NOVEL COMPOUNDS FOR TREATMENT OF OBESITY
FIELD OF THE INVENTION
The present invention relates to the novel thyroid like compounds of general formula I,
useful for the treatment of obesity and to a method for preparation, composition
containing such compounds and use of such compounds and composition in
medicine. Further, compounds of formula I has significantly low binding affinity to
thyroid receptors The invention also relates to the use of the above-mentioned
compounds for the preparation of a medicament for treating obesity.

BACKGROUND OF THE INVENTION AND PRIOR ART
Obesity is a condition of an excessive accumulation of energy in the body, in which
the natural energy reserve, stored in the fatty tissue of humans and other mammals, is
increased to a point where it is associated with certain health conditions or increased
mortality. Obesity develops from an imbalance between energy expenditure and
energy intake, and the physiological approach to obesity treatment is to achieve a
negative energy and fat balance. Indeed the weight loss through diet is effective for
the majority of patient yet very few manage to maintain their initial weight loss over the
long time.
Obesity has reached epidemic proportions globally, with more than 1.6 billion adults
overweight - at least 400 million of them clinically obese - and is a major contributor to
the global burden of chronic disease and disability1. WHO further projects that by
2

2015, approximately 2.3 billion adults will be overweight and more than 700 million will
be obese. At least 20 million children under the age of 5 years are overweight globally
in 2005. Obesity and overweight pose a major risk for serious diet-related chronic
diseases, including type 2 diabetes, cardiovascular disease, hypertension, stroke, and
certain forms of cancer. The health consequences range from increased risk of
premature death, to serious chronic conditions that reduce the overall quality of life. Of
a special concern is the increasing incidence of child obesity.
Although obesity has long been associated with serious health issues, it has only
recently been regarded as a disease in the sense of being a specific target for medical
therapy. Consequently, developing obesity treatments that target novel pathways is a
growing focus for both biopharmaceutical and the medical device industries2.
Other than the over-the-counter (OTC) market, current available therapies for obesity
are based on diet and exercise, a select number of drugs for a fraction of patients, and
stomach (bariatric) surgery for extremely obese individuals2. Although older drugs,
such as generic amphetamine-like agents, are reasonably effective in the short term
they carry the risks of addiction and serious cardiovascular complications3.
Sibutramine, a serotonin- and noradrenaline-reuptake inhibitor, controls appetite by
producing a feeling of satiety. But because its prominent side effect is hypertension, it
is not widely prescribed. Other available antiobesity compound Orlistat reduces weight
by limiting caloric intake through inhibition of the lipase-mediated breakdown of fat in
the gastrointestinal tract. Unfortunately, approximately 20% of patients develop
unacceptable side effects, such as faecal incontinence and urgency, limiting its
broader use2. Very recently a CB1 receptor antagonist, Rimonabant has also been
approved for treatment of obesity. Thus the available therapies for treatment of
obesity have proved to be of limited value and hence there exists a need for better
approach with desired efficacy having low side effects.
Various new therapeutic approaches, such as NPY receptor antagonists, beta 3
receptor agonist, ACC2 inhibitors are underway to find a safe & effective anti-obesity
3

compounds. Many of the compounds are in early stage of development. Recently
selective thyroid receptor ligands are also being explored for the treatment of obesity.
Thyroid gland in response to stimulation by TSH, produces T4, T3 and rT3. Although
T4, T3 and rT3 are generated within the thyroid gland, T4 is quantitatively the major
secondary product. Production of T3 & rT3 within the thyroid is regulated to very small
quantities and is not considered significant compared to peripheral production. T4 is
either converted to T3 or rT3, or eliminated by conjugation, deamination or
decarboxylation. It is estimated that more than 70% of T4 produced in thyroid is
eventually deiodinated in peripheral tissues to form T3 or rT3. Although some T3 is
produced in the thyroid, approximately 80-85% is generated outside the thyroid,
primarily by conversion from T4 in liver and kidney. Further degradation of T3 & rT3
results in the formation of several distinct diiodothyronines: 3,5-T2, 3,3'-T2 and 3,5'-
T24. Structurally all thyroid hormones can be divided into two ring i.e.prime ring and
non-prime ring and its SAR suggests unpredictable behaviour of the effect of
substituents at (3'-,5'-, 3-and 5-) on the prime and non-prime ring respectively5. T3 is
considered to be the most metabolically active thyroid hormone. Various experimental
evidences suggest that major effects of thyroid hormone are mediated by T3. Thyroid
hormones affect the metabolism of virtually every cell of the body. At normal levels,
these hormones maintain body weight, the metabolic rate, body temperature, and
mood, and influence serum low density lipoprotein (LDL) levels. Thus, in
hypothyroidism there is weight gain, high levels of LDL cholesterol, and depression. In
excess with hyperthyroidism, these hormones lead to weight loss, hypermetabolism,
lowering of serum LDL levels, cardiac arrhythmias, heart failure, muscle weakness,
bone loss in postmenopausal women, and anxiety6.
Thyroid hormones are currently used primarily as replacement therapy for patients
with hypothyroidism. However, replacement therapy, particularly in older individuals is
limited by certain of the deleterious effects of thyroid hormones. In addition, some
effects of thyroid hormones may be therapeutically useful in non-thyroid disorders, if
adverse effects can be minimized or eliminated. These potentially useful influences
4

include weight reduction, lowering of serum LDL levels, amelioration of depression
and stimulation of bone formation. Prior attempts to utilize thyroid hormones
pharmacologically to treat these disorders have been limited by manifestations of
hyperthyroidism and in particular by cardiovascular toxicity (Thyrotoxicosis)7.
Thyroid hormone exerts there effects through thyroid receptors. There are two major
subtypes of thyroid receptors located within the nucleus (Genomic effect) TRa and
TRp. TRa1, TR(31 and TR(32 isoforms bind thyroid hormone and acts as a ligand
regulated transcription factors. The TRa2 isoform is prevalent in pituitary and other
parts of the CNS, does not bind thyroid hormones and acts in many context as a
transcriptional repressor. TRa1 is also widely distributed. The literature suggests
many or most effects of thyroid hormones on the heart, and in particular heart rate and
rhythm are mediated through the TRa1 isoform. On the other hand, most actions of
the hormones on the liver and other tissues are mediated more through the (3 forms of
receptors7.
Energy expenditure is an important factor in the maintenance of energy homeostasis.
It is universally recognized that thyroid hormones are unique in their ability to stimulate
thermogenesis. Therefore efforts have been made to synthesize thyroid hormone
beta selective and/or tissue selective compounds for the treatment of metabolic
disorders, such as obesity which are devoid of thyrotoxic side effects mediated by
TRa receptors.
Thus in effort to make specific TRb selective Thyroid ligands many researchers have
tried to synthesize Thyroid mimetics wherein the effect of various prime and non-prime
rings and the substituents on it are studied like, US20050085541, US20040039028,
WO2007003419, WO2006128056, WO200709913, US20010051645,
US20020049226 and US20030040535 all of which are incorporated herein as
reference.
5

Until recently, T3 was found to be more biologically active than T4 and is presently
thought to be the predominant activator of the thyroid hormone receptors5. In the last
decade or so, evidence has accumulated that naturally occurring iodothyronines other
than T3 exerts biological effects. Among these, 3,5-diiodothyronine appears to be
responsible for rapid, short-term effects on cellular oxidative capacity and respiration
rate by direct interaction with mitochondrial binding sites. The accumulated evidence
permits the conclusion that the action of T2 do not simply mimic those of T3 but
instead are specific action exerted through mechanism that are independent of those
actuated by T3 through thyroid hormone receptors8'9.
In summary, thyroid hormones (T4, T3) cause weight reduction via increased
metabolic rate and a LDL cholesterol reduction through both an upregulation of LDL
receptors and increased cholesterol metabolism. However thyroid hormone do not
have sufficiently broad therapeutic window, particularly with regard to cardiac
acceleration, to be useful for treatment of obesity and lipid disorders. Very recently it
has been reported that TR0 selective agonists might be exploited as a therapeutically
effective means to lower weight and plasma cholesterol without eliciting deleterious
cardiac effects. However, recently it has also been found that the TR|3 selective
agonist induce proliferative response like lead to hepatocyte proliferation and also
induced pancreatic acinar cell proliferation10. There are also reports that T3 increases
food consumption at low dosage in animal, independent to its nuclear effects11 and the
increase in energy intake were also displayed by T212, which can be compensatory in
the treatment of obesity.
Growing body of evidences now suggest that, 3,5-diiodothyronine can induce
metabolic inefficiency, possibly by stimulating energy loss via mechanism involving
the mitochondrial apparatus rather that nuclear receptors. Such an action of T2 can
potentially result in a reduced adiposity and less body weight gain without inducing a
clinical syndrome related to thyrotoxic state, by increasing fatty acid influx in to
mitochondria and fatty acid oxidation13'8.
6

From a clinical point of view a scenario involving high level of fatty acid oxidation,
reduced fat storage, reduction in serum triglyceride and cholesterol levels, reduced
lever steatosis, reduced body weight gain without a reduction in calorie/fat intake is an
attractive prospect for an intractable obesity8.
WO2005/009433 discloses the composition of 3,5 T2 in therapeutically effective doses
mainly for use in obesity, hepatic steatosis and dislipidemia.
Further WO2007027842 relates to an anilinopyrazole compounds useful for the
treatment of diabetes and related disorders. US2004110816 discloses certain reverse
transcriptase inhibitors of pyrazole derivatives useful for the treatment of HIV and
WO9716422 discloses certain chromanyl and thiochromanyl compounds having
retinoid like activity.
Thus, there exists a need for novel thyroid like compounds, which are useful for the
treatment of obesity without having undesirable effects of thyrotoxicosis and increase
in food consumption.
7

DESCRIPTION OF THE INVENTION
One embodiment of the present invention is a compound of formula I

Wherein, R1 and R3 is same or different, and is independently selected from H, C1-C6
alkyl, C3-C7 cycloalkyl, halo, CN, CF3, -O-(C1-C6)alkyl, -CO2-(C1-C6)alkyl, -CONH-(C1
C6)alkyl, -CONH-aryl, -CONH-heteroaryl,- CONR5 , -C1-C3alkyl-aryl , -C1-C3alkyl-
heteroaryl, -NH-(C1-C6)alkyl, , -NHaryl, -NH-SO2-(C1-C6)alkyl , -CH2-NH-(C1-C6)alkyl,
-CH2-O-(C1-C6)alkyl, -C1-C3alkyl-NR5 R6, R7, wherein C1-C6alkyl and C3-C6 cycloalkyl
is optionally substituted with one or more substituents selected from (C1-C6)alkyl, halo,
cyano, -OH, oxo, -COOH, -O-(C1-C6)alkyl, -O-benzyl, -COO-(C1-C6)alkyl, -CONH-
(C1-C6)alkyl, -CONR5, -CONH-aryl, -CONH-heteroaryl or -CH2NR5;
R2 is selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)alkenyl, (C3-C6 )alkynyl,
-C(O)-(C1-C3)alkyl-COOH, -C(O)-C(O)O-(C1-C6)alkyl , -C(O)-(C1-C3 )alkyl-NH-(C1
C6)alkyl, -C(O)-O-(C1-C6)alkyl, -C(O)NR5, -C(O)NH-(C1-C6)alkyl, -C(O)-(C1
C3)alkylaryl, -C(O)-(C1-C3)alkylheteroaryl, R6, R7, (C1-C6)alkyl-R6, (C1-C6)alkyl-R7,
wherein said (C1-C6 )alkyl, (C3-C6 )cycloalkyl, (C3-C6 )alkenyl, (C3-C6)alkynyl being
optionally substituted with one or more substituents selected from perhaloalkyl, Oxo, -
C(O)OH, -C(O)-O-(C1-C3)alkyl, -C(O)-O-(C1-C3)alkylaryl, -C(O)-O-(C1-C3)alkyl
heteroaryl, -CONH(C1-C3)alkyl, -C(O)NH-aryl, -C(0)NH-heteroaryl, -CONR5
CONHNH2, -C(=NH)NH-(C1-C6)alkyl, -C(=NH)NH2, -C(O)-R8, -C(O)NHSO2(C1-C6)
alkyl, -C(O)NHSO2-aryl, -C(O)NHOH, -C(O)NHSO2-heteroaryl, -C(O)NHNH-(C1
C6)alkyl, -C(O)NHNH-aryl, -CONH-(C1-C2)alkyl-aryl, -C(O)NH-(C1-C2) alkyl-
heteroaryl, -CH2NR5, -NH2, -NH-(C1-C6)alkyl, , -NH-C(O)-O-(C1-C3)alkyl-NH-C(O)-(C1
8

C3)alkyl, -NHC(O)-aryl, -NHC(0)-(C1-C6)alkylaryl --NHC(0)-heteroaryl, -NH-C(0)NR5,
-NH-C(O)NH-aryl, -NHC(O)NH-(C1-C6)alkyl , -NHSO2(C1-C6)alkyl, -NH-SO2-aryl, -
NH-SO2-heteroaryl, halo, cyano, -OH, -O-(C1-C6)alkyl, -O-aryl, -O-heteroaryl ,-O-(C1
C2) alkyl-aryl, -SO3H, -SO2NH-aryl, -SO2NH-heteroaryl or -SO2NH-(C1-C6)alkyl ,R6 or
R7;
R5 together with Nitrogen atom to which it is attached form a saturated or unsaturated
(C3-C6) membered ring, which may be optionally substituted with one or more
substituents selected from oxo, -COOH, halo,-OH, -O-(CrC6)alkyl, or -(C1-C6)alkyl;
R6 is selected from phenyl or 5-8 membered heteroaryl containing 1-4 heteroatoms
selected from O, N, S, wherein said heteroaryl or phenyl ring being optionally
substituted with one or more substituents selected from halogen, -OH, O-(C1-C6)alkyl,
-perhaloalkyl , (C1-C6)alkyl, (C3-C6)cycloalkyl, cyano, -COOH, -C(O)O-(C1-C6)alkyl, -
C(O)O-CH2-aryl, -C(O)O-aryl, -CONH(C1-C3)alkyl, -NH2, -NH-(C1-C6)alkyl, -NHC(O)-
(C1-C6)alkyl, -NHC(O)-aryl, -NHSO2(C1-C6)alkyl, -CONH2, -SO2-(C1-C6)alkyl, -
NHSO2(C1-C6)alkyl or -COR8;
R7 is a 3-6 membered heterocyclic ring containing 1-4 heteroatom selected from O, N
and S, and the said heterocyclic ring being optionally substituted with one or more
substituents selected from oxo, halogen, -O-(C1-C6)alkyl, -OH, -CF3, (C1-C6)alkyl, (C3-
C6)cycloalkyl, cyano, -COOH, -C(O)O-(C1-C6)alkyl, -C(O)O-CH2-aryl, -C(O)O-aryl, -
NH2, -NH-(C1-C6)alkyl, -NHC(O)- (C1-C6)alkyl, -NHC(O)-aryl, -CONH2, -SO2-(C1
C6)alkyl, -NHSO2(C1-C6)alkyl or -COR8;
R8 is an amino acid which is linked through its nitrogen atom;
Z = O, CH2 or N;
R4 is selected from P, Q or T


R9 is selected from -OH, -O-alkyl, halogen, -C(O)O-(C1-C6)alkyl, -C(O)NHR8 -OC(O)-
(C1-C6)alkyl, -O-perhaloalkyl, -OC(O)O-(C1-C6)alkyl, -CONR5 ,-NHCO-(C1-C6)alkyl, -
NHC(O)-O"(C1-C6)alkyl, -NHC(O)-O-aryl -NHSO2-(C1-C6)alkyl, -NHSO2-aryl or -
NHCONR5;
R10 is selected from H, Halogen, (C1-C6)alkyl, alkoxy, -NHCO-(C1-C6)alkyl, -NHSO2-
(C1-C6)alkylor-NH-SO2-aryl;
R11 is H, (C1-C6)alkyl, -CO-(C1-C6)alkyl, -SO2-(C1-C6)alkyl or-SO2-aryl;
G' is selected from H, halogen or (C1-C6)alkyl;
G" is selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, halogen,
perhaloalkyl, CN, CHO, (C1-C3)alkylaryl, (C1-C6)alkyl-O-(C1-C6)alkyl, -CH2R9, -CH2aryl
-CH2NR5, -COOH, -C(O)O(C1-C6)alkyl, -CONH-(C1-C6)alkyl -CONR5, -SO2NR5, -
SO2NH-(d-C6)alkyl, -SO2NH-aryl; n may be one or two;
including their pharmaceutically acceptable salts and their hydrates, solvates,
atropisomers, regioisomers , enantiomers, diastereomers, tautomers, polymorphs and
prodrugs thereof.
In another embodiment, the present invention pertains to a compound as above,
however only including pharmaceutically acceptable salts thereof.
Another embodiment of the present invention is a method for preparation of a
compound of general formula I as herein described in Scheme 1,2 and 3.
Another embodiment of the present invention is a pharmaceutical composition
comprising a compound as above, in admixture with a pharmaceutically acceptable
adjuvant, diluent or carrier.
Another embodiment of the present invention is a method for treating obesity by
administering a compound as above to a mammal in need thereof.
10

Another embodiment of the present invention is the use of a compound as above for
the preparation of a medicament for treating obesity.
DEFINITIONS
The following definitions apply to the terms as used throughout this specification,
unless otherwise limited in specific instances.
The term "thyroid receptor ligand" or "thyroid ligand" as used herein covers any
chemical substance which can bind to a thyroid receptor. The ligand may act as an
antagonist, an agonist, a partial antagonist or a partial agonist.
The term "thyroid receptor" as used herein represents a molecule that receives a
thyroid hormone and permits it to dock on the nucleus of a cell and that function as
hormone-activated transcription factors and act by modulating the expression of
genes. THRs bind DNA in the absence of hormone, usually suppressing the
transcription of genes. Hormone binding involves a conformational change in the
receptor that lets it to activate transcription.
The use of the terms "a" and "an" and "the" and similar referents in the context of
describing the invention (especially in the context of the following claims) are to be
construed to cover both the singular and the plural, unless otherwise indicated herein
or clearly contradicted by context.
The term "compound" employed herein refers to any compound encompassed by the
generic formula disclosed herein. The compounds described herein may contain one
or more double bonds and therefore, may exist as stereoisomers, such as double-
bond isomers (i.e., geometric isomers). Accordingly, the chemical structures depicted
herein encompass all possible stereoisomers of the illustrated compounds including
the stereoisomerically pure form (e.g., geometrically pure) and stereoisomeric
11

mixtures. The compounds may also exist in several tautomeric forms including the
enol form, the keto form and mixtures thereof. Accordingly, the chemical structures
depicted herein encompass all possible tautomeric forms of the illustrated
compounds. The compounds described also include isotopically labeled compounds
where one or more atoms have an atomic mass different from the atomic mass
conventionally found in nature. Examples of isotopes that may be incorporated into
the compounds of the invention include, but are not limited to 2H, 3H, 13C, 14C, 15N,
18O, 17O, etc. Compounds may exist in unsolvated forms as well as solvated forms,
including hydrated forms. In general, compounds may be hydrated or solvated.
Certain compounds may exist in multiple crystalline or amorphous forms. In general,
all physical forms are equivalent for the uses contemplated herein and are intended to
be within the scope of the present invention.
Further, it should be understood, when partial structures of the compounds are
illustrated, a dash (" -") or "*" indicate the point of attachment of the partial structure
to the rest of the molecule. The nomenclature of the compounds of the present
invention as indicated herein is according to MDL ISIS® Draw Version 2.2.
"Pharmaceutically acceptable salts" includes derivatives of the disclosed compounds,
wherein the parent compound is modified by making non-toxic acid or base addition
salts thereof, and further refers to pharmaceutically acceptable solvates, including
hydrates, of such compounds and such salts. Examples of pharmaceutically
acceptable salts include, but are not limited to, mineral or organic acid addition salts of
basic residues such as amines; alkali or organic addition salts of acidic residues such
as carboxylic acids; and the like, and combinations comprising one or more of the
foregoing salts. The pharmaceutically acceptable salts include non-toxic salts and the
quaternary ammonium salts of the parent compound formed, for example, from non-
toxic inorganic or organic acids. For example, non-toxic acid salts include those
derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,
phosphoric, nitric and the like; other acceptable inorganic salts include metal salts
such as sodium salt, potassium salt, cesium salt, and the like; and alkaline earth metal
12

salts, such as calcium salt, magnesium salt, and the like, and combinations
comprising one or more of the foregoing salts. Pharmaceutically acceptable organic
salts includes salts prepared from organic acids such as acetic, trifluoroacetic,
propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,
maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic,
besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,
ethane disulfonic, oxalic, isethionic, HOOC--(CH2)n--COOH where n is 0-4, and the
like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt,
ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-
dibenzylethylenediamine salt, and the like; and amino acid salts such as arginate,
asparginate, glutamate, and the like; and combinations comprising one or more of the
foregoing salts.
The term "alkyl", used either alone or in attachment with another group refers to a
saturated aliphatic hydrocarbon radical having the indicated number of carbon atoms
and that is unsubstituted or optionally substituted. When a subscript is used with
reference to an alkyl or other group, the subscript refers to the number of carbon
atoms that group may contain. For example, a "CrC6 alkyl" would refer to any alkyl
group containing one to six carbons in the structure. Alkyl may be a straight chain or a
branched chain.
The term "alkenyl", used either alone or in attachment with another group refers to an
unsaturated(=) aliphatic hydrocarbon radical having the indicated number of carbon
atoms and that is unsubstituted or optionally substituted. When a subscript is used
with reference to an alkyl or other group, the subscript refers to the number of carbon
atoms that group may contain. For example, a "C3-C6 alkenyl" would refer to any
alkenyl group containing three to six carbons in the structure. Alkenyl may be a
straight chain or a branched chain.
The term "alkynyl", used either alone or in attachment with another group refers to an
unsaturated( = ) aliphatic hydrocarbon radical having the indicated number of carbon
13

atoms and that is unsubstituted or optionally substituted. When a subscript is used
with reference to an alkyl or other group, the subscript refers to the number of carbon
atoms that group may contain. For example, a "C3-C6 alkynyl" would refer to any
alkenyl group containing three to six carbons in the structure. Alkynyl may be a
straight chain or a branched chain.
The "cycloalkyl" refers to a saturated aliphatic hydrocarbon radical having the
indicated number of carbon atoms and that is unsubstituted or optionally substituted.
When a subscript is used with reference to an alkyl or other group, the subscript refers
to the number of carbon atoms that group may contain. For example, a "C3-C6
cycloalkyl" would refer to any cycloalkyl group containing three to six carbons in. the
structure.
The term "aryl" refers to an aromatic group for example, which is a 6 to 10 membered
monocyclic or bicyclic ring system, which may be unsubstituted or substituted.
Representative aryl groups may be phenyl, naphthyl and the like.
The term "heteroaryl" as used herein, refers to an aromatic group for example, which
is a 5 to 10 membered monocyclic or bicyclic ring system, which has at least one
heteroatom and at least one carbon atom containing ring. The heteroaryl group may
be attached at any available nitrogen or carbon atom of any ring. Exemplary
monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl,
oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl,
tetrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.
Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl,
benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, cinnolinyl,
quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl and the like.
The term "heterocyclic ring" as used herein, refers to a cyclic ring for example, which
is a 3 to 10 membered monocyclic or bicyclic ring system, which has at least one
heteroatom and at least one carbon atom containing ring. The heterocyclic group
14

may be attached at any available nitrogen or carbon atom of any ring. Exemplary
monocyclic heterocyclic ring include groups selected from aziridine, ethylene oxide,
thiiarane, azetidine, oxirane, pyran, thiine, piperidine, piperazine, morpholine,
pyrrolidine, thiazolidine and the like.
The "alkoxy" refers to an alkyl group as defined above attached to the parent
molecular moiety through an oxygen bridge. Representative alkoxy radicals include
methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, sec-butoxy, tert-
butoxy, tert-pentyloxy, and the like.
As used herein, the term "halo" or "halogen" denotes a fluoro, chloro, bromo, or iodo
group.
All substituents (R^ R2 ....) and their further substituents described herein may be
attached to the main structure at any heteroatom or carbon atom which results in
formation of stable compound.
As used herein, the term "mammal" means a human or an animal such as monkeys,
primates, dogs, cats, horses, cows, etc.
As used herein, the term "polymorphs" pertains to compounds having the same
chemical formula, the same salt type and having the same form of hydrate/solvate
but having different crystallographic properties.
As used herein, the term "hydrates" pertains to a compound having a number of
water molecules bonded to the molecule.
As used herein, the term "solvates" pertains to a compound having a number of
solvent molecules bonded to the molecule.
15

The present invention also encompasses prodrugs of compounds of the invention, i
e second compounds which are converted to the first compounds in vivo.
In vivo cleavable esters are just one type of prodrug of the parent molecule. An in
vivo hydrolysable (or cleavable) ester of a compound of the present invention that
contains a carboxy group is, for example, a pharmaceutically acceptable ester which
is hydrolysed in the human or animal body to produce the parent acid. Suitable
pharmaceutically acceptable esters for carboxy include C1-C8 alkoxymethyl esters,
for example, methoxymethyl, C1-C8 alkanoloxymethyl ester, for example,
pivaloyloxymethyl; phthalidyl esters; C3-C8 cyc!oalkoxycarbonyloxy-C1-C8 alkyl
esters, for example, 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters,
for example, 5-methyl-1,3-dioxolen-2-onylmethyl; and CrC8 alkoxycarbonyloxyethyl
esters, for example, 1-methoxycarbonyloxymethyl; and may be formed at any
carboxy group in the compounds of the present invention.
In the context of the present specification, the term "treat" or "treatment" also
includes "prophylaxis" unless there are specific indications to the contrary. The term
"treat" or "treatment" within the context of the present invention further encompasses
to administer a therapeutically effective amount of a compound of the present
invention, to mitigate either a pre-existing disease state, acute or chronic, or a
recurring condition. This definition also encompasses prophylactic therapies for
prevention of recurring condition and continued therapy for chronic disorders.
The phrase "a therapeutically effective amount" means the amount of a compound
that, when administered to a patient for treating a disease, is sufficient to effect such
treatment for the disease. The "therapeutically effective amount" will vary depending
on the compound, mode of administration, the disease and its severity and the age,
weight, etc., of the patient to be treated.
16

When used, the expressions "comprise" and "comprising" denote "include" and
"including" but not limited to. Thus, other ingredients, carriers and additives may be
present.
Pharmaceutical Composition
In another embodiment of the invention is provided a pharmaceutical composition
comprising a therapeutically effective amount of one or more of a compound of
general formula (I). While it is possible to administer therapeutically effective quantity
of compounds of formula (I) either individually or in combination, directly without any
formulation, it is common practice to administer the compounds in the form of
pharmaceutical dosage forms comprising pharmaceutically acceptable excipient(s)
and at least one active ingredient. These dosage forms may be administered by a
variety of routes including oral, topical, transdermal, subcutaneous, intramuscular,
intravenous, intranasal, pulmonary etc.
Oral compositions may be in the form of solid or liquid dosage form. Solid dosage
form may comprise pellets, pouches, sachets or discrete units such as tablets, multi-
particulate units, capsules (soft & hard gelatin) etc. Liquid dosage forms may be in
the form of elixirs, suspensions, emulsions, solutions, syrups etc. The above
pharmaceutical compositions may contain in addition to active ingredients, excipients
such as diluents, disintegrating agents, binders, solubilizers, lubricants, glidants,
surfactants, suspending agents, emulsifiers, chelating agents, stabilizers, flavours,
sweeteners, colours etc. Some example of suitable excipients include lactose,
cellulose and its derivatives such as microcrystalline cellulose, methylcelulose,
hydroxy propyl methyl cellulose, ethylcellylose, dicalcium phosphate, mannitol,
starch, gelatin, polyvinyl pyrolidone, various gums like acacia, tragacanth, xanthan,
alginates & its derivatives, sorbitol, dextrose, xylitol, magnesium Stearate, talc,
colloidal silicon dioxide, mineral oil, glyceryl mono Stearate, glyceryl behenate,
sodium starch glycolate, Cross Povidone, crosslinked carboxymethylcellulose,
various emulsifiers such as polyethylene glycol, sorbitol fattyacid, esters,
17

polyethylene glycol alkylethers, sugar esters, polyoxyethylene polyoxypropyl block
copolymers, polyethoxylated fatty acid monoesters, diesters and mixtures thereof.
Sterile compositions for injection can be formulated according to conventional
pharmaceutical practice by dissolving or suspending the active substance in a
vehicle such as water for injection, N -Methyl-2-Pyrrolidone, propylene glycol and
other glycols, alcohols, a naturally occurring vegetable oil like sesame oil, coconut
oil, peanut oil, cotton sead oil or a synthetic fatty vehicle like ethyl oleate or the like.
Buffers, anti-oxidants, preservatives, complexing agents like cellulose derivatives,
peptides, polypeptides and cyclodextrins and the like can be incorporated as
required,
Dose is appropriately decided by its form of preparation, method of administration,
purpose of use and age, body weight and symptom of the patient to be treated and it
is not constant. But, usually, the amount of at least one of the compound selected
from the compound of the present invention, an optically active substance thereof or
a salt thereof contained in the preparation is from 0.1 microgram to 100 mg/kg per
day (for adults). Thus, the total quantity of compound in a particular pharmaceutical
composition may range from 1 to 1000 mg, at concentration levels ranging from
about 0.5% to about 90% by weight of the total composition. In a preferred
embodiment, the composition may contain 20 to 500 mg of the compound, at
concentration levels ranging from about 10% to about 70% by weight of the total
composition. Of course, the dose may vary depending upon various conditions and,
therefore, the dose less than above may be sufficient in some cases while, in other
cases, the dose more than above may be necessary. The dosage form can have a
slow, delayed or controlled release of active ingredients in addition to immediate
release dosage forms.
18

Abbreviations
TSH - Thyroid-stimulating hormone also known as thyrotropin,
T4 - Thyroxine,
T3 - Triiodothyronine,
T2 - Diiodothyronine,
rT3 - Reverse T3,
SAR - Structure activity relationship,
CB-Cannabinoid,
ACC - Acetyl-CoA Carboxylase,
NPY - Neuropeptide Y.
In the following, reaction schemes are given to disclose the syntheses of the
compounds according to the present invention.


Wherein R1, R2, R3, R4, and Z are as defined above.
In a specific embodiment, the compounds of general formula (I) is obtained from the
pyrazole derivatives of formula II or diketo derivatives of formula III as shown in
scheme-1.
The derivatives of formula II, is reacted with substituted alkyl halide in presence of a
base selected from metal hydride or metal carbonate, in polar aprotic solvent such as
tetrahydrofuran to yield the compounds of general formula (I).
Similarly, the diketo derivative of formula III on reacting with substituted hydrazine
derivatives in alcoholic solvent, yield the compound of general formula I.
The compounds of formula II is obtained by treating the compounds of formula III as
shown in Scheme 1, with hydrazine hydrate under the known condition in the
literature. The compound of formula III is prepared from the compound of formula IV
by reacting it with substituted hydroxy indanes of formula XII, XIV, XVI, or XVII or with
substituted hydroxyl indoles in the presence of base such as metal hydride or metal
carbonate in a polar aprotic solvent such as tetrahydrofuran. The compounds of
formula IV can be obtained from diketo derivative of the formula (V) by dissolving it in
an appropriate solvent such as acetonitrile in the presence of a suitable reagent, like
trimethylsilyl chloride and dimethylsulphoxide.
Alternately, the compounds of formula III is directly obtained by reacting the
compounds of formula V either with aldehyde derivatives of formula XIII in presence of
piperidine-acetic acid followed by hydrogenation in presence of catalyst such as
Pd/BaSO4 under hydrogen atmosphere or with chloro derivative of formula XV in
presence of metal hydride or metal carbonate.
In an alternate process, the compound of formula III can also be prepared from the
compound of formula VI by reacting it with appropriate acid chloride or ethyl ester in
presence of a base such as metal hydride or metal alkoxide. The compound of
20

formula VI is obtained from the compound of formula VII by reacting it with suitable
hydroxy or amino indane of formula XII, XIV, XVI, or XVII or indole derivatives in
presence of a base preferably selected from metal hydride or metal carbonate. The
compound of formula VII, as shown in scheme 1 is obtained by bromination of methyl
ketone of formula VIII in an appropriate solvent such as methanol.
The compounds of formula II and the general formula I can be prepared either from
keto derivative of formula IX or from cyano derivative of formula X .By reacting the
compounds of formula IX with an appropriate substituted or unsubstituted hydrazine
in presence of alcoholic solvent to gave compounds of general formula I and formula
II respectively. The compound of formula IX is obtained by reacting the compound of
formula VI with dimethylformamide diethyl acetal.
Alternatively, the compounds of formula X is reacted with compounds of formula XV
in presence of a base such as metal hydride, followed by treatment with appropriate
substituted or unsubstituted hydrazine in presence of alcoholic solvent to obtain
compounds of general formula I and formula II respectively
As shown in scheme 1, the cyano derivative of formula X is obtained from the
compound of formula VII by dissolving it in an organic solvent such as dimethyl
formamide, in the presence of sodium cyanide. The compound of general formula I as
obtained as per the scheme 1 are either final compounds or else can be converted to
General formula I by appropriate functional group conversion or using conventional
methods known in the art.
The intermediates of formula XII, XIII, XIV and XV can be obtained as shown in
scheme 2 as depicted herein below.
21


As shown in scheme-2, the intermediates (XII) is obtained from substituted
dihydrocoumarin XI or from 4-hydroxyindane. In a specific embodiment, the
substituted dihydrocoumarins of formula (XI), is heated with aluminum trichloride,
followed by reducing the keto group of indanone with triethylsilane in trifluoroacetic
acid to obtain the compound of formula XII. Alternately, 4-hydroxyindane is reacted
with paraformaldehyde to obatin the aldehyde substituted compound, which is either
reduced to methyl group, in presence of a catalyst such as Pd/C under hydrogen
atmosphere or to an acid by oxidizing the aldehyde using the mild oxidizing agent
such as sulfamic acid and sodium chlorite., The acid group thus.obtained , further
reacted with an appropriate alcohol in the presence of mineral acid to obtain ester or
22

using suitable amine and coupling reagent selected from carbodiimide to obtain
amide. Further the aldehyde group of formula XII is also used to obtain the cyano
derivative by using the conventional method. In another alternate process, the
halogen substituted hydroxyindane derivatives of formula (XII) is also prepared by
reacting 4-hydroxyindane with N-halosuccinimide in presence of catalytic amount of
diisopropylamine in solvents preferably tetrahydrofuran or dihaloalkane (G"= halogen)
or by treatment of sulfuryl chloride. (G"= chloro).
Compound of formula XII or 4-hydroxy indane(G"=H) is treated with hexamine in
trifluoroacetic acid, to obatin the compound of formula XIII.
In still another specific embodiment, compound of formula XV can be obtained from
the compound of formula XIII by reacting it with methyl iodide in presence of a base
followed by reduction in presence of a reducing agent such as sodium borohydride
and further reacting the intermediate so obtained with carbon tetrabromide and
triphenyl phosphine or thionyl chloride respectively. In an alternate process, the
compound of formula XIV is also obtained from the compound of formula XII or 4-
hydroxy indane by treating it with nitric acid in presence of acetic acid.
The intermediates of formula XVI and XVII can be obtained as shown in scheme 3 as
depicted herein below.


The intermediate of formula XVI is obtained from the dimethoxy indanone, by reducing
the keto group of indanone, using triethylsilane or Pd-C, followed by reacting with
boron tribromide.
For the compound of formula XVII when G"= methyl is obtained by treating 7-
methoxy-indan-4-ol (XVI) with paraformaldehyde and then reducing the intermediate
by catalyst reducing agent such as Pd/C, under hydrogen atmosphere, in the
presence of a suitable alcoholic solvent selected from methanol. Alternately, for the
compound of formula XVII when G"= ester or amide , the compounds of formula XVI
is reacted with paraformaldehyde which on further oxidation under mild condition as
described herein above can be converted to G"= acid. Further the acid group can be
reacted with an appropriate alcohol in the presence of mineral acid to obtain ester or
with using suitable amine and coupling reagent selected from carbodiimide to obtain
amide. For G"= cyano in formula XVII can be obtained by appropriately selecting
cyano substituted indanone or by converting amide derivative to cyano using
conventional method.
Alternately, the halo substituted compound of formula XVII is obtained by reacting the
7-methoxy-indan-4-ol (XVI) with /V-halosuccinimide in presence of catalytic amount of
diisopropylamine in solvents selected from tetrahydrofuran or by treatment of sulfuryl
chloride (G" = Cl).
In the following, the present invention is illuminated bv the following non-limiting
Examples.
The examples illustrate the preparation of the compounds of formula (1) and their
incorporation into pharmaceutical compositions and as such are not to be considered
or construed as limiting the scope of the invention set forth in the claims appended
thereto.
24

Example-1
(3-[4-(7-Hvdroxv-indan-4-vloxy)-3. 5-dimethvl-pvrazol-1 -vli-propionic acid)
STEP I: Preparation of 4. 7- Dimethoxy indane.
To the cooled and stirred suspension of 4,7-dimethoxyindan-1-one (35gm, 0.182
mole) in triethyl silane (105.7 gm, 0.9090 mole ), added 350 ml of trifluoroacetic acid
at 10-15°C.The stirring was continued at room temperature for 2 hours and quenched
into the water. It was extracted with ethyl acetate. The ethyl acetate layer was
washed with sodium bicarbonate solution, dried over sodium sulphate and evaporated
to give crude mass which was purified by column choromatography using 5% ethyl
acetate in hexane (22.5 gm).
Yield: 69.3%
1H-NMR (400 MHz, DMSO-d6) 6 6.67(2H, s), 3.706(6H, s), 2.74-2.78(4H, m),
1.95- 2.02(2H, m)
STEP-H: Preparation of 7-methoxvindan-4-ol
To the clear solution of 4, 7-dimethoxyindane (22.5 gm, 0.126 mole) in 400 ml
methylene chloride, added boron tribromide (12.27 ml, 0.1298 mole) at 0°C. After 2
hours stirring at 0-10°C, 100ml water was added and then the reaction mixture was
extracted with methylene chloride. The methylene chloride layer was dried over
sodium sulphate and distilled off to give a crude mass which was purified by column
chromatography using 7% ethyl acetate in hexane (9.0 gm).
Yield: 43.4%
1H-NMR (400MHz, DMSO-d6): d 8.66(1 H,s),6.493-6.558(2H,m), 3.66(3H s), 2.71-
2.75(4H,m),1.92-2.00(2H,m)
STEP-III: Preparation of 4-(7-Methoxv-indan-4-vloxv)-3.5-dimethvl-1H-pvrazole
25

To the suspension of 60% sodium hydride (2.0 gm, 0.051 moles) in 20 ml
tetrahydrofuran added a solution of 7-methoxyindan-4-ol (7.0 gm, 0.042 moles) in
30ml tetrahydrofuran at room temperature. After 1 hour stirring added a solution of 3-
chloro 2, 4-pentanedione (9.0 ml, 0.075 mole) in 20 ml tetrahydrofuran followed by
addition of potassium bromide (3.0 gm, 0.025 mole).The reaction mixture was stirred
at 70°C for 6 hours. The water was added and extracted with ether. The ether layer
was separated and distilled off to give an oily mass which was partially purified
through a column using 2% ethyl acetate in hexane to give crude mass (2.7 gm) .The
obtained crude mass was stirred with hydrazine hydrate (1 ml) in 20 ml ethanol at
10°C. Ethanol was evaporated to dryness. The obtained residue was partitioned
between water and ethyl acetate. The separated ethyl acetate layer was dried over
sodium sulphate and distilled off to give desired product (2.0 gm).
Yield: 18.1 % (in two steps)
1H-NMR (400 MHz, DMSO-d6): d 12.12(1 H,s),6.602-6.624(1H,d), 6.287-6.309(1 H,d),
3.696(3H,s), 2.87-2.907(2H,t) 2.784-2.820(2H,t), 2.003-2.071 (5H,m), 1.91(3H,s).
STEP-IV: Preparation of 3-f4-(7-Methoxv-indan-4-vloxv)-3. 5-dimethvl-pvrazol-1-vn-
propionic acid ethvl ester
To the suspension of 60% sodium hydride (0.372 gm 0.0093 mole) in 10 ml
tetrahydrofuran, added solution of pyrazole derivative obtained in step-Ill (2.0 gm,
0.00775 mole) in 10 ml tetrahydrofuran under nitrogen atmosphere at room
temperature After 1 hour stirring at room temperature, a solution of 3-chloro ethyl
propionate (1.15 gm, 0.0084 mole) in 10 ml tetrahydrofuran was added to the reaction
mixture It was stirred at room temperature for 4 hours. The reaction mixture was
poured into the water, extracted with ethyl acetate. The ethyl acetate layer was dried
over sodium sulphate and distilled off. The obtained crude mass was purified by
column chromatography using 20% ethyl acetate in hexane to give the pure product
(0.850 gm).
26

Yield: 30.6 %
1H-NMR (400 MHz, DMSO-d6 ): d 6.592-6.614(1 H,d),6.257-6.278(1H,d), 4.14-
4.173(2H,t),4.03-4.08(2H,q)I 3.696(3H,s), 2.86-2.89(2H,t), 2.78-2.83(4H,m), 1.99-
2.08(5H,m), 1.89(3H,s), 1.15-1.86(3H,t).
STEP-V: Preparation of 3-r4-(7-Hvdroxv-indan-4-vloxv)-3. 5-dimethvl-pvrazol-1-vll-
propionic acid
To the clear solution of ethyl ester obtained in step-IV (0.85 gm, 0.00237 moles) in 15
ml methylene chloride, added a solution of boron tribromide (1.0 ml, 0.01057 moles) in
15 ml methylene chloride at 0°C. Reaction mass was stirred for 2 hours at room
temperature, 10 ml water was added and extracted with ethyl acetate. The ethyl
acetate layer was dried over sodium sulphate and distilled off to give a solid product
(230 mg).
Yield: 30.6 %
1H-NMR (400 MHz, DMSO-d6):): d 12.28-12.36(1 H,bs), 8.68-8.89(1 H,s), 6.41-6.44
(1H.d), 6.14-6.17(1 H,d), 4.09-4.13(2H,t), 2.82-2.86(2H,t), 2.71-2.78(4H,m), 1.98-2.04
(5H,m), 1.88(3H,s)
Mass:315(M+-1)
Following compounds were prepared using the procedure mentioned in reaction
scheme as depicted above:

Table-1:
CompdNo. NAME 'H-NMR (400 MHz, DMSO-d6) MASS IR(KBr,CM"1)
1 3-[4-(7-Hydroxy-indan-4-yloxy)-3, 5-dimethyl-pyrazol-1-yl]-propionic acid 5 12.28-12.36(1 H,bs), 8.68-8.89(1 H,bs), 6.41-6.44 (1H,d),6.14-6.17(1 H,d), 4.09-4.13(2H,t),2.82-2.86(2H,t), 2.71 -2.78(4H,m),1.98-2.04 (5H,m), 1.88(3H,s) 315(M+-1) 3215,1702,1653.1599
27

Compd NAME 1H-NMR(400MHz, DMSO-d6) MASS IR
No. (KBr,
CM"1)
2 3-[4-(1H-lndol-5-ylmethyl)-3, 5- 5 12.20-12.40(1H,bs), 298 3392,
dimethyl-pyrazol-1 -yl]- 10.93(1H,s), 7.21-7.27(3H,m), (M++1) 1710,
propionic acid 6.83-6.86(1 H,dd), 6.31- 1558,
6.32(1 H,t),4.09-4.12(2H,t) 1507
3.69(2H,s), 2.69-2.73(2H,t),
2.17(3H,s),1.99(3H,s).
3 7-[3, 5-Dimethyl-1-(1H-tetrazol- 6 8.85(1 H,s), 6.43-6.45(1 H,d), 325 3313,
5-ylmethyl)-1 H-pyrazol-4- 6.20-6.22(1 H,d), 5.55(2H,s), 2.83- (M+-1) 1589,
yloxy]-indan-4-ol 2.86(2H,t), 2.75-2.78(2H,t), 1553,
2.11(3H,s), 2.00-2.06 (2H,m), 1484
1.88(3H,s).
4 7-{3, 5-Dimethyl-1-[2-(1H- 5.8.68-8.95(1 H,bs), 6.41- 339 3310,
tetrazol-5-yl)-ethyl]-1 H-pyrazol- 6.43(1H,d), 6.08-6.10(1 H,d), (M+-1) 1646,
4-yloxy}-indan-4-ol 4.32-4.35(2H,t), 3.35-3.39(2H,t), 1553,
2.74-2.82(4H,m), 2.01- 1486
2.05(2H,m), 1.89(3H,s),
1.87(3H,s).
5 {2-[4-(7-Hydroxy-indan-4- 6 12.64-12.66(1H,bs), 8.82(1 H,s) 358 3346,
yloxy)-3,5-dimethyl-pyrazol-1 - 8.25-8.28(1 H,t), 6.42-6.44(1 H,d), (M+-1) 1660,
yl]-acetyl amino)-acetic acid 6.20-6.22(1 H,d), 4.69(2H,s), 1553,
3.79-3.80(2H,d),2.84-2.87(2H,t), 1491
2.74-2.78(2H,t), 1.99-2.06 (5H,m),
1.88(3H,s).
6 2-[4-(7-Hydroxy-indan-4- 6 12.44-12.53(1 H,bs), 8.75- 368(M+ 3226,
yloxy)-3, 5-dimethyl-pyrazol-1- 9.02(1 H,bs), 6.43-6.45(1 H,d), -1) 1712,
yl]-N-(1 H-tetrazol-5-yl)- 6.20-6.22(1 H,d), 5.03(2H,s), 1620,
acetamide 2.85-2.89(2H1t),2.75-2.79(2H,t), 1555
1.99-2.07(5H,m), 1.89(3H,s).
7 3-[4-(7-Hydroxy-indan-4- 612.41(1H,s), 9.00(1 H,s), 368.99 3108,
yloxy)-3-thiophen-2-yl-pyrazol- 7.55(1 H,s), 7.43-7.44(1 H,d), 7.28- (M+-1) 1708,
1 -yl]-propionic acid 7.29(1 H,d), 7.04-7.06(1 H,m), 1564,
6.46-6.54(2H,m), 4.23-4.26(2H,t), 1486
2.73-2.84(6H,m), 1.96-
2.06(2H,m).
8 7-[1 -(1 H-Tetrazol-5-ylmethyl)- 6 9.07(1 H,s), 7.69(1 H,s), 7.46- 379 3243,
3-thiophen-2-yl-1 H-pyrazol-4- 7.48(1 H,dd), 7.34-7.35(1 H,dd), (M+-1) 1732,
yloxy]-indan-4-ol 7.06-7.08(1 H,m), 6.61- 1550,
6.64(1 H,d), 6.52-6.55(1 H,d), 1483
5.67(2H,s), 2.77-2.86 (4H, m),
1.99-2.06 (2H,m)
9 3-[4-(7-Hydroxy-6-methyl- 6 12.30-12.32(1H,bs), 8.11(1H,s), 327(M+ 3388,
indan-4-ylmethyl)-3, 5- 6.41 (1H,S), 4.08-4.11(2H,t), -1) 1686,
dimethyl-pyrazol-1 -yl]- 3.43(2H,s), 2.68-2.77(6H,m), 1616,
propionic acid 2.09(3H,s),2.03(3H,s),1.94- 1489
1.99(2H,m), 1.91(3H,s).
28

CompdNo. NAME 'H-NMR (400 MHz, DMSO-d6) MASS IR(KBr,CM'1)
10 5-[4-(7-Hydroxyindan-4-yloxy)-3,5-dimethylpyrazol-1 -ylmethyl]-1 H-pyrazol-3-ol 5 8.81-8.83(1 H,bs), 6.40-6.42(1H,d), 6.14- 6.16 (1H,d),5.22(1 H,bs), 5.01 (2H,s), 2.80-2.84(2H,t), 2.72-2.76(2H,t), 1.93-2.06 (5H,m), 1.84 (3H,s). 339(M+-1) 3143,1581,1546,1483
11 2-[4-(7-Hydroxy-6-methyl-indan-4-ylmethyl)-3, 5-dimethyl-pyrazol-1-yl] - aceticacid 6 12.77-12.96 (1H,bs),8.13(1H,s), 6.44(1 H,s),4.81 (2H,s), 3.45(2H,s), 2.69-2.77(4H,m), 1.89-2.03(11H,m). 312.9(M+-1) 3392,1730,1569,1485
12 7-[1-(2-Hydroxy-ethyl)-3,5-dimethyl-1 H-pyrazol-4-ylmethyl]-5-methyl-indan-4-ol 6 8.11(1H,s), 6.43(1 H,s), 4.79-4.82(1 H,t), 3.93-3.96(2H,t), 3.61-3.65(2H,m), 3.43 (2H,s), 2.69-2.77(4H,m), 2.08(3H,s),2.03(3H,s), 1.92-1.99(5H,m). 301(M++1) 3320,3167,1570,1481
13 [4-(1 H-lndol-5-ylmethyl)-3,5-dimethyl-pyrazol-1 -yl]-aceticacid 6 12.95-12.99(1 H.bs),10.95(1 H,s), 7.25-7.27(2H,m),7.22(1 H,s), 6.85-6.87(1 H,dd),6.315-6.319(1 H,d), 4.78(2H,s),3.71 (2H,s), 2.10(3H,S),1.99(3H,s). 284(M++1) 3401,1712,1640,1470
Following compounds can be prepared using the procedure mentioned in reaction
scheme as depicted above:
14.3-[4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-propionic
acid
15.7-[3,5-Dimethyl-1 -(1 H-tetrazol-5-ylmethyl)-1 H-pyrazol-4-ylmethyl]-5-methyl-
indan-4-ol
16.7-[3,5-Diisopropyl-1-(1H-tetrazol-5-ylmethyl)-1H-pyrazol-4-ylmethyl]-5-methyl-
indan-4-ol
17.3-[3,5-Dicyclopropyl-4-(7-hydroxy-indan-4-yloxy)-pyrazol-1 -yl]-propionic acid
18.3-[4-(7-Hydroxy-6-methyl-indan-4-ylmethyl)-3,5-diisopropyl-pyrazol-1-yl]-
propionic acid
19. [3,5-Diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)-pyrazol-1 -yl]-acetic acid
29

20.3-[3,5-Diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-propionic
acid
21.7-[3,5-Diethyl-1-(1 H-tetrazol-5-ylmethyl)-1 H-pyrazol-4-ylmethyl]-5-methyl-
indan-4-ol
22.3-[4-(1 H-lndol-5-yloxy)-3,5-dimethyl-pyrazol-1 -yl]-propionic acid
23.[4-(1 H-lndol-5-yloxy)-3,5-dimethyl-pyrazol-1 -yl]-acetic acid
24.[4-(7-Hydroxy-6-methyl-indan-4-ylmethyl)-3,5-diisopropyl-pyrazol-1-yl]-acetic
acid
25.[4-(7-Hydroxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1 -yl]-acetic acid
26.2-[4-(1 H-lndol-5-ylmethyl)-3,5-dimethyl-pyrazol-1 -yl]-ethanol
27.3-[3,5-Diethyl-4-(1 H-indol-5-ylmethyl)-pyrazol-1 -yl]-propionic acid
28. [3,5-Dicyclopropyl-4-(7-hydroxy-indan-4-yloxy)-pyrazol-1 -yl]-acetic acid
29.2-[4-(7-Hydroxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-yl]-propionic acid
30.{2-[3,5-Diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-
acetylamino}-acetic acid
31.1 -{2-[3,5-Diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)-pyrazol-1 -yl]-acetyl}-
pyrrolidine-2-carboxylic acid
32.[4-(6-Chloro-7-hydroxy-indan-4-ylmethyl)-3,5-diethyl-pyrazol-1 -yl]-acetic acid
33.2-[3,5-Diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-N-
isopropyl-acetamide
34. [3,5-Diethyl-4-(7-hydroxy-6-pyrrolidin-1 -ylmethyl-indan-4-ylmethyl)-pyrazol-1 -
yl]-acetic acid
35.3-[3,5-Diethyl-4-(7-hydroxy-6-pyrrolidin-1 -ylmethyl-indan-4-ylmethyl)-pyrazol-1 -
yl]-propionic acid
36.3-[3,5-Diethyl-4-(7-methoxy-6-methoxymethyl-indan-4-ylmethyl)-pyrazol-1-yl]-
propionic acid
37.{3,5-Diethyl-4-[7-hydroxy-6-(pyrrolidine-1-carbonyl)-indan-4-ylmethyl]-pyrazol-
1 -yl}-acetic acid
30

38.[3,5-Diethyl-4-(7-methoxy-6-methoxymethyl-indan-4-ylmethyl)-pyrazol-1-yl]-
acetic acid
39.3-[4-(6-Chloro-7-hydroxy-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-propionic
acid
40.3-[4-(6-Chloro-7-hydroxy-indan-4-ylmethyl)-3,5-diethyl-pyrazol-1-yl]-propionic
acid
41.3-{3,5-Diethyl-4-[7-hydroxy-6-(pyrrolidine-1-carbonyl)-indan-4-ylmethyl]-
pyrazol-1-yl}-propionic acid
42.2-[3,5-Diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-N-(1H-
tetrazol-5-yl)-acetamide
43.N-(4-Chloro-phenyl)-2-[3,5-diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)-
pyrazol-1 -yl]-acetamide
BIOLOGICAL ACTIVITY
With the contemplation that metabolically active thyroid like compounds which will
have minimal or no effect on appetite as well as will be lesser affinity towards TRs
would be better effective even at lower dose as an anti-obesity agents, compounds of
the present invention were tested for their effect on 02 consumption (metabolic effect)
and food consumption (appetite stimulant) and also to assess transcriptional activity of
thyroid hormone receptor by in vitro TRE reporter assay for TRa1 and TR|31.
Effect of compounds on transcriptional activity of thyroid hormone receptor
(THR): THR al and THR b1.
Assay procedure:-
C0S7 cells were transiently transfected with pGAL4/Thyroid al or pGAL4/Thyroid b1
and pLucPur. The cells were cotransfected with pLacZNorm for normalization of
transfection efficiency. Transfected cells were then treated with different
concentrations of TRC compounds, vehicle for 24 hours.
31

Cells were the lysed and luciferase activity was monitored in all samples. Results were
expressed as fold activation as compared to vehicle control.
Results :- Thyroid (al/ b1) transactivation in COS7 cells.
Table- 2:

Compound Cone. al b1
(uM) Fold Fold
Activation Activation
Vehicle 10mM 1 1
T3 20 35 29
0.02 17 13
T2 20 20 27
2 14 16
0.2 7 4
0.02 1 2
1 20 1 1
2 20 1 1
3 20 1 1
7 20 3 1
8 20 3 1
9 20 2.5 2
The compounds of the present invention exhibited significantly less transcriptional
activation of THR (al) or THR (pi) as compared to T3 and T2 under experimental
conditions.
In Vivo Assay
Methodology:
C57BL6 mice (14-18 weeks age), fed with 8- 12 weeks HFD (45% kcal fat) were
used for the study. The mice were placed in individual housing for one week.
The mice were then kept in oxymax cages for 48 h for acclimatization. Basal
recordings of oxygen consumption and carbon dioxide production for each
mouse were recorded with indirect open circuit calorimeter (Oxymax, Columbus
Instruments, USA(Ling fu et al., Endocrinology(2004); 145(6); 2591-3). On the
32

basis of body weight and basal oxygen consumption, mice were randomized and
divided into two groups.
I) Vehicle treated group
II) Test compound treated group
III)
The mice were treated with vehicle and test compounds intraperitoneally for 7
days. On the day 8, Oxygen consumption was measured for individual mouse 30
min after the drug treatment and % change with respect to vehicle is calculated.
During the experiment food consumption was monitored daily. At the end of the
experiment the animals are scarified and the heart weights were recorded.
Results:
Table-3: Effect of test compounds on oxygen consumption, feed consumption,
body weight and heart weight

CompoundNos. Dose(uM/kg) increase in02 cons increase in foodconsumptionweight withreference tovehicle increase inHeart weightwithreference tovehicle
T2 0.05 *
T2 0.5 ** + +
T2 2 ** ++ ++
T2 5 ** +++ ++
1 11 * No change No change
2 11 * No change No change
3 11 ** No change No change
6 11 * No change No change
7 11 ** No change No change
8 11 ** No change No change
9 11 ** No change No change
For change in oxygen consumption: * = Increase < 5 %, **= Increase >5%
For change in food consumption: + = Increase by 5-10 %, ++= Increase by 10-20%, +++
increase by >20%
For change in heart weight: + = Increase by 10-15 %, ++= Increase by 15-20%, +++ increase
by >20%
The test compounds of the present invention showed increase in the 02 consumption
without influencing the food consumption.
33

We Claim:
1. A compound of general formula (I)

or its pharmaceutically acceptable salts and their hydrates, solvates, atropisomers,
regioisomers, enantiomers, diastereomers, tautomers, polymorphs, and prodrugs.
Wherein, R1 and R3 is same or different, and is independently selected from H, C1-C6
alkyl, C3-C7 cycloalkyl, halo, CN, CF3, -O-(C1-C6)alkyl, -CO2-(C1-C6)alkyl, -CONH-(C1
C6)alkyl, -CONH-aryl, -CONH-heteroaryl,- CONR5 , -C1-C3alkyl-aryl , -C1-C3alkyl-
heteroaryl, -NH-(C1-C6)alkyl, , -NHaryl, -NH-SO2-(C1-C6)alkyl , -CH2-NH-(C1-C6)alkyl,
-CH2-O-(C1-C6)alkyl, -C1-C3alkyl-NR5 R6, R7, wherein C1-C6alkyl and C3-C6 cycloalkyl
is optionally substituted with one or more substituents selected from (C1-C6)alkyl, halo,
cyano, -OH, oxo, -COOH, -O-(C1-C6)alkyl, -O-benzyl, -COO-(C1-C6)alkyl, -CONH-
(C1-C6)alkyl, -CONR5, -CONH-aryl, -CONH-heteroaryl or -CH2NR5;
R2 is selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)alkenyl, (C3-C6 )alkynyl,
-C(O)-(C1-C3)alkyl-COOH, -C(O)-C(O)O-(C1-C6)alkyl , -C(O)-(C1-C3 )alkyl-NH-(C1
C6)alkyl, -C(O)-O-(C1-C6)alkyl, -C(O)NR5, -C(O)NH-(C1-C6)alkyl, -C(O)-(C1
C3)alkylaryl, -C(O)-(C1-C3)alkylheteroaryl, R6, R7, (C1-C3)alkyl-R6, (C1-C3)alkyl-R7,
wherein said (C1-C6 )alkyl, (C3-C6 )cycloalkyl, (C3-C6 )alkenyl, (C3-C6)alkynyl being
optionally substituted with one or more substituents selected from perhaloalkyl, Oxo, -
C(O)OH, -C(O)-O-(C1-C3)alkyl, -C(O)-O-(C1-C3)alkylaryl, -C(O)-O-(C1-C3)alkyl
heteroaryl, -CONH(C1-C3)alkyl, -C(O)NH-aryl, -C(0)NH-heteroary!, -CONR5
35

CONHNH2, -C(=NH)NH-(C1-C6)alkyl, -C(=NH)NH2, -C(O)-R8, -C(O)NHSO2(C1-C6)
alkyl, -C(O)NHSO2-aryl, -C(O)NHOH, -C(O)NHSO2-heteroaryl, -C(O)NHNH-(C1
C6)alkyl, -C(O)NHNH-aryl, -CONH-(C1-C2)alkyl-aryl, -C(O)NH-(C1-C2) alkyl-
heteroaryl, -CH2NR5, -NH2, -NH-(C1-C6)alkyl, , -NH-C(O)-O-(C1-C3)alkyl-NH-C(O)-(C1
C3)alkyl, -NHC(O)-aryl, -NHC(O)-(C1-C3)alkylaryl --NHC(O)-heteroaryl, -NH-C(O)NR5,
-NH-C(O)NH-aryl, -NHC(O)NH-(C1-C6)alkyl , -NHSO2(C1-C6)alkyl, -NH-SO2-aryl, -
NH-SO2-heteroaryl, halo, cyano, -OH, -O-(C1-C6)alkyl, -O-aryl, -O-heteroaryl ,-O-(C1
C2) alkyl-aryl, -SO3H, -SO2NH-aryl, -S02NH-heteroaryl or -S02NH-(C1-C6)alkyl ,R6 or
R7;
R5 together with Nitrogen atom to which it is attached form a saturated or unsaturated
(C3-C6) membered ring, which may be optionally substituted with one or more
substituents selected from oxo, -COOH, halo,-OH, -O-(C1-C6)alkyl, or -(C1-C6)alkyl;
R6 is selected from phenyl or 5-8 membered heteroaryl containing 1-4 heteroatoms
selected from O, N, S, wherein said heteroaryl or phenyl ring being optionally
substituted with one or more substituents selected from halogen, -OH, O-(C1-C6)alkyl,
-perhaloalkyl , (C1-C6)alkyl, (C3-C6)cycloalkyl, cyano, -COOH, -C(O)O-(C1-C6)alkyl, -
C(O)O-CH2-aryl, -C(O)O-aryl, -CONH(C1-C3)alkyl, -NH2, -NH-(C1-C6)alkyl, -NHC(O)-
(C1-C6)alkyl, -NHC(O)-aryl, -NHSO2(C1-C6)alkyl, -CONH2, -SO2-(C1-C6)alkyl, -
NHSO2(C1-C6)alkyl or -COR8;
R7 is a 3-6 membered heterocyclic ring containing 1 -4 heteroatom selected from O, N
and S, and the said heterocyclic ring being optionally substituted with one or more
substituents selected from oxo, halogen, -O-(C1-C6)alkyl, -OH, -CF3, (C1-C6)alkyl, (C3-
C6)cycloalkyl, cyano, -COOH, -C(O)O-(C1-C6)alkyl, -C(O)O-CH2-aryl, -C(O)O-aryl, -
NH2, -NH-(C1-C6)alkyl, -NHC(O)- (C1-C6)alkyl, -NHC(O)-aryl, -CONH2, -SO2-(C1
C6)alkyl, -NHSO2(C1-C6)alkyl or -COR8;
R8 is an amino acid which is linked through its nitrogen atom;
36

Z = 0, CH2orN;
R4 is selected from P, Q or T

R9 is selected from -OH, -O-alkyl, halogen, -C(O)O-(C1-C6)alkyl, -C(O)NHR8 -OC(O)-
(C1-C6)alkyl, -O-perhaloalkyl, -OC(O)O-(C1-C6)alkyl, -CONR5 ,-NHCO-(C1-C6)alkyl, -
NHC(O)-O--(C1-C6)alkyl, -NHC(O)-O-aryl -NHSO2-(C1-C6)alkyl, -NHSO2-aryl or -
NHCONR5;
R10 is selected from H, Halogen, (C1-C6)alkyI, alkoxy, -NHCO-(C1-C6)alkyl, -NHSO2-
(C1-C6)alkyl or -NH-SO2-aryl;
R11 is H, (C1-C6)alkyl, -CO-(C1-C6)alkyl, -SO2-(C1-C6)alkyl or-SO2-aryl;
G' is selected from H, halogen or (C1-C6)alkyl;
G" is selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, halogen,
perhaloalkyl, CN, CHO, (C1-C3)alkylaryl, (C1-C6)alkyl-O-(C1-C6)alkyl, -CH2R9, -
CH2aryl -CH2NR5, -COOH, -C(O)O(C1-C6)alkyl, -CONH-(C1-C6)alkyl
CONR5, -SO2NR5, -SO2NH-(C1-C6)alkyl, -SO2NH-aryl; n may be one or two.
2. The compound as claimed in claim 1, wherein R4 is selected from P or Q wherein,
said P and Q is further substituted by substitutents represented by R9' R10, R11, G' and
G".
3. The compound as claimed in claim 1, wherein the heteroaryl ring is mono or bicyclic
wherein said monocyclic ring is selected from the group consisting of pyrrolyl,
37

pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,
isothiazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, triazolyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl and triazinyl and the bicyclic ring is selected from the group
consisting of indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl,
quinolinyl, isoquinolinyl, benzimidazolyl, cinnolinyl, quinoxalinyl, indazolyl,
pyrrolopyridyl and furopyridinyl.
4. The compound as claimed in claim 1, wherein the said compound is selected from
the group consisting of:
a) 3-[4-(7-Hydroxy-indan-4-yloxy)-3, 5-dimethyl-pyrazol-1 -yl]-propionic acid
(Compound 1)
b) 3-[4-(1 H-lndol-5-ylmethyl)-3, 5-dimethyl-pyrazol-1 -yl]-propionic acid
(Compound 2)
c) 7-[3, 5-Dimethyl-1 -(1 H-tetrazol-5-ylmethyl)-1 H-pyrazol-4-yloxy]-indan-4-ol
(Compound 3)
d) 7-{3, 5-Dimethyl-1 -[2-(1 H-tetrazol-5-yl)-ethyl]-1 H-pyrazol-4-yloxy}-indan-4-ol
(Compound 4)
e) {2-[4-(7-Hydroxy-indan-4-yloxy)-3, 5-dimethyl-pyrazol-1-yl]-acetyl amino}-
acetic acid (Compound 5)
f) 2-[4-(7-Hydroxy-indan-4-yloxy)-3, 5-dimethyl-pyrazol-1 -yl]-N-(1 H-tetrazol-5-
yl)-acetamide(Compound 6)
g) 3-[4-(7-Hydroxy-indan-4-yloxy)-3-thiophen-2-yl-pyrazol-1 -yl]-propionic acid
(Compound 7)
h) 7-[1 -(1 H-Tetrazol-5-ylmethyl)-3-thiophen-2-yl-1 H-pyrazol-4-yloxy]-indan-4-ol
(Compound 8)
i) 3-[4-(7-Hydroxy-6-methy!-indan-4-ylmethyl)-3, 5-dimethyl-pyrazol-1 -yl]-
propionic acid (Compound 9)
j) 5-[4-(7-Hydroxyindan-4-yloxy)-3,5-dimethylpyrazol-1 -ylmethyl]-1 H-pyrazol-
3-ol (Compound 10)
k) 2-[4-(7-Hydroxy-6-methyl-indan-4-ylmethyl)-3! 5-dimethyl-pyrazol-1-yl] -
acetic acid (Compound 11)
38

I) 7-[1 -(2-Hydroxy-ethyl)-3,5-dimethyl-1 H-pyrazol-4-ylmethyl]-5-methyl-indan-
4-ol (Compound 12)
m) [4-(1 H-lndol-5-ylmethyl)-3,5-dimethyl-pyrazol-1 -yl]-acetic acid (Compound
13).
n) 3-[4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-
propionic acid(Compound 14)
o) 7-[3,5-Dimethyl-1 -(1 H-tetrazol-5-ylmethyl)-1 H-pyrazol-4-ylmethyl]-5-methyl-
indan-4-ol(Compound 15)
p) 7-[3,5-Diisopropyl-1-(1 H-tetrazol-5-ylmethyl)-1 H-pyrazol-4-ylmethyl]-5-
methyl-indan-4-ol(Compound 16)
q) 3-[3,5-Dicyclopropyl-4-(7-hydroxy-indan-4-yloxy)-pyrazol-1-yl]-propionic
acid(Compound 17)
r) 3-[4-(7-Hydroxy-6-methyl-indan-4-ylmethyl)-3,5-diisopropyl-pyrazol-1 -yl]-
propionic acid(Compound 18)
s) [3,5-Diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-acetic
acid(Compound 19)
t) 3-[3,5-Diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-
propionic acid(Compound 20)
u) 7-[3,5-Diethyl-1 -(1 H-tetrazol-5-ylmethyl)-1 H-pyrazol-4-ylmethyl]-5-methyl-
indan-4-ol(Compound 21)
v) 3-[4-(1 H-lndol-5-yloxy)-3,5-dimethyl-pyrazol-1 -yl]-propionic acid(Compound
22)
w) [4-(1 H-lndol-5-yloxy)-3,5-dimethyl-pyrazol-1 -yl]-acetic acid(Compound 23)
x) [4-(7-Hydroxy-6-methyl-indan-4-ylmethyl)-3,5-diisopropyl-pyrazol-1-yl]-
acetic acid(Compound 24)
y) [4-(7-Hydroxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1 -yl]-acetic
acid(Compound 25)
z) 2-[4-(1 H-lndol-5-ylmethy!)-3,5-dimethyl-pyrazol-1 -yl]-ethanol(Compound 26)
aa) 3-[3,5-Diethyl-4-(1 H-indol-5-ylmethyl)-pyrazol-1 -yl]-propionic
acid(Compound 27)
39

bb) [3,5-Dicyclopropyl-4-(7-hydroxy-indan-4-yloxy)-pyrazol-1-yl]-acetic
acid(Compound 28)
cc) 2-[4-(7-Hydroxy-indan-4-yloxy)-3,5-dimethyl-pyrazol-1-yl]-propionic
acid(Compound 29)
dd) {2-[3,5-Diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-
acetylaminoj-acetic acid(Compound 30)
ee) 1 -{2-[3,5-Diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)-pyrazol-1 -yl]-
acetyl}-pyrrolidine-2-carboxylic acid(Compound 31)
ff) [4-(6-Chloro-7-hydroxy-indan-4-ylmethyl)-3,5-diethyl-pyrazol-1-yl]-acetic
acid(Compound 32)
gg) 2-[3,5-Diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-N-
isopropyl-acetamide(Compound 33)
hh) [3,5-Diethyl-4-(7-hydroxy-6-pyrrolidin-1-ylmethyl-indan-4-ylmethyl)-pyrazol-
1-yl]-acetic acid(Compound 34)
ii) 3-[3,5-Diethyl-4-(7-hydroxy-6-pyrrolidin-1-ylmethyl-indan-4-ylmethyl)-
pyrazol-1-yl]-propionic acid(Compound 35)
jj) 3-[3,5-Diethyl-4-(7-methoxy-6-methoxymethyl-indan-4-ylmethyl)-pyrazol-1-
ylj-propionic acid(Compound 36)
kk) {3,5-Diethyl-4-[7-hydroxy-6-(pyrrolidine-1-carbonyl)-indan-4-ylmethyl]-
pyrazol-1-yl}-acetic acid(Compound 37)
II) [3,5-Diethyl-4-(7-methoxy-6-methoxymethyl-indan-4-ylmethyl)-pyrazol-1 -yl]-
acetic acid(Compound 38)
mm) 3-[4-(6-Chloro-7-hydroxy-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-
propionic acid(Compound 39)
nn) 3-[4-(6-Chloro-7-hydroxy-indan-4-ylmethyl)-3,5-diethyl-pyrazol-1-yl]-
propionic acid(Compound 40)
oo) 3-{3,5-Diethyl-4-[7-hydroxy-6-(pyrrolidine-1-carbonyl)-indan-4-ylmethyl]-
pyrazol-1-yl}-propionic acid(Compound 41)
pp) 2-[3,5-Diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)-pyrazol-1 -yl]-N-(1 H-
tetrazol-5-yl)-acetamide(Compound42)
40

qq) N-(4-Chloro-phenyl)-2-[3,5-diethyl-4-(7-hydroxy-6-methyl-indan-4-ylmethyl)
pyrazol-1 -yl]-acetamide(Compound 43)
5. A pharmaceutical composition comprising a therapeutically effective amount of
one or more of a compound of formula (I) as defined in claim 1, in association with
a pharmaceutically acceptable salts, diluents or carriers.
6. Use of one or more compound represented by general formula (1), as defined in
claim 1, in the manufacture of medicament for the treatment of obesity in a living
mammalian organism, including human being.
7. A method of treating obesity in a living mammalian organism, including human
being, comprising administering to the said living mammalian organism in need
thereof a therapeutically effective amount of a compound of formula (I) as defined
in claim 1.
8. A compound of general formula (I), its manufacture and medicament for the
treatment of obesity, as herein described with reference to the examples
accompanying the specification.
41

The present invention relates to the novel thyroid like compounds of general formula I,
useful for the treatment of obesity and to a method for preparation, composition
containing such compounds and use of such compounds and composition in
medicine. Further, compounds of formula I has significantly low binding affinity to
thyroid receptors The invention also relates to the use of the above-mentioned
compounds for the preparation of a medicament for treating obesity.