FIELD OF THE INVENTION:
The present invention relates to novel compounds of general formula (I), or
pharmaceutically acceptable salts thereof, wherein the substituents in formula (I) have the
meanings as defined in the description that follows.

The present invention also relates to a process for the preparation of the said novel
compounds, or their pharmaceutical!}' acceptable salts.
The said compounds of the general formula-I are potent inhibitors of Acetyl-CoA
carboxylase (ACC) in mammals and by virtue of its inhibitory action on an enzyme are
useful in the treatment of obesity, insulin resistance, diabetes and atherosclerosis. The
present invention also relates to pharmaceutical compositions containing them and to
their use as therapeutic agents.
BACKGROUND OF THE INTENTION:
Metabolic syndrome is a common clinical disorder that is defined as the presence of
increased insulin concentrations in association with other disorders including visceral
obesity, hyperlipidemia and dyslipidemia, hyperglycemia hypertension, and sometimes
hyperuricemia and renal dysfunction. Metabolic syndrome is considered by man}' as a
common basic defect for type-2 diabetes, obesity, dyslipidemia, and hypertension,
leading to a clustering of these diseases. This syndrome has particular significance since
it has been shown to be an antecedent of both type-2 diabetes and atherosclerosis, with
cardiovascular events accounting for the majority of deaths.

Recent studies have suggested that abnormal fatty acid metabolism may be a; the core of
metabolic syndrome. (Bjomtorp. 1994; Depres and Marette, 1994; McGarry. 1992).
In recent years obesity has been clearly emerged as an independent major risk factor for
serious chronic diseases like type 2 diabetes, hypertension, stroke, atherosclerosis
particularly coronary artery disease and certain form of cancers Obesity is i. measure of
the fat deposited in the adipose tissue in response to food intake, fatty acid and
triglyceride synthesis, fatty acid oxidation, and energy consumption. Excess food
provides not only the timely energy needs of the body, but promotes glycogen synthesis
and storage in liver and muscle and fatty acid and triglyceride synthesis and storage in the
fat tissues. Calorie restriction or starvation promotes glycogenolysis that supplies glucose
where needed and lipolysis that supplies fatty acids for oxidation and energy production.
Insulin and glucagon are the hormones that coordinate these processes. Currently
available antiobesity medications like sibutramine and oriistat has very limited
therapeutic utility because of prominent side effects like hypertension with sibutramine
and faecal incontinence and urgency with oriistat. Malonyl-CoA is the key intermediate
in fatty acid synthesis, and acts as a second messenger that regulates energy levels (ATP)
through fatty acid oxidation, which in turn affects fatty acid synthesis and carbohydrate
metabolism. The defect in carbohydrate and fatty fatty acid cycling in energ}' metabolism
and cosequently results into pathophysiological conditions such as type 2 diabetes.
dysiipidemia and atherosclerosis.
Type 2 diabetes is a severe and prevalent disease in the major part of the developed and
developing countries. Treatment of Type II diabetes usually consists of a combination of
diet, exercise, oral hypoglycemic agents, e.g., thiazolidenediones, and in more severe
cases, insulin. However, the clinically available oral hypoglycemic agents have multiple
side effects that limit their use. In the case of Type I diabetes, insulin is usually the
primary course of therapy.
Epidemiological evidence has firmly established that hyperlipidemia as a primary risk

factor in causing cardiovascular diseases (CVD) as a consequent profession of
atherosclerosis. Additional independent risk factors include glucose intolerancs, left
ventricular hypertrophy, hypertension. Cardiovascular disease is especially prevalent
among diabetic subjects, at least in part because of the existence of multiple independent
risk factors in this population. Successful treatment of these risk factors in the general
population, and in obese and/or diabetic subjects in particular, is therefore of exceptional
medical importance
Various new therapeutic approaches, such as PPAR delta inhibitions, activation of AMP
activated Protein Kinase and Stearoyl-CoA desaturase 1 (SCD1) inhibition are underway
to find a safe & effective treatment for insulin resistance, diabetes, obesity and
atherosclerosis. Many of the compounds are in early stage of development. Recently
Acetyl-CoA carboxylase (ACC) inhibitors are also being explored for the treatment of
obesity, insulin resistance, diabetes, and atherosclerosis.
Acetyl-CoA carboxylase (ACC), a biotin-containing enzyme, catalyzes the carboxylation
of acetyl-CoA to form malonyl-CoA. In animals, including humans, there are two
isoforms of acetyl-CoA carboxylase expressed in most cells. ACC1 and ACC2. ACC1 and
ACC2 are encoded by two separate genes and displax distinct tissue distribution (Wakil
et al, 1983; Thampy et al, 1989; McGary et al, 1977: McGarry et al, 1997; Abu-Elheiga
et al. 2000; Abu-Elheiga et al, 1995; Abu-Elheiga et al, 1997; Ha et al. 1996: Thampy et
al, 1988; Bianchi et al, 1990). For example, ACC1 is highly expressed in lipogenic
tissues such as liver and adipose tissue and ACC2 is predominantly expressed in heart
and skeletal muscle (Thampy et al, 1989; Abu-Elheiga et al, 1995; Bianchi et al. 1990
and Iverson et al, 1990). Both ACC1 and ACC2 produce malonyl-CoA, which is both an
intermediate in the de novo synthesis of long-chain fatty acids and an inhibitor of
carnitine palmitoyltransferase (CPT1), the enzyme that controls the transfer o: long-chain
fatty acyl CoA into mitochondria (McGarry and Brown, 1997, WO02051355). By virtue
of the latter action, malonyl CoA has been shown to regulate intracellular fatty acid
4

oxidation in a variety of tissues including liver (McGarry and Brown. 1997), muscle
(Alam and Saggerson, 1998; Winder and Hardie. 2999), the pancreatic β- cell (Prentki
and Corkey, 1996), and endothelium (Dagher et al, 2001) This finding provides an
important link between two opposed pathways— fatty-acid synthesis anci fatty-acid
oxidation.
Since acetyl-CoA carboxylase (ACC,1 catalyzes the rate-limiting reactior. in fatty acid
biosynthesis and Maionyl-CoA. the product of the ACC-catalyzed reaction, inhibits
mitochondrial fatty acid oxidation and thus plays key roles both in controlling the switch
between carbohydrate and fatty acid utilization in liver and skeletal muscle and also in
regulating insulin sensitivity in the liver, skeletal muscle, and adipose tissue (McGarry et
al, 1989: McGarry. J. D., and Brown, 1997: Rasmussen et al. 2002). Malonyl-CoA may
also play an important regulatory role in controlling insulin secretion from the pancreas
'Chen et al, 1994; Bran et al, 1996).
Thus, compounds which inhibit both ACC1 & ACC2 are expected both to inhibit fatty
acid synthesis along with increasing fatty acid oxidation. This action in turn may improve
insulin sensitivity in liver, skeletal muscle, and adipose tissue. Additionally, by
increasing fatty acid utilization and by preventing increases in de novo fatty acid
synthesis, chronic administration of an ACC inhibitor may also deplete liver and adipose
tissue triglyceride stores in obese subjects, leading to selective loss of body fat.
Therefore, compounds which inhibits acetyl-CoA carboxylase could effectively and
simultaneously treat the multiple risk factors associated with metabolic syndrome and
could have a significant impact on the prevention and treatment of the cardiovascular
morbidity and mortality associated with obesity, hypertension, diabetes, and
atherosclerosis.
WO2007011809 & WO2007011811 describe novel spirochromanone derivatives having
acetyl coenzyme A carboxylase (ACC) inhibitor)' activity useful as therapeutic agents,
which essentially consists of a quinoline ring as the cyclic substitution.
5

WO2007013691, WO2005113069, WO2005108370, WO2003094912, WO2003072197.
WO2003059886. and WO2003059871, describe the compounds capable of inhibiting
ACC, however, the compounds described in these references are structurally distinct
from the compounds of the present invention.
EP431943 relates to novel spirocyclic compounds, which are useful as class El
amiarrhythmic agents having positive inotropic or cardiotonic effects.
Moreover, various compounds having a spirochromanone skeleton are disclosed in US
5206240. US5633247. JP2005119987A. EP431973A, EP004624 A2, WO9417045, WO
9530642, WO9639140, and WO2004092179. However, these references neither disclose
nor suggest the ACC- inhibiting effect of the compounds disclosed therein or of the
compounds of the present invention.
There still remains a need for potent ACC inhibitors having favorable pharmacokinetic
and pharmacodynarnic and better side effects profiles for use as human Pharmaceuticals.
6

DESCRIPTION OF THE INVENTION:
One embodiment of the invention is a compound of formula (I)

wherein, 'P' is a group selected from -CO and -SO2;
'Cy' is selected from the group consisting of:

wherein the Cy ring may be optionally substituted with one or more group independently
/

selected from (C1-C6)alkyl. COOH ,-COO-(Cl-C6)alkyl. -CH2OH, -CH2 -Phosphate.
-CONH-(C1-C6)alkyl, -CO-(Cl-C6)aIkyl, -S-(C1-C6)alkyl -(C3-C6)cyclcalkyl, aryl,
heteroaryl, heterocyclic, trifluoromethyl. halo, -OH. -O-CH2-aryl, -O-aryl. -O-(C3-
C6)cycloalkyi. -(Cl-C6)alkoxy, cyano. NH2. NH-(C1-C6)alkyl, N.N-di(Cl-C6)alkyl,
NH-CO-(C1-C6) alkyl or NH-SO2-(C1-C6) alkyl:
OR
(ii) a disubstituted 5 or 6-membered heteroaryl ring selected from pyrroje. pyrazole,
isoxazole. thiophene. thiazole, triazine or pyridine which is attached to '?' via carbon
atom of the said heteroaryl ring and the substituent on the said heteroaryl ring is
independently selected from phenyl, pyridine. thiazole. isoxazole, pyrrazole, heterocyclic,
aikynyl. and which ma}' be optionally further substituted with one or more group
independently selected from -(C1-C6) alkyl, -(C2-C6) alkynyl, trifluoromethyl, -OH. -
CH2-OH, -CH:-Phosphate. -(C1-C6) alkcxy. halo, cyano. -NHC(0)CH3, -NH-CO-(C1-
C6) alkyl;
R1 is selected from the group consisting of.
(a) H.
(b) 3-7 membered saturated or partially unsaturated heterocyclic ring containing one to
three hetero atom selected from N. 0 or S which is attached to the ring via its nitrogen
atom and is further optionally substituted with one or more group independently selected
from oxo, oxime. -(C1-C6) alkyl, -(C3-C6) cycloalkyi, trifluoromethyl, -NH2. -NH-(C1-
C6) alkyl. -NH-C(=O)- (C1-C6) alkyl. -NH-SO2-(C1-C6) alkyl, -NH-C(=O)-NH-(C!-C6)
alkyl. -NH-C(=O)O-(C1-C6) alkyl, -NH-C(=O)O-aryl, -N-hydroxylurea, -COCH3, -CO-
aryl, -COOH, -C(=O)O-(C1-C6) alkyl, -C(=O)-NH2. -CH2OH, -CH2-Phosphate, -CH2-
NH-(C1-C6) alkyl. -CH2-NH-(C3-C6) cycloalkyi, OH, -O-(C1-C6) alkyl, -O-(C3-C6;
cycloalkyi, -O-CH2C(=O)-NH-(C1-C6) alkyl, -O-CH2C(=O)NH-(C3-C6) cycloalkyl,
pyrimidine, pyridine, pyrrolidine, or (C3-C7) cycloalkyl attached to ring in a spiro form.
(c) -C=C-CH(CH3)-NH-C(=O)-(C1-C6) alkyl.
8

(d) -C≡C-CH(CH3)-NH-C(=O>-(C3-C6) cycloalkyl,
(e) -C≡C-CH(CH3)-NH-C(=O)-NH-(Cl-C6) alkyl, and
(f) -C≡C-CH(CH3)-NH-Cf=0)-NH-(C3-C6) cycloalkyl.
R2 is selected from the group consisting of H, -NH2 -(Cl-C6)alkyl, trifluororaethyl, halo.
-(C3-C6) cycloalkyl, -(C!-C6)alkoxy, -O-(C3-C6) cycloalkyl. -O-aryl, -OH, -CH2.
Phosphate, -CH2-NH-(C3-C6) cycloalkyl, -CH2-heterocyclic. -O-heteroaryl, -C≡C-
CH(CH3)-NH-C=O)- (C1-C6) alkyl. -C≡C-CH(CH3)-NH-C(=O.)-NH-(Cl-C6)alkyl. -
NH-C(=O)O-(C1-C6) alkyl. -NH-C(=O)O-aryi. -NH-C(=O)-NH-(Cl-C6)alkyl, -NH-
C(=S)-NH-(Cl-C6)alkyl. and -C≡C-CH(CK3)-NH-C(=O)- (C3-C6)cycloalkyl;
R3 is selected from H. -OH, -(Cl-C6)alkyl. -(C1-C6)alkoxy, halo and CF3 with the
proviso that when R1 is H then R3 is selected from furanone, oxazole, isoxazole,
thiazole. triazole, tetrazole, thiadiazole or pyrazole which maybe optionally substituted
with one or more group independently selected from the group H, -OH. -(Cl-C6)alkyl, -
(Cl-C6)alkoxy. halo or CF3:
R4 , R5 is independently selected from H, -(Cl-C6)alkyl or may together form with the
carbon atom to which i: is attached a 3 to 7 membered cycioalkyl ring and the said ring
may be optionally substituted with oxo, ester, alky] or oxime:
X = C. CH, or N;
Y = O, CH2, -N-OH or -N-O-fCl-C6)alkyl:
Z = O or S;
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.
In another embodiment of the present invention provides a method for preparation of a
compound of general formula I as herein described in Scheme 1 and 2.
9

In yet another embodiment the present invention provides a pharmaceutical composition
comprising a compound as above, in admixture with a pharmaceutically acceptable
adjuvant, diluent or carrier.
In yet another embodiment the present invention provides a method of treating the
conditions like insulin resistance, diabetes, obesity and atherosclerosis by administering a
compound as above to a mammal in need thereof.
In yet another embodiment the present invention provides the use of a compound as
above for the preparation of a medicament to treat the conditions like insulin resistance,
diabetes, obesity and atherosclerosis.
DEFINITIONS:
The following definitions apply to the terms as used throughout this specification, unless
otherwise limited in specific instances.
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 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
10

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 soivated forms, including hydrated forms. In general, compounds may
be hydrated or soivated. 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 (" - ") indicate the point of attachment of the partial structure to the
rest of the molecule. All substituents (R1, 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.
"Stereoisomers'' term as used herein, refers to certain compounds of the invention, which
have one or more asymmetric centres and can exist in the form of racenates, single
enantiomers, as individual diastereomers, with all possible isomers. and mixtures thereof,
all of which are within the scope of the invention.
"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 inorgame 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 salts, such as calcium salt, magnesium salt, and
11

the like, and combinations comprising one or more of the foregoing salts.
Pharmaceutical!}' 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'-
dibsnzy]ethylenediamine 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 'C1-C6, 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 'alkynyl". used either alone or in attachment with another group refers to an
unsaturated( ≡ ) aliphatichydrocarbnradical havingthe ind icated number of carbon
atoms and that is unsubstituted or optional!}' 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 'C 2 to C6 alkynyl" would refer to any alk ynyl
group containing two to six carbons in the structure. Alkenyl 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 alky! or other group, the subscript refers to the
12

number of carbon atoms that group may contain. For example, a 'C3-C6 cycloalkyl"
would refer to any alkyl group containing three to six carbons in the structure.
The term 'aryl" unless otherwise specified, refers to an aromatic group for example,
which is a 6 to 10 membered monoeyclic or bicyclic ring system, which may be
unsubstituted or substituted. Representative aryl groups may be phenyl, naphthyl and the
like.
The term "heteroaryl" unless otherwise specified.as used herein, refers to an aromatic
group for example, which is a 5 to 10 membered monoeyclic 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 monoeyclic heteroaryl groups include pyrrolyl, pyrazolyl, oyrazolinyl,
imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furaryl, thienyl,
oxadiazolyl, pyridyl, pyrazinyl. pyrimidinyl, pyridazinyl, triazinyl and the like.
Exemplar}' bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl.
benzoxazolyl. benzotmenyl, quinolinyl, isoquinolinyl, benzimidazolyl, cinnolinyl,
quinoxalinyl. indazolyl, pyrrolopyridyl, furopyridinyl and the like.
The term 'heterocyclic ring'' unless otherwise specified,as used herein, refers to a cyclic
ring for example, which is a 3 to 10 membered monoeyclic or bicyciic ring system, which
has at least one heteroatom and at least one carbon atom containing ring. The
heterocyclic group may be attached at any available nitrogen or carbon atom of any ring.
Exemplary monoeyclic heterocyciic ring include groups selected from aziridine, ethylene
oxide, pyrrolidine, morpholine, piperidine. piperazine, thiiarane, azetidine, oxirane.
pyridine. pyran. thiine.
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.
13

As used herein, the term 'halo" or 'halogen" denotes a fluoro, chloro, brom o, or iodo
group.
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.
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 pharmaceutical}}' 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 alkoxyrnethyl esters, for example,
methoxymethyl. C;-Cg alkanoloxymethy! ester, for example, pivaloyloxymethyl;
phthalidyl esters; C3-C8 cycloalkoxycarbonyloxy-C1-C8 alkyl esters, for example, 1-
cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onyimethyl esters, for example. 5-methyl-
1.3-dioxolen-2-onylmethyI; and C1-C8 alkoxycarbonyloxyethyl esters, for example. 1-
methoxycarbonyloxymethyl; and may be formed at any carboxy group in the compounds
of the present invention.
14

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 panent 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. Such amount can be readily determined by one skilled in the
art, and will not require undue experimentation.
When used, the expressions "comprise" and "comprising" denote 'include" and
'including" but not limited to. Thus, other ingredients, carriers an d additives may be
present.
Pharmaceutical Composition
In another embodiment of the invention there 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.
15

Oral compositions may be in the form of solid or liquid dosage form. Solid ciosage 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, emuisifiers. chelating agents, stabilizers, flavours, sweeteners, colours etc. Some
example of suitable excipients include lactose, cellulose and its derivatives such as
microcrystaliine cellulose, methylcelulose. hydroxy propyl methyl cellulose,
ethylcellylose, dicalcium phosphate, mannitol, starch, gelatin, polyvinyl pyrolidone.
various gums like acadia, tragacanth, xanthan, algmates & its derivatives, sorbitol,
dextrose, xylitol, magnesium Stearate. taic, colloidal silicon dioxide, mineral oil, glyceryl
mono Stearate. glyceryl behenate, sodium starch glycolate, Cross Povidone, crosslinked
carboxymethylcellulose, various emuisifiers such as polyethylene glycol, sorbitol
fattyacid, esters, 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-PyrroIidone, 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
16

contained in the preparation is from 0.1 microgram to 100 mg/kg per da} (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 necessan. The dosage
form can have a slow, delayed or controlled release of active ingredients in addition to
immediate release dosage forms.
The following, reaction schemes gives the routes for the syntheses of the compounds
according to the present invention.

wherein, R6 = halo or OH: X, R, R2, R3, R4 R5, Y, Z, P and Cy are defined hereinabove.
Compounds of formula (I) can be synthesized as shown above in scheme 1.
Compounds of formula I can be synthesized by reacting compounds of formula II with
appropriate acid halide of formula III (R6 = halo) in the presence of base such as
triethylamine, N.N-diisopropylethylamine, N-methylmorpholine. sodium hydride using
appropriate solvents such as tetrahydrofuran. dichloromethane, toluene. Alternatively.
Compounds of formula I can also be synthesized by reacting compounds of formula II
with appropriate acid of formula III (R6 = OH) in the presence of coupling reagent such
as DCC-HOBt. EDCI-HOBt and suitable base such as triethyiamine, N,N-
17

diisopropylethylamine, N-methylmorpholine, using appropriate solvents such as
tetrahydrofuran. dichioromethane, toluene. N,N-dimethylformamide.
Compounds of formula (III) can be used either from commercial sources or can be
synthesized by using conventional methods.
Compounds of formula (II) can be obtained as described in scheme 2.

Compounds of formula II can be obtained from the Boc deprotection of compounds of
formula VI, VII and VIII using appropriate acid such as trifiuoroacetic acid or
acetonitrile-hydrochloric acid mixture using the conventional procedure know n in the art.
18

Compounds of formula VI can be synthesized from the reaction of compounds of formula
IV with compound V in the presence of base such as pyrrolidine and alcoholic solvents
such as methanol or ethanol using the conventional method known in the art.
Compounds of formula IV can be used from commercial sources or can be prepared by
using conventional methods.
Compounds of formula VII can be obtained by reacting compound of formula VI with
alkyl halide such as methyl iodide in the presence of suitable base such as sodium
hydride using appropriate solvent such as tetrahydrofuran. Compounds of formula VIII
can be obtained by reacting compound of formula VI with appropriate hydroxyl amine or
phosphorus ylide (Witting) to provide oxime and methylene derivatives of formula VIII
respectively.
The following examples illustrate the preparation of the compounds of formula (I) 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.
EXAMPLES
General method for the preparation of compounds of formula (VII)
To a cooled solution of tert-butyl 4-oxo-3,4-dihydro-l'H-spiro[chromene-2,4'-piperidine
]-l'-carboxylate (1 eq) in tetrahydrofuran. sodium hydride (3 eq) was added. The reaction
mixture was allowed to stir at 0 °C under nitrogen atmosphere for 30 min and then alkyl
iodide (0.95-4 eq) was added. The reaction mixture was now allowed to stir at room
temperature for 8 hrs under nitrogen atmosphere. It was then quenched with cold water
and extracted with ethyl acetate. The organic layer was separated, dried over sodium
sulfate and concentrated to dryness to get the desired compound, which was used as such
in the further step without purification.
19

General procedure for the preparation of compounds of formula (I):
Compounds of formula (I) can be synthesized from the reaction of appropriate
compounds of formula (IF) and formula (III) by using any of the following two methods
(A and B).
Method-A: Preparation of (10H-phenoxazin-10-ylcarbonyI)spiro[chroman-2,4'-
piperidin}-4-one (Compound No. 2):
To a cooled solution of phenoxazine (1 eq) in dichloromethane. tnethylamine (2 eq)
followed by triphosgene (1 eq) were added. The reaction mixture was stirred at room
temperature under nitrogen atmosphere for 4 hrs. To this solution, triethylamine (2 eq)
was again added under cooling and then spiro[chroman-2,4'-piperidin]-4-one
hydrochloride (1.3 eq) was added. The reaction mixture was allowed to stir at room
temperature for 8 hrs under nitrogen atmosphere. Reaction mixture was quenched with
cold water, organic layer was separated, dried over sodium suifate and concentrated to
dryness to get crude product, which was purified by column chromatography using silica
gel as absorbent and hexane and ethyl acetate as eluent.
Similarly, other compounds of formula (I) can be prepared from the reaction of
appropriate acid halide of formula (III) with compounds of formula (II).
Method-B: Preparation of r-[2,6-diphenyIisonicotinoyI]spiro[chroman-2,4'-
piperidin]-4-one (Compound No. 1):
EDCI (1.5 eq) was added to a mixture of 2.6-diphenylpyridine-4-carboxylic acid (1 eq).
Ar-hydroxybenzotriazole (1.1 eq) and N.N-diisopropylethylamine (5 eq) in dry
tetrahydrofuran at 0 °C. The resulting mixture was stirred at 0 °C to 10 °C for 30 min and
therj spiro[chroman-2,4'-piperidin]-4-one hydrochloride (1.3 eq) was added. Cooling was
now removed and the reaction mixture was further stirred at room temp for 18 hrs.
Reaction mixture was again cooled to 10 °C and excess of cold water was added and
extracted with ethyl acetate. The combined organic layers was washed wi:h water and
saturated sodium carbonate solution successively, dried over sodium sulfate, and
20

concentrated to dryness. The product was purified by column chromatography using
silica gel as absorbent and hexane and ethyl acetate as eluent.
Similarly, other compounds of formula (I) can be prepared from the reaction of
appropriate acid of formula HI with compounds of formula II.
21

26


27


28


BIOLOGICAL ACTIVITY:
In Vitro data:
Streptavidin affinity purified Rat ACC enzymes from liver and skeletal muscls were used
to measure inhibition using HPLC method.
Acetyl-CoA carboxylase catalyzes the two-step reaction. The first half reaction is carried
out by the biotin carboxylase component of acetyl-CoA carboxylase and involves the
ATP-dependent carboxylation of biotin with bicarbonate serving as the source of CO2.
The carboxyl group is transferred from biotin to Acetyl-CoA to form Malonyl-CoA in the
second half reaction, which is catalyzed by carboxyltransferase. The enzyms activity is
detected by HPLC method which can specifically detect the loss of AcetylCoA and/or the
appearance of MalonylCoA.
HPLC based Assay
The assay buffer contains 50 mM HEPES (pH 7.5), 20 mM MgCl2, 10 mM ■xipotassium
citrate, and 0.075 % BSAfBovme Serum Albumin). The reaction was initiated by the
addition of the following substrate mixture in lx assay buffer: 2mM ATP, lmM acetyl-
CoA and 17.6mM NaHCOS. The reaction was carried out at 37°C temperature for 40min.
Stock solutions of Inhibitors were prepared in DMSO and the final concentration of
DMSO in the reaction mixture was 1%. The reaction was stopped by the addition of
perchloric acid. The supernatants analyzed by HPLC for either the production of
malonyl-CoA or the consumption of acetj'l-CoA.
Inhibition of ACC with compounds was calculated considering control as 100%.
29

Results:
% inhibition of rat skeletal muscle and liver acetyl CoA carboxylase enzyme by in house
compounds.

Acetyl-CoA Carboxylase (ACC) inhibition leads to metabolic switch from carbohydrate
to fat metabolism for energy source by increased transport of FA to the mitochondria
through CPT activation. This switch in metabolic energy source result in change in
respiratory quotient. The invivo studies to be carried out to assess the effect of Acetyl-
Coa Carboxylase (ACC) inhibitors on respiratory quotient (RQ) in High Fat and/or
Normal Chow Fed C57W6 Mice.
Mice to be divided into 2 groups:
The animals in each group to be treated with the respective drug or vehicle orally, b.i.d.
for 7 days. On 7th day the mice to be acclimatized in the oxymax chamber for 24 h and on
8th day after morning dosing the animals to be kept in the oxymax chamber to record the
RQ and O2 consumption. The reduction in RQ in treatment group to be calculated.
30

We Claim:

1. A compound of general formula (I)

wherein. 'P' is a group selected from -CO and -SO2;
'Cy' is selected from the group consisting of:

31

wherein the Cy ring may be optionally substituted with one or more group independently
selected from (Cl-C6)alkyl, COOH ,-COO-(Cl-C6)alkyl. -CH2OH. -CH2-
Phosphate, -CONH-(Cl-C6)alkyL -CO-(C1 -C6)alkyl. -S-(C!-C6)all:yl. -(C3-
C6)cycloalkyl, aryl. heteroaryl, heterocyclic. trifluoromethyl, haio, -OH. -O-CH2-aryl, -
O-aryl, -O-(C3-C6)cycloalkyl. -(Cl-C6)alkoxy, cyano, NH2, NH-(C 1-C6)alkyl, N.N-
di(Cl-C6)alkyl. NH-CO-(C1-C6) alkyl or NH-SO2-(C1-C6) alkyl;
OR
(ii)
a disubstituted 5 or 6-membered heteroaryl ring selected from pyrrole, pyrazole
isoxazole, thiophene, thiazole, triazine or pyridine which is attached to 'P* via carbon
atom of the said heteroary] ring and the substituent on the said heteroaryl ring is
independently selected from phenyl. pyridine. thiazole. isoxazole, pyrrazole. heterocyclic.
alkynyl, and which may be optionally further substituted with one or more group
independently selected from -(C1-C6) alkyl, -(C2-C6) alkynyl, trifluoromethyl, -OH, -
CH2-OH, -CH2-Phosphate, -(C1-C6) alkoxy, halo, cyano, -NHC(O)CH3, -NK-CO-(C1-
C6) alkyl;
R1 is selected from the group consisting of:
(a)H,
(b) 3-7 membered saturated or partially unsaturated heterocyclic ring containing one to
three hetero atom selected from N, O or S which is attached to the ring via its nitrogen
atom and is further optionally substituted with one or more group independently selected
from oxo, oxime, -(C1-C6) alkyl, -(C3-C6) cycloalkyl, trifluoromethyl. -NH2, -NH-(C1-
C6) alkyl, -NH-C(=0)- (C1-C6) alkyl, -NH-SO2-(C1-C6) alkyl, -NH-C(=O)-NH-(C1-C6)
alkyl, -NH-C(=0)0-(Cl-C6) alkyl. -NH-C(=O)O-aryl, -N-hydroxylurea, -COCH3, -CO-
aryl. -COOH, -C(=0)0-(Cl-C6j alkyl, -C(=0)-NH2l -CH20H, -CH2-Phosphate, -CH2-
NH-(C1-C6) alkyl, -CH2-NH-(C3-C6) cycloalkyl. OH, -0-(C 1-C6) alkyl. -O-fC3-C6)
cycloalkyl. -O-CH2C(=O)-NH-(C1-C6) alkyl. -O-CH2C(=O)NH-(C3-C6) cycloalkyl,
3°

pyrimidine. pyridine. pyrrolidine, or (C3-C7) cycloalkyl attached to ring in a spiro form,
(c) -C≡C-CH(CH3)-NH-C(=O)-(Cl-C6) alkyl,
(d) -C≡C-CH(CH3)-NH-C(=O)-(C3-C6) cycloalkyl,
(e) -OC-CH(CH3)-NH-C(=O)-NH-(C1-C6) alkyl. or
(f) -C≡C-CH(CH3)-NH-C(=O)-NH-(C3-C6) cycloalkyl.
R2 is selected from the group consisting of H, -NH2 -(Cl-C6)alkyi, trifluoromethyl, halo,
-(C3-C6) cycloalkyl. -(Cl-C6)alkoxy, -O-(C3-C6) cycloalkyl, -O-aryl, -OH, -CH2.
Phosphate, -CH2-NH-(C3-C6) cycloalkyl, -CH2-heterocycIic, -O-heteroeryl, -OC-
CH(CH3)-NH-C(=O)- fCl-C6) alkyl, -C=C-CH(CH3)-NH-C(=O)-NH-(Cl-C6)alkyl, -
NH-C(=0)0-(Cl-C6) alkyl, -NH-C(=O)O-aryl, -NH-C(=O)-NH-(Cl-C6)alkyl, -NH-
C(=S)-NH-(Cl-C6)alkyl, or -C≡C-CH(CH3)-NH-C(=O)- (C3-C6)cycloalkyl;
R3 is selected from H, -OH, -(Cl-C6)alkyl, -(Cl-C6)alkoxy, halo or CF3 with the proviso
that when Rl is H then R3 is selected from furanone, oxazole. isoxazole. thiazole,
triazole, tetrazole, thiadiazole or pyrazoie which maybe optionally substituted with one or
more group independently selected from the group H, -OH. -(Cl-C6)alkyl. -(Cl-
C6)alkoxy, halo or CF3;
R4 , R5 is independently selected from H. -(Cl-C6)alkyl or may together form with the
carbon atom to which it is attached a 3 to 7 membered cycloalkyl ring and the said ring
may be optionally substituted with oxo. ester, alkyl or oxime;
X = C, CH, or N;
Z = O or S;
Y = O, CH2, -N-OH or -N-O-(C1-C6)aikyl:
including their pharmaceutically acceptable salts and their hydrates, solvates.
atropisomers,
regioisomers, enantiomers, diastereomers, tautomers, polymorphs and prodrugs thereof.
33

34
2. A compound selected from the following compounds or their phamaceutically
acceptable salts and their hydrates, solvates, atropisomers, regioisomers, enantiomers,
diastereomers, tautomers, polymorphs and prodrugs thereof:



35


36


37


3. A pharmaceutical composition comprising a therapeutically effective amount of one or
more compound of formula (I) as defined in claim 1 or claim 2. in association with a
pharmaceutically acceptable salts, diluents or carriers.
4. Use of one or more compound represented by general formula (1). as defined in claim
1 or claim 2, in the manufacture of medicament for the treatment of insulin resistance,
diabetes, obesity and atherosclerosis in a living mammalian organism, including human
being.
5. A method of treating insulin resistance, diabetes, obesity and atheroscleros..s 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 or claim 2.
6. Compound, processes for their preparation, pharmaceutical compositions containing
them or methods of treatment and uses involving these compounds as herein described
with reference to the examples accompanying the specification.
38

References:
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Natl cad Sci: 92; 4011-4015.
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39

Thampy, K. G. (1989); J Biol Chem: 264:17631-17634.
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40
Winder WW, & Hardie DG. (1999); Am J Physiol;. 277: E1-E10

The present invention relates to novel compounds of general formula (I), or
pharmaceutically acceptable salt thereof, wherein the substituents in formula ([) have the
meanings as defined in the description that follows.
The present invention also relates to a process for the preparation of the said novel
compounds, or their pharmaceutically acceptable salts.
The said compounds of the general formula-I are potent inhibitors of acy CoA in
mammals and by virtue of its inhibitory action on an enzyme, are useful in the treatment
of obesity, diabetes and metabolic syndrome. The present invention also relates to
pharmaceutical compositions containing them and to their use as therapeutic agents.