Note: Descriptions are shown in the official language in which they were submitted.
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DESCRIPTION
MATERIALS AND METHODS FOR THE TREATMENT OF DIABETES,
HYPERLIPIDEMIA, HYPERCHOLESTEROLEMIA, AND ATHEROSCLEROSIS
Cross-Reference to Related Applications
This application claims priority to United States Provisional Applications
60/199,146, filed April 24, 2000 and 60/281,982, filed April 6, 2001, the
disclosures
of which are each incorporated by reference in their entireties, including all
figures,
tables, and chemical structures.
Background of the Invention
Diabetes is one of the most prevalent chronic disorders worldwide with
significant personal and financial costs for patients and their families, as
well as for
society. Different types of diabetes exist with distinct etiologies and
pathogeneses.
For example, diabetes mellitus is a disorder of carbohydrate metabolism,
characterized by hyperglycemia and glycosuria and resulting from inadequate
production or utilization of insulin.
Noninsulin-dependent diabetes mellitus (NIDDM), often referred to as Type II
diabetes, is a form of diabetes that occurs predominantly in adults who
produce
adequate levels of insulin but who have a defect in insulin-mediated
utilization and
metabolism of glucose in peripheral tissues. Overt NIDDM is characterized by
three
major metabolic abnormalities: resistance to insulin-mediated glucose
disposal,
impairment of nutrient-stimulated insulin secretion, and overproduction of
glucose by
the liver. It has been shown that for some people with diabetes a genetic
predisposition results from a mutation in the genes) coding for insulin and/or
the
insulin receptor and/or insulin-mediated signal transduction factor(s),
thereby
resulting in ineffective insulin and/or insulin-mediated effects thus
impairing the
utilization or metabolism of glucose.
For people with Type II diabetes, insulin secretion is often enhanced,
presumably to compensate for insulin resistance. Eventually, however, the B-
cells
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fail to maintain sufficient insulin secretion to compensate for the insulin
resistance.
Mechanisms responsible for the B-cell failure have not been identified, but
may be
related to the chronic demands placed on the B-cells by peripheral insulin
resistance
and/or to the effects of hyperglycemia. The B-cell failure could also occur as
an
independent, inherent defect in "pre-diabetic" individuals.
NIDDM often develops from certain at risk populations. One such population
is individuals with polycystic ovary syndrome (PCOS). PCOS is the most common
endocrine disorder in women of reproductive age. This syndrome is
characterized by
hyperandrogenism and disordered gonadotropin secretion producing oligo- or
anovulation. Recent prevalence estimates suggest that 5-10% of women between
18-
44 years of age (about 5 million women, according to the 1990 census) have the
full-
blown syndrome of hyperandrogenism, chronic anovulation, and polycystic
ovaries.
Despite more than 50 years since its original description, the etiology of the
syndrome
remains unclear. The biochemical profile, ovarian morphology, and clinical
features
are non-specific; hence, the diagnosis remains one of exclusion of disorders,
such as
androgen-secreting tumors, Cushing's Syndrome, and late-onset congenital
adrenal
hyperplasia. PCOS is associated with profound insulin resistance resulting in
substantial hyperinsulinemia. As a result of their insulin resistance, PCOS
women are
at increased risk to develop NIDDM.
NIDDM also develops from the at risk population of individuals with
gestational diabetes mellitus (GDM). Pregnancy normally is associated with
progressive resistance to insulin-mediated glucose disposal. In fact, insulin
sensitivity
is lower during late pregnancy than in nearly all other physiological
conditions. The
insulin resistance is thought to be mediated in large part by the effects of
circulating
hormones such as placental lactogen, progesterone, and cortisol, all of which
are
elevated during pregnancy. In the face of the insulin resistance, pancreatic B-
cell
responsiveness to glucose normally increases nearly 3-fold by late pregnancy,
a
response that serves to minimize the effect of insulin resistance on
circulating glucose
levels. Thus, pregnancy provides a major "stress-test" of the capacity for B-
cells to
compensate for insulin resistance.
Other populations thought to be at risk for developing NIDDM include
persons with Syndrome X; persons with concomitant hyperinsulinemia; persons
with
insulin resistance characterized by hyperinsulinemia and by failure to respond
to
exogenous insulin; and persons with abnormal insulin and/or evidence of
glucose
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disorders associated with excess circulating glucocorticoids, growth hormone,
catecholamines, glucagon, parathyroid hormone, and other insulin-resistant
conditions.
Failure to treat NIDDM can result in mortality due to cardiovascular disease
and in other diabetic complications including retinopathy, nephropathy, and
peripheral neuropathy. There is a substantial need for a method of treating at
risk
populations such as those with PCOS and GDM in order to prevent or delay the
onset
of NIDDM thereby bringing relief of symptoms, improving the quality of life,
preventing acute and long-term complications, reducing mortality and treating
' accompanying disorders of the populations at risk for NIDDM.
For many years, treatment of NIDDM has involved a program aimed at
lowering blood sugar with a combination of diet and exercise. Alternatively,
treatment
of NIDDM can involve oral hypoglycemic agents, such as sulfonylureas alone or
in
combination with insulin injections. Recently, alpha-glucosidase inhibitors,
such as a
carboys, have been shown to be effective in reducing the postprandial rise in
blood
glucose (Lefevre, et al., Drugs 1992; 44:29-38). In Europe and Canada another
treatment used primarily in obese diabetics is metformin, a biguanide.
Compounds useful in the treatment of the various disorders discussed above,
and methods of making the compounds, are known and some of these are disclosed
in
U.S. Pat. Nos. 5,223,522 issued Jun. 29, 1993; 5,132,317 issued Jul. 12, 1992;
5,120,754 issued Jun. 9, 1992; 5,061,717 issued Oct. 29, 1991; 4,897,405
issued Jan.
30, 1990; 4,873,255 issued Oct. 10, 1989; 4,687,777 issued Aug. 18, 1987;
4,572,912
issued Feb. 25, 1986; 4,287,200 issued Sep. l, 1981; 5,002,953, issued Mar.
26, 1991;
U.S. Pat. Nos. 4,340,605; 4,438,141; 4,444,779; 4,461,902; 4,703,052;
4,725,610;
4,897,393; 4,918,091; 4,948,900; 5,194,443; 5,232,925; and 5,260,445; WO
91/07107; WO 92/02520; WO 94/01433; WO 89/08651; and JP I~okai 69383/92. The
compounds disclosed in these issued patents and applications are useful as
therapeutic
agents for the treatment of diabetes, hyperglycemia, hypercholesterolemia, and
hyperlipidemia. The teachings of these issued patents are incorporated herein
by
reference in their entireties.
Drug toxicity is an important consideration in the treatment of humans and
animals. Toxic side effects resulting from the administration of drugs include
a
variety of conditions that range from low-grade fever to death. Drug therapy
is
justified only when the benefits of the treatment protocol outweigh the
potential risks
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associated with the treatment. The factors balanced by the practitioner
include the
qualitative and quantitative impact of the drug to be used as well as the
resulting
outcome if the drug is not provided to the individual. Other factors
considered
include the physical condition of the patient, the disease stage and its
history of
progression, and any known adverse effects associated with a drug.
Drug elimination is typically the result of metabolic activity upon the drug
and
the subsequent excretion of the drug from the body. Metabolic activity can
take place
within the vascular supply and/or within cellular compartments or organs. The
liver is
a principal site of drug metabolism. The metabolic process can be categorized
into
synthetic anal nonsynthetic reactions. In nonsynthetic reactions, the drug is
chemically altered by oxidation, reduction, hydrolysis, or any combination of
the
aforementioned processes. These processes are collectively referred to as
Phase I
reactions.
In Phase II reactions, also known as synthetic reactions or conjugations, the
parent drug, or intermediate metabolites thereof, are combined with endogenous
substrates to yield an addition or conjugation product. Metabolites formed in
synthetic reactions are, typically, more polar and biologically inactive. As a
result,
these metabolites are more easily excreted via the kidneys (in urine) or the
liver (in
bile). Synthetic reactions include glucuronidation, amino acid conjugation,
acetylation, sulfoconjugation, and methylation.
One of the drugs used to treat Type II diabetes is troglitazone. The major
side
effects of troglitazone axe nausea, peripheral edema, and abnormal liver
function.
Other reported adverse events include dyspnea, headache, thirst,
gastrointestinal
distress, insomnia, dizziness, incoordination, confusion, fatigue, pruritus,
rash,
alterations in blood cell counts, changes in serum lipids, acute renal
insufficiency, and
dryness of the mouth. Additional symptoms that have been reported, for which
the
relationship to troglitazone is unknown, include palpitations, sensations of
hot and
cold, swelling of body parts, skin eruption, stroke, and hyperglycemia.
Accordingly,
forms of glitazones which have fewer, or no, adverse effects (i.e., less
toxicity) are
desirable.
The principal difference between the compounds of the present invention and
related compounds is the presence of a carboxyl group, either OOC- or COO-,
directly attached to the 4-position of the phenyl ring. In the literature,
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thiazolidinediones having similar therapeutic properties have an ether
function at the
4-position of the phenyl ring instead of a carboxyl group.
The presence of the carboxyl group has significant consequences for the
biological behavior of these new compounds. The present compounds are
primarily
5 metabolized by hydrolytic enzymatic systems, whereas compounds having an
ether
function are metabolized only by oxidative enzymes. Hydrolytic enzymatic
systems
are ubiquitous, non-oxidative, not easily saturable, and non-inducible, and,
therefore,
reliable. By contrast, oxidative systems are mediated by the P-450 isozymes.
These
systems are localized, mainly, in the liver, saturable and inducible (even at
low
concentrations of therapeutic compounds) and therefore are highly unreliable.
The compounds of the subject invention do not rely on saturabIe hepatic
systems for their metabolism and elimination, whereas the prior art compounds
exert
a heavy bio-burden on hepatic functions, especially in the presence of other
drugs that
rely on similar enzymes for detoxification. Thus, the present compounds have a
much
more desirable toxicity profile than prior art compounds, especially when
considering
liver toxicity and potentially fatal drug-drug interactions.
Upon metabolism by plasma and tissue esterases, the compounds of this
invention are hydrolyzed into 2 types of molecules: 1 ) an alcohol or a
phenol, and 2) a
carboxylic acid. Therefore, any compound that yields compound 1, compound 2,
compound 3, or compound 4, as defined in Table I, as a primary metabolite
falls
under the definition of this invention. This concept is illustrated in Figure
1, taking
compound 9 (of Table I) and compound 145 (of Table X) as specific examples of
compounds giving 1 and 3, respectively, upon non-oxidative metabolism by
esterases.
Brief Sumxnary_of the Invention
The subject invention provides materials and methods for the safe and
effective treatment of diabetes, hyperlipidemia, hypercholesterolemia, and
atherosclerosis. In a preferred embodiment, the subject invention provides
therapeutic
compounds for the treatment of diabetes. The compounds of the subject
invention can
be used to treat at-risk populations, such as those with PCOS and GDM, in
order to
prevent or delay the onset of NIDDM thereby bringing relief of symptoms,
improving
the quality of life, preventing acute and long-term complications, reducing
mortality
and treating accompanying disorders.
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Advantageously, the subject invention provides compounds that are readily
metabolized by the physiological metabolic drug detoxification systems.
Specifically,
in a preferred embodiment, the therapeutic compounds of the subject invention
contain an ester group, which does not detract from the ability of these
compounds to
provide a therapeutic benefit, but which makes these compounds more
susceptible to
degradation by hydrolases, particularly serum and/or cytosolic esterases. The
subject
invention further provides methods of treatment comprising the administration
of
these compounds to individuals in need of treatment for Type II diabetes,
hyperlipidemia, hypercholesterolemia, and atherosclerosis.
In a further embodiment, the subject invention pertains to the breakdown
products that are formed when the therapeutic compounds of the subject
invention are
acted upon by esterases. These breakdown products can be used as described
herein
to monitor the clearance of the therapeutic compounds from a patient.
In yet a further embodiment, the subject invention provides methods for
synthesizing the therapeutic compounds of the subject invention.
Brief Description of the Figures
Figure 1 depicts exemplary metabolic breakdown products resulting from the
actions of esterases on compounds of the invention.
Figures 2-3 provide an exemplary synthetic scheme for compounds 1 through
4 (of Table I). These compounds can be conveniently prepared by the
I~noevenagel
reaction between an aldehyde and thiazolidine-2,4-dione using, for example,
sodium
acetate in acetic anhydride, or piperidine and benzoic acid in methylene
chloride as a
reaction medium.
Figure 4 illustrates an alternative reaction scheme for the production of
compound 1 (of Table I). In this reaction scheme, para-anisidine undergoes a
diazotation reaction with sodium nitrite and hydrochloric acid. The diazonium
chloride salt undergoing, in turn, a radicalar reaction with methyl acrylate
and then a
cyclization reaction with thiourea, the product of which is hydrolyzed to the
thiazolidinedione molecule.
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Figure S shows an exemplary synthetic scheme for the compounds described
in Table I (compounds 5 to 32). These compounds can be made via an
esterification
reaction between 1 or 2 and an appropriately substituted carboxylic acid, or
between 3
or 4 and an appropriately substituted alcohol. .
Figure 6 depicts the synthesis of the 4-oxazoleacetic acid and the 4-
oxazoleethanol moiety starting from aspartic acid derivatives in which R2 and
R3 are
methyl or hydrogen.
Figure 7 describes the synthesis of the 4-oxazolecarboxylic acid and 4-
oxazolemethanol groups. The synthesis starts from ethyl acetoacetate in which
a 2-
amino-group is introduced via oxime formation followed by reduction with zinc
powder. The synthesis then proceeds as before, where the Rl group is
introduced by
acylating the amino group, followed by cyclization with sulfuric acid in ethyl
acetate,
and finally ester cleavage or reduction to the alcohol.
Figure 8 shows how steric hindrance can be introduced under the form of
methyl groups on the 4-methanol moiety. Starting from pentane-2,4-dione and
following the same synthetic sequence as in Figure 7 leads to the 4-
acetyloxazole
compounds which can be reduced by sodium borohydride to the 4-(1-
ethyl)oxazole,
or which can be transformed to 4-(2-hydroxy-2-propyl) oxazole with a methyl
Grignard reagent such as methyl magnesium iodide.
Figure 9 illustrates an alternative synthetic scheme wherein condensation of a
thioamide with methyl 4-bromo-3-oxopentanoate gives methyl 4-thiazoleacetate.
Ester cleavage with lithium hydroxide or reduction with lithium aluminum
hydride
gives the corresponding acid or the alcohol, respectively.
Figures 10-17 depict the synthesis of compounds 105 to 224 in Tables VI to
VII. These compounds contain an amino acid or an amino alcohol as part of
their
structure.
Figure 18 provides an exemplary synthetic pathway for compounds 225 to 242
(Table XVIII). These compounds are oxazoline-4-carboxylic acid types of
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compounds. Their synthesis (Figure 18) starts from serine (R5=H) or from
threonine
(RS=CH3) benzyl ester. The ester is coupled with an alkyl or an arylcarboxylic
acid
using for example EDC as a coupling agent. The serine or threonine group then
cyclizes into an oxazoline upon treatment with thionyl chloride. Coupling with
5-(4-
hydroxybenzyl)thiazolidine-2,4-dione using DCC/DMAPlmethylene chloride gives
compounds 225 to 242.
Figures 19-20 illustrate the activity of representative compounds on serum
glucose and insulin levels in non-insulin dependent diabetic mellitus (NIDDM)
KI~-
AY male mice. Post-treatment data for each group .were transferred to a
percentage of
pretreatment values and unpaired Student's t test was used for comparison
between
vehicle and test substance treated groups. Results show a significant
reduction of
both serum glucose and serum insulin relative to the vehicle control group.
Reduction
in serum glucose and serum insulin levels were comparable to the reduction
observed
in the troglitazone-treated animals. The results are also presented in Table
XXI.
Brief Descr~tion of the Tables
Tables I-XXII depict exemplary compounds according to the invention. The
term "db" indicates a double bond between P and Q.
Table XXIII illustrates the effects of exemplary compounds on serum glucose
and insulin levels in NIDDM mice.
Detailed Disclosure of the Invention
The subject invention provides materials and methods fox the treatment of
non-insulin dependent diabetes mellitus (NIDDM), hyperlipidemia,
hypercholesterolemia, and atherosclerosis. Advantageously, the therapeutic
compounds of the subject invention are stable in storage but have a shorter
half life in
the physiological environment than other drugs which are available for
treatment of
diabetes; therefore, the compounds of the subject invention can be used with a
lower
incidence of side effects and toxicity, especially in patients having elevated
liver
function or compromised liver function.
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In a preferred embodiment of the subject invention, therapeutic compounds
are provided which are useful in the treatment of diabetes, hyperlipidemia,
hypercholesterolemia, and atherosclerosis and which contain an ester group
which is
acted upon by esterases thereby breaking down the compound and facilitating
its
efficient removal from the treated individual. In a preferred embodiment the
therapeutic compounds are metabolized by the Phase I drug detoxification
system and
are exemplified by the compound of Formula I.
The compounds of Formula I can be generally described as S-benzyl- or 5
benzylidene-thiazolidine-2,4-dione compounds having a carboxyl group directly
attached to the para-position of the phenyl ring. These compounds represent a
new
class of chemical compounds having therapeutic properties for the treatment of
type-
II diabetes mellitus, atherosclerosis, hypercholesterolemia, and
hyperlipidemia.
P Q
Formula I
D2 D3~Da
i\D Ds B A
6
E
O
For compounds of Formula I:
A and B may be the same or different and are C, N, NO, NH, SOo_2, O;
D1-D6 can be the same or different and are C, N, S, or O;
E can be attached to one or more of the atoms located at D1-D6;
P and Q can be a double bond; or
P, Q, and E can be the same or different and are a moiety selected from the
group consisting of H, C1_lo alkyl, substituted alkyl groups, substituted or
unsubstituted carboxylic acids, substituted or unsubstituted carboxylic
esters, halogen,
carboxyl, hydroxyl, phosphate, phosphonate, aryl, CN, OH, COOH, N02, NHa,
502_4,
C1_2o heteroalkyl, C2_zo alkenyl, alkynyl, akynyl-aryl, alkynyl-heteroaryl,
aryl, C1_2o
alkyl-aryl, C2_2o alkenyl-aryl, heteroaryl, Cl_2o alkyl-heteroaryl, CZ_zo
alkenyl-
heteroaryl, cycloalkyl, heterocycloalkyl, C1_2o alkyl-heteroycloalkyl, and
Cl_2o alkyl-
cycloalkyl, any of which may be, optionally, substituted with a moiety
selected from
the group consisting of C1_6 alkyl, halogen, OH, NH2, CN, N02, COOH, or 502.
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Exemplary heterocyclic groups include, but not limited to, morpholine,
triazole,
imidazole, pyrrolidine, piperidine, piperazine, pyrrole, dihydropyridine,
aziridine,
thiazolidine, thiazoline, thiadiazolidine or thiadiazoline.
Substituted carboxylic acids, substituted carboxylic esters, and substituted
5 alkyl groups can be substituted at any available position with a moiety
selected from
the group consisting of C1_io alkyl, halogen, CN, OH, COOH, NOz, NHz, SOz~,
C1_zo
heteroalkyl, Cz_zo alkenyl, alkynyl, akynyl-aryl, alkynyl-heteroaryl, aryl,
C1_zo alkyl-
aryl, Cz_zo alkenyl-aryl, heteroaryl, C1_zo alkyl-heteroaryl, Cz_zo alkenyl-
heteroaryl,
cycloalkyl, heterocycloalkyl, C1_zo alkyl-heteroycloalkyl, and C1_zo alkyl-
cycloalkyl,
10 any of which may be, optionally, substituted with a moiety selected from
the group
consisting of C1_6 alkyl, halogen, OH, NHz, CN, NOz, COOH, or SOz~. Exemplary
heterocyclic groups include, but are not limited to, morpholine, triazole,
imidazole,
pyrrolidine, piperidine, piperazine, pyrrole, dihydropyridine, aziridine,
thiazolidine,
thiazoline, thiadiazolidine, and thiadiazoline.
X is -OH, -COOH, or a substituted carboxylic group having the carboxyl
moiety OOC- or COO- directly attached to the phenyl ring of the compound of
Formula 1. The carboxylic acid group can be substituted with a moiety selected
from
the group consisting of alkyloxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl,
arylcarbonyloxy, heteroalkyloxycarbonyl, heteroalkylcarbonyloxy, heteroaryl-
oxycarbonyl, and heteroarylcarbonyloxy, each of which is, optionally,
substituted
with Ci_io alkyl, CN, COOH, NOz, NHz, SOz_4, Ci_zo heteroalkyl, Cz_zo alkenyl,
alkynyl, akynyl-aryl, alkynyl-heteroaryl, aryl, C1_zo alkyl-aryl, Cz_zo
alkenyl-aryl,
heteroaryl, C1_zo alkyl-heteroaxyl, Cz_zo alkenyl-heteroaryl, cycloalkyl,
heterocycloalkyl, C1_zo alkyl-heteroycloalkyl, and C1_zo alkyl-cycloalkyl, any
of which
may be, optionally, substituted with a moiety selected from the group
consisting of
C1_6 alkyl, halogen, OH, NHz, CN, NOz, COOH, or SOz_4.. In other embodiments,
the
substituted carboxylic group can be substituted with at moiety selected from
the group
consisting of C1_io alkyl, CN, COOH, NOz, NHz, SOz_4, C1_zo heteroalkyl, Cz_zo
alkenyl, alkynyl, akynyl-aryl, alkynyl-heteroaryl, aryl, C1_zo alkyl-aryl,
Cz_zo alkenyl-
aryl, heteroaryl, C1_zo alkyl-heteroaryl, Cz_2o alkenyl-heteroaryl,
cycloalkyl,
heterocycloalkyl, C1_zo alkyl-heteroycloalkyl, and C1_zo alkyl-cycloalkyl, any
of which
may be, optionally, substituted with a moiety selected from the group
consisting of
C1_6 alkyl, halogen, OH, NHz, CN, NOz, COOH, or SOz~. Exemplary heterocyclic
groups include, but are not limited to, morpholine, triazole, imidazole,
pyrrolidine,
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piperidine, piperazine, pyrrole, dihydropyridine, aziridine, thiazolidine,
thiazoline,
thiadiazolidine, and thiadiazoline.
In specific embodiments, X can be hydroxyl, hydroxycarbonyl, 1-methyl-1
cyclohexylcarbonyloxy, 1-methyl-1-cyclohexylmethoxycarbonyl, 5-ethyl-2-pyridyl
acetoxy, 5-ethyl-2-pyridylmeth-oxy-carbonyl, (R)-6-hydroxy-2,5,7,8-tetramethyl
chroman-2-carboxy, (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxy, (R)-6-
hydroxy-2,5,7,8-tetra-methylchroman-2-ylmethoxy -carbonyl, (S)-6-hydroxy-
2,5,7,8-
tetramethylchroman-2-ylmethoxycarbonyl, (R)-5-hydroxy-2,2,4,6,7-pentamethyl-
2,3-
dihydrobenzofuran-3-carboxy, (S)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-
benzofuran-3-carboxy, (R)-5-hydroxy-2,2,4,6,7-penta-methyl-2,3-
dihydrobenzofuran-
3-methoxycarbonyl, (S)-5-hydroxy-2,2,4,6,7-pentamethyl -2,3-dihydrobenzofuran-
3-
methoxycarbonyl, 2-hydroxybenzoyloxy, or 2,4-dihydroxybenzoyloxy.
In other embodiments, X can be
OH OH O
Hetero O'
wherein Hetero is an aromatic, cyclic, or alicyclic moiety that can contain
heteroatoms. In certain specific embodiments, Hetero is an aromatic, cyclic,
or
alicyclic moiety that contains heteroatoms that are generally part of the
structure of
the statin-family of lipid lowering agents. Preferred examples include, but
are not
limited to, 2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-
[(phenylamino)carbonyl]
-1-(1H-pyrrol)yl, a component of atorvastatin, and 1,2,3,7,8,8a-hexahydro-1-(2-
methylbutanoyl)oxy-3,7-dimethyl-8-naphthalenyl, a component of lovastatin.
Alternatively, X can be
O
Fb
O
wherein Fib is an aromatic, cyclic, or alicyclic moiety that can contain
heteroatoms. In certain specific embodiments, Fib moieties are part of the
fibrate-
family of lipid lowering agents. Preferred examples include, but are not
limited to 4-
(4-chlorobenzoyl)phenoxy, a component of fenofibric acid, 4-chlorophenoxy, a
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component of clofibric acid, and 3-(2,5-xylyloxy)-1-propyl, a component of
gemfibrozil.
Alternatively, X can be
R
O
NSA ~I
O
wherein R is hydrogen or methyl, and in which NSAID means an aromatic, alkyl,
or
cycloalkyl moiety that may contain heteroatoms and that are generally part of
the
family of non-steroidal anti-inflammatory agents. Preferred examples include,
but are
not limited to 4-(2-methyl-1-propyl)phenyl, 2-(2,6-dichloro-1-
phenyl)aminophenyl,
6'-methoxy-2'-naphthyl, and 6'-methoxy-2'-naphthylmethyl.
In another embodiment, X can be
i
s
8
where a and (3 are hydrogen or a and (3 form a bond, and where y, 8, and s,
axe
independently hydrogen, hydroxy, fluoro, chloro, or methyl.
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or
X can also be of the general formula
CH3
Rz
R3 n
R ~N O
i
In such embodiments, n is 0 or 1, R2 and R3 are independently hydrogen or
methyl; Z
is N, O, or S; and Rl is aryl or heteroaryl, alkyl or heteroalkyl. Preferred
non-limiting
examples include compounds where Rl is phenyl, 4-fluorophenyl, 4-
methoxyphenyl,
3-methyl-2-thiophenyl, 5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl, 2-
pyridyl, 4-
pyridyl, 2-pyrazinyl, 2-hydroxybenzoyl, or 2,4-dihydroxybenzoyl.
Other embodiments provide compounds wherein X is
CH3
R2
~ R3 n
Ri N O
O
in which n is 0 or l, R2 and R3 are independently hydrogen or methyl; Z is N,
O, or S;
and Rl is aryl or heteroaryl, alkyl or heteroalkyl. Preferred non-limiting
examples
Alternatively, X can be
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include compounds where R1 is phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-
methyl-
2-thiophenyl, 5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl, 2-pyridyl, 4-
pyridyl, 2-
pyrazinyl, 2-hydroxybenzoyl, or 2,4-dihydroxybenzoyl.
In other embodiments, X is a 1-substituted (R)-pyrrolidine-2
methoxycarbonyl, (S)-pyrrolidine-2-methoxycarbonyl, (R)-pyrrolidine-2-carboxy,
or
(S)-pyrrolidine-2-carboxy, having the following formulas
~N~ ~N
Y Y Y
= '
~ O
O "
in which Y is aryl or heteroaryl, alkyl or heteroalkyl. Preferred non-limiting
examples include compounds where Y is (R)-6-hydroxy-2,5,7,8-tetramethylchroman-
2-carboxy, (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxy, (R)-6-hydroxy-
2,5,7,8-tetrameth-ylchroman-2-ylmeth-oxycarbonyl, (S)-6-hydroxy-2,5,7,8-tetra-
methylchroman-2-ylmeth-oxycarbonyl, (R)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3-
dihydrobenzofuran-3-carboxy, (S)-5-hydroxy-2,2,4,6 ,7-pentamethyl-2,3-dihydro-
benzofuran-3-carboxy, (R)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3-
dihydrobenzofuran-
3-methoxycarbonyl, (S) -5-hydroxy-2,2,4, 6,7-pentamethyl-2,3-dihydrobenzofuran-
3-
methoxycarbonyl, 5-chloro-2-pyridyl, 5-methyl-2-pyridyl, 3-chloro-2-pyridyl, 4-
methyl-2-pyridyl, 2-pyridyl, 2-benzoxazolyl, 2-benzothiazolyl, 5-amino=2-
pyridyl, 5-
nitro-2-pyridyl, 2-pyrazinyl, 4-phenyl-2-oxazolinyl, 5-methyl-2-thiazolinyl,
4,5-
dimethyl-2-oxazolinyl, 4,5-dimethyl-2-thiazolinyl, 5-phenyl-2-thiazolinyl, 2-
thiazolinyl, 4-methyl-5-phenyl-2-thiazolinyl, 5-methyl-4-phenyl-2-thiazolinyl,
2-
piperidinyl, 4-phenyl-2-piperidinyl, 6-methyl-2-pyridinyl, 6-methoxy-2-
pyridinyl, 2-
hydroxybenzoyl, or 2,4-dihydroxybenzoyl.
Alternatively X is an N-substituted 2-methylaminoethoxycarbonyl or a N-
substituted 2-methylaminoacetoxy, having the following formulas:
CH3
Y-N CH3 or Y-N~ O
O
O
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in which Y is aryl or heteroaryl, alkyl or heteroalkyl. Preferred non-limiting
examples include compounds where Y is (R)-6-hydroxy-2,5,7,8-tetramethylchroman-
2-carboxy, (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxy, (R)-6-hydroxy-
2,5,7,8-tetramethylchroman-2-ylmeth-oxycarbonyl, (S)-6-hydroxy-2,5,7,8-tetra-
5 methylchroman-2-ylmethoxycarbonyl, (R)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3-
dihydrobenzofuran-3-carboxy, (S)-5-hydroxy-2,2,4,6, 7-pentamethyl-2,3-dihydro-
benzofuran-3-carboxy, (R)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3-
dihydrobenzofuran-
3-methoxycarbonyl, (S)-5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-3-
methoxycarbonyl, 5-chloro-2-pyridyl, 5-methyl-2-pyridyl, 3-chloro-2-pyridyl, 4-
10 methyl-2-pyridyl, 2-pyridyl, 2-benzoxazolyl, 2-benzothiazolyl, 5-amino-2-
pyridyl, 5
nitro-2-pyridyl, 2-pyrazinyl, 4-phenyl-2-oxazolinyl, 5-methyl-2-thiazolinyl,
4,5
dimethyl-2-oxazolinyl, 4,5-dimethyl-2-thiazolinyl, 5-phenyl-2-thiazolinyl, 2
thiazolinyl, 4-methyl-5-phenyl-2-thiazolinyl, 5-methyl-4-phenyl-2-thiazolinyl,
2
piperidinyl, 4-phenyl-2-piperidinyl, 6-methyl-2-pyridinyl, 6-methoxy-2-
pyridinyl, 2
15 hydroxybenzoyl, or 2,4-dihydroxybenzoyl.
X can also be a 1-substituted (R)-pyrrolidine-2-methoxycarbonyl, (S)-
pyrrolidine-2-methoxycarbonyl, (R)-pyrrolidine-2-carboxy, or (S)-pyrrolidine-2-
carboxy, having the following formulas:
,N ~.N~ ,N ,N
Y Y Y Y
O ~O O O O~O
O ~ O
wherein Y is
CH3
R2
N R3 n
Rl O
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16
n is 0 or 1; R2 and R3 are independently hydrogen or methyl; Z is N, O, or S;
and RI is
aryl or heteroaryl, alkyl or heteroalkyl. Preferred non-limiting examples
include
compounds where Rl is phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-methyl-2
thiophenyl, 5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl, 2-pyridyl, 4-
pyridyl, or 2
pyrazinyl; or
Y is
CH3
Z R2
~\ R
/ 'N n
Rl m
n is 0 or 1; m is 0 or 1; R2 and R3 are independently hydrogen or methyl; Z is
N, O, or
S; and Rl is aryl or heteroaryl, alkyl or heteroalkyl. Preferred non-limiting
examples
include compounds where Rl is phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-
methyl-
2-thiophenyl, 5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl, 2-pyridyl, 4-
pyridyl, or
2-pyrazinyl; or
Y is
OH OH O
Hetero ~-'
wherein Hetero is an aromatic, cyclic, or alicyclic moiety that usually
contains
heteroatoms. In certain specific embodiments, these moieties are paxt of the
structure
of the statin-family of lipid lowering agents. Preferred.examples include, but
axe not
limited to, 2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-
[(phenylamino)carbonyl]
-1-(1H-pyrrol)yl, a component of atorvastatin, and 1,2,3,7,8,8a-hexahydro-1-(2
methylbutanoyl)oxy-3,7-dimethyl-8-naphthalenyl, ~a component of lovastatin; or
Y is
O
Fib
wherein Fib is an aromatic, cyclic, or alicyclic moiety that contains
heteroatoms. In
some embodiments, these moieties are part of the fibrate-family of lipid
lowering
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17
agents. Preferred examples include, but are not limited to 4-(4-
chlorobenzoyl)phenoxy, a component of fenofibric acid, 4-chlorophenoxy, a
component of clofibric acid, and 3-(2,5-xylyloxy)-1-propyl, a component of
gemfibrozil; or
Y is
R
NSAI
O
wherein R is hydrogen or methyl, and in which NSAID means an aromatic, alkyl,
or
cycloalkyl moiety that may contain heteroatoms and that are generally part of
the
family of non-steroidal anti-inflammatory agents. Preferred examples include,
but are
not limited to 4-(2-methyl-1-propyl)phenyl, 2-(2,6-dichloro-1-
phenyl)aminophenyl,
6'-methoxy-2'-naphthyl, and 6'-methoxy-2'-naphthylmethyl or
Y can be
i
E
s
where cc and (3 are hydrogen or cc and (3 form a bond, and where y, 8, and s,
are
independently hydrogen, hydroxy, fluoro, chloro, or methyl; or
Y can be
o v o
o
or
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18
Alternatively X can be an N-substituted 2-methylaminoethoxycarbonyl or an
N-substituted 2-methylaminoacetoxy, having the following formulas:
CH CHs
Y -N O
Y -N or
O
O O
wherein Y is
n
R1 O
n is 0 or 1; R2 and R3 are independently hydrogen or methyl; Z is N, O, or S;
and R1 is
aryl, heteroaryl, alkyl or heteroalkyl. Preferred non-limiting examples
include
compounds where Rl is phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-methyl-2-
thiophenyl, 5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl, 2-pyridyl, 4-
pyridyl, or 2-
pyrazinyl, 2-hydroxybenzoyl, or 2,4-dihydroxybenzoyl; or
Y is
CH3
R2
~N R n
R1 m
n is 0 or 1; m is 0 or 1; RZ and R3 are independently hydrogen or methyl; Z is
N, O, or
S; and Rl is aryl or heteroaryl, alkyl or heteroalkyl. Preferred non-limiting
examples
include compounds where Rl is phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-
methyl-
2-thiophenyl, 5-methyl-2-thiophenyl, 5-methyl-3-isoxazolyl, 2-pyridyl, 4-
pyridyl, 2-
pyrazinyl, 2-hydroxybenzoyl, or 2,4-dihydroxybenzoyl; or
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19
Y is
OH OH O
Hetero
wherein Hetero is an aromatic, cyclic, or alicyclic moiety that contains
heteroatoms.
In certain specific embodiments, these moieties are part of the structure of
the statin-
family of lipid lowering agents. Preferred examples include, but are not
limited to, 2-
(4-fluorophenyl)-5-( 1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1-( 1 H-
pyrrol)yI, a component of atorvastatin, and 1,2,3,7,8,8a-hexahydro-1-(2-
methylbutanoyl)oxy-3,7-dimethyl-8-naphthalenyl, a component of lovastatin; or
Y is
O
Fib
wherein Fib is an aromatic, cyclic, or alicyclic moiety that contains
heteroatoms. In
some embodiments, these moieties are part of the fibrate-family of lipid
lowering
agents. Preferred examples include, but are not limited to 4-(4-
chlorobenzoyl)phenoxy, a component of fenofibric acid, 4-chlorophenoxy, a
component of clofibric acid, and 3-(2,5-xylyloxy)-1-propyl, a component of
gemfibrozil; or
Y is
R
NSAI ~ ''
wherein R is hydrogen or methyl, and in which NSAID means an aromatic, alkyl,
or
cycloalkyl moiety that may contain heteroatoms and that are generally part of
the
family of non-steroidal anti-inflammatory agents. Preferred examples include,
but are
not limited to 4-(2-methyl-1-propyl)phenyl, 2-(2,6-dichloro-1-
phenyl)aminophenyl,
6'-methoxy-2'-naphthyl, and 6'-methoxy-2'-naphthylmethyl; or
Y can be
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20
3
s
s
where a and (3 are hydrogen or a and [3 form a bond, and where y, s, and s,
are
independently hydrogen, hydroxy, fluoro, chloro, or methyl; or
Y can be
Other embodiments provide compounds wherein X is
R4
O O
R ~ N O-
s
R4 is hydrogen or methyl, and where RS is aryl or heteroaryl, alkyl or
heteroalkyl.
Preferred non-limiting examples include compounds where RS is phenyl, 4-
fluorophenyl, 4-methoxyphenyl, 3-methyl-2-thiophenyl, 5-methyl-2-thiophenyl, 5-
methyl-3-isoxazolyl, 2-pyridyl, 4-pyridyl, 2-pyrazinyl, (R)-6-hydroxy-2,5,7,8-
tetramethyl-2-chromanyl, (S)-6-hydroxy-2,5,7,8-tetramethyl-2-chromanyl, (R)-5-
hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-3-benzofuranyl, or (S)-5-hydroxy-
2,2,4,6,7-pentamethyl-2,3-dihydro-3-benzo-furanyl.
X can also be
O\
R / 'N O
s
O
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21
wherein R4 is hydrogen or methyl, and where RS is aryl or heteroaryl, alkyl or
heteroalkyl. Preferred non-limiting examples include compounds where RS is
phenyl,
4-fluorophenyl, 4-methoxyphenyl, 3-methyl-2-thiophenyl, 5-methyl-2-thiophenyl,
5-
methyl-3-isoxazolyl, 2-pyridyl, 4-pyridyl, 2-pyrazinyl, (R)-6-hydroxy-2,5,7,8-
tetramethyl-2-chromanyl, (S)-6-hydroxy-2,5,7,8-tetramethyl-2-chromanyl, (R)-5-
hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-3-benzofuranyl, or (S)-5-hydroxy-
2,2,4,6,7-pentamethyl-2,3-dihydro-3-benzofuranyl.
In one embodiment, A is NH; B is sulfur (S); P and Q are a double bond or
hydrogen (H); E is hydrogen (H) and is attached to each of DI through D6; D1
through
D6 are carbon (C); and X can be any of the structures provided supra.
Modifications of the compounds disclosed herein can readily be made by
those skilled in the art. Thus, analogs, derivatives, and salts of the
exemplified
compounds are within the scope of the subject invention. With a knowledge of
the
compounds of the subject invention, and their structures, skilled chemists can
use
known procedures to synthesize these compounds from available substrates.
As used in this application, the terms "analogs" and "derivatives" refer to
compounds which are substantially the same as another compound but which may
have been modified by, for example, adding additional side groups. The terms
"analogs" and "derivatives" as used in this application also may refer to
compounds
which axe substantially the same as another compound but which have atomic or
molecular substitutions at certain locations in the compound.
Analogs or derivatives of the exemplified compounds can be readily prepared
using commonly known, standard reactions. These standard reactions include,
but are
not limited to, hydrogenation, methylation, acetylation, and acidification
reactions.
For example, new salts within the scope of the invention can be made by adding
mineral acids, e.g., HCI, H2S04, etc., or strong organic acids, e.g., formic,
oxalic, etc.,
in appropriate amounts to form the acid addition salt of the parent compound
or its
derivative. Also, synthesis type reactions may be used pursuant to known
procedures
to add or modify various groups in the exemplified compounds to produce other
compounds within the scope of the invention.
The subject invention further provides methods of treating disorders, such as
diabetes, atherosclerosis, hypercholesterolemia, and hyperlipidemia,
comprising the
administration of a therapeutically effective amount of esterified
thiazolidinedione
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22
analogs to an individual in need of treatment. Thiazolidinedione based
compounds
include troglitazone (for example, REZULIN), pioglitazone, and rosiglitazone.
Accordingly, the subject invention provides esterified thiazolidinedione
analogs and
pharmaceutical compositions of these esterified compounds. The compounds and
compositions according to the invention can also be administered in
conjunction with
other therapeutic compounds, therapeutic regimens, compositions, and agents
suitable
for the treatment of disorders, such as diabetes, atherosclerosis,
hypercholesterolemia,
and hyperlipidemia. Thus, the invention includes combination therapies wherein
the
compounds and compositions of the invention are used in conjunction with other
therapeutic agents for the treatment of disorders, such as diabetes,
atherosclerosis,
hypercholesterolemia, and hyperlipidemia.
The compounds of this invention have therapeutic properties similar to those
of the unmodified parent compounds. Accordingly, dosage rates and routes of
administration of the disclosed compounds are similar to those already used in
the art
and known to the skilled artisan (see, for example, Physicians' Desk
Reference, 54th
Ed., Medical Economics Company, Montvale, NJ, 2000).
The compounds of the subject invention can be formulated according to
known methods for preparing pharmaceutically useful compositions. Formulations
are described in detail in a number of sources that are well known and readily
available to those skilled in the art. For example, Remington's Pharmaceutical
Science by E.W. Martin describes formulations that can be used in connection
with
the subject invention: In general, the compositions of the subject invention
are
formulated such that an effective amount of the bioactive compounds) is
combined
with a suitable carrier in order to facilitate effective administration of the
composition.
In accordance with the subject invention, pharmaceutical compositions are
provided which comprise,,as an active ingredient, an effective amount of one
or more
of the compounds of the invention and one or more non-toxic, pharmaceutically
acceptable carriers or diluents. Examples of such carriers for use in the
invention
include ethanol, dimethyl sulfoxide, glycerol, silica, alumina, starch, and
equivalent
carriers and diluents. Additional therapeutic agents suitable for the
treatment of
disorders such as diabetes, atherosclerosis, hypercholesterolemia, and hyper-
lipidemia
can also be incorporated into pharmaceutical agents according to the
invention.
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23
Further, acceptable carriers can be either solid or liquid. Solid form
preparations include powders, tablets, pills, capsules, cachets, suppositories
and
dispersible granules. A solid carrier can be one or more substances that may
act as
diluents, flavoring agents, solubilizers, lubricants, suspending agents,
binders,
preservatives, tablet disintegrating agents or encapsulating materials.
The disclosed pharmaceutical compositions may be subdivided into unit doses
containing appropriate quantities of the active component. The unit dosage
form can
be a packaged preparation, such as packeted tablets, capsules, and powders in
paper or
plastic containers or in vials or ampoules. Also, the unit dosage can be a
liquid based
preparation or formulated to be incorporated into solid food products, chewing
gum,
or lozenge.
Compounds 1 through 4 (of Table I) can be conveniently prepared by the
Knoevenagel reaction between an aldehyde and thiazolidine-2,4-dione, using for
example sodium acetate in acetic anhydride, or piperidine and benzoic acid in
methylene chloride as a reaction medium. This is illustrated in Figure 2 and
Figure 3.
Alternatively, compound I can be prepared by the method described in Figure 4.
In
this reaction scheme, para-anisidine undergoes a diazotation reaction with
sodium
nitrite and hydrochloric acid. The diazonium chloride salt undergoing, in
turn, a
radicalar reaction with methyl acrylate and then a cyclization reaction with
thiourea,
the product of which is hydrolyzed to the thiazolidinedione molecule.
The compounds described in Table I (compounds 5 to 32) can all be made via
an esterification reaction between 1 or 2 and an appropriately substituted
carboxylic
acid, or between 3 or 4 and an appropriately substituted alcohol. The
esterification
reaction can be facilitated by the presence of a catalyst in the reaction
medium, such
as a small amount of concentrated sulfuric acid for example. Preferably,
especially if
the alpha-position to the carbonyl is an asymmetric center, an activated
functional
derivative of the carboxylic acid is made. Numerous functional derivatives of
carboxylic acids used in esterification reactions have been described in the
scientific
literature. The most commonly used activated functional derivatives are acyl
chlorides, anhydrides and mixed anhydrides, and activated esters. In one
aspect of
this invention dicyclohexyl carbodiimide (DCC) was used as an activating agent
(Figure 5).
Compounds 33 to 104 are functionalized 5-methyloxazole and functionalized
5-methylthiazole derivatives. They all have various functional groups attached
to the
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24
2-position (R1 in Tables II to V), and at the 4-position, which is the
enzymatically
labile link with the thiazolidine portion of the molecule. The enzymatically
labile link
is either an ester (COO-) or a reverse ester (00C-) and can be substituted
with 0, 1, or
2 methyl groups at the alpha-position from the oxazole or thiazole ring (R2
and R3 in
Tables II to V).
The synthesis of compounds 33 to 104 is described in general terms in Figures
7-10. Figure 6 describes the synthesis of the 4-oxazoleacetic acid and the 4-
oxazoleethanol moiety starting from aspartic acid derivatives in which RZ and
R3 are
methyl or hydrogen. In a typical example, y-benzyl aspartate is acetylated and
then
decarboxylated to benzyl 3-acetamido-4-oxovalerate using acetic anhydride as
an
acetylating agent followed by potassium hydroxide in order to obtain the
decarboxylated product. This in turn is transformed into methyl 3-amino-4-
oxovalerate using standard hydrolytic and esterification procedures, for
example
refluxing in dilute hydrochloric acid followed by reaction in thionyl chloride
and
methanol. The Rl group is then introduced by acylating the 3-amino group using
the
appropriate acyl or aroyl chloride. There is almost no limitation to the
nature of the
Rl group being introduced at this stage, as shown in Tables II to V where
various RI
groups are described. Cyclization to an oxazole ring is then effected using
sulfuric
acid as a catalyst in ethyl acetate as a solvent. At this stage, ester
hydrolysis using
lithium hydroxide in methanol gives the desired 4-oxazoleacetic acid
derivatives,
whereas reduction of the ester with lithium aluminum hydride or reduction of
the acid
using diborane gives the 4-oxazoleethanol analogs.
Figure 7 describes the synthesis of the 4-oxazolecarboxylic acid and 4
oxazolemethanol groups. The synthesis starts from ethyl acetoacetate in which
a 2
amino-group is introduced via oxime formation followed by reduction with zinc
powder. The synthesis then proceeds as before, where the Rl group is
introduced by
acylating the amino group, followed by cyclization with sulfuric acid in ethyl
acetate,
and finally ester cleavage or reduction to the alcohol.
Figure 8 shows how steric hindrance can be introduced under the form of
methyl groups on the 4-methanol moiety. Starting from pentane-2,4-dione,
following
the same synthetic sequence as in Figure 7 leads to the 4-acetyloxazole
compounds
which can be reduced by sodium borohydride to the 4-(1-ethyl)oxazole.
Alternatively, the compounds can be transformed by methylmagnesium iodide into
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the tertiary alcohol analogs. In another embodiment, condensation of a
thioamide
with methyl 4-bromo-3-oxopentanoate gives methyl 4-thiazoleacetate, as
described in
Figure 9. Ester cleavage with lithium hydroxide or reduction with lithium
aluminum
hydride gives the corresponding acid or the alcohol, respectively.
5 Compounds 105 to 224 in Tables VI to XVII all have an amino acid or an
amino alcohol as part of their structure. Their synthesis is described in
Figures 10 to
18. Any amino acid can be used in the synthesis of compounds according to this
aspect of the invention. In certain embodiments, the amino acid group can be
either
proline or N-methyl glycine and the amino alcohol group is their alcohol
equivalent,
10 i.e., prolinol or N-methyl glycinol, respectively. As shown in Figures 10
to 13, the
reaction of an alkyl chloride or a 2-heteroaryl chloride with proline,
prolinol, N-
methyl glycine, or N-methyl glycinol, in THF and triethylamine gives the
corresponding N-alkyl or N-heteroaryl adduct, respectively. When these adducts
are
carboxylic acids, such as in Figures 10 and 12, they react with 5-(4-
15 hydroxybenzyl)thiazolidine-2,4-dione in the presence of DCC and DMAP to
give
compounds 105-108, 111, 112, 125-128, 131, 132, 185-.188, 191, 192. Carboxylic
acid adducts react with 5-(4-hydroxybenzylidene)thiazolidine-2,4-dione in the
presence of DCC and DMAP to give compounds 115-118, 121, 122, 135-138, 141,
142, 195-I98, 201, 202. When these adducts are alcohols, such as in Figures 11
and
20 13, they react with 5-(4-carboxybenzyl)thiazolidine-2,4-dione in the
presence of DCC
and DMAP to give compounds 145-148, 151, 152, 165-168, 171, 172, 205-208, 211,
212. Alcohol adducts react with 5-(4-carboxybenzylidene)thiazolidine-2,4-dione
in
the presence of DCC and DMAP to give compounds 155-158, 161, 162, 175-178,
181,182, 215-218, 221, 222.
25 Alternatively, the amino acid or amino alcohol group can be linked to
another
group via an amide function, such as described in Figures 14 to 17. The
synthesis of
such compounds is straightforward. When the compounds contain an amino acid,
as
in Figures 14 and 16, the synthetic sequence is an amide bond formation, ester
deprotection, and ester formation.
As an illustrative example, (R)-Trolox° is combined with L-proline
methyl
ester, in the presence of DCC and DMAP in rnethylene chloride to form an amide
intermediate. The methyl ester of the proline group is then cleaved with
lithium
hydroxide in methanol, and the resulting carboxylic acid is combined with 5-(4-
hydroxybenzyl)thiazolidine-2,4-dione in DCC/DMAP/methylene chloride to give
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26
compound 109. The (S)-isomer, compound 110, is made in a similar way. The same
kind of synthetic scheme leads to compounds 113, 114, 119, 120, 123, 124, 129,
130,
133,134,139,140,143,144,189,190,193,194,199, 200, 203, and 204.
When the compounds contain an amino alcohol, as in Figures 15 and 17, the
synthetic sequence is an amide bond formation, followed by an ester bond
formation.
As an illustrative example, (R)-Trolox~ is combined with L-prolinol in the
presence
of DCC and DMAP in methylene chloride to form an amide intermediate. The
resulting amide is combined with 5-(4-carboxybenzyl)thiazolidine-2,4-dione in
DCC/DMAP/methylene chloride to give compound 149. The (S)-isomer, compound
150, is made in a similar way. The same kind of synthetic scheme leads to
compounds 153,154,159,160,163,164,169,170,173,174,179,180, .183,184, 209,
210, 213, 214, 219, 220, 223, and 224.
Compounds 225 to 242 (Table XVIII) are oxazoline-4-carboxylic acid types of
compounds. Their synthesis (Figure 18) starts from serine (RS=H) or from
threonine
(RS=CH3) benzyl ester. The ester is coupled with an alkyl or an arylcarboxylic
acid
using for example EDC as a coupling agent. The serine or threonine group then
cyclizes into an oxazoline upon treatment with thionyl chloride. Coupling with
5-(4-
hydroxybenzyl)thiazolidine-2,4-dione using DCC/DMAP/methylene chloride gives
compounds 225 to 242.
Compounds 243 to 248 (Table XIX) are thiazolidinedione molecules where X
is a group containing a substituted 2-methyl-2-propionyl residue. Examples
include
the 2-methyl-2-(4-chlorophenoxy)propionyl moiety (clofibryl moiety), the 2-
methyl-
2-[4-(4-chlorobenzoyl)phenoxy]propionyl moiety (fenofibryl moiety), and 2,2-
dimethyl-5-(2,5-xylyloxy)valeryl moiety (gemfibrozilyl moiety).
Compounds 249 to 252 (Table XX) are thiazolidinedione molecules where X
is a group containing a substituted (R,R)-3,5-dihydroxyheptanoyl residue.
Examples
include the ((3R, 8R)-2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenyl-
amino)carbonyl] 1H-pyrrole-1-((3,8,dihydroxy)heptanoyl group (atorvastatin),
and the
1,2,3,7,8,8a-hexahydro-1-(2-methylbutanoyl)oxy-3,7-dimethylnaphthalenyl-8-
[(3R,SR)-7-heptan]oyl group (lovastatin). The synthesis of these compounds
proceeds as in the examples of Table I, (i.e., by a simple esterification
procedure
between the lipid-lowering agent and compound 1 or compound 2).
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27
Compounds 253 to 260 (Table XXI) are thiazolidinedione molecules where X
is a group containing an arylacetic acid residue, such as in molecules that
have non-
steroidal anti-inflammatory properties. In these examples, the X group is an
ibuprofen, ibufenac, naproxen, diclofenac, or nabumetone residue. The
synthesis of
these compounds is a simple ester formation reaction between the X group and
compound 1 (P and Q are hydrogen) or compound 2 (P and Q form a bond).
Compounds 261 to 268 (Table XXII) are thiazolidinedione molecules where X
is a group containing a cortienic acid residue, such as in molecules that have
glucocorticoid anti-inflammatory properties. In these examples, the X group is
a
cortienic acid, 1,2-dihydrocortienic acid, 6a, 9a-difluoro-1,2-
dihydrocortienic acid,
and a 9a-fluoro-16a-methyl-1,2-dihydrocortienic acid residue. The synthesis of
these
compounds is a simple ester formation reaction between the X group and
compound 1
(P and Q are hydrogen) or compound 2 (P and Q form a bond). Cortienic acid,
one of
the many metabolites of hydrocortisone in man, can be synthetized from
hydrocortisone by oxidation with sodium periodate. The substituted cortienic
acid
analogs can be made in an identical manner from the corresponding substituted
glucocorticoids. This oxidation procedure is described in detail in [Druzgala
P.:
Novel Soft Anti-inflammatory Glucocorticoids for Topical Application. ~ Ph.D.
Dissertation (I985), University of Florida, Gainesville, FL, hereby
incorporated by
reference in its entirety].
Representative compounds were chosen and evaluated for activity on serum
glucose and insulin levels in non-insulin dependent diabetic mellitus (NIDDM)
I~K-
AY male mice. Post-treatment data for each group were transferred to a
percentage of
pretreatment values and unpaired Student's t test was used for comparison
between
vehicle and test substance treated . groups. Results show a significant
reduction of
both serum glucose and serum insulin relative to the vehicle control group.
Reduction
in serum glucose and serum insulin levels were comparable to the reduction
observed
in the troglitazone-treated animals. The results are presented in Table XXI
and in
Figures 19 and 20.
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EXAMPLES
Example 1- To (S)-2-pyrrolidinemethanol (3.96g) in THF (30m1) is added 2-
chlorobenzoxazole (5.90g) also in THF (80m1) and then, dropwise, triethylamine
(3.96g). Stir at 50°C for 4 hours. Cool to room temperature and filter
out the solid.
Evaporate the solvent and dissolve the crude product in Sml of methylene
chloride.
Pass through a silica plug (50g) in a fritted filter funnel, and elute with
methanol/methylene chloride (10:90), applying suction until the product has
been
collected. The yield of (S)-1-(2-benzoxazolyl)-2-hydroxymethylpyrrolidine is
8.2g.
Example 2-To (S)-2-pyrrolidinemethanol (3.96g) in THF (30m1) is added 2-
chlorobenzothiazole (6.50g) also in THF (80m1) and then, dropwise,
triethylamine
(3.96g). Stir at 50°C for 4 hours. Cool to room temperature and filter
out the solid.
Evaporate the solvent and dissolve the crude product in Sml of methylene
chloride.
Pass through a silica plug (50g) in a fritted filter fiumel, and elute with
methanol/methylene chloride (10:90), applying suction until the product has
been
collected. The yield of (S)-1-(2-benzothiazolyl)-2-hydroxymethylpyrrolidine is
8.8g.
Example 3- To (R)-2-pyrrolidinemethanol (10.1g) in THF (SOmI) is added 4,5-
dimethylthiazole (14.8g) also in THF (100m1) and then, dropwise, triethylamine
(10.1g). Stir at 50°C for 4 hours. Cool to room temperature and filter
out the solid.
Evaporate the solvent and dissolve the crude product in l Oml of methylene
chloride.
Pass through a silica plug (100g) in a fritted filter funnel, and elute with
methanol/methylene chloride (10:90), applying suction until the product has
been
collected. The yield of (R)-1-(4,5-dimethyl-2-thiazolyl)-2-
hydroxymethylpyrrolidine
is 19.5g.
Example 4- 2-chloropyridine (12g) and 2-(methylamino)ethanol (100m1) are
stirred
under nitrogen at 120°C for 18 hours. Cool to room temperature and then
pour into
iced water (250m1). Extract with ethyl acetate (2x200m1). Dry over sodium
sulfate.
Filter. Evaporate to dryness. The crude product is distilled in vacuo to give
10.3g of
N-methyl-N-(2-pyridinyl)-2-aminoethanol, boiling at 110°C/l.OmmHg.
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Example 5- A solution of 2-chlorobenzoxazole (15.3g) in THF (100m1) is added
dropwise to an ice-cold solution of 2-(methylamino)ethanol (8.0g) and
triethylamine
(10.1g) also in THF (100m1). The mixture is stirred at room temperature for 4
hours
and the solid is filtered off. The solvent is evaporated and the residue is
dissolved in
methylene chloride and passed through a silica plug (100g), eluting with
methanol/methylene chloride (10:90) until the product has been collected. The
yield
of N-methyl-N-(2-benzoxazolyl)-2-aminoethanol is 15.7g.
Example 6- Thionyl chloride (2.5m1) was added dropwise to an ice-cold solution
of
(R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylcarbinol (5.1g) in anhydrous
methylene chloride (SOmI). The solution was stirred at 0°C for 1 hour
and then at
room temperature for another period of 2 hours. Wash with saturated sodium
bicarbonate solution (2x25m1), then with brine (25m1), and then with water
(25m1).
Dry over sodium sulfate, filter, and evaporate to dryness. The crude product,
(R)-6-
hydroxy-2,5,7,8-tetramethylchroman-2-ylmethyl chloride (5.2g) is used as is in
the
next step.
Example 7- Thionyl chloride (2.5m1) was added dropwise to an ice-cold solution
of
(S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylcarbinol (5.1g) in anhydrous
methylene chloride (SOmI). The solution was stirred at 0°C for 1 hour
and then at
room temperature for another period of 2 hours. Wash with saturated sodium
bicarbonate solution (2x25m1), then with brine (25m1), and then with water
(25m1).
Dry over sodium sulfate, filter, and evaporate to dryness. The crude product,
(S)-6-
hydroxy-2,5,7,8-tetramethylchroman-2-ylmethyl chloride (5.0g) is used as is in
the
next step.
Example 8- A mixture of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethyl
chloride (8.43g), triethylamine (2.6g), and 2-(methylamino)ethanol (40m1) is
stirred at
120°C under nitrogen for 16 hours. Cool to room temperature and pour
into iced
water (100m1). Extract with ethyl acetate (3x100m1) and wash the combined
organic
extracts with brine (100m1). Dry over sodium sulfate. Filter. Evaporate to
dryness.
The product, (R)-2-[N-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethyl)-N-
methylamino]ethanol weighs 9.0g.
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Example 9- A mixture of (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethyl
chloride (8.43g), triethylamine (2.6g), and 2-(methylamino)ethanol (40m1) is
stirred at
120°C under nitrogen for 16 hours. Cool to room temperature and pour
into iced
water (100m1). Extract with ethyl acetate (3x100m1) and wash the combined
organic
5 extracts with brine (100m1). Dry over sodium sulfate. Filter. Evaporate to
dryness.
The product, (S)-2-[N-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethyl)-N-
methylamino]ethanol weighs 8.9g.
Example 10- A mixture of 2-chlorobenzoxazole (3.7g), (L)-proline methyl ester,
10 hydrochloride salt (4.0g), and triethylamine (4.9g) in anhydrous THF (SOmI)
is stirred
at room temperature for 18 hours. The solid is filtered off and washed with
THF
(lOml). The solution is evaporated to dryness and the crude product is
dissolved in
methylene chloride (5m1) and passed through a plug of silica (50g), eluting
with ethyl
acetate/methylene chloride (10:90). The product, (L)-N-(2-benzoxazolyl)-
proline
15 methyl ester (5.0g) is a crystalline solid.
Example 11- A mixture of 2-chlorobenzoxazole (3.7g), (D)-proline methyl ester,
hydrochloride salt (4.0g), and triethylamine (4.9g) in anhydrous THF (SOmI) is
stirred
at room temperature for 18 hours. The solid is filtered off and washed with
THF
20 (lOml). The solution is evaporated to dryness and the crude product is
dissolved in
methylene chloride (5m1) and passed through a plug of silica (50g), eluting
with ethyl
acetate/methylene chloride (10:90). The product, (D)-N-(2-benzoxazolyl)-
proline
methyl ester (5.5g) is a crystalline solid.
25 Example 12- (L)-N-(2-benzoxazolyl)-proline methyl ester (5.0g) is suspended
in a
mixture consisting of methanol (SOmI), water (5m1), and lithium hydroxide
(0.5g).
Stir for 18 hours at room temperature. Acidify to pH 4.5 with citric acid.
Extract
with ethyl acetate (4x50m1). Dry over sodium sulfate, filter, and evaporate to
dryness.
The product, (L)-N-(2-benzoxazolyl)-proline (4.3 g) is an off white solid.
Example 13- A mixture of (L)-proline (4.6g), 2-chlorobenzoxazole (6.6g), and
triethylamine (4.45g) in anhydrous THF (100m1) is stirred at reflux
temperature for 18
hours. Cool down to room temperature, filter off the solid and wash it with a
THF
(10m1). Evaporate the solvent. Add ethyl acetate (SOmI) and then 1N sodium
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31
hydroxide (SOmI). Stir for 5 minutes. Keep the aqueous phase. Wash again with
ethyl acetate (SOmI). Acidify with citric acid to pH 4.5. Isolate the
precipitate by
f ltration. The aqueous filtrate is extracted with ethyl acetate (4x30m1). Dry
over
sodium sulfate. Filter. Evaporate to dryness. The solids are dried in vacuo at
35°C
for 18 hours. The first crop of product weighs 4.77g. The second crop weighs
3.26g.
The total amount of product, (L)-N-(2-benzoxazolyl)-proline, is 8.038.
Example 14- A mixture of (D)-proline (4.6g), 2-chlorobenzoxazole (6.6g), and
triethylamine (4.45g) in anhydrous THF (100m1) is stirred at reflux
temperature for 18
hours. Cool down to room temperature, filter off the solid and wash it with a
THF
(lOml). Evaporate the solvent. Add ethyl acetate (SOmI) and then 1N sodium
hydroxide (SOmI). Stir for 5 minutes. Keep the aqueous phase. Wash again with
ethyl acetate (SOmI). Acidify with citric acid to pH 4.5. Isolate the
precipitate by
filtration. The aqueous filtrate is extracted with ethyl acetate (4x30m1). Dry
over
sodium sulfate. Filter. Evaporate to dryness. The solids are dried in vacuo at
35°C
for 18 hours. The first crop of product weighs 4.93g. The second crop weighs
2.90g.
The total amount of product; (L)-N-(2-benzoxazolyl)-proline, is 7.83g.
Example 15- A mixture of 4-hydroxybenzaldehyde (122.12g), 2,4-
thiazolidinedione
(117.13g), piperidine (5.1 1g), and benzoic acid (6.11g) in toluene (1,000m1),
is stirred
at 80°C for 16 hours. Cool to room temperature and filter off the
yellow solid. Wash
the solid with methylene chloride (3x100m1) and then with methanol/methylene
chloride (30:70) (2x100m1). Dry in vacuo at 35°C until constant weight.
The yield of
product, 5-(4-hydroxybenzylidene)-2,4-thiazolidinedione, is 217.8g.
Example 16- To p-anisidine (25g) in acetone (400m1) at between 0 and
5°C, add
dropwise a solution of sodium nitrite (15.41g) in water (SOmI) and 12N
hydrochloric
acid (SOmI) from 2 different funnels over a 15-minute period. Stir for another
5
minutes at 0°C. Add methyl acrylate (104.9g) and then warm up the
solution to 35°C.
Transfer into a 2-L Erlenmeyer flask and stir vigorously. While stirring, add
copper(I) oxide (0.7g) in several portions. Keep stirring for as long as
nitrogen gas
evolves from the solution, then stir for another 4 hours. Evaporate the
organic solvent
and dilute the aqueous residue with water (200m1). Extract with methylene
chloride
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(ZOOmI). Dry over sodium sulfate, filter, and evaporate to dryness. The
product,
methyl 2-chloro-3-(4-methoxyphenyl)propanoate, is a dark oil weighing 42.968.
Example 17- Methyl 2-chloro-3-(4-methoxyphenyl)propanoate (31.448), thiourea
(16.898), and anhydrous sodium acetate (11.248) in 2-methoxyethanol (100m1) is
stirred at 100°C for 4 hours. Cool to room temperature and place the
flask at 4°C for
16 hours. The pale yellow solid is filtered off and is washed with hexanes
(SOmI).
Stir for 30 minutes in ethyl acetate/water (100mI:lOm1). Filter. Crystallize
from hot
ethanol (600m1). After leaving at 4°C for 16 hours, the crystals are
filtered off and
stirred at reflux for 8 hours in a mixture of 2-methoxyethanol (100m1) and 2N
hydrochloric acid (20m1). Evaporate the solvent. Add ethyl acetate (200m1) and
water (200m1). Keep the organic phase and wash again with water (200m1). Dry
over
sodium sulfate, filter, evaporate to dryness. The product, 5-(4-
methoxybenzyl)thiazolidine-2,4-dione (16.78) is an oil that solidifies upon
standing.
Example 18- To a solution of 5-(4-methoxybenzyl)thiazolidine-2,4-dione (14.38)
in
anhydrous methylene chloride (100m1) cooled to -40°C, add a 1.0M
solution of boron
tribromide in methylene chloride (63m1). The solution is left to warm up to
23°C and
is then stirred for another 16 hours. Pour into iced water (700m1) and stir
for 15
minutes. Isolate the precipitate by filtration. Wash the product with water
(SOmI) and
then with methylene chloride (SOmI). The yield of 5-(4-
hydroxybenzyl)thiazolidine-
2,4-dione is 12.88.
Example 19- A mixture of methyl 4-formylbenzoate (164.168), 2,4-
thiazolidinedione
(117.138), piperidine (5.118), and benzoic acid (6.118) in toluene (1,000m1),
is stirred
at 80°C for 16 hours. Cool to room temperature and filter off the
yellow solid. Wash
the solid with methylene chloride (3x100m1) and then with methanol/methylene
chloride (30:70) (2x100m1). Dry in vacuo at 35°C until constant weight.
The yield of
product, 5-(4-carbomethoxybenzylidene)-2,4-thiazolidinedione, is 258.08.
Example 20- A suspension of 5-(4-carbomethoxybenzylidene)-2,4-
thiazolidinedione
(26.38) and magnesium turnings (248) in anhydrous methanol (300m1) is stirred
at
45°C for 8 hours. Acidify to pH 5.0 with 6N HCl and then extract with
methylene
chloride (2x250m1). Dry over sodium sulfate, filter, and evaporate to dryness.
The
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33
crude product is chromatographed on silica gel (1,300g), eluting with
methanol/methylene chloride (02:98). The yield of 5-(4-carbomethoxybenzyl)-2,4-
thiazolidinedione is 15.2g.
Example 21- A suspension of 5-(4-carbomethoxybenzylidene)-2,4-
thiazolidinedione
(50g) in 6N HCl (200m1) is stirred at reflux for 4 hours. The mixture is
cooled to 4°C
and the product is filtered off. The product is then washed with water
(2x100m1) and
is dried in vacuo at 40°C. The yield of 5-(4-carboxybenzylidene)-2,4-
thiazolidinedione is 45g.
Example 22- A suspension of 5-(4-carbomethoxybenzyl)-2,4-thiazolidinedione
(50g)
in 6N HCl (200m1) is stirred at reflux for 4 hours. The mixture is cooled to
4°C and
the product is filtered off. The product is then washed with water (2x100m1)
and is
dried in vacuo at 40°C. The yield of 5-(4-carboxybenzyl)-2,4-
thiazolidinedione is
44g.
Example 23- (R)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (9.2g)
and
5-(4-hydroxybenzyl)thiazolidine-2,4-dione (8.3g) are dissolved in methylene
chloride
(100m1) and THF (SOmI). To this add dicyclohexylcarbodiimide (7.6g) and DMAP
(0.5g), and then stir for 4 hours at room temperature. The solid is removed by
filtration and is washed with a small amount of THF (20m1). The solvent is
removed
and the solid residue is stirred with methylene chloride (100m1) and left at
4°C for 16
hours. The product is isolated by filtration and dried in vacuo at
23°C. The yield of
5-{4-[(R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxy]benzyl}thiazolidine-
2,4
dione is 12.4g.
Example 24- (S)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (9.2g)
and
5-(4-hydroxybenzyl)thiazolidine-2,4-dione (8.3g) are dissolved in methylene
chloride
(100m1) and THF (SOmI). To this add dicyclohexylcarbodiirnide (7.6g) and DMAP
(0.5g), and then stir for 4 hours at room temperature. The solid is removed by
filtration and is washed with a small amount of THF (20m1). The solvent is
removed
and the solid residue is stirred with methylene chloride (100m1) and left at
4°C for 16
hours. The product is isolated by filtration and dried in vacuo at
23°C. The yield of
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5-{4-[(S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxy]benzyl)thiazolidine-
2,4-
dione is 13.3g.
Example 25- (R)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carbinol (1.9g) and 5-
(4-
carboxybenzyl)thiazolidine-2,4-dione (1.8g) are dissolved in methylene
chloride
(20m1) and THF (lOml). To this add dicyclohexylcarbodiimide (1.6g) and DMAP
(0.1 g), and then stir for 4 hours at room temperature. The solid is removed
by
filtration and is washed with a small amount of THF (5m1). The solvent is
removed
and the solid residue is stirred with methylene chloride (20m1) and left at
4°C for 16
hours. The product is isolated by filtration and dried in vacuo at
23°C. The yield of
5- f 4-[(R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methoxy]benzyl]thiazolidine-
2,4-
dione is 2.54g.
Example 26- (S)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carbinol (1.9g) and 5-
(4-
carboxybenzyl)thiazolidine-2,4-dione (1.8g) are dissolved in methylene
chloride
(20m1) and THF (lOml). To this add dicyclohexylcarbodiimide (1.6g) and DMAP
(0.1 g), and then stir for 4 hours at room temperature. The solid is removed
by
filtration and is washed with a small amount of THF (5m1). The solvent is
removed
and the solid residue is stirred with methylene chloride (20m1) and left at
4°C for 16
hours. The product is isolated by filtration and dried in vacuo at
23°C. The yield of
5- f 4-[(S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methoxy]benzyl}thiazolidine-
2,4-
dione is 2.17g.
Example 27- (R)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (4.6g)
and
5-(4-hydroxybenzylidene)thiazolidine-2,4-dione (4.2g) are dissolved in
methylene
chloride (SOmI) and THF (25m1). To this add dicyclohexylcarbodiimide (3.8g)
and
DMAP (0.25g), and then stir for 4 hours at room temperature. The solid is
removed
by filtration and is washed with a small amount of THF (lOml). The solvent is
removed and the solid residue is stirred with methylene chloride (SOmI) and
left at
4°C for 16 hours. The product is isolated by filtration and dried in
vacuo at 23°C.
The yield of 5- f 4-[(R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-
carboxy]benzylidene]thiazolidine-2,4-dione is 5.9g.
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Example 28- (S)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (4.6g)
and
5-(4-hydroxybenzylidene)thiazolidine-2,4-dione (4.2g) are dissolved in
methylene
chloride (SOmI) and THF (25m1). To this add dicyclohexylcarbodiimide (3.8g)
and
DMAP (0.25g), and then stir for 4 hours at room temperature. The solid is
removed
5 by ftltration and is washed with a small amount of THF (lOml). The solvent
is
removed and the solid residue is stirred with methylene chloride (SOmI) and
left at
4°C for 16 hours. The product is isolated by filtration and dried in
vacuo at 23°C.
The yield of 5-{4-[(S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-
carboxy]benzylidene}thiazolidine-2,4-dione is 6.2g.
Example 29- (R)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carbinol (3.8g) and 5-
(4-
carboxybenzylidene)thiazolidine-2,4-dione (3.6g) are dissolved in methylene
chloride
(40m1) and THF (20m1). To this add dicyclohexylcarbodiimide (3.2g) and DMAP
(0.2g), and then stir for 4 hours at room temperature. The solid is removed by
filtration and is washed with a small amount of THF (lOml). The solvent is
removed
and the solid residue is stirred with methylene chloride (40m1) and left at
4°C for 16
hours. The product is isolated by filtration and dried in vacuo at
23°C. The yield of
5-{4-[(R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-
methoxy]benzylidene}thiazolidine-2,4-dione is 5.4g.
Example 30- (S)-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carbinol (3.8g) and 5-
(4-
carboxybenzylidene)thiazolidine-2,4-dione (3.6g) are dissolved. in methylene
chloride
(40m1) and THF (20m1). To this add dicyclohexylcarbodiimide (3.2g) and DMAP
(0.2g), and then stir for 4 hours at room temperature. The solid is removed by
filtration and is washed with a small amount of THF (lOml). The solvent is
removed
and the solid residue is stirred with methylene chloride (40m1) and left at
4°C for 16
hours. The product is isolated by filtration and dried in vacuo at
23°C. The yield of
5-{4-[(S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-
methoxy]benzylidene}thiazolidine-2,4-dione is 5.2g.
Example 31- (L)-N-(2-benzoxazolyl)-proline (3.26g) and 5-(4-
hydroxybenzyl)thiazolidine-2,4-dione (3.11 g) are suspended in methylene
chloride
(100m1). Add DCC (2.89g) and DMAP (0.12g) and stir at room temperature for 4
hours. Filter and purify on 114g of silica, eluting with methanol/methylene
chloride
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36
(02:98). The yield of S-{4-[(S)-1-(2-benzoxazolyl)pyrrolidne-2-
carboxy]benzyl}thiazolidine-2,4-dione is 4.55g.
Example 32- (L)-1-(2-benzoxazolyl)pyrrolidine-2-carbinol (3.26g) and 5-(4-
carboxybenzyl)thiazolidine-2,4-dione (3.25g) are suspended in methylene
chloride
(100m1). Add DCC (2.88g) and DMAP (0.12g) and stir at room temperature for 4
hours. Filter and purify on 132g of silica, eluting with methanol/methylene
chloride
(02:98). The yield of 5-{4-[(S)-1-(2-benzoxazolyl)pyrrolidinyl-2-
methoxycarbonyl]benzyl}-thiazolidine-2,4-dione is 4.68g.
Example 33- (D)-1-(2-benzoxazolyl)pyrrolidine-2-carbinol (3.26g) and 5-(4-
carboxybenzylidene)thiazolidine-2,4-dione (3.35g) are suspended in methylene
chloride (100m1). Add DCC (2.91g) and DMAP (0.12g) and stir at room
temperature
for 4 hours. Filter and purify on 108g of silica, eluting with
methanol/methylene
chloride (02:98). The yield of 5-{4-[(R)-1-(2-benzoxazolyl)pyrrolidinyl-2-
methoxycarbonyl]benzylidene}-thiazolidine-2,4-dione is 4.32g.
Example 34- (D)-1-(2-benzoxazolyl)pyrrolidine-2-carbinol (3.26g) and 5-(4-
carboxybenzyl)thiazolidine-2,4-dione (3.25g) are suspended in methylene
chloride
(100m1). Add DCC (2.93g) and DMAP (0.12g) and stir at room temperature for 4
hours. Filter and purify on 162g of silica, eluting with methanol/methylene
chloride
(02:98). The yield of 5-{4-[(S)-1-(2-benzoxazolyl)pyrrolidinyl-2-
methoxycarbonyl]benzyl}-thiazolidine-2,4-dione is 4.77g. .
Example 35- Triethylamine (8.3m1) is added dropwise to a stirred cold solution
of
ethyl 2-aminoacetoacetate hydrochloride (5.4g) and 4-methoxybenzoyl chloride
(5.2g) in dichloromethane (100m1). After stirring for 3 hours, the solution is
washed
with water (100m1), dried over sodium sulfate, filtered, and evaporated to
dryness.
The crude product, ethyl 2-(4-methoxy)phenylaminoacetoacetate weighs 6.7g.
Example 36- Ethyl 2-(4-methoxy)phenylaminoacetoacetate (5.9g) and phosphorus
oxychloride (SOmI) axe stirred at 100C for 30 minutes. The phosphorus
oxychloride is
removed by evaporation, and the residue is diluted with aqueous sodium
bicarbonate
and extracted with methylene chloride. After drying over sodium sulfate, the
solution
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37
is evaporated and the product is crystallized from hexane, giving ethyl 5-
methyl-2-(4-
methoxy)phenyl-4-oxazolecarboxylate (4.5g).
Example 37- A solution of benzoyl chloride (17g) in ethyl acetate (40m1) is
added
dropwise, with stirring, in an ice-cold mixture of L-serine methyl ester,
hydrochloride
(15.5g), water (100m1), sodium bicarbonate (21.8g), and ethyl acetate (100m1).
After
stirring for 2 hours, the organic phase is separated, dried over sodium
sulfate, and
evaporated to give crystalline N-benzoyl-L-serine methyl ester (22.0g).
Example 38- A stirred mixture of N-benzoyl-L-serine methyl ester (21.0g),
thionyl
chloride (21.0g), and methylene chloride (150m1) is stirred at reflux for 1
hour. The
solvent is evaporated and the residue is diluted with cold water. Neutralize
with
sodium bicarbonate, and extract with ethyl acetate. Purification on silica gel
(250g),
eluting with methanol:methylene chloride (01:99), yields methyl (S)-2-phenyl-2
oxazoline-4-carboxylate (15.2g).
Example 39- A solution of benzoyl chloride (17g) in ethyl acetate (40m1) is
added
dropwise, with stirring, in an ice-cold mixture of L-threonine methyl ester,
hydrochloride (16.5g), water (100m1), sodium bicarbonate (21.8g), and ethyl
acetate
(100m1). After stirring for 2 hours, the organic phase is separated, dried
over sodium
sulfate, and evaporated to give crystalline N-benzoyl-L-threonine methyl ester
(21.5g).
Example 40- A stirred mixture of N-benzoyl-L-threonine methyl ester (21.0g),
thionyl
chloride (21.0g), and methylene chloride (150m1) is stirred at reflux for 1
hour. The
solvent is evaporated and the residue is diluted with cold water. Neutralize
with
sodium bicarbonate, and extract with ethyl acetate. Purification on silica gel
(250g),
eluting with methanol:methylene chloride (01:99), yields methyl (R,S)-2-phenyl-
2-
oxazoline-5-methyl-4-carboxylate (14.8g).
Example 41- Activity in NIDDM KID-AY male mice. Non-inslin dependent diabetic
mellitus male mice, weighing 50 +/- $g (9-10 weeks of age) were used. These
animals exhibited hyperinsulinemia, hyperglycemia, and islet atrophy. The test
compounds 105, 115, and 155, and the positive control compound troglitazone
were
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38
suspended in a 1 % carboxymethylcellulose preparation and were given orally at
a
dose of lOmg/kg, twice a day, for 5 consecutive days. Blood sampling was
performed
before the first dose and then 90 minutes after the last dose. Serum glucose
and
insulin levels were measured. Percent reduction of serum glucose and insulin
levels
relative to the pre-treatment values are shown in Table XX and figures 20 and
21.
It should be understood that the reaction schemes and embodiments described
herein are for illustrative purposes only and that various modifications or
changes in
light thereof will be suggested to persons skilled in the art and are to be
included
within the spirit and purview of this application and the scope of the
appended claims.
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39
0
Formula I
W I ~NH
Table I. o
Compound X P and Q*
number
1 H
HO
2 db
3 O H
.\
HO
4 db
O H
O~
6 ~CH3 db
7 O H
-N O~
8 H3C \ / db
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Table T (continued).
Compound X P and Q*
number
CH3 O
9 H3C / ~3C H
O-
HO
10 db
CH3
11 CH3 O ~ H
H3C / O - CH3
12 HO \ db
CH3
CH3
13 H3C O H
CH3
HO \ 'CH3
14 CH H ~O db
CH3
15 H3C O H
CH3
HO \ 'CH3
16 CH3 HO%~O db
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41
Compound X P and QX
number
17 O H
,O
18 CH3 db
19 O H
O
20 CH3 db
21 - N O H
H3C O
22 db
23 O '" H
-N O
24 H3C ~ l db
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42
Compound
X
number P and Q*
CH3
25 H3C / ~3C O O H
HO \
26 db
CH3
27 CH3 O H
H3C / O - CH30
28 HO ~ db
CH3
CH3
29 H3C / O H
CH3
HO ~ ,CH3
H
30 CH3 O db
O
CH3
31 H3C / O H
CH3
HO \ _ 'CH3
H
32 CH3 'O db
O
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43
0
Z CHs
Table II. R,-~~ I o ~ ~ S~ H
N p
Formula II RZ R3 0
Compound
Z R1 R2 R3
number
33 O ~ ~ H H
34 O ~ CH3 H
35 O ~ CH3 CH3
36 S ~ CH3 H
y
F
37 O ~ CH3 H
F
38 S I CH3 H
H3C0
39 O ~ CH3 H
H3C0
40 S ~ GH3 H
S
41 O I ~ CH3 H
CH3
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44
Compound Z R1 R2 R3
number
S
42 S ( ~ CH3 H
CH3
H3C S
43 O I / H H
H3C S
44 O I / CH3 H
HsC S
45 S I / H H
H3C
46 O ~ CH3 H
O,N
H3C
47 S ~ H H
O,N
48 O ~ CH3 H
N
49 O / ~ CH3 H
N
N
50 O ~ CH3 H
N
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0
CH3
Table III. R~Z ~ ° ~ ~ NH
N~O / S
R3 \\O
Rz
Compound
Z . R1 R2 R3
number
51 O I H H
52 O I CH3 H
53 O I CH3 CH3
54 S I CH3 H
F
O I CH3 H
F
56 S I CH3 H
H3C0 /
57 O ( CH3 H
H3C0 /
58 S I CH3 H
\
S
59 O I ~ CH3 H
CH3
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46
Compound
Z R1 R2 R3
number
S
60 S J ~ CH3 H
CH3
H3C S
61 O ~ / H H
HsC S
62 O I / CH3 H
H3C S
63 S I / H H
H3C
64 O ~ CH3 H
O,N
H3C
65 S ~ H ' H
O,N
66 O ~ CH3 H
N
67 O '~ I CH3 H
N
N
68 O ~ CH3 H
N
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47
0
cH,
Table IV. R,--~\Z ~ o
N ~ U
Rz Rs O O
Compound
Z R1 R2 R3
number
69 O ~ H H
/
70 O ~ CH3 H
71 O ~ CH3 CH3
72 S ( CH3 H
F
73 O ~ CH3 H
F
74 S ~ CH3 H
H3C0 /
75 O ~ CH3 H
H3C0 /
76 S ~ CH3 H
S
77 O I ~ CH3 H
CH3
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48
Compound
Z R1 RZ R3
number
S
78 S I ~ CH3 H
CH3
H3C S
79 O I / H H
H3C S
80 O I / CH3 H
H3C S
81 S I / H H
H3C
82 O ~ CH3 H
O,N
H3C
83 S ~ H H
O,N
84 O ~ CH3 H
N
85 O ~ I CH3 H
N
N
86 O ~ ~ CH3 H
N
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49
Table V
0
CHs
Rj~~ ~ O I ~\NH
N
R3 O
RZ O
Compound
Z R1 R2 R3
number
87 O ~ I H H
88 O ~ CH3 H
89 O I CH3 CH3
90 S ~ CH3 H
F
91 O I CH3 H
\
F
92 S I CH3 H
H3C0
93 O ~ CH3 H
H3C0
94 S ~ CH3 H
s
95 O I ~ CH3 H
CH3
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Compound
Z R1 R2 R3
number
S
96 S I ~ CH3 H
CH3
HsC S
97 O I / H H
HsC S
98 O I / CH3 H
H3C S
99 S I / H H
H3C
100 O ~ CH3 H
O~N
H3C
101 S ~ H H
O, N
102 O ~ v CH3 H
N
103 O / I CH3 H
N
N
104 O ~ CH3 H
N
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51
O
N I \ ~\NH
Y~ H~ O / S \\
Table VI.
O O
Compound
Y
number
/ N
105
O
/ N
106
S
107
N
H3C N
108
HsC S
CH3 O
H3C / H03C
109
HO \
CH3
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52
Compound
Y
number
CH3 O
H3C / O - CH3
110
HO
CH3
CH3
H3C / H03C
111
HO
CH3
CH3 .,
H3C / O . CH3
112
HO \
CH3
CH3
H3C / O
113 I CH3
HO \ 'CH3
CH3 H
O
CH3
H3C / O
114 ~ ~ CH3
HO \ 'CH3
CH3 H
O
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53
0
Table VII. N ~ \ ~\NH
Y/ g_--' O / S \\
O O
Compound
Y
number
/ N
115
O
/ N
116
S
117
N
H3C N
118
H3C S
CH3 O
H3C / H03C
119
HO
CH3
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54
Compound
Y
number
CH3 O
H3C / O - CH3
120
HO
CH3
CH3
H3C / HO3C
121
HO
CH3
CH3 ~'~' "
H3C / O - CH3
122
HO
CH3
CH3
H3C / O
123 ~ CH3
HO \ 'CH3
CH3 H
O
CH3
H3C ~. O
124 I CH3
HO \ 'CH3
CH3 O
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O
N~ I \ ~\NH
Table VIII. Y/ H ~--O
O O
Compound
Y
number
/ N
125
O
/ N
126
S
127
N
H3C N
128
H3C S
CH3 O
H3C / H03C
129
HO
CH3
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56
Compound
Y
number
CH3 O
H3C / O - CH3
130
HO
CH3
CH3
H3C / HO3C
13I
HO
CH3
CH3 ~.,
H3C / O - CH3
132
HO
CH3
CH3
H3C / O
133 ~ CH3
HO \ 'CH3
CH3 H
O
CH3
H3C / O
134 ~ CH3
HO \ 'CH3
CH3 H ~
O
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57
O
N I NH
Y~ ~ O / S
Table IX. O O
Compound
Y
number
/ N
135
O
/ N
136
S
137
N
H3C N
138
H3C S
CH3 O
H3C ~ HOsC
139
HO
CH3
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58
Compound
Y
number
CH3 O ,
H3C / O - CH3
140
HO
CH3
CH3
H3C / HO3C
141
HO
CH3
CH3 ~~.' ,
H3C / O - CH3
142
HO
CH3
CH3
H3C / O
143 I CH3
HO \ 'CH3
CH3 H
O
CH3
H3C / O
144 ~ CH3
HO \ 'CH3
CH3 H i
O
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59
0
Table X. I ~ ~ ~NH
N ~O ~ S \\
/ H O O
Y
Compound
Y
number
/ N
145
O
/ N
146
S
147
N
H3C N
148 ( ~
H3C S
CH3 O
H3C / 03C
149
HO
CH3
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WO 01/81328 PCT/USO1/13131
Compound
Y
number
CH3 O
H3C / O - CH3
150
HO
CH3
CH3
H3C ~ H03C
151
HO
CH3
CH3
H3C / O - CH3
152
HO
CH3
CH3
H3C / O
153 ~ CH3
HO \ 'CH3
CH3 H
O
CH3
H3C / O
154 I CH3
HO \ 'CH3
CH3 H
O
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61
0
NH
Table XI. N~o
o O
Y
Compound
Y
number
/ N
155
O
/ N
156
S
157
N
H3C N
158
H3C S
CH3 O
H3C / HOsC
159
HO
CH3
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62
Compound
number
CH3 O
H3C / O - CH3
160
HO
CH3
CH3
H3C ~ HO3C
161
HO
CH3
CH3 ~'~' "
H3C / O - CH3
162
HO
CH3
CH3
H3C / O
163 ' CH3
HO \ 'CH3
CH3 H
O
CH3
H3C / O
164 I CH3
HO \ 'CH3
CH3 H
O
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63
0
~NH
N
H
Table XII. Y o
Compound
Y
number
/ N
165
O
r N
166
S
167
N
H3C N
168
HsC S
CH3 O
H3C / H03C
169
HO
CH3
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64
Compound
Y
number
CH3 O ~"
H3C / O - CH3
170
HO
CH3
CH3
H3C ~ H03C
171
HO
CH3
CH3 ~~,' ,
H3C / O - CH3
172
HO
CH3
CH3
H3C / O
173 ~ CH3
HO \ 'CH3
CH3 H
O
CH3
H3C / O
174 I CH3
HO \ 'CH3
CH3 H
O
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65 O
\NH
Table XIII. ~ , O
N/ L,, ...r
I, H O O
Compound
Y
number
/ N
175
O
/ N
176
S
177
N
H3C N
178
H3C S
CH3 O
H3C / H03C
179
HO
CH3
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66
Compound
Y
number
CH3 O
H3C / O - CH3
180
HO
CH3
CH3
H3C ~ H03C
181
HO
CH3
CH3 ~~' "
H3C / O - CH3
182
HO
CH3
CH3
H3C / O
183 I CH3
HO \ 'CH3
CH3 H
O
CH3
H3C / O
184 ~ CH3
HO \ 'CH3
CH3 H
O
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67
O
H3C
N I ~ NH
Table XIV. y' ~O , S
Compound
Y
number
/ N
185
O
/ N
186
S
187
N
H3C N
188
H3C S
CH3 O
H3C / H03C
189
HO
CH3
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68
Compound
number
CH3 O
H3C / O - CH3
190
HO \
CH3
CH3
H3C / HO3C
191
HO
CH3
CH3
H3C / O - CH3
192
HO \
CH3
CH3
H3C / O
193 ~ CH3
HO \ 'CH3
CH3 H
O
CH3
H3C / O
194 ~ CH3
HO \ 'CH3
CH3 H
O
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69
O
H3 I \ _
N I ~ NH
Table XV. y O / S
O O
Compound
Y
number
/ N
195
O
/ N
196
S
197
N
HsC N
198
H3C S
CH3 O
H C 03C
3
199
HO
CH3
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Compound
Y
number
CH3 O
H3C / O - CH3
200
HO
CH3
CH3
H3C / HO3C
201
HO
CH3
CH3 ~.,
H3C / O - CH3
202
HO
CH3
CH3
H3C / O
203 ~ CH3
HO \ _ 'CH3
CH3 H
O
CH3
H3C / O
204 ( CH3
HO \ 'CH3
CH3 H
O
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71
H3C
Table XVI. N ~/
Y
Compound
Y
number
N
205
O
/ N
206
S
20 7
N
H3C N
208
H3C S
CH3 O
H3C ~ H03C
209
HO
CH3
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72
Compound
Y
number
CH3 O
H3C / O - CH3
210
HO
CH3
CH3
H3C / HO3C
211
HO
CH3
CH3 ~'~' "
H3C / O - CH3
212
HO
CH3
CH3
H3C / O
213 ~ CH3
HO \ 'CH3
CH3 H
O
CH3
H3C / O
214 ~ CH3
HO \ 'CH3
CH3 H
O
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73
H3Cv
Table XVII.
Y
Compound
Y
number
N
215
O
/ N
216
S
217
N
H3C N
218
H3C S
CH3 O
H3C / H03C
219
HO
CH3
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74
Compound
Y
number
CH3 O
H3C / O ' CH3
220
HO
CHI
CH3
H3C / HO3C
221
HO
CH3
CH3
H3C / O - CH3
222
HO
CH3
CH3
H3C / O
223 ~ CH3
HO \ _ 'CH3
CH3 H /~''
O
CH3
H3C / O
224 ~ CH3
HO \ 'CH3
CH3 H
O
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Rs O O
S NH
Table XVIII. ~~N
Compound
R4 R5
number
225 ~ H
/
226 ~ ~ CH3
F
227 ~ H
F
228 ~ CH3
H3C0
229 ~ H
H3C0 /
230 ~ CH3
S
231 ' ~ H
CH3
S
232 I ~ CH3
CH3
H3C S
233 I / H
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76
Compound
R4 R5
number
H3C
234 I / CH3
H3 C
235 ~ H
O,N
H3C
236 ~ C~I3
O,N
237 ~ H
N
238 ~ CH3
N
239 / I H
N
240 / I CH3
N
N
241 ~ H
N
N
242 ~ CH3
N
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Table XIX. O
Compound Fib P and
Q*
number
O
243 Cl ~ j H
244 db
~
O
Cl
245 H
246 O~ db
247 O H
248 db
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78
P
Q O
OH OH O
Hetero O ~ ' S NH
Table XX. O
Compound Hetero P and QX
number
249 ~ O H
H-N
- \ O
N °- OH
OH
250 I ~ db
F
HO
251 ~ H
HO O
O~O
252 db
i i
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79
P
R O
NSAID~O
S
~N
Table XXI //o
Compound NSAID P and Q~
number
253 H
i w
254 H3~~ \ / db
255 H
i ~ w
H3C0
256 db
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Table XXI (continued)
Compound NSAID P and QX
number
257 H
258 ~ I db
259 ~ ~ ~' H
NH
Cl C1
260 ~ ~ db
i
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81
Table XXII
Compound X P and
Q'
number
261 H
0
HO ,",~ OH
2 62 " db
0
263 H
0
HO ..,.,
OH
264 ~' " db
0
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82
Table XXII (continued)
Compound X P and Qx
number
~
265 H
0
HO ,,., OH
266 F db
0
F
267 H
0
HO .,,..OH
..,~~~CH3
268 ~ " db
F
O
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Table XXIII: Activity in NIDDM Mice.
Compound Serum Glucose (%) Serum Insulin
(%)
Vehicle 0 1
105 40 10
115 36 13
155 37 9
Troglitazone 35 15
