mmol) and
4-[2-bromoethoxy]nitrobenzene (1.69g, 6.8 mmol) and K.sub.2CO.sub.3
(1.58 g, 11.49 mmol) as a base by a similar procedure to that
described in preparation 1.
.sup.1H NMR (CDCl.sub.3): .delta. 8.24 (d, J=7.93 Hz, 1H), 8.18 (d,
J=9.20 Hz, 2H), 7.82-7.61 (m, 2H), 7.46 (t, J=7.93 Hz, 1H), 6.94
(d, J=9.20 Hz, 2H), 4.58 (t, J=4.82 Hz, 2H), 4.44 (t, J=4.82 Hz,
2H), 3.09 (q, J=7.38 Hz, 2H), 1.46 (t, J=7.38 Hz, 3H).
Preparation 22
4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]aniline:
##STR00065##
A solution of
4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]nitrobenzen-
e (1.0 g, 3.3 mmol) (obtained from preparation 20) in 1,4-dioxane
(20 ml) was reduced with hydrogen in the presence of 10% palladium
on charcoal (100 mg) at 30 psi for 16 h. The mixture was filtered
through a bed of celite and washed with dioxane and evaporated to
dryness under reduced pressure to yield the title compound (625 mg,
70%). .sup.1H NMR (CDCl.sub.3)L .delta. 6.78-6.52 (m, 4H), 6.18 (s,
1H), 4.38 (t, J=4.98 Hz, 2H), 4.19 (t, J=4.98 Hz, 2H), 2.99 (q,
J=7.47 Hz, 2H), 2.24 (s, 3H), 1.33 (t, J=7.46 Hz, 3H).
Preparation 23
4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]aniline:
##STR00066##
The title compound (1.107 g, 98%) was prepared from
4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinzaoilnyl]ethoxy]nitrobenzene
(1.246 g, 3.67 mmol) (obtained from preparation 21) by a similar
procedure to that described in preparation 22.
.sup.1H NMR (CDCl.sub.3): .delta. 8.24 (d, J=7.93 Hz, 1H),
7.80-7.60 (m, 2H), 7.43 (t, J=7.93 Hz, 1H), 6.80-6.50 (m, 4H), 4.51
(t, J=5.19 Hz, 2H), 4.24 (t, J=5.19 Hz, 2H), 3.10 (q, J=7.34 Hz,
2H), 1.42 (t, J=7.34 Hz, 3H).
Preparation 24
Ethyl
2-bromo-3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]et-
hoxy]phenyl]propanoate:
##STR00067##
To a stirred solution of
4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]aniline
(2.80 g, 10.26 mmol) (obtained from preparation 22) in acetone (10
ml) was added aqueous HBr (47%, 1 ml) and stirred for 10 min. at
0.degree. C. To the above reaction mixture a solutin of NaNO.sub.2
(850 mg, 12.30 mmol) in water (1.7 ml) was added slowly dropwise at
0.degree. C. and stirring was continued further for 30 min at the
same temperature. To this reactin mixture, ethyl acrylate (6.77 ml,
62.0 mmol) was added and allowed to warm to 30.degree. C. Catalytic
amount of copper (I) iodide (20 mg) was added in one portion and
the reaction mixture was stirred further for 1 h at 30.degree. C.
Acetone was removed under reduced pressure and the resultant
residue was extracted with EtOAc (3.times.10 ml). The combined
EtOAc layers were washed with dilute NH.sub.3 solution, water,
followed by brine; dried over anhydrous Na.sub.2SO.sub.4 and
concentrated to afford the crude compound which was purified by
flash chromatography using 40% EtOAc/petroleum ether as eluent to
yield the title compound (2.47 g, 55%).
.sup.1H NMR (CDCl.sub.3): .delta. 7.11 (d, J=8.63 Hz, 2H), 6.78 (d,
J=8.63 Hz, 2H), 6.19 (s, 1H ), 4.50-4.32 (m, 2H), 4.30-4.02 (m,
5H), 3.38 (dd, J=13.72, 8.31 Hz, 1H), 3.17 (dd, J=13.72, 7.06 Hz,
1H), 3.10-2.90 (m, 2H), 2.25 (s, 3H), 1.35 (t, J=7.47 Hz, 3H), 1.24
(t, J=7.05 Hz, 3H).
Preparation 25
Ethyl
2-bromo-3-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phe-
nyl]propanoate
##STR00068##
The title compound (671 mg, 55%) was prepared from
4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]aniline (800
mg, 2.58 mmol) (obtained from preparation 23), NaNO.sub.2 (214 mg,
3.1 mmol) and ethyl acrylate (1.7 ml), 1.574 g, 15.74 mmol) by a
similar procedure to that described in preparation 24.
.sup.1H NMR (CDCl.sub.3): .delta. 8.23 (d, J=7.88 Hz, 1H),
7.80-7.55 (m, 2H), 7.52-7.30 (m, 1H), 7.15-7.01 (m, 2H), 6.77 (d,
J=8.71 Hz, 2H), 4.52 (t, J=5.03 Hz, 2H), 4.45-4.30 (m, 1H), 4.30
(t, J=5.03 Hz, 2H), 4.20-4.00 (m, 2H), 3.35 (dd, J=14.12, 8.71 Hz,
1H), 3.20-3.00 (m, 3H), 1.43 (t, J=7.34 Hz, 3H), 1.20 (t, J=7.34
Hz, 3H).
Preparation 26
5-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]-2-iminothiazolidine-4-one hydrochloride:
##STR00069##
A mixture of ethyl
2-bromo-3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]-
phenyl]propanoate (1.70 g, 3.89 mmol) (obtained from preparation
24), fused sodium acetate (637 mg, 7.78 mmol) and thiourea (592 mg,
7.78 mmol) in ethanol (10 ml) was refluxed for 12 h. The reaction
mixture was cooled to room temperature and the resultant solid was
filtered and dried to afford the title compound (1.35 g, 89%).
.sup.1H NMR (CDCl.sub.3): .delta. 7.12 (d, J=8.59 Hz, 2H), 6.76 (d,
J=8.59 Hz, 2H), 6.12 (s, 1H), 4.50-4.30 (m, 3H), 4.30-4.15 (m, 2H),
3,40 (dd, J=14.11, 3.74 Hz, 1H), 2.98 (q, J=7.47 Hz, 2H), 2.85 (dd,
J=14.11, 9.43 Hz, 1H), 2.23 (s, 3H), 1.32 (t, J=7.47 Hz, 3H).
Preparation 27
5-[4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methyl]-2-imino thiazoidine-4-one hydrochloride:
##STR00070##
The title compound (329 mg, 78%) was prepared from ethyl
2-bromo-3-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl]p-
ropanoate (473 mg, 1.0 mmol) (obtained from preparation 25), sodium
acetate (164 mg, 2.0 mmol) and thiourea (152 mg, 2.0 mmol) by a
similar procedure to that described in preparation 26.
.sup.1H NMR (CDCl.sub.3): .delta. 8.12 (d, J=7.88 Hz, 1H), 7.80 (t,
J=7.03 Hz, 1H), 7.62 (d, J=7.88 Hz, 1H), 7.49 (t, J=7.03 Hz, 1H),
7.12 (d, J=7.58 Hz, 2H), 6.84 (d, J=7.58 Hz, 2H), 4.50 (dd, J=9.43,
3.72 Hz, 1H), 4.46 (t, J=5.31 Hz, 2H), 4.25 (d, J=5.31 Hz, 2H),
3.25 (dd, J=14.11, 3.72 Hz, 1H) 3.04 (q, J=7.17 Hz, 2H), 2.81 (dd,
J=14.11, 9.43 Hz, 1H), 1.31 (t, J=7.19 Hz, 3H).
Preparation 28
3-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl]-2-
-hydroxypropanoic acid:
##STR00071##
A mixture of ethyl
2-bromo-[3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl-ethoxy-
]phenyl]propanoate (438 mg, 1.0 mmol) (obtained from preparation
24), sodium hydroxide (44 mg, 1.1 mmol) and calcium carbonate (100
mg, 1.0 mmol) in 1,4-dioxane (2 ml) and water (3 ml) was refluxed
for 10 h. The reaction mixture was cooled to room temperature and
acidified to pH 4 with 2N HCl and extracted with EtOAc (2.times.10
ml). The combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated to afford the title compound (92
mg, 27%).
.sup.1H NMR (CDCl.sub.3+DMSO-d.sub.6): .delta. 7.12 (d, J=8.61 Hz,
2H), 6.78 (d, J=8.61 Hz, 2H), 6.19 (s, 1H), 4.50-4.32 (m, 2H),
4.30-4.05 (m, 3H), 3.10-2.60 (m, 4H), 2.25 (s, 3H), 1.30 (t, J=7.20
Hz, 3H).
Preparation 29
Ethyl
3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phe-
nyl]-2-hydroxypropanoate:
##STR00072## Method A
A solution of
3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl]--
2-hydroxypropanoic acid (346 mg, 1.0 mmol) (obtained from
preparation 28) in ethanol (3 ml) containing concentrated
hydrochloric acid (0.1 ml) was refluxed for 10 h. The solution was
cooled to room temperature, diluted with water and extracted with
EtOAc (2.times.10 ml). The combined organic extracts were washed
with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated
to yield the title compound (97 mg, 26%).
Method B
A mixture of ethyl
2-bromo-3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidiyl]ethoxy]p-
henyl]propanoate (1.0 g, 2.28 mmol) (obtained from preparation 24)
formamide (225 .mu.l) and water (45 .mu.l, 45 mg, 2.5 mmol) was
heated at 160.degree. C. for 3 h. Water (45 .mu.l) was added
further and stirred for 2 h at 175.degree. C. The reaction mixture
was cooled at room temperature, diluted with EtOAc (10 ml) washed
with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated
to yield the crude compound which was purified by flash
chromatography to afford the title compound (306 mg, 36%).
.sup.1H NMR (CDCl.sub.3): .delta. 7.11 (d, J=8.62 Hz, 2H), 6.77 (d,
J=8.62 Hz, 2H), 6.18 (s, 1H), 4.50-4.31 (m, 2H), 4.30-4.05 (m, 5H),
3.10-2.80 (m, 4H), 2.25 (s, 3H), 1.40-1.15 (m, 6H).
Preparation 30
5-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]-2-thio-1,3-oxazolidine-4-one:
##STR00073##
An intimate mixture of
4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyd-
e (286 mg, 1.0 mmol) (obtained from preparation 3),
2-thio-1,3-oxazolidine-4-one (175 mg, 1.5 mmol) and anhydrous
sodium acetate (246 mg, 3.0 mmol) was heated at 120.degree. C.
under reduced pressure (2.0 ml) for 90 min. After cooling, the
reaction mixture was poured into ethyl acetate (80 ml) and water
(20 ml) and stirred for 30 min, the aqueous layer was separated and
acidified to pH 4 with 2N HCl. The solid separated was filtered and
dried to yield the title compound (207 mg, 54%).
.sup.1H NMR (CDCl.sub.3): .delta. 7.76 (d, J=8.62 Hz, 2H), 6.93 (d,
J=8.62 Hz, 2H), 6.59 (s, 1H), 6.17 (s, 1H), 450-4.30 (m, 4H), 2.98
(q, J=7.47 Hz, 2H), 2.27 (s, 3H), 13.5 (t, J=7.47 Hz, 3H).
Preparation 31
4-[2-[2,5,6-Trimethyl-4-oxo-3,4-dihydro-thieno-[2,3-d]pyrimidin-3-yl]ethox-
y]benzaldehyde:
##STR00074##
The title compound (5.04 g, 27%) was prepared from
2,5,6-trimethyl-4-oxo-thienopyrimidine (10.59 g, 54.6 mmol),
4-[2-bromoethoxy]benzaldehyde (12.82 g, 56 mmol) and
K.sub.2CO.sub.3 (15.04 g, 109 mmol) as base by a similar procedure
to that described in preparation 1.
.sup.1H NMR (CDCl.sub.3): .delta. 9.88 (s, 1H ), 7.82 (d, J=8.72
Hz, 2H), 6.98 (d, J=8.72 Hz, 2H), 4.60-4.30 (m, 4H), 2.78 (s, 3H),
2.46 (s, 3H), 2.37 (s, 3H).
Preparation 32
4-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]nitrobenzene:
##STR00075##
The title compound (1.2 g, 60%) was prepared from
2-methyl-4-oxo-3,4-dihydroquinazoline (1.0 g, 6.25 mmol) and
4-[2-bromoethoxy]nitrobenzene (1.69 g, 6.9 mmol) and
K.sub.2CO.sub.3 (1.73 g, 12.3 mmol) as a base by a similar
procedure to that described in preparation 1.
.sup.1H NMR (CDCl.sub.3): .delta. 8.24 (d, J=7.5 Hz, 1H), 8.18 (d,
J=9.22 Hz, 2H), 7.75 (t, J=7.50 Hz, 1H), 7.63 (d, J=7.50 Hz, 1H),
7.46 (t, J=7.50 1H), 6.94 (d, J=9.22 Hz, 2H), 4.58 (t, J=4.98 Hz,
2H), 4.46 (t, J=4.98 Hz, 2H), 2.82 (s, 3H).
Preparation 33
4-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]aniline:
##STR00076##
The title compound (9.07 mg, 99%) was prepared from
4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]nitrobenzene
(1.0 g, 3.1 mmol) (obtained from preparation 32) by a similar
procedure to that described in preparation 22.
.sup.1H NMR (CDCl.sub.3).delta.: 8.24 (d, J=7.50 Hz, 1H), 7.69 (t,
J=4.13 Hz, 1H), 7.62 (d, J=7.50 Hz, 1H), 7.43 (t, J=7.50 Hz, 1H),
6.64 (d, J=8.8 Hz, 2H), 6.60 (d, J=8.80 Hz, 2H), 4.49 (t, J=4.98
Hz, 2H), 4.26 (t, J=4.98 Hz, 2H), 2.81 (s, 3H).
Preparation 34
Ethyl
2-bromo-3-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazlinyl]ethoxy]phe-
nyl]propanoate:
##STR00077##
The title compound (3.4 g, 58%) was prepared from
4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ehtoxy]aniline
(3.75 g, 12.7 mmol) (obtained from preparation 33, NaNO.sub.2 (955
mg, 13.8 mmol) and ethyl acrylate (8.2 mL, 7.62 g, 76.2 mmol) by a
similar procedure to that described in preparation 24.
.sup.1H NMR (CDCl.sub.3): .delta. 8.23 (d, J=7.50 Hz, 1H),
7.80-7.60 (m, 2H), 7.43 (t, J=7.50 Hz, 1H), 7.31 (d, J=7.50 Hz,
1H), 7.10 (d, J=7.50 Hz, 1H), 6.85-6.70 (m, 2H), 4.53 (t, J=4.98
Hz, 2H), 4.33 (t, J=4.98 Hz, 2H), 4.31 (dd, J=8.71, 3.83 Hz, 1H),
4.12 (q, J=5.80 Hz, 2H), 3.35 (dd. J=14.12, 8.71 Hz, 1H), 3.13 (dd,
J=14.12, 3.83 Hz, 1H), 2.80 (s, 3H), 1.22 (t, J=5.8 Hz, 3H).
Preparation 35
5-[4-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinamlinyl]ehtoxy]phenyl
methyl]-2-imino thiazolidine-4-one hydrochloride:
##STR00078##
The title compound (1.8 g, 60%) was obtained from ethyl
2-bromo-3-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
propanoate (3.4 g, 7.4 mmol) (obtained from preparation 34), sodium
acetate (2.0 g, 14.8 mmol) and thiourea (1.13 g, 14.8 mmol) by a
similar procedure to that described in preparation 26.
.sup.1H NMR (CDCl.sub.3).delta.: 8.79 (bs, 1H, D.sub.2O
exchangeable), 8.11 (d, J=7.50 Hz, 1H), 7.80 (t, J=7.50 Hz, 1H),
7.59 (d, J=7.50 Hz, 1H), 7.48 (t, J=7.50 Hz, 1H), 7.12 (d, J=8.48
Hz, 2H), 6.86 (d, J=8.48 Hz, 2H), 4.51 (dd, J=9.54, 3.91 Hz, 1H),
4.44 (t, J=4.98 Hz, 2H), 4.26 (t, J=4.98 Hz, 2H), 3.22 (dd,
J=14.11, 3.91 Hz, 1H), 2.82 (dd, J=14.11, 9.54 Hz, 1H), 2.71 (s,
3H).
Preparation 36
4-[2-[2-Ethyl-4-trifluoromethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]ben-
zaldehyde:
##STR00079##
The title compound (138 mg, 40%) was prepared from
2-ethyl-4-trifluoro-methyl-(1,6-dihydro-6-pyrimidione (200 mg, 1.04
mmol) and 4-[2-bromoethoxy]benzaldehyde (238.5 mg, 1.04 mmol) in
presence of K.sub.2CO.sub.3 (287.5 mg, 2.08 mmol) as base by a
similar procedure to that described in preparation 1.
.sup.1H NMR (CDCl.sub.3): .delta. 9.89 (s, 1H), 7.83 (d, J=8.67 Hz,
2H), 6.95 (d, J=8.67 Hz, 2H), 6.70 (s, 1H), 4.50 (t, J=4.66 Hz,
2H), 4.39 (t, J=4.66 Hz, 2H), 3.1 (q, J=7.4 Hz, 2H), 1.4 (t, J=7.4
Hz, 3H).
Preparation 37
Ethyl
[4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetate:
##STR00080## Method A:
A solution of ethyl
[4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methylene]phenoxy]acetate (10
g) in 1,4-dioxane (200 mL) was reduced with hydrogen in the
presence of 5% palladium on charcoal (15 g) at 40 psi pressure for
24 h. The mixture was filtered through a bed of celite. The
filtrate was evaporated to dryness under reduced pressure to afford
the title compound (95 g, 95%).
Method B:
To magnesium turnings (6.6 g, 0.277 mol) in methanol (150 mL) was
added a solution of ethyl
[4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methylene]phenoxy]acetate (5
g, 16.3 mmol) in methanol (50 mL) and stirred for 12 h, maintaining
the temperature below 50.degree. C., when the reaction initiates as
evidenced by hydrogen evolution and heat generation. The reaction
mixture was poured into ice water (150 mL), neutralised with 10%
aqueous hydrochloric acid, and the solution was extracted with
ethyl acetate (3.times.100 mL). The combined organic extracts were
washed with water (150 mL) brine (100 mL) and dried (MgSO.sub.4),
and the solvent was removed under reduced pressure. The residue was
chromatographed on silica gel in 2% methanol in dichloromethane to
give the title compound (2.3 g, 46%. mp: 107.degree. C.
.sup.1H NMR (CDCl.sub.3): .delta. 8.5 (bs, 1H, D.sub.2O
exchangeable), 7.20 (d, J=8.50 Hz, 2H), 7.06 (d, J=8.50 Hz, 2H),
4.65 (s, 2H), 4.53 (dd, J=9.39, 3.74 Hz, 1H), 4.32 (q, J=7.20 Hz,
2H), 3.50 (dd, J=14.12, 3.74 Hz, 1H), 3.14 (dd, J=14.12, 9.39 Hz,
1H), 1.34 (t, J=7.17 Hz, 3H).
Preparation 38
[4-[[2,4-Dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic
acid:
##STR00081##
To a stirred solution of ethyl
[4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phetroxy]acetate (110
g, 0.36 mol) in methanol (0.65 L) was added as solution of
Na.sub.2CO.sub.3 (200 g, 1.88 mol) in water (0.65 L) and stirred
for 5 h at 25 to 30.degree. C. After completion of the reaction,
methanol was removed under reduced pressure; water was added to the
residue and was acidified with hydrochloric acid. The precipitated
while solid was filtered and dried to yield the title compound (80
g, 80%). mp: 181-183.degree. C.
.sup.1H NMR (DMSO-d.sub.6): .delta. 12.40 (bs, 1H, D.sub.2O
exchangeable), 8.60 (bs, 1H, D.sub.2O exchangeable), 7.16 (d,
J=8.40 Hz, 2H), 6.50 (d, J=8.40 Hz, 2H), 4.87 (dd, J=9.14, 4.20 Hz,
1H), 4.65 (s, 2H), 3.32 (dd, J=14.12, 4.20 Hz, 1H), 3.05 (dd,
J=14.12, 9.14 Hz, 1H).
Preparation 39
5-[[4-[N[Methyl benazmide-2-yl]aminocarbonyl]methoxy]phenyl
methyl]thiazolidine-2,4-dione:
##STR00082## Method A:
To a stirred solution of
[4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid
(1.9 g, 6.75 mmol) in dichloromethane (15 mL) was added triethyl
amine (1.876 mL, 136 g, 13.48 mmol) followed by pivaloyl chloride
(0.913 mL, 899 mg, 5.46 mmol) at 0.degree. C. and was further
stirred for 1 h at 0.degree. C. The reaction mixture was added to a
solution of 2-amino-N-methyl benzamide (920 mg, 6.13 mmol) in
acetic acid (10 mL) and xylene (10 mL) and the reaction mixture was
stirred for 30 min at 25.degree. C. The solvents were removed under
reduced pressure and the product was purified to yield the title
compound (2.51 g, 91%). mp=201-203.degree. C.
Method B:
To a stirred solution of
[4-[[2.4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy)acetic acid
(1.9 g, 6.75 mmol) in xylene (15 mL) was added thionyl chloride
(2.46 mL, 4.02 g, 33.75 mmol) and refluxed for 1 h. The reaction
mixture was cooled to room temperature and excess thionyl chloride
was removed under reduced pressure. The residue was added to a
solution of 2-amino-N-methyl benzamide (920 mg, 6.13 mmol) in
acetic acid (10 mL) and xylene(10 mL) and stirred for 1 h at
25.degree. C. The solvents were removed under reduced pressure and
the product was purified to yield the title compound (2.4 g,
86%).
.sup.1H NMR (CDCl.sub.3, 200 MHz): .delta. 12.21 (s, 1H, D.sub.2O
exchangeable), 11.7 (bs, 1H, D.sub.2O exchangeable), 8.63 (d,
J=8.30 Hz, in 7.96 (bs, 1H, D.sub.2O exchangeable), 7.65 (d, J=7.80
Hz, 1H), 7.47 (t, J=7.80 Hz, 1H), 7.30-6.96 (m, 5H), 4.60 (s, 2H),
4.48 (dd, J=9.6, 3.70 Hz, 1H), 3,45 (dd, J=13.70, 3.70 Hz, 1H),
3.05 (dd, J=13.70, 9.60 Hz, 1H), 2.94 (d, J=3.74 Hz, 3H).
EXAMPLE 1
5-[4-[2-[4-Methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione:
##STR00083##
A mixture of
4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehy-
de (10 g, 24.5 mmol) (obtained from preparation 1),
thiazolidine-2,4-dione (3.5 g, 30 mmol), benzoic acid (388 mg, 3.18
mmol) and piperidine (352 .mu.l, 303 mg, 3.68 mmol) in toluene (50
ml) was refluxed for 1 h with continuous removal of water. The
reaction was cooled to room temperature and the resultant
crystalline compound was filtered and washed with water and dried
to afford the title compound (12.3 g, 99%), mp 240-242.degree.
C.
.sup.1NMR (DMSO-D.sub.6): .delta. 12.40 (bs, 1H, D.sub.2O
exchangeable), 7.75 (s, 1H), 7.54 (d, J=8.72 Hz, 2H), 7.02 (d,
J=8.72 Hz, 2H), 6.15 (s, 1H), 4.45-4.15 (m, 4H), 2.91 (t, J=7.65
Hz, 2H), 2.20 (s, 3H), 1.90-1.65 (m, 2H), 1.06 (t, J=7.65 Hz,
3H).
EXAMPLE 2
5-[4-[2-[2,4-Dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione
##STR00084##
The title compound (0.98 g, 95%) was obtained from
4-[2-[2,4-dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde
(0.8 g, 2.8 mmol) (obtained from preparation 2) and
thiazolidine-2,4-dione (0.344 g, 2.8 mmol) by a similar procedure
to that described in example 1, mp 235.degree. C.
.sup.1H NMR (CDCl.sub.3): .delta. 8.50) (bs, 1H, D.sub.2O
exchangeable), 7.80 (s, 1H), 7.48 (d, J=8.40 Hz, 2H), 6.98 (d,
J=8.40 Hz), 6.21 (s, 1H), 4.52-4.30 (m, 4H), 2.70 (s, 3H), 2.25 (s,
3H).
EXAMPLE 3
5-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione
##STR00085##
The title compound (2.13 g, 92%) was obtained from
4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyd-
e (1.7 g, 5.94 mmol) (obtained from preparation 3) and
thiazolidine-2,4-dione (0.695 g, 5.94 mmol) by a similar procedure
to that described in example 1, mp 248-250.degree. C.
.sup.1H NMR (CDCl.sub.3+DMSO-d.sub.6): .delta. 12.25 (bs, 1H,
D.sub.2O exchangeable), 7.78 (s, 1H), 7.40 (d, J=7.40 Hz, 2H), 7.0)
(d, J=7.40 Hz, 2H), 6.20 (s, 1H), 4.48-4.24 (m, 4H), 3.0 (q, J=6.4
Hz, 2H), 2.20 (s, 3H), 1.28 (t, J=6.4 Hz, 3H).
EXAMPLE 4
5-[4-[2-[2-Butyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione
##STR00086##
The title compound (1.2 g, 83%) was obtained from
4-[2-[2-butyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyd-
e (1.1 g, 3.5 mmol) (obtained from preparation 4) and
thiazolidine-2,4-dione (410 mg, 3.5 mmol) by a similar procedure to
that described in example 1, mp 209.degree. C.
.sup.1H NMR (CDCl.sub.3): .delta. 7.80 (s, 1H), 7.40 (d, J=8.63 Hz,
2H), 6.93 (d, J=8.63 Hz, 2H), 6.21 (s, 1H), 4.55-4.22 (m, 4H), 2.95
(t, J=7.47 Hz, 2H), 2.25 (s, 3H), 1.85-1.60 (m, 2H), 1.60-1.40 (m,
2H), 0.99 (t, J=7.10 Hz, 3H).
EXAMPLE 5
5-[4-[2-[2-Benzyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione
##STR00087##
The title compound (1.70 g, 66%) was obtained from
4-[2-[2-benzyl-4-methyl-6-oxo-1,6dihydro-1-pyrimidinyl]ethoxy]benzaldehyd-
e (2.0 g, 5.74 mmol) (obtained from preparation 5) and
thiazolidine-2,4-dione (0.74 g, 6.4 mmol) by a similar procedure to
that described in example 1, mp 223.degree. C.
.sup.1H NMR (CDCl.sub.3+DMSO-d.sub.6): .delta. 7.74 (s, 1H), 7.44
(d, J=8.71 Hz, 2H), 7.40-7.10 (m, 5H), 6.95 (d, J=8.71 Hz, 2H),
6.26 (s, 1H), 4.38 (s, 2H), 4.35-4.10 (m, 4H), 2.32 (s, 3H).
EXAMPLE 6
5-[4-[2-[2,5-Diethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]pheny-
l methylene]thiazolidine-2,4-dione
##STR00088##
The title compound (881 mg, 92%) was obtained from
4-[2-[2,3-diethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzald-
ehyde (730 mg, 2.32 mmol) (obtained from preparation 6) and
thiazolidine-2,4-dione (451 mg, 2.55 mmol) by a similar procedure
to that described in example 1, mp 252-254.degree. C.
.sup.1H NMR (CDCl.sub.3+DMSO-d.sub.6): .delta. 12.08 (bs, 1H,
D.sub.2O exchangeable), 7.69 (s, 1H), 7.44 (d, J=8.58 H, 2H), 6.97
(d, J=8.58 Hz, 2H), 4.50-4.20 (m, 4H), 2.93 (q, J=7.43 Hz, 2H),
2.50 (q, J=7.43 Hz, 2H), 2.26 (s, 3H), 1.33 (t, J=7.43 Hz, 3H),
1.07 (t, J=7.43 Hz, 3H).
EXAMPLE 7
5-[4-[2-[2-Ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione
##STR00089##
The title compound (2.2 g, 88%) was obtained from
4-[2-[2-ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyd-
e (2.09 g, 6.0 mmol) (obtained from preparation 7) and
thiazolidine-2,4-dione (0.702 g, 6.0 mmol) by a similar procedure
to that described in example 1, mp 234.degree. C.
.sup.1H NMR (DMSO-d.sub.6): .delta. 12.58 (bs, 1H, D.sub.2O
exchangeable), 8.22-8.05 (m, 2H), 7.74 (s, 1H), 7.66-7.38 (m, 5H),
7.11 (d, J=8.30 Hz, 2H), 6.92 (s, 1H), 4.48-4.20 (m, 4H), 3.06 (q,
J=7.06 Hz, 2H), 1.35 (t, J=7.06 Hz, 3H).
EXAMPLE 8
5-[4-[2-[4-Oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione
##STR00090##
The title compound (1.91 g, 84%) was obtained from
4-[2-[4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde (1.7 g,
5.78 mmol) (obtained from preparation 9) and thiazolidine-2,4-dione
(678 mg, 5.79 mmol) by a similar procedure to that described in
example 1, mp 242-244.degree. C.
.sup.1H NMR (CDCl.sub.3+DMSO-d.sub.6): .delta. 12.56 (bs, 1H,
D.sub.2O exchangeable), 8.42 (s, 1H), 8.18 (d, J=7.89 Hz, 1H), 7.84
(t, J=7.47 Hz, 1H), 7.72 (s, 1H), 7.72-7.50 (m, 2H), 7.54 (d,
J=8.72 Hz, 2H), 7.11 (d, J=8.72 Hz, 2H), 4.40 (s, 4H).
EXAMPLE 9
5-[4-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione
##STR00091##
The title compound (4.28, 93%) was obtained from
4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde
(3.4 g, 11.04 mmol) (obtained from preparation 10) and
thiazolidine-2,4-dione (1.6 g, 13.8 mmol) by a similar procedure to
that described in example 1, mp 278.degree. C.
.sup.1H NMR (DMSO-d.sub.6): .delta. 12.58 (bs, 1H, D.sub.2O
exchangeable), 8.19 (d, J=8.0 Hz, 1H), 7.89-7.44 (m, 6H), 7.03 (d,
J=8.7 Hz, 2H), 4.58-4.42 (m, 2H), 4.42-4.25 (m, 2H), 2.81 (s,
3H).
EXAMPLE 10
5-[4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione
##STR00092##
The title compound (0.42 g, 92%) was obtained from
4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde
(0.35 g, 1.08 mmol) (obtained from preparation 11) and
thiazolidine-2,4-dione (0.16 g, 1.4 mmol) by a similar procedure to
that described in example 1, mp 257.degree. C.
.sup.1H NMR (DMSO-d.sub.6): .delta. 12.58 (bs, 1H, D.sub.2O
exchangeable), 8.15 (d, J=8.0 Hz, 1H), 7.82-7.44 (m, 6H), 7.08 (d,
J=8.0 Hz, 2H), 4.47-4.40 (m, 2H), 4.40-4.30 (m, 2H), 3.08 (q, J=7.0
Hz, 2H), 1.37 (t, J=7.0 Hz, 3H).
EXAMPLE 11
5-[4-[2-[8-Aza-2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione
##STR00093##
The title compound (0.25 g, 68%) was obtained from
4-[2-[8-Aza-2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde
(0.28 g, 0.9 mmol) (obtained from preparation 12) and
thiazolidine-2,4-dione (0.106 g, 0.9 mmol) by a similar procedure
to that described in example 1, mp 276.degree. C.
.sup.1H NMR (CDCl.sub.3+DMSO-d.sub.6): .delta. 9.00-8.90 (m, 1H),
8.51 (d, J=7.30 Hz, 1H), 7.72 (s, 1H), 7.51 (d, J=8.72 Hz, 2H),
7.55-7.45 (m, 1H), 7.05 (d, J=8.72 Hz, 2H), 4.60-4.50 (m, 2H),
4.50-438 (m, 2H), 2.85 (s, 3H).
EXAMPLE 12
5-[4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methylene]thiazolidine-2,4-dione
##STR00094##
The title compound (11.10 g, 96%) was obtained from
4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]benzaldehyde
(9.0 g, 30.61 mmol) (obtained from preparation 13) and
thiazolidine-2,4-dione (3.6 g, 30.61 mmol) by a similar procedure
to that described in example 1, mp 280.degree. C.
.sup.1H NMR (CDCl.sub.3+DMSO-d.sub.6): .delta. 12.38 (bs, 1H,
D.sub.2O exchangeable), 8.19 (d, J=7.47 Hz, 1H), 7.82-7.60 (m, 2H),
7.72 (s, 1H), 7.53 (d, J=8.7 Hz, 2H), 7.60-7.48 (m, 1H), 7.23 (d,
J=8.72 Hz, 2H), 5.35 (s, 2H), 3.68 (s, 3H).
EXAMPLE 13
5-[4-[[3-Ethyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methylene]thiazolidine-2,4-dione
##STR00095##
The title compound (3.3 g, 83%) was obtained from
4-[[3-ethyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]benzaldehyde
(3.0 g, 9.74 mmol) (obtained from preparation 14) and
thiazolidine-2,4-dione (1.14 g, 9.74 mmol) by a similar procedure
to that described in example 1, mp 260-261.degree. C.
.sup.1H NMR (CDCl.sub.3+DMSO-d.sub.6): .delta. 12.58 (bs, 1H,
D.sub.2O exchangeable), 8.18 (d, J=7.88 Hz, 1H), 1H), 7.92-7.74 (m,
1H), 7.78 (s, 1H), 7.74-7.54 (m, 2H), 7.61 (d, J=8.72 Hz, 2H), 7.29
(d, J=8.72 Hz, 2H), 5.40 (s, 2H), 4.14 (q, J=6.84 Hz, 2H), 1.34 (t,
J=6.84 Hz, 3H).
EXAMPLE 14
5-[4-[[1-Methyl-4-oxo-1,4dihydro-2-quinazolinyl]methoxy]phenyl
methylene]thiazolidine-2,4-dione
##STR00096##
The title compound (310 mg, 79%) was obtained from
4-[[1-methyl-4-oxo-1,4-dihydro-2-quinazolinyl]methoxy]benzaldehyde
(294 mg, 1.0 mmol) (obtained from preparation 15) and
thiazolidine-2,4-dione (117 mg, 1.0 mmol) by a similar procedure to
that described in example 1.
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.09 (d, J=7.88 Hz, 1H),
8.00-7.04 (m, 4H), 7.58 (d, J=8.72 Hz, 2H), 7.24 (d, J=8.72 Hz,
2H), 5.41 (s, 2H), 3.86 (s, 3H).
EXAMPLE 15
5-[3-Methoxy-4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methylene]thiazolidine-3,4-dione
##STR00097##
The title (235 mg, 90%) was obtained from
3-methoxy-4-[[3-methyl-4-oxo-3,4-dihydroquinazolinyl]methoxy]benzaldehyde
(200 mg, 0.62 mmol) (obtained from preparation 16) and
thiazolidine-2,4-dione (79 mg, 0.68 mmol) by a similar procedure to
that described in example 1, mp 244-246.degree. C.
.sup.1H NMR (DMSO-d.sub.6+CDCl.sub.3): .delta. 12.25 (bs, 1H,
D.sub.2O exchangeable) 8.02 (d, J=7.20 Hz, 1H), 7.82-7.60 (m, 2H),
7.66 (s, 1H), 7.51 (t, J=7.20 Hz, 1H), 7.38-7.03 (m, 3H), 5.52 (s,
2H), 3.91 (s, 3H), 3.68 (s, 3H).
EXAMPLE 16
5-[4-[2-[4-Acetylamino-2-oxo-1,2-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione
##STR00098##
The title compound (1.8 g, 81%) was obtained from
4-[2-[4-acetylamino-2-oxo-1,2-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde
(1.7 g, 5.65 mmol) (obtained from preparation 8) and
thiazolidine-2,4-dione (0.661 g, 5.65 mmol) by a similar procedure
to that described in example 1, mp 274.degree. C.
.sup.1H NMR (CDCl.sub.3+DMSO-d.sub.6): .delta. 12.56 (bs, 1H,
D.sub.2O exchangeable), 10.85 (s, .sup.3H, D.sub.2O exchangeable),
8.11 (d, J=7.2 Hz, 1H), 7.74 (s, 1H), 7.55 (d, J=8.30 Hz, 2H), 7.17
(d, J=7.20 Hz, 1H), 7.11 (d, J=8.30 Hz, 2H), 4.40-4.05 (m, 4H),
2.08 (s, 3H).
EXAMPLE 17
5-[4-[2-[4-methyl-2-Propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione
##STR00099##
A solution of
5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione (5.0 g, 12.46 mmol) obtained from
example 1 in 1,4-dioxane (75 ml) was reduced with hydrogen in the
presence of 10% palladium on charcoal (12.0 g) at 60 psi pressure
for 40 h. The mixture was filtered through a bed of celite. The
filtrate was evaporated to dryness under reduced pressure, purified
by column chromatography (2:1 EtOAc/petroleum ether as eluent)
followed by crystallisation (CH.sub.2Cl.sub.2) to afford the title
compound (4.6 g, 92%), mp 144-146.degree. C.
.sup.1H NMR (CDCl.sub.3): .delta. 8.25 (bs, 1H, D.sub.2O
exchangeable) 7.12 (d, J=8.48 Hz, 2H), 6.79 (d, J=7.48 Hz, 2H),
6.21 (s, 1H), 4.47 (dd, J=9.36, 4.06 Hz, 1H), 4.41 (t, J=4.47 Hz,
2H), 4.26 (t, J=4,47 Hz, 2H), 3.41 (dd, J=14.11, 4.06 Hz, 1H), 3.10
(dd, J=14.11 9.36 Hz, 1H), 2.92 (t, J=7.63 Hz, 2H), 2.24 (s, 3H),
1.90-1.60 (m, 2H), 1.05 (t, J=7.65 Hz, 3H).
EXAMPLE 18
5-[4-[2-[2,4-Dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione
##STR00100##
The title compound (850 mg, 85%) was obtained from
5-[4-[2-[2,4-dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione (1.0 g) (obtained from example 2)
by a similar procedure to that described in example 17, mp
170.degree. C.
.sup.1H NMR (CDCl.sub.3): .delta. 8.15 (bs, 1H, D.sub.2O
exchangeable), 7.14 (d, J=8.30 Hz, 2H), 6.80 (d, J=8.30 Hz, 2H),
6.21 (s, 1H), 4.50 (dd, J=9.13, 3.73 Hz, 1H), 4.48-4.20 (m, 4H),
3.41 (dd, J=14.12, 3.73 Hz, 1H), 3.13 (dd, J=14.12, 9.13 Hz, 1H),
2.70 (s, 3H), 2.25 (s, 3H).
EXAMPLE 19
5-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione
##STR00101## Method A
The title compound (820 mg, 82%) was obtained from
5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione (1.0 g, 2.6 mmol) (obtained from
example 3) by a similar procedure to that described in example
17.
Method B
To a stirred solution of
5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]-2-iminothiazolidine-4-one (1.93 g, 5.0 mmol) (obtained from
preparation 26) in ethanol (15 ml) was added to 2N HCl (10 ml) and
refluxed for 12 h. The reaction mixture was cooled to room
temperature and ethanol was removed under reduced pressure. The
aqueous layer was neutralised with saturated aqueous NaHCO.sub.3
solution and extracted with EtOAc (3.times.20 ml). The combined
organic layer was washed with brine, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated to yield the title compound (1.63
g, 84%) which was crystallised from CH.sub.2Cl.sub.2-pet. ether, mp
148.degree. C. The title compound upon crystallisation from MeOH
provided another polymorph, mp 155.degree. C.
.sup.1H NMR (CDCl.sub.3): .delta. 8.65 (bs, 1H, D.sub.2O
exchangeable), 7.12 (d, J=8.51 Hz, 2H), 6.79 (d, J=8.51 Hz, 2H),
6.21 (s, 1H), 4.48 (dd, J=9.27, 3.83 Hz, 1H), 4.42 (t, J=4.57 Hz,
2H), 4.26 (t, J=4.57 Hz, 2H), 3.41 (dd, J=14.11, 3.83 Hz, 1H), 3.11
(dd, J=14.11, 9.27 Hz, 1H), 2.99 (q, J=7.47 Hz, 2H), 2.25 (s, 3H),
1.34 (t, J=7.47 Hz, 3H).
EXAMPLE 20
5-[4-[2-[2-Butyl-4methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione
##STR00102##
The title compound (780 mg, 78%) was obtained from
5-[4-[2-[2-Butyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione (1.0 g) (obtained from example 4)
by a similar procedure to that described in example 17, mp
150-152.degree. C.
.sup.1H NMR (CDCl.sub.3): .delta. 9.53 (bs, 1H, D.sub.2O
exchangeable), 7.13 (d, J=8.40 Hz, 2H), 6.79 (d, J=8.40 Hz, 2H),
6.22 (s, 1H), 4.45 (dd, J=9.22, 3.83 Hz, 1H), 4.42 (t, J=4.57 Hz,
2H), 4.26 (t, J=4.57 Hz, 2H), 3.42 (dd, J=14.12 Hz, 3.83 Hz, 1H),
3.09 (dd, J=14.12, 9.22 Hz, 1H), 2.95 (t, J=7.47 Hz, 2H), 2.24 (s,
3H), 1.85-1.65 (m, 2H), 1.58-1.32 (m, 2H), 0.98 (t, J=7.38 Hz,
3H).
EXAMPLE 21
5-[4-[2-[2-Ethyl-4phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione
##STR00103##
The title compound (300 mg, 50%) was obtained from
5-[4-[2-[2-ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione (600 mg, 1.38 mmol) (obtained from
example 7) by a similar procedure to that described in example 17,
mp 178.degree. C.
.sup.1H NMR (CDCl.sub.3): .delta. 8.20-7.95 (m, 2H), 7.55-7.35 (m,
3H), 7.12 (d, J=8.30 Hz, 2H), 6.80 (d, J=8.30 Hz, 2H), 6.80 (s,
1H), 4.60-4.40 (m, 3H), 4.40-4.20 (m, 2H), 3.41 (dd, J=14.1, 3.65
Hz, 1H), 3.09 (dd and q overlap, 3H), 1.46 (t, J=7.30 Hz, 3H).
EXAMPLE 22
5-[4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methyl]thiazolidine-2,4-dione
##STR00104## Method A
The title compound (750 mg, 75%) was obtained from
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methylene]thiazolidine-2,4-dione (1.0 g) (obtained from example 12)
by a similar procedure to that described in example 17.
Method B
To a stirred solution of
[4-[[1,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid
(1.9 g, 6.75 mmol) (obtained form preparation 38) in
dichloromethane (15 ml) was added triethyl amine (1.876 ml, 1.36 g,
13.48 mmol) followed by pivaloyl chloride (0.913 ml, 899 mg, 5.46
mmol) at 0.degree. C. and stirring was continued for 1 h at
0.degree. C. The above reaction mixture was added to a solution of
2-amino-N-methyl benzamide (920 mg, 6.13 mmol) in acetic acid (20
ml) and refluxed for 24 h. The reaction mixture was cooled to room
temperature and acetic acid was removed under reduced pressure. To
the residue water (50 ml) was added and extracted with CHCl.sub.3
(3.times.25 ml). The combined CHCl.sub.3 extracts were washed with
brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated to
yield the title compound (2.16 g, 81%, mp 190.degree. C.
Method C
To a stirred solution of
[4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid (33
g, 0.117 mol) in dichloromethane (300 mL) was added methyl amine
(35.4 mL, 0.254 mol) followed by pivaloyl chloride (17.3 mL, 0.127
mol) at 0.degree. C. and stirred for 1 h at 0.degree. C. The
reaction mixture was added to a solution of 2-amino-N-methyl
benzamide (16 g, 0.106 mol) in a mixture of acetic acid (300 mL)
and xylene (300 mL) and refluxed for 18 h. The reaction mixture was
cooled to room temperature and solvents were removed under reduced
pressure. The product was purified to yield the title compound
(35.5 g, 85%).
Method D
To a stirred solution of
[4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid
(1.9 g, 6.75 mmol) in dichloromethane (15 mL) was added triethyl
amine (1.876 mL, 1.36 g, 13.48 mmol) followed by pivaloyl chloride
(0.913 mL, 899 mg, 5.46 mmol) at 0.degree. C. and stirring was
continued for 1 h at 0.degree. C. The above reaction mixture was
added to a solution of 2-amino-N-methyl benzamide (920 mg, 6.13
mmol) in xylene (20 mL) containing pTsOH.H.sub.2O (646 mg, 3.4
mmol) and refluxed for 24 h. The reaction mixture was cooled to
room temperature and xylene was removed under reduced pressure.
Water (50 mL) was added to the residue and extracted with
CHCl.sub.3 (3.times.25 mL). The combined CHCl.sub.3 extracts were
washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and
concentrated to yield the title compound (1.79 g, 58%).
Method E
To a solution of
[4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid
(1.0 g, 3.56 mmol) in xylene (10 mL) was added thionyl chloride
(1.6 mL, 2.12 g, 17.8 mmol) and refluxed for 1 h. The reaction
mixture was cooled to 25.degree. C. and excess thionyl chloride was
removed and then was added to a solution of 2-amino-N-methyl
benzamide (534 mg, 3.56 mmol) in a mixture of acetic acid (10 mL)
and xylene (5 mL) and refluxed for 20 h. The reaction mixture was
cooled to room temperature and the solvents were removed under
reduced pressure. To the residue water (20 mL) was added and
extracted with CHCl.sub.3 (3.times.25 mL). The combined CHCl.sub.3
extracts were washed with brine, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated to yield the title compound (740
mg, 54%).
Method F
5-[[4-[N-Methyl benzamide-2-yl]aminocarbonyl]methoxy]phenyl
methyl]thiazolidine-2,4-dione (1.0 g) (obtained in preparation 39)
was heated at 180.degree. C. for 8 h. The reaction mixture was
cooled to room temperature diluted with water and extracted with
EtOAc (3.times.20 mL). The combined organic layers were washed with
brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated.
Method G
The title compound (345 mg, 34%) was prepared from
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methylene]thiazolidine-2,4-dione (1.0 g) (obtained from example 12)
by a similar procedure to that described in preparation 37, method
B.
Polymorphs:
Polymorph I:
5-[4-[[3-[methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methyl]thiazolidine-2,4-dione (10 g) obtained from any one of the
above methods was dissolved in dioxane (200 mL) by warming up to
60.degree. C. The solution was concentrated to 30-50 ml to which
methanol was added and stirred for 15-30 min. The white solid
precipitated out was filtered and dried to yield the polymorph I,
which is having DSC endotherm at 198.degree. C.
Polymorph II:
5-[4[-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methyl]thiazolidine-2,4-dione (10 g) obtained from any one of the
methods, was dissolved in acetone (300 mL). The solution was
concentrated to 30-50 ml and methanol was added. After stirring for
15-30 min, the precipitated white solid was filtered and dried to
yield the polymorph II, which is having DSC endotherm at
180.degree. C.
.sup.1H NMR (CDCl.sub.3): .delta. 8.70 (bs, 1H, D.sub.2O
exchangeable), 8.31 (d, J=7.89 Hz, 1H), 7.88-7.68 (m, 2H),
7.60-7.4.5 (m, 1H), 7.19 (d, J=8.46 Hz, 2H), 7.02 (d, J=8.46 Hz,
2H), 5.18 (s, 2H, 4.50 (dd, J=9.22, 3.90 Hz, 1H), 3.75 (s, 3H),
3.45 (dd, J=14.11, 3.90 Hz, 1H), 3.13 (dd, J=14.11, 9.22 Hz,
1H).
EXAMPLE 23
5-[4-[[3-Ethyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methyl]thiazolidine-2,4-dione:
##STR00105## Method A:
The title compound (1.86 g, 58%) was obtained from
5-[4-[[3-ethyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methylene]thiazolidine-2,4-dione (2.035 g, 5.0 mmol) (obtained from
example 13) by a similar procedure to that described in example
17.
Method B:
The title compound (278 mg, 68%) was obtained from
4-[[2,4-2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid
(281 mg, 1.0 mmol) (obtained from preparation 38) and
2-amino-N-methyl benzamide (164 mg, 1.0 mmol) by a similar
procedure to that described in example 22 in method B.
mp=218.degree. C.
.sup.1H NMR (CDCl.sub.3): .delta. 9.20 (bs, 1H, D.sub.2O
exchangeable) 8.30 (d, J=7.84 Hz, 1H), 7.84-7.64 (m, 2H), 7.60-7.48
(m, 1H), 7.19 (d, J=8.46 Hz, 2H), 7.02 (d, J=8.46 Hz, 2H), 5.25 (s,
2H), 4.51 (dd, J=9.30, 3.95 Hz, 1H), 3.94 (q, J=6.92 Hz, 2H), 3.42
(dd, J=14.12, 3.95 Hz, 1H), 3.11 (dd, J=14.2, 9.30 Hz, 1H), 1.35
(t, J=6.92 Hz, 3H).
EXAMPLE 24
5-[4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione:
##STR00106##
The title compound (173 mg, 82%) was obtained from
5-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methyl]-2-iminothiazolidine-4-one (211 mg, 0.5 mmol) (obtained from
preparation 27) by a similar procedure to that described in example
19 (Method B), mp 178-180.degree. C.
.sup.1H NMR (CDCl.sub.3): .delta. 8.24 (d, J=7.88 Hz, 1H),
7.80-7.60 (m, 2H), 7.43 (t, J=7.56 Hz, 1H), 7.10 (d, J=8.63 Hz,
2H), 6.80 (d, J=8.63 Hz, 2H), 4.54 (t, J=5.03 Hz, 2H), 4.46 (dd,
J=9.22, 3.83 Hz, 1H), 4.32 (t, J=5.03 Hz, 2H), 3,40 (dd, J=14.35,
3.83 Hz, 1H), 3.20-2.90 (m, 3H), 1.43 (t, J=7.48 Hz, 3H).
EXAMPLE 25
2-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]-1,2,4-oxadiazolidine-3,5-dione:
##STR00107## Method A
To a stirred solution of
N-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzyl]--
N-hydroxyurea (346 mg, 1.0 mmol) (obtained from preparation 19) in
water (2 ml) was added 1N NaOH (3 ml) followed by ethyl
chloroformate (191 .mu.l, 217 mg, 2.0 mmol) and stirred for 1 h at
30.degree. C. The reaction mixture was diluted with water,
acidified to pH 3.0 and extracted with EtOAc (3.times.10 ml). The
combined organic layers were washed with brine, dried over
anhydrous Na.sub.2SO.sub.4 and concentrated to yield the title
compound (283 mg, 76%).
Method B
To a cold (-5.degree. C.) solution of
4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzyl
hydroxylamine (304 mg, 1.0 mmol) (obtained from preparation 18) in
anhydrous THF (4.0 ml) was added N-(chlorocarbonyl) isocyanate (88
.mu.l, 116 mg, 1.1 mmol) dropwise. The mixture was stirred by 30
min. and poured into 2N HCl followed by extraction with EtOAc
(3.times.10 ml). The combined organic extracts were washed with
brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated to
yield the title compound (264 mg, 71%).
.sup.1H NMR (CDCl.sub.3+DMSO-d.sub.6): .delta. 12.40 (bs, 1H,
D.sub.2O exhangeable), 7.25 (d, J=8.72 Hz, 2H), 6.90 (d, J=8.72 Hz,
2H), 6.15 (s, 1H), 4.70 (s, 2H), 4.40-4.25 (m, 2H), 4.25-4.12 (m,
2H), 2.91 (q, J=7.56 Hz, 2H), 2.12 (s, 3H), 1.20 (t, J=7.56 Hz,
3H).
EXAMPLE 26
5-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]oxazolidine-2.4-dione:
##STR00108##
To a stirred solution of
5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]-2-thio-1,3-oxazolidine-4-one (100 mg, 0.259 mmol)
(obtained from preparation 30) in dry DMF (2 ml) was added
3-chloroperbenzoic acid (179 mg, 0.68 mmol, 65%) at 0.degree. C.
and stirred for 30 min at 0.degree. C. to 10.degree. C. and then at
30.degree. C. for 5 h. The reaction mixture was diluted with ethyl
acetate (10 ml), washed with water (5 ml) and then with brine (5
ml); dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The
crude product was purified by flash chromatography to yield the
title compound (72 mg, 75%).
.sup.1H NMR (CDCl.sub.3+DMSO-d.sub.6): .delta. 7.68 (d, J=8.72 Hz,
2H), 6.91 (d, J=8.72 Hz, 2H), 6.61 (s, 1H), 6.16 (s, 1H), 4.50-4.38
(m, 2H), 4.38-4.00 (m, 2H), 3.12 (q, J=7.47 Hz, 2H), 2.24 (s, 3H),
1.35 (t, J=7.47 Hz, 3H).
EXAMPLE 27
5-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]oxazolidine-2,4-dione:
##STR00109## Method A:
A solution of
5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methylene]oxazolidine-2,4-dione (100 mg) (obtained from example 26)
in 1,4-dioxane (10 ml) was reduced with hydrogen in the presence of
10% palladium on charcoal (20 mg) at 50 psi for 24 h. The mixture
was filtered through a bed of celite. The filtrate was evaporated
to dryness under reduced pressure, purified by column
chromatography (2:1 EtOAc/petroleum ether as eluent) to afford the
title compound (90 mg, 90%).
Method B:
A solution of ethyl
3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl]--
2-hydroxy propanoate (93 mg, 0.25 mmol) (obtained from preparation
29), urea (30 mg, 0.5 mmol) and sodium methoxide (22 mg, 0.4 mmol)
in a mixture of methanol (0.5 ml) and ethanol (2.0 ml) was stirred
for 2 h at 30.degree. C., followed by reflux for 2 h. The reaction
mixture was cooled to room temperature and acidified with 2N HCl to
pH 4 and extracted with ethyl acetate (2.times.10 ml). The combined
organic extracts were washed with water (5 mL), brine (5 mL), dried
over anhydrous Na.sub.2SO.sub.4 and concentrated to yield the title
compound (35 mg, 38%).
.sup.1H NMR (CDCl.sub.3+DMSO-d.sub.6): .delta. 7.14 (d, J=8.51 Hz,
2H), 6.77 (d, J=8.5 Hz, 2H), 6.17 (s, 1H), 4.95 (t, J=4.82 Hz, 1H),
4.42 (t, J=4.94 Hz, 2H), 4.24 (t, J=4.94 Hz, 2H), 3.38-3.00 (m,
2H), 3.00 (q, J=7.42 Hz, 2H), 2.25 (s, 3H), 1.34 (t, J=7.42 Hz,
3H).
EXAMPLE 28
5-[4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methyl]thiazolidine-2,4-dione sodium salt:
##STR00110##
To a stirred suspension of
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methyl]thiazolidine-2,4-dione (21.0 g, 53.2 mmol) (obtained from
example 22) in methanol (200 ml) was added a solution of sodium
methoxide (11.45 g, 212 mmol) in methanol (25 ml) dropwise at
30.degree. C. During this period the suspension slowly dissolved
completely and a white solid precipitated out which was stirred
further for 1 h. The solid was filtered and washed with methanol
(20 ml) and dried to afford the title compound (20.6 g, 93%), mp
235.degree. C.
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.16 (d, J=7.47 Hz, 1H), 7.84
(t, J=7.47 Hz, 1H), 7.69 (d, J=7.47 Hz, 1H), 7.56 (t, J=7.47 Hz,
1H), 7.15 (d, J=8.72 Hz, 2H), 7.00 (d, J=8.72 Hz, 2H), 5.25 (s,
2H), 4.09 (dd, J=10.34, 3.36 Hz, 1H), 3.61 (s, 3H), 3.30 (dd.
J=13.82, 3.36 Hz, 1H), 2.62 (dd, J=13.82, 10.34 Hz, 1H).
Polymorphs:
The reactions were carved out in variety of solvents, using
different equivalents of base and different amounts of
solvents.
Different polymorphs were observed depending on conditions used,
which has shown in the following table:
TABLE-US-00004 CONDITIONS Free eq. DSC S.No Polymorphs Acid
Solvent/mL of NnOMe endotherm 1. Form I 1 g Isoproponol - 10 mL 1.5
eq 280.degree. C. 2. Form II 1 g Methanol - 15 mL 2.0 eq
276.degree. C. 3. Form III 1 g Methanol - 10 mL 2.0 eq 272.degree.
C. 4. Form IV 1 g Ether - 5 mL 1.5 eq 263.degree. C. 5. Form V 1 g
Ethanol - 10 mL 1.1 eq 185.degree. C.
EXAMPLE 29
5-[4-[2-[2,5,6-Trimethyl-4-oxo-3,4-dihydro-thieno-[2,3-d]-pyrimidin-3-yl]e-
thoxy]phenyl methylene]thiazolidine-2,4-dione:
##STR00111##
The title compound (550 mg, 85%) was obtained from
4-[2-[2,5,6-trimethyl-4-oxo-thieno-3-pyrimidinyl]ethoxy]benzaldehyde
(500 mg, 1.46 mmol) (obtained from preparation 31) and
thiazolidine-2,4-dione (257 mg, 2.2 mmol) by a similar procedure to
that described in example 1, mp 280.degree. C.
.sup.1H NMR (DMSO-d.sub.6): .delta. 12.52 (bs, 1H, D.sub.2O
exchangeable), 7.71 (s, 1H), 7.52 (d, J=8.39 Hz, 2H), 7.10 (d,
J=8.39 Hz, 2H), 4.50-4.20 (m, 4H), 2.66 (s, 3H), 2.36 (s, 3H), 2.32
(s, 3H).
EXAMPLE 30
5-[4-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione, sodium salt:
##STR00112##
The title compound (385 mg, 90%) was obtained from
5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione (obtained from example 9) (407 mg,
1.0 mmol) by a similar procedure to that described in example 28.
mp: 280.degree. C. (decomposes).
.sup.1H NMR (DMSO-d.sub.6+CDCl.sub.3): .delta. 8.12 (d, J=8.0 Hz,
1H), 7.78 (t, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.46 (t, J=8.0
Hz, 1H), 7.45 (d, J=8.7 Hz, 2H), 7.25 (s, 1H), 6.98 (d, J=8.7 Hz,
2H), 4.55-4.40 (m, 2H), 4.40-4.25 (m, 2H), 2.75 (s, 3H).
EXAMPLE 31
5-[4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methylene] thiazolidine-2,4-dione, sodium salt:
##STR00113##
The title compound (405 mg, 91%) was obtained from
5-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methylene]thiazolidine-2,4-dione (obtained from example 10) (421
mg, 1.0 mmol), by a similar procedure to that described in example
28. mp: 250.degree. C. (decomposes).
.sup.1H NMR (DMSO-d.sub.6+CDCl.sub.3): .delta. 8.15 (d, J=8.0 Hz,
1H), 7.79 (t, J=8.0 Hz, 1H), 7.65 (s, 1H), 7.60-7.45 (m, 4H), 7.10
(d, J=8.7 Hz, 2H), 4.60-4.45 (m, 2H), 4.45-4.32 (m, 2H), 3.10 (q,
J=7.5 Hz, 2H), 1.35 (t, J=7.5 Hz, 3H).
EXAMPLE 32
5-[4-[2-[4-Methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione, sodium salt:
##STR00114##
The title compound (460 mg, 88.5%) was obtained from
5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione (obtained from example 17) (560 mg,
1.21 mmol) by a similar procedure to that described in example 28,
mp: 230.degree. C.
.sup.1H NMR (DMSO-d.sub.6): .delta. 7.09 (d, J=8.53 Hz, 2H), 6.78
(d, J=8.53 Hz, 2H), 6.15 (s, 1H), 4.38-4.25 (m, 2H), 4.25-4.10 (m,
2H), 4.06 (dd, J=10.47, 3.42 Hz, 1H), 3.28 (dd, J=13.69, 10.47 Hz,
1H), 2.85 (t, J=7.4 Hz, 2H), 2.62 (dd, J=13.69, 3.42 Hz, 1H), 2.15
(s, 3H), 1.71 (q, J=7.47 Hz, 2H), 0.96 (t, J=7.47 Hz, 3H).
EXAMPLE 33
5-[4-[2-[2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione, sodium salt:
##STR00115##
The title compound (0.6 g, 94.6%) was obtained from
5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione (0.6 g, 1.55 mmol) (obtained from
example 19) by a similar procedure to that described in example 28.
mp: 258-260.degree. C.
.sup.1H NMR (DMSO-d.sub.6): .delta. 7.10 (d, J=7.53 Hz, 2H), 6.80
(d, J=7.53 Hz, 2H), 6.16 (s, 1H), 4.32 (t, J=5.26 Hz, 2H), 4.16 (t,
J=5.26 Hz, 2H), 4.10 (dd, J=9.6, 3.4 Hz, 1H), 3.4-3.25 (dd, J=13.6,
9.62 Hz, 1H), 2.91 (q, J=7.3 Hz, 2H), 2.59 (dd, J=13.6, 3.4 Hz,
1H), 2.66 (s, 3H), 1.25 (t, J=7.3 Hz, 3H).
EXAMPLE 34
5-[4-[2-[2-Ethyl-4-trifluoromethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]-
phenyl methylene]thiazolidine-2,4-dione:
##STR00116##
The title compound (550 mg) was obtained from
[4-[2-[2-ethyl-4-trifluoromethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]b-
enzaldehyde (700 mg, 2.05 mmol) (obtained from preparation 36) and
thiazolidine-2,4-dione (240 mg, 3.05 mmol) by a similar procedure
to that described in example 1. mp:>250.degree. C.
.sup.1H NMR (CDCl.sub.3+DMSO-d.sub.6): .delta. 7.70 (s, 1H), 7.45
(d, J=83 Hz, 2H), 6.95 (d, J=8.3 Hz, 2H), 6.69 (s, 1H ), 4.50 (t,
J=4.5 Hz, 2H), 4.35 (t, J=4.5 Hz, 2H), 3.11 (q, J=7.2 Hz, 2H), 1.38
(t, J=7.2 Hz, 3H).
EXAMPLE 35
5-[4-[2-[2-Ethyl-4-trifluoromethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]-
phenyl methyl]thiazolidine-2,4-dione:
##STR00117##
The title compound (0.3 g, 66%) was obtained from
5-[4-[2-[2-ethyl-4-trifluoromethyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy-
]phenyl methylene]thiazolidine-2,4-dione (0.45 g, 1.025 mmol)
obtained from example 34 by a similar procedure to that described
in example 17. mp: 135.degree. C.
.sup.1H NMR (DMSO-d.sub.6): .delta. 7.11 (d, J=8.53 Hz, 2H), 6.77
(d, J=8.53 Hz, 2H), 6.70 (s, 1H), 4.52-4.38 (m, 1H), 4.46 (t,
J=4.68 Hz, 2H), 4.28 (t, J=4.68 Hz, 2H), 3,4 (dd, J=14.21, 3.83 Hz,
1H), 3.20-2.98 (m, 3H), 1.38 (t, J=7.33 Hz, 3H).
EXAMPLE 36
5-[4-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione:
##STR00118##
The title compound (1.6 g, 89%) was obtained from
5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methyl]-2-iminothiazolidine-4-one (1.8 g, 4.4 mmol) (obtained from
preparation 35) by a similar procedure to that described in example
19 (method B), 242-244.degree. C.
.sup.1H NMR (DMSO-d.sub.6): .delta. 11.98 (bs, 1H, D.sub.2O
exchangeable), 8.11 (d, J=7.50 Hz, 1H), 7.80 (t, J=7.50 Hz, 1H),
7.59 (d, J=7.50 Hz, 1H), 7.48 (t, J=7.50 Hz, 1H), 7.14 (d, J=8.35
Hz, 2H), 6.89 (d, J=8.35 Hz, 2H), 4.85 (dd, J=9.03, 4.20 Hz, 1H),
4.45 (t, J=5.14 Hz, 2 H), 4.27 (t, J=5.14 Hz, 2H), 3.28 (dd,
J=14.12, 4.20 Hz, 1H), 3.04 (dd, J=14.12, 9.03 Hz, 1H), 2.71 (s,
3H).
EXAMPLE 37
5[4-[2-[2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione, sodium salt:
##STR00119##
The title compound (348 mg, 81%) was obtained from
5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione (409 mg, 1 mmol) (obtained from
example 36) by a similar procedure to that described in example 28.
mp: 317.degree. C.
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.11 (d, J=7.88 Hz, 1H), 7.79
(t, J=7.05 Hz, 1H), 7.59 (d, J=7.88 Hz, 1H), 7.48 (t, J=7.05 Hz,
1H), 7.08 (d, J=8.40 Hz, 2H), 6.83 (d, J=8.40 Hz, 2H), 4.44 (t,
J=5.40 Hz, 2H), 4.26 (1. J=5.40 Hz, 2H), 4.06 (dd, J=10.43, 3.42
Hz, 1H), 3.28 (dd, J=13.8, 3.42 Hz, 1H), 2.62 (dd, J=13.8, 10.43
Hz, 1H), 2.71 (s, 3H).
EXAMPLE 38
5-[4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione, sodium salt:
##STR00120##
The title compound (700 mg, 68%) was obtained from
5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl
methyl]thiazolidine-2,4-dione (978 mg, 2.3 mmol) (obtained from
example 24) by a similar procedure to that described in example 28.
mp: 280.degree. C.
.sup.1H NM R (DMSO-d.sub.6): .delta. 8.15 (d, J=7.89 Hz, 1H), 7.82
(t, J=7.89 Hz, 1H), 7.65 (d, J=7.89 Hz, 1H), 7.51 (t, J=7.89 Hz,
1H), 7.11 (d, J=8.40 Hz, 2H), 6.83 (d, J=8.40 Hz, 2H), 4.48 (t,
J=5.4 Hz, 2H), 4.27 (t, J=5.40 Hz, 2H), 4.08 (dd, J=10.39, 3.12 Hz,
1H), 3.25 (dd, J=10.39, 3.12 Hz, 1H), 3.06 (q, J=7.15 Hz, 2H), 2.64
(dd, J=13.82, 10.39 Hz, 1H), 1.34 (t, J=7.15 Hz, 3H).
EXAMPLE 39
5-[4-[[6,7-Dimethoxy-3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phe-
nyl methyl]thiazolidine-2,4-dione:
##STR00121##
The title compound (1.0 g, 44%) was obtained from
4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetic acid
(1.05 g, 5.0 mmol) 2-amino-N-methyl benzamide (1.5 g, 5.34 mmol) by
a similar procedure to that described in example 22, method B; mp:
252.degree. C.
.sup.1H NMR (CDCl.sub.3): .delta. 7.61 (s, 1H), 7.46 (s, 1H), 7.14
(d, J=8.72 Hz, 2H), 6.98 (d, J=8.72 Hz, 2H), 5.15 (s, 2H), 4.5 (dd,
J=10.20, 3.30 Hz, 1H), 4.0 (s, 6H), 3.74 (s, 3H), 3.45 (dd, J=14.3,
3.30 Hz, 1H), 3.16 (dd, J=14.3, 10.20 Hz, 1H).
EXAMPLE 40
5-[4-[[6,7-Dimethoxy-3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phe-
nyl methyl]thiazolidine-2,4-dione, sodium salt:
##STR00122##
The title compound (140 mg, 64%) was obtained from
5-[4-[[6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]ph-
enyl methyl]thiazolidine-2,4-dione (210 mg, 0.46 mmol) (obtained
from example 39) by a similar procedure to that described in
example 28. mp: 275.degree. C.
.sup.1H NMR (DMSO-d.sub.6): .delta. 7.46 (s, 1H), 7.16 (s, 1H),
7.14 (d, J=7.50 Hz, 2H), 6.98 (d, J=7.50 Hz, 2H), 5.19 (s, 2H),
4.20 (dd, J=10.50, 3.50 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.60
(s, 3H), 3.32 (dd, J=13.70 Hz, 3.50 Hz, 1H), 2.67 dd, J=13.7, 10.0
Hz, 1H).
EXAMPLE 41
5-[4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methyl]thiazolidine-2,4-dione, potassium salt:
##STR00123##
To a stirred solution of
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methyl]thiazolidine-2,4-dione (10.0 g, 25.3 mmol) t-BuOK (obtained
from example 22) in methanol (100 mL) was added a solution of (3.40
g, 30.3 mmol) in methanol (50 mL) dropwise at 30.degree. C. During
this period the suspension slowly dissolved completely and a white
solid precipitated out which was stirred further for 1 h. The solid
was filtered and washed with methanol (20 mL) and dried to afford
the title compound (9.8 g, 90%). mp: 302.degree. C.
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.17 (d, J=7.89 Hz, 1H) 7.85
(t, J=7.52 Hz, 1H), 7.7 (d, J=7.89 Hz, 1H), 7.58 (t, J=7.52 Hz,
1H), 7.16 (d, J=8.63 Hz, 2H), 7.01 (d, J=8.63 Hz, 2H), 5.25 (s,
2H), 4.12 (dd, J=10.47, 3.56 Hz, 1H), 3.62 (s, 3H), 3.32 (dd,
J=13.70, 3.56 Hz, 1H), 2.65 (dd, J=13.70, 10.47 Hz, 1H).
EXAMPLE 42
5-[4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methyl]thiazolidine-2,4-dione, Calcium salt:
##STR00124##
A mixture of
5-[4-[[3-[methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methyl]thiazolidine-2,4-dione (1.0 g, 2.53 mmol) (obtained from
example 22) and Ca(OH).sub.2 (94 mg, 1.27 mmol) in methanol (40 mL)
was immersed in preheated oil bath at 100.degree. C. and refluxed
for 4 h. The reaction mixture was cooled to room temperature and
methanol was completely removed under reduced pressure at
40-50.degree. C. The resultant foamy solid was triturated with
ether. The white crystalline compound obtained was filtered and
washed with ether (5-10 mL) and dried to afford the title compound
(1.025 g, 94%) mp: 225.degree. C.
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.15 (d, J=7.89 Hz, 1H), 7.83
(t, J=7.89 Hz, 1H), 7.68 (d, J=7.89 Hz, 1H), 7.56 (t, J=7.89 Hz,
1H), 7.16 (d, J=8.35 Hz, 2H), 7.01 (d. J=8.35 Hz, 2H), 5.24 (s,
2H), 4.23 (dd, J=10.38, 3.23 Hz, 1H), 3.61 (s, 3H), 3.33 (dd,
J=13.70, 3.23 Hz, 1H), 2.70 (dd, J=13.7, 10.38 Hz, 1H).
EXAMPLE 43
5-[4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methylene]thiazolidine-2,4-dione, sodium salt:
##STR00125##
The title compound (1.89 g, 90%) was obtained from
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl
methylene]thiazolidine-2,4-dione (2.0 g, 5.09 mmol) (obtained from
example 12) by a similar procedure to that described in example 28.
mp: 299.degree. C.
.sup.1H NMR (DMSO-d.sub.6) .delta.: 8.18 (d, J=7.89 Hz, 1H), 7.86
(t, J=7.89 Hz, 1H), 7.69 (d, J=7.89 Hz, 1H), 7.59 (t, J=7.89 Hz,
1H), 7.52 (d, J=8.72 Hz, 2H), 7.28 (s, 1H ), 7.21 (d, J=8.72 Hz,
2H), 5.35 (s, 2H), 3.64 (s, 3H).
Mutation in colonies of laboratory animals and different
sensitivities to dietary regimens have made the development of
animal models with non-insulin dependent diabetes associated with
obesity and insulin resistance possible. Genetic models such as
db/db and ob/ob (See Diabetes, (1982) 31(1): 1-6) in mice and fa/fa
and zucker rats have been developed by the various laboratories for
understanding the pathophysiology of disease and testing the
efficacy of new antidiabetic compounds (Diabetes, (1983) 32:
830-838: Annu. Rep. Sankyo Res. Lab. (1994) 46: 1-57). The
homozygous animals, C57 BL/KsJ-db/db mice developed by Jackson
Laboratory, US, are obese, hyperglycemic, hyperinsulinemic and
insulin resistant (J. Clip. Invest., (1990) 85: 962-967), whereas
heterozygous are lean and normoglycemic. In db/db model, mouse
progressively develops insulinopenia with age, a feature commonly
observed in late stages of human type II diabetes when blood sugar
levels are insufficiently controlled. The state of pancreas and its
course vary according to the models. Since this model resembles
that of type II diabetes mellitus, the compounds of the present
invention were tested for blood sugar and triglycerides lowering
activities.
The compounds of the present invention showed blood sugar and
triglycerides lowering activates through improved insulin
resistance. This was demonstrated by the following in vivo
experiments.
Male C57BL/KsJ-db/db mice of 8 to 14 weeks age, having body weight
range of 35 to 60 grams, procured from the Jackson Laboraotory,
USA, were used--in the experiment. The mice were provided with
standard feed (National Institute of Nutrition, Hyderabad, India)
and acidified water, ad libitum. The animals having more than 300
mg/dl blood sugar were used for testing. The number of animals in
each group was 4.
The random blood sugar and triglyceride levels were measured by
collecting blood (100 .mu.l) through orbital sinus, using
heparinised capillary in tubes containing EDTA which was
centrifuged to obtain plasma. The plasma glucose and triglycerides
levels were measured spectrometrically, by glucose oxidase and
glycerol-3-PO.sub.4 oxidase/peroxidase enzyme (Dr. Reddy's Lab.
Diagnostic Division Kits, Hyderabad, India) methods respectively.
On 6th day the blood samples were collected one hour after
administration of test compounds/vehicle for assessing the
biological activity.
Test compounds were suspended on 0.25% carboxymethyl cellulose and
administered to test group at a dose of 10 mg to 100 mg/kg through
oral gavage daily for 6 days. The control group received vehicle
(dose 10 ml/kg). Troglitazone (100 mg/kg, daily dose) was used as a
standard drug which showed 28% reduction in random blood sugar
level on 6th day.
The blood sugar and triglycerides lowering activities of the test
compound was calculated according to the formula: .times.
.times..times..times..times. .times..times. .times..times.
##EQU00001## ZC-Zero day control group value DC-Zero day treated
group value TC-Control group value on test day DT-Treated group
value on the test day
No adverse effects were observed for any of the mentioned compounds
of invention in the above test.
The compounds of the present invention also showed cholesterol
lowering activity in the experimental animals used.
TABLE-US-00005 Maximum reduction in Dose Days blodd glucose
Triglyceride Compound mg/kg/da treated level (%) lowering (%)
Example 3 100 6 67 12 Example 6 100 6 41 31 Example 7 100 6 66 35
Example 9 30 6 46 35 Example 12 100 6 71 57 Example 13 100 6 52 57
Example 17 30 6 65 45 Example 19 30 6 73 70 Example 21 30 6 64 76
Example 22 30 6 55 41 Example 24 10 6 63 17 Example 11 30 6 32 42
Example 28 10 6 63 57
The experimental results from the db/db mice suggest that the novel
compounds of the present invention also possess therapeutic utility
as a prophylactic or regular treatment for obesity, cardiovascular
disorders such as hypertension, hyperlipidaemia and other diseases;
as it is known from the literature that such diseases are
interrelated to each other.
* * * * *